Synthesis of 4H-chromene-3carbonitrile derivative froma,a’–dibenzylidenecyclohexanone and malononitrile

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

AbstractSynthesis of 4H-chromene-3-carbonitrile derivative was carried out conveniently using NaOH and KF/Al as catalyst under ultrasonic irradiation. The reactions are completed within 5 min to give satisfactory yields. KF/Al was more effective catalyst in one-pot reaction.

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 whena,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/Al under refluxed methanol, and the results are better than that under conventional heating condition.[5] In the present communication, the results on the KF/Al-catalyzed reaction betweena,a’-dibenzylidenecyclohexanone and malononitrile in different reaction conditions are reported.

a,a’-dibenzylidenecyclohexanone was synthesized according to the literature.[5] Melting points were uncorrected. H NMR spectra were measured on Bruker AM-400S (400 MHz) spectrometer using TMS as internal standard and CDCl 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 C (lit 228-230 C)[4]; H NMR (CDCl,400 MHz):1.58 ~ 1.69 (2H, m, C), 1.96 ~ 2.07 (2H, m, C), 2.60 ~ 2.78 (2H, m, C), 3.99 (1H, s, C), 4.53 (2H, s, N), 6.90 (1H, s, C), 7.27 ~ 7.40 (10H, m, Ar).
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 65C75C for 1 h. The water was removed under reduced pressure. The resulting free flowing powder was dried at 120C for 4 h. The content of KF is about 30% (150mg mixture/mmol KF).
2.2General procedure
Thea,a’-dibenzylidenecyclohexanone (0.5 mmol) and malononitrile (0.6 mmol) are mixed with MeOH or EtOH (20-30 mL). KF-Al (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 ora,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 H NMR spectra.[4]

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 ofa,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/Al 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/Al 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-Al 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 betweena,a’-dibenzylidenecyclohexanone and malononitrile catalyzed by KF-Al or NaOH.

Compound Reaction condition Cat.
Temperature (
yield /%, (lit.) m.p./
3a r.t./MeOH NaOH
180/25 69 229-231/228-230[4]
360/25 74
u.s./MeOH NaOH
5/25 67
15/25 58
30/25 57
5/25 80
10/25 70
r.t./EtOH NaOH
1080/30 94
u.s. /EtOH NaOH
5/30 86
15/30 82
30/30 83
5/30 95
(70[4], 81[6]

The molar ratio ofa,a’-dibenzylidenecyclohexanone to catalyst, mixture ofa,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-Al-catalysis that obtained at 30 oC after 5 min of sonication time. From the Table 1, The reaction ofa,a’-dibenzylidenecyclohexanone () with malononitrile () gave 95% yield of 3a catalyzed by KF-Al 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-Al in DMF within 10-14h at room temperature.[6]
    KF-Al 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.

It was concluded that the best synthetic conditions of the 4H-chromene-3-carbonitrile derivative (3b) used the mole ratio of KF/Al toa,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