Synthesis of α-Thiooximes by Addition of Thiols to N,N-Bis(oxy)-enamines: A Comparative Study of S-, N-, and O-Nucleo­philes in Michael Reaction with Nitrosoalkene Species

Abstract

Nucleophilic addition of thiols to N,N-bis(oxy)enamines (nitrosoalkene acetals) produce valuable α-thiooximes in a highly efficient manner. The reaction was found to be solvent-dependent, likely because of distinct mechanisms operating in nonpolar and basic solvents (involving either Brønsted acid or Lewis base catalysis). By performing a series of competition experiments, the relative reactivity of S-, N-, and O-nucleophiles in reaction with N,N-bis(oxy)enamines was determined for the first time. Interestingly, the relative nucleophilicity was found to be highly dependent on the solvent, which allows regioselective control of these reactions by using an appropriate medium.

Key words

thiols - nitrosoalkenes - oximes - Michael addition - solvent effects

• References and Notes

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• 10 General procedure for the addition of thiophenols to N,N-bis(oxy)enamines 2 (method 1): To a stirred solution of N,N-bis(oxy) enamine 2 (1 mmol) in toluene (6 mL) was added p-thio­cresol (124 mg, 1 mmol) or pyridine-2-thiol (111 mg, 1 mmol). After keeping for 24 h at room temperature, methanol (5 mL) was added and the mixture was stirred for 1 h and concentrated in vacuum (ca. 45 °C). The residue was subjected to column chromatography on silica gel to give the corresponding α-thiooxime 1. Yields are given in Scheme 3 and in the Supporting information.1-(p-Tolylthio)propan-2-one oxime (1a): White crystals; mp 81–83°C (pentane–Et₂O); R_f = 0.29 (EtOAc–hexane, 1:1); dynamic mixture of E/Z-isomers, ratio 3:1. ¹H NMR (300 MHz, CDCl₃, E-isomer): δ = 8.35–8.23 (br, 1 H, NOH), 7.31–7.24 (d, J = 8.1 Hz, 2 H, 2 × =CH), 7.09 (d, J = 8.1 Hz, 2 H, 2 × =CH), 3.56 (s, 2 H, CH₂), 2.32 (s, 3 H, H₃C-Ar), 1.99 (s, 3 H, H₃C-C=N). ¹³C NMR (50 MHz, DEPT135, CDCl₃, E-isomer): δ = 155.09 (C=N), 137.19 (C=C-CH₃), 131.39 and 129.84 (4 × =CH), 131.00 (=C-S), 39.93 (CH₂), 21.16 (H₃ C-Ar), 12.89 (H₃ C-C=N). ¹H NMR (300 MHz, CDCl₃, Z-isomer): δ = 8.53–8.38 (br, 1 H, NOH), 7.31 (d, J = 8.1 Hz, 2 H, 2 × =CH), 7.09 (d, J = 8.1 Hz, 2 H, 2 × =CH), 3.79 (s, 2 H, CH₂), 2.32 (s, 3 H, H₃C-Ar), 1.92 (s, 3 H, H₃C-C=N). ¹³C NMR (50 MHz, DEPT135, CDCl₃, Z-isomer): δ = 154.94 (C=N), 136.84 (C=C-CH₃), 131.78 (=C-S), 130.33 and 129.84 (4 × =CH), 30.68 (CH₂), 21.19 (H₃ C-Ar), 19.22 (H₃ C-C=N). FTIR (KBr): 3239 (s, br), 3104 (s, sh), 3022 (s, sh), 2920 (s), 2870 (s), 1660 (m), 1493 (s), 1448 (s), 1411 (s), 1368 (s), 1270 (m), 1230 (w), 1159 (m), 1091 (m), 1018 (s), 963 (s), 867 (m), 805 (s), 721 (m), 629 (m), 500 (s) cm^–1. HRMS: m/z [M+H]⁺ calcd. for [C₁₀H₁₄NOS]⁺: 196.0793; found: 196.0791.General procedure for the addition of aliphatic thiols to N,N-bis(oxy)enamines 2 (method 2): A solution of thiol (1 mmol) in dimethylformamide (1.5 mL) was added to the corresponding N,N-bis(oxy)enamine 2 (1 mmol; 2 mmol for product 1n) with vigorous stirring. After keeping for 24 h at room temperature, methanol (5 mL) was added and the mixture was stirred for 1 h and concentrated in vacuum (ca. 45 °C). The residue was dried in vacuum (1 Torr, ca. 50 °C) to remove DMF and then subjected to column chromatography on silica gel to give the corresponding α-thiooxime 1. Yields are given in Scheme 3 and in the Supporting information.1-(Heptylthio)propan-2-one oxime (1b): Oil; R_f = 0.89 (EtOAc–hexane, 1:1); single isomer. ¹H NMR (300 MHz, CDCl₃): δ = 8.25 (s, 1 H, NOH), 3.19 (s, 2 H, CH₂C=N), 2.44 (t, J = 7.4 Hz, 2 H, CH₂S), 2.00 (s, 3 H, CH₃), 1.61–1.51 and 1.41–1.24 (2 m, 2 H and 8 H, 5 × CH₂), 0.89 (t, J = 6.8 Hz, 3 H, CH₃). ¹³C NMR (75 MHz, CDCl₃): δ = 155.72 (C=N), 36.47 (CH₂C=N), 31.80, 31.30, 29.27, 28.94, 28.86 and 22.67 (6 × CH₂), 14.13 and 12.64 (2 × CH₃). HRMS: m/z [M+Na]⁺ calcd. for [C₁₀H₂₁NOSNa]⁺: 226.1239; found: 226.1236.
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