Expanding Stereoelectronic Limits of endo-tet Cyclizations: Synthesis of Benz[b]azepines from Donor-Acceptor Cyclopropanes

The importance of intramolecular constraints in cyclic transition-state geometries is especially pronounced in n-endo-tet cyclizations, where the usual backside approach of a nucleophile to the breaking bond is impossible for the rings containing less than eight atoms. Herein, we expand the limits of endo-tet cyclizations and show that donor-acceptor cyclopropanes can provide a seven-membered ring via a genuine 6-endo-tet process. Substrates containing a N-alkyl-N-arylcarbamoyl moiety as an acceptor group undergo Lewis acid-induced cyclization to form tetrahydrobenz[b]azepin-2-ones in high yields. The reaction proceeds with the inversion of the configuration at the electrophilic carbon. In this process, a formally six-membered transition state yields a seven-membered ring as the pre-existing cycle is merged into the forming ring. The stereochemistry of the products can be controlled by the reaction time and by the nature of Lewis acid, opening access to both diastereomers by tuning of the reaction conditions.

Automated summary

This study expands the limits of endo-tet cyclizations by showing that donor-acceptor cyclopropanes can form a seven-membered ring via a genuine 6-endo-tet process, yielding tetrahydrobenz[b]azepin-2-ones. Control of the stereochemistry of the products through reaction conditions allows access to both diastereomers.