Synthesis of 2-Alkylidene-4-(hydroxymethyl)thiazolidines by One-Pot Cyclization of Dilithiated Arylmethylnitriles with Isothiocyanates and Epibromohydrin

Abstract

2-Alkylidene-(4-hydroxymethyl)thiazolidines were regioselectively prepared by one-pot cyclization of dilithiated aryl­methylnitriles with isothiocyanates and epibromohydrin.

cyclizations - epoxides - N-heterocycles - isothiocyanates - one-pot reactions

References

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18

Typical Procedure for the Preparation of (4-Hydroxymethyl)thiazolidines: To a THF solution (10 mL) of 4-tolylmethylnitrile 1c (0.262 g, 2.0 mmol) was added n-BuLi (4.4 mmol, 1.6 M) at 0 °C. After stirring for 1 h, ethylisothiocyanate (2d, 0.174 g, 2.0 mmol) was added and the solution was stirred for 1 h at 0 °C. Subsequently, epibromohydrin (0.274 g, 2.0 mmol) was added. After warming to 20 °C during 16 h, an aqueous solution of HCl (20 mL, 1 M) was added. The organic and the aqueous layers were separated and the latter was extracted with EtOAc (3 × 30 mL). The combined organic layers were extracted with brine (30 mL), dried (Na₂SO₄), filtered and the solvent of the filtrate was removed in vacuo. The residue was purified by chromatography (silica gel, hexane-EtOAc, 3:2) to give 4n as colorless oil (0.491 g, 90%, E/Z = 5:1). ¹H NMR (300 MHz, CDCl₃, signals are given for both E/Z isomers): δ = 0.97, 1.27 (2 × t, ³ J = 7 Hz, 3 H, CH₃), 2.28, 2.30 (2 × s, 3 H, CH₃), 2.94-3.22 (m, 3 H, CH, CH₂), 3.56-3.66 (m, 2 H, CH₂), 3.94-4.08 (m, 2 H, CH₂), 7.09 (d, ³ J = 8 Hz, 2 H, CH), 7.28 (d, ³ J = 8 Hz, 2 H, CH). ¹³C NMR (75 MHz, CDCl₃, signals are given for both E/Z isomers): δ = 12.53, 13.43, 20.74, 21.89 (CH₃), 27.49, 29.39, 43.93, 45.15, 60.30, 60.87 (CH₂), 68.48, 68.57 (CH), 70.88, 73.87, 121.24, 123.47 (C), 127.87, 128.75, 128.76, 128.99 (CH), 130.62, 133.61, 135.78, 136.29, 161.23, 162.62 (C). IR (KBr): 3432 (s), 2975 (w), 2934 (m), 2873 (w), 2177 (s), 1645 (w), 1548 (s), 1461 (m), 1444 (m) cm^-1. MS (EI, 70 eV): m/z (%) = 274 (100) [M⁺], 243 (84), 215 (46), 188 (14), 119 (33); the exact molecular mass for C₁₅H₁₈N₂OS m/z = 274.1140 ± 2mD (M⁺) was confirmed by HRMS (EI, 70 eV). All new compounds gave satisfactory spectroscopic and correct analytical and/or high resolution mass data.