Synthesis of bridged azabicyclic compounds using radical translocation reactions of 1-(o-bromobenzoyl)-2-(prop-2-enyl)pyrrolidines

Abstract

A new synthesis of the 7-azabicyclo[2.2.1]heptane and 8-azabicyclo[3.2.1]octane systems is described in which α-acylamino radicals generated from l-(o-bromobenzoyl)-2-(prop-2-enyl)pyrrolidines by a Bu₃SnH-mediated radical translocation reaction are cyclised. Treatment of methyl l-(o-bromobenzoyl)-2-(prop-2-enyl)pyrrolidine-2-carboxylate 3a with Bu₃SnH in the presence of a catalytic amount of azoisobutyronitrile in boiling toluene gave the 7-azabicyclo[2.2.1]heptane 4a(a 5-exo cyclisation product)[42% yield as a diastereoisomeric mixture (66 : 34)] and the 8-azabicyclo[3.2.1]octane 5a(a 6-endo product)(30%), together with the reduction product 6a(12%). The regiochemistry (5-exo/6-endo) of this cyclisation could be controlled by the introduction of a substituent on the prop-2-enyl group. The substituent(s) at the 2- and/or 4-position(s) of the pyrrolidine ring were found to play an important role in this cyclisation.