Dry Media Reaction Procedure for Synthesis of α,β-Unsaturated Acids, α-Cyanoacrylonitriles and α-Cyanoacrylates via Knoevenagel Condensation Using NaHSO<sub>4</sub>·SiO<sub>2</sub> Catalyst
Dry Media Reaction Procedure for Synthesis of α,β-Unsaturated Acids, α-Cyanoacrylonitriles and α-Cyanoacrylates via Knoevenagel Condensation Using NaHSO4·SiO2 Catalyst
Journal of the Korean Chemical Society. 2007. Aug, 51(4): 346-351
Copyright © 2007, The Korean Chemical Society
  • Received : April 03, 2007
  • Published : August 20, 2007
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M., Gopalakrishnan
P., Sureshkumar
V., Kanagarajan
J., Thanusu
S., Thirunavukkarasu

Efficient stereoselective synthesis of α,β-Unsaturated acids, α-Cyanoacrylonitriles and α-Cyanoacrylates has been carried out in the presence of NaHSO 4 .SiO 2 under conditions with an E -geometry.
One of the more important properties of Knoevenagel condensation from a synthetic perspective is that they offer a route to the formation of C-C bond, by which the arylidene compounds are obtained from carbonyl compounds and active methylene compounds in the presence of a basic catalyst or Lewis acid catalyst. 1 In recent times, there has been a growing interest in Knoevenagel products because many of them have significant biological activity, for example, tyrophostins, such as α-cyanothiocinnamide, are known to inhibit autophosphorylation of the EGF receptor, in addition to possessing antiproliferative effects on human keratinocytes. 2 Knoevenagel condensation reaction has been widely used in organic synthesis to prepare coumarins and their derivatives, which are important intermediates in the synthesis of cosmetics, perfumes and pharmaceuticals. 3 The first procedure for this condensation reaction was reported by Knoevenagel 4 more than a century ago. This has led to the development of several new synthetic strategies involving weak bases 5 and few acid catalysts. 6 More recently, ionic liquids 7 have also been employed to accomplish this reaction. Also, Knoevenagel reaction was enhanced by microwave irradiation. 8 However, all these methods have their own merits and shortcomings. Since Knoevenagel condensation is a versatile reaction in medical and organic chemistry, development of an alternative synthetic methodology is of paramount importance.
Solvent- free solid state synthetic methods have been shown to be very efficient and advantageously coupled with microwave (MW) activation 9 and many organic reactions have been carried out using “microwave induced organic reaction enhancement” (MORE) technique delivering high yields in a short reaction time compared with the conventional heating mode performed in preheated thermostat oil bath. 10 The use of supported reagents has attracted much attention because of the selectivity, reactivity and associated ease of manipulation. 11 Microwave induced chemical reactions 12 especially on solid supports and those conducted in solvent less systems, 13 have gained popularity. While planning to select a suitable mild acid for catalyzing the condensation reaction, we thought that a catalyst known for activation of an electrophile should serve the purpose.
Silica gel supported sodium hydrogen sulfate (NaHSO 4 ·SiO 2 ) 14 a non-toxic and inexpensive catalyst, has been used for a number of organic reactions including one-pot conversion of ketones to amides, 15 and single step synthesis of 4(3H)-quinazolinones. 16
Solvent- free Solid-State organic reactions using dry media techniques under microwave irradiation are a main topic of interest in our laboratory. 17 , 18 , 19 In continuation of these efforts aimed at developing solvent- free procedures we found that the use of silica gel supported sodium hydrogen sulfate (NaHSO 4 ·SiO 2 ) catalyzed nucleophilic attack on the carbonyl group by various active methylene compounds like malonic acid, malononitrile, ethyl cyanoacetate and served as a dehydrating agent to facilitate the removal of water in the final step both under microwave irradiation and thermal conditions. NaHSO 4 ·SiO 2 heterogeneous catalyst reacts with structurally diverse aromatic aldehydes and various active methylene compounds ( 1 ) under mild condition to give the corresponding arylidene compounds in quantitative yields ( 1 ) without any of the environmental disadvantages of using toxic and costly drying reagents such as zirconophosphate oxynitride. 5d NaHSO 4 ·SiO 2 catalyst was shown to be one of the most efficient MW absorber with a very high specificity to MW heating. It was able to reach a temperature of 110 ℃ after 3 minutes of irradiation in a domestic oven (320 W).
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Solid-state Knoevenagel condensation of aromatic aldehydes with active methylene compounds catalyzed by NaHSO4·SiO2.
The reaction has been carried out at different power levels from 80-720 W ( 1 , entries 3, 12 & 19) in order to select the more appropriate power level and found out that power level of 320 W gave the maximum yield.
The reaction is highly stereoselective, results in the formation of arylidene compounds in excellent yields, with an E - geometry. Both electron-rich and electron-deficient aldehydes worked well, affording good to excellent yields of products. Moreover, treatment of heterocyclic aldehyde like furfural with various active methylene compounds resulted in the formation of the corresponding arylidene products in good yield.
Moreover, in order to check the possibility of specific non- thermal effects of microwave irradiation, reactions were carried out using thermostated heating mantle (Δ) under similar sets of conditions of time and temperature as for the microwaveassisted method ( 2 ).
Significant lower yields were obtained under conventional heating than using MW- assisted method under identical conditions of time and temperature. Even by extending reaction times, yields remain lower under thermal conditions when compared to MW activation. This observation clearly demonstrates that the effect of MW irradiation is not purely thermal.
NaHSO4·SiO2catalyzed condensation of aromatic aldehydes with active methylene compounds in solvent-free conditions under microwave irradiation
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aFinal temperature was measured by immersing a glass thermometer in the reaction mixture at the end of the exposure to microwave irradiation and gives an approximate temperature range. bTime at which maximum yield was obtained. cIsolated yields of pure products; all products were characterized by IR, 1H NMR and MS spectra.
A credible reaction pathway for the product formation is depicted in 2 .
Another noteworthy feature of NaHSO 4 .SiO 2 catalyst lies in the fact that it can be recovered and reused by simple washing with diethyl ether after each use and activated in an oven at 120 ℃ for 1 h prior to use, rendering thus the process more economic and green. In total, eight successive re-use runs were possible. However, little palpable decrease in the reaction yield was noted up to five runs ( 1 , entries 3, 12 & 19). All these constitute a green and efficient alternative to the MW assisted method described by Kim et al . 5e using piperidine and chlorobenzene.
In addition, by applying the above synthetic procedure, ( E )-3-(2-butyl-4-chloro-1 H -imidazol-5-yl)acrylic acid, a model compound is synthesized by condensing 2-butyl-4-chloro-1 H -imidazol-5-carbaldehyde with malonic acid in the presence of NaHSO 4 ·SiO 2 catalyst under microwave irradiation at a power level of 320 W for 90 sec/ thermal condition at 60 ℃ for 540 sec. The reaction mixture was cooled and extracted with dichloromethane (3×1O mL). The catalyst was removed by filteration. After drying the dichloromethane extracts over anhydrous Na 2 SO 4 , the combined organic phases were concentrated in vacuo to furnish the product.
Comparison of results under both Microwave Irradiation and Classical thermal conditions (Power = 320 W)
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Comparison of results under both Microwave Irradiation and Classical thermal conditions (Power = 320 W)
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Credible reaction pathway for product formation.
- General remarks
All the inorganic and organic chemicals werepurchased from commercial suppliers and were used without purification prior to use. The reactions were monitored by TLC to ascertain proof of reactions. Melting points were recorded in open capillaries (uncorrected). The FT-IR spectra were recorded on a NICOLET AVATAR-360 FT-IR spectrophotometer. 1 H NMR spectra were recorded on a BRUKER AMX.400 NMR spectrometer (400 MHz) in CDCl 3 using TMS as internal standard. Mass spectra were recorded in FINNIGAN MAT.8230 MASS spectrometer operating at 70 eV. Satisfactory microanalysis was obtained on Carlo Erba 1106 CHN analyzer. A conventional (unmodified) household microwave oven equipped with a turntable (LG, MG.395 WA, 760 W and operating at 2450 MHz) was used for the microwave irradiation experiments. NaHSO 4 ·SiO 2 catalyst was prepared according to the literature. 16
- General procedure for the synthesis of 4-methoxycinnamic acid (Table1, entry 3)
To a mixture of 4-methoxybenzaldehyde (1.36 g, 10 mmol) and NaHSO 4 ·SiO 2 catalyst (50 mg) in a 50 mL borosil beaker, malonic acid (1.04g, 10 mmol) was added. The reaction mixture was mixed properly with the help of a glass rod (10 s) and then irradiated in a domestic microwave oven for 90 s at a power level of 320W (monitored by TLC). The reaction mixture was cooled and extracted with Et 2 O (3×1O mL). The catalyst was removed by filteration and reused. After drying the ether extracts over anhydrous Na 2 SO 4 , the combined organic phases were concentrated in vacuo to furnish the product (1.54 g, 87%).
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Dry media synthesis of (E)-3-(2-butyl-4-chloro-1H-imidazol-5-yl)acrylic acid.
The reaction was also performed with 4-methoxybenzaldehyde (6.80 g, 50 mmol), NaHSO 4 ·SiO 2 catalyst (250 mg) and malonic acid (5.20 g, 50 mmol) in a 150 mL borosil beaker adopting the same procedure. After an irradiation time of 90 s, the product (7.61 g, 86%) was obtained. The structure of the compounds was confirmed by FT.IR, 1 H NMR, MS and comparison with authentic samples obtained commercially or prepared by reported methods.
( E )-3-(2-butyl-4-chloro-1 H -imidazol-5-yl)acrylic acid 26 : m.p. 160-62℃, IR, cm -1 : 3462, 3331, 3028, 2973, 2933, 2857, 2805, 2643, 2542, 1683, 1553; 1 H NMR δ ppm: 0.94 (t, 3H, H 12 , J=6.2 Hz), 1.31-35 (m, 2H, H 11 ), 1.60-1.64 (m, 2H, H 10 ), 2.54 (t, 2H, H 9 , J=6.3 Hz), 6.48 (d, 1H, H 7 , J=15.9 Hz), 7.82 (d, 1H, H 6 , J=16.2 Hz), 11.90 (s, 1H, H 8 ), 11.99 (s, 1H, H 1 ); ESI MS: 229 (M+1) +. ; Carbon: 52.48 found (52.52 cal. ), Hydrogen: 5.69 found (5.73 cal. ); Nitrogen: 12.21 found (12.25 cal. ).
Crisply, this article describes a novel and efficient approach for the rapid synthesis of various arylidene compounds by the condensation of aromatic aldehydes with active methylene compounds under microwave irradiation in solvent- free conditions using re-usable NaHSO 4 ·SiO 2 as an inexpensive and environmentally benign catalytic system. The notable features of this procedure are mild reaction conditions, operational simplicity, improved yields and enhanced reaction rates, cleaner reaction profiles and simple experimental and product separation procedures making this method an attractive one.
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