Mild Arylboration of Cyclic Enones via Cooperative Copper/Palladium Catalysis

Abstract

Cyclic enones are abundant building blocks with diverse applications in the synthesis of complex organic molecules. As such, a variety of methodologies for enone functionalization have been developed, with conjugate addition of cuprates and enolate trapping sequences serving as a dominant strategy. While robust, these approaches are limited by their cryogenic conditions, the need for stoichiometric organometallics, and a narrow range of functional groups which are compatible. Modern advancements in cyclic enone functionalization aim to move away from cuprate chemistry and towards more mild, catalytic conditions which can install a breadth of functionalities. Catalytic methods for cyclic enone mono-functionalization are plentiful, including copper-catalyzed conjugate borylation, the Mizoroki–Heck reaction, Pd-catalyzed α-arylation and rhodium-catalyzed conjugate arylation. Surprisingly, only a handful of direct catalytic difunctionalization reactions have been reported for cyclic enones, while the difunctionalization of other alkenes has been extensively explored in recent years. Alkene arylboration via cooperative Cu/Pd catalysis has emerged as a particularly powerful method for the difunctionalization of a range of alkene classes, but this has never been applied to cyclic enones. Chapter 1 of this thesis provides a literature overview of the existing methods for cyclic enone functionalization, as well as an introduction to alkene arylboration. In Chapter 2, these insights are applied towards the discovery, optimization, and application of a Cu/Pd co-catalyzed method for achieving the anti-selective arylboration of cyclic enones under mild conditions. At the outset of the project, it was hypothesized that trapping of transient copper enolate intermediates with palladium complexes would be challenging, and that in-situ degradation would lead to an undesired conjugate borylation side product. Kinetic reasoning suggested that high Pd:Cu ratio would be required to ensure efficient interception of transient enolate intermediates and enable the desired reaction. High-throughput screening identified an initial hit for the arylboration reaction in 10% yield, which was subsequently optimized to provide room-temperature conditions affording enone arylboration products in moderate yields of around 50%. The optimization results suggest that high Pd:Cu ratio is ideal, as predicted by our mechanistic hypothesis, and that a JohnPhos-Pd catalyst is uniquely privileged for trapping transient enolates. A variety of aryl triflates and hetero-aryl bromides are tolerated in the reaction, along with examples of alkenyl triflates and an allyl carbonate. Diastereoselectivity generally favours the anti products in dr between 5:1 and 8:1, with ortho-substituted aryl triflates providing exclusively anti products (dr > 20:1); this suggests that the diastereo-determining step must be sensitive to sterics. The scope of cyclic enones is shown to be more limited, with reduced yields observed on smaller-ring substrates, and reactions failing entirely with enones bearing α or β substituents. Facial selectivity based on existing bulky groups on the enone substrate was shown to be possible. The reaction can easily be scaled up to 1 mmol with no significant impact on yield. The products of enone arylboration are readily functionalized at the B(pin), ketone, and ring, providing access to a variety of complex carbocycles with high stereochemical control. Mechanistic experiments suggest that the conjugate borylation side product is not a competent intermediate and must be forming in-situ through degradation with an unknown proton source. No evidence of in-situ product epimerization is seen, suggesting a stereo-determining transmetallation or reductive elimination event. An attempt was made to render the reaction asymmetric through use of a chiral NHC ligand for copper, affording an ee of 10%. Though low, this result suggests that the development of an asymmetric cyclic enone arylboration reaction may be possible with further exploration.