1 -1.4 THE QUINAZOLINONES SYNTHESIS OF 2-ARYLINDOLES WITH AMINES UTILIZING CU-MOF-74 AS AN EFFICIENT HETEROGENEOUS CATALYST .... 9: CO2 adsorption–desorption isotherms at different temp
LITERATURE REVIEW
M ETAL - ORGANIC FRAMEWORKS (MOF S )
Metal-organic frameworks (MOFs), also known as porous coordination polymers , are compounds consisting of metal ions clusters linked together by organic bridging ligands with wide range of well – defined topology to form one-, two-, three- dimensional structures [1] MOFs have unusually large surface areas and tailorable pore sizes The most striking properties of MOFs are their large pore volumes that have been unsurpassed by any other porous material to date In comparison with other solid matters such as zeolites, carbons and oxides, the porosity of MOFs have come up to 90% free volume and the enormous internal surface areas have extended beyond 7000 m 2 /g (Figure 1 1) [2] For instance, MOF–200 and MOF–210 (Zn 4 O(BBC) 2 and (Zn 4 O) 3 (BTE) 4 (BPDC) 3 , respectively) act as an extensive class of crystalline materials with the ultrahigh surface areas (4530 m 2 /g and 6240 m 2 /g, respectively) and porosities (90% and 89% volume) [3].
Figure 1 1: Progress in the synthesis of ultrahigh porosity MOFs The values in parentheses represent the pore volume (m 3 / g) of these materials [4].
An almost exponential growth of the structures of MOFs has been seen in the Cambridge Structural Database (CSD) during the last decade The combination of so far unreached porosity, surface area, pore size and wide chemical inorganic–organic composition recently has created a strikingly increasing trend each year for all structure types (Figure 1 2)
Figure 1 2: Growth of the Cambridge Structural Database (CSD) and MOF entries since 1972 [5] The inset shows the MOF self-assembly process from building blocks: metals (red spheres) and organic ligands (blue struts).
Transition metal ions such as copper, zinc, nickel, iron are frequently used as the inorganic components of MOFs For the organic linker, there are an extensive variety of choices Ligands with rigid backbones are often preferred, because the rigidity helps to sustain the open-pore structure and easily predicts the network geometry for expected application The linkers can be neutral, anionic, or cationic The neutral and anionic organic linkers are most commonly use such as pyrazine and 4,4’-bipyridine (bpy) [6] and carboxylates because they have the ability to aggregate metal ions into clusters and therefore the frameworks are more stable [7] Cationic organic ligands are relatively little used, because of their low affinities for cationic metal ions [8]
1.1.2 General methods for the synthesis of MOFs
During the last two decades, the synthesis of MOFs has attracted significant attentions The main goal in MOF synthesis was to establish the synthesis conditions that lead to defined inorganic building blocks without decomposition of the organic linker [9] MOFs are often synthesized by means of solvothermal in which the reactions are carried out in an organic solvent at high-temperature in closed vessels
This method is relatively simple and can produce large-scale MOFs; However, it typically takes long reaction times, from several hours up to several months, depending upon the MOF of interest and the reaction solvents, reaction temperatures, reagent concentrations, and other factors [8] Besides that conventional electric (CE), electrochemistry (EC), mechanochemistry (MC), microwave-assisted and ultrasonic (US) methods have been employed (Figure 1 3)
Figure 1 3: Overview of synthesis methods, possible reaction temperatures, and final reaction products in MOFs synthesis [10].
MOFs with permanent porosity and their variety and multiplicity than any other class of porous materials have made MOFs ideal candidates for storage of fuels (hydrogen and methane), capture of carbon dioxide, (gas adsorption) and catalysis applications [4]
In 1998, MOF-2 [Zn(BDC)] is the first carbon dioxide adsorption material [11] and to date, MOF-200 with 2437 mg/g at 50 bar and 298 K have the best excess carbon dioxide uptake [3] The development in the chemistry of MOFs came in 1999, MOF- 5, the first robust and highly porous material , have gas adsorption measurements, which revealed 61% porosity and a Brunauer- Emmett-Teller (BET) surface area of 2320 m 2 /g (2900m 2 /g Langmuir) These values are substantially higher than those commonly found for zeolites and activated carbon [12] MOFs have also been use to separate toxic molecules, hydrocarbon and water from complex compounds For instance, Cu 2 (PZDC) 2 (Pyz) (PZDC = pyrazine-2,3-dicarboxylate; Pyz = pyrazine) selectively takes up acetylene over carbon dioxide through hydrogen bonding between acetylene and oxygen atoms on the MOF internal surface [13] Besides that, the melamine-MOFs were also used as an absorbent for the removal of heavy metal Pb(II) from waste water [14] One of the earliest examples of a dynamic separation was performed using a gas chromatographic column filled with MOF-508 [Zn 2 (BDC) 2 (BPy)] to separate alkanes such as n-pentane, n-hexane, 2,2- dimethylbutane, and 2-methylpentane [15] In biomedical chemistry, iron-containing BioMIL-1 MOF, which was built up from non-toxic iron and the therapeutically active linker nicotinic acid, showed higher loading for nicotinic acid (up to 75%) as compared to the native MOF structures and exhibited controlled drug delivery [16]
The most attractive application of MOFs is as heterogeneous catalysts for organic chemical reactions due to the fact that they can be easily separated and recycled from the reaction systems [17] MOFs are composed entirely of strong bonds (e.g., C-C, C- H, C-O, and M-O), they show high thermal stability ranging from 250° to 500°C[18]
However, these materials could not compare with zeolites in stability [19] It has been
5 a challenge to make chemically stable MOFs because of their susceptibility to link- displacement reactions when treated with solvents over extended periods of time (days) [4] Moreover, high open metal sites as well as abundant metal content in the structure of MOFs give a higher catalytic activity than zeolites, in comparison [20] So MOFs have several unquestionable advantages included the variety of structures and the ability for large-scale production [21]
Catalysis at the metal sites
Metal ions or clusters in the structure of numerous MOFs can directly coordinate to the substrate to catalyze a chemical transformation, as well as, as-synthesized active MOFs Coordination of the substrate to the metal requires either an expansion of the coordination sphere of the metal ion, or a displacement of one of the ligands (Figure
1 4) However, the crystalline integrity do not collapse as a consequence of the local distortions produced upon substrate coordination [22] For example, employing copper imidazolate, [Cu(im) 2 ] and copper pyrimidinolate, [Cu(2-pymo) 2 ] for aerobic liquid phase oxidation of activated paraffins was investigation In this study, the different reactivities of [Cu(2-pymo) 2 ] and [Cu(im) 2 ] was described by principle DFT calculations on MOF model clusters According to that, [Cu(im) 2 ] has a more adaptable crystalline framework than [Cu(2-pymo) 2 ], which allows that the copper sites expand their coordination sphere from 4 to 5 upon interaction with ãOH radical species On the contrary, binding of the same radical to [Cu(2-pymo) 2 ] produces the displacement of one of the 2-pymo ligands from the coordination sphere around the central Cu site A hypothesis that a higher energy would be required in the case of [Cu(2-pymo) 2 ] to break a Cu-pyrimidine bond than in the case of [Cu(im) 2 ] in which only a rearrangement of the ligands is required to accommodate the ãOH radical leads to the better performance of [Cu(im) 2 ] than [Cu(2-pymo)2] in higher alkane conversion, higher selectivity and low accumulation of alkylhydroperoxides in the reaction medium [23]
Figure 1 4:Interaction of a substrate molecule, S, with a metal site, M, through (a) expansion of the coordination sphere around the metal ion; or (b) (reversible) displacement of one of the ligands [22].
Besides, MOFs with coordinatively unsaturated sites are MOFs in which one of the coordination positions of the metal centers is occupied by a labile ligand, which can be removed without causing the collapse of the crystalline structure In most cases, the labile ligands are solvent molecules that, when thermally removed, leave a free coordination position in the metal, which become available for adsorbed substrates
The correspoding metal center which will be prone to accept electron density from any donor will behave as a Lewis acid center When suitable oxidizing agents, such as O 2 , H 2 O 2 or hydroperoxydes, are present in the reaction medium, the resulting MOF can contribute as redox catalyst [22] For instance, the liquid phase cyanosilylation of benzaldehyde using Cu 3 (BTC) 2 was reported by Kclaus and co-workers In this situation, the Lewis acid copper(II) sites of the Cu 2 -paddle-wheel become accessible for the coordination of the aldehyde It was observed that physically and chemically bound water molecules are easily removed from the host material by heating the compound in vacuum (Figure 1 5) The dehydration makes the copper coordination
7 sites accessible for other molecules [24] Other examples in previous literature were Mukaiyama-aldol condensation [25], Friedel–Crafts benzilation [26], and the oxidation of alcohols [27] sulfides, olefins, paraffins [28]
Figure 1 5: Color changes during the dehydration of Cu 3 (BTC) 2 (H 2 O) 3 xH 2 O to give
Cu 3 (BTC) 2 , and subsequent readsorption of the aldehyde to give
Catalysis at the organic linkers
MOFs catalyze a chemical reaction not only at the metal sites but also at the organic linkers in some cases in which MOFs contain functional groups at the organic linker
Therefore, the catalytic function is located at the organic linker and not at the metal site It is obvious that the linkers that form this type of MOFs need to contain two different types of organic functional groups: coordinative functional groups, G 1 , that coordinate to the metal sites to hold the crystalline framework; and reactive functional groups, G 2 , which are not coordinated to the metals and will be responsible for the catalytic properties of the material (Figure 1 6) However, it is complicated to generate MOFs with reactive functional groups free and accessible to catalytic
I NTRODUCTION TO C U -MOF-74 AS AN EFFICIENT HETEROGENEOUS
Cu-MOF-74 belongs to a class of the M-MOF-74 (or M-CPO-27) series of materials, being 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 valence +2
The structure of these MOF-74s, of general formula M 2 dobdc (dobdc 4- = 2,5- dioxidoterephthalate), consists of metal oxide chains connected by the dobdc4- linkers to form a 3-D structure with honeycomb-like hexagonal that contains 1-D broad channels [31] The metal ions bond to oxygen atoms in square pyramidal geometry with coordination number of five After synthesis, the channels of MOF-74s are lined with guest molecules such as water or DMF molecules because the metal cations
10 coordinate oxygen atoms and guest molecules in octahedral geometry (Figure 1 7)
Upon desolvation, the metal coordination changes from octahedral to square pyramidal without compromising the framework integrity, leaving coordinatively unsaturated metal sites open to channels [32] The desolvated MOFs are called activated ones because they have active metal sites on the channels
Figure 1 7: Crystal structure of a MOF-74 (left) and metal oxide chains connected by organic linkers (right) O, red; C, black, H, white; metal, blue [33].
The synthesis of Cu-MOF-74 is conducted by solvothermal method following the procedure (Figure 1 8) [34] First, a mixture of 2,5-dihydroxyterephthalic acid and
Cu(NO 3 ) 2 3H 2 O was dissolved in a mixture of N,N’ -dimethylformamide (DMF) and isopropanol Then, the resultant solution was placed in an oven at 85 o C for 18 h After cooling the sample to room temperature, the solid product was removed from mother liquor, washed in copious DMF and exchanged with methanol at room temperature
The solid Cu-MOF-74 was then evacuated under vacuum at 150 °C for 5 h
Figure 1 8: Solvothermal synthesis of MOF structures [35].
Cu-MOF-74 contains a permanent microporosity with a BET specific surface area of 1126 m 2 / g, a pore volume of 0.57 cm 3 / g and an average pore diameter 11 o A The decomposition of Cu-MOF-74 is about 375 o C Thus, it shows a high thermal stability similar to that of other MOFs due to the strong bonding between copper ions and oxygen atoms The Properties of Cu-MOF-74 is summarized below (Table 1 1)
Table 1 1:The Properties of Cu-MOF-74 [36].
For the outstanding properties, Cu-MOF-74 has become a promising candidate for heterogeneous catalysis and other application such as gas storage and separations
Shape Large needle-shaped crystals
In fact, there has been an intensive growth on the research of Cu-MOF-74 application, specifically as gas adsorption and heterogeneous catalyst In gas adsorption, Cu-MOF-74 is a promising material for CO 2 separation/purification processes due to the extraordinary development of microporous structures with pore volumes and the ability of the framework components to enhance the affinity of the internal pore surface toward CO 2 molecules The higher affinity between the material structure and the CO 2 molecules is also related to the facts of a higher crystallinity and a more effective activation of coordinately saturated copper sites by the solvent removal when 2-propanol is employed For instance, CO 2 adsorption capacity at 1 bar and 45 °C increases from 3.0 wt% for the sample synthesized with DMF: water to 5.0 wt% for the sample synthesized with DMF : 2-propanol The effect of temperature on CO 2 adsorption has been also tested for the sample synthesized with DMF and 2- propanol Figure 1 9 illustrates that since the amount of CO 2 adsorbed decreases as the temperature increases and when the pressure rises, the CO 2 uptake will increase strongly [34]
Figure 1 9: CO 2 adsorption–desorption isotherms at different temperatures of
Cu-MOF-74 as a heterogeneous catalyst
Due to the conspicuous properties, Cu-MOF-74 as a heterogeneous catalyst has been employed for various organic reactions to create numerous products serving chemical and pharmaceutical industries In particular, Cu-MOF-74 exhibits as the redox catalyst or the catalytic activity in acid or base-catalyzed reaction
Scheme 1 2: The oxidation of cyclohexene [37].
As the redox catalyst, nanocrystalline Cu–MOF-74 material was prepared to use for the catalytic oxidation of cyclohexene using peroxides as oxidizing agents tert- butylhydroperoxide (TBHP) at room temperature (scheme 1 2) This catalytic reaction requires redox centers such as Cu ( the redox active M of the M–MOF-74 materials )
Pressure (bar) CO 2 Uptake (mg/g)
Due to the ultrahigh BET surface area of Cu-MOF-74, The nanocrystalline Cu–MOF- 74 materials were much more active than their micrometer-sized homologues (Figure
1 10) for the heterogeneous catalyst of the oxidation of cyclohexene [37]
Figure 1 10: Total yields of the products that result from the oxidation of cyclohexene in the presence of M–MOF-74 and without catalyst (blank) with TBHP
As a reference acid catalyzed reaction, Cu-MOF-74 with open metal sites performs the catalysis of the reaction between anisole and acetyl chloride to form MAPs
Scheme 1 3: Simplified reaction for the acylation of anisole with acetyl chloride [36].
The catalytic performance Cu-MOF-74 in comparison to other different acid catalysts in terms of relative anisole conversion and p-MAP yield under the same reaction condition is showed in Figure 1 11 These materials include: HKUST-1 as another Cu-based MOF and other conventional inorganic catalysts typically used in
15 acid catalyzed reaction such as H-ZSM-5 and BETA zeolitic materials and Al-MCM- 41 mesoporous materials In comparison with these inorganic catalysts (Figure 1 11), the anisole conversion of Cu-MOF-74 is the highest Therefore, the acid capacity of copper atoms located into the hybrid MOF-74 phase as well as its remarkable surface area makes Cu-MOF-74 a promising material for acid catalyzed reactions, in particular for the acylation of anisole
Figure 1 11: Comparison of different types of acid catalysts for the acylation of anisole [36]
Interestingly, Cu-MOF-74, which acts not only as a Lewis acid catalyst [38], but also a basic catalysts with well-defined active sites [31] For instance, Cu-MOF-74 was introduced by Valvekens as a catalyst in Knoevenagel condensation, Michael conjugate addition reactions in previous report (Scheme 1 4) [31] According to this, Cu-MOF-74 could be catalyzed the Knoevenagel condensation of benzaldehyde to malononitrile and the Michael addition reaction of ethyl cyanoacetate to methyl vinyl ketone, which afforded the moderate product yield The successful application of this MOF for these standard base-catalyzed reactions opens a new window for catalysis research using the intrinsic basicity of MOFs [31]
Scheme 1 4: The catalytic activity of Cu-MOF-74 in some typically base-catalyzed reactions, a) Knoevengel condensation rection b) Micheal reaction [31].
In the framework of Cu-MOF-74, 2,5-dihydroxyterephthalic acid molecules are completely deprotonated, all of their oxygen atoms bond directly with the copper centers (Figure 1 12) Therefore, these oxygen atoms, especially the phenolate ones, exhibit Bronsted basicity, in other words, they have the ability to deprotonate the reactant molecules in the Knoevenagel condensation Furthermore, the coordinatively unsaturated copper ion adjacent to the phenolate oxygen atom can act as a docking site for the deprotonated reactant molecule The interplay of copper ions and phenolate oxygen atoms make up the active sites in Cu-MOF-74
Figure 1 12: Pores in the M 2 dobdc MOF (brown = carbon; orange = metal; red oxygen).[31]
Recently, there are many studies for utilizing Cu-MOF-74 as a heterogeneous catalyst for various reaction Typically, Cu-MOF-74 catalyst using for the coupling reaction of pyrrolidine and phenylglyoxal was reported Truong and co-workers in
2015 (Scheme 1 5) The outstanding result indicated that the reaction obtained 95% yield in the presence of Cu-MOF-74, simultaneously, this heterogeneous catalyst could contribute to be highly recycled with 9 times, being superior to other homogeneous and heterogeneous for this coupling [39]
Scheme 1 5: The coupling reaction of amines and -carbonyl aldehydes [39].
At the first time, the direct esterification to produce O-acetyl substituted phenol esters utilizing dibenzyl ethers as acylating source assisted by Cu-MOF-74 as a recyclable catalyst was explored by Lieu and co-workers (Scheme 1 6) This transformation occurred in ease condition with the aid of DMSO as an effective solvent, t-BuOOH as an oxidant and Cu-MOF-74 as a recyclable catalyst, affording up to 86% in product yield The feature that Cu-MOF-74 could reuse over the 6 th catalytic run without a noticeable deterioration in catalytic efficiency would be fascinated to the chemical industry [40]
Scheme 1 6:The reaction between dibenzyl ether and 2-acetyl phenol utilizing Cu-
I NTRODUCTION TO IRON - BASED METAL - ORGANIC FRAMEWORKS AND IRON -
MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as a heterogeneous catalyst Structure of MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O]
Up to now, a great number of reports using iron-based MOFs have been revealed; however, these works were mainly focused on oxo-centered trimers of octahedral Fe(III) secondary building units (SBUs) In addition to MOFs assembled from a single type of organic linker, a novel iron-based MOF VNU-20 (VNU = Vietnam National University) has been prepared and employed as an efficient heterogeneous catalyst for many coupling transformations MOF VNU-20, formulated as [Fe 3 (BTC)(NDC) 2 ã6.65H 2 O] (BTC = 1,3,5-benzenetricarboxylate; NDC = 2,6- napthalenedicarboxylate), was constructed from mixed linkers of BTC 3− and NDC 2− with an infinite [Fe 3 (CO 2 ) 7 ] ∞ rod SBU, which was rarely seen before (Figure 1 14)
Figure 1 13: The crystal structure of VNU-20 (b) are linked horizontally and vertically by BTC 3− and NDC 2−, respectively (a, e and f) to form the orange-red crystals (d) with structure highlighted with a rectangular window of 6.0 × 8.7 Å2 (c)
Atom colors: Fe, blue and orange polyhedra; C, black; O, red All H atoms are omitted for clarity [44].
Application of iron-based MOFs and the mixed-linker iron-based MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as heterogeneous catalyst
Over the past few years, the applications of iron-based metal-organic frameworks in catalysis have drawn an increased attention, especially in the field of C−H functionalization reactions [45-47] In 2015, Le and co-workers carried out the preparation of 1,5-Benzodiazepine through cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst (Scheme 1 25)
Excellent conversion to the desired product were achieved in the presence of 5 mol%
MOF-235 catalyst and the molecule oxygen as the stoichiometric oxidant at 50 0 C for 180 minutes In addition, the MOF could be reused ten times without degradation in the yield [48]
Scheme 1 10:1,5-benzodiazepine synthesis via cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst [48].
In 2016, Doan and co-workers successfully utilized Fe 3 O(BDC) 3 as recycled heterogeneous catalyst for the direct C-C coupling of indoles with alkylamides via oxidative C-H functionalization (Scheme 1 26) The reaction could only progress in the presence of this Fe-MOF to obtain 90% yield with high selectivity after just 60 minutes Furthermore, this strategy contributes to the green eligibility for the coupling regard to the simplicity of reusability without substantial deterioration in catalytic activity [49]
Scheme 1 11:Direct C-C coupling of indoles with alkylamides via oxidative C−H functionalization using Fe 3 O(BDC) 3 as a productive heterogeneous catalyst [49].
In the meantime, a new method for the direct arylation of benzoazoles with aldehydes in the existence of Fe 3 O(BDC) 3 as a productively heterogeneous catalyst was developed by Doan and co-workers (Scheme 1 27) Instead of aryl halides in the conventional methodology, the precursor benzaldehyde featured inexpensive and commercially available abilities In the catalysis of Fe 3 O(BDC) 3 , the corresponding product was obtained the best yield 93% for 3h when the temperature was raised to 100 0 C [50]
Scheme 1 12:Direct arylation of benzoazoles with aldehydes utilizing metal–organic framework Fe 3 O(BDC) 3 as a recyclable heterogeneous catalyst [50].
Otherwise, many investigations on metal organic framework Fe 3 O(BPDC) 3 have gained intensive concerns for the catalysis chemistry In 2016, Dang and co-worker successfully achieved 2-alkenylazaarenes with 88% yield via direct alkenylation of 2- substituted azaarenes with carbonyls using 10 mol% Fe 3 O(BPDC) 3 (Scheme 1 28)
The Fe 3 O(BPDC) 3 exhibited the better performance in catalytic activity than other heterogeneous and homogeneous catalyst in this transformation; in addition, the combination of Fe 3 O(BPDC) 3 and co-catalyst accelerated the yield significantly [51]
Scheme 1 13:Synthesis of 2-alkenylazaarenes using the direct alkenylation of 2- substituted azaarenes with carbonyls via C−H bond activation [51].
In the same years, the synthesis of coumarins from salicylaldehydes and activated methylene compounds was conducted by Lieu and co-workers (Scheme 1 29) When homogeneous catalysts were using, the reaction yield only gained 20%; In contrast, the heterogeneous catalyst Fe 3 O(BPDC) 3 could promoted the transformation to reach the excellent yield 96% Indeed, this transformation could occur under mild temperature, heterogeneous and base-free conditions should be of an advantage [52]
Scheme 1 14:Oxidant-promoted formation of coumarins using Fe 3 O(BPDC) 3 as an efficient heterogeneous catalyst [52].
Interestingly, for the direct C-N coupling, Nguyen and co-workers proceeded the formation of azole derivatives from azoles with ethers via oxidative C-H activation by using Fe 3 O(BPDC) 3 as recyclable solid catalyst (Scheme 1 30) It was noted that 90% yield of the expected product was also recorded when only 5 mol% Fe-MOF was used in the mild condition, confirming the significance of this chemical activation protocol [53]
Scheme 1 15: Direct C–N coupling of azoles with ethers via oxidative C–H activation under metal–organic framework catalysis [53].
Additionally, Oveisi and co-workers described the potential catalytic utility of Fe(BTC) that makes it quite attractive for sustainable industrial chemistry The porous iron-based MOF, Fe(BTC), showed high activity catalysis in the oxidative cyclization of methylenebisnaphthols to the corresponding spirodienones (Scheme 1 31a)
Simultaneously, the modern tandem process between benzyl alcohols and o- aminobenzamide with the aid of Fe(BTC) and oxidant to produce quinazolin-4(3H)- ones Fe(BTC) was also explored by Oveisi These works consistently have the advantages such as availability of MOF, inexpensive catalyst, mild reaction conditions, reasonable yields, and simple experimental procedures (Scheme 1 31b)
Scheme 1 16: One-pot oxidative synthesis of quinazolinones using Fe(BTC) as efficient heterogeneous catalysts by Oveisi and co-workers [54].
As previously mentioned, although reports on catalytic activity of mixed-linker MOFs were reported widely in recent years, mixed-linker MOFs containing Fe(II)- based SBUs were hardly known before A novel porous metal-organic framework
[Fe 3 (BTC)(NDC) 2 ã6.65H 2 O] called VNU-20 has been recently explored and become a potential candidate in the field of organic reaction catalysis For the first time, in 2018, Pham and co-workers applied MOF VNU-20 into the transformation of coumarins with N,N-dimethylaniline through the direct C–H bond activation (Scheme 1 32) It was noteworthy that the excellent yield was still preserved in the 5th run utilizing the recovered catalyst Furthermore, VNU-20 exhibit the high catalytic performance than that of other MOFs in the coupling transformation, which confirms the practical possibility in catalytic synthesis [55]
Scheme 1 17: Cross-coupling of coumarin and N,N-dimethylaniline utilizing
Besides, To expand the catalytic applications of MOF VNU-20 to the cross- dehydrogenative coupling of coumarins with alkylbenzenes, cycloalkanes, ethers, and formamides, Doan and co-workers conducted the reaction between 6-methylcoumarin and mesitylene using the VNU-20 catalyst (Scheme 1 33) The desired product with
89% yield was obtained with the combination of DTBP as the oxidant and DABCO as the additive led Heterogeneous catalysis was confirmed for the cross-dehydrogenative coupling transformation utilizing the VNU-20 catalyst, and the contribution of active iron species in liquid phase was insignificant [56]
Scheme 1 18: The cross-dehydrogenative coupling of 6-methylcoumarin with mesitylene using the VNU-20 catalyst [56]
T HE QUINAZOLINONES SYNTHESIS OF 2- ARYLINDOLES WITH AMINES
MOF-74 as an efficient heterogeneous catalyst Structure, biological activity and derivatives of Quinazolinones
Quinazolinone is one of the most significant heterocycles and widely exists in natural alkaloids and pharmaceuticals [57] Quinazolinones will be classified into the following five categories, based on the substitution patterns of the ring system
Depending upon the position of the keto or oxo group, these compounds may be classified into three types (Figure 1 13) [58]
Figure 1 14: Three types of Quinazolinones.
Out of the three quinazolinone structures, 4(3H)-quinazolinones are most prevalent, either as intermediates or as natural products in many proposed biosynthetic pathways
Quinazolinones and its derivatives have been found to be with bioactivities, such as antibacterial, antifungal, antimalarial, anticancer, antihypertensive, antitubercular, and anticonvulsant [59] For instance, a quinazolinone alkaloid, 3-[b-keto-g-(3-hydroxy-2- piperidyl)-propyl]-4-quinazolone, found in the early 1950s was extracted from an
Asian plant Dichroafebrifuga, which is an ingredient of a traditional Chinese herbal remedy, effective against malaria [57] And the most well-known synthetic quinazolinone drug, famous for its sedative–hypnotic effects is methaqualone (2- methyl-3-o-tolyl-4-(3H) quinazolinone )[60] Due to the pharmacological and biological properties of quinazolinones, they become a promising candidate in pharmaceutical and fine chemical industries
Conventional synthesis of quinazolinones and its derivatives
Accordingly, numerous methods for synthesis of quinazolinone derivatives have been developed The first quinazolinone was synthesized in the late 1860s from anthranilic acid and cyanogen to give 2-cyanoquinazolinone From past to present, there are many methodology to synthesize quinazolinone derivatives
In 1993, an useful synthetic method to synthesize 4(3H)-Quinazolinone derivatives from N-( 2-Nitrobenzoy1)amides under carbon monoxide pressure was reported by Akazome and co-workers (Scheme 1 10) The transition metal complex as Ru 3 (CO) 12 was employed to upgraded the product yield up to 94% The quinazolinones obtained from this reaction are known to be versatile intermediates in the syntheses of quinazolinone alkaloids being applied for pharmaceutical industries [61]
Scheme 1 19: The reductive N-heterocyclization of N-(2-nitrobenzoyl)azacy- cloheptane to prepare the corresponding azacycloheptano[2,1-b]-4(3H)-quinazolinone
In 2000, a convenient method for the synthesis of 4(3H)-quinazolinone derivatives by treatment of o-iodoanilines with heterocumulenes such as carbodiimides, and ketenimines in the presence of a palladium catalyst system under carbon monoxide pressure was introduced by Chitchamai Larksarp and Howard Alper (Scheme 1 11)
Employing the catalyst system comprising palladium acetate-bidentate phosphine under the reasonable conditions in THF would furnish 98%, 90% in the reaction (a) and (b) yield, respectively [62]
Scheme 1 20: The Palladium-Catalyzed Reaction of o-Iodoanilines with
Carbodiimides and Carbon Monoxidea (a) The Palladium-Catalyzed Cyclocarbonylation Reactions of o-Iodoanilines with Ketenimines (b) [62].
The new synthetic methodologies in 2006 such as the one-pot condensation of anthranilic acid, ortho esters (or formic acid) and amines with the catalyst Bi(TFA) 3 immobilized on [nbp] FeCl 4 is one of the most straightforward procedures for the preparation of 4(3H)-quinazolinones (Scheme 1 12a ) This procedure are mild reaction conditions (room temperature), clear reaction profiles, improved yields for both anilines and primary amines, enhanced rates and simplicity in operation
Moreover, the reusability, stability and non-toxicity of the catalyst and ionic liquid are other noteworthy advantages of this method [63] At the same moment, Narasimhulu and co-workers reported an expeditious one-pot synthesis of 4(3H)-quinazolinones from the reaction of anthranilic acid, trialkyl orthoformate and amines (alkyl or aryl) under solvent-free conditions (Scheme 1 12b) The reaction proceeded at room temperature within few minutes in excellent yields after the addition of the acid catalyst lanthanum(III) nitrate hexahydrate or p-toluenesulfonic acid [64]
Scheme 1 21: One-pot condensation of anthranilic acid, ortho esters (or formic acid) and amines (a) [63] Synthesis of 4(3H)-quinazolinones using La(NO 3 ) 3 6H 2 O and
PTSA under solvent-free conditions (b) [64].
Then, the aza-Wittig reactions of iminophosphoranes (Eguchi protocol) have become a powerful tool towards the construction of nitrogen heterocyclic compounds
In 2008, a fundamental approach has been reported by the Wu group for the synthesis of novel 3-aminoalkyl-2-arylaminoquinazolin-4(3H)-one and 3,3’-disubstituted bis-2- arylaminoquinazolin-4(3H)-ones via a tandem aza-Wittig reaction of 1-aryl-3-(2- ethoxycarbonylphenyl)carbodiimides with primary diamines (Scheme 1 13) The benefits of the method contain mild reaction conditions, high selectivity, good yields, easily accessible starting materials and straightforward product isolation [65]
Scheme 1 22: The synthesis of 3-aminoalkyl-2-arylaminoquinazolin-4(3H)-one and
After that transition metal-catalyzed catalyzed Ullmann N-arylations is considered to be an important strategy that finds wide applications in the synthesis of many substances A simple, practical, and efficient strategy for the synthesis of quinazolinone derivatives was reported in 2009 by using mild copper-catalyzed conditions in the absence of ligands or additives (Scheme 1 14 a)[66]
Simultaneously, towards to the green chemistry, microwave irradiation was used to
29 facilitate an efficient iron-catalyzed cyclization to synthesis of quinazolinone derivatives from substituted 2-halobenzoic acids and amidines (Scheme 1 14 b) In comparison with previous methods, this approach has several distinguishing features such as proceeding faster and affording excellent yields within minutes under microwave irradiation and taking place in aqueous media [67]
Scheme 1 23: Cu-catalyzed synthesis of quinazolinone derivatives (a) [66];
Microwave-assisted synthesis of quinazolinone derivatives via rapid iron-catalyzed cyclization (b) [67].
In 2011, the most common method for 4(3H)-quinazolinone synthesis is based on the Niementowski reaction For instance, the Niementowski synthesis of fused 4(3H)- quinazolinone (Scheme 1 15) was reported a new, rapid and a versatile approach using DMSO and ionic liquid as a chemical catalysts High to excellent isolated yields (83–92%) were obtained with easy workup procedure The enhanced reactivity was attributed to the inherent Bronsted and high polarity of both IL and DMSO [68]
Scheme 1 24: Niementowski synthesis of modified quinazolinones [68].
Since the original works from Heck and co-workers in 1974, Pd-catalyzed carbonylations have experienced impressive progresses during the last decades.[69] In
30 nowadays, Pd-catalyzed carbonylative transformation has already become a unique, powerful, and versatile tool for the synthesis of carbonyl containing heterocyclic compounds In 2012, Willis et al demonstrated that N-(o-halophenyl) imidoyl chlorides or imidates can be utilized as complementary precursors for the synthesis of quinazolinones by incorporation of a palladium-catalyzed aminocarbonylation reaction workers (Scheme 1 16) Under atmospheric pressure of CO, 2,3-disubstituted quinazolinones were produced in good to excellent yields The use of amine nucleophiles bearing a range of substituents delivered quinazolinones in high yields [70]
Scheme 1 25:Synthesis of 2,3-disubstituted quinazolinones from N-(o- halophenyl)imidoyl chlorides or imidates [70].
Concomitantly, a facile and efficient approach for assembling substituted quinazolinones has been developed by Ma and co-workers (Scheme 1 17)
Conveniently available amides could serve as suitable nucleophiles for coupling reactions with N-substituted obromobenzamides, affording 3-substituted and 2,3- disubstituted quinazolinones after spontaneous or HMDS/ZnCl 2 mediated condensative cyclization in excellent yield [71]
Scheme 1 26: Synthesis of 3-substituted and 2,3-disubstituted quinazolinones via Cu- catalyzed aryl amidation [71].
In 2013, Deng et al showed that a series of 2,3-diarylquinazolinones can be synthesized from nitrobenzamides and alcohols using nontoxic iron as catalyst in the absence of external oxidant or reductant (Scheme 1 18) [72] In this straightforward transformation, the alcohol conceivably might serve two possible functions: as hydrogen source for nitro reduction and as alkylating reagent based on the catalytic hydrogen transfer The outstanding point of the reaction is the direct use of commercially available and inexpensive nitroarenes and alcohols as starting materials while the previous method utilizes the amino group which is usually prepared from the corresponding nitro group via a reduction process using a stoichiometric amount of metal/acid or hydrogen
Scheme 1 27: Fe-catalyzed method for the synthesis of 2,3-diarylquinazolinones [72].
T HE CYCLIZATION REACTIONS OF KETOXIME ACETATES AND DIBENZYL
produce pyridines utilizing MOF VNU-20 as a heterogeneous catalyst
Functionalized pyridines have been known as a class of important azaheterocyclic structures which usually exist in broad arrays of natural products, pharmaceuticals, and functional materials [80] In pharmaceutical industry, pyridine derivatives were amongst the most frequently cited heterocyclic compounds in a sample study of 1000 commercial pharmaceutical agents, including numerous antihistamines, as well as antiseptic, antiarrhytmic, antirheumatic For example, nicotinamide (3- pyridinecarboxamide) “vitamin B3” and its derivatives have been widely applied in clinical practice to treat many diseases involving preventing and reversing neuronal and vascular cell injury pellagra and some neurodegenerative diseases [81] such as Alzheimer’s disease, Parkinson’s disease and other cognitive disorders of mammals [82] Besides, it was also used for treating acquired immunodeficiency syndrome (AIDS) inflammatory, allergic, and respiratory diseases [82] Moreover, many pyridine-derived pharmaceuticals, such as atazanavir [83]and imatinib mesylate [84], are prescribed for human immunodeficiency virus (HIV) and chronic myelogenous leukemia
Diploclidine [85] and Nakinadine A [86]are two examples of recently isolated and structurally diverse natural products containing the pyridine core [87] On the other hand, pyridine derivatives are also incorporated into polymers such as polyvinyl pyridine (PVP) Due to the important roles of pyridine structures in both industrial and science applications (Figure 1 15), the synthesis of polysubstituted pyridineshas been paid lots of attentions in synthetic chemistry
Figure 1 15:Pyridine core and several pyridine derivatives [87, 88].
Traditionally, The pyridines have been synthesized by the condensation of amine and carbonyl compounds including condensation of 1,5-dicarbonyls with ammonia (NH 3 ) (has served as the nitrogen source in countless protocols) [89] (Scheme 1 34a), Hantzsch pyridine synthesis [90, 91] (Scheme 1 34b), or the cyclozation of 1,3 dicarbonyl derivatives with vinylogous amides [92] (Scheme 1 34c)
Scheme 1 34:Conventional method for construction of pyridine [89-92]
Otherwise, methods that do not base on condensation chemistry have become increasing notification In 1914, Chichibabin and co-workers conducted a reaction to produce 2-aminopyridine derivatives rely on the electron-deficient character of the pyridine ring and then this reaction was named of the author, interestingly [87]
(Scheme 1 35) The direct amination of pyridine with sodium amide took place in liquid ammonia
In 1981, Boger and co-workers developed an inverse electron depend on aza-Diels–
Alder reaction between enamines and 1,2,4-triazine [93] (Scheme 1 36) Despite the convenience and simplicity of this pyridine annulation, this reaction also met some limitations that have proven to restrict the applicability of the reaction The first one was that the requirement for a preformed pyrrolidine enamine, a venture approached
38 with some concern when complex or valuable synthetic intermediates are involved
The second one was that the instability of some enamines, which often precludes their purification and occasionally isolation
Scheme 1 36: The aza-Diels–Alder approach to pyridine derivatives [93]
The synthesis of optically active 1-substituted 2-[(2S)-2-pyrrolidinyl] pyridine from L-proline was successfully implemented by Chelucci and co-workers in 1990 [94]
(Scheme 1 37) According to authors, the key intermediate 2-[(2S)-2-pyrrolidinyl] pyridine (3) was prepared from (2S)-1-benzyloxycarbonyl-2-cyanopyrrolidine (1) In the beginning, this reaction was carried out in the presence of cobalt (I) catalyzed co- cyclotrimerization of the nitrile with acetylene to gain 82% yield of 2-[(2S)-1- benzyloxycarbonyl-2- pyrrolidinyl] pyridine (2) After that, deprotection of (2) occurred smoothly by heating under reflux for 2 h in 6 N hydrochloric solution, (3) was established with 92% yield At the end, the derivatives were formed by treating
(3) in suitable condition to achieve (4) or (5) with 91% and 93%, respectively
Scheme 1 37: Synthesized 1-substituted 2-[(2S)-2-pyrrolidinyl] pyridine from L-proline
With the evolution of technologies and sciences, in 1997, a modern equipment called microwave was applied for the parallel synthesis of diverse substituted pyridines using the Hantzsch synthesis The microwave-assisted chemistry brings a great number of advantages such as a broad range of available chemistries, simple reaction setup and product recovery readily amenable to automation, extremely short reaction times, and high product yields [95]
The synthetic method was reported to obtain pyridines on a multigram scale in a one pot microwave reaction using bentonite clay as a support and ammonium nitrate as the source of ammonia and oxidant (nitric acid) For instance, utilizing benzaldehyde gave only 5% yield of the 4-phenyl pyridine derivative and a 75% yield of the C4- unsubstituted pyridine (scheme 38a) Moreover, the diversity is further expanded due to the fact that when two different 1,3-dicarbonyl compounds are used together in a single Hantzseh synthesis, three distinct pyridine derivatives can potentially be formed
Scheme 1 38: Microwave-assisted organic synthesis of substituted pyridines from
At the same time, thanks to employing the tert-butylimine instead of methyl,isopropyl, allyl, and benzyl imines, the application of annulation processes substantially improved results with a variety of alkynes The reaction of the tertbutylimines with 2 equiv of an alkyne in the presence of 5 mol % Pd(OAc) 2 , 10 mol % PPh 3 , and 1 equiv of Na 2 CO 3 in DMF as the solvent at 100 °C affords the desired substituted pyridine products in excellent yields in short reaction times (2h)
Scheme 1 39: Synthesis of pyridines via palladium-catalyzed iminoannulation of internal acetylenes [96].
In 2009, Otterlo and Koning successfully applied ring-closing metathesis (RCM) method for synthesis of numerous aromatic compounds, which inspired motivation for vast of scientist in the field of nature compound containing aromatic or heteroaromatic, which is the important skeletal core in many biological processes [97], and subsequently, ring-closing metathesis has proven to be one of the most utilized
41 chemical breakthroughs of the twentieth century Following this great success, Donohoe and co-workers exploited this method for the synthesis of heteroaromatics: evaluating routes to pyridines by applying this technology for the multistep transformation of 2,6-di- and 2,3,6-trisubstituted pyridines with alkyl, aryl, and alkoxy substituents [98] (Scheme 1 40)
Scheme 1 40: Ring-closing metathesis strategy for pyridine synthesis using acrylamide entry to synthesize pyridines [98].
Recently, tremendous efforts have been made in the field of transition metal- catalyzed cyclizations and cross-coupling reactions to afford functionalized pyridine derivatives For example, rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives from alkynes and α,β unsaturated imines has been achieved by Ellman and Cheng [99, 100] (Scheme 1 41a,b) In contrast to other traditional methods for pyridine synthesis, rhodium-catalyzed C-H activation does not require the use of activated precursors and is tolerant of a variety of functional groups Moreover, numerous transition-metal catalysts such as Pd, Fe, Cu could also be used to afford a structurally diverse set of pyridine derivatives through cross-coupling transformation
Scheme 1 41: Rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives [99, 100]
Scheme 1 42: Transition metal -catalyzed cross-coupling of activated pyridines
In 2009, cyclopropanols were used as a precursor of beta-carbonyl radicals and the investigation of their addition reactions toward vinyl azides (Scheme 1 43) The reactions were carried out by treatment of a mixture of vinyl azides (0.3 mmol) and cyclopropanols (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at room temperature under N 2 atmosphere for 5 min followed by addition of AcOH (2 equiv) With the optimized reaction conditions at hand, the scope of this Mn(III)-mediated pyridine formation was investigated to form various 2,6-diarylpyridines in good yields [103]
Scheme 1 43: Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl Azides to form 2,6-diphenylpyridine [103].
Due to the importance of pyridine derivatives in chemical synthesis, the development of a more concise and straightforward procedure for acquisition of pyridine derivatives from easily available starting materials is still highly desirable in order to overcome the limitation of relatively harsh reaction conditions, the utilization of the costly starting materials, unstable nature of the precursors, expensive noble metal catalysts, tedious operations [80] In conventional methodology, ketoxime carboxylates are well-known fruitful candidates for the Beckmann rearrangement reactions to prepare amides or for the dehydration reactions to produce nitriles.
Nowadays, oxime derivatives have emerged as internal oxidants and versatile building blocks for constructing polysubstituted pyridines through transition metal-catalyzed coupling reactions.
In 2015, Jiang and co-workers successfully achieved the Cu-catalyzed three- component cascade annulation reaction from acetophenone oxime acetate, paraformaldehyde and ethyl acetoacetate (Scheme 1 44) This strategy featured inexpensive catalysts, no need of extra oxidant and accessible reagents Notably, various substrate scopes such as activated methylene compounds, oxime acetates and aldehydes were employed for the preparation of 2,3,5-trisubstituted pyridines with the moderate to excellent corresponding yields [81]
Scheme 1 44: Synthesis of functionalized pyridines via Cu-catalyzed three- component cascade annulation reaction [81].
A IMS AND OBJECTIVES
As presented above, Cu-MOF-74 and the mixed-linker VNU-20 demonstrating many advantageous features has been proven as a potential candidate for heterogeneous catalyst Towards the friendly environment, the catalyst recovery has brought many attentions in the future Previous reports, which exploited homogeneous catalysts for many similar transformations [46, 114-116], feature tolerance of a wide range of functional groups, easily available starting materials, simple operation, mild reaction conditions and environmental friendliness, but these homogeneous catalysts cannot be separated from the reaction medium to reused The development of MOFs ,which have special properties such as large specific surface are, unreached porosity, high thermal stability and wide chemical inorganic-organic composition, has created a breakthrough in catalysis for the organic chemistry MOFs not only generate product with high yield but also can reuse several times without any degradation in catalytic activity
Thus, the two reactions in the presence of available reactants making advantage of the metal-organic frameworks were conducted
A new statergy, using Cu-MOF-74 for the reaction of 2-phenylindole and phenethylamine will be introduced for the first time Simultaneously, the reaction will be expanded by varying the scope of amines to obtain various products for the pharmaceutical industry and organic chemistry (Scheme 1 50)
Scheme 1 50:The reaction between 2-phenylindole and 2-phenylethanamine utilizing
The novel cyclization reaction between ketoxime carboxylate and dibenzyl ether to constitute pyridine derivatives, which has not been mentioned before, will be conducted in the presence of the mixed-linker iron-based metal-organic frameworks VNU-20 as efficient heterogeneous catalysts In comparison with MOFs assembled from a single type of organic linker, the new generation of this materials, which not only inherit good properties of present MOFs but also gained more new useful characteristics (Scheme 1 51)
Scheme 1 51:The cyclization of ketoxime acetates and dibenzyl ether using VNU-20 as a heterogeneous catalyst.
EXPERIMENTAL SECTION
M ATERIALS AND I NSTRUMENTATION
All reagents and starting materials were obtained commercially from Sigma–
Aldrich, Across, Guangzhou, and Merck were used as received without any further purification unless otherwise noted (Table 2 1)
Table 2 1:List of the utilized substances and their providers
2-Phenethylamine (99%) C 8 H 11 N Sigma-Aldrich Copper (II) nitrate trihydrate Cu(NO 3 ) 2 3H 2 O Acros
Anhydride acetic (CH 3 CO) 2 O Acros
Ethyl acetate CH 3 COOC 2 H 5 Acros
Iron (II) chloride (anhydrous) FeCl 2 Sigma-Aldrich Hydroxylamine hydrochloride NH 2 OH.HCl Sigma-Aldrich
Potassium carbonate K 2 CO 3 Sigma-Aldrich
Di-tert-butyl peroxide (98%) C 8 H 18 O 2 Sigma-Aldrich 1,3,5-benzenetricarboxylic acid C 9 H 6 O 6 Sigma-Aldrich
Powder X-ray diffraction (PXRD) patterns were recorded using a D8 Advance diffractometer equipped with a LYNXEYE detector Fourier transform infrared (FT- IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets Scanning electron microscopy studies were conducted on a JSM 740 scanning electron microscope (SEM) Transmission electron microscopy studies were performed using a JEOL JEM 1400 transmission electron micro-scope (TEM) at 100 kV The Cu-MOF-74 samples were dispersed on holey carbon grids for TEM observation A NetzschThermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 °C/min under a nitrogen atmosphere Nitrogen physisorption measurements were conducted using an ASAP 2020 system Samples were pretreated by heating under vacuum at 140 °C for 3h The chemisorption experiments were studied in a Micromeritics 2020 analyzer Elemental analysis with atomic absorption spectrophotometry (AAS) was performed on an AA- 6800 Shimadzu
Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 2010- PLUS equipped with a flame ionization detector (FID) and a SPB-5 column (length 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 m) In the first reaction, the temperature program for GC analysis held samples at 100 o C for 0.5 min; heated them from 100 to 130 o C at 40 o C/min; held them at 130 o C for 1 min; heated them from 130 to 180 o C at 40 o C/min; and finally held them at 280 o C for 14 min Inlet and detector temperatures were set constant at 280 o C In the second reaction, the temperature program for GC analysis held samples at 160 o C for 1 min, heated samples from 160 oC to 280 o C at 40 o C/min and were hold for 8 min Inlet and detector temperatures were set constant at 280 o C
Diphenyl ether was used as an internal standard to calculate reaction yields 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
53 temperature program for GC-MS analysis held samples at 50 o C for 2 min; heated samples from 50 to 280 o Cat 10 o C/min and held them at 280 o C for 10 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library The 1 H NMR and 13 C NMR were recorded on Bruker AV 500 spectrometers using residual solvent peak as a reference.
S YNTHESIS OF THE METAL - ORGANIC FRAMWORKS (MOF S )
In a typical preparation (Scheme 2 1), a solid mixture of H 2 dhtp (H 2 dhtp = 2,5- dihydroxyterephthalic acid; 0.94 mmol, 0.186 g), and copper (II) nitrate trihydrate (2.07 mmol, 0.5 g) was dissolved in a mixture of DMF (20 mL) The mixture was vigorously stirred for 10 min, and isopropanol (1 mL) was then added to produce a clear greenish solution Reddish crystals were generated on the wall of the vials during the time of the experiment The resulting solution was then distributed into vials The vials were heated at 85 o C in an isothermal oven for 18 h After cooling the vials to room temperature, the crystals were collected by decantation, and washed carefully with DMF (3 x 20 mL) The solid was then immersed in methanol (3 x 20 mL) at ambient temperature for solvent interchange Afterwards, the product was dried at 150 oC under vacuum in a shlenkline for 5 h, producing 0.260 g of Cu 2 (dhtp) in the shape of reddish black crystals (60 % yield regarding 2,5-dihydroxyterephthalic acid)
Scheme 2 1: Synthetic reaction of Cu 2 (dhtp) or Cu-MOF-74 [34].
According to a previous literature procedure [44], the mixture of FeCl 2 (0.09 g, 0.705 mmol); 1,3,5-benzene tricarboxylic acid (H 3 BTC, 0.03 g, 0.112 mmol)and 2,6- naphthalene dicarboxylic acid (H 2 NDC, 0.09 g, 0.42 mmol) were dissolved in N,N- dimethylformamide (DMF,12 mL), and then were sonicated for 5 minutes to achieve a clear solution Next, this solution was divided into glass tubes, which was sealed and placed in an isothermal oven at 200 o C for 72 h to build the reddish crystal of VNU-20 Then, VNU-20 crystal was purified by DMF (5 x 15 mL, three days) and methanol (5 x 15 mL, four days) Consequently, this crystal was activated under dynamic vacuum to obtain activated VNU-20 (0.057 g, yield: 75 % base on H 3 BTC), which is the sample utilized as a heterogeneous catalyst during the experiment (Scheme 2 2)
Scheme 2 2: Self-assembling synthesis of the reddish-yellow crystal (VNU-20) [44].
C ATALYTIC TESTS
The typical experiments were carried out according to the general procedure To a pressurized vial were introduced a mixture of 2-phenylindole (0.4831 g, 0.25 mmol), 2-phenylethanamine (0.1212 g, 1 mmol) and Cu-MOF-74 (0.0040 g, 10 mol%) as the catalyst The catalyst amount was weighed respecting copper/2-phenylindole mole ratio After that, the reaction solvent, N N’-dimethylformamide, (2 mL) was added into the mixture by a pipette The reaction solution was stirred magnetically at 80 o C for 24h under oxygen atmosphere After the reaction was finished, the internal standard, diphenyl ether (0.0425 g, 0.25 mmol) was introduced to the sample to compare
55 relatively with the amount of desired product The sample was quenched with water (5 mL) and extracted with ethyl acetat (2 x 5 mL) to obtain organic components Then, the solution was dried over anhydrous Na 2 SO 4 and analyzed by GC with reference to diphenyl ether The expected product, 3-phenethyl-2-phenylquinazolin-4(3H)-one, was isolated on silicagel by column chromatography The product character was also authenticated by 1 H-NMR, 13 C-NMR, and GC-MS
During the heterogeneous catalyzed reaction, the catalytically active metal species might be released from the MOFs structure into the liquid phase and furthermore exhibit remarkable catalytic activity, then the reaction is not truly heterogeneously catalyzed To examine the hypothesis, the leaching test was conducted at 80 o C in DMF with the molar ratio of 2-phenylindole:2-phenylethanamine = 1:4 and in the presence of 7.5 mol% Cu 2 (dhtp) as catalyst After 3 h reaction time, the GC-yield was recorded and the solid catalyst was separated from the reaction mixture by centrifugation A reaction solution was then transferred into a new reactor vial, and stirred for further conversion at 80 o C with aliquots being sampled at different time intervals, and analyzed by GC
The recyclability of the Cu 2 (dhtp) were also carried out according to the following procedure in order to test the stability of the solid catalyst The first run of typical reaction was conducted at 80 o C in DMF, using 7.5 mol% Cu 2 (dhtp) as catalyst After 24 h, the copper-based framework was separated by simple filtration, and washed meticulously with large amounts of DMF and dichloromethane, dried at 150 o C under vacuum in a Shlenkline, and reused for new catalytic run until its activity was significantly degraded
2.3.2 Catalytic studies in the cyclization reaction of ketoxime acetates and dibenzyl ether to synthesize 2,4,6-triphenyl pyridine Synthesis of ketoxime acetates
In the first step, a mixture of acetophenones (2.64 g, 22 mmol), hydroxylamine hydrochloride (2.294 g, 33 mmol), ethanol (10 mL) was introduced to a 50 mL erlenmeyer flask The reaction mixture was magnetically stirred for 3 minutes and
56 heated to 80 o C Afterwards, potassium carbonate (K 2 CO 3 , 4.209 g, 30.5 mmol) was slowly added into the mixture The sample was withdrawn and monitored by TLC every 2 hours until acetophenone was completely conversed into the acetophenone oxime Subsequently, the reaction mixture was cooled to room temperature and then transferred to a 250-mL separatory funnel containing 30 mL water and 60 mL ethyl acetat The mixture is partitioned, and the ethyl acetatat layer was obtained The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduce pressure The residue was then purified by recrystallization from hexane to obtain pure acetophenone oxime
In the second step, a mixture of acetophenones oxime, anhydride acetic (3.366 g, 33 mmol), ethyl acetate (10 ml) was added to a 50 mL erlenmeyer flask and magnetically stirred at room temperature Then, potassium carbonate (4.209 g, 30.5 mmol) was slowly added into the mixture The sample was withdrawn and monitored by TLC every 2 hours until acetophenone oxime was completely conversed into the acetophenone oxime acetate The sample was continue to extract and purify as the first step to obtain pure (E)-acetophenone O-acetyl oxime acetate
Catalytic studies in the synthesis of 2,4,6-triphenyl pyridine
In a particular experiment, a mixture of dibenzyl ether (0.0198 g, 0.1 mmol), (E)- acetophenone O-acetyl oxime acetate (0.0708 g, 0.4 mmol), chlorobenzene (1 mL), and diphenyl ether (0.017 g, 0.1 mmol) as an internal standard were added into 12 mL pressurized vial containing pre-determined amount of VNU-20 (0.003 g, 0.01 mmol)
The reaction mixture was magnetically stirred at 140 o C for 5 minutes to disperse the Fe-MOF catalyst in the liquid phase Subsequently, di-tert butyl peroxide (DTBP, 2 equivalents) was injected and the resulting mixture was stirred at 140 o C for 6 hours under an argon atmosphere to obtain the expected product
After the reaction was completed, the resulting sample was cooled down to ambient temperature, soaked with water (5 mL) and extracted with ethyl acetate (2 x 5 mL) to collect the organic layer The solution was then dried over anhydrous Na 2 SO 4 before it was withdrawn to analyze by GC Subsequently, the treated solution was concentrated
57 under reduced pressure The remain residue was further purified by column chromatography on silica gel (ethyl acetate/hexane = 1:20) to afford the product 2,4,6- triphenyl pyridine as white crystalline solid (85%, isolated yield based on the reactant dibenzyl ether) The product characteristic was further authenticated by 1 H NMR, 13 C NMR and GC-MS
For the leaching test, the catalytic reaction was stopped after the first 3 hour, analyzed by GC, and centrifuged to remove the solid catalyst After that, the reaction mixture was continue to heat to 140 o C in the absence of VNU-20 catalyst for extra hours The formation of 2,4,6-triphenyl pyridine during the experiment, if any, was probed by GC
For the catalyst reusability experiment, the VNU-20 catalyst was separated from the reaction mixture by centrifugation, washed with abounding amount of anhydrous DMF and DCM, dried at 100 o C under vacuum condition on a Shlenkline for 6 h, and reused for the next run
RESULT AND DISCUSSION
T HE C U -MO F -74- CATALYZED B AEYER -V ILLIGER OXIDATION EXPANSION
synthesize 2-arylquinazolinones 3.1.1 Synthesis and characterization of Cu-MOF-74
The copper-based metal-organic framework Cu-MOF-74 was synthesized according to a slightly modified literature procedure [40] as described in (Scheme 2 1) After the solvent exchange and activation, the Cu-MOF-74 as black crystal was yielded The synthesis yield was approximately 60% based on H 2 (dhtp).
Figure 3 1:PXRD patterns of the simulated (a) and synthesized (b) Cu-MOF-74 The X-ray diffraction patterns of Cu-MOF-74 (Figure 3 1) demonstrated the presence of very sharp peak at 2ϴ of approximately 7 o and 12 o , proving the highly
59 crystallinity of the Cu-MOF-74 The result was also similar to the simulated patterns previously reported in the literature It could approve that the structure of the Cu- MOF-74 was successfully formed
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 (1670 cm -1 ).This strong peak of Cu-MOF-74 was due to the stretching vibration of carboxylate anions present in the material In comparison of free carboxylic acids, the degradation of this strong peak of Cu-MOF- 74 indicated the deprotonation of –COOH groups in 2,5-dihydroxyterephthalic acid upon the reaction with metal ions The broad peak at 3400 cm−1 displayed the presence of water in the metal coordination sphere (Figure 3 2)
Figure 3 2: FT-IR spectra of terephthalic acid and the Cu-MOF-74
The thermal stability of the Cu-MOF-74 was also examined by the thermalgravimetric analysis (TGA) The TGA profile (Figure 3 3) showed that a significant weight-loss of the Cu-MOF-74 started at 70 o C The initial weight loss of 16% occurred from 70 o C to approximately 150 o C, corresponded well to the loss of DMF, water or solvent molecule per monomer The next remarkable decrease in weight of 43% began at nearly 298 o C, when the pyrolysis 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,[38] and confirmed the high thermal stability of the resulting Cu-MOF-74
Wave number (cm -1 ) Fresh Cu 2 (dhtp)
Figure 3 3: TGA curve of the Cu-MOF-74
The morphology of the crystals Cu-MOF-74 can partially reflect the information through Scanning Electron Microscopy (SEM) Following that, the large needle- shaped crystals of Cu-MOF-74 is shown in Figure 3 4
Figure 3 4: SEM micrograph of the Cu-MOF-74
The internal structure of the Cu-MOF-74 is revealed in the TEM micrographs
(Figure 3 5) According to these micrographs, this material shows uneven colour, which indicates Cu-MOF-74 is a porous materials
D TG( D % Wei gt lo ss/ D o C)
Weightloss (%) DTG(delta(%)/delta(oC))
Figure 3 5: TEM micrograph of Cu-MOF-74 at 500nm and 100nm
Nitrogen physisorption measurements were conducted to figure out the values of surface area and pore size of Cu-MOF-74 In figure 3 6, the average pore diameter is 8.04 Å The adsorption–desorption isotherms of the compound shows a BET surface area of 1209 m 2 /g and a Langmuir surface of 1379 m 2 /g (Figure 3 7)
Figure 3 6: Pore size distribution of Cu-MOF-74
Figure 3 7: Isotherm linear plot of Cu-MOF-74
To conclude, the Cu-MOF-74 was successfully synthesized by the solvothermal method The reaction between copper (II) nitrate trihydrate and H 2 (dhtp) in DMF and isopropanol at 85 o C for 18 h yielded black crystals of Cu-MOF-74 in 60% of yield
The results indicated the formation of the needle crystals of the Cu-MOF-74 with 1209 m 2 /g and 1379 m 2 /g as BET and Langmuir surface areas, respectively In addition, pore size of Cu-MOF-74 was also approximate 8.04 Å Those results, showing in a good agreement with previously literature,[38] indicated that the structure of the desired MOF was successfully formed Hence, the Cu-MOF-74 a promising candidate for heterogeneous catalysis
3.1.2 Catalytic studies in the synthesis of 2-arylquinazolinones
In the presence of Cu-MOF-74 as an efficient heterogeneous catalyst, an expansion reaction was conducted between 2-phenylindole and 2-phenylethanamine to form 3- phenethyl-2-phenylquinazolin-4(3H)-one (Scheme 3 2)
Scheme 3 1: The reaction between 2-phenylindole and 2-phenylethanamine utilizing
The control experiment of 2-phenylindole and 2-phenylethanamine was investigated under different effects such as temperature, reactant molar ratio, catalyst quantity and solvent on the reaction conversion Various kinds of catalysts were also investigated to demonstrate the outstanding features of Cu-MOF-74 Specifically, to a pressurized vial was introduced a mixture of 2-phenylindole, 2-phenylethanamine and Cu-MOF-74 as the catalyst Next, the reaction solvent, N,N’-dimethylformamide (2 mL) was added into the mixture by a pipette The reaction solution was stirred magnetically at 80 o C for 24h under oxygen atmosphere After the reaction completion, the internal standard, diphenyl ether was injected to the sample so as to compare relatively with the amount of an expected product which was then detected by gas chromatography Besides, the general applicability of the catalyst, Cu-MOF-74, was employed to extend the scope of this transformation
3.1.2.1 Effect of temperature on the reaction
An important factor that exhibited a remarkable influence on the ring expansion reaction of 2-phenylindole with 2-phenylethanamine would be a reaction temperature, which contributed to accelerate the conversion rate of this transformation The control experiment was performed in DMF under an oxygen atmosphere for 24 h, in the presence of 7.5 mol% Cu-MOF-74 catalyst, at 2-phenylindole:2-phenylethanamine molar ratio of 1:4 and room temperature, 60 o C, 70 o C, 80 o C, 90 o C, and 100 o C, respectively
Figure 3 8: Effect of temperature on the reaction yield.
As following experiment results (Figure 3 8), the reaction could not occur at room temperature, no product was detected after 24 h However, boosting the temperature led to a noticeable improvement in the yield of the expected product, in other words, the reaction afforded 3-phenethyl-2-phenylquinazolin-4(3H)-one in 48% yield at 60 oC Interestingly, 78% yield was achieved after 24 h with regard to the reaction performed at 70 o C As expected, raising the reaction temperature to 80 o C, the yield of the desired product proceeded to 94% after 24 h There was no considerable change in product yield when the temperature was increasing to more than 80 o C For instance, 94% yield of 3-phenethyl-2-phenylquinazolin-4(3H)-one was also recorded after 24 h when performing the experiment at 100 o C
Previously, Feng and co-workers explored an expansion reaction using CuBr catalyst for synthesis of 2-Arylquinazolinones at 80 o C [59] Xu and co-workers conducted a synthesis of 3-Substituted and 2,3-Disubstituted Quinazolinones via Cu- catalyzed aryl amidation at 80 o C [71] The Niementowski synthesis of fused 4(3H)- quinazolinone, as well as, a new, rapid and versatile approach using DMSO and ionic liquid as a chemical catalysts was exploited at 100 o C by Kathiravan.et.al [68] Sharif and co-workers carried out at 110 o C an oxidative synthesis of quinazolinones from 2- aminobenzamide with aldehydes under catalyst free conditions [76] An preparation of
66 pyrido-fused quinazolinone derivatives via copper-catalyzed domino reaction was implemented at 120 o C by Liu and co-workers [78]
3.1.2.2 Effect of solvent on the reaction
The solvent could exhibit a crucial impact on the reaction rate of numerous organic transformations, so it was necessary to take into account the influence of different solvents on the ring expansion of 2-phenylindole with 2-phenylethanamine to form 3- phenethyl-2-phenylquinazolin-4(3H)-one using Cu-MOF-74 catalyst The reaction was conducted at 80 o C under oxygen atmosphere for 24 h, in the presence of 7.5 mol%
Cu-MOF-74 catalyst, at 2-phenylindole:2-phenylethanamine molar proportion of 1:4, in acetonitrile, N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), m- xylene, p-xylene, clobenzene, diclobenzene (DCB), dimethylfornamide (DMF) as reaction solvent, respectively (Figure 3 9)
Figure 3 9: Effect of solvent on the reaction yield
Among these solvents, DMF exhibited the best performance, with 94% yield of 3- phenethyl-2-phenylquinazolin-4(3H)-one after 24 h, being superior to clobenzene and DCB in product yield such as 82%, 90%, respectively Likewise, there were many previous reports utilizing DMF as effective solvent to synthesize quinazolinone
T HE MIXED - LINKER MOF VNU-20- CATALYZED CYCLIZATION REACTIONS
ketoxime acetates and dibenzyl ether to produce symmetrical pyridines 3.2.1 Synthesis and characterization of VNU-20
MOF-VNU-20 was solvothermally synthesized from the mixture of FeCl 2 , 1,3,5- benzene tricarboxylic acid (H 3 BTC) and 2,6-naphthalene dicarboxylic acid (H 2 NDC) with a certain ratio in N,N- dimethylformamide (DMF,12 mL) as stated by a latter report [55] Following that, the mixture was sonicated for 5 minutes to achieve a clear solution and was then divided into glass tubes, which were sealed and placed in an isothermal oven at 200 o C for 72 h Reddish crystals of VNU-20 were generated at 75
% yield based on H 3 BTC The crystal structure of VNU-20 was consequently
78 characterized after solvent exchange and activation under a vacuum pressure on Shlenkline
3.2.2 Catalytic studies in the synthesis of symmetrical pyridines
The cyclization transformation of (E)-acetophenone O-acetyl oxime acetate and dibenzyl ether to prepare the product 2,4,6-triphenylpyridine (Scheme 3 3) proceeded to reasonable yields with the catalysis of the VNU-20 in the presence of DTBP as the oxidant and chlorobenzene as the solvent
This cyclization reaction using VNU-20 as heterogeneous catalyst was investigated under different conditions to find out the suitable parameters for the formation of the desired product, involving solvents, ratio of reactants, catalyst amounts, catalyst types, oxidant types, oxidant amount, temperature and reaction time Additionally, other experiments such as the leaching test, pyridine test and antioxidant test were conducted to confirm the solidity of catalyst and the plausible mechanism of the reaction
Scheme 3 2:The cyclization of (E)-acetophenone O-acetyl oxime acetate and dibenzyl ether utilizing VNU-20 as a heterogeneous catalyst.
3.2.2.1 Effect of temperature on the reaction
Figure 3 18: Effect of different temperatures on the reaction yield
Firstly, the synthesis of 2,4,6-triphenyl pyridine was conducted with 10 mol% catalyst, 0.1 mmol dibenzyl ether, 0.4 mmol (E)-acetophenone O-acetyl oxime acetate in the presence of 2 equivalents of di-tert-butyl peroxide (DTBP) as an oxidant and monoclobenzene as a solvent under argon atmosphere, at a variety of temperature such as 80 o C, 100 o C, 120 o C and 140 o C (Figure 3 18) There was no any trace of designed product to be formed at room temperature When the temperature was raised to 80 o C and 100 o C, just only 4% of the main product was recorded after 6 h
However, there was a significant enhancement of the corresponding yield at 120 o C with 71% yield Furthermore, the temperature continued proceeding to140 o C so as to obtain a surprisingly 93% yield after 6 h
In the previous publication, Huang and co-workers revealed a Cu-catalyzed synthesis of 2,4,6-triphenylpyridine with acetophenone and benzylamine at 100 o C [110] Cu-catalyzed synthesis of 2,4,6-triphenylpyridine through oxime acetates was conducted by Ren and co-workers at 120 o C [114], Yi and co-workers carried out the transformation between oxime acetate and toluene derivatives for the synthesis of
80 pyridine derivatives based on copper-catalyzed oxidative Csp 3 -H coupling at 120 o C [80] Xu and co-workers also introduced a metal-free synthesis of 2,4,6-trisubstituted pyridines via idodine-initiated reaction of methyl aryl ketones with amines under neat heating at 140 o C [111] and Zi and co-workers performed a synthesis of symmetrical pyridines by iron-catalyzed cyclization of ketoxime acetates and aldehydes at 140 o C [116]
3.2.2.2 Effect of solvent on the reaction
For countless organic transformations executed via heterogeneous catalysis, the efficiency of reactions could be significantly increased by choosing reasonable solvents The investigation was implemented to determine the suitable solvent for the cyclization reaction between (E)-acetophenone O-acetyl oxime acetate and dibenzyl ether to construct 2,4,6-triphenyl pyridine This transformation was injected into 1 mL of diverse solvents (Figure 3 19) with 0.1 mmol dibenzyl ether, 0.4 mmol (E)- acetophenone O-acetyl oxime acetate in the present of 10 mol% VNU-20 as a heterogeneous catalyst, 2 equivalents of DTBP at 140 o C for 6 h under argon atmosphere
Figure 3 19: Effect of solvent to the reaction.
The experimental results confirmed that the choice of solvents have a remarkable influence on the reaction yield It was obviously seen that the aprotic solvents such as DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide) were found to be unfavorable for the desired transformation When DMF was employed as a solvent, just about 9% product yield was obtained DMSO was found to be completely unsuitable for the reaction as the VNU-20 catalyst could be decomposed under the reaction condition with the same problem previously mentioned in literature reports [117-120] The aromatic solvents as anisole, p-xylene, mesitylen and m-xylene, gave the corresponding product in low yield, 38%, 37%, 30% and 23%, respectively
Surprisingly, the reaction was carried out in chlorobenzene, 1,2-dichlorobenzene and toluene as solvent offer the good yields with 93%, 86% and 82% after 6 hours, respectively For the same results, Fu and co-workers employed chlorobenzene as a solvent for the preparation of functionalized pyridine from oximes acetate and toluene derivatives [80] Therefore, chlorobenzene was the suitable solvent for further experiments
In the other previous publication, substituted pyridines were synthesized from O- acetyl ketoxime and α,β-unsaturated aldehyde in the presence of toluene by Huang and co-workers [105] Zhao and co-workers implemented a unprecedented and efficient iron-catalyzed cyclization of ketoxime carboxylates and N,N-dialkylanilines for the modular synthesis of 2,4,6-substituted pyridine in dichloroethane [115] Yi and co- workers reported a synthesis of symmetrical pyridines by iron-catalyzed cyclization of ketoxime acetates and aldehydes in toluene [116] Zhao and co-workers introduced the cyclization of ketoxime acetates for synthesis of symmetrical pyridines in N,N- dimethylformamide [121]
3.2.2.3 Effect of ratio reactants on the reaction
Figure 3 20: Effect of molar ratio of dibenzyl ether /(E)-acetophenone O-acetyl oxime acetate on the reaction yield
The regulation of the molar ratio between dibenzyl ether and (E)-acetophenone O- acetyl oxime acetate was implemented to prompt the yield of generating product, which occurred in the presence of 10 mol% VNU-20 using 2 equivalents of DTBP as an oxidant and 1 mL chlorobenzene as a solvent at 140 o C for 6 h In this circumstance, utilizing more of oxime acetates than dibenzyl ether would lead to the convenience of creating the expected product In particular, the investigation was conducted through the variation from 1 equivalent to 5 equivalents in the proportion of
(E)-acetophenone O-acetyl oxime acetate to dibenzyl ether As expected, increasing the amount of oxime acetate accelerates the yield of 2,4,6-triphenyl pyridines, in other words, the reaction yield doubled when the ratio dibenzyl ether/(E)-acetophenone O- acetyl oxime acetate was risen from 1:1 to 1:2 Noticeably, 93% yield was obtained when the amount of oxime acetate was extended to 4 equivalents, however, it is almost
DBE/Ketoxime acetate molar ratio
83 no remarkable growth in the corresponding yield gaining only 90% when the 5 equivalents of oxime acetate was used (Figure 3 20) Likewise, in previous publication, Yi and co-workers employed 3 equivalents of (E)-acetophenone O-acetyl oxime acetate for the synthesis of symmetrical pyridine in the presence of FeCl 3 as catalyst [116], Xu and co-workers exploited 3.8 equivalents of oxime for the eco- friendly synthesis of pyridines via rhodium-catalyzed cyclization of diyne with oxime [122] Consequently, dibenzyl ether: (E)-acetophenone O-acetyl oxime acetate molar ratio of 1:4 was established for this transformation
3.2.2.4 Effect of catalyst amount on the reaction
Figure 3 21: Effect of catalyst amount on the reaction yield.
The catalyst amount is an crucial point that create a significant impact on the preparation of 2,4,6-triphenyl pyridine from dibenzyl ether and (E)-acetophenone O- acetyl oxime acetate In this work, the cyclization reaction was carried out at 140 o C, after 6h, in the presence of 2 equivalents of DTBP under argon atmosphere, using 0 mol%, 5 mol%, 7 mol%, 10 mol%, 15 mol% VNU-20 catalyst, respectively (Figure 3
21) Only a small trace of the desired product was detected in the absence of VNU-20 catalyst, which authenticated the significance of VNU-20 for this transformation 93% yield after 6h as the best yield which was achieved in the presence of 10 mol% VNU- 20 catalyst Decreasing the amount of catalyst led to a reduction in the reaction yield;
CONCLUSION
In this report, the two metal-organic frameworks were successfully synthesized by a solvothermal method, and were characterized by a variety of different techniques including XRD, SEM, TEM, FT-IR, TGA, AAS, and nitrogen physisorption measurements Firstly, Cu-MOF-74 catalyst was synthesized by Cu(NO 3 ) 2 3H 2 O and 2.5-dihydroxyterephthalic acid with the yield of 60% calculated by H 2 dhtp The physical and chemical analysis results of Cu-MOF-74 properties which are needle- shaped crystals, large specific surface and high thermal stability are solid consistent with those previous publications
In the Baeyer-Villiger oxidation expansion reaction, Cu-MOF-74 was used as an efficient heterogeneous catalyst for the reaction of 2-phenylindole and amines to form quinazolinone’s derivatives with the excellent yield under mild condition with 10 mol% catalyst The Cu-MOF-74 catalyst could be recovered three times without any significant degradation in catalytic activity and perform as a substantial material with no contribution from leach iron sites Simultaneously, the scope of the reaction was expanded by changing a diversity of amine reagents to obtain various products for further application
Secondly, MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O], a mixed-linker iron-based of BTC 3− and NDC 2− , was generated from H 3 BTC, H 2 NDC, and FeCl 2 , which have been rarely seen before The feature shows that VNU-20 was a highly stable and efficient heterogeneous catalysts for this application For the synthesis of 2,4,6- triphenylpyridine via the cyclization between (E)-acetophenone O-acetyl oxime acetate and dibenzyl ether, iron organic framework VNU-20 emerged as an active heterogeneous catalyst and displayed higher catalytic productivity as compared to numerous MOFs based catalysts and conventional homogenous catalysts as well
Furthermore, It could be maintained the catalyst efficiency in the 6 th catalytic run and no availability of homogeneously leached sites Future work may be extended to the
108 study of catalytic activity of the Fe-based MOF VNU-20 towards various organic transformations, as well as screening reactivity of other compounds that serves as suitable partners for the examining cyclization reaction for further expansion of the substrate scope In fact, these results here demonstrated the feasibility of employing these MOFs as a recyclable heterogeneous catalyst for several organic transformations dedicates an intensive contribution in term of the pharmaceutical and chemical application
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When the reaction was completed, a sample was withdrawn and quenched with water before being eluted with ethyl acetate The organic layer was then dried over anhydrous Na 2 SO 4 and analyzed by GC GC yield of the product was calculated using the following formula:
The formula of calibration curve: y=Ax + B
- n Pr (mol): Mole of 3-phenethyl-2-phenylquinazolin-4(3H)-one (or 2,4,6- triphenyl pyridine) obtained
- n Pr ’ (mol): Calculated mole of 3-phenethyl-2-phenylquinazolin-4(3H)-one
(or 2,4,6-triphenyl pyridine) when yield = 100%
- S Pr : Peak area of 3-phenethyl-2-phenylquinazolin-4(3H)-one ( or 2,4,6- triphenyl pyridine) in sample
- S IS : Peak area of diphenyl ether in sample - n IS (mol): Mole of diphenyl ether in sample
GC yield % = n Pr × 100% n Pr ' = S Pr
Calibration curve of the synthesis of 3-phenethyl-2-phenylquinazolin-4(3H)-one via Baeyer-Villiger oxidation expansion reaction y (n Pr /n IS ) x (S Pr /S IS ) 1.36294 2.824274949
Figure AA 1 GC yield of of the synthesis of 3-phenethyl-2-phenylquinazolin-
4(3H)-one with reference to diphenyl ether
Calibration curve of the synthesis of 2,4,6-triphenyl pyridine via MOF VNU-20- catalyzed cyclization reactions y (n Pr /n IS ) x (S Pr /S IS )
Figure AA 2 GC yield of of the synthesis of 2,4,6-triphenyl pyridine with reference to diphenyl ether y = 0.551x + 0.0183 R² = 0.999
Figure AB 1 GC spectra of Cu-MOF-74-catalyzed Baeyer-Villiger oxidation expansion reaction to synthesize 2-arylquinazolinones
Figure AB 2 GC spectra of MOF VNU-20-catalyzed cyclization reaction between ketoxime acetates and dibenzyl ether to produce symmetrical pyridines
Table AB 1:Effect of temperature in the synthesis of 2-arylquinazolinones
S product S diphenyl ether S product / S diphenyl ether
Table AB 2:Effect of solvent in the synthesis of 2-arylquinazolinones
Solvent S product S diphenyl ether S product / S diphenyl ether
Table AB 3: Effect of reactant molar ratio in the synthesis of 2-arylquinazolinones
S product S diphenyl ether S product / S diphenyl ether
Table AB 4:Effect of catalyst quantity in the synthesis of 2-arylquinazolinones
Catalyst quantity S product S diphenyl ether S product / S diphenyl ether
Table AB 5: Effect of heterogeneous catalysts in the synthesis of 2- arylquinazolinones
Heterogeneous catalyst S product S diphenyl ether
Table AB 6: Effect of homogeneous catalysts in the synthesis of 2-arylquinazolinones
Homogeneous catalyst S product S diphenyl ether S product / S diphenyl ether
Table AB 7:Leaching test in the synthesis of 2-arylquinazolinones
Leaching test (h) S product S diphenyl ether S product / S diphenyl ether
Table AB 8: Catalyst reusability test in the synthesis of 2-arylquinazolinones
Run S product S diphenyl ether S product / S diphenyl ether
Table AB 9: Effect of temperature in the synthesis of 2,4,6-triphenylpyridines
Table AB 10:Effect of reactant molar ratio in the synthesis of 2,4,6- triphenylpyridines
Oxime acetate/dibenzyl ether (mole)
Table AB 11: Effect of solvent in the synthesis of 2,4,6-triphenylpyridines
Solvent S product S diphenyl ether S product / S diphenyl ether
Table AB 12: Effect of catalyst quantity in the synthesis of 2,4,6-triphenylpyridines
Catalyst quantity (%) S product S diphenyl ether
Table AB 13: Effect of oxidant in the synthesis of 2,4,6-triphenylpyridines
Oxidant S product S diphenyl ether S product / S diphenyl ether
Table AB 14: Effect of oxidant amount in the synthesis of 2,4,6-triphenylpyridines
Time (Pyridine test)(h) S product S diphenyl ether
Table AB 16:Effect of catalyst reusability test in the synthesis of 2,4,6- triphenylpyridines
Catalytic run S product S diphenyl ether
Table AB 17: Effect of homogeneous catalyst in the synthesis of 2,4,6- triphenylpyridines
Homogeneous catalyst S product S diphenyl ether
S product / S diphenyl ether GC Yield (%)
Table AB 18: Effect of heterogeneous catalyst in the synthesis of 2,4,6- triphenylpyridines
Heterogeneous catalyst S product S diphenyl ether
Characterization data for Quinazolinone derivatives
Figure AC 1 1 H-NMR spectra of 3-phenethyl-2-phenylquinazolin-4(3H)-one
Figure AC 2 13 C-NMR spectra of 3-phenethyl-2-phenylquinazolin-4(3H)-one
3-Phenethyl-2-phenylquinazolin-4(3 H )-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1: 4 (v./v.), TLC silica gel 60 F 254 , R f = 0.5) White solid Yield:
94% 1 H-NMR (500 MHz, CDCl 3 ): δ (ppm) 8.37 (d, J = 8.0 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.55 – 7.48 (m, 4H), 7.40 – 7.38 (m, 2H), 7.18 (s, 3H), 6.88 – 6.87 (m, 2H), 4.20 (t, J = 7.5 Hz, 2H), 2.91 (t, J = 7.5 Hz, 2H); 13 C-NMR (125 MHz, CDCl 3 ): δ (ppm) 162.2, 156.2, 147.2, 137.8, 135.4, 134.4, 129.8, 128.8, 128.6, 127.8, 127.6, 127.1, 126.8, 126.7, 121.0, 47.6, 34.7
Figure AC 3 1 H-NMR spectra of 3-benzyl-2-phenylquinazolin-4(3H)-one
Figure AC 4 13 C-NMR spectra of 3-benzyl-2-phenylquinazolin-4(3H)-one
3-benzyl-2-phenylquinazolin-4(3H)-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 8:1:3 (v./v.), TLC silica gel 60 F 254 , R f = 0.5) White solid Yield: 78% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.378 (d, J=8 Hz, 2H), 7.753 – 7.802 (m, 2H), 7.514 – 7.546 (m, 1H), 7.465 (t, J= 7,5 Hz, 1H), 7.396 (t, J=7,5 Hz, 2H), 7.333 – 7.348 (m, 2H), 7.187 – 7.207 (m, 3H), 6.915 – 6.933 (m, 2H), 5.275 (s, 2H) 13 C-NMR (125 MHz, CDCl 3 , ppm): δ (ppm) 162.48; 156.39; 147.31; 136.62;
Figure AC 5 1 H-NMR spectra of 3-(2-chlorobenzyl)-2-phenylquinazolin-4(3H)-one
Figure AC 6 13 C-NMR spectra of 3-(2-chlorobenzyl)-2-phenylquinazolin-4(3H)-one
3-(2-chlorobenzyl)-2-phenylquinazolin-4(3 H )-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 8:1:3 (v./v.), TLC silica gel 60 F 254 , R f = 0.5)
White solid Yield: 76% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.378 (d, J=8 Hz, 1H), 7.790 – 7.833 (m, 2H), 7.533 – 7.566 (m, 1H), 7.424 – 7.456 (m, 1H), 7.355 (t, J=7,5 Hz, 2H), 7.257 – 7.313 (m, 3H), 7.171 – 7.198 (m, 2H), 6.947 – 6.973 (m, 1H), 5.301 (s, 2H) 13 C-NMR (125 MHz, CDCl 3 ):δ (ppm) 162.38; 156.48; 147.37; 134.94;
Figure AC 7 1 H-NMR spectra of 3-(4-chlorobenzyl)-2-phenylquinazolin-4(3H)-one
Figure AC 8 13 C-NMR spectra of 3-(4-chlorobenzyl)-2-phenylquinazolin-4(3H)-one
3-(4-chlorobenzyl)-2-phenylquinazolin-4(3 H )-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 4:1:2 (v./v.), TLC silica gel 60 F 254 , R f = 0.5)
White solid Yield: 74% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.366 (d, J=7.5 Hz, 1H), 7.752 – 7.808 (m, 2H), 7.520 – 7.563 (m, 1H), 7.471 – 7.501 (m, 1H), 7.421 (t, J=7,5 Hz, 2H), 7.329 – 7.346 (m, 2H), 7.161 – 7.183 (m, 2H), 6.862 (m, 2H), 5.230 (s, 2H) 13 C-NMR (125 MHz, CDCl 3 , ppm):δ 162.43; 156.08; 147.25; 135.19; 135.12;
Figure AC 9 1 H-NMR spectra of 3-(4-methoxybenzyl)-2-phenylquinazolin-4(3H)- one
Figure AC 10 13 C-NMR spectra of 3-(4-methoxybenzyl)-2-phenylquinazolin-4(3H)- one
3-(4-methoxybenzyl)-2-phenylquinazolin-4(3H)-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 4:1:2 (v./v.), TLC silica gel 60 F 254 , R f = 0.5)
White solid Yield: 57% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.363 – 8.379 (m, 1H), 7.738 – 7.787 (m, 2H), 7.467 – 7.534 (m, 2H), 7.424 (t, J=7,5 Hz, 2H), 7.350 – 7.367 (m, 2H), 6.848 (d, J=8.5 Hz, 2H), 6.721 (d, J=8.5 Hz, 2H), 5.216 (s, 2H), 3.742 (s, 3H) 13 C-NMR (125 MHz, CDCl 3 , ppm):δ 162.51; 158.95; 156.37; 147.28; 135.43;
Figure AC 11 1 H-NMR spectra of 2-phenyl-3-(3-phenylpropyl)quinazolin-4(3H)-one
Figure AC 12 13 C-NMR spectra of 2-phenyl-3-(3-phenylpropyl)quinazolin-4(3H)- one
2-phenyl-3-(3-phenylpropyl)quinazolin-4(3 H )-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 4:1:2 (v./v.), TLC silica gel 60 F 254 , R f = 0.5)
White solid Yield: 45% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.333 (m, 1H), 7.718 – 7.771 (m, 2H), 7.485 – 7.54 (m, 6H), 7.163 – 7.192 (m, 2H), 7.105 – 7.134 (m, 1H), 6.971 – 6.984 (m, 2H), 3.982 (t, J=7.5 HZ, 2H), 2.506 (t, J=7.5 Hz, 2H), 1.918 – 1.980 (m, 2H) 13 C-NMR (125 MHz, CDCl 3 , ppm): δ 162.18; 156.10; 147.21; 140.48;
Figure AC 13 1 H-NMR spectra of 3-butyl-2-phenylquinazolin-4(3H)-one
Figure AC 14 13 C-NMR spectra of 3-butyl-2-phenylquinazolin-4(3H)-one
3-butyl-2-phenylquinazolin-4(3 H )-one Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, hexane: ethyl acetate: dichlomethane = 4:1:2 (v./v.), TLC silica gel 60 F 254 , R f = 0.5) White solid Yield: 69% 1 H-NMR (500 MHz, CDCl 3 ) δ (ppm) 8.323 – 8.343 (m, 1H), 7,718 – 7.771 (m, 2H), 7.485 – 7.540 (m, 6H), 3.982 (t, J=8Hz, 2H), 1.560 – 1.621 (m, 2H), 1.139 – 1.213 (m, 2H), 0.760 (t, J=7.5Hz, 3H) 13 C-NMR (125 MHz, CDCl 3 , ppm):δ 162.16; 156.26; 147.23; 135.64; 134.24; 129.76; 128.74; 127.82; 127.46; 126.92, 126.75, 120.97, 45.70, 30.74, 19.89, 13.39
Characterization data for pyridine derivatives
Figure AC 15 1 H-NMR spectra of 2,4,6-triphenylpyridine
Figure AC 16 13 C-NMR spectra of 2,4,6-triphenylpyridine
2,4,6-triphenylpyridine (01) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane
= 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 85% yield (52.3 mg) 1 H- NMR (500 MHz, CDCl 3 ) δ(ppm) 7.43 – 7.47 (m, 2H), 7.49 – 7.57 (m, 7H), 7.74 (d, J
= 7.5 Hz, 2H), 7.89 (s, 2H), 8.19 (d, J = 7.5 Hz, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 117.2, 127.3, 127.3, 128.9, 129.1, 129.2, 139.2, 139.7, 150.3, 157.6
Figure AC 17 1 H-NMR spectra of 4-phenyl-2,6-di-p-tolylpyridine
Figure AC 18 13 C-NMR spectra of 4-phenyl-2,6-di-p-tolylpyridine
4-phenyl-2,6-di-p-tolylpyridine (02) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 78% yield (52.6 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 2.42 (s, 6H), 7.31 (d, J = 8.0 Hz, 4H), 7.44 – 7.47 (m, 1H), 7.50 – 7.53 (m, 2H), 7.72 – 7.74 (m, 2H), 7.81 – 7.84 (t, J 7.5, 2H), 8.09 – 8.11 (d, J = 8 Hz, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 21.3, 116.5, 127.0, 127.2, 128.8, 129.0, 129.4, 136.9, 138.9, 139.3, 150.0, 157.4
Figure AC 19 1 H-NMR spectra of 2,6-bis(4-chlorophenyl)-4-phenylpyridine
Figure AC 20 13 C-NMR spectra of 2,6-bis(4-chlorophenyl)-4-phenylpyridine
2,6-bis(4-chlorophenyl)-4-phenylpyridine (03) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 70% yield (52.8 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.46 – 7.49 (m, 5H), 7.51 – 7.54 (m, 2H), 7.71 (d, J = 7.0 Hz, 2H), 7.84 (s, 2H), 8.11 (d, J = 8.5 Hz, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 117.1, 127.1, 128.3, 128.9, 129.2, 135.3, 137.8, 138.7, 150.6, 156.3
Figure AC 21 1 H-NMR spectra of 2,6-bis(3-chlorophenyl)-4-phenylpyridine
Figure AC 22 13 C-NMR spectra of 2,6-bis(3-chlorophenyl)-4-phenylpyridine
2,6-bis(3-chlorophenyl)-4-phenylpyridine (04) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 75% yield (56.6 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.41 – 7.46 (m, 4H), 7.49 – 7.50 (d, J = 7.0 Hz, 1H), 7.52 (t, J = 7.5, 2H), 7.72 (d, J = 7.5 Hz, 2H), 7.87 (s, 2H), 8.05 –
8.07 (dt, J1 = 7 Hz, J2 = 1.5 Hz, 2 H), 8.18 (m, 2H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 117.7, 125.2, 127.1, 127.2, 129.1, 129.2, 129.2, 130.0, 134.8, 138.5, 141.1, 150.7, 156.2
Figure AC 23 1 H-NMR spectra of for 2,6-bis(4-Methoxyphenyl)-4-phenylpyridine
Figure AC 24 13 C-NMR spectra of for 2,6-bis(4-Methoxyphenyl)-4-phenylpyridine
2,6-bis(4-Methoxyphenyl)-4-phenylpyridine (05) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.3): White solid, 82% yield (60.8 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 3.88 (s, 6H), 7.02 (dt, J 1 = 9 Hz,
J 2 = 2.5 Hz , 4H), 7.46 – 7.47 (m, 1H), 7.50 – 7.53 (m, 2H), 7.72 – 7.74 (m, 2H), 7.77 (s, 2H), 8.14 (dt, J 1 = 9 Hz, J 2 = 2.5 Hz , 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 55.3, 114.0, 115.7, 127.1, 128.3, 128.8, 129.0, 132.4, 139.4, 150.0, 157.0, 160.5
Figure AC 25 1 H-NMR spectra of 4-phenyl-2,6-di(thiophen-2-yl)pyridine
Figure AC 26 13 C-NMR spectra of 4-phenyl-2,6-di(thiophen-2-yl)pyridine
4-phenyl-2,6-di(thiophen-2-yl)pyridine (06) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.40): White solid, 55% yield (35.9 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.12 – 7.14 (m, 2H), 7.41 (dd, J 1 = 5 Hz, J 2 = 1 Hz , 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.50 – 7.53 (m, 2H), 7.68 (s, 2H), 7.69 – 7.71 (m, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 115.1, 124.8, 127.0, 127.8, 127.9, 129.1, 129.1, 138.6, 144.9, 150.2, 152.6
Figure AC 27 1 H-NMR spectra of 2,6-bis(4-bromophenyl)-4-phenylpyridine
Figure AC 28 13 C-NMR spectra of 2,6-bis(4-bromophenyl)-4-phenylpyridine
2,6-bis(4-bromophenyl)-4-phenylpyridine (07) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 78% yield (72.5 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.48 – 7.50 (m, 1H), 7.51 – 7.55 (m, 2H), 7.62 – 7.65 (dt, J 1 = 8.5 Hz, J 2 = 2 Hz, 4H), 7.71 – 7.72 (m, 2H), 7.85 (s, 2H), 8.04 (dt, J 1 = 8.5 Hz, J 2 = 2 Hz , 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 117.1, 123.6, 127.1, 128.6, 129.2, 131.8, 138.2, 138.6, 150.6, 156.4
Figure AC 29 1 H-NMR spectra of for 2,4,6-triphenylpyridine
Figure AC 30 13 C-NMR spectra of for 2,4,6-triphenylpyridine
2,4,6-triphenylpyridine (08) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane
= 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 86% yield (26.4 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.46 – 7.60 (m, 9H), 7.78 (d, J = 7.5 Hz, 2H), 7.92 (s, 2H), 8.24 (d, J = 8.0 Hz, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 117.0, 127.0, 127.1, 128.6, 128.8, 128.9, 129.0, 139.0, 139.5, 150.1, 157.4
Figure AC 31 1 H-NMR spectra of for 4-phenyl-2,6-di-p-tolylpyridine
Figure AC 32 13 C-NMR spectra of for 4-phenyl-2,6-di-p-tolylpyridine
Characterization data for 4-phenyl-2,6-di- p -tolylpyridine (09) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35):
White solid, 75% yield (24.1 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 2.42 (s, 6H), 7.31 (d, J = 8.0 Hz, 4H), 7.45 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 2H), 7.28 (d, J 7.5 Hz, 2H), 7.83 (s, 2H), 8.09 (d, J = 8.0 Hz, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 21.3, 116.5, 127.0, 127.1, 127.1, 128.2, 129.0, 129.4, 136.9, 138.9, 139.3, 150.0, 157.4
Figure AC 33 1 H-NMR spectra of for 4-phenyl-2,6-di(thiophen-2-yl)pyridine
Figure AC 34 13 C-NMR spectra of for 4-phenyl-2,6-di(thiophen-2-yl)pyridine
4-phenyl-2,6-di(thiophen-2-yl)pyridine (10) Prepared as shown in the general experimental procedure and purified on silica gel (230-400 mesh or 37-63 àm, ethyl acetate/hexane = 1:40 (v./v.), TLC silica gel 60 F 254 , R f = 0.35): White solid, 60% yield (19.1 mg) 1 H-NMR (500 MHz, CDCl 3 ) δ(ppm) 7.12 – 7.14 (m, 2H), 7.41 – 7.42 (dd,
J 1 = 5 Hz, J 2 = 1 Hz , 2H), 7.45 – 7.48 (m, 1H), 7.50 – 7.54 (m, 3H), 7.68 (s, 2H), 7.69 – 7.71 (m, 4H) 13 C-NMR (CDCl 3 , 125 MHz) δ(ppm) 115.1, 124.8, 127.0, 127.8, 127.9, 128.4, 128.9, 129.1, 138.6, 144.9, 150.2, 152.6
Figure AC 35 1 H-NMR spectra of for 7-phenyl-5,6,8,9- tetrahydrodibenzo[c,h]acridine
Figure AC 36 13 C-NMR spectra of for 7-phenyl-5,6,8,9- tetrahydrodibenzo[c,h]acridine
2: The oxidation of cyclohexene [37]
As the redox catalyst, nanocrystalline Cu–MOF-74 material was prepared to use for the catalytic oxidation of cyclohexene using peroxides as oxidizing agents tert- butylhydroperoxide (TBHP) at room temperature (scheme 1 2) This catalytic reaction requires redox centers such as Cu ( the redox active M of the M–MOF-74 materials )
Pressure (bar) CO 2 Uptake (mg/g)
Due to the ultrahigh BET surface area of Cu-MOF-74, The nanocrystalline Cu–MOF- 74 materials were much more active than their micrometer-sized homologues (Figure
1 10) for the heterogeneous catalyst of the oxidation of cyclohexene [37]
Figure 1 10: Total yields of the products that result from the oxidation of cyclohexene in the presence of M–MOF-74 and without catalyst (blank) with TBHP
As a reference acid catalyzed reaction, Cu-MOF-74 with open metal sites performs the catalysis of the reaction between anisole and acetyl chloride to form MAPs
3: Simplified reaction for the acylation of anisole with acetyl chloride [36]
Scheme 1 3: Simplified reaction for the acylation of anisole with acetyl chloride [36].
The catalytic performance Cu-MOF-74 in comparison to other different acid catalysts in terms of relative anisole conversion and p-MAP yield under the same reaction condition is showed in Figure 1 11 These materials include: HKUST-1 as another Cu-based MOF and other conventional inorganic catalysts typically used in
15 acid catalyzed reaction such as H-ZSM-5 and BETA zeolitic materials and Al-MCM- 41 mesoporous materials In comparison with these inorganic catalysts (Figure 1 11), the anisole conversion of Cu-MOF-74 is the highest Therefore, the acid capacity of copper atoms located into the hybrid MOF-74 phase as well as its remarkable surface area makes Cu-MOF-74 a promising material for acid catalyzed reactions, in particular for the acylation of anisole
Figure 1 11: Comparison of different types of acid catalysts for the acylation of anisole [36]
Interestingly, Cu-MOF-74, which acts not only as a Lewis acid catalyst [38], but also a basic catalysts with well-defined active sites [31] For instance, Cu-MOF-74 was introduced by Valvekens as a catalyst in Knoevenagel condensation, Michael conjugate addition reactions in previous report (Scheme 1 4) [31] According to this, Cu-MOF-74 could be catalyzed the Knoevenagel condensation of benzaldehyde to malononitrile and the Michael addition reaction of ethyl cyanoacetate to methyl vinyl ketone, which afforded the moderate product yield The successful application of this MOF for these standard base-catalyzed reactions opens a new window for catalysis research using the intrinsic basicity of MOFs [31]
4: The catalytic activity of Cu-MOF-74 in some typically base-catalyzed reactions, a) Knoevengel condensation rection b) Micheal reaction [31]
reactions, a) Knoevengel condensation rection b) Micheal reaction [31].
In the framework of Cu-MOF-74, 2,5-dihydroxyterephthalic acid molecules are completely deprotonated, all of their oxygen atoms bond directly with the copper centers (Figure 1 12) Therefore, these oxygen atoms, especially the phenolate ones, exhibit Bronsted basicity, in other words, they have the ability to deprotonate the reactant molecules in the Knoevenagel condensation Furthermore, the coordinatively unsaturated copper ion adjacent to the phenolate oxygen atom can act as a docking site for the deprotonated reactant molecule The interplay of copper ions and phenolate oxygen atoms make up the active sites in Cu-MOF-74
Figure 1 12: Pores in the M 2 dobdc MOF (brown = carbon; orange = metal; red oxygen).[31]
Recently, there are many studies for utilizing Cu-MOF-74 as a heterogeneous catalyst for various reaction Typically, Cu-MOF-74 catalyst using for the coupling reaction of pyrrolidine and phenylglyoxal was reported Truong and co-workers in
2015 (Scheme 1 5) The outstanding result indicated that the reaction obtained 95% yield in the presence of Cu-MOF-74, simultaneously, this heterogeneous catalyst could contribute to be highly recycled with 9 times, being superior to other homogeneous and heterogeneous for this coupling [39].
5: The coupling reaction of amines and -carbonyl aldehydes [39]
At the first time, the direct esterification to produce O-acetyl substituted phenol esters utilizing dibenzyl ethers as acylating source assisted by Cu-MOF-74 as a recyclable catalyst was explored by Lieu and co-workers (Scheme 1 6) This transformation occurred in ease condition with the aid of DMSO as an effective solvent, t-BuOOH as an oxidant and Cu-MOF-74 as a recyclable catalyst, affording up to 86% in product yield The feature that Cu-MOF-74 could reuse over the 6 th catalytic run without a noticeable deterioration in catalytic efficiency would be fascinated to the chemical industry [40]
Scheme 1 6:The reaction between dibenzyl ether and 2-acetyl phenol utilizing Cu-
In 2016, G.H.Dang et al announced the three-component coupling reaction of 2- pyridincarboxaldehyde, piperidine, and phenylacetylene to form 3-phenyl-1-(piperidin-1-yl)indolizine using Cu-MOF-74 as a heterogeneous catalyst The coupling reaction was carried out in n-butanol under argon for 5 h at 100 o C (Scheme 1 7).The yield of the product was 99% in in the presence of Cu-MOF-74 catalyst And the catalyst could be recovered and reused seven times without a significant degradation in catalytic activity [41]
Scheme 1 7: The three-component coupling reaction of 2-pyridincarboxaldehyde, piperidine, and phenylacetylene using Cu-MOF-74 catalyst [41].
Synthesis of imidazo[1,5-a]pyridines via oxidative amination of the C(sp3)–H bond under air using metal–organic framework Cu-MOF-74 as an efficient heterogeneous catalyst was also reported in 2016 by Nguyen and co-workers (Scheme 1 8) The C-N coupling reaction between 2-benzoyl pyridine and benzylamine obtained the desired product with 71% yield after 8 hours Indeed, the reaction still afforded 67% yield of the product in the 8th run [42]
Scheme 1 8: The synthesis of imidazo[1,5-a]pyridines via oxidative amination of the
C(sp3)–H bond using Cu-MOF-74 [42]
And at that time,Cu-MOF-74 was also assessed for its catalytic activity in the hydroacylation of phenylacetylene with ethyl glyoxalate to form (E)-ethyl 2-oxo-4- phenylbut-3-enoate in a yield of 93% after four hours (Scheme 1 9) Without a significant degradation in catalytic activity of Cu-MOF-74 after reusing and recycling, a 91% yield of product was still achieved in the eighth run [43]
Scheme 1 9: The hydroacylation of 1-alkynes with glyoxal derivatives using the Cu-
1.3 Introduction to iron-based metal-organic frameworks and iron-based
MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as a heterogeneous catalyst Structure of MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O]
Up to now, a great number of reports using iron-based MOFs have been revealed; however, these works were mainly focused on oxo-centered trimers of octahedral Fe(III) secondary building units (SBUs) In addition to MOFs assembled from a single type of organic linker, a novel iron-based MOF VNU-20 (VNU = Vietnam National University) has been prepared and employed as an efficient heterogeneous catalyst for many coupling transformations MOF VNU-20, formulated as [Fe 3 (BTC)(NDC) 2 ã6.65H 2 O] (BTC = 1,3,5-benzenetricarboxylate; NDC = 2,6- napthalenedicarboxylate), was constructed from mixed linkers of BTC 3− and NDC 2− with an infinite [Fe 3 (CO 2 ) 7 ] ∞ rod SBU, which was rarely seen before (Figure 1 14)
Figure 1 13: The crystal structure of VNU-20 (b) are linked horizontally and vertically by BTC 3− and NDC 2−, respectively (a, e and f) to form the orange-red crystals (d) with structure highlighted with a rectangular window of 6.0 × 8.7 Å2 (c)
Atom colors: Fe, blue and orange polyhedra; C, black; O, red All H atoms are omitted for clarity [44].
Application of iron-based MOFs and the mixed-linker iron-based MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as heterogeneous catalyst
Over the past few years, the applications of iron-based metal-organic frameworks in catalysis have drawn an increased attention, especially in the field of C−H functionalization reactions [45-47] In 2015, Le and co-workers carried out the preparation of 1,5-Benzodiazepine through cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst (Scheme 1 25)
Excellent conversion to the desired product were achieved in the presence of 5 mol%
MOF-235 catalyst and the molecule oxygen as the stoichiometric oxidant at 50 0 C for 180 minutes In addition, the MOF could be reused ten times without degradation in the yield [48]
Scheme 1 10:1,5-benzodiazepine synthesis via cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst [48].
In 2016, Doan and co-workers successfully utilized Fe 3 O(BDC) 3 as recycled heterogeneous catalyst for the direct C-C coupling of indoles with alkylamides via oxidative C-H functionalization (Scheme 1 26) The reaction could only progress in the presence of this Fe-MOF to obtain 90% yield with high selectivity after just 60 minutes Furthermore, this strategy contributes to the green eligibility for the coupling regard to the simplicity of reusability without substantial deterioration in catalytic activity [49]
Scheme 1 11:Direct C-C coupling of indoles with alkylamides via oxidative C−H functionalization using Fe 3 O(BDC) 3 as a productive heterogeneous catalyst [49].
In the meantime, a new method for the direct arylation of benzoazoles with aldehydes in the existence of Fe 3 O(BDC) 3 as a productively heterogeneous catalyst was developed by Doan and co-workers (Scheme 1 27) Instead of aryl halides in the conventional methodology, the precursor benzaldehyde featured inexpensive and commercially available abilities In the catalysis of Fe 3 O(BDC) 3 , the corresponding product was obtained the best yield 93% for 3h when the temperature was raised to 100 0 C [50]
Scheme 1 12:Direct arylation of benzoazoles with aldehydes utilizing metal–organic framework Fe 3 O(BDC) 3 as a recyclable heterogeneous catalyst [50].
Otherwise, many investigations on metal organic framework Fe 3 O(BPDC) 3 have gained intensive concerns for the catalysis chemistry In 2016, Dang and co-worker successfully achieved 2-alkenylazaarenes with 88% yield via direct alkenylation of 2- substituted azaarenes with carbonyls using 10 mol% Fe 3 O(BPDC) 3 (Scheme 1 28)
The Fe 3 O(BPDC) 3 exhibited the better performance in catalytic activity than other heterogeneous and homogeneous catalyst in this transformation; in addition, the combination of Fe 3 O(BPDC) 3 and co-catalyst accelerated the yield significantly [51]
Scheme 1 13:Synthesis of 2-alkenylazaarenes using the direct alkenylation of 2- substituted azaarenes with carbonyls via C−H bond activation [51].
In the same years, the synthesis of coumarins from salicylaldehydes and activated methylene compounds was conducted by Lieu and co-workers (Scheme 1 29) When homogeneous catalysts were using, the reaction yield only gained 20%; In contrast, the heterogeneous catalyst Fe 3 O(BPDC) 3 could promoted the transformation to reach the excellent yield 96% Indeed, this transformation could occur under mild temperature, heterogeneous and base-free conditions should be of an advantage [52]
Scheme 1 14:Oxidant-promoted formation of coumarins using Fe 3 O(BPDC) 3 as an efficient heterogeneous catalyst [52].
Interestingly, for the direct C-N coupling, Nguyen and co-workers proceeded the formation of azole derivatives from azoles with ethers via oxidative C-H activation by using Fe 3 O(BPDC) 3 as recyclable solid catalyst (Scheme 1 30) It was noted that 90% yield of the expected product was also recorded when only 5 mol% Fe-MOF was used in the mild condition, confirming the significance of this chemical activation protocol [53]
Scheme 1 15: Direct C–N coupling of azoles with ethers via oxidative C–H activation under metal–organic framework catalysis [53].
Additionally, Oveisi and co-workers described the potential catalytic utility of Fe(BTC) that makes it quite attractive for sustainable industrial chemistry The porous iron-based MOF, Fe(BTC), showed high activity catalysis in the oxidative cyclization of methylenebisnaphthols to the corresponding spirodienones (Scheme 1 31a)
Simultaneously, the modern tandem process between benzyl alcohols and o- aminobenzamide with the aid of Fe(BTC) and oxidant to produce quinazolin-4(3H)- ones Fe(BTC) was also explored by Oveisi These works consistently have the advantages such as availability of MOF, inexpensive catalyst, mild reaction conditions, reasonable yields, and simple experimental procedures (Scheme 1 31b)
Scheme 1 16: One-pot oxidative synthesis of quinazolinones using Fe(BTC) as efficient heterogeneous catalysts by Oveisi and co-workers [54].
7: The three-component coupling reaction of 2-pyridincarboxaldehyde, piperidine, and phenylacetylene using Cu-MOF-74 catalyst [41]
piperidine, and phenylacetylene using Cu-MOF-74 catalyst [41].
Synthesis of imidazo[1,5-a]pyridines via oxidative amination of the C(sp3)–H bond under air using metal–organic framework Cu-MOF-74 as an efficient heterogeneous catalyst was also reported in 2016 by Nguyen and co-workers (Scheme 1 8) The C-N coupling reaction between 2-benzoyl pyridine and benzylamine obtained the desired product with 71% yield after 8 hours Indeed, the reaction still afforded 67% yield of the product in the 8th run [42].
8: The synthesis of imidazo[1,5-a]pyridines via oxidative amination of the C(sp3)–H bond using Cu-MOF-74 [42]
C(sp3)–H bond using Cu-MOF-74 [42]
And at that time,Cu-MOF-74 was also assessed for its catalytic activity in the hydroacylation of phenylacetylene with ethyl glyoxalate to form (E)-ethyl 2-oxo-4- phenylbut-3-enoate in a yield of 93% after four hours (Scheme 1 9) Without a significant degradation in catalytic activity of Cu-MOF-74 after reusing and recycling, a 91% yield of product was still achieved in the eighth run [43]
9: The hydroacylation of 1-alkynes with glyoxal derivatives using the Cu- MOF-74 catalyst [43]
1.3 Introduction to iron-based metal-organic frameworks and iron-based
MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as a heterogeneous catalyst Structure of MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O]
Up to now, a great number of reports using iron-based MOFs have been revealed; however, these works were mainly focused on oxo-centered trimers of octahedral Fe(III) secondary building units (SBUs) In addition to MOFs assembled from a single type of organic linker, a novel iron-based MOF VNU-20 (VNU = Vietnam National University) has been prepared and employed as an efficient heterogeneous catalyst for many coupling transformations MOF VNU-20, formulated as [Fe 3 (BTC)(NDC) 2 ã6.65H 2 O] (BTC = 1,3,5-benzenetricarboxylate; NDC = 2,6- napthalenedicarboxylate), was constructed from mixed linkers of BTC 3− and NDC 2− with an infinite [Fe 3 (CO 2 ) 7 ] ∞ rod SBU, which was rarely seen before (Figure 1 14)
Figure 1 13: The crystal structure of VNU-20 (b) are linked horizontally and vertically by BTC 3− and NDC 2−, respectively (a, e and f) to form the orange-red crystals (d) with structure highlighted with a rectangular window of 6.0 × 8.7 Å2 (c)
Atom colors: Fe, blue and orange polyhedra; C, black; O, red All H atoms are omitted for clarity [44].
Application of iron-based MOFs and the mixed-linker iron-based MOF VNU-20 [Fe 3 (BTC)(NDC) 2 6.65H 2 O] as heterogeneous catalyst
Over the past few years, the applications of iron-based metal-organic frameworks in catalysis have drawn an increased attention, especially in the field of C−H functionalization reactions [45-47] In 2015, Le and co-workers carried out the preparation of 1,5-Benzodiazepine through cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst (Scheme 1 25)
Excellent conversion to the desired product were achieved in the presence of 5 mol%
MOF-235 catalyst and the molecule oxygen as the stoichiometric oxidant at 50 0 C for 180 minutes In addition, the MOF could be reused ten times without degradation in the yield [48]
Scheme 1 10:1,5-benzodiazepine synthesis via cyclocondensation of 1,2-diamines with ketones using MOF-235 as an efficient heterogeneous catalyst [48].
In 2016, Doan and co-workers successfully utilized Fe 3 O(BDC) 3 as recycled heterogeneous catalyst for the direct C-C coupling of indoles with alkylamides via oxidative C-H functionalization (Scheme 1 26) The reaction could only progress in the presence of this Fe-MOF to obtain 90% yield with high selectivity after just 60 minutes Furthermore, this strategy contributes to the green eligibility for the coupling regard to the simplicity of reusability without substantial deterioration in catalytic activity [49]
Scheme 1 11:Direct C-C coupling of indoles with alkylamides via oxidative C−H functionalization using Fe 3 O(BDC) 3 as a productive heterogeneous catalyst [49].
In the meantime, a new method for the direct arylation of benzoazoles with aldehydes in the existence of Fe 3 O(BDC) 3 as a productively heterogeneous catalyst was developed by Doan and co-workers (Scheme 1 27) Instead of aryl halides in the conventional methodology, the precursor benzaldehyde featured inexpensive and commercially available abilities In the catalysis of Fe 3 O(BDC) 3 , the corresponding product was obtained the best yield 93% for 3h when the temperature was raised to 100 0 C [50]
Scheme 1 12:Direct arylation of benzoazoles with aldehydes utilizing metal–organic framework Fe 3 O(BDC) 3 as a recyclable heterogeneous catalyst [50].
Otherwise, many investigations on metal organic framework Fe 3 O(BPDC) 3 have gained intensive concerns for the catalysis chemistry In 2016, Dang and co-worker successfully achieved 2-alkenylazaarenes with 88% yield via direct alkenylation of 2- substituted azaarenes with carbonyls using 10 mol% Fe 3 O(BPDC) 3 (Scheme 1 28)
The Fe 3 O(BPDC) 3 exhibited the better performance in catalytic activity than other heterogeneous and homogeneous catalyst in this transformation; in addition, the combination of Fe 3 O(BPDC) 3 and co-catalyst accelerated the yield significantly [51]
Scheme 1 13:Synthesis of 2-alkenylazaarenes using the direct alkenylation of 2- substituted azaarenes with carbonyls via C−H bond activation [51].
In the same years, the synthesis of coumarins from salicylaldehydes and activated methylene compounds was conducted by Lieu and co-workers (Scheme 1 29) When homogeneous catalysts were using, the reaction yield only gained 20%; In contrast, the heterogeneous catalyst Fe 3 O(BPDC) 3 could promoted the transformation to reach the excellent yield 96% Indeed, this transformation could occur under mild temperature, heterogeneous and base-free conditions should be of an advantage [52]
Scheme 1 14:Oxidant-promoted formation of coumarins using Fe 3 O(BPDC) 3 as an efficient heterogeneous catalyst [52].
Interestingly, for the direct C-N coupling, Nguyen and co-workers proceeded the formation of azole derivatives from azoles with ethers via oxidative C-H activation by using Fe 3 O(BPDC) 3 as recyclable solid catalyst (Scheme 1 30) It was noted that 90% yield of the expected product was also recorded when only 5 mol% Fe-MOF was used in the mild condition, confirming the significance of this chemical activation protocol [53]
Scheme 1 15: Direct C–N coupling of azoles with ethers via oxidative C–H activation under metal–organic framework catalysis [53].
Additionally, Oveisi and co-workers described the potential catalytic utility of Fe(BTC) that makes it quite attractive for sustainable industrial chemistry The porous iron-based MOF, Fe(BTC), showed high activity catalysis in the oxidative cyclization of methylenebisnaphthols to the corresponding spirodienones (Scheme 1 31a)
Simultaneously, the modern tandem process between benzyl alcohols and o- aminobenzamide with the aid of Fe(BTC) and oxidant to produce quinazolin-4(3H)- ones Fe(BTC) was also explored by Oveisi These works consistently have the advantages such as availability of MOF, inexpensive catalyst, mild reaction conditions, reasonable yields, and simple experimental procedures (Scheme 1 31b)
Scheme 1 16: One-pot oxidative synthesis of quinazolinones using Fe(BTC) as efficient heterogeneous catalysts by Oveisi and co-workers [54].
As previously mentioned, although reports on catalytic activity of mixed-linker MOFs were reported widely in recent years, mixed-linker MOFs containing Fe(II)- based SBUs were hardly known before A novel porous metal-organic framework
[Fe 3 (BTC)(NDC) 2 ã6.65H 2 O] called VNU-20 has been recently explored and become a potential candidate in the field of organic reaction catalysis For the first time, in 2018, Pham and co-workers applied MOF VNU-20 into the transformation of coumarins with N,N-dimethylaniline through the direct C–H bond activation (Scheme 1 32) It was noteworthy that the excellent yield was still preserved in the 5th run utilizing the recovered catalyst Furthermore, VNU-20 exhibit the high catalytic performance than that of other MOFs in the coupling transformation, which confirms the practical possibility in catalytic synthesis [55]
Scheme 1 17: Cross-coupling of coumarin and N,N-dimethylaniline utilizing
Besides, To expand the catalytic applications of MOF VNU-20 to the cross- dehydrogenative coupling of coumarins with alkylbenzenes, cycloalkanes, ethers, and formamides, Doan and co-workers conducted the reaction between 6-methylcoumarin and mesitylene using the VNU-20 catalyst (Scheme 1 33) The desired product with
89% yield was obtained with the combination of DTBP as the oxidant and DABCO as the additive led Heterogeneous catalysis was confirmed for the cross-dehydrogenative coupling transformation utilizing the VNU-20 catalyst, and the contribution of active iron species in liquid phase was insignificant [56]
Scheme 1 18: The cross-dehydrogenative coupling of 6-methylcoumarin with mesitylene using the VNU-20 catalyst [56]
30: Direct C–N coupling of azoles with ethers via oxidative C–H activation
Scheme 1 39: Synthesis of pyridines via palladium-catalyzed iminoannulation of internal acetylenes [96].
In 2009, Otterlo and Koning successfully applied ring-closing metathesis (RCM) method for synthesis of numerous aromatic compounds, which inspired motivation for vast of scientist in the field of nature compound containing aromatic or heteroaromatic, which is the important skeletal core in many biological processes [97], and subsequently, ring-closing metathesis has proven to be one of the most utilized
41 chemical breakthroughs of the twentieth century Following this great success, Donohoe and co-workers exploited this method for the synthesis of heteroaromatics: evaluating routes to pyridines by applying this technology for the multistep transformation of 2,6-di- and 2,3,6-trisubstituted pyridines with alkyl, aryl, and alkoxy substituents [98] (Scheme 1 40)
Scheme 1 40: Ring-closing metathesis strategy for pyridine synthesis using acrylamide entry to synthesize pyridines [98].
Recently, tremendous efforts have been made in the field of transition metal- catalyzed cyclizations and cross-coupling reactions to afford functionalized pyridine derivatives For example, rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives from alkynes and α,β unsaturated imines has been achieved by Ellman and Cheng [99, 100] (Scheme 1 41a,b) In contrast to other traditional methods for pyridine synthesis, rhodium-catalyzed C-H activation does not require the use of activated precursors and is tolerant of a variety of functional groups Moreover, numerous transition-metal catalysts such as Pd, Fe, Cu could also be used to afford a structurally diverse set of pyridine derivatives through cross-coupling transformation
Scheme 1 41: Rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives [99, 100]
Scheme 1 42: Transition metal -catalyzed cross-coupling of activated pyridines
In 2009, cyclopropanols were used as a precursor of beta-carbonyl radicals and the investigation of their addition reactions toward vinyl azides (Scheme 1 43) The reactions were carried out by treatment of a mixture of vinyl azides (0.3 mmol) and cyclopropanols (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at room temperature under N 2 atmosphere for 5 min followed by addition of AcOH (2 equiv) With the optimized reaction conditions at hand, the scope of this Mn(III)-mediated pyridine formation was investigated to form various 2,6-diarylpyridines in good yields [103]
Scheme 1 43: Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl Azides to form 2,6-diphenylpyridine [103].
Due to the importance of pyridine derivatives in chemical synthesis, the development of a more concise and straightforward procedure for acquisition of pyridine derivatives from easily available starting materials is still highly desirable in order to overcome the limitation of relatively harsh reaction conditions, the utilization of the costly starting materials, unstable nature of the precursors, expensive noble metal catalysts, tedious operations [80] In conventional methodology, ketoxime carboxylates are well-known fruitful candidates for the Beckmann rearrangement reactions to prepare amides or for the dehydration reactions to produce nitriles.
Nowadays, oxime derivatives have emerged as internal oxidants and versatile building blocks for constructing polysubstituted pyridines through transition metal-catalyzed coupling reactions.
In 2015, Jiang and co-workers successfully achieved the Cu-catalyzed three- component cascade annulation reaction from acetophenone oxime acetate, paraformaldehyde and ethyl acetoacetate (Scheme 1 44) This strategy featured inexpensive catalysts, no need of extra oxidant and accessible reagents Notably, various substrate scopes such as activated methylene compounds, oxime acetates and aldehydes were employed for the preparation of 2,3,5-trisubstituted pyridines with the moderate to excellent corresponding yields [81]
Scheme 1 44: Synthesis of functionalized pyridines via Cu-catalyzed three- component cascade annulation reaction [81].
Notably, heterogeneous catalysis has performed an indispensable task in chemical and pharmaceutical industries as compared to homogeneous one, generally offering the minimization of toxic and hazardous waste In particular, metal –organic frameworks (MOFs) have emerged as environmentally benign alternatives for catalysis Notably, Phuong and co-workers have successfully conducted the cyclization reaction of N,N-dialkylanilines with ketoxime carboxylates to produce aryl-substituted pyridines utilizing Iron-organic framework Fe 3 O(BPDC) 3 as an productive heterogeneous catalyst (Scheme 1 45) This Fe-MOF would be active for organic reactions involving the redox transformation of Fe (II) / Fe (III) [104]
Scheme 1 45: The cyclization between (E)-acetophenone O-acetyl oxime acetate and
N,N-dimethylaniline utilizing iron-organic framework catalyst [104].
In 2016, a metal-free protocol with the combinational employment of iodine and triethylamine has been demonstrated to be effective to trigger the oxime-based synthesis of pyridines with high chemo-selectivity and wide functional group tolerance Herein, the resultant 2-aryl-substituted pyridines were synthesized from O- acetyl ketoxime and α,β-unsaturated aldehyde in the presence of both iodine and triethylamine at 120 o C for 3h (Scheme 1 46a) [105] One year later, the transition-
45 metal-free N−O reduction of Oximes using an NH 4 I-based system was explored by Huang and co-workers In comparison with traditional condensation methods such as Hantzsch pyridine synthesis, this protocol was found to be highly regio- and chemoselective with a broad range of pharmacologically significant fluorinated pyridines and presented broad functional group tolerance (Scheme 1 46b) [106].
Remarkably, these chemical procedures under metal-free conditions are always of significance especially in the pharmaceutical industry and environmental friendliness.
Scheme 1 46: Metal-free assembly of polysubstituted pyridines from oximes [105,
In recent years, the derivatives, 2,4,6-trisubstituted pyridines have been broadly applied for chemosensors [107], asymmetric catalyst [108] or as photosensitizers [109] Such moieties are also very important in building blocks because of their π- stacking ability in conjunction with directional H-bonding capacity Furthermore, they can be used as monometric building blocks in thin films and organometallic polymers thank to its thermal stabilities
For the past few years, the most commonly used approaches to 2,4,6-trisubstituted pyridines involve cyclo-condensation reaction of acetophenone, benzaldehydes with ammonium acetate and a variety of new catalysts or conditions have been reported In 2013, Huang and co-workers revealed a Cu-catalyzed synthesis of 2,4,6- triphenylpyridine with acetophenone and benzylamine under the neat condition [110]
(Scheme 1 47a) Xu and co-workers also introduced a metal-free synthesis of 2,4,6- trisubstituted pyridines via idodine-initiated reaction of methyl aryl ketones with
46 amines under neat heating in 2016 [111] (Scheme 1 47b) In 2017, one-pot synthesis of 2,4,6-triphenylpyridine via copper-catalyzed coupling reactions was reported by Han and co-workers [112] (Scheme 1 47c) and in the same time, Chen and co- workers also conducted cerium(IV) carboxy-methylcellulose as an efficient and reusable catalyst for the one-pot pseudo-four component synthesis of 2,4,6- triphenylpyridines [113] (Scheme 1 47d)
Scheme 1 47: Methodology synthesized 2,4,6, tri-substituted pyridines [110-113].
In traditional strategies, polysubstituted pyridines have been generated via the combination of ketoxime acetates and aldehydes or N,N-dialkylanilines in the presence of transition metal catalysis Recently, a more useful method was explored by Fu and Chen for preparation of polysubstituted pyridines through copper-catalyzed
47 oxidative sp 3 C−H coupling of oxime acetates with toluene derivatives Furthermore, the diversity of this reaction was enriched with the effective participation of benzylamine and p-toluenesulfonylhydrazone (Scheme 1 48) It is worth mentioning that these reactions are fascinating, obtaining a range of polysubstituted pyridines through a useful, efficient, and simple method by using easily available starting materials [80]
Scheme 1 48:Coupling reaction of oximes acetates with toluene derivatives via Csp 3 –
Surprisingly, in the exploration of a 2,4,6-triphenylpyridine synthesis, the way involves reaction of oximes derivatives have gained significantly notification In 2011, Ren and co-workers reported Cu-catalyzed synthesis of 2,4,6-triphenylpyridine with ketoxime acetates (Scheme 1 49a) The challenges of the reactions include the cleavage of the N-O bond in oxime carboxylates and coupling of two electrophiles is subject to an efficient reducing agent in the reaction system In this transformation, NaHSO 3 was discovered as a good inhibitor of hydrolysis of oxime acetates [114]
35: The Chichibabin reaction [87]
In 1981, Boger and co-workers developed an inverse electron depend on aza-Diels–
Alder reaction between enamines and 1,2,4-triazine [93] (Scheme 1 36) Despite the convenience and simplicity of this pyridine annulation, this reaction also met some limitations that have proven to restrict the applicability of the reaction The first one was that the requirement for a preformed pyrrolidine enamine, a venture approached
38 with some concern when complex or valuable synthetic intermediates are involved
The second one was that the instability of some enamines, which often precludes their purification and occasionally isolation.
36: The aza-Diels–Alder approach to pyridine derivatives [93]
The synthesis of optically active 1-substituted 2-[(2S)-2-pyrrolidinyl] pyridine from L-proline was successfully implemented by Chelucci and co-workers in 1990 [94]
(Scheme 1 37) According to authors, the key intermediate 2-[(2S)-2-pyrrolidinyl] pyridine (3) was prepared from (2S)-1-benzyloxycarbonyl-2-cyanopyrrolidine (1) In the beginning, this reaction was carried out in the presence of cobalt (I) catalyzed co- cyclotrimerization of the nitrile with acetylene to gain 82% yield of 2-[(2S)-1- benzyloxycarbonyl-2- pyrrolidinyl] pyridine (2) After that, deprotection of (2) occurred smoothly by heating under reflux for 2 h in 6 N hydrochloric solution, (3) was established with 92% yield At the end, the derivatives were formed by treating
(3) in suitable condition to achieve (4) or (5) with 91% and 93%, respectively
Scheme 1 37: Synthesized 1-substituted 2-[(2S)-2-pyrrolidinyl] pyridine from L-proline
With the evolution of technologies and sciences, in 1997, a modern equipment called microwave was applied for the parallel synthesis of diverse substituted pyridines using the Hantzsch synthesis The microwave-assisted chemistry brings a great number of advantages such as a broad range of available chemistries, simple reaction setup and product recovery readily amenable to automation, extremely short reaction times, and high product yields [95]
The synthetic method was reported to obtain pyridines on a multigram scale in a one pot microwave reaction using bentonite clay as a support and ammonium nitrate as the source of ammonia and oxidant (nitric acid) For instance, utilizing benzaldehyde gave only 5% yield of the 4-phenyl pyridine derivative and a 75% yield of the C4- unsubstituted pyridine (scheme 38a) Moreover, the diversity is further expanded due to the fact that when two different 1,3-dicarbonyl compounds are used together in a single Hantzseh synthesis, three distinct pyridine derivatives can potentially be formed
Scheme 1 38: Microwave-assisted organic synthesis of substituted pyridines from
At the same time, thanks to employing the tert-butylimine instead of methyl,isopropyl, allyl, and benzyl imines, the application of annulation processes substantially improved results with a variety of alkynes The reaction of the tertbutylimines with 2 equiv of an alkyne in the presence of 5 mol % Pd(OAc) 2 , 10 mol % PPh 3 , and 1 equiv of Na 2 CO 3 in DMF as the solvent at 100 °C affords the desired substituted pyridine products in excellent yields in short reaction times (2h)
Scheme 1 39: Synthesis of pyridines via palladium-catalyzed iminoannulation of internal acetylenes [96].
In 2009, Otterlo and Koning successfully applied ring-closing metathesis (RCM) method for synthesis of numerous aromatic compounds, which inspired motivation for vast of scientist in the field of nature compound containing aromatic or heteroaromatic, which is the important skeletal core in many biological processes [97], and subsequently, ring-closing metathesis has proven to be one of the most utilized
41 chemical breakthroughs of the twentieth century Following this great success, Donohoe and co-workers exploited this method for the synthesis of heteroaromatics: evaluating routes to pyridines by applying this technology for the multistep transformation of 2,6-di- and 2,3,6-trisubstituted pyridines with alkyl, aryl, and alkoxy substituents [98] (Scheme 1 40)
Scheme 1 40: Ring-closing metathesis strategy for pyridine synthesis using acrylamide entry to synthesize pyridines [98].
Recently, tremendous efforts have been made in the field of transition metal- catalyzed cyclizations and cross-coupling reactions to afford functionalized pyridine derivatives For example, rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives from alkynes and α,β unsaturated imines has been achieved by Ellman and Cheng [99, 100] (Scheme 1 41a,b) In contrast to other traditional methods for pyridine synthesis, rhodium-catalyzed C-H activation does not require the use of activated precursors and is tolerant of a variety of functional groups Moreover, numerous transition-metal catalysts such as Pd, Fe, Cu could also be used to afford a structurally diverse set of pyridine derivatives through cross-coupling transformation
Scheme 1 41: Rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives [99, 100]
Scheme 1 42: Transition metal -catalyzed cross-coupling of activated pyridines
In 2009, cyclopropanols were used as a precursor of beta-carbonyl radicals and the investigation of their addition reactions toward vinyl azides (Scheme 1 43) The reactions were carried out by treatment of a mixture of vinyl azides (0.3 mmol) and cyclopropanols (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at room temperature under N 2 atmosphere for 5 min followed by addition of AcOH (2 equiv) With the optimized reaction conditions at hand, the scope of this Mn(III)-mediated pyridine formation was investigated to form various 2,6-diarylpyridines in good yields [103]
Scheme 1 43: Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl Azides to form 2,6-diphenylpyridine [103].
Due to the importance of pyridine derivatives in chemical synthesis, the development of a more concise and straightforward procedure for acquisition of pyridine derivatives from easily available starting materials is still highly desirable in order to overcome the limitation of relatively harsh reaction conditions, the utilization of the costly starting materials, unstable nature of the precursors, expensive noble metal catalysts, tedious operations [80] In conventional methodology, ketoxime carboxylates are well-known fruitful candidates for the Beckmann rearrangement reactions to prepare amides or for the dehydration reactions to produce nitriles.
Nowadays, oxime derivatives have emerged as internal oxidants and versatile building blocks for constructing polysubstituted pyridines through transition metal-catalyzed coupling reactions.
In 2015, Jiang and co-workers successfully achieved the Cu-catalyzed three- component cascade annulation reaction from acetophenone oxime acetate, paraformaldehyde and ethyl acetoacetate (Scheme 1 44) This strategy featured inexpensive catalysts, no need of extra oxidant and accessible reagents Notably, various substrate scopes such as activated methylene compounds, oxime acetates and aldehydes were employed for the preparation of 2,3,5-trisubstituted pyridines with the moderate to excellent corresponding yields [81]
Scheme 1 44: Synthesis of functionalized pyridines via Cu-catalyzed three- component cascade annulation reaction [81].
Notably, heterogeneous catalysis has performed an indispensable task in chemical and pharmaceutical industries as compared to homogeneous one, generally offering the minimization of toxic and hazardous waste In particular, metal –organic frameworks (MOFs) have emerged as environmentally benign alternatives for catalysis Notably, Phuong and co-workers have successfully conducted the cyclization reaction of N,N-dialkylanilines with ketoxime carboxylates to produce aryl-substituted pyridines utilizing Iron-organic framework Fe 3 O(BPDC) 3 as an productive heterogeneous catalyst (Scheme 1 45) This Fe-MOF would be active for organic reactions involving the redox transformation of Fe (II) / Fe (III) [104]
Scheme 1 45: The cyclization between (E)-acetophenone O-acetyl oxime acetate and
N,N-dimethylaniline utilizing iron-organic framework catalyst [104].
In 2016, a metal-free protocol with the combinational employment of iodine and triethylamine has been demonstrated to be effective to trigger the oxime-based synthesis of pyridines with high chemo-selectivity and wide functional group tolerance Herein, the resultant 2-aryl-substituted pyridines were synthesized from O- acetyl ketoxime and α,β-unsaturated aldehyde in the presence of both iodine and triethylamine at 120 o C for 3h (Scheme 1 46a) [105] One year later, the transition-
45 metal-free N−O reduction of Oximes using an NH 4 I-based system was explored by Huang and co-workers In comparison with traditional condensation methods such as Hantzsch pyridine synthesis, this protocol was found to be highly regio- and chemoselective with a broad range of pharmacologically significant fluorinated pyridines and presented broad functional group tolerance (Scheme 1 46b) [106].
Remarkably, these chemical procedures under metal-free conditions are always of significance especially in the pharmaceutical industry and environmental friendliness.
Scheme 1 46: Metal-free assembly of polysubstituted pyridines from oximes [105,
In recent years, the derivatives, 2,4,6-trisubstituted pyridines have been broadly applied for chemosensors [107], asymmetric catalyst [108] or as photosensitizers [109] Such moieties are also very important in building blocks because of their π- stacking ability in conjunction with directional H-bonding capacity Furthermore, they can be used as monometric building blocks in thin films and organometallic polymers thank to its thermal stabilities
For the past few years, the most commonly used approaches to 2,4,6-trisubstituted pyridines involve cyclo-condensation reaction of acetophenone, benzaldehydes with ammonium acetate and a variety of new catalysts or conditions have been reported In 2013, Huang and co-workers revealed a Cu-catalyzed synthesis of 2,4,6- triphenylpyridine with acetophenone and benzylamine under the neat condition [110]
(Scheme 1 47a) Xu and co-workers also introduced a metal-free synthesis of 2,4,6- trisubstituted pyridines via idodine-initiated reaction of methyl aryl ketones with
38: Microwave-assisted organic synthesis of substituted pyridines from 1,3-dicarbonyl compounds and aldehydes [95]
At the same time, thanks to employing the tert-butylimine instead of methyl,isopropyl, allyl, and benzyl imines, the application of annulation processes substantially improved results with a variety of alkynes The reaction of the tertbutylimines with 2 equiv of an alkyne in the presence of 5 mol % Pd(OAc) 2 , 10 mol % PPh 3 , and 1 equiv of Na 2 CO 3 in DMF as the solvent at 100 °C affords the desired substituted pyridine products in excellent yields in short reaction times (2h)
39: Synthesis of pyridines via palladium-catalyzed iminoannulation of
In 2009, Otterlo and Koning successfully applied ring-closing metathesis (RCM) method for synthesis of numerous aromatic compounds, which inspired motivation for vast of scientist in the field of nature compound containing aromatic or heteroaromatic, which is the important skeletal core in many biological processes [97], and subsequently, ring-closing metathesis has proven to be one of the most utilized
41 chemical breakthroughs of the twentieth century Following this great success, Donohoe and co-workers exploited this method for the synthesis of heteroaromatics: evaluating routes to pyridines by applying this technology for the multistep transformation of 2,6-di- and 2,3,6-trisubstituted pyridines with alkyl, aryl, and alkoxy substituents [98] (Scheme 1 40).
40: Ring-closing metathesis strategy for pyridine synthesis using
acrylamide entry to synthesize pyridines [98].
Recently, tremendous efforts have been made in the field of transition metal- catalyzed cyclizations and cross-coupling reactions to afford functionalized pyridine derivatives For example, rhodium-catalyzed cycloaddition reaction for the formation of pyridine derivatives from alkynes and α,β unsaturated imines has been achieved by Ellman and Cheng [99, 100] (Scheme 1 41a,b) In contrast to other traditional methods for pyridine synthesis, rhodium-catalyzed C-H activation does not require the use of activated precursors and is tolerant of a variety of functional groups Moreover, numerous transition-metal catalysts such as Pd, Fe, Cu could also be used to afford a structurally diverse set of pyridine derivatives through cross-coupling transformation
41: Rhodium-catalyzed cycloaddition reaction for the formation of pyridine
42: Transition metal -catalyzed cross-coupling of activated pyridines
In 2009, cyclopropanols were used as a precursor of beta-carbonyl radicals and the investigation of their addition reactions toward vinyl azides (Scheme 1 43) The reactions were carried out by treatment of a mixture of vinyl azides (0.3 mmol) and cyclopropanols (1.5 equiv) with Mn(acac)3 (1.7 equiv) in MeOH at room temperature under N 2 atmosphere for 5 min followed by addition of AcOH (2 equiv) With the optimized reaction conditions at hand, the scope of this Mn(III)-mediated pyridine formation was investigated to form various 2,6-diarylpyridines in good yields [103]
43: Mn(III)-Mediated Reactions of Cyclopropanols with Vinyl Azides to
Due to the importance of pyridine derivatives in chemical synthesis, the development of a more concise and straightforward procedure for acquisition of pyridine derivatives from easily available starting materials is still highly desirable in order to overcome the limitation of relatively harsh reaction conditions, the utilization of the costly starting materials, unstable nature of the precursors, expensive noble metal catalysts, tedious operations [80] In conventional methodology, ketoxime carboxylates are well-known fruitful candidates for the Beckmann rearrangement reactions to prepare amides or for the dehydration reactions to produce nitriles.
Nowadays, oxime derivatives have emerged as internal oxidants and versatile building blocks for constructing polysubstituted pyridines through transition metal-catalyzed coupling reactions.
In 2015, Jiang and co-workers successfully achieved the Cu-catalyzed three- component cascade annulation reaction from acetophenone oxime acetate, paraformaldehyde and ethyl acetoacetate (Scheme 1 44) This strategy featured inexpensive catalysts, no need of extra oxidant and accessible reagents Notably, various substrate scopes such as activated methylene compounds, oxime acetates and aldehydes were employed for the preparation of 2,3,5-trisubstituted pyridines with the moderate to excellent corresponding yields [81]
Scheme 1 44: Synthesis of functionalized pyridines via Cu-catalyzed three- component cascade annulation reaction [81].
Notably, heterogeneous catalysis has performed an indispensable task in chemical and pharmaceutical industries as compared to homogeneous one, generally offering the minimization of toxic and hazardous waste In particular, metal –organic frameworks (MOFs) have emerged as environmentally benign alternatives for catalysis Notably, Phuong and co-workers have successfully conducted the cyclization reaction of N,N-dialkylanilines with ketoxime carboxylates to produce aryl-substituted pyridines utilizing Iron-organic framework Fe 3 O(BPDC) 3 as an productive heterogeneous catalyst (Scheme 1 45) This Fe-MOF would be active for organic reactions involving the redox transformation of Fe (II) / Fe (III) [104].
45: The cyclization between (E)-acetophenone O-acetyl oxime acetate and N,N-dimethylaniline utilizing iron-organic framework catalyst [104]
N,N-dimethylaniline utilizing iron-organic framework catalyst [104].
In 2016, a metal-free protocol with the combinational employment of iodine and triethylamine has been demonstrated to be effective to trigger the oxime-based synthesis of pyridines with high chemo-selectivity and wide functional group tolerance Herein, the resultant 2-aryl-substituted pyridines were synthesized from O- acetyl ketoxime and α,β-unsaturated aldehyde in the presence of both iodine and triethylamine at 120 o C for 3h (Scheme 1 46a) [105] One year later, the transition-
45 metal-free N−O reduction of Oximes using an NH 4 I-based system was explored by Huang and co-workers In comparison with traditional condensation methods such as Hantzsch pyridine synthesis, this protocol was found to be highly regio- and chemoselective with a broad range of pharmacologically significant fluorinated pyridines and presented broad functional group tolerance (Scheme 1 46b) [106].
Remarkably, these chemical procedures under metal-free conditions are always of significance especially in the pharmaceutical industry and environmental friendliness.
46: Metal-free assembly of polysubstituted pyridines from oximes [105, 106]
In recent years, the derivatives, 2,4,6-trisubstituted pyridines have been broadly applied for chemosensors [107], asymmetric catalyst [108] or as photosensitizers [109] Such moieties are also very important in building blocks because of their π- stacking ability in conjunction with directional H-bonding capacity Furthermore, they can be used as monometric building blocks in thin films and organometallic polymers thank to its thermal stabilities
For the past few years, the most commonly used approaches to 2,4,6-trisubstituted pyridines involve cyclo-condensation reaction of acetophenone, benzaldehydes with ammonium acetate and a variety of new catalysts or conditions have been reported In 2013, Huang and co-workers revealed a Cu-catalyzed synthesis of 2,4,6- triphenylpyridine with acetophenone and benzylamine under the neat condition [110]
(Scheme 1 47a) Xu and co-workers also introduced a metal-free synthesis of 2,4,6- trisubstituted pyridines via idodine-initiated reaction of methyl aryl ketones with
46 amines under neat heating in 2016 [111] (Scheme 1 47b) In 2017, one-pot synthesis of 2,4,6-triphenylpyridine via copper-catalyzed coupling reactions was reported by Han and co-workers [112] (Scheme 1 47c) and in the same time, Chen and co- workers also conducted cerium(IV) carboxy-methylcellulose as an efficient and reusable catalyst for the one-pot pseudo-four component synthesis of 2,4,6- triphenylpyridines [113] (Scheme 1 47d).
47: Methodology synthesized 2,4,6, tri-substituted pyridines [110-113]
In traditional strategies, polysubstituted pyridines have been generated via the combination of ketoxime acetates and aldehydes or N,N-dialkylanilines in the presence of transition metal catalysis Recently, a more useful method was explored by Fu and Chen for preparation of polysubstituted pyridines through copper-catalyzed
47 oxidative sp 3 C−H coupling of oxime acetates with toluene derivatives Furthermore, the diversity of this reaction was enriched with the effective participation of benzylamine and p-toluenesulfonylhydrazone (Scheme 1 48) It is worth mentioning that these reactions are fascinating, obtaining a range of polysubstituted pyridines through a useful, efficient, and simple method by using easily available starting materials [80]
Scheme 1 48:Coupling reaction of oximes acetates with toluene derivatives via Csp 3 –
Surprisingly, in the exploration of a 2,4,6-triphenylpyridine synthesis, the way involves reaction of oximes derivatives have gained significantly notification In 2011, Ren and co-workers reported Cu-catalyzed synthesis of 2,4,6-triphenylpyridine with ketoxime acetates (Scheme 1 49a) The challenges of the reactions include the cleavage of the N-O bond in oxime carboxylates and coupling of two electrophiles is subject to an efficient reducing agent in the reaction system In this transformation, NaHSO 3 was discovered as a good inhibitor of hydrolysis of oxime acetates [114]
Iron salts represent some of the cheapest and most environmental friendly transition metal catalysts In the past decades, a variety of iron-catalyzed coupling or oxidative reactions have been developed and established to be particularly viable in organic synthesis However, Fe-catalyzed transformations of ketoxime acetates have rarely been studied In the same time, Zhao and co-workers continued to publish a unprecedented and efficient iron-catalyzed cyclization of ketoxime carboxylates and
N,N-dialkylanilines for the modular synthesis of 2,4,6-substituted pyridine [115]
(Scheme 1 49b) In this reaction, the methylene carbon on N-N-dialkylanilines plays a role as the source of one-carbon synthon under oxidative conditions To improve the atom-economy and efficiency of the cyclization reaction, in 2017, Yi and co-workers carried out a synthesis of symmetrical pyridines by using directly aldehyde as the source of one-carbon synthon and ketoxime acetates in the presence of iron catalyst
Scheme 1 49:Some recent methodology synthesized 2,4,6- trisubstituted pyridines via oxime derivatives [80, 114-116].
To sum up, 2,4,6-trisubstituted pyridines with extraordinary benefits, which attracted the interests and curiosity of wide range of researchers all over the world In this context, the transformation of this pyridines through oximes derivatives still remain much potential and need more great discovery Thus, to remedy the demand 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 2,4,6- trisubstituted pyridines derivatives starting from available and green materials One more notice point in this report is that dibenzyl ether seems much more stable when stored in laboratory condition and friendly with environment
49 in comparison with other reactants have been reported before such as benzaldehyde or toluene derivatives To the best of our knowledge, for the first time, we developed a mixed-linker heterogeneous catalytic strategy for the cyclization via C–H bond activation/N–O bond cleavage to produce 2,4,6-trisubstituted pyridines from oxime acetates and dibenzyl ether
As presented above, Cu-MOF-74 and the mixed-linker VNU-20 demonstrating many advantageous features has been proven as a potential candidate for heterogeneous catalyst Towards the friendly environment, the catalyst recovery has brought many attentions in the future Previous reports, which exploited homogeneous catalysts for many similar transformations [46, 114-116], feature tolerance of a wide range of functional groups, easily available starting materials, simple operation, mild reaction conditions and environmental friendliness, but these homogeneous catalysts cannot be separated from the reaction medium to reused The development of MOFs ,which have special properties such as large specific surface are, unreached porosity, high thermal stability and wide chemical inorganic-organic composition, has created a breakthrough in catalysis for the organic chemistry MOFs not only generate product with high yield but also can reuse several times without any degradation in catalytic activity
Thus, the two reactions in the presence of available reactants making advantage of the metal-organic frameworks were conducted
A new statergy, using Cu-MOF-74 for the reaction of 2-phenylindole and phenethylamine will be introduced for the first time Simultaneously, the reaction will be expanded by varying the scope of amines to obtain various products for the pharmaceutical industry and organic chemistry (Scheme 1 50)
Scheme 1 50:The reaction between 2-phenylindole and 2-phenylethanamine utilizing
The novel cyclization reaction between ketoxime carboxylate and dibenzyl ether to constitute pyridine derivatives, which has not been mentioned before, will be conducted in the presence of the mixed-linker iron-based metal-organic frameworks VNU-20 as efficient heterogeneous catalysts In comparison with MOFs assembled from a single type of organic linker, the new generation of this materials, which not only inherit good properties of present MOFs but also gained more new useful characteristics (Scheme 1 51)
Scheme 1 51:The cyclization of ketoxime acetates and dibenzyl ether using VNU-20 as a heterogeneous catalyst.
All reagents and starting materials were obtained commercially from Sigma–
Aldrich, Across, Guangzhou, and Merck were used as received without any further purification unless otherwise noted (Table 2 1)
Table 2 1:List of the utilized substances and their providers
2-Phenethylamine (99%) C 8 H 11 N Sigma-Aldrich Copper (II) nitrate trihydrate Cu(NO 3 ) 2 3H 2 O Acros
Anhydride acetic (CH 3 CO) 2 O Acros
Ethyl acetate CH 3 COOC 2 H 5 Acros
Iron (II) chloride (anhydrous) FeCl 2 Sigma-Aldrich Hydroxylamine hydrochloride NH 2 OH.HCl Sigma-Aldrich
Potassium carbonate K 2 CO 3 Sigma-Aldrich
Di-tert-butyl peroxide (98%) C 8 H 18 O 2 Sigma-Aldrich 1,3,5-benzenetricarboxylic acid C 9 H 6 O 6 Sigma-Aldrich
Powder X-ray diffraction (PXRD) patterns were recorded using a D8 Advance diffractometer equipped with a LYNXEYE detector Fourier transform infrared (FT- IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets Scanning electron microscopy studies were conducted on a JSM 740 scanning electron microscope (SEM) Transmission electron microscopy studies were performed using a JEOL JEM 1400 transmission electron micro-scope (TEM) at 100 kV The Cu-MOF-74 samples were dispersed on holey carbon grids for TEM observation A NetzschThermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 °C/min under a nitrogen atmosphere Nitrogen physisorption measurements were conducted using an ASAP 2020 system Samples were pretreated by heating under vacuum at 140 °C for 3h The chemisorption experiments were studied in a Micromeritics 2020 analyzer Elemental analysis with atomic absorption spectrophotometry (AAS) was performed on an AA- 6800 Shimadzu
Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 2010- PLUS equipped with a flame ionization detector (FID) and a SPB-5 column (length 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 m) In the first reaction, the temperature program for GC analysis held samples at 100 o C for 0.5 min; heated them from 100 to 130 o C at 40 o C/min; held them at 130 o C for 1 min; heated them from 130 to 180 o C at 40 o C/min; and finally held them at 280 o C for 14 min Inlet and detector temperatures were set constant at 280 o C In the second reaction, the temperature program for GC analysis held samples at 160 o C for 1 min, heated samples from 160 oC to 280 o C at 40 o C/min and were hold for 8 min Inlet and detector temperatures were set constant at 280 o C
Diphenyl ether was used as an internal standard to calculate reaction yields 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
53 temperature program for GC-MS analysis held samples at 50 o C for 2 min; heated samples from 50 to 280 o Cat 10 o C/min and held them at 280 o C for 10 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library The 1 H NMR and 13 C NMR were recorded on Bruker AV 500 spectrometers using residual solvent peak as a reference
2.2 Synthesis of the metal-organic framworks (MOFs) 2.2.1 Synthesis of Cu-MOF-74
In a typical preparation (Scheme 2 1), a solid mixture of H 2 dhtp (H 2 dhtp = 2,5- dihydroxyterephthalic acid; 0.94 mmol, 0.186 g), and copper (II) nitrate trihydrate (2.07 mmol, 0.5 g) was dissolved in a mixture of DMF (20 mL) The mixture was vigorously stirred for 10 min, and isopropanol (1 mL) was then added to produce a clear greenish solution Reddish crystals were generated on the wall of the vials during the time of the experiment The resulting solution was then distributed into vials The vials were heated at 85 o C in an isothermal oven for 18 h After cooling the vials to room temperature, the crystals were collected by decantation, and washed carefully with DMF (3 x 20 mL) The solid was then immersed in methanol (3 x 20 mL) at ambient temperature for solvent interchange Afterwards, the product was dried at 150 oC under vacuum in a shlenkline for 5 h, producing 0.260 g of Cu 2 (dhtp) in the shape of reddish black crystals (60 % yield regarding 2,5-dihydroxyterephthalic acid)
Scheme 2 1: Synthetic reaction of Cu 2 (dhtp) or Cu-MOF-74 [34].
According to a previous literature procedure [44], the mixture of FeCl 2 (0.09 g, 0.705 mmol); 1,3,5-benzene tricarboxylic acid (H 3 BTC, 0.03 g, 0.112 mmol)and 2,6- naphthalene dicarboxylic acid (H 2 NDC, 0.09 g, 0.42 mmol) were dissolved in N,N- dimethylformamide (DMF,12 mL), and then were sonicated for 5 minutes to achieve a clear solution Next, this solution was divided into glass tubes, which was sealed and placed in an isothermal oven at 200 o C for 72 h to build the reddish crystal of VNU-20 Then, VNU-20 crystal was purified by DMF (5 x 15 mL, three days) and methanol (5 x 15 mL, four days) Consequently, this crystal was activated under dynamic vacuum to obtain activated VNU-20 (0.057 g, yield: 75 % base on H 3 BTC), which is the sample utilized as a heterogeneous catalyst during the experiment (Scheme 2 2)
Scheme 2 2: Self-assembling synthesis of the reddish-yellow crystal (VNU-20) [44]
2.3 Catalytic tests 2.3.1 Catalytic studies in the expansion reaction to produce 2-arylquinazolinones
2: Self-assembling synthesis of the reddish-yellow crystal (VNU-20) [44]
Scheme 2 2: Self-assembling synthesis of the reddish-yellow crystal (VNU-20) [44]
2.3 Catalytic tests 2.3.1 Catalytic studies in the expansion reaction to produce 2-arylquinazolinones
The typical experiments were carried out according to the general procedure To a pressurized vial were introduced a mixture of 2-phenylindole (0.4831 g, 0.25 mmol), 2-phenylethanamine (0.1212 g, 1 mmol) and Cu-MOF-74 (0.0040 g, 10 mol%) as the catalyst The catalyst amount was weighed respecting copper/2-phenylindole mole ratio After that, the reaction solvent, N N’-dimethylformamide, (2 mL) was added into the mixture by a pipette The reaction solution was stirred magnetically at 80 o C for 24h under oxygen atmosphere After the reaction was finished, the internal standard, diphenyl ether (0.0425 g, 0.25 mmol) was introduced to the sample to compare
55 relatively with the amount of desired product The sample was quenched with water (5 mL) and extracted with ethyl acetat (2 x 5 mL) to obtain organic components Then, the solution was dried over anhydrous Na 2 SO 4 and analyzed by GC with reference to diphenyl ether The expected product, 3-phenethyl-2-phenylquinazolin-4(3H)-one, was isolated on silicagel by column chromatography The product character was also authenticated by 1 H-NMR, 13 C-NMR, and GC-MS
During the heterogeneous catalyzed reaction, the catalytically active metal species might be released from the MOFs structure into the liquid phase and furthermore exhibit remarkable catalytic activity, then the reaction is not truly heterogeneously catalyzed To examine the hypothesis, the leaching test was conducted at 80 o C in DMF with the molar ratio of 2-phenylindole:2-phenylethanamine = 1:4 and in the presence of 7.5 mol% Cu 2 (dhtp) as catalyst After 3 h reaction time, the GC-yield was recorded and the solid catalyst was separated from the reaction mixture by centrifugation A reaction solution was then transferred into a new reactor vial, and stirred for further conversion at 80 o C with aliquots being sampled at different time intervals, and analyzed by GC
The recyclability of the Cu 2 (dhtp) were also carried out according to the following procedure in order to test the stability of the solid catalyst The first run of typical reaction was conducted at 80 o C in DMF, using 7.5 mol% Cu 2 (dhtp) as catalyst After 24 h, the copper-based framework was separated by simple filtration, and washed meticulously with large amounts of DMF and dichloromethane, dried at 150 o C under vacuum in a Shlenkline, and reused for new catalytic run until its activity was significantly degraded
2.3.2 Catalytic studies in the cyclization reaction of ketoxime acetates and dibenzyl ether to synthesize 2,4,6-triphenyl pyridine Synthesis of ketoxime acetates
In the first step, a mixture of acetophenones (2.64 g, 22 mmol), hydroxylamine hydrochloride (2.294 g, 33 mmol), ethanol (10 mL) was introduced to a 50 mL erlenmeyer flask The reaction mixture was magnetically stirred for 3 minutes and
56 heated to 80 o C Afterwards, potassium carbonate (K 2 CO 3 , 4.209 g, 30.5 mmol) was slowly added into the mixture The sample was withdrawn and monitored by TLC every 2 hours until acetophenone was completely conversed into the acetophenone oxime Subsequently, the reaction mixture was cooled to room temperature and then transferred to a 250-mL separatory funnel containing 30 mL water and 60 mL ethyl acetat The mixture is partitioned, and the ethyl acetatat layer was obtained The organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduce pressure The residue was then purified by recrystallization from hexane to obtain pure acetophenone oxime
In the second step, a mixture of acetophenones oxime, anhydride acetic (3.366 g, 33 mmol), ethyl acetate (10 ml) was added to a 50 mL erlenmeyer flask and magnetically stirred at room temperature Then, potassium carbonate (4.209 g, 30.5 mmol) was slowly added into the mixture The sample was withdrawn and monitored by TLC every 2 hours until acetophenone oxime was completely conversed into the acetophenone oxime acetate The sample was continue to extract and purify as the first step to obtain pure (E)-acetophenone O-acetyl oxime acetate
Catalytic studies in the synthesis of 2,4,6-triphenyl pyridine
In a particular experiment, a mixture of dibenzyl ether (0.0198 g, 0.1 mmol), (E)- acetophenone O-acetyl oxime acetate (0.0708 g, 0.4 mmol), chlorobenzene (1 mL), and diphenyl ether (0.017 g, 0.1 mmol) as an internal standard were added into 12 mL pressurized vial containing pre-determined amount of VNU-20 (0.003 g, 0.01 mmol)
The reaction mixture was magnetically stirred at 140 o C for 5 minutes to disperse the Fe-MOF catalyst in the liquid phase Subsequently, di-tert butyl peroxide (DTBP, 2 equivalents) was injected and the resulting mixture was stirred at 140 o C for 6 hours under an argon atmosphere to obtain the expected product
After the reaction was completed, the resulting sample was cooled down to ambient temperature, soaked with water (5 mL) and extracted with ethyl acetate (2 x 5 mL) to collect the organic layer The solution was then dried over anhydrous Na 2 SO 4 before it was withdrawn to analyze by GC Subsequently, the treated solution was concentrated
57 under reduced pressure The remain residue was further purified by column chromatography on silica gel (ethyl acetate/hexane = 1:20) to afford the product 2,4,6- triphenyl pyridine as white crystalline solid (85%, isolated yield based on the reactant dibenzyl ether) The product characteristic was further authenticated by 1 H NMR, 13 C NMR and GC-MS
For the leaching test, the catalytic reaction was stopped after the first 3 hour, analyzed by GC, and centrifuged to remove the solid catalyst After that, the reaction mixture was continue to heat to 140 o C in the absence of VNU-20 catalyst for extra hours The formation of 2,4,6-triphenyl pyridine during the experiment, if any, was probed by GC
For the catalyst reusability experiment, the VNU-20 catalyst was separated from the reaction mixture by centrifugation, washed with abounding amount of anhydrous DMF and DCM, dried at 100 o C under vacuum condition on a Shlenkline for 6 h, and reused for the next run
3.1 The Cu-MOf-74-catalyzed Baeyer-Villiger oxidation expansion reaction to synthesize 2-arylquinazolinones 3.1.1 Synthesis and characterization of Cu-MOF-74
The copper-based metal-organic framework Cu-MOF-74 was synthesized according to a slightly modified literature procedure [40] as described in (Scheme 2 1) After the solvent exchange and activation, the Cu-MOF-74 as black crystal was yielded The synthesis yield was approximately 60% based on H 2 (dhtp).
Figure 3 1:PXRD patterns of the simulated (a) and synthesized (b) Cu-MOF-74 The X-ray diffraction patterns of Cu-MOF-74 (Figure 3 1) demonstrated the presence of very sharp peak at 2ϴ of approximately 7 o and 12 o , proving the highly
59 crystallinity of the Cu-MOF-74 The result was also similar to the simulated patterns previously reported in the literature It could approve that the structure of the Cu- MOF-74 was successfully formed