Palladium‐Catalyzed Oxidative Wacker Cyclizations in Nonpolar Organic Solvents with Molecular Oxygen: A Stepping Stone to Asymmetric Aerobic Cyclizations

Abstract

Catalytic asymmetric oxidation-chemistry involving heteroatom transfer from a reagent to a substrate is perhaps unparalleled in synthetic utility for the construction of enantioenriched materials.[1] Conversely, there is a significant deficiency of asymmetric two-electron oxidations that do not involve heteroatom transfer. Some potentially valuable reactions of this type include the oxidation of secondary alcohols and oxidative heterocyclizations (Scheme 1). The design of efficient processes of this nature requires an abundant, inexpensive, and effective stoichiometric oxidant, and a solvent that is amenable to asymmetric catalysis. To begin to address this general synthetic problem, we recently developed a Pd-catalyzed oxidative kinetic resolution of secondary alcohols in toluene that uses molecular oxygen as the terminal oxidant (Scheme 1). [2,3] Herein we demonstrate the utility of this simple system (Pd catalyst, ligand, PhCH 3 , O 2 ) for the construction of a range of heterocycles by catalytic oxidative cyclization. We also demonstrate for the first time that aerobic cyclizations of this type are amenable to asymmetric catalysis, and thereby establish a critical proof of concept for the further development of catalytic asymmetric oxidative cyclizations that use molecular oxygen as the sole stoichiometric oxidant.Palladium-catalyzed bond-forming constructions have become indispensable in organic chemistry.[4] A favorable property of palladium is that it can serve as both a nucleophile (i.e., Pd 0 ) and an electrophile (i.e., Pd II ), which produces many opportunities for catalysis. Although both modes are prevalent, electrophilic oxidative catalysis by Pd II has garnered less attention in the asymmetric arena. Adding to the disparity is the fact that until recently, cocatalysts (e.g., copper salts) or organic oxidants (e.g., benzoquinone) were necessary for the reoxidation of Pd 0 to Pd II , thus creating a nearly intractable situation for asymmetric catalysis. For example, the use of the traditional copper/O 2 reoxidation system introduces a secondary catalytic cycle, while the benzoquinone system requires the removal of stoichiometric quantities of organic compounds at the end of the reaction. In contrast, reactions that proceed under direct dioxygen coupled catalysis produce H 2 O as the sole byproduct. Despite the difficulties of the traditional systems, seminal works by Hosokawa and Murahashi, [5] Hayashi, [6] Sasai, [7] and Bäckvall [8] have established the potential for enantioselective Pd II -catalyzed oxidative cyclizations and dialkoxylations. [9] To the best of our knowledge, however, there were no examples of direct dioxygen-coupled enantioselective Pd II

Palladium‐Catalyzed Formation of Cyclic Ethers – Regio‐, Stereo‐ and Enantioselectivity of the Reaction

“…The first step is the coordination of PdCl 2 to the double bond and to the allylic hydroxy group to give the π complex A, which is in equilibrium with the π complex B obtained by a simple hydroxy group exchange at Pd. The next step is an intramolecular syn attack of this hydroxy group from the same side of the Pd complex [44,45] www.eurjoc.orglar oxypalladation of hydroxyalkenes leading to dioxabicyclo compounds has already been published. [46][47][48] The high stereoselectivities observed in the formation of heterocycles 10 and 11 in the Pd II -catalyzed cyclization of allylic alcohols 8a-g could be explained according to Figure 3.…”

Palladium-Catalyzed Intermolecular Oxidative Amination of Alkenes with Amines, Using Molecular Oxygen as Terminal Oxidant

“…or in the presence of an external oxidant source such as benzoquinone (BQ), PhBQ, PhI(OAc) 2 , or PhI(OPiv) 2 [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33]. In contrast, the oxidative amination of olefins using more basic, simple amines as substrates has been less explored, and is generally limited to intramolecular reactions [34][35][36][37][38], because of the strong coordination of amines to Pd, which results in catalyst deactivation. The oxidative amination of olefins using primary amines was initially reported in 1981 by Hegedus; the reaction was carried out using an excess of reoxidant and salt [39].…”

Intramolecular Pd-Catalyzed Carboetherification and Carboamination. Influence of Catalyst Structure on Reaction Mechanism and Product Stereochemistry

“…In the presence of NaOtBu there is likely a significant equilibrium concentration of highly nucleophilic alkoxides that result from deprotonation of the substrate alcohol. 43 In contrast, deprotonation of the less acidic aniline nucleophile would occur to a lesser extent, hence the concentration of anilide anion is likely to be low, which may result in relatively slower rates of Wacker-type addition of the nitrogen nucleophiles. The fact that yields of anti-addition products decrease (under identical conditions) with increasing steric bulk of the alcohol nucleophile is consistent with this notion.…”