Stereocontrolled Synthesis of Sulfonyl 2,5-Diaryltetrahydrofurans

Abstract

BF₃·OEt₂-mediated stereocontrolled annulation of 4-alkenols affords sulfonyl 2,5-diaryltetrahydrofurans in good yields. The key synthetic route combines the facile stereoselective reduction of α-styryl-β-ketosulfones and an intramolecular Friedel–Crafts electrophilic cyclization of the resulting 4-alkenols. A plausible mechanism has been studied and proposed.

Key words

2,5-diaryltetrahydrofurans - reduction - 4-alkenols - β-ketosulfones - cyclization

• References and Notes


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• 6 CCDC 1429280 (6a) and 1434699 (6b) contain the supplementary crystallographic data for this paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html [or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail]].
• 7 Representative Synthetic Procedure of Skeleton 6: NaBH₄ (100 mg, 3.0 mmol) was added to a solution of skeleton 4 (1.0 mmol) in a co-solvent of THF (5 mL) and MeOH (5 mL) at 0 °C. The reaction mixture was stirred for 1 h at 0 °C and the solvent was concentrated. The residue was diluted with H₂O (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford the crude product. Without further purification, BF₃·OEt₂ (142 mg, 1.0 mmol) was added to a solution of the resulting skeleton 5 in CH₂Cl₂ (5 mL) at 25 °C. The reaction mixture was stirred at 25 °C for 20 h. The reaction mixture was concentrated and the residue was diluted with H₂O (10 mL) and the mixture was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford the crude product under reduced pressure. Purification on silica gel (hexanes–EtOAc, 8:1 to 3:1) yielded the skeleton 6. Compound 6a: yield: 75% (294 mg); colorless solid; mp 173–174 °C (recrystallized from hexanes and EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 7.39–7.42 (m, 4 H), 7.16–7.30 (m, 8 H), 7.07 (d, J = 8.0 Hz, 2 H), 5.12 (d, J = 8.0 Hz, 1 H), 3.99 (q, J = 8.0 Hz, 1 H), 2.88 (dd, J = 1.2, 8.4 Hz, 2 H), 2.37 (s, 3 H), 1.78 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 145.27, 143.82, 136.26, 135.70, 129.36 (2 ×), 128.62 (2 ×), 128.50 (2 ×), 128.14, 127.82 (2 ×), 127.58 (2 ×), 127.18, 124.50 (2 ×), 83.80, 79.46, 67.64, 40.14, 30.31, 21.48. HRMS (ESI): m/z [M⁺ + 1] calcd for C₂₄H₂₅O₃S: 393.1524; found: 393.1530. Anal. Calcd for C₂₄H₂₄O₃S: C, 73.44; H, 6.16. Found: C, 73.70; H, 6.28. Single-crystal X-ray diagram: crystal of compound 6a was grown by slow diffusion of EtOAc into a solution of compound 6a in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 13.9520(8) Å, b = 14.5100(7) Å, c = 11.1921(6) Å, V = 2096.6(2) ų, Z = 4, d _calcd = 1.243 mg/cm³, F(000) = 832, 2θ range 1.577–26.410°, R indices (all data) R1 = 0.0729, wR2 = 0.1568. Compound 6b: yield: 70% (287 mg); colorless solid; mp 154–155 °C (recrystallized from hexanes and EtOAc). ¹H NMR (400 MHz, CDCl₃): δ = 7.50–7.53 (m, 2 H), 7.37–7.42 (m, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.27–7.29 (m, 3 H), 7.15 (d, J = 8.0 Hz, 2 H), 6.89–6.94 (m, 2 H), 5.49 (d, J = 8.0 Hz, 1 H), 4.39 (q, J = 8.0 Hz, 1 H), 2.85 (dd, J = 10.0, 12.8 Hz, 1 H), 2.56 (dd, J = 8.4, 12.8 Hz, 1 H), 2.39 (s, 3 H), 1.57 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 162.55 (d, J = 244.8 Hz), 146.02, 144.22, 136.30, 134.10 (d, J = 3.0 Hz), 130.26 (d, J = 8.4 Hz, 2 ×), 129.45 (2 ×), 128.24 (2 ×), 127.77 (2 ×), 127.00, 124.48 (2 ×), 114.32 (d, J = 22.0. Hz, 2 ×), 83.24, 78.72, 67.46, 40.53, 27.80, 21.41. HRMS (ESI): m/z [M⁺ + 1] calcd for C₂₄H₂₄FO₃S: 411.1430; found: 411.1435. Single-crystal X-ray diagram: crystal of compound 6b was grown by slow diffusion of EtOAc into a solution of compound 6b in CH₂Cl₂ to yield colorless prisms. The compound crystallizes in the monoclinic crystal system, space group P 21/c, a = 5.8096(3) Å, b = 15.7969(8) Å, c = 22.8181(12) Å, V = 2093.57(19) ų, Z = 4, d _calcd = 1.302 mg/cm³, F(000) = 864, 2θ range 1.568–26.542°, R indices (all data) R1 = 0.0645, wR2 = 0.1086.