1,1′-Sulfinyldipyridinium bis (hydrogen sulfate) ionic liquid: synthesis and application in the temperature-influenced synthesis of novel pyranopyrimidinediones and pyranopyrimidinetriones

Abstract

A novel and robust dication homo-anionic ionic liquid with the properties of a Brønsted acid is shown to efficiently catalyse the reaction of salicylaldehyde and 6-amino uracil in ethanol to produce novel pyranopyrimidinediones and pyranopyrimidinetriones under ambient and reflux conditions, respectively. The ionic liquid can be synthesized from inexpensive, commercially available precursors. A mechanism is suggested for these transformations. The advantages of this method include novelty in terms of the ionic liquid, together with a high efficiency, easy work-up procedure and purification, convenient operation, mild and environmentally benign reaction conditions.

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Introduction

Designing and exploring novel methods to synthesize pharmacological agents within the framework of green chemistry are common goals for organic chemists trying to reduce both costs and potential environmental problems.¹ In this context, ionic liquids (ILs) have been proposed as both green solvents and as catalysts due to their unique chemical and physical properties, which include non-volatility, non-flammability, thermal stability and controlled miscibility.² ILs are now recognized in organic reactions as providing potential improvements in the control of product distribution, enhanced reactivity, ease of product recovery, catalyst immobilization and recycling.³ ILs with sulfate-functionalized Brønsted acid sites have attracted attention because they are non-volatile, non-corrosive, stable in air and can be easily recovered and reused.⁴ ILs have been explored in many organic transformations as they offer advantages of both liquid and solid acids and they have thus emerged as useful alternatives to traditional mineral liquid acids, such as sulfuric acid and hydrochloric acid, in chemical reactions.⁵ Thus they have attracted the attention of researchers looking for new ILs for the synthesis of novel bioactive heterocyclic molecules.

Pyrimidines are six-membered heterocyclic aromatic compounds with two nitrogen atoms at positions 1 and 3. Pyrimidine-embedded heterocyclic molecules are of great interest because they constitute an important class of natural and non-natural products, many of which have biological activity and clinical applications.⁶ Thymine, cytosine and uracil have a pyrimidine skeleton and are the building blocks of the nucleic acids DNA and RNA; they have widespread therapeutic applications. Some pyrimidines show significant in vitro activity against unrelated DNA and RNA, such as against the polio and herpes viruses; they also have diuretic, antitumour, anti-HIV and cardiovascular activities.⁷ In addition, various analogues of pyrimidines have been found to possess antibacterial,⁸ antifungal,⁹ antileishmanial,¹⁰ anti-inflammatory,¹¹ analgesic,¹² antihypertensive,¹³ antipyretic,¹⁴ antiviral,¹⁵ antidiabetic,¹⁶ antiallergic,¹⁷ anticonvulsant,¹⁸ antioxidant,¹⁹ antihistaminic,²⁰ herbicidal²¹ and anticancer activities.²² Many pyrimidines have been reported to potentially possess properties to depress the central nervous system²³ and they also act as calcium channel blockers.²⁴ These varied activities have led to the discovery of a plethora of drugs with a pyrimidine backbone (Fig. 1). Previous investigations have shown that pyrimidine-immobilized heterocyclic molecules such as zidovudine (I) and lamivudine (II) can be used in the treatment of HIV²⁵; brodiprim (III) and flucytosine (IV) are antibacterial and antifungal agents.²⁶ Methylphenobarbital (V) is used as an antiepileptic drug²⁷ and the 6-aryl uracil derivatives (VI) show antitumour activity.²⁸ Brodiprim is an effective antibacterial treatment.²⁹

Fig. 1 Drugs with pyrimidine backbones. I = zidovudine; II = lamivudine; III = brodiprim; IV = flucytosine; V = methylphenobarbital; and VI = 6-aryl uracil derivative.

Results and discussion

As part of our continuing work in devising eco-friendly methodologies for the synthesis of the pyran nucleus,³⁰ we report here the dramatic influence of a new task-specific IL for the synthesis of pyranopyrimidinediones and pyranopyrimidinetriones in an ethanol medium at room temperature and under reflux conditions, respectively (Scheme 1).

Scheme 1 Synthesis of the novel pyranopyrimidinedione and pyranopyrimidinetrione (products 4 and 5).

We first optimized the reaction conditions in terms of the catalyst for the model reaction of salicylaldehyde (1 mmol) and 6-amino uracil (2 mmol). The reaction was first carried out in the absence of a catalyst (entries 1 and 2, Table 1), but the reaction did not proceed, even under reflux conditions. Various Lewis and Brønsted acid catalysts were then screened for the formation of product 4 (Scheme 1). Lewis acids such as AlCl₃, ZnCl₂, FeCl₃, and (CH₂)₄SO₃Mim and Na p-TSA (entries 3–5, 13 and 15, Table 1) did not catalyse this transformation, even after long reaction times. Low yield of the desired product was obtained in the presence of p-TSA (entry 14, Table 1) and ILs such as [PySOCl]Cl, [PySOPy]Cl₂, [BMim]HSO₄, [PySOCl]HSO₄ and [PySOCl]TSO (entries 6, 7 and 10–12, Table 1). These observations suggest that the yield of the reaction could be improved in the presence of a strong Brønsted acidic catalyst. Therefore ILs such as [(CH₂)₄SO₃HMim]HSO₄ and [CMim]HSO₄ were used and yielded 65–75% of the desired product (entries 8 and 9, Table 1). The yield of the product was boosted to 84% in the presence of a catalytic amount of thionyl chloride (entry 16, Table 1). This inspired us to synthesize a novel IL with strong Brønsted acid sites together with thionyl (S=O) functionality to enhance the rate of the reaction. ILs based on pyridinium salts have attracted particular attention as they are easy to prepare and handle, have good solubility for many substrates and act as molecular catalysts. The synthesis of [(Py)₂SO][HSO₄]₂ (hydrophilic IL 3) was achieved in two steps. [(Py)₂SO]Cl₂ was first prepared by the reaction of pyridine with thionyl chloride in dichloromethane, followed by treatment with sulfuric acid to give the desired IL in a quantitative yield (Scheme 2).

Table 1 Screening of catalysts in the formation of product 4^a

Entry	Catalyst	Time (h)	Yield^b (%)
a Salicylaldehyde (1 mmol), 6-amino uracil (2 mmol) and 20 mol% catalyst in ethanol at room temperature.b Isolated yield.c Reflux conditions.
1	No catalyst	3	—
2	No catalyst	3	—^c
3	AlCl3	3	—
4	ZnCl2	3	—
5	FeCl3	3	—
6	[PySOCl]Cl	2	20
7	[PySOPy][Cl]2	2	30
8	[(CH2)4SO3HMim][HSO4]	1	76
9	[CMim][HSO4]	1	66
10	[BMim][HSO4]	3	50
11	[PySOCl][HSO4]	2	53
12	[PySOCl]TSO	3	25
13	(CH2)4SO3Mim	3	—
14	p-TSA	2	45
15	Na-PTSA	3	—
16	SOCl2	1	84
17	[PySOPy][HSO4]2	1	96

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Scheme 2 Synthesis of the novel IL with Brønsted acid properties.

The dicationic homo-anionic IL had exceptional catalytic activity and provided the corresponding product at an excellent yield as a result of its combined Lewis acid and Brønsted acid functionalities (entry 17, Table 1). The effect of the amount of catalyst was evaluated by using 5, 10, 15, 20, 25 mol% of the IL in the model reaction, which gave product 4 at 40, 70, 84, 96 and 96% yields, respectively. It was found that 20 mol% of the catalyst provided maximum yield. More than 20 mol% of the catalyst did not further improve the yield of the product or the reaction time. The performance of the reaction was also assessed using different solvents, such as chloroform, acetonitrile, DCM, acetone, DMF and THF. Non-polar solvents gave lower yields, even after increased reaction times (entries 1–4, Table 2). Ethanol was the best choice for this reaction when using 20 mol% of the catalyst (entry 9, Table 2).

Table 2 Influence of solvent on the synthesis of product 4^a

Entry	Solvent	Time (h)	Yield^b %
a Salicylaldehyde (1 mmol), 6-amino uracil (2 mmol) and catalyst (20 mol%), solvent (5 mL), room temperature.b Isolated yield.
1	Acetonitrile	3	46
2	DCM	3	20
3	Acetone	4	55
4	THF	4	30
5	Chloroform	3	56
6	DMF	4	77
7	Methanol	1	90
8	Water	1	80
9	Ethanol	1	96

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As the reaction proceeds, a nearly homogeneous mixture is formed (Fig. 2A) and the product is precipitated from the ethanol (Fig. 2B). The product was isolated by simple filtration and confirmed by spectral analysis. The ¹H-NMR spectrum (entry a, Table 3) shows remarkable singlets at δ = 4.81 and 5.77 ppm representing the benzylic methine proton and two amine protons, respectively. In the IR spectrum, the absorption bands at 3445, 3388 cm⁻¹ represent the presence of a primary amine and 1695, 1634 cm⁻¹ correspond to the carbonyls of amides, confirming the structure of product 4.

Fig. 2 (A) Reaction mixture at the start of the reaction and (B) reaction mixture after completion of the reaction.

Table 3 Synthesis of novel pyranopyrimidinediones catalysed by the novel dication homo-anionic Brønsted acidic IL in ethanol at room temperature^a

Entry	Product^b (4)	Time (h)	Yield^c (%)
a Reaction conditions: salicylaldehyde (1 mmol); 6-amino uracil (2 mmol); IL 20 mol%; temp = room temp; solvent = 5 mL 95% ethanol.b All products showed satisfactory spectroscopic data (IR, ^1H-NMR, ^13C-NMR and MS).c Yields refer to pure, isolated products.
a	R = H	1	96
b	R = 5-CH3O	1	96
c	R = 3-CH3CH2O	1	98
d	R = 3-OH	1	94
e	R = 4-OH	1	92
f	R = 5-OH	1	94
g	R = 3,4-OH	1	92
h	R = 5-Cl	1.2	95
i	R = 5-Br	1	96
j	R = 5-NO2	1.5	93
k	R = naphthyl	1.5	90

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This serendipitous result led us to further explore the scope and general utility of this novel transformation. A series of salicylaldehydes was treated with 6-amino uracil under the optimized reaction conditions. Both electron-donating (entries b–g, Table 3) and electron-deficient (entries h–k, Table 3) salicylaldehydes gave the corresponding pyranopyrimidinediones in excellent yield (>82–96%), indicating an insignificant stereo-electronic effect (entries a–k, Table 3).

Having succeeded in the synthesis of pyranopyrimidinediones, we investigated the influence of temperature and performed the reaction of salicylaldehyde with 6-amino uracil in 95% ethanol at reflux temperatures in presence of 20 mol% IL 3 (Scheme 3). However, instead of the expected product 7, we observed the unexpected formation of the novel pyranopyrimidinetrione 5 at 87% yield (Scheme 3). Fig. 3 shows the IR spectrum of 6-amino uracil and the products 4 (entry a, Table 3) and 5 (entry a, Table 4). The bands due to the –NH₂ in 6-amino uracil and the product 4 (entry a, Table 3) at 3445 and 3388 cm⁻¹ disappear in product 5 (entry a, Table 4) and confirmed its formation. The pyranopyrimidinediones 4a–4k and the pyranopyrimidinetrione 5a–5d are unequivocally confirmed by FT-IR, ¹H-NMR, ¹³C-NMR and MS analysis. The structure of 5 (entry a, Table 4) was further confirmed by X-ray crystallography, which showed the geometry of the crystal to be monoclinic with the two rings twisted out-of-plane to minimize the steric interactions (Fig. 4) ³¹

Scheme 3 Synthesis of the novel pyranopyrimidinetriones.

Fig. 3 IR spectra of 6-amino uracil and products 4a and 5a.

Table 4 Temperature-influenced synthesis of novel pyranopyrimidinetriones catalysed by the dication homoanionic Brønsted acidic IL in ethanol^a

Entry	Product^b (5)	Time (h)	Yield^c (%)
a Reaction conditions: salicylaldehyde (1 mmol); 6-amino uracil (2 mmol); IL 20 mol%; temp = 80 °C; solvent = 5 mL of 95% ethanol.b All products showed satisfactory spectroscopic data (IR, ^1H-NMR, ^13C-NMR and MS).c Yields refer to pure, isolated products.d For electron-withdrawing substituents, the formation of product 4 was observed instead of product 5.
a	R = H	5	94
b	R = 5-CH3O	6	92
c	R = 3-CH3CH2O	6	94
d	R = 5-OH	6	92
e^d	R = 5-NO2	10	80
f^d	R = 3,5-Cl	10	84

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Fig. 4 ORTEP diagram of product 5a (Table 4).

To explore the scope of the reaction, other salicylaldehydes were tested and the results are summarized in Table 4. We observed that the electron-rich salicylaldehydes underwent a smooth reaction with 6-amino uracil to give the desired pyranopyrimidinetriones at excellent yields. In the case of the electron-deficient salicylaldehydes, product 4 was obtained instead of product 5, even after prolonged heating. We were unable to explain this anomaly.

A speculative mechanism for formation of products 4 and 5 is shown in Scheme 4. The synergistic combination of the acidic group and the thionyl group are the key factors in increasing the electrophilicity of the carbonyl carbon of 1, favoring the nucleophilic attack of 2. This is followed by ring closure, resulting in the formation of intermediate 6. The protonation of 6 by the IL and the subsequent Michael attack of the second molecule of 2 results in the formation of the desired product 4. The protonation of the amino group by IL 3 under thermal conditions is followed by the nucleophilic attack of water, yielding the corresponding product 5 by keto–enol tautomerization.

Scheme 4 Plausible mechanism for formation of products 4 and 5.

Recycling of the catalyst is one of the most significant criteria of green chemistry, hence the recovery and reuse of the IL catalyst was examined. The separation of the product was very easy and could be achieved by filtration through an ordinary filter paper. The IL was conveniently recovered and reused after heat treatment under vacuum at 70 °C for 2 h. The reusability of the recovered catalyst was studied in a fresh reaction and it was found that the IL could be reused at least five times without a significant decrease in the reaction yield (96, 93, 90, 89 and 88% yield, respectively) (Fig. 5).

Fig. 5 Recycling of catalyst.

Conclusion

We introduced a temperature-influenced IL-catalysed reaction of salicylaldehyde and 6-amino uracil that has led to a new class of pyranopyrimidinediones and pyranopyrimidinetriones. A detailed reaction mechanism is suggested. In general, all the reactions are very clean and reasonably fast. This method offers marked improvements with regard to operational simplicity, reaction time, mild reaction conditions, general applicability, high isolated yields of products, greener procedure, avoiding hazardous organic solvents and effective reusability of IL up to five runs without any loss of activity is a bonus advantage of present protocol.

Experimental section

The various substituted salicylaldehydes (Sigma-Aldrich) and 6-amino uracil (Sigma-Aldrich) were used as received. The IR spectra were recorded on a Perkin-Elmer FT-IR-783 spectrophotometer. The NMR spectra were recorded on a Bruker AC-300 (300 MHz for ¹H-NMR and 75 MHz for ¹³C-NMR) spectrometer in DMSO-d₆ and CDCl₃ using TMS as an internal standard; the δ values are expressed in ppm. Single-crystal X-ray crystallography was performed on a Bruker Kappa APEX II (SAIF, IIT, Madras).

General procedures

Synthesis of IL [(Py)₂SO]Cl₂. A three-necked flask (100 mL) equipped with a condenser was charged with pyridine (0.79 g, 10 mmol) in dry dichloromethane (50 mL). Under rigorous stirring, 0.36 mL (5 mmol) of thionyl chloride was added dropwise over a period of 30 min and then the reaction mixture was stirred for 12 h at room temperature. The IL [(Py)₂SO]Cl₂ was obtained by the distillation of dichloromethane, washed with dry diethyl ether (3 × 10 mL) and purified by drying in a vacuum at 80 °C to remove the residual dichloromethane.

Synthesis of IL [(Py)₂SO][HSO₄]₂. A round-bottomed flask (50 mL) was charged with [(Py)₂SO]Cl₂ (10 g, 36 mmol) and sulfuric acid (7.056 g, 72 mmol) was added over a period of 5 min at 0–5 °C. The reaction mixture was then stirred for 12 h at 80 °C to give [(Py)₂SO][HSO₄]₂ at a yield of 98%.

Synthesis of pyranopyrimidinedione. A mixture of salicylaldehyde (1 mmol) and 6-amino uracil (2 mmol) in the Brønsted acid IL [(Py)₂SO][HSO₄]₂ (20 mol%) was stirred at ambient temperature for the times indicated in Table 3. The progress of the reaction was monitored by TLC. After completion of the reaction, the precipitated product was filtered and washed with water and ethanol.

Synthesis of pyranopyrimidinetrione. A mixture of salicylaldehyde (1 mmol), 6-amino uracil (2 mmol) and Brønsted acidic IL [(Py)₂SO][HSO₄]₂ (20 mol%) in refluxing ethanol (5 mL) was stirred for the times given in Table 4. After completion of the reaction had been confirmed by TLC, the reaction mixture was cooled to room temperature. The precipitated product was filtered and washed with water (10 mL) and methanol (5 mL) to give the pure product.

Acknowledgements

Author DMP thanks the DST Fast Track Scheme New Delhi for financial assistance [no. SB/FT/CS-154/2012].

References

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31. ESI.†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1005214. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra10410b

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