Palladium-catalyzed allylic substitution nucleophiles

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. 

A. 1.1. Covalently Functionalized Dendrimers Applied in a CFMR The palladium-catalyzed allylic substitution reaction has been investigated extensively in the preceding decades and provides an important tool for the formation of carbon—carbon and carbon—heteroatom bonds 14). The product is formed after attack of a nucleophile to an (f/ -allyl)Pd(II) species, formed by oxidative addition of the unsaturated substrate to palladium(0) (Scheme 1). To date several nucleophiles have been used, mostly resulting in the formation of carbon—carbon and... 

A sterically demanding group at one terminus of the allyl moiety blocks the incoming nucleophile in palladium-catalyzed allylic substitutions. The Mc Si group in 161 can fulfil such a purpose and prevails over the phenyl group as a controlling element in the... 

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). 

Reactions with Sulfur Nucleophiles. The use of sulfur nucleophiles in palladium-catalyzed allylic substitution reactions is less well documented than that of carbon, nitrogen and oxygen nucleophiles. The asymmetric synthesis of allylic sulfones utilizing a catalytic phase transfer system has been used to produce (35)-(phenylsulfonyl)cyclohex-l-ene on a 45 g scale (eq 10). In many cases, it has been reported that allylic carbonates are more reactive than allylic acetates in asymmetric allylic substitution... 

Heterogeneous aquacatalytic palladium-catalyzed allylic substitution with nitromethane as the Cl nucleophile has been developed by Uozumi (Scheme 3.71). By using an amphiphilic PS-PEG polymer-supported chiral palladium complex, the asymmetric allyhc nitromethylation of cycloalkenyl esters proceeded smoothly in water. For example, when polymer-supported palladium complex 214 was employed in the asymmetric nitromethylation of cycloheptenyl carbonate 215... 

Allylic substitutions are among the most important carbon-carbon bond-forming reactions in organic synthesis. Palladium-catalyzed allylic substitutions and their asymmetric version have been extensively studied and widely used in a variety of total syntheses [78]. The palladium catalysis mostly requires soft nucleophiles such as malonate carbanions to achieve high stereo- and regioselectivity. 

Due to the insolubility of anions in BTF (see Sect. 3.8), a palladium catalyzed allylic substitution reaction using the malonate anion [67] could not be tried. However, an intramolecular version using tosylcarbamate as nucleophile (11.4)... 

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). 

The factors that control regioselectivity of palladium-catalyzed allylic substitutions have been the subject of numerous studies. Experiments that reveal the effects of both symmetric and unsymmetric ancillary ligands on this regioselectivity have been reported, along with experiments that have revealed effects of the type of nucleophile and the effects of basic additives. The following section describes some of this work on palladium-catalyzed processes. 

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. 

Palladium-catalyzed allylic substitution reactions, known as Tsuji-Trost reactions, are a well-established method for carbon-carbon bond forming processes [48]. The generally accepted mechanism for this reaction involves the oxidative addition of the allylic substrate to Pd(0) to provide a Jt-allylpalladium complex. The subsequent reaction of the electrophilic 7t-allylpalladium complex with the nucleophile affords the substituted product and Pd(0), which is regenerated to start the catalytic cycle (Scheme 7.26). 

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]). 

Substitutions of Sn2 type are frequently used for carbon-carbon or carbon-heteroatom bond formation. However, little attention has been devoted to the development of such reactions in water. This is likely due to concerns about competitive hydrolysis of the electrophile in water and SN2-type reactions being slower in aqueous conditions than in aprotic polar solvents due to the higher cost of desolvation of nucleophiles. We shall discuss the ring opening of epoxides and aziridines, palladium-catalyzed allylic substitutions, as well as acylations and sulfonylations of amines and alcohols. 

Palladium-catalyzed allylic substitution may be regarded as a special case of cross-coupling with jr-allylpalladium complexes. First developed as a stoichiometric technique, this reaction was later realized in a catalytic mode, and became a valuable tool of organic synthesis, as it allows for a broad variation of both allylic substrates and nucleophiles. 

Hartwig and coworkers reported an approach to address this limitation involving tandem catalytic reactions. In this tandem process, sequential palladium-catalyzed isomerization of the branched isomer to the linear isomer, followed by iridium-catalyzed allylic substitution leads to the branched product with high enantiomeric excess [105]. More specifically, treatment of branched allylic esters with catalytic amounts of the combination of Pd(dba)2 and PPhs led to rapid isomerization of the branched allylic ester to the linear isomer, and the linear isomer underwent allylic substitution after addition of the iridium catalyst and nucleophile (Scheme 31). 

Palladium-catalyzed allylic oxidations, in contrast, are synthetically useful reactions. Palladium compounds are known to give rise to carbonyl compounds or products of vinylic oxidation via nucleophilic attack on a palladium alkene complex followed by p-hydride elimination (Scheme 9.16, path a see also Section 9.2.4). Allylic oxidation, however, can be expected if C—H bond cleavage precedes nucleophilic attack 694 A poorly coordinating weak base, for instance, may remove a proton, allowing the formation of a palladium rr-allyl complex intermediate (89, path by694-696 Under such conditions, oxidative allylic substitution can compete... 

P-Menthylphosphetanes 77, in which an optical active dioxolane group is introduced at the a-position, have also provided asymmetric catalytic activity in the palladium-catalyzed allylic nucleophilic substitution of 1,3-diphenyl-propenyl acetate with the sodium salt of dimethyl malonate (Equation 12). 

A one-pot procedure for the palladium-catalyzed allylation/cyclization of o-alkynyltrifluoroacetanilides 57a [57] and o-alkynylphenols 57b [58] was developed by Cacchi et al. (Scheme 20). This method provides a valuable tool for the synthesis of 2-substituted-3-allylindoles 58a and 2-substituted-3-allylbenzofurans 58b. It was reported that reaction proceeded through the formation of X-allyl derivatives, which form 7r-allylpalladium species 59. A subsequent rearrangement of 59 would then lead to the 7r-allylpalladium species 60. Intramolecular nucleophilic attack of the hetero atom across the activated carbon-carbon triple bond in 60, followed by reductive elimination of Pd(0) gives the products 58. A similar reaction was reported by Balme et al. [59]. 

A facile synthesis of substituted 2,3-dihydrofurans makes use of a palladium-catalyzed allylation reaction of a propargylic carbonate with either an external or an internal O-nucleophile (Equation 43) <2004TL1861>. 

Fischer-type carbenes can also be modified via transition metal catalyzed reactions. Fischer chromium aminocarbene complexes can be used as nucleophiles in palladium-catalyzed allyUc substitution reactions with aUylic acetates and carbonates, alFording the corresponding allyl-substituted aminocarbenes. For example, reaction of the Uthiated carbene (15) gives (16) in good yield (Scheme 25). ... 

The great importance of nonproteinogenic amino acids including a-substituted derivatives led to numerous investigations of modified amino acid enolates as nucleophiles in both classical alkylation or Mannich reactions and palladium-catalyzed allylic alkylations. 

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