Palladium-Catalyzed Cascade Process Consisting of

Palladium-Catalyzed Cascade Process Consisting of Isocyanide Insertion and Benzylic C(sp3)–H Activation: Concise Synthesis of Indole Derivatives Takeshi Nanjo, Chihiro Tsukano, Yoshiji Takemoto Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan

Table of Contents

General Experimental Details.............S2 Preparation of Arylisocyanides............................................................................S2 Procedure for the Synthesis of 2-Arylindoles..........................S5 Procedure for Domino Reaction...............S11 References................................................S13 NMR spectra............S14

S1

General Experimental Details Unless otherwise noted, all reactions were performed under argon. Pd(OAc)2 and Cs2CO3 were purchased from Sigma Aldrich. Ad2PnBu was purchased from Sigma Aldrich or Stream Chemicals Inc. Toluene was purchased from Kanto Chemical Co., Inc. and dried over molecular sieves. Unless otherwise noted, all other reagents were purchased from commercial suppliers and used as received. Analytical thin-layer chromatography was performed with Merck Silica gel 60. Silica gel column chromatography was performed with Kanto silica gel 60 (particle size, 63–210 µm) or Fuji Silysia BW-300. All melting points (m.p.) were determined on YANAGIMOTO micro melting point apparatus. Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a JEOL JNM-LA 500 at 500 MHz. Chemical shifts are reported relative to Me4Si (δ 0.00). Multiplicity is indicated by one or more of the following: s (singlet); d (doublet); t (triplet); q (quartet); sep (septet); m (multiplet); br (broad). Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a JEOL JNM-LA 500 at 126 MHz. Chemical shifts are reported relative to CDCl3 (δ 77.0). Infrared spectra were recorded on a FT/IR-4100 (JASCO). Low and high resolution mass spectra were recorded on JEOL JMS-HX/HX 110A All GC-MS analyses were conducted with SHIMADZU GCMS-QP2010 equipped with DB5MS column (30 m x 0.25 mm ID, x 0.25 µm film). The temperature for each run was held at 80 °C for 2 min, ramped from 80 °C to 300 °C at 27.5 °C/min, and held at 300 °C for 40 min. n

dodecane was used for GC-MS analyses as internal standard.

Preparation of Arylisocyanides

2,6-Dimethylphenylisocyanide1 (1a): To formic acid (6.60 mL, 175 mmol) was added acetic anhydride (5.91 mL, 62.5 mmol) and the mixure was stirred at room temperature. After stirring for 15 min, to the mixture was added the solution of dimethylaniline (6.06 g, 50.0 mmol) in CH2Cl2 (40 mL) and the mixture was stirred at room temperature. After stirring for 2 h, the mixture was concentrated under reduced pressure to give formanilide (7.19 g, 96%) as white solid. To the solution of the formanilide and Et3N (20.2 mL, 145 mmol) in THF (100 mL) was added POCl3 (5.39 mL, 57.8 mmol) at 0 °C and stirred at the same temperature. After stirring for 2h, the reaction mixture was basified with saturated aqueous solution of NaHCO3, and extracted S2

with Et2O. The combined extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc = 95/5) to give 1a (4.65 g, 74%) as a white solid: m.p. 75.2-75.7 °C;1H NMR (500 MHz, CDCl3) δ 7.18 (t, 1H, J = 7.5 Hz), 7.10 (d, 2H, J = 7.5 Hz), 2.42 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 167.5 (t, J = 6.0 Hz), 134.8, 128.6, 127.7, 126.6 (t, J = 12.6 Hz), 18.8; IR (ATR) 2119, 1949, 1879, 1812, 1471, 1378 cm–1; MS (FAB+) m/z = 132 ([M+H]+); Anal. Calcd for C9H9N: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.17; H, 6.99; N, 10.62.

2,6-Dimethyl-4-nitrophenylisocyanide (1b): The reaction was performed according to the procedure for 1a. A white solid: m.p. 122.4-122.9 °C; 1H NMR (500 MHz, CDCl3) δ 8.01 (s, 2H), 2.55 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 172.8, 146.7, 136.8, 131.3 (t, J = 12.0 Hz), 122.8, 19,2; IR (ATR) 2985, 2118, 1533, 1374, 1355 cm–1; MS (FAB+) m/z = 177 ([M+H]+); Anal. Calcd for C9H8N2O2: C, 61.36; H, 4.58; N, 15.90. Found: C, 61.20; H, 4.40; N, 15.89.

4-Methoxy-2,6-dimethylphenylisocyanide (1c): The reaction was performed according to the procedure for 1a. A white solid: m.p. 55.2-55.7 °C; 1H NMR (500 MHz, CDCl3) δ 6.60 (s, 2H), 3.78 (s, 3H), 2.38 (s, 6H); 13C NMR (126 MHz, CDCl3) δ 166.1 (t, J = 6.0 Hz), 159.1, 136.4, 119.7 (t, J = 13.2 Hz), 112.9, 55.3, 19.1; IR (ATR) 2843, 2115, 1475, 1380 cm–1; MS (FAB+) m/z = 162 ([M+H]+); Anal. Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found: C, 74.35; H, 6.85; N, 8.69.

2-Chloro-6-methylphenylisocyanide (1d): The reaction was performed according to the procedure for 1a. A white solid: m.p. 60.4-60.8 °C; 1H NMR (500 MHz, CDCl3) δ 7.30 (d, 1H, J = 8.0 Hz), 7.23 (dd, 1H, J1 = 8.0 Hz, J2 = 7.4 Hz), 7.18 (d, 1H, J = 7.4 Hz), 2.45 (s, 3H); 13C NMR S3

(126 MHz, CDCl3) δ 170.7, 137.0, 130.6, 129.4, 128.5, 127.2, 125.3 (t, J = 14.4 Hz), 19.1; IR (ATR) 2122, 1958, 1882, 1805, 1459, 1386 cm–1; MS (FAB+) m/z = 152 ([M+H]+); Anal. Calcd for C8H6ClN: C, 63.38; H, 3.99; N, 9.24. Found: C, 63.18; H, 3.97; N, 9.21.

2-Ethyl-6-methylphenylisocyanide (1e): The reaction was performed according to the procedure for 1a. A yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.21 (dd, 1H, J1 = J2 = 7.7 Hz), 7.10 (d, 2H, J = 7.7 Hz), 2.78 (q, 2H, J = 7.7 Hz), 2.42 (s, 3H), 1.26 (t, 3H, J = 7.7 Hz); 13C NMR (126 MHz, CDCl3) δ 167.7 (t, J = 6.0 Hz), 140.5, 134.9, 128.8, 127.7, 126.1, 125.9 (t, J = 12.0 Hz), 25.7, 18.9, 13.8; IR (ATR) 2116, 1475, 1461, 1382 cm–1; MS (FAB+) m/z = 146 ([M+H]+); Anal. Calcd for C10H11N: C, 82.72; H, 7.64; N, 9.65. Found: C, 82.93; H, 7.80; N, 9.64.

2,6-Diethylphenylisocyanide (1f): The reaction was performed according to the procedure for 1a. A yellow oil; 1H NMR (500 MHz, CDCl3) δ 7.25 (t, 1H, J = 7.5 Hz), 7.11 (d, 2H, J = 7.5 Hz), 2.79 (q, 4H, J = 7.5 Hz), 1.26 (t, 6H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 167.8 (t, J = 6.0 Hz), 140.7, 129.0, 126.1, 125.2 (t, J = 12.0 Hz), 25.7, 13.8; IR (ATR) 2116, 1474, 1455, 1377 cm–1; MS (FAB+) m/z = 160 ([M+H]+); Anal. Calcd for C11H13N: C, 82.97; H, 8.23; N, 8.80. Found: C, 83.06; H, 8.52; N, 8.71.

2,4-Dimethylphenylisocyanide (1g): The reaction was performed according to the procedure for 1a. A colorless oil; 1H NMR (500 MHz, CDCl3) δ 7.20 (d, 1H, J = 8.0 Hz), 7.06 (s, 1H), 6.99 (d, 1H, J = 8.0 Hz), 2.37 (s, 3H), 2.32 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 164.8 (t, J = 6.0 Hz), 139.4, 134.5, 131.0, 127.2, 126.1, 123.9 (t, J = 13.2 Hz), 21.1, 18.3; IR (ATR) 2117, 1456, 1382 cm–1; MS (FAB+) m/z = 131 ([M]+); HRMS (FAB+) Calcd for C9H9N [M]+: 131.0735; found: 131.0730.

S4

Procedure for the Synthesis of 2-Arylindoles

7-Methyl-2-phenyl-1H-indole2 (3a): To a stirred solution of iodobenzene 2a (155 mg, 0.760 mmol) in toluene (2 mL) was added Pd(OAc)2 (4.3 mg, 0.0192 mmol), Ad2PnBu (13.7 mg, 0.0382 mmol) and Cs2CO3 (149 mg, 0.457 mmol) at room temperature and the reaction mixture was heated to 100 °C. After stirring for 10 min, 2,6-dimethylphenylisocyanide 1a (50.0 mg, 0.381 mmol) in toluene (2 mL) was added dropwise for 3 h and stirred for 100 °C. After stirring for 1 h, the reaction mixture was neutralized by saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc = 98/2) to give 3a (63.7 mg, 81%) as a white solid: m.p. 116.0-117.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.18 (brs, 1H), 7.68 (d, 2H, J = 8.1 Hz), 7.48 (d, 1H, J = 7.7 Hz), 7.44 (dd, 2H, J1 = 8.1 Hz, J2 = 7.5 Hz), 7.32 (t, 1H, J = 7.5 Hz), 7.04 (dd, 1H, J1 = 7.7 Hz, J2 = 7.2 Hz), 6.99 (d, 1H, J = 7.2 Hz), 6.83 (s, 1H), 2.53 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.6, 136.4, 132.5, 129.0, 128.8, 127.6, 125.2, 122.9, 120.4, 120.0, 118.4, 100.5, 16.7; IR (ATR) 3448, 1447, 1378 cm–1; MS (FAB+): m/z = 207 ([M]+); HRMS (FAB+) Calcd for C15H13N [M]+: 207.1048; found: 207.1041.

7-Methyl-2-(4-nitrophenyl)-1H-indole (3b): The reaction was performed according to the procedure for 3a with 10 mol % of Pd(OAc)2 and 20 mol % of Ad2PnBu and gave 3b in 81% yield as a yellow solid: m.p. 221.2-222.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.31-8.29 (m, 3H), 7.82-7.81 (m, 2H), 7.52 (d, 1H, J = 6.6 Hz), 7.10-7.02 (m, 3H), 2.57 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 146.6, 138.5, 137.3, 134.9, 128.5, 125.1, 124.5, 124.5, 121.2, 120.5, 119.1, 104.1, 16.7; IR (ATR) 3427, 1499, 1430, 1380, 1327, 739 cm–1; MS (FAB+): m/z = 252 ([M]+); HRMS (FAB+) Calcd for C15H12N2O2 [M]+: 252.0899; found: 252.0890.

S5

7-Methyl-2-(4-trifluoromethylphenyl)-1H-indole (3c): According to the procedure for 3b, the reaction gave 3c in 76% yield as a white solid: m.p. 117.2-118.0 °C; 1H NMR (500 MHz, CDCl3) δ 8.17 (brs, 1H), 7.70 (d, 2H, J = 8.6 Hz), 7.63 (d, 2H, J = 8.6 Hz), 7.48 (d, 1H, J = 7.5 Hz), 7.07-7.01 (m, 2H), 6.87 (d, 1H, J = 2.0 Hz), 2.51 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 136.8, 135.8, 135.8, 129.2 (q, J = 32.4 Hz), 128.6, 125.9 (q, J = 3.6 Hz), 125.1, 124.1 (q, J = 272.3 Hz), 123.7, 120.8, 120.3, 118.7, 102.2, 16.7; IR (ATR) 3488, 1429, 1323, 1106 cm–1; MS (FAB+): m/z = 275 ([M]+); HRMS (FAB+) Calcd for C16H12F3N [M]+: 275.0922; found: 275.0928.

4-(7-Methyl-1H-indol-2-yl)benzonitrile (3d): According to the procedure for 3b, the reaction gave 3d in 71% as a white solid: m.p. 169.0-169.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.33 (brs, 1H), 7.75 (d, 2H, J = 8.3 Hz), 7.69 (d, 2H, J = 8.3 Hz), 7.50 (d, 1H, J = 7.5 Hz), 7.09-7.04 (m, 2H), 6.95 (d, 1H, J = 2.0 Hz), 2.55 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.1, 136.7, 135.2, 132.7, 128.5, 125.2, 124.1, 121.0, 120.4, 118.9, 118.9, 110.3, 103.2, 16.7; IR (ATR) 3312, 2227, 1438, 1378 cm–1; MS (FAB+) m/z = 232 ([M]+); HRMS (FAB+) Calcd for C16H13N2 [M+H]+: 233.1079; found: 233.1082.

Methyl 4-(7-methyl-1H-indol-2-yl)benzoate (3e): According to the procedure for 3b, the reaction gave 3e in 83% as a white solid: m.p. 188.7-189.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.31 (brs, 1H), 8.09 (d, 2H, J = 8.0 Hz), 7.73 (d, 2H, J = 8.0 Hz), 7.50 (d, 1H, J = 7.7 Hz), 7.06 (dd, 1H, J1 = 7.7 Hz, J2 = 7.2 Hz), 7.03 (d, 1H, J = 7.2 Hz), 6.94 (d, 1H, J = 2.0 Hz), 3.93 (s, 3H), 2.55 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 166.8, 136.8, 136.6, 136.2, 130.3, 128.7, 128.6, 124.7, 123.7, 120.7, 120.3, 118.7, 102.4, 52.2, 16.7; IR (ATR) 3376, 1694, 1432, 1281 cm–1; MS (FAB+) m/z = 265 ([M]+); HRMS (FAB+) Calcd for C17H15NO2 [M]+: 265.1103; found: 265.1114. S6

2-(4-Chlorophenyl)-7-methyl-1H-indole (3f): According to the procedure for 3b, the reaction gave 3f in 81% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.06 (brs, 1H), 7.50 (d, 2H, J = 8.3 Hz), 7.44 (d, 1H, J = 7.5 Hz), 7.33 (d, 2H, J = 8.3 Hz), 7.03 (d, 1H, J = 7.5 Hz), 6.97 (d, 1H, J = 7.5 Hz), 6.74 (d, 1H, J = 2.3 Hz), 2.47 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 136.5, 136.3, 133.2, 130.9, 129.1, 128.7, 126.2, 123.2, 120.6, 120.1, 118.4, 101.0, 16.6; IR (ATR) 3454, 1480, 1376, 1092 cm–1; MS (FAB+): m/z = 241 ([M]+); HRMS (FAB+) Calcd for C15H12ClN [M]+: 241.0658; found: 241.0660.

2-(4-Methoxyphenyl)-7-methyl-1H-indole (3g): According to the procedure for 3b, the reaction gave 3g in 51% yield as a white solid: m.p. 139.3-139.7 °C; 1H NMR (500 MHz, CDCl3) δ 8.09 (brs, 1H), 7.59-7.56 (m, 2H), 7.45 (d, 1H, J = 8.0 Hz), 7.03 (dd, 1H, J1 = 7.7 Hz, J2 = 7.2 Hz), 6.97-6.94 (m, 3H), 6.70 (d, 1H, J = 2.1 Hz), 3.82 (s, 3H), 2.51 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.3, 137.7, 136.2, 128.9, 126.5, 125.3, 122.5, 120.3, 119.9, 118.1, 114.4, 99.4, 55.3, 16.7; IR (ATR) 3397, 2838, 1455, 1432, 1384 cm–1; MS (FAB+): m/z = 237 ([M]+); HRMS (FAB+) Calcd for C16H14NO [M]+: 237.1154; found: 237.1161.

7-Methyl-2-(4-methylphenyl)-1H-indole (3h): According to the procedure for 3b, the reaction gave 3h in 80% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.15 (brs, 1H), 7.57 (d, 2H, J = 8.3 Hz), 7.47 (d, 1H, J = 7.5 Hz), 7.24 (d, 2H, J = 8.3 Hz), 7.05 (dd, 1H, J1 = J2 = 7.5 Hz), 6.98 (d, 1H, J = 7.5 Hz), 6.78 (1H, d, J = 2.3 Hz), 2.53 (s, 3H), 2.39 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.8, 137.5, 136.3, 129.7, 129.7, 128.9, 125.1, 122.7, 120.3, 119.9, 118.2, 100.0, 21.2, 16.7; IR (ATR) 3451, 1427, 1377, 1354 cm–1; MS (FAB+): m/z = 221 ([M]+); HRMS (FAB−) Calcd for C16H14N [M−H]−: 220.1126; found: 220.1131.

S7

7-Methyl-2-(3-methylphenyl)-1H-indole (3i): According to the procedure for 3b, the reaction gave 3i in 84% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.11 (brs, 1H), 7.46-7.43 (m, 3H), 7.28 (dd, 1H, J1 = J2 = 7.5 Hz), 7.10 (d, 1H, J = 7.5 Hz), 7.02 (dd, 1H, J1 = J2 = 7.5 Hz), 6.96 (d, 1H, J = 7.5 Hz), 6.78 (d, 1H, J = 2.0 Hz), 2.49 (s, 3H), 2.39 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 138.6, 137.7, 136.3, 132.4, 128.8, 128.8, 128.4, 125.8, 122.8, 122.3, 120.4, 120.0, 118.3, 100.4, 21.5, 16.7; IR (ATR) 3371, 1452, 1374, 1362 cm–1; MS (FAB+): m/z = 222 ([M+H]+); HRMS (FAB−) Calcd for C16H14N [M−H]−: 220.1126; found: 220.1136.

Me

N H

Me

7-Methyl-2-(2-methylphenyl)-1H-indole (3j): According to the procedure for 3b, the reaction gave 3j in 45% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.00 (brs, 1H), 7.50-7.46 (m, 2H), 7.30-7.25 (m, 3H), 7.07-7.03 (m, 1H), 6.99 (d, 1H, J = 7.2 Hz), 6.60 (d, 1H, J1 = 2.9 Hz, J2 = 2.0 Hz), 2.49 (s, 3H), 2.48 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 137.0, 136.2, 135.6, 132.8, 131.0, 128.9, 128.3, 127.9, 126.0, 122.6, 120.2, 120.0, 118.2, 103.4, 21.0, 16.7; IR (ATR) 3416, 1488, 1455, 1377, 1349 cm–1; MS (FAB+): m/z = 221 ([M]+); HRMS (FAB−) Calcd for C16H14N [M−H]−: 220.1126; found: 220.1129.

7-Methyl-2-(thiophen-2-yl)-1H-indole (3k): According to the procedure for 3b, the reaction gave 3k in 64% yield as a yellow solid: m.p. 89.5-90.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.05 (brs, 1H), 7.43 (d, 1H, J = 7.4 Hz), 7.25 (d, 2H, J = 4.0 Hz), 7.06 (dd, 1H, J1 = 8.1 Hz, J2 = 4.0 Hz), 7.02 (d, 1H, J = 8.1 Hz), 6.98 (d, 1H, J = 7.5 Hz), 6.72 (d, 1H, J = 2.3 Hz), 2.49 (s, 3H); 13

C NMR (126 MHz, CDCl3) δ 136.1, 135.7, 132.0, 128.6, 127.8, 124.5, 123.1, 122.9, 120.6,

119.9, 118.2, 101.0, 16.7; IR (ATR) 3429, 1454, 1420, 1376 cm–1; MS (FAB+) m/z = 213 ([M]+); HRMS (FAB+) Calcd for C13H11NS [M]+: 213.0612; found: 213.0613.

S8

tert-Butyl 2-(7-methyl-1H-indol-2-yl)-1H-pyrrole-1-carboxylate (3l): According to the procedure for 3b, the reaction gave 3l in 44% as a yellow solid: m.p. 110.1-110.5 °C; 1H NMR (500 MHz, CDCl3) δ 9.80 (brs, 1H), 7.43 (d, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 3.5 Hz), 7.01 (dd, 1H, J1 = 7.8 Hz, J2 = 7.2 Hz), 6.98 (d, 1H, J = 7.2 Hz), 6.71 (d, 1H, J = 2.0 Hz), 6.64 (dd, 1H, J1 = 3.5 Hz, J2 = 2.0 Hz), 6.25 (dd, 1H, J1 = J2 = 3.5 Hz), 2.53 (s, 3H), 1.56 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 150.0, 135.8, 129.8, 127.6, 127.6, 123.2, 122.3, 120.2, 120.0, 117.8, 115.7, 111.3, 103.1, 84.7, 27.9, 16.6; IR (ATR) 3396, 1727, 1530, 1453, 1146 cm–1; MS (FAB+) m/z = 297 ([M+H]+); HRMS (FAB+) Calcd for C18H21N2O2 [M+H]+: 297:1603; found: 297.1605.

7-Methyl-5-nitro-2-phenyl-1H-indole (3m): According to the procedure for 3b, the reaction gave 3m in 77% yield as a yellow solid: m.p. 220.0-220.7 °C; 1H NMR (500 MHz, CDCl3) δ 8.47 (brs, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.69 (dd, 2H, J1 = 7.5 Hz, J2 = 2.0 Hz), 7.48 (dd, 2H, J1 = J2 = 7.5 Hz), 7.39 (t, 1H, J = 7.5 Hz), 6.94 (d, 1H, J = 2.0 Hz), 2.60 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 142.6, 140.8, 139.5, 131.4, 129.3, 128.7, 128.2, 125.5, 120.5, 118.2, 115.6, 102.3, 16.6; IR (ATR) 3394, 1517, 1468, 1301, 732 cm–1; MS (FAB+): m/z = 252 ([M]+); HRMS (FAB+) Calcd for C15H12N2O2 [M]+: 252.0899; found: 252.0888.

5-Methoxy-7-methyl-2-phenyl-1H-indole (3n): According to the procedure for 3b, the reaction gave 3n in 85% yield as a white solid: m.p. 107.0-108.5 °C; 1H NMR (500 MHz, CDCl3) δ 8.11 (brs, 1H), 7.63 (d, 2H, J = 7.8 Hz), 7.39 (dd, 2H, J1 = J2 = 7.8 Hz), 7.27 (dd, 1H, J1 = J2 = 7.8 Hz), 6.91 (d, 1H, J = 2.0 Hz), 6.72 (d, 1H, J = 2.0 Hz), 6.66 (d, 1H, J = 2.0 Hz), 3.81 (s, 3H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 154.5, 138.2, 132.5, 131.7, 129.1, 128.9, 127.4, 125.0, 121.1, 113.3, 100.3, 99.7, 55.7, 16.7; IR (ATR) 3446, 2855, 1476, 1452, 1399, 1203, 1142 cm–1; MS (FAB+): m/z = 237 ([M]+); HRMS (FAB+) Calcd for C16H15NO [M]+: 237.1154; found: 237.1143. S9

7-Chloro-2-phenyl-1H-indole (3o): According to the procedure for 3b, the reaction gave 3o in 34% as a white solid: m.p. 105.7-107.2 °C; 1H NMR (500 MHz, CDCl3) δ 8.46 (brs, 1H), 7.67 (d, 2H, J = 8.3 Hz), 7.51 (dd, 1H, J1 = 7.7 Hz, J2 = 0.9 Hz), 7.44 (dd, 2H, J1 = 8.3 Hz, J2 = 7.8 Hz), 7.34 (dd, 1H, J1 = J2 = 7.7 Hz), 7.18 (dd, 1H, J1 = 7.7 Hz, J2 = 0.9 Hz), 7.04 (t, 1H, J = 7.8 Hz), 6.83 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 138.6, 134.0, 131.7, 130.5, 129.1, 128.1, 125.3, 121.6, 121.0, 119.2, 116.3, 100.8; IR (ATR) 3437, 1451, 1392, 1073 cm–1; MS (FAB+) m/z = 227 ([M]+); Anal. Calcd for C14H10ClN: C, 73.85; H, 4.43; N, 6.15. Found: C, 73.75; H, 4.41; N, 6.30.

7-Ethyl-2-phenyl-1H-indole3 (3p): According to the procedure for 3b, the reaction gave 3p in 78% yield as a yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.17 (brs, 1H), 7.64 (dd, 2H, J1 = 7.2 Hz, J2 = 1.3 Hz), 7.47 (d, 1H, J = 7.8 Hz), 7.40 (ddd, 2H, J1 = J2 = 7.2 Hz, J3 = 1.5 Hz), 7.28 (ddd, 1H, J1 = J2 = 7.5 Hz, J3 = 1.5 Hz), 7.07 (ddd, 1H, J1 = J2 = 7.5 Hz, J3 = 2.3 Hz), 7.02 (d, 1H, J = 7.5 Hz), 6.80 (dd, 1H, J1 = J2 = 2.3 Hz), 2.87 (q, 2H, J = 7.5 Hz), 1.38 (t, 3H, J = 7.5 Hz); 13C NMR (126 MHz, CDCl3) δ 137.5, 135.6, 132.5, 129.0, 128.9, 127.6, 126.2, 125.1, 120.8, 120.5, 118.4, 100.5, 23.9, 13.8; IR (ATR) 3442, 1452, 1432, 1394 cm–1; MS (FAB+): m/z = 222 ([M+H]+); HRMS (FAB−) Calcd for C16H14N [M−H]−: 220.1126; found: 220.1136.

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Procedure for Domino Reaction

1-Methyl-6-phenyl-11H-benzo[a]carbazole (4a): To a stirred solution of 2-iodo-m-xylene (23.2 mg, 0.100 mmol) in toluene (1 mL) was added Pd(OAc)2 (2.3 mg, 0.0102 mmol), Ad2PnBu (7.2 mg, 0.0201 mmol) and Cs2CO3 (97.7 mg, 0.300 mmol) at room temperature and the reaction mixture was heated to 100 °C. After stirring for 10 min, 1-isocyano-2(phenylethynyl)benzene4 (0.200 mmol) in toluene (2 mL) was added for 3 h and stirred for 100 °C. After stirring for 1 h, the reaction mixture was neutralized by saturated aqueous solution of NH4Cl and extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc = 97/3) to give 4 (20.4 mg, 66%) as a colorless crystal: m.p. 154.6-155.3 °C; 1H NMR (500 MHz, CDCl3) δ 9.25 (brs, 1H), 7.84 (d, 1H, J = 8.0 Hz), 7.67 (d, 2H, J = 7.7 Hz), 7.58-7.50 (m, 5H), 7.41-7.33 (m, 4H), 7.03 (dd, 1H, J1 = 8.0 Hz, J2 = 6.9 Hz), 3.14 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 141.2, 138.4, 136.3, 135.9, 133.3, 131.6, 129.3, 128.3, 127.7, 127.5, 127.3, 125.2, 124.4, 122.7, 122.0, 121.9, 120.6, 119.5, 117.5, 110.8, 23.8; IR (ATR) 3498, 1568, 1523, 1445, 1356 cm–1; MS (FAB+): m/z = 307 ([M]+); Anal. Calcd for C23H17N: C, 89.87; H, 5.57; N, 4.56. Found: C, 89.63; H, 5.72; N, 4.56.

1-Methyl-6-(4-nitrophenyl)-11H-benzo[a]carbazole (4b): According to the procedure for 4a, the reaction gave 4b in 57% as a yellow solid: m.p. 229.0-230.0 °C; 1H NMR (500 MHz, CDCl3) δ 9.37 (brs, 1H), 8.40 (d, 2H, J = 8.9 Hz), 7.87 (d, 1H, J = 8.0 Hz), 7.84 (d, 2H, J = 8.9 Hz), 7.63 (d, 1H, J = 8.1 Hz), 7.50 (s, 1H), 7.48-7.40 (m, 2H), 7.34 (d, 1H, J = 7.8 Hz), 7.08 (d, 1H, J1 = 8.0 Hz, J2 = 7.2 Hz), 3.21 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 148.1, 147.4, 138.4, 136.1, 133.7, 133.0, 131.7, 130.3, 128.5, 127.5, 125.6, 124.8, 123.7, 122.2, 122.0, 121.4, S11

121.0, 119.8, 116.4, 111.2, 23.8; IR (ATR) 3481, 1597, 1515, 1345 cm–1; MS (FAB+) m/z = 352 ([M]+); HRMS (FAB−) Calcd for C23H15N2O2 [M−H]−: 351.1134; found: 350.1132.

6-(4-Methoxyphenyl)-1-methyl-11H-benzo[a]carbazole (4c): According to the procedure for 4a, the reaction gave 4c in 50% as a yellow solid: m.p. 168.0-169.0 °C; 1H NMR (500 MHz, CDCl3) δ 9.29 (brs, 1H), 7.84 (d, 1H, J = 8.1 Hz), 7.60-7.58 (m, 3H), 7.49 (s, 1H), 7.47 (d, 1H, J = 8.0 Hz), 7.43-7.34 (m, 1H), 7.10-7.04 (m, 3H), 3.94 (s, 3H), 3.18 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 159.2, 138.4, 136.0, 135.9, 133.6, 133.3, 131.6, 130.4, 127.6, 127.3, 125.1, 124.4, 122.8, 122.0, 121.9, 120.4, 119.4, 117.8, 113.7, 110.7, 55.4, 23.8; IR (ATR) 3489, 2870, 1609, 1506, 1454, 1358 cm–1; MS (FAB+) m/z = 337 ([M]+); HRMS (FAB−) Calcd for C24H18NO [M−H]−: 336.1389; found: 336.1396.

tert-butyl 5-phenylindolo[2,3-a]carbazole-11(12H)-carboxylate (5): The reaction was performed according to the procedure for 4a at 110 °C and gave 5 in 36% yield as a white solid: m.p. 191.2-191.8 °C; 1H NMR (500 MHz, CDCl3) δ 11.06 (brs, 1H), 8.19 (d, 1H, J = 8.1 Hz), 7.69-7.66 (m, 3H), 7.59-7.50 (m, 4H), 7.45 (t, 1H, J = 7.7 Hz), 7.40-7.33 (m, 3H), 6.97, (t, 1H, J = 7.5 Hz), 1.86 (s, 9H); 13C NMR (126 MHz, CDCl3) δ 152.4, 141.6, 138.7, 137.7, 134.2, 129.5, 128.4, 127.7, 127.5, 127.4, 126.3, 125.2, 123.6, 123.4, 123.1, 123.1, 122.0, 121.3, 119.5, 118.7, 116.6, 112.0, 111.0, 85.3, 28.4; IR (ATR) 3393, 1708, 1569, 1360 cm–1; MS (FAB+): m/z = 432 ([M]+); HRMS (FAB+) Calcd for C29H24N2O2 [M]+: 432.1838; found: 432.1834.

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References (1) Kamijo, S.; Jin, T.; Yamamoto, Y. J. Am. Chem. Soc. 2001, 123, 9453-9454. (2) Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 3312-3315. (3) Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332-3335. (4) Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977-1979.

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