Nitration of thiazole

No nitration of thiazole occurs with the classical nitration reagents, even in forcing conditions (341-343). In a study concerning the correlation between the ability of thiazole derivatives to be nitrated and the HNMR chemical shifts of their hydrogen atoms, Dou (239) suggested that only those thiazoles that present chemical shifts lower than 476 Hz can be nitrated. From the lowest field signal of thiazole appearing at 497 Hz one can infer that its nitration is quite unlikely. Thiazole sulfonation occurs... 

From these results it appears that the 5-position of thiazole is two to three more reactive than the 4-position, that methylation in the 2-position enhances the rate of nitration by a factor of 15 in the 5-position and of 8 in the 4-position, that this last factor is 10 and 14 for 2-Et and 2-t-Bu groups, respectively. Asato (374) and Dou (375) arrived at the same figure for the orientation of the nitration of 2-methyl and 2-propylthiazole Asato used nitronium fluoroborate and the dinitrogen tetroxide-boron trifluoride complex at room temperature, and Dou used sulfonitric acid at 70°C (Table T54). About the same proportion of 4-and 5-isomers was obtained in the nitration of 2-methoxythiazole by Friedmann (376). Recently, Katritzky et al. (377) presented the first kinetic studies of electrophilic substitution in thiazoles the nitration of thiazoles and thiazolones (Table 1-55). The reaction was followed spec-trophotometrically and performed at different acidities by varying the... 

TABLE in-45. RATE PROFILE SLOPES FOR NITRATION OF THIAZOLE (242)... 

Table 23 Standard Rate Constants for the Nitration of Thiazoles (75JCS(P2)1614)...

Table 1 gives the relative rate constants for the nitration of thiazoles and isothiazoles. They demonstrate the higher reactivity of the thiazoles during nitration [190, 200], Such high regioselectivity is not observed during the nitration of thiazoles, as during the nitration of isothiazoles. 

Only one example of the nitration of thiazoles at position 2 has been described the action of the sulfuric-nitric acid mixture on 4,5-dimethylthiazole gave 4,5-dimethyl-2-nitrothiazole [199],... 

The nitration of thiazoles can also be conducted in organic solvents (e.g., dichlo-roethane) with a nitrating mixture consisting of trifluoromethanesulfonic acid, its anhydride, and potassium nitrate. Here the yields of the nitro derivatives are substantially higher than with the sulfuric-nitric acid mixture [361],... 

The reactivity of thiazole to nitration has been well reviewed <1984CFIEC(6)235>. Recently, nitration at C-4 of 2,5-dimethylthiazole 62 was accomplished with trifluoroacetic anhydride (TFAA) and fuming nitric acid at —15°C as shown in Scheme 9 to give the product 63 in 67% yield <2005ARK179>. The nitration of thiazole itself was not studied in this work due to poor solubility under the reaction conditions <2005ARK179>. See also Section 4.06.7.2. 

Nitration of thiazoles has not been reported to take place under the classical nitration conditions even under extreme condition. Thiazole itself is untouched by nitric acid or oleum at 160 °C, but methyl thiazoles are sufficiently activated to undergo substitution and preferentially yield the 5-nitro over the 4-nitro regioisomer. ... 

Alkoxythiazoles are easily cleaved by acids yielding A-4-thiazoline-2-ones (36). C-5 Nitration of the thiazole ring is favored by the 2-alkoxy group (288. 297, 307). Recent kinetic investigations have shown that the rate enhancement is 3 log units (893). 

Nitration in the 5-position of 4-methyl- and 2,4-dimethylselenazoles with HNO3-H2SO4 is more rapid than for thiazoles [4-methyl-5-nitroselenazole. m.p. 45°C (19) 2.4-dimethyl-5-nitroselenazole. m.p. 115-120 C (decomp.) (19)]. Direct nitration of 2-amino 4-methyl-selenazole leads to nng rupture (19). 

More quantitative results are available for the nitration of alkyl-thiazoles Dou et al. (373) determined the reactivity, relative to benzene, of the nitration site of various mono- and dialkylthiazole by competition experiments (Table 1-53). 

The overall reactivity of the 4- and 5-positions compared to benzene has been determined by competitive methods, and the results agreed with kinetic constants established by nitration of the same thiazoles in sulfuric acid at very low concentrations (242). In fact, nitration of alkylthiazoles in a mixture of nitric and sulfuric acid at 100°C for 4 hr gives nitro compounds in preparative yield, though some alkylthiazoles are oxidized. Results of competitive nitrations are summarized in Table III-43 (241, 243). For 2-alkylthiazoles, reactivities were too low to be measured accurately. 

The relative ease of preparation of condensed thiazole derivatives is a consequence of facile thiazole ring closure, and therefore also benzothiazole amines with an amino group on the benzene ring (except for the weakly regioselective nitration of benzothiazoles) are very easily accessible and useful substrates for the Gould-Jacobs reaction. 

Phenylthiazole, like 2-phenyloxazole, is also nitrated (and brominated) at the 5-position of the heterocyclic ring. The thiazole is less reactive than the oxazole ring. In nitration of the protonated thiazole, the predominant product is 2-(4-nitrophenyl)-thiazole (85CS295), in contrast to the nitration of 2-phenyloxazole, which gives predominantly 2-(3-nitrophenyl)oxazole (84CHE713). 

Studies of the nitration of 4-chloromethyl-2-phenylthiazole have shown that the action of nitric acid (d 1.40) in sulfuric acid at 60°C gives the 4-nitrophenyl product and the use of nitric acid in acetic anhydride at 60°C forms the 5-nitrothiazole product. Chlorination and bromination also result in 5-substitution in the thiazole ring and nitration of these products using mixed acid gives the 4-nitrophenyl products. 2-(4-Bromophenyl)-4-chloromethylthiazole also nitrates at the 5-position of the thiazole ring using nitric acid in acetic anhydride below 60°C (65CB3446). 

A quantitative study has been carried out by Ridd and co-workers126 on the nitration of imidazole and pyrazole in 98% sulfuric acid the partial rate factors for the 4-positions of imidazolium and pyrazolium cations are 3.0 xlO-9 and 2.1 x 10-10, respectively. Thiazole and isoxazole cations are also far less reactive than benzene. As a consequence, phenyl derivatives give products substituted in the benzene ring, on sulfonation or nitration.208-210... 

No quantitative data are available for the nitration of selenazole, though it is said to be more reactive than thiazole 4-methylselenazole is nitrated at the expected 5-position (48YZ195J97). 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

The nitration of the isothiazole (1,2-thiazole) ring takes place exclusively at position 4. The 4-substituted isothiazoles are either not nitrated at all [189, 190] or, as in the case of 4-phenylisothiazole, are nitrated in the benzene ring [191]. 

Table 1 The relative nitration rates (F) of thiazoles and isothiazoles...

The nitration of 2-amino- and 2-acetamidothiazoles has been studied particularly widely [202-205, 220-226], This is explained by the wide range of biological activity in the respective nitro derivatives. Here, nitroamines can also form in addition to nitration of the thiazole ring [203, 204, 225] (Scheme 21). 

Acetamido-4-phenylthiazole is nitrated at position 5 of the thiazole ring [232], in contrast to 2-amino-4-phenylthiazole, which is nitrated in the phenyl ring [233], This agrees with existing data on the reactivity of thiazoles during electrophilic substitution. N-(2-Thiazolyl)-2-aminopyridine is nitrated exclusively in the thiazole ring [222],... 

The nitration of 2-, 4- and 5-phenylthiazole with 1 mole of HN03 in concentrated H2S04 occurs at para-position of the phenyl ring, but not to thiazole cycle [203, 247]. It can be explained then that these compounds react in so-called conjugated acid form (protonated form), but not in base form. Analogically, 2-substituted 4-(2-furyl)thiazole is nitrated into furyl cycle 5 position however, further nitration with two moles HN03 leads to 2-substituted 5-nitro-4-(5-nitro-2-furyl)-thiazoles along with other products [234] (Scheme 27). 

Data on the nitration of selenazoles are extremely limited. The 4-methyl- and 2,4-dimethylselenazoles are nitrated more quickly than their thiazole analogs [236],... 

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