2-Methyl-4- thiazole quatemization

Mills and Smith (504) were the first, in 1922, to develop a systematic study of the reactivity of methyl groups fixed on nitrogen-containing heterocycles. While in alkylpyridines the 2- (or 6) and 4-positions are activated, only the 2-position in thiazole corresponds to an enhanced reactivity of the methyl groups in condensation with aldehydes 4- and 5-methylthiazoles bear inert methyl groups. Quatemization of the thiazole nitrogen enhances still further the reactivity of the methyl in the 2-position (cf. Chapter IX), but it does not increase the reactivity of a methyl group in the 4-position (504). The authors invoke the possibility for 2- (and 6) methylpyridine and 2-methylthiazole to pass, to some extent, into the reactive enamine form (245), while 4-methylthiazole could adopt such a structure only with the participation of an unusual formula such as 247 (Scheme 112). 

The quatemization of the nitrogen atom of the thiazole ring (the Menschutkin s reaction) by alkyl halide or methyl tosylate can be used to measure the reactivity of this atom and thus to evaluate steric and electronic effects of ring substituents. 

Some studies on the quatemization of arylthiazoles have been published, among them the quatemization of 2-methyI-4-phenyl thiazole in various solvents (263). The order of reactivity is the following 2-methyl-4-phenyl > 2-methyI-4-(3-nitrophenyl) > 2-methyl-4-(2-chlorophenyl) > 2-methyl-4-(4-nitrophenyl). Introduction of a phenyl group in the... 

Thiazole, 2-acetylamino-4-methyl-alkylation, 6, 256 Thiazole, 2-acylamino-4-hydroxy-synthesis, 6, 297 Thiazole, 5-alkoxy-cleavage, 6, 289 synthesis, 6, 302 Thiazole, 2-alkyl-A7-alkylation, 6, 253 hydrogen exchange, 6, 276 methylation, 6, 253 quatemization, 6, 253-254 reactions, S, 88 Thiazole, 4-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 quatemization, 6, 253-254 Thiazole, 5-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 Thiazole, 2-alkylamino-tautomerism, 6, 248 Thiazole, 4-alkyl-2,5-dimethyl-quatemization, 6, 253-254 Thiazole, 2-alkylthio-reactions, S, 103 rearrangement, 5, 103 6, 291 Thiazole, 3-allyl-4-hydroxy-2-imino-synthesis, 6, 297 Thiazole, 2-allyloxy-rearrangement, 6, 289 Thiazole, 2-amino-diazo coupling, 6, 257 nitration, 6, 255... 

Thiamine can be considered to be the product of the quatemization of 4-methyl-5-(2-hydroxymethyl)thiazole (5) by an active derivative of 4-amino-5-(hydroxymethyl)-2-methyl pyrimidine (4) (Scheme 2). In living cells, pyramine can be activated by conversion into the diphosphate 7, via monophosphate 6, and the substrate of the enzyme responsible for the quatemization is not the thiamine thiazole, but its phosphate 8. The product of the condensation, thiamine phosphate (9), is finally converted into diphosphate 2—the biochemically active derivative—by hydrolysis to free thiamine, followed by diphosphorylation, or more directly, in some cases. Enzymes are known for all of the steps depicted in Scheme 2, and adenosine triphosphate (ATP) is, as usual, the phosphate donor. 

Thiazole, 4-isopropyl-2,5-dimethyl-quatemization, 6, 254 Thiazole, 2-lithio-reactions, 5, 106 6, 292 4-substituted synthesis, 6, 305 Thiazole, 2-mercapto-4-phenyl-synthesis, 6, 300 Thiazole, 4-mercapto-2-phenyl-tautomerism, 6, 291 Thiazole, 5-mercapto-2-phenyl-tautomerism, 6, 289 Thiazole, 2-methoxy-reactions, 5, 102 rearrangement, 6, 289 Thiazole, 2-methyl-anions... 

The synthetic applications of benzothiazoles appeared to be limited by the fact that the thiazole ring cannot be hydrolytically cleaved. However, this problem was solved by quatemization followed by reduction with NaBH4 to produce 3-methyl-2,3-dihydrobenzothiazole, as shown in the synthesis of cyclohexene-1-carbaldehyde [104] ... 

The Hantzsch method has been used in the synthesis of the thiazole portion of thiamine. Vitamin Bi (9.25). 4-Methyl-5-hydroxyethy 1-1,3-thiazole (9.24) is prepared for this purpose and then quatemized at the pyridine-like nitrogen atom with a chloromethylpyrimidine derivative, the product being thiamine (Scheme 9.19). 

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