Discovery of oxalohydrazides as a new ligand class for copper-catalyzed C-O and C-N cross-coupling reactions with high turnover numbers

The development of nitrogen- and oxygen-based ligands for copper-catalyzed coupling reactions lags behind that of phosphines for analogous palladium-catalyzed coupling reactions. In particular, ligands that generate copper catalysts that react with lifetimes resembling those of palladium catalysts have been lacking. We developed a class of ligand based on oxalohydrazides containing N-amino pyrrole and N-amino indole groups that generates long-lived copper catalysts for couplings to form C-O bonds in biaryl ethers. Copper-catalyzed coupling of phenols with aryl bromides occurred with 8000 turnovers, which is nearly two orders of magnitude higher than prior couplings to form biaryl ethers and nearly an order of magnitude higher than those of any prior copper-catalyzed coupling of aryl bromides and chlorides. This ligand also led to copper systems that catalyze the coupling of aryl chlorides with phenols and the coupling of aryl bromides and iodides with primary benzylic and aliphatic alcohols. A wide variety of functional groups including nitriles, halides, ethers, ketones, amines, esters, amides, vinylarenes, alcohols and boronic acid esters were tolerated, and reactions occurred with aryl bromides in pharmaceutically related structures.

The activity of the oxalohydrazides in Cu-catalyzed C-N coupling of aryl halides was investigated, and through a systematic screening of reaction parameters, we accomplished the development of a Cu-catalyzed C-N coupling platform where aryl halides coupled with challenging substrates such as ammonia, primary aliphatic and benzylic amines with turnover numbers (TON) approaching 2000. A notable achievement in this regard was the standardization of a Cu-catalyzed C-N coupling protocol for coupling of aryl bromides with free hydrazine with a TON of 1500 by exploiting the unique activity of the oxalohydrazides, with little to no unwanted dehydrohalogenation or polyarylation in these reactions.