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Nickel Shines In Ammonia Coupling Reactions

Organic Synthesis: Chemists use nickel to replace palladium in an important catalytic reaction for making aryl amines

by Stephen K. Ritter
January 14, 2015

Reaction scheme shows how the addition of a single aryl group to ammonia using a nickel catalyst enables the synthesis of a variety of aryl and heteroaryl amines.
The addition of a single aryl group to ammonia using a nickel catalyst enables the synthesis of a variety of aryl and heteroaryl amines, such as in the reaction shown.

By developing a stable nickel catalyst system, a Canadian research team has fulfilled a quest to move beyond using expensive palladium catalysts in cross-coupling reactions to make aryl amines from ammonia. The approach taken by Andrey Borzenko, Mark Stradiotto, and coworkers of Dalhousie University, in Halifax, Nova Scotia, is expected to find quick adoption in the pharmaceutical industry, where it would be used to help synthesize complex drug candidates.

Ammonia is the simplest and most abundant N–H source in chemistry—virtually all synthetic nitrogen-containing compounds originate from the inexpensive feedstock. Industrial syntheses of amines from ammonia, however, typically require heterogeneous catalysts at relatively high temperatures and pressures, resulting in modest product selectivity. Only recently have chemists devised homogeneous palladium catalysts for the task, which allow for more selective ammonia couplings under milder conditions.

The Dalhousie team’s method is the first example of nickel-catalyzed arylation of ammonia to make amines. The researchers used Ni(cyclooctadiene)2 or NiCl2(dimethoxyethane) with a ferrocenyl phosphine ligand known as JosiPhos to link up a range of substituted aryl and heteroaryl bromides, chlorides, and tosylates with ammonia to make diverse aryl and heteroaryl amines (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201410875).

“Catalysis with nonprecious metals is one of our primary goals in the pharmaceutical industry,” says Robert A. Singer, a process chemist at Pfizer. There are a number of attributes to like about the new work, Singer notes. Nickel is much more abundant and less expensive to use than palladium. The new catalyst is also air stable and less susceptible to ammonia deactivation or ligand dissociation.

The method does require more catalyst than might be ideal, however, which could pose a challenge in purifying final products, Singer notes. And the specialty phosphorus ligand is costly, which might require a replacement. But process chemists in pharma “will find this specific work interesting in that Stradiotto’s group demonstrates that nickel-catalyzed arylations of ammonia can be competitive with palladium-catalyzed technology,” Singer says.


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