One-Pot, Sequential Four-Component Synthesis of Thiazepine Derivatives

Abstract

A one-pot, sequential, four-component procedure for the synthesis of thiazepines by the reaction of primary amines, 1,3-dicarbonyl compounds, aryl isothiocyanates, and chloroacetyl chloride at room temperature is described. Advantages of this protocol include ease of handling, regioselectivity, the absence of a metal catalyst, and moderate yields.

Key words

thiazepines - heterocycles - multicomponent reactions - amines - dicarbonyl compounds

• References

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• 16 Thiazepines 5a–h; General Procedure A mixture of primary amine 1 (1 mmol) and 1,3-dicarbonyl compound 2 (1 mmol) was stirred at r.t. for 0.5 h. Aryl isothiocyanate 3 (1 mmol) was then added and the mixture was stirred for another 6 h. Subsequently, a soln of ClCH₂COCl (1 mmol) in MeCN (3 mL) was added. When the reaction was complete (1.5 h, TLC), the solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane–EtOAc, 5:1). Methyl 5-Methyl-3-oxo-7-(phenylimino)-4-propyl-2,3,4,7-tetrahydro-1,4-thiazepine-6-carboxylate (5a) Pale-yellow powder; yield: 0.26 g (78%); mp 137–139 °C; IR (KBr): 1726 (CO₂Me), 1668 (NCO), 1640 (SC=N), 1586, 1482 and 1441 (Ar), 1273 (C–O) cm^–1; ¹H NMR (300 MHz, DMSO-d ₆): δ = 0.87 (t, ³ J _HH = 6.3 Hz, 3 H, CH ₃CH₂CH₂N), 1.37–1.48 (m, 2 H, CH₃CH ₂CH₂N), 2.26 (s, 3 H, Me), 3.11 (dt, ² J _HH = 13.1 Hz, ³ J _HH = 6.4 Hz, 1 H, CH₂N), 3.22 (d, ² J _HH = 13.2 Hz, 1 H, SCH₂CO), 3.76 (s, 3 H, OMe), 3.93 (dt, ² J _HH = 13.1 Hz, ³ J _HH = 6.4 Hz, 1 H, CH₂N), 4.14 (d, ² J _HH = 13.2 Hz, 1 H, SCH₂CO), 6.71 (d, ³ J _HH = 6.8 Hz, 2 H, 2 × CH _ortho of Ph), 7.14 (t, ³ J _HH = 6.2 Hz, 1 H, CH _para of Ph), 7.38 (t, ³ J _HH = 6.8 Hz, 2 H, 2 × CH _meta of Ph); ¹³C NMR (75 MHz, DMSO-d ₆): δ = 11.0 (CH₃), 18.7 (CH₃), 21.1 (CH₂), 32.6 (CH₂S), 43.9 (CH₂N), 52.4 (OMe), 118.8 (2 × CH _ortho of Ph), 124.9 (CH _para of Ph), 125.1 (C _ipso ), 129.4 (2 × CH _meta of Ph), 149.5 (C⁶), 149.6 (C⁷), 160.9 (C⁵), 165.7 (CO₂Me), 167.3 (NCO); MS (EI, 70 eV): m/z = 333 [M + 1]⁺, 332 [M⁺], 229, 200, 187, 158, 142, 116, 84, 77, 51; Anal. Calcd for C₁₇H₂₀N₂O₃S: C, 61.43; H, 6.06; N, 8.43. Found: C, 61.37; H, 6.11; N, 8.50. Crystal data: C₁₇H₂₀N₂O₃S: M_W = 332.42, orthorhombic, space group Pna2₁, a = 17.3838(8) Å, b = 14.3978(6) Å, c = 6.9357(3) Å, V = 1735.93(13) ų, Z = 4, Dc = 1.272 Mg/m³, F(000) = 704; crystal dimensions: 0.38 × 0.26 × 0.23 mm; radiation: Mo Kα (λ = 0.71073Å), 3.06 ≤ 2θ ≤ 25.09. Intensity data were collected at 295(2) K with a Bruker APEX area-detector diffractometer, employing the ω/2θ scanning technique, in the range –20 ≤ h ≤ 20, –17 ≤ k ≤ 17, –8 ≤ l ≤ 8. The structure was solved by a direct method; all nonhydrogen atoms were positioned and anisotropic thermal parameters were refined from 3048 observed reflections with R(int) = 0.0500 by a full-matrix least-squares technique converging to R = 0.0399 and Rw = 0.1080 [I > 2σ(I)].
• 17 Crystallographic data for compound 5a have been deposited with the accession number CCDC 971337, and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; E-mail: [e-mail]; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html.