Cu(II)-Mediated C-H Amidation and Amination of Arenes: Exceptional Compatibility with Heterocycles Ming Shang, † Shang-Zheng Sun, † Hui-Xiong Dai,* ,† and Jin-Quan Yu* ,†,‡ † State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States * S Supporting Information ABSTRACT: A Cu(OAc) 2 -mediated C-H amidation and amination of arenes and heteroarenes has been developed using a readily removable directing group. A wide range of sulfonamides, amides, and anilines function as amine donors in this reaction. Heterocycles present in both reactants are tolerated, making this a broadly applicable method for the synthesis of a family of inhibitors including 2-benzamidobenzoic acids and N- phenylaminobenzoates. D iverse carbon-carbon and carbon-heteroatom bond- forming reactions have been developed using directed C-H functionalizations catalyzed by various transition metals. 1 Notably, Pd catalysts have demonstrated extraordinary versatility by participating in various redox catalysis including Pd(0)/ Pd(II), 2a-c Pd(II)/Pd(0), 2d,e Pd(II)/Pd(IV), 2f and Pd(II)/ Pd(II) 2g manifolds. It is highly desirable to develop analogous reactions using inexpensive metals such as copper 3-6 and iron. 7 Significant progress has been made on both the development 5 and mechanistic studies 8 of Cu-catalyzed C-H functionaliza- tions. We previously reported a diverse range of Cu-catalyzed or -mediated C-H activation/carbon-heteroatom-forming reac- tions of 2-phenylpyridine. 4a It is likely that the diverse reactions we disclosed in that report proceed through different redox manifolds depending on the oxidants employed. 8 For example, Cu(III) species may be involved in C-H activation in the presence of highly oxidizing chacogenide-like oxidants, 4a,8 whereas a single-electron-transfer pathway may be operative in the presence of O 2 or a Ag + oxidant. 4a,8 In light of the broadly encountered heteroatom poisoning effect in Pd-catalyzed C-H aminations, we became particularly intrigued by a single example of Cu-mediated amidation of 2- phenylpyridine with TsNH 2 under aerobic conditions. 4a We wondered whether Cu-catalyzed or -mediated C-H amination could overcome these detrimental heteroatom effects. Here we report Cu-mediated amidation and amination of arenes and heteroarenes with a broad range of sulfonamides, amides, and Received: December 18, 2013 Published: February 17, 2014 Table 1. Reaction Optimization a entry DG [Cu] base temp, °C yield, % b 1 A Cu(OAc) 2 K 2 CO 3 rt 8 2 A Cu(OAc) 2 K 2 CO 3 50 26 3 A Cu(OAc) 2 K 2 CO 3 80 64 4 A Cu(OAc) 2 K 2 CO 3 100 60 5 A CuI K 2 CO 3 80 36 6 A CuCl 2 K 2 CO 3 80 34 7 A Cu(OTf) 2 K 2 CO 3 80 10 8 A Cu(acac) 2 K 2 CO 3 80 trace 9 A Cu(OAc) 2 ·H 2 O K 2 CO 3 80 63 10 A Cu(OAc) 2 Li 2 CO 3 80 68 11 A Cu(OAc) 2 Na 2 CO 3 80 70 12 B Cu(OAc) 2 Na 2 CO 3 80 76 13 C Cu(OAc) 2 Na 2 CO 3 80 66 14 D Cu(OAc) 2 Na 2 CO 3 80 n.d. 15 c B Cu(OAc) 2 Na 2 CO 3 80 85 16 d B Cu(OAc) 2 Na 2 CO 3 80 65 17 c,e B Cu(OAc) 2 Na 2 CO 3 80 78 18 c,f B Cu(OAc) 2 Na 2 CO 3 80 89 (87) g 19 c,f B Cu(OAc) 2 (0.05 mmol) Na 2 CO 3 80 40 20 c,f B Cu(OAc) 2 (0.02 mmol) Na 2 CO 3 80 20 a Conditions: 1 (0.1 mmol), 2 (0.3 mmol), Cu(OAc) 2 (0.0 mmol), base (0.2 mmol), DMSO(1.0 mL), air, 8 h. b Yield determined by 1 H NMR analysis of crude reaction mixture using CH 2 Br 2 as an internal standard. c 2 (0.2 mmol). d 2 (0.1 mmol). e 4 h. f 6 h. g Isolated yield is given in parentheses. Communication pubs.acs.org/JACS © 2014 American Chemical Society 3354 dx.doi.org/10.1021/ja412880r | J. Am. Chem. Soc. 2014, 136, 3354-3357