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Synlett 2006(1): 0091-0095  
DOI: 10.1055/s-2005-922760
LETTER
© Georg Thieme Verlag Stuttgart · New York

Microwave-Assisted, Solvent-Free Bischler Indole Synthesis

Vellaisamy Sridharan, Subbu Perumal, Carmen Avendaño, J. Carlos Menéndez*
Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
Fax: +34(91)3941822; e-Mail: josecm@farm.ucm.es;
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Publication History

Received 6 September 2005
Publication Date:
16 December 2005 (online)

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Abstract

The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate gives N-phenacylanilines. Microwave irradiation of mixtures of these compounds with anilinium bromides at 540 W for 45-60 s provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in 50-56% overall yields. A one-pot variation of the method, involving irradiation of 2:1 mixtures of anilines and phenacyl bromides, was also developed, allowing a simplified experimental procedure and leading to improved yields (52-75%).

Key words

indole synthesis - aniline monoalkylation - solvent-free synthesis - microwave-assisted synthesis

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    General Procedure for the Two-Step Method.N-Alkylation: 2 mmol of the suitable phenacyl bromide (prepared according ref. 26b) was slowly added to a mixture of 2 mmol of the suitable arylamine and 300 mg of NaHCO3 (the order of addition of the reagents is not normally of consequence, but it is important to use the method described here in the case of the anisidine derivatives, which otherwise lead to dialkylation products). The reaction mixture was stirred at r.t. with occasional cooling in tap water, soon becoming semisolid and finally solid. This solid was kept at r.t. for 3 h, when completion of the reaction was verified by TLC. Then, H2O was added to the mixture and the separated solid was filtered, washed with H2O, and dried, giving materials with sufficient purity for the next step. If desired, the N-phenacylanilines can be recrystallized from EtOH. Cyclization: a mixture of 1 mmol of the suitable N-phen-acylaniline and 1.5 mmol of the corresponding anilinium hydrobromide with 3-4 drops of DMF was irradiated in a domestic microwave oven at 540 W for the time period specified in Table [1] . After completion of the reaction the mixture was loaded onto a silica gel column and pure 2-arylindoles were obtained by chromatography, eluting with a gradient starting from 9:1 PE-EtOAc. Alternatively, the mixture could also be extracted with EtOAc, washed with H2O, dried and evaporated before chromatography. All indole derivatives were previously known, and showed the expected 1H NMR and 13C NMR spectra, and melting points very similar to those previously described (Table [1] ).

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1

Permanent address: Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India

36

General Procedure for the One-Pot Synthesis of 2-Arylindoles from Phenacyl Bromides and Anilines under Microwave Irradiation. Phenacyl bromide (1 mmol) was stirred with aniline (2 mmol) at r.t. without any base to neutralize the liberated HBr. The mixture was kept at r.t. with occasional stirring for 3 h. To the solid mixture, containing N-phenacyl aniline and anilinium hydrobromide, was added 3-4 drops of DMF and the mixture was irradiated in a microwave oven at 600 W for 1 min. After completion of the reaction, the mixture was treated as described for the two-step method to give the pure 2-arylindoles.