2013 Fiscal Year Annual Research Report
Iron-Catalyzed C(sp3)-H Bond Functionalization
Publicly Offered Research
| Project Area | Molecule Activation Directed toward Straightforward Synthesis |
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| Project/Area Number |
25105711
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| Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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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), 助教 (40569951)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Keywords | iron / C-H activation |
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| Research Abstract |
Aliphatic hydrocarbons containing various functional groups are ubiquitous in nature and therefore are important synthetic targets. The purpose of this project is the development of synthetic methods to functionalize aliphatic hydrocarbons in a straightforward and step-efficient manner through C-H bond activation, using cheap, abundant, and non-toxic iron as a catalyst under mild reaction conditions.
During FY2013, I have developed an iron-catalyzed reaction of propionamides with organozinc reagents. By contrast to previous reports that used precious transitions metals as the catalyst, the present reaction proceeds under mild reaction conditions and with the tolerance of functional groups such as chloride and bromide. The reaction proceeds regioselectively to give a beta-arylated propionamide with high yield. The obtained compounds can be hydrolysed to the corresponding aliphatic carboxylic acids, compounds of importance for medicinal chemistry and industry.
From a scientific point of view, this work offers insights into the key parameters that govern the activation of a C-H bond with organoiron species. Thus, a bidentate group and a diphoshine ligand are required to stabilise the active iron species, and the appropriate positioning of the C-H bond with respect to the directing group is required in order for the C-H cleavage to proceed smoothly.
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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
The reaction developed in FY2013 is the first iron-catalyzed sp3 C-H activation reported to date. This work demonstrates that iron, which is of interest for environmental and economical reasons, can rival and even surpass precious metals such as palladium in terms of efficiency, selectivity, and mildness of the reaction conditions. This work was published in the top journal for chemistry (Journal of the American Chemical Society) and presented at various national and international conferences. The mechanistic insights into the factors governing the reactivity of iron was further exploited for the development of several related reactions such as the iron-catalyzed allylation and amination through C-H bond activation; these reactions have both been recently published in the Journal of the American Chemical Society.
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| Strategy for Future Research Activity |
While the reaction developed in FY2013 is a pioneering example of iron-catalyzed aliphatic C-H bond activation, this reaction has several drawbacks. For example: 1) a large amount of organozinc reagents, which are sensitive to moisture and air, expensive, and difficult to handle, must be used used as the arylating reagent; 2) the scope of the amide substrate is narrow; 3) the narrow substrate scope together with limitations in the repertoire of the ligand hampered the development of an asymmetric version of this reaction.
In FY 2014, I plan to address these problems through the use of organoboron reagents. Organoborons are commercially available, stable and easy to handle, and functional group tolerant. Moreover, they have lower reducing ability than the organozinc reagents, and therefore it is expected they will not reduce iron to a low-valent species which is difficult to control, resulting in narrow reaction scope.
However, transmetallation of iron with organoboron reagents is difficult. I envision that the use of an appropriate additive may enhance the problematic transmetallation process, and preliminary results showed that a zinc(II) salt may be effective. Based on this initial result, I plan to develop a broad and general reaction of aliphatic amides with organoboron reagents, including aryl, alkenyl, and alkyl reagents. Next, development of chiral ligands for iron will be conduced to achieve iron-catalyzed enantioselective C-H bond activation. These reactions can be of potential use for the synthesis of target molecules for medicinal chemistry.
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[Presentation] Iron-Catalyzed C-H Activation2013
Author(s)
Laurean Ilies, Eiichi Nakamura
Organizer
International Symposium on Catalysis and Fine Chemicals
Place of Presentation
Renmin University, Beijing
Year and Date
20131201-20131205
Invited
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