lec10 1

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

lec10 2

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

lec10 3

-

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

lec10 4

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

lec10 5

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

lec10 6

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 .

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 .

NCOOH

COOH+ NHOOC

HOOCKMnO4

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 .

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 .

lec10 9

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 )

lec10 10

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

NN

lec10 11

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 ) .

lec10 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 ) .

NH1- MeI( excess )

NMe2OH-

2- NaOH

)7(

)8 ( N,N - dimethyl - 2 - vinylaniline

NMe2

+NMe2

OHH

H

H H-H 2O

)6(

lec10 13

NHNa

NHNH3(liq)

1,2 - dihyd -H2

H2/Pt

-3H2NH

Na

N

NH3(liq)-H2

-2H2Sn / HCl

decahydroisoquinoline

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 .

NHNO3(conc)

H2SO4 N

NO2

+ N

NO2

H2SO4(conc) N

SO3H

H2SO4

Br2

N

Br

Br2

AlCl3( 5 ) , ( 5 , 8 ) , ( 5 , 8 , 7 )

lec10 15

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 .

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

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

lec10 18

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

lec10 19

-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

lec10 20

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 .

lec10 21

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

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

N

12

3

456

7

89

+

lec10 23

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

lec10 24

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

lec10 25

N

+

NaBH4EtOH N + N

tetrahydro - decahydro -

NaOAC -H2ON

+

HOH

I -N C - H

C HH

H

+N

-H+

2 - butadienyl pyridine

Reduction

Ring opening