Oxypalladation alkenes

The Pd—C cr-bond can be prepared from simple, unoxidized alkenes and aromatic compounds by the reaction of Pd(II) compounds. The following are typical examples. The first step of the reaction of a simple alkene with Pd(ll) and a nucleophile X or Y to form 19 is called palladation. Depending on the nucleophile, it is called oxypalladation, aminopalladation, carbopalladation, etc. The subsequent elimination of b-hydrogen produces the nucleophilic substitution product 20. The displacement of Pd with another nucleophile (X) affords the nucleophilic addition product 21 (see Chapter 3, Section 2). As an example, the oxypalladation of 4-pentenol with PdXi to afford furan 22 or 23 is shown. 

The isoflavone 406 is prepared by the indirect a-phenylation of a ketone by reaction of phenylmercury(II) chloride with the enol acetate 405, prepared from 4-chromanone[371]. A simple synthesis of pterocarpin (409) has been achieved based on the oxypalladation of the oriho-mercurated phenol derivative 408 with the cyclic alkene 407[372,373]. 

The mechanism of the rearrangement catalyzed by Pd(fl), typically by PdCl2(RCN)2, is explained by the oxypalladation of an alkene to form 810 as an intermediate, or cyclization-induced rearrangement. As a limitation, no rearrangement takes place when the allylie ester 812 is substituted at the C-2 position of the allyl group, while a smooth rearrangement of 811 takes place[500]. 

The unsaturated c.vo-enol lactone 17 is obtained by the coupling of propargylic acetate with 4-pentynoic acid in the presence of KBr using tri(2-furyl)-phosphine (TFP) as a ligand. The reaction is explained by the oxypalladation of the triple bond of 4-pentynoic acid with the ailenyipailadium and the carbox-ylate as shown by 16, followed by reductive elimination to afford the lactone 17. The ( -alkene bond is formed because the oxypalladation is tnins addition[8]. 

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. 

An interesting variant involves the use of an allylic alcohol as the alkene component. In this process, re-oxidation of the catalyst is unnecessary since the cyclization occurs with /Uoxygen elimination of the incipient cr-Pd species to effect an SN2 type of ring closure. Both five- and six-membered oxacycles have been prepared in this fashion using enol, hemiacetal, and aliphatic alcohol nucleophiles.439,440 With a chiral allylic alcohol substrate, the initial 7r-complexation may be directed by the hydroxyl group,441 as demonstrated by the diastereoselective cyclization used in the synthesis of (—)-laulimalide (Equation (120)).442 Note that the oxypalladation takes place with syn-selectivity, in analogy with the cyclization of phenol nucleophiles (1vide supra). 

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. 

Oxypalladation of vinyl ether, followed by alkene insertion, is an interesting synthetic route to functionalized cyclic ethers. In prostaglandin synthesis, the oxypalladation of ethyl vinyl ether (40) with the protected cyclopentenediol 39 generates 41 and its intramolecular alkene insertion generates 42. The intermolecular insertion of the alkene 43, and /1-elimination of 44 occurred as one-pot reaction at room temperature, giving the final product 45 in 72% yield [46], The stereochemistry of the product shows that the alkene insertion (carbopalladation of 41) is syn. It should be noted that the elimination of /1-hydrogen from the intermediate 42 is not possible, because there is no /1-hydrogen syn coplanar to the Pd and, instead, the insertion of alkene 43 occurs. 

Transmetallation of silyl enol ethers of ketones and aldehydes with Pd(II) generates Pd(II) enolates, which are usefull intermediates. Pd(II) enolates undergo alkene insertion and -elimination. The silyl enol ether of 5-hexen-2-one (241) was converted to the Pd enolate 242 by transmetallation with Pd(OAc)2, and 3-methyl-2-cyclopentenone (243) was obtained by intramolecular insertion of the double bond and -elimination [148], Formally this reaction can be regarded as carbopalladation of alkene with carbanion. Preparation of the stemodin intermediate 246 by the reaction of the silyl enol ether 245, obtained from 244, is one of the many applications [149]. Transmetallation and alkene insertion of the silyl enol ether 249, obtained from cyclopentadiene monoxide (247) via 248, afforded 250, which was converted to the prostaglandin intermediate 251 by further alkene insertion. In this case syn elimination from 250 is not possible [150]. However, there is a report that the reaction proceeds by oxypalladation of alkene, rather than transmetallation of silyl enol ether with Pd(OAc)2 [151]. 

A Pd(II) salt such as Pd(OAc)2 adds to an alkene to give, via the 7t complex, a product with Pd at one end of the alkene and OAc at the other. This is oxypalladation but this product is not usually isolated as it decomposes to the substituted alkene. This reaction is occasionally used with various nucleophiles but it needs a lot of palladium. 

An example of catalytic oxypalladation is the rearrangement of allylic acetates with Pd ll). The reaction starts with oxypalladation of the alkene and it is the acetate already present in the molecule that provides the nucleophile to attack... 

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. 

A related reaction is the oxidation of silyl enol ethers to enones. This requires stoichiometric pal-ladium(II), though reoxidation of Pd(0) with benzoquinone can cut that down to about half an equivalent, but does ensure that the alkene is on the right side of the ketone. The first step is again oxypalladation and p elimination puts the alkene in conjugation with the ketone chiefly because there are no P hydrogens on the other side. 

In the presence of CO, terminal alkenes are oxidized by PdCl2 to RCH(C1)CH2C0C1. When the reaction is made catalytic in palladium by the addition of CuCl2 and oxygen, and carried out in alcohols, the products are a, /3-unsaturated esters, /3-alkoxy esters, and, under some conditions, succinate derivatives (equation 87). Two mechanisms are possible for this reaction. In the first, an oxypalladation can produce a Pd-CH2-CH2-X species, which can undergo CO insertion into the Pd-C bond. Alternatively, an XCOPd species can form and add across the double bond. Loss of Pd-H can generate the a, /3-unsaturated ester, or a second carbonylation step can lead to succinate derivatives. 

Cyclic acetals, oxypalladation of alkenes in the synthesis of 90ACR49. 

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. 

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