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Synthesis of indoles

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Fischer Indole Synthesis


Recent Literature


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.


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


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.


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.


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 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.


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 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.

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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.

Novel Synthetic Approaches Toward Substituted Indole Scaffolds