Improved Synthetic Method for 5-[(Phenylthio)methyl]oxazoline Derivatives: Electrophilic Cyclization of Allylic Amide Using a Brønsted Acid and Tetrabutylammonium Chloride under Mild Conditions

Abstract

The synthesis of oxazolines using electrophilic cyclization of allylic amide is a simple and powerful method. However, cyclization involving arylsulfenylation requires harsh reaction conditions. We found that the reaction proceeds under mild heating conditions with the combination of a Brønsted acid and tetrabutylammonium chloride. This method enabled the synthesis of 5-[(arylsulfenyl)methyl]oxazoline derivatives under mild conditions and demonstrated high tolerance for various functional groups.

Key words

oxazoline - oxazine - thioether - sulfide - electrophilic cyclization

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• 14 Experimental Procedure for Substrate Scopes (Scheme 2)A 15 mL test tube equipped with a three-way cock was charged with a magnetic stirrer, N-(2-phenylprop-2-en-1-yl)benzamide (1a, 47.5 mg, 0.20 mmol), N-(phenylthio)pyrrolidine-2,5-dione (2, 49.7 mg, 0.24 mmol, 1.2 equiv), and tetrabutylammonium chloride (11.1 mg, 0.04 mmol, 20 mol%). The test tube was evacuated and refilled with dry argon gas three times. Dry DMF (2.0 mL) was added to give a clear solution. (+)-10-Camphorsulfonic acid (9.2 mg, 0.40 mmol, 20 mol%) was added under a slow stream of argon gas. The reaction mixture was heated to 40 °C for 24 h. After being cooled to room temperature, the reaction mixture was quenched by adding of saturated aqueous Na₂S₂O₃ (1.0 mL) and saturated aqueous NaHCO₃ (1.0 mL). The separated aqueous layer was extracted with EtOAc three times, and the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/EtOAc, 7:3) as eluent to give to 3a (66.4 mg, 0.192 mmol, 96%) as a colorless oil.¹H NMR (500 MHz, CDCl₃): δ = 7.85 (d, J = 8.0 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 2 H), 7.33 (s, 4 H), 7.31–7.27 (m, 2 H), 7.20–7.11 (m, 3 H), 4.45 (d, J = 14.6 Hz, 1 H), 4.17 (d, J = 14.6 Hz, 1 H), 3.57 (d, J = 14.0 Hz, 1 H), 3.49 (d, J = 14.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 162.8, 141.8, 135.9, 133.7, 131.4, 130.4, 128.8, 128.7, 128.3, 128.2, 127.3, 126.5, 126.3, 88.2, 66.5, 45.9.
• 15 Experimental Procedure for the Synthesis of Compound 5To a solution of 5-(4-chlorophenyl)-2-phenyl-5-[(phenylthio)-methyl]-4,5-dihydrooxazole (3n, 51.3 mg, 0.135 mmol) in THF (1.3 mL), dilute hydrochloric acid (1.0 mol/L, 1.3 mL) was added. The reaction mixture stirred at room temperature. After being stirred for 24 h, the reaction mixture was quenched by saturated aqueous NaHCO₃. The organic phase was separated, and the aqueous phase was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/EtOAc, 6:4) as eluent to give to 5 (44.8 mg, 0.113 mmol, 83%) as a white solid.¹H NMR (500 MHz, CDCl₃): δ = 7.64 (d, J = 7.4 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.43–7.36 (m, 4 H), 7.29–7.23 (m, 4 H), 7.22–7.14 (m, 3 H), 6.48 (br s, 1 H), 4.02 (dd, J = 13.9, 6.3 Hz, 1 H), 4.03 (br s, 1 H), 3.68 (dd, J = 13.9, 6.3 Hz, 1 H), 3.58 (d, J = 13.5 Hz, 1 H), 3.39 (d, J = 13.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 168.4, 141.1, 135.5, 133.8, 133.5, 131.8, 130.5, 129.0, 128.6, 128.5, 127.0, 126.9, 126.8, 76.4, 49.0, 45.9.
• 16 Experimental Procedure for the Synthesis of Compound 6To a solution of 5-(4-chlorophenyl)-2-phenyl-5-[(phenylthio)methyl]-4,5-dihydrooxazole (3n, 50.4 mg, 0.127 mmol) in MeCN (2.7 mL), sodium hypochloride solution (10.5%, 0.21 mL, 1.1 equiv) was added. The reaction mixture stirred at room temperature. After completion of the reaction, the reaction mixture was quenched by saturated aqueous Na₂S₂O₃. The organic phase was separated, and the aqueous phase was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane/EtOAc 4:6) as eluent to give an inseparable mixture of diastereoisomers 6a and 6b (46.7 mg, 0.113 mmol, 89%) as a colorless oil.¹H NMR (500 MHz, CDCl₃): δ = 8.08 (d, J = 8.0 Hz, 2 H, diastereomer A), δ = 7.92 (d, J = 8.0 Hz, 2 H, diastereomer B), 7.68–7.40 (m, 8 H, A), 7.68–7.40 (m, 12 H, B), 7.38–7.30 (m, 4 H, A), 4.80 (d, J = 14.9 Hz, 1 H, A), 4.55 (d, J = 14.9 Hz, 1 H, B), 4.28 (d, J = 14.9 Hz, 1 H, B), 4.22 (d, J = 14.9 Hz, 1 H, A), 3.60 (d, J = 13.7 Hz, 1 H, B), 3.51 (d, J = 14.3 Hz, 1 H, A), 3.40 (d, J = 14.3 Hz, 1 H, A), 3.33 (d, J = 13.7 Hz, 1 H, B). ¹³C NMR (125 MHz, CDCl₃): δ = 162.8, 162.6, 144.5, 144.3, 141.6, 140.1, 134.4, 134.1, 131.8, 131.8, 131.3, 131.2, 129.4, 129.4, 129.2, 129.1, 128.5, 128.5, 128.4, 128.2, 127.0, 127.0, 126.5, 125.9, 124.1, 123.9, 86.1, 85.9, 70.1, 69.1, 67.6, 66.8.