Title

Novel palladium-catalyzed synthesis of 3-substituted indoles and its application toward the total synthesis of indolactam V

Semester

Summer

Date of Graduation

2000

Document Type

Thesis

Degree Type

MS

College

Eberly College of Arts and Sciences

Department

Chemistry

Committee Chair

Bjorn C. Soderberg.

Abstract

A novel synthesis of indoles having electron withdrawing substituents in the 3-position has been developed. Various 2-nitrostyrenes were prepared via Stille coupling of 2-tributyl stannyl-2-propenoic acid ethyl ester with substituted 2-bromo-l-nitrobenzenes. Alternatively, sequential vicarious nucleophilic substitution of substituted nitrobenzenes and Knoevenagel condensation with formaldehyde was used to prepare 2-nitrostyrenes. Palladium catalyzed N-heteroannulation of 2-nitrostyrenes yielded indoles in 61--99%. For example, reaction of a 0.5 M solution of 1,1-dimethylethyl 2-(1-nitro-2-napthyl)propenoate (65) in N,N-dimethylformamide with carbon monoxide (4 atm), in the presence of a catalytic amount of bis(dibenzylideneacetone)palladium(0) (6 mol %), 1,3-bis(diphenylphosphino)propane (6 mol %), and 1,10-phenanthroline monohydrate (12 mol %), gave 1H-benzo[g]indole-3-carboxylic acid tert-butyl ester (83) in 99% isolated yield. Substituents on the benzene ring such as methoxy, ester, and halide groups were compatible with the reaction conditions all giving indoles. Additionally, a substituent in the 2-position of the indole can be introduced using aldehydes other than formaldehyde in the condensation step.;This methodology for the preparation of 3-substituted indoles is a key step in a proposed total synthesis of indolactam V. A retrosynthetic analysis of indolactam V affords 1-trifluoromethanesulfonyloxy-2-bromo-3-nitrobenzene, allyl glycine, and L-valine as the starting materials. Coupling of L-valine with 1-trifluoromethanesulfonyloxy-2-bromo-3-nitrobenzene in the presence of a palladium catalyst unexpectantly gave amination between the nitro and the triflate functionalty. This led to a study of the amination of various bromo-triflate and bromo-nitro-triflate substituted benzenes using cesium carbonate, palladium acetate, 2,2'bis(diphenylphosphino)-1,1 '-binapthyl, and morpholine. The purpose of this was to evaluate the site of amination, that is, bromo vs triflate, and examine if conditions can be developed to selectively substitute one.

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