Synthesis of Functionalized Tetrahydropyridine Derivatives via SnCl4-Promoted [4+2] Cycloaddition of Donor-Acceptor Cyclobutanes and Nitriles
Abstract
The formation of carbon-heteroatom bonds is pivotal in obtaining structural frameworks present in a variety of important natural products and bioactive molecules. In that regard, Lewis-acid promoted cycloadditions of strained carbocycles have proven to be powerful tools for the construction of heterocyclic frameworks. The Pagenkopf group was the first to discover the cycloaddition of donor-acceptor (DA) cyclopropanes with nitriles. Since the strain energy of cyclobutane is comparable to that of cyclopropane, our group has sought to extend to the comparatively unexplored homologous cyclobutane scaffold. Disclosed here is the first [4+2] cycloaddition of nitriles with DA cyclobutanes via Lewis-acid activation. This work describes the synthesis of tetrahydropyridine derivatives in moderate to good yields. A variety of electronically diverse cyclobutanes engaged in [4+2] cycloaddition with both aliphatic and aromatic nitriles. Reduction of the cycloadduct affords substituted piperidine exclusively as the cis-2,6-diastereomer in excellent yield, and the cycloadduct also undergoes clean dealkoxycarbonylation.