A Stereoselective One-Pot Synthetic Approach to Functionalized Thietanes

Abstract

A facile synthetic route to functionalized thietanes has been developed by employing one-pot, high-yielding, and highly diastereoselective three-component coupling reaction of O,O-diethyl hydrogen phosphorodithioate, aromatic aldehydes, and activated olefins. The synthesis involves Michael addition of the dithioate to acrylonitrile/methyl acrylate followed by addition of the resulting carbanion to an aldehyde and intramolecular cyclization to afford 2-arylthietane-3-carbonitriles/carboxylates at room temperature.

Key words

thietanes - phosphorodithioates - activated olefins - ­stereoselective synthesis - Michael addition - heterocyclization

References and Notes

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27

General Procedure for the Synthesis of Functionalized Thietanes 4 To a solution of O,O-diethyl hydrogen phosphorodithioate (1, 5 mmol) in dry benzene (5 mL) was added dropwise a suspension of NaH (120 mg, 5 mmol) in dry benzene (10 mL) with stirring at r.t. After the addition was complete, and evolution of hydrogen gas(effervescence) had ceased, the reaction mixture was stirred at 60 ˚C for 30 min and then cooled to r.t. Next, a solution of activated olefin 2 (5 mmol) in dry benzene (5 mL) was added, and the reaction mixture was stirred at r.t. for 1 h followed by the addition of aldehyde 3 (5 mmol) and stirring at r.t. for 2-5 h (Table  [¹] ). Water (20 mL) was added, the mixture was extracted with Et₂O (3 × 20 mL), dried over anhyd MgSO₄, filtered, and evaporated under reduced pressure. The crude product thus obtained was purified by SiO₂ chromatography (hexane-EtOAc, 95:5) to afford an analytically pure sample of 4.
Characterization Data of Representative Compounds Product 4 (entry 1, EWG = CN, Ar = Ph):^²8 white solid; yield 87%; mp 47-48 ˚C. ^¹H NMR (400 MHz, CDCl₃/TMS):^²8 δ = 3.20 (dd, 1 H, J = 2.8, 11.6 Hz), 3.55 (dd, 1 H, J = 7.6, 11. 6 Hz), 4.12 (ddd, 1 H, J = 2.8, 7.6, 8.8 Hz), 4.50 (d,1 H, J = 8.8 Hz), 7.32-7.70 (m, 5 H). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 25.9, 30.9, 42.4, 119.0, 122.2, 126.0, 127.1, 134.5. MS (EI): m/z = 175 [M⁺]. Anal. Calcd for C₁₀H₉NS: C, 68.53; H, 5.18; N, 7.99. Found: 68.21; H, 5.43; N, 8.34.
Product 4 (entry 6, EWG = CN, Ar = 4-MeOC₆H₄): white solid; yield 88%; mp 51-52 ˚C. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 3.22 (dd,1 H, J = 2.8, 11.6 Hz), 3.56 (dd, 1 H, J = 7.6, 11.6 Hz), 3.64 (s, 3 H), 4.13 (ddd, 1 H, J = 2.8, 7.6, 8.8 Hz), 4.52 (d, 1 H, J = 8.8 Hz), 7.37-7.79 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 25.8, 30.6, 42.6, 119.0, 122.3, 126.2, 127.0, 134.3, 156.0 MS (EI): m/z = 205 [M⁺]. Anal. Calcd for C₁₁H₁₁NOS: C, 64.36; H, 5.40; N, 6.82. Found: C, 64.74; H, 5.70; N, 7.15 Product 4 (entry 7, EWG = COOMe, Ar = Ph).^²8 white solid; yield 86%; mp 38-39 ˚C. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 3.24 (dd, 1 H, J = 2.9, 11.5 Hz), 3.58 (dd, 1 H, J = 7.7, 11.5 Hz), 3.84 (s, 3 H), 4.14 (ddd, 1 H, J = 2.9, 7.7, 8.9 Hz), 4.54 (d, 1 H, J = 8.9 Hz), 7.38-7.80 (m, 5 H); there are differences between the spectral data of compounds 4 (enteries 1 and 7) in this paper and the reference paper (ref. 28). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 25.8, 45.0, 49.2, 53.0, 126.0, 127.1, 128.9, 137.5, 170.1. MS (EI): m/z = 208 [M⁺]. Anal. Calcd for C₁₁H₁₂O₂S: C, 63.43; H, 5.81. Found: C, 63.80; H, 5.48.
Product 4 (entry 12, EWG = COOMe, Ar = 4-MeOC₆H₄): white solid; yield 85%; mp 42-43 ˚C. ^¹H NMR (400 MHz, CDCl₃/TMS): δ = 3.26 (dd, 1 H, J = 2.9, 11.5 Hz), 3.59 (dd, 1 H, J = 7.7, 11. 5 Hz), 3.70 (s, 3 H), 3.86 (s, 3 H), 4.15 (ddd, 1 H, J = 2.9, 7.7, 8.9 Hz), 4.53 (d, 1 H, J = 8.9 Hz), 7.39-7.89 (m, 4 H). ^¹³C NMR (100 MHz, CDCl₃/TMS): δ = 25.7, 45.3, 49.1, 53.2, 126.1, 127.0, 128.7, 137.5, 156.9, 170.2. MS (EI): m/z = 238 [M⁺]. Anal. Calcd for C₁₂H₁₄O₃S: C, 60.48; H, 5.92.Found: C, 60.72; H, 6.24.