Thiazolyls

The Curtius rearrangement in acetic anhydride of the azide (8) prepared from 4-carboxythiazole yields 4-acetamidothiazole (Scheme 8) (47). The same reaction starting with ethyl-2-methyl-4-thiazolyl carboxy-late, failed to give the 4-aminothiazole (48). Heterocyclizations are more convenient synthetic methods (Chapter II. Table 40). 

The reaction between 4-aminothiazole and paranitrobenzaldehyde, followed by the cydization of the Schiff base with PfOEtfs, provides 2-(4-thiazolyl)indazole (84a) (1576) (Scheme 59). 

The reaction of 2-amino-5-nitrothiazole with (3-chloroethyl isocyanate gives the corresponding thiazolyl urea (137) (Scheme 90) (298). Other examples are given in Section V.l.B, where the preparation of thiazolyl-thioureas is discussed,... 

The sodium salt of X -2-thiazolyl dithiocarbamic acid (141) is obtained by reaction in NaOH between 2-aminothiazole and CSj (Scheme 93) (305). The product obtained in neutral medium is described as the... 

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). 

Acetamidothiazole is nitrated in the same way (58, 378, 379). 2-Acetamido-4-phenylthiazole is reported to be nitrated on C-5 (380) as opposed to 2-amino-4-phenylthiazole, where nitration occurs on the phenyl ring (381). This latter result is not consistent with the other data on electrophilic reactivity in most cases 2-amino-4-arylthiazole derivatives react with electrophilic reagents at the C-5 position (see Sections rV.l.B and D). Furthermore, N-pyridy]-(2)-thiazolyl-2-amine (178) is exclusively nitrated on the thiazole ring (Scheme 113) (132, 382). 

The 5-position is the preferred site for sulfonation (58. 392). This position is more reactive than any of the pyridine ring in. V-[pyridyl-(2)]-thiazolyl-(2)-amine (178) (132, 382, 383). 

Sulfonation under mild conditions is reported to yield thiazolyl-2-sulfamic acid, which, when heated in H2SO4. rearranges to 2-aminothiazole-5-sulfonic acid (16. 374. 390. 391). Postovskfi. however, reports exactly the opposite rearrangement (367). and spectroscopic evidence supports his conclusion (368) (see Section III.5). 

Acetamidothiazole and its 4-alkyl derivatives react with chloro-sulfonic acid. The structure of the resulting products was a subject of controversy (172. 393-397). N-acetyl-A -(2-thiazolyl)-sulfamoyl chlorides (189) first proposed were then shown to be 2-acetamido-5-chloro-sulfonylthiazoles (190) (Scheme 120) (367. 368. 398). the latter assignment is based on infrared (368) and chemical evidence (367). 

Characteristic spectroscopic data (infrared and NMR) of 2-thiazolyl ureas are given in a recent report (484). Their characteristic ultraviolet absorption is in the 260 to 270 nm region (487). 

Alkylation of bis(4-methyl-2-thiazolyl)urea (257) with dimethyl sulfate gives product 258 dimethylated on the ring nitrogens (Scheme 154) (488). Alkylation of l-alkyl-3-(2-thiazolyl)urea from its derived anion formed by NaH gives 259 (Scheme 155). 

The infrared spectra of a set of 2-thiazolylthioureas are reported in Ref. 486. The ultraviolet spectra of l-aryl-3-(2-thiazolyl)thioureas are characterized by two bands of approximate equal intensity around 282 and 332 nm (492). For l-alkyl-3-(2-thiazolyl)thioureas these bands are shifted to 255 and 291 nm, respectively (492). The shape of the spectrum is modified further when l.l -dialkyl-3-(2-thiazolyl)thioureas are considered (491). Fragmentation patterns of various 2-thiazolylthioureas have been investigated (100, 493), some of which are shown in Scheme 158. Paper and thin-layer chromatography provide an effective tool for the analysis of these heterocyclic thioureas (494. 495). 

When desulfurized with Pb02, l-aryI 3-(4-p-tolyl-2-thiazolyl)thioureas yield the heterocyclic guanidines (262) (Scheme 159) (299, 496, 497). 

The sulfur atom of the thiocarbonyl group is a good nucleophile, and reaction between benzyl bromide and l-(2-thiazolyl)thiourea yields the isothiouronium salt (496). The sulfur atom may also be engaged in a chelate, as exemplified by the Cu chelate of 2-thioureido-4-methylthiazole (491). These chelates with metal ions were thoroughly studied in acidic, neutral, and alkaline media for 66 metal ions in order to define their analytical use. They are formed in the molar ratio of 1 2 for metal II compounds (498). 

An interesting rearrangement of the (4-methyl-2-thiazolyl)thioureas (263) has recently been reported (Scheme 160) (303). The reaction mechanism is currently under investigation. This reaction does not occur if the 4-methyl substituent in the thiazole ring of 263 is replaced by an hydrogen, which suggests an electrophilic attack on C-5 as the mechanism of this reaction. 

The preparation and spectroscopic properties (infrared, ultraviolet, NMR) of iV-alkoxycarbonyl-N -(2-thiazolyl)thioureas (268) have been studied by the Nagano group (78, 264). These compounds react with bromine in acetic acid or chloroform to give 2--alkoxycarbonylimino-thiazolo[3,2-h]thiadiazolines (Scheme 162), whose structures were established by mass spectroscopy, infrared, NMR, and reactivity patterns (481). 

The reaction between ethyl chloroformate and 2-aminothiazoles provides easy synthetic access to thiazolyl 2-carbamaies (269) (Scheme 163)... 

Ethyl-N-(2 thiazolyl)carbainate reacts with aqueous hydrazine to give 271 (Scheme 165) (263). 

N-(2-thiazolyl)dithiocarbamates are prepared by the action of carbon disulfide on 2-aminothiazoles (see Section III.3.C and Ref. 505). When refluxed with secondary amines these heterocyclic dithiocarbamates yield l,T-dialkyl-3-(2-thiazoIyI)thioureas (261) (491). 

N-(2-Thiazolyl)cyanamide may be converted into guanidino derivatives by the action of hydrazines (487). /V-Aryl-N -(4-aryl-2-thiazolybguanidines... 

Amino-5-nitrothiazole, on treatment with arenesulfonyl halides and dimethylformamide at 140 C, gives (5-nitro-2-thiazolyl)amidme (274) (Scheme 168) (507, 508). The condensation products of the reaction of 2-aminothiazole derivatives with various aldehydes are grouped in Tables... 

Acidic hydrolysis of these compounds regenerates the initial 2-aminothiazole (510). The reduction of 2-thiazolylamidines provides a good synthetic route to secondary 2-aminothiazoles (see Section I.l.E). They can be used as starting materials to obtain biheterocyclic products such as l-(5-nitro-2-thiazolyl)-2-thioxoimidazolidine (275) (Scheme 169) (511). 

Alkylidenehydrazinothiazoles (297) can be prepared either from 2-hydrazinothiazoles (549) or by direct heterocyclization (527). Their characteristic infrared bands have been reported (550). The main mass spectrometric peaks of (4-coumarinyl-2-thiazolyl)hydrazone (302) (Scheme 179) (134, 551) are situated at mle = 361. 244, 243, 118, 216, 202, 174, 117 the proposed interpretation of the fragmentation pattern should, however, be reconsidered. Scheme l80 summarizes some representative reactions of this class of compounds. 

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),... 

The 2-imino-4-thiazolines may be used as ultraviolet-light stabilizers of polyolefin compositions (1026). 2-Aminothiazole improves adhesive properties of wood to wood glue (271). Cbmpound 428 exhibits antioxidant properties (Scheme 242) (1027). Ammonium N-(2-thiazolyl)dithio-carbamate (429) is a bactericide and fungicide used in industrial products such as lumber, paint, plastics, and textiles (1037). Compound 430 is reported (1038) to form an excellent volume of foam coating in aluminum pans when ignited with propane. 

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