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Synthesis of indoles

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Fischer Indole Synthesis

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An inexpensive aminoguanidine efficiently catalyzes a reductive cyclization of o-phenylenediamines with CO2 in the presence of triethoxysilane. Various functionalized benzimidazoles, benzoxazole, and benzothiazole were synthesized in high yields. Mechanistic studies indicate that formic acid acts as a cocatalyst.
Y. Sun, K. Gao, J. Org. Chem., 2023, 88, 7463-7468.

A praseodymium-catalyzed aerobic dehydrogenative aromatization of saturated N-heterocycles shows high catalytic activity under mild reaction conditions to produce 7 classes of products with a broad substrate scope.
T. Zhang, Y. Lv, Z. Zhang, Z. Jia, T.-P. Loh, Org. Lett., 2023, 25, 4468-4472.

A transition-metal/quinone complex is an effective catalyst for aerobic dehydrogenation of 3° indolines to the corresponding indoles. The utility of the method is demonstrated in the synthesis of key intermediates to pharmaceutically important molecules.
B. Li, A. E. Wendlandt, S. S. Stahl, Org. Lett., 2019, 21, 1176-1181.

The polystyrene-cross-linking bisphosphine ligand PS-DPPBz was effective for the Ir-catalyzed reversible acceptorless dehydrogenation/hydrogenation of N-heterocycles. Notably, this protocol is applicable to the dehydrogenation of a broad range of indoline derivatives.
D. Zhang, T. Iwai, M. Sawamura, Org. Lett., 2020, 22, 5240-5245.

The quaternary ammonium salts PhMe3NI and PhEt3NI are safe, nontoxic, and easy-to-handle reagents for absolutely monoselective N-alkylations of amides and NH indoles. These convenient reactions offer high yields, high functional group tolerance, and especially excellent monoselectivity for amides. Late-stage methylations of a broad range of bioactive compounds are also described.
J. Templ, E. Gjata, F. Getzner, M. Schnürch, Org. Lett., 2022, 24, 7315-7319.

Tetramethylammonium fluoride (TMAF) enables a direct and selective methylation of various amides, indoles, pyrroles, imidazoles, alcohols, and thiols. The method is characterized by operational simplicity, wide scope, and ease of purification.
H.-G. Cheng, M. Pu, G. Kundu, F. Schoenebeck, Org. Lett., 2020, 22, 331-334.

Due to the poor nucleophilicity of the nitrogen atom of indoles and the competing alkylation reaction at the C-3 position, the use of more sterically hindered ketones with a lower electrophilicity as N-alkylation reagents has been a great challenge. A dearomatization-rearomatization strategy enables a reductive cross-coupling of indoles with ketones in water in good yield.
Z. Wang, H. Zeng, C.-J. Li, Org. Lett., 2019, 21, 2302-2306.

A consecutive detosylation/alkylation transformation of tosylated indoles and phenols with alkoxides/alcohols as the alkylation reagents features mild reaction conditions, high ipso-selectivity, and good functional group tolerance. A one-pot selective N-alkylation of unprotected indoles with alcohols and TsCl is also realized.
M.-H. Zhu, C.-L. Yu, Y.-L. Feng, M. Usman, D. Zhong, X. Wang, N. Nesnas, W.-B. Liu, Org. Lett., 2019, 21, 7073-7077.

In a regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagents, a single air- and moisture-stable manganese catalyst provides access to either C3- or N-alkylated indoles depending on the solvent used.
J. C. Borghs, V. Zubar, L. M. Azofra, J. Sklyaruk, M. Rueping, Org. Lett., 2020, 22, 4222-4227.

Iridium-catalyzed tandem dehydrogenation of N-heterocycles and alcohols enables regio-selective C-H and N-H bond functionalizations of indolines to provide a diverse range of N- and C3-alkylated indolines/indoles. The practical applicability of this methodology was demonstrated by the preparative-scale synthesis and synthesis of a psychoactive drug, N,N-dimethyltryptamine.
M. Maji, I. Borthakur, S. Srivastava, S. Kundu, J. Org. Chem., 2022, 87, 5603-5616.

In a regioselective dehydrogenative alkylation of indolines using readily available alcohols as the alkylating reagents, a single air- and moisture-stable manganese catalyst provides access to either C3- or N-alkylated indoles depending on the solvent used.
J. C. Borghs, V. Zubar, L. M. Azofra, J. Sklyaruk, M. Rueping, Org. Lett., 2020, 22, 4222-4227.

Bulky, electron-rich phosphines as the supporting ligand in combination with Pd2(dba)3 enable N-arylation of indoles with aryl iodides, bromides, chlorides, and triflates.
D. W. Old, M. C. Harris, S. L. Buchwald, Org. Lett., 2000, 2, 1403-1406.

L-methionine ligated Cu catalyzes C-N cross-couplings of aromatic as well as aliphatic amines including tautomerizable N-heteroarenes. The amino, carboxy, and sulfide functions were critical for the ligation efficiency.
G. N. Vaidya, A. Khan, H. Verma, S. Kumar, D. Kumar, J. Org. Chem., 2019, 84, 3004-3010.

A metal-free electrochemical intramolecular C(sp2)-H amination using iodine as a mediator enables a switchable synthesis of indoline and indole derivatives from easily available 2-vinyl anilines.
K. Hu, Y. Zhang, Z. Zhou, Y. Yang, Z. Zha, Z. Wang, Org. Lett., 2020, 22, 5773-5777.

The use of an organic redox catalyst enables an efficient electrocatalytic synthesis of 3-substituted and 2,3-disubstituted indoles through dehydrogenative cyclization of 2-vinylanilides. The reactions do not require any external chemical oxidant.
Y.-T. Zheng, J. Song, H.-C. Xu, J. Org. Chem., 2021, 86, 16001-16007.

Indoles, dihydroisoquinolines, and dihydroquinolines were efficiently prepared by ruthenium-catalyzed heterocyclizations of aromatic homo- and bis-homopropargyl amines or amides in the presence of pyridine. These regioselective 5-endo and 6-endo cyclizations most probably occur by nucleophilic trapping of key ruthenium-vinylidene intermediates.
A. Varela-Fernández, J. A. Varela, C. Saá, Synthesis, 2012, 44, 3285-3295.

Nitrogen-containing heterocycles, including 1H-indoles and electron-deficient 1H-pyrroles, undergo a smoth and mild palladium/norbornene-cocatalyzed regioselective alkylation with primary alkyl bromides at the C-H bond adjacent to the NH group to give 2-alkyl-1H-indoles and 2-substituted or 2,3-disubstituted 5-alkyl-1H-pyrroles in good yields.
L. Jiao, T. Bach, Synthesis, 2014, 46, 35-41.

The use of a Pd/C-ethylene system enables a synthesis of anilines and indoles from cyclohexanones in the presence of NH4OAc. Hydrogen transfer between cyclohexanone and ethylene generates the desired products. The reaction tolerates a variety of substitutions on the starting cyclohexanones.
K. Maeda, R. Matsubara, M. Hayashi, Org. Lett., 2021, 23, 1530-1534.

A wide variety of indoles can be obtained in good yields from readily available vinyl bromides and diaziridinone. The Pd-catalyzed reaction likely proceeds through a sequential aryl C-H activation and bisamination of a resulting pallada(II)cycle.
J.-W. Ren, M.-N. Tong, Y.-F. Zhao, F. Ni, Org. Lett., 2021, 23, 7497-7502.

An efficient palladium-catalyzed annulation of anilines with bromoalkynes provides 2-phenylindoles with excellent regioselectivities and good functional group tolerance. Preliminary mechanistic studies indicate that anilines undergo anti-nucleophilic addition to bromoalkynes followed by sequential C-H functionalization.
C. Zeng, S. Fang, S. Guo, H. Jiang, S. Yang, W. Wu, Org. Lett., 2023, 25, 1409-1414.

An efficient heterocyclization of 2-alkynylanilines provides indoles in very good yields under mild conditions using small amounts of a gold precatalyst. Various functional groups are tolerated.
M. Michalska, K. Grela, Synlett, 2016, 27, 599-603.

A highly efficient Co-based catalytic system, composed of a commercially available Co salt, a tetradentate phosphine ligand, and K2CO3 enables the methylation of C(sp3)-H/C(sp2)-H bonds using methanol as a methylating reagent. The catalytic system showed high catalytic activity for the methylation of C-H bonds in aryl alkyl ketones, aryl acetonitriles, and indoles, with wide substrate scope and good functional group tolerance.
Z. Liu, Z. Yang, X. Yu, H. Zhang, B. Yu, Y. Zhao, Z. Liu, Org. Lett., 2017, 19, 5228-5231.

Cheap and readily available formic acid is an effective reductant for the reductive cyclization of o-nitrostyrenes. The reaction is air and water tolerant and provides the desired indoles in very good yields, at a low catalyst loading and without generating toxic or difficult to separate byproducts. A cheap glass thick-walled "pressure tube" can be used instead of less available autoclaves.
M. A. Fouad, F. Ferretti, F. Ragaini, J. Org. Chem., 2023, 88, 5108-5117.

A single-electron transfer mediates a modular indole formation from a 2-iodoaniline derivative and a ketone. This transition-metal-free reaction offers a broad substrate scope and unconventional regioselectivity trends. Moreover, important functional groups for further transformation are tolerated.
H. Chung, J. Kim,. G. A. González-Montiel, P. H.-Y. Cheong, H. G. Lee, Org. Lett., 2021, 23, 1096-1102.

A palladium-catalyzed tandem addition/cyclization of 2-(2-aminoaryl)acetonitriles with arylboronic acids provides indole skeletons with good functional group tolerance and remarkable chemoselectivity. In particular, halogen substituents are amenable to further synthetic elaborations thereby broadening the diversity of the products. This transformation involves sequential nucleophilic addition followed by an intramolecular cyclization.
S. Yu, L. Qi, K. Hu, J. Gong, T. Cheng, Q. Wang, J. Chen, H. Wu, J. Org. Chem., 2017, 82, 3631-3638.

An operationally simple, atom-economic, palladium-catalyzed cyclization reaction of N-aryl imines, affords indoles via an oxidative linkage of two C-H bonds under mild conditions in the presence of oxygen. The process allows quick assembly of indole rings from inexpensive and readily available anilines and ketones and tolerates a broad range of functional groups.
Y. Wei, I. Deb, N. Yoshikai, J. Am. Chem. Soc., 2012, 134, 9098-9101.

The use of DDQ as an oxidant enables an effective metal-free C-H amination of N-Ts-2-alkenylanilines to afford a diverse range of substituted indoles. This operationally simple and robust protocol obviates the need of expensive transition-metal catalysts, and offers a broad substrate scope. A mechanism involving a radical cation generated by SET and a migratorial process via a phenonium ion intermediate is proposed.
Y. H. Jang, S. W. Youn, Org. Lett., 2014, 16, 3720-3723.

The use of a hypervalent F-iodane enables a regiodivergent synthesis of indoles and tryptophans from styrenes via a spirocyclic F-cyclopropane as the common intermediate.
A. Andries-Ulmer, C. Brunner, J. Rehbein, T. Gulder, J. Am. Chem. Soc., 2018, 140, 13034-13041.

A Cu-catalyzed (4+1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)anilines provides synthetically and structurally interesting 2,3-disubstituted indoles.
X. Yan, C.-F. Liu, X.-T. An, X.-M. Ge, Q. Zhang, L.-H. Pang, X. Bao, C.-A. Fan, Org. Lett., 2021, 23, 8905-8909.

IrCl(DTBM-SEGPHOS)(C2H4) catalyzes an efficient intramolecular addition of a C(sp3)-H bond of the dimethylamino group across the C-C triple bond in 2-alkynyl-N,N-dimethylanilines in mesitylene at 150°C. The intramolecular C(sp3)-H addition is followed by double-bond isomerization to afford 3-substituted indoles in very good yields.
T. Ohmura, K. Yagi, T. Torigoe, M. Suginome, Synthesis, 2021, 53, 3057-3064.

A transition metal-free, tert-butoxide-mediated condensation reaction enables an efficient and facile synthesis of valuable disubstituted 2-aryl indoles and benzofurans in good yields from N- or O-benzyl benzaldehydes using dimethyl sulfoxide as a carbon source. The methodology offers a wide functional group tolerance.
P. Yang, W. Yu, R. Wang, M. Zhang, C. Xie, X. Zeng, M. Wang, Org. Lett., 2019, 21, 3658-3662.

An efficient palladium-catalyzed reaction of 2-iodostyrenes with di-t-butyldiaziridinone provides indoles via a simultaneous installation of two C-N bonds. The reaction likely proceeds through an oxidative insertion of Pd to aryl iodide and subsequent vinyl C-H activation to from a pallada(II)cycle intermediate, which is bisaminated by di-t-butyldiaziridinone.
J. Li, J. Chen, L. Wang, Y. Shi, Org. Lett., 2021, 23, 3626-3630.

Using a scalable and practical synthesis of functionalized indoles via Pd-tBuONO cocatalyzed cycloisomerization of o-allylanilines in the presence of oxygen as a terminal oxidant, a series of substituted indoles were prepared in good yields. The method avoids hazardous oxidants, heavy-metal cocatalysts, and high boiling point solvents such as DMF and DMSO.
X.-S. Ning, M.-M. Wang, J.-P. Qu, Y.-B. Kang, J. Org. Chem., 2018, 83, 13523-13529.

(Phenyliodonio)sulfamate (PISA) is a readily accessible and bench-stable water-soluble hypervalent iodine(III) reagent, that enables the synthesis of various indoles via C-H amination of 2-alkenylanilines involving an aryl migration/intramolecular cyclization cascade with excellent regioselectivity.
H.-D. Xia, Y.-D. Zhang, Y.-H. Wang, C. Zhang, Org. Lett., 2018, 20, 4052-4056.

A cobalt-rhodium heterobimetallic nanoparticle-catalyzed reductive cyclization of 2-(2-nitroaryl)acetonitriles to indoles proceeds without any additives under mild conditions. The catalytic can be reused more than ten times without loss of catalytic activity.
I. Choi, H. Chung, J. W. Park, Y. K. Chung, Org. Lett., 2016, 18, 5456-5459.

A regioselective ring-opening of 2-(2-haloaryl)-3-alkyl-N-tosylaziridines with thiophenol, followed by copper powder-mediated intramolecular C-N cyclization and subsequent aromatization by the elimination of thiophenol enables the synthesis of indoles in good yields.
M. Sayyad, Y. Nanaji, M. K. Ghorai, J. Org. Chem., 2015, 80, 12659-12667.

The reaction of (2-aminobenzyl) triphenylphosphonium bromide with aromatic aldehydes or α,β-unsaturated aldehydes under microwave-assisted conditions allows the synthesis of 2-substituted indoles in high yields in a one-pot reaction.
G. A. Kraus, H. Guo, Org. Lett., 2008, 10, 3061-3063.

The use of PIFA {[bis(trifluoroacetoxy)iodo]benzene} or quinones enables a cyclization of 2-vinylanilines to provide various indoles under mild conditions in good yields.
M. Wu, R. Yan, Synlett, 2017, 28, 729-733.

Functionalized indoles are synthezised under mild conditions in a tartaric acid-dimethylurea melt, that serves as the solvent and as the catalyst. Under these reaction conditions, sensitive functional groups such as N-Boc, N-Cbz, or azides are tolerated.
S. Gore, S. Baskaran, B. König, Org. Lett., 2012, 14, 4568-4571.

A rapid synthesis of indoles from N-Ts-2-alkenylanilines involves a NIS-mediated cascade C-N bond formation/aromatization. A series of indoles with various functional groups have been synthesized in very good yields under mild conditions without any other additives or catalysts.
Y.-L. Li, J. Li, A.-L. Ma, Y.-N. Huang, J. Deng, J. Org. Chem., 2015, 80, 3841-3851.

An efficient cascade methodology toward the synthesis of 2-substituted indoles proceeds via a palladium-catalyzed cross-coupling reaction of o-nitrobenzyl cyanides with boronic acids in the presence of Fe as co-catalyst.
J. Jadhav, V. Gaikwad, R. Kurane, R. Salunkhe, G. Rahsinkar, Synlett, 2012, 23, 2511-2515.

A new selenium-catalyzed protocol for the direct, intramolecular amination of C(sp2)-H bonds of ortho-vinyl anilines and vinylated aminopyridines using N-fluorobenzenesulfonimide as the terminal oxidant enables the facile formation of a broad range of diversely functionalized indoles and azaindoles, respectively. Key factor is the pronounced carbophilicity of selenium electrophiles for the catalytic activation of alkenes.
S. Ortgies, A. Breder, Org. Lett., 2015, 17, 2748-2751.

Indium-catalyzed cyclization of 2-ethynylanilines produced various polyfunctionalized indole derivatives in good yields for substrates having an alkyl or aryl group on the terminal alkyne. In contrast, substrates with a trimethylsilyl group or without substituent on the triple bond afforded polysubstituted quinoline derivatives in good yields via an intermolecular dimerization.
N. Sakai, K. Annaka, A. Fujita, A. Sato, T. Konakahara, J. Org. Chem., 2008, 73, 4160-4165.

Gold(III)-catalyzed annulation of 2-alkynylanilines in EtOH or EtOH-water mixtures at room temperature gives indoles derivatives in good yields. One-flask protocol for the gold-catalyzed conversion of 2-alkynylanilines to 3-bromo and 3-iodoindoles is also reported.
A. Arcadi, G. Bianchi, F. Marinelli, Synthesis, 2004, 610-618.

A Cu(II)-catalyzed domino coupling/cyclization process under aerobic conditions enables a straightforward assembly of a wide range of 1,2-disubstituted indole derivatives from 2-alkynylanilines and boronic acids. 2-(2-Bromoaryl)-1-aryl-1H-indoles, which were selectively generated in one pot under Cu catalysis, can be converted into indolo[1,2-f]phenanthridines via a subsequent Pd-catalyzed intramolecular direct C(sp2)-H arylation.
J. Gao, Y. Shao, J. Zhu, H. Mao, X. Wang, X. Lv, J. Org. Chem., 2014, 79, 9000-9008.

Cross-coupling of 1-alkynes with vinyl iodides catalyzed by CuI/N,N-dimethylglycine affords conjugated enynes in good to excellent yields. Heating a mixture of 2-bromotrifluoroacetanilide, 1-alkyne in the presence of CuI/L-proline leads to the formation of the corresponding indole.
F. Liu, D. Ma, J. Org. Chem., 2007, 72, 4844-4850.

A copper(II)-catalyzed cyclization of 2-ethynylaniline derivatives to indoles can be carried out in a mixture of H2O and MeOH in the presence of 1-ethylpiperidine at room temperature. A catalyst recycling reaction system was established.
K. Hiroya, S. Itoh, T. Sakamoto, Tetrahedron, 2005, 61, 10958-10964.

A palladium-catalyzed coupling of aryl bromides with 2-alkynyl arylazides or 2-alkynyl benzylazides provides straightforward access to indoles and isoquinolines with high efficiency and excellent functional group compatibility. In the cyclization process, an in situ generated iminophosphorane serves as the nucleophile that attacks the alkyne moiety.
Q. Zhou, Z. Zhang, Y. Zhou, S. Li, Y. Zhang, J. Wang, J. Org. Chem., 2017, 82, 48-56.

An efficient strategy for the synthesis of 3-substituted 2-benzylindoles from stable and readily available o-allylanilines occurred via a regioselective 5-exo-trig intramolecular oxidative cycloisomerization using Pd(OAc)2 as catalyst and molecular oxygen as an oxidant. The reaction showed a broad substrate scope with good to excellent yields.
R. Nallagonda, M. Rehan, P. Ghorai, Org. Lett., 2014, 16, 4786-4789.

Pd-catalyzed annulative couplings of 2-alkenylanilines with aldehydes using alcohols as both the solvent and hydrogen source allow divergent syntheses of indoles and quinolines via two distinct mechanisms by simply tuning reaction parameters. Whereas a reaction using Xantphos as ligand in EtOH provides indoles, a reaction with DPEphos in 2,2,2-trifluoroethanol provides quinolines.
S. S. Jang, Y. H. Kim, S. W. Youn, Org. Lett., 2020, 22, 9151-9157.

A Pd(0)-catalyzed C-N bond-forming reaction enables the synthesis of brominated indoles in the presence of PtBu3 as phosphine ligand. The bulky ligand serves to prevent inhibition of the catalyst by facilitating reversible oxidative addition into the product C-Br bond.
S. G. Newman, M. Lautens, J. Am. Chem. Soc., 2010, 132, 11416-11417.

Sulfuryl chlorofluoride is a versatile reagent for controllable chlorination and chlorooxidation of simple unprotected indoles. Three types of products including 3-chloro-indoles, 3-chloro-2-oxindoles, and 3,3-dichloro-2-oxindoles could be selectively obtained in good to excellent yields by switching the reaction solvents. The convenient methods offer broad substrate scope and mild reaction conditions.
T. Ma, Y. Zheng, S. Huang, J. Org. Chem., 2023, 88, 4839-4847.

A highly efficient and stereoselective arylation of in situ-generated azavinyl carbenes affords 2,2-diaryl enamines at ambient temperatures. These transition-metal carbenes are directly produced from readily available and stable 1-sulfonyl-1,2,3-triazoles in the presence of a rhodium carboxylate catalyst. In several cases, the enamines can be cyclized into substituted indoles employing copper catalysis.
N. Selander, B. T. Worrell, S. Chuprakov, S. Velaparthi, V. V. Fokin, J. Am. Chem. Soc., 2012, 134, 14670-14673.

A Co(III)-catalyzed reaction provides indoles from arylhydrazines and alkynes. Notable synthetic features include regioselectivity for a meta-substituted arylhydrazine, regioselectivity for a chain-branched terminal alkyne, formal incorporation of an acetylenic unit through C2-desilylation and formal inversion of regioselectivity through consecutive C3-derivatization and C2-desilylation processes.
S. Zhou, J. Wang, L. Wang, K. Chen, C. Song, J. Zhu, Org. Lett., 2016, 18, 3806-3809.

A decarboxylative N-arylation of indole-2-carboxylic acids with aryl halides proceeds efficiently in the presence of Cu2O as the catalyst to give the corresponding N-aryl indoles in high yields. This method shows good functional group tolerance.
Y. Zhang, Z.-Y. Hu, X.-C. Li, X.-X. Guo, Synthesis, 2019, 51, 1803-1808.

A practical one-pot and regiospecific three-component process gives 2,3-disubstituted indoles from 2-bromoanilides via consecutive palladium-catalyzed Sonogashira coupling, amidopalladation, and reductive elimination.
B. Z. Lu, H.-X. Wei, Y. Zhang, W. Zhao, M. Dufour, G. Li, V. Farina, C. H. Senanayake, J. Org. Chem., 2013, 78, 4558-4562.

Central to an alternative source of substrates for Fischer indolizations was a palladium-catalyzed coupling to prepare N-aryl benzophenone hydrazones. Hydrolysis of the hydrazones in the presence of ketones produced enolizable hydrazones that underwent Fischer indolization.
S. Wagaw, B. H. Yang, S. L. Buchwald, J. Am. Chem. Soc., 1998, 120, 6621-6622.

In a new version of the Fischer indole synthesis, primary and secondary alcohols have been catalytically oxidized in the presence of phenylhydrazines and Lewis acids to give the corresponding indoles in one step. The use of alcohols instead of aldehydes or ketones broadens the scope of available starting materials and offers easy handling and safety.
A. Porcheddu, M. G. Mura, L. De Luca, M. Pizzetti, M. Taddei, Org. Lett., 2012, 14, 6112-6115.

Heck isomerization of aryl bromides and allyl alcohols provides 3-arylpropanals, that can readily be transformed into 3-arylmethylindoles by Fischer indole synthesis in a consecutive three-component fashion in good yields. This sequence can be expanded to a four-component Heck isomerization-Fischer indolization-alkylation (HIFIA) synthesis.
J. Panther, T. J. J. Müller, Synthesis, 2016, 48, 974-986.

A Rh(III)-catalyzed cyclization of N-nitrosoanilines with alkynes enables a streamlined synthesis of indoles. The C-H activation-based intermolecular redox-neutral protocol uses an N-N bond as internal oxidant, which offers a valuable complement to the widely used N-O variants. The reaction tolerates various functional groups and can be conducted under acidic as well as basic conditions.
B. Liu, C. Song, C. Sun, S. Zhou, J. Zhu, J. Am. Chem. Soc., 2013, 135, 16625-16631.

The addition of N-tosyl hydrazones to arynes, generated through fluoride activation of 2-(trimethylsilyl)phenyl triflate precursors, leads to efficient N-arylation. Addition of a Lewis acid to the same reaction pot then affords N-tosylindole products via Fischer cyclization.
D. McAusland, S. Seo, D. G. Pintori, J. Finlayson, M. F. Greaney, Org. Lett., 2011, 13, 3667-3669.

A three-component synthesis of substituted indoles starts from ortho-dihaloarenes through the use of a multicatalytic system consisting of an N-heterocyclic carbene palladium complex and CuI. Indole derivatives are obtained as single regioisomers in high yields.
L. T. Kaspar, L. Ackermann, Tetrahedron, 2005, 61, 11311-11316.

A radical coupling of 2-halotoluenes and imines followed by C-N bond construction enables a transition-metal-free indole synthesis. The standard condition can be used for all halides including F, Cl, Br, and I. No extra oxidant is required.
Y.-W. Li, H.-X. Zheng, B. Yang, X.-H. Shan, J.-P. Qu, Y.-B. Kang, Org. Lett., 2020, 22, 4553-4556.

A Pd-catalyzed cascade process consisting of isocyanide insertion and benzylic C(sp3)-H activation allows the construction of the indole skeleton. Slow addition of isocyanide is effective for reducing the amount of catalyst needed and Ad2PBu is a good ligand for C(sp3)-H activation. The construction of the tetracyclic carbazole skeleton was also achieved by a Pd-catalyzed domino reaction incorporating alkyne insertion.
T. Nanjo, C. Tsukano, Y. Takemoto, Org. Lett., 2012, 14, 4270-4273.

Treatment of o-bromonitrobenzenes with various vinyl Grignard reagents gives 7-bromoindoles in good yields, using the o-bromine atom to direct the cyclization. A subsequent reduction using a heteroaryl radical methodology gives 7-unsubstituted indoles in nearly quantitative yields.
A. Dobbs, J. Org. Chem., 2001, 66, 638-641.

A new, mild, and efficient method for the synthesis of polyfunctionalized indoles by direct reaction of substituted 2-chloroanilines with cyclic or acyclic ketones was developed. This procedure is simple to carry out and broadly applicable.
M. Nazare, C. Schneider, A. Lindenschmidt, D. W. Will, Angew. Chem. Int. Ed., 2004, 43, 4526-4528.

One-pot synthesis of indoles by a palladium-catalyzed annulation of ortho-iodoanilines and aldehydes is realized under mild ligandless conditions, whereas X-Phos is found to be the ligand of choice for coupling reactions involving ortho-chloroanilines/ortho-bromoanilines and aldehydes.
Y. Jia, J. Zhu, J. Org. Chem., 2006, 71, 7826-7834.

A new palladium-catalyzed route to N-functionalized indoles has been developed in which the N fragments are introduced in a single-step cascade sequence onto a acyclic carbon framework.
M. C. Willis, G. N. Brace, I. P. Holmes, Angew. Chem. Int. Ed., 2005, 44, 403-406.

The Pd-catalyzed tandem C-N/Suzuki-Miyaura coupling of readily prepared ortho-gem-dihalovinylanilines with boronic acids, esters, alkyl 9-BBN derivatives, and trialkylboranes gave 2-substituted indoles in good to excellent yields. Optimal conditions used low loadings of a Pd(OAc)2/S-Phos catalyst in the presence of K3PO4ˇH2O.
Y.-Q. Fang, M. Lautens, Org. Lett., 2005, 7, 3549-3552.

The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate or a second equivalent of the aniline followod by microwave irradiation provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in good overall yields.
V. Sridharan, S. Perumal, C. Avendańo, J. C. Menéndez, Synlett, 2006, 91-95.

V. Sridharan, S. Perumal, C. Avendańo, J. C. Menéndez, Synlett, 2006, 91-95.

A practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles based on Cacchi's protocol was developed. This mild Pd-catalyzed domino indolization procedure allows rapid access to various indoles via consecutive Sonogashira coupling, amidopalladation, and reductive elimination.
B. Z. Lu, W. Zhao, H.-X. Wei, M. Dufour, V. Farina, C. H. Senanayake, Org. Lett., 2006, 8, 3271-3274.

A palladium-catalyzed synthesis of free N-H 2,3-disubstituted indoles from arenediazonium tetrafluoroborates and 2-alkynyltrifluoroacetanilides tolerates a variety of useful substituents in the substrates, including bromo and chloro substituents, nitro, cyano, keto, ester, and ether groups.
S. Cacchi, G. Fabrizi, A. Goggiamani, A. Perboni, A. Sferrazza, P. Stabile, Org. Lett., 2010, 12, 3279-3281.

Treatment of 2-alkenylanilines with phenyliodine(III) diacetate (PIDA) and LiBr or KI in HFIP provides the corresponding 3-bromoindoles and 3-iodoindoles via cascade oxidative cyclization/halogenation.
B. Zhao, X. Li, X. Wang, L. Jiang, Z. Li, Y. Du, J. Org. Chem., 2023, 88, 1493-1503.

In an entirely new palladium-catalyzed indole synthesis, 2-(1-alkynyl)-N-alkylideneanilines provide 2-substituted-3-(1-alkenyl)indoles in good yields. The bond formation takes place between C-2
and C-3.
A. Takeda, S. Kamijo, Y. Yamamoto, J. Am. Chem. Soc., 2000, 122, 5662-5663.

A nickel-catalyzed reductive coupling of alkynes and amides, followed by base-free transmetalation provides highly functionalized indoles comprising biologically important trifluoromethyl groups and challenging electron-rich alkenyl groups. The reaction proceeded selectively in the presence of an uncommon bidentate primary aminophosphine ligand.
K. H. Min, N. Iqbal, E. J. Cho, Org. Lett., 2022, 24, 989-994.

A direct decarboxylative cross-coupling of α-oxo/ketoacids with indoles and β-carbolines in the presence of (NH4)2S2O8 enables a metal-free formylation/acylation in moderate to good yields under mild reaction conditions.
V. Dinesh, R. Nagarajan, J. Org. Chem., 2022, 87, 10359-10365.

An efficient iron-catalyzed C3-selective formylation of free or N-substituted provides 3-formylindoles in good yields in fairly short reaction times in the presence of formaldehyde and aqueous ammonia, with air as the oxidant. Moreover, this catalytic formylation of indoles can be applied to gram-scale syntheses.
Q.-D. Wang, B. Zhou, J.-M. Yang, D. Fang, J. Ren, B.-B. Zeng, Synlett, 2017, 28, 2670-2674.

Eosin Y catalyzes a visible-light-mediated C-3 formylation of indole in the presence of tetramethylethylenediamine as a carbon source and air as an oxidant under mild conditions. This protocol tolerates a broad range of functional groups and provides 3-formylated indoles with good yields.
Y. Zhao, H. Li, S. Yin, Y. Wu, G. Ni, Synlett, 2022, 33, 659-663.

A direct metal- and oxidant-free photochemical decarboxylative formylation of indoles with 50% aqueous glyoxylic acid proceeds in good yields.
V. Dinesh, R. Nagarajan, Synlett, 2023, 34, 855-857.

In a Ph3P/ICH2CH2I-mediated formylation of indoles with DMF under mild conditions, a Vilsmeier-type intermediate is readily formed from DMF promoted by the Ph3P/ICH2CH2I system. A one-step formylation process can be applied to various electron-rich indoles, but a hydrolysis needs to be carried out as a second step in the case of electron-deficient indoles.
Y.-R. Zhu, J.-H. Lin, J.-C. Xiao, Synlett, 2022, 33, 259-263.

Indoles are selectively acylated at position 3 in high yields with a broad range of acyl chlorides in the presence of diethylaluminum chloride or dimethylaluminum chloride. The reaction proceeds in CH2Cl2 under mild conditions and is applicable to indoles bearing various functional groups without NH protection.
T. Okauchi, M. Itonaga, T. Minami, T. Owa, K. Kitoh, H. Yoshino, Org. Lett., 2000, 2, 1485-1487.

A Pt(II)-catalyzed intramolecular translocation annulation of ortho-alkynylamides provides indoles. The formation of an acylium intermediate is suggested, which can further react with an indol-3-ylplatinum species in an intramolecular manner, albeit within the same solvent cage to form 3-acyl indoles.
S. R. Patra, S. W. Sangma, A. K. Padhy, S. Bhunia, J. Org. Chem., 2022, 87, 10372-10376.

An efficient, mild Pd-catalyzed oxidative coupling of aromatic primary amines and alkenes under molecular oxygen provides a rapid access to (Z)-enamines with exceptional functional group tolerance and excellent regio- and stereoselectivity. The resultant enamines could be conveniently transformed into a series of N-containing heterocycles, thus illustrating its potential applications in synthetic and medicinal chemistry.
X. Ji, H. Huang, W. Wu, X. Li, H. Jiang, J. Org. Chem., 2013, 78, 11155-11162.

Addition of ethyl diazoacetate (EDA) to 2-aminobenzaldehydes cleanly affords 3-ethoxycarbonylindoles. This mild and efficient synthesis of indoles displays both excellent functional group tolerance and perfect regiochemical control. Various indole building blocks were synthesized from 2-aminobenzaldehydes derived from readily available anthranilic acids.
P. Levesque, P.-A. Forunier, J. Org. Chem., 2010, 75, 7033-7036.

A practical iron-catalyzed intramolecular C-H amination reaction with commercially available iron(II) triflate as catalyst can be used for the synthesis of indole derivatives.
J. Bonnamour, C. Bolm, Org. Lett., 2011, 13, 2012-2014.

A t-BuOK/DMF system without special initiators or additives enables the preparation of N-substituted indole-3-carboxylates in high yields under transition-metal-free conditions. These conditions are particularly attractive for manufacturing halogenated indoles.
D. I. Bugaenko, A. A. Dubrovina, M. A. Yurovskaya, A. V. Karchava, Org. Lett., 2018, 20, 7358-7362.

A tandem Michael addition, C-C bond cleavage, and cyclization of 2-vinylanilines and alkynoates provides 2-substituted indoles and quinolines. Whereas C2-substituted indoles can be accessed in good yields under metal-free conditions, the simple method for the generation of the C2-substituted quinolines in moderate yields is Pd-catalyzed.
J. Ni, Y. Jiang, Z. An, R. Yan, Org. Lett., 2018, 20, 1534-1537.

A Pd(II)-catalyzed C(sp3)-H/C(sp2)-H coupling/annulation of anilides and α-dicarbonyl compounds provides diverse N-acyl indoles with high functional group tolerance and excellent regioselectivity.
R. S. Thombal, Y. R. Lee, Org. Lett., 2020, 22, 3397-3401.

Direct anti-azacarboxylation of 2-alkynylanilines with CO2 mediated by ZnEt2 affords indole-3-carboxylic acids efficiently under 1 atm of CO2. The availability of starting materials and tolerance of various functional groups provide vast opportunities for the efficient construction of diversified libraries for bioactive compounds.
B. Miao, S. Li, G. Li, S. Ma, Org. Lett., 2016, 18, 2556-2559.

A Rh(III)-catalyzed C-H activation/annulation of imidamides with α-diazo β-ketoesters enables the synthesis of N-unprotected indoles. A rhodacyclic intermediate has been isolated and a plausible mechanism has been proposed.
Z. Qi, S. Yu, X. Li, Org. Lett., 2016, 18, 700-703.

A one-pot tandem copper-catalyzed Ullmann-type C-N bond formation/intramolecular cross-dehydrogenative coupling process enables the synthesis of multisubstituted indoles in very good yields from readily available aryl iodides and enamines at 130°C in DMSO.
Y. Li, J. Peng, X. Chen, B. Mo, X. Li, P. Sun, C. Chen, J. Org. Chem., 2018, 83, 5288-5294.

A radical cyclization enables the preparation of indoles and their derivatives from a wide variety of simple enamines only with catalytic amounts of an iridium(III) photosensitizer (PS) in DMSO solution under air atmosphere.
W.-Q. Liu, T. Lei, Z.-Q. Song, X.-L. Yang, C.-J. Wu, X. Jiang, B. Chen, C.-H. Tung, L.-Z. Wu, Org. Lett., 2017, 19, 3147-3150.

In an electrochemical approach for the site-selective C-H cyanation of indoles with readily available TMSCN as cyano source, the use of tris(4-bromophenyl)amine as a redox catalyst achieves better yield and regioselectivity. The reactions are conducted in a simple undivided cell at room temperature and obviate the need for transition-metal catalysts and chemical oxidants.
L. Li, Z.-W. Hou, P. Li, L. Wang, Org. Lett., 2021, 23, 5983-5987.

A Mn(III)-mediated radical cascade cyclization of o-alkenyl aromatic isocyanides with boronic acids provides N-unprotected 2-aryl-3-cyanoindoles. A possible mechanism involves a sequential intermolecular radical addition, intramolecular cyclization, and cleavage of a C-C bond under mild reaction conditions. Either H2O or O2 acts as the oxygen source for the elimination of benzaldehyde.
L. Liu, L. Li, X. Wang, R. Sun, M.-D. Zhou, H. Wang, Org. Lett., 2021, 23, 5826-5830.

Gold(I)-catalyzed cycloisomerization of 1-(2-(tosylamino)phenyl)prop-2-yn-1-ols enables the preparation of 1H-indole-2-carbaldehydes and (E)-2-(iodomethylene)indolin-3-ols in the presence of N-iodosuccinimide (NIS). The reactions were shown to be operationally simplistic and proceed efficiently for a wide variety of substrates, affording the corresponding products in very good yields.
P. Kothandaraman, S. R. Mothe, S. S. M. Toh, P. W. H. Chan, J. Org. Chem., 2011, 76, 7633-7640.

The use 10 mol % of Cu(OTf)2 enables the coupling of α-diazoketones with β-enaminoketones and esters to yield 2,4,5-trisubstituted pyrrole derivatives. A wide range of 2,3-disubstituted indole derivatives were also prepared from α-diazoketones and 2-aminoaryl or alkyl ketones.
B. V. S. Reddy, M. R. Reddy, Y. G. Rao, J. S. Yadav, B. Srighar, Org. Lett., 2013, 15, 464-467.

An effective strategy for oxidative cross-coupling of indoles with various aldehydes is based on a two-step transformation via a well-known Mannich-type reaction and an electrochemical C-N bond cleavage for carbonyl introduction. This method offers excellent functional-group tolerance and enables late-stage functionalization of pharmaceutical molecules.
L. Yang, Z. Liu, Y. Li, N. Lei, Y. Shen, K. Zheng, Org. Lett., 2019, 21, 7702-7707.

An iridium-catalyzed hydrogen transfer in the presence of p-benzoquinone allows the synthesis of various substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.
B. Anxionnat, D. G. Pardo, G. Ricci, K. Rossen, J. Cossy, Org. Lett., 2013, 15, 3876-3879.

An AgOTf-catalyzed reaction of β-(2-Aminophenyl)-α,β-ynones provides 3-unsubstituted 2-acylindoles in good yields under microwave heating. The use of Cu(OTf)2 as a catalyst resulted in a similar reaction outcome, albeit with a lower efficiency.
N. D. Rode, I. Abdalghani, A. Arcadi, M. Aschi, M. Chiarini, F. Marinelli, J. Org. Chem., 2018, 83, 6354-6362.

In a palladium-catalyzed intramolecular addition of C-N and S-N bond to alkynes, a wide range of functional groups including acyl, pyruvoyl, amide, and sulfonyl groups can migrate smoothly and be conveniently introduced at the C-3 position of indoles. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly substituted indoles.
F. Zhao, D. Zhang, Y. Nian, L. Zhang, W. Yang, H. Liu, Org. Lett., 2014, 16, 5124-5127.

A Pd-catalyzed C-N bond coupling of various halo-aryl enamines enables the synthesis of N-functionalized C2-/C3-substituted indoles. Optimized conditions comprising the RuPhos precatalyst and RuPhos in the presence of NaOMe in 1,4-dioxane tolerate a variety of substituents and are scalable for the construction of indoles in multigram quantities.
R. G. Vaswani, B. K. Albrecht, J. E. Audia, A. Côté, L. A. Dakin, M. Duplessis, V. S. Gehling, J.-C. Harmange, M. C. Hewitt, Y. Leblanc, C. G. Nasveschuk, A. M. Taylor, Org. Lett., 2014, 16, 4114-4117.

Palladium-catalyzed isocyanide insertion and oxypalladation of an alkyne enables the synthesis of 3-acyl-2-arylindole derivatives. In addition, domino cyclizations for the synthesis of several tetracyclic indole derivatives were also achieved.
T. Nanjo, S. Yamamoto, C. Tsukano, Y. Takemoto, Org. Lett., 2013, 15, 3754-3757.

Palladium-catalyzed intramolecular N-arylative and N-alkylative/N-arylative trappings of the Blaise reaction intermediates enable the construction of the indole moiety in a tandem one-pot manner from nitriles.
J. H. Kim, S.-g. Lee, Org. Lett., 2011, 13, 1350-1353.

A copper-catalyzed one-pot multicomponent cascade reaction of 1-bromo-2-(2,2-dibromovinyl)benzenes with aldehydes and aqueous ammonia enables a selective synthetis of various indole derivatives. 3-Cyano-1H-indoles, 9H-pyrimido[4,5-b]indoles, or 9H-pyrido[2,3-b]indoles depending on the concentration of ammonia, the molar ratio of reagents, and the structural features of the aldehyde.
B. Li, S. Guo, J. Zhang, X. Zhang, X. Fan, J. Org. Chem., 2015, 80, 5444-5456.

Various 2-aryl-3-arylamino-2-alkenenitriles give N-arylindole-3-carbonitriles in a one-pot manner through NBS- or NCS-mediated halogenation followed by Zn(OAc)2-catalyzed intramolecular cyclization. The process involves the formation of arylnitrenium ion intermediates, which undergo an electrophilic aromatic substitution to give the cyclized N-arylindoles.
Q. Yan, J. Luo, D. Zhang-Negrerie, H. Li, X. Qi, K. Zhao, J. Org. Chem., 2011, 76, 8690-8697.

The reaction of easily accessible N-(2-formylphenyl)trifluoroacetamides and α-bromoacetophenones in the presence of K2CO3 enables a one-pot and environmentally benign approach to the synthesis of highly functionalized 3-unsubstituted 2-aroylindoles. PEG-400 is an efficient and reusable solvent in this process.
Y. Zhao, D. Li, L. Zhao, J. Zhang, Synthesis, 2011, 873-880.

Cu-catalyzed sp3 C-H bond activation α to the nitrogen atom of o-alkynylated N,N-dimethylamines followed by an intramolecular nucleophilic attack with the alkyne, using an aqueous solution of tert-butyl hydroperoxide (TBHP) as the oxidant, enables a tandem catalytic synthesis of 3-aroylindoles. In this synthesis, both C-C and C-O bonds are installed at the expense of two sp3 C-H bond cleavages.
A. Gogoi, S. Guin, S. K. Rout, B. K. Patel, Org. Lett., 2013, 15, 1802-1805.

A copper-catalyzed domino reaction of 2-haloanilines and 1,3-dicarbonyl compounds, 1,3-diketones, β-keto esters and β-keto amides under ligand-free conditions provides a simple, general and atom economical process for the synthesis of polysubstituted indoles at moderate temperature.
M. A. Ali, T. Punniyamurthy, Synlett, 2011, 623-626.

Lewis acids catalyze the cyclization of methyl phenyldiazoacetates with an ortho-imino group, prepared from o-aminophenylacetic acid, to give 2,3-substituted indoles in quantitative yields.
L. Zhou, M. P. Doyle, J. Org. Chem., 2009, 74, 9222-9224.

A general and concise synthesis of functionalized indoles via electrophilic activation of N-aryl amides and addition of ethyl diazoacetate to these highly activated amides offers a great potential for the synthesis of biologically active and naturally occurring indole derivatives.
S.-L. Cui, J. Wang, Y.-G. Wang, J. Am. Chem. Soc., 2008, 130, 13526-13527.

Rhodium(II) perfluorobutyrate-mediated decomposition of vinyl azides allows rapid access to a variety of complex, functionalized N-heterocycles in two steps from commercially available starting materials.
B. J. Stokes, H. Dong, B. E. Leslie, A. L. Pumphrey, T. G. Driver, J. Am. Chem. Soc., 2007, 129, 7500-7501.

Various N-arylated and N-alkylated indoles and pyrrole-fused aromatic compounds were synthesized by a phenyliodine bis(trifluoroacetate) (PIFA)-mediated intramolecular cyclization.
Y. Du, R. Liu, G. Linn, K. Zhao, Org. Lett., 2006, 8, 5919-5922.

2-Cyanoindoles are found in many natural products and have high bioactivity. In an efficient Pd(0)-catalyzed synthesis of 2-cyanoindoles from 2-gem-dihalovinylanilines, Zn(TFA)2 is used to prolong the catalytic activity. Additionally, the amount of cyanide in the reaction phase is minimized due to the better solubility of Zn(CN)2 in a two-solvent mixture.
N. Zeidan, S. Bognar, S. Lee, M. Lautens, Org. Lett., 2017, 19, 5058-5061.

Various substituted enamine derivatives can be conveniently converted to the corresponding 2H-azirines mediated by phenyliodine (III) diacetate (PIDA). The formed 2-aryl-2H-azirines allow the synthesis of indole-3-carbonitriles or isoxazoles via thermal rearrangements.
X. Li, Y. Du, Z. Liang, X. Li, Y. Pan, K. Zhao, Org. Lett., 2009, 11, 2643-2646.

CuI/l-proline-catalyzed cross-coupling of 2-halotrifluoroacetanilides with β-keto esters and amides followed by acidic hydrolysis delivered 2,3-disubstituted indoles. 2-halotrifluoroacetanilides bearing a strong electron-withdrawing group in the 4-position can undergo in situ basic hydrolysis to provide the corresponding indoles.
Y. Chen, X. Xie, D. Ma, J. Org. Chem., 2007, 72, 9329-9334.

The use of a rhodium catalyst enables a catalytic synthesis of 2-substituted indole-3-carboxamides in very good yields from 2-ethynylanilines and isocyanates via a tandem-type, cyclization-addition sequence under mild reaction conditions. The broad substrate scope and good functional group compatibility make the method highly efficient and widely applicable.
A. Mizukami, Y. Ise, T. Kimachi, K. Inamoto, Org. Lett., 2016, 18, 748-751.

A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives occurs via an efficient Pd-catalyzed tandem Buchwald-Hartwig/Heck reaction using a gem-dibromovinyl unit as a readily available starting material.
A. Fayol, Y.-Q. Fang, M. Lautens, Org. Lett., 2006, 8, 4203-4206.

A Ni-catalyzed trans-carboamination enables the synthesis of multifunctionalized indoles from 2-alkynylanilinoacrylates. Notably, the synthesized indoles could be successfully transformed to functionalized carbazoles.
S. D. Tambe, N. Iqbal, E. J. Cho, Org. Lett., 2020, 22, 8550-8554.

The use of a Pd(OAc)2/P(o-tol)3/DIPEA system enables a practical cascade Tsuji-Trost reaction/Heck coupling of N-Ts o-bromoanilines with 4-acetoxy-2-butenonic acid derivatives to provide various substituted indole/azaindole-3-acetic acid derivatives.
D. Chen. Y. Chen, Z. Ma, L. Zou, J. Li, Y. Liu, J. Org. Chem., 2018, 83, 6805-6814.

A Brönsted acid-catalyzed one-pot synthesis of indoles from o-aminobenzyl alcohols and furans via in situ formation of aminobenzylfuran followed by its recyclization into the indole core proved to be efficient for a wide range of substrates. The resulting indoles can easily be transformed into other scaffolds, including 2,3- and 1,2-fused indoles, and indoles possessing an α,β-unsaturated ketone moiety at the C-2 position.
A. Kutznetsov, A. Makarov, A. E. Rubtsov, A. V. Butin, V. Gevorgyan, J. Org. Chem., 2013, 78, 12144-12153.

A trifluoroacetic acid-promoted amino-Claisen rearrangement provides highly functionalized indoles. This metal-free protocol could be performed at room temperature with wide functional group tolerance. The products could be easily transformed into different value-added indole derivatives using convenient methods.
Y. Zhang, Y. He, T. Liu, W. Guo, Org. Lett., 2023, 25, 2680-2684.

Gold(I) catalysis enables an efficient synthesis of N-protected pyrroles and 5,6-dihydropyridin-3(4H)-ones from N-protected and unprotected 5-aminopent-2-yn-1-ol, respectively. Atom-economic syntheses of hydroxyalkyl indoles and benzofurans are also described. The methods offer short reaction time, low catalyst loading, high yield, and simple open-flask reaction conditions.
N. Bera, B. S. Lenka, S. Bishi, S. Samanta, B. Sarkar, J. Org. Chem., 2022, 87, 9729-9754.

2-Ethynylanilines were converted to various substituted 2-(aminomethyl)indoles in good to excellent yields in the presence of a secondary amine and an aldehyde by a copper-catalyzed domino three-component coupling-cyclization. Utilizing this domino reaction and C-H functionalization at the indole C-3 position, polycyclic indoles were readily synthesized.
Y. Ohta, H. Chiba, S. Oishi, N. Fujii, H. Ohno, J. Org. Chem., 2009, 74, 7052-7058.

Upon photoexcitation, homolytic N-O bond cleavage of N-indolyl carbonate in the presence of an Ir complex produced N- and O-centered radicals. The high spin density at the C3 position of indole led to radical recombination with the O-centered radical, affording valuable 3-oxyindole derivatives without decarboxylation.
M. Bera, H. S. Hwang, T.-W. Um, S. M. Oh, S. Shin, E. J. Cho, Org. Lett., 2022, 24, 1774-1779.

Visible light mediates an operationally simple and regioselective synthesis of 2-sulfonamidoindoles and other 2-sulfonamido heteroarenes by an oxidative cross-dehydrogenative coupling of indoles (heteroarenes) with di-p-toluenesulfonamide or N-aryl-p-toluenesulfonamides in the presence of eosin-Y. The reaction enables the synthesis of a wide range of amidated heterocyclic compounds.
A. Paul, A. Sengupta, S. Yadav, J. Org. Chem., 2023, 88, 9599-9614.

In a room temperature redox neutral direct C-H amidation of heteroarenes, easily accessible hydroxylamine derivatives have been employed as tunable nitrogen sources. These highly regioselective reactions were enabled by a visible-light-promoted single-electron transfer pathway without a directing group. A variety of heteroarenes, such as indoles, pyrroles, and furans, could go through this amidation with high yields (up to 98%).
Q. Qin, S. Yu, Org. Lett., 2014, 16, 3504-3507.

CuCl catalyzes a highly efficient electrophilic amination reaction of readily available heteroarenes with O-benzoyl hydroxylamines via a one-pot C-H alumination to afford various heteroaryl amines in very good yields. The reaction can be performed in a single vessel on gram scales.
H. Yoon, Y. Lee, J. Org. Chem., 2015, 80, 10244-10251.

2-Amidoindoles and tetrahydroindolo[1,2-a]quinazolines can be formed directly from gem-dibromovinylanilides and sulfonamides in a one-pot fashion through a Cu(I)-catalyzed in situ generation of ynamides followed by a base-promoted intramolecular hydroamidation.
S. E. Kiruthika, P. T. Perumal, Org. Lett., 2014, 16, 484-487.

A gold-catalyzed C-H annulation of sulfilimines with N-phenylynamides affords 2-aminoindoles bearing a variety of substitution patterns in high selectivities. This reaction offers a facile approach to biologically important 2-aminoindoles by using inexpensive and readily available starting materials.
X. Tian, L. Song, M. Rudolph, F. Rominger, A. S. K. Hashmi, Org. Lett., 2019, 21, 4327-4330.

An environmentally friendly electrochemical approach enables an iodoamination of various indole derivatives with a series of unactivated amines, amino acid derivatives, and benzotriazoles. This strategy was further applied in late-stage functionalization, gram-scale synthesis and radiolabeling.
N. Lei, Y. Shen, Y. Li, P. Tao, L. Yang, Z. Su, K. Zheng, Org. Lett., 2020, 22, 9184-9189.

A rhodium(III)-catalyzed cascade cyclization/electrophilic amidation using N-pivaloyloxylamides as the electrophilic nitrogen source provides 3-amidoindoles and 3-amidofurans under mild conditions with good functional group tolerance. The 3-amidoindoles can be converted to several heterocycle-fused indoles.
Z. Hu, X. Tong, G. Liu, Org. Lett., 2016, 18, 2058-2061.

The synthesis of a series of indole and carbazole derivatives from 2-fluorophenyl imines is reported. 2-Fluoroaniline-d4 is prepared and used to investigate the mechanism of this indolization.
L. V. Kudzma, Synthesis, 2003, 1661-1666.

An effective reductive alkylation of electron-deficient o-chloroarylamines was developed. The derived N-alkylated o-chloroarylamines were elaborated to N-alkylazaindoles and N-alkylindoles via a novel one-pot process comprising copper-free Sonogashira alkynylation and a base-mediated indolization reaction.
M. McLaughlin, M. Palucki, I. W. Davies, Org. Lett., 2006, 8, 3307-3310.

The reaction of Boc-protected ortho-aminostyrenes with alkyllithiums, followed by the addition of specific electrophiles sets up a cascade reaction process between the reacted electrophile and the ortho-amino substituent, facilitating an in situ ring closure and dehydration to generate an indole ring system.
C. M. Coleman, D. F. O'Shea, J. Am. Chem. Soc., 2003, 125, 4054-4055.

C. M. Coleman, D. F. O'Shea, J. Am. Chem. Soc., 2003, 125, 4054-4055.

Y.-Q. Fang, M. Lautens, Org. Lett., 2005, 7, 3549-3552.

[RuCl2(CO)3]2/dppp is a highly effective catalyst system for the intramolecular oxidative amination of various aminoalkenes in presence of K2CO3 and allyl acetate in N-methylpiperidine to give the corresponding cyclic imines and indoles in excellent yields.
T. Kondo, T. Okada, T.-A. Mitsudo, J. Am. Chem. Soc., 2002, 124, 186-187.

Zn(OTf)2 catalyzed the cyclization of propargyl alcohols with anilines and phenols in toluene at 100°C without additive and gave various indole and benzofuran products with different structures. The cyclization of propargyl alcohols and amides gave oxazoles. Mechanisms for the different substituation patterns are discussed.
M. P. Kumar, R.-S. Liu, J. Org. Chem., 2006, 71, 4951-4955.

Various 3-iodoindoles have been prepared in excellent yields by a Sonogashira coupling of terminal acetylenes with N,N-dialkyl-o-iodoanilines, followed by an electrophilic cyclization of the resulting N,N-dialkyl-o-(1-alkynyl)anilines using I2 in CH2Cl2. The reactivity of the carbon-nitrogen bond cleavage during cyclization follows: Me > n-Bu, Me > Ph, and cyclohexyl > Me.
D. Yue, T. Yao, R. C. Larock, J. Org. Chem., 2006, 71, 62-69.

A ruthenium photocatalyst mediates a synthesis of 3-fluoroindoles from N-arylamines substituted with the CF2I group in the presence of a substoichiometric amount of triphenylphosphine upon irradiation with blue light. The starting N-arylamines are readily obtained by nucleophilic iododifluoromethylation of iminium ions.
L. I. Panferova, V. O. Smirnov, V. V. Levin, V. K. Kokorekin, M. I. Struchkova, A. D. Dilman, J. Org. Chem., 2017, 82, 745-753.

A ring-closing olefin metathesis (RCM)/elimination sequence or an RCM/tautomerization sequence of functionalized pyrrole precursors enabled the selective synthesis of substituted indoles. The RCM/elimination sequence was also applied to double ring closure to yield a substituted carbazole.
K. Yoshida, K. Hayashi, A. Yanagisawa, Org. Lett., 2011, 13, 4762-4765.

A reverse aromatic Cope rearrangement of 2-allyl-3-alkylideneindolines obtained by Horner-Wadsworth-Emmons olefination of 2-allylindolin-3-ones with diethyl cyanomethylphosphonate provided α-allyl-3-indole acetonitriles. When 2-allylindolin-3-ones were treated with phosphonium ylides in refluxing toluene, domino Wittig reaction and reverse aromatic Cope rearrangement took place to give α-allyl-3-indole acetate derivatives in good yields.
T. Kawasaki, Y. Nonaka, K. Watanabe, A. Ogawa, K. Higuchi, R. Terashima, K. Masuda, M. Sakamoto, J. Org. Chem., 2001, 66, 1200-1204.

In a highly efficient and general protocol for a regioselective C-H borylation of indoles with [Ni(IMes)2] as the catalyst, the reversible borylation of the nitrogen as a traceless directing group enables the C3-selective borylation of C-H bonds. A subsequent Suzuki-Miyaura cross-coupling of the C-borylated indoles in a one-pot process provides C3-functionalized heteroarenes.
Y.-M. Tian, X.-N. Guo, Z. Wu, A. Friedrich, S. A. Westcott, H. Braunschweig, U. Radius, T. B. Marder, J. Am. Chem. Soc., 2020, 142, 13136-13144.

A Pd-catalyzed heteroannulation approach provides highly functionalized 2-borylated indole scaffolds with complete control of regioselectivity. The utility of the process is demonstrated in the synthesis of borylated sulfa drugs and in the concise synthesis of the Aspidosperma alkaloid Goniomitine.
G. E. Bell, J. W. B. Fyfe, E. M. Israel, A. M. Z. Slawin, M. Campbell, A. J. B. Watson, Org. Lett., 2022, 24, 3024-3027.

An efficient, practical, and highly regioselective direct palladium-catalyzed C-3 arylation of electron-rich free (NH)-indoles with various aryl bromides under ligandless conditions in refluxing toluene in the presence of K2CO3 as the base can be run outside a glovebox without purification of solvent and reagents.
F. Bellina, F. Benelli, R. Rossi, J. Org. Chem., 2008, 73, 5529-5535.

A mild, Pd(OAc)2-catalyzed regioselective cross-coupling between indoles and potassium aryltrifluoroarylborates gives 2-aryl indoles in moderate yields in the presence of Cu(OAc)2 in acetic acid at room temperature.
J. Zhao, Y. Zhang, K. Cheng, J. Org. Chem., 2008, 73, 7428-7431.

A range of biaryl compounds can be efficiently prepared in high yields by a palladium-catalyzed cross-coupling reaction between ortho-substituted triarylindium reagents and aryl halides. The triarylindium reagents are prepared by directed ortho-lithiation and transmetallation to indium from the corresponding benzene derivatives.
M. A. Pena, J. P. Sestelo, L. A. Sarandeses, J. Org. Chem., 2007, 72, 1271-1275.

An electron-withdrawing group on the nitrogen of indoles enables a mild C2 chlorination and bromination with stoichiometric halide and oxone, while C3 halogenation could be selectively achieved by using stoichiometric halide without dependence on the electronic property of the protecting group on the indole nitrogen.
T. Zheng, J. Xu, S. Cheng, J. Ye, S. Ma, R. Tong, J. Org. Chem., 2023, 88, 11497-11503.

An electron-withdrawing group on the nitrogen of indoles enables a mild C2 chlorination and bromination with stoichiometric halide and oxone, while C3 halogenation could be selectively achieved by using stoichiometric halide without dependence on the electronic property of the protecting group on the indole nitrogen.
T. Zheng, J. Xu, S. Cheng, J. Ye, S. Ma, R. Tong, J. Org. Chem., 2023, 88, 11497-11503.

Ag-catalyzed rearrangements of N-indolyl carbonates and esters provide 3-oxyindole derivatives with broad functional-group compatibility. In addition, this concerted [3,3]-rearrangement approach was expanded to the synthesis of phosphonate and sulfonamide derivatives without the use of an Ag catalyst.
K. Ali, M. Bera, E. J. Cho, Synlett, 2023, 34, 1019-1022.

A monoalkoxy phenyl group as a dummy ligand on indolyl(aryl)iodonium imides enables a copper-catalyzed indole-selective C-N coupling reaction to provide 3-bissulfonimido-indole derivatives in high yields. A one-pot synthesis of 3-bissulfonimido-indole derivatives directly from indoles, bissulfonimides, and (diacetoxyiodo)-2-butoxybenzene is also reported.
K. Watanabe, K. Moriyama, J. Org. Chem., 2018, 83, 14827-14833.

Sulfonamidyl (hetero)arenes can be synthesized by a C(sp2)-H amidation with bench-stable amidyl-iminophenylacetic acids in the presence of a hypervalent iodine reagent. The hypervalent iodine reagent covalently activates the iminophenylacetic acid for the facile sulfonamidyl radical generation under mild photocatalytic oxidative conditions.
Y. Pan, Z. Liu, P. Zou, Y. Chen, Y. Chen, Org. Lett., 2022, 24, 6681-6685.

The one-pot reaction of N-(2-formylaryl)sulfonamides, secondary amines, and calcium carbide as convenient alkyne source enables a switchable synthesis of 2-methylene-3-aminoindolines and 2-methyl-3-aminoindoles in good yields.
Z. Wang, Z. Zhang, Z. Li, Org. Lett., 2022, 24, 8067-8071.

A cross-dehydrogenative C(sp2)-H amination of indoles is mediated by 2-tert-butylanthraquinone as a photocatalyst, harmless visible light, and aerobic oxygen as the sole oxidant without a transition-metal catalyst and or external oxidant.
T. Yamaguchi, E. Yamaguchi, A. Itoh, Org. Lett., 2017, 19, 1282-1285.

Rh(III)-catalyzed acylmethylation and trifluoroacetic acid (TFA)-mediated nitroso transfer/cyclization cascade reaction provides 3-nitrosoindoles starting from easily available N-nitrosoanilines and sulfoxonium ylides. This process is scalable and avoids external oxidation. Moreover, further chemical transformations of the 3-nitrosoindoles enhance their synthetic value.
Y. Wu, C. Pi, X. Cui, Y. Wu, Org. Lett., 2020, 22, 331-334.

The use of the well-established fluoroform-derived CuCF3 reagent enables the synthesis of 2-(trifluoromethyl)indoles from easily accessible 2-alkynylanilines via a domino trifluoromethylation/cyclization strategy. 3-formyl-2-(trifluoromethyl)indoles can also be synthesized, which are useful intermediates for the preparation of trifluoromethylated drug analogues.
Y. Ye, K. P. S. Cheung, L. He, G. C. Tsui, Org. Lett., 2018, 20, 1676-1679.

The use of the well-established fluoroform-derived CuCF3 reagent enables the synthesis of 2-(trifluoromethyl)indoles from easily accessible 2-alkynylanilines via a domino trifluoromethylation/cyclization strategy. 3-formyl-2-(trifluoromethyl)indoles can also be synthesized, which are useful intermediates for the preparation of trifluoromethylated drug analogues.
Y. Ye, K. P. S. Cheung, L. He, G. C. Tsui, Org. Lett., 2018, 20, 1676-1679.

N-hydroxyindole derivatives offer an unique structural motif and various biological activities. A Rh(III)-catalyzed reaction of arylnitrones with α-diazoketoesters or α-diazodiketones provides N-hydroxyindole derivatives. The N-hydroxyindole scaffold is built by blocking the cleavage of the N-O bond selectively, while eliminating the acyl group of α-diazoketoesters or α-diazodiketones preferentially.
Y. Li, J. Li, X. Wu, Y. Zhou, H. Liu, J. Org. Chem., 2017, 82, 8984-8994.

Rh(III)-catalyzed coupling of N-Boc hydrazones/N-Boc hydrazines with diazodiesters/diazoketoesters provides convenient access to synthetically and medicinally important N-amino isoquinolin-3-ones and N-amino indoles via a C-H activation-based strategy.
P. Shi, L. Wang, S. Guo, K. Chen, J. Wang, J. Zhu, Org. Lett., 2017, 19, 4359-4362.


N-Indolyltriethylborate is a useful reagent for dearomatizing C3-alkylation of 3-substituted indoles with both activated and nonactivated alkyl halides to give C3-quaternary indolenines, pyrroloindolines, furoindoline, and hexahydropyridoindoline under mild reaction conditions.
A. Lin, J. Yang, M. Hashim, Org. Lett., 2013, 15, 1950-1953.

Iodine-mediated intramolecular cyclization of enamines leads to a various 3H-indole derivatives bearing multifunctional groups in good to high yields under transition metal-free reaction conditions.
Z. He, H. Li, Z. Li, J. Org. Chem., 2010, 75, 4296-4299.

Novel Synthetic Approaches Toward Substituted Indole Scaffolds