2-Sulfinyl Oxetanes: Synthesis, Stability and Reactivity

Dedicated to Professor Steven V. Ley CBE FRS on the occasion of his 70^th birthday. Happy Birthday Steve!

Abstract

The synthesis of 2-sulfinyl oxetanes is described by a C–C bond-forming cyclisation strategy. Oxetanes bearing electron-poor aryl sulfoxides are shown to be viable targets using this strategy. We report investigations into the sulfoxide magnesium exchange on 2-sulfinyl oxetanes, which resulted in products formed via ligand exchange and ligand coupling pathways. The sulfinyl oxetanes can be readily oxidised to the sulfonyl oxetanes.

Key words

oxetanes - heterocycles - cyclisation - sulfoxides - sulfones

• References and Notes


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For deprotonation at C-2 of substituted oxetanes, see:
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• 17 Optimisation of the reaction parameters included base, number of equivalents of base, time, temperature and rate of addition.
• 18 We were unable to determine the relative stereochemistry of the diastereoisomeric oxetane products.
• 19 Typical Procedures; Procedure A: 2-(2-Chlorobenzenesulfinyl)oxetane (2d): A solution of LiHMDS (1.0 M in THF, 0.94 mL, 0.94 mmol) was added dropwise to a solution of sulfoxide 1d (0.30 g, 0.78 mmol) in THF (30 mL) at 0 °C and stirred for 1 h 15 min. The reaction was quenched with sat. aq NH₄Cl (20 mL) and extracted with CH₂Cl₂ (5 × 15 mL). The combined organics were dried (MgSO₄), filtered and the solvent removed under reduced pressure. Purification by flash chromatography (40% EtOAc–hexane) afforded the sulfinyl oxetane as a mixture of two diastereoisomers 2d-A (12 mg, 6%) followed by 2d-B (62 mg, 37%) both as colourless oils. Minor Diastereoisomer 2d-A: R_f 0.22 (40% EtOAc–hexane). IR (film): 2965, 1724, 1573, 1433, 1357, 1248, 1176, 1103, 1026, 914, 815, 752, 660 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (dd, J = 7.3, 1.8 Hz, 1 H, Ar–H), 7.50 (ddd, J = 8.9, 7.3, 1.3 Hz, 1 H, Ar–H), 7.44 (ddd, J = 8.9, 7.8, 1.8 Hz, 1 H, Ar–H), 7.39 (dd, J = 7.8, 1.3 Hz, 1 H, Ar–H), 5.79 (dd, J = 7.4, 5.3 Hz, 1 H, OCHS), 4.81 (ddd, J = 8.9, 6.7, 5.3 Hz, 1 H, OCHH), 4.68 (ddd, J = 8.3, 6.1, 5.3 Hz, 1 H, OCHH), 3.18–3.18 (m, 1 H, OCH₂CHH), 2.47–2.56 (m, 1 H, OCH₂CHH). ¹³C NMR (100 MHz, CDCl₃): δ = 136.9 (C_q), 132.2 (Ar–C), 130.3 (C_q), 129.8 (Ar–C), 127.9 (Ar–C), 126.4 (Ar–C), 97.5 (SCHO), 71.5 (OCH₂), 18.2 (OCH₂ CH₂). HRMS (ES): m/z [M+H] calcd for C₉H₁₀ ³⁵ClO₂S: 217.0090; found: 217.0104 (Δ 6.5 ppm). Major Diastereoisomer 2d-B: R_f 0.15 (40% EtOAc–hexane). IR (film): 2965, 1724, 1573, 1433, 1357, 1248, 1176, 1103, 1026, 914, 815, 752, 660 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (dd, J = 7.7, 1.7 Hz, 1 H, Ar–H), 7.50 (ddd, J = 9.0, 7.7, 1.3 Hz, 1 H, Ar–H), 7.43 (ddd, J = 9.0, 7.9, 1.7 Hz, 1 H, Ar–H), 7.36 (dd, J = 7.9, 1.3 Hz, 1 H, Ar–H), 5.75 (dd, J = 7.7, 5.5 Hz, 1 H, OCHS), 4.79 (ddd, J = 8.8, 6.9, 5.2 Hz, 1 H, OCHH), 4.64 (ddd, J = 8.3, 5.9, 5.2 Hz, 1 H, OCHH), 3.23–3.31 (m, 1 H, OCH₂CHH), 3.04–3.13 (m, 1 H, OCH₂CHH). ¹³C NMR (100 MHz, CDCl₃): δ = 136.8 (C_q), 132.1 (Ar–C), 129.9 (C_q), 129.5 (Ar–C), 128.0 (Ar–C), 127.5 (Ar–C), 94.5 (SCHO), 71.5 (OCH₂), 22.7 (OCH₂ CH₂). HRMS (ES): m/z [M + H] calcd for C₉H₁₀ ³⁵ClO₂S: 217.0090; found: 217.0104 (Δ 6.5 ppm). Procedure B; 2-(Oxetan-2-ylsulfinyl)pyridine (2c): A solution of LDA (1 M in THF, 1.08 mL, 1.08 mmol) was added dropwise to a solution of sulfoxide 1c (0.26 g, 0.71 mmol) in THF (28 mL) at –78 °C and stirred for 15 min. The reaction flask was transferred to a –20 °C bath and stirred for a further 20 min. The reaction was quenched with sat. aq NH₄Cl (50 mL) and extracted with CH₂Cl₂ (5 × 30 mL). The combined organics were dried (MgSO₄), filtered and the solvent removed under reduced pressure. Purification by flash chromatography afforded the oxetane as a mixture of two diastereoisomers 2c-A (50 mg, 38%) (20% EtOAc–hexane) followed by 2c-B (68 mg, 51%) (20% CH₂Cl₂–Et₂O) both as white solids. Minor Diastereoisomer 2c-A: mp 71–73 °C. R_f 0.10 (20% CH₂Cl₂–Et₂O). IR (film): 3502, 2970, 2912, 1575, 1449, 1421, 1240, 1088, 1053, 1009, 975, 915, 774, 739 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.61 (d, J = 4.7 Hz, 1 H, Py–H), 8.04 (d, J = 7.8 Hz, 1 H, Py–H), 7.94 (ddd, J = 7.8, 7.5, 1.7 Hz, 1 H, Py–H), 7.37 (ddd, J = 7.5, 4.7, 1.1 Hz, 1 H, Py–H), 5.78 (dd, J = 7.9, 5.6 Hz, 1 H, OCHS), 4.82 (ddd, J = 8.8, 6.9, 5.4 Hz, 1 H, OCHH), 4.65 (ddd, J = 8.4, 6.0, 5.4 Hz, 1 H, OCHH), 3.28–3.39 (m, 1 H, OCH₂CHH), 3.05–3.17 (m, 1 H, OCH₂CHH). ¹³C NMR (100 MHz, CDCl₃): δ = 161.0 (Py–C_q), 149.5 (Py–C), 137.7 (Py–C), 124.6 (Py–C), 121.4 (Py–C), 97.2 (OCHS), 71.4 (OCH₂), 22.7 (OCH₂ CH₂). HRMS (CI): m/z [M + H] calcd for C₈H₁₀NO₂S: 184.0432; found: 184.0430 (Δ 1.1 ppm). Major diastereoisomer 2c-B: mp 71–73 °C. R_f 0.15 (20% CH₂Cl₂–Et₂O). IR (film): 3398, 2956, 1573, 1564, 1447, 1418, 1332, 1222, 1113, 1083, 1042, 988, 764, 712 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.61–8.63 (d, J = 4.6 Hz, 1 H, Py–H), 7.90–7.98 (m, 2 H, 2 × Py–H), 7.38 (ddd, J = 6.8, 4.8, 2.2 Hz, 1 H, Py–H), 5.82 (dd, J = 7.4, 5.3 Hz, 1 H, OCHS), 4.80 (ddd, J = 12.0, 6.8, 5.4 Hz, 1 H, OCHH), 4.69 (ddd, J = 11.4, 6.0, 5.4 Hz, 1 H, OCHH), 3.47–3.58 (m, 1 H, OCH₂CHH), 3.12–3.22 (m, 1 H, OCH₂CHH). ¹³C NMR (100 MHz, CDCl₃): δ = 161.0 (Py–C_q), 149.7 (Py–C), 137.9 (Py–C), 124.6 (Py–C), 120.5 (Py–C), 100.0 (OCHS), 71.5 (OCH₂), 18.7 (OCH₂ CH₂). HRMS (CI): m/z [M + H] calcd for C₈H₁₀NO₂S: 184.0432; found: 184.0430 (Δ 1.1 ppm).
• 20 para-Nitrophenyl substrate 1h could not be isolated due to instability and therefore was not investigated further.
• 21 The alkylsulfinyl oxetanes were unstable to silica gel. Purification of 6 was achieved from 2e where only a short plug of silica gel was required.
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