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This document describes a study on using the ionic liquid 1-butyl-3-methylimidazolium acetate ([Bmim]OAc) to catalyze Michael additions of active methylene compounds to α,β-unsaturated carboxylic esters and nitriles. The reactions produced bis-addition products in high yields under mild conditions. [Bmim]OAc was found to be an effective catalyst, with the acetate anion and proton on the imidazolium cation both playing important roles in activating the reactants. A variety of active methylene compounds reacted smoothly with different unsaturated substrates to provide the bis-addition products in good to excellent yields.
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BmimOAc Catalyzed Michael Addition of Active Methylene to Unsaturated Carboxylic Esters and Nitriles
This document describes a study on using the ionic liquid 1-butyl-3-methylimidazolium acetate ([Bmim]OAc) to catalyze Michael additions of active methylene compounds to α,β-unsaturated carboxylic esters and nitriles. The reactions produced bis-addition products in high yields under mild conditions. [Bmim]OAc was found to be an effective catalyst, with the acetate anion and proton on the imidazolium cation both playing important roles in activating the reactants. A variety of active methylene compounds reacted smoothly with different unsaturated substrates to provide the bis-addition products in good to excellent yields.
This document describes a study on using the ionic liquid 1-butyl-3-methylimidazolium acetate ([Bmim]OAc) to catalyze Michael additions of active methylene compounds to α,β-unsaturated carboxylic esters and nitriles. The reactions produced bis-addition products in high yields under mild conditions. [Bmim]OAc was found to be an effective catalyst, with the acetate anion and proton on the imidazolium cation both playing important roles in activating the reactants. A variety of active methylene compounds reacted smoothly with different unsaturated substrates to provide the bis-addition products in good to excellent yields.
*Corresponding author. E-mail: ghgao@chem.ecnu.edu.cn Received September 23, 2009; accepted November 16, 2009. Supported by the National Natural Science Foundation of China(Nos.20533010 and 20873041) and Shanghai Leading Aca- demic Discipline Project, China(No.B409).
[Bmim]OAc Catalyzed Michael Addition of Active Methylene to , -Unsaturated Carboxylic Esters and Nitriles YANG Yu, WANG Li-bing, ZHANG Zhan, LI Cai-meng, FU Xian-lei and GAO Guo-hua *
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, P. R. China
Abstract Michael addition of active methylene compounds to ,-unsaturated carboxylic esters and nitriles was ef- fectively catalyzed by a basic ionic liquid, 1-butyl-3-methylimidazolium acetate([Bmim]OAc). The bis-addition products were selectively obtained in high yields under mild reaction conditions. Keywords Michael addition; [Bmim]OAc; Bis-addition; Mild reaction condition Article ID 1005-9040(2010)-04-554-04
1 Introduction Michael addition is one of the most important carbon-carbon bond formation reactions in organic chemistry and is widely applied in organic synthe- ses [13] . Conventionally, this type of addition reac- tions of nucleophiles and unsaturated carbonyl com- pounds is catalyzed by strong bases and Lewis acids, leading to undesired by-products and environmentally hazardous residues [48] . To solve these problems, many catalysts [912] have been developed. However, these catalysts were also suffered from a large amount of catalyst used [9] , long reaction time [10,11] , high temperature [12] and low yields [9,11] . Ionic liquids, as a new kind of solvent and catalyst, have been applied in many organic reactions [1318] . Recently, a task- specific ionic liquid, [Bmim]OH, has been used as a catalyst and a reaction medium in Michael addition of active methylene compounds to conjugated ketones, carboxylic esters and nitriles [19] . However, in this pro- tocol, a large amount of [Bmim]OH was required in order to achieve high yields. In this article, we would like to report a basic ionic liquid, 1-butyl-3-methyli- midazolium acetate([Bmim]OAc) to catalyze Michael addition of active methylene to , -unsaturated car- boxylic esters and nitriles under room temperature. 2 Experimental 2.1 General Procedure N-Methylimidazolium was fractionally distilled. The other reagents were commercial reagents of A. R. grade and used without further purification. Quantita- tive analysis of the reaction mixture was performed with a gas chromatograph(Shimadzu GC-14B). Proton magnetic resonance spectra( 1 H NMR) were recorded on J EOL 400 MHz with tetramethylsilane as the internal standard. 2.2 Synthesis of 1-Butyl-3-methylimidazolium Acetate([Bmim]OAc) AgOAc(0.67 g, 4 mmol) was added to a solution of [Bmim]Cl(0.700 g, 4 mmol) in water(10 mL) and stirred at room temperature for 4 h. The suspension was filtered to remove silver chloride. The water was removed in vacuo to afford 0.69 g(85%) of a colorless oil. 1 H NMR(500 MHz, CDCl 3 ), : 11.10(s, 1H), 7.28(s, 1H), 7.22(s, 1H), 4.29(t, J=8.0 Hz, 2H), 4.05(s, 3H), 1.97(s, 3H), 1.831.89(m, 2H), 1.351.39(m, 2H), 0.96(t, J=8.0 Hz, 3H). 2.3 Typical Experimental Procedure for Michael Reaction [Bmim]OAc(0.099 g, 0.05 mmol) was added to a solution of ethyl cyanoacetate(0.227 g, 2 mmol) and methyl acrylate(0.430 g, 5 mmol) in DMSO(2 mL). The reaction mixture was stirred for 5 min. The reac- tion was quenched by adding water(80 mL). The re- sulting mixture was extracted with ethyl ether(30 mL3). The combined organic phase was dried with anhydrous MgSO 4 , and evaporated. The crude product No.4 YANG Yu et al. 555
was analyzed with a gas chromatograph and purified by column chromatography over silica gel to afford 0.524 g(yield 92%) of the corresponding bis-addition pro- duct(1c) as light yellow oil. 3 Results and Discussion 3.1 Effect of Various Solvents The addition reaction of ethyl cyanoacetate with methyl acrylate was carried out in various solvents in the presence of a catalytic amount of [Bmim]OAc (Scheme 1). As shown in Table 1, the catalytic activity of [Bmim]OAc varied with different solvents. In DMSO, DMF and THF, the same product was ob- tained in the yields of 94%, 87%, and 78%, respec- tively within 5 min at room temperature. However, the catalytic activity of [Bmin]OAc was relatively low in CHCl 3 , acetone and toluene and the same product was obtained in the yields of 77%, 69% and 40% in 1 h, respectively. The addition reaction hardly proceeded in the protonic solvents such as ethanol and water un- der the same reaction condition. It is worth mentio- ning that only a bis-addition product was detected in the reaction mixture.
Scheme 1 Michael addition reaction of ethyl cyanacetate with methyl acrylate Table 1 Effects of various solvents on Michael addition *
Solvent Reaction time/min GC yield(%) DMSO 5 94 DMF 5 87 THF 5 78 CHCl 3 60 77 CH 3 COCH 3 60 69 Toluene 60 40 Ethanol 60 <1 Water 60 5 * Reaction conditions: methyl acrylate: 5 mmol; ethyl cyanoacetate: 2 mmol; [Bmim]OAc: 0.2 mmol; solvent: 2 mL; temperature: 30 C. 3.2 Effects of Various Ionic Liquids In order to check the catalytic species of ionic liquids, ionic liquids with different cations and anions were applied to catalyzing the addition reaction of ethyl cyanoacetate with methyl acrylate. The results are listed in Table 2. In the presence of molar fraction of 2.5% [Bmim]OAc, ethyl cyanoacetate reacted with methyl acrylate, affording the corresponding Table 2 Effect of various ionic liquids on Michael addition *
Entry Ionic liquid(molar fraction) Time/min GC yield(%) 1 [Bmim]OAc (2.5%) 5 92 2 [Bmim]OH (2.5%) 5 10 3 [Bmim]Br (2.5%) 10 0 4 [Bmim]BF 4 (2.5%) 10 0 5 [Bmmim]OAc (2.5%) 5 46 6 [Bmim]OAc (1%) 10 66 7 [Bmmim]OAc (1%) 10 36 * Reaction conditions: methyl acrylate: 5 mmol; ethyl cyanoacetate: 2 mmol; DMSO: 2 mL; temperature: 30 C. product in a yield of 92% within 5 min at room tem- perature(Entry 1). In comparison, [Bmim]OH gave a low yield of 10% under the same reaction condi- tions(Entry 2), and [Bmim]Br and [Bmim]BF 4 did not show any catalytic activity(Entries 3 and 4). These results indicate that the anions of the ionic liquids play a dominating role in the addition reaction. The anion of OAc
showed the highest activity in the addition
reaction. However, when 1,2-dimethyl-3-butyl imida- zolium acetate([Bmmim]OAc), in which the proton in 2-position of imidazolium is replaced by a methyl group, was applied to catalyzing the reaction of ethyl cyanoacetate with methyl acrylate, the activity dropped to 46%(Entry 5). Similar results were also observed in the less amount of ionic liquids(1%). [Bmim]OAc afforded the desired product in a yield of 66%, while [Bmmim]OAc gave a yield of 36% (Entries 6 and 7). The above results show that pro- ton on 2-position in imidazolium cation also plays an important role in catalyzing the reaction of ethyl cya- noacetate and methyl acrylate. Others and we [2022] have found the proton on the 2-position of imidazo- lium cation can activate carbonyl group through the hydrogen bond interaction in the carbomethoxylation and Diels-Alder reactions. The role of proton on the 2-position of imidazolium cation in the addition reac- tion can be explained as the activation of the carbonyl group of methyl acrylate through hydrogen bonding, while the OAc
group acts as a base to form carbanion
by the deprotonation of cyanoacetate(Scheme 2). [Bmim]OAc can activate both the reactants, exhibiting the highest activity among the ionic liquids we ap- plied.
Scheme 2 Deprotonation of cyanoacetate
556 CHEM. RES. CHINESE UNIVERSITIES Vol.26
3.3 Reaction of Various Active Methylene Com- pounds and , -Unsaturated Carboxylic Esters and Nitriles In order to investigate the generalities of this procedure, the reactions of various active methylene compounds with ,-unsaturated carboxylic esters and nitriles were carried out in the presence of [Bmim]OAc(Scheme 3). The results are summarized in Table 3. Ethyl cyanoacetate reacted with methyl acrylate, ethyl acrylate and acrylonitrile, giving the sole bis-addition products(1c, 2c and 3c) in the yields of 92%, 95% and 91%, respectively(Entries 13). The use of malononitrile furnished the corresponding
Scheme 3 Michael addition reaction of various active methylene compounds with , -unsatu- rated carboxylic esters and nitriles in the presence [Bmim]OAc Table 3 Michael addition catalyzed by ionic liquid [Bmim]OAc a
Entry Active methylene compound R 3 Product Reaction time/min Yield(%) b
c. 60 C, [Bmim]OAc: 0.10 mmol; d. [Bmim]OAc: 0.10 mmol. No.4 YANG Yu et al. 557
bis-addition products(4c, 5c and 6c) in high yields(Entries 46). Diethyl malonate reacted with acrylonitrile as well to afford the bis-addition pro- duct(7c) in a good yield(71%) at a relative higher temperature(60 C) in a longer reaction time in the presence of 5% [Bmim]OAc(Entry 7). The reaction of nitroethane with methyl acrylate proceeded well and gave the bis-addition product in a yield of 85%(Entry 8). In terestingly, phthalimide also un- derwent the addition reaction with acrylonitrile and furnished the mono-addition product in a yield of 98%(Entry 9). 3.4 1 H NMR Spectra of Synthesized Compounds Compound 1c: light yellow oil. 1 H NMR(400 MHz, CDCl 3 ), : 4.29(q, J=8.0 Hz, 2H), 3.72(s, 6H), 2.562.64(m, 2H), 2.392.47(m, 2H), 2.272.34 (m, 2H), 2.132.21(m, 2H), 1.34(t, J=8.0 Hz, 3H). Compound 2c: light yellow oil, 1 H NMR(500 MHz, CDCl 3 ), : 4.28(q, J=7.0 Hz, 2H), 4.134.18 (m, 4H), 2.552.59(m, 2H), 2.412.44(m, 2H), 2.282.30(m, 2H), 2.172.20(m, 2H), 1.35(t, J=7.0 Hz, 3H), 1.27(t, J=7.2 Hz, 6H). Compound 3c: light yellow oil, 1 H NMR(400 MHz, CDCl 3 ), : 4.38(q, J=8.0 Hz, 2H), 2.622.71 (m, 2H), 2.502.58(m, 2H), 2.382.45(m, 2H), 2.172.24 (m, 2H), 1.39(t, J=8.0 Hz, 3H). Compound 4c: white solid, 1 H NMR(500 Hz, CDCl 3 ), : 3.74(s, 6 H), 2.702.75(m, 4H), 2.312.35(m, 4H). Compound 5c: light yellow oil, 1 H NMR(400 Hz, CDCl 3 ), : 4.20(q, J=8.0 Hz, 4H), 2.702.74(m, 4H), 2.322.36(m, 4H), 1.29(t, J=8.0 Hz, 6H). Compound 6c: white solid, 1 H NMR(500 MHz, CDCl 3 ), : 2.802.83(m, 4H), 2.432.46(m, 4H). Compound 7c: white solid, 1 H NMR(400 MHz, CDCl 3 ), : 4.28(q, J=8.0 Hz, 4H), 2.47(t, J=8.0 Hz, 4H), 2.26(t, J=8.0 Hz, 4H), 1.30(t, J=8.0 Hz, 6H). Compound 8c: yellow oil, 1 H NMR(500 MHz, CDCl 3 ), : 3.69(s, 6H), 2.282.38(m, 6H), 2.15 2.19(m, 2H), 1.54(s, 3H). Compound 9c: white solid, 1 H NMR(500 MHz, CDCl 3 ), : 7.757.77(m, 2H), 7.887.90(m, 2H), 4.01(t, J=6.9 Hz, 2H), 2.81(t, J=6.9 Hz, 2H). 4 Conclusions In summary, basic ionic liquid, [Bmim]OAc, is an effective catalyst for Michael addition of active methylene compounds with ,-unsaturated carboxy- lic esters and nitriles. The [Bmim]OAc catalyzed pro- tocol has the advantages of mild reaction condition, short reaction time and high selectivity for bis- addition products.
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