Acyl sulfonamides

Methyl pyrazine-2-carboxylic acid is refluxed with thionyl chloride in anhydrous benzene for approximately 12 hours. Benzene and thionyl chloride excess is removed by distillation. Then some anhydrous dioxane is added and this acid chloride solution is allowed to drop into p-(/3-aminoethyl)-benzenesulfonamide suspension in dioxane and anhydrous pyridine. The resulting mixture is then refluxed for 3 hours. Dioxane is removed by distillation and then the residue is washed with water and acetic acid. The raw acylated sulfonamide is then filtered and crystallized from 95% ethanol, thus obtaining a product of MP 200 to 203 C. 

Acyl sulfonamides have been reduced (RC0NHS02Ph-... 

After the initial reports of the antiviral efficacy of BILN 2061 a large number of reports disclosing macrocyclic (Figure 2.10) [71, 119-124] and acyclic (Figure 2.11) [125-135] analogues have appeared. For some of these compounds an acyl sulfonamide has been also reported at the C-terminus. 

Particularly, some newly developed drags, which incorporate the N-acyl sulfonamide moiety [8-10], are synthesized from the parent sulfonamides, by their coupling with acid chlorides or carboxylic anhydrides in basic conditions [11-15]. Unfortunately all these methods lead to substantial waste products. Less common reports mentioning this transformation under acidic conditions (Bronsted or Lewis acids) do not systematically examine the purpose and limitations of the reaction [16]. 

As an extension to thep-carboxybenzenesulfonamide safety-catch linker [43,44], alkanesulfonamide handle 37 was developed [45]. This linker tethers carboxylic acids to the solid support to give an acylated sulfonamide which is stable to both basic and acidic conditions (Scheme 12). Products were released by treatment with iodoacetonitrile followed by the addition of a nucleophile. 

The stability of these compounds is maximal at pH 4 - 6, and decreases very sharply at lower and higher pH values, and the mechanism and products of the reaction differed with pH. In the neutral range, hydrolysis yielded the aromatic sulfonamide and the ester, whereas, under acid catalysis in the low pH range, the products were the AT-acyl sulfonamide and an alcohol (R OH, Fig. 11.9). Of particular interest is that the tm values for hydrolysis of the N-sulfonyl imidates in 80% human plasma were 3-150 times lower than in buffer solution at identical pH and temperature. This was taken as evidence for enzymatic hydrolysis by human plasma hydrolases. Hydrolysis under these conditions yielded the sulfonamide and the ester in quantitative amounts. 

Microwave irradiation was also successfully used to synthesize 26 different acyl sulfonamides through carbonylation of sulfonamides with (hetero)aryl halides in only 15 min, using Pd(OAc)2 as catalyst and Mo(CO)6 as source of... 

Acyl sulfonamides have been reduced (RCONHSCLPh — RCFLNHSCLPh) with BH,-SMe,.550... 

Addition of sulfonamides to olefins 9-39 Reduction of acyl sulfonamides 9-53 Reduction of sulfonyl azides... 

A quaternary ammonium hydroxide ion exchange resin 6 was shown to sequester phenols, hydroxypyrazoles, and other weakly acidic heterocycles.25 The sequestered nucleophiles could also be used as polymer-supported reactants. Similarly, the guanidine-functionalized resin 7 was also shown to be a useful capture agent for weakly acidic nucleophiles, including phenols and cyclic iV-acyl sulfonamides.26... 

Acidic ionizable center (negatively charged at physiological pH of about 7) (e.g., carboxylic acid, unsubstituted tetrazole, acyl sulfonamide)... 

Griswold, K S, Horstmann, T E, Miller, S J, Acyl sulfonamide catalysts for glycosylation reactions with trichloroacetimidate donors, Synlett, 1923-1926, 2003. 

Symmetrical A-sulfonyl sulfonamides, i.e., sulfonimides, can be prepared from the amine and two equivalents of sulfonyl chloride and base. The unsym-metrical A/-sulfonyl sulfonamides and the related A-acyl sulfonamides can be obtained by the reaction of a sulfonamide or carboxamide with an acid halide. 

M o o H " V Acyl-sulfonamides Glycine, GABA, and p-alanine analogs Antiatherosclerotics pKj, 4,5 Adrenergic receptor agonist hepatitis C virus Drummond and Johnson Albright et alP Uehling el alP Johansson et alP )... 

Johansson, A., Poliakov, A., Akerblom, E., Wiklund, K., Lindeberg, G., Winiwarter, S., Danielson, U. H., Samuelsson, B., Hallberg, A. Acyl sulfonamides as potent protease inhibitors of the hepatitis C virus full-length NS3 (protease-helicase/NTPase) a comparative study of different C-terminals. Bioorg. Med. Chem. 2003, 77(12), 2551-2568. 

L. M., McCann, D. J., Molero, V., Reilly, J. E., Richett, M. E., Shih, C., Teicher, B., Wikel, J. H., White, W. T., Mader, M. M. Acyl sulfonamide anti-prolrferatives benzene substituent structure-activity relationships for a novel class of antitumor agents. J. Med. Chem. 2004,47(22), 5367-5380. 

Z., Reilly, J. E., Dinn, S. R. Acyl sulfonamide anti-prohferatives. Part 2 activity of heterocycUc sulfonamide derivatives. Bioorg. Med. Chem. Lett. 2005, 75(3), 617-620. 

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