Revealing a Second Transmetalation Step in the Negishi Coupling and Its Competition with Reductive Elimination: Improvement in the Interpretation of the Mechanism of Biaryl Syntheses

Abstract

This paper presents an experimental and theoretical investigation of the Pd-catalyzed Negishi coupling reaction and reveals a novel second transmetalation reaction between an Ar(1)-Pd-Ar(2) species and the organozinc reagent Ar(2)-ZnX. Understanding of this second step reveals how homocoupling and dehalogenation products are formed. Thus, the second transmetalation generates Ar(2)PdAr(2) and Ar(1)ZnCl, which upon reductive elimination and hydrolysis, respectively, give the homocoupling product Ar(2)-Ar(2) and the dehalogenation product Ar(1)H. The ratio of the cross-coupling product Ar(1)-Ar(2) and the homocoupling product Ar(2)-Ar(2) is determined by competition between the second transmetalation and reductive elimination steps. This mechanism is further supported by density functional theoretical calculations. Calculations on a series of reactions suggest a strategy in controlling the selectivity of cross-coupling and homocoupling pathways, which we have experimentally verified.

Structure–Activity Relationship Analysis of Pd–PEPPSI Complexes in Cross‐Couplings: A Close Inspection of the Catalytic Cycle and the Precatalyst Activation Model

“…The effects were pronounced with complex 10, which was less reactive towards the bulkier aryl bromides and allowed for less ambiguity in the determination of the rate-limiting step. The complete absence of the cross-coupled product, along with significant amounts of 23, suggests that a second transmetalation step that competes with reductive elimination may be in effect, leading to the homocoupled products as suggested recently by Lei et al [25] Taken together, the abovementioned coupling results are consistent with transmetalation being the rate-limiting step, with the organozincs being more active. This higher activity observed with organozinc reagents may be attributed to better solubility than the Grignard reagents and/or the principle of hard and soft Lewis acids and bases.…”

Catalyst Activation, Deactivation, and Degradation in Palladium‐Mediated Negishi Cross‐Coupling Reactions

“…We attempted such modeling, which cannot be limited to the main catalytic cycle furnishing the cross-coupling product, however, but must also take into account the formation of the ArH and Ar 2 byproducts (see Scheme S1 and Figure S75 and S76 in the Supporting Information). [39] The resulting complexity leads to such a flexibility of the model that it is no longer sensitive to small modifications and indiscriminately reproduces the measured data within their scattering. We therefore were not able to discern the indi-vidual effects of RZnBr and ZnBr 2 .…”

C-C Cross-Coupling: New Methodologies, Applications and Discoveries over the Last Few Years

“…[62][63][64][65] 66 Dentre todos os complexos de paládio testados na reação modelo entre iodobenzeno e trifenilfosfino-vinil-ouro, o melhor resultado foi obtido na presença de PdCl 2 (dppf). Ligantes bidentados, como o dppf, são incapazes de quelar espécies de Au (I), através de geometria de coordenação linear, e por isso a transferência do mesmo do complexo de paládio, ao centro de ouro é impossibilitado.…”