Reactions of Aminothiazoles

or OH). A more efl cient approach to these 2-amino-heterocycles is the nitration of 2-dimethylamino(piperidino or morpholino)thiazoles, which proceeds in 70—75% yields.  

Diazotization of 2-aminothiazoles (71) in borofluoric-phosphoric acids affords high yields of thiazolyl-2-diazonium tetrafluoroborates (72) as yellow crystalline fairly stable solids. These afford 2-fluorothiazoles (73 X = F) on being carefully heated under reduced pressure in admixture with sand and potassium fluoride, or on being warmed to 60—80 °C in 

The action of the appropriate alkali-metal salts yields 2-halogeno- (73) or 2-thiocyanato-derivatives (74) [and thence thiazoline-2-thiones (75)]. Sodiiun azide at — 5 C produces thiazolo[3,2-rf]tetrazoles (76). Thiourea in acetonitrile at - 5 C reacts additively, affording yellow crystalline thiazol-2-yldiazo-isothiuronium tetrafluoroborates (77), but action of an excess of the reagent on either (72) or (77) caues loss of nitrogen and formation of the thiones (75).  

3-Diphenyl-4-aminothiazolium chloride (78) reacts with aniline at room temperature to give a product formulated as 2-phenyl-4-anilino-thiazole (80). Since the same product arises under the influence of o-toluidine, the 4-anilino-group is apparently not derived from the arylamine used as the reagent, but is formed by rearrangement of cyano-methyl 7V-phenylbenzthioimidate (79), which is also found to yield (80) on treatment with aniline. However, the action of other amines is not entirely consistent with this interpretation.  

The amino-group in thiazoles undergoes the expected condensation reactions with activated methylene and related groupings. 2-Amino-4-(3-methyl-4-isothiazolyl)thiazole (81) is convertible, by means of diethyl 

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Two of the most frequently used approaches for halothiazole synthesis are direct halogenation of thiazoles and the Sandmeyer reaction of aminothiazoles. The third method, an exchange between a stannylthiazole and a halogen, is not practical in the context of palladium chemistry simply because the stannylthiazole can be used directly in a Stille coupling. 

Thiazolo- and benzothiazolopyrimidines are generally prepared by thermal cyclization of the enaminones prepared from 2-aminothiazoles and 2-aminobenzothiazoles with diethyl ethoxymethylenemalonate (Table IX). Two methods have been employed. Method A is a one-pot reaction of aminothiazoles with malonate in refluxing 1,2,4-trichlorobenzene without isolation of the enaminone intermediates. In method B. isolation of the enaminone intermediates prior to cyclization in trichlorobenzene usually provides purer products (72JMC1203). 

Reaction of 2-aminothiazole with -phenethylchloride in anhydrous pyridine is reported to yield 76% 2-(/3-phenethylamino)thia2ole (43), the remaining 24% could be 2-imino-30-phenethylamino)-4-thiazoline (44) (Scheme 32) (188). 

Both carbonyl groups of terephthaldehyde are reported to react with the exocyclic nitrogen of 2-aminothiazole yielding 1.4-phenylene bis(2-methyleneamino)thiazole. The same report describes the reactions of 2-amino-4-phenylthiazole with terephth aldehyde and salicylaldehyde as yielding 64 and 65, respectively (Scheme 45) (215), whose structures are based on ultraviolet and infrared spectra. 

Maleic anhydride condenses with 2-aminothiazole-4-carboxylic acid giving the raaleimide 107 (269) another report claims, however, that the reaction of 2-amino-4-methylthiazole with this anhydride gives the N-substituted maleamic acid (108) (Scheme 73) (270). 

The reaction of propiolic acid or its esters with 2-aminothiazole yields 7H-thiazolo[3.2o]pyTimidine 7-one (109) (Scheme 74) (273), The reaction probably proceeds by initial nucleophilic attack of 2-aminothiazole on the sp C followed by intramolecular addition of ring nitrogen to spC. 

Reaction of 2-aminothiazole with ethyl acrylate yields 5.6-dihydro-7H-thiazolo[3,2a]pyrimidin-7-one (116) (Scheme 78) (169). 

The reaction of 2-aminothiazole derivatives with the 1,3,5-oxadiazine 2,4.6-trione shown leads to biuret derivatives (126) (Scheme 83) (287). 

It has been reported that the reactions of 2-aminothiazoles and sulfonyl halides generally afford mono sulfonyl and disulfonyl (171) compounds (Scheme 109) (355-362). Angyal (358) explained this result by a mechanism where in. the first reaction the product would be the cation (172)... 

Aminothiazole (58, 235, 391) and 2-amino-4-alkylthiazoles (391. 399) couple with diazonium salts. This reaction takes place in the 5-position and is possible even when bulky substituents occupy the 4-position. as exemplified by the reaction of 191 (Scheme 121) (400. 401). Me... 

An interesting set of results was obtained by Burmistrov et al, (242. 444-448) when they studied the reaction of 2-aminothiazole and derivatives with various alcohols in concentrated sulfuric acid (see Section III.l.Cl. 

Reaction of 2-aminothiazoles with alkyl isocyanates yields 2-thiazolylureas (256) (Scheme 153) (479-483). This reaction is general and works with acyl isocyanates (484. 485). These heterocyclic ureas are also prepared by the reaction of H2O on 2-thia2olylcyanamide (486) or by action of HjOj on the corresponding thiourea (303, 481). 

The reaction of 2-aminothiazoles with alkyl isothiocyanates yields 2-thiazolylthioureas (30.3, 490), otherwise usually obtained by direct heterocyclization (Chapter II. Section II.4). Other synthetic methods... 

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... 

This set of compounds is the most thoroughly studied among derivatives of 2-aminothiazole, thanks to the Beyer group. Heterocychzation methods are most commonly used for their preparation (see Chapter II and Refs. 37, 341, and 513-520). Reaction of 2-diazothiazoles (277) with organometallics provides another synthetic method (Scheme 1711 (521). 2-Hydrazinothiazoles may also be obtained by the action of hydrazine on 2-bromothiazoles (388) or on 2-mercaptothiazoles (522). 

These compounds may be obtained by the Hantszch heterocyciization method (see Chapter II, Section 11.3). A -widely used two-step preparative method (Scheme 195) involves initial reaction of a 2-amiriothiazole -with 339 in pyridine (631-638) in aqueous sodium carbonate (639) or by fusion without solvent (640). The formed 340 is then hydrolyzed in acidic (641, 642, 1593) or alkaline medium (643-646). The direct reaction of 342 (Scheme 196) -with 2-aminothiazoles is less common and takes place in... 

Imino-4-thiazolines are far more basic than their isomeric 2-aminothiazoles (see Table VI-1). They react with most electrophDic centers through the exocyclic nitrogen and are easily acylated (37, 477, 706) and sulfonated (652). The reaction of 2-imino-3-methyi-4-thiazoline (378) with a-chloracetic anhydride yields 379 (Scheme 217) (707). This exclusive reactivity of the exocyclic nitrogen precludes the direct synthesis of endocyclic quaternary salts of 2-imino-4-thiazolines. although this class of compounds was prepared recently according to Scheme 218 (493). 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

Very few 4-aminothiazoles have been synthetized directly. The reaction of a-halonitriles with thioamides generally fails and only extensive decomposition results. However, the benzene sulfonic ester of mandelonit-rile reacts with thiobenzamide to give 2,5-diphenyl-4-aminothiazole (257), Ri = R2 = Ph, in 37% yield (Scheme 132) (417) Similarly, a-cyano-a-acetylthioacetamide condensed with a-chloroacetonitrile give 257, Ri = CH(CN)CH3 and R2 = H (804). 

Amongst the more unusual reactions, 2,3-thiazolo fused pyrido[3,2-d]pyrimidines have been prepared from 3-aminopicolinic acid and 2-bromothiazoles, whilst a similar derivative resulted with allyl isothiocyanate (221 222) <72IJC602). Similar products are also produced in [3 + 3] reactions of 2-aminothiazoles (Section 2.15.5.7.1). 

The reactions of the benzenesulfonyl ester of mandelonitrile (177) provide another illustration of the masked bielectrophile approach. On reaction with a primary thioamide the 4-aminothiazole (178) was obtained and this is a convenient route to these derivatives. With a thiourea, the thiazoline (179) was the initial product, and this on treatment with water gave the thiazolidin-4-one (180) (61JOC2715). 

The Cook-Heilbron reaction involves the reaction of a-aminonitriles with salts and esters of dithioacids, carbon disulfide, carbon oxysulfide, and isothiocyanates under extremely mild conditions to form 5-aminothiazoles. 

The reaction of a-aminonitriles and carbon disulphide was stated by Cook and Heilbron to give 5-amino-2-mercaptothiazoles however, they later found that the same reaction with aminoacetonitrile was more complex. When aminoacetonitrile sulphate in ethanolic solution was treated with carbon disulphide, the dithiodicarbamate 9 was formed. Benzylation was then carried out treatment of the resulting ester 10 with phosphorus tribromide with subsequent loss of water gave 5-amino-2-benzylthiothiazole 11 in a quantitative fashion. The rapid reaction was thought to be the first example of the formation of a 5-aminothiazole from an a-aminoamide. 

The synthesis of 5-aminothiazoles via the reaction of isocyanate derivatives with aminomalononitrile p-toluenesulfonate (AMNT) has been investigated. It was found that AMNT 12 reacted with alkyl and aryl isothiocyanates in l-methyl-2-pyrrolidine (NMP) to furnish 5-amino-2-(alkylamino)-4-cyanothiazoles (13a) and 5-amino-2-(arylamino)-4-cyanothiazoles (13b-c) in 44-81 % yields. " ... 

The synthesis of 5-amino-4-carbethoxy-2-benzylthiazole 17 via the reaction of ethyl aminocyanoacetate 15 with methyl dithiophenylacetate 16 provided the first general synthesis of the previously little known 5-aminothiazoles. Similarly, the reaction between aminoacetonitrile 18 and sodium dithiophenylacetate 19 at room temperature gave 5-amino-2-benzylthiazole 20 in excellent yield. 

Cook and Heilbron report the formation of highly crystalline Schiff bases via the reaction of 5-aminothiazoles and acetone, aldehydes such as cinnamaldehyde, or ketones such as... 

The ultraviolet and infrared spectra of 2-aminothiazole and the methyl derivatives of both the imino and the amino forms have been compared and discussed by Sheinker, Kushkin, and Postovskii ° who showed that the amino form predominates in the solid state and in various solvents. The reaction of 2-aminothiazoles with methyl iodide in the presence or in the absence of sodium ethoxide has been considered to give information concerning the proportion of the amino and imino forms present under these conditions, ... 

The aminothiazole, 123, required for preparation of sulfa-thiazole (102), one of the older sulfonamides still in use, is available directly from the reaction of 1,2-dichloroethoxyethane with thiourea. The intermediate, 122, is not observed, as elimination of ethanol is spontaneous under the reaction conditions. 

A heterocyclic ring may be used in place of one of the benzene rings without loss of biologic activity. The first step in the synthesis of such an agent starts by Friedel-Crafts-like acylation rather than displacement. Thus, reaction of sulfenyl chloride, 222, with 2-aminothiazole (223) in the presence of acetic anhydride affords the sulfide, 224. The amine is then protected as the amide (225). Oxidation with hydrogen peroxide leads to the corresponding sulfone (226) hydrolysis followed by reduction of the nitro group then affords thiazosulfone (227). ... 

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