Thiazoles isothiazoles

Details of bond lengths and bond angles for the X-ray structures of heterocyclic compounds through 1970 are listed in Physical Methods in Heterocyclic Chemistry , volume 5. This compilation contains many examples for five-membered rings containing two heteroatoms, particularly pyrazoles, imidazoles, isoxazoles, oxazoles, isothiazoles, thiazoles, 1,2-dithioles and 1,3-dithioles. Further examples of more recent measurements on these heterocyclic compounds can be found in the monograph chapters of CHEC and CHEC-II. 

Isoxazolc Oxazole Isothiazole Thiazole Pyrazole Imidazole ... 

Isothiazole gave a low yield of thiazole on irradiation in propylamine, but the reverse reaction was not observed.149 Phenyl- and diphenyl-isothiazoles gave thiazoles on irradiation,150 and the reverse reactions have also been reported.84,151 It appears likely that isothiazole-thiazole photorearrangements proceed through a common intermediate, possibly a tricyclic species in which the negative charge is stabilized by resonance with the phenyl group (Scheme 42).80,150... 

The photoisomerization of isothiazole (47a) (Scheme 24) to thiazole (48a) was the first reported phototransposition in the isothiazole-thiazole heterocyclic system <69CC1018>. 

Thiete structures have been suggested as fragmentation products in the mass spectra of a thietane fused to a 3-lactam, an ortho disulfide of a thiolbenzoate ester, -propanethiol, thiirane carboxylic acid esters, isothiazoles, thiazoles, 1,3-dithiole 2-thiones, 1,3-dithiolene-2-ones, S-ethyl thio-benzoate, and thianaphthene sulfones. Tetramethylthiete may have been formed on thermolysis of the p-toluenesulfonyl-hydrazone of 2,2,4,4-tetramethyl-3-thietanone. " Thiete 2-thione may be an intermediate in the decomposition of 1,2-ditholium salts by the action of bases. " 2,2-Diphenyl-2H-thiete is suggested as an intermediate in the reaction of diphenyldiazomethane with 1,2,3-benzo-thiadiazole which yields 9-phenylthioxanthene and three other products. ... 

Table 17 Comparative aromaticity criteria for isothiazole, thiazole, pyrazole, and isoxazole.

The photoisomerization of isothiazole 3 to thiazole 4 was the first reported phototransposition in the isothiazole-thiazole heterocyclic system [3]. Methylisothiazoles have also been shown to undergo transposition. In neutral solvents, Lablache-Combier and coworkers reported that 3-methylisothiazole 41 and 4-methylisothiazole 42 each transpose to a single product, 2-methylthiazole 44 and 4-methylthiazole 45 respectively. According to this report, however, 5-methyl-isothiazole 43 transposes to three primary products, 5-methylthiazole 46, 3-methylisothiazole 41, and 4-methylisothiazole 42 [26]. 

Convincing evidence for the involvement of an isocyanide in the P4 isothiazole -> thiazole phototransposition was obtained by studying the photochemistry of 4-benzylisothiazole 55. In this case, irradiation in methanol containing ammonia led to the formation of the nitrile photocleavage product 56, which was trapped by reaction with benzylbromide to yield benzylthioether 57,... 

The P4 isothiazole -> thiazole transposition is thus mechanistically quite similar to the analogous pyrazole imidazole isomerization. Scheme 14 shows that both reactions involve competition between ring cleavage to yield a nitrile cleavage product and to transposition involving an isocyanide intermediate. 

The photoisomerization of isothiazole 5 to thiazole 6 (Scheme 3) was the first reported phototransposition in the isothiazole-thiazole heterocyclic system. Later work published during the period 1971 to 1978 by Lablache-Combier and co-workers, by Vernin and colleagues,"" andby Maeda and Kojima " also showed that methylisothiazoles phototranspose to methylthiazoles and that phenyl-substituted isothiazoles and thiazoles also undergo phototransposition reactions. A surprising finding, however, was that phenyhsothiazoles were not observed to react via the N2—C3 interchange pathway, an important pathway in pyrazole photochemistry. Furthermore, a common conclusion of these studies was that these photoisomerizations proceed by way of tricyclic zwitterionic intermediates, which had no counterparts in pyrazole photochemistry. 

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). 

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

It has been recently found that upon irradiation isothiazoles can be converted to thiazole and isothiazole isomers among other products (Scheme 153). 

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). 

Alkyl- and arylthiazoles rearrange undernltraviolel irradiation in different solvents to yield the corresponding isothiazoles or isomeric thiazoles. With alkylthiazoles the overall yields are very low, and it is not possible to use this method preparatively. For arylthiazoles it is possible 2-arylthiazoles. for instance, can be used to prepare 3-arylisothiazoles that are otherwise very difficult to obtain. 

Various other cycHc compounds can be built using thioglycoic acid, eg, thiazohdinone, thiazole, isothiazole, and thiazine-type stmctures, leading to intermediates for the agricultural and pharmaceutical industries (69). Eungicidal organotin mercaptocarboxylates have also been claimed (70). 

Irradiation of isothiazole gives thiazole in low yield. In phenyl-substituted derivatives an equilibrium is set up between the isothiazole (59) and the thiazole (61) via intermediate (60) (72AHC(14)l). 

In azole chemistry the total effect of the several heteroatoms in one ring approximates the superposition of their separate effects. It is found that pyrazole, imidazole and isoxazole undergo nitration and sulfonation about as readily as nitrobenzene thiazole and isothiazole react less readily ica. equal to m-dinitrobenzene), and oxadiazoles, thiadiazoles, triazoles, etc. with great difficulty. In each case, halogenation is easier than the corresponding nitration or sulfonation. Strong electron-donor substituents help the reaction. 

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

Isothiazoles with electron-releasing substituents such as amino, hydroxy, or alkoxy in the 3- or 5-position are brominated in high yield in the 4-position. Alkylisothiazoles give lower yields, but 3-methylisothiazole-5-carboxylic acid has been brominated in 76% yield (72AHC(14)1). Again, thiazoles with an electron-releasing substituent in the 2- or 4-position are brominated at the 5-position (79HC(34-1)5). 

In contrast to thiazoles, certain isothiazoles and benzisothiazoles have been directly oxidized to sulfoxides and sulfones. 4,5-Diphenyl-l,2,3-thiadiazole is converted by peracid into the trioxide (146). Although 1,2,5-thiadiazole 1,1-dioxides are known, they cannot be prepared in good yield by direct oxidation, which usually gives sulfate ion analogous to the results obtained with 1,2,4- and 1,3,4-thiadiazoles (68AHC 9)107). 

Thus quaternized thiazoles (170) consume two equivalents of OH on titration because the pseudo bases (171) ring open to (172), which form anions (173). Quaternized oxazoles (174) are readily attacked by hydroxide to give open-chain products such as (175) (74AHC(17)99), and quaternized 1,3,4-oxadiazoles behave similarly. Quaternary isothiazoles (e.g. 176) are cleaved by hydroxide (72AHC(l4)l), as are 1,2,4-thiadiazolium salts (177 178). 

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

The 4- and 5-hydroxy-imidazoles, -oxazoles and -thiazoles (499, 501) and 4-hydroxy-pyrazoles, -isoxazoles and -isothiazoles (503) cannot tautomerize to an aromatic carbonyl form. However, tautomerism similar to that which occurs in hydroxy-furans, -thiophenes and -pyrroles is possible (499 500 503 504 501 502), as well as a zwitterionic... 

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