Catalytic sp3–sp3 Functionalisation of Sulfonamides: Late‐Stage Modification of Drug‐Like Molecules

• Published in: Chemistry : a European journal Vol. 23; no. 7; pp. 1494 - 1497
• Main Authors: Abdulla, Othman, Clayton, Adam D., Faulkner, Robert A., Gill, Duncan M., Rice, Craig R., Walton, Scarlett M., Sweeney, Joseph B.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 31.01.2017
• Subjects: Binders; catalysis; Chemistry; late-stage functionalisation; palladium; sigma receptor; sulfonamides
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.201605464

A new application of Pd‐catalysed allylation is reported that enables the synthesis of a range of branched sp3‐functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and base at room temperature, direct allylation was efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction was performed under mild conditions and could be applied to nanomolar sigma‐receptor binders, thus enabling a late‐stage functionalisation and efficient expansion of drug‐like chemical space. Obtaining the elusive sulfonamides: A new application of Pd‐catalysed allylation is reported that enables the synthesis of a range of branched sp3‐functionalised sulfonamides, a compound class for which few reported methods exist. By reacting benzyl sulfonamides with allylic acetates in the presence of Pd0 catalysts and base at room temperature, direct allylation can be efficiently performed, yielding products that are analogues of structural motifs seen in biologically active small molecules. The reaction is performed under mild conditions and can be applied to nanomolar sigma‐receptor binders, thus enabling a late‐stage functionalisation and efficient expansion of drug‐like chemical space.