Thia-Michael Addition Using Cheap and Odorless S-Alkylisothiouronium Salts as Thiol Equivalents in Water

Yan Zhao; Ze-Mei Ge; Tie-Ming Cheng; Run-Tao Li

doi:10.1055/s-2007-982530

LETTER

Thia-Michael Addition Using Cheap and Odorless S-Alkylisothiouronium Salts as Thiol Equivalents in Water

Yan Zhao^a, Ze-Mei Ge*^a, Tie-Ming Cheng^a, Run-Tao Li*^a,b
^a School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. of China
^b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. of China
Fax: +86(10)82716956; e-Mail: zmge@bjmu.edu.cn;

Abstract

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Abstract

S-Alkylisothiouronium salt has been found to be a nontoxic, odorless and simply operational alternative of thiol for the thia-Michael addition with electron-deficient olefins. The reactions were carried out under alkaline conditions in water at room temperature within 5-20 minutes to afford the expected products in good to excellent yields.

Key words

thia-Michael addition - thiol equivalent - S-alkylisothiouronium salts - electron-deficient olefins - green chemistry

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References and Notes

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Typical Procedure for the Thia-Michael Addition of S -Alkylisothiouronium Salts to Electron-Deficient Olefins: To a magnetically stirred solution of an S-alkylisothio-uronium salt (3 mmol) and an electron-deficient olefin (3 mmol) in H₂O (5 mL) was slowly added an aq NaOH solution (7.5 mmol NaOH in 2 mL H₂O), and then the mixture was stirred at r.t. for the indicated time in Table [1] . Then, the reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic extracts were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using EtOAc-PE as eluent to afford the corresponding product. All the new compounds were characterized on the basis of ¹H NMR and elemental analysis and the structures of the known compounds were confirmed by ¹H NMR spectra, which were consistent with literature data.

Spectroscopic data of the selected compound:
3-Methylthiopropanenitrile ¹⁴ (3j; Table 1, entry 10): colorless liquid. ¹H NMR (300 MHz, CDCl₃): δ = 2.20 (s, 3 H), 2.67 (t, J = 6.9 Hz, 2 H), 2.78 (t, J = 6.9 Hz, 2 H).
3-Cyclopentylthiopropanenitrile (3u; Table 1, entry 21): colorless liquid. ¹H NMR (300 MHz, CDCl₃): δ = 1.48-1.62 (m, 4 H), 1.73-1.77 (m, 2 H), 1.97-2.05 (m, 2 H), 2.64 (t, J = 7.2 Hz, 2 H), 2.81 (t, J = 7.2 Hz, 2 H), 3.13-3.23 (m, 1 H). Anal. Calcd for C₈H₁₃NS: C, 61.89; H, 8.44; N, 9.02. Found: C, 61.92; H, 8.274; N, 8.902.
3-Phenyl-3-benzylthiopropanenitrile (3v; Table 1; entry 22): colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.80 (dd, J = 2.5, 7.5 Hz, 2 H), 3.52 (d, J = 13.8 Hz), 3.66 (d, J = 13.8 Hz, 1 H), 3.90 (t, J = 7.2 Hz, 1 H), 7.21-7.41 (m, 10 H). Anal. Calcd for C₁₆H₁₅NS: C, 75.8; H, 5.91; N, 5.53. Found: C, 75.70; H, 6.04; N, 5.41.