CHEM. RES. CHINESE UNIVERSITIES 2010, 26(2), 263—267

Poly(ethylene glycol)-supported Piperazine ―Synthesis and Application in Knoevenagel Condensation WANG Cui-e, JIN Jie, ZHANG Min, YU Shu-yan, SHANG Yong-jia* and HU Jin-song College of Chemistry and Materials Science, Anhui Key Laboratory of Functional Molecular Solids, Anhui Key Laboratory of Molecular Based Materials, Anhui Normal University, Wuhu 241000, P. R. China Abstract A soluble, poly(ethylene glycol)-supported piperazine catalyst was prepared. This soluble catalyst efficiently catalyzes the Knoevenagel condensation of various aromatic aldehydes with diethyl malonate or ethyl acetoacetate in a homogeneous phase to afford the desired alkenes in good purity and yield with a facile work-up process. It was found that the polymer reagent could be repeatedly used at least four times without the too much loss of activity. The catalyst has shown a good activity, stability, and recycling capability. Keywords Piperazine; Polymer-supported catalyst; Knoevenagel condensation Article ID 1005-9040(2010)-02-263-05

1

Introduction

The Knoevenagel condensation[1―4] is well known for its immense potential application in the synthesis of electrophilic olefins from active methylene and carbonyl compounds[5―7]. Ever since its discovery, the Knoevenagel reaction has been widely used in organic syntheses to prepare coumarins and their derivatives, which are important intermediates in the syntheses of cosmetics, perfumes, and pharmaceuticals[8,9]. Recently, there has been a growing interest in Knoevenagel products because of their significant biological activities[10―12]. Knoevenagel condensation in the synthesis of natural products[13―15] and semiconductor materials[16] was also much reported. Soluble polymer-supported organic synthesis, termed ‘liquid-phase’ organic synthesis, has coupled the advantages of traditional homogeneous solution chemistry(high reactivity, lack of diffusion phenomena and ease of analysis) with those of solid phase methods(use of excess reagents and easy isolation and purification of products)[17―19]. So, the synthetic approaches that utilize a soluble polymer have been developed by many workers in the past decades[20―28]. Polymer-supported organic catalysts with the aim of facilitating catalyst recovery and recycling have proved to be the powerful synthetic ones readily available to the chemical communities in organic

synthesis[29]. For example, Zhao and coworkers[30] developed a poly(ethylene-glycol)-supported proline for catalyzing asymmetric Michael addition in a good yield and high enantiomeric excess. Recently, Hong et al.[31] reported that a poly(ethylene glycol) supported N-heterocyclic carbene-based ruthenium complex can catalyze ring-closing metathesis(RCM) reactions, and the ruthenium byproducts can be efficiently removed by simple aqueous extraction. Bandini et al.[32] also found complex poly(ethylene glycol)-modified DAT2-Cu(OAc)2 can smoothly catalyze a base-free nitroaldol condensation in a highly enantioselective manner(e.e. up to 93%) also in a reagent-grade solvent and in the presence of air. As a continuation of our researches, in the development of PEG-supported organic synthesis[33―36], we will report a rapid and efficient synthesis of poly(ethylene glycol)-supported piperazine and its application in Knoevenagel condensations as a homogeneous catalyst. More over, it was found that the polymer reagent could be repeatedly used at least four times without the too much loss of activity.

2 2.1

Experimental General

All the chemicals and resins were obtained from commercial suppliers and used without further purification. IR spectra were recorded on a Perkin-Elmer

——————————— *Corresponding author. E-mail: [email protected] Received March 3, 2009; accepted June 28, 2009. Supported by the National Natural Science Foundation of China(No.20872001) and the Natural Science Foundation of Education Administration of Anhui Province, China(No.KJ2008A064).

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CHEM. RES. CHINESE UNIVERSITIES 1

983 FTIR spectrometer. H NMR spectra were recorded on a Bruker Avance DMX 500 instrument. GC-MS analyses were performed on an HP-5973 spectrometer. Elemental analyses were carried out on an EA-1110 elemental analyzer. X-ray crystallographic data were obtained on a Rigaku Mercury CCD X-ray diffractmeter(3 kV, sealed tube) at 193 K under the irradiation of graphite monochromated Mo Kα (λ=0.071070 nm). 2.2 (3)

Synthesis of PEG-supported Benzyl Chloride

To a solution of PEG(10 g, 5 mmol) in 50 mL of THF were added 1,4-bis(chloromethyl)benzene(3.5 g, 20 mmol), NaI(1.5 g, 10 mmol) and NaH(0.24 g, 10 mmol). The mixture was stirred at room temperature for 5 d. The polymer was precipitated by the addition of 300 mL of diethyl ether, for completion of the precipitation, and the suspension was left at 0 °C for another 30 min. And the polymer was then filtered, rinsed with 50 mL of diethyl ether(two times), and dried for 5 h at 66.7 Pa in vacuo. Thus, the PEGsupported benzyl chloride(3) was obtained as a yellow powder, yield 98%. 1H NMR(300 MHz, CDCl3), δ: 7.37(m, 4H, ArH), 4.61(s, 2H, ―CH2Cl), 4.58(s, 2H, ―OCH2―), 3.35―3.90(m, PEG). 2.3

Synthesis of PEG-supported Piperazine(4)

Piperazine(1.72 g, 20 mmol) and K2CO3(0.345 g, 2.5 mmol) were added to PEG-supported benzyl chloride(10 g, 5 mmol) in 50 mL of DCM. The mixture was stirred in reflux for 8 h, and then the mixture was cooled to room temperature. The insoluble substances were filtrated. And the polymer was precipitated by the addition of 300 mL of diethyl ether, and the suspension was left at 0 °C for another 30 min. After that, the polymer was filtered, rinsed with 0.1 L of diethyl ether, and dried for 5 h at 66.7 Pa in vacuo. Thus, the PEG-supported piperazine(4) was obtained as a yellow powder, yield 95%. 1H NMR(300 MHz, CDCl3), δ: 7.37(m, 4H, ArH), 4.61(s, 2H, ―CH2Cl), 4.58(s, 2H, ―OCH2―), 3.35―3.90(m, PEG). 2.4 General Procedure for Knoevevnagel Condensation of Malonic Acid Diethyl Ester with Aromatic Aldehydes PEG-supported piperazine(4, 1 g, 0.5 mmol) was added into the solution of acetic acid(0.1 mmol) in 15

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mL of DCM and the obtained mixture was stirred for 5 min. After the mixture was stirred for 5 min, PEG-supported piperazine acetate was obtained. Then, malonic acid diethyl ester(4 mmol) and aromatic aldehyde(4 mmol) were added to PEG-supported piperazine acetate(1 g, 0.05 mmol) in 5 mL of dichloromethane. The obtained mixture was stirred for 2 h at 30 °C. The polymer was precipitated by the addition of 30 mL of diethyl ether, and the suspension was left at 0 °C for another 30 min. After that, the polymer was filtered; the removal of Et2O gave the products 7. Analytical samples were prepared by column chromatography on silica gel[V(EtOAc):V(hexane)= 1:7]. 2-Benzylidenemalonic acid diethyl ester(7a)[37], 1 H NMR(CDCl 3 , 300 MHz), δ: 1.32(m, 6H, ―CH2CH3), 4.33(m, 4H, ―CH2CH3), 7.43(m, 5H, ArH), 7.75(s, 1H, C=CH―). IR(KBr), ߥ෤/cm−1: 1730, 1631, 1379. MS(ESI), m/z: 271.3(M+Na+). 2-(4-Methylbenzylidene)malonic acid diethyl ester(7b)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.25(m, 6H, ―CH2CH3), 2.30(s, 3H, ―CH3), 4.29(m, 4H, ―CH2CH3), 7.13(d, J=6.0 Hz, 2H, ArH), 7.32(d, J= 6.0 Hz, 2H, ArH), 7.66(s, 1H, C=CH―). IR(KBr), ߥ෤ /cm−1: 1730, 1629, 1378. MS(ESI), m/z: 285.1 (M+Na+). 2-(4-Methoxybenzylidene)malonic acid diethyl ester(7c)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.32(m, 6H, ―CH2CH3), 3.83(s, 3H, ―OCH3), 4.32(m, 4H, ―CH2CH3), 6.90(d, J=6.5 Hz, 2H, ArH), 7.42(d, J=6.5 Hz, 2H, ArH), 7.68(s, 1H, C=CH―). IR(KBr), ߥ෤ /cm−1: 1729, 1625, 1377. MS(ESI), m/z: 301.3 (M+Na+). 2-(2-Methoxybenzylidene)malonic acid diethyl ester(7d)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.23(t, J=2.5 Hz, 3H, ―CH2CH3), 1.32(t, J=2.8 Hz, 3H, ―CH2CH3), 3.83(s, 3H, ―OCH3), 4.28(m, 4H, ―CH2CH3), 6.90(t, J=7.2 Hz, 2H, ArH), 7.37(m, 2H, ArH), 8.09(s, 1H, C=CH―). IR(KBr), ߥ෤/cm−1: 1730, 1626, 1377. MS(ESI), m/z: 301.3(M+Na+). 2-(3,4-Methylenedioxybenzylidene)malonic acid diethyl ester(7e), 1H NMR(CDCl3, 300 MHz), δ: 1.32(m, 6H, ―CH2CH3), 4.30(m, 4H, ―CH2CH3), 6.00(s, 2H, ―OCH2O―), 6.80(d, J=6.8 Hz, 1H, ArH), 6.99(t, J=7.3 Hz, 2H, ArH) 7.61(s, 1H C=CH―). IR(KBr), ߥ෤/cm−1: 1728, 1630, 1368. MS(ESI), m/z: 315.2(M+Na+). Elemental Anal.(%): C 61.64, H 5.52, O 32.84.

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2-(4-Bromobenzylidene)malonic acid diethyl ester(7f)[13], 1H NMR(CDCl3, 300 MHz), δ: 1.31(m, 6H, ―CH2CH3), 4.30(m, 4H, ―CH2CH3), 7.33(d, J=8.0 Hz, 2H, ArH), 7.50(d, J=7.9 Hz, 2H, ArH), 7.65(s, 1H, C=CH―). IR(KBr), ߥ෤/cm−1: 1729, 1620, 1375. MS(ESI), m/z: 349.1; 351.1(M+Na+). 2-(4-Chlorobenzylidene)malonic acid diethyl ester(7g)[13], 1H NMR(CDCl3, 300 MHz), δ: 1.31(m, 6H, ―CH2CH3), 4.32(m, 4H, ―CH2CH3), 7.37(m, 4H, ArH), 7.68(s, 1H, C=CH―). IR(KBr), ߥ෤/cm−1: 1729, 1620, 1375. MS(ESI), m/z: 305.2(M+Na+). 2-(2,4-Dichlorobenzylidene)malonic acid diethyl ester(7h)[13], 1H NMR(CDCl3, 300 MHz), δ: 1.21(t, J=3.2 Hz, 3H, ―CH2CH3), 1.33(t, J=2.9 Hz, 3H, ―CH2CH3), 4.28(m, 4H, ―CH2CH3), 7.24(d, J= 6.3 Hz, 1H, ArH), 7.37(d, J=6.3 Hz, 1H, ArH), 7.44(s, 1H, ArH), 7.93(s, 1H, C=CH―). IR(KBr), ߥ෤/cm−1: 1732, 1636, 1378. MS(ESI), m/z: 339.0(M+Na+). 2-(4-Nitrobenzylidene)malonic acid diethyl ester(7i)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.32(m, 6H, ―CH2CH3), 4.33(m, 4H, ―CH2CH3), 7.63(d, J=7.6 Hz, 2H, ArH), 7.76(s, 1H, C=CH―), 8.23(d, J=7.9 Hz, 2H, ArH). IR(KBr), ߥ෤/cm−1: 1730, 1626, 1375. MS(ESI), m/z: 316.3(M+Na+). 2-(4-Formylbenzylidene)malonic acid diethyl ester(7j), 1H NMR(CDCl3, 300 MHz), δ: 1.27(m, 6H, ―CH2CH3), 4.29(m, 4H, ―CH2CH3), 7.59(d, J=5.9 Hz, 2H, ArH), 7.73(s, 1H, C=CH―), 7.85(d, J=6.4 Hz, 2H, ArH), 9.99(s, 1H, ―CHO). IR(KBr), ߥ෤ /cm−1: 1730, 1630, 1380. MS(ESI), m/z: 299.1 (M+Na+). Elemental Anal.(%) calcd.: C 65.21, H 5.84, O 28.95. 2-(3-Formylbenzylidene)malonic acid diethyl ester(7k), 1H NMR(CDCl3, 300 MHz), δ: 1.32(m, 6H, ―CH2CH3), 4.31(m, 4H, ―CH2CH3), 7.54(t, J=7.1 Hz, 1H, ArH), 7.68(d, J=8.0 Hz, 1H, ArH), 7.75(s, 1H, C=CH―), 7.87(d, J=7.5 Hz, 1H, ArH), 7.93(s, 1H, ArH), 9.99(s, 1H, ―CHO). IR(KBr), ߥ෤/cm−1: 2733, 1730, 1700, 1633, 1376. MS(ESI), m/z: 299.1(M+Na+). Elemental Anal.(%) calcd.: C 65.21, H 5.84, O 28.95. 2.5 General Procedure for Knoevevnagel Condensation of Acetlacetic Ether with Aromatic Aldehydes PEG-supported piperazine(4, 1 g, 0.5 mmol) was added to the solution of acetate(0.1 mmol) in 15 mL of DCM and the obtained mixture was stirred for 5 min.

265

After that, PEG-supported piperazine acetate was obtained. Then, acetylacetic ether(4 mmol) and aromatic aldehyde(4 mmol) were added to PEG-supported piperazine acetate(1 g, 0.05 mmol) in 5 mL of DCM. And the mixture was stirred for 2 h at 30 °C. The precipitation was completed by the addition of 30 mL of diethyl ether and the polymer was precipitated. And then the suspension was left at 0 °C for another 30 min. The polymer was filtered; the removal of Et2O gave the compounds 9. Analytical samples were prepared by column chromatography on silica gel [V(EtOAc):V(hexane)=1:7]. 2-Acetyl-3-phenylacrylic acid ethyl ester(9a)[38], 1 H NMR(CDCl 3 , 300 MHz), δ: 1.30(m, 3H, ―CH 2 CH 3 ), 2.35(s, 3H, ―CH 3 ), 4.31(m, 2H, ―CH2CH3), 7.49(m, 5H, ArH), 7.67(s, 1H, C=CH―). 2-Acetyl-3-(4-chlorophenyl) acrylic acid ethyl ester(9g)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.29(m, 3H, ―CH2CH3), 2.34(s, 3H, ―CH3), 4.30(m, 2H, ―CH2CH3), 7.37(m, 4H, ArH), 7.59(s, 1H, C=CH―). 2-Acetyl-3-(4-nitrophenyl) acrylic acid ethyl ester(9i)[38], 1H NMR(CDCl3, 300 MHz), δ: 1.35(t, J= 1.9 Hz, 3H, ―CH2CH3), 2.17(s, 3H, ―CH3), 4.33(q, J=2.3 Hz, 2H, ―CH2CH3), 7.56(d, J=5.9 Hz, 2H, ArH), 7.68(s, 1H, C=CH―), 8.22(d, J=6.8 Hz, 2H, ArH).

3

Results and Discussion

We chose to synthesize the PEG-supported piperazine on the soluble polymer support poly(ethylene glycol)(PEG) with an average molecular weight of 4000. This inexpensive polymer is attractive as a support since it is soluble in many organic solvents, with the notable exception of ethers and hexane, and especially is a solid at room temperature. Not only does solubility allow for solution reactivity but also intermediate products can easily be adequately characterized by 1H NMR. As shown in Scheme 1, the treatment of dihydroxy-PEG 4000 with NaH in THF in the presence of NaI followed by the addition of 1,4-bis(chloromethyl) benzene could afford the polymeric benzyl chloride 3 in a nearly quantitatively yield. The polymeric benzyl chloride was converted to PEG-supported piperazine 4 by adding excess piperazine in the presence of K2CO3 in CH2Cl2.

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Syntheses of 2-arylidene malonic acid diethyl esters catalyzed by PEG-piperazine

Entry(Aldehyde)

Yield*(%)

Product (7a)

(5a)

89

(5b) (5c)

Synthesis routes of poly(ethylene glycol)-supported piperazine

We next examined the application of this catalyst in the Knoevenagel condensation(Scheme 2). We chose diethyl malonate to react with various aromatic aldehydes, bearing a variety of functional groups such as electron donating groups(methoxy, chloro and methyl) and electron withdrawing groups(nitro). It could be found that the electron-rich and electron-deficient aldehydes were all converted into the Knoevenagel condensation products in quite good yields. The results are summarized in Table 1. And the structures of the products were further established by the X-ray diffraction analysis of compound 7i(Fig.1): space group P21/c, a=0.81651(9) nm, b=0.71553(8) nm, c=2.4815(3) nm, α= 90.00°, β= 99.017(2)°, γ= 90.00°, V=1.4319(3) nm3, T=293(2) K, Z=4. Crystallographic data has been deposited with the Cambridge Crystallographic Data Centre[CCDC 623497] for compound 7i. Copies of the data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.

Scheme 2

91

(7c)

91 90

(7d)

(5d)

Scheme 1

(7b)

(5e)

(7e)

87

(5f)

(7f)

96

(5g)

(7g)

93

(5h)

(7h)

94

(5i)

(7i) (7j)

(5j)

90 64 (7j′) 19

(5k)

(7k)

(7k′)

69

16

* Isolated yield.

In order to further investigate the PEG-supported piperazine catalyzed Knoevenagel condensation between various active methylene compounds and aldehydes, we next chose ethyl acetoacetate to react with three aromatic aldehydes(Scheme 3), and it was found that the yields were also high with the results summarized in Table 2.

Knoevenagel condensation of diethyl malonate with aldehydes catalyzed by PEG-piperazine Scheme 3

Fig.1

Structure of compound 7i

Knoevenagel condensation of ethyl acetoacetate with aldehydes catalyzed by PEG-piperazine

Another important issue concerning the use of PEG-supported piperazine is its reusability and stability in Knoevenagel condensation. To gain insight into this issue, we performed four consecutive uses of the PEG-supported piperazine after filtration and washing with diethyl ether. The results are shown in Table 3. And it was found that PEG-supported piperazine

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WANG Cui-e et al.

catalyst could be repeatedly used at least four times without the too much loss of activity. Table 2

Syntheses of 2-acetyl-3-arylacrylic acid ethyl esters catalyzed by PEG-piperazine

Entry(Aldehyde)

Yield*(%)

Product

(5a)

(9a)

89

267

[6]

Leelavathi P., Kumar S. R., J. Mol. Catal. A: Chem., 2005, 240, 99

[7]

Knoevenagel E., Berichte, 1898, 31, 2585

[8]

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(5g)

(9g)

(5i)

(9i)

88

85

* Isolated yield.

Table 3

Reuse of PEG-supported catalyst*

Inokuchi T., Kawafuchi H., J. Org. Chem., 2006, 71, 947

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Yield(%)

Mass of recycled catalyst/g

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1 2

90 85

1.9 1.8

[20]

Chen S., Janda K. D., J. Am. Chem. Soc., 1997, 119, 8724

[21]

Lopez-Pelegrin J. A., Janda K. D., Chem. Eup. J., 2000, 6, 1917

3

80

1.7

[22]

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4 78 * Reaction was shown in Scheme 2.

4

[12]

1.6

Conclusions

In conclusion, we have developed a soluble polymer-supported piperazine for the efficient Knoevenagel condensation in which the polymeric catalyst can be recovered and reused. It is environmentally friendly since the polymer can be recycled and it is amenable to use in medicinal chemistry parallel synthesis procedures where small quantities of highly pure products are desired with minimal purification necessary.

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