Synthesis of novel 2, 5-dihydrofuran derivatives and evaluation of their anticancer activity

Article abstract of DOI:10.1016/j.ejmech.2011.11.036

According to metal-catalyzed [3 + 2] cycloaddition reaction, we synthesized a series of novel 2, 5-dihydrofuran derivatives and evaluated their in vitro anti-cancer activities via MTT method. The bioassay showed that the majority of the resultant compounds exerted anti-tumor effect against four human cancer cell lines to various extents, which supported the rationale of the design. Compounds 9e and 10g showed the highest activity with broad anti-cancer spectrum, which were good candidates for further evaluation.

Full text of DOI:10.1016/j.ejmech.2011.11.036

European Journal of Medicinal Chemistry 48 (2012) 69e80
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel 2, 5-dihydrofuran derivatives and evaluation of their
anticancer activity
1
1
*
Yikai Zhang , Hanyu Zhong , Tiantian Wang, Dongping Geng, Mingfeng Zhang, Ke Li
Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
According to metal-catalyzed [3 þ 2] cycloaddition reaction, we synthesized a series of novel 2, 5-
dihydrofuran derivatives and evaluated their in vitro anti-cancer activities via MTT method. The
bioassay showed that the majority of the resultant compounds exerted anti-tumor effect against four
human cancer cell lines to various extents, which supported the rationale of the design. Compounds 9e
and 10g showed the highest activity with broad anti-cancer spectrum, which were good candidates for
further evaluation.
Received 18 September 2011
Received in revised form
19 November 2011
Accepted 23 November 2011
Available online 1 December 2011
Ó 2011 Elsevier Masson SAS. All rights reserved.
Keywords:
2, 5-Dihydrofuran derivatives
Metal-catalyzed cycloaddition reaction
Synthesis
Crystal structure
Anti-cancer activity
1. Introduction
According to domino reaction [14,15], metal-catalyzed [3 þ 2]
cycloaddition reaction is one of the most efficient approaches in the
The development of new anti-tumor agents is an important
field in medicinal chemistry, due to the increasing problems of
toxic side effects of recent marketed drugs. For example, 5-
fluorouracil and doxorubicin (Fig. 1) anti-cancer drugs are a class
of broad-spectrum anti-tumor agents. However, the drawback is
that the effective dose and toxic dose medication are similar,
which results in that they could kill both cancer cells and normal
cells [1,2]. Accordingly, it is meaningful for us to find a novel kind
of structure with safe and effective properties in the progress of
cancer treatment.
In the last decades, medicinal chemists have paid great attention
to the development of novel lead from natural products. Most
interestingly, existence of heterocyclic unit in numerous natural
products often plays an essential role in their biological activity,
particularly in anti-cancer effect [3e7]. Among these heterocycles
reported, some five-membered oxygen heterocycles derivatives
found or synthesized represent wide range of biological activities
and thus they could be used as versatile intermediates [8e13].
Therefore, our focus was on the design and synthesis of five-
membered oxygen heterocycles.
synthesis of five-membered heterocycles [16e20]. In general,
strategies for substituted 2, 5-dihydrofuran reported need expen-
sive catalysts and harsh reaction conditions, which include RCM
reaction, Ag (I)-catalyzed rearrangement cyclization and Prins
reaction. Nevertheless, our group has developed an efficient and
mild approach for synthesizing functionalized 2, 5-dihydrofuran
derivatives. By this method, we have introduced a wide range of
substituents on the 2-, 3- and 4-positions, especially carboxylic acid
group on the 3-position, of 2, 5-dihydrofuran. Herein, we reported
an efficient and straightforward method for the syntheses of
a series of substituted 2, 5-dihydrofuran derivatives and we also
investigated the anti-cancer activities of the desired compounds.
2. Chemistry
The chemical synthesis of 2, 5-dihydrofuran derivatives was
achieved by a 3-step protocol, as illustrated in Scheme 1. Compound
3 was synthesized through a conventional Knoevenagel Conden-
sation between compound 1 and compound 2 refluxing in toluene
with the catalytic piperidine and glacial acetic acid [21]. Compound
3 was reacted with 1, 4-butynediol in the presence of NaH and CuI
at 40 ꢀC in THF, within 15e22 h and product 5 with 77e92% yield
was formed sequentially after compound 4 as an intermediate
(compound 4c was separated successfully and determined via X-
* Corresponding author. Tel.: þ86 21 81871237.
E-mail address: proflike@sina.com (K. Li).
1
These two authors contributed equally to this work.
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.11.036

70
Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
inhibitory effect to 5-Fu (IC50 ¼ 16.32
mM) but lower activity than
M). It could suggest that the 3, 4-
O
O
OH
O
H
N
doxorubicin (IC50 ¼ 1.12
m
OH
OH
O
O
F
disubstituted benzene at position-2 could increase the activity for
inhibiting HeLa cell line. However, these four compounds displayed
poor activities against other three cell lines.
OH
O
HN
H
The introduction of amide group on position-3 of the 2, 5-
dihydrofuran led to the different situation of anti-cancer activity.
Firstly, the carboxylic acid group of compound 5a was changed into
substituted amide group (compounds 6ae6s). Interestingly, the
anti-tumor activities in HeLa cell was totally disappear, while
moderate inhibitory activity in QGY-7701 cell was observed in
compounds 6ae6o whose side chains on C-3 were substituted
benzene rings or cyclohexane. Compared with the ring group, the
introduction of an aliphatic side chain (compounds 6pe6s) resulted
in the loss of activity against the four cancer cell lines. Among
compounds 6, 6k was not only the best one with the IC50 value of
O
OH
O
5-Fluorouracil
Doxorubicin
NH2
Fig. 1. Chemical structures of 5-fluorouracil and doxorubicin.
ray crystallographic structure - Fig. 2). This step could be acceler-
ated with electron-withdrawing aryl-substituted group (Table 1,
entries 1, 2), while decelerated with electron-donating aryl-
substituted one (Table 1, entries 3, 4). On the contrary, the yield of
electron-rich group was higher than that of electron-deficient one.
Compounds 5 acid chloride formed by thionyl chloride were reac-
ted with substituted amines to afford compounds 6a - 6s, 7a - 7g, 8a
29.66
mM against QGY-7701 but also it was the only one found
effective against the cell line SW480 (IC50 ¼ 35.95
mM). Likewise,
we also modified the compound 5b at position-3 with a series of
amide groups, but the result was another story. In this subseries,
amides linked with ring groups were negative of all four cell lines.
On the country, the compounds with aliphatic side chains,
compounds 7d, 7e and 7f, have moderate effect on QGY-7701,
SW480 and HeLa cell line, respectively.
-
8s and 9ae9f and with substituted piperazines to afford
compounds 10ae10g. The chemical structures of these compounds
were confirmed by ESIMS, NMR spectroscopic analysis, IR and
elemental analyses. The purity of final compounds was assessed on
the basis of analytical HPLC (ꢁ95%). (see Supplementary Data).
Additionally, the structure of compounds 4c and 5c was further
confirmed by X-ray diffraction. Their crystal data are presented in
Table 2, and Fig. 2 gives ORTEP III views of both compounds.
Moreover, postion-3 substituent groups on compounds 8ae8s
derived from compound 5c were exactly the same as the subseries
6. Nevertheless, the bioactivities of these compounds displayed
some dissimilarity, which means the influence of changing 4-fluoro
benzene to 4-methoxyl benzene is obvious. In A-549 cell line,
almost all the tested compounds showed no anti-tumor effect
except compounds 8e and 8q which exhibited moderate inhibitory
3. Results and discussion
effect (IC50 ¼ 17.55
m
M and IC50 ¼ 36.48
mM). This could suggest that
3.1. Reaction mechanism
these two compounds had unique mechanism for inhibiting A-549
cell line. Subseries 6 did exert moderate activity against QGY-7701
cell line. Nevertheless, compounds 8 demonstrated a stronger
decrease in growth inhibitory activity except compound 8g
Based on the fact that intermediate 4c was successfully sepa-
rated and determined, we could propose a tentative reaction
mechanism (Scheme 2). First of all, 1, 4-butyne-diol was treated
with NaH to produce alcohol sodium which could attack double
bond of the substrate alkynylmalonate to yield the intermediate A,
followed by cyclization reaction promoted via CuI connecting at
triple bond and then intermediate C was formed. Subsequently, the
other ring was cyclized with an ethanol molecule leaving via an
intramolecular ester exchange reaction to form intermediate D.
Furthermore, the Cu atom took off to yield compound 4 which then
undergone a [3,3]-sigmatropic reaction to produce product 5.
(IC50 ¼ 43.14
demonstrated moderate to good activity against HeLa cell line, of
which 8g (IC50 ¼ 15.85 M) and 8p (IC50 ¼ 13.98 M) had the similar
activity to the 5-Fu (IC50 ¼ 16.32 M) but not as good as doxorubicin
(IC50 ¼ 1.12 M). Investigation of anti-tumor activities in SW480
mM). Synthesized compounds 8g, 8l, 8m, 8o and 8p
m
m
m
m
cells suggested that benzyl amide with electron-donating group
(compounds 8f, 8g and 8h) may play a pivotal role in the modu-
lation of cytotoxic activity and the effect could increase with the
stronger ability of the electron donation. In addition, in order to
further investigate the compound 5d, compounds 9ae9f were
synthesized as well and the bioactivities result was exhilarating us.
Compound 9e presented remarkable activity against three human
tumor cell lines, being the most sensitive to growth inhibition of
3.2. Pharmacology
All the synthesized compounds (5e10) were evaluated for their
in vitro cytotoxic activities against four human cancer cell lines via
MTT method, including A-549 (human lung adenocarcinoma cell
line), HeLa (human cervical carcinoma cell line), SW480 (human
colon carcinoma cell line) and QGY-7701 (human hepatoma cell
line). 5-Fluorouracil (5-Fu) and doxorubicin were used as positive
controls.
The results of the assay are summarized in Table 3 (where the
IC50 value is defined as the concentration of a compound that
corresponds to 50% growth inhibition). Data in the table showed
the most of the synthesized compounds displayed certain anti-
tumor activities against the four human cancer cell lines.
Compounds 5ae5d have different patterns of substituted
benzene that attach to the C-2 of 2, 5-dihydrofurans. As shown in
Table 3, these compounds generally exhibited moderate to good
potency against HeLa cell line, especially compound 5b
HeLa with IC50 value of 5.54 mM which is similar to the doxorubicin.
Besides, compared with the reference drugs, it had homogeneous
activities against QGY-7701 cell line and SW480 cell line, respec-
tively. Both 9a and 9e had much better anti-HeLa effect than the
compound 5d, which means our modification is successful.
The most encouraging result to us was the compounds with
substituted piperazinyl amide group at C-3 of 2, 5-dihydrofuran
(compounds 10ae10g). The most potent compound in this subse-
ries was compound 10g that presented good activity against four
human tumor cell lines, being the most sensitive to growth inhi-
bition QGY-7701 of cancer panel with IC50 value of 4.96
HeLa cancer panel displaying a IC50 value of 4.00 M. Moreover,
compound 10d and 10f showed best activity against SW480 and A-
549, respectively. The result indicated that the benzyl group with
electron-withdrawing connecting to piperazinyl amide was
important for the anti-cancer activity.
mM and
m
(IC50 ¼ 10.26
mM) and 5d (IC50 ¼ 18.00
mM) exhibited comparable

Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
71
Scheme 1. Synthesis of title compounds. Reagents and conditions: (1) Piperidine, CH3COOH, Toluene, Reflux, 6 h; (2) 1, 4-butyne-diol, NaH, CuI, THF, 40 ꢀC, 15e22 h; (3) a. SOCl2,
Reflux, 4 h; b. Substituted amines or piperazidines, THF, r.t., Overnight.

72
Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
Fig. 2. ORTEP drawing of 4c and 5c.
acquisition of highly substituted 2, 5-dihydrofuran derivatives with
Table 1
good yields. The results of preliminary anti-cancer assays of 2, 5-
dihydrofuran derivatives indicated that introduction of benzene
ring with electron-rich group at position-3 and piperazinyl amide
group at position-2 could improve the anti-cancer activities effec-
tively. Among all the tested compounds, compounds 9e and 10g
showed the highest activity with broad anti-cancer spectrum,
which were good candidates for further evaluation. Studies on the
mechanism of action; influence of chirality; whether a given
compound exerts cytotoxic, anti-adhesive or cytostatic effects;
in vivo anti-tumor effects of this novel structure are still going on.
Synthesis of 2, 5-dihydrofuran derivatives.a
Entry
Compd.
Substrate R1¼
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5a
5b
5c
5d
4-F
40
40
40
40
15
15
22
22
77
78
92
87
3,4-Cl2
4-OMe
3,4-(OMe)2
5. Experimental protocols
a
Reaction conditions: Alkylidene malonate (20 mmol), 1,4-butyne-diol
(30 mmol), CuI (2 mmol), NaH (24 mmol), THF (35 ml).
Melting points were measured on an uncorrected X-5 digital
melting point apparatus (Gongyi City Yuhua Instrument Co., Ltd.;
China). 1H NMR and 13C NMR spectra were recorded on a BRUKER
AVANCE 300 spectrometer (Bruker Company, Germany), using TMS
as an internal standard and CDCl3 (99.8% D, Cambridge Isotope
Laboratories) or DMSO-d6 (99.9% D, Cambridge Isotope Laborato-
b
Isolated yield.
Table 2
Crystallographical and experimental data for compounds 4c and 5c.
ries) as solvents. Chemical shifts (d values) and coupling constants
Data
Compound
(J values) are given in ppm and Hz, respectively. Elemental analyses
were performed with a MOD-1106 instrument and were consistent
with theoretical values within 0.4%. The mass spectra were recor-
ded on an Esquire 3000 LC-MS mass spectrometer. Crystal structure
was determined on a Bruker SMART CCD (Bruker Company, Ger-
many). Purity analysis was determined on Agilent 1100 Serial HPLC
(Agilent Company, US); A C18 column (ZORBAXÔ 4.6 ꢂ 150 mm,
4C
5C
CCDC deposition no.
Empirical Formula
Formula weight
Temperature (k)
Wavelength (Å)
Crystal system
Space group, Z
a (Å)
780473
C17 H19 O6
319.32
293(2)
0.71073
Monoclinic
P2(1)/n
10.124(4)
11.754(4)
13.792(5)
90
111.533(3)
90
1.389
842494
C14 H14 O4
246.25
293(2)
0.71073
Monoclinic
P2(1)/c
9.049(12)
18.06(2)
7.994(11)
90
106.340(16)
90
5 mm, PN: 993967906 SN: USRK042041). TLC analysis was carried
out on silica gel plates GF254 (Qindao Haiyang Chemical, China).
Silica gel thin-layer chromatography was performed with Silica gel
60G (Qindao Haiyang Chemical, China). All solvents and reagents
were analytically pure, and no further purification was needed. All
starting materials were commercially available.
b (Å)
c (Å)
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
Dcalc. (Mg/m3)
F(000)
1.305
520
676
q
range (ꢀ)
2.16e26.01
0.30 ꢂ 0.26 ꢂ 0.23
6721/2993
[R(int) ¼ 0.0842]
0.9762 & 0.9691
2.26e25.02
0.20 ꢂ 0.10 ꢂ 0.02
4325/2173
[R(int) ¼ 0.0435]
0.9981 & 0.9811
5.1. General procedure for the synthesis of compounds 5
Crystal size (mm3)
Reflections
NaH (60% in mineral oil, 24 mmol) was added to a solution of
but-2-yne-1,4-diol (2.58 g, 30 mmol) in THF (50 mL) under
nitrogen, and the solution was stirred for 5 min at room tempera-
ture. Alkylidene malonate (1, 20 mmol) and CuI (0.38 g, 2 mmol)
were then added successively. When consumption of the starting
materials was observed by TLC, the reaction mixture was quenched
by dropwise addition of a 20% solution of HCl, immediately cooled
to room temperature. The mixture was further diluted and
extracted twice with CH2Cl2, and the organic layer was washed
successively with saturated solution of brine, and water. The
organic extracts were dried over MgSO4, filtered, concentrated, and
the residue purified by flash column chromatography to afford
compound 5.
collected/unique
Max. & min.
transmission
Data/restraints/
parameters
2993/0/208
2173/0/169
R, Rw[I>2
s(I)]
0.0449/0.1250
1.043
0.0449/0.1250
1.040
Goodness-of-fit on F2
4. Conclusion
We have developed an efficient and mild stepwise reaction of 1,
4-butyne-diol and alkylidene malonates that allows controlled

Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
73
Scheme 2. Putative reaction mechanism.
Table 3
In vitro anti-cancer activity of target compounds.
Compd.
Cytotoxicity IC50
(m
M)b
Compd.
Cytotoxicity IC50 (m
M)b
A-549a
QGY-7701
HeLa
SW480
A-549
QGY-7701
HeLa
SW480
5a
5b
5c
5d
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
7a
7b
7c
7d
7e
7f
>100
>100
>100
>100
>100
>100
>100
>100
NAd
>100
>100
>100
>100
46.74
56.44
59.16
52.82
61.58
67.57
62.13
87.32
51.37
36.93
29.66
35.05
59.80
87.25
40.47
>100
>100
>100
>100
>100
>100
>100
31.29
>100
>100
>100
>100
>100
67.37
10.26
44.26
18.00
>100
NAd
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
NAd
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
60.07
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
35.95
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
27.54
>100
>100
>100
>100
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
8s
9a
9b
9c
9d
9e
9f
10a
10b
10c
10d
10e
10f
10g
>100
>100
17.55
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
36.48
>100
>100
>100
>100
>100
>100
>100
>100
22.96
20.67
10.26
35.34
26.83
8.31
>100
>100
>100
>100
43.14
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
69.10
>100
7.49
>100
>100
>100
>100
15.85
>100
>100
>100
>100
37.46
31.36
>100
24.75
13.98
>100
>100
>100
5.03
>100
>100
>100
5.54
>100
>100
15.30
>100
>100
>100
9.86
>100
>100
>100
39.47
31.68
13.49
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
45.11
>100
>100
>100
19.13
>100
>100
25.02
44.15
13.14
>100
>100
29.24
15.71
65.25
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
>100
23.55
17.95
>100
>100
>100
10.98
4.96
7g
8a
8b
8.86
5.64
6.61
4.00
16.32
1.12
5-Fuc
Doxorubicinc
14.30
8.65
a
Abbreviations: A-549: human lung adenocarcinoma cell line; HeLa: human cervical carcinoma cell line; QGY-7701: human hepatoma cell line; SW480: human colon
carcinoma cell line.
b
The IC50 value was defined as the concentration at which 50% survival of cells was observed.
Used as a positive control.
NA: Not active.
c
d

74
Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
5.1.1. Ethyl 3-(4-methoxyphenyl)-4-oxo-3,3a,4,6-tetrahydro-1H-
furo[3,4-c]pyran-3a-carboxylate (4c)
5.2. General procedure for the synthesis of compounds 6e10
Color: White; m.p. 95.4e95.9 ꢀC; Yield: 11%; IR: 3462, 3435,
3074, 3007, 2986, 2964, 2937, 2917, 2860, 2840, 2360, 2045, 1940,
1908, 1723, 1610,1583,1511,1452,1421,1386,1358,1303,1246,1175,
1112, 1083, 1032, 983, 967, 921, 852, 837, 816, 797, 775, 74 cmꢃ1; 1H
To a solution of compounds 5 (2 mmol) in the SOCl2 (15 ml)
were stirred in refluxing for 4 h. The solvent was then removed
under reduced pressure and white solids were obtained. The solids
dissolving in THF (10 ml) was added dropwise to the solution of
substituted amine or piperazidine (3 mmol) in THF (10 ml) with
stirring at room temperature overnight. The mixture was poured
into 10% HCl ice-water (150 ml) with stirring. The resulting solid
was filtered, dried and purified by flash column chromatography to
yield compounds 6e10.
NMR: (300 MHz, DMSO)
d
: 7.61(d, 2H, J ¼ 9.0 Hz), 6.86(d, 2H,
J ¼ 9.0 Hz), 6.02e6.06 (m, 1H), 5.40 (s, 1H), 4.95 (d, 1 H, J ¼ 11.7 Hz),
4.81e4.84 (m, 2H), 4.61(d,1 H, J ¼ 11.7 Hz), 3.78e3.85 (m, 5H), 0.9(t,
3H, J ¼ 7.2 Hz); 13C NMR (300 MHz, DMSO)
d: 167.51, 164.94, 159.45,
141.98, 128.18, 115.55, 113.16, 83.93, 68.59, 67.56, 64.17, 62.16, 55.15,
13.51 ppm; ESIMS: m/s (%): 317.71 [M ꢃ H]ꢃ; Anal. calcd for
C
17H18O6: C 64.14, H 5.70. Found: C 54.33, H 5.67%.
5.2.1. 2-(4-Fluorophenyl)-N-phenyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6a)
Color: White; m.p. 140.3e140.8 ꢀC; Yield: 92%; 1H NMR:
5.1.2. 2-(4-Fluorophenyl)-4-vinyl-2,5-dihydrofuran-3-carboxylic
acid (5a)
(300 MHz, CDCl3)
1H), 5.52 (d, 1H), 5.21 (dd, 1H), 5.08 ppm (dd, 1H); 13C NMR
(300 MHz, CDCl3) : 163.8, 160.2, 155.1, 141.0, 137.2, 130.5, 129.2,
d: 7.34 (m, 9H), 7.05 (m, 2H), 6.61 (m, 1H), 5.60 (d,
Color: White; m.p. 155.1e155.7 ꢀC; Yield: 77%; IR: 3456, 2860,
2580, 2015,1671, 1603,1509,1450,1384,1331, 1282, 1218,1158,1132,
1099,1072,1014,946, 854, 824,746cmꢃ1;1HNMR:(300MHz,DMSO)
d
128.8, 128.7, 128.1, 120.3, 117.4, 115.1, 86.1, 74.6 ppm; ESIMS: m/s (%):
309.39 [M ꢃ H]ꢃ; Anal. calcd for C19H16FNO2: C 73.77, H 5.21 N 4.53.
Found: C 73.29, H 5.69, N 4.32%.
d: 12.83 (br, 1H), 7.24e7.34 (m, 3H), 7.11e7.18 (m, 2H), 5.87 (dd, 1H,
J ¼ 5.1, 3.0 Hz), 5.60 (d, 1H, J ¼ 14.4 Hz), 5.50 (d, 1H, J ¼ 18.0 Hz), 5.13
(dd,1H, J ¼ 14.4, 5.1 Hz), 4.95 ppm (dd,1H, J ¼ 14.4, 3.0 Hz); 13C NMR
(300 MHz, DMSO) d: 163.8, 163.4, 160.2, 146.5, 137.9, 129.2, 127.7,
5.2.2. 2-(4-Fluorophenyl)-N-m-tolyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6b)
123.5, 115.1, 87.5, 74.8 ppm; ESIMS: m/s (%): 233.42 [M ꢃ H]ꢃ; Anal.
Color: White; m.p. 115.1e115.7 ꢀC; Yield: 92%; 1H NMR:
calcd for C13H11FO3: C 66.66, H 4.73. Found: C 66.69, H 4.76%.
(300 MHz, CDCl3)
1H), 5.45 (d, 1H), 5.23 (dd, 1H), 5.05 (dd, 1H), 2.36 ppm (s, 3H); 13
NMR (300 MHz, CDCl3) : 163.8, 156.1, 159.1, 138.2, 141.2, 138.2,
d: 7.41 (m, 6H), 7.09 (m, 4H), 6.61 (m, 1H), 5.60 (d,
5.1.3. 2-(3,4-Dichlorophenyl)-4-vinyl-2,5- dihydrofuran-3-
carboxylic acid (5b)
C
d
Color: White; m.p. 102.6e103.0 ꢀC; Yield: 78%; IR: 3440, 2900,
2859, 2621, 1687, 1667, 1637, 1589, 1468, 1429, 1406, 1384, 1319,
1282, 1202, 1132, 1070, 1029, 1014, 940, 926, 883, 824, 789, 747,
137.8, 130.5, 129.2, 128.8, 128.7, 126.9, 124.1, 120.3, 117.6, 115.1, 86.5,
75.6, 23.2 ppm; ESIMS: m/s (%): 323.58 [M ꢃ H]ꢃ; Anal. calcd for
C20H18FNO2: C 74.29, H 5.61 N 4.33. Found: C 74.02, H 5.39, N 4.37%.
705 cmꢃ1 1H NMR: (300 MHz, DMSO)
; d: 12.94 (s, 1H), 7.53e7.60
(m, 2H), 7.24e7.34 (m, 2H), 5.89 (dd, 1H, J ¼ 5.4, 3.0 Hz), 5.61 (d, 1H,
5.2.3. 2-(4-Fluorophenyl)-N-p-tolyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6c)
J ¼ 11.1 Hz), 5.51 (d, 1H, J ¼ 18.0 Hz), 5.21 (dd, 1H, J ¼ 14.4, 5.4 Hz),
4.95 ppm (dd, 1H, J ¼ 14.4, 3.0 Hz); 13C NMR (300 MHz, DMSO)
d:
Color: White; m.p. 160.1e161.0 ꢀC; Yield: 92%; 1H NMR:
163.7, 147.1, 130.9, 130.5, 129.3, 128.3, 127.7, 127.5, 124.8, 123.9, 69.0,
(300 MHz, CDCl3) d: 7.50 (m, 3H), 7.29 (m, 4H), 7.07 (m, 3H), 6.69
75.2 ppm; ESIMS: m/s (%): 285.54 [M ꢃ H]ꢃ; Anal. calcd for
(m, 2H), 5.59 (d, 1H), 5.39 (d, 1H), 5.19 (dd, 1H), 5.03 (dd, 1H),
C
13H10Cl2O3: C 54.76, H 3.54. Found: C 55.11, H 4.74%.
2.30 ppm (s, 3H); ESIMS: m/s (%): 323.58 [M ꢃ H]ꢃ; Anal. calcd for
C20H18FNO2: C 74.29, H 5.61 N 4.33. Found: C 74.14, H 5.43, N 4.32%.
5.1.4. 2-(4-Methoxyphenyl)-4-vinyl-2,5- dihydrofuran-3-carboxylic
acid (5c)
Color: White; m.p. 160.1e160.4 ꢀC; Yield: 92%; IR: 3446, 3035,
3964, 2889, 2855, 2839, 2670, 2621, 2574, 2360, 2340, 1672, 1612,
1588,1440,1384,1513,1440,1384,1320,1303,1273,1248,1174,1125,
5.2.4. 2-(4-Fluorophenyl)-N-(2-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6d)
Color: White; m.p. 108.7e109.1 ꢀC; Yield: 92%; 1H NMR:
1113, 1073, 1034, 1019, 947, 852, 824, 809, 742 cmꢃ1 1H NMR:
;
(300 MHz, CDCl3) d: 7.32 (m, 8H), 6.93 (s, 1H), 6.81 (m, 2H), 6.59 (m,
1H), 5.59 (d, 1H), 5.39 (d, 1H), 5.19 (dd, 1H), 5.05 (dd, 1H), 3.80 ppm
(300 MHz, DMSO)
d
: 12.71 (s, 1H), 7.29 (dd, 1H, J ¼ 18.0, 11.1 Hz),
(m, 3H); ESIMS: m/s (%): 338.12 [M ꢃ H]ꢃ; Anal. calcd for
7.14e7.19 (m, 2H), 6.84e6.89 (m, 2H), 5.82 (dd, 1H, J ¼ 5.4, 3.0 Hz),
5.58 (d, J ¼ 11.1 Hz,1H), 5.48 (d,1H, J ¼ 18.0 Hz), 5.07 (dd,1H, J ¼ 14.4,
5.4 Hz), 4.89 (dd, 1H, J ¼ 14.4, 3.0 Hz), 3.72 ppm (s, 3H); 13C NMR
C20H18FNO3: C 70.78, H 5.35 N 4.13. Found: C 70.65, H 5.30, N 4. 26%.
5.2.5. N-(4-Ethoxyphenyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6e)
(300 MHz, DMSO) d: 163.8, 158.9, 146.0, 133.5, 129.3, 128.3, 127.7,
123.1, 113.5, 87.7, 74.3, 55.0 ppm; ESIMS: m/s (%): 245.70 [M ꢃ H]ꢃ;
Color: White; m.p. 155.2e155.9 ꢀC; Yield: 92%; 1H NMR:
Anal. calcd for C14H14O4: C 68.28, H 5.73. Found: C 68.46, H 7.89%.
(300 MHz, CDCl3)
1H), 5.59 (d, 1H), 5.39 (d, 1H), 5.19 (dd, 1H), 5.05 (dd, 1H), 3.99 (m,
2H), 1.39 ppm (m, 3H); 13C NMR (300 MHz, CDCl3)
: 163.3, 162.7,
d: 7.39 (m, 6H), 6.93 (b, 1H), 6.81 (m, 2H), 6.60 (m,
5.1.5. 2-(3,4-Dimethoxyphenyl)-4-vinyl-2,5- dihydrofuran-3-
carboxylic acid (5d)
d
Color: White; m.p. 180.3e180.9 ꢀC; Yield: 87%; IR: 3446, 3009,
2961, 2946, 2836, 1868, 1072, 1646, 1592, 1558, 1520, 1467, 1423,
1384, 1357, 1310, 1264, 1237, 1193, 1161, 1141, 1114, 1062, 1019, 932,
155.6, 155.1, 141.0, 131.5129.2, 128,3, 128.5, 121.7, 117.4, 115.4, 115.2,
86.1, 74.6, 64.7, 15.2 ppm; ESIMS: m/s (%): 352.14 [M ꢃ H]ꢃ; Anal.
calcd for C21H20FNO3: C 71.37, H 5.70 N 3.96. Found: C 71.11, H 5.56,
N 4.74%.
871, 807, 795, 768, 705 cmꢃ1; 1H NMR: (300 MHz, DMSO)
d: 12.76
(s, 1H), 7.30 (dd, 1H, J ¼ 18.0, 11.1 Hz), 6.76e6.91 (m, 3H), 5.82 (dd,
1H, J ¼ 5.4, 3.0 Hz), 5.60 (d, 1H, J ¼ 11.1 Hz), 5.50 (d, 1H, J ¼ 18.0 Hz),
5.09 (dd, 1H, J ¼ 14.4, 5.4 Hz), 4.90 (dd, 1H, J ¼ 14.4, 3.0 Hz), 3.72 (s,
5.2.6. N-Benzyl-2-(4-fluorophenyl)-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6f)
3H), 3.71 ppm (s, 3H); 13C NMR (300 MHz, DMSO)
d: 164.0, 152.7,
Color: White; m.p. 119.1e119.8 ꢀC; Yield: 93%; 1H NMR:
146.3, 137.2, 137.0, 129.0, 127.7, 123.3, 104.4, 88.3, 74.6, 59.9,
(300 MHz, CDCl3)
(m, 2H), 5.36 (d, 2H), 5.18 (dd, 1H), 4.99 (dd, 1H), 4.39 (m, 2H) ppm
13C NMR (300 MHz, CDCl3)
: 163.9, 160.7, 150.8, 141.0, 137.2, 131.5,
d: 7.29 (m, 7H), 6.93 (m, 1H), 6.49 (m, 1H), 5.56
55.8 ppm; ESIMS: m/s (%): 275.70 [M ꢃ H]ꢃ; Anal. calcd for
C
15H16O5: C 65.21, H 5.84. Found: C 65.31, H 5.90%.
d

Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
75
129.2, 128.8, 127.7, 127.0, 125.6, 117.7, 115.1, 85.6, 74.1, 44.8 ppm;
5.2.14. 2-(4-Fluorophenyl)-N-(3-methoxyphenethyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6n)
Color: White; m.p. 109.6e110.4 ꢀC; Yield: 93%; 1H NMR:
(300 MHz, CDCl3) : 7.29 (m, 6H), 6.92 (m, 2H), 6.49 (m, 1H), 5.78 (b,
ESIMS: m/s (%): 322.34 [M ꢃ H]ꢃ; Anal. calcd for C20H18FNO2: C
74.29, H 5.61 N 4.33. Found: C 74.01, H 5.56, N 4.50%.
d
5.2.7. 2-(4-Fluorophenyl)-N-(4-methylbenzyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6g)
1H), 5.53 (d, 1H), 5.39 (d, 1H), 5.18 (dd, 1H), 4.99 (dd, 1H), 4.39 (m,
2H), 3.78 ppm (m, 2H); ESIMS: m/s (%): 366.28 [M ꢃ H]ꢃ; Anal. calcd
for C22H22FNO3: C 71.92, H 6.04 N 3.81. Found: C 71.89, H 5.99, N
3.92%.
Color: White; m.p. 113.9e114.6 ꢀC; Yield: 91%; 1H NMR:
(300 MHz, CDCl3) d: 8.56 (m, 1H), 7.41 (m, 4H), 6.90 (m, 5H), 6.49
(m, 1H), 5.49 (d, 1H), 5.25 (d, 1H), 4.96 (m, 2H), 4.21 (m, 2H),
2.23 ppm (s,3H); ESIMS: m/s (%): 336.12 [M ꢃ H]ꢃ; Anal. calcd for
5.2.15. N-Cyclohexyl-2-(4-fluorophenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (6o)
C
20H18FNO3: C 74.76, H 5.97 N 4.15. Found: C 74.59, H 5.77, N 4. 31%.
Color: White; m.p. 72.3e72.8 ꢀC; Yield: 93%; 1H NMR: (300 MHz,
5.2.8. N-(3,4-Dimethoxybenzyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6h)
CDCl3)
(dd, 1H), 4.97 (dd, 1H), 3.19 (m, 1H), 1.29 (m, 6H), 1.05 (m, 2H),
0.83 ppm (m, 2H); 13C NMR (300 MHz, CDCl3)
: 166.3, 162.6, 150.6,
d: 7.33 (m, 5H), 6.49 (m, 1H), 5.49 (d, 1H), 5.32 (m, 2H), 5.18
Color: White; m.p. 98.2e98.8 ꢀC; Yield: 92%; 1H NMR:
d
(300 MHz, CDCl3)
d
: 7.30 (m, 5H), 6.83 (m, 1H), 6.54 (m, 2H), 6.49
138.0,130.1,129.2,128.7,117.4,115.1, 82.5, 52.3, 31.8, 25,4, 25.9 ppm;
ESIMS: m/s (%): 314.74 [M ꢃ H]ꢃ; Anal. calcd for C19H22FNO2: C
72.36, H 7.03 N 4.44. Found: C 72.35, H 7.11, N 4.37%.
(m, 1H), 5.73 (b, 1H), 5.54 (d, 1H), 5.38 (d, 1H), 5.18 (dd, 1H), 4.99
(dd, 1H), 4.30 (m, 2H), 3.83 (m,3H), 3.78 ppm (m,3H); ESIMS: m/s
(%): 382.85 [M ꢃ H]ꢃ; Anal. calcd for C22H22FNO4: C 68.92, H 5.78 N
3.65. Found: C 70.04, H 5.73, N 3.63%.
5.2.16. 2-(4-Fluorophenyl)-N-propyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6p)
5.2.9. N-(2-Fluorobenzyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6i)
Color: White; m.p. 87.5e88.2 ꢀC; Yield: 93%; 1H NMR: (300 MHz,
CDCl3) d: 7.33 (m, 5H), 6.49 (m, 1H), 5.51 (d, 1H), 5.31 (m, 2H), 5.12
Color: White; m.p. 106.5e107.0 ꢀC; Yield: 93%; 1H NMR:
(dd, 1H), 4.97 (dd, 1H), 3.16 (m, 2H), 1.29 (m, 2H), 0.82 ppm (m, 3H);
ESIMS: m/s (%): 274.54 [M ꢃ H]ꢃ; Anal. calcd for C16H18FNO2: C
69.80, H 6.59 N 5.09. Found: C 69.99, H 6.55, N 5.03%.
(300 MHz, CDCl3) d: 7.30 (m, 6H), 6.96 (m, 3H), 6.49 (m, 1H), 5.79 (b,
1H), 5.52(d, 1H), 5.34 (d, 1H), 5.18 (dd, 1H), 4.99 (dd, 1H), 4.41 ppm
(m, 2H); ESIMS: m/s (%): 340.11 [M ꢃ H]ꢃ; Anal. calcd for
C
20H17F2NO2: C 70.37, H 5.02 N 4.10. Found: C 70.18, H 5.02, N 4.13%.
5.2.17. 2-(4-Fluorophenyl)-N-pentyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6q)
5.2.10. N-(4-Chlorobenzyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6j)
Color: White; m.p. 78.5e78.9 ꢀC; Yield: 94%; 1H NMR:
(300 MHz, CDCl3) d: 7.33 (m, 5H), 6.49 (m, 1H), 5.49 (d, 1H), 5.32 (m,
Color: White; m.p. 137.5e138.0 ꢀC; Yield: 92%; 1H NMR:
2H), 5.18 (m, 2H), 4.97 (dd, 1H), 3.78 (m, 2H), 1.54 (m, 4H), 1.09 (m,
2H), 0.83 ppm (m, 3H); ESIMS: m/s (%): 302.20 [M ꢃ H]ꢃ; Anal. calcd
for C18H22FNO2: C 71.26, H 7.31, N 4.62. Found: C 71.45, H 7.25, N
4.60%.
(300 MHz, CDCl3) d: 7.30 (m, 5H), 6.89 (m, 4H), 6.49 (m, 1H), 5.74 (b,
1H), 5.54 (d, 1H), 5.38 (d, 1H), 5.18 (dd, 1H), 4.99 (dd, 1H), 4.41 (m,
1H), 4.28 ppm (m,1H); ESIMS: m/s (%): 356.33 [M ꢃ H]ꢃ; Anal. calcd
for C20H17ClFNO2: C 67.14, H 4.79 N 3.91. Found: C 67.01, H 4.56, N
3.52%.
5.2.18. 2-(4-Fluorophenyl)-N-isobutyl-4-vinyl-2,5-dihydrofuran-3-
carboxamide (6r)
5.2.11. N-(4-Fluorophenethyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6k)
Color: White; m.p. 91.1e91.7 ꢀC; Yield: 93%; 1H NMR: (300 MHz,
CDCl3)
d
: 7.33 (m, 5H), 6.49 (m, 1H), 5.48 (d, 1H), 5.32 (d, 1H), 5.09
Color: White; m.p. 120.3e120.8 ꢀC; Yield: 91%; 1H NMR:
(m, 3H), 1.18 ppm (m, 9H); 13C NMR (300 MHz, CDCl3)
d
: 166.3,
(300 MHz, CDCl3)
1H), 5.32 (m, 2H), 5.09 (dd, 1H), 4.99 (dd, 1H), 3.48 (m, 2H),
2.73 ppm (m,2H); 13C NMR (300 MHz, CDCl3)
: 168.1, 160.2, 150.5,
d
: 7.31 (m, 4H), 6.91 (m, 4H), 6.39 (m, 1H), 5.51 (d,
162.6, 150.6, 138.0, 130.1, 129.2, 128.7, 117.4, 115.1, 85.8, 82.5, 41.3,
28.1, 21.4 ppm; ESIMS: m/s (%): 288.34 [M ꢃ H]ꢃ; Anal. calcd for
d
C17H20FNO2: C 70.57, H 6.97 N 4.84. Found: C 70.44, H 7.96, N 4.80%.
141.0, 136.7, 131.7, 130.5, 129.1, 128.7, 117.4, 115.1, 114.6, 86.1, 74.6,
41.5, 37.2 ppm; ESIMS: m/s (%): 354.28 [M ꢃ H]ꢃ; Anal. calcd for
5.2.19. N-tert-Butyl-2-(4-fluorophenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (6s)
C
21H19F2NO2: C 70.97, H 5.39 N 3.94. Found: C 71.00, H 5.92, N
3.62%.
Color: White; m.p. 84.9e85.6 ꢀC; Yield: 94%; 1H NMR:
(300 MHz, CDCl3) d: 7.33 (m, 5H), 6.49 (m, 1H), 5.51 (d, 1H), 5.31 (m,
5.2.12. N-(2-Fluorophenethyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6l)
2H), 5.12 (dd, 1H), 4.97 (dd, 1H), 3.09 (m, 1H), 2.91 (m, 1H), 1.56 (m,
1H), 0.62 ppm (m, 6H); ESIMS: m/s (%): 288.21 [M ꢃ H]ꢃ; Anal. calcd
for C17H20F2NO2: C 70.57, H 6.97 N 4.84. Found: C 70.66, H 6.85, N
4.75%.
Color: White; m.p. 92.1e92.9 ꢀC; Yield: 97%; 1H NMR: (300 MHz,
CDCl3) d: 7.29 (m, 6H), 6.96 (m, 3H), 6.40 (m, 1H), 5.49 (d, 1H), 5.36
(m, 2H), 5.18 (dd, 1H), 4.99 (dd, 1H), 3.49 (m, 2H), 2.73 ppm (m,2H);
ESIMS: m/s (%): 354.21 [M ꢃ H]ꢃ; Anal. calcd for C21H19F2NO2: C
70.97, H 5.39 N 3.94. Found: C 71.01, H 5.85, N 3.75%.
5.2.20. 2-(3,4-Dichlorophenyl)-N-phenyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (7a)
Color: White; m.p. 179.4e179.8 ꢀC; Yield: 85%; 1H NMR:
5.2.13. N-(3-Fluorophenethyl)-2-(4-fluorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (6m)
(300 MHz, CDCl3) d: 7.50 (m, 2H, Ph-H); 7.34 (m, 5H, Ph-H); 7.17 (m,
1H, Ph-H); 7.11 (m, 1H, C]CHe); 7.01 (s, 1H, eCONH); 6.08 (t, 1H,
eCHePh); 5.59 (d, 1H, CH2]Ce); 5.43 (d, 1H, CH2]Ce); 5.21 (dd,
1H, eCH2eO); 5.02 ppm (dd, 1H, eCH2eO); 13C NMR (300 MHz,
Color: White; m.p. 96.8e97.5 ꢀC; Yield: 96%; 1H NMR:
(300 MHz, CDCl3) d: 7.29 (m, 6H), 6.90 (m, 1H), 6.88 (m, 2H), 6.39
(m, 1H), 5.51 (d, 1H), 5.35 (m, 2H), 5.18 (dd, 1H), 4.99 (dd, 1H), 3.49
(m, 2H), 2.79 ppm (m, 2H); ESIMS: m/s (%): 354.16 [M ꢃ H]ꢃ; Anal.
calcd for C21H19F2NO2: C 70.97, H 5.39 N 3.94. Found: C 71.01, H
5.47, N 3.93%.
CDCl3) d: 163.8, 143.4, 133.5, 130.3, 130.0, 129.8, 129.2, 128.0, 127.8,
127.5, 127.2, 126.4, 125.3, 124.7, 123.4, 68.7, 75.9 ppm; ESIMS: m/s
(%): 358.28 [M ꢃ H]ꢃ; Anal. calcd for C19H15Cl2NO2: C 63.35, H
4.20 N 3.89. Found: C 63.66, H 4.43, N 3.68%.

76
Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
5.2.21. 2-(3,4-Dichlorophenyl)-N-(2-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (7b)
5.2.27. 2-(4-Methoxyphenyl)-N-phenyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8a)
Color: White; m.p. 142.9e144.1 ꢀC; Yield: 88%; 1H NMR:
Color: White; m.p. 116.5e116.8 ꢀC; Yield: 85%; 1H NMR:
(300 MHz, CDCl3)
d: 8.30 (m, 1H, eCONH); 7.53 (m, 1H, Ph-H); 7.42
(300 MHz, CDCl3) d: 7.40 (q, 1H, C]CHe); 7.37 (m, 2H, Ph-H); 7.24
(m,1H, Ph-H); 7.33 (q,1H, C]CHe); 7.28 (m, 2H, Ph-H); 7.03 (m,1H,
Ph-H); 6.93 (m, 1H, Ph-H); 6.81 (m, 1H, Ph-H); 6.04 (t, 1H,
eCHePh); 5.59 (d, 1H, CH2]Ce); 5.43 (m, 1H, CH2]Ce); 5.18 (dd,
1H, eCH2eO); 5.02 (dd, 1H, eCH2eO); 3.74 ppm (m, 3H, eOCH3);
ESIMS: m/s (%): 390.07 [M þ H]þ; Anal. calcd for C20H17Cl2NO3: C
61.55, H 4.39 N 3.59. Found: C 61.59, H 4.40, N 3.57%.
(m, 2H，Ph-H); 7.21 (m, 2H，Ph-H); 7.07 (m, 1H, Ph-H); 6.98 (m,
2H, Ph-H); 6.87 (s, 1H, eCONH); 5.99 (t, 1H, eCHePh); 5.56 (d, 1H,
CH2]Ce); 5.40 (d, 1H, CH2]Ce); 5.15 (dd, 1H, eCH2eO); 4.99 (dd,
1H, eCH2eO); 3.84 ppm (s, 3H, eOCH3); 13C NMR (300 MHz, CDCl3)
d: 163.8, 158.2, 148.4, 135.3, 136.7, 129.3, 128.2, 128.3, 128.0, 127.7,
123.1, 121.4, 113.5, 87.7, 74.3, 55.0 ppm; ESIMS: m/s (%): 320.14
[M ꢃ H]ꢃ; Anal. calcd for C20H19NO3: C 74.75, H 5.96 N 4.36. Found:
C 74.48, H 5.75, N 4.32%.
5.2.22. N-Benzyl-2-(3,4-dichlorophenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (7c)
Color: White; m.p. 149.3e149.5 ꢀC; Yield: 80%; 1H NMR:
5.2.28. 2-(4-Methoxyphenyl)-N-m-tolyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8b)
(300 MHz, CDCl3) d: 7.41 (m, 2H, Ph-H); 7.31 (m, 1H, Ph-H); 7.25 (m,
Color: White; m.p. 138.6e140.4 ꢀC; Yield: 95%; IR (KBr, cmꢃ1):
3294, 2923, 2853, 1637, 1611, 1591, 1528, 1515, 1456, 1383, 1301,
1281, 1253, 1173, 1110, 1069, 1020, 918, 836, 808, 773, 738, 688, 603,
4H, Ph-H); 7.18 (m, 1H, Ph-H); 7.06 (q, 1H, C¼CH-); 6.95 (m, 1H, Ph-
H); 5.99 (t, 1H, eCHePh); 5.52 (d, 1H, CH2]Ce); 5.38 (s, 1H, CH2]
Ce); 5.32 (s, 1H, eCONH); 5.15 (dd, 1H, eCH2eO); 4.97 (dd, 1H,
eCH2eO); 4.40 ppm (m, 2H, eNeCH2); 13C NMR (300 MHz, CDCl3)
551, 439; 1H NMR: (300 MHz, CDCl3)
d: 7.49 (q, 1H, C]CHe); 7.39
d: 165.8, 147.2, 134.3, 131.5, 130.0, 129.3, 128.2, 128.0, 127.8, 127.3,
(m, 2H, Ph-H); 7.26 (s, 1H, Ph-H); 7.07 (m, 1H, Ph-H); 6.99 (m, 2H,
Ph-H); 6.88 (m, 2H, Ph-H); 6.81 (s, 1H, eCONH); 5.99 (t, 1H,
eCHePh); 5.55 (d, 1H, CH2]Ce); 5.40 (d, 1H, CH2]Ce); 5.15 (dd,
1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 3.84 (s, 3H, eOCH3);
2.28 ppm (s, 3H, eCH3); ESIMS: m/s (%): 334.53 [M ꢃ H]ꢃ; Anal.
calcd for C21H21NO3: C 75.20, H 6.31 N 4.18. Found: C 75.12, H 6.39,
N 4.26%.
126.9, 126.4, 125.3, 124.7, 122.3, 68.7, 75.9, 45.2 ppm; ESIMS: m/s
(%): 374.07 [M þ H]þ; Anal. calcd for C20H17Cl2NO2: C 64.18, H
4.58 N 3.74. Found: C 64.11, H 4.53, N 3.73%.
5.2.23. 2-(3,4-Dichlorophenyl)-N-propyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (7d)
Color: White; m.p. 149.2e149.6 ꢀC; Yield: 80%; 1H NMR:
(300 MHz, CDCl3) d: 7.44 (m, 2H, Ph-H); 7.24 (m, 1H, Ph-H); 7.04 (q,
5.2.29. 2-(4-Methoxyphenyl)-N-p-tolyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8c)
1H, C]CHe); 5.99 (s, 1H, eCHePh); 5.52 (d, 1H, CH2]Ce); 5.37 (s,
1H, CH2]Ce); 5.31 (s,1H, eCONH); 5.14 (dd,1H, eCH2eO); 4.97 (dd,
1H, eCH2eO); 3.19 (m, 2H, -N-CH2); 1.40 (m, 2H, CH2); 0.85 ppm (m,
3H, CH3); ESIMS: m/s (%): 324.17 [M ꢃ H]ꢃ; Anal. calcd for
Color: White; m.p. 201e201.3 ꢀC; Yield: 88%; IR (KBr, cmꢃ1):
3299, 2923, 2852, 1635, 1596, 1517, 1459, 1402, 1383, 1317, 1253,
1173, 1110, 1069, 1024, 994, 945, 920, 894, 803, 778, 743, 702, 570,
C
16H17Cl2NO2: C 58.91, H 5.25 N 4.29. Found: C 58.90, H 5.32, N 4.21%.
545, 509, 458; 1H NMR: (300 MHz, CDCl3)
d: 7.50 (q, 1H, C]CHe);
7.40 (m, 2H, Ph-H); 7.07 (m, 4H, Ph-H); 6.97 (m, 2H, Ph-H); 6.80 (s,
1H, eCONH); 5.98 (t, 1H, eCHePh); 5.55 (d, 1H, CH2]Ce); 5.36 (m,
1H, CH2]Ce); 5.14 (dd, 1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 3.84
(s, 3H, eOCH3); 2.27 ppm (s, 3H, CH3); ESIMS: m/s (%): 334.55
[M ꢃ H]ꢃ; Anal. calcd for C21H21NO3: C 75.20, H 6.31 N 4.18. Found:
C 75.12, H 6.41, N 4.20%.
5.2.24. 2-(3,4-Dichlorophenyl)-N-pentyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (7e)
Color: White; m.p. 126.9e127.6 ꢀC; Yield: 80%; 1H NMR:
(300 MHz, CDCl3) d: 7.43 (m, 2H, Ph-H); 7.23 (m, 1H, Ph-H); 7.04 (q,
1H, C]CHe); 5.98 (t, 1H, eCHePh); 5.51 (d, 1H, CH2]Ce); 5.35 (m,
1H, CH2]Ce); 5.30 (m, 1H, eCONH); 5.14 (dd, 1H, eCH2eO); 4.95
(dd, 1H, eCH2eO); 3.20 (m, 2H, -N-CH2); 1.29 (m, 4H, CH2); 1.11 (m,
2H, CH2); 1.06 (m, 2H, CH2); 0.84 ppm (m, 3H, CH3); ESIMS: m/s (%):
352.12 [M ꢃ H]ꢃ; Anal. calcd for C18H21Cl2NO2: C 61.02, H 5.97 N
3.95. Found: C 61.00, H 5.94, N 3.98%.
5.2.30. N-(2-Methoxyphenyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8d)
Color: White; m.p.110e110.5 ꢀC; Yield: 82%; 1H NMR: (300 MHz,
CDCl3) d: 8.35 (q, 1H, eCONH); 7.53 (m, 2H, Ph-H); 7.34 (m, 2H, Ph-
H); 6.95 (m, 4H, Ph-H); 6.75 (m, 1H, C]CHe); 6.02 (m, 1H,
eCHePh); 5.55 (d, 1H, CH2]Ce); 5.40 (d, 1H, CH2]Ce); 5.14 (dd,
1H, eCH2eO); 4.98 (dd, 1H, eCH2eO); 3.85 (s, 3H, eOCH3);
3.61 ppm (s, 3H, eOCH3); ESIMS: m/s (%): 350.12 [M ꢃ H]ꢃ; Anal.
calcd for C21H21NO4: C 71.78, H 6.02 N 3.99. Found: C 71.66, H 6.11, N
3.91%.
5.2.25. 2-(3,4-Dichlorophenyl)-N-isobutyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (7f)
Color: White; m.p. 158.5e159.2 ꢀC; Yield: 87%; 1H NMR:
(300 MHz, CDCl3)d: 7.45 (m, 2H, Ph-H); 7.24 (m,1H, Ph-H); 7.07 (q,1H,
C]CHe); 5.99 (t, 1H, eCHePh); 5.52 (d, 1H, CH2]Ce); 5.38 (s, 1H,
CH2]Ce); 5.31 (m,1H, eCONH); 5.15 (dd,1H, eCH2eO); 4.97 (dd,1H,
eCH2eO); 3.05 (m, 2H, eNeCH2); 1.63 (m, 1H, eNeCH); 0.81 ppm
(m, 6H, CH3); ESIMS: m/s (%): 338.08 [M ꢃ H]ꢃ; Anal. calcd for
5.2.31. N-(4-Ethoxyphenyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8e)
C17H19Cl2NO2: C 60.01, H 5.63 N 4.12. Found: C 60.34, H 5.56, N 4.24%.
Color: White; m.p. 188.1e188.4 ꢀC; Yield: 90%; IR (KBr, cmꢃ1):
3334, 2955, 2924, 2851, 1635, 1598, 1517, 1476, 1409, 1384, 1303,
1249, 1174, 1116, 1073, 1048, 1026, 932, 817, 805, 662, 592, 519; 1H
5.2.26. N-tert-Butyl-2-(3,4-dichlorophenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (7g)
Color: White; m.p. 108.8e109.3 ꢀC; Yield: 75%; 1H NMR:
NMR: (300 MHz, CDCl3) d: 7.50 (q,1H, C]CHe); 7.38 (m, 2H, Ph-H);
(300 MHz, CDCl3) d: 7.45 (m, 2H, Ph-H); 7.23 (m, 1H, Ph-H); 6.95 (q,
7.27 (s, 1H, eCONH); 7.10 (m, 2H, Ph-H); 6.98 (m, 2H, Ph-H); 6.76
(m, 2H, Ph-H); 5.99 (t, 1H, eCHePh); 5.54 (d, 1H, CH2]Ce); 5.36 (t,
1H, CH2]Ce); 5.14 (dd, 1H, eCH2eO); 4.98 (dd, 1H, eCH2eO); 3.97
1H, C]CHe); 5.97 (t, 1H, eCHePh); 5.48 (d, 1H, CH2]Ce); 5.30 (d,
1H, CH2]Ce); 5.14 (m, 1H, eCONH); 5.10 (m, 1H, eCH2eO); 4.95
(dd, 1H, eCH2eO); 1.26 ppm (m, 9H, CH3); 13C NMR (300 MHz,
(m, 2H, OeCH2e); 3.84 (s, 3H, eOCH3); 1.40 ppm (m, 3H, CH3); 13
C
CDCl3) d: 165.8, 147.1, 131.5, 130.5, 129.3, 128.3, 127.2, 127.5, 124.8,
NMR (300 MHz, CDCl3) d: 169.2, 158.1, 156.2, 143.8, 139.3, 136.7,
123.9, 69.0, 75.2, 64.3, 26,9 ppm; ESIMS: m/s (%): 338.16 [M ꢃ H]ꢃ;
Anal. calcd for C17H19Cl2NO2: C 60.01, H 5.63 N 4.12. Found: C 60.06,
H5.73, N 4.21%.
129.3, 128.0, 127.8, 127.4, 123.1, 121.1, 113.5, 85.3, 74.3, 70.0, 53.5,
13.4 ppm; ESIMS: m/s (%): 364.49 [M ꢃ H]ꢃ; Anal. calcd for
C22H23NO4: C 72.31, H 6.34 N 3.83. Found: C 72.01, H 6.56, N 3.77%.

Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
77
5.2.32. N-Benzyl-2-(4-methoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8f)
eNeCH2e); 2.61 ppm (m, 2H, eCH2-Ph); ESIMS: m/s (%): 366.38
[M ꢃ H]ꢃ; Anal. calcd for C22H22FNO3: C 71.92, H 6.04 N 3.81. Found:
C 71.88, H 6.10, N 3.72%.
Color: White; m.p. 165.1e165.5 ꢀC; Yield: 93%; IR (KBr, cmꢃ1):
3300, 3062, 3032, 3002, 2925, 2848, 1658, 1624, 1588, 1510, 1454,
1424, 1384, 1354, 1314, 1247, 1175, 1148, 1112, 1077, 1030, 986, 945,
934, 914, 849, 813, 768, 737, 723, 697, 602, 566, 537, 484; 1H NMR:
5.2.38. N-(2-Fluorophenethyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8l)
(300 MHz, CDCl3)
d: 7.40 (q, 1H, C]CHe); 7.26 (d, 2H, Ph-H); 6.88
Color: White; m.p. 123.3e123.6 ꢀC; Yield: 94%; 1H NMR:
(d, 2H, Ph-H); 5.92 (m, 1H, eCHePh); 5.50 (d, 1H, CH2]Ce); 5.41 (s,
1H, eCONH); 5.34 (d, 1H, CH2]Ce); 5.11 (dd, 1H, eCH2eO); 4.94
(dd, 1H, eCH2eO); 4.36 (m, 2H, -NeCH2e); 3.80 ppm (s, 3H,
(300 MHz, CDCl3) d: 7.30 (q, 1H, C]CHe); 7.20 (m, 2H, Ph-H); 7.00
(m, 2H, Ph-H); 6.90 (m, 1H, Ph-H); 6.84 (m, 2H, Ph-H); 5.82 (t, 1H,
eCHePh); 5.46 (d, 1H, CH2]Ce); 5.30 (d, 1H, CH2]Ce); 5.19 (s, 1H,
eCONH); 5.06 (dd, 1H, eCH2eO); 4.90 (dd, 1H, eCH2eO); 3.80 (s,
3H, eOCH3); 3.42 (m, 2H, eNeCH2e); 2.68 ppm (m, 2H, eCH2-Ph);
ESIMS: m/s (%): 366.05 [M ꢃ H]ꢃ; Anal. calcd for C22H22FNO3: C
71.92, H 6.04 N 3.81. Found: C 71.85, H 6.10, N 3.79%.
eOCH3); 13C NMR (300 MHz, CDCl3)
d: 163.8, 158.9, 150.8, 141.0,
133.2, 131.5, 128.1, 128.9, 127.7, 125.8, 125.6, 116.7, 115.1, 85.6, 74.2,
53.6, 44.8 ppm; ESIMS: m/s (%): 334.14 [M ꢃ H]ꢃ; Anal. calcd for
C
21H21NO3: C 75.20, H 6.31 N 4.18. Found: C 75.02, H 6.43, N 4.30%.
5.2.33. 2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8g)
5.2.39. N-(3-Fluorophenethyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8m)
Color: White; m.p. 150.4e150.7 ꢀC; Yield: 92%; 1H NMR:
Color: White; m.p. 114.9e115.8 ꢀC; Yield: 90%; IR (KBr, cmꢃ1):
3310, 3064, 3013, 2953, 2924, 2858, 1621, 1588, 1540, 1511, 1486,
1446, 1383, 1249, 1195, 1173, 1139, 1110, 1062, 1032, 1004, 935, 919,
857, 830, 807, 787, 747, 690, 561, 520, 456; 1H NMR: (300 MHz,
(300 MHz, CDCl3) d: 7.40 (q, 1H, C]CHe); 7.25 (m, 2H, Ph-H); 7.02
(t, 2H, Ph-H); 6.86 (m, 2H, Ph-H); 6.77 (d, 2H, Ph-H); 5.91 (t, 1H,
eCHePh); 5.50 (d, 1H, CH2]Ce); 5.51 (s, 1H, eCONH); 5.49 (d, 1H,
CH2]Ce); 5.11 (dd, 1H, eCH2eO); 4.94 (dd, 1H, eCH2eO); 4.29 (m,
2H, eNeCH2e); 3.81 (s, 3H, eOCH3); 2.31 ppm (s, 3H, eCH3);
ESIMS: m/s (%): 348.12 [M ꢃ H]ꢃ; Anal. calcd for C22H23NO3: C
75.62, H 6.63 N 4.01. Found: C 75.59, H 6.77, N 4. 08%.
CDCl3) d: 7.33 (m, 1H, C]CHe); 7.20 (m, 1H, Ph-H); 7.14 (m, 2H, Ph-
H); 6.92 (m, 1H, Ph-H); 6.86 (m, 2H, Ph-H); 6.70 (m, 2H, Ph-H); 5.80
(t,1H, eCHePh); 5.48 (m,1H, CH2]Ce); 5.32 (d,1H, CH2]Ce); 5.17
(s, 1H, eCONH); 5.06 (dd, 1H, eCH2eO); 4.91 (dd, 1H, eCH2eO);
3.85 (s, 3H, eOCH3); 3.43 (m, 2H, eNeCH2e); 2.64 (m, 2H, eCH2-
Ph); ESIMS: m/s (%): 366.06 [M ꢃ H]ꢃ; Anal. calcd for C22H22FNO3: C
71.92, H 6.04 N 3.81. Found: C 71.76, H 6.07, N 3.77%.
5.2.34. N-(3,4-Dimethoxybenzyl)-2-(4-methoxyphenyl)-4-vinyl-
2,5-dihydrofuran-3-carboxamide (8h)
Color: White; m.p. 162.4e162.5 ꢀC; Yield: 92%; 1H NMR:
(300 MHz, CDCl3)
d
: 7.37 (q,1H, C]CHe); 7.25 (m, 2H， Ph-H); 6.84
5.2.40. N-(3-Methoxyphenethyl)-2-(4-methoxyphenyl)-4-vinyl-
2,5-dihydrofuran-3-carboxamide (8n)
(m, 2H, Ph-H); 6.70 (d, 1H, Ph-H); 6.46 (m, 2H, Ph-H); 5.91 (t, 1H,
eCHePh); 5.50 (d, 1H, CH2]Ce); 5.39 (s, 1H, eCONH); 5.37 (d, 1H,
CH2]Ce); 5.10 (dd, 1H, eCH2eO); 4.94 (dd, 1H, eCH2eO); 4.26 (m,
2H, eNeCH2e); 3.86 (s, 3H, eOCH3); 3.76 ppm (m, 6H, eOCH3);
ESIMS: m/s (%): 394.55 [M ꢃ H]ꢃ; Anal. calcd for C23H25NO5: C
69.86, H 6.37 N 3.54. Found: C 70.00, H 6.16, N 3.53%.
Color: White; m.p. 145.5e145.7 ꢀC; Yield: 91%; 1H NMR:
(300 MHz, CDCl3) d: 7.30 (q, 1H, C]CHe); 7.20 (m, 2H, Ph-H); 7.00
(m, 2H, Ph-H); 6.90 (m, 1H, Ph-H); 6.84 (m, 2H, Ph-H); 5.82 (t, 1H,
eCHePh); 5.46 (d, 1H, CH2]Ce); 5.30 (d, 1H, CH2]Ce); 5.19 (s, 1H,
eCONH); 5.06 (dd, 1H, eCH2eO); 4.90 (dd, 1H, eCH2eO); 3.80 (s,
3H, eOCH3); 3.42 (m, 2H, -NeCH2e); 2.68 ppm (m, 2H, eCH2-Ph);
5.2.35. N-(2-Fluorobenzyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8i)
13C NMR (300 MHz, CDCl3)
d: 168.0, 160.6, 159.7, 150.3, 138.6, 137.2,
130.3, 129.0, 128.4, 123.3, 118.4, 114.5, 113.4, 115.2, 88.3, 80.4, 55.8,
Color: White; m.p. 142.3e142.9 ꢀC; Yield: 87%; 1H NMR:
40.3, 35.4 ppm; ESIMS: m/s (%): 378.29 [M ꢃ H]ꢃ; Anal. calcd for
(300 MHz, CDCl3)
d
: 7.37 (q, 1H, C]CHe); 7.27 (m, 2H, Ph-H); 7.20
C23H25NO4: C 72.80, H 6.64 N 3.69. Found: C 72.89, H 6.59, N 3.72%.
(m, 1H, Ph-H); 6.98 (m, 2H, Ph-H); 6.88 (m, 2H, Ph-H); 5.90 (t, 1H,
eCHePh); 5.50 (d,1H, CH2]Ce); 5.34 (d,1H, CH2]Ce); 5.10 (dd,1H,
eCH2eO); 4.93 (dd,1H, eCH2eO); 4.37 (d, 2H, eNeCH2e); 3.85 ppm
(s, 3H, eOCH3); ESIMS: m/s (%): 352.67 [M ꢃ H]ꢃ; Anal. calcd for
5.2.41. N-Cyclohexyl-2-(4-methoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8o)
Color: White; m.p. 167.2e167.5 ꢀC; Yield: 91%; 1H NMR:
C
21H20FNO3: C 71.37, H 5.70 N 3.96. Found: C 71.18, H 5.59, N 4.02%.
(300 MHz, CDCl3) d: 7.38 (q, 1H, C]CHe); 7.28 (m, 2H, Ph-H); 6.92
(m, 2H, Ph-H); 5.88 (t, 1H, eCHePh); 5.48 (d, 1H, CH2]Ce); 5.31
(m, 1H, CH2]Ce); 5.11 (m, 1H, eCH2eO); 5.06 (m, 1H, eCONH);
4.92 (dd, 1H, eCH2eO); 3.81 (s, 3H, eOCH3); 1.24 ppm (m, 10H,
5.2.36. N-(4-Chlorobenzyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8j)
Color: White; m.p. 166.8e167.2 ꢀC; Yield: 92%; 1H NMR:
CH2); 13C NMR (300 MHz, CDCl3)
d: 164.2, 158.9, 146.1, 133.5, 129.3,
(300 MHz, CDCl3)
d
: 7.39 (q, 1H, C]CHe); 7.25 (d, 2H， Ph-H); 7.15
128.3, 127.7, 123.2, 114.5, 85.7, 74.3, 55.1, 52.5, 31.9, 27.3, 24.2 ppm;
ESIMS: m/s (%): 326.76[M ꢃ H]ꢃ; Anal. calcd for C20H25NO3: C 73.37,
H 7.70 N 4.28. Found: C 73.16, H 7.84, N 4.44%.
(d, 2H，Ph-H); 6.87 (d, 2H，Ph-H); 6.77 (d, 2H, Ph-H); 5.90 (t, 1H,
eCHePh); 5.51 (d, 1H, CH2]Ce); 5.41 (s, 1H, eCONH); 5.31 (d, 1H,
CH2]Ce); 5.11 (dd, 1H, eCH2eO); 4.94 (dd, 1H, eCH2eO); 4.30 (m,
2H, eNeCH2e) 3.81 ppm (s, 3H, eOCH3); ESIMS: m/s (%): 368.28
[M ꢃ H]ꢃ; Anal. calcd for C21H20ClNO3: C 68.20, H 5.45 N 3.79.
Found: C 68.07, H 5.56, N 3.80%.
5.2.42. 2-(4-Methoxyphenyl)-N-propyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8p)
Color: White; m.p. 128.4e128.7 ꢀC; Yield: 93%; IR (KBr, cmꢃ1):
3286, 3083, 2958, 2924, 2853, 1625, 1540, 1513, 1462, 1383, 1301,
1279, 1251, 1174, 1154, 1110, 1066, 1030, 995, 946, 919, 820, 773,
5.2.37. N-(4-Fluorophenethyl)-2-(4-methoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (8k)
709, 571, 542; 1H NMR: (300 MHz, CDCl3)
d: 7.40 (q, 1H, C]
Color: White; m.p. 120.3e120.8 ꢀC; Yield: 91%; 1H NMR:
CHe); 7.28 (m, 2H, Ph-H); 6.91 (m, 2H, Ph-H); 5.88 (t, 1H,
eCHePh); 5.48 (d, 1H, CH2]Ce); 5.32 (d, 1H, CH2]Ce); 5.10 (m,
1H, eCONH); 5.06 (m, 1H, eCH2eO); 4.93 (dd, 1H, eCH2eO);
3.81 (s, 3H, eOCH3); 3.09 (m, 2H, eNeCH2); 1.28 (m, 2H, CH2);
0.85 ppm (m, 3H, CH3); ESIMS: m/s (%): 288.16 [M þ H]þ; Anal.
(300 MHz, CDCl3) d: 7.34 (q, 1H, C]CHe); 7.20 (m, 2H, Ph-H); 6.89
(m, 6H, Ph-H); 5.80 (t, 1H, eCHePh); 5.48 (d, 1H, CH2]Ce); 5.32
(m, 1H, CH2]Ce); 5.12 (s, 1H, eCONH); 5.06 (dd, 1H, eCH2eO);
4.90 (dd, 1H, eCH2eO); 3.81 (s, 3H, eOCH3); 3.40 (m, 2H,

78
Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
calcd for C17H21NO3: C 71.06, H 7.37 N 4.87. Found: C71.01, H
7.45, N 4.71%.
[M ꢃ H]ꢃ; Anal. calcd for C22H23NO4: C 72.31, H 6.34 N 3.83. Found:
C 72.54, H 6.27, N 3.81%.
5.2.43. 2-(4-methoxyphenyl)-N-pentyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8q)
5.2.48. 2-(3,4-Dimethoxyphenyl)-N-(4-methylbenzyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (9c)
Color: White; m.p. 112.4e112.8 ꢀC; Yield: 91; IR (KBr, cmꢃ1):
3319, 3078, 3013, 2954, 2929, 2852, 1621, 1546, 1514, 1464, 1438,
1383, 1351, 1305, 1245, 1172, 1151, 1108, 1071, 1034, 1005, 949, 922,
Color: White; m.p. 153.6e153.8 ꢀC; Yield: 94%; 1H NMR:
(300 MHz, CDCl3) d: 7.44 (q, 1H, C]CHe); 7.02 (m, 2H, Ph-H); 6.89
(m,1H, Ph-H); 6.78 (m, 4H, Ph-H); 5.89 (t,1H, eCHePh); 5.51 (d,1H,
CH2]Ce); 5.45 (s, 1H, eCONH); 5.35 (d, 1H, CH2]Ce); 5.12 (dd, 1H,
eCH2eO); 4.94 (m, 1H, eCH2eO); 4.28 (m, 2H, -N-CH2); 3.88 (s, 3H,
eOCH3); 3.81 (s, 3H, eOCH3); 2.30 ppm (s, 3H, CH3); ESIMS: m/s (%):
378.53 [M ꢃ H]ꢃ; Anal. calcd for C23H25NO4: C 72.80, H 6.64 N 3.69.
Found: C 72.77, H 6.58, N 3.68%.
840, 811, 769, 729, 692, 575, 537; 1H NMR: (300 MHz, CDCl3)
d: 7.43
(q, 1H, C]CHe); 7.29 (m, 2H, Ph-H); 6.92 (m, 2H, Ph-H); 5.89 (t, 1H,
eCHePh); 5.49 (d, 1H, CH2]Ce); 5.33 (d, 1H, CH2]Ce); 5.11 (m,
1H, eCONH); 5.07 (m, 1H, eCH2eO); 4.93 (dd, 1H, eCH2eO); 3.81
(s, 3H, eOCH3); 3.14 (m, 2H, eNeCH2); 1.22 (m, 4H, CH2); 0.95 (m,
2H, CH2); 0.84 ppm (m, 3H, CH3); ESIMS: m/s (%): 314.47 [M ꢃ H]ꢃ;
Anal. calcd for C19H25NO3: C 72.35, H 7.99, N 4.44. Found: C 72.43, H
7.25, N 4.40%.
5.2.49. N-(4-Chlorobenzyl)-2-(3,4-dimethoxyphenyl)-4-vinyl-2,5-
dihydrofuran-3-carboxamide (9d)
Color: White; m.p. 157.4e157.9 ꢀC; Yield: 90%; 1H NMR:
5.2.44. N-Isobutyl-2-(4-methoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8r)
(300 MHz, CDCl3) d: 7.45 (q, 1H, C]CHe); 6.97 (m, 2H, Ph-H); 6.89
(m, 3H, Ph-H); 6.78 (m, 2H, Ph-H); 5.88 (t, 1H, eCHePh); 5.52 (m,
1H, CH2]Ce); 5.47 (s, 1H, eCONH); 5.36 (d, 1H, CH2]Ce); 5.12 (dd,
1H, eCH2eO); 4.94 (dd, 1H, eCH2eO); 4.28 (m, 2H, eNeCH2); 3.87
(s, 3H, eOCH3); 3.81 ppm (s, 3H, eOCH3); ESIMS: m/s (%): 398.63
[M ꢃ H]ꢃ; Anal. calcd for C22H22ClNO4: C 66.08, H 5.55 N 3.50.
Found: C 66.21, H 5.24, N 3.43%.
Color: White; m.p. 140.2e140.4 ꢀC; Yield: 93%; IR (KBr, cmꢃ1):
3280, 3089, 3005, 2960, 2925, 2855, 1621, 1591, 1547, 1513, 1468,
1434, 1384, 1311, 1293, 1277, 1252, 1175, 1157, 1061, 1030, 1006, 923,
829, 816, 764, 700, 598, 543, 471; 1H NMR: (300 MHz, CDCl3)
d:
7.43 (q, 1H, C]CHe); 7.29 (m, 2H, Ph-H); 6.92 (m, 2H, Ph-H); 5.88
(t, 1H, eCHePh); 5.48 (d, 1H, CH2]Ce); 5.32 (m, 1H, CH2]Ce);
5.13 (m, 1H, eCONH); 5.09 (m, 1H, eCH2eO); 4.93 (dd, 1H,
eCH2eO); 3.80 (s, 3H, eOCH3); 2.95 (m, 2H, -N-CH2); 1.52 (m, 1H,
CH); 0.85 ppm (m, 6H, CH3); ESIMS: m/s (%): 300.24 [M ꢃ H]ꢃ;
Anal. calcd for C18H23NO3: C 71.73, H 7.69 N 4.65. Found: C 71.64, H
7.56, N 4.37%.
5.2.50. 2-(3,4-Dimethoxyphenyl)-N-phenyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (9e)
Color: White; m.p. 165.0e165.8 ꢀC; Yield: 91%; 1H NMR:
(300 MHz, CDCl3) d: 7.42 (q, 1H, C]CHe); 6.95 (m, 1H, Ph-H); 6.88
(m,1H, Ph-H); 6.84 (m,1H, Ph-H); 5.87 (t,1H, eCHePh); 5.49 (d,1H,
CH2]Ce); 5.33 (m, 1H, CH2]Ce); 5.13 (s, 1H, eCONH); 5.10 (m, 1H,
eCH2eO); 4.93 (m, 1H, eCH2eO); 3.89 (s, 6H, eOCH3); 3.75 (m, 1H,
5.2.45. N-tert-Butyl-2-(4-methoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (8s)
-N-CH); 1.33 ppm (m, 10H, CH2); 13C NMR (300 MHz, CDCl3)
d:
Color: White; m.p. 151.2e151.4 ꢀC; Yield: 80%; IR (KBr, cmꢃ1):
3341, 3039, 2999, 2966, 2925, 2836, 1628, 1589, 1533, 1512, 1452,
1384, 1365, 1301, 1278, 1242, 1174, 1108, 1076, 1035, 997, 923, 911,
164.0, 153.9, 146.4, 137.2, 135.8, 129.0, 127.7, 125.3, 104.9, 88.5, 74.6,
63.6, 59.9, 55.8, 34.5, 26.4, 22.0 ppm; ESIMS: m/s (%): 356.29
[M ꢃ H]ꢃ; Anal. calcd for C21H27NO4: C 70.56, H 7.61 N 3.92. Found:
C 70.68, H 7.71, N 3.88%.
836, 810, 779, 736, 625, 570, 543, 505; 1H NMR: (300 MHz, CDCl3)
d:
7.37 (q,1H, C]CHe); 7.28 (m, 2H, Ph-H); 6.91 (m, 2H, Ph-H); 5.84 (t,
1H, eCHePh); 5.45 (d, 1H, CH2]Ce); 5.29 (m, 1H, CH2]Ce); 5.07
(dd, 1H, eCH2eO); 4.93 (m, 1H, eCONH); 4.89 (m, 1H, eCH2eO);
3.81 (s, 3H, eOCH3); 1.13 ppm (m, 9H, CH3); ESIMS: m/s (%): 300.11
[M ꢃ H]ꢃ; Anal. calcd for C18H23NO3: C 71.73, H 7.69 N 4.65. Found:
C 71.66, H 7.75, N 4.51%.
5.2.51. 2-(3,4-Dimethoxyphenyl)-N-propyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (9f)
Color: White; m.p. 134.2e134.6 ꢀC; Yield: 90%; 1H NMR:
(300 MHz, CDCl3) d: 7.42 (q, 1H, C]CHe); 6.94 (m, 1H, Ph-H); 6.88
(s, 1H, Ph-H); 6.84 (m, 1H, Ph-H); 5.88 (t, 1H, eCHePh); 5.50 (d, 1H,
CH2]Ce); 5.33 (d, 1H, CH2]Ce); 5.19 (s, 1H, eCONH); 5.10 (dd, 1H,
eCH2eO); 4.93 (m, 1H, eCH2eO); 3.88 (s, 6H, eOCH3); 3.10 (m, 2H,
eNeCH2); 1.85 (m, 2H, CH2); 0.68 ppm (m, 3H, CH3); ESIMS: m/s
(%): 316.57 [M ꢃ H]ꢃ; Anal. calcd for C18H23NO4: C 68.12, H 7.30 N
4.41. Found: C 68.04, H 7.45, N 4.43%.
5.2.46. 2-(3,4-Dimethoxyphenyl)-N-phenyl-4-vinyl-2,5-dihydrofuran-
3-carboxamide (9a)
Color: White; m.p. 161.1e161.8 ꢀC; Yield: 91%; 1H NMR:
(300 MHz, CDCl3) d: 7.51 (q, 1H, C]CHe); 7.25 (m, 2H, Ph-H); 7.19
(m, 2H, Ph-H); 7.06 (m, 2H, Ph-H); 6.94 (m, 2H, Ph-H); 5.98 (s, 1H,
eCHePh); 5.57 (d, 1H, CH2]Ce); 5.41 (d, 1H, CH2]Ce); 5.32 (s, 1H,
eCONH); 5.14 (dd, 1H, eCH2eO); 5.02 (m, 1H, eCH2eO); 3.91 (m,
3H, eOCH3); 3.75 ppm (m, 3H, eOCH3); 13C NMR (300 MHz, CDCl3)
5.2.52. (2-(4-Methoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-yl)(4-
(2-methoxyphenyl)piperazin-1-yl)methanone (10a)
Color: White; m.p. 109.6e110.4 ꢀC; Yield: 80%; 1H NMR:
d: 164.0, 152.7, 146.3, 138.7, 136.2, 135.7, 129.0, 128.5, 128.0, 127.7,
(300 MHz, CDCl3) d: 7.29 (m, 2H, Ph-H); 7.01 (m, 1H, Ph-H); 6.88 (m,
123.3, 121.5, 104.4, 88.5, 74.6, 59.5, 55.4 ppm; ESIMS: m/s (%):
350.29 [M ꢃ H]ꢃ; Anal. calcd for C21H21NO4: C 71.78, H 6.02 N 3.99.
Found: C 71.88, H 6.11, N 3.82%.
1H, Ph-H); 6.85 (m, 3H, Ph-H); 6.67 (m, 1H, Ph-H); 6.40 (q, 1H, C]
CHe); 6.14 (t, 1H, eCHePh); 5.38 (m, 1H, CH2]Ce); 5.24 (m, 1H,
CH2]Ce); 5.20 (m, 1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 4.03 (m,
2H, NeCH2e); 3.85 (s, 3H, eOCH3); 3.74 (s, 3H, eOCH3); 3.44 (m,
3H, NeCH2e); 3.34 (d, 1H, NeCH2e); 2.52 ppm (d, 2H, NeCH2e);
ESIMS: m/s (%): 419.73 [M ꢃ H]ꢃ; Anal. calcd for C25H28N2O4: C
71.41, H 6.71 N 6.66. Found: C 71.34, H 6.75, N 6.55%.
5.2.47. N-Benzyl-2-(3,4-dimethoxyphenyl)-4-vinyl-2,5-dihydrofuran-
3-carboxamide (9b)
Color: White; m.p. 143.1e143.7 ꢀC; Yield: 89%; 1H NMR:
(300 MHz, CDCl3) d: 7.44 (q, 1H, C]CHe); 7.23 (m, 3H, Ph-H); 6.89
(m, 3H, Ph-H); 6.79 (m, 2H, Ph-H); 5.89 (t,1H, eCHePh); 5.53 (s,1H,
CH2]Ce); 5.50 (s, 1H, eCONH); 5.36 (d, 1H, CH2]Ce); 5.12 (dd,1H,
eCH2eO); 4.95 (m, 1H, eCH2eO); 4.33 (m, 2H, eNeCH2); 3.87 (s,
3H, eOCH3); 3.80 ppm (s, 3H, eOCH3); ESIMS: m/s (%): 364.93
5.2.53. (2-(4-Methoxyphenyl)-4-vinyl-2,5-dihydrofuran-3-yl)(4-
(3-methoxyphenyl)piperazin-1-yl)methanone (10b)
Color: White; m.p. 105.8e106.9 ꢀC; Yield: 86%; IR (KBr, cmꢃ1):
3421, 3087, 3002, 2974, 2941, 2892, 2852, 2815, 1621, 1512, 1490,

Y. Zhang et al. / European Journal of Medicinal Chemistry 48 (2012) 69e80
79
1461,1437, 1382, 1342, 1303, 1278, 1248,1196, 1169, 1150, 1112,1068,
1056, 1028, 1007, 988, 946, 845, 812, 766, 692, 609, 547; 1H NMR:
ESIMS: m/s (%): 407.14 [M ꢃ H]ꢃ; Anal. calcd for C24H25FN2O3: C
75.57, H 6.17 N 6.86. Found: C 75.42, H 6.33, N 6.60%.
(300 MHz, CDCl3) d: 7.28 (m, 2H, Ph-H); 7.26 (m, 1H, Ph-H); 6.85 (m,
2H, Ph-H); 6.41 (m, 3H, Ph-H); 6.33 (m, 1H, C]CHe); 6.12 (t, 1H,
eCHePh); 5.38 (m, 1H, CH2]Ce); 5.25 (m, 1H, CH2]Ce); 5.19 (dd,
1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 4.02 (d, 2H, NeCH2e); 3.79
(s, 3H, eOCH3); 3.71 (s, 3H, eOCH3); 3.30 (m, 4H, NeCH2e); 2.88 (d,
1H, NeCH2e); 2.73 ppm (m, 2H, NeCH2e); 13C NMR (300 MHz,
5.2.58. (4-(2,3-Dichlorophenyl)piperazin-1-yl)(2-(4-methoxyphenyl)-
4-vinyl-2,5-dihydrofuran-3-yl)methanone (10g)
Color: White; m.p. 149.8e149.3 ꢀC; Yield: 92%; 1H NMR:
(300 MHz, CDCl3) d: 7.32 (m, 2H, Ph-H); 7.28 (m, 1H, Ph-H); 7.12 (m,
1H, Ph-H); 6.89 (m, 2H, Ph-H); 6.67 (m, 1H, Ph-H); 6.39 (q, 1H, C]
CHe); 6.14 (t, 1H, eCHePh); 5.39 (m, 1H, CH2]Ce); 5.25 (m, 1H,
CH2]Ce); 5.19 (dd, 1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 4.20 (d,
2H, NeCH2e); 3.77 (s, 3H, eOCH3); 3.37 (m, 2H, NeCH2e); 3.05 (d,
2H, NeCH2e); 2.69 ppm (d, 2H, NeCH2e); ESIMS: m/s (%): 457.33
[M ꢃ H]ꢃ; Anal. calcd for C24H24Cl2N2O3: C 62.75, H 5.27 N 6.10.
Found: C 62.71, H 5.26, N 6.12%.
CDCl3) d: 163.8, 160.1, 154.6, 150.5, 146.3, 133.5, 129.9, 129.8, 128.3,
127.7, 123.1, 113.5, 110.4, 110.0, 103.4, 84.7, 75.1, 55.8, 55.0, 55.4,
54.7 ppm; ESIMS: m/s (%): 419.25 [M ꢃ H]ꢃ; Anal. calcd for
C
25H28N2O4: C 71.41, H 6.71 N 6.66. Found: C 71.48, H 6.70, N 6.62%.
5.2.54. (4-(2,3-Dimethylphenyl)piperazin-1-yl)(2-(4-methoxyphenyl)-
4-vinyl-2,5-dihydrofuran-3-yl)methanone (10c)
Color: White; m.p. 176.3e176.5 ꢀC; Yield: 96%; 1H NMR:
5.3. Antitumor screening
(300 MHz, CDCl3) d: 7.32 (m, 2H, Ph-H); 7.06 (m, 1H, Ph-H); 6.92 (m,
1H, Ph-H); 6.89 (m, 2H, Ph-H); 6.61 (m, 1H, Ph-H); 6.40 (q, 1H, C]
CHe); 6.15 (t, 1H, eCHePh); 5.39 (d, 1H, CH2]Ce); 5.25 (m, 1H,
CH2]Ce); 5.20 (m, 1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 3.79 (s,
3H, eOCH3); 3.37 (m, 4H, NeCH2e); 2.84 (m, 2H, NeCH2e); 2.52 (d,
2H, NeCH2e); 2.25 (s, 3H, CH3); 2.18 ppm (s, 3H, CH3); ESIMS: m/s
(%): 417.16 [M ꢃ H]ꢃ; Anal. calcd for C26H30N2O3: C 74.61, H 7.22 N
6.69. Found: C 74.55, H 7.27, N 6.63%.
5.3.1. Methodology of the in vitro cancer screen
In vitro anti-cancer activity was measured by means of the IC50
using the MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium
bromide] assay method [22e25]. Test cancer cell lines were obtained
from the Navy Medical College. The IC50 determination was performed
according to the National Committee for Clinical Laboratory Standards
(NCCLS) recommendations. All compounds were dissolved in DMSO
with the stock concentration of 10 g/L, and diluted with medium
freshly before drug administration. Cell lines were seeded into 96-well
plates at density of 8000 cells/well. 24 h after seeding, each compound
dilution was added in duplicate and incubation continued at 37 ꢀC in
5.2.55. (4-(2-Chlorophenyl)piperazin-1-yl)(2-(4-methoxyphenyl)-
4-vinyl-2,5-dihydrofuran-3-yl)methanone (10d)
Color: White; m.p. 118.7e119.4 ꢀC; Yield: 85%; IR (KBr, cmꢃ1):
3423, 3093, 2971, 2942, 2912, 2847, 2829, 1665, 1632, 1592, 1564,
1508,1482,1462,1435,1382,1334,1302,1275,1244,1169,1151,1102,
1068,1023,1003, 990, 930, 849, 812, 783, 741, 692, 637, 612, 545, 451;
a humidified atmosphere containing 5% CO2. After 24 h, add 20 mL MTT
(Sigma) at 5 mg/mL in PBS (filter sterilized, light protected, and stored
at 4 ꢀC) per well, and after 4 h of incubation at 37 ꢀC, MTT is converted
to a blue formazan product by mitochondrial succinate dehydroge-
nase. This product was eluted from cells by addition of 150 mL of
DMSO. The absorbance at 570 nm was determined by an ELISA using
a ELX800 microplate spectrophotometer. The IC50 value was defined as
the concentration at which 50% of the cells could survive.
1H NMR: (300 MHz, CDCl3)
d: 7.31 (m, 2H, Ph-H); 7.27 (m,1H, Ph-H);
7.19 (m, 1H, Ph-H); 6.99 (m, 2H, Ph-H); 6.75 (m, 1H, Ph-H); 6.39 (q,
1H, C]CHe); 6.14 (t,1H, eCHePh); 5.38 (m,1H, CH2]Ce); 5.23 (m,
1H, CH2]Ce); 5.19 (m,1H, eCH2eO); 4.99 (m,1H, eCH2eO); 4.13 (d,
2H, NeCH2e); 3.76 (s, 3H, eOCH3); 3.36 (m, 2H, NeCH2e); 3.03 (d,
2H, NeCH2e); 2.66 ppm (d, 2H, NeCH2e); 13C NMR (300 MHz,
CDCl3) d: 169.7, 159.7, 150.8, 150.0, 138.3, 133.3, 130.2, 129.4, 129.1,
Acknowledgment
127.2,123.9,117.6,114.2,113.1, 86.1, 80.9, 55.8, 52.8, 49.8 ppm; ESIMS:
m/s (%): 425.16 [M þ H]þ; Anal. calcd for C24H25ClN2O3: C 67.84, H
5.93 N 6.59. Found: C 67.87, H 5.90, N 6.62%.
This work was supported by the National Natural Science
Foundation of China (Grant No. 30973640), Key laboratory of drug
research for special environments, PLA and Shanghai Rising-Star
Program (Grant No. 09QA1407000).
5.2.56. (4-(3-Chlorophenyl)piperazin-1-yl)(2-(4-methoxyphenyl)-
4-vinyl-2,5-dihydrofuran-3-yl)methanone (10e)
Color: White; m.p. 105.4e106.2 ꢀC; Yield: 88%; 1H NMR:
Appendix. Supplementary material
(300 MHz, CDCl3) d: 7.28 (m, 2H, Ph-H); 7.16 (m, 1H, Ph-H); 6.86 (m,
3H, Ph-H); 6.72 (m, 1H, Ph-H); 6.65 (m, 1H, Ph-H); 6.38 (q, 1H, C]
CHe); 6.12 (t, 1H, eCHePh); 5.38 (m, 1H, CH2]Ce); 5.28 (m, 1H,
CH2]Ce); 5.20 (m, 1H, eCH2eO); 4.99 (dd, 1H, eCH2eO); 4.07 (m,
2H, NeCH2e); 3.71 (s, 3H, eOCH3); 3.30 (m, 4H, NeCH2e); 2.87 (d,
1H, NeCH2e); 2.74 ppm (m, 1H, NeCH2e); ESIMS: m/s (%):425.16
[M þ H]þ; Anal. calcd for C24H25ClN2O3: C 67.84, H 5.93 N 6.59.
Found: C 67.79, H 5.93, N 6.62%.
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.ejmech.2011.11.036.
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2H, NeCH2e); 3.75 (s, 3H, eOCH3); 3.41 (m, 2H, NeCH2e); 3.11 (d,
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123.3, 117.3, 111.3, 104.3, 88.5, 74.6, 59.5, 55.8, 55.7, 53.25 ppm;

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