Chapter 13Pyrroles

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

Protonated pyrroles ≈ iminium ionsReactive intermediates in many react.

NH

HNH

HH

Decomposition

React. under strongly acidic conditions

NH

HH

Nu Iminium ion

Reaction with electrophiles - E-fil Ar. Subst.

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

NSi

ENSi

NSi

EH

EH

- HNSi

E

Steric hindrance in 2-pos.

-Halogenation

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

-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

NH O

HNH H

O

NH

O

-Alkylation

NR

RX, Lewis acid

F.C.-alkyl.

Low reactivity, unselective, polymerization etc

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

2:1 adducts

NH

R

EWGH+, MeCHO

NH H

Me

EWG

R

NH

R

EWG

NH

R

EWG

MeNH

EWG

R

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

O

Nu

OHNu

Aldehyde / KetoneProtonatedAldehyde / Ketone

NH

NHNu

Nu

N

Nu

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 unstable in acidic media

Mannich react.

CH2O, R2NH, H+

NR

RNH iminium ion gen. in situ

NH

HNR

RH-

NH

N R

R

Vilsmeier react. (Vilsmeier-Haack): Formylation

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 nucleophiles

Electron rich ring - not very reactive towards Nu

NH

NO2

O2NNu

NH

Nu

O2N

Reaction with base and further react. with E-files

NH

BaseN N N

pKa 17.5

NH

pKa 44

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

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

O

O

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.

Reaction with carbenes / carbenoids

NR

R'R''

NR

R'R'' Rearrangements

NH

N

Cl

Cl

H N

Cl

-HCl

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

Pyrrole Carboxylic Acids

NR

CO2R1Ringsynthesis

NR O

O ENR O

OE

-CO2NR

E

E: H, halogen

Oxypyrroles

NH

OH NH

ONH

O

Major tautomer

NH

O NH

O

NB! sp3 C NB! sp3 C

NH

OH

NH

O

NH

O

NH

O H

RO N

H

O

RO

O OH

O O

Aminopyrroles-Amino (not iminoform) - unstable

Synthesis of PyrrolesCarbonyl 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

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

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

RN

R4

CO2R3

R'imin

taut.

OR

HNR4

CO2R3

R'enamin

N

CO2R3

R4R'

RHO

HH

- H2O

OR

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

CO2R3

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.

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

bc

d e d e

cb

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: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

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

R

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