Supporting Information for. Catalytic C H α-trifluoromethylation of α,β-unsaturated Carbonyl Compounds

Supporting Information for Catalytic C H α-trifluoromethylation of α,β-unsaturated Carbonyl Compounds Zhongxue Fang, a Yongquan Ning, a Pengbing Mi, a Peiqiu Liao, a Xihe Bi* a,b a Department of Chemistry, Northeast Normal University, Changchun 130024, China. b State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China. E-mail: bixh507@nenu.edu.cn Contents I. General information..s2 II. Synthesis and spectra data of compounds 3, 5, 7 and drug derivatives..s2-s7 III. Crystallography..S8-S13 IV. NMR spectra copies S14-S47 S1

I. General information All reagents were purchased from commercial sources and used without treatment, unless otherwise indicated. The products were purified by column chromatography over silica gel. 1 H-NMR, 13 C-NMR and 19 F NMR spectra were recorded at 25 ºC on a Varian 500 MHz, 125 MHz and 470.2 MHz, respectively, and TMS was used as internal standard. Mass spectra were recorded on BRUKER AutoflexIII Smartbeam MS-spectrometer. High resolution mass spectra (HRMS) were recorded on Bruck microtof by using ESI method. II. Synthesis and spectra data of compounds 3, 5, 7 and drug derivatives Typical synthetic procedure (with 3a as an example): Togni reagent (474 mg, 1.5 mmol) and CuI (19 mg, 0.1 mmol) was added into a flame-dried vial with a magnetic stir bar, and then sealed with a septum. After the vial was evacuated and backfilled with N 2 for three times, 2a (238 mg, 1.0 mmol) in DMF (2.0 ml) was then added via syringe. The reaction mixture was heated to 80 o C and stirred for 26 h until the disappearance of substrate 2a as indicated by TLC. The resulting mixture was concentrated and the residue was taken up in DCM. The organic layer was washed with brine, dried over MgSO 4 and concentrated. Purification of the crude product by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 100:1) to afford the product 3a (238 mg, 78%) as yellowish liquid. (3a) Yellowish liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.94-7.90 (m, 2H), 7.52 (t, J = 7.5 Hz, 1H), 7.43-7.41 (m, 1H), 7.41-7.34 (m, 2H), 7.21-7.16 (m, 2H), 6.73-6.68 (m, 2H), 3.72 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 193.1, 161.0, 136.4 (q, J = 5.9 Hz), 135.5, 134.2, 131.5, 129.6, 128.7, 126.2 (q, J = 30.0 Hz),124.4, 123.6 (q, J = 272.5 Hz), 114.1, 55.2; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.1 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 14 F 3 O 2 [M+H] + : 307.0946, found 307.0950. (3b) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.93-7.85 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 (s, 1H), 7.37 (m, J = 7.5 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 2.24 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 192.9, 140.6, 136.8 (q, J = 5.9 Hz), 135.4, 134.2, 129.66, 129.63, 129.4, 129.1, 128.7, 127.6 (q, J = 30.0Hz), 123.4 (q, J = 272.8 Hz), 21.3; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.3 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 14 F 3 O [M+H] + : 291.0997, found 291.0994. S2

(3c) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.89 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.39 (t, J = 7.5 Hz, 2H), 7.21-7.14 (m, 4H); 13 C-NMR (CDCl 3, 125 MHz) δ 192.3, 136.2, 135.4 (q, J = 5.9 Hz), 135.1, 134.5, 130.7, 130.3, 129.5, 129.0, 128.9, 128.8, 123.1 (q, J = 272.8 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.6 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 11 ClF 3 O [M+H] + : 311.0451, found 311.0449. O F 3 C Ph F (3d) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.89 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.45 (s, 1H), 7.37 (t, J = 8.0 Hz, 2H), 7.26-7.20 (m, 2H), 6.88 (t, J = 8.5 Hz, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 192.5, 164.4 (d, J = 250.8 Hz), 135.6 (q, J = 6.0 Hz), 135.2, 134.4, 131.6 (d, J = 8.5 Hz), 129.5, 128.8, 128.1 (d, J = 3.5 Hz), 123.2 (q, J = 272.8 Hz), 116.0 (d, J = 21.8 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.6 (s, 3F), -111.04--111.07 (m, 1F); HRMS (ESI) m/z calculated for C 16 H 11 F 4 O [M+H] + : 295.0746, found 295.0756. (3e) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 8.02 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.32 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 3.5 Hz, 1H), 6.95-6.91 (m, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 192.3, 135.5, 134.7, 134.5, 132.8, 130.7, 129.7, 128.9, 128.8 (q, J = 6.3 Hz), 127.6, 125.7 (q, J = 31.0 Hz), 123.4 (q, J = 272.1 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -63.8 (s, 3F); HRMS (ESI) m/z calculated for C 14 H 10 F 3 OS [M+H] + : 283.0404, found 283.0404. (3f) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.91-7.86 (m, 2H), 7.53-7.48 (m, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.26-7.22 (m, 2H), 7.22-7.16 (m, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 192.6, 136.9 (q, J = 5.9 Hz), 135.4, 134.2, 131.9, 130.1, 129.6, 129.5, 128.8, 128.7, 128.6, 123.3 (q, J = 272.9, Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.5 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 12 F 3 O [M+H] + : 277.0840, found 277.0835. S3

(3g) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.82 (d, J = 8.5 Hz, 2H), 7.52 (s, 1H), 7.34 (d, J = 8.5 Hz, 2H), 7.28-7.18 (m, 5H); 13 C-NMR (CDCl 3, 125 MHz) δ 191.4, 140.9, 137.3 (q, J = 5.9 Hz), 133.7, 131.7, 130.8, 130.3, 129.4, 129.1, 128.8, 128.3 (q, J = 30.0 Hz), 123.2 (q, J = 272.9 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.4 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 11 ClF 3 O [M+H] + : 311.0451, found 311.0435. (3h) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.89 (d, J = 9.0 Hz, 2H), 7.42 (s, 1H), 7.29-7.25 (m, 2H), 7.24-7.17 (m, 3H), 6.84 (d, J = 9.0 Hz, 2H), 3.80 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 190.9, 164.5, 136.0 (q, J = 5.9 Hz), 132.1, 130.0, 129.5, 129.0 (q, J = 29.0 Hz), 128.6, 128.5, 123.4 (q, J = 273.8 Hz), 114.0, 55.4; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.6 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 14 F 3 O 2 [M+H] + : 307.0946, found 307.0951. (3i) Yellow solid, m.p. 138-139 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.84 (d, J = 8.5 Hz, 2H), 7.43 (s, 1H), 7.28-7.17 (m, 5H), 6.79 (d, J = 8.0 Hz, 2H), 6.03 (s, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 191.5, 161.5, 136.4 (q, J = 5.8 Hz), 132.7, 132.6, 131.9, 130.1, 129.5, 128.7, 128.5, 128.4, 123.3 (q, J = 272.7 Hz), 115.7; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.6 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 12 F 3 O 2 [M+H] + : 293.0789, found 293.0786. (3j) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.68-7.64 (m, 1H), 7.53 (d, J = 3.5 Hz, 1H), 7.46 (s, 1H), 7.35-7.32 (m, 2H), 7.30-7.22 (m, 3H), 6.99-6.96 (m, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 184.2, 142.9, 136.9 (q, J = 5.8 Hz), 136.3, 135.6, 132.0, 130.2, 129.5, 128.9, 128.7, 128.4, 123.2 (q, J = 272.8); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.7 (s, 3F); HRMS (ESI) m/z calculated for C 14 H 10 F 3 OS [M+H] + : 283.0404, found 283.0398. O F 3 C Ph S4

(3k) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.45-7.36 (m, 4H), 7.34-7.30 (m, 2H), 2.21 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 199.2, 137.1 (q, J = 6.0 Hz), 132.2, 131.7 (q, J = 30.0 Hz), 131.4, 130.4, 129.1, 128.9, 123.1 (q, J = 272.6 Hz), 31.1; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -65.4 (s, 3F); HRMS (ESI) m/z calculated for C 11 H 10 F 3 O [M+H] + : 215.0684, found 215.0682. (3l) Yellow solid, m.p. 104-105 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 8.20-8.15 (m, 1H), 8.14-8.09 (m, 1H), 7.88-7.80 (m, 2H), 7.30 (s, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 183.4, 179.6, 136.9 (q, J = 6.0 Hz), 136.7 (q, J = 30.0 Hz), 136.4, 134.8, 134.6, 131.6, 131.4, 127.0, 126.5, 121.8 (q, J = 273.8 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -67.4 (s, 3F); HRMS (ESI) m/z calculated for C 11 H 6 F 3 O 2 [M+H] + : 227.0320, found 227.0312. O CF 3 N Ph Ph (3m) Yellow solid, m.p. 259-260 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 8.54 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.41 (t, J = 7.0 Hz, 1H), 7.34-7.27 (m, 3H), 7.19-7.15 (m, 3H), 7.13-7.08 (m, 2H), 7.08-7.04 (m, 2H), 6.71 (d, J = 8.5 Hz, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 174.6, 154.0, 141.8, 138.3, 133.2, 132.7, 130.1, 129.5, 129.08, 129.01, 128.7, 127.5, 126.5, 126.3, 124.9, 122.6 (q, J = 272.3 Hz), 118.4, 111.8 (q, J = 27.5 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -57.0 (s, 3F); HRMS (ESI) m/z calculated for C 22 H 15 F 3 NO [M+H] + : 366.1106, found 366.1109. (3n) Yellow solid, m.p. 127-128 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.83 (d, J = 8.5 Hz, 2H), 7.37 (s, 1H), 7.20-7.15 (m, 4H), 6.82 (d, J = 9.0 Hz, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 191.0, 161.2, 136.2, 134.9 (q, J = 5.8 Hz), 132.5, 130.7, 130.4, 129.0, 128.9 (q, J = 24.0 Hz), 128.2, 123.2 (q, J = 273.0 Hz), 115.9; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.7 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 11 ClF 3 O 2 [M+H] + : 327.0400, found 327.0397. S5

(5a) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.60-7.58 (m, 1H), 7.52-7.48 (m, 2H), 7.45-7.40 (m, 3H), 7.39-7.34 (m, 2H), 7.26-7.21 (m, 1H), 7.05-7.00 (m, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 161.7, 149.9, 141.5 (q, J = 5.6 Hz), 132.1, 130.6, 129.5, 129.3, 128.7, 128.3, 126.3, 123.2 (q, J = 31.5 Hz), 121.0 (q, J = 273.8 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -65.5 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 12 F 3 O 2 [M+H] + : 293.0789, found 293.0789. (5b) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.76 (s, 1H), 7.11-7.66 (m, 2H), 7.62 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 7.28-7.22 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 161.0, 149.7, 140.3 (q, J = 5.6 Hz), 132.9, 132.2, 131.4 (q, J = 32.0 Hz), 129.6, 129.3, 127.1 (q, J = 3.6 Hz), 126.5, 125.9 (q, J = 3.6 Hz), 124.6 (q, J = 273.0 Hz), 122.8 (q, J = 274.0 Hz), 120.9; 9 F-NMR (470.2 MHz, CDCl 3 ) δ -64.7 (s, 3F), -65.8 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 11 F 6 O 2 [M+H] + : 361.0663, found 361.0656. (5c) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.53 (s, 1H), 7.48-7.43 (m, 2H), 7.42-7.37 (m, 4H), 7.28-7.24 (m, 1H), 7.07-7.03 (m, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 161.4, 149.8, 140.7 (q, J = 5.6 Hz), 136.8, 130.7, 130.4, 129.6, 129.08, 129.02, 126.5, 123.5 (q, J = 32.0 Hz), 123.0 (q, J = 272.4 Hz), 121.0; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -65.5 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 11 ClF 3 O 2 [M+H] + : 327.0400, found 327.0392. (5d) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.52 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.27-7.19 (m, 3H), 7.07 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 161.9, 149.9, 141.7 (q, J = 5.5 Hz), 141.3, 129.6, 129.5, 129.4, 129.0, 126.3, 123.3, 121.7, 121.5, 121.1, 21.4; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -65.2 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 14 F 3 O 2 [M+H] + : 307.0946, found 307.0944. (5e) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.44-7.37 (m, 2H), 7.37-7.33 (m, 1H), 7.33-7.28 (m, 3H), 7.27-7.25 (m, 3H), 7.23-7.18 (m, 2H), 5.22 (s, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 163.1, 140.4 (q, J = 5.6 Hz), 134.3, 132.0, 130.2, 129.0, S6

128.6, 128.54, 128.52, 128.4, 128.2, 128.1, 123.4, 123.1 (q, J = 271.5 Hz); 9 F-NMR (470.2 MHz, CDCl 3 ) δ -65.6 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 13 F 3 NaO 2 [M+Na] + : 329.0765, found 329.0765. (5f) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 751-736 (m, 8H), 7.25 (d, J = 8.5 Hz, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 188.9, 138.1 (q, J = 5.6 Hz), 136.5, 136.1, 135.5, 131.6, 130.8, 129.7, 128.7, 124.6, 122.4 (q, J = 272.8 Hz); 9 F-NMR (470.2 MHz, CDCl 3 ) δ -65.4 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 11 ClF 3 OS [M+H] + : 343.0171, found 343.0173. (5g) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.49-7.29 (m, 5H), 7.17-7.15 (m, 1H), 3.01 (s, 3H), 2.77 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 164.0, 134.3 (q, J = 5.7 Hz), 132.2, 130.2, 128.9, 128.7, 125.6 (q, J = 30.0 Hz), 123.4 (q, J = 272.0 Hz), 9 F-NMR (470.2 MHz, CDCl 3 ) δ -65.8 (s, 3F); HRMS (ESI) m/z calculated for C 12 H 13 F 3 NO [M+H] + : 244.0949, found 244.0946. (5h) Yellow liquid; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.54-7.47 (m, 2H), 7.38-7.32 (m, 3H), 7.08 (s, 1H), 4.00-3.84 (m, 1H), 3.42-3.27 (m, 1H), 1.48 (d, J = 7.0 Hz, 6H), 1.08 (d, J = 6.5 Hz, 3H), 0.48 (d, J = 6.5 Hz, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 162.6, 132.8 (q, J = 5.7 Hz), 132.7, 129.9, 129.5, 129.1, 128.5, 127.2 (q, J = 30.0 Hz), 123.5 (q, J = 272.2 Hz), 51.1, 46.1, 20.3, 20.1, 19.8, 19.1; 9 F-NMR (470.2 MHz, CDCl 3 ) δ -65.6 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 21 F 3 NO [M+H] + : 300.1575, found 300.1571. Cl O F 3 C N H Ph (5i) White solid, m.p. 147-148 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.47-7.40 (m, 3H), 7.40-7.34 (m, 3H), 7.40-7.28 (m, 3H), 7.27-7.23 (m, 1H); 13 C-NMR (CDCl 3, 125 MHz) δ 161.0, 136.9 (q, J = 5.6 Hz), 135.2, 131.4, 130.7, 130.4, 130.0, 129.2, 129.1, 129.0, 128.3, 126.6 (q, J = 30.0 Hz), 123.3 (q, J = 272.0 Hz), 121.5; 9 F-NMR (470.2 MHz, CDCl 3 ) δ -65.8 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 12 ClF 3 NO [M+H] + : 326.0560, found 326.0559. S7

(5j) White solid, m.p. 113-114 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 7.39-7.32 (m, 3H), 7.30-7.23 (m, 5H), 7.19 (s, 1H), 7.14-7.08 (m, 2H), 6.12 (s, 1H), 4.43 (d, J = 6.0 Hz, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 162.8, 136.6, 135.9 (q, J = 5.8 Hz), 131.7, 130.1, 129.1, 128.7, 128.6, 127.9, 127.6, 126.8 (q, J = 30.0 Hz), 123.3 (q, J = 271.8 Hz), 43.8; 9 F-NMR (470.2 MHz, CDCl 3 ) δ -66.0 (s, 3F); HRMS (ESI) m/z calculated for C 17 H 15 F 3 NO [M+H] + : 306.1106, found 306.1108. (5k) White solid, m.p. 169-170 o C; 1 H-NMR (500 MHz, DMSO) δ 8.12 (s, 1H), 7.80 (s, 1H), 7.64-7.59 (m, 2H), 7.46-7.41 (m, 3H), 7.26-7.24 (m, 1H); 13 C-NMR (125 MHz, DMSO) δ 158.9, 127.9 (q, J = 5.6 Hz), 126.8, 124.5, 123.7, 123.2, 121.0 (q, J = 29.5 Hz), 118.4 (q, J = 271.6 Hz); 9 F-NMR (470.2 MHz, DMSO) δ -59.8 (s, 3F); HRMS (ESI) m/z calculated for C 10 H 9 F 3 NO [M+H] + : 216.0636, found 216.0638. (7a) White solid, m.p. 109-110 o C; 1 H-NMR (500 MHz, DMSO) δ 7.6 (d, J = 16.0 Hz, 1H), 7.50-7.46 (m, 2H), 7.46-7.42 (m, 2H), 7.42-7.38 (m, 3H), 7.36-7.30 (m, 3H), 7.26-7.24 (m, 1H), 6.27 (d, J = 16.0 Hz, 1H), 6.17-6.08 (m, 1H), 4.24 (t, J = 5.0 Hz, 2H), 3.66-3.62 (m, 2H); 13 C-NMR (DMSO, 125 MHz) δ 166.7, 163.2, 145.5, 136.2 (q, J = 5.5 Hz), 134.0, 131.8, 130.5, 130.4, 129.0, 128.9, 128.8, 128.0, 126.8 (d, J = 29.6 Hz), 123.3 (q, J = 271.8 Hz), 117.0, 62.4, 39.1; 9 F-NMR (470.2 MHz, DMSO) δ -66.1 (s, 3F); HRMS (ESI) m/z calculated for C 21 H 19 F 3 NO 3 [M+H] + : 390.1317, found 390.1319. (7b) Yellow liquid; 1 H-NMR (500 MHz, DMSO) δ 7.71 (d, J = 7.5 Hz, 1H), 7.64 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H),7.48-7.40 (m, 5H), 7.34 (t, J = 7.5 Hz, 1H), 7.28-7.12 (m, 6H); 13 C-NMR (CDCl 3, 125 MHz) δ 191.3, 161.1, 150.1, 142.5 (q, J = 5.5 Hz), 137.8 (q, J = 5.7 Hz), 136.8, 131.9, 131.6, 130.7, 130.3, 129.8, 129.4, 129.2, 128.79, 128.78, 127.6, 127.1, 123.1 (q, J = 272.8 Hz), 123.0 (q, J = 272 Hz), 121.7; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -64.5 (s, 3F), -65.5 (s, 3F); HRMS (ESI) m/z calculated for C 26 H 17 F 6 O 3 [M+H] + : 491.1082, found 491.1090. S8

(Trifluridine) White solid, m.p.199-200 o C; 1 H-NMR (500 MHz, DMSO) δ 11.8 (s, 1H), 8.73 (s, 1H), 6.08 (t, J = 6.0 Hz, 1H), 5.31-5.20 (m, 2H), 4.27-4.21 (m, 1H), 3.84-3.80 (m, 1H), 3.70-3.52 (m, 2H), 2.22-2.17 (m, 2H); 13 C-NMR (DMSO, 125 MHz) δ 159.6, 150.1, 142.87, 142.83, 124.3 (q, J = 267.7 Hz), 103.3 (q, J = 6.6 Hz), 88.1, 85.9, 69.8, 60.7, 41.4; 19 F-NMR (470.2 MHz, DMSO) δ -58.7 (s, 3F); HRMS (ESI) m/z calculated for C 10 H 11 F 3 N 2 NaO 5 [M+Na] + : 319.0518, found 319.0507. (TF-Hymecromone) White solid, m.p. 190-191 o C; 1 H-NMR (500 MHz, DMSO) δ 11.0 (s, 1H), 7.85 (d, J = 9.0 Hz, 1H), 6.85 (d, J = 9.0 Hz, 1H), 6.69 (s, 1H), 2.56 (s, 3H); 13 C-NMR (DMSO, 125 MHz) δ 163.9, 157.0, 156.3, 155.2, 129.2, 125.0 (q, J = 272.6 Hz), 114.4, 111.4, 109.7 (q, J = 29.2 Hz), 102.3, 15.9 (q, J = 3.7 Hz); 9 F-NMR (470.2 MHz, DMSO) δ -52.2 (s, 3F); HRMS (ESI) m/z calculated for C 11 H 8 F 3 O 3 [M+H] + : 245.0426, found 245.0426. (TF-Flavone) White solid, m.p. 85-86 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 8.27 (dd, J = 1.5, 8.0 Hz, 1H), 7.76-7.70 (m, 1H), 7.62-7.56 (m, 3H), 7.55-7.50 (m, 2H), 7.49-7.45 (m, 2H); 13 C-NMR (CDCl 3, 125 MHz) δ 174.3, 167.03, 167.01, 155.4, 134.7, 132.3, 131.3, 128.5 (q, J = 1.5 Hz), 128.3, 126.1, 126.0, 123.6, 123.2, 121.5 (q, J = 272.4 Hz), 117.9, 113.4 (q, J = 30.0 Hz); 19 F-NMR (470.2 MHz, CDCl 3 ) δ -58.1 (s, 3F); HRMS (ESI) m/z calculated for C 16 H 10 F 3 O 2 [M+H] + : 291.0633, found 291.0633. (TF-Tranilast) White solid, m.p. 134-135 o C; 1 H-NMR (500 MHz, CDCl 3 ) δ 11.0 (s, 1H), 8.83 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J = 8.5 Hz, 1H), 3.80 (s, 3H), 3.59 (s, 3H); 13 C-NMR (CDCl 3, 125 MHz) δ 171.9, 162.2, 148.8, 140.9, 136.8 (q, J = 5.6 Hz), 135.9, S9

135.8, 131.9, 124.3, 123.8, 123.6 (q, J = 271.6 Hz), 120.7, 114.4, 111.2, 110.7, 55.7, 55.5; 19 F-NMR (470.2 MHz, CDCl 3 ) δ -65.3 (s, 3F); HRMS (ESI) m/z calculated for C 19 H 16 F 3 NNaO 5 [M+Na] + : 418.0878 found 418.0875. (2k-d) Yellow solid, 1 H-NMR (500 MHz, CDCl 3 ) δ 7.57-7.52 (m, 2H), 7.50 (s, 1H), 7.40 (t, J = 8.0 Hz, 3H). S10

III. Crystallography Single-crystal X-ray diffraction data for the reported complex was recorded at a temperature of 293(2) K on a Oxford Diffraction Gemini R Ultra diffractometer, using a ω scan technique with Mo-Kα radiation (λ = 0.71073 Å). The structure was solved by Direct Method of SHELXS-97 and refined by full-matrix least-squares techniques using the SHELXL-97 program. 1 Non-hydrogen atoms were refined with anisotropic temperature parameters, and hydrogen atoms of the ligands were refined as rigid groups. Basic information pertaining to crystal parameters and structure refinement is summarized in Table 1-3 1 (a) G. M. Sheldrick, SHELXS-97, Program for Solution of Crystal Structures, University of Göttingen, Germany, 1997; (b) G. M. Sheldrick, SHELXL-97, Program for Refinement of Crystal Structures, University of Göttingen, Germany, 1997. OH F 3 C O Cl 3n Table 1. Crystal data and structure refinement (CCDC 984080). Empirical formula C 16 H 10 ClF 3 O 2 Formula weight 326.03 Temperature 293(2) K Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 7.9820(10) Å b = 17.645(2) Å c = 10.5260(13) Å alpha = 90.000(5) deg. beta = 93.310(5) deg. gamma =90.000(5) deg. Volume 1480.0(3) Å 3 Z 4 Calculated density 1.421 Mg/m 3 Absorption coefficient 0.292 mm -1 S11

F(000) 624.0 Crystal size 0.21 x 0.18 x 0.14mm Theta range for data collection 2.31 to 26.04 deg. Reflections collected / unique 7769 / 2899 [R(int) = 0.0427] Data / restraints / parameters 2899 / 0 / 199 Goodness-of-fit on F 2 1.050 Final R indices [I>2sigma(I)] R1 = 0.0788, wr2 = 0.2135 R indices (all data) R1 =0.1198, wr2 = 0.2421 Table 2. Crystal data and structure refinement (CCDC 984079). Empirical formula C 10 H 8 F 3 NO Formula weight 215.05 Temperature 293(2) K Crystal system Trigonal Space group R-3 Unit cell dimensions a = 5.1491(18) Å b = 8.215(4) Å c = 23.503(9) Å alpha = 89.92(3) deg. beta = 89.79(3) deg. gamma = 84.28(4) deg. Volume 989.2(7) Å 3 Z 16 Calculated density 1.666 Mg/m 3 Absorption coefficient 0.187 mm -1 F(000) 496 Crystal size 0.21 x 0.18 x 0.14mm Theta range for data collection 2.89 to 25.50 deg. Reflections collected / unique 26036 / 5172 [R(int) = 0.0597] Data / restraints / parameters 2684 / 7 / 121 S12

Goodness-of-fit on F 2 1.108 Final R indices [I>2sigma(I)] R1 =0.1365, wr2 = 0.3127 R indices (all data) R1 = 0.2443, wr2 = 0.3567 Table 3. Crystal data and structure refinement (CCDC 984082). Empirical formula C 19 H 16 F 3 NO 5 Formula weight 395.09 Temperature 293(2) K Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 15.2942(12) Å b = 8.3891(7) Å c = 14.6278(12) Å alpha = 90.000(5) deg. beta = 102.291(2)deg. gamma =90.000(5) deg. Volume 1833.8(3) Å 3 Z 4 Calculated density 1.373 Mg/m 3 Absorption coefficient 0.121 mm -1 F(000) 752.0 Crystal size 0.21 x 0.18 x 0.14mm Theta range for data collection 2.73 to 26.04 deg. Reflections collected / unique 9584 / 3616 [R(int) = 0.0281] Data / restraints / parameters 3616 / 0 / 253 Goodness-of-fit on F 2 1.068 Final R indices [I>2sigma(I)] R1 = 0.0819, wr2 = 0.2395 R indices (all data) R1 = 0.1002, wr2 = 0.2641 S13

IV. NMR spectra copies S14

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