Studies on Antispasmodics. VI. Synthesis of N-Alkyl 6- and 7-Diarylmethyleneindolizidinium Bromides

As part of a search for new antispasmodics, we have synthesized N-alkyl 6- and 7-diarylmethyleneindolizidinium bromides (1-8), which might be expected to exhibit potent anticholinergic activities due to the rigid piperidine ring structure, by analogy with N-alkyl 2- and 3-diarylmethylenequinolizidinium bromides (I). Treatment of ethoxycarbonylindolizidines (13 and 22) with phenyllithium or 2-thienylmagnesium bromide, followed by dehydration, afforded diarylmethyleneindolizidines (25, 26, 29 and 30). Quaternization of the 6-substituted derivatives (25 and 26) with methyl bromide afforded two isomeric methobromides, the trans- (1a and 2a) and the cis-methobromides (1b and 2b), and the 7-substituted derivatives (29 and 30) also afforded the corresponding trans- (5a and 6a) and cis-methobromides (5b and 6b). The stereochemistries of these methobromides were confirmed by the chemical shifts of the N+-methyl signals in the 1H- and 13C-NMR spectra. The stereochemistries of 6- and 7-diarylhydroxymethylindolizidines (23, 24, 27 and 28) were also determined from their IR and 13C-NMR spectra.