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. 2017 Sep 20;139(37):13092-13101.
doi: 10.1021/jacs.7b06847. Epub 2017 Sep 8.

Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control

Mohammad B Khaled  1 , Roukaya K El Mokadem  1 , Jimmie D Weaver 3rd  1
Affiliations

Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control

Mohammad B Khaled et al. J Am Chem Soc. .

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Abstract

The photocatalytic C-F functionalization of highly fluorinated arenes is a powerful method for accessing functionalized multifluorinated arenes. The decisive step in the determining regioselectivity in fluorine functionalization is fluoride fragmentation from the radical anion of the multifluorinated arene. To date, the availability of regioisomers has been dictated by the innate electronics of the fluorinated arene, limiting the synthetic utility of the chemistry. This study investigates the remarkable ability of a strategically located hydrogen bond to transcend the normal regioselectivity of the C-F functionalization event. A significant rate acceleration is additionally observed for hydrodefluorination of fluorines that can undergo intramolecular hydrogen bonds that form 5-8-membered cycles with moderately acidic N-H's. The hydrogen bond is expected to facilitate the fragmentation not only by bending the C-F bond of the radical anion out of planarity but also by increasing the exothermicity of the fluoride extrusion step through protonation of the naked fluoride. Finally, the synthetic utility of the method is demonstrated in an expedited synthesis of the trifluorinated α-phenyl acetic acid derivative required for the commercial synthesis of Januvia, an antidiabetic drug. This represents the first synthesis of a commercially important multifluorinated arene via a defluorination strategy and is significantly shorter than the current strategy.

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Figures

Figure 1.
Figure 1.
A pseudo-Hammett plot of the directed photo-HDF reaction of tetrafluoropyridine. The average rate at ca. 20% conversion is plotted against the σ-para values.
Figure 2.
Figure 2.
A linear free energy relationship of the HDF regioselectivity as a function of σp− Hammett values in the methyl benzoate series with a remote directing group.
Scheme 1.
Scheme 1.
Multifluorinated Arenes, Current Technology, Novel Approaches
Scheme 2.
Scheme 2.
Working Mechanism of Photo-HDF
Scheme 3.
Scheme 3.
Initial Results in the Directed Photo-HDF
Scheme 4.
Scheme 4.
Directly Attached Directing Groups
Scheme 5.
Scheme 5.
Exploration of other directing groups for tetrafluoropyridine
Scheme 6.
Scheme 6.
Exploration of other polyfluoroarenes in the directed photo-HDF reaction
Scheme 7.
Scheme 7.
Exploration of 6-membered hydrogen bonding substrates
Scheme 8.
Scheme 8.
Directed HDF with sterically hindered amides.
Scheme 9.
Scheme 9.
Exploration of 6-membered hydrogen bonding substrates (continued).
Scheme 10.
Scheme 10.
Exploration of 7-membered hydrogen bonding substrates.
Scheme 11.
Scheme 11.
Exploration of benzoate motif
Scheme 12.
Scheme 12.
Synthesis of key fluorinated starting material for Januvia
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References

    1. a) Sakamoto Y; Suzuki T; Miura A; Fujikawa H; Tokito S; Taga Y J. Am. Chem. Soc 2000, 122, 1832;
    2. b) Hird M Chem. Soc. Rev 2007, 36, 2070. - PubMed
    1. a) Wang J; Sanchez-Rosello M; Acena JL; Del Pozo C; Sorochinsky AE; Fustero S; Soloshonok VA; Liu H Chem. Rev 2014, 114, 2432; - PubMed
    2. b) Purser S; Moore PR; Swallow S; Gouverneur V Chem. Soc. Rev 2008, 37, 320. - PubMed
    1. a) Selby TP; Bereznak JF; Bisaha JJ; Ding AX; Gopalsamuthiram V; Hanagan MA; Long JK; Taggi AE Substituted azoles as fungicides and their preparation.E. I. du Pont de Nemours and Company, USA: 2009, WO2009137651A2;
    2. b) Gregory V; Taggi AE Preparation of fungicidal imidazole derivatives, their mixtures with other fungicides, and use for controlling plant diseases caused by fungal plant pathogens.E. I. Du Pont de Nemours and Company, USA: 2011, WO2011056463A2.
    1. a) Wang J; Yao E; Chen Z; Ma Y Macromolecules 2015, 48, 5504;
    2. b) Kui SCF; Zhu N; Chan MCW Angew. Chem. Int. Ed 2003, 42, 1628. - PubMed
    1. a) There are only a handful of fluorinated natural products and they are all C(sp3)-F, see;
    2. b) Murphy CD; Schaffrath C; O’Hagan D Chemosphere 2003, 52, 455. - PubMed

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