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Synthesis of indoles
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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 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.
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.
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 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.
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.
The Benzyne Fischer-Indole Reaction
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.
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 K3PO4·H2O.
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. Avendaño, J. C. Menéndez, Synlett,
2006, 91-95.
V. Sridharan, S. Perumal, C. Avendaño, 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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
Related
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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