Sequential Selective C−H and C(sp3)−+P Bond Functionalizations: An Entry to Bioactive Arylated Scaffolds

K. Naresh Babu, Fedaa Massarwe, Israa Shioukhi, Ahmad Masarwa*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Organophosphonium salts containing C(sp3)−+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(sp3)−+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(sp3)−+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.

Original languageAmerican English
Pages (from-to)26199-26209
Number of pages11
JournalAngewandte Chemie - International Edition
Volume60
Issue number50
DOIs
StatePublished - 6 Dec 2021

Bibliographical note

Publisher Copyright:
© 2021 Wiley-VCH GmbH

Keywords

  • C−H functionalization
  • amination
  • phosphorus
  • reaction mechanisms
  • synthetic methods

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