Copper-Catalyzed Direct Acyloxylation of C(sp 2 ) H Bonds. in Aromatic Amides

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1 Supporting Information for Copper-Catalyzed Direct Acyloxylation of C(sp 2 ) H Bonds in Aromatic Amides Feifan Wang, Qiyan Hu, Chao Shu, Zhiyang Lin, Dewen Min, Tianchao Shi and Wu Zhang* Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, College of Chemistry and Materials Science, Anhui ormal University, Wuhu , China. Table of Contents General Information...S2 General Procedures...S2 General Procedure for Copper-Catalyzed C H Acyloxylation...S2 Copper-Catalyzed C H Acyloxylation of 1a with benzoic acid (2 mmol scale)...s2 Characterization Data of Products 3aa-7a...S3 S23 X-ray Crystal Structure of the compound 5ba...S24 The hydrolyzation of 5ba...S24 Mechanistic Investigation S25 Radical Experiments......S25 Deuteration Experiments S26 KIE Studies...S27 Copies of 1 H and 13 C MR Spectra...S28 S72 S1

2 General Information All starting materials and reagents were commercially available and used directly without further purification. All carboxamides were synthesized by the reactions between the corresponding acyl chlorides or acids and 8-aminoquinolines according to the literature procedures. 1 All known products gave satisfactory analytical data by MR spectra, corresponding to the reported literature values. In addition, unknown compounds were confirmed by HRMS. Melting points were determined using X-4 micro melting point apparatus and are uncorrected. MR spectra were recorded at room temperature on a Bruker Avance-300 or Bruker Avance-500 at 300 MHz or 500 MHz with tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. High-resolution mass spectra (HRMS) were recorded on Agilent 6200 LC/MS TF using APCI or ESI in positive mode. General Procedures General Procedure for Copper-Catalyzed C H Acyloxylation To a 10 ml reaction tube was added amide 1a (0.2 mmol), acid (0.3 mmol), CuBr (5.7 mg, 20 mol %), Ag 2 C 3 (110.3 mg, 2 equiv), and toluene/dmf (1.5 ml/0.5 ml) in air. The mixture was stirred at 130 for 15 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and quenched with saturated sodium chloride. The aqueous phase was extracted with ethyl acetate (3 10 ml). The organic layer was dried over a 2 S 4. After concentration, the resulting residue was purified by flash chromatography to afford the product. Copper-Catalyzed C H Acyloxylation of 1a with benzoic acid (2 mmol scale) To a 50 ml reaction tube was added amide 1a (524 mg, 2 mmol), benzoic acid 2a (366 mg, 3 mmol), CuBr (57 mg, 20 mol %), Ag 2 C 3 (1103 mg, 2 equiv), and toluene/dmf (15 ml/5 ml) in air. The mixture was stirred at 130 for 15 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and quenched with saturated sodium chloride. The aqueous phase was extracted with ethyl acetate (3 40 ml). The organic layer was dried over a 2 S 4. After concentration, the resulting residue was purified by flash chromatography on silica gel (eluent: petroleum ether/ethyl acetate = 12/1) to afford the desired alkylated product 3aa (581 mg, 76%) as a white solid. 1 (a) Grigorjeva, L.; Daugulis,. rg. Lett. 2014, 16, (b) Khan, B; Kant, R.; Koley, D.; Adv. Synth. Catal. 2016, 358, (c) Roane, J.; Daugulis,. J. Am. Chem. Soc. 2016, 138, S2

3 Characterization Data of Products 3-methyl-2-(quinolin-8-ylcarbamoyl)phenyl benzoate 3aa H The compound 3aa was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3aa as a white solid (68 mg, 89% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.86 (dd, J = 6.3, 1.8 Hz, 1H), 8.74 (d, J = 3.6 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 7.8 Hz, 2H), (m, 5H), (m, 4H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 24 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-methylbenzoate 3ab The compound 3ab was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ab as a white solid (69.7 mg, 88% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.86 (dd, J = 6.3, 2.4 Hz, 1H), 8.74 (d, J = 3.0 Hz, 1H), 8.11 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), (m, 2H), (m, 2H), (m, 2H), 6.98 (d, J = 7.8 Hz, 2H), 2.53 (s, 3H), 2.26 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.61, 19.56; HRMS (APCI): Calcd for C 25 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-3-methylbenzoate 3ac S3

4 The compound 3ac was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ac as a white solid (68.9 mg, 87% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.88 (dd, J = 6.3, 2.4 Hz, 1H), 8.75 (d, J = 2.7 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), (m, 4H), (m, 3H), (m, 1H), 2.53 (s, 3H), 2.07 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , 20.87, 19.55; HRMS (APCI): Calcd for C 25 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-2-methylbenzoate 3ad H The compound 3ad was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ad as a white solid (66.5 mg, 84% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.79 (dd, J = 6.6, 1.8 Hz, 1H), 8.63 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), (m, 4H), (m, 3H), 6.97 (d, J = 7.5 Hz, 1H), 6.83 (m, 1H), 2.43 (s, 3H), 2.38 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , 20.59, 18.47; HRMS (APCI): Calcd for C 25 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-methoxybenzoate 3ae H S4

5 The compound 3ae was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ae as a white solid (58.5 mg, 71% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.86 (dd, J = 6.3, 2.1 Hz, 1H), 8.74 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 7.2 Hz, 1H), 7.96 (d, J = 8.7 Hz, 2H), (m, 4H), (m, 2H), 6.65 (d, J = 9.0 Hz, 2H), 3.74 (s, 3H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , 55.36, HRMS (APCI): Calcd for C 25 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-3-chlorobenzoate 3af H Cl The compound 3af was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3af as a white solid (57.4 mg, 69% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.87 (dd, J = 6.0, 2.7 Hz, 1H), 8.77 (d, J = 3.3 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), 7.88 (d, J = 7.5 Hz, 1H), (m, 2H), (m, 2H), 7.35 (d, J = 7.8 Hz, 1H), (m, 2H), (m, 1H), 2.54 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , HRMS (ESI): Calcd for C 24 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-2-chlorobenzoate 3ag The compound 3ag was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ag as a white solid (51.6 mg, 62% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.90 (d, J = 5.1 Hz, 1H), 8.73 (d, J = 2.7 Hz, 1H), 8.13 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.5 Hz, 1H), (m, 8H), (m, 1H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , S5

6 126.35, , , , , , 19.53; HRMS (ESI): Calcd for C 24 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-chlorobenzoate 3ah H Cl The compound 3ah was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ah as a white solid (63.2 mg, 76% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.85 (dd, J = 6.3, 2.7 Hz, 1H), 8.72 (d, J = 3.0 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H), 7.92 (d, J = 8.4 Hz, 2H), (m, 4H), (m, 4H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 18.51; HRMS (APCI): Calcd for C 24 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-bromobenzoate 3ai The compound 3ai was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ai as a white solid (69.0 mg, 75% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.84 (d, J = 3.3 Hz, 1H), 8.73 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H), (m, 4H), 7.31 (d, J = 8.1 Hz, 2H), (m, 2H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 19.56; HRMS (ESI): Calcd for C 24 H Br [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-fluorobenzoate 3aj S6

7 The compound 3aj was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3aj as a white solid (68.8 mg, 86% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.85 (dd, J = 6.0, 2.7 Hz, 1H), 8.73 (dd, J = 2.7, 1.2 Hz, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.01 (dd, J = 8.4, 5.4 Hz, 2H), (m, 4H), (m, 2H), (m, 2H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ (d, J C-F = Hz), , , , , , , , , (d, J C-F = 9.5 Hz), , , , , , (d, J C-F = 2.5 Hz), , , , , (d, J C-F = 21.9 Hz), 19.56; HRMS (APCI): Calcd for C 24 H F [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-3-(trifluoromethyl)benzoate 3ak The compound 3ak was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ak as a white solid (53.1 mg, 59% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.84 (dd, J = 6.0, 3.0 Hz, 1H), 8.73 (dd, J = 4.2, 1.2 Hz, 1H), 8.23 (s, 1H), 8.18 (d, J = 7.8 Hz, 1H), (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), (m, 7H), 2.55 (s, 3H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , , , , , , (q, 2 J C-F = 32.8 Hz), , , , , , , , , (q, 3 J C-F = 3.8 Hz), (q, 1 J C-F = Hz), , , , , 19.57; HRMS (ESI): Calcd for C 25 H F 3 [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl[1,1'-biphenyl]-4-carboxylate 3al S7

8 The compound 3al was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3al as a white solid (70.5 mg, 77% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.88 (dd, J = 7.2, 1.5 Hz, 1H), 8.75 (dd, J = 2.7, 1.5 Hz, 1H), (m, 3H), (m, 11H), (m, 2H), 2.54 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 19.57; HRMS (APCI): Calcd for C 30 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-2-naphthoate 3am The compound 3am was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3am as a white solid (63.1 mg, 73% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.87 (dd, J = 7.2, 1.2 Hz, 1H), 8.74 (dd, J = 4.2, 1.2 Hz, 1H), 8.54 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 8.00 (dd, J = 8.1, 0.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), (m, 9H), (m, 1H), 2.55 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , , , 19.59; HRMS (APCI): Calcd for C 28 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl thiophene-2-carboxylate 3an S8

9 The compound 3an was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3an as a white solid (54.3 mg, 70% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.87 (dd, J = 6.3, 2.1 Hz, 1H), 8.75 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), (m, 6H), (m, 1H), (m, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , 18.50; HRMS (ESI): Calcd for C 22 H S [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl isobutyrate 3ao The compound 3ao was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ao as a yellow liquid (42.4 mg, 61% yield). 1 H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.93 (dd, J = 6.6, 1.5 Hz, 1H), 8.77 (d, J = 3.9 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), (m, 2H), 7.44 (dd, J = 8.4, 4.2 Hz, 1H), (m, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 8.1 Hz, 1H), (m, 1H), 2.48 (s, 3H), 1.02 (d, J = 7.2 Hz, 6H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , 32.98, 18.33, 17.58; HRMS (ESI): Calcd for C 21 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl 2-phenylbutanoate 3ap The compound 3ap was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3ap as a white solid (44.9 mg, 53% yield). Mp = H MR (500 MHz, CDCl 3 ): δ 9.88 (s, 1H), (m, 1H), (m, 1H), 8.18 (d, J = 7.0 Hz, 1H), 7.56 (d, J = 3.0 Hz, 2H), 7.46 (dd, J = 7.0, 2.0 Hz, 1H), (m, 1H), 7.15 (d, J = 7.5 Hz, 1H), (m, 2H), 6.95 (d, J = 8.0 Hz, 1H), (m, 3H), 3.53 (t, J = 7. 0 S9

10 Hz, 1H), 2.44 (s, 3H), (m, 1H), (m, 1H), 0.70 (t, J = 7.5 Hz, 3H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 53.36, 26.45, 19.45, 11.87; HRMS (ESI): Calcd for C 27 H [M + H] , found (quinolin-8-ylcarbamoyl)phenyl-4-methylbenzoate 3bb H The compound 3bb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3bb as a white solid (29.8 mg, 39% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.91 (dd, J = 7.2, 1.2 Hz, 1H), 8.37 (dd, J = 4.2, 1.2 Hz, 1H), (m, 3H), 8.11 (dd, J = 8.1, 1.2 Hz, 1H), (m, 4H), (m, 2H), 7.18 (d, J = 7.8 Hz, 2H), 2.38 (s, 3H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.74; HRMS (APCI): Calcd for C 24 H [M + H] , found (quinolin-8-ylcarbamoyl)-1,3-phenylene bis(4-methylbenzoate) 3bb The compound 3bb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3bb as a white solid (26.8 mg, 26% yield). Mp = HMR (300 MHz, CDCl 3 ): δ (s, 1H), (m, 2H), 8.08 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 4H), (m, 6H), 7.07 (d, J = 8.1 Hz, 4H), 2.31 (s, 6H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , S10

11 144.43, , , , , , , , , , , , , , , 21.67; HRMS (APCI): Calcd for C 32 H [M + H] , found (quinolin-8-ylcarbamoyl)phenyl-4-bromobenzoate 3bi The compound 3bi was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3bi as a white solid (33.9 mg, 38% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.89 (d, J = 6.9 Hz, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.12 (d, J = 7.8 Hz, 4H), (m, 8H). 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , ; HRMS (APCI): Calcd for C 23 H Br [M + H] , found (quinolin-8-ylcarbamoyl)-1,3-phenylene bis(4-bromobenzoate) 3bi The compound 3bi was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3bi as a white solid (10.3 mg, 8% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.70 (d, J = 3.9 Hz, 2H), 8.14 (d, J = 7.8 Hz, 1H), 7.95 (d, J = 8.1 Hz, 4H), (m, 1H), (m, 9H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , ; HRMS (APCI): Calcd for C 30 H Br 2 [M + H] , found S11

12 4-methyl-2-(quinolin-8-ylcarbamoyl)phenyl 4-methylbenzoate 3cb The compound 3cb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3cb as a white solid (32.5 mg, 41% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.91 (d, J = 6.6 Hz, 1H), (m, 1H), 8.17 (d, J = 7.5 Hz, 2H), 8.10 (d, J = 7.8 Hz, 1H), 7.96 (s, 1H), (m, 4H), (m, 3H), 2.46 (s, 3H), 2.38 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.72, 20.88; HRMS (APCI): Calcd for C 25 H [M + H] , found methoxy-2-(quinolin-8-ylcarbamoyl)phenyl-4-methylbenzoate 3db The compound 3db was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3db as a white solid (14.8 mg, 18% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.33 (d, J = 3.9 Hz, 1H), 8.18 (d, J = 8.1 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 3.0 Hz, 1H), (m, 2H), 7.53 (dd, J = 8.4, 4.2 Hz, 1H), (m, 4H), 3.92 (s, 3H), 2.38 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 55.85, 21.74; HRMS (APCI): Calcd for C 25 H [M + H] , found methoxy-6-(quinolin-8-ylcarbamoyl)phenyl-4-methylbenzoate 3db S12

13 The compound 3db was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3db as a white solid (15.7 mg, 19% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (dd, J = 7.5, 0.9 Hz, 1H), (m, 3H), 8.09 (d, J = 8.4 Hz, 1H), 7.79 (dd, J = 7.8, 0.6 Hz, 1H), (m, 5H), (m, 2H), 3.85 (s, 3H), 2.42 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 56.43, 21.78; HRMS (APCI): Calcd for C 25 H [M + H] , found methoxy-2-(quinolin-8-ylcarbamoyl)-1,3-phenylene bis(4-methylbenzoate) 3db The compound 3db was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ ethyl acetate = 8/1 gave 3db as a yellow solid (25.1 mg, 23% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.74 (d, J = 3.6 Hz, 1H), 8.70 (dd, J = 6.0, 2.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 7.8 Hz, 2H), (m, 4H), (m, 5H), 3.88 (s, 3H), 2.33 (s, 3H), 2.32 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 56.58, 21.67; HRMS (APCI): Calcd for C 33 H [M + H] , found S13

14 5-methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-methylbenzoate 3eb The compound 3eb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 3eb as a white solid (36.4 mg, 46% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.90 (d, J = 7.2 Hz, 1H), 8.29 (d, J = 3.9 Hz, 1H), 8.19 (d, J = 7.8 Hz, 2H), 8.08 (d, J = 8.1 Hz, 2H), (m, 2H), 7.32 (dd, J = 8.4, 4.2 Hz, 1H), (m, 3H), 7.11 (s, 1H), 2.44 (s, 3H), 2.38 (s, 3H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 21.75, 21.37; HRMS (APCI): Calcd for C 25 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)-1,3-phenylene bis(4-methylbenzoate) 3eb The compound 3eb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether /ethyl acetate = 10/1 gave 3eb as a white solid (15.9 mg, 15% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.70 (d, J = 3.6 Hz, 2H), 8.07 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.8 Hz, 4H), (m, 3H), 7.14 (s, 2H), 7.07 (d, J = 7.5 Hz, 4H), 2.47 (s, 3H), 2.31 (s, 6H); 13 C MR (125 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , 21.67, 21.56; HRMS (APCI): Calcd for C 33 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl-4-bromobenzoate 3ei S14

15 The compound 3ei was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 10/1 gave 3ei as a white solid (32.2 mg, 35% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.89 (d, J = 7.2 Hz, 1H), 8.38 (d, J = 3.6 Hz, 1H), (m, 3H), 8.04 (d, J = 8.1 Hz, 1H), (m, 4H), 7.37 (dd, J = 8.1, 4.2 Hz, 1H), (m, 1H), 7.12 (s, 1H), 2.46 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , ,121.54, , 21.39; HRMS (APCI): Calcd for C 24 H Br [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)-1,3-phenylene bis(4-bromobenzoate) 3ei Br H Br The compound 3ei was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 10/1 gave 3ei as a white solid (6.6 mg, 5% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.69 (d, J = 3.9 Hz, 2H), 8.16 (d, J = 7.5 Hz, 1H), 7.95 (d, J = 8.4 Hz, 4H), (m, 3H), 7.41 (d, J = 8.4 Hz, 4H), 7.16 (s, 2H), 2.49 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , 21.58; HRMS (APCI): Calcd for C 31 H Br 2 [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl cinnamate 5aa S15

16 H The compound 5aa was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5aa as a white solid (49.8 mg, 61% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (dd, J = 7.2, 1.2 Hz, 1H), 8.78 (dd, J = 3.9, 1.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 16.2 Hz, 1H), (m, 4H), (m, 7H), 6.41 (d, J = 15.9 Hz, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , 19.57; HRMS (APCI): Calcd for C 26 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-methoxyphenyl)acrylate 5ab The compound 5ab was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ab as a white solid (62.2 mg, 71% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (d, J = 6.9 Hz, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 15.9 Hz, 1H), (m, 4H), (m, 4H), 6.77 (d, J = 8.1 Hz, 2H), 6.28 (d, J = 15.9 Hz, 1H), 3.79 (s, 3H), 2.51 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , 55.35, 19.56; HRMS (APCI): Calcd for C 27 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(3-methoxyphenyl)acrylate 5ac S16

17 The compound 5ac was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ac as a white solid (56.9 mg, 65% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.93 (dd, J = 6.9, 1.5 Hz, 1H), 8.78 (dd, J = 2.7, 1.2 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 15.9 Hz, 1H), (m, 4H), (m, 3H), (m, 2H), 6.76 (s, 1H), 6.41 (d, J = 15.9 Hz, 1H), 3.75 (s, 3H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , 55.26, 19.57; HRMS (APCI): Calcd for C 27 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(2-methoxyphenyl)acrylate 5ad H The compound 5ad was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ad as a white solid (49.1 mg, 56% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (d, J = 6.9 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 16.2 Hz, 1H), (m, 4H), (m, 4H), (m, 2H), 6.53 (d, J = 16.2 Hz, 1H), 3.74 (s, 3H), 2.51 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , 55.32, 19.56; HRMS (APCI): Calcd for C 27 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(p-tolyl)acrylate 5ae S17

18 The compound 5ae was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ae as a white solid (55.7 mg, 66% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (dd, J = 6.9, 1.5 Hz, 1H), 8.78 (dd, J = 4.2, 1.5 Hz, 1H), 8.12 (dd, J = 8.4, 1.2 Hz, 1H), 7.63 (d, J = 15.9 Hz, 1H), (m, 4H), (m, 6H), 6.37 (d, J = 16.2 Hz, 1H), 2.52 (s, 3H), 2.31 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 21,47, 19.58; HRMS (APCI): Calcd for C 27 H [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-chlorophenyl)acrylate 5af The compound 5af was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5af as a white solid (53.9 mg, 61% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.93 (d, J = 6.9 Hz, 1H), (m, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 16.2 Hz, 1H), (m, 4H), (m, 6H), 6.38 (d, J = 15.6 Hz, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 19.55; HRMS (APCI): Calcd for C 26 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(3-chlorophenyl)acrylate 5ag S18

19 The compound 5ag was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ag as a white solid (52.2 mg, 59% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.93 (dd, J = 7.2, 1.5 Hz, 1H), 8.79 (dd, J = 4.5, 1.5 Hz, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 15.9 Hz, 1H), (m, 4H), (m, 4H), (m, 1H), 7.04 (s, 1H), 2.53 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , , 19.58; HRMS (APCI): Calcd for C 26 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(2-chlorophenyl)acrylate 5ah The compound 5ah was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ah as a white solid (46.9 mg, 53% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 3.0 Hz, 1H), (m, 2H), (m, 10H), 6.41 (d, J = 15.9 Hz, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 26 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-fluorophenyl)acrylate 5ai S19

20 The compound 5ai was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ai as a white solid (53.7 mg, 63% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.93 (d, J = 6.6 Hz, 1H), 8.78 (d, J = 3.0 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 16.2 Hz, 1H), (m, 4H), (m, 4H), (m, 2H), 6.33 (d, J = 15.9 Hz, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , (d, J C-F = Hz), , , , , , , , , (d, J C-F = 3.8 Hz), , , , , , , , , , (d, J C-F = 1.7 Hz), , , 19.53; HRMS (APCI): Calcd for C 26 H F [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-bromophenyl)acrylate 5aj The compound 5aj was prepared according to general procedure. A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5aj as a white solid (57.3 mg, 59% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.92 (dd, J = 6.9, 1.5 Hz, 1H), 8.78 (d, J = 3.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 16.2 Hz, 1H), (m, 6H), (m, 2H), (m, 2H), 6.39 (d, J = 15.9 Hz, 1H), 2.52 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , 19.54; HRMS (APCI): Calcd for C 26 H Br [M + H] , found (quinolin-8-ylcarbamoyl)phenyl cinnamate 5ba H S20

21 The compound 5ba was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ba as a white solid (43.3 mg, 55% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.98 (d, J = 7.2 Hz, 1H), 8.76 (d, J = 3.0 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 15.9 Hz, 1H), (m, 3H), (m, 8H), 6.84 (d, J = 15.9 Hz, 1H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 25 H [M + H] , found chloro-2-(quinolin-8-ylcarbamoyl)phenyl cinnamate 5fa The compound 5fa was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5fa as a white solid (35.1 mg, 41% yield). Mp: ; 1 H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.95 (d, J = 6.3 Hz, 1H), 8.76 (d, J = 2.7 Hz, 1H), (m, 2H), 7.89 (d, J = 15.9 Hz, 1H), (m, 3H), (m, 7H), 6.83 (d, J = 16.2 Hz, 1H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 25 H Cl [M + H] , found methyl-2-(quinolin-8-ylcarbamoyl)phenyl cinnamate 5da The compound 5da was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5da as a white solid (35.1 mg, 43% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 2.7 Hz, 1H), (m, 2H), 7.89 (d, J = 16.2 Hz, 1H), S21

22 (m, 2H), (m, 6H), (m, 1H), 7.15 (s, 1H), 6.86 (d, J = 16.2 Hz, 1H), 2.46 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 26 H [M + H] , found fluoro-2-(quinolin-8-ylcarbamoyl)phenyl cinnamate 5ga The compound 5ga was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5ga as a white solid (29.7 mg, 36% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.96 (d, J = 7.2 Hz, 1H), 8.74 (d, J = 2.7 Hz, 1H), (m, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.90 (d, J = 15.9 Hz, 1H), (m, 2H), (m, 6H), (m, 2H), 6.85 (d, J = 15.9 Hz, 1H); 13 C MR (75 MHz, CDCl 3 ): δ , (d, J C-F = Hz), , , , , , , , (d, J C-F = 9.9 Hz), , , , , , , , , , (d, J C-F = 21.2 Hz), (d, J C-F = 24.9 Hz). HRMS (APCI): Calcd for C 25 H F [M + H] , found (quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-bromophenyl)acrylate 5bj The compound 5bj was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 12/1 gave 5bj as a white solid (54.8 mg, 58% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.97 (d, J = 7.2 Hz, 1H), 8.75 (d, J = 3.0 Hz, 1H), 8.16 (d, J = 8.1 Hz, 2H), 7.80 (d, J = 15.9 Hz, 1H), (m, 10H), 6.80 (d, J =15.9 Hz, 1H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , S22

23 HRMS (APCI): Calcd for C 25 H 18 Br 2 3 [M + H] , found (quinolin-8-ylcarbamoyl)phenyl (E)-3-(4-methoxyphenyl)acrylate 5bb The compound 5bb was prepared according to general procedure (the reaction time was extended to 30 h). A purification by flash chromatography in petroleum ether/ethyl acetate = 10/1 gave 5bb as a white solid (37.3 mg, 44% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.97 (d, J = 7.2Hz, 1H), 8.75 (d, J = 3.0 Hz, 1H), 8.19 (d, J = 7.2 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.83 (d, J = 15.9 Hz, 1H), (m, 8H), 6.85 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 15.9 Hz, 1H), 3.82 (s, 3H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 26 H [M + H] , found hydroxy--(quinolin-8-yl)benzamide 7a The compound 7a was prepared according to the hydrolyzation of 5ba. A purification by flash chromatography in petroleum ether/ethyl acetate = 8/1 gave 7a as a white solid (47.0 mg, 89% yield). Mp = H MR (300 MHz, CDCl 3 ): δ (s, 1H), (s, 1H), 8.87 (d, J = 3.0 Hz, 1H), 8.81 (dd, J = 5.7, 3.0 Hz, 1H), 8.20 (d, J = 5.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), (m, 4H), (m, 2H); 13 C MR (75 MHz, CDCl 3 ): δ , , , , , , , , , , , , , , , HRMS (APCI): Calcd for C 16 H [M + H] , found S23

24 X-ray crystal structure of the compound 5ba Figure S1. RTEP view of 5ba. [2] The hydrolyzation of 5ba Scheme S1 The compound 5ba was prepared according to general procedure (the reaction time was extended to 30 h). To a 10 ml reaction tube was added amide 5ba (0.2 mmol) and aqueous ah (2 ml). The mixture was stirred at 110 for 24 h in air, and reflux. The reaction mixture was then cooled to room temperature and added aqueous HCl, adjusted the ph of the solution to 6~7. The aqueous phase was extracted with ethyl acetate (3 10 ml) and the organic layer was dried over a 2 S 4. After concentration, the resulting residue was purified by flash chromatography to afford the product 7a. [2] CCDC (for 5ba) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via S24

25 Radical Experiments Scheme S2 S25

26 Deuteration Experiments Scheme S3 To a 10 ml reaction tube was added amide (0.2 mmol), acid (0.3 mmol), CuBr (5.7 mg, 20 mol %), Ag 2 C 3 (110.3 mg, 2 equiv), and toluene/dmf (1.5 ml/0.5 ml) in air. The mixture was stirred at 130 for 24 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and quenched with saturated sodium chloride. The aqueous phase was extracted with ethyl acetate (3 10 ml). The organic layer was dried over a 2 S 4. After concentration, the resulting residue was purified by flash chromatography to afford the product. The product was analyzed by 1 H MR. 1 H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.91 (d, J = 7.2 Hz, 1H), 8.34 (d, J = 3.3 Hz, 1H), 8.29 (d, J =7.8 Hz, 2H), 8.12 (d, J = 8.4 Hz, 1H), (m, 3H), (m, 3H). D D D D H Figure S2 S26

27 KIE Studies Scheme S4 To a 10 ml reaction tube was added amide 1 (0.2 mmol), d 5-1 (0.2 mmol), acid (0.6 mmol), CuBr (11.4 mg, 0.08 mmol), Ag 2 C 3 (220.6 mg, 0.8 mmol), and toluene/dmf (3 ml/1 ml) in air. The mixture was stirred at 130 for 24 h. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and quenched with saturated sodium chloride. The aqueous phase was extracted with ethyl acetate (3 10 ml). The organic layer was dried over a 2 S 4. After concentration, the resulting residue was purified by flash chromatography to afford the product. 1 H MR analysis of the mixture showed a modest value of k H /k D = 1.4 (see the attached spectrum). 1 H MR (300 MHz, CDCl 3 ): δ (s, 1H), 8.91 (d, J = 6.3 Hz, 1H), (m, 3H), 8.17 (dd, J = 7.5, 1.2 Hz, 0.58H), 8.09 (dd, J = 8.1, 0.9 Hz, 1H), (m, 5H), (m, 4H). Figure S3 S27

28 Copies of 1 H and 13 C MR Spectra S28

29 S29

30 S30

31 S31

32 S32

33 S33

34 S34

35 S35

36 S36

37 S37

38 S38

39 S39

40 S40

41 S41

42 S42

43 S43

44 S44

45 S45

46 H 3bi Br H 3bi Br S46

47 S47

48 S48

49 S49

50 S50

51 H 3db H 3db S51

52 H 3eb H 3eb S52

53 S53

54 S54

55 S55

56 S56

57 S57

58 S58

59 S59

60 H 5ae H 5ae S60

61 S61

62 S62

63 S63

64 S64

65 S65

66 S66

67 S67

68 S68

69 S69

70 S70

71 H 5bb H 5bb S71

72 S72