Intramolecular carbolithiation reactions for the preparation of Azabicyclo

Abstract

Tin-lithium exchange and intramolecular carbolithiation (anionic cyclization) have been used to construct the three nitrogen-positional isomers of the azabicyclo[2.2.1]heptane ring system. The 7-azabicyclo[2.2.1]heptane ring system is accessed from either diastereomer of a 2,5-disubstituted pyrrolidine, via a chiral organolithium intermediate. The 2-azabicyclo[2.2.1]heptane ring system is formed stereoselectively in low yield by a tandem cyclization, together with the product from monocyclization. Better yields of the 2-aza ring system can be obtained using an alternative approach from a 2-tributylstannyl-4-allylpyrrolidine, despite the trans arrangement of the tin (and, hence, lithium) atom and the allyl unit. The 1-azabicyclo[2.2.1]heptane ring system is accessed in just three steps from 4-piperidone.