Efficient Synthesis of 3,4-Disubstituted 7-Azaindoles Employing SEM as a Dual Protecting–Activating Group

Abstract

An efficient method for nucleophilic aromatic substitution on 7-azaindoles has been developed. The reaction is facilitated by the unique dual influence of SEM as both protecting and activating group, permitting mild conditions and short reaction times that are compatible with sensitive functional groups. The method is suitable for the synthesis of a broad range of products, most notably ethers.

Key words

heterocycles - aromatic substitution - 7-azaindole - ethers

• References and Notes

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• 29 General Procedure: 2-{(4-Isopropoxy-3-phenylpyrrolo[2,3-b]pyridin-1-yl)methoxy}ethyltrimethylsilane (9)To a mixture of isopropanol (300 μL, 3.94 mmol) in dry dimethyl sulfoxide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 157 mg, 3.92 mmol) in small portions. The reaction mixture was stirred at room temperature for 15 min. To the reaction mixture was added a solution of 2-[(4-fluoro-3-phenylpyrrolo[2,3-b]pyridin-1-yl)methoxy]ethyltrimethylsilane (150 mg, 0.438 mmol) in dry dimethyl sulfoxide (3 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 min. The reaction mixture was poured into water (60 mL) and extracted with a mixture of chloroform and 2-propanol (3:1, 3 × 15 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated to give the title compound (165 mg, 0.431 mmol, 98%) as a pale yellow oil.¹H NMR (500 MHz, DMSO-d ₆): δ = 8.17 (d, J = 5.5 Hz, 1 H), 7.69–7.56 (m, 3 H), 7.41–7.32 (m, 2 H), 7.31–7.19 (m, 1 H), 6.78 (d, J = 5.5 Hz, 1 H), 5.63 (s, 2 H), 4.91–4.79 (m, 1 H), 3.57 (t, J = 8.1 Hz, 2 H), 1.30 (d, J = 6.0 Hz, 6 H), 0.85 (t, J = 8.0 Hz, 2 H), –0.07 (s, 9 H). ¹³C NMR (126 MHz, DMSO-d ₆): δ = 158.80, 150.72, 145.46, 135.21, 129.52, 128.01, 126.30, 125.64, 116.38, 108.39, 100.83, 72.94, 70.48, 65.89, 22.04, 17.65, –0.90. HRMS (ESI): m/z calcd for C₂₂H₃₁N₂O₂Si: 383.2155 [M + H]⁺; found: 383.2138.