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Cross-Coupling Triple Play

Green Chemistry: Popular reactions using specialized boron reagents can now be run in water

by Stephen K. Ritter
November 21, 2013 | A version of this story appeared in Volume 91, Issue 47

A reaction scheme showing a 2-pyridyl boronate undergoing a Suzuki-Miyaura coupling in aqueous micelle solutions made with the surfactant TPGS-750-M.
In aqueous micelle solutions made using the surfactant TPGS-750-M, even unstable 2-pyridyl boronates readily undergo Suzuki-Miyaura cross-coupling.

Chemists have taken one of the most widely used reactions in organic synthesis—the Suzuki-Miyaura cross-coupling reaction—and made it even more versatile by melding it with an award-winning green chemistry technology. The new development will help researchers, particularly those working in drug discovery, expand the range of compounds that can be made using the cross-coupling approach and create safer and environmentally friendly processes that avoid organic solvents, excess reagents, and high temperatures.

“It is interesting to see the Suzuki-Miyaura reaction being treated in this way,” says organic chemistry professor Cathleen M. Crudden of Queen’s University, in Kingston, Ontario. “I think it demonstrates the continued importance of this reaction in the synthesis of advanced organic compounds.”

Suzuki-Miyaura cross-couplings link an organohalide and an organoboron compound with the aid of a palladium catalyst, typically to form biaryl products, which are common intermediates in drug synthesis. The reaction is one of several cross-coupling strategies for which the developers received the 2010 Nobel Prize in Chemistry.

As an integral part of the chemistry, Martin D. Burke and coworkers of the University of Illinois, Urbana-Champaign, in recent years have created a family of efficient aryl boronate coupling reagents—now widely used and commercially available—based on N-methyliminodiacetic acid (MIDA). And in an independent development, Bruce H. Lipshutz of the University of California, Santa Barbara, designed a surfactant (TPGS-750-M) specifically to use with transition-metal catalysts. When mixed with water, the commercially available surfactant creates optimally sized micelles that serve as nanoreactors for common organic reactions. Lipshutz received a 2011 Presidential Green Chemistry Challenge Award for the technology.

In the new study, Lipshutz and Nicholas A. Isley at UC Santa Barbara in collaboration with Fabrice Gallou of Novartis, in Basel, Switzerland, show how the micellar system can be used to carry out Suzuki-Miyaura cross-couplings with Burke’s MIDA boronates in water and in most cases at room temperature—a cross-coupling triple play (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja409663q).

Several features of the new reaction system weren’t possible before, Lipshutz says. These include using a 1:1 ratio of the coupling partners, rather than an excess of one partner, and the ability to use aryl bromides or aryl chlorides with the MIDA boronate partner, rather than only aryl chlorides. The strategy capitalizes on the environmentally friendly advantages of Lipshutz’s micelles, including the need for only a small amount of catalyst, easy recovery of the products by precipitation and filtration without using any organic solvent, the ability to repeatedly recycle the aqueous reaction mixture and catalyst, and essentially no waste generation (Angew. Chem. Int. Ed. 2013, DOI: 10.1002/anie.201302020).

Organic reactions that run in water typically still require extracting the product with an organic solvent, and both the water and solvent must later be treated as waste, Crudden explains. That makes the green benefits for using water as a solvent appear slim, she says. “But the new approach is an example of an effective, useful reaction run in recyclable water.”

Besides using the reaction for standard aryl-aryl cross-couplings, the system can be used to carry out couplings involving 2-pyridyl units, which are popular in pharmaceutical compounds but normally unstable in standard cross-couplings.

“This breakthrough unites powerful methodologies to achieve even very challenging cross-couplings under exceptionally mild and environmentally friendly conditions,” Burke tells C&EN. Until recently, cross-coupling of 2-pyridyl boronates still represented a major challenge, he says. “Having such reactions now accessible in water using all commercially available building blocks and reagents reflects substantial progress.”


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