Mechanistically guided survey of enantioselective palladium-catalyzed alkene functionalization

Abstract

Palladium-catalyzed alkene functionalization was discovered more than 60 years ago and is now a commonly used strategy for the synthesis of pharmaceuticals and materials. The development of asymmetric variants of this reaction is described in this short review. The review is organized around the mechanistic challenges that have hampered the development of these transformations for various substrate classes, as well as the strategies, ligand classes, and additives that have been introduced to overcome them. New methodologies for Heck, oxidative Heck, dehydrogenative Heck, and Wacker-type reactions are highlighted, with a special focus on the progression from cyclic to acyclic to electronically unbiased olefin substrates.Historical background: Mizoroki-Heck-and Wacker-type chemistry Palladium-catalyzed methodologies are ubiquitous in synthetic chemistry and key to their successful implementation has been obtaining a detailed mechanistic understanding of these reactions. Specifically, the two-electron nature of oxidative addition (see Glossary) and reductive elimination, facile β-hydrogen elimination, and high π-Lewis acidity have enabled the organometallic community to rationally design a myriad of Pd-catalyzed strategies to efficiently build molecular complexity [1][2][3][4][5][6][7][8]. The versatility of Pd catalysis has been described in many reviews [9][10][11][12][13][14], but herein we focus on Pd-mediated enantioselective functionalization of alkenes. In particular, this review highlights the different strategies developed to control the regio-and stereoselectivity of the key elementary steps in these processes.The discovery of the Pd(II)-catalyzed water addition to ethylene to give acetaldehyde by researchers in Wacker Chemie in 1959 [15,16] inspired numerous chemists to study the use of transition-metal complexes to catalyze organic transformations. Shortly after, in 1970, the laboratories of Mizoroki and Heck reported the use of Pd(0) complexes to promote olefin arylations and alkylations [17,18]. The general mechanism of Heck-type transformations is outlined in Figure 1 (Key figure), where a Pd(0) complex (A) engages in oxidative addition with an alkenyl or aryl halide to generate Pd(II) intermediate B. Migratory insertion of the alkene into the Pd-C bond forges the new C−C bond and yields Pd-alkyl intermediate C. Subsequently, a β-hydrogen elimination delivers the alkene product 3, and a base-mediated reductive elimination of the Pd-hydride species (D) regenerates the Pd(0) catalyst to restart the cycle. Key to the development of asymmetric variants of this transformation is to favor the β-hydrogen elimination of H b , away from the newly formed stereocenter to render chiral product 3a, over H a , which would deliver achiral product 3b. Although early Heck reaction development attracted the attention of numerous research groups, asymmetric variants of these methodologies remained elusive until 1989, when the groups of Overman and Shibasaki described the use of bisphosphine HighlightsThe mechanistic rat...

Asymmetric Pd(II)‐Catalyzed C−O, C−N, C−C Bond Formation Using Alkenes as Substrates: Insight into Recent Enantioselective Developments

“…In particular, on this latter Overman carried out an extensive work on the use of a particular complex, [COPÀ OAc] 2 , for the enantioselective synthesis of branched allylic ether or esters, starting from prochiral (E)-allylic trichloroacetimidates in the presence of different oxygen nucleophile, such as phenols and carboxylic acids. [27,35] Since the same substrates are also used for the [3,3]-sigmatropic rearrangement, the intramolecular N-attack could also be observed, mostly when (E)-alkenes were employed. In 2010, the Overman's group applied the developed system to investigate different carboxylic acids and di-and trisubstituted alkenes.…”

“…Starting from the discovery of the Wacker process, [1] where the presence of Pd(II) facilitates the addition of oxygen to ethylene, Pd(II)-catalyzed addition of nucleophiles on sp 2 carbon has become a benchmark in metal-catalyzed alkenes functionalization. [2][3][4] Using simple substrates, such as alkenes, transformations involving CÀ O, CÀ N and CÀ C bond formation have been made feasible, including intra-and intermolecular process. These reactions generally rely on the strong interaction of Pd(II) salts with the π-orbitals of the alkenes, as well as of alkynes and arenes.…”

“…The discussed Wacker-and Heck-type products, resulting from the β-hydride elimination, are not the only products which can be obtained after nucleopalladation of alkenes (Scheme 1). Indeed, after the initial formation of the alkyl palladium specie B, different scenarios are possible: (1) in absence of a second nucleophile, the reductive elimination affords, in function of the bond formed in the nucleopalladation step (CÀ O, CÀ N, CÀ C), Wacker-type, aza-Wacker-type and Heck products (2 a), respectively; (2) when a particular class of substrates is employed, redox-relay Heck reactions might also take place, affording products 2 b; (3) in the presence of a second nucleophile, alkenes difunctionalization can be achieved, allowing the construction of complex molecules in one step (2 c). If hydride sources, such as silanes or alcohol solvents, are used in the reaction mixture, (4) hydrofunctionalization are possible, too (2 d).…”

Unique phosphine ligand synergy in asymmetric hydroformylation of styrene over the Rh@MOF-5 heterogeneous catalysis system

“…Asymmetric carbonylation is a great versatile and atomically efficient synthesis method to produce enantiomerically pure carbonyl compounds (optically active aromatic aldehydes, propionic acids, and propionic esters). [1][2][3][4][5][6] In recent decades, asymmetric hydroformylation (AHF) has been extensively studied due to its ability to produce enantiomerically pure isomeric aldehydes (iso-aldehydes) with chiral carbon atoms. Compared with the hydroformylation process, the development of the AHF process was slow.…”

Palladium-Catalyzed Reductive Heck Hydroarylation of Unactivated Alkenes Using Hydrosilane at Room Temperature

“…In the main cycle, Pd II I is first reduced to Pd 0 II by hydrosilane, 43 followed by the oxidative addition of Ar–I to Pd 0 . The resulting Ar–Pd II –I species III is coordinated by the AQ directing group of the substrate and undergoes regioselective migratory insertion 53 to form the key intermediate ( V ) of the five- or six-membered palladacycle. After transmetalation 40 with the pentacoordinated silicate generated from Si–H and CsF, the alkyl–Pd II –H intermediate ( VI ) is obtained.…”