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 language | American English |
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Pages (from-to) | 26199-26209 |
Number of pages | 11 |
Journal | Angewandte Chemie - International Edition |
Volume | 60 |
Issue number | 50 |
DOIs | |
State | Published - 6 Dec 2021 |
Bibliographical note
Funding Information:This research was supported by grants from The Azrieli Foundation, The Israel Science Foundation (Grant No. 287/21), The Casali Foundation, and The Hebrew University. We are grateful to Dr. Manuella Jakob for obtaining HRMS data. We thank Dr. Benny Bogoslavsky (The Hebrew University of Jerusalem, Israel) for X‐ray crystallographic analysis. K.N.B. is grateful for a fellowship from The Hebrew University of Jerusalem, Israel.
Publisher Copyright:
© 2021 Wiley-VCH GmbH
Keywords
- C−H functionalization
- amination
- phosphorus
- reaction mechanisms
- synthetic methods