Hydroxythiazoline

The mechanism of the Hantzsch s synthesis was studied at a very early stage by several authors. The intermediates were generally assumed to be open-chain a-thioketones, but in a series of papers by Murav eva and Schukina (470, 490) the isolation of hydroxythiazolines from the reaction between a-haloketones and a variety of thioureas was reported. 

It is interesting to note that in each of these cases only one intermediate, either the a-thioketone (93) or the hydroxythiazoline (94), was isolated from the reaction mixture, thus suggesting that hydroxythiazolines are in equilibrium with the corresponding a-thioketones. Similar conclusions are implicit in Baganz and Roger s production of 4-formylthiazoles by this synthesis (625). 

As reported by Simiti and co-workers (87AP528) the 5-alkylated product of 5-phenyl-3-mercapto- 1,2,4-triazole with chloroacetaldehyde exists exclusively as the hydroxythiazoline. 

The mechanism of this cyclization is similar to that proposed for the Hantzsch synthesis. Hydroxythiazoline intermediates have been isolated which, on heating with dilute HC1, lead to A4-thiazoline-2-thione. The precise control of the pH during the reaction permits the isolation of an acyclic intermediate (248) which is in equilibrium with its cyclic isomer (249 Scheme 182). The large influence of steric effects on the 3-position has been demonstrated with R4 = Me and R3 = Bu dealkylation at nitrogen is observed upon dehydration of the intermediate thiazoline (Scheme 183) (67BSF1948). 

Hydroxythiazolines (347) are obtained by reacting a-thioacetic acid with carbonyl compounds in the presence of ammonium carbamate as a source of nitrogen (Scheme 86) <86ZN(B)134>. 

Hydroxythiazolines (353) which are in tautomeric equilibrium with the oxothiazolidine form are prepared by addition of a-thioacetic acid to imines (Scheme 88) <92JMC2910,94MI 3064)3>. The thiazolines (353) are obtained in 33-86% chemical yield. 

A ring closure of this type is carried out for the synthesis of 4-hydroxythiazolin-2-ones (354) using iV,iV-disubstituted hydrazines, sodium a-chloroacetate, and carbonyl sulfide as starting materials (Scheme 89) <87AP(108)367>. 

In addition, dehydration of 4-hydroxy-2-thiazolines also leads to the fully conjugated derivatives. In general, the hydroxythiazolines are intermediates in various synthetic approaches to thiazoles (see Section 3.06.9). 

Thiazole a,) -dehydro amino add (447) is prepared by cyclization of the corresponding thioamide with ethyl bromopyruvate (Equation (92)). The reaction occurs through the hydroxythiazoline intermediate which dehydrates in the presence of trifluoroacetic anhydride (TFAA) <92CL1005>. 

On a related front, the reactions of carbonyl compounds with metaliated derivatives of 2-methylthia-zoline furnish adducts (85). Although the initial nucleophilic addition occurs smoothly with a wide variety of aldehydes and ketones, the intermediate P-hydroxythiazolines (85) suffer thermal reversion upon attempted purification by distillation. Moreover, attempted cleavage of the corresponding P-hydroxythia-zolidines, which are readily produced from (85) upon dissolving metal reduction (Al-Hg), leads to the formation of p-hydroxy aldehydes only in simple systems numerous complications arising from dimerization, dehydration and retroaldol processes of the products usually intervene. Consequently it is necessary to protect the initial 1,2-adducts (85 = H) as the corresponding 0-methoxymethyl ether... 

This method was successful in producing a wide range of optically pure thiazoles however, with some amino acids a small amount of racemization was still observed. Further studies by Meyers and co-workers examined both the initial hydroxythiazoline formation as well as several variations in the dehydration step. Optimal conditions were to conduct the hydroxythiazoline formation step at -15 °C elimination of the intermediate hydroxythiazoline used a 2,6-dimethylpyridine and TFAA mixture while maintaining the temperature at -15 °C. This method produced the valine derived thiazole with an enantiomeric excess of >99% and Meyers subsequently used this method to complete a total synthesis of bistatramide... 

Nicolaou and co-workers revisited these general conditions during their landmark total synthesis of thiostrepton. Notable features in ring construction during this synthesis include higher reaction temperatures than those used in the Meyers method and the isolation of the crude hydroxythiazoline before the elimination step, which was then conducted employing TFAA in the presence of pyridine followed by triethylamine. These reaction conditions also led to A -trifluoroacetylation of the free —NH... 

Similar to esters derived from N -hydroxypyridine-2(lH)-thione 1, the O-esters of 4-methyl and 4-phenyl N-hydroxythiazoline-2-thiones (7a and 7b) undergo smooth thermal decarboxylative rearrangement in refluxing toluene but require UV photolysis at -320 nm (medium mercury pressure) for the photochemical reaction. 

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