Sulfonyl chlorides aromatic, from amines

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

Alternatively, sulfonamides can also be prepared by oxidation of sulfinamides with periodate (Entry 3, Table 8.8) or with MCPBA [125]. Polystyrene-bound sulfonyl chlorides, which can be prepared from polystyrene-bound sulfonic acids by treatment with PCI5, SOCI2 [126-129], CISO3H [130], or SO2CI2/PPI13 [131], react smoothly with amines to yield the corresponding sulfonamides (Entry 4, Table 8.8). Support-bound carbamates of primary aliphatic or aromatic amines can be N-sulfonylated in the presence of strong bases, and can therefore be used as backbone amide linkers for sulfonamides (Entries 5 and 6, Table 8.8). 

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. 

Acetylation of aniline produces acetanilide (2) and protects the amino group from the reagent to be used next. Treatment of 2 with chlorosulfonic acid brings about an electrophilic aromatic substitution reaction and yields/>-acetamidobenzene-sulfonyl chloride (3). Addition of ammonia or a primary amine gives the diamide, 4 (an amide of both a carboxylic acid and a sulfonic acid). Finally, refluxing 4 with dilute hydrochloric acid selectively hydrolyzes the carboxamide linkage and produces a sulfanilamide. (Hydrolysis of carboxamides is much more rapid than that of sulfonamides.)... 

The procedure for the chlorosulfonation of azobenzene was first reported by PearP and was successfully repeated by Cremlyn. The comparatively drastic conditions required for the reaction 414— 415 (Equation 128) are probably due to initial protonation of the azido group in the strongly acidic medium. Attempts were made to extend the procedure to the chlorosulfonation of other azobenzenes. With 4-acetamidoazobenzene, extensive decomposition occurred at 125 °C, which may arise from acid-catalysed migration of the acetyl group into the aromatic nucleus, followed by decomposition of the resultant free amine intermediate. However, when the reaction temperature was reduced to 80 C, a low yield of the 4 -sulfonyl chloride was isolated. On the other hand, similar efforts to chlorosul-fonate p-(A iV-dimethylamino)azobenzene failed to yield a pure product,but more recently debsyl chloride 416 has been synthesized and is used as a derivatization reagent in HPLC for the separation of amines and amino acids. ... 

Some of these transformations were accompanied by additional reactions, e.g. formylation of the aromatic or heteroaromatic - nucleus or CH-acidic methyl groups further dehydration of amides to nitriles was observed. Adducts from amides and PCI3, sulfonyl halides or SO2CI2/SCXZI2 from which amidines can be obtained by reaction with amine derivatives (compare Section 2.7.2.5 and refs. 5 and 14) have not found wide application for this purpose. An interesting reaction is the preparation of the amidine (294 equation 158) from 7V-pentafluorophenylformamide. By thermal decomposition of the adducts from secondary amides and 7V,iV-dialkylcarbamoyl chlorides amidinium salts were synthesized from which the amidines (295 equation 159) were set free by treatment with bases. " ... 

Villalgordo et al. [22, 23] as well as Gayo and Suto [25] developed a strategy to cleave pyrimidines from the solid support. After oxidation of the thioether-linkage 17, aromatic substitution of the sulfonyl unit was performed with different N-nucleophiles as amines and azides to give free amino- or azido-pyrimidines 19 (Scheme 16.5). To demonstrate the stability of the linker, the resin-bound derivatives were subjected to different reactions such as saponification, ester reduction, acid chloride formation or Mitsunobu alkylation. A similar approach was presented later on by Hwang and Gong in the SPOS of 2-aminobenzoxazoles [26]. 

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