Synthesis, characterization, and anticancer effect of trifluoromethylated aurone derivatives

Article abstract of DOI:10.1002/jhet.1969

A series of trifluoromethylated aurone derivatives were synthesized, and the structure of 6-hydroxy- 4-trifluoromethylated aurone was determined by single crystal X-ray analysis. Their anticancer activities against leucocythemia (HL-60) and colorectal ade

Full text of DOI:10.1002/jhet.1969

Month 2014 Synthesis, Characterization, and Anticancer Effect of Trifluoromethylated
Aurone Derivatives
a
a
a
c
a
b
Xing Zheng,a,b Hui Wang, Yun-Mei Liu, Xu Yao, Min Tong, Yu-Hong Wang, and Duan-Fang Liao
*
*
aInstitute of Pharmacy and Pharmacology, University of South China, Hengyang 421001, Hunan, China
bDivision of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine
Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha 410208, Hunan, China
cXianyang Central Hospital, Xianyang 712000, Shanxi, China
*
E-mail: dfliao66@yahoo.com.cn
Received November 6, 2012
DOI 10.1002/jhet.1969
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
A series of trifluoromethylated aurone derivatives were synthesized, and the structure of 6-hydroxy-
4-trifluoromethylated aurone was determined by single crystal X-ray analysis. Their anticancer activities
against leucocythemia (HL-60) and colorectal adenocarcinoma (HT-29) were evaluated by the standard
MTT method in vitro with 5-fluorouracil as a positive contrast drug. The results showed that all the
(Z)-trifluoromethylated aurone derivatives had potential anticancer activities.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
interesting biological activities, and these natural products
and their synthetic analogues have proved to be promising
bioactive compounds with a broad spectrum of activities
including anticancer [6,7] and antioxidant [8,9] properties
while they possess enzyme inhibitory [10,11] or enzyme
inducing activity [12]. The aurone derivatives also have been
used in the treatment of thyroid disease [13]. However, most
of the anticancer activities were low. It is known that fluorine
is the most electronegative element, and the van der Waals
radius of fluorine is close to that of hydrogen. The introduc-
tion of the CF3 group into organic molecules often changes
their physiological, physical, and chemical properties
dramatically, without the introduction of extra steric demand.
Many efforts were made to introduce the trifluoromethyl
group into different types of organic molecules for
improving their stability and lipophilicity [14]. To our best
knowledge, the introduction of fluorine moiety into the aryl
part of the flavonoid molecule can enhance their biological
activities including antibacterial activity, antifungal activity,
and antiviral activity [15]. Earlier studies of B-ring
Acute leukemia is a neoplastic disease resulting from
hyperplasia of myelohlast and other immature granulocyte.
It can cause death rapidly without treatment [1]. Colorectal
cancer is the third most common malignant tumors in Western
countries [2], and it also has an increasing trend in China
recently. Such diseases should be given due attention.
Aurone is a heterocyclic chemical compound that has two
isomers of the molecule, with (E)- and (Z)-configurations [3].
Most aurones are in the (Z)-configuration, which is the
more stable configuration according to Austin Model 1
computation, but there are some in the (E)-configuration
such as (E)-30-O-b-D-glucopyranosyl-4,5,6,40-tetrahydroxy-
7,20-dimethoxyaurone, found in Gomphrena agrestis [4].
The molecule contains a benzofuran element associated with
a benzylidene linked in position 2. In aurone, a chalcone-like
group is closed into a 5-membered ring instead of the
6-membered ring more typical of flavonoids [5]. Recently,
aurones have received much attention because of their
© 2014 HeteroCorporation

X. Zheng, H. Wang, Y.-M. Liu, X. Yao, M. Tong, Y.-H. Wang, and D.-F. Liao
Vol 000
Table 1
Crystal date and structure refinement for compounds 5.
Identification code
Empirical formula
Formula weight
Compounds 5
16H9F3O3
306.23
C
Temperature
293(2) K
Wavelength
0.71073 Å
Crystal system, space group
Unit cell dimensions
Monoclinic, P2(1)/n
a = 7.1950(11) Å
b = 12.780(2) Å
c = 15.066(3) Å
1363.9(4) Å3
4, 1.491 Mg/m3
0.130 mmꢂ1
624
a = 90ꢁ
b = 100.096(4)ꢁ
g = 90ꢁ
Volume
Figure 1. X-ray crystal Structure of compound 5.
Z, calculated density
Absorption coefficient
F(000)
trifluoromethylated aurones in our laboratory showed some
activities against SGC-7901 tumor cell [16]. In order to
search for anticancer substances with high efficacy, low
toxicity, and minimum side effects, we describe a series of
aurone’s synthesis and evaluate their anticancer activities
against HL-60 and HT-29 cells, then confirm the configura-
tion of trifluoromethylated aurone 5 by X-ray.
Crystal size
0.314 ꢀ 0.268 ꢀ 0.087 mm
Theta range for data collection 2.10 to 28.26ꢁ
Limiting indices
ꢂ9 ≤ h≤8, ꢂ16 ≤ k ≤16,
ꢂ15 ≤ l ≤20
Reflections collected/unique
Completeness to theta = 28.26 93.2%
Absorption correction
Max and min transmission
Refinement method
8181/3155 [R(int) = 0.0779]
Sadabs
1.00000 and 0.64376
Full-matrix least-squares on F2
3155/0/245
Data/restraints/parameters
Goodness-of-fit on F~2
0.745
RESULTS AND DISCUSSION
Final R indices [I > 2sigma (I)] R1 = 0.0466, wR2 = 0.0723
R indices (all data)
Extinction coefficient
Largest diff. peak and hole
R1 = 0.1252, wR2 = 0.0862
0.0059(6)
Single crystal X-ray analysis of compound 5.
The
procedure as described in the experimental can smoothly
convert resorcinol to compound 5. To confirm its
configuration, a yellow prismatic crystal of 5 with
dimensions 0.314ꢀ 0.268ꢀ 0.087 mm was mounted on a
glass fiber with grease. Diffraction experiments were
performed on graphite-monochromator diffractometer using
the Ф–o scan technique. The X-ray crystal structure of
compound 5 is shown in Figure 1. It proves that compound
5 is in the (Z)-configuration. The packing diagram of
compound 5 in a unit cell is shown in Figure 2. Refined
cell dimensions and their standard deviations were obtained
from Full-matrix least-squares on F2. Empirical absorption
0.210 and ꢂ0.205 e∙Åꢂ3
Table 2
Atomic coordinates (ꢀ104) and equivalent isotropic displacement
parameters (Å2 ꢀ 103) of compound 5 (U(eq) is defined as one-third of the
trace of the orthogonalized Uij tensor).
x
y
z
U(eq)
O(1)
O(2)
O(3)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
F(1)
647(2)
1764(2)
ꢂ2892(3)
206(3)
ꢂ541(3)
ꢂ2117(3)
ꢂ2857(3)
ꢂ2053(3)
ꢂ472(3)
704(3)
2107(3)
3476(3)
4873(3)
4942(3)
6290(3)
7569(3)
7534(3)
6191(3)
8993(4)
10654(2)
8444(2)
9434(15)
9110(30)
8935(1)
6889(1)
4330(1)
6503(2)
5536(2)
5274(2)
5963(2)
6916(2)
7199(2)
8112(2)
7881(2)
8503(2)
8353(2)
7473(2)
7385(2)
8172(2)
9049(2)
9137(2)
8085(2)
8508(1)
8604(2)
7087(9)
7249(15)
7599(1)
6229(1)
6490(1)
6549(2)
6336(2)
6702(2)
7273(2)
7479(2)
7110(1)
7175(2)
6593(1)
6423(2)
5845(1)
5311(2)
4771(2)
4754(2)
5274(2)
5813(2)
4145(2)
4481(1)
3377(1)
3989(7)
3759(12)
61(1)
55(1)
78(1)
48(1)
57(1)
54(1)
52(1)
51(1)
44(1)
48(1)
47(1)
48(1)
43(1)
51(1)
53(1)
45(1)
56(1)
53(1)
62(1)
88(1)
114(1)
122(4)
86(5)
F(2)
F(3)
F(30)
Figure 2. Unit-cell packing diagram of compound 5.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and Anticancer Effect of
Trifluoromethylated Aurone Derivatives
Table 3
Selected bond lengths (Å) of compound 5.
corrections were applied on the basis of Sadabs, which
resulted in transmission factors ranging from 0.64376 to
1.00000. The important crystal data: C16H9F3O3,
Mr = 306.23, monoclinic, space group P2(1)/n, a = 7.1950
(11) Å, b = 12.782(2) Å, c = 15.066(3) Å, b = 100.096(4)ꢁ,
V = 1363.9(4) Å3, Z = 4, Dc = 1.491 Mg/m3, F(000) = 624,
absorption coefficient 0.130 mmꢂ1. The detailed crystal data
and structure refinement are shown in Table 1. Atomic
coordinates and equivalent isotropic displacement parameter
U(eq) are shown in Table 2. Bond lengths and angles are
shown in Tables 3 and 4, respectively. Anisotropic
displacement parameters are shown in Table 5. Hydrogen
coordinates and isotropic displacement parameters are
shown in Table 6. Torsion angles are shown in Table 7.
It was observed that the whole molecule was planar with
the torsion angle: C(7)─C(8)─C(9)─C(10) torsion angle
is ꢂ178.1(2)ꢁ; C(8)─C(9)─C(10)─C(11) torsion angle
is 2.7(4)ꢁ; and O(2)─C(1)─C(6)─C(5) torsion angle is
179.55(18)ꢁ.
Anticancer activity. All the trifluoromethylated aurone
derivatives were tested for their anticancer activities
in vitro against HL-60 and HT-29 by MTT-based assay.
The assays were performed in 96-well plates essentially as
described by Mosmann [17]. The results in Table 8 showed
that all the trifluoromethylated aurone derivatives had
potential anticancer activities. Although general structure–
activity relationship of those trifluoromethylated aurone
derivatives was not elucidated from these data, the
Bond
Bond lengths
Bond
Bond lengths
O(1)─C(7)
O(2)─C(8)
O(2)─C(1)
O(3)─C(3)
O(3)─H(9)
C(1)─C(2)
C(1)─C(6)
C(2)─C(3)
C(3)─C(4)
C(4)─C(5)
C(5)─C(6)
C(6)─C(7)
C(7)─C(8)
1.235(2)
1.387(2)
1.387(2)
1.344(3)
0.88(2)
1.363(3)
1.375(3)
1.386(3)
1.400(3)
1.361(3)
1.398(3)
1.435(3)
1.497(3)
C(8)─C(9)
C(9)─C(10)
C(10)─C(15)
C(10)─C(11)
C(11)─C(12)
C(12)─C(13)
C(13)─C(14)
C(14)─C(15)
C(16)─F(3)
C(16)─F(2)
C(16)─F(1)
C(16)─F(30)
1.324(3)
1.454(3)
1.386(3)
1.388(3)
1.375(3)
1.380(3)
1.373(3)
1.01(2)
1.227(15)
1.329(3)
1.332(3)
1.345(11)
Table 4
Selected bond angles (ꢁ) of compound 5.
Bond angles
Bond angles
value
Bond angles
value
106.68(16)
124.3(2)
123.4(2)
112.3(2)
116.2(2)
117.2(2)
121.6(2)
121.2(2)
120.7(2)
118.9(2)
118.5(2)
107.45(19)
134.0(2)
130.9(2)
124.4(2)
104.7(2)
124.0(2)
127.0(2)
108.95(19)
130.7(2)
Bond angles
C(8)─O
(2)─C(1)
C(2)─C
(1)─C(6)
C(2)─C
(1)─O(2)
C(6)─C
(1)─O(2)
C(1)─C
(2)─C(3)
O(3)─C
(3)─C(2)
O(3)─C
(3)─C(4)
C(2)─C
(3)─C(4)
C(5)─C
(4)─C(3)
C(4)─C
(5)─C(6)
C(1)─C
(6)─C(5)
C(1)─C
(6)─C(7)
C(5)─C
(6)─C(7)
O(1)─C
(7)─C(6)
O(1)─C
(7)─C(8)
C(6)─C
(7)─C(8)
C(9)─C
(8)─O(2)
C(9)─C
(8)─C(7)
O(2)─C
(8)─C(7)
C(8)─C
(9)─C(10)
C(15)─C
(10)─C(11)
C(15)─C
(10)─C(9)
C(11)─C
(10)─C(9)
C(12)─C
(11)─C(10)
C(11)─C
(12)─C(13)
C(14)─C
(13)─C(12)
C(14)─C
(13)─C(16)
C(12)─C
(13)─C(16)
C(15)─C
(14)─C(13)
C(14)─C
(15)─C(10)
F(30)─C
118.1(2)
118.3(2)
123.5(2)
120.6(2)
120.3(2)
119.6(2)
120.6(2)
119.8(2)
120.1(2)
121.3(2)
113.6(9)
93.2(11)
103.8(2)
18.7
Table 5
Anisotropic displacement parameters (A2 ꢀ 103) of compound 5 (the
anisotropic displacement factor exponent takes the form: ꢂ2p2
[h~2a*2U11 + ⋯ + 2hka*b*U12].
U11
U22
U33
U23
U13
U12
O(1)
O(2)
O(3)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
F(1)
64(1)
62(1)
89(2)
50(2)
67(2)
62(2)
52(2)
54(2)
45(1)
50(2)
53(2)
50(2)
44(1)
51(2)
56(2)
41(1)
54(2)
57(2)
52(2)
50(1)
48(1)
55(1)
48(2)
47(2)
44(2)
52(2)
47(2)
42(1)
47(2)
39(2)
41(2)
44(2)
50(2)
53(2)
50(2)
54(2)
46(2)
79(2)
76(1) ꢂ11(1)
66(1)
ꢂ6(1)
29(1)
37(1)
57(1) ꢂ23(1)
1(1)
ꢂ5(1)
105(2) ꢂ12(1)
(16)─F(1)
52(2)
67(2)
62(2)
61(2)
57(2)
49(2)
49(2)
53(2)
53(2)
43(1)
57(2)
8(1)
ꢂ6(1)
4(1)
8(1)
4(1)
5(1)
4(1)
ꢂ1(1)
ꢂ3(1)
2(1)
ꢂ7(1)
26(1)
38(2)
26(1)
31(1)
25(1)
17(1)
14(1)
19(1)
12(1)
12(1)
0(1)
ꢂ5(1)
ꢂ2(1)
1(1)
9(1)
8(1)
8(1)
1(1)
2(1)
ꢂ1(1)
F(30)─C
(16)─F(2)
F(1)─C
(16)─F(2)
F(30)─C
(16)─F(3)
F(1)─C
(16)─F(3)
F(2)─C
103.2(5)
111.3(5)
118.1(8)
113.4(2)
111.8(2)
112.7(5)
(16)─F(3)
22(1) ꢂ15(1)
F(30)─C
54(2) ꢂ13(1)
19(1)
11(1)
ꢂ9(1)
ꢂ6(1)
(16)─C(13)
F(1)─C
(16)─C(13)
F(2)─C
(16)─C(13)
F(3)─C
47(2)
63(2)
57(2)
58(2)
2(1)
0(1)
22(1) ꢂ15(1)
ꢂ8(1)
18(1)
ꢂ8(1)
0(2)
13(2) ꢂ16(1)
21(1) ꢂ26(1)
48(1) 129(2)
83(1) 194(2)
119(5)
90(1) ꢂ25(1)
F(2)
72(1) 34(1)
32(1)
ꢂ3(1)
(16)─C(13)
F(3)
84(4)
189(9) ꢂ14(4) 102(5)
11(3)
F(30)
89(7) 102(11)
82(5) ꢂ56(7) 56(5) ꢂ51(8)
Symmetry transformations used to generate equivalent atoms.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X. Zheng, H. Wang, Y.-M. Liu, X. Yao, M. Tong, Y.-H. Wang, and D.-F. Liao
Vol 000
Table 6
Table 8
The anticancer activities of the target compounds 5 and 6a–e in vitro.
Hydrogen coordinates (ꢀ104) and parameters (A2 ꢀ 103) of compound 5.
x
y
z
U(eq)
Compound
HL-60 (IC50 mmol/L)
HT-29(IC50 mmol/L)
H(1)
H(2)
H(3)
H(4)
H(5)
H(6)
H(7)
H(8)
H(9)
ꢂ40(30)
ꢂ3940(20)
ꢂ2500(30)
3490(20)
3980(30)
6340(20)
8470(30)
6150(30)
ꢂ3780(30)
5071(15)
5753(13)
7433(15)
9154(13)
6944(16)
6762(14)
9621(18)
9738(14)
4238(19)
5949(13)
7500(11)
7873(14)
6725(11)
5297(13)
4419(12)
5225(14)
6169(12)
6814(17)
52(7)
42(6)
64(7)
34(6)
61(7)
45(6)
90(8)
48(6)
98(10)
4
5
6a
6b
6c
6d
6e
3.74
1.54
2.59
1.65
3.53
3.46
2.67
12.92
9.12
8.90
5.90
9.12
4.12
4.12
4.32
9.56
5-Fluorouracil
The given values are the average values of three experiments.
following points are noteworthy: (1) All the
trifluoromethylated aurone derivatives (compounds 5 and
6a–e) showed stronger cytotoxicity toward HL-60 cell than
6-hudroxy-aurone 4. (2) Except compound 6b, all the
trifluoromethylated aurone derivatives showed better
Table 7
Torsion angles (ꢁ) of compound 5.
C(8)═O(2)─C(1)─C(2)
C(8)═O(2)═C(1)═C(6)
C(6)═C(1)═C(2)═C(3)
O(2)═C(1)═C(2)═C(3)
C(1)═C(2)═C(3)═O(3)
C(1)═C(2)═C(3)═C(4)
O(3)═C(3)═C(4)═C(5)
C(2)═C(3)═C(4)═C(5)
C(3)═C(4)═C(5)═C(6)
C(2)═C(1)═C(6)═C(5)
O(2)═C(1)═C(6)═C(5)
C(2)═C(1)═C(6) – C(7)
O(2)═C(1)═C(6)═C(7)
O(4)═C(5)═C(6)═C(1)
C(4)═C(5)═C(6)═C(7)
C(1)═C(6)═C(7)═O(1)
C(5)═C(6)═C(7)═O(1)
C(1)═C(6)═C(7)═C(8)
C(5)═C(6)═C(7)═C(8)
C(1)═O(2)═C(8)═C(9)
C(1)═O(2)═C(8)═C(7)
O(1)═C(7)═C(8)═C(9)
C(6)═C(7)═C(8)═C(9)
O(1)═C(7)═C(8)═O(2)
C(6)═C(7)═C(8)═O(2)
O(2)═C(8)═C(9)═C(10)
C(7)═C(8)═C(9)═C(10)
C(8)═C(9)═C(10)═C(15)
C(8)═C(9)═C(10)═C(11)
C(15)═C(10)═C(11)═C(12)
C(9)═C(10)═C(11)═C(12)
C(10)═C(11)═C(12)═C(13)
C(11)═C(12)═C(13)═C(14)
C(11)═C(12)═C(13)═C(16)
C(12)═C(13)═C(14)═C(15)
C(16)═C(13)═C(14)═C(15)
C(13)═C(14)═C(15)═C(10)
C(11)═C(10)═C(15)═C(14)
C(9)═C(10)═C(15)═C(14)
C(14)═C(13)═C(16)═F(30)
C(12)═C(13)═C(16)═F(30)
C(14)═C(13)═C(16)═F(1)
C(12)═C(13)═C(16)═F(1)
C(14)═C(13)═C(16)═F(2)
C(12)═C(13)═C(16)═F(2)
C(14)═C(13)═C(16)═F(3)
C(12)═C(13)═C(16)═F(3)
ꢂ179.6(2)
ꢂ0.4(2)
1.8(4)
inhibitory activities toward
HT-29 cell than 6-hudroxy-
ꢂ179.1(2)
179.2(2)
ꢂ1.4(4)
ꢂ180.0(2)
0.5(4)
aurone 4. (3) All the trifluoromethylated aurone derivatives
showed better inhibitory activities toward HT-29 and HT-29
cell than 5-fluorouracil.
0.1(4)
ꢂ1.3(4)
179.55(18)
179.1(2)
ꢂ0.1(3)
0.3(3)
179.8(2)
ꢂ179.9(2)
0.6(4)
CONCLUSIONS
A series of trifluoromethylated aurone derivatives were syn-
thesized, and the structure of 6-hydroxy-4-trifluoromethylated
aurone was in the (Z)-configuration determined by single crys-
tal X-ray analysis. All the (Z)-trifluoromethylated aurone deriv-
atives had potential anticancer activities against leucocythemia
(HL-60) and colorectal adenocarcinoma (HT-29).
0.5(2)
ꢂ179.0(2)
ꢂ178.7(2)
0.7(2)
ꢂ1.0(4)
178.7(2)
179.6(2)
ꢂ0.8(2)
1.3(4)
ꢂ178.1(2)
ꢂ178.3(2)
2.7(4)
0.3(3)
179.3(2)
0.1(4)
ꢂ0.5(4)
ꢂ177.7(2)
0.6(4)
177.8(2)
ꢂ0.2(4)
ꢂ0.3(3)
ꢂ179.3(2)
173.2(12)
ꢂ9.7(12)
36.6(4)
ꢂ146.2(2)
ꢂ80.4(3)
96.8(3)
153.3(5)
ꢂ29.5(6)
EXPERIMENTAL
General.
Analytical TLC was carried out with silica gel
(HSGF 254). Melting points were determined with an X-5
digital micromelting point apparatus and are uncorrected.
1H-NMR spectra were recorded on a Bruker Avance 30 (Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences)
(300 MHz) spectrometer, using CDCl3 or CD3COCD3 as solvent
and TMS internal standard. 19F-NMR spectra were obtained on
Bruker AM-300 (282 MHz). IR spectra were measured as KBr
plates with a Shimadzu IR-440 infrared spectrometer. Elemental
analyses were performed by Italian Carlo-Erba 1106. Reagents and
solvents used were commercially available analytical grade
materials used as supplied, without further purification.
General procedure for the synthesis of 6-hydroxy-
40-trifluoromethylated aurone 5 and some alkylated derivatives
of 5. The synthetic route started from resorcinol. Condensation
of resorcinol with chloroacetonitrile catalyzed by ZnCl2 and
followed by hydrolysis with HCl gas provided ketone 2 [18].
Treatment of
2 with sodium methoxide in MeOH gave
benzofuranone 3. Condensation of 3 with a,a,a-trifluoro-p-
tolualdehyde in the presence of excess NaOH in H2O/EtOH and
followed by acidification with aqueous HCl gave the
expected compound 5 (Scheme 1). The alkylation of 5 was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Synthesis, Characterization, and Anticancer Effect of
Trifluoromethylated Aurone Derivatives
Scheme 1. Conditional and reagent: (a) ClCH2CN, HCl(g); (b) NaOMe; (c) C6H5CHO/NaOH, NaOMe; (d) a,a,a-trifluoro-p-tolualdehyde/NaOH, HCl;
(e) RX/K2CO3.
carried out with alkyl halides in the presence of K2CO3 in
acetone to afford compounds 6a-e (Scheme 1). In order to
confirm the structure of these compounds, our research group
bred the single crystal of compound 5 in acetone successfully.
The same procedure as described above can smoothly convert
resorcinol to 6-hydroxy-aurone 4 via intermediates 2 and 3
(Scheme 1).
1475, 1498, 1589, 1613, 1657, 1700 (C═O), 2980; 1H-NMR
(300 MHz, CDCl3): 1.499 (t, 3H, J = 6.9 Hz), 4.175 (q, 2H,
J = 6.9 Hz), 6.760 (dd, 1H, J = 2.1, 7.8 Hz), 6.784 (d, 1H,
J = 2.1 Hz), 6.799 (s, 1H), 7.690 (d, 2H, J = 8.4 Hz), 7.715
(d, 1H, J = 7.8 Hz), 7.990 (d, 2H, J = 8.4 Hz); ms (EI, 70 eV)
m/z: 333 (100.00), 334 (M+, 92.51), 305 (77.39), 237 (20.55),
265 (19.59), 335 (17.93), 306 (15.58), 63 (7.45); 19F-NMR
(282 MHz): –73.059. Anal. Calcd for C18H13F3O3: C, 64.67; H,
6-Hydroxy-40-trifluoromethylated aurone (5).
Yield 45%.
m.p. 166–167ꢁC. IR υmax (cmꢂ1, KBr): 1416, 1458, 1500,
1530, 1580, 1614, 1643, 1683, 1778 (C═O), 2899,
3.92. Found: C, 65.45; H, 4.22.
6-Ethoxy-40-trifluoromethylated aurone (6c). Yield 82.2%.
m.p. 122–124ꢁC. IR υmax (cmꢂ1, KBr): 1417, 1448, 1494, 1602,
1617, 1660, 1707 (C═O); 1H-NMR (300 MHz, CDCl3):
4.664–4.691 (m, 2H), 5.369–5.515 (m, 2H), 6.033–6.126
(m, 1H), 6.787 (s, 1H), 6.814 (d, 1H, J = 2.1 Hz), 7.671
(d, 2H, J = 7.8 Hz), 7.675 (d, 1H, J = 7.5 Hz), 7.719 (dd, 1H,
J = 2.1, 7.5 Hz), 7.978 (d, 2H, J = 7.8 Hz); ms (EI, 70 eV) m/z:
346 (M+, 100.00), 345 (83.84), 41 (26.47), 347 (21.66), 305
(18.62), 236 (18.19), 327 (12.72), 277 (12.24); 19F-NMR
(282 MHz): –56.761. Anal. Calcd for C19H13F3O3: C, 65.89;
H, 3.78. Found: C, 65.76; H, 3.99.
2965, 3072; 1H-NMR (300 MHz, CD3COCD3):
d 6.781
(s, 1H), 6.822 (dd, 1H, J = 2.1, 7.8 Hz), 6. 864 (d, 1H,
J = 2.1 Hz), 7.656 (d, 2H, J = 8.4 Hz), 7.821 (d, 1H, J = 7.8 Hz),
8.174 (d, 2H, J = 8.4 Hz), 10.118 (s, 1H); ms (EI, 70 eV) m/z:
305 (100.00), 63 (89.26), 92 (86.98), 237 (81.48), 306
(M+, 51.14), 108 (49.43), 69 (40.98), 159 (39.83); 19F-NMR
(282 MHz): –70.772. Anal. Calcd for C16H9F3O3: C, 62.75; H,
2.96. Found: C, 62.69; H, 2.97.
6-Methoxy-40-trifluoromethylated aurone (6a).
Yield
62.3%. m.p. 227–230ꢁC. IR υmax (cmꢂ1, KBr): 1416, 1446,
1501, 1593, 1609, 1659, 1702 (C═O), 2959; 1H-NMR
(300 MHz, CDCl3): 3.974 (s, 3H), 6.798 (s, 1H), 6.818 (dd, 1H,
J = 2.1, 7.8 Hz), 7.710 (d, 1H, J = 2.1 Hz), 7.715 (d, 2H,
J = 8.4 Hz), 7.747 (d, 1H, J = 7.8 Hz), 8.004 (d, 2H, J = 8.4 Hz);
ms (EI, 70 eV) m/z: 319 (100.00), 320 (M+, 60.41), 251 (24.18),
57 (22.11), 43 (15.95), 63 (12.95), 321 (11.35), 69 (11.34);
19F-NMR (282 MHz): –70.493. Anal. Calcd for C17H11F3O3:
C, 63.75; H, 3.46. Found: C, 63.53, H, 3.51.
6-Benzyloxy-40-trifluoromethylated aurone (6d).
Yield
89.6%. m.p. 148–149ꢁC. IR υmax (cmꢂ1, KBr): 1417, 1446,
1471, 1496, 1593, 1610, 1656, 1699 (C═O); 1H-NMR
(300 MHz, CDCl3): 5.221 (s, 2H), 6.815 (s, 1H), 6.880 (dd, 1H,
J = 2.1, 9.0 Hz), 7.425–7.470 (m, 5H), 7.456 (d, 1H, J = 2.1 Hz),
7.703 (d, 2H, J = 7.8 Hz), 7.747 (d, 1H, J = 9.0 Hz), 7.996
(d, 2H, J = 7.8 Hz); ms (EI, 70 eV) m/z: 91 (100.00), 396 (M+,
24.75), 92 (8.76), 65 (7.15), 236 (6.75), 397 (6.26), 63 (6.25),
377 (4.25); 19F-NMR (282 MHz): –74.146. Anal. Calcd for
C23H15F3O3: C, 69.70; H, 3.81. Found: C, 69.76; H, 3.91.
6-Methoxy-40-trifluoromethylated aurone (6b).
66.4%. m.p. 149–151ꢁC. IR υmax (cmꢂ1, KBr): 1415, 1447,
Yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

X. Zheng, H. Wang, Y.-M. Liu, X. Yao, M. Tong, Y.-H. Wang, and D.-F. Liao
Vol 000
6-Heptyloxy-40-trifluoromethylated aurone (6e).
Yield
[4] Rahman, A. U.; Choudhary, M. I.; Hayat, S.; Khan, A. M.;
Ahmed, A. Chem Pharm Bull 2001, 49, 105.
82.2%. m.p. 112–113ꢁC. IR υmax (cmꢂ1, KBr): 1414, 1447,
1476, 1497, 1592, 1612, 1656, 1699 (C═O), 2926, 2957;
1H-NMR (300 MHz, CDCl3): 0.887 (t, 3H, J = 6.9 Hz),
0.925–1.873 (m, 10H), 4.079 (t, 2H, J = 6.9 Hz), 6.756 (dd, 1H,
J = 2.1, 9.0Hz), 6.773 (d, 1H, J = 2.1 Hz), 6.777 (s, 1H), 7.677
(d, 2H, J = 7.8 Hz), 7.696 (d, 1H, J = 9.0 Hz), 7.972 (d, 2H,
J = 7.8 Hz); ms (EI, 70eV) m/z: 305 (100.00), 404 (M+, 72.77),
306 (45.08), 237 (29.49), 403 (22.04), 405 (18.99), 57 (16.12),
307 (9.87); 19F-NMR (282 MHz): –67.871. Anal. Calcd for
C23H15F3O3: C, 69.70; H, 3.81. Found: C, 69.76; H, 3.91.
[5] Ferreira, E. O.; Salvador, M. J.; Pral, E. M.; Alfieri, S. C.; Ito,
I. Y.; Dias, D. A. Z Natuiforsch C 2004, 59, 499.
[6] Cheng, H.; Zhang, L.; Liu, Y.; Chen, S.; Cheng, H.; Lu, X.;
Zheng, Z.; Zhou, G. C. Eur J Med Chem 2010, 45, 5950.
[7] Sim, H. M.; Lee, C. Y.; Ee, P. L.; Go, M. L. Eur J Pharm
Sci 2008, 35, 293.
[8] Bandgar, B. P.; Patil, S. A.; Korbad, B. L.; Biradar, S. C.; Nile,
S. N.; Khobragade, C. N. Eur J Med Chem 2010, 45, 3223.
[9] Venkateswarlu, S.; Panchagnula, G. K.; Gottumukkala, A. L.;
Subbaraju, G. V. Tetrahedron 2007, 63, 6909.
[10] Detsi, A.; Majdalani, M.; Kontogiorgis, C. A.; Litina, D. H.;
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[11] Haudecoeur, R.; Belkacem, A. A.; Yi, W.; Fortune, A.; Brillet,
R.; Belle, C.; Nicolle, E.; Pallier, C.; Pawlotsky, J. M.; Boumendjel, A. J
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Acknowledgments. This research was supported by the National
Natural Science Foundation of China (no. 81273537), Scientific
Research Fund of Hunan Provincial Education Department (no.
12K095), and the Key Project of Ministry of Education of the
People’s Republic of China (no. 20809).
[13] Okombi, S.; Rival, D.; Bonnet, S.; Mariotte, A. M.; Perrier, E.;
Boumendjel, A. J Med Chem 2006, 49, 329.
[14] (a) Welch, J. T.; Eswarakrishnan, S. Fluorine in bioorganic
chemistry; J. Wiley Sons: New York, 1991; (b) Singh, R. P.; Shreeve,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet