Wacker oxidations, the conversion of terminal olefins to methyl ketones with Pd(II) catalysts, have seen widespread use in synthetic applications. Standard synthetic Wacker conditions use catalytic PdCl2 with stoichiometric CuCl under an aerobic atmosphere in a mixed-solvent system of N,N-dimethylformamide and H2O. Though much attention has been directed toward elucidating the rate-determining step and the mechanism of nucleopalladation, the assumption that Cu does not participate in this portion of the catalytic cycle has recently been called into question based on an isolated Pd/Cu bimetallic species and the influence of Cu on product selectivity. Fortunately, recent advancements have been made toward the elimination of Cu additives, thereby alleviating these issues. Success in this area has come from the application of information gained in studying other direct-O2-coupled Pd(II) oxidation systems, including ligand modulation, something which could not be achieved in the presence of Cu. The developments in peroxide-mediated and direct-O2-coupled Wacker oxidations are highlighted herein.

The oxidation of terminal olefins to methyl ketones with Pd(II) complexes, known as the Wacker oxidation, is a well-established synthetic transformation used in the production of acetaldehyde on an industrial scale. 1 Classically, this reaction requires catalytic Pd-(II) and stoichiometric CuCl 2 under aerobic conditions. Chlorinated byproducts and palladium decomposition limit the exploitation of the Wacker oxidation. 1a Many modifications have been developed allowing for oxidation of more complex targets, but most still utilize the addition of a copper cocatalyst. 1c Copper additives severely limit the use of ligands with Pd. Ligand modulation of Pd catalysis has proven to be vital in the development of more effective and asymmetric catalysts for the mechanistically related aerobic alcohol oxidation. 2 Consequently, we were interested in developing a catalytic system for the Wacker oxidation that would alleviate the need for copper additives. 3 We report herein the discovery and preliminary mechanistic considerations of a promising new N-heterocyclic carbene-modulated Pdcatalyzed Wacker oxidation that uses tert-butylhydroperoxide (TBHP).The effectiveness of Pd(IiPr)(OAc) 2 •(H 2 O) (1) in aerobic alcohol oxidations led us to test this catalyst for the Wacker oxidation of styrene. Styrene derivatives are generally problematic substrates for these oxidations due to polymerization or oxidative cleavage to benzaldehyde and/or benzoic acid. 1b,4 Oxidation of styrene with 2.5 mol % 1 at 0.3 M in THF leads primarily to acetophenone with 95% conversion at 24 h (Figure 1). Monitoring the reaction via in situ FTIR spectroscopy reveals a ca. 10 h induction period, which was presumed due to the formation of an active catalyst species. 5 To explore if the active catalyst was cationic in nature, a range of counterions was evaluated. Less basic counterions show a significant decrease in induction period. 6 Optimization of the reaction solvent illustrated the unusual nature of this oxidation in which THF proved to be the only competent reaction solvent. 7 Of note, no oxidation was observed in 2,2,5,5-tetramethyl-THF. On further examination of the in situ FTIR data, two other carbonyl stretches were observed and attributed to γ-butyrolactone and succinic dialdehyde, products of THF oxidation. Additionally, the THF oxidation rate is qualitatively similar to that of the Wacker oxidation.One plausible explanation of these data is that a cationic Pd complex catalyzes an aerobic oxidation of THF to 2-tetrahydrofuryl hydroperoxide. The peroxide can then act as a reagent or an oxidant in the Wacker process. This type of coupled oxidation has been previously observed by Alper and co-workers. 4c To test if a peroxide is involved in the catalysis, styrene was submitted to catalytic Pd-(IiPr)(OTs) 2 and 5 equiv of TBHP in toluene under anaerobic conditions. Complete conversion of styrene to >97% acetophenone was observed without an induction period. This is especially noteworthy since other Wacker oxidations of styrenes, which do not...

Utilizing the rapidly synthesized Quinox ligand and commercially available aqueous TBHP, a Wacker-type oxidation has been developed, which efficiently converts the traditionally challenging substrate class of protected allylic alcohols to the corresponding acyloin products. Additionally, the catalytic system is general for several other substrate classes, converting terminal olefins to methyl ketones, with short reaction times. The system is scalable (20 mmol) and can be performed with a reduced catalyst loading of 1 mol%. Enantioenriched substrates undergo oxidation with complete retention of enantiomeric excess.

The discovery of a direct O2-coupled Wacker oxidation with use of balloon pressure of O2 and low catalyst loading is described. Use of (-)-sparteine as a ligand on Pd prevents olefin isomerization and leads to selective formation of methyl ketones from terminal olefins in good yields. Oxidation of enantiomerically enriched substrates is reported with no observed racemization.

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