2,4-Disubstituted thiazoles, formation

Depending on the starting ketone (6), the reaction leads to the formation of 4-monosubstituted or 4,5-disubstituted thiazoles (7) as shown in Scheme 4. 

Li and co-workers introduced a rapid and efficient microwave-assisted method to prepare new disubstituted 1,3,4-thiazoles from 1,4-disubtituted thiosemicarbazides with the objective to obtain biologically active molecules. The intermediate l-aryloxyacetyl-4-(4-methoxybenzoyl)thiosemicarbazide was irradiated in an excess of glacial acetic acid in a domestic microwave oven and led to the formation of 2-(methoxybenzoyl-5-aryloxymethyl)-l,3,4-dithiazoles in good yields [30] (Scheme 20). 

Ketone semicarbazones undergo acid catalyzed reversible cyclization to 3,3-disubstituted 1,2,4-triazolidinones (76JHC1257). The only example available in the literature where a fused triazoline was obtained involves the nitrosation of ethyl 2-isopropylidenehydrazonothiazole-4-acetate, resulting in the formation of a 3,3-dimethyl-2H-s-triazolo[3,4-f ]thiazole (Scheme 14) (78JHC40l).The reaction may be classified as a 1,5-electrocydization. 

N-Arylation of azonane with 2-chloro-5-nitrobenzoic acid was reported <1998JME5219>. Arylation of anion formed from 1,6-diazonane (PhLi, diethyl ether) with 4-chloropyridine resulted in mixture of mono- (38%) and disubstituted (13%) products <1998CC1625>. A novel 1,4,7-triazonanes bearing thiazol-2-yl and benzoxazol-2-yl substituents were synthesized by high-pressure S r reactions <1995H(41)237>. Arylation of 1,4,7-triazonane with 5equiv of 4,7-dichloroquinoline in dimethylformamide (DMF) at reflux in the presence of potassium carbonate afforded a mixture of mono- and disubstituted products, while formation of the trisubstituted derivative was not indicated <2001JME1658>. 

In analogy to thiophene formation (cf. p. 96), thiazoles (mainly of the 2,5-disubstituted type) are obtained from (a-acylamino)ketones by sulfurization with P4S10 and subsequent cyclodehydration Gabriel synthesis) ... 

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