One-Pot Coupling–Cyclization–Alkylation Synthesis of 1,2,5-Trisubstituted 7-Azaindoles in a Consecutive Three-component Fashion

Published as part of the ISHC Conference Special Section

Abstract

1,2,5-Trisubstituted 7-azaindoles are rapidly and efficiently prepared in a one-pot, copper-free alkynylation–cyclization–alkylation sequence starting from unprotected 2-aminopyridyl halides in a consecutive three-component fashion. By extension to a consecutive four-component coupling–cyclization–iodination–alkylation synthesis of 3-iodo-1-methyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine, a concise synthesis of SIS3, a selective TGF-β1 and signaling inhibitor, was realized.

Key words

7-azaindoles - alkylation - alkynylation - cyclization - multi-component reaction

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• 14 Typical Procedure for the Synthesis of 1,5-Dimethyl-2-phenyl-1H-pyrrolo[2,3-b]pyridine (4b): In a dry screw-cap Schlenk tube with a magnetic stir bar were placed 2-amino-3-bromo-5-methyl pyridine (1a; 93 mg, 0.50 mmol), Pd(PPh₃)₂Cl₂ (9.0 mg, 13 μmol), and (1-Ad)₂PBn·HBr (12 mg, 25 μmol) and the vessel was evacuated. After flushing the vessel with nitrogen, anhydrous DMSO (1.0 mL), the corresponding phenyl acetylene (2a; 61 mg, 0.60 mmol) and DBU (225 mg, 1.50 mmol) were added and the reaction mixture was stirred at 100 °C under nitrogen for 1 h until the bromide was completely consumed (reaction monitored by TLC). After cooling to rt KOt-Bu (253 mg, 2.25 mmol) and DMSO (0.50 mL) were added and the mixture was stirred at 100 °C under nitrogen for 0.25 h. After cooling to rt, methyliodide (3b; 142 mg, 1.00 mmol) was added to the reaction mixture, which was stirred at rt for 5 min. Then, deionized water or brine (20 mL) was added to the mixture. The aqueous layer was extracted several times with ethyl acetate or dichloromethane. The combined organic phases were dried (anhydrous sodium sulfate) and, after filtration, the solvents were removed in vacuo. The residue was adsorbed on silica and purified by chromatography on silica gel (SNAP cartridge 100 g, hexanes/ethyl acetate) with a Biotage SP-1 flash chromatography purification system to give analytically pure 4b as a yellow solid. Yield: 72 mg (65%); mp 65 °C. IR (ATR): 3119 (w), 3078 (w), 3055 (w), 3005 (w), 2980 (w), 2945 (w), 2916 (w), 1599 (w), 1566 (w), 1532 (w), 1485 (m), 1296 (m), 748 (s), 694 (m) cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.45 (s, 3 H), 3.86 (s, 3 H), 6.44 (s, 1 H), 7.42–7.52 (m, 5 H), 7.70–7.71 (m, 1 H), 8.19 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 18.7 (CH₃), 30.1 (CH₃), 99.0 (CH), 120.7 (C_quat), 125.1 (C_quat), 128.3 (CH), 128.4 (CH), 128.7 (CH), 129.2 (CH), 132.6 (C_quat), 142.1 (C_quat), 143.5 (CH), 148.1 (C_quat). MS (EI, 70 eV): m/z (%) = 223 (15), 222 (100) [M]⁺, 221 (84), 220 (5), 205 (6), 152 (5), 145 (17) [M-C₆H₅]⁺, 111 (7), 110 (11). Anal. calcd. for C₁₅H₁₄N₂ (222.3): C 81.05, H 6.35, N 12.60; Found: C 80.92, H 6.07, N 12.40.
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