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= Tsuji-Wacker Oxidation = The advent of Wacker Process has spurred on many investigations into the utility and applicability of the reactions to more complex terminal olefins. The Tsuji-Wacker Oxidation is the palladium(II)-catalyzed transformation of such olefins into carbonyl compounds. Clement and Selwitz were the first to find that using an aqueous DMF as solvent allowed for the oxidation of of 1-dodecene to 2-dodecanone, which addressed the insolubility problem of higher order olefins in water. Fahey noted the use of 3-methylsulfolane in place of DMF as solvent increased the yield of oxidation of 3,3-Dimethylbut-1-ene. Two years after, Tsuji applied the Selwitz conditions for selective oxidations of terminal olefins with multiple functional groups, and demonstrated its utility in synthesis of complex substrates. Further development of the reaction has led to various catalytic systems to address selectivity of the reaction, as well as introduction of intermolecular and intramolecular oxidations with non-water nucleophiles.

Markovnikov Addition
The Tsuji-Wacker Oxidation oxidizes terminal olefin to the corresponding methyl ketone under the Wacker process condition. Almost identical to that of Wacker Process, the proposed catalytic cycle (Figure 1) begins with complexation of PdCl2 and two chloride anions to PdCl4, which then undergoes subsequent ligand exchange of two chloride ligand for water and alkene to form Pd(Cl2)(H2O)(alkene) complex. A water molecule then attacks the olefin regioselectively through an outer sphere mechanism in a Markovnikov fashion, to form the more thermodynamically stable Pd(Cl2)(OH)(-CH2-CHOH-R) complex. Dissociation of a chloride ligand to the three coordinate palladium complex promotes β-hydride elimination, then subsequent 1,2-hydride insertion generates Pd(Cl2)(OH)(-CHOHR-CH­3) complex. This undergoes β-hydride elimination to release the ketone, and subsequent reductive elimination produces HCl, water, and palladium(0). Finally palladium(0) is reoxidized to PdCl2 with two equivalents of Cu(II)Cl2, which in turn can be reoxidized by O2.

The oxidation of terminal olefins generally provide the Markovnikov ketone product, however in cases where substrate favors the aldehyde (discussed below), different ligands can be used to enforce the Markovnikov regioselectivity. The use of sparteine as a ligand (Figure 2, A) favors nucleopalladation at the terminal carbon to minimize steric interaction between the palladium complex and substrate. The Quinox-ligated palladium catalyst is used to favor ketone formation when substrate contains a directing group (Figure 2, B). When such substrate bind to Pd(Quinox)(OOtBu), this complex is coordinately saturated which prevents the binding of the directing group, and results in formation of the Markovnikov product. The efficiency of this ligand is also attributed to its electronic property, where anionic TBHP prefers to bind trans to the oxazoline and olefin coordinate trans to the quinoline.

Anti-Markovnikov Addition
The anti-Markovnikov selectivity to aldehyde can be achieved through exploiting inherent stereoelectronics of the substrate. Placement of directing group at homo-allylic (i.e. Figure 3, A) and allylic position (i.e. Figure 3, B) to the terminal olefin favors the anti-Markovnikov aldehyde product, which suggests that in the catalytic cycle the directing group chelates to the palladium complex such that water attacks at the anti-Markovnikov carbon to generate the more thermodynamically stable palladocycle. Anti-Markovnikov selectivity is also observed in styrenyl substrates (i.e. Figure 3, C), presumably via η4-palladium-styrene complex after water attacks anti-Markovnikov. More examples of substrate-controlled, anti-Markovnikov Tsuji-Wacker Oxidation of olefins are given in reviews by Namboothiri, Feringa , and Muzart.

Grubbs and co-workers paved way for anti-Markovnikov oxidation of stereoelectronically unbiased terminal olefins, through the use of palladium-nitrite system (Figure 2, D). In his system, the terminal olefin was oxidized to the aldehyde with high selectivity through a catalyst-control pathway. The mechanism is under investigation, however evidence suggests it goes through a nitrite radical adds into the terminal carbon to generate the more thermodynamically stable, secondary radical. Grubbs expanded this methodology to more complex, unbiased olefins.

Oxygen Nucleophiles
The intermolecular oxidations of olefins with alcohols as nucleophile typically generate ketals, where as the palladium-catalyzed oxidations of olefins with carboxylic acids as nucleophile genreats vinylic or allylic carboxylates. In case of diols, their reactions with alkenes typically generate ketals, whereas reactions of olefins bearing electron-withdrawing groups tend to form acetals.

Palladium-catalyzed intermolecular oxidations of dienes with carboxylic acids and alcohols as donors give 1,4-addition products. In the case of cyclohexadiene (Figure 4, A), Backvall found that stereochemical outcome of product was found to depend on concentration of LiCl. This reaction proceeds by first generating the Pd(OAc)(benzoquinone)(allyl) complex, through anti-nucleopalladation of diene with acetate as nucleophile. The absence of LiCl induces an inner sphere reductive elimination to afford the trans-acetate stereochemistry to give the trans-1,4-adduct. The presence of LiCl displaces acetate with chloride due to its higher binding affinity, which forces an outer sphere acetate attack anti to the palladium, and affords the cis-acetate stereochemistry to give the cis-1,4-adduct. Intramolecular oxidative cyclization: 2-(2-cyclohexenyl)phenol cyclizes to corresponding dihydro-benzofuran (Figure 4, B) ; 1-cyclohexadiene-acetic acid in presence of acetic acid cyclizes to corresponding lactone-acetate 1,4 adduct (Figure 4, C), with cis and trans selectivity controlled by LiCl presence.

Nitrogen Nucleophiles
The oxidative aminations of olefins are generally conducted with amides or imides; amines are thought to be protonated by the acidic medium or to bind the metal center too tightly to allow for the catalytic chemistry to occur. These nitrogen nucleophiles are found to be competent in both intermolecular and intramolecular reactions, some examples are depicted (Figure 5, A, B )