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

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

Mechanism lec10

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

OR lec10

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

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

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

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

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

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

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 - 2 - vinylaniline e 2 + O H -H ( 6 ) lec10

Reduction lec10

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

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

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

N - ( 2 - phenyl ethyl ) acetamide enol form 3 -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 lec10

Pictet and Gams synthesis Pictet and spengler synthesis lec10

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

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

Mechanism lec10

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

Synthesis δ -δ I- lec10

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

Reduction Ring opening lec10