Rhodium-catalyzed allylic alkylation

The formation of a branched chiral product from the alkylation of monosubstituted substrates is not limited to the catalysis of metals described thus far. Allylic alkylation reactions catalyzed with rhodium [211] and iridium [212] complexes have been shown to occur at the more... 

By 1984, the palladium-catalyzed aUyhc alkylation reaction had been extensively studied as a method for carbon-carbon bond formation, whereas the synthetic utility of other metal catalysts was largely unexplored [1, 2]. Hence, prior to this period rhodium s abihty to catalyze this transformation was cited in only a single reference, which described it as being poor by comparison with the analogous palladium-catalyzed version [6]. Nonetheless, Yamamoto and Tsuji independently described the first rhodium-catalyzed decarboxylation of allylic phenyl carbonates and the intramolecular decarboxylative aUylation of aUyl y9-keto carboxylates respectively [7, 8]. These findings undoubtedly laid the groundwork for Tsuji s seminal work on the regiospecific rho-... 

Evans and Nelson reexamined the rhodium-catalyzed allylic substitution reaction, in which they demonstrated that a triorganophosphite-modified Wilkinson s catalyst facilitates the allylic alkylation of secondary and tertiary aUyhc carbonates with excellent regioselectivity (Eq. 2). This work provided a convenient method for the construction of ternary and quaternary allylic products [11]. Additionally, they demonstrated that the modification of Wilkinson s catalyst with triorganophosphites serves to increase the re-... 

Evans and Kennedy later combined the regioselective rhodium-catalyzed allylic alkylation, using a-substituted malonates, with ring-closing metathesis for the construction of five-, six-, and seven-membered carbocycles (Scheme 10.2) [13]. The combination of these methodologies allowed for the rapid and flexible assembly of carbocycles possessing vicinal ternary-quaternary or quaternary-quaternary stereogenic centers. 

Evans and Nelson examined the stereospecificity of the rhodium-catalyzed allylic alkylation, with the expectation that it would provide additional insight into the mechanism for this particular reaction [16]. They reasoned that the enantiomerically enriched allylic alcohol derivative i would furnish the enantioenriched product iv, provided the initial enyl intermediate ii does not isomerize to the achiral rr-organorhodium intermediate iii prior to alkylation (k2>ki Scheme 10.3). Alternatively, the product of re-... 

Rhodium-Catalyzed Allylic Alkylation Reaction with Stabilized Carbon Nucleophiles... 

Rhodium-catalyzed allylic alkylation provides an expeditious entry into a variety of useful synthons for asymmetric synthesis. For example, the application of this reaction to a range of enantiomerically enriched allylic carbonates with the sodium salt of methyl phenylsulfonylacetate provides products that represent important synthons for target-directed synthesis (Tab. 10.1) [17]. 

Tab. 10.1 Regioselective and enantiospecific rhodium-catalyzed allylic alkylation of enantiomerically enriched allylic carbonates.

Tab. 10.2 The scope of rhodium-catalyzed allylic alkylation with enantiomerically enriched a-branched malonates.

Ketones and Esters as Nucleophiles for Rhodium-Catalyzed Allylic Alkylation... 

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. 

In light of these significant challenges, Evans and Leahy reexamined the rhodium-catalyzed allylic alkylation using copper(I) enolates, which should be softer and less basic nucleophiles [23]. The copper(I) enolates were expected to circumvent the problems typically associated with enolate nucleophiles in metal-allyl chemistry, namely ehmina-tion of the metal-aUyl intermediate and polyalkylation as well as poor regio- and stereocontrol. Hence, the transmetallation of the lithium enolate derived from acetophenone with a copper(I) hahde salt affords the requisite copper] I) enolate, which permits the efficient regio- and enantiospecific rhodium-catalyzed allylic alkylation reaction of a variety of unsymmetrical acychc alcohol derivatives (Tab. 10.3). 

Tab. 10.3 The scope of the regioselective rhodium-catalyzed allylic alkylation with copper(l) enolates.

Extension of the rhodium-catalyzed allylic alkylation to a-subshtuted enolates was found to facilitate the introduction of an additional stereogenic center (Eq. 5). 

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... 

Tab. 10.7 summarizes the results of the application of rhodium-catalyzed allylic etherification to a series of ortho-substituted phenols. The etherification tolerates alkyls, including branched alkanes (entries 1 and 2), aryl substituents (entry 3), heteroatoms (entries 4 and 5), and halogens (entry 6). These results prompted the examination of ortho-disubstituted phenols, which were expected to be more challenging substrates for this type of reaction. Remarkably, the ortho-disubstituted phenols furnished the secondary aryl allyl ethers with similar selectivity (entries 7-12). The ability to employ halogen-bearing ortho-disubstituted phenols should facilitate substitutions that would have proven extremely challenging with conventional cross-coupling protocols. 

Tab. 10.8 summarizes the application of rhodium-catalyzed allylic etherification to a variety of racemic secondary allylic carbonates, using the copper(I) alkoxide derived from 2,4-dimethyl-3-pentanol vide intro). Although the allyhc etherification is tolerant of linear alkyl substituents (entries 1-4), branched derivatives proved more challenging in terms of selectivity and turnover, the y-position being the first point at which branching does not appear to interfere with the substitution (entry 5). The allylic etherification also proved feasible for hydroxymethyl, alkene, and aryl substituents, albeit with lower selectivity (entries 6-9). This transformation is remarkably tolerant, given that the classical alkylation of a hindered metal alkoxide with a secondary alkyl halide would undoubtedly lead to elimination. Hence, regioselective rhodium-catalyzed allylic etherification with a secondary copper(l) alkoxide provides an important method for the synthesis of allylic ethers. 

Rhodium-catalyzed allylic etherification could also be extended to the more challenging tertiary alcohols (Eq. 7). Although preliminary attempts revealed that the alkylation of the allylic carbonate 51 was feasible, the reaction required increased catalyst loading (20 mol%), affording the allylic ether 52 in 67% yield (2° 1°=47 1). 

Tab. 10.12 Enantioselective rhodium-catalyzed allylic alkylations with dimethyl malonate.

The regio- and diastereoselective rhodium-catalyzed sequential process, involving allylic alkylation of a stabilized carbon or heteroatom nucleophile 51, followed by a PK reaction, utilizing a single catalyst was also described (Scheme 11.14). Alkylation of an allylic carbonate 53 was accomplished in a regioselective manner at 30 °C using a j-acidic rhodium(I) catalyst under 1 atm CO. The resulting product 54 was then subjected in situ to an elevated reaction temperature to facilitate the PK transformation. 

A combination of rhodium complexes and phosphates promotes a highly regioselective allylic alkylation of unsym-metric allylic esters, where alkylation occurs at the more substituted allylic terminus of the esters (Equation (46)). As Evans and his co-workers reported, both the regio- and stereochemistry of the starting allylic esters are maintained in the allylic alkylated products (Equation (47)). Thus, the rhodium-catalyzed allylic alkylation takes place at the carbon substituted by a leaving group with net retention of configuration. A variety of carbon-centered... 

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