Categories: Synthesis of N-Heterocycles > benzo-fused N-Heterocycles >
Synthesis of indoles
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Recent Literature
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 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.
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.
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.
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.
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.
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,
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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.
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.,
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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.
Related
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.
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Novel Synthetic Approaches Toward Substituted Indole Scaffolds |