Catalytic Asymmetric Thioacetalization of Aldehydes

Abstract

A catalytic enantioselective thioacetalization reaction has been developed. Various aldehydes react with unsymmetrical 1,3- or 1,2-dithiols to furnish chiral, enantioenriched thioacetals in excellent enantioselectivities upon treatment with a nitrated imidodiphosphoric acid catalyst. The transformation is assumed to proceed via a thionium ion intermediate.

Key words

thioacetals - imidodiphosphates - Brønsted acid catalysis

• References and Notes

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• 11 Representative Procedure for the Synthesis of a Dithiolanes Freshly distilled hydrocinnamaldehyde (2a, 26.0 μL, 0.2 mmol, 1 equiv) was added to a mixture of 2-methylpropane-1,2-dithiol (1a, 29 μL, 0.24 mmol, 1.2 equiv), catalyst 6 (5.8 mg, 4 μmol, 2 mol%), and 5 Å MS (40 mg) in α,α,α-trifluorotoluene (2 mL). The mixture was stirred vigorously at r.t. for 24 h and then treated with an aqueous saturated solution of NaHCO₃. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. Purification was performed by column chromatography on silica gel using 2% EtOAc in hexane as the eluents to obtain product 3a as a colorless oil (43 mg, 90% yield); er = 98:2. ¹H NMR (500 MHz, CDCl₃): δ = 7.31–7.26 (m, 2 H), 7.22–7.17 (m, 3 H), 4.52 (t, J = 7.0 Hz, 1 H), 3.09 (d, J = 11.5 Hz, 1 H), 2.96 (d, J = 11.5 Hz, 1 H), 2.75 (m, 2 H), 2.19–2.15 (m, 2 H), 1.59 (s, 3 H), 1.55 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 141.0, 128.6, 128.5, 126.1, 77.4, 77.2, 76.9, 60.3, 53.2, 50.9, 40.7, 35.4, 29.7, 29.4. HRMS (APPI pos.): m/z calcd for C₁₃H₁₉O₂ [M + H]⁺: 239.0928; found: 239.0924. [α]_D ²⁵ –20.2 (c 1.00, CHCl₃). HPLC (Chiralpak OJ-H, n-heptane–i-PrOH = 99:1, flow rate: 0.5 mL/min, λ = 254 nm): t _R (minor) = 14.76 min, t _R (major) = 16.89 min.
• 12 Representative Procedure for the Synthesis of Dithianes Freshly distilled hydrocinnamaldehyde (26.0 μL, 0.2 mmol, 1 equiv) was added to a mixture of 2-methylpropane-1,3-dithiol (1b, 29 μL, 0.4 mmol, 1.2 equiv), catalyst 6 (14.6 mg, 10 μmol, 5 mol%), and 5 Å MS (40 mg) in α,α,α-trifluorotoluene (2 mL). The mixture was stirred vigorously at 0 °C for 24 h and then quenched with an aqueous saturated solution of NaHCO₃. The aqueous layer was extracted three times with EtOAc, and the combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Purification was performed by column chromatography on silica gel using 30% CH₂Cl₂ in hexane as the eluents to get product 3f as a colorless oil (37 mg, 73% yield); er = 90:10. ¹H NMR (500 MHz, CDCl₃): δ = 7.30–7.27 (m, 2 H), 7.21–7.18 (m, 3 H), 4.16 (t, J = 7.2 Hz, 1 H), 3.09 (ddd, J = 15.4, 12.6, 3.1 Hz, 1 H), 2.86 (m, 2 H), 2.74 (ddd, J = 15.4, 4.5, 3.1 Hz, 1 H), 2.05 (m, 2 H), 1.88–1.77 (m, 2 H), 1.34 (s, 3 H), 1.28 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 140.9, 128.5, 128.4, 126.0, 43.1, 41.5, 39.5, 36.5, 32.5, 32.0, 26.7, 26.5. HRMS (EI, FE): m/z calcd for C₁₄H₂₀S₂ [M]: 252.1006; found: 252.1006. [α]_D ²⁵ –54.9 (c 0.85, CHCl₃). HPLC (Chiralpak Cellucoat RP, MeCN–H₂O = 60:40, flow rate: 1 mL/min, λ = 207 nm): t _R (minor) = 9.90 min, t _R (major) = 10.84 min.