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Salt Additives Can Be Used To Tailor Negishi Cross-Couplings

Organic Synthesis: Chemists find that adding a salt affects aryl- and alkylzinc reagents differently

by Stephen K. Ritter
April 3, 2014 | A version of this story appeared in Volume 92, Issue 14

Reaction scheme shows how a salt additive such as LiCl is necessary in some cases for Negishi cross-couplings to succeed.
A salt additive such as LiCl is necessary in some cases for Negishi cross-couplings to succeed.

Since its discovery in 1977, the Nobel Prize-winningNegishi cross-coupling reaction has been widely used for stitching together two organic groups to make complex molecules, ranging from antibiotics to electroactive compounds in light-emitting diodes. After nearly 40 years of using this popular reaction, chemists have found new insight into how salt additives can drive specific types of Negishi couplings.

This fundamental observation means that chemists no longer need to rely on one set of standard conditions that always seems to work for Negishi couplings. Instead, they can pick and choose reaction conditions to optimize couplings, in some cases eliminating salt additives to create greener reaction conditions.

In Negishi cross-couplings, a zinc reagent is typically prepared from an organometallic precursor and a zinc halide. The zinc reagent then transfers its organic group to a palladium catalyst, a process known as transmetalation. The palladium complex then mediates C–C coupling of the organic group with a second organic group contributed by an organohalide.

Lucas C. McCann and Michael G. Organ of York University, in Toronto, find that aryl- and alkylzinc reagents used to supply one of the coupling partners require different amounts of a metal halide salt additive such as LiCl for cross-coupling to occur (Angew. Chem. Int. Ed. 2014, DOI: 10.1002/anie.201400459).

The new salt discovery is the culmination of a 10-year-long research odyssey for Organ’s group to understand unusual effects involving organozinc reagents in Negishi cross-couplings. In 2012, Organ’s team reported that an alkylzinc dianion, RZnX32– (where R is an alkyl group and X is a halide), not a monoanion RZnX2 as previously thought, is the active transmetalating reagent in Negishi alkyl cross-coupling reactions.

During a series of further experiments, McCann and Organ have now found that diarylzinc compounds (R2Zn) don’t form zinc anionic species and they participate in cross-coupling without the aid of a salt additive and in a relatively nonpolar solvent such as tetrahydrofuran (THF). But monoarylzinc compounds (RZnX) fail to couple in THF without the salt, although the reactions do proceed without salt when a polar cosolvent such as N,N'-dimethyl-2-imidazolidinone (DMI) is included.

The key, Organ explains, is selecting the right combination of zinc reagent and solvent polarity, which can be adjusted as needed by adding the salt, to prevent zinc aggregates from forming and inhibiting transmetalation. “Some reactions may have failed in the past only because they were not salty enough,” Organ says.

Alkylzinc reagents (RZnX32–) require both salt and a high-polarity solvent such as DMI, he adds. The Organ group’s systematic experiments to understand the role of salt additives reveal that dialkylzinc reagents (R2Zn), unlike their diaryl counterparts, don’t transmetalate and undergo cross-coupling at all, despite previous claims in the literature that they do. “The misunderstanding has its origin in the preparation of these organozinc reagents that is invariably accompanied by the production of salt by-products, which are typically not removed in commercially supplied material,” Organ says. “The salt has been present all along, and chemists have not realized the essential role salt plays in the Negishi reaction.”

“This interesting manuscript gives new information on the behavior of zinc reagents and is a fundamental contribution to the understanding of Negishi reactions,” says Paul Knochel of Ludwig Maximilian University of Munich, who specializes in palladium-catalyzed cross-coupling reactions. In particular, the ability of diarylzinc to undergo transmetalation in low-polarity solvents without a salt is an important finding, Knochel notes. “It will certainly lead to improved reaction conditions for performing Negishi cross-couplings.”


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