Cu-Catalyzed C–N Coupling with Sterically Hindered Partners

Abstract

Copper, an earth-abundant metal, has reemerged as a viable alternative to the versatile Pd-catalyzed C–N coupling. Coupling sterically hindered reaction partners, however, remains challenging. Herein, we disclose the discovery and development of a pyrrole-ol ligand to facilitate the coupling of ortho-substituted aryl iodides with sterically hindered amines. The ligand was discovered through a library screening approach and highlights the value of mining heteroatom-rich pharmaceutical libraries for useful ligand motifs. Further evaluation revealed that this ligand is uniquely effective in these challenging transformations. The reaction enables the coupling of sterically hindered primary and secondary amines, anilines, and amides with broad functional group tolerance.

Recent Advances in Nonprecious Metal Catalysis

“…In fact, cross-coupling of bulky and/or less reactive substrates remains a problem to be addressed in copper catalysis. Along these lines, a collaboration between the Cook group at Indiana University and process chemists at AbbVie recently discovered a novel pyrrole-ol-based N,O ligand by mining through a library of heteroatom-rich compounds with the assistance of high-throughput screening . Interestingly, subsequent screening of 46 established ligands for copper catalysis led to insignificant yields in the model reaction, thus highlighting the unprecedented and unique reactivity of the novel pyrrole-ol ligand.…”

“…Along these lines, a collaboration between the Cook group at Indiana University and process chemists at AbbVie recently discovered a novel pyrrole-ol-based N,O ligand by mining through a library of heteroatom-rich compounds with the assistance of highthroughput screening. 58 Interestingly, subsequent screening of 46 established ligands for copper catalysis led to insignificant yields in the model reaction, thus highlighting the unprecedented and unique reactivity of the novel pyrrole-ol ligand. Although the ligand is prone to decomposition under basemediated conditions and high temperature, addition of Hantzsch ester increased the catalyst lifetime.…”

Pd-Catalyzed Cross-Coupling of Hindered, Electron-Deficient Anilines with Bulky (Hetero)aryl Halides Using Biaryl Phosphorinane Ligands

“…Also rare are reactions of ortho , ortho′ -disubstituted ArX with ortho -substituted, electron-poor anilines . This class of C–N couplings is also not well precedented with Ni- and Cu-catalyzed methods. , …”

Divergent oxidative dearomatization coupling reactions to construct polycyclic cyclohexadienones

“…If so, we could design copper- and palladium-catalyzed C–H oxidative dearomatization/Heck or Ullmann coupling domino reactions to synthesize polyfunctionalized cyclohexadienones, because palladium-catalyzed Heck coupling reaction and copper-catalyzed Ullmann coupling reaction are very important strategies for the construction of C–C and C-heteroatom bonds. 7,8 The You group has reported a copper catalyzed intermolecular oxidative dearomatization reaction of naphthols via cross-etherification using air as an oxidant (Scheme 1b). 9 This kind of reaction path is also possible in our reaction design.…”