Intermolecular Pd(0)-Catalyzed Atropo-enantioselective C-H Arylation of Heteroarenes and Other Investigations into the Enantioselective Activation of Challenging C(sp3)-H Bonds

The direct construction of stereogenic axes by enantioselective C-H arylation has been regarded as a very challenging transformation. Very few examples have been reported, despite the indisputable straight-forwardness of the methodology. This is due to the antagonistic relationship between the steric requirement of the substrates for atropostability and their chemical reactivity. This thesis focuses on our efforts to develop an efficient catalytic system to achieve the atropo-enantioselective C-H arylation of heteroarenes.

Following an investigation of various MOP-type and bisphosphine monoxide ligands, it was identified that H8-BINAPO enables a highly atropo-enantioselective C-H functionalization of 1,2,3-triazoles and pyrazoles, heteroarenes of great relevance in medicinal chemistry and agrochemistry. Careful optimization of reaction parameters (notably temperature and time) ensured that the erosion of enantioselectivity is minimized. A double C-H functionalization was also demonstrated in order to provide a compound with two stereogenic axes. The C-H arylation of other heteroarenes, namely imidazo[1,2-a]pyrimidines and thiazoles, was also explored.

Mechanistic investigation by KIE studies led to conclusions that the rate-determining C-H activation step operates mainly through the concerted metalation-deprotonation mechanism. Experimental data combined with DFT calculations suggested a relation between the dihedral angle of the ligands and the origin of the enantioselectivity of the process. The successful development of this atropo-enantioselective transformation allows for the construction of complex three-dimensional scaffolds from much simpler starting materials.