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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).
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
2
Doebner-von Miller Variation of the Skraup Reaction
Overall transformation R3
R3
R2 R2
O
NH2 N R1
R1
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
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
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 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
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
NH N
CH3 CH3
H3C H2C
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.