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

Abstract

Direct methods for stereoselective functionalization of 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 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 90-99% 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.

Highly Enantioselective Oxidation of Nonactivated Aliphatic C–H Bonds with Hydrogen Peroxide Catalyzed by Manganese Complexes

“…The high reactivity of alkyl radicals seems a priori incompatible with their use as radical relays, in a similar way as done in recent benzylic C–H functionalization reactions. 17 More definitively, however, this latter mechanism is incompatible with the desymmetrization reactions described herein. In the current reactions enantioselectivity must be necessarily introduced in the C–H lysis step, which has been previously established to entail HAT from the aliphatic C–H bond to a high valent manganese-oxo species Mn V (O) (carboxylate) moiety, followed by a fast hydroxyl rebound toward the incipient carbon centered radical.…”

Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines

“…Here Ag 2 CO 3 acts as a chloride scavenger via the formation of insoluble AgCl in organic solution, thereby minimizing the strong acid HCl-associated unselective background reactions. The subsequent addition of R f radical to alkene gives the α-R f alkyl radical C , which could be trapped by Cu(II) phosphate B or B′ to form a Cu(II) species D , in which alkyl radical intermediate could be trapped by Cu(II) phosphate to generate a Cu(III) species E (refs 28, 29, 34, 63, 64, 65, 66, 67, 68; path a). During this process, the chiral phosphate could control the facial selectivity of such reaction via both hydrogen-bonding interactions with the N–H bond adjacent to the aryl group and ion-pairing interactions in a concerted transition state.…”

Rhodium‐Catalyzed Enantioselective Radical Addition of CX4 Reagents to Olefins

“…[19] More recently Liu and Stahl reported a related Cu-catalyzed benzylic cyanation. [20,21] Cu-catalyzed α-amination of amides [22] and difunctionalization of olefins [23] likely operate through similar inner-sphere mechanisms, although complete mechanistic details are not available.…”