Palladium catalysts allylic substitution

The chloro group in l-acetoxy-4-chlorocyclohexene is more readily substituted by nucleophiles than the acetoxy group. Direct 8 2 attack of a nucleophile leads to inversion of configuration at carbon. In the presence of palladium catalyst, allylic substitution of chloride trans to the metal centre occurs. 

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

In an effort to extend the use of the Pyrphos-derived dendrimers to asymmetric Pd-catalyzed coupling reactions, strongly positive selectivity effects were observed upon going to very large multi-site chiral dendrimer catalysts. This enhancement of the catalyst selectivity was observed in palladium-catalyzed allylic substitutions, such as that displayed in Scheme 3, which are known to be particularly sensitive to small changes in the chemical environment of the active catalyst sites [17]. 

Fig. 6. Two binuclear palladium-bridged allylic complexes discovered by ES1(+)-MS analysis. They are proposed to serve as reservoirs for the active catalyst in a palladium-catalyzed allylic substitution reaction 2f. ...

The concept of surfactant-type catalysts described above was also found to be applicable to catalytic systems other than Lewis acid-catalysed reactions. For example, we have developed palladium-catalysed allylic substitution reactions using a combination of Pd(PPh3)4 and a non-ionic surfactant, Triton X-100 [32]. 

In order to permit complete conversion to one product enantiomer under the influence of a chiral catalyst, substrates for palladium-catalyzed allylic substitution either have to possess a meso structure (equation 1) or else give rise to complexes with 7t-allyl ligands as depicted in equations 2 and 3. Whereas oxidative addition of the substrate to the palladium(O) species constitutes the enantioselective step for meso compounds (equation 1), nucleophilic attack determines the absolute configuration of the product for reactive intermediates with a meso tt-allyl ligand (equation 2) or a zr-allyl unit that undergoes rapid epimerization by the n-a-n mechanism10-59 relative to substitution (equation 3). 

An S—P-type chiral phosphinooxathiane was developed as an effective ligand for palladium-catalyzed allylic substitution reactions [131]. A polymer-supported chiral phosphinooxathiane 208 was also prepared and applied to asymmetric alkylations and aminations of acetate 201 [132]. Enanhoselechvihes of up to 99% ee were obtained in asymmetric Pd-catalyzed allylic amination of acetate 201 using the polymeric catalyst prepared from a PS-diethylsilyl support (Scheme 3.68). 

The generally accepted mechanism of palladium-catalyzed allylic substitutions is shown in Scheme 1. An allylic substrate 1, typically an acetate or a carbonate, reacts with the catalyst, which enters the catalytic cycle at the Pd(0) oxidation level. Both Pd(0) and Pd(II) complexes can be used as precatalysts, because Pd(II) is easily reduced in situ to the active Pd(0) form. Presumably, the reaction is initiated by formation of a Ji-complex which eliminates X to produce an (ri -allyl)palladium(II) complex. The product of this oxidative addition can... 

In the absence of nucleophiles, the intermediate allyl complexes are stable and can be isolated. This is an attractive, quite unique feature of palladium-catalyzed allylic substitutions, because in most catalytic processes it is difficult to isolate or even merely detect intermediates of the catalytic cycle. The vast amount of data on the structure and reactivity of (allyl)palladium complexes that is available, has led to valuable insights into the mechanism of allylic substitutions and the origin of enantioselection in reactions with chiral catalysts (see Sect. 7). 

We recently studied if it is possible to device a selection strategy based on the relative stability of the intermediate of a reaction [24]. It is known that in the palladium-catalyzed allylic substitution, the rate-determining step is the attack of the nucleophile on the n-allyl-palladium species. The transition state of this step is believed to be late when carbon nucleophiles are used. In this scenario, an inverse correlation of the energy of the intermediate and the reaction rate is expected, as the transition state is more product-like (see Figure 4.10). Based on this hypothesis, the selection of catalyst among a dynamic mixture of palladium complexes was studied. 

Thanks to the fundamental studies of Tsuji, Trost, and others, palladium-catalyzed allylic substitution has become a versatile, widely used process in organic synthesis [40]. The search for efficient enantioselective catalysts for this class of reactions is an important goal of current research in this field [41]. It has been shown that chiral phosphine ligands can induce substantial enantiomeric excesses in Pd-catalyzed reactions of racemic or achiral allylic substrates with nucleophiles [42]. Recently, promising results have also been obtained with chiral bidentate nitrogen ligands [43]. We have found that palladium complexes of neutral aza-semicorrin or methylene-bis(oxazoline) ligands are effective catalysts for the enantioselective allylic alkylation of l,3-diphenyl-2-propenyl acetate or related substrates with dimethyl malonate (Schemes 18 [25,30] and 19 [44]). 

Palladium-catalyzed allylic substitution has been accomplished in water. Sinou and CO workers showed for the first time that a water-soluble paUadium(O) catalyst, prepared in situ from palladium acetate and P(C6H4- 7-S03Na)3, was an efficient catalyst for allylic substitution with various carbon- and heteronucleophiles in an aqueous/organic medium, allowing for easy separation of the product(s) and recycling of the catalyst (Scheme 8.21... 

Interestingly, the palladium-catalyzed allylic substitution of ( )-l,3-diphenylprop-2-enyl acetate as a model reaction has been performed with a chiral diketimine and dialdimine (eq 44). The Pd complex derived the diketimine turned out to be an active catalyst as the corresponding allylated derivative was isolated in 78% yield and 92% ee. Surprisingly, the Pd complex derived Irom dialdimine showed no activity even after four days at room temperature. This extreme difference in catalyst activity between these two systems can be understood by applying the AMS model. 

Allylic acetoxy groups can be substituted by amines in the presence of Pd(0) catalysts. At substituted cyclohexene derivatives the diastereoselectivity depends largely on the structure of the palladium catalyst. Polymer-bound palladium often leads to amination at the same face as the aoetoxy leaving group with regioselective attack at the sterically less hindered site of the intermediate ri -allyl complex (B.M. Trost, 1978). 

Alkynes react with indium reagents such as (allyl)3ln2l3 to form dienes (allyl substituted alkenes from the alkyne). Allyltin reagents add to alkynes in a similar manner in the presence of ZrCU Alkylzinc reagents add to alkynes to give substituted alkenes in the presence of a palladium catalyst. ... 

Allylic substitutions catalysed by palladium NHC complexes have been studied and the activity and selectivity of the catalysts compared to analogous Pd phosphine complexes. A simple catalytic system involves the generation of a Pd(NHC) catalyst in situ in THF, from Pdj(dba)j, imidazolium salt and Cs COj. This system showed very good activities for the substitution of the allylic acetates by the soft nucleophilic sodium dimethyl malonate (2.5 mol% Pdj(dba)3, 5 mol% IPr HCl, 0.1 equiv. C (CO ), THF, 50°C) (Scheme 2.22). Generation of the malonate nncleophile can also be carried out in situ from the dimethyhnalonate pro-nucleo-phile, in which case excess (2.1 equivalents) of Cs COj was used. The nature of the catalytic species, especially the number of IPr ligands on the metal is not clear. 

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