Assembly of α‐(Hetero)aryl Nitriles via Copper‐Catalyzed Coupling Reactions with (Hetero)aryl Chlorides and Bromides

Abstract

a-(Hetero)aryl nitriles are important structural motifs for pharmaceutical design. The known methods for direct synthesis of these compounds via coupling with (hetero)aryl halides suffer from narrow reaction scope. Herein, we report that the combination of copper salts and oxalic diamides enables the coupling of a variety of (hetero)aryl halides (Cl, Br) and ethyl cyanoacetate under mild conditions, affording a-(hetero)arylacetonitriles via one-pot decarboxylation. Additionally, the CuBr/oxalic diamide catalyzed coupling of (hetero)aryl bromides with a-alkyl-substituted ethyl cyanoacetates proceeds smoothly at 60 8C, leading to the formation of a-alkyl (hetero)arylacetonitriles after decarboxylation. The method features a general substrate scope and is compatible with various functionalities and heteroaryls.

Cu-Mediated Ullmann-Type Cross-Coupling and Industrial Applications in Route Design, Process Development, and Scale-up of Pharmaceutical and Agrochemical Processes

“…89 Very recently, Ma and co-workers discovered that the coupling of (hetero)aryl chlorides with ethyl cyanoacetate underwent a one-pot C(sp 3 )−H arylation and decarboxylation process with the assistance of ligand L50 in the presence of sodium tert-butoxide (NaOt-Bu), thus providing a facile method for the preparation of diverse α-(hetero)aryl nitriles (Scheme 17). 90 When using (hetero)aryl bromides as the coupling partners, a series of α-alkyl ethyl cyanoacetates reacted smoothly in the presence of a modified ligand.…”

Room Temperature Cu-Catalyzed N-Arylation of Oxazolidinones and Amides with (Hetero)Aryl Iodides

“…Recently, our group has revealed oxalic diamides as the second generation of ligands for the Cu-catalyzed arylation of nucleophiles, which not only activated humble reactive aryl chlorides but also made the coupling of aryl halides (Br and I) more efficient even at lower catalytic loadings and reaction temperatures . As an extension of this work, in this paper we explored the possibility of applying oxalic diamide ligands to promote the Cu-catalyzed N -arylation of 2-oxazolidinones.…”

Rapid and Simple Access to α-(Hetero)arylacetonitriles from Gem-Difluoroalkenes

“…Recently, Liu's group 25 described an effective cyanation of δdisubstituted para-quinone methides with TMSCN, affording a series of diarylmethane derivatives. Very recently, Ma et al 26 reported a convenient approach for preparing α-(hetero)arylnitriles by Cu-catalyzed coupling reaction of (hetero)aryl halides (Cl, Br) with ethyl cyanoacetate. This method features a broad substrate scope and is compatible with a variety of functional groups and heteroaryls.…”