PYRROLES

NH

NH

Pyrrole (kap 13)

Indole(kap 17)

N

Indolizine(kap 25)

NH

Isoindole(kap 19)

Reaction with electrophiles - Protonation

NH

N NHH H

least stable

H

H

H

HH N

H

HH N

H

HH

NH

HH

NH

HH

most stable

pKA -3.8

NH

H

pKA -3.5 NH

H H

NH

H H

most stableH

NH

HH N

H

HH N

H

HH

NH

HH N

H

HH

Protonated pyrroles ≈ iminium ionsReactive intermediates in many react.

Reaction with electrophiles - E-fil Ar. Subst.

NH

ENH

EH N

H

EH N

H

EH

- HNH

E

React. i 2-pos - Best stabilized intermed.

NSi

ENSi

NSi

HH

HH

- HNSi

E

Steric hindrance in 2-pos.

•Nitration•Sulfonation•Halogenation•FC-acylation•(FC-alkylation)

NH

NH

E H

NH

E HE

- H

React. in 3-pos - Best stabilized intermed.

NH

E

NH

HNH

HH

Decomposition

React. under strongly acidic conditions

NH

HH

Nu Iminium ion

Reaction with electrophiles - E-fil Ar. Subst.-Halogenation

NR

"X+"NR

X

Mechanisms may be complex

NR

1) LDA2) "X+"

NR

X

NH

"X+"NH

XX

X X

NBoc

(NBS)NBoc

BrBr

NN

O Br

BrO

AIBNNBoc

Br

N OOBr

NSi

NBS (1 equiv.) NSi

Br

Steric hindrance in 2/5-pos.

NBS (1 equiv.) NSi

BrBr

NH

EWG

ex. -CO2Medeactivatingm-directing

Br2

NH

EWG

Br

N XR=H: UnstableR=EWG (i.e. Boc): More stable

R

Haloindoles (esp. 2-halo-) unstable

Reaction with electrophiles - E-fil Ar. Subst.-Acylation

NSO OPhEWG

Deactivating

Lewis acid requir.

AcClAlCl3

N

OAc2OBF3

NPhO2S

O

Strong L.A.Strong E+

Weak L.A.Weak E+

SO2Ph

NH

Ac2ONH200 oC O

major prod.

NH

minor prod.

O

NO

not formed

NO

NN

O

NMet

Met: i.e. TlAc2Oor AcCl

H+/H2Oor OH-

NH

Ac2O140 oC N

O

O

NH

O

Base

NAc2O

N

O

NH O

HNH H

O

NH

O

Reaction with electrophiles - E-fil Ar. Subst.

-Alkylation

NR

RX, Lewis acid

F.C.-alkyl.

Low reactivity, unselective, polymerization etc

-HNR

NR

MeMeI110 oC

Scatole

Me-I

NR

Me Me

NR

MeH

Me

NR

Me

Me

Plancher rearrangement

NR

Me Me

Me

NR

X Lewisacid

NR Plancher

rearrangementNR

Reaction with electrophiles - Condensation with aldehydes / ketones

NH

H+, RCHONHR=H, alkyl H

OHR

H±H+

NH R H

OH2- H2O N

H RH Polymer

red.

NH R

Reductive trapping sometimes possible

With electron rich arylaldehydes

NH

NMe2O

NH

N

NH

N

NH

NH

NH

NH

ONH

NH

Indoles

2:1 adducts

NH

R

EWGH+, MeCHO

NH H

Me

EWG

RNH

R

EWG

NH

R

EWG

MeNH

EWG

R

NH

H+, RCR'ONH

RR'

Somewhat more stable

Application in Porphyrine Synthesis

NHNNH

N

NNN

NMet

NNN

NMg

O

CO2MeH

H

HO

O

Chlorophyll A

NNN

NFe

CO2H

CO2H

Heme

•Hemoglobine•Myoglobine•Cytochromes

NNN

NCu

Copper PhtalocyaninBlue synthetic dye

Vit. B12

Application in Porphyrine Synthesis

NH N

H H

OH

NH

OH2NH

H+, CH2O

R=H, alkyl

±H+

- H2OPolymer

React. under acidic conditions

NH

K2CO3(aq)

NO

N HOH

±H+

NH

OH

React. under alkaline conditions

No highly reactive iminium salts

NH

OHHO

NH

HCl (0.15M)

NH

NH

NH

NH

OHHO

BF3N

HNNHN

NH

HNNHHN

Porphyrinogen

Chloranil

Porphyrin

NHNNH

N

Reaction with electrophiles - Condensation with Imines / Iminum Ions

OH

OHNu

Nu

ONu

OHNu

Aldehyde / KetoneProtonatedAldehyde / Ketone

NH

NHNu

Nu

NNu

NHNu

R

R R

R

Imine Iminium ion

NH

HNH

Iminium ionH

NH

HH

HH N

HNH HNH

H

H- NH HNH

Enamine

H

NH HNH

Iminium ions

HH

POLYMERHCl 6M, 0oC, 30 sec

Pyrrole punstable in acidic media

Reaction with electrophiles - Condensation with Imines / Iminum IonsMannich react.

CH2O, R2NH, H+

NR

RNH iminium ion gen. in situ

NH

HNR

RH-

NH

N RR N

H

CH2O, R2NH, H+

NR

R

H-NH

NR

R

acidic cond.

N CH2O, R2NH NNR

R

Neutral cond. 0 oC

AcOH

Vilsmeier react. (Vilsmeier-Haack): Formylation

NH

DMF, POCl3NH

O

NOP

O

ClClCl N

OPO

ClCl

Cl

NCl

ClNH

NH

HNCl-H

NH

NCl

NH

N

Cl

H+/H2ONHO

NH

1) POCl3, DMF2) H+/H2O

NH O

Generation of Vilsmeier reagentE-fil Ar. subst.Hydrolysis of iminium salt

NH

N MeXN

N

HN

Nu

Hsoft Nu(malonate etc.)

NH

Nu

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

BaseN N N

pKa 17.5

NH

pKa 44NH

pKa 16.2

N-alkylation favoured by:-Ionic N-Met bond (Li)-High solvating power of solvent (DMF, DMSO etc., crown ethers, PTC)

NH

BaseNMet R-X

R-X

R-X

NR

NRH

±H+

NH

R

N

RH ±H+

NH

R

C-metallation and further react.

NR

BuLiNR

Li

TMS-Cl NR

SiMe3

Bu3SnClNR

SnBu3

MgX2

NR

MgXB(OMe)3, H3O+

NR

B(OH)2Suzuki

Stille

NBS

NR

Br

ZnX2

NR

ZnXNegishi

R-X

NR

R

RCOX

RR'CO

NR R R

OHNR

O

R

NR

BrBuLi

NR

LiE

NR

E

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

ENR

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

Radical Reactions

NR

R=H

Decomposition ("Tar")

R≠HBu3SnHAIBN N

RSnBu3

(PhCO2)2

NR

OCOPh

+ 2,6-disubst

NR

(PhCO2)2NR

OCOPh

NOTs

X

Bu3SnHAIBN

NX

X=H NSnBu3

NX=Br

Cyclo Additions

NH

+NH

low yield

HN

The less aromatic furane reacts

NEWG

EWGR

(or alkene)

N-EWG

R

EWGPyrrole as diene (4π component)

Vinylpyrrole as diene

NSO2Ph

OO

O

NPhO2S

H OO

ON

PhO2SO

O

O

Pyrrole as dienophile (2π component)

EWG: Less interact. Between Lone pair on N and “diene”

NNN

N N NNN N N

H

H

H

H - N2N N- H2

A few intramolek. ex.

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 nN

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

Reaction with carbenes / carbenoids

NR

R'R''

NR

R'R'' Rearrangements

NH

N

ClCl

H N

Cl

-HCl

Indoles: No cyclopropanes isolated from carben(oid) react.

Pyrrole / Indole Carboxylic Acids

NR

CO2R1Ringsynthesis

NR O

O ENR O

OE-CO2

NR

E

E: H, halogen

Also decarboxylation of indole carboxylic acids

Oxypyrroles

NH

OH NH

ONH

O

Major tautomer

NH

O NH

O

NB! sp3 C NB! sp3 C

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

NH

OH

NH

O

NH

O

NH

O H

RO N

H

O

RO

O OH

O O

Aminopyrroles-Amino (not iminoform) - unstable

Aminoindoles

NH

NH2 N NH2 N NH23-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- HNH

NX

XNu

No Nu substin pyrrole ring

Nu

Nu-subst if X α or γ to N

Synthesis of Pyrroles and IndolesCarbonyl 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

CO2HO2CHO OH

RNH3

ΔOO

HO2C CO2H

RNH2

NR''

OHCO2H

HOHO2C - 2 H2O N

R''CO2HHO2C -2 CO2 N

R''

R, R' = H: OO Unstable

Synthons:

O OMeMeO OHHOCO2HO2C

HO OH

BuNH3

X

a

bX

X

X

c

Not useful for indoles

NR

X

OR

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

R4R2R5

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/bX

ORCl

CO2R3

O R4

NR'

R R4

CO2R3

NH2R'

OHR4

CO2R3

HNR'

CO2R3

NR'

R4

imin

taut.CO2R3

HNR'

R4

enamin- HCl- H2O O

RN

R4

CO2R3

R'imin

taut.

OR

HNR4

CO2R3

R'enamin

N

CO2R3

R4R'

RHO

HH

- H2O

ORClR, R4: alkyl, aryl

R': H, alkyl, arylCO2R3

O R4 NR'

R R4

CO2R3

May be removed;hydrol, decarbox.NH2

R'

X

a

bX

X

X

c

Strategy cX

a

bX

X

X

c

R2

RO

O

R, R2: H, alkyl, aryl

HNR'

CO2R3

glycine der.

R2

R OHO N

R'- H2O

R2

R ONR'CO2R3 CO2R3

Base

R2

R ONR' CO2R3

N

R2OH

CO2R3

H

R'R - H2O N

R'CO2R3R

R2

R2

O

HNTs

CO2R3

R2

R ONTs CO2R3

Base

R2

R ONTs CO2R3

N

R2OH

CO2R3

H

TsR - H2O N

R2

CO2R3

H

TsR

BaseHN

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

OCO2Et

H2 / cat.

NH2

OCO2Et

-H2O NH

CO2Et

N O

O

- Modified Reissert synth.; Leimbruger-BatchoCH3

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

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

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

HR

SMeH2 / cat.

NH

R

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

bc

d e d e

cb

a

X X

alkene / alkyne1,3-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:N

NN

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

O O- CO2 N

H

R R2

R4R3

O

HN R4

O

R3O

N R4

O

R3H

- 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

NO2Δ

N

NO2

NH

NO2

N+H R NH

RR 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

REWG

EWGBaseH

NTs

I

R EWG N

I

R EWG

tautHH

HH H

H

NH

I

EWGR

JOC 2003, 7853R

HN'R

R: alkyl, alkenyl

cat. Pd(II) or Cu(II)

NR'

R R

HN'R

Metn+

NR'H

RMet

(n-1)+

- Metn+NR'

R

H tautHH

H

H NR'

R

R

HN'R

R: H, Ph, THP

NR'

Spont.1) PBr32) R'NH2 RR

OH

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

Miscellaneous indol syntheses

Bartoli synthesis

NO

O XMgNO

O

MgX

NO XMg

N OMgX

O

NMgX

N

HOMgXH

H XMg

NOMgXH

MgX-H2O

H+

NH

Fürstner synthesisO

ClNO2

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

NH OCOMe

CO2MeOH

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

Vinca alkaloidsfrom Vinca roseaAnticancer comp.