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

Abstract

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 sp² 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 sp² 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 sp² C–H cyanation of trisubstituted allenes. This reaction was catalyzed by CuOAc and Box ligand L1 in a mixture solvent of tert-amyl alcohol (^tAmOH), 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.

Keywords

Asymmetric copper catalysis / Radical cyanation / sp² C−H functionalization / Hydrogen atom abstract / Nitrogen centered radicals / Chiral tetra-substituted allenic nitriles / Site-selectivity / Box ligand

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