Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium

Abstract

Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCFH), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CFH) from ClCFH into aromatics has not been reported. Here, we describe a direct palladium-catalysed difluoromethylation method for coupling ClCFH with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal-difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal-difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understand metal-difluorocarbene complex catalysed reactions.

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

“…Based on our observation and the recent mechanistic studies, we propose the mechanism depicted in Scheme for mono‐difluoromethylation of quinoline. Specifically, we proposed that the formation of difluoromethyl radical is evoked by silver(I)‐catalyzed oxidative decarboxylation of difluoroacetic acid by persulfate and subsequent addition to the heteroaromatic ring.…”

“…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 .…”

Difluoroacetaldehyde N‐Triftosylhydrazone (DFHZ‐Tfs) as a Bench‐Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

“…[12] Particularly,t he difluoromethyl group can also act as ab ioisostere for carbinol, thiol, hydroxamic acid, and amide groups. [13] Surprisingly,our initial study on the reaction of p-methylstyrene 1a with DFHZ-Tfs by iron catalysis under alkaline aqueous conditions exclusively afforded cyclopropane carboxaldehyde 2a in 91 %y ield with high diastereomeric ratio (9:1), rather than the expected difluoromethylated cyclopropane (Scheme 1b). This result suggests the exclusive formation of adiazoacetaldehyde species (for optimization details,see the Supporting Information, Table S1).…”

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.…”