Enantioselective cyanation of benzylic C-H bonds via copper-catalyzed radical relay

Abstract

Direct methods for stereoselective functionalization of sp³-hybridized carbon-hydrogen [C(sp³)-H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C-H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp³)-CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C-H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.

Fig. 1. Strategies for hydrogen-atom-transfer-mediated C–H oxidation

(A) Radical rebound mechanism for enzymatic and biomimetic C–H hydroxylation and halogenation (X = halide). (B) Radical relay pathway for C–H oxidation involving formation of a free radical that is trapped by a reactive metal center. (C) Proposed mechanism for Cu-catalyzed enantioselective cyanation of benzylic C–H bonds via radical relay.

Figure 2. Reaction optimization and representative ligand screening data

General reaction conditions: 1a (0.2 mmol), TMSCN (0.6 mmol), NFSI (0.3 mmol), CuOAc (0.02 mmol), ligand (0.024 mmol) in 1.0 mL of solvent at r.t. for 10 h. Yield determined by ¹H NMR, CF₃CONMe₂ as internal standard. The ee (enantiomertic excess) value was determined by HPLC with a chiral stationary phase. * Reaction conducted in PhH; ^† Reaction conducted in PhCl.

Figure 3. Substrate scope and synthetic applications of Cu-catalyzed cyanation of benzylic C–H bonds

* All the reactions were conducted with alkylarenes as the limiting reagent in 0.2-1 mmol scale; isolated yields reported. ^† Chlorobenzene used as the solvent. ^‡ ee value of product after recrystallization. ^§ See ref. 34.

Figure 4. Experimental and computational studies providing insight into the mechanism of the copper-catalyzed cyanation reaction

These include (A) reaction selectivity studies, (B) kinetic isotope effects, (C) radical trapping experiments, and (D) DFT computational studies.