Copper-Catalyzed Oxidative Amination of Benzoxazoles via C-H and C-N Bond Activation: A

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1 Supporting Information for: Copper-Catalyzed xidative Amination of Benzoxazoles via C-H and C- Bond Activation: A ew Strategy for Using Tertiary Amines as itrogen Group Sources Shengmei Guo, Bo Qian, Yinjun Xie, Chungu Xia, and Hanmin Huang* State Key Laboratory for xo Synthesis and Selective xidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou , China, and State Key Laboratory of Applied rganic Chemistry, Lanzhou University, Lanzhou , China hmhuang@licp.cas.cn CTETS 1 General experimental details and materials 2 ptimization of the reaction conditions 3 General procedure Cu-catalyzed oxidative amination 4 Experimental characterization data for products 5 Copies of product 1 H MR and 13 C MR 1. General experiment detail and materials Experimental: All non-aqueous reactions and manipulations were performed in air atmosphere using standard Schlenk techniques. All solvents before use were dried and degassed by standard methods and stored under nitrogen. All reactions were monitored by TLC with silica gel-coated plates. MR spectra were recorded on BRUKER DRX 400 spectrometers. Chemical shifts are reported in parts per million (ppm) down field from TMS with the solvent resonance as the internal standard. Coupling constants (J) are reported in Hz and refer to apparent peak multiplications. High resolution mass spectra (HRMS) were recorded on Bruker MicroTF-QII mass instrument(esi). The METEK Dycor-200M four-grade mass spectrometer was used for checking water(gas) formed during this reaction(in the presence of 18 2 ).GC-MS was recored on Agilent 5973 etwork. GC analysis was performed on Agilent 7890 with Hp-5 as column. Benzoxazole and benzothiazole were purchased from Alfa Aesar and used as received ( 18, 95-98%) and H 18 2 ( 18, 97%) were purchased from Cambridge Isotope Laboratories (CIL). ther substituted azoles are known compounds and synthesized according to the reported methods 1,2. The tertiary amines used here are known compounds and purchased from Alfa Aesar and used as received. 2. Synthesis of the Substituted Azoles S1

2 H 2 CH(Et) R 3 R H reflux In a 100 ml flask, 2-aminophenol derivative (20 mmol) was added to triethyl orthoformate (30 ml) under an argon atmosphere, the resulting mixture was refluxed for 5-8 h and monitored by TLC. After cooling to room temperature, triethyl orthoformate was removed under reduced pressure at o C; the residue was purified by column chromatography afforded to the desired products. Me 3b 6-Methylbenzoxazole: white solid (90%); 1 HMR (400 MHz, CDCl 3 ) δ 8.03 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 2.50 (s, 1H). Me 3c 4-Methylbenzoxazole: colorless oil (64%); 1 HMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 8.4 Hz, 1H), 7.14 (d, J = 7.2 Hz,1H) 2.64 (s, 1H); 13 CMR (100 MHz, CDCl 3 ) δ 151.7, 149.7, 139.2, 131.0, 125.3, 125.0, 108.2, Me 5-Methylbenzoxazole: white solid (68%); 1 HMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.58 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 2.48 (s, 1H); 3d Cl 3f 5-Chlorobenzoxazole: pink solid (83%); 1 HMR (400 MHz, CDCl 3 ) δ 8.70 (s, 1H), 8.37 (d, J = 6.8 Hz, 1H), 8.31 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H). 3g 5-Phenylbenzoxazole: bronzing solid (90%); 1 HMR (400 MHz, CDCl 3 ) δ 8.13 (s, 1H), 7.99 (s, 1H), (m, 4H), (m, 2H), (m, 1H); 13 CMR (100 MHz, CDCl 3 ) δ 153.2, 149.6, 140.9, 140.8, 138.7, 129.0, 127.6, 127.5, 125.4, 119.2, Br 3l S2

3 5-bromobenzoxazole: white solid (83%); 1 HMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.95 (s, 1H), (m, 3H); 13 CMR (100 MHz, CDCl 3 ) δ 153.5, 149.0, 141.7, 128.8, 123.7, 117.4, Tert-butylbenzoxazole: yellow solid (64%); 1 HMR (400 MHz, CDCl 3 ) δ 8.06 (s, 1H), 7.81 (s, 1H), 7.43 (m, 2H), 1.38 (s, 9H). 3h 2 3i 5-itrobenzoxazole: yellow solid (54%); 1 HMR (400 MHz, CDCl 3 ) δ 8.11 (s, 1H), 7.78 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.35 (d, J =7.2 Hz, 1H). 3j 2-Phenyl-1, 3, 4-oxadiazole: yellow solid (65%); 1 HMR (400 MHz, CDCl 3 ) δ 8.49 (s, 1H), (m, 2H), (m, 3H); 13 CMR (100 MHz, CDCl 3 ) δ 164.7, 148.1, 152.6, 132.0, 129.1, 127.1, ptimization of the Reaction Conditions Catalyst (0.1 eq), benzoxazole (0.5 mmol, 1 eq) were added to a 25 ml flame-dried Young-type tube under air. After vacuum the tube under reduced pressure, the 2 (1 atm) was introduced. Solvent (1 ml), tertiary amine (1.0 mmol) and additive (20 mol%) were added under oxygen atmosphere, and then sealed the Young-type tube and the resulting mixture was stirred at the desired temperature under 1atm oxygen. After stirred for 8 h, the mixture was cooled to room temperature and degassed in liquid nitrogen and supplied 1atm 2 again. The mixture was continued to stir another 8 h at the desired temperature. The mixture was allowed to cooling to room temperature, and washed with water, extract with diethyl ether for three times. The organic layer dried over anhydrous a 2 S 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with EtAc/hexanes (1/40 1/10) to afford the desired product. Table 1. Screening of catalysts a entry catalyst Yield (%) b 1 no 0 S3

4 2 CuCl 24 3 CuI trace 4 CuBr 12 5 CuF 2 trace 6 Cu 2 trace 7 CuCl CuBr Cu(Tf) 2 trace 10 Cu(Ac) 2. H 2 trace 11 Cu(Ac) 2 trace 12 c CuBr 2 trace 13 FeCl Sc(Tf) Pd(Ac) 2 trace 16 Pd(dba) 2 trace 17 Co(acac) ibr AgTf 0 20 Ir(CD) 2 Cl [Rh(CD)Cl] AuCl 3 0 a Benzoxazole 3a (0.5 mmol), Et 3 1a (1.0 mmol), catalyst (10 mol%), toluene (1 ml), 2 (1 atm) at 80 o C for 16h; b isolated yield. c CuBr 2 (100 mol%) in the argon atmosphere Table 2. Screening of Solvents a entry Solvent (1mL) Yield (%) b 1 DMS 9 2 THF 19 3 Dioxane 34 4 CH 3 C 31 5 Et DMF 26 S4

5 7 1.2-DCE trace 8 Xylene 27 9 DMA trace 10 CCl 4 trace 11 DCM trace 12 c EA Toluene TBAB Mesitylene trace a Benzoxazole 3a (0.5 mmol), Et 3 1a (1.0 mmol), CuBr 2 (10 mol%), solvent (1mL), 2 (1 atm) at 80 o C for 16h. b isolated yield. Table 3. Screening of Additives a entry acid (20 mol%) T( o C) Yield (%) b 1 CF 3 CH PhCH CH 3 CH t-bu-ch HCH H 2 S 3 H TsH CH 3 CH 2 CH (CH 3 ) 2 CHCH HCCH 2 CH (4-Me)C 6 H 4 CH (CHHCH) 2 80 trace 13 (4-Me)C 6 H 4 CH HC 6 H 4 CH H 3 P 4 80 trace 16 c CH 3 CH CH 3 CH S5

6 18 CH 3 CH d CH 3 CH e CH 3 CH a Benzoxazole 3a (0.5 mmol), Et 3 1a (2 eq), CuBr 2 (10 mol%), dioxane (1 ml), 2 (1 atm) at 80 o C for 16 h. b isolated yield; c 15 mol% CuBr 2; d 5 mol% CuBr 2 ; e no catalyst. General procedure Cu-catalyzed oxidative amination CuBr 2 (11.2 mg, 10 mol%), benzoxazole derivative (0.5 mmol, 1eq) were added to a 25 ml flamedried Young-type tube under air, then vacuum the tube under reduced pressure and the 2 (1 atm) was introduced. Dioxane (1 ml), tertiary amine (1.0 mmol) and acetic acid (6 µl, 20 mol%) were added under oxygen atmosphere, and then sealed the Young-type tube and the resulting mixture was stirred for 8 h at 120 o C under 1atm oxygen. The mixture was cooled to room temperature and degassed by the freeze-thaw method and supplied with 1atm 2 again. The mixture was continued to stir for another 8 h at 120 o C. The mixture was allowed to cool to room temperature, and washed with water, extracted with diethyl ether for three times. The organic layer was dried over anhydrous a 2 S 4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with EtAc/hexanes (1/40 1/10) to afford the desired product. 3.1, -Diethylbenzoxazol-2-amine (4aa): The title compound was prepared according to the general procedure and purified by column chromatography to give a colorless liquid, 89% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 7.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.96 (t, J = 8.0 Hz, 1H), 3.56 (dd, 4aa J 1 = 7.2 Hz, J 2 = 14.4 Hz, 4H), 1.26 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 161.2, 147.8, 142.6, 122.7, 118.9, 114.8, 107.4, 41.9, 12.4; HRMS (ESI) calcd. for C 11 H 14 2 [M+1]: , found: , -Dipropylbenzoxazol-2-amine (4ab): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 92% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), 3.45 (t, J = 7.6 Hz, 4H), ab 1.76 (m, 4H), 0.94 (t, J = 7.6Hz, 6H); 13 CMR (100 MHz, CDCl3) δ 162.7, 148.7, 143.7, 123.7, 119.9, 115.8, 108.4, 50.3, 21.2, 11.2; HRMS (ESI) calcd. for C 13 H 18 2 [M+1]: , found: , -Dibutylbenzoxazol-2-amine (4ac): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 82 % yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 8.0 Hz, 4ac S6

7 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 3.48 (t, J = 7.6 Hz, 4H), (m, 4H), (m, 4H), 0.94 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.7, 148.7, 143.7, 123.7, 119.8, 115.8, 108.5, 48.3, 30.1, 20.0, 13.9; HRMS (ESI) calcd. for C 15 H 22 2 [M+1]: , found: , -Diisobutylbenzoxazol-2-amine (4ad): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 78% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.33 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 8. 0 Hz, 1H), 6.95 (t, J = 8. 0 Hz, 1H), 3.35 (d, J 4ad = 7.6 Hz, 4H), (m, 2H), 0.94 (d, J = 6.4 Hz, 12H); 13 CMR (100 MHz, CDCl 3 ) δ 163.0, 148.6, 143.7, 123.7, 119.9, 115.8, 108.4, 56.3, 26.9, 20.0; HRMS (ESI) calcd. for C 15 H 22 2 [M+1]: , found: , -Dioctylbenzoxazol-2-amine (4ae): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 82% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 4ae 7.6 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 3.47 (d, J = 7.6 Hz, 4H), (m, 4H), (m, 20H), 0.86 (t, J = 6.8 Hz, 3H); 13 CMR (100 MHz, CDCl 3 ) δ 162.6, 148.8, 143.7, 123.7, 119.8, 115.8, 108.4, 48.6, 31.8, 29.4, 29.2, 28.0, 26.8, 22.6, HRMS (ESI) calcd. for C 23 H 38 2 [M+1]: , found: , -Dibenylbenzoxazol-2-amine (4af): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless 4af oil, 54% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.40 (d, J = 8.0 Hz, 1H), (m, 11H), 7.17 (t, J = 7.6 Hz, 1H), 7.02 (t, J = 8.0 Hz, 1H), 4.70 (s, 4H); 13 CMR (100 MHz, CDCl 3 ) δ 163.2, 148.9, 143.5, 136.3, 128.7, 127.8, 127.7, 124.0, 120.6, 116.3, 108.9, HRMS (ESI) calcd. for C 21 H 18 2 [M+1]: , found: , -Diallylbenzoxazol-2-amine (4ah): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 24% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), (m, 2H), 4ah 5.22 (t, J = 9.2 Hz, 4H), 4.15 (d, J = 5.6 Hz, 4H); 13 CMR (100 MHz, CDCl 3 ) δ 162.4, 148.9, 143.4, 132.6, 123.9, 120.4, 117.9, 116.1, 108.7, 49.9; HRMS (ESI) calcd. for C 13 H 14 2 [M+1]: , found: Ethyl--isopropylbenzoxazol-2-amine (4ai): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless 4ai S7

8 oil, 20% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.34 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 6.96 (t, J = 7.6 Hz, 1H), (m, 1H), 3.46 (dd, J 1 = 6.8 Hz, J 2 = 14.4 Hz, 2H), (m, 9H); 13 CMR (100 MHz, CDCl 3 ) δ 162.3, 148.6, 143.5, 123.7, 119.8, 115.7, 108.4, 49.4, 38.1, 20.6, 15.4; HRMS (ESI) calcd. for C 12 H 16 2 [M+1]: , found: , -Diisopropylbenzoxazol-2-amine (4ai ): The title compound was prepared according to the general procedure and purified by column chromatography to give a white solid, 20% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.33 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 6.94 (t, J = 8.0 Hz, 1H), (m, 2H), 4ai' 1.36 (d, J = 6.8 Hz 12H); 13 CMR (100 MHz, CDCl3) δ 162.3, 148.6, 143.1, 123.7, 119.8, 115.6, 108.4, 47.7, 20.9; HRMS (ESI) m/z calcd. For C 12 H 16 2 [M+1]: , found: Benzyl--ethylbenzoxazol-2-amine (4aj): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless oil, 34% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.32 (d, J = 6.8 Hz, 1H), (m, 5H), 7.15 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.6 Hz, 1H), 4.77 (s, 2H), 3.53 (dd, J 1 = 7.2 Hz, J 2 = 14.4 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H); 13 CMR (100 MHz, 4aj CDCl 3 ) δ 162.6, 148.8, 143.5, 137.0, 128.7, 127.6, 123.9, 120.2, 116.0, 108.7, 51.1, 42.7, 12.7; HRMS (ESI) calcd. for C 16 H 16 2 [M+1]: , found: Morpholinobenzoxazole (4ak): The title compound was prepared according to the general procedure and purified by column chromatography to give a beige solid, 74% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.36 (d, J = 7.2 Hz, 1H), 7.26 (d, J = 8.0Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 3.80 (t, J = 5.2 Hz, 4H ), 3.67 (t, J = 4.4 Hz, 4ak 4H); 13 CMR (100 MHz, CDCl 3 ) δ 161.1, 147.7, 141.8, 123.1, 119.9, 115.4, 107.8, 65.1, 44.7; HRMS (ESI) calcd. for C 12 H [M+1]: , found: (Piperidin-1-yl)benzoxazole (4am): The title compound was prepared according to the general procedure and purified by column chromatography to give a light yellow solid, 82% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 3.66 (s, 4H ), 4am 1.68 (s, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.4, 148.7, 143.4, 123.8, 120.3, 115.9, 108.5, 46.6, 25.2, 24.1; HRMS (ESI) calcd. for C 12 H 14 2 [M+1]: , found: , -Diethyl-6-methylbenzoxazol-2-amine (4ba): The title compound was prepared according to the General Procedure and purified by column chromatography to give colorless oil, 84% yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.20 (d, J = 8.0 Hz, Me 1H), 7.06 (s, 1H), 6.93 (d, J = 8.0 Hz, 1H), 3.54 (dd, J 1 =7.2 Hz, J 2 = ba S8

9 Hz, 4H ), 2.39 (s, 3H), 1.25 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.0, 149.0, 141.2, 129.9, 124.4, 115.2, 109.1, 42.9, 21.4, 13.5; HRMS (ESI) calcd. for C 12 H 16 2 [M+1]: , found: , -Diethyl-4-methylbenzoxazol-2-amine (4ca): The title compound was prepared according to the general procedure and purified by column chromatography to give colorless Me oil, 82 % yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.06 (d, J = 7.6 Hz, 1H), 6.93 (d, 4ca J = 7.6 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 3.54 (dd, J 1 =7.2 Hz, J 2 = 14.4 Hz, 4H ), 2.49 (s, 3H), 1.24 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 161.8, 148.4, 142.6, 125.9, 124.5, 119.5, 105.9, 42.6, 16.5, 13.4; HRMS (ESI) calcd. for C 12 H 16 2 [M+1]: , found: , -Diethyl-5-methylbenzoxazol-2-amine (4da): The title compound was prepared according Me to the general procedure and purified by column chromatography to give colorless oil, 88 % yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.14 (s, 1H), da (d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 3.52 (dd, J 1 = 7.2 Hz, J 2 = 14.4 Hz, 4H ), 2.37 (s, 3H), 1.23 (t, J = 6.8 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 161.3, 145.9, 142.7, 132.3, 119.5, 115.2, 106.8, 41.8, 20.5, 12.4; HRMS (ESI) calcd. for C 12 H 16 2 [M+1]: , found: Cholro-, -diethylbenzoxazol-2-amine (4ea): The title compound was prepared according to the general procedure and purified by column chromatography to give a Cl beige solid, 82 % yield. 1 HMR (400 MHz, CDCl 3 ) δ 7.23 (d, J = 3.6 Hz, 4ea 1H), 7.21 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.54 (dd, J 1 = 7.2 Hz, J 2 = 14.4 Hz, 4H ), 1.26 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.7, 149.1, 142.7, 125.1, 124.1, 116.1, 109.4, 43.2, 13.5; HRMS (ESI) calcd. for C 11 H 13 Cl 2 [M+1]: , found: Cholro-, -diethylbenzoxazol-2-amine (4fa): The title compound was prepared according to the general procedure and purified by column chromatography to give a yellow solid, 99 % yield. Cl 1 HMR (400 MHz, CDCl 3 ) δ 7.29 (s, 1H), 7.11 (d, J = 7.6Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H ), 3.54 (dd, J 1 =7.2 Hz, J 2 = 14.4 Hz, 4H ), 1.26 (t, J 4fa = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 163.0, 147.5, 145.1, 129.1, 119.1, 115.9, 109.0, 43.1, 13.5; HRMS (ESI) calcd. for C 11 H 13 Cl 2 [M+1]: , found: , -Diethyl-5-phenylbenzoxazol-2-amine (4ga): The title compound was prepared according to the general procedure and purified by column chromatography to give a bronzing solid, 98% yield. 1 HMR (400 MHz, CDCl 3 ) δ (m, 3H), 7.40 (t, J = 8.0 Hz, 4ga 2H), (m, 2H ), 7.20 (d, J = 8.0 Hz 1H), 3.56 (dd, J 1 =7.2 Hz, S9

10 J 2 = 14.4 Hz, 4H ), 1.26 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.7, 148.6, 144.3, 141.9, 137.6, 128.8, 127.4, 126.9, 119.4, 114.6, 108.5, 43.1, 13.6; HRMS (ESI) calcd. for C 17 H 18 2 [M+1]: , found: Tert-tutyl-,-diethylbenzoxazol-2-amine (4ha): The title compound was prepared according to the general procedure and purified by column chromatography to give a 4ha light yellow solid, 87 % yield. HMR (400 MHz, CDCl 3 ) δ 7.42(s, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H ), 3.54 (dd, J 1 =7.2 Hz, J 2 = 14.4 Hz, 4H), 1.33 (s, 9H), 1.24 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.4, 147.2, 146.7, 143.4, 117.0, 113.0, 107.6, 42.9, 34.8, 31.8, 13.5; HRMS (ESI) calcd. for C 15 H 22 2 [M+1]: , found: , -Diethyl-5-nitrobenzoxazol-2-amine (4ia): The title compound was prepared 1.1eq CuBr 2 instead of 10 mol% and purified by column chromatography to give a light yellow solid, 36 % yield. 2 1 HMR (400 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 1H ), 3.59 (dd, J 1 =7.2 Hz, J 2 = 14.4 Hz, 4H ), 1.30 (t, J = 7.2 Hz, 4ia 6H); 13 CMR (100 MHz, CDCl 3 ) δ 163.8, 153.0, 145.2, 144.8, 116.7, 111.3, 108.1, 43.4, 13.5; HRMS (ESI) calcd. for C 11 H [M+1]: , found: , -Diethyl-5-phenyl-1,3,4-oxadiazol-2-amine (4ja): The title compound was prepared according to the general procedure and purified by column chromatography to give a beige solid, 30 % yield. 1 HMR (400 MHz, CDCl 3 ) δ (m, 2H), (m, 3H), 3.51 (dd, J 1 = 6.8 Hz, J 2 = 14.0 Hz, 4H), 1.26 (t, J = 4ja 6.8 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 163.8, 158.7, 130.2, 128.8, 125.6, 124.8, 43.4, 13.2; HRMS (ESI) calcd. for C 12 H 15 3 [M+1]: , found: Morpholinobenzothiazole (4ka): The title compound was prepared by benzoic acid (20 mol%) was employed in this reaction instead of acetic acid and purified by column chromatography to give a yellow solid, 10 % yield; HMR (400 MHz, S CDCl 3 ) δ 7.60 (d, J = 7.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 4ka Hz 1H), 7.01(t, J = 8.4 Hz, 1H), 3.82 (dd, J 1 = 4.4 Hz, J 2 = 4.8 Hz, 4H ), 3.61 (t, J = 4.4 Hz, 4H); 13 CMR (100 MHz, CDCl 3 ) δ 169.0, 152.5,130.6, 126.1, 121.7, 120.8, 119.3, 66.2, HRMS (ESI) calcd. for C 11 H 12 2 S [M+1]: , found: , -Diethyl-5-bromobenzoxazol-2-amine (4la): The title compound was prepared according to Br the general procedure and purified by column chromatography to give a light yellow solid, 93 % yield. HMR (400 MHz, CDCl 3 ) δ 7.43(s, 1H), 4la 7.08 (m, 2H), 3.55 (dd, J 1 =6.8 Hz, J 2 = 14.0 Hz, 4H), 1.26 (t, J = 7.2 Hz, 6H); 13 CMR (100 MHz, CDCl 3 ) δ 162.8, 147.9, 145.6, , 118.8, 116.5, 109.5, 43.0, 13.4; HRMS (ESI) calcd. for C 11 H 14 Br 2 : , found: S10

11 Experiment for Mechanism studies We first conducted the reaction in gram scale with 3a and 1l as reactants which afforded the desired aminated product 4ak in 75% yield and inherently together with the benzaldehyde in 87% yield (based on 3a). The concomitant isolation of benzaldehyde in amounts a little more than that of the desired products, might indicate that C- bond cleavage took place prior to the new C- formation step. The radical scavengers, such as TEMP and 1,1-diphenylethylene, were employed in the standard reaction, the desired product 4aa was still obtained in 62% and 81% yield, respectively. This result suggested that a free radical process is not a requirement for the present oxidative C-H amination reaction. H + 3a (1.19g,10mmol) Ph 1l (2.34g,20mmol) CuBr 2 (10 mol%) CH 3 CH (20 mol%) 2 (1 atm) dioxane, 120 o C 75% yield 4ak (1.53 g, 7.5 mmol) + PhCH (0.93 g, 8.7 mmol) (equ-1) 3a (0.5 mmol) H + Et 3 + 1a (1.0 mmol) Ph Ph (0.75 mmol) CuBr 2 (10 mol%) CH 3 CH (20 mol%) 2 (1 atm) dioxane, 120 o C 4aa 81% yield (equ-2) 3a (0.5 mmol) H + Et 3 + 1a (1.0 mmol) (0.6 mmol) CuBr 2 (10 mol%) CH 3 CH (20 mol%) 2 (1 atm) dioxane, 120 o C 4aa 62% yield (equ-3) 18 -Labelled Experiment The experiment was conducted in the presence of 18 2 as the general procedure. After the reaction was finished, the Young-type tube was warmed to o C, and then use a syringe to take the gas (should contain some water) to be checked by the Four-grade mass spectrometer. The corresponding spectra (Figure 2) clear demonstrated that H 18 2 was produced. Take some sample from the reaction mixture and checked by the GC-MS and the PhCH 18 was found (Figure 1). This experiment clear suggested that the PhCH and H 2 were formed as by products for this reaction. S11

12 Abundance TIC: D 1.05e+07 1e Time--> Abundance m/z--> Scan 402 (3.410 min): D Figure S1 GC-MS of product of PhCH 18 in presence of E-009 ( m/z=20) ( m/z=19) 5.00E E E-009 Y Axis Title 3.50E E E E E E E X Axis Title Figure S2 Four-grade mass spectrometer of the product of H 2 18 in the presence of S12

13 CuBr 2 (11.2 mg, 10 mol%), benzoxazoles (59.5 mg, 0.5 mmol, 1 equal), 4-benzylmorpholine (177.0 mg, 1.0 mmol), acetic acid (6 µl, 20 mol%), H 2 (90 µl, 10 equal) and 1,4-dioxane (1 ml) were added to a 25 ml flame-dried Young-type tube. The solution was degassed three times by the freeze-thaw method and then the 18 2 (1 atm) was introduced into the vacuum tube. Then sealed the Young-type tube and the resulting mixture was stirred for 8 h at 120 o C under 1atm oxygen. The mixture was cooled to room temperature and degassed by the freeze-thaw method and supplied with 1atm 18 2 again. The mixture was continued to stir for another 8 h at 120 o C. The mixture was allowed to cool to room temperature and took some sample and diluted with Et 2 to be checked by GC-MS. The GC-MS spectra (Figure 3) disclosed that the produced aldehyde was PhCH. This result suggested that the oxygen of aldehyde is from the water. Abundance Time--> TIC: D Abundance Scan 560 (3.463 min): D m/z--> Figure S3 GC-MS of product of PhCH in the presence of 10 equal H 2 and 18 2 S13

14 CuBr 2 (11.2 mg, 10 mol%), benzoxazoles (59.5 mg, 0.5 mmol, 1 equal), 4-benzylmorpholine (177.0 mg, 1.0 mmol), acetic acid (6 µl, 20 mol%), H 18 2 (90 µl, 10 equal) and 1,4-dioxane (1 ml) were added to a 25 ml flame-dried Young-type tube. The solution was degassed three times by the freeze-thaw method and then the 2 (1 atm) was introduced into the vacuum tube. Then sealed the Young-type tube and the resulting mixture was stirred for 8 h at 120 o C under 1atm oxygen. The mixture was cooled to room temperature and degassed by the freeze-thaw method and supplied with 1atm 2 again. The mixture was continued to stir for another 8 h at 120 o C. The mixture was allowed to cool to room temperature and took some sample and diluted with Et 2 to be checked by GC-MS. The GC-MS spectra (Figure 3) disclosed that the produced aldehyde was PhCH 18. This result further confirmed that the oxygen of aldehyde is from the water. Abundance TIC: D 1.3e e e+07 1e Time--> Abundance Scan 550 (3.417 min): D m/z--> Figure S4 GC-MS of product of PhCH 18 in the presence of 10 equal H 2 18 and 16 2 Experimental Procedure for the Comparison of Initial Relative Rates (KIE) S14

15 CuBr 2 (11.2 mg, 10 mol%), 2-deuterated-5-methylbenzoxazole (67 mg, 0.5 mmol, 1 equal) or 5- methylbenzoxazole (66.5 mg, 0.5 mmol, 1 equal), Et 3 (101.0 mg, 1.0 mmol), acetic acid (6 µl, 20 mol%), biphenyl (10 mg, used as an internal standard) and 1,4-dioxane (1 ml) were added to a 25 ml flame-dried Young-type tube. The solution was degassed three times by the freeze-thaw method and then the 2 (1 atm) was introduced into the vacuum tube. Then sealed the Young-type tube and the resulting mixture was stirred at 120 o C under 1atm oxygen. After stirred for desired time at 120 o C, the mixture was cooled to room temperature quickly and took some crude mixture. The crude mixture was diluted with Et 2 and the product yield was determined by GC using biphenyl as an internal standard. Initial Rate Difference Conv (%) y = x R 2 = y = x R 2 = H D time(min) Figure S5 Reaction yields over time between 2-deuterated-5methylbenzoxazole and 5-methylbenzoxazole H + or Ph H H Ph D D CuBr 2 (10 mol%) CH 3 CH (20 mol%) 2 (1 atm) dioxane, 120 o C k H/D =2.7 S15

16 CuBr 2 (11.2 mg, 10 mol%), 4-(dideuterio(phenyl)methyl)morpholine (179.0 mg, 1.0 mmol), or 4- benzylmorpholine (177.0 mg, 1.0 mmol), benzoxazoles (59.5 mg, 0.5 mmol, 1 equal) acetic acid (6 µl, 20 mol%), biphenyl (10 mg, used as an internal standard) and 1,4-dioxane (1 ml) were added to a 25 ml flame-dried Young-type tube. The solution was degassed three times by the freeze-thaw method and then the 2 (1 atm) was introduced into the vacuum tube. Then sealed the Young-type tube and the resulting mixture was stirred at 120 o C under 1atm oxygen. After stirred for desired time at 120 o C, the mixture was cooled to room temperature quickly and took some crude mixture. The crude mixture was diluted with Et 2 and the product yield was determined by GC using biphenyl as an internal standard. Initial Rate Difference Conv (%) y = x R 2 = y = x R 2 = Time (min) H D Figure S5 Reaction yields over time between 4-benzylmorpholine and 4-(dideuterio(phenyl)methyl)morpholine References: 1. Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem. Int. Ed. 2009, 48, Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, Copies of product 1 H MR and 13 C MR S16

17 4aa S17

18 4aa S18

19 4ab S19

20 4ab S20

21 4ac S21

22 4ac S22

23 4ad S23

24 4ad S24

25 4ae S25

26 4ae S26

27 4af S27

28 4af S28

29 4ah S29

30 4ah S30

31 4ai S31

32 4ai S32

33 4ai' S33

34 4ai' S34

35 4aj S35

36 4aj S36

37 4ak S37

38 4ak S38

39 4am S39

40 4am S40

41 Me 4ba S41

42 Me 4ba S42

43 Me 4ca S43

44 Me 4ca S44

45 Me 4da S45

46 Me 4da S46

47 Cl 4ea S47

48 Cl 4ea S48

49 Cl 4fa S49

50 Cl 4fa S50

51 4ga S51

52 4ga S52

53 4ha S53

54 4ha S54

55 2 4ia S55

56 2 4ia S56

57 4ja S57

58 4ja S58

59 S 4ka S59

60 S 4ka S60

61 Br 4la S61

62 Br 4la S62

63 D S63

64 Ph D D S64

65 Ph D D S65