Thiazol-4- and

Thiazol 2-ones, 49-50, 62, 254 Thiazol-4- and -5-ones, 51-52 Thiazolo-[4,5-6]- and -[5,4-6]-quinolines, methylation of, 259 Thiocoumarin-3,4-diols, methylation of, 276... 

Barton A (nee Beer), Breukelman SP, Kaye PT, Meakins GD, Moigan DJ (1982) The preparation of thiazole-4- and -5-carboxylates, and an infrared study of their rotational isomers. J Chem Soc Perkin Trans 1, 159-164... 

TABLE 1. HMO CALCULATED ENERGIES FOR 2-XH-SUBSTITUTED THIAZOLES (1) AND 2-X-SUBSTTTUTED 4-THI-AZOLINES (2) ... 

The HSAB pattern may also be reversed by steric effects a Japanese patent describes the preparation of 3-(4-R-thiazolyl-2)thioallophanic acid esters (151) by reaction between 2-amino-4-R-thiazoles (4-R = H or low alkyl) and isothiocyanate formic acid ester (Scheme 96) (309). 

An interesting set of central nervous system properties has also been discovered and studied (Table VI-10). The work devoted to piscaine must be emphasized besides finding hypnotic properties of 2-amino-4-phenyl-thiazole on fish, the authors studied the structure of the metabolite, as well as the localization of the (radio labeled) metabolic product in various organs. Recently, thiazol-4-yl methoxyamine was shown to inhibit the development of morphine tolerance (1607). 5-Aminothiazole derivatives such as 419a were proposed as cardiovascular agents (1608, 1610). Substitution of the 5-aminothiazole radical on the cephalophosphorin structure gives a series of antibacterial products (1609). 

COMPARISON OF TYPICAL PHYSICOCHEMICAL PROPERTIES OF A-4-THIAZOLINE-2-THJONE (Ii WITH THOSE OF 2-(METHYLTHIO)THIAZOLE (II) AND 3-METHYL-A-4-TH1AZO-LINE-2-THIONE (UIF... 

Direct sulfonation of thiazole, as well as of 2-substituted thiazoles, leads mostly to substitution m the 5-position (330-332). 4-Thiazole sulfonic acid has been prepared through direct sulfonation of 2.5-dibromothiazole with subsequent Rane% Ni reduction (330). Sulfonation of 2.5-dimethyl- and 2-piperidyl-5-methylthiazoles affords the corresponding 4-sulfonic acids as barium salts (247). The 2-hydroxy group facilitates the sulfonation (201. 236). When the 4- and 5-positions are occupied direct sulfonation can occur in the 2-position. 5-hydroxyethyl-4-methyl-2-thiazole sulfonic acid has been prepared in this manner (7). 

Mercaptothiazoles. Hydroxythiazoles and their Derivatives II. 4- AND 5-SUBSHTUTED THIAZOLES... 

The basicity of a 4-phenyl-substituted thiazole is less than the corresponding methyl-substituted thiazole (16) and the pKa values of quaiemarv salts are in the same order (25). 

Nitration in the 5-position of 4-methyl- and 2,4-dimethylselenazoles with HNO3-H2SO4 is more rapid than for thiazoles [4-methyl-5-nitroselenazole. m.p. 45°C (19) 2.4-dimethyl-5-nitroselenazole. m.p. 115-120 C (decomp.) (19)]. Direct nitration of 2-amino 4-methyl-selenazole leads to nng rupture (19). 

C- (112, 113), 4- C- and 5- C-thiazoles (112) were prepared by the same general pathway from the corresponding " C-labeled 2-aminothiazoles synthesized by the Hantzsch cyclization of C-thiourea, l- C-2-bromoethanal, and 2- C-2-bromoethanal, respectively (112). A mixture of 4- and 5- C-thiazoles was prepared by the same general... 

The frequencies of suite IV are generally near those of the CO4 mode of thiazole, except for 2,4- and 4,5-disubstituted derivatives for which they are tower. 

The variable frequencies of suites V and VIII on one side, and VI and VIII on the other, correspond to oscillations resulting from the coupling of the v(C-X) vibration with the cjf mode in the case of 2- or 5-substituted derivatives and with the mode in the case of 4-substituted derivatives. For 2,5-disubstituted thiazoles the ojf, vibration is only slightly different from that of thiazole itself and the 5 oscillation is coupled with both v(C(2iX) and vfC(5,X or Y) modes, giving rise to three frequencies, two of which are higher and classified in suites V and V, the third, being lower, is assigned to suite VIII. 

From these results it appears that the 5-position of thiazole is two to three more reactive than the 4-position, that methylation in the 2-position enhances the rate of nitration by a factor of 15 in the 5-position and of 8 in the 4-position, that this last factor is 10 and 14 for 2-Et and 2-t-Bu groups, respectively. Asato (374) and Dou (375) arrived at the same figure for the orientation of the nitration of 2-methyl and 2-propylthiazole Asato used nitronium fluoroborate and the dinitrogen tetroxide-boron trifluoride complex at room temperature, and Dou used sulfonitric acid at 70°C (Table T54). About the same proportion of 4-and 5-isomers was obtained in the nitration of 2-methoxythiazole by Friedmann (376). Recently, Katritzky et al. (377) presented the first kinetic studies of electrophilic substitution in thiazoles the nitration of thiazoles and thiazolones (Table 1-55). The reaction was followed spec-trophotometrically and performed at different acidities by varying the... 

The thermal decomposition of thia2ol-2-yl-carbonyl peroxide in benzene, bromobenzene, or cumene affords thiazole together with good yields of 2-arylthiazoles but negligible amounts of esters. Thiazol-4-ylcarbonyl peroxide gives fair yields of 4-arylthiazoles, but the phenyl ester is also a major product in benzene, indicating reactions of both thiazol-4-yl radicals and thiazol-4-carbonyloxy radicals. Thiazole-5-carbonyl peroxide gives... 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

The first identified complexes of unsubstituted thiazole were described by Erlenmeyer and Schmid (461) they were obtained by dissolution in absolute alcohol of both thiazole and an anhydrous cobalt(II) salt (Table 1-62). Heating the a-CoCri 2Th complex in chloroform gives the 0 isomer, which on standirtg at room temperature reverses back to the a form. According to Hant2sch (462), these isomers correspond to a cis-trans isomerism. Several complexes of 2,2 -(183) and 4,4 -dithiazolyl (184) were also prepared and found similar to pyridyl analogs (185) (Table 1-63). Zn(II), Fe(II), Co(II), Ni(II) and Cu(II) chelates of 2.4-/>is(2-pyridyl)thiazole (186) and (2-pyridylamino)-4-(2-pyridy])thiazole (187) have been investigated. The formation constants for species MLr, and ML -" (L = 186 or 187) have been calculated from data obtained by potentiometric, spectrophotometric, and partition techniques. 

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). 

These products are used as starting material for the preparation of 2-substituted thiazol-4-ylacetic acids. a-Benzoyloxythiopropionamide and a-benzoyloxy-a-benzoylthioacetamide condensed with an equimolar amount of an a-haloketone in alcoholic solution yield the following compounds (409, 419, 569) 24, Rj = CH3, PhCO, R2 = Me... 

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