Of saccharin derivatives

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. 

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>. 

Saccharin is approximately 300 times as sweet as sucrose but can have a bitter after-taste in concentrated solution it is non-calorific, does not contribute to the problem of obesity or tooth decay, and can be used by diabetics as a sugar substitute. Saccharin is stable to heat and so can be used in cooking. A number of saccharin derivatives, e.g. (88a)-(88e), have been synthesised as potential sweetening agents (Figure 12). 

Scheme 95 Synthesis of saccharin derivatives containing a piperidine side chain...

The 3- and 5-hydroxy isothiazoles and the corresponding thiol compounds are either O- and S-or V-alkylated. Hydroxy compounds are readily converted to chloro derivatives. 3-Methoxy groups are reported not to be displaced by nucleophiles <84CHEC-I(6)l3l>, yet both alkoxy groups in a 3,4-diethoxy isothiazole can be displaced (see Section 3.05.7.5). 3-Methoxy-1,2-benzisothiazole and the 3- and 5-alkylthio groups in isothiazoles undergo displacement reactions. New reactions at the carbonyl group of saccharin derivatives have been reported (see Section 3.05.7.5). 

The chlorosulfonation of toluene by treatment with excess chlorosulfonic acid yields a mixture of the ortho and para sulfonyl chlorides, but the mixture may be separated by freezing out the solid p-isomer (see Chapter 4, p 37). Saccharin 25 contains an acidic hydrogen atom and is generally formulated as the sodium salt to increase water solubility. It is some 300 times sweeter than sucrose and is non-calorific so can be used by diabetics as a sugar substitute. A number of saccharin derivatives have been synthesized as potential sweetening agents (Chapter 6, ref. 33). 

Pseudo-saccharin ethers. Pseudo-saccharin chloride (Section VII,26) reacts with alcohols to give ethers (0 alkyl derivatives of saccharin) ... 

Pseudo-saccharin ethers. When pseudo-saccharin chloride is heated with an excess of a phenol, 0-aryl derivatives of saccharin are produced (compare Section 111,27, 7). 

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°. 

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. 

Both Watts and sulfamate baths are used for engineering appHcation. The principal difference in the deposits is in the much lower internal stress obtained, without additives, from the sulfamate solution. Tensile stress can be reduced through zero to a high compressive stress with the addition of proprietary sulfur-bearing organic chemicals which may also contain saccharin or the sodium salt of naphthalene-1,3,6-trisulfonic acid. These materials can be very effective in small amounts, and difficult to remove if overadded, eg, about 100 mg/L of saccharin reduced stress of a Watts bath from 240 MPa (34,800 psi) tensile to about 10 MPa (1450 psi) compressive. Internal stress value vary with many factors (22,71) and numbers should only be compared when derived under the same conditions. 

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

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

For example, if saccharin (33) is methylated in benzene suspension, then only iV-methylsaccharin is isolated. If an ethereal saccharin solution is added to a concentrated solution of diazomethane in excess, then 10% of 0-methylsaecharin (34) can be detected in addition to the A"-raethy] derivative. Finally, if the diazomethane solution is gradually added to a saturated ethereal solution of saccharin, the proportion of 0-methylation increases to 24%. " ... 

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. 

Two new pyridone derivatives (14) and (15) have been prepared by cycloaddition of saccharin pseudochloride (16 R = Cl) with Danishefsky s diene and by treatment of (16 R = Me) with ciimamoyl chloride. The synthesis of two more ting expanded derivatives (17) and (18) via cycloaddition to benzisothiazoles was also described <96T3339>. 

Moncrief summarized the work of Cohn and the information in the early literature. As early as 1923, it was known that rupture of the heterocyclic ring, as well as substitution of the imino hydrogen atom, results in the loss of sweetness. Thus, o-carboxybenzenesulfonamide and N-alkyl derivatives of saccharin are tasteless. This loss of sweetness would be expected, as the NH group is the only proton-donor function available in the molecule. 

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 saccharinic acids formed from hexoses have been especially examined because of the relationships of the a and /8 isomers (C-2 epi-mers). Structures of saccharinic acids derived from D-glucose are glu-cometasaccharinic acid (51), glucoisosaccharinic acid (52), and glucosaccharinic acid (53). The a- and /3- isomers of metasaccharinic acid can reversibly isomerize when exposed to base because of the labile proton at C-2. 

Every patient with diabetes requires some form of dietary assessment, and often therapy. This is important to allocate the relative amounts of energy derived from carbohydrate, protein and fat of total recommended daily calories in proportion to the patient s body weight and height and daily requirements, while avoiding atherogenic diets. Diets with high carbohydrate content (50-60%), low fat (30-35%) and adequate protein (10-15%) is recommended. Fibre-rich foods are preferable. The use of non-nutritive sweeteners (saccharin, aspartame, ace-sulfame K and sucralose) are acceptable. Alcohol intake should be assessed since excess consumption... 

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 separation of saccharinic acids as their O-trimethylsilyl derivatives has also been used by Feather and Harris512 in a study on decomposition of sugars and in studies on bacterial polysaccharides.434... 

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