Decarbonylative Fluoroalkylation at Palladium(II): From Fundamental Organometallic Studies to Catalysis

Abstract

This Article describes the development of a decarbonyl­ative Pd-catalyzed aryl–fluoro­alkyl bond-forming reaction that couples fluoro­alkyl­carboxylic acid-derived electro­philes [RFC­(O)­X] with aryl organo­metallics (Ar–M′). This reaction was optimized by interrogating the individual steps of the catalytic cycle (oxidative addition, carbonyl de-insertion, trans­metalation, and reductive elimination) to identify a compatible pair of coupling partners and an appropriate Pd catalyst. These stoichio­metric organo­metallic studies revealed several critical elements for reaction design. First, uncatalyzed background reactions between RFC­(O)­X and Ar–M′ can be avoided by using M′ = boronate ester. Second, carbonyl de-insertion and Ar–RF reductive elimination are the two slowest steps of the catalytic cycle when RF = CF3. Both steps are dramatically accelerated upon changing to RF = CHF2. Computational studies reveal that a favorable F2C–H---X interaction contributes to accelerating carbonyl de-insertion in this system. Finally, trans­metalation is slow with X = difluoro­acetate but fast with X = F. Ultimately, these studies enabled the development of an (SPhos)­Pd-catalyzed decarbonyl­ative difluoro­methyl­ation of aryl neopentyl­glycol boronate esters with difluoro­acetyl fluoride.

Mechanism-Driven Development of Group 10 Metal-Catalyzed Decarbonylative Coupling Reactions

“…We hypothesized that amidation could be minimized by two key modifications: (1) using silylamines (R′ 3 SiNR 2 ) as weakly nucleophilic N-sources and (2) conducting the reactions under base-free conditions, wherein selective transmetalation between R′ 3 with the other two partners), indicating that the phenolate ester is a good choice to minimize background reactivity.…”

Recent Advances in C–F Bond Activation of Acyl Fluorides Directed toward Catalytic Transformation by Transition Metals, N-Heterocyclic Carbenes, or Phosphines

“…Given the importance of fluoroalkyl groups in the field of biopharmaceuticals, in addition to Schoenebeck’s research on the decarbonylative trifluoromethylation of acyl fluorides, 46 Sanford et al have recently developed a palladium-catalyzed decarbonylation coupling of difluoroacetyl fluoride as the substrate (Scheme 27 ). 58 Arylboronic esters were employed as coupling partners because of their superior transmetalation capabilities, and a wide variety of difluoroalkylated arenes were synthesized in excellent yields. Furthermore, stoichiometric experiments were performed for each sub-step of the reaction to demonstrate its feasibility, and possible mechanisms were proposed based on these studies.…”

Pd‐Catalyzed Difluoromethylations of Aryl Boronic Acids, Halides, and Pseudohalides with ICF2H Generated ex Situ

“…Several elegant Pd‐catalyzed cross‐coupling procedures have been established by Zhang and others, involving the use of difluorocarbene precursors (BrCF 2 CO 2 Et, BrCF 2 PO(OEt) 2 , Ph 3 P + CF 2 CO 2 − , ClCF 2 H) and aryl boronic acid derivatives [6] . A recent report from the Sanford group demonstrated the worth of a Pd‐catalyzed decarbonylative Suzuki coupling between difluoroacetyl fluoride and aryl neopentylglycol boronate esters [7] . Several methods for radical‐based difluoromethylations depending on peroxides or light and photocatalysts as activators have been developed [8] .…”

“…[6] A recent report from the Sanford group demonstrated the worth of a Pd-catalyzed decarbon-ylative Suzuki coupling between difluoroacetyl fluoride and aryl neopentylglycol boronate esters. [7] Several methods for radicalbased difluoromethylations depending on peroxides or light and photocatalysts as activators have been developed. [8] Transition metal catalyzed cross-couplings of aryl (pseudo)halides and nucleophilic difluoromethyl sources, including TMSCF 2 H, [9] ligated Zn(CF 2 H) 2 [10] and more [11] have also been reported, but display limited substrate scopes.…”