J.T.S.S.P.

MS
Shri Shiv Chhatrapati
College, Junnar.
Dist:-Pune
Department of Chemistry

M.Sc Project
2015-16

Synthesis Of 2Phenyl Indole

derivatives
Submitted By
Misbah
Miss. Shaikh
Mohammed Yunus
Under Guidance of

Mr. S.S. Thorve

Department Of Chemistry,
Shri Shiv Chhatrapati College,
(Arts Commerce & Science)
Junnar (Pune)

CONTENTS
Introduction
Reported Work
Retro-Synthetic Analysis
Our Approach
Experimental Work
Spectral data
Result & Conclusion
References

INTRODUCTION

Indoles are an organic heterocyclic compounds having general

formula C8H7N1. This aromatic heterocycle is classified as an

alkaloid.
Indoles were first prepared by Baeyer in 1866 by zinc dust
distillation of oxindoles. It finds important place in chemistry
because of its relationships to the naturally occurring dye,
indigo.
The chemical degradation of this dye yields indoxyl, oxindole
and finally indole. Indole is found in coal tar and in essential
oils (jesamine oil, orange oil) of many plants. It also occurs in
amino acids (tryptophan) as a plant growth harmone (indole-3acetic acid), in alkaloids and dye stuff (indigo).The indole ring
comprises of a benzene ring fused to the 2 -and 3-positions of
pyrrole nucleus.

The IUPAC name of indole is 1H-benzo [b] pyrrole, it being the

b-face benzo-fused isomer. The bridgehead carbons are
assigned positions 3a and 7a. Positions-2 and-3 are also
sometimes designated as and respectively. Many
substituted indoles have acquired trivial names such as
skatole , gramine, tryptophan, etc.
Indoles and simple alkyl indoles are colorless crystalline
solids. Indole melts at 520C an boils at 2540C. It is soluble in
most organic solvents. While pure indole has pleasant smell
and is use as a perfume base, impure indole and skatole
have unpleasant odour. Many indoles are quite stable in air
with exception of those which carry a simple alkyl group at
2-positions.Indole is a planar molecule with conjugated
system of 10-electrons.

Indole and its derivatives are common heterocyclic compounds in

nature which have attracted considerable interest in recent year
due to their therapeutic pharmacological activities. Indole and its
derivatives have a variety of physiological activities and play a vital
role in the life processes of living organisms. Indole ring is present
in many natural products and synthetic compounds having
medicinal properties. It is a structural elements in many biologically
and pharmaceutically active compounds with antibacterial,
antimicrobial, inflammatory and other activities. Indolic compounds
are also known as antidepressants, tranquilizers and analgetics.
Indole is widely distributed in the natural environment and can be
produced by a variety of bacteria. As an intercellular signal
molecule, indole regulates various aspects of bacterial physiology,
including spore formation, plasmid stability, and resistance to
drugs, biofilm formation, and virulence. The amino acid tryptophan
is an indole derivative and the precursor of the neurotransmitters
serotonin.

Indole derivatives display a diversity of pharmacological

activities that are useful in the treatment of fibromyalgia, chronic
fatigue, and irritable bowel syndrome. Besides being biologically
active, they are also used extensively as a synthons in organic
synthesis that possesses potentially reactive site for a variety of
chemical reactions.

Indole-3-carboxaldehyde is a naturally occurring component of

Brassica vegetables. It induces a G-1 cell cycle arrest of human

breast cancer. some indole derivatives, such as melatonin and
serotonin act as antioxidant and play an important role in the
immune system. Due to the important role of free radicals in the
pathophysiology of novel antioxidant compounds containing
indole moiety as a clinically effective drug for treatment of these
disorders

 Several potent antitumor, antibiotic natural products such as dynemicin,

calichemicin and neocarzinostatin cleave DNA hydrogen atom
abstraction from deoxyribose sugars. It was that some indole
derivatives have been reported as efficient DNA cleavage agent.
The reaction of indolyl chalcones with thiobarbituric acid gave indolyl
pyrimidine derivatives. Pyrimidine based heterocycles are potent
bioactive molecules and exhibit antibacterial, anti-inflammatory,
antioxidant, antitumoral , analgesics, antitubercular and antiviral
activities.
5-Fluoro-uracil and fturafur are reported to be potent anticancer agents.
Many classes of chemotherapeutic agents containing pyrimidine nucleus
are in clinical use such as antibacterial (Sulfadiazine, sufamerazime),
antiviral (Iodoxiuridine, terifloridine ), antifungal (flucytocine) and
antimalarial (pyrimethamine) agents.
It has been observed that the incorporation of fluorine atom into the
indole ring would tend to increase drug persistence by increasing its
solubility in lipid material and fat deposits in the body.

a)
b)
c)
d)
e)

Through the years different methods have been devised for

the synthesis of indole and its derivatives. These methods
differ in range and applicability. A number of general
methods are also known in which the pyrrole ring is formed
through ring closure reactions.
The Fischer-Indole Synthesis.
The Madelung Synthesis.
The Nenitzescu Synthesis.
The Bischler Synthesis.
The Reissert Synthesis.

Indoles can be prepared by numerous methods. However,

all these methods have their own limitations and a
number of drawbacks such as use of toxic solvents,
expensive reagents, and amount of waste solvents.
Amongst the various approaches for the synthesis of
indole, Fischer indole synthesis has mentioned its
prominent role. It is easy method and chemicals are easily
available and carried out in a short time with high yield. It
is oldest and classical method for synthesis of indole
hence by using Fischer indole synthesis we were prepare
indole derivatives.

Chemistry of 2-Phenyl Indole

1) Structure :-

Ph
N
H

Molecular Formula: C14H11N

Molecular Weight: 193.09
Percentage of elements contains:- It contains on the basis of
their molecular formula and weight:C =87.01%
H =5.74%
N =7.25 %
Nature: - Light brown powdered
Melting Point: 187oC
Therapeutic Use: Used as antifungal ,antibacterial, antitumor
agent.
Industrial Application: Ionic liquid synthesis

O
H

Ph
N
H

Chemistry of 3-formyl-2-phenyl indole

Structure:-

Molecular Formula: -C15H11NO

Molecular Weight:221.25
Percentage of elements contains:-

Nature: - Light brown powdered

Melting Point: 240oC
Therapeutic Use: Free radical scavenging and DNA cleavage activity
Therapeutic Use :
Tryptophan dioxygenase inhibitors pyridyl-ethenyl-indoles as potentia
anticancer immune modulators.
Pyrimidinones via Biginelli reaction as antimicrobial agents
[(phenyl)pyrazolyl]indole derivatives as antiinflammatory agents and
analgesics

 Chemistry of 2-phenyl-1-(2-phenyl)-1-H-indole-3yl methylene

hydrazine.
Structure:

Molecular Formula: - C21H17N3

Molecular Weight : 311.38g
Percentage of elements contains:- It contains on the basis of their
molecular formula and weight:
C = 81.00%

H = 5.50%

N = 13.49%
Nature: - Light brown solid
Melting Point: 260OC
Therapeutic Use: - Anticancer Agents For Breast Cancer Therapy
Industrial Application: Ionic liquid synthesis

Reported
Methods

STAGE I:-

R2

R1

R1
R3

R2

Conc.H2SO4
R3

NHNH2

EtOH

R4
O

N
H

R5

R5

ketone

Phenyl hydrazine

R4

Indole derivative

STAGE II:O
H
Me
Ph
N
H

2-phenyl-1H-indole

Me

POCl3
CH
O

N,N-dimethylformamide

Ph
N
H

2-phenyl-1H-indole-3-carbaldehyde

Retro Synthetic
Analysis
OH

1)

CH

NNHPh

CH

NHNHPh

FGI

Ph

Ph
N
H

N
H

Target molecule

OH
H

+
Ph

PhNHNH

Ph

N
H

Synthon

N
H

Synthetic.
equivalent

Synthon

FGI

OH
CH2
OH

Ph
Ph

N
H

N
H

CH2

Synthon

Synthon

H
H3C

Ph

FGI

H3C

CH

CHCl

H3C

OH

H3C

H2 O

H3C

CHCl

H3C

N
H

DMF

Analysis from: Vilsmeier Haack reaction

2)
O

CH3

Ph
N
H

2-Phenyl hydrazine

Acetophenone

Analysis from:from fischer indole synthesis

PhNNH 2
Phenyl hydrazine

PhNHNH2
Synthetic.
equivalent

Our
Approach

Reactions
STAGE I:O

NHNH2
CH3

1)CH3COOH

+
acetophenone

H
N
Ph

2)EtOH
phenyl hydrazine

3)PPA
2-phenylindole

STAGE II:O
H

1)DMF
2)POCl3

Ph

Ph
N
H

2-phenyl indole

cooling at 10-15 C
3)NaOH
4)H2O

N
H

2-phenyl-1H-indole-3-carbaldehyde
(3-formyl-2-phenyl indole)

STAGE III:-

CHO
CHNNHPh

1) CH3COOH
Ph
N
H

3-formyl-2-phenyl indole

Ph

NHNH2

phenyl hydrazine

2) Ethanol
3) PPA

Ph
N
H

2-phenyl-1-((2-phenyl-1H-indol-3-yl)methylene)hydrazine

Experiment No :- 1
Aim:- Synthesis of 2-Phenyl indole from acetophenone.
Reaction:

O
NHNH2
CH3

1)CH3COOH

+
acetophenone

H
N
Ph

2)EtOH
phenyl hydrazine

3)PPA
2-phenylindole

Procedure:Place a mixture of 1.0 gm. Acetophenone 1.0 ml. Phenyl hydrazine and 3.0 ml. Ethanol and one drop
of Glacial acetic acid in beaker, warm the mixture at 100 0C for 15 minute .Cool the mixture and filter the product
and wash with dilute HCl and Ethanol.
In a conical flask place above product (1.161gm.) with Poly phosphoric acid and heat it on boiling
water bath for 10 minute, cool the flask and add 20ml. water. The product will separate out as solid, filter the
product, recrystallized with suitable solvent. Report yield, melting point and TLC.

Result:Melting point of product: 187oC

Practical yield
: 1.096 gm.

T.L.C:-

Rf value of reactant = 0.71

Rf values of product = 0.28
Solvent used for TLC = n-hexane

Calculations:1) Theoretical yield:Acetophenone

120gm.
1

x
=
2) Practical yield:W gm
3) Percentage yield: -

2-Phenyl indole

193gm .

x
1.608gm.
=

1.096gm.
68.15 %

4) Solvent used for Recrystallization: Ethanol

Experiment
No
:-2
Aim :-Synthesis of 3-formyl-2-phenyl indole from 2-phenyl indole.
Reaction
O
H

1)DMF
2)POCl3
Ph

Ph
N
H

2-phenyl indole

cooling at 10-15 C
3)NaOH
4)H2O

N
H

2-phenyl-1H-indole-3-carbaldehyde
(3-formyl-2-phenyl indole)

Procedure:Phosphorous oxychloride 0.4765ml. was add slowly with stirring

to DMF 1.5525ml. at 10-150C. to the resultant solution, 2-Phenyl
indole (0.5gm.) was add in portions with stirring. The
solution was further stirred for 45 min. and then poured into
ice water (5.1755 ml. ). Sodium hydroxide solution (2N, 5.1755
ml.) was add to it and the mixture was heated on a water
bath for 1hr. It was cooled, recrystallizsed from acetone
(80%) to obtain pure compound.

TLC:

Rf values of reactant = 0.72

Rf value of product = 0.41
solvent used for TLC = 2 % Ethyl acetate in nhexane

Calculations:1) Theoretical yield:2-phenyl indole

2-phenyl-1-H-indole-3-carbaldehyde
193 gm.

221 gm.
0.5gm.

x
x

0.57 gm.
2) Practical yield:W gm =
0.485 gm.
3) Percentage yield :85.87 %
4) Solvent used for Recrystallization: 80% Acetone

Experiment No :3
Aim Synthesis of 2-phenyl -1-((2-phenyl-1-H-indole-3-yl)
methylene)hydrazine from 3-formyl-2phenyl indole

Reaction:O
H

CHNNHPh

1)EtOH
Ph +
N
H

PhNHNH2

2)CH3COOH
Ph

1-phenylhydrazine 3)100 C 15 min.

2-phenyl-1H-indole-3-carbaldehyde

N
H

2-phenyl-1-((2-phenyl-1H-indol-3yl)methylene)hydrazine

Procedure:Place a mixture of 0.25 gm. Of 3- formyl-2-phenyl indole

, 0.25ml. Phenyl hydrazine and 1.5 ml. ethanol and one
drop of Glacial acetic acid in a beaker, warm the
mixture and filter the product and wash with dilute HCl
and ethanol .
Result:Melting point of product: 260oC
Practical yield
: 0.125. gm

T.L.C:Rf values of reactant = 0.76

Rf values of product = 0.25
Solvent used for TLC = 2% ethyl acetate in n-hexane.

yl-

Calculations:1) Theoretical yield:3-formyl-2-phenyl indole

2-phenyl -1-((2-phenyl )-1-H-indolyl-3-

methylenehydrazine.
221 gm.
0.5gm
2) Practical yield:W gm
=
3) Percentage yield :-

311gm.
x
x

0.125 gm.
35.71 %

0.35gm.

Result Table
Description

Compound

Name & structure

N
Cl
N

2-(-4-Chloro-phenyl)-4,5-diphenyl-1H-imidazole

Time
Theoretical yield
Practical yield
%Practical yield
Solvent used
Melting point

5 hrs.
1.17 gm
0.791 gm
67.60%
Ethanol
2620 C

Result and
conclusion:2-Phenyl Indole derivatives:Indoles are an organic heterocyclic compounds having general formula
C8H7N1. This aromatic heterocycle is classified as an alkaloid.
Indole is an aromatic heterocyclic organic compound. It has a bicyclic
structure, consisting of a six-membered benzene ring fused to a fivemembered nitrogen-containing pyrrole ring. Indole is widely distributed
in the natural environment and can be produced by a variety of
bacteria. As an intercellular signal molecule, indole regulates various
aspects of bacterial physiology, including spore formation, plasmid
stability, resistance to drugs, biofilm formation, and virulence. The amino
acid tryptophan is an indole derivative and the precursor of the neutron
transmitter serotonin.
I have done synthesis of 2- Phenyl Indole derivative from
acetophenone.., which are interesting compounds with potential
pharmaceutical application

H1-NMR of 2-Phenyl
Indole:
7.67

6.84

7.71

7.50 H

7.17
H

7.14 H

N
H
H

7.46

8.36

7.71

7.17

7.10


1H NMR 3-formyl -2phenyl indole:
7.65

9.31
O

8.20
H

7.54 H

8.44
H

7.64 H

N
H
H

7.52

10.03 H
8.20

8.44

8.39

H1-NMR of 2-Phenyl-1-(2-phenyl)-1H-indole-3yl
methylene hydrazine :

7.21
H

7.13

H 7.21

7.67
H

7.38

7.17

7.63

6.85

CHNNH
H

7.71

H
H

7.13
7.38
H

N
H 8.35

7.63 H
H

7.46

7.71

7.38

7.38

T h u 1 a v 2 # 1 5 4 .0 0 1 .0 0 1 .1 r.e s p

7.30

CHLOROFORM-d

7.28

7.31
7.30

1.0

8.02

8.01

7.31

7.31

0.9

7.98

0.8
0.7

8.01

8.02

7.30

N
H

7.24

7.31
7.30

0.6

2.19

2,4,5-triphenyl-1H-imidazole

0.5

8.02
8.01
7.98
7.57 7.53 7.31
7.30
7.24

Normalized Intensity

7.24

0.4
0.3
0.2
0.1
0

1.99 4.41 4.46 5.03

14

13

12

11

10

8
7
6
Chemical Shift (ppm)

H1 NMR Spectra of 2, 4, 5-triphenyl-1H Imidazole

Referenc
es and
1) International Journal of pharmacy
pharmaceutical sciences
Vol-7, Issue 7, 2015.
2) Indian Journal of chemistry Vol-51B, October 2012, PP
1462-1469
3) Journal of Medicinal &Organic Chemistry RRJOMC |
Volume 1 | Issue 1| March April, 2015
4) Chem. Sci Trans., 2013 ,2(2) ,584-588
DOI:10.7598/cst2013.427
5) Journal of the Korean Chemical Society
2010, Vol. 54, No. Printed in the Republic of Korea
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7) International Journal of Scientific and & Engineering
Research,
Volume 4, Issue 5, May-2013 ISSN 2229-5518
8) Int. J Pharm. Sci., Vol.7, Issue 7, 97-103
9) Heterocyclic Chemistry by Raj K Bansal.
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