A novel catalyst-free route was utilised for the first time to achieve a synthesis of fourteen new 3-methyl-1,4,8,9-tetrahydro-5H-pyrazolo[4,3:5,6]pyrido[2,3-d]pyrimidine-5,7(6H)-diones via a one-pot five-component reaction of substituted aromatic/hetero aromatic aldehydes, barbituric acid, ethyl acetoacetate, hydrazine hydrate and ammonium acetate in water under ultrasonication. The reaction conversion took place between 15 and 18 min, with the yield ranging from 85% to 98%; and it was found that five compounds gave <90% yield and nine compounds accorded yields >90%. The methodology is expeditious and furnishes varied advantages like shorter reaction time, energy efficiency, eco-sustainability and work under mild condition.
Keywords
one-pot five-component reaction
catalyst-free
ultrasound
water
minimum waste
pyrazolo-pyrido-pyrimidine-diones
Author information
Introduction
Multicomponent reactions (MCRs) [1–3] play an essential role in modern organic and applied chemistry, wherein, the target molecules are obtained from three or more divergent substrates through reactions in well-defined approaches [4]. They deliver considerable advantages over linear-stepwise syntheses and reduction in waste production [4, 5]. With the aim to avoid the formation of toxic materials and byproducts arising from chemical processes, chemists need to cultivate environmentally-friendly strategies [6]. Nowadays, ultrasound has emerged as a dynamic tool in the synthesis of novel heterocycles owing to distinctive and advantageous features such as greater selectivity, low energy utilisation, excellent acoustic cavitation, better consumption of raw materials, high yields of products and reduced reaction durations [7]. The method is safe, efficient and involves the use of green solvents such as water and/or EtOH. Hence, ultrasonication has emerged as an innocuous, green technique in organic synthesis and has been proved beyond doubt to be an advanced technique over conventional methods [8].
On the other hand, water is used as one of the most promising solvents in the design of new synthetic pathways for the preparation of a wide range of compounds [9]. Compared to most organic solvents, water is easy to handle, economically viable, easily sourced natural resource, non-volatile, nonflammable, eco-friendly and it is easy to isolate the products from water. For these reasons, a great number of dominant heterocyclic compounds like pyrans, furans, pyridines, quinolines, indoles, triazines, acridines, pyrazines and pyrimidines have been synthesized in aqueous media [10–16]. Therefore, design of new heterocycles in water as a reaction medium continues to inspire synthetic organic chemists and pharmacologists.
Pyrimidine skeleton contributes to a large family of medicinally active molecules and represents one of the most copious chemo-types in modern drug discovery including quinazolines in which one of the rings is a pyrimidine nucleus (Figure 1).
Figure 1.
Biologically active functionalized pyrimidine derivatives.
A number of pyrimidine-based derivatives have been found to exhibit various biological and pharmaceutical activities [15–29]. Literature has elucidated that fused pyrazolo[3,4-d] pyrimidines [30] and pyrimidine fused pyrazoles [31] possess diverse medicinal properties.
Pyridopyrimidine scaffolds have numerous substantial biological applications and have also established a remarkable place in the area of pharmaceutical chemistry [32–43]. Their analogues comprise a novel class of selective antagonists of cholecystokinin receptor subtype-1 (CCK1R) [44], diuretics [45], tyrosine kinase inhibitors [46] and antiviral agents [47]. Additionally, divergent scales of pharmaceutical potency are recorded for these classes of compounds including apoptosis inducers, antibacterials, antihypertensives, bronchodilators, cardiotonics, antileishmanials, analgesics, EGFR inhibitors, antifolate and antihistaminics, as well for treatment of diarrhoea [48–55].
Numerous examples of hetereocycles developed in aqueous medium exist in literature. Pagadala et al. developed an ultrasound-mediated straightforward protocol for the synthesis of pyridines and pyrimidines in aqueous medium [56]. Ali et al. developed an ultrasound-assisted one-pot technique for the synthesis of imidazopyrimidines by employing Fe3O4@clay as a catalyst in water [57]; the authors also prepared pyrimidine-6-carboxylic esters under the said conditions [58]. Pyrazoles and pyranopyrazoles are also synthesized in water under the influence of ultrasound [59]. Manisha et al. worked on the construction of pyrano[2,3-c] pyrazoles and bis-pyranopyrazoles in water and catalytic 18-crown-[6]-ether [60]. Similarly, several simple as well as complex heterocycles of biological interest have been prepared in water as a solvent under ultrasonication [61].
Recently, pyrazolopyranopyrimidines (Figure 2) were prepared by Satish et al. by ultrasonication in the presence of catalytic 𝛽-CD at 50 °C [62]. Pyridodipyrimidines were synthesized by Hossein et al. in a one-pot four-component reaction [63].
Figure 2.
Synthesis of pyrazolopyranopyrimidines by ultrasonication.
Taking note of the above-mentioned applications of pyrimidopyridine derivatives, attention has been directed to the development of new methodologies to design pyrimidopyridine ring systems [64]. Consequently, several synthetic protocols have been reported across studies, employing a variety of catalysts. However, few of the reported synthetic techniques have one or more shortcomings such as: low yield, use of extreme conditions, use of toxic reagents and solvents; a few of the developed methods require longer reaction durations [65]. Thus, an expedition for the development of green and efficient methods for the synthesis of fused heterocycles is much needed. Herein, we report a catalyst-free one-pot five-component approach for rapid synthesis of substituted novel pyrimidine scaffolds from one molecule of an aldehyde, ethyl acetoacetate, hydrazine, barbituric acid and ammonium acetate in water as a solvent under ultrasonic condition as depicted in Scheme 1.
Scheme 1.
Synthesis of substituted pyrazolopyridopyrimidine-diones.
Experimental
Instruments and reagents
Sigma-Aldrich, SD Fine Chem, Spectrochem, Merck and other certified chemicals such as aldehydes, barbituric acid, ethyl acetoacetate, hydrazine hydrate, ammonium acetate and other chemicals and solvents were procured through local dealers; M/s Labsuppplies India Pvt. Ltd., M/s Polysales, M/s Aspire Inc., and others in Bengaluru, INDIA. Melting points were determined on a Raaga melting point apparatus (Made in India). The progress of the reactions was monitored by thin layer chromatography [(TLC) analytical silica gel plates (Merck 60 F250), observed under ultraviolet (UV) light]. 1H NMR spectra were recorded at 400 MHz and 13C NMR spectra were recorded on a Varian Mercury Spectrophotometer at 100 MHz in DMSO-d6 respectively and TMS as an internal standard. The chemical shifts are expressed in 𝛿 ppm and the coupling constants (J) are given in hertz (Hz). Mass spectra were recorded on an Agilent Technologies 1200 series instrument. Ultrasonication was performed using SIDILU, Indian make sonic bath operating at 35 kHz (constant frequency, 80 W) maintained at 28 °C by continuously circulating water.
General procedure for the preparation of compounds (6a–6n)
In a 25 mL conical flask, a mixture of aldehyde (1 mmol), hydrazine hydrate (1 mmol), ethyl acetoacetate (1 mmol), barbituric acid (1 mmol), ammonium acetate (1.2 mmol) and water (5 mL) was taken and sonicated in a cleaning bath working at 35 kHz for 15 min. After completion of the reaction [thin layer chromatography (eluent:4:6::MeOH: MDC)], the reaction mixture was poured onto crushed ice; the formed precipitate was filtered, repeatedly washed with water (5 × 3 mL) and left in the oven at 80 °C for 30 min. MeOH (6 mL) was then added to dissolve the solid and the solution was dried over anhydrous Na2SO4; the solvent was removed by suction and the impure product thus obtained was further purified by recrystallization using MeOH (6 mL) to get the desired products (6a–6n) at 85–98% yield. The structures of the products were confirmed by 1H NMR, 13C NMR and Mass spectral analysis.
To identify the viability and overview of the present one-pot five-component domino reaction, the reaction conditions including reaction solvent, time consumption and energy efficiency were studied to examine their roles in enhancing the rate of the reaction and the yield of the product by taking 4-chlorobenzaldehyde, ethyl acetoacetate, hydrazine hydrate, barbituric acid and ammonium acetate as model substrates. Various solvents (polar, nonpolar, polar protic and aprotic solvents) were studied under different reaction conditions (28 °C, reflux temperature of the solvent and ultrasonic condition) and the results of these findings are presented in Chart 1. We primarily carried out this reaction under solvent-free condition and observed that ultrasonication gave 6a in low yield (30%, reaction 1), whereas yields obtained under other conditions were also unsatisfactory even after prolonged duration. Solvent was found to have a pronounced effect on the sonochemical reaction rates, and in the present sonochemical reaction, water is responsible for the enhanced yield of the product and the rate of the reaction when compared to the other solvents. Hence, the rate of the reaction is significantly increased under ultrasonic condition in aqueous medium when compared to the reaction in other solvents as shown in Chart 1 (reaction 10).
Chart 1.
Effect of solvent on the synthesis of 4-(4-chlorophenyl)-3-methyl-1,4,8,9-tetrahydro-5H-pyrazolo[4,3:5,6]pyrido[2,3-d]pyrimidine-5,7(6H)-dione (6a).
It is evident from Chart 1 that the use of nonpolar solvents significantly slowed the reactions and recorded very low yields (reactions 2–4), whereas in the case of polar aprotic solvents, moderate yields were obtained (reactions 5–7) and polar protic solvents gave good to excellent yield of the desired product (reactions 8–10). Hence, it is very clear that water works as an excellent solvent under sonication for the synthesis of the target compound and has a prominent effect in improving the yield with a shorter reaction duration (entry 10). This good result prompted us to further optimize the reaction conditions. We reviewed different amounts of solvent and determined that 5 mL of water gave the highest yield of the product as shown in Table 1 (entry 3). Further increase in the amount of solvent had no considerable effect on the yield and rate of the reaction (entries 4–6). We also performed reactions at different time intervals of 5, 10, 15 and 20 min, by keeping the amount of solvent (water) constant (5 mL) and observed that 15 min of ultrasonic irradiation furnished the highest product amount and a further increase in time duration (entry 9) provided the same product yield.
Entry
Water (mL)
Time (min)
Yield (%)b
1
2
15
65
2
4
15
78
3
5
15
98
4
6
15
98
5
8
15
98
6
10
15
98
7
5
5
45
8
5
10
54
9
5
20
98
Table 1
Optimization of the amount of the water and time duration for the synthesis of 6aa.
Under standardized conditions, the synthesis of fourteen pyrazolo-pyrido-pyrimidine-dione derivatives was carried out. Pleasantly, we succeeded in the preparation of the desired target molecules 6 (a–n) in excellent yields as shown in the Table 2. It is worth mentioning that electron withdrawing groups enhance the product yield and electron-donating groups lower the product yield. It was also observed that ortho-, meta- and para-substituted aldehydes gave good yield of the products and di-, tri-substituted (Cl, OCH3) aldehydes accorded lower yields (85–89%).
Entry
Aldehyde
Product
Time (min)
Yielda, b(%)
1
4-ClC6H4CHO
6a
15
98
2
3,4-(CH3O)2C6H3CHO
6b
18
89
3
4-NO2C6H4CHO
6c
15
96
4
3,4,5-(CH3O)3C6H2CHO
6d
18
88
5
3-ClC6H4CHO
6e
15
98
6
Indole-2-CHO
6f
18
88
7
2,4-Cl2C6H3CHO
6g
15
90
8
3,5-(OCH3)2C6H3CHO
6h
15
89
9
2-ClC6H4CHO
6i
15
96
10
4-FC6H4CHO
6j
15
92
11
2-Naphthaldehyde
6k
15
94
12
4-BrC6H4CHO
6l
15
98
13
3-HO,4-CH3OC6H3CHO
6m
18
85
14
3-NO2C6H4CHO
6n
15
95
Table 2
Synthesis of 6 (a–n) under ultrasonic condition.
aCharacterized by 1H NMR, 13C NMR and Mass spectral analysis; bIsolated yield.
Thus, this elegant energy efficient protocol can be utilized in constructing combinatorial libraries of the desired products.
A detailed extract of the present study is illustrated in Chart 2.
Chart 2.
Extract of the present work.
Furthermore, in the 1H NMR spectrum of the compound 6a, the methine proton appeared at 𝛿 4.81 ppm as a singlet, the pyrazole −NH proton appeared at 𝛿 10.10 ppm as singlet, two −NH protons of barbituric acid are observed at 𝛿 8.69 and 𝛿 7.90 ppm as singlets and a signal at 𝛿 3.69 ppm as singlet is observed for −NH proton of the pyrido group. Methyl group protons resonated at 𝛿 2.09 ppm as singlet and the rest four protons at 𝛿 6.99 ppm and at 𝛿 7.10 ppm protons are allocated for aromatic protons which appeared as two doublets.
13C NMR spectrum of 6a revealed that the two carbonyl carbons of barbituric acid appeared at 𝛿 159.0 and at 𝛿 158.0 ppm. The peaks at 𝛿 149.3 ppm and at 𝛿 134.3 ppm were observed for fused pyrazole and fused barbituric acid carbons next to −NH groups. The peak at 𝛿 132.6 ppm is identified as the quaternary carbon of the aryl ring connected to the chiral carbon. The signal at 𝛿 130.8 ppm is observed for the imine carbon of the pyrazole ring; at 𝛿 129.8 ppm carbon atom linked to the chloro group of the aryl ring and the two sets of identical carbon atoms of the aryl group are observed at 𝛿 128.2 ppm and 125.1 ppm respectively. At 𝛿 29.3 ppm we detected chiral carbon and at 𝛿 10.5 ppm, a methyl carbon group attached to the pyrazole moiety was noticed. It is also elucidated that the quaternary carbons fused between pyrazole and barbituric acid moieties are merged with the NMR noise due to the solubility factors, therefore peaks were not identified in 5 compounds (6a, 6c, 6g, 6h, 6m) but, rest of the compounds showed the expected peaks.
The mass spectrum of compound 6a exhibited the molecular ion peak at m/z 329.20 which matched the exact molecular weight.
The compounds 6b–6n exhibited the expected characteristics in their respective mass spectra, and similar chemical shifts in the diagnostic and the other respective regions of both 1H NMR and 13C NMR spectra, thus confirming the structures of the compounds
6a–6n.
Mechanistic role of ultrasonication
In chemical reactions, the use of ultrasound in a solution provides specific activation based on a physical phenomenon called acoustic cavitation. Under ultrasonication, compression of the liquid follows rarefaction (expansion), in which a sudden pressure drop produces small, oscillating bubbles of gaseous substances; these bubbles expand with each cycle of the applied ultrasonic energy until they reach an unstable size; they then collide and/or violently collapse to generate very high temperatures (5000 K) and pressures (10,000 atm) [66]. This in turn sets the podium for the formation of highly reactive species (chemical effects of ultrasound), which are responsible for activation and facilitating the rate of the chemical reactions. The distribution of ultrasonic energy is superior in the case of water and also the predominance of cavitation effect is greater in water when compared to the other solvents.
A plausible mechanism has been suggested for the formation of products 6 (a–n) and involves sequential conversions as depicted in Scheme 2. The first step involves the condensation of ethyl acetoacetate with hydrazine to give pyrazolone (I). The next step involves the Knoevenagel condensation of pyrazolone (I) with an aldehyde to deliver benzylidene-pyrazolone ring adduct II; subsequently, the active methylene of the barbituric acid reacts with the benzylidene-pyrazolone intermediate (II) through Michael addition to give the intermediate III; the lone pair of electrons present on the nitrogen is involved in a reaction with the intermediate III to give the intermediate IV, which may undergo intramolecular cyclization by the nucleophilic addition of enamine to carbonyl group to yield the desired products 6 (a–n) after losing a molecule of water as shown in Scheme 2.
Scheme 2.
A plausible mechanism for formation of 6 (a–n).
Conclusions
In this study, we developed a novel ultrasound-assisted, catalyst-free one-pot five-component synthesis of fourteen new pyrazolo-pyrido-pyrimidine-diones in water as a medium. The significant description of this strategy highlights green solvent usage, readily available starting materials, energy efficiency, absence of catalyst, simple product isolation, avoiding column purification steps, cost-effective, absence of hazardous organic solvents, good to excellent yields, versatility, promoting good reaction rate, minimization of waste and easy to handle. Moreover, the protocol represents a better and more innovative green methodology towards the synthesis of the target compounds.
Acknowledgments
The authors acknowledge the support of Sophisticated Instrument Facility, Indian Institute of Science, Bengaluru, and the University of Mysore Instrumentation facility for providing the 1H, 13C NMR spectra and the mass spectra.
Amreen Khanum acknowledges the Minority Welfare Department, Government of Karnataka, India, for financial assistance towards a fellowship.
Dr. Mohamed Afzal Pasha acknowledges the University Grants Commission, New Delhi, India, for the BSR Faculty Fellowship: No. F.18-1/2011 (BSR); November, 2019.
Conflict of interest
The authors declare that they have no conflict of interest.
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