Uphill Catalysis
Electron Transfer Mediated Cross-Couplings
C-F Functionalization
Uphill Catalysis
Electron Transfer Mediated Cross-Couplings
C-F Functionalization

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C–F Functionalization

                Fluorine has become an indispensable feature of anthropogenic chemistry and is incorporated into some of the most important man-made molecules.  Arguably, no other single atom has such a profound impact when it comes to altering the properties of a molecule.  Consequently, organofluorine chemistry is an essential part of drug discovery programs as well as agrochemical programs and even plays a major role in materials chemistry.  Despite the undeniable importance of fluorinated organic molecules, our ability to synthesize these substrates is lacking-though arguably it is better than that of Nature.  Consequently, methods that allow facile access to fluorinated molecules are important especially when they provide unique access to fluorinated chemical space.  One important class of these molecules are partially fluorinated arenes, i.e. Januvia.  In the case of multifluorinated arenes there are two  strategies to consider.  The classic strategy is one in which the fluorines are systematically installed around the core of the molecule.  This strategy relies on harsh and lengthy reaction sequences such as iterative nitration, halex, reduction, Balz-Schieman.  An alternative strategy is to start with a completely or nearly completely fluorinated arene and selectively functionalize or reduce the C–F bonds to build the desired molecule.  This approach is ideal because many perfluoroarenes are commercially available.  Furthermore, since every carbon is substituted with a fluorine it has some potential for functionalization which can allow the perfluoroarene to serve as a synthetic lynchpin.  In practice, this has not yet been accomplished.  The Weaver lab is actively developing strategies to achieve  this  goal.  For representative publications in this area, see below.

  

Amandeep Arora and Jimmie D. Weaver*"Visible Light Photocatalysis for the Generation and Use of Reactive Azolyl and Polyfluoroaryl Intermediates" Acc. Chem. Res. 2016, ASAP, DOI:10.1021/acs.accounts.6b00259.

In this review, we discuss the fundamentals of radical anion fragmentation which provides a mechanistic framework from which all of the results can be understood.

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A. Singh, C.J. Fennell andJ. D. Weaver,"Photocatalyst size controls electron and energy transfer: selectable E/Z isomersynthesis via C–F alkenylation" Chem. Sci.,2016, DOI:10.1039/C6SC02422J.

This work contributes to both the photocatalytic C-F functionalizion efforts as well as the photocatalytic uphill isomerization work.  The products of electron transfer lead to a styrenoid that can then undergo photocatalytic isomerization.  In order to be able to control the olefin geometry outcome we needed to better understand the features that control the two mechanistic pathways.  We found that the photocatalyst volume, and not so much its emisive energy, made a dramatic difference in the rate of isomerization.Furthermore, we showed that this was true of other photocatalytic reactions in which energy transfer was involved and even that two types of photocatalysts could be employed simultaneously to accomplish both electron transfer and isomerization; a feat that neither could do individually.

 

Energy v

 

Sameera Senaweera and Jimmie D. Weaver, "Dual C–F, C–H Functionalization viaPhotocatalysis: Access to Multifluorinated Biaryls" J. Am. Chem. Soc. 2016, 138, 2520.

This work builds off of our ability to form the perfluoroaryl radical via photocatalytic C-F cleavage, where we show that the radical can successfully be intercepted with arenes via C-H functionalization. The ability to directly couple arenes that have not been prefunctionalized makes it attractive as this shortens the synthetic sequence to this important motif by multiple steps.  This paper also demonstrates the perfluoroaryl radical's ability to make highly hindered C-C bonds as well as strategies for selective reduction in the presence of redox sensitive groups.

This paper was highlighted in C&En News,http://cen.acs.org/articles/94/i10/Dual-CFCH-functionalization-unveiled.html 

C F arylation

 

 A. Singh,J. J. KubikandJ. D. Weaver, "Photocatalytic C–F alkylation; facile access to multifluorinated arenes"Chem. Sci., 2015, 6, 7206.

In this exciting extension of our photocatalytic C-F functionalization, we show that the fluoroaryl radical can be generated directly from the C-F bond and that this radical can be utilized in intermolecular additions to alkenes which can then undergo subseqent reduction. We show that when performed iteratively, this is an extremely powerful strategy that greatly expands the fluoroaryl motiffs that are accesible. 

C F alkylation TOC

  

Senaweera, S. M.; Weaver, J.D. "Selective Perfluoro- and Polyfluoroarylation of Meldrum's Acid" J. Org. Chem.,  2014, 79, 10466.

The ability to photocatalytically functionalize fluoroarenes, has generated an increased need to access more elaborate starting materials. Given the utility of Meldrum's acid derivatives, arylations are arguablly underinvestigated. This method allows the facile isolation (no chromatography) of the ammonium salts which are bench stable and are rapidly converted into more elaborate molecules. These reagents are now available at Aspira Scientific FAYE-block reagents (FluoroAryl acYl Equivalents) and soon from Sigma Aldrich as well.

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 Senaweera, S. M.; Weaver, J.D. "C-F Activation and Functionalization of Perfluoro- and PolyfluoroarenesTetrahedron,2014, 70, 7413.

This review covers aromatic C-F substitution that leads to C-C bond forming products which still contain at least one C-F bond.  This review predates our involvement in the field. 

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Senaweera, S. M.; Singh, A.; Weaver, J.D. "Photocatalytic Hydrodefluorination; Facile Access to Partially Fluorinated Aromatics"  J. Am. Chem. Soc., 2014, 136, 3002.

This was our intial work in which we demonstrated that a photocatalyst could be used to facilitate an electron transfer to a perfluoroarene which results in C-F fragmentation followed by H-atom abstration to give the reduced product.  The method is remakably functional group tolerant and provides excellent turnover.  This is impart due to the avoidance of strong carbon-metal or metal-fluoride bonds that are prevalent in other catalytic systems.

This article was featured as a JACS spotlight, see:Spotlights on Recent JACS Publications.J. Am. Chem. Soc.,2014,136, 4091.

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