Isothiazoles reduction

Isothiazoles are reductively desulfurized by Raney nickel, e.g. as in Scheme 31 (72AHC(l4)l). 1,2,5-Thiadiazoles are subject to reductive cleavage by zinc in acid, sodium in alcohol, or Raney nickel, e.g. Scheme 32 (68AHC(9)107). 

Isothiazole-4,5-dicarboxylic acid, 3-phenyl-dimethyl ester synthesis, S, 150 Isothiazole-5-glyoxylic acid ethyl ester reduction, 6, 156 Isothiazole-4-mercurioacetate reactions, 6, 164 Isothiazole-5-mercurioacetate reactions, 6, 164 Isothiazoles, 6, I3I-I75 acidity, 6, 141 alkylation, 6, 148 aromaticity, S, 32 6, 144-145 basicity, 6, I4I biological activity, 6, 175 boiling points, 6, I43-I44, 144 bond fixation, 6, 145 bond orders, 6, I32-I34 calculated, 6, 133 bromination, S, 58 6, 147 charge densities, 6, 132-134 cycloaddition reactions, 6, 152 desulfurization, S, 75 6, 152 deuteration, S, 70... 

Bicyclic isothiazole dioxides 81 (99JHC(36)161), on treatment with Ai-nucleo-philes such as benzylamine, afforded isothiazole dioxides 82a,b together with a minor amount of compounds 83. Alternatively, 82b could be obtained from 84 by reduction with 1,2-dimethylhydrazine and DBU. By using r-butylamine as the A-nucleophile, due to steric reasons, the formation of the isothiazole dioxide 85 could also be observed followed by transformation in the bicyclic system 86. 

To further illustrate the diversity of hydrolytic opening reactions, we turn our attention to an isothiazole ring as found in the antipsychotic agent ziprasidone (11.129). This drug is subject to various reactions of oxidation and reduction, but also undergoes hydrolytic cleavage of the C=N bond of the isothiazole ring. Evidence for this reaction was afforded by detection of radioactive metabolite 11.130, a sulfonamide, in the urine of patients dosed... 

The reduction of some thiazole and isothiazole derivatives was discussed in Part I. 

Acetyl- and 5-formylisothiazoles are readily available from 5-lithioisothiazoles.71,102 However, 3-methyl-4-nitroisothiazole does not form a lithium derivative,72 and 4-formyl-3-methyl-4-nitro-isothiazole was prepared by reduction of the appropriate acid chloride with lithium tri-Lbutoxyaluminum hydride.140 A 5-formyl-4-hydroxy-isothiazole has been prepared by direct ring synthesis [Eq. (12)].29... 

Isothiazoles are reductively desulfurized by Raney nickel, and this method has been used to confirm structures.3,51 In his remarkable synthesis of colchicine, Woodward employed the isothiazole nucleus as a template on which the various rings were constructed, and finally removed the sulfur with Raney nickel to leave a nitrogen function in the correct position [Eq. (22)].e7,68... 

Few other reactions of simple 1,2-benzisothiazoles have been described in the literature. There is, for example, no report of the formation of a quaternary salt directly from the parent compound. The isothiazole ring is generally quite stable to oxidation or reduction ... 

The exocyclic carbonyl group of isothiazol-3-ones absorbs in the region 1610-1660 cm-1 (71JHC591). 2-Methylisothiazol-3-one itself has the C=0 and C=C bands at 1660 and 1629 cm-1, respectively, in CCLt solution (64TL1477). The low carbonyl frequency is due in part to contributions from the resonance form (20b). The carbonyl frequency increases in sulfoxides (1660-1730 cm-1) and 1,1-dioxides (1690-1740 cm-1) where such forms are not favourable. Sulfoxides (1060-1190 cm-1) and sulfones (1330-1360 and 1150-1190 cm-1) absorb in the regions expected (e.g. saccharin, 1353 and 1162 cm-1), but resonance forms related to (13) cause a reduction of the frequency of the asymmetric S02 vibration to near 1280 cm-1 (70CB3166). A similar situation arises in 3-amino-l,2-benzisothiazole 1-oxides. 

A special reaction is the reduction of certain acetylenes to thiophenes [97a] and dimeric isothiazoles from sulfonyl-substituted 2-alkenenitriles [97b] at a compact sulfur/ graphite electrode [98]. 

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