Synthesis of New 3-[(Alkylthio)methyl]-1-hydroxy-2-phenylindoles

Abstract

The syntheses of new 3-[(alkylthio)methyl]-1-hydroxy-2-phenylindoles are presented. The substrates, obtained by efficient three-step synthesis, were treated with various thiol nucleophiles in the presence of SnCl₂·2H₂O to provide target compounds, through the consecutive processes of reduction, condensation, and addition in one pot. The mechanistic studies on reaction pathways and the involved intermediates are described.

Keywords

indoles - heterocycles - nucleophilic addition - tin - reduction

• References and Notes

• 1 Acheson RM, Littlewood DM, Rosenburg HE. J. Chem. Soc., Chem. Commun. 1974; 671
• 2a Somei M. Adv. Heterocycl. Chem. 2002; 82: 101
• 2b Somei M. Heterocycles 1999; 50: 1157
• 3 Bartsch A, Bross M, Spiteller P, Spiteller M, Steglich W. Angew. Chem. Int. Ed. 2005; 44: 2957
• 4 Lavrenov SN, Korolev AM. Nucleosides, Nucleotides Nucleic Acids 2001; 20: 1881
• 5 Granchi C, Calvaresi EC, Tuccinardi T, Paterni I, Macchia M, Martinelli A, Minutolo F. Org. Biomol. Chem. 2013; 11: 6588
• 6 Somei M, Yamada K, Hasegawa M, Tabata M, Nagahama Y, Morikawa H, Yamada F. Heterocycles 1996; 43: 1855
• 7 Rosen GM, Tsai P, Barth ED, Dorey G, Casara P, Spedding M, Halpern HJ. J. Org. Chem. 2000; 65: 4460
• 8 Nicolaou KC, Lee SH, Estrada AA, Zak M. Angew. Chem. Int. Ed. 2005; 44: 3736
• 9 Nicolaou KC, Estrada AA, Lee SH, Freestone GC. Angew. Chem. Int. Ed. 2006; 45: 5364
• 10 Nicolaou KC, Estrada AA, Freestone GC, Lee SH, Alvarez-Mico X. Tetrahedron 2007; 63: 6088
• 11 Coffman KC, Palazzo TA, Hartley TP, Fettinger JC, Tantillo DJ, Kurth MJ. Org. Lett. 2013; 15: 2062
• 12 Nishijima K, Shinkawa T, Ito M, Nishida H, Yamamoto I, Onuki Y, Inaba H, Miyano S. Eur. J. Med. Chem. 1998; 33: 763
• 13 Okuro K, Gurnham J, Alper H. J. Org. Chem. 2011; 76: 4715
• 14 Bellamy FD, Ou K. Tetrahedron Lett. 1984; 25: 839
• 15 Typical Procedure for 2-Phenyl-1-hydroxyindoles (1) To a stirred solution of SnCl₂·2H₂O (74 mg, 0.33 mmol, 3.3 equiv) and 4 Å MS (10 wt%) in DME (0.5 mL) was added thiol nucleophile (0.5 mmol, 5.0 equiv), and the mixture was stirred for 30 min at r.t. To this was added conjugate nitro ketones 2 (0.1 mmol, 1.0 equiv) at 25 °C, and the reaction mixture was warmed to 40 °C. After stirring for 3–7 h in the dark, the reaction mixture was cooled to r.t. and purified by PTLC or column chromatography to afford the title compounds 1. Use of benzylmercaptan (60 μL, 0.50 mmol, 5.0 equiv) as a nucleophile according to the general procedure (3 h) afforded compound 1av (29 mg, 84%) as a white solid; mp 81–82 °C; R_f = 0.76 (1:3 EtOAc–hexanes). HPLC t _R = 27.4 min. IR (KBr): 3434, 3025, 1601, 1492, 1451, 702 cm^–1. ¹H NMR (300 MHz, CD₃CN): δ = 8.35 (s, 1 H), 7.61–7.57 (m, 3 H), 7.50–7.41 (m, 4 H), 7.30–7.18 (m, 6 H), 7.13–7.08 (m, 1 H), 3.87 (s, 2 H), 3.68 (s, 2 H). ¹³C NMR (75 MHz, CD₃CN): δ = 140.5, 137.7, 136.8, 131.6, 130.8, 130.2, 129.8, 129.5, 128.8, 128.1, 124.9, 124.1, 121.3, 120.5, 110.2, 106.8, 37.7, 27.5.MS: m/z = 368 [M + Na]⁺. HRMS (ESI+): m/z calcd for C₂₂H₁₉NNaOS [M + Na]⁺: 368.1085; found: 368.1080.