2 – Friedlander's synthesis
It involves the condensation of α aminobenzaldhyde with acetaldehyde
in the presence of an alkali
H
C=O
+
N:
H
CH3
|
CH
H
O
H
C CH
3
NaOH
-H2O
N
O
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CH
-H2O
H
C
N
CH
CH
1
3 – Dobner – Miller synthesis .
consist of heating primary aromatic amine with aldehyde or ketone
in presence of conc . HCl
NH2
O
+ 2CH3 - C - H
N
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CH3
2
Mechanism
O
OH
-
CH3 - C - H
O
+ H CH2 - C - H
CH3 - C - H
O
CH3 - CH =CH - C - H
-H2O
O
CH2 - C - H
ald . Cond
H OH
C
H CH
H
H
C=O
H
CH
||
CH - CH3
+
N
..
N
H
-H2O
CH - CH3
CH
CH
N
H
CH - CH3
-H2
N
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CH3
3
4 – Condensation between β ketonic ester and primary aromatic amine produces
quinolines .
EtO2C
H
EtOOC
NH2
CH2
+
C - CH3
O
Room
temp
- H2 O
N
H
CH
CH - CH3
250 C0
-EtOH
O
C
OH
CH
N
H
CH - CH3
N
CH3
4 - hydroxy - 2 - methyl quinoline
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4
OR
O
CH3
C
NH2
+
CH
EtOOC
110 C0
-EtOH
N
H
CH3
C
CH
CH3
N
CH3 - CO
H CH
2
OH
N
H
C=O
H2SO4
-H2O
OH
CH3 - C
H CH
C =O
N
H
C=O
2 - hydroxy - 4 - methyl quinoline
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5
Isoquinoline
Isoquinoline contain a benzene ring fused as shown with a
pyridine ring .It closely resembles quinoline in physical and
chemical properties .
5
4
6
3
7
N2
8
1
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6
It isolated from coal – tar in the form of a sparingly soluble sulphate ,it also found
as a part of the total structure of a number of alkaloide e.g. papaverine and
morphine .Isoquinoline is one of the very few heterocyclic compounds in which
numbering of the ring atoms does not start on the hetero atom as in the case of
naphthalene the numbering starts adjacent to the benzene ring .The bicyclic
structure was first proposed on the basis of oxidation to phthalic and pyridine 3,4
– dicarboxylic acid .
N
COOH
KMnO4
HOOC
+
COOH
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HOOC
N
7
The chemical reactions as in the case of quinoline suggest that the
symmetrical double bond structure is the major contribiotor to the
hybrid .
Calculation of the π electron densities at the various position in the
ring are as follows .
0.94
1
0.94
0.94
0.98
N 1.59
0.11
0.95
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8
Isoquinoline is a resonance hybrid of uncharged structure (1,1a and
1 b ) and charged structure ( 1c and 1d )
N
N
1
N
1b
1a
+
N+
N-
1d
1c
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9
Chemical reaction
Isoquinoline resemble quinoline in many ways
1 – Basicity
Isoquinoline is a stronger base than quinoline
N
N
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10
2 – Addition and ring opening
Isoquinoline reacts with alkylating agents at the nitrogen atom give
quaternary salt such as ( 2 ) the corresponding hydroxide (3) is
obtain when treated with sodium hydroxide which is in equilibrium
with ( 4 ) (1,2 – hydro – 1- hydroxy – 2 – methylisoquinoline ) and
on oxidation give isoquinoline ( 5 ) .
Me+ I-
+
N
..
NMe
I-
NaOH
(2)
HO
(4)
NMe
H
+
NMe
OH-
(3)
K3[Fe(CN)6]
NMe
O
(5)
NMe
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O
N - methyl isoquinolinone
11
1,2,3,4 – tetrahydroisoquinoline when treated with excess methyl
iodide followed by alkali give 1,2,3,4 – tetrahydro – 2,2 – dimethyl
isoquinolinum hydroxide ( 7 ) which on degradation by Hofmann's
method the rings breaks between position 2 and 3 giving ( 8 ) .
H
1-MeI( excess )
NH
(6)
+ NMe2OH-
2-NaOH
H
H
OH
H
-H2O
NMe2
(7)
NMe2
( 8 ) N,N - dimethyl - 2 - vinylaniline
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12
Reduction
Na
NH NH (liq)
3
1,2 - dihyd
-H
2
Na
H2/Pt
NH
-3H2
NH
decahydroisoquinoline
-2H2
Sn / HCl
NH3(liq)
-H2
N
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13
Electrophilic substation
Should give the 5 – substituent isoquinoline ( see the π electron
density picture ) . Nitration occurs at position 5 and 8 in isoquinoline
the former agrees with expectation from charge densities , but
position 7 would have bean expected to be the next position to
attacked .
NO2
N
HNO3(conc)
H2SO4
N +
NO2
SO3H
H2SO4
(conc)
N
N
Br
Br2
N
H2SO4
Br2
AlCl3
(5),(5,8),(5,8,7)
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14
Nucleophilic subistitution
Should take place at position ( 1 ) in agreement with the π
electron density calculation .
N
NaNH2
N
NH2 1 - amino isoquinoline
NaOH
fusion
N
OH 1 - hydroxy isoquinoline
CH3I
N
CH3 1 - methyl isoquinoline
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15
Synthesis of isoquinoline
1 – Bischler – Napieralski synthesis
Acyle derivatives of β phenyl – ethylamine are cyclised by
treatment with acids after ( P2O5) to yield dihydroisoquinoline
,which can then be aromatized as shown .
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16
CH2
CH2
CH2
NH
NH
H
C
CH3
OH
O=C
CH3
keto form
N - ( 2 - phenyl ethyl ) acetamide
CH2
CH2
P2O5
-H2O
C
CH2
N
CH3
enol form
- H2 Pd / C
PCl5
-POCl3
CH2
+
Cl
Cl
N
CH2
N-H
C
CH3
CH3
AlCl3
1 - methyl isoquinoiline
-HCl
-HCl
CH2
H
Cl
CH2
N
C
CH3
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17
Pictet and Gams synthesis
R
OH
C
CH2
NH
OC
'R
P2O5 boil
toluene
-H2O
N - acyl -2-alkyl - 2 - hydroxy
2 - phenyl ethane amine
R
C
-H2O
R
C
R
C
CH.
NH
CH
H N
HO - C
|
R'
O=C
'R
keto form
enol form
CH
N
C
'R
1,4 - dialkylisoquinoline
Pictet and spengler synthesis
CH2
CH2
NH2
O
+R-C-H
N
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18
Mechanism
CH2
+
O
CH2
CH2
NH2
CH2
CH2
-H2O
N
CH
NH
R - CH
-
CH2
shift base
R
OH
R-C-H
+
CH2
CH2
CH2
-
H
NR-C +
+
R-C
H
CH2
CH2
NH
NH
C
R
CH2
H
1 - alkyl - 1,2,3,4 - tetrahydro
H
-2H2
N
R
1 - alkyl isoquinoline
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19
Pomeranz and Fritsch synthesis
Start from aromatic aldehyde converted into shift base with
aminoacetal followed by cyclization gives isoquinoline .
H2NCH2CH(OEt)2
CHO 2 - diethoxy ethan amine
N
benzaldehyde
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20
Mechanism
OH H
OEt
C=O
+|
H
HO
HC
CH2
NH
C
H OH
+
OEt
H OEt
CH
CH
CH2
CH2
|
:NH2
C
H
OH
H
C
H
OEt OH
-3H2O
C
H
H2SO4
hydrolysis
NH
OH
CH
N
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21
Quinolizine
Although a number of alkaloide are complex derivative of
Quinolizine, some time called pyridocoline , the parent compound
has attracted attention only in recent year
9
1
2
8
+
N
7
6
5
3
4
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22
Synthesis
- +
CH2Li
N
OδCH2
OLi
CH
N
CH2
HC
2
OEt
H-C
+δ CH2
+
CH2
EtO
H
H
OH-
CH2
OH
CH
N
CH2
CH2
OEt
H2O
H+
H
OH
H+ IK2CO3
N
+
I-
Ac2O
concH2SO4
-H2O
Pd
N
-H2
+
H
-I
H
N
+
+ Halide ione
quinolizinium cation
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23
Properties
All efforts to prepare Hquinolizine which can be written in three
structure have been unsuccessful although complex derivatives
of both 4H and 9aH – Quinolizine are well known
N
+
quinolizinium cation
8
9
9 9a 1
2
N
7
6
5 4
3
9aH -quinolizine
1
8
N
7
6
5 4
9
2
8
3
7
2
N
6
2H -quinolizine
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1
5 4
3
4H -quinolizine
24
Reduction
NaBH4
EtOH
N
+
+
N
tetrahydro -
N
decahydro -
Ring opening
H
OH
N
+
I-
NaOAC
-H2O
H
C-H
+C
H H
-H+
N
N
2 - butadienyl pyridine
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25