Metal-Free One-Pot Chemoselective Thiocyanation of Imidazothiazoles and 2-Aminothiazoles with in situ Generated N-Thiocyanatosuccinimide

Abstract

A chemoselective thiocyanation of imidazothiazoles and 2-aminothiazoles with use of in situ generated N-thiocyanatosuccinimide (NTS) at room temperature is described. The protocol offers mild reaction conditions and high chemoselectivity for electrophilic substitution in imidazothiazoles over nucleophilic substitution. This method provides metal-free and easy conversion of imidazothiazoles and 2-aminothiazoles into their corresponding C-3 and C-5 thiocyanates, respectively, in good to excellent yield. The present protocol also offers the effective thiocyanation of bifunctional imidazothiazoles containing ­aliphatic –OH and C(sp²)–H bond functionalities.

Keywords

N-thiocyanatosuccinimide - thiocyanation - imidazothia­zoles - 2-aminothiazoles - PEG-400

• References

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• 25 Procedure for the Synthesis of 1-(6-(4-Chlorophenyl)-3-methyl-5-thiocyanatoimidazo[2,1-b]thiazol-2-yl)ethanol (2a) (Table [1]) A dried 50 mL round-bottomed flask was charged with NBS (177.98 mg, 1 mmol), NH₄SCN (152.24 mg, 2.0 mmol) in PEG-400 (3 mL) and the reaction mixture was stirred at r.t. for 15 min. The reaction mixture turned milky indicating generation of NTS (shown by TLC). Next, reactant 1a (292.78 mg, 1 mmol) was added slowly, and the reaction mixture was further stirred for 3 h. After completion of the reaction as indicated by TLC, cold water (20 mL) was added to separate the solid product. The white solid was filtered, dried, and washed with cold aqueous ethanol (0.93 mmol, 93% yield). Compound 2a: Mp 111–113 °C. FT-IR: 3195, 2966, 2154, 1893, 1644 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.94 (d, 2 H, J = 8.0 Hz), 7.62 (s, 2 H), 5.96 (s, 1 H), 5.17 (s, 1 H), 2.73 (s, 3 H), 1.41 (s, 3 H) ppm. ¹³C{¹H} NMR (100 MHZ, DMSO-d ₆): δ = 152.62, 152.11, 134.68, 134.20, 131.36, 129.84, 128.87, 124.27, 111.02, 97.97, 62.25, 25.24, 12.39 ppm. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₅H₁₂ClN₃OS₂: 349.0110; found: 350.0174. Procedure for the Synthesis of 5-thiocyanato-4-(p-tolyl)thiazol-2-amine (4f) (Scheme [4]) A dried round-bottomed flask was charged with NBS (177.98 mg, 1.0 mmol) and NH₄SCN (152.24 mg, 2.0 mmol). PEG-400 (3 mL) was added and reaction mixture was stirred at r.t. for 15 min. Formation of a milky color indicated the generation of NTS (shown by TLC). Then, 4-(p-tolyl)thiazol-2-amine (190.26 mg, 1 mmol) was added slowly, and the reaction mixture was further stirred for 3 h. When completion of the reaction was indicated by TLC, the product was separated by addition of cold water (20 mL). The white solid product was filtered, dried, and washed with cold aqueous ethanol (0.78 mmol, 78% yield). Compound 4f: Mp 134–136 °C. FT-IR: 3372, 3269, 3045, 2100, 1612 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 7.88 (s, 2 H), 7.69–7.31 (m, 4 H), 2.52 (s, 3 H) ppm. ¹³C{¹H} NMR (100 MHZ, DMSO-d ₆): δ = 171.25, 259.25, 139.14, 130.64, 129.39, 129.18, 129.01, 112.57, 21.39 ppm. HRMS (ESI-TOF): m/z [M + H]⁺ calcd for C₁₁H₉N₃S₂: 247.0238; found: 248.0305.