Luận văn thạc sĩ Kỹ thuật hóa học: Magnetic copper ferrite nanoparticles as an efficient and reusable catalyst for zomilidine synthesis

LAM THI THU DUNGMagnetic copper ferrite nanoparticles as an efficient and reusable catalyst for zomilidine synthesis Major : Chemical Engineering Major ID: 60 52 03 01 MASTER OF SCIENCE

LAM THI 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 cham nhận xét 1 : PGS.TS NGUYEN BINH THÀNH

Cán bộ cham nhận xét 2 : TS TRAN NGOC QUYẼN - 5s:

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

Thanh phan Hội đồng đánh giá luận văn thạc sĩ gồm:(Ghi rõ ho, tên, học hàm, học vi của Hội đồng cham bảo vệ luận văn thạc sĩ)1 PGS.TS PHAM THÀNH QUẦN

2.PGS.TS NGUYEN ĐÌNH THÀNH 3.TS TRAN NGỌC QUYEN 4.TS NGUYEN QUỐC THIET 5.TS NGUYÊN HOANG OANH

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

CHỦ TỊCH HỘI ĐÔNG TRƯỞNG KHOA

Họ tên học viên:Lâm Thị Thu Dung ««« «<< <<<52 MSHV: 13051164 Ngày, thang, năm sinh: 16/05/1991 << sseeses Nơi sinh: Dak Lak Chuyên ngành: Kỹ Thuật Hóa Học - << ceeees Mã số : 60 52 03 01

I TÊN DE TÀI: Magnetic copper ferrite nanoparticles as an efficient and reusablecatalyst for Zomilidine Synthesis << 0000 nh

H NHIEM VU VA NOI DUNG: Tổng hợp imidazo (1.2-ơ) pyridine sử dung nanotr tim LAM XUC ta Ni

HI NGÀY GIAO NHIỆM VU : 8/2015 v.ceccccccccccccccscsescscscscsssscsesssessssesesssssssesescseeeeesIV NGÀY HOÀN THÀNH NHIEM VU: 8/2016 c.ccccccccscscscsseescesesesesseseseeseeeeesV CAN BO HUONG DAN : TS TR ONG VŨ THANH - 2 255 55s+csc<e:

Tp HCM, ngày thang năm 20

CAN BO HUONG DAN CHU NHIEM BO MON DAO TAO

(Họ tên va chữ ky) (Họ tên và chữ ký)

TRUONG KHOA

(Họ tên và chữ ký)

ACKNOWLEDGEMENTSI would like to express my deepest gratitude to my supervisor, Dr Truong VuThanh for his support and guidance during the research I am also grateful to allteaching staffs of the Organic Chemical Engineering Department I would like toextend my appreciation to Mr Nguyen Thai Anh, Ms Nguyen Thi Hoai Huong, Mr.Ong Duc Toan and other members in the Manar laboratory where I have done thisthesis for their meaningful encouragement and help.

I wish to thank all of my friends for their moral support during the course ofmy study Good luck to all of you in the future endeavors

I am especially grateful to my family for their unconditional love and supportthrough my difficult times They have always accompanied with every achievement inmy life

ABSTRACT.This is the first successful method using magnetic copper ferrite nanoparticlesCuFe,O, as an efficient and reusable catalyst for imidazo[1 ,2-a]pyridine synthesisfrom readily available starting materials including 4’iodoacetophenone and 2-

aminopyridine The reaction was carried out under oxygen atmosphere at 100°C, using

0.6 equivalents of iodine, in the presence of 10 mol% unfunctionalized CuFe,O4catalyst for 24 hours The catalyst was not only easily recovered by applying externalmagnetic field but also reused several times without a significant loss of catalyticactivity

TOM TATĐây là phương pháp dau tiên sử dung nano từ tinh dé tong hop imidazo[ 1 ,2-ơ]pyridine từ những nguyên vật liệu sẵn có bao gồm 4’iodoacetophenone và 2-aminopyridine Phản ứng được thực hiện trong điều kiện khí oxy ở 100°C, sử dụng 0.6đương lượng l;, 10% xúc tác nano từ trong vòng 24 tiếng Xúc tác không những dễdàng được thu hồi bang việc áp dụng từ trường ngoài, mà còn được sử dụng vài lần màkhông mat hoạt tính xúc tác.

LỜI CAM ĐOANTôi xin cam đoan răng:

Số liệu trong luận văn hoàn toàn do tôi thực hiện và chưa từng được sử dụng trong cácbài 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 nguôn gôc rõ ràng

Tac giả luận van

DECLARATIONI assure that:

The data in thesis completed by myseft and have not been used in the article or otherworks

All assistance for the implementation of this thesis was to thank and the informationwas used which clear origins

Author essay

Table of ContentsACKNOWLEDGEMENTTTS HH nọ kh |CHAPTER 1: LITERATURE REVIEW 0 ecceessssneeeeeeeesssaeeeeeeeesssaaeees 10

LL ZOMMICING 2 3Ả -Ã 10[.[.1 Introduction wee ee eeesssneceeccesssseceeecessssneceesceesssaeeeeseesssaaeeeeseesssaaeees 101.1.2 Traditional approaches to Zolimidine framewWOrK «««««<<++ 101.2 Magnetic copper ferrite Nanoparticles - «c1 9 1 ke ree 13[.2.1 Introduction wee ecessssneceeccessssneceeecesssseeeesceesssaaeeeeseessssaeeeeseesssaaeees 131.2.2 Application of using magnetic copper ferrite nanoparticles as catalysts fororganic transformation In PreViOUS FePOTFTts 11111 eeeeeeee 14CHAPTER 2: EXPERIMENLẦLL - - 5G << 1900 S990 ng re 172.1 Materials and instruMentation + «nhe 172.2 Synthesis of imidazo[1 ,2-G] pyridine - «<< eree 192.2.1 Reaction Procedure - - << 5G S000 nọ re 192.2.2 GC yield deteríminnafIOTN - - << << + 110010111 ng ke 20CHAPTER 3: OPTIMIZATION, RESULTS, AND HH 21DISCUSSIONS2I

3.1 Characterized CafaÏlVSK - cọ nà 213.2 The premise reaction COTCIfIOIN << 1 119990301 11 re 213.3 Effect of temperature - <1 00 nà 213.4 Effect of SỌVTIES Gv 223.4.1 Effect of different solvents eessseececceesssseceeeceessseeeeeseessseeaaeees 223.4.2 Effect of solvent concenfrafIOTI - - << s cv re 233.5 Effect of reagent molar ratio lee - << <5 1199000011 ng re 243.6 Effect of CafẠWVSÍ Gv 253.6.1 Effect of different cataÌWWSS HH re 25

3.6.2 Effect of catalyst loadings - Ăn re 263.6.3 Leaching Ẩ€SK cọ re 273.6.4 Recovery and TÊ€CVCÌÏ©- cọ re 28CHAPTER 4: CONCLUSION HH ng re 30358835005117 3l

LIST OF FIGURES

Figure 1.1 Zolimidine eee eeeeececceesssneceeeceessseeeeeceesssneeeesceesssseeeeeseesssaeeeeeees 10Figure 1.2 The effect of magnetic field on superparamagnetic material 13Figure 1.3 Catalyst CuFe2O, MNPs in front (on the left) and behind when ( on theright) applied magnetic field [ Í-4] - eeessseneeeeeeeeeeeeeeessessssnaaeeeeeeeeeeeeeeesssssesaaaneeeeees 14

Figure 2.1 Calibration curve of imidazo[1 ,2-œ] pyr1dine - - << «««««<<<++2 20Figure 3.1 The influence of temperature on the GC yield .««««««<<++ 22Figure 3.2 The influence of different solvents on GC yield ««««<<<<<2 23Figure 3.3 The influence of solvent volume on GC yieÌd «««««««<<++ 24Figure 3.4 The influence of reagent ratio on GC vI€Ìd - «s55 < <<sseeess 25Figure 3.5 The influence of different catalysts on GC yIeÌd «««««<< «+2 26Figure 3.6 The influence of catalyst loadings on GC yield -« «<< «<5 27Figure 3.7 Leaching Ẩ€Sí - - << s0 nọ và 28Figure 3.8 Recyclability of CafaÏyS( - c0 nhe 29

Scheme 1.7 The CuFe2O,4 catalyzed N-arylation 0 eee eeeeeesssreceeeeeessseeeeeeees 15Scheme 1.8 C-S coupling reaction between iodobenzene va benzenethiol 16Scheme 1.9 Our approach G5 G000 nọ và 17Scheme I1.10 Synthesis of imidazo[1 ,2-ơ | pyridine using magnetic CuFezOx 19Scheme 1|.11 Synthesis of imidazo[1 ,2-a] pyridine using CuCl,/nano-TiQg 21

LIST OF TABLES

Table 2.1 List of chemicals purchase€d - s1 ng 1 ke 18

CHAPTER 1: LITERATURE REVIEW1.1 Zolimidine

1.1.1 Introduction

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

Zolimidine is a molecule with imidazopyridine structure, (methylsulfonylphenyl)imidazo(1 ,2-a)pyridine] A series of pharmacologicalproperties was conducted on zolimidine The principal characteristics of thiscompound are the vital absence of toxicity and the very pronounced antagonismagainst gastric ulcers of neurogenic origin At doses slightly higher than anticulcerdoses, zolimidine exerted an anti-inflammatory and antipyretic action, while furtherdoses it exerted central sedation without affecting reflex activity [3]

[2-N Qo

(1)

Figure 1.1 ZolimidineBecause of an importance of pharmaceutical applications, there is a high demand ofdeveloping synthetic methods to form zolimidine, which has a simple and directprocedure, offers high yield and utilizes reusable catalysis

1.1.2 Traditional approaches to Zolimidine framework

Traditionally, zolimidine were obtained by condensations between 2-aminopyridinesand per-functionalized carbonyl compounds under various conditions (scheme 1.1) [4]

In 2012, Lei's group discovered a silver mediated oxidative coupling/cyclizationusing 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 ahomogeneous Cul/O, system for the synthesis of zolimidine by a reaction between 2-aminopyridines and unactivated methyl ketones and revealed an iodine-promotedOrtoleva-King reaction rather than the previously reported C—H functionalization,which was involved in this transformation most probably (Scheme 1.4) [7]

ONH; :

“Ni cà

2mCPB

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

CuCl-/nano-TiO-Z NH (1.2 mol %) CuCl-/nano-TiO-Z¬sN ý 0+ | > N pr S—Me

about exploiting heterogeneous catalyst which can exhibit good recyclability andreusability catalysts, economic practicability as the demand of green chemistry.1.2 Magnetic copper ferrite nanoparticles

1.2.1 Introduction

Magnetic nanoparticles have received the great attention of the researchers inthe variety of applications such as catalysis and biomedicine, etc [9] Magneticnanoparticles (MNPs) is the type of three-dimensional materials with the size from

Inm to 100 nm The MNPs contain about 10-10000 atoms in this size range [10].when the size of MNPs further decreases below the critical size of single domain, forexample about 20 nm for iron oxide, then such particles present superparamagneticbehaviour at room temperature [11] Superparamagnetism nanoparticles becomemagnetized in the presence of an external magnet, but demagnetized when the externalmagnet is removed As the result of this, MNPs can be easily separated from the

reaction mixture by magnetic decantation

Among these MNPs utilized as catalyst, CuFeaOx have shown the high activity inawide range of organic transformations More details will be mentioned in the nextsection.

Figure 1.3 Catalyst CuFe;O¿ MNPs in front (on the left) and behind when ( onthe right) applied magnetic field [14]

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

Using unfunctionalized magnetic copper ferrite nanoparticles, CuFe,O, directlyas catalyst has gained more attention and significant achievements In particular, Sunand coworkers reported CuFe,O, catalyst in the C-O coupling reaction of phenol witharyl halides (Scheme 1.6) [15]

CuFezOx 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

Riu „ + Rate 2 = Rio Z | Re

O

X= |, Br, Cl DMF, 135 °C, 24hRạ= H, NO;, tBu, CH;

6 o Á 2

Wo Á po)

84 % 99 % 88 %cy TÔ jon

MeO

75% 83 %Scheme 1.6 The CuFe,0,-catalyzed C-O coupling reaction of phenol with arylhalides

CuFe,O, was recovered and reused 3 times without significant loss of catalytic activity[17].

,Ph

SCuFe2O4

homogeneous catalytic systems Especially, the purification of product is infinitelyimportant in pharmaceutical industry, in which heavy metals contamination istolerated in such a strictly low level Thus, there is a high demand of usingheterogeneous catalytic system Currently, there have just been few studies employingheterogeneous catalyst Specifically, only one study of utilizing catalytic system ofCuCl,-nano TiO, was reported by Meng et al.’s, however the catalytic activity declinedsignificantly after using centrifugation to recover the catalyst In the meanwhile,

magnetic copper ferrite nanoparticles have emerged as a potential catalyst in a varietyof organic transformation due to the high capacity of separation and recovery fromreaction medium in the presence of external magnet [18]

Accordingly, our group herein wishes to propose a simple procedure for synthesis ofzolimidine with only two steps using magnetic copper ferrite nanoparticles CuFe2O, ascatalyst from commercially available materials

Scheme 1.9 Qur approachDue to the time limitation, we have just researched the method to produceimidazo(1 ,2-a)pyridine 1a, which is the first step of synthesis zolimidine in this thesis.

CHAPTER 2: EXPERIMENTAL2.1 Materials and instrumentation

All reagents, starting materials and catalyst were obtained commercially fromSigma-Aldrich, Acros and Merck, and were used as received without any furtherpurification unless otherwise noted

Table 2.1 List of chemicals purchasedName Producer4’-iodoacetophenone 99% Acros

Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010 Plusequipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m,inner diameter = 0.25 mm, and film thickness = 0.25 um) The temperature program

for GC analysis heated samples 100 °C for 1 minute and heated them from 70°C to 280

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

The 'H and '°C NMR spectra were recorded on a Bruker AV 500 MHz spectrometeroperating at 500 MHz for 'H and 125 MHz for '°C, respectively, using

tetramethylsilane as standard The chemical shifts (5) are expressed as values in partsper million (ppm) and the coupling constant (7) 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-a] pyridine

2.2.1 Reaction procedure

184.5 mg (0.75 mmol) of 4’-idoacetophenone la, 47.1 mg (0.5 mmol) of aminopyridine, 0.6 equivalent of iodine (76,2mg ; 0.3 mmol), 10 mol % of CuFe,0O4(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 andstirred in an oil bath at 100°C for 24h under an oxygen atmosphere (balloon) Reactionyield was monitored by withdrawing aliquots from reaction mixture at different timeintervals, diluted with ethyl acetate (2 mL), dried over an anhydrous Na2SOg, and thenanalyzed by GC with reference to the diphenyl ether After completion, the catalystwas separated by applying an external magnet, then the liquid phase was extractedwith ethyl acetate and dried with an anhydrous NazSOx Removal of the solvent underreduced pressure left a residue that was purified through column chromatographyusing silica gel as the stationary phase The product identity was confirmed by GC-MSand NMR (see Appendices:)

2.2.2 GC yield determinationAfter the reaction was completed, a sample was withdrawn and quenched withthe mixture of ethyl acetate and water (ratio 4:1) to take organic layer This layer thenwas dried over anhydrous NazSOx and analyzed by GC The yield of reaction wascalculated by using the following formula:

Spr 1 17225) x moles of ISGC yield (9 = (yield (%) = |< x 07239" 0.7239 moles of reactantWhere:

- Spt Peak area of product on chromotogram.- Sys: 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

1.2

y = 0.7239x - 0.0081

1 R? = 0.9998

0.80.6 ;

=@Series10.4

0.2

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