N-Heterocyclic Carbenes in Late Transition Metal Catalysis

Palladium-catalyzed C-C and C-N bond-forming reactions are among the most versatile and powerful synthetic methods. For the last 15 years, N-heterocyclic carbenes (NHCs) have enjoyed increasing popularity as ligands in Pd-mediated cross-coupling and related transformations because of their superior performance compared to the more traditional tertiary phosphanes. The strong sigma-electron-donating ability of NHCs renders oxidative insertion even in challenging substrates facile, while their steric bulk and particular topology is responsible for fast reductive elimination. The strong Pd-NHC bonds contribute to the high stability of the active species, even at low ligand/Pd ratios and high temperatures. With a number of commercially available, stable, user-friendly, and powerful NHC-Pd precatalysts, the goal of a universal cross-coupling catalyst is within reach. This Review discusses the basics of Pd-NHC chemistry to understand the peculiarities of these catalysts and then gives a critical discussion on their application in C-C and C-N cross-coupling as well as carbopalladation reactions.

Palladium Complexes of N-Heterocyclic Carbenes as Catalysts for Cross-Coupling Reactions—A Synthetic Chemist's Perspective

On the Interpretation of Deuterium Kinetic Isotope Effects in C ? H Bond Functionalizations by Transition-Metal Complexes

This critical review discusses historical and contemporary research in the field of transition metal-catalyzed carbon–hydrogen (C–H) bond activation through the lens of stereoselectivity. Research concerning both diastereoselectivity and enantioselectivity in C–H activation processes is examined, and the application of concepts in this area for the development of novel carbon–carbon and carbon–heteroatom bond-forming reactions is described. Throughout this review, an emphasis is placed on reactions that are (or may soon become) relevant in the realm of organic synthesis (221 references).

Transition metal-catalyzed C–H activation reactions: diastereoselectivity and enantioselectivity

The development of catalytic reactions of alkenes transformed the chemical industry in the mid-20th century. Representative reactions included hydrogenation, oxidation, hydroformylation, oligomerization and polymerization. In 1959, researchers at Wacker Chemie developed a Pd-catalyzed method for the aerobic oxidative coupling of ethylene and water to produce acetaldehyde (eq 1, Scheme 1).1,2,3 This reaction represented the starting point for the development of numerous other Pd-catalyzed reactions in subsequent decades, ranging from alkene and diene oxidation reactions to cross-coupling reactions of aryl halides. 




(1)





Scheme 1

The Wacker Reaction.




The stoichiometric oxidation of ethylene by aqueous PdII salts had been known since the 19th century;4 however, the industrial Wacker Process owes its success to the recognition that the oxidized catalyst could be regenerated by molecular oxygen in the presence of cocatalytic CuCl2 (Scheme 1). The reaction proceeds through a β-hydroxyethyl-PdII intermediate that forms via the net addition of hydroxide and Pd across the C–C double bond of ethylene. This seemingly straightforward “hydroxypalladation” step has been the subject of extensive mechanistic research and controversy over the past five decades. A major focus of this debate has centered on whether the reaction proceeds by a cis-hydroxypalladation pathway, involving migration of a coordinated water or hydroxide to the ethylene molecule (eq 2), or a trans-hydroxypalladation pathway, involving nucleophilic attack of exogenous water or hydroxide on the coordinated ethylene molecule (eq 3). The current mechanistic understanding of the hydroxypalladation step in the Wacker Process is the subject of an excellent recent review by Keith and Henry.3




(2)







(3)



Soon after the discovery of the Wacker process, a number of research groups demonstrated that PdII could facilitate the addition of several different nucleophiles to alkenes, and a variety of oxidative and non-oxidative C–O, C–N, and C–C bond-forming transformations have been developed, including intra- and intermolecular reactions.5 The PdII-alkyl intermediate formed in the nucleopalladation step can participate in a number of subsequent transformations (e.g., see Scheme 2). Such opportunities, together with the broad functional-group compatibility and air- and moisture-tolerance of the PdII-catalysts, enable the preparation of important organic building blocks as well as useful hetero- and carbocyclic molecules.



Scheme 2

Versatility of the PdII-Alkyl Intermediate Arising from Alkene Nucleopalladation.



Nucleopalladation of an alkene often generates a new stereogenic center, and the synthetic utility of the catalytic reactions is enhanced significantly if the stereochemical course of C–Nu bond formation can be controlled. Enantioselective PdII-catalyzed functionalization of alkenes has experienced considerably less success than have many other classes of enantioselective transformations, despite the extensive history of the Wacker process and related oxidation reactions. The former reactions face several challenges. Phosphine ligands, which have been highly successful in other enantioselective processes, are often incompatible with the oxidants used in these reactions (such as O2), and their σ-donating ability can attenuate the electrophilicity and/or oxidizing ability of the PdII salts. A mechanistic basis for the difficulty in achieving effective enantioselective catalysis is that nucleopalladation reactions are capable of proceeding by two stereochemically different pathways: cis- or trans-nucleopalladation (Scheme 3). Experimental results obtained over the past 40 years, especially in the last decade, demonstrate that the energy barriers associated with these different pathways can be very similar, in some cases similar enough that both pathways operate in parallel. This mechanistic scenario can increase the difficulty of achieving high levels of enantioinduction.



Scheme 3

Stereochemical Pathways of Nucleopalladation.



In the present review, we summarize recent progress in two synergistic areas: (1) mechanistic studies of the stereochemical pathway of nucleopalladation reactions of alkenes (i.e., cis- vs. trans-nucleopalladation) under catalytically relevant reaction conditions and (2) advances in the development of enantioselective Pd-catalyzed reactions that proceed via nucleopalladation of an alkene substrate. The results summarized in the first portion of this review highlight the mechanistic complexity of these reactions and illustrate how subtle changes to the catalyst, substrate, and/or the reaction conditions can alter the stereochemical course of the reaction. Despite the challenges associated with enantioselective PdII-catalyzed reactions of alkenes, important progress has been made over the past 10–15 years. These advances are surveyed in the second portion of this review. The comprehensive coverage of this review begins with results from the late 1990s and early 2000s, when several important advances were made, including the first examples of highly enantioselective reactions proceeding via nucleopalladation6,7,8,9 and the development of ligand-supported Pd-catalysts for aerobic Wacker-type cyclization reactions.10,11 It is hoped that the collective presentation of mechanistic insights and empirical reaction-discovery efforts in this review will provide a foundation for accelerated progress in this important field.

Palladium(II)-Catalyzed Alkene Functionalization via Nucleopalladation: Stereochemical Pathways and Enantioselective Catalytic Applications

A well-defined complex for palladium-catalyzed aerobic oxidation of alcohols: design, synthesis, and mechanistic considerations.

The mechanistic details of aerobic alcohol oxidation with catalytic Pd(IiPr)(OAc)2(H2O) (IiPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) are disclosed. Under optimal conditions, β-hydride elimination is rate-limiting supported by kinetic studies including a high primary kinetic isotope effect (KIE) value of 5.5 ± 0.1 and a Hammett ρ value of −0.48 ± 0.04. On the basis of these studies, a late transition state is proposed for β-hydride elimination, which is further corroborated by theoretical calculations using density functional theory. Additive acetic acid modulates the rates of both the alcohol oxidation sequence and regeneration of the Pd catalyst. With no additive [HOAc], turnover-limiting reprotonation of intermediate palladium peroxo is kinetically competitive with β-hydride elimination, allowing for reversible oxygenation and decomposition of Pd(0). With additive [HOAc] (>2 mol %), reprotonation of the palladium peroxo is fast and β-hydride elimination is the single rate-controlling step. ...

Elucidating the Significance of β-Hydride Elimination and the Dynamic Role of Acid/Base Chemistry in a Palladium-Catalyzed Aerobic Oxidation of Alcohols

The mechanistic details of the Pd(II)/(−)-sparteine-catalyzed aerobic oxidative kinetic resolution of secondary alcohols were elucidated, and the origin of asymmetric induction was determined. Saturation kinetics were observed for rate dependence on [(−)-sparteine]. First-order rate dependencies were observed for both the Pd((−)-sparteine)Cl2 concentration and the alcohol concentration at high and low [(−)-sparteine]. The oxidation rate was inhibited by addition of (−)-sparteine HCl. At low [(−)-sparteine], Pd-alkoxide formation is proposed to be rate limiting, while at high [(−)-sparteine], β-hydride elimination is proposed to be rate determining. These conclusions are consistent with the measured kinetic isotope effect of kH/kD = 1.31 ± 0.04 and a Hammett ρ value of −1.41 ± 0.15 at high [(−)-sparteine]. Calculated activation parameters agree with the change in the rate-limiting step by increasing [(−)-sparteine] with ΔH⧧ = 11.55 ± 0.65 kcal/mol, ΔS⧧ = −24.5 ± 2.0 eu at low [(−)-sparteine], and ΔH⧧ = 20....

Mechanistic investigations of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols using (-)-sparteine.

The mechanistic details of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols have been elucidated. (−)-Sparteine was found to have a dual role as a chiral ligand and an exogenous base. Saturation kinetics were observed for the dependence on (−)-sparteine concentration. A first-order dependence on [alcohol] and [catalyst] as well as inhibition by addition of (−)-sparteine HCl were observed. These results are consistent with rate-limiting deprotonation under low (−)-sparteine concentrations and rate-limiting β-hydride elimination using saturating (−)-sparteine concentrations. This conclusion is further supported by a kinetic isotope effect of 1.31 ± 0.04 under saturation. The enantioselectivity events are also controlled by addition of (−)-sparteine in which high concentrations afford a more selective kinetic resolution.

Dual role of (-)-sparteine in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols.

A kinetic investigation into the origin of enantioselectivity for the Pd[(−)-sparteine]Cl2-catalyzed aerobic oxidative kinetic resolution (OKR) is reported. A mechanism to account for a newly discovered chloride dissociation from Pd[(−)-sparteine]Cl2 prior to alcohol binding is proposed. The mechanism includes (1) chloride dissociation from Pd[(−)-sparteine]Cl2 to form cationic Pd(−)-sparteine]Cl, (2) alcohol binding, (3) deprotonation of Pd-bound alcohol to form a Pd−alkoxide, and (4) β-hydride elimination of Pd−alkoxide to form ketone product and a Pd−hydride. Utilizing the addition of (−)-sparteine HCl to control the [Cl-] and [H+] and the resulting derived rate law, the key microscopic kinetic and thermodynamic constants were extracted for each enantiomer of sec-phenethyl alcohol. These constants allow for the successful simulation of the oxidation rate in the presence of exogenous (−)-sparteine HCl. A rate law for oxidation of the racemic alcohol was derived that allows for the successful prediction ...

/pdf/origin-of-enantioselection-in-chiral-alcohol-oxidation-3h2s4a26ly.pdf

Jaime A. Mueller

Papers

A well-defined complex for palladium-catalyzed aerobic oxidation of alcohols: design, synthesis, and mechanistic considerations.

Elucidating the Significance of β-Hydride Elimination and the Dynamic Role of Acid/Base Chemistry in a Palladium-Catalyzed Aerobic Oxidation of Alcohols

Mechanistic investigations of the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols using (-)-sparteine.

Dual role of (-)-sparteine in the palladium-catalyzed aerobic oxidative kinetic resolution of secondary alcohols.

Origin of enantioselection in chiral alcohol oxidation catalyzed by Pd[(-)-sparteine]Cl2.