Of isothiazole

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). 

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. 

Numerous examples of N—S bond formation using oxidative conditions have been described in the literature. A convenient synthesis of isothiazoles involves the direct oxidation of -y-iminothiols and numerous variations have been studied (see Chapter 4.17), The oxidation of the amidine (248) to give the 3-aminoisothiazole (249) illustrates the reaction scheme (65AHC(4)107, 72AHC(14)1), which has been extended to the synthetically useful 5-amino-4-cyano-3-methylisothiazole (251) obtained by oxidation of (250) with hydrogen peroxide (75JHC883). 

Table 2 Ionization Potentials and Orbital Energies of Isothiazole...

The microwave spectrum of isothiazole shows that the molecule is planar, and enables rotational constants and NQR hyperfine coupling constants to be determined (67MI41700>. The total dipole moment was estimated to be 2.4 0.2D, which agrees with dielectric measurements. Asymmetry parameters and NQR coupling constants show small differences between the solid and gaseous states (79ZN(A)220>, and the principal dipole moment axis approximately bisects the S—N and C(4)—C(5) bonds. 

Table 5 Typical H Coupling Constants of Isothiazoles (74CJC833)...

H NMR Chemical Shifts and Coupling Constants of Isothiazoles (IS) with Exocyclic Conjugation X... 

Isothiazole has an absorption maximum in ethanol solution at 244 nm, with a molar absorptivity of 5200. This absorption occurs at a longer wavelength than with pyrazole or isoxazole, the displacement being due to the presence of the sulfur atom. A series of approximate additive wavelength shifts has been drawn up in Table 11 and this should enable prediction of UV maxima of isothiazoles with reasonable accuracy, even for multiply substituted compounds. The longest wavelength band results from a electronic... 

The relative basicity and acidity of isothiazole and its methyl derivatives have been compared by IR spectroscopy (77MI41702). The isothiazoles, dissolved in inert solvents (e.g. CCI4, CS2) containing traces of butanol (a proton donor), interact with the butanol OH... 

The exoeyelie earbonyl group of isothiazol-3-ones absorbs in the region 1610-1660 em <7lJHC59l). 2-Methylisothiazol-3-one itself has the C=0 and C=C bands at 1660 and 1629 em respeetively, in CCI4 solution <64TL1477). The low earbonyl frequeney is due in part to eontributions from the resonanee form (20b). The earbonyl frequeney inereases in sulfoxides (1660-1730 em ) and 1,1-dioxides (1690-1740 em ) where sueh forms are not favourable. Sulfoxides (1060-1190 em ) and sulfones (1330-1360 and 1150-1190 em ) absorb in the regions expeeted (e.g. saeeharin, 1353 and 1162 em ), but resonanee forms related to (13) eause a reduetion of the frequeney of the asymmetrie SO2 vibration to near 1280 em (70CB3166). A similar situation arises in 3-amino-1,2-benzisothiazole 1-oxides. 

Data are given for substituents in the 4-position of isothiazole and the 3-position in the benzisothiazoles, except where indicated. Boiling points of liquids (at 760 mmHg) are given in brackets. 

The stability of isothiazole derives from the fact that it has an aromatic delocalized ir-electron system. The NMR chemical shifts, which depend, inter alia, on ring currents, and the high stability of the molecular ions in mass spectrometry, are typical of aromatic compounds, and X-ray measurements confirm the partial double bond character of all the bonds of the ring. 

The isothiazole ring is very stable to moderate heating, but quaternized compounds are dequaternized by this means (see Section 4.02.3.12). Photolysis of isothiazole itself causes loss of hydrogen cyanide, forming thiirene, but substituted compounds are converted into mixtures of thiazoles and isothiazoles isomeric with the starting compound (Section 4.1.1.2). 

One of the best methods of synthesis of isothiazoles is by direct oxidation of y- iminothiols (169) or their tautomers. The reaction is capable of many ramifications and is represented by the general equation shown in Scheme 27. The substituents represent a wide range of groups. Thus, iminothioamides (169 R = NH2) are oxidized to give 3-alkyl-5-aminoisothiazoles (170 = NH2), amidines (169 R = NH2) produce 3-amino compounds,... 

Hiibenett and his colleagues have shown that propylene reacts with sulfur dioxide and ammonia in the presence of a catalyst such as activated alumina to give a high yield of isothiazole [Eq. (1)]- This reaction is applicable to certain substituted propenes thus, isobutylene... 

The 4-position of isothiazole is attacked by electrophilic reagents, and many simple derivatives are thus readily available by direct substitution followed, if necessary, by suitable transformation of the group introduced. For example, bromination of 3-methylisothiazole... 

The substitution properties of isothiazole are in broad agreement with the electron distribution pattern. Thus, electrophilic substitution occurs predominantly in the 4-position, if this is free, and metalation in the 5-position. The ring appears to be stable to acid, alkali, and mild oxidation and forms a chloroplatinate and an unstable merouriohloride. ... 

In general, the carbonyl derivatives of isothiazole behave normally and condense readily with carbonyl reagents. The aldehydes reduce ammoniacal silver nitrate and undergo the Cannizzaro reaction. ... 

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