Copper‐Catalyzed Site‐ and Enantioselective C–H Cyanation of Trisubstituted Allenes

Comprehensive Summary Chiral allenes are privileged structural motifs found in numerous natural products and bioactive molecules, consequently, the synthesis of these scaffolds—especially polysubstituted chiral allenes—has garnered significant research interest. Among these methods, direct asymmetric functionalization of allenic sp 2 C−H bond has been recognized as a powerful strategy for the modification of allenes, enabling late‐stage functionalization (LSF) of allene‐containing bioactive compounds. In recent years, Cu(II)‐bound nitrogen‐centered radicals (NCRs) have been demonstrated to override innate radical preferences to achieve site‐selective C−H functionalizations, achieving the site‐selective C−H cyanation, arylation and alkynylation of allenes via a copper‐catalyzed radical relay process, where the HAA process exclusively occurs at sp 2 C−H bonds. Although the enantioselective version has been achieved for the reaction of 1,3‐disubstituted allenes, which afforded the chiral trisubstituted allenic nitriles with excellent enantioselectivities, the reactions of trisubstituted allenes exhibited significantly poor enantioselectivity. Herein, we report a copper‐catalyzed site‐ and enantioselective sp 2 C–H cyanation of trisubstituted allenes. This reaction was catalyzed by CuOAc and Box ligand L1 in a mixture solvent of tert ‐amyl alcohol ( t AmOH), acetone and (trifluoromethyl)benzene at –40 °C. This method efficiently afforded a broad array of tetrasubstituted axially chiral allenic nitriles in good to excellent yields with excellent enantioselectivities.