Luận văn thạc sĩ Kỹ thuật hóa học: Synthesis of quinazolinones using metal-organic frameworks (VNU-21 and sulfated mof-808) as heterogeneous catalysts

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 AS HETEROGEN

LITTERATURE REVIEW

Introduction to Metal-organic frameworks

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 m 2 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 – friendly [16] MOFs have also proven themself to be promising heterogeneous catalysts

3 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

4 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]

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 such as catalyst amount, reaction temperature, the use of different bases, solvents, different

5 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 Fe 3+ /Fe 2+ 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

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

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

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)2ã6.65H2O] 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]

The synthesis of quinazolinones

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]

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

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

FG x Limited scope x High temparature x Limited starting material

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]

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

Scheme I.7 Microwave-assisted Niementowski reaction for the synthesis of novel pentacyclic heterocycles

By using microwave techniques, Maria et.al presented a convenient synthesis of novel tetraaza-pentaphene-5,8-diones in two steps, from anthranilic acid derivatives, via a microwave-assisted Niementowski reaction This route could improve the yield and reduced the reaction time comparing to Niementowski reaction [68]

2)UHP, K 2 CO 3 MW, 500W 1.5h, 70 o C 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

11 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]

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]

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]

12 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]

R 2 = aryl or alkyl R 3 = H or Et

Scheme I.12 Oxidative cyclization between o-substituted anilines and in situ aldehydes [71]

In situ aldehydes were formed by aerobic oxidation of sp 3 C-H bonds followed by decarboxylation, and then oxidative cyclization with o-substituted anilines in one pot

However, due to the use of homogenous catalyst (FeCl3), strict purification is required to prevent metal contamination in medicine application; in addition, the reaction time was long 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]

Scheme I 13 Synthesis of quinazolinone catalyzed by phosphorous acid

13 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

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 sp 3 C-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

14 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

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

SYNTHESIS OF ARYL-SUBSTITUTED QUINAZOLINONES

Experimental

All reagents and starting materials were obtained commercially from Sigma-Aldrich, Acros, Merck, Tokyo Chemical industry CO.LTD (TCI) and were used as received without any further purification unless otherwise noted

Powder X-ray diffraction (PXRD) patterns were recorded using a D8 Advance diffractometer equipped with a LYNXEYE detector

The single crystal of VNU-20 was mounted on a cryoloop and cooled down by a nitrogen flow controlled by a Kryoflex II system A Bruker D8 Venture diffractometer was used with X-rays generated by a monochromatic microfocus Cu Kα radiation source (λ 1.54178 Å) at 50 kV and 1.0 mA The diffraction data was collected by a PHOTON-100 CMOS detector The unit cell was determined using Bruker SMART APEX II software suite

The data set was reduced and data correction was carried out by a multi-scan spherical absorption method The structure was solved by direct methods and further refinement was carried out using the full-matrix least-squares method in the SHELX-97 program package

The crystallographic information file (CIF) of VNU-21 can be obtained, free of charge, via the Cambridge Structural Database (CCDC number: 1572921)

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

16 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 o C to 280 o C at 40 o C/min and were hold for 5 min Inlet and detector temperatures were set constant at 280 o C Diphenyl ether was used as an internal standard to calculate GC yield

GC-MS analyses were performed using a Shimadzu GCMS-QP2010Ultra 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 held samples at 50 o C for 2 min; heated samples from 50 to 280 o C at 10 o C/min and held them at 280 o C for 10 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library

The 1 H NMR and 13 C 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)

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

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 o C 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, 1 H NMR and 13 C 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 o C under an oxygen atmosphere The yield of benzaldehyde was monitored by GC.

Result and Discussion

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

18 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)

19 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 m 2 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 m 2 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 o C and the surface area achieved 1440m 2 /g

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

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 2- 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]

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 o C for 3 h under an oxygen atmosphere,

20 with 0.01 mmol VNU-21 catalyst After that, the catalyst was removed, 0.20 mmol 2- aminobenzamide in 0.5 mL solvent 2 was added, and the resulting mixture was heated at 120 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 2- phenylquinazolin-4(3H)-one a

25 DMF 0.30 0.01 120 0.20 tert-butanol 14 b a The first step was conducted for 3 h under an oxygen atmosphere; the second step was conducted for 5 h under an oxygen atmosphere; DMF: N,N’-dimethylformamide; DMA:

Dimethylacetamide; DMSO: Dimethyl sulfoxide; NMP: N-Methyl-2-pyrrolidone; DCB: dichlorobezene; DEC: diethyl carbonate; DCE:dichloroethane b The first step was conducted for 4 h under an oxygen atmosphere GC yield of 2-phenylquinazolin-4(3H)-one

Having these results, we consequently investigated the impact of phenyl acetic acid : 2- 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)

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 Csp 3 -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 o C 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 o C 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 Csp 3 -H bond activation of phenylacetic acid to produce benzaldehyde (step 1, Scheme II.2) only proceeded in the presence of the solid VNU- 21 catalyst

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 o C 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 o C 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 2- phenylquinazolin-4(3H)-one, while 33% yield was obtained for the case of FeSO4 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 Csp 3 -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

Fe 3O(BDC)3 Fe 3O(BPDC)3 nano Fe2O

Fe Cl3 Fe SO4 Cu2(

24 catalysts, the VNU-21 displayed the best performance, providing 89% yield of 2- phenylquinazolin-4(3H)-one (Figure II.3)

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 o C 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 o C 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% yield of 2-phenylquinazolin-4(3H)-one was obtained in the 5th run (Figure II.4) The FT-IR

Conclusion

A new iron-based MOF, VNU-21 (Fe3(BTC)(EDB)2•12.27H2O), constructed from mixed-linkers of BTC 3- and EDB 2- with infinite [Fe3(CO2)7]∞ rod SBU, was synthesized and characterized by several techniques The VNU-21 was consequently used as a recyclable heterogeneous catalyst in the one-pot synthesis of quinazolinones via two steps under oxygen atmosphere The first step involved the decarboxylation of phenylacetic acids via iron- catalyzed oxidative Csp 3 -H bond activation The second step was the metal-free oxidative cyclization of intermediate products with 2-aminobenzamides to produce corresponding quinazolinones The transformation was remarkably regulated by the solvent, in which DMF should be used for the first step, while DMSO emerged as the solvent of choice for the second step The VNU-21 was more active towards the one-pot synthesis of quinazolinones than a series of heterogeneous and homogeneous catalysts It was possible to reutilize the iron-based framework without a considerable deterioration in catalytic performance The point that quinazolinones were generated via one-pot sequential transformations with a recyclable catalyst was consequently valuable to organic synthesis and the chemical industry

CHAPTER III - SYNTHESIS OF ALKYL- SUBSTITUTED QUINAZOLINONE AND THEIR

1 Experimental Material and Instrument 1.1.1 Material

All reagents and starting materials were obtained commercially from Sigma-Aldrich, Acros, Merck, Tokyo Chemical industry CO.,LTD (TCI) and were used as received without any further purification unless otherwise noted

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 = 0.25 μm) The temperature program for GC analysis heated samples from 150 o C to 280 o C at 40 o C/min and were hold for 5 min Inlet and detector temperatures were set constant at 280 o C Diphenyl ether was used as an internal standard to calculate GC yield

GC-MS analyses were performed using a Shimadzu GCMS-QP2010Ultra 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 held samples at 50 o C for 2 min; heated samples

32 from 50 to 280 o C at 10 o C/min and held them at 280 o C for 10 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library

The 1 H NMR and 13 C NMR spectra were recorded on Bruker AV 500 spectrometers using residual solvent peak as a reference

Synthesis of catalyst 1.2.1 Synthesis of MOF-808

MOF-808 was synthesized following a literature procedure H3BTC (H3BTC benzene-1,3,5-tricarboxylic acid, 0.66 g, 0.31 mmol), and zirconium(IV) oxychloride octahydrate ZrOCl2ã8H2O (1.012 g, 0.31 mmol) was added to a mixture of DMF/HCOOH (54 mL/72 mL) in a 250 mL screw capped erlenmeyer flask The mixture sonicated for 10 min to obtain a clear solution After that, the solution was divided into two 100 mL pressurized flasks, and heated at 135 o C for 48 h in an isothermal oven Subsequently, the flasks were cooled to ambient temperature, and colorless crystals were collected by decantation The material was thoroughly washed with DMF (3 x 25 mL), and immersed in of ethanol (3 x 25 mL) for solvent exchange MOF crystals were then dried under vacuum at room temperature, and then at 70 o C for 12 h, achieving 0.702 g of MOF-808 (69 % yield based on ZrOCl2.8H2O)

Sulfated MOF-808 was synthesized according to a literature procedure [52]

Typically, aqueous sulfuric acid solution (0.1 M, 50 mL) was added to a round-bottom flask containing MOF-808 (0.5 g) The mixture was magnetically stirred for 1 min about once every 2 h, and the procedure was repeated for 24 h Subsequently, the crude product was washed with water (3 x 25 mL), acetone (3 x 25 mL), and chloroform (3 x 25 mL), respectively, and then dried under vacuum at room temperature, and then at 150 o C for 24 h to obtain final product The sulfated MOF-808 was stored in an argon atmosphere to avoid hydration

In a representative experiment, 2-aminobenzamide (0.034 g, 0.25 mmol), methyl acetoacetate (36 àL, 0.31 mmol), glycerol (1 mL), and diphenyl ether (0.043 g) as an internal standard, and the sulfated MOF-808 were added into an 8 mL screw-capped vial The catalyst concentration was calculated regarding zirconium/2-aminobenzamide molar ratio The mixture was vigorously stirred on a magnetic hot plate at 100 o C for 6 h (Scheme III.1)

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

After reaction, the vial was then cooled to ambient temperature, diluted with ethyl acetate (1 mL) The desired product was extracted into ethyl acetate (2 mL) The organic phase was then dried over anhydrous Na2SO4 and was analyzed by GC regarding diphenyl ether internal standard The expected product, 2-methylquinazolin-4(3H)-one, was isolated by recrystallizing with ethyl acetate GC-MS, 1 H NMR, and 13 C NMR analyses were subsequently implemented to verify the product identity In order to explore the recyclability of the catalyst, the sulfated MOF-808 catalyst was collected by centrifugation, washed respectively with water (2 x 25 mL), acetone (2 x 25 mL) and chloroform (2 x 25 mL) to remove excess reagents, activated under vacuum on a Schlenk line at 150 o C for 12 h, and then reutilized for a new catalytic run.

Results and discussion

The sulfated MOF-808 was synthesized from benzene-1,3,5-tricarboxylic acid and zirconium(IV) oxychloride octahydrate, and post-functionalized with aqueous sulfuric acid following a literature procedure [52] The catalyst was subsequently characterized utilizing a series of techniques

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

PXRD was used to determine the extent of formation and crystallinity of the sulfated

MOF-808 in comparison to simulated sulfated MOF-808 (Figure III.1) In pattern in Figure III.1, very sharp diffraction peaks are observed at 2 of approximately 5 o (single peak) and 9 o (double peak), which is representative of sulfated MOF-808 in the well-form crystalline phase The result was also similar to the simulated patterns previously reported in the literature (Figure III.1b) [52] Elemental analysis by AAS was also used to further confirm the chemical fomular of sulfated MOF-808 The zirconium and sulfur contents in sulfated MOF- 808 were presented as 40% and 5.47%, respectively There are no significantly different from the calculated values of 41 % of zirconium and 5.21% of sulfur

FT-IR spectroscopy analysis was also conducted (Figure III.2), in which, the FT-IR spectrum of 1,3,5-benzenetricarboxylic acid shows a strong peak at approximately 1721 cm -1 ascribed to C=O stretching vibration in free carboxylic acid and several strong and broad O-H bands between 3000 and 2500 cm -1 The corresponding peak for carboxylate groups in the spectrum of the sulfated MOF-808 was shifted to 1623 cm -1 Besides, no broad bands observed in the spectrum of the sulfated MOF-808, these observations indicated that carboxylate groups of H3BTC were coordinated on metal ions The broad bands at 3500 – 3000 cm −1 in the spectrum of the sulfated MOF-808 are also the indication of the presence of O-H in the catalyst’s structure

Figure III.2 FT-IR spectra of H 3 BTC (a), and sulfated MOF-808 (b)

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

The morphology of sulfated MOF-808 was measured by SEM As shown in Figure III.3.(a), the morphology of sulfated MOF-808 exhibits a octahedral crystal Meanwhile, to further characterize the structure of sulfated MOF-808, TEM studies were carried out Figure III.3 (b) displays typical TEM image of crystalline sulfated MOF-808

36 The Nitrogen uptake is another important characterization employed to determine the values of surface area and pore size of the porous material The nitrogen adsorption and desorption isotherms of the sulfated MOF-808 are shown in Figure III.4

Figure III.4 The Nitrogen adsorption and desorption isotherms for sulfated

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

The adsorption–desorption isotherms of the compound show a BET surface area of 806.81 m 2 /g and a Langmuir surface of 1139.79 m 2 /g (Figure III.4) Sulfated MOF-808

Quan tity Ad so rbe d (c m³/g ST P)

Diff ere ntia l S urfa ce Ar ea (m²/g )

37 containing micro pores in the range of 11 – 18 Å were confirmed by pore size distribution (Figure III.5)

The thermal stability and structural robustness of the sulfated MOF-808 were investigated by thermogravimetric analysis (TGA)

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

The TGA curve of evacuated sulfated MOF-808 was investigated and divided into four parts: (i) the weight loss of about 10% occurred below 200 o C; (ii) the weight loss of about 5% took place between 200 o C and 590 o C; (iii) the weight loss of more than 45% occurred between 590 o C and 610 o C; (iv) the TGA curve remained unchanged from 610 o C to 900 o C

Accordingly, the weight loss in the TGA curve can most probably be attributed to free solvent (DMF) or water in storage time, coordinated formate, and 1,3,5‐benzenetricarboxylic acid (BTC)‐linker loss, respectively

In conclusion, the obtained sulfated MOF-808 was successfully synthesized through solvothermal method followed by sulfated step post-synthesis The characterization of sulfated MOF-808 showed their crystalline structure, thermal stability and porosity

Weightloss (%) DTG(delta(%)/delta(oC))

Catalytic Studies 2.2.1 The effect of solvent on the reaction yield

Initially, the sulfated MOF-808 was utilized as a heterogeneous catalyst for the cyclocondensation reaction between 2-aminobenzamide and methyl acetoacetate to form 2- methylquinazolin-4(3H)-one (Figure III.7) A series of different solvents were employed for transformation

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

The reaction was conducted at 100 o C for 6 h, using 2-aminobenzamide:methyl acetoacetate molar ratio of 1:1.25, in the presence of 8 mol% catalyst In the first example of the cyclocondensation protocol to prepare quinazolinones from β-ketoesters and benzamides using H3PO3 catalyst, Zhou and co-workers screened a series of solvents, and pointed out that ethanol was the solvent of choice [52] For the sulfated MOF-808 catalyst, the reaction conducted in ethanol afforded 58% yield Many candidates, including both protic and aprotic solvents, expressed poor performance for this transformation Interestingly, among these solvent, glycerol displayed the best result, producing 2-methylquinazolin-4(3H)-one in 93% yield Ethylene glycol, diethylene glycol, and triethylene glycol were also less effective than glycerol

2.2.2 The effect of ratio reactants to the reaction

The impact of 2-aminobenzamide:methyl acetoacetate molar ratio on the formation of the desired product was also explored

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

The reaction was not favored significantly by using excess 2-aminobenzamide; while excess methyl acetoacetate led to higher yields of 2-methylquinazolin-4(3H)-one Best yield was obtained for the reaction employing 1.25 equivalents of methyl acetoacetate

2.2.3 The effect of temperature on the reaction yield

Another factor to be considered was the reaction temperature

Figure III.9 Effect of temperature on reaction yield

It was noticed that the reaction should be performed at 100 o C Regarding experimental point of view, it was noted that decreasing the temperature to lower than 100 o C led to difficulty in stirring due to the high viscosity of glycerol Boosting the temperature to 120 o C was noticed to be unnecessary, since the yield of the expected product was not improved remarkably

2.2.4 Effect of Catalyst amoun on reaction yield

Moreover, the catalyst concentration also exhibited influence on the reaction

Figure III.10 Effect of catalyst amount on reaction yield

41 The reaction progressed to 11% yield in the absence of catalyst, thus verifying the significant role of the sulfated MOF-808 in the cyclocondensation transformation The yield of 2-methylquinazolin-4(3H)-one was upgraded to 79% in the presence of 2 mol% catalyst

Best result was achieved for the reaction utilizing 8 mol% catalyst, with 93% yield being recorded Indeed, using more than 8 mol% catalyst did not led to higher yields

2.2.5 The effect of reaction time on the reaction

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

The kinetic study for this reaction using the sulfated MOF-808 was also addressed The transformation was conducted in glycerol at 100 o C, using 1.25 equivalents of methyl acetoacetate, in the presence of 8 mol% of sulfated MOF-808 as catalyst for 1 hour, 2 hour, 3 hour, 4 hour, 5 hour, 6 hour, 8 hour, respectively

It was presented that the GC yield increased significantly from 0% to 85% over the first 5 hours prior to reaching the peak of 93% at 6 hours No more products were produced in the next 2 hours The reaction time of 6 hours was therefore chosen for further studies

CONCLUSION

Concluding remarks

In summary, a novel mixed-linkers iron-based metal organic frameworks-VNU-21 (Fe3(BTC)(EDB)2•12.27H2O ) and sulfated MOF-808 were successfully synthesized through solvothermal methods The obtained MOFs were characterized for different techniques including Single Crystal X-ray Diffraction, Powder X-ray Diffraction, Scanning Electron Microscopy, Transmission Electron Microscopy, Thermogravimetric Analysis, Fourier Transform Infrared Spectroscopy, Atomic Adsorption Spectrophotometry and nitrogen physisorption measurements

Two kinds of MOFs were used as heterogeneous catalyst for the synthesis of aryl- substituted and alkyl- substituted quinazolinone and their derivatives The VNU-21 was consequently used as a recyclable heterogeneous catalyst in the one-pot synthesis of aryl- substituted quinazolinones and derivatives via two steps under oxygen atmosphere The first step involved the decarboxylation of phenylacetic acids via iron-catalyzed oxidative Csp 3 -H bond activation The second step was the metal-free oxidative cyclization of intermediate products with 2-aminobenzamides to produce corresponding quinazolinones Meanwhile, the sulfated MOF-808 was utilized as a 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 and glycerol was used as green solvent for this reaction It was possible to reutilize both VNU-21 and the sulfated MOF-808 catalyst while its catalytic activity was maintained for several cycles.

Suggestions for future works

Both of MOFs VNU-21 and sulfated MOF-808 are still new and could be utilized for various organic transformations as heterogeneous catalyst, as well as screening reactivity of other compounds that serves as suitable partners for the examining coupling reaction for further expansion of the substrate scope

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73 Xiuling Chen, et al., (2015), "Iron-catalyzed aerobic oxidative functionalization of sp3 C-H bonds: a versatile strategy for the construction of N-heterocycles"

SUPPORTING INFORMATION

Aryl-Substituted Quinazolinone

The ratios of the peak area of the product to the peak area of the internal standard were calculated as follow: product

Where: S product and Sinternal standard are respectively the peak areas of 2- phenylquinazolin-4(3H)-one and diphenyl ether measured on the GC chromatogram

Peak area ratio Molar ratio

GC yield of the reaction was calculated as follows : product o product product o product n 100%

Where : product n (mol) : mole of the product obtained, o product n (mol) : calculated mole of the product when reaction yield equals 100%, ninternal standard(mol) : mole of diphenyl ether in the sample

Calibration curve

Figure V.1 GC yield of the reaction with reference to diphenyl ether.

Characterization data

Section 2.1: Single Crystal X-rays Diffraction Analysis

Table V.1 Crystal data and structure refinement for VNU-21 with guest molecules inside y = 1.1468x + 0.0186 R² = 0.9989

Completeness to θ = 65.083° 0.999 Data / restraints / parameters 50185/ 0 / 523

R 1, wR 2 (all data) 0.087, 0.1906 Largest diff peak and hole

Section 2.3: Powder X-ray Diffraction Patterns

Figure V.2 Powder X-ray diffraction patterns of VNU-21 after multistep-steps treatments

Activated under CO2 super-critical condition

Section 2.4: Fourier Transform Infrared Analysis

Figure V.3 Fourier transform infrared analysis (FT-IR) of activated VNU-21

Figure V.4 TGA analysis of VNU-21

Section 2.6: Surface Area Analysis for VNU-21

Figure V.5 N 2 uptake of VNU-21 at 77 K The closed and open circles represent the adsorption and desorption branches of the isotherm, respectively The connecting line functions as a guide for the eye

Characterization data of quinazolinone derivatives: NMR data

Figure V.6 1 H-NMR spectra of 2-phenylquinazolin-4(3H)-one

Figure V.7 13 C-NMR spectra of 2-phenylquinazolin-4(3H)-one

Characterization data for 2-phenylquinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified on silica gel column chromatography (hexane/ethyl acetate = 1:1): white solid, 87% yield 1 H NMR (500 MHz, CDCl3, ppm) δ 11.54 (s, 1H), 8.34 (d, J = 7.5 Hz, 1H), 8.28 – 8.22 (m, 2H), 7.86 – 7.79 (m, 2H), 7.62 – 7.58 (m, 3H), 7.55 – 7.48 (m, 1H) 13 C NMR (125 MHz, CDCl3, ppm) δ 163.9, 151.8, 149.6, 135.1, 133.0, 131.8, 129.2, 128.2, 127.5, 127.0, 126.5, 121.0

Figure V.8 1 H-NMR spectra of 2-(4-bromophenyl)quinazolin-4(3H)-one

Figure V 9 13 C-NMR spectra of 2-(4-bromophenyl)quinazolin-4(3H)-one

Characterization Data for 2-(4-bromophenyl)quinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 73% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.61 (s, 1H), 8.18 – 8.11 (m, 3H), 7.85 (t, J = 7.5 Hz, 1H), 7.80 – 7.72 (m, 3H), 7.54 (t, J = 7.5 Hz, 1H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 162.2, 134.7, 132.0, 131.6, 129.8, 126.8, 125.9, 125.2, 122.3, 121.0

Figure V 10 1 H-NMR spectra of 2-(4-chlorophenyl)quinazolin-4(3H)-one

Figure V 11 13 C-NMR spectra of 2-(4-chlorophenyl)quinazolin-4(3H)-one

Characterization Data for 2-(4-chlorophenyl)quinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and purified by recrystallization: white solid, 78% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.60 (s, 1H), 8.20 (d, J = 8.5 Hz, 2H), 8.15 (d, J = 8.0 Hz, 1H), 7.87 – 7.82 (m, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.56 – 7.51 (m, 1H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ = 162.2, 151.3, 148.6, 136.3, 134.7, 131.6, 129.6, 128.7, 127.5, 126.8, 125.9, 121.0

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 86% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.64 (s, 1H), 8.26 (s, 1H), 8.17 (d, J = 6.5 Hz, 2H), 7.87 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.63 – 7.54 (m, 2H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 162.1, 148.5, 134.7, 134.7, 133.4, 131.1, 130.5, 127.6, 127.5, 126.9, 126.4, 125.9, 121.1

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 93% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.62 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.88 – 7.83 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 7.5, 1.5 Hz, 1H), 7.62 (dd, J = 8.0, 1.0 Hz, 1H), 7.60 – 7.54 (m, 2H), 7.50 (td, J = 7.5, 1.0 Hz, 1H)

Figure V 16 1 H-NMR spectra of 2-(4-methoxyphenyl)quinazolin-4(3H)-one

Figure V 17 13 C-NMR spectra of 2-(4-methoxyphenyl)quinazolin-4(3H)-one

Characterization Data for 2-(4-methoxyphenyl)quinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 97% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.42 (s, 1H), 8.20 (d, J = 9.0 Hz, 2H), 8.16 – 8.12 (m, 1H), 7.82 (t, J = 7.0 Hz, 1H), 7.71 (d, J = 8.0

Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 162.3, 161.9, 151.9, 148.9, 134.5, 129.4, 127.3, 126.1, 125.8, 124.8, 120.7, 114.0, 55.5

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 96% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.55 (s, 1H), 8.19 – 8.14 (m, 1H), 7.85 (t, J = 7.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.80 – 7.72 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 3.87 (s, 3H)

Figure V 20 1 H-NMR spectra of 2-o-tolylquinazolin-4(3H)-one

Figure V 21 13 C-NMR spectra of 2-o-tolylquinazolin-4(3H)-one

Characterization Data for 2-o-tolylquinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 74% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.44 (s, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.83 (t, J = 7.5 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.58 – 7.47 (m, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.38 - 7.29 (m, 2H), 2.38 (s, 3H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 161.8, 154.4, 148.7, 136.1, 134.5, 134.2, 130.5, 129.9, 129.1, 127.4, 126.6, 125.8, 125.7, 121.0, 19.5

Figure V 22 1 H-NMR spectra of 2-(thiophen-3-yl)quinazolin-4(3H)-one

Figure V 23 13 C-NMR spectra of 2-(thiophen-3-yl)quinazolin-4(3H)-one

Characterization Data for 2-(thiophen-3-yl)quinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 79% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.47 (s, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 5.0 Hz, 1H), 7.82 (t, J 7.5 Hz, 1H), 7.74 – 7.66 (m, 2H), 7.50 (t, J = 7.5 Hz, 1H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 162.1, 148.9, 148.3, 135.4, 134.6, 128.7, 127.4, 127.3, 127.0, 126.4, 125.9, 121.0

Figure V 24 1 H-NMR spectra of 7-methyl-2-phenylquinazolin-4(3H)-one

Figure V 25 13 C-NMR spectra of 7-methyl-2-phenylquinazolin-4(3H)-one

Characterization Data for 7-methyl-2-phenylquinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 90% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.45 (s, 1H), 8.20 – 8.14 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.63 – 7.52 (m, 4H), 7.35 (dd, J = 8.0, 1.0 Hz, 1H), 2.48 (s, 3H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 162.1, 152.3, 148.9, 145.1, 132.8, 131.3, 128.6, 128.0, 127.7, 127.2, 125.7, 118.6

Figure V 26 1 H-NMR spectra of 6-fluoro-2-phenylquinazolin-4(3H)-one

Figure V 27 13 C-NMR spectra of 6-fluoro-2-phenylquinazolin-4(3H)-one

Characterization Data for 6-fluoro-2-phenylquinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 87% yield 1 H NMR (500 MHz, DMSO, ppm) δ 12.67 (s, 1H), 8.17 (d, J = 7.0 Hz, 2H), 7.86 – 7.80 (m, 2H), 7.74 (td, J = 8.5, 3.0 Hz, 1H), 7.63 – 7.53 (m,

3H) 13 C NMR (125 MHz, DMSO, ppm) δ = 161.68, 159.9 (d, J = 245.5 Hz) 51.88, 145.60, 132.56, 131.42, 130.28, 128.62, 127.74, 123.07 (d, J = 24.0 Hz), 122.22, 110.61, 110.51 (d, J

Figure V 28 1 H-NMR spectra of 6-chloro-2-phenylquinazolin-4(3H)-one

Characterization Data for 6-chloro-2-phenylquinazolin-4(3H)-one

Prepared as shown in the general experimental procedure and was purified by recrystallization: white solid, 90% yield 1 H NMR (500 MHz, DMSO-d6, ppm) δ 12.71 (s, 1H), 8.16 (d, J = 7.5 Hz, 2H), 8.08 (d, J = 2.5 Hz, 1H), 7.86 (dd, J = 8.5, 2.5 Hz, 1H), 7.76 (d,

J = 8.5 Hz, 1H), 7.52 – 7.63 (m, 3H) 13 C NMR (125 MHz, DMSO-d6, ppm) δ 161.3, 152.9, 147.5, 134.7, 132.5, 131.6, 130.8, 129.8, 128.7, 127.9, 124.9, 122.3

Calibration curve calculation for 2-methylquinazolin-4(3H)-

Figure V 30 GC yield of the reaction with reference to diphenyl ether

From the calibration curve, GC yield of 2-methylquinazolin-4(3H)-one can be calculated by this formula (1a): y = 1.8046x + 0.0217 R² = 0.9993

92 Where: nPr (mole): Mole of 2-methylquinazolin-4(3H)-one obtained nPr’ (mole): Calculated mole of 2-methylquinazolin-4(3H)-one when yield = 100%

SPr: Peak area of 2-methylquinazolin-4(3H)-one in sample

SIS: Peak area of internal standard in sample nIS (mole): mole of diphenyl ether in sample

Figure V 31 X-ray powder diffractograms of the catalyst

Figure V 32 SEM micrograph of the catalyst

Figure V 33 TEM micrograph of the catalyst

Figure V 34 Pore size distribution of the catalyst

Figure V 35 Nitrogen adsorption/desorption isotherm of the catalyst

Figure V 36 TGA analysis of the catalyst.

Figure V 37 FT-IR spectra of 4,4’-biphenyldicarboxylic acid (a), and the catalyst (b)

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