Nitrothiazoles

Aminothiazole and derivatives have been reported in reactivity studies starting from 2-p-nitrophenylsulfenylaminothiazole (4) (32), 2-tritylaminothiazole (5) (33), 2-nitrothiazole (34,35), and 5-methyI-2-phenylimino-4-thiazolidinone (36) (Scheme 4). 

Reduction of 2.4-dimethyl-5-nitrothiazole with activated iron gives a product that after acetylation yields 25% 2.4-dimethyl-5-acetamido-thiazole (58). The reduction of 2-methyl 5-nitrothiazole is also reported (351 to give a mixture of products. The nitro group of 2-acetylhydrazino-5-nitrothiazole is reduced by TiCl in hydrochloric acid or by Zn in acetic acid (591. 

In the NMR spectrum of cis-l,2-bis[2-diethylamino-5-nitrothiazol-4-yl] ethylene (17) (1570), the nonequivalence of olefinic protons requires that the rotation of the NO2 group be hindered. 

R is a r-Bu group, ring nitrogen alkylation is preferred (191). Alkylation of the sodium salt of 2-formamido-5-nitrothiazole (48) (R = H)... 

An alkyi group occupying the 4-position of the thiazole ring may condense if the 5-position is substituted. 2-Acetamido-4-methy]-5-nitrothiazole (80) and p-cyanobenzaldehyde when refluxed with small amounts of piperidine yield the 4-styryl derivative (81) (Scheme 57) (238, 239). 

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,... 

That numerous 2-amino-5-nitrothiazole derivatives exhibit antiamebic, antihistomonal, antitrichomonal, and antischistosomal properties (see Section VI.2) explains the large number of nitration reactions reported. Nitration in a mixture of concentrated nitric and concentrated sulfuric acids IS among the most common experimental methods (16, 27, 58, 374-377). 

Taurins reported that nitration of 2-nitramino-5-nitrothiazole yields the fully nitrated 2-imino-4-thiazoline (184) (Scheme 117) (87). This interesting compound should be studied by spectroscopic 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... 

Nitraminothiazole. treated for 12 hr with 96% sulfuric acid, gives 2-amino-5-nitrothiazole (194). The mechanism of this rearrangement is not yet quite resolved even for nitraminobenzene derivatives (617). The series of kinetic determinations and appropriate labeling performed by Toth et al. provide, however, precious hints for this difficult problem (1578. 1579). 

Methoxy-5-nitrothiazole (127) reacts with an equivalent of methox-ide ion to give complexes 128 and 129. which decompose (Scheme 65). 3-NO-.-thiazoline-2 One is also observed in that reaction (297). 

Anion-radicals derived from the reduction of nitrothiazoles were studied by Tordo et al. (285). The reaction scheme is the following ... 

CALCULATED AND EXPERIMENTAL COUPLING CONSTANTS FOR VARIOUS NITROTHIAZOLES (285)... 

These preceding properties imply that the thiazole has to be introduced in various molecules, by direct cyclization or with precursors already bearing the thiazole ring. Among these last products the clomethiazole. nitrothiazole, and aryl or alkylthiazoles with the functional group on the aryl or alkyl substituent have been widely used. 

Nitrothiazole and 5-nitrothiazole are known products, while 4-nitrothiazole does not appear to have been prepared. 2-Nitrothiazole (2,... 

Nitrothiazole is obtained by reductive dehaiogenation of 2-bromo-5-nitrothiazole (2, 14, 83). 

The 2-nitrothiazole can be reduced to the corresponding aminothiazole by catalytic or chemical reduction (82, 85, 89). The 5-nitrothiazole can also be reduced with low yield to impure 5-aminothiazole (1, 85). All electrophilic substitution reactions are largely inhibited by the presence of the nitro substituent. Nevertheless, the nitration of 2-nitrothiazoIe to 2,4-dinitrothiazole can be accomplished (see Section IV). 

Some 2-halogeno-5-nitrothiazoles and 2-nitro-5-halogenothiazoles are known. 2-Halogeno-5-nitrothiazoles can be prepared by a Sandmeyer reaction from 2-amino-5-nitrothiazole (1, 85), while 2-nitro-5-halo-genothiazoles can be analogously prepared by decomposition of dia-zonium salts arising from 2-amino-5-halogenothiazoles in presence of nitrite anion (82, 84). 

Many 2-substituted 5-nitrothiazoles are prepared (by nucleophilic substitution reactions on 2-halogeno-5-nitrothiazoles) for use as biocides or for their biological activity (31, 91-95). 

Taking into account the previous discussion of the reactivities of simple halogenothiazoles or nitrothiazoles, the mechanism of nucleophilic reac tivity of 2-halogeno-5-nitrothiazoles with an excess of basic nucleophile such as CHjO can be proposed (Scheme 14). 

If the reactions are carried out using a concentration of CHsO slightly less than that of halogenothiazole, the reaction almost quantitatively yields the 2-methoxy-5-nitrothiazole. The reaction of methoxide ion in excess with regard to 2-haiogeno-5-nitrothiazole, previously reported as leading to a mixture of unidentified products together with the expected 2-methoxy-5-nitrothiazole in low yields (97), can be explained on the basis of Scheme 14. 

Ilvespaa (98) has demonstrated that, using some amines, the 2-chloro-5-nitrothiazole undergoes an opening reaction in a competitive reaction parallel to the normal substitution process. This confirms the sensitivity of position 4 to nucleophilic attack when a nitro group is present in position 5 (Scheme 16). 

When 5-halogeno-2-nitrothiazole reacts with methoxide ion. the leaving group is the nitro group in position 2, following Scheme 17 (86). 

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