Thiazole 2- -, nitrosation

The incorporation of complex side chains at the 7 position based on alkyloximes of 2-amino-thiazole-5-gyloxylamides has provided drugs with very wide antibacterial activity that extend to hitherto resistant species such as pseudomonas. The preparation of one of the simpler side chains involves, first, the formation of the methyl ether from the oxime obtained by the nitrosation of methyl acetoacetate. Chlorination of the product, for example with sulfuryl chloride, gives the intermediate (21-1). The aminothiazole ring is then formed by reaction of that with thiourea to give (21-2). The free acid (21-3) is obtained by saponification of the product. The protected acid chloride (21-5) is obtained by sequential acylation of the amino group with chloroacetyl chloride and then reaction with thionyl chloride. 

Very little is known about the reactivity of imidazo[5,l-h]thiazoles. It seems that for 3,5-di, and 2,3,5-trisubstituted compounds, nitrosation occurs at the 7-position (64LA144). 

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. 

Under alkaline conditions, alkyl nitrites nitrosate imidazoles that possess a free NH group, at the 4-position. Nitrosation of 3,5-dimethylpyrazoles gives the 4-diazonium salt by further reaction of the nitroso compound with more NO+. 4-Nitrosopyrazoles 188 can be used as spin traps. 5-Pyrazolinones are nitrosated readily at the 4-position. Imidazo[l,2-tf] benzimidazoles are nitrosated with NaN02 in acetic acid giving 3-nitrosoderivatives 189. Nitrosation of 2-(dimethyla-mino)thiazoles under acid conditions gives 5-nitroso-derivatives 190. 3-Alkyl-5-acetamidoisothiazoles undergo 4-nitrosation. 

Combinations of N- and 5-alkylation in 2-imidazoline-2-thiols can lead to 5,6-dihydro-4//-imidazo[2,l-6]thiazoles when the heterocycles are treated with ketones in the presence of a halo-genating agent. This is a variant of the Hantzsch thiazole synthesis <92SC1293>. A further example of A-acylation in combination with nucleophilic substitution is the conversion of 2-chloro-2-imi-dazoline into (131) when it is treated with pyridine and an aryl isocyanate <87JCS(P1)1033>. 2-Imidazolines like clonidine are also known to A-nitrosate <93JCS(P2)59l>. Intramolecular alkylation is exemplified in the base-induced rearrangement of 2,5-diaryl-4-chloromethyl-2-imidazolines (132) into pyrimidines (Scheme 64) <93JOC6354>. 

Nitrosation of 2-(dimethylamino)thiazoles under acid conditions gives 5-nitroso-derivatives... 

IJC(B)132 86JHC1439]. Attempted nitrosation of the methylene group of 1,3-thiazol-2-ylhydrazone (115) proceeded with the simultaneous formation (80JHC1321) of the title fused-ring system to give 116. 

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