Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed C-H Activation Using Dioxygen as the Oxidant Zhuangzhi Shi, Chun Zhang, Si Li, Delin Pan, Shengtao Ding, Yuxin Cui, and Ning Jiao Angew. Chem. Int. Ed. 2009, ASAP DOI: 10.1002/anie.200901484 Marie-Céline Frantz Wipf Group, Current Literature May 23, 2009 Marie-Céline Frantz @ Wipf Group Page 1 of 14 5/27/2009
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Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed
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Indoles from Simple Anilines and Alkynes: Palladium-Catalyzed C-H Activation Using
Dioxygen as the Oxidant
Zhuangzhi Shi, Chun Zhang, Si Li, Delin Pan, Shengtao Ding, Yuxin Cui, and Ning Jiao
One-pot: InBr3-catalyzed enamination of Me acetoacetate Pd(OAc)2-catalyzed oxidative cyclization
• Examples:
Rh(III)-catalyzed oxydative cyclization with N-acetyl anilines Acetyl = directing group
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T.M.—catalyzed cyclization with alkynes
• Direct approach from simple anilines
Challenge Goal of the title paper
Liu, JOC 2006, 71, 4951-5
From anilines and propargyl alcohols: Zn(OTf)2-catalyzed C-2 addition of the alcohol Zn(OTf)2-catalyzed intramolecular cyclization of the α-amino-ketone intermediate
• A unique example:
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Title paper: reaction optimization
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Title paper: substrates scope
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Title paper: reaction applications
3ua
NH
CO2Me
CO2Me
3aa
E E
NH21
Title paper: mechanistic considerationsProposed mechanismC-H activation not reversible:
Potential intermediate:
Intramolecular isotope effect study:
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Title paper: conclusions
• Direct approach for indole synthesis from simple and readily available anilines and alkynes by C-H activation.
• Unexpensive catalyst. No ligand. No base.
• O2 used as the oxidant: green chemistry.
Limitations:• Need high temperature (120°C).
• Poor investigation of the alkyne substrate scope and R1/R2 regioselectivity.
• Monosubstitution at position 4 not possible.• Scalable? 5
67
4
NH
1
2
3
?
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