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Synthesis

Chemists Couple Nucleophiles From Two Name Reactions

Organic Synthesis: New reaction is first to marry Suzuki and Hiyama reagents selectively

by Stu Borman
February 12, 2015 | APPEARED IN VOLUME 93, ISSUE 7

Biaryl compounds result from Hiyama coupling reagents (blue) plus Suzuki coupling reagents (red). R1 and R2 are substituent groups, Ac is acetyl, and new C–C bond is black.

Researchers have developed a cross-coupling reaction that yields paired-ring compounds by marrying the reactive starting materials from two well-known C–C bond-forming reactions.

Arylsilanes and arylboronic acids are two nucleophilic reagents widely used in “name” reactions to form cross-coupling products with other compounds. But they have never before been convinced to walk down the aisle together. The new reaction fills a niche in chemists’ C–C bond-forming arsenal, easing the way to products that are difficult or impossible to make with existing cross-coupling reactions.

Transition-metal-catalyzed C–C bond-forming reactions are among the most widely used transformations in organic synthesis. In name reactions such as Suzuki and Hiyama coupling, an organic electrophile such as an alkyl or aryl halide combines with an organometallic nucleophile to form a cross-coupling product.

A few cross-coupling reactions that combine two electrophilic reagents or two nucleophilic compounds have been developed previously, but they are much more rare. A common problem with these reactions is strong competition from undesired homocoupling—addition of a compound to itself, instead of to its reaction partner—making it difficult to achieve high selectivity for desired products.

Now, Yanghui Zhang and coworkers at Tongji University, in Shanghai, have developed a reaction that cross-couples two nucleophilic compounds highly selectively (Angew. Chem. Int. Ed. 2015, DOI: 10.1002/anie.201412288). It combines aryl trialkoxysilanes, Hiyama reagents, with aryl boronic acids, Suzuki reagents, to form predominantly cross-coupled products. Palladium(II) with a commercially available 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) ligand catalyzes the reaction through a mechanism that suppresses homocoupling.

Jin-Quan Yu of Scripps Research Institute California, an expert in C–C bond formation, comments that the new reaction successfully addresses the major hurdle of a preference for homocoupling in coupling reactions of two nucleophiles. “It could prove handy in scenarios where Suzuki and Hiyama coupling cannot be used,” he says. For example, “Suzuki cross-coupling is often not compatible with boronic acid reagents containing a bromine or iodine substituent, but with the new reaction that may not be a problem.” If the reaction can be extended to coupling alkyl reagents, “it could become a broadly useful method for making carbon-carbon bonds.”

Indeed, Zhang confirms that “extending the protocol to other substrates, including alkylboronic acids and alkylsilanes,” is under way in his lab. He says he and his coworkers also hope to extend it to the synthesis of chiral biphenyl compounds.

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