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, ASAPDOI: 10.1002/anie.200901484

Marie-Céline FrantzWipf Group, Current Literature

May 23, 2009

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History of indoles

• 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.

Baeyer, Chem. Ber. 1868, 1, 17

5

67

4

NH

1

2

3

N

NO

O

H

HIndigo

NH

O

ONH

O

Isatin Oxindole

NH

OH

O

Dioxindole

NH

Indole

[O] Zn dust ZnO+

• 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

NH

L-TryptophanEssential amino-acid

NH2

OH

O

NH

SerotoninNeurotransmitter

NH2

HO

NH

MelatoninNeurohormone

HN

O

O

NH

IAA (indole-3-acetic acid)Phytohormone

OH

O

• Others natural alkaloids

For some reviews on indole alkaloids, see:

Kawasaki and Higuchi, Nat. Prod. Rep. 2005,

22, 761-93; Ishikura and Yamada, Nat.

Prod. Rep. 2009, DOI 10.1039/b820693g

NH

NH

Ergoline

NH

N

β-Carboline

ErgolinesPsychedelic drugs

β-CarbolinesCNS drugs

NH

N

HH

OH

H

OOYohimbine

Stimulant drug & aphrodisiac

Yohimbans

Vinca alkaloidsAnti-mitotic & anti-microtubule agents

Vinblastine

N

NH

MeOOCNO

N

COOMe

H

OH

Et

H

Et

COOMe

OH

NH

N

OH

OOMitragynine

Psychostimulant

Kratom alkaloids

O

NH

IbogainePsychoactive drug

Iboga alkaloids

O N

N

N

O

H

O

H

HStrychnineToxic pesticide

Strychnos nux-vomica alkaloids

H

H

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Biological importance of indoles

• Synthetic drugs

www.chem.cornell.edu/jn96/outreach.html

• Indole = "privileged structure"(Horton, Chem. Rev. 2003, 103, 893-930)

-> "A single molecular framework able

to provide ligands for diverse receptors."(Evans, J. Med. Chem. 1988, 31, 2235-46)

N

IndomethacinNon-steroidal anti-inflammatory drug

OH

O

O

O Cl

O

OHHN

HN

PindololBeta-blocker

• Top 200 brand-name drugs in 2007

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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)

O

R2

R1NH

R1

R2

TsOHRR

NH

N

PhPhR

NNH2

PhPh

Br+

Pd

BINAP

Buchwald, JACS 1998, 120, 6621-2

• Nucleophilic cyclization: Madelung, Schmid, Wender, Couture, Smith, Kihara, Nenitzescu, Engler, Bailey-Liebeskind, Saegusa

– Example: Madelung indole synthesis (1912) – Houlihan modification (1981)

Madelung, Chem. Ber. 1912, 45, 1128Houlihan, JOC 1981, 46, 4511-5N

H

nBuLi (3 eq.)

NH

R2

R1R1

R2

O

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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)

• Reductive cyclization: Reissert, Leimgruber-Batcho, Makosza– Example: Leimgruber-Batcho indole synthesis (1973)

NO2 NO2

N

OMeMeO

N

NHNH

Ra-Ni

NH2NH2

Batcho and Leimgruber, US Patent 3 732 245, 1973; Org. Synth. 1985, 63, 214

• Oxidative cyclization: Watanabe, Knölker

Watanabe, TL 1986, 27, 377-80

NHR1

+

R3HO

R2HO

RuCl2(PPh3)3

N

R3

R2

R1

– Example: Watanabe indole synthesis (1986)

Möhlau, Chem. Ber. 1881, 14, 173; 1882, 15, 2480Bischler, Chem. Ber. 1892, 25, 2860; 1893, 26, 1336

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Methodologies for indole synthesis

• Radical cyclization: Murphy, Fukuyama– Example: Fukuyama indole synthesis (1999)

• 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)

Fukuyama, JACS 1999, 121, 3791-2

For a review on indole synthesis, see: Gribble, JCS Perkin Trans. 1, 2000, 1045-75Pd catalysis: Cacchi, Chem. Rev. 2005, 105, 2873-920

Alkyne-based Pd-catalyzed assembly of the indole ring

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T.M.—catalyzed cyclization with alkynes

• With ortho-halogenated anilines

Limitations:

Ortho-halogenated anilines required Halide byproducts

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

Ackermann, Tetrahedron 2008, 64, 769-777

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

• Examples:

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T.M.—catalyzed cyclization with alkynes

• Directing group assisted approach

Limitations:

Directing group required

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

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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