2-Methyl-4- thiazole, from

In NRPS, the cyclization domain catalyzes cyclization of the side-chain nucleophile from a dipeptide moiety such as AA-Ser or AA-Cys (AA = amino acids) to form a tetrahedral intermediate, followed by dehydration to form oxazolines and thiazolines (Scheme 7.1) [20]. The synthesis of a 2-methyl oxazoline from threonine follows a similar mechanism. Once a heterocycle is formed, it can be further modified by reductase to form tetrahydro thiazolidine in the case of pyochelin biosynthesis. Conversely, oxidation of the dehydroheterocycles lead to heteroaro-mahc thiazoles or oxazoles as in the case of epothilone D (Figure 7.2) [21]. 

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. 

The addition of DMAD to 2-aminothiazole (25) gave 26, whereas propiolic ester gave 27, 28 and 29, all derived by Michael-type additions.549 Dunwell and Evans550,551 have also added acetylenic esters to 2-amino- (and 2-amino-4-methyl)thiazole and obtained 26 and 27 from DMAD and EP, and similar compounds from tetrolic and phenyl-propiolic esters. By independent synthesis, these compounds were shown not to have the isomeric structures derived by initial addition to the exocyclic nitrogen. 

Two different strategies for the incorporation of the thiazole moiety were used so far either Stille coupling reactions of 4-stannylthiazoles by one group [18, 19] or Wittig-type ole-fination reactions by all others. The latter approach requires either 2-methyl-thiazole-4-carbaldehyde (4, Scheme 1) available from the corresponding ester by reduction [13, 20, 29, 30] or suitable 4-phosphorusmethyl derivatives (3a-d. Schemes 1 and 4) for the more common inverse approach. 

A true experimental value for the heat of formation of unsubstituted thiazole is not known. However, a close estimation of an experimental SHf° for thiazole can be obtained by using the experimental SHf° for 4-methylthiazole and the enthalpic additivity value for the methyl substituent from Benson s method. This method gives a value of SHf° (thiazole) = 36.78 kcal mol which has been compared with those calculated through several computational methods (see Section 3.06.2). 

The interaction of comparable heterocyclic methylureas (177) and chloro-thioformyl chloride (179) gives in some, but not all, cases identical results, due to initial loss of methyl isocyanate from 177. Alternatively, the urea moiety may be preserved, when 2-heteryl-l,2,4-thiadiazolidine-3,5-diones are formed, as described immediately above. The observations on record are too varied and extensive to be adequately summarized. A typical example of the reaction is the production of 2-(thiazol-2-yl)-4-methyl-1,2,4-thiadiazoli-dine-3,5-diones (169, Aik = Me, Ar = thiazol-2-yl).163... 

MEASUREMENT OF THE HEAT CAPACITY OF METHYL-2 THIAZOLE FROM 5 TO 300 K. 

Free-radical and Photolytic Reactions.—In the course of their systematic study of the free-radical phenylation in the heterocyclic series, Metzger et have examined the behaviour of isothiazole and its 3-, 4-, and 5-methyl homologues from this point of view. The reaction is induced by benzoyl peroxide in the presence of traces of copper at 110 C, and the proportion of the resulting phenylated isomers was estimated by gas chromatography. Analysis of the extensive numerical results shows that the radical activity of isothiazole and its homologues exceeds that of thiazole. The observed free-valency distribution and the radical localization energies are similar for the 3- and 5-positions in isothiazole the observations conflict with the theoretical calculations, and are rationalized by introducing suitable corrections. 

Remote Functionalization C-H Activation. Substituted 7V (alkoxy)thiazolethiones have been applied in selective C-EI activation reactions. For example, 5-bromohydrins that serve as starting materials for succeeding polar transformations have been prepared from 7V-(l-pentyloxy)-5-(jO-methoxyphenyl)-4-methyl-thiazole-2(3//) thione and BrCCl3 (eq 8). This reaction is preferentially conducted under thermal conditions since the effectiveness of the underlying 1,5-hydrogen translocation benefits from elevated temperatures. ... 

There are only a few studies concerning the degradation and elimination of thiamin in animals. Most excess thiamin is eliminated as such by the kidneys. In a couple of older studies (Neal and Pearson 1964 Pearson et al. 1966), radioactive thiamin was administered in rats and the urines were analysed. Several radioactive degradation products of thiamin (2-methyl-4-amino-5-pyrimidine carboxylic acid and 4-methyl-thiazole-5-acetic acid), resulting from the cleavage between the thiazole and the pyrimidine moieties, were excreted in the urine. Other products were also detected but not identified. No enzymes specifically involved in thiamin degradation in mammals have been identified. 

The interaction of chlorothioformyl chloride and comparable heterocyclic methylureas (92) proceeds partly with identical results. Loss of methyl isocyanate from (92) yields the parent amine (93) and thence the condensed bicyclic products (97), as described immediately above. Simultaneous direct condensation of the urea (92) affords, by way of the hypothetical intermediate (94), the fused thiatriazepinediones (96) as well as 1,2,4-thiadiazoli-dinediones (95), generally in moderate yields. The observations on record are too varied to be adequately summarized examples of the structures obtained are 2H-thiazolo[3,2-b][l,2,4,6]thiatriazepine-2,4(3H)-diones (98) and 2-(thiazol-2-yl)-4-methyH,2,4-thiadiazolidine-3,5-diones (99). ... 

Neal, R. A. Bacterial Metabolism of Thiamine III. Metabolism of Thiamine to 3-(2 -Methyl-4 -Amino-5 -Pyrimidylmethyl)-4-Methyl-thiazole-5-aceticAcid(Thiamine Acetic Acid) by a Flavoprotein isolated from a soil Microorganism. J. Biol. Chem. 245, 2599(1970). 

Chapter V. Quinaldine (V,2) 2-methyl-, 2 5-dimethyl- and 2-acetyl-thiophene (V,8-V,10) 2 5-dimethyl and 2 4-dimethyl-dicarbethoxy-p3nrole (V,12-V,13) 2-amino- and 2 4 dimethyl-thiazole (V,15-V,16) 3 5-dimethyl-pyrazole (V,17) 4-ethylp3rridine (from pyridine) (V,19) n-amyl-pyridines from picolines) (V,28) picolinic, nicotinic and isonicotinic acid (V,21-V,22) (ethyl nicotinate and p-cyanop3n idine (V,23-V,24) uramil (V,25) 4-methyl-(coumarin (V,28) 2-hyi-oxylepidine (V,29). 

Grote s reagent is useful for the determination of 2-aminothiazoie in blood and wine (145), This thiazole may be extracted from its aqueous solution and then titrated in nonaqueous medium (MeOH) with HCIO4 in the presence of a mixed methyl red-methylene blue indicator (146). 

Diazo coupling involves the N exocyclic atom of the diazonium salt, which acts as an electrophilic center. The diazonium salts of thiazoles couple with a-naphthol (605). 2-nitroresorcinol (606), pyrocatechol (607-609), 2.6-dihydroxy 4-methyl-5-cyanopyridine (610). and other heteroaromatic compounds (404. 611) (Scheme 188). The rates of coupling between 2-diazothicizolium salts and 2-naphthol-3.6-disulfonic acid were measured spectrophotometrically and found to be slower than that of 2-diazopyridinium salts but faster than that of benzene diazonium salts (561 i. The bis-diazonium salt of bis(2-amino-4-methylthiazole) couples with /3-naphthol to give 333 (Scheme 189) (612). The products obtained from the diazo coupling are usuallv highly colored (234. 338. 339. 613-616). 

Quantum chemistry methods allow the prediction of the ultraviolet transitions in good agreement with the experimental values in the case of thiazole and its three methyl derivatives (Table 1-18). A very weak absorption has been indicated at 269.5 nm that could correspond to an n- TT transition given by calculation at 281.5 nm (133). Ultraviolet absorption spectroscopy has been investigated in connection with steric interactions in the A-4-thiazoline-2-thione (74) series (181). It was earlier demonstrated by NMR technique that 4-alkyl-3 isopropyl-A-4-thiazoline-2-thiones exist in solution as equilibrium mixtures of two conformers (75 and 76), the relative populations of which vary with the size of R4 (182) for R4 = rBu the population of rotamer A is 100%, whereas for R4 = Me it is only 28%. Starting from the observed absorption wavelength for... 

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