Allylation of Stabilized Carbon Nucleophiles

Extensive studies have been devoted to allylation of earbon pronucleophiles as important methods of C—C bond formation. As described before briefly, reactions with allylic carbonates and alkenyloxiranes proceed under neutral conditions due to in situ generation of alkoxides which abstract protons from nucleophiles. Also allylation with allyl aryl ethers can be carried out without addition of bases. Reactions of allylic acetates and other allylic compounds are carried out in the presence of bases [5]. 

Intramolecular reaction of the cyclic fi-keto ester 141 proceeded with high enantio- and diastereoselectivities. When (/ ,/ )-Trost L-1 was used, a mixture of the [2.2.2]bicycles 142 (99 % ee) and 143 was obtained in 84% yield in a ratio of 4.6 1. On the other hand, Eu(fod)3 as an additive showed a remarkable effect. The diastereoselectivity was reversed when (5,5)-Trost L-1 and Eu(fod)3 were used to give a mixture of 142 and 143 (68 % ee) in a ratio of 1 8 in 85 % yield [51]. 

Intramolecular allylation with alkenyloxiranes offers a good method of macro-cyclization. In the total synthesis of roseophilin by Fiirstner, the alkenyloxirane 144 was cyclized smoothly to yield the 13-membered carbocycle 145 in high yield (85%) in the presence of two ligands DPPE and PPh3. Then Pd-catalyzed reaction of the allylic lactone 146 with benzylamine afforded the pyrrole carboxylic acid 147 cleanly in 70 % yield via regioselective allylation of benzylamine at the electron-deficient terminus of the allylic lactone 146 [52], 

Usually no reaction of alkenyloxiranes bearing a methyl group at the terminus as in 149 takes place instead isomerization to enone occurs. The reaction of the epoxide 149 with the Meldrum s acid derivative 148 proceeded at room temperature in THF using a precatalyst generated by mixing Pd2(dba)3 (1.5 mol%) and cyclic phosphite TMPP (III-2) (20 mol%) to afford 150 in 75 % yield, and macrolactam aglycon of fluviricin B1 was synthesized [53]. 

In the reaction of the activated alkene 151 with allyl carbonate, Michael attack of an alkoxide to the alkene occurs at first. Then the generated anion 152 is allylated to afford 153. The THF derivative 155 was obtained in high yield by the coupling of the alkene 151 with monocarbonate of 2-buten-l,4-diol 154 in the absence of a base [54], 

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Interestingly, the allylation of stabilized carbon nucleophiles has been found to be reversible. Complete transfer of dimethyl methylmalonate moiety, involving C—C bond cleavage, from the secondary carbon 115 to the primary carbon 116 was observed by treatment with a Pd catalyst for 24 h, showing that the allylic C—C bond cleavage proceeds slowly [61], Ni(dppb)2 was found a more efficient catalyst for the rearrangement [62],... 

Further examples of allylation of stabilized carbon nucleophiles. ... 

The Pd(0)-catalyzed allylation of stabilized carbon nucleophiles proved to be reversible in those cases where the final product is thermodynamically substantially more stable, for example, due to conjugation (Scheme 25). Thus, 45 can be quantitatively isomerized to... 

For trisubstituted olefins, the nucleophile attacks predominantly at the less substituted end of the allyl moiety, e.g. to afford a 78 22 mixture of 13 and 14 (equation 7). Both the oxidative addition of palladium(O) and the subsequent nucleophilic attack occur with inversion of configuration to give the product of net retention7. The synthesis of the sex pheromone 15 of the Monarch butterfly has been accomplished by using bis[bis(l,2-diphenylphosphinoethane)]palladium as a catalyst as outlined in equation 87. A substitution of an allyl sulfone 16 by a stabilized carbon nucleophile, such as an alkynyl or vinyl system, proceeds regioselectively in the presence of a Lewis acid (equation 9)8. The... 

The first examples of iridium-catalyzed allylic substitution [1] occurred between stabilized carbon nucleophiles and both alkyl- and aryl-substituted allylic alcohol derivatives with exceptional selectivity for the branched substitution product. 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

The vinylogous elimination to give alkenylcyclopropanes may also be effected via rt-allyl palladium complexes34,35. The palladium(0)-catalyzed substitution of allylic esters with stabilized carbon nucleophiles via 7i-allyl palladium derivatives stereospecifically proceeds with net retention (double inversion) of configuration. Thus, the chirality of an allylic substrate is transferred to resultant alkenylcyclopropanes in the intramolecular S J/ reaction via 7i-allyl palladiums (equation 21)36,3. ... 

In principle, allylic sulfoximines can be used as substrates for the allylation of an external nucleophile (Nu) if that nucleophile can compete with the sulfinamide anion C for the palladium(0) complex B or if the formation of D is reversible. In 1997 Pyne and co-workers99 reported that stabilized carbon and nitrogen nucleophiles can be efficiently allylated in a regioselective manner using allylic sulfoximines and palladium(O) catalysis (Eq. 5). 

Cyclization reactions via coupling of an aryl group and a stabilized carbon nucleophile to the 1,4-positions of a diene were reported by Grigg and Sridharan [40]. The reaction proceeds via a spirocyclic jr-allyl intermediate. Diethyl malonate and dicyanomethane were used as the stabilized carbon nucleophiles. In one example, spirocyclic compound 21 was obtained from 18 in 60% yield [Eq.(25)]. 

Allylation of Stabilized Anions. Electrophilic 7r-allyl Pd(0) complexes can be generated from Pd(dba)2 and functionalized allylic acetates, carbonates, halides, etc. These complexes are susceptible to reaction with a range of stabilized nucleophiles, such as malonate anions. Alkylation usually occurs at the less-substituted allylic terminus. Silyl-substituted r-allyl complexes undergo re-gioselective alkylation at the allyl terminus farthest removed from the silyl group (eq 14). ... 

The mechanism of the nucleopliilic attack on the allyl intermediate has been studied in deptli, and this process was discussed in Chapter 11. In general, stabilized carbon nucleophiles containing two electron-withdrawing groups on the methylene carbon, as well as... 

A final approach to enantioselective allylic substitution is the reaction of prochiral nucleophiles with allylic esters. In this case, the stereocenter is not generated on the allyl unit it is generated at the nucleophilic carbon. This chemistry has been conducted with cyanoesters and related unsymmetrical stabilized carbon nucleophiles, including azlactones, which are a protected form of ammo acids. This generation of a stereocenter in the nucleophile is thought to be particularly challenging because the position at which the stereocenter is formed is further from the metal than it is in reactions that form a stereocenter at the allyl group. 

Further examples of stabilized carbon-centered nucleophiles used in Pd-catalyzed allylic substitution are given in Scheme ii.wo]-[47] noteworthy that the dichloroben-zoate group of substrate 55 leaves selectively over the acetate, and that the (Z)-stereo-chemistry of the substrate becomes ( )-stereochemistry in the product 68. Nitromethane 66 is sufficiently acidic that there are no problems in the substitution reaction with acetate 59. Relative stereochemistry is preserved in the product 73. 

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. ... 

Moreover, in 1982 a patent was filed in which the use of allylic carbonates for the allylation of stabilized nucleophiles is mentioned.Other colleagues were aware very soon of the advantages of using carbonates instead of acetates. Therefore, several papers appeared in this early historical period that we, arbitrarily, have... 

Stabilized carbon nucleophiles under neutral conditions. The formation of an eight-membered ring instead of the also possible six-membered ring is remarkable (Scheme 12). The polycyclic skeleton of gelsemium-type alkaloid family has been prepared by an intramolecular allylation using allyl carbonate as electrophilic reagent. ... 

Although this review is not intended to cover catalysis by other metals, it is worth mentioning that nickel(O) has met with some success in the allylation of stabilized nucleophiles and phenols with allylic carbonates. ... 

The direct, Pd(II)-catalyzed addition of heteroatom and stabilized carbon nucleophiles to alkenes is generally not a successful reaction. An exception is the addition of water, which gives carbonyl compounds and has been developed into an important indnstrial process, the Wacker process. This has been reviewed extensively.By contrast, the stoichiometric addition of nucleophiles such as amines is facile. - However, if alkenes could be converted catalytically into Tr-allylpalladium complexes, the problems with nucleophilic addition to alkenes could be circumvented and amines and other heteroatom nucleophiles could be employed. A range of alkenes have been converted into rr-allyl complexes in a stoichiometric fashion,t "t but catalytic reactions have proved more difficult. However, aUyl acetates and similar compounds readily exchange the acetate group for heteroatom nucleophiles in a Pd(0)-catalyzed reaction, which proceeds via 7T-allylpalladinm(ll) intermediates (Scheme 1). Since this reaction has been developed into a very important synthetic reaction, an efficient procedure for catalytic conversion of alkenes into aUyl acetates would have great synthetic potential. 

TT-Allylpalladium complexes have long been recognized as an allyl cation equivalent and widely utilized for the allylation of a variety of hard and stabilized carbon nucleophiles. Both allenylpalladium and vinylpalladium complexes are chemically neutral, or very feebly nucleophilic, if any. Under conditions described below, however, these rr-allyl-, vinyl-, and allenylpalladium complexes alter their reactivity in mode and behave as nucleophilic species. "... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

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