HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

HOMEWORK / REVISION / TEST YOURSELF QUESTIONS - ANSWERS

A1:- Naming heterocycles Match the following heterocycles with the names given

H3C
CH3
N
2,7-dimethylquinoline
O

Ph
N
2-phenyl-3,4-dihydroquinoline

N
H

H3C

CH3
N
H
2,7-dimethylquinolin-(1H)4-one

Br
7-bromo-2,3-dihydroindole
OMe

H
N

NH
O
5-methoxyisoquinolin-(2H)1-one

Ph
4-phenyl-1,2-dihydroquinoline
CH3

H
N

N
Br

CH3
3,8-dimethylisoquinoline

2-bromoindole
A2 Name the following heterocycles

O
H3C

Br
N
H

N
H

CH3

6-bromo-2-methyl-1,2-dihydroquinoline

CH3

2,6-dimethylquinolin-(1H)4-one
H
N

MeO
NH
6-methoxy-1,2,3,4-tetrahydroisoquinoline
CH3
CH3
N
H
2,4-dimethylindole

OMe
4-methoxy-2,3-dihydroindole

N
H
1,2,3,4,5,6,7,8-octahydroquinoline

page 1

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

N
Ph
1-phenylisoquinoline

OMe
5-methoxy-7,8-dihydroquinoline

B:- Formulation of heterocyclic products

B1 Formulate the products from the following reactions, all of which are the Doebnervon Miller variation of the Skraup quinoline synthesis. Identify key pre-cyclisation
intermediates in each case.
H
+

H3C

NH2

Br
2

Br

CH3

Ph

H2N

Ph

O
4

Br
+

Br

H
Ph

NH2

Ph

O
5
NH2

Ph

Et
6

CH3

Et

NH2

O
+

Ph

Ph

Et

Ph
N

F
Et

page 2

CH3

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14
CH3

Br
7

H2N

H3C
N

CH2CH3

CH2CH3

Br

B2 Formulate the products from the following reactions, all of which are quinoline,
quinolone or isoquinoline syntheses. Identify key pre-cyclisation intermediates in
each case.
MeO

CH3

H+

NH2

H3C

MeO

CH3
NH

CH3
MeO

MeO
O

H+

+
O2N

O2N

NH

NH2

Cyclisation is to the less hindered para position in the more electron rich ring
Cl
1. Et3N
2. POCl3, heat

Cl
3
Cl

NH2

+
H3C

CH3

O
4

Cl

1. Et3N
2. POCl3, heat
3. Pd-C, heat (no H2)

NH2

H3C
+

1. AcOH, 40 oC,
with azeotropic
removal of H2O

Ph

OEt

NH2

O
H3C

2. Ph2O, 250 oC

N
H

Ph

Ph
o

H3C
+

Ph

1. 150 C,
2. conc. H2SO4

O
OEt

NH2

page 3

H3C
N
H

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

Br
7

H2N
O

Br

NaOH, 0 oC

H3C

Ph
Ph

CH3

CH3

Br

Br
8

NH2
H

H2SO4, heat

B3 Formulate the products from the following reactions, all of which are Fischer
indole syntheses. In each case identify the enamine intermediate prior to the [3,3]sigmatropic rearrangement step.
O
1
NHNH2

H3C

N
H

O
2
NHNH2

H3C

CH3

N
H

CH3

+
NHNH2

N
H
O

Br
4

CH3CH2

H2NHN

Br

CH2CH3

+
NHNH2

H3C

N
H

CH2CH3

Br

CH3

Br

CH3

N
H

CH3

O
NHNH2

MeO
+

6
MeO

N
H
O

7
NHNH2

H3C

Ph

CH3

CH3

page 4

N
H

Ph

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

O
8

+
CH3
NHNH2

CH3

N
H

+
N
H

NHNH2
F

B4 From what starting materials could you make these two indoles? In these
examples, could there be any problems with formation of isomeric indole products? If
so what is (are) their structure(s)?
H3C

CH3

H3C

+
NHNH2

CH3

N
H

only isomer

+
MeO

MeO

NH-NH2

N
H
major isomer
OMe

N
H
minor isomer

C:- Effect of substituents on reaction rate

For each of the following pairs of reactions, which will have the faster rate of reaction
and why?
C1
O
MeO

MeO

H
+

reaction A

NH2

CH3

CH3

CH3

O
O2N

O2N

H
+
NH2

CH3

reaction B

Reaction A is faster than reaction B. MeO is electron releasing making the ring more
nucleophilic than when the electron withdrawing NO2 is present.
C2
page 5

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

O
MeO

MeO

H
+

reaction A

NH2

CH3

CH3

CH3

O
H
+
MeO

NH2

CH3

MeO

reaction B

Reaction B is faster than reaction A. MeO is o/p director so the position ortho to the
NH2 and para to the OMe is more readily attacked than the one meta to the MeO in A.
C3
MeO

MeO

MeO

CH2O
NH2

NC

NC

NC

NC

NH

NC

NC
reaction B

CH2O
NH2

MeO

MeO

reaction A

NH

MeO

Reaction A is faster than reaction B. As above the MeO is an o/p director but CN is a
deactivating meta director. So the position para to the OMe is more readily attacked
than the one para to the CN.
D:- Electrophilic and nucleophilic reactions of heterocycles

Cl
1

Cl

+
N

heat

HN

Cl
N

(1 mole equivalent)

Cl

heat

Cl

Na O

(1 mole equivalent)
O

Cl

Cl

+
N

Cl

heat

Cl

H2N
(1 mole equivalent)

page 6

N
H

HETEROCYCLIC CHEMISTRY Part 2

Modules 06710-12-14

CH3

CH3

HNO3 / H2SO4

heat

N
NO2

Br
CH3

N
H

CH3

Br2

N
H

CH3
6

CH3
Br

Br2

N
H

N
H

HO
O
7

N
H

H+ cat
H

N
H

N
O
8

N
H

Br

H+ cat
H

N
H

N
H

Br
CH3I

CO2Et
CO2Et
Br

Cl
9

N
H

I +
N

NaOEt
+
EtO2C
heat

CO2Et
N
H

Br

H
N

N
Cl
N
H

NH2

page 7

N
Cl
N
H