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

Electrophilic Activation of Alkenes by Platinum(II): So Much More Than a Slow Version of Palladium(II)

“…The selectivity for hydroalkoxylation (oxyplatination followed by Pt À C protonolysis) in the platinum system contrasts markedly with palladium-based systems, which tend to give oxidized products through a Wacker-type oxypalladation/b-hydride elimination mechanism. [84][85][86] …”

Detection of Palladium(I) in Aerobic Oxidation Catalysis

“…[1] Reactions that proceed via a Pd II /Pd 0 cycle are appealing because they are often compatible with the use of O 2 as the terminal oxidant. [2] Prominent examples include the Wacker process, [3] alcohol oxidation, [4] Wacker-type cyclization [5] and the Fujiwara-Moritani (dehydrogenative/oxidative Heck) reaction. [ 6] The majority of Pd-catalyzed aerobic oxidations proceed through a catalytic cycle wherein Pd II mediates substrate oxidation and Pd 0 is reoxidized by O 2 (Scheme 1).…”

Transition Metal Catalyzed Approaches to Lactones Involving CO Bond Formation

“…After elimination of HX to form Pd(0), aerobic oxidation is required to regenerate a Pd(II) species. The net result is olefin transposition to an adjacent position [80].…”