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Synlett 2007(10): 1529-1532  
DOI: 10.1055/s-2007-982530
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Yan Zhaoa, Ze-Mei Ge*a, Tie-Ming Chenga, 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;
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Publication History

Received 2 February 2007
Publication Date:
06 June 2007 (online)

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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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15

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.

16

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.