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Design, Synthesis and Biological Evaluation of N-((2-phenyloxazol-4-yl)methyl) Pyrimidine Carboxamide Derivatives as Potential Fungicidal Agents

  • Danling Huang , Shumin Zheng and Yong-Xian Cheng EMAIL logo
Published/Copyright: December 31, 2020
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 26 Issue 1

Abstract

Twelve N-((2-phenyloxazol-4-yl)methyl) pyrimidine carboxamide derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR, and HRMS. The fungicidal activities of these new compounds against Sclerotinia sclerotiorum, Botrytis cinereal, and Colletotrichum fragariae were evaluated. The results indicated that compounds 5b, 5f, and 5g displayed potential fungicidal activities against tested fungi, especially 5f exhibited IC50 value of 28.9 mg/L against S. sclerotiorum. Moreover, the compounds 5f and 5g showed IC50 values of 54.8 mg/L and 62.2 mg/L against C. fragariae respectively, which shows that they were more active than the commercial fungicide hymexazol. The superficial structure-activity relationships were discussed, which may be of benefit for the development of fungicides and discovery of novel fungicides.

Keywords: Oxazole derivative; Synthesis; Fungicidal activities; Structure-activity relationship

Introduction

Plant diseases are one of the main causes of crops reduction, around 80% of which result from fungi infections [1,2]. Furthermore, human health is harmed because of the mycotoxins that are produced by the fungi [3,4]. Undoubtedly, rational application of fungicides is an effective method for fungal control. However, most fungi have developed resistances or cross-resistances to the commercial fungicides [5]. Therefore, development and discovery of novel fungicides with high-efficiency and lower toxicity is tremendously necessary and needed with great urgency.

The oxazole skeleton is of extraordinary importance in the design of active fungicidal molecules. Recently, lots of oxazole derivatives with potential fungicidal activity have been discovered [6, 7, 8, 9]. Studies suggest that the oxazole derivatives display a broad spectrum of antifungal activity. Moreover, there are many oxazole derivatives being developed for the commercial fungicides (Figure 1a), such as famoxadone [10], hymexazol [11], and oxadixyl [12]. On the other hand, the pyrimidine ring is a remarkable moiety in various bioactive molecules including anti-fungal, antimicrobial, anticancer and anti-inflammatory agents [13]. In particular, pyrimidine derivatives hold a pivotal position in the structure of fungicides design, and have yielded the commercial products of pyrimethanil [14], fenarimol [15], mepanipyrim [16], and ferimzone [17] (Figure 1b). Literature showed that the introduction of a pyrimidine fragment was beneficial to the improvement of fungicidal activities of compounds [18, 19, 20]. Toshihiro et al. [21] gave the systematic structure-activity relationship (SAR) of pyrimidine derivatives. They found that the pyrimidine ring introduced the same substituents at the different positions and influenced the bioactivities of the compounds remarkably. Inspired by this work, formamide derivatization on different positions of pyrimidine was considered in our design strategy. In our effort to seek novel compounds with potential fungicidal activities, we tried to use a molecular hybridization strategy to combine the active fragment oxazole and pyrimidine via an amido bond (Figure 1c), in which R was chosen as a hydrogen atom, methyl, methoxyl, or trifluoromethyl and Ar was fixed as 2 - pyrimidinyl, 4 – pyrimidinyl or 5 – pyrimidinyl. Herein, we report the synthesis of 12 pyrimidine amide derivatives containing 2-phenyl-oxazole and their fungicidal activities against three fungi, Sclerotinia sclerotiorum, Botrytis cinereal, and Colletotrichum fragariae, which are known as the main pathogenic fungi in agriculture. Furthermore, the apparent SAR of these compounds were discussed.

Figure 1 The design of fungicidal 2-aryl-oxazole derivatives containing pyrimidine
Figure 1

The design of fungicidal 2-aryl-oxazole derivatives containing pyrimidine

Result and discussion

The target compounds, N-((2-(4-substituted-phenyl)oxazol-4-yl)methyl)pyrimidine carboxamides (5a-5l) were synthesized as outlined in Scheme 1. Initially, the skeleton of the oxazole ring was built by a Bredereck reaction [22]. The 2-aryl-4-chloromethyl oxazole (2a-2d) was obtained via reaction between 1,3-dichloroacetone and amide (1a-1d) and heating at 130 oC. The Gabriel reaction [23] was carried out to shift 2a-2d to the key intermediates 4a-4d. In brief, potassium phthalimide was reacted with the corresponding 4-chloromethyl oxazole (2a-2d) in N,N-dimethylformamide (DMF) at 80 oC. Then, these synthesized phthalimide derivates (3a-3d) were further treated with hydrazine hydrate in ethanol at reflux temperature to result in the corresponding (2-aryloxazol-4-yl)methanamine. Afterwards, amine hydrochloride derivatives 4a-4d were generated by addition of concentrated hydrochloric acid to (2-aryl-oxazol-4-yl) methanamine.

Finally, condensation reaction between 4a-4d and pyrimidine carboxylic acid was carried out in the presence of 2-(7-Azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU) to obtain target compounds 5a-5l, whose structures were identified by 1H NMR, 13C NMR, and HRMS as detailed in the experimental section. The final step of the synthesis gave satisfactory yields (≥ 80%) and the overall yield of the synthesis route reported here was over 50%, which demonstrated that the synthesis pathway shown in Scheme 1 is reasonable and available.

The structures and fungicidal activities against S. sclerotiorum, B. cinereal, and C. fragariae were shown in Table 1. All target compounds were screened at three concentrations including 100 mg/L, 50 mg/L, and 30 mg/L. As a result, 5f and 5g showed better fungicidal activities against the three test fungi (Figure 2). In detail, for S. sclerotiorum, 5f, 5g, 5j displayed over 60% inhibition rate at the concentration of 100 mg/L. In particular, 5f displayed 45.6% inhibition rate against S. sclerotiorum at 30 mg/L, while 5g and 5j showed less activities (13.0% and 28.7%) at the equivalent concentration. On the other hand, 5f and 5g exhibited over 50% inhibition against B. cinerea at 100 mg/L. In addition, 5f and 5g showed similar effects against C. fragariae to the commercial product hymexazol. Finally, as shown in Table 2, the IC50 values of the better bioactive compounds (5b, 5f and 5g) were given. It revealed that 5f (54.8 mg/L) and 5g (62.2mg/L) display lower IC50 value against C. fragariae than that of hymexazol (148.9mg/L).

Figure 2 The fungicidal efficacy of 5f and 5g
Figure 2

The fungicidal efficacy of 5f and 5g

Table 1

Inhibition ratio(%) of compounds 5a-5l and hymexazol against S. sclerotiorum, B. cinerea, and C. fragariae

CompoundArRS. Sclerotiorum (mg/L)B. Cinerea (mg/L)C. Fragariae (mg/L)
305010030501003050100
5aA1H-[a]---5.8012.56-19.5919.92
5bA1CF3-4.785.2213.0418.3638.6520.2729.7343.24
5cA1OCH3-4.785.22-2.423.8610.1413.5125.00
5dA1CH3-3.710.0-6.87.9--6.3
5eA2H3.0418.2639.1310.1418.8427.0512.1614.8624.32
5fA2CF345.6566.0975.6538.1649.7653.1429.0545.2757.43
5gA2OCH313.0467.8369.1310.6331.4051.6923.6548.6552.03
5hA2CH3-19.817.213.317.228.616.322.930.8
5iA3H-19.1334.78-6.767.7310.1410.8113.51
5jA3CF328.7050.8762.1716.919.1829.9510.8117.5737.16
5kA3OCH3-12.1728.264.353.388.7018.9217.5721.62
5lA3CH3-8.94.9--14.8---
6[b]88.592.810072.478.982.238.836.944.6
Table 2

IC50 values of the target compounds against S. sclerotiorum, B. cinerea, and C. fragariae

CompoundS. sclerotiorumB. cinereaC. fragariae
IC50 (mg/L)Regression equationR2IC50 (mg/L)Regression equationR2IC50 (mg/L)Regression equationR2
5b92.6y=0.0061x0.780146.0y=0.0038x0.992118.8y=0.004xc0.971
+0.1139+0.0378+0.0968
5f28.9y=0.00730.84551.7y=0.0051x0.75554.8y=0.0049x0.941
+0.1792+0.1596+0.1851
5g40.0y=0.0065x0.654116.8y=0.004x0.45962.2c0.0053x0.832
+0.1533+0.0664+0.116
Hymexazol10.4y=0.0072x0.6424.4y=0.003x0.774148.9y=0.0038x0.908
+0.4217+0.575+0.0619

The superficial structure-activity relationship presented a general trend. On the basis of the bioassay data, the substituents R and Ar reflected a momentous relationship with the activities. When Ar remained constant, the influence of R on the fungicidal activities showed a regular change. The fungicidal activities of target compounds is enhanced when the R is a CF3 rather than any other substituent. Taking the assay concentration of 100 mg/L for example, compound 5f (75.6% inhibition rates) is more active than 5e (69.1% inhibition rates), 5g (39.1% inhibition rates), or 5h (no effect) against S. sclerotiorum. Ordinarily, the influence of R on improved activity may be concluded as follows: CF3 > OCH3 > H > CH3. In addition, when R is kept invariant, modification of the Ar moiety from A3 and A1 to A2 group increased the fungicidal activity evidently. For example, the fungicidal activities against S. sclerotiorum are correlated as follows: 5e > 5i > 5a, 5f > 5j > 5b, and 5g > 5h > 5c.

Scheme 1 Synthesis The synthesis route of a compound library based on oxazole derivatives as building blocks 5a-5i. Reagents and conditions: i) 1,3-dichloroacetone, neat, 130 oC; ii) Potassium phthalimide, DMF, 80 oC; iii) Hydrazine hydrate, EtOH, reflux, then 37% HCl, rt; iv) Pyrimidine carboxylic acid, HATU, Et3N, DMAP, DCM, 0 oC and then room temperature
Scheme 1

Synthesis The synthesis route of a compound library based on oxazole derivatives as building blocks 5a-5i. Reagents and conditions: i) 1,3-dichloroacetone, neat, 130 oC; ii) Potassium phthalimide, DMF, 80 oC; iii) Hydrazine hydrate, EtOH, reflux, then 37% HCl, rt; iv) Pyrimidine carboxylic acid, HATU, Et3N, DMAP, DCM, 0 oC and then room temperature

Conclusion

In this paper, we synthesized and investigated N-((2-phenyloxazol-4-yl)methyl) pyrimidine carboxamide derivatives in vitro for their fungicidal activities against three fungi, namely S. sclerotiorum, B. Cinerea, and C. fragariae. It was noted that compounds 5f and 5g showed fungicidal activities against these three fungi. Especially, 5f and 5g displayed lower IC50 values than hymexazol (a positive control) against C. fragariae. With these findings, the apparent structure–activity relationships were discussed. Our current study indicated that the present target compounds should be worthwhile for further study as the lead compounds in the search for discovering potential fungicides.

Experimental Section

Synthesis and characterization

Melting points (m.p.) were measured on a MP450 melting-point apparatus (Shandong Nanon Instrument LTD, CITY, China). The NMR spectra were recorded on a Bruker AV-500 spectrometer (Bruker, Karlsruhe, Germany) with TMS as an internal standard. HRESIMS was measured by a Shimazu LC-20AD AB SCIEX triple TOF 5600+ MS spectrometer (Shimadzu Corporation, Tokyo, Japan). Column chromatography was performed using 200-300 mesh silica gels. The solvents and reagents were dried prior to use. The general synthetic methods for compounds 5a-5l are detailed in Scheme 1 and brief procedures are shown below. Each target compound was identified and verified by 1H NMR, 13C NMR, and HRESIMS.

Synthesis of 4-(chloromethyl)-2-arlyloxazole (2a) and its analogues (2b-2d)

A mixture of benzamide (1.81 g, 15 mmol) and 1,3-dichloroacetone (1.9 g, 17 mmol) was ground thoroughly. Then the mixture was heated to liquation and the reaction temperature was kept at 130 oC for 4 h. Once cooled to room temperature, 150 mL EA was poured into the product and it was washed twice with saturated Na2CO3 solution. The EA layer was dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography on a silica gel column using petroleum ether (PE) and ethyl acetate (EA) as the eluents to afford 2a as a white powder 2.6 g (90% yield). The analogues (2b-2d) could be synthesized by the method similar to that described in the synthesis of 2a.

4-(Chloromethyl)-2-phenyloxazole (2a): White solid; 90% yield; 1H NMR (600 MHz, CDCl3) δ 8.02 (dd, J = 6.7, 3.0 Hz, 2H), 7.67 (s, 1H), 7.58 – 7.35 (m, 3H), 4.56 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 162.3, 138.8, 136.2, 130.7, 128.8, 127.0, 126.5, 37.1.

4-(Chloromethyl)-2-(4-(trifluoromethyl)phenyl) oxazole (2b): White solid; 85% yield;1H NMR (500 MHz, CDCl3) δ 8.16 (d, J = 8.1 Hz, 2H), 7.76 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 4.59 (d, J = 0.8 Hz, 2H).13C NMR (125 MHz, CDCl3) δ 160.9, 139.3, 136.9, 132.31 (q, J = 32.7 Hz), 130.1, 126.8, 125.85 (q, J = 3.8 Hz), 124.8, 122.7, 36.8.

4-(Chloromethyl)-2-(4-methoxyphenyl)oxazole (2c): White solid; 87% yield; 1H NMR (600 MHz, CDCl3) δ 8.10 – 7.87 (m, 1H), 7.66 (t, J = 0.8 Hz, 1H), 7.08 – 6.79 (m, 1H), 4.57 (d, J = 0.9 Hz, 2H), 3.86 (s, 2H). 13C NMR (150 MHz, CDCl3) δ 162.5, 161.6, 138.5, 135.6, 128.2, 119.8, 114.2, 55.4, 37.2.

4-(Chloromethyl)-2-(p-tolyl)oxazole (2d): White solid; 92% yield; 1H NMR (500 MHz, CDCl3) δ 7.93 (d, J = 8.2 Hz, 2H), 7.68 (s, 1H), 7.26 (d, J = 8.0 Hz, 2H), 4.57 (d, J = 0.7 Hz, 2H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.6, 141.1, 138.6, 135.9, 130.0, 129.5, 129.3, 126.5, 124.3, 37.2, 21.5.

Synthesis of 4-(aminomethyl)-2-arlyl oxazole (4a) and its analogues (4b- 4d)

To a solution of 2a (2.6 g, 13.5 mmol) in 30 mL DMF was added potassium phthalimide (3.0g, 16.2mmol) in portions. After the mixture was stirred at 80 oC for 5 h, the mixture was poured into ice water and the precipitate was collected by filtration and washed with water. 3a was obtained as blown solid. Then 3a was mixed with 150 mL ethanol and hydrazine hydrate (50%, 5.2 g, 53.0 mmol). After 5 h under reflux, the precipitate was separated by filtration and the solvent of filtrate was removed under reduced pressure. The mixture was poured into ice water and the aqueous phase was extracted with EA. The organic layer was washed twice with water and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain blown oil. Then the oil was dissolved in 10 mL acetone, then added 0.5 mL concentrated hydrochloric acid to precipitate a large amount of solid. The precipitate was separated by filtration and washed twice with 20 mL acetone, dried in vacuum to afford 4a as white solid (2.4 g, 88% yields for two steps). The analogues (4b-4d) could be synthesized by the method similar to that described in the synthesis of 4a.

(2-Phenyloxazol-4-yl)methanamine hydrochloride (4a): White solid; 88% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.59 (s, 3H), 8.30 (s, 1H), 8.09 – 7.87 (m, 2H), 7.66 – 7.41 (m, 3H), 4.03 (d, J = 0.8 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 161.4, 138.8, 135.8, 131.5, 129.8, 126.9, 126.4, 34.7.

(2-(4-(Trifluoromethyl)phenyl)oxazol-4-yl)methanamine hydrochloride (4b): Brown solid; 73% yield ;1H NMR (600 MHz, DMSO-d6) δ 8.68 (s, 3H), 8.40 (s, 1H), 8.19 (d, J = 8.1 Hz, 2H), 7.94 (d, J = 8.3 Hz, 2H), 4.05 (q, J = 5.7 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) δ 160.0, 139.7, 136.2, 131.07 (q, J = 32.0 Hz), 130.4, 127.2, 126.80 (q, J = 3.6 Hz), 124.32 (q, J = 272.3 Hz), 34.6.

(2-(4-Methoxyphenyl)oxazol-4-yl)methanamine hydrochloride (4c): White solid; 85% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.59 (s, 3H), 8.21 (s, 1H), 8.08 – 7.81 (m, 2H), 7.13 – 7.04 (m, 2H), 3.99 (s, 2H), 3.83 (s, 3H).13C NMR (150 MHz, DMSO-d6) δ 161.8, 161.5, 138.0, 135.5, 128.2, 119.5, 115.2, 55.9, 34.7.

(2-(p-Tolyl)oxazol-4-yl)methanamine hydrochloride (4d): White solid; 82% yield; 1H NMR (600 MHz, DMSO-d6) δ 8.58 (brs, 3H), 8.25 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 4.01 (s, 2H), 2.38 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 161.6, 141.4, 138.4, 135.6, 130.3, 126.4, 124.3, 34.7, 21.5.

Synthesis of N-((2-phenyloxazol-4-yl)methyl)pyrimidine-2-carboxamide (5a) and its analogues (5b-5i)

To a solution of pyrimidine-2-carboxamide (58.5 mg, 0.48 mmol), Et3N (202 mg, 2.0 mmol), HATU (273.6 mg, 0.72 mmol) and 4-dimethylaminopyridine (DMAP, 87.8 mg, 0.72 mmol) in 10 mL dichloromethane (DCM), 4a (100 mg, 0.48 mmol) was added under 0–5 oC and kept stirring for 30 minutes. Then the mixture was stirred at ambient temperature for 5 h. The reaction mixture was poured into saturated NH4Cl aqueous solution (10 mL). The organic layer was washed twice with 5 mL saturated sodium chloride solution and dried over Na2SO4 and evaporated. The residue was recrystallized from ethanol to afford 5a as a white powder (123.6 mg, 92% yield). The derivatives (5b-5i) could be synthesized by the method similar to that described in the synthesis of 5a.

N-((2-phenyloxazol-4-yl)methyl)pyrimidine-2-carboxamide (5a): White solid; 92% yield; m.p. 145 - 146 °C; 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J = 4.9 Hz, 2H), 8.07 – 8.00 (m, 3H), 7.72 (s, 1H), 7.46 – 7.43 (m, 3H), 4.69 (d, J = 5.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 162.3, 162.1, 157.5, 157.5, 138.2, 135.8, 130.5, 128.8, 127.3, 126.4, 122.6, 35.9. HRMS m/z calcd for C15H12N4O2 (M-H)- 279.0887; Found 279.0887.

N-((2-(4-(trifluoromethyl)phenyl)oxazol-4-yl) methyl)pyrimidine-2-carboxamide (5b): White solid; 90% yield ; m.p. 139 - 140 °C; 1H NMR (500 MHz, CDCl3) δ 8.89 (d, J = 4.9 Hz, 2H), 8.15 (d, J = 8.2 Hz, 2H), 7.78 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.46 (t, J = 4.9 Hz, 1H), 4.70 (d, J = 5.9 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 162.3, 160.6, 157.5, 157.5, 138.8, 136.7, 126.7, 130.4, 25.9, 125.8, 122.7, 35.8. HRMS m/z calcd for C16H11F3N4O2 (M-H)- 347.0761; Found 347.0759.

N-((2-(4-methoxyphenyl)oxazol-4-yl)methyl) pyrimidine-2-carboxamide (5c): White solid; 93% yield; m.p. 59 - 60 °C; 1H NMR (500 MHz, CDCl3) δ 8.88 (d, J = 4.8 Hz, 2H), 7.96 (d, J = 8.7 Hz, 2H), 7.67 (s, 1H), 7.45 (d, J = 4.8 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 4.66 (d, J = 5.7 Hz, 3H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.3, 162.2, 161.5, 157.5, 157.5, 137.9, 135.2, 128.1, 122.6, 120.1, 114.2, 76.8, 55.4, 35.9. HRMS m/z calcd for C16H14N4O3 (M-H)- 309.0993; Found 309.0991.

N-((2-(p-tolyl)oxazol-4-yl)methyl)pyrimidine-2-carboxamide (5d): White solid; 89% yield; m.p. 170 - 172 °C; 1H NMR (600 MHz, DMSO-d6) δ 9.30 (t, J = 5.9 Hz, 1H), 8.98 (d, J = 4.9 Hz, 2H), 8.01 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.70 (t, J = 4.9 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 4.47 (dd, J = 6.0, 0.9 Hz, 2H), 2.37 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 162.9, 161.2, 158.4, 158.2, 141.0, 139.7, 136.6, 130.2, 126.3, 124.7, 123.5, 35.9, 21.5. HRMS m/z calcd for C16H14N4O2 (M-H)- 293.1044; Found 293.1040.

N-((2-phenyloxazol-4-yl)methyl)pyrimidine-4-carboxamide (5e): White solid; 90% yield; ; 1H NMR (500 MHz, CDCl3) δ 9.25 (d, J = 1.2 Hz, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.49 (brs, 1H), 8.14 (dd, J = 5.0, 1.3 Hz, 1H), 8.09 – 7.99 (m, 2H), 7.70 (s, 1H), 7.53 – 7.36 (m, 4H), 4.65 (d, J = 5.8 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 162.7, 162.2, 159.2, 157.9, 156.0, 138.0, 135.6, 130.6, 128.8, 127.2, 126.4, 118.6, 35.6. HRMS m/z calcd for C15H12N4O2 (M-H)- 279.0887; Found 279.0886.

N-((2-(4-(trifluoromethyl)phenyl)oxazol-4-yl) methyl)pyrimidine-4-carboxamide (5f): White solid; 90% yield; m.p. 122 - 124 °C 1H NMR (500 MHz, CDCl3) δ 9.26 (d, J = 1.0 Hz, 1H), 8.99 (d, J = 5.0 Hz, 1H), 8.53 (s, 1H), 8.16 – 8.13 (m, 3H), 7.76 (s, 1H), 7.72 (d, J = 8.3 Hz, 2H), 4.67 (d, J = 5.9 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 162.8, 160.7, 159.3, 157.9, 155.9, 138.6, 136.4, 132.14 (q, J = 32.7 Hz), 130.3, 126.7, 125.83 (q, J = 3.8 Hz), 123.76 (d, J = 272.4 Hz), 118.6, 35.5. HRMS m/z calcd for C16H11F3N4O2 (M-H)- 347.0761; Found 347.0758.

N-((2-(4-methoxyphenyl)oxazol-4-yl)methyl) pyrimidine-4-carboxamide (5g): White solid; 87% yield; m.p. 127 - 129 °C 1H NMR (500 MHz, CDCl3) δ 9.25 (d, J = 1.2 Hz, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.48 (brs, 1H), 8.13 (dd, J = 5.0, 1.3 Hz, 1H), 8.07 – 7.87 (m, 2H), 7.65 (s, 1H), 7.08 – 6.79 (m, 2H), 4.63 (d, J = 5.8 Hz, 2H), 3.86 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.7, 162.3, 161.5, 159.2, 157.8, 156.1, 137.8, 135.1, 128.1, 120.0, 118.6, 114.2, 55.4, 35.7. HRMS m/z calcd for C16H14N4O3 (M-H)- 309.0993; Found 309.0989.

N-((2-(p-tolyl)oxazol-4-yl)methyl)pyrimidine-4-carboxamide (5h): White solid; 80% yield; m.p. 157- 159 °C 1H NMR (600 MHz, DMSO-d6) δ 9.30 (t, J = 5.9 Hz, 1H), 8.97 (d, J = 4.9 Hz, 2H), 8.00 (s, 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.69 (t, J = 4.9 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H), 4.46 (dd, J = 6.0, 0.8 Hz, 2H), 2.35 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 162.9, 161.2, 158.3, 158.2, 141.0, 139.7, 136.6, 130.2, 126.3, 124.7, 123.6, 35.9, 21.5. HRMS m/z calcd for C16H14N4O2 (M-H)- 293.1044; Found 293.1047.

N-((2-phenyloxazol-4-yl)methyl)pyrimidine-5-carboxamide (5i): White solid; 83% yield; m.p. 134 - 136 °C 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 9.16 (s, 1H), 8.00 (dd, J = 6.6, 2.9 Hz, 2H), 7.73 (s, 1H), 7.47 (dd, J = 4.9, 1.6 Hz, 3H), 7.22 (s, 1H), 4.63 (d, J = 5.4 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 163.3, 162.4, 160.6, 155.7, 137.5, 135.8, 130.8, 128.9, 127.6, 126.9, 126.4, 35.7. HRMS m/z calcd for C15H12N4O2 (M-H)- 279.0887; Found 279.0887.

N-((2-(4-(trifluoromethyl)phenyl)oxazol-4-yl) methyl)pyrimidine-5-carboxamide (5j): White solid; 81% yield; m.p. 170 - 172 °C 1H NMR (500 MHz, CDCl3) δ 9.32 (s, 1H), 9.16 (s, 2H), 8.11 (d, J = 8.2 Hz, 3H), 7.77 (s, 1H), 7.71 (d, J = 8.3 Hz, 3H), 7.19 (brs, 1H), 4.64 (d, J = 5.4 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 163.4, 160.9, 160.7, 155.7, 138.1, 136.6, 132.37 (d, J = 32.8 Hz), 130.1, 127.5, 126.7, 126.0, 125.9 (q, J = 3.7 Hz), 123.71 (d, J = 272.3 Hz), 35.8. HRMS m/z calcd for C16H11F3N4O2 (M-H)- 347.0761; Found 347.0759.

N-((2-(4-methoxyphenyl)oxazol-4-yl)methyl) pyrimidine-5-carboxamide (5k): White solid; 83%yield; m.p. 166 – 167 °C 1H NMR (500 MHz, CDCl3) δ 9.27 (s, 1H), 9.15 (s, 2H), 7.89 (d, J = 8.9 Hz, 2H), 7.63 (s, 1H), 7.51 (s, 1H), 6.93 (d, J = 8.9 Hz, 2H), 4.57 (d, J = 5.3 Hz, 2H), 3.83 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 163.8, 162.7, 162.0, 160.9, 156.2, 137.7, 135.6, 128.4, 128.0, 120.1, 114.7, 55.8, 39.0, 36.2. HRMS m/z calcd for C16H14N4O3 (M-H)- 309.0993; Found 309.0991.

N-((2-(p-tolyl)oxazol-4-yl)methyl)pyrimidine-5-carboxamide (5l): White solid; 89% yield; m.p. 158 - 159 °C 1H NMR (600 MHz, DMSO-d6) δ 9.38 (t, J = 5.5 Hz, 0H), 9.32 (s, 0H), 9.20 (s, 1H), 8.11 (s, 1H, 7.85 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 4.54 – 4.37 (m, 2H), 2.36 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 163.6, 161.3, 160.5, 156.4, 141.0, 139.5, 136.9, 130.2, 128.1, 126.3, 124.7, 36.0, 21.5. HRMS m/z calcd for C16H14N4O2 (M-H)- 293.1044; Found 293.1042.

Antifungal assay

The antifungal activities of the above compounds against S. sclerotiorum, B. cinerea, and C. fragariae were tested by the method described in the literature [24]. Briefly, 0.5 mL mycelial plugs of the pathogens were prepared and transferred into PDA plates supplemented with indicated concentration of the compounds, respectively. The same volumes of DMSO were used as a control and all the plates were incubated at room temperature and the growth rate was evaluated by the colony diameters in triplicate. The experiment was repeated thrice. The inhibition rate of the test compounds against three fungi was calculated by the below formula, where C represents the diameter of fungi growth on untreated PDA, T represents the diameter of fungi on treated PDA, and I is the inhibition rate.

I (%) = [(C - T) ∕ (C-0.4)] × 100%.

Funding statement: This work was financially supported by the National Key Research and Development Program of China “Research and Development of Comprehensive Technologies on Chemical Fertilizer and Pesticide Reduction and Synergism” (2017YFD0201402).

  1. Conflict of interest: Authors state no conflict of interest.

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Received: 2020-10-14
Accepted: 2020-11-28
Published Online: 2020-12-31

© 2020 Huang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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https://doi.org/10.1515/hc-2020-0117
Keywords for this article
Oxazole derivative; Synthesis; Fungicidal activities; Structure-activity relationship
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BY 4.0

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