A New, Simple and Efficient Method for the Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives: Formal Total Synthesis of Epibatidine

The base-mediated heterocyclization of alkyl N-(c-3,t-4-dibromocyclohex-1-yl)carbamates (5, 7, 10), or N-(c-3,t-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (12) is a convenient method for the synthesis of the 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of t-butyl N-(c-3,t-4-dibromocyclohex-1- yl)carbamate (5) with sodium hydride in DMF at room temperature provided (1RS,2SR,4SR)-2-bromo-7-[(tbutoxy) carbonyl]-7-azabicyclo[2.2.1]heptane (2) in 52% yield. The t-BuOK promoted hydrogen bromide elimination of compound 2 affording 7-[(t-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (14) in 78% yield constitutes a new formal total synthesis of epibatidine (1).