Palladium‐Catalyzed Allylic Alkylation of Simple Ketones with Allylic Alcohols and Its Mechanistic Study

Abstract

Allylic alcohols were directly used in Pd-catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20 8C by the concerted action of a Pd catalyst, a pyrrolidine co-catalyst, and a hydrogen-bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the p-allylpalladium complex by lowering the activation barrier.The palladium-catalyzed allylic alkylation is a powerful synthetic tool for CÀC bond formation and has a broad range of applications in the synthesis of biologically important molecules. [1,2] One of the general features of this transformation is that substrates with a wide range of activated leaving groups (acetates, carbonates, etc.) can be utilized to form pallylpalladium complexes.[3] However, the direct use of the accessible allylic alcohols in Pd-catalyzed allylic alkylations remains a challenge. It is worth noting that the use of allylic alcohols as substrates would help to avoid the additional steps required for the preparation of the corresponding activated substrates and the formation of at least stoichiometric amounts of waste both in the preparation and substitution steps. Therefore, allylic alcohols are gaining increasing attention as ideal substrates for palladium-catalyzed allylic alkylation reactions [4][5][6][7] with regard to waste minimization and sustainability.[8] While there have been some reports of Pdcatalyzed allylic alkylations using allylic alcohols, most of these methods required activators [4,6] or special ligands. [7] Therefore, a simple and convenient method for the direct use of allylic alcohols is highly desired. We have demonstrated that allylic amines and allylic alkyl ethers possessing challenging leaving groups have been successfully utilized to form p-allylpalladium complexes through hydrogen-bond activation (Scheme 1).[9] Just before the submission of this manuscript, Ohshima and co-workers reported an interesting platinum-and pyrrolidine-catalyzed direct allylic alkylation of b-keto carbonyl compounds with allylic alcohols using acetic acid as an additive under high temperature and microwave conditions. [5h, 10] We herein report a simple method for the direct use of allylic alcohols in Pd-catalyzed allylic alkylations of simple ketones in the presence of a pyrrolidine co-catalyst in alcohol solvents under mild conditions, and a mechanistic study of this reaction (Scheme 1).Initially, we investigated the Pd-catalyzed allylic alkylation of cyclohexanone with cinnamyl alcohol in several solvents, using a [Pd(h 3 -C 3 H 5 )Cl] 2 /dppf catalyst system and 1.0 equivalent of pyrrolidine at 20 8C.[11] We found that the reaction proceeded well in alcohol solvents and that methanol showed the most promising results. The reaction temperature and the amounts of cyclohexanone and pyrrolidine were also screened and the optimal reaction conditions were: cinnamyl alcohol/ketone = 1.1:1, 20 mol % pyrrolidine, and 2.5 mol % [Pd(...

Kinetics and Inverse Temperature Dependence of a Tsuji–Trost Reaction in Aqueous Buffer

“…Hydrogen-bond-driven activation of allylic ethers has been previously reported in methanol. 21 DFT calculations showed that hydrogen bonding could lower the activation energy by more than 20 kcal/mol. 21 In the oxidative addition step, the counteranion may be rapidly exchanged from the phenolic oxide anion to a phosphate ion (Figure 4c).…”

“…22 In addition to the kinetic studies, mechanistic investigations have elucidated the structures of actual catalysts. For example, (π-allyl)palladium with two phosphine ligands is generally considered a key intermediate, 21 but the complex with a single phosphine may be more reactive. 23,24 Palladium dimers have also been shown to be active catalysts in some instances.…”

Stereoselective Modification of N-(α-Hydroxyacyl)-glycinesters via Palladium-Catalyzed Allylic Alkylation

“…Among the many transition metals used in allylic alkylations, palladium is generally recognized as the most versatile metal due to its ability to catalyze a variety of different reactions. In early reports, stabilized carbanions such as malonates were generally used as nucleophiles, but more recently, nonstabilized enolates of esters, amides, and ketones have received more attention . The decarboxylative allylic alkylation of ketones has found widespread applications.…”

Enamine/Transition Metal Combined Catalysis: Catalytic Transformations Involving Organometallic Electrophilic Intermediates

“…The employment of allylic alcohols in the α-allylic alkylation by combined catalysis (enamine and transition metal catalysis) has also been expanded by several other groups [31]. For example, Bandini et al [32] used gold as the co-catalyst, Yasuda et al [33] and Yoshida et al [34, 35] used palladium as co-catalyst, and Zhou et al [36] employed β-ketocarbonyl compounds as substrates.…”