A Project Report On

“Highly Efficient Synthesis of β-Amino Ketones/aldehyde via Direct Mannich-type

Reaction Catalyzed by Acidic Ionic Liquid”
Submitted to
Sant Gadge Baba Amravati University, Amravati

Project report submitted for the Partial Fulfillment of Requirement for the Award of
Degree of Master of Science
In Chemistry
(Session: 2023-2024)
By
Ms. Priyanka Shrihari Jumale
(M.Sc.-II SEM-IV)
(Enrolment Number:- 193010741)
Under the Guidance of
Prof. Punam. S. Takarde
[M.Sc, NET, SET]
Professor
Department of Chemistry,
G.S. Science, Arts and Commerce College, Khamgaon, Dist-Buldana-444303

Center Code: 301

City Code: 061
May-2024

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 Certificate

This is to certify that the work presented in this project entitled “Highly Efficient

Synthesis of β-Amino Ketones/aldehyde via Direct Mannich-type Reaction

Catalyzed by Acidic Ionic Liquid” has been completed and submitted as bonafide

work carried out by Ms. Priyanka Shrihari Jumale, for the partial fulfilment of degree

of Master of Science in Chemistry. The project work is satisfactorily carried out

under my supervision in the PG Department of Chemistry, G.S Science, Arts and

Commerce College ,Khamgaon District Buldana. During the academic session 2023-

2024 and to the best of my knowledge the matter embodied in this project report has

not been submitted elsewhere for any diploma or degree.

Date: .../.../2024
Prof. Punam. S. Takarde

Place: Khamgaon ( Project Guide)

Prof. Dr. Hemantkumar. S Chandak

Professor and HoD
Department of Chemistry

G.S Science, Arts and

Commerce College,
Khamgaon

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 Declaration

The work presented in this project entitled “Highly Efficient Synthesis of β-Amino

Ketones/aldehyde via Direct Mannich-type Reaction Catalyzed by Acidic Ionic

Liquid” under the guidance of Professor Punam. S. Takarde, during the academic

year 2023-2024 as a partial fulfillment of project of MSc-II Semester-IV at P.G.

Department of Chemistry ,G.S Science, Arts and Commerce College, Khamgaon. I

further declare that this project work or any of this work has not been previously

submitted for any degree in this university or any other university.

Date: .../.../2024
Ms. Priyanka S. Jumale

Place: Khamgaon (MSc-II Sem-IV)

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 Acknowledgement

It is my pleasure to place on record my sincere gratitude towards my guide

Professor Punam. S. Takarde, Department of Chemistry, G.S Science, Arts and

Commerce College Khamgaon, whose guidance I received. It was his direction and

encouragement at every moment and step that motivated me to steer research

(project) work complet confidently and successfully.

I deem it great pleasure privilege to offer my sincere and cordial thanks to the

people who helped us who spend their precious time providing continuous idea and

exert guidance and constant encouragement throughout the course of this research

(Project) work.

We also extend our thanks to College Management and Principle, G. S. Arts

and Commerce College, Khamgaon for providing all the necessary facilities and

valuable support.

Also we would like to thank to all PG Chemistry teaching and non-teaching

staff of the department for their valuable guidance, encouragement, co-operation

and helps.

Our great thank to all who wished us success especially parents, friends

whose support and care makes us stay on earth.

Ms. Priyanka S. Jumale

(MSc-II SEM-IV)

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 “Highly Efficient Synthesis of β-Amino Ketones/aldehyde via Direct Mannich-type
Reaction Catalyzed by Acidic Ionic Liquid”

Table of Contents
1. Title of project 6
2. Abstract 6
3. Keywords 6
4. Introduction 6
5. Research Problem 8
6. Literature review 8
7. Research gap in previous work 12
8. Aims and objectives 12
9. Importance of project work in the context of the current status 13
10. Originality of project work 13
11. Methodology 13
11.1 Material 13
11.3 Experimental procedure 14
12. Scope and implication of project work 16
13. Outcomes of project work 16
14. Result and discussion 16
15. Conclusion 17
16. Reference 17

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1. Title of project

“ Highly Efficient Synthesis of β-Amino Ketones/aldehyde via Direct Mannich-type

Reaction Catalyzed by Acidic Ionic Liquid”

2. Abstract
A convenient, simple and efficient protocol for the β-amino carbonyl derivatives
using L-proline Nitrate as an Bronsted acid catalyst. The synthesis of highly
functionalized β-amino carbonyl derivative has been methodically retrieved via
organo-catalytic three components, reaction of a aldehyde, ketone and amine
compound. The reaction of β-amino carbonyl compounds carried out under solvent
condition at room temperature and give on to β-amino carbonyl derivative in high
yields.

3. Keywords
L-proline Nitrate, β-amino carbonyl compounds, aldehyde, ketone and amine, solvent,
room temperature

4. Introduction
1) L-proline Nitrate
Ionic liquid based on amino acids such as proline are one of the most important
groups of a little while back developed. Ionic liquid referred to as fully green
ionic liquid based on natural products. Their importance comprises two
different aspects. Bio renewability and economical benefits are the major
1
characteristics of materials of this kind .
https://doi.org/10.1039/C5RA08022C.Ionic liquid have attracted considerable
interest in organic synthesis. Primarily, Ionic liquid exist in synthesis
quaternary nitrogen organic salts expected to their high selectivity which
2
added green affluence in progress organic research .

6
 https://doi.org/10.1080/00397911.2020.1811987.

2) β-amino ketones and aldehyde

Β-amino ketones are versatile intermediate for the synthesis of nitrogen
containing compounds. Also, they are main subunits present in some
biologically important natural products as well as therapeutic agents3.
https://doi.org/10.3390/molecules15064359. Β-amino aldehydes constitute
an important class of functionalized building blocks. They have proved
themselves valuable intermediates for the synthesis of biologically active
compounds, such as α- and β-amino acids, heterocyclic derivatives etc4.
https://doi.org/10.1055/s-2003-44974

5. Research Problem
Assorted heterocyclic analogues have been classify for their unique and diverse
biological actions and heterocyclic scaffold like, β-amino carbonyl compounds is of
considerable implication to the deliberate design of drugs of several manufactured
drugs with differing medicinal effectiveness. But all these compounds are missing in
the study of their design, synthesis using amino acid derived L-proline nitrate as
greener ionic liquids Bronsted acid catalyst.

6. Literature review

S.N Author Journal/DOI Title Source Research

Gap
01 Benjamin 2001. J. L-proline catalyst direct Google 1. S-proline
5
List et al . AM.CHEM.Soc asymmetry three component schola used as
DOI:1021/ja0174231 Mannich reaction: Scope r catalyst
optimization of application 2. L-proline
to the highly enantioselective Nitrate is not
synthesis of 1,2-amino explored
alcohol

7
02 Nghi H @ 2014 Bentham Stereoselective Synthesis Google 1. K2CO3,H2O
Nguyen Science Publishers and Application of Amino schola is used as
6
et al . Ketones r catalyst
2. L-proline
Nitrate is not
explored

03 Teck- 1997 Tetrahedron Novel one spot Mannich type Google 1. InCl3 is
peng Loh letter reaction in water Indium schola used as
et al7. trichloride catalyst r catalyst
condensation of the 2. . L-proline
aldehyde, amine and silyl Nitrate is not
ether for the synthesis of explored
beta amino enol
04 W. Bentham science Green trends in Mannich Google 1. Liquid
sreevali publisher 2012 Reaction schola trifluorometh
et al8. r enesulfonic
acid is used
as catalyst
2. . L-proline
Nitrate is not
explored

05 Neghi H 2024 Bentham Stereoselective Synthesis Google 1.Di-

Nguyen science publisher and Application of Beta schola isopropyleth
6
et al . vol.18 Amino Ketones r ylamine
(DIPEA) is
used as
catalyst
2. . L-proline
Nitrate is not
explored

8
06 Nikita R 2015 L-proline nitrate: A recyclable Google 1. Synthesis
Agrawal DOI: and green catalyst for the schola of Piperidine
1
et al . 10.1039/C5RA08022C synthesis of highly r (Heterocycli
functionalize piperidines c organic
compound)
2. Beta-
amino
ketone not
explored
(class of
amino acid)

07 M. 2005 Alfa-Methylene-a-amino Google 1.CuO is

Antoniett DOI: Ketone Derivatives from beta schola used as a
a Loreto 10.1021/jo052330d -Ketoallylsilanes r catalyst
9
et al . 2. L-proline
Nitrate is not
explored

08 Barry M. 2005 J.AM CHEM Soc A direct catalytic asymmetric Google 1. Zn is used
Trost 2006 mannich type reaction via a schola as a catalyst
10
et a l. dinuclear zinc r 2. L-proline
catalyst:synthesis of either Nitrate is not
anti or syn beta hydroxy, beta explored
amino ketones

9
09 Yunfei cai DOI: Catalytic asymmetry Google 1. So(OTF)3
et al11. 10.1002/anie.201002 bromoamination of schola is used as a
355 chalcones: highly efficient r catalyst
synthesis of chiral alfa 2. L-proline
bromo amino ketone Nitrate is not
derivative explored

01 Wen- DOI: A new mild base-catalyzed Google 1. Potassium

0 Juan Hao 10.1039/b819763f Mannich reaction of hetero- schola carbonate
et al12. arylamines in water: highly r (K2CO3)is
efficient stereoselective used as a
synthesis of β amino catalyst
ketones under microwave 2. L-proline
heating Nitrate is not
e

Scheme: 1

Scheme: 2
10
Scheme: 3

Scheme: 4

7. Research gap in previous work

From the review of literature, it is noticeable that β-amino aldehyde and ketone
derivatives have recently received much more attention in the field of organic
synthesis due to versatile intermediate, great biological potential, building block for
drug design and extensively use in pharmaceuticals and agrochemicals. After
extensive literature review, we were convinced to focus on synthesis of β-amino
aldehyde and ketone derivatives using L-proline nitrate amino acid derived ionic
liquids Bronsted acid catalyst which are largely unexplored. Thus, we intend to
develop a green strategy/ protocol for the synthesis of β-amino aldehyde and
ketones derivatives using L-proline nitrate as a versatile ionic liquid Bronsted acid
greener catalyst.

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8. Aims and objectives
8.1 Aim:

“Highly Efficient Synthesis of β-Amino Ketones/aldehyde via Direct

Mannich-type Reaction Catalyzed by Acidic Ionic Liquid”

8.2 Objectives:

The specific objectives of present project work are

1) To synthesized L-proline nitrate as a versatile ionic liquid Bronsted

acid greener catalyst.

2) To synthesis β-amino aldehyde and ketones derivatives.

3) To study and characterize the newly synthesized β-amino aldehyde and

ketones derivatives with the help of 1H and 13CNMR, Mass etc.

Importance of project work in the context of the current status

Importance of the present project covers the following points:

 This project work includes a green protocol for the synthesis of β-amino
aldehyde and ketones by using greener and eco-friendly L-proline nitrate
ionic liquid Bronsted acid catalyst from aldehyde, ketone and amine

 The scope of this project is limited to β-amino ketones, derivatives and L-

proline nitrate.

 There is a possibility in developing various derivatives of β-amino

aldehyde and ketone derivatives which have great pharmaceuticals and
agrochemical importance.

 This project study will be helpful in the method development of a valuable

intermediate for the synthesis of molecules of great biological importance.

 β-amino aldehyde and ketone compound are used as versatile

intermediate in the field of organic synthesis.

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9. Originality of project work

This project report is in its original form and has not been conducted by any other
researchers in any institution, university jurisdiction, or in any Indian university. Our
findings may contribute a new method, knowledge, observations and new approach
in the synthesis of β-amino carbonyl compounds. This has never been investigated
by any other researchers. So far, the originality is concerned.

10.Methodology
10.1 Material
Melting point were measured using a melting point instrument and are uncorrected
1H and 13C NMR spectra were recorded on a 400 MHz NMR spectrometer. TLC was
performed using commercially available 100-400 mesh silica gel plates (GF254).
Unless otherwise noted, purchased n-hexane as an eluent was used with purification.

10.2 General schemes

Preparation of L-Proline nitrate:

1.15 g (0.01 mol ) of L-Proline nitrate was dissolved in 5 ml water. An equimolar

nitric acid (0.3 mol) was added to the solution in a round bottom flask. The reaction
0 0
mixture was then warmed to 60 c for 24 hour After evaporating in vacuum at 60 c,
1.78 g of the light yellow transparent liquid L-Proline nitrate was obtained.

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 11.3 Experimental procedure

Experiment No: 1

Procedure:
A mixture of p-bromo benzaldehyde 1a (185.02 mg ) , acetophenone 2a ( 120.15 mg),
aniline 3a ( 93.13 mg), L-proline nitrate in a round bottom flask was stirred with
magnetic stirrer for 24 hr at room temperature . After completion of reaction
(monitored by TLC), mixture was diluted with ethyl acetate and wash with water.
Separate the organic phase and aqueous phase. The aqueous layer was extracted
with ethyl acetate. The combine organic phase were wash with brine,to remove
emulsion and organic phase was re-extracted with ethyl acetate and dried using
sodium sulphate the solvent was evaporated, and crude product was purified by
silica gel column chromatography. (Hexane 100%) to afford 4a in a good yield

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 Experiment No: 2

Procedure:
A mixture of benzaldehyde 1b (26.53 mg ) , acetophenone 2b (30.04 mg ), p-nitro
aniline 3b ( 34.53 mg), L-proline nitrate in a round bottom flask was stirred with
magnetic stirrer for 24 hr at room temperature . After completion of reaction
(monitored by TLC), mixture was diluted with ethyl acetate and wash with water.
Separate the organic phase and aqueous phase. The aqueous layer was extracted
with ethyl acetate. The combine organic phase were wash with brine,to remove
emulsion and organic phase was re-extracted with ethyl acetate and dried using
sodium sulphate the solvent was evaporated, and crude product was purified by
silica gel column chromatography. (Hexane 100%) to afford 4a in a good yield

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 Experiment No. 3

Procedure:

A mixture of p-hydroxy benzaldehyde 1c (12.21 mg ) , acetophenone 2c (12.02 mg ),

p-nitro aniline 3c (13.81 mg ), L-proline nitrate in a round bottom flask was stirred
with magnetic stirrer for 24 hr at room temperature . After completion of reaction
(monitored by TLC), mixture was diluted with ethyl acetate and wash with water.
Separate the organic phase and aqueous phase. The aqueous layer was extracted
with ethyl acetate. The combine organic phase were wash with brin,to remove

16
emulsion and organic phase was re-extracted with ethyl acetate and dried using
sodium sulphate the solvent was evaporated, and crude product was purified by
silica gel column chromatography. (Hexane 100%) to afford 4a in a good yield .

11.Scope and implication of project work

1. Scope of the present project covers the following points:

 This project work includes a green protocol for the synthesis of β-amino
aldehyde and ketones by using greener and eco-friendly L-proline nitrate ionic
liquid Bronsted acid catalyst from aldehyde, ketone and amine

 The scope of this project is limited to β-amino ketones, derivatives and L-

proline nitrate.

2. Some of the possible implications of the present project work includes:

 There is a possibility in developing various derivatives of β-amino aldehyde

and ketone derivatives which have great pharmaceuticals and agrochemical
importance.

 This project study will be helpful in the method development of a valuable

intermediate for the synthesis of molecules of great biological importance.

 β-amino aldehyde and ketone compound are used as versatile intermediate in

the field of organic synthesis.

12.Outcomes of project work

The expected outcomes of the proposed research work are:

1) The research is expected to yield the discovery and development of new ,

highly efficient catalysts tailored for multi-component reactions

2) The optimization of catalytic systems likely to result in higher yields and

selectivity in the synthesis of heterocycles and their precursors

3) The integration of green chemistry principles can lead to more

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 environmentally friendly and sustainable processes for heterocycle synthesis

4) If the research facilitates the rapid and efficient synthesis of diverse

heterocyclic compounds, it can revolutionize the drug discovery process,
enabling the discovery of new therapeutic agents and chemical probes

5) The research is expected to contribute to the scientific knowledge base,

fostering further exploration and advancements in the field of catalysis,
multicomponent reactions and heterocyclic chemistry

13.Result and discussion

Firstly we have prepared L-proline nitrate and then perform some one-pot three-
component Mannich- type reaction at room temperature using solvent ( ethanol)
with aldehydes, ketones and amines the product was confirmed by physical
properties while 1HNMR spectra doesn’t match with the expected compounds.

Table 1:

Entry Time (hrs) L-proline Product Isolated Yield

nitrate

4a 24 10 mol% 54.45%

4b 24 10 mol% 48.33%

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 4c 24 10 mol% 45.55%

Conclusion

In conclusion, we have observed that the use of L-proline nitrate efficiently catalyzes
the condensation of aromatic β-amino carbonyl compound with various aromatic
aldehydes and ketones and aromatic amines. The formation of β-amino carbonyl
compounds have been obtained in mild conditions with low yield. Finally, the reaction
constitutes a sustainable and eco-friendly approach for the development of versatile
intermediate in the field of organic synthesis, biological and agrochemical interest
compounds.

14.Reference
(1) Online, V. A.; Bahekar, P.; Sarode, P. B.; Zade, S. S.; Chandak, H. S. RSC
Advances. 2015. https://doi.org/10.1039/C5RA08022C.

(2) Patil, P. G.; Satkar, Y.; More, D. H. L-Proline Based Ionic Liquid: A Highly
Efficient and Homogenous Catalyst for Synthesis of 5-Benzylidene-1,3-
Dimethylpyrimidine-2,4,6(1H,3H,5H)-Trione and Pyrano[2,3-d] Pyrimidine
Diones under Ultrasonic Irradiation. Synth. Commun. 2020, 50 (24),
3804–3819. https://doi.org/10.1080/00397911.2020.1811987.

(3) Salaheldin, A. M.; Al-Sheikh, M. A. β-Enamino Esters in Heterocyclic Synthesis:

Synthesis of Pyrazolone and Pyridinone Derivatives. Molecules 2010, 15 (6),
4359–4368. https://doi.org/10.3390/molecules15064359.

(4) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre, P.; Sambri, L.
Zn(ClO4)2·6H2O as a Powerful Catalyst for the Conversion of β-Ketoesters
into β-Enamino Esters. Synlett 2004, No. 2, 239–242.

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 https://doi.org/10.1055/s-2003-44974.

(5) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. The Proline-Catalyzed Direct
Asymmetric Three-Component Mannich Reaction : Scope , Optimization , and
Application to the Highly Enantioselective Synthesis of 1 , 2-Amino Alcohols.
2002, 124 (5), 827–833. https://doi.org/1021/ja0174231.

(6) Nguyen, N. H.; Hughes, A. S. and A. of-A. K. B.; Sleebs, B. E. Stereoselective

Synthesis and Application of -Amino Ketones. 2014, No. 061 3, 260–289.

(7) Loh, T.; Wei, L. Novel One-Pot Mannich-Type Reaction in Water: Indium
Trichloride-Catalyzed Condensation of Aldehydes, Amines and Silyl Enol Ethers
for the Synthesis of [3-Amino Ketones and Esters. 1998, 39, 323–326.

(8) Sreevalli, W.; Ramachandran, G.; Madhuri, W.; Sathiyanarayanan, K. I. Green

Trends in Mannich Reaction. 2014, 97–115.

(9) Loreto, M. A.; Migliorini, A.; Tardella, P. A.; Chimica, D.; Uni, V.; Roma, S.;
Chimica, D. R -Methylene- -Amino Ketone Derivatives from -Ketoallylsilanes.
2006, No. 2, 5011–5014.

(10) Trost, B. M.; Jaratjaroonphong, J.; Reutrakul, V. A Direct Catalytic Asymmetric

Mannich-Type Reaction via a Dinuclear Zinc Catalyst : Synthesis of Either Anti-
or Syn- r -Hydroxy- -Amino Ketones. 2006, 2778–2779.

(11) Cai, Y.; Liu, X.; Hui, Y.; Jiang, J.; Wang, W.; Chen, W.; Lin, L. Catalytic
Asymmetric Bromoamination of Chalcones : Highly Efficient Synthesis of
Chiral a -Bromo- b -Amino Ketone Derivatives **. 2010, 6160–6164.
https://doi.org/10.1002/anie.201002355.

(12) Chemistry, B.; Hao, W.; Jiang, B.; Tu, S.; Cao, X.; Wu, S.; Yan, S.; Zhang, X.; Han,
Z.; Shi, F. A New Mild Base-Catalyzed Mannich Reaction of Hetero-Arylamines
in Water : Highly Efficient Stereoselective Synthesis of b -Aminoketones under
Microwave Heating †. 2009, 1410–1414. https://doi.org/10.1039/b819763f.

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