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Phosphorus-mediated sp2sp3 couplings for C–H fluoroalkylation of azines

Abstract

Fluoroalkyl groups profoundly affect the physical properties of pharmaceuticals and influence almost all metrics associated with their pharmacokinetic and pharmacodynamic profile1,2,3,4. Drug candidates increasingly contain trifluoromethyl (CF3) and difluoromethyl (CF2H) groups, and the same trend in agrochemical development shows that the effect of fluoroalkylation translates across human, insect and plant life5,6. New fluoroalkylation reactions have undoubtedly stimulated this shift; however, methods that directly convert C–H bonds into C–CF2X groups (where X is F or H) in complex drug-like molecules are rare7,8,9,10,11,12,13. Pyridines are the most common aromatic heterocycles in pharmaceuticals14, but only one approach—via fluoroalkyl radicals—is viable for achieving pyridyl C–H fluoroalkylation in the elaborate structures encountered during drug development15,16,17. Here we develop a 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 preinstalled 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 through initial formation of phosphonium salts followed by sp2sp3 coupling of phosphorus ligands—an underdeveloped manifold for forming C–C bonds.

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Fig. 1: Importance of fluoroalkylated pyridines and methods in making C–CF2X bonds (where X = F or H).
Fig. 2: Design and optimization of a phosphorus-mediated process for azine fluoroalkylation.
Fig. 3: Scope of building-block azines amenable to fluoroalkylation.
Fig. 4: Direct fluoroalkylation of complex azine-containing molecules.

Data availability

All data generated or analysed during this study are included in the published article (and its Supplementary Information files). The computational chemistry datasets generated and analysed here are available in Zenodo at https://doi.org/10.5281/zenodo.4554587.

Code availability

Computational chemistry datasets were analysed with Goodvibes version 3.0.0, available at Github (https://github.com/bobbypaton/GoodVibes) and Zenodo (https://github.com/bobbypaton/GoodVibes).

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Acknowledgements

This work was supported by the National Science Foundation (NSF) under grant number 1753087. We acknowledge the Rocky Mountain Advanced Computing Consortium (RMACC) Summit supercomputer, supported by the NSF (grants ACI-1532235 and ACI-1532236), and the Extreme Science and Engineering Discovery Environment (XSEDE) (allocations TG-CHE180056 and TG-CHE200033). We thank M. J. Gaunt for help in preparing the manuscript. We dedicate this paper to the memory of Robert M. Williams.

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Contributions

X.Z., K.G.N., C.P. and J.N.L. carried out and analysed the experiments. A.M. directed the project. A.M., R.S.P. and K.G.N. wrote the manuscript. J.V.A.-R. and R.S.P. designed, carried out and analysed the computational experiments.

Corresponding authors

Correspondence to Robert S. Paton or Andrew McNally.

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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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Supplementary Information

This file contains Supplementary Sections 1-18, including Supplementary Figures 1-18, Supplementary Tables 1-10 and 1H, 13C, 19F, and 31P Spectra data- see Contents page for details.

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Zhang, X., Nottingham, K.G., Patel, C. et al. Phosphorus-mediated sp2sp3 couplings for C–H fluoroalkylation of azines. Nature 594, 217–222 (2021). https://doi.org/10.1038/s41586-021-03567-3

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