Polyethylene glycol (PEG) as a benign solvent for Knoevenagel condensation

Available online at www.sciencedirect.comCHINESEScienceDirectC HEMICALL .ETTERSELSEVIERChinese Chemical Letters 19 (2008) 1043-1046www.elsevier.com/locate/ccletPolyethylene glycol (PEG) as a benign solvent forK noevenagel condensationYang Liu, Jun Liang, Xiu Hong Liu, Ji Cai Fan, Zhi Cai Shang *Department of Chemistry, Zhejiang University, Hangzhou 310027, ChinaReceived 19 March 2008AbstractThe Knoevenagel condensation of aromatic aldehydes with active methylene compound proceeded efficiently in polyethyleneglycol at room temperature with L-proline as catalyst. The yield is high and the products had E-isomer dominantly. Polyethyleneglycol containing L-proline could be recycled and reused for several times without noticeably decreasing in productivity.C 2008 Zhi Cai Shang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.Keywords: Polyethylene glycol; L-Proline; Knoevenagel condensationKnoevenagel condensation is one of the fundamental and essential reactions in organic chemistry and the researchmethod of this reaction developed very quickly. In tradition, it carried out in the presence of harmful organic solvent[1] and catalyst such as AIPO4- Al2O3 [2], ZnCl2 [3], K3PO4 [4]. Additionally, this reaction could also performed bymicrowave iradiation [5] or infrared [6], but it requires special reaction instruments and conditions. In recent years,though ionic liquids (IL) as effective solvent to improve the Knoevenagel condensation could get good result [7-10],the limitation of the use of IL as solvent is that the price is usually expensive and it is hard for vast use in industry.Green chemistry is one of the important purposes of organic synthesis, thus it attracts more scientists andresearchers to this area. Polyethylene glycol (PEG), which is benign medium due to low vapor pressure, non-flammable, their ease of workup, the ability to act as phase transfer catalysts, good reaction medium, inexpensive priceand eco- friendly for nature [11-14], seem a perfect solvent alternative to volatile organic solvent and IL promotedreactions. In fact, polyethylene glycol has universal use in organic reaction for a long time [15]. Various kinds ofresearch have been reported that PEG as solvent or medium for organic chemistry, e.g. synthesis of 3,4-dihydropyimidinones [16], the synthesis of β-ketosulfones [17] and the Michael addition reaction [18]. Cao et al.reported a new method that improves the Knoevenagel condensation catalysed by PEG400 and K2CO3 [19], but theprocedure of it had to have a high reaction temperature and also need long reaction time.Proline is a kind of fundamental natural organic molecular and possessed the special molecular structureand property. In recent years, L-proline has been prevalently used as catalyst in many reactions, such as Mannichreaction [20,21] and asymmetry reaction in aldol reaction [22,23]. Karade et al. reported that their group used* Corresponding author.E-mail address: shangzc@ zju.edu.cn (Z.C. Shang).中国煤化工1001-8417/$ - see front matter◎2008 Zhi Cai Shang. Published by Elsevier B.V. on|.MYHCNMHGAll rights reserved.doi: 10.1016/.cclet.2008.06.0161044Y Liu et al./Chinese Chemical Leters 19 (2008) 1043- 1046L-proline as catalyst for synthesis of 3-substituted coumarins and attained good result [24], however, it requireda bit high temperature.Considered the two factors of mentioned above, so we use the facile method which is the combination of L prolineand PEG as a system in the Knoevenagel condensation for synthesis of arylidene derivatives.1. ExperimentalA mixture of aromatic aldehyde 1 (10 mmol), active methylene compounds 2 (10 mmol) and L-proline (4.0 mmol)was resolved in PEG400 (1 mL) at room temperature with stirring for an appropriate time treated with some coolwater. The products were directly filtered, dried and the desired product was given in high and the reaction process wasmonitored by TLC. After completion of the reaction, the reaction mixture was yield with essential purity. In therecycled reaction, after isolation of the product from the reaction system, the mother liquor, which is the mixture ofPEG400, L-proline and water, was dried for 4 h under the infrared light or distill directly to eliminate water. The nextrun was performed at the same conditions.2. Results and discussionOur efforts began with the reaction of various aromatic and heteroaromatic aldehydes with active methylene such asmalononitile and ethyl cyanoacetate in PEG (400 MW) without L proline catalyst at room temperature (Scheme 1),the corresponding product was obtained and the result was summarized in Table 1From Scheme 1, we found that the Knoevenagel condensation of various aromatic and heteroaromatic aldehydeswith malononitrile could get high yield and require a bit long reaction time, but the reaction of various aromatic andheteroaromatic aldehydes with ethyl cyanoacetate did not take place.So we carried out the reaction of various aromatic and heteroaromatic aldehydes with active methylene such asmalononitrile, ethyI cyanoacetate in the presence of L-proline in PEG (400 MW) at room temperature (Scheme 2) andthe achieved results were summarized in Table 2.From the results of two reactions, three points are demonstrated as follows.Firstly, L-proline is very important and indispensable in the reaction. If without L -proline, only Reaction 1 canhappen can happen but it requires longer time and gives lower yield compared with Reaction 2; for the more, thepresence of L-proline lead to the product which have the structure of double bonds possess the E-isomer dominatelybecause of steric effects and was confirmed by 'H NMR [9,25].CN PEG400R,CNH2CHr.t23Scheme 1.Table 1Knoevenagel condensation in PEG400EntryProductCNCH2YTime (h)Yield (%)3aC&HsY=CN83.63bp-CHsC.H480.33cp-CHzOC;H478.83dp-NO2CH490.93ep-CIC.H4Y=C中国煤化工3f2-Furfuraly87.83gp-Me2NC&H4TYHCNMH G .81.33hp-0HC.H4Y =CN69.7Y Liu et al./Chinese Chemical Letters 19 (2008) 1043- -10461045CNPEG400 r.CHHL-Proline3Scheme 2.Table 2L-Proline catalyzed Knoevenagel condensation in PEG400EntryProductCNCH2YTime (min)Yield (%)Lit. mp (C)"3aC6HsY=CN94.882- -8383- 84[7]3bp-CH3C6H493.0132-133133-134 [26]3cp-CHzOCgH496.5110- -112114-115[7]p-NO2C&H491.7154- 156160-161 [7]p-CIC6H4 .92.4166- 167161-162 [7]3ep_CIC&H4Y= CN90.6p-CIC.H490.243f2- Furfuraly093.465-6668- 69 [9]3gp-Me2NC&H495.5177- -179179-180 [7]thp-HOC,H484.2179- 181183- -184 [9]1ip-CHzC6H4Y = COOEt24084.488- -8992- -93 [26]123jp-CHzOC.H4Y=COOEt:77-793kp-NO2CH492.2166-167168-169 [9]4p-CIC,H45082.087- -8889- 90 [9]5im2-FurfuralyY=CoOEt:84.786- -8793- 94[9]6)np-Me2NC&HsY= COOEt21081.2120-122124- -126 [26]73op-HOC6H482.5162 -164Isolated yield.b Meling point, NMR had report.The second run.dThe third run.Secondly, the group on the aromatic aldehyde influenced the reaction obviously. From Schemes 1 and 2, we foundthat the Knoevenagel condensation reaction of aromatic aldehyde with the withdrawing group such as -NO2, - _CI usedless reaction time than that with donating group such as -N(Me)2, - CH3, - _OCH3 on the aromatic rings. Meanwhile it isshown that the condensation reaction of aldehydes, which possesses donating group on the aromatic compound, withthe active methylene substance can be carried out in higher yield than that with electron withdrawing group. Thereason we considered maybe the nitrogen atom of intermedia imine which formed by aromatic aldehyde with L prolinepossses positive charge so that the donating group on the aromatic aldehyde could have the function that decentralizethe part of positive charge and make it more stable.At last, since the L-proline and PEG400 were soluble in water, they could be easily isolated by simple extractionwith water and the highly pure products can be obtained simply by filtration. The remaining PEG400 containing L-proline could be recycled and reused at least three times without noticeably decreasing the productivity (Table 2,entries 5- -7).3. ConclusionIn conclusion, we have demonstrated that the Knoevenagel condensation between aromatic aldehydes and activemethylene compounds can be effectively carried out at the room temperature with L-proline as catalyst in PEG400. Thepresent method has some notable advantages compared to the previous methods such as using cheap solvent andcatalyst, more benign to environment, good capability as recycled solver中国煤化工ducts, the simpleprocess and the high yield. We indicated that the PEG400 can replace tnt and some ionicliquids in the Knoevenagel condensation reaction, so it is a favorable||YHCNMH(CGinstance of greenchemistry.1046Y Liu et al./Chinese Chemical Letters 19 (2008) 1043- .1046References[1] G. Jones, Organic Reactions, vol. 15, Wiley, New York, 1967, p. 20.[2] JA. Cabello, J.M. Campelo, A. Garcia, D. Luna, J.M. 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