Enantioselective Cyanation of Remote C-H Bonds via Cooperative Photoredox and Copper Catalysis

Optically pure alkylnitriles are important structural motifs found in agrochemicals, pharmaceuticals, and natural products, which can be further transferred to acids, amines and amides. Direct asymmetric cyanation of sp(3) C-H bonds represents the most efficient synthetic pathway to these optically pure alkylnitriles. However, selective functionalization of sp(3) C-H bonds remains a crucial issue due to the inertness of sp(3) C-H bonds as well as the difficulties in the control of stereo- and regioselectivity. Inspired by enzymatic oxygenases and halogenases, such as cytochrome P450 and nonheme iron enzymes, the radical-based C-H functionalization has received much attention, which was initiated with a hydrogen atom transfer (HAT) process. Recently, numerous reports have been disclosed for the highly efficient functionalization of C-H bonds with an intramolecular HAT process as a key step to govern the reactivity and site selectivity. Our group has developed a copper-catalyzed radical relay process for the enantioselective cyanation and arylation of benzylic C-H bonds using TMSCN and ArB(OH)(2) as nucleophiles respectively. Mechanistic studies indicated that a benzylic radical generated via a radical replay process can be trapped by a reactive chiral copper(II) cyanide enantioselectively, delivering optically pure benzyl nitriles efficiently. Herein, we communicate the catalytic asymmetric cyanation of remote C-H bonds by merging photoredox catalysis with copper catalysis. This reaction proceeds under mild reaction conditions and exhibits good functional group compatibility as well as wide substrates scope. Additionally, the nitrile group was further reduced to amide under hydrogen atmosphere. This reaction provides an efficient pathway to synthesize chiral delta-cyano alcohols and 1,6-amino alcohols. The general procedure is as following: in a dried sealed tube, substrate 1 (0.2 mmol, 1.0 equiv.), Cu(CH3CN)(4)PF6 (0.01 mmol, 5 mol%), L (0.015 mmol, 7.5 mol%) and Ir(ppy)(3) (0.002 mmol, 1 mol%) were dissolved in dichloromethane (4.0 mL) under N-2 atmosphere, and stirred for 30 min. Then, TMSCN (50 mu L, 0.4 mmol, 2 equiv.) was added slowly under N-2 atmosphere. The tube was sealed with a Teflon-lined cap, and the mixture was stirred under the irradiation of blue LED for 1 similar to 7 d. The reaction mixture was diluted with dichloromethane, filtered through a short pad of celite. A solution of TBAF (3 equiv.) and HOAc (3 equiv.) was added to the filtration. The mixture was stirred for 5 min and then washed with water (3x10 mL) and dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate) to afford target product.