Direct Aerobic Carbonylation of C(sp 2 )-H and C(sp 3 )-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source

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1 Direct Aerobic Carbonylation of C(sp 2 )-H and C(sp 3 )-H Bonds through Ni/Cu Synergistic Catalysis with DMF as the Carbonyl Source Xuesong Wu, Yan Zhao, and Haibo Ge* Table of Contents General Information... S2 Structures of Starting Materials... S3 Procedure for the Preparation of Starting Materials 3i... S5 Table S1. Optimization of Reaction Conditions a... S6 General Procedure for Carbonylation of Aromatic Amides... S7 General Procedure for Carbonylation of Aliphatic Amides... S7 Analytical Data of Products... S8 13 C Labeled DMF Test... S18 Procedure for the Preparation of Potential Intermediate Compounds (10-13)... S19 Deuterium Labeling Experiments... S24 Parallel KIE Experiments... S26 Procedure for the Derivatization of Succinimides... S27 References... S29 1 H, 13 C and 19 F NMR Spectra... S30 S1

2 General Information 1 H, 13 C and 19 F NMR spectra were recorded on a Bruker 500 MHz NMR Fourier transform spectrometer (500 MHz and 125 MHz, respectively) using tetramethylsilane as an internal reference, and chemical shifts (δ) and coupling constants (J) were expressed in ppm and Hz, respectively. Infrared spectra were obtained using a Thermo Nicolet IR 330 spectrometer. Mass (MS) analysis were abtained using Agilent 1100 series LC/MSD system with Electrospray Ionization (ESI). All the solvents and commercially available reagents were purchased from commercial sources and used directly. Starting materials 1a-o and [D 5 ]-1a were prepared according to literature procedures. 1,2 3a-h, 3j-l, 5-9 and [D 3 ]-3c were prepared based on reported reaction protocol. 3 S2

3 Structures of Starting Materials S3

4 S4

5 Procedure for the Preparation of Starting Materials 3i A mixture of mono-ethyl malonate (0.66 g, 5.0 mmol), 8-aminoquinoline (0.72 g, 5.0 mmol), HOBt H 2 O (0.84 g, 5.5 mmol) and DIPEA (0.71 g, 5.5 mmol) in anhydrous CH 2 Cl 2 (20 ml) was stirred at 0 o C for 15 min. After EDC (1.05 g, 5.5 mmol) was added, the mixture was stirred for another 15 min at 0 o C and 12 h at room temperature. Then water was added and the mixture was extracted with CH 2 Cl 2 (50 ml). The organic layer was washed with water and brine, dried over Na 2 SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/hexane (1:20, v/v), to afford ethyl 3-oxo-3-(quinolin-8-ylamino)propanoate. K 2 CO 3 (1.66 g, 12 mmol) was added dropwise to a solution of ethyl 3-oxo-3- (quinolin-8-ylamino)propanoate (0.90g, 0.35 mmol) in acetone (10 ml). The mixture was set to reflux. Once the reaction had reached refluxe temperature, iodomethane (1.42 g, 10 mmol) was added, and the reaction was allowed to reflux overnight. Then the solvent was reduced to 1/5 of the original volume by evaporation, poured into a beaker containing 20 ml of ice-water, extracted with CH 2 Cl 2 (5 5 ml). The combined organic layers were dried over Na 2 SO 4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/hexane (1:20, v/v), to afford compound 3i in 65% yield over two steps. Compound 3i, colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ (brs, 1H), (m, 2H), 8.12 (dd, J = 8.3, 1.6 Hz, 1H), (m, 3H), 4.29 (q, J = 7.1 Hz, 2H), 1.67 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 173.9, 170.4, 148.4, 138.8, 136.3, 134.5, 127.9, 127.3, 121.8, 121.6, 116.5, 61.8, 51.6, 23.6, 14.0; IR (neat) ν 3325, 3049, 2983, 2939, 1733, 1683, 1538, 1487, 1386, 1269, 1141, 1024, 916, 826, 792, 757; Ms (ESI): m/z = [M+H] +. S5

6 Table S1. Optimization of Reaction Conditions a a Reaction conditions: 1a (0.2 mmol), Ni source (10 mol%), Cu source (20 mol%), base, additive (1.0 equiv), O2 (1 atm), 3.0 ml of solvent, 160 o C, 24 h. b Yields and conversions are based on 1a, determined by 1 H NMR using dibromomethane as the internal standard. c Isolated yields. d At 140 o C. TBAB = tetrabutylammonium bromide. TBAI = tetrabutylammonium iodide. TBAPF6 = tetrabutylammonium hexafluorophosphate. THAB = tetraheptylammonium bromide. Q = 8- quinolinyl. S6

7 General Procedure for Carbonylation of Aromatic Amides A 100 ml Schlenk tube was charged with amide (1, 0.20 mmol), NiI 2 (6.2 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Li 2 CO 3 (5.9 mg, mmol), tetraheptylammonium bromide (98.1 mg, 0.20 mmol), DMF (3.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 24h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml). The organic layer was washed with water (3 20 ml), brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:4 ~ 1:2, v/v), to afford corresponding product 2. General Procedure for Carbonylation of Aliphatic Amides A 100 ml Schlenk tube was charged with amide (1, 0.20 mmol), NiBr 2 (4.4 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Na 2 CO 3 (6.4 mg, mmol), tetrabutylammonium hexafluorophosphate (116 mg, 0.30 mmol), DMF (5.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 24h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml). The organic layer was washed with water (3 20 ml), brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:4 ~ 1:1, v/v), to afford corresponding product 4. S7

8 Analytical Data of Products Compound 2a, 2 white solid, yield: 79%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.6 Hz, 1H), (m, 2H), 7.95 (dd, J = 8.2, 1.3 Hz, 1H), (m, 2H), 7.75 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), 7.43 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 168.1, 151.0, 144.4, 136.3, 134.3, 132.6, 130.3, 129.9, 129.7, 129.4, 126.2, 124.0, Compound 2b, 2 white solid, yield: 85%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.94 (dd, J = 8.2, 1.4 Hz, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.74 (dd, J = 7.3, 1.4 Hz, 1H), 7.66 (dd, J = 8.1, 7.4 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 7.24 (dd, J = 8.3, 2.3 Hz, 1H), 3.94 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.9, 167.8, 165.0, 151.0, 144.5, 136.3, 135.2, 130.4, 130.1, 129.6, 129.4, 126.2, 125.7, 124.5, 122.0, 120.4, 108.4, Compound 2c, 2 white solid, yield: 82%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.20 (dd, J = 8.3, 1.7 Hz, 1H), 7.94 (dd, J = 8.2, 1.3 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.74 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), (m, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 2.55 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 168.3, 168.1, 151.0, 145.6, 144.5, 136.3, 134.9, 132.9, 130.4, 130.1, 130.0, 129.6, 129.4, 126.2, 124.5, 123.9, 122.0, S8

9 Compound 2d, white solid, yield: 62%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.23 (dd, J = 8.3, 1.7 Hz, 1H), (m, 2H), 7.75 (dd, J = 7.3, 1.4 Hz, 1H), (m, 2H), (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.0, (d, J CF = 255 Hz), (d, J CCCCF = 2.8 Hz), 151.1, 144.3, 136.3, (d, J CCCF = 9.5 Hz), 130.3, 129.9, 129.8, 129.4, (d, J CCCCF = 2.8 Hz), (d, J CCCF = 9.3 Hz), 126.3, 122.1, (d, J CCF = 23.5 Hz), (d, J CCF = 24.8 Hz); 19 F NMR (471 MHz, CDCl 3 ) δ ; IR (neat) ν 3072, 2928, 2856, 1782, 1726, 1615,1475, 1398, 1262, 1107, 884, 806, 743; Ms (ESI): m/z = [M+H] +. Compound 2e, 2 white solid, yield: 72%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.23 (dd, J = 8.3, 1.6 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), (m, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.75 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.3, 166.7, 151.1, 144.3, 137.4, 136.4, 134.3, 131.2, 130.3, 129.9, 129.7, 129.5, 129.3, 127.4, 126.3, 125.4, Compound 2f, white solid, yield: 65%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.23 (dd, J = 8.3, 1.7 Hz, 1H), (m, 3H), (m, 1H), (m, 1H), 7.45 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.1, 166.8, 151.1, 144.3, 141.0, 136.3, 134.4, 134.3, 130.7, 130.3, 129.9, 129.7, S9

10 129.5, 126.3, 125.3, 124.4, 122.1; IR (neat) ν 2924, 2854, 1780, 1721, 1396, 1100, 883, 828, 791, 739; Ms (ESI): m/z = [M+H] +. Compound 2g, 2 white solid, yield: 51%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.83 (dd, J = 4.2, 1.7 Hz, 1H), (m, 2H), (m, 2H), 8.01 (dd, J = 8.2, 1.4 Hz, 1H), 7.76 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 166.3, 166.0, 151.2, 144.1, 138.1, 136.4, 135.6, 133.3, (2C), 129.5, 129.3, 127.5, 126.3, 124.8, 122.3, 118.1, Compound 2h, 2 white solid, yield: 55%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.28 (s, 1H), 8.25 (dd, J = 8.3, 1.5 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.00 (dd, J = 8.2, 1.0 Hz, 1H), 7.77 (dd, J = 7.2, 1.1 Hz, 1H), (m, 1H), 7.46 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 166.7, 166.6, 151.2, 144.2, (q, J CCF = 33.1 Hz), 136.4, 135.4, 133.3, (q, J CCCF = 3.5 Hz), 130.3, 130.1, 129.5, 129.4, 126.3, 124.6, (q, J CF = 271 Hz), 122.2, (q, J CCCF = 3.7 Hz). Compound 2i, 2 yellow solid, yield: 52%. 1 H NMR (500 MHz, CDCl 3 ) δ (m, 2H), 8.70 (dd, J = 8.1, 2.0 Hz, 1H), 8.26 (dd, J = 8.3, 1.6 Hz, 1H), 8.20 (d, J = S10

11 8.1 Hz, 1H), 8.01 (dd, J = 8.2, 1.3 Hz, 1H), 7.78 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), 7.47 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 166.0, 165.7, 152.1, 151.2, 144.0, 137.0, 136.4, 134.0, 130.3, 130.2, 129.5, 129.5, 129.3, 126.3, 125.2, 122.3, Compound 2j, 2 white solid, yield: 78%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.21 (dd, J = 8.3, 1.6 Hz, 1H), 7.94 (dd, J = 8.2, 1.4 Hz, 1H), 7.82 (d, J = 7.3 Hz, 1H), 7.73 (dd, J = 7.3, 1.4 Hz, 1H), (m, 2H), 7.54 (d, J = 7.7 Hz, 1H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 2.76 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 168.8, 168.1, 151.1, 144.5, 138.6, 136.7, 136.3, 133.8, 133.0, 130.4, 130.1, 129.6, 129.4, 129.2, 126.2, 122.0, 121.6, Compound 2k, white solid, yield: 90%. 1 H NMR (500 MHz, CDCl 3 ) δ (m, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), (m, 2H), (m, 3H), 7.81 (dd, J = 7.3, 1.4 Hz, 1H), (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 169.3, 168.7, 151.1, 144.7, 136.9, 136.4, 135.3, 131.9, 130.7, 130.1, 129.7, 129.6, 129.5, 128.9, 128.9, 128.5, 127.9, 126.3, 125.4, 122.0, 119.1; IR (neat) ν 2926, 2855, 1773, 1715, 1398, 1110, 830, 796, 766; Ms (ESI): m/z = [M+H] +. S11

12 Compound 2l, 2 yellow solid, yield: 81%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.86 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (s, 2H), 8.23 (dd, J = 8.3, 1.5 Hz, 1H), (m, 2H), 7.98 (dd, J = 8.3, 1.1 Hz, 1H), 7.81 (dd, J = 7.2, 1.2 Hz, 1H), (m, 3H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 167.8, 151.1, 144.4, 136.3, 135.8, 130.5, 130.3, 130.2, 129.8, 129.5, 129.3, 128.3, 126.3, 125.5, Compound 4a, colorless oil, yield: 80%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.18 (dd, J = 8.3, 1.7 Hz, 1H), (m, 1H), (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 2.95 (d, J = 18.0 Hz, 1H), 2.82 (d, J = 18.0 Hz, 1H), 1.61 (s, 3H), 1.50 (s, 3H) ); 13 C NMR (125 MHz, CDCl 3 ) δ 183.1, 175.8, 151.1, 143.8, 136.2, 130.5, 129.7, 129.5, 129.3, 126.2, 122.1, 44.4, 41.1, 26.4, 25.6; IR (neat) ν 2968, 1733, 1712, 1399, 1239, 1154, 908, 829, 793; Ms (ESI): m/z = [M+H] +. Compound 4b, colorless oil, yield: 81%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 1.1:1.0, the minor one is marked with an *) δ (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 2.89 (d, J = 18.2 Hz, 1H), 2.83 (d, J = 18.2 Hz, 1H), (m, 1H), (m, 1H), 1.58 (s, 3H), 1.06 (t, J = 7.5 Hz, 3H); (m, 1H)*, (m, 1H)*, (m, 1H)*, (m, 2H)*, (m, 1H)*, 3.03 (d, J = 18.2 Hz, 1H)*, 2.68 (d, J = 18.2 Hz, 1H)*, (m, 1H)*, (m, 1H)*, 1.47 (s, 3H)*, 1.17 (t, J = 7.5 Hz, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 182.6, 176.1, 150.9, 143.7, 136.1, 130.5, 129.7, 129.4, 129.3, 126.1, 122.0, 45.1, S12

13 41.2, 31.2, 24.5, 9.0; 182.7*, 176.0*, 151.1*, 143.8*, 136.1*, 130.6*, 129.6*, 129.5*, 129.3*, 126.1*, 122.0*, 45.1*, 41.2*, 21.5*, 24.1*, 8.9*; IR (neat) ν 2967, 2930, 1780, 1716, 1399, 1210, 1153, 829, 793; Ms (ESI): m/z = [M+H] +. Compound 4c, colorless oil, yield: 76%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.1, 1.5 Hz, 1H), 8.16 (dd, J = 8.3, 1.5 Hz, 1H), 7.90 (dd, J = 7.9, 1.6 Hz, 1H), (m, 2H), 7.40 (dd, J = 8.3, 4.2 Hz, 1H), 2.94 (d, J = 18.4 Hz, 1H), 2.75 (d, J = 18.4 Hz, 1H), (m, 2H), (m, 2H), 1.17 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 182.0, 176.4, 151.0, 143.8, 136.1, 130.7, 129.7, 129.4, 129.3, 126.1, 122.0, 49.4, 38.0, 30.2, 30.2, 8.8 (2C); IR (neat) ν 2966, 2937, 1780, 1711, 1398, 1201, 1152, 864, 829, 793; Ms (ESI): m/z = [M+H] +. Compound 4d, colorless oil, yield: 73%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 1.0:0.4, the minor one is marked with an *) δ (m, 1H), (m, 1H), 7.90 (dd, J = 8.0, 1.6 Hz, 1H), (m, 2H), (m, 1H), 2.95 (d, J = 18.4 Hz, 1H), 2.77 (d, J = 18.4 Hz, 1H), (m, 6H), 1.16 (t, J = 7.5 Hz, 3H), (m, 3H); (m, 1H)*, (m, 1H)*, 7.90 (dd, J = 8.0, 1.6 Hz, 1H)*, (m, 2H)*, (m, 1H)*, 2.95 (d, J = 18.4 Hz, 1H)*, 2.76 (d, J = 18.4 Hz, 1H)*, (m, 6H)*, (m, 6H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 182.1, 176.4, 151.0, 143.8, 136.1, 130.7, 129.7, 129.4, 129.3, 126.1, 122.0, 49.1, 39.7, 38.6, 30.5, 17.8, 14.7, 8.8; 182.1*, 176.4*, 150.1*, 143.8*, 136.1*, 130.7*, 129.7*, 129.4*, 129.3*, 126.1*, 122.0*, 49.0*, 39.6*, 38.5*, 30.5*, 17.7*, 14.5*, 8.8*; IR (neat) ν 2962, 2933, 2873, 1779, 1712, 1398, 1199, 1149, 884, 828, 793; Ms (ESI): m/z = [M+H] +. S13

14 Compound 4e, white solid, yield: 72%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 1.0:1.0, the minor one is marked with an *) δ (m, 1H), 8.21 (d, J = 8.3 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 1H), 3.40 (d, J = 18.2, 1H), 3.12 (d, J = 18.4 Hz, 1H), 2.01 (s, 3H); (m, 1H)*, 8.21 (d, J = 8.3 Hz, 1H)*, (m, 1H)*, (m, 1H)*, (m, 2H)*, (m, 1H)*, (m, 3H)*, (m, 1H)*, 3.37 (d, J = 18.3 Hz, 1H)*, 3.26 (d, J = 18.1 Hz, 1H)*, 1.93 (s, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 181.1, 175.6, 151.2, 143.8, 142.7, 136.3, 130.5, 129.9, 129.8, 129.4, 129.1, 127.7, 126.5, 126.2, 122.2, 48.9, 46.8, 26.5; 180.8*, 175.6*, 151.1*, 143.8*, 142.3*, 136.2*, 130.5*, 129.9*, 129.5*, 129.3*, 128.9*, 127.6*, 126.2*, 126.0*, 121.2*, 48.7*, 45.7*, 25.2*; IR (neat) ν 3056, 2969, 2926, 1780, 1715, 1398, 1206, 1153, 892, 809, 765, 734, 700, 618; Ms (ESI): m/z = [M+H] +. Compound 4f, yellow oil, yield: 61%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 1.0:0.4, the minor one is marked with an *) δ 8.83 (d, J = 3.9 Hz, 1H), (m, 1H), 7.86 (d, J = 8.3 Hz, 1H), (m, 1H), (m, 6H), 7.14 (d, J = 7.2 Hz, 1H), 3.34 (d, J = 13.3 Hz, 1H), (m, 1H), (m, 2H), 1.69 (s, 3H); 8.77 (d, J = 3.9 Hz, 1H)*, (m, 1H)*, (m, 1H)*, (m, 2H)*, (m, 6H)*, 3.40 (d, J = 13.7 Hz, 1H)*, 3.17 (d, J = 18.1 Hz, 1H)*, (m, 1H)*, 2.55 (d, J = 18.1 Hz, 1H)*, 1.51 (s, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 182.0, 175.5, 151.1, 143.8, 136.5, 136.1, 130.7, 130.2, 129.7, 129.4, 128.8, 128.6, 127.5, 126.1, 122.0, 46.2, 44.1, 40.4, 25.8; 182.4*, 175.7*, 150.9*, 143.7*, 136.5*, 136.1*, 130.4*, 130.3*, 129.7*, 129.4*, 129.3*, 129.2*, 127.1*, 126.1*, 122.0*, 45.8*, 43.3*, 40.8*, 24.9*; S14

15 IR (neat) ν 3028, 2967, 2928, 1780, 1713, 1399, 1197, 829, 793, 736, 704, 668; Ms (ESI): m/z = [M+H] +. Compound 4g, white solid, yield: 70%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 1.5:1.0, the minor one is marked with an *) δ 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.16 (dd, J = 8.2, 1.2 Hz, 1H), (m, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 2H), (m, 4H), (m, 4H), 1.07 (t, J = 7.4 Hz, 3H); 8.84 (dd, J = 4.2, 1.7 Hz, 1H)*, 8.16 (dd, J = 8.2, 1.2 Hz, 1H)*, (m, 1H)*, (m, 2H)*, (m, 1H)*, (m, 3H)*, (m, 2H)*, (m, 4H)*, (m, 4H)*, 1.19 (t, J = 7.4 Hz, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 181.7, 176.1, 151.0, 143.7, 142.0, 136.1, 130.6, 129.8, 129.5, 129.3, 128.6, 128.5, 126.4, 126.1, 122.1, 49.1, 39.4, 38.6, 30.9, 30.4, 8.8; 181.7*, 176.1*, 151.0*, 143.7*, 141.1*, 136.1*, 130.6*, 129.7*, 129.5*, 129.3*, 128.7*, 128.5*, 126.4*, 126.1*, 122.0*, 48.9*, 39.2*, 38.6*, 30.9*, 30.5*, 8.8*; IR (neat) ν 3025, 2965, 2934, 1778, 1712, 1398, 1192, 828, 793, 755, 701, 668; Ms (ESI): m/z = [M+H] +. Compound 4h, colorless oil, yield: 63%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 3.0:1.0, the minor one is marked with an *) δ 8.84 (dd, J = 4.2, 1.6 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 3.32 (d, J = 18.4 Hz, 1H), 2.99 (d, J = 18.4 Hz, 1H), 1.86 (s, 3H); 8.87 (dd, J = 4.0, 1.4 Hz, 1H)*, (m, 1H)*, (m, 2H)*, (m, 1H)*, (m, 1H)*, 3.46 (d, J = 18.4 Hz, 1H)*, 2.84 (d, J = 18.4 Hz, 1H)*, 1.75 (s, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ (q, J CCCF = 1.8 Hz), 173.0, 151.2, 143.3, 136.4, 130.2, 129.7, 129.5, 129.3, 126.2, (q, J CF = 280 Hz), 122.2, 49.8 (q, J CCF = 27.6 Hz), 38.1, 19.0 (q, J CCCF = 2.0 Hz); (q, J CCCF S15

16 = 1.8 Hz)*, 172.9*, 151.4*, 143.4*, 136.0*, 130.2*, 129.6*, 129.3*, 129.1*, 126.0*, (q, J CF = 280 Hz)*, 122.2*, 49.6 (q, J CCF = 28.3 Hz)*, 38.1*, 19.2 (q, J CCCF = 1.5 Hz)*; IR (neat) ν 3055, 2993,2850, 1796, 1727, 1403, 1196, 1116, 846, 829, 793; Ms (ESI): m/z = [M+H] +. Compound 4i, yellow oil, yield: 66%. 1 H NMR (500 MHz, CDCl 3, a mixture of atropisomers in ration 2.6:1.0, the minor one is marked with an *) δ (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.42 (d, J = 18.0 Hz, 1H), 2.97 (d, J = 18.0 Hz, 1H), 1.84 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); (m, 1H)*, (m, 1H)*, (m, 1H)*, (m, 2H)*, (m, 1H)*, 4.31 (q, J = 7.1 Hz, 2H)*, 3.66 (d, J = 18.0 Hz, 1H)*, 2.81 (d, J = 18.1 Hz, 1H)*, 1.76 (s, 3H)*, 1.34 (t, J = 7.1 Hz, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 176.3, 174.7, 170.5, 151.2, 143.6, 136.3, 130.1, 130.0, 129.5, 129.4, 126.2, 122.2, 62.6, 51.7, 41.7, 21.1, 14.2; 176.0*, 174.5*, 170.0*, 151.0*, 143.7*, 136.1*, 130.1*, 130.0*, 129.5*, 129.4*, 126.1*, 123.4*, 62.6*, 51.6*, 41.4*, 21.5*, 14.2*; IR (neat) ν 2964, 2877, 1719, 1717, 1474, 1400, 1234, 1133, 877, 841, 796; Ms (ESI): m/z = [M+H] +. Compound 4j, colorless oil, yield: 83%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), (m, 1H), (m, 2H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), 2.99 (d, J = 18.0 Hz, 1H), 2.85 (d, J = 18.0 Hz, 1H), (m, 1H), (m, 1H), (m, 3H), (m, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 183.1, 176.1, 151.1, 143.7, 136.1, 130.6, 129.7, 129.5, 129.3, 126.1, 122.0, 51.2, 44.4, 39.1, 38.3, 25.5, 25.5; IR (neat) ν 3050, 2954, 2873, 1778, 1712, 1397, 1191, 830, 794, 734; Ms (ESI): m/z = [M+H] +. S16

17 Compound 4k, colorless oil, yield: 69%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.17 (dd, J = 8.3, 1.5 Hz, 1H), (m, 1H), (m, 2H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), 2.98 (d, J = 18.1 Hz, 1H), 2.80 (d, J = 18.1 Hz, 1H), (m, 3H), (m, 2H), (m, 2H), (m, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ 182.8, 176.2, 151.1, 143.8, 136.1, 130.5, 129.7, 129.5, 129.3, 126.1, 122.0, 45.9, 40.8, 33.9, 33.6, 25.2, 22.4, 22.3; IR (neat) ν 3050, 2932, 2857, 1780, 1711, 1398, 1198, 829, 793, 733; Ms (ESI): m/z = [M+H] +. Compound 4l, colorless oil, yield: 62%. 1 H NMR (500 MHz, CDCl 3 ) δ 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), (m, 1H), (m, 2H), 7.41 (dd, J = 8.3, 4.2 Hz, 1H), 2.96 (d, J = 18.0 Hz, 1H), 2.81 (d, J = 18.0 Hz, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 183.6, 176.2, 151.1, 143.9, 136.2, 130.4, 129.7, 129.5, 129.3, 126.1, 122.0, 48.3, 42.8, 37.7, 37.5, 29.0 (2C), 23.9, 23.8; IR (neat) ν 3051, 2925, 2856, 1778, 1712, 1399, 1217, 1180, 828, 793, 734; Ms (ESI): m/z = [M+H] +. S17

18 13 C Labeled DMF Test A 100 ml Schlenk tube was charged with 1a (24.8 mg, 0.10 mmol), NiI 2 (3.1 mg, mmol), Cu(acac) 2 (5.2 mg, mmol), Li 2 CO 3 (2.9 mg, mmol), tetraheptylammonium bromide (49.0 mg, 0.10 mmol), DMF-(carbonyl- 13 C) (0.40 ml, purchased from Aldrich) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 24h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (15 ml). The organic layer was washed with water (3 10 ml), brine (5 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:4 ~ 1:2, v/v), to afford 14.0 mg of [ 13 C]-2a (51% yield). The percent 13 C incorporation of [ 13 C]-2a were calculated from the integrated resonances detected by inverse gated decoupling 13 C NMR comparing with 2a. Compound 2a. Inverse gated decoupling 13 C NMR (125 MHz, CDCl 3 ) δ (int. = 0.82), (int. = 1.00). Natural abundance of 13 C: 1.1%. Compound [ 13 C]-2a. Inverse gated decoupling 13 C NMR (125 MHz, CDCl 3 ) δ (int. = 2.09), (int. = 1.00). 3.4% of 13 C incorporated. S18

19 Procedure for the Preparation of Potential Intermediate Compounds (10-13) A solution of compound S1 (1.65 g, 10 mmol, prepared from 2-carboxybenzaldhyde according to literature procedures 4 ) in a mixture of 1,4-dioxane (30 ml) and 1M aq. NaOH (40 ml) was added di-tert-butyldicarbonate (4.37 g, 20 mmol). The resulting solution was stirred at room temperature for 2h. Then 1,4-dioxane was removed under reduced pressure and ph was adjusted to 3 by the addition of 1N HCl. The aqueous phase was extracted with EtOAc (3 50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the compound S2, which was used directly for the next step without further purification. To a 100mL flask was added compound S2 (2.39 g, 9.0 mmol), 8-aminoquinoline (1.30 g, 9.0 mmol), DCC (2.16 g, 10.8 mmol), DMAP (0.36 g, 2.7 mmol) and dry CH 2 Cl 2 (30 ml). The mixture was stirred at room temperature for 12h. Then the reaction mixture was diluted by CH 2 Cl 2 (60 ml) and filtered. The filtrate was concentrated under reduced pressure to give compound S3. The crude compound S3 was dissolved in CH 2 Cl 2 (60 ml). Then TFA (15 ml) was added. After stirring at room temperature for 4h, the mixture was concentrated to dryness, diluted with CH 2 Cl 2, washed with saturated aq. NaHCO 3 and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH/Et 3 N (100:1:0.5, v/v), to afford 1.49 g of compound 13. S19

20 Compound 13, white solid, yield: 57%. 1 H NMR (500 MHz, CDCl 3 ) δ (brs, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 4H), 3.92 (s, 2H), 2.45 (s, 3H), 2.04 (brs, 1H); 13 C NMR (125 MHz, CDCl 3 ) δ 168.1, 148.4, 139.5, 138.0, 137.2, 136.4, 135.6, 130.9, 130.7, 129.2, 128.4, 127.9, 127.5, 122.3, 121.6, 118.2, 54.7, 36.1; IR (neat) ν 3462, 3334, 3035, 2915, 1685, 1116, 1506, 1475, 1371, 821, 792, 734; Ms (ESI): m/z = [M+H] +. A mixture of formic acid (0.19 ml, 5.0 mmol) and acetic anhydride (0.47 ml, 5.0 mmol) was stirred at 50 o C for 1h. After cooling to room temperature, sodium formate (102 mg, 1.5 mmol) and compound 13 (291 mg, 1.0 mmol) were added in two portions and then the resulting mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated aq. NaHCO 3 and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:20 ~ 1:4, v/v), to afford 272 mg (85%) of compound 10. S20

21 Compound 10, colorless oil, yield: 85%. 1 H NMR (500 MHz, CDCl 3, a mixture of rotamers in ration 2.0:1.0, the minor one is marked with an *) δ (brs, 1H), (m, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.27 (s, 1H), (m, 1H), 7.81 (dd, J = 7.5, 1.3 Hz, 1H), (m, 5H), 7.34 (d, J = 7.6 Hz, 1H), 4.83 (s, 2H), 2.82 (s, 3H); (brs, 1H)*, (m, 1H)*, 8.80 (dd, J = 4.2, 1.6 Hz, 1H)*, (m, 2H)*, 7.74 (dd, J = 7.5, 1.3 Hz, 1H)*, (m, 6H)*, 4.92 (s, 2H)*, 2.95 (s, 3H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 167.1, 163.7, 148.5, 138.7, 136.6, 136.0, 135.9, 134.5, 131.2, 128.9, 128.4, 128.2, 127.8, 127.6, 122.4, 121.9, 116.8, 51.0, 29.8; 167.5*, 163.1*, 148.6*, 138.7*, 136.6*, 136.5*, 135.6*, 134.7*, 131.2*, 129.4*, 128.2*, 127.9*, 127.5*, 127.3*, 122.3*, 121.9*, 116.7*, 44.8*, 34.7*; IR (neat) ν 3343, 2922, 1669, 1523, 1481, 1386, 826, 791, 730; Ms (ESI): m/z = [M+H] +. Compound 13 (582 mg, 2.0 mmol) was dissolved in CH 2 Cl 2 (10 ml). Formaldehyde (37% in water, 0.45 ml, 6.1 mmol) was added, followed by acetic acid (0.12 ml, 2.1 mmol) and sodium triacetoxyborohydride (1.27 g, 6.0 mmol). After stirring for 12h at room temperature, the reaction mixture was diluted with CH 2 Cl 2 (50 ml), washed with saturated aq. NaHCO 3 and brine, dried over anhydrous manganese sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH/Et 3 N (100:1:0.5, v/v), to afford 348 mg (57%) of compound 12. S21

22 Compound 12, colorless oil, yield: 57%. 1 H NMR (500 MHz, CDCl 3 ) δ (brs, 1H), 8.93 (dd, J = 7.5, 0.9 Hz, 1H), 8.79 (dd, J = 4.1, 1.6 Hz, 1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), (m, 1H), (m, 2H), (m, 4H), 3.69 (s, 2H), 2.27 (s, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 168.2, 148.4, 139.9, 138.1, 136.3, 135.9, 135.5, 131.5, 130.4, 130.1, 128.4, 128.2, 127.4, 122.3, 121.5, 118.6, 62.0, 44.6; IR (neat) ν 2944, 2858, 2818, 2772, 1660, 1525, 1482, 1324, 826, 791, 747; Ms (ESI): m/z = [M+H] +. A mixture of formic acid (0.95 ml, 25 mmol) and acetic anhydride (2.35 ml, 25 mmol) was stirred at 50 o C for 1h. After cooling to room temperature, sodium formate (0.51 g, 7.5 mmol) and compound S4 (0.76 g, 5.0 mmol, prepared from phthalide according to literature procedures 5 ) were added in two portions and then the resulting mixture was stirred at room temperature for 4h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 3N HCl (3 ml) and extracted with EtOAc (15 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4, and then concentrated to dryness under reduced pressure to afford 0.80 g of compound S5, which was used directly for the next step without further purification. To a solution of the crude compound S5 (0.80 g, ~4.5 mmol) in dry THF (15 ml) at 0 o C were added N-methylmorpholine (0.51 ml, 4.6 mmol) and isobutyl chloroformate (0.59 ml, 4.5 mmol). After strring for 30 min, 8-aminoquinoline (0.65 g, 4.5 mmol) was added. The reaction mixture was stirred for 6h at room temperature, and then concentrated under reduced pressure. The residue was diluted with EtOAc, washed with water, brine, dried over Na 2 SO 4, and then under reduced S22

23 pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:5 ~ 1:1, v/v), to afford 151 mg (11%) of compound 11. Compound 11, white solid, yield: 11%. 1 H NMR (500 MHz, CDCl 3, a mixture of rotamers in ration 9:1, the minor one is marked with an *) δ (brs, 1H), 8.87 (dd, J = 6.6, 2.3 Hz, 1H), 8.82 (dd, J = 4.2, 1.6 Hz, 1H), (m, 2H), (m, 1H), (m, 3H), (m, 3H), 7.24 (brs, 1H), 4.62 (d, J = 6.5 Hz, 2H); (brs, 1H)*, 8.87 (dd, J = 6.6, 2.3 Hz, 1H)*, 8.82 (dd, J = 4.2, 1.6 Hz, 1H)*, (m, 2H)*, (m, 1H)*, (m, 3H)*, (m, 3H)*, 7.24 (brs, 1H)*, 4.59 (d, J = 6.7 Hz, 2H)*; 13 C NMR (125 MHz, CDCl 3 ) δ 168.0, 162.8, 148.6, 138.8, 138.0, 136.6, 135.9, 134.5, 132.3, 131.8, 128.4, 128.2, 127.5, 127.4, 122.5, 122.0, 116.8, 40.9; 167.2*, 164.1*, 148.6*, 138.8*, 138.0*, 135.5*, 134.5*, 133.9*, 131.9*, 131.8*, 128.7*, 128.2*, 127.8*, 127.5*, 122.4*, 122.0*, 116.9*, 45.1*; IR (neat) ν 3351, 3289, 2922, 1657, 1532, 1488, 1384, 826, 793, 752, 668; Ms (ESI): m/z = [M+H] +. S23

24 Deuterium Labeling Experiments A 100 ml Schlenk tube was charged with amide [D 5 ]-1a (50.6mg, 0.20 mmol), NiI 2 (6.2 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Li 2 CO 3 (5.9 mg, mmol), tetraheptylammonium bromide (98.1 mg, 0.20 mmol), DMF (3.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 24h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml). The organic layer was washed with water (3 20 ml), brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:20 ~ 1:2, v/v), to give the desired product [D 4 ]-2a (13.3 mg, 24%) and recovered [D 5 ]-1a (34.8 mg, 69%). The ratio of deuterium was determined by 1 H NMR. [D 4 ]-2a, 1 H NMR (500 MHz, CDCl 3 ) δ 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.22 (dd, J = 8.3, 1.7 Hz, 1H), 8.00 (s, 0.45H), 7.96 (dd, J = 8.2, 1.4 Hz, 1H), 7.75 (dd, J = 7.3, 1.4 Hz, 1H), (m, 1H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H). Recovered [D 5 ]-1a, 1 H NMR (500 MHz, CDCl 3 ) δ (brs, 1H), 8.95 (dd, J = 7.6, 1.2 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.17 (dd, J = 8.3, 1.6 Hz, 1H), 8.10 (s, 1.32H), (m, 1H), 7.54 (dd, J = 8.2, 1.2 Hz, 1H), 7.47 (dd, J = 8.2, 4.2 Hz, 1H). S24

25 A 100 ml Schlenk tube was charged with amide [D 3 ]-3c (51.8 mg, 0.20 mmol), NiBr 2 (4.4 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Na 2 CO 3 (6.4 mg, mmol), tetrabutylammonium hexafluorophosphate (116 mg, 0.30 mmol), DMF (5.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 6h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml). The organic layer was washed with water (3 20 ml), brine (10 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:20 ~ 1:2, v/v), to give the desired product [D 2 ]-4c (9.7 mg, 17%) and recovered [D 3 ]-3c (39.8 mg, 77%). The ratio of deuterium was determined by 1 H NMR. [D 2 ]-4c, 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.7 Hz, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), (m, 0.22H), (m, 0.22H), (m, 2H), (m, 2H), 1.17 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.5 Hz, 3H). Recovered [D 3 ]-3c, 1 H NMR (500 MHz, CDCl 3 ) δ (s, 1H), (m, 2H), 8.15 (dd, J = 8.3, 1.6 Hz, 1H), (m, 3H), (m, 2H), (m, 2H), (m, 0.07H), 0.94 (t, J = 7.5 Hz, 6H). A 100 ml Schlenk tube was charged with amide [D 2 ]-4c (78% D, 9.5 mg), NiBr 2 (4.4 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Na 2 CO 3 (6.4 mg, mmol), tetrabutylammonium hexafluorophosphate (116 mg, 0.30 mmol), DMF (5.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C for 12h. Then the reaction mixture was cooled to room temperature, diluted with EtOAc (30 ml). The organic layer was washed with water (3 20 ml), brine (10 ml), dried over anhydrous sodium sulfate, and S25

26 concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/Hexane (1:4 ~ 1:2, v/v), to give the recovered 4c-1 (8.6 mg, 90% yield). The ratio of deuterium was determined by 1 H NMR. 4c-1, 1 H NMR (500 MHz, CDCl 3 ) δ 8.84 (dd, J = 4.1, 1.7 Hz, 1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.91 (dd, J = 8.1, 1.5 Hz, 1H), (m, 2H), 7.42 (dd, J = 8.3, 4.2 Hz, 1H), 2.94 (d, J = 18.4 Hz, 1.00H), 2.75 (d, J = 18.4 Hz, 1.00H), (m, 2H), (m, 2H), 1.17 (t, J = 7.5 Hz, 3H), 1.06 (t, J = 7.4 Hz, 3H). Parallel KIE Experiments A 100 ml Schlenk tube was charged with amide 3c (51.2 mg, 0.20 mmol) or [D 3 ]- 3c (51.8 mg, 0.20 mmol), NiBr 2 (4.4 mg, mmol), Cu(acac) 2 (10.5 mg, mmol), Na 2 CO 3 (6.4 mg, mmol), tetrabutylammonium hexafluorophosphate (116 mg, 0.30 mmol), DMF (5.0 ml) and two magnetic stir bars. The tube was evacuated and filled with O 2 (1 atm), and stirred rigorously at 160 C. The reaction was stopped by rapid cooling in the indicated reaction period, and analyzed by GC using benzophenone as the internal standard. The GC yield was calculated after calibrating the response of GC. Time (min) Yield of 4c (%) Time (min) Yield of 4c (%) Time (min) Yield of [D2]-4c (%) Time (min) Yield of [D2]-4c (%) S26

27 15 10 Yield (%) 5 0 4c [D 2 ]-4c 4c [D 2 ]-4c Time (min) Equation for 4c: y = x R 2 = Equation for [D 2 ]-4c: y = x R 2 = k H /k D = / KIE value determined from parallel reactions is 2.1. Procedure for the Derivatization of Succinimides A 25 ml Schlenk tube was charged with 4j (42.0 mg, 0.15 mmol), trifluoroacetic acid (1.0 ml) and conc. HCl (1.0 ml). The reaction mixture was stirred at 120 o C for 36h. After cooling to room temperature, the reaction mixture was concentered under reduced pressure to remove trifluoroacetic acid. The residue was diluted with 3N HCl (2 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine, dried over Na 2 SO 4, and then evaporated in vacuo to afford 21.9 mg of the carboxylic acid 14. S27

28 Compound 14, 6 white solid, yield: 85%. 1 H NMR (500 MHz, DMSO-d 6 ) δ (brs, 2H), (m, 2H), (m, 2H), (m, 6H); 13 C NMR (125 MHz, DMSO-d 6 ) δ 178.0, 172.8, 49.9, 42.5, 36.1, A solution of 4j (42.0 mg, 0.15 mmol) and MeONa (12.4 mg, 0.23 mmol) in MeOH (1 ml) was stirred for 12h at room temperature. The reaction mixture was diluted with EtOAc (10 ml). The organic layer was washed with saturated aqueous NaHCO 3, brine, dried over Na 2 SO 4, and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/hexane (1:20, v/v), to afford 34.6 mg of compound 15. Compound 15, pale yellow solid, yield: 74%. 1 H NMR (500 MHz, CDCl 3 ) δ 9.85 (brs, 1H), 8.80 (dd, J = 4.2, 1.7 Hz, 1H), 8.75 (dd, J = 7.1, 1.9 Hz, 1H), 8.15 (dd, J = 8.3, 1.7 Hz, 1H), (m, 2H), 7.44 (dd, J = 8.3, 4.2 Hz, 1H), 3.76 (s, 3H), 2.97 (s, 2H), (m, 2H), (m, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ 177.7, 169.7, 148.2, 138.6, 136.5, 134.7, 128.1, 127.6, 121.7, 121.5, 116.8, 52.4, 51.8, 46.4, 36.9, 25.4; IR (neat) ν 3348, 2951, 2870, 1732, 1687, 1525, 1485, 1324, 1165, 827, 792, 757; Ms (ESI): m/z = [M+H] +. S28

29 A 5 ml flask was charged with 2l (48.6 mg, 0.15 mmol) and ammonia in MeOH (2M, 1.5 ml). The reaction mixture was stirred at room temperature for 12h, and then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/hexane (1:5, v/v), to afford 23.2 mg of compound 16. Compound 16, 7 white solid, yield: 78%. 1 H NMR (500 MHz, DMSO-d 6 ) δ (brs, 1H), 8.46 (s, 2H), (m, 2H), (m, 1H); 13 C NMR (125 MHz, DMSO-d 6 ) δ 168.9, 135.1, 130.3, 129.1, 128.8, References 1. (a) Nichino, M.; Hirano, K.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, (b) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53, (c) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, (a) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, (b) Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem., Int. Ed. 2014, 53, (c) Wu, X.; Zhao, Y.; Ge, H. Chem. Eur. J. 2014, 20, Seio, K.; Utagawa, E.; Sekine, M. Helvetica Chimica Acta 2004, 87, Lattuada, L.; Cappelletti, E.; Linder, K. E.; Nunn, A. D. US Patent , Oct 13, Obniska, J.; Kaminski, K. Acta Poloniae Pharmaceutica 2006, 63, Coyle, J. D.; Smart, L. E.; Challiner, J. F.; Haws, E. J. J. Chem. Soc., Perkin Trans. 1, 1985, 121. S29

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