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Synlett 2010(3): 411-414  
DOI: 10.1055/s-0029-1219201
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Synthesis of Unsymmetrical 2,3-Diarylindoles by Site-Selective ­Suzuki-Miyaura Reactions of N-Methyl-2,3-dibromoindole

Muhammad Farooq Ibada, Munawar Hussaina, Obaid-Ur-Rahman Abida, Asad Alia, Ihsan Ullaha, Dhafer Saber Zinada, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
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Publication History

Received 16 November 2009
Publication Date:
15 January 2010 (online)

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Abstract

The Suzuki-Miyaura reaction of N-methyl-2,3-dibromoindole with two equivalents of boronic acids gave symmetrical 2,3-diarylindoles. The reaction with one equivalent of arylboronic acid resulted in site-selective formation of 2-aryl-3-bromoindoles. The one-pot reaction of 2,3-dibromoindole with two different arylboronic acids afforded unsymmetrical 2,3-diarylindoles containing two different aryl groups.

Key words

catalysis - palladium - Suzuki-Miyaura reaction - site-selectivity - indole

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13

General Procedure for the Synthesis of 3a-e and 4a-e
The reaction was carried out in a pressure tube. A 1,4-dioxane solution (4 mL) of 1, K3PO4, Pd(PPh3)4, and arylboronic acid 2 was stirred at 110 ˚C or 70 ˚C for 6 h or 8 h. After cooling to 20 ˚C, a sat. aq solution of NH4Cl was added. The organic and the aqueous layer were separated, and the latter was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, heptanes).

14

2,3-Bis(4-ethylphenyl)-1-methyl-1 H -indole (3c)
Starting with 1 (289 mg, 1.0 mmol), 2c (262 mg, 2.3 mmol), K3PO4 (446 mg, 2.1 mmol), Pd(PPh3)4 (3 mol%), and 1,4-dioxane (4 mL), 3c was isolated as a yellowish oil (291 mg, 86%). ¹H NMR (300 MHz, CDCl3): δ = 1.01 (t, J = 7.5 Hz, 3 H, CH3), 1.05 (t, J = 7.5 Hz, 3 H, CH3), 2.40 (q, J = 7.5 Hz, 2 H, CH2), 2.48 (q, J = 7.5 Hz, 2 H, CH2), 3.42 (s, 3 H, NCH3), 6.90-6.96 (m, 3 H, ArH), 7.02-7.10 (m, 7 H, ArH), 7.25 (d, J = 8.2 Hz, 1 H, ArH), 7.51 (d, J = 7.8 Hz, 1 H, ArH). ¹³C NMR (75.47 MHz, CDCl3): δ = 15.8 (CH3), 16.0 (CH3), 29.1 (CH2), 29.2 (CH2), 31.2 (CH3), 110.7 (CH), 115.4 (C), 120.0 (CH), 121.0 (CH), 123.0 (CH), 128.1 (C), 128.5 (2 CH), 128.7 (2CH), 130.3 (C), 130.6 (2 CH), 132.0 (2 CH), 133.7 (C), 138.3 (C), 138.4 (C), 142.0 (C), 144.9 (C). IR (ATR): ν = 3047 (w), 3022 (w), 2961 (s), 2928 (w), 1797 (w), 1765 (w), 1726 (w), 1519 (m), 1463 (s), 1362 (m), 1325 (m), 1257 (m), 1131 (w), 1115 (w), 1089 (m), 1060 (w), 1017 (m), 967 (w), 923 (w), 869 (m), 836 (s), 801 (w), 740 (s), 652 (w), 629 (m), 545 (m) cm-¹. MS (EI, 70 eV):
m/z (%) = 340 (28) [M + 1]+, 339 (100) [M+], 324 (34), 309 (5), 294 (5), 281 (5), 278 (4), 146 (5). HRMS (EI): m/z calcd for C25H25N [M+]: 339.19815; found: 339.197901.

15

3-Bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1 H -indole (4d)
Starting with 1 (289 mg, 1.0 mmol), 2i (200 mg, 1.1 mmol), K3PO4 (318 mg, 1.5 mmol), Pd(PPh3)4 (3 mol%), and 1,4-dioxane (4 mL), 4d was isolated as a yellowish solid (272 mg, 79%), mp 146-148 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 3.59 (s, 3 H, NCH3), 3.84 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 6.93-6.95 (m, 2 H, ArH), 7.11-7.27 (m, 4 H, ArH), 7.50-7.53 (m, 1 H, ArH). ¹³C NMR (62.89 MHz, CDCl3): δ = 30.6 (CH3), 54.9 (OCH3), 55.0 (OCH3), 88.9 (C), 108.6 (CH), 109.9 (CH), 112.8 (CH), 118.2 (CH), 119.5 (CH), 121.7 (CH), 121.8 (C), 122.4 (CH), 126.1 (C), 135.7 (C), 137.0 (C), 147.8 (C), 148.4 (C). IR (ATR): ν = 3052 (w), 2960 (w), 2924 (w), 1607 (w), 1584 (w), 1502 (m), 1462 (m), 1445 (m), 1404 (w), 1379 (w), 1339 (w), 1317 (w), 1257 (s), 1239 (s), 1168 (m), 1136 (s), 1022 (s), 945 (m), 911 (w), 858 (m), 812 (m), 777 (w), 750 (s), 654 (m), 575 (w), 547 (w) cm-¹. MS (EI, 70 eV): m/z (%) = 348 (18) [M + 1, 8¹Br]+, 347 (100) [M+, 8¹Br], 346 (19) [M + 1, 79Br]+, 345 (98) [M+, 79Br], 331 (3), 302 (5), 302 (5), 300(4), 267 (3), 251 (5), 223 (24), 180 (10), 152 (7), 102 (5), 89 (2).
HRMS (EI, 70 eV): m/z calcd for C17H16O2NBr [M+, 8¹Br]: 347.03385; found: 347.033958; m/z calcd for C17H16O2NBr [M+, 79Br]: 345.03589; found: 345.035679.

16

General procedure for the synthesis of 5a-e
The reaction was carried out in a pressure tube. To a dioxane suspension (4 mL) of 1 (215 mg, 0.75 mmol), Pd(PPh3)4 (3 mol%), and Ar¹B(OH)2 (0.82 mmol) was added K3PO4 (238 mg, 1.1 mmol), and the solution was degassed by bubbling argon through the solution for 10 min. The mixture was heated at 70 ˚C under argon atmosphere for 6 h. The mixture was cooled to 20 ˚C. To the solution was added Ar²B(OH)2 (0.90 mmol) and K3PO4 (238 mg, 1.1 mmol), and the solution was degassed again. The reaction mixture was heated under argon atmosphere for 8 h at 110 ˚C. After cooling to 20 ˚C, the solution was diluted with H2O and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, heptanes).

17

2-(2,5-Dimethoxyphenyl)-1-methyl-3-phenyl-1 H -indole (5a) Starting with 1 (215 mg, 0.75 mmol), 2k (150 mg, 0.82 mmol), 2a (110 mg, 0.9 mmol), K3PO4 (488 mg, 2.3 mmol), Pd(PPh3)4 (4 mol%), and 1,4-dioxane (4 mL), 5a was isolated as a yellowish oil (177 mg, 69%). ¹H NMR (250 MHz, CDCl3): δ = 3.40 (s, 3 H, NCH3), 3.44 (s, 3 H, OCH3), 3.52 (s, 3 H, OCH3), 6.54 (d, J = 3.1 Hz, 1 H, ArH), 6.77-6.82 (m, 1 H, ArH), 6.87-6.98 (m, 3 H, ArH), 7.04-7.18 (m, 5 H, ArH), 7.28 (d, J = 8.3 Hz, 1 H, ArH), 7.56 (d, J = 7.8 Hz, 1 H, ArH). ¹³C NMR (62.9 MHz, CDCl3): δ = 30.7 (NCH3), 55.9 (OCH3), 56.3 (OCH3), 110.5 (CH), 113.3 (CH), 115.7 (C), 115.8 (CH), 119.5 (CH), 119.8 (CH), 120.6 (CH), 122.5 (C), 122.6 (CH), 126.2 (CH), 127.7 (C), 129.0 (2 CH), 130.1 (2 CH), 135.7 (C), 136.7 (C), 138.1 (C), 153.7 (C), 154.4 (C). IR (ATR): ν = 3051 (w), 2936 (w), 2832 (w), 1736 (w), 1712 (w), 1602 (w), 1549 (w), 1502 (m), 1485 (m), 1463 (m), 1366 (m), 1273 (m), 1225 (m), 1210 (m), 1039 (m), 1020 (m), 941 (w), 918 (w), 876 (w), 805 (w), 772 (m), 735 (s), 700 (s), 616 (w), 570 (w), 531 (w) cm-¹. MS (EI, 70 eV): m/z (%) = 344 (26) [M + 1]+, 343 (100) [M+], 342 (15), 328 (6), 311 (4), 297 (7), 268 (5), 230 (5), 171 (4), 121 (5). HRMS (EI, 70 eV): m/z calcd for C23H21O2N [M+]: 343.15668; found: 343.156144.