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Zhuangzhi Shi, Chun Zhang, Si Li, Delin Pan, Shengtao Ding, Yuxin Cui, and Ning Jiao
Marie-Céline Frantz
Wipf Group, Current Literature
May 23, 2009
History of indoles
5
2
6 N
7 H
1
• Indole = indigo + oleum, since indole was first isolated by the treatment of
the indigo dye with oleum.
• First prepared synthetically by Adolf von Baeyer in 1868.
OH
Baeyer, Chem. Ber. 1868, 1, 17
O
N
H
O H O Dioxindole
+
N [O] Zn dust ZnO
O O
N N N N
H H H
H O Oxindole Indole
Isatin
Indigo
• Indole derivatives = important dyestuffs until the end of the 19th century.
• In the 1930s, intensified interest in indole when it was discovered its
presence in natural products and bioactive molecules.
www.chem.cornell.edu/jn96/outreach.html
Marie-Céline Frantz @ Wipf Group Page 4 of 14 5/27/2009
Methodologies for indole synthesis
• Examples:
One-pot:
intermolecular TiCl4-catalyzed hydroamination
intramolecular Pd(OAc)2-catalyzed aza-Heck
• Examples:
Glorius, ACIE 2008, 47, 7230-3 Fagnou, JACS 2008, 130, 16474-5
Challenge
Goal of the title paper
• A unique example:
CO2Me
N
H
3aa
3ua
Potential intermediate:
NH2
1
• 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
4 3
2
6 N
7 H
1
Marie-Céline Frantz @ Wipf Group Page 14 of 14 5/27/2009