Synlett 2017; 28(14): 1743-1747
DOI: 10.1055/s-0036-1590837
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© Georg Thieme Verlag Stuttgart · New York

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

Timo Lessing
Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany   Email: [email protected]
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Institut für Organische Chemie und Makromolekulare Chemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany   Email: [email protected]
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Further Information

Publication History

Received: 05 May 2017

Accepted after revision: 20 June 2017

Publication Date:
24 July 2017 (online)


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.

Supporting Information

 
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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 (Cquat), 125.1 (Cquat), 128.3 (CH), 128.4 (CH), 128.7 (CH), 129.2 (CH), 132.6 (Cquat), 142.1 (Cquat), 143.5 (CH), 148.1 (Cquat). 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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