Concise Synthesis of Furo[2,3-b]indolines via [3,3]-Sigmatropic Rearrangement of N-Alkenyloxyindoles

Published as part of the Cluster Modern Heterocycle Synthesis and Functionalization

Abstract

A concise new synthetic route to furo[2,3-b]indolines has been developed by taking advantage of the reactivity of N-alkenyloxyindole intermediates. These compounds spontaneously undergo [3,3]-sigmatropic rearrangement followed by cyclization to form hemiaminals as single diastereomers. Tin-promoted N-hydroxyindole formation followed by conjugate addition to activated alkynes provides simple and modular access to a diverse array of N-alkenyloxyindoles and their corresponding furo[2,3-b]indolines. Microscale high-throughput experimentation was used to facilitate investigation of the scope and tolerance of this transformation and related studies on the nucleophilic aromatic substitution and rearrangement of N-hydroxyindoles with halogenated arenes have also been evaluated.

Key words

N-hydroxyindole - [3,3]-sigmatropic rearrangement - heterocycle - hemiaminal - high-throughput experimentation

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• 18 Synthesis of 2b – Typical Procedure To a 40 mL vial equipped with a magnetic stirbar, 4.26 g (23.5 mmol) 1-fluoro-2-nitro-3-(prop-1-en-2-yl)benzene, 4.90 g (25.9 mmol, 1.1 equiv) SnCl₂, and 25 mL DMA were added to give a homogeneous pale yellow solution. The mixture was heated to 80 °C with stirring overnight, then transferred to a 1 L separatory funnel containing 500 mL 10 wt% tartaric acid and extracted three times with MTBE. The combined organics were dried over MgSO₄, concentrated on a rotary evaporator, and chromatographed on a 220 g silica cartridge with a 2–20% EtOAc/hexane gradient. The desired product fractions were sequentially concentrated to approximately 50 mL volume and diluted with hexane three times. The product solution was then concentrated to approximately 10 mL volume and diluted with a small amount of MTBE (to maintain solubility) to give 9.70 g of a 32.5 wt% solution (81%). ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.28 (s, 1 H), 7.32–7.25 (m, 1 H), 7.24 (q, J = 1.1 Hz, 1 H), 6.98–6.85 (m, 2 H), 2.22 (d, J = 1.1 Hz, 3 H). ¹³C{¹H} NMR (101 MHz, DMSO-d ₆): δ = 148.35 (d, J = 244.4 Hz), 128.31 (d, J = 4.9 Hz), 125.62, 121.65 (d, J = 9.6 Hz), 118.50 (d, J = 6.2 Hz), 114.74 (d, J = 3.5 Hz), 107.00 (d, J = 16.8 Hz), 106.06 (d, J = 1.8 Hz), 9.25. HRMS (ESI/QTOF): m/z [M – H]^– calcd for C₉H₇FNO: 164.0517; found: 164.0521.
• 19 Synthesis of 4ba – Typical Procedure To a 20 mL vial equipped with a magnetic stirbar, 165 mg (1.0 mmol) 2b, 10 mL DMF, and 183 mg (1.05 mmol, 1.05 equiv) 3a. The reaction was cooled below 0 °C, and 200 μL (1 M in THF, 200 μmol, 20 mol%) KOt-Bu was added dropwise. The reaction was stirred for 1 h and transferred to a 250 mL separatory funnel containing 100 mL water, 10 mL saturated NH₄Cl, and MTBE. The aqueous layer was extracted twice with MTBE, and the combined organics were dried over MgSO₄, concentrated on a rotary evaporator, and chromatographed on a 120 g silica cartridge with a 2–20% EtOAc/hexane gradient to give 243 mg (72%) of a white solid. ¹H NMR (500 MHz, CDCl₃): δ = 7.61 (d, J = 7.6 Hz, 2 H), 7.46 (d, J = 7.5 Hz, 1 H), 7.44–7.29 (m, 3 H), 6.98–6.83 (m, 1 H), 6.83–6.69 (m, 1 H), 6.01 (d, J = 2.8 Hz, 1 H), 5.18 (s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 1.80 (s, 3 H), 1.19 (t, J = 7.2 Hz, 3 H). ¹⁹F{¹H} NMR (471 MHz, CDCl₃): δ = –135.67. ¹³C{¹H} NMR (126 MHz, CDCl₃): δ = 166.14, 164.80, 148.03 (d, J = 240.5 Hz), 136.72 (d, J = 3.5 Hz), 134.33 (d, J = 12.5 Hz), 130.63, 130.21, 129.27, 127.53, 120.57 (d, J = 3.1 Hz), 120.20 (d, J = 5.5 Hz), 114.65 (d, J = 16.9 Hz), 108.81, 103.63, 59.81, 59.24 (d, J = 2.1 Hz), 24.01, 14.00. HRMS (ESI/QTOF): m/z [M + H]⁺ calcd for C₂₀H₁₉FNO₃: 340.1343; found: 340.1384.