Synergistic Effect of a Bis(proazaphosphatrane) in Mild Palladium‐Catalyzed Direct α‐Arylations of Nitriles with Aryl Chlorides

Abstract

The effect of a bis(proazaphosphatrane) ligand on the palladium‐catalyzed direct α‐arylation of nitriles with various aryl chlorides under mild conditions is reported. Comparisons of the catalytic properties of this ligand with those of three related mono(proazaphosphatrane)s under the same reaction conditions revealed that bis(proazaphosphatrane) displayed a synergistically enhanced activity. In the presence of the bis(proazaphosphatrane) ligand, ethyl cyanoacetate and primary as well as secondary nitriles were efficiently coupled with a wide variety of aryl chlorides that contained electron‐rich, electron‐poor, and electron‐neutral groups.

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

“…In particular, they have been frequently used as starting materials for preparing a-aryl amides and carboxylic acids, including manufacturing some non-steroidal antiinflammatory drugs (NSAIDs). [2] Over the past two decades, many excellent methods for preparing a-aryl nitriles, [3][4][5][6] aaryl carboxyl acids, [7] a-aryl esters [8] and amides [9] have been developed through different coupling approaches. Among them, metal-catalyzed coupling of aryl halides with nitriles is a promising one for large-scale synthesis because both coupling partners are conveniently available and cost effective.…”

Recent Advances in Nonprecious Metal Catalysis

“…Ma and co-workers reported the preparation of α-(hetero)­aryl nitriles via Cu-catalyzed coupling of (hetero)­aryl bromides and chlorides with ethyl cyanoacetate and its α-monoalkylated derivatives (Scheme ). The reported method is a significant improvement over the known Cu-catalyzed methods, which work well only with aryl iodides, as well as the Pd-catalyzed methods, which have limited substrate scope with respect to heteroaryl halides and ethyl cyanoacetates. − Very broad functional group compatibility was observed with both (hetero)­aryl bromides and chlorides. Not surprisingly, a higher catalyst loading and reaction temperature were required for chlorides (method A) compared with bromides (method B).…”

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

“…However, it remains to be developed for the practical applications in organic synthesis. For example, Cu‐catalyzed arylation only worked well for aryl iodides, [11, 12] while Pd‐catalyzed version, albeit using rather expensive metal and ligands, is still problematic to most heteroaryl halides and α‐alkyl substituted ethyl cyanoacetate [13, 5a] . Thus, our primary goal was to develop a powerful catalytic system for Cu‐catalyzed arylation with ethyl cyanoacetate and its derivatives.…”