1,1-Difluoroethyl chloride (CH₃CF₂Cl), a novel difluoroalkylating reagent for 1,1-difluoroethylation of arylboronic acids

Abstract

1,1-Difluoroethylated aromatics are of great importance in medicinal chemistry and related fields.

Nickel‐Catalyzed 1,1‐Difluoroethylation of (Hetero)aryl Halides with 1,1‐Difluoroethyl Chloride (CH3CF2Cl)

“…It was found that the reaction of 2 a with 1 b afforded trace of the desired product and the residual 1 b (determined by GC-MS) (Scheme 3). It should be noted that the result is in sharp contrast to the nickel-catalyzed Suzuki-type reaction, [14] which had similar reaction activity between CH 3 CF 2 Cl and ClCH 2 CH 2 Cl.…”

“…1,1‐Difluoroethyl chloride (CH 3 CF 2 Cl, HCFC‐142b), an inexpensive and readily available raw material, is regarded as an ideal reagent to synthesis 1,1‐difluoroethyled compounds. Previously, we developed nickel‐catalyzed difluoroethylation of arylboronic acids with CH 3 CF 2 Cl . However, this method needs large excess of CH 3 CF 2 Cl and afforded low product yields due to the homo‐coupling and protodeborylation of arylboronic acids.…”

“…Owning to the residual aryl halide, we examined different nickel sources and ligands to improve the reaction efficiency (Table , entries 2–6, for details, see Supporting Information). It was noted that NiCl 2 (PPh 3 ) 2 , used in nickel‐catalyzed 1,1‐difluoroethylation of arylboronic acids, resulted in no desired product (Table , entry 2). The survey of other ligands revealed that diNH 2 ‐bpy ( L4 ) improved the yield of 3 a to 16% (Table , entry 6), while diMe‐bpy ( L1 ), di t Bu‐bpy ( L2 ) and diOMe‐bpy ( L3 ) afforded poor yields (Table , entries 3–5).…”

“…Previously, we developed nickel-catalyzed difluoroethylation of arylboronic acids with CH 3 CF 2 Cl. [14] However, this method needs large excess of CH 3 CF 2 Cl and afforded low product yields due to the homo-coupling and protodeborylation of arylboronic acids. Given this, we envisioned an alternative strategy to synthesis the 1,1-difluoroethyled aromatics through nickel-catalyzed reductive cross-coupling reaction [15] using CH 3 CF 2 Cl.…”

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

“…Furthermore, the C−Cl bond provides a handle for further product derivatization. The mild reduction to the −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 −CF 2 Cl group in previous literature. The chlorodifluoromethyl group has also been demonstrated as a valuable precursor for late‐stage selective radiolabeling with nucleophilic 18 F sources [27] .…”