Introduction

Natural product-based lead derivation is one of the most important methods for novel pesticide development [1]; however, heterocyclic compounds are important source of pharmaceuticals, agrochemicals and materials [1,2,3]. The introduction of heteroatoms into drug leads often to improve their biological activity and permeability [4]. In addition, nitrogen- or oxygen-containing heterocyclic compounds are widely used as pesticide for plant protection [5,6,7,8]. Medium-size heterocycles attract the attention of chemists, especially seven-member heterocycles. Compounds containing a seven-member heterocycle skeleton have aroused great interest from chemists and have been reported to have various kinds of activities including antitumor, anticancer, anti-histamine and mammalian target of rapamycin inhibitory effect [9,10,11,12,13]. Benzoxazepinones are bicyclic compounds consisting benzene and an oxazepane ring, and were described to possess a wide range of biological activities [14, 15].

In view of the outstanding biological activity of benzoxazinone, the search for the methods for synthesizing such compounds has become a topic of great interest to chemists. The groups of Pifferi presented a one-step transformation of o-bromomethylphenethyl bromide and the potassium salt of N-hydroxyurethan into 1,2-benzoxazepinone (Fig. 1 eq. 1) [16]. Bailey and Bremner reported a Meisenheimer rearrangement method to prepare benzoxazepines from dibenzazepine N-oxide derivative (Fig. 1 eq. 2) [17, 18]. Seomoon and co-workers reported palladium-catalyzed cross-coupling reactions of allyl to form benzoxazepines (Fig. 1 eq. 3) [19]. However, methods for the synthesis of 1,2-benzoxazepinone skeleton from commercial available materials and their applications in agriculture are still limited.

Fig. 1
figure 1

1,2-benzoxazepinone skeleton synthesis

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In recent decades, more and more fungicides targeting at respiratory chain complex III have been developed, for example trifloxystrobin, azoxystrobin and kresoxim-methyl [20]. Based on the pesticide design principle, we reported the synthesis of a novel compound by combining active substructures of plant elicitor with strobilurins, the compound exhibited excellent fungicidal activities [21]. During the preparation of compound I, compound II was obtained as a main by-product. For the interest in bicyclic compounds, especially nitrogen- and oxygen-containing heterocycles and in order to investigate the structure–activity relationship in agriculture and as a continuation of our previous work [22], we modified this skeleton of benzoxazepinone as a lead compound to obtain a series of title compounds (Fig. 2). Here, we present a mild and easy method to construct (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues through four steps with the commercially available reagent as a starting material, and antifungal activity against nine common plant pathogens of all target compounds was evaluated, and several derivatives exhibited excellent antifungal activity and were chosen for EC50 assessment.

Fig. 2
figure 2

Designation approach for novel benzoxazepinone molecules

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Results and discussion

Chemistry

The synthetic route to target compounds 5a–5u from the commercially available starting materials is given in Scheme 1. The starting material 1 was an important intermediate of agricultural fungicide strobilurin, which was widely used for efficient fungicide production and was mass produced. The starting material 1 was reacted with N-hydroxyphthalimide to yield the intermediate 2; hydrazinolysis of the intermediate 2 in the solution of hydrazine hydrate in methanol obtained the key intermediate 3. The precursor 4 (E)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one was obtained by intramolecular cyclization of the intermediate 3 at sodium methoxide–methanol solution under reflux condition. Target compounds 5a–5u were synthesized by an amidation reaction from the precursor 4 with different acyl chloride in the presence of triethylamine and had favorable yields. In the last step reaction progress (Scheme 2), we found that 4 reacted with p-toluoyl chloride, giving not only compound 5k but also by-product 5k-2. The reason was that 4 underwent prototropic tautomerism resulting enol species, and then underwent acylation in amidation reaction. In the literature, only a fewer examples reported tautomerism when acyl chloride reacted with acylamide [23]. In addition, the structures of 5k and 5k-2 were further identified by X-ray diffraction studies.

Scheme 1
scheme 1

General synthesis procedure for compounds 5a–5u

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Scheme 2
scheme 2

Side reactions in the amidation progress

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Crystal structure analysis

In order to confirm the structure of the target compounds and by-products, the crystal of compound 5k and 5k-2 were cultured from the corresponding solvent mixture of CH2Cl2 and n-hexane (v/v = 1:5), and the structures are shown in Figs. 3 and 4. Single-crystal X-ray diffraction analysis showed that the crystal structure of compound 5k belonged to the orthorhombic crystal system, space group Pca2(1), and compound 5k-2 belonged to the triclinic crystal system, space group P-1. As shown in Figs. 3 and 4, The seven-membered ring of compound 5k and 5k-2 were twisted and the two amide bonds of compound 5k were opposite which was contrast to 5k-2. The details of the crystallographic data and structure refinement parameters were summarized and listed in the supporting information.

Fig. 3
figure 3

X-ray crystal structure of 5k (CCDC-1953743)

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Fig. 4
figure 4

X-ray crystal structure of 5k-2 (CCDC-1953744)

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Antifungal activity

Initially antifungal activities of 5a–5u against nine common phytopathogens at 50 μg/mL and by-product 5k-2 were evaluated under the same conditions. The results are given in Table 1. As can be seen, most of target compounds exhibited certain-to-high antifungal activities at 50 μg/mL. Several compounds exhibited excellent antifungal activity against B. cinerea and S. sclerotiorum at 50 μg/mL in vitro. Compounds 5a, 5j, 5o and 5r showed higher than 70% inhibition against B. cinerea. In particular, 5a and 5r exhibited outstanding activity (> 90%), which was comparable to the positive controls trifloxystrobin and azoxystrobin. Compounds 5n, 5p and 5r and by-product 5k-2 showed higher than 80% inhibition rate against S. sclerotiorum. In general, compounds with aryl group substitution (5i–5s) showed better antifungal activity than alkyl substitute compounds (5c–5h, 5t, 5u). As compared with commercial strobilurin fungicides, target compounds were not as broad spectrum as trifloxystrobin and azoxystrobin.

Table 1 In vitro antifungal activity of target compounds against phytopathogens
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On the basis of the results of initial antifungal activities at 50 μg/mL, the compounds with good inhibition were selected for further potency determination. As shown in Table 2, 5p and 5r exhibited good antifungal activity against S. sclerotiorum with an EC50 value of 8.72 μg/mL, 7.21 μg/mL, respectively, at the same level as that of the positive control azoxystrobin with an EC50 value of 2.52 μg/mL. Compound 5j with 4-OCH3-ph substitution and 5r with 4-N,N-(CH3)2Ph substitution were not only effective against S. sclerotiorum but also B. cinerea. Compound 5r exhibited strong inhibition of the growth of B. cinerea, with an EC50 value of 7.92 μg/mL, it was much better than those of positive control trifloxystrobin and azoxystrobin with a corresponding EC50 value of 21.96 μg/mL and 9.43 μg/mL, respectively. Compound 5r with 4-N,N-(CH3)2-ph substitution was the most effective agent against these fungi and could be as an antifungal lead for further optimization.

Table 2 In vitro antifungal EC50 (μg/mL) of the selected compounds
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Conclusions

In summary, the (E)-3-acyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one analogues were prepared and systematically evaluated for their antifungal activities. Most of these seven-member heterocyclic contained compounds showed certain-to-high antifungal activity. In particular, 5r showed excellent activity against B. cinerea and S. sclerotiorum with the EC50 value 7.92 μg/mL, 7.21 μg/mL, respectively. Combining the active substructure in hand, this work is significantly important for the investigation of the structure–activity relationship of the novel nitrogen- and oxygen-containing heterocyclic benzoxazepine derivatives.

Experimental

Instrumentation and materials

The melting points of all compounds were determined using an X-4 microscope (Gongyi Technical Instrument Co., Chengzhou, China), and the thermometer was not corrected. 1HNMR and 13C NMR spectra were obtained at 400 MHz using a Bruker Avance AV400 spectrometer in CDCl3 with tetramethylsilane as the internal standard. Chemical shift values (δ) were given in parts per million. High-resolution mass spectrometry data were obtained with an Agilent 6520 Q-TOF LC/MS system equipped with electrospray ionization (ESI) source. The single-crystal structure analysis was performed using X-ray diffraction with a Rigaku 007 Saturn 70 diffractometer. The yields of target compounds were not optimized. For all reactions, solvents and chemical reagents were of analytical or synthetic grade and used without further purification. The key intermediates 3 and 4 were prepared in our laboratory before [22, 24]. All the target compounds were confirmed by 1H NMR, 13C NMR and HRMS.

General procedures for the preparation of target compounds 5a–5u

Compounds 5a–5u were synthesized by the reaction of intermediate 4 with corresponding acyl chloride. The mixture of intermediate 4 (0.40 mmol) and triethylamine (Et3N) (1.2 mmol) was stirred in dry CH2Cl2 (10 mL) in an ice water bath for 10 min. Then, corresponding acyl chloride (0.44 mmol) was dissolved in 10 mL of CH2Cl2 and added to the mixture solution. The reaction mixture was then stirred at room temperature for 2–4 h and monitored with thin layer chromatography (TLC). Subsequently, 20 mL of water was added to the mixture, and the reaction was extracted with CH2Cl2 (3 × 20 mL). The combined organic layers were washed with saturated sodium bicarbonate (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate, and then concentrated in vacuum. The residue was purified by column chromatography on silica gel to give compounds 5a–5u.

Data for (E)-5-(methoxyimino)-3-(2-phenylacetyl)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5a): Yield 71%; white solid; mp 115–116 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 (td, J = 7.5, 1.4 Hz, 1H), 7.41–7.24 (m, 6H), 7.16–7.07 (m, 1H), 5.34 (s, 2H), 4.20 (s, 2H), 4.10 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.44 (td, J = 7.5, 1.4 Hz, 1H), 7.41–7.24 (m, 6H), 7.16–7.07 (m, 1H), 5.34 (s, 2H), 4.20 (s, 2H), 4.10 (s, 3H). HRMS (ESI) m/z calcd for C18H17N2O4 (M + H)+ 325.1183, found 325.1185.

Data for (E)-5-(methoxyimino)-3-(2-(4-methoxyphenyl)acetyl)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5b): Yield 82%; white solid; mp 120–121 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 7.9, 1.4 Hz, 1H), 7.39 (dtd, J = 26.4, 7.5, 1.4 Hz, 2H), 7.22–7.13 (m, 2H), 7.10 (d, J = 7.7 Hz, 1H), 6.91–6.72 (m, 2H), 5.31 (s, 2H), 4.12 (s, 2H), 4.08 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.35, 164.45, 158.85, 151.68, 134.89, 131.19, 130.73, 130.53, 127.13, 125.25, 124.48, 123.67, 114.00, 75.94, 63.42, 55.24, 42.67. HRMS (ESI) m/z calcd for C19H19N2O5 (M + H)+ 355.1288, found 355.1288.

Data for (E)-3-(cyclopropanecarbonyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5c): Yield 73%; white solid; mp 126–127 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.7 Hz, 1H), 7.54–7.31 (m, 2H), 7.13 (d, J = 7.7 Hz, 1H), 5.33 (s, 2H), 4.08 (s, 3H), 2.89–2.73 (m, 1H), 1.23 (t, J = 4.0 Hz, 2H), 1.05 (dq, J = 7.8, 3.9 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 171.43, 164.71, 151.93, 135.03, 131.21, 130.48, 127.10, 125.23, 123.90, 76.06, 63.37, 14.74, 11.27. HRMS (ESI) m/z calcd for C14H15N2O4 (M + H)+ 275.1026, found 275.1028.

Data for (E)-3-(3-cyclopentylpropanoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5d): Yield 83%; white solid; mp 121–122 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.8 Hz, 1H), 7.39 (dt, J = 28.3, 7.5 Hz, 2H), 7.12 (d, J = 7.7 Hz, 1H), 5.33 (s, 2H), 4.07 (s, 3H), 2.83 (t, J = 7.7 Hz, 2H), 1.74 (ddq, J = 31.2, 14.5, 7.1 Hz, 5H), 1.60 (td, J = 7.6, 3.2 Hz, 2H), 1.55–1.42 (m, 2H), 1.19–0.99 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 170.26, 164.36, 151.82, 134.99, 131.20, 130.52, 127.13, 125.25, 123.75, 76.00, 63.39, 39.53, 36.83, 32.41, 30.21, 25.11. HRMS (ESI) m/z calcd for C18H23N2O4 (M + H)+ 331.1652, found 331.1659.

Data for (E)-3-cinnamoyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5e): Yield 81%; white solid; mp 127–128 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 15.7 Hz, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.64–7.56 (m, 2H), 7.51 (d, J = 15.7 Hz, 1H), 7.47–7.34 (m, 5H), 7.15 (d, J = 7.7 Hz, 1H), 5.43 (s, 2H), 4.11 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.62, 162.80, 151.84, 147.58, 134.95, 134.27, 131.20, 131.00, 128.96, 128.68, 127.15, 125.26, 123.86, 117.94, 99.99, 76.22, 63.41. HRMS (ESI) m/z calcd for C19H17N2O4 (M + H)+ 337.1183, found 337.1188.

Data for isobutyl (E)-5-(methoxyimino)-4-oxo-4,5-dihydrobenzo[e][1,2]oxazepine-3(1H)-carboxylate (5f): Yield 91%; white solid; mp 132–133 °C. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.9 Hz, 1H), 7.42 (td, J = 7.6, 1.4 Hz, 1H), 7.35 (td, J = 7.7, 1.3 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 5.35 (s, 2H), 4.13 (d, J = 6.5 Hz, 2H), 4.06 (s, 3H), 2.06 (dp, J = 13.3, 6.7 Hz, 1H), 1.00 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 162.79, 151.80, 150.04, 134.54, 131.23, 130.43, 127.12, 125.18, 124.09, 76.23, 73.98, 63.33, 27.78, 18.88. HRMS (ESI) m/z calcd for C15H19N2O5 (M + H)+ 307.1288, found 307.1295.

Data for (E)-3-acetyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5g): Yield 75%; white solid; mp134–135 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 8.0, 1.4 Hz, 1H), 7.43 (td, J = 7.6, 1.4 Hz, 1H), 7.36 (td, J = 7.6, 1.3 Hz, 1H), 7.18–7.07 (m, 1H), 5.34 (s, 2H), 4.08 (s, 3H), 2.52 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.71, 164.46, 151.64, 134.89, 131.21, 130.55, 127.16, 125.25, 123.70, 76.05, 63.41, 25.39. HRMS (ESI) m/z calcd for C12H13N2O4 (M + H)+ 249.0870, found 249.0873.

Data for (E)-5-(methoxyimino)-3-propionyl-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5h): Yield 83%; white solid; mp 105–106 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (dd, J = 7.9, 1.3 Hz, 1H), 7.47–7.29 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 5.34 (s, 2H), 4.07 (s, 3H), 2.84 (q, J = 7.3 Hz, 2H), 1.19 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.82, 164.41, 151.79, 134.99, 131.19, 130.51, 127.11, 125.24, 123.75, 75.99, 63.36, 31.13, 8.13. HRMS (ESI) m/z calcd for C13H15N2O4 (M + H)+ 263.1026, found 263.1030.

Data for (E)-3-benzoyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5i): Yield 30%; white solid; mp 164–165 °C. 1H NMR (400 MHz, CDCl3) δ 7.80–7.71 (m, 1H), 7.61 (d, J = 7.4 Hz, 2H), 7.58–7.51 (m, 1H), 7.46 (tt, J = 7.6, 1.3 Hz, 1H), 7.43–7.35 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 5.37 (s, 2H), 4.08 (d, J = 1.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.75, 164.66, 151.49, 134.76, 132.97, 132.81, 131.42, 130.57, 128.92, 128.27, 127.19, 125.33, 124.22, 76.77, 63.48. HRMS (ESI) m/z calcd for C17H15N2O4 (M + H)+ 311.1026, found 311.1031.

Data for (E)-3-(4-methoxybenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5j): Yield 67%; white solid; mp 129–130 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 1H), 7.68–7.57 (m, 2H), 7.51–7.31 (m, 2H), 7.15 (d, J = 7.7 Hz, 1H), 6.91–6.74 (m, 2H), 5.35 (s, 2H), 4.07 (d, J = 1.5 Hz, 3H), 3.84 (d, J = 2.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.04, 165.02, 163.70, 151.69, 134.88, 131.77, 131.39, 130.51, 127.12, 125.29, 124.66, 124.35, 113.63, 76.75, 63.43, 55.50. HRMS (ESI) m/z calcd for C18H17N2O5 (M + H)+ 341.1132, found 341.1132.

Data for (E)-5-(methoxyimino)-3-(4-methylbenzoyl)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5k): Yield 61%; white solid; mp 165–166 °C. 1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.60–7.54 (m, 2H), 7.45 (dtd, J = 26.6, 7.5, 1.4 Hz, 2H), 7.26–7.13 (m, 3H), 5.39 (s, 2H), 4.11 (s, 3H), 2.43 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.67, 164.77, 151.61, 144.03, 134.83, 131.40, 130.53, 129.85, 129.23, 128.99, 127.15, 125.31, 124.28, 76.76, 63.45, 21.76. HRMS (ESI) m/z calcd for C18H17N2O4 (M + H)+ 325.1183, found 325.1187.

Data for (E)-5-(methoxyimino)-3-(4-methylbenzoyl)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5k-2): Yield 17%; white solid; mp 156–157 °C. 1H NMR (400 MHz, CDCl3) δ 8.08–7.98 (m, 2H), 7.89–7.82 (m, 1H), 7.46–7.35 (m, 2H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (dd, J = 7.2, 1.7 Hz, 1H), 5.27 (s, 2H), 3.95 (s, 3H), 2.44 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.79, 159.80, 146.62, 145.34, 135.52, 130.67, 130.58, 130.51, 129.42, 127.72, 127.47, 126.60, 125.16, 73.98, 63.61, 21.86. HRMS (ESI) m/z calcd for C18H17N2O4 (M + H)+ 325.1183, found 325.1188.

Data for (E)-3-(3-chloro-4-fluorobenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5l): Yield 65%; white solid; mp 170–171 °C. 1H NMR (400 MHz, CDCl3) δ 7.84–7.66 (m, 2H), 7.56–7.35 (m, 3H), 7.24–7.05 (m, 2H), 5.38 (s, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.72, 164.59, 162.11, 159.56, 151.15, 134.49, 131.81, 131.48, 130.68, 129.89, 129.85, 129.51, 129.42, 127.33, 125.30, 123.99, 116.72, 116.50, 76.93, 63.57. HRMS (ESI) m/z calcd for C17H13ClFN2O4 (M + H)+ 363.0542, found 363.0540.

Data for (E)-5-(methoxyimino)-3-(4-(trifluoromethyl)benzoyl)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5m): Yield 36%; white solid; mp 119–120 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.72–7.63 (m, 4H), 7.48 (td, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.1 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 5.40 (s, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.61, 164.53, 151.06, 136.26, 134.49, 134.28, 133.94, 131.46, 130.69, 129.01, 127.33, 125.38, 125.33, 125.31, 125.27, 123.98, 122.07, 76.89, 63.58. HRMS (ESI) m/z calcd for C18H14F3N2O4 (M + H)+ 379.0900, found 379.0902.

Data for (E)-3-(4-(tert-butyl)benzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5n): Yield 40%; white solid; mp 174–175 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.9 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.50–7.33 (m, 4H), 7.15 (d, J = 7.7 Hz, 1H), 5.35 (s, 2H), 4.07 (d, J = 0.9 Hz, 3H), 1.31 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 166.63, 164.80, 156.91, 151.56, 134.82, 131.41, 130.52, 129.73, 129.10, 127.15, 125.30, 124.32, 76.77, 63.47, 35.16, 31.05. HRMS (ESI) m/z calcd for C21H23N2O4 (M + H)+ 367.1652, found 367.1656.

Data for (E)-3-(2-fluorobenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5o): Yield 70%; white solid; mp 189–190 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.9 Hz, 1H), 7.47 (ddt, J = 45.6, 30.7, 7.3 Hz, 4H), 7.31–7.10 (m, 2H), 6.99 (t, J = 9.3 Hz, 1H), 5.43 (s, 2H), 4.06 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.85, 161.83, 159.30 (d, J = 252.2 Hz), 151.21, 134.66, 133.83 (d, J = 8.7 Hz), 131.30, 130.52, 129.97 (d, J = 2.2 Hz), 127.15, 125.30, 124.46 (d, J = 3.4 Hz), 123.94, 122.39 (d, J = 14.1 Hz), 115.78 (d, J = 21.5 Hz), 76.61, 63.53. HRMS (ESI) m/z calcd for C17H14FN2O4 (M + H)+ 329.0932, found 329.0937.

Data for (E)-3-(3-fluorobenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5p): Yield 62%; white solid; mp 143–144 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.8 Hz, 1H), 7.51–7.33 (m, 4H), 7.31 (dd, J = 8.9, 2.5 Hz, 1H), 7.24 (q, J = 3.3 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 5.37 (s, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.56, 164.61, 162.16 (d, J = 248.1 Hz), 151.23, 134.78 (d, J = 7.7 Hz), 134.56, 131.46, 130.65, 130.04 (d, J = 7.9 Hz), 127.29, 125.32, 124.57 (d, J = 3.1 Hz), 124.07, 119.95 (d, J = 21.2 Hz), 115.88 (d, J = 23.6 Hz), 76.86, 63.55. HRMS (ESI) m/z calcd for C17H14FN2O4 (M + H)+ 329.0932, found 329.0940.

Data for (E)-3-(4-fluorobenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5q): Yield 52%; white solid; mp 153–154 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.0 Hz, 1H), 7.70–7.61 (m, 2H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.12–7.04 (m, 2H), 5.38 (s, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.82, 165.63, 164.80, 164.29, 151.37, 134.67, 132.84 (d, J = 9.9 Hz), 131.75 (d, J = 9.8 Hz),130.60, 128.89 (d, J = 4.3 Hz), 127.24, 125.30, 124.16, 115.58 (d, J = 22.8 Hz), 76.84, 63.51. HRMS (ESI) m/z calcd for C17H14FN2O4 (M + H)+ 329.0932, found 329.0935.

Data for (E)-3-(4-(dimethylamino)benzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5r): Yield 43%; yellow solid; mp 119–120 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 7.9, 1.4 Hz, 1H), 7.70–7.59 (m, 2H), 7.42 (dtd, J = 25.1, 7.5, 1.4 Hz, 2H), 7.15 (dd, J = 7.9, 1.3 Hz, 1H), 6.64–6.54 (m, 2H), 5.36 (s, 2H), 4.09 (s, 3H), 3.06 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 165.98, 165.33, 153.82, 152.08, 135.18, 132.19, 131.36, 130.36, 126.97, 125.25, 124.62, 118.34, 110.42, 76.67, 63.34, 40.01. HRMS (ESI) m/z calcd for C19H20N3O4 (M + H)+ 354.1448, found 354.1454.

Data for (E)-3-(4-chlorobenzoyl)-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5s): Yield 42%; white solid; mp 183–184 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.7 Hz, 1H), 7.60–7.53 (m, 2H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.43–7.35 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 5.38 (s, 2H), 4.08 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.78, 164.69, 151.29, 139.42, 134.62, 131.44, 131.14, 130.62, 130.41, 128.65, 127.27, 125.30, 124.11, 76.86, 63.53. HRMS (ESI) m/z calcd for C17H14ClN2O4 (M + H)+ 345.0637, found 345.0636.

Data for (E)-3-acryloyl-5-(methoxyimino)-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5t): Yield 64%; white solid; mp 119–120 °C. 1H NMR (400 MHz, CDCl3) δ 7.73 (dt, J = 7.9, 1.4 Hz, 1H), 7.49–7.29 (m, 2H), 7.19–7.00 (m, 2H), 6.63 (dq, J = 17.0, 1.7 Hz, 1H), 5.94 (dq, J = 10.5, 1.7 Hz, 1H), 5.37 (s, 2H), 4.07 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 164.47, 162.34, 151.64, 134.84, 133.02, 131.23, 130.58, 128.41, 127.18, 125.27, 123.73, 76.15, 63.46. HRMS (ESI) m/z calcd for C13H13N2O4 (M + H)+ 261.0870, found 261.0871.

Data for (E)-5-(methoxyimino)-3-pentanoyl-1,5-dihydrobenzo[e][1,2]oxazepin-4(3H)-one (5u): Yield 85%; white solid; mp 78–79 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 7.9, 1.3 Hz, 1H), 7.44 (td, J = 7.6, 1.5 Hz, 1H), 7.37 (td, J = 7.6, 1.3 Hz, 1H), 7.14 (dd, J = 7.9, 1.3 Hz, 1H), 5.35 (s, 2H), 4.09 (s, 3H), 2.84 (t, J = 7.5 Hz, 2H), 1.68 (p, J = 7.3 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 170.11, 164.37, 151.81, 134.98, 131.20, 130.51, 127.12, 125.24, 123.75, 76.01, 63.37, 37.17, 26.08, 22.16, 13.77. HRMS (ESI) m/z calcd for C15H19N2O4 (M + H)+ 291.1339, found 291.1338.

X-ray diffraction

Compounds 5k and 5k-2 were recrystallized by diffusion method from two different polar solvents solution to afford a single crystal suitable for X-ray crystallography determination. Compounds 5k and 5k-2 were dissolved in CH2Cl2 separately, and excess n-hexane was added to the solution. Several days later, crystals were appeared and collected for X-ray diffraction. Compound 5k and 5k-2 were mounted in inert oil and transferred to the cold gas stream of the diffractometer, respectively. Cell dimensions and intensities were measured using a Rigaku 007 Saturn 70 diffractometer with graphite monochromated Mo Kα radiation. Compound 5k: orthorhombic, a = 16.747 (3) Å, b = 4.1793 (8) Å, c = 21.916 (4) Å, U = 1533.9(5) Å3, F = 680, space group Pca2(1), Z = 4. A total of 16,116 reflections were measured, of which 3637 were unique (Rint = 0.0538) in the range of 1.858 < 2Θ < 27.860° (− 21 ≤ h ≤ 21, − 5 ≤ k ≤ 5, − 28 ≤ l ≤ 28), and 3276 observed reflections with I > 2σ(I) were used in the refinement on F2. Compound 5k-2: triclinic, a = 7.7125(15) Å, b = 7.7471(15) Å, c = 14.847(3) Å, U = 766.3(3) Å3, F = 340, space group P-1, Z = 2. A total of 9195 reflections were measured, of which 3639 were unique (Rint = 0.0381) in the range of 1.397 < 2Θ < 27.904° (− 10 ≤ h ≤ 9, − 10 ≤ k ≤ 10, − 19 ≤ l ≤ 19), and 2721 observed reflections with I > 2σ(I) were used in the refinement on F2. The structure of 5k and 5k-2 were solved by direct method with the SHELXTL-97 program. The absorption correction was according to semiempirical from equivalents. All of the non-H atoms were refined anisotropically by full-matrix least squares on F2. The atomic coordinates for 5k and 5k-2 have been deposited at the Cambridge Crystallographic Data Centre. CCDC-1953743 and CCDC-1953744 contain the supplementary crystallographic data for this paper.

Antifungal activity test

The antifungal activities against Alternaria solani, Botrytis cinerea, Cercospora arachidicola, Gibberella zeae, Phytophthora infestans (Mont) de Bary, Physalospora piricola, Pellicularia sasakii, Rhizoctonia cerealis and Sclerotinia sclerotiorum were conducted in vitro at 50 μg/mL by using the mycelium growth-inhibition method according to a reported method [25]. Trifloxystrobin and azoxystrobin which were commercially available fungicides were chose as positive control. The synthesized compounds and controls were dissolved in DMSO to prepare 20 mg/mL stock solutions. The stock solution mixed with molten potato dextrose agar (PDA) and the media containing compounds at a concentration of 50 μg/mL were obtained for the initial antifungal activities screening.

Their relative inhibition ratio (%) was calculated using the following equation:

$$ I\left( \% \right) = [(C - T)/(C - 4)] \times 100\% $$

I means the inhibition ratio, C (mm) means the average growth colony diameter of control and T (mm) means the average growth colony diameter of treatment.

Compounds with growth inhibition > 70% at 50 μg/mL and their median effective concentrations (EC50) were determined. A 20 mg/mL stock solution was diluted with PDA to obtain a series of concentrations, repeating the experiments above, and the inhibition rates were calculated separately. The EC50 value was calculated by using linear regression equation [26].