Synthesis and Suzuki–Miyaura Reactions of 3,6,8-Tribromoquinoline: A Structural Revision

Abstract

It was earlier reported that the bromination of 1,2,3,4-tetrahydroquinoline with NBS would give 4,6,8-tribromoquinoline. This reaction was reinvestigated, and the structure was assigned to be 3,6,8-tribromoquinoline. Suzuki–Miyaura cross-coupling reactions of this molecule allowed for a convenient synthesis of 3,6,8-triarylquinolines.

Key words

catalysis - heterocycles - palladium - cross-coupling reactions - nitrogen - quinoline

• References and Notes

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• 22 Synthesis of 3,6,8-Tribromoquinoline (4) To a solution of 1,2,3,4-tetrahydroquinoline (1, 0.5 g, 3.76 mmol) in dry benzene (50 mL), NBS (4.0 g, 22.5 mmol, 6 equiv), and AIBN (0.12 g, 0.75 mmol, 20 mol%) were added under an argon atmosphere, and the reaction mixture was stirred under reflux for 12 h. The reaction was monitored by TLC (EtOAc–heptanes, 0.5:9.5). After cooling, distilled H₂O (5 mL) and Et₃N (1 mL) were added, then the organic layer was extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc–heptanes, 10:0.1) to give 4 as a white solid (1.36 g, 98%); mp 170–172 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.78 (d, 1 H, J = 1.8 Hz, ArH), 8.06 (d, 1 H, J = 2.0 Hz, ArH), 8.14 (d, 1 H, J = 2.2 Hz, ArH), 8.90 (d, 1 H, J = 2.2 Hz, ArH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 119.3, 121.2, 126.0 (C), 128.7 (CH), 130.6 (C), 136.2, 136.6 (CH), 142.3 (C), 152.4 (CH). IR (KBr): ν = 3086, 3074, 3052 (w), 1588, 1579, 1568, 1540, 1504, 1488 (m), 1456 (s), 1410, 1384, 1354, 1327, 1316, 1305, 1262, 1233, 1197, 1173, 1146 (m), 1082 (br), 1071 (br), 967 (br), 924 (w), 903 (s), 894 (s), 871, 855, 814 (m), 779 (s), 680 (s), 648, 615, 594 (m), 526 (s) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 369 (32) [M, ⁸¹Br⁸¹Br⁸¹Br]⁺, 367 (97) [M, ⁸¹Br⁸¹Br⁷⁹Br]⁺, 365 (100) [M, ⁷⁹Br⁷⁹Br⁸¹Br]⁺, 363 (34) [M, ⁷⁹Br⁷⁹Br⁷⁹Br]⁺, 286 (17), 205 (22), 178 (5). HRMS (ESI-TOF/MS, 70 eV): m/z calcd for C₉H₅NBr₃ [M + H, ⁷⁹Br⁷⁹Br⁷⁹Br]⁺: 363.79666; found: 363.79681; calcd for C₉H₅NBr₃ [M + H, ⁸¹Br ⁷⁹Br⁷⁹Br]⁺: 365.79463; found: 365.79471; calcd for C₉H₅NBr₃ [M + H, ⁸¹Br⁸¹Br⁷⁹Br]⁺: 367.79261; found: 367.79279; calcd for C₉H₅NBr₃ [M + H, ⁸¹Br⁸¹Br⁸¹Br]⁺: 369.79064; found: 369.79081.
• 23 General Procedure for the Suzuki–Miyaura Reactions A dioxane solution of 3,6,8-tribromoquinoline (4, 0.21 mmol), arylboronic acid (3.5 equiv), Pd(PPh₃)₄ (9 mol%), and K₂CO₃ (2 M, 2 mL) was stirred at the indicated temperature and for the indicated time under an argon atmosphere. After cooling to 20 °C, distilled H₂O was added. The organic and aqueous layers 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 column chromatography (silica gel, EtOAc–heptanes). 3,6,8-Triphenylquinoline (6a) Starting with 1 (75 mg, 0.21 mmol), 5a (90 mg, 0.74 mmol), Pd(PPh₃)₄ (21 mg, 9 mol%), K₂CO₃ (2 M, 2 mL), and dioxane (2 mL), 6a was isolated as a white solid (65 mg, 92%); mp 174–176 °C (EtOAc–heptanes, 0.1:10). ¹H NMR (300 MHz, CDCl₃): δ = 7.25–7.44 (m, 9 H, ArH), 7.59 (m, 6 H, ArH), 7.87 (d, 1 H, J = 2.0 Hz, ArH), 7.91 (d, 1 H, J = 2.0 Hz, ArH), 8.23 (d, 1 H, J = 2.3 Hz, ArH), 9.09 (d, 1 H, J = 2.3 Hz, ArH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 124.2, 126.2, 126.4, 126.5, 126.7, 127.0, 127.1 (CH), 127.7 (C), 127.9, 128.1, 128.9, 129.5 (CH), 132.4, 132.8 (C), 136.7 (CH), 138.3, 138.4, 139.1, 140.1, 143.4 (C), 148.5 (CH). IR (KBr): ν = 3101, 3053, 3029 (w), 1596, 1477, 1442, 1376, 1344 (m), 1260 (w), 1177, 1153, 1075, 1022, 973 (m), 898, 805, 757, 694 (s), 614, 574, 546 (m) cm^–1. GC–MS (EI, 70 eV): m/z (%) = 356 (100) [M⁺], 280 (6), 178 (4). HRMS (ESI-TOF/MS, 70 eV): m/z calcd for C₂₇H₂₀N [M + H]⁺: 357.15903; found: 357.15950.