CLASSICAL METHODS OF SYNTHESIZING QUINOLINES

The most obvious starting material for making a quinoline is aniline (aminobenzene) as this
and substituted variants can be readily obtained (e.g. via the sequence of nitration and NO2
reduction).

Skraup Synthesis of Quinolines (1880)

HO

HO

NH2

C
C

OH
N

Doebner-von Miller Variation of the Skraup Synthesis (1887)

R3
C

NH2

R3
C
C

R2

R2
N

R1

R1

Friedlaender Synthesis of Quinolines (1882)

O
C

R3

H R
2
H C
C
O
R1

R3

NH2

R2
N

R1

Conrad-Limpach Synthesis of Quinolones (1887)

O

NH2

O
C

O
C

R
and/or

OR1

N
H

N
H

Combes Synthesis of Quinolines (1888)

NH2

O
C R1
C
C R1
O

R1

R1

This reaction will not specifically covered. The mechanism is basically like the first
half of the Friedlaender method (imine formation) and second half of the Skraup
(acid-catalyzed condensation of the second ketone with the aromatic ring).

Skraup Synthesis of Quinolines

Overall transformation
HO

HO

NH2

H
glycerol

5
6

130 oC

7
8

4a

8a

4
3

H
H

OH

HO

PhNO2
c. H2SO4

OH

-H2O

HO

tautomerize

HO

-H2O

H
O

acrolein

Glycerol is dehydrated in situ to give acrolein.

Mechanism

H
OH

H
NH2

N
H2

OH
re-aromatize

-H
tautomerize

H
N
H

OH

OH
H

N
H
+H

-H

N
H

N
H

-H2O
oxidation*
N
H

*oxidation can be acheived in situ by using nitrobenzene as co-solvent or by

using an oxdxant such as iodine or an iron(III) salt.

Doebner-von Miller Variation of the Skraup Reaction

Overall transformation

R3

R3

O
NH2

R2

R2
N

R1

R1

* Uses pre-formed ,-unsaturated carbonyl compounds instead of acrolein

* Used to provide alkyl and aryl substituents in the "pyridine half" of the quinoline
* The intermediate -aminocarbonyl compound can be isolated.
* Shows the mechanism starts with a conjugate addition.
R3
R2

O
R2

1,4-addition

NH2

R3

R1
N
H

R1

R1
R2
O

NH2

R3

R1

1,2-addition
R2

R3

crotonaldehyde
O

CH3
NH2

N
H

CH3

CH3

2-methylquinoline
(quinaldine)

CH3 methyl vinyl ketone

O

CH3
CH3

NH2

N
H

N
4-methylquinoline
(lepidine)

Skraup / Doebner-von Miller Syntheses:

using substituted anilines
para-substituted aniline
O
O
R

R
NH2

N
H

both positions ortho to the

amine are equivalent

6-substituted isomer

NH

ortho-substituted aniline
8-substituted isomer

O
H

NH2
R

N
H

can only cyclize to the unsubstituted ortho position

meta-substituted aniline - electronic and steric factors influence cyclization orientation
O
O

NH2

N
H

can cyclize to either ortho

positions but this gives rise
to two possible isomers

7-substituted isomer
favoured
if R is +M R

N
+

5-substituted isomer
R

favoured
R

NH
O

if R is -M

N
N

Rate of Reaction: as the ring acts as a nuclophile to attack the protonated aldehyde (see
previous slide), an electron withdrawing group R group slows the rate of cyclization whereas
an electron donating group increases the rate of cyclization.

Conrad-Limpach Synthesis of Quinolones

Overall transformation
O
H3C

NH2

CH3
and/or

OEt

N
H

-ketoester

CH3

N
H

water must be removed using

a Dean-Stark trap or MgSO4

Mechanism

O
H3C

between RT and 110oC

cat. H
OEt

imine-enamine
tautomerization
O

kinetic
product

EtO

Ph2O, heat
~250 oC

-H

OH

thermodynamic
product

H3C
O

N
H

c.H2SO4

+H

HO CH3
H
CH3

-EtOH

N
H

imine formation is still

faster, but reversible
if water is not removed

150oC
-EtOH

EtO O
H
N
H

OEt

-H2O

CH3

N
H

NH2

CH3 O
N

N
H
-H

-H2O

CH3

CH3

4-quinolone

N
H

2-quinolone

Friedlaender Synthesis of Quinolines

Overall transformation
O
H
H
R3

R2

R1

NH2

R3
R2
N

R1

Mechanism - using an unsymmterical dialkyketone as an example

CH3
O
NH2

H
H

-H+ / -H2O
CH3
imine formation

CH3

CH3

base conditions and

lower T leads to
kinetic product

O
N
H3C

CH3
aq. KOH,EtOH, 0 oC

c. H2SO4, AcOH,

acid conditions and

higher T leads to
themodynamic product

different reaction
conditions will
alter ratio of
enamines formed

OH

CH3

CH3

NH

N
CH3

H3C

more substituted enamine

(thermodynamic product)

CH3

H2C

less substituted azaenolate

(enamine anion) (kinetic product)

base catalyzed
aldol-like reaction

acid catalyzed
aldol-like reaction
HO

CH3
CH3
H
N
H

CH3

-H2O

-H

CH3

H3C

CH2CH3

-H2O
CH3

CH3
CH3

CH2CH3

Product distribution is dependent on both reaction conditions and the ketone used (see
Fischer indole synthesis for a related discussion). Even different acids (i.e acid strength)
can produce different product ratios.