Isothiazoles 2, 365 since

The chemistry of mononuclear isothiazoles has been developed since 1956 without the aid of thiohydroxylamine, the preparation of this very unstable substance having only recently been reported. Bicyclic and polycyclic systems involving the isothiazole (1,2-thiazole) structure have long been known and were fully reviewed in 1952, but little new work has been reported since then and the present review... 

Rees and co-workers in their study of the reactions of trithiazyl trichloride in the preparations of heterocyclic compounds have noted that the isothiazolo[5,4-, isothiazole compound 140 was produced in low yield on reaction with conjugated dienes, along with the other heterocyclic systems 142-145 in much higher yields (Equation 28). Since it is known that trithiazyl trichloride is in thermal equilibrium with its monomer NSCl (Equation 29), the authors propose the so-called criss-cross cycloaddition reaction (Equation 30) which has been reported for azabu-tadienes, but this represents the first example of such a criss-cross cycloaddition to an all-carbon diene <1998CC1207>. 

Much has been said about the application of this heterocyclic system in supramolecular chemistry and in materials chemistry, particularly in the preparation of organic conductors and superconductors. It should not be forgotten however that heterocyclic compounds in general are extremely important medicinal compounds. Although medicinal applications of this heterocyclic system have been rare in the years since CHEC-II(1996), some have been reported. Townsend and co-workers have described the preparation of imidazo[4,5-r/ isothiazole nucleosides 174-177 and have demonstrated their properties as antiproliferative and antiviral analogues of the antibiotic nebularine 172 and the highly cytotoxic 6-methylpurine nucleoside 173 <1997JME771>. 

It is also possible that the order of activating power NH > O > S observed in the rings with only one heteroatom, is also retained in the corresponding azalogs, i.e., imidazole > oxazole > thiazole pyrazole > isoxazole > isothiazole. So far, however, this is a pure speculation since there are no data for a serious homogeneous comparison. 

Few examples of photochemical transformations of the 10n heterocycles in this series have been reported. Notable is the conversion of thieno[2,3-c]isothiazoles (33) to thiophenes (37) by homolytic cleavage of the nitrogen-sulfur bond (Scheme 4). The enedithione (34) which arises from the initial diradical may undergo (a) cyclization via the bicyclic thiirane (35) or (b) electrocyclization to the 1,2-dithiine (36) <88H(27)2539>. Since similar rearrangements do not occur with isothiazoles, benzoisothiazoles, or the isomeric thieno[3,2-d]isothiazoles, this unique transformation is a direct consequence of the thieno[2,3-c]annelation. However, substituent effects on the efficiency of the transformation have not been explored. 

Lithiation at C-5 in isothiazoles occurs rapidly with the formation of relatively stable metallated derivatives whereas lithiation at C-3 gives rise to N—S cleavage and nitrile formation. Hence cleavage reactions by base of isothiazoles fused to azines are predictable, especially since the acidity of H-3 is increased in the fused systems. Such cleavage reactions are shown for the quinoline-fused isothiazole (124) (75JCS(P1)2271, 78JHC1527). 

The photochemistry of TV-substituted pyrazoles and of isothiazoles has been of considerable interest <76PHC123 80RGES501 94PP803 94PP1063 970P57> since the first report that 1-methylpyrazole (1) undergoes photoisomerization to 1-methylimidazole (Scheme 1) <67HCA44>. 

The 2-position in azoles with 1,3-heteroatoms should be more reactive than the 5-position of azoles with 1,2-heteroatoms, but for reactions of the free base this turns out not to be the case because of the adjacent lone pair effect illustrated by the relative reaction rates in Scheme 7.3. Thus the 2-position of thiazole is 7 times less reactive than the 5-position of isothiazole. The same reasoning accounts for the 3-position of isothiazole being less reactive than the 4-position of thiazole. The former should be the more reactive since the electron-withdrawing effect of nitrogen should be greater across the bond of higher order, and the fact that it is not more reactive suggests that the effect of the adjacent lone pair is more severe across the shorter C-3—N bond in isothiazole. For reaction of the azol-... 

Since its discovery in 1985, Appel salt 770 has been exploited for nucleophilic displacement reactions. For example, it reacts readily with amines, e.g., Scheme 150 <2002J(P1)1535> (or hydrazine <1996TL3709>), a more exotic example being its reaction with methyl 3-aminocrotonate resulting in formation of an isothiazole 771 (Scheme 151) <1998J(P1)77>. 

The parent alcohol is conveniently liberated from 3 on treatment with gaseous ammonia3,96 or a primary or secondary amine.13 Since the resulting 3-aminobenz[sparingly soluble in most solvents, separation from the alcohol offers no problem. 

Isothiazoles and benzisothiazoles were described in the first edition of Comprehensive Heterocyclic Chemistry (CHEC-I) <84CHEC-i(6)i3i>. The present work summarizes and augments, where appropriate, information from the first edition, but concentrates very much on literature published since 1982. Wherever possible, information is arranged in a similar format to that used in the first edition to facilitate comparisons. The chemistry of isothiazoles is regularly reviewed in Progress in Heterocyclic Chemistry, and specific subjects are discussed occasionally in Advances in Heterocyclic Chemistry, for example benzisothiazoles <85AHC(38)105> and aromaticity <93AHC(56)303>. 

Another possible criterion of aromaticity, the tendency of Jj c coupling constants in C NMR to converge toward that of benzene (56 Hz) as the degree of aromaticity increases (i.e., single/double bond fixation decreases), has since been proposed <94MRC62). The coupling constants of isothiazole are 52.5 Hz and J4 5 62.2 Hz. These compare with the more divergent pair J34 48.7... 

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