- 1 -

PEG- 400 Mediated One-pot Multicomponent

Reaction Towards the Synthesis of Novel Molecular

Frameworks

A Project Report Submitted

As part of the Requirement for the Degree of Master of Science

In Chemistry

By

Shoibam Anilkumar Singh

12CHMS48

School Of Chemistry

University of Hyderabad

Hyderabad 500046.

INDIA

- 2 -

Dedicated to My family

- 3 -

Contents Page No.

1. Statement 4

2. Certificate 5

3. Acknowledgement 6

4. Abstract 7

5. Introduction 7-8

6. Results and Discussion 9-11

7. Experimental Section 12-14

8. Conclusion 15

9. References 16

- 4 -

Statement

I hereby declare that the matter embodied in this project report is the result

of investigations carried out by me in Dr. Perali Ramu Sridhar research group,

School of Chemistry, University of Hyderabad, Hyderabad, India.

In keeping with the general practice of reporting scientific observations,

due acknowledgment has been made wherever the work described is based on the

findings or other investigators. Any omission which might have occurred by

oversight or error is regretted.

Shoibam Anilkumar Singh

April 2014

Statement verified

Dr. Perali Ramu Sridhar

Project supervisor

- 5 -

Certificate

This is to certify that Shoibam Anilkumar Singh has satisfactorily completed the courses

required for the degree of M.Sc Chemistry.

The courses taken are as below:

I Semester:

CY401 Basic concepts and coordination chemistry

CY402 Basic concepts of Organic chemistry

CY403 Quantum chemistry

CY404 Mathematics and computer program

CY405 Inorganic Chemistry Lab-1

CY406 Organic chemistry Lab-1

II Semester: CY451 Chemistry of Main group and Inner Transition Elements

CY452 Organic Reactions and Mechanisms

CY453 Symmetry and Spectroscopy

CY454 Chemical and Statistical Thermodynamics

CY455 Inorganic Chemistry Lab-II

CY456 Physical chemistry Lab.

III Semester:

CH501 Spectroscopic and Other Physical methods

CH502 Reactive intermediates and synthesis in Organic chemistry

CH503 Chemical Dynamics

CH504 Chemical Binding

CH505 Organo metallic and Bio-Inorganic Chemistry

CH506 Organic Chemistry Lab-II

CH507 Instrumentation and computer applications lab

IV Semester:

CY551 Chemistry of Materials

CY552 Biological chemistry

CY553 Seminar Course

CY574 Advance magnetic resonance

CY582 Molecules and materials for energy production and storage

CY554 Project work

Dean

School of Chemistry

University of Hyderabad

- 6 -

Acknowledgments

I owe my sincere thanks and deepest sense of gratitude Dr. Perali Ramu

Sridhar who gave me the golden opportunity to do this wonderful project which

helped me in doing a lot of research and invoked in me the spirit of opting

research as my future career.

I would like extend my thanks to the Prof. M. Durga Prasad, Dean and all

other faculty members of School of Chemistry, for their utmost cooperation.

I am grateful to Dr. Ragu, Dr. Kishore for his constant support and guidance.

I am very much thankful to lab mates, Mr. Prakash kankipati and Mr.

Surendra for helping during my lab work.

I special thank to Ph.d students of Dr. Akhil kumar Sahoo, Dr. K.

Murlidharan, Dr. D. B Ramachary and Dr. Goverdhand Mehata‘s lab

Mr.Nagarjuna, Mr. Koushik, Mr. Raja, Mr. Dharavath Srinivas Mr. Rashid and

our lab members for their immoral guidance and helping even at night time during

my course of lab work .

Finally, I am thankful to My parents for their love, encouragement, care for

me and believing me in my study and for their everlasting support.

Shoibam Anilkumar Singh

- 7 -

Abstract:

As we know heterocyclic compounds have great importance in pharmaceuticals as medicine.

However, the synthesis of functionalized heterocyclic compounds and their derivatives require

multiple reactions and often need a catalyst. Frequently there is less yield of the final product

was observed because of multistep reactions. In the last decade research work on one pot

synthesis of heterocyclic compounds by using the catalyst, separating the catalyst for recycling,

from the reaction mixture is an arduous task. So people look on various alternatives for the

catalyst. Among several methods, one is using the solvent which works as medium for the

reaction as well as accelerates the rate of reaction. We choose the polyethylene glycol-400 as a

solvent, which is a mild and an efficient solvent for the synthesis of heterocyclic compounds.

Interestingly, a one-pot three component reaction is developed using polyethylglycol as solvent

without any catalyst. By using polyethylene glycol-400 we successfully synthesized a series of

novel heterocyclic derivatives 4, 6, 9 and 11 in good yield. All the compounds were

characterized by 13

C and 1H NMR spectroscopy.

Introduction:

Organic chemistry is the science of the rules of how chemical entities react with each other to

form new molecules. When three or more compounds react to form a single product is known as

multicomponent reaction. Recently, multicomponent reactions have gained much attention in

synthetic organic chemistry due to their advantages of intrinsic atom-economy, single

procedures, structural diversity, and energy saving, reduced waste and saving time. It is one of

the effective tools to find new drug discovery process. It takes less purification steps and avoids

protection and deprotection steps. Therefore, design and development of novel, efficient, and

green MCRs focused on a target product is one of the most challenging tasks in organic

chemistry. As MCRs proceed with high chemoselectivity, and often broad scope of functional

groups is tolerated. In addition, multiple bonds are formed in a single operation.1

In recent years, use of alternative solvent such as ionic liquids, polyethyleneglycol and

supercritical fluids has gained importance as green reaction media in view of environmental

perception. The use of water as a green solvent for organic chemistry has recently attracted

considerable attentions.2

Since Breslow demonstrated hydrophobic effects could strongly

- 8 -

increase the rate of some organic reactions and fostered the use of water as solvent in organic

chemistry in 1980s.3 There has been a growing recognition that water is an attractive medium

for many organic reaction, such as Claisen rearrangement, Diels-Alder, Reformatsky, and

pinacol-coupling reactions.4-6

Though water is a green solvent, it is not always possible to use

water as a solvent due to hydrophilic nature of the reactants and the sensitivity of many catalysts

to aqueous conditions. In this context, PEG has become an alternative reaction media to perform

organic synthesis due to its inherent advantages over toxic solvents. Furthermore, PEG is

inexpensive easy to handle, thermally stable, non-toxic and inexpensive.7

In one of three substrate used in our synthesis is pyridine derivative i.e., 2,6-lutidine. The

pyridine ring system is one of the most important heterocyclic motifs in numerous area of

organic chemistry and widely found in the core of alkaloids biologically active substances, chiral

liqands and clinical drugs. Consequently, the development of methods for the preparation of

polysubstituted pyridine derivatives is of importance to medicinal chemistry and represents a

worthwhile goal of organic synthesis.8

From 1850, first syntheses of α-amino cyanide, many researchers are working on MCRs

reaction. The efforts of the scientific community towards the application of MCRs in eco-

friendly solvents has been reviewed comprehensively in 2012.9

The surveyed list of novel

MCRS or improved variants running in water, ionic liquids, polyethyleneglycol polymer,

supercritical carbon dioxide,bioderived solvent and neat systems is impressive. Furthermore,

multicomponent chemistry is well represented in another 2012 review summarizing the progress

of organic synthesis in water.10

The general compatibility of MCRs with ionic liquids was also

recently demonstrated.11

A vast number of nitrogen containing heterocyclic compound find application in

pharmaceuticals, agrochemical research and drug discovery. In our reaction we use

polyethyleneglycol-400 as a solvent. PEG-400 have low vapor pressure, non-flammable,

involves simple workup procedures and inexpensive also. For these reasons PEG-400 is

considered to be a highly practical medium for organic reactions.

To the best of our knowledge, there are no reports for the synthesis of 4, 6, 9 and 11 using PEG-

400 as a reaction medium under catalyst-free condition.

- 9 -

Results and Discussion:

Scheme 1: Synthesis of 2-(1-(4-bromophenyl)-2-(6-methylpyridin-2-yl)ethyl)malononitrile (4)

Scheme 2: Synthesis of 2-(2-(6-methylpyridin-2-yl)-1-(3-nitrophenyl)ethyl)malononitrile (6)

Scheme 3: Synthesis of ethyl 4-(6-methylpyridin-2-yl)-2-nitro-3-(4-nitrophenyl)butanoate (9)

- 10 -

Scheme 4: Synthesis of 2-(1-(4-isopropylphenyl)-2-(6-methylpyridin-2- yl)ethyl)malononitrile

(11)

Use of multicomponent reaction to find new drug synthesis is an emerging field. We synthesis

some functionalized heterocyclic compounds with the use of PEG-400 as a solvent. The three

components mixtures 2,6-lutidine, aldehyde and activated methylene precursor were mixed in

1.1:1:1.2 equivalents, respectively. The reaction was heated upto 110 0C for 12 hours. When we

check with more heat in short time, we did not get our product. It shows that moderate

temperature for long time is necessary for our method of reaction. We monitored the rate of

reaction by TLC most of the compounds are active in long ultra violet (365 nm) and some are

iodine active. All the synthesized compound shows satisfactory result with 1H-NMR and

13C

NMR spectra which obtained on solution in CDCl3 using TMS as internal standard.

- 11 -

Reaction scheme:

Table 1:

- 12 -

Experimental Section:

Scheme 1:

Procedure: Synthesis of 2-(1-(4-bromophenyl)-2-(6-methylpyridin-2-yl)ethyl)malononitrile

(4)

2,6-lutidine (0.27 mL), 4-bromobenzaldehyde (374 mg) and malononitrile (0.12 mL) were

transferred to a 25 mL round bottom flask containing 5 mL of polyethyleneglycol to serve as

solvent. The round bottom was stirred under reflux condition. The temperature was maintained at

110 0C for 12 hr .The progress of reaction was monitored by TLC using 30% ethyl acetate in

hexane as a mobile phase. After completion of reaction the reaction mixture was cooled to room

temperature. The reaction mixture was poured with water and ethyl acetate .The organic layer

was removed under reduced pressure. Lastly the mixture was purified by column

chromatography on silica gel using ethyl acetate: hexane mixture and purified by column

chromatography and finally got yellow solid.

13C NMR (100 MHz, CDCl3): δ = 24.5, 28.4, 39.0, 44.5, 111.6, 112.2, 121.0, 122.9, 123.0,

129.7, 132.2, 136.20 137.2, 155.7, 158.6.

Scheme 2:

Procedure: Synthesis of 2-(2-(6-methylpyridin-2-yl)-1-(3-nitrophenyl)ethyl)malononitrile (6)

- 13 -

2,6-lutidine (3.70 mmol, 0.43 mL), 3-nitrobenzaldehyde (280 mg) and malononitrile

(2.03 mmol, 0.12 mL) were transferred to a 25 mL round bottom flask containing 5 mL of

polyethyleneglycol to serve as solvent. The round bottom was stirred under reflux condition. The

temperature was maintained at 110 0C for 12 hr .The progress of reaction was monitored by TLC

using 30% ethyl acetate in hexane as a mobile phase. After completion of reaction the reaction

mixture was cooled to room temperature. The reaction mixture was poured with water and ethyl

acetate .The organic layer was removed under reduced pressure. Lastly the mixture was purified

by column chromatography on silica gel using ethyl acetate: hexane mixture. The compound was

brown black in colour.

13C NMR (100 MHz, CDCl3): δ = 24.5, 28.2, 38.8, 44.5, 111.3, 112.9, 122.1, 123.3, 130.2,

134.2, 137.3, 139.1, 148.5, 155.1, 158.7

Scheme 3:

Procedure: Synthesis of ethyl 4-(6-methylpyridin-2-yl)-2-nitro-3-(4-nitrophenyl)butanoate(9)

2,6-lutidine (2.73 mmol, 3.17 mL), 4-ethyl-2-nitroacetate (2.51 mmol , 0.28 mL) were

transferred to a 25 mL round bottom flask containing 5 mL of polyethyleneglycol to serve as

solvent. The round bottom was stirred under reflux condition. The temperature was maintained at

110 0C for 12 hr .The progress of reaction was monitored by TLC using 30% ethyl acetate in

hexane as a mobile phase. After completion of reaction the reaction mixture was cooled to room

temperature. The reaction mixture was poured with water and ethyl acetate .The organic layer

was removed under reduced pressure. Lastly the mixture was purified by column

chromatography on silica gel using ethyl acetate: hexane mixture. The compound was pale

yellow in colour and got 60% yield.

- 14 -

13C NMR (100 MHz, CDCl3): δ = 22.7, 24.1, 29.3, 29.7, 31.9, 44.6, 61.7, 70.6, 72.6, 120.8,

121.8, 123.5, 126.6, 130.8, 137.6, 147.1, 151.5, 157.4, 157.9.

Scheme 4:

Procedure: Synthesis of 2-(1-(4-isopropylphenyl)-2-(6-methylpyridin-2-yl)ethyl)malononitrile

(11)

2,6-lutidine (2.20 mmol, 0.25 mL), 4-isopropylbenzaldehyde (2 mmol, 0.30 mL)

and malononitrile (2.4 mmol, 0.15 mL) were transferred to a 25 mL round bottom flask

containing 5 mL of polyethyleneglycol to serve as solvent. The round bottom was stirred under

reflux condition. The temperature was maintained at 110 0C for 12 hr .The progress of reaction

was monitored by TLC using 30% ethyl acetate in hexane as a mobile phase. After completion of

reaction the reaction mixture was cooled to room temperature. The reaction mixture was poured

with water and ethyl acetate .The organic layer was removed under reduced pressure. Lastly the

mixture was purified by column chromatography on silica gel using ethyl acetate: hexane

mixture and got 55% of yield.

13C NMR (100 MHz, CDCl3 ): δ = 23.8, 28.7, 33.8, 39.7, 44.8, 112.0, 112.6, 120.9, 121.7, 127.1,

128.0, 134.5, 137.1, 149.1, 156.4, 158.5.

- 15 -

Materials:

1H NMR (400 MHz) and

13C NMR (100 MHz) spectra are recorded in deuterochloroform

(CDCl3) on a Bruker-AVANCE-400 spectrometer using tetramethylsilane (TMS, δ = 0) as an

internal standard.

Chromatography:

Thin layer chromatography is performed on the TLC silica gel-60 from Merck. Column

chromatography is carried out on silica gel (100-200 mesh size) from Merck.

Reagents:

All the chemicals and solvents used in this study were of ananlytical grade and were used

without further purification.

.CONCLUSION

A simple, eco-friendly, and cost-effective method for the synthesis of novel heterocyclic

derivatives compounds like 4 ,6, 9 and 11 by using PEG-400 was developed under catalyst free-

condition for the first time. As to our knowledge such novel compounds has not previously

reported which is synthesis without any protection deprotection, any additive or co-solvent or

catalyst. This simple method which was performed under mild reaction condition has potential

for future application.

- 16 -

Reference:

1) Abu, T.; Sidick, B. S.; Mohan, L.; Mir, M. RSC Adv. 2012, 2, 5506–5509.

2) (a) Umkeherer, M.; Kalinki, C.; Kolb, J.; Burdack, C. Tetrahedron Lett. 2006, 47, 2391.

(b) Tejedor, D.; Garcia, T. F. Chem. Soc. Rev. 2007, 36, 484.

3) (a) Breslow, R.; Rideout, D. C. J. Am. Chem. Soc. 1980, 102, 7816. (b) Breslow, R. Acc. Chem.

Res. 1991, 24, 159. (c) Breslow, R.; Maitra, U. Tetrahedron Lett. 1984, 25, 1239.

4) (a) Ponaras , A . A . J . Org . Chem . 1983, 48, 3866. (b) Coates, R. M.; Rogers, B.

D.; Hobbs, S. J.; Peck, D. R.; Curran, D. P. J. Am. Chem. Soc. 1987, 109, 1160.

5) (a) Mattes, H.; Benezra, C. Tetrahedron Lett. 1985, 26, 5697. (b) Zhou, J. Y.; Lu, G.

D.; Wu, S. H. Synt. Commun. 1992, 22, 481.

6) Delair, P.; Luche, J. L. J. Chem. Soc.; Chem. Commun. 1989, 398.

7) Lingaiah, N.; Raghu, M.; Glory, A.; Yeramanchi, L. Eur. J. Chem. 2010, 1, 228-231.

8) Shao, J.; Wanwan, Y.; Shao, Z.; Yongping, Y. Chem. Commun. 2012, 48, 2785-2787.

9) Gu, Y. Green Chem. 2012, 14, 2091-2128.

10) Simon, M. O.; Li, C. Chem. Soc. Rev. 2012, 41, 1415-1427.

11) Isambert, M.; Duque, D.; Plaquevent, J.; Genisson, Y.; Rodriquez, J.; Constantieux, T.

Chem. Soc. Rev. 2011, 40, 1347-1357.

12) Kishor, P.; Jaganmohan, M. Org. Lett. 2012, 14, 6144.