Progress in Difluoroalkylation of Organic Substrates by Visible Light Photoredox Catalysis

Abstract

Thes electivei ncorporation of fluorinated motifs, in particularC F 2 FG (FG = af unctional group) and CF 2 Hg roups,i ntoo rganic compounds has attrracted increasing attention since organofluorine molecules are of the utmost importance in the areas of nuclear imaging,pharmaceutical, agrochemical, and material sciences.Avariety of synthetic approachesh as been employed in late-stage difluoroalkylationr eactions.V isible light photoredox catalysis for the production of CF 2 FG and CF 2 Hr adicalsh as providedamore sustainable alternative to other conventional radical-triggered reactions from the viewpoint of safety,c ost, availability,a nd "green"c hemistry.Awide range of difluoroalkylating reagents has been successfully implemented in these organic transformationsi nt he presence of transitionm etal complexes or organic photocatalysts.I nmost cases, upon excitation via visible light irradiation with fluorescent light bulbs or blue light-emitting diode (LED) lamps,t hese photocatalysts can act as both reductivea nd oxidative quenchers,t hus enabling the applicationo fe lectron-donoro re lectron-acceptor difluoroalkylating reagents for the generation of CF 2 FG andC F 2 Hr adicals.S ubsequent radical addition to substrates and additional organic transformations affordt he corresponding difluoroalkylatedd erivatives.T he presentr eview describes the distinct strategies for the transitionm etal-and organic-pho-tocatalyzed difluoroalkylation of ab road range of organic substrates by visible light irradiationr eported in the literature since 2014.

Recent Synthetic Applications of the Hypervalent Iodine(III) Reagents in Visible-Light-Induced Photoredox Catalysis

“…On account of the smooth occurrence of the SET processes, the redox (oxidation/reduction) potentials of both photocatalysts and HIRs must be taken into consideration in order to find the best-matched partners in a photoredox catalysis/HIR reaction. The oxidative/reductive abilities of commonly used transition metal and organic photocatalysts are relatively well investigated ( Table 1 ) (Reckenthaler and Griesbeck, 2013 ; Koike and Akita, 2014 ; Romero and Nicewicz, 2016 ; Roth et al, 2016 ; Lemos et al, 2019 ). However, despite the practical significance of HIRs, redox potentials of them has not been sufficiently evaluated until now, only limited of redox potential values of HIRs were reported in literatures ( Figure 2 ) (Charpentier et al, 2015 ; Roth et al, 2016 ; Vaillant and Waser, 2017 ).…”

Development of a General Automated Flow Photoredox 18F-Difluoromethylation of N-Heteroaromatics in an AllinOne Synthesizer

“…Additionally, the introduction of difluoromethylated group on some heteroaromatics has been shown to prevent the metabolism (N-oxidation) from aldehyde oxidases 12 . Despite the current advances in the synthesis of difluoromethylated (hetero)arenes [13][14][15] , the labeling of (hetero)aryl-CHF 2 derivatives with fluorine-18 is still underdeveloped.…”

“…Pioneering methods implemented in the radiosynthesis of [ 18 F]aryl-CHF 2 relied on silvermediated 18 F-fluorination processes using either electrophilic fluorinating reagents, such as [ 18 F]Selectfluor bis(triflate) 15 , (Figure 1a) or cyclotron-produced [ 18 F]fluoride 17 (Figure 1b). In 2016, Ritter developed an alternative approach for the construction of [ 18 F]aryl-CHF 2 functionalities starting from aryl (pseudo)halides, via activation of a benzoyl auxiliary, followed by benzylic bromination and in situ halogen-exchange with [ 18 F]fluoride 18 (Figure 1c).…”

Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis

“…Among the existent fluorinated motifs, the difluoromethyl (CF2H) group has recently attracted considerable attention in medicinal chemistry due to its lipophilic hydrogen-bond donor properties [20][21][22][23][24]. The CF2H substitution may offer a viable alternative to conventional hydrogen-bond donors (e.g., hydroxy (OH) and thiol (SH) groups) in terms of lipophilicity, cell membrane permeability, and metabolic stability, thus modulating the pharmacological activity of pharmaceuticals and agrochemicals [25][26][27][28][29][30][31]. Despite the recent progresses in the preparation of CF2H-containing derivatives in organofluorine chemistry, methodologies for the 18 F-labeling of CF2H groups are still relatively scarce.…”