Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-piperidine and -pyrrolidine with chloropyruvates for the efficient synthesis of substituted 4,5,6,7-tetrahydro-1H-indole derivatives

Abstract

Sequential substitution/ring cleavage/addition reaction of 1-(cyclohex-1-enyl)-piperidine and -pyrrolidine with chloropyruvates has been accomplished for the synthesis of various polysubstituted 4,5,6,7-tetrahydroindoles. This one-pot, general and highly regioselective method avoids harsh conditions and expensive catalysts. It proceeds with high atom-efficiency and shows a broad substrate scope and functional group tolerance, making it a highly practical approach for the preparation of various tetrahydroindole derivatives. A family of 17 tetrahydroindoles was synthesized in good yields, which is indicative of the general character of this reaction. 10 of the tetrahydroindole derivatives with various substituents were successfully transformed into the corresponding indoles. This methodology allows access to indoles bearing ω-halo- (mostly chloro-)butyl and pentyl substituents at the nitrogen atom (by variation of enamines) and at the C2, C3 positions (by variation of pyruvates, including bromoaryl and chloroalkyl derivatives). The reaction can be used in conjunction with enamine synthesis offering a practical three-component heteroannulation methodology to produce 4,5,6,7-tetrahydroindoles from cyclohexanone, pyrrolidine and arylchloropyruvates.