Convenient Synthesis of N-Tosyl-2-(difluoromethyl)aziridine and Its Application to the Preparation of Difluoromethyl-β-tryptamine Analogues

Abstract

N-Tosyl-2-(difluoromethyl)aziridine was easily prepared from p-toluenesulfonamide (TsNH₂) and β-(difluoromethyl) vinyl sulfonium salt in excellent yield. The reaction of the aziridine and a wide range of indoles in the presence of Et₂Zn proceeded smoothly to give the corresponding difluoromethyl-β-tryptamine analogues in good to excellent yields and with excellent regioselectivity.

Key words

organofluorine - aziridine - ring-opening - indole - tryptamine

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• 9 Experimental Procedure for 1a: A-100 mL round-bottom flask equipped with a magnetic stir bar was charged with K₂CO₃ (2.11 g, 15.0 mmol) and p-toluenesulfonamide (865.0 mg, 5.0 mmol) in EtOAc (10 mL). To this suspension was added β-(difluoromethyl)vinyl diphenyl sulfonium triflate (2.21 g, 5.25 mmol; see ref. 6) and the resulting suspension was stirred at r.t. for 1 h. The reaction was carefully quenched with aq NH₄Cl solution (10 mL) and extracted with hexane–EtOAc (3:1). The extraction was repeated twice. The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (hexane–Et₂O, 1:1) to give the desired product 1a as white solid (1.23 g, 98%); mp 48.6–48.9 °C. IR (ATR): 3057, 1599, 1319, 1161, 1098, 1051, 992, 974, 878, 801, 727, 662 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.2 Hz, 2 H), 5.57 (td, J = 55.1, 4.1 Hz, 1 H), 3.05–3.20 (m, 1 H), 2.77 (d, ­J = 7.0 Hz, 1 H), 2.47 (s, 3 H), 2.42 (d, J = 4.1 Hz, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 145.3, 134.0, 129.9, 128.1, 113.1 (t, J = 241.3 Hz), 37.9 (t, J = 32.7 Hz), 28.7 (t, J = 3.9 Hz), 21.7. ¹⁹F NMR (376 MHz, CDCl₃): δ = –120.9 (ddd, J = 296.8, 55.1, 7.1 Hz), –124.4 (ddd, J = 296.8, 55.1, 7.1 Hz). GC–MS (EI, 70 eV): m/z = 247 (11) [M⁺], 155 (50), 92 (58), 91 (100), 89 (8), 65 (26), 63 (7), 51 (5). Anal. Calcd for C₁₀H₁₁F₂NO₂S: C, 48.57; H, 4.48; N, 5.66. Found: C, 48.58; H, 4.40; N, 5.65.
• 10 Schirlin D, Gerhart F, Hornsperger JM, Hamon M, Jung MJ. J. Med. Chem. 1988; 31: 30
• 11 Experimental Procedure for 3a: A 25-mL two-neck flask equipped with a magnetic stir bar, a stopcock and, a three-way stopcock was charged with o-xylene (1 mL) under argon. To this solution were successively added indole 2a (37.0 mg, 0.32 mmol), 2-CF₂H-N-Ts-aziridine 1a (60.1 mg, 0.24 mmol), and Et₂Zn (1.06 M in hexane solution, 0.30 mL). After the mixture was stirred for 5 min at r.t., the flask was immersed in a preheated (150 °C) oil bath and stirred at this temperature for 1 h until the complete consumption of 1a (checked by TLC and GC–MS). After the reaction mixture was cooled to r.t., to the mixture was added a sat. aq solution of NH₄Cl (1 mL), and the resulting mixture was extracted with EtOAc (2 mL) three times. The combined organic fractions were dried over Na₂SO₄. The residue was purified by chromatography on a silica gel column (hexane–EtOAc = 10:1, 3:1, then 1:1 as an eluent) to give 3a (96%, 84.4 mg) as a pale pink solid; mp 152.0–153.0 °C. IR (ATR): 1597, 1319, 1159, 1087, 1066, 1038, 747, 667, 572, 549, 524, 507 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.98 (s, 1 H), 7.36 (d, J = 7.1 Hz, 2 H), 7.26–7.31 (m, 2 H), 7.17 (t, J = 7.5 Hz, 1 H), 7.02 (t, J = 7.2 Hz, 1 H), 6.92 (d, J = 8.6 Hz, 3 H), 5.94 (t, J = 55.7 Hz, 1 H), 4.79 (d, J = 6.6 Hz, 1 H), 3.69–3.73 (m, 1 H), 3.14 (dd, J = 14.8, 4.9 Hz, 1 H), 2.90 (dd, J = 14.8, 8.8 Hz, 1 H), 2.28 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 143.3, 136.3, 135.8, 129.2, 126.7, 126.6, 123.3, 122.3, 119.8, 118.2, 115.0 (t, J = 246.1 Hz), 111.2, 108.9, 54.9 (t, J = 25.7 Hz), 23.3, 21.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = ­–128.4 (ddd, J = 282.0, 55.7, 9.5 Hz), –134.1 (ddd, J = 282.0, 55.7, 16.3 Hz). GC–MS (EI, 70 eV): m/z = 364 (7) [M⁺], 193 (2), 155 (2), 130 (100), 103 (4), 91 (7), 77 (5), 65 (2). HRMS (ESL–TOF): m/z [M + Na]⁺ calcd for C₁₈H₁₈F₂N₂O₂SNa: 387.0955; found: 387.0950.
• 12 CCDC 1059066 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].