Amino functionalized mesoporous silica decorated with iron oxide nanoparticles as a magnetically recoverable nanoreactor for the synthesis of a new series of 2,4-diphenylpyrido[4,3-d]pyrimidines

Abstract

(Fe₂O₃)–MCM-41–nPrNH₂ as a magnetically recoverable nanoreactor, was prepared through the reaction of (Fe₂O₃)–MCM-41 with 3-aminopropyltriethoxysilane in refluxing dry toluene. The catalyst with 10 wt% of loaded iron oxide nanoparticles was found to be a highly efficient nanocatalyst for the synthesis of a new class of 2,4-diphenylpyrido[4,3-d]pyrimidines under solvent free conditions in high to quantitative yields. By using an external magnet the catalyst was recovered and reused several times without any loss of efficiency. The prepared catalyst was characterized by transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy, X-ray powder diffraction (XRD), and nitrogen physisorption measurements.

---

Introduction

Recently, mesoporous molecular sieves have attracted significant attention in the field of adsorption, catalysis, and separation as they exhibit excellent characteristics such as a high surface area up to 1500 m² g⁻¹, a large pore volume, and a narrow pore size distribution between 1.5 and 10 nm. In addition, they are highly efficient, sustainable, recyclable, and eco-friendly materials. MCM-41 (Mobil Composition of Matter no. 41) is a mesoporous material and consists of a hexagonal array of unidirectional pore structures which has been synthesized under basic condition using cationic surfactants as a structure-directing agent. Pure MCM-41 is neutral in charge and exhibits only weak hydrogen-bonding type sites which limit its application in catalysis.^1–5 An additional possibility to develop basic catalysts is modification of supports, as the chemical functionalities of these materials can be uniformly achieved by covalent anchoring of different organic moieties.⁶ One of the modified organic–inorganic hybrid materials that have been applied as effective solid base catalyst in organic transformations is 3-aminopropylated silica (MCM-41–nPrNH₂).^7–10 The functional aminopropyl group was anchored on MCM-41 silica by the post-modification method and was prepared according to the procedure reported in the literature from the reaction of MCM-41 with 3-aminopropyltriethoxysilane in refluxing dry toluene.¹¹

The integration of functionalized mesoporous silica with magnetic nanoparticles to form porous magnetic nanocomposite is undoubtedly of great interest for practical applications. This type of magnetic nanocomposites, have the advantages of both mesoporous silica and magnetic nanoparticles. Also magnetic separation by an appropriate magnetic field provides a convenient and low cost method for the separation of these magnetic catalysts in a multiphase suspension without using extra organic solvents and additional filtration steps or tedious work-up.¹²

Pyrido[4,3-d]pyrimidines display various remarkable biological activities such as antibacterial,¹³ antiallergic,¹⁴ fungicidal, antiviral, anti-inflammatory, and antimicrobial properties.^15–20 Inhibition of the adenosine kinase enzyme,²¹ or dihydrofolate reductase, and irreversible inhibition of epidermal growth factor receptor²² stimulated our interest immensely. Also, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine and related compounds have been used as starting materials for the multi-step synthesis of tetrahydropteroic acid derivatives.²³

In view of the useful properties of pyrido[4,3-d]pyrimidines and since there are no reports for the synthesis of these interesting compounds in the literature, herein, following our immense desire to adopt rather greener and economical reaction conditions,²⁴ we report an efficient synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidines (3) through the two component reactions between (E)-3,5-bis(benzylidene)-4-piperidones (1) and benzamidine hydrochloride (2) in the presence of a magnetically recoverable nanoreactor [(Fe₂O₃)–MCM-41–nPrNH₂] under solvent free conditions (Scheme 1).

Scheme 1 Synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives in the presence of (Fe₂O₃)–MCM-41–nPrNH₂.

Results and discussion

At first the (Fe₂O₃)–MCM-41 with 10 wt% of loaded iron oxide nanoparticles was prepared according to the method reported in literature with some modifications.²⁵

The prepared magnetic nanocatalyst was characterized by Fourier transform infrared (FT-IR), X-ray powder diffraction (XRD), and nitrogen physisorption measurements.

The TEM images showed that the encapsulated nanoparticles were present as uniform particles and the size of encapsulated nanoparticles was about 100 nm. Fig. 1 shows TEM images of mesoporous (Fe₂O₃)–MCM-41–nPrNH₂ in which all the materials possess hollow structures. They provide a large active surface area for the efficient synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidines (3) through the two component reactions between (E)-3,5-bis(benzylidene)-4-piperidones (1) and benzamidine hydrochloride (2). Also, TEM micrograph confirms that (Fe₂O₃)–MCM-41–nPrNH₂ have typical MCM-41 type, highly parallel channel-like porous structure packed in a hexagonal symmetry.

Fig. 1 TEM image of (Fe₂O₃)–MCM-41–nPrNH₂.

The IR spectrum of catalyst before and after functionalization was shown in Fig. 2. In IR spectra, the band from 400–650 cm⁻¹ is assigned to the stretching vibrations of the (Fe–O) bond in Fe₂O₃, and the band at about 1100 cm⁻¹ belongs to the stretching of the (Si–O) bond (Fig. 2a and b). After functionalization with amine groups, the absorption bands at 1550 cm⁻¹ and at 1650 cm⁻¹ belong to the bending vibration of N–H groups. It should be mentioned that the C–N stretching vibration in the region of 1030–1230 cm⁻¹ overlap with the broad absorption band of the silanol group and the Si–O–Si vibrations (Fig. 2b).

Fig. 2 The IR spectra of (a) (Fe₂O₃)–MCM-41 and (b) (Fe₂O₃)–MCM-41–nPrNH₂.

The XRD analysis of prepared catalyst was performed from 2.0° (2θ) to 80.0° (2θ). XRD pattern in this region confirmed that the change of sample's color from black to brick-red after calcination of the catalyst is due to the oxidation of embedded Fe₃O₄ to Fe₂O₃ nanoparticles (Fig. 3).

Fig. 3 The XRD pattern of prepared catalyst in the region of 2.0° (2θ) to 80.0° (2θ).

The specific surface area and pore volume obtained by the N₂ adsorption isotherms and calculated by the Brunauer–Emmett–Teller (BET) method²⁶ were 362 m² g⁻¹ and 0.35 cm³ g⁻¹ respectively. The pore diameter of the (Fe₂O₃)–MCM-41–nPrNH₂ was 3.93 nm derived from the adsorption and desorption branches by the Broekhoff and de Boer model (Fig. 4).²⁷

Fig. 4 (a) Nitrogen adsorption/desorption isotherm, (b) BJH and (c) pore size distribution of (Fe₂O₃)–MCM-41–nPrNH₂.

The results of N₂ sorption experiments of (Fe₂O₃)–MCM-41 and (Fe₂O₃)–MCM-41–nPrNH₂ are summarized in Table 1, in which the surface area and pore volume of functionalized magnetic MCM-41 were lower than those of corresponding mesoporous silica due to the grafting of -nPrNH₂ groups.

Table 1 Surface area, average pore size, and pore volume of (Fe₂O₃)–MCM-41 and (Fe₂O₃)–MCM-41–nPrNH₂

Adsorbent	Surface area (m^2 g^−1)	Average pore size^a (nm)	Pore volume^b (cm^3 g^−1)
a Pore size is calculated by method described by Brunauer–Emmett–Teller.b Pore volume determined from nitrogen physisorption isotherm.
(Fe2O3)–MCM-41	1213	5.26	1.59
(Fe2O3)–MCM-41–nPrNH2	362	3.93	0.35

---

Initially for optimization of the reaction conditions, the reaction involving (E)-3,5-bis(4-methylbenzylidene)-4-piperidones (1a) and benzamidine hydrochloride (2) was chosen as a model reaction (Scheme 2).

Scheme 2 A model reaction for the optimization.

In order to show the unique catalytic behavior of (Fe₂O₃)–MCM-41–nPrNH₂, the reaction was performed in the presence of MCM-41–SO₃H under reflux conditions in H₂O and H₂O–DMF in which no product was formed (Table 2, entries 1, 2). It was observed that only basic catalysts were able to catalyze this reaction. When the reaction was done in the presence of sodium hydroxide under reflux condition in aqueous ethanol and methanol for 120 min (Table 2, entries 3, 4), in addition to the desired product (3a), the non-aromatic product (3h) was also formed as major component. However, in the presence of (Fe₂O₃)–MCM-41–nPrNH₂ and solvent free conditions only the product 3a was formed.

Table 2 Comparing the efficiency of different catalysts and solvents in the synthesis of 3a

Entry	Catalyst	Solvent	Reaction condition	Time (h)	Yield (%)
a In this case the major product was 3h.
1	MCM-41–SO3H	H2O	Reflux	2:00	—
2	MCM-41–SO3H	H2O–DMF	Reflux	2:00	—
3	NaOH	EtOH	Reflux	1:00	90^a
4	NaOH	MeOH	Reflux	1:00	90^a
5	No catalyst	—	Solvent free/130 °C	3:00	81
6	KF/Al2O3	—	Solvent free/130 °C	2:00	89
7	Nano MgO	—	Solvent free/130 °C	1:30	92
8	MCM-41–nPrNH2		Solvent free/130 °C	2:00	90
9	(Fe2O3)–MCM-41–nPrNH2 (0.02 g)	—	Solvent free/130 °C	2:00	90
10	(Fe2O3)–MCM-41–nPrNH2 (0.03 g)	—	Solvent free/130 °C	1:30	98
11	(Fe2O3)–MCM-41–nPrNH2 (0.04 g)	—	Solvent free/130 °C	1:20	98

---

Comparative yields were also obtained in the presence of catalytic amount of other catalysts such as KF/Al₂O₃, nano MgO, and MCM-41–nPrNH₂ (Table 2, entries 6–8). The results of Table 2 show that (Fe₂O₃)–MCM-41–nPrNH₂ is an effective basic catalyst for this transformation and 30 mg of the catalyst was the optimum amount under solvent free conditions. It is worth mentioning that, the yield of product 3 did not increase largely with a larger amount of the catalyst (Table 2, entry 11).

Solvent screening also revealed that the solvent free condition is the best condition for this transformation. The higher concentration of reactants in the absence of solvents usually leads to more favorable kinetics than in solution.²⁸ Hence the solvent free condition has been selected as optimized condition.

With these results in hand, a variety of 3,5-dibenzylidenepiperidin-4-one possessing both electron-donating and electron-withdrawing groups were employed for the synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives in which those with electron-withdrawing groups reacted rapidly whereas for those with electron-rich groups longer reaction times were required. Electron-withdrawing groups on the phenyl rings induce greater electronic positive charge on the corresponding β-atoms than electron donating moieties (Table 3).

Table 3 The reaction time (h) and the yield (%) of 2,4-diphenylpyrido[4,3-d]pyrimidine products

Entry	Product	Time (h)	Yield (%)	M.P. (°C) found	M.P. (°C) reported
a In this case reaction was performed in the presence of NaOH and refluxing in ethanol.
3a		3:00	84	155–156	—
3b		3:00	80	182–184	—
3c		2:00	92	206–207	—
3d		1:45	89	160–162	—
3e		1:15	92	100–102	—
3f		1:30	98	187–188	—
3g		3:00	75	188–190	—
3h^a		1:30	90	103–104	—
3i^a		1:00	92	105–107	—
3j^a		1:00	95	140–142	—

---

The proposed mechanism was shown in Scheme 3. Because of two-dimensional pores of MCM-41, the reactants easily transfer toward the nanocatalyst channels, and they are accompanied by the inherent hydrogen bonding of –OH and –NH₂ groups which both are capable of bonding with the carbonyl oxygen of the 3,5-dibenzylidenepiperidin-4-one moiety to increase its electrophilicity. It should be mentioned that the presence of a base (NH₂ groups) is essential to convert the benzamidine hydrochloride to free base. At first, intermediate (A), (B) was generated by Michael addition of the free base of benzamidine hydrochloride (2) to 3,5-dibenzylidenepiperidin-4-one (1). Subsequently, elimination of water occurred and finally after aromatization the product (3) was formed (Scheme 3).

Scheme 3 A provisional mechanism for the synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives in the presence of (Fe₂O₃)–MCM-41–nPrNH₂.

It should be noted that the catalyst was unaffected under the condition of the reaction. Therefore, the catalyst was effectively collected from the reaction mixture and the recovered catalyst was used in subsequent runs without observation of significant decrease in activity even after 5 runs (Fig. 5). This type of magnetic nanocatalyst, have the advantages of both mesoporous silica and magnetic nanoparticles. The immobilization of homogeneous catalysts on magnetic nanocomposite facilitates easy catalyst recovery and recycling, as well as product separation, is a longstanding pursuit of catalysis.

Fig. 5 Catalytic recyclability of (Fe₂O₃)–MCM-41–nPrNH₂.

Conclusion

In summary, (Fe₂O₃)–MCM-41–nPrNH₂ was found as an efficient catalyst for the synthesis of new class of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives under solvent free conditions. This novel synthetic method is especially favoured because it provides a synergy of the nanosized (Fe₂O₃)–MCM-41–nPrNH₂ and solvent-free conditions which offers the advantages of high yields, simplicity and easy workup. Most significantly, this solid basic catalyst has large surface area (362 m² g⁻¹), thermal stability, and reusable for a number of times with consistent activity. Also, magnetic nanocomposite facilitates easy catalyst recovery and recycling, as well as product separation.

Experimental section

General remarks

Melting points were recorded on a Buchi B-540 apparatus. IR spectra were recorded on an ABB Bomem Model FTLA200-100 instrument. ¹H and ¹³C NMR spectra were measured on a Bruker DRX-300 spectrometer, at 300 and 75 MHz, using TMS as an internal standard. Chemical shifts (δ) were reported relative to TMS, and coupling constants (J) were reported in hertz (Hz). Mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer with 70 eV ionization potential.

Preparation of (Fe₂O₃)–MCM-41

A solution with molar composition of 3.2FeCl₃ : 1.6FeCl₂ : 1CTABr : 39 NH₄OH : 2300H₂O was used for preparation of naked Fe₃O₄ nanoparticles at room temperature. Typically, 2 g of iron(III) chloride (FeCl₃·6H₂O) and 0.8 g of iron(II) chloride (FeCl₂·4H₂O) were dissolved in 10 mL of distilled water under N₂ atmosphere. The resultant solution dropwise was added to a 100 mL solution of 1.0 M NH₄OH containing 0.4 g of cetyltrimethylammonium bromide (CTABr) to construct a colloidal suspension of iron oxide magnetic nanoparticles. The magnetic MCM-41 was prepared by adding 20 mL of the magnetic colloid to a 1 L solution with the molar composition of 292NH₄OH : 1CTABr : 2773H₂O under vigorous mixing and sonication. Then sodium silicate (16 mL) was added, and the mixture was allowed to react at room temperature for 24 h under stirring. The magnetic MCM-41 was filtered and washed with alcoholic ammonium nitrate. The surfactant template was then removed from the synthesized material by calcination at 450 °C for 4 h and the (Fe₃O₄)–MCM-41 converted to (Fe₂O₃)–MCM-41. It is worth mentioning that in the absence of nitrogen the magnetic property of Fe₃O₄ is decreased.

Preparation of (Fe₂O₃)–MCM-41–nPrNH₂

Then, functionalized catalyst [(Fe₂O₃)–MCM-41–nPrNH₂] was prepared according to the method reported in the literature with some modifications from the reaction of (Fe₂O₃)–MCM-41 with 3-aminopropyltriethoxysilane in refluxing dry toluene.¹¹ (Scheme 4).

Scheme 4 Functionalization of the (Fe₂O₃)–MCM-41 with 3-aminopropyltriethoxysilane in dry toluene.

General procedure for the synthesis of 3,5-dibenzylidenepiperidin-4-one

In a 50 mL reaction vial, a mixture of the 4-piperidone (10 mmol), the appropriate aldehyde (20 mmol), 10% NaOH (1 mL) and 95% EtOH (30 mL) was stirred at room temperature for 0.5–2 h. The separated solid was collected by filtration and for further purification was recrystallized from ethanol.

General procedure for the synthesis of 2,4-diphenylpyrido[4,3-d]pyrimidine derivatives

To the mixture of 3,5-dibenzylidenepiperidin-4-one (0.33 mmol), and benzamidine hydrochloride (0.33 mmol) was added (Fe₂O₃)–MCM-41–nPrNH₂ (30 mg); it was then stirred at 130 °C for an appropriate period of time (Table 3). After completion of the reaction (monitored by thin-layer chromatography, TLC; petroleum ether and EtOAc, 12 : 2), the reaction mixture was cooled to room temperature and a minimum amount of ethylacetate was added. Then, the catalyst was collected with an external magnet. The product was concentrated under reduced pressure and purified by recrystallization from 1 : 1 EtOH–H₂O.

Compounds characterization data

(E)-8-(4-Methylbenzylidene)-4-(4-methylphenyl)-5,6,7,8-tetrahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3a). IR (KBr, cm⁻¹) ν_max: 3068, 2942, 1616, 1539, 1409; ¹H NMR (300 MHz, DMSO-d₆): 2.31 (3H, s, N–CH₃), 2.34 (3H, s, CH₃), 2.39 (3H, s, CH₃), 3.64 (2H, s, N–CH₂), 3.69 (2H, s, N–CH₂), 7.26 (2H, d, J = 7.9 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.39 (2H, d, J = 7.9 Hz), 7.51–7.55 (3H, m), 7.62 (2H, d, J = 7.9 Hz), 8.32 (1H, s, C=CH), 8.52–8.55 (2H, m); ¹³C NMR (75 MHz, DMSO-d₆): 20.9, 45.1, 54.6, 55.5, 122.7, 127.7, 128.5, 128.9, 129.1, 129.9, 130.4, 131.0, 132.8, 134.3, 137.5, 137.7, 139.4, 158.1, 160.4, 163.4; MS (EI): m/z = 43 (31), 91 (50), 158 (33), 196 (22), 214 (25), 312 (88), 375 (18), 417 (100).

(E)-8-(4-(Benzyloxy)benzylidene)-4-(4-(benzyloxy)phenyl)-5,6,7,8-tetrahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3b). IR (KBr, cm⁻¹) ν_max: 3034, 2931, 1611, 1504; ¹H NMR (300 MHz, DMSO-d₆): 2.34 (3H, s, N–CH₃), 3.67 (2H, s, N–CH₂), 3.70 (2H, s, N–CH₂), 5.15 (2H, s, O–CH₂), 5.19 (2H, s, O–CH₂), 7.10 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.34–7.53 (15H, m), 7.71 (2H, d, J = 8.4 Hz), 8.3 (1H, s, C=CH), 8.53–8.56 (2H, m); ¹³C NMR (75 MHz, DMSO-d₆): 45.1, 55.6, 69.2, 69.3, 114.6, 114.9, 122.3, 127.7, 127.8, 128.3, 128.4, 128.5, 129.7, 129.9, 130.4, 130.6, 131.6, 136.7, 136.8, 137.6, 158.2, 159.5, 160.3, 162.8; MS (EI): m/z = 42 (5), 65 (22), 91 (100), 168 (10), 314 (16), 404 (74), 510 (97), 601 (23).

(E)-8-(3-Bromobenzylidene)-4-(3-bromophenyl)-5,6,7,8-tetrahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3c). ¹H NMR (300 MHz, DMSO-d₆): 2.34 (3H, s, N–CH₃), 3.66 (2H, s, N–CH₂), 3.71 (2H, s, N–CH₂), 7.43–7.59 (7H, m), 7.71–7.77 (3H, m), 7.92 (1H, s), 5.34 (1H, s), 8.56–8.57 (2H, m); MS (EI): m/z = 42 (22), 114 (20), 142 (41), 181 (24), 240 (21), 378 (82), 547 (100).

(E)-8-Benzylidene-5,6,7,8-tetrahydro-6-methyl-2,4-diphenylpyrido[4,3-d]pyrimidine (3d). ¹H NMR (300 MHz, DMSO-d₆): 2.34 (3H, s, N–CH₃), 3.68 (2H, s, N–CH₂), 3.74 (2H, s, N–CH₂), 7.36–7.55 (11H, m), 7.73–7.74 (2H, d, J = 3.7 Hz), 8.38 (1H, s, C=CH), 8.54–8.55 (2H, m); ¹³C NMR (75 MHz, DMSO-d₆): 45.1, 54.5, 55.4, 123.0, 127.7, 128.1, 128.4, 128.6, 128.9, 129.0, 129.7, 129.9, 130.5, 131.8, 135.6, 137.2, 137.4, 158.1, 160.5, 163.7; MS (EI): m/z = 57 (67), 77 (95), 115 (100), 142 (42), 167 (21), 298 (37), 389 (52).

(E)-8-(2,4-Dichlorobenzylidene)-4-(2,4-dichlorophenyl)-5,6,7,8-tetrahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3e). IR (KBr, cm⁻¹) ν_max: 2947, 1596, 1540, 1463; ¹H NMR (300 MHz, DMSO-d₆): 2.28 (3H, s, N–CH₃), 3.55 (2H, s, N–CH₂), 3.58 (2H, s, N–CH₂), 7.47–7.69 (6H, m), 7.77–7.79 (1H, m), 7.87 (1H, d, J = 1.5 Hz), 8.37 (1H, s, C=CH), 8.40–8.43 (3H, m); ¹³C NMR (75 MHz, DMSO-d₆): 44.9, 53.2, 124.3, 127.5, 127.7, 127.9, 128.7, 129.1, 129.3, 130.9, 132.1, 132.2, 132.7, 133.6, 133.8, 134.4, 134.5, 134.8, 136.8, 157.2; MS (EI): m/z = 42 (63), 149 (90), 178 (37), 212 (47), 240 (62), 268 (30), 319 (44), 353 (100), 392 (91), 492 (21), 527 (12).

(E)-8-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3f). IR (KBr, cm⁻¹) ν_max: 2947, 1596, 1534, 1488; ¹H NMR (300 MHz; DMSO-d₆): 2.34 (3H, s, N–CH₃), 3.68 (2H, s, N–CH₂), 3.71 (2H, s, N–CH₂), 7.54–7.58 (7H, m), 7.63 (2H, d, J = 8.3 Hz), 7.78 (2H, d, J = 8.3 Hz), 8.35 (1H, s, C=CH), 8.55 (2H, m); ¹³C NMR (75 MHz, DMSO-d₆): 45.0, 123.2, 127.7, 127.9, 128.6, 130.9, 131.6, 132.5, 132.8, 134.5, 134.7, 135.9, 137.2, 158.1, 160.6, 162.5; MS (EI): m/z = 42 (30), 91 (33), 139 (49), 260 (51), 332 (100), 415 (21), 457 (88), 458 (78).

(E)-8-(4-Methoxybenzylidene)-5,6,7,8-tetrahydro-4-(4-methoxyphenyl)-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3g). IR (KBr, cm⁻¹) ν_max: 2921, 1606, 1534, 1499; ¹H NMR (300 MHz, DMSO-d₆): 2.35 (3H, s, N–CH₃), 3.68 (2H, s, N–CH₂), 3.71 (2H, s, N–CH₂), 3.80 (3H, s, O–CH₃), 3.84 (3H, s, O–CH₃), 7.04 (2H, d, J = 8.5 Hz), 7.10 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.52–7.53 (3H, m), 7.02 (2H, d, J = 8.5 Hz), 8.30 (1H, s, C=CH), 8.53–8.55 (2H, m); ¹³C NMR (75 MHz, DMSO-d₆): 45.2, 55.2, 55.3, 113.8, 114.1, 122.3, 127.7, 128.2, 128.5, 129.9, 130.4, 130.7, 131.6, 137.6, 158.3, 159.2, 160.3, 160.5, 162.9; MS (EI): m/z = 43 (35), 65 (21), 91 (60), 119 (100), 138 (61), 239 (10), 256 (75), 449 (5).

(8E)-8-(4-Methylbenzylidene)-4-(4-methylphenyl)-2,3,5,6,7,8-hexahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3h). IR (KBr, cm⁻¹) ν_max: 3275, 2788, 1591, 1555; ¹H NMR (300 MHz, DMSO-d₆): 2.16 (3H, s, N–CH₃), 2.27 (3H, s, CH₃), 2.29 (3H, s, CH₃), 2.62 (1H, d, J = 16.4 Hz, N–CH), 2.95 (1H, d, J = 16.5 Hz, N–CH), 3.25 (1H, d, J = 13.9 Hz, N–CH), 3.45 (1H, d, J = 13.9 Hz, N–CH), 5.07 (1H, s), 7.14–7.16 (6H, m), 7.21 (2H, d, J = 8.0 Hz), 7.41–7.44 (4H, m), 7.93–7.96 (2H, m), 8.15 (1H d, J = 1.5 Hz); ¹³C NMR (75 MHz, DMSO-d₆): 18.5, 20.7, 20.8, 45.2, 55.2, 55.8, 113.9, 121.7, 126.5, 126.7, 128.1, 128.8, 129.1, 132.5, 133.5, 134.5, 135.1, 135.4, 136.8, 142.2, 151.5; MS (EI): m/z = 42 (10), 104 (18), 207 (32), 299 (100), 328 (27), 375 (15), 419 (64).

(8E)-8-(2,4-Dichlorobenzylidene)-4-(2,4-dichlorophenyl)-2,3,5,6,7,8-hexahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3i). IR (KBr, cm⁻¹) ν_max: 3234, 3075, 1617, 1550; ¹H NMR (300 MHz; DMSO-d₆): 2.14 (3H, s, N–CH₃), 2.64 (1H, d, J = 16.5 Hz, N–CH), 3.00 (1H, d, J = 16.5 Hz, N–CH), 3.18 (1H, d, J = 13.8 Hz, N–CH), 3.30 (1H, d, J = 13.8 Hz, N–CH), 5.65 (1H, s), 7.28 (1H, d, J = 8.5 Hz), 7.38–7.52 (7H, m), 7.60 (1H, d, J = 8.5 Hz), 7.63 (1H, s), 7.90–7.93 (2H, m), 8.30 (1H, s). ¹³C NMR (75 MHz, DMSO-d₆): 44.9, 52.4, 54.4, 56.0, 114.3, 118.2, 126.7, 127.0, 128.2, 128.6, 128.7, 130.4, 131.3, 131.8, 133.0, 133.8, 133.9, 134.3, 134.7, 135.1, 141.2, 152; MS (EI): m/z = 42 (10), 77 (14), 104 (22), 299 (30), 319 (51), 353 (100), 382 (11), 417 (10), 529 (17).

(8E)-8-(2,3-Dichlorobenzylidene)-4-(2,3-dichlorophenyl)-2,3,5,6,7,8-hexahydro-6-methyl-2-phenylpyrido[4,3-d]pyrimidine (3j). IR (KBr, cm⁻¹) ν_max: 3234, 3075, 1617, 1550; ¹H NMR (300 MHz; DMSO-d₆): 2.14 (3H, s, N–CH₃), 2.64 (1H, d, J = 16.8 Hz, N–CH), 3.03 (1H, d, J = 16.8 Hz, N–CH), 3.30 (1H, d, J = 13.8 Hz, N–CH), 3.4 (1H, d, J = 14.3 Hz, N–CH), 4.36 (1H, s), 5.75 (1H, s), 7.24 (1H, d, J = 7.6 Hz), 7.31–7.57 (8H, m), 7.92 (2H, d, J = 5.6 Hz), 8.32 (1H, s); ¹³C NMR (75 MHz, DMSO-d₆): 44.9, 53.7, 54.4, 56.0, 114.4, 119.3, 126.7, 127.7, 128.2, 128.5, 128.6, 129.2, 129.3, 128.8, 130.4, 130.7, 131.8, 131.9, 134.0, 134.7, 135.1, 137.9, 144.6, 152.1; MS (EI): m/z = 42 (10), 77 (14), 104 (22), 299 (30), 319 (51), 353 (100), 382 (11), 417 (10), 529 (17).

Acknowledgements

We gratefully acknowledge the support of this work by Drug Applied Research Center, Tabriz University of Medical Sciences, Iran.

References

1. J. Deutsch, H. A. Prescott, D. Muller, E. Kemnitz and H. Lieske, J. Catal., 2005, 231, 269–278.
2. D. Zhao, Q. Huo, J. Feng, B. F. Chmelka and G. D. Stucky, J. Am. Chem. Soc., 1998, 120, 6024–6036.
3. W. Zhang, T. R. Pauly and T. J. Pinnavaia, Chem. Mater., 1997, 9, 2491–2498.
4. A. Galarneau, D. Desplantier-Giscard, F. Di Renzo and F. Fajula, Catal. Today, 2001, 68, 191–200.
5. V. Y. Gusev, X. Feng, Z. Bu, G. L. Haller and J. A. O'Brien, J. Phys. Chem., 1996, 100, 1985–1988.
6. F. Hoffmann, M. Cornelius, J. Morell and M. Fröba, Angew. Chem., Int. Ed., 2006, 45, 3216–3251.
7. X. Wang and S. Cheng, Catal. Commun., 2006, 7, 689–695.
8. D. Macquarrie and D. Jackson, Chem. Commun., 1997, 1781–1782.
9. J. Mdoe, J. Clark and D. Macquarrie, Synlett, 1998, 625–627.
10. G. Sartori, F. Bigi, R. Maggi, R. Sartorio, D. Macquarrie, M. Lenarda, L. Storaro, S. Coluccia and G. Martra, J. Catal., 2004, 222, 410–418.
11. A. Cauvel, G. Renard and D. Brunel, J. Org. Chem., 1997, 62, 749–751.
12. (a) L. Ma'mani, A. Heydari and M. Sheykhan, Appl. Catal., A, 2010, 384, 122–127; (b) Y. H. Liu, J. Deng, J. W. Gao and Z. H. Zhang, Adv. Synth. Catal., 2012, 354, 441–447.
13. B. S. Huber and B. F. Valenti, J. Med. Chem., 1968, 11, 708–710.
14. T. H. Althins, S. B. Kadin, L. J. Czuba, P. F. Moore and H. J. Hess, J. Med. Chem., 1980, 23, 262–269.
15. W. Y. Mo, Y. Y. Yao, Y. L. Shen, H. W. He and Y. C. Gu, J. Heterocycl. Chem., 2009, 46, 579–583.
16. R. E. Hacker and G. P. Jourdan, EP 0414386, Chem. Abstr., 1991, 115, 71630j.
17. H. Yamada, EP 0665224, Chem. Abstr., 1994, 121, 230784e.
18. E. F. Elselarge, J. Clarke and P. Jacob, J. Heterocycl. Chem., 1972, 9, 1113–1121.
19. A. Rosowsky, C. E. Mota and S. F. Queener, J. Heterocycl. Chem., 1995, 32, 335–340.
20. H. I. El-Subbagh, S. M. Abu-Zaid, M. A. Mahran, F. A. Badria and A. M. Al-Obaid, J. Med. Chem., 2000, 43, 2915–2921.
21. G. A. Gfesser, E. K. Bayburt, M. Cowart, S. Didomenico, A. Gomtsyan, C. H. Lee, A. O. Stewart, M. F. Jarvis, E. A. Kowaluk and S. S. Bhagwat, Eur. J. Med. Chem., 2003, 38, 245–252.
22. A. Rosowsky, H. Chen, H. Fu and S. F. Queener, Bioorg. Med. Chem., 2003, 11, 59–67.
23. A. Rosowsky, H. Bader, R. G. Moran and J. H. Freisheim, J. Heterocycl. Chem., 1989, 26, 509–516.
24. (a) S. Rostamizadeh, M. Azad, N. Shadjou and M. Hasanzadeh, Catal. Commun., 2012, 25, 83–91; (b) S. Rostamizadeh, A. M. Amani, G. H. Mahdavinia, G. Amiri and H. Sepehrian, Ultrason. Sonochem., 2010, 17, 306–309; (c) S. Rostamizadeh, A. Amirahmadi, N. Shadjou and A. M. Amani, J. Heterocycl. Chem., 2012, 49, 111–115.
25. X. Chen, K. F. Lam, Q. Zhang, B. Pan, M. Arruebo and K. L. Yeung, J. Phys. Chem. C, 2009, 113, 9804–9813.
26. H. Takahashi, B. Li, T. Sasaki, C. Miyazaki, T. Kajino and S. Inagaki, Microporous Mesoporous Mater., 2001, 44–45, 755–762.
27. E. P. Barrett, L. G. Joyner and P. H. Halenda, J. Am. Chem. Soc., 1951, 73, 373–380.
28. K. Tanaka, Solvent free organic synthesis, Wiley-VCH, Weinheim, 2003.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra00038b

---