Wacker oxypalladation

Early mechanistic studies have indicated that the oxypalladation step in the Wacker process proceeds through an <37z/z-pathway,399 although recent deuterium-labeling experiments have shown the viability of a yy/z-mechanism involving insertion of a metal-coordinated oxygen into the alkene.400,401 For example, with excess chloride ion present, the Wacker-type cyclization of a deuterated phenol system occurred in a primarily //-pathway, whereas the oxypalladation step favored a yy/z-mode in the absence of excess chloride ion (Scheme 16). Thus, either mechanism may be operative under a given set of experimental conditions. 

When 1,3-dienes containing a tethered alcohol are subjected to Wacker-type reactions, the initial intramolecular oxypalladation event creates a 7r-allylpalladium species, which can then undergo an additional bond-forming process to effect an overall 1,4-difunctionalization of the diene with either cis- or // -stereochemistry (Scheme 18).399 An array of substrate types has been shown to participate in this reaction to generate both five- and six-membered fused or ro-oxacycles.435-437 Employing chiral benzoquinone ligands, progress toward the development of an asymmetric variant of this reaction has also been recorded, albeit with only modest levels of enantioselectivity (up to 55% ee).438... 

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. 

A development of the last two decades is the use of Wacker activation for intramolecular attack of nucleophiles to alkenes in the synthesis of organic molecules [9], In most examples, the nucleophilic attack is intramolecular, as the rates of intermolecular reactions are very low. The reaction has been applied in a large variety of organic syntheses and is usually referred to as Wacker (type) activation of alkene (or alkynes). If oxygen is the nucleophile, it is called oxypalladation [10], Figure 15.4 shows an example. During these reactions the palladium catalyst is often also a good isomerisation catalyst, which leads to the formation of several isomers. 

Extensive studies on the Wacker process have been carried out in industrial laboratories. Also, many papers on mechanistic and kinetic studies have been published[17-22]. Several interesting observations have been made in the oxidation of ethylene. Most important, it has been established that no incorporation of deuterium takes place by the reaction carried out in D20, indicating that the hydride shift takes place and vinyl alcohol is not an intermediate 1,17]. The reaction is explained by oxypalladation of ethylene, / -elimination to give the vinyl alcohol 6, which complexes to H-PdCI, reinsertion of the coordinated vinyl alcohol with opposite regiochemistry to give 7, and aldehyde formation by the elimination of Pd—H. 

The conditions for allylic acyloxylation of internal olefins are, for reasons which are not clear, unsuitable for terminal olefins. They undergo Wacker oxidation (Markovnikov oxypalladation//) - h yd ride elimination) to yield mixtures of vinyl acetates and methyl ketones [37a]. A combination of Pd(OAc)2/BQ with air as cooxidant in a mixture of DMSO/AcOH (1 1) enables conversion of a broad range of functionalized terminal olefins to the corresponding linear allylic acetates in acceptable yields (Scheme 5) [41]. 

This combination of reagents h s been used to oxidize terminal vinyl groups to methyl ketones and is known as the Wacker oxidation. The nucleophile is simply water, which attacks the activated alkene at the more substituted end in an oxypalladation step. (3-Hydride elimination from the resulting a-alkyl palladium complex releases the enol, which is rapidly converted into the more stable keto form. Overall, the reaction is a hydration of a terminal alkene that can tolerate a range of functional groups. 

Satisfy yourself that you can at least see what is happening here—if you are stuck on the Pd(ii)-cataiysed reaction, refer to Chapter 48 and look at oxypalladation and the Wacker reaction for clues. 

It is assumed that in the first step of the domino Wacker-Heck Reaction the chiral catalyst generated from Pd(II) and an enantiomeri-cally pure BOXAX-ligand 5 coordinates enantiofacially to the aliphatic double bond in 6. The resulting intermediate 7 further reacts by oxypalladation to give 8 with enantioselective formation of the chroman. A p-hydride elimination is not possible because of the absence of H-atoms in the P-position. Thus, the palladium species then forms intermediate 11 in a subsequent Heck reaction with methyl acrylate (10) or methyl vinyl ketone (9) providing the final product 12 and Pd(0) after a P-hydride elimination. 

As in the Wacker reaction, the 1,2-oxypalladation adduct then decomposes by a deuterium shift. 

Wacker oxidation11 provides a way to add water to an alkene 8 and oxidise the product to a ketone 72 all in the one step using oxygen under palladium (II) catalysis. The key to the difference between these two superficially rather similar sequences lies in the great tendency for palladium to undergo p-elimination 70. Oxypalladation 69 gives an unstable alkyl-palladium o-complex which decomposes at once to regenerate the double bond. 

In 2003, Stoltz at CalTech described a palladium-catalyzed oxidative Wacker cyclization of o-allylphenols such as 55 in nonpolar organic solvents with molecular oxygen to afford dihydrobenzofurans such as 56.44 Interestingly, when (-)-sparteine was used in place of pyridine, dihydrobenzofuran 56 was produced asymmetrically. The ee reached 90% when Ca(OH)2 was added as an additive. Stoltz considered it a stepping stone to asymmetric aerobic cyclizations. In 2004, Mufiiz carried out aerobic, intramolecular Wacker-type cyclization reactions similar to 55—>56 using palladium-carbene catalysts.45 Hiyashi et al. investigated the stereochemistry at the oxypalladation step in the Wacker-type oxidative cyclization of an o-allylphenol. Like o-allylphenol, o-allylbenzoic acid 57 underwent the Wacker-type oxidative cyclization to afford lactone 58.47... 

As mentioned earlier, the oxypalladation step is discussed controversially. Thus, Backvall et al. [22] reacted -(ethylene)-ii2 (C2H2D2) with palladium chloride and cupric chloride under extreme conditions, that is, extremely high chloride ion concentration as cupric and lithium chlorides. Under such conditions, 2-chloroethanol is formed as the main product besides some acetaldehyde [23] this is not the normal product of the Wacker reaction. In this study, the formation of cz s-l,2-dideuterioethylene oxide, evidently via t/zreo-l,2-dideuterio-chloroethanol, suggests trans-addition of water (antz -hydroxypalladation). 

Assuming the same intermediate for both products, the oxypalladation step should be trans-orientated. The authors of these studies claim the mechanism of the Wacker reaction, although the conditions and the products are different from it. This is also the case with the hydroxypalladation of cyclooctadiene [26] where the chelated Pd complex is rigid and the rotation of the complexed olefin is prevented to enable the cfs-interaction. 

A more extensive discussion of these facts can be found in [30, p. 395]. Further examples for the discussion of the oxypalladation step in the Wacker reaction can be found in Keith s paper [16]. 

The selective oxidation of ethylene to acetaldehyde with Pd VCu° chloride solutions has attained major industrial importance (Wacker process). This reaction can be regarded as an oxidative olefin substimtion (oxypalladation). Once again the in-... 

In catalytic reactions involving Pd(II) salts, carboxypalladation yields an alkylpal-ladium species that can often undergo (3-H elimination instead of protonolysis. Subsequently, Stoltz and coworkers demonstrated that Wacker-type processes can also afford lactones under oxidative conditions (Scheme 2.35). The proposed mechanism involves Pd(II) coordination to the alkene, followed by oxypalladation and (3-H elimination. After elimination of HX to form Pd(0), aerobic oxidation is required to regenerate a Pd(II) species. The net result is olefin transposition to an adjacent position [80]. 

Buchwald described an oxypalladation reaction, followed by a C-H functionalization. This entirely intramolecular reaction is initiated through a 5-exo Wacker-type cychzation of 84. The resulting a-alkyl-paUadium intermediate M provides subsequent C-H activation at the neighboring arene, which allows a paUadium(II) intermediate N bearing a-alkyl and o-aryl substituents, respectively. Reductive elimination provides the C-C bond installation of 85 with the concomitant release of a paUadium(O) catalyst state. Reoxidation imder aerobic conditions, most probably through a palladium(II) -peroxo complex and protonolysis with the acetic add hber-ated in the previous steps, regenerates the original paUadium(II) diacetate catalyst. 

Stoichiometric amounts of Pd(II) and exchange of the CuCl by CaClj led to no chlorohydrin formation. Jira proposed a reaction sequence of oxypalladation to AJ as observed in the Wacker process and oxidative-induced reductive C-Cl bond formation of the Pd alkyl intermediate AK (Scheme 16.41). 

The Wacker reaction of ethylene or terminal aUcenes proceeds via nncleophilic attack of water to coordinated alkenes to give oxypalladation intermediates from which /3-Pd-H elimination takes place. This process produces vinyl alcohols, which, nnder the influence of palladium, lead to acetaldehyde or methyl ketones as the final prodnct (Scheme 1). 

B. SYNTHESIS OF NATURAL PRODUCTS VIA THE WACKER OXIDATION AND RELATED OXYPALLADATIONS... 

The Wacker-type oxypalladation can take place both intermolecularly (Sect. V.3.1) and intramolecularly (Sect. V.3.2). The intermolecular Wacker oxidation of terminal alkenes provides the corresponding 2-ketones rather than aldehydes. This reaction has widely been used as a step in the syntheses of natural products and related compounds, as exemplified by Scheme 2 " and no attempts are made to thoroughly catalogue such examples here. 

Another prototypical example of the application of intermolecular oxypalladation to the synthesis of natural products and related compounds is shown in Scheme 3. Unlike the Wacker oxidation of alkenes to give ketones, the conversion of alkynes to ketones is a net nonredox process involving hydration of the triple bond. It should also be clearly noted that the observed high regioselectivity can most readily be explained in terms of intramolecular oxypalladation involving anchimeric participation by the cyclopentanone moiety followed by hydrolysis. 

TABLE 1. Synthesis of Natural Products Via the Wacker Oxidation and Related Oxypalladations... 

Unlike the cases of alkenes, Wacker-type intermolecular oxypalladation reactions of alkynes have not been extensively investigated, although their intramolecular cyclization reactions have been developed into synthetically useful procedures (Sects. V3.2). In principle, they can proceed by a few alternative paths shown for the cases of terminal alkynes in Scheme 14. In reality, however, alkynyl C—H activation by Pd to give alkynylpalladium derivatives shown in Scheme 3 may well be the dominant path, as suggested by the carbonylative oxidation of terminal alkynes to give alkynoic acid esters shown in Scheme 15. Oxidative dimerization of alkynes is a potentially serious side reaction. Further systematic investigation of this fundamentally important process appears to be highly desirable. 

Organopalladium derivatives containing Pd(II) can serve as sources of carbocationic species. Both alkene-Pd Tr-complexes and oxypalladated intermediates in the Wacker oxidation reactions can therefore generate carbocationic intermediates, which may then undergo anionotropic rearrangements (Scheme 6). In fact, it is rather remaikable that, despite the well-known involvanent of alkene-Pd Tr-complexes and oxypalladated intermediates, the Wacker-type oxidation of alkenes is relatively free from various possible rearrangement reactions. 

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