Synlett, Table of Contents Synlett 2021; 32(02): 197-201DOI: 10.1055/s-0040-1707250 cluster © Georg Thieme Verlag Stuttgart · New York Concise Synthesis of Furo[2,3-b]indolines via [3,3]-Sigmatropic Rearrangement of N-Alkenyloxyindoles Michael Shevlin a Department of Process Research & Development, Merck & Co., Inc., 126 E Lincoln Ave, Rahway, NJ 07065, USA b Department of Chemistry, University of Illinois at Chicago, 845 W Taylor St, Chicago, IL 60607, USA Email: lauralin@uic.edu , Neil A. Strotman a Department of Process Research & Development, Merck & Co., Inc., 126 E Lincoln Ave, Rahway, NJ 07065, USA , Laura L. Anderson∗ b Department of Chemistry, University of Illinois at Chicago, 845 W Taylor St, Chicago, IL 60607, USA Email: lauralin@uic.edu › Author Affiliations Recommend Article Abstract Buy Article All articles of this category 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 Key words N-hydroxyindole - [3,3]-sigmatropic rearrangement - heterocycle - hemiaminal - high-throughput experimentation Full Text References References and Notes 1a Tomasz M. Chem. Biol. 1995; 2: 575 1b Baggaley KH, Brown AG, Schofield CJ. Nat. Prod. Rep. 1997; 14: 309 1c Behenna DC, Stockdill JL, Stoltz BM. Angew. Chem. Int. Ed. 2008; 47: 2365 1d Ramírez A, Garcia-Rubio S. Curr. Med. Chem. 2003; 10: 1891 2a Nicolaou KC, Chen DY.-K, Huang X, Ling T, Bella M, Snyder SA. J. Am. Chem. Soc. 2004; 126: 12888 2b Matsuura T, Overman LE, Poon DJ. J. Am. Chem. Soc. 1998; 120: 6500 2c Sunazuka T, Hirose T, Shirahata T, Harigaya Y, Hayashi M, Komiyama K, Ōmura S, Smith AB. J. Am. Chem. 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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. Supplementary Material Supplementary Material Supporting Information
