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

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 4 3

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

• In 1869, he proposed the formula of indole that is accepted today.

Baeyer, Chem. Ber. 1869, 2, 679

• 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.

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 Biological importance of indoles

• Bioactive molecules: tryptophane, tryptamines, auxins

NH2 NH2 HN O
O
OH OH
HO O
O
N N N N
H H H H
L-Tryptophan Serotonin Melatonin IAA (indole-3-acetic acid)
Essential amino-acid Neurotransmitter Neurohormone Phytohormone

• Others natural alkaloids

Ergolines β-Carbolines Yohimbans K r at om alkaloids
Psychedelic drugs CNS drugs
O
NH N H
N
H
N N H O
H N H
H H H
N O OH
O
NH H Yohimbine O Mitragynine O For some reviews on
β-Carboline Stimulant drug & aphrodisiac Psychostimulant
Ergoline indole alkaloids, see:
V inca alkaloids Kawasaki and Higuchi,
St ry chnos nux-vomica alkaloids I boga alkaloids Anti-mitotic & anti-microtubule agents
Et
Nat. Prod. Rep. 2005,
N
N OH 22, 761-93; Ishikura
O
H
N and Yamada, Nat.
N N
Et Prod. Rep. 2009, DOI
H
O O
N N H COOMe 10.1039/b820693g
H H
H OH
MeOOC
Strychnine Ibogaine N H COOMe
O
Toxic pesticide Psychoactive drug Vinblastine
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 Biological importance of indoles

• Indole = "privileged structure" • Synthetic drugs

(Horton, Chem. Rev. 2003, 103, 893-930) O
OH
OH H
O O N
-> "A single molecular framework able
N
to provide ligands for diverse receptors."
HN
O Cl
(Evans, J. Med. Chem. 1988, 31, 2235-46)
Indomethacin Pindolol
Non-steroidal anti-inflammatory drug Beta-blocker

• Top 200 brand-name drugs in 2007

www.chem.cornell.edu/jn96/outreach.html
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 Methodologies for indole synthesis

• Sigmatropic rearrangments: Fischer, Gassman, Bartoli, Thyagarajan, Julia

– Example: Fischer indole synthesis (1883) Fischer, Chem. Ber. 1883, 16, 2241

– Buchwald modification (1998) Buchwald, JACS 1998, 120, 6621-2

R1
R R Ph Ph R
Ph Ph Pd TsOH
+ R2
NNH2 BINAP N O
Br N N
H R1 H
R2

• Nucleophilic cyclization: Madelung, Schmid, Wender, Couture, Smith, Kihara,

Nenitzescu, Engler, Bailey-Liebeskind, Saegusa
– Example: Madelung indole synthesis (1912) – Houlihan modification (1981)
R1 R1
O nBuLi (3 eq.)
R2 Madelung, Chem. Ber. 1912, 45, 1128
N R2 N
H
Houlihan, JOC 1981, 46, 4511-5
H

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 Methodologies for indole synthesis
• Electrophilic cyclization: Bischler, Nordlander, Cadogan-Sundberg, Sundberg,
Hemetsberger, Iwao, Magnus, Feldman
– Example: Bischler-Möhlau indole synthesis (1881)

Möhlau, Chem. Ber. 1881, 14, 173; 1882, 15, 2480

Bischler, Chem. Ber. 1892, 25, 2860; 1893, 26, 1336
• Reductive cyclization: Reissert, Leimgruber-Batcho, Makosza
– Example: Leimgruber-Batcho indole synthesis (1973)
MeO OMe
N
Batcho and Leimgruber, US Patent
N Ra-Ni 3 732 245, 1973; Org. Synth. 1985,
NO2 NO2 NH 2NH2 N 63, 214
NH H

• Oxidative cyclization: Watanabe, Knölker

– Example: Watanabe indole synthesis (1986)
R3
HO R3
RuCl2 (PPh3 )3 Watanabe, TL 1986, 27, 377-80
+ R2
NHR 1 HO R2 N
R1
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 Methodologies for indole synthesis
• Radical cyclization: Murphy, Fukuyama
– Example: Fukuyama indole synthesis (1999)
Fukuyama, JACS 1999, 121, 3791-2

Alkyne-based Pd-catalyzed assembly

of the indole ring

• Cycloaddition and electrocyclization:

Diels-Alder, photocyclization, Chapman,
dipolar cycloaddition

• Metal-catalyzed indole synthesis:

– Pd (Hegedus-Mori-Heck,
Yamanaka-Sakamoto, Larock)
– Rh, Ru, Ti (Fürstner), Zr, Cr, Mo,
Cu (Castro)
For a review on indole synthesis, see:
Gribble, JCS Perkin Trans. 1, 2000, 1045-75
Pd catalysis: Cacchi, Chem. Rev. 2005, 105, 2873-920
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 T.M.—catalyzed cyclization with alkynes

• With ortho-halogenated anilines

Limitations:
 Ortho-halogenated anilines required
 Halide byproducts

• Examples:

One-pot:
 intermolecular TiCl4-catalyzed hydroamination
 intramolecular Pd(OAc)2-catalyzed aza-Heck

Ackermann, Tetrahedron 2008, 64, 769-777

Larock, JACS 1991, 113, 6689-90
Larock, JOC 1998, 63, 7652-62

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 T.M.—catalyzed cyclization with alkynes

• Directing group assisted approach

Limitations:
 Directing group required

• Examples:

One-pot:  Rh(III)-catalyzed oxydative cyclization with

 InBr3-catalyzed enamination of Me acetoacetate N-acetyl anilines
 Pd(OAc)2-catalyzed oxidative cyclization  Acetyl = directing group

Glorius, ACIE 2008, 47, 7230-3 Fagnou, JACS 2008, 130, 16474-5

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 T.M.—catalyzed cyclization with alkynes

• Direct approach from simple anilines

 Challenge
 Goal of the title paper

• A unique example:

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

Liu, JOC 2006, 71, 4951-5

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 Title paper: reaction optimization

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 Title paper: substrates scope

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 Title paper: reaction applications
CO2 Me

CO2Me
N
H
3aa

3ua

Title paper: mechanistic considerations

C-H activation not reversible: Proposed mechanism
E E

Potential intermediate:

Intramolecular isotope effect study:

NH2
1

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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
4 3

2
6 N
7 H
1
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