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)

C OH
HO C
C
NH2 HO N

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

R3 R3
C R2 R2
O C
NH2 C N R1
R1

Friedlaender Synthesis of Quinolines (1882)

O H R R3
2
C H C R2
R3
C
O R1
NH2 N R1

Conrad-Limpach Synthesis of Quinolones (1887)

O R
O O
C C and/or
NH2 R C OR1
N R N O
H H

Combes Synthesis of Quinolines (1888)

O R1
C R1
C
NH2 C R1
O N 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).

1
 Skraup Synthesis of Quinolines

Overall transformation
PhNO2 5 4
OH 6 4a
HO c. H2SO4 3
R R
7
NH2 HO 130 oC 8a N 2
8
1

H
H
OH H H
HO O tautomerize
glycerol acrolein
O
HO -H2O HO -H2O
H
Glycerol is dehydrated in situ to give acrolein.

Mechanism H
O
H
OH O
H -H
H H
NH2 tautomerize
N N
H2 H

OH OH OH
H
re-aromatize
H
N -H N
H H N
H

+H -H2O

oxidation*

N 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.

2
 Doebner-von Miller Variation of the Skraup Reaction

Overall transformation R3
R3
R2 R2
O
NH2 N R1
R1

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

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

R3
R2 O
O
1,4-addition R2
R3
R1
NH2
N R1
H
R1
R2 1,2-addition R1
R2
NH2
O R3 X
N R3

H
crotonaldehyde
O O

CH3 H
NH2 N CH3
N CH3
H 2-methylquinoline
(quinaldine)
CH3 methyl vinyl ketone
O CH3
O
CH3
NH2 N
H N
4-methylquinoline
(lepidine)

3
 Skraup / Doebner-von Miller Syntheses:
using substituted anilines

para-substituted aniline
O
O
R R R

NH2 N N
H
6-substituted isomer
both positions ortho to the R R
amine are equivalent R
NH N
N
O

ortho-substituted aniline
O 8-substituted isomer
O

H
NH2 N
N
R H R
R

can only cyclize to the unsubstituted ortho position

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

O
7-substituted isomer
O
favoured

R NH2 if R is +M R N
R N
H +
can cyclize to either ortho
positions but this gives rise 5-substituted isomer
to two possible isomers R
favoured
R NH R N
if R is -M
O 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.

4
 Conrad-Limpach Synthesis of Quinolones

Overall transformation
O CH3
O O

H3C OEt and/or

NH2 N CH3 N O
β-ketoester H H

water must be removed using

Mechanism a Dean-Stark trap or MgSO4 O O

H3C OEt
between RT and 110oC
NH2
CH3 O cat. H -H2O
N OEt imine formation is still
150oC
faster, but reversible
imine-enamine -EtOH
if water is not removed
tautomerization

O thermodynamic OH

EtO kinetic product H3C

product
N CH3 N O
H H

Ph2O, heat +H c.H2SO4

~250 oC

EtO O HO CH3
H H

N CH3 N O
H H

-H -EtOH -H -H2O

O CH3

N CH3 N O
H H
4-quinolone 2-quinolone

5
 Friedlaender Synthesis of Quinolines
Overall transformation
O H R3
R2
H R2
R3
O R1
NH2 N R1

Mechanism - using an unsymmterical dialkyketone as an example

CH3
CH3 -H+ / -H2O
H CH3 base conditions and
imine formation O
O H lower T leads to
O CH3 N kinetic product
NH2 CH3
H3C

c. H2SO4, AcOH, ∆ aq. KOH,EtOH, 0 oC

different reaction
acid conditions and conditions will
higher T leads to OH
alter ratio of
O
themodynamic product enamines formed
CH3 CH3

NH N
CH3 CH3
H3C H2C

more substituted enamine less substituted azaenolate

(thermodynamic product) (enamine anion) (kinetic product)

acid catalyzed base catalyzed

aldol-like reaction aldol-like reaction

HO CH3 H3C O
CH3
H
N CH3 N CH2CH3
H

-H -H2O -H2O

CH3 CH3
CH3

N CH3 N 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.