Thiazoles from Isothiazoles

310 General Synthetic Methods for Thiazole and Thiazolium Salts 3. Thiazoles from Isothiazoles 

Isothiazole itself (283), Rx = Rj = Rj - H, is converted to thiazole in 7% yield, in propylamine as solvent using a low-pressure mercury lamp (642). 

When Rj, Rj, and R3 are methyl or alkyl groups, yields are low, while the yields with phenyl groups are higher. Thu 3-phenylisothiazoIe (283), Rx = Ph, Rj = R3 = H, gave 4-phenylthiazole (285), R, = Ph, Ro = R, = H and diphenyl-3,5-isothiazole gave 2,4-diphenylthiazole (285), Ri = R3 = Ph, R2 = H, in 12 and 48% yields, respectively (684). But these reactions are of little interest given the difBculty in preparing isothiazoles themselves. 

On the other hand, 2-arylthiazoles are easily isomerized to 3-aryliso-thiazoles in 407o yield upon irradiation with a high-pressure mercury lamp, in benzene solution in the presence of iodine (738). A valence bond isomerization was proposed among several alternatives to account for these results. 

A computer assisted approach of heterocyclic structures (825, 826) predicted a new method of synthesis for the thiazole (826). This method was reported soon after by P. Dubs (807). The same program proposed two other methods not yet experimentally checked (827). 

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Hydrogen chloride Thiazole from isothiazole ring... 

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. 

Although isothiazole (pK = 1.90) is less basic than thiazole, its rale of quaternization by dinitrophenyl acetate in water at 52°C is approximately 2.5 times higher (447). This deviation from the Bronsted relationship (A log k - 0.ApK, with positive) is interpreted as a consequence of the or effect of the adjacent sulfur lone pair in isothiazole that is responsible for its higher nucleophilicity (448, 449). 

There are two series of benzisothiazoles, derived from benz[c]iso-thiazole (2) and benz[d]isothiazole (3), and both, if the benzene ring were suitable weakened, could doubtless be oxidized to isothiazole-dicarboxylic acids. In their first synthesis Adams and Slack... 

Simple isothiazole-4-carboxylic acids have been made from the corresponding nitriles, which are available in turn from the halogeno derivatives, or directly by the olefin route.5-Aminoiso-thiazole-4-esters and -nitriles are readily obtained by the thioamide route. The 4-acids behave normally and form acid chlorides, esters, amides, and hydrazides. In contrast to the 5-series... 

The Balz-Schiemann synthesis can be applied not only to substituted anilines but also to aminobiphcnyls1,131 or amino-substituted fused polyaromatic compounds, such as naphthalene,1114,119,129 anthracene,136 phenanthrene,1135 acenaphthene,133 fluorene,1,131,134 benzanthracene,130 136 pyrene,136 chrysene,136 fluoranthene,131 fluorenone,1,131 anthra-quinone,1,137,139,140 benzanthrone,1,117,118 phenanthraquinone,138 or xanthone.132 Fluorinated pyridines,1,141"146 methylpyridincs,126,147 149 pyridinecarboxylic acids,150 quinolines,1,151 isoquinolines,152 quinazolone,1 thiazoles,153,154 isothiazoles,156 benzothiazoles,157 thiadiazoles,155 and thiophenes154 can also be obtained from the corresponding aminated heterocycles. Modified Balz-Schiemann methods are recommended for amino nitrogen-containing heterocycles, the diazonium salts of which are rather water-soluble and unstable (a violent explosion was reported for pyridine-3-diazonium tetrafluoroborate).159 These new techniques have also been specially adapted for pyrazol-, imidazol-, or triazolamines which fail to react under classical conditions.158... 

In analogy to the isoxazole-to-oxazole rearrangement, thiazoles can be obtained photochemically from irradiation of the corresponding isothiazoles. In several cases, however, irradiations have been conducted for mechanistic purposes only, and mixtures of photoisomers arising from competing reaction mechanisms are often formed [4, 6]. 

Irradiation of bromothiazoles in various organic solvents (methanol, ether, cyclohexane) produces thiazole (and the isomeric isothiazole) as the main reaction product386. The reactivity decreases in the order 2-bromothiazole > 5-bromothiazole 4-bromoth-iazole, and is probably related to the C—Br bond strengths. The mechanism is considered to involve homolytic cleavage of the C—Br bond, followed by abstraction of a hydrogen atom from the solvent. Oxygen does not exhibit any noticeable effect upon the reaction, but the debromination is accelerated by triethylamine. 

Raubenheimer et al. have developed a third route for transition metal NHC complexes with thiazol-2-ylidene, benzothiazol-2-yUdene and even isothiazol-5-ylidene ligands [45 9]. This method uses a thiazolyl transfer from lithium to a transition metal with subsequent protonation [47,49-54] or alkylation [41,45,46,48,51-56] of the nitrogen atom to generate the transition metal NHC complex. In this way, carbene complexes of copper(I)... 

The 3-thiono-3//-l, 2-dithioles 334a,b in poor yields and the dealkylated iso-thiazoles 335 resulted from the treatment of salts 27a,b,30a,45a and 75j,333 (R = Me, Ph) with sulfur in pyridine (72CJC2568, Scheme 111). The reaction of salts 27a,333 (R = t-Bu, R2 = R3 = H) with toluene yielded isothiazole 335a (83PS119). 

Amino-l,2,4-thiadiazoles are diazotized at — 10°C in phosphoric acid, and couple with naphthol to give moderate yields of diazo dyes.182,388 In their limited stability, the 3-diazonium salts resemble those of 3-aminoiso-thiazole, but differ from the more stable 1,2,4-thiadiazole- and isothiazole-5-diazonium salts a consideration of the 7t-electron densities leads to the opposite conclusion.182... 

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