Synthesis and Biological Activities of 6-Hydroxyaurone Derivatives

Article abstract of DOI:10.1002/jhet.2497

A series of 6-hydroxyaurone derivatives were synthesized in satisfactory yields and characterized by IR, ¹H NMR, ¹³C NMR, and HRMS or elemental analysis. The structure of compound 3e was further confirmed by X-ray crystal analysis. B

Full text of DOI:10.1002/jhet.2497

March 2016
Synthesis and Biological Activities of 6-Hydroxyaurone Derivatives
637
a
a
a
a
a
b
a
Yong-Tuan Bao, Min Zhang, Ting Li, Hui-Feng Xiao, Ting Zhao, Xiao-Hua Xu, and Liu-Qing Yang *
a
School of Chemistry and Chemical Engineering, Jiangsu University, Zhenjiang 212013, Jiangsu, China
b
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin 300071, China
*
E-mail: yangliuqing@ujs.edu.cn
Received April 12, 2015
DOI 10.1002/jhet.2497
Published online 15 July 2015 in Wiley Online Library (wileyonlinelibrary.com).
A series of 6-hydroxyaurone derivatives were synthesized in satisfactory yields and characterized by IR,
H NMR, C NMR, and HRMS or elemental analysis. The structure of compound 3e was further confirmed
1
13
by X-ray crystal analysis. Bioassay results indicated that some of the target compounds displayed moderate
ꢀ
1
herbicidal activity against the dicotyledonous plant Brassica campestris L. at 100 μg·mL , and some com-
pounds also showed significant antiproliferative activity against tumor cell lines Hela, HepG-2, and MCF-7.
J. Heterocyclic Chem., 53, 637 (2016).
INTRODUCTION
RESULTS AND DISCUSSION
Synthesis. As shown in Scheme 1, 2-chloro-1-(2,4-
Aurones, 2-benzylidene-3(2H)-benzofuranone (Fig. 1),
as a class of flavonoids [1], are common structures found
in flowers, seeds, leafs, and heartwood of higher plants
2], as well as in marine organisms [3]. They are not only
responsible for yellow and orange flower pigmentation
4], but also play an important role in protecting plant from
rot [5,6], insects [7], and phytoalexin [8,9]. In addition, the
therapeutic potential of aurones for humans is very promis-
ing [1,10], with a wide range of activity including antitu-
mor [11–13], antioxidant [14,15], antileishmanial [16], and
antimicrobial [17] activities whereas they possess enzyme
inhibitory [18], or enzyme-inducing [19] properties. Thus
numerous efforts have been devoted to modification of the
scaffold of aurone to obtain new chemical entity with de-
sired biological activity.
dihydroxyphenyl)ethanone (1) was prepared from resorcinol
and 2-chloroacetonitrile in the presence of dry hydrogen
chloride gas and anhydrous zinc chloride followed by
hydrolyzation in good yield according to a reported method
[21]. Reaction of compound 1 with the requisite aromatic
aldehyde in the presence of potassium hydroxide gave
6-hydroxyaurone analogues 2 in exclusively the (Z)-
configuration which was confirmed according to reference
[21]. Accordingly, alkylation of 6-hydroxyaurones 2 with
1-chloroacetone under basic conditions afforded their
corresponding methylketone derivatives 3. All of the target
[
[
1
13
compounds 2 and 3 were characterized by H NMR,
C
NMR, and HRMS or elemental analysis.
Crystal structure.
Light yellow single crystals of
Most of the aurones existing in nature are 4,6-substituted
10] and the previous research presented that 4,6-
compound 3e suitable for analysis were obtained by slowly
evaporating from ethyl acetate and petroleum ether at
room temperature for a few days. A single crystal with
dimensions of 0.20 mm× 0.20mm× 0.20mm was put on a
Rigaku Saturn 724 CCD area-detector diffractometer with a
graphite-monochromated Mo Ka radiation (λ =0.71073Å)
at 293(2) K using a muti-scan mode in the ranges of
3.21 ≤ θ≤ 25.36 . The structure of compound 3e was
solved by direct method with SHELXS-97 and refined
with SHELXTL-97 [23]. Figure 2 shows the molecular
structure of compound 3e with atomic numbering scheme.
The torsion angles O(3)–C(11)–C(12)–C(13) and C(10)–C
(11)–C(12)–C(13) are 2.4(3)° and ꢀ174.6(2)°, respectively,
[
dihydroxylated aurones demonstrated moderate to good
herbicidal activity against the dicotyledonous plant Bras-
sica campestris L. [20,21]. However, there are few reports
concerning the herbicidal activity of aurones with a substitu-
ent only on 6-position of ring A, especially with a 6-hydroxyl
group [22]. To continue our study on the ornamentation of
aurone [20–22], herein we describe the synthesis, structural
characterization, and herbicidal evaluation of 6-hydroxyaurone
derivatives, as well as their antiproliferative activity against hu-
man liver carcinoma (HepG-2), cervix epithelioid carcinoma
o
o
(
HeLa), and breast cancer cell line (MCF-7).
©
2015 HeteroCorporation

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Y.-T. Bao, M. Zhang, T. Li, H.-F. Xiao, T. Zhao, X.-H. Xu, and L.-Q. Yang
Vol 53
Figure 1. Chemical structure and numbering of the aurone scaffold.
which indicates that the exocyclic C¼C double bond is in
(
Z)-configuration.
Herbicidal activity. The herbicidal activity of the target
compounds against B. campestris and E. crus-galli has been
investigated according to the method described in the
experimental section, and the results were listed in Table 1.
As shown in Table 1, some of the target compounds pos-
sessed moderate herbicidal activity against dicotyledonous
plant (B. campestris). For example, compounds 2b, 2g, and
Figure 2. Molecular structure of compound 3e.
study the function of 6-hydroxyl group, modification of
-hydroxyl group by alkylation with 1-chloroacetone was
6
carried out. And it was found that the alkylation could in-
crease the herbicidal activity, for example, compounds 3c
and 3e exhibited higher activity than the corresponding 2c
and 2e. The results indicated that 6-substituted aurones
showed herbicidal potential against dicotyledonous plant
B. campestris, and highly active aurones are expected to
be found through further structure modification.
Antitumor activity. The synthesized compounds were
subjected to the antiproliferative assay against cancer cell
lines HepG-2, HeLa, and MCF-7. And the antiproliferative
IC50 values were summarized in Table 2.
As shown in Table 2, unsubstituted 6-hydroxyaurone
(2a) was not active against the cell growth; meanwhile 2j
containing a furan ring was also found inactive. However,
aurones bearing substituents on ring B generally exhibited
antiproliferative activity against cancer cell. Fluorides 2b–2d
exhibited inhibitory activity against both HepG-2 and
Hela proliferation; furthermore, fluoro substituent at the
3′-position of aurone (2c) possessed higher activity than
2′,4′-fluorinated compounds. In addition, the introduction
3
e displayed >50% inhibitory activity against B.
ꢀ
1
campestris at the concentration of 100 μg·mL . Further-
more, most of target compounds exhibited stronger inhibitory
activity against dicotyledonous plant (B. campestris) than
that of monocotyledonous plant (E. crus-galli). The
results revealed that 6-hydroxyaurones possessed the same
selectivity as 4,6-dihydroxyaurones, but showed slightly
lower herbicidal activity than the latter [21].
From the data listed in Table 1, it was also found that, in
the case of 6-hydroxyaurones (2a–2j), introducing substit-
uents on ring B of aurones increased the inhibitory activity
1
against B. campestris. Compared with compound 2a (R =H),
1
1
1
compounds 2b (R =2′-F), 2d (R =4′-F), 2e (R =3′-CF ),
3
1
and 2 g (R = 3′,5′-(OCH ) -4′-OBn) exhibited higher in-
hibitory activity against B. campestris at 100 μg·mL
3
2
ꢀ
1
.
When the phenyl ring B was replaced by a furan ring, the
resulted molecule (2j) showed a low herbicidal activity
ꢀ
1
against B. campestris at 100 μg·mL , which is consistent
with that of 4,6-dimethoxyaurones [21]. In an effort to
Scheme 1. Synthesis of 6-hydroxyaurone derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2016
Synthesis and Biological Evaluation of 6-Substituted Aurones
639
Table 1
antitumor activity against HepG-2, Hela, and MCF cell lines.
The results of preliminary bioassay indicated that some com-
pounds displayed moderate herbicidal activity against dicot-
yledonous plant B. campestris at 100μg·mL , and some
compounds also showed significant antiproliferative activity
against tumor cell lines Hela, HepG-2, and MCF-7.
Herbicidal activity of the target compounds on rape root and barnyard
grass seeding growth (% inhibition, concentration, μg/mL).
ꢀ
1
B. campestris
E. crus-galli
Compd
100
1000
100
1000
a
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
a
22.4
52.4
29.0
44.0
48.2
42.6
54.0
26.4
31.8
26.4
1.9
75.0
83.2
76.7
78.2
67.1
65.9
77.5
91.9
91.5
91.9
22.7
50.9
60.0
80.5
78.2
20.0
28.2
10.1
7.0
5.0
5.0
0
4.0
4.8
4.0
0
35.1
45.1
16.2
29.7
27.0
25.8
36.6
46.7
38.1
46.7
25.7
18.9
21.6
24.3
24.3
b
a
EXPERIMENTAL
c
d
e
b
Melting points were determined on an X-4 binocular mi-
croscope melting point apparatus (Beijing Tech Instruments
Co., Beijing, China) and are uncorrected. Nuclear magnetic
resonance (NMR) spectra were recorded on a Bruker
AVANCEII400 MHz instrument at room temperature in
a
f
g
h
i
j
CDC1 or DMSO-d . Elemental analysis was carried out
a
b
c
d
e
3
6
8.0
0
0
3.0
0
with a Perkin–Elmer 240C analyzer. High resolution mass
spectra (HRMS) were recorded on a VARIAN 7.0T direct
inlet instrument. Infrared (IR) spectra were measured on a
Nicolet Nexus 470 infrared spectrometer as KBr pellets
and are reported in terms of frequency of absorption
(cm ). X-ray diffraction was carried out on a Rigaku Sat-
urn 724 CCD diffractometer (Tokyo, Japan). Common re-
agents and materials were purchased from commercial
sources and were used directly without further purification.
All solvents were dried and redistilled before use.
10.9
26.2
50.8
a
Compounds 2a, 2c, and 2f and their herbicidal activity were reported in
ref. [22], while all of the data here of them came from our own work.
ꢀ
1
b
Compound 2d was reported in Ref. [24], but the herbicidal and antitumor
activity had not been reported.
Table 2
Antiproliferative action of synthesized compounds against three cancer
a
Synthetic procedure for 2-chloro-1-(2,4-dihydroxyphenyl)
cell lines (IC50, μg/mL) .
ethanone (1).
To a mixture of resorcinol (20.00 g,
Compd
HepG-2
Hela
MCF-7
181.6mmol) and 2-chloroacetonitrile (12.70mL, 200.0 mmol)
in anhydrous ether (420 mL) was added dry ZnCl (12.56 g,
2
2
2
2
2
2
2
2
2
2
3
a
b
c
d
e
f
h
i
j
/
ND
7.7
9.3
11.2
3.3
/
/
/
/
/
ND
ND
ND
7.1
/
9
2.4 mmol). The solution was cooled to below 0°C, and
12.5
7.9
9.1
8.4
ND
/
5.0
/
14.9
dry HCl gas was bubbled through the reaction for 3 h. The
solution was left in the cold-room overnight, and HCl
gas was bubbled again for 3 h. Then the solution was left
again in the cold-room for 3 days. The precipitate was
filtered off and washed three times with ether, then
followed by dissolving in 150-mL hot water and refluxed
for 3 h. After cooling, the solid was filtered off, washed
three times with water, and dried to yield 2-chloro-1-(2,4-
dihydroxyphenyl)ethanone (1) as a light yellow solid,
/
15.5
/
ND
b
9.5
a
/
ND, not detected.
No activity.
which was used without further purification, yield 77.2%,
1
of 3′-trifluoromethyl group dramatically increased inhibi-
m.p. 129–131°C. H NMR (300 MHz, DMSO-d ) δ: 4.98
6
tion on the proliferation of HepG-2, Hela, and MCF-7 cells
(s, 2H, CH Cl), 6.33 (d, J = 2.1 Hz, 1H, H-3), 6.39 (dd,
2
ꢀ
1
with IC50 values 8.4, 3.3, and 7.1 μg·mL , respectively.
The introduction of electron-donating groups made the in-
hibitory activity of 2f and 2h completely disappear; how-
ever, 2i possessed the strongest antitumor activity against
HepG-2. Comparing 3b with 2b, it was also found that
the alkylation of 6-hydroxyl group led to decreasing anti-
proliferative activity against cancer cells. On the basis of
these data, it is concluded that these compounds are selec-
tive against the proliferation of three cancer cell lines.
In summary, a variety of 6-hydroxyaurone derivatives
have been synthesized and tested for their herbicidal activity
against B. campestris and E. crus-galli, as well as their
J = 8.7, 2.1 Hz, 1H, H-5), 7.72 (d, J= 8.7 Hz, 1H, H-6),
13
10.70 (brs, 1H, OH), 11.67 (brs, 1H, OH); C NMR
(75 MHz, DMSO-d ) δ: 47.3, 102.4, 108.4, 111.6, 132.8,
6
ꢀ
163.1, 164.8, 193.4. MS (ESI, m/z) 185.15 (M ).
General synthetic procedure for 6-hydroxyaurone analogues
(2a–2j).
To a solution of compound 1 (12.0mmol) in
methanol (5mL) was added requisite aromatic aldehyde
(14.7mmol) followed by the addition of 10% aqueous
KOH solution (30mL). The solution was stirred at ambient
temperature until the starting 1 disappeared by TLC analysis.
The solvent was removed under reduced pressure and ice-
cold water (30mL) was added. The crude product was
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DOI 10.1002/jhet

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Y.-T. Bao, M. Zhang, T. Li, H.-F. Xiao, T. Zhao, X.-H. Xu, and L.-Q. Yang
Vol 53
collected by filtration, washed with ice-cold water (10mL),
and recrystallized from ethanol–dichloromethane (1:1) to
give the target compound.
129.9, 133.2, 134.3, 148.1, 166.8, 168.0, 181.3; IR (KBr)
v: 3450, 3158, 3068, 2868, 1687, 1650, 1587, 1491,
ꢀ
1
1352, 1299, 1266, 1135, 1090cm . Anal. Calcd. for
(
Z)-2-Phenylmethylene-6-hydroxy-3(2H)-benzofuranone (2a).
C H F O : C 62.75, H 2.96; found: C 63.02, H 2.86.
16 9 3 3
1
Light yellow solid, m.p. 262–264°C, yield 89.8%;
H
(Z)-2-(4-Hydroxy-3,5-dimethoxyphenyl)methylene-6-hydroxy-
NMR (400MHz, DMSO-d ) δ: 6.73 (dd, J=2.0, 8.4Hz,
3(2H)-benzofuranone (2f). Yellow solid, m.p. 218–223°C,
6
1
1
7
H, H-5), 6.79 (s, 1H, ¼CH), 6.82 (d, J=1.6Hz, 1H, H-7),
yield 90.6%; H NMR (400MHz, DMSO-d ) δ: 3.84 (s,
6
.40–7.46 (m, 1H, ArH), 7.46–7.53 (m, 2H, ArH), 7.64
6H, 2×OCH
3
), 6.70–6.75 (m, 2H, ¼CH+H-5), 6.82 (d,
13
(d, J=8.4Hz, 1H, H-4), 7.92–7.97 (m, 2H, ArH);
C
J=1.6Hz, 1H, H-7), 7.29 (s, 2H, ArH), 7.61 (d, J=8.4Hz,
1
3
NMR (100MHz, DMSO-d ) δ: 98.6, 110.4, 112.8, 113.0,
1H, H-4); C NMR (100MHz, DMSO-d ) δ: 56.1
6
6
1
1
1
26.0, 128.9(2C), 129.6, 131.0(2C), 132.1, 147.4, 166.4,
67.8, 181.5; IR (KBr) v: 3417, 3069, 1673, 1644, 1581,
(2C), 98.6, 109.2(2C), 112.0, 112.8, 113.2, 122.3, 125.7,
138.1, 146.0, 148.0(2C), 165.9, 167.5, 181.2. HRMS (ESI,
+
450, 1375, 1330, 1316, 1285, 1250, 1155, 1131, 1111.
m/z) calcd for [C17
H
14
O
6
+H] 315.0863, found 315.0864.
+
(Z)-2-(3,5-Dimethoxy-4-benzyloxyphenyl)methylene-6-hydroxy-
HRMS (ESI, m/z) calcd for [C H O +H] 239.0703,
1
5 10 3
3
2
(2H)-benzofuranone (2g). Bright yellow solid, m.p. 235–
found 239.0706.
1
37°C, yield 81.4%; H NMR (400MHz, DMSO-d ) δ:
(
Z)-2-(2-Fulorophenyl)methylene-6-hydroxy-3(2H)-benzofuranone
6
1
(
2b). Yellow solid, m.p. 275–276°C, yield 83.0%; H NMR
3.84 (s, 6H, 2×OCH ), 4.97 (s, 2H, CH O), 6.69–6.75 (m,
3 2
(
6
400MHz, DMSO-d ) δ: 6.73 (dd, J=2.0, 8.4Hz, 1H, H-5),
.76 (s, 1H, ¼CH), 6.79 (d, J=2.0Hz, 1H, H-7), 7.29–7.38
2H, ArH), 6.80 (s, 1H, ¼CH), 7.27 (s, 2H, ArH), 7.29–7.40
(m, 3H, ArH), 7.43–7.49 (m, 2H, ArH), 7.59 (d, J=8.4Hz,
6
13
(m, 2H, ArH), 7.45–7.52 (m, 1H, ArH), 7.63 (d, J=8.4Hz,
1H, ArH), 11.18 (brs, 1H, OH); C NMR (100MHz,
DMSO-d ) δ: 56.0(2C), 74.1, 98.8, 108.7(2C), 110.9, 112.9,
13
1
H, H-4), 8.17–8.25 (m, 1H, ArH); 11.31 (s, 1H, OH);
C
6
NMR (100MHz, DMSO-d ) δ: 98.7, 100.2, 112.4, 113.2,
113.0, 125.9, 127.7, 127.8, 128.0(2C), 128.1(2C), 137.7,
137.9, 146.9, 153.2(2C), 166.5, 167.8, 181.4; IR (KBr) v:
3419, 3029, 3002, 2971, 2940, 2840, 1671, 1637, 1583,
1499, 1450, 1421, 1307, 1276, 1230, 1209, 1152, 1133,
6
115.7, 119.7, 125.0, 126.1, 131.1, 131.7, 148.3, 160.5, 166.8,
1
68.0, 181.1; IR (KBr) v: 3423, 3062, 1675, 1650, 1585,
ꢀ
1
1303,1231, 1136, 1111cm . Anal. Calcd. for C H FO : C
15 9 3
ꢀ
1
+
7
0.31, H 3.54; found: C 70.16, H, 3.65.
1104cm . HRMS (ESI, m/z) calcd for [C24H O +Na]
20 6
(
Z)-2-(3-Fulorophenyl)methylene-6-hydroxy-3(2H)-benzofuranone
427.1152, found 427.1146.
1
(2c). Light yellow solid, m.p. 272–274°C, yield 74.4%; H
(Z)-2-(3-Methoxy-4-benzyloxyphenyl)methylene-6-hydroxy-
NMR (400MHz, DMSO-d ) δ: 3.83 (s, 3H, CH ), 3.86
3(2H)-benzofuranone (2h). Bright yellow solid, m.p. 255–
6
3
1
(
s, 3H, CH ), 6.75 (dd, J= 8.4, 1.6Hz, 1H, H-5), 6.81
257°C, yield 80.4%; H NMR (400 MHz, DMSO-d
6
) δ:
3
(
2
1
2
d, J=1.6 Hz, 1H, H-7), 6.98 (s, 1H, ¼CH), 7.14–7.25 (m,
H, ArH), 7.65 (d, J= 8.4Hz, 1H, ArH), 7.78 (d, J=8.0Hz,
H, H-4), 11.3 (br, 1H, OH); IR (KBr) v: 3452, 2790, 2843,
361, 2345, 1670, 1580, 1552, 1442, 1392, 1290, 1106,
3.84 (s, 3H, OCH
3
), 5.17 (s, 2H, CH
2
O), 6.72 (d,
J = 8.0 Hz, 1H, ArH), 6.77 (s, 1H, ¼CH), 6.79–6.85 (m,
1H, ArH), 7.16 (d, J = 8.4 Hz, 1H, ArH), 7.30–7.51 (m,
5H, ArH), 7.51–7.66 (m, 3H, ArH), 11.16 (brs, 1H, OH);
ꢀ
1
13
1
037cm . Anal. Calcd. for C H O F: C 70.31, H 3.54;
C NMR (100 MHz, DMSO-d ) δ: 55.6, 69.8, 98.6,
6
15 9 3
found C 70.26, H 3.70.
111.1, 112.9, 113.1, 113.5, 114.5, 124.9, 125.1, 125.8,
127.9(2C), 128.0, 128.5(2C), 136.7, 146.3, 149.0, 149.3,
(
Z)-2-(4-Fulorophenyl)methylene-6-hydroxy-3(2H)-benzofuranone
1
(2d). Yellow solid, m.p. 268–269°C, yield 84.1%; H NMR
1
66.2, 167.6, 181.3. HRMS (ESI, m/z) calcd for
(
400MHz, DMSO-d ) δ: 6.72 (dd, J=2.0, 8.4Hz, 1H, H-5),
+
6
[
C H O + Na] 397.1046, found 397.1042.
23 18 5
6
.79 (d, J= 2.0Hz, 1H, H-7), 6.81 (s, 1H, ¼CH), 7.28–7.37
(
Z)-2-(4-Benzyloxyphenyl)methylene-6-hydroxy-3(2H)-
(m, 2H, ArH), 7.62 (d, J=8.4Hz, 1H, H-4), 7.97–8.04
benzofuranone (2i). Light yellow solid, m.p. 258–260°C,
13
1
(m, 2H, ArH), 11.24 (s, 1H, OH); C NMR (100MHz,
yield 86.7%; H NMR (400MHz, DMSO-d ) δ: 5.15
6
DMSO-d ) δ: 98.6, 109.2, 112.7, 113.0, 116.0(2C), 125.9,
(s, 2H, CH O), 6.72 (d, J = 8.4 Hz, 1H, ArH), 6.75–6.78
6
2
1
28.7, 133.3 (2C), 147.0, 162.4, 166.5, 167.9, 181.3; IR (KBr)
(m, 1H, ArH), 6.78–6.83 (m, 1H, ArH), 7.11 (d, J=8.4Hz,
2H, ArH), 7.30–7.50 (m, 5H, ArH), 7.61 (d, J=8.4Hz, 1H,
ArH), 7.90 (d, J=8.4Hz, 2H, ArH), 11.19 (brs, 1H, OH);
ν: 3448, 3121, 3068, 1679, 1646, 1589, 1503, 1450, 1372,
ꢀ
1
1315, 1241, 1136, 1119cm . Anal. Calcd. for C H FO : C
15 9 3
13
70.31, H 3.54; found: C 70.48, H 3.74.
C NMR (100MHz, DMSO-d ) δ: 69.4, 98.6, 110.7,
6
(
Z)-2-(3-Trifuloromethylphenyl)methylene-6-hydroxy-3(2H)-
1
1
1
3
12.9, 113.2, 115.4(2C), 124.8, 125.8, 127.8(2C), 128.0,
benzofuranone (2e). Yellow solid, m.p. 259–260°C, yield
6
J =8.4, 2.0Hz, 1H, H-5), 6.78 (d, J = 1.6Hz, 1H, H-7),
28.5(2C), 133.0(2C), 136.6, 146.3, 159.5, 166.3, 167.7,
1
0.4%; H NMR (400MHz, DMSO-d ) δ: 6.72 (dd,
+
6
81.3. HRMS (ESI, m/z) calcd for [C H O +Na]
2
2 16 4
67.0941, found 367.0942.
6
7
.89 (s, 1H, ¼CH), 7.63 (d, J= 8.4Hz, 1H, H-4),
(
Z)-2-(2-Furanyl)methylene-6-hydroxy-3(2H)-benzofuranone
1
.67–7.78 (m, 2H, ArH), 8.20–8.28 (m, 2H, ArH), 11.29
(2j). Silver brown solid, m.p. 281–282°C, yield 87.5%; H
13
(s, 1H, OH); C NMR (100MHz, DMSO-d ) δ: 98.6,
NMR (400MHz, DMSO-d ) δ: 6.70–6.77 (m, 3H, ArH),
6
6
1
08.3, 112.4, 113.2, 123.9, 125.6, 126.1, 127.1, 129.6,
6.78–6.82 (m, 1H, ArH), 7.16 (d, J=3.6Hz, 1H, ArH),
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641
7
1
9
1
.62 (d, J=8.4Hz, 1H, ArH), 7.96–7.98 (m, 1H, ArH),
(m, 1H, H-5), 7.08–7.17 (m, 2H, ArH), 7.72 (d, J=8.8Hz,
1H, H-4), 7.83–7.92 (m, 2H, ArH); C NMR (100MHz,
13
13
1.23 (brs, 1H, OH); C NMR (100MHz, DMSO-d ) δ:
6
8.6, 99.2, 113.0, 113.2, 113.3, 117.0, 125.9, 145.3, 146.1,
CDCl ) δ: 26.5, 73.1, 97.6, 111.1, 112.2, 115.7, 116.0 (2C),
3
48.1, 166.3, 167.6, 180.9. HRMS (ESI, m/z) calcd for
126.2, 128.5, 133.3 (2C), 147.2, 163.3, 165.1, 168.1, 182.7,
+
[C H O +Na] 251.0315, found 251.0316.
203.3; IR (KBr) ν: 3064, 1720, 1695, 1653, 1603,
13 8 4
ꢀ
1
General synthetic procedure for compounds 3a–3e. To a
solution of requisite 2 (2.1 mmol) and 1-chloroacetone
0.30mL, 3.8mmol) in DMF (N,N-dimethylformamide,
mL) was added K CO (0.50 g, 3.6mmol). The mixture
1511, 1449, 1344, 1270, 1233, 1157, 1046cm . Anal.
Calcd. for C H FO : C 69.23, H 4.20; found: C 69.29,
18 13
4
H 4.26.
(
5
(
Z)-2-(3-Trifuloromethylphenyl)methylene-6-(2-oxopropoxy)-
2
3
3
1
(2H)-benzofuranone (3e). Light yellow solid, m.p. 123–
24°C, yield 88.6%; H NMR (400MHz, CDCl ) δ: 2.34
3
was stirred at room temperature for 48h and then was
poured into water (100mL). The precipitate was collected
on a filter, washed well with water, and dried to afford a
crude product. Further purification by recrystallization
from ethyl acetate and petroleum ether gave a pure product.
1
(
s, 3H, CH ), 4.71 (s, 2H, CH ), 6.75 (d, J=2.4Hz, 1H,
3 2
H-7), 6.81 (dd, J =2.4, 8.8Hz, 1H, H-5), 6.81 (s, 1H,
CH, overlapped by the signal of H-5), 7.54–7.60 (m,
¼
1
H, ArH), 7.61–7.66 (m, 1H, ArH), 7.75 (d, J=8.4Hz,
H, ArH), 8.01 (d, J= 7.6Hz, 1H, ArH), 8.15 (s, 1H,
(
Z)-2-Phenylmethylene-6-(2-oxopropoxy)-3(2H)-benzofuranone
1
1
(3a). Earth yellow solid, m.p. 123–124°C, yield 70.3%; H
13
ArH); C NMR (100MHz, CDCl ) δ: 26.6, 73.1, 97.8,
NMR (400MHz, CDCl ) δ: 2.33 (s, 3H, CH ), 4.68 (s, 2H,
CH ), 6.73 (d, J=2.0Hz, 1H, H-7), 6.79 (dd, J=8.4, 2.0Hz,
3
3
3
1
10.1, 112.5, 115.4, 123.9, 126.0, 126.3, 127.6, 129.3,
2
1
31.4, 133.1, 134.2, 148.3, 165.4, 168.3, 182.6, 203.1; IR
1
H, H-5), 6.84 (s, 1H, ¼CH), 7.38–7.48 (m, 3H, ArH), 7.44
(
KBr) ν: 3066, 1724, 1695, 1656, 1603, 1450, 1425, 1326,
(d, 1H, H-4), 7.88–7.90 (m, 2H, ArH); IR (KBr) ν: 3099,
ꢀ
1
ꢀ
1
1302, 1264, 1170, 1132, 1098, 1075cm . Anal. Calcd
1717, 1611, 1426, 1383, 1279, 1156, 1127, 1095cm .
for C H F O : C 62.99, H 3.62; found: C 62.89, H 3.74.
Anal. Calcd. for C H O : C 73.46, H 4.79; found: C 73.19,
19 13 3 4
18 14 4
H 5.02.
Herbicidal activity. Treatment. The emulsions of the
evaluated compounds were prepared by dissolving them
in 100 μL of DMF, adding a few drops of Tween 20 and
dispersing in water. The mixture of the same amount of
water, DMF, and Tween 20 was used as control. There
(
Z)-2-(2-Fulorophenyl)methylene-6-(2-oxopropoxy)-3(2H)-
benzofuranone (3b).
Yellow solid, m.p. 98–99°C, yield
1
6
4
7.3%; H NMR (400MHz, CDCl ) δ: 2.33 (s, 3H, CH ),
.68 (s, 2H, CH ), 6.71 (d, J=2.0Hz, 1H, H-7), 6.78 (dd,
3
3
2
J=8.4, 2.0Hz, 1H, H-5), 7.09–7.15 (m, 2H, ¼CH+ArH),
were three replicates for each treatment.
7
.22–7.27 (m, 1H, ArH), 7.33–7.40 (m, 1H, ArH), 7.73 (d,
Inhibition of the root growth of rape (B. campestris). Rape
13
J=8.8Hz, 1H, H-4), 8.22–8.28 (m, 1H, ArH); C NMR
100MHz, CDCl ) δ: 26.6, 73.1, 97.6, 103.3, 112.2, 115.6,
seeds were soaked in distilled water for 4h before being
placed on a filter paper in a 6-cm Petri plate, to which
2 mL of inhibitor solution had been added in advance.
Usually, 15 seeds were used on each plate. The plate
was placed in a dark room and allowed to germinate for
65h at 28 (±1)°C. The lengths of 10 rape roots selected
randomly from each plate were measured, and the means
were calculated. The inhibition rate was calculated from
the root length by use of the equation:
(
3
1
1
1
15.7, 120.5, 124.4, 126.3, 131.3, 131.7, 148.3, 161.5,
65.2, 168.2, 182.5, 203.4; IR (KBr) ν: 3060, 1701, 2890,
658, 1608, 1485, 1449, 1344, 1270, 1238, 1131, 1100,
ꢀ
1
1
049cm . Anal. Calcd. for C H FO : C 69.23, H 4.20;
18 13 4
found: C 69.29, H 4.46.
(
Z)-2-(3-Fulorophenyl)methylene-6-(2-oxopropoxy)-3(2H)-
benzofuranone (3c).
yield 68.9%; H NMR (400 MHz, CDCl ) δ: 2.33 (s, 3H,
Yellow solid, m.p. 112–113°C,
1
3
CH ), 4.70 (s, 2H, CH ), 6.72 (d, J = 2.4 Hz, 1H, H-7),
3
2
Inhibition rate ð%Þ ¼ ½ðC-TÞ=Cꢁ ꢂ 100
6
7
7
.76 (s, 1H, ¼CH), 6.79 (dd, J = 2.4, 8.4 Hz, 1H, H-5),
.05–7.12 (m, 1H, ArH), 7.36–7.44 (m, 1H, ArH), 7.52–
.58 (m, 1H, ArH), 7.64–7.70 (m, 1H, ArH), 7.72 (d,
where C is the average root length during the control assay
and T is the average root length after treatment during
testing.
Inhibition of the seedling growth of barnyard grass (E. crus-
galli). A total of 10 barnyard grass seeds were placed into
a 50-mL cup covered with a layer of glass beads and a piece
of filter paper at the bottom, to which 5mL of inhibitor
solution had been added in advance. The cup was placed in
a bright room, and the seeds were allowed to germinate for
65h at 28±1°C. The heights of seedlings of above-ground
plant parts from each cup were measured, and the means
were calculated. The inhibition rate was calculated from the
plant height by use of the equation:
1
3
J = 8.4 Hz, 1H, H-4); C NMR (100 MHz, CDCl ) δ:
3
2
1
1
1
6.5, 73.1, 97.6, 110.6, 112.4, 115.5, 116.6, 117.4,
26.2, 127.2, 130.2, 134.3, 148.0, 162.8, 165.3, 168.2,
82.6, 203.1; IR (KBr) ν: 3066, 1720, 1654, 1610, 1443,
ꢀ
1
334, 1274, 1235, 1155, 1127, 1047 cm . Anal.
Calcd. for C H FO : C 69.23, H 4.20; found: C 69.16,
1
8
13
4
H 4.23.
(
Z)-2-(4-Fulorophenyl)methylene-6-(2-oxopropoxy)-3(2H)-
benzofuranone (3d). White solid, m.p. 135–136°C, yield
1
7
4
1.2%; H NMR (400 MHz, CDCl ) δ: 2.33 (s, 3H, CH ),
3 3
.68 (s, 2H, CH ), 6.71 (d, J = 2.0 Hz, 1H, H-7), 6.77
2
(
s, 1H, ¼CH, overlapped by the signal of H-5), 6.75–6.81
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

6
42
Y.-T. Bao, M. Zhang, T. Li, H.-F. Xiao, T. Zhao, X.-H. Xu, and L.-Q. Yang
Vol 53
REFERENCES AND NOTES
Inhibition rate ð%Þ ¼ ½ðC ꢀ TÞ=Cꢁ ꢂ 100
[
[
1] Boumendjel, A. Curr Med Chem 2003, 10, 2621.
2] Perrier, E.; Okombi, S.; Rival, D.; Boumendjel, A.; Mariotte,
where C is the average plant height during the control assay
and T is the average plant height after treatment during testing.
A.-M. EP 1709964, 2006; Chem Abstr 2006, 145, 425283.
3] Atta-Ur-Rahman; Choudhary M. I.; Hayat, S.; Khan, A. M.;
Ahmed, A. Chem Pharm Bull 2001, 49, 105.
4] Ono, E.; Fukuchi-Mizutani, M.; Nakamura, N.; Fukui, Y.;
[
Antiproliferative activity. Cell lines and culture
conditions.
Human liver carcinoma (HepG-2), cervix
epithelioid carcinoma (HeLa), and breast cancer cell line
MCF-7) were provided by the School of Pharmacy,
[
Yonekura-Sakakibara, K.; Yamaguchi, M.; Nakayama, T.; Tanaka, T.;
Kusumi, T.; Tanaka, Y. Proc Natl Acad Sci U S A 2006, 103, 11075.
(
[
5] Gomez-Garibay, F.; Reyes-Chilpa, R.; Quijano, L.; Pardo,
J. S. C.; Castillo, T. R. Phytochemistry 1990, 29, 459.
6] Reyes-Chilpa, R.; Viveros-Rodriguez, N.; Gomez-Garibay, F.;
Alavez-Solano, D. J Chem Ecol 1995, 21, 455.
7] Morimoto, M.; Fukumoto, H.; Nozoe, T.; Hagiwara, A.;
Komai K J Agric Food Chem 2007, 55, 700.
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30, 1133.
[9] Farag, M. A.; Deavours, B. E.; de Fatima, A.; Naoumkina, M.;
Dixon, R. A.; Sumner, L. W. Plant Physiol 2009, 151, 1096.
10] Haudecoeur, R.; Boumendjel, A. Curr Med Chem 2012,
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[11] Cheng, H. M.; Zhang, L. W.; Liu, Y. X.; Chen, S. P.;
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ChemMedChem 2011, 6, 713.
14] Venkateswarlu, S.; Panchagnula, G. K.; Subbaraju, G. V.
Biosci Biotechnol Biochem 2004, 68, 2183.
Jiangsu University, Zhenjiang, China. All cells were
grown in Dulbecco’s modified eagle minimum essential
medium (DMEM) medium supplemented with 10%
fetal bovine serum (FBS), 100 units/mL penicillin and
[
[
1
3
00 μg/mL streptomycin. All cells were incubated at
7°C in a humidified atmosphere with 5% (v/v) CO2.
[
Cell antiproliferative assay.
Evaluation of cancer cell
growth inhibition was assessed by 3-(4,5-dimethyl-2-
thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT)
[
1
assay. Exponentially growing cancer cells were seeded into
3
9
6-well culture plates (4×10 cells/well) and incubated
4
at 37°C in a humidified incubator with 5% CO for 24h.
2
[
Cells were incubated with different concentrations of
sample for another 48h. Untreated cells were used as
negative control. Then, MTT solution (100μL/well,
4
[
1
mg/mL) was added to each well and incubated again for
[
4
h. After the removal of MTT, the precipitate was
[
[
15] Nenadis, N.; Sigalas, M. P. Food Res Int 2011, 44, 114.
16] Roussaki, M.; Lima, S. C.; Kypreou, A.-M.; Kefalas, P.;
da Silva, A. C.; Detsi, A. Int J Med Chem 2012, DOI: 10.1155/2012/
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17] Shin, S. Y.; Shin, M. C.; Shin, J. S.; Lee, K. T.; Lee, Y. S.
Bioorg Med Chem Lett 2011, 21, 4520.
18] Haudecoeur, R.; Ahmed-Belkacem, A.; Yi, W.; Fortune, A. F.;
solubilized in dimethyl sulfoxide (DMSO) (100μL/well),
and the absorbance was measured on a microplate ELISA
reader (Spectra MAX 190, Molecular Devices Corporation,
USA) at a wavelength of 570nm. The inhibition ratio of
the tumor cells proliferation was determined as follows:
[
[
Brillet, R.; Belle, C.; Nicolle, E.; Pallier, C.; Pawlotsky, J.-M.;
Boumendjel, A. J Med Chem 2011, 54, 5395.
À
Á
Inhibition rate ð%Þ ¼ 1-Abssample=Abscontrol ꢂ 100:
[
[
19] Lee, C. Y.; Chew, E. H.; Go, M. L. Eur J Med Chem 2010, 45, 2957.
20] Zhang, M.; Chen, G.-Y.; Li, T.; Liu, B.; Deng, J.-Y.;
Zhang, L.; Yang, L.-Q.; Xu, X.-H.
0.1002/jhet.2298.
21] Zhang, M.; Xu, X. H.; Cui, Y.; Xie, L. G.; Kong, C. H. Pest
Manag Sci 2012, 68, 1512.
22] Liu, B.; Zhang, M.; Xie, L. G.; Li, Y. H.; Xu, X. H. Chem J
Chin Univ 2011, 32, 2335 (in Chinese).
23] Crystallographic data for compound 3e has been deposited at
J Heterocyclic Chem DOI:
IC50 values of some compounds against HepG-2, Hela,
and MCF-7 were calculated with SPSS 16.0 version (SPSS
Inc., Chicago, USA).
1
[
[
[
Acknowledgments. We are grateful for financial support by the
Natural Science Foundation of Jiangsu Province (BK20140536),
and Jiangsu University (09JDG064).
the Cambridge Crystallographic Data Centre (CCDC No. 1401706).
[24] Teo, C. C.; Kon, O. L.; Sim, K. Y.; Ng, S. C. J Med Chem
1992, 35, 1330.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet