# Synthesis and Biological Evaluation of Novelγ-Alkylidene Butenolides

Authors: Gai-Zhi Liu; Yan-Bin Guan; Ya Wu; Hong-Min Liu
Journal: Journal of Chemistry
 (2013)

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## Abstract

Three new series of 4-substituted-5-alkylidene-2,5-dihydrofuran-2-ones were synthesized. The in vitro activity test results showed that some of them exhibited good antibacterial and cytotoxic activities. Among them compound5c showed the most potent antibacterial activity against Escherichia coli with the MIC value of 20.00 μg/mL. Compound 9c showed good cytotoxic activity against Ec9706 cells with IC50 value of 19.39 μM, better than that of the reference compound fluorouracil (IC50=37.74 μM).


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## Body

## 1. Introduction

The biological importance of unsaturated lactones is well known [1–8]. In particular, γ-alkylidene butenolide is an important class of organic compounds that is present in many synthetic bioactive molecules and natural products, such as rubrolides (a) [9, 10], nostoclides (b) [11–13], and uncinine (1) [14, 15] (Figure 1). Most of them exhibit various interesting biological activities, such as antibacterial, anticancer, antibiotic, and phospholipase A2 inhibition activity [16–26]. Over the past few decades, many researchers have been engaged in the synthesis of γ-alkylidene butenolides and their analogues due to their promising biological activities.Figure 1
Representative examples ofγ-alkylidene butenolides.In the previous literatures [27, 28], pulvinones (2) were synthesized and evaluated as inhibitors of early stage cell wall biosynthesis enzymes MurA-MurD. Several pulvinones inhibited Mur enzymes with IC50s  in the 1–10 μM range and demonstrated antibacterial activity against Gram-positive bacteria including methicillin-resistant Staphyloccucos aureus, vancomycin-resistant Enterococcus faecalis, and penicillin-resistant Streptococcus pneumoniae. A series of α,β-unsaturated-γ-lactone-free nitrogen-containing heterocyclic analogues of solamin, a natural mono-THF acetogenin, have been synthesized, and their cytotoxicity was investigated against 39 tumor cell lines. One of them, 1-methyl -pyrazol-5-yl derivative, showed selective increase of cytotoxicity against NCI-H23 with 80 times higher potency than solamin [29–37]. The synthesis and bioactivity of the α,β-unsaturated-γ-alkylidene butenolides containing nitrogen atom or nitrogen heterocyclic unit were reported few times [14, 15].


## 2. Results and Discussion

Based on the previous researches and our previous work on the synthesis and bioactivity ofγ-alkylidene buteno-lides [38–41], series of new α,β-unsaturated-γ-lactones bearing a nitrogen-containing unit such as piperazine and piperidine are designed and synthesized in the present work. The antibacterial and cytotoxic activities of the synthetic compounds were also evaluated.The synthesis of compound3 was reported in early studies [42–44]. The butenolide intermediates 4, 6, and 8 were prepared via introducing nitrogen-containing moiety such as piperazine or piperidine to the C-4 position of the lactone 3 in good yields (Scheme 1). In this reaction, secondary amines were logical choice as nucleophiles because of the base-sensitive nature of the butenolide 3. In addition, lower alkalinity catalysts such as Na2CO3 were used in the nucleophilic substitution reaction. The corresponding amines piperidine, methyl benzylamine, and benzoyl piperazine are all secondary amines, so the catalyst must be relatively weak alkaline in order to avoid the occurrence of adverse reaction. Compounds 4, 6, and 8 were reacted with various aromatic aldehydes to produce a series of novel γ-alkylidene butenolides 5, 7, and 9 except for compound 5d (compound 4 was reacted with acetone to produce 5d). The structures of compounds 5, 7, and 9, including the stereochemistry of the exocyclic carbon-carbon double bond, were established by 1D and 2D NMR spectroscopy. In the NMR spectrum of 5c and 9c (Figure 2), single peaks at δH 6.41 and δH 6.40, respectively, could be observed, suggesting the products were single isomers. In order to determine the geometry at the double bonds (Δ5,11) of 5c and 9c (Figure 2), NOESY experiment was investigated. The correlation between H-11 at δH 6.41 of 5c and H-6 proved that the geometry of the double bond (Δ5,11) in the structure of 5c is Z configuration. The stereochemistry of 9c was similar to that of 5c. Similarly, most of the other synthetic compounds were confirmed to be single isomers, in which the geometry of the double bond (Δ5,11) is Z configuration.Scheme 1
Reagents and conditions: (i) 1.2 eq. piperidine, CH3CN, Na2CO3, r.t. 3 h, 85%; (ii) 1.2 eq. aldehyde, Na2CO3, CH3OH, r.t. 3–12 h; (iii) 1.2 eq. methyl benzylamine, CH3CN, Na2CO3, 60°C, 3 h, 90%; (iv) 1.1 eq. benzoyl piperazine, CH3CN, Na2CO3, r.t.  2 h, 95%.Figure 2
The NOE spectra of compounds5c and 9c.The antibacterial activity1  in vitro of compounds 5, 7, and 9 was evaluated against Escherichia coli and Staphylococcus aureus as described in Table 1. Among them is compound 5c with potent antibacterial activity against Escherichia coli (MIC = 20 μg/mL), which was better than antibacterial drug chloramphenicol (MIC90 = 110 μg/mL). The results indicated that the introduction of the nitrogen heterocyclic and γ-alkylidene to the lactone was favorable for the antibacterial activity in some cases.Table 1
MICa,b of butenolide derivatives against Escherichia coli and Staphylococcus aureus.
Com
ECc
SAd
Com
ECc
SAd
3
120.13
101.46
7b
82.58
82.58
4
90.83
90.83
7c
Nde
Nd
5a
79.30
93.59
7d
Nd
Nd
5b
>200
>200
8
93.59
93.59
5c
20.00
99.10
9a
132.58
132.58
5d
82.58
100.56
9b
93.59
93.59
5e
82.58
82.58
9c
90.83
110.62
5f
93.59
93.59
9d
90.83
90.83
6
Nde
Nd
9e
82.58
82.58
7a
82.58
>200
Chloramphenicol
64
110f
aMIC (µg/mL): minimum inhibitory concentration.
bDefined as 100% inhibition of the growth of control. cEscherichia coli; dStaphylococcus aureus. eNo detection. fMIC90 (µg/mL).The cytotoxic activity2  in vitro of synthetic γ-alkylidene butenolides was also investigated against Ec9706 cells, Hela cells, SPCA1 cells, and HepG-2 cells. In cytotoxic activity test, first, each compound was tested at 100 μM concentration if the compounds show no inhibitory activity for each selected cell, their IC50 values would not be tested. The results were described in Table 2. Some of them showed good cytotoxic activity. Among them compound 9c showed excellent cytotoxic activity against Ec9706 cells with IC50 value of 19.39 μM, which was better than that of the standard drug Fluorouracil (IC50=37.74μM). Meanwhile, it exhibited good cytotoxic activity against HepG-2 and SPCA1 with IC50 values of 49.96 μM and 50.15 μM, respectively. The results indicated that the introduction of the nitrogen heterocyclic and γ-alkylidene to the lactone was efficient for the cytotoxic activity in some case.Table 2
aIC50 values of butenolides against Ec9706 cells, Hela cells, SPCA1 cells and HepG-2 cells.
Com
Ec9706
HepG-2
SPCA1
Hela
Com
Ec9706
HepG-2
SPCA1
Hela
3
89.45
97.38
100.02
92.87
7b
81.34
NI
NI
113
4
78.23
80.16
108
70.36
7c
NIb
116
NI
84.28
5a
50.69
56.87
NI
NI
7d
104
178
89.19
Ndc
5b
100
88.64
200
90.16
8
NIb
102
116
128
5c
76.34
66.58
80.25
56.37
9a
77.59
67.51
102
86.31
5d
NI
NI
NI
Nd
9b
131
59.13
106
156
5e
96.12
132
101
87.69
9c
19.39
49.96
50.15
80.04
5f
55.87
86.92
NI
77.42
9d
Nd
200
Nd
Nd
6
98.39
123
147
NI
9e
151
125
143
74.13
7a
69.36
86.29
73.56
99.13
5-Fu
d
37.74
18.26
32.50
25.39
aIC50 (µM): the concentration of substance that provides 50% inhibition.
bNo inhibition at 100 μM. cNo detection. dFluorouracil.


## 3. Experimental

### 3.1. Chemistry

All reagents and solvents were obtained from commercial suppliers. All the reactions were monitored by TLC. Melting points were determined on a Beijing Keyi XT5 apparatus, and the temperature was not corrected. IR spectra were recorded as KBr pellets on a Thermo Nicolet (IR200) Spectrometer.1H and 13C NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400 and 100 MHz with TMS as internal standard. Mass spectra were taken by Waters Q-Tof micromass spectrometer.


#### 3.1.1. 4-(Piperidin-1-ylmethyl)furan-2(5H)-one (4)

To an CH3CN (50 mL) solvent of compound 3 (0.1 mol) and anhydrous sodium carbonate (0.06 mol) 1.2 eq. piperidine (0.12 mol) was added. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC until completion, the solid salt was filtered, and the filtrate was evaporated under reduced pressure to steam out of most of the acetonitrile, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 3 : 1) which afforded 15.4 g compound 4. Yield: 85%, yellow oil. IR (KBr, cm−1): 1762, 1630, 1489, 1462, 1438, 1284, 1247, 1024, 994, and 758. 1H NMR (400 MHz, CDCl3, ppm) δ: 5.98 (s, 1H, =CH), 4.82 (s, 2H), 3.31 (s, 2H), 2.38 (s, 4H), and 1.61–1.26 (m, overlap, 6H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.8 (C2), 168.4, 117.1, 72.7, 56.7, 55.0, 25.8, and 23.9. HR-MS (ESI), calcd. C10H15NO2: [M+H]+  m/z: 182.1181; found: 182.1160 (see Supplementary Material available online at http://dx.doi.org/10.1155/2013/926723).


#### 3.1.2. General Procedure for the Preparation of (5a–f)

Compound4 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in MeOH (50 mL) solvent, then the respective aromatic aldehyde (acetone for compound 5d) (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. the reaction mixture was washed with water and ethyl acetate, dried, and purified by column chromatography.(Z)-5-(Furan-2-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5a). Yield: 60%, brown oil. IR (KBr, cm−1): 2923, 2848, 1627, 1446, and 1382. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.50 (d, J = 1.38 Hz, 1H, Ar), 7.05 (d, J = 3.39 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.53 (s, 1H, =CH), 6.09 (s, 1H, =CH), 3.42 (s, 2H), 2.43 (s, 4H), 1.63 (m, 4H), and 1.47 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 168.9 (C2), 156.4, 149.0, 146.1, 143.9, 116.0, 115.3, 113.0(C11), 100.2, 54.9, 25.9, and 24.0. HR-MS (ESI), calcd. C15H17NO3: [M+H]+  m/z: 260.1287; found: 260.1243.(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5b). Yield: 65%, yellow oil. IR (KBr, cm−1): 2924, 1623, 1516, 1382, and 1124. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.53 (d, J = 1.76 Hz, 1H, Ph), 7.18 (dd, J = 1.80 Hz, 8.24 Hz, 1H, Ph), 6.93 (d, J = 8.24 Hz, 1H, Ph), 6.34 (s, 1H, =CH), 6.08 (s, 1H, =CH), 3.96 (s, 3H, OCH3), 3.46 (s, 2H), 2.46 (s, 4H), 1.63 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.6 (C2), 157.2, 147.1, 146.8, 146.5, 127.5, 125.7, 115.0, 114.6, 111.5, 111.7 (C11), 56.1, 54.9, 54.8 (OCH3), 25.9, and 24.0. HR-MS (ESI), calcd. C18H21NO4: [M+H]+  m/z: 316.1549; found: 316.1537.(Z)-5-(4-Hydroxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5c). Yield: 85%, sallow crystal mp: 178.3–179.5°C. IR (KBr, cm−1): 3347, 3103, 2935, 2800, 2758, 1749, 1605, 1588, 1515, 1445, 1278, 1227, 1172, 944, 840. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.73 (d, J = 8.72 Hz, 2H, Ph), 6.96 (d, J = 8.56 Hz, 2H, Ph), 6.41 (s, 1H, =CH), 6.10 (s, 1H, =CH), 3.46 (s, 2H), 2.46 (s, 4H), 1.65 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 157.7 (C2), 146.4, 132.8, 125.5, 116.1, 114.8, 112.0, 55.0, 25.9, and 24.0. HR-MS (ESI), calcd. C17H19NO3: [M+H]+  m/z: 286.1443; found: 286.1459.4-(Piperidin-1-ylmethyl)-5-(propan-2-ylidene)furan-2(5H)-one   (5d). Yield: 50%, brown oil. IR (KBr, cm−1): 2938, 2856, 1744, 1624, 1588, 1447, 1129, 1032, 947, 909, and 876. 1H NMR (400 MHz, CDCl3, ppm) δ: 6.07 (s, 1H, =CH), 3.37 (d, J = 1.13 Hz, 2H), 2.42 (s, 4H), 2.04, 2.03 (s, 6H, =(CH3)2), 1.61 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.2 (C1), 155.9 (C3), 145.2 (C4), 124.2 (C11), 118.1 (C2), 57.3, 54.9, 26.0, 24.1, 21.0, and 19.1. HR-MS (ESI), calcd. C13H19NO2: [M+H]+  m/z: 222.1494; found: 222.1468.(Z)-5-(2-Methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5e). Yield: 46%, pink oil. IR (KBr, cm−1): 2932, 1740, 1638, 1596, 1491, 1461, 1239, 1023, 982, and 754. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.29–6.80 (overlap, m, 4H, Ph), 6.23 (s, 1H, =C(11)H), 5.89 (s, 1H, =C(2)H), 3.86 (s, 3H, OCH3), 3.73 (m, 2H), 2.53 (br, 4H), 1.72 (m, 4H), and 1.51 (m, 2H). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 171.7, 166.2, 157.2, 129.2, 128.5, 127.4, 121.8, 120.8, 111.0, 87.6, 68.7, 56.6, 55.6, 54.6, 25.4, and 23.6. HR-MS (ESI), calcd. C18H21NO3: [M+H]+  m/z: 300.1600; found: 300.1598.(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5f). Yield: 55%, pink oil. IR (KBr, cm−1): 2929, 2854, 1761, 1623, 1489, 1447, 1005, and 470. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.48 (s, 1H, Ph), 7.18 (d, J = 7.68 Hz, 1H, Ph), 6.83 (d, J = 8.13 Hz, 1H, Ph), 6.34 (s, 1H, =C(11)H), 6.08 (s, 1H, =C(2)H), 6.01 (s, 2H, OCH2O), 3.49 (d, J= 19.46 Hz, 2H), 2.44 (s, 4H), 1.62 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.5 (C1), 157.4 (C3), 148.4 (C4), 148.2 (Ph), 146.6 (Ph), 127.2 (Ph), 126.1 (Ph), 115.0 (Ph), 111.3 (Ph), 110.1 (OCH2O), 108.4 (C2), 101.4 (C11), 54.9, 25.9, 24.0. HR-MS (ESI), calcd. C18H19NO4: [M+H]+  m/z: 314.1392; found: 314.1362.


#### 3.1.3. 4-((Benzyl(methyl)amino)methyl)furan-2(5H)-one (6)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.2 eq methyl benzylamine (0.12 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 3 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 4 : 1) which afforded 19.5 g compound 6. Yellow oil. Yield: 90%. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.31 (m, 5H, Ph), 6.01 (s, 1H, =C(2)H), 4.81 (s, 2H, C(4)H2), 3.54 (s, 2H, C(7)H2), 3.34 (s, 2H, C(7)H2), 2.25 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.7 (C1), 168.5 (C3), 138.0 (Ph), 128.6 (Ph), 127.4 (Ph), 117.0 (C2), 72.4 (C4), 62.2 (C5), 54.5 (C6), 42.8 (NCH3). HR-MS (ESI), calcd. C13H15NO2: [M+H]+  m/z: 218.1181; found: 218.1149.


#### 3.1.4. General Procedure for the Preparation of (7a–d)

Compound5 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in methanol solvent, and then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. The reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (7a).Yield: 44%, thick brown oil. IR (KBr, cm−1): 1755, 1645, 1607, 1470, 1145, 994, 745. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51 (d, J = 1.96 Hz, 1H, Ar), 7.32–7.26 (m, 5H, Ph), 7.07 (d, J = 3.60 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.27 (s, 1H, =C(8)H), 5.74 (s, 1H, =C(2)H), 3.77 (d, J = 14.08 Hz, 1H), 3.37 (d, J = 14.08 Hz, 1H), 3.66–3.45 (m, 2H), and 2.21 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3,   ppm) δ: 167.6 (C2), 154.2 (C4), 149.0 (C5), 145.5 (Ph), 135.6, 129.7, 128.7, 128.0 (Ph), 115.8, 113.3, 110.4, 99.8, 62.7, 51.1, and 41.8 (NCH3). HR-MS (ESI), calcd. C18H17NO3: [M+H]+  m/z: 296.1287; found: 296.1277.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(4-(dimethylamino) benzylidene)furan-2(5H)-one   (7b). Yield: 70%, thick brown. oil. IR (KBr, cm−1): 2917, 2848, 2801, 1744, 1604, 1526, 1444, 1367, 1168, 930, and 818. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.69 (d, J = 8.96 Hz, 2H, Ph), 7.36–7.26 (m, 5H, Ph), 6.69 (d, J = 8.96 Hz, 2H, Ph), 6.22 (s, 1H, =C(8)H), 6.05 (s, 1H, =C(2)H), 3.58 (s, 2H), 3.08 (s, 2H), 3.03 (s, 6H, N(CH3)2), and 2.12 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ:   170.2 (C1), 157.2 (C3), 150.8 (C4), 145.1, 138.4, 132.6, 129.0, 128.5, 127.4, 120.9, 113.6, 112.7, 112.0, 111.0, 62.4 (C5), 52.8 (C6), 42.9 (NCH3), and 40.1 (N(CH3)2). HR-MS (ESI), calcd. C22H24N2O2: [M+H]+  m/z: 349.1916; found: 349.1934.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (7c). Yield: 65%, light yellow oil. IR (KBr, cm−1): 2926, 1767, 1642, 1599, 1491, 1460, 1247, 1025, 929, 764. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.41–7.26 (m, 9H, Ph), 7.01 (s, 1H, =C(8)H), 6.19 (s, 1H, =C(2)H), 3.91 (s, 3H, OCH3), 3.54 (s, 2H), 3.37 (s, 2H), 2.28 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.1 (C3), 157.6, 147.7, 138.4, 131.9, 130.6, 128.8, 128.7, 128.5, 128.4, 127.4, 121.8, 121.1, 115.6, 110.5 (C2), 105.3 (C8), 62.6 (C5), 55.66 (C6), 53.2 (OCH3), 42.7 (NCH3). HR-MS (ESI), calcd. C21H21NO3: [M+H]+  m/z: 336.1600; found: 336.1598.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(3,4,5-trimethoxybenzylidene)furan-2(5H)-one   (7d). Yield: 58%, light yellow oil. IR (KBr, cm−1): 2939, 2841, 1753, 1585, 1504, 1457, 1422, 1331, 1235, 1126, 1001. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.37 (m, 4H, Ph), 7.14 (s, 1H, Ph), 7.01 (s, 2H, Ph), 6.18 (s, 1H, =C(8)H), 6.17 (s, 1H, =C(2)H), 3.89 (s, 6H, OCH3), 3.88 (s, 3H, OCH3), 3.61 (s, 2H), 3.49 (s, 2H), 2.33 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.2, 157.6, 147.7, 138.5, 131.9, 131.6, 130.6, 130.5, 128.8. 128.4, 127.4, 121.8, 121.2, 115.6, 115.0, 110.4, 105.3, 103.8, 62.6, 55.6, 53.2, 42.7, and 29.7. HR-MS (ESI), calcd. C23H25NO5: [M+H]+  m/z: 396.1811; found: 396.1807.


#### 3.1.5. 4-((4-Benzoylpiperazin-1-yl)methyl)furan-2(5H)-one (8)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.1 eq. benzoyl piperazine12 (0.11 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by ethyl acetate crystallize to afforded 27.2 g compound 8. White crystal. Yield: 95%, mp: 112.5–113.0°C. IR (KBr, cm−1): 2820, 1787, 1742, 1624, 1434, 1275, 1143, 1025, 894, 868, 709. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.43 (m, 5H, Ph), 6.02 (d, J = 1.42 Hz, 1H, =C(2)H), 4.82 (d, J = 1.54 Hz, 2H), 3.80–3.46 (br, 4H), 3.40 (s, 2H), 2.56–2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.4 (C1), 170.4, 166.6 (C3), 135.4, 129.9, 128.7, 127.0 (Ph), 117.9 (C2), 72.4 (C4), 55.7 (C5), 53.7, 53.7, 47.5, 41.9. HR-MS (ESI), calcd. C16H18N2O3: [M+H]+  m/z: 287.1396; found: 287.1392.


#### 3.1.6. General Procedure for the Preparation of (9a–f)

Compound8 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) was dissolved in methanol solvent, then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC to complete. The reaction solution was vaporated under reduced pressure to steam out of most of the methanol solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (9a). Yield: 82%, brown-red oil. IR (KBr, cm−1): 1757, 1629, 1466, 1435, 1282, 997, and 742. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51–7.07 (m, overlap, 6H, Ar), 6.34 (m, 2H, Ar), 6.31 (s, 1H, =C(11)H), 5.73 (s, 1H, =C(2)H), 3.88–3.51 (br, 4H), 3.50 (d, J = 14.28 Hz, 2H), 2.75–2.56 (br, 4H); 13CNMR (100.6 MHz, CDCl3, ppm) δ:  170.4 (C1), 167.4, 153.9 (C3), 148.8 (C4), 147.2, 135.1, 130.0, 128.6, 127.0, 116.0, 113.3, 110.6, 107.4 (C11), 100.0 (C2), 62.9 (C5), 51.7, 47.6, and 42.1. HR-MS (ESI), calcd. C21H20N2O4: [M+H]+  m/z: 365.1501; found: 365.1497.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxy-3-methoxybenzylidene)furan-2(5H)-one   (9b). Yield: 88%, brown solid mp: 79.0–80.6°C. IR (KBr, cm−1): 2921, 2852, 1752, 1630, 1580, 1515, 1431, 1284, 1163, 1131, and 1026. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.40 (s, 1H, Ph), 7.36 (m, 5H, Ph), 7.15 (m, 1H), 6.86 (d, J = 8.24 Hz, 1H, Ph), 6.23 (s, 1H, =C(11)H), 6.05 (s, 1H, =C(2)H), 3.85 (s, 3H, OCH3), 3.80, 3.44 (br, 4H), 3.48 (s, 2H), 2.58, 2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.5 (C1), 169.5 (C10), 156.1 (C3), 147.5, 147.1, 145.9, 135.3, 129.9, 128.5, 127.0, 125.6, 125.1, 115.0, 112.7 (C2), 112.1 (C11), 56.0 (C5), 53.7 (OCH3), 53.5, 53.1, 47.6, and 42.1. HR-MS (ESI), calcd. C24H24N2O5: [M+H]+  m/z: 421.1763; found: 421.1735.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxybenzylidene)furan-2(5H)-one   (9c). Yield: 89%, yellow crystals, mp: 239.1–240.0°C. IR (KBr, cm−1): 3447, 1762, 1604, 1513, 1446, 1279, 1021, and 998. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.72 (d, J = 8.72 Hz, 2H, Ph), 6.92 (d, J = 6.92 Hz, 2H, Ph), 7.42 (m, 5H, Ph), 6.40 (s, 1H, =C(11)H), 6.11 (s, 1H, =C(3)H), 3.85–3.46 (br, 4H), 3.85 (s, 2H), and 2.66–2.49 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 169.4, 156.1, 145.9, 129.9, 128.6, 127.1, 124.8, 116.1, 115.0, 56.0, 53.5, 47.6. HR-MS (ESI), calcd. C23H22N2O4: [M+H]+  m/z: 391.1658; found: 391.1627.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-benzylidenefuran-2(5H)-one    (9d). Yield: 78%, light yellow solid, mp: 65.2–66.4°C. IR (KBr, cm−1): 1758, 1627, 1434, 1280, 994, 697. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.80 (d, J = 7.38 Hz, 2H, Ph), 7.44–7.21 (m, 8H, Ph), 6.21 (s, 1H, =C(11)H), 5.86 (s, 1H, =C(2)H), 3.76–3.43 (br, 4H), 3.39 (d, J = 10.70 Hz, 2H), and 2.72–2.53 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4 (C1), 168.6, 147.6, 147.4, 141.9, 135.0, 132.5, 132.5, 130.8, 130.1, 129.6, 128.9, 128.6, 128.6, 128.4, 128.4, 127.7, 127.0, 125.8, 125.4, 111.1 (C11), 67.6 (C5), 53.2, 52.9, 47.0, 41.5. HR-MS (ESI), calcd. C23H22N2O3: [M+H]+  m/z: 375.1709; found: 375.1716.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (9e). Yield: 85%, light yellow solid, mp: 199.3–200.5°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.42–6.83 (m, 9H, Ph), 6.68 (s, 1H, =C(11)H), 5.93 (s, 1H, =C(2)H), 3.90, 3.55 (br, 4H, C(7,8,)H2), 3.74 (s, 3H, OCH3), 3.29 (m, 2H, C(5)H2), and 2.92–2.53 (br, 4H, C(6,9) H2). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 168.3, 157.4, 156.2, 147.4, 132.6, 131.6, 130.7, 128.9, 128.6, 128.5, 127.1, 127.0, 125.7, 121.1, 120.0, 110.6, 103.8, 63.6, 55.6, 55.3, and 50.7. HR-MS (ESI), calcd. C24H24N2O4: [M+H]+  m/z: 405.1814; found: 405.1846.


## 3.1. Chemistry

All reagents and solvents were obtained from commercial suppliers. All the reactions were monitored by TLC. Melting points were determined on a Beijing Keyi XT5 apparatus, and the temperature was not corrected. IR spectra were recorded as KBr pellets on a Thermo Nicolet (IR200) Spectrometer.1H and 13C NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400 and 100 MHz with TMS as internal standard. Mass spectra were taken by Waters Q-Tof micromass spectrometer.


### 3.1.1. 4-(Piperidin-1-ylmethyl)furan-2(5H)-one (4)

To an CH3CN (50 mL) solvent of compound 3 (0.1 mol) and anhydrous sodium carbonate (0.06 mol) 1.2 eq. piperidine (0.12 mol) was added. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC until completion, the solid salt was filtered, and the filtrate was evaporated under reduced pressure to steam out of most of the acetonitrile, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 3 : 1) which afforded 15.4 g compound 4. Yield: 85%, yellow oil. IR (KBr, cm−1): 1762, 1630, 1489, 1462, 1438, 1284, 1247, 1024, 994, and 758. 1H NMR (400 MHz, CDCl3, ppm) δ: 5.98 (s, 1H, =CH), 4.82 (s, 2H), 3.31 (s, 2H), 2.38 (s, 4H), and 1.61–1.26 (m, overlap, 6H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.8 (C2), 168.4, 117.1, 72.7, 56.7, 55.0, 25.8, and 23.9. HR-MS (ESI), calcd. C10H15NO2: [M+H]+  m/z: 182.1181; found: 182.1160 (see Supplementary Material available online at http://dx.doi.org/10.1155/2013/926723).


### 3.1.2. General Procedure for the Preparation of (5a–f)

Compound4 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in MeOH (50 mL) solvent, then the respective aromatic aldehyde (acetone for compound 5d) (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. the reaction mixture was washed with water and ethyl acetate, dried, and purified by column chromatography.(Z)-5-(Furan-2-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5a). Yield: 60%, brown oil. IR (KBr, cm−1): 2923, 2848, 1627, 1446, and 1382. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.50 (d, J = 1.38 Hz, 1H, Ar), 7.05 (d, J = 3.39 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.53 (s, 1H, =CH), 6.09 (s, 1H, =CH), 3.42 (s, 2H), 2.43 (s, 4H), 1.63 (m, 4H), and 1.47 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 168.9 (C2), 156.4, 149.0, 146.1, 143.9, 116.0, 115.3, 113.0(C11), 100.2, 54.9, 25.9, and 24.0. HR-MS (ESI), calcd. C15H17NO3: [M+H]+  m/z: 260.1287; found: 260.1243.(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5b). Yield: 65%, yellow oil. IR (KBr, cm−1): 2924, 1623, 1516, 1382, and 1124. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.53 (d, J = 1.76 Hz, 1H, Ph), 7.18 (dd, J = 1.80 Hz, 8.24 Hz, 1H, Ph), 6.93 (d, J = 8.24 Hz, 1H, Ph), 6.34 (s, 1H, =CH), 6.08 (s, 1H, =CH), 3.96 (s, 3H, OCH3), 3.46 (s, 2H), 2.46 (s, 4H), 1.63 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.6 (C2), 157.2, 147.1, 146.8, 146.5, 127.5, 125.7, 115.0, 114.6, 111.5, 111.7 (C11), 56.1, 54.9, 54.8 (OCH3), 25.9, and 24.0. HR-MS (ESI), calcd. C18H21NO4: [M+H]+  m/z: 316.1549; found: 316.1537.(Z)-5-(4-Hydroxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5c). Yield: 85%, sallow crystal mp: 178.3–179.5°C. IR (KBr, cm−1): 3347, 3103, 2935, 2800, 2758, 1749, 1605, 1588, 1515, 1445, 1278, 1227, 1172, 944, 840. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.73 (d, J = 8.72 Hz, 2H, Ph), 6.96 (d, J = 8.56 Hz, 2H, Ph), 6.41 (s, 1H, =CH), 6.10 (s, 1H, =CH), 3.46 (s, 2H), 2.46 (s, 4H), 1.65 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 157.7 (C2), 146.4, 132.8, 125.5, 116.1, 114.8, 112.0, 55.0, 25.9, and 24.0. HR-MS (ESI), calcd. C17H19NO3: [M+H]+  m/z: 286.1443; found: 286.1459.4-(Piperidin-1-ylmethyl)-5-(propan-2-ylidene)furan-2(5H)-one   (5d). Yield: 50%, brown oil. IR (KBr, cm−1): 2938, 2856, 1744, 1624, 1588, 1447, 1129, 1032, 947, 909, and 876. 1H NMR (400 MHz, CDCl3, ppm) δ: 6.07 (s, 1H, =CH), 3.37 (d, J = 1.13 Hz, 2H), 2.42 (s, 4H), 2.04, 2.03 (s, 6H, =(CH3)2), 1.61 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.2 (C1), 155.9 (C3), 145.2 (C4), 124.2 (C11), 118.1 (C2), 57.3, 54.9, 26.0, 24.1, 21.0, and 19.1. HR-MS (ESI), calcd. C13H19NO2: [M+H]+  m/z: 222.1494; found: 222.1468.(Z)-5-(2-Methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5e). Yield: 46%, pink oil. IR (KBr, cm−1): 2932, 1740, 1638, 1596, 1491, 1461, 1239, 1023, 982, and 754. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.29–6.80 (overlap, m, 4H, Ph), 6.23 (s, 1H, =C(11)H), 5.89 (s, 1H, =C(2)H), 3.86 (s, 3H, OCH3), 3.73 (m, 2H), 2.53 (br, 4H), 1.72 (m, 4H), and 1.51 (m, 2H). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 171.7, 166.2, 157.2, 129.2, 128.5, 127.4, 121.8, 120.8, 111.0, 87.6, 68.7, 56.6, 55.6, 54.6, 25.4, and 23.6. HR-MS (ESI), calcd. C18H21NO3: [M+H]+  m/z: 300.1600; found: 300.1598.(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5f). Yield: 55%, pink oil. IR (KBr, cm−1): 2929, 2854, 1761, 1623, 1489, 1447, 1005, and 470. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.48 (s, 1H, Ph), 7.18 (d, J = 7.68 Hz, 1H, Ph), 6.83 (d, J = 8.13 Hz, 1H, Ph), 6.34 (s, 1H, =C(11)H), 6.08 (s, 1H, =C(2)H), 6.01 (s, 2H, OCH2O), 3.49 (d, J= 19.46 Hz, 2H), 2.44 (s, 4H), 1.62 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.5 (C1), 157.4 (C3), 148.4 (C4), 148.2 (Ph), 146.6 (Ph), 127.2 (Ph), 126.1 (Ph), 115.0 (Ph), 111.3 (Ph), 110.1 (OCH2O), 108.4 (C2), 101.4 (C11), 54.9, 25.9, 24.0. HR-MS (ESI), calcd. C18H19NO4: [M+H]+  m/z: 314.1392; found: 314.1362.


### 3.1.3. 4-((Benzyl(methyl)amino)methyl)furan-2(5H)-one (6)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.2 eq methyl benzylamine (0.12 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 3 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 4 : 1) which afforded 19.5 g compound 6. Yellow oil. Yield: 90%. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.31 (m, 5H, Ph), 6.01 (s, 1H, =C(2)H), 4.81 (s, 2H, C(4)H2), 3.54 (s, 2H, C(7)H2), 3.34 (s, 2H, C(7)H2), 2.25 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.7 (C1), 168.5 (C3), 138.0 (Ph), 128.6 (Ph), 127.4 (Ph), 117.0 (C2), 72.4 (C4), 62.2 (C5), 54.5 (C6), 42.8 (NCH3). HR-MS (ESI), calcd. C13H15NO2: [M+H]+  m/z: 218.1181; found: 218.1149.


### 3.1.4. General Procedure for the Preparation of (7a–d)

Compound5 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in methanol solvent, and then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. The reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (7a).Yield: 44%, thick brown oil. IR (KBr, cm−1): 1755, 1645, 1607, 1470, 1145, 994, 745. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51 (d, J = 1.96 Hz, 1H, Ar), 7.32–7.26 (m, 5H, Ph), 7.07 (d, J = 3.60 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.27 (s, 1H, =C(8)H), 5.74 (s, 1H, =C(2)H), 3.77 (d, J = 14.08 Hz, 1H), 3.37 (d, J = 14.08 Hz, 1H), 3.66–3.45 (m, 2H), and 2.21 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3,   ppm) δ: 167.6 (C2), 154.2 (C4), 149.0 (C5), 145.5 (Ph), 135.6, 129.7, 128.7, 128.0 (Ph), 115.8, 113.3, 110.4, 99.8, 62.7, 51.1, and 41.8 (NCH3). HR-MS (ESI), calcd. C18H17NO3: [M+H]+  m/z: 296.1287; found: 296.1277.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(4-(dimethylamino) benzylidene)furan-2(5H)-one   (7b). Yield: 70%, thick brown. oil. IR (KBr, cm−1): 2917, 2848, 2801, 1744, 1604, 1526, 1444, 1367, 1168, 930, and 818. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.69 (d, J = 8.96 Hz, 2H, Ph), 7.36–7.26 (m, 5H, Ph), 6.69 (d, J = 8.96 Hz, 2H, Ph), 6.22 (s, 1H, =C(8)H), 6.05 (s, 1H, =C(2)H), 3.58 (s, 2H), 3.08 (s, 2H), 3.03 (s, 6H, N(CH3)2), and 2.12 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ:   170.2 (C1), 157.2 (C3), 150.8 (C4), 145.1, 138.4, 132.6, 129.0, 128.5, 127.4, 120.9, 113.6, 112.7, 112.0, 111.0, 62.4 (C5), 52.8 (C6), 42.9 (NCH3), and 40.1 (N(CH3)2). HR-MS (ESI), calcd. C22H24N2O2: [M+H]+  m/z: 349.1916; found: 349.1934.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (7c). Yield: 65%, light yellow oil. IR (KBr, cm−1): 2926, 1767, 1642, 1599, 1491, 1460, 1247, 1025, 929, 764. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.41–7.26 (m, 9H, Ph), 7.01 (s, 1H, =C(8)H), 6.19 (s, 1H, =C(2)H), 3.91 (s, 3H, OCH3), 3.54 (s, 2H), 3.37 (s, 2H), 2.28 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.1 (C3), 157.6, 147.7, 138.4, 131.9, 130.6, 128.8, 128.7, 128.5, 128.4, 127.4, 121.8, 121.1, 115.6, 110.5 (C2), 105.3 (C8), 62.6 (C5), 55.66 (C6), 53.2 (OCH3), 42.7 (NCH3). HR-MS (ESI), calcd. C21H21NO3: [M+H]+  m/z: 336.1600; found: 336.1598.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(3,4,5-trimethoxybenzylidene)furan-2(5H)-one   (7d). Yield: 58%, light yellow oil. IR (KBr, cm−1): 2939, 2841, 1753, 1585, 1504, 1457, 1422, 1331, 1235, 1126, 1001. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.37 (m, 4H, Ph), 7.14 (s, 1H, Ph), 7.01 (s, 2H, Ph), 6.18 (s, 1H, =C(8)H), 6.17 (s, 1H, =C(2)H), 3.89 (s, 6H, OCH3), 3.88 (s, 3H, OCH3), 3.61 (s, 2H), 3.49 (s, 2H), 2.33 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.2, 157.6, 147.7, 138.5, 131.9, 131.6, 130.6, 130.5, 128.8. 128.4, 127.4, 121.8, 121.2, 115.6, 115.0, 110.4, 105.3, 103.8, 62.6, 55.6, 53.2, 42.7, and 29.7. HR-MS (ESI), calcd. C23H25NO5: [M+H]+  m/z: 396.1811; found: 396.1807.


### 3.1.5. 4-((4-Benzoylpiperazin-1-yl)methyl)furan-2(5H)-one (8)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.1 eq. benzoyl piperazine12 (0.11 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by ethyl acetate crystallize to afforded 27.2 g compound 8. White crystal. Yield: 95%, mp: 112.5–113.0°C. IR (KBr, cm−1): 2820, 1787, 1742, 1624, 1434, 1275, 1143, 1025, 894, 868, 709. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.43 (m, 5H, Ph), 6.02 (d, J = 1.42 Hz, 1H, =C(2)H), 4.82 (d, J = 1.54 Hz, 2H), 3.80–3.46 (br, 4H), 3.40 (s, 2H), 2.56–2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.4 (C1), 170.4, 166.6 (C3), 135.4, 129.9, 128.7, 127.0 (Ph), 117.9 (C2), 72.4 (C4), 55.7 (C5), 53.7, 53.7, 47.5, 41.9. HR-MS (ESI), calcd. C16H18N2O3: [M+H]+  m/z: 287.1396; found: 287.1392.


### 3.1.6. General Procedure for the Preparation of (9a–f)

Compound8 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) was dissolved in methanol solvent, then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC to complete. The reaction solution was vaporated under reduced pressure to steam out of most of the methanol solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (9a). Yield: 82%, brown-red oil. IR (KBr, cm−1): 1757, 1629, 1466, 1435, 1282, 997, and 742. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51–7.07 (m, overlap, 6H, Ar), 6.34 (m, 2H, Ar), 6.31 (s, 1H, =C(11)H), 5.73 (s, 1H, =C(2)H), 3.88–3.51 (br, 4H), 3.50 (d, J = 14.28 Hz, 2H), 2.75–2.56 (br, 4H); 13CNMR (100.6 MHz, CDCl3, ppm) δ:  170.4 (C1), 167.4, 153.9 (C3), 148.8 (C4), 147.2, 135.1, 130.0, 128.6, 127.0, 116.0, 113.3, 110.6, 107.4 (C11), 100.0 (C2), 62.9 (C5), 51.7, 47.6, and 42.1. HR-MS (ESI), calcd. C21H20N2O4: [M+H]+  m/z: 365.1501; found: 365.1497.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxy-3-methoxybenzylidene)furan-2(5H)-one   (9b). Yield: 88%, brown solid mp: 79.0–80.6°C. IR (KBr, cm−1): 2921, 2852, 1752, 1630, 1580, 1515, 1431, 1284, 1163, 1131, and 1026. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.40 (s, 1H, Ph), 7.36 (m, 5H, Ph), 7.15 (m, 1H), 6.86 (d, J = 8.24 Hz, 1H, Ph), 6.23 (s, 1H, =C(11)H), 6.05 (s, 1H, =C(2)H), 3.85 (s, 3H, OCH3), 3.80, 3.44 (br, 4H), 3.48 (s, 2H), 2.58, 2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.5 (C1), 169.5 (C10), 156.1 (C3), 147.5, 147.1, 145.9, 135.3, 129.9, 128.5, 127.0, 125.6, 125.1, 115.0, 112.7 (C2), 112.1 (C11), 56.0 (C5), 53.7 (OCH3), 53.5, 53.1, 47.6, and 42.1. HR-MS (ESI), calcd. C24H24N2O5: [M+H]+  m/z: 421.1763; found: 421.1735.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxybenzylidene)furan-2(5H)-one   (9c). Yield: 89%, yellow crystals, mp: 239.1–240.0°C. IR (KBr, cm−1): 3447, 1762, 1604, 1513, 1446, 1279, 1021, and 998. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.72 (d, J = 8.72 Hz, 2H, Ph), 6.92 (d, J = 6.92 Hz, 2H, Ph), 7.42 (m, 5H, Ph), 6.40 (s, 1H, =C(11)H), 6.11 (s, 1H, =C(3)H), 3.85–3.46 (br, 4H), 3.85 (s, 2H), and 2.66–2.49 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 169.4, 156.1, 145.9, 129.9, 128.6, 127.1, 124.8, 116.1, 115.0, 56.0, 53.5, 47.6. HR-MS (ESI), calcd. C23H22N2O4: [M+H]+  m/z: 391.1658; found: 391.1627.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-benzylidenefuran-2(5H)-one    (9d). Yield: 78%, light yellow solid, mp: 65.2–66.4°C. IR (KBr, cm−1): 1758, 1627, 1434, 1280, 994, 697. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.80 (d, J = 7.38 Hz, 2H, Ph), 7.44–7.21 (m, 8H, Ph), 6.21 (s, 1H, =C(11)H), 5.86 (s, 1H, =C(2)H), 3.76–3.43 (br, 4H), 3.39 (d, J = 10.70 Hz, 2H), and 2.72–2.53 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4 (C1), 168.6, 147.6, 147.4, 141.9, 135.0, 132.5, 132.5, 130.8, 130.1, 129.6, 128.9, 128.6, 128.6, 128.4, 128.4, 127.7, 127.0, 125.8, 125.4, 111.1 (C11), 67.6 (C5), 53.2, 52.9, 47.0, 41.5. HR-MS (ESI), calcd. C23H22N2O3: [M+H]+  m/z: 375.1709; found: 375.1716.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (9e). Yield: 85%, light yellow solid, mp: 199.3–200.5°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.42–6.83 (m, 9H, Ph), 6.68 (s, 1H, =C(11)H), 5.93 (s, 1H, =C(2)H), 3.90, 3.55 (br, 4H, C(7,8,)H2), 3.74 (s, 3H, OCH3), 3.29 (m, 2H, C(5)H2), and 2.92–2.53 (br, 4H, C(6,9) H2). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 168.3, 157.4, 156.2, 147.4, 132.6, 131.6, 130.7, 128.9, 128.6, 128.5, 127.1, 127.0, 125.7, 121.1, 120.0, 110.6, 103.8, 63.6, 55.6, 55.3, and 50.7. HR-MS (ESI), calcd. C24H24N2O4: [M+H]+  m/z: 405.1814; found: 405.1846.


## 3.1.1. 4-(Piperidin-1-ylmethyl)furan-2(5H)-one (4)

To an CH3CN (50 mL) solvent of compound 3 (0.1 mol) and anhydrous sodium carbonate (0.06 mol) 1.2 eq. piperidine (0.12 mol) was added. The mixture was stirred at room temperature for 3 h, and the reaction was monitored by TLC until completion, the solid salt was filtered, and the filtrate was evaporated under reduced pressure to steam out of most of the acetonitrile, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 3 : 1) which afforded 15.4 g compound 4. Yield: 85%, yellow oil. IR (KBr, cm−1): 1762, 1630, 1489, 1462, 1438, 1284, 1247, 1024, 994, and 758. 1H NMR (400 MHz, CDCl3, ppm) δ: 5.98 (s, 1H, =CH), 4.82 (s, 2H), 3.31 (s, 2H), 2.38 (s, 4H), and 1.61–1.26 (m, overlap, 6H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.8 (C2), 168.4, 117.1, 72.7, 56.7, 55.0, 25.8, and 23.9. HR-MS (ESI), calcd. C10H15NO2: [M+H]+  m/z: 182.1181; found: 182.1160 (see Supplementary Material available online at http://dx.doi.org/10.1155/2013/926723).


## 3.1.2. General Procedure for the Preparation of (5a–f)

Compound4 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in MeOH (50 mL) solvent, then the respective aromatic aldehyde (acetone for compound 5d) (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. the reaction mixture was washed with water and ethyl acetate, dried, and purified by column chromatography.(Z)-5-(Furan-2-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5a). Yield: 60%, brown oil. IR (KBr, cm−1): 2923, 2848, 1627, 1446, and 1382. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.50 (d, J = 1.38 Hz, 1H, Ar), 7.05 (d, J = 3.39 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.53 (s, 1H, =CH), 6.09 (s, 1H, =CH), 3.42 (s, 2H), 2.43 (s, 4H), 1.63 (m, 4H), and 1.47 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 168.9 (C2), 156.4, 149.0, 146.1, 143.9, 116.0, 115.3, 113.0(C11), 100.2, 54.9, 25.9, and 24.0. HR-MS (ESI), calcd. C15H17NO3: [M+H]+  m/z: 260.1287; found: 260.1243.(Z)-5-(4-Hydroxy-3-methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5b). Yield: 65%, yellow oil. IR (KBr, cm−1): 2924, 1623, 1516, 1382, and 1124. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.53 (d, J = 1.76 Hz, 1H, Ph), 7.18 (dd, J = 1.80 Hz, 8.24 Hz, 1H, Ph), 6.93 (d, J = 8.24 Hz, 1H, Ph), 6.34 (s, 1H, =CH), 6.08 (s, 1H, =CH), 3.96 (s, 3H, OCH3), 3.46 (s, 2H), 2.46 (s, 4H), 1.63 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.6 (C2), 157.2, 147.1, 146.8, 146.5, 127.5, 125.7, 115.0, 114.6, 111.5, 111.7 (C11), 56.1, 54.9, 54.8 (OCH3), 25.9, and 24.0. HR-MS (ESI), calcd. C18H21NO4: [M+H]+  m/z: 316.1549; found: 316.1537.(Z)-5-(4-Hydroxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5c). Yield: 85%, sallow crystal mp: 178.3–179.5°C. IR (KBr, cm−1): 3347, 3103, 2935, 2800, 2758, 1749, 1605, 1588, 1515, 1445, 1278, 1227, 1172, 944, 840. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.73 (d, J = 8.72 Hz, 2H, Ph), 6.96 (d, J = 8.56 Hz, 2H, Ph), 6.41 (s, 1H, =CH), 6.10 (s, 1H, =CH), 3.46 (s, 2H), 2.46 (s, 4H), 1.65 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 157.7 (C2), 146.4, 132.8, 125.5, 116.1, 114.8, 112.0, 55.0, 25.9, and 24.0. HR-MS (ESI), calcd. C17H19NO3: [M+H]+  m/z: 286.1443; found: 286.1459.4-(Piperidin-1-ylmethyl)-5-(propan-2-ylidene)furan-2(5H)-one   (5d). Yield: 50%, brown oil. IR (KBr, cm−1): 2938, 2856, 1744, 1624, 1588, 1447, 1129, 1032, 947, 909, and 876. 1H NMR (400 MHz, CDCl3, ppm) δ: 6.07 (s, 1H, =CH), 3.37 (d, J = 1.13 Hz, 2H), 2.42 (s, 4H), 2.04, 2.03 (s, 6H, =(CH3)2), 1.61 (m, 4H), and 1.46 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.2 (C1), 155.9 (C3), 145.2 (C4), 124.2 (C11), 118.1 (C2), 57.3, 54.9, 26.0, 24.1, 21.0, and 19.1. HR-MS (ESI), calcd. C13H19NO2: [M+H]+  m/z: 222.1494; found: 222.1468.(Z)-5-(2-Methoxybenzylidene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5e). Yield: 46%, pink oil. IR (KBr, cm−1): 2932, 1740, 1638, 1596, 1491, 1461, 1239, 1023, 982, and 754. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.29–6.80 (overlap, m, 4H, Ph), 6.23 (s, 1H, =C(11)H), 5.89 (s, 1H, =C(2)H), 3.86 (s, 3H, OCH3), 3.73 (m, 2H), 2.53 (br, 4H), 1.72 (m, 4H), and 1.51 (m, 2H). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 171.7, 166.2, 157.2, 129.2, 128.5, 127.4, 121.8, 120.8, 111.0, 87.6, 68.7, 56.6, 55.6, 54.6, 25.4, and 23.6. HR-MS (ESI), calcd. C18H21NO3: [M+H]+  m/z: 300.1600; found: 300.1598.(Z)-5-(Benzo[d][1,3]dioxol-5-ylmethylene)-4-(piperidin-1-ylmethyl)furan-2(5H)-one   (5f). Yield: 55%, pink oil. IR (KBr, cm−1): 2929, 2854, 1761, 1623, 1489, 1447, 1005, and 470. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.48 (s, 1H, Ph), 7.18 (d, J = 7.68 Hz, 1H, Ph), 6.83 (d, J = 8.13 Hz, 1H, Ph), 6.34 (s, 1H, =C(11)H), 6.08 (s, 1H, =C(2)H), 6.01 (s, 2H, OCH2O), 3.49 (d, J= 19.46 Hz, 2H), 2.44 (s, 4H), 1.62 (m, 4H), and 1.26 (m, 2H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.5 (C1), 157.4 (C3), 148.4 (C4), 148.2 (Ph), 146.6 (Ph), 127.2 (Ph), 126.1 (Ph), 115.0 (Ph), 111.3 (Ph), 110.1 (OCH2O), 108.4 (C2), 101.4 (C11), 54.9, 25.9, 24.0. HR-MS (ESI), calcd. C18H19NO4: [M+H]+  m/z: 314.1392; found: 314.1362.


## 3.1.3. 4-((Benzyl(methyl)amino)methyl)furan-2(5H)-one (6)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.2 eq methyl benzylamine (0.12 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 3 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography (elution with chloroform ether-ethylacetate, 4 : 1) which afforded 19.5 g compound 6. Yellow oil. Yield: 90%. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.31 (m, 5H, Ph), 6.01 (s, 1H, =C(2)H), 4.81 (s, 2H, C(4)H2), 3.54 (s, 2H, C(7)H2), 3.34 (s, 2H, C(7)H2), 2.25 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.7 (C1), 168.5 (C3), 138.0 (Ph), 128.6 (Ph), 127.4 (Ph), 117.0 (C2), 72.4 (C4), 62.2 (C5), 54.5 (C6), 42.8 (NCH3). HR-MS (ESI), calcd. C13H15NO2: [M+H]+  m/z: 218.1181; found: 218.1149.


## 3.1.4. General Procedure for the Preparation of (7a–d)

Compound5 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) were dissolved in methanol solvent, and then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the methanol solvent. The reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (7a).Yield: 44%, thick brown oil. IR (KBr, cm−1): 1755, 1645, 1607, 1470, 1145, 994, 745. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51 (d, J = 1.96 Hz, 1H, Ar), 7.32–7.26 (m, 5H, Ph), 7.07 (d, J = 3.60 Hz, 1H, Ar), 6.54 (m, 1H, Ar), 6.27 (s, 1H, =C(8)H), 5.74 (s, 1H, =C(2)H), 3.77 (d, J = 14.08 Hz, 1H), 3.37 (d, J = 14.08 Hz, 1H), 3.66–3.45 (m, 2H), and 2.21 (s, 3H, CH3); 13C NMR (100.6 MHz, CDCl3,   ppm) δ: 167.6 (C2), 154.2 (C4), 149.0 (C5), 145.5 (Ph), 135.6, 129.7, 128.7, 128.0 (Ph), 115.8, 113.3, 110.4, 99.8, 62.7, 51.1, and 41.8 (NCH3). HR-MS (ESI), calcd. C18H17NO3: [M+H]+  m/z: 296.1287; found: 296.1277.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(4-(dimethylamino) benzylidene)furan-2(5H)-one   (7b). Yield: 70%, thick brown. oil. IR (KBr, cm−1): 2917, 2848, 2801, 1744, 1604, 1526, 1444, 1367, 1168, 930, and 818. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.69 (d, J = 8.96 Hz, 2H, Ph), 7.36–7.26 (m, 5H, Ph), 6.69 (d, J = 8.96 Hz, 2H, Ph), 6.22 (s, 1H, =C(8)H), 6.05 (s, 1H, =C(2)H), 3.58 (s, 2H), 3.08 (s, 2H), 3.03 (s, 6H, N(CH3)2), and 2.12 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ:   170.2 (C1), 157.2 (C3), 150.8 (C4), 145.1, 138.4, 132.6, 129.0, 128.5, 127.4, 120.9, 113.6, 112.7, 112.0, 111.0, 62.4 (C5), 52.8 (C6), 42.9 (NCH3), and 40.1 (N(CH3)2). HR-MS (ESI), calcd. C22H24N2O2: [M+H]+  m/z: 349.1916; found: 349.1934.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (7c). Yield: 65%, light yellow oil. IR (KBr, cm−1): 2926, 1767, 1642, 1599, 1491, 1460, 1247, 1025, 929, 764. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.41–7.26 (m, 9H, Ph), 7.01 (s, 1H, =C(8)H), 6.19 (s, 1H, =C(2)H), 3.91 (s, 3H, OCH3), 3.54 (s, 2H), 3.37 (s, 2H), 2.28 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.1 (C3), 157.6, 147.7, 138.4, 131.9, 130.6, 128.8, 128.7, 128.5, 128.4, 127.4, 121.8, 121.1, 115.6, 110.5 (C2), 105.3 (C8), 62.6 (C5), 55.66 (C6), 53.2 (OCH3), 42.7 (NCH3). HR-MS (ESI), calcd. C21H21NO3: [M+H]+  m/z: 336.1600; found: 336.1598.(Z)-4-((Benzyl(methyl)amino)methyl)-5-(3,4,5-trimethoxybenzylidene)furan-2(5H)-one   (7d). Yield: 58%, light yellow oil. IR (KBr, cm−1): 2939, 2841, 1753, 1585, 1504, 1457, 1422, 1331, 1235, 1126, 1001. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.37 (m, 4H, Ph), 7.14 (s, 1H, Ph), 7.01 (s, 2H, Ph), 6.18 (s, 1H, =C(8)H), 6.17 (s, 1H, =C(2)H), 3.89 (s, 6H, OCH3), 3.88 (s, 3H, OCH3), 3.61 (s, 2H), 3.49 (s, 2H), 2.33 (s, 3H, NCH3); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 169.7 (C1), 158.2, 157.6, 147.7, 138.5, 131.9, 131.6, 130.6, 130.5, 128.8. 128.4, 127.4, 121.8, 121.2, 115.6, 115.0, 110.4, 105.3, 103.8, 62.6, 55.6, 53.2, 42.7, and 29.7. HR-MS (ESI), calcd. C23H25NO5: [M+H]+  m/z: 396.1811; found: 396.1807.


## 3.1.5. 4-((4-Benzoylpiperazin-1-yl)methyl)furan-2(5H)-one (8)

To a CH3CN (50 mL) solvent of compound 3 (0.1 mol) 1.1 eq. benzoyl piperazine12 (0.11 mol) and catalytic amount of anhydrous sodium carbonate were added. The mixture was stirred at room temperature for 2 h, and the reaction was monitored by TLC until completion. The reaction solution was evaporated under reduced pressure to steam out of most of the CH3CN solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by ethyl acetate crystallize to afforded 27.2 g compound 8. White crystal. Yield: 95%, mp: 112.5–113.0°C. IR (KBr, cm−1): 2820, 1787, 1742, 1624, 1434, 1275, 1143, 1025, 894, 868, 709. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.43 (m, 5H, Ph), 6.02 (d, J = 1.42 Hz, 1H, =C(2)H), 4.82 (d, J = 1.54 Hz, 2H), 3.80–3.46 (br, 4H), 3.40 (s, 2H), 2.56–2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 173.4 (C1), 170.4, 166.6 (C3), 135.4, 129.9, 128.7, 127.0 (Ph), 117.9 (C2), 72.4 (C4), 55.7 (C5), 53.7, 53.7, 47.5, 41.9. HR-MS (ESI), calcd. C16H18N2O3: [M+H]+  m/z: 287.1396; found: 287.1392.


## 3.1.6. General Procedure for the Preparation of (9a–f)

Compound8 (0.01 mol) and anhydrous sodium carbonate (0.01 mol) was dissolved in methanol solvent, then the respective aromatic aldehyde (0.012 mol) was added. The mixture was stirred at room temperature for 3–12 h and the reaction was monitored by TLC to complete. The reaction solution was vaporated under reduced pressure to steam out of most of the methanol solvent, the reaction mixture was washed with water and ethyl acetate, dried and purified by column chromatography.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(furan-2-ylmethylene)furan-2(5H)-one    (9a). Yield: 82%, brown-red oil. IR (KBr, cm−1): 1757, 1629, 1466, 1435, 1282, 997, and 742. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.51–7.07 (m, overlap, 6H, Ar), 6.34 (m, 2H, Ar), 6.31 (s, 1H, =C(11)H), 5.73 (s, 1H, =C(2)H), 3.88–3.51 (br, 4H), 3.50 (d, J = 14.28 Hz, 2H), 2.75–2.56 (br, 4H); 13CNMR (100.6 MHz, CDCl3, ppm) δ:  170.4 (C1), 167.4, 153.9 (C3), 148.8 (C4), 147.2, 135.1, 130.0, 128.6, 127.0, 116.0, 113.3, 110.6, 107.4 (C11), 100.0 (C2), 62.9 (C5), 51.7, 47.6, and 42.1. HR-MS (ESI), calcd. C21H20N2O4: [M+H]+  m/z: 365.1501; found: 365.1497.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxy-3-methoxybenzylidene)furan-2(5H)-one   (9b). Yield: 88%, brown solid mp: 79.0–80.6°C. IR (KBr, cm−1): 2921, 2852, 1752, 1630, 1580, 1515, 1431, 1284, 1163, 1131, and 1026. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.40 (s, 1H, Ph), 7.36 (m, 5H, Ph), 7.15 (m, 1H), 6.86 (d, J = 8.24 Hz, 1H, Ph), 6.23 (s, 1H, =C(11)H), 6.05 (s, 1H, =C(2)H), 3.85 (s, 3H, OCH3), 3.80, 3.44 (br, 4H), 3.48 (s, 2H), 2.58, 2.42 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.5 (C1), 169.5 (C10), 156.1 (C3), 147.5, 147.1, 145.9, 135.3, 129.9, 128.5, 127.0, 125.6, 125.1, 115.0, 112.7 (C2), 112.1 (C11), 56.0 (C5), 53.7 (OCH3), 53.5, 53.1, 47.6, and 42.1. HR-MS (ESI), calcd. C24H24N2O5: [M+H]+  m/z: 421.1763; found: 421.1735.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(4-hydroxybenzylidene)furan-2(5H)-one   (9c). Yield: 89%, yellow crystals, mp: 239.1–240.0°C. IR (KBr, cm−1): 3447, 1762, 1604, 1513, 1446, 1279, 1021, and 998. 1H NMR (400 MHz, CDCl3 and CD3COCD3, ppm) δ: 7.72 (d, J = 8.72 Hz, 2H, Ph), 6.92 (d, J = 6.92 Hz, 2H, Ph), 7.42 (m, 5H, Ph), 6.40 (s, 1H, =C(11)H), 6.11 (s, 1H, =C(3)H), 3.85–3.46 (br, 4H), 3.85 (s, 2H), and 2.66–2.49 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 169.4, 156.1, 145.9, 129.9, 128.6, 127.1, 124.8, 116.1, 115.0, 56.0, 53.5, 47.6. HR-MS (ESI), calcd. C23H22N2O4: [M+H]+  m/z: 391.1658; found: 391.1627.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-benzylidenefuran-2(5H)-one    (9d). Yield: 78%, light yellow solid, mp: 65.2–66.4°C. IR (KBr, cm−1): 1758, 1627, 1434, 1280, 994, 697. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.80 (d, J = 7.38 Hz, 2H, Ph), 7.44–7.21 (m, 8H, Ph), 6.21 (s, 1H, =C(11)H), 5.86 (s, 1H, =C(2)H), 3.76–3.43 (br, 4H), 3.39 (d, J = 10.70 Hz, 2H), and 2.72–2.53 (br, 4H); 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4 (C1), 168.6, 147.6, 147.4, 141.9, 135.0, 132.5, 132.5, 130.8, 130.1, 129.6, 128.9, 128.6, 128.6, 128.4, 128.4, 127.7, 127.0, 125.8, 125.4, 111.1 (C11), 67.6 (C5), 53.2, 52.9, 47.0, 41.5. HR-MS (ESI), calcd. C23H22N2O3: [M+H]+  m/z: 375.1709; found: 375.1716.(Z)-4-((4-Benzoylpiperazin-1-yl)methyl)-5-(2-methoxybenzylidene)furan-2(5H)-one   (9e). Yield: 85%, light yellow solid, mp: 199.3–200.5°C. 1H NMR (400 MHz, CDCl3, ppm) δ: 7.42–6.83 (m, 9H, Ph), 6.68 (s, 1H, =C(11)H), 5.93 (s, 1H, =C(2)H), 3.90, 3.55 (br, 4H, C(7,8,)H2), 3.74 (s, 3H, OCH3), 3.29 (m, 2H, C(5)H2), and 2.92–2.53 (br, 4H, C(6,9) H2). 13C NMR (100.6 MHz, CDCl3, ppm) δ: 170.4, 168.3, 157.4, 156.2, 147.4, 132.6, 131.6, 130.7, 128.9, 128.6, 128.5, 127.1, 127.0, 125.7, 121.1, 120.0, 110.6, 103.8, 63.6, 55.6, 55.3, and 50.7. HR-MS (ESI), calcd. C24H24N2O4: [M+H]+  m/z: 405.1814; found: 405.1846.


## 4. Conclusions

In summary, a series of novelγ-alkylidene butenolides bearing nitrogen unit have been synthesized by a simple and general method in good yields. Their antibacterial activity and cytotoxic activity were evaluated. The results revealed that the introduction of nitrogen heterocyclic and γ-alkylidene to the lactone was efficient for the bioactivities.



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*Source: 926723-2013-09-10.xml*