Acta Chimica Sinica ›› 2019, Vol. 77 ›› Issue (9): 856-860.DOI: 10.6023/A19070252 Previous Articles     Next Articles

Special Issue: 有机自由基化学



成忠明, 陈品红, 刘国生*()   

  1. 金属有机化学国家重点实验室和沪港化学合成联合实验室 分子合成卓越中心 中国科学院上海有机化学研究所 中国科学院大学 上海 200032
  • 投稿日期:2019-07-04 发布日期:2019-08-15
  • 通讯作者: 刘国生
  • 基金资助:
    项目受国家重点基础研究发展计划(973计划)(No.973-2015CB856600);国家自然科学基金(Nos.21532009);国家自然科学基金(21790330);国家自然科学基金(21821002);上海市科委(Nos.17XD1404500);上海市科委(17QA1405200);上海市科委(17JC1401200);中国科学院前沿重点项目资助(No. QYZDJSSWSLH055)

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

Cheng, Zhongming, Chen, Pinhong, Liu, Guosheng*()   

  1. State Key Laboratory of Organometallic Chemistry, and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032
  • Received:2019-07-04 Published:2019-08-15
  • Contact: Liu, Guosheng
  • Supported by:
    Project supported by the National Basic Research Program of China(No.973-2015CB856600);the National Natural Science Foundation of China(Nos.21532009);the National Natural Science Foundation of China(21790330);the National Natural Science Foundation of China(21821002);the Science and Technology Commission of Shanghai Municipality(Nos.17XD1404500);the Science and Technology Commission of Shanghai Municipality(17QA1405200);the Science and Technology Commission of Shanghai Municipality(17JC1401200);the Key Research Program of Frontier Science of the Chinese Academy of Sciences(No. QYZDJSSWSLH055)

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 δ-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)4PF6 (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 N2 atmosphere, and stirred for 30 min. Then, TMSCN (50 μL, 0.4 mmol, 2 equiv.) was added slowly under N2 atmosphere. The tube was sealed with a Teflon-lined cap, and the mixture was stirred under the irradiation of blue LED for 1~7 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 (3×10 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.

Key words: enantioselective cyanation, C—H bonds, copper catalysis, photoredox catalysis, 1,5-hydrogen atom transfer