Allylic substitutions metal-catalyzed

Iridium-catalyzed allylic substitution was first investigated after many years of development of allylic substitution reactions catalyzed by a variety of complexes of other metals, particularly those containing palladium. While iridium-catalyzed... 

Most allylic substitution reactions catalyzed by other metals are selective for the formation of branched products. Although this had been demonstrated for a large portion of the d-block before Takeuchi s work with iridium, most of the progress in this area was restricted to stabilized enolate nucleophiles. 

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

In addition to the applications reported in detail above, a number of other transition metal-catalyzed reactions in ionic liquids have been carried out with some success in recent years, illustrating the broad versatility of the methodology. Butadiene telomerization [34], olefin metathesis [110], carbonylation [111], allylic alkylation [112] and substitution [113], and Trost-Tsuji-coupling [114] are other examples of high value for synthetic chemists. 

A review8 with more than 186 references discusses the synthesis of Rh and Pd complexes with optically active P,N-bidentate ligands and their applications in homogeneous asymmetric catalysis. The effect of the nature of the P,N-bidentate compounds on the structure of the metal complexes and on enantioselectivity in catalysis was examined. Allylic substitution, cross-coup-ling, hydroboration and hydrosilylation catalyzed by Rh or Pd complexes with optically active P,N-bidentate ligands are considered. 

Asymmetric synthesis of tricyclic nitro ergoline synthon (up to 70% ee) is accomplished by intramolecular cyclization of nitro compound Pd(0)-catalyzed complexes with classical C2 symmetry diphosphanes.94 Palladium complexes of 4,5-dihydrooxazoles are better chiral ligands to promote asymmetric allylic alkylation than classical catalysts. For example, allylic substitution with nitromethane gives enantioselectivity exceeding 99% ee (Eq. 5.62).95 Phosphi-noxazolines can induce very high enatioselectivity in other transition metal-catalyzed reactions.96 Diastereo- and enantioselective allylation of substituted nitroalkanes has also been reported.9513... 

The palladium-catalyzed asymmetric allylic substitution using seven different phosphano-oxazoline ligands at various ligand-to-metal ratios was also studied.112 An aluminum block containing 27 wells was placed in a dry box in which the reactions were carried out in parallel. Analyses were performed by conventional chiral GC equipped with an autosampler. Such a setup allowed about 33 catalyst evaluations per day. Apparently, only a few dozen were carried out in the study, resulting in the identification of a catalyst showing an ee-value of 74% in the reaction of 4-acyloxy-2-pentene with malonate.112 It is not clear whether further ligand diversification would lead to catalysts more selective than the record set in this case by the Trost-catalyst (92% ee).113... 

An important variant for transition metal-catalyzed carbon-nitrogen bond formation is allylic substitution (for reviews, see1,la lh). Nucleophilic attack by an amine on an 7r-allyl intermediate, generated from either an allylic alcohol derivative,2 16,16a 16f an alkenyloxirane,17-19,19a-19d an alkenylaziridine19,19a 19d, or a propargyl alcohol derivative,21,21a 21d gives an allylic amine derivative. 

Pd-catalyzed allylic alkylation with soft nucleophiles1151 is probably the most important categoiy within the more general area of transition metal-catalyzed allylic substitution (Scheme 6).116,171... 

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. 

General Mechanism of Metal-Catalyzed Allylic Substitution. 195... 

Scheme 21 General mechanism for metal-catalyzed allylic substitution...

Generally, alkoxides are problematic nucleophiles because of their basic character. In metal-catalyzed allylic substitutions, superior results were obtained with Zn-alkoxides (achiral Ir-catalysts) [66] and Cu-alkoxides (achiral Rh-catalyst with chiral substrates) [67]. Shu and Hartwig developed aUyUc substitutions with alkoxides using Ir/phosphoramidite catalysts [68] these authors used catalysts obtained from [Ir(COD)Cl]2 and LI or L3 without explicit base activation [procedure (a) in Section 9.2.4.2) (Scheme 9.34). 

Although the Ir-catalyzed aUyhc substitution was developed only recently, several applications in the areas of medicinal and natural products chemistry have aheady been reported. In many syntheses the allylic substitution has been combined with a RCM reaction [71]. Examples not directed at natural products targets have aheady been described in Sections 9.4 and 9.5. It has also been mentioned that this strategy had previously been used in conjunction with aUyhc substitutions catalyzed by other transition metals (Figure 9.5). This was pioneered by P. A. Evans and colleagues, who used Rh-catalyzed allylic amination (compound A in Figure 9.5) [72] and etherification (compound B) [73], while Trost and coworkers demonstrated the power of this concept for Pd-catalyzed aUyhc alkylations (compound C) [74] and Alexakis et al. for Cu-catalyzed (compound D) aUyhc alkylations [75]. 

Metal-catalyzed allylic substitution reactions have been a mainstay of synthetic chemistry because of their ability to proceed irreversibly and with high selectivity [42]. It is also feasible, however, to produce analogous systems that are completely reversible and nonselective, or ideally situated for use in DCC. These are essentially metal-catalyzed transesterification reactions, with the added feature of potentially providing stereochemical scrambling (and selection) as well as constitutional variation. An early example of this was provided in 2000 by Kaiser and Sanders [43]. In the absence of a template, reaction of diallyl diacetate 22 with a dicarboxylic acid in the presence of catalytic Pd(0) produced a negligible amount of the cycfized compound 23 (Fig. 1.9). However, when templated with 1,3-bis(4-pyridyl) benzene, yield of the cyclic structure increased to roughly 10%, independent of the dicarboxylic acid used. 

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... 

Tab. 10.6 summarizes the application of this transformation to a variety of racemic secondary allylic carbonates using the lithium anion of 4-methoxy-N-(p-toluidine)-benzene sulfonamide. The excellent regioselectivity obtained for this type of substitution provided an important advance in the synthesis of N-(arylsulfonyl)anihnes using the metal-catalyzed allyhc amination reaction. The allyhc alcohol derivatives examined... 

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. 

For lead references on other transition metal-catalyzed allylic substitution reactions, see (a) Cobalt Bhatia, B. Reddy, M.M. Iqbal, J. Tetrahedron Lett. 1993, 34, 6301. 

For recent examples of halide effects on en-antioselectivity in transition metal-catalyzed allylic substitutions, see (a) Bartels, B. Helmchen, G. Chem. Commun. 1999, 741. (b) Burckhardt, U. Baumann, M. ... 

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