Ketosulfonic acids

Ethyl stearate added with stirring at 0° under Ng to 2 equivalents of a ca. 1 M soln. of methylsulfingl carbanion (prepn. s. Synth. Meth. 17, 895) in dimethyl sulfoxide-tetrahydrofuran, allowed to warm to room temp, over 30 min., then water added j6-ketosulfoxide (Y > 98%) stirred and refluxed 60-90 min. with Al-amalgam in tetrahydrofuran containing 10% water n-heptadecyl methyl ketone (Y > 98%). F. e. also ketones from -ketosulfones and )6-ketosulfonic acid amides by the same reduction method, s. E. J. Gorey and M. Chaykovsky, Am. Soc. 86, 1639 (1964). 

Ketones containing sulfur or nitrogen atoms bound to a-carbons suffer carbon-sulfur or carbon-nitrogen bond cleavage under the conditions of the Clemmensen reduction [159, 864 (p. 118). A ketosulfone was reduced to a sulfone-alcohol with zinc in refluxing 80% acetic acid in 70% yield [920]. 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

Three-component treatment of ketosulfones and related CH-acids with aldehydes and 5-aminopyrazoles was also patented by Han and Hu [74]. They used stirring of the starting materials in THF at 70°C and HPLC purification to synthesize biologically active pyrazolopyrimidines containing sulfonic group. 

Esters of chlorodifluoroacetic acids, like the esters of monofluoroacetic acid, can acylate anions (e.g., organometallic derivatives, enolates, lithiated sulfones). They lead to chlorodifluoromethylketones and to S-ketosulfones and jS-ketoesters which have the —CFj motif (Figure 2.16). ... 

The reaction of 6-methylpyridine-3-carboxylic acid methyl ester with N,0-dimethylhydroxylamine and isopropyl-magnesium chloride in toluene gives the N-methoxyamide derivative (x), which is reduced with diisobutyl aluminium hydride (DIBAL) to afford 6-methylpyridine-3-carbaldehyde (xi). The reaction of the aldehyde (xi) with a phosphite provides the diphenyl phosphonate derivative, which is condensed with 4-(methylsulfonyl)benzaldehyde in the presence of potassium fe/f-butoxide in HF to yield the enimine (xii). Finally, this compound is hydrolyzed with HCI to yield the ketosulfone (ix). 

Alternatively the oxidation of 4 -(methylsulfonyl) acetophenone with S8 and morpholine produces the 2-(4-(methylsulfonyl)phenyl)acetic acid ethyl ester (xiv), which is condensed with 2-methylpyridine-3-carboxylic acid methyl ester by means of terf-butyl magnesium chloride in hot tetrahydrofurane to give the ketosulfone (ix). 

Reaction of the ketosulfone (ix) with 2-chloro-1,3-bis(dimethylamino)trimethinium salt (xix) in the presence of an equimolar amount of tert-BuOK followed by treatment with acetic acid and TFA and reflux with an excess of ammonium hydroxide. 2-Chloro-1,3-bis(dimethylamino)trimethinium hexafluoro-phosphat (xix) is obtained by reaction of chloroacetic acid with hot dimethylformamide and POCI3. Finally the reaction mixture is treated with NaOH and hexafluorophosphoric acid in water. 

Elimination of sulfinic acid from ketosulfones was also a key step in an expedient synthesis of a,0-unsaturated ketones via the Michael adducts of sulfonyl carbanions to nitroalkenes. Conversion of the resulting nitronates into ketones was most conveniently realized by ozonolysis. DBU-promoted elimination of sulfinic add completed the process. Overall yields range from 71 to 88% for the examples reported [425]. 

Other Reducing Agents. 1,4-Dihydropyridines have been successfully employed for the reductive desulfonylation of functionalized sulfones. Of special interest is the desulfonylation of a-nitro sulfones with BNAH under sunlight irradiation to give the corresponding nitro compounds in good yields.90,91 The reaction takes place under mild conditions and tolerates ketones, nitriles, and isolated double bonds (Eq. 120).91 A photo-induced electron-transfer employing ascorbic acid as electron donor is also an efficient approach for the reductive desulfonylation of (3-ketosulfones.197... 

Aoai, Y. Aotani, A. Umehara, and T. Kokubo, Apphcation of silylether and silylester polymer for chemical amplification system, J. Photopolym. Sci. Technol 3, 389 (1990) M. Tsunooka, H. Yanai, M. Kitayama, and M. Shiraj, Photo initiated acid formation and its applications the acid formation mechanism in photolysis of p ketosulfones inpolymer matrices, J. Photopolym. Sci. Technol. 4, 239 (1991). 

Asymmetric reduction of the ketosulfone (490) has been tried under three different protocols (i) (—)-B-chlorodiisopinocamphenylborane, (ii) yeast reduction, and (iii) borane reduction catalyzed by chiral 1,3,2-oxazaborolidine. Of these, the third method gave the best results for large-scale process development <92JHC627>. The product (491) could be converted to (492) by tosylation and subsequent displacement of the —OTs group by isobutylamine (Scheme 100). This was then sulfonated (oleum) to yield a 90 10 mixture of the 2- and 3-sulfonic acids. 

Davies et al. have described a new synthetic strategy to obtain the Cox-2 specific inhibitor 251. They heated a mixture of chloromalonaldehyde 249, ammonium acetate, and ketosulfone 250 with propionic acid at 125°C. Pyridine 245 is produced in 62% yield together with furan impurity 252 in approximately 15% yield (Scheme 51) (OOJOC8415). 

Potassium tert-butoxide/dimethylsulfoxide j -Ketosulfones from carboxylic acid esters... 

N2O2SC a-Diazosulfones a-Ketosulfone hydrazones Monosulfonylcarbodimides Sulfonylamidines Sulfonic acid amidines 5 N-Sulfonylformamidines 20 N -Sul fony Icyanamides Sulfonylformaldehyde hydrazones Sulfonylhydrazones Thiourea S-dioxides... 

Selective hydrolysis s. 19, 27 a-Ketosulfone hydrazones from a-azo- -ketosulfones Japp-Klingemann cleavage also ring opening s. 19, 28 Garbamyl disulfides from dithioformimidic acid esters s. 16,626... 

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