Chemoselective Metallation of Arenes and Heteroarenes
and 3-bromocyclohexene (355 mg, 2.20 mmol). Metallation condi-
tions: –50 °C, 1 h. Flash chromatography on silica (n-pentane/di-
quenched by the addition of a satd. aq. NH4Cl solution (15–30 mL)
and added to a separating funnel with Et2O (10–20 mL) and EtOAc
(10–20 mL). The organic layer was extracted with a satd. aq.
ethyl ether, 9:1) gave 66 as yellow solid (410 mg, 79%). M.p. 97.0–
1
98.3 °C. H NMR (300 MHz, CDCl3): δ = 8.8, (s, 1 H), 8.4 (d, J NH4Cl solution (3ϫ15 mL). The combined aqueous layers were
= 8.9 Hz, 1 H), 8.1 (d, J = 8.9 Hz, 1 H), 6.1–6.1 (m, 1 H), 5.9–6.0
(m, 1 H), 4.0–4.1 (m, 1 H), 2.2–2.3 (m, 3 H), 1.9–2.0 (m, 1 H), 1.7–
extracted with EtOAc (2ϫ20 mL). The organic layers were washed
with brine (20 mL), dried with anhydrous MgSO4, filtered and con-
1.9 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 183.2, 157.2, centrated in vacuo. Flash chromatography on silica (n-pentane/di-
144.6, 135.4, 131.6, 125.8, 122.9, 121.5, 118.2, 41.1, 30.2, 24.8,
20.4 ppm. MS (70 eV, EI): m/z (%) = 261 (16), 260 (100) [M]+, 259
(32), 245 (22), 232 (13), 231 (49), 214 (18), 213 (19), 194 (46), 79
ethyl ether, 5:1) gave 69 as a colourless solid (417 mg, 75%). M.p.
89.8–91.3 °C. H NMR (300 MHz, CDCl3): δ = 7.9–8.0 (m, 1 H),
7.7 (dd, J = 5.0, 1.2 Hz, 1 H), 7.6 (td, J = 8.1, 5.4 Hz, 1 H), 7.4–
1
(16), 67 (13), 63 (21), 44 (19). IR (ATR): ν = 3109, 2952, 2927, 7.4 (m, 2 H), 7.1 (dd, J = 5.0, 3.7 Hz, 1 H), 4.2 (q, J = 7.2 Hz, 2
˜
2905, 1569, 1559, 1512, 1444, 1429, 1340, 1333, 1291, 1281, 1245,
1223, 1172, 1129, 1120, 1072, 1041, 972, 908, 891, 867, 838, 814,
H), 1.2 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 184.5, 164.6 (d, JC-F = 3 Hz), 159.1 (d, JC-F = 248 Hz), 144.6
750, 728, 723, 675, 653, 638, 622 cm–1. HRMS (EI): calcd. 134.7, 134.1, 130.9, 130.8, 130.8, 128.5 (d, JC-F = 20 Hz), 126.3 (d,
260.0619; found 260.0608.
JC-F = 3 Hz), 120.30 (d, JC-F = 22 Hz), 61.91, 13.63 ppm. MS
(70 eV, EI): m/z (%) = 278 (46) [M]+, 234 (27), 233 (36), 167 (31),
Synthesis of 2-(Cyclohex-2-enyl)-1-methyl-1H-indole-3-carbaldehyde
(67): The title compound was prepared according to TP1 and TP5
from 1-methyl-1H-indole-3-carbaldehyde (58, 318 mg, 2.00 mmol),
Zn base 54 (2.4 mL, 0.5 in THF, 1.20 mmol), CuCN·2LiCl
(0.2 mL, 1 in THF, 10 mol-%) and 3-bromocyclohexene (355 mg,
2.20 mmol). Metallation conditions: 25 °C, 1.25 h. Flash
chromatography on silica (n-pentane/diethyl ether, 3:1) gave 67 as
a yellow oil (240 mg, 50%). 1H NMR (300 MHz, CDCl3): δ = 10.3
(s, 1 H), 8.3–8.4 (m, 1 H), 7.3–7.4 (m, 3 H), 6–00–6.1 (m, 1 H),
5.8–5.9 (m, 1 H), 3.8 (s, 3 H), 3.8–3.9 (m, 1 H), 2.1–2.2 (m, 3 H),
1.9–2.1 (m, 1 H), 1.8–1.9 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 185.3, 153.6, 137.2, 129.4, 127.5, 125.7, 123.3, 123.0,
121.7, 114.3, 109.3, 34.1, 30.8, 30.5, 24.6, 22.2 ppm. MS (70 eV,
EI): m/z (%) = 240 (14), 239 (100) [M]+, 238 (13), 222 (19), 210
111 (100). IR (ATR): ν = 3094, 2986, 1716, 1650, 1606, 1577, 1560,
˜
1522, 1517, 1476, 1448, 1419, 1413, 1391, 1363, 1353, 1278, 1237,
1194, 1158, 1148, 1112, 1085, 1067, 1051, 1024, 994, 957, 928, 914,
884, 863, 849, 824, 813, 803, 763, 752, 725, 684, 667, 648, 633, 621,
615, 607 cm–1. HRMS: calcd. 278.0413; found 278.0405.
Synthesis of Ethyl 3-Cyano-2-[2-(ethoxycarbonyl)allyl]benzoate (70):
The title compound was prepared according to TP1 and TP5 from
ethyl 3-cyanobenzoate (60, 350 mg, 2.00 mmol), Zn base 54
(2.4 mL, 0.5 in THF, 1.20 mmol), CuCN·2LiCl (0.2 mL, 1 in
THF, 10 mol-%) and ethyl 2-(bromomethyl)acrylate (420 mg,
2.20 mmol). Metallation conditions: 25 °C, 30 h. Flash chromatog-
raphy on silica (n-pentane/diethyl ether, 2:1) gave 70 as a yellow oil
(413 mg, 72%). 1H NMR (300 MHz, CDCl3): δ = 8.1 (dd, J = 7.9,
1.5 Hz, 1 H), 7.8 (dd, J = 7.7, 1.5 Hz, 1 H), 6.2–6.3 (m, 1 H), 5.0–
5.1 (m, 1 H), 7.5 (t, J = 7.9 Hz, 1 H), 4.3 (q, J = 7.2 Hz, 2 H), 4.3
(s, 2 H), 4.3 (q, J = 7.2 Hz, 2 H), 1.4 (t, J = 7.1 Hz, 3 H), 1.3 (t, J
= 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.2, 166.0,
143.1, 138.5, 136.1, 134.8, 132.7, 127.4, 125.5, 117.3, 116.0, 61.8,
61.0, 34.0, 14.2, 14.1 ppm. MS (70 eV, EI): m/z (%) = 287 (4)
[M]+, 242 (24), 241 (60), 214 (14), 213 (74), 186 (30), 185 (100), 170
(73), 169 (57), 168 (35), 167 (17), 158 (10), 156 (12), 141 (16), 140
(11), 210 (14), 184 (38), 182 (14), 167 (17), 157 (12). IR (ATR): ν
˜
= 2930, 2859, 1739, 1683, 1641, 1611, 1580, 1517, 1468, 1447, 1413,
1386, 1323, 1294, 1246, 1223, 1218, 1186, 1156, 1126, 1104, 1073,
1048, 1038, 1015, 982, 932, 917, 890, 860, 818, 801, 747, 729, 702,
674, 656, 642, 635, 631, 626, 622, 616, 611, 605 cm–1. HRMS (EI):
calcd. for C16H17NO 239.1310; found 239.1302.
Synthesis of 3-Bromo-2-(3-nitrophenyl)quinoline (68): The title com-
pound was prepared according to TP1 and TP3 from 3-bromoquin-
oline (21, 416 mg, 2.00 mmol), Zn base 54 (2.4 mL, 0.5 in THF,
1.20 mmol), [Pd(dba)2] (56 mg, 5 mol-%), P(o-furyl)3 (46 mg,
10 mol-%) and 3-iodonitrobenzene (500 mg, 2.00 mmol). Metalla-
tion conditions: 25 °C, 4 h. Recrystallization from CH2Cl2 and
Et2O gave 68 as a colourless solid (564 mg, 86%). M.p. 209.8–
211.3 °C. 1H NMR (300 MHz, CDCl3): δ = 8.7 (t, J = 1.7 Hz, 1
H), 8.6 (s, 1 H), 8.4 (ddd, J = 8.3, 2.4, 1.0 Hz, 1 H), 8.1–8.2 (m, 2
H), 7.8–7.9 (m, 2 H), 7.7–7.8 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 155.4, 151.7, 148.0, 146.6, 140.5, 135.7, 130.6, 129.6,
129.1, 128.5, 128.2, 126.6, 124.9, 123.7 ppm. MS (70 eV, EI): m/z
(%) = 331 (10), 330 (60), 329 (13), 328 (60) [M]+, 285 (18), 284
(100), 283 (18), 282 (95), 249 (49), 219 (11), 204 (12), 203 (71), 202
(33), 201 (13), 176 (12), 142 (13), 141 (11), 127 (10), 101 (22), 88
(36). IR (ATR): ν = 2984, 2940, 2901, 2230, 1714, 1635, 1583, 1448,
˜
1393, 1367, 1268, 1207, 1190, 1173, 1130, 1095, 1084, 1066, 1057,
1022, 947, 863, 818, 766, 754, 682, 669, 646, 641, 635, 623,
601 cm–1. HRMS: calcd. 287.1158; found 287.1156.
Synthesis of Ethyl 6-Bromo-3-chloro-3Ј-methylbiphenyl-2-carboxyl-
ate (71): The title compound was prepared according to TP1 and
TP3 from ethyl 5-bromo-2-chlorobenzoate (61, 525 mg,
2.00 mmol), Zn base 54 (2.4 mL, 0.5 in THF, 1.20 mmol),
[Pd(dba)2] (56 mg, 5 mol-%), P(o-furyl)3 (46 mg, 10 mol-%) and 3-
iodotoluene (436 mg, 2.00 mmol). Metallation conditions: 25 °C,
60 h. Flash chromatography on silica (n-pentane/diethyl ether, 19:1)
1
gave 71 as a red oil (470 mg, 67%). H NMR (300 MHz, CDCl3):
δ = 7.6 (d, J = 8.4 Hz, 1 H), 7.2–7.3 (m, 2 H), 7.2 (d, J = 7.7 Hz,
1 H), 7.1 (d, J = 7.7 Hz, 2 H), 4.0 (q, J = 7.1 Hz, 2 H), 2.4 (s, 3
H), 1.0 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 165.6, 141.7, 137.7, 137.6, 135.8, 135.3, 134.2, 134.0, 129.9, 129.5,
129.1, 127.9, 126.4, 122.2, 61.7, 21.4, 13.6 ppm. MS (70 eV, EI):
m/z (%) = 356 (22), 355 (14), 354 (82), 353 (10), 352 (62) [M]+, 326
(17), 324 (12), 311 (27), 310 (29), 309 (100), 308 (32), 307 (77), 295
(35), 294 (27), 230 (22), 229 (19), 228 (60), 200 (12), 199 (19), 166
(17), 75 (14). IR (ATR): ν = 2989, 2970, 1739, 1530, 1488, 1482,
˜
1435, 1400, 1394, 1372, 1366, 1348, 1300, 1276, 1270, 1262, 1241,
1229, 1217, 1195, 1147, 1130, 1103, 1087, 1072, 1058, 968, 955,
907, 902, 892, 857, 818, 790, 781, 749, 743, 740, 709, 682, 669, 661,
622, 606, 603 cm–1. HRMS (EI): calcd. 327.9847; found 327.9841.
Synthesis of Ethyl 3-Fluoro-2-(2-thienylcarbonyl)benzoate (69): The
title compound was prepared according to TP1 from ethyl 3-fluoro-
benzoate (59, 416 mg, 2.00 mmol) and Zn base 54 (2.4 mL, 0.5
in THF, 1.20 mmol). After cooling to –40 °C, CuCN·2LiCl
(18), 165 (55), 164 (25), 163 (22), 44 (14). IR (ATR): ν = 2980,
˜
1732, 1606, 1586, 1574, 1461, 1436, 1403, 1386, 1364, 1281, 1257,
(2.2 mL, 1 in THF, 2.2 mmol) was added, followed by 2-thio- 1241, 1162, 1135, 1098, 1057, 1010, 912, 876, 859, 811, 793, 777,
phenoyl chloride (322 mg, 2.20 mmol). The mixture was briefly
warmed to 25 °C and stirred for 12 h. The metallation was
762, 752, 702, 654, 645, 620, 612, 606 cm–1. HRMS: calcd.
351.9866; found 351.9859.
Eur. J. Org. Chem. 2009, 1781–1795
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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