One‐Pot Synthesis of Cyclopropane‐Fused Cyclic Amidines: An Oxidative Carbanion Cyclization

Abstract

A novel and efficient one‐pot method has been developed for the synthesis of cyclopropane‐fused bicyclic amidines on the basis of a CuBr2‐mediated oxidative cyclization of carbanions. The usefulness of this unique multicomponent strategy has been demonstrated by the use of a wide variety of substrates to furnish novel cyclopropane‐containing amidines with a quaternary center in very good yields. This ketenimine‐based approach provides straightforward access to biologically active and pharmaceutically important 3‐azabicyclo[n.1.0]alkane frameworks under mild conditions. The synthetic power of this methodology is exemplified in the concise synthesis of the pharmaceutically important antidepressant drug candidate GSK1360707 and key intermediates for the synthesis of amitifadine, bicifadine, and narlaprevir.

Synthesis of 3‐Azabicyclo[3.1.0]hexane Derivates

“…In 2017, a novel and efficient copper‐mediated one‐pot method for the synthesis of 3‐azabicyclo[3.1.0]alkane frameworks 11 through new insight gained into the reactivity of ketenimine intermediates Int‐15 was documented by Baskaran and co‐workers (Table 2 and Scheme 5). [33] The screening of catalysts, solvents, and bases revealed that the combination of CuCN and DBU in THF was the ideal choice. When cupric bromide was used as an external oxidant, the yield was extremely increased, thus single‐electron transfer (SET) oxidant appears to be the key to the successful transformation.…”