Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes

Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes

ACS Catalysis

10.1021/acscatal.3c02975

http://dx.doi.org/10.1021/acscatal.3c02975

Sandip Porey, Yogesh Bairagi, Srimanta Guin, Xinglong Zhang, Debabrata Maiti

17 October 2023

Porey, S., Bairagi, Y., Guin, S., Zhang, X., & Maiti, D. (2023). Nondirected C–H/C–F Coupling for the Synthesis of α-Fluoro Olefinated Arenes. ACS Catalysis, 13(21), 14000–14011. https://doi.org/10.1021/acscatal.3c02975

The fluorinated entities are considered a privileged structure class in the field of medicinal chemistry because of the amplified bioactivity they exhibit. In this regard, developments in C–H fluorination and trifluoromethylation have been mostly targeted. The α-fluoro olefins also show potential applications as bioisosteres of amides and are also prevalent in drug candidates, but their synthetic accessibility by a C–H activation strategy remains an elusive domain. The assistance of the directing group (DG) does enable the fluoroalkenylation but also constrains the scope in terms of expansion of chemical space for drug development programs. The nondirected strategy is a “one-shot” solution to the existing issues on the use of DGs. With this perspective, we herein report the nondirected protocol on Pd-catalyzed C–H/C–F coupling for accessing α-fluoro olefins in a regioselective fashion. The transformation is governed by the dual control of a pyridine and amino acid-based ligand, which dictate the complementary selectivity achieved. The protocol allows for the late-stage derivatization of drugs and natural products and also enables the conjugation of the drug with the natural product by means of a fluoro-olefin bridge. The incorporation of these fluorinated moieties can potentially modulate the parent bioactivity of drugs. Mechanistic investigations and DFT calculations suggest the vital role of monoprotected amino acid ligand in the C–H activation step through concerted metalation deprotonation, which is the overall turnover frequency-determining state of the catalytic cycle.

Publisher Copyright

This research / project is supported by the A*STAR - MTC Young Individual Research Grants
Grant Reference no. : M22K3c0091

This research / project is supported by the A*STAR - Career Development Fund Grant Reference
Grant Reference no. : C210812008

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Catalysis, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acscatal.3c02975

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