4- Aminothiazole, diazotization

The weakly basic 2-aminothiazoles are most readily diazotized in concentrated solutions of oxygen containing acids such as sulfuric acid, 40 to 50% (322-326) fiuoroboric phosphoric acids (589) phosphoric acid (327, 328) and mixtures of phosphoric and nitric acid (74. 322, 323. 329-331). From strong acid solutions, solid diazonium salts can be isolated (34, 332. 333). 

Even when deactivated by nitro substitution on C-5, the 2-aminothiazoles still undergo diazotization (35, 338-340). As with carbonyl derivatives (Section III.2.B), competition may occur between N nucleophilic reactivity and nitrosation of the 5-position when it is unsubstituted (341-344). 

In 1889, Popp (104) confirmed the structure of 2-aminothiazole (72) by diazotization and reduction he obtained thiazole itself (73). 

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... 

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). 

All possible dichloro- or dibromothiazoles are known. The 2.5-dihalogeno derivatives can be prepared from the 5-halogeno-2-aminothiazoles by diazotization/decomposition with CuCl or CuBr (3, 12, 13, 18, 75). The 5-halogeno-2-aminothiazoles can be easily prepared by halogenation of 2-aminothiazole (65, 76-79) 2,5-dibromothiazole can also be prepared by direct bromination of 2-bromothiazole (5). 

Aromatic diazonium compounds became industrially very important after Griess (1866a) discovered in 1861/62 the azo coupling reaction, by which the first azo dye was made by C. A. Martius in 1865 (see review by Smith, 1907). This is still the most important industrial reaction of diazo compounds. Hantzsch and Traumann (1888) discovered that a heteroaromatic amine, namely 2-aminothiazole, can also be diazotized. Heteroaromatic diazonium compounds were, however, only used for azo dyes much later, to a small extent in the 1930 s, but intensively since the 1950 s (see Zollinger, 1991, Ch. 7). 

Aminopyridines, aminopyridine oxides, and 3-aminoquinoline are obviously diazotized by analogous mechanisms. Kalatzis (1967 b) studied the diazotization of 4-aminopyridine over a very large range of acid concentrations (0.0025-5.0 m HC104). This compound is comparable to 2-aminothiazole in its acid-base properties the heterocyclic nitrogen is easily protonated at pH 10, whereas the amino group is a very weak base (pKa = -6.5). Therefore, the kinetics indicate that the (mono-protonated) 4-aminopyridinium ion reacts with the nitrosyl ion. The... 

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... 

Aminopyridines90 91, aminopyridine-1 -oxides25, 3-aminoquinoline92 and 2-aminothi-azole93 are obviously diazotized by analogous processes. For 4-aminopyridine, 3-aminoquinoline and 2-aminothiazole it was shown that the monocation, protonated at the heterocyclic nitrogen, is nitrosated preferentially. 

Diazadimethinecyanine dyes are formed by coupling diazotized N-heterocyc-lic amines in the b-position to the nitrogen atom of other heterocycles followed by alkylation. The most important coupling agent is l-methyl-2-phenylindole. Reaction of this compound with diazotized 2-aminothiazole and subsequent methylation with dimethyl sulfate, yields 43, a dye that draws up very quickly on polyacrylonitrile and dyes it a lightfast red shade [102],... 

Diazotized 2-aminothiazole (4) with potassium ethylxanthate yields ethylthiazolyl-2-xanthate (5), which is then hydrolyzed to 2-mercaptothiazole (3) (8). Similarly, treatment of (4) by potassium thiocyanate gives the 2-thiocyano derivative (6), which is hydrolyzed to 2-mercaptothiazole (3) by 50% sulfuric acid (Scheme 2) (9). 

Hetaryl-2-aminothiazoles, 178-182 Hetaryne, in diazotations, 67 Heterocyclization of 2-imino-4-thiazoline, 127... 

Sulfonimidothiazolines, 317, 318 Sulfonyl halides, with 2-aminothiazoles, 69 Sulfur (Sg), in synthesis of, A-4-thiazoline-2-thione, 373 Sulfur compounds, 69 Sulfuric acid, with alcohols, 38, 47, 80, 90 in bromination, 77 dealkylation by, 39 deuterated, 92 diazotization with, 66 in nitrations, 72 rearrangements in, 73, 113 Sulfuryl chloride, 432 Symbiotic behavior, see HSAB theory Symmetry. C2v and C2p, 120 Synthetic fibers, 154... 

Methyl-5-aminothiazole-4-carboxylic acid is diazotized with isoamyl nitrite in the presence of furan in 1.2-dichloroethane to give a mixture of products 163 (53%), 164 (33%). 165 (11%), and 166 (3%) (Scheme 104) (334). This reactivity experiment was carried out to examine the possibility of the occurrence of 4,5-dehydrothiazole (hetaryne). Hetaryne intermediates seem not to be involved as an intermediate in the reaction. The formation of 163 through 166 can be rationalized in terms of the intermediacy of 166a. 

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). 

Aminothiazoles are invaluable intermediates for the preparation of 2-unsubstituted-thiazoles by diazotization followed by reduction with hypophosphorous acid. Application of the Sandmeyer reaction leads to 2-halogeno- and 2-cyano-thiazoles. 

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>. 

A study of the diazotization mechanism of 2-aminothiazole has shown that 2-aminothiazole is protonated at the endocyclic nitrogen and then attacked by the NO ion, the final status of the process being an equilibrium between the protonated form and the diazonium salt <89hcA800>. 

Aminothiazole can be diazotized. The diazonium salt is reduced to thiazole by hypophosphorous acid. By means of the Sandmeyer reaction, 2-halothiazoles and 2-cyanothiazole are obtained. 

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