Saccharin 1,1-dioxide

Acesulfame-K. Acesulfame-K [55589-62-3] (4), the potassium salt of acesulfame [33665-90-6] (6-methyl-l,2,3-oxathiaziQ-4(3ff)-one 2,2-dioxide), is a sweetener that resembles saccharin in stmcture and taste profile. 5,6-Dimethyl-l,2,3-oxathiazine-4(3ff)-one 2,2-dioxide, the first of many sweet compounds belonging to the dihydrooxathia2inone dioxide class, was discovered accidentally in 1967 (63). From these many sweet compounds, acesulfame was chosen for commercialisation. To improve water solubiUty, the potassium salt was made. Acesulfame-K (trade name Sunette) was approved for dry product use in the United States in 1988 and in Canada in October, 1994. Later, it was approved by the FDA for additional food categories such as yogurts, frosen and refrigerated desserts, and baked goods. 

Saccharin. Saccharin [81-07-2] 3-oxo-2,3-dihydro-l,2-ben2isothia2ole 1,1-dioxide (i9-sulfoben2imide or (9-ben2osulfimide), (5) was accidentally discovered to be a sweet compound in 1878. A pilot plant was set up in New York to manufacture saccharin, which was displayed in a London exposition in 1885 (70). Since that time, saccharin has been used in many parts of the world. 

Many analogues of saccharin have been synthesized since its discovery. With the exception of one compound, thieno[3,4-i/ isothiazolone dioxide [59337-79-0] lOOOX, this effort has not generated more potent compounds. Acesulfame-K could be considered a ring-modification derivative of saccharin, however. 

Benzisothiazoles suffer straightforward ring cleavage, but their 1,1-dioxides, 2,1-benzisothiazoles and derivatives of saccharin give products containing no sulfur. 

Benzisothiazoles also suffer N—S bond cleavage, following attack at sulfur, but 1,2-benzisothiazole 1,1-dioxides are cleaved at the C—N bond. Saccharin derivatives are attacked at the carbonyl function. In cases where N—S bond cleavage occurs, recyclization can sometimes occur, often producing thiophene compounds. 

Few isothiazoles undergo simple cycloaddition reactions. 4-Nitroisothiazoles add to alkynes (see Section 4.17.7.4). With 5-thiones (84) and dimethyl acetylenedicarboxylate, addition to both sulfur atoms leads to 1,3-dithioles (85) (77SST(4)339, 80H(14)785, 81H(16)156, 81H(16)595). Isothiazol-3-one 1-oxide and the corresponding 1,1-dioxide give normal adducts with cyclopentadiene and anthracene (80MI41700), and saccharin forms simple 1 1 or 1 2 adducts with dimethyl acetylenedicarboxylate (72IJC(B)881). 

When saccharin is treated with diethyl phosphorothiolothionate, the 3-ethylmercapto compound is obtained, rather than the expected organophosphorus compound (77 ACS(B)460). Treatment of saccharin with phosphorus pentoxide and amines gives 3-(substituted-amino)-1,2-benzisothiazole 1,1-dioxides, via an intermediate phosphate (81ZN(B)1640). Reduction of saccharin with zinc and hydrochloric acid gives 2,3-dihydro-l,2-benzisothiazole 1,1-dioxide, the method being used to estimate saccharin in foodstuffs (75MI41701). 

Benzisothiazole 1,1-dioxides and saccharin derivatives are best prepared by cyclization of o-substituted benzenesulfonamides (see Section 4.17.9.1.2). 

Structurally related to saccharin are the oxathiazinone dioxides (104). Clauss and coworkers synthesized a series of these compounds, and demonstrated that they possess intense sweetness. Acesulfame-K, the potassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazin-4-one 2,2-dioxide (104) has a sweetness intensity 130 times that of sucrose. 

Chiral A-substitutcd benzisothiazole-3-one-1,1-dioxide (saccharin) derivatives 258 are synthesized via the direct ortho-lithiation of 3-A-arylsulfonyloxazolidine-2-ones 257 using LDA and HMPA <06TL6405>. Compounds 257 are readily prepared from (X)-amino acids. 

Saccharin is l,2-benzisothiazol-3(2H)-on-1,1-dioxide, often also called o-benzoic acid sulfimide. Discovered in 1878, it is the oldest available intense sweetener. 

Soil. In unsterilized soils, 58% of C-labeled sulfometuron-methyl degraded after 24 wk. Metabolites identified were 2,3-dihydro-3-oxobenzisosulfonazole (saccharin), methyl-2-(amino-sulfonyl) benzoate, 2-aminosulfonyl benzoic acid, 2-(((aminocarbonyl)amino)sulfonyl) benzoate, and [ C]carbon dioxide. The rate of degradation in aerobic soils was primarily dependent upon pH and soil type (Anderson and Dulka, 1985). The reported half-life in soil was approximately 4 wk (Hartley and Kidd, 1987). 

Chemical/Physical Sulfometuron-methyl is stable in water at pH values of 7 to 9 but is rapidly hydrolyzed at pH 5.0 forming methyl-2-(aminosulfonyl) benzoate and saccharin. When sulfometuron-methyl in an aqueous solution was exposed to UV light (k = 300-400 nm), it degraded to the intermediate methyl benzoate which then mineralized to carbon dioxide (Harvey et ah, 1985). 

Piroxicam Piroxicam, 1,1 -dioxid-4-hydroxy-2-methyl-iV-2-pyradyl-2//-1,2-benzothiazine-3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). Two methods for saccharin synthesis are described. It usually comes from toluene, which is sulfonated by chlorosulfonic acid, forming isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride (3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted with ammonia, giving 2-toluenesul-fonylamide (3.2.69). Oxidation of the product with sodium permanganate or chromium (VI) oxide in sulfuric acid gives saccharin—o-sulfobenzoic acid imide (3.2.70) [123-126]. 

The percarboxylic acid proton of 3-oxo-l,2-benzisothiazole-2(377)-peroxypropanoic acid 1,1-dioxide (51) (Pnma, 0—0 = 1.469, C—O—O—H = 180.0°) was located on the difference Fourier map . Hydrogen bonding in the peracid 51 (Figure 22) occurs from the peracid proton to the carbonyl O of the saccharin entity (O O = 2.618 A) to provide chains of peracid molecules that are stacked via additional C—H O contacts (not shown in Figure 22) in sheets along the b axis. 

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. 

The use of chiral A-acylated sultams 1 as auxiliaries for diastereoselective alkylation and related reactions has emerged as a useful and versatile method for the construction of chiral compounds. Both enantiomers of 10.10-dimethyl-4-a2a-3-thiatricyclo[S.2.1,0 -5]decane 3,3-dioxide (bomane-10,2-sultam) have been employed1-6 and are now commercially available. A chiral sultam prepared from saccharin has also been used for a variety of asymmetric transformations8,9. 

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