1. 2 – Friedlander's synthesis
It involves the condensation of α­ aminobenzaldhyde with acetaldehyde in the presence of an alkali
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2. 3 – Dobner – Miller synthesis .
consist of heating primary aromatic amine with aldehyde or ketone in presence of conc . HCl
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3. Mechanism
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4. 4 – Condensation between β­ ketonic ester and primary aromatic amine produces quinolines .
- H2O
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5. OR
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6. Isoquinoline
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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7. 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 .
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8. 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 .
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9. Isoquinoline is a resonance hybrid of uncharged structure (1,1a and 1 b ) and charged structure ( 1c and 1d )
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10. Chemical reaction Isoquinoline resemble quinoline in many ways
1 – Basicity
Isoquinoline is a stronger base than quinoline
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11. 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 ) .
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12. 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 ) . NH 1-
MeI( excess ) N M e2 OH - 2-
NaOH
( 7 )
( 8 ) N,N - dimethyl vinylaniline e 2 + O H -H
( 6 )
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13. Reduction
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14. 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 .
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15. Nucleophilic subistitution
Should take place at position ( 1 ) in agreement with the π­ electron density calculation .
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16. 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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17. N - ( 2 - phenyl ethyl ) acetamide enol form3
-HCl
AlCl 2 N O =
keto form
N - ( 2 - phenyl ethyl ) acetamide
enol form P 5 -H
- H
Pd / C
1 - methyl isoquinoiline
PCl
-POCl - + NH
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18. Pictet and Gams synthesis
Pictet and spengler synthesis
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19. Mechanism C H 2 N +
R - C - H O - -H R
shift base
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20. Pomeranz and Fritsch synthesis
Start from aromatic aldehyde converted into shift base with aminoacetal followed by cyclization gives isoquinoline .
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21. Mechanism
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22. 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
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23. Synthesis δ -δ I-
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24. 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
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25. Reduction
Ring opening
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