Exceptional reactivity of the bridgehead amine on bicyclo[1.1.1]pentane

Bicyclo[1.1.1]pentane (BCP) has received substantial interest in the field of synthetic chemistry recently for its potential use as a benzene isostere in medicinal chemistry. Whereas bicyclo[2.2.2]octane (BCO) has also been used as a bioisostere of benzene, the condensation of BCP-amine with nadic anhydride is significantly easier than that of BCO-amine. Analyses of the geometries and the frontier molecular orbitals of these amines suggest that the low steric hindrance and high intrinsic nucleophilicity of BCP-amine together contribute to its exceptional reactivity.