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Keywords:
2-aminothiazoles; electrosynthesis; indirect electrolysis; halide ion
Abstract
The electrochemical preparation of 2-aminothiazoles has been achieved by the reaction of active methylene ketones with thioureas assisted by DL-alanine using NH4I as a redox mediator. The electrochemical protocol proceeds in an undivided cell equipped with graphite plate electrodes under constant current conditions. Various active methylene ketones, including β-keto ester, β-keto amide, β-keto nitrile, β-keto sulfone and 1.3-diketones. can be converted to the corresponding 2-aminothiazoles. Mechanistically, the in situ generated α-iodoketone was proposed to be the key active species.
Introduction
Thiazoles are prevalent structural motifs in a wide range of natural products [1] and synthetic molecules possessing various pharmaceutical activities such as antimicrobial [2.3], antiviral [4], antitumor [5.6], anti-inflammatory [7.8] and so on. Moreover. as a type of important intermediates, thiazole is of prime importance in organic synthesis [9.10] which is used ly in the of flavors [11], polymers [12], dyes [13], etc. These important features of thiazoles have driven intense interests in their facile synthesis [14-17]. Among various synthetic routes to the thiazole unit, the Hantzsch condensation of α-halo ketones (dielectrophiles) with various thioureas (dinucleophiles) should be the most well-known method (Scheme la) [18]. Since active methylene ketones are able to be in situ α-halogenated. the modified Hantzsch condensation of active methylene ketones with thioureas has attracted increasing attention in thiazoles' synthesis, thereby saving costs and time needed to prepare the required α-halogenated dielectrophiles. Along this line, in situ a-halogenation strategies have been developed, using various halogenating reagents including Br2 [19.20], I2 [21.22], NBS [23-25], tribromoisocyanuric acid [26], 1.3-dichloro-5.5-dimethylhydantoin [27], HBr or HI. DMSO [28] etc. (Scheme lb). Alternatively, the oxidation of α-C-H of active methylene ketones generate α-carbon-centered radicals, thus providing another way to obtain thiazoles. Recently. Sun et al. reported a tert-butyl hydroperoxide/azodi-isobutyronitrile-mediated synthesis of 2-aminothiazoles from active methylene ketones and thiourea via an oxidative cyclization initiated by a radical process and a following condensation reaction (Scheme 1c) [29]. Although these methods are practical. most of these strategies require stoichiometric or excess amounts of halogenating reagents or oxidants, which are toxic, hazardous and would lead to a large quantity of waste. Considering the importance of thiazoles in synthetic and medicinal chemistry, the development of greener and more atom...