Isothiazole, 1,1-dioxide

The possible structures for isothiazoles are discussed in Section 4.01.1, and attention in this chapter will be directed mainly towards the aromatic systems, as defined in Section 4.01.1. The saturated isothiazole 1,1-dioxides (5) are known as sultams, and bicyclic compounds of structure (6) are called isopenems. Isothiazoles readily coordinate to metals (76MI41703, 78MI41701, 79MI41700, 80MI41701). Coordination usually takes place through the nitrogen atom, but sulfur coordination can occur with soft metals such as cadmium or mercury. Some specific coordination complexes are discussed in later sections. 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Thiophene-1-oxide and 1 -substituted thiophenium salts present reduced aromaticity.144 A variety of aromaticity criteria were used in order to assess which of the 1,1-dioxide isomers of thiophene, thiazole, isothiazole, and thiadiazole was the most delocalized (Scheme 46).145 The relative aromaticity of those molecules is determined by the proximity of the nitrogen atoms to the sulfur, which actually accounts for its ability to participate in a push-pull system with the oxygen atoms of the sulfone moiety. The relative aromaticity decreases in the series isothiazole-1,1-dioxide (97) > thiazole-1,1 -dioxide (98) > thiophene-1-dioxide (99) then, one has the series 1,2,5 -thiadiazole-1,1 -dioxide (100) > 1, 2,4-thiadiaz-ole-1,1-dioxide (101) > 1,2,3-thiadiazole-1,1 -dioxide (102) > 1,3,4-thiadiazole-l,1-dioxide (103) in the order of decreasing aromaticity. As 1,2,5-thiadiazole-1,1-dioxide (100) was not synthesized, the approximations used extrapolations of data obtained for its 3,4-dimethyl-substituted analogue 104 (Scheme 46). 

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). 

Dihydro-4,5-dimethyl-3-(hydroperoxy)-2-[4-(methoxycarbonyl)phenyl]isothiazole 1,1-dioxide (AFUPOG) 1.461 1.417 106.6 97... 

Clerici and co-workers (105,106) investigated the behavior of mtinchnones with an isothiazole 1,1-dioxide and a vinylisothiazole 1,1-dioxide. The initial... 

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 isothiazole-1,1-dioxide 211 has been shown to react with 2 equiv of sodium azide affording the corresponding 4/7-1,2-thiazete carbonitrile 18 accompanied by the [l,2]thiazine carbonitrile 212 and the acyclic sulfamic acid derivative 213 (Equation 21). Prolonged heating of the mixture results only in the formation of the thermally stable 4/7-1,2-thiazete carbonitrile and the 1,2-thiazine carbonitrile <2002T5173>. 

Few examples of substitution reactions on intact heterocycles have been reported. Notable is the synthesis of 3-aminothieno[3,4-d]isothiazole 1,1-dioxides (51) by the fusion of thieno[3,4-d]iso-... 

Dihydro-3-oxothieno[3,4-rf]isothiazole 1,1-dioxide was obtained from methyl 4-sulfamoylthiophene-3-carboxylate in the presence of sodium methoxide (equation 21) (80JOC617). 

Dihydro-3-oxothieno[3,4-artificial sweeteners (thiophenesaccharins). The [3,4-d] isomer is 1000 times sweeter than sucrose and does not have the bitter metallic after-taste of saccharin. 

The reaction of sodium azide with 5-substituted 3-diethylamino-4-(4-methoxyphenyl)-isothiazole 1,1-dioxides afforded [l,2]thiazete 5,5-dioxides 56. It has been proposed that a nucleophilic addition of the azide ion to C-5 followed by ring closure gave a triazoline intermediate, which cyclized intramolecularly with concomitant nitrogen extrusion <02T5173>. 

Metalation of the phenyl-substituted cis-aziridine 25 followed by methyl iodide quench afforded the tricyclic isothiazole 1,1-dioxide 26 as a single diastereoisomer in 75% yield. The reaction was proposed to proceed via metalation of the benzylic position of the aziridine, rather than the position a to the silicon. Subsequent intramolecular attack of the benzylic anion 27 at the tosyl group ortho to the sulfonyl group gave 28 which was trapped with Mel to give the single diastereoisomer 26, whose structure was confirmed by X-ray analysis <02JOC2335>. 

Oxazole chemistry, advances in, 17, 99 Oxazolone chemistry new developments in, 21, 175 recent advances in, 4, 75 Oxidation of monocyclic pyrroles, 15, 67 Oxidative transformations of heteroaromatic iminium salts, 41, 275 3-Oxo-2,3-dihydrobenz[d]isothiazole 1,1-dioxide (saccharin) and derivatives, IS, 233... 

The present review deals with 3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (l)1 (saccharin) and in particular with such derivatives thereof which are formally on the same level of oxidation, e.g., 3-thioxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (2) (thiosaccharin) and the so-called pseudosaccharins (3)-(6)2> 3 which correspond to the lactim form of 1. The topic has been thoroughly reviewed by Bambas in 1952.4... 

NMR studies showed that barriers to rotation exist for 3-dialkyl-aminobenz[d]isothiazole-1,1-dioxides their numerical values, coalescence temperatures, etc., are, however, dependenton the sol vent system.14 From frequency shifts in t.he infrared it is known that vibrations of S-0 bonds15 in sulfonamides, particularly those attributed to antisymmetric (v3) vibrations16 are susceptible to solvent influences. 

From the results of 4H NMR studies14 and X-ray analysis of 712 the conclusion was drawn that the ground state of substituted 3-amino-benz[d]isothiazole-1,1-dioxides is best represented by structures (7a) and (9a). 

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). 

Hauser s approach was extended to cover 1 and 3-oxo-2,3-dihydrobenz-[d]isothiazole-1,1-dioxides with suitable substituents in the phenyl ring by employing iV-<-butylarylsulfonamides.57 The substituted 2-(N-t-butylsulfamoyl)benzoic acids are cyclized and dealkylated in one step by polyphosphoric acid.57... 

Oxo-2-vinyl-2,3-dihydrobenz [d]isothiazole-1,1 -dioxide (N-vinyl saccharin) (24) has been synthesized in various ways, e.g., by transvinyla-tion of vinyl acetate with saccharin (1) in the presence of mercuric sulfate,136 by addition of 1 to acetylene with zinc acetate as a catalyst,136 or by ester pyrrolysis of A-(acetoxyethyl)saccharin.137 19b reacts with ethylene chlorohydrin at 140°-150° to yield Ar-(2-hydroxyethyl)-saccharin (25). The compound is esterified with acetic anhydride and pyrolyzed at 460°-470° to give (24).137... 

Oxo-2-hydroxymethyl-2,3-dihydrobenz [d isothiazole-1,1 -dioxide (21) (A-hydroxymethylsaccharin, m.p. 128°),83,140 is formed in the reaction of saccharin (1) with an excess of formaldehyde in ethanol.83 Earlier work141,142 on 21 reported a melting point of 2250141 indicating... 

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... 

Ozo-2-halo-2,3-dihydrobenz[d]isothiazole-l, 1 -dioxides Free halogen reacts with the saccharin anion (19). The standard procedure for preparing 3-oxo-2-chloro-2,3-dihydrobenz[d]isothiazole-1,1-dioxide (iV-chlorosaccharin) (40) is still passing of chlorine gas through a cold aqueous solution of 19a.173,174... 

---