Organophotocatalytic Deuteration of α-Amino/Oxy C-H Bonds via H/D Exchange With D2O

Abstract

In the past decade, photoredox catalysis and photoinduced HAT (hydrogen atom transfer) catalysis have undergone substantial development and come to the forefront of organic chemistry. Recently, photoinduced hydrogen isotope exchange (HIE) reactions have emerged as a viable strategy for deuteration reaction. HIE reactions allow a late-stage incorporation of hydrogen isotopes in a single synthetic step, thus representing an advantageous alternative to conventional multistep synthesis approaches which are time- and resource-consuming. The development of novel photoinduced HIE reactions, especially those difficult to achieve by other means, could make a significant impact on streamlined synthesis, molecular modification and drug discovery. The aim of our study detailed in this thesis is to develop photoinduced strategies for selective deuteration of hydridic C-H bonds. By leveraging the advantages of photoredox and HAT catalysis, these synthetic methodologies would offer efficient and green approaches to the synthesis of valuable chemicals as well as the late-stage functionalization of pharmacophores and natural products. We hope our study could inspire more aspects of organic synthesis in a green manner.In the first effort, we developed a straightforward H/D exchange method for the synthesis of α-deuterated primary amines from a diverse set of primary amines with high levels of deuteration and chemo- and site selectivity and preparative utility. This cost-effective strategy enables the direct conversion of primary amines to α-deuterated counterparts using D2O as the deuterium source under mild reaction conditions without requiring additional functionality manipulation and with minimal byproduct production. In the second effort, a mild metal- and oxidant-free visible-light photoredox mediated selective deuteration of α-C-H bonds of secondary alcohols, masked secondary amines and secondary amides via H/D exchange with D2O is developed. The prevalence of “O” and “N” adjacent metabolically labile C-H bonds in pharmaceuticals demands the efficient methods for replacement by deuterium. However, selective deuteration of these C-H bonds has been challenged by ubiquitous C-H bonds and the structural diversity of these heteroatom associated functional groups. We have developed a mild organophotoredox and hydrogen atom transfer co-promoted H/D exchange strategy for selective deuteration of secondary alcohols using D2O as deuterium source with high level of deuterium incorporation (up to 100%). Furthermore, through temporary masking secondary amines with Boc group, excellent and highly regio-selective deuteration can be achieved with the catalytic system. We also expended the strategy for the unprecedented deuteration of secondary amides highly efficiently.