Ligand Relay for Nickel‐Catalyzed Decarbonylative Alkylation of Aroyl Chlorides

Abstract

Transition metal‐catalyzed direct decarboxylative transformations of aromatic carboxylic acids usually require high temperatures, which limit the substrate's scope, especially for late‐stage applications. The development of the selective decarbonylative of carboxylic acid derivatives, especially the most fundamental aroyl chlorides, with stable and cheap electrophiles under mild conditions is highly desirable and meaningful, but remains challenging. Herein, a strategy of nickel‐catalyzed decarbonylative alkylation of aroyl chlorides via phosphine/nitrogen ligand relay is reported. The simple phosphine ligand is found essential for the decarbonylation step, while the nitrogen ligand promotes the cross‐electrophile coupling. Such a ligand relay system can effectively and orderly carry out the catalytic process at room temperature, utilizing easily available aroyl chlorides as an aryl electrophile for reductive alkylation. This discovery provides a new strategy for direct decarbonylative coupling, features operationally simple, mild conditions, and excellent functional group tolerance. The mild approach is applied to the late‐stage methylation of various pharmaceuticals. Extensive experiments are carried out to provide insights into the reaction pathway and support the ligand relay process.

Decarbonylative C(sp2)–C(sp2) reductive cross-coupling of aroyl fluorides with aryl bromides by palladium/cobalt co-catalysis

“…Considering certain stability and moderate reactivity of aroyl fluorides among aryl carboxylic acid derivatives, 1 c , d we first selected 4-methoxybenzoyl fluoride 1a and bromobenzene 2a as model substrates to establish catalytic conditions (Table 1). Despite previous successes for nickel-catalyzed decarbonylative C(sp 2 )–C(sp 3 ) reductive cross-coupling, 8 unfortunately, we did not observe the desired coupling product 3a under nickel catalysis. 11 Subsequently, inspired by the remarkable performance of a palladium catalyst and an electron-rich phosphine ligand in decarbonylative coupling reactions, 2 a , c ,12 we found that the decarbonylative reductive coupling product 3a could be detected in 42% yield with minor homo-coupling of 1a in the presence of Pd(OAc) 2 (5.0 mol%) as a catalyst, L1 as a ligand, and Zn dust as a reductant in 2-Me-THF at 130 °C for 24 h. The typical polar solvents such as DMA, DMPA and non-polar solvent toluene had no effect on this transformation (Table 1, entries 2–4).…”

“…7 Very recently, a few examples have been reported on decarbonylative C(sp 2 )–C(sp 3 ) reductive cross-coupling of aromatic carboxylic acid derivatives with alkyl electrophiles by Nishihara, Cernak, Weix and Liang. 8 With our continuous interest in reductive cross-coupling of inert aryl electrophiles, 9 herein, we disclose the first decarbonylative C(sp 2 )–C(sp 2 ) reductive cross-coupling of aroyl fluorides with aryl bromides by palladium and cobalt co-catalysis. 10…”

N-Alkoxyphthalimides as Nitrogen Electrophiles to Construct C–N Bonds via Reductive Cross-Coupling

“…On the basis of the above experimental results and literature reports, − we proposed the corresponding mechanism cycles for this Ni-catalyzed reductive coupling for the construction C–N bonds (Scheme ). Initially, the active Ni 0 A was formed via reduction of Ni II with Mn followed by the oxidative addition into the N–O bond to form Ni II intermediate B , which then captured the alkyl radical to give Ni III intermediate C .…”

“…Nickel, one of the most earth-abundant transition metals, has always been widely used in reductive cross-couplings thanks to its strong catalytic ability, relative low price, and widespread existence . Over the past decade, construction of C–C bonds using this tactic has been deeply explored, and many elegant works have thus been reported . Construction of carbon–hetero bonds using a reductive cross-coupling strategy also received much attention, and many developments have been made in recent years.…”