Review ArticleAdvances in the Preparation of Fluorinated IsoquinolinesA Decade of Progress

Joseph C Sloop

School of Science and Technology Georgia Gwinnett College 1000 University Center Lane Lawrenceville GA 30043 USA

Correspondence should be addressed to Joseph C Sloop jsloopggcedu

Received 30 October 2016 Revised 5 December 2016 Accepted 14 December 2016 Published 23 January 2017

Academic Editor Esteban P Urriolabeitia

Copyright copy 2017 Joseph C Sloop This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Heterocyclic molecules incorporating fluorinated isoquinoline components are found in many medicinally and agriculturallyimportant bioactive products as well as industrially impactful materials Within the past decade a variety of isoquinolinic ringassembly techniques has enabled the introduction of diverse fluorine-containing functionalities which can enhance potentialbioactivity and industrial utility This review examines recent noncatalyzed and transition metal catalyzed synthetic approachesto the assembly of isoquinoline derivatives that are ring-fluorinated andor result in the incorporation of fluorine-containingfunctional groups Specifically efficient synthetic methods and regioselectivity in the incorporation of functional groups intoisoquinoline ring systems are examined

1 Introduction

11 Discovery of Isoquinoline and Early Synthesis EffortsIsoquinoline the bicyclic aromatic heterocycle shown inFigure 1 was first isolated as the sulfate salt from coal tarin 1885 by Hoogewerf and van Dorp [1] By 1893 severalsyntheses of isoquinolinoid compounds were published byPomeranz Fritsch Bischler andNapieralski reactions whichbear their names [2ndash4] Early in the 20th century PictetGams and Spengler developed slightly different approachesto prepare isoquinoline derivatives [5 6]

While the synthetic methods shown in Figure 1 enabledconstruction of different parts of the ldquoArdquo ring componentof the isoquinoline heterocycle most early preparationsrequired strong acids and refluxing conditions or dehydratingagents and dehydrogenation catalysts which limited func-tional group survival during the reactions

12 Medicinal and Industrial Uses of Isoquinolines Since itsdiscovery isoquinoline has remained an aromatic heterocycleof broad appeal to the synthetic organic materials sciencepharmaceutical and agrochemical communities Isoquino-line derivatives have important industrial applications wherethey serve as solvents for aromatic molecules fluorosensors

as components in paints dyes and electronic devices [7ndash9] Isoquinoline derivatives such as papaverine have beenisolated fromnatural sources and the isoquinolinoid pharma-core can be found in numerous drugs that possess antitumoranesthetic and antibiotic properties [10ndash12] Figure 2 showssome representative examples of important isoquinoline-based molecules

13 Effects of Fluorine Incorporation on Molecular PropertiesWhen fluorine and fluorine-containing groups are incorpo-rated into molecules dramatic shifts of molecular propertiesoccur in many instances The inductive effect brought aboutby fluorinersquos high electronegativity and its small van derWaals radius of 147 A changes molecular structural andstereoelectronic properties such as conformation p119870a polar-ity solubility and hydrogen-bonding capacity [13ndash18] Anexample of how these alterations bear directly on materialsscience applications is found in the fluorinated isoquinoline-based electrophosphorescent iridium complexes used incolor displays [9] See Figure 3

For a number of years the pharmaceutical industryhas leveraged these fluorine-induced molecular propertymodulations in drug discovery strategies when constructing

HindawiJournal of ChemistryVolume 2017 Article ID 2860123 15 pageshttpsdoiorg10115520172860123

2 Journal of Chemistry

1

2N

3

4 56

7

8

Bischler-Napieralski reactionPictet-Gams reaction

A B

Pictet-Spengler reaction

Ring A assembly

Pomeranz-Fritsch reaction

C3-C4 and N2-C3

Ring A assembly at C1-N2

4f

8f

Ring A assembly C4-C4f

Ring assembly at C8f-C1

Figure 1 Isoquinoline ring assembly methods

heteroaromatic pharmacores Today nearly 20 of FDA-approved drugs contain fluorine [19] The very strong 120590sp3C-F bond (110 kcalmol) increases the metabolic stability ofdrugs enabling better bioavailability and binding affinity [19ndash22] Isoquinolines functionalized with fluorine and fluorine-containing groups the focus of this review are key phar-macores with many applications For example isoquinolinecarboxamides labeled with 18F have found use as radiola-beling ligands for positron emission tomography [22] Addi-tionally the preparation of fluorinated fluoroalkylated andfluoroarylated isoquinoline variants with antibacterial andantiparasitic properties continues to be an area of significantinterest to themedicinal chemistry community Figure 3 con-tains several examples of medicinally important isoquinolinederivatives which bear fluorine in their structure

14 Recent Synthesis Efforts in the Preparation of FluorinatedIsoquinolines This review examines a number of fluorinatedisoquinoline preparations which capitalize on noncatalyzedreactions and cyclizations as well as those which employ tran-sitionmetal catalysis to achieve the isoquinoline architectureAs Figure 4 shows multiple methods that permit construc-tion of the isoquinoline ring A and ring B components havebeen advanced and will be examined

More specifically we will consider those processes shownin Figure 4 which result in isoquinoline ring fluorinationsdi- and trifluoromethylations fluoroarylations and triflu-oromethylarylations As Figure 5 indicates fluorine func-tionality may be introduced at every carbon center of theisoquinoline core and more than fifty-five examples will beexplored in this review

We will first examine nontransition metal mediated pro-cesses and then discuss the scope of transition metal catalysisin the preparation of fluorine-containing isoquinolines

2 Ring-Fluorinated Di- and Trifluo-romethylated Perfluoroalkylated andFluoroarylated Isoquinoline Synthesis viaNontransition Metal Mediated Processes

This portion of the review catalogues a broad cross section ofisoquinoline preparations reported in the last decade whichare not catalyzed by transition metal complexes Methods

TsHN

R

KH (xs) DMF

N

F

R

1

0∘C to RT 4ndash9h

(90ndash95)2a-b

b R = sec-Bua R = n-Bu

F2C

Scheme 1 11-Difluorostyrene aminotosylate cyclization

N

F

X RNX

R LDA (25 eq) THF

NXR

CF3

3 4andashi (38ndash57)

a 1-pyrrolyl b 1-indolyl c 1-(2-Me-pyrrolyl)d 1-(24-diMe-pyrrolyl) e 1-pyrazolylf 1-(3-cyclopropylpyrazolyl) g 1-(5-Cl-indolyl)h 1-(5-MeO-indolyl) i 1-(3-Ph-pyrazolyl)

minus70∘C-RT 3 h

Scheme 2 Fused-ring 4-fluoroisoqinoline derivative synthesis

examined include both intramolecular and intermolecularcycloadditions tandem reactions and multicomponent andsingle-pot processes which produce a wide array of A and Bring-fluorinated di- and trifluoromethylated perfluoroalky-lated and fluoroarylated polyfunctional isoquinolines Inaddition several trifluoromethylation and perfluoroalkyla-tion reactions are shown that produce polyfunctional iso-quinolines with a high degree of Rf substitution site regios-electivity

21 3- and 4-Fluoroisoquinolines via Intramolecular Ring ACyclization at N2-C3 and C3-C4 Ichikawa and coworkerscyclized the difluoroalkene aminotosylate 1 (Scheme 1) underbasic conditions in a 6-endo-trig fashion at N2-C3 to obtainthe 4-butylated 3-fluoroisoquinoline series2 in excellent yield[23]

Kiselyov reported a base-promoted intramolecular ringclosure of ortho-trifluoromethyl benzyl heterocycles 3 enroute to nine tricyclic 4-fluoroisoquinoline derivatives 4See Scheme 2 The reaction likely proceeds through a C3-C4cyclization of a quinone methide intermediate arising fromelimination of fluoride anion [24]

22 6- and 7-Fluoroisoquinolines via Intermolecular Ring ACyclization at C8119891-C1 N2-C3 C1-N2 and C3-C4 In a recentNature communication Xie et al noted that assembly ofisoquinoline ring systems at C8f -C1 and N2-C3 by metal-free [4 + 2] cycloadditions was rare [25] An example oftheir efforts is shown in Scheme 3 where a microwave-mediated Broslashnsted acid-catalyzed [4 + 2] cycloaddition ofthe p-fluorophenyl ynamide 5 and nitriles 6a-b produces 7-fluoroisoquinolines 7a-b in good yield Conversely Feng andWu reported in 2016 the base-promoted C1-N2 and C3-C4

Journal of Chemistry 3

N

MeO

MeO

OMe

MeO

Papaverine (antispasmodic)

N

Quinisocaine(anesthetic)

N

MeO

MeO

OMe

MeO

Pyrrolo(21-a)isoquinoline (dye-paint component)

Ph

CHO

N

N

Antitumor agent

N

NIr

O

O

2

1-Phenylisoquinolinyliridium complex(electrophosphorescent-color display)

n-Bu

n-Bu

OCH2CH2N(CH3)2

Figure 2 Selected medicinal agricultural and industrial isoquinoline derivatives

MeO

MeO

Tetrahydroisoquinoline carbamate(antibacterial)

N

FF

Cl

NNOH

Tipifarnib analog(antiparasitic)

O

F

N

F

IrO

O

F

2

1-Phenylisoquinolinyliridium complex(electrophosphorescent-color display)

NN

O

I

[18]F-isoquinoline carboxamide derivative (PET radiolabeling ligand)

18F

(CH2)5 OCNH

NCH3

Figure 3 Selected fluorinated isoquinoline derivatives with medicinal and industrial applications

cycloaddition of benzonitriles8 and9 to prepare the 1-amino-isoquinolines 10a-b which are fluorinated at the 6- and 7-positions in moderate yields [26]

Yang et al employed a tandem C8f -C1 and C1-N2bond-forming process with azidoacrylate 11 and asymmetric

diazo diketone 12 (Scheme 4) to obtain a 1 1 ratio of 7-fluoroisoquinoline isomers 13a and 13b in good yield [27]This interesting reaction cascade begins with the in situphosphazene formation of 11 via the Staudinger-Meyerreaction with concomitant ketene formation from 12 via a

4 Journal of Chemistry

microwave promoted intermolecular cycloaddition

electrocyclic ring closureIr catalysis

microwave promotedintermolecular cycloaddition

Mn catalysis

base initiated intramolecular ring closure Cu Ag catalysis

Mn Co Ni Cu Ru Rh catalysis

Aryne-alkene cyclizationRh Pd catalysis

Rh catalyzed oxidative annulation

Ring A assembly at C3-C4 and N2-C3

Ring A assembly at C1-N2

1

2N

3

4 56

7

8

A B

4f

8f

Ring B assembly at C4f -C5 and C8f -C8

Ring A assembly at C4f -C4 and C8f -C1

Ring A assembly at C4-C4f

Ring A assembly at C8f -C1

Figure 4 Recent isoquinoline synthesis methods

1

N2

3

4 5

6

7

8

A B8 processes

7 processes

11 processes1 process

12 processes

16 processes

2 processes F incorporation at C8

F Rf incorporation at C7

F Rf incorporation at C6

F incorporation at C5F Arf incorporation at C4

F Rf ORf SRf Arf incorporation at C1

F Rf Arf incorporation at C3

Figure 5 Isoquinoline fluorination fluoroalkylation and fluoroarylation sites

PhToluene

t-BuOK

N

N

F

NRN

OO

+

F

R

OO

5 6

NN

9

N

8

X

+ X

NH2

(35ndash40)10a-b

100∘C 16h

b R = CH2CO2Mea R = Me (58ndash62)

7a-b

TfOH (11 eq)

120∘C (MW) 1hDCE (005M)

b X = 5-Fa X = 4-F

Scheme 3 Preparation of 6- and 7-fluoroisoquinolines via ynamide-nitrile and nitrile-nitrile cycloadditions

Journal of Chemistry 5

N

F(60)

O

F

O O

+ N

O

F +

13a 13bStaudinger-

Meyerreaction

Wolffrearrangement

F N

C

O

F N

C

O

+

aza-Wittig[13]-H

shift

11 12

Electrocyclic ring closure

N2N3

PPh3 tolueneCO2Et

CO2Et CO2Et

CO2Et CO2Et

100∘C 2 h

Scheme 4 Triphenylphosphine-mediated 7-fluoroisoquinoline synthesis

N

R

TBAT (2 eq)

R N

O

H

OTf

TMS

+

151416b (78)16a (57)

b R = CH3 R998400 = F

R998400

R998400

R998400

R998400

a R = CF3 R998400 = H

CO2Me

CO2Me THF 23∘C 6ndash8 h

Scheme 5 67-Difluoro- and 1-trifluoromethylisoquinolines via aryne annulation

Wolff rearrangement An aza-Wittig reaction between thephosphazene and ketene yields the isomericN-vinylic keteneimines in brackets Finally electrocyclic ring closure anda subsequent [13]-H migration leads to the formation ofisoquinoline isomers

23 Trifluoromethylated Ring-Fluorinated and Perfluori-nated Isoquinolines via Inter- and Intramolecular Ring ACyclizations at C8119891-C1 and C4119891-C4 Stoltzrsquos team leveragedtheir success in C-C bond insertion reactions to develop aBu4NPh3SiF2 (TBAT) promotedN-acyl dehydroamino ester-(14) aryne (15) C8f -C1C4f -C4 annulation that resulted in thesuccessful synthesis of a series of polysubstituted isoquino-lines and indoles [28] TBAT serves as the fluoride anionsource that desilylates 15 to generate the aryne upon lossof the triflate Scheme 5 depicts the preparation of methyl-3-carboxy-1-trifluoromethylisoquinoline (16a) and methyl-3-carboxy-67-difluoro-1-methylisoquinoline (16b) in goodoverall yield

Zhang and Studer [29] recently reported the C8f -C1intramolecular cyclization of 120573-aryl-120572-isocyano-acrylates 17and radical perfluoroalkylation using Togni reagents 18

as the Rf source to produce eighteen examples of highlyfunctionalized 1-trifluoromethyl- 1-pentafluoroethyl- and 1-heptafluoropropylisoquinolines 19 in good overall yields SeeScheme 6

24 Preparation of Selectively Trifluoromethylated and Diflu-oromethylated Isoquinolines at C1 and C4 Kuninobu et alsuccessfully conducted a benzylic trifluoromethylation of theisoquinolinium N-oxide 20 using KBF3CF3 in BF3OEt2 toproduce the 1-(222-trifluoroethyl)isoquinoline 21 in 71yield [30] See Scheme 7 As shown in Scheme 8 Ichikawaemployed a dehydrogenation treatment of dihydroisoquino-line 22 to achieve the 4-trifluoromethylisoquinoline 23 inhigh yield The same substrate was subjected to dehydroflu-orination (with subsequent alkene isomerization) to obtain4-difluoromethylisoquinoline 24 in good yield [31]

25 Preparation of 4-Fluoroarylated Isoquinolines Duringan examination of tipifarnib analogs for bioactivityChennamaneni and coworkers coupled the trityl-protectedtetrahydroisoquinoline 25 with the heterocyclic ketone26 (Scheme 9) en route to the 4-(26-difluorophenyl)isoquinoline 27 in 60 yield [32]

6 Journal of Chemistry

14-dioxane NC

Ar

17 18

NO

I

O

+

r R1 = Ph R2 = HAlk = t-Bu Rf = CF3

Alk = Me Rf = (CF2)2CF3

q R1 = Ph R2 = H

Alk = Me Rf = CF2CF3Alk = Me Rf = CF3

R1

R1

AlkO2C

p R1 = Ph R2 = H

Rf

Rf

R2

19andashr(53ndash80)

80∘C 3h

Bu4NI (5mol)CO2Alk

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = 4-MeC6H4 R2 = 7-Mee R1 = 4-MeOC6H4 R2 = 7-OMef R1 = 4-ClC6H4 R2 = 7-Clg R1 = 4-BrC6H4 R2 = 7-Brh R1 = H R2 = 7-OMei R1 = Me R2 = Hj R1 = Me R2 = 7-Mek R1 = n-Pr R2 = Hl R1 = i-Pr R2 = Hm R1 = 4-ClC6H4 R2 = Hn R1 = 4-BrC6H4 R2 = Ho R1 = cyclohexyl R2 = H

Scheme 6 1-Perfluoroalkylisoquinolines via isonitrile cyclization and radical fluoroalkylation

(2) TMAF MeCN

(71)

2021

NO⊖

oplusN

CF3

(1) KBF3CF3 BF3OEt2

EtOAc 65∘C

Scheme 7 Benzylic trifluoromethylation of 1-methylisoquinoliniumN-oxide

Using amine 28 and 4-fluorobenzaldehyde shown inScheme 10 Awuah and Capretta combined microwave con-ditions and acid-catalysis to condense and cyclize the imineadduct at C8f -C1 followed by dehydrogenation to pro-duce the 2-(4-fluorophenyl) isoquinoline 29a in excellentoverall yield In a second reaction 28 was reacted with4-fluorophenylacetic acid under microwave conditions inthe presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33]

3 Fluorinated Trifluoromethylated Fluo-roarylated and TrifluoromethylarylatedIsoquinoline Synthesis via TransitionMetal Mediated Processes

This section catalogues a representative sample of isoquino-line preparations catalyzed by periods 4 5 and 6 tran-sition metal complexes Methods examined include thosewhich produce a wide array of A and B ring-fluorinatedtrifluoromethylated and fluoroarylated polyfunctional iso-quinolines In addition several selective fluorination and

trifluoromethylation reactions done in concert with transi-tion metal catalysts are shown that produce polyfunctionalisoquinolines with a high degree of fluorination and trifluo-romethylation site regiocontrol

31 Period 4 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 and C1-C4

311 Manganese Catalysis He et al researchers utilized themanganese catalystMnBn(CO)5 in a [4 + 2] annulation atN2-C3 andC4f -C4 of imines 30 and alkynes 31 to prepare six fluo-rinated isoquinolines 32 in good to excellent yields shown inScheme 11 [34] Their strategy affords three ring B fluoroiso-quinoline regioisomers (32andashc) and a trifluoromethyliso-quinoline (32d) as well as a ring A fluorophenylisoquinoline(32e) and a ring A trifluoromethylphenylisoquinoline (32f)Maorsquos group recently reported the manganese catalyzedcoupling and cyclization of vinyl isocyanides 33 and assortedarylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a the 1-(4-fluorophenyl)-isoquinoline35b and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c ingood overall yields [35]

312 Cobalt Catalysis Cobalt (III) catalysis has been effec-tively utilized in N2-C3 and C4f -C4 bond formationcyclizations of oximes amidines and hydrazones to preparea broad array of isoquinolines bearing fluorine and fluorine-containing groups Examples are depicted in Scheme 12 Sunand coworkers used CplowastCoI2(CO) to catalyze the regios-elective cyclization of the acyl oxime series 36 with bothinternal and terminal alkynes 37 en route to a diverse set

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

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Carbohydrate Chemistry

International Journal of

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Theoretical ChemistryJournal of

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Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

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CatalystsJournal of

Journal of Chemistry 3

N

MeO

MeO

OMe

MeO

Papaverine (antispasmodic)

N

Quinisocaine(anesthetic)

N

MeO

MeO

OMe

MeO

Pyrrolo(21-a)isoquinoline (dye-paint component)

Ph

CHO

N

N

Antitumor agent

N

NIr

O

O

2

1-Phenylisoquinolinyliridium complex(electrophosphorescent-color display)

n-Bu

n-Bu

OCH2CH2N(CH3)2

Figure 2 Selected medicinal agricultural and industrial isoquinoline derivatives

MeO

MeO

Tetrahydroisoquinoline carbamate(antibacterial)

N

FF

Cl

NNOH

Tipifarnib analog(antiparasitic)

O

F

N

F

IrO

O

F

2

1-Phenylisoquinolinyliridium complex(electrophosphorescent-color display)

NN

O

I

[18]F-isoquinoline carboxamide derivative (PET radiolabeling ligand)

18F

(CH2)5 OCNH

NCH3

Figure 3 Selected fluorinated isoquinoline derivatives with medicinal and industrial applications

cycloaddition of benzonitriles8 and9 to prepare the 1-amino-isoquinolines 10a-b which are fluorinated at the 6- and 7-positions in moderate yields [26]

Yang et al employed a tandem C8f -C1 and C1-N2bond-forming process with azidoacrylate 11 and asymmetric

diazo diketone 12 (Scheme 4) to obtain a 1 1 ratio of 7-fluoroisoquinoline isomers 13a and 13b in good yield [27]This interesting reaction cascade begins with the in situphosphazene formation of 11 via the Staudinger-Meyerreaction with concomitant ketene formation from 12 via a

4 Journal of Chemistry

microwave promoted intermolecular cycloaddition

electrocyclic ring closureIr catalysis

microwave promotedintermolecular cycloaddition

Mn catalysis

base initiated intramolecular ring closure Cu Ag catalysis

Mn Co Ni Cu Ru Rh catalysis

Aryne-alkene cyclizationRh Pd catalysis

Rh catalyzed oxidative annulation

Ring A assembly at C3-C4 and N2-C3

Ring A assembly at C1-N2

1

2N

3

4 56

7

8

A B

4f

8f

Ring B assembly at C4f -C5 and C8f -C8

Ring A assembly at C4f -C4 and C8f -C1

Ring A assembly at C4-C4f

Ring A assembly at C8f -C1

Figure 4 Recent isoquinoline synthesis methods

1

N2

3

4 5

6

7

8

A B8 processes

7 processes

11 processes1 process

12 processes

16 processes

2 processes F incorporation at C8

F Rf incorporation at C7

F Rf incorporation at C6

F incorporation at C5F Arf incorporation at C4

F Rf ORf SRf Arf incorporation at C1

F Rf Arf incorporation at C3

Figure 5 Isoquinoline fluorination fluoroalkylation and fluoroarylation sites

PhToluene

t-BuOK

N

N

F

NRN

OO

+

F

R

OO

5 6

NN

9

N

8

X

+ X

NH2

(35ndash40)10a-b

100∘C 16h

b R = CH2CO2Mea R = Me (58ndash62)

7a-b

TfOH (11 eq)

120∘C (MW) 1hDCE (005M)

b X = 5-Fa X = 4-F

Scheme 3 Preparation of 6- and 7-fluoroisoquinolines via ynamide-nitrile and nitrile-nitrile cycloadditions

Journal of Chemistry 5

N

F(60)

O

F

O O

+ N

O

F +

13a 13bStaudinger-

Meyerreaction

Wolffrearrangement

F N

C

O

F N

C

O

+

aza-Wittig[13]-H

shift

11 12

Electrocyclic ring closure

N2N3

PPh3 tolueneCO2Et

CO2Et CO2Et

CO2Et CO2Et

100∘C 2 h

Scheme 4 Triphenylphosphine-mediated 7-fluoroisoquinoline synthesis

N

R

TBAT (2 eq)

R N

O

H

OTf

TMS

+

151416b (78)16a (57)

b R = CH3 R998400 = F

R998400

R998400

R998400

R998400

a R = CF3 R998400 = H

CO2Me

CO2Me THF 23∘C 6ndash8 h

Scheme 5 67-Difluoro- and 1-trifluoromethylisoquinolines via aryne annulation

Wolff rearrangement An aza-Wittig reaction between thephosphazene and ketene yields the isomericN-vinylic keteneimines in brackets Finally electrocyclic ring closure anda subsequent [13]-H migration leads to the formation ofisoquinoline isomers

23 Trifluoromethylated Ring-Fluorinated and Perfluori-nated Isoquinolines via Inter- and Intramolecular Ring ACyclizations at C8119891-C1 and C4119891-C4 Stoltzrsquos team leveragedtheir success in C-C bond insertion reactions to develop aBu4NPh3SiF2 (TBAT) promotedN-acyl dehydroamino ester-(14) aryne (15) C8f -C1C4f -C4 annulation that resulted in thesuccessful synthesis of a series of polysubstituted isoquino-lines and indoles [28] TBAT serves as the fluoride anionsource that desilylates 15 to generate the aryne upon lossof the triflate Scheme 5 depicts the preparation of methyl-3-carboxy-1-trifluoromethylisoquinoline (16a) and methyl-3-carboxy-67-difluoro-1-methylisoquinoline (16b) in goodoverall yield

Zhang and Studer [29] recently reported the C8f -C1intramolecular cyclization of 120573-aryl-120572-isocyano-acrylates 17and radical perfluoroalkylation using Togni reagents 18

as the Rf source to produce eighteen examples of highlyfunctionalized 1-trifluoromethyl- 1-pentafluoroethyl- and 1-heptafluoropropylisoquinolines 19 in good overall yields SeeScheme 6

24 Preparation of Selectively Trifluoromethylated and Diflu-oromethylated Isoquinolines at C1 and C4 Kuninobu et alsuccessfully conducted a benzylic trifluoromethylation of theisoquinolinium N-oxide 20 using KBF3CF3 in BF3OEt2 toproduce the 1-(222-trifluoroethyl)isoquinoline 21 in 71yield [30] See Scheme 7 As shown in Scheme 8 Ichikawaemployed a dehydrogenation treatment of dihydroisoquino-line 22 to achieve the 4-trifluoromethylisoquinoline 23 inhigh yield The same substrate was subjected to dehydroflu-orination (with subsequent alkene isomerization) to obtain4-difluoromethylisoquinoline 24 in good yield [31]

25 Preparation of 4-Fluoroarylated Isoquinolines Duringan examination of tipifarnib analogs for bioactivityChennamaneni and coworkers coupled the trityl-protectedtetrahydroisoquinoline 25 with the heterocyclic ketone26 (Scheme 9) en route to the 4-(26-difluorophenyl)isoquinoline 27 in 60 yield [32]

6 Journal of Chemistry

14-dioxane NC

Ar

17 18

NO

I

O

+

r R1 = Ph R2 = HAlk = t-Bu Rf = CF3

Alk = Me Rf = (CF2)2CF3

q R1 = Ph R2 = H

Alk = Me Rf = CF2CF3Alk = Me Rf = CF3

R1

R1

AlkO2C

p R1 = Ph R2 = H

Rf

Rf

R2

19andashr(53ndash80)

80∘C 3h

Bu4NI (5mol)CO2Alk

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = 4-MeC6H4 R2 = 7-Mee R1 = 4-MeOC6H4 R2 = 7-OMef R1 = 4-ClC6H4 R2 = 7-Clg R1 = 4-BrC6H4 R2 = 7-Brh R1 = H R2 = 7-OMei R1 = Me R2 = Hj R1 = Me R2 = 7-Mek R1 = n-Pr R2 = Hl R1 = i-Pr R2 = Hm R1 = 4-ClC6H4 R2 = Hn R1 = 4-BrC6H4 R2 = Ho R1 = cyclohexyl R2 = H

Scheme 6 1-Perfluoroalkylisoquinolines via isonitrile cyclization and radical fluoroalkylation

(2) TMAF MeCN

(71)

2021

NO⊖

oplusN

CF3

(1) KBF3CF3 BF3OEt2

EtOAc 65∘C

Scheme 7 Benzylic trifluoromethylation of 1-methylisoquinoliniumN-oxide

Using amine 28 and 4-fluorobenzaldehyde shown inScheme 10 Awuah and Capretta combined microwave con-ditions and acid-catalysis to condense and cyclize the imineadduct at C8f -C1 followed by dehydrogenation to pro-duce the 2-(4-fluorophenyl) isoquinoline 29a in excellentoverall yield In a second reaction 28 was reacted with4-fluorophenylacetic acid under microwave conditions inthe presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33]

3 Fluorinated Trifluoromethylated Fluo-roarylated and TrifluoromethylarylatedIsoquinoline Synthesis via TransitionMetal Mediated Processes

This section catalogues a representative sample of isoquino-line preparations catalyzed by periods 4 5 and 6 tran-sition metal complexes Methods examined include thosewhich produce a wide array of A and B ring-fluorinatedtrifluoromethylated and fluoroarylated polyfunctional iso-quinolines In addition several selective fluorination and

trifluoromethylation reactions done in concert with transi-tion metal catalysts are shown that produce polyfunctionalisoquinolines with a high degree of fluorination and trifluo-romethylation site regiocontrol

31 Period 4 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 and C1-C4

311 Manganese Catalysis He et al researchers utilized themanganese catalystMnBn(CO)5 in a [4 + 2] annulation atN2-C3 andC4f -C4 of imines 30 and alkynes 31 to prepare six fluo-rinated isoquinolines 32 in good to excellent yields shown inScheme 11 [34] Their strategy affords three ring B fluoroiso-quinoline regioisomers (32andashc) and a trifluoromethyliso-quinoline (32d) as well as a ring A fluorophenylisoquinoline(32e) and a ring A trifluoromethylphenylisoquinoline (32f)Maorsquos group recently reported the manganese catalyzedcoupling and cyclization of vinyl isocyanides 33 and assortedarylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a the 1-(4-fluorophenyl)-isoquinoline35b and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c ingood overall yields [35]

312 Cobalt Catalysis Cobalt (III) catalysis has been effec-tively utilized in N2-C3 and C4f -C4 bond formationcyclizations of oximes amidines and hydrazones to preparea broad array of isoquinolines bearing fluorine and fluorine-containing groups Examples are depicted in Scheme 12 Sunand coworkers used CplowastCoI2(CO) to catalyze the regios-elective cyclization of the acyl oxime series 36 with bothinternal and terminal alkynes 37 en route to a diverse set

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

4 Journal of Chemistry

microwave promoted intermolecular cycloaddition

electrocyclic ring closureIr catalysis

microwave promotedintermolecular cycloaddition

Mn catalysis

base initiated intramolecular ring closure Cu Ag catalysis

Mn Co Ni Cu Ru Rh catalysis

Aryne-alkene cyclizationRh Pd catalysis

Rh catalyzed oxidative annulation

Ring A assembly at C3-C4 and N2-C3

Ring A assembly at C1-N2

1

2N

3

4 56

7

8

A B

4f

8f

Ring B assembly at C4f -C5 and C8f -C8

Ring A assembly at C4f -C4 and C8f -C1

Ring A assembly at C4-C4f

Ring A assembly at C8f -C1

Figure 4 Recent isoquinoline synthesis methods

1

N2

3

4 5

6

7

8

A B8 processes

7 processes

11 processes1 process

12 processes

16 processes

2 processes F incorporation at C8

F Rf incorporation at C7

F Rf incorporation at C6

F incorporation at C5F Arf incorporation at C4

F Rf ORf SRf Arf incorporation at C1

F Rf Arf incorporation at C3

Figure 5 Isoquinoline fluorination fluoroalkylation and fluoroarylation sites

PhToluene

t-BuOK

N

N

F

NRN

OO

+

F

R

OO

5 6

NN

9

N

8

X

+ X

NH2

(35ndash40)10a-b

100∘C 16h

b R = CH2CO2Mea R = Me (58ndash62)

7a-b

TfOH (11 eq)

120∘C (MW) 1hDCE (005M)

b X = 5-Fa X = 4-F

Scheme 3 Preparation of 6- and 7-fluoroisoquinolines via ynamide-nitrile and nitrile-nitrile cycloadditions

Journal of Chemistry 5

N

F(60)

O

F

O O

+ N

O

F +

13a 13bStaudinger-

Meyerreaction

Wolffrearrangement

F N

C

O

F N

C

O

+

aza-Wittig[13]-H

shift

11 12

Electrocyclic ring closure

N2N3

PPh3 tolueneCO2Et

CO2Et CO2Et

CO2Et CO2Et

100∘C 2 h

Scheme 4 Triphenylphosphine-mediated 7-fluoroisoquinoline synthesis

N

R

TBAT (2 eq)

R N

O

H

OTf

TMS

+

151416b (78)16a (57)

b R = CH3 R998400 = F

R998400

R998400

R998400

R998400

a R = CF3 R998400 = H

CO2Me

CO2Me THF 23∘C 6ndash8 h

Scheme 5 67-Difluoro- and 1-trifluoromethylisoquinolines via aryne annulation

Wolff rearrangement An aza-Wittig reaction between thephosphazene and ketene yields the isomericN-vinylic keteneimines in brackets Finally electrocyclic ring closure anda subsequent [13]-H migration leads to the formation ofisoquinoline isomers

23 Trifluoromethylated Ring-Fluorinated and Perfluori-nated Isoquinolines via Inter- and Intramolecular Ring ACyclizations at C8119891-C1 and C4119891-C4 Stoltzrsquos team leveragedtheir success in C-C bond insertion reactions to develop aBu4NPh3SiF2 (TBAT) promotedN-acyl dehydroamino ester-(14) aryne (15) C8f -C1C4f -C4 annulation that resulted in thesuccessful synthesis of a series of polysubstituted isoquino-lines and indoles [28] TBAT serves as the fluoride anionsource that desilylates 15 to generate the aryne upon lossof the triflate Scheme 5 depicts the preparation of methyl-3-carboxy-1-trifluoromethylisoquinoline (16a) and methyl-3-carboxy-67-difluoro-1-methylisoquinoline (16b) in goodoverall yield

Zhang and Studer [29] recently reported the C8f -C1intramolecular cyclization of 120573-aryl-120572-isocyano-acrylates 17and radical perfluoroalkylation using Togni reagents 18

as the Rf source to produce eighteen examples of highlyfunctionalized 1-trifluoromethyl- 1-pentafluoroethyl- and 1-heptafluoropropylisoquinolines 19 in good overall yields SeeScheme 6

24 Preparation of Selectively Trifluoromethylated and Diflu-oromethylated Isoquinolines at C1 and C4 Kuninobu et alsuccessfully conducted a benzylic trifluoromethylation of theisoquinolinium N-oxide 20 using KBF3CF3 in BF3OEt2 toproduce the 1-(222-trifluoroethyl)isoquinoline 21 in 71yield [30] See Scheme 7 As shown in Scheme 8 Ichikawaemployed a dehydrogenation treatment of dihydroisoquino-line 22 to achieve the 4-trifluoromethylisoquinoline 23 inhigh yield The same substrate was subjected to dehydroflu-orination (with subsequent alkene isomerization) to obtain4-difluoromethylisoquinoline 24 in good yield [31]

25 Preparation of 4-Fluoroarylated Isoquinolines Duringan examination of tipifarnib analogs for bioactivityChennamaneni and coworkers coupled the trityl-protectedtetrahydroisoquinoline 25 with the heterocyclic ketone26 (Scheme 9) en route to the 4-(26-difluorophenyl)isoquinoline 27 in 60 yield [32]

6 Journal of Chemistry

14-dioxane NC

Ar

17 18

NO

I

O

+

r R1 = Ph R2 = HAlk = t-Bu Rf = CF3

Alk = Me Rf = (CF2)2CF3

q R1 = Ph R2 = H

Alk = Me Rf = CF2CF3Alk = Me Rf = CF3

R1

R1

AlkO2C

p R1 = Ph R2 = H

Rf

Rf

R2

19andashr(53ndash80)

80∘C 3h

Bu4NI (5mol)CO2Alk

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = 4-MeC6H4 R2 = 7-Mee R1 = 4-MeOC6H4 R2 = 7-OMef R1 = 4-ClC6H4 R2 = 7-Clg R1 = 4-BrC6H4 R2 = 7-Brh R1 = H R2 = 7-OMei R1 = Me R2 = Hj R1 = Me R2 = 7-Mek R1 = n-Pr R2 = Hl R1 = i-Pr R2 = Hm R1 = 4-ClC6H4 R2 = Hn R1 = 4-BrC6H4 R2 = Ho R1 = cyclohexyl R2 = H

Scheme 6 1-Perfluoroalkylisoquinolines via isonitrile cyclization and radical fluoroalkylation

(2) TMAF MeCN

(71)

2021

NO⊖

oplusN

CF3

(1) KBF3CF3 BF3OEt2

EtOAc 65∘C

Scheme 7 Benzylic trifluoromethylation of 1-methylisoquinoliniumN-oxide

Using amine 28 and 4-fluorobenzaldehyde shown inScheme 10 Awuah and Capretta combined microwave con-ditions and acid-catalysis to condense and cyclize the imineadduct at C8f -C1 followed by dehydrogenation to pro-duce the 2-(4-fluorophenyl) isoquinoline 29a in excellentoverall yield In a second reaction 28 was reacted with4-fluorophenylacetic acid under microwave conditions inthe presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33]

3 Fluorinated Trifluoromethylated Fluo-roarylated and TrifluoromethylarylatedIsoquinoline Synthesis via TransitionMetal Mediated Processes

This section catalogues a representative sample of isoquino-line preparations catalyzed by periods 4 5 and 6 tran-sition metal complexes Methods examined include thosewhich produce a wide array of A and B ring-fluorinatedtrifluoromethylated and fluoroarylated polyfunctional iso-quinolines In addition several selective fluorination and

trifluoromethylation reactions done in concert with transi-tion metal catalysts are shown that produce polyfunctionalisoquinolines with a high degree of fluorination and trifluo-romethylation site regiocontrol

31 Period 4 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 and C1-C4

311 Manganese Catalysis He et al researchers utilized themanganese catalystMnBn(CO)5 in a [4 + 2] annulation atN2-C3 andC4f -C4 of imines 30 and alkynes 31 to prepare six fluo-rinated isoquinolines 32 in good to excellent yields shown inScheme 11 [34] Their strategy affords three ring B fluoroiso-quinoline regioisomers (32andashc) and a trifluoromethyliso-quinoline (32d) as well as a ring A fluorophenylisoquinoline(32e) and a ring A trifluoromethylphenylisoquinoline (32f)Maorsquos group recently reported the manganese catalyzedcoupling and cyclization of vinyl isocyanides 33 and assortedarylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a the 1-(4-fluorophenyl)-isoquinoline35b and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c ingood overall yields [35]

312 Cobalt Catalysis Cobalt (III) catalysis has been effec-tively utilized in N2-C3 and C4f -C4 bond formationcyclizations of oximes amidines and hydrazones to preparea broad array of isoquinolines bearing fluorine and fluorine-containing groups Examples are depicted in Scheme 12 Sunand coworkers used CplowastCoI2(CO) to catalyze the regios-elective cyclization of the acyl oxime series 36 with bothinternal and terminal alkynes 37 en route to a diverse set

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Journal of Chemistry 5

N

F(60)

O

F

O O

+ N

O

F +

13a 13bStaudinger-

Meyerreaction

Wolffrearrangement

F N

C

O

F N

C

O

+

aza-Wittig[13]-H

shift

11 12

Electrocyclic ring closure

N2N3

PPh3 tolueneCO2Et

CO2Et CO2Et

CO2Et CO2Et

100∘C 2 h

Scheme 4 Triphenylphosphine-mediated 7-fluoroisoquinoline synthesis

N

R

TBAT (2 eq)

R N

O

H

OTf

TMS

+

151416b (78)16a (57)

b R = CH3 R998400 = F

R998400

R998400

R998400

R998400

a R = CF3 R998400 = H

CO2Me

CO2Me THF 23∘C 6ndash8 h

Scheme 5 67-Difluoro- and 1-trifluoromethylisoquinolines via aryne annulation

Wolff rearrangement An aza-Wittig reaction between thephosphazene and ketene yields the isomericN-vinylic keteneimines in brackets Finally electrocyclic ring closure anda subsequent [13]-H migration leads to the formation ofisoquinoline isomers

23 Trifluoromethylated Ring-Fluorinated and Perfluori-nated Isoquinolines via Inter- and Intramolecular Ring ACyclizations at C8119891-C1 and C4119891-C4 Stoltzrsquos team leveragedtheir success in C-C bond insertion reactions to develop aBu4NPh3SiF2 (TBAT) promotedN-acyl dehydroamino ester-(14) aryne (15) C8f -C1C4f -C4 annulation that resulted in thesuccessful synthesis of a series of polysubstituted isoquino-lines and indoles [28] TBAT serves as the fluoride anionsource that desilylates 15 to generate the aryne upon lossof the triflate Scheme 5 depicts the preparation of methyl-3-carboxy-1-trifluoromethylisoquinoline (16a) and methyl-3-carboxy-67-difluoro-1-methylisoquinoline (16b) in goodoverall yield

Zhang and Studer [29] recently reported the C8f -C1intramolecular cyclization of 120573-aryl-120572-isocyano-acrylates 17and radical perfluoroalkylation using Togni reagents 18

as the Rf source to produce eighteen examples of highlyfunctionalized 1-trifluoromethyl- 1-pentafluoroethyl- and 1-heptafluoropropylisoquinolines 19 in good overall yields SeeScheme 6

24 Preparation of Selectively Trifluoromethylated and Diflu-oromethylated Isoquinolines at C1 and C4 Kuninobu et alsuccessfully conducted a benzylic trifluoromethylation of theisoquinolinium N-oxide 20 using KBF3CF3 in BF3OEt2 toproduce the 1-(222-trifluoroethyl)isoquinoline 21 in 71yield [30] See Scheme 7 As shown in Scheme 8 Ichikawaemployed a dehydrogenation treatment of dihydroisoquino-line 22 to achieve the 4-trifluoromethylisoquinoline 23 inhigh yield The same substrate was subjected to dehydroflu-orination (with subsequent alkene isomerization) to obtain4-difluoromethylisoquinoline 24 in good yield [31]

25 Preparation of 4-Fluoroarylated Isoquinolines Duringan examination of tipifarnib analogs for bioactivityChennamaneni and coworkers coupled the trityl-protectedtetrahydroisoquinoline 25 with the heterocyclic ketone26 (Scheme 9) en route to the 4-(26-difluorophenyl)isoquinoline 27 in 60 yield [32]

6 Journal of Chemistry

14-dioxane NC

Ar

17 18

NO

I

O

+

r R1 = Ph R2 = HAlk = t-Bu Rf = CF3

Alk = Me Rf = (CF2)2CF3

q R1 = Ph R2 = H

Alk = Me Rf = CF2CF3Alk = Me Rf = CF3

R1

R1

AlkO2C

p R1 = Ph R2 = H

Rf

Rf

R2

19andashr(53ndash80)

80∘C 3h

Bu4NI (5mol)CO2Alk

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = 4-MeC6H4 R2 = 7-Mee R1 = 4-MeOC6H4 R2 = 7-OMef R1 = 4-ClC6H4 R2 = 7-Clg R1 = 4-BrC6H4 R2 = 7-Brh R1 = H R2 = 7-OMei R1 = Me R2 = Hj R1 = Me R2 = 7-Mek R1 = n-Pr R2 = Hl R1 = i-Pr R2 = Hm R1 = 4-ClC6H4 R2 = Hn R1 = 4-BrC6H4 R2 = Ho R1 = cyclohexyl R2 = H

Scheme 6 1-Perfluoroalkylisoquinolines via isonitrile cyclization and radical fluoroalkylation

(2) TMAF MeCN

(71)

2021

NO⊖

oplusN

CF3

(1) KBF3CF3 BF3OEt2

EtOAc 65∘C

Scheme 7 Benzylic trifluoromethylation of 1-methylisoquinoliniumN-oxide

Using amine 28 and 4-fluorobenzaldehyde shown inScheme 10 Awuah and Capretta combined microwave con-ditions and acid-catalysis to condense and cyclize the imineadduct at C8f -C1 followed by dehydrogenation to pro-duce the 2-(4-fluorophenyl) isoquinoline 29a in excellentoverall yield In a second reaction 28 was reacted with4-fluorophenylacetic acid under microwave conditions inthe presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33]

3 Fluorinated Trifluoromethylated Fluo-roarylated and TrifluoromethylarylatedIsoquinoline Synthesis via TransitionMetal Mediated Processes

This section catalogues a representative sample of isoquino-line preparations catalyzed by periods 4 5 and 6 tran-sition metal complexes Methods examined include thosewhich produce a wide array of A and B ring-fluorinatedtrifluoromethylated and fluoroarylated polyfunctional iso-quinolines In addition several selective fluorination and

trifluoromethylation reactions done in concert with transi-tion metal catalysts are shown that produce polyfunctionalisoquinolines with a high degree of fluorination and trifluo-romethylation site regiocontrol

31 Period 4 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 and C1-C4

311 Manganese Catalysis He et al researchers utilized themanganese catalystMnBn(CO)5 in a [4 + 2] annulation atN2-C3 andC4f -C4 of imines 30 and alkynes 31 to prepare six fluo-rinated isoquinolines 32 in good to excellent yields shown inScheme 11 [34] Their strategy affords three ring B fluoroiso-quinoline regioisomers (32andashc) and a trifluoromethyliso-quinoline (32d) as well as a ring A fluorophenylisoquinoline(32e) and a ring A trifluoromethylphenylisoquinoline (32f)Maorsquos group recently reported the manganese catalyzedcoupling and cyclization of vinyl isocyanides 33 and assortedarylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a the 1-(4-fluorophenyl)-isoquinoline35b and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c ingood overall yields [35]

312 Cobalt Catalysis Cobalt (III) catalysis has been effec-tively utilized in N2-C3 and C4f -C4 bond formationcyclizations of oximes amidines and hydrazones to preparea broad array of isoquinolines bearing fluorine and fluorine-containing groups Examples are depicted in Scheme 12 Sunand coworkers used CplowastCoI2(CO) to catalyze the regios-elective cyclization of the acyl oxime series 36 with bothinternal and terminal alkynes 37 en route to a diverse set

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

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International Journal ofPhotoenergy

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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CatalystsJournal of

6 Journal of Chemistry

14-dioxane NC

Ar

17 18

NO

I

O

+

r R1 = Ph R2 = HAlk = t-Bu Rf = CF3

Alk = Me Rf = (CF2)2CF3

q R1 = Ph R2 = H

Alk = Me Rf = CF2CF3Alk = Me Rf = CF3

R1

R1

AlkO2C

p R1 = Ph R2 = H

Rf

Rf

R2

19andashr(53ndash80)

80∘C 3h

Bu4NI (5mol)CO2Alk

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = 4-MeC6H4 R2 = 7-Mee R1 = 4-MeOC6H4 R2 = 7-OMef R1 = 4-ClC6H4 R2 = 7-Clg R1 = 4-BrC6H4 R2 = 7-Brh R1 = H R2 = 7-OMei R1 = Me R2 = Hj R1 = Me R2 = 7-Mek R1 = n-Pr R2 = Hl R1 = i-Pr R2 = Hm R1 = 4-ClC6H4 R2 = Hn R1 = 4-BrC6H4 R2 = Ho R1 = cyclohexyl R2 = H

Scheme 6 1-Perfluoroalkylisoquinolines via isonitrile cyclization and radical fluoroalkylation

(2) TMAF MeCN

(71)

2021

NO⊖

oplusN

CF3

(1) KBF3CF3 BF3OEt2

EtOAc 65∘C

Scheme 7 Benzylic trifluoromethylation of 1-methylisoquinoliniumN-oxide

Using amine 28 and 4-fluorobenzaldehyde shown inScheme 10 Awuah and Capretta combined microwave con-ditions and acid-catalysis to condense and cyclize the imineadduct at C8f -C1 followed by dehydrogenation to pro-duce the 2-(4-fluorophenyl) isoquinoline 29a in excellentoverall yield In a second reaction 28 was reacted with4-fluorophenylacetic acid under microwave conditions inthe presence of phosphoryl chloride to prepare the 1-(4-fluorobenzoyl)isoqionoline 29b in good yield [33]

3 Fluorinated Trifluoromethylated Fluo-roarylated and TrifluoromethylarylatedIsoquinoline Synthesis via TransitionMetal Mediated Processes

This section catalogues a representative sample of isoquino-line preparations catalyzed by periods 4 5 and 6 tran-sition metal complexes Methods examined include thosewhich produce a wide array of A and B ring-fluorinatedtrifluoromethylated and fluoroarylated polyfunctional iso-quinolines In addition several selective fluorination and

trifluoromethylation reactions done in concert with transi-tion metal catalysts are shown that produce polyfunctionalisoquinolines with a high degree of fluorination and trifluo-romethylation site regiocontrol

31 Period 4 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 and C1-C4

311 Manganese Catalysis He et al researchers utilized themanganese catalystMnBn(CO)5 in a [4 + 2] annulation atN2-C3 andC4f -C4 of imines 30 and alkynes 31 to prepare six fluo-rinated isoquinolines 32 in good to excellent yields shown inScheme 11 [34] Their strategy affords three ring B fluoroiso-quinoline regioisomers (32andashc) and a trifluoromethyliso-quinoline (32d) as well as a ring A fluorophenylisoquinoline(32e) and a ring A trifluoromethylphenylisoquinoline (32f)Maorsquos group recently reported the manganese catalyzedcoupling and cyclization of vinyl isocyanides 33 and assortedarylhydrazines 34 en route to three new examples of 7-fluoroisoqinoline 35a the 1-(4-fluorophenyl)-isoquinoline35b and the 1-(4-trifluoromethylphenyl)-isoquinoline 35c ingood overall yields [35]

312 Cobalt Catalysis Cobalt (III) catalysis has been effec-tively utilized in N2-C3 and C4f -C4 bond formationcyclizations of oximes amidines and hydrazones to preparea broad array of isoquinolines bearing fluorine and fluorine-containing groups Examples are depicted in Scheme 12 Sunand coworkers used CplowastCoI2(CO) to catalyze the regios-elective cyclization of the acyl oxime series 36 with bothinternal and terminal alkynes 37 en route to a diverse set

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Journal of Chemistry 7

DBU (12 eq) LiBr (1 eq)

DMSO

PdC

Reflux 4 days xylene

24(80)

23(80)

22

NNN 100∘C 3h

CF3 CF3 CHF2

Scheme 8 Preparation of 4-trifluoromethyl- and 4-difluoromethylisoquinolines

BrOH

ClCl

(60)25 26 27

NN

FF

NN

O+

FFNN

CPh3

(2) TFA CH2Cl2(3) MnO2 dioxane 90∘C

(4) SOCl2 rt(5) MeOH 90∘C

(1) n-BuLi THF minus78∘C

Scheme 9 Preparation of difluoroarylated tipifarnib analog

MeO

MeO

CHO

(2) 10 PdC toluene reflux

MeO

MeO

MeO

MeO

(2) air

28

N

F

F

N

F

O

F

29b (60)

29a (85)

(3) 10 PdC toluene 150∘C 30min

140∘C 30min

NH2

CH2CO2H

(1)POCl3 toluene 120583 waves 140∘C 30min

(1) TFA (8 eq) toluene120583 waves

Scheme 10 Synthesis of fluorophenyl- and fluorobenzoylisoquinolines

of eleven fluorine-containing isoquinolines 38 [36] Lirsquos teamused the same catalyst system with a slightly different base tocouple aryl amidines 39 and diazo compounds 40 to deliverfive examples of monofluorinated and trifluoromethylated 1-aminoisoquinolines 41 in fair to excellent yields [37] Pawaret al just released a study of Co(III)-catalyzed CndashHNndashNbond functionalization of arylhydrazones 42 with internalalkynes 43 for the synthesis of three ring-fluorinated andfluoroarylated isoquinoline derivatives 44 in very good yields

[38] while a 2016 report by Yu et al catalogued the cycload-dition of oxadiazolones 45 with alkynes 46 to prepare eightring-fluorinated trifluoromethylated and fluoroarylated iso-quinolines 47 in yields ranging from 45 to 85 [39] Therelatively mild reaction conditions used in these processespermit toleration of a wide scope of substrates

313 Nickel Catalysis Yoshidarsquos group conducted a nickelcatalyzed N2-C3C4f -C4 bond formationcycloaddition of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

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Carbohydrate Chemistry

International Journal of

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

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Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

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Journal of

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Analytical ChemistryInternational Journal of

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Quantum Chemistry

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Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

8 Journal of Chemistry

NHAr Ar

Ar

Ar

Ar

Ar

ArAr

PhPh

PhPh

Ph

PhPh

30 31

TBPB (6 eq) MeCN

33 34NC

+ N

+ N

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

n-Bun-Bun-Bun-Bu

4-FC6H4

4-CF3C6H4

4-FC6H44-FC6H4

CO2Me

CO2Me

(66ndash78)70∘C

Mn(OAc)∙4H2O (02 eq)NHNH2

R6

R5

R4R3

R3

R2

R2

R1

R1

R2

R2

R2

R2

R1

R1

(58ndash86)105∘C 12h under N2

14-dioxane (01M)MnBn(CO)5 (10mol)

32a R5 = F R3 = R4 = R6 = H32b R4 = F R3 = R5 = R6 = H32c R3 = F R4 = R5 = R6 = H32d R4 = CF3 R3 = R5 = R6 = H32e R4 = MeO R3 = R5 = R6 = H32f R4 = MeO R3 = R5 = R6 = H

35a R3 = F35b R3 = H35c R3 = H

a 4-FC6H4

a 4-FC6H4

b 3-FC6H4

c 2-FC6H4

d 3-CF3C6H4

e 4-MeOC6H4

f 4-MeOC6H4

b Phc Ph

Scheme 11 Manganese catalyzed fluoroisoquinoline synthesis

aromatic ketoximes 48 with 4-octyne 49 to prepare fluorine-containing isoquinolines 50a and 50b in good overall yield[40] See Scheme 13

314 Copper Catalysis Ohto et al developed a copper(I)-catalyzed four-component coupling reaction whereby 2-ethynylbenzaldehydes 51 paraformaldehyde diisopropy-lamine and 119905-BuNH2 were cyclized at N2-C3 to give 6-fluoro- and 7-fluoroisoquinolines 52 [41] See Scheme 14Fan et al used isoquinoline-N-oxides 53 and the Tognireagent 54 catalyzed by copper(II) triflate to prepare six-teen 1-(trifluoromethyl)isoquinolines 55 [42] Mormino etal subjected 3-bromoisoquinoline 56 to the phenanthroline-ligated copper trifluoromethylating reagent (phen)CuCF357 preparing the 4-trifluoromethylisoquinoline 58 via aradical substitution [43] These processes provide the targetisoquinolines in good overall yields

32 Period 5 Transition Metal Catalysis Ring-FluorinatedTrifluoromethylated Fluoroarylated and Trifluoromethy-larylated Isoquinolines via Inter- and Intramolecular RingA Cyclization at N2-C3 C4119891-C4 C8119891-C8 and C1-C4

321 Ruthenium Cataliysis Scheme 15 depicts two ruthe-nium catalyzed cyclizations to produce fluorine-containingisoquinolines via N2-C3 and C4f -C4 bond formation He etal cyclized several diaryl imines 59 with diarylacetylenes60 with a ruthenium catalyst to prepare six tetrasubstitutedring-fluorinated trifluoromethylated fluoroarylated and tri-fluoromethylarylated isoquinolines 61 in yield ranging from

40 to 86 [44] Chinnagolla and coworkers used a similarmethodology and cyclized several diaryl imine chlorides 62with diarylacetylenes 63with a ruthenium catalyst to preparea series of six tetrasubstituted trifluoroethoxyisoquinolines64 in yield ranging from 61 to 81 [45]

322 Rhodium Catalysis Two rhodium-catalyzed prepara-tions of isoquinolines that incorporate fluorine and triflu-oromethyl groups are shown in Scheme 16 Qianrsquos groupconducted a rhodium-catalyzed C8f -C8C4f -C4 annulation offluoropicolinamide 65 with diphenylacetylene 66 to producethe tetraphenyl 4-fluoroisoquinoline 67 in excellent yield[46] Guimond and Fagnou performed a highly efficientrhodium-catalyzed oxidative cross-coupling and C4f -C4N2-C3 cycloaddition of aldimines 68 and 4-octyne 69 en routeto 6-fluoro- and 6-trifluoromethylisoquinolines 70a and 70b[47] These catalyzed processes are believed to occur via asequence involving Rh (III) insertion followed by reductiveeliminationelectrocyclization to produce the isoquinolines

323 Palladium Catalysis Scheme 17 depicts work con-ducted by Pilgrim and coworkers in which the protectedaryl bromide series 71 acetophenone 72 an electrophileand ammonium chloride were combined in a palladiumcatalyzed three-step one-pot C4f -C4N2-C3 cycloadditionprocess to furnish ring-fluorinated isoquinoline 73a a triflu-oromethylated isoquinoline 73b and trifluoromethylarylatedisoquinolines 73cndashd in overall yields ranging from 46 to73 [48] This procedure begins with the arylation reactionof an enolate followed by reaction with Selectfluor II

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

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Advances in

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Analytical Methods in Chemistry

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Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

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Medicinal ChemistryInternational Journal of

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Chromatography Research International

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CatalystsJournal of

Journal of Chemistry 9

OAc36 37

NH

39 40

42 43

45 46

NN +

N

O

+

NN +

N

R+

R

RR

YN

ONO

HW

XY

Z

Z

XW(45ndash85)

20h N2

TFE 120∘C

AdCOOH (20mol)

(78ndash85)14h air

TFE 80ndash120∘C

PivOH (20mol)

(42ndash83)

KOPiv (20mol)

NHR1

NHR1

24h ArDCE 80ndash120∘C

47andashh

NH2

N2

NH2

R1R1R3

R3

R2

R2

R4

R3R2 R4

R3

R2

R5

R4

R4

R1 R3

R2R3

R2

AgSbF6 (20mol)

AgSbF6 (20mol)

AgSbF6 (20mol)

KOAc (20mol)

38a R1 = 7-Cl R2 = 4-FC6H4 R3 = H38b R1 = 7-Br 4-F R2 = 2-MeC6H4 R3 = H

38i R1 = 6-Cl R2 = 4-FC6H4 R3 = H38j R1 = 6-F R2 = Ph R3 = H38k R1 = 6-CF3 R2 = Ph R3 = H

a R1 = 3-Cl R2 = 4-FC6H4 R3 = Hb R1 = 3-Br 4-F R2 = 2-MeC6H4 R3 = H

i R1 = 4-Cl R2 = 4-FC6H4 R3 = Hj R1 = 4-F R2 = Ph R3 = H

41a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 6-F41b R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-F41c R1 = t-Bu R2 = Me R3 = CO2Et R4 = 7-CF341d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 8-F41e R1 = t-Bu R2 = H R3 = Ph R4 = 6-F

a R1 = t-Bu R2 = Me R3 = CO2Et R4 = 4-Fb R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-Fc R1 = t-Bu R2 = Me R3 = CO2Et R4 = 3-CF3d R1 = t-Bu R2 = Me R3 = CO2Et R4 = 2-Fe R1 = t-Bu R2 = H R3 = Ph R4 = 4-F

44a R2 = Ph R3 = R4 = 4-CF3C6H4 R5 = H44b R2 = 4-FC6H4 R3 = R4 = Ph R5 = F44c R2 = Ph R3 = R4 = 4-FC6H4 R5 = H

a R1 = R2 = Ph R3 = R4 = 4-CF3C6H4b R1 = R2 = 4-FC6H4 R3 = R4 = Phc R1 = R2 = Ph R3 = R4 = 4-FC6H4

a Y = F W = X = Z = Hb Y = 4-CF3 W = X = Z = Hc W = F X = Y = Z = Hd Y = 4-CF3W = X = Z = He W = H X = Y = Z = Ff Y = Cl W = X = Z = Hg Y = Cl W = X = Z = Hh Y = Cl W = X = Z = H

R = PhR = PhR = PhR = PhR = Ph

R = 4-FC6H4R = 2-FC6H4R = 3-FC6H4

c R1 = 3-CF3 R2 = 2-MeC6H4 R3 = Hd R1 = 3-CF3 R2 = (CH2)2Ph R3 = He R1 = 3-CF3 R2 = (CH2)2Me R3 = Hf R1 = 3-CF3 R2 = (CH2)4Me R3 = Hg R1 = 3-CF3 R2 = cyclohexyl R3 = Hh R1 = 3-CF3 R2 = R3 = Ph

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

CplowastCoI2(CO) (10 mol)

(45ndash98)

38c R1 = 7-CF3 R2 = 2-MeC6H4 R3 = H38d R1 = 7-CF3 R2 = (CH2)2Ph R3 = H38e R1 = 7-CF3 R2 = (CH2)2Me R3 = H38f R1 = 7-CF3 R2 = (CH2)4Me R3 = H38g R1 = 7-CF3 R2 = cyclohexyl R3 = H38h R1 = 7-CF3 R2 = R3 = Ph

k R1 = 4-CF3 R2 = Ph R3 = H

KOAc (30 mol)

TFE 110∘C 16 h N2

Scheme 12 Cobalt catalyzed fluoroisoquinoline syntheses

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

10 Journal of Chemistry

NOBn

(60ndash67)48 49

+N

50a R2 = 4-FC6H4 R3 = R4 = Pr R5 = F50b R2 = 4-MeOC6H4 R3 = R4 = Pr R5 = F

a R1 = R2 = 4-FC6H4 R3 = R4 = Prb R1 = 4-FC6H4 R2 = 4-MeOC6H4 R3 = R4 = Pr

Ni(cod)2 (10mol)

R1

R2R2

R3 R4R3

R4

R5toluene 110∘C 24hdppf (10mol)

Scheme 13 Nickel catalyzed 6-fluoro and 1-(4-fluorophenyl)isoquinoline synthesis

+

51

53 54

(67)56 58

CuBr

NO

O

I

N

ORR

H

NN

N N

(1) (HCHO)n HN(i-Pr)2CuI (10mol)

(2) t-BuNH2 DMF 140∘C(60ndash88)

52a R = 6-F52b R = 7-F

N(i-Pr)2

CF3

CF3

CF3

55andashp

Cu(OTf)2(10mol)

DMAP MeCN40∘C

(56ndash87)

a R1 = Ph R2 = Hb R1 = Ph R2 = 6-OMe 7-OMec R1 = Ph R2 = 7-Cld R1 = Ph R2 = 7-Mee R1 = t-Bu R2 = Hf R1 = n-Bu R2 = 7-Clg R1 = Ph R2 = 7-Fh R1 = Ph R2 = 6-F

i R1 = Ph R2 = 5-OMej R1 = t-Bu R2 = Hk R1 = n-Bu R2 = 7-Cll R1 = p-Anisyl R2 = Hm R1 = p-ClC6H4 R2 = Hn R1 = cyclopropyl R2 = Ho R1 = cyclopropyl R2 = 7-Fp R1 = cyclopropyl R2 = 7-Cl

(10mol)F3C

DMF 80∘C

R1

R2R1

R2Noplus

O⊖

Scheme 14 Copper catalyzed fluoroisoquinoline synthesis

allyl bromide or 4-bromobenzotrifluoride respectively andaromatization with ammonium chloride

Scheme 18 shows two Pd(OAc)2 catalyzed isoquinolineproducing cyclizations Tian et al developed an efficient Pd-catalyzed Heck reaction in which the 2-triflate substitutedaryl ketone series 74 was coupled and intramolecularlycyclized with enamine 75 at C4f -C4N2-C3 and isomerized

to produce four examples of ring-fluorinated and fluoroary-lated isoquinolines 76 [49] Yangrsquos group conducted a palla-dium catalyzed microwave-assisted one-pot reaction via aC4f -C4N2-C3 cyclization for the synthesis of isoquinolines[50] The coupling-imination-annulation sequence of reac-tions using 119900-bromoarylaldehydes 77 and terminal alkynes78 with ammonium acetate produced three disubstituted

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Journal of Chemistry 11

NH

Ar ArAr

Ar

ArPhPh

PhOMeCl

Ph

F

MeOMeOMeOMeO

59 60

62 63

+

N

NN +

(61ndash81)64andashf

CsOAc (25mol)

(3mol)

[RuCl2(p-cymene)]2

(40ndash86)61andashf

145∘C 24hSulfolane (050M)

(1mol)

[RuCl2(p-cymene)]2

R1

R1

R1

R2

R2

R1

R2

R2

R2

R3

R3

a 4-FC6H4

b 4-CF3C6H4

c 4-MeOC6H4

d 4-MeOC6H4

e 4-MeOC6H4

f 4-MeOC6H4

4-FC6H4

4-CF3C6H4

4-FC6H4

4-CF3C6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

4-MeOC6H4

Ph 4-CF3C6H4

4-CF3C6H4 4-CH3C6H4

CF3

a R1 = F R2 = Meb R1 = Cl R2 = Etc R1 = Cl R2 = n-Bud R1 = Cl R2 = allyle R1 = Cl R2 = Phf R1 = Br R2 = Ph

OCH2CF3

CF3CH2OH 100∘C 16 h

Scheme 15 Ruthenium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline synthesis

67

PhPh

66

Ph

Ph

PhPh

65

69

(88)

NN

+

F

F

N

R

R

N+

(76ndash81)68b R = CF3

68a R = F 70a-b

(25mol)

DCE 83∘C 16h

t-Bu n-Prn-Pr

n-Prn-Pr

CONEt2

CONEt2

Cu(OAc)2 DCE 120∘C 24h

AgSbF6 (10mol)

[CplowastRh(MeCN)3][SbF6]2

[CplowastRhCl2]2 (25mol)

Cu (OAc)2middotH2O (21 equiv)

Scheme 16 Rhodium-catalyzed fluoroisoquinoline and trifluoroisoquinoline synthesis

6-fluoroisoquinolines 79 These reactions feature a widerange of substrates with various functional groups and thecorresponding products were obtained in good yields

324 Silver Catalysis Several silver (I) catalyzedN2-C3 cycli-zations of o-iminylaryl alkynes have been employed suc-cessfully to prepare a broad selection of fluorinated tri-fluoromethylthiolated fluoroarylated and trifluoromethy-larylated isoquinolines See Scheme 19 Xiao et al used a

silver(I)-catalyzed reaction of 2-alkynylbenzaldoximes 80with silver (trifluoromethyl)thiolate 81 in the presence of 119901-methoxybenzenesulfonyl chloride to synthesize eleven new1-[(trifluoromethyl)thio]isoquinolines 82 in yields rangingfrom 36 to 85 [51] Xu and Lui utilized an Ag(I)-catalyzedNFSI aminofluorination of aryliminoalkynes 83 in the devel-opment of an efficient synthesis of thirteen examples of 4-fluoroisoquinolines 84 [52] Jeganathan and Pitchumani useda Ag(I)-exchanged K10-montmorillonite clay catalyzed ring

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

12 Journal of Chemistry

Ph

Ph

Br

Ph

71 72

N

F

O

O O

+ N

N

C6H4CF3R1

R2

73c-d (68ndash73)

R1

73b (60)

73a (46)

R2

a R1 = R2 = Hb R1 = CF3 R2 = Hc R1 = R2 = Hd R1 = R2 = OMe

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(2) Selectfluor II THF 0∘C 8h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

(1) (DtBPF)PdCl2 (25mol)NaOtBu (25 eq) THF 70∘C 32h

(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O90∘C 24h

(1) (DtBPF)PdCl2 (50mol)NaOtBu (25 eq) in Ar THF 70∘C 6h

(2) 4-Br-benzotrifluoride THF 100∘C 18h(3) HCl (1M)NH4Cl (1M) in 3 1 EtOHH2O

90∘C 24h

F3C(2) allyl bromide THF 90∘C 5 d

Scheme 17 Di-t-butylphosphinoferrocene-based palladium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

OTf (Br)NHBoc

CHO

Br

74 75

77

NO R

R +

+ R N

RF

F

R998400

R998400

78andashc 79andashc

76andashda R = 3-F R998400 = Meb R = 4-F R998400 = Phc R = H R998400 = 4-FC6H4d R = H R998400 = 4-CF3C6H4

Pd(OAc)2 (005mmol)dppp (01mmol)

NaOAC (20mmol)

Ethylene glycol 120∘C

(1) Pd(OAc)2 (2mol)PPh3 (4mol) KOAc (2 eq)microwave DMF 80∘C 1h

(2) NH4OAc (2 eq)microwave 150∘C 2h

(65ndash86)

(63ndash67)

a R = (CH2)3CNb R = (CH2)12CH3c R = 2-MeOC6H4

12 h under argon

Scheme 18 Pd(OAc)2 catalyzed fluoroisoquinoline syntheses

closure of iminoalkynes 85 to prepare three fluoroarylatedisoquinolines 86 in good overall yield [53] This effectivecyclization accommodates a variety of iminoalkynes andis noteworthy for its catalyst reusability simplicity andenvironmentally responsible process

33 Period 6 Transition Metal Catalyzed Ring-FluorinatedTrifluoromethylated and Fluoroarylated Isoquinolines viaIntermolecular Ring A Cyclization at C8119891-C1

331 Iridium Catalysis Our final entry highlighted inScheme 20 is the iridium catalyzed fluoroisoquinoline syn-thesis via a C8f -C1 bond-formingcyclization reaction con-ducted by Jiang et al [54] This synthesis uses a visi-ble light-promoted insertion of vinyl isocyanides 87 with

diphenyliodonium tetrafluoroborate 88 at room tempera-ture to prepare six multisubstituted ring-fluorinated trifluo-romethylated and fluoroarylated isoquinoline derivatives 89

4 Conclusion

The past decade has been a period of intense exploration ofnew approaches to the preparation of industrially andmedici-nally important isoquinolineswhich incorporate fluorine andfluorine-containing functional groupsThis review has exam-ined both nonmetal catalyzed and transition metal catalyzedprocesses that lead to a wide array of isoquinolines that havefluorine and fluorine-containing groups installed at nearlyevery position on the fused-ring isoquinoline heterocycleThe reactions reviewed span processes which construct the

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Journal of Chemistry 13

OH

NFSI (15 eq)

DMA rt

Ag(I) Clay

80 81

83

85

N

N

+

N

FN

N

N

R1

R2

R1

R2

R1R2

R1

R2

R1

R2

R1R2

86andashc

(36ndash85)DMF 100∘C

84andashm(56ndash87)

Li2CO3 (1 eq)

AgNO3 (20mol)t-Bu

t-Bu

SCF3

AgSCF3

82andashk(36ndash85)K3PO4 DMA

4-MeOC6H4SO2Cl

AgOTf (10mol)

a R1 = Ph R2 = Hb R1 = 4-MeC6H4 R2 = Hc R1 = 4-MeOC6H4 R2 = Hd R1 = 4-FC6H4 R2 = He R1 = 4-ClC6H4 R2 = Hf R1 = cyclopropyl R2 = H

g R1 = n-butyl R2 = Hh R1 = Ph R2 = Mei R1 = Ph R2 = OMej R1 = Ph R2 = Fk R1 = Ph R2 = Cl

a R1 = Bu R2 = Hb R1 = Bu R2 = Clc R1 = Bu R2 = Fd R1 = Bu R2 = OMee R1 = t-Bu R2 = Hf R1 = Ph R2 = Hg R1 = CH2NTsBoc R2 = H

h R1 = CH2CH2OAc R2 = Hi R1 = (CH2)3CO2Me R2 = Hj R1 = p-Anisyl R2 = Hk R1 = p-FC6H4 R2 = Hl R1 = cyclohexenyl R2 = Hm R1 = cyclopropyl R2 = H

b R1 = 3-CF3C6H4 R2 = Hc R1 = 3-FC6H4 R2 = OMe

a R1 = 4- CF3C6H4 R2 = H

Scheme 19 Silver catalyzed fluoroisoquinoline syntheses

NC

NC

Ph Ph

Ph

87a

87b

88

I

N

oplus

(53ndash90)

89andashf

R3

CO2Me

CO2Me

CO2Me

R2

MeOH (005M)Na2CO3 (10 eq)

Ir(ppy)3 (10mol)

⊖BF4R1

R2

R1

R4R1 = 4-FC6H4 R2 = PhR1 = R2 = 4-FC6H4R1 = 4-FC6H4 R2 = 4-MeOC6H4

R1 = Me R2 = 4-CF3C6H4

a R3 = F R4 = Phb R3 = F R4 = 4-FC6H4c R3 = H R4 = 4-FC6H4d R3 = MeO R4 = 4-FC6H4e R3 = F R4 = 4-MeOC6H4f R3 = CF3 R4 = Me

rt N23W white LED

Scheme 20 Iridium catalyzed fluoroisoquinoline and trifluoromethylisoquinoline syntheses

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

14 Journal of Chemistry

isoquinoline core via both A ring and B ring cyclizationsAdditionally these investigations have led to the discoveryof milder reaction conditions improved yields enhancedregioselectivity and site-specific ring monofluorination aswell as difluoromethylation trifluoromethylation perfluo-roalkylation fluoroarylation and trifluoromethylarylationexamples In all more than 30 processes producing over 160new isoquinoline examples have been highlighted

Competing Interests

The author declares that there are no competing interestsregarding the publication of this paper

References

[1] S Hoogewerf and W van Dorp ldquoSur un isomere de laquinoleinerdquo Recueil des Travaux Chemiques des Pays-Bas vol 4no 4 pp 125ndash129 1885

[2] C Pomeranz ldquoUber eine neue Isochinolinsyntheserdquo Monat-shefte fur Chemie vol 14 no 1 pp 116ndash119 1893

[3] P Fritsch ldquoSynthesen in der Isocumarinminus und Isochinolin-reiherdquo Berichte der Deutschen Chemischen Gesellschaft vol 26no 1 pp 419ndash422 1893

[4] A Bischler and B Napieralski ldquoZur Kenntniss einer neuenIsochinolinsyntheserdquo Berichte der deutschen chemischenGesellschaft vol 26 no 2 pp 1903ndash1908 1893

[5] A Pictet and A Gams ldquoUber eine neueMethode zur synthetis-chen Darstellung der Isochinolinbasenrdquo Berichte der DeutschenChemischen Gesellschaft vol 43 no 2 pp 2384ndash2391 1910

[6] A Pictet and T Spengler ldquoUber die Bildung von Isochinolinminusderivaten durch Einwirkung von Methylal auf Phenylminusathylamin Phenylminusalanin und Tyrosinrdquo Berichte der DeutschenChemischen Gesellschaft vol 44 no 3 pp 2030ndash2036 1911

[7] D Collado E Perez-Inestrosa R Suau J-P Desvergne andH Bouas-Laurent ldquoBis(isoquinoline N-oxide) pincers as a newtype of metal cation dual channel fluorosensorrdquoOrganic Lettersvol 4 no 5 pp 855ndash858 2002

[8] G Cuny Minnesota Mining and Manufacturing CompanyPatent Pyrrolo(21-a)isoquinoline dyes EP 0780443 A2 June1997

[9] Y Kuramochi and O Ishitani ldquoIridium(III) 1-phenylisoquin-oline complexes as a photosensitizer for photocatalytic CO2reduction a mixed system with a Re(I) catalyst and asupramolecular photocatalystrdquo Inorganic Chemistry vol 55 no11 pp 5702ndash5709 2016

[10] E Schlittler and J Muller ldquoEine neue Modifikation der Isochi-nolinsynthese nach PomerazminusFritschrdquo Helvetica Chimica Actavol 31 no 3 pp 914ndash924 1948

[11] A L Smith F F DeMorin N A Paras et al ldquoSelectiveinhibitors of the mutant B-Raf pathway discovery of a potentand orally bioavailable aminoisoquinolinerdquo Journal ofMedicinalChemistry vol 52 no 20 pp 6189ndash6192 2009

[12] A Galan L Moreno J Parraga et al ldquoNovel isoquinolinederivatives as antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 21 no 11 pp 3221ndash3230 2013

[13] D OrsquoHagan ldquoUnderstanding organofluorine chemistry Anintroduction to the CndashF bondrdquo Chemical Society Reviews vol37 no 2 pp 308ndash319 2008

[14] S Purser P RMoore S Swallow and V Gouverneur ldquoFluorineinmedicinal chemistryrdquoChemical Society Reviews vol 37 no 2pp 320ndash330 2008

[15] W K Hagmann ldquoThe many roles for fluorine in medicinalchemistryrdquo Journal of Medicinal Chemistry vol 51 no 15 pp4359ndash4369 2008

[16] S Lee J-S Park and T R Lee ldquoAnalysis of the wettability ofpartially fluorinated polymers reveals the surprisingly strongacid-base character of poly(vinylidene fluoride)rdquo Bulletin of theKorean Chemical Society vol 32 no 1 pp 41ndash48 2011

[17] J Yun S Park J Heo et al ldquoEnhancement of charge transportproperties of small molecule semiconductors by controllingfluorine substitution and effects on photovoltaic properties oforganic solar cells and perovskite solar cellsrdquo Chemical Sciencevol 7 pp 6649ndash6661 2016

[18] T Fujita and J Ichikawa ldquoFluorinated isoquinolines synthe-sis properties and applicationsrdquo in Fluorine in HeterocyclicChemistry Volume 2 6-Membered Heterocycles V NenajdenkoEd pp 181ndash210 Springer International Publishing ChamSwitzerland 2014

[19] Z Y Li and Z-X Jiang ldquoFluorine is flourishing in pharmaceu-ticalsrdquo Journal of Biomolecular Research amp Therapeutics vol 1article 2 2012

[20] H-J Bohm D Banner S Bendels et al ldquoFluorine in medicinalchemistryrdquo ChemBioChem vol 5 no 5 pp 637ndash643 2004

[21] E P Gillis K J Eastman M D Hill D J Donnelly and NA Meanwell ldquoApplications of fluorine in medicinal chemistryrdquoJournal of Medicinal Chemistry vol 58 no 21 pp 8315ndash83592015

[22] W Yu E Wang R J Voll A H Miller and M M GoodmanldquoSynthesis fluorine-18 radiolabeling and in vitro characteri-zation of 1-iodophenyl-N-methyl-N-fluoroalkyl-3-isoquinolinecarboxamide derivatives as potential PET radioligands forimaging peripheral benzodiazepine receptorrdquo Bioorganic andMedicinal Chemistry vol 16 no 11 pp 6145ndash6155 2008

[23] J Ichikawa K Sakoda H Moriyama and Y Wada ldquoSyn-theses of ring-fluorinated isoquinolines and quinolines viaintramolecular substitution cyclization of 11-difluoro-1-alkenesbearing a sulfonamide moietyrdquo Synthesis no 10 pp 1590ndash15982006

[24] A S Kiselyov ldquoA convenient procedure for the synthesis offused fluoro isoquinolinesrdquo Tetrahedron vol 62 no 4 pp 543ndash548 2006

[25] L-G Xie S Niyomchon A J Mota L Gonzalez andN Maulide ldquoMetal-free intermolecular formal cycloadditionsenable an orthogonal access to nitrogen heterocyclesrdquo NatureCommunications vol 7 Article ID 10914 pp 1ndash9 2016

[26] J-B Feng and X-F Wu ldquoPotassium tert-butoxide-promotedsynthesis of 1-aminoisoquinolines from 2-methylbenzonitrilesand benzonitriles under catalyst-free conditionsrdquo AdvancedSynthesis and Catalysis vol 358 no 13 pp 2179ndash2185 2016

[27] Y-Y Yang W-G Shou Z-B Chen D Hong and Y-GWang ldquoA tandem approach to isoquinolines from 2-azido-3-arylacrylates and 120572-diazocarbonyl compoundsrdquo The Journal ofOrganic Chemistry vol 73 no 10 pp 3928ndash3930 2008

[28] C D Gilmore K M Allan and B M Stoltz ldquoOrthogonalsynthesis of indolines and isoquinolines via aryne annulationrdquoJournal of the American Chemical Society vol 130 no 5 pp1558ndash1559 2008

[29] B Zhang and A Studer ldquo1-Trifluoromethylated isoquinolinesvia radical trifluoromethylation of isonitrilesrdquo Organic andBiomolecular Chemistry vol 12 pp 9895ndash9898 2014

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Journal of Chemistry 15

[30] YKuninobuMNagase andMKanai ldquoBenzylic C(sp3)-Hper-fluoroalkylation of six-membered heteroaromatic compoundsrdquoAngewandte ChemiemdashInternational Edition vol 54 no 35 pp10263ndash10266 2015

[31] J Ichikawa ldquoSynthetic methods for heterocycles and carbo-cycles bearing fluorinated one-carbon units (=CF2 CHF2 orCF3) intramolecular reaction of 2-Trifluoromethyl-1-alkenesrdquoJournal of Synthetic Organic Chemistry Japan vol 68 no 11 pp1175ndash1184 2010

[32] N K Chennamaneni J Arif F S Buckner and M H GelbldquoIsoquinoline-based analogs of the cancer drug clinical candi-date tipifarnib as anti-Trypanosoma cruzi agentsrdquo Bioorganicand Medicinal Chemistry Letters vol 19 no 23 pp 6582ndash65842009

[33] E Awuah and A Capretta ldquoStrategies and synthetic methodsdirected toward the preparation of libraries of substitutedisoquinolinesrdquo Journal of Organic Chemistry vol 75 no 16 pp5627ndash5634 2010

[34] R He Z-T Huang Q-Y Zheng and C Wang ldquoManganese-catalyzed dehydrogenative [4 + 2] annulation of NndashH iminesand alkynes by CndashHNndashH activationrdquo Angewandte ChemiemdashInternational Edition vol 53 no 19 pp 4950ndash4953 2014

[35] H Mao M Gao B Liu and B Xu ldquoManganese(II)-catalyzedmodular synthesis of isoquinolines from vinyl isocyanides andhydrazinesrdquo Organic Chemistry Frontiers vol 3 no 4 pp 516ndash521 2016

[36] B Sun T Yoshino M Kanai and S Matsunaga ldquoCplowastCoIIIcatalyzed site-selective C-H activation of unsymmetrical O-acyloximes synthesis of multisubstituted isoquinolines from termi-nal and internal alkynesrdquo Angewandte ChemiemdashInternationalEdition vol 54 no 44 pp 12968ndash12972 2015

[37] J Li M Tang L Zang X Zhang Z Zhang and L Acker-mann ldquoAmidines for versatile cobalt(III)-catalyzed synthesis ofisoquinolines through CndashH functionalization with diazo com-poundsrdquo Organic Letters vol 18 no 11 pp 2742ndash2745 2016

[38] A Pawar D Agarwal and D Lade ldquoCplowastCo(III)-Catalyzed CndashHNndashN functionalization of arylhydrazones for the synthesis ofisoquinolinesrdquoThe Journal of Organic Chemistry vol 81 no 22pp 11409ndash11415 2016

[39] X Yu K Chen F Yang S Zha and J Zhu ldquoOxadiazolone-enabled synthesis of primary azaaromatic aminesrdquo OrganicLetters vol 18 no 20 pp 5412ndash5415 2016

[40] Y Yoshida T Kurahashi and S Matsubara ldquoNickel-catalyzedcycloaddition of aromatic (O-benzyl)ketoximes with alkynesto produce isoquinoline and isoquinoline N-oxide derivativesrdquoChemistry Letters vol 40 no 10 pp 1140ndash1142 2011

[41] Y Ohta S Oishi N Fujii and H Ohno ldquoFacile synthesis of 3-(aminomethyl)isoquinolines by copper-catalysed domino four-component coupling and cyclisationrdquo Chemical Communica-tions no 7 pp 835ndash837 2008

[42] C Fan J Song G Qiu G Liu and J Wu ldquoGeneration of 1-(trifluoromethyl)isoquinolines via a copper-catalyzed reactionof isoquinoline-N-oxide with Togni reagentrdquo Organic Chem-istry Frontiers vol 1 no 8 pp 924ndash928 2014

[43] M G Mormino P S Fier and J F Hartwig ldquoCopper-mediatedperfluoroalkylation of heteroaryl bromides with (phen)CuRFrdquoOrganic Letters vol 16 no 6 pp 1744ndash1747 2014

[44] K-H He W-D Zhang M-Y Yang et al ldquoRedox-divergenthydrogen-retentive or hydrogen-releasing synthesis of 34-dihydroisoquinolines or isoquinolinesrdquo Organic Letters vol 18no 12 pp 2840ndash2843 2016

[45] R K Chinnagolla S Pimparkar and M Jeganmohan ldquoA re-gioselective synthesis of 1-haloisoquinolines via ruthenium-catalyzed cyclization of O-methylbenzohydroximoyl halideswith alkynesrdquo Chemical Communications vol 49 no 35 pp3703ndash3705 2013

[46] Z-C Qian J Zhou B Li and B-F Shi ldquoEfficient synthesisof isoquinolines via Rh(III)-catalyzed oxidative annulation ofpicolinamides with alkynesrdquo Synlett vol 25 no 7 pp 1036ndash1040 2014

[47] N Guimond and K Fagnou ldquoIsoquinoline synthesis via rho-dium-catalyzed oxidative cross-couplingcyclization of arylaldimines and alkynesrdquo Journal of the American ChemicalSociety vol 131 no 34 pp 12050ndash12051 2009

[48] B S Pilgrim A E Gatland C T McTernan P A Procopiouand T J Donohoe ldquoModular isoquinoline synthesis using cat-alytic enolate arylation and in situ functionalizationrdquo OrganicLetters vol 15 no 24 pp 6190ndash6193 2013

[49] Y Tian J Qi C Sun D Yin X Wang and Q XiaoldquoOne-pot synthesis of 4-methylisoquinolines via a sequentialPd-catalyzed Heck reaction and intramolecular cyclizationrdquoOrganic and Biomolecular Chemistry vol 11 no 42 pp 7262ndash7266 2013

[50] D Yang S Burugupalli D Daniel and Y Chen ldquoMicrowave-assisted one-pot synthesis of isoquinolines furopyridines andthienopyridines by palladium-catalyzed sequential coupling-imination-annulation of 2-bromoarylaldehydes with terminalacetylenes and ammonium acetaterdquo Journal of Organic Chem-istry vol 77 no 9 pp 4466ndash4472 2012

[51] Q Xiao J Sheng Q Ding and J Wu ldquoFacile assemblyof 1-[(trifluoromethyl)thio]isoquinolines through reaction of2-alkynylbenzaldoxime with silver (trifluoromethyl)thiolaterdquoEuropean Journal of Organic Chemistry vol 2014 no 1 pp 217ndash221 2014

[52] T Xu and G Liu ldquoAg(I)-catalyzed aminofluorination ofalkynes efficient synthesis of 4-fluoroisoquinolines and 4-fluoropyrrolo[120572]isoquinolinesrdquo Organic Letters vol 14 no 21pp 5416ndash5419 2012

[53] M Jeganathan andK Pitchumani ldquoSynthesis of substituted iso-quinolines via iminoalkyne cyclization using Ag(i) exchangedK10-montmorillonite clay as a reusable catalystrdquo RSC Advancesvol 4 no 73 pp 38491ndash38497 2014

[54] H Jiang Y Cheng R Wang Y Zhang and S Yu ldquoSynthesisof isoquinolines via visible light-promoted insertion of vinylisocyanides with diaryliodonium saltsrdquo Chemical Communica-tions vol 50 no 46 pp 6164ndash6167 2014

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of

Submit your manuscripts athttpswwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Carbohydrate Chemistry

International Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Chromatography Research International

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Applied ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Theoretical ChemistryJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Spectroscopy

Analytical ChemistryInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Quantum Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Organic Chemistry International

ElectrochemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

CatalystsJournal of