recent advances in the regioselective synthesis of indoles

23
2655 © Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2655–2677 I. Kumar et al. Review Syn thesis Recent Advances in the Regioselective Synthesis of Indoles via C–H Activation/Functionalization Inder Kumar a,b Rakesh Kumar a,b Upendra Sharma* a,b a Natural Product Chemistry and Process Development Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176061, India b Academy of Scientific and Innovative Research, CSIR-IHBT, Palampur, Himachal Pradesh 176061, India [email protected] [email protected] These authors contributed equally to this review. N R 1 R 2 R 3 NHR 1 R 2 NHR 1 R 2 R 3 R 3 R 3 R 1 R 2 N R 1 R 2 N Intramolecular cyclization Intermolecular cyclization Metal or metal-free Metal-catalyzed N O Cl CH2CO2H MeO Me N NMe2 N Me O NH N Me Lotronex Indomethacin Iprindole Indole-based bioactive molecules Received: 25.01.2018 Accepted after revision: 05.03.2018 Published online: 28.05.2018 DOI: 10.1055/s-0037-1609733; Art ID: ss-2018-m0041-r Abstract Indole is an important heterocyclic motif that occurs ubiqui- tously in bioactive natural products and pharmaceuticals. Immense ef- forts have been devoted to the synthesis of indoles starting from the Fisher indole synthesis to the recently developed C–H activation/func- tionalization-based methods. Herein, we have reviewed the progress made on the regioselective synthesis of functionalized indoles, includ- ing 2-substituted, 3-substituted and 2,3-disusbstituted indoles, since the year 2010. 1 Introduction 2 Metal-Catalyzed Synthesis of 2-Substituted Indoles 3 Metal-Catalyzed Synthesis of 3-Substituted Indoles 4 Metal-Free Synthesis of 3-Substituted Indoles 5 Metal-Catalyzed 2,3-Disubstituted Indole Synthesis 5.1 Metal-Catalyzed Intramolecular 2,3-Disubstituted Indole Synthe- sis 5.2 Metal-Catalyzed Intermolecular 2,3-Disubstituted Indole Synthe- sis 6 Metal-Free 2,3-Disubstituted Indole Synthesis 6.1 N-Protected 2,3-Disubstituted Indole Synthesis 6.2 N-Unprotected 2,3-Disubstituted Indole Synthesis 7 Applications 8 Summary and Outlook Key words indoles, C–H activation, catalytic, metal-free, natural products 1 Introduction The indole moiety is one of the key heterocyclic motifs that occur ubiquitously in bioactive natural products, phar- maceuticals, agrochemicals, fragrances, pigments and in optoelectronic functional materials. 1 Examples of indole- containing biologically active compounds include arbidol (1), indomethacin (2), PD-0298029 (3), reserpine (4), iprin- dole (5) and dimebon (6) (Figure 1). 2 The synthesis of indole and its derivatives has been the topic of research for over 130 years, and a variety of classical methods have been dis- covered during this time including: Fisher, Bischler, Gassmann and Batcho–Leimgruber syntheses of indoles. 3 However, these methods have several limitations, for exam- ple, in the case of the Fischer indole synthesis, toxic hydra- zine hydrate is required along with highly acidic conditions and overall, the functional group tolerance is moderate. Over the last two decades, various methodologies have been developed to overcome the existing limitations of the synthesis of indole derivatives. Several metal-catalyzed and metal-free approaches have been reported for the synthesis of indole derivatives. Different research groups have com- piled the literature on the synthesis of indoles with focus on diverse aspects. 4 Figure 1 Selected examples of bioactive indoles The present review focuses on the recent advancements in the regioselective synthesis of substituted indole deriva- tives, covering the literature from 2011 to present. N Me Br HO N Me Me S O O Me arbidol (1) antiviral for influenza infection N H N O Me O O Me MeO PD-0298029 (3) M4 muscarinic receptor antagonist N COOH Me O Cl MeO indomethacin (2) anti-inflammatory drug N N Me N Me Me dimebon (6) anti-histamine drug N iprindole (5) N H MeO N H H H O OMe O OMe OMe OMe O OMe NMe2 3 reserpine (4) antipsychotic and antihypertensive drug antidepressant drug SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2018, 50, 2655–2677 review en This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

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2655

I. Kumar et al. ReviewSyn thesis

SYNTHESIS0 0 3 9 - 7 8 8 1 1 4 3 7 - 2 1 0 X© Georg Thieme Verlag Stuttgart · New York2018, 50, 2655–2677reviewen

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Recent Advances in the Regioselective Synthesis of Indoles via C–H Activation/FunctionalizationInder Kumar ‡ a,b Rakesh Kumar ‡ a,b Upendra Sharma*a,b

a Natural Product Chemistry and Process Development Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, 176061, India

b Academy of Scientific and Innovative Research, CSIR-IHBT, Palampur, Himachal Pradesh 176061, [email protected]@gmail.com

‡ These authors contributed equally to this review.

NR1

R2

R3

NHR1

R2

NHR1

R2

R3

R3

R3

R1R2N

R1R2N

Intramolecularcyclization

Intermolecularcyclization

Metal or metal-free Metal-catalyzed

N

O

Cl

CH2CO2HMeO

Me

N

NMe2

NMe

O NH

N

Me

Lotronex Indomethacin Iprindole

Indole-based bioactive molecules

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Received: 25.01.2018Accepted after revision: 05.03.2018Published online: 28.05.2018DOI: 10.1055/s-0037-1609733; Art ID: ss-2018-m0041-r

Abstract Indole is an important heterocyclic motif that occurs ubiqui-tously in bioactive natural products and pharmaceuticals. Immense ef-forts have been devoted to the synthesis of indoles starting from theFisher indole synthesis to the recently developed C–H activation/func-tionalization-based methods. Herein, we have reviewed the progressmade on the regioselective synthesis of functionalized indoles, includ-ing 2-substituted, 3-substituted and 2,3-disusbstituted indoles, sincethe year 2010.1 Introduction2 Metal-Catalyzed Synthesis of 2-Substituted Indoles3 Metal-Catalyzed Synthesis of 3-Substituted Indoles4 Metal-Free Synthesis of 3-Substituted Indoles5 Metal-Catalyzed 2,3-Disubstituted Indole Synthesis5.1 Metal-Catalyzed Intramolecular 2,3-Disubstituted Indole Synthe-

sis5.2 Metal-Catalyzed Intermolecular 2,3-Disubstituted Indole Synthe-

sis6 Metal-Free 2,3-Disubstituted Indole Synthesis6.1 N-Protected 2,3-Disubstituted Indole Synthesis6.2 N-Unprotected 2,3-Disubstituted Indole Synthesis7 Applications8 Summary and Outlook

Key words indoles, C–H activation, catalytic, metal-free, naturalproducts

1 Introduction

The indole moiety is one of the key heterocyclic motifsthat occur ubiquitously in bioactive natural products, phar-maceuticals, agrochemicals, fragrances, pigments and inoptoelectronic functional materials.1 Examples of indole-containing biologically active compounds include arbidol(1), indomethacin (2), PD-0298029 (3), reserpine (4), iprin-dole (5) and dimebon (6) (Figure 1).2 The synthesis of indole

and its derivatives has been the topic of research for over130 years, and a variety of classical methods have been dis-covered during this time including: Fisher, Bischler,Gassmann and Batcho–Leimgruber syntheses of indoles.3However, these methods have several limitations, for exam-ple, in the case of the Fischer indole synthesis, toxic hydra-zine hydrate is required along with highly acidic conditionsand overall, the functional group tolerance is moderate.Over the last two decades, various methodologies havebeen developed to overcome the existing limitations of thesynthesis of indole derivatives. Several metal-catalyzed andmetal-free approaches have been reported for the synthesisof indole derivatives. Different research groups have com-piled the literature on the synthesis of indoles with focuson diverse aspects.4

Figure 1 Selected examples of bioactive indoles

The present review focuses on the recent advancementsin the regioselective synthesis of substituted indole deriva-tives, covering the literature from 2011 to present.

NMe

Br

HO

NMe

Me

S

OO

Me

arbidol (1)antiviral for influenza infection

NH

N

O

Me

OO

Me

MeO

PD-0298029 (3)M4 muscarinic receptor antagonist

N

COOH

Me

O Cl

MeO

indomethacin (2)anti-inflammatory drug

N

NMe

N

Me

Me

dimebon (6)anti-histamine drug

N

iprindole (5)

NH

MeO

N

H

H

H

O

OMe

O

OMe

OMe

OMe

OOMe

NMe23

reserpine (4)antipsychotic and antihypertensive drug antidepressant drug

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2 Metal-Catalyzed Synthesis of 2-Substitut-ed Indoles

For many alkaloids and pharmacologically significantcompounds, 2-substituted indoles are important interme-diates. Many research groups have focused their work onthe synthesis of 2-functionalized indoles, mainly throughtransition-metal-catalyzed C–H bond activation strategies.Furthermore, photocatalytic approaches have also beenused for their synthesis.

In 2012, Maity et al. reported on the ruthenium(II)-cata-lyzed photocatalytic synthesis of N-arylindoles 8 using an18 W white-light LED (Scheme 1).5 An appealing methodol-ogy involving oxidative C–N bond formation leads to thesynthesis of indoles under aerobic oxidation conditions.However, the role of the p-alkoxyphenyl group and the sili-ca gel used in the reaction was not clear, the p-alkoxyphe-nyl group on the nitrogen atom being essential for the reac-tion. This methodology is applicable to a broad range ofsubstrates giving the desired indoles in moderate to goodyields. Electron-donating and electron-withdrawing groupson the aryl ring were well tolerated. Alkenes with differentsubstituents such as alkanes, alkenes, arenes and furansgave the desired products in good yields and the methodwas also applicable for the synthesis of 2,3-disubstitutedindoles.

Scheme 1 Ruthenium(II)-catalyzed intramolecular photocatalytic syn-thesis of N-arylindoles

The proposed catalytic cycle for this transformation in-volves conversion of the amine into a nitrogen-centeredradical cation using photoexcited [Ru(bpz)3](PF6)2, followedby the generation of benzylic radical I. Oxidation of thebenzylic radical resulted in benzylic cation II, which finallyundergoes aromatization to form the indole ring (Scheme2).

NH

OR

NR1

OR

[Ru(bpz)3](PF6)2 (4 mol%)

N

OnBu

N

OMe

F

MeN

nC6H13

OMe

F3C

N

OtBu

OO

O N

OMe

N

OMe

Me

MeMe

Me

74% 83% 73%

60% 68% 81%

R1

N

OMe80%

silica gel, MeCN, air, rt white-light LED, 5 h

7 8

r pe

rson

a

Biographical Sketches

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Inder Kumar (right) graduated in Sciencefrom Himachal Pradesh University, Shimla, in2011. He obtained his M.Sc. (2013) andM.Phil. (2014) in Chemistry from HPU, Shim-la, and then joined the group of Dr. Sharmain 2015 to undertake doctoral studies. Cur-rently, he is working on first row transition-metal-catalyzed C–H activation/functional-ization.

Rakesh Kumar (left) graduated in Sciencefrom Himachal Pradesh University, Shimla, in

2011. He completed his M.Sc. in organicchemistry at HPU, Shimla, in 2013, beforejoining Dr. Sharma’s group in 2015 for hisdoctoral studies. Currently, he is working ontransition-metal-catalyzed C–H activa-tion/functionalization.

Upendra Sharma (center) is currently ascientist and assistant professor at CSIR-IHBT, Palampur. He completed his Ph.D. onnatural product chemistry and metal-phtha-locyanine-catalyzed reactions in the fall of

2012, under the supervision of Dr. BikramSingh. He then joined Prof. Debabrata Mai-ti’s group at IIT Bombay, India as a postdoc-toral researcher. In March 2014, Dr. Sharmacontinued his postdoctoral studies with Prof.Sukbok Chang at KAIST, Daejeon, Korea. InSeptember 2014, he started his indepen-dent research as a Scientist at NPC&PD Divi-sion, CSIR-IHBT, Palampur, India. Hisresearch is focused on transition-metal-cata-lyzed C–H activation/functionalization andnatural product chemistry.

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Scheme 2 Proposed mechanism for the photocatalytic synthesis of N-arylindoles

The involvement of benzylic carbocation II in the visi-ble-light-mediated reaction was further supported by theformation of 2,3-disubstituted indole 10 from gem-styryl-aniline 9 through a 1,2-carbon shift under the optimizedreaction conditions (Scheme 3).

Scheme 3 Proof for the involvement of a benzylic carbocation in visi-ble-light-mediated reaction

In 2012, Yoshikai et al. reported the palladium-cata-lyzed cyclization reaction of N-arylamines 11 forming C-2substituted indoles 12 via the oxidative linkage of two C–Hbonds (Scheme 4).6 The methodology gave rapid, atom-eco-nomic and regioselective access to various indole deriva-tives under mild reaction conditions using molecular oxy-gen as the solitary oxidant. Inexpensive and readily avail-able anilines and ketones were used to prepare imines,which were cyclized to form indole moieties; the reactionwas also successfully carried out on gram scale. Indole de-rivatives with heterocyclic substituents such as pyridineand furan at the C-2 position were obtained in excellent

yields. This mode of cyclization was also applicable for thesynthesis of 2,3-diarylindoles, overcoming the difficultiesof the Larock- and Fagnou-type annulation reactions.

The authors observed a KIE value of 5.2 indicating a con-certed metalation–deprotonation mechanism. The plausi-ble mechanism for this transformation involves aPd(II)/Pd(0) redox process proceeding via electrophilic at-tack of Pd(OAc)2 on enamine III generated via tautomeriza-tion (Scheme 5).

Scheme 5 Proposed mechanism for the palladium(II)-catalyzed intra-molecular synthesis of indoles

This is followed by elimination of AcOH to give α-palla-dated imine intermediate IV, which after intramolecular ar-omatic C–H palladation gave palladacycle V, thus forming a3H-indole and Pd(0) after reductive elimination. The 3H-in-dole undergoes tautomerization rapidly to give the indole,while combination of molecular oxygen and AcOH oxidizesPd(0) back to Pd(II), thus completing the catalytic cycle.

In 2012, Yoshiji Takemoto and co-workers synthesizedthe indole skeleton 15 using a palladium-catalyzed cascadeprocess involving isocyanide 13 insertion and benzylicC(sp3)–H activation (Scheme 6).7 This represents the firstreport on the use of a combination of palladium-catalyzedisocyanide insertion and C(sp3)–H activation for the syn-thesis of heterocycles. The synthesis of different 2-arylin-doles can be achieved by changing the coupling partnersand represents a unique palladium-catalyzed strategy forC–C bond formation between the 2- and 3-position of in-dole. The slow addition of the isocyanide was adopted toavoid catalyst deactivation. Using different aryl halides 14as coupling partners resulted in the synthesis of a range ofindoles with different substituents. Electron-donating andelectron-withdrawing groups at the para position of aryl io-dides were well tolerated, whereas the introduction of amethyl group at the ortho position led to a lower yield ofthe final product. Bromobenzene gave the desired productin good yield, but chlorobenzene did not react under theseconditions. Diethylphenyl isocyanide and 2,4-dimethylphe-nyl isocyanide were also found to unsuitable under the de-veloped conditions.

NHAr

Ru(II)

Ru(I)Ru(II)*

O2

NHAr

NAr

H

HO2

NArO2

HO2HO2

NAr

HO2

HO2H2O2

NAr HO2

O2

O2 O2

I

II

NHPh

Ph

OMe

N

OMe

PhPh

H

N

OMe

Ph

Ph[Ru(bpz)3](PF6)2 (4 mol%)

60%

1,2-phenyl shiftand

aromatization

silica gel, MeCN, air, rt white-light LED, 4 h9 10

Scheme 4 Palladium(II)-catalyzed intramolecular synthesis of indoles

N R2

Pd(OAc)2 (10 mol%)

NH

R2

NH

MeOF

F

NH

MeO

NH

MeO

NH

MeOR

H

88%

78%

R3

R1

R3

R1

R = H, 89%; NO2, 92% CF3, 86%; OMe, 82% Cl, 90%

NH

PhR

R = CO2Et, 82%; CF3, 81% NHAc, 64%; Me, 92%

ONH

MeON

76%80%

NH

MeO Ph

78%

NH

MeOCN

NH

MeOPh

R

R = OMe, 82%; F, 74%85%

Bu4NBr (2 equiv), O2 (1 atm) DMSO, 60 °C, 24 h11 12

N R

Me

NH

R

Pd(OAc)2

NH

R

PdOAc

–OAc

N R

PdOAc

N R

Pd

NR

NH

R

Pd0

O2, 2 H2O

H2O21/2 O2 + H2O

AcOH

AcOH

H

H

H

H

III

IVV

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Scheme 6 A palladium(II)-catalyzed cascade process for the synthesis of 2-substituted indoles

In 2013, Zhang’s group delineated the synthesis N-pro-tected C-2 functionalized indoles 18 through combinedgold/zinc catalysis using N-arylhydroxamic acids/N-hy-droxycarbamates 16 and alkynes 17 (Scheme 7).8

Scheme 7 Gold-catalyzed synthesis of 2-susbtituted indoles

The limitations associated with the well-known Fischerindole synthesis and Bartoli reaction, such as strong acidicconditions, regioselectivity, tolerance to sensitive moietieslike the Boc protecting group and limited substrate scope,were overcome by employing this synthetic strategy. In-doles with different functional groups, such as aliphatic al-kanes, cyclohexane, and cyclopropane, were easily pre-pared.

Indoles with a methyl group at the C-2 position were fa-vored with high regioselectivity, possibly because of lesssteric hindrance. The authors proposed that the pathwayinvolves activation of the hydroxamic acid or a related sub-strate via zinc chelate formation (Scheme 8). Gold-activatedalkyne VI was then effectively attacked by the more O-nuc-leophilic zinc chelate VII, which upon subsequent protode-auration formed a precursor for 3,3-sigmatropic rearrange-ment. Finally, the Lewis acid Zn(OTf)2-assisted cyclodehy-dration leads to the desired indole product.

Scheme 8 Proposed mechanism for the gold-catalyzed synthesis of indoles

In 2013, Cossy’s group carried out the synthesis of 1,2-disubstituted indoles from benzyl alcohols through an iridi-um-catalyzed hydrogen atom transfer process (Scheme 9).9p-Benzoquinone was used as the co-oxidant in the reaction.

Scheme 9 Iridium-catalyzed synthesis of 2-susbtituted indoles

The proposed mechanism of the reaction involves theconversion of the alcohol into an aldehyde VIII through hy-drogen atom transfer involving the iridium catalyst. p-Benzo-quinone regenerates the catalyst through oxidation. The in-termediate VIII then undergoes intramolecular cyclizationin the presence of a base to give IX, which may aromatizewith removal of water to give the 1,2-disubstituted indole.Removal of the tosyl protecting group from IX in the pres-ence of the base generates X, which upon further rear-rangement gives the expected indole (Scheme 10).

Scheme 10 Predicted mechanism for the synthesis of 2-susbtituted in-doles

In 2013, Kiruthika and Perumal disclosed an efficientstrategy for the synthesis of 2-amidoindoles 23 through insitu generated ynamides followed by hydroamidation

X

Pd(OAc)2 (10 mol%)Ad2PnBu (20 mol%)

NH

Ar

NH

Me

NO2NH

Me

CF3NH

Me

CO2Me

NH

Me MeNH

Me

NBoc

NH

Me

MeO

NH

Cl

NH

Et

Me

NH

Me

81% 76%

45% 44% 85%

34% not detected

Ar R

not detected

83%

slow addition of isocyanideNC

HR

Cs2CO3 (1.2 equiv), toluene, 100 °C

13 14 15

NOH

OR

H

R2

(ArO)3PAuNTf2 (5 mol%)Zn(OTf)2 (5 mol%)

N

OR

R2R1 R1

NBoc

NBoc

NBoc

Ph

83% 84% 96%

NBoc

Me

9

F

NCO2Me

Me

9

MeO2C

NCO2Me

NBoc

Br

68% 65% 94%80%

NBoc

Me

9

MeO

toluene (0.1 M), 60 °C, 2–8 h

16 17 18

NOH

OR

H

Zn(OTf)2N

R

H

OZn

O L'

OTf

R2AuL

HOTfN

OR

OR2

AuL

O Zn OTfTf

H

N

OR

OR2

H

+AuL+

Zn(OTf)2

3,3-sigmatropicrearrangement

H

N

OR

O

R2HZn(OTf)2

N

OR

R2

VI

VII

OH

NR

CO2tBu

[IrCp*Cl2]2 (2.5 mol%)p-benzoquinone (1.1 equiv)

Cs2CO3 (1.5 equiv)1,4-dioxane, 20 h, 110 °C

NR

CO2tBu

NMe

CO2tBuNBn

CO2tBuNBn

CO2tBuNH

CO2tBuMe

OH

83% 78% 86% 80%

19 20

OH

NTs

CO2tBu

[Ir] [Ir]H

O

NTs

CO2tBu

H

NTs

CO2tBu

OH

NCO2tBu

OH

NH

CO2tBu

OH

base

basep-MeC6H4SO2

BQHQ

VIII IX

X

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(Scheme 11).10 The method involves the intermolecularcoupling of gem-dibromovinylanilide 21 and sulfonamides22 using Cu(I) iodide as the catalyst.

Scheme 11 CuI-catalyzed synthesis of 2-susbtituted indoles

Acetamide derivatives 21 were used as the product yieldwas low in the case of an aniline derivative. The presence ofan electron-withdrawing group such as tosyl or mesitylsul-fonyl was essential on the nitrogen of 22 for the reaction toprogress.

The plausible mechanism for the reaction involves theoxidative insertion of the more reactive trans C–Br bond of21 into XI to furnish intermediate XII (Scheme 12). Reduc-tive elimination followed by dehydrobromination in thepresence of a base provides the ynamide. Further base-pro-moted intramolecular hydroamidation and deacetylationresults in the formation of the desired 2-substituted indole.

May and co-workers reported the copper-catalyzed syn-thesis of N-substituted indoles 25 from the correspondingprimary amines and carbonyl compounds 24 through atwo-step, one-pot approach (Scheme 13).11 The authors op-timized the reaction conditions separately for imine 26 for-mation and cyclization.

Scheme 12 Plausible catalytic cycle

Imine formation was efficient in benzene whereas forcyclization DMF was used as the reaction medium. Themethod was applicable for anilines, benzylamines, and ali-phatic amines providing the desired indoles in good yields.Further, diversified 3- or 2,3-substituted indoles could alsobe synthesized through this method by using α-aryl orcyclic ketones, respectively.

Yu et al. reported the synthesis of functionalized indoles29 through palladium-catalyzed, copper-mediated oxida-tive annulations of in situ generated enones with N-substi-tuted pyrroles 27 (Scheme 14).12 Various 3-chloroalkyl ke-tones and pyrrole derivatives were well tolerated under thereported reaction conditions providing the correspondingindole products in moderate to good yields. Although themethod was applicable for the synthesis of multi-substitut-ed indoles, the reaction conditions were very harsh whichlimits the scope of the reaction on industrial scale. The au-thors proposed that the reaction proceeds through a se-quence of dehydrochlorination, C–H activation, Diels–Aldercycloaddition and dehydrogenative aromatization.

Scheme 14 Pd(II)-catalyzed, Cu(II)-mediated synthesis of indoles through annulations of enones with N-substituted pyrroles

Otani and co-workers examined the Lewis acid promot-ed cycloisomerization of N-imidoyl-2-alkynylanilines 30with substituents such as alkyl or aryl (Scheme 15).13 Theyshowed the formation of indole derivatives via a 5-endo-digcyclization mode.

The electronic effects of the R1 substituent affect thecyclization selectivity; the plausible mechanism for thecyclization involves the Ag–alkyne complex species XIII inthe stereoelectronically favorable 5-endo-dig mode of cy-clization (Scheme 16).

NHAcBr

R1

Br

NH

R3R2R1

NH

NR3

R2

CuI ( 5 mol%)1,10-phenanthroline (10 mol%)

Cs2CO3 (4 eqiuv) THF, 80 °C, 2–9 h

NH

NTs

NH

NTsCl

NH

NTs

OMe

86% 80% 84%

NH

NTs

SNH

NMs

NH

NTs

MeO OMe

81% 79% 87%

21 22 23

LnCuX

NH

R3R2

NR3R2

CuLn

NHAcBr

Br

NHAc

BrLnCu

Br

NR2

R3

NHAcBr

NR3

R2

NHAc

NR3

R2

NAc

NR3

R2NH

NR3

R2

LnCuBr

base

base

baseXI

XII

Scheme 13 Cu(I)-catalyzed synthesis of indoles from primary amines

Br

Me

O

1) R-NH2, p-TsOH (0.1 equiv) benzene, reflux (–H2O)

2) CuI (0.1 equiv), K3PO4 (2 equiv) DMF, 110 °C

NMe

R

Br

Me

NR

NMe

84%

NMe

83%

NMe

80%

NMe

87%

NMe

72%

OMe Cl

OMe

MeF

24 25

26

NR1

R2 +R3

O

Cl NR1

R2

O

R3

OR3

DMF/DMSO (9:1), air, 130 °C, 24 h

Pd(OAc)2 (10 mol%) Cu(OAc)2·H2O (4 equiv), NaOAc (4 equiv) TBAB (0.5 equiv), PivOH (1 equiv)

NR4

Ph

O

Ph

OPh

NMeO

Ph

OPh

R1 = Me, 68%R1 = Et, 62%R1 = allyl, 61%R1 = Bn, 50%

R5

R5 = Me, 68%R5 = OMe, 51%R5 = F, 59%R5 = CN, 52%

NMe

Ph

O

Ar

OAr

Ar = 4-Me-C6H4, 73%Ar = 4-MeO-C6H4, 69%Ar = 4-Ph-C6H4, 71%Ar = 4-F-C6H4, 67%

NMeO

Ph

OPh

S

NMe

Ph

O

O

S

S

NMe

Ph

O

Et

OEt

42% 35%63%

27 28 29

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In 2015, Ghorai’s group developed a two-step, one-potstrategy to synthesize 2-alkylindoles 33 via thiophenol-me-diated regioselective ring-opening of 2-(2-haloaryl)-3-al-kyl-N-tosylaziridines 32, followed by copper-mediated in-tramolecular C–N cyclization with subsequent aromatiza-tion by thiophenol elimination (Scheme 17).14 This methodovercomes the limitation of the synthesis of halogenated 2-alkylindoles, which otherwise were impossible to synthe-size by alpha-lithiation of indoles.15 Various halogenated in-doles were prepared in good to excellent yields using eithera cis/trans mixture or mono-substituted aziridines, thoughtrans disubstituted aziridines were found to be more reac-tive than the cis isomer due to steric reasons.

Scheme 17 Synthesis of 2-alkylindoles

The mechanism of the reaction possibly follows thecopper-powder-mediated C–N cyclization as described inGhorai’s earlier report,16 with the final aromatization stepinvolving Cu(I)-mediated desulfonylation via the formationof cationic thioether intermediate XIV (Scheme 18).

Scheme 18 Reaction pathway for the Cu-mediated C–N cyclization

3 Metal-Catalyzed Synthesis of 3-Substitut-ed Indoles

The regioselective synthesis of C-3 functionalized in-doles 36 and 37 from the aryl azides 34 having exceptionalreactivity toward alkynes 35 was reported by Gallo’s groupin 2014 (Scheme 19).17 This ruthenium–porphyrin-com-plex-catalyzed methodology furnished indoles instead oftriazoles and is attractive for the synthesis of C-3 function-alized indoles having electron-withdrawing substituents onthe azide fragment. Only C-3 functionalized indoles wereobtained in high yield with aromatic terminal alkynes. Thesteric hindrance caused by the alkynes was responsible forthe low reaction yield observed for C-2 functionalized in-doles when using internal alkynes as coupling partners. Al-so, aliphatic alkynes were not suitable for indole synthesisunder the reported conditions. It was observed that whenR1 = R3, the reaction yield was high, while with differentsubstituents the product was obtained in a lower yield, andwhen only one substituent was present on the benzene ringof the azide, the indole yield was lower. The proposedmechanism for this reaction involves initially the formationof N-substituted-1H-azirine intermediate XV. The polariza-tion of a sp2 C–H aromatic bond ortho to the electron-with-drawing group assists a hydrogen transfer reaction, whichis responsible for the indole cyclization (Scheme 20).

Scheme 19 Ruthenium-catalyzed regioselective synthesis of indoles

Scheme 15 Silver(I)-promoted intramolecular synthesis of indoles

NH

N R2

R3

R1

N

R3R2

R1

AgOTf (10 mol%)

N

PhPh

MeN

EtPh

MeN

PhPh

tBu

N

PhPh

iPrN

EtnPr

tBu

99% 68% 78%

97% 65%

CH2Cl2/DCE 0.5–3 h, rt to reflux30 31

Scheme 16 Proposed pathway for the silver(I)-promoted intramolecu-lar synthesis of indoles

NR3

R1

HN R2

Ag

NH

R3

N

R1

Ag

R2 N

R3 NR2

R15-endo-dig

(π-complex) (π-complex)

XIII

TsN

R2

R1

X

1. PhSH, BF3·OEt2 (15 mol%)CH2Cl2, rt, 15 min to 2 h

2. Cu powder (2.0 equiv)DMF, 120–125 °C, 8–24 h

R1

NTs

R2

X = Br, Cl

NTs

EtNTs

MeF

NTs

nPrCl

NTs

NTs

NTs

F

Cl

Cl

70% 65% 65% 80% 82% 80%

32 33

TsN

R2

XX

SPh

NHTs

R2

NTs

SPh

R2

NTs

SPh

R2

NTs

H

R2

HNTs

R2

PhSH

BF3·OEt2

Cu

Cu(I)

– CuSPh

– PhSH + [Cu]

XIV

R5

R3

R2

R1 N3

R4

NH

R5

C6H4-pR4R3

R2

R1

NH

R5

C6H4-pR4R1

R2

R3

H[Ru(TPP)(N(3,5-(CF3)2C6H3)2)]

(2.0 mol%)

C6H6, reflux, N20.5–16 h

NH

PhCF3

F3C NH

C6H4pMeCF3

F3C NH

C6H4pCF3CF3

F3C NH

C6H4pFCF3

F3C

NH

PhCF3

F3CPh

NH

PhNO2

O2N NH

PhCl

Cl NH

PhCF3

82%60%37% 82%

86% 75% 70% 90%

H

34 35

36

37

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Scheme 20 Proposed mechanism for the synthesis of C-3 functional-ized indoles

Choi et al. reported the Co–Rh heterobimetallicnanoparticle-charcoal-catalyzed reductive cyclization of2-(2-nitroaryl)-acetonitriles 38 to give indole motifs 39(Scheme 21).18 The catalyst can be reused more than tentimes without any loss of activity and the developed strate-gy was also applicable for gram-scale reactions. Under theoptimized conditions, several functional groups were toler-ated affording high product yields.

Scheme 21 Heterobimetallic nanoparticle-charcoal-catalyzed synthe-sis of 3-susbtituted indoles

4 Metal-Free Synthesis of 3-Substituted In-doles

Recently, Ito et al. developed a novel transition-metal-free reductive Fischer indole synthesis by reacting easilyavailable N-aryl hydrazones 40 with tert-butyl iodide as asource of anhydrous HI, which acts as Bronsted acid as wellas a reducing agent (Scheme 22).19 The developed method

represents the first ever report on a 1,4-reduction of a con-jugated hydrazone with a sequential Fischer indolizationreaction of an in situ generated enamine, and can be ap-plied to the synthesis of biologically active C-3 substitutedindole derivatives. The role of the solvent was crucial for thetransformation as only polar solvents were able to give thedesired product.

Various substituted N-aryl hydrazones were selectivelyconverted into the corresponding indoles 41, including sub-strates with an electron-donating methoxy group at thepara position of the benzene ring, amide, halogen atoms,etc., or substrates without substituents. As electron-with-drawing groups were not suitable for the 3,3-sigmatropicrearrangement step, an indole with a cyano group at the C-5 position was not observed under these conditions.Heterocyclic, electron-donating and electron-withdrawinggroups at the R4 position were well tolerated.

Scheme 23 Proposed mechanism for the metal-free synthesis of 3-substituted indoles

A plausible mechanism for this transformation involvesthe initial attack of tert-butyl iodide at MeCN to give HI,which then regioselectively protonates the N-aryl hydra-zone to give azonium ion XVII. The addition of an iodideanion to the azonium ion converts it into another interme-diate XVIII, which was further reduced by HI to give enam-ine XIX. After the 3,3-sigmatropic rearrangement of theenamine, subsequent cyclization and aromatization withthe loss of ammonium iodide gives the desired indole(Scheme 23).

5 Metal-Catalyzed 2,3-Disubstituted Indole Synthesis

Over the last two decades, many new methodologieshave been reported for the synthesis of indole derivatives toovercome the existing limitations. Various metal-catalyzedas well as metal-free approaches have been developed forthe synthesis of 2,3-disubstituted indole derivatives.20

NRuNHAr

CF3

F3C

Ph

H NRuNAr

CF3

F3C

H H Ph

+ ArN3, – N2

CF3

F3C NH

H

Ph

XV XVI

NO2

CN

R1

R2 R2

NH

R1Co2Rh/C (5 mol%)H2 (1 atm, balloon)

MeOH (3 mL), 24 h, rt

NH

NH

C6H4pF

NH

Ph

NH

CO2Et

ClNH

C6H4oNO2

NH

MeO

MeO68% 86% 79% 27% 91% 59%

38 39

Scheme 22 Fischer indole synthesis of C-3 substituted indoles

NR2

N

R3

R4R1tBuI (3.0 equiv)

MeCNreflux, 0.5 h

NR2

R3R1

R4H

NH

CO2EtBnO

NH

CO2EtHN

MeOC

NH

CO2EtMeS

NH

CO2Et

NH

CO2EtF

NH

CO2Et

NH

CO2EtNC

NBn

CO2EtMeO

NPh

NPh

CN

NPh

S

81% 98% 62%

79%

n.d. 82%

51%

83%

67%

77%83%

NBn

CO2EtMeO

93%

Ph

40 41

tBuI NMe

MeMe Me HI

MeMe

NH

N R

I

NH

N R

H

I

NH

N R

H

I

HI

NH

N R

H

I

NH

HN R

H I2

HI

H R

NH2NH

H

NH

NH3

HR

NH

HR

NH4I

[3,3]

MeCN

HI

I

XVII XVIII

XIX+

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5.1 Metal-Catalyzed Intramolecular 2,3-Disubsti-tuted Indole Synthesis

Considering the high importance of the 2,3-disubstitut-ed indole structural motif in the pharmaceutical industryand in medicinal chemistry, a large number of efforts havebeen made in the last few years to develop simple and cost-effective methods for their synthesis.

In 2010, Cacchi’s group disclosed the synthesis of 2,3-disubstituted indoles 44 from arenediazonium tetrafluo-roborates 42 and 2-alkynyltrifluoroacetanilides 43 using apalladium catalyst. The method showed excellent function-al group tolerance both in the alkyne and the arenediazoni-um component, including halo substituents. Arenediazoni-um salts containing ortho substituents gave the corre-sponding products in good to high yields (Scheme 24).21

This reaction proceeds through an iododediazonizationstep (Scheme 25, path a) followed by oxidative addition toPd(0) to afford the arylpalladium iodide XX that coordi-nates with the alkyne to give palladium complex XXI. Asubsequent intramolecular aminopalladation generates σ-intermediate XXII, which via reductive elimination and hy-drolysis gives the desired product.21 Alternative mecha-nisms, which appear less likely, involve the formation ofarylpalladium iodides through the reaction of σ-arylpalladi-um cation XXIII with iodide anions (Scheme 25, path b).

Scheme 24 Synthesis of 2,3-disubstituted indoles

In 2011, the Waser group reported the one-pot synthe-sis of 3-silylethynyl indoles 47 via the cyclization of 2-alky-nylanilines 45 using NaAuCl4 as the catalyst. The intermedi-ate indoles 46 underwent C3-alkynylation with AuCl andTIPS-EBX to afford the products 47. This reaction was alsoapplicable for unprotected anilines, demonstrated goodfunctional group tolerance and was very easy to carry out(Scheme 26).22

Scheme 26 Gold-catalyzed synthesis of 2-substituted 3-silylethynyl in-doles from unprotected o-alkynylanilines

Ghorai and co-workers reported the palladium-cata-lyzed synthesis of 3-substituted 2-benzylindoles 49through oxidative annulations of o-allylanilines 48 with O2as the oxidant (Scheme 27).23 The same authors also report-ed the one-pot synthesis of indoles from 48, which are pre-pared from aniline and substituted allyl alcohols using anoxorhenium catalytic system.23 The reported catalytic sys-tem provided good regioselectivity and was amenable to abroad substrate scope with high functional group tolerance.

Scheme 27 Palladium-catalyzed intramolecular synthesis of 3-substi-tuted 2-benzylindoles from o-allylanilines

The catalytic cycle of this reaction was initiated by pal-ladium-catalyzed aminopalladation of the 2-allylaniline viaan intramolecular 5-exo-trig cyclization to generate inter-mediate XXIV, followed by β-hydride elimination to form

ArN2+BF4

R2

R1

NHCOCF3

Pd(PPh3)4, TBAI (3-4 equiv) K2CO3 (2 equiv)

MeCN, 1–5 h, 60 °C NH

Ar

R2

R1

NH

Ar

Ph

Ar = 4-MeOC6H4, 69%; 2-MeC6H4, 84% 4-MeCOC6H4, 96%; Ph, 72% 4-O2NC6H4, 93% N

H

Ar

Ar = Ph, 82%4-CNC6H4, 86%

NH

C6H4p-CN

PhF

NH

C6H4p-F

PhMe

Me 71%

NH

C6H4p-Cl

nC5H11

Me

Me70% 89%

OMe

42 43 44

Scheme 25 A plausible catalytic cycle for the synthesis of 2,3-disubsti-tuted indoles

Pd(0)

ArPdI

NHCOCF3

R

N

PdAr

R

COCF3

ArPdI

ArI

NHCOCF3

R

NH

Ar

R – N2

I–ArN2

+

Pd(0)

ArN2Pd+

– N2

ArPd+

path a

path b

I–

XX

XXI

XXII

XXIII

NH2

R

NH

RNH

R

Si(iPr)3

NaAuCl4·2H2O (2 mol%)

iPrOH AuCl (4 mol%), rt

TIPS-EBX

NH

Si(iPr)3

NH

Si(iPr)3

NH

Si(iPr)3

Me F

NH

nBu

Si(iPr)3

NH

Si(iPr)3

96% 74% 73%

Cl

SiMe3

85% no reactionNH

Si(iPr)3

OMeNC

79%

I(iPr)3Si O

O

45 46 47

NH2

R2 R3

R1Pd(OAc)2 (5 mol%), PPh3 (10 mol%)

DMF, 80 °C, O2 (balloon) NH

R2

R3R1

NH

Ph

Ph

O2N

81%, 10 h

NH

Ph

Ph

NC

83%, 16 hNH

Ph

Ph

F

50%, 24 hNH

Ph

Ph

F3CO

79%, 6 h

NH

Ph

Ph

Me

60%, 6 h

NH

Ph

Ph

75%, 10 h

NH

Ph

Ph

66%, 3 hMe

O

O NH

Ph

Ph

F

75%, 4 hCl

NH

Ph

Ph

65%, 6 h

NH

R4

R5

Cl

R4 = R5 = p-MeC6H4, 50%,10 hR4 = R5 = p-ClC6H4, 51%, 8 hR4 = R5 = 1-naphthyl, 60%,18 h

NH

Ph

Me

OAc

65%, 7 h

48 49

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intermediate XXV. Isomerization of this intermediate givesthe final product 49 and O2 oxidizes Pd(0) to regenerate theactive catalytic cycle (Scheme 28).

Scheme 28 A plausible catalytic cycle for the synthesis of 3-substitut-ed 2-benzylindoles from o-allylanilines

In 2014, Li’s group reported the Rh(III)-catalyzed intra-molecular annulations of alkynes 50 via C–H activation forthe synthesis of 3,4-fused indoles 51.24 The indoles weresynthesized in moderate to good yields with excellent regio-selectivity and broad substrate scope. Substrates containingboth electron-donating and electron-withdrawing groupsat ortho, para and meta positions of the aryl ring of thealkynes were well tolerated. 3,4-Fused indoles with six- tonine-membered rings were generated in relatively lowyields (Scheme 29).24

Scheme 29 Rhodium(III)-catalyzed intramolecular synthesis of 3,4-fused indoles

The reaction was initiated by ortho C–H bond activationof 50 to form intermediate XXVI. Alkyne insertion to XXVIgives rhodacycle XXVII, which on reductive eliminationprovides the desired product 51 and Rh(I). Finally, the ac-tive catalytic species was regenerated by Cu(II) (Scheme30).

Scheme 30 A plausible catalytic cycle to construct 3,4-fused indoles

In 2016, Dilman et al. described the photocatalyzed con-version of CF2I-substituted N-arylamines 52 into the corre-sponding 3-fluoroindoles 53.25 The starting materials wereobtained by nucleophilic iododifluoromethylation of imini-um ions. The developed strategy utilized blue LEDs for irra-diation of the reaction mixture for 12 hours. A series of 3-fluoroindoles was synthesized effectively with excellentyields using the developed photocatalytic methodology(Scheme 31).

Mechanistic studies involved measurements of the re-dox potentials of the catalyst, the starting material andtriphenylphosphine to check the feasibility of the elec-tron-transfer step. The reduction potential studiessuggested the initial conversion of photoexcited Rh(II)*into Rh(I) [ERh(II)*/Rh(I) = +0.84 V] by triphenylphosphine[EPPh3+

./PPh3 = +0.77 V]. Rh(I) then generates the difluorinated

radical XXVIII via a single electron transfer and the catalystis regenerated. Intramolecular attack of the radical onto thearomatic ring furnished XXIX, oxidation of which by thetriphenylphosphine radical cation produced aromatic cat-ion XXX. Elimination of a proton from XXX followed by re-moval of HF provided the expected indole product (Scheme32).

Scheme 31 Photocatalyzed synthesis of 3-fluorinated indoles

In 2016, Miao et al. reported the ZnEt2-mediated anti-azacarboxylation of 2-alkynylanilines 54 with CO2 for thesynthesis of 2,3-disubstituted indoles 55 (Scheme 33).26

The method represents an easy access to indole moieties asit involves the use of readily available starting materials andvarious functional groups are tolerated. Trifluoromethyl-and nitro-substituted reactants provided indoles in good to

[O]

NH2

R2

R3Pd(0)

N

R2

R3

HPd(II)

5-exo-trigNH

R2

R3

Pd(II)

NH

R2

R3

NH

R2

R3Pd(II)

XXIV

XXV

49

X

R2

NHAc

R1

a) [RhCp*(MeCN)3](SbF6)2 (2.5 mol%) Cu(OAc)2·H2O (20 mol%) under O2, t-AmOH, 60 °C, 15 h

X

R2

NAc

R1

NAc

Ph

O

70%aNAc

O

74%a

NAc

O

80%a

NAc

O

50%a

S

NAc

Ph

O

60%a

MeO

NAc

Ph

65%b

O

NAc

Ph

orb) [RhCp*Cl2]2 (2.5 mol%), AgSbF6 (10 mol%) CuOAc·H2O (2 equiv), t-AmOH (2 mL) 110 °C, 0.5 h

c) Rh(III) (2.5 mol%) AgSbF6 (10 mol%) CuOAc·H2O (2 equiv) acetone, rt, 15 h

or

35%c

O

Cl

COOEtMe

Me

EtOOCMe

Rh Cl

Cl

Rh(III) complex2

OMe

Me

NAc

O

Cl

62%b

50 51

AcOH

O2

[Cp*RhCl2]2

Cp*Rh(OAc)2

OR

NHAc

OR

NHAc

RhCp*

R

RhCp*NAc

O

NAc

R

O

Rh(I)

Cu(OAc)2

CuOAc

XXVI

XXVII

50

51

R3

N R2

R1

I FF Ru(bpy)3(BF4)2 (0.5 mol%)

PPh3 (20 mol%), blue LEDs

rt, 12 hthen silica gel

R3

NR1

F

R2

NMe

FBr

NC3H7

F

PhNMe

F

PhSMeO Br

F

Np-OMeC6H4

98% 85% 98% 88%

52 53

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excellent yields. The utility of this method involves the syn-thesis of the drug Lotronex, which is used for the treatmentof irritable bowel syndrome.

Scheme 33 Diethylzinc-mediated intramolecular cyclization for the synthesis of indoles

The reaction was proposed to proceed through initialactivation of the alkyne by diethylzinc making it suscepti-ble to intramolecular nucleophilic attack by nitrogen togenerate intermediate XXXI (Scheme 34). The insertion ofcarbon dioxide into the C–Zn bond leads to the formation ofXXXII, which on demetalation in the presence of an acidgives the indole.

Scheme 34 A plausible reaction mechanism for the synthesis of 2,3-disubstituted indoles

5.2 Metal-Catalyzed Intermolecular 2,3-Disubsti-tuted Indole Synthesis

Beyond intramolecular indole synthesis, Maurizio Tad-dei and co-workers reported the Ru-catalyzed H-transferFischer indole synthesis of 58, from primary and secondaryalcohols 57 and aryl hydrazines 56 (Scheme 35).27 The useof alcohols in place of aldehydes or ketones makes this sys-

tem more advantageous compared to the classical Fischerindole synthesis.27

This reaction may proceed through oxidation of thealcohol into a carbonyl compound XXXIII by transfer of a H2molecule to the crotononitrile. Compound XXXIII is imme-diately converted into hydrazone XXXIII by reaction witharyl hydrazine 56 and finally, an acid-catalyzed aromatic[3+3] sigmatropic rearrangement gives the desired indolering (Scheme 36).

Scheme 35 Ruthenium-catalyzed hydrogen transfer Fischer indole synthesis

In 2013, Liang and Zhan reported the copper-catalyzedformation of enehydrazine intermediates 61 through thecoupling of phenyl hydrazines 59 with vinyl halides 60, andits synthetic application for the synthesis of indoles 62.28

This catalytic system tolerates ester, hydroxy and aminefunctional groups leading to the selective synthesis of iso-meric indoles and has been employed for the interruptedindolization to synthesize the pyrrolidinoindoline 62(Scheme 37). This catalytic system opens a new way for theasymmetric synthesis of indoles.29

Zhu and co-workers reported a Rh(III)-catalyzed, C–Hactivation based intermolecular redox neutral strategy forthe synthesis of indoles 65 by cyclization of N-nitrosoani-lines 63 with alkynes 64 using the N–N bond as an internaloxidant. This catalytic procedure showed good functionalgroup tolerance and the compatibility of seemingly dichot-omous acidic and basic conditions makes it a versatilemethod (Scheme 38).30

Scheme 32 Mechanistic cycle for the ruthenium-photocatalyzed reac-tion

N ArMe

I FF

N ArMe

FF

NMe

FF

NMe

FF

H

NMe

FF

PPh3

PPh3

Ru(II)*

Ru(II)

Ru(I)

hvHF

NMe

F

XXVIII

XXIX

XXX

NHTs

R1

R2R3

R4 ZnEt2 (3.0 eqiuv)CO2 (balloon)

DMSO, 25 °C, 10 h

R2R3

R4

NTs

R1

COOH

NTs

nBu

COOH

NTs

nBu

COOHF3C

NTs

nBu

COOHO2N

NTs

CH2OBn

COOH

93% 91% 60% 57%

54 55

NH

R1

ZnEt2

N

R1Et2Zn

Ts

NTs

ZnEt

R1

NTs

COOZnEt

R1

CO2

H

NTs

COOH

R1

TsXXXI

XXXII

NNH2

R

R1

R3

HOR2

[Ru3(CO)12], BIPHEP CH3CHCHCN, ZnCl2

2-methyl-2-butanol MW,130 °C, 3 h

NR

R3

R2R1

NBu 80%

NMe

Me

Me

80%NMe

Me

61%

NMe

Me

62%

Me

NMe 52%

OH

NMe 62%

COOEt

NMe

Me

Me

NMe

Me

Me

65%

65%

56 57 58

Scheme 36 A plausible catalytic cycle for the synthesis of substituted indoles from aryl hydrazines and alcohols

HO

R3R2

2-methyl-2-butanolMW,130 °C, 3 h

aryl hydrazinecrotononitrile

[Ru3(CO)12], BIPHEP, ZnCl2

N

R2

R3

R

R1

O

R3R2

NN

R

R3R2

R1

ZnCl2

NR

NH2

Ru

[RuH2]H3CHC CHCN

CH3CH2CH2CN

XXXIII XXXIV

R1

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Scheme 38 Rh(III)-catalyzed synthesis of indoles from N-nitrosoanilines and alkynes using the N–N bond as an internal oxidant

A detailed mechanistic study proved that the generationof [RhCp*]2+ leads to reversible coordination of tBuCOO– andN-nitrosoaniline derivative to give XXXV, and the turnover-limiting C–H activation then forms rhodium intermediateXXXVI via a tBuCOO–-assisted CMD (concerted metallationdeprotonation) pathway. Interaction of the alkyne withXXXVI followed by migratory insertion leads to the forma-tion of intermediate XXXVII. Concerted N–N bond cleavageand C–N bond formation leads to formation of the finalproduct with the abstraction of NO+ by H+ and regenerationof the active [RhCp*]2+ species (Scheme 39).30

In 2013, Senanayake and co-workers disclosed the one-pot synthesis of indoles 69 by reacting 2-bromoanilides 66,terminal alkynes 67, and aryl halides 68 via a palladium-catalyzed reaction sequence involving Sonogashira cou-pling, aminopalladation and reductive elimination (Scheme40).31 All the reactions were carried under normal condi-tions without the use of nBu4NBr and good to excellentyields were achieved.

Scheme 40 Synthesis of 2,3-disubstituted indoles from 2-bromo- or 2-chloroanilides, terminal alkynes and aryl halides

In 2013, Ding et al. reported the Ru complex and p-TSAcatalyzed synthesis of indole derivatives 72 from anilines70 and vicinal diols 71. Electron-donating substituents onthe aryl ring of the aniline gave the products in higher

Scheme 37 Copper-catalyzed Fischer indole synthesis through forma-tion of enehydrazine intermediates from phenyl hydrazines and vinyl halides

NNHAc

R

Br ( )nN

NAc

R

( )nXX

NR

X( )n

CuI (5 mol%)DMEDA (10 mol%)

K2CO3 (2 equiv)toluene, 110 °C

ZnCl2 (2.2 equiv) toluene, 90 °C

NMe 61%

NMe 92%

NMe 92%

R1

R1

F Cl

NMe 82%

MeO

NBn83%

OBz

R1

NAllyl 78%

OH

NMe 92%

Me

Me

NMe 95%

Me

MeF

59 60 61

62

H

NR2

NO

R1

a) [RhCp*Cl2]2 (4 mol%), AgSbF6 (16 mol%) tBuCOOH (1 equiv), H2O (8 equiv) MeCN, 80 °C, 16 h

R1NR2

R3

R4

orb) [RhCp*Cl2]2 (4 mol%), AgSbF6 (16 mol%) NaOAc (0.4 equiv) MeCN, 80 °C, 16 h

N(CH2)2CN

Ph

Me

47%,a 68%b

NMe

Ph

Me

74%,a 68%b

Me

NMe

Ph

Me

58%,a 84%b

F

NEt

Ph

COMe

54%a

NEt

Ph

COOMe

59%,a 31%b

NEt

Ph

35%a

NMe

Ph

Me

NMe

Ph

Me

MeO

OMe

50% (1:2.57),a 52% (1:2.45)b

R3

R4

63 64 65

Scheme 39 Proposed mechanism for the intermolecular redox neutral synthesis of indoles

NEt

NO

Me Ph

Rh Cp*

NN

OEt

Rh Cp*

PhMe

tBuCOOHPhMe

NN

OEt

Rh Cp*

tBuCOOH

NN

OEt

Rh

Cp*tBuCOO

turnover-limiting C–H activation

RhBuCtOO Cp*tBuCOOH

NEt

Ph

Me

HNOH

0.5 N2O 0.5 H2O

tBuCOOH

RhCp*

tBuCOO– H+

H

NEt

NO

0.5 [RhCp*Cl2]2 + 2 AgSbF6

N–N bond as an internal oxidant

tBuCOOH

2+

XXXV

XXXVI

XXXVII

Br

NH

O CF3

R1R1

NH

R3

R2

PdCl2(PhCN)2 (3 mol%) X-Phos (12 mol%)R2

Cs2CO3 (3 equiv) DMF, 80 °C, (1.5–7 h)

NH

83%

NH

74%

NH

81%

NH

73%

NC

NH

72%

NH

60%

MeO2CSO3H

R3X (X = Br, Cl)

+

CO2Me

OMe SO3H

66

67

68 69

Scheme 41 Indole synthesis from anilines and vicinal diols by coopera-tive catalysis of a ruthenium complex and an acid

NH

R2

R1R3

OHR4

OH

[Ru(CO)2(Xantphos)]2 (1 mol%), 120 °C

p-TSA (10 mol%), t-amyl alcohol, 16 hR1 N

R2

R4

R3

NH

Me

Me

66%NH

Me

Me

79%NH

Me

Me

82% 73%

Me MeO

NH

Me

Me

65%OMe

NH 61%

PhMe

NH 53%

OMe

Cl

66%

Me

NH

Me

Me

NH

70 71 72

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yields, while strong electron-withdrawing groups (i.e., NO2or CF3) failed to give the expected products. An ortho-sub-stituted aniline gave a lower yield because of steric hin-drance (Scheme 41).32

A year later, Driver and co-workers reported a Suzukicross-coupling reaction for the regioselective synthesis of2,3-fused indole heterocycles 76 from 2-azidoarylboronicesters 73 and vinyl triflates 74.33 The 5-substituted arylazides smoothly gave the indole products; these productscannot be accessed as single regioisomers using the Fisherindole reaction. The conversion of androsterone into an in-dole proved that this method is applicable for complex mol-ecules, albeit a reduced yield was obtained (Scheme 42).33

Scheme 42 The synthesis of 2,3-fused indole heterocycles

In the same year (2104), Cho and co-workers reportedthe synthesis of ene-hydrazides 79 from bis-Boc-hydrazide77 and enol triflates 78, and their subsequent enolizationreaction to give the regioselective Fischer indole products80. The catalytic system showed broad substrate scope andenabled the synthesis of indole natural products with excel-lent regioselectivities (Scheme 43).34

Scheme 43 Regioselective Fischer indole synthesis from ene-hydra-zides

In 2014, Wu’s group reported the synthesis of N-(2-pyr-idyl)indoles 83 from internal alkynes 82 and N-phenylpyri-din-2-amines 81 catalyzed by palladium@cerium(IV) oxide.This method affords better yields compared to other hetero-geneous catalytic methods and demonstrates good func-tional group tolerance; however, the nitro functional groupwas not tolerated (Scheme 44).35

Scheme 44 Oxidative synthesis of N-(2-pyridyl)indoles

The regio- and enantioselective synthesis of N-allyl in-doles 86 and 87 was reported by You’s group in 2014.36 Thisreaction proceeds through an Ir-catalyzed asymmetric al-lylic amination with 2-alkynylanilines 84 and subsequentAu-catalyzed cyclization. The catalytic system proved wasapplicable to a broad substrate scope, affording high yieldsand good enantiomeric excess. The reaction was also com-patible with a one-pot procedure and cascade reaction(Scheme 45).36

Scheme 45 Ir-catalyzed allylic amination and subsequent Au-catalyzed cyclization

The Yu group reported, in 2015, the Pd(II)-catalyzedsynthesis of functionalized indoles 90 from simple N-sub-stituted pyrroles 88 and 3-chloropropiophenones 89 and

N3

R H

R1 Rh(esp)2(5 mol%)

PhMe80 °C

96%NH

NBoc

83%NH

S NH

Me

H

HMe

HAcO 25%

NaHCO3

(Ph3P)2PdCl2 (2 mol%)R

Bpin

N3

R1

OTf

NH

R1

R

NH

N Fmoc

54%NH

N Boc

65%NH

N Boc

81%NH

O

83%

F

Me

73 74 75 76

(Boc)N

N(Boc)

R

n

ZnCl2 1,4-dioxane

90 °C, 4 h

HN

n

R

94% 87% 92%

HN

97%

(Boc)N

NHBoc

TfO

n

R

Pd(OAc)2 P(tBu)3·HBF4

CsCO3,LiCl, PhMe 110 °C, 9 h

HN

HN

HN

HN

95%

Me

MeEt

77

78 79 80

HN

2-Py R1

R2

Pd/CeO2 (5 mol%)

Cu(TFA)2·xH2O (20 mol%) DMF (2 mL) 120 °C

N2-Py

R1

R2

R3R3

N2-Py

Ph

Ph

82% 99%

N2-Py

92%

OMe

OMe

N2-Py

92% CF3

CF3

N2-Py

Ph

PhF3CO

81 82 83

R3

R2

NH2

R1

OCO2Me

1) Ir(dbcot)Cl2 (2 mol%) Ligand (4 mol%), CH2Cl2 reflux

2) PdCl2 (5 mol%) KI (50 mol%) DMF, 80 °C, air

OR4

O

N

OR4O

R2

R1

R3

N

OR4O

R2R3

R1

N

OnBuO

Ph65% (>97:3, ee 97%) 60% (>96:4, ee 96%) 47% (>96:4, ee 92%) 71% (>97:3, ee 96%)

O

OP

ligand

C6H4-2-OMe

C6H4-2-OMe

BrN

OnBuO

2-thienyl

Ph

N

OnBuO

Ph

Ph

N

OMeO

Ph

Ph

Cl

84

85

86

87

Scheme 46 Pd(II)-catalyzed synthesis of functionalized indoles from pyrroles and enones

N R1

R3

H

R2

R4 Cl

O

Pd(OAc)2 (10 mol%)NaOAC (4 equiv)

Cu(OAc)2·H2O (6 equiv)

NR1

R3

R2R4 O

R4

O

NPh

Me

Ph O

Ph

O63%

NMe

Ph O

Ph

O

R

R = F, 59%; CN, 52%; OMe, 51% CO2Me, 62%; NO2, 38%

NMe

Ph O

Ph

O

S

62%

Me

TBAB/PivOH (0.5/ 1.0 equiv), N2DMF/DMSO (9:1), 100 °C, 24 h

88 89 90

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their analogues. This reaction proceeds through the con-struction of a benzene ring onto a pyrrole backbone usingenones 89 (Scheme 46).12

The proposed catalytic cycle started with palladation atthe C-5 position of pyrrole 88 giving intermediate XXXVIIIwith simultaneous removal of acetic acid. IntermediateXXXVIII then reacts with the enone XXXIX, generated from3-chloropropiophenone 89, to form palladium intermediateXL. Reductive elimination leads to the formation of pyrrolederivative XLI, which undergoes a Diels–Alder cycloaddi-tion with another molecule of the enone to form tetrahy-droindole XLII. Finally, the tetrahydroindole is oxidized toindole 90 and catalytic system is regenerated by Cu(II) oxi-dant or air (Scheme 47).

Scheme 47 Proposed mechanism for the synthesis of functionalized indoles from pyrroles and 3-chloropropiophenones

In 2015, Dong and co-workers reported the Ru(II)-cata-lyzed oxidative coupling via C–H activation of NH proticamides 91 with alkynes 92 for the synthesis of N-acylindolederivatives 93. This catalytic method shows good functionalgroup tolerance and affords moderate yields of the products(Scheme 48).37

Scheme 48 Synthesis of indoles via ruthenium(II)-catalyzed C–H acti-vation and annulations

A plausible mechanism was proposed in which the in-sertion of Ru(II) metal activates the ortho C–H bond of am-ide 91 to form the six-membered ruthenacycle XLII. Alkyne

interaction with XLIII followed by migratory insertion leadsto the formation of another ruthenacycle (XLIV). Finally, re-ductive elimination provides the product 93 (Scheme 49).37

Scheme 49 Proposed catalytic cycle for the synthesis of N-acylindoles from NH protic amides and alkynes

In 2015, Hwang’s group reported the visible-light-medi-ated CuCl-catalyzed regioselective synthesis of indoles 97via coupling of arylamines 94, terminal alkynes 95 and qui-nines 96 at room temperature (Scheme 50). This photoin-duced method showed broad substrate scope with good toexcellent selectivities. However, the use of meta-substitutedanilines resulted in the formation of a mixture of regio-isomers.38

Scheme 50 Photoinduced copper-catalyzed synthesis of indoles from arylamines, terminal alkynes and quinines

This reaction was proposed to commence by photoirra-diation of in situ generated XLV by blue LEDs. This producesthe photoexcited triplet state XLVI (τ = 15.95 μs) by ligand-to-metal charge transfer (LMCT).39 This is followed by inter-system crossing of the singlet excited state of copper(I) phe-nylacetylide to the triplet excited state.40 Next, a SET pro-cess with benzoquinone gives the copper(II) pheny-lacetylide XLVII and benzoquinone radical XLVIII, whichhas the tendency to attack XLVII to regenerate the copper(I)catalyst and form copper(I)-coordinated alkyne complexXLIX. The electrophilicity of the triple bond in the disubsti-tuted alkyne moiety must be enhanced through coordina-tion with CuCl,41 facilitating nucleophilic attack by anilineto provide complex L, thus leading to the formation of com-

Pd(0) Pd(OAc)2

NMe

Ph

NMe

PhAcOPd

NMe

Ph

PdOAc

O

Ph

NMe

Ph

OPh

Ph

O

NMe

PhO

Ph

OPh

NMe

PhO

Ph

OPh

Cu(OAc)2 (or O2)

CuOAc + AcOH (or H2O)

Cu(OAc)2 or O2/AcOH CuOAc or H2O

Ph

O

Ph

ONaOAc

– HCl Cl

AcOH

XXXVIII

XXXIX

XL

XLI

XLII

88

90

HN R2

OR1

R3

R4H

[RuCl2/p-cymene]2 (5 mol%)Cu(OAc)2·H2O (0.6 equiv) N

R4

R3

R2

O

R1

N

Ph

Ph

MeO

87%

N

Ph

Ph

MeO

Me N

Ph

Ph

MeO

Cl N

Ph

Ph

MeO

MeO

N

Ph

Ph

MeO

O2N

N

Ph

Ph

O

N

Ph

Ph

O

N

Ph

Ph

O

Me Me

Me

64% 70% 59% 34%

50% 40% 75%

N

nBu

nBu

MeO

N

Ph

nBu

MeO

33%45%

CH3SO2OAg (0.3 equiv)toluene, Ar, 110 °C

91 92 93

+

[Ru]

HN R2

OH

HN

OH[Ru]

HN R2

O[Ru]

R4

R3

[Ru]N

R3R4

Cu+/Cu

Cu2+

H+R3

R4

N

R3

R4

OR2

H+O R2

XLIII

XLIV

91

93

NH

H

H

R2

O

O

CuCl (5 mol%)

MeOH, N2, 6 hblue LEDs, rt

NH

R2

R1 R3

OH

R3

R1

NH

C6H4p-OH

85%NH

C6H4p-OH

R1 R1 = 2-Me 86% 4-Br 67% 4-CH2CN 82%

NH

C6H4p-OH

88%

NH

C6H4p-OH

R2R2 = 4-tBuC6H4, 88% 4-FC6H4, 82% 4-HOC6H4, 84% 4-NCCH2C6H4, 83%

NH

C6H4p-OH

NH

C6H4p-OH

72%74%

Me

94 95 96 97

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plex LI. Friedel–Crafts-type cyclization then generates theintermediate LII42 and finally, a rearomatization processprovides the indole product (Scheme 51).

Scheme 51 Proposed mechanism for the photoinduced synthesis of indoles

Lu’s group reported the Rh(III)-catalyzed synthesis ofindoles 100 by annulation of arylnitrones 98 and alkynes 99without using any external oxidant. Symmetric diarylacety-lenes bearing various substituents at the para and meta po-sitions gave the best results.43 While ortho-methyl-substi-tuted diarylacetylene gave a low yield, an unsymmetricaldiarylacetylene afforded a mixture of two regioisomers.para-Cyano-substituted N-phenyl-C-mesitylnitrone ap-peared to be a less effective substrate, affording the desiredproduct in a low yield with a higher catalyst loading at100 °C (Scheme 52).43

Scheme 52 Rh(III)-catalyzed synthesis of indole derivatives from aryl-nitrones and alkynes

The catalytic cycle was initiated with the formation ofrhodacycle LIII followed by insertion of the alkyne to givethe seven-membered intermediate LIV. Reductive elimina-tion leads to the formation of intermediate LV. This result-ing Rh(I) intermediate could be oxidized by the N–O bondvia oxidative addition to provide enolate LVI, which uponprotonolysis provides intermediate LVII and regeneratesRh(III) to complete the cycle. Enolate intermediate LVII is inequilibrium with keto intermediate LVIII, which gives theindole by imine hydrolysis and intramolecular cyclization(Scheme 53).

Scheme 53 Proposed catalytic cycle for indole synthesis from arylni-trones and alkynes

In 2015, Wan and co-workers reported the synthesis ofunsymmetrical 2,3-diaryl-substituted N-unprotected in-doles 103 via rhodium-catalyzed C–H annulations of ni-trones 101 with symmetrical alkynes 102 (Scheme 54).44

The catalytic system showed tolerance of various functionalgroups on the aryl rings of the nitrones and the symmetri-cal alkynes for the regioselective preparation of the 2,3-disubstituted indoles 103.

Scheme 54 Rhodium-catalyzed synthesis of 2,3-diaryl-substituted indoles from nitrones and alkynes

PhNH3

CuCl

Ph

Ph CuI Ph CuIδ− O

O

O

O

Ph CuII

PhNH2+ Cl -

CuCl

PhNH2

O

HO

Ph

NH2

Cl

Cu

H+

Ph

NH

CuI

O

H2O

Cl–

CuCl

H2O

OPh

NHCu

ClNHH

PhCuO

Cl–

CuCl(rearomatization)

HNPh

OH

SET

blue LEDs

XLV

XLVI

XLVII

XLVIII

XLIX

LLILII

PhNH2+ Cl–

NO

HR3R2

[RhCp*(MeCN)3](SbF6)2 (5 mol%)PivOH (2 equiv)

HN

R3

R2

Me

MeMe

HN

60%

HN

C4H9

R

R = H (26%); NO2 (56%) CO2Et (53%); COMe (41%)

HN

Ph

Me

HN

Ph

tBu19%72%

HN

Ph

Ph

HN

MeOPh

Ph

HN

FPh

Ph

HN

NCPh

Ph84% 77% 63% 31%

R1 R1

MeOH (0.1 M), 80 °C, 24 h

98 99 100

[RhCp*]2+H

NO

Mes

Rh

NO

Mes

RhON

Mes

R1 R2

Cp*

ON

R1R2

Rh(I)Cp*

Mes

ORhCp*

N

R1 R2

Mes

N

Mes

RhCp*

R1 R2

O

R1

OR2

OH

N

R1 R2

Mes

O

N

R1 R2

Mes

H+/H2O

O

NH2

R1 R2

cyclization– H2O

HN

R1

R2

R1

R2

- H+H+

X

hydrolysis of imine– MesCHO

LIII

LIVLV

LVI

LVIILVIII

NO

R1HR2

R2

[RhCp*Cl2]2 (2.5 mol%)AgSbF6 (10 mol%)

NH

R2

R1

H

NH

Ph

R

R = OMe, 81%; CF3, 85% F, 72%; NO2, 88% Br, 65%

NH

Ph

NH

PhX

X = S, 71% O, 63%

75%NH

Ph

R

R = OMe, 81% CF3, 80% Cl, 80%

NH

Ph

OMe

NH

NO2

Me

65%R = 5-Br, 79%; 5-CO2Et, 80% 6-Cl, 52%; 7-OMe 80%

R

Cu(OAc)2 (1 equiv)DCE (0.4 mL), EDE (1.6 mL) 100 °C, 12 h

101 103102

EDE (1,2-diethoxyethane)

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The catalytic cycle of this reaction also involves the for-mation of a rhodacyclic intermediate LIX, which undergoesinsertion with the alkyne to give the seven-membered in-termediate LX (Scheme 55, path a). Reductive eliminationthen provides the intermediate LXI. Intramolecular oxygenatom transfer and subsequent oxidative addition of LXIIand electrophilic cyclization generates intermediate LXIII.Intermediate LXV is formed by transmetalation and subse-quent β-hydride elimination,45 finally leading to the forma-tion of product 103 by elimination of PhCHO.46 Alternative-ly, the reaction can proceed through LIX and intermediateLXVI (Scheme 55, path b).

Wang and Huang, in 2015, developed a general protocolfor the synthesis of N-alkylindoles 105 using a traceless ni-troso directing group via redox neutral C–H activation(Scheme 56).47 This rhodium-based catalytic system pro-vided N-alkylindoles regioselectively, with a broad scope ofsubstituents, in good to excellent yields and without theuse of any oxidant or other additive.

Scheme 56 Redox neutral C–H activation for the regioselective syn-thesis of N-alkylindoles

Though the full catalytic cycle of the reaction remainselusive, the C–H activation step may proceed via a concert-ed metalation–deprotonation (CMD) mechanism.

In 2010, the Knochel group reported a microwave-as-sisted Fischer indole synthesis for the preparation of poly-functional indoles 109 from aryldiazonium tetrafluoro-borates 108 and functionalized alkylzinc halides 107, whichwere generated from substituted bromobutanes 106(Scheme 57).48 The catalytic system showed a broad sub-strate scope with excellent regioselectivity, and with manyfunctional groups such as nitro, ester, keto, cyano and iodobeing tolerated. This catalytic method was successfully usedfor the synthesis of indole-containing drug molecules.

Scheme 57 Preparation of polyfunctional indoles by the addition of alkylzinc reagents to aryldiazonium tetrafluoroborates

Hui Jiang and co-workers reported the rhodium(III)-cat-alyzed regioselective synthesis of indole-3-carboxylic acidesters 112 using a pyrimidyl directing group.49 N-Substitut-ed anilines 110 and diazo compounds 111 were used as thestarting materials and the reactions proceeded via aromaticC–H bond activation followed by C–N bond formation togive 2,3-difunctionalized indoles (Scheme 58). The pres-ence of the pyrimidyl directing group was essential for thesynthesis of the desired indoles under the specified condi-tions, and it can be reutilized for further functionalizationof the synthesized indoles, or can be easily removed to pro-vide different free N–H indoles. The limitations of preacti-vated substrates, the requirement for excess oxidant and

Scheme 55 A plausible catalytic cycle for the synthesis of unsymmetrical 2,3-disubstituted indoles

[RhCp*X]*N

O

ArH

H

NO

ArH

RhCp*

Ph

Ph

N O

ArH

Rh

Ph Ph

Cp*

ON

H Ar

PhPh

ON

H Ar

PhPh

N

H Ar

Rh Cp*

Ph COPh

N O

ArH

Rh

*Cp Ph

Ph

N O

ArH

Rh

*Cp Ph

Ph

N

Ph COPh

Ar

Ph COPh

N[Cu]

AcO

[*PCRh]

ArPh COPh

N[Cu]

Ar

HN

Ar

Ph

Ph COPh

HN

Ar

[RhCP*]

[RhCP*]

– HX

[Cu]H

[Cu]PhCHO

+ H+

[Cu]H

+ H+

HN

Ar

Ph

transmetalation

path a

path b

X

LIX

LX

LXILXII

LXIII

LXIVLXV

LXVI

NN

R1

O

H

R2

R3

R4N

R2

R3

R1

R4[RhCp*(OAc)2] (8 mol%)

MeOH, 90 °C

N

Ph

Ph

Me

90%

N

Ph

Ph

iPrN

Ph

Ph

Me

MeO2C

N

Ar

Ar

Me

Ar = p-MeOC6H4, 94% p-BrC6H4, 88%

N

Ph

Ph

54% 92% 89%

104 10599

R1

ZnBr·LiCl NH

R3

R2

R1

MeR1

Br

MeMe

Zn (2 equiv)LiCl (1.1 equiv)

ZnBr2 (2 equiv)THF, 50 °C, 12 h

R3

R2N2

+BF4–

–60 °C to 25 °C, then Me3SiCl (1 equiv)125 °C, 90 min, MW

NH

CO2Et

MeO

NO2

MeNH

CO2Et

PivOMe

NH

MeEtO2C

Me

69% 65% 75%

NH

MeI

Me

85%

106 107 109

108

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the substrate scope associated with the previous reports ofGlorius,50 Jiao51 and Cacchi21 for the synthesis of indole-3-carboxylic acid esters were overcome by using this method.Various alkyl, halogen and ester substituents on the phenylring were well tolerated under the reported conditions.Substituents with strong-electron withdrawing effects suchas CF3 and NO2 and electron-donating methoxy substitu-ents afforded the expected products, exclusively. The de-sired indole was obtained with a morpholinyl substituent atthe para position of the phenyl ring. Also, the reaction wassuccessful on gram scale.

Scheme 58 Regioselective synthesis of indole-3-carboxylic acid esters

In 2016, Li’s group described the synthesis of 2,3-disub-stituted indoles 115 via C–H activation/annulation of imid-amides 113 with diaza-ketoesters 114 using a Rh(III) cata-lyst (Scheme 59).52 This redox-neutral strategy proceededunder mild conditions with a variety of substrates.

Scheme 59 Rhodium-catalyzed synthesis of 2,3-disubstituted indoles

The mechanistic studies of the reaction revealed the ki-netic isotope effect (KIE) value to be 3.3, which indicates C–H bond cleavage may be involved in the rate-determiningstep. The proposed mechanism of the reaction includes the

initial generation of an active catalyst through anion ex-change. Insertion of the active catalyst into the ortho C–Hbond followed by cyclization gives the six-membered rho-dacycle LXVII. Elimination of nitrogen with subsequent in-sertion of the diazo substrate generates LXVIII and migra-tory insertion of the Rh–C bond into the C=N bond providesLXIX. Protonolysis of LXIX generates LXX and the activecatalyst. The elimination of acetamide from LXX gives thefinal product (Scheme 60).

Scheme 60 Suggested catalytic cycle for the C–H activation/annula-tion of imidamides with diaza-ketoesters

Recently, in 2016, Wu et al. developed an oxidant-freeintramolecular C–C bond-formation strategy for the regio-selective synthesis of indoles 117 using an iridium(II) photo-sensitizer and a cobaloxime catalyst under visible light irra-diation (LEDs, 450 nm). This procedure successfully con-verted N-arylenamines 116 into indoles in good to excellentyields, while producing H2 as the only side product (Scheme61).53 The reported method overcomes the limitations ofGlorius and co-worker’s50 procedure using a stoichiometricamount of oxidant, which can lead to the formation of sideproducts. Under the optimized reaction conditions, variouselectron-withdrawing as well as electron-donating substit-uents were well tolerated, affording the corresponding in-doles in high yields. When meta-substituted enamines were

R2

O

N2

OR3

O [RhCp*Cl2]2 (2.5 mol%)AgSbF6 (10 mpl%)

N

CO2R3

N

CO2Et

MeN

CO2Et

MeN

Me

85% 84% 80%

71% 70% 76% 71%

R1 R2R1

N

H

NN

NN

H

NN

nBu

NN

FCO2Et

NN

NMe

EtO2CCO2Et

NN

NMe

F3CCO2Et

NN

NMe

O2NCO2Et

NN

NMe

CO2Et

NN

NMe

NCO2Et

NN

O

CH3COOH (0.5 equiv) DCE

74%

N

CO2Me

Me

57% 76% 76% 88%49%N

N

N

CO2tBu

Me

NN

N

CO2Bn

Me

NN

N

CO2Et

NN

Me

N

Ts

Me

NN

110 111 112

NH

R1

NHH

R2

Ac CO2Et

N2

R2

NH

R1

CO2Et[RhCp*Cl2]2 (4 mol%)

CsOAc (30 mol%)

AcOH (1.0 equiv), DCE80 °C, 12 h

NH

Me

CO2Et

NH

Me

CO2EtF

89% 82%

NH

Me

CO2Et

Me

87%

NH

Me

CO2Et

F 66%

NH

Me

CO2Et

82%

NH

iPr

CO2Et

66%

NH

CO2Et

NH

CO2Et

NH

CO2Et

NH

Bn

CO2Et

66% 84% 78% 74%

113 114 115

[RhCp*Cl2] [RhCp*Cl2]2

[RhCp*(OAc)2]

2CsOAc2CsCl

NH

Me

NHH

NH

Me

NHRh

OAc*Cp

NH

Me

NHRh

Cp*EtO2CAc

NH

NHRh

Me

EtO2C Ac Cp*

NH

EtO2C

Me

OMe

NHRhCp*OAc

NH

EtO2C

Me

NH

OHMe

NH

Me

CO2Et

– AcNH2

AcOH

AcOH

OAc

OAc

LXVII

LXVIII

LXIX

LXX

Scheme 61 Photocatalyzed regioselective synthesis of indoles

NH

Ph

CO2Et

H

R RNH

CO2Et

PhIr(ppy)3 (3 mol%)

Co(dmgH)2(4-CO2Mepy)Cl (7 mol%) N2, LEDs (450 nm), 20 h

NH

CO2Et

PhNH

CO2Et

PhX X = F, 90%

Cl, 90% Br, 88% N

H

CO2Et

PhMeO

MeO

NH

CO2Et

Ph

Me

NH

CO2Et

PhMeN

H

CO2Et

PhNH

CO2Et

OMe

NH

CONHPh

Ph

93% 90% 55%

95% 93%92%, 1:2.7

116 117

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used as the starting materials, more than one product couldbe obtained. The desired indole product could also be ob-tained on gram scale in 82% yield.

A plausible mechanism for the reaction involves initialphotoirradiation of the Ir(ppy)3 photosensitizer to produceIr(ppy)3*, which transfers an electron to the cobaloximecomplex, thus forming Ir(IV) and Co(II). The Ir(IV) soformed abstracts an electron from 116 to produce LXXI andregenerate the photosensitizer Ir(ppy)3. Intermediate LXXIloses a proton to give LXXII that undergoes intramolecularradical cyclization to produce LXXIII. Finally, oxidation anddeprotonation followed by tautomerization of LXXIII af-forded the desired indole product (Scheme 62).

In 2014, Zhang et al. developed a regioselective synthe-sis of polysubstituted indoles 120 via an Ru-catalyzed re-dox-neutral C–H activation reaction involving N–N bondcleavage.54 The C–H annulation reaction of alkynes 119 wascarried out using pyrazolidin-3-one 118 as the internal oxi-dant as well as the directing group (Scheme 63). The use ofruthenium metal avoided homocoupling of the terminalalkynes, which was a major side reaction when usingRh(III). Also, the oxidative potential of the N–N bond of thealiphatic hydrazine was not enough to regenerate the Ru(II)catalyst. So, the authors used cyclic hydrazides with in-creased ring strain to activate the N–N bond. The designedprotocol was effective for a broad range of functionalgroups on the arene moiety: electron-withdrawing as wellas electron-donating substituents were well tolerated. Sym-metrical, unsymmetrical and 1-substituted alkynes gavesingle regioisomers, exclusively. The utility of the developedmethod was demonstrated by the synthesis of a P2 inhibi-tor,55 a SIRT1 activator56 and an NS5B inhibitor.57

A plausible Ru(II)–Ru(IV)–Ru(II) catalytic mechanism forthe reaction was proposed on the basis of redox-neutral Rhcatalysis reported in the literature.58 Ru(II) amido complexLXXIV is obtained by initial insertion of the active Ru(II) ac-etate into the N–H bond of pyrazolidin-3-one, which under-goes metalation–deprotonation to give LXXV. Subsequentalkyne insertion followed by oxidation to Ru(IV) by the N–N

bond gives LXXVI, which upon reductive elimination givesthe final product and regenerates the active Ru(II) catalyst(Scheme 64).

Scheme 64 Proposed catalytic cycle for the synthesis of polysubstitut-ed indole derivatives

In 2016, Zhou et al. developed a versatile, traceless,Rh(III)-catalyzed annulation of arylhydrazines 121 andalkynes 99 for the synthesis of indoles 122, with a very lowcatalyst loading (0.1 mol%) on gram-scale reactions(Scheme 65).59 The N-amino-directed C–H alkenylationgenerated indoles in a step- and atom-economic manner at

Scheme 62 A plausible mechanism for the photocatalytic synthesis of indole derivatives

NH

PhH

NH

Ph

CO2Et

H

CO2EtNH

Ph

CO2Et

H

N

Ph

CO2Et

H– H+

N Ph

H CO2Et

N

H

Ph

CO2Et

– e–– H+

tautomerizationNPh

CO2Et

SET CoII

CoI

CoIII-H

CoIII

IrIII

IrIII*

IrIV

SET

e–

H2

H+

hv

LXXI LXXII

LXXIII

Scheme 63 Ruthenium-catalyzed redox-neutral C–H activation, regi-oselective synthesis of N-substituted indoles

NHN

O

R3

R1R4

R5

R2

R1

N

R2

R3

NH2O

R4

R5[RuCl2(p-cymene)2]2 (2.5 mol%)

NaOAc (2 equiv), PhCl, 110 °C

N

NH2O

Ph

Ph

91%

N

Me

Me

NH2O

Ph

PhR1

R1 = Me, 88%, F, 92% CN, 72%, OMe, 91% CF3, 94%, NO2, 93%

N

NH2O

Ph

Me5

N

NH2O

OBn

93% 77%

N

NH2O

Ph

Cl

89%

118 120119

+

N

HN

O

NN

ORuAcO

L

(II)

NN

O

RuL

(II)NN

ORuR4

R5 (II)

RuN NH

O

R4R5OAc

N

NH2O

R4

R5

Ru dimer

RuL(OAc)2

NaOAc

AcOH

(IV)

AcOH

R4R5

CMD

AcOH

reductiveelimination

internaloxidation

alkyneinsertion

LXXIV

LXXV

LXXVI

Scheme 65 Traceless synthesis of indoles at room temperature

NNH2

R2

H

R1

R3

R4

R1

NR2

R4

R3

[RhCp*Cl2]2 (2 mol%)AgSbF6 (8 mol%)

AcOH (1.2 equiv), MeOH, rt, 12 h

NMe

Ph

Me

NMe

Ph

Me

NPh

Me

F

NMe

Ph

Me

NMe

Ph

MeCl

Cl

NMe

Ph

MeR

R = OMe, 89% COOMe, 61% CN, 69% Br, 83% N

Et

Et

Me

NMe

PhNMe

Ph

Ph

73%, 1:0.08

59% 86% 53%

90% 81% 74%

121 99 122

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room temperature and showed tolerance toward a broadrange of functional groups on the arylhydrazines andalkynes. The room-temperature conditions for the tracelessindole synthesis are unexcelled via C–H activation strategy.

In 2014, Liu’s group reported the Rh-catalyzed synthesisof 1-aminoindole derivatives 124 via oxidative annulationof hydrazines 123 with alkynes 99 (Scheme 66).60 The au-thors described the use of 1,3-dinitrobenzene as an oxidantin transition-metal-catalyzed C–H activation for the firsttime.58a

Scheme 66 Oxidative annulations of hydrazines and alkynes to give indoles

The course of the reaction includes formation of rhoda-cycle LXXVII by insertion of the active metal catalyst intothe hydrazine. Alkyne coordination and insertion gives amore stable six-membered intermediate LXXVIII, whichundergoes internal oxidation to release the indole in thepresence of AcOH. The active catalyst is regenerated by theexternal oxidant, 1,3-dinitrobenzene (Scheme 67).

Scheme 67 A plausible reaction mechanism

In 2016, Zhang and co-workers developed a new strate-gy for the synthesis of indoles 126 via Co(III)-catalyzed oxi-dative annulations of N-arylureas 125 and alkynes 99 pos-sessing a broad range of synthetically useful substituents(Scheme 68).61 However, the strategy is limited to the use of

less electrophilic ureas other than acetamide as the direct-ing groups, and gave the products in good to excellentyields.

Scheme 68 Co(III)-catalyzed oxidative coupling of N-arylureas and internal alkynes

A plausible mechanism for the reaction involves thegeneration of an active cationic Co(III) catalyst followed byirreversible C–H bond activation affording six-memberedmetallacycle LXXIX. Coordination and migratory insertionof the alkyne generates the species LXXX, which upon elim-ination of HX yields intermediate LXXXI. Reductive elimi-nation of the C–N bond generates the desired indole alongwith Co(I), which is further oxidized by silver and oxygen toregenerate the active catalyst (Scheme 69).

A Co(III)-catalyzed regioselective synthesis of indolemotifs 129 was reported by Zhu’s group (Scheme 70).62 In-ternal and terminal alkynes 128 were compatible with N-aminoaniline derivatives 127 for cyclization. This strategyovercomes the drawbacks of earlier Co(III)-catalyzed redox-neutral methods for indole synthesis including high reac-tion temperatures, retention of bulky groups in the prod-ucts and the generation of side products from external oxi-dants. The method provided the indole skeleton with di-verse functional groups in moderate to excellent yields.Both electron-rich and electron-deficient substituents weretolerated, but steric effects played a dictating role in the re-action yield.

R1

NH

NHCOR2

HR3

R4

R1

NR4

R3

NHCOR2

[RhCp*Cl2]2 (5 mol%)1,3-dinitrobenzene (2.0 equiv)

NaOAc (30 mol%), DCE60–80 °C, 24–36 h

NPh

Ph

NHAc

R R = H (92%) OMe (93%) Cl (85%) CF3 (48%) CN (45%)

NPh

Ph

NHAcF

50%

NPh

Ph

HNO

NNHAc

S

S

69%

83%

NPh

76%

NHAc

Ph

NNHAc Ph

Ph

NNHAc

Ph

OH

63% 62%

123 99 124

NH

H

[RhCp*(OAc)2]

NHAc

NH

NAcRh

Cp*

Ph

Ph

NH

NAcRhCp*

PhPh

NRh Cp*

PhPh

NHAc

NPh

Ph

NHAc

[RhCp*] NO2

2 AcOH

NO2

H2O

[RhCp*Cl2]2 2[RhCp*Cl2]

2NaOAc

2NaCl

2 AcOHNO2

NO

LXXVII

LXXVIII

NH

OMe2N

HR1

R2

R3

R1

NR3

R2

Me2NO

[CoCp*(CO)I2] (10 mol%)AgSbF6 (20 mol%)

NaH2PO4 (2.0 equiv)

Ag2CO3 (1.2 equiv)DCE, 130 °C, O2, 24 h

NPh

Ph

Me2NO

NPh

Ph

Me2NO

NPh

Ph

NO N

Me2NO

NPh

Me

Me2NO

94%

MeO2C

60% 74%

S

S

65% 81%

125 12699

Scheme 69 The catalytic cycle for coupling of N-arylureas with internal alkynes

[CoCp*(CO)I2]

AgSbF6AgI

CoCp*X2

N

Co

NH

OMe2N

H

NMe2

OX

*Cp

H Ph

Ph

NOCo

NMe2H

Ph PhXCp*

X = SbF6

NCo

PhPh

Cp*

OMe2N

NPh

Ph

Me2NO

Co(I)

Ag2CO3 + O2oxidation C–H

activation

migratoryinsertion

reductiveelimination

H3PO4, NaX NaH2PO4

LXXIX

LXXX

LXXXI

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Scheme 70 Co(III)-catalyzed regioselective synthesis of indole motifs

The mechanism of the reaction involves the initial co-baltation of 127 and Co(II)-promoted alkyne–allene isom-erization. The insertion of allene LXXXIII via the internalC=C bond into five-membered cobaltacycle LXXXII fol-lowed by cyclization provided the desired product (Scheme71).

Scheme 71 Proposed mechanism for the reaction involving cyclization of alkynes with N-aminoanilines

In 2016, Liu reported the synthesis of 3-amidoindoles132 via Rh(III)-catalyzed cascade cyclization/electrophilicamidation of o-alkynylanilines 130 (Scheme 72).63 The au-thors used N-pivaloyloxyamides 131 as the electrophilic ni-trogen source. The developed strategy provided 3-amidoin-doles under mild conditions with good to excellent yields.Different functional groups present on both reactants weretolerated.

Scheme 72 Rh(III)-catalyzed cascade cyclization/electrophilic amida-tion of o-alkynylanilines

The proposed mechanism of the reaction involves theinitial coordination of rhodium with 130. This makes thetriple bond more susceptible to intramolecular nucleophilicattack by nitrogen and generates intermediate LXXXIV. Theintermediate LXXXIV then reacts with 131 to furnishLXXXV through deprotonation of 131 and ligand exchangeon LXXXIV. The expected product can be obtained fromLXXXVI via two pathways (paths a and b). Path a, involvesconcerted N–O bond cleavage with C–N bond formationand regeneration of the catalyst. In path b, reductive elimi-nation followed by oxidative addition through pivaloylgroup migration generates intermediate LXXXVI, which onprotonolysis furnishes the indole product (Scheme 73).

Scheme 73 Proposed mechanistic pathways

6 Metal-Free 2,3-Disubstituted Indole Syn-thesis

6.1 N-Protected 2,3-Disubstituted Indole Synthesis

Zhao et al. reported the synthesis of indoles 135 via in-tramolecular amination (Scheme 74).64 They used an orga-noselenium catalyst under mild conditions and obtainedproduct yields of up to 99%. Polar solvents were ineffectivein this transformation and an electron-donating protectinggroup on the nitrogen disfavored the transformation, prob-ably because the nitrogen of the substrate becomes less nu-cleophilic, hence preventing attack by the intermediateseleniranium ion. Only a trace amount of the product wasobtained when using unsubstituted terminal alkenes. Dif-ferent substituents on the aromatic ring of the substrateonly slightly influenced the nitrogen nucleophilicity andhence the C–H bond amination. Electron-donating Me andelectron-withdrawing CF3 groups at the same position ofthe benzene ring gave the desired products in high yields(91% and 93%).

NNH2

R1

R2

[Cp*CoI2]2 (2 mol%)AgSbF6 (8 mol%)

Zn(OTf)2 (1.2 equiv)DCE, 50 °C, 12 h

R2

NR1

R3

R4

R3

R4

NMe

Ph

PhNMe

PhN

Ph

Ph

NMe

Ph

PhMeO2C

NMe

nPr

nPr

88% 65% 41% 61% 63%

NMe

TIPSNMe

Me

Et

NMe

Me

n-Pentyl

NMe

MeNMe

Me

CH2C6H5

83% 46% 45% 29% 51%

127 128 129

NNH2

Me

Cp*Co(III)

NNH2

CoCp*

Me

HR

H

R

N NH2

Co

Me

R

Cp*NMe

Me

Rcyclization

LXXXIILXXXIII

.

NHTs

R1

R2 NHOPivR3

O

R2

NTs

HNO

R3

R1[Cp*RhCl2]2 (1.25 mol%)

K2CO3 (1.0 equiv)MeOH, rt

NTs

HNO

Bn

Bu

R2

R2 = NO2 (95%) CO2Et (99%)N

Ts

HNO

Bn

R1

R1 = Ph (85%) p-BrC6H4 (32%)

NTs

HNO

Bn

OTBS

NTs

HNO

Bn

69%

45%

NTs

HNO

Bu

C6H4-p-OMe

75%

NTs

HNO

Bu

Cl

98%

NTs

HNO

Bu

Me

Me

64%

130 131 132

+

Cp*RhX2

NHTs

R1Cp*RhX2

NTs

RhX

Cp*

R1

NTs

RhCp*

R1

NOR

R3OCNTs

R1

NR3OC

RhICp*OR

NTs

R1

NR3OC

RhCp*OR

NTs

RhCp*

R1

O

ON

O

R3

tBu

path a

path b

reductiveelimination

oxidativeaddition

HX

HX

HX

130

131LXXXIV

LXXXV

LXXXVI

132

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Scheme 74 Organocatalyst-catalyzed intramolecular synthesis of in-doles

Otani and co-workers examined the Lewis acid- orbase-promoted cycloisomerization of N-imidoyl-2-alky-nylanilines 136 with substituents such as alkyl or aryl.13

They described the formation of indole derivatives 137 via a5-endo-dig cyclization mode (Scheme 75).

Scheme 75 Lewis acid/base-promoted cycloisomerization of N-imido-yl-2-alkynylanilines

In 2012, Li’s group reported the reaction of enaminones138 with 2,2-dihydroxyindene-1,3-dione (139) on heatingin acetic anhydride at 120 °C under microwave irradiationconditions. Polyfunctionalized tetracyclic indeno[1,2-b]in-doles 140 were obtained with different substitution pat-terns.65 This catalytic system showed excellent regioselec-tivity, short reaction times, mild conditions and good func-tional group tolerance at the N-protected aryl ring of theenaminones 138 (Scheme 76).

Scheme 76 Synthesis of indeno[1,2-b]indoles under microwave irradi-ation

In 2014, Youn’s group reported a metal-free synthesis ofsubstituted indoles 142 and 143 via C–H amination of N-Ts-2-alkenylanilines 141.66 This method showed broad sub-strate scope, good functional group tolerance and affordedgood to excellent yields of the products. In the case of elec-tron-withdrawing groups [CO2nBu, CONMe2, CN, PO(OEt)2]on the alkene moiety, no product was formed and mostlystarting material was recovered. The reactions of β,β-disub-stituted 2-alkenylanilines proceeded as expected to gener-ate 2,3-disubstituted indoles, which showed that electron-rich aryl groups migrated preferentially (Scheme 77).

Scheme 77 Metal-free C–H amination for the synthesis of indoles

The mechanism of the reaction was proposed after con-ducting a series of experiments. It was suggested that intra-molecular nucleophilic attack by the N-tosyl group ofLXXXVII towards an olefin radical cation generates inter-mediate LXXXVIII. Oxidation of carbon radical of LXXXVIIIgives the corresponding benzylic carbocation intermediateLXXXIX. This was followed by deprotonation to form theproduct via path a, which is much faster than alternativepath b (Scheme 78).

H

R2

NTs

R1

dioxane, 30 °C, 18 hS N S

FO

O

O

O NR2

Ts

R1

NTs

NTs

Me NTs

O

OPh

NTs

Ph

NTs CN

NTs

RR = Me, 98%; OMe,97% F, 99%; NO2, 98%

trace 70% 64% 31%

60%NTs

MePh

NTs

F3CPh

NTs

FPh

NTs

PhCl N

Ts

PhMe

91%

96% 93% 95% 88%

PhSeSePh (10 mol%)

133 134 135

NH

N R2

R3

R1

N

R3 NR2

R1TBAF (0.5–3.0 equiv)

N

PhN

iPr

OMeN

PhNPh

CF3

N

PhN

iPr

N

PhNPh

tBu

86% n.d.

87%97%

N

PhN

iPr 76%

Me

N

PhN

tBu 80%

Me

N

PhN

iPr

nPr

97%

CH3CN, 0.5–3 h, rt or reflux

136 137

n.d. = not detected

Ac2O

MW, 120 °C, 20-32 min N

OAc

R1

R1 R

O

N

OAc

MeMe C6H4-p-F

O

85%

N

OAc

MeMe Me

O

74%

N

O

MeMe

O

74%

O

R1R1

NHR

O

O

HO

HO

OMe

138 139 140

+

R1

NHTs

DDQ (2 equiv)

CH3CCl3 (0.1 M) 120 °C, 2–24 h

N

R2

R1

TsN

R1

R2

Ts

NPh

TsN

Ph

Ts

100% (10:1)

OMe

OMeN

Ph

TsNTs

30% (0:1)

CF3

CF3

N

Ph

Ph

Ts

87%

R2

N

Ph

Me

TsN

Me

Ph

Ts

48% (1.1:1)

141 142 143

+

Scheme 78 Proposed mechanism for the metal-free indole synthesis

NHTs

R1

R2R3

NTs

R1

R2

DDQ

SET

R3 = Hpath a

NTs

R1

R3

R2

b Cl Cl

NC CN

OHOa

SET

path b

R1 = HR2 = ArR3 = H

R1

R2

R3

NHTs

NHTs

R1

R2

R3

Cl Cl

NC CN

OO

NTs

R1

R3

R2

Cl Cl

NC CN

OO

N

H

R3

Ts

Cl

Cl

NC

NC

OH

O

NTs

R2

R3

Cl Cl

NC CN

OHO

H

NTs

R2

R3

Cl Cl

NC CN

OH2HO

DDQH2

DDQH2

LXXXVII

LXXXVIII

LXXXIX

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In 2015, Deng’s group reported the metal-free synthesisof indoles 145 from N-Ts-2-alkenylanilines 144 via a NIS-mediated cascade C–N bond formation/aromatization.67

This reaction showed broad substrate scope and providedgood to excellent yields under mild reaction conditions(Scheme 79).

Primarily, the iodonium ion intermediate XC is formedas NIS reacts with the substrate alkene, which undergoesintramolecular amination by the amino group to form indo-line XCI. This is followed by aromatization to form the in-dole product or 1,2-arylation occurs to form intermediateXCII, which after aromatization gives the final product(Scheme 80).

6.2 N-Unprotected 2,3-Disubstituted Indole Syn-thesis

König and co-workers reported the synthesis of func-tionalized indoles 148 in a tartaric acid–dimethylurea [L-(+)-TA–DMU] melt under solvent- and catalyst-free condi-tions, starting from phenylhydrazine (146) and alde-hydes/ketones 147.68 Examination of substrate scopeshowed that it tolerated sensitive functional groups such asN-Boc, N-Cbz and azides with excellent yields of productsregioselectively. In addition, the method is environmentallybenign and applicable for the synthesis of bioactive indoles(Scheme 81).

Scheme 81 Fischer indole synthesis in low melting mixtures

Zheng’s group reported a one-pot procedure for theFischer indole synthesis of compounds 151 from quinonemonoketals 149 and aliphatic hydrazines 150 in chloroformwith two equivalents of pyridine or under microwave con-ditions.69 The method showed good functional group toler-ance, broad substrate scope and gave good to excellentyields of the indole products. An unsymmetrical hydrazinegave the cyclization product regioselectively (Scheme 82).

Scheme 82 Synthesis of indoles by condensation of quinone monoke-tals and aliphatic hydrazines

The condensation of quinone monoketals 149 with hy-drazines 150 through 1,2-addition gave intermediate XCIII,which on dehydration gave intermediate XCIV. Subsequentaromatization gave the alkylaryldiazene XCV, which under-went isomerization to afford intermediate XCVI. The indoleproduct was obtained after elimination/cyclization process(Scheme 83).

Scheme 83 Proposed mechanism for the Fischer indole synthesis of compounds 151

Scheme 79 NIS-mediated metal-free indole synthesis

R2R1

NHTs

NIS (2.0 equiv)

NTs

R1

R2

NTs

R2R2

= C6H5, 99%; 2-MeC6H4, 96% 4-tBuC6H4, 91%; 4-FC6H4, 91% 3-MeOC6H4, 54% N

Ts

PhNTs83% 21%

Me Ph

CH2Cl2, rt, 0.5–48 h

144 145

Scheme 80 Proposed mechanistic pathway for the metal-free indole synthesis

R2

NHTs

R1

NHTs

IR1

R2

NO ONH

O

O

NTs

R1I

R2

NTs

R1

R2NTs

R1

R2

– I

aromatization

I

H– HI

N

O

O

I

XC XCI

XCII

NHNH2⋅HCl OR

L-(+)-TA–DMU melt at 70 °C

0.25–0.5 h N

R

N

Me

99%

N 94%N 92%

COOEtN3

N 90%N 90%

CN

N 97% NH

Me95% N

N

85%

Boc

N

N

94%

CbzMeMe

N 95%

Me

Me

146 147 148

+

R1OR

O

R3

R4–Cl+H3NHN

CHCl3

pyridine

R1

R2 R2

68% 71% 80% 69%

NH

R3

R4

MeO

NH

MeO

NH

Me

Me

MeO

NH

Ph

MeMeO

NH

149 150 151

R

MeO

OR1

R2H2NHN

1,2 additionR

MeO

HNHN

HO

R2R1

H

H

dehydrationR

MeO

N NH R1

R2

aromatization

N N R1

R2

Risomerization

NH

N R1

R2

RR

one-pot

XCIII XCIV

XCVXCVI

NH

R1

R2

+

151

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7 Applications

Knochel and co-workers successfully synthesized indo-methacin (2) and iprindole (5). Organozinc reagent 153 re-acts with aryldiazonium salt 152 to produce the indole 154,which is further converted into indomethacin (2).48 Similar-ly, the reaction of cyclooctylzinc 155 with aryldiazoniumsalt 152 under standard reaction conditions provides indole156, which was N-alkylated to generate iprindole (5)(Scheme 84).48

Scheme 84 The synthesis of indomethacin (2) and iprindole (5)

8 Summary and Outlook

In this review, we have described the recent progress inthe field of the regioselective synthesis of indoles. We havediscussed transition-metal-catalyzed methodologies via C–Hactivation and have also described metal-free approachesfor the synthesis of 2,3-disubstituted indoles with mecha-nisms. Some limitations of the classical Fisher indole syn-thesis were overcome by applying these new procedures.There is scope for the further development of new method-ologies and for improvement of the reaction conditions. Fu-ture studies will provide new applications for the synthesisof complex bioactive molecules.

Funding Information

This work is supported by the Science and Engineering ResearchBoard, India (EMR/2014/001023). R.K. and I.K. acknowledge UGC,New Delhi for Junior Research Fellowships.I (J)

Acknowledgment

The authors are grateful to the Director, CSIR-IHBT for providing nec-essary facilities. CSIR-IHBT communication no. for this publication is4233.

References

(1) (a) Sundberg, R. J. Indoles 1996. (b) Kawasaki, T.; Higuchi, K. Nat.Prod. Rep. 2005, 22, 761. (c) d’Ischia, M.; Napolitano, A.;Pezzella, A. In Comprehensive Heterocyclic Chemistry III;Vol. 3Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.,Eds.; Elsevier: Oxford, 2008, 353–388. (d) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.(e) Xu, W.; Gavia, D. J.; Tang, Y. Nat. Prod. Rep. 2014, 31, 1474.(f) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep.2015, 32, 1389.

(2) (a) Chen, F.-E.; Huang, J. Chem. Rev. 2005, 105, 4671.(b) Boriskin, Y. S.; Leneva, I. A.; Pecheur, E. I.; Polyak, S. J. Curr.Med. Chem. 2008, 15, 997. (c) Shen, T. Y.; Windholz, T. B.;Rosegay, A.; Witzel, B. E.; Wilson, A. N.; Willett, J. D.; Holtz, W.J.; Ellis, R. L.; Matzuk, A. R.; Lucas, S.; Stammer, C. H.; Holly, F.W.; Sarett, L. H.; Risley, E. A.; Nuss, G. W.; Winter, C. A. J. Am.Chem. Soc. 1963, 85, 488. (d) Augelli-Szafran, C. E.; Jaen, J. C.;Moreland, D. W.; Nelson, C. B.; Penvose-Yi, J. R.; Schwarz, R. D.Bioorg. Med. Chem. Lett. 1998, 8, 1991. (e) Rice, L. M.; Hertz, E.;Freed, M. E. J. Med. Chem. 1964, 7, 313. (f) Baxter, B. L.;Gluckman, M. I. Nature 1969, 223, 750. (g) Chen, H.; Eberlin, L.S.; Nefliu, M.; Augusti, R.; Cooks, R. G. Angew. Chem. Int. Ed.2008, 47, 3422.

(3) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry;Vol. 4Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984, 313.

(4) (a) Song, J. J.; Reeves, J. T.; Fandrick, D. R.; Tan, Z.; Yee, N. K.;Senanayake, C. H. ARKIVOC 2010, (i), 390. (b) Cacchi, S.; Fabrizi,G. Chem. Rev. 2011, 111, PR215. (c) Guo, T.; Huang, F.; Yu, L.; Yu,Z. Tetrahedron Lett. 2015, 56, 296.

(5) Maity, S.; Zheng, N. Angew. Chem. Int. Ed. 2012, 51, 9562.(6) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098.(7) Nanjo, T.; Tsukano, C.; Takemoto, Y. Org. Lett. 2012, 14, 4270.(8) Wang, Y.; Liu, L.; Zhang, L. Chem. Sci. 2013, 4, 739.(9) Anxionnat, B.; Gomez Pardo, D.; Ricci, G.; Rossen, K.; Cossy, J.

Org. Lett. 2013, 15, 3876.(10) Kiruthika, S. E.; Perumal, P. T. Org. Lett. 2014, 16, 484.(11) Besandre, R.; Jaimes, M.; May, J. A. Org. Lett. 2013, 15, 1666.(12) Guo, T.; Jiang, Q.; Yu, Z. Org. Chem. Front. 2015, 2, 1361.(13) Otani, T.; Jiang, X.; Cho, K.; Araki, R.; Kutsumura, N.; Saito, T.

Adv. Synth. Catal. 2015, 357, 1483.(14) Sayyad, M.; Nanaji, Y.; Ghorai, M. K. J. Org. Chem. 2015, 80,

12659.(15) Gschwend, H. W.; Rodriguez, H. R. Org React. 1979, 26, 1.(16) Ghorai, M. K.; Sayyad, M.; Nanaji, Y.; Jana, S. Chem. Eur. J. 2015,

10, 1480.(17) Zardi, P.; Savoldelli, A.; Carminati, D. M.; Caselli, A.; Ragaini, F.;

Gallo, E. ACS Catal. 2014, 4, 3820.(18) Choi, I.; Chung, H.; Park, J. W.; Chung, Y. K. Org. Lett. 2016, 18,

5508.(19) Ito, Y.; Ueda, M.; Takeda, N.; Miyata, O. Chem. Eur. J. 2016, 22,

2616.(20) Taber, D. F.; Tirunahari, P. K. Tetrahedron 2011, 67, 7195.(21) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Perboni, A.; Sferrazza, A.;

Stabile, P. Org. Lett. 2010, 12, 3279.(22) Brand, J. P.; Chevalley, C.; Waser, J. Beilstein J. Org. Chem. 2011, 7,

565.(23) Nallagonda, R.; Rehan, M.; Ghorai, P. Org. Lett. 2014, 16, 4786.(24) Zhou, B.; Yang, Y.; Tang, H.; Du, J.; Feng, H.; Li, Y. Org. Lett. 2014,

16, 3900.(25) Panferova, L. I.; Smirnov, V. O.; Levin, V. V.; Kokorekin, V. A.;

Struchkova, M. I.; Dilman, A. D. J. Org. Chem. 2017, 82, 745.(26) Miao, B.; Li, S.; Li, G.; Ma, S. Org. Lett. 2016, 18, 2556.

EtO2C

Me

ZnX NH

MeOCO2Et

Me

OMe

N2+BF4

–60 °C to 25 °C

N

O

Cl

COOHMeO

Me

N

NMe2

67%

1. KOtBu (1.2 equiv) 0 °C, 20 min, then p-ClC6H4COCl (1.2 equiv) 25 °C, 10 h

2. LiOH (10 equiv) H2O, THF 25 °C, 6 h

KOtBu (1.2 equiv) 0 °C, 20 min

72%

+then Me3SiCl (1 equiv) 125 °C, 30 min, MW

NH

OMe

N2+BF4

–60 °C to 25 °C

80% then Me3SiCl (1 equiv)125 °C, 30 min, MW

ZnX

then p-Cl(CH2)3NMe2 (1.2 equiv) 125 °C, 3 h, MW

152 153 154

2

155 156 5

© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, 2655–2677

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Thi

s do

cum

ent w

as d

ownl

oade

d fo

r pe

rson

al u

se o

nly.

Una

utho

rized

dis

trib

utio

n is

str

ictly

pro

hibi

ted.

(27) Porcheddu, A.; Mura, M. G.; De Luca, L.; Pizzetti, M.; Taddei, M.Org. Lett. 2012, 14, 6112.

(28) Müller, S.; Webber, M. J.; List, B. J. Am. Chem. Soc. 2011, 133,18534.

(29) Zhan, F.; Liang, G. Angew. Chem. Int. Ed. 2013, 52, 1266.(30) Liu, B.; Song, C.; Sun, C.; Zhou, S.; Zhu, J. J. Am. Chem. Soc. 2013,

135, 16625.(31) Lu, B. Z.; Wei, H.-X.; Zhang, Y.; Zhao, W.; Dufour, M.; Li, G.;

Farina, V.; Senanayake, C. H. J. Org. Chem. 2013, 78, 4558.(32) Zhang, M.; Xie, F.; Wang, X.; Yan, F.; Wang, T.; Chen, M.; Ding, Y.

RSC Adv. 2013, 3, 6022.(33) Jana, N.; Nguyen, Q.; Driver, T. G. J. Org. Chem. 2014, 79, 2781.(34) Lim, B.-Y.; Jung, B.-E.; Cho, C.-G. Org. Lett. 2014, 16, 4492.(35) Chen, J.; He, L.; Natte, K.; Neumann, H.; Beller, M.; Wu, X.-F. Adv.

Synth. Catal. 2014, 356, 2955.(36) Ye, K.-Y.; Dai, L.-X.; You, S.-L. Chem. Eur. J. 2014, 20, 3040.(37) Lin, H.; Li, S.-S.; Dong, L. Org. Biomol. Chem. 2015, 13, 11228.(38) Sagadevan, A.; Ragupathi, A.; Hwang, K. C. Angew. Chem. Int. Ed.

2015, 54, 13896.(39) (a) Sagadevan, A.; Ragupathi, A.; Lin, C.-C.; Hwu, J. R.; Hwang, K.

C. Green Chem. 2015, 17, 1113. (b) Mylnikov, V. S. Zh. Strukt.Khim. 1974, 15, 244.

(40) (a) Majek, M.; Jacobi von Wangelin, A. Angew. Chem. Int. Ed.2013, 52, 5919. (b) Yam, V. W.-W.; Lo, K. K.-W.; Wong, K. M.-C.J. Organomet. Chem. 1999, 578, 3.

(41) Díez-González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem. Eur. J.2006, 12, 7558.

(42) Zhang, G.; Miao, J.; Zhao, Y.; Ge, H. Angew. Chem. Int. Ed. 2012,51, 8318.

(43) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Adv. Synth. Catal. 2015, 357,2944.

(44) Yan, H.; Wang, H.; Li, X.; Xin, X.; Wang, C.; Wan, B. Angew. Chem.Int. Ed. 2015, 54, 10613.

(45) Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc.2011, 133, 2154.

(46) Kim, T.; Kim, K. Tetrahedron Lett. 2010, 51, 868.(47) Wang, C.; Huang, Y. Org. Lett. 2013, 15, 5294.(48) Haag, B. A.; Zhang, Z.-G.; Li, J.-S.; Knochel, P. Angew. Chem. Int.

Ed. 2010, 49, 9513.

(49) Jiang, H.; Gao, S.; Xu, J.; Wu, X.; Lin, A.; Yao, H. Adv. Synth. Catal.2016, 358, 188.

(50) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius, F.Angew. Chem. Int. Ed. 2008, 47, 7230.

(51) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.; Jiao, N. Angew.Chem. Int. Ed. 2009, 48, 4572.

(52) Qi, Z.; Yu, S.; Li, X. Org. Lett. 2016, 18, 700.(53) Wu, C.-J.; Meng, Q.-Y.; Lei, T.; Zhong, J.-J.; Liu, W.-Q.; Zhao, L.-

M.; Li, Z.-J.; Chen, B.; Tung, C.-H.; Wu, L.-Z. ACS Catal. 2016, 6,4635.

(54) Zhang, Z.; Jiang, H.; Huang, Y. Org. Lett. 2014, 16, 5976.(55) Miyanaga, W.; Sugiki, M.; Ejima, C.; Tokumasu, M.; Yoshida, T.

WO2014/003158 A1, 2014.(56) Layek, M.; Reddy, M. A.; Dhanunjaya Rao, A. V.; Alvala, M.;

Arunasree, M. K.; Islam, A.; Mukkanti, K.; Iqbal, J.; Pal, M. Org.Biomol. Chem. 2011, 9, 1004.

(57) Ding, M.; He, F.; Hudyma, T. W.; Zheng, X.; Poss, M. A.; Kadow, J.F.; Beno, B. R.; Rigat, K. L.; Wang, Y.-K.; Fridell, R. A.; Lemm, J. A.;Qiu, D.; Liu, M.; Voss, S.; Pelosi, L. A.; Roberts, S. B.; Gao, M.;Knipe, J.; Gentles, R. G. Bioorg. Med. Chem. Lett. 2012, 22, 2866.

(58) (a) Zhao, D.; Shi, Z.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52,12426. (b) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.; Xia, Y. J. Org.Chem. 2012, 77, 3017.

(59) Zhou, S.; Wang, J.; Zhang, F.; Song, C.; Zhu, J. Org. Lett. 2016, 18,2427.

(60) Li, D. Y.; Chen, H. J.; Liu, P. N. Org. Lett. 2014, 16, 6176.(61) Zhang, Z.-Z.; Liu, B.; Xu, J.-W.; Yan, S.-Y.; Shi, B.-F. Org. Lett.

2016, 18, 1776.(62) Zhou, S.; Wang, J.; Wang, L.; Chen, K.; Song, C.; Zhu, J. Org. Lett.

2016, 18, 3806.(63) Hu, Z.; Tong, X.; Liu, G. Org. Lett. 2016, 18, 2058.(64) Zhang, X.; Guo, R.; Zhao, X. Org. Chem. Front. 2015, 2, 1334.(65) Jiang, B.; Li, Q.-Y.; Tu, S.-J.; Li, G. Org. Lett. 2012, 14, 5210.(66) Jang, Y. H.; Youn, S. W. Org. Lett. 2014, 16, 3720.(67) Li, Y.-L.; Li, J.; Ma, A.-L.; Huang, Y.-N.; Deng, J. J. Org. Chem. 2015,

80, 3841.(68) Gore, S.; Baskaran, S.; König, B. Org. Lett. 2012, 14, 4568.(69) Zhang, J.; Yin, Z.; Leonard, P.; Wu, J.; Sioson, K.; Liu, C.; Lapo, R.;

Zheng, S. Angew. Chem. Int. Ed. 2013, 52, 1753.

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