Development of Palladium-Catalyzed Oxidation Reactions
Palladium-Catalyzed Oxidation Chemistry | Catalytic Reaction Mechanisms | Palladium-Oxygen Reactivity
Amide Metathesis and Transamidation | Polymerization of β-Lactams
Nitrogen-containing functional groups and heterocycles are ubiquitous in biologically active molecules. Synthetic methods for the incorporation of nitrogen into organic molecules are generally less well developed than those for oxygen, and this principle is particularly evident in oxidative functionalization of alkenes. The oxidation of ethylene to acetaldehyde (the Wacker Process) has been known for nearly 50 years; however, the analogous Pd-catalyzed oxidative amination of alkenes was previously unknown. We have recently reported the simple intramolecular oxidative amination of unactivated alkenes using a palladium catalyst and molecular oxygen as the stoichiometric oxidant (a functional �Aza-Wacker� reaction). Oxidative amination should proceed via aminopalladation of an olefin (boxed reaction above), resulting in an intermediate which may be channeled to different fates depending on reaction conditions. Namely, we have developed reaction conditions which provide β-hydride elimination (left), olefin insertion (top right), acetoxylation by oxidative cleavage (bottom right), and non-oxidative β-alkoxy elimination (bottom) from this intermediate. Each of these reactions employ molecular oxygen as the stoichiometric oxidant except the highly regio- and diastereoselective aminoacetoxylation, which utilizes stoichiometric PhI(OAc)2 (bottom right).
Mechanistic insights into aerobic alcohol oxidation reactions catalyzed by the highly successful Pd(OAc)2 / pyridine system led us to investigate N-heterocyclic carbene (NHC) ligands in oxidative amination reactions. NHCs are strong σ-donor ligands capable of stabilizing Pd(0) , and NHC-Pd(O2CR)2 complexes resemble the putative active catalytic species in the aerobic oxidation of alcohols by the Pd(OAc)2 /pyridine system, which bears a single pyridine ligand. We have recently demonstrated that NHC-Pd(O2CR)2 catalysts are competent in intramolecular aerobic oxidative amination, often providing catalysts capable of using molecular oxygen derived solely from ambient air. In pursuit of asymmetric Pd-catalyzed oxidation reactions, we have recently reported a new class of chiral 7-membered N-heterocyclic carbene ligands and their Pd complexes. These NHCs are unique due to their intrinsic chirality associated with the antiaromatic 7-membered heterocycle. The development of enantioselective aerobic oxidative amination reactions with these chiral NHCs is ongoing.
