REVIEW 537 - Thieme...Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece Fax +30(2310)997679; E-mail:

REVIEW ▌537

reviewDimethyl Acetylenedicarboxylate: A Versatile Tool in Organic SynthesisDimethyl AcetylenedicarboxylateConstantinos G. Neochoritis, Tryfon Zarganes-Tzitzikas, Julia Stephanidou-Stephanatou*Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Macedonia, GreeceFax +30(2310)997679; E-mail: [email protected]

Received: 03.10.2013; Accepted after revision: 05.11.2013

Abstract: This review presents the recent progress in the chemistryof dimethyl acetylenedicarboxylate (DMAD). The interest in andapplications of this powerful reagent with more than 135 years ofhistory have greatly increased in the last 10 years, further provingits versatility. Undoubtedly, DMAD can be a multi-tool in the questof molecular complexity and diversity. The extreme structural di-versity of the products described in this review illustrates the pow-erful potential of DMAD as a building block in organic synthesis.

1 Introduction

2 Michael Reactions

2.1 Sulfur as Nucleophile

2.2 Nitrogen as Nucleophile

2.3 Oxygen as Nucleophile

2.4 Addition to Carbon–Carbon Double Bonds

3 Cycloaddition Reactions

3.1 Diels–Alder Reactions ([4+2] Cycloadditions)

3.2 1,3-Dipolar Reactions ([3+2] Cycloadditions)

3.3 [2+2] Cycloadditions


4 DMAD and the Generation of Zwitterions; MulticomponentReactions (MCRs)

4.1 Phosphines and Derivatives

4.2 Amines

4.3 Isocyanides

4.4 Carbenes

4.5 Miscellaneous Reactions

5 Conclusion

Key words: DMAD, dimethyl acetylenedicarboxylate, Michael re-actions, cycloadditions, multicomponent reactions

1 Introduction

Dimethyl acetylenedicarboxylate, commonly abbreviatedas DMAD, is an electro-deficient alkyne diester. This es-ter, which exists as a liquid (density: 1,156 g/mL, 25 °C)at room temperature (boiling point: 95–98 °C), is highlyelectrophilic. As such, DMAD is used as a dienophile anda dipolarophile in cycloaddition reactions. Today, it is be-ing used increasingly in chemical synthesis as it has prov-en useful in carbon–carbon bond formations. DMAD is anextremely versatile tool for organic chemists and com-

pletely new avenues have been explored for its use incombinatorial and multicomponent chemistry and hetero-cyclic synthesis.1 Following the pioneering discovery byDiels and Alder,2,3 the reactions of dimethyl acetylenedi-carboxylate with heterocyclic compounds have been thesubject of a great number of publications4,5

This treatise assembles and presents the fundamentalcharacteristics of DMAD chemistry, as well as current de-velopments thereof. The focus is placed on Michael reac-tions, cycloadditions (Diels–Alder, 1,3-dipolar and [2+2]cycloadditions), and, of course, multicomponent reactionsby generation of zwitterions (Scheme 1). Recent literatureexamples that are both illustrative of the power of this re-agent in the construction of complex heterocyclic mole-cules and pivotal for the design of synthetic strategiestoward natural or designed targets are discussed herein.This review seeks to highlight the ‘power of DMAD’ byexamining selected examples of its elegant applications.

Scheme 1

DMAD is inexpensive and widely available, or it can beprepared from maleic acid (1) via a bromination–dehydro-halogenation sequence to furnish acetylene dicarboxylicacid (4), which upon esterification with methanol usingsulfuric acid gives the desired dimethyl acetylenedicar-boxylate (5). It is noteworthy that DMAD is still synthe-sized in exactly the same way as it was originally obtained(Scheme 2).6

Scheme 2

2 Michael Reactions

DMAD is a powerful Michael acceptor and can take upvarious nucleophiles, most commonly sulfur and nitrogen

multicomponent reactions by generations of zwitterions

Michael reactions cycloaddition reactionsDMAD

O

OH

OHOO

OH

OHO

Br

Br

KOH

H2SO4 (excess)

CO2KKO2C

CO2HHO2CMeOH

H2SO4CO2MeMeO2C

1

2

3

45

Br2, H2O

SYNTHESIS 2014, 46, 0537–0585Advanced online publication: 07.02.20140 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 XDOI: 10.1055/s-0033-1340615; Art ID: SS-2013-E0659-R© Georg Thieme Verlag Stuttgart · New York

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538 C. G. Neochoritis et al. REVIEW

Synthesis 2014, 46, 537–585 © Georg Thieme Verlag Stuttgart · New York

(Scheme 3). A common strategy is to use it in an initial re-action as a Michael acceptor and then carry out a cycliza-tion, usually through loss of –OMe or –CO2Me. Themajority of reactions have been carried out on heteroaro-matic systems, such as pyridines, quinolines, isoquino-lines, thiazoles, imidazoles, phenanthridines,quinoxalines, pyridazines and their substituted deriva-tives, with DMAD being used as a cyclizing agent.

Scheme 3

2.1 Sulfur as Nucleophile

2.1.1 Reactions with Thiourea, Thioamide and Thiosemicarbazide Derivatives

Thiazole, thiazolidines, thiazolidinones and thiazinonesare very important groups of heterocyclic compounds

covering a broad spectrum of biological activity. The re-action between thioamides, thiosemicarbazides and thio-urea derivatives 7 with DMAD is known to be aconvenient and effective method for the preparation of theaforementioned heterocycles depending on the reactionconditions. Generally, the sulfur attacks the triple bond,resulting in the formation of thiolactam intermediate 8,followed by the aminolysis of an ester group (Scheme4),7,8 thus leading to the formation of either 1,3-thiazoli-din-4-ones 9 or 1,3-thiazin-4-ones 10.

Ahmadi et al.9 developed a general strategy based on thereaction of thiourea derivatives 11 with DMAD (Scheme5) to prepare 4-thiazolidinone derivatives 12. Further-more, various thiosemicarbazone derivatives 13 (furfural,benzophenone, butanal, p-methoxybenzaldehyde, etc.)and DMAD reacted in ethyl acetate to give compounds 14as the only products, although from the reaction in anhy-drous methanol only compounds 15 were formed. It isnoteworthy that the adducts 14 could be converted intoproducts 15 by refluxing the reaction mixture in anhy-drous methanol (Scheme 6).10

(Z)-6a

CO2MeMeO2CRNu CO2Me

MeO2C

RNu

CO2MeMeO2C

RNu

+

(E)-6b

Biographical Sketches█

Constantinos G. Neochori-tis was born in Thessaloni-ki, Macedonia, Greece in1982. He received his MSc(2006) and his PhD (2011)in organic chemistry under

the guidance of Professors J.Stephanidou-Stephanatouand C. Tsoleridis from theDepartment of Chemistry ofAristotle University ofThessaloniki. His research

interests include bioactiveheterocycles, drug designand multicomponent reac-tions. He has produced morethan 12 peer-reviewed pa-pers.

Tryfon Zarganes-Tzitzi-kas was born in Thessaloni-ki, Greece in 1988. Heobtained his BSc degree inchemistry from the Aristotle

University of Thessalonikiin 2010. In March 2012 hereceived his MSc with em-phasis in organic chemistryunder the guidance of

Professors J. Stephanidou-Stephanatou and C. Tsoleridisat Aristotle University ofThessaloniki.

Julia Stephanidou-Stephanatou was born inThessaloniki, and studiedchemistry at Aristotle Uni-versity of Thessaloniki. Shecompleted her PhD underthe supervision of ProfessorW. D. Ollis and Sir J. F.

Stoddart at the University ofSheffield England, whereshe worked on the synthesisand conformational behav-iour of medium-sized ringcompounds. Then she re-turned to the University ofThessaloniki and after ha-

bilitation in 1982, she rosethrough the ranks to Profes-sor of Organic Chemistry(1992). She currently workson multicomponent reac-tions and heterocyclicchemistry.

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REVIEW Dimethyl Acetylenedicarboxylate 539

© Georg Thieme Verlag Stuttgart · New York Synthesis 2014, 46, 537–585

Scheme 5

In a more characteristic example, compounds 16, upon re-action with DMAD, yielded the 1,3-thiazol-4-ones 17 asthe major products (Scheme 7) rather than the 1,3-thiazin-4-ones 18.8 Likewise, an acridine reactant with a bulkysubstituent on N-1, such as 19, produced the thiazolidi-none 21 upon cyclization with DMAD (Scheme 8).11

Moreover, reactions of DMAD with the N-imidoylthio-ureas 22 in acetic acid afforded the thiadiazepines 23 in65–84% yield (Scheme 9).12

Scheme 4

S

N

CO2Me

O

R1NR2

R2

NH

S

NH

R1 SN

O

NR2

CO2MeO

O

OMe

OMe

+

NS

NR2

R1H

O

OMeO

OMe

a

bpath a

path b

R1

9

10

7 8

PhHN NH

S

NN S

NPh

N

CO2MeO

1211

DMADTHF, r.t.

92%

Scheme 6

13 R1

R2NNH

S

H2N

MeOH EtOAc

S

N

CO2Me

OH

NNR1

R2 15

reflux

DMAD

SHN

O

NN

R2 R1

14

CO2Me

MeOH

82–94%

Scheme 7

NH

NN

RNH2

S

NH

NN

R

S

N

CO2Me

O

NH

NN

R

S

N

O

CO2Me

DMADDMAD

16 1718R = H, Me

MeOH, r.t.

64%

X

Scheme 8

N

HN NH

S

t-Bu

DMAD

MeOH, 6 h

HN

NH

N NH

S

t-Bu

HN

N

NS

NCO2Me

O

HNt-Bu

2120 1964%

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Scheme 9

In recent decades, ferrocenes (Fc) have attracted attentionbecause of their wide utility in materials science and ca-talysis.13 Therefore, the DMAD-mediated cyclization of1,5-bis(ferrocenylmethylene)thiocarbono hydrazide (24)and its S-methyl derivative 25 were studied, leading to thepreparation of biologically promising sulfur heterocycles26 and 27, and the methylthio-substituted nitrogen hetero-cycles 28 and 29, respectively (Scheme 10).14

In addition, by treatment of the ferrocenyl thiosemicarba-zone derivatives 30 with DMAD in refluxing acetonitrile,three types of cyclic products (31, 32 and 33) were isolat-ed in moderate to good yields. The methylthio derivatives34, obtained by selective alkylation of 30, were also al-lowed to react with DMAD under the same conditions,thereby affording complex mixtures of methylthio-substi-tuted products including pyrimidones 35, imidazolones 36and fumarates 37 (Scheme 11).15

Reaction of DMAD with dithizone (2:1 molar ratio) inmethanol resulted in the formation of thiadiazine 39through a Michael-type addition and a Diels–Alder [4+2]-cycloaddition reaction. In contrast, the reaction of DMADwith dithizone (1:1 molar ratio) in methanol gave com-pound 40 (Scheme 12).16 Thiadiazine derivatives arewidely used as nematicides, fungicides, herbicides and in-secticides. In addition, some thiadiazine derivatives showactivity against tripanosoma cruzi amastigotes.17

HN

NHPh

S

NPh

Ar

DMAD

AcOH, reflux NS

NPhNPh

CO2MeMeO2C

Ar

23

Ar = 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4, 4-O2NC6H4, Ph

22

65–84%

Scheme 10

NH

N

S

HN DMAD

Fc

N

Fc

NHNS

NH

Fc

NFc

CO2Me

MeO2CMeCN, reflux

N

S

ONFc

N

CO2Me

N

Fc

H26

N

S

NFc

N

N

Fc

H 27

CO2MeH

CO2Me

NH

N

SMe

HN

Fc

N

Fc

DMAD

3 h

8 h

N

N

N

SMe

N

Fc

Fc +

N

N

N

SMe

N

Fc

Fc

MeO2C

CO2Me

54% 21%

24

25 28 29

MeINaOMeMeOH

77%

93%

MeCN, reflux

Scheme 11

R

NHN

S

H2N

Fc

DMAD

MeCNreflux, 1–3 h

R

NHN

S

N

Fc

CO2Me

MeO2C

31R

NN

S

HN

Fc

O

32

CO2Me

+ +

R

NNFc

33

S

HN

O

CO2Me

30 R = H, Me

MeI, NaOMe MeOH

R

NN

S

H2N

Fc

MeR

NFc

N

N

MeS

MeO2C

ODMAD+

35

R

NFc

N+

36

N

MeO2CO

MeSR

NFc

N

OOMe

37

MeS N

34

H

13% 28% 45%

85–91% 20–30% 15–18% 32%

MeCNreflux, 1–3 h

COOMe

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Scheme 12

2.1.2 Reaction with Thiones and Thiols

An example of the ‘DMAD strategy’ for the synthesis ofheterocycles was described by Neochoritis et al.18 It iswell known that Michael-type amine and thione additionto acetylenic esters leads to E/Z isomeric mixtures. The re-action of DMAD with 1-arylaminoimidazole-2-thiones 41in the presence of a base through a Michael reaction af-

forded imidazolothiazoles 43. However, in the reaction of41 with DMAD in the absence of a base, only the S-sub-stituted products 42 were formed as an E/Z mixture. Athorough investigation of this thio-Michael-type additionof DMAD and an explanation of the reaction’s stereo-specifity were reported (Scheme 13).

A systematic study of the reactions of DMAD with 5-mer-captoazoles 44, 47, 49 and pyridine-2-thiones 52 was alsocarried out and, as a result, a number of novel imidazothi-azinones 45, imidazothiazolones 46, triazoles 48, pyr-azolothiazinones 51 and thiazolopyridines 53 wereobtained. The size of the ring, formed in the reactions ofcyclic thioamides with DMAD, was found to be depen-dent on the size of the starting heterocycle. Thus, a five-membered thiazolidine ring condenses onto the pyridinering whereas a six-membered thiazine ring is fused onto afive-membered azole ring (Scheme 14).19

38

NN N

H

HN

Ph

S

Ph

N

N

S

NNPh

Ph

CO2Me

CO2MeN

N

NN

S

HMeO2C

O

Ph

CO2Me

CO2Me

Ph

40

39

MeOHreflux

92%

82%

DMAD(2 equiv)

DMAD(1 equiv)

MeOHreflux

Scheme 13

N N

MeR

S

O

MeO2C

N

H

Ar

N NH

MeR

SHN

Ar

41

+

CO2Me

CO2Me

EtOAc or CH2Cl2

r.t., 24 h

NaH (2.2 equiv)

THF, r.t., 24 h

N N

MeR

SHN

Ar

MeO2C

CO2Me

N N

MeR

S

HN

Ar

MeO2C CO2Me

+

(E)-42a

NaH

(2 e

quiv)

THF, r.t.

, 24

h

43

R = Me, PhAr = Ph, 4-ClC6H4

(Z)-42b

71–82%

53–54%(E/Z 4:1)

Scheme 14

N NH

SH2N

X

HDMAD

N N

SH2N

X

O

+N N

SH2N

X

O44 45 46

X = O, S

NN

N

H2NSC SH

DMADN

NN

H2NSC S

R

47 48

R

CO2Me

R = Me, Ph

NNH

N S

DMAD, Et3N

49

NH

Ar

MeN N

N

S

50

HN

Ar

Me

CO2Me NN

N S

51

NAr

Me

CO2Me

O

NH

NC

H2N

R2

COR1

S N

NC

H2N

R2

COR1

S

53

Ar = 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4, 4-EtO2CC6H4

R1 = NH2, OEtR2 = Ph, thienyl

O CO2Me52

CO2Me

CO2Me

CO2Me

CO2Me

r.t.

48–66% (45/46 9:1)

MeOH, r.t.

68–85%

MeOH, r.t.

DMAD, Et3NCHCl3, r.t.

42–71%

43–44%

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Furthermore, the reaction of quinazoline derivatives 54with DMAD affording compounds 56 was investigatedwithin a study of the varying reactivity of nitrogen andsulfur as nucleophiles with an electron-deficient ester(Scheme 15).9

Scheme 15

The reaction of DMAD with thiols 57 in water was report-ed to lead to E/Z isomeric mixtures of 58 in quantitativeyield (Scheme 16).20

Scheme 16

In 2008, DMAD was used in the synthesis of 3-substitutedthieno[3,2-b]furan derivatives 61. The Michael reactionbetween methyl thioglycolate and DMAD, followed by insitu intramolecular cyclization, afforded the 3-hydroxy-thiophene 60 in 85% yield (Scheme 17).21

The reaction of DMAD with arylidenemalononitriles 62,in the presence of potassium isothiocyanate in acetoni-trile, led to a mixture of cyanothiophene 63 and dicyano-cyclopenta-1,3-diene derivatives 64. It was proposed that

this multicomponent reaction could have been startedwith the addition of isothiocyanate ion to DMAD (Michaelreaction) followed by addition of 62 (Scheme 18).22

Scheme 18

2.2 Nitrogen as Nucleophile

2.2.1 Reactions with Tertiary Amines and Hetero-cycles

In recent years, there has been considerable interest in in-vestigations of the reactivity of nitrogen-containing het-erocycles with DMAD affording a wide range ofproducts. For example, benzothiazines and benzothiaze-pines 65 and 68 were allowed to react with DMAD inmethanol, affording the corresponding pyrrolo- and oxa-zolo- benzothiazines and benzothiazepines 67 and 70. Itwas suggested that the products were formed by the addi-tion of one molecule of DMAD to one molecule of benzo-thiazine or benzothiazepine, with elimination of onemolecule of methanol (Scheme 19).5

N

NNH2

SH

O

+

CO2Me

CO2Me

reflux, 12 hDMF

N

NNH2

S

O

CO2Me

N

N NH

S

O

CO2Me

CO2Me

54 55

56

CO2Me

92%

SHR +

CO2Me

CO2Me

H2O SR CO2Me

MeO2C

+

SR

CO2MeMeO2C

58a-(Z)R = naphthyl, s-Bu

57

58b-(E)

Scheme 17

CO2Me

SH+

CO2Me

CO2Me

1. K2CO3

2. H2SO4 SMeO2C

OH

CO2Me

60

SMeO2C

61

OCO2Me

OH59

85%

CN

CN

Ar

DMAD, KSCNS

+CO2Me

CO2Me

NC

Ar

CN

Ar

MeO2C

N

CN

CO2Me

Ar62 63 64

Ar = 4-MeOC6H4, 4-MeC6H4, 4-ClC6H4, 4-O2NC6H4, Ph

16–30% 10–15%

MeCN, r.t.

Scheme 19

N

(CH2)SMeO

MeO

R

n DMADN

(CH2)SMeO

MeO

R

n

CO2Me

CO2Me

N

(CH2)SMeO

MeO

n

O

CO2Me

H

R(Z)-67

6665

N

(CH2)SMeO

MeO

Ar

n

N

(CH2)SMeO

MeO

n

Ar CO2Me

CO2Me

N

(CH2)SMeO

MeO

n

O

O

CO2Me

H

(Z)-706968OH Ar

R = H, Me, Phn = 1, 2Ar = 2-ClC6H4, 4-O2NC6H4, Ph

DMAD

H2O, MeOH

H2O, MeOH

68–76%

69–72%

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Fodor et al.23 reported that benzothiazines 71 reacted withDMAD in acetonitrile at room temperature, affording theregioisomeric ring systems 1,5-thiazocines 73 and 75 in aratio of approximately 1:1. DMAD was found to attackeither the nitrogen or sulfur atom of 71. The key interme-diates in the formation of 5,6-dihydro-2H-1,5-benzothia-zocines 73 were most probably the zwitterions 72,whereas the unexpected formation of 5,6-dihydro-4H-1,5-benzothiazocines 75 was explained by invoking interme-diates 74 (Scheme 20).

The reaction of pyrrolopyrimidine 76 with DMAD afford-ed, depending on the reaction conditions, the trifluoro-acetylpyrroles 79 and 80 through the zwitterionicintermediates 77 and 78 (Scheme 21).24

Tetrahydropyrrolopyridines 81 and tetrahydropyridoin-doles 86 underwent piperidine ring opening under the ac-tion of DMAD in acetonitrile, alcohols or aqueous

dioxane, providing substituted pyrroles 82–85 and 87, re-spectively (Scheme 22).25,26

In 2008, reactions of quinoline derivatives with DMADwere reported. The reaction began with a Michael addi-tion of the tertiary amine in benzonaphthyridines 88 to thetriple bond of the alkyne. The intermediate zwitterion 89was further transformed by two pathways, A and B. Path-way A was conditioned by the acidic character of the CH2

group and led to ylide 90, which, by Stevens rearrange-ment (characteristic of ylides), was transformed into acry-loyl-substituted naphthyridines 92. The implementationof pathway B was caused by the nucleophilic attack of thezwitterion on the nitrile group. The intermediate 91 wasconverted into succinate 93. Naphthyridines 94 (R1 = Bn,R2 = H and R1 = iPr, R2 = Br) did not react with DMAD inmethanol at room temperature, whereas reflux led to theelimination of benzyl or isopropyl substituents and theformation of N-substituted derivatives 95 (Scheme 23).27

Scheme 20

N

SMeO

MeO

DMAD

MeCN, r.t.8–10 d

71R

N

SMeO

MeO

72

RCO2Me

MeO2C

DMAD

N

SMeO

MeO

74

R

MeO2C

N

S CO2Me

CO2Me

R

MeO

MeO

73

N

S

CO2Me

CO2Me

R

MeO

MeO

75

R = Me, EtCO2Me

MeCN, r.t.8–10 d

30–32%

35–36%

+

Scheme 21

N NMe

MeMe

COCF3

76

DMAD N NMe

MeMe

COCF3

MeO2C

MeO2C

N NMe

MeMe

COCF3MeO2C

MeO2CMeOH

OMeH

77 78

MeCN

NH

MeMe

NMeO2C

MeO2C

COCF3

Me79

N

MeMe

NMeO2C

MeO2C

COCF3

Me

80

CH2OMe

r.t., 7 d

reflux48 h

60% 45%

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Scheme 23

Tetrahydropyridines, [c]-condensed with π-excessive pyr-role, indole, and thiophene units or with a benzene ring,were converted to either condensed azocines26 or

azonines28 under the influence of DMAD. However, in thecase of tetrahydropyridines 96, the reaction most probablybegins with the addition of the nitrogen atom of the tetra-hydropyridine moiety of 96 to the triple bond of DMAD,resulting in the formation of an ammonium zwitterionleading, finally, to compounds 97, 98 and 99 (Scheme24).29

Scheme 24

Analogous opening of the tetrahydropyridine ring was ob-served by the reaction of thiazolo- and thiadiazolo-condensed pyridopyrimidines 100 and 102 with DMADin methanol, at temperatures from –15 to –20 °C. Thesereactions led to the 5-vinyl-substituted thiazolopyrimi-dines 101 in 56–95% yields and to the thiadiazolo-pyrido-pyrimidines 103 in 20–60% yields, respectively (Scheme25).29

Scheme 22

Me

OR2

N

NH

Me

Me

Me

R1 DMADMeCN, r.t.

4-6 h NH

R1

N

Me Me82

NH

NR1

MeMeO2C

MeO2C

Me

Me

83

+

NH

R1

Me

Me

N

MeO2C

MeO2C

84

+NH

R1

Me

Me

N

MeO2C

MeO2C

Me

OR2

85R1 = CHO, COCF3, CH=C(CN)2

R2 = Me, Et, H

N

NH

OMeEt

DMAD

MeOH, r.t.

N

NH

OMeEt

CO2Me

MeO2COMe

81

86 87

MeO2C

CO2Me

MeOH orEtOH

15–25%

20–35%

35–85%

70%

DMAD4–6 h

N

CN

NR1R2

88

DMAD

N

CN

N R1R2

CO2Me

CO2Me

A

N

CN

NR1R2

CO2Me

CO2Me

92

N

NR1R2

CO2MeCO2Me

N

N

N R1R2

MeO2CNH2

93

MeO2C O

B

N

CN

N R1R2

CO2Me

CO2Me

R1 = i-Pr, Me, BnR2 = H, F, Br

89

90

91

MeOH, r.t.

13–69%

26–32%

N

CN

NR1R2

94

DMAD

MeOH, ΔN

CN

NR2

95

CO2Me

CO2Me

R2 = H, Br

R1 = Bn, i-Pr 24–47%

N

N

NOMe

RO

96

N

N

NOMe

O

97

CO2Me

CO2Me

R

DMAD N

N

NOMe

O

98

CO2Me

CO2Me

N

N

OMe

OMe

O

99

CO2Me

CO2MeN

Ph

20 °C

MeOH

78 °C

–20 °C

EtOH

MeOH

50–85%

30%

74%

R = Me, Bn, i-Pr, CH2CH2Ph

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Scheme 25

In 2012, the synthesis of various highly functionalized thi-azolopyridines 105, along with the open chain products106, was accomplished by the reactions of keto–enol tau-tomeric pairs of heterocycles 104 with DMAD (Scheme26).30

Scheme 26

It was reported that the parent Tröger base 107 reactedwith DMAD in the presence of boron trifluoride–diethyletherate to give compound 108 in 60% yield (Scheme27).31

Hydrogenated γ-carbolines 109 underwent tandem piper-idine ring cleavage on treatment with DMAD in the pres-ence of alcohols, producing 3-alkoxymethyl-substituted

indoles 112 in good yields. These compounds were cy-clized to tetrahydroazocino[4,5-b]indoles 113 in the pres-ence of aluminum trichloride (Scheme 28).32

González-Gómez et al.33 reported novel domino reactionsin β-carbolines with DMAD. Vinylpyrrolo-[2,1-a]-β-car-bolines 114 gave different products upon reaction with di-enophiles as, with DMAD, a novel domino process tookplace, involving Michael attack and rearrangement, af-fording complex polycycles like 115, 116 and 117.

In addition, the reaction of 2-allyl-1-vinyl-β-carboline118 with DMAD gave a mixture of products 119 and 120in a 1:3 ratio, 120 being an unstable product. These prod-ucts resulted from the same rearrangement reaction. Thereaction began with the nucleophilic attack on DMAD,behaving as a Michael acceptor, followed by nucleophilicattack on one unsaturated carbon which led to new poly-cycles with an increase in skeletal complexity (Scheme29).

2.2.2 Reactions with Primary and Secondary Amines

Zewge et al.34 described a mild and efficient synthesis ofthe quinoline derivatives 122 through a Michael reactionof commercially available aryl amines with DMAD in al-coholic solvents (Scheme 30).

N

N

N

S

RO

100

DMAD

MeOH, –20 °C

N

NS

O

101

Me Me

N

N

NN

S

R

O

102

MeN

N

NN

SMe

O

103

CO2Me

CO2Me

R


DMAD

MeOH, –20 °C

56–95%

20–60%

N

CO2Me

CO2Me

R


N S

R

Ph

HO

N S

R

Ph

OH

H

H

DMADr.t. or reflux N SO

MeO2C

R104a 104b 105

R = H, Me 32–70%

Ph

O

N S

R

MeO2C O

PhMeO2C

+

1069–26%

24 h

Scheme 27

N

NMe

Me

Me

Me

DMAD

BF3⋅OEt2, 110 °C N

NMe

Me

Me

Me

CO2Me

HH

MeO2C

107 108

Scheme 28

NH

109

DMAD

NH

NR2

CO2Me

CO2Me MeOH

110

R1

R1

111

N

R2

MeOH

NH

NO

R1

R2Me CO2Me

112

CO2MeN

MeO2C CO2Me

Et

NH

113

R1 = H, F, OMeR2 = Et, i-Pr, Me

AlCl3

r.t., 4–6 h

56–70%60–65%

r.t., 6 hMeOH

MeCNr.t., 24 h

NH

NR1

H

OMe

CO2Me

CO2Me

R2

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Scheme 30

Τhe reaction of primary and secondary aliphatic amines123 and 125 with DMAD, for less than two hours, in aque-ous medium afforded compounds 124 and 126, respec-tively (Scheme 31).20

Scheme 31

Reaction of 1,2-diaminocyclohexane (127) with DMADgave quinoxaline derivatives 128 and/or 129, dependingon the molar ratio of the starting materials (Scheme 32).35

Scheme 32

The reaction of diamine 130 with DMAD afforded the ni-trogen-bridgehead pyrido-triazepine 131 (Scheme 33).36

Scheme 33

In the next example, the initial Michael reaction on nitro-gen (amine group) was followed by a reaction with a thirdcomponent. Ramesh et al.37 described a simple and effi-cient three-component protocol for the synthesis of highlysubstituted pyrroles 134 by using amines 132, DMAD andglyoxal (133), with DABCO as a catalyst (Scheme 34).Highly functionalized pyrroles were also synthesized byusing amines, DMAD, triphenylphosphine and arylglyox-als.38

Scheme 34

Scheme 29

N

N

RTs

DMAD

N

N

RTs

MeO2CCO2Me

N

N

RTs

MeO2C CO2Me

N

N

RTs

CO2Me

CO2Me++

115 116 117114

R = H, Me

N

N

Ts

DMAD

118

N

N

Ts

CO2Me

CO2MeN

Ts

NMeO2C

MeO2C

+

119120

5% 56% 17%

(2 equiv)

r.t., 3 d

NH2

R1

R2 R4

R3

DMAD

MeOH or IPA0–50 °C

NH

R1

R2 R4

R3

CO2MeMeO2C

Eaton's reagent

NH

CO2Me

OR1

R2

R3

R450 °C, 1–3 h

R1 = OMe, Cl, H, Br, i-PrR2 = H, ClR3 = H, OMe, CO2Me, C6H11

R4 = H, Cl

121 12288–95% 90–98%

NH +

CO2Me

CO2Me

N

CO2Me

CO2Me

+ N

MeO2C

CO2Me

100% 0%(E)-126a (Z)-126b

73% 27%

NH2

+

CO2Me

CO2Me

HN CO2Me

CO2Me

HN CO2Me

MeO2C

123 (E)-124a (Z)-124b

H2O+

H2O

125

NH2

NH2

DMAD

NH

N

O OMe

O

H

NH

N

O OMe

O

H

CO2Me

CO2Me

128 129127reflux, 30 min

65% 82%

DMAD

reflux, 1 hMeOH MeOH

N

O

NH2

NH2

NC

CNCl

130

DMADN

OHN

NH

NC

CNCl

131

CO2Me

ODMF

reflux, 8 h

76%

CHO

CHON

R

CO2Me

CO2Me

HO

MeCNR

NH2

+ DMAD +DABCO

R = H, F, Cl, Br, NO2, Me, OMe, i-Pr

132 133

13475–91%

50–55 °C

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In 2011, three-component reactions involving 3-amino-carbazoles 135, DMAD and aromatic or aliphatic alde-hydes affording carboline derivatives 137 and 138 weredescribed (Scheme 35).39

Although the reaction of thiosemicarbazones with DMADwas used for the synthesis of thiazolidinones9 (Scheme 5),Vijesh et al.40 reported the synthesis of imidazole deriva-tives 141, containing a substituted pyrazole moiety, by re-flux of the thiosemicarbazones 140 with DMAD inmethanol (Scheme 36).

Scheme 36

Moreover, reaction of thiosemicarbazide 142 withDMAD, either in hot methanol or in a solventless systemunder microwave irradiation (Scheme 37), afforded thetriazine derivative 143.41

Scheme 37

The reaction of DMAD with guanidines 144 yielding thefive-membered imidazolin-4-ones 145 was also reported(Scheme 38).42

Scheme 38

The biological activity of 1,4-diazepine derivatives hasbeen widely explored. Zaleska et al.43 studied the forma-tion of new tricyclic ring systems of fused 1,4-diazepines.They found that reaction of the zwitterionic compound146 with DMAD led to the formation of diazepine 149, in57% yield, through a Michael reaction (Scheme 39).

Scheme 39

Scheme 35

138

135

137

136

N

NH

R2

OO

MeO2C

R1

+

CHO

DMAD

N NHMe Bu

BF4–

N

NH2

R2

N

N

R2

R1

N

CO2Me

MeO2C

N

R2

R1HCHO

KOH

R4

R3

R4

R3

R1 = H, Cl, BrR2 = Et, Me, BnR3 = H, Cl, BrR4 = NO2, F, Cl, Br, Me, OMe, H

R1

60–90%

75–85%

NNH

ArO

NH2NHCSNH2

EtOH, reflux, 8 hN

NH

ArN

HN

NH2

SDMAD

MeOH, reflux, 1 h

N

HN

ArN

NHN

S

OOMeO139 140

141Ar = 2,4-Cl2C6H3, 4-MeSC6H4, 2,5-dichlorothiophenyl, 4-MeC6H4

80–86%

143

H2NNH

NH2

S

DMAD

HNNH

HN OS

CO2Me

H

hot MeOH or MW

142

85%

N N

N NH2

NHR1

R2

Me Me

DMAD

N N

N NH

N

R1

R2

Me Me

O

OMe

O

144 145

R1 = H, 3-Me, 3-MeO, 3-ClR2 = H, 2-Me, 4-Me, 4-MeO, 4-EtO, 4-Et, 3-F, 4-F, 4-Ph, 4-Bu, 4-Cl, 2-MeO

29–65%

r.t., 1 hCHCl3

146

HN NH

MeOH

SN

DMADN NH

MeOH

S

N

Ph

CO2Me

CO2MePh

N N

N

O

O

Me

S Ph

CO2Me

147

149

reflux, 40 minMeOH

57%

148

N NH

N

O

MeS

Ph

CO2Me

CO2Me

– MeOH

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2.3 Oxygen as Nucleophile

Humphrey et al.44 reported that Michael reaction of oxime151 afforded, through oxygen, a Z/E mixture of adducts152 (Scheme 40). The final target of this synthesis was anHIV integrase inhibitor.

Scheme 40

Furthermore, a gold-catalyzed approach for the regiose-lective synthesis of highly substituted pyrroles 155 direct-ly from oximes 153 and DMAD was recently developed(Scheme 41).45

2.4 Addition to Carbon–Carbon Double Bonds

Nitrogen heterocycles containing phosphorus functionalgroups are compounds of interest in many areas of indus-trial chemistry such as the textile, pharmaceutical, and ag-ricultural fields.46 A useful strategy for the preparation ofsuch compounds is based on the cyclization of functional-ized enamines. β-Enamine phosphine oxides were pre-pared by a one-pot process involving the sequentialreaction of triphenylphosphine oxide with methyllithiumand then with alkyl and aryl nitriles. The enamines addedregioselectively, through the β-carbon, to the carbon–carbon triple bond of DMAD with a stereoselectivity thatdepended on the substituent of the enamine. Heating thephosphoryl enamines afforded phosphorus-substituted 2-pyridones 159 and 2-pyrrolidones 160 in good to excellentyields (Scheme 42).47

A general and versatile high-yielding method for the di-vergent and diastereoselective synthesis of polyhydroxyl-ated indolizidines such as 163 has been established usingDMAD. At ambient temperature, the reaction of 161 withDMAD proceeded rapidly to form a yellow-colored com-pound, which was isolated and identified as the adduct162 (Scheme 43).48 In warm methanol, 162 was convertedinto 5-indolizinone-7,8-dicarboxylate in 88% yield; thiswas then itself converted into the polyhydroxylated indol-izidine 163 in good yield through practical hydrogenationand reduction reactions.

Scheme 43

The indole ring system exists ubiquitously in natural prod-ucts and many indole-containing compounds exhibit im-portant biological and pharmaceutical activities. o-Alkynylanilines 164 reacted with DMAD under the catal-ysis of platinum(II) chloride to generate the correspond-ing 2,3-disubstituted indoles 165 (Scheme 44). Thereaction proceeded by a sequential cyclization–intermo-lecular addition pathway.49

Scheme 44

Indigotin (166) is the major chemical constituent of indi-go, which has been used as a dyestuff for at least 4000years. The reduced monomeric unit of indigotin, 3-hy-droxyindole (167) is much less studied owing to its easyoxidative dimerization to indigotin 166. The pyrrolone de-

Me CN

Me OH

Me

Me NH

NOH

NH2

DMAD Me

Me NH

NO

NH2

Cbz

MeO2CCO2Me

150

151

CHCl3

152

Cbz

99% (Z/E 65:35)

Scheme 41

R2

R1

NOH

+

CO2Me

CO2Me

Ph3PAuCl (10 mol%)AgOTf (10 mol%)

toluene, 35 °C, 18 h R2

R1

NO

CO2Me

CO2Me

Ph3PAuCl (10 mol%)AgOTf (10 mol%)

toluene, 100 °C, 12–18 hNH

R1

R2

CO2Me

CO2Me

153 154 15551–89% 59–88%

Scheme 42

Ph2PMe

R1 NH2

HPh2P

NCOPh DMAD

CH2Cl2, 25 °C

R1 NH2

Ph2P

NCOPh

HMeO2C

MeO2C

NH

Ph2P

NCOPh

CO2Me

O R1

+

NH

O

Ph2P

NCOPh

H

MeO2C

toluenereflux

159 160

158

157156

R1

80–90%

40% 60%

NH

OO

Me Me

CO2Me

DMAD

MeOH, r.t. NH

O

OMe

Me CO2Me

CO2Me

CO2Me

161 162

NHO

HO CH2OH

CH2OHH

163

R2

NH2

+

CO2Me

CO2Me

PtCl2

THF, reflux NH

R2

164

R1 R1

CO2MeMeO2C

165

R1 = H, Me, Cl, NO2

R2 = H, TMS, Ph, Bu

40–85%

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rivative 168, a monomeric unit of indigotin 166 with thebenzene ring being replaced by a heterocyclic ring, under-went a Michael reaction with DMAD, giving 169 (30%)as a single isomer. Reactions of 1-substituted pyrrol-3(2H)-ones with DMAD could also take place at the cor-responding 2-position, though the tautomeric nature of theproduct was different (Scheme 45).50

Scheme 45

3 Cycloaddition Reactions

As previously stated, DMAD is a powerful dienophilewidely used in cycloaddition reactions. The most impor-tant examples of cycloadditions are the Diels–Alder reac-tions, in which very often DMAD is used as a standard tocheck the efficiency of various dienes, and also the 1,3-di-polar cycloaddition reactions. Moreover, [2+2] cycloaddi-tions involving DMAD are also reported. There are alsosome examples of other cycloadditions, such as [8+2], in-volving this useful alkyne diester (Scheme 46).

Scheme 46

3.1 Diels–Alder Reactions ([4+2] Cycloaddi-tions)

3.1.1 Reactions with Dienes and Triple Bonds

An important strategy for the construction of aromaticsystems or heterocyclic cores in one stage relies on the[4+2] cycloaddition of 1,3-dienes with DMAD and this isusually followed by an oxidation. The reaction of DMADwith various dienes leading to the preparation of function-alized arenes and heterocycles are numerous since as it iswell known that they represent important building blocksin organic and medicinal chemistry.51 As an example the[4+2] cycloaddition of trimethylsilyloxy-1,3-diene 170with DMAD afforded dimethyl 4-chloro-3,5-dihy-droxyphthalate 172 (Scheme 47).52

Kotha et al.53 introduced a new method for the synthesisof constrained phenylalanine derivatives. The Diels–Alder reaction of the diene 173 with DMAD, followed byoxidation of the resulting cycloadduct, gave highly substi-tuted phenylalanine derivatives 175 (Scheme 48).

Scheme 48

The reaction of 176 with DMAD afforded a new Diels–Alder adduct 177 in 58% isolated yield (Scheme 49).However, when the reaction was carried out with 1,1,2,2-tetracyanoethylene (TCNE) under the same reaction con-ditions, no reaction was observed.54

Dendralenes are cross-conjugated hydrocarbons thatquickly became attractive starting materials for organicsynthesis. The following example shows a diene-trans-missive Diels–Alder addition of DMAD to dendralene178. The process could be stopped at the mono adductstage 179, but it could also be performed, under harsherconditions, to yield directly the 2:1 adduct 180 (Scheme50).55

NH

HN

O

O166

NH

OH

NH

O

167a 167b

NH

OH

NH

O

168a 168b

SS DMAD

NH

O

169

S CO2Me

CO2MeDMSOr.t., 1 h

30%

CO2Me

CO2Me

a ba

b c

d

Diels–Alder

a b

MeO2C CO2Me

c

ba

d CO2Me

CO2Me

a b c

ac

b

MeO2CCO2Me

[2+2]

[3+2]

Scheme 47

OEtCl

170

2. HCl

CO2Me

CO2Me

OH

Cl

HO

171

CO2Me

CO2Me

OTf

Cl

TfO

172

1. pyridine CH2Cl2, –78 °C

2. Tf2O –78 to 0 °C, 4 h

TMSO OTMS 1. DMAD –78 to 20 °C, 20 h

87%

OAc

NHAcMeO2C

173

DMAD

toluenereflux, 36 h

OAc

CO2Me

CO2Me

AcHN CO2Me

DDQ

benzene

OAc

CO2Me

CO2Me

AcHN CO2Me

175174

reflux, 48 h

40% 80%

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Scheme 50

Ferrocenophane 181, obtained by the ene–yne metathesismethod, possessing a conjugated diene functionality in thebridging side chain could be further modified via a Diels–Alder cycloaddition with DMAD, in a highly diastereose-lective fashion, affording compound 182 (Scheme 51).56

Scheme 51

Nair et al.57,58 reported the facile Diels–Alder reaction ofcompound 183 with DMAD affording a hexasubstitutedbenzene derivative 184 (Scheme 52).

Scheme 52

DMAD is often used in natural product synthesis in keytransformation steps. A recent example presenting astereoselective synthesis of marine sesterterpenes 188 and189 included a Diels–Alder addition with DMAD(Scheme 53).59

Scheme 53

Sher et al.60 showed that the reaction of compound 192with DMAD, in the presence of a catalytic amount of p-toluenesulfonic acid (PTSA; 5 mol%), afforded 193(Scheme 54).

Scheme 49

Me

NMe

Me

Me

Me

Me

Me

NMe

Me

Me

Me

Me

DMAD

tolueneargon, reflux

176

MeO2C

CO2Me

17758%

DMAD, benzene

reflux ,12 h

CO2Me

CO2Me

179178

DMAD, toluene CO2Me

CO2MeMeO2C

CO2Me

18080% 72%

reflux, 24 h

Fe DMAD

toluene90 °C, 12 hMe

t-Bu

t-Bu

181

Fe

Me

t-Bu

t-Bu

182

MeO2C

CO2Me

93%>98% selectivity

Ph

H Ph

PMP

CO2Me

CO2MePh

H Ph

PMP

183 184

1. DMAD, toluenesealed tube, 12 h

2. DDQ, CH2Cl2 6 h

65%

Me Me

Me

OHMe

OHMe

Me Me

MeCHO

Me

OH

186

Me Me

Me

Me

Me

187

DMAD110 °C, N2 sealed tube

24 h

Me Me

Me

Me

BnO

188

CO2Me

CO2MeMe

+

Me Me

Me

Me

BnO

189

CO2Me

CO2MeMe

sclareol (185)

OBn

Me

26% 52%

Scheme 54

R1

OR2

O O

190

+ ArAr

O

O

LDA

THF ArOH

R1CO2R2

Ar

O

191192

PTSA

Ar

R1CO2R2

Ar

O

193

DMAD

MeO2C CO2Me

CO2R2R1

Ar Ar

R1 = H, EtR2 = Me, Et, i-PrAr = Ph, 4-MeC6H4, 4-MeOC6H4

– CO32–60%

33–86%

toluene100 °C

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The Diels–Alder reaction of α-tropolone 194 withDMAD, promoted by triethylamine or silica gel, yieldedadduct 195 as reported by Okamura et al. (Scheme 55).61

Scheme 55

The synthesis of 198 commenced with 1,6-metha-no[10]annulene 196, which added DMAD via its ring-closed bis-norcaradiene valence isomer (Scheme 56).62

Scheme 56

DMAD has also been employed in materials synthesis.Recently, a Diels–Alder reaction of compound 199 withDMAD affording compound 200, a useful intermediatefor the synthesis of photoalignment layers for liquid crys-tals, was reported (Scheme 57).63

Allenes, by virtue of their reactive and cumulative doublebonds, are excellent partners for both [4+2] and [2+2] cy-

cloadditions. Allenylphosphonates (phosphorylated al-lenes) and allenylphosphine oxides constitute a class ofcompounds that are more readily accessible (and inexpen-sive) than most of the other allenes.64,65 Allenes 201(R = Ph, p-tolyl, bromophenyl, p-anisyl) with a terminal=CH2 group gave products 202–204. Even more interest-ing was the reaction of vinyl allenes 205 with three equiv-alents of DMAD that led to products 206–209 (Scheme58).66

DMAD was also used recently in a transition-metal-medi-ated annulation in which polyfunctionalized arenes wereconstructed. This strategy is based on an enyne metathesisfollowed by Diels–Alder cycloaddition and oxidation.Treatment of diphenylacetylene (210) with the second-generation Grubbs catalyst and DMAD, in the absence ofadditives, gave a mixture of 211, resulting from enynemetathesis, and the non-metathesis product 212 (Scheme59).67

OOH

DMAD

SiO2, 50 °C

O

HO

CO2Me

CO2Me194

19550%

196 197

DMADCO2Me

CO2Me CO2Me

CO2Me

– 198

Scheme 57

TMS

TMS

1. TBAF, THF, 12 h, r.t.

2. DMAD, reflux, 12 h

MeO2C

MeO2C

199 20072%

Scheme 58

C

H

HPO

O

OMe

Me

201

p-xylenereflux, 12 h

R

P

O

O O

Me

Me

R

CO2Me

CO2Me

Me

P

O

O O

Me

R

CO2MeCO2Me

CO2Me

CO2Me+

202 203

+

P

O

O O

MeMe

R

CO2MeCO2Me

204

P O

O

O

Me

Me

DMAD (3 equiv)

Me

55–65% 10–15% 20–25%R

C

HP

O

O

OR

R

205

p-xylene, reflux

206 207

+

208Me

CO2Me

CO2MeP

OO

O

RR

CO2Me

CO2MeP

OO

O

RR

MeO2CCO2Me

P

OO

O

RR

CO2Me

CO2Me

P

OO

O

RR

CO2Me

CO2Me

209

+ + DMAD (3 equiv)

22–28% 13–15% 40–43%

R = H, Me, Br, OMe

R = Me, Et

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Scheme 59

3.1.2 Reactions with o-Quinodimethanes

The elusive intermediate o-quinodimethane, also namedo-xylylene, has attracted much attention from both theo-retical and synthetic chemists over the past 30 years. Ascis-dienes, o-quinodimethanes have a remarkable Diels–Alder reactivity and are often used as building blocks inthe syntheses of cyclic organic compounds by inter- orintramolecular [4+2] trapping.

As an example, the efficient procedure for the generationof the imidazole-4,5-quinodimethane intermediate 214,from imidazole derivative 213 and its first-time capture byDMAD to afford the corresponding Diels–Alder benz-imidazole adducts 215 and 216, was reported (Scheme60).68

Bicyclic o-quinodimethanes were also prepared from thetricyclic sulfones 217. However, reactions had to be car-ried out by heating the sulfones with an excess amount ofDMAD, in the absence of solvent at 250–320 °C, in orderto afford the corresponding cycloadduct 219 (Scheme61).69

Benzopentathiepins 220 reacted slowly with DMAD togive the benzodithiins 221 as the only reaction products,with the reaction being greatly accelerated by the additionof triphenylphosphine. The pentathiepin 222 also reactedwith DMAD in the presence of triphenylphosphine in di-chloromethane, at room temperature, to give the 1,4-dithi-in 223 in 78% yield. Triphenylphosphine presumablyinitiates the reaction by nucleophilic attack on sulfur,opening the pentathiepin ring 220 and removing sulfur at-oms, possibly to give intermediate 224,70 which is inter-cepted by DMAD (Scheme 62).71

Scheme 62

3.1.3 Heterocycles as Dienes

Functionalized arenes 227 were also synthesized throughsubstituted α-pyrones 226, which have been used as im-portant synthetic intermediates72 and are found in a widevariety of biologically interesting natural substances(Scheme 63).73

Scheme 63

Ph

Ph

1. Grubbs II additive CH2=CH2 (1 atm) toluene, 24 h

2. DMAD, 24 h3. DDQ

Ph

Ph

CO2Me

CO2Me

+

Ph

Ph

CO2Me

CO2Me

210 211 21222% 48%

Scheme 60

N NNAr

MeBr

CH2BrBrH2C

NaItoluene

18-crown-6N NN

Ar

Me Br

213 214

DMAD

N NNAr

Me Br215

MeO2C CO2Me

N NNAr

MeBr216

MeO2C CO2Me

+

Ar = 4-BrC6H435% 44%

Scheme 61

SO2 DMAD

n

217

n

CO2Me

CO2Me

n

CO2Me

CO2Me

218 219

n = 2, 3

250–320 °C15–20 min

15–65%

S S

S

SSRDMAD

R

S

S CO2Me

CO2Me

221220

S S

S

SS

S

S CO2Me

CO2Me

223222

S

Et2N

Et2N

S

Et2N

Et2N

S S

S

SS

S

S

224a220

S

S

224b

DMAD

15-84%

78%

225

PhCO2Me

OH

Baylis–Hillman adduct

O

Ph

R2

Me

R1

O

DMAD

Ph

R2

Me

R1

CO2Me

CO2Me

227226 R1 = Ph R2 = Ph, H

xylenesealed tube

R1–R2 = (CH2)4

94–98%R1–R2 =

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Narayan and Sarpong74 reported the reaction of DMADwith indolizinone 228, a nitrogen heterocycle recently re-ported in the literature as a very useful precursor to indol-izidine natural products, pharmaceutical agents and newmaterials. It was supposed to give the product 229; this,however, proved to be unstable and afforded instead theretro-Diels–Alder product 230 (Scheme 64).

Scheme 64

It has been known for a long time that the reaction of al-kynes with heterocyclic dienes, such as furans, results inthe formation of bridged oxacycles, which can be trans-formed into functionalized benzene derivatives by acidichydrolysis. Diels–Alder reactions of 4-substituted 2-(2-furyl)-, 2-styryl-, and 2-crotyl-3-chlorofurans such as 231with DMAD occurred exclusively on the chlorofurano di-ene moiety and not on the non-chlorinated furano diene orthe chlorinated exocyclic diene alternatives, demonstrat-ing the predominance of the halogen effect in the furanDiels–Alder reaction as shown by Ram and Kumar.75,76

For example, chlorobifuryl, having a chlorofuran ring anda non-halogenated furan ring, on heating with DMADgave exclusively the corresponding furylchlorophenol233 in 74% yield by cycloaddition to the chlorofuran ring(Scheme 65).

Scheme 65

Moreover, Diels–Alder reactions of furano derivativessuch as 234 with DMAD affording functionalized phenols236 (Scheme 66) have been reported.77

Scheme 66

Furthermore, the reaction of DMAD at the furan fragmentof 3,4-fused 2-furyltetrahydroquinoline derivatives 237according to the [4+2] cycloaddition pattern was studied.The reaction proved not to be stereoselective, yielding

two diastereoisomeric 7-oxabicyclo[2.2.1]hepta-2,5-di-enes 238a,b in 32–88% total yield (Scheme 67).78

Scheme 67

Reactions of DMAD with pyrroles have been studied ex-tensively. The [4+2] cycloaddition between pyrroles anddienophiles has been shown to be a general method for thesynthesis of 7-azabicyclo[2.2.1]hepta-2,5-diene and7-azabicyclo[2.2.1]hept-2-ene derivatives. However, pyr-role is a poor diene for the [4+2] cycloaddition and usuallyreacts with DMAD to give Michael addition products.Moreover, when a pyrrole nitrogen atom bears an elec-tron-withdrawing group, the aromatic ring was found tobe more reactive as a diene toward DMAD.26 Neverthe-less, application of ultrasound to the reaction of pyrrole239 with DMAD in an aqueous solution resulted in the cy-cloaddition adduct 240 in 60% yield without the forma-tion of Michael-type products (Scheme 68).79

Scheme 68

The [4+2] cycloaddition of 1-(alkylamino)pyrroles or 1-(alkoxycarbonylamino)pyrroles with electron-deficientalkynes was shown to follow a predictable pathway andprovide a remarkably simple route for the preparation ofsubstituted benzenes. Upon heating 241 with three equiv-alents of DMAD, benzene derivatives 243 were obtainedin good yields (50–90%; Scheme 69).79

Scheme 69

229 230228

N

Me O

DMAD

benzene reflux

N

MeOMeO2C

MeO2C

MeO2C

MeO2C

DMAD

100 °C, 10 hO

MeO2C CO2Me

Me Cl

Me

Cl

CO2Me

CO2Me

HO

231 233232

O

Me Cl

O

O

O

74%

O RDMAD

IrCl3·3H2OO

R

CO2Me

CO2Me

OH

R

CO2Me

CO2Me

236

234

235

toluene, 70 °C

25–98%R = Me, C5H11, CH2OH, OMe, Ph, 4-MeC6H4, 4-MeOC6H4, 4-O2NC6H4, 4-NCC6H4, 4-F3CC6H4, 4-FC6H4, CO2Me

N

R2

R3

R4 O

R1

237

DMAD, toluene

reflux, 10 h

N

R2

R3

R4

R1

238a (cis)

O

CO2Me

CO2Me

N

R2

R3

R4

R1

238b (trans)

O

CO2Me

CO2Me

+

N

CO2Me

DMAD

NMeO2C

CO2Me

CO2Me

240239

Me Me))), H2O

Me

Me

60%

N

NHR1

DMAD (3 equiv)

N

R1HN

CO2Me

CO2Me

242241

R4 MeR4

MeR3 R2

R3

R2

Me

R4

R2

R3

CO2Me

CO2Me

243

R1 = H, Me, Me2, CO2MeR2 = H, Me, CO2EtR3 = H, Me, Et

50–90%

CHCl3, reflux

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Pyrrolo[3,4-b]pyrrole 244 afforded the cycloadduct 245on treatment with DMAD. Oxidation of the latter with m-chloroperbenzoic acid, followed by thermolysis, gave theindole derivative 246 (Scheme 70).80

Scheme 70

3.1.4 Heterocycles with an Exocyclic Double Bond

Ikeuchi et al.81 described a ‘Cp2Zr’-mediated reaction andsubsequent copper(I)-catalyzed carbon–carbon bond for-mation for the construction of biologically attractive mol-ecules such as compounds 250. In order to examine thereaction’s utility, preliminary reactions of the latter com-pounds to obtain polycyclic heterocyclic systems were ex-amined (Scheme 71). To this end, the reaction of theallylation product 248 gave the unstable diene 249 in goodyield, through intramolecular enyne metathesis82 usingthe second-generation Grubbs catalyst (ambient tempera-ture for 15 hours); 249 was then used directly for the sub-sequent Diels–Alder reaction with DMAD at ambienttemperature for 10 hours leading to compound 250 as amajor product (250/251 = 24:1 in the case of X = NMe).

Interaction of pyrrole 252 with DMAD afforded, after ex-posing adduct 253 to air, the hydroxyindole 254 and thebis-adduct 7-vinylindole 255 (Scheme 72). The lattercompound was formed as a result of the 1,2-addition of

the primary cycloadduct 253 to a second DMAD moleculefollowed by elimination of trimethylsilanol. When the re-action was performed without solvent, under an oxygenatmosphere, indole 254 was mainly formed (254/255 =72:28).83

Indoles 257 and 259 were obtained, in 17% and 27% yieldrespectively, by reaction of 3-vinylpyrroles 256 and 258with DMAD (Scheme 73).83c

Scheme 73

2-Vinylpyrrolo[2,3-b]pyridine 261 afforded, upon reac-tion with 1.5 equivalents of DMAD, compound 262, theunexpected derivative 263, and trace amounts of an aro-matized derivative from 262. Attempts to carry out the cy-cloaddition reaction under atmospheric pressure gavesolely 262 in 30% yield. Cycloaddition of 261 to DMAD(5 equiv) led to compound 263, in low yield, due to the de-creased reactivity of the diene (22% of the starting mate-rial was recovered) and the formation of cyclodimer 264,resulting from an intermolecular hetero-Diels–Alder reac-

N

SO2C6H4-4-OMe

N BnDMAD

benzene25 °C, 4 h

N

N

SO2C6H4-4-OMe

Bn

CO2Me

CO2Me N

SO2C6H4-4-OMe

CO2Me

CO2Me

24624524484%

Scheme 71

X

TMS

TBAF

THF, r.t.X

Grubbs II (5 mol%)

CH2Cl2X

DMAD (2 equiv)CH2Cl2

X

CO2Me

CO2Me

+

X

CO2Me

CO2Me

247 248249

251 250

X = NMe, O, S

30–66%

r.t.

Scheme 72

N

OTMS

CO2Et

252

DMAD

toluenereflux N

MeO2C CO2Me

OTMSCO2Et

253

N

MeO2CCO2Me

OHCO2Et

254

+

N

MeO2CCO2Me

25528% 11%

EtO2CMeO2C CO2Me

256

DMAD

N

BnS

CO2MeH

257

N

BnS

H

CO2Me

sealed tube, 110 °C24 h

DMAD

sealed tube, 110 °C8 h

NH

S

MeO2C

NH

S

CO2Me

CO2Me

MeO2C

NH

CO2Me

CO2Me

S

MeO2C

Me

260258 259

THF

THF

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tion of 261 with itself. Similarly, 3-vinylpyrrolo[2,3-b]pyridine 265 was treated with DMAD (1.2 equiv) togive the indole derivative 266 (Scheme 74).83d

3.1.5 Hetero-Diels–Alder Reactions

The reaction of equimolar amounts of enaminones84 267with DMAD resulted to the formation of a variety of py-ran and pyrrole-3-ylidene derivatives 268 and 269(Scheme 75) having pharmacological and medicinal sig-nificance. The mechanism concerning pyran derivatives268 involves an initial [4+2] cycloaddition followed by a1,3-hydride shift, whereas for 269 an initial enamine-typenucleophilic attack of the α-carbon of 267 at the acetyle-nic carbon of DMAD is proposed.85

Scheme 75

Compound 270 reacted with DMAD under microwaveconditions to yield the pyridine derivative 273, most like-ly formed via intermediate cycloadduct 271. The latter un-derwent retroaddition via loss of methylene aniline toyield 272, the conversion of which, under the reactionconditions, led to 273 (Scheme 76).86

Scheme 76

The reaction of thiazoles 274 with DMAD gave pyridines275 through a hetero-Diels–Alder reaction and furthersulfur extrusion,87 although, in this case, extremely harshconditions were required. The activating effect of the ami-no functionality in the reaction of 2-(dimethylamino)thia-zole toward electron-poor reagents, such as DMAD, tosylisocyanate, and ketenes has been also demonstrated.88

Nevertheless, no cycloadducts were formed in these reac-tions, but only Michael-type products resulting from thefunctionalization at the 5-position of the thiazole ring.This activating effect was evident when 2-amino-4-meth-ylthiazole (276) was allowed to react with DMAD. Fromthis reaction, conducted at room temperature, a new ad-duct 277 was isolated in 42% yield, along with the thiazo-lopyrimidinone 278 formed in 30% yield. The formationof 277 was explained as the result of a [4+2] cycloadditionin which the heterocycle acts as heterodiene (Scheme77).87b

Scheme 74

DMAD

N

SO2Ph

N

MeO2CCO2Me

N

SO2Ph

N

MeO2CCO2Me

+ CO2Me

262 263

N

SO2Ph

N

264

CO2Me

OOMe

NN

N

PhO2S +

N

SO2Ph

N R

R = H, CO2Me

263

N

Me

N

265

DMAD

toluene110 °C, 24 h N

Me

N

266

CO2Me

CO2Me

261toluene

110 °C, 14 h

90 °C, 5 h

DCE

25% 28%

20%

17%

40%

Ph

O

NHR1

267

DMAD O

CO2Me

CO2Me

Ph

NHR

+N

O

CO2Me

R

Ph

O

269268

R = Ph, 4-MeOC6H4, 4-MeC6H4

toluenereflux, 13–15 h

35–42% 32–45%

270

NN

CN

Ph

DMADMW, 180 °C, 5 min N N

MeO2C

MeO2C CN

Ph– H2C=NPh

N

CO2Me

CO2Me

CN

NPhCO

CN

O

O

O273272

271

PhCO

PhCO

57%

PhCO

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3.2 1,3-Dipolar Reactions ([3+2] Cycloadditions)

Although 1,3-dipoles have been known for more than acentury, their cycloaddition reactions are nowadays pow-erful synthetic tools, providing access to highly function-alized oxygen-, sulfur- and nitrogen-containingheterocycles. The synthetic utility of these cycloadditionshas been further enhanced by the development of tandemprocesses that allow the preparation of complex mole-cules starting from relatively simple materials.

3.2.1 Azomethine Ylides

Azomethine ylides have become one of the most investi-gated classes of 1,3-dipoles.89 The substituted pyrroles280 were obtained by a one-pot reaction between quina-zolinonium bromides 279 and DMAD in 1,2-epoxybutaneas the reaction medium and acid acceptor (Scheme 78).90

Scheme 78

Bridgehead nitrogen heterocycles are important naturalproducts. Among them, indolizines have received muchattention in recent years owing to both their intriguingmolecular structures featuring 10 π-delocalized electronsand their important biological activities. These moleculeshave been used in various pharmaceutical applications.The synthesis of indolizine 282 in 53% yield, via the 1,3-dipolar cycloaddition between pyridinium bromide 281and DMAD, using Amberlite IRA-402 (OH) ion-exchange resin as a base, was recently described (Scheme79).91,92

Scheme 79

1,3-Dipolar cycloaddition of 285 with DMAD as dipola-rophile yielded the pyrazole derivative 286 in low yield.Attempts to improve the yield by insertion of a spaceryielded pyrazoles 287 and 288 as a result of overreactionin a Michael fashion with DMAD. The polymer-support-ed azomethine imines which were generated from poly-mer-supported silylnitrosoamides by a 1,4-silatropic shiftgave pyrazole derivatives. A feature of this reaction is thatno cleavage operations are required after the cycloaddi-tion. Thus, azomethine imine 290, which was generatedvia a 1,4-silatropic shift of the silyl group onto the oxygenof the nitroso group, underwent 1,3-dipolar cycloadditionwith DMAD to give the five-membered-ring adduct 291.It is interesting that the acyl group was spontaneouslyeliminated as a silyl ester and N-unsubstituted pyrazoles292 were obtained after aromatization. If a polymer is at-tached to the acyl group of 289, the versatility of the reac-tion is greatly enhanced (Scheme 80).93,94

Scheme 77

276

NS

Ph

TBSOR

N

MeO2C

CO2Me

Ph OTBS

275274

195 °C, 3 h

NS

NH2

Me

DMAD, MeCN NCO2Me

CO2MeMe

NH2

Me

S

277

R

48–73%

42%

N

NS O

CO2MeMe

30%

+

278

r.t., 1 h

DMAD (4 equiv)

R = H, alkyl, aryl

N

N

O

Cl

Me

CH2COArBr

DMAD

O

Et

O

NHMe

NCl CO2Me

CO2MeAr

O

279280

Ar = Ph, 3-O2NC6H4, 4-BrC6H4, 4-MeOC6H4, 4-ClC6H4

45–85%

N

O

Ph

BrDMAD

281

N

O

PhCO2Me

CO2Me

282

H2O, CHCl3IRA-402(OH)

Scheme 80

283 284

Pol OH

O

Pol = TentaGel

+ H2N SiMe3

R

Pol N

O R

SiMe3

NO

DMAD

toluene NH

N

MeO2CCO2Me

R

286

NN

MeO2C CO2Me

R

MeO2CCO2Me

288

NN

MeO2C CO2Me

R

MeO2C

CO2Me

287

+

285

80 °C, 1 h

5–7%

11–21% 12–70%

R = H, Ph, 4-MeOC6H4, 4-FC6H4

SiMe3

NN

OR1

O R2

DMADR1 N

N

OSiMe3

O R2

NN OSiMe3

CO2MeMeO2C

R1

NH

N

CO2MeMeO2C

R1

289 290 291 292R2O

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3.2.2 Nitrones

Mlostoń et al.95 described a new method for the prepara-tion of 1,4,5-trisubstituted (imidazol-2-yl)acetates 296,based on the reaction of the corresponding imidazole 3-oxides 293 with DMAD. Formation of the products wasrationalized by a formal 1,3-dipolar cycloaddition andsubsequent oxaloyl cleavage (Scheme 81).

Scheme 81

Chakraborty and Luitel96 reported the cycloaddition of N-benzyl fluoro nitrones 298 with DMAD, accelerated byionic liquids, to afford novel isoxazoline and isoxazoli-dine derivatives 299 in a one-pot reaction process(Scheme 82).

Scheme 82

3.2.3 Azides

The 1,3-dipolar cycloaddition reaction between alkynesand azides, developed by Huisgen,97 is one of the mostpopular reactions because of the resulting five-memberedsubstituted 1,2,3-triazole heterocyclic ring. It was foundto have a wide range of industrial applications such as fordyes, photostabilizers and agrochemicals and also in thedesigning of new drugs. Adducts of azidomethylamines300 and 302 with DMAD afforded compounds 301 and303, respectively (Scheme 83).98

In 2009, a fast one-pot, microwave-assisted, solvent-freeand high-yielding synthesis of dimethyl 1H-1,2,3-tri-azole-4,5-dicarboxylate (305) by 1,3-dipolar cycloaddi-tion reaction with trimethylsilyl azide 304 and DMADwas described (Scheme 84).99

Scheme 84

Kumar and Rode100 reported the first general approach forthe synthesis of fused 1,2,3-triazolo-δ-lactams 309 usinga Huisgen [3+2]-dipolar cycloaddition reaction in water,between activated alkynes and azides such as 307 derivedfrom different amino acids, this ‘click’ reaction was fol-lowed by cyclization (Scheme 85).

Scheme 85

Semakin et al.101 reported that α-azidooximes, readily ob-tained from aliphatic nitro compounds, were cleanly con-verted into previously unknown pyrazinones 313. Here,oximes 310 reacted with DMAD via [3+2] cycloadditionat room temperature affording triazoles 311. However, thecycloaddition was accompanied by partial hydrolysis ofthe oximino group leading to carbonyl derivatives 312.This side process could be avoided by carrying out the[3+2] cycloaddition of 310 with DMAD in toluene. Ox-imes 311 were readily reduced with Raney nickel when R1

was not an ester giving the target heterocycles 313(Scheme 86).

N

NR2

R3

R1

O

DMAD

N

NR2

R3

R1

O CO2Me

CO2Me N

HN

R2

R3

R1

OCO2Me

CO2Me

293 29560–83%

H2OCHCl3

reflux, 2 h

CO2H

CO2Me

_

N

NR2

R3R1

CO2Me

296

R1, R2, R3 = alkyl, aryl294

33–64%

CHCl3, r.t., 2 h

RCHO + BnNHOH[bmim]BF4

r.t., 2 hN

R

H Bn

O

DMAD

[bmim]BF4

O N

Bn

MeO2CCO2Me

H

R

297298 299

89–93%R = 2-FC6H4, 2,6-F2C6H3, 3,4-F2C6H3

Scheme 83

NCH2N3

n = 1, 2

DMAD

Et2ONCH2

n = 1, 2

NN

NCO2Me

CO2Me300 301

BnN(CH2N3)2

DMAD (2 equiv)

N

Bn

N N

N

NN

N

CO2Me

CO2Me

MeO2C

MeO2CEt2O302

303

93%

61%

CO2Me

CO2Me

+ N N NMW

304305

N

NNH

CO2Me

CO2Me

77–83%

solvent-freeTMS

NH2

HO

O

OH

O

NBocMe

Me

N3 DMAD

309

308

307L-serine (306)

NN

N

O

BocN

MeMe

MeO2CCO2Me

HN

NN

NN3

O CO2Me

95%

H2O, 70 °C, 1 h

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Scheme 86

3.2.4 Nitriloxides

Tandem electrophilic cyclization, [3+2] cycloadditionand rearrangement reactions of 2-alkynylbenzaldoximes314 (R1 = H, F; R2 = Ph, 4-MeOC6H4, etc.), DMAD andbromine afforded the unexpected isoquinoline-based azo-methine ylides 315 in good to excellent yields. The prod-ucts could be further worked upon via palladium-catalyzed cross-coupling reactions to generate highlyfunctionalized isoquinoline-based stable azomethineylides (Scheme 87).102

Scheme 87

3.2.5 Diazoalkanes

In the last ten years, the range of indazole derivatives withvaluable biological activities increased substantially.Among them, agonists of estrogen receptors and dopa-mine D3 receptors, HIV protease inhibitors and new anti-inflammatory substances have been discovered. Strakovaet al.103 described the [3+2] cycloadditions of a series oftetrahydroindazoles 316 with DMAD that gave the spiroderivatives 317 (Scheme 88).

Scheme 88

3.2.6 Sulfur Dipoles

Indoles fused with the 1,2-dithiole-3-thione ring, as incompound 318, could be of interest because such com-pounds have a broad spectrum of biological activity andmay be useful synthons for many sulfur heterocycles.104 Aone-pot synthesis of derivatives 319 and 320 from 318with DMAD by 1,3-dipolar cycloaddition was reported(Scheme 89).105,106

Scheme 89

Since the famous work by Wudl et al. on tetrathiafulva-lene (TTF),107 long after dibenzotetrathiafulvalene wasfirst reported, interest in this exceptional π-donor in thefield of materials chemistry has been on a constant in-crease. DMAD, which is of particular interest due to its di-enophilic and dipolarophilic properties, in combinationwith its electrophilicity, has been widely exploited in thedevelopment of highly functionalized tetrathiafulvalenes.A one-step synthesis of tetrathiafulvalenes 321 from car-bon disulfide and DMAD, under high pressure (5000 atm)was proposed.108 Replacing carbon disulfide by carbondiselenide and carbon sulfide selenide allowed this reac-tion to be used to access analogues of tetrathiafulvalene(Scheme 90).

Scheme 90

2-Thioxo-1,3-dithioles 323, which are good precursors oftetrathiafulvalenes upon dimerization–desulfurization,can also be obtained from DMAD, carbon disulfide andeither bis(2,2,6,6-tetramethylpiperidine) disulfide orbis(morpholino) disulfide 322 at 140 °C under nitro-gen.109 This methodology is not restricted to electrophilicalkynes since it also works with terminal alkynes. Amechanism involving a 1,3-dipolar cycloaddition be-tween carbon disulfide and a transient thioketocarbenewas proposed (Scheme 91).

R2N

N3

R1

DMAD

MeCN–H2O NN

NMeO2C

MeO2C

R2

N

R1

+N

NNMeO2C

MeO2C

R2

O

R1

310

311 312

H2Ni/Ra80 °C

N

NHR2

R1

ONN

313

R1 = R2 = H; R1 = H, R2 = Me;R1 = Me, R2 = H; R1 = Bn, R2 = H; R1 = CO2Me, R2 = Me; R1 = CH2OH, R2 = H; R1 = CH2CH2CO2Me, R2 = H

OH

OH

CO2Me

58–86%

70–87%

r.t., 96 h

315314

NOH

R2

R1

DMAD

Br2, NaOAcR1

N

CO2Me

O

CO2Me

R2

Br

52–98%

CH2Cl2, r.t.

NN

N2

Me

Me

O

R

Me

316

DMAD NN

MeMe

O

R

Me

317

NNMeO2C

R = 2-pyridyl, 3,5-(CF3)2C6H3

MeO2C

56–95%

CH2Cl2, r.t.

N

R

SS

S DMAD (2.4 equiv)

benzene, reflux, 1 h N

R

S

S

S

CO2Me

CO2Me

CO2Me

CO2Me318 320

N S

S CO2Me

CO2Me

S

R

319

R= Me, Et, i-Pr, Bn

+ 320

25–35%

48–55%

100%

DMAD DMAD

CO2Me

CO2Me

+ CXY100 °C

5000 atmY

X

Y

XMeO2C

MeO2C CO2Me

CO2Me

X = Y = S or Se orX = S, Y = Se

321

90%

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Scheme 91

In 1979, Cava and co-workers suggested a modification ofHartzler’s procedure by adding a mixture of DMAD andtetrafluoroboric acid etherate, at –65 °C, to tributylphos-phine–carbon disulfide complex. The thus-formed ylidewas protonated and then trapped as its phosphonium salt326, which was isolated in 72% yield.110 This salt provedto be of high synthetic value in 1,3-dithiole and tetrathia-fulvalene chemistry, affording compounds such as the de-rivatives 327 (Scheme 92). This general scheme wasextended to the synthesis of diselenadithiafulvalene 330,the first step being a cycloaddition of DMAD to 2-thioxo-1,3-diselenolane 328. It was also used for the synthesis oftetraselenafulvalene from ethylene triselenocarbonate(Scheme 93).111

Scheme 92

Scheme 93


Reactions of enamines of cyclic ketones with DMAD canbe manipulated to achieve ring enlargement by a unit oftwo carbon atoms. The reactions proceed via [2+2] cyclo-addition and subsequent ring opening of the intermediate

cyclobutenes (Scheme 94). This becomes a valid strategyfor constructing an extended π-conjugated system whenapplied to cyclic π-conjugated enamines. This methodwas also successfully used to achieve ring enlargementsof thiophenes to thiepines, benzofurans to benzoxepines,indoles to benzazepines and pentalenes to azulenes. Di-pyrrolidinyl-annulene 332 reacted with an excess ofDMAD in refluxing toluene to give ring-enlarged annu-lene 333 (Scheme 95).112

Scheme 95

Microwave-assisted regiospecific [2+2] cycloadditions ofDMAD to derivatives 334, resulting in the formation ofbutadienes 335, were reported in 2008 (Scheme 96).113

Scheme 96

Moreover, the microwave-assisted [2+2] cycloaddition ofDMAD to imidazolidine-2,4-dione 336a, or to the corre-sponding thioxo derivative 336b, in acetonitrile, producedthe highly functionalized imidazolidine-2,4-dione deriva-tives 337 and 338 (Scheme 97).114

Scheme 97

CO2Me

CO2Me

+ N S

R2

R1

2

+ CS2N2

SMeO2C

MeO2CS

SS

MeO2C

MeO2C323322

140 oC

33%

325

327

324

Bu3P

S

S DMAD

– 65 °C

S

SBu3P

CO2Me

CO2Me

Et3N

HBF4

S

S

Bu3PCO2Me

CO2MeH

BF4

326

R1COR2

S

S

CO2Me

CO2Me

R1

R2

60–82%

329 330328

Se

X

CO2Me

CO2MeSe

SeX

DMAD– C2H4

Se

XSe

CO2Me

CO2Me

Ph3P Se

X

MeO2C

MeO2C

X = S, Se 50% (E/Z)

Scheme 94

N

H

DMAD

[2+2]

CO2Me

CO2Me

N

H

ring openingCO2Me

CO2Me

N

CO2Me

CO2Me

N

or

cis,cis-diene cis,trans-diene

S

O

O

NH

TiCl4 toluene

S

N

NCO2Me

S

CO2Me

N CO2Me

toluenereflux

331

332333

N

MeO2C

30%

DMAD(excess)

CO2Me

NHZMe2NDMAD

334

MeCN, MW

335

Z = COPh, COMe, Cbz 75–84%

NMe2 NMe2

MeO2C CO2Me

CO2Me

MeCN, MW

336 337

NH

NX

R

NMe2

ODMAD N

H

NX

RO

NMe2

MeO2C

MeO2C

338

HNN

NMe2

MeO2C

MeO2C

+O

X

R

a R = Me, X = Ob R = Ph, X = S

a R = Me, X = O, 84% (337)b R = Ph, X = S, 89% (337/338 54:46)

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The reaction of the thiazole derivatives 339 with DMADled unexpectedly to compounds 341, which resulted froma sequence of reactions initiated by a [2+2] cycloadditionof DMAD to the formal carbon–carbon double bond ofthe thiazole ring (Scheme 98).115

Scheme 98

Sajna et al.66 described the reaction of allenylphosphonate342 with DMAD under neat conditions to afford com-pounds 343, 344 and 345 following a plausible [2+2] cy-cloaddition (Scheme 99).


Orbital-symmetry-allowed [8+2] cycloadditions betweentetraenes 346 and tetraenophiles 348, can in theory pro-vide a straightforward approach for the synthesis of 10-membered-ring compounds. Before the year 2003, how-ever, all of the reported [8+2] cycloadditions were limitedto geometrically constrained tetraenes (such as heptaful-venes, tropones, and indolizines), in which the terminalcarbons or heteroatoms at positions 1 and 8 were rigidlyheld in close proximity.116

Kuznetsov et al.117 reported that although 5-bromoindoli-zine 350 was found to be passive toward nucleophiles, itsreaction with DMAD led to cycl[3.2.2]azine 351 in 87%yield, through an [8+2] cycloaddition (with HBr elimina-tion). This [8+2] cycloaddition of dienophiles, across po-sitions 3 and 5, is a well-known type of indolizinereactivity (Scheme 100).

In 2003, it was reported that dienylisobenzofurans 352could react with DMAD to furnish, as the major products,[8+2] adducts possessing the 11-oxabicyclo[6.2.1]undec-ane ring system 353.118a It was later noted that dienylfu-rans 354 could also participate in [8+2] cycloadditionswith DMAD, affording compounds 355 (Scheme 101).118b

Scheme 101

These [8+2] cycloadditions provided a direct approach forthe synthesis of ring skeletons such as eleutherobin, bri-arellins and other natural products that have anticancer ac-tivity. Ten-membered-ring compounds with an oxygenbridge can also be readily synthesized through these [8+2]cycloadditions.

Roy and Ghorai119 reported a one-pot three-componentcoupling of o-alkynylheteroaryl carbonyl derivatives 356

N

S

R

Me2N

339

DMAD

MeCN, 25 °C, 6 dN

S

R

Me2N

340

CO2Me

CO2Me

H

N

CO2Me

CO2Me

Me2N R

341

R = Ar, Me, CH=CHAr 36–91%

Scheme 99

+C

Me

MeP

H

O

O

OMe

Me

342

150 °C, 24 h

343

P

O

O

OMe

Me

344

Me

Me

MeO2C CO2Me

PO

O

OMe

Me

MeO2CCO2Me

Me

Me

H

345

+ DMAD P

H

O

O

OMe

Me

Me

MeO2C CO2Me

neat

20% 10% 15%

Scheme 100

346 347

X

DMAD

XCO2Me

CO2Me

N

DMAD N

MeO2C CO2Me

X

X

348349

N

Br

Me

Me

Me

Me

350

DMAD

80 °C, 2 h

N

Me

Me

Me

Me

351

MeO2C CO2Me

O

R1 OMe

R2

R3

R4

DMADO

R1 OMe

R2

R3

R4 CO2Me

CO2Me

O

R1 R2

R3

R4

R5

DMADO

R1 R2

R3

R4

R5 CO2MeCO2Me

R1–R2 = -(CH2)4-, H-HR4–R5 = -(CH2)4-, H-HR5 = H, Me, OMe

352 353

354 355

dioxane, 80 °C

58–78%

dioxane, 85 °C

H

R1 = H, Me, Bu, TMSR2–R3 = -(CH2)3-, -O(CH2)3, Me-HR4 = Ph, 2-benzofuryl

39–76%

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with α,β-unsaturated Fischer carbene complexes andDMAD, leading to the synthesis of heterocyclic analoguesof furanophane derivatives 358 through an [8+2] cycload-dition reaction (Scheme 102).

Scheme 102

4 DMAD and the Generation of Zwitterions; Multicomponent Reactions (MCRs)

Zwitterions are transient intermediates formed by the ad-dition of neutral nucleophiles to electrophilic receptors.Zwitterions are a unique tool in organic synthesis leadingto a variety of heterocycles. These reactive intermediatescan be captured by suitable substrates (e.g., nucleophiles),after a series of transformations. In fact, it was found thatin the case of acetylenedicarboxylate, three reaction pathsare possible (paths A, B and C). Basically, in both paths Aand C the nucleophile is added irreversibly, leading to amulti-component reaction. On the other hand, in path Bthe nucleophile gets eliminated from the system, and thusplays a catalytic role, conducting a two-component reac-tion. Path B usually involves nucleophiles, such as phos-phines and tertiary amines such as pyridines andquinolines, while paths A and C involve mainly nucleo-philic heterocyclic carbenes (NHCs) and isocyanides(Scheme 103).

Scheme 103

4.1 Phosphines and Derivatives

The importance of organophosphoric compounds as re-agents in organic synthesis and as transition-metal-cata-

lyst ligands has been very actively studied and proven inorganic laboratories in recent years. Particular attentionhas been paid, by synthetic researchers, to both the prop-erties and the reactive behavior of phosphorus ylides in amultitude of applications in natural product synthesis,which is of course vital in biomedicinal chemistry andpharmaceutical design. Phosphorus ylides, endowed byunique electronic and molecular structures, are classed asspecial zwitterions, useful in diverse reactions. They arecharacterized by electron-rich carbanions, decisively nu-cleophilic; thus availing themselves to deployment asstarting reagents in organic synthesis projects. Most im-portantly, phosphorus ylides are readily obtainable fromabundantly available inexpensive reagents and have beencorrespondingly researched in depth with respect to theirreactive properties and their potential in both reagentpreparation and industrial-level organic synthesis. Ylidepreparation usually involves the treatment of a phospho-nium salt (normally from phosphine and an alkyl halide)with a base. Phosphines and DMAD in the presence of or-ganic acids could also be used for the preparation of ylides(Scheme 104).120

Scheme 104

4.1.1 Reactions of Triphenylphosphine, DMAD and C–H Acids

There are many studies on the reaction between trivalentphosphorus nucleophiles and acetylenic esters in the pres-ence of C–H acids. In some cases the ylide products arestable, but in other cases they cannot be isolated and ap-pear to occur as intermediates on the pathway to an (even-tually) observed product.

Stabilized phosphorus ylides have also been isolated fromthe related reactions of triphenylphosphine, DMAD andacyclic and cyclic 1,3-diketones. The reaction of DMADwith keto-nitriles 360 in the presence of triphenylphos-phine (359) led to the stabilized phosphorus ylides 361(Scheme 105).121

The reaction of trifluoro diones 362 with DMAD, in thepresence of triphenylphosphine, provided a simple one-pot reaction for the synthesis of polyfunctionalized tri-fluoromethylated cyclobutene derivatives 363 via an intra-molecular Wittig reaction in high yield (Scheme 105).122

2-Acetylbutyrolactone (364) underwent a smooth reactionwith triphenylphosphine and DMAD to produce stabi-lized diastereomeric phosphorus ylides 365 possesing twostereogenic centers. These compounds underwent, in boil-

N

R

O

Me

Cr(CO)5

OMe

N

ODMAD

N

O

Me

OMe

MeO2C

CO2MeRR

Me

OMe356 357 358

R = Ph, 4-MeC6H4

Cr(CO)3

THF, reflux THF reflux, 2 h

+

CO2Me

CO2Me

a b

a b

a b

CO2Me

NuR

CO2MeR Nu Nu

ba

CO2MeMeO2C

R

MeO2C

CO2Me

a bMeO2C

CO2Me

a bH+ R1 Nu

Nu

Rb

a

CO2Me

CO2Me

or

zwitterion

nucleophile gets eliminated

path A

path B

path C

Ph3PCO2RRO2C

RO2C

CO2RPh3P

A-H = C–H, N–H, O–H or S–H acid

Ph3P C CH

CO2R

CO2R + A

Ph3P

RO2C CO2R

A

H

A-H

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ing benzene, an intramolecular Wittig reaction to producehighly strained spiro compounds 366 which spontaneous-ly underwent ring-opening to produce functionalized 1,3-dienes 367 (Scheme 105).123

On the other hand, 3,4-diacetylhexane-2,5-dione (368) inits reaction with DMAD, in the presence of triphenylphos-phine, underwent a diastereoselective intramolecularWittig reaction to produce the cyclopentene derivative369 in good yield (Scheme 105).124

4.1.2 Reactions of Triphenylphosphine, DMAD and N–H Acids

Reaction of the reactive 1:1 intermediate adduct of triphe-nylphosphine and DMAD with 3-chloroindole-2-carbal-dehyde (370)125 led to a vinylphosphonium salt whichunderwent an intramolecular Wittig reaction to producethe corresponding pyrrole derivative 372 (Scheme 106).Moreover, the reaction of the 1:1 triphenylphosphine–DMAD adduct with some other N–H acids delivered thecorresponding pyrrole derivatives via an intramolecularWittig reaction.

The reaction of arylsulfonamide derivatives of 2-amino-benzaldehyde 373, DMAD and triphenylphosphine pro-duced dihydroquinoline derivatives 375 in excellentyields (Scheme 106).126

In addition, the DMAD–triphenylphosphine intermediatewas trapped by ethyl 1H-pyrimidine-2-carboxylate 376 tothe pyrimidine derivatives 377 and 378 in a nearly 7:1 ra-tio and overall good yields (Scheme 106).127

A series of triazene derivatives 380 with polyfunctionalsubstituents, such as the ylide moiety and ester groups,were synthesized by the reaction of DMAD with 1,3-di-aryl-1-triazenes 379 in the presence of triphenylphos-phine in ethyl acetate (Scheme 106).128

A convenient synthesis of highly functionalized phospho-rus ylides was achieved by the reaction of DMAD with N-phenylacetamides 381 in the presence of triphenylphos-phine. The intramolecular cyclization of ylide 382 in tol-uene, at reflux, gave the pyrazole derivative 383 in a highyield (Scheme 106).129

4.1.3 Reactions of Triphenylphosphine, DMAD and O–H Acids

Johnson and Tebby130 established the intermediacy of azwitterion in the reaction of triphenylphosphine withDMAD, which proved to form the basis of a wide varietyof later transformations. These zwitterionic species wereshown to undergo annulation reactions with electrophiles,such as aldehydes, α-keto nitriles, α-keto esters and N-to-sylimines, to provide highly substituted unsaturated γ-lac-tones and lactams.131

Recently, the reaction between DMAD and various arylaldehydes in the presence of triphenylphosphine was re-ported, leading to unsaturated γ-butyrolactone derivatives385 and highly substituted enones 386 in fairly goodyields at room temperature (Scheme 107).132

Scheme 105

Ph3P + DMAD

Ph

CN

R

O

EtOAc, r.t., 2 hMeO2C PPh3

MeO2C

NC

R

O

Ph

R = Me, Et

Me

Me Me

Me

O O

OO

toluene, reflux

Me

Me

O OMe

O

Me

CO2Me

CO2Me

R CF3

O O

MeO2C CO2Me

F3C COR

362

O

O

Me

O

O

O

365

O

O

Me

O

MeO2CPPh3

CO2Me

MeCO2Me

CO2Me

Hbenzene

reflux

O

O

Me

CO2Me

CO2Me

363

359

360

361

364

366

367

368

369

88–90%

77–90%

CH2Cl2r.t., 24 h

75%

CH2Cl2r.t., 24 h

80% (mixture of diastereomers)

76%

6 h

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Scheme 107

The reaction between arylglyoxal monohydrates 387,DMAD and triphenylphosphine led to the dihydrofuranderivatives 389 by a simple and efficient method (Scheme108).133

The one-pot reaction between ninhydrin 391, amide deriv-atives 390, DMAD and triphenylphosphine led to oxacy-clopenta[a]indene derivatives 392 (Scheme 109).134 Scheme 109

Scheme 106

Ph3P + DMAD

NH

ClH

O

N

Cl

H

O

MeO2CPPh3

CO2Me

N

Cl

MeO2CCO2Me

CHO

NH

SO2Ar

CHO

N

SO2Ar

PPh3

CO2Me

CO2Me

N

SO2Ar

CO2Me

CO2Me

NHN

EtO O

NN

EtO OO

CO2Me

+

NN

EtO OO

CO2Me

CO2MeMeO2C

R1

R2 NH

NN

R2

R1

R1

R2

NN

N

R2

R1

MeO

O

PPh3

O OMe

N

O

O N

O

H

R

N

O

O

NO

R

PPh3

CO2MeMeO2C

N

O

O

NO

N

MeO2CCO2Me

O

382

383

R1 = H, Me, NO2, ClR2 = H, Cl

R = Ph, 4-MeC6H4, Bn

N

O

O

371

372

379

380

373

374

375

376

377378

381

98%

CH2Cl2r.t., 15 min

80–85%

CH2Cl2r.t., 24 h

EtOAcr.t., 20 min

75–81%

CH2Cl2r.t., 5 h

70%10%

EtOAcr.t., 24 h

toluenereflux

90–95%

75%

– Ph3PO

– Ph3PO

370

Ph3P, CH2Cl2r.t.

Ar H

O

O

MeO CO2Me

ArO

DMAD

Ar = 4-ClC6H4, 4-O2NC6H4, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 3-O2NC6H4, 2,6-Cl2C6H3

Ar

MeO2C

O

CO2Me

H384

385 386

+

48–75% 20–45%

Scheme 108

Ph3P + DMAD +

HO OH

OAr

CH2Cl2

r.t., 24 h

Ph3P

MeO2C CO2Me

O

OH

OAr

O

Ar CO2Me

HO CO2Me

Ar = Ph, 4-BrC6H4, 4-O2NC6H4

387 388 38971–85%

(cis/trans)

Ph3P + DMAD +

R NH2

O+

O

O

Oacetone

r.t., 24 h

O

MeO2CCO2Me

O

HN

R

O

390 391392

75–80%R = Me, Et, Ph

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Yavari et al.135 described a new and operationally conve-nient approach to the synthesis of 4-carboxymethylcou-marins based on the aromatic electrophilic substitutionbetween the conjugate base of a substituted phenol and avinyltriphenylphosphonium salt derived from the reactionof DMAD with triphenylphosphine. In this context, 4-car-boxyalkyl-8-formyl coumarins 394 were synthesizedfrom 2-hydroxybenzaldehydes 393 in good yields via vi-nyltriphenylphosphonium salt mediated electrophilic aro-matic substitution. The salt was generated in situ byprotonation of the reactive 1:1 intermediate produced bythe reaction of triphenylphosphine and DMAD with the 2-hydroxybenzaldehyde (Scheme 110).136

Scheme 110

Moreover, Symeonidis et al.137 reported the synthesis oflinear [6,7]-fused coumarins 396, along with a minorproduct 397, which were obtained from the reaction of[3,4]-fused phenols 395 with DMAD and triphenylphos-phine (Scheme 110). The synthesis of angular [7,8]-fusedcoumarins from the reaction of [2,3]-fused phenols withDMAD and triphenylphosphine was also reported.137

Novel spirocyclic lactones 399 and 401 were synthesizedby Nair et al.131 who carried out a phosphine-mediated re-action of DMAD with o- and p-quinones 398 and 400.The zwitterion, not surprisingly, exhibited a completepreference for the quinone carbonyl group, leaving theenone double bond intact (Scheme 111).

4.1.4 Reactions of Triphenylphosphine, DMAD and S–H Acids

Stable crystalline phosphorus ylides 403 were obtained inexcellent yields from the 1:1:1 addition reaction betweentriphenylphosphine and DMAD in the presence of 1-meth-ylimidazole-2-thiol (402). These sulfur-containing phos-phoranes 403 existed in solution as a mixture of twogeometrical isomers, owing to restricted rotation aroundthe carbon–carbon double bond resulting from conjuga-tion of the ylide unit with the adjacent carbonyl group(Scheme 112).138

Analogously, the reaction of triphenylphosphine andDMAD in the presence of thiophenol derivatives 404 pro-ceeded spontaneously, at room temperature, to producestable phosphorus ylides 405 (Scheme 112).139 The reac-tion of some other strong S–H acids with DMAD, in thepresence of triphenylphosphine, led to the correspondingphosphoranes.140

Crystalline phosphorus ylides 407 were obtained in excel-lent yields from the 1:1:1 addition reaction between tri-phenylphosphine, DMAD and N–H or S–H acids 406such as 2-amino-4-phenylthiazole, 2-amino-5-(3-chloro-benzyl)thiadiazole, 3-amino-2-methylquinazolin-4-oneand 3-amino-2-mercaptoquinazolin-4-one (Scheme113).141

OH

CHO

DMFO O

CHO

CO2Me

R3

R2

R1

R1

R2

R3

DMAD + Ph3P

R4

R5

OHO O

R5

R4

CO2Me

R5

R4 OO

MeO2C

+

R1 = H, MeR2 = H, t-Bu, Me, OMe, Cl, BrR3 = H, MeR4–R5 = OCH2O, (CH2)3

393

394

395

396

397

50 °C, 12 h

60–85%

CH2Cl2reflux, 24 h

3%

42–83%

Scheme 111

DMAD + Ph3P

O O

t-Bu

O

Ot-BuO

O

O OMe

CO2Me

401

399

400 398

O

t-Bu

t-Bu

O CO2Me

OMe

O

benzene, 80 °C benzene, 80 °C

48%

88%

Scheme 112

Ph3P + DMAD

N N

SH

Me N N

S

MeO2C

Me

CO2Me

PPh3

SH

R

hexane–EtOAc

S

R

CO2Me

CO2Me

PPh3

R = H, F

402

403

404

405

96–98%

r.t.92–95%

r.t.EtOAc

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Scheme 113

4.1.5 Reactions of Triphenylphosphine, DMAD and Oxa- or Azadienes

Waldmann and co-workers,142 wishing to synthesize com-pound collections inspired by natural products for chemi-cal biology and medicinal chemistry research, developedan enantioselective triphenylphosphine- or tributylphos-phine-organocatalyzed asymmetric [4+2] annulation be-tween electron-deficient heterodienes and acetylenederivatives. By using 3-formylchromones 408, DMADand triphenylphospine (up to 30 mol%), tricyclic benzo-pyrones 409 (X = O) were isolated in high yields; thesewere further used for an efficient synthesis of tetrahydro-indolo[2,3-a]quinolizidines (centrocountins). Analogous-ly, from the reaction of 3-formylchromone N-tosylimines408 (X = NTs) the tricyclic products 409 (X = NTs) alongwith the hydroxybenzoylpyridines 410 were formed. Fi-nally, the reaction of acyclic electron-poor oxadienes 411with DMAD and triphenylphosphine was also studied,whereupon the initially detected [4+2]-annulation prod-ucts underwent a subsequent Claisen rearrangement toyield dehydropyrans 412 (Scheme 114).

4.1.6 Reactions of Phosphine Derivatives with DMAD

The nucleophilic addition of trialkyl phosphites to elec-tron-deficient triple bonds led to highly reactive zwitter-ionic intermediates, which could be trapped by variouselectrophiles. Phosphonate esters are an important class ofcompounds obtained by the sequential addition reactionof trivalent phosphite with α,β-unsaturated carbonyl mol-ecules in the presence of C–H or N–H acids. Synthesis ofphosphonato esters 414 and 415 was accomplished via re-action between DMAD and triphenyl phosphite in thepresence of biological compounds 413 such as theophyl-line, 4-hydroxypyrimidine, 2H-3,1-benzoxazine-2,4(1H)-dione, 2-chloroaniline or 3-nitroaniline at ambient tem-perature (Scheme 115).143,144

Scheme 115

Adib et al.145 described an efficient and chemoselectivesulfonamide N-alkylation of sulfonyl ureas. The sulfonylurea derivatives, prepared in situ by the addition of an ar-

N

NNH2

SH

+ Ph3PMeO2C

PPh3

CO2Me

DMAD +

406 407

EtOAc

87%

O

N

NNH2

S

O

Scheme 114

O

O

CH

R3

R2

R1+

CO2Me

CO2Me

O

O

R3

R2

R1X

CO2Me

CO2Me

R1 = H, Me, i-PrR2 = H, OBnR3 = H, MeX = O, NTs

408 40960–92% when X = O

Ph3P or Bu3P

toluene

X

41–61% when X = NTs

O

R1

R2

R3 N

CO2Me

CO2Me

OH

410

22–35%

+

N

O OH

NH

MeO2C

MeO2C

centrocountins

R1

R2

R3

9 steps

+

CO2Me

CO2Me

R1 = H, EtR2 = Bn, Ac, EtR3 = H, CO2Me

412

r.t., 2–3 htoluene

411

54–68%

O

R2O

R1O2C

R3

Ph3P O

CO2Me

CO2Me

R2O

R1O2C

R3

O

CO2Me

CO2Me

OR2

R1O2C

Z-H

MeCN

r.t., 24 h HZ

CO2MeMeO2C

(PhO)2OP

acetone

PO(OPh)2

MeO2CZ

CO2MeH

H

P(OPh)3 + DMAD

Z = heterocyclic biological base

413

414

415

+

r.t., 24 h

85–95%

H

80–95%

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omatic amine 416 to an arylsulfonyl isocyanate 417, wereselectively alkylated to give 418 in excellent yields underneutral and mild conditions by treatment with trialkylphosphite–DMAD at ambient temperature (Scheme 116).

A three-component reaction between DMAD and trialkylphosphites in the presence of N-aryl-3-hydroxynaphtha-lene-2-carboxamide 419 led to dialkyl 2-(dimethoxyphos-phoryl)-3-[2-hydroxy-3-(arylcarbamoyl)naphthalen-1-yl]succinates 420 in excellent yields (Scheme 116).146

Protonation of the reactive intermediate produced in thereaction between trialkyl(aryl) phosphites and DMAD byC–H acids 421 such as indane-1,3-dione and N,N′-dimeth-ylbarbituric acid, led to functionalized phosphonates 422in good yields (Scheme 116).146

Deng et al.147 reported the synthesis of aryl-substituted γ-lactones 425 bearing an α-phosphorus ylide moiety, inmoderate to good yields, through the assembly of DMAD,electron-deficient aldehydes 423, and triaryl- or trialkyl-phosphanes (Scheme 117).

Scheme 117

A new class of phosphorus-ylide containing conjugateheterocycles was isolated from a mixture of colored prod-ucts of the reaction of a silylphosphine 426 and DMAD.The indigo-like bis-phosphole structure 427 appearedwith a green to blue color because of the low energy gapof the phosphole (Scheme 118).148

Scheme 118

The reaction of dihydrophosphete 428 with an excess ofDMAD was found to give the ring-expanded product 429(Scheme 119),149a fully characterized by X-ray crystalstructure analysis. A similar rearrangement was proposedin the case of 1-phenyl-3,4-dimethylphosphole (430)149b

yielding the ring-expanded product 431. However, fairlyrecently Duan et al.149c reinvestigated the reaction and es-tablished the formation of the stable ylide 432.

Scheme 119

Scheme 116

R2NH2

ArSO2NCO

CH2Cl2r.t., 2 h

Ar

SN N

H

R2O

O

R1

O

acetone

OH

HN

O

ArMeO2C

PO(OR1)2

CO2Me

OH

O

NH

Ar DMAD

Z

O O

MeO2CCO2Me

P

ZO OR1

OR1OCH2Cl2

R1 = Me, Et, i-Pr, n-BuR2 = Ph, Bn, 4-MeC6H4CH2, 4-FC6H4CH2, 2-ClC6H4CH2, Ph, 4-ClC6H5

Ar = MeC6H4, Ph

416

417

418

419

420

421

422OR1

P(OR1)3 +

85–98%

Z = ONMe

NMe,

83–87%89-95%

r.t., 24 hr.t., 20 h

R1 = Me, Et, BuAr = 2-MeC6H4, Ph

H

O

+ DMAD + R3P0 °C or r.t.

THF

O

MeO2CPR3

O

423

425

60–80%

EWG

EWG

R = Me, Et, Pr, n-Bu, 4-MeC6H4

424

2 Ph2PX

X = H, TBS

P

PMeO2C

MeO2C

O

Ph

Ph

CO2Me

CO2MeO

426

427

Ph

Ph

+ 3 DMADr.t., 3 h

THF

33–54%

P

Me Me

Ph

P

Me

Me

CO2Me

CO2Me

MeO2C CO2Me

Ph

P

Ph Ph

Ph

P

Ph

PhPh

CO2MeCO2Me

CO2MeMeO2C

DMAD (2 equiv)

430

431

428

42925%

39%

PMe

Me Ph CO2Me

MeO2C

MeO2C

CO2Me

432

22%

DMAD (2 equiv)

CH2Cl2r.t., 10 min

excess DMAD

benzenereflux, 30 min

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4.2 Amines

4.2.1 Reactions of Primary Aromatic or Aliphatic Amines

Although not quite as productive as phosphine catalysis,amines can also initiate various transformations by gener-ating zwitterionic intermediates from activated olefinsand acetylenes.

A protocol has been developed for the efficient synthesisof structurally diverse 3,4-dihydropyridin-2(1H)-ones436 and 3,4-dihydro-2H-pyrans 438 via four-componentreactions of arylamines 433, DMAD, aromatic aldehydes434 and cyclic 1,3-diketones 435 and 437, respectively.The selective formation of the very different pyridinone orpyran derivatives was found to depend on the structure ofthe cyclic 1,3-diketone (Scheme 120).150

In addition, a practical and efficient procedure for thepreparation of the polysubstituted dihydropyridines 440was developed through a unique four-component reactionof aromatic aldehydes, nitriles 439, arylamines andDMAD (Scheme 120).151

A facile and efficient synthesis of tetrasubstituted 1,4- and1,6-dihydropyridines 443 and 444 was achieved by em-ploying a three-component domino reaction usingDMAD, aliphatic amines 441 and α,β-unsaturated alde-hydes 442 in the presence of trifluoroacetic acid. Interest-ingly, regioselectivity in the synthesis of 1,4-dihydropyridines was increased by using triflic acid(Scheme 121).152

The 1,4-dihydropyridines 443 were further used for thesynthesis of fused-naphthyridine derivatives 447 and 448by reaction with aromatic amines 445 and aromatic alde-hydes 446 catalyzed by boron trifluoride–diethyl etheratein acetonitrile (Scheme 122).152

Scheme 122

Polyethylene glycol (450) and iron(III) chloride werefound to be an inexpensive, non-toxic and effective medi-

Scheme 120

Ar1CHO + Ar2NH2 + DMAD

O

OMe

Me

O

O Ar1

CO2Me

CO2Me

NHAr2Me

Mer.t., EtOH

O

OMe

Me

O

O

N O

Ar2

Ar1

MeO2C

MeO2C Et3N, EtOH

Et3N

EtOH

N

MeO2C

Ar1

R

NH2

Ar2

MeO2C

R = CN, CO2Et, COt-Bu, CONH2

NCCH2RAr1 = Ph, 4-i-PrC6H4, 4-ClC6H4, 3-ClC6H4, 3-O2NC6H4

Ar2 = 4-MeC6H4, Ph, 4-ClC6H4

Ar1 = Ph, 4-i-PrC6H4, 4-ClC6H4, 3-ClC6H4, 3-O2NC6H4, 4-MeC6H4,

4-MeOC6H4, 4-FC6H4, 4-BrC6H4

Ar2 = 4-MeC6H4, Ph, 4-ClC6H4, 3-ClC6H4, 4-ClC6H4, 4-MeOC6H4

433434

435

436

437

438

439

44036–82%

41–60%

62–85% (6:1 trans/cis)

Scheme 121

R2 H

O

TFA or TfOH

N

MeO2C

MeO2C

and/orN

MeO2C

MeO2C R2

R1

R2

R1

R1NH2 = 1°, 2° or heterocyclic amine

R2 = Me, Ph

441 442

443 444

+ DMADR1NH2 +THF, r.t.

56–83%

ratio with TFA 88:12

N

MeO2C

MeO2C

CHO

R3

NH2

R4

N

NHMeO2C

MeO2C

R1

H

H

R4

R3

N

NHMeO2C

MeO2C

R2

R1

H

H

R4

R3

R2

R1

+ +BF3⋅OEt2

+

443 445 446

447 (major)

448 (minor)

R2

H

H

54–76%

ratio from 2:1 to 4:1

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um and catalyst, respectively, for the one-pot synthesis ofhighly functionalized pyrroles 451 using bromides 449,amines and DMAD. Utilizing this protocol, various pyr-role derivatives were synthesized in excellent yields. En-vironmental acceptability, low cost, high yields and therecyclability of the polyethylene glycol are the importantfeatures of the protocol (Scheme 123).153a,b

Scheme 123

The four-component reaction of DMAD, aromatic alde-hydes 452, benzylamines 453 and malononitrile (454) ledto polyfunctionalized 1,4-dihydropyridine derivatives 455(Scheme 124).154

Scheme 124

4.2.2 Reactions of Tertiary Amines

Stereoselective reaction of various substituted phenols456 with DMAD, in the presence of a catalytic amount ofan aqueous solution of a trialkylamine 457 in dichloro-methane, led to dimethyl 2-phenoxymaleates 458 in goodto excellent yields under mild conditions (Scheme 125).155

The 1,4-dipole derived from 4,5-dimethylthiazole (460)and DMAD was shown to react readily with chromone-3-carboxaldehydes 459, resulting, after an unusual rear-

rangement, in the facile synthesis of thiazolo[3,2-a]pyri-dine derivatives 462. In some instances, tetracyclicchromenothiazolopyridines 461 were formed (Scheme126).156

Scheme 126

Pyridines and quinolines generally deserve special atten-tion owing to the variety of transformations that mediate.Following the observations made by Diels and Alder ofthe reaction of pyridine with DMAD (affording deriva-tives 465 and 466),157a Huisgen was successful in inter-cepting the 1,4-dipole 464 with phenyl isocyanate (467),leading to a pyrimidinedione derivative 470 with eventualelimination of pyridine during the course of the reaction(Scheme 127).157b

R2

O

Br + R1NH2

PEG-400

60 °C NR2

CO2Me

CO2Me

R1

R1 = Ph, 4-MeC6H4, 4-FC6H4, 4-MeOC6H4, Bn, Me, Et, or R1NH2 = NH4OAcR2 = Ph, 4-O2NC6H4, 4-BrC6H4, t-Bu

451

449

450 DMAD+

81–89%

H2O–EtOH (2:1) N

Ar

CNMeO2C

MeO2C

Bn

NH2

(NH4)2HPO4

Ar = Ph, 4-BrC6H4, 4-ClC6H4, 4-NCC6H4, 3-HOC6H4, 3-O2NC6H4, 4-O2NC6H4

452 453 454

455

ArCHO + BnNH2 + DMAD + CH2(CN)2

75–98%

Scheme 125

+ArOHr.t., 2 h

CO2MeArO

CO2Me

R = Me, Et, n-BuAr = 4-ClC6H4, 2,4-Cl2C6H3, 2-AcC6H4, 2-HOCC6H4, 2-MeOC6H4, 2-MeO-4-HOCC6H3, 1-naphthyl, 2-naphthyl, 2-O2NC6H4, 3-O2NC6H4, 4-O2NC6H4

CH2Cl2

456 457458

+DMAD R3N

84–96%

O

R3

R2

R1

O

O + DMAD +

N

S

Me

MeDME

–10 °C to r.t.

N

S

O

Me

Me

R1

R2

R3

OH

CO2MeCO2Me

O

R3

R2

R1

O

N

S

CO2Me

CO2Me

Me

Me

H

H

R1 = H, Me, Cl, NO2, BrR2 = H, MeR3 = H, Br

459

460

461

462

x

X = CHO

23–45%

5–38%

Scheme 127

NN

CO2Me

MeO2C

CO2Me

CO2Me

N

CO2Me

CO2Me

CO2Me

CO2Me

464

[1,5]-H shift

N

CO2Me

CO2Me

CO2Me

CO2Me

PhNCO

N

CO2Me

MeO2C

NPh

O

PhNCONPhN

O

Ph

O

Py CO2Me

CO2Me N

NO

O

CO2Me

CO2Me

Ph

Ph

463

465 466

467

468 469 470

DMAD

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The 1,4-zwitterionic intermediate generated from pyri-dine and DMAD was added to aldehydes 471 in a formal[2+2] manner, resulting in the facile synthesis of 2-oxo-3-benzylidenesuccinates 472 (Scheme 128).157c

Pyridine catalyzed the reaction of 1,2-diaryl diones 473with DMAD to afford diaroyl maleates 474. This un-precedented rearrangement involved a unique benzoylmigration and proceeded with complete stereoselectivity(Scheme 128).158

In 2009, an efficient synthesis of the 2H-pyridinyl-2-bu-tenedioate 476 was described via the reaction of dimethylmethoxymalonate (475) and DMAD in the presence of anitrogen nucleophile (Scheme 128).159

Maghsoodlou et al.160 reported a three-component reac-tion between aromatic ketones 477 and DMAD in thepresence of pyridines (Scheme 129).

A route towards stereoselective and regioselective halo-genated pyrido[2,1-b][1,3]oxazines 481 in high yieldswas recently described by Asghari et al.161 The productswere isolated in moderate to excellent yields through athree-component reaction involving pyridines 479,DMAD and different α-halo ketones 480 (Scheme 130).

Scheme 130

The pyridine-mediated reaction of DMAD and cyclobu-tene-1,2-diones 482 afforded selective access to eitherhexasubstituted benzene derivatives 483 or cyclopentene-dione derivatives 484, depending on the concentration ofpyridine (Scheme 131).162

Terzidis et al.163 reported an efficient synthesis of func-tionalized benzophenones 485, polysubstituted xanthones486 or pyranochromenes 487 through the reaction of chro-mones 459 and DMAD catalyzed by a pyridine derivative(4-picoline or DMAP). The outcome of the reactions wasfound to depend on both the nature of the chromone sub-stituents and the basicity of the organocatalyst (Scheme132). Pyranochromenes 487 were also isolated by usingDABCO or β-isoquinidine as organocatalysts.142

Scheme 128

+ DMADCO2Me

O

CO2Me

43-85%DME

ArAr

O

O

N

O O

ArAr

MeO2C CO2Me

MeO OMe

O

OMe

O

H2O, r.t., 4 h

Ar = Ph, 3,4-Cl2C6H3, 4-O2NC6H4, 4-MeC6H4, 4-F3CC6H4, 3-ClC6H4, 2-furyl, 2-naphthyl

476

475 471

472

473

474

CO2Me

CO2Me

HN

MeO2C CO2Me

ArCHO

ArDME, –10 °C to r.t.

–10 °C to r.t.

Ar = Ph, 3,4-Cl2C6H3, 4-MeOC6H4, 4-MeC6H4, 4-F3CC6H4, 3-ClC6H4, 4-ClC6H4, 4-BrC6H4, 2-thienyl

64–91%

92%

Scheme 129

+r.t., 6 h

CH2Cl2

N

NO

R1

R2

N

N R1

R2

O

N

O

MeO2C

OMe

477

N

R1, R2 = H, Me478

DMAD+

81–91%

also quinoline or isoquinoline

N

X CO2Me

CO2Me

YCl

Z

OEt2O–CH2Cl2

r.t., 8–24 h

N

O

CO2Me

CO2Me

YCl

Z

XH

X = H, Me, Br, ClY = Me, CH2Cl, PhZ = H, Me, Cl

++

479 480 481

50–95%

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Quinoline is widely known to form a 1,4-zwitterion withDMAD, which can be trapped by various dipolarophilessuch as compounds 489, 491, 493, 495 and 497 to yield avariety of pyridoquinoline and oxazinoquinoline deriva-tives including 490, 492, 494, 496 and 498 and 499(Scheme 133).164

The reaction of isoquinoline (500) with two equivalents ofDMAD was originally developed by Diels and Alder in1933. The reaction proceeded through the zwitterionic in-termediate 501, which then underwent a domino Michaeladdition and Mannich reaction with a second equivalentof DMAD to afford benzoquinolizine 502 (Scheme134).164b

In 1967, Huisgen et al.165 reported three multicomponentvariations of this reaction in which intermediate 501 wastrapped with several different dipolarophiles, includingdimethyl azodicarboxylate (503), diethyl mesoxalate(505) and phenyl isocyanate (507), to form the tricyclicscaffolds 504, 506 and 508, respectively (Scheme 134).

Later, some more examples were reported by Nair etal.,166–168 who used benzoquinone 509 and arylidenemalo-nonitriles 511 to obtain the spiro-isoquinoline 510 and tet-rahydrobenzoquinolizine derivatives 512, respectively(Scheme 134).

More recently, Yavari et al.169 reported a new three-com-ponent reaction in which intermediate 501 was trapped

with aroylnitromethanes 513 to give pyrroloisoquinolines514 (Scheme 134).170

Multicomponent reactions involving azines [isoquinoline(500; Scheme 135) or phenanthridine (524; Scheme 136)]and DMAD were executed in the presence of heterocyclicN–H compounds (indole, methylindole, 3,6-dibromocar-bazole) or 1,3-dicarbonyl compounds (N,N-dimethylbar-bituric acid, 1,3-diethyl-2-thiobarbituric acid,acetylacetone, 1,3-diphenylpropane-1,3-dione, cyclopen-tane-1,3-dione) 515 to generate enamino esters 516 and526 in good yields.171,172

Isoquinoline reacted smoothly with DMAD in the pres-ence of amides 517 to produce the derivatives 518(Scheme 135).173

The 1,4-dipole derived from isoquinoline and DMAD wasalso shown to react readily with N-tosylimines 519, result-ing in the diastereoselective synthesis of 2H-pyrimi-do[2,1-a]isoquinoline derivatives 520 (Scheme 135).167

Moreover, the reaction of isoquinoline 500 and DMADwith benzoquinone 521, at room temperature, afforded thespiro-oxazino isoquinoline derivatives 522 and 523 as amixture of regioisomers in a 2:1 ratio and 91% yield(Scheme 135).168

Li et al.174 described an efficient synthesis of [1,3]oxazi-no[3,2-f]phenanthridine derivatives 525 via a three-

Scheme 131

O

O

R

R

+

E = CO2MeR = 4-MeC6H4, 3,4-Me2C6H3, 4-ClC6H4, 4-BrC6H4, 2-thienyl

Py (solvent)

–10 °C to r.t.12 h

OH

R

R

OH

E

EOH

R

R

OH

E

E Py (cat)

DME –10 °C to r.t.

+

O

O

R

R

E

EE

E

482 483483 484

DMAD

65–72%10–13% 43–55%

Scheme 132

O

O

CHO

R3

R2

R1

4-picoline (20 mol%)

4-picoline or DMAPDMAP

DME, –18 °C to r.t.

DME–18 °C to r.t.

DME–18 °C to r.t.

+

CO2Me

CO2Me

O

O

H

R2

R1O

CO2Me

CO2Me

R1, R2 = EDG

O

O

R3

H

R1

CO2Me

CO2Me

R1, R3 = EWG

CO2MeO

R1

R2

H

CO2Me

CO2Me

CO2Me

OH

R1, R2 = EDG R1 = H, Me, Cl, NO2, BrR2 = H, MeR3 = H, Br

459

487

485 48657–63% 53–64%

38–51%

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Scheme 133

N

CHO

CF3

N O

MeO2C

CO2Me

H

CF3

S

O

O

S

N O

MeO2C

MeO2C

S

O

S

EtO2CCN

N

MeO2C

CO2Me

CN

CO2Et

R

Br

NO

O

N O

MeO2C

MeO2C

O

CMe3

CMe3

+ DMAD

N O

MeO2C

MeO2C

HN

Br

O

t-Bu

O

Ot-Bu

N O

MeO2C

t-Bu

O

+

(i) toluene, 110 °C sealed tube 12 h

(i)

(i)

(i)

488

489

490

492

494

495

496a + 496b

497

498

499

MeO2Ct-Bu

92%

52%

49%

N O

MeO2C

MeO2C

HN

Br

O

71% (ratio 4:1)

+

66% (ratio 4:1)

491

493(i)

(i)

Scheme 134

N+

CO2Me

CO2Me

N CO2Me

CO2Me

N CO2Me

CO2Me

CO2Me

MeO2C

N

N

MeO2C

CO2Me

N

NN

CO2Me

CO2Me

CO2Me

MeO2C

O

CO2EtEtO2C

N

O

CO2Me

CO2Me

CO2EtEtO2C

PhNCO

N

N

CO2Me

CO2MePh

O

OO

Me

Me

N

O

CO2Me

CO2Me

O

Me

Me

N CO2Me

CO2MeNC

Ar

NC

CN

CN

Ar

NO2

ArOC

N

ArOC

CO2Me

CO2Me

500501

50286%

503

50438%

505

506

507

508

509

510

511

512a

513

514

46%

70%

H

76%

H

H

DME, Arr.t., 6 h

THF, Arr.t., 23 h

N CO2Me

CO2MeNC

Ar

NC

512b

H

H

43–89%ratio from 100:0 to 1:1

H2O–MeOH r.t., 6 h

71–85%

benzener.t.

Et2Or.t.

DMAD

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component reaction of phenanthridine 524, DMAD andaromatic aldehydes (Scheme 136).

The reaction of 3-methylisoquinoline (527) with chro-mone-3-carboxaldehydes 459 and DMAD to produce

chromenopyridoisoquinoline dicarboxylates 528 was alsostudied (Scheme 137).175

Safaei et al.176 reported a novel, facile and environmental-ly benign one-pot three-component synthesis of pyrazo-lines 530 from arylaldehydes, hydrazines 529 and DMAD

Scheme 135

N+ DMAD

Y HCH2Cl2

N O

OMeO OMe

Y H

R2 NHR1

O

CH2Cl2

N

NR1

O

R2

CO2Me

CO2Me

DME, Arr.t., 3 h

N

NTs

CO2Me

CO2Me

Ar

H

43–93%

OMe

PhPh

Ph

Ph

O

O

DME, Arr.t., 6 h

N

O

CO2Me

CO2Me

O

(Ph)2HCOMe

(Ph)2HC

H

+

N

O

CO2Me

CO2MeOMe

(Ph)2HCCH(Ph)2

O

R1 = H, Me, PhR2 = H, Me, Et, CH2Cl, Ph, 3-pyridyl

Ar = Ph, 2-ClC6H4, 3,4-Cl2C6H3, 3-O2NC6H4, 2-naphthyl, 2-furyl

500

515

516

517

518

519

520

521

522 523

Y–H = heterocycle (indole, methylindole, etc.) or 1,3-dicarbonyl compound (acetylacetone, N,N-dimethyl barbituric acid, etc.)

80–95%

90–98%

r.t., 24 h

ArNTs

91%ratio 2:1

H

Scheme 136

Y–H = heterocycle (indole, methylindole, etc.) or 1,3-dicarbonyl compound (acetylacetone, N,N-dimethyl barbituric acid, etc.)

N

H

Y

MeO2CCO2Me

+ DMADY H

CH2Cl2CH2Cl2, ArO

N

H

Ar

CO2Me

CO2Me

N

Ar = 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 2,4-Cl2C6H3, 4-MeC6H4, 2-FC6H4, 3-FC6H4, 4-O2NC6H4, 2-BrC6H4

524

525 52689–96%

r.t., 24 h

55–70%

ArCHO

r.t., 15 h

Scheme 137

O

O

CHO

R3

R2

R1+

CO2Me

CO2Me

O

O

R3

R2

R1N

CO2Me

CO2MeH

X

X = CHO

Me

DME+

N

Me

R1 = H, Me, Cl, NO2, BrR2 = H, MeR3 = H, Br

459527

528

r.t., 12 h

46–54%

H

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with excellent yields and diastereoselectivities using a bi-functional Brønsted acidic ionic liquid as a safe, inexpen-sive and reusable catalyst under solvent-free conditions(Scheme 138).

Scheme 138

4.3 Isocyanides

Hundreds of multicomponent reactions have been de-scribed over the years. Isocyanide-based multicomponentreactions (IMCRs) constitute a special subclass. They areparticularly interesting because they are more versatileand diverse than the other multicomponent reactions. Thegreat potential of isocyanides for the development of mul-ticomponent reactions lies in the diversity of bond-form-ing processes available, their functional group toleranceand the high levels of chemo-, regio- and stereoselectivityoften observed. The outstanding position of IMCRs canbe traced back to the exceptional reactivity of the func-tional group of the isocyanides. No other functional groupreacts with both nucleophiles and electrophiles on thesame atom, leading to the so-called R-adduct. Winterfeldtet al. were the first to describe the reactions of DMADwith isocyanides in their pioneering work published in1969.177a A large number of IMCRs were described byDömling in his reviews.177b,c

4.3.1 Synthesis of Five-Membered Heterocycles with One Heteroatom

4.3.1.1 Nitrogen-Containing Heterocycles

The zwitterion generated by the addition of alkyl(aryl)isocyanides 531 to DMAD was trapped by benzoyl chlo-ride (532) to yield functionalized 2,5-dihydro-1H-pyr-roles 533 (Scheme 139). However, in the presence ofelectron-withdrawing groups at the para-position of thebenzoyl chloride, tetrasubstituted furans 534 were isolat-ed instead.178

The 1:2 zwitterion, generated by the addition of triphe-nylphosphine to DMAD, was protonated by trifluoroace-

tic acid and subsequently attacked by isocyanide andwater in a pseudo-seven-component diastereoselective re-action giving compounds 535 with three stereogenic cen-ters and a phosphorane group in good yields (Scheme140).179

Scheme 140

The three-component reaction of the zwitterion generatedfrom DMAD and isocyanides with various quinoneimidessuch as 536 and 538 afforded the corresponding γ-spi-roiminolactams 537 and 539 in good yields (Scheme141).180

4.3.1.2 Oxygen-Containing Heterocycles

In 2004, the three-component reaction of cyclohexyl iso-cyanide with DMAD and various aromatic or aliphatic al-dehydes 540 was reported to have gone to completion inless than two hours when carried out in ionic liquids, af-fording the expected heterocycles 542 in high yields.181

Water was reported as a novel reaction medium for thesynthesis of highly functionalized 2-aminofuran deriva-tives 542, via the coupling of aldehydes 540, with DMADand cyclohexyl isocyanide (Scheme 142).182 3-Aromaticaldehydes,183a formylindoles183b and quinoline-3-car-baldehydes183c were also found to undergo smooth con-densation with the zwitterions derived from isocyanidesand DMAD either in benzene or in acetonitrile to give thecorresponding furanyl derivatives in good yields.

Ar H

ORNHNH2

CO2Me

CO2MeN

N

CO2MeMeO2C

Ar R NN

CO2MeMeO2C

Ar R

NN

SO3H

SO3H

HSO4

HSO4

529major minor

530b

(30 mol%)

solvent-free, 100 °C++ +

66–93%530aAr = Ph, 4-ClC6H4, 4-BrC6H4, 4-MeOC6H4,

4-MeC6H4, 2-FC6H4, 2-thienyl

R = Ph, 4-ClC6H4, 4-MeC6H4, 4-MeOC6H4, Me(ratio 98:2)

Scheme 139

RNC + DMAD Cl

O

N

MeO2C CO2Me

OHO

RR = Cy, 2,6-Me2C6H3

+

531

533

75–82%

CH2Cl2, r.t.

O

MeO2C CO2Me

RNH

534

70–80%

X

RNC + DMAD Cl

O

R = Cy, 2,6-Me2C6H3, t-Bu, t-Oct

+

531

532

CH2Cl2, r.t.

X

X = Cl, NO2

532

NCCy2 + Ph3P 2 DMAD+ 2 H2OTFA

solventr.t., 24 h

N

N

O

O

Ph3P

O O

MeO2C

CO2Me

Cy

Cy535

+

95%

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Scheme 142

In addition, the reaction of 1:1 zwitterionic intermediatesgenerated in situ from either tert-butyl isocyanide or cy-clohexyl isocyanide and DMAD with 3-formylchromones459 was reported to lead to chromenylfurandicarboxyl-ates 543 or to cyclopenta[b]chromenedicarboxylates 544,depending on the nature of the chromone 6-position sub-stituent (Scheme 143).184

The reaction of alkyl isocyanides with DMAD, in thepresence of pyridine-containing carbonyl compounds 545or 547, led to the stable products 546 or 548 in excellentyields (Scheme 144).185

The reaction of DMAD and isocyanides with vicinal tri-carbonyl systems 549 and 550 produced highly substitut-ed furan derivatives 551 and 552 respectively, whereaswhen the diphenyl triketone 553 was used, the pyran de-rivative 554 was the only reaction product (Scheme145).186

The zwitterion formed from an alkyl isocyanide andDMAD reacted with acetic anhydride (555) or phthalicanhydride (556) to form methylfurans or benzo-fused spi-rolactones 557 or 558 in relatively good yields, at roomtemperature and without using a catalyst (Scheme 145).187

Reaction of tert-butyl isocyanide with DMAD in the pres-ence of 2-acetylbutyrolactone (559) led to the formationof the furanylidenebutenedioate 560 (Scheme 145).188

The reaction between alkyl isocyanides and phenan-threne-9,10-dione (561) or dione 563 in the presence ofDMAD was found to afford γ-dispiroiminolactones 562and 564, respectively, in high yields (Scheme 146).189

1,2-Benzoquinones are inert towards isocyanides andelectron-deficient alkynes at ambient temperature; how-ever, they readily react with the zwitterions generatedfrom these two. For example, the reaction of cyclohexylisocyanide and DMAD generated a zwitterion which, on

Scheme 141

+ DMADR4 NC

NR1

NR2

R3

R5

N

R4N

NR2

R5

R3

CO2Me

CO2MeR1

R2

R1

NR3

NR3NR2

R1

NR4

CO2Me

CO2MeNR3

R3

benzene, Ar

R1, R2 = COPh, SO2Ph, TsR3 = H, Me, ClR4 = t-Bu, CyR5 = H, Me

R1, R2 = H, MeR3 = SO2Ph, COPhR4 = t-Bu, Cy

536

537

538

53948-64%

reflux, 4 h

benzene, Arreflux, 4 h

57–82%

+ DMAD +OR

H

[bmim]BF4

r.t., 0.5–2 h

O

MeO2C CO2Me

R NH

N

MeO2C CO2Me

OR

79–89%

Cy NC

H2O, PTC

80 °C, 1–2 hR = Ph, 4-ClC6H4, 4-FC6H4, 2-O2NC6H4, 3-O2NC6H4, Cy, thienyl, furyl, C9H19

540541

542

Scheme 144

R NC + DMADO

MeO2C CO2Me

HN

NRR = Cy, t-Bu

N CHON

O

N

O

MeO2C CO2Me

N

NR

N547545

548546

38 °C, 15–22 hCH2Cl2 benzene

75 °C, 48 h

94-95%90–95%

Scheme 143

O

O

O

R2

R1 + NCR3 + DMADbenzene

40 °C, 12 h

O

O

O

MeO2CCO2Me

NHR3

R2

R1

O

O

R2

R1

+ CO2Me

CO2Me

HN R3R1 = H, Me, i-Pr, Cl, NO2

R2 = H, MeR3 = t-Bu, Cy

459

543

54431-60%

3–48%

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Scheme 145

R NC + DMAD

OO

O Ph OR1

HO OH

O O O CO2R1RHN

MeO2C CO2Me

O

PhOC CO2Me

CO2Me

NHNRR

Ph Ph

HO OH

O O

NH

NH

O

O

O

HO

HO

NH

NH

O

O

O

O

MeO2CCO2Me

N

RCH2Cl2

Me O Me

O O

ONO

Me

CO2MeMeO2C

RMe

O

O

O

O

O

O

CO2Me

CO2Me

O

NR

CH2Cl2

R = Cy, t-Bu,

R1= Me, Et, Bu, Bn, CH2CH=CHPh

551

550

554

552

556

557

558

R = Cy, t-Bu

37–60%

r.t., 12 h

83–85%

33%

t-Oct47–60%

75-80%R = Cy, t-Bu,

t-Oct

r.t., 2 h

R = t-Bu

R = Cy, t-Bu

O

H

CO2Me

MeO2C

RN

O

H

R = t-Bu

56067%

Et2O–10 °C to r.t.

24 h

CH2Cl2r.t., 12 h

549559

CH2Cl2r.t., 12 h 553

555 CH2Cl2r.t., 12 h

Scheme 146

R NC + DMAD

t-Bu

t-Bu

O

O

t-Bu

t-Bu

O

O

CO2Me

CO2Me

N R

+ O

Ot-Bu

t-Bu

CO2Me

CO2Me

N R

O

O

Me

Me

benzene, Ar

O

O

O O

O OCO2Me

CO2Me

NN

MeO2C

MeO2C

RR

O O

N

CO2Me

CO2Me

MeO2C

MeO2C

NR R

CH2Cl2

R = Cy, Bn, t-Bu

R = Cy

O

Me

MeO

N

CO2Me

CO2MeR

569

R = Cy

561

562

563

564

565

566 567

568

82–90%

38 °C, 48 h

38 °C, 48 h

CH2Cl2 91% R = t-Bu

benzeneAr

80 °C, 4 h

92%

58% (ratio 2:3)

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interception with 3,5-di-tert-butyl-1,2-benzoquinone(565), yielded a regioisomeric mixture of spiroiminolac-tones 566 and 567 reacting exclusively with the carbonylfunctionalities of the quinone (Scheme 146).190

Nair et al.191 found that DMAD could be induced to additself to the most electron-deficient carbonyl of variousbenzoquinones in the presence of some nucleophilic initi-ator, such as triphenylphosphine or an isonitrile. In partic-ular, benzoquinone 568 underwent cyclization in thepresence of cyclohexyl isocyanide and DMAD to affordthe iminolactone 569 in 92% yield (Scheme 146).192

Isocyanides reacted smoothly with DMAD in the pres-ence of hexachloroacetone (570) to produce the furan de-rivatives 571 in high yields (Scheme 147).193

Benzoyl chlorides 572 with electron-withdrawing substit-uents at the para-position led to tetrasubstituted furans573 (Scheme 147).178

A three-component condensation reaction between an iso-cyanide, DMAD and 2-bromo-1-(4-bromophenyl)eth-anone (574) efficiently provided fully substitutediminolactones 575 in high yields in a one-pot condensa-tion reaction without any activation or modification(Scheme 147).194

Moreover, a new and efficient method for preparing elec-tron-poor imides 577 and fully substituted furans 578from triphenylphosphine, 1,1,3,3-tetramethylbutyl isocy-anide, DMAD and benzoic acid (576) under neutral con-ditions has been reported (Scheme 147).195

The reaction between alkyl(aryl) isocyanides, DMAD andalkyl cyanoformates 579 under solvent-free conditionsled to furan derivatives 580 in high yields (Scheme147).196

The highly reactive 1:1 adducts produced from the reac-tion between DMAD and alkyl isocyanides were trappedby benzoyl cyanide derivatives 581 to afford furan deriv-atives 582 in good yields (Scheme 147).197

4.3.2 Synthesis of Six-Membered Heterocycles with One Heteroatom


A three-component condensation reaction between an iso-cyanide, DMAD and triphenylphosphonium bromide 583efficiently provided fully substituted N-alkyl-2-triphe-nylphosphoranylidene glutarimides 584 in a one-pot reac-tion without any activation (Scheme 148).198

Scheme 147

R1 NC + DMAD

Cl3C CCl3

O

O

MeO2C CO2Me

NR1

CCl3

CCl3

Cl

O

CH2Cl2, r.t.

X

O

MeO2C CO2Me

N

X

H

R1

Br

OBr

O

CO2MeMeO2C

Br

Br

N

R1

R1 = Cy, t-Bu

OH

ON

O

OCO2Me

R1

+

O

CO2MeMeO2C

NH

R1N

Ph O

R1 = t-Oct

R1

CN

OR2O

O

MeO2C CO2Me

NOR2

CNR1

CN

O

O

CO2MeMeO2C

CN

N

R1

R1 = Cy, t-BuR2 = H, Cl

R2

R2

R1 = t-Bu, Cy, 2,6-Me2C6H3,

t-Oct

R1 = t-Bu, Cy, 2,6-Me2C6H3, t-Oct, CH2CO2Et

R1 = Cy, 2,6-Me2C6H3,

R2 = Me, Et

572

573

574

575

576577

578

580

581

582

570

571

MeO2C

65–95%

70–80%

X = Cl, NO2

90–97%

91%(ratio 3:7)

85–95%

t-Oct62–91%

Ph3P, CH2Cl2r.t., 48 h

CH2Cl2r.t., 12 h

CH2Cl2, r.t.

benzene80 °C, 2 hsolvent-free

r.t., 12 h

579

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Scheme 148

Li et al.199 reported a facile, efficient and regioselectivesynthetic approach for the construction of highly substi-tuted pyridine-2(1H)-ones 586 and allenyl derivatives587. Their synthesis involved a one-pot three-componentreaction between N-arylidene-2-cyanoacetohydrazides585, DMAD and isocyanides (Scheme 149).

4.3.2.2 Oxygen-Containing Heterocycles

Functionalized dihydroindenopyrans 589 were synthe-sized from the reaction of alkyl(aryl) isocyanides, DMADand indane-1,3-dione (588; Scheme 150).200

+ DMAD +R1NCCH2Cl2

r.t., 24 hR1 = t-Bu, Cy

Ph3P

O

OEtBr N

CO2Me

CO2Me

O

R1

O

Ph3P

583

58451–63%

Scheme 149

CO2Me

CO2Me

+

NC

O

NH

N

NNC

O

N

CO2Me

CO2Me

NH

R1

585

586

R1 = Cy, CH2CO2Et

R2

R2

CH2Cl2, r.t.

t-BuN

C

MeO2C

CO2Me

NN

O

CN

R2

587

t-BuNC

CH2Cl2, r.t.

46–73%

65–76%

R2 = H, 4-F, 4-Cl, 4-Br, 2-F, 3-Br, 3-NO2, 4-OMe

18–28 h

20–24 h

R1NC

Scheme 150

O

O

CH2Cl2

O

O

CO2Me

NR1

O

OMe

OO

NHR1

CO2Me

CO2Me

OHO

N

HN

O

O

CO2R2

OH

N

HN

O

O

O

MeO2C

CO2R2

O

X

Y

O

OH

X-Y = ,

OO

O

O

O

O

HN

MeO2C

R1

+ DMADR1-NCacetone

R1 = Cy, t-Bu, t-Oct, Bn,

2,6-Me2C6H3

OHO

O

O CO2Me

O

OMe

N

R1

NN

Me

PhO

NN

O

Me

Ph

MeO2C CO2Me

NH

R1

R2R2

O O

OR2

R2

O CO2Me

CO2Me

NH

MeMe

R2 = H, Me

R1 = Cy, t-Bu, t-Oct

588 589

590

591592

593

594

595

596

597

598

599

601

602

603

H

H

CO2Me

r.t.R1 = Cy, t-Bu, 2-morpholinoethyl, t-Oct

47–65%

65–86%

63-88%

R1 = Cy, t-Bu, t-Oct, 2,6-Me2C6H3

70–75%

r.t., 48 h

55-63%

93–96%

74–82%R1 = Cy, 2,6-Me2C6H3

R1 = Cy, t-Bu, Bn, CH2COOEt, t-Oct, 2,6-Me2C6H3

R1 = Cy, t-Bu, 2-morpholinoethyl, t-Oct

600

64–79%

O

XY O

O CO2Me

NH

O

R1

OMe

O

N

MeO

Me

DMF100 °C, 24 h

MeCNr.t., 12 h

CH2Cl2

CH2Cl2r.t., 12 h

CH2Cl2r.t., 24 h

CH2Cl2r.t., 24 h

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Fused heterocycles were prepared in a one-pot three-com-ponent reaction of alkyl isocyanide, DMAD and α-tropo-lone (590). The reaction proceeded smoothly at roomtemperature and under neutral conditions to afford tropo-lone derivatives 591 in good to high yields (Scheme150).201

Chemoselective reaction of isocyanides with DMAD inthe presence of relatively strong cyclic C–H acids 592,such as 4-hydroxy-6-methyl-2H-pyran-2-one or 4-hy-droxycoumarin, led to a facile synthesis of highly func-tionalized chromeno or pyrano derivatives 593,respectively, in good yields (Scheme 150).202

A three-component reaction of an isocyanide, DMAD andtetronic acid (594) in dichloromethane at room tempera-ture afforded 4H-furo[3,4-b]pyran derivatives 595(Scheme 150).203

The reaction between alkyl or aryl isocyanides andDMAD with 3-hydroxy-1H-phenalene-1-one 596 pro-duced a vinylisonitrilium cation, which subsequently un-derwent an addition reaction with the conjugate base ofthe 3-hydroxy-1H-phenalene-1-one to produce biologi-cally interesting compounds 597 in moderate to fairlygood yields (Scheme 150).204

The reaction between 2,6-dimethylphenyl isocyanide,1,3-cyclohexanediones 598 and DMAD provided a sim-ple one-pot entry into the synthesis of polyfunctional 4H-chromene derivatives 599 (Scheme 150).205

A three-component reaction of isocyanides, DMAD and3-methyl-1-phenyl-1H-pyrazol-5(4H)-one 600 led to the

synthesis of fully substituted pyrano[2,3-c]pyrazole de-rivatives 601 (Scheme 150).206

Pyrano-pyrido quinoxaline derivatives 603 were synthe-sized in good yields by a three-component reaction of iso-cyanides, DMAD and pyrido[1,2-a]quinoxalinetriones602 in N,N-dimethylformamide at 100 °C (Scheme150).207

4.3.3 Synthesis of Six-Membered Heterocycles with Two Heteroatoms


Reaction of alkyl isocyanides, DMAD and dimethylurea(604) in glucose provided novel 2,6-dioxohexahydropy-rimidines 605 (Scheme 151).208

A one-pot, three-component synthesis of pyrimidine de-rivatives 607, from the reaction of isocyanides, DMADand N-(2-heteroaryl)amides 606, was also reported(Scheme 151).209

A three-component reaction of isocyanides, DMAD andN-(2-pyridyl)amides 608 led to the synthesis of the corre-sponding 4H-pyrido[1,2-a]pyrimidines 609 (Scheme151).210

The one-pot, three-component condensation reaction ofalkyl isocyanides with DMAD in the presence of phthal-hydrazide 610 was successfully applied to the synthesis ofcompounds 611 (Scheme 151).211

Scheme 151

+ DMADR1NC

R1 = t-Bu, Cy, t-OctR2 = CO2Et, OEtX = N, CHY = N, CH

N

XY

NHCOR2

N

XY

N

MeO2C

MeO2C

NCOR2

R1

N NHCOR3

N N

MeO2C

CO2Me

NCOR3

R1

R2

R2

NH

NH

O

O

N

N

O

O

CO2Me

O

OMe

N

R1H

1 M aq glucose

Me

HN

HN

O

Me

N N

O

MeMe

MeO2C O

O NHR1

R1 = t-Bu, Cy, 2,6-Me2C6H3, t-Oct, 2-morpholinoethyl

R1 = t-Bu, CyR2 = H, 7-Me, 8-MeR3 = CO2Et, OEt

R1 = t-Bu, Cy, t-Oct

604

605

606

607

608

609

610

611

85–98%

–5 °C to r.t., 2 h

79–94%

82–92%

55–77%

CH2Cl2r.t., 24 h

acetoner.t., 48 h

CH2Cl2r.t., 24 h

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4.4 Carbenes

Over the past half-century and specifically ever since Bre-slow’s original demonstration of the role of thiazole car-benes as nucleophilic catalysts in enzymatic reactions,212

the intensive studies of N-heterocyclic carbenes (NHCs)as reaction intermediates by Wanzlick213 and the first iso-lation of stable diaminocarbene by Arduengo and co-workers in 1991,214 these species have attracted consider-able attention. Their role as excellent ligands for transitionmetals215 and their ability to catalyze various carbon–car-bon coupling reactions, namely benzoin condensation,transesterification216 and Stetter reaction,217 have contrib-uted significantly to the tremendous interest in N-hetero-cyclic carbenes.

A straightforward preparation of 3-aminofuran deriva-tives 614 via multicomponent reactions of thiazole car-benes 612, aldehydes 613 and DMAD was reported. Inthis process, the thiazole carbenes, generated in situ fromthiazolium salts, reacted with aldehydes and DMAD to af-ford the substituted furans 614 in moderate to good yields.Eight substituted thiazolium salts were employed as car-bene precursors in the reaction. In addition to aryl alde-hydes, α,β-unsaturated aldehydes 615 were alsoinvestigated and found to be applicable to this reaction(Scheme 152).218

A three-component synthesis of the unique polysubstitut-ed furan-fused 1,4-thiazepines 618 from thiazolium salts612, 1,1-disubstituted ketenes 617 and DMAD was alsoreported (Scheme 152).219

Nair et al.220 described the reaction of carbenes 620 withDMAD and aromatic aldehydes 619, which proceeded

smoothly to deliver four-component acyclic adducts 621in good yields (Scheme 153).

Scheme 153

1-Thiocarbamoylimidazo[1,5-a]pyridinium inner salts624, which were obtained readily from the addition of theC,N-substituted heterocyclic carbenes, imidazo[1,5-a]pyridin-1-ylidenes 622, to isothiocyanates 623, arepowerful ambident nucleophilic zwitterions. When treat-ed with DMAD, they behaved exclusively as sulfur nu-cleophiles to afford fully substituted thiophenes 625 inexcellent yields, providing an efficient orthogonal synthe-sis of polyfunctionalized thiophenes not easily obtainedby other chemical means (Scheme 154).221

Pan et al.222 reported a multicomponent reaction usingboth N-heterocyclic carbenes and substituted phthalalde-hydes. The imidazo[1,5-a]pyridine carbenes 626 reactedwith phthalaldehydes 627 and DMAD to produce diaste-reomeric benzo[d]furo[3,2-b]azepine derivatives 628 and629. The carbene underwent a nucleophilic addition to thephthalaldehyde to form a dipolar intermediate which thenunderwent [3+2] cycloaddition with DMAD (Scheme155).

Scheme 152

CO2Me

CO2Me

+

N

S

R1X

Ar CHO

NaH, CH2Cl2–78 to 0 °C

OAr

CO2Me

HNCO2MeR1

R3CHO

R2

NaH, CH2Cl2–78 to 0 °C

OCO2Me

HNCO2MeR1

R2

R3

O

C

R3R2

NaHiPr2NEt

N

S

O

R2

R3

MeO2C

CO2MeMe

R1

X = Br, IR1 = Me, Et, n-BuR2 = Ph, 4-FC6H4, 4-MeC6H4, MeR3 = H, Me

R1 = Me, Et, n-Bu, BnAr = Ph, 4-NO2C6H4, 3,4-(MeO)2C6H3, 4-ClC6H4,1-naphthyl, 2-thienyl, 2-furyl

612

617

613

614

615

616

618

29–78%44–84%

R1 = Et, BnR2 = Me, EtR3 = Ph, 4-MeC6H4

78–86%

CH2Cl2–78 to 0 °C

CO2Me

CO2Me

+ +N

N

R

R

ClN

O

Ar

N

MeO2C

MeO2C

CO2Me

CO2Me

Ar = 3,4-Cl2C6H3, 3-ClC6H4, 4-BrC6H4, 4-F3CC6H4, 4-O2NC6H4, 4-MeC6H4, 1-naphthyl, 2-thienylR = t-Bu

R R619

620 621

argon, r.t.,12 h

NaH, THFArCHO

20–65%

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4.5 Miscellaneous Reactions

Chaniyara et al.,223 in continuation of their research intonew bifunctional DNA-crosslinking agents for antitumorapplication, used benzothiazole derivative 630 andDMAD in order to gain access to diesters 631 and ulti-mately, after two steps, to the bis(alkylcarbamate) deriva-tives 632 for antitumor studies (Scheme 156).

In 2011, an efficient synthesis of iminothiopyran and iso-thiochromene derivatives 635 and 637, via one-pot reac-tions between DMAD, aryl isothiocyanates 633 and

enaminones 634 and 636 in dichloromethane at room tem-perature, was described (Scheme 157).224

The zwitterion formed by the reaction of dimethoxycar-bene and DMAD added efficiently to one of the carbonylgroups of 1,2-dicarbonyls and anhydrides to generate di-hydrofurans and spirodihydrofurans 639–642 in goodyields. In many cases, the carbene is inserted into the car-bon–carbon bond of the dione to yield masked vicinal tri-carbonyl systems (Scheme 158).225

Ding et al.226 reported a 1-methylimidazole-catalyzed re-action of DMAD with in situ generated ketenes by the ac-tion of Hunig’s base on acyl halides (Scheme 159).

Scheme 154

NN

Ph

Ar1Ar2N=C=S

NN

Ph

Ar1

NAr2S

DMAD

SMeO2C

MeO2C

NPh

N

N

Ar2

Ar1

Ar1 = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4

Ar2 = Ph, 4-BrC6H4, 4-MeOC6H4

622

623

624 625

84–94%

THF, r.t. 2 h

Scheme 155

NN Ar

Cl

+

R

R

CHO

CHO

+ DMADNaH,

N

HO

O CO2Me

CO2Me

Ar

R

R

N

+ N

HO

O CO2Me

CO2Me

Ar

R

R

N

626 627

628 629

CHCl3

Ar = Ph, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 4-CF3C6H4, Bz, n-Bu, i-Pr

R = H, Me, OMe, Br37–59% 12–39%

reflux, 2–4 h

Scheme 156

N

S

OR1

CNN

S

R1

CO2Me

CO2Me

N

S

R1

CH2OCONHR2

CH2OCONHR2

630 631 632

R1 = aryl, alkylR2 = Et, i-Pr

1. HBF4, Et2O

17–32%

2. DMAD, DMF, r.t.

Scheme 157

NO

S

O

N

Ar

CO2Me

CO2Me

+ DMAD

Me Me

NO

S

Me

CO2Me

CO2Me

O

Me

N

Ar

Ar = Ph, 4-O2NC6H4, 4-BrC6H4, 2-FC6H4, 3-BrC6H4, 3-FC6H4, 4-MeC6H4, 4-MeOC6H4

633

634636

635637

CH2Cl2, r.t., 6 hN C SAr

85–94%84–87%

CH2Cl2, r.t., 6 h

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Scheme 159

5 Conclusion

In conclusion, we have presented here an overview of therecent progress in the chemistry of DMAD as a unique re-agent with significant application in organic synthesis andmedicinal chemistry. It also plays a pivotal role in multi-component chemistry, participating in many diverse syn-thetic pathways. The high synthetic potential of this veryaccessible reagent has resulted in numerous applications,especially for the synthesis of complex heterocyclic struc-tures. The increasing number of citations clearly showsthe great importance of this simple but powerful reagent,and it is believed that additional new and useful DMADchemistry will be discovered in the future.

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Scheme 158

NN

O

Me

Me

OMe

OMe+

CO2Me

CO2Me

diaryl1,2-dione

O

MeO2C

MeO2C

OMeOMe

ArO

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cyclicanhydride

(i)(i)O

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MeO2C

MeO2C

OMe

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(i)1,2-diaryl

cyclobutenedione

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MeO2COMe

OMe

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N-alkyl isatin(i)

O

N

MeOOMe

CO2Me

CO2MeO

R

(i) toluene, 110 °C, sealed tubeAr = aryl, R = alkyl

638

639

640

641

64231–83%

42–80%

62%

32–50%

ArCl

O

+

N NMe

iPr2NEt,CH2Cl2Ar

CO2Me

CO2Me

643 644

1. ,

2. H2O, r.t.

CO2Me

CO2Me

35–64%Z/E mixture

Ar = Ph, 4-ClC6H4, 4-FC6H4,

4-MeC6H4, 2-ClC6H4, 2-FC6H4, 3-ClC6H4, 2-MeC6H4, 2,4-Cl2C6H3, 3,4-Cl2C6H3, 1-naphthyl

Thi

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