Ionic Liquid Mediated Synthesis Of Novel Chromone-Pyrimidine Coupled Derivatives .

The work reports synthesis of twelve novel ethyl 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6methyl-2-thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 4(a-f) and 4-(6substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2thioxo/oxo-1,2,3,4-tetrahydropyrimidine-5carbohydrazide derivatives 6(a-f). The novel chromone-pyrimidine coupled derivatives were synthesized under solvent-free condition using Triethyl ammonium sulphate [Et3NH][HSO4] as an efficient, eco-friendly and reusable catalyst. Compared to other methods, this new method consistently has advantages, including excellent yields, a short reaction time, mild reaction conditions and catalyst reusability. The heterocyclic compound Chromone, is associated with diverse biological activities of immense importance. The nitrogen containing heterocycle such as pyrimidine has attracted continuing interest because of its varied biological activities and its occurrence in natural medicinal plants. Pyrimidine and its derivatives are used as antifungal agents, antibacterial agents, anticancer agents, etc. Considering the importance of the two pharmacophores, promoted us to club both the pharmacophores in a single molecule using green protocol. The structures of the synthesized compounds were confirmed by spectral characterization such as IR, H NMR, CNMR and Mass spectral studies.

The nitrogen containing heterocycle such as pyrimidine has attracted continuing interest because of its varied biological activities and its occurrence in natural medicinal plants.Pyrimidine and its derivatives are used as pesticides, herbicides and insecticides [11,12].Marketed antifungal drugs such as Flucytosine, Voriconazole and Albaconazole, also contain pyrimidine nucleus [13].
The molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected characteristics of the original templates [14].It is a new concept in drug design and development to produce a new hybrid compound with improved affinity, potency and efficacy, when compared to the parent drugs [25].The selection of the two principles in the dual drugs is usually based on their observed (or anticipated) synergistic or additive pharmacological activities to enable the identification of highly active novel chemical entities.Hybrid drugs are basically designed to counterbalance the known side effects associated with the other hybrid part or to amplify its effect through action on another bio target or to interact with multiple targets as one single molecule [16,17] lowering the risk of drug-drug interactions and minimizing the drug resistance [18].The designing protocol of the synthesized derivatives is as shown in Figure 1.
Considering the focus on green synthesis in recent years, ionic liquid have attracted attention many of researchers.Ionic liquid have been referred as "designer solvents/ green solvents" because their physical and chemical properties can be adjusted by varying the cation and anion.
Taking in consideration the above mentioned points we have carried out the synthesis of coumarin-pyrimidine coupled hybrid derivatives 4(a-f) and 6(a-f) using [Et3NH][HSO4] as an solvent and easily recoverable Green catalyst (Scheme 1).

Figure 1.
The designing protocol of the synthesized derivatives.

Chemistry
Herein, we describe the utility of [Et3NH][HSO4] in molten state (Scheme 1), which is a low cost, mild, non-volatile and non-corrosive acidic ionic liquid, as an efficient Bronsted acid catalyst in solvent-free conditions for the Biginelli reaction.
We began our study with the model reaction of [HSO4] that was optimized by investigating various parameters such as mol percentage of catalyst at various temperatures.We screened the [Et3NH][HSO4] ionic liquid as catalyst at various loads such as 5, 10, 15, 20 mol % and at various temperatures such as 80, 90, 100, 110 °C as shown in Table 1.When 5 mol % of the catalyst was used at 100 °C the product 4a was obtained in 72 % yield in 150 min.Furthermore, the effect of the amount of catalyst was examined.We have studied the effect on various loads of catalyst such as 10, 15 and 20 mol % at 100 °C which gave the compound 4a with 76 % in 105 min, 95 % in 60 min and 95 % in 60 min., respectively.Therefore, considering 15 mol % as an efficient amount the reaction was carried out at various temperatures like 80 °C, 90 °C, 100 °C and 110 °C.The use of 15 mol % catalyst at 100°C gave the compound 4a with 95 % in 60 min.Therefore, 15 mol % of the [Et3NH][HSO4] ionic liquid as catalyst and solvent was considered to ensure the best yield (95 %) in short reaction time (60 min) at 100 °C (Entry 3 of Table 1).These observations make the process under study more expeditious and economic, safe and eco-friendly.The recovery and reusability of the catalyst was investigated for the synthesis of compound 4a.The findings are explained in Table 2; the recovered catalyst can be reused at least four additional times in subsequent reactions without a considerable decrease in its catalytic activity.
Total six novel ethyl 4-(6-substituted-4-oxo-4H-chromen-3-yl)-6-methyl-2-thioxo/oxo-1,2,3,4tetrahydropyrimidine-5-carboxylate derivatives 4(a-f) were synthesized following this synthetic protocol.The reactions were completed in about 60-85 min (monitored by TLC).The yields of synthesized novel compounds were in the range of 86-95 %.Melting points were determined in open capillary tubes and are uncorrected.The physical data for the compounds are presented in Table 3.The formation of the synthesized compounds was confirmed by IR, 1 H NMR, 13 C NMR, mass spectral analysis and elemental analysis.
Entry Temperature ( 0 C) Catalyst (mol %) Time(min) Yield (%) The synthesized derivatives 4(a-f) (1mmol) was allowed to react with hydrazine hydrate (1.2 mmol) under solvent free condition using [Et3NH][HSO4] as catalyst.The catalyst load and the temperature required for the synthesis of 6(a-f) was also studied.We had screened the [Et3NH][HSO4] ionic liquid as catalyst at various loads such as 5, 10, 15 mol % and at various temperatures such as 70, 80, 90 and 100 °C as shown in Table 4.When 5 mol % of the catalyst was used at 90 °C the product 6a was obtained in 88 % yield in 30 min.Furthermore, the effect of the amount of catalyst was examined.We have studied the effect on various loads of catalyst such as 10 and 15 mol % at 90 °C which gave the compound 6a with 87 % in 30 min and 85 % in 30 min., respectively.Therefore, considering 5 mol % as an efficient amount the reaction was carried out at various temperatures like 70 °C, 80 °C, 90 °C and 100 °C.The use of 5 mol % catalyst at 90°C gave the compound 6a with 88 % in 30 min.Therefore, 5 mol % of the [Et3NH][HSO4] ionic liquid as catalyst and solvent was considered to ensure the best yield (88 %) in short reaction time (30 min) at 90 °C (Entry 3 of Table 4).The recovery and reusability of the catalyst was investigated for the synthesis of compound 6a.The findings are explained in Table 5; the recovered catalyst can be reused at least four additional times in subsequent reactions without a considerable decrease in its catalytic activity.

Chemistry
All chemicals, unless otherwise specified, were purchased from commercial sources and were used without further purification.The major chemicals were purchased from Sigma Aldrich and Avra labs.The development of reactions was monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica gel 60 F254 aluminum sheets, visualized by UV light.
Infrared (IR) spectra were recorded on JASCO FTIR (PS 4000) using KBr pallet.Melting points were determined in open capillary tubes and are uncorrected.The 1 H-NMR and 13 C-NMR spectra of synthesized compounds were recorded on Bruker Advance II 400 NMR Spectrometer (Billerica, MA, USA) at 400 MHz Frequency in deuterated DMSO using TMS as internal standard (chemical shift δ in ppm).The chemical shifts are reported as NMR spectra δppm units.

Conclusion
In this study, a suite of novel chromone-pyrimidine coupled hybrid derivatives 4(a-f) and 6(a-f) has been synthesized using Green protocol.Use of green method, i.e. use of ionic liquid helped us in the synthesis of excepted derivatives in good yield and proving its advantage by avoiding pollution in the environment caused by hazardous chemicals.The mild reaction conditions, excellent yields in shorter reaction time and evasion of cumbersome work-up procedures make this process economically lucrative for industrial application with the advantage of reusability of catalyst.

Table 3 .
The formation of the synthesized compounds was confirmed by IR, 1 H NMR,13C NMR, mass spectral analysis and elemental analysis.