Synthesis of quinazolinones using metal organic frameworks (vnu 21 and sulfated mof 808) as heterogeneous catalysts

Tên đề tài Synthesis of quinazolinones using metal-organic frameworks VNU-21 and sulfated MOF-808 as heterogeneous catalysts Tổng hợp các dẫn xuất quinazolinone sử dụng vật liệu khung hữ

VIETNAM NATIONAL UNIVERSITY - HO CHI MINH CITY

BACH KHOA UNIVERSITY

-

VO HOANG YEN

SYNTHESIS OF QUINAZOLINONES

USING METAL-ORGANIC FRAMEWORKS

(VNU-21 AND SULFATED MOF-808)

CÔNG TRÌNH ĐƯỢC HOÀN THÀNH TẠI TRƯỜNG ĐẠI HỌC BÁCH KHOA –ĐHQG -HCM

Cán bộ hướng dẫn khoa học 1: GS TS Phan Thanh Sơn Nam

ĐẠI HỌC QUỐC GIA TP.HCM CỘNG HÒA XÃ HỘI CHỦ NGHĨA VIỆT NAM

TRƯỜNG ĐẠI HỌC BÁCH KHOA Độc lập – Tự do – Hạnh phúc

NHIỆM VỤ LUẬN VĂN THẠC SĨ

Chuyên ngành: Kỹ thuật Hóa học Mã số: 60.52.75

I Tên đề tài

Synthesis of quinazolinones using metal-organic frameworks (VNU-21 and sulfated

MOF-808) as heterogeneous catalysts (Tổng hợp các dẫn xuất quinazolinone sử dụng

vật liệu khung hữu cơ-kim loại (VNU-21 và MOF-808 sulfate hóa) làm xúc tác dị

thể)

Nhiệm vụ và nội dung:

1 Khảo sát hoạt tính xúc tác của MOF VNU-21 cho phản ứng tổng hợp các dẫn

xuất quinazolinone có nhóm thế vòng thơm

2 Khảo sát hoạt tính xúc tác của MOF-808 sulfate hóa cho phản ứng tổng hợp

các dẫn xuất quinazolinone có nhóm thế alkyl

II Ngày giao nhiệm vụ: 15/01/2018

III Ngày hoàn thành nhiệm vụ: 15/06/2018

IV Cán bộ hướng dẫn: GS.TS Phan Thanh Sơn Nam

TP.HCM, ngày 16 tháng 06 năm 2018

CÁN BỘ HƯỚNG DẪN CHỦ NHIỆM BỘ MÔN ĐÀO TẠO

TRƯỞNG KHOA KỸ THUẬT HÓA HỌC

ACKNOWLEDGEMENT

First of all, I would like to express my gratitude to my advisor, Prof Dr Phan Thanh Son Nam, for his guidance, care, providing for a good condition and particularly financial support I would never accomplish this work without them

Next, I would like to express my sincere thanks to To Anh Tuong, my best colleague

in MANAR laboratory I always remember the time we spent together with all the joys, sorrows and challenges

I also want to thank Ms Ha Thanh My Phuong and Mr Doan Hoai Son, my first supervisors in our laboratory Although the time we worked together was short, your guidance was the base for me to complete my thesis

Furthermore, I want to thank all the co-authors in my papers, including Dr Tu Ngoc Thach, Ha Quang Hiep, Nguyen Dang Hieu, Le Van Thanh and Nguyen Thi Thu Hue for all the great supports and cooperation

Next, I would like to say thank to my friends on MANAR laboratory: Duong Ngoc Tan Xuan, Pham Huy Hoang, Pham Hoang Phuc, Nguyen Ha Huy Vu and Nguyen Thi Bao Tran for all the joys and sorrows we shared together

Last but not least, I would like to express my special thanks to my family Their constant encouragement gave me the important strength to successfully finish this research work

Vo Hoang Yen

ABSTRACT

Herein, we would like to present two approaches for the synthesis of quinazolinone and their derivatives New iron-based metal organic framework, VNU-21, and Zirconium-based MOF, MOF-808 were synthesized, characterized and employed as efficient heterogeneous catalyst for the synthesis of aryl-substituted and alkyl- substituted quinazolinone and their derivatives, respectively

VNU-21 (formula as Fe3(BTC)(EDB)2•12.27H2O) was successfully synthesized by sovolthermal method and characterized for their properties such as chemical formula crystalinity, thermal stability, surface area The obtained VNU-21 was used as efficient heterogeneous catalyst for the decarboxylation of phenylacetic acids via oxidative Csp3-H following by oxidative cyclization of intermediate products with 2-aminobenzamides to produce corresponding quinazolinones Wide scopes with high to excellent yields were achieved and the VNU-21 was reused and recycled many times without catalytic degradation

Zirconium-based metal-organic framework MOF-808 was synthesized, and sulfated with aqueous sulfuric acid solution The sulfated MOF-808 was utilized as a recyclable heterogeneous catalyst for the synthesis of alkyl- substituted quinazolinones from β-ketoesters and benzamides, and for the synthesis of benzimidazoles from β-ketoesters and o-phenylenediamines in glycerol as environmentally benign solvent The sulfated MOF-808 was reused and recycled several times without catalytic degradation

CONTENTS

ACKNOWLEDGEMENT iv

ABSTRACT v

CONTENTS vi

LIST OF FIGURES viii

LIST OF TABLES x

LIST OF SCHEMES xi

ABBREVIATION AND SYMBOLS xii

CHAPTER I - LITTERATURE REVIEW 1

1 Introduction to Metal-organic frameworks 1

General introduction 1

Applications in catalysis 4

2 The synthesis of quinazolinones 8

Introduction 8

Conventional approaches 9

Our approach 13

CHAPTER II - SYNTHESIS OF ARYL-SUBSTITUTED QUINAZOLINONES 15

1 Experimental 15

Material and Instrument 15

Synthesis of metal-organic framework VNU-21 16

Catalytic studies 17

2 Result and Discussion 17

Synthesis and characterization of VNU-21 17

Catalytic studies 19

3 Conclusion 30

CHAPTER III - SYNTHESIS OF ALKYL-SUBSTITUTED

QUINAZOLINONE AND THEIR DERIVATIVES 31

1 Experimental 31

Material and Instrument 31

Synthesis of catalyst 32

Catalytic experiments 33

2 Results and discussion 33

Synthesis and Charecterization of MOF-808 and sulfated MOF-808 33

Catalytic Studies 38

Conclusions 52

CHAPTER IV - CONCLUSION 54

1 Concluding remarks 54

2 Suggestions for future works 54

CHAPTER V - SUPPORTING INFORMATION 60

1 Aryl-Substituted Quinazolinone 60

Appendix 1: Calibration curve 60

Appendix 2: Characterization data 61

Appendix 3: Characterization data of quinazolinone derivatives: NMR data for all products 67

2 Alkyl-Substituted Quinazolinone 91

Appendix 1: Calibration curve calculation for 2-methylquinazolin-4(3H)-one 91

Appendix 2: Characterization data 92

Appendix 3: Characterization data of alkyl-substituted quinazolinone and derivatives 96

LIST OF FIGURES

Figure II.1 The crystal structure of VNU-21 was assembled from sinusoidal rod [Fe3(CO2)7]∞ (b) that are stitched horizontally by BTC3- and vertically by EDB2- (a,

e and f) to form the red crystals (d) with structure highlighted by a rectangular window of 8.9 × 12.6 Å (c) Atom colors: Fe, blue, light blue and orange polyhedra;

C, black; O, red All H atoms are omitted for clarity 18

Figure II 2 Leaching test showed that the first step did not proceed in the absence of the VNU-21 22

Figure II 3 Yield of 2-phenylquinazolin-4(3H)-one vs different catalysts 23

Figure II 4 Catalyst reutilization studies 24

Figure II.5 FT-IR spectra of the fresh (a) and recovered (b) VNU-21 catalyst 25

Figure II.6 X-ray powder diffractograms of the fresh (a) and recovered (b) VNU-21 catalyst 26

Figure III.1 X-ray powder diffractograms of the sulfated MOF-808 (a) and the simulated sulfated MOF-808 34

Figure III.2 FT-IR spectra of H3BTC (a), and sulfated MOF-808 (b) 35

Figure III.3 Scanning electron microscopy (SEM) (a) and Transmission electron microscopy (TEM) (b) images of the sulfated MOF-808 35

Figure III.4 The Nitrogen adsorption and desorption isotherms for sulfated MOF-808 36

Figure III.5 Pore size distribution of sulfated MOF-808 36

Figure III.6 TGA curve of the sulfated MOF-808 37

Figure III.7 The effect of solvents to the reaction yield 38

Figure III.8 Efect of different reactant molar ratio on reaction yield 39

Figure III.9 Effect of temperature on reaction yield 40

Figure III.10 Effect of catalyst amount on reaction yield 40

Figure III.11 The effect of reaction time to the reaction yield 41

Figure III.12 Leaching test 42

Figure III.13 The effect of other heterogeneous catalysts on reaction yield 43Figure III 14 The effect of various homogenous catalysts on reaction yield 44Figure III.15 Catalyst recycling studies 45Figure III.16 X-ray powder diffractograms of the fresh (a) and recovered (b) catalyst 45Figure III.17 FT-IR results of the fresh (a) and recovered (b) catalyst 46

LIST OF TABLES

Table II 1 Screening reaction conditions to maximize yield of 4(3H)-onea 20Table II.2 Synthesis of different quinazolinones via oxidative Csp3-H bond activation using VNU-21 catalysta 27

2-phenylquinazolin-Table III.1 Synthesis of various quinazolinones utilizing the sulfated MOF-808 as catalysta 47Table III.2 Synthesis of benzimidazoles utilizing the sulfated MOF-808 catalysta 48Table III.3 Synthesis of benzothiazoles utilizing the sulfated MOF-808 catalysta 51

LIST OF SCHEMES

Scheme II.1 Synthetic scheme for self-assembling the reddish-yellow crystal of

VNU-21 16

Scheme II.2 Synthesis of 2-phenylquinazolin-4(3H)-one via one-pot two-step 19

Scheme II.3 Control experiments 26

Scheme II.4 Proposed reaction pathway 27

Scheme III.1 The reaction between 2-aminobenzamide with methyl acetoacetate in glycerol utilizing the sulfated MOF-808 as catalyst 33

Scheme III.2 Proposed reaction mechanism 47

ABBREVIATION AND SYMBOLS

FT-IR Fourier transform infrared

NMP N-methyl-2-pyrrolidone

SC-XRD Single Crystal X-Ray Diffraction

TEM Transmission electron microscopy

TEMPO 2,2,6,6-tetramethylpiperidin-1-yl)oxy

CHAPTER I - LITTERATURE REVIEW

1 Introduction to Metal-organic frameworks

General introduction

Metal-organic frameworks (MOFs) are a class of hybrid material constructed from coordination of nodes (metal clusters or ions, also known as secondary building units-SBUs) with organic linkers [1] (Figure I.1) MOFs have a crystal structure, high specific surface area, flexible frame structure, and ability to change their size, shape, and functional groups inside its pores [1-4]

Figure I.1 (a) Schematic representation of synthesis of MOFs, (b) attractive MOF applications [3]

MOFs are constructed by joining SBUs with organic linkers, using strong bonds to create open crystalline frameworks with permanent porosity [4] The combination of diverse organic linker and SBUs with different geometries and connectivities generates a wide range

of framework topologies [5] Figure I.2 displays some typical examples for the components of MOFs’ structures The organic units are ditopic or polytopic organic carboxylates (and other similar negatively charged molecules) Long organic linkers can provide large pore size and hence improve the storage space and number of adsorption sites However, the large space within the crystal framework makes it prone to form interpenetrating structures (two or more frameworks grow and mutually intertwine together) [6]

Figure I.2 Examples of secondary building units (SBUs), organic linkers and topologies reported in MOFs and ZIFs [7]

Due to the distinct structure built from SBUs and organic linker, MOFs show glamorous features as their high specific surface area (up to 10400 m2 g-1) [1], large pore apertures (up to roughly 98 Å) [8], and low density (about 0.13 g cm-3) [9] As a result, MOFs have attracted enormous interests in different applications such as gas storage [10], gas separation [11], drug delivery [12], biomedicine [13] and especially catalysis [14]

Nowadays, green chemistry has emerged as a vital part of the chemical field Consequently, heterogeneous catalysis is highly preferred because of easier separation, reusability, minimized waste and synthesizing clean products [15] MOFs with features such

as high specific surface area, having open metal sites as well as high metal content could assure its highly heterogeneous catalytic activity [14] Compared with conventional inorganic homogeneous catalysts, MOFs are not only higher effective, but also more environmental –

through the past studies [17-19] Therefore, the use of MOFs in catalysis has been increasing continuously in the past decade [3] (Figure I.3)

Figure I.3 Publications related to MOFs in catalysis since 2005 [3]

Because of their useful applications, the synthesis of MOFs has attracted immense attention throughout the years A great number of methods have been carefully researched, such as: solvothermal/hydrothermal synthesis, microwave-assisted, sonochemical, electrochemical, mechanochemical, ionothermal, drygel conversion, microfluidic synthesis methods [20, 21] (Figure I.4)

Figure I.4 The most commonly used methods for MOF preparation [7]

Among these methods, the most common method generating MOFs is solvothermal synthesis [7] by heating the mixture of metal salt and organic ligand in a solvent system at certain temperature [28, 32] The advantage of this method is the ability of obtaining MOFs

crystals with quality high enough for their structure determination by Single Crystal X-Ray Diffraction (SC-XRD) However, this method exhibits some drawbacks such as long reaction time, difficulty in large-scale synthesis and many trials and errors are needed in order to gain crystals [31-33]

Scheme I.1 The general strategy of the solvothermal synthesis [21]

Applications in catalysis

The application of MOFs as heterogeneous catalyst has attracted tremendous interests and numerous MOFs structures have been designed and synthesized [22] The potential of MOFs in heterogeneous catalysis base on catalyst sites on both SBUs and organic linkers along with the advantages of easy separation and recycling [3] The merits of diversified metal clusters and designable and tailorable organic ligands give a rise in numerous MOFs topologies and porosities according to the requirements of reaction [3, 22]

Many organic transformations employed MOFs as an efficient heterogeneous catalyst, such as Knoevenagel condensation [3, 23, 24], Aldol condensation [25-28], oxidation reactions [29-31], Suzuki coupling [32, 33], ring-opening [34-37] In 2010, Phan et.al used MOF-5 as an efficient heterogeneous acid catalyst for Friedel–Crafts alkylation reactions [38] In this work, quantitative conversion was achieved under mild conditions without the need for an inert atmosphere and the MOF-5 catalyst could be reused several times without significant catalytic activity degradation In 2011, the oxidative behavior of two vanadium-containing metal organic frameworks MIL-47 and MOF-48 for the conversion of methane to acetic acid (AcOH) was evaluated by Yaghi et al The vanadium-containing metal–organic frameworks (MOFs) MIL-47 and MOF-48 could convert methane selectively to acetic acid with 70% yield (490 TON) based on K2S2O8 as an oxidant [39] Nguyen et.al employed highly porous metal-organic framework (MOF-199) for Ullmann-type coupling reactions between aryl iodides and phenols to form diaryl ethers [40] They optimized some factors

substrates and reaction time, in other to reach optimum reaction condition High conversions were achieved for the transformation at the catalyst concentration of 5 mol%, in the presence

of MeONa as a base and the catalyst could be recycled many times without degradation in catalytic activity

1.2.1 Iron-based metal organic frameworks as a heterogeneous catalyst

Among numerous MOFs structures applied in catalysis, iron containing MOFs have attracted many interests because of the high Lewis acid, strong coordinating bond in structure and high oxidation state of active metal sites in nodes The applications of iron based MOFs

in catalysis have been mentioned in many research works before, concentrating on the Lewis acid catalyzed reactions or oxidation reactions [22]

Dhakshinamoorthy et.al developed an approach for aerobic oxidation of styrene to benzaldehyde, styrene oxide, and derivatives catalyzed by Fe(BTC) Different reaction conditions were studied and extremely high selectivity was achieved [41] In 2012, they continuously studied the structure defects and stability on catalyst activity of Basolite F300 and MIL-100(Fe) for Lewis acid and oxidation reaction The well-define crystalline structure

of catalysts were compared as heterogeneous catalysts for four different reactions The result showed that commercial Fe(BTC) was the best catalyst for Lewis acid reactions because of its additional Brönsted acid sites, MIL-100(Fe) would be the best choice for oxidation reactions due to the presence of Fe3+/Fe2+ pairs, which seem to give rise to an interchange without compromising the crystal structure [42]

Scheme I.2 Recent publications on Fe-MOFs as heterogeneous catalyst by Dhakshinamoorthy and co-workers

In 2016, Hang et al synthesized and utilized Fe3O(BPDC)3 as an efficient heterogeneous catalyst for direct alkenylation of 2-substituted azaarenes with carbonyls via C-

H bond activation High yields of 2-alkenylazaarenes were achieved and the catalyst could be recovered and reused many time without catalytic activity degradation [43] Ha et al also employed Fe3O(BPDC)3 as catalyst for the synthesis of aryl-substituted pyridines via

cyclization of N,N-dialkylanilines with ketoxime carboxylates Excellent yields were obtained and the catalyst could reuse many times without degradation [44]

N O

O

+

N

Fe3O(BPDC)3TBHP

N R

R R

Scheme I.3 The synthesis of aryl-substituted pyridines via cyclization of dialkylanilines with ketoxime carboxylates catalyzed by Fe 3 O(BPDC) 3 [44]

N,N-In 2017, Ha and co-workers used MOF 235 as an effective heterogeneous catalyst for the synthesis of α-acyloxy The catalyst was synthesized, and utilized as an effective heterogeneous catalyst for the synthesis of α-acyloxy ethers via direct esterification of carboxylic acids with Csp3-H bonds The iron-based framework showed higher catalytic productivity than numerous homogeneous catalysts and various MOFs in the direct esterification reaction [45]

Phuc et.al reported the synthesis and catalytic studies of a new mixed-linker iron-based MOF VNU-20 [Fe3(BTC)(NDC)2·6.65H2O] as a recyclable catalyst for the functionalization

of coumarins with N,N-dimethylanilines via direct C–H bond activation This was the first time that [Fe3(CO2)7]∞ SBUs were evaluated for their catalytic activity [46]

Scheme I.4 The cross-coupling of coumarin and N,N-dimethylaniline utilizing VNU-20 as a heterogeneous catalyst [46]

In 2018, the iron–organic framework VNU-20 was continuously synthesized and utilized as an active heterogeneous catalyst for the cross-dehydrogenative coupling of coumarins with Csp3–H bonds in alkylbenzenes, cyclohexanes, ethers, and formamides Different reaction conditions were studied to understand the influence on catalytic yield The iron-based framework was reutilized many times for the functionalization of coumarins without a remarkable decline in catalytic efficiency [47]

1.2.2 Zirconium-based metal organic framewoks as an heterogeneous catalyst

Comparing with MOFs structures constructed from other common metal ions (Fe3+,

Cu2+, Al3+ …), zirconium-based MOFs (Zr-MOFs) are relatively less Nevertheless, because

of the strong Zr–O bonds within the SBUs and the high degree of interlinking of these SBUs, Zr-MOFs exhibited high stability Thermal stability of Zr-MOFs could be up to 540 oC made Zr-based MOFs become a superior candidate for harsh organic reaction, in which other metal-based MOFs could not be used due to their low thermal and chemical stability [22] As the result, Zr-MOFs and their functionalized derivatives with outstanding stability, intriguing properties and functions, were foreseen as one of the most promising MOF materials for practical applications [48]

In catalyst application, Zr-MOFs and their functionalized derivatives showed their potential candidate in Lewis acid reaction Because of unsaturated sites in structure, Zr-MOFs act as electron pair acceptors capable of accelerating the reaction process Vermoortele et al reported that the number of open sites in open framework of Uio-66 (Zr) could be drastically increased by using a modulation approach They combined the use of trifluoroacetic acid and HCl during the synthesis along with thermal activation of the material lead to explore a more open framework with a large number of open sites Consequently, the material was a highly active catalyst for several Lewis acid catalyzed reactions as the Meerwein reduction of 4-tert-butylcyclohexanone with isopropanol [49]

A new Zr-MOF was introduced by Wang et.al in 2014 By remove water from Zr6(μ3O)4(μ3-OH)4(OH)6(H2O)6(CO2)6 SBUs in Zr-BTB, more unsaturated metal sites were generated, result in the enhancement in Lewis acid activity The obtained material exhibited high catalyst activity on the reaction of carbonyl compounds with cyanide The conversion reached 100% in 24 hours at room temperature [50]

-Another approach was post-synthesis Zr-MOFs Many Zr-MOFs were functional modified to reach the reaction requirements In 2013, Mondloch et al used the AIM strategy

to introduce trimethylaluminum (AlMe3) or diethylzinc (ZnEt2) inside the porous structure of Nu-1000 by atomic layer deposition (ALD), namely as Al-AIM and Zn-AIM, respectively The result materials turned to chemical catalysis The Knoevenagel condensation between ethyl cyanoacetate and benzaldehyde can be catalyzed by Lewis acid; the prove Nu-1000 showed inactive catalyst toward Knoevenagel condensation while Al-AIM and Zn-AIM showed their active catalyst activity with the contribution of high Lewis acid AlIII and ZnII

spieces [51]

In 2014, Jiang at.el reported a sulfated metal–organic framework obtained by treating the microcrystalline form of MOF-808 with aqueous sulfuric acid to generate its sulfated analogue This material was defined as a superacid with a Hammett acidity function H0 ≤

−14.5 [52] and could be used in acid catalyzed reactions

2 The synthesis of quinazolinones

Introduction

Quinazolinones are a significant class of heterocycles, exist in a large number of bioactive natural products, synthetic drugs, pharmaceuticals, and agrochemicals [53] They exhibits many kinds of bioactivities, such as antibacterial, antifungal, antimalarial, anticancer, antihypertensive, antitubercular, inhibitors of derived growth factor receptor phosphorylation, anticonvulsant, selective COX-II inhibitors, and other activities [54-60]

2-methyl-4(3H)-quinazolinone

N N

N

Luotonin A, B, E

N N O

O

Tryptanthrin

N N

HN O

Rutaecarpine

N

O O

Loutonin F

Figure I.5 Quinazolinone skeleton containing natural products [53]

Regarding the importance of quinazolinones and their derivatives, numerous efficient routes for these heteroaromatic structures have been researched over years

Conventional approaches

Classical methods for synthesis of quinazolinones and their derivatives rely primarily upon condensation pathway from 1,2-disubstituted aromatic followed by oxidation of the aminal intermediate [61-64] Though providing the desired scaffold, those strategies suffer from certain drawbacks such as harsh condition with high temperature, the use of acid/base promoted, or the excess of stoichiometric or toxic oxidation agent (such as DDQ), long time reaction and low yields [65] In addition, most of the protocols are not well successful for 2-alkyl-substituted quinazolinones synthesis [66] because of the instability of aliphatic aldehydes or the in situ-generated aliphatic aldehydes under harsh conditions

Figure I.6 Classical approach

The most common method for 4(3H)-quinazolinone synthesis is based on the Niementowski reaction of anthranilic acid analogues with amides (Scheme I.6 ) [67]

N NH O

FG COOH

Scheme I.6 Niementowski reaction for 4(3H)-quinazolinone synthesis

Despite the desired product, this reaction showed many significant limits as narrow scope and starting material, low yield, high temperature, complex product purification Some modified Niementowski reactions were studied to improve their limitations

O OMe

O

NH2

NH2OH

NH2

+ Cl

O Cl

1) MW, 300W 5min, 50oC

2)UHP, K2CO3

MW, 500W 1.5h, 70oC UHP = urea hydrogen peroxide

Scheme I.8 The preparation of 2-substituted quinazolines

Another microwave-assisted reaction for quinazolinone preparation was studied by Kabri at.el Using dedicated microwave irradiation in aqueous medium, the Niementowski reaction was easily and rapidly performed in good yield and fast reaction [69]

Whilst methods of this nature are well established and able to provide the desired scaffolds, the main problems were narrow scope and limited stating material Over recent years, attempts to improve upon classical syntheses have moved in the direction of catalytic methodologies in order to overcome these limitations Indeed, catalysis offers numerous

synthetic benefits including shorter reaction times, extended scope and reduced reaction temperatures, as well as offering the opportunity to explore exciting new methodologies

In 2007, Bakavoli et al presented a one-pot protocol for 4(3H)-quinazolines synthesis involving the oxidative heterocyclization of o-aminobenzamides with aldehydes using KMnO4 as an stoichiometric oxidant under microwave irradiation (Scheme I.9)[70]

H KMnO4

R1

N NH O

R2

Scheme I.9 Synthesis of quinazolinones under microwave irradiation [70]

Although the reaction time was fast (within a few minutes), this method needed harsh condition (under microwave) and the using stoichiometric KMnO4 as oxidation at stoichiometric amount, that could lead to heavy metal contamination in the product and poor atom economy

In 2013, Dan and co-worker developed a protocol for synthesis of 2-substituted and

2,3-disubstituted 4(3H)-quinazolinones involving anthranilamides and aromatic aldehydes

catalyzed by 3 mol% CuO powder under air atmosphere (Scheme I.10) [63]

N H

"R O

Scheme I.10 CuO-catalyzed synthesis of quinazolinones between aldehyde and o-aminobenzamides [63]

In 2014, Kim et al presented a metal-free protocol for the synthesis of quinazolinones from anthranilamides and aldehydes via aerobic oxidation in wet DMSO (Scheme I.11) [64]

Scheme I.11 Metal-free synthesis of quinazolinones [64]

This method had many advantages such as metal-free reaction, aerobic oxidation, short time at moderate temperature In addition, due to the large of aldehyde derivatives, the scope was wide including aryl substitute and alkyl substitute The only limitation was the instability

of aldehydes in storage

To address this issue, alcohol was usually used to form in situ aldehyde through oxidation However, the oxidation should be under well controlled to prevent carboxylic formation Another approach for in situ aldehyde recently developed is decarboxylation [71, 72] Decarboxylation reactions are emerging as the powerful methodology for the construction of carbon-carbon bonds and carbon-heteroatom bonds in organic synthesis due to the readily available substrates, simple operation and clean byproduct (only CO2 as the byproduct) [71] Inspired by this trend, Chen et.al developed a protocol for the construction of N-heterocycles from easily available carboxylic acid derivatives and o-substituted anilines ( Scheme I.12)[71]

N H

NH2

R1O

up to 12 hours

In 2015, Li et.al presented a metal- and oxidant-free condition, giving both 2-alkyl- and 2-aryl-substituted quinazolinones in excellent yields Indeed, the reaction of β-ketoesters with o-aminobenzamides via selective C−C bond cleavage were catalyzed by phosphorous acid (Scheme I.13) [66]

NH2O

R1cat H2PO3

EtOH, 50oC

In summary, those methods still suffers the drawback of using acid catalysis or homogenous catalyst, in which catalyst recovery and reusability were not mentioned In the view of green chemistry, there is a need of finding a new alternative heterogeneous catalyst emphasized for the sake of environment and sustainable development

Our approach

In summary, quinazolinone and their derivatives are important organic scaffold that have attracted considerable attentions in the organic synthesis As a result, numerous studies concerning the synthesis of quinazolinone derivatives have been published throughout the years In particular, among methods, the advanced aerobic oxidative functionalization of sp3C-H bonds showed many strong points and should be further studied In spite of continuous improvement on this synthesis, most of routes still employ homogeneous catalyst whose reusability has not been mentioned in these studies It is therefore meaningful to develop new heterogeneous protocols to overcome the obstacles In that situation, Fe-MOFs have recently emerged as a new class of MOFs with considerable properties favoring the catalysis and, indeed, have also been proven as an effective heterogeneous catalyst for several organic transformations in many reports We therefore strongly believe that Fe-MOFs are a worthy subject for the catalytic study in the synthesis of quinazolinone derivatives

Inspired from Chen’s work and the work of Kim et al, we combine their protocols with some modifications to improve the drawbacks; we present an approach for the aryl-substituted quinazolinones (Scheme I.14) Instead of using only DMF as solvent (in Chen’s work) we add DMSO after the transformation of carboxylic acid derivatives to form in situ aldehydes followed the protocol of Kim et.al At this step, catalyst is removed to prevent damage so that they could remain their feature structure for the recyclability Moreover, the use of DMSO at the second step could reduce the reaction time

Scheme I.14 Our approach for aryl-substituted quinazolinone and their derivatives

Another approach for alkyl-substituted quinazolinone and their derivatives is inspired form the report of Li at.el using the reaction of β-ketoester and 2-amino benzamide in oxidant

free condition catalyzed by phosphorous acid (Scheme I.15) [66] In this reaction, we would like to replace acid catalyst (toxic catalyst) by a super acid MOF as sulfated MOF-808 [52] in order to prevent the toxic catalyst and the catalyst could be reused and recycled many times

NH2O

R1Sulfated MOFs

Scheme I.15 Our approach for alkyl-substituted quinazolinone and their derivatives

CHAPTER II - SYNTHESIS OF

Thermogravimetric analysis (TGA) was performed using a TA Instruments Q-500 thermal gravimetric analyzer under a gas mixture of O2 (20%) and N2 (80%) with temperature ramp of 5 °C min-1

Fourier transform infrared (FT-IR) spectra were measured on a Bruker ALPHA FTIR spectrometer using Attenuated Total Reflection (ATR) sampling technique

Low-pressure N2 adsorption measurements were carried out on the Micromeritics volumetric gas adsorption analyzer (3-FLEX Surface Characterization) A liquid N2 bath was used for measurements at 77 K Helium was used as estimation of dead space Ultrahigh-purity-grade N2, and He (99.999% purity) were used throughout adsorption experiments

Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25μm) The temperature program for GC analysis heated samples from 150 oC to 280 oC at 40 oC/min and were hold for 5 min Inlet and detector temperatures were set constant at 280 oC Diphenyl ether was used as an internal standard to calculate GC yield

GC-MS analyses were performed using a Shimadzu GCMS-QP2010Ultra with a 5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) The temperature program for GC-MS analysis held samples at 50oC for 2 min; heated samples from 50 to 280oC at 10oC/min and held them at 280 oC for 10 min Inlet temperature was set constant at 280oC MS spectra were compared with the spectra gathered in the NIST library The 1H NMR and 13C NMR spectra were recorded on Brucker AV 500 spectrometers using residual solvent peak as a reference

Synthesis of metal-organic framework VNU-21

The mixture of H2EDB (0.12 g, 0.45 mmol), H3BTC (0.021 g, 0.1 mmol), and FeCl2

(0.12 g, 0.94 mmol) was added to DMF (12 mL), and sonicated for 5 min to afford a clear solution Subsequently, this solution was divided into glass tubes, which was sealed and placed in an isothermal oven, pre-heated at 175 °C, for 72 h, to achieve reddish rhombic prism shape crystals of VNU-21 Consequently, the VNU-21 crystals were exchanged by DMF (5 x 15 mL), and methanol (5 x 15 mL) The VNU-21 crystals were then exchanged by liquid CO2, evacuated under CO2 supercritical condition, and activated under dynamic vacuum at room temperature to obtain dried VNU-21 (0.068 g, 75% yield based on H3BTC)

Catalytic studies

In a typical experiment, a solution of phenylacetic acid (0.3 mmol, 40.8 mg) in DMF (0.5 mL) was added to a 10 mL vial with the VNU-21 catalyst The mixture was stirred at

120 °C for 4 h under an oxygen atmosphere After that, the catalyst was removed by filtration

A solution of 2-aminobenzamide (0.2 mmol, 27.2 mg) in DMSO (0.5 mL) was then added to the reactor The mixture was additionally stirred at 120 oC for 5 h under oxygen The GC yield of benzaldehyde and 2-phenylquinazolin-2(3H)-one were monitored by withdrawing samples from the reaction mixture, quenching with brine (1 mL), extracting with ethyl acetate (3 x 1 mL), drying over anhydrous Na2SO4, and analyzing by GC regarding diphenyl ether as internal standard After the completion of the second step, the reaction mixture was cooled to room temperature Resulting solution was quenched with brine (5 mL), extracted by ethyl acetate (3 x 5 mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum The crude product was purified by silica gel column chromatography using hexane and ethyl acetate (1:1, v/v) as eluent The structure of 2-phenylquinazolin-4(3H)-one was verified by GC-MS, 1H NMR and 13C NMR For the leaching test, after the first 4 h reaction time, the catalyst was removed by filtration The solution phase was transferred to a new and clean reactor New phenylacetic acid was added, and the resulting mixture was subsequently stirred for additional 4 h at 120 oC under an oxygen atmosphere The yield of benzaldehyde was monitored by GC

2 Result and Discussion

Synthesis and characterization of VNU-21

The iron-based MOF VNU-21 was synthesized in 75% yield via mixed-linker synthetic strategy using 1,3,5-benzenetricarboxylic acid, 4,4'-ethynylenedibenzoic acid, and FeCl2 Single crystal X-rays diffraction results indicated that the VNU-21 crystallized in the orthorhombic space group, Pbcn (No 60), with unit cell parameters, a = 25.26917, b = 33.43879, and c = 13.62934Å Indeed, the VNU-21 was identified to possess the same topology with the VNU-20 [25]; however, with the larger pore dimension Particularly, this material was built from H3BTC and H2EDB linkers (Figure II.1a) and the sinusoidal [Fe3(CO2)7]∞ iron-rod SBU [26, 27](Figure.II.1b), which was constructed from three distinct octahedral iron centers in consecutive order The iron centers then connected each other through the sharing edge and vertex to infinite Fe-rod SBU (Figure II.1b) The sinusoidal [Fe3(CO2)7]∞ iron-rod metal cluster was finally joined by the horizontal BTC3- linker (Figure II.1e) and the vertical EDB2- linker (Figure II.1f) to form the 3-dimensional architecture of the VNU-21 (Figure II.1c, d) It should be noted that the VNU-21 possessed

open rectangular window of 8.9 × 12.6 Å with thick walls architecture, constructed of infinite rings to rings π-π interaction of EDB2- linkers (Figure II.1c, f)

Figure II.1 The crystal structure of VNU-21 was assembled from sinusoidal rod [Fe 3 (CO 2 ) 7 ]∞ (b) that are stitched horizontally by BTC 3 - and vertically by EDB 2 - (a, e and f) to form the red crystals (d) with structure highlighted by a rectangular window of 8.9 × 12.6 Å (c) Atom colors: Fe, blue, light blue and orange polyhedra; C, black; O, red All H atoms are omitted for clarity

Furthermore, PXRD analysis of the as-synthesized and simulated sample confirmed the bulk phase purity of the obtained VNU-21 (Figure V.2)

The VNU-21 was consequently exchanged and activated under CO2 supercritical condition, for which, the structural maintenance after the activation step was verified by PXRD analysis (Figure V.2) Elemental microanalysis (EA) additionally confirmed the chemical formula of the VNU-21 as Fe3(BTC)(EDB)2•12.27H2O (Cal: %C= 43.77; %H = 3.87; %N = 0 Found: %C = 43.23; %H = 3.33; %N = 0.26) FT-IR spectroscopy analysis indicated the existence of the bands centering at 1610 cm-1, which was assigned to -C=O stretch vibration of coordinated carboxylate species in the framework (Figure V.3)

The thermal stability of the VNU-21 was investigated by thermogravimetric analysis (TGA) (Figure V.4) Indeed, the residual metal oxides, ascribed to Fe2O3, in good agreement with those from model formula

The permanent porosity of VNU-21 was explored via nitrogen adsorption at 77 K with BET surface areas of 1440 m2 g-1 being recorded (Figure V.5) Certainly, this number was consistent with the simulated surface areas calculated by utilizing Material Studio 6.0 software (1419 m2 g-1)

In conclusion, a novel mixed-linkers iron-based MOF, VNU-21 was successfully synthesized through a solvothermal method The obtained VNU-21 was characterized by many characterization techniques such as single crystal XRD, PXRD, AAS, TGA, FTIR, nitrogen adsorption The results showed their formula as Fe3(BTC)(EDB)2•12.27H2O with high crystalinity, high thermal stability up to 300 oC and the surface area achieved 1440m2/g

Catalytic studies

2.2.1 Effect of reaction conditions to maximize yield of 2-phenylquinazolin-4(3H)-one

COOH

VNU-21 DMF, O2

2.

1.

Scheme II.2 Synthesis of 2-phenylquinazolin-4(3H)-one via one-pot two-step

The VNU-21 was utilized as a heterogeneous catalyst for the one-pot synthesis of phenylquinazolin-4(3H)-one, including iron-catalyzed oxidative Csp3-H bond activation of phenylacetic acid (step 1, Scheme II.2), and subsequent oxidative cyclization with 2-aminobenzamide (step 2, Scheme II.2) Chen and co-workers previously performed this one-pot transformation to achieve quinazolinones in the presence of FeCl3 catalyst for 12 h [71]

2-As the second step proceeded in the absence of the iron-based catalyst, it was decided to separate the VNU-21 after the first step to increase the catalyst lifetime Preliminary results also indicated that the yield of 2-phenylquinazolin-4(3H)-one was considerably improved if DMSO was utilized as a co-solvent in the second step Reaction conditions were screened to maximze the yield of the quinazolinone (Table II.1) The first step was conducted using 0.22 mmol phenylacetic acid in 0.5 mL solvent 1 at 120 oC for 3 h under an oxygen atmosphere,

with 0.01 mmol VNU-21 catalyst After that, the catalyst was removed, 0.20 mmol aminobenzamide in 0.5 mL solvent 2 was added, and the resulting mixture was heated at 120

2-oC for 5 h under an oxygen atmosphere Initially, the impact of solvent in the first step was explored (Entries 1-8, Table II.1) It was observed that the first step of the transformation was favored in DMF as solvent, affording 2-phenylquinazolin-4(3H)-one in 36% yield (Entry 1, Table II.1) DMA exhibited similar performance with 31% yield being detected, while NMP, chlorobenzene, dichlorobenzene, p-xylene, diglyme, and diethyl carbonate should not be used (Entries 2-8, Table II.1)

Table II 1 Screening reaction conditions to maximize yield of phenylquinazolin-4(3H)-one a

Catalys

t (mmol)

Temperatur

e (oC)

Reactan

t 2 (mmol)

Solvent 2 (0.5 mL)

Yiel

d (%)

Having these results, we consequently investigated the impact of phenyl acetic acid : aminobenzamide molar ratio on the yield of 2-phenylquinazolin-4(3H)-one (Entries 9-13, Table II.1) Experimental results indicated that the reaction was favored by excess amounts of phenylacetic acid The reaction afforded 34% yield when 1 equivalent of phenylacetic acid was used (Entry 9, Table II.1) Increasing the amount of phenylacetic acid to 1.5 equivalents, the yield of 2-phenylquinazolin-4(3H)-one was improved to 67% (Entry 12, Table II.1) One more factor that must be explored is the amount of the VNU-21 catalyst (Entries 15-18, Table II.1) Noted that only 3% yield was recorded in the absence of the catalyst, thus verifying the requirement of the iron-organic framework for the transformation (Entry 15, Table II.1) The yield was considerably improved in the presence of the framework catalyst, affording 67% for the reaction utilizing 3.3 mol% catalyst (Entry 16, Table II.1) In was noticed that by increasing the reaction of the first step to 4 h, the yield of 2-phenylquinazolin-4(3H)-one was remarkably upgraded to 89% in the presence of 3.3 mol% catalyst (Entry 19, Table II.1) The influence of solvent in the second step on the yield of 2-phenylquinazolin-4(3H)-one was also studied (Entries 19-25, Table II.1) It was noted that DMSO was the solvent of choice for the second step (Entry 19, Table II.1) Other solvents, including DMF, chlorobenzene, dichloroethane, diethyl carbonate, dioxane, and tert-butanol exhibited low performance for the transformation (Entries 20-25, Table II.1)

2-2.2.2 Leaching test

Since the one-pot synthesis of 2-phenylquinazolin-4(3H)-one from phenyacetic acid and 2-aminobenzamide utilizing the VNU-21 catalyst was conducted in liquid phase, an essential aspect that should be studied is the leaching of iron species from the framework to the solution Control experiments were consequently performed to verify if the transformation proceeded via truly heterogeneous catalysis or not (Figure II.2)

Figure II 2 Leaching test showed that the first step did not proceed in the absence of the VNU-21

Noted that the first step involved iron-catalyzed oxidative Csp3-H bond activation of phenylacetic acid to produce benzaldehyde (step 1, Scheme II.2), while the oxidative cyclization of benzaldehyde with 2-aminobenzamide (step 2, Scheme II.2) proceeded under metal-free conditions We consequently explored the contribution of soluble iron species, if any, to the formation of benzaldehyde in the first step The first step was conducted using 0.3 mmol phenylacetic acid in 0.5 mL DMF at 120 oC for 4 h under an oxygen atmosphere, with 0.01 mmol VNU-21 catalyst After the experiment, the VNU-21 catalyst was separated from the mixture The liquid phase was transferred to a second reactor, and fresh phenylacetic acid was subsequently added to the reactor The resulting mixture was the heated at 120 oC for 4 h under an oxygen atmosphere Yield of benzaldehyde was monitored by GC It was noticed that almost no additional benzaldehyde was generated under these conditions (Fig II.2) These data would verify that the oxidative Csp3-H bond activation of phenylacetic acid to produce benzaldehyde (step 1, Scheme II.2) only proceeded in the presence of the solid VNU-

0 20

2.2.3 Effect of different catalysts on yield of 2-phenylquinazolin-4(3H)-one

To emphasize the positive aspects of utilizing the VNU-21 as catalyst for the one-pot synthesis of 2-phenylquinazolin-4(3H)-one from phenylacetic acid and 2-aminobenzamide, a series of heterogeneous and homogenous catalysts were also tested for this transformation (Figure II.3) The first step was conducted using 0.22 mmol phenylacetic acid in 0.5 mL DMF

at 120 oC for 4 h under an oxygen atmosphere, with 0.01 mmol catalyst After that, the solid catalyst was removed, 0.20 mmol 2-aminobenzamide in 0.5 mL DMSO was added, and the resulting mixture was heated at 120 oC for 5 h under an oxygen atmosphere

Figure II 3 Yield of 2-phenylquinazolin-4(3H)-one vs different catalysts

It was noted that the reaction using FeCl3 proceeded to 67% yield of phenylquinazolin-4(3H)-one, while 33% yield was obtained for the case of FeSO4

2-Fe3O(BDC)3 was more active towards the reaction, affording 72% yield Fe3O(BPDC)3 was noticed to exhibit higher activity, with 85% yield of 2-phenylquinazolin-4(3H)-one being achieved MOFs containing other metals were less active than Fe-MOFs in the oxidative Csp3-H bond activation of phenylacetic acid, producing the desired quinazolinone product in lower yields The reaction using Cu2(OBA)2(BPY) catalyst afforded 46% yield, while only 12% yield was noticed for that utilizing Cu-MOF-199 as catalyst Zr-MOF-808 was almost inactive for the reaction, affording only 3% yield Similarly, the reaction utilizing Co-ZIF-67 catalyst progressed with difficulty, with only 2% yield being detected Compared to these

0 20 40 60 80 100

VNU-21

Fe3O(BDC)3Fe3O(BPDC)3nano Fe2O

3

nano CuF

e2O4FeCl3

FeSO4Cu2(

OBA)2BPY Cu-MOF-1

99

Zr-MOF-8

08 Co-ZI F-6 7

Catalyst

catalysts, the VNU-21 displayed the best performance, providing 89% yield of phenylquinazolin-4(3H)-one (Figure II.3)

2-2.2.4 Catalyst recycling and reusing

More previously mentioned, the VNU-21 exhibited higher catalytic performance than a variety of homogeneous and heterogeneous catalysts To additionally highlight the environmentally benign aspect of this iron-based framework, the readiness of catalyst recovery and reutilization was consequently studied The first step was carried out using 0.3 mmol phenylacetic acid in 0.5 mL DMF at 120 oC for 4 h under an oxygen atmosphere, with 0.01 mmol catalyst After that, the solid VNU-21 catalyst was removed by centrifugation, 0.20 mmol 2-aminobenzamide in 0.5 mL DMSO was added, and the resulting mixture was heated at 120 oC for 5 h under an oxygen atmosphere The recovered framework was then washed thoroughly with DMF, and methanol to get rid of any physisorbed materials, and consequently activated under vacuum at ambient temperature on a Shlenk line for 1 h New catalytic experiment was thereafter carried out using the recovered catalyst under the same conditions

Figure II 4 Catalyst reutilization studies

Experimental data indicated that it was possible to reuse the VNU-21 catalyst for the one-pot synthesis of 2-phenylquinazolin-4(3H)-one from phenylacetic acid and 2-aminobenzamide without a noticeable deterioration in catalytic efficiency Certainly, 88%

0 20

analysis results of both fresh reutilized VNU-21 samples displayed similar absorption characteristics (Figure II.5) Additionally, PXRD result of the reutilized catalyst suggested that the iron-based framework maintained its crystallinity under these reaction conditions, though a slight difference was recorded (Figure II.6)

Figure II.5 FT-IR spectra of the fresh (a) and recovered (b) VNU-21 catalyst

600 1000 1400 1800 2200 2600 3000 3400 3800

Wavenumber (cm-1)

(a)

(b)

0 2000

Figure II.6 X-ray powder diffractograms of the fresh (a) and recovered (b)

VNU-21 catalyst 2.2.5 Plausible Mechanism

To gain insight into the reaction pathway, several control experiments were carried out (Scheme II.3) First, the yield of benzaldehyde (2) in the first step was significantly decreased

in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) as a radical scavenger (Scheme II.3a) This result verified that the oxidative decarboxylation of phenylacetic acid (1) progressed via a radical pathway In the next two experiments, we tried to determine intermediates of this process (Scheme II.3b and II.3c) High yields of 2 were obtained when mandelic acid (A) and benzoylfomic acid (B) (absence of VNU-21) were employed as reactant in the first step of our protocol, so these two acids could be the intermediates

Scheme II.3 Control experiments

The second step pathway was also investigated by the next two experiments (Scheme II.3d and II.3e) 2-phenylquinazolin-4(3H)-one (4) was produced in excellent yield when 2-aminobenzamide (3) and benzaldehyde (2) was employed (Scheme II.3d) while the yield declined to 59% when molecular sieve was added (Scheme II.3e) Since, water could play a

vital role on this step On the basis of these results and previous reports in the literature [64, 71], a plausible mechanism was proposed (Scheme II.4)

Scheme II.4 Proposed reaction pathway

Under VNU-21 catalysis, α-hydroxycarboxylic acid A was formed by aerobic oxidation via radical pathway following by dehydrogenation to afford α-ketoacid B Aromatic aldehyde 2 was then produced by decarboxylation of B [73] After the first step, 3 was added to the reaction and reacted with 2 to obtain imine C Intermediate E was formed by a 6-endo-trig cyclization of C The presence of H2O in the reaction media could accelerate the cyclization

through intermediate D which was produced by nucleophilic addition of H2O and C 6-exo-tet cyclization of D then occurred, creating intermediate E Finally, product 4 was formed by oxidative dehydrogenation of E in the presence of O2 [64]

2.2.6 Effect of different substituents on the reaction

The scope of this work was additionally extended to the synthesis of different quinazolinones via oxidative Csp3-H bond activation using the VNU-21 catalyst (Table II.2) The first step was conducted using 0.3 mmol phenylacetic acid in 0.5 mL DMF at 120 oC for

4 h under an oxygen atmosphere, with 0.01 mmol catalyst After that, the solid catalyst was removed, 0.20 mmol 2-aminobenzamide in 0.5 mL DMSO was added, and the resulting mixture was heated at 120 oC for 5 h under an oxygen atmosphere

Table II.2 Synthesis of different quinazolinones via oxidative Csp 3 -H bond

activation using VNU-21 catalyst a