Taurine an ecofriendly bioorganic catalyst for the synthesis of dihydropyrido [2,3-d] pyrimidine and pyrimido[4,5-b]quinoline derivatives under ultrasonication

doi:10.21203/rs.3.rs-3336927/v1

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Taurine an ecofriendly bioorganic catalyst for the synthesis of dihydropyrido [2,3-d] pyrimidine and pyrimido[4,5-b]quinoline derivatives under ultrasonication

https://doi.org/10.21203/rs.3.rs-3336927/v1

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Ultrasound-assisted multicomponent reaction in aqueous taurine as an efficient and green method developed for the synthesis of 5-phenyl-5,6-dihydropyrido [2,3-d] pyrimidine-2,4,7(1H,3H,8H)-triones and 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H,7H,10H)-triones in excellent yields with high purity. In the present work, 2-amino ethane sulfonicacid (Taurine) as green bio-organic catalyst is used for the cyclocondensation of substituted aldehydes, 6-amino uracil and meldrum acid/dimedone in water under ultrasonication. The key benefits of the present methodology are the use of cheap universal solvent water, recyclability of bioorganic catalyst, less reaction time, high yields of the product and avoiding toxic chemicals.

2-Aminoethanesulfonic acid (Taurine)

Water

Ultrasonication

Bioorganic catalyst

Dihydropyrido [2

3-d] pyrimidine

Pyrimido[4

5-b]quinoline

The approach, which are applied for the discovery of new drug molecules, the identification and advantage of structure gained a particular attention in the last decades [1, 2]. Uracil, is one of the pharmacophore of pyrimidine family present in wide spread heterocycle in nature [3, 4]. It is an important component of nucleic acids and the versatile building blocks for the synthesis of nitrogen containing six-member heterocycles and useful starting material for their various type of fused derivatives such as pyramidopyrimidines [5], pyridopurines [6], Several drug molecules containing the dihydropyrido[2,3-d] pyrimidine having variety of applicable biological activities such as anticancer [7], antibacterial [8], anti-inflammatory [9], antimalarial [10], antitumor activites [11]. Owing to their wide range of application and interesting properties to development of novel selective methodology for the synthesis of particular, dihydropyrido[2,3-d]pyrimidine derivatives is of practical importance and highly desirable.

Heterocyclic motifs such as dihydropyrido [2,3-d] pyrimidine have a broad range of application, In a very recent, A. Zegaet al. demonstrated 6-aryldihydropyrido[ 2,3-d]pyrimidine-2,4,7(1H,3H ,8H)-trione as new adenosine triphosphate ATP-competitive inhibitors of bacterial D-alanine ligase. Hence, there has been flurry of synthetic and biological activities [12, 13], only few methods for the synthesis of dihydropyrido [2,3-d] pyrimidine derivative have been reported, which involved more than two component reactions between substituted aldehyde, 6-aminouracil and 1,3-dicarbonyl using different catalyst at reflux conditions [14, 15]. Sudhan and co-workers developed the multicomponent reaction catalyzed by β-CD-PSA to synthesize indeno fused Pyrido[2,3-d]Pyrimidine derivatives [16]. B. Alimadadi et al. reported one-pot three-component reaction in the presence of nano silica supported preysslerH14 [NaP₅W30O110]/SiO₂ catalyst [17]. Free radical attack has observed for pyrimidine and photochemical synthesis of substituted pyrimidines [18]. Whereas M. Moona et al. and D. Anshu et al. also documented pyrido[2,3-d]pyrimidine derivatives [19, 20]. Most of the reported procedures with several disadvantage such as toxic solvents, unsatisfactory yield, long reaction time, occurrence of side products and sophisticated treatment. Thus, the enlargement of new and simple synthetic strategies for creation of these molecules using nontoxic reagent and green solvent is therefore an interesting challenge.

During the past years, multicomponent reaction (MCR) has major research attention in many useful organic transformations because of their wide spread biological and medicinal application. However, multicomponent reaction is best method that provide more benefits, such as high atom economy, high yield, less formation of byproducts, short reaction time and avoidance complex isolation and purification of intermediate [21–24]. Bhat A. R. et al. reported the MCR catalyzed by DBU using aqueous ethanol medium to synthesize pyrido [2,3-d: 6,5-d] dipyrimidine derivatives at reflux condition [25]. In addition to this, replacement of hazardous chemicals and solvent with environmentally benign solvents [26, 27], is one of the major focus areas of green chemistry and these synthetic approaches are important issues in organic synthesis.

Taurine (2-aminoethanesulfonic acid) is an inexpensive, nontoxic and commercially available catalyst and abundantly available at high concentrations in animal tissues and also used in energy drinks, dietary supplements [28]. It comes in the form of a zwitterionic shape in water, which leads to essential biological and medicinal properties [29]. Taurineis one of the constituent members of the bile present in the large intestine, the average quantity of which represents one-tenth of the total weight of the human body [30]. In recent times, taurine was used for the preparation of bio-active barbituric and thiobarbituric acid derivatives. Silica gel supported 2-aminoethanesulfonic acid was also reported in the oxidation reaction of sulfides to their corresponding disulfides [31]. Moreover,very few literature reports are available for taurine as catalyst such as C. Jadhav et al. reported the taurine as a catalyst in Michel addition and Knoevenagel condensation [32]. M. Bhosle and co-workers developed the MCR, catalysed by taurine to synthesized new thiazole based decahydroacridine-1,8-dionesand dihydropyrido[2,3-d:6,5d']dipyrimidines in water and highlighted its antimicrobial activites [33]. Perhaps, the reason behind such a selectivity with respect to a specific catalyst is still unknown and yet to be reported.

Consequently, we are taking more efforts to overcome some drawbacks from privileged heterocyclic scaffolds and trying to develop an effective method for the one pot multicomponent synthesis of dihydropyrido [2,3-d] pyrimidine under ecofriendly condition as show in (scheme 2).

General information

All the chemicals used were laboratory grade and reaction performed in standard glassware. All commercially available chemicals were used without further purification. The reaction product purified by filtration and recrystallization technique. Reactions were monitored by Thin Layer Chromatography (TLC) n Merck’s silica plates and visualization by using ultraviolet light (254/365nm) to check the progress of reaction and confirmation of completion. Melting points of all the synthesized derivatives were determined in open capillary tube and are uncorrected. IR spectra were obtained on Bruker ALPHA (Eco-ATR) spectrometer. ¹H and ¹³C NMR spectra were recorded with Bruker AvIII HD-400 MHz spectrometer operating at 300 MHz by using DMSO solvent and trimethylsilane (TMS) as the internal standard and chemical shift in δ ppm. Mass spectra were recorded on a Waters UPLC- TQD (ESI-MS and APCI-MS) Instrument. The multiplicity of all signals was described with standard abbreviations: singlet (s); doublet (d); double doublet (dd); broad singlet (bs); triplet (t); quartet (q); multiplet (m).

General procedure for the synthesis of 5-phenyl-5,6 – dihydropyrido [2,3-d] pyrimidine-2,4,7(1H,3H,8H)-triones and 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H,7H,10H)-trione

A equimolar mixture of 6-amino uracil (1mmol), substituted aldehydes 1a-p (1mmol) and meldrum acid / dimedone (1mmol) and 25 mol% of taurine was taken in 15 mL water in 100 mL round bottom flask and the mixture was sonicated under silent condition by ultrasound at 60˚C for appropriate time, as shown in Table 1. After completion of the reaction (indicated by TLC), the free flowing solid was filtered, washed with water (8–10 mL) and dried under reduced pressure. The obtained product was crystallized from ethanol to get pure compounds crystals. The isolated compounds were well characterized by IR, ¹H NMR, ¹³C NMR and Mass (LCMS) spectra.

To develop more ecologically benign protocols, together with catalysts, there is necessity of careful selection of the medium. Initially, to find the optimum conditions, the reaction of benzaldehyde (1m) (1 mmol), 6-aminouracil (2)(1 mmol) and meldrum acid (3) (1 mmol) was carried out as a model reaction for the synthesis of 5- phenyl − 5,6-dihydropyrido[2,3-d] pyrimidine 2,4,7 (1H,3H,8H)-trione (4m) (scheme 1) under different solvent condition e.g. water, PEG-400, dicationic ionic liquid, ChCl:ZnCl₂. The titled product was obtained in optimum 58, 60, 72, 68% of yield respectively (Table 1).

Use of water as the reaction medium provides the best promising selection in the search for more efficient, cheaper, and cleaner technologies for organic transformations [34–36]. Water is an abundant solvent often limited scope due to poor solubility of organic precursors. To solve solubility problem, we examined the model reaction in presence of different catalyst, i.e., CTAB, p-TSA, L-proline and taurine by keeping water as a green solvent at reflux condition.With this optimized result, taurine was found to be the most efficient catalyst and gave the desired product 5-phenyl-5,6-dihydropyrido[2,3-d] pyrimidine 2,4,7 (1H,3H,8H)-trione (4m), with 45, 50, 60 and 75% yield respectively (entries 5–8, Table 1). It is worth mentioning that there is not even a trace amount of formation of another isomer 4m′ observed; instead, the reaction preceded selectively that led to 4m as the only product.

Taurine is a β-amino acid, it improves water solubility and is capable of forming H-bonds, while its strong inductive effect can be utilized to tune pKa values of adjacent or remote amino groups [37]. On the other hand, the structural and electronic properties might mimic transition states to tetrahedral intermediates [38]. Therefore, it can be thought that taurine is green and a superior to any of the other optimized catalysts shown in Table 1.

Sonochemistry is used to describe the effect of ultrasound waves on chemical reactivity. There are various applications of ultrasound method in chemistry like milder condition, less reaction time, higher efficiencies of products, ecofriendly and energy saving in comparison with conventional heating method [39–43]. When ultrasound applied to solution, they give rise to acoustic cavitations such as the formation, growth and implosive collapse of bubbles in liquid. during the collapse of a cavity, the local temperature and pressure reach 5000 and 2000 atmosphere which leads to an increase in the rate of reaction [44]. The cavitations effect produces effective physical, chemical and biological transformations. Model reaction in taurine under ultrasonication was found to proceed with excellent yield (94%) to obtained dihydropyrido[2,3-d] pyrimidine 4m in 45 min (Table 1).

The amount of the catalyst is another critical parameter in terms of reaction efficiency. In order to improve the rate and yield of reaction we had optimized different reaction parameters like solvent, the effect of temperature and catalyst concentration was also examined. To study the catalytic effect, different mol% of taurine such as 10, 15, 20, and 25 was used. The yield of product obtained at respective mole percent is shown in (Table 1 entry 9). This optimization indicates that 25mol% taurine was sufficient to carryout reaction smoothly.

Along with the catalytic activity of taurine solvent optimization was also done under ultrasonication. We tried model reaction in ethanol, ethanol: water (1:1), acetonitrile, dichloromethane and methanol.The best result for reaction was obtained when taurine catalyst is used along with water. Dichloromethane, acetonitrile did not bring the reaction to completion under ultrasonic irradiation (Table 1 entries 8–15), but in contrast methanol found to furnish the product in a moderate 58% yield (Table 1 entry 15). Reaction in ethanol and aqueous ethanol resulted in good yields 65% and 70%, respectively. The effect of reaction medium was truly gratifying to notice an appreciable increase in 95% yield (Table 1 entry 10) of the desired product (4m).

Having optimized reaction conditions in hand, we next focused on exploring the substrate scope and checking the generality of the reaction; Various substituted aromatic aldehydes having electron-donating (4-OEt, 2-OH, 4-OCH₃, 4-OH) and electron withdrawing (4-F, 4-Cl, 2-NO₂, 4-Br, 3-NO₂) groups reacted with 6-amino uracil (2) and meldrum acid (3) to obtain corresponding dihydropyrido[2,3-d]pyrimidines (4a-p) with excellent yields under ultrasonication in aqueous medium (scheme 2). In all cases the reaction was completed within 40–60 minute with high yields and avoided complicated purification operations, thus allowing the saving of both solvents and reagents. Structures of all the synthesized analogues bearing dihydropyrido [2,3-d] pyrimidine (4a-p) were confirmed unambiguously from their spectroscopic analysis (¹H NMR, ¹³C NMR and LCMS) that was in fully agreement with the reported literature data.

In addition, this procedure was successfully extended to synthesis of 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H,7H,10H)-triones (6a-j) (Table 3) by the cyclocondensation of substituted aromatic and aliphatic aldehydes (1a-j), 6-amino uracil (2) and dimedone (5) (scheme 3) using taurine as bio-organo promoter/catalyst in water.

Plausible reaction mechanism

A plausible mechanism for the above mentioned taurine catalyzed green multicomponent reaction of benzaldehyde (1m), 6-amino uracil (2) and meldrum acid (3) is outlined in (scheme 4). Taurine plays animportant role as a bifunctional donor-acceptor reagent, inwhich the carbonyl group of aldehyde (1) electrophilc site gets activated by taurine andthen attacked by the negatively activated group in thenucleophile methylene group of meldrum acid (3) by Knovengel condensation removing H₂O molecule, benzylidene intermediate (4) was obtained. Subsequently, the benzylidene (4) attacked by 6- amino uracil (5), which gives Michael type addition to furnish condensed intermediate (6). Finally imine-enamine tautomerization (7) release of CO₂ and acetone, resulted into the formation of 5-phenyl-5,6-dihydropyrido [2,3-d] pyrimidine-2,4,7(1H,3H,8H)-trione. Moreover, we used dimedone as an starting material instead of meldrum acid gives intermediate product (7a) by hydrogen shift occurs through taurine catalyst release H₂O molecule, resulting in high yields of the desired product of 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H,7H,10H)-trione (8a).

Reusability and recycling of the catalyst

A further important feature of our proposed protocol is the stability and recyclability of the taurine catalyst. The physical properties of taurine demonstrate that it is soluble in water. Then, after completion of the reaction, the products were easily separated by simple filtration. The filtered solution was evaporated and thus obtained taurine reused for next two consecutive cycles for the synthesis of (4m). The isolated yields were almost similar until the third recycling (Fig. 2), without the loss of any catalytic activity. The purification of taurine after the recycling was confirmed by FT-IR spectrum which determines structural information about the molecule. No change was observed in the IR spectra before and after third recycle accordingly, the catalyst can be reused for aminimum of three times with little deactivation, still being an essential aspect of green chemistry (Fig. 3).

In conclusion, an efficient and environmentally being protocol have been developed for one pot multicomponent synthesis of 5-phenyl-5,6-dihydropyrido [2,3-d] pyrimidine-2,4,7(1H,3H,8H)-trione and 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b] quinoline-2,4,6-(1H,3H,5H,7H,10H)-trione derivatives by using taurine as reusable green bio-organic catalyst under ultrasonication. Advantages of this protocols are mild and environmentally friendly reaction conditons, products obtained in high to excellent yields, low catalyst loading, short reaction times, simple and clean workup procedures.

*sı Supporting Information

Spectral data for synthesized compounds and copy of ¹HNMR, ¹³C NMR, LCMS, and FT-IR of products

Acknowledgments

All the authors are thankful to the Authority of Department of Chemistry, Dr.Babasaheb Ambedkar Marathwada University, Aurangabad-431004, and Central Drug Research Institute (CDRI), Lucknow, India for providing laboratory facilities and spectral analysis respectively.

Author information

Corresponding Author

Giribala M. Bondle - Department of chemistry, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004, Maharashtra, India; Email: [email protected]

Authors

Bhavana G. Polke – Email: [email protected]

Manisha R. Bhosle - Email: [email protected]

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript and the Supporting Information.

Funding Not applicable.

Data availability Not applicable.

Conflict of interest Not applicable.

Ethical approval Not applicable.

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Tables 1-3 is available in the Supplementary Files section.

Schemes 1-4 are available in the Supplementary Files section

No competing interests reported.

Table13.docx
SUPPORTINGINFORMATIONpyrimidine.docx
floatimage1.png
Scheme1.png
Scheme 1. Synthesis of 5- phenyl -5,6-dihydropyrido[2,3-d] pyrimidine-2,4,7 (1H,3H,8H)- trione.
Scheme2.png
Scheme 2. Synthesis of 5-phenyl-5,6-dihydropyrido[2,3-d] pyrimidine-2,4,7-(1H,3H,8H)-triones
Scheme3.png
Scheme 3. Synthesis of 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6-(1H,3H,5H,7H,10H)-triones
Scheme4.png
Scheme 4. Plausible reaction mechanism for the synthesis of dihydropyrido[2,3-d]pyrimidine (4a-p).

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Taurine an ecofriendly bioorganic catalyst for the synthesis of dihydropyrido [2,3-d] pyrimidine and pyrimido[4,5-b]quinoline derivatives under ultrasonication

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Version 1

Abstract

Figures

Introduction

Experimental section

General information

General procedure for the synthesis of 5-phenyl-5,6 – dihydropyrido [2,3-d] pyrimidine-2,4,7(1H,3H,8H)-triones and 5-(phenyl)-8,9-dihydro-8,8-dimethylpyrimido[4,5-b]quinoline-2,4,6(1H,3H,5H,7H,10H)-trione

Results and discussion

Plausible reaction mechanism

Reusability and recycling of the catalyst

Conclusion

Declarations

References

Tables

Scheme

Additional Declarations

Supplementary Files

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