Three-Component Synthesis of Pyrimidine and Pyrimidinone Derivatives in the Presence of High-Surface-Area MgO, a Highly Effective Heterogeneous Base Catalyst

Abstract

Magnesium oxide (MgO) effectively catalyzes the three-component reaction of aldehydes, amidine systems, and malononitrile or ethyl cyanoacetate to form 4-amino-5-pyrimidine carbonitrile and pyrimidinone derivatives, respectively. The salient features of this method include high conversions, short reaction times, cleaner reaction profiles, and the use of inexpensive and readily available catalyst.

Keywords:

• Amidines
• 4-amino-5-pyrimidinecarbonitriles
• magnesium oxide (MgO)
• malononitrile
• three-component reaction

INTRODUCTION

In recent years, pyrimidines and dihydropyrimidinones (DHPMs) have occupied an important position in natural and synthetic organic chemistry, due mainly to their wide range of biological activities.^{[ 1 ]} such as antibacterial, antiviral, antihypertensive, and antitumor effects and their effect as calcium channel blockers.^{[ 2 ]} Moreover, some bioactive alkaloids such as batzelladine B, containing the dihydropyrimidine unit, have been isolated from marine sources and show anti-HIV activity.^{[ 3 ]} The development of efficient and environmentally acceptable synthetic methods is an important task of modern chemistry. Conventional organic syntheses are generally based on homogeneous catalysts. However, homogeneous reactions suffer disadvantages in separation, regeneration, and so forth. From the viewpoint of green chemistry, the use of heterogeneous catalysts is desirable. The consequential advantages of heterogeneous catalysts from the environmental and economic points of view are clearly understandable, because these procedures allow money to be saved and the production of waste material to be minimized.

In contrast to the extensive studies involving heterogeneous acid catalysts, fewer efforts have been made to develop heterogeneous base catalysts.^{[ 4 ]} Several solid bases have been reported as being effective in this respect, such as zeolites,^{[ 5 ]} alkali metals supported on alumina (Na/NaOH/g-Al₂O₃),^{[ 6 ]} clay minerals,^{[ 7 ]} hydrotalcites (HDT),^{[ 8 ]} metal oxides such as magnesium oxide (MgO), and mixed metal oxides, for example magnesium–lanthanum mixed oxide.^{[ 9 ]} Among these solid bases, MgO recently has been studied the most.^{[ 10 ]} MgO, obtained using a novel but simple procedure, was systematically investigated as a heterogeneous base catalyst for reactions taking place in the liquid phase, specifically the Michael addition and the Knoevenagel condensation.^{[ 10 ]} More recently, we described the synthesis of 2-amino-5-pyrimidinecarbonitriles 4 based on the three-component reaction of malononitrile 3, aromatic aldehydes 1, and amidines 2 under thermal aqueous conditions and microwave irradiation in the presence of sodium acetate.^{[ 11 ]} As part of our research program aimed at the preparation of nitrogen-containing heterocycles,^[ 12-14 ^] we performed the synthesis of 4-amino-5-pyrimidinecarbonitrile 4 and dihydro-5-pyrimidinonecarbonitrile 5 derivatives through a three-component reaction in the presence of MgO as a highly effective heterogeneous base catalyst.

RESULTS AND DISCUSSION

In the present protocol as exhibited in Scheme 1, the three-component reaction of ethyl cyanoacetate, arylaldehydes, and amidines under thermal aqueous conditions did not afford the dihydropyrimidinone-5-carbonitrile derivatives 5, although these compounds were prepared in the presence of MgO under reflux condition.

Scheme 1 Three component reactions of aldehydes, amidine systems, and malonitrile or ethyl cyanoacetate in the presence of magnesium oxide (MgO).

Xu and co-workers investigated the reaction of a high-surface-area form of MgO as a catalyst for a number of different Michael additions and Knoevenagel condensations, and it was found to be very active and reusable.^{[ 10 ]} We sought to develop a route that is simple to perform and that allows reuse of the catalyst for a number of times. We tried to focus on aqueous media, where the product would be precipitated out from the reaction mixture when the reaction is completed. Yields are relatively low when water was used as a solvent in comparison with an anhydrous solvent such as acetonitrile. The results are summarized in Table 1.

Table 1. Solvent effects on the synthesis of compounds and

Compound	Solvent	Time (min)	Yield (%)
4a	EtOH/H2O	30	72
4a	MeOH	25	78
4a	MeCN	20	85
5a	EtOH/H2O	50	76
5a	MeOH	45	79
5a	MeCN	40	82

Because the three-component reaction of malononitrile or ethyl cyanoacetate, aromatic aldehydes, and amidines involves both Knoevenagel condensation and Michael addition, we have separately studied the effectof catalytic activity of MgO on the Knoevenagel condensation of malononitrile or ethyl cyanoacetate and aldehydes 1 to afford theα-cyanocinnamonitrile 6a or ethyl-2-cyano-3-aryl-2-propenoate 6b derivatives, respectively, and also the Michael addition of amidine systems with compounds 6 in the same conditions. The catalyst plays a crucial role in the success of the reaction in terms of the rate and the yields. Our observations are recorded in Tables 2 and 3.

Table 2. Knoevenagel condensation of aldehydes with malononitrile or ethyl cyanoacetate catalyzed by MgO in CH₃CN

Compound	Ar	X	Time (min)	Yield (%)	MP [Ref.] (°C)
6a	C6H5	CN	5	94	82–83^[ ^15 ^]
6b	C6H5	CO2Et	10	90	48–50^[ ^15 ^]
6c	4-ClC6H4	CN	5	96	158^[ ^16 ^]
6d	4-ClC6H4	CO2Et	8	91	93^[ ^16 ^]
6e	4-O2NC6H4	CN	4	98	160^[ ^17 ^]
6f	4-O2NC6H4	CO2Et	7	92	170^[ ^17 ^]

Table 3. Michael additions of with amidines catalyzed by MgO in CH₃CN

Compound	Ar	R	Time (min)	Yield (%)
4a	C6H5	C6H5	18	90
4b	C6H5	NH2	13	92
5a	C6H5	C6H5	26	97
4h	4-ClC6H4	C6H5	13	96
4i	4-ClC6H4	NH2	11	97
5b	4-ClC6H4	C6H5	32	95

On basis of these results, we report a novel, three-component, one-pot synthesis of functionalized 4-amino-5-pyrimidinecarbonitrile 4 and dihydro-5-pyrimidinonecarbonitrile 5 derivatives in the presence of high-surface-area MgO, a highly effective heterogeneous base catalyst in acetonitrile at reflux conditions. This is an efficient synthesis in operational simplicity and also gives the corresponding products in high yields in a very short experimental time. The reaction conditions and results are shown in Table 4.

Table 4. Synthesis of and under thermal conditions without catalyst and in the presence MgO as a highly effective heterogeneous base catalyst

			Thermal conditions		Commercially available MgO		High-surface-area MgO
Compound	Ar	R	Time (h)	Yield (%)	Time (min)	Yield (%)	Time (min)	Yield (%)
4a	C6H5	Ph	6	78	60	83	20	85
4b	C6H5	NH2	5	81	55	86	15	88
4c	4-MeC6H4	Ph	4	79	65	81	20	83
4d	4-MeC6H4	NH2	5	64	60	84	22	86
4e	4-MeOC6H4	Ph	8	60	70	80	30	82
4f	4-(Me)2N C6H4	Ph	12	78	90	80	40	83
4g		Ph	6	46	70	65	30	70
4h	4-ClC6H4	Ph	4	73	50	87	15	89
4i	4-ClC6H4	NH2	3	82	45	90	13	91
4j	4-BrC6H4	Ph	4	80	58	84	18	87
4k	4-BrC6H4	NH2	4	78	52	87	15	89
4l	4-FC6H4	NH2	4	63	48	88	14	90
4m	4-FC6H4	Ph	4	66	45	91	12	92
4n	3-FC6H4	Ph	3	80	50	87	10	90
4o	3-FC6H4	NH2	4	68	45	92	8	96
4p	3-FC6H4	Me	5	60	60	83	20	85
4q	4-CF3C6H4	Ph	2	70	53	83	17	88
4r	4-CF3C6H4	NH2	4	72	50	87	15	90
4s	4-CF3C6H4	Me	5	60	65	80	25	83
5a	C6H5	ph	—	—	120	80	40	82
5b	4-ClC6H4	ph	—	—	110	84	35	85
5c	3-FC6H4	ph	—	—	100	84	33	86
5d	4-CF3C6H4	ph	—	—	110	82	36	84
5e	2,4-ClC6H3	ph	—	—	105	86	33	88
5f	4-NO2C6H4	ph	—	—	100	87	33	89

Structures 4a–s were established on the basis of infrared (IR), which showed the presence of a CN group at a region of 2235–2238 cm⁻¹ and two sharp bands at 3500–3450 and 3390–3380 cm⁻¹, which are due to the asymmetric and symmetric vibrations of NH₂ group. The ¹H and ¹³C NMR spectroscopic data were comparable with reported data.^{[ 11 ]} The structures of 5a–f were determined on the basis of their elemental analyses, mass spectra, ¹H and ¹³C NMR data, and IR spectral data.

The mechanism of the present reaction (Scheme 1) initially proceeds by Knoevenagel condensation, as the catalyst possesses strong basic sites, which promote the reaction by abstracting a proton from the active methylene component. As a result, an alkene intermediate may form with the aldehyde. This in turn reacts with amidines via Michael addition to give the polyfunctionalized pyrimidine and dihydropyrimidinone derivatives (Scheme 2).

Scheme 2 Mechanism for the formation of compounds 4 and 5.

CONCLUSION

In summary, an efficient heterogeneous strong base such as MgO catalyst with high surface area is reported for the synthesis of 4-amino-5-pyrimidinecarbonitrile and pyrimidinones derivatives in a three-component reaction of aldehydes, amidin systems, and malononitrile or ethyl cyanoacetate respectively. Advantages of the strategy include simple catalyst preparation, mild reaction temperature, easy recovery, and reusability of the catalyst with consistent activity and short reaction times.

EXPERIMENTAL

Melting points were determined on an Gallenkamp melting-point apparatus and are uncorrected. IR spectra were measured on a Mattson 1000 Fourier transform infrared (FT-IR) spectrometer. ¹H NMR and ¹³C NMR spectra were determined on a Bruker DRX-300 Avance spectrometer at 300.13 and 75.47 MHz, respectively. Mass spectra (MS) were recorded on a Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer.

Preparation of High-Surface-Area MgO

A simple method for the preparation of MgO, a catalyst that exhibits high activity for base-catalyzed reactions, is described.^{[ 10 ]} The experimental results showed that an optimal calcination temperature in the range of 400–500 °C gives poorly crystalline, high-surface-area MgO, which can be regenerated by washing and then reused.^{[ 10 ]} MgO can be recovered and reused twice without loss of activity of the catalyst.

General Procedure for the Preparation of Pyrimidine and Pyrimidinone Derivatives

A mixture of the aldehyde (2 mmol), amidines hydrochloride (2 mmol), malononitrile or ethyl cyanoacetate (2 mmol), and MgO (0.25 g) in CH₃CN (5 mL) was refluxed with stirring for the time reported in Table1. The progress of the reaction was monitored by thin-layer chromatography (TLC), and hexane/ethyl acetate was used as an eluent). After completion of the reaction, the catalyst was separated from the reaction mixture by centrifugation. The excess acetonitrile was removed by evaporation and then was poured into ice-cold water; the crude product was filtered, dried, and recrystallized from 96% ethanol.

Data

6-Oxo-2,4-diphenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4a)

Yellow crystals; mp 105 °C. IR (KBr, ν_max/cm⁻¹): 3329 (NH), 2212 (CN), 1691 (C=O), 1617 (C=N), 1542, 1492 (C=C); ¹H NMR (300 MHz, DMSO-d₆): 9.62 (s, 1H, NH), 8.32–7.29 (m, 10 H, Ar). ¹³C NMR (75 MHz, DMSO-d₆): 173.50, 168.29, 166.51, 138.96, 138.55, 130.72, 130.34, 129.40, 128.89, 128.66, 128.63, 120.88 (CN), 91.47 (C₅). MS (m/z): 273 (M⁺) (30), 245 (35), 170 (50), 142 (15), 120 (60), 104 (87), 77 (50), 53 (25). Anal. calcd. for C₁₇H₁₁N₃O: C, 74.71; H, 4.06; N, 15.38%. Found: C, 74.37; H. 3.92; N; 15.05%.

4-(4-Chlorophenyl)-6-oxo-2phenyl-1,6dihydro-5-pyrimidinecarbonitrile (4b)

Yellow crystals; mp 210–212 °C. IR (KBr, ν_max/cm⁻¹): 3478 (NH), 2212 (CN), 1690 (C=O), 1617 (C=N), 1542 (C=C). ¹H NMR (300 MHz, DMSO-d₆): 9.35 (s, 1H, NH); 8.31–7.33 (m, 9H, Ar). ¹³C NMR (75MHz, DMSO-d₆): 173.29, 167.00, 164.95, 138.82, 137.23, 135.16, 130.81, 130.61, 128.76, 128.60, 128.54, 120.12 (CN), 91.37 (C₅). MS (m/z): 307 (M⁺) (40), 272 (45), 145 (60), 104 (60), 77 (55), 51 (35). Anal. calcd. for C₁₇H₁₀ClN₃O: C, 66.35; H, 3.28; N, 13.65%. Found: C, 66.12; H. 3.08; N; 13.31%.

4-(3-Fluorophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4c)

White crystals; mp 105 °C. IR (KBr, ν_max/cm⁻¹): 3329 (NH), 2212 (CN), 1691 (C=O), 1617 (C=N), 1542, 1492 (C=C). ¹H NMR (300 MHz, DMSO-d₆): 9.35 (s, 1H, NH); 8.32–7.36 (m, 9H, Ar). ¹³C NMR (75 MHz, DMSO-d₆) 169.92, 166.81, 163.48, 162.30 (d, ¹ J _=C–F 241.50 Hz), 140.27 (d, ³ J _=C–F 7.50 Hz), 137.01, 131.48, 130.88 (d, ³ J _=C–F 7.50 Hz), 128.76, 128.74, 125.03, 119.13 (CN), 117.58 (d, ² J _=C–F 21 Hz), 115.59 (d, ² J _=C–F 22.50 Hz), 92.79 (C₅). MS (m/z): 291 (M⁺) (60), 263 (65), 188 (90), 160 (25), 138 (20), 104 (75), 77 (80), 51 (35). Anal. calcd. for C₁₇H₁₀FN₃O: C, 70.10; H, 3.46; N, 14.43%. Found: C, 69.86; H, 3.22; N; 14.05%.

6-Oxo-2-phenyl-4-[4-trifluoromethyl)phenyl]-1,6-dihydro-5-pyrimidinecarbonitrile (4d)

Yellow crystals; mp 125 °C. IR (KBr, ν_max/cm⁻¹): 3503 (NH), 2212 (CN), 1641(C=O), 1592 (C=N), 1567 (C=C). ¹H NMR (300 MHz, DMSO-d₆) 9.55 (s, 1H, NH), 8.32–7.44 (m, 9H, Ar). ¹³C NMR (75 MHz, DMSO-d₆): 172.72, 166.83, 165.04, 142.64, 139.06, 131.81 (q, ² J _=C–F 22.50 Hz), 130.01, 129.58, 128.01 (q, ¹J_C-F 270.75 Hz, CF₃), 125.86 (q, ³ J _=C–F 3.75 Hz), 120.04 (CN), 91.91 (C₅). MS (m/z): 341 (M⁺) (60), 313 (65), 238 (80), 221 (15), 194 (10), 172 (10), 145 (40), 104 (85), 77 (90), 51 (50). Anal. calcd. for C₁₈H₁₀F₃N₃O: C, 63.35; H, 2.95; N, 12.31%. Found: C, 63.01; H. 2.90; N; 12.18%.

4-(2,4-Dichlorophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4e)

Yellow crystals; mp 110°C. IR (KBr, ν_max/ cm⁻¹): 3379 (NH), 2212 (CN), 1690 (C=O), 1617 (C=N), 1542, 1492 (C=C). ¹H NMR (300 MHz, DMSO-d₆): 9.37 (s, 1H, NH), 8.20–7.41 (m, 9H, Ar). ¹³C NMR (75 MHz, DMSO-d₆): 171.84, 167.26, 166.29, 138.94, 137.19, 134.59, 132.82, 132.13, 130.64, 129.51, 129.42, 128.78, 127.88, 119.15 (CN), 94.13 (C₅). MS (m/z): 341 (M⁺) (90), 313 (75), 238 (85), 221 (60), 194 (25), 171 (20), 145 (65), 104 (80), 77 (90), 51 (40). Anal. calcd. for C₁₇H₉Cl₂N₃O: C, 59.67; H, 2.65; N, 12.28%. Found: C, 59.35; H. 2.56; N; 12.14%.

4-(4-Nitrophenyl)-6-oxo-2-phenyl-1,6-dihydro-5-pyrimidinecarbonitrile (4f)

Brown crystals; mp 105 °C. IR (KBr, ν_max/cm⁻¹): 3379 (NH), 2212 (CN), 1680 (C=O), 1592 (C=N), 1517 (C=C). ¹H NMR (300 MHz, DMSO-d₆): 9.52 (s, 1H, NH); 8.34–7.44 (m, 9H, Ar). ¹³C NMR (75 MHz, DMSO-d₆): 172.53, 166.16, 165.03, 148.47, 144.81, 138.95, 130.74, 130.14, 128.54, 123.88, 120.04 (CN), 91.91 (C₅). MS (m/z): 318 (M⁺) (10), 215 (10), 176 (15), 136 (70), 103 (7), 77 (75), 63 (90), 45 (40). Anal. calcd. for C₁₇H₁₀N₄O₃: C, 64.15; H, 3.17; N, 17.60%. Found: C, 64.03; H. 3.02; N; 17.45%.

ACKNOWLEDGMENTS

The authors express their appreciation to the Shahid Bahonar University of Kerman Faculty Research Committee for its support of this investigation.