Copper-Catalyzed Difluoromethylation of Aryl Iodides with (Difluoromethyl)zinc Reagent

Abstract

The combination of difluoroiodomethane and zinc dust or diethylzinc can readily lead to (difluoromethyl)zinc reagents. Therefore, the first copper-catalyzed difluoromethylation of aryl iodides with the zinc reagents is accomplished to afford the difluoromethylated arenes. The reaction proceeds efficiently through the ligand/activator-free operation without addition of ligands for copper catalyst (e.g., phen and bpy) and activators for zinc reagent (e.g., KF, CsF, and NaO-t-Bu). Moreover, transmetalation of the CF2H group from zinc reagent to copper catalyst proceeds even at room temperature to form the cuprate [Cu(CF2H)2](-).

Difluoroacetic Acid as a New Reagent for Direct C−H Difluoromethylation of Heteroaromatic Compounds

“…Currently, synthetic chemists pay great attention to the development of novel metal‐catalyzed difluoromethylation reactions . Nevertheless, these reactions rely on substitution of a halogen atom,– a boronic acid, a triflyloxy group or diazonium salt with the difluoromethylated sources, respectively. The preparation of difluoromethylated compounds via silver‐catalyzed decarboxylation of α‐fluoroarylacetic acids, α,α‐difluoroarylacetic acids were also reported .…”

Key Green Chemistry research areas from a pharmaceutical manufacturers’ perspective revisited

“…162 Beatty et al use blue LEDs and a ruthenium catalyst to generate the trifluoromethyl radical from trifluoroacetic anhydride to achieve aryl and heteroaryl trifluoromethylation. 163 The zinc reagent [(DMPU) 2 Zn(CF 2 H) 2 ] has been used for the copper catalysed difluoromethylation of aryl and heteroaryl iodides at 60°C 164 or for room temperature, nickel catalysed difluoromethylation of aryl and heteroaryl iodides, aryl bromides and triflates. 165 While geminal difluoroolefins have been prepared via carbene insertion of :CF 2 .…”

Difluoromethylation Reactions of Organic Compounds

“…Perhaps the mosti mpressive feature of the methodology is the reactivity with ArBr. Until this report,t he only other known methodf or catalytically difluoromethylating ArBr operateda t8 0 8C, [55] whereas the methodr eported by Vicic [53] operates at room temperature. Scheme 1s hows that ArBr (7-9)s ubstrates afford cross-coupled products in yields that are roughlyi dentical to those seen for the ArI counterparts (3-6).…”

“…Late-stage introduction of CF 2 Hand CF 2 Y groups into organic molecules Synthesis of C Ar(Het) ÀCF 2 Ha nd C Ar(Het) ÀCF 2 Ycompounds Vicic and colleagues [53] introduced the use of zinc reagent (DMPU) 2 Zn(CF 2 H) 2 for the direct difluoromethylation of ArÀX (X = I, [54,27] Br,O T f ), using Ni(COD) 2 as catalyst, and DPPF (1,1'bis(diphenylphosphino)ferrocene) as ligand in DMSO as solvent. The scope of the transformation is illustrated in Scheme 1.…”

“…The difluoromethylating reagents used by Vicic [53] and Mikami [56] necessitate volatile startingm aterials such as HCF 2 I. Furthermore, all the above methods require the presence of a leaving group on the arene ring.…”