Thiazoles hydroxy

Beyond pharmaceutical screening activity developed on aminothiazoles derivatives, some studies at the molecular level were performed. Thus 2-aminothiazole was shown to inhibit thiamine biosynthesis (941). Nrridazole (419) affects iron metabohsm (850). The dehydrase for 5-aminolevulinic acid of mouse liver is inhibited by 2-amino-4-(iS-hydroxy-ethyl)thiazole (420) (942) (Scheme 239). l-Phenyl-3-(2-thiazolyl)thiourea (421) is a dopamine fS-hydroxylase inhibitor (943). Compound 422 inhibits the enzyme activity of 3, 5 -nucleotide phosphodiesterase (944). The oxalate salt of 423, an analog of levamisole 424 (945) (Scheme 240),... 

Perfused rat liver rapidly converts 4-m thyI-5-/3-chloroethy]thiazole to 2-hydroxy -4-methylthiazol-5-y) acetic acid (40. 41). Finally, tw o new human metabolites of chlormethiazole have been isolated and identified by mass spectra as 2-hydroxy-4-methyl-5-/S-chloroethylthiazole and 2-hydroxy-4-methyl-5-ethylthiazole (42). 

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). 

In the first chapter, devoted to thiazole itself, specific emphasis has been given to the structure and mechanistic aspects of the reactivity of the molecule most of the theoretical methods and physical techniques available to date have been applied in the study of thiazole and its derivatives, and the results are discussed in detail The chapter devoted to methods of synthesis is especially detailed and traces the way for the preparation of any monocyclic thiazole derivative. Three chapters concern the non-tautomeric functional derivatives, and two are devoted to amino-, hydroxy- and mercaptothiazoles these chapters constitute the core of the book. All discussion of chemical properties is complemented by tables in which all the known derivatives are inventoried and characterized by their usual physical properties. This information should be of particular value to organic chemists in identifying natural or Synthetic thiazoles. Two brief chapters concern mesoionic thiazoles and selenazoles. Finally, an important chapter is devoted to cyanine dyes derived from thiazolium salts, completing some classical reviews on the subject and discussing recent developments in the studies of the reaction mechanisms involved in their synthesis. 

The 4-Hydroxy-thiazoles are characterized by infrared absorption near 1610 cm (KBr) (3) or 1620 to 16.S0cm (CCI4) (8), indicating a strongly polarized carbonyl group. H-5 resonates near 5.6 ppm in the NMR spectrum like similar protons in other mesoionic compounds (3). Two fragmentations of the molecular ion are observed in the mass spectra. The first involves rupture of the 1,2 and 3,4 bonds with loss of C2R 0S . In the second, the 1,5 and 3,4 bonds are cleaved with elimination of C2R 0. ... 

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. 

In a similar way, dl-2-(q-hydroxyalkyl)- and 2-(a-alkoxycarbonyl)-4-methyl-5-(/3-hydroxyethyl)thiazoles were synthetized from the corresponding thioamides and 4-hydroxy-3-bromo-2-pentanone (615). 

Similarly, 5-thiazole alkanoic acids and their salts are obtained from thioamides and /3-halo -y-keto acids (695). Thus thioarylamides condensed with 3-aroyl-3-bromopropionic acid (88) in isopropanolic solution in the presence of Na COs give first 4-hydroxy-2-aryl-A-2-thiazoline-5-acetic acid intermediates (89), which were dehydrated in toluene with catalytic amounts of p-toluene sulfonic acid to 2,4-diaryl-5-thiazole acetic acid (90) (Scheme 39) (657), with R = H or Me Ar = Ph, o-, m- or p-tolyl, o-, m-, or P-CIC6H4, 0-, m-, or p-MeOC(iH4, P-CF3C6H4, a-thienyl, a-naphthyl (657). 

Although not fully characterized, 2-carbethoxy-4-hydroxythiazole (230a), R, = C02Et, R2 = H, apparently results from the reaction of chloroacetonitrile with ethyl thiooxamate (2), Ri = C02Et (417). a-Chlorothioacids (232) condensed with thiobenzamide in the presence of carbon disulfide (542) yield the corresponding 2-phenyl-4-hydroxy-thiazole (234). The same product was obtained from 233 (Scheme 121). 

This method has mainly been used to prepare thiazoles nonsubstituted in the 2-position and involves the replacement of a functional substituent (amino, halo, mercapto, hydroxy, or carboxy) by a hydrogen. In this way the often delicate cyclization of thioformamide can be avoided. 

The replacement of 2-amino group by a hydrogen can be achieved by diazotization, followed by reduction with hypophosphorous acid (1-8, 13). Another method starting from 2-aminothiazole is to prepare the 2-halo-thiazole by the Sandmeyer reaction (prepared also from the 2-hydroxy-thiazole), which is then dehalogenated chemically or catalytically (1, 9, 10). 

A large number of variously 2-, 4-, and 5-substituted thiazoles with alkyl, aryl, hydroxy, methylthio, mercapto, halo, and nitro groups have been analyzed by thin-layer chromatography on silica and alumina by the Stahl s technique (167, 170, 172). Among the many systems recommended for the elution of these compounds are the following ... 

A number of other heterocycHc diazo components such as thiazole, iadazole, thiophenes, and thiadiazole types (see Fig. 1), as well as heterocycHc couplers, ie, 6-hydroxy-2-pyridinone [626-06-2] barbituric acid [67-52-7] and tetrahydroquiaoline [25448-04-8] h.2L e been cited ia the Hterature (90,91). Reviews on disperse dyes have been pubUshed (92,93). 

Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-position are brominated in high yield in the 4-position. Alkylisothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid has been brominated in 76% yield (72AHC(14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position are brominated at the 5-position (79HC(34-1)5). 

Hydroxy-imidazoles, -oxazoles and -thiazoles (484 Z = NR, O, S) can isomerize to 2-azolinones (485a). These compounds all exist predominantly in the azolinone form and show many reactions similar to those of the pyridones. They are mesomeric with zwitterionic and carbonyl canonical forms e.g. 485a 485b Z = NR, O, S). 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

Thiazole, 2-acetylamino-4-methyl-alkylation, 6, 256 Thiazole, 2-acylamino-4-hydroxy-synthesis, 6, 297 Thiazole, 5-alkoxy-cleavage, 6, 289 synthesis, 6, 302 Thiazole, 2-alkyl-A7-alkylation, 6, 253 hydrogen exchange, 6, 276 methylation, 6, 253 quatemization, 6, 253-254 reactions, S, 88 Thiazole, 4-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 quatemization, 6, 253-254 Thiazole, 5-alkyl-A7-alkylation, 6, 253 methylation, 6, 253 Thiazole, 2-alkylamino-tautomerism, 6, 248 Thiazole, 4-alkyl-2,5-dimethyl-quatemization, 6, 253-254 Thiazole, 2-alkylthio-reactions, S, 103 rearrangement, 5, 103 6, 291 Thiazole, 3-allyl-4-hydroxy-2-imino-synthesis, 6, 297 Thiazole, 2-allyloxy-rearrangement, 6, 289 Thiazole, 2-amino-diazo coupling, 6, 257 nitration, 6, 255... 

Thiazole, 5-amino-4-ethoxycarbonyl-2-methyl-synthesis, 6, 306 Thiazole, 2-amino-4-(2 -furyl)-bromination, 6, 256 Thiazole, 2-amino-4-hydroxy-synthesis, 6, 296 Thiazole, 5-amino-2-hydroxy-synthesis, 6, 301 Thiazole, 5-amino-2-mercapto-synthesis, 6, 301 Thiazole, 2-amino-4-methyl-alkylation, 6, 256 synthesis, 6, 300 Thiazole, 2-amino-5-nitro-antiparasitic activity, 1, 180... 

Thiazole, 2-( D-galactopentaacetoxypentyl)-4-methyl-synthesis, 6, 295 Thiazole, 2-hydrazi nosynthesis, 6, 297 Thiazole, 2-hydroxy-reactions, 6, 285-286 synthesis, 6, 298, 299 tautomerism, 5, 99 6, 247, 269 Thiazole, 4-hydroxy-reactions, 5, 101 6, 287-288 synthesis, 6, 303 tautomerism, 6, 248, 269 Thiazole, 2-hydroxybenzyl-biosynthesis, 1, 96 Thiazole, 2-hydroxy-4-methyl-arylation, 6, 256 Thiazole, 2-iodo-photolysis, 6, 244 Thiazole, 2-isobutyl-occurrence, 6, 327... 

Thiazolidine-2-thione, 4-hydroxy-synthesis, 6, 314 Thiazolidinethiones tautomerism, 6, 273 1,2,4-thiazoles from, 5, 776 Thiazolidine-2-thiones reactions... 

The reaction of carbon oxysulphide with a-aminonitriles results in 5-amino-2-hydroxy thiazoles these are structurally similar to the 2-mercaptothiazoles but are found to be less stable, readily undergoing cleavage or rearrangement to give 4-thiohydantoins. Thus the reaction between ethyl aminocyanoacetate and carbon oxysulphide 31 in ether afforded 5-amino-2-hydroxy-4-carbethoxythiazole 32, which in the presence of aqueous ammonia was converted into 5-carbethoxy-4-thiohydantoin 33. When using sodium... 

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

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