Fused-ring heterocyclic chemistry

Heterocyclic ring systems common in

drug structures
Rings contain in addition to carbon, other atoms like
nitrogen, oxygen, sulfur

Benzo-fused heterocycles:
Indole
Indole : Such bicyclic heterocyclic structures which has a benzene ring and a pyrrole ring
sharing one double bond.
Indole is an important heterocyclic
system because it is built into proteins in
the form of the amino acid tryptophan. It
is the basis of important drugs such as
indomethacin, and because it provides
the skeleton of the indole alkaloids
biologically active compounds from
plants including strychnine and LSD

Medicinal compounds contain indole

Serotonin is a monoamine neurotransmitter (derived
from Trp) synthesized in serotonergic neurons in the
central nervous system (CNS) and enterochromaffin
cells in the gastrointestinal (GIT)tract of animals
including humans. Serotonin is also found in many
mushrooms and plants, including fruits and
vegetables.

Serotonin antagonists

Antiemetic: treatment of vomiting

Medicinal compounds contain indole

LSD stands for LySergic acid Diethylamide. It is the hallucinogenic drug acid. When people walk
off a building claiming that they can fly, they are probably on LSD. It contains an indole ring
made up of a benzene ring and a pyrrole ring fused together.

Isoindole is more basic than indole

Six-membered
ring corresponds
to benzene

According to lewis definition

Acid e
Base e

The lone pair of sp3 N in indole are

delocalized into the aromatic ring,
thus less available to give.
While in isoindole it is not delocalized
into the aromatic ring, thus available
to give.
Indole is more stable than isoindole.

Six-membered
ring does not have
same pattern of
bonds as benzene

Rxns of Indole in Electrophilic Aromatic

Substitution (EAS)
The chemistry of Indole is similar to that of
pyrrole ring with a relatively unreactive
benzene ring due to the electron
withdrawing effect of the nitrogen.

However, pyrrole reacts with electrophiles

at all positions but prefers the 2- and 5positions, while indole much prefers the 3position.
WHY????
In indole: reaction at the 3-position simply
involves the rather isolated enamine
system in the five-membered ring and does
not disturb the aromaticity of the benzene
ring.

Nitration

Sulphonation

Halogenation

Fischer indole synthesis

The Fischer indole synthesis, which was first discovered in 1883, is still considered as the most popular,
general and efficient approach.
The aryl hydrazones are easily obtained by condensation of a ketone with an aryl hydrazine
The acid-catalyzed cyclization of aryl hydrazones generate indole with loss of ammonia.

The method can be used to generate substituted endols at 2-position (R2 in figure below) which is difficult
to obtain by EAS
R1
R1
R1
R2
R2
R2
R1

Basicity of purine
Purine has three basic, pyridine-like
nitrogens with lone-pair electrons in sp2
orbitals in the plane of the ring. The
remaining purine nitrogen is nonbasic and
pyrrole-like, with its lone-pair electrons as
part of the aromatic p electron system.

Although this N is sp3 hybridized, the lone e are

involved in the aromatic p system. Thus the lone
e are not available.

Basicity of

3
sp

The indole sp3 N is more

basic than that of purine.
Since purine has three
aromatic sp2 N withdrawing
the electrons, the sp3 N has
less electron to give (less
basic)

N in Indole and purine

Purine

Two purine bases of nucleic acids:

(pyrimidinoimidazole)
NH2
OH
6
1

7
8

N
3

N
H
adenine

atypical numbering!

HO

hypoxanthine

xanthine

6-hydroxypurine

2,6-dihydroxypurine

HO

OH

N
H

uric acid (2,6,8-trihydroxypurine)

OH

N
H
ammonium hydrogen urate

HO

Lactam is cyclic amide

(NH-C=O) which
undergo tautomerism
to lactim (N=C-OH)

O NH4+

N
H

OH

HO

2-amino-6-hydroxypurine

OH

N
H

N
H

N
guanine

OH

H2N

6-aminopurine

OH

N9
H

OH

N
H

lactim form

lactam form of uric acid

13

DNA base pairing

Methylxanthines are N-methyl derivatives of xanthines, known

alkaloids in coffee, tea, and cocoa.

caffeine

theophylline

theobromine

1,3,7-trimethyxanthine

1,3-dimethylxanthine

1,7-dimethylxanthine

Allopurinol is an isomer of hypoxanthine, which is used in treatment of hyperuricacidaemia and

gout. It inhibits xanthine oxidase the enzyme that transforms hypoxanthine and xanthine to
urate.
Mercaptopurine (6-sulfanylpurine) inhibits the biosynthesis of purine bases and is used in
chemotherapy of cancer.
OH
SH
N

N
N
allopurinol

N
H

N
H

mercaptopurine
15

Purine synthesis
Traube synthesis:
Reacting 4,5-diaminopyrimidine
with formic acid to give purine, or
acetic anhydride to give methyl
substituted purine at imidazole ring.

Or

4,5-diaminopyrimidine

Reacting substituted imidazole with

formamide to give substituted
purine at pyrimidine ring

3-methyl-5-aminoimidazole-4-carbonitrile

8-methyl-9H-purine

Quinoline and Isoquinoline

A benzene ring can be fused on to the pyridine ring in two
ways giving the important heterocycles quinoline, with the
nitrogen atom next to the benzene ring, and isoquinoline,
with the nitrogen atom in the other possible position
Quinoline forms part of quinine (antimalarial alkaloid) and isoquinoline forms
the central skeleton of the papaverine
(antispasmodic opium alkaloid).

Numbering

The presence of nitrogen in this

structure produces an irregular
distribution of the electron density in
both heterocyclic and carbocyclic
rings, a situation that alters the
physicochemical properties and
reactivity.

Napthalene

Quinoline

Basicity of quinolone and isoquinoline

Both N are sp2
The lone-pair electrons of N
are close to benzene ring and
thus get involved with the p
electrons of benzene
(play with neighbor kids)

The lone-pair electrons of N

are far from benzene ring and
thus get not involved with the
p electrons of benzene
(no neighbor kids to play with)

Basicity depends on the ability of N to give electrons for

Reactivtiy of quinolines
The chemistry quinolines = pyridine
Quinoline and isoquinoline both have
1.

Have basic, pyridine-like nitrogen atoms, which undergo electrophilic substitutions.

2.

Are less reactive toward electrophilic substitution than benzene because of the
electronegative nitrogen atom that withdraws electrons from the ring.

3.

Electrophilic substitution occurs on the benzene ring rather than on the nitrogen-containing
pyridine ring, and a mixture of substitution products is obtained.

This N is sp2 hybridized, thus

electrons are swimming close
to their mother (nucleus),
thus wolf can not attack

This is a hateful
electron greedy wolf
In quinolone and isoquinoline the N withdraw electrons in
pyridine ring thus few are available for EAS, therefore Br
prefers to go to benzene
Note: EAS reactivity for the fused benzene ring in both of
quinolone and isoquinoline is much lower than that for nonfused benzene (Because of the deactivating effect of N)
While pyrrole ring of indole is most reactive
to EAS
This N is sp3 hybridized, thus
electrons are swimming away
from their mother (nucleus) ,
thus wolf can attack

Rxns of quinolone
Electrophilic substitution
Quinoline chemistry is a mixture of that of benzene and pyridine. Electrophilic substitution
favours the benzene ring and nucleophilic substitution favours the pyridine ring.
So nitration of quinoline gives two productsthe 5- nitroquinolines and the 8-nitroquinolines
in about equal quantities (though you will realize that the reaction really occurs on protonated
quinolone).

Here we pull e by
protonation, to destroy any
hope for NO2 to come to
pyridine ring

Rxns of quinolone
Electrophilic substitution
Acridine, with two benzene rings, which gives four nitration products, all on the benzene rings.
IF you want electrophils to come to pyridine ring, then give the ring some electrons, e.g. by
formation of N-oxide.
The acridine-N-oxide gives just one product in good yieldnitration takes place at the only
remaining position on the pyridine ring.

Here we fuel N with e

to enable EAS at
pyridine

Rxns of isoquinoline
Electrophilic substitution
The nitration of isoquinoline is rather better behaved, giving 72% of one isomer (5nitroisoquinoline) at 0 C.

Synthesis of quinolines
Anilines Plus 1,3-Dielectrophiles:
Condensation of a 1,3-dielectrophile, in the simplest case a 1, 3-dicarbonyl derivative, with an
aniline furnishes a -aminoenone, which can evolve to an aromatic derivative by treatment with
concentrated acid.
C
C

Synthesis of quinolines

This Zigzag bond

indicate unknown
isomer

o-Acylanilines Plus Carbonyl Compounds

o-Acylanilines condense with enolizable
carbonyl (keto group with adjacent H) to
give quinolines.

The outcome of the condensation was

found to be dependent on the type of
catalyst (acid or base)

Here we have
tautomerizatoin also

Synthesis of quinoline
Skraup reaction
conjugate addition of the amine. Under acid catalysis the ketone now cyclizes to give a
dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step
accomplished by many possible oxidants.
Unsaturated
keton

Aniline

Synthesis of quinoline
Simple example of Skraup reaction
Traditionally, the Skraup reaction was carried out by mixing everything together and letting it rip.
A typical mixture to make a quinoline without substituents on the pyridine ring would be the
aromatic amine, concentrated sulfuric acid, glycerol, and nitrobenzene all heated up in a large
flask at over 100 C with a wide condenser.

The glycerol was to provide acrolein (CH2=CHCHO) by dehydration, which provide the necessary 3C to close the ring
The nitrobenzene was to act as oxidant

Synthesis of isoquinoline
Alkylation of phenylethylamine by acyl halide, then electrophile is made from an amide and
POCl3 to close the ring and generate dihydroisoquinoline, which is then reduced to isoquinoline