Palladium-catalyzed aerobic oxidative amination of alkenes: development of intra- and intermolecular aza-Wacker reactions

Palladium-catalyzed methods for the aerobic oxidative coupling of alkenes and oxygen nucleophiles (e.g., water and carboxylic acids) have been known for nearly 50 years. The present account summarizes our development of analogous aerobic oxidative amination reactions, including the first intermolecular aza-Wacker reactions compatible with the use of unactivated alkenes. The reactions are initiated by intra- or intermolecular aminopalladation of the alkene. The resulting alkylpalladium(II) intermediate generally undergoes beta-hydride elimination to produce enamides or allylic amide products, but in certain cases, the Pd-C bond can be trapped to achieve 1,2-difunctionalization of the alkene, including carboamination and aminoacetoxylation. Mechanistic studies have provided a variety of fundamental insights into the reactions, including the effect of ancillary ligands on palladium catalysts, the origin of the Br?nsted-base-induced switch in regioselectivity in the oxidative amination of styrene, and evidence that both cis- and trans-aminopalladations of alkenes are possible. Overall, these reactions highlight the potential utility of an "organometallic oxidase" strategy for the selective aerobic oxidation of organic molecules.     

Mechanism of the palladium-catalyzed addition of arylboronic acids to enones: a computational study

The palladium(II)-catalyzed addition of arylboronic acids to β,β-disubstituted enones has been investigated with the BP86 density functional. The results show that the mechanism requires three steps: transmetalation, alkene insertion, and protonation. The alkene insertion is the rate-determining step. For unactivated alkenes, the Heck-type β-hydride elimination is more favored than protonation.     

Highly regioselective Pd-catalyzed intermolecular aminoacetoxylation of alkenes and evidence for cis-aminopalladation and S(N)2 C-O bond formation

Synthetic methods that achieve oxidative 1,2-difunctionalization of alkenes are very powerful in organic chemistry. Here we report the first examples of intermolecular Pd-catalyzed aminoacetoxylation of alkenes with phthalimide as the nitrogen source and PhI(OAc)2 as the stoichiometric oxidant and source of acetate. These reactions are highly regio- and diastereoselective, and mechanistic studies reveal that the reaction proceeds via cis-aminopalladation of the alkene followed by oxidative cleavage of the intermediate Pd-C bond with inversion of stereochemistry.     

Convenient preparation of trans-arylalkenes via palladium(II)-catalyzed isomerization of cis-arylalkenes

A convenient method for the isomerization of cis-arylalkenes to their trans isomers using a palladium(II) catalyst is described. The reaction conditions are mild and general across a range of arylalkenes. The synthesis of a trans-resveratrol derivative from a mixture of alkene isomers was also completed.     

The Mechanism of the Palladium Hydride β-Elimination Step in the Heck Reaction

The kinetics of competitive phenylation of alkenes with iodobenzene over palladium complexes (the Heck reaction) was studied. The effect of one alkene on the arylation rate of another alkene conflicts with the conventional mechanism of the Heck reaction in which the arylated alkene is formed through the unimolecular step of palladium hydride -elimination. Based on experimental data obtained, another mechanism is proposed in which a reaction product is formed through the transfer of palladium hydride to the initial alkene molecule.     

Iodoetherification of unactivated alkenes catalyzed by diphosphine palladium(II) complexes

A palladium-catalyzed intramolecular iodoetherification of alkenes is reported. The reaction is efficient and highly diastereoselective for disubstituted alkenes. The tether length between the alcohol and alkene can be varied to produce tetrahydrofuran and tetrahydropyran rings. Diphosphine palladium(II) salts are highly active catalysts enabling future studies on the development of an enantioselective process.     

Air- and moisture-stable cationic (diphosphine)palladium(II) complexes as hydroamination catalysts: X-ray crystal structures of two [(diphosphine)Pd(NCMe)(OH2)]2+[OTf]−2 complexes

A series of cationic (diphosphine)palladium(II) complexes have been prepared and fully characterized, including two crystal structures. These complexes were evaluated as catalysts for the hydroamination of acyclic alkenes. The reactivity of the catalysts is dependent on the nature of the diphosphine ligand and the substituents on the amine and alkene substrates.     

Synthesis and reactivity of azapalladacyclobutanes

N-Sulfonyl aziridines undergo oxidative addition to palladium(0) complexes generated in situ from mixtures of Pd2(dba)3 and 1,10-phenanthroline. The resulting azapalladacyclobutane complexes undergo intramolecular carbopalladation in the presence of copper(I) iodide to afford azapalladabicyclo[3.2.1]octanes. A deuterium-labeling experiment indicates that the oxidative addition proceeds via SN2-type attack of palladium(0) on the less-hindered carbon of the aziridine ring and that alkene insertion occurs in a syn fashion. The azapalladabicyclo[3.2.1]octane complexes undergo oxidative palladium-carbon bond functionalization in the presence of copper(II) bromide.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Catalytic,Enantioselective α‐Alkylation of Azlactones with Nonconjugated Alkenes by Directed Nucleopalladation

A palladium(II)‐catalyzed enantioselective α‐alkylation of azlactones with nonconjugated alkenes is described. The reaction employs a chiral BINOL‐derived phosphoric acid as the source of stereoinduction, and a cleavable bidentate directing group appended to the alkene to control the regioselectivity and stabilize the nucleopalladated alkylpalladium(II) intermediate in the catalytic cycle. A wide range of azlactones were found to be compatible under the optimal reaction conditions to afford products bearing α,α‐disubstituted α‐amino‐acid derivatives with high yields and high enantioselectivity.     

Oxidative diamination of alkenes with ureas as nitrogen sources: mechanistic pathways in the presence of a high oxidation state palladium catalyst

A first palladium-catalyzed intramolecular diamination of unfunctionalized terminal alkenes has recently been reported. This study investigates the details of its mechanistic course based on NMR titration, kinetic measurements competition experiments, and deuterium labeling. It concludes a two-step procedure consisting of syn-aminopalladation with an unligated palladium(II) catalyst state followed by oxidation to palladium(IV) and subsequent C-N bond formation to give the final products as cyclic diamines. Related reactions employing sulfamides give rise to aminoalkoxy-functionalization of alkenes. This process was investigated employing deuterated alkenes and found to follow an identical mechanism where stereochemistry is concerned. It exemplifies the importance of cationic palladium(IV) intermediates prior to the final reductive elimination from palladium and proves that the nucelophile for this step stems from the immediate coordination sphere of the palladium(IV) precursor. These results have important implications for the general development of alkene 1,2-difunctionalization and for the individual processes of aminopalladation and palladium-catalyzed C(alkyl)-N bond formation.     

pi-Acidic alkene ligand effects in Pd-catalysed cross-coupling processes: exploiting the interaction of dibenzylidene acetone (dba) and related ligands with Pd(0) and Pd(II)

pi-Acidic alkene (olefin) ligands positively influence Pd-catalysed cross-coupling processes, interacting with both palladium(0) and palladium(ii) species, in some cases stabilising key catalytic intermediates. Rates of oxidative addition and reductive elimination are both affected. In certain cases, beta-hydrogen elimination can be slowed down by pi-acidic alkenes, which opens up new reaction pathways (e.g. interception of sigma-alkylpalladium(ii) species by appropriate nucleophiles). pi-Acidic alkene ligands can act independently or in a synergistic fashion with another two-electron donor ligand (e.g. amine, phosphine or N-heterocyclic carbene). The purpose of this perspective article is to highlight the impressive results that can be obtained using pi-acidic alkene ligands, with a particular focus on dibenzylidene acetone (dba) derivatives. Other types of alkene ligands, e.g. macrocyclic alkenes, are also discussed.     

Competitive hydrogenation in alkene–alkyne–diene systems with palladium and platinum catalysts

Competitive hydrogenation of alkene, alkyne and diene substrates (C₆–C₈) over palladium and platinum catalysts were studied at 20°C and atmospheric pressure. Selectivities of these reactions were determined and the substrates relative adsorption coefficients calculated. It was found that hydrogenations of alkynic and dienic substrates were preferred in alkyne–alkene and diene–alkene systems, respectively. In these systems palladium catalyst selectivity was higher than selectivity of the platinum catalyst, due to higher relative adsorption coefficients of corresponding substrate couples on the palladium catalyst.     

Mechanism of the cobalt oxazoline palladacycle (COP)-catalyzed asymmetric synthesis of allylic esters

The catalytic enantioselective S(N)2' displacement of (Z)-allylic trichloroacetimidates catalyzed by the palladium(II) complex [COP-OAc](2) is a broadly useful method for the asymmetric synthesis of chiral branched allylic esters. A variety of experiments aimed at elucidating the nature of the catalytic mechanism and its rate- and enantiodetermining steps are reported. Key findings include the following: (a) the demonstration that a variety of bridged-dipalladium complexes are present and constitute resting states of the COP catalyst (however, monomeric palladium(II) complexes are likely involved in the catalytic cycle); (b) labeling experiments establishing that the reaction proceeds in an overall antarafacial fashion; (c) secondary deuterium kinetic isotope effects that suggest substantial rehybridization at both C1 and C3 in the rate-limiting step; and (d) DFT computational studies (B3-LYP/def2-TZVP) that provide evidence for bidentate substrate-bound intermediates and an anti-oxypalladation/syn-deoxypalladation pathway. These results are consistent with a novel mechanism in which chelation of the imidate nitrogen to form a cationic palladium(II) intermediate activates the alkene for attack by external carboxylate in the enantiodetermining step. Computational modeling of the transition-state structure for the acyloxy palladation step provides a model for enantioinduction.     

Oxygen donor-mediated equilibration of diastereomeric alkene-palladium(II) intermediates in enantioselective desymmetrizing Heck cyclizations

This investigation examines the origin of enantioselection in the desymmetrization of an acyclic prochiral Heck cyclization precursor. High asymmetric induction (97-98% ee) is attributed to a temporary interaction of a Lewis basic oxygen donor with weakly Lewis acidic palladium(II). A series of control experiments combined with quantum-chemical model calculations provided sound evidence for a mechanism involving oxygen donor-mediated, rapid equilibration of diastereomeric alkene-palladium(II) complexes prior to the selectivity-determining ring-closing event, a Curtin-Hammett scenario. Our study also highlights the importance of the cationic pathway (triflate counter anions versus halido ligand) and alkene stereochemistry (E versus Z) in asymmetric Heck reactions.     

Palladium‐Catalyzed Direct Stereoselective Synthesis of Deoxyglycosides from Glycals

Palladium(II) in combination with a monodentate phosphine ligand enables the unprecedented direct and α‐stereoselective catalytic synthesis of deoxyglycosides from glycals. Initial mechanistic studies suggest that in the presence of N ‐phenyl‐2‐(di‐tert‐butylphosphino)pyrrole as the ligand, the reaction proceeds via an alkoxy palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is demonstrated with a wide range of glycal donors and acceptors, including substrates bearing alkene functionalities.     

Palladium(II)-catalyzed direct intermolecular alkenylation of chromones

A new efficient method for the direct alkenylation of chromones via a palladium(II)-catalyzed C-H functionalization reaction was developed. The use of pivalic acid with Cu(OAc)(3)/Ag(2)CO(3) provided superior reactivity in the cross-coupling of chromones with alkene partners. This approach represents a significant advance over the existing two-step method and afforded various 3-vinylchromone derivatives, which are privileged structures in many biologically active compounds and versatile synthetic building blocks.     

Mechanistic studies of Wacker-type intramolecular aerobic oxidative amination of alkenes catalyzed by Pd(OAc)2/pyridine

Wacker-type oxidative cyclization reactions have been the subject of extensive research for several decades, but few systematic mechanistic studies of these reactions have been reported. The present study features experimental and DFT computational studies of Pd(OAc)(2)/pyridine-catalyzed intramolecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism that consists of (1) steady-state formation of a Pd(II)-amidate-alkene chelate with release of 1 equiv of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible β-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of palladium(0) to regenerate the active trans-Pd(OAc)(2)(py)(2) catalyst. Evidence is obtained for two energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a pyridine-dissociated Pd(II) species. Analysis of natural charges and bond lengths of the alkene-insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic attack of the amidate ligand on the coordinated alkene.     

Competitive hydrogenation in alkene–alkyne–diene systems with palladium and platinum catalysts

Competitive hydrogenation of alkene, alkyne and diene substrates (C₆–C₈) over palladium and platinum catalysts were studied at 20°C and atmospheric pressure. Selectivities of these reactions were determined and the substrates relative adsorption coefficients calculated. It was found that hydrogenations of alkynic and dienic substrates were preferred in alkyne–alkene and diene–alkene systems, respectively. In these systems palladium catalyst selectivity was higher than selectivity of the platinum catalyst, due to higher relative adsorption coefficients of corresponding substrate couples on the palladium catalyst.     

Isotope effects and the nature of stereo- and regioselectivity in hydroaminations of vinylarenes catalyzed by palladium(ii)-diphosphine complexes

[reaction: see text] The hydroamination of styrene with aniline catalyzed by phosphine-ligated palladium triflates exhibits a substantial (13)C isotope effect at the benzylic carbon. This supports rate-determining nucleophilic attack of amine on a eta(3)-phenethyl palladium complex. Deuterium exchange observations and predicted isotope effects based on DFT calculations support this mechanism. Selectivity in these reactions is determined by the facility of palladium displacement after reversible hydropalladation of the alkene.