Sequential Selective C−H and C(sp3)−+P Bond Functionalizations: An Entry to Bioactive Arylated Scaffolds. Issue 50 (3rd November 2021)

• Record Type: Journal Article
• Authors: Babu, K. Naresh; Massarwe, Fedaa; Shioukhi, Israa; Masarwa, Ahmad
• Is Part Of: Angewandte Chemie international edition. Volume 60:Issue 50(2021)
• Page Start: 26199
• Page End: 26209
• Publication Date: 2021-11-03
• Subjects: amination -- C−H functionalization -- phosphorus -- reaction mechanisms -- synthetic methods; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.202111164
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Organophosphonium salts containing C(sp 3 )− + P bonds are among the most utilized reagents in organic synthesis for constructing C−C double bonds. However, their use as C‐selective electrophilic groups is rare. Here, we explore an efficient and general transition‐metal‐free method for sequential chemo‐ and regioselective C−H and C(sp 3 )− + P bond functionalizations. In the present study, C−H alkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one‐pot, four‐component cross‐coupling reactions of simple and commercially available starting materials. The utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post‐functionalization of benzylic C(sp 3 )− + PPh3 groups to achieve aminations, thiolations, and arylations. In this way, benzhydrylamines, benzhydrylthioethers, and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals, are readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps. Additionally, a protocol for late‐stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts. This new approach should provide novel transformations for application in both academic and pharmaceutical research. Abstract : A broadly unified, straightforward method of direct sequential C−H/C−P bond functionalization has been developed to access a variety of synthetically and highly useful bioactive benzhydrylamine, benzhydrylthioether, and triarylmethane motifs from commercially available arenes and simple aldehydes.