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Design and Synthesis of Aromatics through [2+2+2] Cyclotrimeriza-tionSambasivarao Kotha*a Kakali Lahiri*b Gaddamedi Sreevania

a Department of Chemistry, Indian Institute of Technology-Bombay, Powai, Mumbai 400076, Indiasrk@chem.iitb.ac.in

b Department of Chemistry, V. K. Krishna Menon College of Commerce & Economics, Bhandup East, Mumbai 400042, India

Rh(

PP

h 3) 3

Cl

CpCo(

CO) 2

Mo(CO)6

OH

OHCO2Et

TsN

TMS

TMS

R

R

RO

O

O

Br

Rh(PPh3 )3 Cl

Cp*RuCl(cod) CO2Me

MeO2C

MeO2C

CO2Me

O

O

O

O

N

N

O

O

O

BocNsteps

O

O

O

O

OH

PBr3

[CpRu(C10H

8)] +Cl –

Mo(

CO

) 6

HO

OH

O

MeN

NN

Hsp90 InhibitorAT13387

Br

[2+2+2]Cycloaddition

Cl2(PPh3)2Ru=CHPh

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Received: 12.02.2018Accepted after revision: 18.06.2018Published online: 08.08.2018DOI: 10.1055/s-0037-1609584; Art ID: st-2018-a0062-a

Abstract The [2+2+2] cycloaddition reaction is a useful tool to realizeunusual chemical transformations which are not achievable by tradi-tional methods. Here, we report our work during the past two decadesthat involve utilization of transition-metal complexes in a [2+2+2] cy-clotrimerization reaction. Several key “building blocks” were assembledby a [2+2+2] cycloaddition approach and they have been further ex-panded by other synthetic transformations to design unusual amino ac-ids and peptides, diphenylalkanes, bis- and trisaryl benzene derivatives,annulated benzocycloalkanes, spirocycles, and spirooxindole deriva-tives. Furthermore, we have also discussed about alkyne surrogates, en-vironmentally friendly, and stereoselective [2+2+2] cycloaddition reac-tions. Application of the [2+2+2] cycloaddition reaction in totalsynthesis is also covered. In this review we also included others work togive a balanced view of the recent developments in the area of [2+2+2]cycloaddition.1 Introduction2 Unusual Amino Acids and Peptides3 Heteroanalogues of Indane4 Diphenylalkane Derivatives5 Multi-Armed Aryl Benzene Derivatives6 Annulated Benzocycloalkanes7 Spirocycles8 Selectivity in [2+2+2] Cycloaddition of Alkynes9 [2+2+2] Cycloaddition Reactions under Environmentally Friendly

Conditions10 Alkyne Surrogates11 Domino Reactions involving a [2+2+2] Cycloaddition12 Biologically Important Targets/Total Synthesis13 Conclusions

Key words [2+2+2] cyclotrimerization, Diels–Alder, sultine, amino ac-ids and peptides, spirocycles, Wilkinson’s catalyst, Vollhardt’s catalyst,alkyne surrogates

1 Introduction

[2+2+2] Cycloaddition is a useful tool to assembledensely functionalized aromatics in one step starting withalkynes. Moreover, this method is also applicable to annu-lated benzenes by precise selection of the starting materi-als. The most common product of the acetylene cyclotri-merization is benzene. Regioisomers 2a, 2b are generatedwhen substituted alkyne 1 is used. If two different alkynes(diyne 3, monoyne 1) were tethered, annulated benzene de-rivatives 4a–c would be generated, whilst, if all threealkynes were connected such as 5, a tricyclic ring 6 wouldbe formed (Scheme 1). The driving force for the [2+2+2] cy-clotrimerization reactions is the gain of aromaticity, andthe reaction is exothermic. This intramolecular approach iseffective for the synthesis of sterically demanding mole-cules such as helicenes.1a

Scheme 1

R1

R1

R1R1

R1 R1

R1

[M]3

XR2

R3

R1[M]

X

R2

R3

R1

X

R2

R3

R1

X

R2

R3

R1

XR1

Y

R2

[M]X

R1

R2

Y

Intermolecular

Partially intermolecular

Intramolecular

1 2a 2b

3 1 4a 4b 4c

5 6

R2 = R3 R2 = R3

+

+ ++

R2 = R3/ /

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In 1866, Bertholet first reported the thermal [2+2+2] cy-clotrimerization of acetylene to benzene.1b The reaction isexothermic (experimental data ΔH0 = –143 kcal/mol) andsuffered from the formation of a large amount of byprod-ucts. Despite a loss in entropy, the reaction occurs at hightemperature to overcome the large energy barrier (activa-tion barrier at least 36 kcal/mol) of the reaction. In 1948,Reppe reported the first transition-metal-mediated [2+2+2]cyclotrimerization, which occurrs at low temperature withfewer byproducts.2 Since then, seventeen transition-metalcatalysts based on Ni, Co, Pd, Cr, Rh, Ru, Fe, Zr, Nb, Ir, Ta, Ti,Re, etc. have been used for the cyclotrimerization reactionof alkynes and some of them are included in the recent re-views.3 These transition-metal catalysts are not used to the

same extent. Transition-metal catalysts of group 9 such asCo, Rh, and Ir are mostly used in this reaction. Zirconiumonly allows cyclotrimerization in the presence of anothermetal catalyst such as nickel. Recently, besides the develop-ment of transition-metal catalyzed [2+2+2] cyclotrimeriza-tion reactions, several transition-metal-free [2+2+2] cyclo-trimerizations have also been reported.3c

Transition-metal complexes used in [2+2+2] cyclotri-merization have emerged as indispensible tools in syntheticorganic chemistry because they can tolerate a variety offunctional groups, and this process allows incorporation ofdiverse substituents at a late stage of the synthetic se-quence. Interestingly, the [2+2+2] cyclotrimerization reac-tion allows multiple bond formation exhibiting a high de-

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Sambasivarao Kotha gradu-

ated with M.Sc. degree in chem-istry from the University ofHyderabad and then obtainedhis Ph.D. in organic chemistryfrom the University of Hyder-abad (1985). He continued hisresearch at the University of Hy-derabad as a postdoctoral fellowfor one and half years. Later, hemoved to UMIST Manchester,UK and the University of Wis-consin, USA as a research associ-ate. Subsequently, he wasappointed as a visiting scientist

at Cornell University and as a re-search chemist at Hoechst Cel-anese Texas prior to joining IITBombay in 1994 as an assistantprofessor. Later, in 2001, he waspromoted to Professor. He haspublished 250 publications inpeer-reviewed journals and is anelected fellow of various acade-mies (FNASc, FASc, FRSC, andFNA). He was also associatedwith the editorial advisoryboard of several journals (IndianJ. Chem., Sec-B, J. Amino Acids,Catal. J., Eur. J. Org. Chem., and

J. Chem. Sci.). His research in-terests include: Organic synthe-sis, green chemistry,development of new syntheticmethods for unusual amino ac-ids, peptide modification, cross-coupling reactions, metathesis,chemistry of benzocyclobuet-ene, and theoretically interest-ing molecules. Currently, heoccupies Pramod ChaudhariChair Professor in green chemis-try.

Kakali Lahiri (néeChakraborty) was born inHooghly, West Bengal, India.She obtained her Ph.D. in 2002under the guidance of ProfessorS. Kotha at IIT-Bombay. Sheworked as a research associatein the same department for sev-

en years. Her research interest isrelated to development of newsynthetic methodologies. Shereceived the ADANI Award forthe Best Teaching Assistantshipfrom the Department of Chem-istry, IIT-Bombay. She was alsothe recipient of IIT-Bombay Best

Review Paper Award in 2005,2010 and IIT-Bombay ResearchDissemination Award 2016.Since 2009, she is working asAssistant Professor in V. K. K.Menon College, Bhandup, Ma-harashtra, India.

Gaddamedi Sreevani wasborn in Rimmanguda (village),Telangana. After her early edu-cation in Sree Triveni Junior Col-lege for Girls, Hyderabad, shejoined Sri Sathya Sai Institute ofHigher Learning (for Women),Anantapur for her B.Sc. (honors)in chemistry, and obtained herdegree in 2006. Later, she

joined the Department ofChemistry, A. V. College PostGraduate Centre, Hyderabad(affiliated to the Osmania Uni-versity) for her M.Sc. degree. In2018, she obtained her Ph.D.degree under the guidance ofProfessor S. Kotha from the De-partment of Chemistry, IndianInstitute of Technology Bombay,

Mumbai. Currently, she is work-ing as a Research Associate inthe Department of BiomedicalEngineering, Indian Institute ofTechnology Hyderabad. Her cur-rent research interests are thesynthesis of biopolymers for 3Dbio printing, development ofanticancer drugs, and drug re-lease studies by 3D printing.

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gree of selectivity in some cases. It is an efficient protocolfor assembling aromatic compounds, which can act as func-tional materials. This operation is an atom-economic pro-cess leading to the formation of unsaturated six-membered,highly substituted carbo- and heterocycles such as ben-zenes, pyridines, pyridones, and 1,3-cyclohexadienes etc.,in a single operation involving catalytic amounts of organo-metallic complexes. Owing to the several advantages of a[2+2+2] cycloaddition sequence, this strategy has been ex-panded into several areas and found diverse applications inorganic synthesis.

Traditional methods to generate functionalized aromaticrings rely on stepwise electrophilic or nucleophilic aromat-ic substitution reactions. These approaches have severallimitations with regard to regiochemical issues and func-tional-group tolerance. The [2+2+2] cycloaddition strategyseems to be a better option to design substituted benzenesbecause of its convergent nature. In addition, functionaliza-tion of the aromatic ring by this method can be aceived in apredetermined manner and this approach provides betterregiocontrol while incorporating various substituents inthe benzenoid systems.

The exact mechanism for [2+2+2] cyclotrimerizationdepends on the nature of the metal and alkyne partners. Ageneral mechanism is shown in Figure 1. When twoalkynes coordinate to a metal center, oxidative cyclizationoccurs forming metallacyclopentadiene intermediate B ormetallacyclopentatriene intermediate C.4 Coordination ofthe third alkyne generates a new complex, which could betransformed either into metallacycloheptane complex D ora bicyclic complex E by an intramolecular Diels–Alder (DA)-type reaction or complex F through a [2+2] cycloadditionreaction. Finally, a reductive elimination process affords thearomatized product, by completing the catalytic cycle.

Figure 1 A general mechanism to benzene derivatives by [2+2+2] cy-clotrimerization

To test the scope and limitations of the [2+2+2] cycload-dition approach we have prepared new building blocks, andutilized them during the past two decades in a diversity-oriented synthesis. This approach has now widespread usein pharmaceutical industry. In this review, we would like todemonstrate how the “building block approach”5f has been

used to prepare several complex targets using the [2+2+2]cycloaddition reaction as a key step. Some relevant ap-proaches described in the literature are also covered.

2 Unusual Amino Acids and Peptides

Indane-based α-amino acid (AAA) is a constrained ana-logue of phenylalanine (Phe) and it is used extensively inthe design and synthesis of a variety of bioactive peptides.Utilization of unusual AAAs in physical and life sciencescontinues to grow at an impressive rate. They are useful asbuilding blocks for peptides, proteins, and natural productsand used extensively in pharmaceutical, agrochemical, andfood industry. The design and synthesis of peptides[5a–c]

with predetermined structure is a challenging task in thepresent day peptide chemistry. In this regard, conforma-tionally restricted Phe analogues have proven to be usefultools as they can control the secondary structure of a pep-tide.5d,e Moreover, incorporation of unusual AAAs into pep-tides may provide unique analogues which are biologicallymore active and resistant to enzymatic degradation. To syn-thesize diverse unusual AAA derivatives, we have adoptedthe “building block approach” involving a [2+2+2] cycload-dition as a key step.

Scheme 2

This methodology involves the preparation of diynebuilding block 7 containing an AAA moiety which on[2+2+2] cycloaddition reaction in the presence of Wilkin-son’s catalyst or Vollhardt’s catalyst CpCo(CO)2 with variousmonoynes 8a–h delivers indane-based AAA derivativessuch as 9 (Scheme 2).6 This methodology is strategically dif-ferent from the other routes because the benzene ring isgenerated during the cycloaddition sequence, while theother methods involve manipulation of preformed benzenederivatives. Since the cycloaddition reaction can generatecomplex targets by judicious selection of the reacting part-ners, we obtained a variety of unusual AAA derivatives. Si-lylated benzene derivatives underwent electrophilic substi-tution reactions ipso to the silyl group, and therefore themodification of the bis-silyl indane derivative 9b was alsoexplored (Scheme 3).

Since o-xylylene intermediate 12 can be trapped with asuitable dienophile to produce new AAA derivatives 117a

the attention was focused on the generation of the sultinederivative 13 (Scheme 4).

[M]

[M]

[M]

or

[M]

[M]

[M]

[M]or or A

B

Insertion D[4+2] CA E

[2+2] CA F

C

8

+CO2Et

NHR3

NHR3

CO2Et

R1

R2

R1, R2 = H (8a), TMS (8b), CH2OH (8c), (CH2)2OH (8d), (CH2)3OH (8e),

(CH3)2COH (8f), CO2Me (8g), Ph (8h)

9 (22–97%)R2

R11. RhCl(PPh3)3/EtOH reflux

or2. CpCo(CO)2, toluene/ n-octane, reflux7a R3 = Ac

7b R3 = Boc

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Scheme 3

Towards the synthesis of 11, the required indane deriva-tive 16 was synthesized through a [2+2+2] cycloaddition of2-butyne-1,4-diol (8c) and the diyne derivative 7a, ob-tained from ethyl isocyanoacetate 14. The dihydroxy indanederivative 16 was then converted into the corresponding di-bromide 17 with use of PBr3. Next, a reaction of dibromocompound 17 was performed with sodium hydroxymeth-anesulfinate (rongalite)7b in the presence of tetrabutylam-monium bromide (TBAB) in DMF at 0 °C, and the two iso-meric sultine-based AAA derivatives 18 were obtained in72% combined yield (1:1) (Scheme 5). Having the sultines18 in hand, we explored their DA chemistry with variousdienophiles to produce DA adducts. Subsequent oxidationof the DA adducts with DDQ gave benzoannulated deriva-tives (11a,b). The DA reaction of 18 with other dienophilessuch as 1,4-benzoquinone, 1,4-naphthaquinone, and 1,4-

anthraquinone delivered the products 11c–e. In view ofvarious applications of fullerene-based AAA derivatives inbioorganic chemistry, we turned our attention to incorpo-rate the AAA moiety in the fullerene system and successful-ly obtained compound 11f in 49% yield (Figure 2). The hy-drophobic character of the fullerene moiety and its abilityto act as an electron sink may make the fullerene-basedAAA derivative an attractive building block for biologicalapplications.

Dixneuf and co-workers have developed an impressiveapproach to CF3-substituted benzoproline and tetrahy-droisoquinoline-3-carboxylic acid derivatives 20 and 21,which is based on ruthenium-catalyzed cyclotrimerizationof 1,6- and 1,7-azadiynes 19 and alkynes 8 with Cp*Ru-Cl(cod) and the Grubbs catalyst (Scheme 6).8

Scheme 6

Along similar lines, Roglans and co-workers adoptedthis methodology to synthesize nonproteinogenic Phe de-rivatives using enantiopure and racemic propargylglycine22 with different diynes 3 (Scheme 7).9 When they usedWilkinson’s catalyst or a cationic rhodium [Rh(cod)2]BF4/BINAPcatalyst the required product was not formed; only homo-coupling product was observed. However, Wilkinson’s cata-lyst in ethanol heated to reflux gave the desired cycloaddi-tion product in good yields. The reaction worked well withsymmetric as well as unsymmetric 1,6-diynes; however,the regioselectivity was poor in the case of unsymmetricdiynes. Very recently, our group has shown the synthesis ofbenzyl halo derivatives of aminoindane carboxylic acid(Aic) derivatives directly through a [2+2+2] cyclotrimeriza-tion using propargyl halides as co-partners with Mo(CO)6under microwave irradiation (MWI).10

Scheme 7

In 2016, Shibata et al. reported the enantioselective syn-thesis of Aic derivatives through a Rh-catalyzed intramolec-ular [2+2+2] cycloaddition reaction. When the intermolec-ular [2+2+2] cycloaddition was carried out in the presenceof a Rh catalyst using (S)-BINAP as a chiral ligand, the enan-tioselectivity was very poor. Hence, they realized that the

NHAc

CO2Et

TMS

TMS

NHAc

CO2Et

X

X

1. Br2, CCl4

or2. ICl9b 10a, X = Br, 81%

10b, X = I, 93%

Scheme 4

R

R

NH2

CO2H

NH2

CO2H

11 12

CO2H

NH2S

O

O

13

Scheme 5

CN

EtO2C EtO2C

NHAc

CO2Et

NHAc

CO2Et

S

O

O NHAc

CO2Et

NHAc

CO2Et

R2R1

14

16 17

18 11a, 78%, R1 = R2 = CO2Me11b, 43%, R1 = CO2Me, R2 = H

AcHNBrK2CO3, TBAHS

CH3CN, 80 °C

CN

EtO2C

1. HCl, EtOH, r.t.

2. Ac2O, DCM, r.t.

RhCl(PPh3)32-butyne-1,4-diol (8c)

EtOH, 80 °C, 65%

PBr3, C6H6

r.t., 81%

rongalite, TBAB

DMF, 0 °C, 72%

HO

HO

Br

Br

R2

R1

1a 15

1. toluene, 120 °C

2. DDQ, C6H6, 80 °C

7a

+

Figure 2 List of indane derivatives prepared

NHAc

CO2Et

O

O

NHAc

CO2Et

O

O

NHAc

CO2Et

O

O

NHAc

CO2Et

11c 90% 11d 89%

11e 92% 11f 49%

C60

N

CO2MeF3C

Boc

R1

R2

N

R1

R2

Boc

CF3

CO2MeG I

DCE, r.t.

89%

19 20 n = 08

( )n

+

( )n

RuH

PhPCy3

PCy3

Cl

Cl

21 n = 1

G I

XR1

R2

+

R2

R1

XNHFmoc

CO2Me

3 22

23

X = NTs, O, C(CO2Me)2

R2

R1

X

1.3–3.1:1R1 = H, R2 = MeR1 = Me, R2 = CH2OHR1 = R2 = MeR1 = R2 = Et

24

NHFmoc

CO2Me

FmocHN CO2Me

RhCl(PPh3)3

EtOH,r.t./reflux1–72 h,

71–100%

+

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enantioselectivity could be improved by intramolecular[2+2+2] cycloaddition. Starting with triynes 25, the teth-ered Aic derivatives 26 were generated. Subsequently, re-moval of the tether gave chiral Aic derivatives 27 (Scheme 8).11

Scheme 8

Similarly, they developed the synthesis of cyclic pep-tides. In this regard, they prepared the triynes from 1,6-diyne and alkyne connected by a di- or tri-, or tetrapeptidetether. Later, intramolecular [2+2+2] cycloaddition of thepeptide-tethered triynes 28 in the presence ofRh(COD)2OTf/(S)-tolBINAP complex gave cyclic peptides 29in moderate chemical yields and good diastereoselectivity.When they used bulky ligand (S)-xylBINAP a higher diaste-reoselectivity was achieved. However, (R)-tolBINAP alsogave the same stereoisomer suggesting that the stereoselec-tivity was controlled by the chiral peptide tether, but not bychiral Rh catalysts. Moreover, achiral ligand BIPHEP provid-ed similar results (Scheme 9).12

Scheme 9

1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid(Tic),13a,b a constrained analogue of Phe, is an importantstructural component present in several biologically activenatural products. Incorporation of Tic in opioid receptorsenhances their affinity and selectivity. Tic can be preparedby traditional methods such as Bischler–Napieralski orPicter–Spengler reaction, etc. These methods can accom-modate limited functionalities in the aryl ring. Tic preparedby a [2+2+2] cycloaddition process provides an opportunityto incorporate various substituents in Tic derivatives in apredetermined manner.13c In this regard, the diyne 34 wasprepared from the benzophenone Schiff’s base derivedfrom glycine ester by a four-step sequence (Scheme 10).Treatment of the diyne 34 with various monoynes 8 usingWilkinson’s or Vollhardt’s catalyst gave a variety of Tic-based AAA derivatives in good to moderate yields. It is

worth mentioning that similarly, Tic derivatives were alsoprepared by using enyne metathesis and DA reaction as thekey steps.13c

Scheme 10

Recently, Zotova et al. demonstrated the trifluorometh-yl-substituted phosphonate analogues of Tic derivatives 38based on N-propargylation of α-alkynyl-α-CF3-α-amino-phosphonates 36 to form 1,7-azadiynes 37, followed by co-cyclotrimerization with terminal alkynes 1b–d using twotypes of ruthenium catalysts: Cp*RuCl(cod) and preferablythe alkene-metathesis14a,b Grubbs second-generation cata-lyst (Scheme 11).14c

Scheme 11

Kotha and Banerjee have developed a short and efficientsynthetic route to Tic-quinone hybrids 42a–d using a[2+2+2] and a [4+2] cycloaddition reaction as the key steps.The o-xylylene intermediate required for the DA reactionwas prepared through the sultine methodology by usingrongalite (Scheme 12, Figure 3).15 The required diol buildingblock 35a used for the preparation of sultine 40, was pre-pared by following a [2+2+2] procedure starting withalkyne building block 34, which in turn can be obtainedfrom benzophenone imine 30. The starting material 32 iscommercially available in enantiomerically pure form. Themethod can be easily extended to the preparation of opti-cally active Tic derivatives 42a–d (Figure 3). The com-pounds prepared here may find further applications in drugdesign and peptide modifications. They can be used as

HN

R1

R1

O

PG

XR2

[2+2+2] cycloaddition

HN

O

PG

X

R1

R2

R1

chiral tethered Aic derivative

HN

O

PG

R1

R2

R1

OH

R3

chiral Aic derivative

removal of tether X

amino acid-tethered triyne

25 26 27

**

CbzHN

Ph

Ph

ONH

NHO

O

NH

CbzHN

[Rh(COD)2]OTf (10 mol%)BIPHEP (10 mol%)

1,2-dichloroethane40 °C, 1 h

Ph

Ph

CbzHN

NHO

HN

O HN O

NHCbz

29, 76%, dr = >20:128

33

CO2Et

NPh

Ph

CO2Et

NPh

Ph

CO2Et

NHTs

N

CO2Et

Ts

R = H, 99%R = TMS, 98%

R1 (8)R2

NTs

CO2EtR1

R2

R1 & R2 = H, CH2OH, Ph, (CH2)2OH,

TMS, CO2Me

Br

R

RhCl(PPh3)3

orCpCo(CO)2,

15–65%

30 31

32

3435R

R

33

Br1. 1N HCl ether, 80%

2. Et3N, TsCl, CH2Cl2 r.t., 78%

K2CO3CH3CN

1a

+K2CO3, CH3CN

86%

F3C

(OEt)2(O)P NH

Cbz

PhR1

1

[Ru] (5 mol%)DCE, 80 °C

N

CF3

P(O)(OEt)2

CbzR1

N

CF3

P(O)(OEt)2

Cbz

Ph

R1

+

36 37

38a

38b

NaH, DMF

propargyl bromide, 90%

Ph

Cp*RuCl(cod) G II 38a/38b 38a/38b 93:7 60% R1 = Bu (1b) 77% 93:7 93:7 51% R1 = Ph (1c) 63% 93:7 92:8 57% R1 = C6H13 (1d) 68% 94:6

F3C

(OEt)2(O)P N

Cbz

Ph

RuH

Ph

PCy3

Cl

Cl

NN MesMes

G-II

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building blocks in pharmaceutically active molecules, li-gands for catalysis, liquid crystals, organic semiconductor,polymers, and sensors.

Scheme 12

A general goal of peptide research is to design modifiedpeptides that may enhance the pharmacological profile ofthe native peptide. In this connection, Kotha and co-work-ers were interested in peptide modifications by adaptingthe “building block approach” to generate a large number ofcompounds starting with a common precursor.16 For thefirst time, a new strategy for the modification of Phe pep-tides by a [2+2+2] cycloaddition reaction was developedand these peptides might be useful in developing combina-torial libraries of peptidomimetics. In this regard, the di-peptide precursor 44 was easily synthesized by a standardpeptide synthesis protocol starting with the dipropargylglycine 43 as the key amino acid building block. The diprop-argyl glycine was prepared from ethyl isocyanoacetate 14 ina four-step sequence (Scheme 13). The dipeptide precursor44 was treated with five-fold excess of but-2-yn-1,4-diol(8c). Here, the monoyne was chosen to avoid the formationof diastereomers and the representative constrained Phepeptides 45 were obtained in good yield.16

Scheme 13

Later, the dihydroxy derivative 45 was treated with PBr3in benzene to obtain the corresponding dibromide. Howev-er, several attempts could not deliver the desired product.Either, decomposed product or starting material was recov-ered under these conditions. However, recently we have de-veloped a new protocol using a [2+2+2] cyclotrimerizationwith propargyl halides to generate halide derivatives di-rectly in a one-step procedure without the formation of thehydroxy derivative. By using this protocol, dipropargyl pep-tide was treated with propargyl halides in the presence ofMo(CO)6 under MWI conditions to generate the trimerizedhalo derivatives.10

3 Heteroanalogues of Indane

Kotha and co-workers synthesized 1,3-dihydroisoben-zofuran 46 derivatives starting with propargyl halides (1a,8i, 8j, 8k) and dipropargylether 3a through a [2+2+2] cyc-loaddition reaction (Scheme 14). In this regard a minoramount of dimer 47 is observed. Furthermore, the dibromoderivative of 1,3-dihydroisobenzofuran 46b was used toprepare benzosultine-sulfone 51 by using rongalite(Scheme 15).17a Benzosultine-sulfone 51 is a hybrid mole-cule which can participate in the DA reaction in a stepwisemanner by opening the sultine or the sulfone fragment atdifferent temperatures, and the respective o-xylylene inter-mediate can be trapped with different dienophiles. This ap-proach delivers densely functionalized polycyclic com-pounds.

Scheme 14

NTs

CO2EtHO

HO NTs

CO2EtBr

Br

NTs

O

SO

CO2Et

O

O

NTs

O

O

CO2Et

35a 39

40 4241

PBr3, CHCl3

r.t., 83%

rongalite, TBAB

DMF, 69%

1. toluene, reflux

2 MnO2, dioxane+

Figure 3 List of Tic derivatives prepared with use of rongalite

NTs

O

O

CO2Et

NTs

O

O

CO2Et

NTs

O

O

CO2Et

NTs

O

O

CO2Et

42a 71% 42b 72%

42c 77% 42d 82%

CO2Et

NC

CO2Et

NHBoc

CO2H

NHBoc

CNHCH(R)OMe

NHBoc

O

CNHCH(R)OMe

NHBoc

O

14

15 7b 43

4445 54–75%

1. HCl, EtOH

2. CHCl3, (Boc)2O

aq NaOH

MeOH

HCl, H2NCH(R)CO2MeHOBt, THF, NMM

8c, RhCl(PPh3)3

EtOH, refluxHO

HO

1a

-CH(R)- = L-Leu, D-Val, D-Leu, D-Val-L-Leu, L-Leu-L-Ala, L-Leu-D-Val-L-Leu

K2CO3,TBAB

MeCN+

OBr

R1

R2

Mo(CO)6

(0.05 equiv)

MeCN, 90 °CMW, 15 min

O

R1

R2

CH2OH

1e 1a 3a46

O O O

O

Br Br

Br

Cl

Cl

Cl

46a 50% 46b 48% 46c 51%

46d 47%

OO

47 10–12%

R1 = H, R2 = CH2Br (1a), R1 = H, R2 = CH2Cl (8j)R1, R2 = -CH2Br (8i), -CH2Cl (8k)

NaOH

70 °C+ +

Scheme 15

OBr

Br

rongalite, TBAB

DMF, 0 °C to r.t., 6 hO

S

O

O toulene

reflux, 5 hO S

O

O

Br

Brrongalite, TBAB

DMF, 0 °C to r.t., 6 hO

SO

SO

O

46b 48 49 65%

50 85%51 61%

SO

O

reflux3 h

48% HBr in waterone drop conc. H2SO4

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Later on, Kotha and Sreevani have shown the synthesisof dipropargyl sulfone 3b from rongalite and propargyl bro-mide in a single step. The building block 3b was also con-verted into benzosultine-sulfone 51 through [2+2+2] cyclo-trimerization reaction by using 1,4-dibromo-2-butyne (8i)and Mo(CO)6 as a catalyst in a short two-step synthetic se-quence (Scheme 16).17b

Furthermore, the methodology has been extended toprepare isoindoline and isoindolinone halide derivatives(Schemes 17 and 18).17c

Scheme 16

Witulski and co-workers reported a [2+2+2] cyclotri-merization18a for the synthesis of 4,6- or 4,5-substituted in-doline derivatives 55 and 56 using Grubbs and Wilkinson’scatalysts, respectively (Scheme 19).

Scheme 19

4 Diphenylalkane Derivatives

The diphenylalkane moiety is present in a variety ofnatural products and in biologically important molecules.For example, 1,3-diphenylpropane (viscoline) isolated fromhemiparasitic herb is used in Chinese medicine for a num-ber of diseases such as haemorrhage, gout, heart diseases,epilepsy etc. 1,2-Diphenylethane derivatives possess cyto-toxic activity towards genital fibroblasts and also show an-tiestrogenic activity. In 1980, Ibuki et al. demonstrated ageneral method for the preparation of diphenylalkane de-rivatives of varied chain lengths using a benzenoid precur-sor.19a Recently, Kotha and Khedkar have developed a newapproach to diphenylalkane derivatives using a [2+2+2] cy-cloaddition, cross-enyne metathesis (CEM), and DA reac-tions as the key steps.19b In this connection, various α,ω-diynes such as 1,5-hexadiyne (3e, n = 0), 1,6-heptadiyne(3f, n = 1), 1,7-octadiyne (3g, n = 2), and 1,8-nonadiyne (3h,n = 3) were subjected to a [2+2+2] cyclotrimerization reac-tion with dimethyl acetylenedicarboxylate (DMAD, 8g) us-ing Wilkinson’s catalyst, and the polysubstituted benzenederivatives 57 were produced in 41–48% yield. Alkynes 57were subjected to CEM with ethylene in the presence of a GII catalyst, by using toluene as the solvent, and the diene de-rivatives 58 were obtained in excellent yields. Microwave ir-radiation of the reaction mixture with DDQ delivered thecorresponding aromatized diphenylalkane derivatives 60 ingood yields (Scheme 20). The methodology is suitable for adiversity-oriented approach to synthesize densely func-tionalized diphenylalkane derivatives. The two differentpolysubstituted aromatic rings are built at the two ends ofthe α,ω-diyne scaffold in a stepwise manner.

Scheme 20

5 Multi-Armed Aryl Benzene Derivatives

Kotha and co-workers have prepared bis- and trisarylbenzene derivatives through a [2+2+2] cyclotrimerizationreaction using the Grubbs first generation catalyst (G I).20a Itwas found that the G I catalyst is more suitable for cyclotri-

O

SO

SO

O

61%

r.t., 5–6 hO2S

O

OS

Br

Br

Mo(CO)6rongalite TBAB

50 51

MeCN/dioxaneMWI

DMF, 0 °C to r.t., 6 h

rongalite,DMSO

1a

3b

Br8i

Br

Scheme 17

TsN

R2R1

Mo(CO)6 (5 mol%)

MeCN, 90 °CMW, 15 min

TsN

R1

R2

TsNBr

TsNBr

TsNCl

TsNCl

Br Cl

52a 80% 52b 69% 52c 78% 52d 73%

1a 3c 52, R1, R2 = H, -CH2Br, -CH2Cl

Br TsNH2

Cs2CO3, acetone24 h, 97%

Scheme 18

MeN

O

Mo(CO)6 (5 mol%)

MeCN, 90 °CMW, 15 min

MeN

R1

R2

O

53, R1, R2 = H, -CH2Br, -CH2Cl

MeN

O

MeN

O

MeN

O

MeN

O

Br

Br

Cl

Cl

53a 51%

53c 56%

MeN

O

Br

Br

MeN

O

Cl

Cl

53b 48%

53d 50%

R2R1

3d

TsN

R2

H R1 NTs

R2

R1 NTs

R2

cat

R1 catalyst meta/ortho yield (%)CH2OH Grubbs 9:1 70CH2OH Wilkinson's 1:20 67(CH2)2OH Grubbs 9:1 51(CH2)2OH Wilkinson's 1:3 66

55, meta 56, ortho54 1

R1

++

n(H2C)

CO2Me

CO2Me

n

CO2Me

MeO2C

MeO2C

CO2Me

CO2Me

MeO2C

MeO2C

CO2Me

n

CO2Me

MeO2C

MeO2C

CO2Me

n

CO2Me

CO2Me

n = 1 2 3 4yield (%) = 41 44 45 48

n = 1 2 3 4yield (%) = 91 85 87 91

CO2Me

MeO2C

MeO2C

CO2Me

n

CO2Me

CO2Me

n = 1 2 3 4yield (%) = 64 71 59 72

n = 1 2 3 4yield (%) = 68 67 56 81

3e–h 5758

5960

8g

G II

ethylene,toluene

r.t.

DMADtoluene80 °C

DDQ, toluene

MWI

RhCl(PPh3)3

EtOH, reflux+

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merization than the Grubbs second generation (G II) cata-lyst. The G I catalyst shows higher initiation and low propa-gation rates, whereas the G II catalyst has low initiation andhigh propagation rates. To this end, commercially availableacetophenone derivatives 61 were converted into acety-lenes 63 through the Vilsmeier reaction. Acetylenes 63were subjected to a [2+2+2] cyclotrimerization with DMADin the presence of the G I catalyst (5 mol%) in toluene heat-ed to reflux to deliver the terphenyl systems 64 in 62–75%yield (Scheme 21). The [2+2+2] cycloaddition reaction ofacetylenes 63 was also studied with other acetylenic part-ners, such as 1,4-dibromobut-2-yne, 1,4-diacetylbut-2-yne,and 1,4-dihydroxybut-2-yne but the desired [2+2+2] cyclo-trimerized product was not observed. Therefore, acetylenederivatives with electron-withdrawing groups such asDMAD are required for the successful implementation ofthe [2+2+2] cyclotrimerization reaction with phenylacety-lene derivatives. As an extension to the above methodology,products 64 were subjected to a Suzuki–Miyaura (SM)cross-coupling reaction20b–d with different boronic acidssuch as 4-acetyl-, 4-formyl-, and 4-methoxyphenylboronicacid using Pd(PPh3)4 catalyst (5–9 mol%) in a tetrahydrofu-ran/toluene/water (1:1:1) mixture in the presence of sodi-um carbonate as a base. The SM cross-coupling products(65a–f) were hydrolyzed during the course of the reaction.

Scheme 21

To synthesize 1,3,5-triaryloxymethylbenzene deriva-tives through a [2+2+2] methodology using Grubbs catalyst,(prop-2-ynyloxy)benzenes 67 were prepared by reaction ofphenol derivatives 66 with propargyl bromide (1a) in ace-tone heated to reflux in the presence of K2CO3. The propar-gylated compounds 67 were then treated with G I catalyst(7.5 mol%) in toluene at 80 °C. A mixture of symmetric1,3,5- and unsymmetric 1,2,4-triaryl benzene derivatives68 and 69 were obtained as white solids along withdepropargylated product 66. It was observed that the G Icatalyst was more effective for the [2+2+2] cyclotrimeriza-tion than the G II catalyst. With catalysts G III and G IV thedepropargylated product 66 was obtained as a major prod-uct (Scheme 22).21

Along similar lines, Tanaka and co-workers found that acationic rhodium(I)–H8-BINAP complex catalyzes the com-plete intermolecular homo- and a cross- [2+2+2] cycloaddi-

tion of aryl ethynyl ethers 70 at room temperature, withelectron-deficient internal monoalkynes, leading to tri- anddiaryloxybenzenes, respectively (Scheme 23).22

Scheme 23

Feng et al. reported the synthesis of two different tetra-substituted benzenes 74 and 75 (Scheme 24) from the samestarting material 8h simply by catalysis with G II in thepresence of an additive CuI (73a) or AgOTf (73b).18b

Scheme 24

Chen and co-workers reported the intermolecular cy-clotrimerization of unsymmetric diarylalkynes 76 in thepresence of Co2(CO)8 to produce the corresponding 1,2,4-re-gioisomers 77 or 1,3,5-regioisomers 78 with excellentyields and high regioselectivity (Scheme 25).18c

6 Annulated Benzocycloalkanes

Kotha and Khedkar reported an interesting reactivitypattern of hybrid o-quinodimethane precursor 82. This hy-brid compound containing benzocyclobutane and benzo-

X

O

X

Cl

CHO X

CO2Me

CO2Me

X

X

CO2H

CO2H

X = Br, I

R

R

X = Cl, Br, I, OMe

61

62 63

64

65

DMF,POCl3

76%

DMAD, G I (5 mol%)

toluene, reflux 62–75%

RC6H4B(OH)2, Pd(PPh3)4

Na2CO3, THF/toluene/water (1:1:1)

No. X R Yield (%)65a I CHO 7465b Br CHO 6365c I COMe 8365d Br COMe 6865e I OMe 5365f Br OMe 48

NaOH

78%

Scheme 22

OH

R

R = CO2Et, H, Me, OMe, tBu

O

R

+

OH

R

+

66 67 72–98%

68

6966 13–37%

68 & 69 24–71% (combined yield)

O

OO

O

O

O

R

R

R

R

R

R

Bracetone, K2CO3

reflux

1a

Ru

O

PCy3Cl

Cl

Ph

Ru

PCy3

PCy3

Cl

Cl

G III G IV

G I

toluene, 80 °C+

R

O

R

R R

O

OO

[Rh(COD)2]BF4

H8-BINAP (5 mol%) CH2Cl2, r.t., 40–55%

MeO2C

MeO2C

O

O

R

R

DMAD, [Rh(COD)2]BF4

H8-BINAP (5 mol%) CH2Cl2, r.t., 19–60%

70 7271

Ph

Ph

Ph

Ph

CO2Me

CO2Me

Ph

Ph

CO2Me

CO2Me

1. G II, additive ethylene (1 atm) toluene, 24 h

2. DMAD, 24 h3. DDQ (1.2 equiv) 4 h

additive = CuI (73a) 85% 5% AgOTf (73b) <5% 75%

8h 74 75

+

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sulfone moieties was prepared by a [2+2+2] cycloadditionreaction and utilization of rongalite (Scheme 26).23 The DAreaction of o-quinodimethane precursor 82 can generatevarious annulated benzocycloalkanes. For example, the se-lective DA reaction was realized at the sultine 82 or the sul-fone 84 frame and not at the other end of o-quinodimeth-ane precursor, i.e. the benzocyclobutane moiety. The DA re-action was studied under different conditions such asconventional heating, MWI, in the presence of an excessamount of dienophile, removal of SO2 as it is generated inthe reaction by continuous bubbling of N2 gas. This hybridsystem with differential reactivity pattern is likely to findinteresting applications in organic synthesis.

Scheme 26

7 Spirocycles

The spiro unit is an important structural element pres-ent in several natural products (e.g. terpenoids and alka-loids) and non-natural products. Recently, they have foundimportant applications in materials science and also in me-dicinal chemistry. The attractive conformational feature ofthe spiro center is responsible for the biological activity. Be-cause of the presence of an axial chirality, these compoundsare useful in designing new chiral ligands and catalysts ap-plicable in asymmetric synthesis. Hudlicky has once re-marked that the generation of a spiro center is a highly dif-

ficult task because it involves the generation of a quaterna-ry center.24a There are many methods known in theliterature for the synthesis of spirocyclic compounds24 butmany of these methods have several limitations such as lowfunctional group tolerance, restriction to particular substi-tution patterns etc. In this regard, there is a compellingneed to develop new methods to form spirocycles. Duringthe past few years, Kotha and co-workers have made con-tinuous effort to prepare diverse spirocycles24c–f using the“building block approach” and some of them are describedhere.

Kotha and Manivannan envisaged the spiro compound86 as a useful precursor for the synthesis of unsymmetricbenzoannulated systems.24g They have found that there aretwo possible retrosynthetic routes for the preparation of86; one using a [2+2+2] cycloaddition (path A, Scheme 27)and the other using [4+2] cycloaddition (path B, Scheme27). These routes are strategically different and, using theabove methodologies, they have shown that [2+2+2] and[4+2] cycloaddition strategies are useful to prepare various2,2-spirobisindane-1,3-dione derivatives. To realize the[2+2+2] strategy the key intermediate was prepared by bis-propargylation of 1,3-indanedione (89) with propargyl bro-mide (1a) by using a phase-transfer catalyst (Scheme 28).With the prepared compound 87 a [2+2+2] cycloadditionsequence was performed with use of η5-cyclopentadienyl-cobalt complex CpCo(CO)2 as a catalyst. Here, slow additionof diyne 87 and catalyst in dry toluene to a solution ofalkyne heated to reflux under inert conditions gave the re-quired linear spiro derivatives 86. Various monoynes under-went the cyclotrimerization reaction under these condi-tions.

Scheme 27

Starting with same material (1,3-indanedione, 89)Kotha and co-workers have prepared several angularly aswell as linearly fused spirocyclic derivatives. To this end, a[2+2+2] cycloaddition and DA reaction were used sequen-tially as the key steps.25 The [2+2+2] cycloaddition of

Scheme 25

R1

Co2(CO)8

1,4-dioxane, reflux

R1

R2

R1

R2

R2

R1 R2

R1

R2

R1

R2

R1

R1 = F, R2 = C12H25 77 72% 78 8%R2

76

+

+

CO2Me

CO2Me

MeO2C

MeO2C

HO

HO

Br

Br

CO2Me

CO2Me

O

O

S

O

OS+

MeO2C

MeO2C

MeO2C

MeO2C

39% combined yield

MeO2C

MeO2C

+

DMAD, DPE190–210 °C

MnO2, 1,4-dioxane95%

7980

81 82

83 45% 84 52%

8385

3e8g

CpCo(CO)2

toluene/n-octane125 °C, 35%

LiAlH4, THF

0 °C–r.t., 67%

NaBr-BF3•OEt2

acetonitrile0 °C–r.t., 55%

rongalite, TBAB

DMF, 0 °C–r.t.75%

DMAD, toluene

N2 bubbling 100 °C

85 95%

R

R

O

O

[2+2+2] [4+2]

O

O

O

O87 86 88

Path A Path B

Scheme 28

R2

R1O

O

O

O

O

O

R1 R2

R1

R2

=CO2Me TMS CO2Me Ts TMSTs

CO2Me Ts TMS

N

O

O

Ph

O

O

O

O

87 58% 86 22–87%89

Br K2CO3,TBAHS

MeCN, r.t

CpCo(CO)2

toluene/n-octane125 °C

1a

+

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dipropargylated compound 87 with 2-butyne-1,4-diol indry ethanol in the presence of Wilkinson’s catalyst gave diol90 in 39% yield along with a small amount (4%) of the dimer(Scheme 29). Since Ti(OiPr)4 facilitates enyne metathesis,25c

a similar role was anticipated in a [2+2+2] cycloaddition se-quence. When Ti(OiPr)4 was used in catalytic amount, theyield of diol 90 increased to 46% along with a minor amount(7%) of the dimer. Diol 90 was then converted into the di-bromo derivative 91 by using PBr3 in dry benzene at roomtemperature, and this dibromide was then converted intosultine derivative 92 by treatment with rongalite in di-methylformamide. The diene intermediate was generatedfrom sultine 92 in toluene heated to reflux and was trappedwith 1,4-naphthoquinone to deliver the corresponding DAadduct. Dehydrogenation of the DA adduct with DDQ in tol-uene heated to reflux produced the aromatized product93a. Other linearly fused spirocycles 93b–d prepared bythis methodology are shown in Figure 4.

Figure 4 Linearly fused spiro derivatives

Although a [2+2+2] cycloaddition reaction has been ap-plied with several substrates, limited examples are availablewhere propargyl halides are used as co-partners. In allthese examples propargyl diol is used as co-trimerizedpartner and the resulting dihydroxy derivative obtained ina [2+2+2] cycloaddition reaction is transformed into thecorresponding bromide by using PBr3. This strategy couldnot be extended to sensitive substrates such as Meldrum’sacid, peptides, ethers, and these substrates decomposeduring the bromination sequence. To expand its utility inorganic synthesis, we have studied the use of propargyl ha-lides in a [2+2+2] cycloaddition under different cata-lysts/conditions. Kotha and Sreevani have demonstrated a[2+2+2] cycloaddition strategy with propargyl halides usinga Mo catalyst, Mo(CO)6, under MWI conditions.10a Mo com-

plexes are not the regular catalysts for a [2+2+2] cyclotri-merization sequence. The mechanism may involve the for-mation of molybdenacyclopentadiene which would reactwith the alkyne partner to produce the cyclotrimerizedproduct. In this context dipropargylated 1,3-indane dione87 was chosen as a model substrate (Scheme 30). Diyne 87was then subjected to a [2+2+2] cycloaddition sequencewith propargyl bromide (1a) in the presence of a catalyticamount of Mo(CO)6 in THF heated to reflux for 10 hours.The desired [2+2+2] cycloaddition product 94 was obtained(34%) along with self-dimerized product 96 (5%) and theunsaturated aldehyde 95. After considerable amount of ex-perimentation, it was found that the reaction was success-ful with acetonitrile under MWI conditions at 90 °C. Theyield of the trimerized product 94 was improved to 75%.This may be due to in situ formation of the air-sensitive cat-alyst (CH3CN)3Mo(CO)3 when Mo(CO)6 was heated withacetonitrile, and this could facilitate the reaction. Addition-ally, the high dielectric constant of acetonitrile facilitatesthe absorption of MW radiation to enhance the rate of thereaction. The [2+2+2] cyclotrimerization was achieved witha variety of active methylene-based diynes and differentpropargyl halides under similar reaction conditions and thecorresponding benzyl halide derivatives were isolated ingood yields.

Scheme 30

Later, this technology has been extended to barbituricacid, Meldrum’s acid, hydantoin derivatives, thiazolidines,amino acids, and peptides to synthesize the correspondinghalo(methyl)benzene derivatives 102–106 and 17 in mod-erate to good yields (Scheme 31).10b

Scheme 29

OH

OH

Br

Br

O

SO

O

O

O

O

O

O

O

O

O

O

O

O

87 90 46% 91 54%

92 75% 93a 61%

2-butyne-1,4-diol

RhCl(PPh3)3, Ti(OiPr)4

EtOH, reflux, 24 h

PBr3, benzene

r.t., 26 h

rongalite

TBAB, DMF r.t., 6 h

a) naphthaquinone, toluene, reflux, 24 h

b) DDQ, toluene, reflux, 24 h

O

O

O

O

O

O

CO2Me

CO2Me

NPh

O

O

CNCN

CNCN

93b 63% 93c 68%

93d 81%

O

O

Br

+Br

O

O

Br

O

O

O

O

O

O

O

O

CHO

94

94 96

95871a

Mo(CO)6, THF reflux

10 h, 34%

orMo(CO)6

1,4-dioxane MW, 110 °C,15 min, 45%Mo(CO)6

MeCN MW, 90 °C

10 min, 75%

+

+

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Scheme 31 Preparation of halo(methyl)benzene derivatives contain-ing different heterocycles

In continuation of our efforts to the synthesis of spiro-cycles, Kotha and Ali have developed a new strategy26a in-volving a sequential usage of [2+2+2] and [4+2] cycloaddi-tions. To design intricate spirocycles, readily available car-bonyl compounds (i.e. mono ketones 107) weretetrapropargylated. Later, reactions of the tetrapropargylketones 108 with 2-butyne-1,4-diol (8c) were performed inthe presence of Wilkinson’s catalyst and a catalytic amountof Ti(OiPr)4 to deliver [2+2+2] cycloaddition products 109(Scheme 32). Next, the tetraol derivatives 109 were directlyconverted into tetra-bromides 110 so that they can betransformed into sultines 111 by using rongalite. Then, re-actions of these sultines were performed with different di-enophiles in a DA fashion to generate various complex bis-armed spirocycles 112 (Figure 5) in excellent yield. Unex-pectedly, the DA reaction with 1,4-naphthaquinone andDMAD (8g) gave the corresponding mono-DA adductswhich on subsequent dehydrogenation furnished the aro-matized products.

Later on, this strategy has been extended to bis-armedspirocycles 115 and 116 containing a bicyclo[2.2.2]octanesystem through a [2+2+2] cyclotrimerization followed by aDA reaction.26b The required tetrayne 114 was prepared bypropargylation of dione 113 (Scheme 33), which was syn-thesized from commercially available hydroquinone. Fur-ther, the tetrayne 114 was treated with 1,4-dihydroxy-2-butyne (8c) in the presence of Wilkinson’s catalyst to ob-tain tetraol 115, which on treatment with PBr3 in CH2Cl2

without isolating the intermediate tetraol afforded the de-sired tetrabromo derivative 116. In this context, we directlytreated the tetrapropargylated compound 114 with 2-bu-tyne-1,4-dibromide (8i) in the presence of Wilkinson’s cat-alyst; however, unfortunately, we did not achieve the de-sired product. Later on, we treated the propargyl buildingblock 114 with 8i and Mo(CO)6 under MWI conditions inCH3CN at 90 °C and the spiro-annulated building block 116was obtained in 40% yield. Next, tetrabromide 116 was suc-cessfully converted into the sultine derivative 117 by usingrongalite followed by the DA sequence with tetracyanoeth-ylene, which delivered the cyclo adduct 119 in 67% yield(Scheme 34). Moreover, the sultine derivative 117 was rear-ranged to bis-sulfone derivative 118 in toluene heated to re-flux in good yield.

The spirooxindole moiety is a critical structural unitpresent in drugs, which show antimalarial, anticancer, andantimicrobial activity. To this end, to synthesize variousspirooxindole derivatives, Kotha and Ali conceived a strate-

CH2Br

102 70%

104 72%

105 (X = O, 75%, X = S, 69%)

CH2Br

CH2Br

103 38%

CH2Br

CH2BrCH2Br

CH2Br

CH2Br

N

N

O

O

CH2Br

CH2Br

S

N

O

X

AcHN

Peptide

CH2Br

CH2Br

N

N

O

O

O

O

O

O

O

AcHN

EtO2C CH2Br

CH2Br

17 70%

106 46%

N

N

O

O

O

O

O

O

O

N

N

O

O

S

N

O

X

AcHN

EtO2C

AcHN

Peptide

97

98

99

100

7a

101

+

+

+

8i

8i

8i

+ 8i

+ 8i

+ 8i

Mo(CO)6

MeCN, MW90 °C

Mo(CO)6

MeCN, MW90 °C

Mo(CO)6

MeCN, MW90 °C

Mo(CO)6

MeCN, MW90 °C

Mo(CO)6

MeCN, MW90 °C

Mo(CO)6

MeCN, MW90 °C

Scheme 32

Br

+

1a

OO

O

OHOHHO

HOO

BrBrBr

Br

sultineO

R

R

R

R

107108

109110

112

111

NaH, THF

r.t., 12–24 h70–85%

2-butyne-1,4-diol (8c)RhCl(PPh3)3, Ti(OiPr)4

EtOH, reflux, 24–30 h

rongalite, TBAB

DMF, 0 °C to r.t.

3–5 h, 68–75%

1. dienophiles, toluene reflux, 12–24 h, 78–88%,

2. DDQ, toluene, reflux 24 h, 56–60%

PBr3, CH2Cl2, r.t.

15–30 h, 41–52%

Figure 5 Bis-spirocycles prepared with use of rongalite and a DA strat-egy

O

CNCN

CN

CN

NCNC

NC

NC

O

CNCN

CN

CN

NCNC

NC

NC

ON

N

O

O

O

O

PhPh

O

CNCN

CN

CN

CNNC

NC

NC

112a 88%

112b 80%

112c 83%

112d 88%

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gy on the basis of a [2+2+2] cycloaddition and a DA reac-tion.27 In this regard, N-methyl derivative of oxindole 120was dipropargylated and subsequent [2+2+2] cycloadditionyielded diol 122, which on treatment with PBr3 in CH2Cl2 af-forded the dibromo building block 123. Later, the dibromoderivative 123 was converted into the sultine derivative 124(76%), and subsequent treatment with tetracyanoethylenedelivered the DA adduct 125 (72%, Scheme 35).

Kotha and Ali reported several linearly annulated spiro-cyclic compounds starting with inexpensive and commer-cially available active methylene compounds (AMCs) 126a–g (Figure 6). These AMCs were dipropargylated; the selec-tion of the base used during the dipropargylation step de-pends on the acidity of the AMCs.28 The dipropargylatedcompounds were further subjected to a [2+2+2] cycloaddi-tion reaction with 2-butyne-1,4-diol with the aid ofWilkinson’s catalyst and a catalytic amount of Ti(OiPr)4 toafford the diol. Next, treatment with PBr3 delivered the di-bromo compounds in good yield. Further, these dibromo

compounds were treated with rongalite in DMF to deliverthe sultine derivatives, which on reaction with dienophilesin a DA fashion produced the cycloadducts. Finally, dehy-drogenation delivered several linearly fused spirocycles127a–h (Figure 7). Interestingly, fluorenes are a uniqueclass of blue-emitting molecular entities used in polymerlight-emitting diodes (PLEDs). Moreover, they also founduseful applications as sensors, and their remarkable quan-tum efficiency has made them important in the field of op-toelectronics. Recently, much attention has been paid to-wards the synthesis of ladder-type oligomers and polymersof fluorenes with a rigid spiro linkage in their structures.Therefore, these fluorene-based spirocycles (e.g. 131) pre-pared by this simple methodology (Scheme 36) may finduseful application in polymer chemistry and materials sci-ence.

Kotha and co-workers also have reported spirobarbi-turic acid derivatives 134a–d using a similar methodologystarting from barbituric acid (Scheme 37).29

Scheme 33

O

O

HO

HOOH

OH

RhCl(PPh3)3, Ti(OiPr)4 EtOH, reflux, 24 h

not isolatedStep I

O

O

Br

BrBr

Br

(combined yield of steps I and II )

Step IIMo(CO)6, CH3CNMW, 90 °C, 10 min

115

116 40%

8iRh(PPh3)3Cl, Ti(OiPr)4

EtOH, reflux, 24 h

116

PBr3, CH2Cl2r.t., 15 h

116, 33%

O

O

113 O

ONaH, HMPA

THF, r.t., 20 h 55%

114

1a

8i

R1

R2

8c R1, R2 = CH2OH

Scheme 34

O

O

O

SO

S O

O

O

S

OO

S OO

NC

NC CN

CNtoluene, 100 °C

3 h, 67%

toluene, 100 °C20 h, 88%

O

O

NC

NC

CN

CNCN

CN

CN

NC

O

rongalite, TBAB

DMF, 0 °C–r.t., 3 h85%

116

119

118O

O

SSO

O

O

O

117

+

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Figure 6 List of active methylene compounds used for the synthesis of 1,6-diynes

8 Selectivity in [2+2+2] Cycloaddition of Alkynes

One of the disadvantages of a [2+2+2] cyclotrimeriza-tion reaction is the formation of regioisomeric products, i.e.the lack of selectivity. This problem can be addressed by us-ing some of the strategies mentioned here. For example, useof a temporary tether to combine two alkynes allows over-coming the problems associated with the formation of re-gioisomers in intermolecular reactions or avoids the forma-tion of isomers in partially intermolecular [2+2+2] cycload-

EtO

EtO

O

O

O

O

O

n

n = 1, 2

O

R

R

O

126a 126b 126c 126d 126e

126fR = Br, NO2

126g

Scheme 35

N

O

N

O

N

O

OH

OH

N

O

Br

Br

N

O

N

O

O

S

S

O

O

O

N

O

+CN

CN

CNCN

120 121 122

123

124a

124b

125

Br 2-butyne-1,4-diol (8c)RhCl(PPh3)3, Ti(OiPr)4

EtOH, reflux, 18 h

PBr3, CH2Cl2 r.t., 15 h, 48%

rongalite, TBAB

DMF, 0 °C–r.t.6 h, 76%

tetracyanoethylene

toluene, reflux12 h, 72%

1a

+NaH, THF

2 h, 70%

Figure 7 Compounds prepared by [2+2+2] cycloaddition followed by DA reaction

EtO

EtO

O

O

O

O

O

O

O

CNCN

CNCN

N

O

O

Ph

O

O

O

MeO

NN N

O

O

Ph

N

O

O

PhCN

CN

CNCN

Br

Br

O

O

NO2

NO2

O

O

127a 90% 127b 83% 127c 86%

127d 80%

127e 89% 127f 83% 127g 67% 127h 68%

Scheme 36

Br

Br

O

SO

N

O

O

Ph

126e 128

129

130131

Br 50% aq NaOH BTEAC

r.t., 15 h, 72%

1. 2-butyne-1,4-diol (8c), RhCl(PPh3)3,Ti(OiPr)4

EtOH, reflux, 24 h2. PBr3, CH2Cl2 r.t., 18 h, 62%

rongalite, TBABDMF, 0 °C–r.t.

4 h82%

1. N-phenylmaleniimide, toluene, reflux

2. DDQ, toluene, reflux, 24 h, 75%

1a

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dition reactions. Yamamoto and co-workers reported achemo- and regioselective ruthenium-catalyzed intermo-lecular cyclotrimerization of three different unsymmetricalkynes by means of a temporary tethering approach in-volving boron. Alkynylboronates 135, propargylic alcohol1e, and terminal alkynes were cyclotrimerized in the pres-ence of Cp*RuCl(cod) generating an arylboronate interme-diate 138 which could be isolated or subjected to furthersynthetic manipulations such as Suzuki–Miyaura couplingwith various aryl iodides or palladium(II)-catalyzed carbon-ylation reaction (Scheme 38).30

Scheme 38

Selectivity in intermolecular cyclization of differentpartners (1b, 1e, and 141) can be achieved by using dispos-able linkers such as temporary silyl tethers. In this context,Malacria and co-workers utilized silicon tether 142 that al-

lowed the transformation of intermolecular reactions intointramolecular versions in the presence of a cobalt(I) cata-lyst, generating a highly chemo- and regioselective product143. Finally, the tethers could be selectively removed afterthe reaction heading to the creation of functionalizedarenes 144 (Scheme 39).31

Mori et al. have reported a highly regioselective Ni-cata-lyzed [2+2+2] cycloaddition of two distinct alkynes usingadditives such as diethyl zinc and phenol. Reaction of meth-yl propiolate (1g) with trimethylsilyl protected propargylalcohol 1h afforded the cycloadducts 145 and 146 in 95:5regioselectivity (Scheme 40).32

Scheme 40

The regioselectivity problem was addressed by a reac-tion of alkynes together with a suitable linker (e.g. 1,6-diynes or 1,7-diynes). The 1,2-bis(diphenylphosphino)eth-ane (DPPE)-bound Ni catalyst can facilitate the reaction of1,6 diynes 3e with 1,3-diyne 147. The diynes bearing elec-tron-withdrawing ester groups on the termini gave excel-

Scheme 37

N

NO

O

O

O

O

N

NO

O

O

CN

CN

CN

CN

N

O

O

Ph

N

N

O

O

O

134a 70% 134b 78%

134c 86%

N

NO

O

OCO2Me

CO2Me

134d 73%

N

NO

O

O

OH

OHN

NO

O

O

R1

R2

RhCl(PPh3)3

EtOH, reflux62%

Br

BrN

NO

O

O

rongaliteTBAB

N

NO

O

O

O

SO

N

NO

O

O

R

R

DMF, 0 °C–r.t. 87%

97 8c R1, R2 = CH2OH 132102

133134

dienophile

DA

+PBr3, DCM

81%

R1(iPrO)2B

HOH2C

R2

Cp*RuCl(COD) (5 mol%)

DCE, r.t., 5 h

R1BO

iPrO

RuO

R1

Cp*

Cl

iPrO

BO

R1

R2

iPrO Pd2(dba)3/PCy3

ArI

toluene, 70 °Caq. K2CO3

53–76%

Ar

R1

R2

HO

Pd(OAc)2/PPh3 (5 mol%)p-benzoquinone, CX

MeOH, r.t., 36–73%O

R1

R2

X

X = CO, tBuN

135

1e 136 137

138 140139

+

Scheme 39

CH2OH

Bu

OH

Ph

O Si

iPr

iPr O

SiiPr

iPr

nBuPh

CpCo(CO)2

(3 mol%)

xylene, reflux hν, 67%

Si

O

Ph

nBu

iPr

iPr

Si OiPriPr

OH

Ph

nBu

HO141

1e

1b

142 143 144

TBAF

THF, Δ76%

+

CO2Me Ni(acac)2 (5 mol%)PPh3 (10 mol%)

Et2Zn, PhOHtoluene, 80 °C, 60%

CO2Me

CO2Me

OTMS

CO2Me

OTMSMeO2C

95:5

1g 1h

145 146

OTMS

+ +

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lent yields. Furthermore, unsymmetric 1,3-diyne 149 cou-pled regioselectively with 1,6-diyne 3f to give arylalkyne150 (Scheme 41).33

Scheme 41

Deiters and co-workers developed solid-supporteddiyne substrates for controlling the regioselectivity during a[2+2+2] cyclotrimerization sequence. A variety of diyneswere immobilized on polystyrene resin by using trityl orcarboxy linkers, and a [2+2+2] cyclotrimerization was con-ducted with various symmetric as well as unsymmetricalkynes in the presence of Wilkinson’s catalyst or Cp*Ru-Cl(cod) catalyst. Unsymmetric alkynes in the presence ofWilkinson’s catalyst showed poor regioselectivity; however,using Cp*RuCl(cod) catalyst, high regioselectivity was ob-served (meta/ortho 9:1) (Scheme 42). This method avoidsself-coupling reaction of diynes and facilitates easy separa-tion of cross-cycloaddition products. The compounds wereobtained in good to excellent yields and with high puritiesafter cleavage from the solid support.34a Later, the samegroup reported solid-supported [2+2+2] cycloaddition reac-tions under MWI conditions using Cp*RuCl(cod) catalyst.34b

By an intramolecular cycloaddition strategy, one cansolve selectivity issues (Scheme 43). Totally intramolecular[2+2+2] cyclotrimerization was observed in 15- and 25-membered polyacetylenic azamacrocycles with Wilkinson’scatalyst. The expected cyclotrimerized compound was ob-tained in 54 and 50% yield, respectively. However, 20-mem-bered azamacrocyle gave no product because of the lack of

reactivity.34c,d This reaction is very attractive and of highsynthetic potential because of its chemo- and regioselectiv-ity. Limited reports are available, which is due to the diffi-culty in designing of the triyne substrate.

Scheme 43

Peters and Blechert were the first to report fully intra-molecular cyclotrimerization using Grubbs catalyst.35a Themechanistic explanation for the reaction involves a cascadeof four metathesis reactions occurring to isomerize thetriynes to benzene derivatives using Grubbs catalyst.35a Ya-mamoto and co-workers demonstrated that 1,6,11-triyne 5on cyclization in the presence of 1 mol% catalyst 156 pro-duced the tricyclic compound 6 in 82% yield (Scheme 44).35b

Scheme 44

9 [2+2+2] Cycloaddition Reactions under Evironmentally Friendly Conditions

Despite several advances in metal-catalyzed [2+2+2] cy-cloaddition processes for laboratory uses, this process stillneeds additional improvements with respect to the devel-opment of environmentally friendly and scalable proce-dures that are applicable on industrial scale. In this regard,Oshima and co-workers, in 2003, reported a rhodium-cata-lyzed [2+2+2] cyclotrimerization of triynes in a water-or-ganic biphasic system.36a Later, Cadierno et al. have report-

CO2Me

CO2Me

R1

R1

Ni(dppe)Br2 (5 mol%)Zn

MeCN, 80 °C

R

R

R1

R1

R = CO2Me, R1 = Ph 88%R = CO2Me, R1 = nBu 72%R = H, R1 = Ph 53%

3e

147

148

CO2Et

CO2Et

nBu

Ph

Ni(dppe)Br2 (5 mol%)Zn

MeCN, 80 °C

CO2Et

CO2Et

nBu

Ph

150149

3f

+

+

Scheme 42

O OO

H

(CH2)4Cl

Rh or Ru cat. (10 mol%)

DME, r.t./80 °C, 24 h O

(CH2)4ClO

(CH2)4Cl

THF/MeOH (4:1)r.t., 12 h, 95%

K2CO3

O

(CH2)4ClO

(CH2)4Cl

RhCl(PPh3)3 68% 1:2Cp*RuCl(cod) 95% 9:1

O O

HO HO

151 152a 152b

153a 153b

+

+

+

N

N

NTs Ts

TsN

N

N

Ts

Ts

Ts

154

155

RhCl(PPh3)3 (5 mol%)

toluene, reflux

X

Y

Ru cat. (1 mol%)DCM

r.t., 2 h

X Y

82%Ru

Cl

Ru cat.5 (X, Y = O; R1, R2 = H) 1566 (X, Y = O; R1,R2 = H)

R1

R2 R1 R2

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ed intermolecular cyclotrimerization of alkynes (1b, 1c,and 1j) in aqueous medium using a commercially availableruthenium(IV) dimer (Scheme 45).36b

Scheme 45

In 2010, Tsai and co-workers demonstrated a [2+2+2]cycloaddition of α,ω-diynes (3a, 3c, and 3g) catalyzed by[Rh(COD)Cl]2/cationic 2,2'-bipyridyl system 158, with ter-minal (1c, 1e, and 1k) and internal alkynes (8k and 8l) inwater in the presence of air at 60 °C (Scheme 46). After sep-aration of the organic products from the reaction mixtureby extraction, the residual aqueous solution could be re-used for further reactions until complete degradation of itscatalytic activity.36c

Scheme 46

Recently, Goswami and co-workers prepared an iron-based catalytic system FeCl2·4H2O/dipimp/Zn to accomplish[2+2+2] cycloaddition reactions. They reported an eco-friendly [2+2+2] partially intramolecular reaction using thesame catalytic system in ethanol to prepare N-substitutedindolyl-aryl derivatives 160 in good yields (Scheme 47).Here, the reaction was carried out in ethanol as the solventand iron(II)chloride tetrahydrate acts as the metal source,2-[(2,6-diisopropylphenyl)iminomethyl]pyridine (dipimp)as the ligand, and zinc as the reducing agent.37

Scheme 47

10 Alkyne Surrogates

Synthesis of fused benzene rings can also be accom-plished by using alkyne surrogates during the [2+2+2] cyc-loaddition reaction with diynes. This alternate methodavoids the selectivity problems. Several groups have report-ed the use of enol ethers or easily enolizable ketones asalkyne equivalents that undergo dehydration after the cy-clotrimerization giving the aromatic products. Some recentexamples, depicted in Scheme 48, show diynes reactingwith rhodium(I)/BINAP catalyst system with enolethers38a

161, vinylene carbonates38b 163, or 2-oxazolones38c 167.The regioselectivity of the enol ether insertion is thought tobe controlled by coordination of the enol carbonyl moietyto the cationic Rh center in the metallacyclopentadiene in-termediate. If the enol ether component is replaced by vi-nylene carbonate 163, a phenol derivative 164 is obtained,whereas the reaction with ketene acetal 165 gives aromaticether 166, and the reaction with 2-oxazolones 167 givesanilines 168. In addition, Matsuda and co-workers showedthat substituted maleic anhydride functioned as syntheticequivalent of alkynes in a rhodium(III)-catalyzed [2+2+2]cyclotrimerization reaction with 1,6-diynes.38d

Scheme 48

In 2015, Ichikawa and co-workers demonstrated thesynthesis of fluorobenzene derivatives 172 through a nick-el-catalyzed intermolecular [2+2+2] cycloaddition reactionusing 1,1-difluoroethylene 169 as an alkyne surrogate(Scheme 49). They have also demonstrated that this reac-tion works with 1,6-enynes in a partially intramolecularfashion.38e

For the first time in 1973, Yamazaki reported the appli-cation of a [2+2+2] cycloaddition reaction for the synthesisof heterocycles where nitrile 173 has been used as a co-partner with two acetylenes in the presence of a cobalt cat-alyst leading to the formation of pyridines 174.39a Later on,

HR13

[{Ru(η3:η3-C10H16)(μ-Cl)Cl}2](2.5 mol%)

H2O/MeOH, 90:10 v/v 75 °C, 0.5–24 h

72–99%

R1

R1 R1

R1

R1

R1

R1 = nBu (1b), Ph (1c), CO2Et (1j)

2b2a1

+

X

R1

R2

[Rh(COD)Cl]2 (3 mol%)/L (6 mol%)

KOH (20 mol%), H2O, 60 °C, in air54–90%

X

R1

R2

N N

NMe3BrBrMe3N

L =

X = O (3a), NTs (3c), C(CO2Me)2 (3g)R1 = Ph, R2 = H (1c)R1 = CH2OH, R2 = H (1e)R1 = CH2OCOMe, R2 = H (1k)R1 = R2 = Et (8k)R1 = R2 = CH2OCOMe (8l)

3157

158

+

X

R1

N

O

R2 dipimp (6 mol%)FeCl2⋅4H2O (5 mol%)

Zn (10 mol%)

EtOH, r.t., 15–25 min70–89% X

N

R1

R2

O

R1 = Ph, nBu, TMSR2 = H, OMe, Me

X = C(CO2Et)2 (3h)X = NCH2Ph (3i)

159

160

+

R2

R3O

BINAP, CH2C

l2, r.t.

X

R1

R1

R2

[enol ether surro

gate]

OMe

MeO

X

R1

R1

MeO

OO

O

OHN

O

, [Rh(COD)2]BF4

BINAP, THF, 60 °C

X

R1

R1

H2N

[2-oxazolone surrogate]

, [Rh(COD)2]B

F4

BINAP, CH2C

l2, r.t.

[ketene acetal surrogate]

BINAP, CH2Cl2 , 40–80 °C X

R1

R1

HO

[vinylene carbonate surrogate]

XR1

R1

3

167

168

161

162

163

164

165

166

, [Rh(COD)2]B

F4

, [Rh(COD)2]BF4

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it was found that not only acetylenes and nitriles, but alsoother partners such as cyanates, isocyanates 175, carbonyls179, and carbon disulfide (183) etc.39b participate in the[2+2+2] cycloaddition reaction, thereby enabling the for-mation of a variety of heterocyclic aromatic as well as non-aromatic compounds such as pyridones, pyrans, pyranones,etc. (Scheme 50).39

Double bonds that form parts of heterocycles are alsoknown to participate in the [2+2+2] cycloaddition reactionwith alkynes. Although they are resonance stabilized, co-balt-mediated heterocyclic activation allows these systemsto participate readily in cyclization reactions. Thus, π-en-riched systems, such as furans,40a thiophenes,40a,b pyr-roles,40c and imidazoles40d deliver fused dihydro heterocy-cles. Recently, this methodology has been extended to in-doles,41 pyrimidines,42a,b pyridines, and pyrazinones.42c

11 Domino Reactions Involving [2+2+2] Cy-cloaddition

A useful approach to accomplish molecular complexityin one step is the domino reaction. This theme has drawnincreasing attention in recent years. However, unfortunate-ly only a limited number of domino reactions are knownwhere a [2+2+2] cycloaddition is used in combination withother reactions. Benzolactones and lactams are found inplants and they show pharmacological activity.43a Changand co-workers demonstrated a one-pot synthesis of ben-

zolactone 185 and lactam 186 through a cobalt-catalyzedregioselective [2+2+2] cyclotrimerization and trans-esteri-fication of alkynyl alcohols 1f and amines 1l with propio-lates 1g (Scheme 51).43b Tanaka and co-workers have pre-pared enantioenriched tricyclic phthalide derivatives 188by a cationic Rh(I)/SOIPHOS complex-catalyzed asymmetricone-pot trans-esterification and a [2+2+2] cycloaddition re-action (Scheme 52).44

Scheme 51

Scheme 52

Li and Bonfield have prepared isoindoline derivatives192 by treating amines 190 with aldehyde 191 and alkynes1c (Scheme 53). Three consecutive reactions take place in asingle synthetic operation. First, one molecule of aminecombines with two molecules of aldehyde and two mole-cules of alkyne to give the starting diyne which on cycload-dition with a third alkyne gives the final isoindoline deriva-tive. The first coupling reaction is catalyzed by CuBr and thecycloaddition reaction is catalyzed by Wilkinson’s catalyst.Therefore, both are added from the beginning.45

Scheme 53

Scheme 49

FF

R

R

[Ni(COD)2] (5 mol%)PCy3 (5 mol%)

Et3B (100 mol%)

iPrOLi (100 mol%)toulene, 40 °C

12–16 h, 39–82%

NiII

RR

R

R

FF F

NiII

R

RR

RF

R

RR

R

F

2

R = Ph (8h), C6H4(m-Me) (8m), C6H4(p-Me) (8n), C6H4(p-CF3) (8o), Pr (8p)

169 170 171 1728

+

Scheme 50

NX

O

R

pyridinone

OX

O

NX

R

R N C O

pyridines pyranones

R N O C O

X

SX

NRO

X

SX

SR

R1/H

S C S

S C NR

R R1/H

O

pyranthiopyranthionethiopyranimines

3

176

178

180

182

174

184

175

177

179

181

183

173

CO2Me

CoI2(dppe), Zn

CH3CN/THF1. r.t., 1 h2. 80 °C, 16 h

O

O

MeO2C

CH2NHTs

CO2Me

CoI2(dppe), Zn

CH3CN/THF1. r.t., 1 h2. 80 °C, 12 h

MeO2C186 75%

NTs

O

1f 1g 185 70%

1l 1g

(CH2)2OHH

H

+

+

XCO2Me

R

[Rh(COD)2]BF4 (5 mol%)(R)-soLPHOS

CH2Cl2, r.t., 1 h

HO Ph

X = O (3j), NTs (3k)

X

O

O

R Ph

(R)-soLPHOS O

N

O

N

PPh2

PPh2

187 188

189

+

ArNH2H H

O

2 3 PhRhCl(PPh3) (3 mol%)

CuBr (30 mol%)neat 40–80 °C, 8 h

N

Ph

Ph

Ph

Ar

190 191 1c192

+ +

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12 Biologically Important Targets/ Total Synthesis

Ramana and co-workers also used a [2+2+2] cycloaddi-tion to synthesize bicyclic and tricyclic derivatives. They re-ported the application of intermolecular [2+2+2] alkyne cy-clotrimerization reactions for the construction of benzan-nulated 8-oxabicyclo[3.2.1]octane systems 194 (Scheme54) and this strategy was applied for the synthesis of (–)-bruguierol A.46a

Scheme 54

A similar strategy was employed to construct the cen-tral 4/5/6 tricyclic framework of 6-(1-hydroxyethyl)-cyclo-nocardicin trinems 196 (Scheme 55).46b

Scheme 55

The same group has also synthesized 6,7-cyclopropylal-locolchicinoids 198 using cobalt-catalyzed [2+2+2] cyclotri-merization to construct the ABC ring system (Scheme56).46c Along similar lines, they have also shown the totalsynthesis of (±)-allocolchicine and its analogues.46d Kothaand Sreevani have demonstrated a formal total synthesis ofan isoindoline derivative of Hsp90 inhibitor AT13387(Scheme 57).17c

Scheme 56

13 Conclusions

In this account, we have demonstrated that a [2+2+2]cycloaddition sequence is a useful tool to assemble various

carbo- and heterocycles, spirocycles and polycycles includ-ing unusual amino acids and peptides. In this regard, wehave used Wilkinson’s catalyst, Vollhardt’s catalyst, andGrubbs catalyst. More interestingly, we found that propar-gyl halides can be useful co-partners when Mo(CO)6 is ap-plied as a catalyst. For the first time, we have used Ti(OiPr)4to improve the [2+2+2] cycloaddition with Wilkinson’s cat-alyst. We also included the work of others to keep a bal-anced view of the theme. The strategies and the compoundsdeveloped here are likely to find useful applications in ma-terials science and in the design of pharmaceutically im-portant drugs. Since a [2+2+2] cycloaddition is consideredas an atom-economic process, our results may be of interestto several chemists working in the area of green chemistry.Although this strategy has witnessed several advances, itsapplication on industrial scale is yet to be seen.

Funding Information

S.K. thanks the Department of Science and Technology (DST), NewDelhi for the financial support (EMR/2015/002053). G.S. thanks theCSIR-New Delhi for the award of a research fellowship. S.K. thanks theDST for the award of a J. C. Bose fellowship (SR/S2/JCB-33/2010) andPraj industries for a Chair Professor (green chemistry). ()

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O CH2OH

CH2OH

+

RhCl(PPh3)3

toluene, 80 °C3 h, 85%

193 1948c

O

HO

HO

N

OH

O

H H

R

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toluene/EtOH, 80 °C, 12 h, 64%

MeO

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1,4 dioxane, 150 °C, 15 h79%

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6,7-cyclopropylallocolchicinoids197

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+

Scheme 57

X

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BocNMo(CO)6 (0.05 equiv)

MeCN, MWI, 90 °C15 min, 55%

1-methylpiperazine

K2CO3, MeCNr.t., 3 h, 99%3l, X = NBoc 1a 199

BrBocN

N

NMe

200

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