Allylic reactions with hard nucleophile

Evans and Uraguchi also examined the rhodium-catalyzed allylic alkylation with hard nucleophiles [31]. Aryl organozinc halides proved optimal nucleophiles for the regio- and stereospecific allylic alkylation of enantiomerically enriched unsymmetrical allylic alcohol derivatives (Tab. 10.4). The reaction occurs with net inversion of absolute... 

An attempt has been made to predict the sites of nucleophilic attack on [M(CO)3(fl--hydrocarbon)] complexes using the perturbation theory of reactivity. For the model allyl substrate [Co(CO)3( j -C3H5)] the site preference CO > M > C3H5 was predicted for reaction with hard nucleophiles in polar solvents. On the other hand, with soft nucleophiles initial attack at the ir-allyl ligand was favored. Mechanistic studies have suggested only a small energy difference between attack by alkoxide ions on the allyl ligand and the metal in related ( Tr-allyl) palladium(II) complexes. ... 

TT-Aliylpalladium chloride reacts with a soft carbon nucleophile such as mal-onate and acetoacetate in DMSO as a coordinating solvent, and facile carbon-carbon bond formation takes place[l2,265], This reaction constitutes the basis of both stoichiometric and catalytic 7r-allylpalladium chemistry. Depending on the way in which 7r-allylpalladium complexes are prepared, the reaction becomes stoichiometric or catalytic. Preparation of the 7r-allylpalladium complexes 298 by the oxidative addition of Pd(0) to various allylic compounds (esters, carbonates etc.), and their reactions with nucleophiles, are catalytic, because Pd(0) is regenerated after the reaction with the nucleophile, and reacts again with allylic compounds. These catalytic reactions are treated in Chapter 4, Section 2. On the other hand, the preparation of the 7r-allyl complexes 299 from alkenes requires Pd(II) salts. The subsequent reaction with the nucleophile forms Pd(0). The whole process consumes Pd(ll), and ends as a stoichiometric process, because the in situ reoxidation of Pd(0) is hardly attainable. These stoichiometric reactions are treated in this section. 

Depending on the strength of the nucleophile, the reaction can take two different pathways. Soft nucleophiles, such as those derived from conjugate acids with a pKa < 25, normally add directly to the allyl moiety, whereas hard nucleophiles first attack the metal centre, followed by reductive elimination to give the allylation product ... 

In contrast to soft nucleophiles which attack the allyl face opposite the palladium complex, hard nucleophiles (e.g., organozinc reagents) first coordinate to the metal center and then are transferred intramolecularly to the allyl ligand (see, e.g.. Table 1 in [13]). Therefore, the reaction of allyl-palladium complexes with hard nucleophiles usually involves retention of configuration. However, the classification as soft and hard nucleophiles is not always unambiguous. With acetate as the nucleophile, e.g., the stereoselectivity depends on the reaction conditions and both overall inversion as well as retention have been observed [18]. 

Among asymmetric bond-forming reactions, the metal-catalyzed asymmetric ally lie alkylation (AAA) is versatile and has found numerous applications [49], While palladium involves a net retention via a double inversion mechanism with soft nucleophiles and a net inversion path with hard nucleophiles, many other metals also catalyze allylic alkylation (e.g., Rh, Ru, Ir, Mo, W, and Cu), which may involve different stereochemical courses [49]. 

Nickel catalysts have been shown to promote allylic substitutions with hard organometallic nucleophiles and allylic ethers or acetals as the electrophiles [38, 105, 106]. In a series of investigations, Hoveyda has documented the use of chiral nickel catalysts for asymmetric allylic substitution reactions [38]. A brilliant illustration is the conversion of acetal 120 into cyclohexanone 123 (90 %, 92 % ee) by employment of EtMgBr in the presence of a chiral Ni catalyst prepared in situ from diphosphine 121 (Equation 11) [106]. 

Addition of carbon nucleophiles to vinylepoxides is of particular importance, since a new carbon-carbon bond is formed. It is of considerable tactical value that conditions allowing for regiocontrolled opening of vinyloxiranes with this type of nucleophiles have been developed. Reactions that proceed through fonnation of a rr-allyl metal intermediate with subsequent external delivery of the nucleophile, or that make use of a soft carbon nucleophile, generally deliver the SN2 product. In contrast, the Sn2 variant is often the major reaction pathway when hard nucleophiles are employed. In some methods a nucleophile can be delivered selectively at either the Sn2 or SN2 positions by changing the reaction conditions. 

Transition metal-catalyzed allylic substitution with phenols and alcohols represents a fundamentally important cross-coupling reaction for the construction of allylic ethers, which are ubiquitous in a variety of biologically important molecules [44, 45]. While phenols have proven efficient nucleophiles for a variety of intermolecular allylic etherification reactions, alcohols have proven much more challenging nucleophiles, primarily due to their hard, more basic character. This is exemphfied with secondary and tertiary alcohols, and has undoubtedly limited the synthetic utihty of this transformation. 

In the Zr-catalyzed enantioselective alkylation reactions discussed above, we discussed transformations that involve the addition of alkylmagnesium halides and alkylaluminum reagents to olefins. With the exception of studies carried out by Negishi and coworkers, all other processes involve the reaction of a C-C n system that is adjacent to a C-0 bond. Also with the exception of the Negishi study [Eqs. (6) and (7)], where direct olefin carbometallation occurs, all enantioselective alkylations involve the intermediacy of a metallacyclopentane (cf. Scheme 3). In this segment of our discussion, we will examine the Ni-catalyzed addition of hard nucleophiles (e.g., alkylmagnesium halides) to olefins that bear a neighboring C-0 unit. These reactions transpire by neither of the above two mechanistic manifolds (metallacyclopentane intermediacy or direct carbometallation). Rather, these processes take place via a Ni-Ti-allyl complex. 

In general, the catalytic cycle for the transition-metal catalyzed allylic substitution reactions involves initial attack of the metal at the double bond followed by oxidative insertion into the antiperiplanar C-0 bond to afford the Ti-allyl system. At this point, depending on whether soft or hard nucleophiles are used, however, the alkylation reaction proceeds through distinctly different pathways (Scheme 10). With soft nucleophiles, where Pd is often the metal center of choice. 

Allylic alkylations. Highly regioselective alkylation of both hard and soft nucleophiles (phenolates, sulfonamides, and phenylsulfonylacetic esters, respectively) is also possible with the Rh catalyst modified by the added (MeOl P, The countercation seems to play an important role in the displacement with alkali phenolates to afford branched allylic ethers thus, reaction with Li salts shows the highest regioselectivity but the product yields are low. The best compromise is to use Na phenolates. 

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