2 – Friedlander's synthesis

1. 2 – Friedlander's synthesis It involves the condensation of α­ aminobenzaldhyde with acetaldehyde in the presence of an alkali lec10

2. 3 – Dobner – Miller synthesis . consist of heating primary aromatic amine with aldehyde or ketone in presence of conc . HCl lec10

3. Mechanism lec10

4. - H2O 4 – Condensation between β­ ketonic ester and primary aromatic amine produces quinolines . lec10

5. OR lec10

6. Isoquinoline Isoquinoline contain a benzene ring fused as shown with a pyridine ring .It closely resembles quinoline in physical and chemical properties . lec10

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 . lec10

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 . lec10

9. Isoquinoline is a resonance hybrid of uncharged structure (1,1a and 1 b ) and charged structure ( 1c and 1d ) lec10

10. Chemical reaction Isoquinoline resemble quinoline in many ways 1 – Basicity Isoquinoline is a stronger base than quinoline lec10

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 ) . lec10

12. H H O H 1- MeI( excess ) -H O H - 2 OH H NH + N M e2 2- NaOH N M e 2 ( 6 ) ( 7 ) N M e 2 ( 8 ) N,N - dimethyl - 2 - vinylaniline 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 ) . lec10

13. Reduction lec10

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 . lec10

15. Nucleophilic subistitution Should take place at position ( 1 ) in agreement with the π­ electron density calculation . lec10

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 . lec10

17. C H C H C H 2 C H 2 C H 2 C H 2 2 2 P O 2 5 N H N -H O H 2 C O = C C C H 3 C H O H 3 C H 3 enol form keto form N - ( 2 - phenyl ethyl ) acetamide - H Pd / C 2 PCl 5 -POCl 3 N C H 2 C H C H 2 3 N - H AlCl + 3 C 1 - methyl isoquinoiline - C l C l C H 3 -HCl -HCl C H 2 C H 2 N H C C l C H 3 NH lec10

18. Pictet and Gams synthesis Pictet and spengler synthesis lec10

19. C H C H C H 2 C H 2 2 C H C H 2 2 2 O -H 2 N H N N H 2 + C H R - C H O - shift base R O H R - C - H + Mechanism lec10

20. Pomeranz and Fritsch synthesis Start from aromatic aldehyde converted into shift base with aminoacetal followed by cyclization gives isoquinoline . lec10

21. Mechanism lec10

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 lec10

23. -δ δ I- Synthesis lec10

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 lec10

25. Reduction Ring opening lec10