2,2‐Difluoroethylation of Heteroatom Nucleophiles via a Hypervalent Iodine Strategy

Das, Suman; McIvor, Charlotte; Greener, Andrew; Suwita, Charlotte; Argent, Stephen P.; O'Duill, Miriam L.

Abstract

The 2,2-difluoroethyl group is an important lipophilic hydrogen bond donor in medicinal chemistry, but its incorporation into small molecules is often challenging. Herein, we demonstrate electrophilic 2,2-difluoroethylation of thiol, amine and alcohol nucleophiles with a hypervalent iodine reagent, (2,2-difluoro-ethyl)(aryl)iodonium triflate, via a proposed ligand coupling mechanism. This transformation offers a complementary strategy to existing 2,2-difluoroethylation methods and allows access to a wide range of 2,2-difluoroethylated nucleophiles, including the drugs Captopril, Normorphine and Mefloquine.

Citation

Das, S., McIvor, C., Greener, A., Suwita, C., Argent, S. P., & O'Duill, M. L. (2024). 2,2‐Difluoroethylation of Heteroatom Nucleophiles via a Hypervalent Iodine Strategy. Angewandte Chemie, 136(40), Article e202410954. https://doi.org/10.1002/ange.202410954

• Journal Article Type: Article
• Acceptance Date: Jun 11, 2024
• Online Publication Date: Aug 8, 2024
• Publication Date: 2024-10
• Deposit Date: Mar 13, 2025
• Publicly Available Date: Mar 14, 2025
• Journal: Angewandte Chemie
• Print ISSN: 0044-8249
• Electronic ISSN: 1521-3757
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 136
• Issue: 40
• Article Number: e202410954
• DOI: https://doi.org/10.1002/ange.202410954
• Public URL: https://nottingham-repository.worktribe.com/output/45161841
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/ange.202410954
• Additional Information: Received: 2024-06-11; Published: 2024-08-08