Custom Synthesis of Versatile Chalcone-4’-sulfonyl Derivatives

Functionalized benzylidene acetophenones (chalcones) are attractive building blocks for introducing a conjugated motif of a carbonyl group and a carbon-carbon double bond into potential drugs, such as covalent inhibitors,¹ or monomers for synthetic polymers.² The substructure of chalcone (Figure 1) is found in many marketed and investigational drugs, as well as in other biologically active compounds.³

Figure 1. Structure and aromatic carbon atom numbering scheme of the parent chalcone.

Consequently, development of reliable methods for preparation of building blocks bearing the chalcone unit is of importance in drug discovery and materials chemistry. There are methods for incorporation of the chalcone subunit, including the use of chalcone acyl² or sulfonyl⁴ chlorides. The latter are especially useful synthetic building blocks since a biologically relevant sulfo-group is introduced along with the valuable chalcone fragment. The preparation and use of diverse chalcone-2-, 3-, and 4-sulfonyl chlorides via direct sulfochlorination of the chalcone styrene ring with chlorosulfonic acid has been described.⁴ We have recently developed synthesis of first chalcone sulfonyl chlorides in which the chlorosulfo-group is attached to the phenone ring (Figure 1).⁵

Accordingly, we can offer custom synthesis of chalcone-4’-sulfonyl chlorides and fluorides. Structural diversity of these building blocks is controlled by highly variable substituents at the styrene ring. Representative structures of the synthesized chalcone-4’-sulfonyl halides are given in Figure 2.

Figure 2. Examples of synthesized chalcone-4’-sulfonyl chlorides and fluorides. 

References:

1. (a) Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M. Nature 2013, 503, 548. (b) Lewis, H. D.; Liddle, J.; Coote, J. E. et al. Nat. Chem. Biol. 2015, 11,189.
2. van Heijst, J,; Corda, M.; Lukin, O. Polymer 2015, 70, 1.
3. (a) According to www.drugbank.ca (accessed in December 2019) there are 13 marketed and over 20 investigational drugs bearing the chalcone substructure. (b) León-González, A. J.; Acero, N. et al. Curr. Med. Chem. 2015, 22, 3407.
4. (a) Cremlyn, R. J.; Swinbourne, F. J.; Bassin, P.; Dane, D.; Higgins, K.; Mitchell, P. Phosphorus
5. Sulfur Silicon 1991, 63, 385. (b) Patel, C.; Bassin, J. P.; Scott, M. et al. Molecules 2016, 21, 861.
6. Semenok, D.; Kletskov, A.; Dikusar, E.; Potkin, V.; Lukin, O. Tetrahedron Lett. 2018, 59, 372.