3- isothiazole

In isothiazole (1,2-thiazole), the pyridine-like N-atom is bonded to the S-atom. This cr-bond is also the weakest link in the molecule and is cleaved by ring-opening reactions. 

The isothiazole molecule is planar its ionization energy amounts to 9.42 eV and its dipole moment to 2.4 D. Isothiazole absorbs at longer wavelengths than isoxazole and thiazole, due to a n- n transition  

Isothiazole is aromatic. The NMR spectra confirm a largely undisturbed delocalization of the tt-electrons. In consequence, the aromaticity of isothiazole is greater than that of isoxazole, just as the aromaticity of thiophene is greater than that of furan. From the calculated r-electron densities, it follows by analogy to isoxazole (see p 138) that electrophilic substitution should occur at the 4-position, while nucleophiles should attack the 3-position. The most important reactions of isothiazoles can be summarized as follows  

Isothiazoles are weak bases with a Ka value of -0.51. Protonation occurs on the N-atom. Liquid isothiazoles can be characterized by their crystalline perchlorates, e.g.  

Isothiazoles unsubstituted in the 5-position are metalated by -butyllithium [95]. 5-Lithioisothiazoles react with electrophilic reagents, e.g. with haloalkanes to give 5-alkylisothiazoles. 

Isothiazoles are N-quaternized by iodoalkanes, dialkyl sulfates, and trialkyloxonium tetrafluoroborates. 

For example, the ethyl acetate anion 2, generated in situ by thermal decarboxylation of the K-salt of monoethyl malonate, cleaves the isothiazolium ion 1 by S-attack and formation of the ring-open iminothiolate 3, which cydizes to the 3-aminothiophene-2-carboxylate 5 by intramolecular aza-analogous aldol addition ( 4) and elimination of methyl mercaptan. 

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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). 

In 1969 Lablache-Combi er et al. (110) found that in the presence of primary amines isothiazole photoisomerizes to thiazoie (Scheme 100). 

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. 

TABLE III-39. RELATIVE PERCENTAGE OF ISOMERS BY IRRADIATION OF PHENYLTHIAZOLES AND ISOTHIAZOLES (217)... 

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). 

Substituted isoxazoles, pyrazoles and isothiazoles can exist in two tautomeric forms (139, 140 Z = 0, N or S Table 37). Amino compounds exist as such as expected, and so do the hydroxy compounds under most conditions. The stability of the OH forms of these 3-hydroxy-l,2-azoles is explained by the weakened basicity of the ring nitrogen atom in the 2-position due to the adjacent heteroatom at the 1-position and the oxygen substituent at the 3-position. This concentration of electron-withdrawing groups near the basic nitrogen atom causes these compounds to exist mainly in the OH form. 

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). 

Acid-catalyzed hydrogen exchange is used as a measure of the comparative reactivity of different aromatic rings (see Table 5). These reactions take place on the neutral molecules or, at high acidities, on the cations. At the preferred positions the neutral isoxazole, isothiazole and pyrazole rings are all considerably more reactive than benzene. Although the 4-position of isothiazole is somewhat less reactive than the 4-position in thiophene, a similar situation does not exist with isoxazole-furan ring systems. 

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). 

Isothiazoles and isothiazolium cations are attacked by carbanions at sulfur and on recyclization can give thiophenes, illustrated by (147) -> (148). 2-Alkyl-3-isothiazolinones e.g. 149) are also vulnerable to nucleophilic attack at sulfur (72AHC 14)1). 

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