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Chemists Merge Two Fundamental Reactions To Achieve A New Cross-Coupling Scheme

Organic Chemistry: Combining a Suzuki-Miyaura catalytic cycle with a stoichiometric metallate rearrangement yields a novel synthetic platform

by Stephen K. Ritter
January 7, 2016 | A version of this story appeared in Volume 94, Issue 2

Reaction scheme depicting conjunctive cross-coupling.
Conjunctive cross-coupling combines transmetallation steps from two reactions to create a new reaction pathway to chiral products.

In a case of teaching an old dog a new trick, Boston College researchers have discovered how to merge two important chemical transformations involving widely used organoboron reagents into one. Liang Zhang, James P. Morken, and coworkers combined key steps of the Suzuki-Miyaura cross-coupling catalytic cycle with a stoichiometric metallate rearrangement process to generate a multicomponent catalytic reaction that delivers chiral products. This new concept, which they call conjunctive cross-coupling, could have major implications in the broad field of cross-coupling reactions (Science 2016, DOI: 10.1126/science.aad6080).

Suzuki-Miyaura cross-coupling typically proceeds by insertion of a palladium catalyst into the carbon-halogen bond of an aryl halide electrophile (oxidative addition). This process is followed by a ligand passing from an organoboron reagent to palladium (transmetallation) and concluded by the catalyst coupling the aryl group and ligand together via formation of a new C–C bond and shedding the product molecule (reductive elimination).

In contrast, noncatalytic stoichiometric processes with organoboron reagents operate by addition of a metal partner such as an organolithium reagent to the organoboron reagent to form an intermediate metal boronate complex. Addition of an electrophilic reagent then promotes migration of the organoboron reagent’s ligand (1,2-metallate rearrangement), resulting in formation of two new bonds that meld the boron center, ligand, and electrophile together into the product molecule.

Chemists have generally explored these two reactions as separate occurrences. But the Morken group found a way to splice them together in a one-pot reaction. The team uses an organolithium reagent with an organoboron reagent to generate a boronate species that is intercepted by an electrophilic palladium species containing a chiral ligand that is formed by oxidative addition. The intermediate doesn’t undergo the typical Suzuki-Miyaura transmetallation step with the vinyl boronate but instead adds to the π bond of the vinyl boronate, triggering a 1,2-metallate rearrangement.

Following a reductive elimination step, the overall reaction leads to formation of two new C–C bonds and a new C–B stereocenter, delivering the product molecule with high enantioselectivity. The products are convenient organoboron compounds that can be oxidized to alcohols or used as reagents in sequential syntheses.

“It is astonishing that in the nearly 40-year history of what is probably the most-used organometallic reaction in organic synthesis—Suzuki-Miyaura coupling—a new pathway has been discovered,” says Varinder K. Aggarwal, an organoboron specialist at the University of Bristol. “Perhaps this achievement reflects our still-limited understanding of some of the key steps in cross-couplings. But those brave enough to challenge the dogma of what really goes on during the transmetallation step may find further rich veins of untapped opportunities.”



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