Synthesis from 2-Aminothiazoles

In 2013, Adimurthy and co-workers reported a TM-free NaOH-catalyzed N-alkylation reaction of 2-aminothiazoles, 2-aminobenzothiazoles, aminopyrimidines, and aminopyridines with benzyhc and heterobenzyhc alcohols under air (Scheme 43) [203]. In condition optimization, the authors found the model reaction of 2-aminobenzothiazole and 4-chlorobenzylalcohol under air afforded a higher yield of the product (93 %) than the one under nitrogen (90 %). Therefore, along with other results of mechanistic studies and the authors own previous work on based-catalyzed imine synthesis from alcohols and amines [204], they proposed that alcohol oxidation to aldehyde by air in the presence of bases is the initiation step of... 

Aminothiazole itself (104a), R, = R2 = H (an intermediate in the preparation of sulfathiazole), was synthetized as early as 1888 from a,p-dihalogenoethylethers, which give chloroacetaldehyde in addic medium (8). Many other derivatives have now been used for this synthesis, and they are listed in Table IT12. All give excellent yields. 

Labeled 2-aminothiazole (an intermediate in the synthesis of an antiparasitic drug) has been obtained from "C-thiourea (666). 

A new synthesis of 2-bromo-4-aminothiazole was reported from a-cyanoalkylthiocyanates and hydrogen bromide (189), Rj = H... 

Uses Removing barks from trees manufacture of 2-aminothiazole chemical intermediate organic synthesis. 

A benzotriazole-assisted synthesis of ethyl 5-aminoimidazo[2,l-h]thia-zole-6-carboxylate 65 has been developed (96TL1787). Traces of compound 63 were isolated from 2-aminothiazole 23 using benzotriazole and freshly distilled ethyl glyoxylate in benzene, whereas by application of a-benzotria-zolyl-a-morpholino acetate with methyl iodide in THF, 63 was isolated in 40% yield. Subsequent treatment of 63 with potassium cyanide in ethanol at rt involves substitution of the benzotriazole moiety. Intramolecular cycli-zation of 64 yields 65, albeit in 10% yield. a-Ketoester 66 is also obtained (Scheme 3). 

A further synthesis of thiazolo[3,2-6][l,2,4]triazoles starts with 2,3-diaminothiazoles. Treatment of 2-aminothiazole with O-mesitylensulfonyl-hydroxylamine results in the formation of salt 171, which on heating with acetic anhydride (140-150°C) gives a mixture of 172 and 173. 2-Phenylthia-zolo[3,2-h]-5-triazole could be obtained from 171 and benzoylchloride ( 200°C) in 68% yield. When 2-acylamino-3-aminothiazolium salts 174 are heated 20-30°C above their melting point for 1 h the corresponding thiazolo[3,2-h]-5-triazoles were obtained. Much better results were achieved by using PPA (100-110°C, 1.5 h 97% yield) (73JHC947). 

Nizatidine Nizatidine is N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl] thio] ethyl]-2-nitro-l,l-ethenediamine (16.2.15). According to its chemical structure, nizatidine is somewhat of a hybrid structure of ranitidine and famotidine, in which a side chain of ranitidine and carrying heterocycle, 2-aminothiazol, are used. Likewise, its synthesis also is a specific combination of pathways used for making both prototype drugs. 2-(Dimethyl-aminomethyl)-4-hydroxymethylthiazol serves as the initial compound, from which the desired nizatidine (16.2.15) is synthesized by subsequent reaction with 2-mercaptoethy-lamine hydrochloride and then with iV-methyl-l-methythio-2-nitroethenamine [71,72]. 

The addition of DMAD to 2-aminothiazole (25) gave 26, whereas propiolic ester gave 27, 28 and 29, all derived by Michael-type additions.549 Dunwell and Evans550,551 have also added acetylenic esters to 2-amino- (and 2-amino-4-methyl)thiazole and obtained 26 and 27 from DMAD and EP, and similar compounds from tetrolic and phenyl-propiolic esters. By independent synthesis, these compounds were shown not to have the isomeric structures derived by initial addition to the exocyclic nitrogen. 

The thioamides themselves are conveniently prepared from the corresponding amides by treatment with phosphorus (V) sulphide (see the Paal—Knorr synthesis of thiophenes, Chapter 2, for this type of conversion). A variation of the Hantzsch reaction utilises thioureas, where R3 in 3.30 is a nitrogen and not a carbon substituent. For instance, thiourea itself is used in the preparation of 2-aminothiazoles such as 3.32. 

The latter approach has been exemplified in a number of published cases. An indication of the development requirements of well-known reactions for successful employment in array synthesis is provided by the work ofWatson and co-workers [15] to prepare thiazole derivatives. Adaptation of the Hantzch synthesis of 2-aminothiazoles (Fig. 2) from a-haloketones and thioureas was used in the one-step preparation of discrete samples. Inclusion in the array of a compound of known biological activity provided a valuable internal control. 

Synthesis of imidazoles, oxazoles, and thiazoles by CC bond formation or 1,3-dipolar addition 4-Aminoimidazoles 266 are formed on base treatment of the appropriate precursors 265 (Scheme 130) <1975HCA2192>. Similarly the 4-aminothiazole 268 is obtained from the cyanoamidine 267 (Scheme 131) <1973JPR497>. 

A new synthesis of 2-bromo-4-atninothiazole was reported from a-cyanoalkylthiocyanates and hydrogen bromide (189), R, = NH2, R2 = H (Scheme 98) (523). Hydrogen chloride is unsatisfactory as a cyclizing agent, whereas hydrogen iodide causes further reduction and leads directly to derivatives of the previously inaccessible 4-aminothiazoles (see Section VII. 2). 

Aminothiazole is easily diazotized in a concentrated solution of nitric and phosphoric acid. A large-scale procedure for the diazotization of 2-aminothiazole and its conversion to 2-bromothiazole has been reported . The synthesis of 2-halothiazoles can be easily achieved from 2-aminothiazole by (i) diazotization and (ii) treatment with CuCl, CuBr, or Nal <85JHC1621>. When the diazonium salt derived from 2-aminothiazole is treated with sodium azide the 2-azido derivative in equilibrium with its tetrazole cyclization product are obtained <92BMC1603>. 

Both phosphorus pentasulfide and Lawesson s reagent can be used as sulfurating agent in the synthesis of 5-aminothiazoles from amides (284) (Equation (51)) <87RRC1175, 94JHC877>. 

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