Racemization Hantzsch thiazole synthesis

This reaction was first reported by Hantzsch and Weber in 1887. It is the formation of thiazole derivatives by means of condensation of a-haloketones (or aldehydes) and thioamides. Therefore, it is generally known as the Hantzsch thiazole synthesis. In addition, other names, including the Hantzsch synthesis, Hantzsch reaction, and Hantzsch thiazole reaction are also used from time to time. Besides thioamides, other thio-ketone derivatives such as thiourea, dithiocarbamates, and ketone thiosemicarbazone can also condense with a-halo ketones (or aldehydes) to form thiazoles. This reaction occurs because of the strong nucleophilicity of the sulfur atom in thioamides or thioureas, and normally gives excellent yields for simple thiazoles but low yields for some substituted thiazoles, as of dehalogenation. This reaction has been proven to be a multistep reaction, and the intermediates have been isolated at low temperatures, in which the dehydration of cyclic intermediates seems to be the slow step. It is found that a variety of reaction conditions might result in the racemized thiazoles that contain an enolizable proton at their chiral center, and it is the intermediate not the final product that is involved in the racemization. Therefore, some modifications have been made to reduce or even eliminate the epimeriza-tion upon thiazole formation. In addition, this reaction has been modified using a-tosyloxy ketones to replace a-haloketones. ... 

The Hantzsch thiazole synthesis, which occurs between a-haloketones and thiourea or thioamides, generally proceeds smoothly to yield the desired thiazole. Most of the efforts that have been made to improve this reaction have focused on controlling the undesired racemization that occurs with chiral starting materials. One of the most important modifications is the Holzapfel modification, which uses neutral reaction conditions and lower temperatures to eliminate potential epimerization reactions. 

The most widely employed synthetic approach for the preparation of thiazoles is the condensation of an a-halocarbonyl compound with a reactant bearing the N—C—S fragment such as thioamides, thioureas, or dithiocarbamic acid derivatives <84CHEC-i(6)294>. When the Hantzsch s synthesis is employed for the preparation of chiral substituted thiazoles such as 2-aminomethyl thiazoles some foresight must be considered in order to prevent racemization (see Section 3.06.11). 

Various more or less efficient methods have been reported for the synthesis of 2-(l-ami-noalkyl)thiazole-4-carboxylic acids and their suitably protected derivatives. 237,539,541,558-568 Optimal conditions must be selected in these syntheses to prevent racemization at the chiral aminoalkyl moiety, e.g. when applying a modified Hantzsch synthesis 559 racemization has been observed to occur at the level of the starting Na-protected amino acid thioamide as well as in the base-mediated dehydration step of the intermediate hydroxydihydrothiazoles. 558 The 2-(aminoalkyl)thiazole-4-carboxylic acids are incorporated into the linear precursors by standard procedures of peptide synthesis, 237,514,529,539,552,555,558,564,569 and cyclization is pref-... 

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