NIH Public Access Author Manuscript Chem Rev. Author manuscript; available in PMC 2011 September 9. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Chem Rev. 2011 March 9; 111(3): 1846±1913. doi:10.1021/cr1002744. Transition Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions Jimmie D. Weaver, Antonio Recio III, Alexander J. Grenning, and Jon A. Tunge* Department of Chemistry, The University of Kansas, Lawrence, KS 66045 Abstract A review. Transition metal catalyzed decarboxylative allylations, benzylations, and interceptive allylations are reviewed. Keywords Decarboxylative; allylation; benzylation; cross-coupling 1 Introduction to Decarboxylative-Coupling Catalytic cross-coupling reactions have had profound impact on the synthesis of pharmaceuticals, biologically active natural products, and materials.1 Such reactions typically involve the oxidative addition of an aryl or alkyl halide to a low-valent metal, followed by transmetalation and reductive elimination of the desired product (Scheme 1).2 The transmetalation steps in cross-coupling reactions often use relatively expensive, toxic, or highly basic reagents that must be prepared from other functional precursors. In addition, the reagents required for transmetalation necessarily produce stoichiometric quantities of hazardous byproducts that can complicate product purification. With this in mind, it has been recognized that it is highly desirable to develop new strategies for the generation of organometallic intermediates that utilize inexpensive substrates, proceed under mild conditions, and are environmentally benign. One such strategy is decarboxylative coupling. Decarboxylative coupling reactions utilize decarboxylative metalation to generate organometallic intermediates that are coupled via reductive elimination (Scheme 1). As compared to traditional cross-coupling methods, decarboxylative coupling has several potential advantages: 1) carboxylic acid derivatives are ubiquitous and inexpensive reactants, 2) decarboxylation can drive the formation of reactive intermediates under neutral conditions, and 3) the only stoichiometric byproduct is CO2, which is non-flammable, non- toxic, and easily removed from the reaction medium. Moreover, decarboxylation allows the site-specific generation and coupling of reactive intermediates, in contrast to reactions that generate reactive intermediates by C-H activation where regioselective formation of specific intermediates can be difficult.3 In this review, we will focus on discussion of homogeneous catalysis of decarboxylative allylation and benzylation reactions, a subject that highlights the breadth of nucleophilic species that can be generated by decarboxylation. In addition, studies of decarboxylative allylations have shown that there are several mechanisms for decarboxylative coupling that do not necessarily follow the simplified rubric shown in Scheme 1. While several accounts have been published on this topic in the last several years,4 none has done so in the [email protected]. Weaver et al. Page 2 comprehensive manner of this review which covers relevant publications through August 2010. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript 2 Decarboxylative Allylation of Enolates 2.1 Introduction to Decarboxylative Allylation The Tsuji-Trost reaction is a reaction that has garnered much attention due to its ability to couple allyl electrophiles with nucleophiles in a chemo-, regio-, and stereoselective fashion.5,6 In a typical Tsuji-Trost reaction, an allyl acetate or carbonate reacts with a palladium catalyst by displacement of the leaving group to give a π-allyl palladium intermediate which can undergo substitution by a nucleophile. Frequently, the nucleophiles have been limited to “soft” nucleophiles, like malonates, whose corresponding pKa’s are <20. However, successful allylation of monostabilized enolates has been achieved using preformed tin,7 boron,8 magnesium,9 and lithium enolates,10 as well as silyl enol ethers.11 While these methods have demonstrated the ability to form a new carbon–carbon bond selectively, they all suffer from the need to make a preformed organometallic which typically requires subjecting the substrate to highly basic conditions and results in a stoichiometric amount of metal salt waste. An ideal alternative synthesis would be one in which the same reaction can be accomplished yet produces only easily removed waste and does not require preformed nucleophiles, thus allowing a greater synthetic efficiency. Such a strategy requires an alternative method for the in situ generation of enolates. This review will focus on synthetic strategies that involve the direct generation of enolates and other nucleophiles via decarboxylation. Indeed, the in situ generation of nucleophiles via decarboxylation distinguishes decarboxylative allylation (DcA) reactions as an important subset of Tsuji-Trost reactions. In 1950, Nesmayanov showed that metal enolates can be readily accessed under neutral conditions and without additives by the decarboxylation of metal β-ketocarboxylates (Scheme 2).12 While Nesmayanov utilized this decarboxylative metalation in stoichiometric transformations, he set the stage for later catalytic transformations. In the early 60’s, divalent metals like Ni(II) and Mn(II) were shown to decarboxylate malonic acids and were proposed to form intermediate metal enolates.13 While the knowledge of these transformations was applied to understanding enzymatic decarboxylations, the synthetic potential of the intermediates was not realized. Then in 1980, Tsuji14 and Saegusa15 almost simultaneously reported the decarboxylative allylation of β-keto allyl esters (eq 1). In this method the loss of CO2 replaces the need to selectively prepare preformed enolate equivalents. A further potential benefit of the decarboxylative allylation (DcA) is the ability to generate both nucleophile and electrophile in situ. Thus, greater functional group compatibility can be expected since the high energy intermediates are formed in catalytic concentration and the pH is formally neutral. Consequently, decarboxylative allylation is a valuable addition to the toolbox of the organic chemist. In the following section of the review, we cover the developments whose chemical lineage can be traced back to these seminal works. (1) Chem Rev. Author manuscript; available in PMC 2011 September 9. Weaver et al. Page 3 2.1.1 Decarboxylative Allylation: Scope and Chemoselectivity—In the first disclosure of a decarboxylative allylation (DcA) reaction by Tsuji,14 allyl esters of NIH-PA Author Manuscript NIH-PA Author Manuscriptacetoacetic NIH-PA Author Manuscript acid were subjected to a catalytic amount of Pd(OAc)2 and PPh3 (Method A, Chart 1), providing γ,δ-unsaturated methyl ketones in high yield. Alternatively, Saegusa demonstrated that a variety of acyclic and cyclic ketoesters would undergo decarboxylative 15 coupling using 5 mol % Pd(PPh3)4 as the catalyst (Method B, Chart 1). While these reports did not detail the functional group compatibility of decarboxylative allylation (DcA) reactions, they did demonstrate that the reaction could tolerate β-hydrogens on the allyl fragment, however the yield is significantly reduced when the product is derived from the geranyl ester (4, Chart 1). This illustrates a common challenge in decarboxylative allylation; substitution and elimination are often competitive. A recent report illustrates that substitution is favored when the α-position of the β-keto ester is unsubstituted while elimination is favored when the α-position is substituted (Scheme 3).16 This may reflect different mechanisms of allylation for the two substrates as discussed vida infra. While β-ketoester substrates that contain an α-hydrogen are less prone to competing elimination, they do suffer competing diallylation. For example, allyl acetoacetate undergoes decarboxylative coupling to give a poor yield of the desired monoallylation product due to competing diallylation (eq 2). The diallylation can be thought to result from a combination of Tsuji-Trost allylation of the ketoester followed by decarboxylative allylation. The problematic diallylation is reduced when the substrate is an aryl or cyclic ketone (2,3,5, Chart 1). Alternatively, diallylation can also be mitigated by additional substitution on the allyl electrophile (1, Chart 1). (2) 2.1.2 Ester Enolates—Tsuji and co-workers showed that it was also possible to perform the decarboxylative allylation of malonate derivatives (eq 3);17 however, the reactions were much slower than their ketone counterparts and required heating at or above 100 °C. In doing so, Tsuji also reported the concomitant formation of a byproduct resulting from protonation of the ester enolate; such protonation products are commonly observed byproducts of DcA reactions. Finally, the researchers found that the DcA of α- monoalkylated substrates worked similar to that of the α,α-dialkyl derivative; however they took place at slightly lower temperature (eq 4). (3) Chem Rev. Author manuscript; available in PMC 2011 September 9. Weaver et al. Page 4 NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript (4) More recently, Ohata et al. investigated the DcA reactions of α-aryl malonic acid derivatives (Chart 2).18 Unlike Tsuji’s report,17 the DcA of α-phenyl substituted malonic ester derivatives took place readily at room temperature. This highlights the dependence of the rate of DcA reactions