Advances in the Stille reaction and new methods for continuous flow Pd-catalyzed C-N bond forming reactions

Abstract

Chapter 1: A highly active catalyst system based upon a biaryl monophosphine ligand, XPhos, for the palladium-catalyzed Stille reaction has been developed. This method allows for the coupling of aryl chlorides with a range of tributylarylstannanes to produce the corresponding biaryl compounds in good to excellent yields (61-98%) in short reaction times (4 h). Palladium(II) acetate [Pd(OAc)2] and XPhos in a 1:1.1 ratio were milled into a fine powder that was used as pre-catalyst for these reactions. Chapter 2: A catalyst system for the Stille cross-coupling reactions of aryl mesylates and tosylates is reported. Using the combination of Pd(OAc)2, XPhos, and CsF in t-BuOH an array of aryl and heteroaryl sulfonates were successfully employed in these reactions. Morever, heteroarylstannanes, such as furyl, thienyl, and N-methylpyrrolyl, which are often prone to decomposition, were efficiently coupled under these conditions. Ortho-substitution on the stannane coupling partner was well tolerated; however, the presence of ortho substituents on the aryl sulfonates greatly reduced the efficiency of these reactions. Chapter 3: A continuous-flow, multistep Heck synthesis was made possible by integrating microreactors, liquid-liquid extraction, and microfluidic distillation. The microfluidic distillation enabled solvent exchange from CH2Cl2 in the first reaction step to N,N-dimethylformamide (DMF) in the final reaction step. Chapter 4: A method to mitigate clogging of microsystems during Pd-catalyzed C-N bond-forming reactions under continuous flow conditions was developed. Bridging of particles across the channel and deposition of materials on the walls of the microreactor were both found to be causes that led to clogging and techniques to minimize their effects using sonication were developed. This system allows Pd-catalyzed amination reactions for the formation of a diaryl amines to proceed for extended periods of time without significant pressure increase in the reactor. Chapter 5: A highly efficient method for the Pd-catalyzed coupling of aryl chloride and anilines has been developed. Catalysts based on allyl palladium chloride dimer and BrettPhos, using biphasic reaction conditions of toluene and water with KOH as a base, provided excellent yields for these reactions. The use of a packed bed reactor allowed for these reactions to be run in a continuous flow manner.