Solvent-free mechanochemical synthesis of arylcyanomethylenequinone oximes from phenylacetonitriles and 4-unsubstituted nitroaromatic compounds using KF/nano-γ-Al₂O₃ as catalyst

Abstract

Solvent-free condensation of phenylacetonitriles with 4-unsubstituted nitroaromatic compounds to produce a series of arylcyanomethylenequinone oximes was described in the presence of KF/nano-γ-Al₂O₃ under high-speed vibration milling conditions, and the products were obtained in moderate to excellent yields at short reaction times. Moreover, the product α-(3-methyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene) benzeneacetonitrile 3b has been confirmed by X-ray diffraction analysis. The formation of nitroso isomer from oxime was measured by ¹H NMR in acetone-d₆ under different temperatures. In vitro antitumor studies showed that several arylcyanomethylenequinone oximes displayed strong antitumor activity against Caki-1 and 769-P.

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Introduction

The synthesis of substituted oximes is an area of continuing interest in organic chemistry due to their various applications in antidotes,^1,2 anti-skinning agents,³ materials of nylon resin and fibre,^4,5 antitumor agents,⁶ intermediates of organic synthesis and so on.^7–9 It is well known that oximes could be synthesized from aldehydes or ketones with hydroxylamine (Scheme 1a),¹⁰ or prepared by nitrite and those compounds containing active hydrogen (Scheme 1b).¹¹ In 1960, Davis et al.¹² reported a new method for preparation of arylcyanomethylenequinone oximes, which were condensed from the corresponding phenylacetonitriles with 4-unsubstituted nitrobenzenes in methanol catalyzed by potassium hydroxide. After that time, several attempts have been carried out to prepare more arylcyanomethylenequinone oximes including 4-chloro-α-(2-chloro-4-(hydroxyimino)-5-methyl-2,5-cyclohexadien-1-ylidene)-benzeneacetonitrile, which used as one of the key intermediates of anthelmintic closantel sodium.^13,14 However, the catalytic reaction systems were rarely concerned, only MgCl₂-DBU/HMPA and KOH/CH₃OH or pyridine have been used to catalyze this process (Scheme 1c).^15–20 Despite the impressive progress, these reaction systems suffered from some limitations, such as tedious workup procedures, the need for excess of catalysts and long time from 4 h to 3 day.¹⁸ Therefore, it was desirable to develop an efficient and more convenient method for the synthesis of arylcyanomethylenequinone oximes.

Scheme 1 The summarizes of the existing methods for preparation of aldoximes or ketoximes (a), α-oximinoesters (b), arylcyanomethylenequinone oximes (c).

Supporting reagents on inorganic oxides, such as silica, zeolites, clays and alumina, are a well-known approach to increase reactivity or selectivity of these solid supports catalysts.²¹ In 1979, Ando et al.²² originally introduced KF/Al₂O₃ (adsorption of potassium fluoride on the surface of neutral alumina) as a strongly basic heterogeneous catalyst to a number of reactions, such as oxidation,²³ cross coupling reaction,²⁴ Bargellini reaction,²⁵ transesterification,²⁶ Hofmann rearrangement,²⁷ Suzuki reactions²⁸ and so on. This catalyst had been demonstrated excellent characteristics of simple work-up and isolation of product, shorter reaction time, and increased yield.²⁹ It is well-known that the size of the vector, Al₂O₃, has great effect on the properties of KF/Al₂O₃.³⁰ Recently, many studies have focused on the preparation of KF/Al₂O₃ nano-composite catalyst and optimization of its grain size. Boz et al. reported that KF-impregnated nanoparticles of γ-Al₂O₃ were calcinated and used as heterogeneous catalysts for the transesterification of vegetable oil with methanol. The biodiesel were gotten with excellent yields (97.7 ± 2.14%), because of the relatively high basicity of the catalyst surface (1.68 mmol g⁻¹) and the high surface to volume ratio of the nanoparticles of γ-Al₂O₃ (17.5 m² g⁻¹).³¹

Recently, the mechanical milling technique via high-speed vibrating ball mill (HSVM) had been used as a powerful tool to promote many organic reactions,^32–34 due to their advantages on the absence of solvent, highly activated local sites in the reacting species by mechanical energy to speed up the reaction and improve the chemical yield, diastereo- and enantioselectivities in generally.³⁵ With our continuous interest in organic reactions under ball milling conditions, we set out to investigate the solvent-free condensation of phenylacetonitriles (1) with 4-unsubstituted nitroaromatic compounds (2) to produce a series of arylcyanomethylenequinone oximes (3) in the presence of KF/nano-γ-Al₂O₃ under HSVM conditions (Scheme 2).

Scheme 2 The synthesis of arylcyanomethylenequinone oximes from phenylacetonitriles and 4-unsubstituted nitroaromatic compounds catalyzed by KF/nano-γ-Al₂O₃ under HSVM conditions.

Results and discussion

Initially, we chose phenylacetonitrile 1a (1.17 g, 10.0 mmol) with nitrobenzene 2a (1.23 g, 10.0 mmol) as standard starting materials to establish the best reaction conditions for the synthesis of α-(4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene)benzeneacetonitrile 3a. The reactions were conducted in a custom-made 50 mL screw-capped stainless steel vial and milled with stainless steel balls (three balls of 20.0 mm diameter, five balls of 10.0 mm diameter and fifteen balls of 5.0 mm diameter) in a high-speed vibrating ball mill at a rate of 1200 rounds per minute at room temperature. The reaction process was monitored by taking out a mixture example and dissolved in methanol using TLC, the cycle can be repeated until the reaction was completed. At the end of the experiment, all the reaction mixture was washed off from the vessel by methanol and water, adjust pH to 2 by 5% HCl, filtered, recrystallized with toluene. The influence of time, amount of KF supported on nano-composite γ-Al₂O₃, amount of KF/nano-γ-Al₂O₃ were examined under similar reaction conditions. The results are summarized in Table 1. It was found that using KF (0.58 g, 10.0 mmol), neutral Al₂O₃ (1.02 g, 10.0 mmol) or nano-composite γ-Al₂O₃ (1.02 g, 10.0 mmol) did not proceed at all (Table 1, entries 1–3) even the time was extended to 60 min. The various KF/γ-Al₂O₃ supports were found to be chemically different as a function of their preparation conditions (Table 1, entries 4–18).^36,37 Therefore, the identification of each KF/γ-Al₂O₃ support will be expressed by its KF loading percent, preparation medium, and drying temperature, respectively, summarized in the attached parenthesis. Many literature reported the drying temperature of KF/Al₂O₃ different from each other (from 50 °C (ref. 38) to 600 °C (ref. 31)), however, in general the treating KF/Al₂O₃, at high temperature (100–400 °C) under high vacuum is essential for obtaining high catalytic activity for many reaction.^39,40 In view of these, various KF/nano-γ-Al₂O₃ were prepared at drying temperature of 100 °C or 150 °C or 200 °C in this paper.

Table 1 Effect of the reaction condition on synthesis of 4-(phenylcyanomethylene)-cyclohexa-2,5-diene-1-one oxime under HSVM conditions^a

Entry	Catalyst	Amount of catalyst (g)	Time (min)	Yield (%)
a Reaction conditions: phenylacetonitrile (1.17 g, 10.0 mmol), nitrobenzene (1.23 g, 10.0 mmol).
1	KF	0.58	60	0
2	Neutral Al2O3	1.02	60	0
3	Nano-γ-Al2O3	1.02	60	0
4	KF/neutral Al2O3 (10, H2O, 200)	1.60	30	61
5	KF/nano-γ-Al2O3 (10, H2O, 200)	1.60	30	68
6	KF/nano-γ-Al2O3 (20, H2O, 200)	1.60	30	73
7	KF/nano-γ-Al2O3 (30, H2O, 200)	1.60	30	76
8	KF/nano-γ-Al2O3 (40, H2O, 200)	1.60	30	78
9	KF/nano-γ-Al2O3 (50, H2O, 200)	1.60	30	78
10	KF/nano-γ-Al2O3 (40, H2O, 200)	1.80	30	80
11	KF/nano-γ-Al2O3 (40, H2O, 200)	2.00	30	82
12	KF/nano-γ-Al2O3 (40, H2O, 200)	2.20	30	83
13	KF/nano-γ-Al2O3 (40, H2O, 200)	2.00	40	83
14	KF/nano-γ-Al2O3 (40, H2O, 200)	2.00	50	82
15	KF/nano-γ-Al2O3 (40, H2O, 100)	2.00	40	75
16	KF/nano-γ-Al2O3 (40, H2O, 150)	2.00	40	78
17	KF/nano-γ-Al2O3 (40, MeOH, 200)	2.00	40	25
18	KF/nano-γ-Al2O3 (40, dry, 200)	2.00	40	10
19	KOH/nano-γ-Al2O3 (40, H2O, 200)	2.00	40	52
20	KOH	0.56	40	47
21	K2CO3	1.38	40	23
22	Et3N	1.01	60	15

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For example, the expression KF/nano-γ-Al₂O₃ (10, H₂O, 200) refers to KF/nano-γ-Al₂O₃ that contains 10 wt% of KF, prepared in water, and finally dried at the temperature of 200 °C under vacuum. While the use of KF/neutral Al₂O₃ (10, H₂O, 200) led to the production in 61% yield (Table 1, entry 4). Bearing in mind that KF/nano-γ-Al₂O₃ as an environmentally friendly base catalyst has advantages such as small particle, big specific surface area, high activity, and so on. We then add 1.60 g KF/nano-γ-Al₂O₃ (10, H₂O, 200) as catalyst to the reaction mixture. To our excitement, the expected product 3a was obtained with an improved yield (Table 1, entry 5, 68%). Further studies showed that the yield could be increased to as high as 82% within 30 min when 2.00 g KF/nano-γ-Al₂O₃ (40, H₂O, 200) was used (Table 1, entry 11). Excess KF/nano-γ-Al₂O₃ (40, H₂O, 200) (beyond this amount) or extended the time did not lead to an obviously increase in yield (Table 1, entries 12–14). On the other hand, the lower drying temperature of the catalysts could reduce of the yields slightly (Table 1, entries 15–16).

As for the possible mechanism of this catalytic reaction, we believe that the high basicity play an important role in the formation of benzyl cyanide anion which nucleophilic attack at the p-position of nitrobenzene, followed by the addition of a proton at an oxygen of the nitro group, and then elimination of a molecule of water, formed the nitroso compound which rapidly converted to its potassium salt.¹² It was proposed that formation of KOH on the surface of KF/nano-γ-Al₂O₃ or the remaining coordinative unsaturated fluoride ions (not bound to Al³⁺ ions) might play an important role in activity of this solid support.^21,22,29,41 In order to clarify the role of the formation of KOH and the remaining coordinative unsaturated fluoride ions, three kinds of catalysts were also prepared and tested as the catalysts for this transformation (Table 1, entries 17–19). Among these catalysts, KOH/nano-γ-Al₂O₃ (40, H₂O, 200) obtained better yield, but much lower than the catalyst of KF/nano-γ-Al₂O₃ (40, H₂O, 200). At this stage, it might be safe to say that the catalytic capacity of formation of KOH (Table 1, entry 19) was better than the remaining coordinative unsaturated fluoride ions (Table 1, entries 17–18), while it could be obtain much higher yield together with each ether (Table 1, entry 11). Other catalysts such as KOH, K₂CO₃ and Et₃N were also tested under similar condition, but none of them obtain satisfactory yields.

Based on the above results, this process was then extended to other phenylacetonitriles and 4-unsubstituted nitroaromatic compounds to investigate its scope and generality. The results are listed in Tables 2 and 3. It can be seen that under these similar conditions, a wide range of phenylacetonitriles and 4-unsubstituted nitrobenzenes easily undergo condensation to give arylcyanomethylenequinone oximes with short reaction time and in moderate to excellent yields (Table 2, entries 1–19). Compared to the literature, the yields of selected compounds have improved from 53% to 78% (Table 2, entry 4),¹⁵ and 77% to 90% (Table 2, entry 9).¹²

Table 2 Condensation of phenylacetonitriles with 4-unsubstituted nitrobenzenes catalyzed by KF/nano-γ-Al₂O₃ under HSVM conditions^a

Entry	R^1	R^2	Product	Time (min)	Yield (%)
a Reaction conditions: 10.0 mmol phenylacetonitriles, 10.0 mmol 4-unsubstituted nitrobenzenes, and 2.00 g KF/nano-γ-Al2O3 (40, H2O, 200) were used.
1	H	H	3a	40	83
2	H	2-CH3	3b	40	85
3	H	2-OCH3	3c	40	86
4	H	2,3-diCl	3d	40	78
5	4-OCH3	H	3e	40	89
6	4-OCH3	3-CH3	3f	60	76
7	4-OCH3	2-OCH3	3g	40	92
8	4-OCH3	2,5-diCl	3h	50	75
9	4-Cl	H	3i	40	90
10	4-Cl	3-CH3	3j	60	71
11	4-Cl	2-OCH3	3k	40	85
12	4-Cl	2,5-diCl	3l	60	81
13	4-Br	3-CH3	3m	40	86
14	4-Br	2-OCH3	3n	50	80
15	4-Br	2,3-diCl	3o	60	70
16	4-Br	2,5-diCl	3p	60	75
17	3,4-diOCH3	2-CH3	3q	50	87
18	3,4-diOCH3	2-OCH3	3r	50	88
19	3,4-diOCH3	2,3-diCl	3s	60	71

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Table 3 Condensation of phenylacetonitriles with 1-nitronaphthale or 5-nitroisoquinoline catalyzed by KF/nano-γ-Al₂O₃ under HSVM conditions^a

Entry	R^1	X	Product	Time (min)	Yield (%)
a Reaction conditions: 10.0 mmol phenylacetonitriles, 10.0 mmol 1-nitronaphthale or 5-nitroisoquinoline, and 2.00 g KF/nano-γ-Al2O3 (40, H2O, 200) were used.
1	H	N	5a	60	70
2	4-OCH3	C	5b	60	71
3	4-Cl	C	5c	40	75

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It is worthwhile noting that both 1-nitronaphthalene and 5-nitroisoquinoline give the products in good yields too (Table 3, entries 1–3).

Until recently, there were two different views on the structure of arylcyanomethylenequinone oximes. Davis et al. concluded that arylcyanomethylenequinone oximes exist as oxime structure. Their ¹H NMR spectra showed typical peaks of oxime hydrogen, while no peak was found corresponding to a hydrogen attached to a tertiary carbon atom which would be expected for the nitroso structure in hexadeuterated acetone solution in room temperture.¹² However, Foguet Ambrós et al.⁴² and Wróbel¹⁸ indicated that oxime derivative could be change to its nitroso tautomer. In order to figure out the question of whether arylcyanomethylenequinone oximes could isomerize from oxime to corresponding nitroso tautomer and their extra structure, α-(3-methyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene)benzeneacetonitrile 3b was chosen to detect by variable-temperature ¹H NMR and monocrystal X-ray analysis to reveal these phenomena (Scheme 3).

Scheme 3 Oxime–nitroso tautomerism equilibrium of 3b.

The results of ¹H NMR spectroscopy of 3b indicates that it could isomerize from oxime to corresponding nitroso tautomer in solution under different temperature, and the former is more stable than the latter (Fig. 1). The oxime hydrogen show more clearly double singlet from 25 °C to −50 °C with its chemical shift changing from 11.81 ppm to 12.30 ppm in variable-temperature ¹H NMR spectra. It was proposed that the Z/E configuration change speed of oxime slow down at lower temperature. The chemical shift of double singlet of tertiary hydrocarbon also moved from 5.81 ppm to 6.35 ppm at 25 °C to −50 °C. And these evidence also suggest the positively relationship between the oxime hydrogen and tertiary hydrocarbon of 3b.

Fig. 1 Variable-temperature ¹H NMR spectra of oxime hydrogen (left) and tertiary hydrocarbon (right) of 3b in acetone-d₆.

Furthermore, the peak area ratio between oxime and nitroso of ¹H NMR spectroscopy of 3b under different temperature were calculated (Fig. 2). It indicates that the tautomerism of compound 3b in the temperature range of −50 to −40 °C and 10 to 25 °C remain almost unchanged respectively, and it have linear relationship between tautomerism ratio and temperature in the range of −30 to 10 °C.

Fig. 2 The peak area ratio between oxime and nitroso of ¹H NMR spectroscopy of 3b under different temperature.

The single-crystal X-ray diffraction also proved that the oxime structure of 3b was dominant in the solid state (Fig. 3).

Fig. 3 ORTEP diagram of the single-crystal X-ray structure of 3b.

In recent years, many compounds that contain the oxime group other than arylcyanomethylenequinone oximes have been used widely in medicinal study, because of their strong antitumor activities.^43–45 Hence, it was of interest to find whether some of the substituted arylcyanomethylenequinone oximes exhibited similar biological activities or not. To our excitement, the preliminary bioassay showed that some of arylcyanomethylenequinone oximes have strong antitumor activity. Especially 4-chloro-α-(4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene)-benzeneacetonitrile 3i, which exhibited strong antitumor activity against 769-P with a concentration of 4.5199 μmol L⁻¹ of IC₅₀. The preliminary bioassay results of some products are listed in Table 4.

Table 4 The antitumor activity of some products against Caki-1 and 769-P in the preliminary bioassay^a

Entry	Product	Caki-1	769-P
a The IC50 value of antitumor activity of each products was tested at a concentration of μmol L^−1.
1	3a	24.3881	6.7993
2	3b	15.3469	9.3588
3	3d	26.4083	8.6359
4	3h	66.4275	27.3985
5	3i	64.9663	4.5199
6	3k	17.5174	6.7098
7	3l	57.1277	14.3637
8	3n	10.2221	16.0997
9	3p	17.6058	7.9097
10	3q	15.1887	7.2797
11	3r	38.9989	16.0311
12	3s	38.5726	31.0185

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Conclusions

KF/nano-γ-Al₂O₃ has become popular and efficient catalyst system because of their super basic properties. The results presented in this work demonstrated that a mild and efficient method for the condensation of phenylacetonitriles with 4-unsubstituted nitroaromatic compounds afforded the corresponding arylcyanomethylenequinone oximes under solvent-free HSVM conditions using KF/nano-γ-Al₂O₃ as catalyst. These catalysts can be prepared easily with available and inexpensive reagents. Moreover, this method offers several advantages over traditional methods: it leads to good yields, short time and is environmentally friendly, and the products are easily isolated. All of these advantages make this process useful for the synthesis of arylcyanomethylenequinone oximes containing whether aromatic ring or heteroaromatic ring. In addition, some of the arylcyanomethylenequinone oximes showed strong antitumor activities against Caki-1 and 769-P in the preliminary bioassay. The synthesis and screening of some derivatives of arylcyanomethylenequinone oxime such as oxime–ether and oxime–ester compounds with high antitumor activities are in process.

Experimental section

Material and methods

All reagents were commercially available and used without any purification except KF/nano-γ-Al₂O₃. The melting points were recorded with a Büchi melting point M-560 and are uncorrected. ¹H and ¹³C NMR spectra were obtained on a Varian Mercury plus-400 spectrometer using DMSO-d₆ or acetone-d₆ as the solvent with TMS as the internal standard. Infrared spectra were recorded on a Shimadzu FTIR-8400 spectrometer. The high-resolution mass spectra were measured with a HRMS-APCI instrument, and the low-resolution mass spectra were performed on a Finnigan Trace DSQ spectrometer. The ball mill was a QM-3B high-speed vibration mill. The single crystal X-ray diffraction data were collected on a Bruker SMART APEX II diffractometer.

Preparation of the KF/nano-γ-Al₂O₃ (40, H₂O, 200) (refers to KF/nano-γ-Al₂O₃ that contains 40 wt% of KF, prepared in water, and finally dried at the temperature of 200 °C under vacuum): potassium fluoride (20 g, 0.34 mol) was dissolved in deionized water (200 mL) in an Erlenmeyer flask, and then nano-γ-Al₂O₃ (30 g, 0.29 mol) was slowly added to the solution under fast stirring. When adding complete, the reaction mixture heated to 70 °C, and maintain this temperature for 3 h, and then the water was evaporated under vacuum, the residue was dried at 200 °C under vacuum for 10 h.

Typical procedure for the synthesis of arylcyanomethylenequinone oximes

In a typical experiment, a mixture of phenylacetonitrile (10.0 mmol), 4-unsubstituted nitroaromatic compound (10.0 mmol) and KF/nano-γ-Al₂O₃ (40, H₂O, 200) (2.0 g) were added to a custom-made 50 mL screw-capped stainless steel vial and milled with stainless steel balls (three balls of 20.0 mm diameter, five balls of 10.0 mm diameter and fifteen balls of 5.0 mm diameter) in a high-speed vibrating ball mill at a rate of 1200 rounds per minute at room temperature. The milling paused every 10 min to measure the temperature of the reaction mixture and indicate the reaction by TLC. The cycle can be repeated until the reaction is completed. All the reaction mixture was washed off the milling beaker using methanol (30 mL) and then cold water (50 mL) to a 250 mL beaker, adjust pH to 2 by 5% HCl, a large number of solid was precipitated. And the mixture was filtered, recrystallized with toluene, to provide the pure products. The colorless crystals of 3b suitable for X-ray diffraction were obtained by slow evaporation of the dichloromethane solution at room temperature.

Representative spectral data

4-Methoxyl-α-[2-methyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3f). Yield: 2.02 g (76%). Yellow powder, mp: 172.9–174.0 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.52 (s, 1H, =N–OH), 7.39–7.32 (m, 2H, ArH), 7.17–7.01 (m, 3H, ArH), 6.89–6.65 (m, 2H, ArH), 3.83 (s, 3H, OCH₃), 2.55 (d, J = 16 Hz, 3H, CH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 160.42, 150.58, 142.85, 137.66, 134.27, 131.87, 130.89, 128.93, 128.05, 121.55, 119.98, 117.71, 115.03, 109.44, 55.87, 23.09. IR (KBr), ν (cm⁻¹): 3244.3, 3076.5, 2966.5, 2189.2, 1602.9, 1573.9, 1510.3, 1269.2, 1180.4, 827.5. HRMS (ESI) calcd for C₁₆H₁₄N₂O₂ + H⁺: 267.2798 found 267.2801.

4-Methoxyl-α-[3-methoxyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3g). Yield: 2.60 g (92%). Orange powder, mp: 192.5–193.9 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.73 (s, 1H, =N–OH), 7.53 (d, J = 8 Hz, 1H, ArH), 7.39 (d, J = 8 Hz, 1H, ArH), 7.33–7.22 (dd, J₁ = J₂ = 10 Hz, 1H, ArH), 7.14–6.86 (m, 3H, ArH), 3.83 (s, 3H, OCH₃), 3.78 (d, J = 62.8 Hz, 3H, OCH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 160.32, 155.75, 145.72, 142.30, 131.65, 131.40, 127.95, 125.66, 120.00, 119.06, 115.15, 107.86, 101.82, 99.82, 55.84, 55.63. IR (KBr), ν (cm⁻¹): 3424.4, 3218.0, 3148.6, 2363.6, 2193.9, 1613.3, 1557.4, 1507.3, 1254.6, 1015.5, 835.1. HRMS (ESI) calcd for C₁₆H₁₄N₂O₃ + H⁺: 283.2788 found 283.2792.

4-Bromo-α-[2-methyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3m). Yield: 2.71 g (86%). Yellow powder, mp: 166.3–167.3 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.66 (d, J = 22.8 Hz, 1H, =N–OH), 7.73–7.66 (m, 2H, ArH), 7.41–7.09 (m, 3H, ArH), 6.95–6.62 (m, 2H, ArH), 2.55 (d, J = 15.6 Hz, 2H, CH₃), 1.55 (d, J = 14.8 Hz, 1H, CH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 143.90, 137.54, 135.17, 132.61, 132.50, 132.42, 130.42, 127.38, 123.26, 121.08, 120.33, 118.20, 108.15, 23.00, 22.26. IR (KBr), ν (cm⁻¹): 3249.8, 3088.8, 2198.7, 1581.5, 1558.4, 1395.4, 1077.2, 1001.0, 818.7, 788.8. HRMS (ESI) calcd for C₁₅H₁₁BrN₂O + H⁺: 316.0136 found 316.0139.

4-Bromo-α-[3-methoxyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3n). Yield: 2.65 g (80%). Orange powder, mp: 205.6–207.4 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.88 (s, 1H, =N–OH), 7.73–7.70 (m, 2H, ArH), 7.54 (d, J = 8.4 Hz, 1H, ArH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 7.37–7.24 (dd, J₁ = J₂ = 10 Hz, 1H, ArH), 7.15–6.82 (m, 1H, ArH), 6.40–6.25 (dd, J₁ = J₂ = 1.6 Hz, 1H, ArH), 3.79 (d, J = 65.6 Hz, 3H, OCH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 156.33, 145.69, 143.84, 132.67, 132.55, 132.21, 131.92, 127.80, 125.34, 123.02, 119.60, 106.46, 101.66, 99.46, 55.80. IR (KBr), ν (cm⁻¹): 3212.2, 3075.3, 2195.8, 1612.4, 1582.5, 1419.5, 1212.2, 1013.5, 837.0, 802.3, 733.9. HRMS (ESI) calcd for C₁₅H₁₁BrN₂O₂ + H⁺: 332.0126 found 332.0128.

4-Bromo-α-[2,3-dichloro-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3o). Yield: 2.59 g (70%). Orange powder, mp: 182.1–184.3 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 13.63 (brs, 1H, =N–OH), 7.76–7.66 (m, 2H, ArH), 7.47–7.40 (m, 2H, ArH), 7.19 (d, J = 10 Hz, 1H, ArH), 6.75 (d, J = 10.4 Hz, 1H, ArH). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 148.21, 139.88, 135.11, 134.80, 132.73, 132.59, 132.39, 131.95, 128.83, 128.64, 124.13, 119.50, 118.03, 111.58. IR (KBr), ν (cm⁻¹): 3191.4, 3137.4, 2197.0, 1579.8, 1507.4, 1484.3, 1391.7, 1080.2, 1040.6, 1007.9, 870.9, 824.6, 758.1. HRMS (ESI) calcd for C₁₄H₇BrCl₂N₂O + H⁺: 369.9106 found 369.9111.

4-Bromo-α-[2,5-dichloro-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3p). Yield: 2.78 g (75%). Orange powder, mp: 181.6–183.5 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 13.76 (s, 1H, =N–OH), 7.75 (d, J = 8.4 Hz, 2H, ArH), 7.47 (d, J = 8 Hz, 3H, ArH), 6.81 (s, 1H, ArH). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 146.42, 139.16, 134.33, 132.85, 132.79, 132.74, 132.46, 132.42, 131.92, 126.88, 124.40, 121.14, 119.01, 111.27. IR (KBr), ν (cm⁻¹): 3197.2, 3082.4, 2197.0, 1576.9, 1539.3, 1479.5, 1279.8, 1054.1, 1037.8, 950.0, 890.2, 829.4, 762.9. HRMS (ESI) calcd for C₁₄H₇BrCl₂N₂O + H⁺: 369.9106 found 369.9113.

3,4-Dimethoxyl-α-[3-methyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3q). Yield: 2.58 g (87%). Orange powder, mp: 181.2–182.0 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.64 (s, 1H, =N–OH), 7.37–6.89 (m, 6H, ArH), 3.82 (d, J = 3.2 Hz, 3H, OCH₃), 3.80 (d, J = 2 Hz, 3H, OCH₃), 2.13 (d, J = 37.6 Hz, 1H, CH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 150.86, 150.33, 149.31, 141.57, 138.85, 129.58, 127.42, 126.09, 125.61, 123.16, 119.45, 113.17, 112.41, 109.98. IR (KBr), ν (cm⁻¹): 3248.1, 3014.7, 2935.7, 2197.0, 1595.1, 1518.0, 1261.5, 1143.8, 989.5, 852.5, 806.3. HRMS (ESI) calcd for C₁₇H₁₆N₂O₃ + Na⁺: 319.2643 found 319.2637.

3,4-Dimethoxyl-α-[3-methoxyl-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3r). Yield: 2.75 g (88%). Orange powder, mp: 187.4–187.7 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 12.71 (s, 1H, =N–OH), 7.32–7.21 (dd, J₁ = J₂ = 10 Hz, 1H, ArH), 7.15–7.05 (m, 3H, ArH), 6.99–6.92 (m, 1H, ArH), 6.39 (s, 1H, ArH), 3.85–3.71 (m, 9H, OCH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 155.72, 150.12, 145.74, 142.34, 127.96, 125.85, 122.94, 119.00, 112.36, 108.10, 101.84, 100.09, 56.19, 56.08, 56.05, 55.76, 55.67. IR (KBr), ν (cm⁻¹): 3142.0, 3010.9, 2935.7, 2189.2, 1593.2, 1556.6, 1514.1, 1460.1, 1423.5, 1257.6, 1219.0, 995.3, 862.2, 814.0. HRMS (ESI) calcd for C₁₇H₁₆N₂O₄ + Na⁺: 335.2633 found 335.2628.

3,4-Dimethoxyl-α-[2,3-dichloro-4-(hydroxyimino)-2,5-cyclohexadien-1-ylidene]benzeneacetonitrile (3s). Yield: 2.49 g (71%). Deep red powder, mp: 196.9–198.5 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 13.41 (s, 1H, =N–OH), 7.39–7.04 (m, 4H, ArH), 6.90 (d, J = 10.4 Hz, 1H, ArH), 3.84 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 56.21, 112.48, 113.36, 113.84, 117.45, 119.82, 123.89, 127.86, 129.07, 129.55, 134.34, 138.84, 148.30, 149.34, 150.90. IR (KBr), ν (cm⁻¹): 3120.6, 3021.3, 2942.2, 2190.0, 1597.9, 1572.8, 1514.2, 1444.6, 1266.2, 1075.2, 823.5, 725.2. HRMS (ESI) calcd for C₁₆H₁₂Cl₂N₂O₃ + Na⁺: 373.1829 found 373.1834.

α-[5-(Hydroxyimino)-8-isoquinolyl]benzeneacetonitrile (5a). Yield: 1.91 g (70%). Brown powder, mp: 232.4–236.4 °C. ¹H NMR (DMSO-d₆, 400 MHz), δ (ppm): 13.03 (s, 1H, =N–OH), 9.97–7.95 (m, 4H, ArH), 7.66–6.97 (m, 6H, ArH). ¹³C NMR (DMSO-d₆, 100 MHz), δ (ppm): 150.39, 149.36, 148.08, 146.09, 140.24, 138.17, 134.69, 131.87, 130.37, 129.78, 129.49, 124.30, 121.16, 119.16, 116.53, 112.20, 109.69. IR (KBr), ν (cm⁻¹): 3130.5, 2187.3, 1606.7, 1539.2, 1437.0, 1398.4, 991.4, 808.2, 700.2. HRMS (ESI) calcd for C₁₇H₁₁N₃O + H⁺: 274.2733 found 274.2735.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 81201530) and National Natural Science Foundation of Zhejiang Province (No. LY13B020015) for financial support. And we also thank Taizhou University Medical School for bioactivity determination.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Typical prints of the recorded NMR, IR, MS and melting point data. CCDC 1435701. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra23606a

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