key: cord-0842262-b6nwr40i authors: Moghaddampour, Issa Mousazadeh; Shirini, Farhad; Langarudi, Mohaddeseh Safarpoor Nikoo title: Agar-entrapped sulfonated DABCO: A gelly acidic catalyst for the acceleration of one-pot synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine derivatives date: 2020-09-26 journal: J Mol Struct DOI: 10.1016/j.molstruc.2020.129336 sha: 01cbb3d8c75764da9ce3bac9dc099a69d78a5f79 doc_id: 842262 cord_uid: b6nwr40i In this project, a recently synthesized DABCO-based catalyst is entrapped in agar to reduce its moisture sensitivity leading to enhancement of its stability and catalytic activity. After preparation and identification this new reagent is used as an efficient and environmentally safe catalyst for the preparation of 1, 2, 4-triazoloquinazolinone and some pyrimidine derivatives. This method is accompanied with some superiorities such as, simple operation, mild and green conditions, use of low cost and non-hazardous natural material, short reaction times, easy preparation methods and simple work-up procedures. The prepared catalyst can be re-used for several times in all of the studied reactions without any appreciable loss in its activity. Agar is a hydrophilic, colloidal substance consisting of the polysaccharides extracted from Gelidium cartilogineumn Gaillon, Gracilaria confervoides Greville, and related red algae [1] , probably existing in the form of its calcium salt or a mixture of calcium and magnesium salts. It is a complex mixture of polysaccharides composed of two major fractions agarose, a neutral polymer, and agaropectin, a charged, sulfated polymer. Agarose, the gelling fraction, is a neutral linear molecule essentially free of sulfates, consisting of chains of repeating alternate units of β-1,3-linked D-galactose and α-1,4-linked 3,6-anhydro-L-galactose. Agaropectin, the non-gelling fraction, is a sulfated polysaccharide (3% to 10% sulfate), composed of agarose and varying percentages of ester sulfate, D-glucuronic acid, and small amounts of pyruvic acid. Agarose normally represents at least two-thirds of the natural agar ( Figure 1 ). Because of their special structural characteristics, triazoles are considered as important class of heterocyclic compounds showing interesting biological, pharmaceutical and therapeutic activities including antifungal [2] , antimicrobial [3] [4] [5] [6] [7] [8] , anti-cancer [9] , anticonvulsant [10] , antihypertensive [11] , and anti-viral [12] . In this regard many drugs containing triazole moiety are manufactured, which of them Ribavirin or Copegus (an antiviral), Alprazolam (an anxiolytic), Letrozole (an anticancer), and Flusilazole (an organosilicon fungicide) [13] are examples ( Figure 2a) . Uracil, as one of the four nucleobases in the nucleic acid, is a common and naturally occurring pyrimidine derivative. In RNA uracil binds to adenine via two hydrogen bonds, and in DNA the uracil nucleobase is replaced by thymine. This considerable interest is correlated with a huge range of biological activities such as, antitumor [14] , antifolate [15] , antihypertensive [16] , and cardio tonic (may be prescribed when the heart is not pumping enough blood to supply other organs) [17] . A number of popular drugs including the uracil moiety are Sofosbuvir (a new antiviral for COVID-19) [18] , Uramustine (a chemotropic drug that damage DNA) [19] and Uridine monophosphate (a nucleotide that is used as a monomer in RNA) [20] (Figure 2b ). Recently the remedial effect in COVID-19 (human coronavirus) patients was also observed that it has been proven by Ribavirin [21] . In recent years, a gel-entrapped-base catalysts (GEBCs), which in them the advantages of alkali and organic bases with those of heterogeneous supports are combined with each other is going to become an attractive concept for organic chemists. In this line, Salunkhe and co-workers reported the preparation of agar-agar entrapped-DABCO and its applicability in the promotion of the synthesis of 2-amino-4H-chromenes [22] . This strategy causes to reduce the amounts of the base used in the reactions and ease of the product isolation, along with making a cut in moisture absorption by the catalyst [23] . Recently we have reported the preparation of [DABCO] (SO 3 H) 2 (Cl) 2 as an acidic IL and its use in the acceleration of some of the multi-component reactions [24] , although the method is useful but its ability in the adsorption of moisture causes that its efficiency to be reduced. For this reason we motivated to use the above mentioned strategy to prepare, a gel entrapped acidic ionic liquid (GEAIL) by the entrapping of this reagent in agar for the first time. After identification the effect of this method on the moisture adsorption and catalytic ability of this reagent is studied in the synthesis of some triazole and uracil containing derivatives as an example. All solvents and materials, employed in this study, were purchased form Aldrich (Mumbai) and Merck Chemical Companies (Munich) and utilized without any further purification. Solvents were stored in airtight containers and had been distilled before being applied. To ensure about the purity of materials, they were checked with thin layer chromatography (TLC) on silica-gel poly-gram SILG/UV 254 plates and their melting points were compared with authenticated melting points in Merck and Aldrich indexes . Melting points were determined by electro-thermal IA9100 melting point apparatus in capillary tubes. The melting point range was input manually through keyboard and the material changes were visually monitored. FT-IR spectra were recorded on a Perkin-Elmer spectrum BX series with KBr plates for solid samples. 1 H NMR and 13 C NMR spectra were recorded on Bruker AV-400 and -500 using TMS (0.00 ppm) as internal standard and DMSO-d 6 as the solvent. The acidic ionic liquid was precisely prepared according to the reported procedure in the article [24] . In a 150 mL flask, 5.0 g agar in 50 mL water was heated at boiling point to be completely dissolved (Figure 3 To a mixture of aromatic aldehyde 1 (1 mmol), 3-amino-1,2,4-triazole 2 (1 mmol), and βdiketone (dimedone 3 , methyl acetoacetate 4 or 1,3-cyclohexadione 5) (1mmol), agar-entrapped catalyst (0.03 g for 6, 0.02 g for 7 and 8) was added in a 25 mL round-bottom flask. Then the mixture was stirred magnetically in the absence of solvent in an oil bath (100 o C) for the appropriate time. The reaction process was carefully monitored by TLC (n-hexane: ethyl acetate; 8:3). After completion of the reaction, 5 mL water was poured into the reaction medium and filtered off to separate the catalyst. Finally, the obtained precipitate was recrystallized from ethanol to afford the required product (6a-j, 7a-f, and 8a-g). The spectral data of new compounds are as follow: [1, 2, 4] Diethyl-7,7'-((hexane-1,6-diyl-bis(oxy))bis(4,1-phenylene))bis (5-methyl-4,7- 9-(2-Nitrophenyl)-5,6,7,9-tetrahydro- [1, 2, 4] triazolo [5,1- 9,9'-((Butane-1,4-diylbis(oxy))bis(4,1-phenylene))bis (5,6,7,9- 9,9'-((Hexane-1,6-diylbis(oxy))bis(4,1-phenylene))bis (5,6,7,9-tetrahydro-[1,2,4] triazolo [5,1-b] b]quinazolin-8(4H)-one (8d) IR (KBr, υ, To a mixture of aromatic aldehyde 1 (1 mmol), 3-amino-1,2,4-triazole 2 (1 mmol), and malononitrile 9 (1 mmol), in a 25 mL round-bottom flask, agar-entrapped catalyst (0.02 g) was added. Then the mixture was stirred magnetically under solvent-free conditions in an oil bath (100 o C) for the appropriate time. The progress of the reaction was carefully monitored by TLC (n-hexane: ethyl acetate; 4:1). After completion of the reaction, 5 mL water was poured into the reaction medium and then filtered off to separate the catalyst. Finally, the obtained precipitate was recrystallized from ethanol to afford the required product (10a-f). 2.6. General procedure for the preparation of pyrido [4,5- To a mixture of aromatic aldehyde 1 (1 mmol), 6-amino-1,3-dimethyluracil 11 (1 mmol), dimedone 3 (1 mmol) in a 25 mL round-bottom flask, 0.02 g agar-entrapped catalyst was added and 5 mL of ethanol/water (2:1) was poured on it. The mixture was stirred magnetically to dissolve all components at reflux temperature. The reaction process was carefully checked by TLC (n-hexane: ethyl acetate; 4: 1). After completion, the mixture was filtered off to separate the catalyst, which is solvated in the solvent. Recrystallization of the product from absolute ethanol led to the pure product (12a-h). Into a 25 mL round-bottom flask containing aldehyde 1 (1 mmol), 6-amino-1,3-dimethyluracil 11 (1 mmol), and malononitrile 9 (1 mmol), 5 mL ethanol and 0.03 g agar-entrapped catalyst were added. The mixture was stirred magnetically at 70 o C to dissolve all components. The precipitate of the product is appeared in the reaction medium after a short time. The reaction progress was traced to completion by TLC (n-hexane: ethyl acetate; 1: 4). After completion of the reaction, the mixture was filtered off and the obtained residue was washed with water to remove the catalyst. Finally, the crude product was recrystallized from ethanol if necessary (13a-i). When a molecule is entrapped in a linear polysaccharide through hydrogen bonding, it can be expected that the number and intensity of the peaks of its functional groups be decreases due to a lock in the structure (Figure 4 ). This phenomena can be seen by the comparison of the FT-IR spectra of free IL and agar-entrapped IL ( Figure 5 ). As shown in Figure 6 , the morphology of DABCO changed going through the entrapping process. However, DABCO has porous and irregular shape with tiny holes, it change to an aggregated particles due to hydrogen bonding between hydroxyl groups of IL and agar. TGA diagrams of agar, IL, and agar-entrapped IL are represented at Figure 7 , As shown, the major weight loss from agar-entrapped IL are happened between 369-681 o C (44.3 %) which is related to decomposition of the catalyst. Before that, the weight loss (28.89%) between 219 and 312 o C is attributed to the thermal decomposition of IL which is entrapped in agar. The weight loss from the catalyst between 62-157 o C is owing to the decomposition of agar and the removal of physically adsorbed water and organic solvents, which were used in creating the catalyst. In spite of great features of ionic liquids such as non-flammability, no miscibility with non-polar solvents, and negligible vapor pressure, these compounds are very sensitive on exposure to air and moisture. Moisture adsorption can be impacted on the properties of ILs; for example, can lead to a cut in the thermal stability or catalytic activity. For this reason, finding a protocol which increases the moisture resistance can be thoroughly vital. In order to show the effect of agar-trapping on the moisture adsorption of the selected IL, we carried out loss on drying test for agar, IL, and agar-entrapped IL using Karl-Fischer method in 4 steps during 36 hours at a standard temperature (23 o C) and 63 % relative humidity in the laboratory. The obtained results show an acceptable decrease in the amount of the moisture which can be observed by IL after its entrapping in agar ( Figure 8 ). As shown, the moisture adsorption decreased when the IL trapped in agar. It can be related to an increase in the H-bonding of catalyst with agar, as shown in Figure 4 , which cause to a cut in the positions which can H-bond with water [25] . After ensuring about the preparation of the catalyst, the catalytic activity of the entrapped IL was investigated in the synthesis of 1,2,4-triazolo[4,3-a]pyrimidine, pyrido [2,3-d] pyrimidine, pyrido [4,5-b] pyrimidine and 1,2,4triazoloquinazolinone derivatives. At first, to gain the best conditions for the reactions, the synthesis of 4-cholorobenzaldehyde derivatives of these types of compounds (6b, 8b, 10b, 12b, 13b) was investigated as models for all reactions. In the case of compounds 7a-f the optimization studies were done on benzaldehyde as a selected model. The results are collected in Table 1 . As shown, different amounts of catalyst and various conditions were used to optimize the reaction conditions in accuracy. Which is distinguished in the table, agar-entrapped IL is more effective when thermal conditions and protic solvents were used (7a, 8b, 12b, and 13b). However, this catalyst was able to accelerate the synthesis of 6b and 10b in the absence of solvent. On the basis of the obtained results the best conditions are determined as shown in Scheme 1. After optimization of the reaction conditions, we have developed our studies by utilization of miscellaneous aldehydes with withdrawal and/or donor functional groups. The obtained outcomes were collected in Table 2 . These results show that under the selected conditions the requested products can be obtained in high yields during accepteble reaction times with no considerable effect of the substituents on the aromatic ring. Because that, in spite of the aromatic aldehydes, a mixture of unidentified products were formed when aliphatic aldehydes were employed, the related results were not included in Table 2 . In this study some new triazole derivatives are prepared from bisaldehydes which their results are highlited in Table 2 . The mechanism starts from activation of aldehyde 1 via catalyst through H-bonding (intermadiate a). After that, the route divides to two pathways. In route 1, activated 1,3-diketone (enol b) makes for intermadiate a comes to c after loss water. If 3-amino-1,2,4-triazole 2 reacts with c through N 2 or N 3 H 2 , the obtained products can be different. If happened, aliphatic -CH in ring, assigned with red circle, should be split as a doublet with J=2 Hz. This peak appeared as a singlet in the 1 H NMR spectra of 6h, 7e, 7f, 8f, and 8g which approves 3-amino-1,2,4-triazole 2 participates in reaction through N 2 . On the other hand, owing to the replacement of 3-amino-1,2,4-triazole 2 with 6amino-1,3-dimethyluracil 11, the products 12a-h were produced path through intermediate f. In route 2, malononitrle 9 gets activated by catalyst to attack intermediate a and produce h as a key intermediate. Then whether 3-amino-1,2,4-triazole 2 or 6-amino-1,3-dimethyluracil 11, products 10a-f or 13a-i can be produced, going through intermediates i and k, respectively. But, by contrast, to produce product 10a-f, N 3 H 2 from 3-amino-1,2,4-triazole 2 should attack h, if not, product B prepares. The doublet peak about 5.5 ppm with J=2Hz in the 1 H NMR of 10f confirmed that the aliphatic -CH and -NH are in the neighborhood (Scheme 2) A brilliant feature of a catalyst which changes it as a convenient one is its recyclability. For investigation of this feature of our new catalyst, the synthesis of 4-chlorobenzaldehyde derivative in each reaction (6a, 8b, 10b, 12b, and 13b except 7a-f which benzaldehyde was used for the synthesis of 7a) is selected as model. After completion of the reaction and separation of the product the solvent is removed under vacuum at 50 o C. The obtained precipitate was eluted by diethyl ether and used for another reaction. This study showed that the catalyst can be reused at least for 3 consecutive runs without considerable decrease in its activity (Figure 9 ). In order to show the catalytic ability of the prepared reagent, the efficiency of agar-entrapped IL with some of the other catalysts in the synthesis of 5-amino-7-(4-chlorophenyl)-7,8-dihydro [1, 2, 4] triazolo [4,3-a] pyrimidine and 7amino-5-(4-chlorophenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile, is compered in Table 3 . This comparison implies that the selected reactions are carried out better using this new catalyst. We We hope that this newly reported idea can be a useful way for the stabilization of other moisture sensitive reagents leading to their broad range of applications in organic transformations. This article Agar-entrapped sulfonated DABCO: A gelly acidic catalyst for the acceleration of one-pot synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine derivatives The main advantages of this method are: introduction of novel protocols for the synthesis of 1,2,4-triazoloquinazolinone and some pyrimidine derivatives in mild and green conditions. Moreover, using small amounts of non-metal catalysts, high yields of products, no by-product and simple work-up procedures are added advantages of these procedures. It should be emphasized that the submission is original, not under consideration for publication elsewhere, and that all authors are aware of the submission and agree to its publication. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 2-b]-1,2,4-triazole-5(6H)-onessubstituted with ibuprofen: synthesis, characterization and evaluation of anti-inflammatory activity Sustainable synthesis of uridine-5′-monophosphate analogues by immobilized uracil phosphoribosyltransferase from Thermus thermophilus Studies on some N-bridged heterocycles derived from bis-[4-amino-5-mercapto-1,2,4-triazol-3-yl] alkanes Synthesis and antimicrobial activity of N-[(α-methyl)benzylidene]-(3-substituted-1,2,4-triazol-5-yl-thio)acetohydrazides, II Farmaco Synthesis and antimicrobial activities of some new Antimicrobial activities of some 4H-1,2,4-triazoles Design and synthesis of 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9-Aryl-6,6-dimethyl-5 Sulfamic acid-catalyzed, three-component, one-pot synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives A simple and convenient synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone and [1,2,4]triazolo[1,5-a]pyrimidine derivatives catalyzed by DABCO-based ionic liquids A three component one-pot procedure for the synthesis of [1,2,4]triazolo/benzimidazolo-quinazolinone derivatives in the presence of H 6 P 2 W 18 O 62 ·18H 2 O as a green and reusable catalyst A simple, convenient one-pot synthesis of [1,2,4]triazolo/benzimidazolo quinazolinone derivatives by using molecular iodine Synthesis of tetrahydrobenzimidazo[1,2-b]quinazolin-1(2H)-one and tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-one ring systems under solvent-free conditions An expeditious synthesis of tetrahydro-1,2,4-triazolo[5,1-b]quinazolin-8(4H)-ones and dihydro-1,2,4-triazolo[1,5-a]pyrimidines A rapid combinatorial library synthesis of benzazolo[2,1-b]quinazolinones and triazolo[2,1-b]quinazolinones, Iran Efficiency of NaHSO 4 modified periodic mesoporous organosilica magnetic nanoparticles as a new magnetically separable nanocatalyst in the synthesis of [1,2,4]triazolo quinazolinone/pyrimidine derivatives An efficient three component one-pot synthesis of 5-amino-7-aryl-7,8-dihydro DABCO-based ionic liquids: introduction of two metal-free catalysts for one-pot synthesis of 1,2,4-triazolo Cellulose sulfuric acid catalyzed multicomponent reaction for efficient synthesis of pyrimido and pyrazolo[4,5-b]quinolines under solvent-free conditions ]pyrimidine derivatives via multicomponent reactions in ionic liquid 1, 3-Disulfonic acid imidazolium hydrogen sulfate: a reusable and efficient ionic liquid for the one-pot multi-component synthesis of pyrimido An efficient synthesis of pyrido[2,3-d]pyrimidine derivatives via one-pot three-component reaction in aqueous media Efficient one-pot synthesis of pyrido[2,3-d]pyrimidines catalyzed by nanocrystalline MgO in water, Int One-pot synthesis of pyrido[2,3-d]pyrimidines via efficient three-component reaction in aqueous media Efficient synthesis of pyrano[2,3-d]pyrimidinone and pyrido[2,3-d]pyrimidine derivatives in presence of novel basic ionic liquid catalyst Efficient one-pot synthesis of multi-substituted triazolopyrimidines by using DBU as basic catalyst via MCR's Facile synthesis of pyridopyrimidine and coumarin fused pyridine libraries over a Lewis base-surfactantcombined catalyst TEOA in aqueous medium Al-HMS-20 catalyzed synthesis of pyrano[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines via three-component reaction We are thankful to the Research Council of University of Guilan for the partial support of this research.