Formation of Sulfonamides

Sulfonyl chlorides are the acid chlorides of sulfonic acids. Like acyl chlorides, sulfonyl chlorides are strongly electrophilic. 

A primary or secondary amine attacks a. sulfonyl chloride and displaces chloride ion to give an amide. Amides of sulfonic acids are called sulfonamides. This reaction is similar to the formation of a sulfonate ester from a sulfonyl chloride (such as tosyl chloride) and an alcohol (Section 11-5). 

What would happen in the synthesis of sulfanilamide if the amino group were not protected as an amide in the chlorosulfonation step  

The biological activity of sulfanilamide has been studied in detail. It appears that sulfanilamide is an analogue of p-aminobenzoic acid. Streptococci use p-aminobenzoic acid to synthesize folic acid, an essential compound for growth and 

Sulfanilamide cannot be used to make folic acid, but the bacterial enzymes cannot distinguish between sulfanilamide and p-aminobenzoic acid. The production of active folic acid is inhibited, and the organism stops growing. Sulfanilamide does not kill the bacteria, but it inhibits their growth and reproduction, allowing the body s own defense mechanisms to destroy the infection. 

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The generation of active radicals as a result of bond breakage makes cation-radicals useful as syn-thons. For example, arylsulfenamide cation-radicals may be used as sources of sulfenyl radicals. The reaction of 4 -nitrobenzenesulfenanilide with Lewis acids, such as BF3 and AICI3, leads to the formation of sulfonamide cation-radical. The latter appears to be an active sulfenyl transfer species. In the presence of anisol, ethenes, or ethynes, it gives phenylthiyl derivatives (Benati et al. 1990, Gross and Montevecchi 1993). 

Amines may also behave as nucleophiles (Lewis bases). Primary amines are stronger nucleophiles than secondary amines, which, in turn, are stronger nucleophiles than tertiary amines. As nucleophiles, amines attack acid chlorides to form amides. Later in this chapter you see that they re important in the formation of sulfonamides. 

Attack by Nitrogen. Formation of Sulfonamides S-Amino-de-chlorination... 

B sulfonyl chloride is an amine-reactive reagent made by converting the 5-sulfonate group over to the reactive sulfonyl halide. Reaction with proteins and other amine-containing molecules results in the formation of sulfonamide bonds (Fig. 214). Lis-samine is a trademark erf Imperial Chemical Industries. 

Mechanism 19-3 Acylation of an Amine by an Acid Chloride 901 19-13 Formation of Sulfonamides 903... 

These are all reactions that you know, with the exception of the oxidation with KMn04 (Chapter 25) to carboxylic acids but the formation of sulfonamides is like that of ordinary amides. This synthesis is discussed in Chapter 25. 

The reaction of primary amines with arenesulfenyl halides leads to the formation of sulfonamides (12). ° These compounds are most stable when the aryl group has electron-withdrawing substituents at Ae 2- and 4-positions. Selenamides are formed in an analogous manner but are somewhat less stable aliphatic amines give isolable compounds, but most anilines react with selenyl halides to give products of ring substitution. An example of an isolable selenamide is compound (13), which was prepared (79%) from the amine and 2-nitrobenzeneselenyl chloride. This compound was used as an intermediate in the preparation of 7a-methoxycephalosporins. 

Two additional routes gave low yields12 of l,2-benzothiazine-3-carbox-amide 20 (sudoxicam). Thus, (V-carbobenzyloxysarcosine was converted to the sarcosine amide 18. Formation of sulfonamide 19 using the sulfonyl chloride 17 followed by cyclization produced the 3-carboxamide 20 (Scheme 1). 

Protection of Nitrogen Formation of Sulfonamides. Unlike the corresponding arenesulfonyl chlorides, benzenesulfonyl bromide has been used much less extensively in organic synthesis. Primary amines and imidazoles (eq 1) have been converted to the corresponding benzenesulfonamides and, with indoles, bromi-nation at C-3 occurs with concomitant sulfonamide formation (eq 2). ... 

N-protection of amines formation of sulfonamides, sulfonate esters, and carbodiitnides)... 

This work was subsequently extended to other benzene thiols2 and to 6- and 7-mercapto-2-aminobenzothiazoles which cleanly underwent the conversion to the mixed thiolsulfonates, with pyridine as the base, with no observed formation of sulfonamide from competing sulfonylation of the 2-amino group.2 ... 

In the case of 3-(2 -thienylidene) camphor 243 chlorosulfonation, under similar conditions, gave the 5 -sulfonyl chloride (sulfonation adjacent to the electron-donating heterosulfur atom). 4-Benzylidenepinocamphorone 244 reacted with excess chlorosulfonic acid (six equivalents) at room temperature (1 week), followed by treatment with thionyl chloride-DMF catalyst, to give the /7-sulfonyl chloride, characterized by formation of sulfonamide deiivatives. 2-Thienylideneacetone 245, together with the benzylidene derivatives of ethyl methyl ketone 246 and diethyl ketone 247, by treatment with excess chlorosul-... 

Arylsulfonyl chlorides react with primary and secondary amines with the formation of sulfonamides, which are used both for the separation of primary, secondary, and tertiary amines, and for the identification of the former two types of compounds. For identification benzenesulfonyl chloride (80, 81) and p-toluenesulfonyl chloride (82) are especially suitable. 

To circumvent the use of highly toxic sulfur dioxide gas, Willis and coworkers explored amine-S02 complexes as sulfur dioxide surrogates. Willis demonstrated that l,4-diazabicyclo[2.2.2]octane (DABCO)-bis sulfur dioxide (DABSO, Figure 13.2) is a useful replacement for sulfur dioxide gas for the formation of sulfonamides from Grignard reagents (Scheme 13.15). DABSO is commercially available and may be prepared quantitatively from DABCO and sulfur dioxide. 

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