Palladium! 11 , addition with nucleophiles stereochemistry

In the case of certain diolefins, the palladium-carbon sigma-bonded complexes can be isolated and the stereochemistry of the addition with a variety of nucleophiles is trans (4, 5, 6). The stereochemistry of the addition-elimination reactions in the case of the monoolefins, because of the instability of the intermediate sigma-bonded complex, is not clear. It has been argued (7, 8, 9) that the chelating diolefins are atypical, and the stereochemical results cannot be extended to monoolefins since approach of an external nucleophile from the cis side presents steric problems. The trans stereochemistry has also been attributed either to the inability of the chelating diolefins to rotate 90° from the position perpendicular to the square plane of the metal complex to a position which would favor cis addition by metal and a ligand attached to it (10), or to the fact that methanol (nucleophile) does not coordinate to the metal prior to addition (11). In the Wacker Process, the kinetics of oxidation of olefins suggest, but do not require, the cis hydroxypalladation of olefins (12,13,14). The acetoxypalladation of a simple monoolefin, cyclohexene, proceeds by trans addition (15, 16). 

Oxidative Addition of Alkyl Halides to Palladium(0). The stereochemistry of the oxidative addition (31) of alkyl halides to the transition metals of group VIII can provide information as to which of the many possible mechanisms are operative. The addition of alkyl halides to d8-iridium complexes has been reported to proceed with retention (32), inversion (33), and racemization (34, 35) via a free radical mechanism at the asymmetric carbon center. The kinetics of this reaction are consistent with nucleophilic displacement by iridium on carbon (36). Oxi-... 

Substitution reactions of allylic substrates with nucleophiles have been shown to be catalyzed by certain palladium complexes [2, 42], The catalytic cycle of the reactions involves Jt-allylpalladium as a key intermediate (Scheme 2-22). Oxidative addition of the allylic substrate to a palladium(o) species forms a rr-allylpal-ladium(n) complex, which undergoes attack of a nucleophile on the rr-allyl moiety to give an allylic substitution product. The substitution reactions proceed in an Sn or Sn- manner depending on catalysts, nucleophiles, and substituents on the substrates. Studies on the stereochemistry of the allylic substitution have revealed that soft carbon nucleophiles represented by sodium dimethyl malonate attack the TT-allyl carbon directly from the side opposite to the palladium (Scheme 2-23). 

The stereochemistry of oxypalladation and other additions of nucleophiles with palladium(II) has received considerable attention, and in the last 3 years a number of stereochemical studies have been carried out. These have been mentioned in the appropriate portion of the text. It seems fitting to conclude with a brief discussion of this subject. 

Many studies of the addition of nucleophiles to palladium-allyl complexes have been conducted. Hayashi has shown that the additions of stabilized anions, such as malonate anions or amine nucleophiles, to chiral, non-racemic allyl complexes occur with inversion of configuration.Addition of excess phosphine and either diethyl malonate or dimethylamine to a chiral, non-racemic allyl complex results in nucleophilic attack with nearly complete inversion. The reaction with sodium dimethylmalonate is shown at the right of Equation 11.40. In contrast, nonstabilized carbanions such as allyl or phenyl magnesium chloride react with the same Ti -allylpalladium complex with retention of configuration as shown at the left of Equation 11.40. The stereochemistry from reaction of the Grignard reagents likely results from nucleophilic attack at the metal, followed by reductive elimination. 

A stereochemical study reported by Henry illustrated that the formation of aldehyde and formation of chlorohydrin occur with different stereochemistry, and this result implies that one process occurs by syn addition and one by anti addition of water and palladium across the olefin. This study is summarized in Scheme 16.24. Oxidation of the non-race-mic, chiral allyl alcohol in the absence of added chloride forms the (R)-(E)-alcohol, whereas reaction of the allyl alcohol in the presence of added chloride forms the product with stereochemistry resulting from the opposite mode of attack. Because it is known that the allylic alcohol binds to palladium with hydrogen bonding between the hydroxyl group and the bound chloride, Henry concluded that the reaction conducted in the presence of high concentrations of added diloride occurs by external attack of the oxygen nucleophile, while the reaction with low concentrations of added chloride occurs by insertion of the olefin into a Pd-0 bond. ... 

The C-0 and C-N bond in the product of the oxidations with oxygen and nitrogen donors forms by either nucleophilic attack on the coordinated olefin or by insertion of the olefin into a palladium-oxygen or palladium-nitrogen bond. More detailed descriptions of the nucleophilic attack on coordinated ligands were provided in Chapter 11 and a more detailed description of migratory insertions was provided in Chapter 9. These reactions are discussed in the context of the effect of additives on the stereochemistry of the catalytic processes in several earlier sections on the Wacker process. Henry conducted the same stereochemical study for reactions of alcohols with the resolved allylic alcohol in Scheme 16.24 as was conducted for reactions of water. The results of these experiments were similar to those on the reactions of water. ... 

Wacker-type chemistry can be combined with other aspects of palladium chemistry to create tandem reactions. For instance, the -intermediate can be intercepted by carbon monoxide giving ester products. This chemistry has been found to be useful in the formation of tetrahydrofurans and tetrahydropyrans as the stereochemistry of the newly formed ring is usually eontroUed quite well (Scheme 6.21 For tetrahydrofuran formation, the substituent in the allylic position seems to have the most stereochemical-directing effect (Scheme 6.22). For tetrahydropyran formation, the 2,6-cis isomer, with both a-substituents equatorial, is favoured. If a disubstituted alkene is used, an additional ehiral eentre is created, and the two geometrical isomers of the alkene starting material give different diastereoisomers of the product (Scheme 6.23). The stereochemistry is consistent with nucleophilic attack trans to palladium, followed by CO insertion with retention. For most substrates, eyehzation is found to be exo, but there are exceptions (Scheme 6.24). 

Competitive experiments of allyl phenyl sulfide and allyl phenyl selenide with this system indicate that oxidative addition of the organic selenide is faster. The equilibrium displacement between the allylic sulfide and 7 -allylic complex depends on the actual precursor for Pd(0) phosphine complexes (Equation (41)). The stereochemistry of the reverse reaction on 7/ -cyclohexenyl palladium thiolate dimers (nucleophilic attack of sulfide) has been determined to be trans. According to the principle of microscopic reversibility, the oxidative addition of allylic sulfides must occur with inversion of configuration. 

The stereochemistry of Pd -catalyzed allylic alkylation is net retention (equation 62). This arises from sequential inversion steps. Initially, the Pd approaches from the face of the C3 unit opposite the leaving group, to form the jt-allyl complex. Subsequently, the nucleophile adds to the face of the TT-allyl opposite palladium. If a bulky or umeactive nucleophile is used with allylic acetates, the acetoxy group can add again to the complex. Ultimately, this results in the production of a mixture of stereoisomers upon nucleophihc addition. As an example of the range of allylic substrates that react, nitrogen nucleophiles, in particular primary and secondary amines, undergo palladium-catalyzed substimtion with aUyhc alcohols, acetates, and ethers (equation 63). 

Intramolecular reactions of allylic acetates with conjugated dienes catalyzed by Pd(0) lead to a 1,4-addition of a carbon and an oxygen nucleophile to the diene. The reaction, which is formally an isomerization, involves tw different yr-allyl complexes (Scheme 8-4) [44]. Reaction of 22 in the presence of the Pd(0) catalyst Pd2(dba)3-CHCl3 (dba = dibenzyl-ideneacetone) and LiOAc/HOAc in acetonitrile at reflux produces the cyclized isomer 25 in 62% yield. The double bond was exclusively of E stereochemistry, while the ring stereochemistry was a mixture of cis and tram isomers. Oxidative addition of the Pd(0) to the allylic acetate gives the intermediate jr-allyl complex 23. Subsequent insertion of a diene double bond into the allyl-palladium bond produces another jr-allyl intermediate (24), which is subsequendy attacked by acetate to give the product 25. 

Addition of a variety of nucleophiles to rf-alkene and alkyne ligands has been investigated, particularly when these ligands are complexed with iron and palladium. Reactions shown in equation 8.39 demonstrate well the typical stereochemistry resulting from the trans mode of attack by external nucleophiles on t 2—7t systems.56 Careful analysis of the reaction of amines with ( )- and (Z)-2-butenyl iron complexes (the CpFe(CO)2 group is abbreviated Fp, which is pronounced fip ) showed the stereochemistry to be cleanly anti.51... 

An alternative mechanism applies to the chemistry surrounding the pyranose analogs utilized in Schemes 4.3.2, 4.3.4, and 4.3.5. Addition of palladium to these species forms a ji-allylpalladium complex. As shown in Scheme 4.4.2, approach of the palladium is from the side of the sugar opposite that of the glycosidic substituent. This allows the nucleophilic species to approach from the opposite side of the palladium giving the product with a net retention of stereochemistry. Further insight into the mechanistic aspects of this chemistry is available from any of the references cited within this chapter. 

Palladium-catalyzed intermolecular oxidations of dienes with carboxylic acids and alcohols as donors give 1,4-addition products. This chemistry has been studied extensively by Backvall. Early studies involved 1,4-additions of two acetoxy or alkoxy groups across a diene,More recently, intermolecular additions of two different nucleophiles have been developed. The ability to control the stereochemistry of the additions across cyclic dienes makes this procedure particularly valuable. As shown in Scheme 16.25, conditions for either cis or trans additions have been developed. Reactions conducted in the absence of added chloride form products from trans 1,4-addition, while reactions conducted in the presence of added chloride form products from cis 1,4-addition. 

Addition of the nucleophile can take place by two sterically different pathways. In the first (path (a)), direct attack on the rj -allyl group occurs trans to palladium. This is by far the commoner route and is followed by stabilized carbanions such as CH(C02R)2, CH(C0R)2, PhCHCN and CgHg , and normally also with amines. Aryl and alkyl carbanions (e.g. R CuLi) or hydride however add initially to the metal centre and then migrate to the allyl group (path (b)). The stereochemistry of the product depends on which mechanism is followed (v.i.). 

The reactions of some optically active benzyl halides have provided further evidence for the nucleophilicities of the [Pd(PR3)j] species (Lau et al., 1974, 1976 Wong et al., 1974 Stille and Lau, 1976). The salient features of these studies are summarised in Scheme 6. The stereochemistry of the addition is established by reaction of the palladium-alkyl complex with carbon monoxide (this insertion is known to take place by an intramolecular migration process, with retention of configuration in the migrating alkyl group), and subsequent formation of an ester from this acyl complex. 

In a variant of the Wacker process, Stille and co-workers coupled the anti-addition of HO-Pd-X to an olefin with a lactonization process to confirm the stereochemistry of the hydroxypalladation of olefins (Scheme 31).[" 3],[44] -pjjg j-gsuit supports the notion that the nucleophile attacks the olefin-palladium complex in an anti fashion. Further evidence for this came from the reaction of the di-dideuterated ethylene with CO and water, which led to a lactone with the two deuterium atoms tmns to each other. 

It has been shown earlier that the presence of electron-withdrawing ligands favors the reductive elimination in palladium 77 -allyl complexes. Benzoquinone has been used to perform the clean reductive elimination in -allyl aryl palladium complexes, that otherwise decompose by other competing routes such as /3-H elimination. The intermediate complex with a coordinated benzoquinone molecule has been characterized in solution (Scheme 72). Benzoquinones have also been used to promote the reductive elimination of chloro and an -allyl Cl as a nucleophile toward Pd 77 -allyls usually attacks in a trans- (or exo-) fashion. A different stereochemistry (cis- or /rrfo-attack) has been achieved in this work. It was found that the more electron withdrawing the quinone the more favored the m-attack, as supported by theoretical calculations. Allyltin trichloride can be obtained by a reductive elimination reaction from Pd(SnCl3)(77 -allyl)L. The reaction is accelerated by addition of an electron-withdrawing olefin such as allyl chloride. Tin dichloride also increases the reaction rate. ... 

Another important consideration is the stereoselectivity of the reaction. Oxidative addition occurs under stereoelectronic control and one can think of this step as an SN2-like displacement of the leaving group by the incoming palladium nucleophile . In the case of a substrate such as 4, oxidative addition occurs with inversion of stereochemistry, to give complex 16. 

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