Allylation of Nucleophiles

The efficient catalytic cycle is ascribed to the characteristic feature that Pd(0) is more stable than Pd(II). Reactions of 7t-allylpalladium complexes with carbon nucleophiles are called Tsuji Trost reactions. In addition to Pd, other transition metal complexes, such as those of Mo [26], Rh [27] and other metals, are used for catalytic allylation. 

In addition to the formation of 70 by the usual nucleophilic attack at the terminal carbon of allylic system, the substituted cyclopropanes 72 are formed by the attack at 

The stereochemistry of the Pd-mediated or -catalysed allylation of nucleophiles has been studied extensively [34—36]. In the first step, formation of 7r-allylpalladium complex 74 by the attack of Pd(0) on an allylic acetate moiety of 73 proceeds by inversion (anti attack). Subsequent reaction of soft carbon nucleophiles, N— and O— nucleophiles gives 75 by inversion. Thus the overall retention is observed. However, 

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Nucleophilic Substitution of xi-Allyl Palladium Complexes. TT-Allyl palladium species are subject to a number of useful reactions that result in allylation of nucleophiles.114 The reaction can be applied to carbon-carbon bond formation using relatively stable carbanions, such as those derived from malonate esters and (3-sulfonyl esters.115 The TT-allyl complexes are usually generated in situ by reaction of an allylic acetate with a catalytic amount of fefrafcz s-(triphenylphosphine)palladium... 

The Tsuji-Trost reaction is the palladium-catalyzed allylation of nucleophiles [110-113]. In an application to the formation of an A-glycosidic bond, the reaction of 2,3-unsaturated hexopyranoside 97 and imidazole afforded A-glycopyranoside 99 regiospecifically at the anomeric center with retention of configuration [114], Therefore, the oxidative addition of allylic substrate 97 to Pd(0) forms the rc-allyl complex 98 with inversion of configuration, then nucleophilic attack by imidazole proceeds with a second inversion of configuration to give 99. 

Allylation of nucleophiles. jr-Allyl palladium complexes (a) of a,/S-unsaturated epoxides react with active methylene compounds to give 1,4-adducts [allylic alcohols, equation (I)].10... 

Although the C—N bond of allylamines is difficult to cleave, it can be cleaved in AcOH, probably by forming amine salt. However, the allylation of nucleophiles with the allylamine 138 is catalysed by Ni DPPB [72], Removal of the allyl group from allylamines is possible with Ni(dppp)Cl2 DIBAL and used for deprotection of amines, which are protected as allylamines [73], Pd DPPB is less active. 

The Tsuji-Trost Reaction (or Trost Allylation) is the palladium-catalyzed allylation of nucleophiles such as active methylenes, enolates, amines and phenols with allylic compounds such as allyl acetates and allyl bromides. 

Palladium(0)-catalyzed allylation of nucleophiles (the Tsuji-Trost reaction) is a versatile synthetic method that has gained immense popularity in recent years. Rarely applied to ambident nucleophilic aromatic heterocycles before 1991, the Tsuji-Trost reaction has been extensively used in the chemistry of these compounds since 1991. Two factors have played decisive roles in this increased interest in the Pd(0)-catalyzed allylation of such heterocyclic rings one is that, unlike other alkylation procedures, the Pd(0)-catalyzed allylation can sometimes give the product of thermodynamic control when applied to ambident nucleophiles and the second is that the Tsuji-Trost allylation has become one of the standard methods for synthesizing carbanucleosides, which are important antiviral compounds (93MI1, 93MI2). Of course, the double bond of an allylic system can be modified in different directions, thus adding versatility to the Tsuji-Trost reaction. 

Palladium(0)-catalyzed allylation of nucleophiles (Tsuji-Trost reaction) has become a powerful synthetic method owing to its versatility, broad... 

This stereochemistry results in overall retention (inversion + inversion) of configuration in the Pd(0)-catalyzed allylation of nucleophiles. This reten-... 

Two types of palladium-catalyzed asymmetric reaction have been reported. One is the allylation of nucleophiles in which a new chiral carbon center is created in the nucleophile and the other is the allylic substitution reaction in which it is created in the allylic substrate (Scheme 2-24). Chiral ferrocenylbisphosphines designed and modified on the side chain have been successfully used for both of the two types of asymmetric reaction [5 c, d]. 

The use of C2-symmetric aziridines as chiral auxiliaries has been reviewed by Tanner <94AG(E)599>. Chiral A-acylaziridines such as (143) have been used in enolate chemistry (see Section 1.01.8.2). Aziridine-containing ligands such as (144) have been used for a variety of metal-catalyzed reactions such as the asymmetric dihydroxylation of alkenes, the palladium-catalyzed allylation of nucleophiles, asymmetric cyclopropanation, and aziridination <94AG(E)599,94TL4631). 

The Tsuji-Trost reaction is the Pd-catalyzed allylation of nucleophiles [105] with allylic halides, acetates, carbonates, etc. This transformation proceeds via intermediate allylpalladium complexes (e.g. 110), and typically proceeds with overall retention of stereochemistry. In addition, the trapping of the intermediate allylpalladium complex usually occurs at the least hindered carbon. A representative example of this transformation is shown below in an application to the formation of an 7V-glycosidic bond. Treatment of 2,3-unsaturated hexopyranoside 109 with imidazole in the presence of a Pd(0) catalyst... 

The Tsuji-Trost reaction is the Pd(O)-catalyzed allylation of nucleophiles [110]. Even though extensive applications of Tsuji-Trost reaction can be found in many areas, including heterocycles, applications to the indole field have been relatively rare. Nevertheless, several elegant total syntheses of indole alkaloids have used the Tsuji-Trost reaction as the key feature of the synthetic approaches to achieve great convergency. 

In contrast to the processes based on the external attack of a nucleophile on the coordinated CO or olefin ligands on Pd(II) species, where re-oxidation of the Pd(0) produced to reactive Pd(II) presents a considerable problem, no such problem is involved in reaction of a Pd(0) complex with allylic substrates. As we have already discussed in Schemes 1.9 and 1.10, allylic compounds such as allylic acetates or carbonates readily oxidatively add to Pd(0) species to form 7 -allyl palladium(II) complexes that are susceptible to nucleophilic attack. The catalytic process converting allylic substrates to produce allylation products of nucleophiles has found extensive uses in organic synthesis, notably in the work of Tsuji and Trost. Employment of a chiral ligand in the catalytic allylation of nucleophiles allows catalytic asymmetric synthesis of allylation... 

Ruthenium complexes attract recent interest as new promising candidates for efficient, specific and environmentally benign allylation catalysts. It is noticeable that some J7 -allylruthenium(II) complexes have an ambiphilic property in catalysis involving the C-0 bond activation [52]. When allyl carboxylates or carbonates are treated with nucleophilic 1,3-dicarboxylates or electrophilic aldehyde in the presence of Ru complexes, catalytic allylations of nucleophiles or electrophiles take place [53]. In both reactions, J7 -allylruthenium complexes are assumed to be intermediates. Independent synthesis and reactions of the model compounds support this observation (Scheme 3.28). This ambiphilicity of the allylruthenium(II) may arise from the different reactivity of and rf forms in the allylic moiety [54]. 

The Pd(0)-catalyzed reactions of Ar-X and B-H (or B-Y) can be expressed by the following general equations, which involve no oxidation. The Mizoroki-Heck reaction, allylation of nucleophiles, and cross-couplings are typical reactions of this type. They are treated in Chapters 3-8. 

Stereochemistry of Pd-catalyzed allylation of nucleophiles has been studied extensively. In the first step, formation of 7r-allylpalladium complexes 37 by the attack of Pd(0) on allylic compounds 36 proceeds with inversion of configuration (anti attack). Subsequent reaction of 37 with nucleophiles occurs in different stereochemistry depending on the nature of the nucleophiles. The soft (stabilized) nucleophiles which are derived from conjugate acids with < 25, such as active methylene compounds, attack 37 from the backside of the Pd atom to give 38 with inversion of stereochemistry. Thus overall retention is observed. On the other hand, hard nucleophiles (pK > 25), typically organometallic compounds of main group metals (Mg, Zn, B, Sn and others) generate 39 by transmetallation, and subsequent reductive elimination affords 40. Both the transmetallation and... 

Palladium-catalyzed allylation of nucleophiles proceeding in an Sn2 or Sn2 fashion depending on the catalyst, nucleophile, and substituents on the substrate ... 

The catalytic version of allylation of nucleophiles via 7r-allylpaUadium intermediates was discovered in 1970 using allylic esters and aUyl phenyl ethers as substrates (Scheme Formation of 7r-allylpaUadium complexes by oxidative addition of various allylic compounds to Pd(0) and subsequent reaction of electrophilic rr-allylpalladium complexes with soft carbon nucleophiles are the basis of the catalytic allylation. After the reaction, Pd(0) is regenerated, which undergoes oxidative addition to the allylic compounds again, making the whole reaction catalytic. The efficient catalytic cycle is ascribed to the characteristic feature that Pd(0) is more stable than Pd(II). Allylation of carbon nucleophiles with allyhc compounds via TT-allylpalladium complexes is called the Tsuji-Trost reaction. The reaction has wide synthetic applications, particularly for cyclization. " ... 

Stereochemistry of the allylation of nucleophiles has been studied extensively using substituted 2-cyclohexenyl acetate (Scheme As the first step, formation of tt-... 

In 1982 Jiro Tsuji and co-workers published a conununication launching allyl carbonates as substrates in the Pd(0)-catalyzed allylation of nucleophiles. It was followed three years later by a full paper. The overall reaction and catalytic cycle are shown in Scheme 1. One of the advantages over acetates is that addition of external base is not required. Indeed, the pronucleophile Nu-H reacts with the in situ generated alkoxide to form the actual nucleophile. The maximal concentration of base at any moment in the reaction medium depends on the relative rates of the individual steps of the cycle, but cannot be higher than the maximal quantity of the catalytic species PdL2. Therefore, the reaction takes place formaUy in... 

Nucleophiles used in the seminal papers by Tsuji and co-workers were mostly stabilized carbon nucleophiles, and the method found an early synthetic application in a preparation of steroids." It soon became evident that many other types of nucleophiles could be used. In particular, hydride ion equivalents led to l-olefinsf ° " (see Sect. V.2.3.1), Silyl and stannyl enolates of simple ketones and aldehydes and esters can be aUylated, as well as allyl enol carbonates (see Sect. V.2.1.4), This is an indirect a-aUylation of ketones, aldehydes, and esters. Enol derivatives can take another reaction course under Pd(0) catalysis (Scheme 2). Thus, oxidation to a,/3-unsaturated carbonyl compounds ensues if reactions are performed in acetonitrile under precise sources of catalyst precursor. "" "" A full discussion on the dichotomy of allylation-oxidation has been published, as well as a comparison of the usefulness of several transition metals as catalysts in allylation of nucleophiles. ... 

The success of carbonates depends on the full deprotonation of pronucleophile Nu-H by liberated alkoxide anion. Otherwise, attack of alkoxide on the cationic i7 -allylpalladium(n) complex would afford aUyl ethers, and this is sometimes a side reaction. Allylation of nucleophiles by allylic carbonates is customarily carried out in more or less polar aprotic solvents (THF, DMSO, DMF), and less frequently in dichloromethane, toluene, and even in water. The orders of acidity in dipolar aprotic solvents and in water are quite different, and this should be taken into account to know the position of the acid-base equilibrium. Lists of pA values in DMSO are availablc. - Orders of acidities in THF and in DMSO are probably not different. Examples of pA (DMSO) are MeCOCH2COOEt (14.4), CH2(COOEt)2 (16.4), PhOH (18.0), methanol (29.0), aniline (30.6), water (31.2), and ammonia (estimated 40). 

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