Synthesis of Pyrroles and Indoles

Carbonyl condensations (c.f. chapt. 3) - Pyrroles

Strategy a; Paal-Knorr synth.

OR'

OR

NH2R''

NR''

OHR'

HOR N

R''R'R

- 2 H2O

R''=H, alkyl, aryl

- 2 H2OOHHO

CO2HO2C

HO OH

RNH3

ΔOO

HO2C CO2H

RNH2

NR''

OHCO2H

HOHO2C - 2 H2O N

R''CO2HHO2C

-2 CO2 NR''

R, R' = H: OOUnstable

Synthons:

O OMeMeO OHHO

CO2HO2C

HO OH

BuNH3

X

a

b

X

X

X

c

Not useful for indoles

NR

X

O

R

H2N-R

Would requireNu.Ar subst.

Strategy b; Knorr synth.

OR3

HNR5

RO2C

O R2R4

Base

R2, R3 ≠H

RO2C

O R2

OR3

HNR5

R4

Neccesary for easy enolization

NR5

R2HO

RO2CR4

OHH

H

R3

- 2 H2O N

RO2C R3

R4R2

R5

Can be removed;hydrol., decarbox.

If R2=CO2RCan be removed;hydrol., decarbox.

May be H

Alkyl,aryl

Strategy a and b combined; Hantzsch synth.

X

a/b

X

OR

Cl

CO2R3

O R4

NR'

R R4

CO2R3

NH2R'

OHR4

CO2R3

HNR'

CO2R3

NR'

R4

imin

taut.CO2R3

HNR'

R4

enamin

- HCl- H2O O

R

N

R4

CO2R3

R'imin

taut.

O

R

HN

R4

CO2R3

R'enamin

N

CO2R3

R4

R'

RHO

HH

- H2O

OR

ClR, R4: alkyl, arylR': H, alkyl, aryl

CO2R3

O R4NR'

R R4

CO2R3

May be removed;hydrol, decarbox.NH2

R'

X

a

b

X

X

X

c

Strategy cX

a

b

X

X

X

c

R2

RO

O

R, R2: H, alkyl, aryl

HNR'

CO2R3

glycine der.

R2

R O

HO NR'

- H2O

R2

RO

NR'CO2R3 CO2R3

Base

R2

RO

NR' CO2R3

N

R2OH

CO2R3

H

R'R - H2O N

R'

CO2R3R

R2

R2

O

HNTs

CO2R3

R2

R O

NTs CO2R3

Base

R2

RO

NTs CO2R3

N

R2OH

CO2R3

H

TsR

- H2O N

R2

CO2R3

H

Ts

RBaseH

N

R2

CO2R3RH

taut.

Carbonyl condensations (c.f. chapt. 3) - Indoles

Strategy b -Reissert synth.

N

Na

NC

b

CH3

NO2

Base CH2

NO2

O O

OEtEtO

NO2

O

CO2EtH2 / cat.

NH2

O

CO2Et-H2O N

H

CO2Et

NO

O

- Modified Reissert synth.; Leimbruger-Batcho

CH3

NO2p 358 NO2

X

X: NO2, NMe2

TiCl3

NH

-Madelung synth.

CH2Br

NO2

PPh3CH2PPh3

NO2

Br1) Zn /H+

2) RCOClCH2PPh3

NH

Br

O

R

Base

NH

R

Carbonyl condensations (c.f. chapt. 3) - Indoles

Strategy a -Bischler synth.

N

Na

NC

b

NH2

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

NTf

OEtEtO

- H2ONTf

-Gassman synth.

NH2

t-BuOClNH

Cl

O

RS

NH

S

O

R

Cl

Base

NH

S

O

R

ON

SCH3

R

H

H

Base

NH

MeS HOHR- H2ON

H

R

SMe

H2 / cat.

NH

R

Cycloadditions with 1,3-dipoles (c.f. chapt. 3)a

bc

d e d e

c

b

a

X X

alkene / alkyne

1,3-dipole

N CR isocyanate

Base

N CR

EWG

'R

N

EWG

R

'RH

HH

R=Ts (TsMIC)R=Benzotriazolyl (BetMIC)R=-CO2R

EWG= NO2, COR

MIC: methyl isocyanate

Bet:

NN

N

Reaction with isocyanide

Alt. I; van Leusen synth.

R: Ts or Bet (Good leaving groups)EWG: -COR

N

COR

Ar

'RH

HH

N

COR

Ar

'RH

HN

R'H

COR taut.

NH

'R COR

Alt. II; Barton Zard synth.

R: -CO2REWG: -NO2

N

NO2

H

'RH

RO2CH

N

NO2'RH

RO2CH

N

R'H taut.

NH

'R

RO2CRO2C

Reaction with mesoionic oxido-oxazoliums

R R2

O

HN R4

O

R3

NH

R R2

R3 R4

OO

- CO2 NH

R R2

R4R3

O

HN

R4

O

R3O

N R4

O

R3

H

- H2O

HNO

HO OR3

R4

N-acylaminoacid

Mesoionic:Zwitter ion - no unchargedres. form

NH

O NH

O

Not mesoionic

Reaction with nitrenes

N3

CHO MeNO2Base

N3

NO2 Δ

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

HNTs

I I

BaseNTs

I

R

EWG

EWGBaseH

NTs

I

R EWG N

I

R EWG

tautH

HH

HH

H

NH

I

EWGR

JOC 2003, 7853

R

HN'R

R: alkyl, alkenyl

cat. Pd(II) or Cu(II)

NR'

R R

HN'R

Metn+

N

R'HR

Met(n-1)+

- Metn+NR'

R

H tautH

H

H

H NR'

R

R

HN'R

R: H, Ph, THP

NR'

Spont.1) PBr32) R'NH2 RR

OH

N

N NH

N

OH

TCB

N

N NH

N

O

R

NHR'

cat. Pd(II)

NR'

PdX

RH+

NR'

R

I

NHR'

Pd(0)PdX

NHR'

R TMS

NHR'

R

PdX

TMS

NPd

RTMS

R'

base

- HX red, elimPd(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

RH

R'

R' R' R' R' R'H

NH2NH2

RR'H

NH

RNH2

H R'H+

NH

RNH3

H R'

- NH4+

NH

R

R'

Br H2NNR

R'

+

cat. Pdbase

May also be cat. by Lewis acids

Synthesis from pyrroles

NTsO

XMg O

O

NTsHO

OO

H+

NTsHO

OH

protected aldehyde

E-fil. Ar. subst

NHO

OH

Ts- 2 H2O N

Ts

Miscellaneous indol syntheses

Bartoli synthesis

N

O

O XMgN

O

O

MgX

NO XMg

NO

MgX

O

NMgX

N

H

OMgXH

H XMg

N

OMgXH

MgX-H2O

H+

NH

Fürstner synthesisO

Cl

NO2

Ar-SnBu3

(Pd not required)

Ar

O

NO2

1) H2 / cat2) HCO2H, Ac2O

Ar

O

NH

O

TiCl3, Zn

McMurry coupling

NH

Ar

Pd-cat. couplings

NH

R

R'Brcat. Pd, base

NH

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

Tryptophan

Essential amino acid

NH

NH2

SerotoninNeurotransmitter

HO

NH

CO2H

Auxine Plant growth hormone

Psilocybe 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

O

OOMe

OMe

OMe

OMe

Reserpinefrom Rauwolfia sp.Reduce blood pressure

NH

NH

R'O

RSecale 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

N

O N

O

HO

O

NNH

O

N

NH

N

O N

O

HO

O

Rauwolfia serpentinaIndia, Thailand etc

Vinca rosea (Catharantus roseus)From MadagaskarPerivinkle

NH

N

HO

MeO2CMeO

NR

N

H OCOMe

CO2MeOH

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

Vinca alkaloidsfrom Vinca roseaAnticancer comp.