Msc 4d83o

J.T.S.S.P.M’S 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 α and β 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 10π-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.

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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.

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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.

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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

N

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

O

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

N

Ph

FGI

H3C

N

CH

CHCl

H3C

H

O

OH

H3C

H2 O

H3C

N

CHCl

H3C

N H

H

DMF

Analysis from: Vilsmeier Haack reaction 2) O

H

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

r

p

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

r

p

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-2—phenyl 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.

r

yl-

p

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

H

H

H

7.71

H

7.50 H

7.17 H

7.14 H

N H H

7.46

8.36

H

7.71

H

7.17

7.10

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

9.31 O

H

H

H

8.20 H

7.54 H

8.44 H

7.64 H

N H H

7.52

10.03 H 8.20

H

8.44

8.39

H1-NMR of 2-Phenyl-1-(2-phenyl)-1H-indole-3yl methylene hydrazine :   7.21 H

H

7.13

H 7.21

H

7.67 H

7.38

H

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

H

H

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

N

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

9

8 7 6 Chemical Shift (ppm)

5

4

3

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

2

1

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 6) General Papers ARKIVOC 2012 (vi) 143-154 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. 10)Heterocyclic Chemistry by J. A. Joule and K. Mills. 11) www.sciencedirect.com , www.pubchem.com. 12) www.google.co.in 13) www.msn.com .