Cooperative dual palladium/silver catalyst for direct difluoromethylation of aryl bromides and iodides

Abstract

Difluoromethylated arenes are one of the privileged structural motifs that are important for fine tuning the biological properties of drug molecules. No general catalytic method exists for the formation of difluoromethylarenes. Previous methods for the preparation of difluoromethylarenes typically required harsh conditions, multiple steps or stoichiometric amount of catalysts. Here we report a cooperative dual palladium/silver catalyst system for direct difluoromethylation of aryl bromides and iodides under mild conditions. We develop the system by initial preparation of the putative intermediates in the dual-catalytic cycles, followed by studying the elemental steps to demonstrate the viability of the proposed cooperative catalytic cycle. The reaction is compatible with a variety of functional groups such as ester, amide, protected phenoxide, protected ketone, cyclopropyl, bromide and heteroaryl subunits such as pyrrole, benzothiazole, carbazole or pyridine.

Asymmetric Difluoromethylthiolation of Carbon Nucleophiles with Optically Pure Difluoromethylthiolating Reagents Derived from Camphorsultam

“…Our initial efforts to synthesize (1 S )‐(–)‐ N ‐difluoromethylthio‐2,10‐ camphorsultam by reaction of (1S)‐(–)‐ N ‐chloro‐2,10‐camphorsultam with a combination of TMSCF 2 H and sulfur in the presence of various activators such as cesium fluoride or potassium tert ‐ butoxide were unsuccessful. Alternatively, reaction of (1 S )‐(–)‐ N ‐ chloro‐2,10‐camphorsultam with nucleophilic difluoromethylthiolating reagent [(SIPr)Ag(SCF 2 H)] (SIPr = 1,3‐bis(2,6‐di iso propyl phenyl) imidazolin‐2‐ylidene) did not generate the desired product. Finally, it was found that treatment of difluoromethanesulfenyl chloride, which was in situ generated from difluoromethyl‐benzylthioether with a solution of chlorine in chloroform, with the Oppolzer's sultam sodium salt at room temperature afforded reagent 9a after 5 h in 74% yield (Figure ).…”

Sustainable Knowledge‐Driven Approaches in Transition‐Metal‐Catalyzed Transformations

“…In both cases, the corresponding difluoromethylated products (palladium complexes or directly the organic molecules due to fast reductive elimination) were obtained in quantitative yields. With this fundamental knowledge in hand, the authors developed a catalytic difluoromethylation protocol of aryl halides (by using catalytic amounts of silver in the case of ref ), whereas in the case of heteroaryl halides fine‐tuning of the ligand (DPEPhos instead of XantPhos) was needed to obtain high yields of the corresponding organic products (Scheme b)…”

Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

“…6 In an effort to fulfill the ever-increasing demand [ for discovering new bioactive molecules, there are increasing requirements to synthesize diversified difluoromethylated structures in an efficient, straightforward, and economical way. In this context, tremendous efforts have been made in the catalytic synthesis of difluoromethylated arenes over the past decade [7][8][9][10][11][12][13][14] ; nonetheless, efficient and direct catalytic difluoromethylation processes of terminal alkynes remain elusive. We envisaged that since alkynes are a versatile building block in organic synthesis, 15 the connection with a CF 2 H to terminal alkynes would lead to a series of synthetically useful synthons for the construction of a wide range of difluoromethylated structures that would be of great interest in medicinal chemistry, chemical biology, and advanced functional materials.…”