Tetrahedron Letters 56 (2015) 296–302

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Tetrahedron Letters

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Digest Paper

Indole synthesis through transition metal-catalyzed C–H activation

http://dx.doi.org/10.1016/j.tetlet.2014.11.1140040-4039/� 2014 Elsevier Ltd. All rights reserved.

⇑ Corresponding author.E-mail address: zkyu@dicp.ac.cn (Z. Yu).

Tenglong Guo a, Fei Huang a, Likun Yu b, Zhengkun Yu a,⇑a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, Chinab Fertilizer Analysis Station of Technology Center, SINOPEC Baling Petrochemical Company, Qilishan, Yueyang Tower Region, Yueyang, Hunan 414003, China

a r t i c l e i n f o a b s t r a c t

Article history:Received 19 August 2014Revised 20 November 2014Accepted 22 November 2014Available online 3 December 2014

Keywords:IndoleC–H activationTransition-metal-catalyzed

Indole synthesis is among one of the most important tasks in N-heterocyclic chemistry. Versatile syn-thetic methods have been developed for the establishment of an indole backbone, but concise andstraightforward routes to access indole derivatives have been strongly desired. This digest paper summa-rizes the major advances in catalytic synthesis of indoles through transition-metal-catalyzed C–H activa-tion during the last five years. Brief discussions are given for possible applications of these syntheticprotocols.

� 2014 Elsevier Ltd. All rights reserved.

Contents

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 296Intramolecular C–H/C–H cross-couplings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297Annulation of anilides (anilines) with alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298

Annulation of arylamides (anilides) with alkynes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298Annulation of anilines with alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299

Annulation of arylhydrazines and related compounds with alkynes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299Cyclization of o-alkynylanilines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300C–H amination of aryl and alkenyl azides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Cyclization of aryl isocyanides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Intramolecular C–H/C-halo cross-coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Versatile synthesis of indoles involving C–H activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302

Introduction

Indole functionality exists in many natural products and phar-maceuticals. A lot of efforts have been devoted to develop syntheticmethods to access diverse indoles1 since Fisher indoles were pre-pared in 1883.2 Although indole derivatives can be obtained byfunctionalizing simple indoles,3 specific methodologies have tobe established to synthesize various indoles. Transition-metal-cat-alyzed cross-couplings involving C–H activation have recently

been paid considerable attention for the construction of C–C4 andC–N5 bonds. For the synthesis of indole derivatives, C–H activationhas been considered as an alternative strategy to supplement therelevant traditional synthetic protocols.1 Åkermark and Knölkerreported the first examples of palladium-catalyzed oxidative intra-molecular C–H/C–H cross-coupling of ArXAr0 (X = O, NY) to synthe-size carbazoles and dibenzofurans, respectively,6 which initiatedthe investigation on transition-metal-catalyzed cross-dehydroge-native coupling (CDC) to prepare heterocyclic compounds.7 Todate, the CDC strategy has become a promising strategy for theconstruction of an indole backbone. Herein, the major advancesduring the last five years in transition-metal-catalyzed indole

NR1

NH

R1 R2

R310 mol % Pd(OAc)2Bu4NBr (2 equiv)

O2 (1 atm)DMSO, 60 oC, 24 h

up to 93% yieldR2 = alkyl, aryl, (hetero)arylR3 = H, Ph, CN

R2

R3

Scheme 3.

N NPh Ph NH

NHPh Ph

N NPMP PMP

(PMP = 4-MeOC6H4)

as aboveHNNH

MeO OMe

50%

90%

20 mol % Pd(OAc)2Bu4NBr (2 equiv)

O2 (1 atm)DMSO, 60 oC, 24 h

Scheme 4.

20 mol % Pd(OAc)2Cu(OAc)2 (3 equiv)

DMSO, 40 oC, 24 h NH

RMeO

+

(5 equiv) 55% (R = Me)41% (R = CO2Et)

O

R

OMe

NH2

Scheme 5.

DMF/DMSO120 °C, Ar

H

NH

SR1

H

R2OR3

CuCl2 (3 equiv)K3PO4 (3 equiv)

NH

COR2

SR1

R3

up to 96% yield

T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302 297

synthesis through C–H activation, usually under oxidative condi-tions, are summarized with brief discussion of their possible appli-cations. This digest is presented by the classifications of reactiontypes.

Intramolecular C–H/C–H cross-couplings

The intramolecular CDC reactions have been applied as a pow-erful tool to access functionalized indoles. Glorius et al. reportedpalladium(II)-catalyzed, copper(II)-mediated cyclization of enam-ine methyl (Z)-3-phenyl(amino)but-2-enoate and its analogues toform indoles (Scheme 1).8 A proposed mechanism suggests thatthe reaction begins with an electrophilic palladation of the nucle-ophilic enamine at a-C atom, followed by deprotonation, resultingin a palladium complex intermediate suitable for intramolecularC–H activation. Subsequent reductive elimination generates theindole product and a Pd(0) species which can be reoxidized tothe Pd(II) complex by the terminal oxidant Cu(OAc)2.8a With simi-lar substrates by means of 10 mol % FeCl3/1.5 equiv Cu(OAc)2-

�CuCl2/K2CO3/DMF as the catalytic system, Liang et al. preparedthe same types of indole products.9 In the presence of PdCl2/Cu(OAc)2/TFA/CH3CN, 1,3-disubstituted indoles were synthesizedthrough the cyclization of N-alkyl aryl tertiary enamines.10 Forthese transformations, solvents were found to play an importantrole.11

Multisubstituted indoles were also prepared from N-arylenaminones through C–H activation under copper catalysis. With5 mol % CuI as the catalyst and 35 mol % 1,10-phenanthroline asthe ligand in the presence of a base such as Li2CO3 (2 equiv), intra-molecular oxidative C–H/C–H cross-coupling of N-aryl enaminonesoccurred in N,N-dimethylformamide (DMF) to afford the corre-sponding indole products in up to 83% yields (Scheme 2).12 In thiscase, air acted as the effective terminal oxidant, featuring a mono-metallic catalyst system.

Due to the possible tautomerization of imines to enamines,N-aryl imines were rendered to undergo intramolecular CDCreactions to form indoles, providing a new route to indoles fromanilines and ketones (Scheme 3).13 A KIE of 5.2 was obtained forthe aromatic C–H of the N–Ar moiety, which is of a similar magni-tude to those commonly observed in palladium-catalyzed aromaticC–H functionalization involving a concerted metalation–deproto-nation mechanism. Two-fold oxidative cyclizations also occurredto give the fused indoles or bis(indolyl)benzene (Scheme 4).

NH

R2

EWG

R1

NH

R1 R2

EWG5-10 mol % Pd(OAc)2Cu(OAc)2 (3 equiv)

K2CO3 (3 equiv), DMF80-140 oC, 0.5-16 h

up to 85% yieldEWG = CO2R3 (R3 = Me, Et, tBu)CN

R2 = alkyl, aryl, OEt, CF3,(hetero)aryl

Scheme 1.

N

Ar1

COAr2

R1

NR1 Ar1

COAr25 mol % CuI

35 mol % 1,10-phen

Li2CO3 (2 equiv), DMF100 oC, 24 h, air

up to 83% yieldR2 = H, Me

R2 R2

Scheme 2.

Scheme 6.

NH

R1

N

R25 mol %[Cp*Rh(MeCN)3][SbF6]

53-80%

R2

+Cu(OAc)2.H2O (2.1 equiv)toluene, O2, 60

oC, 12 hMe2N OR3

R3

Me2NO

R1

Scheme 8.

NAcH

R1

NAc

R1 R3

R22.5 mol % [Cp*RhCl2]210 mol % AgSbF6

50-83%R2, R3 = alkyl, aryl,(hetero)aryl

R2

R3+

Cu(OAc)2.H2O (2.1 equiv)tAmOH, 120 oC, 1 h

Scheme 7.

HN NMe2

OH

+ Me BO O

NMe

N

Me2N

Me

O

10 mol %[Cp*Rh(MeCN)3][SbF6]

Cu(OAc)2 (2.2 equiv)acetone, 80 oC, 18 h

10 mol % Pd(OAc)220 mol % Sphos

PhBr, K3PO4THF/H2O, 60 oC, 18 h

N

Me2N

Me

Ph

O

O O

BO O

NMe

O O

42% 59%

Scheme 9.

NH2

10 mol % Pd(OAc)2O2 (1 atm)

DMA/PivOH (4:1)120 oC, 12 h

NH

CO2Me+

up to 99% yield

CO2Me

CO2Me

R

CO2Me

R

Scheme 11.

N

MeO2C CO2Me

N

MeO2C CO2Me

MeN

MeO2C CO2MeNH

46% 71% 83% 60%

Scheme 12.

NH2R1

NH

R1 R3

R25 mol % Cp*Rh(H2O)3(OTf)2

up to 93% yield

+Ac2O (1.5 equiv), tAmOHO2 (1 atm), then NaOH

100 oC, 24 h

R2

R3

Scheme 13.

N

HN

R1+

R3

R2

4 mol % Pd(MeCN)2Cl2CuCl2 (2.1 equiv)

DMF, 105 oC, 12 h

up to 90% yield

N N

R2R3

R1

Scheme 14.

NR1 N

R1 R3

R22.5 mol % [RuCl2(p-cymene)]2

20 mol % KPF6Cu(OAc)2.H2O, H2O

100 oC, 22 h

up to 95% yield

+or 10 mol % Ni(cod)220 mol % dppf160 oC, 20 h

H

2-pymN

N

NaOH, DMSO

120 oC, 24 hR1 = H, R2 = R3 = Ph

NH

Ph

Ph

92%

R2

R3

Scheme 15.

R22.5 mol % [Cp*RhCl2]2R2

298 T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302

The one-pot oxidative condensation of aniline and ketone wasalso realized by means of the Pd(OAc)2/Cu(OAc)2 catalyst system.Thus, p-anisidine reacted with acetone and ethyl pyruvate toafford the corresponding indoles derivatives (Scheme 5), whileonly trace amount of the target products was observed withthe Pd(OAc)2/O2 system. A copper(II)-mediated indole synthesishas recently been documented by means of a-oxo ketene N,S-acetals as the substrates and CuCl2 as the mediator (Scheme 6).14

The presence of a thioalkyl was crucial for the intramoleculardehydrogenative C–H/C–H coupling to form an indole core. Sucha thioalkyl can be rendered diverse transformations that thismethod provides a concise route to access highly functionalizedindole derivatives.

It is noted that iridium(I)-induced, visible light-driven intramo-lecular C–H functionalization of tertiary amines,15 metal-freeiodine-catalyzed,16 and PhI(OAc)2-mediated17 cyclizations of N-aryl enamines were achieved for indole synthesis, and Larock-typem-iodoaryl substituted anilines could also be employed to preparevinyl indoles in the presence of an alkyne under palladiumcatalysis.18

Annulation of anilides (anilines) with alkynes

Annulation of arylamides (anilides) with alkynes

Fagnou and co-workers first reported indole synthesis via rho-dium-catalyzed oxidative coupling of acetanilides and internalalkynes (Scheme 7).19a With [Cp*Rh(MeCN)3][SbF6] as the precata-lyst under atmospheric oxygen the same reactions could be con-ducted at 60 �C to achieve up to 90% yield for the target indoleproducts.19b Using enynes as the functionalized alkyne substrates,2-alkenylindoles were constructed in a similar fashion(Scheme 8).19c In the presence of 5 mol % Pd/C catalyst, the 2-alke-nylindoles were efficiently reduced to the corresponding 2-alkylin-doles by 1 atm H2, and the dimethylurea protecting group could beremoved by saturated aqueous potassium hydroxide in ethanol.Under Rh(I) catalysis, the urea-protected aniline reacted withan alkynyl MIDA (N-methyliminodiacetic acid) boronate to form

R2 = Me, Et, iPr, tBuR3 = H, Me, EtR4 = Me, tBu

+

HN R2

OOR3

OR4O

2.5 mol % [Cp*RhCl2]213 mol % AgSbF6

Cu(OAc)2.H2O (2.1 equiv)tAmOH, 120 oC, 24 h

-CO

N

OR2

R3

up to 75% yield

R1R1

Scheme 10.

NHNHAc

R1

NAc

R1 R325 mol % CsOAc

up tp 93% yield

R3

+AcOH (1.2 equiv)

DCE, 70-100 oC, 16 h

Scheme 16.

an indole MIDA boronate, which was transformed to the corre-sponding indole in a reasonable yield (Scheme 9).20

The Rh(III)-catalyzed reaction of N-tolyl trans-crotyl-amidewith an alkyne also gave the indole product.21 It is noteworthy that

NH

R3

R25 mol % [Cp*RhCl2]220 mol % AgSbF6

up to 95% yield

R3

+Cu(OAc)2.H2O (2 equiv)MeOH, 90 oC, 2 h, Ar

NNNR1

R1R2

Scheme 19.

NR1R2

+ TsN3

CuTC(10 mol)

toluener.t., 2 h NR1

R2

NNN

Ts

NR1

R2

TsN

Rh2(oct)4 (2 mol %)60 o, DCE, 4 h

K2CO3, MeOH

60 oC, 2h

N2

NR1 R2

O

Scheme 20.

R2

NMe2

+

R3

H

5 mol % Pd(OAc)2nBu4NI (1 equiv)

HOAc (1 equiv)DMSO, 50-80 oC, air

R1R1

NMe

R2

R3

Scheme 21.

Ar

NH2

+N Y

X

X = O, SY = CH, N

20 mol % Cu(OAc)220 mol % 1,10-phen

K2CO3 (1 equiv)toluene, refluxO2 (1 atm), 10 h

up to 90% yield

NAr

(hetero)Ar

RR

Scheme 22.

NHBoc

OR2

+OTIPS

Me10 mol % PtCl2

20 mol % P(C6F5)3

Na2CO3, dioxane80 oC, 12 h

N

MeOTIPS

R1 R1

T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302 299

the cyclization of an anilide with alkenes such as allyl carbonatescan also be used to synthesize indole derivatives (Scheme 10).22

Annulation of anilines with alkynes

N-Unprotected anilines reacted with functionalized alkynes toform 2,3-disubstituted indoles in up to 99% yields by means of10 mol % Pd(OAc)2 as the catalyst and dioxygen as the oxidant(Scheme 11).23 A mixture of DMA and PivOH (4:1) as the solventis crucial for the reactions to occur efficiently. With N-monosubsti-tuted anilines as the substrates annulated indoles were obtained in46–83% yields, while in the presence of an aryne carbazole was gen-erated in a moderate yield (60%) (Scheme 12). Through the in situgeneration of acetanilides from the reactions of anilines and Ac2O,anilines underwent rhodium-catalyzed oxidative C–H/activation/annulation with alkynes to furnish indoles (Scheme 13).24

[Cp�RhCl2]2/Cu(OAc)2 catalyzed the oxidative coupling of N-aryl-2-aminopyridines with alkynes to afford N-(2-pyridyl)indoles,25

while the Pd(II) catalyst promoted the same transformations undermilder conditions (Scheme 14).26 With a Ru(II) catalyst andCu(OAc)2�H2O as the oxidant,27a or with a Ni(0) catalyst in theabsence of an oxidant,27b N-(2-pyrimidyl)anilines reacted withalkynes to give N-(2-pyrimidyl)indoles. The 2-pyrimidyl groupcan be readily removed under basic conditions, demonstrating auseful method to access bioactive indoles (Scheme 15). Visiblelight-driven gold catalysis was also used for the same purpose.28

Annulation of arylhydrazines and related compounds withalkynes

Through a mechanism different from that for Fischer indolesynthesis, Glorius et al. developed a Rh(III)-catalyzed hydrazine-directed C–H activation protocol for the synthesis of indoles.29

With arylhydrazines as the substrates to be annulated with alkynesthrough N–N bond cleavage indole derivatives were efficiently pro-vided in up to 93% yields (Scheme 16). Acetic acid promoted thereaction as an additive. The three-component reaction of arylhydr-azine, C@O compound, and alkyne was also utilized to synthesizeN-unprotected indoles under Rh(III) catalysis by in situ condensa-tion of arylhydrazine with the C@O source to form an hydrazoneintermediate (Scheme 17).30 Rh(III)-catalyzed cyclization of N-nitr-osoanilines with alkynes underwent to give indoles in the absenceof an external oxidant (Scheme 18).31a Such a strategy was alsoapplied under neutral conditions.31b Aryl triazines were used forthe aromatic C–H annulation with alkynes, affording 2,3-disubsti-tuted indoles (Scheme 19).32 The N–N bond cleavage seems to befacilitated by acetic acid generated from the C–H activation. A broadscope of substrates was well tolerated to construct unprotected

NHNH2 +

R2

R1iPr

O+

2.5 mol % [Cp*RhCl2]2KOAc (1.1 equiv)

MeOH, N280 oC, 12-18 h

NH

R1 R3

R2

.HCl

R1

56-92%

Scheme 17.

NN

R1

NR1 R4

R34 mol % [Cp*RhCl2]216 mol % AgSbF6

up to 87% yield

+NaOAc (4 equiv)MeCN, 100 oC, 20 h

R2 ≠ HR2

OR2

R3

R4

Scheme 18.

5 equiv 50-90% Boc

Scheme 23.

NMe2

10 mol % CuBraq TBHP (3 equiv)

80 oC, 2.5-4 h60-82%

NMe

ArO

R1 R1

Ar

Scheme 24.

indoles with excellent regioselectivity. An efficient Cu/Rh-catalyzedmethod was developed to synthesize substituted 3-indolyliminesand indole-3-carboxaldehydes from N-propargylanilines throughRh(II)-catalyzed denitrogenative annulation of N-sulfonyl-1,2,3-

+

R4

R3

10 mol % Pd(OAc)220 mol % Cu(OAc)2.CuCl2

NaOAc (3 equiv)TBAB (1 equiv)PivOH (2 equiv)DMAc, O2 (1 atm)90 oC, 10 h

NMe2NMe

R2R3R4

R1R1 R2

Scheme 25.

10 mol % Pd(OAc)2nBu4NI (1 equiv)

HOAc (2 equiv), DMSOair, 50 oC, 12 h

NMe2

NMe

N

R3

OR1

R2R2

O

R1HNR3

or5 mol % Pd(OAc)2nBu4NI (0.1 equiv)

HOAc (2 equiv), DMSOair, 80 oC, 12 h

Scheme 26.

OR2

n

NHAc

5 mol % [Cp*Rh(MeCN)3][SbF6]220 mol % Cu(OAc)2.H2O

O2 (1 atm), acetone, r.t., 16-72 h

R1NAc

O

up to 99%

n

R1

Scheme 27.

1 mol % [Rh2 (esp)2]

4A MS ( 100 wt %)toluene, 75 oC, 16 hup to 99% yield

+

> 95:1 to < 5:95

NO2

N3R1

NH

NH

R1R1

NO2

NO2

Scheme 29.

5 mol %[Rh2 (O2CC3F7)4]

4A MS ( 100 wt %)toluene, 75 oC, 16 h

90-99%

> 95:5

N3 NHR1

R2

R3

R1

R3

R2

NH

R1

R3

R2+

Scheme 30.

10 mol % Fe(OTf)2

THF, 80 oC, 24 h

56-99%

R2

O

N3R1

R1NH

O

R2

Scheme 31.

+ B2pin2

10 mol % CuOAc20 mol % PPh3MeOH (1 equiv)THF, r.t., N2, 5 h

R2 = CO2Me, COMe,CONMe2, CN

NCR1

R2

NH

R1

R2

Bpin

Scheme 32.

300 T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302

triazoles (Scheme 20).33 Further hydrolysis or reduction ofthe imine intermediates afforded the corresponding aldehydeproducts.

Cyclization of o-alkynylanilines

Palladium-catalyzed coupling of ortho-alkynylanilines with ter-minal alkynes34 or alkenes34 gave 3-alkynyl- or 3-alkenylindoles.The reaction media and atmosphere played an important role inthe reaction efficiency. 2,3-Disubstituted 3-alkynylindoles werethus obtained in moderate to excellent yields (Scheme 21).34 Inthe presence of a heteroarene copper-catalyzed C–H/N–H couplingannulation of o-alkynylanilines was conducted to produce N-het-eroaryl substituted indoles (Scheme 22).35 With a diene as the cou-pling partner, rhodium- and platinum-catalyzed [4+3]cycloaddition of o-alkynylanilines underwent with concomitantindole annulation to afford cyclohepta[b]indoles (Scheme 23).36

Furans participated in the reactions to afford tetracyclic indolederivatives in moderate to good yields. 3-Aroylindoles were con-structed by copper-catalyzed oxidative cyclization of o-alkynylatedN,N-dimethylamines via a sp3 C–H activation a to the nitrogenatom (Scheme 24).37 In the overall reaction, tert-butyl hydroperox-ide (TBHP) acted as the oxidant. The combination of 10 mol %PdBr2/10 mol % CuI/LiCl (2 equiv)/TBHP also enabled the same

M.G.R2

OEt20 mol % FeBr2

toluene, 140 oC

42-98%M.G. = Migrating Group

N3 NH

M.G.

R2

R1 R1

Scheme 28.

reactions in toluene at 100 �C.38 Variation of the reaction parame-ters made the reactions of o-alkynylanilines with internal alkynesyield carbazole derivatives (Scheme 25).39 Palladium(II)-catalyzedoxidative intramolecular diamination of internal diarylalkynesafforded indolo[3,2-c]iso-quinolinones (Scheme 26).40 This proto-col combined the cyclization of o-(1-alkynyl)benzamides and theCacchi indole synthesis under oxidative conditions. In a similarfashion, rhodium(III)-catalyzed intramolecular annulation of

NC

10 mol % Pd(OAc)220 mol % Ad2PnBu

Cs2CO3 (1.2 equiv)toluene, 120 oC

NH

Ar+

34-85%

R1 R1CH3

ArX

X = I, Br, Cl

Scheme 33.

YR1

X

X

H2N R2 R4R3

O

2 mol % [Pd2dba3]5 mol % dppf

Cs2CO3 (2.2 equiv)MgSO4 (10 equiv)toluene, 130 oC, 48 h

+ +

YR1

NR2

R4

R3

up to 69% yield

X = Cl, Br, IY = CH, N

Scheme 35.

NH Cl

R 10 mol % Pd(OAc)2Cu(OAc)2 (1.5 equiv)

DMF, HOAc100 oC, 12 h

N

Cl

R

87-98%

Scheme 36.

OH

NH2

cat. Ru/CeO2

mesitylene140 oC, 18 h, Ar

- H2

NH

>99%

Scheme 37.

R1 N

R3R25 mol % FeCl2

THF, 70 oC, 24 hup to 93% yield

NH

R1 R3

R2

Scheme 38.

2.5 mol % [Cp*RhCl2]225 mol % CsOAc

up to 91% yield

+AcOH (50 mol %)H2O, 100 oC, 1 h

HNNHAc

N

CO2Et

ON2

EtOO

NHAcR1 R1

Scheme 39.

T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302 301

alkyne-tethered acetanilides proceeded to give fused tricyclicindoles (Scheme 27).41 It is noted that under reductive conditions,nitroaromatics42a and nitrosoarenes42b can be used as the precur-sors to anilines for annulation with alkynes to form indoles.

C–H amination of aryl and alkenyl azides

Aryl and alkenyl azides were used as the starting substrates toconstruct indoles with release of nitrogen gas. FeBr2-catalyzedintramolecular C–H amination/[1,2]-shift tandem reactions of arylazides afforded 2,3-disubstituted indoles (Scheme 28).43 The pref-erence for the 1,2-shift component of the tandem reaction wasestablished to be Me < 1� < 2� < Ph. Similar reactions occurred fromb-nitro styryl azides under rhodium(III) catalysis, undergoing nitro-group migration to give 3-nitroindoles (Scheme 29).44 Using otherb-electron-withdrawing group-substituted styryl azides as the sub-strates led to the same type of indole products. Rhodium carboxyl-ate complexes catalyzed cascade reactions of b,b-disubstitutedstyryl azides to produce 2,3-disubstituted indoles.45 Thus, polycy-clic complex functionalized N-heterocycles were constructed(Scheme 30). A one-pot CuI-catalyzed SNAr reaction of o-bromoch-alcones with sodium azide and subsequent intramolecular cycliza-tion through nitrene C–H insertion produced 2-carbonylsubstituted indoles.46 Azidoacrylates also underwent the similarintramolecular C–H amination by means of Fe(OTf)2 as the catalyst(Scheme 31).47

Cyclization of aryl isocyanides

Copper(I)-catalyzed borylative cyclization of 2-alkenyl-aryl iso-cyanides using diboronate B2pin2 was realized to prepare 2-bory-lindoles which can be applied as versatile intermediates inorganic synthesis (Scheme 32).48 The reactions proceeded at ambi-ent temperature under neutral conditions and showed high toler-ance to functional groups, such as Br, CO2R, COR, CONMe2, andCN. A palladium-catalyzed tandem process consisting of isocyanideinsertion and benzylic C(sp3)–H activation was achieved to give thecorresponding indoles (Scheme 33).49 A bulky phosphine ligand isnecessary for the reaction to smoothly occur.

Intramolecular C–H/C-halo cross-coupling

Transition-metal-catalyzed tandem C–H alkynylation and aryla-tion provides a convenient route to polycyclic aromatic compounds.Intramolecular C–H/C-halo cross-coupling has recently become acommon method to access an indole core. Niobium-catalyzedC(sp3)-H insertion to an in situ generated fluorine-substituted carb-enoid intermediate gave N-fused indoles (Scheme 34).50 Multi-component reactions were also employed to synthesize indolederivatives by dual palladium-catalyzed coupling reactions(Scheme 35).51

Versatile synthesis of indoles involving C–H activation

2-Chloro-N-(2-vinyl)anilines underwent oxidative cyclization toproduce indole products in good to excellent yields (Scheme 36),52

Ph

N

CF3

X

n

1) 30 mol % NbCl5NaAlH4 (4 equiv)dioxane, reflux

2) 10 mol % RuZr-P1 atm O2tolunene, reflux

N X

Ph

52-87%

n

X = CH2, O, S, NMe

Scheme 34.

while the C–H/C–Cl cross-coupling occurred under basic condi-tions. Acetanilides reacted with allyl acetates to afford N-Ac indolesunder Rh(III) catalysis.53 Heterogenous ceria-supported rutheniumcatalysts effected the synthesis of indole (>99%) via dehydrogena-tive N-heterocyclization (Scheme 37).54 An iron(II)-catalyzed C–Hamination via ring opening of 2H-azirines efficiently formed 2,3-disubstituted indoles (Scheme 38).55 Rh(III)-catalyzed cyclizationof 2-acetyl-1-arylhydrazines with diazo compounds via C–H activa-tion was developed to prepare 1-aminoindoles (Scheme 39).56

Conclusions and perspectives

The present results summarize and highlight the recent majoradvances in the synthesis of indoles through processes involvingtransition-metal-catalyzed C–H bond activation. Development ofconcise and straightforward synthetic approaches to construct

302 T. Guo et al. / Tetrahedron Letters 56 (2015) 296–302

indoles has been the challenging task for organic chemists. Transi-tion-metal-catalyzed dehydrogenative C–H/C–H and C–H/N-Hcoup-lings are among the most concise and straightforward routesto indole motifs although preparation of the starting substrates isnot so easy in some cases. In a view of application, one-potprotocols are desired to produce highly functionalized or function-alizable indole derivatives, and the relevant metal-free syntheticmethodologies should also be paid considerable attention in thisarea.

Acknowledgements

We are grateful to the National Natural Science Foundation ofChina (21472185) and the National Basic Research Program ofChina (2015CB856600) for support of this research.

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