Reactions of Amines with Sulfonyl Chlorides

Azo compounds can be reduced to amines by a variety of reagents including stannous chloride (SnCl2)  

This reduction can be useful in synthesis as the following example shows 4-Ethoxyaniline 

Give a structure for phenacetin and for the intermediates A, B, and C. (Phenacetin, formerly used as an analgesic, is also the subject of Problem 17.45.) 

Primary and secondary amines react with sulfonyl chlorides to form sulfonamides  

When heated with aqueous acid, sulfonamides are hydrolyzed to amines  

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Reactions of Amines with Sulfonyl Chlorides 926 THE CHEMISTRY OF... Essential Nutrients and Antimetabolites 927... 

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. 

Predict the products of reactions of amines with ketones and aldehydes, alkyl halides and tosylates, acid chlorides, sulfonyl chlorides, nitrous acid, and oxidizing agents. Propose mechanisms where appropriate. 

Seheme 1.10 Reaction of primary amines with sulfonyl chlorides. 

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, IJ5 acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). ... 

Amines can react with sulfonyl chlorides, but the product of the reaction depends upon the type of amine. 

Amino groups react very easily with aldehydes or ketones, and with aldehydes in the presence of amines, they can be acylated by the usual acylating agents, and they react with amidacetals, Vilsmeier reagents and nitroso compounds (Scheme 12). As mentioned earlier, alkylation leads mainly to AT(2)-alkylated products. The hydrazino group reacts in the same way as the amino group with aldehydes or ketones, with acyl chlorides or carboxylic anhydrides, with sulfonyl chlorides, ortho esters, carbon disulfide and with nitrous acid. The last three reactions have mainly been used for the synthesis of condensed 1,2,4-triazines. 

The clean conversion of support-bound, primary amines into sulfonamides by treatment with sulfonyl chlorides is more difficult to perform than the acylation of amines with carboxylic acid derivatives, probably because of the oxidizing properties of sulfonyl chlorides and because primary amines can be doubly sulfonylated. Weak bases (pyridine, 2,6-lutidine, NMM, collidine), short reaction times, and only a slight excess of sulfonyl chloride should therefore be used to convert primary amines into sulfonamides (Table 8.7). 

Reaction of 9-chloroacridine with aryl sulfonyl hydrazides results in aminodechlo-rination to give the corresponding A-acridinylbenzenesulfonyl hydrazides kinetic studies in methanol and DMSO have been reported.44 Reaction of electron-deficient heteroaryl chlorides with tertiary amines may proceed by quaternization and dealkylation, as shown in Scheme 3. These reactions occur under mild conditions, e.g. acetonitrile solvent at room temperature, and in THF may be accelerated by the addition of lithium chloride.45... 

Amines react with sulfonyl chlorides to produce sulfonamides. A typical example is the reaction of benzene sulfonyl chloride with aniline. 

CSI (57) (see p. 157) is a useful reagent for the synthesis of sulfamides. CSI (57) by sequential treatment with 2-chloroethanol and a primary or secondary amine affords the corresponding chloroethoxycarbonylsulfamide (144). In the reaction with the amine, the sulfonyl chloride is more reactive than the alkyl chloride and is therefore selectively substituted to yield (144) (Scheme 58). 

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. 

With pyridine, acid chlorides and acid anhydrides yield A-acyl pyridinium salts 6 which are very reactive and sensitive to hydrolysis, unlike the quaternary salts 2-5 they are involved in the acylation of alcohols and amines in pyridine as solvent (Einhorn variant of the Schotten-Baumann reaction). However, 4-dimethylaminopyridine 12 (Steglich reagent) and 4-(pyrrolidin-l-yl)pyridine 13 are better acylation catalysts by a factor of 10 [46a]. Reactions with sulfonyl chlorides in pyridine proceed via A-sulfonylpyridinium salts 14. 

The use of molybdenum compounds in organic synthesis has attracted greater attention. Thus, molybdenum hexacarbonyl has been used in various reactions, such as the preparation of disulfides from sulfonyl chlorides, the alkylation of aryl derivatives, and the synthesis of 4-quinazolones from amines Oxygen has been replaced by fluorine with molybdenum hexafluoride. Molybdenum pentachloride in combination with hydroperoxides has served as oxidant Chelates of MoOg " have been investigated as catalysts for oxidations with molecular oxygen 2,2-Dichloro-7-butyrolactones have been prepared from olefins and methyl trichloracetate with cyclopentadienylmolyb-denum tricarbonyl dimer as catalyst ... 

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. ... 

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