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

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.

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

References and Notes

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<A NAME="RG38909ST-13">13</A>

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).

<A NAME="RG38909ST-14">14</A>

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.

<A NAME="RG38909ST-15">15</A>

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.

<A NAME="RG38909ST-16">16</A>

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 Ar^¹B(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 Ar^²B(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).

<A NAME="RG38909ST-17">17</A>

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.

<A NAME="RG38909ST-18">18</A> Billingsley K. Buchwald SL. J. Am. Chem. Soc.  2007,  129:  3358 ; and references cited therein