Saccharin derivatives

The melting points of some 0-aryl saccharin derivatives are phenol, 182° o-cresol, 163° m-cresol, 146° p-cresol, 172° o-nitrophenol, 236° p-nitrophenol, 192°. 

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. 

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

The most widely used variant of the Gabriel-Colman is the conversion of saccharine derivatives to benzothiazine derivatives. The reaction has been extensively studied as benzothiazines are important pharmacophores, particularly in the oxicam class of antiinflammatories. The first reported instance of this transformation was in 1956 where 43 was treated with sodium methoxide to provide 44. The rearrangement also works with esters " and some amides " in addition to ketones. 

The mechanism of this variant of the Gabriel-Colman reaction has been investigated. Treatment of saccharine derivatives 45-48 with 1-2 equivalents of sodium alkoxide at room temperature provides esters 49-52 in good yields treatment of 45-48 with sodium alkoxide at reflux provides the expected benzothiazines 53-56. Increased concentration leads to higher yields. 

When the related saccharin derived sultam (R)-29 is converted into the (Z)-boron enolate and subsequently treated with aldehydes,. vy -diastereomers 30 result almost exclusively. Thus, the diasteromeric ratios, defined as the ratio of the major product to the sum of all other stereoisomers, surpass 99 1. Hydroperoxide assisted saponification followed by esterification provides carboxylic esters 31 with recovery of sultam 32106a. 

Bode and co-workers have used NHCs to form y-butyrolactams 34 from enals 27 and saccharin-derived cyclic sulfonylimines 32. A range of [3-alkyl and [3-aryl substituted enals, and a variety of substituted imines, are tolerated in this reaction,... 

Bode and co-workers have demonstrated the application of such substrates in a number of reactions, including cyclopentene ring formation and y-lactamisation [15]. For example, y-lactamisation to give 56 with saccharin-derived sulfonylimines 54 was achieved from a-hydroxyenone 53 with moderate to excellent stereocontrol (Scheme 12.10). 

Bode and co-workers have extended the synthetic ntility of homoenolates to the formation of enantiomerically enriched IV-protected y-butyrolactams 169 from saccharin-derived cyclic sulfonylimines 167. While racemic products have been prepared from a range of P-alkyl and P-aryl substitnted enals and substitnted imi-nes, only a single example of an asymmetric variant has been shown, affording the lactam prodnct 169 with good levels of enantioselectivity and diastereoselectivity (Scheme 12.36) [71], As noted in the racemic series (see Section 12.2.2), two mechanisms have been proposed for this type of transformation, either by addition of a homoenolate to the imine or via an ene-type mechanism. 

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. 

Various saccharin derivatives 260 have been prepared by chromium (VI) oxide catalyzed H5IO6 oxidation of substituted ort/ro-toluenesulfonamides 259 <06T7902>. The reaction presumably proceeds through a benzylic radical intermediate 261 generated from the... 

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. 

Nitro- benzoate °C Phenyl- urethan °C 1- Hydrogen Naphthyl- 3-nitro-urethan phthalate °C °C O-Alkyl Other saccharin derivatives °C °C ... 

O-Aryl saccharin derivatives of o-nitrophenol and p-nitrophenol have m.p.s. 236 °C and 192 °C respectively. 

Based on dilution in distilled water to threshold sweetness 1 is about 300 times as sweet as sucrose.30 Results with about 80 saccharin derivatives indicate that substitution in the 2- or 3-position gives tasteless compounds.82 Exceptions are Mannich bases (20) and 3-oxo-2-hydroxy-methyl-2,3-dihydrobenz[d]isothiazole-l,1-dioxide (21) which possess a... 

An alternative and surprising transformation to the 2//-azepin-2-one system has been noted on reaction of DBU, normally regarded as non-nucleophilic, with saccharin derivatives <03SC1937>. 

Syn-aldol derivatives may also be obtained directly from bo-ryl enolates of the same M-acyl-a-methyltoluene-2,a-sultams by condensation with aliphatic and aromatic aldehydes (eq 4). The high C(a)-it topicity of these reactions parallels but exceeds that when using the 10,2-camphorsultam auxiliary and is the result of an analogous transition state. It is noteworthy, however, that al-dolizations of a-methyltoluene-2,a-sultam derivatives generally proceed to completion with just a small excess of aldehyde (1-1.2 equiv, cf. 2-3 equiv when 10,2-camphorsultam mediated). This may be ascribed to the lack of acidic protons a to the SO2 group in the Saccharine-derived auxiliary. 

In 1,1-dioxides, loss of SO2 occurs in different fragmentation pathways and McLafferty rearrangement dominates the fragmentation of suitable 3-alkyl derivatives. The fragmentation of N-substituted saccharin derivatives was discussed in CHEC-II(1996) and is dominated by loss of SO2 <1996CHEC-II(3)319>. 

IR spectra of saccharin derivatives 46-48 present the amide-1 and amide-2 bands at high values (1740-1690 and 1715-1690 cm respectively) <2001JML223>. 

The oxidation of 2-methylbenzenesulfonamide is a known method affording saccharin derivatives. Sodium dichromate in sulfuric acid has been proposed as the most efficient oxidation system <2003CHE119>. 

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