2 – friedlander's synthesis
DESCRIPTION
2 – Friedlander's synthesis . It involves the condensation of α aminobenzaldhyde with acetaldehyde in the presence of an alkali . 3 – Dobner – Miller synthesis . consist of heating primary aromatic amine with aldehyde or ketone in presence of conc . HCl . Mechanism . - H 2 O. - PowerPoint PPT PresentationTRANSCRIPT
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2 – Friedlander's synthesis
+
CH3|CH
O
NaOH-H2O
C = OH
N :HH
CH
N CH
OCH3
-H2O
CHN
CH
CH
It involves the condensation of α aminobenzaldhyde with acetaldehyde in the presence of an alkali
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3 – Dobner – Miller synthesis .
NH2
+ 2CH3 - C - H O
N CH3
consist of heating primary aromatic amine with aldehyde or ketone in presence of conc . HCl
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-
ald . Cond
CH3 - C - H O
CH2 - C - H O
H+ -
-H2OCH3 - CH =CH - C - H
CH3 - C - H
OH
CH2 - C - H O
O
N H
H..
HC = O
CH ||CH - CH3+
-H2OH
NH
CH - CH3
CHC
OHH
CHCH
CH3NH
CH - -H2
N CH3
Mechanism
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4 – Condensation between β ketonic ester and primary aromatic amine produces quinolines .
NH2 250 C0
-EtOH
H
NH
CH - CH3
CH
EtO2C
CH
CH3NH
CH - N CH3
OH
+
EtOOC CH2
C - CH3O
Room
temp
C
O
4 - hydroxy - 2 - methyl quinoline
-H2O
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OR
NH2 110 C0
-EtOH+
C O
CH EtOOC
CH3H
NH
C = O
CH3 - CO
CH2 H2SO4
-H2O
H
NH
C = O
CH
CH3 - COH
CH
2 - hydroxy - 4 - methyl quinoline
CH3
N OH
CH3 C
C =ONH
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Isoquinoline
N1
2
3
45
6
7
8
Isoquinoline contain a benzene ring fused as shown with a pyridine ring .It closely resembles quinoline in physical and chemical properties .
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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 .
NCOOH
COOH+ NHOOC
HOOCKMnO4
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The chemical reactions as in the case of quinoline suggest that the symmetrical double bond structure is the major contribiotor to the hybrid .
N0.11
1.59
0.94
0.941
0.94
0.98
0.95
Calculation of the π electron densities at the various position in the ring are as follows .
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N
1N N
N - -N+
1a 1b
1c 1d+
Isoquinoline is a resonance hybrid of uncharged structure (1,1a and 1 b ) and charged structure ( 1c and 1d )
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Chemical reaction Isoquinoline resemble quinoline in many ways 1 – Basicity Isoquinoline is a stronger base than quinoline
NN
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2 – Addition and ring opening
NMe+ I-
.. NMe+ I- NaOH
( 2 ) ( 3 )
OH-+NMe
HHONMe
K3[Fe(CN)6]NMe
O-( 4 ) ( 5 ) N - methyl isoquinolinone
NMe
O
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 ) .
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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 ) .
NH1- MeI( excess )
NMe2OH-
2- NaOH
)7(
)8 ( N,N - dimethyl - 2 - vinylaniline
NMe2
+NMe2
OHH
H
H H-H 2O
)6(
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NHNa
NHNH3(liq)
1,2 - dihyd -H2
H2/Pt
-3H2NH
Na
N
NH3(liq)-H2
-2H2Sn / HCl
decahydroisoquinoline
Reduction
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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 .
NHNO3(conc)
H2SO4 N
NO2
+ N
NO2
H2SO4(conc) N
SO3H
H2SO4
Br2
N
Br
Br2
AlCl3( 5 ) , ( 5 , 8 ) , ( 5 , 8 , 7 )
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Nucleophilic subistitution
NNaNH2
N
NH2
NaOH
fusion
CH3I
1 - amino isoquinoline
N
OH 1 - hydroxy isoquinoline
1 - methyl isoquinoline
N
CH3
Should take place at position ( 1 ) in agreement with the π electron density calculation .
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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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Cl
CCH3
-HCl
AlCl3
-HCl
CH2 CH2
NHO = C
CH3
keto formN - ( 2 - phenyl ethyl ) acetamide
COH
CH3
CH2 CH2
H
enol form
P2O5-H 2O N
C
CH2CH2
CH3
-H 2 Pd / C
N
CH3
1 - methyl isoquinoiline
PCl5-POCl 3
CH2 CH2
N - H CCH3
ClCl-
+
N
CH2 CH2
H
NH
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CR OH
CH2NH
OC 'R
P2O5 boiltoluene-H2O
C CH.NH
O = C 'R
R
C CH N
R
HHO - C | R'
N - acyl -2-alkyl - 2 - hydroxy2 - phenyl ethane amine
keto form enol form
-H2O C CH N
R
C'R
1,4 - dialkylisoquinoline
Pictet and Gams synthesis
CH2 CH2
NH2+ R - C - H
O
N
R
Pictet and spengler synthesis
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-2H2N
R1 - alkyl isoquinoline
-CH2
N -
CH2
HR - C H
+
CH2
NH
CH2
R - C H
+
CH2
NH C
R H
CH2
1 - alkyl - 1,2,3,4 - tetrahydro
CH2 CH2
NH2+
R - C - H
O -
+
-H 2OCH2
NH
CH2
R - CH OH
CH2
N
CH2
CH R
shift base
Mechanism
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Pomeranz and Fritsch synthesis
CHO
H2NCH2CH(OEt)2
2 - diethoxy ethan amine
benzaldehyde
N
Start from aromatic aldehyde converted into shift base with aminoacetal followed by cyclization gives isoquinoline .
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C = O |H
+ -+
CH2 |:NH2
OEt OEt
CH
C NH
CH2
OHH
OEt OEt
CH
OHH
H
OH
H2SO4hydrolysis
OHHO
H OH
HCH CH2NH
C-3H2O C
H
NCHC
H
Mechanism
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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
N
12
3
456
7
89
+
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H+ I-K2CO3
I-N
H HOH
+Ac2O concH2SO4
-H2O-H2
Pd N
HH
+N+
+ Halide ione
quinolizinium cationI-
N
CH2Li- +
+
H - C CH2CH2EtO
O
+N
CH2 OLi
OEt2HC
CH2
CH
H OH-
H2OH+ N
CH2 OH
OEtCH2
CH2
CH δ
-δ
Synthesis
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Properties
N+
quinolizinium cation
9aH -quinolizine
N
12
3456
7
89 9a
98
76 5 4
3
21
N
2H -quinolizine
98
76 5 4
3
21
N
4H -quinolizine
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
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N
+
NaBH4EtOH N + N
tetrahydro - decahydro -
NaOAC -H2ON
+
HOH
I -N C - H
C HH
H
+N
-H+
2 - butadienyl pyridine
Reduction
Ring opening