Volume 29, Issue 7 (10-2022)
RJMS 2022, 29(7): 117-124 |
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Research code: 01
Ethics code: 01
Clinical trials code: 01
Department of Organic Chemistry, Faculty of Science, Sharif University of Technology, Tehran, Iran , mhashemi@sharif.edu
Abstract: (773 Views)
Background & Aims: Ionic liquids are organic salts composed of organic cations and organic and / or inorganic anions that have many remarkable properties and properties, such as wide liquid state range, low vapor pressure, easy recovery process, high ionic conductivity, wide electrochemical window and design capability. Structural engineering with appropriate modification to represent cations or anions. Recently, many researchers have focused on the development of a new branch of ionic fluids called dichotomous ionic fluids (DILs); These fluids usually consist of two cationic groups that are connected to each other by a rigid or flexible spacer and are connected to two counter anions. Compared to mono-cationic ionic liquids, multi-cations have higher melting point, viscosity, surface tension and thermal stability, have a wider liquid range and more stable physical and chemical properties. Therefore, these liquids have a wide range of applications; Including solar cells, fuel cells, batteries, lubricants, reaction media, separation technology, material preparation, catalytic reactions and most recently, improving the normal isomerization rate of pentane and electrolytes for photo-harvesting. Structures containing xanthine are known for their wide range of biological and pharmacological activities, such as antibacterial, anti-inflammatory, and anti-viral activities. In addition, xanthine ions are present as structural units in a large number of natural products.
Methods: In this paper, for the first time, the catalyzed synthesis of xanthenedione and 4,3-dihydropyrimidine-2 (1H) - they are under Solvent-free conditions have been reported by the Brunsted ionic acid liquid. Ionic liquids are organic salts composed of organic cations and organic and / or inorganic anions that have many remarkable properties and properties, such as wide liquid state range, low vapor pressure, easy recovery process, high ionic conductivity, wide electrochemical window and design capability. Structural engineering with appropriate modification to represent cations or anions All reagents and solvents were commercially available and used without further purification. 1H NMR and 13C NMR in DMSO-d6 were recorded on a Bruker Avance Ultrashield spectrometer at 500 and 125 MHz, respectively. Chemical shifts were reported in parts per millions (δ), relative to the internal standard of tetramethylsilane (TMS). Thermal analysis (TG–DTA) of the DIL was recorded on a STA-1500 Rheometric Scientific TGA. Mass spectrometry (MS) studies were performed using 5957C VL MSD with a triple-axis detector, Agilent Technologies (ion source: electron impact (IE) 70 eV, ion source temperature: 230 °C, analyzer: Quadrupole). FTIR spectrum was taken on a FTIR PerkinElmer Spectrum Version 10.51 with KBr plates. Melting points were recorded on a Mettler Toledo Type FP62 in open capillary. Generally To a mixture of aromatic aldehyde (1 mmol) and 5, 5-dimethyl-1, 3 cyclohexanedione (2 mmol), 25 mol% of {[SO3H–Pyrazine–SO3H]Cl2} (0.25 mmol) was added and the reaction mixture was heated at 100 °C with stirring. After completion of the reaction monitored by thin-layer chromatography (TLC), the reaction mixture was allowed to cool at room temperature. Water (10 mL) was added and filtered to separate the catalyst. Then, the obtained solid product was filtered and then recrystallized from ethanol to afford the pure product. The products were identified by IR, 1H NMR and physical data (M.P.) with those reported in the literature. Also To a mixture of aromatic aldehyde (1 mmol), ethyl acetoacetate (1 mmol) and urea (2 mmol), 25 mol% of {[SO3H–Pyrazine–SO3H]Cl2} (0.25 mmol) was added and the reaction mixture was heated at 120 °C with stirring. After completion of the reaction evident from thin-layer chromatography (TLC), the reaction mixture was allowed to cool at room temperature. Water (10 mL) was added and the obtained solid product was filtered and then recrystallized from ethanol. The products were identified by IR, 1H NMR and physical data (M.P.) with those reported in the literature. The spectra data for some selected compounds are presented in the following.
Results: To achieve the appropriate reaction conditions, the reaction of 4-chlorobenzaldehyde and 5,5 dimethyl-1,3-cyclohexanedione catalyzed by {[SO3H–Pyrazine–SO3H]Cl2} was chosen as model reaction, and the reaction was carried out under different sets of conditions with respect to solvents, amounts of catalyst and temperatures. Initially, the model reaction was investigated in different solvents. The solvents did not improve the yield of the reaction in the presence of the catalyst. Therefore, we carried out the model reaction under solvent-free conditions. The result indicates that the yield of the reaction under solvent-free conditions was higher and the reaction time was shorter in comparison with solvent conditions. To optimize the reaction temperature, the model reaction was heated at 90 and 110 °C .The results showed that the 100 °C led to highest yield; therefore, it was selected as the reaction temperature for all further reactions. Finally, the model reaction was optimized by varying the amounts of catalysts (20 and 30 mol%) at 100 °C under solvent-free conditions. The results show that 25 mol% of the catalyst is sufficient for the best results. To determine the role of the catalyst, the model reaction was performed in the absence of the catalyst at the same condition, which results in very low yield of the product, which indicates the high catalytic activity of {[SO3H–Pyrazine–SO3H]Cl2} in the synthesis. To evaluate the scope and the limitations of this method, we extended our studies to various aldehydes under the optimized conditions. From the results, we could see that all reactions proceeded smoothly to afford the corresponding xanthenediones in high to excellent yields in the short reaction times. Various functional groups present in the aryl aldehydes such as halogen, methoxy, hydroxy and nitro groups were tolerated. Extension of this methodology to heterocyclic aldehyde was also successful. In view of green chemistry, reusability of the catalyst is important. Therefore, some experiments were run under the same optimal conditions mentioned above over the {[SO3H–Pyrazine–SO3H]Cl2}. The results showed that the catalyst could accelerate the reaction three runs without a significant loss in its catalytic activity. The mechanism of the reaction starts with facilitating Knoevenagel condensation due to activating carbonyl group of aldehyde by acidic property of catalyst. In the following, the catalyst again plays a significant role in accelerating the Michael addition and dehydration.
Conclusion: A comparative study on the catalytic activity of the introduced catalyst in this paper with some reported catalysts was carried out using 3a as a model compound. From this study, {[SO3H–Pyrazine–SO3H]Cl2} can be regarded as a more powerful catalyst for the synthesis of xanthenediones in terms of the yield and the reaction time. Multicomponent reactions (MCRs) are defined as one-pot processes that combine at least three reactants to selectively form single complex compounds as well as small heterocycles containing essentially all the atoms of the reactants. Among MCRs, the Biginelli reaction allows for the straight access of multifunctionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) through one-pot cyclocondensation of an aldehyde, a β-keto ester and urea in the presence of catalytic amount of acid Molecules containing DHPM core and its derivatives are of immense biological importance due to a wide range of pharmaceutical and therapeutic properties such as antiviral , antitumor,antibacterial ,anti-inflammatory , anti-HIV agents mitotic kinesin inhibition , calcium channel modulation , α1a-adrenergic antagonists and A2B adenosine receptor antagonists . In the classical Biginelli conditions, low yields and difficult isolation of the products are the main drawbacks due to strongly acidic conditions. Hence, many catalytic methods including Brönsted and Lewis acid , ionic liquids polymer-supported catalyst and nanoparticles have been introduced to enhance the efficiency of the synthesis of these important heterocycles. After obtaining acceptable results from xanthenediones synthesis catalyzed by {[SO3H–Pyrazine–SO3H]Cl2}, we decided to study its efficiency in the synthesis of DHPMs. In order to obtain the optimized conditions, the model reaction involving cyclocondensation of 4 chlorobenzaldehyde, ethyl acetoacetate and urea was examined. The best result was obtained when the reaction was carried out at 120 °C in the presence of 25 mol% of {[SO3H–Pyrazine–SO3H] Cl 2} under solvent-free conditions. After getting the satisfactory reaction condition in hand, the scope and efficiency of this approach were examined with respect to aldehydes. Fortunately, a variety of functional groups, such as halo, methoxy, hydroxy and nitro, were all well tolerated. In addition, heterocyclic aromatic aldehyde afforded the corresponding product with high yield. A plausible one-pot reaction pathway for the synthesis of DHPMs catalyzed by {[SO3H–Pyrazine–SO3H]Cl2}. Initially, acyl imine intermediate (I) is produced via condensation of aryl aldehyde and urea in the presence of the catalyst as a Brönsted acidic catalyst. Next, ethyl acetoacetate attacks the (I), followed by intramolecular cyclization and dehydration reaction under acidic condition to yield the Biginelli product. Next, the reusability of {[SO3H–Pyrazine–SO3H]Cl2} was examined in the reaction of 4-chlorobenzaldehyde, ethyl acetoacetate and urea under optimized conditions. The catalyst could be reused three times without a significant loss in its catalytic activity. In order to show the efficacy of {[SO3H–Pyrazine–SO 3H]Cl2}, a comparison of the present method and some reported methods is shown in results. As revealed from this table, the catalyst can be considered as a more powerful catalyst for the synthesis of DHPMs in terms of the yield and reaction time.
Methods: In this paper, for the first time, the catalyzed synthesis of xanthenedione and 4,3-dihydropyrimidine-2 (1H) - they are under Solvent-free conditions have been reported by the Brunsted ionic acid liquid. Ionic liquids are organic salts composed of organic cations and organic and / or inorganic anions that have many remarkable properties and properties, such as wide liquid state range, low vapor pressure, easy recovery process, high ionic conductivity, wide electrochemical window and design capability. Structural engineering with appropriate modification to represent cations or anions All reagents and solvents were commercially available and used without further purification. 1H NMR and 13C NMR in DMSO-d6 were recorded on a Bruker Avance Ultrashield spectrometer at 500 and 125 MHz, respectively. Chemical shifts were reported in parts per millions (δ), relative to the internal standard of tetramethylsilane (TMS). Thermal analysis (TG–DTA) of the DIL was recorded on a STA-1500 Rheometric Scientific TGA. Mass spectrometry (MS) studies were performed using 5957C VL MSD with a triple-axis detector, Agilent Technologies (ion source: electron impact (IE) 70 eV, ion source temperature: 230 °C, analyzer: Quadrupole). FTIR spectrum was taken on a FTIR PerkinElmer Spectrum Version 10.51 with KBr plates. Melting points were recorded on a Mettler Toledo Type FP62 in open capillary. Generally To a mixture of aromatic aldehyde (1 mmol) and 5, 5-dimethyl-1, 3 cyclohexanedione (2 mmol), 25 mol% of {[SO3H–Pyrazine–SO3H]Cl2} (0.25 mmol) was added and the reaction mixture was heated at 100 °C with stirring. After completion of the reaction monitored by thin-layer chromatography (TLC), the reaction mixture was allowed to cool at room temperature. Water (10 mL) was added and filtered to separate the catalyst. Then, the obtained solid product was filtered and then recrystallized from ethanol to afford the pure product. The products were identified by IR, 1H NMR and physical data (M.P.) with those reported in the literature. Also To a mixture of aromatic aldehyde (1 mmol), ethyl acetoacetate (1 mmol) and urea (2 mmol), 25 mol% of {[SO3H–Pyrazine–SO3H]Cl2} (0.25 mmol) was added and the reaction mixture was heated at 120 °C with stirring. After completion of the reaction evident from thin-layer chromatography (TLC), the reaction mixture was allowed to cool at room temperature. Water (10 mL) was added and the obtained solid product was filtered and then recrystallized from ethanol. The products were identified by IR, 1H NMR and physical data (M.P.) with those reported in the literature. The spectra data for some selected compounds are presented in the following.
Results: To achieve the appropriate reaction conditions, the reaction of 4-chlorobenzaldehyde and 5,5 dimethyl-1,3-cyclohexanedione catalyzed by {[SO3H–Pyrazine–SO3H]Cl2} was chosen as model reaction, and the reaction was carried out under different sets of conditions with respect to solvents, amounts of catalyst and temperatures. Initially, the model reaction was investigated in different solvents. The solvents did not improve the yield of the reaction in the presence of the catalyst. Therefore, we carried out the model reaction under solvent-free conditions. The result indicates that the yield of the reaction under solvent-free conditions was higher and the reaction time was shorter in comparison with solvent conditions. To optimize the reaction temperature, the model reaction was heated at 90 and 110 °C .The results showed that the 100 °C led to highest yield; therefore, it was selected as the reaction temperature for all further reactions. Finally, the model reaction was optimized by varying the amounts of catalysts (20 and 30 mol%) at 100 °C under solvent-free conditions. The results show that 25 mol% of the catalyst is sufficient for the best results. To determine the role of the catalyst, the model reaction was performed in the absence of the catalyst at the same condition, which results in very low yield of the product, which indicates the high catalytic activity of {[SO3H–Pyrazine–SO3H]Cl2} in the synthesis. To evaluate the scope and the limitations of this method, we extended our studies to various aldehydes under the optimized conditions. From the results, we could see that all reactions proceeded smoothly to afford the corresponding xanthenediones in high to excellent yields in the short reaction times. Various functional groups present in the aryl aldehydes such as halogen, methoxy, hydroxy and nitro groups were tolerated. Extension of this methodology to heterocyclic aldehyde was also successful. In view of green chemistry, reusability of the catalyst is important. Therefore, some experiments were run under the same optimal conditions mentioned above over the {[SO3H–Pyrazine–SO3H]Cl2}. The results showed that the catalyst could accelerate the reaction three runs without a significant loss in its catalytic activity. The mechanism of the reaction starts with facilitating Knoevenagel condensation due to activating carbonyl group of aldehyde by acidic property of catalyst. In the following, the catalyst again plays a significant role in accelerating the Michael addition and dehydration.
Conclusion: A comparative study on the catalytic activity of the introduced catalyst in this paper with some reported catalysts was carried out using 3a as a model compound. From this study, {[SO3H–Pyrazine–SO3H]Cl2} can be regarded as a more powerful catalyst for the synthesis of xanthenediones in terms of the yield and the reaction time. Multicomponent reactions (MCRs) are defined as one-pot processes that combine at least three reactants to selectively form single complex compounds as well as small heterocycles containing essentially all the atoms of the reactants. Among MCRs, the Biginelli reaction allows for the straight access of multifunctionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) through one-pot cyclocondensation of an aldehyde, a β-keto ester and urea in the presence of catalytic amount of acid Molecules containing DHPM core and its derivatives are of immense biological importance due to a wide range of pharmaceutical and therapeutic properties such as antiviral , antitumor,antibacterial ,anti-inflammatory , anti-HIV agents mitotic kinesin inhibition , calcium channel modulation , α1a-adrenergic antagonists and A2B adenosine receptor antagonists . In the classical Biginelli conditions, low yields and difficult isolation of the products are the main drawbacks due to strongly acidic conditions. Hence, many catalytic methods including Brönsted and Lewis acid , ionic liquids polymer-supported catalyst and nanoparticles have been introduced to enhance the efficiency of the synthesis of these important heterocycles. After obtaining acceptable results from xanthenediones synthesis catalyzed by {[SO3H–Pyrazine–SO3H]Cl2}, we decided to study its efficiency in the synthesis of DHPMs. In order to obtain the optimized conditions, the model reaction involving cyclocondensation of 4 chlorobenzaldehyde, ethyl acetoacetate and urea was examined. The best result was obtained when the reaction was carried out at 120 °C in the presence of 25 mol% of {[SO3H–Pyrazine–SO3H] Cl 2} under solvent-free conditions. After getting the satisfactory reaction condition in hand, the scope and efficiency of this approach were examined with respect to aldehydes. Fortunately, a variety of functional groups, such as halo, methoxy, hydroxy and nitro, were all well tolerated. In addition, heterocyclic aromatic aldehyde afforded the corresponding product with high yield. A plausible one-pot reaction pathway for the synthesis of DHPMs catalyzed by {[SO3H–Pyrazine–SO3H]Cl2}. Initially, acyl imine intermediate (I) is produced via condensation of aryl aldehyde and urea in the presence of the catalyst as a Brönsted acidic catalyst. Next, ethyl acetoacetate attacks the (I), followed by intramolecular cyclization and dehydration reaction under acidic condition to yield the Biginelli product. Next, the reusability of {[SO3H–Pyrazine–SO3H]Cl2} was examined in the reaction of 4-chlorobenzaldehyde, ethyl acetoacetate and urea under optimized conditions. The catalyst could be reused three times without a significant loss in its catalytic activity. In order to show the efficacy of {[SO3H–Pyrazine–SO 3H]Cl2}, a comparison of the present method and some reported methods is shown in results. As revealed from this table, the catalyst can be considered as a more powerful catalyst for the synthesis of DHPMs in terms of the yield and reaction time.
Keywords: Dicationic ionic liquid, Pyrazine, Xanthenediones, 3, 4-Dihydropyrimidin-2(1H)-ones, Solvent-free
Type of Study: Research |
Subject:
Biochemistry
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