Palladium-Catalyzed Regioselective C-H Fluoroalkylation of Indoles at C4-Position

Transcription

1 Electronic Supplementary Material (ESI) for ChemComm. This journal is The Royal Society of Chemistry 2017 Palladium-Catalyzed Regioselective C-H Fluoroalkylation of Indoles at C4-Position (Supporting Information) Arun Jyoti Borah and Zhuangzhi Shi* State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, anjing University, anjing , China Table of Contents 1. General Information. S2 2. Preparation of starting materials.. S2-S6 3. General procedure for the synthesis of (1H, 1H-perfluoroalkyl)mesityliodonium triflate salts S6-S7 4. Characterization of starting materials.. S8-S13 5. Synthesis of C-4 trifluoroalkylated Indoles.. S13 6. Characterization of the products S13-S22 7. Procedure for removal of directing group S22-S24 8. Procedure for the synthesis of 1-methyl-3,4-bis(2,2,2-trifluoroethyl)- 1H-indole.. S24-S25 9. RTEP diagram of 3a S25-S References S MR Spectra of substrates ( 1 H and 13 C)... S29-S MR Spectra of (1H, 1H-perfluoroalkyl)mesityliodonium triflate.. S75-S MR Spectra of products ( 1 H, 13 C and 19 F)... S84-S-176 S1

2 1.General Information All new compounds were fully characterized. MR-spectra were recorded on Bruker ARX-400 MHz. Mass spectra were conducted at Micromass Q-Tof instrument (ESI) and Agilent Technologies 5973 (EI). IR spectra were recorded on a FT-IR spectrometer. All reactions were carried out in inert atmosphere. Before using all solvents were dried over molecular sieves. All the starting materials were synthesized using standard procedures, except 1-(benzo[b]thiophen-3- yl)ethanone. 2. Preparation of starting materials 2.1. Preparation of starting materials 1a-b, 1d-g, 1j-m, 1o-u General procedure of acylation of indoles at the 3-position (B) 1 To a CH 2 Cl 2 solution (13 ml) of indole (A, 3 mmol) was added 2.26 ml ( 1.5 equiv) of Et 2 AlCl (2 mol/l in hexane) dropwise at 0 C. The mixture was stirred at 0 C for 30 min. Then CH 2 Cl 2 solution (10 ml) of acetyl chloride (1.5 equiv) was added dropwise at 0 C. The resulting solution was stirred at same temperature for an appropriate of time (2-4 hrs). After completion of the reaction it was quenched with aqueous buffer (ph 7). After usual workup, the crude product was purified by either trituration or flash column chromatography to provide the 3-acetylindole, B (60-94% yield). S2

3 General procedure of -Methylation of indoles (1): To a solution of 3-Acetylindole (B, 2 mmol) in, -dimethylformamaide (5 ml) was added ah (1.05 equiv) under ice cooled conditions. MeI (1.1 equiv) was added dropwise to this solution and allowed to stir at room temperature for appropriate time. After completion of the reaction it was quenched with water and extracted by Et 2. The organic layer was dried over anhydrous a 2 S 4 and filtered, concentrated under pressure and then purified by silica gel flash column chromatography (75-95% yield). 2.2 General procedure for the synthesis of starting materials 1c, 1o : 2 To a solution of bromoindole (1 mmol) and boronic acid (2 mmol) in 1:1 toluene-eth (2.5 ml), was added a solution of aqueous a 2 C 3 (1 M solution, 2.35 mmol) and Pd(Ph 3 P) 4 (2 mol%) in 1:1 toluene-eth (2.5 ml). The resulting mixture was heated at reflux under argon for 1 h. Another portion of Pd(Ph 3 P) 4 (2 mol%) in 1:1 toluene-eth (2.5 ml) was added and heating was continued for further 4 h. After completion of the reaction, the solvent was evaporated under reduced pressure and and the resulting crude was purified by silica flash-chromatography (petroleum ether-etac) yielding the product as a white solid Experimental procedure for the synthesis of starting material 1h: 3 S3

4 A dried Schlenk tube was charged with K 3 P 4 (1.40 mmol) and DMA (1.0 ml) under Ar atmosphere. To this soloution, 1-(7-bromo-1-methyl-1H-indol-3-yl)ethanone (1e, 1mmol) and styrene (1.20 mmol) were added via syringes. A solution of Pd(Ac) 2 (5 mol%) in DMA was then added and the reaction system was allowed to stir at 140 C for 24 hrs. After being cooled to room temperature, the reaction mixture was added with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over a 2 S 4 and concentrated to dryness under vacuum. The crude product was purified by flash chromatography on silica to provide pure solid product (193 mg, 70% yield). 2.4 Experimental Procedure for the synthesis of starting material 1i: Pd/C (10%) H 2 /EtAc Ph 1h Ph 1i, 65% (E)-1-(1-methyl-7-styryl-1H-indol-3-yl)ethanone (1h, 200 mg, mmol) was dissolved in EtAc (15 ml) and was hydrogenated using a hydrogen balloon for 4 h at room temperature with 10% Pd/C (10 mol%) as a catalyst. Then the reaction mixture was filtered through a Celite pad and was concentrated in vacuum. The crude product was purified by flash chromatography using petroleum ether/etac as eluent, which yielded 65% of 1i (130 mg). 2.5 Experimental Procedure for the synthesis of starting material 1j: S4

5 Experimental procedure for the synthesis of 1-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1h-indole (C) 4 To a solution of PdCl 2 (dppf) (3 mol%) in dioxane (4 ml) was added 7-bromo-1-methyl-1Hindole (230 mg, 1.1 mmol), Et 3 (3 equiv), and pinacolborane (1.5 equiv). After being stirred for 36 h at 150 o C the mixture was extracted with EtAc. The extract was washed with water, dried over anhydrous a 2 S 4 and concentrated. The residue was purified by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent (100:2) to provide white solid (141 mg, 50%). 1 H (400 MHz, CDCl 3 ): 7.65 (dd, J = 7.8 Hz, 1H), 7.59 (dd, J = 7.1 Hz, 1H), (m, 1H), 7.03 (d, J = 3.1 Hz, 1H), 6.51 (d, J = 3.1 Hz, 1H), 3.98 (s, 3H), 1.41 (s, 12 H); 13 C (100 MHz, CDCl 3 ): 139.3, 130.4, 130.2, 128.8, 124.0, 118.5, 101.0, 83.8, 36.2, 24.7; IR (KBr, cm -1 ): 1577, 1520, 1402, 1357, 1315, 1276, 1140, 723; HRMS calculated for C 15 H 21 B 2 [M+H] + : ; found [M+H] + : Experimental procedure for the synthesis of 1-(1-methyl-7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1h-indol-3-yl)ethanone (1j) 1 S5

6 To a CH 2 Cl 2 solution (2 ml) of indole (C, 120 mg, mmol) was added 0.4 ml ( 1.5 equiv) of Et 2 AlCl (2 mol/l in hexane) dropwise at 0 C. The mixture was stirred at 0 C for 30 min. To this solution was added dropwise CH 2 Cl 2 solution (1 ml) of acetyl chloride (1.5 equiv) at 0 C. The resulting solution was stirred at same temperature for an appropriate of time (4 hrs). After completion of the reaction it was quenched with aqueous buffer (ph 7). After usual workup, the crude product was purified by flash column chromatography on silica gel providing 1j as a white solid (100 mg, 72%). 1 H (400 MHz, CDCl 3 ): 8.55 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.66 (s, 1H), 7.29 (t, J = 7.5 Hz, 1H), 4.02 (s, 3H), 2.50 (s, 3H), 1.39 (s, 12H); 13 C (100 MHz, CDCl 3 ): 192.9, 140.2, 137.3, 132.0, 126.6, 125.6, 121.8, 116.5, 84.2, 37.1, 27.5, 24.7; IR (KBr, cm -1 ): 1683, 1658, 1400, 1345, 1258, 1122; HRMS calculated for C 17 H 23 B 3 [M+H] + : ; found [M+H] + : General procedure for the synthesis of (1H, 1H-perfluoroalkyl)mesityliodonium triflate salts (2a-2c) : 5 An oven dried 100 ml round-bottom flask was charged with 2,2,2-trifluoroacetic anhydride (6.5 equiv) and trifluoroacetic acid (10 mol%). The mixture was cooled to 0 C and then H 2 2 (30% aqueous solution, 1.5 equiv) was added dropwise and was stirred for 5 minutes. 1-iodo-1H,1Hperfluoroalkane (1 equiv) was added dropwise and then the reaction mixture was allowed to warm up to room temperature and it was stirred for 20 hours. The volatile was evaporated under S6

7 reduced pressure and colorless oil was obtained in quantitative yield (2A-2C) which was directly utilized in the next step. 1-[Bis(trifluoroacetoxy)iodo]-1H, 1H-perfluoroalkane (2A-2C, 1equiv) was dissolved in dichloromethane, then the solution was cooled to 0 C and mesitylene (1.5 equiv) was added. After that, trifluoromethanesulfonic acid (1 equiv) was added dropwise. The reaction mixture turned into a dark red solution and it was kept at 0 C for 24 hours. Then the solvent was evaporated under reduced pressure and added with diethyl ether. White solid precipitated from the mixture. The product was filtered off and washed with diethyl ether (2a-2c, 60-87%). 2,2,2-Trifluoroethyl(mesityl)iodonium trifluorormethanesulfonate (2a) 5b,c : White solid; 87% yield; 1 H (400 MHz, CD 3 C): 7.27 (s, 2H), 4.66 (q, J = 9.9 Hz, 2H), 2.63 (s, 6H), 2.40 (s, 3H); 13 C (100 MHz, CD 3 C): 146.3, 144.3, 131.1, 128.8, 27.1, 21.0; 19 F (376 MHz, CD 3 C): -62.8, -79.3; IR (KBr, cm -1 ): 1402, 1262, 1175, 1049, 653; HRMS m/z [M] + calculated for C 11 H 13 F 3 I : ; found ,3,3,2,2-Pentafluoropropyl(mesityl)iodonium trifluorormethanesulfonate (2b): White solid; 85% yield; 1 H (400 MHz, CD 3 C): 7.28 (s, 2H), 4.67 (t, J = 17.6 Hz, 2H), 2.65 (s, 6H), 2.40 (s, 3H); 13 C (100 MHz, CD 3 C): 144.4, 138.7, 131.2, 27.3, 21.0; 19 F (376 MHz, CD 3 C): -79.3, -84.0, ; IR (KBr, cm -1 ): 1400, 1262, 1173, 1037, 651; HRMS m/z [M] + calculated for C 12 H 13 F 5 I : ; found ,4,4,3,3,2,2-Heptafluorobutyl(mesityl)iodonium trifluorormethanesulfonate (2c): White solid; 60% yield; 1 H (400 MHz, CD 3 C): 7.27 (s, 2H), 4.71 (t, J = 18.0 Hz, 2H), 2.65 (s, 6H), 2.40 (s, 3H); 13 C (100 MHz, CD 3 C): 144.4, 131.1, 27.3, 21.0; 19 F (376 MHz, CD3C): , (t, J = 9.7 Hz), , ; IR (KBr, cm -1 ): 1400, 1262, 1173, 1025, 637; HRMS m/z [M] + calculated for C 13 H 13 F 7 I : ; found S7

8 4. Characterization of starting materials (1a-1v): 1-(1-methyl-1H-indol-3-yl)ethanone (1a) : White solid; 1 H (400 MHz, CDCl 3 ): (m, 1H), 7.70 (s, 1H), (m, 3H), 3.84 (s, 3H), 2.52 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 137.4, 135.7, 126.2, 123.3, 122.6, 122.5, 116.9, 109.6, 33.5, 27.5; IR (KBr, cm -1 ): 1641, 1528, 1468, 1369, 1228, 1098; HRMS m/z [M+H] + calculated for C 11 H 12 : ; found (1,7-dimethyl-1H-indol-3-yl)ethanone (1b): White solid; 1 H (400 MHz, CDCl 3 ): 8.26 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 4.08 (s, 3H), 2.75 (s, 3H), 2.49 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.8, 137.4, 136.1, 127.3, 126.0, 122.7, 121.4, 120.6, 116.3, 37.7, 27.5, 19.6; IR (KBr, cm -1 ): 1623, 1595, 1462, 1389, 1247, 1109; HRMS m/z [M+H] + calculated for C 12 H 14 : ; found (1-methyl-7-phenyl-1H-indol-3-yl)ethanone (1c): Ph White solid; 1 H (400 MHz, CDCl 3 ): 8.44 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 (s, 1H), (m, 5H), 7.30 (t, J = 7.6 Hz, 1H), (m, 1H), 3.33 (s, 3H), 2.52 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.9, 139.4, 137.8, 134.7, 130.0, 127.8, 127.5, 127.3, 127.2, 125.8, 122.1, 121.8, 116.5, 37.6, 27.6; IR (KBr, cm -1 ): 1640, 1596, 1536, 1448, 1367, 1239, 1103; HRMS m/z [M+H] + calculated for C 17 H 16 : ; found (7-methoxy-1-methyl-1H-indol-3-yl)ethanone (1d): Me White solid; 1 H (400 MHz, CDCl 3 ): 7.95 (dd, J = 8.1, 0.8 Hz, 1H), 7.56 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 6.70 (d, J = 7.7 Hz, 1H), 4.08 (s, 3H), 3.92 (s, 3H), 2.49 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.8, 147.6, 136.5, 128.6, 127.0, 123.2, 116.7, 115.0, 104.0, 55.4, 37.5, 27.6; IR (KBr, cm -1 ): 1652, 1612, 1579, 1455, 1391, 1322, 1266, 1107; HRMS m/z [M+H] + calculated for C 12 H 14 2 : ; found (7-bromo-1-methyl-1H-indol-3-yl)ethanone (1e): S8

9 Br White solid; 1 H (400 MHz, CDCl 3 ): 8.39 (dd, J = 8.0, 1.0 Hz, 1H), 7.62 (s, 1H), 7.43 (dd, J = 7.7, 1.0 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 4.20 (s, 3H), 2.49 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.5, 138.4, 133.9, 129.3, 128.4, 123.6, 121.9, 116.2, 104.0, 37.9, 27.5; IR (KBr, cm -1 ): 1639, 1600, 1534, 1452, 1373, 1243, 1105, 777; HRMS m/z [M+H] + calculated for C 11 H 11 Br: ; found (7-chloro-1-methyl-1H-indol-3-yl)ethanone (1f): Cl White solid, 1 H (400 MHz, CDCl 3 ): 8.32 (dd, J = 8.0, 1.2 Hz, 1H), 7.59 (s, 1H), 7.22 (dd, J = 7.7, 1.1 Hz, 1H), 7.15 (t, J = 7.8 Hz, 1H), 4.15 (s, 3H), 2.48 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.5, 138.1, 132.8,129.2, 124.8, 123.2, 121.3, 117.2, 116.5, 37.7, 27.5; IR (KBr, cm -1 ): 1637, 1534, 1454, 1307, 1241, 1175, 845; HRMS m/z [M+H] + calculated for C 11 H 11 Cl: ; found (7-fluoro-1-methyl-1H-indol-3-yl)ethanone (1g): F Light brown color solid; 1 H (400 MHz, CDCl 3 ): 8.12 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.15 (td, J = 8.0, 4.6 Hz, 1H), (m, 1H), (s, 3H), 2.48 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.7, (d, J = Hz), 136.9, (d, J = 4.1 Hz), (d, J = 9.6 Hz), (d, J = 6.4 Hz), (d, J = 3.8 Hz), 117.3, (d, J = 17.2 Hz), 36.5 (d, J = 5.6 Hz), 27.6; IR (KBr, cm -1 ): 1641, 1573, 1534, 1464, 1367, 1254, 1109; HRMS m/z [M+H] + calculated for C 11 H 11 F: ; found (E)-1-(1-methyl-7-styryl-1H-indol-3-yl)ethanone (1h): Ph Light brown color solid; 1 H (400 MHz, CDCl 3 ): (m, 1H), 7.75 (d, J = 15.8 Hz, 1H), 7.59 (s, 1H), (m, 2H), (m, 3H), (m, 2H), 6.95 (d, J = 15.9 Hz, 1H), 4.07 (s, 3H), 2.49 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.8, 137.6, 137.2, 134.8, 132.2, 128.8, 127.9, 127.5, 126.4, 125.0, 124.0, 123.0, 122.9, 122.3, 116.5, 38.2, 27.5; IR (KBr, cm -1 ): 1631, 1592, 1536, 1474, 1336, 1241, 1105; HRMS m/z [M+H] + calculated for C 19 H 18 : ; found (1-methyl-7-phenethyl-1H-indol-3-yl)ethanone (1i): S9

10 Ph White solid; 1 H (400 MHz, CDCl 3 ): 8.32 (dd, J = 8.0, 1.1 Hz, 1H), 7.59 (s, 1H), (m, 2H), (m, 4H), 7.07 (d, J = 6.7 Hz, 1H), 4.02 (s, 3H), (m, 2H), (m, 2H), 2.5 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.7, 141.0, 137.8, 135.4, 128.5, 128.3, 127.8, 126.3, 125.6, 125.3, 122.8, 120.8, 116.5, 38.9, 37.7, 34.0, 27.5; IR (KBr, cm -1 ): 1637, 1598, 1538, 1476, 1369, 1239, 1103, 754; HRMS m/z [M+H] + calculated for C 19 H 20 : ; found (1,2-dimethyl-1H-indol-3-yl)ethanone (1k): Light brown color solid; 1 H (400 MHz, CDCl 3 ): (m, 1H), (m, 1H), (m, 2H), 3.70 (s, 3H), 2.78 (s, 3H), 2.69 (s, 3H); 13 C (100 MHz, CDCl 3 ): 194.5, 145.1, 136.6, 126.3, 122.0, 121.9, 120.6, 114.1, 109.5, 31.7, 29.4, 12.6; IR (KBr, cm -1 ): 1644, 1509, 1468, 1334, 1210, 1103, 740; HRMS m/z [M+H] + calculated for C 12 H 15 : ; found (2-butyl-1-methyl-1H-indol-3-yl)ethanone (1l): 3 White solid; 1 H (400 MHz, CDCl 3 ): (m, 1H), (m, 1H), (m, 2H), 3.72 (s, 3H), (m, 2H), 2.68 (s, 3H), (m, 2H), (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13 C (100 MHz, CDCl 3 ): 194.1, 149.7, 136.6, 126.3, 121.9, 120.7, 113.4, 109.6, 31.7, 31.2, 29.4, 25.8, 22.9, 13.8.; IR (KBr, cm - 1 ): 1623, 1594, 1538, 1462, 1365, 1243, 1111, 781; HRMS m/z [M+H] + calculated for C 15 H 20 : ; found (1-methyl-2-phenyl-1H-indol-3-yl)ethanone (1m): Ph Light yellow color solid; 1 H (400 MHz, CDCl 3 ): (m, 1H), (m, 3H), (m, 2H), (m, 3H), 3.50 (s, 3H), 1.96 (s, 3H); 13 C (100 MHz, CDCl 3 ): 194.6, 146.6, 136.6, 132.2, 130.2, 129.6, 128.8, 126.6, 123.3, 122.9, 122.8, 115.9, 109.4, 30.8, 30.1; IR (KBr, cm -1 ): 1617, 1573, 1522, 1470, 1388, 1177, 1097; HRMS m/z [M+H] + calculated for C 17 H 16 : ; found (1,6-dimethyl-1H-indol-3-yl)ethanone (1n): S10

11 Light brown color solid; 1 H (400 MHz, CDCl 3 ): 8.22 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), (m, 2H), 3.78 (s, 3H), 2.49 (s, 6H); 13 C (100 MHz, CDCl 3 ): 192.8, 137.8, 135.3, 133.2, 124.2, 123.9, 122.1, 116.9, 109.5, 33.4, 27.5, 21.8; IR (KBr, cm -1 ): 1630, 1590, 1460, 1385, 1250, 1111; HRMS m/z [M+H] + calculated for C 12 H 14 : ; found (1-methyl-6-p-tolyl-1H-indol-3-yl)ethanone (1o): White solid; 1 H (400 MHz, CDCl 3 ): 8.39 (d, J = 8.3 Hz, 1H), 7.70 (s, 1H), (m, 3H), 7.48 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H); 13 C (100 MHz, CDCl 3 ): 193.0, 138.8, 138.0, 136.9, 136.8, 136.2, 129.5, 127.2, 125.2, 122.6, 122.2, 116.9, 107.8, 35.5, 27.6, 21.1; IR (KBr, cm -1 ): 1648, 1551, 1526, 1464, 1367, 1221, 1103; HRMS m/z [M+H] + calculated for C 18 H 17 : ; found (6-fluoro-1-methyl-1H-indol-3-yl)ethanone (1p): F Light brown color solid; 1 H (400 MHz, CDCl 3 ): 8.30 (dd, J = 8.7, 5,5 Hz, 1H), 7.63 (s, 1H), (m, 1H), 6.97 (d, J = 9.2 Hz, 1H), 3.76 (s, 3H), 2.47 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.7, (d, J = Hz), (d, J = 11.7 Hz), 136.0, (d, J = 9.7 Hz), 122.5, 116.9, (d, J = 23.7 Hz), 96.2 (d, J = 26.2 Hz), 33.5, 27.3; IR (KBr, cm -1 ): 1625, 1584, 1530, 1464, 1373, 1231, 1084; HRMS m/z [M+H] + calculated for C 11 H 11 F: ; found (6-bromo-1-methyl-1H-indol-3-yl)ethanone (1q): Br Light brown color solid; 1 H (400 MHz, CDCl 3 ): 8.21 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 8.4, 1.6 Hz, 1H), 3.76 (s, 3H), 2.47 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.7, 138.2, 136.0, 125.6, 125.0, 123.8, 116.9, 116.8, 112.7, 33.5, 27.4; IR (KBr, cm -1 ): 1635, 1595, 1530, 1460, 1380, 1247, 1111, 780; HRMS m/z [M+H] + calculated for C 11 H 11 Br: ; found (6-chloro-1-methyl-1H-indol-3-yl)ethanone (1r): S11

12 Cl Light brown color solid; 1H (400 MHz, CDCl 3 ): 8.26 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.27 (br, 1H), 7.23 (dd, J = 8.5, 1.7 Hz, 1H), 3.75 (s, 3H), 2.47 (s, 3H); 13 C(100 MHz, CDCl 3 ): 192.7, 137.8, 136.1, 129.3, 124.6, 123.4, 123.0, 116.8, 109.7, 33.5, 27.4; IR (KBr, cm -1 ): 1640, 1610, 1536, 1460, 1310, 1242, 1167, 840; HRMS m/z [M+H] + calculated for C 11 H 11 Cl: ; found (6-methoxy-1-methyl-1H-indol-3-yl)ethanone (1s): Me White solid; 1 H (400 MHz, CDCl 3 ): 8.23 (d, J = 8.7 Hz, 1H), (s, 1H), 6.93 (dd, J = 8.8, 2.4 Hz, 1H), 6.74 (d, J = 2.2 Hz, 1H), 3.86 (s, 3H), 3.75 (s, 3H), 2.47 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.8, 157.1, 138.3, 134.9, 123.2, 120.2, 116.9, 111.7, 93.2, 55.6, 33.4, 27.3; IR (KBr, cm -1 ): 1660, 1620, 1575, 1450, 1385, 1315, 1260, 1110 HRMS m/z [M+H] + calculated for C 12 H 14 2 : ; found acetyl-1-methyl-1H-indole-6-carbonitrile (1t): C White solid; 1 H (400 MHz, CDCl 3 ): 8.46 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.67 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 3.90 (s, 3H), 2.53 (S, 3H); 13 C (100 MHz, CDCl 3 ): 192.5, 138.2, 136.4, 129.3, 125.3, 123.5, 119.8, 117.3, 114.4, 106.2, 33.7, 27.6; IR (KBr, cm -1 ): 2217, 1644, 1613, 1532, 1464, 1373, 1237, 1171; HRMS m/z [M+H] + calculated for C 12 H 11 2 : ; found (1,5-dimethyl-1H-indol-3-yl)ethanone (1u): light violet color solid; 1 H (400 MHz, CDCl 3 ): 8.17 (s, 1H), 7.62 (s, 1H), (m, 2H), 3.78 (s, 3H), 2.48 (s, 6H); 13 C (100 MHz, CDCl 3 ): 192.9, 135.8, 132.1, 126.4, 124.8, 122.2, 116.4, 109.2, 33.5, 27.5, 21.5; IR (KBr, cm -1 ): 1635, 1593, 1465, 1380, 1255, 1105; HRMS m/z [M+H] + calculated for C 12 H 14 : ; found (5-chloro-1-methyl-1H-indol-3-yl)ethanone (1v): S12

13 Cl White solid; 1 H (400 MHz, CDCl 3 ): 8.42 (d, J = 1.2 Hz, 1H), 7.72 (s, 1H), (m, 2H), 3.88 (s, 3H), 2.54 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.5, 136.5, 135.8, 128.5, 127.1, 123.6, 122.0, 116.4, 110.6, 33.7, 27.4; IR (KBr, cm -1 ): 1641, 1608, 1540, 1450, 1310, 1245, 1177, 842; HRMS m/z [M+H] + calculated for C 11 H 11 Cl: ; found General Procedure for the Synthesis of C-4 trifluoroalkylated Indole (3) A 10 ml Schlenk tube was charged with indole substrates 1 (0.1 mmol), (1H, 1Hperfluoroalkyl)mesityliodonium triflate (2, 1.1 equiv) and Pd(Ac) 2 (10-15 mol%). The mixture was dissolved in 1.5 ml dichloromethane followed by addition of trifluoroacetic acid (1-3 equiv). The reaction mixture was stirred for 24 hours at room temperature. After that it was filtered through a short pad of silica gel and washed with ethyl acetate. The solvent was then evaporated under reduced pressure and the crude was purified by column chromatography on silica gel to afford the pure product. 5. Characterization of the products 1-(1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3aa): F 3 C Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3aa; white solid (21.1 mg, 83%). 1 H (400 MHz, CDCl 3 ): 7.79 (s,1h), (m, 2H), (m, 1H), 4.48 (q, J = 11.2 Hz, 2H), 3.84 (s, 3H), 2.55 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.1, 138.6, 138.2, (q, 1 J C-F = Hz), 126.3, 125.6, (q, 3 J C-F = 3.2 Hz), 123.5, 118.0, 109.6, 39.0 (q, 2 J C-F = 28.5 Hz), 33.6, 28.4; 19 F (376 MHz, CDCl 3 ): -65.4; HRMS m/z [M+H] + calculated for C 13 H 13 F 3 : ; found (1,7-dimethyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ba): S13

14 Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ba; white solid (21 mg, 78%); 1 H (400 MHz, CDCl 3 ): 7.65 (s, 1H), (m, 2H), 4.40 (q, J = 11.2 Hz, 2H), (m, 3H), 2.74 (s, 3H), 2.52 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 140.0, 137.3, (q, 1 J C-F = Hz), 126.6, 126.5, (q, 3 J C-F = 3.0 Hz), 121.6, 117.6, 117.5, 38.7 (q, 2 J C-F = 28.6 Hz), 38.1, 28.6, 19.7; 19 F ( 376 MHz, CDCl 3 ): (t, J = 11.2 Hz); IR (KBr, cm -1 ): 1641, 1582, 1534, 1361, 1256, 1233, 1113, 946, 796; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 : ; found (1-methyl-7-phenyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ca): Ph Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 6:1) to provide 3ca; white solid (25 mg, 76%); 1 H (400 MHz, CDCl 3 ): 7.71 (s, 1H), (m, 3H), (m, 2H), 7.19 (d, J = 7.5 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 4.50 (q, J = 11.2 Hz, 2H), 3.30 (s, 3H), 2.55 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 140.3, 139.2, 135.8, 130.0, 127.8, 127.7, 127.2, (q, 1 J C-F = Hz), 126.4, 126.1, 125.8, (q, 3 J C-F = 3.3 Hz), 117.7, 38.9 (q, 2 J C-F = 28.5 Hz), 38.0, 28.6; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1654, 1575, 1530, 1437, 1363, 1252, 1158, 1082, 761; HRMS m/z [M+H] + calculated for C 19 H 17 F 3 : ; found (7-methoxy-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3da): Me Following the general procedure with 15 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3da; white solid (20 mg, 70%); 1 H (400 MHz, CDCl 3 ): 7.62 (s, 1H), 7.04 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 4.36 (q, J = 11.2 Hz, 2H), 4.08 (s, 3H), 3.91 (s, 3H), 2.52 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 147.6, 139.1, 128.1, 127.7, 126.8, (q, 1 J C-F = Hz), 117.8, (q, 3 J C-F = 3.1 Hz), 104.2, 55.5, 38.4 (q, 2 J C-F = 28.6 Hz), 38.0, 28.5; 19 F (376 MHz, CDCl 3 ): -65.8; IR (KBr, cm -1 ): 1641, 1613, 1516, 1437, 1363, 1262, 1105, 1076, 794; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 2 : ; found S14

15 1-(7-bromo-1-methyl-1H-indol-3-yl)ethanone (3ea): Br Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ea; white solid (26 mg, 78%); 1 H (400 MHz, CDCl 3 ): 7.72 (s, 1H), 7.43 (d, J = 8Hz, 1H), 6.98 (d, J = 8Hz, 1H), 4.38 (q, J = 11.2 Hz, 2H), 4.21 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.1, 140.9, 134.9, 128.7, 128.5, 127.3, (q, 1 J C-F = Hz), (q, 3 J C-F = 3.3Hz), 117.6, 104.4, 38.6 (q, 2 J C-F = 28.8Hz), 38.5, 28.7; 19 F ( 376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1652, 1596, 1532, 1468, 1437, 1365, 1254, 1134, 1091, 963; HRMS m/z [M+a] + calculated for C 13 H 11 BrF 3 a: ; found (7-chloro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3fa): Cl Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3fa; white solid (24 mg, 83%); 1 H (400 MHz, CDCl 3 ): 7.71 (s, 1H), 7.23 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 4.40 (q, J = 11.2 Hz, 2H), 4.19 (s, 3H), 2.54 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.2, 140.7, 133.8, 128.4, 126.9, (q, 1 J C-F = Hz), 125.1, (q, 3 J C-F = 3.1 Hz), 117.8, 117.6, 38.6 (q, 2 J C-F = 28.8 Hz), 38.3, 28.7; 19 F (376 MHz, CDCl 3 ): (t, J = 11.1 Hz); IR (KBr, cm -1 ): 1650, 1596, 1532, 1441, 1373, 1254, 1134, 1091, 969; HRMS m/z [M+H] + calculated for C 13 H 12 ClF 3 : ; found (7-fluoro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ga): F Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ga; white solid (21 mg, 77%); 1 H (400 MHz, CDCl 3 ): 7.70 (s, 1H), (m, 1H), (m, 1H), 4.38 (q, J = 11.2 Hz, 2H), 4.04 (d, J = 2.7 Hz, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.2,150.1 (d, J = Hz), 139.3, (d, J = 4.0 Hz), (q, J = Hz), (d, J = 7.0 Hz), (d, J = 1.7 Hz), (q, J = 3.4 Hz), 118.5,109.1 (d, J = 17.7 Hz), 38.4 (q, J = 28.8 Hz), 36.8 (d, J = 7.0 Hz), 28.6; 19 F (376 MHz, CDCl 3 ): -65.7, ; IR (KBr, cm -1 ): 1654, 1627, 1536, 1450, 1371, 1245, 1122, 798; HRMS m/z [M+H] + calculated for C 13 H 12 F 4 : ; found S15

16 (E)-1-(1-methyl-7-styryl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ha): Ph Following the general procedure with 15 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ha; white solid (26 mg, 73%); 1 H (400 MHz, CDCl 3 ): 7.72 (d, J = 15.9 Hz, 1H), 7.69 (s, 1H), (m, 2H), (m, 4H), 7.16 (d, J = 7.6 Hz, 1H), 6.92 (d, J = 15.9 Hz, 1H), 4.45 (q, J = 11.2 Hz, 2H), 4.05 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 140.1, 137.0, 136.0, 132.7, 128.8, 128.0, (q, 1 J C-F = Hz), 126.7, 126.5, (q, 3 J C-F = 3.4 Hz), 124.9, 124.2, 123.4, 117.8, 38.9, 38.9 (q, 2 J C-F = 28.7 Hz), 38.5, 28.6; 19 F (376 MHz, CDCl 3 ): -65.2; IR (KBr, cm -1 ): 1641, 1573, 1534, 1483, 1363, 1256, 1130, 1093, 746; HRMS m/z [M+H] + calculated for C 21 H 19 F 3 : ; found (1-methyl-7-phenethyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ia): Ph Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ia; white solid (28 mg, 78%); 1 H (400 MHz, CDCl 3 ): 7.67 (s, 1H), (m, 2H), (m, 1H), 7.16 (d, J = 6.8 Hz, 2H), (m, 2H), 4.42 (q, J = 11.2 Hz, 2H), 4.03 (s, 3H), (m, 2H), (m, 2H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.3, 140.8, 140.4, 136.6, 128.5, 128.3, 127.1, (q, 1 J C-F = Hz), 126.6, 126.3, 125.7, 125.6, (q, 3 J C-F = 3.1 Hz), 117.8, 38.8 (q, 2 J C-F = 28.6 Hz), 38.6, 38.1, 33.9, 28.6; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1654, 1582, 1534, 1433, 1365, 1256, 1237, 1126, 1080, 705; HRMS m/z [M+H] + calculated for C 21 H 21 F 3 : ; found (1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(2,2,2-trifluoroethyl)-1Hindol-3-yl)ethanone (3ja: B Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ja; white solid (16 mg, 42%); 1 H (400 MHz, CDCl 3 ): 7.77 (s, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 7.4 Hz, 1H), 4.48 (q, J = 11.2 Hz, 2H), 4.01 (s, 3H), 2.55 (s, 3H), 1.40 (s, 12H); 13 C (100 MHz, CDCl 3 ): 192.3, 141.4, 139.8, S16

17 131.9, (q, 1 J C-F = Hz), (q, 3 J C-F = 3.4 Hz), 125.8, 125.6, 117.8, 84.4, 39.1 (q, 2 J C-F = 28.6 Hz), 37.2, 28.5, 24.7; 19 F (376 MHz, CDCl 3 ): -65.1; IR (KBr, cm -1 ): 1648, 1536, 1400, 1322, 1262, 1122, 1082, 678; HRMS m/z [M+H] + calculated for C 19 H 24 BF 3 3 : ; found (1,2-dimethyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ka): Following the general procedure with 10 mol% Pd(Ac) 2 and 1 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ka; white solid (18 mg, 67%); 1 H (400 MHz, CDCl 3 ): (m,1h), (m, 1H), (m, 1H), 4.06 (q, J=11.3 Hz, 2H), 3.68 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H); 13 C (100 MHz, CDCl 3 ): 198.0, 140.7, 137.4, (q, 1 J C-F = Hz), 126.1, 124.8, (q, 3 J C-F = 3.2 Hz), 122.2, 117.6, 109.2, 38.2 (q, 2 J C-F = 28.8 Hz), 31.9, 29.8, 13.0; 19 F ( 376 MHz, CDCl 3 ): -65.0; IR (KBr, cm -1 ): 1644, 1575, 1511, 1435, 1402, 1363, 1260, 1124, 748; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 : ; found (2-butyl-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3la): Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether:etac=9:1) to provide 3la; light yellow liquid (21 mg, 68%); 1 H (400 MHz, CDCl 3 ): 7.34 (dd, J =8.2, 1.0 Hz, 1H), (m, 2H), 7.14 (d, J = 7.1 Hz, 1H), 4.06 (q, J = 11.2 Hz, 2H), 3.75 (s, 3H), (m, 2H), 2.66 (s, 3H), (m, 2H), (m, 2H), 1.04 (t, J = 7.3 Hz, 3H); 13 C(100 MHz, CDCl 3 ): 198.4, 144.7, 137.5, (q, 1 J C-F = Hz ), 126.1, 124.8, (q, 3 J C-F = 3.1 Hz), 122.3, 117.0, 109.3, 38.1 (q, 2 J C-F = 28.7 Hz), 32.2, 31.5, 29.8, 26.0, 22.8, 13.7; 19 F (376 MHz, CDCl 3 ): (t, J = 11.2 Hz); IR (KBr, cm -1 ): 1641, 1575, 1505, 1435, 1406, 1365, 1258, 1120, 1066, 752; HRMS m/z [M+H] + calculated for C 17 H 21 F 3 : ; found (1-methyl-2-phenyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ma): Ph Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 9:1) S17

18 to provide 3ma; white solid (28 mg, 85%); 1 H (400 MHz, CDCl 3 ): (m, 3H), (m, 2H), 7.38 (dd, J = 8.4, 1.2 Hz, 1H), (m, 1H), 7.18 (d, J = 7.1 Hz, 1H), 4.15 (q, J = 11.2 Hz, 2H), 3.56 (s, 3H), 1.93 (s, 3H); 13 C (100 MHz, CDCl 3 ): 198.8, 145.0, 137.6, 131.6, 130.5, 129.7, 128.9, (q, 1 J C-F = Hz), 126.5, 124.7, (q, 3 J C-F = 3.1 Hz), 123.0, 118.3, 109.9, 38.2 (q, 2 J C-F = 28.7 Hz), 31.4, 31.0; 19 F (376 MHz, CDCl 3 ): (t, J = 11.2 Hz); IR (KBr, cm -1 ): 1654, 1575, 1524, 1474, 1392, 1362, 1256, 1144, 1122, 748; HRMS m/z [M+H] + calculated for C 19 H 17 F 3 : ; found (1,6-dimethyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3na): F 3 C Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3na; white solid (18.8 mg, 70%). 1 H (400 MHz, CDCl 3 ): 7.72 (s,1h), 7.09 (s, 1H), 7.03 (s, 1H), 4.44 (q, J = 11.2 Hz, 2H), 3.78 (s, 3H), 2.52 (s, 3H), 2.48 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.0, 139.0, 137.9, 133.5, 127.9, (q, 1 J C-F = Hz), (q, 3 J C-F = 3.1 Hz), 123.5, 117.8, 109.7, 38.9 (q, 2 J C-F =28.5 Hz), 33.5, 28.2, 21.4; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1639, 1585, 1530, 1367, 1250, 1233, 1115, 794; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 : ; found (1-methyl-6-p-tolyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3oa): Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3oa; white solid (20.7 mg, 60%); 1 H (400 MHz, CDCl 3 ): 7.78 (s, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.45 (br, 2H), 7.28 (d, J = 8.0 Hz, 2H), 4.53 (q, J = 11.2 Hz, 2H), 3.84 (s, 3H), 2.41 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.0, 139.3, 138.6, 137.9, 137.1, 137.0, 129.6, 127.1, (q, 1 J C-F = Hz), 125.8, (q, 3 J C-F = 3.2 Hz), 124.6, 117.9, 107.7, 39.1 (q, 2 J C-F = 28.6 Hz), 38.6, 28.3, 21.1; 19 F (376 MHz, CDCl 3 ): -65.2; IR (KBr, cm -1 ): 1652, 1557, 1530, 1443, 1365, 1249, 1130, 1089, 808; HRMS m/z [M+H] + calculated for C 20 H 19 F 3 : ; found S18

19 1-(6-fluoro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3pa): F Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3pa; white solid (15 mg, 55%); 1 H (400 MHz, CDCl 3 ): 7.78 (s, 1H), 7.00 (s, 2H), 6.98 (s, 1H), 4.45 (q, J = 11.2 Hz, 2H), 3.78 (s, 3H), 2.52 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.1, (d, J = Hz), (d, J = 11.8 Hz), (d, J = 2.5 Hz), (d, J = 3.5 Hz), (q, J = Hz), 122.2, 118.2, (d, J = 24.0 Hz), 96.2 (d, J = 25.5 Hz), 38.8 (q, J = 28.8 Hz), 33.7, 28.3 ; 19 F (376 MHz, CDCl 3 ): -65.2, ; IR (KBr, cm -1 ): 1634, 1612, 1530, 1450, 1375, 1242, 1120; HRMS m/z [M+H] + calculated for C 13 H 12 F 4 : ; found (6-bromo-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3qa): Br Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether:etac=4:1) to provide 3qa; white solid (16 mg, 48%); 1 H (400 MHz, CDCl 3 ): (s, 1H), 7.47 (d, J = 1.7 Hz, 1H), 7.32 (s, 1H), 4.43 (q, J = 11.2 Hz, 2H), 3.80 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.0, 139.3, 138.5, 129.0, (q, 3 J C-F = 3.3 Hz), (q, 1 J C-F = Hz), 124.6, 118.2, 116.8, 112.8, 38.7 (q, 2 J C-F = 29.1 Hz), 37.7, 28.4 ; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1648, 1575, 1537, 1450, 1435, 1361, 1254, 1132, 1088, 955; HRMS m/z [M+H] + calculated for C 13 H 12 BrF 3 : ; found (6-chloro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ra): Cl Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ra; white solid (14 mg, 48%); 1 H (400 MHz, CDCl 3 ): 7.77 (s, 1H), 7.31 (d, J = 1.9 Hz, 1H), 7.19 (s, 1H), 4.43 (q, J = 11.2 Hz, 2H), 3.80 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.0, 139.0, 138.7, 129.3, (q, 3 J C-F = 3.2 Hz), (q, 1 J C-F = Hz), 126.4, 124.3, 118.1, 109.7, 38.8 (q, 2 J C-F = 29.1 Hz), 33.7, 28.4; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1645, 1590, 1536, 1442, 1365, 1250, 1130, 1088, 955; HRMS m/z [M+H] + calculated for C 13 H 12 ClF 3 : ; found S19

20 1-(6-methoxy-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3sa): Me Following the general procedure with 15 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3sa; white solid (12 mg, 43%); 1 H (400 MHz, CDCl 3 ): 7.69 (s, 1H), 6.86 (s, 1H), 6.73 (d, J = 2.3 Hz, 1H), 4.43 (q, J = 11.2 Hz, 2H), 3.88 (s, 3H), 3.78 (s, 3H), 2.51 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.0, 156.8, 139.6, 137.5, (q, 1 J C-F = Hz), (q, 3 J C-F = 3.3 Hz), 119.8, 118.0, 115.4, 93.0, 55.6, 38.9 (q, 2 J C-F = 28.6 Hz), 33.6, 28.2 ; 19 F (376 MHz, CDCl 3 ): -65.3; IR (KBr, cm -1 ): 1641, 1617, 1523, 1430, 1365, 1262, 1108, 1072, 793; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 2 : ; found (1,5-dimethyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3ua): Following the general procedure with 10 mol% Pd(Ac) 2 and 1 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ua; white solid (8 mg, 30%); 1 H (400 MHz, CDCl 3 ): 7.57 (s, 1H), 7.21 (s, 2H), 4.62 (q, J = 10.8 Hz, 2H), 3.80 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H); 13 C(100 MHz, CDCl 3 ): 192.5, 138.2, 137.3, 132.5, (q, 1 J C-F = Hz), 126.7, 126.4, (q, 3 J C-F = 3.1 Hz), 118.1, 109.4, 34.5 (q, 2 J C-F = 28.5 Hz), 33.5, 28.7, 20.3; 19 F (376 MHz, CDCl 3 ): IR (KBr, cm -1 ): 1635, 1575, 1538, 1357, 1252, 1230, 1111, 790; HRMS m/z [M+H] + calculated for C 14 H 15 F 3 : ; found (5-chloro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indol-3-yl)ethanone (3va): Cl Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc=4:1) to provide 3va; white solid (11 mg, 38%); 1 H (400 MHz, CDCl 3 ): 7.82 (s, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 1.4 Hz, 1H), (m, 2H), 3.85 (s, 3H), 2.57 (s, 3H); 13 C(100 MHz, CDCl 3 ): 192.3, 138.7, 136.9, 130.7, 126.9, 126.8, (q, 1 J C-F = Hz), (q, 3 J C-F = 3.1 Hz), 118.3, 110.7, 35.1 (q, 2 J C-F = 29.3 Hz), 33.7, 28.7; 19 F (376 MHz, CDCl 3 ): -64.5; IR (KBr, cm -1 ): 1649, 1586, 1531, 1442, 1375, 1257, 1131, 1090, 970; HRMS m/z [M+H] + calculated for C 13 H 12 ClF 3 : ; found S20

21 1-(4-(2,2,2-trifluoroethyl)benzo[b]thiophen-3-yl)ethanone (3wa): S Following the general procedure with 10 mol% Pd(Ac) 2 and 3 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether:etac=19:1) to provide 3wa; colorless liquid (20 mg, 80%); 1 H (400 MHz, CDCl 3 ): 8.15 (s, 1H), 7.89 (dd, J = 8.0, 1.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), (m, 1H), 4.13 (q, J = 11.2 Hz, 2H), 2.69 (s, 3H); 13 C (100 MHz, CDCl 3 ): 195.2, 141.8, 139.5, 135.4, 134.6, 130.5, (q, 3 J C-F = 3.2 Hz), (q, 1 J C-F = Hz), 125.2, 122.9, 38.8 (q, 2 J C-F = 29 Hz), 29.9; 19 F (376 MHz, CDCl3): -64.9; IR (KBr, cm -1 ): 1681, 1619, 1398, 1258, 1124, 1097, 800, 758; HRMS m/z [M+H] + calculated for C 12 H 10 F 3 S: ; found (1-methyl-4-(2,2,3,3,3-pentafluoropropyl)-1H-indol-3-yl)ethanone (3ab): F F Following the general procedure with 10 mol% Pd(Ac) 2 and 1 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ab; white solid (21 mg, 69%); 1 H (400 MHz, CDCl 3 ): 7.79 (s, 1H), (m, 2H), (m, 1H), 4.48 (t, J = 19.2 Hz, 2H), 3.83 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.1, 138.6, 138.2, 126.9, 126.1, 124.3, 123.3, 118.1, 109.7, 35.5 (t, J = 20.3 Hz), 33.6, 28.3; 19 F (376 MHz, CDCl 3 ): -84.7, (t, J = 19.2 Hz); IR (KBr, cm -1 ): 1652, 1571, 1526, 1452, 1377, 1210, 1095, 1033, 752; HRMS m/z [M+H] + calculated for C 14 H 13 F 5 : ; found (4-(2,2,3,3,4,4,4-heptafluorobutyl)-1-methyl-1H-indol-3-yl)ethanone (3ac): F F F F Following the general procedure with 10 mol% Pd(Ac) 2 and 1 equivalent TFA. Purified by column chromatography on silica gel (Petroleum ether : EtAc = 4:1) to provide 3ac; white solid (25 mg, 70%); 1 H (400 MHz, CDCl 3 ): 7.78 (s, 1H), 7.33 (s, 1H), 7.32 (d, J = 1.5 Hz, 1H), (m, 1H), 4.51 (t, J = 19.6 Hz, 2H), 3.82 (s, 3H), 2.53 (s, 3H); 13 C (100 MHz, CDCl 3 ): 192.1, 138.6, 138.2, 127.1, 126.2, 124.1, 123.3, 118.1, 109.7, 35.5 (t, J = 20.2 Hz), 33.6, 28.3; 19 F (376 MHz, CDCl3): (t, J = 9.7 Hz, 3F), {-113.8} (m, 2F), (t, J = 2.25 Hz, 2F); IR (KBr, cm -1 ): 1637, 1577, 1534, 1445, 1377, 1225, 1157, 1095, 752; HRMS m/z [M+H] + calculated for C 15 H 13 F 7 : ; found S21

22 7. Procedure for removal of directing group: 6 A mixture of indole substrate 3 (0.1 mmol), ethylene glycol (0.1 ml) and p-toluenesulfonic acid monohydrate (1.1 equiv, 21 mg) in dry benezene (2 ml) was heated under reflux condition for 6 hours. The progress of the reaction was monitored by TLC. Then the reaction mixture was cooled and saturated sodium bicarbonate solution was added. The benzene layer was separated, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to provide 4. 1-methyl-4-(2,2,2-trifluoroethyl)-1H-indole (4aa): Purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:1) to provide 4aa; white solid (17 mg, 78%). 1 H (400 MHz, CDCl 3 ): 7.33 (d, J = 8.3 Hz, 1H), (m, 1H), 7.12 (d, J = 3.2 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.54 (d, J = 3.1 Hz, 1H), 3.81 (s, 3H), 3.67 (q, J = 10.9 Hz, 2H); 13 C (100 MHz, CDCl 3 ): 136.7, 129.2, 128.8, (q, 1 J C-F = Hz), (q, 3 J C-F = 2.9 Hz), 121.6, 121.5, 109.3, 99.2, 37.7 (q, 2 J C-F = 29.9 Hz), 32.9; 19 F (376 MHz, CDCl 3 ): (t, J = 10.9 Hz); IR (KBr, cm -1 ): 1503, 1452, 1351, 1264, 1124, 1091, 748; HRMS m/z [M+H] + calculated for C 11 H 11 F 3 : ; found bromo-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indole (4ea): Br Purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:1) to provide 4ea; white solid (26 mg, 93%). 1 H (400 MHz, CDCl 3 ): 7.34 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 3.2 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.49 (d, J = 3.2 Hz, 1H), 4.16 (s, 3H), 3.59 (q, J = 10.8 Hz, 2H); 13 C (100 MHz, CDCl 3 ): 132.9, 132.2, 131.8, 126.4, (q, 1 J C-F = Hz), 122.6, 121.5, 104.1, 99.4, 37.2 (q, 2 J C-F = 30 Hz), 36.9; 19 F (376 MHz, CDCl 3 ): -64.9; IR (KBr, cm -1 ): 1510, 1457, 1365, 1242, 1125, 1075, 963. S22

23 7-chloro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indole (4fa): Cl Purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:1) to provide 4fa; white solid (22.3 mg, 90%). 1 H (400 MHz, CDCl 3 ): 7.14 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 3.2 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 4.16 (s, 3H), 3.61 (q, J = 10.8 Hz, 2H); 13 C (100 MHz, CDCl 3 ): 131.9, 131.8, (q, 1 J C-F = Hz), 122.9, 122.2, 120.9, 117.2, 117.1, 99.6, 37.2 (q, 2 J C-F = 30,0 Hz), 36.8; 19 F (376 MHz, CDCl 3 ): -65.0; IR (KBr, cm -1 ): 1508, 1462, 1362, 1252, 1132, 1078, methyl-2-phenyl-4-(2,2,2-trifluoroethyl)-1H-indole (4ma): Purified by column chromatography on silica gel (Petroleum ether : EtAc = Ph Me 100:1) to provide 4ma; white solid (27.3 mg, 95%). 1 H (400 MHz, CDCl 3 ): (m, 4H), (m, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 7.4 Hz,1H), 7.10 (d, J = 7.2 Hz, 1H), 6.60 (s, 1H), 3.75 (s, 3H), 3.67 (q, J = 10.9 Hz, 2H); 13 C (100 MHz, CDCl 3 ): 142.0, 138.3, 132.4, 129.3, 128.5, 128.3, 127.7, (q, 1 J C-F = Hz), 122.0, 121.6, 109.6, 99.9, 37.7 (q, 2 J C-F = 29.8 Hz), 31.3; 19 F (376 MHz, CDCl 3 ): ; IR (KBr, cm -1 ): 1510, 1457, 1365, 1255, 1135, 1082; HRMS m/z [M+H] + calculated for C 17 H 15 F 3 : ; found ,6-dimethyl-4-(2,2,2-trifluoroethyl)-1H-indole (4na): Purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:1) to provide 4na; white solid (16.5 mg, 73%). 1 H (400 MHz, CDCl 3 ): 7.11 (s, 1H), 7.04 (d, J = 3.1 Hz, 1H), 6.90 (s, 1H), 6.47 (d, J = 3.1 Hz, 1H), 3.76 (s, 3H), 3.61 (q, J=11.1 Hz, 2H), 2.50 (s, 3H); 13 C (100 MHz, CDCl 3 ): 137.1, 131.4, 128.6, 126.6, (q, 1 J C-F = Hz) , (q, 3 J C-F = 2.9 Hz); 109.3, 99.0, 37.7 (q, 2 J C-F = 29.8 Hz), 32.8, 21.7; 19 F (376 MHz, CDCl 3 ): (t, J = 10.9 Hz); IR (KBr, cm -1 ): 1507, 1460, 1355, 1255, 1120, 1081, 752; HRMS m/z [M+H] + calculated for C 12 H 13 F 3 : ; found fluoro-1-methyl-4-(2,2,2-trifluoroethyl)-1H-indole (4pa): S23

24 F Purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:1) to provide 4pa; white solid (17 mg, 74%). 1 H (400 MHz, CDCl 3 ): 7.08 (d, J=3.2 Hz, 1H), 7.00 (dd, J = 9.5, 1.5 Hz, 1H), 6.87 (dd, J = 10.0, 1.6 Hz, 1H), 6.49 (d, J = 3.2 Hz, 1H), 3.75 (s, 3H), 3.62 (q, J = 10.8 Hz, 2H); 13 C (100 MHz, CDCl 3 ): (d, J = Hz), (d, J = 12.3 Hz), (d, J = 3.5 Hz), (q, J = Hz), (q, J = 3.1 Hz), 123.0, (d, J = 25.3 Hz), 99.4, 95.7 (d, J = 25.8 Hz), 37.5 (q, J = 30.2 Hz), 33.0; 19 F (376 MHz, CDCl 3 ): (t, J = 10.9 Hz), (t, J = 9.7 Hz); IR (KBr, cm -1 ): 1504, 1465, 1360, 1249, 1128, 1075, In situ removal of the directing group A 10 ml Schlenk tube was charged with indole substrate 1a (0.2 mmol), (1H, 1Hperfluoroalkyl)mesityliodonium triflate (2a, 1.1 equiv) and Pd(Ac) 2 (10 mol%). The mixture was dissolved in 2.5 ml dichloromethane followed by addition of trifluoroacetic acid (3 equiv). The reaction mixture was stirred for 24 hours at room temperature. After that p-toluenesulfonic acid monohydrate (1.1 equiv) and ethylene glycol (0.16 ml) was added to the schlenk tube and allowed to stir over night at o C. Then the reaction mixture was cooled and saturated sodium bicarbonate solution was added. After as usual work up the crude was purified by column chromatography on silica gel to afford the pure product (29 mg, 70%). 8. Procedure for the synthesis of 1-methyl-3,4-bis(2,2,2-trifluoroethyl)-1H-indole (5aa): 5b In a 10 ml schlenk tube indole 4 (42.6 mg, 0.2 mmol) was dissolved in dichloromethane (2 ml) and 2,6-di-tert-butylpyridine (86 μl, 0.4 mmol) was added. The mixture was stirred for 5 min, then 2,2,2-trifluoroethyl(mesityl)iodonium trifluoromethanesulfonate 2a (124 mg, 0.26 mmol) was added. The reaction was stirred overnight. Then the reaction mixture was passed through a short pad of celite and washed with EtAc. The solvent was evaporated under reduced pressure and the crude was purified by column chromatography on silica gel (Petroleum ether : EtAc = 100:2) to provide 5aa as colorless liquid (39.5 mg, 67%) CF 3 1 H (400 MHz, CDCl 3 ): 7.37 (dd, J = 8.3, 0.8 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 7.14 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.81 (q, J = 10.4 Hz, 2H), 3.71 (q, J = 10.5 Hz, 2H); 13 C (100 MHz, CDCl 3 ): 137.6, 130.8, 126.3, (q, 1 J C-F S24

25 = Hz), (q, 1 J C-F = Hz), 123.9, (q, 3 J C-F = 2.9 Hz), 121.7, 109.9, (q, 3 J C-F = 3.4 Hz), 37.3 (q, 2 J C-F = 29.4 Hz), 32.9, 31.7 (q, 2 J C-F = 31.0 Hz); 19 F (376 MHz, CDCl 3 ): -65.0, -66.1; IR (KBr, cm -1 ): 1460, 1402, 1256, 1136, 1093, RTEP diagram of 3aa Bond lengths [Å] and angles [ ] for szzindia_0m_a. C(1)-F(1) 1.337(2) C(1)-F(3) 1.343(2) C(1)-F(2) 1.351(2) C(1)-C(2) 1.490(3) C(2)-C(3) 1.507(2) C(2)-H(2A) C(2)-H(2B) C(3)-C(4) 1.387(3) C(3)-C(8) 1.412(2) C(4)-C(5) 1.399(3) C(4)-H(4) C(5)-C(6) 1.371(3) S25 C(5)-H(5) C(6)-C(7) 1.392(3) C(6)-H(6) C(7)-(1) 1.380(2) C(7)-C(8) 1.416(2) C(8)-C(9) 1.457(2) C(9)-C(12) 1.382(2) C(9)-C(10) 1.453(2) C(10)-(1) 1.226(2) C(10)-C(11) 1.512(2) C(11)-H(11A) C(11)-H(11B) C(11)-H(11C) C(12)-(1) 1.345(2)

26 C(12)-H(12) C(13)-(1) 1.455(2) C(13)-H(13A) C(13)-H(13B) C(13)-H(13C) F(1)-C(1)-F(3) (16) F(1)-C(1)-F(2) (15) F(3)-C(1)-F(2) (15) F(1)-C(1)-C(2) (15) F(3)-C(1)-C(2) (16) F(2)-C(1)-C(2) (16) C(1)-C(2)-C(3) (14) C(1)-C(2)-H(2A) C(3)-C(2)-H(2A) C(1)-C(2)-H(2B) C(3)-C(2)-H(2B) H(2A)-C(2)-H(2B) C(4)-C(3)-C(8) (16) C(4)-C(3)-C(2) (15) C(8)-C(3)-C(2) (15) C(3)-C(4)-C(5) (17) C(3)-C(4)-H(4) C(5)-C(4)-H(4) C(6)-C(5)-C(4) (17) C(6)-C(5)-H(5) C(4)-C(5)-H(5) C(5)-C(6)-C(7) (16) C(5)-C(6)-H(6) C(7)-C(6)-H(6) (1)-C(7)-C(6) (16) (1)-C(7)-C(8) (15) C(6)-C(7)-C(8) (16) C(3)-C(8)-C(7) (15) C(3)-C(8)-C(9) (15) C(7)-C(8)-C(9) (14) C(12)-C(9)-C(10) (15) C(12)-C(9)-C(8) (14) C(10)-C(9)-C(8) (14) (1)-C(10)-C(9) (16) (1)-C(10)-C(11) (15) C(9)-C(10)-C(11) (14) C(10)-C(11)-H(11A) C(10)-C(11)-H(11B) H(11A)-C(11)-H(11B) C(10)-C(11)-H(11C) H(11A)-C(11)-H(11C) H(11B)-C(11)-H(11C) (1)-C(12)-C(9) (15) (1)-C(12)-H(12) C(9)-C(12)-H(12) (1)-C(13)-H(13A) (1)-C(13)-H(13B) H(13A)-C(13)-H(13B) (1)-C(13)-H(13C) H(13A)-C(13)-H(13C) H(13B)-C(13)-H(13C) C(12)-(1)-C(7) (13) C(12)-(1)-C(13) (16) C(7)-(1)-C(13) (16) Torsion angles [ ] for szzindia_0m_a. F(1)-C(1)-C(2)-C(3) -57.6(2) F(3)-C(1)-C(2)-C(3) 63.11(19) F(2)-C(1)-C(2)-C(3) (15) C(1)-C(2)-C(3)-C(4) -88.6(2) C(1)-C(2)-C(3)-C(8) 89.0(2) C(8)-C(3)-C(4)-C(5) -1.7(3) C(2)-C(3)-C(4)-C(5) (16) C(3)-C(4)-C(5)-C(6) 0.8(3) C(4)-C(5)-C(6)-C(7) 0.6(3) C(5)-C(6)-C(7)-(1) (17) S26

27 C(5)-C(6)-C(7)-C(8) -1.3(3) C(4)-C(3)-C(8)-C(7) 1.0(2) C(2)-C(3)-C(8)-C(9) 1.7(3) (1)-C(7)-C(8)-C(3) (14) C(6)-C(7)-C(8)-C(3) 0.4(2) (1)-C(7)-C(8)-C(9) 0.92(17) C(6)-C(7)-C(8)-C(9) (16) C(3)-C(8)-C(9)-C(12) (18) C(7)-C(8)-C(9)-C(12) -0.25(17) C(3)-C(8)-C(9)-C(10) 4.8(3) C(7)-C(8)-C(9)-C(10) (17) C(12)-C(9)-C(10)-(1) (16) C(8)-C(9)-C(10)-(1) 8.0(3) C(12)-C(9)-C(10)-C(11) 10.8(2) C(8)-C(9)-C(10)-C(11) (17) C(10)-C(9)-C(12)-(1) (15) C(8)-C(9)-C(12)-(1) -0.53(18) C(9)-C(12)-(1)-C(7) 1.13(19) C(9)-C(12)-(1)-C(13) (15) C(6)-C(7)-(1)-C(12) (16) C(8)-C(7)-(1)-C(12) -1.27(18) C(6)-C(7)-(1)-C(13) 0.6(3) C(8)-C(7)-(1)-C(13) (15) C(2)-C(3)-C(8)-C(7) (14) C(4)-C(3)-C(8)-C(9) (18) S27

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