Synthesis of 2-Substituted 8-Azabicyclo[3.2.1]octan-3-ones in Aqueous NaOH Solution of Low Concentration

Abstract

The tropane class of alkaloids has continued to elicit the unabated interests among organic chemists because of their pharmacological significance, and a great deal of efforts has been focused on the stereochemical synthetic methodologies. Cocaine, a notorious member of this alkaloidal family, is found in erythroxylon coca, indigenous to the higher elevations of peru. The natives of this region, descendants of the Incas, still chew the coca leaf for its stimulatory properties. In particular, a series of tropans showed anticonvulsant activity against pentylenetetrazolinduced convulsions in mice and antiarrhythmic activity in rabbit previously treated with ouabain. As a part of ongoing research for the pharmacologically interesting tropane compounds, herein we report a new synthetic conditions of corresponding 2-substituted 8-azabicyclo[3.2.1]octan-3-one, 3, by aldol condensation from 8substituted 8-azabicyclo[3.2.1]octan-3-one, 1. We already reported a synthesis of 2,4-disubstituted 8-azabicyclo[3.2.1]octan-3-one, 2, derived from the reaction of N-substituted 8azabicyclo[3.2.1]octan-3-one, 1, with aldehydes (R1CHO) in the presence of ethanol and aqueous 5 N NaOH. We also reported the synthesis of di-(N-tropinonyl)alkanes from the reaction of phenylenediamines (or diaminoalkanes) with 2,5-dimethoxytetrahydrofuran and acetonedicarboxylic acid. Then our attempt to prepare 2-substituted 8-azabicyclo[3.2.1]octan-3-one, 3, from 8-substituted 8-azabicyclo[3.2.1]octan-3-one, 1, was unsuccessful, under various reaction conditions: sodium hydride, sodium methoxide, or butyl lithium. But M. Majewski and R. Lazny reported that their synthesized compound, 2-benzylidene-8-methyl-8-azabicyclo[3.2.1]octan-3-one was done through three-step treatment of chiral lithium amide, Ac2O, and SiO2 (Scheme 1). In brief, as their synthetic method had three-step reactions and three times work-ups, it was so complicated. Recently, Peter A. Crooks et al. reported two-step synthesis by treatment of lithium diisopropylamide or lithium bis(trimethylsilyl)amide. In order to synthesize 2-substituted 8-azabicyclo[3.2.1]octan-3-one, 3, simply and efficiently, we conducted research on the effect of aqueous NaOH concentration variations (1 N, 0.5 N, 0.1 N, 0.02 N, or 0.01 N). Yield comparison of compound 3e according to concentration variation of aqueous NaOH solution is expressed in Table 1. In case of higher concentrations over aqueous 0.01 N NaOH solution, the ratio of 2,4-disubstituted 8-azabicyclo[3.2.1]octan-3-one, 2, was produced somewhat higher than that of 2-substituted 8-azabicyclo[3.2.1]octan-3-one, 3. Yield of 8-benzylidene-8-phenyl-8-azabicyclo[3.2.1]octan-