Magnetic copper ferrite nanoparticles as an efficient and reusable catalyst for zomilidine synthesis

LÂM THỊ THU DUNG Magnetic copper ferrite nanoparticles as an efficient and reusable catalyst for zomilidine synthesis Major : Chemical Engineering Major ID : 60 52 03 01 MASTER OF SCI

LÂM THỊ THU DUNG

Magnetic copper ferrite nanoparticles as an efficient and

reusable catalyst for zomilidine synthesis

Major : Chemical Engineering Major ID : 60 52 03 01

MASTER OF SCIENCE THESIS

Ho Chi Minh, 2016

Cán bộ chấm nhận xét 1 : PGS.TS NGUYỄN ĐÌNH THÀNH

Cán bộ chấm nhận xét 2 : TS TRẦN NGỌC QUYỂN

Luận văn thạc sĩ được bảo vệ tại Trường Đại học Bách Khoa, ĐHQG Tp HCM ngày 23 tháng 8 năm 2016

Thành phần Hội đồng đánh giá luận văn thạc sĩ gồm:

(Ghi rõ họ, tên, học hàm, học vị của Hội đồng chấm bảo vệ luận văn thạc sĩ)

1 PGS.TS PHẠM THÀNH QUÂN

2 PGS.TS NGUYỄN ĐÌNH THÀNH

3 TS TRẦN NGỌC QUYỂN

4 TS NGUYỄN QUỐC THIẾT

5 TS NGUYỄN HOÀNG OANH

Xác nhận của Chủ tịch Hội đồng đánh giá LV và Trưởng Khoa quản lý chuyên ngành sau khi luận văn đã được sửa chữa (nếu có)

Họ tên học viên:Lâm Thị Thu Dung MSHV: 13051164

Ngày, tháng, năm sinh: 16/05/1991 Nơi sinh: Dak Lak

Chuyên ngành: Kỹ Thuật Hóa Học Mã số : 60 52 03 01 I TÊN ĐỀ TÀI: Magnetic copper ferrite nanoparticles as an efficient and reusable catalyst for zomilidine synthesis

II NHIỆM VỤ VÀ NỘI DUNG: Tổng hợp imidazo (1,2-α) pyridine sử dụng nano từ tính làm xúc tác

III NGÀY GIAO NHIỆM VỤ : 8/2015

IV NGÀY HOÀN THÀNH NHIỆM VỤ: 8/2016

V CÁN BỘ HƯỚNG DẪN : TS TRƯƠNG VŨ THANH

Tp HCM, ngày tháng năm 20

CÁN BỘ HƯỚNG DẪN (Họ tên và chữ ký) CHỦ NHIỆM BỘ MÔN ĐÀO TẠO (Họ tên và chữ ký) TRƯỞNG KHOA….………

(Họ tên và chữ ký)

Student: Lam Thi Thu Dung Page 1

I wish to thank all of my friends for their moral support during the course of

my study Good luck to all of you in the future endeavors

I am especially grateful to my family for their unconditional love and support through my difficult times They have always accompanied with every achievement in

my life

Student: Lam Thi Thu Dung Page 2

This is the first successful method using magnetic copper ferrite nanoparticles CuFe2O4 as an efficient and reusable catalyst for imidazo[1,2-α]pyridine synthesis from readily available starting materials including 4’iodoacetophenone and 2-

aminopyridine The reaction was carried out under oxygen atmosphere at 1000C, using 0.6 equivalents of iodine, in the presence of 10 mol% unfunctionalized CuFe2O4

catalyst for 24 hours The catalyst was not only easily recovered by applying external magnetic field but also reused several times without a significant loss of catalytic activity

LỜI CAM ĐOAN

Tôi xin cam đoan rằng:

Số liệu trong luận văn hoàn toàn do tôi thực hiện và chưa từng được sử dụng trong các bài báo, công trình nào khác

Mọi sự giúp đỡ cho việc thực hiện luận văn này đã được cảm ơn và thông tin trích dẫn đều có nguồn gốc rõ ràng

Student: Lam Thi Thu Dung Page 3

Tác giả luận văn

Student: Lam Thi Thu Dung Page 4

Table of Contents

ACKNOWLEDGEMENTS 1

CHAPTER 1: LITERATURE REVIEW 10

1.1 Zolimidine 10

1.1.1 Introduction 10

1.1.2 Traditional approaches to Zolimidine framework 10

1.2 Magnetic copper ferrite nanoparticles 13

1.2.1 Introduction 13

1.2.2 Application of using magnetic copper ferrite nanoparticles as catalysts for organic transformation in previous reports 14

CHAPTER 2: EXPERIMENTAL 17

2.1 Materials and instrumentation 17

2.2 Synthesis of imidazo[1,2-α] pyridine 19

2.2.1 Reaction procedure 19

2.2.2 GC yield determination 20

CHAPTER 3: OPTIMIZATION, RESULTS, AND 21

DISCUSSIONS21 3.1 Characterized catalyst 21

3.2 The premise reaction condition 21

3.3 Effect of temperature 21

3.4 Effect of solvents 22

3.4.1 Effect of different solvents 22

3.4.2 Effect of solvent concentration 23

3.5 Effect of reagent molar ratio 24

3.6 Effect of catalyst 25

3.6.1 Effect of different catalysts 25

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3.6.2 Effect of catalyst loadings 26

3.6.3 Leaching test 27

3.6.4 Recovery and recycle 28

CHAPTER 4: CONCLUSION 30

REFERENCES 31

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LIST OF ABBREVIATIONS

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LIST OF FIGURES

Figure 1.1 Zolimidine 10

Figure 1.2 The effect of magnetic field on superparamagnetic material 13

Figure 1.3 Catalyst CuFe2O4 MNPs in front (on the left) and behind when ( on the right) applied magnetic field [14] 14

Figure 2.1 Calibration curve of imidazo[1,2-α] pyridine 20

Figure 3.1 The influence of temperature on the GC yield 22

Figure 3.2 The influence of different solvents on GC yield 23

Figure 3.3 The influence of solvent volume on GC yield 24

Figure 3.4 The influence of reagent ratio on GC yield 25

Figure 3.5 The influence of different catalysts on GC yield 26

Figure 3.6 The influence of catalyst loadings on GC yield 27

Figure 3.7 Leaching test 28

Figure 3.8 Recyclability of catalyst 29

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LIST OF SCHEMES

Scheme 1.1 Synthesis zolimidine by condensation between 2-aminopyridines and

per-functionalized carbonyl compounds 11

Scheme 1.2 Synthesis zolimidine by Silver-mediated condition 11

Scheme 1.3 Synthesis of zolimidine using Fe-catalyzed [6] 12

Scheme 1.4 Synthesis of zolimidine using CuI/O2 system 12

Scheme 1.5 Synthesis of zolimidine using CuCl2/nano-TiO2 12

Scheme 1.6 The CuFe2O4-catalyzed C-O coupling reaction of phenol with aryl halides 15

Scheme 1.7 The CuFe2O4 catalyzed N-arylation 15

Scheme 1.8 C-S coupling reaction between iodobenzene và benzenethiol 16

Scheme 1.9 Our approach 17

Scheme 1.10 Synthesis of imidazo[1,2-α] pyridine using magnetic CuFe2O4 19

Scheme 1.11 Synthesis of imidazo[1,2-α] pyridine using CuCl2/nano-TiO2 21

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LIST OF TABLES

Table 2.1 List of chemicals purchased 18

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CHAPTER 1: LITERATURE REVIEW

1.1 Zolimidine

1.1.1 Introduction

Imidazo[1,2-α]pyridine (IP) scaffolds are found in many pharmacologically important compounds [1] Such compounds display antiviral, antibacterial, fungicidal and anti-inflammatory properties [2]

Zolimidine is a molecule with imidazopyridine structure,

[2-(methylsulfonylphenyl)imidazo(1,2-α)pyridine] A series of pharmacological

properties was conducted on zolimidine The principal characteristics of this

compound are the vital absence of toxicity and the very pronounced antagonism

against gastric ulcers of neurogenic origin At doses slightly higher than anticulcer doses, zolimidine exerted an anti-inflammatory and antipyretic action, while further doses it exerted central sedation without affecting reflex activity [3]

(1) Figure 1.1 Zolimidine

Because of an importance of pharmaceutical applications, there is a high demand of developing synthetic methods to form zolimidine, which has a simple and direct

procedure, offers high yield and utilizes reusable catalysis

1.1.2 Traditional approaches to Zolimidine framework

Traditionally, zolimidine were obtained by condensations between 2-aminopyridines

and per-functionalized carbonyl compounds under various conditions (scheme 1.1) [4]

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In 2012, Lei's group discovered a silver mediated oxidative coupling/cyclization

using 2-aminopyridines and terminal alkynes to produce zolimidine (scheme 1.2) [5]

In another study, Hajra's group discovered a Fe-catalyzed method using

2-aminopyridines and nitroolefins ( scheme 1.3) [6] Later, Su and co-workers reported a

homogeneous CuI/O2 system for the synthesis of zolimidine by a reaction between aminopyridines and unactivated methyl ketones and revealed an iodine-promoted Ortoleva-King reaction rather than the previously reported C–H functionalization,

2-which was involved in this transformation most probably (Scheme 1.4) [7]

Scheme 1.1 Synthesis zolimidine by condensation between 2-aminopyridines and per-functionalized carbonyl compounds

Scheme 1.2 Synthesis zolimidine by Silver-mediated condition

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Scheme 1.3 Synthesis of zolimidine using Fe-catalyzed [6]

Most recently, Meng et al employed heterogeneous CuCl2/nano-TiO2-catalyzed

aerobic synthesis of zolimidine from 2-aminopyridines and readily available ketones using air as the oxidant under iodine-, ligand- and additive-free conditions However, the recycling of CuCl2/nano-TiO2 is reduced significantly overtime [8]

Although most of methods shown above are effective in preparing zolimidine, they just have some drawbacks in respect of product separation and catalyst reuseability due to the use of homogeneous catalytic system Whereby, there are just few studies

Student: Lam Thi Thu Dung Page 13

about exploiting heterogeneous catalyst which can exhibit good recyclability and reusability catalysts, economic practicability as the demand of green chemistry

1.2 Magnetic copper ferrite nanoparticles

magnetized in the presence of an external magnet, but demagnetized when the external magnet is removed As the result of this, MNPs can be easily separated from the

reaction mixture by magnetic decantation

Figure 1.2 The effect of magnetic field on superparamagnetic material

Due to the aforementioned benefits, MNPs have long been exploited in catalysis as the support to offer recyclability for homogeneous transition metal catalyst [12] It is

noteworthy that many recent reports have indicated that unfunctionalized MNPs can

be employed directly as catalyst for many reactions [13]

magnetic

Without magnetic field

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Among these MNPs utilized as catalyst, CuFe2O4 have shown the high activity in a wide range of organic transformations More details will be mentioned in the next section

the right) applied magnetic field [14]

1.2.2 Application of using magnetic copper ferrite nanoparticles as catalysts for organic transformation in previous reports

Using unfunctionalized magnetic copper ferrite nanoparticles, CuFe2O4, directly

as catalyst has gained more attention and significant achievements In particular, Sun and coworkers reported CuFe2O4 catalyst in the C-O coupling reaction of phenol with

aryl halides (Scheme 1.6) [15]

CuFe2O4 was also employed in the C-N coupling reaction by Panda’s research group

(Scheme 1.7) [16] This protocol was successfully applied to a wide range of

substrates and taken place under the mild conditions with high yields

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halides

In the Organic and Biomolecular Chemistry, Kokkirala Swapna’s group reported the use of CuFe2O4 catalyst for C-S coupling reaction of thiophenol and aryl halides [17]

In the report, many types of oxide catalysts were used such as SnO2, Y2O3, NiFe2O4, ZnFe2O4, CuFe2O4, YFe2O4 và CoFe2O4 Among these catalysts, CuFe2O4 showed the highest activity with different derivatives of aryl halides Besides that, CuFe2O4 was also applicable to a wide range of aryl iodide and bromide, as well as different

derivatives of thiol All these reaction offer the yield from 70% to 98% In addition,

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CuFe2O4 was recovered and reused 3 times without significant loss of catalytic activity [17]

Scheme 1.8 C-S coupling reaction between iodobenzene và benzenethiol 1.3 Our approach

Although many recent methods were shown as the convenient and effective approaches in preparing zolimidine, there are still some disadvantages remaining in terms of seperation of product and reusability of catalyst due to the use of

homogeneous catalytic systems Especially, the purification of product is infinitely important in pharmaceutical industry, in which heavy metals contamination is

tolerated in such a strictly low level Thus, there is a high demand of using

heterogeneous catalytic system Currently, there have just been few studies employing heterogeneous catalyst Specifically, only one study of utilizing catalytic system of CuCl2-nano TiO2 wasreported by Meng et al.’s, however the catalytic activity declined significantly after using centrifugation to recover the catalyst In the meanwhile,

magnetic copper ferrite nanoparticles have emerged as a potential catalyst in a variety

of organic transformation due to the high capacity of separation and recovery from reaction medium in the presence of external magnet[18].

Accordingly, our group herein wishes to propose a simple procedure for synthesis of zolimidine with only two steps using magnetic copper ferrite nanoparticles CuFe2O4 as catalyst from commercially available materials

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Step 1

Step 2

Scheme 1.9 Our approach

Due to the time limitation, we have just researched the method to produce

imidazo(1,2-α)pyridine 1a, which is the first step of synthesis zolimidine in this thesis

CHAPTER 2: EXPERIMENTAL

2.1 Materials and instrumentation

All reagents, starting materials and catalyst were obtained commercially from Sigma-Aldrich, Acros and Merck, and were used as received without any further

purification unless otherwise noted

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Table 2.1 List of chemicals purchased

C at 40 oC/min and held for 6.5 minutes Inlet and detector temperatures were set constant at 280 oC Diphenyl ether was used as an internal standard to calculate

reaction conversions

GC-MS analyses were performed using a GCMS-QP2010 Ultra with a ZB-5MS

column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) The temperature program for GC-MS analysis heated samples at 50 oC for 2 min, then heated them from 50 to 280 oC at 10oC/min and held for 15 min Inlet temperature was set constant at 280oC

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The 1H and 13C NMR spectra were recorded on a Bruker AV 500 MHz spectrometer operating at 500 MHz for 1H and 125 MHz for 13C, respectively, using

tetramethylsilane as standard The chemical shifts (δ) are expressed as values in parts

per million (ppm) and the coupling constant (J) is given in hertz (Hz) Spin

multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet)

2.2 Synthesis of imidazo[1,2-α] pyridine

2.2.1 Reaction procedure

184.5 mg (0.75 mmol) of 4’-idoacetophenone 1a, 47.1 mg (0.5 mmol) of aminopyridine, 0.6 equivalent of iodine (76,2mg ; 0.3 mmol), 10 mol % of CuFe2O4(0.05 mmol ; 12 mg), 59,5 mg (0.3 mmol) of diphenyl ether as an internal standard, 2ml of 1,2 dichlorobenzene were placed into a 8 ml vial The mixture was heated and stirred in an oil bath at 1000C for 24h under an oxygen atmosphere (balloon) Reaction yield was monitored by withdrawing aliquots from reaction mixture at different time intervals, diluted with ethyl acetate (2 mL), dried over an anhydrous Na2SO4, and then analyzed by GC with reference to the diphenyl ether After completion, the catalyst was separated by applying an external magnet, then the liquid phase was extracted with ethyl acetate and dried with an anhydrous Na2SO4 Removal of the solvent under reduced pressure left a residue that was purified through column chromatography using silica gel as the stationary phase The product identity was confirmed by GC-MS

2-and NMR (see Appendices:)

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2.2.2 GC yield determination

After the reaction was completed, a sample was withdrawn and quenched with the mixture of ethyl acetate and water (ratio 4:1) to take organic layer This layer then was dried over anhydrous Na2SO4 and analyzed by GC The yield of reaction was calculated by using the following formula:

( ) (

)

Where:

- Spr: Peak area of product on chromotogram

- SIS: Peak area of diphenyl ether on chromotogram

- Moles of reactant: the number of moles of reactant

- Moles of IS: the number of moles of dipenyl ether

Figure 2.1 Calibration curve of imidazo[1,2-α] pyridine

y = 0.7239x - 0.0081 R² = 0.9998

0 0.2

0.4

0.6

0.8

1 1.2

Series1