One-Pot Oxidative Conjugate Hydrothiocyanation-Hydrosulfenylation of Baylis-Hillman Alcohols Promoted by a Protic Ionic Liquid

Abstract

The first example of one-pot oxidative conjugate hydro­thiocyanation-hydrosulfenylation of acrylic ester derived Baylis-Hillman alcohols, that is, methyl 3-aryl-3-hydroxy-2-methylene­propanoate, is reported. The reaction involves protic ionic liquid [Hmim]HSO₄-mediated oxidation of Baylis-Hillman alcohols with NaNO₃ to give methyl (E)-α-formylcinnamates followed by conjugate addition of sulfur-centered nucleophiles (NH₄SCN/PhSH) to afford the corresponding methyl β-thiocyanato (or β-phenylsulfenyl)-α-formylhydrocinnamates diastereoselectively in 74-87% yields in a one-pot procedure. After isolation of the product, the ionic liquid [Hmim]HSO₄ could be easily recycled for further use without any loss of efficiency.

Key words

Baylis-Hillman alcohols - conjugate addition - oxidation - protic ionic liquids - methyl cinnamates - stereoselective synthesis

References and Notes

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16

General Procedure for the Synthesis of Methyl β-Thiocyanato-α-formylhydrocinnamates 3 and Methyl β-Phenylsulfenyl-α-formylhydrocinnamates 4 A mixture of BH alcohol 1 (1 mmol) and NaNO₃ (1 mmol) was stirred in 1 mL of [Hmim]HSO₄ at 80 ˚C for 1-3 h (Table  [²] ). The reaction mixture was cooled to r.t. and NH₄SCN or PhSH (1.1 mmol) was added. The mixture was further stirred at r.t. for 2-3 h. After completion of the reaction (monitored by TLC), the product was extracted with EtOAc (3  10 mL). The combined extract was dried over MgSO₄, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane-EtOAc, 8.5:1.5) to afford the desired product 3 or 4. After isolation of the product, the remaining ionic liquid was washed with Et₂O (2  10 mL) to remove any organic impurity, then H₂SO₄ (2.1 mmol in the case of compound 3 and 1 mmol in the case of 4) was added, the mixture was stirred at 80 ˚C for 1 h, and cooled to about -5 ˚C in an ice-salt bath. The precipitated solid [Na₂SO₄, (NH₄)₂SO₄] was filtered out, and the filtrate was dried under vacuum to afford the IL [Hmim]HSO₄, which was used in subsequent runs.
Data of Representative Compounds Compound 3a: white solid, yield 78%, mp 104-105 ˚C. IR (KBr): 3026, 2115, 1745, 1718, 1603, 1578, 1460, 1284, 1194, 764, 714 cm^-¹. ^¹H NMR (400 MHz, CDCl₃, TMS): d = 3.68 (dd, 1 H, J = 3.9, 2.1 Hz, 2-H), 3.82 (s, 3 H, MeOCO), 4.86 (d, 1 H, J = 3.9 Hz, 3-H), 7.14-7.32 (m, 5 H_arom), 9.56 (d, 1 H, J = 2.1 Hz, CHO). ^¹³C NMR (100 MHz, CDCl₃, TMS): d = 36.6, 63.9, 52.8, 112.4, 126.9, 128.6, 129.2, 140.9, 169.1, 198.3. MS (EI): m/z = 249 [M⁺]. Anal. Calcd (%) for C₁₂H₁₁NO₃S: C, 57.82; H, 4.45; N, 5.62. Found: C, 57.56; H, 4.57; N, 5.43.
Compound 4f: yellowish solid, yield 76%, mp 132-133 ˚C. IR (KBr): 3055, 2932, 1746, 1721, 1586, 1520, 1345, 1280, 1186, 760, 710 cm^-¹. ^¹H NMR (400 MHz, CDCl₃, TMS): d = 3.72 (dd, 1 H, J = 3.9, 2.1 Hz, 2-H), 3.81 (s, 3 H, MeOCO), 4.68 (d, 1 H, J = 3.9 Hz, 3-H), 7.24-8.27 (m, 9H_arom), 9.54 (d, 1 H, J = 2.1 Hz, CHO). ^¹³C NMR (100 MHz, CDCl₃, TMS): d = 30.6, 52.7, 64.2, 121.6, 124.9, 127.4, 129.2, 129.8, 135.8, 148.2, 149.4, 169.0, 198.3. MS (EI): m/z = 345 [M⁺]. Anal. Calcd (%) for C₁₇H₁₅NO₅S: C, 59.12; H, 4.38; N, 4.06. Found: C, 59.33; H, 4.74; N, 3.89.

22

General Procedure for the Synthesis of Methyl ( E )-α-Formylcinnamates 2 A stirred solution of BH alcohols 1 (1 mmol) and NaNO₃ (1 mmol) in 1 mL of [Hmim]HSO₄ was heated at 80 ˚C for 1-3 h (Table  [²] ). The reaction progress was monitored by TLC. Upon completion, the reaction mixture was cooled to r.t. and extracted with EtOAc (3 × 10 mL).The combined organic phase was dried over MgSO₄, filtered, and evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using a gradient mixture of hexane-EtOAc (8:2) as eluent to give the pure cinnamates 2. The remaining ionic liquid was recycled for subsequent runs as described above using H₂SO₄ (1 mmol).^¹6
Data of Representative Compound Compound 2a: white solid, yield 80%, mp 91-92 ˚C. IR (KBr): 3076, 2809, 2740, 1724, 1684, 1578, 1462, 1286, 1190, 760, 712 cm^-¹. ^¹H NMR (400 MHz, CDCl₃, TMS): δ = 3.87 (s, 3 H, MeOCO), 7.48-7.70 (m, 3 H_arom), 7.86 (s, 1 H, CHPh), 8.04-8.12 (m, 2 H_arom), 9.66 (s, 1 H, CHO). ^¹³C NMR (100 MHz, CDCl₃, TMS): δ = 52.6, 127.7, 129.4, 130.2, 131.3, 134.7, 154.6, 167.9, 187.6. MS (EI): m/z = 190 [M⁺]. Anal. Calcd (%) for C₁₁H₁₀O₃: C, 69.46; H, 5.30. Found: C, 69.81; H, 5.14.