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

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. No stopping! An efficient one‐pot multistep process enabled the synthesis of novel cyclopropane‐fused cyclic amidines with a quaternary center in good yields (see scheme). This method provides ready access to the 3‐azabicyclo[n.1.0]alkane framework. The synthetic utility of the CuBr2‐mediated oxidative cyclization was demonstrated by a short (four‐step) synthesis of the antidepressant drug candidate GSK1360707.