The Negishi Reaction Mechanism

The results presented in this chapter have been published in the following two articles Article 1 Puentes, B. Garcia-Mdchor, M. Lledos, A. Maseras, F Casares, J. A. Ujaque, G. Espinet, P. Cherru Ear. J. 2010,16, 8596-8599. 

Melchor, A Theoretical Study of Pd-Catalyzed C-C Cross-Coupling Reactions, Springer Theses, DOI 10.1007/978-3-319-01490-6 4, 

As in all C-C cross-coupling reactions, the Negishi reaction mechanism consists in three steps (Fig.4.1) oxidative addition, transmetalation, and reductive elimination. The former and the latter are common to all the other cross-coupling reactions, whereas the transmetalation step is particular of this reaction. Unfortunately, this transmetalation has been less studied compared to the ones in the Stille [12-17] or Suzuki reactions, [18-21] in spite of the fact that the transmetalation between organozinc and palladium complexes is also involved in other relevant processes, such as the hydroalkylation of styrenes, [22] the asymmetric allylation of aryl aldehydes, [23] the coupling propargylic benzoates and aldehydes, [24] or the double-transmetalation oxidative cross-coupling reaction [25, 26]. 

It is worth mentioning that, besides the studies of Espinet et al. [27] and Lei et al. [29] above mentioned, the number of mechanistic studies reported to date concerning the Negishi reaction are more than scarce. In fact, to our knowledge, there are only the ones from Organ et al. [30] and M6zailles et al. [31] The former, published the same year than Lei et al. s paper, [29] involved the theoretical investigation of the 

2 The Transmetalation Step in the Negishi Coupling of 7 a s-[PdMeCl(PMePh2)2] with ZnMeCI 

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Acmeilly, when we started our studies on the Negishi reaction mechanism, no related studies had been reported yet. 

Until recently, little was known about the mechanism of the Negishi reaction mediated by NHC-Pd complexes. Over the past decade, the Organ group has studied the Negishi reaction intensely using its Pd-PEPPSl complexes and many important details about the mechanism of transmetalation as well as the role of additives and polar co-solvents have been discovered. 

Scheme 2.15 Mechanism of the Negishi reactions cataiyzed by complex 41.

Scheme 10.11 Possible mechanisms of the Negishi reaction catalyzed by the adamantyl-derived, phosphine-based palladium pincer complex [C- QH- 3-l,3-(CH2P(Cy2)2)Pd(CI)] (22), of which only path C (bold arrows) explains all the experimental observations. The relative energies are given for aryl Ar = Ar = phenyl.

Scheme 4.11 Plausible mechanism of the palladium 1,2-migration in the Negishi reaction...

In 1978, Negishi et al. reported highly regio- and stereoselective methylalumination of alkynes with Me3Al using a zirconocene catalyst [59]. The involvement of cationic zirconocene species in the activation of carbon—carbon triple bonds was suggested in a reaction mechanism featuring electrophilic activation by aluminum (Scheme 8.30). 

In 2009, Organ and co-workers studied the mechanism of the alkyl-alkyl Negishi reaction and, through DFT computations, revealed transmetalation to be the rate-limiting step and not oxidative addition A key Pd-Zn interaction was also identified in the mechanism to persist beyond reductive elimination. This interaction, in combination with the NHC ligand was shown to help facilitate reductive elimination by creating a highly sterically crowded environment in the Pd coordination sphere. 

The mechanisms for Negishi reactions catalyzed by a Ni(0) or Ni(II) species combined with a terpy- or Pybox-type ligand warrant some discussion. If the conventional cross[Pg.136]

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