Allylic substitutions hard nucleophiles

In general, Pd-catalyzed allylic substitutions with soft nucleophiles involve nudeophilic attack directly on the allyl unit, on the opposite face to that occupied by the metal. This is contrasted with the situation for hard nucleophiles where the initial attack occurs at the metal, with subsequent migration of the nudeo-phile to the allyl moiety - the addition to the allyl unit therefore occurring from the same face as the metal. Obviously, this has profound implications on the stereochemical outcome. 

Allylic Substitution with Hard Carbon Nucleophiles... 

The transition metal-catalyzed allylic substitution using hard or unstabilized nucleophiles has not been extensively studied, particularly with unsymmetrical allylic alcohol derivatives. This may be attributed to the highly reactive and basic nature of these nucleophiles and the inability to circumvent regiochemical infidehty in unsymmetrical systems. Hard nucleophiles may be characterized as those that undergo substitution with net inversion of stereochemistry [29], due to their propensity to add directly to the... 

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. 

Allylic substitution using hard nucleophiles proceeds through a different mechanism. Instead of attacking the allyl group of the 71 allyl-metal complex, hard nucleophiles attack the metal first and the product is subsequently formed by reductive elimination. Nickel(O) complexes have often been used for this purpose. Reports of good enantioselectivities in this type of reaction are limited. 

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. 

The scope of enantioselective, copper-catalyzed allylic substitution reactions is not limited to so-called hard carbon nucleophiles and achiral acyclic linear electrophiles. A recent report from Ito, Sawamura, and co-workers showed that a diboron reagent can serve as a pronucleophile for enantioselective, copper-catalyzed boronation of (Z)-aUylic carbonates (Equation 20.85). The corresponding chiral allylboronates were isolated in good yields with high enantioselectivities. 

Hard nucleophiles (hNus) have not often been used in Irotalyzed allylic substitution reactions. Alexakis et al. [160] have investigated the use of arylzinc reagents as nonstabihzed nucleophilic partners. Despite different attempts to optimize the reaction conditions, the desired branched adducts were obtained only with moderate regioselectivities, but with good enantioselectivities. 

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]. 

The addition of Grignards and organolithium reagents proceeds by attack at the metal center in ir-allylpalladium complexes. The regiochemical selectivity exhibited by these hard carbon nucleophiles with ir-allyl complexes substituted at the termini with alkyl or aryl groups is comparable to the soft carbon nucleophiles (ligand attack) in most cases, with addition occurring predominantly at the less substituted terminus (equations 248 and 249).1591387... 

Allylic electrophiles can react with nucleophiles either with or without allylic rearrangement [213], The outcome of such reactions will depend on whether or not an allylic carbocation is formed as intermediate, and on the steric requirement and hardness of the two electrophilic centers and the nucleophile. Bimolecular substitutions at allylic electrophiles which occur with rearrangement are called Sn2 reactions. 

An electrophile will attack a diene to produce the delocalized allylic cation. The partial charge on each end of the allylic system will be different if the substitution at each end of the allylic unit is different. Since the attraction of unlike charges contributes greatly to the bringing of nucleophile and electrophile together (hard-hard), the latter the partial plus is on an atom, the greater a n atively charged nucleophile is attracted to it. 

Enantiosdective allyic substitution processes have been developed over the course of 30 years. Initial observations of the reactions of nucleophiles with paUadium-allyl complexes led to the observation of catalytic substitutions of aUylic ethers and esters, and then catalytic enantioselective aUylic substitutions. The use of catalysts based on ottier metals has led to reactions that occur with complementary regiochemistry. Moreover, flie scope of the reactions has expanded to include heteroatom and unstabilized carbon nucleophiles. Suitable electrophiles for these reactions indude allyhc esters of various types, allyhc ethers, aUylic alcohols, and aUylic halides. Enantioselective reactions can be conducted with monoesters or by selection for deavage of one of two equivalent esters. The mechanism of these reactions occurs by initial oxidative addition to form a metal-aUyl complex. The second step involves nudeophilic attadc on ttie aUyl ligand for reaction of "soft" nudeophiles or inner-sphere reductive eUmination for reactions of "hard" nudeophiles. The external nudeophilic attack typicaUy occurs by reaction of the nudeophile with a cationic aUyl complex at the face opposite to that to which Uie metal is bound. Exceptions indude reactions of certain molybdenum-aUyl complexes. Dissociation of product then regenerates the starting catalyst. Because of the diversity of the classes of these reactions, aUylic substitution—in particular asymmetric aUylic substitution—has been used to prepare a wide variety of natural products. 

The [i-aUyl complexes can react with several types of nucleophiles, giving rise to the corresponding substitution products. O- and N-nucleophiles as well as soft carbon nucleophiles attack the t-allyl complex directly at the aUylic position, while hard C-nucleophiles react via transmetaUations [2c, 3]. If the nucleophihc attack occurs under an atmosphere of CO, insertion of CO can occur, yielding carbonyl compounds [4]. Alkenes and aUcynes can also insert into allyhnetal bonds, a protocol that is used preferentially for cycUzations [5]. Cyclizations can also occur, if the 7t-allylmetal complex contains an internal nucleophilic center. If the metalallyl complex acts as a nucleophile, direct coupling with aryl halides [6] or additions to electrophiles such as aldehydes, ketones, or imines are possible [7]. This review focuses on C-C coupling reactions via these tt-allyhnetal (or in some cases, a-allyhnetal) intermediates. 

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