Ruthenium-catalyzed Late Stage Amination of arenes

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Amines are ubiquitous in biologically active compounds, with a vast range of motifs and configurations. In particular, aromatic amines are found in pharmaceuticals, agrochemicals and functional materials. Thus selective methods for the formation of C-N bonds are prized synthetic tools. One of the most commonly used C-N bond forming reactions is the Buchwald-Hartwig amination. However, this method requires the prefunctionalization of the coupling partner, limiting application to substrates containing a suitable C-X bond. Instead, direct C-H amination represents a powerful strategy that could lead to the formation of any aromatic amine if we were able to selectively activate any C-H bond.Direct C-H amination has received significant attention over the last decade, however, many challenges remain. For example, most amination reactions operate just in simple substrates, with more complex molecules leading to no reactivity or side reactions. Furthermore, when using directing groups to control the C-H activation step, most methods are limited to ortho-selective amination, with meta-selective processes being very rare.In the Larrosa group, we have recently developed a novel class of small molecule Ru-catalysts that can mediate the late stage arylation and alkylation of complex molecules bearing nitrogen-based directing groups. These catalysts proceed via the formation of key highly electron-rich biscycloruthenated species, bringing large reactivity improvements over previous Ru-catalysts. While these reactions normally lead to ortho-functionalization, we have uncovered that for some classes of reactions (eg alklyations with secondary alkyl halides) both ortho and meta regioselective transformations are possible, by simply modifying the ligand sphere in the catalyst.The Green group specialises on the development of engineered enzymes to catalyze synthetic processes that have until now been the exclusive domain of homogeneous catalysts. These new enzymes combine the synthetic versatility of chemo-catalysis with the precise control afforded by enzymes. The Larrosa and the Green work are also working together on the development of transition metal based metalloenzymes, that could be used for the precise control of C-H functionalization processes.In this project, we aim at developing novel Ru-based catalytic systems capable of performing regioselective C-H amination of arenes bearing N-based directing groups, with emphasis on developing methods capable of operating on complex molecules (late stage functionalization) and on controlling access to both ortho- and meta-amination regioselectivities. To achieve these ambitious aims, we plan to combine state-of-the-art organometallic chemistry, photocatalysis and electrochemical approaches that will allow us to fine tune the reactivity of catalytic intermediates, in situ. In addition, we will explore enzymatic approaches being pioneered by the Larrosa & Green groups for the formation and use of Ru-based metalloenzymes with the objective of carrying out asymmetric C-H aminations.The student will be trained in state-of-the-art chemocatalysis, including organometallic chemistry, organic chemistry and physical chemistry techniques for the design, synthesis and investigation of small molecule ruthenium based transition-metal catalysts, within the Larrosa group. The student will receive training on enzymology, genetically encoding of unnatural aminoacids, directed evolution and assessment of enzymatic reactions within the Green group.