INDOLES

Reaction with electrophiles - Reacts preferably at C-3 !!

NH

NH

H E

NH

H E

most stable

NH

E

H NH

E

H NH

E

H

NH

E

H NH

E

H

E

E

NH

E

NH12

33a4

5

67 7a

NH pKA -3.5 N

H

H H

NH

H H

most stable

NH

H

H NH

H

H NH

H

H

NH

H

H NH

H

H

H

H

ProtonationWeak base, pKa ca as for pyrrol Nitration

at C-3

Halogenation

Haloindoles (esp. 2-halo-) unstable

NR

1) LDA2) "X+"

NR

X

NR

"X+"

NR

X

Mechanisms may be complex

Alkylation Low reactivity, unselective, polymerization etc

AcylationH+/H2Oor OH-

NH

140 oC N

O

O

NH

O

Base

N N

O

Ac2O

Ac2O

X

RX, Lewis acid

F.C.-alkyl.

-HNR N

R

Me

110 oC

Scatole

NR

Me Me

NR

MeH

Me

NR

Me

Me

Plancher rearrangement

NR

Me Me

MeMeI Me-I

NR

Lewisacid

NR Plancher

rearrangementNR

X

Condensation with aldehydes / ketones

NH

H+, RCHONHR=H, alkyl

H

OHR

H±H+

NH R H

OH2NH R

H Polymer- H2O

NH

H+, RCR'O

NH

RR'

Somewhat more stable

Condensation with Imines / Iminum Ions

NH

CH2O, R2NH, H+

NR

R

-NH

NR

R

acidic cond.

N CH2O, R2NH N

NR

R

Neutral cond. 0 oC

H

AcOH

NH

DMF, POCl3NH

O

"Vilsmeier!

Reaction with nucleophilesElectron rich ring - not very reactive towards Nu

NH

NO2

O2NNu

NH

Nu

O2N Indole: React. In benzene ring prefered

Reaction with base and further react. with E-files

NH

pKa 17.5

NH

pKa 44NH

pKa 16.2N N

Most important res. formsAmbident nucleophile

React at N: Polar solvents Ionic (Na, K counter ions)

React at C: Less polar solvents More covalent bound metal (Grignard etc)

C-metallation and further react.

NR

X t-BuLi

t-BuLiX=H

X=BrNR

LiE

NR

E

NR

Li ENR

E

Simple routes to 2- or 3-subst. indoles

NR

NR

E

NR

E

E-fil Ar Subst1) RLi2) E+

NR

Pd(OAc)2N

H PdOAc

R

OAc

NR

PdOAcEWG

NR

EWG

Heck

+ Pd(0)

Cu(II)

Electrophilic Palladation

Cyclo AdditionsIndole as diene (4π component)

Vinylindole as diene

Indole as dienophile (2π component)

NR

No examples

NEWG

generaldienophile

NEWG

NEWGH

Also

NEWG

N

O n

N

O n

N NO2 NNO

1,3-dipole

N

NO

NMgBr

EWG

H+/H2O

NH

EWG

Formally reverse ecetron demand DA,might be step wise mechanism

Oxyindoles

NH N

Hdetectableminor taut.

OH O

Inoxyl

NH

OH NH

Onot detectable

NH

O

Inoxyl

BaseNH

O

NH

O

- e

2 2NH

O2

NH

O

NH

O

H H NH

OHN

OIndigo

Aminoindoles

NH

NH2 N NH2 N NH2 3-Amino - unstable

Azaindoles (Pyrrolopyridines)

NH

N

4-azaindole

NH

N

5-azaindole

NH

N

6-azaindole

NH

N

7-azaindole

5-membered ring≈ pyrrol (less electron rich)6-membered ring≈pyridine (more electron rich)

NH

N

pyrrolo[2,3-b]pyridine

largest ring

N

NH1

23 4

5

ab

cdef

NH

N E NH

NE

NH

N

E- H NH

NX

XNu

No Nu substin pyrrole ring

Nu

Nu-subst if X α or γ to N

NH12

33a4

5

67 7a

Synthesis of Indoles

Paal-Knorr synth.

OR'

OR

NH2R''

NR''

OHR'

HOR N

R''R'R

- 2 H2O

R''=H, alkyl, aryl

Not useful for indoles

NR

X

OR

H2N-R

Would requireNu.Ar subst.

N

Na

NC

b

Strategy b -Reissert synth. N

Na

NC

b

CH3

NO2

Base CH2

NO2

O O

OEtEtO

NO2

OCO2Et

H2 / cat.

NH2

OCO2Et

-H2O NH

CO2Et

N O

O - Modified Reissert synth.; Leimbruger-Batcho

CH3

NO2p 358 NO2

X

X: NO2, NMe2

TiCl3NH

-Madelung synth.

CH2Br

NO2

PPh3CH2PPh3

NO2

Br 1) Zn /H+

2) RCOCl CH2PPh3

NH

BrO

R

BaseNH

R

Strategy a -Bischler synth. N

Na

NC

b

NH2

1) BrCH2CH(OEt)22) (CF3CO)2O

NTf

OEtEtO

- H2O NTf

-Gassman synth.

NH2t-BuOCl

NH

Cl

OR

SNH

S

OR

ClBase

NH

S

OR

ON

SCH3R

H

H

Base

NH

MeS HOHR- H2ON

H

R

SMeH2 / cat.

NH

R

Reaction with nitrenes

N3

CHO MeNO2Base

N3

NO2Δ

N

NO2

NH

NO2

N+H R NH

R

R N N N R N N N R N

azid(1,3-dipol)

- N2

Δ or hν

Nitren

Synthesis from aminoalkynes

R

NHR'

cat. Pd(II)

NR'

PdX

RH+

NR'

R

I

NHR'

Pd(0)PdX

NHR'

R TMS

NHR'

R

PdXTMS

N Pd

RTMS

R'

base- HX red, elim

Pd(0)NR'

TMS

R

Miscellaneous indol syntheses

Fischer indol synthesis

NH

NRNHNH2

OR+

- H2O H+

NH

NR

H

H

iminiumhydrazone

NH

NR

Henamin

HNH

NR

H HNH NH2

RHR'

R' R' R' R' R'H

NH2NH2

RR'H

NH

RNH2

H R'H+

NH

RNH3

H R'

- NH4+N

HR

R'

Br H2NNR

R'+

cat. Pdbase

May also be cat. by Lewis acids

Synthesis from pyrroles

NTsO

XMg OO

NTsHO

OO

H+

NTsHO

OHprotected

aldehyde

E-fil. Ar. subst

NHO

OH

Ts- 2 H2O N

Ts

Bartoli synthesis

NO

O XMgNO

O

MgX

NO XMg

N O

MgX

O

NMgX

N

HOMgXH

H XMg

NOMgXH

MgX-H2O

H+

NHFürstner synthesis

OCl

NO2

Ar-SnBu3

(Pd not required)

ArO

NO2

1) H2 / cat2) HCO2H, Ac2O

ArO

NH O

TiCl3, Zn

McMurry couplingNH

Ar

Pd-cat. couplings

NH

R

R'Br cat. Pd, baseNH

R'

R

Heck ?

Br

I H2N R

R' cat. Pd, base

Hartvig-Buchwald+

Bioactive Indoles

NH

N

Sumatriptan, Imigran Drug against Migraineserotonin reseptor antagonist

SO2

HN

®NH

HN

MelatoninHormone

MeOO

NH

CO2H

NH2

TryptophanEssential amino acid

NH

NH2

SerotoninNeurotransmitter

HO

NH

CO2H

Auxine Plant growth hormonePsilocybe Mexicana

Psilocybe semilanceata(Spiss fleinsopp)

OR

NH

NHalucinogens from Psilocybe sopper

R=H: PsilocinR=PO3H: Psilocybin

Serotoninagonists, not broken down in the bodystrong, continuos nerve impulse

in vivo

Bioactive Indoles

NHMeO

N

H

H

HMeO2C

OO

OMe

OMeOMe

OMe

Reserpinefrom Rauwolfia sp.Reduce blood pressure

NH

NHR'O

R Secale alkaloids and derivativesfrom Claviceps purpurea (meldrøye)

X=H, R'=Me, R=OH: Lysergic acidX=H, R'=Me, R=NEt2: LSD

X=H, R'=Me, R=-NHCH(Et)CH2OH: Metylergometrin, Uterus contractions, drug used after birth

X=Br, R'=Me, R=Bromokriptin, Parlodel®Prolactine inhibitor

X=H, R'=Allyl, R=Kabergolin, Dostinexl®Prolactine inhibitor

X=H, R'=Me, R=Ergotamin, Anervanel®Drug against migraine

X

NH

NO N

O

HO

O

NNH

O

N

NH

NO N

O

HO

O

Rauwolfia serpentinaIndia, Thailand etc

Vinca rosea (Catharantus roseus)From MadagaskarPerivinkle

NH

NHO

MeO2CMeO N

R

N

H OCOMeCO2Me

OH

R=-Me: Vinblastin, Oncovin®R=-CHO: Vinkristin, Velbe®

Vinca alkaloidsfrom Vinca roseaAnticancer comp.