Abstract
A gentisic acid based-Deep Eutectic Solvent (MTPPBr/GA-DES) was synthesized by mixing one mole of methyl triphenylphosphonium bromide (MTPPBr) and one mole of gentisic acid (GA: 2,5-dihydroxy-benzoic acid) based on the eutectic point phase diagram. Then, it was characterized by FT-IR, NMR, densitometer, and TGA/DTA techniques and used as a potent and novel catalyst for the fast and green synthesis of: (i) Five new 2(a-e) and five known 2(f-j) benzo[6,7]chromeno[2,3-d]pyrimidines and (ii) One new (3a) and eleven known 3(b-l) pyrano[2,3-d]pyrimidines, in solvent-free conditions, short reaction times, and high yields. It is important to mention that for the synthesis of 2(a-j), there is only one reference which states that the reaction times are extremely long (720–2400 min), while these times are reduced to approximately 35–50 min in our proposed strategy, indicatinging that the rate of reactions will be 20–48 times faster, which is the clear and most obvious advantage of our approach.
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Introduction
In the early 2000s, Abbott’s research group published findings that led to the development of DESs1,2,3, which were presented as viable alternatives to ionic liquids and overcome their limitations.
Ionic liquids were first described by Paul Walden in 19144, originally thought to be non-volatile, non-flammable and environmentally friendly solvents. However, recent studies have shown that many of them are actually volatile, flammable, unstable, and even toxic.
Ionic liquids consist of organic heterocyclic cations and organic or inorganic anions, while DESs are formed by combining different types of hydrogen bond acceptors (HBAs) and hydrogen bond donors (HBDs)5. DES usually consists of a blend of two or three ionic compounds, which are often more affordable and safer and have lower melting points than the original materials. When two high-melting salts are combined, they create a eutectic alloy with a lower melting point than each of its components6,7,8.
DESs, which are secure and environmentally friendly fluids known for their ability to donate or accept electrons or protons, can dissolve a wide range of compounds including salts, proteins, polysaccharides, amino acids, sugars, surfactants, and drugs. DESs are used to create an environment to promote contact between reactants and ultimately to expand the production of natural compounds and catalysts. In addition, they can be used as catalysts as well in environmentally friendly environments such as electrophilic substitution9,nucleophilic reactions10, Diels-Alder condensation, carbon–carbon catalytic bond (Heck or Suzuki)11, copolymerization12, dehydration of carbohydrates13, reduction reactions, and multi-component reactions. For example, Davis and his colleagues reported the Diels-Alder reaction in ChCl/MCl2 (M = Zn or Sn) in 2002 and showed that the Lewis acid property of this DES significantly increases the reaction rate. Various dienes and dienophiles were used and Diels-Alders products with efficiencies ranging from 85 to 91% and endo/exo selectivities ranging from 83:17 and 97:314.
A multicomponent reaction involves three or more reactants reacting in sequence to produce highly selective products, retaining most of the atoms of the substances involved, and offers advantages such as mild reaction conditions, short reaction times, environmental friendliness, ease of product purification, and reduction in the use of reactive materials and solvents15,16,17,18.
Dihydropyrimidines (DHPMs) are of great significance in the field of organic synthesis and pharmaceutical chemistry, attracting the attention of organic chemists for over a century. They are widely studied due to their chemical and biological importance, exhibiting antioxidant, anti-inflammatory, immunomodulatory, antibacterial, antiviral, and antitumor activities. Furthermore, specific functional DHPMs are believed to possess substantial potential for clinical applications in calcium channel blocking, adrenergic antagonism, neuropeptide Y antagonism, and other related areas19,20,21,22,23,24,25,26. Below we examine some of the corresponding essential compounds27. In addition to purines, pyrimidines are organic bases that participate in the structure of DNA in the form of nucleotides. The three organic bases uracil, cytosine, and thymine found in the structure of DNA and RNA are pyrimidine derivatives and have many medicinal uses. Studies show that pyrimidines have, antiviral, antiHIV, antithyroid, antimalarial, anticancer, and antihypertensive properties. Also, in the following, some compounds that have a pyrimidine ring in their structure and are used as medicine are mentioned. For example, minoxidil acts directly on the smooth muscles of the vascular wall and reduces peripheral vascular resistance and blood pressure28. Cytarabine has anti-cancer properties and is easily converted into nucleotides inside the cells to inhibit DNA synthesis and has a strong effect of suppressing the immune system29. Propylthiouracil inhibits the synthesis of thyroid hormones and has antithyroid activity30. Primethamine has anti-infection and anti-malarial activity31. Lamivudine is an antiseptic drug and is used for HIV infections32. Trimethoprim is an antibiotic with a wide application range, which is used in the treatment of infections, especially urinary infections.
Barbiturates are six-membered heterocyclic compounds with a pyrimidine-based structure and are a vital course of pharmaceutically promising pyrimidines. They are used as hypnotics, sedatives, anticonvulsants, anesthetics, antioxidants, antifungals, and central nervous system depressants and are used as part of a series of barbiturate drugs. Butalbital, phenobarbital, barbital, and thialbarbital are among the most commonly used barbiturate and thiobarbiturate drugs33,34,35.
Polyfunctional heterocycles occupy a key position in the drug development process, and it has recently been estimated that about 70% or more of all drugs and pesticides in use have at least one heterocycle36.
1,4-Naphthoquinone is commonly found in both natural products (present in plants, fungi, and some pigmented animals) and synthetic products and has several biological activities37,38,39. Previous studies have shown that they are classified as having molluscicidal, antiproliferative, antifungal, antimalarial, anti-bacterial, and antiviral activities40,41,42,43,44,45. One of their derivatives with impressive structure and biological activity is lawsone (2-hydroxy-1,4-naphthoquinone = HONAPH), the main dye found in the henna plant (Lawsonia inermis L.)38. It has been reported to have biological activities such as antibacterial, antifungal, and antitumor impacts, and is broadly utilized as a UV filter in sunscreens and hair colors46,47,48,49,50.
Pyranopyrimidine is composed of a pyran ring fused to a pyrimidine, so its basic structure is composed of both nitrogen and oxygen. They have important pharmacological properties such as antihypertensive, cardiotonic, bronchodilatory, antibronchial, and antitumor effects51,52,53,54,55.
In recent years, many routes have been proposed for the synthesis of pyranopyrimidines, which include the DABCO base-catalyzed56, γ-Fe2O3@HAp-Ni2+ ref.57, KAl(SO4)2 ref.58, [BMIm]BF4 ref.59, (NH4)2HPO4(DAHP)60, and catalyst-free synthesis61.
However, many of the above-mentioned methods suffer from disadvantages, therefore, in continuing our research about green syntheses62,63,64,65, we would like to report the preparation of a novel DES from the reaction of MTPPBr and GA (Fig. 1).
Preparation of the DES catalyst.
Then, the obtained DES was used as a powerful and new catalyst for the synthesis of two sets of compounds with potential biological properties:
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(i) Five new 2(a-e) and five known compounds 2(f-j) from the reaction of barbituric acid (BA), aromatic aldehydes, and HONAPH in solvent-free conditions at 60 ℃; and
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(ii) One new (3a) and eleven known compounds 3(b-l) from the reaction of BA, malononitrile, and aromatic aldehydes in solvent-free conditions at 70 ℃ (Fig. 2).
Synthesis of 2(a-j) and 3(a-l) by DES.
The main advantages of this newly developed protocol are the clean reaction profile, the use of DESs as green catalysts, the absence of toxic and hazardous solvents, mild reaction conditions, short reaction times, easy purification, high atom economy, excellent yield and the use of commercially available low-cost starting materials.
Experimental
General
All reagents were provided by the foreign chemical companies. Thin layer chromatography (TLC) was performed on silica gel 60 F-254. TGA-DTA analysis was performed on an SDT Q600 V20.9 Build 20 and a densitometer was performed using AND-HR200. FT-IR (KBr) spectra were recorded on a Perkin Elmer spectrometer. Melting points were measured using a Stuart melting point meter. NMR spectra were recorded on a Bruker DRX-250.
General procedure for preparation of DES
A mixture of MTPPBr and GA (molar ratio 1:1) was stirred and heated to 50 ℃ (~ 30 min) until a homogeneous liquid was obtained.
When it cools slowly at room temperature, it turns into a transparent solid. Since the DES catalyst is soluble in aqueous phase, and insoluble in ethyl acetate, the mixture of water/ethyl acetate was then added and the aqueous layer containing DES was separated, dried at room temperature in a fume hood and stored as a potent catalyst for further reactions.
General procedure for the synthesis of 2(a-j)
The reaction of BA (1 mmol, 128 mg), HONAPH (1 mmol, 174 mg), and aldehyde (1.0 mmol) was carried out in the presence of the DES catalyst (1 mmol = 0.511 g, one mole of the DES catalyst is equal to the sum of the molecular mass of MTPPBR and GA (357 + 154 = 511)) at 60 ℃ at the appropriate time (Table 2) and progress of the reaction monitored by TLC (n-hexane/ethyl acetate: 2/8). After completion of the reaction, the reaction mixture was filtered, washed with ethanol, and characterized by FT-IR, 1HNMR, 13C NMR, mass spectrum, and melting points. The reaction mixture is insoluble in ethanol and DES is soluble.
General procedure for the synthesis of 3(a-l)
The reaction of BA (1 mmol, 128 mg), malononitrile (1 mmol, 66 mg), and aldehyde (1.0 mmol) was carried out by DES (1 mmol, 0.511 g) at 70 ℃ at appropriate times (Table 4). After completion of the reaction (TLC: n-hexane/ethyl acetate: 2/8), the reaction mixture was filtered, washed with ethanol, and characterized by FT-IR, 1HNMR, 13C NMR, mass spectrum, and melting points.
Results and discussion
Preparation of the DES catalyst
The mixture of MTPPBr and GA (mole ratio 1:1) was heated at 50 ℃ and stirred until a homogeneous transparent liquid (DES) was obtained.
Note that DES can be prepared by simply mixing and heating the ingredients without purification. The DES can be efficiently used not only as a cheap, and environmentally friendly solvent but also as a recyclable and reusable organocatalyst to promote various organic transformations.
Characterization of the DES catalyst
DES was characterized by FT-IR, 1H NMR, TGA-DTA, Densitometer, and Eutectic points.
Characterization by FT-IR
Figure 3 shows the IR spectra of MTPPBr (a), GA (b), the fresh DES (c), and the recovered DES (d).
The FT-IR spectra of (a), (b), (c), and (d).
In a, the peaks at about 2900–3100 cm−1 are associated with aromatic and aliphatic C–H, and the peaks at about 750 and 1480 cm−1 are related to C–P and C = C bonds, respectively. In b, the peaks at 3315 and 1672 cm−1 belong to the O–H and the C = O bonds of the –COOH group, respectively. In c, the peaks shown in a and b are visible, confirming the structure of the DES catalyst.
Also, a comparison of c and d shows that there is no significant difference between the original and used DES.
Characterization by 1H NMR
The 1H NMR spectrum of MTPPBr
Figure 4 shows the 1H NMR spectrum of MTPPBr. Peaks at 3.18–3.24 (d, 3H), and 7.63–7.79 (m, 15H) ppm correspond to CH3 hydrogens, and hydrogens of phenyl rings, respectively.
The 1H NMR of MTPPBr.
The 1H NMR spectrum of GA
Figure 5 shows the 1H NMR spectrum of GA. The peaks at 13.78 (s, 1H), and 9.16 (s, 1H) ppm correspond to hydrogens of the two hydroxy groups. Peaks at 10.67 (s, 1H), 7.15 (s, 1H), 6.97–6.94 (m, 1H), and 6.79 (d, J = 8.9 Hz, 1H) ppm correspond to a hydrogen of the -COOH group and three hydrogens of a phenyl ring, respectively.
The 1H NMR spectrum of GA.
The 1H NMR spectrum of the DES catalyst
Figure 6 shows the 1H NMR spectrum of DES. Peaks at 3.17 (d, J = 14.7 Hz, 6H) ppm correspond to hydrogens of the two CH3 groups. The peaks at 6.78 (d, J = 8.9 Hz, 2H), 6.96 (dd, J = 8.9, 3.1 Hz, 2H), and 7.16 (d, J = 3.1 Hz, 2H) ppm correspond to hydrogens of the two phenyl rings of GA. The peak at 7.91–7.75 (m, 30H) ppm corresponds to hydrogens of the six phenyl rings of MTPPBr. Peaks at 9.16, and 13.30 ppm correspond to hydrogens of four hydroxy groups, and peaks at 11.17 ppm correspond to hydrogens of -COOH groups of GA.
The 1H NMR of the DES catalyst.
Interestingly, when DES is formed, the signal intensity of hydrogens weakens and shifts to a low field. These observations indicate the presence of new hydrogen bond formation and their interaction between MTPPBr and GA66, which confirms the newly prepared DES structure.
Characterization by TGA-DTA
As we know, the TGA/DGA analysis shows the thermal behavior of the target molecule during the temperature increase and characterizes the molecule thermally rather than structurally. We also had the same goal of using this technique and saw two main weight reductions (Fig. 7). The initial weight loss is likely due to the water removal, and the subsequent weight loss, which occurs after reaching 200 ℃, is attributed to removing acidic compounds, breaking hydrogen bonds, and eventual decomposition.
The TGA-DTA pattern.
Characterization by densitometer
DESs usually have a density of 1.0 to 1.35 g/cm3, so a certain weight of DES was mixed with a certain volume of water, and its density was calculated using the relevant formula, which is about 1.36167 g/mL67.
Characterization by eutectic points
To prepare the best new DES, it was necessary to find the optimal ratio of MTPPBr and GA. Therefore, the phase diagram of the eutectic point was designed by creating different ratios of MTPPBr (m.p.: 230 ℃) and GA (m.p.: 204–208 ℃). The data indicated that the optimal ratio was one mole of MTPPBr to one mole of GA. Only at this ratio (1:1) a transparent homogeneous mixture was obtained as a new DES (m.p.: 50 ℃) (Fig. 8).
The eutectic points phase diagram.
Optimization of the reaction conditions for the synthesis of 2a
To optimize the reaction condition, a model reaction [reaction between BA, HONAPH, 4-chloro-benzaldehyde (ClBZ), and DES with different molar ratios] was carried out in various solvents, temperatures, and amounts of the DES catalyst in 60 mim. The best result was obtained with a 1:1:1 molar ratio of BA, HONAPH, and ClBZ with 1 mol of the DES catalyst at 60 ℃ under solvent-free conditions with high yields and short reaction times (Table 1).
Furthermore, additional reactions were designed and performed under the same reaction conditions in the absence of DES and in the presence of ethanol to investigate the catalytic role of ethanol in the synthesis of 2a. The results were very interesting: the reaction was completed after 720 min with a yield of 75%. It is obvious that ethanol has the solvation effect to solvate DES, so the efficiency of the reaction was decreased.
Also, the yield of the addition reaction with MTPPBr was very low (negligible) under the same reaction condition, but with GA, for 2a, the reaction was completed in about 70% yield (24.7% lower) in about 45 min (28.6% higher).
Synthesis of diverse 2(a-j)
Based on the results for the synthesis of 2a, 2(a-j) were synthesized from the reaction of BA, HONAPH, aldehydes and DES in similar reaction conditions (Table 2).
According to Table 2, the electron-withdrawing (-F, -Cl, -NO2) or electron-releasing groups (-CH3, -OMe, -CHMe2) did not show meaningful effects on the reaction rates. Probably, the rate-determining step is independent of these groups, since it did not show meaningful changes.
A proposed mechanism for the synthesis of 2(a-j)
A possible mechanism for the synthesis of 2(a-j) is shown in Fig. 9. The carbonyl group of an aldehyde is activated by DES with the subsequent attack of BA and removing of water to form (I). (II) is then formed by the reaction of (I) with HONAPH, and cyclization and removal of water produces (III)56.
Proposed mechanism for the synthesis of 2(a-j).
Reusability of DES in the synthesis of 2(a-j)
Figure 10 shows the recyclability of the DES catalyst. Since the DES catalyst is soluble in the aqueous phase, and insoluble in ethyl acetate, at the end of each reaction run, the mixture of water/ethyl acetate was added and the DES catalyst was decanted from the reaction mixture by the liquid–liquid extraction of the water/ethyl acetate mixture (1:1) and separated from the aqueous phase. Then, it was dried at r.t. and reused in the next consecutive reaction runs (93, 90, 79, and 71%). There is relatively a decrease in catalytic activity in the third and fourth runs.
Reusability of DES.
Comparison of the catalyst activities in the synthesis of 2(a-j)
Comparing the performance of our proposed method with the only previously reported method68 clearly shows the advantage of our method. The reported reaction times are very long (2400–720 min), while the time of our proposed method is about 35–50 min, indicating that our reactions are about 20–48 times faster.
Optimization of the reaction conditions for the synthesis of 3c
The effects of different solvents, temperatures, and amounts of DES were studied on model reaction (reaction between BA, malononitrile, ClBZ and DES) to optimize the reaction conditions in 45 min. So, the reactions were carried out in different reaction conditions and the best result was found to be the 1:1:1 mol ratio of BA, malononitrile, and ClBZ with 1.0 mmol of the DES catalyst at 70 ℃ in solvent-free conditions (Table 3).
Furthermore, additional reactions were designed and performed under the same reaction conditions in the absence of DES and in the presence of ethanol to investigate the catalytic role of ethanol in the synthesis of 3c. The results were very interesting, the reaction was complete after 400 min with a yield of 60%.
Also, the yield of the addition reaction with MTPPBr was very low (negligible) under the same reaction condition, but with GA, for 3c, the reaction was completed in about 75% yield (21% lower) in about 20 min (33% higher).
Synthesis of diverse 3(a-l)
Based on the results obtained from the synthesis of 3a, 3(b-l) were synthesized from the reaction of BA, malononitrile, aldehydes and DES in similar reaction conditions (Table 4).
According to Table 4, the electron-withdrawing (-COOH, -F, -Cl, -NO2) and electron-releasing groups (-CH3, -OMe, -OEt, -OH, -CHMe2) did not show meaningful effects on the reaction rates. Probably the rate-determining step is independent of the electron withdrawing or electron releasing groups since it did not show meaningful changes.
A proposed mechanism for the synthesis 3(a-l)
The C = O group is activated by DES for the subsequent nucleophilic attack of malononitrile (Fig. 11). Removal of water produces (I), the nucleophilic attack of the enol form of the BA produces (II), and the cyclization yields (III)72.
Proposed mechanism for the synthesis of 3(a-l).
Reusability of DES in the synthesis of 3(a-l)
Since DES is soluble in an aqueous phase, and insoluble in ethyl acetate, at the end of each reaction run, the mixture of water/ethyl acetate (1:1) was added and DES was decanted from the mixture. Then, it was dried at r.t. and reused in the next consecutive reaction runs (95, 87, 76, and 70%), which relatively shows no significant loss of activity (Fig. 12).
Reusability of DES.
Comparison of the DES activity with other catalysts in the synthesis of 3c
Table 5 shows the comparison of different methods for the synthesis of 3c to show the advantages of our proposed procedure (high yield, short reaction time) with other reported methods.
Conclusion
In conclusion, a new gentisic acid based-Deep Eutectic Solvent (MTPPBr/GA-DES) was designed, synthesized by mixing one mole of methyl triphenylphosphonium bromide (MTPPBr) and one mole of gentisic acid (GA: 2,5-dihydroxy-benzoic acid) based on the eutectic point phase diagram, characterized with different methods and used as an efficient catalyst for the eco-friendly synthesis of 2(a-j) and 3(a-l) compounds under solvent-free conditions, in short reaction times and high yields.
In addition, as previously mentioned, the only method for the preparation of 2(a-j) involves a very long reaction time (2400–720 min), while in our proposed method these reactions are performed in 35–50 min, which is approximately 20–48 is faster and represents a key advantage of our newly synthesized DES catalyst.
Data availability
All data generated or analyzed during this study are included in this published article and its Supplementary Information files.
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We acknowledge the support from the Bu-Ali Sina University, Hamedan Iran.
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Arezo Monem: She did all the experiments in the lab as a PhD student. Davood Habibi: He provided the idea and oversaw the research as a supervisor. Hadis Goudarzi: She played the role of advisor. The manuscript was written by all authors and they approved the final version of the manuscript.
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Monem, A., Habibi, D. & Goudarzi, H. A potential DES catalyst for the fast and green synthesis of benzochromenopyrimidines and pyranopyrimidines. Sci Rep 14, 18924 (2024). https://doi.org/10.1038/s41598-024-69817-2
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DOI: https://doi.org/10.1038/s41598-024-69817-2
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