| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 2020: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 2019: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2018: ¥800,000 (Direct Cost: ¥800,000)
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| Outline of Annual Research Achievements |
The proposed research aims at the development of regioselective functionalization of simple arenes, through the design of ligands capable of recognizing the substrate intermolecularly through non-covalent interactions.
Fluoroarenes are important scaffolds for drug discovery, and their late-stage functionalization is important for tuning bioactivity, in order to create more potent and less cytotoxic drug molecules. Such functionalization methods must be regioselective, because separation of mixture of isomers is time- and material-consuming. We designed and synthesized a new terpyridine ligand ortho-substituted with an aryl group, and we found that it enables iridium-catalyzed ortho-borylation of fluoroarenes, priviledged compounds compounds for drug design. The reaction proceeded with a stoichiometric amount of various fluoroarenes with high ortho-selectivity and tolerance of functional groups such as bromide, chloride, ester, ketone, amine, and in situ-borylated hydroxyl. As a highlight, we demonstrated the selective borylation, followed by palladium-catalyzed cross-coupling of the complex drug molecule haloperidol, one of the most commonly used antipsychotic drugs.
We also investigated the origins of the high ortho selectivity induced by our ligand, both by experiment and computation. Thus, we found that the terpyridine ligand undergoes rollover cyclometalation to produce an N,N,C-coordinated iridium complex, which may either selectively borylate the fluoroarene by itself or undergo reductive elimination to produce a borylated ligand.
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