Aryl sulfonyl chlorides

Diaryl sulfones can be formed by treatment of aromatic compounds with aryl sulfonyl chlorides and a Friedel-Crafts catalyst. This reaction is analogous to Friedel-Crafts acylation with carboxylic acid halides (11-14). In a better procedure, the aromatic compound is treated with an aryl sulfonic acid and P2O5 in polypho-sphoric acid. Still another method uses an arylsulfonic trifluoromethanesulfonic anhydride (ArS020S02CF3) (generated in situ from ArS02Br and CF3S03Ag) without a catalyst. ... 

Reaction of 3-phenyl-1,2,4-thiadiazole-5-thiol (10) (R = Ph) with formaldehyde and with aryl-sulfonyl chlorides leads to N-4 derivatives (26) and (27) (Scheme 8) <89MI 408-01 >. 

Arylsulfonyl chlorides are reduced by zinc dust and sulfuric acid at 0° to give high yields of thiophenols Tin and hydrochloric acid and a mixture of phosphorus, potassium iodide, and phosphoric acid have also been used. Preliminary experiments with lithium aluminum hydride on both alkyl- and aryl-sulfonyl chlorides gave 45 50% yields of mercaptans. Halogen atoms on the benzene ring are stable during the reduction. ... 

Similar reactions occur with a-chloromercury ketones. Reactions of type (a) are less representative than those of type (b) acyl chlorides, aryl sulfonyl chlorides, and dialkylchlorophosphites react according to type (b) and display reaction site transfer. Is this a result of keto-enol tautomerism ( mercurotropy ) Can metallotropic tautomerism occur Or, alternatively, can the ambivalent behavior be explained by reaction site transfer, which in this case involves the a, 77-conjugated system ... 

Acylation of 2-pyrazolin-5-ones having no substituent at N-l occurs readily with such agents as acetyl chloride,1499,1598 acetic anhydride,1499,1598 benzoyl chloride1056,1598 and aryl sulfonyl chlorides.1199 The usual product is a l-acyl-2-pyrazolin-5-one, but acylation may also occur on oxygen, or both on oxygen and at N-2.1598... 

Polymer-supported sulfonyl chlorides can be used for the selective monosulfonyl-ation of anilines, as demonstrated by the Ley group [71, 72], Commercially available polystyrene-DMAP (4-dimethylaminopyridine) was treated with different aryl sulfonyl chlorides to form polymer-bound sulfonylation reagents. These were reacted with substituted anilines to form an array of hydroxamic acids (Scheme 6.17), using a synthetic strategy involving polymer-bound reagents in all steps. The products were subsequently evaluated as histone deacetylase inhibitors. 

Aliphatic and aryl sulfonyl chlorides can be cleaved thermally to the alkyl or aryl chlorides and S02, although there are usually side reactions that often... 

There is a great deal of difierence in the reactivity of different acid chlorides thhse derived from aromatic aCMs react much more slowly than those from aliphatic acids, and aryl sulfonyl chlorides react even more slowly. Thus, when benzoyl chloride is dissolved in an excess of ethyl alcohol and kef>t at 0 G, 4 hr is required for complete reaction, but acetyl chloride reacts practically instantly. To speed up the reaction of a sluggish acid chloride, the mixture may be heated, or the Schotten-Bauihann method may be used [Reaction (17)], i.e., the alcohol or phenol is mixed with 10 or even 25 per cent sodium hydroxide solution, and the acid chloride is added slowly with dgorous agitation, while the temperature of the mixture is kept at or below 0°G. Instead of aqueous alkali, anhydrous tertiary amines may be used. The cold reactants are mixed, but the mixture may be heated later. 

Numerous examples of acylation at C-3 have appeared. Reactions have been carried out with acid anhydrides <92CPB631>, acid halides <86CPB2833, 85MI 8l0-0i>, aryl sulfonyl chlorides <93JMC1425> and under Vilsmeier-Haack conditions <93H(35)915>. Yields were generally better, and the required conditions milder, when C-2 carried an electron-releasing group. No reaction occurred when ethyl 2-pyrazolo[l,5-a]pyridinecarboxylate was heated with benzoyl chloride <93H(35)915>. 

Aroyl chlorides and aryl sulfonyl chlorides can also be employed as arylating agents under decarbonylative and desulfitative conditions respectively. Improved yields were reported by Dubbaka and Vogel [64] using Herrmann s palladacycle [63], arenesul-fonyl chlorides and bulky trioctylmethylammonium chloride under reflux conditions (Figure 3.11). 

While other more costly catalysts such as a variety of palladium salts also enabled direct 2-sulfonylation of the quinoline A/-oxides, the copper salts are more flexible and inexpensive. While a number of aryl sulfonyl chlorides coupled with quinoline N-oxides and isoquiniohne-AT-oxide, related compounds (N-oxides of pyridine and pyrazines) failed to react under these conditions. 

Miscellaneous Transformations. Cyanotrimethylsilane effects the transformation of acyl chlorides to acyl cyanides, a-chloro ethers and a-chloro thioethers to a-cyano ethers and a-cyano thioethers (eq 19), t-butyl chlorides to nitriles (eqs 20 and 21), 1,3,5-trisubstituted hexahydro-l,3,5-triazines to amino-acetonitriles, the cyanation of allylic carbonates and acetates (eqs 22 and 23), and the formation of aryl thiocyanates from aryl sulfonyl chlorides and sulfinates. The reagent has been used effectively in peptide synthesis and in a range of other synthetic applications. " ... 

B. Benzenesulfonyl chloride (and other aryl sulfonyl chlorides) possess an advantage over the usual acyl chlorides of the acetyl or benzoyl type in that the sulfonyl derivatives of primary amines may be differentiated from the corresponding derivatives of secondary amines due to the solubility of the former in alkali. This reaction will be discussed further in Chapter XII in connection with its application to mixtures. 

In 2009, Miller et al. explored the extension of their studies using 7i-methyl histidine-containing peptides as nucleophilic catalysts for group transfer reactions to the mono-sulfonylation of myo-inositol derivatives by aryl sulfonyl chlorides. Catalyst screening identified tetrapeptide derivative 92 as being efficient for distinguishing the enantiotopic secondary alcohol groups at the 1- and 3-positions... 

Direct preparation of aryl sulfonyl chlorides from arenes has been achieved through electrophilic aromatic substitution with excess chlorosulfonic acid. ° This method was used in the initial medicinal chemistiy route for the preparation of Viagra, which relied on a penultimate chloro-sulfonylation reaction with chlorosulfonic acid (Scheme 13.3). ... 

The authors note that the scale-up of chlorosulfonylation reactions is difficult due to high toxicity, competitive hydrolysis during the increased quench times, and a high environmental burden. Additionally, the acidic conditions required for electrophilic aromatic substitution for die synthesis of aryl sulfonyl chlorides greatly limits the scope of the arene that can be used, and furthermore, the desired substitution pattern may be inaccessible based on the intrinsic electronic properties of the aromatic ring. Therefore, the discovery of alternative methods for sulfonyl chloride synthesis is a worthy objective. 

Figure 13.3 Conversion of chlorosulfates to aryl sulfonyl chlorides.

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. 

The main limitation of this methodology is that the initial coupling only works for aryl iodides and not for aryl bromides. However, a large number of aryl iodides are available, and the ability to convert these into aryl sulfonyl chlorides in a one-pot protocol clearly enhances the available chemical space accessible with sulfonamides. 

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