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. 2020 May 20;142(20):9181-9187.
doi: 10.1021/jacs.0c03881. Epub 2020 May 11.

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery

Jeroen B I Sap  1 , Natan J W Straathof  1 , Thomas Knauber  2 , Claudio F Meyer  1   3 , Maurice Médebielle  4 , Laura Buglioni  5 , Christophe Genicot  6 , Andrés A Trabanco  3 , Timothy Noël  5 , Christopher W Am Ende  2 , Véronique Gouverneur  1
Affiliations

Organophotoredox Hydrodefluorination of Trifluoromethylarenes with Translational Applicability to Drug Discovery

Jeroen B I Sap et al. J Am Chem Soc. .

Abstract

Molecular editing such as insertion, deletion, and single atom exchange in highly functionalized compounds is an aspirational goal for all chemists. Here, we disclose a photoredox protocol for the replacement of a single fluorine atom with hydrogen in electron-deficient trifluoromethylarenes including complex drug molecules. A robustness screening experiment shows that this reductive defluorination tolerates a range of functional groups and heterocycles commonly found in bioactive molecules. Preliminary studies allude to a catalytic cycle whereby the excited state of the organophotocatalyst is reductively quenched by the hydrogen atom donor, and returned in its original oxidation state by the trifluoromethylarene.

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Conflict of interest statement

The authors declare the following competing financial interest(s): T.K. and C.W.A. are employees of Pfizer Inc.; C.F.M. and A.A.T. are employees of Janssen; C.G. is an employee of UCB Biopharma Sprl.

Figures

Scheme 1
Scheme 1. Hydrodefluorination of Trifluoromethylarenes in Drug Discovery
Scheme 2
Scheme 2. Electrochemical Reductive Cleavage of Trifluoromethylarenes: Standard Reduction Potentials (V vs Standard Calomel Electrode (SCE) in DMF) and Cleavage Rate Constants
E1/2 (V vs SCE in DMF).
Scheme 3
Scheme 3. Scope of HDF
Yields and CF2H/CH2F ratio determined by quantitative 19F NMR spectroscopy using 4-fluoroanisole as internal standard. Yields of isolated products (RCF2H only) are given in parentheses. 2.5 mol % 4-DPA-IPN. Solvent is DCE/DMSO (19:1, v/v, c = 0.025 M).
Scheme 4
Scheme 4. Additive-Based Screening
All reactions were performed on 2.5 μmol scale in a 96-well plate suited for photoredox chemistry. Crude mixtures were analyzed by GC-FID/MS.
Scheme 5
Scheme 5. Photoredox Hydrodefluorination under Continuous-Flow Conditions
Yields of isolated products.
Scheme 6
Scheme 6. (A) Mechanistic Experiments; (B) Stern–Volmer Luminescence Quenching Studies; (C) Proposed Reaction Mechanism
Yields determined by quantitative 19F NMR using 4-fluoroanisole as internal standard.
See this image and copyright information in PMC

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