Boric Acid Mediated N-Acylation of Sulfoximines

Abstract

The N-acylation of a sulfoximine with carboxylic acids was accomplished with boric acid and several boronic acids. Aliphatic acids give fair yields of products while acids related to phenylacetic and phenoxyacetic acids perform much better. Aromatic acids are ineffective in this process.

sulfoximine - boric acid - boronic acid - amidation - acylation

References and Notes

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Typical Procedure: A flame-dried, 50-mL single-neck round-bottomed flask was equipped with a Dean-Stark trap topped with a reflux condenser fitted with nitrogen inlet, and a Teflon-coated magnetic stirring bar. The reaction vessel was charged with racemic 1 (1 g, 6.45 mmol), carboxylic acid (7.09 mmol, 1.1 equiv), boric acid (310 mg, 0.8 equiv, 5.12 mmol) and toluene (20 mL, 0.32 M). The apparatus (save the condenser) was wrapped in aluminum foil to prevent heat loss. The reaction mixture was heated at reflux for 24 h, and H₂O (ca. 0.1 mL) was collected in the Dean-Stark trap. The remaining volume of toluene in the flask
was ca. 10 mL, corresponding to approximately 0.645 M concentration of the reactants. The mixture was allowed to cool at ambient temperature and worked up in one of two ways.
The reaction mass was dissolved in EtOAc (50 mL) and washed with sat. NaHCO₃ (3 × 50 mL) solution to remove any unreacted carboxylic acid and boric acid present. The collected organic layer was washed once with 3 N HCl (50 mL), followed by brine (50 mL). The organic layers were collected, dried with MgSO₄ and filtered and the solvent was removed under vacuum. The crude product was pure in many cases and did not need further purification.
In an alternative workup, the reaction mass was dissolved in EtOAc (50 mL) and washed with brine (50 mL) and the organic layer was dried with MgSO₄ and filtered and the solvent was removed under vacuum. The crude product was purified by flash column chromatography using 20-40% EtOAc-hexanes mixtures to afford pure product.

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Data for selected compounds: Compound 3: crystalline white solid; R _f 0.48 (40% EtOAc-hexanes); mp 94.5-98 ˚C; yield: 80%. IR (KBr): 3313, 3056, 2943, 2916, 1667, 1488, 1205, 981, 830, 744 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.86 (d, J = 7.5 Hz, 2 H), 7.66 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.30 (t, J = 7.5 Hz, 2 H), 6.98-6.93 (m, 3 H), 4.67 (s, 2 H), 3.38 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 177.3, 158.2, 138.2, 133.9, 129.6, 129.3, 127.0, 121.1, 114.6, 68.9, 44.0. HRMS: m/z [M + Na⁺] calcd for C₁₅H₁₅NO₃S: 312.0664; found: 312.0655. Compound 7: white solid; R _f 0.48 (40% EtOAc-hexanes); mp 82.5-84 ˚C; yield: 75%. IR (KBr): 3059, 3017, 2924, 1634, 1445, 1209, 974, 837, 743 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.83 (d, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.29-7.33 (m, 4 H), 7.23 (m, 1 H), 3.70 (s, 2 H), 3.28 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 180.2, 138.6, 135.8, 133.6, 129.5, 129.4, 128.2, 128.2, 127.0, 126.5, 57.8, 57.6, 47.0, 46.6. HRMS: m/z [M + Na⁺] calcd for C₁₅H₁₅NO₂S: 296.0716; found: 296.0713. Compound 11: fluffy white solid; R _f 0.45 (40% EtOAc-hexanes); mp 131-133 ˚C; yield: 70%. IR (KBr): 3026, 3037, 2926, 1649, 1445, 1165, 973, 837, 744 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.76 (d, J = 7.5 Hz, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.29-7.33 (m, 10 H), 5.12 (s, 1 H), 3.27 (s, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 180.2, 140.0, 139.9, 138.5, 133.6, 129.4, 128.87, 128.86, 128.2, 127.0, 61.3, 43.9. HRMS: m/z [M + Na⁺] calcd for C₂₁H₁₉NO₂S: 372.1029; found: 372.1019. Compound 15: white solid; R _f 0.38 (40% EtOAc-hexanes); mp 59-60.5 ˚C; yield: 64%. IR (KBr): 3060, 3024, 2964, 2931, 1626, 1437, 1354, 1200, 979, 832, 743 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 7.97 (d, J = 7.5 Hz, 2 H), 7.68 (t, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 2 H), 3.34 (s, 3 H), 2.43 (q, J = 7.5 Hz, 2 H), 1.14 (t, J = 7.5 Hz, 3 H). ^¹³C NMR (125 MHz, CDCl₃): δ = 183.5, 138.9, 133.6, 129.5, 127.0, 44.1, 32.7, 9.6. HRMS: m/z [M + Na⁺] calcd for C₁₀H₁₃NO₂S: 234.0559; found: 234.0560.

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Crystallographic data for 3 (CCDC 794098), 5 (CCDC 794100), 13 (CDDC 794099) and 19 (CCDC 794097) may be obtained from the Cambridge Crystallographic Data Centre (www.ccdc.cam.ac.uk/data_request/cif or by E-mail to [e-mail]).