2015 Fiscal Year Annual Research Report
Iron-Catalyzed C-H Activation using Organoboron Compounds
| Project/Area Number |
26708011
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| Research Institution | The University of Tokyo |
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Principal Investigator |
イリエシュ ラウレアン 東京大学, 理学(系)研究科(研究院), 准教授 (40569951)
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| Project Period (FY) |
2014-04-01 – 2017-03-31
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| Keywords | 有機合成 |
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| Outline of Annual Research Achievements |
The purpose of this research is to develop a novel organoiron catalytic system using organoboron compounds or other mild organometallic regents, and utilize the new iron catalyst for C-H functionalization. The novel organoiron catalyst is specifically designed to address the limitations of low-valent organoiron catalysts that have been used to date for C-H activation or cross-coupling.
During FY2015, we discovered that trimethylaluminum can be used as a mild base and methylating reagent to generate a high-valent iron catalyst in the presence of a diphosphine ligand, and this catalyst was able to methylate a C-H bond in a variety of aromatic, heteroaromatic, olefinic, and aliphatic carboxamides and anilides. The use of the mild aluminum reagent and of a dichloroalkane as an oxidant prevented undesired reduction of iron and allowed the reaction to proceed with catalyst turnover numbers as high as 6500. The mild reaction conditions tolerated various functional groups such as chloride, bromide, ester, dimethylamine, and allowed the methylation of heteroaromatic amides such as pyridine-, indole-, thiophene-, and furanamide.
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
Organoiron catalysis to date, including cross-coupling, C-H activation, carbometalation, etc. has been plagued by low catalyst efficiency and narrow substrate scope (poor chemoselectivity), presumably because of the involvement of mixtures of low-valent organoiron species. We envisioned that by the design of ligands for iron, and by the use of mild organometalic bases we could generate a high-valent iron catalyst that may be more efficient and chemoselective. We discovered in FY2014 that a bidentate aminoqinoline directing group, a diphosphine ligand, and an organoborate compound can indeed generate a high-valent organoiron species that cleaves the C-H bond of a large variety of amide substrates. However, the reaction suffered from poor catalyst efficiency. The discovery in FY2015 that an aluminum reagent creates an organoiron species that activates a C-H bond with a catalyst efficiency surpassing an of the precious metal catalysts known to date opens a new horizon for the design of highly efficient iron catalysis, and will impact the field of iron catalysis not only for C-H activation, but also for a plethora of reactions such as cross-coupling, carbometalation, addition, etc.
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| Strategy for Future Research Activity |
The use of a mild organoaluminum reagent as a base, in combination with a bidentate directing group and a diphosphine ligand enabled the creation of an iron species that catalyzed the functionalization of a C-H bond with high catalyst efficiency. However, the catalytic system was limited to methylation of carboxamides and congeners. In FY2016, I plan to create a new catalytic system that has both high catalytic activity and versatility, and allows the reaction of a variety of substrates.
1) The reaction of various C-H substrates: I will design a new ligand for iron in order to activate the C-H bond of simple substrates. Preliminary results showed that a new triphosphine ligand enables the methylation of carboxylic acids, esters, amides, and ketones with trimethylaluminum.
2) The reaction of a C-H bond with electrophiles: in order to diversify the coupling partner, I plan to use a mild organometallic reagent (aluminum or boron) as a base for the C-H cleaving step, followed by reaction with a large variety of electrophiles. Preliminary results showed that a base generated from diisobutylaluminum hydride and a Grignard reagent or potassium t-butoxide effects the alkylation of an aromatic carboxamide with octyl bromide.
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| Causes of Carryover |
Next FY I intend to design new ligands for in order to activate the C-H bond of simple substrates. These ligands, such as specially designed di- or triphosphines require expensive starting materials for their synthesis. Also, during the next FY, I intend to develop mild organometallic reagents as a base for the C-H cleaving step. The starting materials for the synthesis of these reagents, such as organoboron and organoaluminum reagents, are typically commercially available but expensive.
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| Expenditure Plan for Carryover Budget |
With the new ligands, I will develop a new iron catalyst for the activation of simple substrates such as simple carbonyl compounds, carboxylic acids, heteroaromatic compounds, etc.
Also, I plan to develop new mild organometallic reagents as a base for the C-H cleaving step, followed by reaction with a large variety of electrophiles. This strategy will enable high catalyst efficiency and versatility of the coupling partner in iron catalysis.
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