COURSE: B.

PHARMACY, 4 Sem Unit-4: SYNTHESIS, REACTIONS AND MEDICINAL USES OF

FOLLOWING COMPOUNDS/ DERIVATIVES

Dr. Bintoo Sharma

D.PHARM

B. PHARM

PHARM D (POST BACCALAUREATE)

Assistant professor, JGIPT, (AHERA)

Course: B. Pharmacy 4th Sem

UNIT-4: SYNTHESIS, REACTIONS AND MEDICINAL USES OF FOLLOWING

COMPOUNDS/ DERIVATIVES

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 COURSE: B. PHARMACY, 4 Sem Unit-4: SYNTHESIS, REACTIONS AND MEDICINAL USES OF
FOLLOWING COMPOUNDS/ DERIVATIVES

PYRAZOLE: Pyrazoles are the derivatives of a five-membered heterocyclic ring system called
pyrazole. Pyrazole consists of two nitrogen atoms at 1 and 2 positions of the cyclic system.

N
N
H
Physical Properties: 1. Pyrazole is a colourless solid.
2. It possesses a pleasant smell.
3. Pyrazole is soluble in water.
4. Pyrazole exhibits tautomerism.
5. Pyrazole has aromatic properties.

N NH
N N
H

Synthesis

1. From 1,3-dicarbonyl compounds- 1,3-Dicarbonylcompounds react with hydrazine or

hudroxylamine and gives pyrazoles.
CH3
O 4 3
O - -H2O
C NH 2 NH3 HSO4 5
H3 C C C H3 C N2
H2 CH3 N
H1
Acetylacetone
3,5-Dimethylpyrazole

2. From 1,3-di polar compounds- Pyrazole derivatives can also be prepared by adding a
diazo compound to an acetylenic derivative.
C6 H 5 COOCH3

C 6H 5 C C COOCH3 N2CH-COOCH3
H3 COOC N
Methylphenyl propiolate Methyldiazo acetate N
H
3,5-Dicarbomethoxy-4-phenylpyrazole

Chemical Properties: 1. Oxidation: Pyrazole is resistant to oxidizing agents but the side chain
may be oxidized to carboxylic acid group in presence of potassium permanganate.

N N OH
N N
3-Methyl-1-phenyl pyrazole
1-phenyl pyrazole-3-carboxylic acid
2. Reduction: Pyrazole ring system can be reduced with molecular hydrogen and metal catalyst.
Pyrazolene and pyrazolidine are stronger bases than Pyrazole.

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NH
NH reduction reduction NH
N
N NH
pyrazoline
pyrazole pyrazolidine
3. Electrophilic aromatic substitutions: Pyrazole is an aromatic compound. It readily undergoes
electrophilic substitution at position 4 through the intermediate formation of arsenium ion. The
electrophilic substitutiou is favoured in neutral or basic medium but not in acidic medium.
NH
Chlorination Cl
SO2 Cl2 or Cl 2 N
4-chloropyrazole

NH
Bromination Br
Br2/ dioxane N
NH 4-bromopyrazole
N
O
pyrazole Nitration N
N+
HN O-
HNO 3/H2SO4
4-nitropyrazole

O
N
Sulphonation S OH
HN
H2S2O7 O
pyrazole-4-sulphonic acid
Medicinal compounds: 1. Analgin- Analgin is a pyrazoline derivative. It is an analgesic agent.
It is also used as antipyretic.

2.Phenazone- Phenazone is 2,3-dimethyl-1-phenyl-3-pyrazolin-5-one. It is used orally as an

analgesic and antipyretic.

IMIDAZOLE: Imidazoles are the derivatives of imidazole. Imidazole is a five-membered

heterocyclic compound possessing of two nitrogen atoms at 1 and 3 positions. Imidazole is
isomeric with Pyrazole and occurs in purine nucleus and in histidine.

HN
N
Imidazole

Physical Properties: 1. Imidazole is a colourless solid.

2. It exhibits amphoteric properties. It is more basic than Pyrazole and pyridine. It also contains
pyrrole type of amino nitrogen in the ring structure and shows acidic properties.

Synthesis:

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1. From dicarbonyl compounds: Imidazoles can be prepared by condensing a dicarbonyl

compound with an aldehyde in presence of ammonia.
C 6H 5
O
O N
C
C 6H 5 H C 3H 2O
2NH 3
C6H5 C C6H5 C 6H 5
O CH
6 5 N
Dicarbonyl compound H
2,4,5-Triphenyl imidazole

2. By dehydrogenation of Imidazolines: Imidazolines are the dihydrogenated derivatives of

Imidazoles.TheseImidazolines can be readily dehydrogenated to imidazoles in presence of
sulphur.
N N NH

N N N
H H H
2- Imidazole 3- Imidazole 4-Imidazole

Chemical Reaction: 1. Basicity: Imidazole is a weak base forms salts with acids. It is more
basic than Pyrazole, pyrrole and pyridine. Imidazole also has acidic properties the hydrogen
atom of -NH can be displaced by metal. It is more acidic than pyrrole and pyridine.
H
HN H N

N
N
Imidazole H
Protonated imidazole

OXAZOLE:- A group of 5-membered cyclic compounds composed of oxygen and nitrogen as

heteroatoms are oxazoles. In oxazoles the oxygen and nitrogen atoms are separated by one
carbon atom.
O

N
oxazole

Synthesis:- 1. From α-acylamino carbonyl compound:- Oxazole is prepared by refluxing α-

acylamino carbonyl compound with acid or phosphorous pentaoxide. This is the most common
method to prepare oxazoles which involve cyclization and dehydration in presence of
phosphorous pentaoxide or strong mineral acid.

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H2C NH N N
H C6H5 -H2O
C6H5 C C CH3 CH CH3
CH
HO 3 6 5 O
O
O O
-Acylaminocarbonyl compound 5-Methyl-2-phenyloxazole

Physical Properties: 1. Oxazole are liquids. They have pyridine like odour and boil at 69ᵒC.

2. Oxazole are weakly basic in nature.

Chemical Reactions:- 1. Electrophilic Substitution:- Oxazole undergoes electrophilic aromatic

substitution reactions. The preferred attack is at position-5. These reactions occur more readily
when the oxazole ring is activated by electron-donating group. Oxazole is more reactive with
electrophiles than thiazole but less than imidazole.

O Br O
Bromination
N N
5-Bromo-2-phenyloxazole
2-phenyloxazole

Medicinal uses: Oxazole show broad biological activities like antibacterial, antifungal, antiviral,
antitubercular, anticancer and anti-inflammatory.

THIAZOLE:- Thiazoles are five membered heterocyclic compounds consisting of nitrogen and
sulphur heteroatoms. The numbering in thiazole starts from the sulphur atom.

N
Thiazole

Physical Properties:- 1. Thiazole is a colourless liquid.

2. It has the characteristic odour like pyridine and is miscible with water.

3. It is weakly basic and behaves as a tertiary base.

Synthesis:-1. Condensation of α-chlorocarbonyl compounds with thioamides:- Thiazoles

are synthesized by condensing α-chlorocarbonyl compounds with thioamides.
R1
C O
R1 H2N R3 1.) -HCl N
C
CH
R2 S 2.) -H2O
Cl
R2 R3
S

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2.Condensation of α-chloroketones with ammonium dithiocarbonate:- Thiazoles may also be

prepared by the condensation of α-chloroketones with ammonium dithiocarbonate.
R1
C O SH
R1 H 2N
C N
CH H 2O NH4Cl
R2 S
Cl
R2 SH
S

2-Mercaptothiazole

Chemical Properties:- 1. Electrophilic substitution reactions:- Thiazole undergoes

electrophilic substitution reactions. The reactivity of thiazole is intermediate to pyridine and
thiophene. It is resistant to substitution reactions but if an electron donating group is present at
positions 2, thiazole readily undergoes the following substitution reactions.

N
N Br/CHCl 3
Br OH
S S
5-Bromo-2-hydroxythiazole
2-Hydroxythiazole

N N
N-Bromosuccinimide

Br
S S
2-Bromothiazole
Thiazole

N
N H 2SO4/mercuric
sulphate Br
Br HSO3 S
S

2-Bromothiazole 2-Bromothiazole-5-sulphonic acid

Medicinal Uses:- Thiazoles include mainly dyes and fungicides. Another widely used thiazole
derivative is the non-steroidal anti-inflammatory.

PYRIDINE:- Pyridine is a six membered heterocyclic ring system containing nitrogen as

heteroatom. Pyridine is a liquid of characteristic odour.

Pyridine

Preparation:- 1. Pyridine is present in light oil fraction of coal tar distillation. The light oil
fraction is treated with dilute sulphuric acid. This dissolves basic substances including pyridine.
The acid layer is isolated, neutralised and fractionated several times to get pure pyridine.

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2. Pyridine is prepared by passing a mixture of acetylene and HCN through a red hot tube.

N
2C2H2 HCN
Pyridine

3.From picoline:- On oxidation with potassium dichromate and sulphuric acid β-picoline
changes into nicotinic acid. This on decarboxylation with calcium oxide gives rise to pyridine.

CH3 COOH
K Cr O /H SO
2 2 7 2 4
CO2
N
N N
-picoline
Nicotinic acid Pyridine

Structure of Pyridine: Pyridine has a cyclic, planar structure. In pyridine the aromatic sextet is
complete without using the nitrogen lone pair of electrons. This unshared electron pair occupies
an sp2 orbital.

N
Unshared electron pair in sp2 hybrid orbital

Properties:- 1. Basicity:- Pyridine is basic in nature and reacts with acids to forms salts. The
basicity of pyridine is due to the availability of lone pair of electrons on nitrogen atom. Pyridine
is a much weaker base than alkylamines because the lone pair of electrons of nitrogen are present
in sp2 hybrid orbital instead of sp3 hybrid orbital. Consequently, the lone pair is more tightly held
and is less available for protonation due to more S character of pyridine nitrogen.

N ClH
Cl-
N
Pyridine H
Pyridinium hydrochloride

Medicinal Uses:- Used in antitubercular drug, normal functioning of skin, intestinal tract and
nervous system.

QUINOLINE AND ISOQUINOLINE: Quinoline and isoquinoline are condensed heterocyclic

systems. They are also known as benzopyridines because they have fused benzene and pyridine
rings. They are aromatic compounds.

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N
N

Quinoline Isoquinoline

Preparation: Naturally quinoline and isoquinoline are available in coal tar, bone oil and
alkaloids. Synthetically they are prepared by the following methods:

a. Quinoline is prepared by the reaction of aniline with glycerol, conc. Sulphuric acid,
nitrobenzene and ferrous sulphate. This reaction is known as Skraup synthesis.
1. Glycerol on dehydration with hot H2SO 4 gives acrolein.

OH O
HO
OH Acrolein
Glycerol

2.Nucleophilic addition of aniline to acrolein form β-phenylamino propionaldehyde.

O H2 O
NH Acrolein C CH
2
N C
Aniline H H2
-Phenylamino propionaldehyde
b. Isoquinoline is prepared by Bischler-Napieralski synthesis:- In Bischler-Napieralski
synthesis β-phenylethylamine is allowed to undergo cyclodehydration on heating with
phosphoryl chloride to form substituted isoquinoline.

Medicinal Uses: It is used for the suppression and treatment of malaria by interfering with DNA.
It is used as an anthelmintic drug. It is used as high boiling basic solvent in organic reaction. It is
used in manufacturing of pharmaceutical dyes.

ACRIDINE: Acridine is a condensed heterocyclic system. It is a tertiary base. Acridine is also

known as benzoquinoline or dibenzpyridine.

N
Acridine

Acridine is colourless solid. It occurs in anthracene fraction of coal tar.

Preparation: 1. Oxidation of dihydroacridine with oxidizing agent.

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O
COOH
Cyclization
Na/Amylalcohol
N N
H H N
H
Diphenylamine-2-carboxylic acid Acridinone 9,10-Dihydroaciridine
Oxidation

N
Acridine

2. Acridine can also be prepared by passing o-aminodiphenylmethane through a red hot tube.

H2C

NH2 N
Acridine

Acridine is a potent substance of a number of dyes and antiseptic. Acridine ring system is present
in dyes and pharmaceutical substances.

1. Proflavine: Chemically proflavine is 3,6-diaminoacridine. It is effective against many

gram positive bacteria hence it is used as a disinfectant and antiseptic.

H2N N NH 2
2. Aminacrine: Chemically aminacrine is 9-amino Acridine. It is effective against many
gram positive bacteria hence it is used as a antiseptic and disinfectant.
NH2

3. Quinacrine: Chemically quinacrine is N-(6-chloro-2-methoxy-9-Acridinyl)-N,N-

diethylpentanediamine. Quinacrine was formerly used for the treatment of malaria but it
has been replaced by chloroquine.
CH3 H H2 C2 H5
2
CH C C C
HN N
H2
OCH3 C2 H5

Cl N

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INDOLE: Bayer first synthesized Indole in 1866. Indole consists of a pyrrole moiety which is
fused to benzene ring. The two rings are flat and associate with Pi-delocalized electrons.
Therefore Indole exhibits aromatic properties. The IUPAC name of Indole is 1H-benzopyrrole.

N
H
Indole

Indole exhibits tautomerism. The tautomeric form of Indole are

N
N
H

Physical properties: 1. Indole is colourless solid.

2. It has pleasant odour.

3. It behaves as a weak acid and a weak base.

Synthesis: Fischer -Indole synthesis: In this method phenylhydrazoneof aldehyde or ketone is

cyclized with acid catalyst.

CH3
O C
NH2 C CH N CH
NH C6 H5 3 N 6 5
H
Zncl2
Phenylhydrazine Acetophenone

C 6 H5
N
H
2-Phenylindole

Bischler synthesis: In this method Indole derivatives can be prepared by heating aryl amine with
haloketones.

H
O CH3 N
C
CH 3
NH 2 Br CH3
CH3
Arylamine -haloketone Indolederivative

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Chemical reaction: Reduction: Electrolytic reduction or metal and acid reduction of Indole
gives 2,3-dihydroindole. Catalytic reduction of Indole with molecular hydrogen and metal gives
octahydroindole.

Zn/HCl
N N
Indole H H
2,3-Dihydroindole
H2/Ni

N
H
Octahydroindole

Oxidation: In presence of peroxy acid or ozone Indole is oxidized to form 2-

formamidobenzaldehyde by opening the heterocyclic ring.

CHO
C6 H 5 COOH

N or Ozonolysis
NHCHO
H
Indole 2-Formamidobenzaldehyde

Uses: It is used in cancer prevention.

It is used in tumors inside respiratory tract.

PYRIMIDINE:- Pyrimidines are the derivatives of pyrimidine. Pyrimidine is a six membered

heterocyclic ring system consisting of two nitrogen atoms at 1 and 3 positions.

N
Pyrimidine

Synthesis:-

1. From barbituric acid:- Pyrimidine is prepared from barbituric acid by the following
reactions:-
O OH Cl
HN N
N POCl 3 N Zn/dust
Hot water N
O N O HO N OH Cl
H N Cl Pyrimidine
Barbituric acid
2. From alkylpyrimidines:- Alkylpyrimidines on oxidation followed by decarboxylation
yield pyrimidine.

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CH
3
Oxidation N
N Decarboxylation N
N
Pyrimidine
4-Methylpyrimidine

3. From chloropyrimidines:- Catalytic reductive dechlorination of 2,4-dichloropyrimidine

yields pyrimidine.
Cl
N
N H2
Pd-C N
Cl N Pyrimidine
2,4-Dicholropyrimidine
Physical Properties:- Pyrimidine is a colourless solid.
It is weakly basic.
Pyrimidine has a dipole moment of 2.4D.
Chemical Properties:-
Basicity:- Pyrimidine is weakly basic than pyridine due to the electron withdrawing effect of
the second nitrogen atom present in pyrimidine. Pyrimidine is protonated in acidic medium.
Presence of electron releasing groups enhances the basicity.
N H N
N N
H
Pyrimidine
AZEPINES:- Azepines are unsaturated seven membered heterocyclic compounds containing
nitrogen atom as heteroatom.

HN
1H-Azepine
Four tautomeric azepines were identified. They are 1H, 2H, 3H and 4H-azepine. The
numbering commences from the nitrogen atom. All azepines only 3H-azepine was isolated
because of its high stability. 1H-azepine is unstable and immediately rearranges to 3H-
azepine.
1. Azepines are not planar compounds.
2. They do not comply Huckel rule of π-electrons. Hence they are non-aromatic.
3. They are highly reactive.

Synthesis:-
1. From benzene:- Benzene on treating with ethoxy carbonyl nitrene gives N-
ethoxycarbonyl 1H-azepine which on heating with alkali followed by isomerisation
yields 3H-azepine. This reaction is an example of valence bond isomerisation.

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N3 COOC2 H5 OH
N 
N
COOC 2 H5
3H-Azepine
2. From phenylazide:- Phenylazide on decomposition in presence of primary and
secondary amines yields 3H-azepine derivative.

N
(C2 H5 )2 NH Isomerisation C H
 CH N 2 5
N 2 5 N
N
C2 H 5
C 2 H5
PURINES:- Purines are the cyclic compounds having two urea residues. It consists of a
pyrimidine ring fused with an imidazole ring. It structure is given as follows:-

H
N N N
N
N N N N
H

Fischer method:- This is the oldest method for synthesis of purines like adenine and guanine.
This method involves conversion of uric acid into 2,6,8-trichloropurine by reaction with PoCl3 .
Excess of chlorine atoms are removed by reduction with HI to form the required purine.

Cl I
H H H
N
N POCl3 N N HI-CH I N
HN
O Cl 3
N Cl N N
N N I N
H H
2,6,8-Trichloro 2,6-Diodopurine
Uric acid purine
Boiling Zn dust
H
N N

N N
H
Purine

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