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Phosphorus-Mediated sp2-sp3 Couplings for Selective C–H Fluoroalkylation of Complex Azines

preprint
submitted on 25.01.2021, 00:13 and posted on 27.01.2021, 09:47 by Xuan Zhang, Kyle G. Nottingham, Chirag Patel, Juan V. Alegre-Requena, Jeffrey N. Levy, Robert S. Paton, Andrew McNally
Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence virtually all metrics associated with their pharmacokinetic and pharmacodynamic profile.1-4 Drug candidates increasingly contain CF3 and CF2H groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect, and plant life.5,6 New fluoroalkylation reactions have undoubtedly stimulated this uptake; however, methods that directly convert C–H bonds into C–CF2X (X = F or H) groups in complex drug-like molecules are rare.7-13 For pyridine, the most common aromatic heterocycle in pharmaceuticals,14 only one approach, via fluoroalkyl radicals, is viable for pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development.15-17 Here, we have developed a new set of bench-stable fluoroalkylphosphines that directly convert the C–H bonds in pyridine building blocks, drug-like fragments, and pharmaceuticals into fluoroalkyl derivatives. No pre-installed functional groups or directing groups are required; the reaction tolerates a variety of sterically and electronically distinct pyridines and is exclusively selective for the 4-position in most cases. The reaction proceeds via initial phosphonium salt formation followed by sp2-sp3 phosphorus ligand-coupling, an underdeveloped manifold for C–C bond formation.

Funding

CAREER: New methods to functionalize pyridines and diazines

Directorate for Mathematical & Physical Sciences

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MRI Collaborative Consortium: Acquisition of a Shared Supercomputer by the Rocky Mountain Advanced Computing Consortium

Directorate for Computer & Information Science & Engineering

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MRI Collaborative Consortium: Acquisition of a Shared Supercomputer by the Rocky Mountain Advanced Computing Consortium

Directorate for Computer & Information Science & Engineering

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Extreme Science and Engineering Discovery Environment (XSEDE) allocations TG-CHE200033 and TG-CHE180056

History

Email Address of Submitting Author

andy.mcnally@colostate.edu

Institution

Colorado State University

Country

United States

ORCID For Submitting Author

0000-0002-8651-1631

Declaration of Conflict of Interest

A patent application based on the subject matter of this manuscript has been filed with the United States Patent and Trademark Office

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