Palladium‐Catalyzed Difluoroalkylation of Aryl Boronic Acids: A New Method for the Synthesis of Aryldifluoromethylated Phosphonates and Carboxylic Acid Derivatives

Abstract

The palladium-catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed. This method provides a facile and useful access to a series of functionalized difluoromethylated arenes (ArCF2 PO(OEt)2 , ArCF2 CO2 Et, and ArCF2 CONR(1) R(2) ) that have important applications in drug discovery and development. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.

Copper‐Mediated Synthesis of Aryldifluoromethylphosphonates: A Sandmeyer Approach

“…To date, since Shibuya's pioneering work regarding the copper-mediated Negishi cross-coupling reaction of vinyl halide with BrZnCF 2 PO(OEt) 2 , [8] the introduction of the CF 2 PO(OR) 2 unit into arenes has focused on: (1) the addition of fluorinated radicals to arenes, [9] (2) the copper-catalyzed cross-coupling reaction of the iodoarenes, iodobenzoate and haloaryl triazenes, with in situ prepared MCF 2 PO(OEt) 2 (M = ZnX or CdX), [10] (3) the palladiumcatalyzed Suzuki cross-coupling reaction with BrCF 2 PO-(OEt) 2 , [11] and (4) the copper-mediated oxidative addition of the TMSCF 2 PO(OR) 2 (TMS = trimethylsilyl) reagent to an aryl boronic acid.…”

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). …”

“…[29] This process was applied to a broad range of aryl boronic acids (17 examples, 44-86 % yields). Electron-donating substituents on the aromatic ring were compatible and the corresponding products were isolated in high yields.…”

Recent Developments in Inter- and Intramolecular Enolate Arylation

“…Reliable methods to form a C-C bond between an aryl electrophile and a difluoroalkyl nucleophile have not been developed. 17 However, Hartwig and coworkers had described the synthesis of a wide range of a-aryl-and a-heteroaryl-a,a-difluoroketones by palladium-catalyzed coupling of difluoroacetophenones with aryl and heteroaryl bromides and chlorides (Scheme 6). 18 In general, a wide range of electronically varied aryl bromides and aryl chlorides are tolerated with a,a-difluoroacetophenone in comparably high yields.…”