the pyrrole - reactivity

The Pyrrole - reactivity

HN

Jan Lewtak

Pyrrole - numbering

NH1

2

34

5

Plan of the lecture. Review of the reactions with pyrrole

Electrophilic attack at carbon Condensation Oxidising Reducing Cycloaddition Toxicity

Protonation

Stability:

Most stable medium least stable

NH

NNH

+ H++ H+

H

H

H H

++N

H

HH

No mesomeric stabilisation

Nitration & Sulfonation

NH

NH

NH

NO2

NO2AcONO2AcOH, -10°C

4 : 1

NH

NH

SO3H1) PySO3, 100°C2) H+

Halogenation

NH

1) or 2) or 3)

NH

X

XX

XNH

ClSO2Cl2 (1equiv)0°C

X = Cl(1), Br(2), I(3)1) SO2Cl2(4equiv)2) Br2, 0°C3) KI, AcOH

Bromination

NH

N

Boc

Br

1) bromohydantoin, AIBN2) (Boc)2O, NEt3

N

N

Boc

NBS, THF, -78°C

N

Boc

Br Br

Sii-Pr3

NBS, THF, -78°C

N

Sii-Pr3

N

Sii-Pr3

Br Br Br

1equiv NBS 2equiv NBS

Acylation

NH

NH

CCl3

O

Cl3CCOCl

NH

Vilsmeier formylationDMF, POCl3

NH

H

O

N

Tos

PhCOOH, TFAA

N

Ph

OTos

MeCOCl, AlCl3

N

Tos

OFriedel - Crafts acylation

Modified Vilsmeier method:

NH

DMF, oxalyl chloride

NH

CN

Acylation

NH

R

O

NH

O

R

RCOCl, AlCl3

NH

R

O

O

R

Basic conditions

N

PG

1.BuLi 2. PhCONR2 3.OH-

NH

Ph

O

Alkylation

NH

CH3I orBr

poly-alkylated derivatives, oligomers

NH

PhSOCH=CHCOMe

NH

O

98%

NH

EtO2C CO2Et

N2

NH CO2Et

CO2Et

71%

Condensation

NH

HCHO, Na2CO3

NH OHHO

NH

NH

N

NH

N

p-Me2NC6H4CHO

HCl, EtOH

84%

90%

coloured

Condensation of pyrrole with itself

NH

NH

H

H+

N

H

HH

HClconc

NH HN

H+

NH HN

H

H

pyrroleNH HN

HN

polymer

Oxidising of C-substituents

NH

NH

CHOOHC

N N CHOOHC

NH

PG PG

EtO2C CO2Et

NH

CHOOHC

EtO2C CO2Et

CAN, 8equiv

CAN, 8equiv

CAN, 8equiv

MeCN/H2O

MeCN/H2O

MeCN/H2O

25%

20%

15%

NH

Me

EtMe

EtO2CCAN, THF, AcOH

NH

EtMe

EtO2CO

H

Mr Voloshchukconditions

Oxidation of the heterocyclic ring

N

O

CO2ButNO

O

CO2ButOH

CO2Me

N

O

N

O

O

CO2But

lactam cleavage product epoxide

45% 35% 10%

O2

Reactions of C-metallated pyrroles

N

n-BuLiN Li

85% MgBr2

N MgBrN Br

PdCl2N

N

EtI

N Et

N

Boc

Br Br

1) BuLi, THF2) CO2

N

Boc

HO2C CO2H

Reactions of C-metallated pyrroles

N

CO2But

SnMe3 N

CO2But

Br Br 30%N

CO2ButN

CO2But

N

CO2But

tripyrrole

NH

NH

OPOCl3

NH

N NH

NH

Pd-C

NH

NH

NH

N

Pd-C

bipyrrole

Reducing in acidic conditions

NH

NH

NH

Zn, AcOH

25%

H2, Pt, AcOH

63%

Decarboxylation, bromination and formylation of carboxylic derivatives

NH

CO2H

Me Me

NH

Me MeNH2C2H4OH

NH

CO2EtBr2, Py

NH

CO2Et

Br

75%

50%

NH

EtO2C

MeOCHCl2

AlCl3, DCM80%

NH

EtO2C

CHO

Cycloaddition

N

CO2EtOTMS

CO2Et

17%N

CO2Et

CO2EtOH

N

Ts

Br

Br

BrBr

NH

Br

Br

And now… important type of reactivity in laboratory work. „In vivo” reactivity.

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