Part I: Palladium PEPPSI-IPENT CI, A Useful Catalyst for Challenging Amination Reactions Part II: Generation Of Benzynes in Flow Reactors followed by Subsequent Diels-Alder Reactions

The first part of this research focuses on developing efficient methods to address challenging Buchwald Hartwig amination reactions using Pd-NHC pre-catalysts. Specifically, we focused on: a) coupling of sterically hindered primary and secondary amines and b) coupling of 2-aminopyridine derivatives with aryl and heteroaryl halides. Although several approaches have been developed and proven to be effective for coupling of sterically hindered amines, they have limited utility and substrate scope. Pd-PEPPSI-IPentCl (Pyridine Enhanced Pre-catalyst Preparation Stabilization and Initiation) proved to be a very effective catalyst for coupling hindered primary and secondary amines under mild reaction conditions (i.e. Na-BHT (BHT = 2,6-Di-tert-butyl hydroxyl toluene), 80 C, DME) tolerating base sensitive functional groups such as ester, keto, and nitrile groups. While the synthesis of 2-aminopyridine derivatives is commonly carried out by metal-catalyzed coupling of 2-halopyridines with aniline derivatives, the use of 2-aminopyridine as a nucleophilic partner in Pd catalysis is very difficult as these substrates tend to bind irreversibly to the palladium center and shut down the catalytic cycle. However, Pd-PEPPSI-IPentCl has been found to resist the binding of 2-aminopyridines, making it a very active catalyst for these couplings. The steric bulk of the 3-pentyl substituents on the aryl rings of the NHC ligand that drives the cross-coupling by facilitating reductive elimination also mitigates the poisoning effect of the 2-aminopyridine functionality in the starting material/and or products. We also found that placing electron-donating or electron-withdrawing substituents at the 6-position of the 2-aminopyridine ring reduces the poisoning effect and facilitate the catalytic cycle with mild bases (i.e. Na-BHT).

The second part of this research investigated the formation of benzyne derivatives from ortho-trimethylsilyl triflates using tetra-n-butylammonium fluoride (TBAF) as the benzyne-forming trigger in the flow system. The numerous advantages of microfluidic devices enabled the formation of these species at room temperature which were immediately trapped in Diels-Alder reactions with five-membered heterocyclic dienes to generate bicyclic alkenes of biological interest. The yields of Diels-Alder reaction with benzynes follow the order: furans > pyrroles > thiophene.