Negishi Coupling
The Negishi coupling is a prominent transition metal-catalyzed cross-coupling reaction that forms carbon-carbon (C-C) bonds by coupling organic halides or triflates with organozinc compounds. This reaction is named after Ei-ichi Negishi, who was one of the pioneers in developing this methodology. The reaction typically employs a palladium (0) species as the metal catalyst, although nickel catalysts can also be used, including those in either the Ni(0) or Ni(II) oxidation states. The versatility of the Negishi coupling is evident in its ability to couple a wide range of organic residues, including alkenyl, aryl, allyl, alkynyl, or propargyl groups, with organozinc compounds that may contain chloride, bromine, or iodine as the halide, and various organic residues such as alkenyl, aryl, allyl, alkyl, benzyl, homoallyl, and homopropargyl[1].
The reaction mechanism involves several key steps: oxidative addition of the palladium catalyst into the organic halide, transmetalation where the organozinc reagent exchanges its organic substituent with the halide in the palladium complex, and finally, reductive elimination to form the coupled product and regenerate the palladium catalyst[2]. Nickel-catalyzed systems can operate under different mechanisms depending on the coupling partners, with one possible mechanism beginning with the transmetalation step first[2].
Despite its utility in forming C-C bonds between sp3, sp2, and sp carbon atoms, the Negishi coupling is not as frequently employed in industrial applications compared to its cousins, the Suzuki and Heck reactions, mainly due to the moisture and air sensitivity of the required aryl or alkyl zinc reagents[1]. However, it has found significant use in the synthesis of complex molecules, including unnatural amino acids and natural products, due to its functional group tolerance and ability to form complex structures[6].
The Negishi coupling was first published in 1977 and represented a significant advancement in the field of organic synthesis by enabling the preparation of unsymmetrical biaryls in good yields. It has since been expanded to include a broad scope of substrates beyond biaryls, demonstrating its versatility and importance in organic chemistry[4].
Citations:
[1] https://en.wikipedia.org/wiki/Negishi_coupling
[2] https://www.youtube.com/watch?v=A1XnlvGfC8Q
[3] https://pubs.acs.org/doi/10.1021/jo9018792
[4] https://www.organic-chemistry.org/namedreactions/negishi-coupling.shtm
[5] https://pubs.acs.org/doi/10.1021/acscatal.5b02718
[6] https://pubs.rsc.org/en/content/articlehtml/2018/ob/c7ob02682j
[7] https://www.sciencedirect.com/topics/chemistry/negishi-coupling
[8] https://www.youtube.com/watch?v=6IOvMpIckek
[9] https://link.springer.com/article/10.1007/s41981-022-00253-x
[10] https://www.rsc.org/publishing/journals/prospect/ontology.asp?id=RXNO%3A0000088
[11] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220771/
[12] https://www.name-reaction.com/negishi-cross-coupling
[13] https://pubs.rsc.org/en/content/articlelanding/2023/ob/d3ob00784g/unauth
[14] https://chem.libretexts.org/Bookshelves/Organic_Chemistry/Supplemental_Modules_%28Organic_Chemistry%29/Reactions/Named_Reactions/Negishi_cross-coupling
[15] https://www.chemeurope.com/en/encyclopedia/Negishi_coupling.html
[16] https://nrochemistry.com/negishi-coupling/