Acidity, of 2-aminothiazoles

Alkylation of 2-methylaminothiazole (204) with ROH in 85% sulfuric acid gives 2-methylimino-3-alkyl-4-thiazoIine (54). 2-Amino-4-rnethyl-thiazoie alkylated with an excess of isopropanol, however, gives 95% of 2-isopropylamino-4-methyl-5-isopropylthiazole (56). The same result is obtained with cyclohexanol (242). These results and those reported in Sections III.l.C and IV.l.E offer interesting new synthetic possibilities in thiazole chemistry. The reactive species in these alkylations is the conjugate acid of 2-aminothiazole. and the diversity of the products obtained suggests that three nucleophilic centers may be operative in this species. 

Reactivity of the conjugate acid of 2-aminothiazoles seems more clearly defined. The 5-carbon is the most reactive toward electrophilic... 

Dyatlova (193) reports the preparation of product 49, resulting from the dialkylation of 2-aminothiazole with a-chloroacetic acid under mild conditions (Scheme 36). 

Nucleophilic addition of 2-aminothiazole to the double bond of di-maleic acid hydrazine has been reported (206). No spectroscopic proof, however, is given to establish the proposed structure (60) for the resulting product (Scheme 41). 

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. 

Boiling acetic acid converts 2-aminothiazole into the 2-acetamido derivative far more easily when catalytic amounts of diketene are added to the reaction mixture (277),... 

Halogenation of 2-aminothiazole and derivatives has been reported under a wide variety of experimental conditions in water (161, 405. 406) in aqueous acids (16. 172, 407, 408) in solvents such as chloroform (27. 172), carbon disulfide (162, 166. 320. 409). benzene (165), acetic acid (410-413, 1580). or hydrochloric acid (414) or in 20% sulfuric acid (415-417). 

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. 

In 1882, Nencki and Sieber (98), condensing dibromopyruvic acid with thiourea, obtained a compound they named sulfuvinuric acid (Sulfuvinursaure), which was later demonstrated (99) to be a derivative of 2-aminothiazole. The same year Will (100) observed that the sulfur atom of 56 is masked to Pb(N03)2 and to alkalis. 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

Hydroxythiazoles give 2-chIorothiazole derivatives almost quantitatively upon treatment with phosphorus oxychloride (221, 229, 428). This constitutes a convenient synthesis method for these compounds when the conversion of 2-aminothiazoles to 2-chlorothiazole derivatives fails. Esters of thiocarbamic acid or thiourethanes also react with a-halocarbonyl compounds to give the corresponding 2-alkoxythiazoles (50, 68, 209, 272). 

Reductions carried out with lithium aluminium hydride are not always so successful. As noted by Sprague (46) the esters of 2-aminothiazole carboxylic acids behave somewhat differently with AlLiH4 (55). 

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). 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

A quantitative determination of a heteroaromatic diazotization equilibrium has been made only recently. Diener et al. (1989) determined the equilibrium concentrations of thiazole-2-diazonium ion in diazotization of 2-aminothiazole with nitrosyl sulfuric acid in 70% H2SO4. The two reagents were applied in equimolar concentrations of 0.001, 0.01 and 0.1 m. If the concentration ratios (RNJ)oo/(RNH2) = r are... 

The reaction of 2-aminothiazole and isopropylidene bis(methylthio)-methylenemalonate (459, R2 = R3 = SMe) or 1-methylthioalkylidenema-lonates (459, R2 = Me, Et, Ph R3 = SMe) in boiling ethanol for 2.5 hr or in dimethylformamide at 120-130°C for 4-5 hr, gave 2-substituted 5-oxo-5//-thiazolo[3,2-a]pyrimidine-6-carboxylates (462) in good yields (89S-317). Similarly, in boiling ethanol, 2-substituted 4-oxo-4//-pyrido[l,2-a]-pyrimidine-3-carboxylic acids (463) were obtained in 80-85% yields. When anilines were reacted with isopropylidene bis(methylthio)methy-lenemalonate (459, R2 = R3 = MeS), (methylthio)(arylamino)methylene-malonates (464) were obtained 61-88% yields. 

For instance, the treatment of 2-aminothiazole or 2-amino-1,3,4-thiadiazole with a equimolar amounts of appropriate (hetero)aromatic or aliphatic aldehydes in the presence of an excess of mercaptoacetic acid under refluxing in anhydrous benzene gave diverse 2-substituted 3-(2-thiazolyl)- and 3-[2-( 1,3,4-thiadiazolyl)]-4-thiazolidinones 115a or 115b, respectively (Scheme 54). 

Crysts, mp—explodes at 162—7°. Was prepd by treating a sulfuric acid soln of 2-aminothiazole with 90—95% nitric acid mixed with coned sulfuric acid. Abs ale was added drop wise to destroy the excess of nitric acid (Ref 3) (See also Ref 2)... 

Nitration of 2-aminothiazole with nitric—sulfuric acids was normally effected by mixing the reactants at low temperature, heating to 90°C during 30 min and then applying cooling. When the cooling was omitted, a violent explosion occurred. 

Aminothiazole and Sulfuric Acid. Nitration of 2-aminothiazole with H2S04/HN03 may result in a violent explosion if cooling is omitted.15... 

When carried out in dilute acid, diazotization of 2-aminothiazole may provide unstable diazohydroxides (164, 335, 336), differing in that respect from 2-aminopyridines which give 2-pyridones when the reaction is carried out in weak acids (337). 

The general pattern of alkylation of 2-acylaminothiazoles parallels that of 2-aminothiazole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161, 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an add-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

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