For your convenience, Ph.D. and M.Sc. thesis of our graduate students are compiled and can be viewed through Papyrus, the institutional repository of Université de Montréal. A link is provided below to access the full PDF document.
The search for novel, atom economical and sustainable approaches to form C–C bonds continues to stimulate the chemical community. As an emerging synthetic tool, C–H functionalization offers both alternative and complementary reactions to traditional cross- coupling and other environmentally hazardous classical methods. Cyclopropane incorporation can offer a beneficial strategy to improve both target binding and metabolic stability. In addition to the diverse pharmacological profile, cyclopropanes can be used as valuable synthetic precursors en route to highly complex molecular architectures. Compared to other more challenging sp3 centers, cyclopropanes are highly primed for C−H functionalization due to enhanced cyclopropyl C−H bond acidity and increased reactivity from ring strain. This thesis will disclose explorations towards both intramolecular palladium-catalyzed C−H arylation and alkenylation of cyclopropane systems, including recent efforts towards enantioselective C(sp3)−H functionalization. Chapter One will introduce key concepts regarding palladium-catalyzed C–H functionalization with emphasis on cyclopropanes and sp3 centers. Additionally, properties, applications, synthetic approaches and functionalization of cyclopropanes will be discussed with a focus on aminocyclopropanes. Herein, previous Masters work on C–H arylation will be summarized and a context for the work presented in this dissertation will be established. Chapter 2 will describe intramolecular palladium-catalyzed C–H functionalization of cyclopropyl α-amino acid-derived benzamides to access six-membered tetrahydroquinolones and tetrahydroisoquinolones motifs. Herein, a reductionist approach will be applied through exploring the role of additives in cyclopropyl C–H functionalization. Notably, this system served as a model reaction for our initial investigations into asymmetric C–H functionalization and will consequently be revisited (Chapter 4). Chapter 3 will address the current paucity of methodologies targeting systems with increasing Fsp3. The motivation to “escape Flatland” contributed to investigating intramolecular palladium-catalyzed cyclopropyl direct alkenylation. This chapter will also elaborate on our search for a novel asymmetric catalyst system and our discovery that bisphosphine monoxide ligands can be employed in enantioselective C–H functionalization. Initial investigations into iii asymmetric cyclopropyl alkenylation using both a BINOL-based phosphoramidite ligand and (R,R)-BozPhos will be provided. Chapter 4 will describe our discovery that (R,R)-BozPhos can be employed in combination with Pd(0) to achieve asymmetric induction of cyclopropyl and related sp3 centers. Herein, we will readdress the work of Kagan, and demonstrate that (R,R)-BozPhos, not (R,R)- MeDUPHOS is the active ligand for this system. Finally, the use of Buchwald 4th generation palladacycle dimer to achieve unprecedented enantioselectivities compared to other established literature benchmarks for sp3 asymmetric arylation will be presented.
This work is separated in two distinct parts aiming to describe the recent advances concerning the use of highly reactive molecules such as trifluoromethanesulfonic anhydride (Tf2O) and trifluormethyldiazomethane in organic synthesis. In the first section, the amide activation strategy using triflic anhydride was applied in order to synthesize free secondary and tertiary amidines. Those molecules find numerous applications, particularly in natural product synthesis and medicinal chemistry. Although their purification on small scale is quite difficult, their synthesis and caracterization were successfully achieved. Next, investigations were conducted towards the trifluoromethylation of organic compounds. The idea was to trifluoromethylate highly electronegative activated amides in order to transform them into trifluoromethylketones. Unfortunately, this route appeared to be uneffective and was switched to another promising trifluoromethylating source : Trifluormethyldiazomethane. In the second section, the safe and efficient synthesis of trifluoromethyldiazomethane in continuous flow is described. That diazo compound was then used in the synthesis of trifluoromethylated pyrazolines. A reactivity trend was unveiled as those molecules spontaniously tautomerize (or not) depending on the nature of the substrate. Trifluoromethylated pyrazolines are interesting compounds on their own, especially for the pharmaceutical industry, but also serve as precursors to trifluoromethylated cyclopropanes. Finaly, some ideas and related future projects are discribed, in particular in what should be an efficient and possibly enantioselective synthesis of trifluoromethylated cyclopropanes in continuous flow.