Thiazole compounds

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

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. 

These subjects have been reviewed up the year 1975 in various works. Prij s Card Index (363) of thiazole compounds provides swift access to information on individual compounds. Syntheses of thiazoles have been carefully reviewed by Wiley etal. (361), and in 1957 the subject was dealt with in an excellent survey by Sprague and Land (448). 

Several methods for the synthesis of thiazole compounds are available, which can be classified into the partial structures illustrated in Scheme 1. The first of these structures (la) is by far the most useful and versatile of all the thiazole syntheses. By a judicious choice of reactants it allows... 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar parts of thiourea (103) and a-haloketones or aldehydes to yield the corresponding 2-aminothiazoles (104a) or their 2-imino-A-4-thiazoline tautomers (104b) with no by-products (Method A, Scheme 46). 

In this chapter we examine in turn the properties of alkyl and aryl-thiazoles that do not possess functional groups bonded directly to the thiazole ring. The general trends are underlined, and the applications of certains thiazole compounds in such areas as polymers, flavorings, and pharmacological and agricultural chemicals are discussed. 

The polarographic properties of the halogenothiazoles in comparison with other thiazole compounds have also been investigated (73, 74). Infrared, Raman, ultraviolet, and NMR spectra of mono-halogenothiazoles have been measured (2, 3, 6, 10, 15, 17, 24, 29) (Table V-4). 

Amino-5-bromoselenazole is mentioned in a patent without further details. It is stated to be a starting material for pharmaceutical products. In analogy to the corresponding thiazole compounds, it is stated to be prepared by heating 2-aminoselenazole in aqueous hydrobromic acid under reflux and slow addition of an equivalent amount of bromine. 

NMR experiments where undertaken to determine the site of coordination of the two other complexes. The thioether complex showed an upheld shift for the N-atom in the thioether gold complex and a similar result was obtained in the case of the thiazole compound, confirming imine coordination. 

Davies et al. describe the preparation of both oxazole- and thiazole-containing derivatives of combretastatin. By formation of the ketoamide intermediate 60, in a 54% yield (Scheme 14), both classes of compounds may be obtained by altering the last step of the reaction [58]. To produce the oxazole 61 a cyclo-dehydration reaction was performed using triphenylphosphine-iodine-triethylamine, and the thiazole compound 62 was formed by thiona-tion using Lawesson s reagent, with an excellent yield (94%). 

Among the volatile compounds listed in Table II, only thiazole compounds are derived from the thermal degradation of thiamin. 5-(2-hydroxyethyl)-4-methylthiazole and 4-methyl-5-vinylthiazoIe are well-known thermal degradation products of thiamin. 5-(2-Chloro-ethyl)-4-methylthiazole may form through the interaction of 5-(2-hydroxyethyl)-4-methylthiazole with hydrogen chloride. However, the most abundant product, 4-methylthiazole, has never been identified as a decomposition product of thiamin. The mechanism for its formation is not clear. 

Of all the methods described for the synthesis of thiazole compounds, the most efficient involves the condensation of equimolar quantities of thiourea and a-halo ketones or aldehydes to yield the corresponding 2-aminothiazoles (Scheme 167) (l888LA(249)3l). The reaction occurs more readily than that of thioamides and can be carried out in aqueous or alcoholic solution, even in a distinctly acid medium, an advantage not shared by thioamides which are often unstable in acids. The yields are usually excellent. A derived method condenses the thiourea (2 mol) with the non-halogenated methylene ketone (1 mol) in the presence of iodine (1 mol) or another oxidizing agent (chlorine, bromine, sulfuryl chloride, chlorosulfonic acid or sulfur monochloride) (Scheme 168) (45JA2242). 

B. Prijs, Card Catalogue of Thiazole Compounds. Karger, Basel. 

From this virtual screening, 31 compounds (compound e. Fig. 16) have been identified to show the activity at IC50 < 10 xM. Among these a thiazole analogue, 2-(3-benzonitrile)amino-5-benzoyl-thiazole (compound f. Fig. 16), has been found to be the most active compound with an IC50 of 40 nM for the mouse Y5 receptor and even showed activity in a mice feeding model at... 

Fig. 13. Chemical structures for allosteric and ATP-competitive Eg5 inhibitors, (a) Monastrol ((S)-ethyl 1,2,3,4-tetrahydro-4-(3-hydroxyphenyl)-6-methyl-2-thioxopyrimidine-5-carboxylate), the first compound discovered which bound to the allosteric pocket the compound has an IC50 of 22 uM. (b) CK-f 06023 (N-((R)-f-(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)propyl)-4-bromo-N-(3-(dimethylamino)propyl) benzamide), which binds to the same allosteric pocket as Monastrol and has a Ki of f 2 nM. (c) CK-238273 N-(3-aminopropyl)-N-((R)-f -(3-benzyl-7-chloro-3,4-dihydro-4-oxoquinazolin-2-yl)-2-methylpropyl)-4-methylbenzamide), an optimized analog of CK-f 06023 which is in phase II and has a Ki of f. 7 nM. (d) 4-(2-(f -phenylethyl)thiazol-4-yl)pyridine, an ATP-competitive thiazole compound which was an initial hit from the Merck compound collection the compound has an IC50 of f f uM. (e) 4-(2-(f -(4-chlorophenyl)cyclo-propyl)thiazol-4-yl)pyridine, an optimized ATP-competitive thiazole compound with an IC50 of 290 nM.

Oxidation of 4-carboxyoxazolines and thiazolines 48 (Eq. 5) can be performed efficiently using a modified version of the Kharasch-Sosnovsky reaction (CuCl, CuBr2, and t-butyl perbenzoate). The conditions are compatible with a broad range of substituents in position 2, and the reaction has been applied in the total synthesis of several biologically active oxazole or thiazole compounds 51. Captodative substitution is essential, since removing the 4-carboalkoxy substituent, which stabilizes the intermediate 49, prevents the reaction from occurring [34]. 

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