Thiols from sulfonamides

The synthesis of alkynyl sulfides from sulfonamides using potassium thiolate salts generated moderate yields of the alkynyl sulfides after only a few minutes (Scheme 5.68) [107]. The synthesis was carried out in two stages. The first step entailed the synthesis of thiolate anions through the addition of potassium hydride to solutions of the thiol. The addition of the sulfonamide along with dimethylamine comprised the second step. While the role of the amine was not fully elucidated, it was needed for a successful conversion as its absence led to poor conversions. There is a level of operational complexity to this approach since potassium hydride needed to be handled in the first step of the synthesis. 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

General Reaction Chemistry of Sulfonic Acids. Sulfonic acids may be used to produce sulfonic acid esters, which are derived from epoxides, olefins, alkynes, aHenes, and ketenes, as shown in Figure 1 (10). Sulfonic acids may be converted to sulfonamides via reaction with an amine in the presence of phosphoms oxychloride [10025-87-3] POCl (H)- Because sulfonic acids are generally not converted directiy to sulfonamides, the reaction most likely involves a sulfonyl chloride intermediate. Phosphoms pentachlotide [10026-13-8] and phosphoms pentabromide [7789-69-7] can be used to convert sulfonic acids to the corresponding sulfonyl haUdes (12,13). The conversion may also be accompHshed by continuous electrolysis of thiols or disulfides in the presence of aqueous HCl [7647-01-0] (14) or by direct sulfonation with chlorosulfuric acid. Sulfonyl fluorides are typically prepared by direct sulfonation with fluorosulfutic acid [7789-21-17, or by reaction of the sulfonic acid or sulfonate with fluorosulfutic acid. Halogenation of sulfonic acids, which avoids production of a sulfonyl haUde, can be achieved under oxidative halogenation conditions (15). 

Endothelin receptor antagonists 134 and 135 were prepared from the triflated oxicam derivative 136 (Scheme 18) <1998BMC1447>. Addition of aryl thiol 137 to the position gave product 134. Palladium-catalyzed Suzuki coupling of aryl boronic acid 138 and aryl triflate 136 affords the sulfonamide product 135. 

Chlorobenz[d]isothiazole-l, 1-dioxide ( pseudosaccharin chloride ) (6)3,24.25, lee, 25i, 26i, 262 displays the reactivity of a cyclic imidoyl chloride263 resembling very much carboxylic acid halides. In previous sections preparation of 3, 4, 5, 13, 68, 86, 89 from 6 has been mentioned. Derivatives of 6 substituted in the phenyl ring have been described.250 Interestingly, Meadow observed231 that crude 6 and material that contained phosphorus pentachloride reacted with thiols more readily than the pure compound. In the reaction of 6 with aromatic sulfonamides, aluminum chloride had been added for activation.252... 

Glutamylcysteine synthetase, cysteine, or methionine was 100 times more reactive to hypochlorous acid in comparison with amino acids that did not contain thiol groups (Folkes et al., 1995). Sublethal exposures to HOCl decreased GSH levels in several cell types (Vissers and Winterboum, 1995 Pullar et al., 1999). In a study by Pullar et al. (1999) using human umbilical vein endothelial cells, doses of 25 nmol of HOCl and less were sublethal when the exposure was done over 10 min, there was a concentration-dependent loss of intracellular GSH. Tissue exposure to HOCl resulted in a reduction of GSH. The metabolite of the HOCl interaction with GSH was an unexpected cyclic sulfonamide that was exported from the cell. The expected metabolites of glutathione disulfide (GSSH) and GSH sulfonic acid were actually minimal (Pullar et al., 2001). Inactivation of acetylcholinesterase by HOCl could be a contributory cause of airway hyperreactivity (den Hartog et al., 2002). 

Active hydrogen compounds such as alcohols, thiols, amides, urethans, and sulfonamides can be alkylated by N-vinyl-amides, -urethans, or -sulfonamides in high yields. A one-step conversion of ar. nitro compounds to isocyanates has been reported Aliphatic isothiocyanates can be prepared from amines and carbon disulfide with dicyclohexylcarbodiimide under remarkably mild conditions... 

Literature survey reveals that the Michael addition reaction is highly accelerated in IL. Copper(II)triflate immobilized in [bmimJBF IL is used as reaction medium for Michael addition of p-ketoesters to alkenes [10,11]. [bmim]OH has been used in Michael addition of active methylene corrtpotmds to corrugated ketones, carboxylic esters, and nitriles [12]. Michael addition of thiols and thiophosphate to conjugated alkenes in IL [pmim]Br [13] has been reported. Conjugate addition of azide ion to a,p-unsaturated carbonyl compoimds and aza-Michael addition reactions are also reported [14-17]. Recently, Zare et al. [18] reported MW-assisted aza-Michael addition of aromatic sulfonamides to various a,P-unsatirrated esters [ 19] in the presence of a catalytic amount of MgO or ZnO with [bmim]Br as the reaction solvent. Aryl nitriles can be synthesized via the Rosenmimd von Braim reaction from the corresponding hahdes in IL imder MW [20]. 

Preparation of sulfonamide 4 A mixture of thiol compound (1 2 mmol), 30% hydrogen peroxide (6 mmol, 0.6 mL) and thionyl chloride (2 mmol, 0.14 mL) was stirred in acetonitrile at room temperature for an appropriate time. After completion of the reaction as indicated by TLC, a solution of amine (3 2 mmol) in pyridine (1 mL) was added to the reaction mixture. The resulting mixture was then continued to stir at room temperature until completion of the reaction. On completion of the reaction, the resulting mixture was acidified with 2 N HCl solution, and extracted with EtOAc. The organic layer was washed with water and brine, and dried over magnesium sulfate. The filtrate was evaporated to obtain pure sulfonamide derivative 4 crystalline solid. Recrystallization from a mixture of ethanol and water afforded analytically pure product. AU the products were characterized by analytical and spectral studies. 

Alternatively, heteroaryl sulfonamides may be prepared from thiols hy S-N bond formation followed by oxidation (Scheme 13.7). Standard conditions utilise chloramines as iV-electrophiles to provide the corresponding sulfe-namides, followed by oxidation with mCPBA or potassium permanganate to afford the sulfonamides. Likely due to thermal hazard implications, this approach has seen limited use however, it has been employed on large scale in the preparation of topically active carbonic anhydrase inhibitors (Scheme 13.8). ... 

Scheme 13.5 Synthesis of heteroaryl sulfonamides from thiols.

In summary, sulfonamides are most commonly prepared by the reaction of amines with sulfonyl halides. Aryl sulfonyl chlorides may be accessed from C-H bonds by chlorosulfonylation, from C-S bonds by oxidation, from C-N bonds by diazotization, or from C-X bonds by metalation. Approaches to all l sulfonamides are more limited as they are typically prepared by either oxidative chlorination of thiols or addition of organometallic nucleophiles to sulfur electrophiles. Traditional sulfonamide preparation has frequently necessitated harsh reagents and conditions, but the development of Pd-catalysed approaches and discovery of new sulfur dioxide sources allow for operationally simple sulfonamide synthesis under mild conditions. Future directions in sulfonamide synthesis will likely involve the direct C-H installation of sulfonamides without the use of hazardous reagents. 

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