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

Abstract

An expedient ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation of aryl boronic acids and ester derivatives in a two-chamber reactor is reported. Heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane proved to be effective for the generation of near stoichiometric amounts of DFIM for the ensuing catalytic coupling step. A two-step difluoromethylation of aryl (pseudo)halides with tetrahydroxydiboron as a low-cost reducing agent, both promoted by Pd catalysis, proved effective to install this fluorine-containing C 1 group onto several pharmaceutically relevant molecules. Finally, the method proved adaptable to deuterium incorporation by simply adding D 2 O to the DFIMgenerating chamber.

Tetrahydroxydiboron (Bis‐boric Acid): a Versatile Reagent for Borylation, Hydrogenation, Catalysis, Radical Reactions and H2 Generation

“…Skrydstrup's group very recently applied the Pd‐catalyzed aryl(pseudo)halide borylation with THDB to a two‐chamber process in which difluoroiodomethane, ICF 2 H, is stoichiometrically generated in the first chamber from bromodifluoroacetic acid and sodium iodide in sulfolane, and the difluoromethylarene is generated in the second chamber from reaction of ICF 2 H with aryl boronic acid (synthesized from aryl(pseudo)halides as in Scheme 2) upon Pd catalysis in toluene/water: 10/1 and K 2 CO 3 at 60 °C. It was also possible to incorporate deuterium by adding D 2 O to the first chamber [15d] …”

A Difluoromethylation Reagent: Access to Difluoromethyl Arenes through Palladium Catalysis

“…The second comprises a relatively large number of nucleophilic difluoromethylation reagents (Scheme b) that react with an aryl electrophile via – CF 2 H anion [HF 2 C–SiMe 3 , HF 2 C–AuPAr 3 , HF 2 C–SnBu 3 , HF 2 C–Ag(SIPr), (HF 2 C) 2 Zn(DMPU) 2 , and (HF 2 C) 2 Zn(TMEDA)] or F 2 C:carbene intermediate (HF 2 C–Cl) . The third group consists of electrophilic difluoromethylation reagents (Scheme c), containing HF 2 C–I, HF 2 C–COF, HF 2 C–CI, BrF 2 C–COOEt, and Ph 3 P + CF 2 –COO – . The first two electrophilic difluoromethylation reagents undergo oxidative addition with Ni(0) or Pd(0) to generate HF 2 C–M–X (M = Ni or Pd; X = I of F) intermediates, which subsequently go through transmetalation reaction with an aryl nucleophile and finally reductive elimination reaction to produce difluoromethyl arene.…”

Two-Step Synthesis of 2-Trifluoromethylated and 2-Difluoromethylated Benzoheteroles Starting from HFO-1224yd(Z) and HFO-1233yd(Z)

“…Since benzoheteroles bearing fluoroalkyl groups, especially fluorinated one-carbon units, have attracted significant attention as promising substructures for pharmaceuticals and agrochemicals, their synthetic methods are highly desirable. Furthermore, in the past decade, there has been increasing interest in the direct trifluoro- and difluoromethylation of benzoheteroles on the 2-position. However, these reactions require the use of expensive trifluoro- and difluoromethylating reagents and often result in poor regioselectivity.…”