Wackers Oxidation

The oxidation of ethylene to acetaldehyde by palladium chloride in water has been known since the nineteenth century. However, the reaction requires the use of a stoichiometric amount of PdCl2, resulting in Pd(0) deposit. Anderson, in 1934, observed a similar reaction (but 

The mechanism for the product formation was originally proposed to involve a cis transfer of OH to a metal-bound alkene. However, stereochemical studies carried out by Backvall and by Stille proved otherwise, demonstrating that a trans addition is involved (Eq. 3.17). 

Besides Wacker oxidation, other transition-metal catalyzed oxidations have also been carried out in aqueous medium. For example, methyl groups can be selectively hydroxylated by platinum salts in 

The oxidative cleavage of C=C bond is a common type of reaction encountered in organic synthesis and has played a historical role in the stmctural elucidation of organic compounds. There are two main conventional methods to oxidatively cleave a C=C bond (1) via ozonol-ysis and (2) via oxidation with high-valent transition-metal oxidizing reagents. A more recent method developed is via the osmium oxide catalyzed periodate oxidative cleavage of alkenes. All these methods can occur under aqueous conditions. 

Depending on the synthetic purpose, the 1,2,4-trioxolane can be transformed to alcohols, aldehydes (and ketones), or carboxylic acids. 

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METHOD 2 Without a doubt, this is the current world favorite for making P2Ps. This method is known as the Wacker oxidation and involves mixing safrole (or any other allylbenzene), palladium chloride, cuprous chloride and dimethylformamide in an oxygen atmosphere to get MD-P2P very quickly and in a totally clean manner [11, 12]. There s also a very nice review in ref. 13. 

Well, that should be enough examples to give you a good idea of how this Wacker oxidation method works. There are a lot more interesting variations that bees have been posting on the Hive if you wish to read more. 

The method is basically an application of the Wacker oxidation except that the catalyst used is palladium acetate ( Pd(AcO)2 or Pd(02CCH3)2). the solvent is acetic acid or tert-butyl alcohol and the oxygen source is the previously suggested hydrogen peroxide (H202)[17]. 

Strike got the journal article for this recipe as literature citation used in the original Wacker oxidation Strike used for Method 2. In it both mercuric acetate, and to an extent, lead acetate produced ketones as described. Someone-Who-ls-Not-Strike also got a certain ketone. But maybe they were lucky or just plain wrong. Most people on Strike s site say this mercuric acetate thing... 

The following procedure may prove to be one of the largest advances in the field of MDMA chemistry since the perfection and dissemination of the Wacker oxidation procedure for producing MDP2P. This reaction is based on a published process that somehow has escaped discovery by underground chemistry until... 

Retrosynthetic path e in Scheme 2.2 requires a regioselective oxidation of an o-nitrostyrene to the corresponding phenylacetaldehyde. This transformation has been accomplished hy Wacker oxidation carried out in such a way as to ensure the desired regioselectivity. The required o-nitrostyrenes can be prepared by Heck vinylation. One procedure for oxidation uses 1,3-propaiiediol to trap the product as a l,3-dioxane[15]. These can then be hydrogenated over Rh/C and cyclized by treatment with dilute HCl,... 

These reactions constitute the cycle their sum gives the stoichiometry of the Wacker oxidation ... 

In 1974, Hegedus and coworkers reported the pa]ladium(II)-promoted addition of secondary amines to a-olefins by analogy to the Wacker oxidation of terminal olefins and the platinum(II) promoted variant described earlier. This transformation provided an early example of (formally) alkene hydroamination and a remarkably direct route to tertiary amines without the usual problems associated with the use of alkyl halide electrophiles. 

Table 10.7 Copper-free Wacker oxidation of substituted styrenes [41]...

The relative reactivity profile of the simple alkenes toward Wacker oxidation is quite shallow and in the order ethene > propene > 1-butene > Zi-2-butene > Z-2-butene.102 This order indicates that steric factors outweigh electronic effects and is consistent with substantial nucleophilic character in the rate-determining step. (Compare with oxymercuration see Part A, Section 5.8.) The addition step is believed to occur by an internal ligand transfer through a four-center mechanism, leading to syn addition. 

Both the regiochemistry and stereochemistry of Wacker oxidation can be influenced by substituents that engage in chelation with Pd. Whereas a single y-alkoxy function leads to a mixture of aldehyde and ketone, more highly oxygenated systems such as the acetonide or carbonate of the diol 1 lead to dominant aldehyde formation.107 The diol itself gives only ketone, which perhaps indicates that steric factors are also important. 

Under the conditions of the Wacker oxidation, 4-trimethylsilyl-3-alkyn-l-ols give 7 -lactones. Similarly, A-carbamoyl or A-acetyl 4-trimethylsilyl-3-alkynamines cyclize to y -lactams. Formulate a mechanism for these reactions. (Hint In DzO,... 

For internal olefins, the Wacker oxidation is sometimes surprisingly regioselective. By using aqueous dioxane or THF, oxidation of P,y-unsaturated esters can be achieved selectively to generate y-keto-esters (Eq. 3.18).86 Under appropriate conditions, Wacker oxidation can be used very efficiently in transforming an olefin to a carbonyl compound. Thus, olefins become masked ketones. An example is its application in the synthesis of (+)-19-nortestosterone (3.11) carried out by Tsuji (Scheme 3.5).87... 

Besides Wacker oxidation, other transition-metal catalyzed oxidations have also been carried out in aqueous medium. For example, methyl groups can be selectively hydroxylated by platinum salts in water.88 In this way, p-toluenesulfonic acid was oxidized to benzy-lic alcohol, which was subsequently oxidized into the aldehyde (Eq. 3.19).89... 

The most important reaction based on Pdn-catalysis is the Wacker oxidation [171], which is used industrially for the synthesis of acetaldehyde, starting from ethane. This process can be combined with a Heck reaction and has been used by Tietze and coworkers [172] for an efficient enantioselective synthesis of vitamin E (6/1-... 

The latest example of a Pdn-catalyzed Wacker/Heck methodology was published by Rawal and coworkers. During the total synthesis of mycalamide A, an inter-molecular Wacker oxidation with methanol acting as nucleophile and a subsequent ring closure via Heck reaction led to a tetrahydropyran moiety in a 5.7 1 diastereom-eric mixture [184]. 

PdCl2/CuCl catalyzes the deprotection of prop-2-enyl ethers in moderate yield under Wacker-oxidation conditions (Equation (19)).60... 

The phenolic oxygen on 2-allyl-4-bromophenol (7) readily underwent oxypalladation using a catalytic amount of PdCl2 and three equivalents of Cu(OAc)2, to give the corresponding benzofuran 8. This process, akin to the Wacker oxidation, was catalytic in terms of palladium, and Cu(OAc)2 served as oxidant [17]. Benzofuran 10, a key intermediate in Kishi s total synthesis of aklavinone [18], was synthesized via the oxidative cyclization of phenol 9 using stoichiometric amounts of a Pd(II) salt. 

Wacker oxidation of l-alkenes. The Wacker oxygenation of 1-alkenes to methyl ketones involves air oxidation catalyzed by PdCl2 and CuCU, which is necessary for reoxidation of Pd(0) to Pd(II).1 This oxygenation is fairly sluggish and can result in chlorinated by-products. A new system is comprised of catalytic amounts of Pd(OAc)2, hydroquinone, and 1, used as the oxygen activator.2 The solvent is aqueous DMF, and a trace of HClOj is added to prevent precipitation of Pd(0). Oxygenation using this system of three catalysts effects Wacker oxidation of 1-alkenes in 2-8 hours and in 67-85% yield. 

Wacker oxidation of styrene has also been performed in [bmim][BF4] and [bmim][PF6], at 60 °C with H2O2 and PdCF as a catalyst [19]. This system gave yields of acetophenone as high as 92 % after 3 h. Hydrogen peroxide may also be used under phase transfer conditions for alkene bond cleavage, to produce adipic acid (an intermediate in the synthesis of nylon-6) from cyclohexene (Scheme 9.9). 

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