Palladium-catalyzed oxidative wacker cyclizations in nonpolar organic solvents with molecular oxygen: a stepping stone to asymmetric aerobic cyclizations.

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, PhCH3, O2) 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., Pd0) and an electrophile (i.e., PdII), which produces many opportunities for catalysis. Although both modes are prevalent, electrophilic oxidative catalysis by PdII 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 Pd0 to PdII, thus creating a nearly intractable situation for asymmetric catalysis. For example, the use of the traditional copper/O2 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 H2O as the sole byproduct. Despite the difficulties of the traditional systems, seminal works by Hosokawa and Murahashi,[5] Hayashi,[6] Sasai,[7] and B7ckvall[8] have established the potential for enantioselective PdII-catalyzed oxidative cyclizations and dialkoxylations.[9] To the best of our knowledge, however, there were no examples of direct dioxygen-coupled enantioselective PdII-catalyzed cyclizations prior to this report. In fact, the work on the enantioselective oxidation of secondary alcohols stands as the benchmark for copper-free aerobic asymmetric palladium catalysis.[2,3] To address this general problem in asymmetric catalysis, we needed to establish the feasibility of aerobic cyclizations under conditions that would eventually be amenable to the introduction of chiral ligands for palladium. Thus, we began our investigation of aerobic oxidative cyclizations with Pd(OAc)2, pyridine, O2, and MS3: in PhCH3 at 80 8C (Table 1).[10] We intentionally avoided the more common DMSO-based conditions because of the highly donating nature of DMSO as a ligand for palladium and its use as solvent in such reactions.[11] This would preclude the use of chiral ligands and thus prevent a general entry into asymmetric catalysis. Treatment of phenol 1 under a range of aerobic oxidation conditions in PhCH3 led to the discovery that the electrondeficient Pd(TFA)2 in conjunction with Na2CO3 as a stoichiometric base rapidly produces dihydrobenzofuran 2 in excellent yield (entry 5). Similar to the reactivity observed in the oxidation of secondary alcohols,[9a,c] the absence of pyridine causes a pronounced rate deceleration, and reactions typically proceed to low conversion (entry 6). Scheme 1. Some aerobic oxidation reactions.