Mechanistic Insight into Palladium-Catalyzed Cycloisomerization: A Combined Experimental and Theoretical Study

Abstract

The cycloisomerization of enynes catalyzed by Pd(OAc) and bis-benzylidene ethylenediamine (bbeda) is a landmark methodology in transition-metal-catalyzed cycloisomerization. However, the mechanistic pathway by which this reaction proceeds has remained unclear for several decades. Here we describe mechanistic investigations into this reaction using enynamides, which deliver azacycles with high regio- and stereocontrol. Extensive H NMR spectroscopic studies and isotope effects support a palladium(II) hydride-mediated pathway and reveal crucial roles of bbeda, water, and the precise nature of the Pd(OAc) pre-catalyst. Computational studies support these mechanistic findings and lead to a clear picture of the origins of the high stereocontrol that can be achieved in this transformation, as well as suggesting a novel mechanism by which hydrometalation proceeds.

Mechanism of Mechanochemical C−H Bond Activation in an Azobenzene Substrate by PdII Catalysts

“…These experiments suggest that AZB , along with the liquid additive, plays an important role in breaking of the trimeric structure to either a trimeric open structure, dimeric or even monomeric species (Scheme ). Similar ligand effect was observed for cycloisomerization of enynes catalyzed by [Pd(OAc) 2 ] 3 in solution . Taking into account that LAG reactions are faster than analogous ILAG reactions, we suggest that di‐ or monomeric species, which are formed in AcOH solution of [Pd(OAc) 2 ] 3 and NaOAc, are not prevailing in LAG but might occur under ILAG conditions.…”

“…Similar ligand effect was observed for cycloisomerization of enynes catalyzed by [Pd(OAc) 2 ] 3 in solution. [20] Ta king into account that LAG reactions are fastert han analogous ILAG reactions, we suggest that di-or monomeric species, which are formed in AcOH solution of [Pd(OAc) 2 ] 3 and NaOAc, [21] are not prevailing in LAG butm ight occuru nder ILAG conditions. This is supported by PXRD (FigureS53)a nd IR ( Figure S36) analysis of the mixture obtained by IAG milling of [Pd(OAc) 2 ] 3 with NaOAc for 2hours.…”

Palladium‐Catalyzed Intramolecular Alder‐Ene Type Cycloisomerization Reactions

“…However, the exact role of the ligand BBEDA and its interaction with palladium pre-catalyst were unclear until Paton and Anderson delineated a combined experimental and theoretical study of the cycloisomerization of enynamides 6 to pyrrolidines 7 (Scheme 7). [12] Under experimental conditions, lesser conversion and slower rate of reaction were observed in the absence of BBEDA and water (Scheme 7). [12] Extensive 1 H NMR spectroscopic studies, a study of isotope effects, and computational studies supported a Pd(II)-hydride mediated pathway.…”

“…[12] Under experimental conditions, lesser conversion and slower rate of reaction were observed in the absence of BBEDA and water (Scheme 7). [12] Extensive 1 H NMR spectroscopic studies, a study of isotope effects, and computational studies supported a Pd(II)-hydride mediated pathway. These studies also revealed the crucial roles of BBEDA, water, and the pre-catalyst [Pd(OAc) 2 ].…”

“…Based on extensive experimental and theoretical analysis, it was suggested that the activated enynamides Q undergo hydropalladation to generate R, which further undergoes carbopalladation to generate a stable alkylpalladium species S (Scheme 8). [12] Next, decomplexation of the enamide S occurs followed by the CÀ C bond rotation (to T) and β-hydride elimination to afford U. A subsequent reductive elimination completes the catalytic cycle and generates 1,3-dienes 7.…”