Palladium-Catalyzed Heck-Type Difluoroalkylation of Alkenes with Functionalized Difluoromethyl Bromides

Abstract

+ PdCl 2 (MeCN) 2 (10 mol%) K 2 CO 3 , 1,4-dioxane, 80 °C Xantphos (20 mol%) BrCF 2 R 4 29 examples, up to 90% yield Abstract An efficient method for the synthesis of difluoroalkylated alkenes through palladium-catalyzed Heck-type reaction with functionalized difluoromethyl bromides has been developed. The advantages of this protocol are its synthetic simplicity, excellent functional group compatibility, and efficient late-stage difluoroalkylation of biologically relevant molecules, thus paving a new way for application in drug discovery and development. Mechanistic studies revealed that the free difluoroalkyl radicals, initiated by a [Pd(0)L n ] via a single-electron-transfer (SET) pathway, were involved in the Heck-type catalytic cycle.

New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics

“…Mechanistic studies were conducted and the authors proposed a Pd-initiated SET pathway through a Heck-type reaction, as already proposed in an early study. [29,37] This proposed mechanism was supported by a radical-clock experiment and addition of radical inhibitors in the reaction mixture (Scheme 15). …”

Pd-Catalyzed Mizoroki-Heck Reactions Using Fluorine-Containing Agents as the Cross-Coupling Partners

“…Furthermore, other competitive side reactions, such as oligomerization of 197 with alkene (path C, Scheme 40) and dimerization of 197 (path D, Scheme 40), were also reasonable pathways, for which the corresponding byproducts (201 and 202) were observed in the conversions [101]. Again, other functionalized difluoromethyl bromides (204 and 206) were employed as crosscoupling reagents in the Pd-catalyzed Mizoroki-Heck reactions by Zhang's research group (Scheme 41) [103,104]. With an analogous catalytic system mentioned above, a variety of difluoroalkylated alkenes (205) were synthesized from 203 and 204 under mild reaction conditions, showing excellent functional group compatibility (Scheme 41a) [103].…”

“…Again, other functionalized difluoromethyl bromides (204 and 206) were employed as crosscoupling reagents in the Pd-catalyzed Mizoroki-Heck reactions by Zhang's research group (Scheme 41) [103,104]. With an analogous catalytic system mentioned above, a variety of difluoroalkylated alkenes (205) were synthesized from 203 and 204 under mild reaction conditions, showing excellent functional group compatibility (Scheme 41a) [103]. The mechanistic studies revealed again that free fluoroalkyl radicals initiated by [Pd(0)Ln] complexes via a SET pathway were involved in the catalytic cycle, and that the bidentate ligand Xantphos was essential for the transformation.…”

“…Presumably, perfluoroalkyl radical (Rfn•) and LnPd(I)I species are first generated from RfnI and Pd(0)Ln in the reaction. Then, the Rfn• radical adds to alkene (208) to afford an alkyl radical (211), which reacts with LnPd(I)I to give a benzylic iodide (212) Again, other functionalized difluoromethyl bromides (204 and 206) were employed as cross-coupling reagents in the Pd-catalyzed Mizoroki-Heck reactions by Zhang's research group (Scheme 41) [103,104]. With an analogous catalytic system mentioned above, a variety of difluoroalkylated alkenes (205) were synthesized from 203 and 204 under mild reaction conditions, showing excellent functional group compatibility (Scheme 41a) [103].…”

Copper‐Catalyzed C−H Difluoroalkylation of Coumarins with Fluoroalkyl Bromides

“…[14] Copper-catalyzed CÀ H fluoroalkylation has been recognized as a powerful method to access complex fluorinated molecules and biomolecules. [15] On the other hand, direct CÀ H fluoroalkylation of coumarin derivatives by photoexcited catalysis, [16] palladium catalysis, [17] Rh(III) catalysis [18] and EDA complexes or halogen bond initiator [19] has proved to be capable for the post-modification of pharmaceutical significant molecules. Nevertheless, Cu-catalyzed CÀ H fluoroalkylation of heteroarenes, e. g. coumarin derivatives, has not been systematically investigated previously and the reaction yield was not satisfying (Scheme 2), [20] especially considering the appealing fact of utilizing fluoroalkylated heteroarenes as pharmacophores.…”