Sulfonamides, synthesis

Preparative Methods The enantiopure sulfonamide la is prepared via sulfonylation of (7 ,7 )-l,2-diaminocyclohexane 2 in the presence of an excess of triethylamine (eq 1). Use of excess amine base is essential for obtaining a high yield of the bis-sulfonamide. Synthesis of related bis-sulfonamides is easily accomplished by substituting the desired sulfonyl chloride in the former procedure. Recrystallization of the bis-sulfonamide la from hexane/ethyl acetate and drying over P2O5 allows for isolation of the analytically pure reagent. Methanesulfonyl chloride and (7 ,/ )-l,2-diaminocyclohexane 2 are commercially available from a number of sources. However it should be noted that racemic 1,2-diaminocyclohexane 2 can be resolved via formation of the tartrate salt. Typically, the diamine can be obtained in >99 1 enantiomeric ratio (er) after two crystallizations from water. Determination of the enantiopurity of the diamine is accomplished via formation of the bis-3-toluyl amide and anal-... 

Figure 15.3 Urea and sulfonamide synthesis from carbamate derivatized oxime (19), thiophenol (16) and Wang (4) resins.

Sulfonamide Synthesis. The classical routes to sulfonylchlorides were not adequate for the preparation of the broad range of ortho substituted derivatives required for this program. Chlorosulfonation ( uation 6) generally yields the ortho isomer as a... 

Once it was realized that heteroaromatic sulfonamides could be prepared and converted to sulfonylureas, and that these compounds possessed many of the desirable hebicidal qualities of the benzene sulfonylureas, a large synthetic effort was started to prepare more examples. Using thiophene and pyrazole as representative examples, we have been able to synthesize all of the positional isomers of the mono- and di-substituted sulfonamides. This paper will outline the major synthetic pathways that we have discovered, emphasizing directed metallation processes and nucleophilic substitution reactions, leading to the preparation of these heterocyclic sulfonamides. Many of tiie methods developed for thiophene and pyrazole sulfonamide synthesis have been extended to the synthesis of pyridine and other heteroaromatic sulfonamides. 

Sulfonamide iV-alkylation with alcohols is an important transformation due to the abundance of the sulfonamide moiety in drugs. Traditional sulfonamide synthesis involves the reaction of a sulfonyl chloride with a primary or secondary amine. However, these methods require the use of unstable sulfonyl chlorides and generate stoichiometric salt waste. In contrast, the N-alkylation of sulfonamides with alcohols presents a convenient alternative that utilises stable starting materials and produces water as the... 

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. 

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