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

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.

Name thesis:degree_name

MS

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Chemistry

Year dc:date.available

2000

Author dc:creator

• Turner, Michael Robert

Contributors dc:contributor

• Bjorn C. Soderberg.

• Organic chemistry

Identifier

https://researchrepository.wvu.edu/etd/1148

OAI identifier oai:identifier

oai:researchrepository.wvu.edu:etd-2151