2-unsubstituted thiazoles

Treatment of (64) by ammonium persulfate in water at ambient temperature is said, however, to give the 2-unsubstituted-thiazole (65) (Scheme 30) instead of the expected disulfide (152)... 

The methylthio group is removed by treatment with zinc powder in HCl (276) to give the 2-unsubstituted thiazole. The action of aluminum-mercury amalgam in methanol on various thioethers is reported to yield the expected thiazole (108) when Rj is an alkyl group and the corresponding A-4-thiazoline-2-thione (109) when Rj PhCH - (Scheme 55) (169). 

Another possible route to 2-unsubstituted thiazoles is replacement of a mercapto group by a hydrogen. Various methods have been used hydrogen peroxide in acid medium (17-19) dilute nitric acid (17), and metallic catalysts (20-22). 

Aminothiazoles are invaluable intermediates for the preparation of 2-unsubstituted-thiazoles by diazotization followed by reduction with hypophosphorous acid. Application of the Sandmeyer reaction leads to 2-halogeno- and 2-cyano-thiazoles. 

The only method that yields the 2-unsubstituted thiazole derivatives directly involves the condensation of a-haloketones with thioformamide. As in the case of previously reported a-haloaldehydes, yields are better when more reactive bromoketones are used instead of o-chloroketones. Cyclization can be achieved by adding ketones dissolved in dioxane in small quantities to the thioformamide formed in situ at below 40°C. The temperature is kept below 70°C during the addition, and then the... 

Thioacetyl derivatives (155) are obtained by direct heterocyclization reactions (365. 378, 563) and by a sulfur-oxygen exchange" reaction involving thioacetic acid and A-2-oxazoline-5-one (154) or A-2-thiazoline-5-one (156) (Scheme 81) (365, 378, 379). Ra-Ni reduction of 155 affords the 5-unsubstituted thiazole (379). 

Symbols show the variations of bond order relative to unsubstituted thiazole — AfJ<... 

For the methyl-substituted compounds (322) the increase in AG and AHf values relative to the unsubstituted thiazole is interpreted as being mainly due to polar effects. Electron-donating methyl groups are expected to stabilize the thiazolium ion, that is to decrease its acid strength. From Table 1-51 it may be seen that there is an increase in AG and AH by about 1 kcal mole for each methyl group. Similar effects have been observed for picolines and lutidines (325). 

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. 

In this chapter we intend to outline the general methods by which the thiazolic ring is synthetized from open-chain compounds. The conversion of one thiazole compound to another is not discussed here, but in appropriate later chapters. Thus the conversion of thiazole carboxylic acids, halogeno-, amino-, hydroxy-, and mercaptothiazoles, to the corresponding unsubstituted thiazoles is treated in Chapters IV through VII, respectively. 

Thiamine is present in cells as the free form 1, as the diphosphate 2, and as the diphosphate of the hydroxyethyl derivative 3 (Scheme 1) in variable ratio. The component heterocyclic moieties, 4-amino-5-hydroxymethyl-2-methylpyrimidine (4) and 4-methyl-5-(2-hydroxyethyl)thiazole (5) are also presented in Scheme 1, with the atom numbering. This numbering follows the rules of nomenclature of heterocyclic compounds for the ring atoms, and is arbitrary for the substituents. To avoid the use of acronyms, compound 5 is termed as the thiazole of thiamine or more simply the thiazole. This does not raise any ambiguity because unsubstituted thiazole is encountered in this chapter. Other thiazoles are named after the rules of heterocyclic nomenclature. Pyrimidine 4 is called pyramine, a well established name in the field. A detailed account of the present status of knowledge on the biosynthesis of thiamine diphosphate from its heterocyclic moieties can be found in a review by the authors.1 This report provides only the minimal information necessary for understanding the main part of this chapter (Scheme 2). 

Heterocycles were explored as replacements for the nonphenolic ring (Table 3) [19]. Unsubstituted thiazoles, pyridines, and thiophenes gave active agonists, but with little or no selectivity. While an TV-methyl imidazole had little if any opioid agonist activity in this series, often additional substituents on the heterocycles provided potent compounds with delta opioid receptor selectivity. For instance, compound 34, a thiophene with a diethyl carboxamide, displayed selective delta opioid receptor agonism (although no binding selectivity was observed). 

Unsubstituted thiazole does not react with chlorine or bromine in an inert solvent. Of the monomethylthiazoles only the 2-isomer undergoes bromination giving the 5-bromo derivative. When the 5-position is not free, as in 2,5-dimethylthiazole, no reaction occurs. 2-Hydroxy and 2-amino groups strongly activate the 5-position. However, bromination of 2-amino-4-(2-furyl)thiazole under mild conditions occurs successively on the furan and thiazole rings (Scheme 16). 

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). 

A large-scale synthesis of the unsubstituted thiazole has been described starting from chloro-acetaldehyde and methyl dithiocarbamate <85S948>. Condensation of the two reagents affords 2-methylthiothiazole (272) which upon treatment with lithium in liquid ammonia and protonation with ammonium chloride yields thiazole (Scheme 69). 

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