A radical chlorodifluoromethylation protocol for late-stage difluoromethylation and its application to an oncology candidate

Visible Light‐Mediated Metal‐Free Chlorodifluoromethylation of Arenes and Heteroarenes by a Hypervalent Iodine EDA Complex

“…Unlike •CF 2 H, the chlorodifluoromethyl radical (•CF 2 Cl) shows electrophilic character and acts as a À CF 2 H surrogate to deliver the difluoromethyl moiety to traditionally inaccessible/less accessible electron-rich sites. [23,24] Furthermore, the CÀ Cl bond provides a handle for further product derivatization. The mild reduction to the À CF 2 H unit with H 2 -Pd/C, [23] Ni-catalysed cross coupling with aryl boronic acids, [25] methanolysis with sodium acetate, [23] and substitution with diverse nucleophiles [26] have all been demonstrated with the À CF 2 Cl group in previous literature.…”

“…[27] In 2021, Meng and co-workers utilized sodium chlorodifluoromethylsulfinate (ClCF 2 SO 2 Na) for the α-difluoromethylation of a pyridinone-containing scaffold to yield a Pfizer-nominated CDK2/4/6 inhibitor for the treatment of cancer (Scheme 1a). [24] While there have been many radical difluoromethylation methods reported in recent years, radical chlorodifluoromethylation procedures remain scarce and underexplored. Current methods require strong oxidants [28] (Scheme 1a, b, c, d) and freons [29,30] (Scheme 1c, Scheme 1d), require multistep reagent synthesis [24] (Scheme 1b), or use exogenous photocatalysts [23,31] (Scheme 1e, Scheme 1f).…”

“…[24] While there have been many radical difluoromethylation methods reported in recent years, radical chlorodifluoromethylation procedures remain scarce and underexplored. Current methods require strong oxidants [28] (Scheme 1a, b, c, d) and freons [29,30] (Scheme 1c, Scheme 1d), require multistep reagent synthesis [24] (Scheme 1b), or use exogenous photocatalysts [23,31] (Scheme 1e, Scheme 1f).…”

“…The corresponding halodifluoromethylation (−CF 2 X, X=Cl, Br, I) methods have been much less explored. Unlike ⋅CF 2 H, the chlorodifluoromethyl radical (⋅CF 2 Cl) shows electrophilic character and acts as a −CF 2 H surrogate to deliver the difluoromethyl moiety to traditionally inaccessible/less accessible electron‐rich sites [23,24] . Furthermore, the C−Cl bond provides a handle for further product derivatization.…”

“…The chlorodifluoromethyl group has also been demonstrated as a valuable precursor for late‐stage selective radiolabeling with nucleophilic 18 F sources [27] . In 2021, Meng and co‐workers utilized sodium chlorodifluoromethylsulfinate (ClCF 2 SO 2 Na) for the α‐difluoromethylation of a pyridinone‐containing scaffold to yield a Pfizer‐nominated CDK2/4/6 inhibitor for the treatment of cancer (Scheme 1a) [24] . While there have been many radical difluoromethylation methods reported in recent years, radical chlorodifluoromethylation procedures remain scarce and underexplored.…”