Introduction

2-oxo/thioxo/imino-1,2,3,4-tetrahydropyrimidines (THPMs; Fig. 1) are a bunch of key heterocycle compounds introduced by an Italian chemist, Pietro Biginelli, during a one-pot reaction. THPM is obtained from the reaction of three components urea (thiourea), an aldehyde, and a 1,3-dicarbonyl compound (Kappe 2000). The change in three types of starting material provides a variety of THPOs that can show a wide range of biological activities, including antiviral I (Chitra et al. 2010; Kim et al. 2012) anticancer II (Mayer et al. 1999; Milović et al. 2022b), antibacterial III (Yadlapalli et al. 2012; Milović et al. 2022a) antifungal IV (Rajanarendar et al. 2010), anticancer (Ismaili et al. 2008; Janković et al. 2019) anti-inflammatory activity V (Gijsen et al. 2012), antioxidant agents VI (Ismaili et al. 2008) and Calcium channel inhibition VII (Ismaili et al. 2008). Due to these features, very quickly studies were conducted on THPMs, and almost all of the main chemistry publications contained articles about of the Biginelli reaction (Dallinger et al. 2004; Kolosov et al. 2009). Years after the discovery of THPMs, researchers still emphasize the introduction of new synthetic methods, the production of new THPM-based compounds, and their application in the industry, particularly new drug applications (Ling et al. 2021).

Fig. 1
figure 1

Structure of Biginelli adducts

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Although, so far, various methods for synthesizing THPMs have been based on using strong Lowry-Bronsted acids such as as H2SO4 (Folkers and Johnson 1933b), HCl (Folkers and Johnson 1933a), Lowry-Bronsted bases such as t-BuOK (Shen et al. 2010), Lewis acids such as InCl3 (Ranu et al. 2000; Nebo et al. 2019), Lewis bases such as (Debache et al. 2008), metal complex (Jankovic et al. 2015) and other types of conditions such as and zeolite (Rani et al. 2001) metal triflates (Su et al. 2005), such as ultrasonic in the presence of dendrimer-attached phosphotungstic acid nanoparticles immobilized on nanosilica (Safaei-Ghomi et al. 2018), low melting acidic (Gore et al. 2011) methods and ionic liquid (Valizadeh and Shockravi 2009) media have been presented in articles, the report of the new methods with mild conditions in terms of operation simplicity, economic viability, and greater selectivity for the preparation of potentially bioactive THPMs is still noticeable (Fig. 2).

Fig. 2
figure 2

Representative of some biological active THPOs

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From the point of view of the discovery of new drugs, bio-compound screening programs can be very effective for using natural compounds as starting materials in the preparation of new drugs from the category of known drug compounds (Newman and Cragg 2007). One class of these natural compounds are 4-hydroxy-2-pyridones (HPOs) alkaloids (Jessen and Gademann 2010). HPO derivatives are six-membered heterocycles that are mainly produced by fungi, and cause pathogenicity or incapacitate insects and actually regulate insect behavior (Molnár et al. 2010). Most of them were isolated from fungi (Hubka et al. 2015) and some from plants (Nebo et al. 2019). These compounds have many biological activities such as antifungal (Breinholt et al. 1997) (A), antibiotic (Singh et al. 2012) (B), insecticidal (Wachira et al. 2014) (C), cytotoxic (Bergmann et al. 2007), neurotoxic (Ferraz et al. 1999), anti-proliferative (Ding et al. 2014), antibacterial (Alfatafta et al. 1994), and anti-oxidant (D) (Kamali et al. 2020).

In continuation of our previous research (Kamali and Keramat Pirolghor 2022), we wish to present an efficient one-pot multicomponent synthesis of a new series of THPMs using HPOs and aromatic aldehydes and urea/thiourea/guanidine in the presence of ZnCl2.2H2O as the catalyst (Fig. 3).

Fig. 3
figure 3

Representative of some biological active 4-hydroxy-2-pyridones

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Results and discussion

According to the main goal of this research, the synthesis of 4-hydroxy-2-pyridones-based THPM, we first treated 1-ethyl-4-hydroxy-6-methylpyridin-2-one (1a), benzaldehyde (2a) and urea (3a) in the presence of HCl as the catalyst in ethanol under reflux conditions (Scheme 1 and Table 1; entry 1). As a result, it was afforded 4a (65% yield). For synthesizing of THMP (5a), this reaction was done in the presence of p-TSA instead of HCl (Scheme 1 and Table 1; Entry 2). In this reaction, the product 5a was not obtained, too. We repeated this reaction in the presence of a basic catalyst (Et3N; Table 1, Entry 3), and also with p-chlorobenzaldehyde (2b; Table 1, Entry 4). But 5a or 5b were not observed. Therefore, it was tested this reaction in the presence of SnCl2.2H2O (based on our previous work(Kamali and Keramat Pirolghor 2022)) as Lewis acid catalysts (Table 2; Entry 5). As a result, SnCl2.2H2O unlike to HCl or p-TSA (Brønsted-Lowry acids) and TEA (base catalyst) produced 5a as a main product. This behavior is probably due to the effect of tin chloride in the accumulation of substrates, and iminium intermediate, which provides a better catalytic role, and also causes dehydration in the last step of the reaction (Scheme 2) (Kamali and Keramat Pirolghor 2022). So we turned to some other metal chlorides (Table 2; Entry 1–3) to optimize the reaction conditions, and also performed a reaction without of any catalyst for a more investigation (Table 1; Entry 6). The SnCl2.2H2O gave better yield product (63%) than the other metal chloride salts (Table 2; Entry 1–3). But, because of more eco-friendly, ZnCl2.2H2O with slightly lower product yield (59%) than SnCl2.2H2O was selected as main catalyst for this reaction. For optimization of other reaction condition, the reaction was performed in some other solvents (Table 2; Entry 4–7), different amounts of catalyst (Table 1; Entry 4 and Table 3; Entry 1–3), different temperatures and times (Table 3; Entry 4–9). Consequently, the best amount of catalyst, solvent type, temperature and time of reaction for synthesis of 5a with 83% yield were 20 mol%, ethanol, 70 °C and 3 h, respectively. This reaction was economic and environmental friendly.

Scheme 1
scheme 1

Multicomponent reaction of aldehydes, 4-hydroxy-pyridine-2-ones and urea/thiourea/guanidine

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Table 1 Synthesis of THPM (5a and 5b) in the presence of different catalysts
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Table 2 Synthesis of 4a and 5a with different Lewis acid catalysts and solvents
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Scheme 2
scheme 2

Proposed mechanism

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Table 3 Synthesis of 5a with different amounts of catalyst, times and temperature’s reaction
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To further investigations and extend the library synthesis of THPM, some aromatic aldehydes (2a–2h) with electron withdrawing or donating groups, two 2-pyridones (1a, 1b) and urea/thiourea/guanidine (3a–3b) were treated to give the THPMs (5a–5l) in good to excellent yields (Scheme 1 and Table 4). It was seen that aldehydes with donor groups, didn’t afford the THPMs and the bis-product such as 6 (Table 4, Entry 15, in the presence of urea) were produced. This is probably due to that the reaction goes forward from other pathway (in compare to proposed mechanism; Scheme 2) (Kamali et al. 2020) in which first one pyridone molecule interact with an aldehyde, and the knoevenagel reaction occurs, and then the second pyridone molecule be added to knoevenagel intermediate and produces product 4. It should also be mentioned that the aldehydes having the strong acceptor groups such as NO2, the better reacts to urea/thiourea/guanidine, and as a result, THPM are obtained with more yield (Table 4, 5c, 5i and 5l). Also, the reaction with this method, in the presence of aliphatic aldehydes (formaldehyde, acetaldehyde and butyraldehyde) instead of aromatic aldehydes did not produce THPM. At last, generally, the yield of THPMs were lower using pyridone 1b than 1a (Table 4, 5h–5l), this is probably due to the more aromatic property and less acidic character of alpha hydrogen of carbonyl of 1b which itself is a result of the tautomerization of the carbonyl group and NH (Hejazi et al. 2016) (2-Hydroxypyridine/2-Pyridone; Scheme 3).

Table 4 Synthesized of THPM derivatives (5a–5l), (4a, 4b) and 6
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Scheme 3
scheme 3

Tautomerization of 4-hydrxoy-2-pyridone 1b

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Experimental section

The 4-hydroxy-6-methylpyridine-2-ones were synthesized according to known method (Kraus et al. 2016). The other starting materials were purchased from Merck and Fluka chemical companies. Melting points were determined with a Branstead Electrothermal model 9200 apparatus and are uncorrected. IR spectra were recorded on a Perkin Elmer RX1 Fourier transform infrared spectrometer. The 1H and 13C NMR spectra were recorded in DMSO-d6 on Bruker Avance 300 MHz spectrometers. Elemental analyses were carried out by a Perkin Elmer 2400 series II CHN/O analyzer.

Synthesis of 5a as a general procedure

The 1-ethyl-4-hydroxy-6-methylpyridine-2-one (1 mmol), the benzaldehyde (1 mmol) and the urea (1 mmol) were added to a solution of ZnCl2.2H2O (20 mol%) in absolute ethanol (1 mL), and the mixture was stirred at 70 ℃ for 3 h. Then the reaction mixture was poured in ice water (5 mL) and the precipitated was collected by filtration, washed with distilled water (5 mL). The resulting product was recrystallized from DMF/H2O (1 mL; V/V = 2:1) to give the pure 5a as White solid in 81% yield; m.p.: 188–190 °C. Compounds 4a–4b, 5b–5l and 6 were obtained in the same way. Only in the cases of 4a and 4b products, p-TSA (50 mol%) was used instead ZnCl2.2H2O and for isolation of them, after washing with water, the precipitate was added to ethanol 95% (5 mL), stirred for 0.5 h, and filtered. The filtrate solution was evaporated, and the solid recrystallized from ethanol 95%/water (4 mL; v/v = 3:1). The physical properties of products are in below, and the 1H NMR, 13C NMR, and IR spectra attached in the Supporting Information.

(±)-1-((1-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)(phenyl)methyl)urea (4a) White solid in 83% yield; m.p.: 228–230 °C; IR (KBr) υ: 3336 (NH), 3204 (NH), 2983 (CH), 2038 (CH), 1647 (C=O cm−1, 1H NMR (300 MHz, DMSO-d6) δ: 10.53 (s, 1H, OH of pyridone), 7.38–7.14 (m, 5H, ArH), 7.11 (d, J = 7.2 Hz, 1H, NH of urea), 6.24 (d, J = 7.2 Hz, 1H, CH residue of CHO), 5.87 (s, 1H, CH of pyridone), 5.81 (s, 2H, NH2 of urea), 3.88 (2dq, J = 13.6, 6.8 Hz, 2H, CH2 of pyridone), 2.29 (s, 3H, CH3 of pyridone), 1.10 (t, J = 6.9 Hz, 3H, CH3 pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.7 (=C–OH of pyrdone), 160.8 (C=O of urea), 158.1 (N–C=O of pyridone), 145.2 (=C–N of pyridone), 144.7 (C of ArH), 127.5 (CH of ArH), 126.1 (CH of ArH), 125.8 (CH of ArH), 109.1 (=CH of pyridone), 99.5 (=C of pyridone), 46.9 (CH residue of CHO), 19.5 (CH2 of pyridone), 13.8 (CH3 of pyridone) ppm. Anal. Calcd for C16H19N3O3 (301.14): C, 63.77; H, 6.36; N, 13.94. Found: C, 63.64; H, 6.36; N, 14.08.

(±)-1-((4-chlorophenyl)(1-ethyl-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)urea (4b) White solid in 87% yield; m.p.: 199–200 °C; IR (KBr) υ: 3345 (NH), 3196 (NH), 2989 (CH), 1647 (C=O) cm−1, 1H NMR (300 MHz, DMSO-d6) δ: 10.62 (s, 1H, OH of pyridone), 7.23–7.27 (m, 4H, CH of ArH), 7.13 (d, J = 7.2 Hz, 1H, NH of urea), 6.21 (d, J = 7.2 Hz, 1H, residue CH of CHO), 5.87 (s, 1H, CH of pyridone), 5.84 (s, 2H, NH2 of urea), 3.88 (2dq, J = 13.6, 7.0 Hz, 2H, CH2 of pyridone), 2.29 (s, 3H, CH3 of pyridone), 1.10 (t, J = 7.0 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.7 (=C–OH of pyridone), 161.0 (C=O of urea), 158.1 (C=O of pyridone), 145.5 (=C–N of pyridone), 143.8 (C of ArH), 130.2 (C of ArH), 127.6 (CH of ArH), 127.5 (CH of ArH), 108.7 (=CH of pyridone), 99.5 (=C of pyridone), 46.6 (CH residue of CHO), 35.8 (CH2 of pyridone), 19.6 (CH3 of pyridone), 13.9 (CH3 of pyridone) ppm. Anal. Calcd for C16H18ClN3O3 (335.10): C, 57.23; H, 5.40; N, 12.51. Found: C, 57.09; H, 5.31; N, 12.83.

(±)-6-ethyl-7-methyl-4-phenyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5a) White solid in 81% yield; m.p.: 188–190 °C; IR (KBr) υ:3341 (NH), 3196 (NH), 2956 (CH), 1661 (C=O) cm−1, 1H NMR (300 MHz, DMSO-d6) δ: 10.33 (s, 1H, NH of pyrimidine), 7.57 (d, J = 7.6 Hz, 1H, NH of pyrimidine), 7.14–7.18 (m, 5H, CH of ArH), 6.39 (d, J = 7.6 Hz, 1H, CH of pyrimidine), 5.69 (s, H, CH of pyridone), 3.83–3.97 (m, 2H, CH2 of pyridone), 2.29 (s, 3H, CH3 of pyridone), 1.03 (t, J = 9.2 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.6 (C=O pyridone), 160.2 (C=O of pyrimidine), 154.2 (N–C= of pyridone), 147.3 (C of ArH), 144.8 (=C–NH of pyridone), 127.6 (CH of ArH), 126.0 (CH of ArH), 124.3 (CH of ArH), 106.6 (=CH of pyridone), 98.0 (=C of pyridone), 48.6 (CH of pyrimidine), 34.0 (CH of pyridone), 17.6 (CH3 of pyridone), 11.2 (CH3 of pyridone). Anal. Calcd for C16H17N3O2 (283.13): C, 67.83; H, 6.05; N, 14.83. Found: C, 67.71; H, 5.94; N, 14.94.

(±)-4-(4-chlorophenyl)-6-ethyl-7-methyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5b) White solid in 86% yield; m.p.: 180–182 °C; IR (KBr) υ: 3346 (NH), 3207 (NH), 2969 (CH), 2942 (CH), 1658 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 10.08 (s, 1H, NH of pyrimidine), 7.58 (d, J = 7.7 Hz, 1H, NH of pyrimidine), 7.25 (d, 2H, J = 7.9 Hz, CH of ArH), 7.18 (d, 2H, J = 7.9 Hz, CH of ArH), 6.32 (d, J = 7.7 Hz, 1H, CH of pyrimidine), 5.72 (s, H, CH of pyridone), 3.85–39.98 (m, 2H, CH2 of pyridone), 2.24 (s, 3H, CH3 of pyridone), 1.03 (t, J = 9.2 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.8 (C=O of pyrimidine), 161.0 (C=O pyridone), 155.0 (N–C of pyridone), 145.6 (C of ArH), 142.3 (C of ArH), 130.7 (=C–N of pyridone), 129.9 (CH of ArH), 127.8 (CH of ArH), 106.4 (=CH of pyridone), 98.3 (=C of pyridone), 48.6 (CH of pyrimidine), 34.0 (CH of pyridone), 19.2 (CH3 of pyridone), 14.1 (CH3 of pyridone) ppm. Anal. Calcd for C16H16ClN3O2 (317.09): C, 60.48; H, 5.08; N, 13.22. Found: C, 60.39; H, 4.96; N, 13.34.

(±)-6-ethyl-7-methyl-4-(4-nitrophenyl)-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5c) Yellow solid in 92% yield; m.p.: 183–185 °C; IR (KBr) υ: 3304 (NH), 3190 (NH), 2992 (CH), 2943 (CH), 1642 (C=O cm−1, 1H NMR (300 MHz, DMSO-d6) δ: 10.68 (s, 1H, NH of pyrimidine), 8.08 (d, J = 8.0 Hz, 2H, CH of ArH), 7.69 (d, J = 7.6 Hz, 1H, NH of pyrimidine), 7.47 (d, J = 8.0 Hz, 2H, CH of ArH), 6.35 (d, J = 7.6 Hz, 1H, CH of pyrimidine), 5.86 (s, H, CH of pyridone), 3.90 (m, 2H, CH2 of pyridone), 2.30 (s, 3H, CH3 of pyridone), 1.12 (t, J = 9.2 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.4 (C=O pyridone), 161.3 (C=O of pyrimidine), 153.6 (N–C= of pyridone), 145.7 (C of ArH), 137.5 (C of ArH), 127.0 (=C–NH of pyridone), 126.9 (CH of ArH), 122.9 (CH of ArH), 108.2 (=CH of pyridone), 99.3 (=C of pyridone), 47.6 (CH of pyrimidine), 35.7 (CH of pyridone), 19.6 (CH3 of pyridone), 13.8 (CH3 of pyridone) ppm. Anal. Calcd for C16H16N4O4 (328.12): C, 58.53; H, 4.91; N, 17.06. Found: C, 58.40; H, 4.81; N, 17.21.

(±)-4-(2-chlorophenyl)-6-ethyl-7-methyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5d) White solid in 78% yield; m.p.: 184–185 °C; IR (KBr) υ: 336 (NH), 3067 (CH), 3158 (NH), 2988 (CH), 1646 (C=O), cm−1, 1H NMR (300 MHz, DMSO-d6) δ: 10.39 (s, 1H, NH of pyrimidine), 7.67 (d, J = 7.5 Hz, 1H, NH of pyrimidine), 7.08–7.29 (m, 4H, CH of ArH), 6.28 (d, J = 7.5 Hz, 1H, CH of pyrimidine) 5.76 (s, 1H, CH of pyridone), 3.93 (dq, J = 13.1, 7.0 Hz, 1H, CH2 of pyridone), 3.74 (dq, J = 13.1, 7.0 Hz, 1H, CH2 of pyridone), 2.26 (s, 3H, CH3 of pyridone), 1.10 (t, J = 7.0 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 162.7 (C=O of pyridone), 162.5 (C=O of pyrimidine), 161.6 (N–C= of pyridone), 157.8 (C of ArH), 156.3 (=C–N of pyridone), 145.3 (C of ArH), 141.3 (CH of ArH), 131.7 (CH of ArH), 128.6 (CH of ArH), 125.5 (CH of ArH), 107.2 (=CH of pyridone), 99.5 (=C of pyridone), 47.1 (CH of pyrimidine), 35.8 (CH3 of pyridone), 19.6 (CH3 of pyridone),14.0 (CH3 of pyridone) ppm. Anal. Calcd for C16H16ClN3O2 (317.09): C, 60.48; H, 5.08; N, 13.22. Found: C, 60.32; H, 4.95; N, 13.41.

(±)-4-(4-chlorophenyl)-6-ethyl-7-methyl-2-thioxo-2,3,4,6-tetrahydropyrido[4,3-d]pyrimidin-5(1H)-one (5e) White solid in 65% yield; m.p.: 187–189 °C; IR (KBr) υ: 3294 (NH), 3161 (CH), 2983 (CH), 1640 (C=O), 1090 (C=S) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 10.61 (s, 1H, NH of pyrimidine), 7.22 (d, J = 6.9 Hz, 2H, CH of ArH), 7.13 (d, J = 6.0 Hz, 1H, NH of pyrimidine), 6.94 (d, J = 6.9 Hz, 2H, CH of ArH), 6.10 (d, J = 6.0 Hz, 1H, CH of pyrimidine), 5.91 (s, 1H, CH of pyridone), 3.91 (m, 2H, CH2 of pyridone), 2.31 (s, 3H, CH3 of pyridone), 1.11 (t, J = 6.0 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 182.5 (C=S of pyrimidine), 162.2 (C=O of pyridone), 161.2 (=C–NH of pyridone), 145.5 (=C of pyridone), 143.4 (C of ArH), 128.5 (C of ArH), 127.6 (CH of ArH), 126.1 (CH of ArH), 107.93 (=C of pyridone), 99.6 (CH of pyridone), 52.3 (CH of pyrimidine), 35.4 (CH2 of pyridone), 19.5 (CH3 of pyridone), 13.7 (CH3 of pyridone) ppm. Anal. Calcd for C16H16ClN3OS (333.07): C, 57.57; H, 4.83; N, 12.59. Found: C, 57.39; H, 4.60; N, 12.73.

(±)-4-(2-chlorophenyl)-6-ethyl-2-imino-7-methyl-2,3,4,6-tetrahydropyrido[4,3-d]pyrimidin-5(1H)-one (5f) White solid in 78% yield; m.p.: 231–233 °C; IR (KBr) υ: 3324 (NH), 3140 (CH), 2978 (CH), 1640 (C=O). cm−1 .1H NMR (300 MHz, DMSO-d6) δ: 11.53 (s, 1H, NH of pyrimidine), 7.37 (s, 1H, = NH of pyrimidine), 7.13–7.26 (m, 4H, CH of ArH), 6.98 (d, J = 6.9 Hz, 1H, NH of pyrimidone), 6.23 (d, J = 6.9 Hz, 1H, CH of pyrimidone), 5.96 (s, 1H, CH of pyridone), 3.91 (m, 2H, CH2 of pyridone), 2.33 (s, 3H, CH3 of pyridone), 1.09 (t, J = 7.2 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 164.4 (C=O of pyridone), 162.3 (=C–NH of pyridone), 164.0 (C=NH of pyrimidine), 144.9 (=C–N of pyridone), 138.7 (C of ArH), 130.7 (C of ArH), 130.0 (CH of ArH), 129.5 (CH of ArH), 127.2 (C of ArH), 126.2 (CH of ArH), 108.8 (=C of pyridone), 99.8 (CH of pyridone), 46.2 (CH of pyrimidine), 34.5 (CH2 of pyridone), 19.3 (CH3 of pyridone), 13.6 (CH3 of pyridone) ppm. Anal. Calcd for C16H17ClN4O (316.11): C, 60.66; H, 5.41; N, 17.69. Found: C, 60.41, H, 5.32, N, 17.83.

(±)-4-(4-chlorophenyl)-6-ethyl-2-imino-7-methyl-2,3,4,6-tetrahydropyrido[4,3-d]pyrimidin-5(1H)-one (5g) White solid in 87% yield; m.p.: 209–210 °C;; IR (KBr) υ: 3305 (NH), 3194 (NH), 3082 (CH), 2922 (CH), 1646 (C=O). cm−1 .1H NMR (300 MHz, DMSO-d6) δ: 11.97 (s, 1H, NH of pyrimidine), 7.78 (s, 1H, NH of pyrimidine), 7.26 (d, J = 7.25, 2H, CH of ArH), 7.24 (d, 1H, J = 6.96 Hz, = NH of pyrimidine), 6.94 (d, J = 6.96 Hz, 2H, CH of ArH), 6.13 (d, 1H, J = 6.96 Hz, CH of pyrimidine), 5.96 (s, 1H, CH of pyridone), 3.95 (m, 2H, CH2 of pyridone), 2.37 (s, 3H, CH3 of pyridone), 1.13 (t, J = 7.1 Hz, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 164.8 (C=O of pyridone), 164.4 (=C–NH of pyridone), 159.2 (NH =C of pyrimidine), 145.6 (=C–N of pyridone), 138.0 (C of ArH), 129.8 (C of ArH), 128.1 (CH of ArH), 127.7 (CH of ArH), 109.8 (=C of pyridone), 103.3 (=C of pyridone), 45.2 (CH of pyrimidine), 35.0 (CH2 of pyridone), 19.2 (CH3 of pyridone), 13.6 (CH3 of pyridone) ppm. Anal. Calcd for C16H17ClN4O (316.11): C, 60.66; H, 5.41; N, 17.69. Found: C, 60.41; H, 5.32; N, 17.83.

(±)-7-methyl-4-phenyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5h) White solid in 61% yield; m.p.: 275–277 °C; IR (KBr) υ: 3376 (NH), 3286 (NH), 3058 (CH), 1616 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 11.19 (s, 1H, NH of pyridone), 10.48 (s, 1H, NH of pyrimidine), 7.93 (d, J = 8.6 Hz, 1H, NH of pyrimidine), 7.17–7.29 (m, 5H, CHs of ArH), 6.19 (d, J = 8.6 Hz, 1H, CH of primidine), 5.72 (s, 1H, CH of pyridine), 2.05 (s, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 163.6 (C=O of pyridone), 162.1 (=C–NH of pyridone), 156.8 (O=C of pyrimidine), 145.0 (=C–NH of pyridone), 144.4 (C of ArH), 128.1 (CH of ArH), 127.7 (CH of ArH), 126.1 (CH of ArH), 107.9 (=C of pyridone), 96.1 (=C of pyridone), 50.0 (CH of pyrimidine), 18.3 (CH3 of pyridone) ppm. Anal. Calcd for C14H13N3O2 (255.10): C, 65.87; H, 5.13; N, 16.46. Found: C, 65.71; H, 4.98; N, 16.57.

(±)-7-methyl-4-(4-nitrophenyl)-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5i) Yellow solid in 85% yield; m.p.: 209–211 °C; IR (KBr) υ: 3359 (NH), 3263 (NH), 3048 (CH), 1616 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 11.13 (s, 1H, NH of pyridone), 10.70 (s, 1H, NH of pyrimidine), 8.12 (d, J = 8.0 Hz, 2H, CH of ArH), 7.66 (d, J = 7.7 Hz, 1H, NH of pyrimidine), 7.49 (d, J = 8.0 Hz, 2H, CH of ArH), 6.30 (d, J = 7.7 Hz, 1H, CH of pyrimidine), 5.74 (s, 1H, CH of pyridone), 2.07 (s, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 164.1 (C=O of pyridone), 162.0 (=C–NH of pyridone), 156.9 (O=C of pyrimidine), 152.0 (C of ArH), 151.8 (C of ArH), 147.0 (=C of pyridone), 129.5 (CH of ArH), 123.2 (CH of ArH), 108.7 (=C of pyridone), 106.6 (=C of pyridone), 49.9 (CH of pyrimidine), 18.2 (CH3 of pyridone) ppm. Anal. Calcd for C14H12N4O4 (300.09): C, 56.00; H, 4.03; N, 18.66. Found: C, 55.87; H, 3.91; C, 18.81.

(±)-4-(4-chlorophenyl)-7-methyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5j) White solid in 68% yield; m.p.: 204–206 °C; IR (KBr) υ: 3359 (NH), 3267 (NH), 2924 (CH), 1620 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 11.08 (s, 1H, NH of pyridone), 10.72 (s, 1H, NH of pyrimidine), 7.55 (d, J = 7.6 Hz, 1H, NH of pyrimidine), 7.25 (d, br, 4H, CHs of ArH), 6.16 (d, J = 7.6 Hz, 1H, CH of pyrimidine), 5.77 (s, 1H, CH of pyridone), 2.06 (s, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 163.7 (C=O of pyridone), 163.0 (=C–NH of pyridone), 156.8 (O=C of pyrimidine), 145.7 (=C–NH of pyridone), 143.4 (C of ArH), 132.4 (C of ArH), 129.9 (CH of ArH), 127.7 (CH of ArH), 113.4 (=C of pyridone), 107.4 (=C of pyridone), 49.9 (CH of pyrimidine), 18.3 (CH3 of pyridone) ppm. Anal. Calcd for: C14H12ClN3O2 (289.06): C, 58.04; H, 4.18; N, 14.50. Found: C, 58.17; H, 4.01; N, 14.69.

(±)-4-(4-bromophenyl)-7-methyl-4,6-dihydropyrido[4,3-d]pyrimidine-2,5(1H,3H)-dione (5k) White solid in 84% yield; m.p.: 208–210 °C; IR (KBr) υ: 3356 (NH), 3110 (CH), 3077 (CH), 2932 (CH), 1619 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 11.13 (s, 1H, NH of pyridone), 10.69 (s, 1H, NH of pyrimidine), 7.54 (d, J = 7.58 Hz, 1H, NH of pyrimidine), 7.36 (d, J = 7.52 Hz, 2H, CH of ArH), 7.21 (d, J = 7.52 Hz, 2H, CH of ArH), 6.15 (d, J = 7.58 Hz, 1H, CH of pyrimidine), 5.73 (s, 1H, CH of pyridone), 2.05 (s, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 164.0 (C=O of pyridone), 162.5 (=C–NH of pyridone), 157.0 (C=O of pyrimidine), 144.9 (=C–NH of pyridone), 143.7 (C of ArH), 130.5 (CH of ArH), 128.1 (CH of ArH), 122.4 (C of ArH), 112.7 (=C of pyridone), 107.9 (=C of pyridone), 47.8 (CH of pyrimidine), 19.6 (CH3 of pyridone)Anal. Calcd for: C14H12BrN3O2 (333.01): C, 50.32; H, 3.62; N, 12.57. Found: C, 50.17; H, 3.62; N, 12.73.

(±)-2-imino-7-methyl-4-(4-nitrophenyl)-2,3,4,6-tetrahydropyrido[4,3-d]pyrimidin-5(1H)-one (5l) yellow solid in 90% yield; m.p.: 256–258 °C; IR (KBr) υ: 3328 (NH), 3312 (NH), 2952 (CH), 3077 (CH), 2932 (CH), 1657 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 11.21 (s, 1H, NH of pyridone), 10.86 (s, 1H, NH of pyrimidone), 8.37 (d, J = 7.5 Hz, 1H, CH of ArH), 7.58 (d, J = 7.1 Hz, 1H, NH of pyrimidine), 7.53 (s, 1H, NH of pyrimidine), 7.30 (d, J = 7.5 Hz, 2H, CH of ArH), 6.46 (d, J = 7.1 Hz, 1H, CH of pyrimidine), 5.97 (s, 1H, CH of pyridone), 2.21 (s, 3H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 164.1 (C=O of pyridone), 162.0 (=C–NH of pyridone), 157.0 (NH=C of pyrimidine), 152.0 (=C–NH of pyridone), 151.8 (C of ArH), 146.0 (C of ArH), 129.5 (CH of ArH), 123.2 (CH of ArH), 114.1 (=C of pyridone), 106.6 (=C of pyridone), 48.4 (CH of pyrimidine), 19.6 (CH3 of pyridone). Anal. Calcd for: C14H13N5O3 (299.10): C, 56.18; H, 4.38; N, 23.40. Found: C, 56.01; H, 4.29, N, 23.57.

2,8-diethyl-10-(4-methoxyphenyl)-3,7-dimethyl-8,10-dihydro-1H-pyrano[3,2-c:5,6-c']dipyridine-1,9(2H)-dione (6) White solid in 56% yield; m.p.: 228–229 °C; IR (KBr) υ: 3076 (CH), 2975 (CH), 1638 (C=O) cm−1. 1H NMR (300 MHz, DMSO-d6) δ: 6.75–6.84 (m, 4H, CH of ArH), 6.05 (s, 2H, CH of pyridone), 5.89 (s, 1H, CH residue of CHO), 3.91–3.98 (m, 2H, CH2 of pyridone), 3.68 (s, 3H, CH3 of aldehyede), 2.36 (s, 6H, CH3 of pyridone), 1.12 (t, J = 6.2 Hz, 6H, CH3 of pyridone) ppm. 13C NMR (75 MHz, DMSO-d6) δ: 168.9 ((=C of pyridone), 155.2 (C=O of pyridone), 154.2 (C-N of ArH),145.7 (=C of pyridone), 137.0 (C of ArH), 130.7 (CH of ArH), 114.1 (CH of ArH), 105.2 (=C of pyridone), 97.6 (=C of pyridone), 54.8 (O-CH3), 50.0 (CH of pyran), 48.7 (CH2 of pyridone), 20.3 (CH3 of pyridone), 13.7 (CH3 of pyridone).Anal. Calcd for: C24H26N2O4 (406.19): C, 70.92; H, 6.45; N, 6.89. Found: C, 70.73; H, 6.21; N, 6.61.

Conclusion

The multicomponent synthesis of a novel potentially bioactive series of dihydropyrimidin-2(1H)-ones/thione/imine based on 4-hydroxy-2-pyridone alkaloids has been provided by a rapid, straight, and efficient method using ZnCl2.2H2O as inexpensive catalyst. The advantages of this reaction consist generality and simplicity operational, short reaction time, simple workup, and high to excellent yields and eco-compatibility.