Negishi Cross Coupling Reaction

• General Characteristics

-While cross coupling reactions based on organolithium and Grignard reagents (Kumada-Tamao-Corriu cross coupling) tend to suffer from unwanted side reactions when applied to complex systems due to the naturally high reactivity of the reagents, the reaction using organozinc reagents (formed by transmetallation with zinc chloride) enables cross couplings under milder conditions.

-The reactivity is generally high.

-Alkyl(sp³)zinc compounds are viable substrates.

-The reaction has high functional group tolerance.

-The reactions based on organoaluminum and organozirconium reagents are also considered as variants of Negishi coupling.

• General References

・King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun. 1977, 683. DOI: 10.1039/C39770000683
・Negishi, E; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821. DOI: 10.1021/jo00430a041
・Negishi, E. Acc. Chem. Res. 1982, 15, 340. DOI: 10.1021/ar00083a001
・Erdik, E. Tetrahedron 1992, 48, 9577. doi:10.1016/S0040-4020(01)81181-9
・Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117. DOI: 10.1021/cr00022a008
・Negishi, E. et al. Aldrichimica Acta 2005, 38, 71. [PDF]
・Pd-Catalyzed Cross Coupling in Total Synthesis: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. doi:10.1002/anie.200500368

•  Reaction Mechanism

The basic generic catalytic cycle is same as other palladium-catalyzed cross coupling reactions. (Ref: J. Am. Chem. Soc. 2007, 129, 3508.)

An example in the context of total synthesis of scabronine G.^[1]

Newer systems in which secondary alkyl halides (for which β-hydride elimination is notoriously fast) can be used have been developed. An example shown below is one of the asymmetric versions reported by Fu.^[2]

• Experimental Procedure

• Experimental Tips

• References

[1] Waters, S. P.; Tian, Y.; Li, Y.-M.; Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 13514. DOI: 10.1021/ja055220x
[2] Arp, F. O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482. DOI: 10.1021/ja053751f

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cross-coupling, nobel prize, organozinc, palladium