Sulfonyl Chlorides and Sulfonamides
Sulfonyl chlorides and sulfonamides are organic compounds containing sulfonyl groups , which are rich in chemical reactivity and diverse chemical structures and are therefore widely used in synthetic chemistry and medicinal chemistry, among other fields.
Sulfonyl chlorides are a class of compounds with the general structure R-SO2-Cl. Sulfonyl chlorides are highly reactive and can be used as electrophilic reagents to react with various nucleophilic reagents to form new compounds. They are commonly used in sulfonylation reactions, where sulfonyl chlorides are reacted with amines or alcohols to form the corresponding sulfonamides or sulfonate esters. In addition, sulfonyl chlorides can be used to synthesize compounds such as chlorides, esters, amides and ethers.
Sulfonamides are a class of compounds containing sulfonyl groups, usually with the structure R-SO2-NH2. Sulfonamides are commonly used in medicinal chemistry as one of the important functional groups in drug molecules. They can act as structural backbone or pharmacodynamic groups of drugs and are involved in a variety of important mechanisms of drug action. Sulfonamide compounds have good biological activity and pharmacokinetic properties, and are widely used in the research and development of antibacterial drugs, antitumor drugs, steroid hormones and other drugs.
In medicinal chemistry applications, the resulting sulfonyl chloride readily reacts with heterocyclic amines to form complex sulfonamides and is therefore often selected as one of the building block types for the construction of drug molecules. One report details the application of cyclopropanesulfonyl chloride and cyclopentanesulfonyl chloride as building blocks involved in the synthesis of TNF-α converting enzyme (TACE) inhibitors (Scheme 1).[1] This cyclopropyl variant exhibited better selectivity for TACE relative to MMP-2 and -13.
Scheme 1. Involvement of cyclopropanesulfonyl chloride and cyclopentanesulfonyl chloride in the synthesis of TACE inhibitors
A related study describes the synthesis of α-methyltryptamine sulfonamide, a novel human glucocorticoid receptor (hGR) ligand.[2] In this study, sulfonamides synthesized by α-methyltryptamine and 2,4,5-trichlorobenzenesulfonyl chloride (Scheme 2) showed micromolar levels of hGR activity. Furthermore, it was demonstrated in this study that the sulfonamide moiety is the key place for effective binding of hGR.
Scheme 2. 2,4,5-trichlorobenzenesulfonyl chloride is involved in the synthesis of novel human glucocorticoid receptor (hGR) ligands
(2-trimethylsilyl)ethanesulfonamide (SES-NH2) has been shown to be effective in introducing nitrogen-containing functional groups with protecting groups directly into the molecules of compounds. One example is the study by Bolm and Mancheño, where Fe(III) catalyzed the reaction of sulfoxide and sulfide with sulfonamide in the presence of iodine. When Fe(acac)3 was used as a catalyst in combination with iodoalkylbenzene, it provided an efficient alternative (stereospecific) route to the imination of the product of sulfinimide (Scheme 3). [3]
Scheme 3. Iron-catalyzed imidation of sulfoxide reaction
Lamaty and colleagues prepared a series of β-amino esters protected by SES protecting groups by using SES-NH2 in the aza-Baylis-Hillman reaction. And then a series of 2,3-disubstituted pyrroles were obtained by dehydrodesulfurization/aromatization through closed-loop complexation (Scheme 4) with further improved modification of these β-amino esters. [4]
Scheme 4. Synthesis of SES-protected pyrroline intermediates using SES-NH2
In conclusion, sulfonyl chlorides and sulfonamide compounds have a wide range of applications in organic synthesis and medicinal chemistry, providing synthetic chemists and drug researchers with important tools and building blocks in the development of new drugs and advancing the development of new drugs and synthetic methods.
Reference
1.Condon JS, Joseph-McCarthy D, Levin JI, Lombart H, Lovering FE, Sun L, Wang W, Xu W, Zhang Y. 2007. Identification of potent and selective TACE inhibitors via the S1 pocket. Bioorganic & Medicinal Chemistry Letters. 17(1):34-39. https://doi.org/10.1016/j.bmcl.2006.10.004
2.Marshall DR, Rodriguez G, Thomson DS, Nelson R, Capolina A. 2007. ?-Methyltryptamine sulfonamide derivatives as novel glucocorticoid receptor ligands. Bioorganic & Medicinal Chemistry Letters. 17(2):315-319. https://doi.org/10.1016/j.bmcl.2006.10.058
3.Mancheño OG, Bolm C. 2006. Iron-Catalyzed Imination of Sulfoxides and Sulfides. Org.Lett.. 8(11):2349-2352. https://doi.org/10.1021/ol060640s
4.Declerck V, Ribière P, Martinez J, Lamaty F. 2004. Sequentialaza-Baylis?Hillman/Ring Closing Metathesis/Aromatization as a Novel Route for the Synthesis of Substituted Pyrroles. J. Org.Chem.. 69(24):8372-8381. https://doi.org/10.1021/jo048519r