9 CHAPTER 2: RESEARCH OF CATALYTIC ACTIVITY OF BASED METAL-ORGANIC FRAMEWORK Cu-MOF-74 IN THE SYNTHESIS OF 1,4-BENZOTHIAZINE .... Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitril
LITERATURE REVIEWS
Introduction to metal-organic frameworks
Metal-organic frameworks (MOFs) have received much attention in recent years especially as newly developed porous coordination polymers, have emerged as a new family of crystalline materials composed of organic linkers that connect metal ions or metal clusters to produce one-, two-, or three-dimensional networks [1] Flexibility or the rigidity of the frameworks is greatly affected by the choice of organic linker in the structure [2]
Furthermore, the tendency of metal ions can make different coordination numbers of metal, which can influence the geometric configuration of MOF structures [3] The abundant structures of MOFs (1D, 2D and 3D) are reported in the Cambridge Structural Database (CSD) (Figure 1.1)
Figure 1.1 Growth of the Cambridge structural database (CSD) from 1972 to 2016, the red bar shows structures added annually
MOFs are constructed by joining secondary building units (SBUs) with organic linkers, using strong bonds to create open crystalline frameworks with permanent porosity
3 The great diversity of metal SBUs and organic linkers have led to thousands of MOFs being synthesized and studied These metal-containing SBUs are essential to the design of directionality for the construction of MOFs and to the achievement of robust frameworks
The organic units are ditopic or polytopic organic carboxylates (and other similar negatively charged molecules) [4] Longer organic linkers provide larger storage space and a greater number of adsorption sites within a given material Containing both organic linkers and metal ions in the frameworks, MOFs possess several interesting properties, such as well-defined structures, high surface areas, high porosity, structural diversity, the ability to tune the pore size, and the possibility to modify the surface hydrophobicity/ hydrophilicity [5] These unique properties have paved the way for MOFs research to grow substantially, and applications are being considered in many areas including gas storage [6, 7], separation [8], catalysis [9] and carbon capture as well as biomolecule encapsulation [10], drug delivery [11], and imaging [12]
1.1.2 General methods for the synthesis of metal-organic frameworks
Figure 1.2 Structural model of MOF (top row) and the representative SBUs (middle row), as well as ligands (down row)
4 MOFs are typically synthesized by combining metal salts clusters as connectors and organic ligands as linkers (Figure 1.2) The characteristics of the ligand (bond angles, ligand length, bulkiness, chirality, etc.) play a crucial role in dictating what the resultant framework will be Additionally, the tendency of metal ions to adopt certain geometries also influences the structure of the MOFs Generally, MOFs are crystallized from solution
The reactants are mixed in high boiling, polar solvents such as water, dialkyl formamides, dimethyl sulfoxide or acetonitrile [2]
Many methods of MOFs synthesis have been reported, such as solvothermal, hydrothermal, microwave-assisted heating, etc (Figure 1.3) However, solvothermal is the most popular method thanks to its ability to produce high quality single crystals adequate for structural analysis in dilute liquid phase conditions and accelerate the discovery of new MOF structures The most important parameters of solvothermal MOFs synthesis are temperature, the concentrations of metal salt and ligand (which can be varied across a large range), the extent of solubility of the reactants in the solvent, and the pH of the solution [13, 14] One of the most promising alternatives is microwave irradiation which allows
Figure 1.3 Synthesis methods of metal-organic frameworks
5 access to a wide range of temperatures and can be used to shorten crystallization times while controlling face morphology and particle size distribution [15, 16]
1.1.3 Applications of metal–organic frameworks
Even though more endeavors are demanded for the development of these materials, possible applications of MOFs have attracted notable attention throughout the most recent years These properties, together with the extraordinary degree of variability for both the organic and inorganic components of their structures, make MOFs of interest for potential applications in a number of fields such as storage, separation [12], optics, magnetic and catalysis [1] These are based on pore size and shape of MOFs and the interactions between host framework and guest molecules [17], as well as the choice of appropriate metal ions and organic ligands In addition, biomedical applications, sensors and devices are also involved [18]
Figure 1.4 Applications of metal–organic frameworks
MOFs have been extensively explored as drug delivery devices in the past decade for delivering loaded cargoes to desired sites Although many carriers have been reported, MOFs garnered much attention owing to their porous structure containing voids, which
6 provides high drug loading capacity and a controlled drug-release profile A wide range of drug molecules with hydrophilic, hydrophobic and amphiphilic natures can be encapsulated in the MOFs [19] Based on the loading approaches discussed earlier, drugs can be encapsulated in the MOFs cavity and/or tethered with the framework structure [20, 21] The drug molecules functionalized by covalent conjugation with the MOFs provide higher ability for controlled drug release action over the drugs adsorbed in the cavity of MOFs
Applications of MOFs in cancer therapy have been extensively explored for accomplishing desired targeted action for prolonged periods of time Nano MOFs are highly useful in treating diverse human cancers [22] Applications of Fe3O4-UiO66 MOFs for delivering an anticancer agent (i.e., doxorubicin) revealed improvement in the biopharmaceutical characteristics including controlled drug-release properties up to 40 days, superior anticancer activity in HeLa cells and significant reduction in the tumor volume [23]
There are many applications of MOFs beyond drug delivery, thus they have gained wider attention in delivery of biological molecules like DNA, RNA, siRNA, etc [22]
Recent instances of MOFs used for biomedical applications include utility of high porosity nano MOFs encapsulated with chemotherapeutic agents withpooled multidrug-resistance (MDR) gene silencing siRNAs for action against drug-resistant ovarian cancer cells In another case, the approach of delivering the prodrug of cisplatin by encapsulation within the MOF structure along with siRNA has been employed to provide improved anticancer action In this context, not only do MOFs help in protecting the siRNA from ribonuclease degradation in the body but they also enhance cellular uptake and promote escape from endosomal enzymes for silencing MDR genes, leading eventually to enhanced chemotherapeutic efficacy [24]
Storage of medical gases in the inert porous carriers is highly useful in biomedical applications Extremely high surface area and pore volume facilitate storage of gases within
7 the void space of the materials [25] Examples of MOFs include M-CPO-27, which shows exceptional ability for the delivery of medial gases like nitric oxide and hydrogen sulfide
HKUST-1 MOFs have also been investigated for their applicability in the storage and delivery of nitric oxide gas [26]
MOFs possess excellent utility in designing the biosensing devices as diagnostic tools for disease identification [27, 28] Magnetism, photostablity, light-sensing and luminescence are the vital properties of MOFs, making them capable of biosensing applications Moreover, other useful characteristics of MOFs including channel size, specific coordination or H-bonding ability, and degree of chirality in the framework are considered to be influential on biosensing applications
Figure 1.5 The active catalytic sites in MOFs
8 Schematic showing the generation of unsaturated metal connecting points as active catalytic sites (a), the use of functional groups in the bridging ligands as active catalysts
(b), trapping catalytic active species inside MOFs (c)
Although a number of homogeneous organometallic catalysts have been successfully adopted in industrial processes [30], they often suffer from several shortcomings including tedious separation and recycling of expensive catalysts [31] The employment of corresponding heterogeneous catalysts can thus improve the processes by offering a number of advantages over homogeneous catalysts, including easy separation, efficient recycling, minimization of metal traces in the product, and improved handling and process control [18] Moreover, heterogeneous catalysts are more selective than their homogeneous counterparts in some cases [32] Several different approaches for the development of heterogeneous catalysts have been taken including immobilization of homogeneous catalysts on solid supports and introduction of chiral modifiers on catalytically active surfaces One of the latest developments in this field involved catalysis based on metal- organic frameworks [33] Many advantages of metal- organic framework systems such as the high density of active catalytic centers, high level of porosity, crystalline nature enabling elucidation of structural details, and relatively easy immobilization as compared to other heterogeneous systems make these materials invaluable for heterogeneous asymmetric catalysis [34]
As porous materials, MOFs may prove to be very useful in catalysis All metal cations or functional groups on the organic bridging ligands in MOFs structure could be useful for catalytic reactions; therefore, the dispersion and the loading of active sites on the solid framework could be maximized By definition, porous metal-organic frameworks are formed by the coordinative polymerization of metal ions or clusters and polyfunctional linker molecules They can acquire catalytic activity in a variety of ways; for exhaustive compilations of all MOF-related catalysis studies, the reader is referred to a number of excellent recent reviews [33, 35] First, the metal or metal cluster connecting points can be used to catalyze organic transformations As shown in Figure 1.6a, a metal connecting point with a free coordinating site can be used as a Lewis acid catalyst after removal of
9 coordinating solvent molecules from the axial positions of the metal center [36] When the MOFs are used in oxidation or hydrogenation reactions, there can be an additional requirement for the framework to accommodate metal ions with changing coordinative demands or even oxidation states Especially when the metal ions of the MOF are alkaline earths, the MOF can also be used as a base catalyst, where the metal–ligand ensemble abstracts a proton from the reactant molecules [29] Second, active catalytic sites can be generated from the functional groups within a MOF scaffold (Figure 1.7b) Third, the catalytic activity of MOFs can result from entrapped active catalysts, such as palladium or ruthenium nanoparticles (Figure 1.8c) [37] Note that the catalytic performance of a solid catalyst with low porosity or with narrow pores with respect to the substrate dimensions can be severely decreased by diffusion control of the reaction rate.
Copper-based metal-organic frameworks as heterogeneous catalyst
As porous materials, MOFs may prove to be very useful in catalysis During the last few years, a variety of MOFs have been explored for catalysis applications, including direct oxidative C -C coupling reactions, cyclization reactions, aza-Michael reactions, Ulmann- type reactions, etc In 2003, Wang and co-workers showed that the cycloaddition of benzyl azide to phenylacetylene through Cu(2-pymo)2, Cu3(BTC)2 and Cu(BDC) [38, 39] It is intriguing to see that Cu 2+ -MOFs are active as this type of reaction is generally accepted to be catalyzed by Cu + species (Scheme 1.1) [40]
Scheme 1.1 The cycloaddition of benzyl azide and phenylacetylene using Cu-MOFs
In 2008, Dongmei Jiang and co-workers also showed that the crystallineCu(bpy)(H2O)2(BF4)2(bpy) is a highly active and selective Lewis acid catalyst in the ring- opening reaction of epoxides with methanolat room temperature [41] 93% of the desired product was achieved employing 9% Cu(bpy)(H2O)2(BF4)2(bpy) as heterogeneous catalyst, low to moderate yields were observed when using other MOFs and homogeneous
10 transition metal catalysts This was an evidence that the use of Cu(bpy)(H2O)2(BF4)2(bpy) was compulsory for a range of effective organic transformations (Scheme 1.2)
Scheme 1.2 Ring-opening of styrene oxide with methanol using metal–organic framework Cu(bpy)(H2O)2(BF4)2(bpy)
In 2013, Lien T.L Nguyen and co-workers have revealed that Cu-MOF-199 as an efficient heterogeneous catalyst for the aza-Michael reaction (Scheme 1.3) Excellent conversions were achieved under mild conditions in the presence of 5 mol% catalyst The Cu-MOF- 199 catalyst could be reused several times without a significant degradation in catalytic activity No contribution from homogeneous catalysis of active species leaching into the liquid phase was detected [42]
Scheme 1.3 The aza-Michael reaction using the MOF-199 catalyst
In 2015, Hanh T N Le and co-workers successfully also synthesized and applied Cu2(BDC)2(BPY) as a catalyst for oxidative amidation reaction of terminal alkyne (Scheme 1.4) The Cu2(BDC)2(BPY) exhibited excellent catalytic activity and selectivity as compared to other Cu-MOFs on broad reaction scope Interestingly, the presence of bipyridine ligand was showed to enhance the catalyst stability Consequently, the Cu2(BDC)2(BPY) catalyst could be simply separated from the reaction mixture by centrifugation reused several times without a significant degradation in catalytic activity [43]
Scheme 1.4 The Cu2(BDC)2(BPY) was used as catalyst for the reaction of phenylacetylene with 2-oxazolidinone
In 2016, Sadegh Rostamnia and co-workers showed that the palladium ion was coordinated onto the Schiff base-decorated Cu-BDC pore cage (Scheme 1.5) Pd@Cu- BDC/Py-SI as a new material was found to be an efficient nanoporous MOFs with hydrophobic nature which had high capacity for the catalysis of the Suzuki- Miyaura cross- coupling reaction at reflux conditions in short reaction time Interestingly, the catalyst was investigated for recoverability and reusability in the Suzuki coupling reaction over 7 successive runs [44]
Scheme 1.5 The Suzuki coupling reaction using Pd@CuBDC
In 2017, Armaqan Khosravi’s Group has revealed that nanoporous Cu2(BDC)2(BPY)- MOF was used as efficient and reusable heterogeneous catalyst to effect the aerobic cross- coupling of aromatic amines and phenyl boronic acid (Chan–Lam coupling) (Scheme 1.6) [45] A comparison with other catalytic systems in the cross-coupling reaction of aniline with phenylboronic acids demonstrated that Cu-MOF catalyst system exhibited a higher conversion and yield under optimized reaction condition Ball-milling strategy was utilized for the first as a powerful green and energy-efficient method for the synthesis of this nanoporous metal–organic framework
Scheme 1.6 The aerobic cross-coupling of aromatic amines and phenyl boronic acid
(Chan–Lam coupling) through Cu2(BDC)2(BPY)–MOF
12 Recently, in 2018 Ha V Dang and co-workers reported synthesis of benzo[1,4]thiazines via ring expansion of 2-aminobenzothiazoles with terminal alkynes under Cu-MOF-74 (Scheme 1.7) Different from previous works, the reaction proceeded readily in the presence of lower catalyst concentration, at lower temperature, and under ligand-free conditions This copper-based framework demonstrated higher catalytic efficiency than a series of MOF-based heterogeneous catalysts and traditional homogeneous catalysts The copper–organic framework was reutilized without a remarkable decline in catalytic efficiency although this ring expansion reaction was not previously performed with a recyclable catalyst [46]
Scheme 1.7 The ring expansion reaction of 2-aminobenzothiazole with phenylacetylene utilizing Cu–MOF-74 catalyst
In conclusion, MOFs materials are of great interest to the chemical field Promising fields of applications are gas storage, gas purification, separations and catalysis Gas storage, gas purification and separation are the most mature fields of research Therefore, it is most likely that the first application will come from one of these fields However, research on the catalytic properties of MOFs is gaining momentum Due to their unique properties, MOFs are likely to give new impulses to catalysis research as a whole and may also be beneficial for existing processes All in all, as an emerging class of porous materials, MOFs are being investigated more and more Consequently, an increasing number of new materials are being discovered and novel applications are being identified Since there is virtually infinite number of possible combinations of linker molecules and metal ions, it can be expected that academic and industrial research activities in this field will continue to be vigorous In the next section, the catalytic activity of the metal-organic framework Cu2(OBA)2(BPY) – a hopeful candidate for catalysis – is reviewed
RESEARCH OF CATALYTIC ACTIVITY OF COPPER-
The Cu-MOF-74 metal-organic framework
Cu-MOF-74 belongs to the M-MOF-74 (or M-CPO-27) series of materials which is formed from a 2.5-dihydroxyterephthalic acid (dhtp 4- ) organic linkers linking with metal cations (M = Cu, Fe, Mn, Co, Ni or Zn) which are of divalence The structure of these MOF-74s, of general formula M2dobdc (dobdc 4- = 2.5-dioxidoterephthalate), consists of metal oxide chains connected by the dobdc 4- linkers forming a 3-D structure with honeycomb-like hexagonal that contains 1-D broad channels [47] The metal ions bond with oxygen atoms in square pyramidal geometry with coordination number of five (Figure 2.1)
Figure 2.1 Crystal structure of a MOF-74 (left) and the metal oxide chains connected by organic linkers (right) O, red; C, black; H, white; metal, blue After synthesis, the channels of MOF-74s are lined with guest molecules such as water or DMF molecules because the metal cations coordinate oxygen atoms and guest molecules in octahedral geometry (Figure 2.2) Upon desolvation, the metal coordination changes from octahedral to square pyramidal without compromising the framework integrity, leaving coordinatively unsaturated metal sites open to channels [47] The desolvated MOFs are called activated because they have active metal sites on the channels
Figure 2.2 Structure of Cu-MOF-74 before and after activation
In the past decades, Cu-MOFs, more specifically Cu-MOF-74, have been rising as one of the most highly studied MOFs in the literature in the past years In 2014, Pieterjan Valvekens and co-workers successfully synthesized and applied MOF-74 as active catalysts in previously base-catalyzed reactions such as Knoevenagel condensations or Michael additions [64]
Scheme 2.1 Knoevenagel condensations (top) and Michael additions (bottom) using
MOF-74 In the same year, G Calleja and co-workers also showed that copper-based MOF-74 can act as effective acid catalyst in Friedel–Crafts acylation of anisol This research has pointed out that using Cu-MOF-74 as the catalyst can yield product up to 90%, and the
15 catalyst can be reused up to 7 times while its catalytic activity was not significantly decreased [65]
Scheme 2.2 Simplified reaction scheme for the acylation of anisole with acetyl chloride using Cu-MOF-74 as catalyst
And recently, our group has reported the alkylation of amides via direct oxidative C(sp 3 )-H/N-H coupling catalyzed by Cu-MOF-74 under ligand-free condition High yields of N-alkyl amides were achieved The Cu-MOF-74 was more catalytically active than other Cu-MOFs such as Cu3(BTC)2, Cu(BDC), Cu(EDB), Cu2(BPDC)2(BPY), Cu2(BDC)2(DABCO), and Cu2(EDB)2(BPY) The Cu-MOF-74 also exhibited advantages as compared to several copper-based salts, including Cu(OAc)2, CuCl2, CuBr, CuI, CuCl, Cu(NO3)2, and CuSO4 The Cu-MOF-74 catalyst could be reused several times for the amidation transformation without a noteworthy deterioration in catalytic efficiency [66]
Scheme 2.3 Amidation of alkanes by amides catalyzed by Cu-MOF-74
Overall, Cu-MOF-74 is the new member of MOF-74 analogs which had been developed recently with many advantages such as open metal sites, Lewis acid sites, and Lewis base sites As a result, Cu-MOF-74 is a potential heterogeneous catalyst with not only efficient catalytic activity but also the excellent feature of reusability and recyclability for several organic syntheses, especially in oxidative cross-coupling reactions
The 1,4-benzothiazines and conventional synthesis
Benzo[1,4]thiazine is emerged as a promising substance in pharmaceutical and agrochemical sites, which displays a variety of functions such as antibacterial [48], antidiabetic [49], antiarrhythmic[50], antitumor [51], and neurodegenerative diseases [52]
In addition, the similar in structure between this and phenothiazines, which are well established drugs namely Chlorpromazine, Fluphenazine, Mesoridazine, potentially shows the use as antipsychotic and antihistaminic drugs [53]
Figure 2.3 Antipsychotic and antihistaminic drugs from phenothiazines
Cyanamides are commonly utilized to prepare herbicides [54] and various heterocycles [55], which are probably beneficial in manipulate the growth of tumor [56]
To illustrate the applicability of 1,4-benzothiazines several further transformations have been carried out Accordingly, some strong antimicrobial compounds have been derivable from this
Scheme 2.4 Derivable antimicrobial compounds from 3-phenyl-4H- benzo[b][1,4]thiazine-4-carbonitrile In the past decades, several approaches have been found in the synthesis of 1,4-benzothiazines Firstly, in 2014, Mitra and co-workers accidentally found the way to
17 synthesize 1,4-benzothiazines while investigating the synthesis of 2- phenylbenzo[d]imidazo[2,1-b]thiazole [57] The reaction was carried out using 2- aminobenzothiazole and phenylactylene under the catalyst system of copper salt and ligand in 1,2-dichlorobenzene at 100 o C for 6 hours The highest yield on isolated product was 82
% with CuI and 1,10-phenanthroline, meanwhile using copper (II) salt did not cause the formation of target molecule (Scheme Error! No text of specified style in document 12)
Scheme 2.5 The exploration of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile synthesis In 2015, Qiu and co-workers modified the synthesis by changing the reagent from phenylacetylene to 3-phenylpropionic acid [58] The improvement of this modification was the elimination of ligand in the system However, the large amount of base need to be added to gain good yield The result of this research suggested that homogeneous copper catalyst play an key role in the ring-opening of 2-aminobenzothiazole
Scheme 2.6 The synthesis 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile found by
In 2016, Chu and co-workers explored another method to prepare the substance, the Three-component tandem cyclization between 1-iodo-2-isothiocyanatobenzene with ethynylbenzene and aqueous ammonia [59] The obtained yield was up to 85%
Nevertheless, there are several drawbacks which need to be considered Firstly, the three reactants posed the potential of undesired products Secondly, 1-iodo-2-
18 isothiocyanatobenzene is unavailable Finally, the condition used in the reaction was more sophisticated
Scheme 2.7 The three-component tandem cyclization to synthesis 1,4-benzothiazines
In the same year, a development in preparation of this valuable compound was achieved The team of Balwe successfully synthesized this under solvent free condition with microwave assistance [60] The reaction got high yield in a significantly short time
Scheme 2.8 Microwave-assisted synthesis of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile However, these methods to synthesize benzo[1,4]thiazine derivatives still suffers the drawback of using homogeneous catalysis, in which catalyst recovery and reusability were not mentioned as well as well the possibility of metal contamination in products could increase significantly Nowadays, the viewpoint of green chemistry have been increasingly emphasized for the sake of environment and sustainable development so that there is a need of finding alternative heterogeneous catalysts.
Experimental
All reagents and starting materials were obtained commercially from SigmaAldrich, and Chemsol Chemical and used as received without any further purification unless otherwise noted
1 Copper (II) nitrate trihydrate Sigma Aldrich
5 Cesium carbonate ReagentPlus ® , Sigma Aldrich 6 Luperox ® Di, tert-butyl peroxide Sigma Aldrich
In terms of instrument, Powder X-ray diffraction patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer GC analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25
m) The temperature program for GC analysis held samples at 160 o C for 1 min; heated them from 160 to 280 o C at 40 o C/min; and held them at 280 o C for 3.5 min Inlet and detector temperatures were set constant at 280 o C Diphenyl ether was used as an internal standard to calculate the GC yield GC–MS analyzes were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 m) 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 Scanning electron microscopy studies were conducted on a S4800 scanning electron microscope Transmission electron microscopy studies were performed using a JEOL JEM 1400 transmission electron microscope at 80 kV Fourier transform infrared spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets
The Cu-MOF-74 was prepared according to a slightly modified literature procedure [61] In a typical preparation, a solid mixture of H2dhtp (H2dhtp = 2.5- dihydroxyterephthalic acid; 0.495 g, 2.5 mmol), and Cu(NO3)2.3H2O (1.21 g, 5 mmol) was dissolved in a mixture of DMF (47 mL) and 2-propanol (3 mL) The suspension was stirred to achieve a homogeneous solution The resulting solution was then distributed to ten 8 mL vials The vials were then heated at 85 o C in an oven for 18 hours After cooling the vials to room temperature, the solid product was removed by decanting the mother liquor and daily washed with DMF for 3 days (3×20 mL) Solvent exchange was carried out with 2- propanol (3×20 mL) at room temperature The material was then evacuated under vacuum at 150 o C for 5 hours
2.3.3 Catalytic studies on the synthesis of 3-phenyl-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
In an experiment, 2-aminobenzothiazole (0.0375 g, 0.25 mmol) was added to an 8 mL cap-equipped vials, following by acetonitrile (1mL) was used to completely dissolve the white powder in order to form a colorless solution Then, Cs2CO3 (0.016 g, 0.05 mmol) was added in the vial The amount of Cu-MOF-74 was determined by using the ratio of 2- aminobenzothiazole to copper In this experiment, 5 mol % of copper catalyst was employed Next, Di tert-butyl peroxide (0.1095g, 0.75mmol) was utilized as oxidant The mixture was magnetically stirred in half a minute to stabilize the medium Finally, phenylacetylene (0.0765 mg, 0.75 mmol) was gradually dropped into this The vials were capped and heated at 80 o C for 3 hours After the reaction was finished, the mixture was cool to room temperature and diphenyl ether (0.0425 g, 0.25 mmol) was used as internal standard for initially calculate the yield The aliquot was then processed under liquid-liquid extraction using 5 mass % KHCO3 solution and 3 mL of ethyl acetate The organic layer was dehydrated using anhydrous sodium sulfate The organic substances were analyzed by Gas chromatography and Flame ionization detector with reference to diphenyl ether The calibration curve was shown in the appendix.
Results and discussions
The copper-based metal-organic framework Cu-MOF-74 was synthesized according toa description in Scheme 2.9
Scheme 2.9 Synthesis of Cu-MOF-74
After the solvent exchanging and activation, the Cu-MOF-74 as black crystal was yielded The crystals was obtained in the appearance described The characteristics of Metal–organic framework were initially analyzed using XRD, which offered the graph below
Figure 2.4 Powder X-ray diffraction patterns of Cu-MOF-74 a) The activated CuMOF-74; b) The simulated Cu-MOF-74 [61]
In the Figure 2.4, it is clearly seen that the X-ray diffraction patterns of the Cu-MOF-74 illustrated the presence of very sharp peaks at 2 of approximately 7 o and 12 o , proving the highly crystallinity of the Cu-MOF-74 The simulated patterns previously reported in the literature, Sanz, R., et al Dalton Transactions, 2013 [61] strengthened the results as it had the similar to the attained graph
22 FT-IR spectra of the Cu-MOF-74 exhibited the stretching vibration of a strong peak at 1560 cm −1 , which was lower than the value for the C-O stretching vibration observed in free carboxylic acids observed at 1690 cm -1 (Figure 3.2 b).This strong peak of Cu-MOF- 74 was due to the stretching vibration of carboxylate anions present in the material The absence of strong absorption bands at 1760–1690 cm −1 , where the –COOH group was expected to appear, indicated the deprotonation of –COOH groups in 2.5- dihydroxyterephthalic acid upon the reaction with metal ions The broad bands at 3500–
3104 cm −1 were indicative of the presence of –OH group in acid form (Figure 3.2 a)
Figure 2.5 FT-IR spectra of the Cu-MOF-74 (a), and dihydroxyterephtalic acid (b)
Figure 2.6 SEM and TEM micrographs of Cu-MOF-74
23 The morphology of Cu-MOF-74 was studied by Scanning Electron Microscopy The SEM micrograph indicates that large needle-shaped crystals of the Cu-MOF-74 were obtained Furthermore, to confirm the porosity, one of most important characteristics of MOF materials, the transmission electron microscopy test was done As expected, the TEM micrograph shows that Cu-MOF-74 has porous structure
In this work, based on nitrogen physisorption measurements, it was found that the Cu-MOF-74 has BET surface area of 816 m 2 /g and an average pore diameter of 8.04 Å
(Figure 2.8) These values are slightly lower than those reported in the literature This is may be due to incomplete activation conditions
Table 2.1 Some physical properties of synthesised Cu-MOF-74 compared with the literatures
Figure 2.7 Isotherm linear plot of Cu-MOF-74
Quan tity Ads orb ed (c m³/g STP)
Figure 2.8 Poresize distribution of Cu-MOF-74
Figure 2.9 TGA curve of the Cu-MOF-74
The thermal stability of the Cu-MOF-74 was also examined by the thermalgravimetric analysis (TGA) The TGA profile in Error! Reference source not found showed that a significant weight-loss of the Cu-MOF-74 started at 75.6 o C The initial weight loss of 16.2%, occurring from 75.6 o C to approximately 150 o C, corsresponded well to the loss of DMF, water or solvent molecule per monomer The next remarkable decreasing in weight of 42.9% began at nearly 297.8 o C, when the pyrolysis
Differ en tia l P ore Vo lume (c m³/g)
Weightloss (%) DTG(delta(%)/delta(oC))
25 began to occur The thermal degradation proceeded until the structure of Cu-MOF-74 was completely decomposed at about 480 o C The mass percentage of the remained Cu-MOF- 74 was about 42.4%, corresponding with the copper oxide and carbon content in the Cu- MOF-74 The TGA curve was comparable to the previous report, and confirmed the high thermal stability of the resulting Cu-MOF-74
2.4.2 Catalytic studies on the synthesis of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Scheme 2.10 The ring expansion reaction of 2-aminobenzothiazole with phenylacetylene utilizing Cu-MOF-74 catalyst
The copper-organic framework was explored as heterogeneous catalyst for the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl- 4H-benzo[b][1,4]thiazine-4-carbonitrile as major product (Scheme 2.10) Mitra et al previously performed this reaction under air at 100 o C with 10 mol% CuI catalyst and 10 mol% 1,10-phenanthroline as ligand [64] In this work, we found that by using Cu-MOF- 74 catalyst, Cs2CO3 as base, and DTBP as oxidant, the reaction could proceeded at lower catalyst concentration, lower temperature, and without added ligand Initially, the influence of temperature on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was investigated (Figure 2.10) The reaction was conducted at 5 mol% catalyst in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at room temperature, 40 o C, 60 o C, 80 o C, and 100 o C, respectively The reaction did not occur at 40 o C, with less than 2% yield being recorded after 3 h Boosting the temperature led to higher yield of the expected product
The reaction performed at 60 o C afforded 53% yield after 3 h, while 85% yield was achieved for the reaction carried out at 80 o C Increasing the temperature to 100 o C resulted in higher initial rate, and the reaction reached 75% yield after 3 h Indeed, GC and GC-MS
26 analyses indicated that a large amount of homocoupling product of phenylacetylene was produced at 100 o C, resulting in lower yield for the major product
Figure 2.10 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs reaction time at different temperatures
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL)
As the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile, the solvent might control the reaction rate significantly The influence of solvent on the yield of the major product was then studied, having conducted the reaction in DMA, DMF, DMSO, NMP, THF, and acetonitrile, respectively (Figure 2.11) The reaction was carried out at 5 mol% catalyst for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at 80 o C THF was noticed to be inappropriate for this reaction, producing 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile in 45% yield after 3 h The reaction executed in DMA progressed to 56% yield, while 57% yield was detected for the reaction conducted in NMP Using DMF as solvent for the reaction, the
RT40 oC60 oC80 oc100 oC
27 yield of the desired product was improved to 74% after 3 h This value was upgraded to 83% for the reaction conducted in DMSO Compared to other solvents, acetonitrile emerged as the best candidate, with 8% yield being recorded after 3 h It was also noted that nonpolar solvents were not suitable for this reaction Moreover, the amount of solvent, or the concentration of reactants displayed a noticeable impact on the reaction, and best yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was achieved at 2- aminobenzothiazole concentration of 0.25 M
Figure 2.11 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time in different solvents
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), solvent (1 mL), 80 o C
DMADMFDMSOTHFNMPMeCN
2.4.2.3 Effect of catalyst and molar ratio
Figure 2.12 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different catalyst concentrations
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
DTBP (0.75 mmol), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
One more factor to be studied for the ring expansion reaction of 2- aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine- 4-carbonitrile is the catalyst concentration Mitra et al previously employed 10 mol% CuI [64], Qiu et al utilized 10 mol% CuCl [65], and Balwe et al used 10 mol% FeF3 [66] as catalyst for this transformation The influence of Cu-MOF-74 catalyst concentration on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was accordingly explored (Figure 2.12) The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at 1 mol%, 3 mol%, 5 mol%, 7 mol%, and 10 mol% catalyst, respectively In was noted that the ring expansion reaction did not progress in the absence of the Cu-MOF-74 catalyst, with less than 2% yield of the desired product being recorded Increasing the catalyst amount to 1 mol% also did not accelerate the reaction
29 When 3 mol% catalyst was employed, the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile was improved to 55% after 3 h Extending the catalyst concentration to 5 mol%, the reaction proceeded readily to afford 85% yield after 3 h Utilizing more than 5 mol% catalyst led to higher initial rate for the reaction However, after 3 h, the same yield of the expected product was obtained Moreover, the quantity of phenylacetylene also displayed a remarkable impact on this reaction, and best result was observed for the reaction using 3 equivalents of phenylacetylene (Fig 2.13)
Figure 2.13 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different reactant molar ratios
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), DTBP (0.75 mmol), Cu-MOF-
74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Figure 2.14 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different oxidants
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), oxidant (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Having these results in mind, we consequently investigated the impact of oxidant on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile, using di tert-butyl peroxide (DTBP), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), di-tert-butyl azodicarboxylate (DBAD), tert-butyl hydroperoxide in decane (TBHP in decane), tert- butyl hydroperoxide in water (aqueous TBHP), and hydrogen peroxide (H2O2), respectively (Fig 2.14) The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of the oxidant, at 5 mol% catalyst It was noticed that DBAD and aqueous TBHP were almost ineffective for the reaction, with 4% and 9% yields being detected after 3 h, respectively TBHP in decane and TEMPO were also not suitable for this transformation, affording 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile in 22% and 25% yields after 3 h, respectively Interestingly, the reaction utilizing H2O2 as oxidant proceeded to 79% yield after 3 h Compared to these oxidants, DTBP was the oxidant of
DTBP aqueous TBHPTBHP in decaneTEMPOH2O2DBAD
31 choice for the ring expansion reaction, generating the major product in 85% yield after 3 h Additionally, the reaction was also adjusted by the amount of DTBP (Fig 2.15) The reaction employing 1 equivalent of the oxidant afforded 66% yield, while 76% yield was recorded for that utilizing 2 equivalents of DTBP Best result was noted in the presence of 3 equivalents of DTBP, while extending the amount of the oxidant did not led to higher yield of the expected product
Figure 2.15 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different DTBP amounts
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Figure 2.16 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different bases
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), base(20 mol%), acetonitrile (1 mL), 80 o C
Qiu et al previously carried out the CuCl-catalyzed synthesis of benzo[1,4]thiazines via ring expansion of alkynyl carboxylic acids with 2-aminobenzothiazoles in the presence of 2 equivalents of K3PO4 as base [65] Balwe et al conducted the same transformation utilizing FeF3 catalyst and 10 mol% Cs2CO3 under microwave irradiation [66] We then screened different bases for the ring expansion reaction with Cu-MOF-74 catalyst (Fig 2.16) The reaction was performed at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of base and 3 equivalents of the oxidant, at 5 mol% catalyst It was noticed that diethylenediamine as organic base was not effective for the reaction system, affording 44% yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile after 6 h Strong base like KOH was also inappropriate for this transformation, with 59% yield of the desired product being recorded after 3 h K2CO3 expressed better performance, and the reaction progressed to 68% yield after 3 h Moving to t-BuOK, 72% yield was obtained for the reaction Among these bases, Cs2CO3 emerged as the best option, and the reaction utilizing this base proceeded to 85% yield after 3 h Furthermore, changing
Cs2CO3K2CO3 tBuOKKOHDiamine
Conclusions
Copper-organic framework Cu-MOF-74 was synthesized by a solvothermal protocol, and consequently utilized as a heterogeneous catalyst for the synthesis of benzo[1,4]thiazines via ring expansion of 2-aminobenzothiazoles with terminal alkynes
Different from previous works, the reaction proceeded readily in the presence of lower catalyst concentration, at lower temperature, and under ligand-free conditions The reaction was remarkably adjusted by the oxidant By using 5 mol% framework catalyst, 20 mol%
Cs2CO3, and 3 equivalents of di tert-butyl peroxide, high yields of benzo[1,4]thiazines were achieved This copper-based framework expressed higher catalytic efficiency for the ring expansion of 2-aminobenzothiazoles with terminal alkynes than a series of MOF-based heterogeneous catalysts and traditional homogeneous catalysts The transformation required the presence of the framework catalyst, and in this system, the donation of soluble active copper species to the formation of benzo[1,4]thiazines was trivial The copper- organic framework was reutilized without a remarkable decline in catalytic efficiency The advantages that benzo[1,4]thiazines were generated by using a heterogeneous catalyst, and the catalyst was recyclable, would attract considerable attention from pharmaceutical and agrochemical industries
CHAPTER 3: COPPER-CATALYZED ONE-POT DOMINO REACTIONS VIA C-H BOND ACTIVATION: SYNTHESIS OF 3-AROYLQUINOLINES FROM 2-AMINOBENZYLALCOHOLS AND PROPIOPHENONES UNDER
The Cu 2 (OBA) 2 (BPY) metal-organic framework
3.1.1 Structure and Properties of Cu 2 (OBA) 2 (BPY)
The Cu2(OBA)2(BPY) framework was synthesized by solvothermal method, as developed by Long Tong and co-workers (2008) [67] Cu2(OBA)2(BPY) is formed from 4,4′-oxybis(benzoic) acid (H2OBA) and 4,4′-bipyridine (BPY) organic linkers linking with metal cation Cu 2+ Additionally, H2OBA can be deprotonated to HOBA and OBA forms
This ligand, as a V-shaped, flexible and long spacer with two carboxylate groups, shows versatile coordination modes, which makes it a useful bridge to construct coordination polymers [68] 4,4’-bipyridine is a typical example of N-donor ligand, which assembly helices into interesting 3D architectures through covalent or supramolecular interactions [69]
The Cu (II) ions in complex Cu2(OBA)2(BPY) are linked by the carboxylate groups OBA to form an eight-membered ring chains, the connectivity between the corner-shared eight-membered ring chains are further bridged by the bent OBA ligands to produce 2D helical layer containing the right-handed helical chains Furthermore, the adjacent helical layers are connected by bpy pillars to form a novel 3D framework with an unprecedented topology (Figure 3.1) [67]
Figure 3.1 The structure of Cu(OBA)2BPY
(a)The coordination environments of Cu atoms in complex Cu2(OBA)2(BPY) All hydrogen atoms are omitted for clarity in the left figure; (b) The eight-membered ring chains of complex Cu2(OBA)2(BPY); (c) The 2D helical layers of complex Cu2(OBA)2(BPY) viewed lying the ac plane; (d) The 3D network of complex
Cu2(OBA)2(BPY) viewed along the c-axis [67]
3.1.2 Applications of Cu 2 (OBA) 2 (BPY) in catalysis
Apart from the continuous development and application of traditional noble metals, such as palladium [70], rhodium [71] and ruthenium [72], other cheap metal (Copper, Iron, Nickel, Cobalt) catalysts have also attracted increasing attention recently because of their a b c ) d
48 easy-handling in use and absolute competitiveness in price For more than one century, copper salts as catalysts have served well for C–N, C–S, C–O and other bond formation reactions [73] Copper catalysts fascinate chemists for several reasons First of all, copper is very cheap compared to palladium and since the amount of copper on earth is vast
Furthermore, copper salts generally present a low toxicity More importantly, copper can take part in cross-coupling chemistry in a way strikingly similar to palladium and possesses unique chemoselectivity and reactivity
Scheme 3.1 Reaction of benzothiazole with iodobenzene using Cu2(OBA)2(BPY) catalyst [74]
Consequently, Cu-MOFs, more specifically Cu2(OBA)2(BPY), have been rising as one of the most highly studied MOFs in the literature in the past years In 2014, Thanh Truong and co-workers had successfully synthesized and applied Cu2(OBA)2(BPY) as active catalysts in direct arylation of heterocycles through C-H bond cleavage (Scheme 1.9) [74]
Scheme 3.2 The direct C–S coupling reaction utilizing Cu2(OBA)2(BPY) catalyst (a), and the hydrolysis step to form β-ketosulfone (b)
In 2018, Tuong A To and co-workers utilized copper-based framework Cu2(OBA)2(BPY) as recyclable heterogeneous catalyst for the synthesis of β- sulfonylvinylamines from sodium sulfinates and oxime acetates via direct C–S coupling reaction (Scheme 1.10) [75] These β–sulfonylvinylamines were readily converted to the corresponding β-ketosulfones via a hydrolysis step with aqueous HCl solution
49 In conclusion, the Cu2(OBA)2(BPY) is the new member of copper based MOFs which had been developed recently with features favoring catalysis such as open metal sites, high surface area with uniform porosity and cavity sizes as well as significant stability As a result, the Cu2(OBA)2(BPY) catalyst can possibly act as a potential heterogeneous catalyst with not only efficient catalytic activity but also considerable reusability for organic syntheses.
The quinoline derivatives
Figure 3.2 Biologically active molecules containing 3-substituted quinolones
Organic compounds that contain heterocyclic moieties are quite significant because of their interesting biological properties [76-78] Indeed, nitrogen-containing heterocycles are omnipresent structural motifs in many natural products and small molecules of biomedical relevance [79-81] Among these structure, quinoline derivatives attract great interest as a major class of nitrogen heterocyclic compounds because of various important
50 pharmacological and biological applications including antimalarial, antiasthmatic, antihypertensive, antibacterial and tyrosine kinase inhibiting agents [82]
3.2.2 Synthesis route of quinoline derivatives
Quinoline derivatives display as one of the most important heterocyclic families In particular, 3-acyl quinoline derivatives are novel 4-hydroxyphenyl pyruvate dioxygenase inhibitorsand [83] antihypetensive agents [84] Owning to their significant contributions to the pharmaceutical and fine chemical industries, various synthetic protocols have been recently explored for the construction of these heterocycles
One-pot phosphine-catalyzed syntheses of quinolines
In 2012, San Khong and Ohyun Kwon developed an efficient one-pot process for the preparation of 3-substituted and 3,4-disubstituted quinolines from stable starting materials (activated acetylenes reacting with o-tosylamidobenzaldehydes and o- tosylamidophenones, respectively) under mild reaction (Scheme 3.3) [85]
Scheme 3.3 One-pot phosphine-catalyzed syntheses of quinolones
This approach provides a convenient and direct route toward 3-substituted quinolines
Besides, the reaction conditions are mild and many different substituents can be introduced without compromising yields However, tosylation was not commercially available and was required to prepare substrates from corresponding o-aminoaryl ketones beforehand
Additionally, the synthesis of 3-substituted quinolines through one-pot phosphine- catalyzed heterocyclization method required aldehyde group that is generally less stable because of the aldol condensation and using phosphine as catalyst which is also high toxicity Therefore, the synthesis using alcohols as substrates to replace aldehydes and discovering a new type of catalyst are two of such methods and will be presented in the next section
One-pot synthesis of heteroaryl and diheteroaryl ketones through Palladium- catalyzed 1,2-addition and oxidation
51 In 2013, Masami Kuriyama and co-works developed for the preparation of heteroaryl and diheteroaryl ketones from aldehydes and organoboronic acids through using an aryl iodide as the oxidant In this publication, palladium/thioether-imidazolinium chloride system was discovered to achieve high catalytic performance with broad substrate tolerance in the 1,2-additions of organoboronic acids to aldehydes as well as in Suzuki–
Miyaura cross-coupling reactions (Scheme 3.4) [86]
Scheme 3.4 Synthesis of quinoline-based lead agonist and its derivatives
This investigation contributes to generate many valuable quinoline derivatives and other heterocyclic compounds with excellent yields However, utilizing catalyst system revealing palladium faces the difficulty in reusability and is quite expensive Therefore, it is meaningful and challenging to develop new protocols to obtain substituted-quinolines in a more effective and environmentally benign manner
Efficient synthesis of functionalized dihydroquinolines, quinolines and dihydrobenzo[b]azepine via an iron(III) chloride-catalyzed intramolecular alkynecarbonyl metathesis of alkyne tethered 2-aminobenzaldehyde/ acetophenone derivatives
In this study, Jalal and partners have developed an efficient synthesis of 1,2- dihydroquinoline and dihydrobenzo[b]-azepine derivatives involving the iron(III) chloride intramolecular alkyne–carbonyl metathesis reaction for the first time (2014) This methodology was further extended to the one-pot synthesis of 3-acyl quinolines via alkyne–carbonyl metathesis/detosylation/aromatization of N-propargyl-2- aminobenzaldehyde/acetophenone derivatives by the addition of NaOH/EtOH (Scheme
3.5) [87] While many Lewis acid and Bronsted acid catalysts were investigated, anhydrous iron(III) chloride turned out to be the best catalyst for this transformation which is environmentally friendly and inexpensive
Scheme 3.5 Strategy for the synthesis of 1,2-dihydroquinolines, quinolines and benzo[b]azepine derivatives
Overall, the reactions are highly regioselective, worked under mild conditions and operational simplicity in good to excellent yield However, this method still suffers the drawback of using aldehyde group as the reagent which is less stable and catalyst recovery and reusability will be difficult in the case of using homogeneous catalyst like FeCl3
CuSO 4 -D-glucose an inexpensive and eco-efficient catalytic system: direct access to diverse quinolines through modified Friedlọnder approach involving S N Ar/reduction/annulation cascade in one-pot
In 2015, a highly efficient and scalable multicomponent domino reaction for the synthesis of functionalized/annulated quinolines is devised directly from 2-bromoaromatic aldehydes/ketones in H2O-EtOH mixture for the first time by Namrata Anand and co- workers (Scheme 3.6) [88]
Scheme 3.6 Synthesis quinolines through modified Friedlọnder approach involving
SNAr/reduction/annulation cascade in one-pot in the presence of CuSO4-D-glucose
In summary, the authors have successfully designed and developed an operationally simple, highly efficient one-pot practical and convenient method for the synthesis of diverse quinolines directly from 2-bromobenzaldehydes/2-bromobenzophenone An inexpensive and easily prepared eco-efficient CuSO4-D-glucose catalyst system and aqueous ethanol as the green solvent are the key features of this novel method with promising synthetic applications The salient features of this domino protocol are its methodical simplicity, structural diversity, perfect carbon-economy, high product yields, readily available substrates and formation of three new bonds (one C–C and two C–N) and one ring in a single operation Nevertheless, one more time, most relevant limitation in this study is the use of the 2-aminobenzaldehyde as a substrate, which is highly prone to self- condensation Moreover, using CuSO4-D-glucose as the catalyst also suffers from recovery and reusability issues
ZnCl 2 -promoted Friedlọnder-type synthesis of 4-substituted 3-aroyl quinolines from o -aminoaryl ketones and enaminones
In 2016, a practical synthesis of 4-substituted 3-aroyl quinolines via Friedlọnder-type reaction from readily available o-aminoaryl ketones and enaminones was developed by Laichun Luo and co-workers In the presence of ZnCl2, the reaction proceeded smoothly affording the desired products with various functional groups (Scheme 3.7) [89]
Scheme 3.7 Synthesis of 4-substituted 3-aroyl quinolines from o-aminoaryl ketones and enaminones
54 This cascade protocol provides an efficient and straightforward access to 4-substituted 3-aroyl quinolines from easily available starting materials, which may find practical applications in the synthesis and discovery of bioactive quinoline derivatives However, desired products of this study were only produced with moderated yields and the problem of reusing the catalyst is still limited
Branched C=C and C-N bond cleavage on enaminones toward the synthesis of 3-acyl quinolines; and transition-metal-free quinoline synthesis from acetophenones and anthranils via sequential one-carbon homologation/ conjugate addition/annulation cascade
Experimental
All reagents and starting materials were obtained commercially from Sigma-Aldrich, Acros and Merck as listed in Table 3.1, and were used as received without any further purification unless otherwise noted
Table 3.1 List of the utilized substances and their providers
Copper (II) nitrate trihydrate Cu(NO3)2.3H2O Merck
4,4′-oxybis(benzoic) acid C14H10O5 Sigma-Aldrich
2-amino-4-chlorobenzylalcohol C7H8ClNO Sigma-Aldrich 2-amino-4-bromophenyl methanol C7H8BrNO Sigma-Aldrich 2-amino-5-bromo phenyl methanol C7H8BrNO Sigma-Aldrich
2-amino-3-methylbenzyl alcohol C8H11NO Sigma
1-(2-thienyl)-1-propanone C7H8OS Sigma-Aldrich 4’-methoxypropiophenone C10H12O2 Sigma-Aldrich
2’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich 3’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich
4’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich
Nitrogen physisorption measurements were conducted using a Micromeritics 2020 volumetric adsorption analyzer system Samples were pretreated by heating under vacuum at 150 o C for 3 h
A Netzsch Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 o C/min under a nitrogen atmosphere
X-ray powder diffraction (XRD) patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer
Scanning electron microscopy studies were conducted on a S4800 Scanning Electron Microscope (SEM)
Transmission electron microscopy studies were performed using a JEOL JEM 1400 Transmission Electron Microscope (TEM) at 100 kV The Cu2(OBA)2(BPY) sample was dispersed on holey carbon grids for TEM observation Fourier transform infrared (FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets
59 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 àm) The temperature program for GC analysis held samples at 100 o C for 1 min, heated samples from 100 to 180 o C at 40 oC/min; heated them from 180 to 290 o C at 50 o C/min and held them at 290 o C for 2 min
Inlet and detector temperatures were set constant at 290 o C Diphenyl ether was used as an internal standard to calculate reaction conversions
GC-MS analyses were performed using a Hewlett Packard GC-MS 5972 with a RTX- 5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 àm) The temperature program for GC-MS analysis heated samples from 60 to 280 o C at 10 o C/min and held them at 280 o C for 2 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 were recorded on a Bruker AV 500 spectrometers using residual solvent peak as a reference
3.3.2 Synthesis of Cu 2 (OBA) 2 (BPY) catalyst
The catalyst was synthesized in compliance with a procedure previously reported by Long Tang and co-workers [67] In a typical synthesis, three solutions of copper (II) nitrate trihydrate (Cu(NO3)2.3H2O) (0.242 g, 1 mmol) in DMF (DMF = N,N’ dimethylformamide;
5 ml), 4,4′-oxybis(benzoic) acid (H2OBA) (0.258 g, 1 mmol) in DMF (3 ml), and 4,4′- bipyridine (BPY) (0.078 g, 0.5 mmol) in DMF (3 mL), respectively, were introduced into round-bottomed flask Distilled water was then added dropwise into the DMF solution of Cu(NO3)2.3H2O (2 mL water) and the DMF solution of H2OBA (1 mL water) in the order, and the resulting solutions were vigorously stirred for 5 min After that, the solution of H2OBA and the solution of BPY were added dropwise into the solution of Cu(NO3)2.3H2O, and the mixture was magnetically stirred to gain a clear solution Next, the reaction solution was equally distributed to three 10-mL pressurized vials The vials were tightly covered and heated at 85 o C in an isothermal oven for 48 h Green crystals were produced on the wall of the vials throughout the time of the experiment After cooling the vials under ambient temperature, the crystals were separated by decantation and washed with in DMF
60 (3 x 10 mL) for 3 days, methanol (3 x 10 mL) for 2 days Afterward, the product was dried under vacuum in a Schlenk line at 150 o C for 6h, obtaining 0.284 g of Cu2(OBA)2(BPY) in the shape of green light crystals (71% yield, with regard to copper (II) nitrate trihydrate)
3.3.3 The catalytic studies on the synthesis of phenyl(quinolin-3-yl)methanone
In a representative experiment, 2-aminobenzyl alcohol (0.0246 g, 0.2 mmol) and propiophenone (0.0536 g, 0.4 mmol) was introduced to a pressurized vial accommodating the catalyst Cu2(OBA)2(BPY) (0.00796 g, 10 mol %) The catalyst concentration was calculated in relation to the copper/2’-aminobenzylalcohol ratio Then, the mixture was then added with TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) (0.0624 g, 0.4 mmol) as the oxidant, pyridine as the ligand and DMF in the role of solvent (0.5 mL) Subsequently, reaction mixture was magnetically stirred at 120 o C for 16 h After finishing the reaction time and cooling the vial to ambient temperature, diphenyl ether was added into the mixture as an internal standard The reaction yield was monitored by withdrawing aliquots from the reaction mixture, quenched with brine and the organic components were then extracted into ethyl acetate (2 mL), dried over anhydrous Na2SO4 and analyzed by GC with reference to diphenyl ether
After the reaction was monitored by GC and TLC, the reaction mixture was diluted with ethyl acetate The ethyl acetate solution was washed with brine solution four times
The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure The resulting residue was further purified by column chromatography on silica gel (ethyl acetate/hexane = 1/4) to afford the product phenyl(quinolin-3-yl)methanone as white crystalline solid (91%, isolated yield based on the reactant 2-aminobenzylalcohol)
The product identity was further confirmed by GC-MS, 1 H NMR and 13 C NMR
In the catalyst recycling studies, the Cu2(OBA)2(BPY) catalyst was separated from the reaction mixture by simple centrifugation, washed with copious amount of anhydrous DMF and methanol, heated at 150 o C in a shlenkline under vacuum in 6 h and then reutilized for new catalytic transformation
For the leaching test, a catalytic reaction heated to 120 o C was stopped after 8 hours, analyzed by GC, and centrifuged to remove the solid catalyst The reaction solution was
61 subsequently heated in the absence of Cu2(OBA)2(BPY) catalyst at 120 o C for a further 8 hours Reaction progress was monitored by GC as previously described.
Results and discussions
Cu2(OBA)2BPY was solvothermally synthesized from Cu(NO3)2.2H2O, H2OBA, 4,4’-BPY, H2O in N,N-dimethylformamide (DMF) Generally, the reaction mixture was sealed in a borosilicate tube under ambient atmosphere and placed in an isothermal oven at 85 °C for two days, producing the green light crystal of Cu2(OBA)2BPY at 71% yield based on Cu(NO3)2.2H2O The crystal structure of Cu2(OBA)2BPY was consequently characterized after solvent exchange and activation steps
Scheme 3.12 Synthetic scheme for self-assembling the light green crystal of
Figure 3.3 X-ray powder diffractograms of the Cu2(OBA)2(BPY)
As can be seen in Figure 3.3, the X-ray diffraction patterns of the Cu2(OBA)2(BPY) demonstrated the presence of very sharp peaks at 2Ө of approximately 8 o (single peak), proving the highly crystallinity of the Cu2(OBA)2(BPY) There were some peak above 10 o which proved that Cu2(OBA)2(BPY) MOF was high porosity The result was also similar to the simulated patterns previously reported in the literature [67], so it could be approved that the structure of the MOF-Cu2(OBA)2(BPY) was successfully formed
Figure 3.4.FT-IR spectra of the Cu2(OBA)2(BPY) (a), H2OBA (b), 4,4-bipyridine (c).
Figure 3.2 compares the FT-IR spectra of the Cu2(OBA)2(BPY) with the ligand 4,4’-
Oxybis(benzoic acid) and 4,4’-Bipyridine
Firstly, the FT-IR spectrum of 4,4’-Oxybis(benzoic acid) shows strong peak at approximately 1680 cm - 1, this is due to the C=O stretching vibration in free carboxylic acid In the FT-IR spectrum of the Cu2(OBA)2(BPY), the corresponding signal were shifted to 1610 cm -1 Besides, several strong and broad O-H bands between 3000 and 2500 cm -1 observed in H2OBA’s FT-IR spectrum but not in case of the Cu2(OBA)2(BPY) indicated the deprotonation of –COOH groups in H2OBA upon the reaction with metal ions
Secondly, when observing the FT-IR spectrum of 4,4’-Bipyridine, strong peak at approximately 1596 cm -1 represent the C=N stretching vibration in the imine It was found that this value was decreased to 1539 cm -1 in the spectra of the Cu2(OBA)2(BPY), confirming the coordination of the nitrogen with metal ions
Figure 3.5 TGA analysis of the Cu2(OBA)2(BPY)
The thermal stability of the Cu2(OBA)2(BPY) was also examined by the thermalgravimetric analysis (TGA) (Figure 3.3) It was observed that the decomposing temperature of Cu2(OBA)2(BPY) was nearly 350 o C (high peak in derivative weight curve in Figure 3.5 Indeed, the curve roughly unchanged from 50 o C to 330 o C, indicated that there is no significant weight change until pyrolysis at 330 o C This first weight loss of only about 1% below 330 °C may be relating to the departure of free solvent (DMF and methanol from washing and solvent exchanging) and water adsorbed on the material in storage condition This result corresponded well to the high stability of the phase of Cu2(OBA)2(BPY) and its application in the wide range of temperature Nevertheless, the weight loss was recorded at about 57% in the range about 330 °C to 460 °C, showing that at this temperature, Cu2(OBA)2(BPY) started to decompose significantly The results obtained in this study were in agreement with the previous report of Tang et al [67]
Figure 3.6 Pore size distribution of the fresh Cu2(OBA)2(BPY)
Figure 3.7.Nitrogen adsorption/desorption isotherm of the Cu2(OBA)2(BPY)
Adsorption data are shown as closed circles and desorption data as open circles
66 Surface area and pore size distribution are essential properties for studying porous material characterization Therefore, nitrogen physisorption measurements were also conducted to figure out these features The pore volume and pore size distribution were calculated by the Horvath-Kawazoe approach, giving a pore volume of 0.13 cm 3 g -1 and an average micropore diameter of around 5.69 Å (Figure 3.6) By collecting high resolution nitrogen sorption isotherms at 77.3K, the permanent porosity of the Cu2(OBA)2(BPY) was confirmed with Langmuir’s and BET surface areas of 379 m 2 g -1 and 254 m 2 g -1 , respectively (Figure 3.7)
Figure 3.8 SEM (a) and TEM (b) micrograph of Cu2(OBA)2(BPY)
Additionally, the morphology, size and regularity of Cu2(OBA)2(BPY) were revealed through Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) results The SEM micrograph indicates the formation of the three- dimensional well sharped crystals of Cu2(OBA)2(BPY) The porous structure of Cu2(OBA)2(BPY) was also demonstrated in the TEM micrograph (Figure 3.8)
3.4.2 The catalytic studies on the synthesis of phenyl(quinolin-3-yl)methanone 3.4.2.1 Effect of temperature
67 Initial studies determined the effect of temperature on the yield of phenyl(quinolin- 3-yl)methanone The reaction was performed in 0.5 mL DMF, in the presence of 10 mol%
Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO, using 2- aminobenzylalcohol : propiophenone molar ratio of 1:2 at the room temperature, 60 o C, 80 oC, 100 o C, 120 o C and 140 o C respectively Aliquots were withdrawn from the mixture after 16h and analyzed by GC (Figure 3.9)
Figure 3.9 Effect of temperature on reaction yield
From the experimental point of view, it was found that the reaction proceeded with difficulty at room temperature, 60 o C and 80 o C with around nearly 3% of the product recorded after 16h The transformation performed at 100 o C afforded the product in 38% yield and as expected, increasing the reaction temperature led to a significant enhancement in the reaction yield The yield of desired reaction climbed dramatically to the peak with 91% yield by rising the reaction temperature to 120 o C Conducting reaction at higher temperature; however, was noted to be unnecessary since the improvement in reaction yield was trivial Indeed, 91% yield of phenyl(quinolin-3-yl)methanone was produced at 140 o C
Overall, the most suitable temperature of this reaction was 120 o C
68 The impact of solvents on liquid-phase organic transformations has to be addressed with careful consideration In various circumstances, the yield of the desired product remarkably changed when performing the reaction in different solvents [93, 94] Therefore, it was necessary to screen to investigate the appropriate solvent on generation of phenyl(quinolin-3-yl)methanone from 2-aminobenzyl alcohol and propiophenone utilizing Cu2(OBA)2(BPY) as heterogeneous catalyst The reaction was conducted in 0.5 mL of numerous solvents at 2-aminobenzyl alcohol concentration of 0.4 M, with 2-aminobenzyl alcohol/ propiophenone ratio of 1:2, in the present of 10% Cu2(OBA)2BPY catalyst, 1.5 equivalent of pyridine and 2 equivalent of TEMPO at 120 o C for 16 h (Figure 3.10)
It was obviously observed that the yield of phenyl-(quinolin-3-yl)methanone was significantly affected by the solvent The cyclization reaction proceeded with difficulty in N-methyl-2-pyrrolidone, ethylbenzene, and cumene, affording 19%, 40%, and 48% yields after 16 h Remarkable improvements in yield was discovered when conversions were carried out under non-polar solvents, including o-xylene, m-xylene, p-xylene, granting the expected product in 56%, 59% and 69% yields, respectively, after 16 h Dichlorobenzene also expressed medium performance, producing phenyl(quinolin-3-yl)methanone in 64% after 16 h, whereas performing the reaction in toluene, the reaction yield was amended to 77% This number could be also enhanced to 78% for the transformation executed in DMA, while only 55% for that carried out in DMSO though both of them are polar aprotic solvents Compared with these solvents, another polar aprotic solvent-DMF revealed the best presentation, with 91% yield of desired product recorded after 16 h
Figure 3.10 Effect of different solvents on reaction yield
When DMF was initially chosen as the solvent for the optimization of the reaction based on these experimental results Different amounts of DMF solvent were also tested to boost the yield of reaction, at the temperature of 120 o C, in the presence of 10 mol%
Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO, with 2- aminobenzyl alcohol/propiophenone ratio of 1:2, the resulting mixtures were magnetically stirred for 16 hours (Figure 3.11)
Form the experimental result, the conversion happened in difficulty without the presence of solvent, at only 37% yield When the quantity of solvent was grown to 0.25 mL, the reaction yield was also upgraded to 83% This can be explained that components in the vial have enough space to dissolve and interact to each other Like that, the amount of solvent was subsequently increased to 0.5, 1, 2, 3, and 4 mL to find the best of choice
While 0.5 mL was the most appropriate volume in this transformation, with 91% yield, a significant drop in the reaction yield was observed form 75% to 15% when quantity of
70 DMF rose from 1 mL to 4 mL, this was almost certainly due to low reaction rate at low concentration of reactants
Figure 3.11 Effect of amount of DMF on the reaction yield
3.4.2.3 Effect of reactant molar ratio on the reaction yield
Another concern that should be evaluated for this reaction is the influence of reactant molar ratios It was therefore decided to carry out the reaction in DMF at 120 o C, using 10 mol% Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO with the 2-aminobenzyl alcohol:propiophenone molar ratio of 1:1, 1:1.5, 1:2, 1:2.5, 1:3 and 1:4, respectively (Figure 3.12)
As expected, increasing the reagent ratio from 1:1 to 1:2 led to a significant improvement in the reaction rate, with more than 90% conversion being achieved after 16 hours However, it was observed that the reaction rate was not enhanced dramatically when the reagent ratio increased from 1:2 to 1:2.5, 1:3 and even 1:4 Hence, the 2- aminobenzylalcohol : propiophenone molar ratio of 1:2 was utilized for further studies
Figure 3.12 Effect of the 2-aminobenzyl alcohol : propiophenone molar ratio on the reaction yield
Ring-opening of styrene oxide with methanol using metal–organic
framework Cu(bpy)(H2O)2(BF4)2(bpy)
In 2013, Lien T.L Nguyen and co-workers have revealed that Cu-MOF-199 as an efficient heterogeneous catalyst for the aza-Michael reaction (Scheme 1.3) Excellent conversions were achieved under mild conditions in the presence of 5 mol% catalyst The Cu-MOF-199 catalyst could be reused several times without a significant degradation in catalytic activity No contribution from homogeneous catalysis of active species leaching into the liquid phase was detected [42].
The aza-Michael reaction using the MOF-199 catalyst
In 2015, Hanh T N Le and co-workers successfully also synthesized and applied Cu2(BDC)2(BPY) as a catalyst for oxidative amidation reaction of terminal alkyne (Scheme 1.4) The Cu2(BDC)2(BPY) exhibited excellent catalytic activity and selectivity as compared to other Cu-MOFs on broad reaction scope Interestingly, the presence of bipyridine ligand was showed to enhance the catalyst stability Consequently, the Cu2(BDC)2(BPY) catalyst could be simply separated from the reaction mixture by centrifugation reused several times without a significant degradation in catalytic activity [43]
The Cu2(BDC)2(BPY) was used as catalyst for the reaction of
In 2016, Sadegh Rostamnia and co-workers showed that the palladium ion was coordinated onto the Schiff base-decorated Cu-BDC pore cage (Scheme 1.5) Pd@Cu-BDC/Py-SI as a new material was found to be an efficient nanoporous MOFs with hydrophobic nature which had high capacity for the catalysis of the Suzuki- Miyaura cross- coupling reaction at reflux conditions in short reaction time Interestingly, the catalyst was investigated for recoverability and reusability in the Suzuki coupling reaction over 7 successive runs [44].
The Suzuki coupling reaction using Pd@CuBDC
In 2017, Armaqan Khosravi’s Group has revealed that nanoporous Cu2(BDC)2(BPY)-MOF was used as efficient and reusable heterogeneous catalyst to effect the aerobic cross- coupling of aromatic amines and phenyl boronic acid (Chan–Lam coupling) (Scheme 1.6) [45] A comparison with other catalytic systems in the cross-coupling reaction of aniline with phenylboronic acids demonstrated that Cu-MOF catalyst system exhibited a higher conversion and yield under optimized reaction condition Ball-milling strategy was utilized for the first as a powerful green and energy-efficient method for the synthesis of this nanoporous metal–organic framework.
The aerobic cross-coupling of aromatic amines and phenyl boronic acid (Chan–Lam coupling) through Cu2(BDC)2(BPY)–MOF
(Chan–Lam coupling) through Cu2(BDC)2(BPY)–MOF
12 Recently, in 2018 Ha V Dang and co-workers reported synthesis of benzo[1,4]thiazines via ring expansion of 2-aminobenzothiazoles with terminal alkynes under Cu-MOF-74 (Scheme 1.7) Different from previous works, the reaction proceeded readily in the presence of lower catalyst concentration, at lower temperature, and under ligand-free conditions This copper-based framework demonstrated higher catalytic efficiency than a series of MOF-based heterogeneous catalysts and traditional homogeneous catalysts The copper–organic framework was reutilized without a remarkable decline in catalytic efficiency although this ring expansion reaction was not previously performed with a recyclable catalyst [46].
The ring expansion reaction of 2-aminobenzothiazole with
In conclusion, MOFs materials are of great interest to the chemical field Promising fields of applications are gas storage, gas purification, separations and catalysis Gas storage, gas purification and separation are the most mature fields of research Therefore, it is most likely that the first application will come from one of these fields However, research on the catalytic properties of MOFs is gaining momentum Due to their unique properties, MOFs are likely to give new impulses to catalysis research as a whole and may also be beneficial for existing processes All in all, as an emerging class of porous materials, MOFs are being investigated more and more Consequently, an increasing number of new materials are being discovered and novel applications are being identified Since there is virtually infinite number of possible combinations of linker molecules and metal ions, it can be expected that academic and industrial research activities in this field will continue to be vigorous In the next section, the catalytic activity of the metal-organic framework Cu2(OBA)2(BPY) – a hopeful candidate for catalysis – is reviewed
CHAPTER 2: RESEARCH OF CATALYTIC ACTIVITY OF COPPER- BASED METAL-ORGANIC FRAMEWORK Cu-MOF-74 IN THE
SYNTHESIS OF 1,4-BENZOTHIAZINE 2.1 The Cu-MOF-74 metal-organic framework
Cu-MOF-74 belongs to the M-MOF-74 (or M-CPO-27) series of materials which is formed from a 2.5-dihydroxyterephthalic acid (dhtp 4- ) organic linkers linking with metal cations (M = Cu, Fe, Mn, Co, Ni or Zn) which are of divalence The structure of these MOF-74s, of general formula M2dobdc (dobdc 4- = 2.5-dioxidoterephthalate), consists of metal oxide chains connected by the dobdc 4- linkers forming a 3-D structure with honeycomb-like hexagonal that contains 1-D broad channels [47] The metal ions bond with oxygen atoms in square pyramidal geometry with coordination number of five (Figure 2.1)
Figure 2.1 Crystal structure of a MOF-74 (left) and the metal oxide chains connected by organic linkers (right) O, red; C, black; H, white; metal, blue After synthesis, the channels of MOF-74s are lined with guest molecules such as water or DMF molecules because the metal cations coordinate oxygen atoms and guest molecules in octahedral geometry (Figure 2.2) Upon desolvation, the metal coordination changes from octahedral to square pyramidal without compromising the framework integrity, leaving coordinatively unsaturated metal sites open to channels [47] The desolvated MOFs are called activated because they have active metal sites on the channels
Figure 2.2 Structure of Cu-MOF-74 before and after activation
In the past decades, Cu-MOFs, more specifically Cu-MOF-74, have been rising as one of the most highly studied MOFs in the literature in the past years In 2014, Pieterjan Valvekens and co-workers successfully synthesized and applied MOF-74 as active catalysts in previously base-catalyzed reactions such as Knoevenagel condensations or Michael additions [64].
Knoevenagel condensations (top) and Michael additions (bottom) using MOF-74
MOF-74 In the same year, G Calleja and co-workers also showed that copper-based MOF-74 can act as effective acid catalyst in Friedel–Crafts acylation of anisol This research has pointed out that using Cu-MOF-74 as the catalyst can yield product up to 90%, and the
15 catalyst can be reused up to 7 times while its catalytic activity was not significantly decreased [65].
Simplified reaction scheme for the acylation of anisole with acetyl
using Cu-MOF-74 as catalyst
And recently, our group has reported the alkylation of amides via direct oxidative C(sp 3 )-H/N-H coupling catalyzed by Cu-MOF-74 under ligand-free condition High yields of N-alkyl amides were achieved The Cu-MOF-74 was more catalytically active than other Cu-MOFs such as Cu3(BTC)2, Cu(BDC), Cu(EDB), Cu2(BPDC)2(BPY), Cu2(BDC)2(DABCO), and Cu2(EDB)2(BPY) The Cu-MOF-74 also exhibited advantages as compared to several copper-based salts, including Cu(OAc)2, CuCl2, CuBr, CuI, CuCl, Cu(NO3)2, and CuSO4 The Cu-MOF-74 catalyst could be reused several times for the amidation transformation without a noteworthy deterioration in catalytic efficiency [66].
Amidation of alkanes by amides catalyzed by Cu-MOF-74
Overall, Cu-MOF-74 is the new member of MOF-74 analogs which had been developed recently with many advantages such as open metal sites, Lewis acid sites, and Lewis base sites As a result, Cu-MOF-74 is a potential heterogeneous catalyst with not only efficient catalytic activity but also the excellent feature of reusability and recyclability for several organic syntheses, especially in oxidative cross-coupling reactions
2.2 The 1,4-benzothiazines and conventional synthesis
Benzo[1,4]thiazine is emerged as a promising substance in pharmaceutical and agrochemical sites, which displays a variety of functions such as antibacterial [48], antidiabetic [49], antiarrhythmic[50], antitumor [51], and neurodegenerative diseases [52]
In addition, the similar in structure between this and phenothiazines, which are well established drugs namely Chlorpromazine, Fluphenazine, Mesoridazine, potentially shows the use as antipsychotic and antihistaminic drugs [53]
Figure 2.3 Antipsychotic and antihistaminic drugs from phenothiazines
Cyanamides are commonly utilized to prepare herbicides [54] and various heterocycles [55], which are probably beneficial in manipulate the growth of tumor [56]
To illustrate the applicability of 1,4-benzothiazines several further transformations have been carried out Accordingly, some strong antimicrobial compounds have been derivable from this.
Derivable antimicrobial compounds from 3-phenyl-4H- benzo[b][1,4]thiazine-4-carbonitrile
benzo[b][1,4]thiazine-4-carbonitrile In the past decades, several approaches have been found in the synthesis of 1,4-benzothiazines Firstly, in 2014, Mitra and co-workers accidentally found the way to
17 synthesize 1,4-benzothiazines while investigating the synthesis of 2- phenylbenzo[d]imidazo[2,1-b]thiazole [57] The reaction was carried out using 2- aminobenzothiazole and phenylactylene under the catalyst system of copper salt and ligand in 1,2-dichlorobenzene at 100 o C for 6 hours The highest yield on isolated product was 82
% with CuI and 1,10-phenanthroline, meanwhile using copper (II) salt did not cause the formation of target molecule (Scheme Error! No text of specified style in document 12)
The exploration of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
synthesis In 2015, Qiu and co-workers modified the synthesis by changing the reagent from phenylacetylene to 3-phenylpropionic acid [58] The improvement of this modification was the elimination of ligand in the system However, the large amount of base need to be added to gain good yield The result of this research suggested that homogeneous copper catalyst play an key role in the ring-opening of 2-aminobenzothiazole.
The synthesis 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile found
In 2016, Chu and co-workers explored another method to prepare the substance, the Three-component tandem cyclization between 1-iodo-2-isothiocyanatobenzene with ethynylbenzene and aqueous ammonia [59] The obtained yield was up to 85%
Nevertheless, there are several drawbacks which need to be considered Firstly, the three reactants posed the potential of undesired products Secondly, 1-iodo-2-
18 isothiocyanatobenzene is unavailable Finally, the condition used in the reaction was more sophisticated.
The three-component tandem cyclization to synthesis 1,4-benzothiazines
In the same year, a development in preparation of this valuable compound was achieved The team of Balwe successfully synthesized this under solvent free condition with microwave assistance [60] The reaction got high yield in a significantly short time.
Microwave-assisted synthesis of 3-phenyl-4H-benzo[b][1,4]thiazine-4-
carbonitrile However, these methods to synthesize benzo[1,4]thiazine derivatives still suffers the drawback of using homogeneous catalysis, in which catalyst recovery and reusability were not mentioned as well as well the possibility of metal contamination in products could increase significantly Nowadays, the viewpoint of green chemistry have been increasingly emphasized for the sake of environment and sustainable development so that there is a need of finding alternative heterogeneous catalysts
All reagents and starting materials were obtained commercially from SigmaAldrich, and Chemsol Chemical and used as received without any further purification unless otherwise noted
1 Copper (II) nitrate trihydrate Sigma Aldrich
5 Cesium carbonate ReagentPlus ® , Sigma Aldrich 6 Luperox ® Di, tert-butyl peroxide Sigma Aldrich
In terms of instrument, Powder X-ray diffraction patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer GC analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25
m) The temperature program for GC analysis held samples at 160 o C for 1 min; heated them from 160 to 280 o C at 40 o C/min; and held them at 280 o C for 3.5 min Inlet and detector temperatures were set constant at 280 o C Diphenyl ether was used as an internal standard to calculate the GC yield GC–MS analyzes were performed using a Hewlett Packard GC-MS 5972 with a RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 m) 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 Scanning electron microscopy studies were conducted on a S4800 scanning electron microscope Transmission electron microscopy studies were performed using a JEOL JEM 1400 transmission electron microscope at 80 kV Fourier transform infrared spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets
The Cu-MOF-74 was prepared according to a slightly modified literature procedure [61] In a typical preparation, a solid mixture of H2dhtp (H2dhtp = 2.5- dihydroxyterephthalic acid; 0.495 g, 2.5 mmol), and Cu(NO3)2.3H2O (1.21 g, 5 mmol) was dissolved in a mixture of DMF (47 mL) and 2-propanol (3 mL) The suspension was stirred to achieve a homogeneous solution The resulting solution was then distributed to ten 8 mL vials The vials were then heated at 85 o C in an oven for 18 hours After cooling the vials to room temperature, the solid product was removed by decanting the mother liquor and daily washed with DMF for 3 days (3×20 mL) Solvent exchange was carried out with 2- propanol (3×20 mL) at room temperature The material was then evacuated under vacuum at 150 o C for 5 hours
2.3.3 Catalytic studies on the synthesis of 3-phenyl-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
In an experiment, 2-aminobenzothiazole (0.0375 g, 0.25 mmol) was added to an 8 mL cap-equipped vials, following by acetonitrile (1mL) was used to completely dissolve the white powder in order to form a colorless solution Then, Cs2CO3 (0.016 g, 0.05 mmol) was added in the vial The amount of Cu-MOF-74 was determined by using the ratio of 2- aminobenzothiazole to copper In this experiment, 5 mol % of copper catalyst was employed Next, Di tert-butyl peroxide (0.1095g, 0.75mmol) was utilized as oxidant The mixture was magnetically stirred in half a minute to stabilize the medium Finally, phenylacetylene (0.0765 mg, 0.75 mmol) was gradually dropped into this The vials were capped and heated at 80 o C for 3 hours After the reaction was finished, the mixture was cool to room temperature and diphenyl ether (0.0425 g, 0.25 mmol) was used as internal standard for initially calculate the yield The aliquot was then processed under liquid-liquid extraction using 5 mass % KHCO3 solution and 3 mL of ethyl acetate The organic layer was dehydrated using anhydrous sodium sulfate The organic substances were analyzed by Gas chromatography and Flame ionization detector with reference to diphenyl ether The calibration curve was shown in the appendix
The copper-based metal-organic framework Cu-MOF-74 was synthesized according toa description in Scheme 2.9.
Synthesis of Cu-MOF-74
After the solvent exchanging and activation, the Cu-MOF-74 as black crystal was yielded The crystals was obtained in the appearance described The characteristics of Metal–organic framework were initially analyzed using XRD, which offered the graph below
Figure 2.4 Powder X-ray diffraction patterns of Cu-MOF-74 a) The activated CuMOF-74; b) The simulated Cu-MOF-74 [61]
In the Figure 2.4, it is clearly seen that the X-ray diffraction patterns of the Cu-MOF-74 illustrated the presence of very sharp peaks at 2 of approximately 7 o and 12 o , proving the highly crystallinity of the Cu-MOF-74 The simulated patterns previously reported in the literature, Sanz, R., et al Dalton Transactions, 2013 [61] strengthened the results as it had the similar to the attained graph
22 FT-IR spectra of the Cu-MOF-74 exhibited the stretching vibration of a strong peak at 1560 cm −1 , which was lower than the value for the C-O stretching vibration observed in free carboxylic acids observed at 1690 cm -1 (Figure 3.2 b).This strong peak of Cu-MOF- 74 was due to the stretching vibration of carboxylate anions present in the material The absence of strong absorption bands at 1760–1690 cm −1 , where the –COOH group was expected to appear, indicated the deprotonation of –COOH groups in 2.5- dihydroxyterephthalic acid upon the reaction with metal ions The broad bands at 3500–
3104 cm −1 were indicative of the presence of –OH group in acid form (Figure 3.2 a)
Figure 2.5 FT-IR spectra of the Cu-MOF-74 (a), and dihydroxyterephtalic acid (b)
Figure 2.6 SEM and TEM micrographs of Cu-MOF-74
23 The morphology of Cu-MOF-74 was studied by Scanning Electron Microscopy The SEM micrograph indicates that large needle-shaped crystals of the Cu-MOF-74 were obtained Furthermore, to confirm the porosity, one of most important characteristics of MOF materials, the transmission electron microscopy test was done As expected, the TEM micrograph shows that Cu-MOF-74 has porous structure
In this work, based on nitrogen physisorption measurements, it was found that the Cu-MOF-74 has BET surface area of 816 m 2 /g and an average pore diameter of 8.04 Å
(Figure 2.8) These values are slightly lower than those reported in the literature This is may be due to incomplete activation conditions
Table 2.1 Some physical properties of synthesised Cu-MOF-74 compared with the literatures
Figure 2.7 Isotherm linear plot of Cu-MOF-74
Quan tity Ads orb ed (c m³/g STP)
Figure 2.8 Poresize distribution of Cu-MOF-74
Figure 2.9 TGA curve of the Cu-MOF-74
The thermal stability of the Cu-MOF-74 was also examined by the thermalgravimetric analysis (TGA) The TGA profile in Error! Reference source not found showed that a significant weight-loss of the Cu-MOF-74 started at 75.6 o C The initial weight loss of 16.2%, occurring from 75.6 o C to approximately 150 o C, corsresponded well to the loss of DMF, water or solvent molecule per monomer The next remarkable decreasing in weight of 42.9% began at nearly 297.8 o C, when the pyrolysis
Differ en tia l P ore Vo lume (c m³/g)
Weightloss (%) DTG(delta(%)/delta(oC))
25 began to occur The thermal degradation proceeded until the structure of Cu-MOF-74 was completely decomposed at about 480 o C The mass percentage of the remained Cu-MOF- 74 was about 42.4%, corresponding with the copper oxide and carbon content in the Cu- MOF-74 The TGA curve was comparable to the previous report, and confirmed the high thermal stability of the resulting Cu-MOF-74
2.4.2 Catalytic studies on the synthesis of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
The ring expansion reaction of 2-aminobenzothiazole with
The copper-organic framework was explored as heterogeneous catalyst for the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl- 4H-benzo[b][1,4]thiazine-4-carbonitrile as major product (Scheme 2.10) Mitra et al previously performed this reaction under air at 100 o C with 10 mol% CuI catalyst and 10 mol% 1,10-phenanthroline as ligand [64] In this work, we found that by using Cu-MOF- 74 catalyst, Cs2CO3 as base, and DTBP as oxidant, the reaction could proceeded at lower catalyst concentration, lower temperature, and without added ligand Initially, the influence of temperature on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was investigated (Figure 2.10) The reaction was conducted at 5 mol% catalyst in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at room temperature, 40 o C, 60 o C, 80 o C, and 100 o C, respectively The reaction did not occur at 40 o C, with less than 2% yield being recorded after 3 h Boosting the temperature led to higher yield of the expected product
The reaction performed at 60 o C afforded 53% yield after 3 h, while 85% yield was achieved for the reaction carried out at 80 o C Increasing the temperature to 100 o C resulted in higher initial rate, and the reaction reached 75% yield after 3 h Indeed, GC and GC-MS
26 analyses indicated that a large amount of homocoupling product of phenylacetylene was produced at 100 o C, resulting in lower yield for the major product
Figure 2.10 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs reaction time at different temperatures
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL)
As the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile, the solvent might control the reaction rate significantly The influence of solvent on the yield of the major product was then studied, having conducted the reaction in DMA, DMF, DMSO, NMP, THF, and acetonitrile, respectively (Figure 2.11) The reaction was carried out at 5 mol% catalyst for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at 80 o C THF was noticed to be inappropriate for this reaction, producing 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile in 45% yield after 3 h The reaction executed in DMA progressed to 56% yield, while 57% yield was detected for the reaction conducted in NMP Using DMF as solvent for the reaction, the
RT40 oC60 oC80 oc100 oC
27 yield of the desired product was improved to 74% after 3 h This value was upgraded to 83% for the reaction conducted in DMSO Compared to other solvents, acetonitrile emerged as the best candidate, with 8% yield being recorded after 3 h It was also noted that nonpolar solvents were not suitable for this reaction Moreover, the amount of solvent, or the concentration of reactants displayed a noticeable impact on the reaction, and best yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was achieved at 2- aminobenzothiazole concentration of 0.25 M
Figure 2.11 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time in different solvents
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), solvent (1 mL), 80 o C
DMADMFDMSOTHFNMPMeCN
2.4.2.3 Effect of catalyst and molar ratio
Figure 2.12 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different catalyst concentrations
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
DTBP (0.75 mmol), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
One more factor to be studied for the ring expansion reaction of 2- aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine- 4-carbonitrile is the catalyst concentration Mitra et al previously employed 10 mol% CuI [64], Qiu et al utilized 10 mol% CuCl [65], and Balwe et al used 10 mol% FeF3 [66] as catalyst for this transformation The influence of Cu-MOF-74 catalyst concentration on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was accordingly explored (Figure 2.12) The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP as oxidant, at 1 mol%, 3 mol%, 5 mol%, 7 mol%, and 10 mol% catalyst, respectively In was noted that the ring expansion reaction did not progress in the absence of the Cu-MOF-74 catalyst, with less than 2% yield of the desired product being recorded Increasing the catalyst amount to 1 mol% also did not accelerate the reaction
29 When 3 mol% catalyst was employed, the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile was improved to 55% after 3 h Extending the catalyst concentration to 5 mol%, the reaction proceeded readily to afford 85% yield after 3 h Utilizing more than 5 mol% catalyst led to higher initial rate for the reaction However, after 3 h, the same yield of the expected product was obtained Moreover, the quantity of phenylacetylene also displayed a remarkable impact on this reaction, and best result was observed for the reaction using 3 equivalents of phenylacetylene (Fig 2.13)
Figure 2.13 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different reactant molar ratios
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), DTBP (0.75 mmol), Cu-MOF-
74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Figure 2.14 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different oxidants
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), oxidant (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Having these results in mind, we consequently investigated the impact of oxidant on the yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile, using di tert-butyl peroxide (DTBP), (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), di-tert-butyl azodicarboxylate (DBAD), tert-butyl hydroperoxide in decane (TBHP in decane), tert- butyl hydroperoxide in water (aqueous TBHP), and hydrogen peroxide (H2O2), respectively (Fig 2.14) The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of the oxidant, at 5 mol% catalyst It was noticed that DBAD and aqueous TBHP were almost ineffective for the reaction, with 4% and 9% yields being detected after 3 h, respectively TBHP in decane and TEMPO were also not suitable for this transformation, affording 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile in 22% and 25% yields after 3 h, respectively Interestingly, the reaction utilizing H2O2 as oxidant proceeded to 79% yield after 3 h Compared to these oxidants, DTBP was the oxidant of
DTBP aqueous TBHPTBHP in decaneTEMPOH2O2DBAD
31 choice for the ring expansion reaction, generating the major product in 85% yield after 3 h Additionally, the reaction was also adjusted by the amount of DTBP (Fig 2.15) The reaction employing 1 equivalent of the oxidant afforded 66% yield, while 76% yield was recorded for that utilizing 2 equivalents of DTBP Best result was noted in the presence of 3 equivalents of DTBP, while extending the amount of the oxidant did not led to higher yield of the expected product
Figure 2.15 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different DTBP amounts
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Figure 2.16 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different bases
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), base(20 mol%), acetonitrile (1 mL), 80 o C
Qiu et al previously carried out the CuCl-catalyzed synthesis of benzo[1,4]thiazines via ring expansion of alkynyl carboxylic acids with 2-aminobenzothiazoles in the presence of 2 equivalents of K3PO4 as base [65] Balwe et al conducted the same transformation utilizing FeF3 catalyst and 10 mol% Cs2CO3 under microwave irradiation [66] We then screened different bases for the ring expansion reaction with Cu-MOF-74 catalyst (Fig 2.16) The reaction was performed at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of base and 3 equivalents of the oxidant, at 5 mol% catalyst It was noticed that diethylenediamine as organic base was not effective for the reaction system, affording 44% yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile after 6 h Strong base like KOH was also inappropriate for this transformation, with 59% yield of the desired product being recorded after 3 h K2CO3 expressed better performance, and the reaction progressed to 68% yield after 3 h Moving to t-BuOK, 72% yield was obtained for the reaction Among these bases, Cs2CO3 emerged as the best option, and the reaction utilizing this base proceeded to 85% yield after 3 h Furthermore, changing
Cs2CO3K2CO3 tBuOKKOHDiamine
33 the amounts of Cs2CO3 led to different yields of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile In the absence of base, only 9% yield was detected after 3 h Experimental results showed that 20 mol% of Cs2CO3 should be used for this reaction Utilizing more than 20 mol% Cs2CO3 was not necessary, while employing less than 20 mol% resulted in lower yields (Fig 2.17)
Figure 2.17 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time at different Cs2CO3 amounts
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), acetonitrile (1 mL), 80 o C
Since the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was executed in solution phase, the leaching test would be essential The generation of the major product might be owing to active copper sites dissolved into acetonitrile In order to clarify this issue, control experiments was accordingly performed The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP, at 5 mol% catalyst After the initial 1 h reaction time with 46% yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile being recorded, the Cu-MOF-74 was isolated out of the reaction mixture The acetonitrile solution was
34 subsequently transferred to a new and clean reactor, and the reaction was allowed to proceed at 120 o C for additional 2 h The reaction progress was then monitored during this period Under these experimental conditions, almost no additional product was generated
This result explained that the ring expansion reaction required the presence of the copper- based framework catalyst, and in this system, the donation of soluble active copper species to the formation of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was trivial (Fig
Figure 2.18 Leaching test showed that 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was not produced after the isolation of the catalyst
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol),
DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 oC
2.4.2.7 Effect of different homogeneous and heterogeneous catalysts
Figure 2.19 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different homogeneous catalysts
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), catalyst (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
To emphasize the meaning of using the Cu-MOF-74, the its activity in the ring expansion reaction of 2-aminobenzothiazole with phenylacetylene to produce 3-phenyl- 4H-benzo[b][1,4]thiazine-4-carbonitrile was correlated to many catalysts First, conventional homogeneous catalysts were employed (Fig 2.19) The reaction was conducted at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP, at 5 mol% catalyst It was noted that iron-based salts like FeCl2 and FeCl3 were completely inactive for this reaction, with no evidence of the major product being probed after 3 h Moving to copper salts, CuCl2 was also inappropriate, affording 8% yield after 3 h Under similar conditions, the reaction employing CuBr and CuCl as catalyst progressed to 29% and 46% yields, respectively Cu(OAc)2 noticed to be more active, resulted in 69% yield after 3 h, while the reaction using CuI catalyst afforded 72% yield In the second experiment series, several MOF-based catalysts were tested (Fig 2.20) As expected, Fe3O(BPDC)3 and Fe3O(BDC)3 exhibited no catalytic activity for the transformation The reaction using
Cu-MOF-74CuCl2CuBrCu(OAc)2CuClCuI
36 MOF-199 catalyst afforded 15% yield, while 25% yield was obtained for the case of Cu(BDC) catalyst Cu2(BPDC)2(DABCO) and Cu2(BDC)2(BPY) were more active, resulting in 36% and 45% yields, respectively Up to 75% yield was obtained for the reaction utilizing Cu2(OBA)2(BPY) catalyst Apparently, the Cu-MOF-74 displayed higher efficiency, with 85% yield being achieved after 3 h
Figure 2.20 Yield of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile vs time with different heterogeneous catalysts
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), catalyst (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C
Cu2(BPDC)2(DABCO) Cu2(OBA)2(BPY)
Reaction conditions: 2-aminobenzothiazole (0.25 mmol), phenylacetylene (0.75 mmol), DTBP (0.75 mmol), Cu-MOF-74 (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 oC, 3 h
Proposed reaction pathway
To obtain more information about the pathway of the ring expansion reaction of 2- aminobenzothiazole with phenylacetylene to produce 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile, some control experiments were conducted Noted that only 8% yield of 3- phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile was detected in the absence of DTBP,
40 while 85% yield was achieved if 3 equivalents of DTBP was employed, verifying that an oxidant was required for the catalytic cycle The reaction was performed at 80 o C in acetonitrile for 3 h, with 3 equivalents of phenylacetylene, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP, at 5 mol% catalyst In the first experiment, ascorbic acid as antioxidant was added to the mixture at the beginning of the reaction It was noticed that the transformation could not proceed in the presence of ascorbic acid This observation suggested that the interaction between ascorbic acid and the oxidant stopped the reaction In the second experiment, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as a radical scavenger was used Experimental results showed that the reaction progressed to 55% yield in the presence of TEMPO, implying that the reaction would not proceed via radical mechanism On the basis of these data and based on previous reports in the literature [64-66], a plausible pathway was proposed for the ring expansion reaction of 2- aminobenzothiazole with phenylacetylene (Scheme 2.11) Copper acetylide was initially produced, and the attack of this acetylide to 2-aminobenzothiazole resulted in the ring opening transformation Next, reductive elimination occurred, forming N-(iminomethylene)-2-(phenylethynylthio)benzenamine, and regenerating the copper acetylide in the presence of phenylacetylene and the oxidant The tautomerization of N-(iminomethylene)-2-(phenylethynylthio)benzenamine afforded N-(2-(phenylethynylthio)phenyl)cyanamide Finally, intermolecular hydroamination occurred to produce the expected product
2.4.2.10 Effect of different substituents on the reaction Table 2.2 The synthesis of benzo[1,4]thiazines from 2-aminobenzothiazoles and terminal alkynes utilizing Cu-MOF-74 catalyst a
80 a Reaction conditions: reactant 1 (0.25 mmol), reactant 2 (0.75 mmol), DTBP (0.75 mmol), catalyst (5 mol%), Cs2CO3 (20 mol%), acetonitrile (1 mL), 80 o C, 3 h
44 The work was accordingly extended to the synthesis of benzo[1,4]thiazines from different 2-aminobenzothiazoles and terminal alkynes The reaction was executed at 80 o C in acetonitrile for 3 h, with 3 equivalents of alkyne, in the presence of 20 mol% of Cs2CO3 as base and 3 equivalents of DTBP, at 5 mol% catalyst In the first experiment series, the ring expansion reaction of 2-aminobenzothiazole with phenylacetylenes containing substituents were explored Benzo[1,4]thiazines were subsequently purified by column chromatography Following this procedure, 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile (Entry 1) was achieved in 81% isolated yield Moving to 4- methylphenylacetylene, the reaction produced 3-p-tolyl-4H-benzo[b][1,4]thiazine-4- carbonitrile (Entry 2) in 84% yield Similarly, 3-(4-methoxyphenyl)-4H- benzo[b][1,4]thiazine-4-carbonitrile (Entry 3) was generated in 83% yield 4- Bromophenylacetylene and 4-fluorophenylacetylene were reactive towards the ring expansion reaction, affording 3-(4-bromophenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 4) and 3-(4-fluorophenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 5) in 68% and 86% yields, respectively Non-aromatic substrates were also employed, leading to the formation of 3-cyclopentyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 6), 3- cyclohexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 7), and 3-(4-hexylphenyl)-4H- benzo[b][1,4]thiazine-4-carbonitrile (Entry 8) in 78%, 63%, and 75% yields, respectively
In the second experiment series, 2-aminobenzothiazoles containing substitutent were explored for the 6-fluoro-2-aminobenzothiazole was used for the ring expansion reaction Following this protocol, 7-fluoro-3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile (Entry 9), 7-fluoro-3-p-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 10), 7-fluoro-3-(4-hexylphenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 11), and 3-cyclohexyl-7-fluoro-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 12) were achieved in high yields Similarly, 6-chloro-2-aminobenzothiazole was also reactive towards the reaction with different terminal alkynes in the presence of the Cu-MOF-74 catalyst The reaction of 6-chloro-2-aminobenzothiazole with phenylacetylene afforded 7-chloro-3- phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 13) in 80% yield, while 77% yield of 7-chloro-3-p-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 14) was obtained for
45 the case of 4-methylphenylacetylene Moving to non-aromatic alkynes, 7-chloro-3-(4- hexylphenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 15) and 7-chloro-3- cyclohexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 16) were generated in 76% and 78% yields, respectively 2-aminobenzothiazole containing an electron-donating subtituent such as 6-methyl-2-aminobenzothiazole was also reactive, producing 7-methyl-3-phenyl- 4H-benzo[b][1,4]thiazine-4-carbonitrile (Entry 17), 7-methyl-3-p-tolyl-4H- benzo[b][1,4]thiazine-4-carbonitrile (Entry 18), 3-(4-hexylphenyl)-7-methyl-4H- benzo[b][1,4]thiazine-4-carbonitrile (Entry 19), and 3-cyclohexyl-7-methyl-4H- benzo[b][1,4]thiazine-4-carbonitrile (Entry 20) in reasonable yields
Copper-organic framework Cu-MOF-74 was synthesized by a solvothermal protocol, and consequently utilized as a heterogeneous catalyst for the synthesis of benzo[1,4]thiazines via ring expansion of 2-aminobenzothiazoles with terminal alkynes
Different from previous works, the reaction proceeded readily in the presence of lower catalyst concentration, at lower temperature, and under ligand-free conditions The reaction was remarkably adjusted by the oxidant By using 5 mol% framework catalyst, 20 mol%
Cs2CO3, and 3 equivalents of di tert-butyl peroxide, high yields of benzo[1,4]thiazines were achieved This copper-based framework expressed higher catalytic efficiency for the ring expansion of 2-aminobenzothiazoles with terminal alkynes than a series of MOF-based heterogeneous catalysts and traditional homogeneous catalysts The transformation required the presence of the framework catalyst, and in this system, the donation of soluble active copper species to the formation of benzo[1,4]thiazines was trivial The copper- organic framework was reutilized without a remarkable decline in catalytic efficiency The advantages that benzo[1,4]thiazines were generated by using a heterogeneous catalyst, and the catalyst was recyclable, would attract considerable attention from pharmaceutical and agrochemical industries
CHAPTER 3: COPPER-CATALYZED ONE-POT DOMINO REACTIONS VIA C-H BOND ACTIVATION: SYNTHESIS OF 3-AROYLQUINOLINES FROM 2-AMINOBENZYLALCOHOLS AND PROPIOPHENONES UNDER
METAL-ORGANIC FRAMEWORK CU(OBA) 2 BPY CATALYSIS 3.1 The Cu 2 (OBA) 2 (BPY) metal-organic framework
3.1.1 Structure and Properties of Cu 2 (OBA) 2 (BPY)
The Cu2(OBA)2(BPY) framework was synthesized by solvothermal method, as developed by Long Tong and co-workers (2008) [67] Cu2(OBA)2(BPY) is formed from 4,4′-oxybis(benzoic) acid (H2OBA) and 4,4′-bipyridine (BPY) organic linkers linking with metal cation Cu 2+ Additionally, H2OBA can be deprotonated to HOBA and OBA forms
This ligand, as a V-shaped, flexible and long spacer with two carboxylate groups, shows versatile coordination modes, which makes it a useful bridge to construct coordination polymers [68] 4,4’-bipyridine is a typical example of N-donor ligand, which assembly helices into interesting 3D architectures through covalent or supramolecular interactions [69]
The Cu (II) ions in complex Cu2(OBA)2(BPY) are linked by the carboxylate groups OBA to form an eight-membered ring chains, the connectivity between the corner-shared eight-membered ring chains are further bridged by the bent OBA ligands to produce 2D helical layer containing the right-handed helical chains Furthermore, the adjacent helical layers are connected by bpy pillars to form a novel 3D framework with an unprecedented topology (Figure 3.1) [67]
Figure 3.1 The structure of Cu(OBA)2BPY
(a)The coordination environments of Cu atoms in complex Cu2(OBA)2(BPY) All hydrogen atoms are omitted for clarity in the left figure; (b) The eight-membered ring chains of complex Cu2(OBA)2(BPY); (c) The 2D helical layers of complex Cu2(OBA)2(BPY) viewed lying the ac plane; (d) The 3D network of complex
Cu2(OBA)2(BPY) viewed along the c-axis [67]
3.1.2 Applications of Cu 2 (OBA) 2 (BPY) in catalysis
Apart from the continuous development and application of traditional noble metals, such as palladium [70], rhodium [71] and ruthenium [72], other cheap metal (Copper, Iron, Nickel, Cobalt) catalysts have also attracted increasing attention recently because of their a b c ) d
48 easy-handling in use and absolute competitiveness in price For more than one century, copper salts as catalysts have served well for C–N, C–S, C–O and other bond formation reactions [73] Copper catalysts fascinate chemists for several reasons First of all, copper is very cheap compared to palladium and since the amount of copper on earth is vast
Furthermore, copper salts generally present a low toxicity More importantly, copper can take part in cross-coupling chemistry in a way strikingly similar to palladium and possesses unique chemoselectivity and reactivity.
Reaction of benzothiazole with iodobenzene
using Cu2(OBA)2(BPY) catalyst [74]
Consequently, Cu-MOFs, more specifically Cu2(OBA)2(BPY), have been rising as one of the most highly studied MOFs in the literature in the past years In 2014, Thanh Truong and co-workers had successfully synthesized and applied Cu2(OBA)2(BPY) as active catalysts in direct arylation of heterocycles through C-H bond cleavage (Scheme 1.9) [74].
The direct C–S coupling reaction utilizing Cu2(OBA)2(BPY) catalyst (a),
and the hydrolysis step to form β-ketosulfone (b)
In 2018, Tuong A To and co-workers utilized copper-based framework Cu2(OBA)2(BPY) as recyclable heterogeneous catalyst for the synthesis of β- sulfonylvinylamines from sodium sulfinates and oxime acetates via direct C–S coupling reaction (Scheme 1.10) [75] These β–sulfonylvinylamines were readily converted to the corresponding β-ketosulfones via a hydrolysis step with aqueous HCl solution
49 In conclusion, the Cu2(OBA)2(BPY) is the new member of copper based MOFs which had been developed recently with features favoring catalysis such as open metal sites, high surface area with uniform porosity and cavity sizes as well as significant stability As a result, the Cu2(OBA)2(BPY) catalyst can possibly act as a potential heterogeneous catalyst with not only efficient catalytic activity but also considerable reusability for organic syntheses
Figure 3.2 Biologically active molecules containing 3-substituted quinolones
Organic compounds that contain heterocyclic moieties are quite significant because of their interesting biological properties [76-78] Indeed, nitrogen-containing heterocycles are omnipresent structural motifs in many natural products and small molecules of biomedical relevance [79-81] Among these structure, quinoline derivatives attract great interest as a major class of nitrogen heterocyclic compounds because of various important
50 pharmacological and biological applications including antimalarial, antiasthmatic, antihypertensive, antibacterial and tyrosine kinase inhibiting agents [82]
3.2.2 Synthesis route of quinoline derivatives
Quinoline derivatives display as one of the most important heterocyclic families In particular, 3-acyl quinoline derivatives are novel 4-hydroxyphenyl pyruvate dioxygenase inhibitorsand [83] antihypetensive agents [84] Owning to their significant contributions to the pharmaceutical and fine chemical industries, various synthetic protocols have been recently explored for the construction of these heterocycles
One-pot phosphine-catalyzed syntheses of quinolines
In 2012, San Khong and Ohyun Kwon developed an efficient one-pot process for the preparation of 3-substituted and 3,4-disubstituted quinolines from stable starting materials (activated acetylenes reacting with o-tosylamidobenzaldehydes and o- tosylamidophenones, respectively) under mild reaction (Scheme 3.3) [85].
One-pot phosphine-catalyzed syntheses of quinolones
This approach provides a convenient and direct route toward 3-substituted quinolines
Besides, the reaction conditions are mild and many different substituents can be introduced without compromising yields However, tosylation was not commercially available and was required to prepare substrates from corresponding o-aminoaryl ketones beforehand
Additionally, the synthesis of 3-substituted quinolines through one-pot phosphine- catalyzed heterocyclization method required aldehyde group that is generally less stable because of the aldol condensation and using phosphine as catalyst which is also high toxicity Therefore, the synthesis using alcohols as substrates to replace aldehydes and discovering a new type of catalyst are two of such methods and will be presented in the next section
One-pot synthesis of heteroaryl and diheteroaryl ketones through Palladium- catalyzed 1,2-addition and oxidation
51 In 2013, Masami Kuriyama and co-works developed for the preparation of heteroaryl and diheteroaryl ketones from aldehydes and organoboronic acids through using an aryl iodide as the oxidant In this publication, palladium/thioether-imidazolinium chloride system was discovered to achieve high catalytic performance with broad substrate tolerance in the 1,2-additions of organoboronic acids to aldehydes as well as in Suzuki–
Miyaura cross-coupling reactions (Scheme 3.4) [86]
Synthesis of quinoline-based lead agonist and its derivatives
This investigation contributes to generate many valuable quinoline derivatives and other heterocyclic compounds with excellent yields However, utilizing catalyst system revealing palladium faces the difficulty in reusability and is quite expensive Therefore, it is meaningful and challenging to develop new protocols to obtain substituted-quinolines in a more effective and environmentally benign manner
Efficient synthesis of functionalized dihydroquinolines, quinolines and dihydrobenzo[b]azepine via an iron(III) chloride-catalyzed intramolecular alkynecarbonyl metathesis of alkyne tethered 2-aminobenzaldehyde/ acetophenone derivatives
In this study, Jalal and partners have developed an efficient synthesis of 1,2- dihydroquinoline and dihydrobenzo[b]-azepine derivatives involving the iron(III) chloride intramolecular alkyne–carbonyl metathesis reaction for the first time (2014) This methodology was further extended to the one-pot synthesis of 3-acyl quinolines via alkyne–carbonyl metathesis/detosylation/aromatization of N-propargyl-2- aminobenzaldehyde/acetophenone derivatives by the addition of NaOH/EtOH (Scheme
3.5) [87] While many Lewis acid and Bronsted acid catalysts were investigated, anhydrous iron(III) chloride turned out to be the best catalyst for this transformation which is environmentally friendly and inexpensive
Strategy for the synthesis of 1,2-dihydroquinolines, quinolines and benzo[b]azepine derivatives
Overall, the reactions are highly regioselective, worked under mild conditions and operational simplicity in good to excellent yield However, this method still suffers the drawback of using aldehyde group as the reagent which is less stable and catalyst recovery and reusability will be difficult in the case of using homogeneous catalyst like FeCl3
CuSO 4 -D-glucose an inexpensive and eco-efficient catalytic system: direct access to diverse quinolines through modified Friedlọnder approach involving S N Ar/reduction/annulation cascade in one-pot
In 2015, a highly efficient and scalable multicomponent domino reaction for the synthesis of functionalized/annulated quinolines is devised directly from 2-bromoaromatic aldehydes/ketones in H2O-EtOH mixture for the first time by Namrata Anand and co- workers (Scheme 3.6) [88]
Synthesis quinolines through modified Friedlọnder approach involving SNAr/reduction/annulation cascade in one-pot in the presence of CuSO4-D- glucose
SNAr/reduction/annulation cascade in one-pot in the presence of CuSO4-D-glucose
In summary, the authors have successfully designed and developed an operationally simple, highly efficient one-pot practical and convenient method for the synthesis of diverse quinolines directly from 2-bromobenzaldehydes/2-bromobenzophenone An inexpensive and easily prepared eco-efficient CuSO4-D-glucose catalyst system and aqueous ethanol as the green solvent are the key features of this novel method with promising synthetic applications The salient features of this domino protocol are its methodical simplicity, structural diversity, perfect carbon-economy, high product yields, readily available substrates and formation of three new bonds (one C–C and two C–N) and one ring in a single operation Nevertheless, one more time, most relevant limitation in this study is the use of the 2-aminobenzaldehyde as a substrate, which is highly prone to self- condensation Moreover, using CuSO4-D-glucose as the catalyst also suffers from recovery and reusability issues
ZnCl 2 -promoted Friedlọnder-type synthesis of 4-substituted 3-aroyl quinolines from o -aminoaryl ketones and enaminones
In 2016, a practical synthesis of 4-substituted 3-aroyl quinolines via Friedlọnder-type reaction from readily available o-aminoaryl ketones and enaminones was developed by Laichun Luo and co-workers In the presence of ZnCl2, the reaction proceeded smoothly affording the desired products with various functional groups (Scheme 3.7) [89].
Synthesis of 4-substituted 3-aroyl quinolines from o-aminoaryl ketones
54 This cascade protocol provides an efficient and straightforward access to 4-substituted 3-aroyl quinolines from easily available starting materials, which may find practical applications in the synthesis and discovery of bioactive quinoline derivatives However, desired products of this study were only produced with moderated yields and the problem of reusing the catalyst is still limited
Branched C=C and C-N bond cleavage on enaminones toward the synthesis of 3-acyl quinolines; and transition-metal-free quinoline synthesis from acetophenones and anthranils via sequential one-carbon homologation/ conjugate addition/annulation cascade
In 2017, by using easily available and stable N,N-dimethyl functionalized enaminones and anilines as starting materials, Jie-Ping Wan and co-workers have identified an unprecedented synthetic protocol to access 3-acyl quinolines using only TfOH The construction of these quinoline products is furnished via the formation of multiple new chemical bonds enabled by the featured cleavage of C=C double bond and C-N bond in the same enaminone substrate (Scheme 3.8) [90] The totally metal-free catalytic condition and easy availability of the stable starting materials in the synthesis demonstrated the important potential of this new method in the quinoline synthesis However, this investigation made a trouble in the low conversion yield of expected product and its scope.
Designation on 3-acylquinoline synthesis via enaminone C=C bond
In the same year, Wakade and co-workers also performed transition-metal-free procedure for the construction of functionalized quinolines from readily available acetophenones and anthranils This one-pot reaction cascade involves in situ generation of α,β-unsaturated ketones from the acetophenone via one-carbon homologation by DMSO followed by the aza-Michael addition of anthranils and subsequent annulation (Scheme
3.9) [91] DMSO acted in this reaction not only as solvent but also as one carbon source, thus providing a highly atom-economical and environmentally benign approach for the synthesis of 3-substituted quinolines However, a similar result happened in this
55 transformation when reaction yields of desired products were quite low Furthermore, it was found that nitrogen atmosphere was applied and reaction time still lasted so long.
Transition-metal-free synthesis of 3-ketoquinolines
Synthesis of 3-acylquinolines through Cu-catalyzed double C(sp 3 )–H bond functionalization of saturated ketones
In 2017, Ze Wang and co-workers conducted a novel synthesis of 3-acylquinolines from Cu-catalyzed one-pot reactions of 2-aminoaryl aldehydes/ketones with inactivated ketones Mechanistically, the formation of the compounds involves a cascade procedure including C(sp 3 )–H bond amination, enaminone formation, and enamine carbonyl condensation (Scheme 3.10) [92] With notable features such as simple substrates, easy operating procedure, broad substrate scope, high efficiency and atom-economy, and good tolerance of functional groups, this novel method is expected to find wide applications in related areas.
Synthesis of 3-acylquinolines through Cu-catalyzed double C(sp3)–H
However, this method still suffers the drawback of using homogeneous catalysis, in which catalyst recovery and reusability were not mentioned as well as the possibility of metal contamination in products could increase significantly Nowadays, the viewpoint of green chemistry has been increasingly emphasized for the sake of environment and sustainable development so that there is a need of developing alternative protocols using heterogeneous catalysts Besides, the 2-aminobenzaldehyde reagent is unstable at room temperature due to the imine reaction between –NH2 and –CHO groups in its structure
56 In conclusion, many approaches were explored to create new chemical, physical, and biological performance In this context, organic transformations proceeded with minimum synthetic steps are preferable, avoiding the disadvantages of unstable starting substrates and not environmentally friendly catalysts Thus, to remedy the problems that have been mentioned, it is meaningful and challenging to develop new methods that can be carried out in less strict conditions but still be able to give high yield as well as selectivity of quinoline derivatives To the best of our knowledge, there has not yet been any reports on the reaction between 2-aminobenzyl alcohol and propiophenone to achieve phenyl(quinolin-3-yl)methanone utilizing the Cu2(OBA)2(BPY) catalyst as a heterogeneous solid material (Scheme 3.11).
The cyclization of 2-aminobenzyl alcohol and propiophenone utilizing Cu2(OBA)2(BPY) as a heterogeneous catalyst
Cu2(OBA)2(BPY) as a heterogeneous catalyst
All reagents and starting materials were obtained commercially from Sigma-Aldrich, Acros and Merck as listed in Table 3.1, and were used as received without any further purification unless otherwise noted
Table 3.1 List of the utilized substances and their providers
Copper (II) nitrate trihydrate Cu(NO3)2.3H2O Merck
4,4′-oxybis(benzoic) acid C14H10O5 Sigma-Aldrich
2-amino-4-chlorobenzylalcohol C7H8ClNO Sigma-Aldrich 2-amino-4-bromophenyl methanol C7H8BrNO Sigma-Aldrich 2-amino-5-bromo phenyl methanol C7H8BrNO Sigma-Aldrich
2-amino-3-methylbenzyl alcohol C8H11NO Sigma
1-(2-thienyl)-1-propanone C7H8OS Sigma-Aldrich 4’-methoxypropiophenone C10H12O2 Sigma-Aldrich
2’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich 3’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich
4’-(trifluoromethyl) propiophenone C10H9OF3 Sigma-Aldrich
Nitrogen physisorption measurements were conducted using a Micromeritics 2020 volumetric adsorption analyzer system Samples were pretreated by heating under vacuum at 150 o C for 3 h
A Netzsch Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 o C/min under a nitrogen atmosphere
X-ray powder diffraction (XRD) patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer
Scanning electron microscopy studies were conducted on a S4800 Scanning Electron Microscope (SEM)
Transmission electron microscopy studies were performed using a JEOL JEM 1400 Transmission Electron Microscope (TEM) at 100 kV The Cu2(OBA)2(BPY) sample was dispersed on holey carbon grids for TEM observation Fourier transform infrared (FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets
59 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 àm) The temperature program for GC analysis held samples at 100 o C for 1 min, heated samples from 100 to 180 o C at 40 oC/min; heated them from 180 to 290 o C at 50 o C/min and held them at 290 o C for 2 min
Inlet and detector temperatures were set constant at 290 o C Diphenyl ether was used as an internal standard to calculate reaction conversions
GC-MS analyses were performed using a Hewlett Packard GC-MS 5972 with a RTX- 5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 àm) The temperature program for GC-MS analysis heated samples from 60 to 280 o C at 10 o C/min and held them at 280 o C for 2 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 were recorded on a Bruker AV 500 spectrometers using residual solvent peak as a reference
3.3.2 Synthesis of Cu 2 (OBA) 2 (BPY) catalyst
The catalyst was synthesized in compliance with a procedure previously reported by Long Tang and co-workers [67] In a typical synthesis, three solutions of copper (II) nitrate trihydrate (Cu(NO3)2.3H2O) (0.242 g, 1 mmol) in DMF (DMF = N,N’ dimethylformamide;
5 ml), 4,4′-oxybis(benzoic) acid (H2OBA) (0.258 g, 1 mmol) in DMF (3 ml), and 4,4′- bipyridine (BPY) (0.078 g, 0.5 mmol) in DMF (3 mL), respectively, were introduced into round-bottomed flask Distilled water was then added dropwise into the DMF solution of Cu(NO3)2.3H2O (2 mL water) and the DMF solution of H2OBA (1 mL water) in the order, and the resulting solutions were vigorously stirred for 5 min After that, the solution of H2OBA and the solution of BPY were added dropwise into the solution of Cu(NO3)2.3H2O, and the mixture was magnetically stirred to gain a clear solution Next, the reaction solution was equally distributed to three 10-mL pressurized vials The vials were tightly covered and heated at 85 o C in an isothermal oven for 48 h Green crystals were produced on the wall of the vials throughout the time of the experiment After cooling the vials under ambient temperature, the crystals were separated by decantation and washed with in DMF
60 (3 x 10 mL) for 3 days, methanol (3 x 10 mL) for 2 days Afterward, the product was dried under vacuum in a Schlenk line at 150 o C for 6h, obtaining 0.284 g of Cu2(OBA)2(BPY) in the shape of green light crystals (71% yield, with regard to copper (II) nitrate trihydrate)
3.3.3 The catalytic studies on the synthesis of phenyl(quinolin-3-yl)methanone
In a representative experiment, 2-aminobenzyl alcohol (0.0246 g, 0.2 mmol) and propiophenone (0.0536 g, 0.4 mmol) was introduced to a pressurized vial accommodating the catalyst Cu2(OBA)2(BPY) (0.00796 g, 10 mol %) The catalyst concentration was calculated in relation to the copper/2’-aminobenzylalcohol ratio Then, the mixture was then added with TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl) (0.0624 g, 0.4 mmol) as the oxidant, pyridine as the ligand and DMF in the role of solvent (0.5 mL) Subsequently, reaction mixture was magnetically stirred at 120 o C for 16 h After finishing the reaction time and cooling the vial to ambient temperature, diphenyl ether was added into the mixture as an internal standard The reaction yield was monitored by withdrawing aliquots from the reaction mixture, quenched with brine and the organic components were then extracted into ethyl acetate (2 mL), dried over anhydrous Na2SO4 and analyzed by GC with reference to diphenyl ether
After the reaction was monitored by GC and TLC, the reaction mixture was diluted with ethyl acetate The ethyl acetate solution was washed with brine solution four times
The organic layer was then dried over anhydrous Na2SO4 and concentrated under reduced pressure The resulting residue was further purified by column chromatography on silica gel (ethyl acetate/hexane = 1/4) to afford the product phenyl(quinolin-3-yl)methanone as white crystalline solid (91%, isolated yield based on the reactant 2-aminobenzylalcohol)
The product identity was further confirmed by GC-MS, 1 H NMR and 13 C NMR
In the catalyst recycling studies, the Cu2(OBA)2(BPY) catalyst was separated from the reaction mixture by simple centrifugation, washed with copious amount of anhydrous DMF and methanol, heated at 150 o C in a shlenkline under vacuum in 6 h and then reutilized for new catalytic transformation
For the leaching test, a catalytic reaction heated to 120 o C was stopped after 8 hours, analyzed by GC, and centrifuged to remove the solid catalyst The reaction solution was
61 subsequently heated in the absence of Cu2(OBA)2(BPY) catalyst at 120 o C for a further 8 hours Reaction progress was monitored by GC as previously described
3.4 Results and discussions 3.4.1 Synthesis and characterization of Cu 2 (OBA) 2 (BPY)
Cu2(OBA)2BPY was solvothermally synthesized from Cu(NO3)2.2H2O, H2OBA, 4,4’-BPY, H2O in N,N-dimethylformamide (DMF) Generally, the reaction mixture was sealed in a borosilicate tube under ambient atmosphere and placed in an isothermal oven at 85 °C for two days, producing the green light crystal of Cu2(OBA)2BPY at 71% yield based on Cu(NO3)2.2H2O The crystal structure of Cu2(OBA)2BPY was consequently characterized after solvent exchange and activation steps.
Synthetic scheme for self-assembling the light green crystal of Cu2(OBA)2(BPY)
Figure 3.3 X-ray powder diffractograms of the Cu2(OBA)2(BPY)
As can be seen in Figure 3.3, the X-ray diffraction patterns of the Cu2(OBA)2(BPY) demonstrated the presence of very sharp peaks at 2Ө of approximately 8 o (single peak), proving the highly crystallinity of the Cu2(OBA)2(BPY) There were some peak above 10 o which proved that Cu2(OBA)2(BPY) MOF was high porosity The result was also similar to the simulated patterns previously reported in the literature [67], so it could be approved that the structure of the MOF-Cu2(OBA)2(BPY) was successfully formed
Figure 3.4.FT-IR spectra of the Cu2(OBA)2(BPY) (a), H2OBA (b), 4,4-bipyridine (c).
Figure 3.2 compares the FT-IR spectra of the Cu2(OBA)2(BPY) with the ligand 4,4’-
Oxybis(benzoic acid) and 4,4’-Bipyridine
Firstly, the FT-IR spectrum of 4,4’-Oxybis(benzoic acid) shows strong peak at approximately 1680 cm - 1, this is due to the C=O stretching vibration in free carboxylic acid In the FT-IR spectrum of the Cu2(OBA)2(BPY), the corresponding signal were shifted to 1610 cm -1 Besides, several strong and broad O-H bands between 3000 and 2500 cm -1 observed in H2OBA’s FT-IR spectrum but not in case of the Cu2(OBA)2(BPY) indicated the deprotonation of –COOH groups in H2OBA upon the reaction with metal ions
Secondly, when observing the FT-IR spectrum of 4,4’-Bipyridine, strong peak at approximately 1596 cm -1 represent the C=N stretching vibration in the imine It was found that this value was decreased to 1539 cm -1 in the spectra of the Cu2(OBA)2(BPY), confirming the coordination of the nitrogen with metal ions
Figure 3.5 TGA analysis of the Cu2(OBA)2(BPY)
The thermal stability of the Cu2(OBA)2(BPY) was also examined by the thermalgravimetric analysis (TGA) (Figure 3.3) It was observed that the decomposing temperature of Cu2(OBA)2(BPY) was nearly 350 o C (high peak in derivative weight curve in Figure 3.5 Indeed, the curve roughly unchanged from 50 o C to 330 o C, indicated that there is no significant weight change until pyrolysis at 330 o C This first weight loss of only about 1% below 330 °C may be relating to the departure of free solvent (DMF and methanol from washing and solvent exchanging) and water adsorbed on the material in storage condition This result corresponded well to the high stability of the phase of Cu2(OBA)2(BPY) and its application in the wide range of temperature Nevertheless, the weight loss was recorded at about 57% in the range about 330 °C to 460 °C, showing that at this temperature, Cu2(OBA)2(BPY) started to decompose significantly The results obtained in this study were in agreement with the previous report of Tang et al [67]
Figure 3.6 Pore size distribution of the fresh Cu2(OBA)2(BPY)
Figure 3.7.Nitrogen adsorption/desorption isotherm of the Cu2(OBA)2(BPY)
Adsorption data are shown as closed circles and desorption data as open circles
66 Surface area and pore size distribution are essential properties for studying porous material characterization Therefore, nitrogen physisorption measurements were also conducted to figure out these features The pore volume and pore size distribution were calculated by the Horvath-Kawazoe approach, giving a pore volume of 0.13 cm 3 g -1 and an average micropore diameter of around 5.69 Å (Figure 3.6) By collecting high resolution nitrogen sorption isotherms at 77.3K, the permanent porosity of the Cu2(OBA)2(BPY) was confirmed with Langmuir’s and BET surface areas of 379 m 2 g -1 and 254 m 2 g -1 , respectively (Figure 3.7)
Figure 3.8 SEM (a) and TEM (b) micrograph of Cu2(OBA)2(BPY)
Additionally, the morphology, size and regularity of Cu2(OBA)2(BPY) were revealed through Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) results The SEM micrograph indicates the formation of the three- dimensional well sharped crystals of Cu2(OBA)2(BPY) The porous structure of Cu2(OBA)2(BPY) was also demonstrated in the TEM micrograph (Figure 3.8)
3.4.2 The catalytic studies on the synthesis of phenyl(quinolin-3-yl)methanone 3.4.2.1 Effect of temperature
67 Initial studies determined the effect of temperature on the yield of phenyl(quinolin- 3-yl)methanone The reaction was performed in 0.5 mL DMF, in the presence of 10 mol%
Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO, using 2- aminobenzylalcohol : propiophenone molar ratio of 1:2 at the room temperature, 60 o C, 80 oC, 100 o C, 120 o C and 140 o C respectively Aliquots were withdrawn from the mixture after 16h and analyzed by GC (Figure 3.9)
Figure 3.9 Effect of temperature on reaction yield
From the experimental point of view, it was found that the reaction proceeded with difficulty at room temperature, 60 o C and 80 o C with around nearly 3% of the product recorded after 16h The transformation performed at 100 o C afforded the product in 38% yield and as expected, increasing the reaction temperature led to a significant enhancement in the reaction yield The yield of desired reaction climbed dramatically to the peak with 91% yield by rising the reaction temperature to 120 o C Conducting reaction at higher temperature; however, was noted to be unnecessary since the improvement in reaction yield was trivial Indeed, 91% yield of phenyl(quinolin-3-yl)methanone was produced at 140 o C
Overall, the most suitable temperature of this reaction was 120 o C
68 The impact of solvents on liquid-phase organic transformations has to be addressed with careful consideration In various circumstances, the yield of the desired product remarkably changed when performing the reaction in different solvents [93, 94] Therefore, it was necessary to screen to investigate the appropriate solvent on generation of phenyl(quinolin-3-yl)methanone from 2-aminobenzyl alcohol and propiophenone utilizing Cu2(OBA)2(BPY) as heterogeneous catalyst The reaction was conducted in 0.5 mL of numerous solvents at 2-aminobenzyl alcohol concentration of 0.4 M, with 2-aminobenzyl alcohol/ propiophenone ratio of 1:2, in the present of 10% Cu2(OBA)2BPY catalyst, 1.5 equivalent of pyridine and 2 equivalent of TEMPO at 120 o C for 16 h (Figure 3.10)
It was obviously observed that the yield of phenyl-(quinolin-3-yl)methanone was significantly affected by the solvent The cyclization reaction proceeded with difficulty in N-methyl-2-pyrrolidone, ethylbenzene, and cumene, affording 19%, 40%, and 48% yields after 16 h Remarkable improvements in yield was discovered when conversions were carried out under non-polar solvents, including o-xylene, m-xylene, p-xylene, granting the expected product in 56%, 59% and 69% yields, respectively, after 16 h Dichlorobenzene also expressed medium performance, producing phenyl(quinolin-3-yl)methanone in 64% after 16 h, whereas performing the reaction in toluene, the reaction yield was amended to 77% This number could be also enhanced to 78% for the transformation executed in DMA, while only 55% for that carried out in DMSO though both of them are polar aprotic solvents Compared with these solvents, another polar aprotic solvent-DMF revealed the best presentation, with 91% yield of desired product recorded after 16 h
Figure 3.10 Effect of different solvents on reaction yield
When DMF was initially chosen as the solvent for the optimization of the reaction based on these experimental results Different amounts of DMF solvent were also tested to boost the yield of reaction, at the temperature of 120 o C, in the presence of 10 mol%
Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO, with 2- aminobenzyl alcohol/propiophenone ratio of 1:2, the resulting mixtures were magnetically stirred for 16 hours (Figure 3.11)
Form the experimental result, the conversion happened in difficulty without the presence of solvent, at only 37% yield When the quantity of solvent was grown to 0.25 mL, the reaction yield was also upgraded to 83% This can be explained that components in the vial have enough space to dissolve and interact to each other Like that, the amount of solvent was subsequently increased to 0.5, 1, 2, 3, and 4 mL to find the best of choice
While 0.5 mL was the most appropriate volume in this transformation, with 91% yield, a significant drop in the reaction yield was observed form 75% to 15% when quantity of
70 DMF rose from 1 mL to 4 mL, this was almost certainly due to low reaction rate at low concentration of reactants
Figure 3.11 Effect of amount of DMF on the reaction yield
3.4.2.3 Effect of reactant molar ratio on the reaction yield
Another concern that should be evaluated for this reaction is the influence of reactant molar ratios It was therefore decided to carry out the reaction in DMF at 120 o C, using 10 mol% Cu2(OBA)2(BPY), 1.5 equivalent of pyridine and 2 equivalent of TEMPO with the 2-aminobenzyl alcohol:propiophenone molar ratio of 1:1, 1:1.5, 1:2, 1:2.5, 1:3 and 1:4, respectively (Figure 3.12)
As expected, increasing the reagent ratio from 1:1 to 1:2 led to a significant improvement in the reaction rate, with more than 90% conversion being achieved after 16 hours However, it was observed that the reaction rate was not enhanced dramatically when the reagent ratio increased from 1:2 to 1:2.5, 1:3 and even 1:4 Hence, the 2- aminobenzylalcohol : propiophenone molar ratio of 1:2 was utilized for further studies
Figure 3.12 Effect of the 2-aminobenzyl alcohol : propiophenone molar ratio on the reaction yield
The catalyst amount is an important factor that should be taken into accounts when investigating the Cu2(OBA)2(BPY)-catalyzed cyclization reaction of 2- aminobenzylalcohol and propiophenone The reaction was executed at 120 o C with 2- aminobenzyl alcohol concentration of 0.4 M in DMF, 2-aminobenzylalcohol : propiophenone molar ratio of 1:2 in the presence of 1.5 equivalent of pyridine, 2 equivalent of TEMPO and 0 mol%, 1 mol%, 3 mol%, 5 mol%, 7 mol%, 10 mol%, 20 mol% of Cu2(OBA)2(BPY) as catalyst (Figure 3.13)
Proposed reaction mechanism
10 mol% catalystAscorbic acid test 1Ascorbic acid test 2
86 A plausible reaction pathway was proposed for the one-pot domino reaction between 2- aminobenzylalcohol and propiophenone to produce phenyl(quinolin-3-yl)methanone (Scheme 3.13) Initially, copper species coordinated with ketone 2 to form the Ln-Cu(II)- enolate complex A Under reaction conditions, A underwent single electron transfer (SET) process to generate Cu(I) species, and α-C-centered radical B This radical consequently interacted with TEMPO to form α-TEMPO-substituted ketone C [95, 96] Through Cope- like elimination, the intermediates C released 4-OH-TEMPO via five centered cyclic transition state to give α, β -unsaturated ketone D [97] The TEMPO as an oxidant converted the alcohol group of 1 to aldehyde E, which subsequently underwent a conjugate addition with D to afford β-aminoketone F [98] Through another Cu(II)/TEMPO- catalyzed dehydrogenation, F was transformed into enaminone G Finally, G underwent an intramolecular enamine-ketone condensation to generate product 3 via the formation of
3.4.2.12 Effect of different substituents on the reaction
Table 3.2 Table Synthesis of 3-aroylquinolines via Cu2(OBA)2(BPY)-catalyzed one-pot domino reactions a
Entry Reactant 1 Reactant 2 Product Yield
16 63 aReaction conditions: 2-aminobenzylalcohol (0.2 mmol); propiophenone (0.4 mmol);
Cu2(OBA)2(BPY) (10 mol%); pyridine (0.3 mmol); TEMPO (0.4 mmol); DMF (0.5 mL);
The scope of this work was subsequently expanded to the Cu2(OBA)2(BPY)- catalyzed one-pot domino reactions of different 2-aminobenzylalcohols and propiophenones (Table 3.2) The reaction was conducted in DMF at 120 o C for 16 h with 10 mol% catalyst, using 2 equivalents of propiophenone, in the presence of 2 equivalents of TEMPO and 1.5 equivalents of pyridine 3-Aroylquinolines were then purified by column chromatography In the first experiment series, different propiophenones were employed for the reaction with 2-aminobenzylalcohol (Entries 1-8, Table 3.2)
Phenyl(quinolin-3-yl)methanone was achieved in 89% yield via the reaction between 2- aminobenzylalcohol and propiophenone (Entry 1) Halogen-containing propiophenones were reactive towards the reaction, producing (3-chlorophenyl)(quinolin-3-yl)methanone (Entry 2), (4-fluorophenyl)(quinolin-3-yl)methanone (Entry 3), and (4- bromophenyl)(quinolin-3-yl)methanone (Entry 4) in 75%, and 80% yield, respectively
Similarly, (3-nitrophenyl)(quinolin-3-yl)methanone (Entry 5), and quinolin-3-yl(2-(trifluoromethyl)phenyl)methanone (Entry 6) obtained in 77% and 92% yields,
89 respectively Propiophenones containing an electron-donating substituent were good starting materials for the synthesis of 3-aroylquinolines (Entries 7-8) In the second experiment series, 2-aminobenzylalcohols possessing substituents were utilized for the one-pot domino reactions, affording corresponding 3-aroylquinolines in high yields (Entries 9-15, Table 3) Additionally, (2-aminophenyl)(phenyl)methanol was also reactive, producing (4-phenylquinolin-3-yl)(p-tolyl)methanone in 63% yield (Entry 16)
Metal-organic framework Cu2(OBA)2(BPY) was synthesized from copper (II) nitrate trihydrate, 4,4′-oxybis(benzoic) acid, and 4,4′-bipyridine The Cu-MOF was utilized as a heterogeneous catalyst for the synthesis of 3-aroylquinolines via one-pot domino reactions of 2-aminobenzylalcohols with propiophenones The transformation was significantly controlled by the nature of oxidant, and TEMPO emerged as the only effective oxidant for the formation of 3-aroylquinolines The ligand also displayed a noticeable impact on the reaction, and pyridine should be the best candidate The Cu2(OBA)2(BPY) was more active towards the one-pot domino reaction than a series of conventional transition metal salts, as well as nano oxide and MOF-based catalysts Leaching studies verified that the one-pot domino reaction utilizing the Cu2(OBA)2(BPY) catalyst proceeded under heterogeneous catalysis conditions It was possible to reuse the copper-based framework catalyst for the synthesis of 3-aroylquinolines without an appreciable decline in catalytic performance
Utilizing 2-aminobenzylalcohols for the synthesis of 3-acylquinolines via one-pot domino reactions was not previously mentioned in the literature, and this protocol would be complementary to previous strategies for the synthesis of these valuable heterocycles
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The ratios of the peak area of the product to the peak area of the internal standard was calculated as follows : product
, (1) where S product and Sinternal standard are respectively the peak areas of phenyl(quinolin-3- yl)methanone and diphenyl ether measured on the GC chromatogram
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
Table A1 Calibration curve calculation for 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Figure A.1 Calibration curve of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile with reference to diphenyl ether
Table A2 Calibration curve calculation for of phenyl(quinolin-3-yl)methanone
Figure AA Calibration Curve of phenyl(quinolin-3-yl)methanone with reference to diphenyl ether
APPENDIX B: GC AND MS RESULTS y = 0.7532x + 0.0206 R² = 0.9996
Figure B1 GC spectra of the synthesis of 3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Figure B2 MS spectrum of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Figure B3 GC spectra of the synthesis of phenyl(quinolin-3-yl)methanone
Figure B4 MS spectra of phenyl(quinolin-3-yl)methanone
Fig C1 1 H-NMR spectra of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
106 Fig C2 13 C-NMR spectra of 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization data for 3-phenyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate = 9/1): yellow solid, 81 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.46 – 7.41 (m, 5H), 7.38 (dd, J = 8.1, 1.0 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.17 (td, J = 7.6, 1.0 Hz, 1H), 7.11 (dd,
107 Fig C3 1 H-NMR spectra of 3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
108 Fig C4 13 C-NMR spectra of 3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-( p -tolyl)-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane : ethyl acetate = 9 : 1), yellow solid, 84 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.4 Hz, 1H), 7.23 (d, J = 7.9 Hz, 2H), 7.16 (t, J 7.5 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.71 (s, 1H), 2.38 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 140.3, 137.9, 136.6, 129.8, 129.7, 128.2, 127.4, 127.3, 127.3, 125.7, 118.7, 110.7, 105.3, 89.8, 21.5
109 Fig C5 1 H-NMR spectra of 3-(4-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
110 Fig C6 13 C-NMR spectra of 3-(4-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 3-(4-methoxyphenyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 82 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.39 – 7.36 (m, 3H), 7.29 – 7.26 (m, 1H), 7.16 (td, J = 7.6, 1.1 Hz, 1H), 7.10 (dd, J = 7.7, 1.4 Hz, 1H), 6.96 – 6.93 (m, 2H), 5.64 (s, 1H), 3.84 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 161.0, 137.6, 136.6, 128.9, 128.1, 127.3, 127.3, 125.8, 124.9, 118.7, 114.5, 110.7, 104.3, 55.5
111 Fig C7 1 H-NMR spectra of 3-(4-bromophenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
112 Fig C8 13 C-NMR spectra of 3-(4-bromophenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-(4-bromophenyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 68 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.59 – 7.55 (m, 2H), 7.36 (dd, J = 8.1, 1.0 Hz, 1H), 7.30 (ddd, J = 6.9, 4.5, 1.8 Hz, 3H), 7.18 (td, J 7.6, 1.2 Hz, 1H), 7.11 (dd, J = 7.8, 1.3 Hz, 1H), 5.79 (s, 1H) 13 C-NMR (126 MHz, CDCl3) δ 136.6, 136.2, 132.4, 131.5, 128.9, 128.4, 127.5, 127.4, 125.3, 124.3, 118.8, 110.4, 107.3
113 Fig C9 1 H-NMR spectra of 3-(4-fluorophenyl)-4H-benzo[b][1,4]thiazine-4-carbonitrile
114 Fig C10 13 C-NMR spectra of 3-(4-fluorophenyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 3-(4-fluorophenyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 86 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.45 – 7.41 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 11.4, 4.1 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 7.12 (dt, J = 6.8, 5.9 Hz, 3H), 5.72 (s, 1H) 13 C NMR (126 MHz, CDCl3) δ 164.7, 163.8, 162.7, 136.8, 136.3, 129.5, 129.5, 128.7, 128.3, 127.4, 127.4, 125.4, 118.7, 116.4, 116.2, 110.4, 106.4
115 Fig C11 1 H-NMR spectra of 3-cyclopentyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
116 Fig C12 13 C-NMR spectra of 3-cyclopentyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-cyclopentyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 78 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.21 (dtd,
J = 9.6, 8.1, 1.5 Hz, 2H), 7.11 – 7.07 (m, 1H), 7.04 (dd, J = 7.7, 1.3 Hz, 1H), 5.36 (d, J 1.0 Hz, 1H), 2.95 – 2.85 (m, 1H), 2.09 – 2.01 (m, 2H), 1.63 – 1.72 (m, 4H), 1.46 – 1.53 (m, 2H) 13 C-NMR (126 MHz, CDCl3) δ 140.9, 136.2, 127.9, 127.1, 126.8, 124.8, 117.7, 110.5, 100.1, 42.5, 31.1, 24.8
117 Fig C13 1 H-NMR spectra of 3-cyclohexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
118 Fig C14 13 C-NMR spectra of 3-cyclohexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-cyclohexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 63 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.22 (q, J
= 8.4 Hz, 2H), 7.12 – 7.03 (m, 2H), 5.33 (s, 1H), 2.43 (t, J = 11.6 Hz, 1H), 1.99 (d, J = 12.6 Hz, 2H), 1.82 (d, J = 13.5 Hz, 2H), 1.74 (d, J = 13.2 Hz, 1H), 1.34 – 1.42 (m, 2H), 1.22 – 1.12 (m, 3H) 13 C-NMR (126 MHz, CDCl3) δ 142.2, 136.5, 128.0, 127.2, 126.8, 125.2, 117.9, 110.3, 101.2, 40.9, 31.7, 26.2
119 Fig C15 1 H-NMR spectra of 3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
120 Fig C16 13 C-NMR spectra of 3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-hexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 75 % yield 1 H NMR (500 MHz, CDCl3) δ 7.23 – 7.16 (m, 2H), 7.11 – 7.06 (m, 1H), 7.02 (d, J = 7.6 Hz, 1H), 5.28 (s, 1H), 2.44 – 2.34 (m, 2H), 1.59 – 1.52 (m, 3H), 1.36 – 1.27 (m, 6H), 0.87 (t, J = 6.7 Hz, 3H) 13 C NMR (126 MHz, CDCl3) δ 136.6, 135.6, 127.8, 127.1, 126.7, 123.8, 117.5, 109.9, 101.1, 32.9, 31.4, 28.4, 27.1, 22.5, 13.9
121 Fig C17 1 H-NMR spectra of 7-fluoro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
122 Fig C18 13 C-NMR spectra of 7-fluoro-3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-fluoro-3-phenyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 85 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.44 (s, 5H), 7.33 (dd, J = 8.9, 4.6 Hz, 1H), 6.98 (ddd, J = 8.8, 7.8, 2.7 Hz, 1H), 6.86 (dd, J = 7.9, 2.7 Hz, 1H), 5.76 (s, 1H) 13 C-NMR (126 MHz, CDCl3) δ 162.2, 160.2, 138.2, 132.5, 132.2, 130.3, 129.2, 128.2, 128.1, 127.4, 120.0, 119.9, 115.0, 114.9, 114.5, 114.3, 110.5, 105.6
123 Fig C19 1 H-NMR spectra of 7-fluoro-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
124 Fig C20 13 C-NMR spectra of 7-fluoro-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-fluoro-3-( p -tolyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 88 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.32 (dt, J
= 4.4, 2.6 Hz, 3H), 7.24 (d, J = 8.1 Hz, 2H), 7.00 – 6.94 (m, 1H), 6.87 – 6.83 (m, 1H), 5.69 (s, 1H), 2.38 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 162.1, 160.1, 140.6, 138.4, 132.6, 129.7, 129.4, 128.3, 128.2, 127.3, 120.0, 119.9, 115.0, 114.8, 114.5, 114.3, 110.6, 104.5, 21.5
125 Fig C21 1 H-NMR spectra of 7-fluoro-3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
126 Fig C22 13 C-NMR spectra of 7-fluoro-3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 7-fluoro-3-hexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 79 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.16 (dd, J
= 8.9, 4.6 Hz, 1H), 6.89 (ddd, J = 8.9, 7.7, 2.8 Hz, 1H), 6.77 (dd, J = 8.0, 2.8 Hz, 1H), 5.26 (s, 1H), 2.43 – 2.36 (m, 2H), 1.52 – 1.57 (m, 3H), 1.36 – 1.26 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H) 13 C-NMR (126 MHz, CDCl3) δ 161.8, 159.8, 137.2, 131.8, 126.5, 126.4, 118.8, 118.7, 114.6, 114.4, 114.4, 114.2, 109.9, 100.6, 32.9, 31.5, 28.6, 27.2, 22.6, 14.1
127 Fig C23 1 H-NMR spectra of 3-cyclohexyl-7-fluoro-4H-benzo[b][1,4]thiazine-4- carbonitrile
128 Fig C24 13 C-NMR spectra of3-cyclohexyl-7-fluoro-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-fluoro-3-hexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 81 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.17 (dd, J
= 8.9, 4.6 Hz, 1H), 6.94 – 6.87 (m, 1H), 6.79 (dd, J = 8.0, 2.7 Hz, 1H), 5.30 (s, 1H), 2.40 (ddd, J = 11.5, 7.2, 2.9 Hz, 1H), 1.97 (d, J = 12.6 Hz, 2H), 1.73 – 1.83 (m, 3H), 1.43 – 1.33 (m, 2H), 1.23 – 1.12 (m, 3H) 13 C-NMR (126 MHz, CDCl3) δ 161.8, 159.8, 142.6, 132.4, 127.7, 127.6, 119.0, 118.9, 114.7, 114.5, 114.3, 114.1, 110.1, 100.6, 40.8, 31.6, 26.1, 26.1
129 Fig C25 1 H-NMR spectra of 7-chloro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
130 Fig C26 13 C-NMR spectra of 7-chloro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 7-chloro-3-phenyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 80 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.46 – 7.40 (m, 5H), 7.29 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.6, 2.1 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 5.73 (s, 1H) 13 C-NMR (126 MHz, CDCl3) δ 138.0, 135.1, 132.8, 132.2, 130.3, 129.1, 128.1, 127.5, 127.4, 126.9, 119.6, 110.1, 105.6
131 Fig C27 1 H-NMR spectra of 7-chloro-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
132 Fig C28 13 C-NMR spectra of 7-chloro-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-chloro-3-( p -tolyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 77 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.32 (dt, J
= 4.4, 2.6 Hz, 3H), 7.24 (d, J = 8.1 Hz, 2H), 7.00 – 6.94 (m, 1H), 6.87 – 6.83 (m, 1H), 5.69 (s, 1H), 2.38 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 162.1, 160.1, 140.6, 138.4, 132.6, 129.7, 129.4, 128.3, 128.2, 127.3, 120.0, 119.9, 115.0, 114.8, 114.5, 114.3, 110.6, 104.5, 21.5
133 Fig C29 1 H-NMR spectra of 7-chloro-3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
134 Fig C30 13 C-NMR spectra of 7-chloro-3-hexyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 7-chloro-3-hexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 76 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.08 (d, J
= 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.83 (s, 1H), 5.25 (s, 1H), 2.43 – 2.35 (m, 2H), 2.26 (s, 3H), 1.36 – 1.25 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H) 13 C-NMR (126 MHz, CDCl3) δ 136.8, 136.6, 133.1, 128.5, 127.6, 123.5, 117.4, 110.2, 100.9, 33.0, 31.5, 28.6, 27.2, 22.6, 20.7, 14.1
135 Fig C31 1 H-NMR spectra of 7-chloro-3-cyclohexyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
136 Fig C32 13 C-NMR spectra of 7-chloro-3-cyclohexyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-chloro-3-hexyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 78 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.19 – 7.11 (m, 2H), 7.04 (d, J = 1.9 Hz, 1H), 5.29 (s, 1H), 2.37 – 2.43 (m, 1H), 1.96 (d, J = 12.5 Hz, 2H), 1.87 – 1.77 (m, 2H), 1.74 (d, J = 13.0 Hz, 1H), 1.32 – 1.41 (m, 2H), 1.22 – 1.10 (m, 3H) 13 C-NMR (126 MHz, CDCl3) δ 142.4, 135.2, 132.1, 127.8, 127.2, 126.8, 118.7, 109.8, 100.6, 40.8, 31.6, 26.1, 26.1
137 Fig C33 1 H-NMR spectra of 7-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
138 Fig C34 13 C-NMR spectra of 7-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-methyl-3-phenyl-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane : ethyl acetate = 9 : 1), yellow solid, 81 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.37 (d, J
7.16 (t, J = 7.5 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 5.71 (s, 1H), 2.38 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 140.3, 137.9, 136.6, 129.8, 129.7, 128.2, 127.4, 127.3, 127.3, 125.7, 118.7, 110.7, 105.3, 89.8, 21.5
139 Fig C35 1 H-NMR spectra of 7-methyl-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
140 Fig C36 13 C-NMR spectra of 7-methyl-3-(p-tolyl)-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 7-methyl-3-( p -tolyl)-4 H -benzo[ b ][1,4]thiazine-4- carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow solid, 82 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.32 (d, J 8.2 Hz, 2H), 7.24 (d, J = 8.4 Hz, 3H), 7.06 (dd, J = 8.2, 1.1 Hz, 1H), 6.91 (s, 1H), 5.69 (s, 1H), 2.38 (s, 3H), 2.30 (s, 3H) 13 C-NMR (126 MHz, CDCl3) δ 140.2, 137.9, 137.4, 133.9, 129.8, 129.6, 128.8, 127.6, 127.3, 125.3, 118.5, 110.9, 105.1, 21.5, 20.8
141 Fig C37 1 H-NMR spectra of 3-hexyl-7-methyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
142 Fig C38 13 C-NMR spectra of 3-hexyl-7-methyl-4H-benzo[b][1,4]thiazine-4-carbonitrile
Characterization Data for 3-hexyl-7-methyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 79 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.15 (dd, J
= 8.6, 2.2 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 5.25 (s, 1H), 2.42 – 2.38 (m, 2H), 1.59 – 1.48 (m, 5H), 1.35 – 1.25 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H) 13 C-NMR (126 MHz, CDCl3) δ 137.0, 132.2, 127.2, 126.9, 126.0, 118.5, 100.6, 32.98, 31.5, 28.6, 27.2, 22.6, 14.1
143 Fig C39 1 H-NMR spectra of 3-cyclohexyl-7-methyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
144 Fig C40 13 C-NMR spectra of 3-cyclohexyl-7-methyl-4H-benzo[b][1,4]thiazine-4- carbonitrile
Characterization Data for 3-cyclohexyl-7-methyl-4 H -benzo[ b ][1,4]thiazine-4-carbonitrile
Prepared as shown in the general experimental procedure and purified on silica gel (hexane: ethyl acetate = 9 : 1), yellow liquid, 80 % yield 1 H-NMR (500 MHz, CDCl3) δ 7.11 (d, J = 8.2 Hz, 1H), 6.99 (dd, J = 8.2, 1.0 Hz, 1H), 6.86 (s, 1H), 5.30 (d, J = 0.6 Hz, 1H), 2.44 – 2.38 (m, 1H), 2.27 (s,
Fig D1 1 H-NMR spectra of phenyl(quinolin-3-yl)methanone
146 Fig D2 13 C-NMR spectra of phenyl(quinolin-3-yl)methanone
Characterization data for phenyl(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =4 /1): white solid, 89% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.32 (s, 1H), 8.54 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.96 – 7.78 (m, 4H), 7.71 – 7.59 (m, 2H), 7.53 (t, J = 7.2 Hz, 2H) 13 C NMR (126 MHz, CDCl 3 ) δ 195.0, 150.5, 149.6, 138.9, 137.2, 133.2, 131.9, 130.2, 130.1, 129.6, 129.3, 128.8, 127.7, 126.7
147 Fig D3 1 H-NMR spectra of (3-chlorophenyl)(quinolin-3-yl)methanone
148 Fig D4 13 C-NMR spectra of (3-chlorophenyl)(quinolin-3-yl)methanone
Characterization data for (3-chlorophenyl)(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel
(hexane/ ethyl acetate =4 /1): yellow solid, 75% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.31 (s, 1H), 8.55 (d, J = 1.7 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.92 – 7.80 (m, 2H), 7.80 – 7.71 (m, 1H), 7.70 – 7.61 (m, 2H), 7.49 (t, J = 7.9 Hz, 1H) 13 C NMR (126 MHz, CDCl 3 ) δ 193.7, 150.2, 149.8, 139.1, 138.8, 135.2, 133.2, 132.3, 130.1, 130.0, 129.7, 129.6, 129.4, 128.2, 127.9, 126.7
149 Fig D5 1 H-NMR spectra of (4-fluorophenyl)(quinolin-3-yl)methanone
150 Fig D6 13 C-NMR spectra of (4-fluorophenyl)(quinolin-3-yl)methanone
Characterization data for (4-fluorophenyl)(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel
(hexane/ ethyl acetate = 4/1): yellow solid, 80% yield 1 H NMR (500 MHz, CDCl 3 ) δ 8.96 (d, J = 1.8 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.62 – 7.51 (m, 4H), 7.32 (t, J = 7.5 Hz, 1H), 6.93 – 6.87 (m, 2H) 13 C NMR (126 MHz, CDCl 3 ) δ 193.4, 166.8, 150.1, 149.5, 138.6, 132.7, 132.7, 132.0, 130.0, 129.5, 129.1, 127.7, 126.6, 116.0
151 Fig D7 1 H-NMR spectra of (4-bromophenyl)(quinolin-3-yl)methanone
152 Fig D8 13 C-NMR spectra of (4-bromophenyl)(quinolin-3-yl)methanone
Characterization data for (4-bromophenyl)(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =3 /2): white solid, 80% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.30 (s, 1H), 8.54 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.88 (t,
J = 7.7 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.72 – 7.65 (m, 3H) 13 C NMR (126 MHz, CDCl 3 ) δ 193.9, 150.1, 149.5, 139.0, 135.8, 132.3, 132.2, 131.6, 129.8, 129.5, 129.3, 128.5, 127.96, 126.7
153 Fig D9 1 H-NMR spectra of (3-nitrophenyl)(quinolin-3-yl)methanone
154 Fig D10 13 C-NMR spectra of (3-nitrophenyl)(quinolin-3-yl)methanone
Characterization data for (3-nitrophenyl)(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel
(hexane/ ethyl acetate =3 /2): yellow solid, 77% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.28 (s, 1H), 8.65 (d, J = 1.2 Hz, 1H), 8.52 (s, 1H), 8.50 – 8.42 (m, 1H), 8.17 (t, J
155 Fig D11 1 H-NMR spectra of quinolin-3-yl(2(trifluoromethyl)phenyl)methanone
156 Fig D12 13 C-NMR spectra of quinolin-3-yl(2 (trifluoromethyl)phenyl) methanone
Characterization data for quinolin-3-yl(2-(trifluoromethyl)phenyl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =3 /2): white solid, 92% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.34 (s, 1H), 8.43 (s, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.86 (t, J = 7.6 Hz, 3H), 7.72 – 7.68 (m, 2H), 7.64 – 7.60 (m, 1H), 7.47 (d, J = 3.1 Hz, 1H) 13 C NMR (126 MHz, CDCl 3 ) δ 194.3, 150.0, 149.9, 140.0, 137.5, 132.8, 131.9, 130.6, 129.7, 129.6, 129.0, 128.3, 127.9, 127.2, 127.1, 127.1, 126.7
157 Fig D13 1 H-NMR spectra of (4-methoxyphenyl)(quinolin-3-yl)methanone
158 Fig D14 13 C-NMR spectra of (4-methoxyphenyl)(quinolin-3-yl)methanone
Characterization data for (4-methoxyphenyl)(quinolin-3-yl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =3 /2): white solid, 90% yield 1 H NMR (500 MHz, CDCl 3 ) δ 9.11 (s, 1H), 8.36 (d, J = 1.7 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.81 – 7.64 (m, 4H), 7.47 (t, J = 7.5 Hz, 1H), 6.88 – 6.82 (m, 2H), 3.75 (s, 3H) 13 C NMR (126 MHz, CDCl 3 ) δ 193.5, 163.8, 150.3, 149.2, 138.3, 132.6, 131.6, 130.9, 129.7, 129.4, 129.1, 127.6, 126.7, 114.0, 55.6
159 Fig S22 1 H-NMR spectra of quinolin-3-yl(p-tolyl)methanone
Fig D15 1 H-NMR spectra of quinolin-3-yl(p-tolyl)methanone
Fig D16 13 C-NMR spectra of quinolin-3-yl(p-tolyl)methanone
Characterization data for quinolin-3-yl(p-tolyl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =3 /2): white solid, 85% yield 1 H NMR (500 MHz, CDCl3) δ 9.31 (s, 1H), 8.55 (s, 1H), 8.20 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.85 (t, J = 7.7 Hz, 1H),
161 Fig D17 1 H-NMR spectra of (7-chloroquinolin-3-yl)(phenyl)methanone
162 Fig D18 13 C-NMR spectra of (7-chloroquinolin-3-yl)(phenyl)methanone
Characterization data for (7-chloroquinolin-3-yl)(phenyl)methanone
Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ ethyl acetate =3 /2): white solid, 81% yield 1 H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 8.54 (s, 1H), 8.21 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.72 – 7.65 (m, 3H) 13 C NMR (126 MHz, CDCl3) δ 193.6, 149.8, 149.2, 138.8, 135.6, 132.0, 131.9, 131.4, 129.6, 129.3, 129.1, 128.2, 127.7, 126.5
163 Fig D19 1 H-NMR spectra of (7-bromoquinolin-3-yl)(phenyl)methanone
164 Fig D20 13 C-NMR spectra of (7-bromoquinolin-3-yl)(phenyl)methanone
Characterization data for (7-bromoquinolin-3-yl)(phenyl)methanone