Gold(I)-Catalyzed Ring-Opening Hydroamination of Methylenecyclopropanes with Aniline Derivatives

Abstract

Methylenecyclopropanes (MCPs) are highly strained and serve as useful building blocks in organic synthesis. When activated by a gold catalyst, subsequent nucleophilic attack can result in ring opening (ring-expansion) of the cyclopropane moiety. Gold(I)-catalyzed ring-opening of MCPs at the distal carbons can result in an exo or internal allylic amine, with exo double bonds providing an important handle for further functionalization in natural product synthesis. This work explores the scope of MCP ring opening reactions with aniline derivatives with the goal of optimizing for the exo allylic amine. Although nonpolar solvent resulted in a clean and fast reaction, the selectivity between isomers was minimal. With increasing polarity of coordinating solvents there was an increase in selectivity for the desired isomer, but with reaction rates slowing dramatically. Lewis basicity of the aniline nucleophile proved to be a crucial aspect in the progress of the reaction, with electron rich anilines failing to proceed. MCP scope showed that larger ring sizes of bicyclic MCPs favor the competing reaction, hydroamination of the C1 carbon. Overall, ring opening reactions of bicyclic MCPs with electron deficient aniline derivatives proved to offer high selectivity and moderate to high yields.