lable at ScienceDirect

Tetrahedron 67 (2011) 7195e7210

Contents lists avai

Tetrahedron

journal homepage: www.elsevier .com/locate/ tet

Tetrahedron report number 945

Indole synthesis: a review and proposed classification

Douglass F. Taber a,*, Pavan K. Tirunahari b

aDepartment of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USAbAccel Synthesis, Inc., Garnet Valley, PA 19060, USA

a r t i c l e i n f o

Article history:Received 1 June 2011Available online 21 June 2011

* Corresponding author. E-mail address: taberdf@u

0040-4020/$ e see front matter � 2011 Elsevier Ltd.doi:10.1016/j.tet.2011.06.040

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71952. Type 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71963. Type 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71984. Type 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71995. Type 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72006. Type 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72017. Type 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72048. Type 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .72059. Type 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720610. Type 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .720711. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7208

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7208References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7208Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7210

1. Introduction

The indole alkaloids, ranging from lysergic acid to vincristine,have long inspired organic synthesis chemists. Interest in de-veloping newmethods for indole synthesis has burgeoned over thepast few years. These new methods have been fragmented acrossthe literature of organic chemistry. In this review, we presenta framework for the classification of all indole syntheses.

As we approach the classification of routes for the preparation ofindoles, we are mindful that the subject has occupied the minds oforganic chemists for more than a century. There have been manyreviews of indole synthesis.1 We were also aware that much morecould be said than we have written. We have only briefly coveredthe conversion of indolines into indoles, and the reduction ofoxindoles to indoles. We have not covered the extensive literatureon the modification of existing indoles. Throughout, our interest

del.edu (D.F. Taber).

All rights reserved.

has been to be illustrative, not exhaustively inclusive. It is apparent,however, that every indole synthesis must fit one or the other of thenine strategic approaches adumbrated here. The web of scientificcitations unites and organizes the world-wide research effort. It isour intention that the system put forward here for classifying in-dole syntheses will be universally understood. As authors conceiveof new approaches to the indole nucleus, they will be able toclassify their approach, and so readily discover both the history andthe current state of the art with that strategy for indole construc-tion. In addition to avoiding duplication, it is also our hope thatefforts will then be directed toward the very real challenges thatremain to be overcome. It is noteworthy that, in the most recentyear we have covered, 2009, significant new contributions werereported for each of these nine strategies. We have highlightedthese at the end of each section.

There are four bonds in the five-membered indole ring. Inclassifying methods for synthesis (Fig. 1), we have focused on thelast bond formed. We have also differentiated, in distinguishingType 1 versus Type 2 and Type 3 versus Type 4, between forming

Type 1

H

NH

X

NH

HN

XN

NH2 N

NH

Type 2

Type 3

Type 4

Type 5 Type 6

Type 7

Type 8

Type 9

O

NHIndole

Fischer

Mori

Hemetsberger

Buchwald

Sundberg Madelung

Nenitzescu

van Leusen

Kanematsu

Fig. 1. The nine types of indole synthesis.N

+O N

H1 2 3

ZnCl2

NH2

OH

H

SO2NHMe SO2NHMe

Scheme 1.

Br

Br

MeO

N BocNH2

MeO

Br NH

4

Br

+

O

5

p-TsOH

6

Scheme 2.

PhCO2Et

N2 NH

CO2Et

PhMeO

7

+

8 9

MeO

Li

Scheme 3.

H

OEtEtO

TiCl4

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107196

a bond to a functionalized aromatic carbon, and forming a bond toan aromatic carbon occupied only by an H. Type 5 has as the laststep CeN bond formation, while with Type 6 the last step is CeCbond formation. In Type 7, the benzene ring has been derived froman existing cyclohexane, and in Type 8, the benzene ring has beenbuilt onto an existing pyrrole. Finally, in Type 9, both rings havebeen constructed.

There are several name reactions associated with indole syn-thesis. We have tried to note these in context, and to group ex-amples of a particular name reaction together. For convenience, the‘name reaction’ indole syntheses mentioned in this review are:

Bartoli indole synthesisdType 1Bischler indole synthesisdType 5Fischer indole synthesisdType 1Hemetsberger indole synthesisdType 3Julia indole synthesisdType 5Larock indole synthesisdType 5LeimgrubereBatcho indole synthesisdType 5Madelung indole synthesisdType 6Nenitzescu indole synthesisdType 7Reissert indole synthesisdType 5Sundberg indole synthesisdType 5

While it might be sufficient to merely label the nine strategies1e9, for ease of recollection we have also associated each strategywith the name of an early or well-known practitioner. The divisionof strategies is strictly operational. Thus, the Fischer indole syn-thesis is classified as Type 1, AreH to C2, since that is the way it iscarried out, even though the last bond formed, as the reactionproceeds, is in fact N to C1.

N NMs

NMs Ms

10 11 12

Scheme 4.

O

2. Type 1

N

H

HNH

Fischer strategy

Type 1 synthesis (Scheme 1e17) involves aromatic CeH func-tionalization. Although CeH activation is thought of as a moderntopic, the venerable Fischer indole synthesis (still under activedevelopment, Schemes 1e3) falls under this heading. PaulR. Brodfuehrer and Shaopeng Wang of Bristol-Myers Squibb de-scribed2 the convenient (Scheme 1) reaction of an aryl hydrazine 1with dihydropyran 2 to give the 3-hydroxypropylindole 3. StephenL. Buchwald of MIT developed3 an elegant (Scheme 2) amination ofaryl iodides to give Boc-protected aryl hydrazines, such as 4. Acid-mediated condensation of 4 with the ketone 5 delivered the indole6. The condensation of 4 and 5 proceeded with high regiose-lectivity. Norio Takamura of Musashino University, Tokyo pre-sented4 a complementary approach (Scheme 3), the addition of anaryllithium 8 to an a-diazo ester 7, followed by acid-mediated cy-clization. The ester of 9 is easily manipulated, and can also be re-moved altogether. Several other useful variations on the Fischerindole synthesis have been reported.5e7

Indoles can also be formed by acid-mediated cyclization of al-dehydes. Richard J. Sundberg of the University of Virginia described8

the preparation from 10 (Scheme 4) and cyclization of acetals, suchas 11 to give the indole 12. The Bischler indole synthesis9a,b is a var-iation on this approach. Chan Sik Cho and Sang Chul Shim ofKyungpook National University, Taegu devised9c a route to indoles(Scheme 5) based on Ru-mediated addition of an aniline 13 to anepoxide 14. An interesting oxidationereduction cascade led to the 2-alkyl indole 15, probably via a Bischler-like tautomerization.

NH2 NH

Cl Cl

13 14 15

+Ru cat. Ph

Scheme 5.

+N2

O

OEtNH

NH

OCO2Et

2-ClPy2,6-Cl2PyTf2O

BrBr30 31 32

Scheme 11.

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7197

Other transition-metal-mediated protocols for indole synthesishave been developed. In a variant on the Bartoli indole synthesis,Kenneth M. Nicholas of the University of Oklahoma reported10 theRu-catalyzed reductive coupling of a nitrosoaromatic, such as 16(Scheme 6) with an alkyne 17 to give the indole 18. Akio Saito andYuji Hanzawa of Showa Pharmaceutical University described11 theRh-catalyzed cyclization of 19 (Scheme 7) to 20. The reaction wasthought to proceed via the allene 21.

NO

+

Ph

HNH

Ru cat.

CO

Ph

16 17 18

Scheme 6.

NRh cat.

19 20

MeO

N

MeO

ArN

21

Scheme 7.

NH2

O2NCl

Cl

O2NCl

ClN

SMe

O

H

O2NCl

ClNH

33 34 35

BH3

Scheme 12.

N

MeO

MeO

NMs

Ms

N O

ON

O

36

37

cat. lauroylperoxide

SOEtO

O

38

Scheme 13.

Several other Type 1 indole syntheses have been described. Inthe examples cited so far, only one regioisomeric aryl H could besubstituted. In an ortho-metalation approach, Francis Johnson ofSUNY Stony Brook showed12 that (Scheme 8) the anion from cy-clization of 22 could be alkyated with an electrophile, such as 23 togive the indole 24. Darrell Watson and D.R. Dillin at the Universityof Mary Hardin-Baylor reported13 a photochemical route (Scheme9) to indoles. Irradiation of 25 in an oxygen atmosphere led to 26.When the photolysis was carried out under nitrogen, the productwas 27. Frank Glorius of the Universit€at M€unster devised14 a relatedcatalytic oxidation of enamines, such as 28 (Scheme 10) to the in-dole 29. Just recently, Yan-Guang Wang of Zhejian University,Hangzhou described15 the coupling (Scheme 11) of a wide range ofanilides, such as 30with ethyl diazoacetate 31 to give the indole 32.

N

MeO

NCH2CF322

n-BuLi x 4;

O Cl O23

24

MeOH

Scheme 8.

N N

CO2Me

28 29H H

Cu(OAc)2cat. Pd(OAc)2MeOCO2Me

MeO

Scheme 10.

NN

O

OhνO2

25 26 27

N

Scheme 9.

Indoles, such as 35 (Scheme 12) can also be prepared fromoxindoles, such as 34, prepared from 33. Wendell Wierenga, then atUpjohn, optimized16 both the Gassman synthesis of oxindoles fromanilines, and the subsequent reduction. This is a net Type 1synthesis.

Samir Z. Zard of Ecole Polytechnique described17 the cyclization(Scheme 13) of allyl anilines, such as 36 to the indoline 38 using 37.As indolines can be converted into indoles by oxidation18 or bybase-mediated elimination of an N-sulfonyl group19 this is alsoa net Type 1 indole synthesis.

In 2009, four interesting new examples of Type 1 indole syn-thesis were described. It had been thought that the cyclization of anacetal (Scheme 4) to the indole would only work with electron-richaromatic rings. Dali Yin of the Institute of Materia Medica, Beijing20

observed that 39 (Scheme 14), readily prepared by sequential dis-placement on the corresponding difluorodintrobenzene, smoothlycyclized to 40.

N

O2N

NO239 40

TFA

NH

N

O2N

NO2

NH

OEt

OEt

Scheme 14.

Following up on the work of Glorius (Scheme 10), Ning Jiao ofPeking University found21 that, under oxidizing conditions, an an-iline derivative, such as 41 (Scheme 15) could be condensed withthe diester 42 to give the indole 43. Note that the cyclization pro-ceeded with high regioselectivity. The product was easily hydro-lyzed and decarboxylated to give the 2,3-unsubstituted indole.

NH2 NH

CO2Me

41

CO2Me

43

MeO2C CO2Me42

Pd cat.O2

Scheme 15.

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107198

Akio Saito and Yuji Hanazawa of Showa Pharmaceutical Uni-versity published22 a full account of the Rh-mediated cyclization ofpropargylaniline derivatives, such as 44 (Scheme 16) that theydeveloped. This reaction is apparently proceeding via rearrange-ment to an intermediate o-allenylaniline, that then cyclizes to theproduct, 45.

Br

N

53 54

Pd cat.

Et3NBrO CF3

NCbz

BrNH

NCbz

SNO

O SNO

O

HH

Scheme 20.

Br Br B(OH)2+

N N

44 45

MeORh cat.

(F3C)2CHOH

MeO

Scheme 16.

Erik J. Sorensen of Princeton University uncovered23 a route toindoles (Scheme 17) based on an interrupted Ugi reaction, thecombination of 46 and tert-butyl isocyanide to give the amino-indole 48. The acid 47 was particularly effective at mediating thisreaction.

N O N O

NPh

55 56

Pd cat.

57

P(OPh)2O

Boc

BocBoc

Scheme 21.

N NPh

N

46 48H

Ph

HMeO

MeO

cat.F3CSO2 N

P

H

OOPh

OPh47

MeO

MeO t-BuNC

Scheme 17.

3. Type 2

X

NH

Mori strategy

Br

I

H2N

N58

OMe OMe

H59

Pd cat

Scheme 22.

In a landmark paper in 1977, MiwakoMori, working with YoshioBan at Hokkaido University, reported24 the first intramolecularHeck cyclization, converting the 2-bromoaniline derivative 49(Scheme 18) into the N-acetyl indole 50 with a Pd catalyst. In 1980,Louis S. Hegedus at Colorado State University showed25 that iodideswere superior to bromides for the cyclization, and that free amines,such as 51 (Scheme 19) were compatible with the reaction condi-tions, forming 52.

Br

N N49 50

Pd cat.

TMEDA

CO2Me

O O

CO2Me

Scheme 18.

Ι

N N51 52

Pd cat.

H H

Et3N

Scheme 19.

This approach has been extended in several directions. JohnE. Macor at Pfizer found26 that cyclization of the dibromide 53 to 54(Scheme 20) was more efficient than cyclization of the corre-sponding monobromide. Note that the potentially labile allyliccarbamate survived the Pd reaction conditions. Haruhiko Fuwa andMakoto Sasaki of Tohoku University devised27 the conversion of theN-acetyl aniline 55 (Scheme 21) into the enol phosphonate 56.Consecutive Suzuki coupling followed by Heck cyclization de-livered the indole 57.

Morten Jørgensen of H. Lundbeck A/S, Denmark took advan-tage28 of the more facile oxidative addition of aryl iodides com-pared to aryl bromides to accomplish sequential N-arylation andHeck cyclization, converting 58 (Scheme 22) into the indole 59. LutzAckermann of the Ludwigs-Maxmilian-Universit€at M€uncheneffected29 regioselective Ti-mediated hydroamination of the alkyne61 (Scheme 23) with the aniline 60. Pd-mediated cyclization of thenucleophilic enamine so formed gave the indole 62.

Cl

NH2

Ph

N

Ph1.TiCl4

2. Pd cat.H

60 62

61

Scheme 23.

Indoles can also be prepared by free radical cyclization. Athel-stan L. J. Beckwith of the University of Adelaide cleverly employed30

the nitroxide 64 (Scheme 24) to effect first reduction, to facilitateloss of N2 from the diazonium salt 63, then radical cyclization, thenradical-radical coupling with the nitroxide, followed by loss of theamine to give the indole aldehyde 65. Richard P. Hsung, now at theUniversity of Wisconsin, demonstrated31 that a more conventionalreductive cyclization of the allenylaniline 66 to form 67 (Scheme25) was also effective.

N

N2

O

N

O63

NO64

65

HO

Scheme 24.

I

N N

Boc Boc

Bu3SnHAIBN

66 67

Scheme 25.

I

N

CO2Me

N

CO2MePd cat.K2CO3phenol

78 79

Scheme 30.

I

N NH

80 81

HPh O

Cu cat.Ph

O

Scheme 31.

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7199

Lanny S. Liebeskind of Emory University showed32 that ortho-bromo allyl anilines, such as 68 (Scheme 26) could, on trans-metalation, be induced to cyclize to the indoline anion. The anioncould be trapped with a variety of electrophiles. The productindoline was readily oxidized to the indole 69. Professor Buchwaldgenerated33 from 70 (Scheme 27) a zirconocene benzyne complexthat inserted into the pendent alkene. Iodination delivered theindoline 71, that via elimination and bromination was carried on tothe indole 72.

Br

N N68 69

MeO MeO N1. t-BuLi;

2. chloranil

N

Scheme 26.

Br

N N

II

N

IBr

tert-BuLi;

Cp2ZrCl

I2

1. DBU

2. NBS

70 71 72

Scheme 27.

I

N NO

82 83

Ocat. Pd(dba)2

BINAP

HN

O

HN

O

Scheme 32.

HN

Hemetsberger strategy

Brian M. Stoltz of Caltech added34 the anion derived from 74(Scheme 28) to the benzyne derived from 73 to give the indoline 75.The authors did not oxidize 75 to the corresponding indole, but thisshould be straightforward.

TMS

OTf Boc NH

CO2MeN

CO2Me

FMeO

Boc

MeO

73 74 75

Scheme 28.O

H

N3

CO2Et

84 85

N3 CO2Et

EtONa

As described35 by Brigitte Jamart-Gr�egoire of the Universit�e deNancy, a benzynewas also the intermediate in the cyclization of theanion derived from 76 (Scheme 29) to the indole 77. Daniel Sol�e ofthe Universitat de Barcelona effected36 the conceptual alternative,

N NH

Cl

76 77H

NaNH2

t-BuONa

Scheme 29.

the Pd-mediated arylation of the anion derived from 78 (Scheme30). Depending on the reaction conditions, the dominant productcould be either the indoline, or the indole 79.

Among the several Type 2 indole syntheses reported in 2009,two were particularly interesting. Sandro Cacchi of the Universit�adegli Studi ‘La Sapienza‘, Roma, prepared37 the enaminone 80(Scheme 31) by condensation of the iodoaniline with the acetylenicketone. On exposure to a Cu catalyst, 80 cyclized to the indole 81.

Luc Neuville and JZhu of CNRS Gif-sur-Yvette assembled38

(Scheme 32) the amide 82 by a four-component coupling. Withthe proper choice of ligand, 82 could be cyclized to 83. The con-version of an oxindole into the indole is described in the precedingsection.

4. Type 3

The lead Type 3 approach is the Hemetsberger39 indole syn-thesis, as, for instance, employed40 by John K. MacLeod of AustraliaNational University in his synthesis (Scheme 33) of cis-trikentrin A.The aldehyde 84 was homologated to the azido ester 85, that wasthen heated to convert it into the indole 86.

NH

CO2Et

86

Scheme 33.

The thermal conversion of azido styrenes, such as 85 into theindole had been shown39 to proceed by way of the azirine. Wetherefore developed41 a general method for the conversion of an a-

OO

1. t-BuOCl

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107200

aryl ketone, such as 87 (Scheme 34) into the azirine 88. Thermolysisof the azirine gave the indole 89. Subsequently, Koichi Narasaka ofthe University of Tokyo demonstrated42 that Rh trifluoroacetatecatalyzed the conversion of azirines, such as 88 into indoles at roomtemperature. Tom G. Driver of the University of Illinois, Chicagolater found43 that the same catalyst converted azido styrenes, suchas 85 (Scheme 33) into the indole, also at room temperature.

87

Br

ONH2OH;

MsCl; DBU

88

Br

N

NHBr

89

Scheme 34.

N N

N

CO2H

NHAc

101

H OMe2. AgOAc

OMe

OMe

1. LiAlH4

2.H+/ CO2H

NHAc

102

103 104

Scheme 38.

Kang Zhao of Tianjin University established44 that PIFA oxidationof an enamine, such as 92 (Scheme 35), prepared from 90 and 91,offered a convenient route to the N-aryl indole 93. This cyclizationmay likely also be proceeding by way of the intermediate azirine.

CNR2

HN

N

CNF

CN

O

Cl

F

F

Cl

NH2Cl

90

91

92

PIFA

93

Scheme 35.

NO2NH105

Pd cat.

CO

106

Scheme 39.

N

NTf107

Pd cat.

ox.

108

Tf

HBrBr

Scheme 40.

H. Personof theUniversit�e deRennes found45 that exposure of ab-nitro styrene 94 (Scheme 36) to an isonitrile 95 led to the N-hydroxyindole96. GlenA. Russell of Iowa StateUniversity reported46 a relatedreductive cyclization of a b-nitro styrene with triethyl phosphite.

NCO2Me

NO

OH

NO2

CO2Me

94

O2N O2N

NC 95

96

H

Scheme 36.

XN

Buchwald strategy

The coupling of a phenol 97 (Scheme 37) with a diazonium salt98 is a well-known process. Masato Satomura of Fuji Photo Film Co.discovered47 that exposure of the adduct 99 to mild acid led tocyclization to the indole 100. The NeN bond was readily cleaved byRaney nickel to give the free amine.

N

97

HO

N2 HO

NN

98

99

HO

NH

H+

100

Scheme 37.

The cyclic heptadepsipeptide HUN-7293 contains the N-methoxy tryptophan 104 (Scheme 38). To prepare 104, Dale L.Boger of Scripps/La Jolla took advantage48 of the Kikugawa oxindolesynthesis to convert 101 into 102. Reduction followed by acid-catalyzed condensation with the enamide 103 then delivered 104.

In 2009, VyM. Dong of the University of Toronto found49 that COcould serve (Scheme 39) as the reductant for the cyclization of a b-nitro styrene 105 to the indole 106. Jin-Quan Yu, also of Scripps/LaJolla, developed50 an oxidant that enabled the Pd-mediated cycli-zation of 107 (Scheme 40) to the indole 108.

Br

Br N

NH2

Ph

Pd cat.

Ph

NH

HCO2NH4

Pd/C

109 110

111

Scheme 41.

5. Type 4

The development of transition-metal-mediated aryl halideamination opened the way to Type 4 indole synthesis. In 1998,Stephen L. Buchwald of MIT reported51 that on exposure to ben-zylamine in the presence of a Pd catalyst, the dibromide 109(Scheme 41) smoothly cyclized to the indoline 110. Ammoniumformate in the presence of Pd/C converted 110 into the indole 111.

Cl

O2NO

1.

Cl

O2N SN

NNNH2

CO2EtH

2. SOCl2

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7201

In the course of a synthesis of the duocarmycins, TohruFukuyama of the University of Tokyo employed52 a similar ap-proach, cyclizing 112 (Scheme 42) to 113. By that time, the Cucatalysts for aryl halide amination had been developed.

BrN

CO2Me

Cbz

CO2MeNCbz

H

MeOMeO

MeOMeO

MeOMeO

Cu cat.

112 113

Scheme 42.

NSH

O2N

122 123

124

NH2

K2CO3

Scheme 46.

Jos�e Barluenga of the University of Oviedo took advantage53 ofthe greater reactivity of an aryl bromide compared to the chlorideas he developed the convergent coupling of 114 (Scheme 43) with115 to give the indole 116. For this coupling, a Pd catalyst wasrequired.

Br

Cl

114

BnO+

OMe

NPh

115

Pd cat.

N116

BnOPh

OMe

NaOt-Bu

Scheme 43.

O

Br NH

125 127

Br

CuI

CO2EtNC

126

CO2EtBr

OMe

N

128 129

CuICO2Me

CO2Me

N

I

H

Scheme 48.

Alexander V. Karchava of Moscow State University devised54

a route to indoles from ortho-bromophenylacetic acid esters, suchas 117 (Scheme 44). Formylation followed by condensation with anamine 118 set the stage for the Cu-mediated intramolecular ami-nation to give the indole 119.

BrN

CO2MeCO2Me1. NaH/Me formate

2.NH2

3. Cu cat.117 118 119

Scheme 44.

NH2

Sundberg strategy

Phenols, under photolysis, can activatemeta-substituted halidesfor nucleophilic displacement. Nien-chu C. Yang of the University ofChicago devised55 an indoline synthesis based on this effect, irra-diating 120 (Scheme 45) to give 121.

HO Cl NHO

CO2Me

hνMeOH

NH

MeO2C

O

O120 121

Scheme 45.

N3 NH

130 131

Scheme 49.

NO2 NH

132 133

P(OEt)3

Scheme 50.

Similarly, nitro groups can activate para-substituted halides fornucleophilic displacement. Douglas C. Neckers of Bowling GreenState University observed56 that exposure to a primary amineconverted the thiadiazole 123 (Scheme 46), prepared from 122, intothe indole-2-thiol 124. The reaction is thought to be proceeding byway of the alkyne thiol.

In 2009, Qian Cai and Ke Ding of the Institute of BiologicalChemistry, Guangzhou described57 (Scheme 47) the CuI-mediatedcondensation of the isocyano ester 126 with o-halo aromatic ke-tones and aldehydes, such as 125 to give directly the correspondingindole 127. Stuart L. Schreiber of Harvard University took58 a relatedapproach, cyclizing 128 (Scheme 48), prepared via the corre-sponding aziridine, to the indole 129.

Scheme 47.

6. Type 5

In 1969, Richard J. Sundberg of the University of Virginiareported59 that ortho-azido styrenes, such as 130 (Scheme 49) wereconverted on thermolysis into the corresponding indole 131. Helater found60 that heating ortho-nitro styrenes, such as 132(Scheme 50) with P(OEt)3 also delivered the indole. Aryl migrationdominated over alkyl migration, leading to 133. Recently, Tom G.Driver of the University of Illinois, Chicago showed61 that the azideversion of the Sundberg indole synthesis could be carried out atlower temperature with a Rh catalyst.

N

TBSO

MeO2C1. NPIF

2. TiCl3

NMeO2C

N

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107202

Benzylic methyl groups are acidic enough to be deprotonated,especially when there is an ortho-nitro group. This is the basis forthe Reissert indole synthesis62 (134 to 135, Scheme 51) and theLeimgrubereBatcho indole synthesis63 (136 to 138, Scheme 52).

H147 148

Scheme 56.

NO2 NH

CH3OO

H 1.

2. H2 - Pd/C

N2

CO2Et/ Fp

CO2EtCH3O

149 150

Scheme 57.

NO2 NH

CO2Me

134 135

I

Cl

I

Cl

1. (CO2Me)2t-BuOK

2. SnCl2

Scheme 51.

NO2 NH

136 138

OMe 1.

2. H2 - Pd/C

OMeOMe

OMeN 137

Scheme 52.

Amos B. Smith III of the University of Pennsylvania took ad-vantage64 of the acidity of 139 (Scheme 53). Double deprotonationfollowed by condensation with 140 delivered the indole 141.

NH NH

139 141SiMe3

2 x n-BuLi;

O

O

OH

140

Scheme 53.

NH2

OH

NH

MeO MeOIr cat

151 152

Scheme 58.

Donal F. O’Shea of University College Dublin demonstrated65

that an alkyllithium first deprotonated 142 (Scheme 54), and thenadded to the pendent alkene. Benzonitrile 143 was added to theresulting carbanion to give the indole 144.

NH N

142 144Boc

2 x n-BuLi;Ph

143

CH3O CH3O

Ph-CN

Boc

Scheme 54.

NH2

CN

NH

153 154

H2Pd - C

Scheme 59.

O

CO2Me

NO2NOH

CO2Me

BrSiMe3

SnCl2 . 2H2O

155

156

157

Scheme 60.

It is clear that any synthetic route to ortho-amino or ortho-nitroa-aryl ketones or aldehydes can be used to prepare indoles. JosephF. Bunnett of the University of California, Santa Cruz observed66

that, under SRN1 conditions, acetone enolate displaced the bro-mide of 145 (Scheme 55), leading to the indole 146. Viresh H. Rawalof the University of Chicago arylated67 the silyl enol ether 147(Scheme 56) with an ortho-nitrophenyl iodinium salt (NPIF) to give,after reduction, the indole 148. M. Mahmoun Hossain of the Uni-versity of Wisconsin, Milwaukee inserted68 ethyl diazoacetate intothe aldehyde 149 (Scheme 57), converting it, via reduction, into theindole 150.

Br

NH2

O

NH

hν

145 146

Scheme 55.

As demonstrated69 by Ken-ichi Fujita and Ryohei Yamaguchi ofKyoto University, in situ oxidation of the alcohol 151 (Scheme 58)led to the indole 152. With added 2-propanol, an alcohol with anortho-nitro group was also converted into the indole.

Hironao Sajiki and Kosaku Hirota of Gifu Pharmaceutical Uni-versity showed70 that reduction of an ortho-amino nitrile, such as153 (Scheme 59) delivered the indole 154, presumably by trappingof the intermediate imine. It may well be that an ortho-nitro sub-stituent would work as well, but such a transformation was notincluded in this report.

K. C. Nicolaou of Scripps/La Jolla prepared71 the enone 155(Scheme 60) from the intermediate in the Bischler indole synthesis.Reduction of 155 gave an intermediate that reacted with mild nu-cleophiles, such as the allylsilane 156 to give the indole 157.

In 1986, Sylvestre A. Julia of the Ecole Normale Sup�erieure, Parisreported72 that sulfinamides, such as 159 (Scheme 61), readilyprepared from the aniline 158, were converted by heating into theindole 161 via 160. It is striking that the Julia indole synthesis hasbeen little used since it was reported.

171

NH2N

172

Pd catH

BrBr

Et3B

Scheme 65.

173

NHN

175

TsTs

SS

174

Scheme 66.

158

MeO

NH2

1. SOCl2 / im

2.MgBr

MeO

NH

OS

MeO

NH2

SO MeO

NH

159

160 161

Scheme 61.

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7203

The preparation of indoles from ortho-haloanilines by conden-sationwith an alkyne goes back at least to 1963, when C. E. Castro ofthe University of California, Riverside, observed73 (Scheme 62) thatcoupling of 162 with 163 led not to the diaryl alkyne, but to theindole 164.

176

N N

177Ph

BrBu3SnHAIBN

Ph

Scheme 67.

162

NH2

I Cu Ph

NH

164

163 Ph

Scheme 62.

O N2

SiMe3

179

In 1985, Edward C. Taylor of Princeton University and AlexanderMcKillop of the University of East Anglia showed74 that Pd waseffective at cyclizing ortho-alkynylanilines to the correspondingindole. This led to the 1989 report75 by J. K. Stille of Colorado StateUniversity that the two-step coupling described by Castro (Scheme62) could be carried out at much lower temperature using Pd ca-talysis. With this precedent, in 1991 Richard C. Larock of Iowa StateUniversity disclosed76 that, using Pd catalysis (Scheme 63), internalalkynes, such as 166 could be condensed with an ortho-iodoaniline165 under Pd catalysis to give the 2,3-disubstituted indole 167withhigh regiocontrol. One of the advantages of the Larock indolesynthesis is the malleability of the 2-silyl substituent on theproduct indole.

165

NH2

I SiMe3

NH

167

166 SiMe3Pd cat.

Scheme 63.

178

NH N

180

TsTs

Scheme 68.

181

NH2 N

183H

O182

SiMe3

1.

2. Pd cat.MeOH/CO

CO2Me

More recently, (the late) Keith Fagnou of the University of Ot-

tawa demonstrated77 that Rh catalysis could effect ortho function-alization of acetanilides, such as 168 (Scheme 64). Subsequentcoupling with internal alkynes, such as 169 led to the indole 170with high regiocontrol.

168

N

Ph

N

170

169 PhRh cat.Cu(OAc)2

MeO MeOOO

H8:1

Scheme 64.

Scheme 69.

184

NH2 NH

185

Pt cat.

H2CN

Scheme 70.

Several other flexible routes to indoles have been developed.Mark Lautens of the University of Toronto established78 that orthodihaloalkylidene anilines, such as 171 (Scheme 65) could be con-densed with alkyl, alkenyl or aryl boranes or boronic acids to givethe 2-substituted indole, in this case 172. Kentaro Okuma ofFukuoka University found79 that the sulfonium salt 174 (Scheme66) effected cyclization of an ortho alkenyl aniline, such as 173 tothe indole 175. Jeffrey N. Johnston, now at Vanderbilt University,effected80 free radical reductive cyclization of halides, such as 176(Scheme 67), to give the indole 177.

Toyohiko Aoyama of Nagoya City University reacted81 ortho-acylanilines, such as 178 (Scheme 68) with lithio TMS diazo-methane 179 to give an alkylidene carbene, that inserted into theadjacent NH to give the indole 180. Bartolo Gabriele of the Uni-versit�a della Calabria added82 acetylides, such as 182 (Scheme 69)to ortho-acylanilines, such as 181 to give alkynyl alcohols, thatunderwent carbonylative cyclization with Pd catalysis to give theindole 183.

In 2009, Hideo Nagashima of Kyushu University reported83 thatan o-nitrophenyl acetonitrile 184 could indeed (Scheme 70) bereductively cyclized to the indole 185. Yanxing Jia of Peking Uni-versity prepared84 188, a key intermediate in the synthesis of(�)-cis-clavicipitic acid, by selective condensation of the aldehyde187 (Scheme 71) with the iodoaniline 186.

186

NH2N

188

Pd cat.H

ICl

N(Boc)2MeO2C

OH

187

ClN(Boc)2

MeO2C

Scheme 71.

NH2 NH197

1.

199

PPh3

2. t-BuOK

H

O / H+198

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107204

Sandro Cacchi of the Universit�a ‘La Sapienza‘, Rome, extended85

the Gabriele approach, cyclizing (Scheme 72) the propargylic car-bonate 189 to 190. This transformation may be proceeding by wayof the intermediate allene. Two related approaches to indole syn-thesis86,87 also appeared.

189

NN

190H

CF3

H

O

OCO2Et

Pd cat.

CO/MeOH CO2Me

Scheme 72.

Scheme 76.

N

Rh cat.

N

200 201

CO2CH3

N2

NO

Ts O

CO2CH3

N

O

TsO

Scheme 77.

Tao Pei of Merck Rahway developed88 a powerful new approach

to substituted indoles, based on the addition (Scheme 73) of anorganometallic to a chloro ketone 191. The conversion into 192proceeded by 1,2-migration of the arene with nucleophilic dis-placement of chloride.

191

NH2 NH192

Cl

Cl

O

MgBr

Cl

Scheme 73.

NC

Ru cat.

NH

202 203

Scheme 78.

7. Type 6

N

Madelung strategy

N N

O

CO2Me

MeONaCO2Me

The Madelung indole synthesis, as exemplified by the cycliza-tion (Scheme 74) of 193 to 194, was originally carried out atelevated temperature with bases, such as NaNH2. Willam J. Houli-han of Sandoz, Inc. (now Novartis) showed89 that, with BuLi, thecyclization of 193 to 194 was facile below room temperature. D. N.Reinhoudt of the University of Twente found90 that phenyl-acetonitriles, such as 195 (Scheme 75) could be cyclized under evenmilder conditions, to form 196.

N PhH

NH

Ph193

MeOO 3 n-BuLi

MeO

194

Scheme 74.

NH

NH195

O 1. NaH/TMSCl

196

CNCN

2. t-BuOK

Scheme 75.

George A. Kraus of Iowa State University described91 a concep-tually related cyclization (Scheme 76). Condensation of an aldehyde198with the aniline 197 gave the imine, that on exposure to strongbase gave the indole 199. Gary A. Sulikowski, now at VanderbiltUniversity, showed92 that cyclization of the carbene derived from200 (Scheme 77) proceeded to give 201 with high regiocontrol.

Bond formation in the opposite direction has also been de-veloped. William D. Jones reported93 that a Ru complex catalyzedthe conversion of the isonitrile 202 (Scheme 78) into the indole203. This reaction may be proceeding by way of the Ru vinylidenecomplex.

Charles D. Jones of Lilly described94 an anionic cyclization in thisdirection, converting 204 (Scheme 79) into 205. Yoshinori Naka-mura of the Tanabe Seiyaku Co. contributed95 the Rh-mediatedcoupling of the diazophosphonate 207 (Scheme 80) to an ortho-acylaniline, such as 206, to give, after cyclization, the indole 208.Note that, in the cyclization of 209 (Scheme 81) developed96 byRodneyW. Stevens of Pfizer Nagoya, re-aromatization to the indole210 was achieved by elimination of arenesulfinate.

204 205TsTs

Scheme 79.

NH2 N

206 208

O

Ts

CO2Me1. CO2Et

P(OEt)2O

N2

207

/ Rh cat

2. DBU

Scheme 80.

N N210 HTs

DBU

Ph

O

CO2Me

O

PhCO2Me

209

Scheme 81.

O

Nenitzescu strategy

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7205

In 1994, Tohru Fukuyama, now at the University of Tokyo, dis-closed97a the cascade radical cyclizationof the isonitrile211 (Scheme82) to the indole 212. Later, he applied97b a variant of this cyclizationin the total synthesis of a complex indole alkaloid. JonD.Rainier, nowat theUniversityof Utah, has explored97c related radical cyclizations.

O

ON

HO

Bn

ONH2

221

NPNHBn

OH;

TFA

222

223

Scheme 87.

N N212 H211

OBn

C

Bu3SnH/AIBN; H+

OBn

Scheme 82.

Alois F€urstner of the Max-Planck-Institute M€ulheim devel-oped98a,b a reductive coupling of acyl anilides, such as 213 to give214 (Scheme 83). In the presence of a silyl chloride, the reactionwascatalytic in Ti. Bruce C. Lu of Boehringer Ingelheim employed98c thisreductive coupling in a combinatorial route to indoles.

N N214

H

HTiCl3

PhPh

213

O

O

Zn

Scheme 83.

NTs

O

CH3O CH3O

224

225

226

TfO

O

H

NHTs

OH

In 2009, Professor Doyle reported99 an alternative (Scheme 84)

diazo-based approach to indoles, Lewis acid-mediated cyclizationof 215 to 216.

N N

215 216

CO2Me

N2

HPh

Zn(OTf)2

CO2Me

Ph

Scheme 84.

NTsCH3O

227

Scheme 88.

Churl Min Seong of the Korea Research Institute of ChemicalTechnology described100 the facile cyclization (Scheme 85) of an o-cyano N-benzyl aniline 217 to the indole 218. Andrew D. Hamiltonemployed101 a related protocol (Scheme 86), the cyclization of 219to 220.

CN

N

NaH/DMF;

N

217 218Ph

Ac2OPh

OAc

Scheme 85.

CO2H

N N

219 220

OAcBr

MeO

HOAc/NaOAc

CO2Me

H

O

Scheme 86.

8. Type 7

Type 7 includes all routes to indoles from cycloalkane de-rivatives. The earliest such approach is the Nenitzescu indole syn-thesis, exemplified (Scheme 87) in a modern manifestation102 byDaniel M. Ketcha of Wright State University and Lawrence J. Wilsonof Procter & Gamble. The combination of the benzoquinone 221with the resin-bound enamine 222 gave, after release from theresin, the indole 223.

MichaelA. Kerrof theUniversityofWesternOntariodeveloped103

(Scheme 88) a complementary protocol for the conversion of a ben-zoquinone into the indole. DielseAlder cycloaddition of the imine224 to the diene 225 gave the adduct 226. Protection followed byoxidative cleavage and condensation delivered the indole 227.

Fused pyrroles, such as 231 (Scheme 89) and 235 (Scheme 90)are readily aromatized. Brian L. Pagenkopf of the University ofWestern Ontario established104 a pyrrole synthesis from cyclo-hexanone, by cyclopropanation of the enol ether 228 followed bycondensation with the nitrile 230. The aromatization of 231 to 232was accomplished by heating with Pd/C in mesitylene.

OMe

NH

CO2Et

228

1. N2

CO2Et

2.N

OBn

NC

229

230

ONBn

231

NH

CO2EtO

NBn

232

Pd-C

Scheme 89.

233

1.

2. BnNH2

234

235

O OPh

NO2

NBn

PhO

Ac2OO2

236

NBn

PhAcO

Scheme 90.

NH

van Leusen strategy

NH

O

O

NCTsPh

PhO

245

246

247

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107206

Teruhiko Ishikawa and Seiki Saito of Okayama University con-densed105 (Scheme 90) cyclohexane-1,3-dione 233 with the nitro-alkene 234, leading after exchange with benzylamine to the pyrrole235. Aromatization gave the 4-oxygenated indole 236. ChihiroKibiyashi of the Tokyo College of Pharmacy reported106 a relatedapproach to 4-oxygenated indoles.

Michel Pfau of ESPCI Paris devised107 an intriguing protocol forindole construction, starting with the benzyl imine of the monop-rotected cyclohexane-1,4-dione 237 (Scheme 91). Metalation of theimine followed by condensation with maleic anhydride 238, withmethanol workup, delivered the lactam 239. Exposure of 239 toPOCl3 effected aromatization to the 5-methoxyindole 240.

237

1. BnNH2

2.

238

239

NBn

O

POCl3

240

NBn

O

OO

OO O

MeOCO2Me

MeOCO2Me

Scheme 91.

NH

Ph

248

DDQ

Scheme 94.

NBs N

OCl CO2Et

ArS

In 2009, Yong-Qiang Tu of Lanzhou University described108 the

ring expansion (Scheme 92) of 241 to 242. The aromatization of 242to the indole should be facile. Tsutomu Inokuchi of Okayama Uni-versity showed109 that reduction (Scheme 93) of the Michael ad-duct 243 followed by aromatization delivered the indole 244.

241

NPh

242

N NPhTh

TBSOPh Au cat.

NPhTh

Scheme 92.

O

NO2Ph

242

MeOZn/NH4Cl

MeO N

Ph

O

1. Ac2O

2. DDQMeO N

Ph

O

243

244

Scheme 93.

9. Type 8

Type 8 indole syntheses include all those that proceed by way ofthe preformedN-containing five-membered ring. In 1986, AlbertM.van Leusen of Groningen University established110 a route to highlysubstituted indoles, based on the condensation of isonitriles, suchas 245 (Scheme 94) with unsaturated ketones, such as 246 to givethe 2,3-bisalkenylpyrrole 247. Heating followed by aromatizationwith DDQ completed the synthesis of the indole 248.

Hiroyuki Ishibashi of Kyoto Pharmaceutical University demon-strated111 (Scheme 95) a route to 4-substituted indoles from pyrroleitself. Condensation of 249 with the chlorosulfide followed by sa-ponification and intramolecular FriedeleCrafts acylation deliveredthe versatile intermediate 250. Oxidation gave the indole 251. Theaddition of nucleophiles to 250 followed by dehydration gave the 4-alkylindole (not illustrated).

Bs249

ArS

MCPBA

NBs

OH 250

251

Scheme 95.

Pedro Mancini of the Universidad Nacional de Litoral showed112

that nitropyrroles, such as 252 (Scheme 96) were effective Diel-seAlder dienophiles. Regiocontrol was poor with isoprene,whereas addition to the more activated diene 253 proceeded togive the 5-hydroxyindole 254 with complete regiocontrol.

NO2N

Ts

CO2Me

NTs

254

CO2MeHO

252 OMe

OTMS+

253

Scheme 96.

HN Ph

H

Pt cat. N

Ph

O O

265266

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e7210 7207

Edwin Vedejs of the University of Michigan optimized113 theacetic anhydride-mediated cyclization of the Stobbe condensationproduct 255 (Scheme 97) to the indole 256. Although this cycliza-tion had been reported earlier, Vedejs found that the conditionsoriginally described also delivered substantial quantities of anindolizidine by-product.

N

Ph

267

268

Scheme 101.NH

MeO2C

HOOC

NH

OH

MeO2C

Ac2O

255 256

Scheme 97.

Masanobu Hidai of the University of Tokyo developed114 the Pd-catalyzed cyclocarbonylation of the allylic acetate 257 (Scheme 98)to the 4-acetoxyindole 258. It seems likely that a more highlysubstituted version of 257 would cyclize with equal facility.

NAcO

N

OAcAc2O/CO

Pd. cat

OMe OMe257 258

Scheme 98.

Kanematsu strategy

N NAr

O

OCl

H269

1. CH2=O/CuBriPr2NH

2. DDQAr O OCl

270

Alan R. Katrizky of the University of Florida devised115 an ap-proach to indoles with more highly substituted benzene rings.Addition of the benzotriazolyl anion 259 (Scheme 99) to an enone,such as 260 followed by acid-catalyzed dehydrative cyclizationdelivered the indole 261.

NBs

LiN

NBs

Ph

Ph

O

259 260 261

N

N

+

Scheme 99.

Scheme 102.

OO

Bn

SiMe3 Ac2O

Naoki Asao of Tohoku University found116 that AuBr3 was aneffective catalyst for the cyclocondensation (Scheme 100) of 262with 263 to give the indole 264. F. Dean Toste of the University ofCalifornia, Berkeley uncovered117 a related Au-catalyzed cyclizationleading to indoles.

NTs

CHO

Ph

N

OPh

Ts

cat. AuBr3

OMe

262

263

264

Scheme 100.

NBn

N

O

CO2H

271 272

Scheme 103.

NTs

cat. AuCl3

273 274

HOO

NTs

Scheme 104.

In 2009, Chi-Meng Che of the University of Hong Kong118 de-scribed (Scheme 101) the Pt-mediated intramolecular hydro-amination of the alkyne 265. Condensation of the cyclic enamine266 so prepared with a b-diketone 267 proceeded with highregioselectivity to give the indoline 268. For the aromatization ofa similar N-benzyl indoline, see Scheme 41.

10. Type 9

The least developed approach to indoles is Type 9, the simul-taneous construction of both rings of the indole. This route waspioneered in 1986119 by Ken Kanematsu of Kyushu University.Homologation of 269 (Scheme 102) to the allene led to the intra-molecular DielseAlder cyclization product, that was readily aro-matized to the indole 270.

Three related approaches have been put forward since that time.Michael J. Martinelli, then at Lilly, established120 that aceticanhydride-mediated decarboxylation of 271 (Scheme 103) led toa 1,3-dipole, that added in an intramolecular fashion to the alkyne,delivering the dihydro indole 272. In a complementary approach, A.Stephen K. Hashmi of Ruprecht-Karls-Universit€at Heidelbergfound121 that with catalytic AuBr3, 273 (Scheme 104) cyclized ef-ficiently to 274. As outlined earlier in this review, both 272 and 274would be readily aromatized to the corresponding indoles.

In 2009, Peter Wipf of the University of Pittsburgh described122

the intramolecular DielseAlder cyclization (Scheme 105) of theallylic alcohol 275. Microwave heating led directly to the doublyaromatized product 276.

NH

microwave

275 276

O NBoc

OH

Ph

Ph

D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107208

11. Conclusions

In this review, we have tried to be inclusive, but certainly notcomprehensive. We hope that the scheme outlined here for theclassification of synthetic routes to indoles will be useful to futurepractitioners of the art, and will stimulate new thinking in the field.

Scheme 105.

Acknowledgements

The authors thank Professor Gordon W. Gribble for his adviceand encouragement. PKT thanks Randy W. Jackson for his un-derstanding and support.

References and notes

1. For recent reviews of indole synthesis, see (a) Patil, S. A.; Patil, R.; Miller, D. D.Curr. Med. Chem. 2011, 18, 615e637; (b) Cacchi, S.; Fabrizi, G.; Goggiamani, A.Org. Biomol. Chem. 2011, 9, 641e652; (c) Song, J. J.; Reeves, J. T.; Fandrick, D. R.;Tan, Z.; Yee, N. K.; Senanayake, C. H. ARKIVOC 2010, 390e449; (d) Palmisano,G.; Penoni, A.; Sisti, M.; Tibiletti, F.; Tollari, S.; Nicholas, K. M. Curr. Org. Chem.2010, 14, 2409e2441; (e) Patil, S. A.; Patil, R.; Miller, D. D. Curr. Med. Chem.2009, 16, 2531e2565; (f) Barluenga, J.; Rodriguez, F.; Fananas, F. J. Chem.dAsian J. 2009, 4, 1036e1048; (g) Russel, J. S.; Pelkey, E. T. Prog. Heterocycl.Chem. 2009, 20, 122e151; (h) Kr€uger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal.2008, 350, 2153e2167; (i) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,2875e2911; (j) Gribble, G. W. Pure Appl. Chem. 2003, 75, 1417e1432; (k)Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045e1075.

2. Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R., Sr.; Smith, P. R.; Reddy, J. P.;Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil, J. K.; Wang, S. J. Org. Chem.1997, 62, 9192e9202.

3. Chae, J.; Buchwald, S. L. J. Org. Chem. 2004, 69, 3336e3339.4. Yasui, E.; Wada, M.; Takamura, N. Tetrahedron Lett. 2006, 47, 743e746.5. Maruoka, K.; Oishi, M.; Yamamoto, H. J. Org. Chem. 1993, 58, 7638e7639.6. Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853e2856.7. Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121,

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D.F. Taber, P.K. Tirunahari / Tetrahedron 67 (2011) 7195e72107210

Biographical sketch

Douglass F. Taber was born in 1948 in Berkeley, California. He earned a B.S. in Chem-istry with Honors from Stanford University in 1970, and a Ph.D. in Organic Chemistryfrom Columbia University in 1974 (G. Stork). After a postdoctoral year at the Universityof Wisconsin (B.M. Trost), Taber accepted a faculty position at Vanderbilt University. Hemoved to the University of Delaware of Delaware in 1982, where he is currently Pro-fessor of Chemistry. Taber is the author of more than 200 research papers on organicsynthesis and organometallic chemistry. He is also the author of the weekly OrganicHighlights published at http://www.organic-chemistry.org/.

Pavan K. Tirunahariwas born in Warangal, A.P, India in 1968. He received his Bachelorof Science and Master of Science degrees from Osmania University, Hyderabad. He thenjoined the group of Dr. B. G. Hazra at National Chemical Laboratory, Pune, Maharastra.He received his Ph.D degree in Organic Chemistry from the University of Pune. He didhis postdoctoral studies in the group of Professor James. P. Morken at the University ofNorth Carolina. Currently he is working at Accel Synthesis, Inc., Garnet Valley, PA. Hisresearch interests include process research, synthetic methodologies, medicinal chem-istry, and pharmacology.