Oxidations Wacker

Palladium-catalyzed oxidation of olefins to ketones, and aldehydes in certain cases. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 263, Springer-Verlag Berlin Heidelberg 2009 

Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecule 1994, University Science Books Mill Valley, CA, pp 199-208. (Review). 

PeUissier, H. Michellys, P.-Y. SanteUi, M. Tetrahedron 1997, 53, 10733—10742. Feringa, B. L. Wacker oxidation. In Transition Met. Org. Synth. Beller, M. Bohn, C., eds. WUey-VCH Weinheim, Germany. 1998, 2, 307-315. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 282, Springer International Publishing Switzerland 2014 

Sieber, R. Angew. Chem. Int. Ed. 1962, 1, 80-88. Wacker is not a person, but a place in Germany where Wacker Chemie developed this process. Since Hoechst AG later refined the reaction, this is sometimes called Hoechst-Wacker process. 

The Pd(II) hinge in cage 2 can also participate in a chemical transformation. The catalytic Wacker-type oxidation of olefins took place when 8-nonen-l -ol (32) was heated for 5 h at 80 °C in the presence of cage 2 (5 mol%), giving 9-hydroxynonan-2-one (33) 

Conversion of ethylene to acetaldehyde with a soluble palladium complex was one of the early applications of homogeneous catalysis. As most of the acetic acid-manufacmring processes were based on acetaldehyde oxidation, the easy conversion of ethylene to acetaldehyde by the Wacker process was historically a significant discovery. With the advent of the methanol carbonylation process for the manufacture of acetic acid, the industrial importance of the Wacker process has diminished. 

R = alkyl, substituted alkyl R = alkyl, aryl, O-alkyl 

Certain steps in the mechanism of the Wacker oxidation are still unclear despite intensive research. One of these steps, the attack of the coordinated alkene by the nucleophile (OfT or H2O), could be both intra- or intermolecular as the observed rate law is consistent with either possibility. One of the plausible catalytic cycles is presented. 

The asymmetric total synthesis of the putative structure of the cytotoxic diterpenoid (-)-sclerophytin A was accomplished by L.A. Paquette and co-workers/ At the beginning of the synthesis, a bicyclic intermediate was subjected to the Wacker oxidation to oxidize its terminal alkene into the corresponding methyl ketone. The oxidation took place in high yield, although the reaction time was long. The spectra obtained for the final product (proposed structure) did not match that of the natural product, consequently a structural revision was necessary. 

The antiviral marine natural product, (-)-hennoxazole A, was synthesized in the laboratory of F. Yokokawa. The highly functionalized tetrahydropyranyl ring moiety was prepared by the sequence of a Mukaiyama aldol reaction, cheiation-controiied 1,3-syn reduction, Wacker oxidation, and an acid catalyzed intramolecular ketalization. The terminal olefin functionality was oxidized by the modified Wacker oxidation, which utilized Cu(OAc)2 as a co-oxidant. Interestingly, a similar terminal alkene substrate, which had an oxazole moiety, failed to undergo oxidation to the corresponding methyl ketone under a variety of conditions. 

The first synthesis of the hexacyclic himandrine skeleton was achieved by L.N. Mander and co-workers. The last six-membered heterocycle was formed via an intramolecular Wacker-type oxidation in which the terminal alkene side-chain reacted with the secondary amine functionality. The oxidation was conducted in anhydrous acetonitrile to insure that the Pd-alkene complex was substituted exclusively by the internal nucleophile. The resulting six-membered enamine was then hydrogenated and the MOM protecting groups removed to give the desired final product. 

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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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