A direct retro-Reformatsky fragmentation: formal ring enlargement of cyclic ketones for novel and practical synthesis of heterocyclic enamines.

A novel and practical synthesis of heterocyclic enamines has been developed from the formal ring enlargement of cyclic ketones, which comprised the retro-Reformatsky fragmentation reaction as a key step. Under alkaline bromination conditions, the Reformatsky adducts derived from five- to seven-membered cyclic ketones underwent efficiently a direct retro-Reformatsky fragmentation, followed by spontaneous alpha,alpha-dibromination, to produce alpha,alpha,omega-tribromo-beta-ketoester compounds in a one-pot reaction. Highly regioselective reduction of alpha,alpha,omega-tribromo-beta-ketoesters with Cu-Zn alloy under mild conditions afforded omega-bromo-beta-ketoesters in good to excellent yields. Treatment of omega-bromo-beta-ketoesters with sodium azide followed by intramolecular aza-Wittig reaction or catalytic hydrogenation furnished heterocyclic secondary enamines, while a straightforward cyclocondensation of omega-bromo-beta-ketoesters with amines led to the formation of heterocyclic tertiary enamines.