Dimethylthiazole

2 4-Dimethylthiazole (III) may be prepared from thioacetamide (I) and monochloroacetone (II). The thioacetamide is conveniently formed in the reaction mixture from acetamide and phosphorus pentasulphide. 

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As early as 1889 Walker (320), using samples of thiazole, 2,4-dimethylthiazoie, pyridine, and 2,6-dimethylpyridine obtained from Hantzsch s laboratory, measured the electrical conductivity of their chlorhydrates and compared them with those of salts of other weak bases, especially quinoline and 2-methylquinoline. He observed the following order of decreasing proton affinity (basicity) quinaldine>2,6-dimethyl-pyridine>quinoline>pyridine>2,4-dimethylthiazole> thiazole, and concluded that the replacement of a nuclear H-atom by a methyl group enhanced the basicity of the aza-aromatic substrates. 

Acheson et al. (336) by the condensation of DMA with 2,4-dimethyl-thiazole in THF (Scheme 56). As Reid et al. (335) first proposed, the adduct of 2,4-dimethylthiazole with DMA in DMF (93) results from the normal cyclo-addition with rearrangement (Scheme 57). The conclusive demonstration of this structure was recently given by Acheson et al. (339)... 

Hydroxy-4-methylthiazole failed to react when submitted to Friedel-Crafts benzoylation conditions (349) on the other hand, it reacted normally in Gattermann and in Reimer-Tiemann formylation reactions, affording the 5-formyl derivative (348). 4-Methylthiazole is insufficiently activated and fails to react under the same conditions. 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200° for 8 hr in a sealed tube with perfluoropropyl iodide and sodium acetate (116) (358). 

A similar observation was made more recently in the case of 4-substituted 2-methylthiazoles by A. I. Meyers (442-444), who could identify the product resulting from a temperature increase from -78°C to room temperature of the lithio salt of 2,4-dimethylthiazole (161). 

Thiazole-N-oxides are prepared by the action at low temperature (-10°C) of hydrogen peroxide in acetic acid (474). 4-MethyIthiazole and 2,4-dimethylthiazole afforded the corresponding N-oxides with yields of 27 and 58%, respectively (Scheme 88). Thiazole-N-oxides without a methyl group in the 2-position are so unstable that they have a tendency to form 2-hydroxythiazoles and are decomposed by oxidation, whereas a 2-methyl group would prevent such rearrangement (474). 

In 1937, Kondo and Nagasawa confirmed the reactivity of the sole 2-methyl group in the condensation of 2,4-dimethylthiazole with benzal-dehyde (505) and in the cyclizafion to tbiazolopyrrole in the reaction with phenacyl bromide (506) (Scheme 113). 

Ohta (344) prepared 2,4-dimethylthiazole (10), Rj=R2 = Me, Rj H, in fairly low yield by condensing a-mercaptoacetone with acetamide in the presence of anhydrous zinc chloride. 

Methyl and 2,4-dimethylthiazole were prepared by the vapor-phase reaction (450 to 500°C) of sulfur with diethylamine and diisopropylamine, respectively (816) yields were 66 and 59%. 

The first mass spectrometric study of thiazoles was carried out by Clark et al. (115), who investigated the method of fragmentation of thiazole, and 4-methyl- and 2,4-dimethylthiazole. 

With 2-methyl- and 2,4-dimethylthiazole, the methyl thiirenium ion (m/e 72) is obtained, which can easily lose a hydrogen radical to give the ml ell ion (confirmed by the metastable peak). This latter can rearrange by ring expansion to give the thietenyl cation whose structure was confirmed in certain spectra by the presence of a metastable peak corresponding to the decomposition of the m/e 71 ion to give the thioformyl cation m/e 45, probably by elimination of acetylene. 

TABLE 111-24. PRODUCTS FORMED BY THE DECOMPOSITION OF BENZOYL PEROXIDE IN THIAZOLE, 4-METHYLTHIAZOLE, AND 2.4-DIMETHYLTHIAZOLE WITH A MOLAR RATIO OF AND A REACTION TIME OF 20 hr AT 78°C (184)... 

The reaction of 2.4-dimethylthiazole with butyllithium shows that, in contrast to 2-methylthiazole, the benzyl position (the 2-position) is the most reactive. The effect of the substituent in the 4-position may well be steric 4-r-butyl-2-methylthiazole in the same reaction gives no 5-substituted product (223). 

If the organolithium derivative of 2.4-dimethylthiazole or 2-methyl-4-phenylthiazole (prepared at -78°C) is allowed to warm to room temperature, the 2-lithium compound reacts with the nonmetallated thiazole (Scheme 5) (225). 

Halogenation (e.g., bromination) takes place in chloroform for the 2,4-dialkylthiazoles, and the majority of studies have been of 2,4-dimethylthiazole (227, 228). In other cases and in acetic or stronger acids, substitution occurs at the 5-position and is promoted by electronreleasing groups in the 2-position. When the releasing group is in the 4-(or 5-)-position, steric hindrance may decrease the yield of substitution at the 5- (or 4-) position. Nevertheless, the thiazole nucleus is not very reactive since 4-methylthiazole and 2.5-dimethylthiazole are inert in dilute sulfuric acid with bromine (229-231). 

Methylthiazole-3-oxide in the same conditions gave both 4-ace-toxymethylthiazole and 2-acetoxy-4-methylthiazole but in low yields. The reaction of 2,4-dimethylthiazole-3-oxide with p-tolyl chloride has also been studied (268), substitution occurring on the 2- and 4-methyl groups. 

Various substituted benzaldehydes react with 2,4-dimethylthiazole at the 2-methyl group (6, 282). Results have been obtained with... 

Dimethylisoxazole, 2,4-Dimethylthiazole, and 1-Acetylimidazole. Org. Mass Spec-trom. 1981,16,55-61. 

The results obtained in the photostimulated Sj l reaction between carbanions from 2,4,4-trimethyl-2-oxazoline or 2,4-dimethylthiazole and 2-bromopyridine are also consistent with the incomplete formation of the carbanions in KNH2-NH3(ii ) system. In these cases, 2-aminopyri-dine is formed alongside the corresponding pyridyl-2-methylene oxazolinyl or thiazolyl substitution products (Wong et al. 1997). When the Sr I pathway is impeded by conducting the reaction in the dark or in the presence of di(tert-butyl) nitroxide, the ionic amination reaction dominates. 

The treatment of thiazole with n-butyl- or phenyllithium leads to exclusive deprotonation at C-2. When the 2-position is blocked, deprotonation occurs selectively at C-5. However, if the substituent at C-2 is an alkyl group, the kinetic acidities of the protons at the a-position and at the 5-position are similar. The reaction of 2,4-dimethylthiazole with butyllithium at -78°C yields the 5-lithio derivative (289) as the major product but if the reaction is carried out at higher temperature the thermodynamically more stable 2-lithiomethyl derivative (290) is obtained (Scheme 37). The metallation at these two positions is also dependent on the strength and bulk of the base employed (74JOC1192) lithium diisopropylamide is preferred for selective deprotonations at the 5-position. 

About 750 ml. of water is added to the mixture with shaking. After 30 minutes the mixture is poured into a separatory funnel, and the reddish upper layer containing the benzene with some impurities is discarded. The lower layer is made alkaline (Note 5) by the addition of 5 A sodium hydroxide or potassium hydroxide, and the crude thiazole, which separates as a black upper layer, is removed with ether, and the aqueous lower layer is extracted with five 120-ml. portions of ether. The combined ethereal extracts are dried over anhydrous sodium sulfate and filtered through glass wool. The ether is removed by distillation from a steam bath (Note 6), and the residual oil is fractionated at atmospheric pressure the fraction boiling at 140-150° is collected and redistilled. The yield of 2,4-dimethylthiazole boiling at 143-145° (Note 7) is 210-230 g. (41-45% based on the phosphorus pentasulfide). 

Dimethylthiazole has been prepared from chloroacetone and thioacetamide,1 but forming the required thioacetamide in the reaction mixture is to be preferred since no additional manipulation is involved. The method here described is substantially that of E. Merck.2 Other substituted thiazoles can be prepared by practically the same method.2 2,4-Dimethylthiazole has been obtained by dry distillation of 2-methylthiazyl-4-acetic acid,3 and also by heating 2,4-dimethylthiazole-5-carboxylic acid with calcium oxide.4... 

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