Synthetic routes to secondary azacyclononanes

Abstract

Three synthetic methods for preparing secondary azacyclononanes from suitably 9-substituted indolizidines were investigated. In the first method, 9-vinylindolizidine was converted directly to a mixture of secondary azacyclononanes and 9-ethylindolizidine by reaction with lithium aluminum hydride and nickel chloride in tetrahydrofuran (Tweedie reaction). This reaction was of little synthetic use because of the difficulty in separating the products. In the second method, 9-vinylindolizidine and 9-benzylindolizidine were converted to azacyclononanecarbamates by reaction with chloroformate esters. Removal of the carbamate group in one case resulted in a transannular ring-closure. The third method proved to be the most useful synthetically. In this method the benzyl quaternary ammonium salt of 9-vinylindolizidine was ring-opened to the N-benzyl- 9-substituted azacyclononane by nucleophilic attack with lithium aluminum hydride or phenylmagnesium bromide. The benzyl group was removed via the carbamate. The most useful of the chloroformate esters was 2,2,2-trichloroethyl chloroformate. This compound gave almost quantitative yields of the carbamate in the dealkylation step and was readily removed in high yield by mild conditions.