Synthesis of 2-(Benzylthio)-4-(trifluoromethyl)thiazole-5-carboxylates Using S-Benzylisothiouronium Halides as Thiol Equivalents

Abstract

S-Benzylisothiouronium halides are used as shelf-stable, odorless thiol equivalents. The method developed is used to access 2-(benzylthio)-4-(trifluoromethyl)thiazole carboxyl building blocks. Using the latent trifluoromethyl substituent the reactions could be monitored using ¹⁹F NMR spectroscopy.

Key words

thioether - isothiouronium halide - ¹⁹F NMR spectroscopy - nucleophilic aromatic substitution - thiazole

• References and Notes

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• 11 Example Procedure: Ethyl 2-[(4-Bromobenzyl)thio]-4-(trifluoromethyl)thiazole-5-carboxylate (12) A mixture of 2-bromothiazole 8 (152 mg, 0.50 mmol), Et₃N (0.28 mL, 2.0 mmol, 4.0 equiv), and 6e (326 mg, 1.00 mmol, 2.0 equiv) in MeCN–PhCF₃ (5 mL, Table 1) was heated at 120 °C for 60 min using MW irradiation. The reaction mixture was diluted using MeOH and concentrated onto SiO₂ and then purified by column chromatography using CH₂Cl₂–petroleum spirits (1:3 to 1:1) to give 12 (178 mg, 84%) as a clear oil. ¹H NMR (500 MHz, CDCl₃): δ = 7.47–7.44 (m, 2 H), 7.31–7.28 (m, 2 H), 4.43 (s, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 169.2, 158.5, 145.7 (q, ² J _CF = 37.9 Hz), 134.6, 131.8, 130.9, 129.3, 122.0, 119.5 (q, ¹ J _CF = 271.1 Hz), 62.6, 37.2, 13.9. ¹⁹F NMR (470 MHz, CDCl₃): δ = –61.93 (s). ESI-HRMS: m/z calcd for C₁₄H₁₁ ⁷⁹BrF₃NO₂S₂ [M + H⁺]: 425.9439; found: 425.9446.