3034-52-4

Pale yellow liquid

ChEBI: 2-chlorothiazole is a member of 1,3-thiazoles and an organochlorine compound.

Halogen atoms in the 4- and 5-positions of thiazoles exhibit different reactivities depending on the nucleophile: with methoxide ion in methanol the reactivity sequence is 5-chlorothiazole > 2-chlorothiazole > 4-chlorothiazole. In contrast, with thiophenoxide ion or piperidine in methanol, the sequence 2 > 4 > 5 is observed. With the series of alkoxide ions methoxide, ethoxide, isopropoxide and t-butoxide in the corresponding alcohol, the reactivity ratios of 4-chlorothiazole versus 2-chlorothiazole are: 0.07, 0.6, 4, 42. The nucleophilic reactivity of 2-halogenothiazoles is strongly affected by substituents: 2-chloro-5-nitrothiazole is more reactive than 2-chlorothiazole by a factor of 10.

General procedure for the synthesis of 2-chlorothiazole from thiazole: To an anhydrous THF (60 mL) solution of thiazole (5.0 g, 58.7 mmol) was added n-butyllithium (1.6 M hexane solution, 44 mL, 70.4 mmol) slowly and dropwise over a period of 20 min at -78 °C with stirring. The reaction mixture was kept at 0 °C for 15 min, followed by dropwise addition of anhydrous THF (40 mL) solution of 2,2,2-trichloroacetyl chloride (6.6 mL, 58.7 mmol) to the orange colored mixture. The reaction mixture was continued to be stirred at -78 °C for 30 min, after which the reaction was quenched with saturated ammonium chloride solution (100 mL). After extraction with ether (2 x 150 mL), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-20% ether/pentane gradient elution) to afford the target compound 2-chlorothiazole (4.95 g, isolated yield 71%).1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H).

[1] Patent: WO2008/150446, 2008, A1. Location in patent: Page/Page column 29
[2] Journal of Organometallic Chemistry, 1999, vol. 588, # 2, p. 155 - 159
[3] Journal of Organometallic Chemistry, 2000, vol. 601, # 2, p. 233 - 236