Sulfonyl Chlorides and Sulfonamides

Sulfonyl chlorides are often chosen as building blocks in medicinal chemistry for their ability to easily react with heterocyclic amines to create complex sulfonamides. One such report details the use of cyclopropanesulfonyl chloride and cyclopentanesulfonyl chloride as building block in the synthesis of TNF-a converting enzyme (TACE) inhibitors (Scheme 1).¹ The cyclopropyl variant exhibited good selectivity for TACE over MMP-2 and -13.

Scheme 1. Product Number: 640573 & 656607

Another recent communication describes the synthesis of human glucocorticoid receptor (hGR) ligands.² This sulfonamide created from a-methyltryptamine and 2,4,5-trichlorobenzenesulfonyl chloride (Scheme 2) exhibited micromolar hGR potency. The sulfonamide moiety was also demonstrated to be crucial for effective hGR binding in the study.

Scheme 2. Product Number: 680125

(2-Trimethylsilyl)ethanesulfonamide (SES-NH₂) has proven effective at directly introducing a protected nitrogen-functionality into a molecule. One example is in the work of Bolm and Mancheño, who reported the use of SES-NH₂ in the iron-catalyzed imination of sulfoxides to yield sulfoximines (Scheme 3).³

Scheme 3.

Lamaty and co-workers have prepared a series of SES-protected b-aminoesters by using SES-NH₂ in an aza-Baylis-Hillman reaction. These b-aminoesters were then further elaborated to provide a series of 2,3-disubstituted pyrroles through a ring-closing metathesis protocol (Scheme 4).⁴

Scheme 4.

References

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