Wacker Oxidation Research Articles

Formal Asymmetric Hydration of Non‐Activated Alkenes in Aqueous Medium through a “Chemoenzymatic Catalytic System”

A direct one-pot conversion of (substituted) styrene(s) into the corresponding (substituted) (R)-phenylethan-1-ol(s) in a highly enantioselective manner has been achieved by using a “chemoenzymatic catalytic system”, comprising a palladium-catalyzed Wacker–Tsuji oxidation and subsequent enantioselective enzymatic reduction of the in situ formed (substituted) acetophenone(s) (see scheme).

Imparting Catalyst Control upon Classical Palladium-Catalyzed Alkenyl C–H Bond Functionalization Reactions

The functional group transformations carried out by the palladium-catalyzed Wacker and Heck reactions are radically different, but they are both alkenyl C-H bond functionalization reactions that have found extensive use in organic synthesis. The synthetic community depends heavily on these important reactions, but selectivity issues arising from control by the substrate, rather than control by the catalyst, have prevented the realization of their full potential. Because of important similarities in the respective selectivity-determining nucleopalladation and β-hydride elimination steps of these processes, we posit that the mechanistic insight garnered through the development of one of these catalytic reactions may be applied to the other. In this Account, we detail our efforts to develop catalyst-controlled variants of both the Wacker oxidation and the Heck reaction to address synthetic limitations and provide mechanistic insight into the underlying organometallic processes of these reactions. In contrast to previous reports, we discovered that electrophilic palladium catalysts with noncoordinating counterions allowed for the use of a Lewis basic ligand to efficiently promote tert-butylhydroperoxide (TBHP)-mediated Wacker oxidation reactions of styrenes. This discovery led to the mechanistically guided development of a Wacker reaction catalyzed by a palladium complex with a bidentate ligand. This ligation may prohibit coordination of allylic heteroatoms, thereby allowing for the application of the Wacker oxidation to substrates that were poorly behaved under classical conditions. Likewise, we unexpectedly discovered that electrophilic Pd-σ-alkyl intermediates are capable of distinguishing between electronically inequivalent C-H bonds during β-hydride elimination. As a result, we have developed E-styrenyl selective oxidative Heck reactions of previously unsuccessful electronically nonbiased alkene substrates using arylboronic acid derivatives. The mechanistic insight gained from the development of this chemistry allowed for the rational design of a similarly E-styrenyl selective classical Heck reaction using aryldiazonium salts and a broad range of alkene substrates. The key mechanistic findings from the development of these reactions provide new insight into how to predictably impart catalyst control in organometallic processes that would otherwise afford complex product mixtures. Given our new understanding, we are optimistic that reactions that introduce increased complexity relative to simple classical processes may now be developed based on our ability to predict the selectivity-determining nucleopalladation and β-hydride elimination steps through catalyst design.

ChemInform Abstract: Organized Molecular Systems as Reaction Media

AbstractReview: 63 refs.

Bulky and Modular 3,3′‐Bipyrazoles as Ligands: Synthesis, Characterization, and Catalytic Activity of Pd Complexes

AbstractIn the present study, the properties of a new bidentate N,N′‐chelating ligand class that bears an electron‐excessive 3,3′‐bipyrazole core have been investigated. The ligands are easily accessible in a three‐step procedure by condensation with diethyl oxalate followed by tandem condensation with hydrazine hydrate and finally by aryl‐ or alkylation exclusively at the N‐1,1′‐pyrazole positions to furnish overall eleven new ligands with different electronic properties. After structural analysis of the ligands, their coordination to palladium, copper, and cobalt has been studied. These ligands coordinate the 2,2′‐pyrazolyl nitrogen atoms in a bidentate fashion to the metals to realize complexes with an (L)MX2 motif. We present two crystal structures of Pd and Cu complexes, which to the best of our knowledge represent the first d8 and d9 2,2′‐bipyrazole compounds coordinated through bidentate complexation. Initial catalytic experiments have been performed with palladium complexes with three bipyrazole ligands of this new class; the palladium‐catalyzed copper‐free Wacker oxidation of different alkenes showed superior activity compared to 2,2′‐bipyridines. We attribute this to a higher redox potential of the 3,3′‐bipyrazoles, which are ― besides electronic effects ― also strongly influenced by steric effects. These might be enforced by the extended ligand backbone, the choice of the wingtip substitution, and the smaller coordination cavity within the N2,N2′ atoms compared to 2,2′‐bipyridine ligands.

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

AbstractReview: 262 refs.

First Total Synthesis of Prionoid E, A Bioactive Rearranged Secoabietane Diterpene Quinone from Salvia prionitis

AbstractThe first total synthesis of prionoid E (1), a rearranged secoabietane diterpene quinone isolated from Salvia prionitis, was achieved efficiently by means of Wacker oxidation (Scheme 5) and aldol condensation (Scheme 7) as the key steps in the synthetic sequence. Thus 1 was prepared in 15 steps in 3.7% yield starting on one hand from anisole (=methoxybenzene) and methylsuccinic anhydride (=dihydro‐3‐methylfuran‐2,5‐dione) via 4 (Scheme 3 and 5), and on the other hand from 2‐hydroxy‐2‐methylpropanoic acid via 5 (Scheme 6).

Synthesis of the Purported ent-Pochonin J Structure Featuring a Stereoselective Oxocarbenium Allylation

The synthesis of the alleged natural product pochonin J is presented. Key steps of this convergent synthesis include a chemoselective Wacker oxidation, and an Evans' anti-reduction of the resulting ketone. Upon ozonolysis, this intermediate undergoes a 6-exo-trig cyclization to give a hemiketal intermediate, the key oxocarbenium precursor. The construction of the α-C-glycoside subunit is highlighted by a mismatched oxocarbenium cation formation/allylation sequence. An olefin metathesis afforded the 14-membered macrolactone, and final oxidation provided the "desired" compound that does not spectroscopically correlate to the initially described natural product.

Catalyst-Controlled Wacker-Type Oxidation of Homoallylic Alcohols in the Absence of Protecting Groups

Homoallylic alcohols are oxidized to β-hydroxy ketones using a TBHP-mediated Pd-catalyzed Wacker-type oxidation. The use of a bidentate ligand, quinoline-2-oxazoline (Quinox), and TBHP((aq)) as the terminal oxidant provides good yields of the desired products with reaction times significantly reduced as compared to the Tsuji-Wacker oxidation. Additionally, bis- and tris-homoallylic alcohols are oxidized to provide cyclic peroxyketals, presumably via nucleophilic attack of the methyl ketone product.

First total syntheses of (±)-3-aza-11-selena and (±)-3-aza-11-tellura steroids

An efficient synthesis of 11-selena and 11-tellura steroids bearing a pyridine as an A ring was achieved via an intramolecular Diels–Alder cycloaddition of o-quinodimethanes, which were generated from a 3-azabicyclo[4.2.0]octa-1,3,5-trien-7-one ketal. The major isomer matches the trans- anti- trans ring configuration of natural products. Finally, the vinyl groups of the synthesized 11-hetero steroids have been oxidized by the Wacker process in good yields. The characteristic 1H and 13C NMR spectroscopic features of the synthesized compounds are reported.

Organized molecular systems as reaction media

Abstract Media are among the most important factors to be considered for organic synthesis in soft and non-polluting conditions satisfying the conditions for sustainable development. Organized Molecular Systems (OMS) are very useful when efforts are being made to apply the twelve green chemistry principles, more precisely to replace organic solvents, to carry out reactions in water, to employ catalysis and biocatalysis, to economize molecules (and, of course, of atoms) and to work with low-energy conditions. These OMS posses a number of advantages: solubilization of substances that are not normally soluble in the continuous phase of OMS, localization of reactants and products, and selective orientation and stabilization of the various entities in the various stages of the reaction. Rapid and selective reactions of preparative amounts of substrate can be carried out in such media, which are also very suitable for mechanistic studies. First, we performed organic photoreactions in microemulsions (macroscopically homogeneous and transparent media). Thus, we were able to confirm the interfacial localization of the processes by means of chemical internal sensors and infrared spectroscopy; to propose a formulation strategy for diminishing the number of substrates in the medium (molecular economy principle); and to use high interfacial concentration to carry out reactions in the liquid phase although they are generally only possible in the solid state. The most important scientific point was the demonstration of the generalization of the amphiphilicity concept, by using polar non-aqueous solvents. 1986 saw the end of a controversy concerning the use of formamide in place of water. With this type of solvent, we have been able to perform important reactions: the Wacker process, Diels-Alder reactions, and olefin amidations. Then we postulated the formation of aggregates without surfactants if differential solvations were operative. All organic reactions can be influenced by the spontaneous formation of aggregates. To finish, with such systems, it is possible to orientate the reactivity of competitive reactions (e.g. cyclization and polymerization) and help to protect the environment, for example in the synthesis of clean surfactants in clean conditions. With the extension of these observations and results to the use of rigid objects (similar to rigid micelles) we were able to obtain very high enantioselective excess in chiral processes.

Palladium(II)-catalyzed alkene functionalization via nucleopalladation: stereochemical pathways and enantioselective catalytic applications.

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.

Total Synthesis of (±)-Sacidumlignan D

The first total synthesis of (±)-sacidumlignan D featuring a Zn-mediated Barbier reaction and reverse Wacker oxidation to form the key γ-lactone, its diastereoselective α-methylation followed by reduction cyclization, was documented.

Ligand Exchanges and Hydroxypalladation Reactions of the Wacker Process in Aqueous Solution at High Cl− Concentration

Reaction mechanisms and associated free energies of various reaction steps involved in the Wacker process in aqueous acidic conditions at high Cl(-) concentration were investigated using accelerated ab initio molecular dynamics techniques. Several ligand exchange reactions of the catalytic precursor [PdCl(4)](2-) and nucleophilic attack of water at Pd-coordinated ethene (hydroxypalladation) were looked at in great molecular level detail. This work underlines the key role of the trans effect of Pd-coordinated ethene in the structure and dynamics of solvated Pd(II) complexes. Irrespective of Cl or water ligation at the trans position, the hydroxypalladation proceeds through an anti mechanism where an outer-sphere water attacks an ethene carbon atom in an anti fashion. Extensive molecular dynamics simulations were used to analyze various reaction mechanisms and unravel the stereochemistry of the crucial hydroxypalladation step.

A mild, large-scale synthesis of 1,3-cyclooctanedione: expanding access to difluorinated cyclooctyne for copper-free click chemistry

We report the large-scale synthesis of 1,3-cyclooctanedione in five steps with 29% yield. This molecule is a synthetic precursor to difluorinated cyclooctyne, which participates in a bioorthogonal copper-free click reaction with azides. The final step demonstrates the first successful application of the Wacker–Tsuji oxidation to form a cyclic 1,3-dione.

Styrene oxidation by hydrogen peroxide in ionic liquids: the role of the solvent on the competition between two Pd-catalyzed processes, oxidation and dimerization

A series of hydrophilic N,N-dimethylpyrrolidinium- and N,N-dimethylpiperidinium-based ionic liquids (ILs) have been prepared and applied as reaction media in the Wacker oxidation of styrene by hydrogen peroxide using PdCl2 as the catalyst. The efficiency of these ILs was compared with hydrophilic and hydrophobic imidazolium systems (including those with nitrile functionalities). The nature of the ionic liquid strongly influences the product distribution. In particular, in hydrophobic ILs, relevant amounts of 1,3-diphenyl-1-butene arising from styrene dimerization were detected, in addition to the expected phenylmethylketone. The formation of 1,3-diphenyl-1-butene may be attributed to the formation of Pd(0) species from “ClPdOH” (probably formed during the Wacker process) in a side-reaction. Consequently, the ability of the IL to favor or disfavor the reoxidation of “ClPdOH” to “ClPdOOH” by hydrogen peroxide, giving an homogeneous phase or a biphasic system, appears to be the main factor affecting selectivity.

Heteroatom-Directed Reverse Wacker Oxidations. Synthesis of the Reported Structure of (−)-Herbaric Acid

A microwave-assisted chemoenzymatic resolution has been used to install the C3 stereocenter of the reported structure of the fungal metabolite herbaric acid in high enantiomeric excess. The synthesis and stereochemical assignment was accomplished using a completely regioselective anti-Markovnikov addition of water to vinylphthalide 3, achieved using a heteroatom-directed Wacker oxidation that proceeds with retention of stereochemistry. These results establish that so-called "reverse" Wacker oxidations are a viable alternative to hydroboration/oxidation procedures.

Catalyst‐Controlled Wacker‐Type Oxidation of Protected Allylic Amines

Catalyst‐Controlled Wacker‐Type Oxidation of Protected Allylic Amines

ChemInform Abstract: Syntheses of (‐)‐Hygrine (V) and (‐)‐Norhygrine (VI) via Wacker Oxidation.

AbstractKey step is the Wacker oxidation for the formation of carbonyl compound (IV) in a regioselective manner.

The Efficient and Enantiospecific Total Synthesis of Cyclopenta[b]phenanthrenes Structurally‐Related to Neurosteroids

We report an efficient synthesis of cyclopenta[b]phenanthrenes functionalized at C-3 and C-8 from an optically pure Hajos-Parrish ketone. The key step is a neutral alumina catalyzed Michael addition of a Hajos-Parrish ketone derivative (4) to 1,7-octadien-3-one (2) in 98% yield. This Michael addition product went through Krapcho decarbomethoxylation, aldol condensation, lithium liquid ammonia reduction, Wacker oxidation and acid catalyzed cyclization to form cyclopenta[b]phenanthrene (1a) in 37% overall yield for the 7 steps.

Experimental and computational study of a direct O2-coupled Wacker oxidation: water dependence in the absence of Cu salts.

The kinetics of the Pd[(-)-sparteine]Cl(2) catalyzed oxidation of decene using oxygen as the sole oxidant have been studied in the absence of copper salts and high [Cl(-)]. Saturation kinetics are observed for [decene] as well as a third order dependence on [water]. A mechanism is proposed involving the dissociation of two chlorides and rate-limiting formation of a three-water hydrogen bridged network and subsequent oxypalladation as supported by computational studies.