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

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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

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Dedicated to My family

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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

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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

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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

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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

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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 13C 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

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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.

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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)

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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.

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Reaction scheme:
Table 1:

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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)

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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.

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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.

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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.

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