Synthesis of 4H-chromene-3carbonitrile derivative from a,a'--dibenzylidenecyclohexanone and malononitrile

Yang Wenzhi, Li Haiying, Zhang Hongle
(College of Pharmacy, Hebei University, Baoding 071002, China)

Received Nov. 26, 2006.

Abstract Synthesis of 4H-chromene-3-carbonitrile derivative was carried out conveniently using NaOH and KF/Al₂O₃ as catalyst under ultrasonic irradiation. The reactions are completed within 5 min to give satisfactory yields. KF/Al₂O₃ was more effective catalyst in one-pot reaction.
Keywords: a,a'-dibenzylidenecyclohexanone; malononitrile; 4H-chromene-3-carbonitrile derivative; potassium fluoride supported on alumina

1 INTRODUCTION
The pyridine derivatives have shown important biological activities as pharmaceuticals and potential agrochemicals such as herbicides, and pyrans ring can be transformed to pyridine systems related to pharmacological important calcium antagonists of the DHP type.^[1-3] It was also reported previously that when a,a'-dibenzylidenecyclohexanone was mixed with malononitrile using different solvent and basic catalysts under microwave irradiation, 4H-quinoline-3-carbonitrile derivatives were obtained in excel yields and 4H-chromene-3-carbonitrile derivatives were in mild yields respectively.^[4] Our laboratory has reported the Claisen-Schmidt condensation of cyclohexanone with benzaldehyde catalyzed by KF/Al₂O₃ under refluxed methanol, and the results are better than that under conventional heating condition.^[5] In the present communication, the results on the KF/Al₂O₃-catalyzed reaction between a,a'-dibenzylidenecyclohexanone and malononitrile in different reaction conditions are reported.

2 EXPERIMENTAL
a,a'-dibenzylidenecyclohexanone was synthesized according to the literature.^[5] Melting points were uncorrected. ¹H NMR spectra were measured on Bruker AM-400S (400 MHz) spectrometer using TMS as internal standard and CDCl₃ as solvent. Sonication was performed in a KQ-500B ultrasonics cleaner with a frequency of 25 kHz and a normal power of 500 W. The reaction flask was located on the maximum energy area in the cleaner and addition or removal of water was used to control the temperature of the water bath.
    Compound 3a. 2-Amino-8-benzylidene-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile: white needle，m.p. 229-231 ^oC (lit 228-230 ^oC)^[4]; ¹H NMR (CDCl₃，400 MHz) d_H：1.58 ~ 1.69 (2H, m, CH₂), 1.96 ~ 2.07 (2H, m, CH₂), 2.60 ~ 2.78 (2H, m, CH₂), 3.99 (1H, s, CH), 4.53 (2H, s, NH₂), 6.90 (1H, s, CH), 7.27 ~ 7.40 (10H, m, ArH).
2.1 Preparation of the catalyst (KF-solid supports)
Anhydrous potassium fluoride (20 g) was dissolved in distilled water (80 ml) and mixed with solid supports (30 g), such as neutral alumina or molecular sieve respectively. The mixture was stirred at 65–75^oC for 1 h. The water was removed under reduced pressure. The resulting free flowing powder was dried at 120^oC for 4 h. The content of KF is about 30% (150mg mixture/mmol KF).
2.2 General procedure
The a,a'-dibenzylidenecyclohexanone (0.5 mmol) and malononitrile (0.6 mmol) are mixed with MeOH or EtOH (20-30 mL). KF-Al₂O₃ (75 mg) or NaOH is added. The mixture was irradiated in the water bath of an ultrasonic cleaner at the temperature for the period as indicated in Table (Sonication was continued until crystals were appeared or a,a'-dibenzylidenecyclohexanone was disappeared indicated by TLC). The catalyst was removed by filtration and washed with boiled ethanol or 70% ethanol. The solvent was evaporated under reduced pressure and the residue was crystallized with boiled EtOH to give 4H-chromene-3-carbonitrile derivative. The authenticity of the products was established by comparing their melting points with that in the literature and data of m.p. and ¹H NMR spectra.^[4]

3 RESULTS AND DISCUSSION
Zhou^[4] reported a synthesis of 4H-quinoline-3-carbonitrile derivatives by using NaOH in MeOH under microwave irradiation, while by using piperidine in EtOH under microwave irradiation, 4H-chromene-3-carbonitrile derivatives were obtained. The results stated above spur us to study the possibility of synthesis of 4H-quinoline-3-carbonitrile or 4H-chromene-3-carbonitrile derivatives (3) in different solvent and catalysts under ultrasonic irradiation. Herein, we wish to report the results of the reaction of a,a'-dibenzylidenecyclohexanone (1) and malononitrile (2) under ultrasonic irradiation (Scheme 1). As shown in Scheme 1 and Table 1, a,a'-dibenzylidenecyclohexanone (1) and malononitrile (2), was transferred to its 4H-chromene-3-carbonitrile derivative, when it was treated with different catalysts and solvent under irradiation of ultrasonic to only give one product (3a) in excellent yields. Two kinks of catalyst, NaOH and KF/Al₂O₃ were investigated in this reaction. The catalyst plays a crucial role in the success of the reaction in terms of the rate and the yields. KF/Al₂O₃ was more effective in this reaction, product (3a) gave out 80% yield in MeOH and 95% yield in EtOH within 5 min under ultrasonic irradiation respectively. In contrast, 3a obtained 67% yield in MeOH and 86% yield in EtOH using NaOH-catalysis at the same reaction condition. Irradiation time significantly affected the yields. Thus, whether using KF-Al₂O₃ or NaOH, the reaction time up to 5 min enhance the yield but not improve the yield by prolonged irradiation after 5 min.


Table 1 The reaction between a,a'-dibenzylidenecyclohexanone and malononitrile catalyzed by KF-Al₂O₃ or NaOH.

A The molar ratio of a,a'-dibenzylidenecyclohexanone to catalyst, mixture of a,a'-dibenzylidenecyclohexanone: malononitrile=1:1.2 mol/mol

    We can also observe that the reaction takes place slowly without sonication at room temp. It was necessary to stir the mixture using NaOH-catalysis at 1080 min in EtOH and obtain 95% yield, a similar yield using KF-Al₂O₃-catalysis that obtained at 30 oC after 5 min of sonication time. From the Table 1, The reaction of a,a'-dibenzylidenecyclohexanone (1) with malononitrile (2) gave 95% yield of 3a catalyzed by KF-Al₂O₃ in 5 min under ultrasound irradiation, and the yield 3a is higher than that obtained 70% yield catalyzed by piperidine-ethanol in 5 min under microwave irradiation,^[4] and also higher than 81% yield catalyzed by KF-Al₂O₃ in DMF within 10-14h at room temperature.^[6]
    KF-Al₂O₃ catalysis usually gave better yields, simpler reaction conditions, successfully reused,^[5] and easier product mixture nonaqueous workup than NaOH. Compared with the product separation from the unreacted substrates, crystallized from ethanol, when using NaOH the disposing of process was more tedious.

4 CONCLUSION
It was concluded that the best synthetic conditions of the 4H-chromene-3-carbonitrile derivative (3b) used the mole ratio of KF/Al₂O₃ to a,a'-dibenzylidenecyclohexanone (1/1) in ethanol under ultrasonic irradiation for 5 min, and the yield of 3a was up to 95%.

ACKNOWLEDGEMENT  The work were supported by the Natural Science Instruction Project of Hebei Province and Natural Science Pre-Research Foundation of Hebei University

REFERENCES
[1] Temple C, Rener G A, Waud W R et al. J. Med. Chem., 1992, 35: 3686
[2] Marco J L, Martin N, Grau A M et al. Tetrahedron, 1994, 50: 3509
[3] Albert D A, Cano F H, Martin N et al. J. Chem. Soc. Perkin Trans(I), 1997, 3401
[4] Zhou J F. Synth. Commun., 2003, 33(1): 99
[5] H.Y. Li, W. Z. Yang, J. B. Yang et al; J. Chem. Res., 2004, 11, 744-746; Yang W Z, Li H Y, Wang S X et al. Chemical Journal on Internet, 2004, 6(4): 25
[6] Wang X S, Shi D Q, Du Y, et al. Synth. Commun., 2004, 34(8), 1425-1432

催化a,a'-二苯叉环己酮与丙二腈反应合成 4H-苯并吡喃-3-腈衍生物
杨文智，李海鹰，张红乐
(河北大学药学院，河北 保定 071000)
摘要在超声辐射下，分别使用NaOH 和KF/Al₂O₃催化a,a'-二苯叉环己酮与丙二腈反应，反应5 min，合成较好产率的4H-苯并吡喃-3-腈衍生物。KF/Al₂O₃是催化此反应的良好催化剂。
关键词 a,a'-二苯叉环己酮；丙二腈；4H-苯并吡喃-3-腈衍生；氧化铝固载氟化钾

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