The cross-coupling reaction is old enough that even I, no longer a young scientist, learned about it in college. Indeed, the problem of coupling sp-based carbon nucleophiles and electrophiles was recognized as being important but difficult as long ago as 1941 by Kharasch, who found that coupling reactions of Grignard reagents worked better when traces of transition metals were present in the system. As it often happens in science, the seeds for the discovery of this excitingmodern synthetic tool lay dormant in the fertile soil of the scientific literature until the groups of Kochi, Corriu, and Kumada, among others, realized in 1971–1972 that discrete transition metal catalysts (Ag, Fe, Ni) can be devised to carry out these reactions in good yield and with some generality. Palladium rose to center stage more slowly a few years later, through thework ofMurahashi, followedbymanyothers. But Grignard reagents were not the only organometallic species in the world, and indeed not the most synthetically useful. Negishi and co-workersmust be credited with bringing more practical reagents into the menu of the synthetic organic chemist, i.e., Al, Zr and the now very popular Zn derivatives. Indeed, among practitioners, cross-coupling reactions involving organozinc reagents are now referred to as “Negishi couplings”. In 1968, even before the cross-coupling reactionmade it to the forefront of organic synthesis, Richard Heck had brought to light the reaction that now bears his name. His first entry into the field was a stunning series of seven consecutive papers with his name as the only author. The innumerable important observations contained in these early papers and those which soon followed transformed this unusual reaction into a general synthetic method. It has taken the synthetic community many years to realize the immense potential of theHeck reaction, and in the last 20 years countless refinements, extensions (e.g., enantioselective cyclizations), and applications have been reported. In 1975, Sonogashira found that alkynes could be coupled directly with carbon electrophiles, without preparing first an organometallic reagent, if both a Pd and aCu catalyst were used in tandem. The Sonogashira coupling is now a very popular synthetic tool in academia as well as in industry. In the late 1970s, tin derivativeswere shown to also undergo Pd-catalyzed coupling with a broad range of electrophiles, mainly through the work of Kosugi and Migita and Stille. These couplings are now referred to as the “Stille reaction”, and constitute an extremely important tool in the discovery of pharmaceuticals, the total synthesis of complex natural products, the synthesis of materials and devices, etc. It turned out to be more difficult to induce boron to undergo this reaction. I was a graduate student at the University of Alberta when I saw Akira Suzuki lecture for the first time. I was told by the organizers that Prof. Suzuki was going to disclose an important unpublished result. I listened carefully as he told us how he andNorio Miyaura had just found that organoboron compounds, easily available through a variety of synthetic means, can be made to cross-couple through the formation of “ate” complexes. The Suzuki reaction had been born. For us in the pharmaceutical industry, this is now the most practical way to cross-couple aromatics and heteroaromatics, and we have become quite skilled COMMENTARIES
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Jan 1, 2017
Darren J Dixon + 1
