Mn doped ZrO₂ as a green, efficient and reusable heterogeneous catalyst for the multicomponent synthesis of pyrano[2,3-d]-pyrimidine derivatives

Abstract

A simple and an efficient method has been developed for the one-pot multicomponent synthesis of pyrano[2,3-d]-pyrimidine derivatives. This was achieved through the condensation reaction between dimethylbarbituric acid, aromatic aldehyde and malononitrile in the presence of a Mn/ZrO₂ heterogeneous catalyst with ethanol/water mixture as solvent for only 1 hour. Further advantages of this synthesis methodology include excellent yields, mild reaction conditions, atom economy, environmentally friendliness, reusable catalyst and no need for chromatographic separations.

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Multicomponent reactions (MCRs) have emerged as an exciting field of research where three or more reactants are all added together in a single-step to afford pure products in high yield. MCRs are mostly used in organic synthesis, biological discovery, combinatorial libraries and agrochemical synthesis.^1–4 The simple protocols, inexpensive reactants and green principles involved make MCRs an attractive field of study.4 well planned MCRs afford higher chemical yields than multiple-step syntheses, resulting in conservation of energy and manpower and are often complete in relatively short reaction times⁵ making it an environmentally benign and elegant process.^1,6,7

The use of heterogeneous catalysts with recyclability and reusability potential add value to the one-pot reactions involving MCRs.⁸ The use of heterogeneous catalysts has gained prominence in the field of heterocyclic synthesis because of simple work-up, cost effectiveness, mild reaction conditions, atom economy, good activity, easy recyclability and scope to modify the surface properties.^9,10 Heterogeneous materials are used as green reaction media due to their distinct chemical and physical properties such as non-volatility, thermal stability, non-inflammability, controlled miscibility¹⁰ and playing a vital role as catalysts in the MCRs. Metal oxides are good contenders in this regard as they have a proven track record as catalysts and supports. Thermal calcination of such materials at 773 K, lead to the formation of acidic/basic mixed metallic oxides with moderate surface-area and can act as catalysts for various condensation reactions.

Zirconia (ZrO₂) is an interesting support material where a particular zirconia phase (cubic, tetragonal etc.) can be stabilized down to room temperature by the amount of dopant added and this can promote the activity of the supported metal catalysts. ZrO₂ has good redox and chemical stability and is an acid-based bi-functional catalyst, which is stable in alkaline or acidic solutions.¹¹ ZrO₂ in combination with metals (cermets) have been used in organic synthesis¹² and manganese has previously been used as dopant in zirconia. The crystalline structure of ZrO₂ is one of the key factors affecting the structure–activity relationships of Mn-based catalysts.¹³ The Mn/ZrO₂ solid material possesses both Bronsted and Lewis acids centers.

Pyranes and pyrimidine derivatives are an important class of heterocyclic compounds that feature in a number of pharmaceutical drugs and natural products of medicinal interest. This class of compounds exhibit a range of sought after features including antimicrobial,¹⁴ antioxidant,¹⁵ anti-tumor,¹⁶ antimalarial,¹⁷ antimetabolite,¹⁷ antileishmanial,¹⁸ antiviral,¹⁹ antihypertensive,²⁰ anti-convulsant,²¹ and anti-inflammatory activities.²² The computational chemistry of many of pyrimidine derivatives has also been documented.²³

Literature search shows several described methods for synthesis of various pyrano[2,3-d]pyrimidine derivatives. Such protocols employed [Ch–OSO₃H]₃W₁₂PO₄₀,²⁴ diammoniunhydrogenphosphate²⁵ microwave irradiation,^26,27 DABCO,²⁸ electrolysis,^29,30 γ-Fe₂O₃@HAp–Si(CH₂)₃SO₃H,³¹ L-proline,³² NaHCO₃ (ref. 33) and urea³⁴ etc. as catalysts. In general terms, many of these approaches face few or more of the limitations such as using toxic reagents, strong acidic or basic conditions, costly reagents and catalysts, strict reaction conditions, tedious steps, and low product yields or long reaction times, which limit their use in practical applications. Thus, researchers are compelled to find new and improved approaches for environmental friendly synthesis of these heterocyclic molecules with impressive yields. The best of our knowledge there are no reports on the multicomponent facile one-pot synthesis of pyrano[2,3-d]pyrimidine derivatives and with EtOH–water mixture as solvent system. In this manuscript we report the synthesis of pyrano[2,3-d]-pyrimidine derivatives by using Mn/ZrO₂ as a catalyst in the presence of equal ratio of EtOH :water for the first time. We report a novel protocol for the synthesis of those derivatives using an inexpensive and robust catalyst which accomplishes the reactions in short reaction times.

Reactions were carried out during preliminary investigations to screen for various catalysts and under catalyst-free conditions and varying solvents. Reactions with 1,3-dimethylbarbituric acid (1 mmol), substituted aldehyde (1 mmol) and malononitrile (1.1 mmol) and water or ethanol as solvent and no catalyst showed no reaction at RT even after 12 h under reflux conditions, (Table 1, entries 1–4). To obtain the most efficient catalytic conditions, the title reaction was investigated in the presence of different catalyst materials such as alumina, silica, MnCl₂, and ZnCl₂ and in the presence of EtOH and water (50 : 50 v/v). The obtained results are summarized in (Table 1, entries 5–8) and indicate that the reaction did not occur in the presence of alumina or silica, and the yield obtained was very low with MnCl₂ or ZnCl₂. Further, we tested the scope of reaction in the presence of ionic liquids such as L-proline, (Bmim)BF₄ and (Bmim)OH, but yields were low (Table 1, entry 9–11).

Table 1 Optimization of reaction conditions of the three-component synthesis^a

Entry	Catalyst	Solvent	Condition	Time (h)	Yield^b (%)
a Reaction conditions: dimethylbarbituric acid (1 mmol), substituted aldehyde (1 mmol) and malononitrile (1.1 mmol) and EtOH : water (1 : 1 v/v, 10 mL), R.T.b Isolated yields. — no reaction.
1	No catalyst	H2O	R.T	24	—
2	No catalyst	EtOH	R.T	24	—
3	No catalyst	H2O	Reflux	12	Trace
4	No catalyst	EtOH	Reflux	12	Trace
5	Al2O3	EtOH : H2O	R.T	10	—
6	SiO2	EtOH : H2O	R.T	10	—
7	MnCl2	EtOH : H2O	R.T	5	28
8	ZnCl2	EtOH : H2O	R.T	8	18
9	L-Proline	EtOH : H2O	Reflux	3	48
10	(Bmim)BF4	EtOH : H2O	Reflux	4	44
11	(Bmim)OH	EtOH : H2O	Reflux	3.5	51
12	CuO (30 mg)	EtOH : H2O	R.T	6	42
13	MnO (30 mg)	EtOH : H2O	R.T	3.5	53
14	ZrO2 (30 mg)	EtOH : H2O	R.T	4	48
15	1% Mn/ZrO2 (30 mg)	EtOH : H2O	R.T	3	76
16	2.5% Mn/ZrO2 (30 mg)	EtOH : H2O	R.T	1	90
17	5% Mn/ZrO2 (30 mg)	EtOH : H2O	R.T	1	88
18	2.5% Mn/ZrO2 (40 mg)	EtOH : H2O	R.T	1	89
19	2.5% Mn/ZrO2 (50 mg)	EtOH : H2O	R.T	1.5	87
20	2.5% Mn/ZrO2 (20 mg)	EtOH : H2O	R.T	2	73
21	2.5% Mn/ZrO2 (10 mg)	EtOH : H2O	R.T	2	67
22	2.5% Mn/ZrO2 (40 mg)	CH3CN	R.T	3.5	46
23	2.5% Mn/ZrO2 (40 mg)	DMF	R.T	4	35
24	2.5% Mn/ZrO2 (30 mg)	EtOH	R.T	3	74
25	2.5% Mn/ZrO2 (30 mg)	H2O	R.T	3.5	69

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The reactions were also investigated using 30 mg of CuO, MnO₂, ZrO₂, as catalysts under room temperature conditions in 1 : 1 ethanol–water mixture. The CuO, MnO₂ and ZrO₂ gave yields of 42%, 53% and 48%, respectively (Table 1 entry 12–14). The reaction was repeated under similar conditions using Mn/ZrO₂ which gave an excellent yield of 90% in 1 h once optimum dopant percentage had been established. The impact of Mn loading on zirconia in tuning its catalytic efficiency was further investigated. To find the ideal loading of Mn on ZrO₂ on catalyst activity, reactions with 1%, 2% and 5% Mn doped ZrO₂ were carried out under otherwise comparable conditions. The percentage of Mn loading was found to have an influence on the reaction yield as well as reaction time (Table 1, entries 15–17). Using 1% Mn/ZrO₂ catalyst yielded 76% product in 3 h under EtOH–water mixture solvent conditions (Table 1, entry 15). A 2.5% Mn loading was found optimal with 90% yield in 1 h (Table 1, entry 16). A further increase of metal (5%) loading led to a slight decreased yield (88%) (Table 1, entry 17).

In an effort to find the optimal reaction conditions, the reaction was carried out using various amounts of catalyst at RT. It was found that 30 mg catalyst gave a maximum yield of 90% in 1 h. Using more than 30 mg of catalyst for the reaction had no significant improvement on the yield or the reaction time. However, the decrease in amount of the catalyst to 20 and 10 mg, decreased the product yield to 89%, 87%, 73% and 67%, respectively (Table 1, entries 18–21).

An interrogation of the experimental results and the effect of various polar and non-polar solvents on the three component reaction clearly indicate that the EtOH–water solvent system plays a vital role in facilitating the reaction (Table 1), comparatively less polar solvents like CH₃CN, DMF afforded poor yields (Table 1, entries 22 and 23). The protic polar (ethanol, water) solvents on their own failed to produce the anticipated high yield (Table 1, entry 24 and 25) but interestingly, the miscible mixture of EtOH : H₂O (50 : 50 v/v) gave a high 90% yield. This effect can be explained by a simple acid–base bi-functional catalysis mechanism facilitated by the strong hydrogen bond interaction at the organic–aqueous ethanol interface which stabilizes the reaction intermediate. A highly-polar solvent which dissipates heat faster possibly provide optimum conditions for the formation of intermediates, and their conversion to final products on the catalyst surface.

Using the optimised reaction conditions, the applicability of the protocol was evaluated for the synthesis of other pyrano[2,3-d]pyrimidine derivatives with various aromatic aldehydes. The Mn/ZrO₂ heterogeneous catalyst proved to be an ideal material to catalyse the facile one-pot synthesis of pyrano[2,3-d]-pyrimidine derivatives with good to excellent yields. All the reaction products with other details are depicted in Table 2. Interestingly, the substrates used and reaction yields obtained suggest that irrespective of electron-withdrawing and electron donating groups in ortho, meta and para positions of the aromatic ring, using Mn/ZrO₂ as catalyst, all the substrates gave good to excellent yields of desired pyrano[2,3-d]-pyrimidine derivatives (Table 2). The plausible reaction pathway is shown in Scheme 2. All the resultant products were characterized and molecular structures were confirmed by FTIR, ¹H NMR, ¹³C NMR and ¹⁵N NMR (GHSQC) spectral analysis (ESI†).

Table 2 Synthesis of pyrano[2,3-d]-pyrimidines derivatives catalyzed by Mn/ZrO₂ catalyst^a,b

Entry	R	Product	Yield (%)	Mp °C	Lit Mp °C
a Reaction conditions: 1,3-dimethylbarbituric acid (1 mmol), substituted aldehyde (1 mmol) and malononitrile (1.1 mmol) and EtOH : water (1 : 1 v/v, 10 mL), R.T.b All synthesized compounds are identified and their structures were conformed with IR, ^1H NMR, ^13C NMR spectral data and melting points as compared with literature values. — new compounds/no literature available.
1	4-MeO–Ph	4a	85	225–226	225–227 (ref. 29 and 30)
2	2,3-(MeO)2–Ph	4b	86	216–218	—
3	2,5-(MeO)2–Ph	4c	85	231–233	—
4	2-Br–Ph	4d	84	202–203	—
5	4-Br–Ph	4e	79	210–211	—
6	2-Cl–Ph	4f	78	235–237	237–238 (ref. 29)
7	3-NO2–Ph	4g	83	221–223	—
8	3-OH–Ph	4h	79	196–198	—
9	Ph	4i	84	219–220	219–222 (ref. 29)
10	2-F–Ph	4j	90	237–238	—
11	3-F–Ph	4k	84	214–215	—

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Scheme 1 Synthesis of pyrano[2,3-d]-pyrimidine derivatives.

Scheme 2 Plausible reaction mechanism for the formation of pyrano[2,3-d]-pyrimidine derivatives.

BET surface and ICP analysis

Fig. 1 illustrates the N₂ adsorption–desorption isotherms and pore size distribution curves for the Mn doped ZrO₂. The catalyst displays the characteristic hysteresis loop of a Type IV isotherm (IUPAC) lying in the p/p_o range of 0.6–0.95 typical for mesoporous materials. The pore size distribution and specific area was calculated from the Barrett–Joyner–Halenda (BJH adsorption) and Brunauer–Emmett–Teller methods respectively. The BET surface area of Mn/ZrO₂ was confirmed to be 188.47 m² g⁻¹ with an average pore size and volume of 11.9 nm and 0.567 cm³ g⁻¹ respectively. The metal wt% obtained from ICP is in correlation with the nominal weight loading.

Fig. 1 BET surface of Mn/ZrO₂ catalyst.

Powder X-ray diffractogram (XRD) analysis

The XRD patterns of the calcined 2% Mn on ZrO₂ catalyst are demonstrated in Fig. 2. The high intensity of the peaks suggested that all the prepared catalysts are polycrystalline in nature. The d-spacing's at 2 theta angles of 25.3, 34.9, 38.9, and 55.3 for Mn₂O₃ respectively. This is in good agreement with the ICDD PDF no. 65-7467. From the XRD diffractograms it is evidenced that Mn₂O₃ is the major phase in all the catalysts. There is a formation of additional phase i.e. Mn₃O₄ is observed. The d-spacing's at a 2 theta angles of 32.5, 54.6 and 63.1 for Mn₃O₄ which is correspond to the ICDD PDF no. 39-1218 for Mn₃O₄ phase. The ZrO₂ showed the sharp peaks corresponding to tetragonal ZrO₂ ICDD PDF no. 88-1007, 2θ = 25.7, 38.2, 49.8, and 55.7.

Fig. 2 Powder X-ray diffractogram spectra of Mn/ZrO₂ catalyst.

Infrared-spectra (FT-IR)

Fig. 3 displays FT-IR spectra of mesoporous Mn on ZrO₂ catalyst exhibited characteristic absorption band at 3368.6 cm⁻¹, 1655.4 cm⁻¹ and 1368.3 cm⁻¹ corresponding to the vibration of hydroxyl group, which involve the O–H vibrating mode of traces of adsorbed water. Absorption band at 749.8 cm⁻¹ and 492.3 cm⁻¹ was due to stretching peaks of Mn–O–Mn and Mn–O vibrations, respectively in accord with literature values.³⁵ A strong absorption band was observed at 1136.3 cm⁻¹ for the asymmetric stretching of Zr–O group, supporting the formation of ZrO₂ groups on their surfaces. No organic groups were found to be surface adsorbed based on IR results.

Fig. 3 FT-IR image of Mn/ZrO₂ catalyst.

SEM & TEM analysis

The SEM image of the prepared catalyst is shown in Fig. 4. The catalyst was crystalline in nature but with a coarse surface morphology. The manganese oxide particles were observed as hexagonal-shaped particles which were dispersed on the surface of the zirconia. The manganese oxide particles are shown in a red colour circles in Fig. 4. These observations are also in agreement with literature.³⁶ The TEM images showed that the zirconia particles are irregular and oval-shaped. The red circles in Fig. 5 shows the manganese oxide particles which might be agglomerated on the surface of zirconia.

Fig. 4 SEM image of Mn/ZrO₂ catalyst.

Fig. 5 TEM image of Mn/ZrO₂ catalyst.

Reusability of Mn/ZrO₂

To test reusability, a recycling experiment was employed using a model reaction. Thus, after completion of reaction, the catalyst was recovered by filtration, washed with ethanol and dried under vacuum. The recovered catalyst was re-used for six times with a slight loss in catalytic activity (Fig. 6). The minor loss perceived in the catalytic activity after 6th run could be due to poisoning by organic impurities.

Fig. 6 Recyclability of Mn/ZrO₂ catalyst.

Conclusions

In conclusion, we report an environmentally benign and an efficient one-pot multicomponent green synthesis of pyrano-[2,3-d]-pyrimidine derivatives using Mn/ZrO₂ as catalyst in green solvent media and with good atom efficiency. This simple and recyclable heterogeneous catalyst, Mn/ZrO₂ shows high catalytic activity for multicomponent reactions. The current method deals several advantages such as short reaction time, cost-effectiveness, purity of products, excellent yields, use of small amount of inexpensive catalyst and environmentally benign green solvent.

Experimental

Catalyst preparation

Mn doped ZrO₂ of various wt% was prepared by a wet impregnation technique as described in our earlier reports.^37,38 5.0 g of zirconium oxide powder (Alfa Aesar Chemical) was suspended in 250 mL of double distilled water and mixed with the desired masses of MnCl₂ (manganese(II) chloride tetrahydrate, Aldrich) based on the weight percentages of interest. The mixture was stirred for 4 h using a magnetic stirrer at room temperature (RT) and then heated to 90 °C for 4 h. The precipitate was dried in an air oven at 110–120 °C for 12 h, followed by calcination at 450 °C for 5 h to afford the 1%, 2.5% & 5% w/w of the Mn/ZrO₂ catalysts.

General procedure for the synthesis of pyrano[2,3-d]-pyrimidines

A solution containing dimethylbarbituric acid (1 mmol), substituted aldehyde (1 mmol), malononitrile (1.1 mmol) and Mn/ZrO₂ (30 mg) in mixture of EtOH : H₂O (1 : 1 v/v, 10 mL) was continuously stirred for 1.0 h at RT using a magnetic stirrer (Scheme 1). The progress and completion of the reaction was monitored by TLC. The reaction mixture was then filtered, and the filtrate was subsequently evaporated under reduced pressure to obtain the crude product which was recrystallized with ethanol to afford pure product (4a–k). The recovered catalyst was subjected to washing with ethanol, dried and re-used for up to six cycles.

7-Amino-5-(4-methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4a). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.07 (s, 3H, NCH₃), 3.36 (s, 3H, NCH₃), 3.72 (s, 3H, OCH₃), 4.31 (s, 1H, CH), 6.83 (d, J = 8.2 Hz, 2H, ArH), 7.14 (d, J = 8.04 Hz, 2H, ArH), 7.29 (s, 2H, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.64, 29.74, 35.81, 55.02, 58.55, 89.09, 113.64, 119.17, 128.18, 136.81, 149.95, 150.87, 157.88, 158.38, 160.45; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.29 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3368, 3307, 3181, 2965, 2188, 1682, 1680, 1605, 1508; HRMS of [C₁₇H₁₆N₄O₄ − H] (m/z): 339.2011; calcd: 339.2021.

7-Amino-5-(2,3-dimethoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4b). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.06 (s, 3H, NCH₃), 3.36 (s, 3H, NCH₃), 3.75 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 4.61 (s, 1H, CH), 6.71 (d, J = 7.04 Hz, 1H, ArH), 6.87 (d, J = 8.00, 1H, ArH), 6.94 (t, J = 7.96, 1H, ArH), 7.22 (s, 2H, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.59, 29.07, 31.06, 55.49, 58.15, 59.90, 83.77, 111.29, 119.07, 120.70, 123.60, 136.99, 146.32, 149.94, 151.28, 152.24, 157.85, 160.37; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.22 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3317, 2937, 2188, 1681, 1645, 1474; HRMS of [C₁₈H₁₈N₄O₅ + Na] (m/z): 393.1166; calcd: 393.1175.

7-Amino-5-(2,5-dimethoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4c). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.07 (s, 3H, NCH₃), 3.38 (s, 3H, NCH₃), 3.65 (s, 3H, OCH₃), 3.69 (s, 3H, OCH₃), 4.58 (s, 1H, CH), 6.64 (d, J = 3.02 Hz, 1H, ArH), 6.74 (dd, J = 8.9, 3 Hz, 1H, ArH), 6.89 (d, J = 8.9 Hz, 1H, ArH), 7.15 (s, 2H, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.59, 29.00, 31.32, 55.22, 56.34, 57.63, 88.05, 111.51, 112.76, 115.37, 119.02, 130.99, 150.00, 150.23, 151.52, 153.15, 158.15, 160.34; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.15 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3302, 3175, 2934, 2194, 1715, 1683, 1634, 1599, 1487; HRMS of [C₁₈H₁₈N₄O₅ − H] (m/z): 369.0389; calcd: 371.0395.

7-Amino-5-(2-bromophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4d). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.05 (s, 3H, NCH₃), 3.36 (s, 3H, NCH₃), 4.86 (s, 1H, CH), 7.11–7.15 (m, 1H, ArH), 7.28 (d, J = 4.2 Hz, 2H, ArH), 7.33 (s, 2H, NH₂), 7.53 (d, J = 8.00 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.58, 29.12, 35.80, 57.36, 88.23, 118.42, 122.77, 128.07, 128.64, 130.25, 132.45, 149.97, 151.47, 157.64, 160.28; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.33 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3310, 2930, 2913, 1684, 1637, 1470; HRMS of [C₁₆H₁₃BrN₄O₃ − H] (m/z): 387.0103; calcd: 387.0093.

7-Amino-5-(4-bromophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4e). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.07 (s, 3H, NCH₃), 3.34 (s, 3H, NCH₃), 4.32 (s, 1H, CH), 7.21 (d, J = 8.00 Hz, 2H, ArH), 7.35 (s, 2H, NH₂), 7.47 (d, J = 8.00 Hz, 2H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.62, 29.09, 36.04, 58.03, 88.22, 118.85, 119.80, 129.67, 131.07, 143.54, 149.95, 151.15, 157.57, 160.43; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.35 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3426, 3299, 2930, 2189, 1683, 1633, 1487.

7-Amino-5-(2-chlorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4f). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.06 (s, 3H, NCH₃), 3.36 (s, 3H, NCH₃), 4.86 (s, 1H, CH), 7.23–7.36 (m, 6H, ArH, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.59, 29.11, 33.52, 57.18, 87.97, 118.52, 127.46, 128.37, 129.24, 132.17, 141.08, 149.97, 151.50, 157.76, 160.28; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.30 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3382, 3310, 3193, 2959, 2193, 1703, 1684, 1638, 1474; HRMS of [C₁₆H₁₃ClN₄O₃ − H] (m/z): 343.0992; calcd: 343.1008.

7-Amino-5-(3-nitrophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4g). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.01 (s, 3H, NCH₃), 3.34 (s, 3H, NCH₃), 5.12 (s, 1H, CH), 7.43 (d, J = 8.00 Hz, 1H, ArH), 7.48 (s, 2H, NH₂), 7.51 (s, 1H, ArH), 7.64 (t, J = 8.00, 1H, ArH), 7.83 (d, J = 8.00 Hz, 1H, ArH); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.57, 29.11, 30.77, 56.62, 88.33, 118.40, 123.63, 128.02, 130.73, 133.42, 138.38, 149.05, 149.87, 151.82, 158.31, 160.50; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.48 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3373, 3306, 3184, 2957, 2196, 1706, 1683, 1632, 1522, 1490; HRMS of [C₁₆H₁₃N₅O₅ − H] (m/z): 354.0844; calcd: 354.0838.

7-Amino-5-(3-hydroxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4h). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.09 (s, 3H, NCH₃), 3.35 (s, 3H, NCH₃), 4.21 (s, 1H, CH), 6.58–6.66 (m, 3H, ArH), 7.06 (t, J = 8.00 Hz, 1H, ArH), 7.29 (s, 2H, NH₂), 8.42 (s, 1H, OH); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.65, 29.05, 36.35, 58.62, 88.98, 113.76, 114.15, 117.92, 119.05, 129.19, 145.48, 149.94, 150.96, 157.22, 160.43, 165.86; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.29 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3370, 3303, 3199, 2965, 2197, 1783, 1636, 1598, 1484; HRMS of [C₁₆H₁₄N₄O₄ − H] (m/z): 325.0894; calcd: 325.0900.

7-Amino-1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4i). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.07 (s, 3H, NCH₃), 3.35 (s, 3H, NCH₃), 4.31 (s, 1H, CH), 7.18–7.28 (m, 5H, ArH), 7.30 (s, 2H, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.63, 29.07, 36.47, 58.63, 88.78, 119.01, 126.73, 127.28, 129.49, 130.44, 144.08, 149.97, 151.09, 157.63, 160.45; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.30 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3380, 3307, 3193, 2866, 2196, 1703, 1682, 1639, 1607, 1493; HRMS of [C₁₆H₁₄N₄O₃ − H] (m/z): 309.0984; calcd: 309.0988.

7-Amino-5-(2-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4j). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.06 (s, 3H, NCH₃), 3.35 (s, 3H, NCH₃), 4.61 (s, 1H, CH), 7.11 (t, J = 7.68 Hz, 2H, ArH), 7.24–7.27 (m, 2H, ArH), 7.35 (s, 2H, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.60, 29.07, 30.42, 57.16, 87.59, 115.36, 118.74, 124.43, 128.70, 128.78, 129.69, 149.95, 151.43, 157.93, 158.78, 160.75; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.35 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3384, 3311, 3194, 2962, 2195, 1683, 1637, 1509, 1488; HRMS of [C₁₆H₁₃FN₄O₃ − H] (m/z): 327.0889; calcd: 327.0893.

7-Amino-5-(3-fluorophenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrano[2,3-d]-pyrimidine-6-carbonitrile (4k). ¹H NMR (400 MHz, DMSO-d₆) δ = 3.07 (s, 3H, NCH₃), 3.34 (s, 3H, NCH₃), 4.36 (s, 1H, CH), 7.02–7.10 (m, 3H, ArH), 7.32–7.34 (m, 3H, ArH, NH₂); ¹³C NMR (100 MHz, DMSO-d₆): δ 27.62, 29.08, 36.20, 58.10, 88.11, 113.89, 114.50, 118.85, 123.45, 130.05, 147.01, 147.07, 149.99, 151.29, 157.62, 160.51; ¹⁵N NMR (40.55 MHz, DMSO-d₆) δ 7.32 (s, 2H, NH₂); IR (KBr, cm⁻¹): 3382, 3305, 3192, 2194, 1711, 1683, 1635, 1613, 1490.

Acknowledgements

Authors are grateful to the National Research Foundation of South Africa for financial support and University of KwaZulu-Natal for the research facilities.

Notes and references

1. A. Sanchez, L. Quijano, M. Melguizo and M. Nogeras, Monatsh. Chem., 1989, 120, 1119.
2. C. Kalinski, M. Umkehrer, L. Weber, J. Kolb, C. Burdack and G. Ross, Mol. Diversity, 2010, 14, 513–522.
3. B. B. Toure and D. G. Hall, Chem. Rev., 2009, 109, 4439–4486.
4. C. C. Razvan, E. Ruijter and R. V. A. Orru, Green Chem., 2014, 16, 2958–2975.
5. Y. Huang, A. Yazbak and A. Domling, in Green Techniques for Organic Synthesis and Medicinal Chemistry, John Wiley & Sons, Ltd, Chichester, UK, 2012, pp. 497–522.
6. A. Domling, W. Wang and K. Wang, Chem. Rev., 2012, 112, 3083–3135.
7. J. M. Quintela, C. Peinador and M. J. Moreira, Tetrahedron, 1995, 51(20), 5901–5912.
8. M. J. Climent, A. Corma and S. Iborra, RSC Adv., 2012, 2, 16–58.
9. S. Marc-Olivier and L. Chao-Jun, Chem. Soc. Rev., 2012, 41, 1415–1427.
10. J. H. Clark, Acc. Chem. Res., 2002, 35, 791–797.
11. K. Tanabe and W. F. Holderich, Appl. Catal., A, 1999, 181, 399–434.
12. R. Pagadala, D. R. Kommidi, S. Rana, S. Maddila, B. Moodley, N. A. Koorbanally and S. B. Jonnalagadda, RSC Adv., 2015, 5, 5627–5632.
13. M. D. Rhodes, K. A. Pokrovski and A. T. Bell, J. Catal., 2005, 233, 210–220.
14. A. H. Bedair, H. A. Emam, N. A. El-Hady, K. A. R. Ahmed and A. M. El-Agrody, Il Farmaco, 2001, 56, 965–973.
15. B. C. Venkatesh, A. Muralikrishna and A. Padmaja, Arch. Pharm., 2012, 345, 745–752.
16. E. M. Grivsky, S. Lee, C. W. Sigel, D. S. Duch and C. A. Nichol, J. Med. Chem., 1980, 23, 327–329.
17. J. Davoll, J. Clarke and E. F. Elslager, J. Med. Chem., 1972, 15, 837–839.
18. A. Agarwal, R. Ashutosh, N. Goyal, P. M. S. Chauhan and S. Gupta, Bioorg. Med. Chem., 2005, 24(13), 6678–6684.
19. A. H. Shamroukh, M. A. Zaki, E. M. H. Morsy, F. M. Abdel- Motti and F. M. E. Abdel-Megeid, Arch. Pharm., 2007, 340, 236–243.
20. L. R. Bennett, C. J. Blankely, R. W. Fleming, R. D. Smith and D. K. Tessonam, J. Med. Chem., 1981, 24, 382–389.
21. K. N. Mohana, B. N. P. Klumar and L. Mallesha, Drug Invent. Today, 2013, 5, 216–222.
22. M. S. Mohamed, R. Kamel and S. S. Fatahala, Eur. J. Med. Chem., 2010, 45, 2994–3004.
23. A. M. Fargualy, N. S. Habib, K. A. Ismail, A. M. M. Hassan and M. T. M. Sarg, Eur. J. Med. Chem., 2013, 66, 276–295.
24. S. P. Satasia, P. N. Kalaria, J. R. Avalani and D. K. Raval, Tetrahedron, 2014, 70, 5763–5767.
25. S. Balalaie, S. Abdolmohammadi, H. R. Bijanzadeh and A. M. Amani, Mol. Diversity, 2008, 12, 85–91.
26. Y. Gao, S. Tu, T. Li, X. Zhang, S. Zhu, F. Fang and D. Shi, Synth. Commun., 2004, 34(7), 1295–1299.
27. I. Devi, B. S. D. Kumar and P. J. Bhuyan, Tetrahedron Lett., 2003, 44, 8307–8310.
28. R. Baharfar and R. Azimi, Synth. Commun., 2014, 44, 89–100.
29. M. N. Elinson, A. I. Ilovaisky, V. M. Merkulov, T. A. Zaimovskay and G. I. Nikishin, Mendeleev Commun., 2011, 21, 122–124.
30. F. Seeliger, S. T. A. Berger, G. Y. Remennikov, K. Polborn and H. Mayr, J. Org. Chem., 2007, 72, 9170–9180.
31. L. Jalili-Baleh, N. Mohammadi, M. Khoobi, L. Maimani, A. Foroumadi and A. Shafiee, Helv. Chim. Acta, 2013, 96, 1601–1609.
32. D. S. Raghuvanshi and K. N. Singh, J. Heterocycl. Chem., 2010, 47, 1323–1327.
33. Y. He, H. Guo and J. Tian, J. Chem. Res., 2011, 528–530.
34. G. Brahmachari and B. Banerjee, ACS Sustainable Chem. Eng., 2014, 2, 411–422.
35. X. J. Yang, Y. Makia, Z. H. Liu, K. Sakane and K. Ooi, Chem. Mater., 2004, 16, 5581–5589.
36. Q. Zhao, W. Y. Shih, H.-L. Chang and W.-H. Shih, Ind. Eng. Chem. Res., 2010, 49, 1725–1731.
37. S. Maddila, V. D. B. C. Dasireddy and S. B. Jonnalagadda, Appl. Catal., B, 2014, 150–151, 305–314.
38. S. Maddila, V. D. B. C. Dasireddy and S. B. Jonnalagadda, Appl. Catal., B, 2013, 138–139, 149–160.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra06373f

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