Diverse ortho-C(sp2)-H Functionalization of Benzaldehydes Using Transient Directing Groups
Xi-Hai Liu1, Hojoon Park2, Jun-Hao Hu1
1School of Chemistry, Chemical Engineering and Life Sciences, Wuhan University of Technology , Wuhan 430070, People's Republic of China.
Journal of the American Chemical Society
|December 23, 2016
Summary
This study introduces a new transient directing group strategy for versatile ortho-C(sp2)-H functionalizations of benzaldehydes. This method enables palladium-catalyzed arylation, chlorination, bromination, and iridium-catalyzed amidation without auxiliary groups.
Area of Science:
- Organic Chemistry
- Catalysis
- Synthetic Methodology
Background:
- Palladium-catalyzed C-H functionalizations using transient directing groups are primarily limited to C-H arylation.
- Benzaldehyde substrates possess unique reactivity challenges for C-H activation due to potential catalyst poisoning and competing directing groups.
Purpose of the Study:
- To develop a versatile ortho-C(sp2)-H functionalization strategy for benzaldehydes.
- To expand the scope of metal-catalyzed C-H functionalization beyond arylation using transient directing groups.
- To demonstrate the applicability of the developed method in complex molecule synthesis.
Main Methods:
- In situ formation of transient directing groups via imine linkage on benzaldehyde substrates.
- Palladium(II)-catalyzed C-H arylation, chlorination, and bromination.
- Iridium(III)-catalyzed C-H amidation.
Main Results:
- Achieved diverse ortho-C(sp2)-H functionalizations of benzaldehydes, including arylation, chlorination, bromination, and amidation.
- Demonstrated that the transient directing groups effectively override other coordinating functional groups.
- Successfully applied the methodology for late-stage diversification of a drug analogue.
Conclusions:
- The transient directing group strategy significantly broadens the scope of metal-catalyzed C-H functionalization for benzaldehydes.
- This approach offers a powerful tool for synthesizing complex organic molecules and functionalizing drug analogues.
- The developed method overcomes limitations of previous strategies, enabling multiple reaction types with high efficiency.
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