Negishi cross-coupling reactions mechanisms

Fig. 4.10 Simplified reaction mechanism for the Pd-catalyzed Negishi cross-coupling reaction with ZnMeCl (L = PMePhi)...

Phapale VB, Cardenas DJ (2009) Nickel-catalyzed Negishi cross-coupling reactions scope and mechanisms. Chem Soc Rev 38 1598-1607... 

Consequently, to narrow the definition a bit further, we will adhere to Negishi s suggestion and define cross-coupling reactions as those that follow some variation of the mechanism depicted in Scheme 1 (where Mt is a transition metal, L is an ancillary hgand see Ancillary Ligand), and n is the oxidation state of the reduced metal in the catalytic cycle). This mechanism is supported by stoichiometric studies on isolated metal complexes (mostly where Mt = Pd, n = 0, L = triphenylphosphine) thought to be the intermediates in this cycle. 

Scheme 1.16 (a) General conditions for the Negishi-Baba cross-coupling reaction, (b) The proposed mechanism for the Negishi-Baba cross-coupling arylation procedure [12a],... 

W. S. Knowles, R. Noyori, K. B. Sharpless enantioselective catalysis) 2005 Y. Chauvin, R. H. Grubbs, R. R. Schrock (alkene metathesis) 2007 G. Ertl chem. processes on solid surfaces/mechanisms of heterogeneous catalysts) 2010 R. F. Heck, E. Negishi, A. Suzuki Pd Catalyzed cross coupling reactions). 

Preparations of all these organic materials involve the constmction of new carbon-carbon bonds and have prompted the development of many catalytic cross-coupling reactions. One of the most reliable synthetic methods to form carbon-carbon bonds is transition metal-catalyzed cross-coupling between organo-metallic nucleophiles and electrophilic organic halides or pseudohalides, respectively (Scheme 2a). The mechanisms of common cross-coupling reactions such as the Suzuki, Negishi, or Stille catalysis can be described by a catalytic cycle, differ in detail, but all include three main steps in the order oxidative addition, transmetallation, and reductive elimination (Scheme 1). 

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]. 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

Negishi, E., Takahashi, T., Baba, S., Van Horn, D. E., Okukado, N. Nickel- or palladium-catalyzed cross coupling. 31. Palladium- or nickel-catalyzed reactions of alkenylmetals with unsaturated organic halides as a selective route to arylated alkenes and conjugated dienes scope, limitations, and mechanism. J. Am. Chem. Soc. 1987,109, 2393-2401. 

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