Synthesis of Sulfonamides

The imidazolides required for these reactions can be prepared from sulfonyl chlor-ides[1] or sulfonic anhydrides[2] and imidazole, or by treatment of the corresponding sulfonic acid with CDI,[1] ImSOIm,[3] or ImS02Im[3] (see Section 10.1.1). However, for the synthesis of sulfonamides it is more convenient to employ a one-pot reaction starting from the free sulfonic acid, CDI or ImSOIm, and the appropriate amine [1]... 

Raju, B. Kogan, T. P. Solid Phase Synthesis of Sulfonamides Using a Carbamate Linker, Tetrahedron Lett. 1997, 38, 3373-3376. 

Van Ameijde, J., and Liskamp R. M. J. (2000) Peptidomimetic building blocks for the synthesis of sulfonamide peptoids. Tetrahedron Lett. 41, 1103-1106. 

Ladlow and coworkers recently developed an acid-labile fluorous benz-aldehyde protecting group 43 to facilitate the parallel synthesis of sulfonamides 44 (Scheme 25) [56]. The Suzuki coupling reaction was conducted under microwave irradiation. All the intermediates and the final products were purified by F-SPE. 

Raju B, Kogan TP, Use of halomethyl resins to immobilize amines an efficient method for synthesis of sulfonamides and amides on a solid support,... 

Raju B, Kogan TP, Solid phase synthesis of sulfonamides using a carbamate linker, Tetrahedron Lett., 38 3373-3376, 1997. 

In the early part of the twentieth century the synthesis of sulfonamide drugs such as anti-bacterials led to the first effective treatments of the fatal diseases septicaemia, bacterial meningitis and the killer disease, pneumonia. The active form of the drug is p-aminobenzenesulphonamide (Figure 14.4). 

Shi, R, Tse, M.K., Zhou, S., Pohl, M.-M., Radnik, J., Hobner, S., Jahnisch, K., Brockner, A., and BeUer, M. 2009. Green and efficient synthesis of sulfonamides catalyzed by nano-Ru/Fe304. Journal of American Chemical Society, 131 1775-79. 

Anions derived from halogenated imidazoles are frequently utilized in the formation of (7-heteroatom bonds. Bromolithium exchange of 961 (Scheme 233) followed by azidation 962 and reduction leads to 2-aminoimidazole 963 (PMB = -methoxybenzyl) <2003H(60)583>. The Mg-imidazolide intermediate from I/Mg exchange of 964, PBB = -bromobenzyl) reacts with sulfur dioxide for the synthesis of sulfonamide 965 <2003TL6509>. 

A quite different synthesis of sulfonamides treated allyltributyltin with Phl=NTs, in the presence of copper (11) triflate. another alternative method treats sUyl enol ethers with sulfur dioxide, and subsequent and reaction with a secondary amine gave the p-sulfonamido ester. ... 

Resistance to sulfonamides is widespread in bacteria isolated from animals, and may involve chromosomal mutations or plasmid-mediated mechanisms. Chromosomal mutations cause impaired drug penetration, production of altered forms of dihydropteroate synthetase for which sulfonamides have a lowered affinity, or production of excessive PABA that overcomes the metabolic block imposed by the inhibition of dihydropteroate synthetase. A more common cause of bacterial resistance to sulfonamides is plasmid-mediated mechanisms, which may result in impaired drug penetration or the synthesis of sulfonamide-resistant dihydropteroate synthetase. There is cross-resistance among sulfonamides. 

An analogous approach was employed in the synthesis of sulfonamide 172, which is a potential non-peptide fibrinogen receptor antagonist (99JMC2409). 

The N-triazolo[l,5-c]pyrimidine sulfonamides and related compounds differ from their sulfonanilide counterparts by the orientation of the linkage between the triazoloazine and the aryl or heteroaryl ring. However, in most cases synthesis of sulfonamides is similar to the sulfonanilides, as the target molecules are formed by reaction of a sulfonyl chloride and an amine in the final step. Notably, the synthesis of arylsulfonyl chlorides account for much of the diversity in these molecules [32-36]. 

Fig. 16.6. Plot of symmetric-NHj vs the antisymmetric-NHj stretching frequencies (Table 16.8 column 3) of the anilines used for the synthesis of sulfonamides. (Seydel, 1966.)...

Synthesis of Sulfonamides. Sulfonamides are formed in moderate to good yields by the reaction of methoxycarbonylmethanesulfonyl chloride with the desired amine in the presence of triethylamine (eq 2). This reaction is usually carried out using arylamines, but can be extended to peptidic amines. ... 

X. B. Li, J. Pennington,. F. Stobaugh and C. Schoneich, Synthesis of sulfonamide- and sulfonyl-phenylboronic acid-modified silica phases for boronate affinity chromatography at physiological pH, Anal. Biochem., 2008, 372(2), 227-22,6. 

Thus a variety of methods have been developed for the synthesis of sulfonamides. These will be discussed in subsequent chapters, and only some highlights are given here. 

The actual synthesis of sulfonamide 21, which was ultimately converted to the target sulfonylureas, is depicted in Scheme HI. 

Kim, J.-G., and Jang, D. O. (2007). Mild and efficient indium metal catalyzed synthesis of sulfonamides and sulfonic esters. Synlett, 2501-2504. 

Scheme 12.12 The synthesis of sulfonamides using biodegradahle PEG as the solvent.

M.K. Muthayala, B.S. Chhikara, K. Parang, A. Kumar, Ionic liquid-supported synthesis of sulfonamides and carboxamides, ACS Comb. Sci. 14 (2012) 60-65. 

The presence of the ortho-riiXro group allowed nucleophilic cleavage to liberate the desired amine [6]. An amidine linker [7,8] provided a resin bound amine that was stable to oxidative, reductive, and alkylative conditions. The use of 2-chlorotrityl resin proved to be useful for the preparation of a secondary amine library [9] as well as hydroxamic acids [10]. Tertiary amines were prepared by 1,4 addition to a resin bound acrylate followed quatemization and a retro-Michael reaction [11]. The p-nitrophenyl carbonate linker has been shown to be useful for the inunobilization of ben-zamidines [12] and for the synthesis of sulfonamides [13]. Sulfonamides and amides were also prepared using a halogenated Wang resin [14]. 

This could then be directly captured by amines to obtain the sulfonamides in one pot. Utilisation of boronic acids in the synthesis of sulfonamides is an attractive approach as a diverse range of aryl and heteroatyl boronie aeids are readily available from commercial vendors. 

This same methodology can produce sulfonamides via SO2CI2 mediated oxidation of the intermediate metal sulfinate, which has itself come from an all l or aryl Grignard (Scheme 18.8). This has been applied to the parallel synthesis of sulfonamides. ... 

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