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.
Highlights
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
Molecular editing enabling precision hydrodefluorination (HDF) of trifluoromethylarenes into difluoromethylarenes for applications in drug discovery remains a highly challenging endeavor because the bond dissociation energy (BDE) of C−F bonds decreases as fluorine substitution takes place (Scheme 1A).3,4a Pioneering studies have reported strategies employing boron, silylium or phosphine adducts,[5] and metals, but uncontrolled defluorination could not be avoided for many of these processes.[6]
Jui and co-workers demonstrated that hydrofluorination is accomplished with cesium formate and the Miyake phenoxazine photocatalyst under blue light activation (Scheme 1B).7a This protocol is applicable to unactivated trifluoromethylarenes adorned with electron-donating groups
Summary
23 no photocatalyst aCombined yields of 1b and 1c determined by 19F NMR using 4fluoroanisole as internal standard; the ratio of 1b:1c is given in parentheses. bReaction carried out on 14a. cConditions of ref 7c with no alkene. dConditions of ref 7b with no alkene. Slightly modified in order to solubilize the starting material (solvent mixture of DCE/ DMSO), gave CF2H-bendroflumethiazide 12b in 56% yield with decreased selectivity (CF2H/CH2F ratio = 4:1) This result is significant because sulfonamides and/or amines can coordinate some metals, rendering late-stage crosscoupling strategies toward aryl−CF2H bond construction more challenging.[13] Enzalutamide, a hormonal therapy drug used to treat prostate cancer, underwent HDF. This reaction yielded with excellent selectivity the difluoromethylated analogue 13b isolated in 40% yield.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
