Palladium-catalyzed allylic substitution substrates

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... 

Vinyloxazolidin-2-ones 224 were used as substrates for palladium catalyzed allylic substitutions showing an unexpected regioselectivity towards the branched product 226. This effect was rationalised on the basis of an hydrogen bond interaction<03JA5115>. 

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). 

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... 

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]). 

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. 

Scheme 5.21 Stereochemical course of the palladium-catalyzed allylic substitution at the substrate (Z)-60 as a diastereomerically and enantiomerically pure probe.

A salient feature of palladium-catalyzed allylic substitution reactions is the exquisite reactivity differences that are observed for various allylic leaving groups. This permits substrates with more than one allylic nucleofuge to be selectively and sequentially elaborated [27]. A series of elegant experiments that utilizes such reactivity differences can be found in Backvall s work (Scheme 14.5) [49]. Cyclohexa-1,3-diene (20) was shown to be selectively oxidized to either the trans- or the cis-diacetates 21 and 22, respectively. 

Depending on the substrate and the other reaction parameters, very high re-gioselectivities towards either a or y substitution can be obtained. In certain cases, the regioselectivity can easily be switched between the two modes by changing the reaction conditions [11]. Compared to, for example, palladium(0)-catalyzed allylic substitution reactions, the possibility of switching between Sn2 and Sn2 selectivity... 

Nonracemic, axially stereogenic allylamine 8 is obtained by palladium(0)-catalyzed allylic substitution of meso-diastereomers 7 with morpholine using (S,S)-Diop (D)62. From both substrates, the product 8 displays an optical rotation unequal to zero. The corresponding enantiomeric excess values have not been determined. 

Palladium-catalyzed nucleophilic substitution reactions of allylic substrates have become useful in organic synthesis. As allylic substrates, allyl alcohols, halides, carboxylates, phosphates or vinyl epoxides can be utilized. 

Palladium-catalyzed nucleophilic substitution of allylic substrates (Tsuji-Trost coupling) is a most important methodology in organic synthesis and therefore it is no wonder that such reactions have been developed also in aqueous systems. Carbo- and heteronucleophiles have been found to react with allylic acetates or carbonates in aqueous acetonitrile or DMSO, in water or in biphasic mixtures of the latter with butyronitrile or benzonitrile, affording the products of substitution in excellent yields (Scheme 6.19) [7-11,14,45,46], Generally, K2C03 or amines are used as additives, however in some cases the hindered strong base diazabicycloundecene (DBU) proved superior to other bases. 

The stereospecificity of the palladium-catalyzed nucleophilic substitution of cyclic allylic substrates is addressed in the following diagram and in Table 3. Allyl chloride and carbonate derivatives arc included in these examples for the sake of comparison. The substrates listed form meso-n-a ]y complexes avoiding regioselectivity problems. Furthermore, the n--allyl complexes involved cannot isomerize through n-a-n rearrangement. 

More recently, Alper and colleagues described a convenient protocol for the synthesis of substituted benzazepine derivatives (Scheme 2.44) [286]. This protocol is based on the sequential palladium-catalyzed allylic amination and a subsequent intramolecular carbonylation reaction. The substrates were obtained by a Baylis-HiUman reaction. 

The generally accepted mechanism for Pd-catalyzed allylic substitution involves association of the palladium(0) catalyst to the substrate, and oxidative addition to provide a ir-aUyl complex. The equilibrium between the neutral 7r-allyl complex and the more reactive cationic 7r-allyl complex depends on the nature/concentration of phosphine Ugand. Nucleophilic addition to the ligand involves direct attack on the ligand when stabilized enolates are employed. After dissociation of the product, the palladium is able to continue in the next catalytic cycle (Scheme 2). In general, the reaction proceeds via a Pd(0)/Pd(II) shuttle, although a Pd(II)/Pd(IV) pathway is also possible. 

Pd-catalyzed allylic substitution reactions can also be performed using water-soluble phosphine ligands, including TPPTS 132, as shown by the reaction of nitroester 48 with allyl acetate 133 to give the substitution product 134 (Scheme 24). The use of water-soluble palladium catalysts has been the subject of a review.t Water-soluble catalysts have also been applied to supported Uquid phase reactions. A silica bead supports a thin film of polar solvent in which the palladium complex resides.t The substrates and product reside in the bulk organic phase and can be decanted from the glass bead catalyst at the end of the reaction. 

Although dramatic progress has been made in the enantio-control of palladium-catalyzed allylic alkylation, the lack of re-giocontrol is often a problem in the case of monosubstituted allylic substrates. The use of ferrocene-based ligands afforded the chiral-substituted derivative in good regioselectivity and in 94% ee (eq 60). ... 

Chiral pyridine-based ligands were, among various Ar,AT-coordinating ligands, more efficient associated to palladium for asymmetric nucleophilic allylic substitution. Asymmetric molybdenum-catalyzed alkylations, especially of non-symmetric allylic derivatives as substrates, have been very efficiently performed with bis(pyridylamide) ligands. 

Palladium(0)-catalyzed coupling reactions - i. e. the Heck and Sonogashira reactions, the carbonylative coupling reactions, the Suzuki and Stille cross-coupling reactions, and allylic substitutions (Fig. 11.1) - have enabled the formation of many kinds of carbon-carbon attachments that were previously very difficult to make. These reactions are usually robust and occur in the presence of a wide variety of functional groups. The reactions are, furthermore, autocatalytic (i.e. the substrate regenerates the required oxidation state of the palladium) and a vast number of different ligands can be used to fine-tune the reactivity and selectivity of the reactions. 

Molybdenum-catalyzed allylic alkylation has been used as a complementary synthetic procedure to the palladium-catalyzed process/ because allylic alkylation of unsymmetrical substrates takes place mostly at the more substituted carbon atom, in contrast to the palladium case. 

---