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Communication

Synthesis and Antifungal Activities of Some Novel Pyrimidine Derivatives

by
Li Sun
,
Jie Wu
,
Lingzi Zhang
,
Min Luo
and
Dequn Sun
*
Marine College, Shandong University, Weihai Wenhua West Road, No.180, Weihai 264209, China
*
Author to whom correspondence should be addressed.
Molecules 2011, 16(7), 5618-5628; https://doi.org/10.3390/molecules16075618
Submission received: 24 May 2011 / Revised: 16 June 2011 / Accepted: 17 June 2011 / Published: 30 June 2011
Browse Figures
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Abstract

:
Three series of new pyrimidine derivatives were synthesized and their antifungal activities were evaluated in vitro against fourteen phytopathogenic fungi. The results indicated that most of the synthesized compounds possessed fungicidal activities and some of them are more potent than the control fungicides. Preliminary SAR was also discussed.

1. Introduction

Phytopathogenic fungi that easily infect many crops are hard to control and risk resistance to the widely used commercial fungicides [1], therefore, there is a continuous need for new classes of antifungal agents. Natural compounds containing pyrimidine skeletons, such as vitamin B1 [2,3], and nucleotide bases [4] play an important role in life science studies. Pyrimidine derivatives have attracted great interest due to their diverse biological activities. For example, Rashad [5] synthesized a series of 4-hydrazinopyrimidine derivatives with in vitro antimicrobial activity. Rotili [6] reported a novel series of diarylpyrimidine and dihydrobenzyloxopyrimidine hybrids endowed with high and wide-spectrum anti-HIV-1 activity both in cellular and enzyme assays. Different classes of pyrimidine derivatives were synthesized and screened for antitumor activity to give candidates in drug discovery [7,8]. Pyrimidine derivatives have also occupied a prominent place in the field of agrochemicals because of their significant properties as fungicides in agriculture. To date, some important commercial pyrimidine fungicides, such as azoxystrobin [9,10], cyprodinil [11], pyrimethanil [12], and diflumetorim [13] (Figure 1) have been used in agriculture. Encouraged by the numerous pharmacological activities of pyrimidine derivatives, we were prompted to develop some novel pyrimidine fungicides. Three series of new pyrimidine derivatives 1–4 were designed and synthesized. The synthetic routes are shown in Scheme 1. All of the new compounds were evaluated in vitro for their antifungal activities against fourteen phytopathogenic fungi and the results of preliminary bioassays were compared with those of some commercial agricultural fungicides: flumorph, dimethomorph, carbendazim, hymexazole and pyrimethanil (Figure 1), which were currently used in the field in China. The results indicated that most of the pyrimidine derivatives possessed certain fungicidal activities, and the preliminary SAR of these compounds was investigated.
Molecules 16 05618 g001 550
Figure 1. Chemical structures of several commercial fungicides.
Figure 1. Chemical structures of several commercial fungicides.
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Molecules 16 05618 g004 550
Scheme 1. Synthetic routes to the three series of pyrimidine derivatives.
Scheme 1. Synthetic routes to the three series of pyrimidine derivatives.
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2. Results and Discussion

2.1. Synthesis

Compounds 1a and 1b were prepared by an improved method using NaH and TBAB in freshly distilled DCM since they couldn’t be obtained according to the method reported in the literature [14]. Compounds 2a and 2b were obtained according to the similar method in literature [15] in the presence of KI. Using POCl3 as chlorination reagent [16], the intermediate 4-chloro-2-isopropyl-6-methyl-pyrimidine was synthesized and used for the next substitution directly without purification in a small-scale synthesis. Reacting 4-chloro-2-isopropyl-6-methylpyrimidine with the corresponding aminesin different solvents afforded 3a [17], 3b [18] and 3c [19], however, it was not necessary to use K2CO3 in the preparation of 3a. In the preparation of compound 4a, the 4-morpholinecarbonyl chloride must be prepared freshly before use. Et3N and K2CO3 were employed in preparation of 4b and 4c respectively, since there were more by-products when Et3N was used in preparing 4b while few impurities were noted while synthesizing 4c. After the 3,4,5-trimethoxybenzoic acid was ready, the condensation with 6-hydroxy-2-isopropyl-4-methylpyrimidine using EDCI as coupling reagent gave 4c. Most of the compounds were prepared is yields of over 50%.

2.2. Antifungal Bioassay: Inhibitory Effects on Phytopathogenic Fungi

The fourteen phytopathogenic fungi chosen included Alternaria kukuchiana (AK), Alternaria mali (AM), Alternaria solani (AS), Botrytis cinerea (BC), Bipolaris maydi (BM), Cercospora arachidicola (CA), Gibberella zeae (GZ), Gibberella fujikuroi (GF), Macrophoma kuwatsukai (MK), Phytophthora infestans (Mont) de Bary (PI), Rhizoctonia solani (RS), Rhizoctonia cerealis (RC), Sclerotinia sclerotiorum (SS), Thanatephorus cucumeris (Frank), Domk (TC). All the fungi are typical and often occur in the Chinese agro-ecosystem. The antifungal activities of the eleven pyrimidine derivatives were investigated in vitro by poisoned food technique [20,21,22] at the concentration of 50 μg/mL. The commercial fungicides flumorph, dimethomorph, carbendazim, hymexazol and pyrimethanil were used as positive controls and they are widely used in field in China. The antifungal screening data are recorded in Table 1.
Table
Table 1. The fungicidal activities of three series of pyrimidine derivatives.
Table 1. The fungicidal activities of three series of pyrimidine derivatives.
Compd. No.Fungicidal activities (50 μg/mL, inhibition rate %)
AKAMASBCBMCAGFGZMKPIRCRSSSTC
1a45.521.441.229.634.813.32025.931.322.735.063.5080.4
1b18.2007.417.402014.831.303061.903.9
2a18.20040.717.4020046.99.15.054.0202.0
2b31.821.45.937.017.413.326.729.646.905.060.302.0
3a27.321.411.87.426.133.307.421.905.057.1039.2
3b63.65035.325.939.146.74044.425.036.425.066.7076.5
3c27.321.403.713.046.713.322.2036.4055.633.352.9
4a40.90018.517.46.76.77.431.302061.9019.6
4b27.321.4014.813.0046.714.846.918.2055.64015.7
4c22.721.4033.326.16.753.340.737.513.6061.9600
4d31.828.6014.826.16.7207.440.613.615.063.566.79.8
Pyri.10021.410096.391.31002044.410022.74077.886.798.0
Flu.18.221.407.417.4013.37.421.94.52061.909.8
Dim.22.77.15.918.517.402006.39.14068.32023.5
Carb.81.878.676.563.069.653.36059.343.827.310010073.398.0
Hym.81.885.788.270.434.893.34033.35036.425.063.566.778.4
Flu. = flumorph, Dim. = dimethomorph, Carb. = carbendazim, Hym. = hymexazol, Pyri. = pyrimethanil.
As shown in Table 1, all of the new pyrimidine derivatives exhibited certain growth inhibition effects against most of the tested fungi, and the results provided useful information to study the structure-activity relationshipx for these new structures shown in Scheme 1. The inhibition of most compounds was equal to or higher than that of the positive controls, flumorph and dimethomorph (Figure 2).
Molecules 16 05618 g002 550
Figure 2. Parallel inhibition rate contrasts between positive controls (flumorph and dimethomorph) and representative pyrimidine derivatives 1a, 3b.
Figure 2. Parallel inhibition rate contrasts between positive controls (flumorph and dimethomorph) and representative pyrimidine derivatives 1a, 3b.
Molecules 16 05618 g002
Especially, to PI, the activities of 1a, 3b, 3c, 4b (22.7%, 36.4%, 36.4%, 18.2%, respectively) were 1-3 times higher than dimethomorph (9.1%) which is widely used to prevent phytophthora infestans in filed [23,24]. Thus, the findings demonstrate that the new synthesized pyrimidine derivatives represent a new structure skeleton for inhibiting PI. The activities of carbendazim and hymexazol were excellent (>50%) to most of tested fungi, however, they showed rather lower inhibition to BM, GZ, MK and PI than several new synthesized compounds (3b, 3c, 4b, et al.). The leading compound pyrimethanil showed excellent effect on most of the tested fungi, except on AM, GF GZ and PI (21.4%, 20%, 44.4%, and 22.7%). It exhibited parallel activity with 3b to GZ (44.4%), lower than 3b and 3c to PI (36.4% and 36.4%, respectively), at least 1-fold lower than 3b, 4b and 4c to GF (40%, 46.7% and 53.3%, respectively) and 2-fold lower to AM than 3b (50%). 1a and 3b provided certain broad-spectrum to the tested fungi, and showed relatively higher activities, especially to TC (80.4% and 76.5% respectively) (Figure 3).
Molecules 16 05618 g003 550
Figure 3. Parallel inhibition rate contrasts between leading compound pyrimethanil and 1a, 3b.
Figure 3. Parallel inhibition rate contrasts between leading compound pyrimethanil and 1a, 3b.
Molecules 16 05618 g003
The inhibition against the fungi except RS, GF, SS was significantly decreased when the (6-chloropyridin-3-yl)methyl of 1a was replaced by (6-chlorothiazole-3-yl) methyl in 1b, especially against TC, a 12-fold decrease in activity was observed, whereas no similar SAR was observed for 2a, 2b. Comparing pyrimethanil and compound 2 with compound 3, preliminary SAR presumed that 2-substituted pyrimidinamine was effective to Botrytis while 4-substituted pyrimidinamine was more potent to Cercospora, and the two classes possessed a certain degree of selectivity in inhibition to different genus. Compound 3b with a trifluoromethoxy on the 4-position of the phenyl ring was more effective than 3a on the tested fungi, except AS, CA, PI, SS. To a certain extent, the results indicated that –OCF3 containing derivatives may have good activity because of their special atom size and their characteristics to form a H bond with the potential target. S. sclerotiorum (SS) is one of the most nonspecific, omnivorous and successful plant pathogens with an extensive host range. At least 361 species in 64 families of plants are susceptible to SS [25]. Compounds 4b, 4c, 4d showed better fungicidal activities to SS (40%, 60%, 66.7%) than 4a (0%), which showed that fungicidal activity increased smoothly with increasing density of the electron cloud on the benzene ring. The inhibition of 4c was equal to that of pyrimethanil (66.7%), lower than carbendazim (73.3%) and hymexazole (86.7%). Encouragingly, all of the derivatives showed good activity to RS (>50%).

3. Experimental

3.1. General

All reactions using air- or moisture-sensitive reagents were conducted under an inert nitrogen atmosphere. Anhydrous solvents were distilled prior to use. THF was distilled from sodium/benzophenone. DCM and CH3CN were distilled from CaH2 and DMF was dried over P2O5. Silica (200–300 mesh) was used for column chromatography. The IR spectra were recorded on a Bruker VERTEX 70 FT-IR. 1H-NMR spectra were recorded on a 400 MHz spectrometer at 25 °C using TMS as an internal reference. Coupling constants (J) are reported in Hertz (Hz). 1H-NMR splitting patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Melting points of the products were determined in open capillary tubes and uncorrected. Mass spectra were recorded with a JEOL MS-D 300 mass spectrometer. Elemental analysis was performed on a Carlo-1106 model automatic instrument.

3.2. Procedures for the Preparation of Title Compounds 1-4

4-[(6-Chloropyridin-3-yl)methoxy]-2-isopropyl-6-methylpyrimidine (1a). To a solution of 6-hydroxy-2-isopropyl-4-methylpyrimidine (0.30 g, 2 mmol) and 2-chloro-5-(chloromethyl)pyridine (0.33 g, 2 mmol) in DCM (20 mL) was added NaH (0.14 g, 6 mmol) and TBAB (0.12 g, 0.37 mmol). The mixture was refluxed for 4 h. After being cooled, the mixture was poured into water (100 mL) and DCM (80 mL), the organic layer was separated and washed by water twice, then dried over anhydrous MgSO4, concentrated and the residue was chromatographed to give 1a as a white solid (0.27 g, 49%), m.p. 34–37 °C. IR (film, cm−1): 2966, 2929, 2871, 1589, 1566, 1460, 1338, 1163, 1105, 1043, 848, 821. 1H-NMR (CDCl3) δ 1.29 (d, J = 5.6 Hz, 6H, 2CH3), 2.42 (s, 3H, pyrimidine-CH3), 3.07 (m, 1H, CH), 5.44 (s, 2H, OCH2), 6.43 (s, 1H, pyrimidine–H), 7.33 (d, J = 8 Hz, 1H, pyridine–H), 7.77 (d, J = 8 Hz, 1H, pyridine–H), 8.51 (s, 1H, pyridine–H). m/z (EI) 277 (M+). Anal. Calc. for C14H16ClN3O (277.75): C, 60.54; H, 5.81; N, 15.13; found: C, 60.61; H, 5.93; N, 15.31.
4-[(5-Chlorothiazole-2-yl)methoxy]-2-isopropyl-6-methylpyrimidine (1b). 1b was prepared from 6-hydroxy-2-isopropyl-4-methylpyrimidine (0.30 g, 2 mmol) and 2-chloro-5-(chloromethyl)thiazole (0.34 g, 2 mmol) by the same procedure as that of 1a. Compound 1b was obtained as a white solid (0.22 g, 39%), m.p. 114–118 °C. IR (film, cm−1): 2970, 2933, 2871, 1666, 1525, 1417, 1392, 1363, 1095, 1049, 846. 1H-NMR (CDCl3) δ 1.30 (d, J = 8.8 Hz, 6H, 2CH3), 2.25 (s, 3H, pyrimidine–CH3), 3.17 (m, 1H, CH), 5.29 (s, 2H, OCH2), 6.21 (s, 1H, pyrimidine–H), 7.53 (s, 1H, thiazole–H). m/z (EI) 283 (M+). Anal. Calc. for C12H14ClN3OS (283.78): C, 50.79; H, 4.97; N, 14.81; found: C, 50.67; H, 4.54; N, 14.68.
2-[(6-Chloropyridin-3-yl)methyl]amino-4,6-dimethoxypyrimidine (2a). A mixture of 2-amino-4,6- dimethoxypyrimidine (0.31 g, 2 mmol), 2-chloro-5-(chloromethyl)pyridine (0.33 g, 2 mmol) and KI (0.34 g, 2 mmol) in i-PrOH (10 mL) was refluxed for 6–7 h, then KOH (0.12 g, 2 mmol) was added and the mixture was stirred for another 0.5 h. After being cooled to r.t., the mixture was poured into crushed ice water, the precipitate was collected and recrystallized to give 2a as a white solid (0.39 g, 70%), m.p. 81–83 °C. IR (film, cm−1): 3030, 2970, 2949, 1737, 1591, 1365, 1207, 750, 663. 1H-NMR (CDCl3) δ 3.82 (s, 6H, 2OCH3), 4.59 (d, J = 6.4 Hz, 2H, CH2), 5.30 (m, 1H, NH), 5.45 (s, 1H, pyrimidine–H), 7.29 (d, J = 9.6 Hz, 1H, pyridine–H), 7.67 (dd, J = 2.4 Hz, 9.6 Hz, 1H, pyridine–H), 8.39 (d, J = 1.6 Hz, 1H, pyridine–H). m/z (EI) 280 (M+). Anal. Calc. for C12H13ClN4O2 (280.71): C, 51.34; H, 4.67; N, 19.96; found: C, 51.48; H, 4.85; N, 20.04.
2-[(2-Chlorothiazol-5-yl)methyl]amino-4,6-dimethoxypyrimidine (2b). 2b was prepared from 2-amino-4,6-dimethoxypyrimidine (0.31 g, 2 mmol) and 2-chloro-5-(chloromethyl)thiazole (0.34 g, 2 mmol) by the same procedure as that of 2a. Compound 2b was obtained as a white solid (0.19 g, 33%), m.p. 155–157 °C. IR (film, cm−1): 3242, 2970, 2947, 2349, 2337, 1737, 1591, 1365, 1215, 1051, 673, 663. 1H-NMR (CDCl3) δ 3.87 (s, 6H, 2OCH3), 4.69 (d, J = 6.4 Hz, 2H, CH2), 5.49 (s, 1H, pyrimidine–H), 5.56 (t, J = 6.4 Hz, 1H, NH), 7.43 (s, 1H, thiazole–H). m/z (EI) 286 (M+). Anal. Calc. for C10H11ClN4O2S (286.74): C, 41.89; H, 3.87; N, 19.54; found: C, 41.75; H, 3.95; N, 19.39.
Preparation of 4-chloro-2-isopropyl-6-methylpyrimidine. 6-hydroxy-2-isopropyl-4-methylpyrimidine (1.52 g, 10 mmol) was added to a 100mL flask, followed by addition of POCl3 (15 mL). The mixture was stirred at 70 °C for 2 h. The residuary POCl3 was distilled out and the residue was redissolved in EtOAC (200 mL). The mixture was poured into 200 mL of ice water, alkalified to pH 7 by Na2CO3 powder. The EtOAC layer was separated and washed by water twice. The organic layer was dried over anhydrous MgSO4 and concentrated. The obtained crude product was purified by gel silica column chromatography to give a light-yellow oil (1.55 g, 91%) which was used for the next step.
2-Isopropyl-6-methyl-N-phenylpyrimidin-4-amine (3a). A mixture of 4-chloro-2-isopropyl-6-methyl- pyrimidine (0.34 g, 2 mmol) and aniline (0.28 g, 3 mmol) in DMF (10 mL) was stirred at ~90 °C for 2 h. After the mixture was cooled to r.t., 200 mL of water was added and the mixture was extracted with EtOAC. The combined organic layer was dried over anhydrous MgSO4, concentrated and the residue was purified by silica gel column chromatography to give 3a as a brown solid (0.36 g, 79%), m.p. 80–81 °C. IR (film, cm−1): 3286, 3172, 2927, 2869, 1581, 1510, 1498, 1442, 1363, 1247, 979, 754. 1H-NMR (CDCl3) δ 1.32 (d, J = 7.2 Hz, 6H, 2CH3), 2.34 (s, 3H, CH3), 3.02 (m, 1H, CH), 6.41 (s, 1H, pyrimidine–H), 7.06 (s, 1H, NH), 7.10–7.42 (m, 5H, Ph–H). m/z (EI) 227 (M+). Anal. Calc. for C14H17N3 (227.30): C, 73.98; H, 7.54; N, 18.49; found: C, 73.67; H, 7.62; N, 18.33.
2-Isopropyl-6-methyl-N-(4-(trifluoromethoxy)phenyl)pyrimidin-4-amine (3b). To a solution of 4-chloro-2-isopropyl-6-methylpyrimidine (0.17 g, 1 mmol) and 4-(trifluoromethoxy)aniline (0.27 g, 1.5 mmol) in i-PrOH (20 mL) was added anhydrous powdered K2CO3 (0.14 g, 1 mmol). The mixture was refluxed overnight. The i-PrOH was removed in vacuo, and the residue was disssolved in DCM and water. The DCM layer was seperated and the water layer was extracted with DCM, the combined organic layer was dried over anhydrous MgSO4, concentrated and the residue was purified by column chromatography on silica gel to give 3b as an orange solid (0.25 g, 80%), m.p. 104–109 °C. IR (film, cm−1): 3296, 3198, 2970, 2931, 2873, 1587, 1508, 1415, 1247, 1201, 1163, 1016, 981, 839. 1H-NMR (CDCl3) δ 1.32 (d, J = 4.8 Hz, 6H, 2CH3), 2.37 (s, 3H, pyrimidine–CH3), 3.04 (m, 1H, CH), 6.35 (s, 1H, pyrimidine–H), 6.72 (s, 1H, NH), 7.47 (d, J = 16.4 Hz, 2H, Ph–H), 7.22 (d, J = 11.2 Hz, 2H, Ph–H). m/z (EI) 311 (M+). Anal. Calc. for C15H16F3N3O (311.30): C, 57.87; H, 5.18; N, 13.50; found: C, 57.74; H, 5.21; N, 13.68.
N-cyclohexyl-2-isopropyl-6-methylpyrimidin-4-amine (3c). To a solution of 4-chloro-2-isopropyl-6- methylpyrimidine (0.17 g, 1 mmol) and cyclohexane (1.0 g, 10 mmol) in CH3CN (10 mL) was added powdered K2CO3 (0.14 g, 1 mmol). The mixture was stirred at reflux for 7 h. After the solvent was removed in vacuo, the residue was dissolved in DCM and water, acidified by cold 0.5 N HCl aqueous to pH 7~7.5. The DCM layer was separated and the water layer was extracted with DCM for three times. The combined organic layer was dried over anhydrous MgSO4. The solvent was evaporated in vacuo to give 3c as a light-brown solid (0.16 g, 69%), m.p. 93–97 °C. IR (film, cm−1): 3263, 2929, 2854, 1598, 1500, 1448, 1359, 1191, 975, 839. 1H-NMR (CDCl3) δ 1.18–1.27 (m, 10H, 2CH3, cyclohexane–H), 1.33–2.03 (m, 7H, cyclohexane–H), 2.33 (s, 3H, CH3), 2.92 (m, 1H, CH), 4.81 (m, 1H, NH), 5.97 (s, 1H, pyrimidine–H). m/z (EI) 233 (M+). Anal. Calc. for C14H23N3 (233.35): C, 72.06; H, 9.93; N, 18.01; found: C, 72.17; H, 9.87; N, 17.92.
Preparation of 4-morpholinecarbonyl chloride. Triphogene (1.49 g, 5 mmol) was dissolved in DCM (150 mL), then a solution of morpholine (0.87 g, 10 mmol) and triethylamine (1.52 g, 15 mmol) in DCM (30 mL) was added dropwise slowly in a salt-ice bath. After the reaction was completed (monitored by Iodine smoked TLC), phosgene was blown away by N2, then the mixture was filtered and the filtrate was concentrated to give a light-brown oil (1.41 g, 94%, with a content of about 70%) which was used for the next step without further purification.
2-Isopropyl-6-methylpyrimidin-4-yl morpholine-4-carboxylate (4a). To a stirred solution of 6-hydroxy- 2-isopropyl-4-methylprimidine (0.15 g, 1 mmol) and 4-morpholinecarbonyl chloride (crude product, 0.28 g, about 1.3 mmol) in DCM (15 mL) was added a solution of Et3N (0.20 g, 2 mmol) in DCM (5 mL), followed by addition of DMAP (0.03 g, 0.25 mmol). The mixture was stirred at r.t. for 5 h. 80 mL of DCM was added and the mixture was washed by cold sat. Na2CO3 aqueous and water sequentially. The DCM layer was separated and dried over anhydrous MgSO4, concentrated in vacuo to give crude product, which was purified by column chromatography on gel silica to give 4a as a light-yellow oil (0.19 g, 72%). IR (film, cm−1): 2968, 2927, 2864, 1733, 1585, 1421, 1342, 1274, 1230, 1155, 1118, 1060, 848, 746. 1H-NMR (CDCl3) δ 1.32 (d, J = 6.8 Hz, 6H, 2CH3), 2.52 (s, 3H, CH3), 3.14 (m, 1H, CH), 3.58–3.78 (m, 8H, morpholine–H), 6.86 (s, 1H, pyrimidine–H). m/z (EI) 265 (M+). Anal. Calc. for C13H19N3O3(265.31): C, 58.85; H, 7.22; N, 15.84; found: C, 58.78; H, 7.41; N, 15.98.
2-Isopropyl-6-methylpyrimidin-4-yl 4-fluorobenzoate (4b). To a solution of 6-hydroxy-2-isopropyl- 4-methylpyrimidine (1.00 g, 6.5 mmol) in anhydrous THF (30 mL) was added the p-fluorobenzoyl chloride (1.43 g, 9 mmol) dropwise in an ice-water bath, followed by addition of K2CO3 powder (0.55 g, 4.0 mmol). The mixture was stirred overnight at r.t. After the THF was evaporated in vacuo, DCM (200 mL) was added and washed by water three times. The DCM solution was dried over MgSO4 and concentrated to give a crude product, which was purified by column chromatography on gel silica to give 4b as a white solid (1.6 g, 90%), m.p. 36–37 °C. IR (film, cm−1): 2968, 2929, 2875, 2360, 2341, 1749, 1733, 1716, 1699, 1558, 1541, 1456, 1419, 1247, 1149, 1060,852. 1H-NMR (CDCl3) δ 1.49 (d, J = 9.2 Hz, 6H, 2CH3), 2.57 (s, 3H, CH3), 3.19 (m, 1H, CH), 6.94 (s, 1H, pyrimidine–H), 7.19 (t, J = 11.2 Hz, 2H, Ph–H), 8.24 (dd, J = 11.2 Hz, 7.2 Hz, 2H, Ph–H). m/z (EI) 274 (M+). Anal. Calc. for C15H15FN2O2(274.29): C, 65.68; H, 5.51; N, 10.21; found: C, 65.84; H, 5.66; N, 10.17.
2-Isopropyl-6-methylpyrimidin-4-yl 4-chlorobenzoate (4c). To a stirred solution of 6-hydroxy- 2-isopropyl-4-methylpyrimidine (0.30 g, 2 mmol), Et3N (0.30 g, 3 mmol) and DMAP (0.06 g, 0.5 mmol) in DCM (20 mL) was added, then a solution of p-chlorobenzoyl chloride (0.42 g, 2.4 mmol) in DCM was added dropwise in an ice-water bath. The mixture was warmed to r.t. and stirred for 0.5 h, then washed by water. The organic layer was dried over anhydrous MgSO4 and concentrated to afford a crude product, which was purified by column chromatography on gel silica to give 4c as a colorless oil (0.41 g, 71%). IR (film, cm−1): 2970, 2929, 2873, 1747, 1587, 1562, 1508, 1249, 1149, 1060, 1012, 852, 757. 1H-NMR (CDCl3) δ 1.35 (d, J = 6.8 Hz, 6H, 2CH3), 2.57 (s, 3H, pyrimidine–CH3), 3.18 (m, 1H, CH), 7.18 (s, 1H, pyrimidine–H), 7.20 (d, 2H, J = 8.4 Hz, Ph–H), 8.24 (d, 2H, J = 8.8 Hz, Ph–H). m/z (EI) 290 (M+). Anal. Calc. for C15H15ClN2O2(290.74): C, 61.97; H, 5.20; N, 9.64; found: C, 62.06; H, 5.36; N, 9.53.
2-Isopropyl-6-methylpyrimidin-4-yl-3,4,5-trimethoxybenzoate (4d). To a solution of 3,4,5-trimethoxy-benzoicacid (0.21 g, 1 mmol) and 6-hydroxy-2-isopropyl-4-methylpyrimidine (0.15 g, 1 mmol) in DCM(10 mL) was added EDCI (0.28 g, 1.5 mmol). The mixture was stirred for 4 h. 90 mL of DCM was added and washed by water and the organic layer was separated, dried over MgSO4. The solvent was evaporated and the crude product was purified by chromatography on gel silica to give 4d as a white solid (0.19 g, 55%). m.p. 97–99 °C. IR (film, cm−1): 2970, 2943, 2841, 1739, 1587, 1504, 1415, 1326, 1207, 1128, 974, 750. 1H-NMR (CDCl3) δ 1.35 (d, 6H, J = 6.8 Hz, 2CH3), 2.57 (s, 3H, CH3), 3.20(m, 1H, CH), 3.94 (s, 6H, 2OCH3), 3.95 (s, 3H, OCH3), 6.91 (s, 1H, pyrimidine–H), 7.45 (s, 2H, Ph–H). m/z (EI) 346 (M+). Anal. Calc. for C18H22N2O5 (346.38): C, 62.42; H, 6.40; N, 8.09; found: C, 62.63; H, 6.61; N, 7.98.

4. Conclusions

Eleven novel pyrimidine derivatives of three classes had been synthesized and identified. The bioactivity tests showed that most of them had antifungal activities. The antifungal activities of most of compounds were equal to or higher than those of the commercial fungicides flumorph and dimethomorph. Compounds 3b, 4b and 4c showed better activity than the lead compound, pyrimethanil to GF. Compound 3b was more potent to AM than pyrimethanil. Compounds 1a and 3b displayed certain broad-spectrum activity towards the tested fungi. Compounds 4a, 4b, 4c and 4d showed relatively moderate antifungal activity. The preliminary SAR can offer great help to design more active compounds as potent fungicides.

Supplementary Materials

Supplementary File 1

Acknowledgements

We thank Zhijin FAN from Nankai University for the great help in antifungal bioactivity test and for his generous suggestions for our work. Authors are also grateful to his group for very detailed discussions.

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Sun, L.; Wu, J.; Zhang, L.; Luo, M.; Sun, D. Synthesis and Antifungal Activities of Some Novel Pyrimidine Derivatives. Molecules 2011, 16, 5618-5628. https://doi.org/10.3390/molecules16075618

AMA Style

Sun L, Wu J, Zhang L, Luo M, Sun D. Synthesis and Antifungal Activities of Some Novel Pyrimidine Derivatives. Molecules. 2011; 16(7):5618-5628. https://doi.org/10.3390/molecules16075618

Chicago/Turabian Style

Sun, Li, Jie Wu, Lingzi Zhang, Min Luo, and Dequn Sun. 2011. "Synthesis and Antifungal Activities of Some Novel Pyrimidine Derivatives" Molecules 16, no. 7: 5618-5628. https://doi.org/10.3390/molecules16075618

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