Isothiazole 1,1-dioxides rearrangement

The standard means for preparing oxicams 285, initially developed by Lombardino, is through the base-promoted rearrangement reaction of isothiazole dioxides 286, which in turn are prepared from saccharin derivatives such as 287 (Scheme 40) <1981AHC(28)73>. The oxicam core can be further derivatized by N-alkylation of oxicam 285 and amidation of the C-3 ester functionality of 288 to form the common drug scaffold 289. 

In the presence of various metal ions, 2-(fluoroenone)benzothiazoline has been found to rearrange to A-2-mercaptophenylenimine, while a free radical mechanism involving the homolysis of C-S and C-N bonds has been invoked to explain the formation of 3-phenyl-1,2,4-triazole derivatives from the thermal fragmentation and rearrangement of 2-(arylidenehydrazino)-4-(5//)-thiazolone derivatives. The cycloadducts (36) formed from the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxide (34) with nitric oxides or miinchnones (35) have been found to undergo pyrolytic transformation into a, jS-unsaturated nitriles (38) by way of pyrrole-isothiazoline 1,1-dioxide intermediates (37). 

Clerici et al. studied the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxides 15 with nitrile oxides and with munchnones. These reactions produced cycloadducts such as 16 and 17 which underwent thermal rearrangement to a, P-unsaturated nitriles <98T11285>. 

The mass spectrometric fragmentation of selected compounds representing most of what is covered in this review has been analyzed recently.20 Apart from typical fragmentations (loss of SO 2 rearrangement followed by loss of CO, etc.) the pattern is frequently dominated by the fragmentation of substituents. The MacLafferty rearrangement of 3-substituted benz[d]isothiazole-1,1 -dioxides with a proton in the appropriate position resembles the thermal fragmentation28 (cf. Section XII). 

Acids or salts are utilized directly in Stephen s method 166 (iii) reaction with 3-chlorobenz[d]isothiazole-1,1-dioxide (6) (pseudosaccharin chloride3,166). The initial step is presumably formation of 29, followed by Mumm rearrangement. Frequently one obtains pseudosaccharin anhydride (32)25,162 as a by-product. From the reactions with silver acetate and below 3° only A-acetylsaccharin (33) besides 32 was isolated.167 In this context reexamination of the reported 3-O-benzene-sulfonylbenz[d] isothiazole-1,1-dioxide42 and the supposed 3-O-benzoyl... 

The most convenient method for preparing 4 is, however, the reaction of 3-chlorobenz[d ]isothiazole-1,1-dioxide (6) with thiols or alkali thiolates.231 All attempts to rearrange 4 to A-alkylthiosaccharins have failed.17,96 Hydrazinolysis of 4 as well as 3 has been used for preparing 3-hydrazinobenz[djisothiazole-1,1-dioxide (68).160... 

The critical temperature for the thermal rearrangement of 3a under various conditions (in the melt,96 in quinoline20 or naphthalene17) appears to be in the vicinity of 180°. The 3-methoxy derivative (70) isomerizes readily with lithium iodide (in methyl ethyl ketone at 64°).17,96 When ethyl iodide is added to this reaction, i r-methylsaccharin (8) and iV-ethylsaccharin (22) are formed together.96 Lithium iodide catalysis is particularly useful in rearranging nucleoside derivatives, e.g., 71.17 The 3-benzyloxy derivative (73) reacts with debenzylation.17 Even more complex systems like derivatives of steroid alcohols17,20 are isomerized on heating in reasonable yields. When the optically active 3-(2-(cZ)octyloxy)benz[d]isothiazole-l, 1-dioxide was thermally re-... 

All attempts to isomerize 3-alkyl thiobenz [d]isothiazole-1,1 -dioxides (4) in a similar fashion have failed.17,96 This is in agreement with Chapman s findings that sulfur analogs of aryl imidates show little tendency to rearrange.240... 

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