Synthesis and evaluation of the cytotoxicities of neoflavenes

Article abstract of DOI:10.1002/jccs.200800137

The synthesis of neoflavene and neoflavenes with methoxy substituents at different positions are described. As starting materials, various salicylaldehydes were run through sequential reactions such as O-allylation, Grignard reaction, oxidation, Wittig reaction, and ring-closing metathesis to yield the target neoflavenes in good yield. Among the prepared neoflavenes, 7-methoxy-4′-methoxyneoflavene (6e) and 8-methoxy-4′- methoxyneoflavene (6f) exhibiting potential cell toxicities against various cells were disclosed. In particular, 6f which exhibited an IC₅₀ value of 6.5 ± 2.0 and 5.1 ± 1.1 μM against gastric carcinoma and lung carcinoma cells in vitro was found, respectively. Meanwhile, the structure and activity relationship of our synthesized neoflavenes is further discussed briefly.

Full text of DOI:10.1002/jccs.200800137

Journal of the Chinese Chemical Society, 2008, 55, 923-932
923
Synthesis and Evaluation of the Cytotoxicities of Neoflavenes
Sie-Rong Lia (
Jui-Chi Tsaia (
Yi-Ting Huangd (
), Hsing-Ming Chenb (
), Liang-Yeu Chena (
), Yun-Chen Weid (
), Po-Yuan Chenc (
), Eng-Chi Wangc* (
) and Pei-Jung Lud* (
),
),
)
aInstitute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan, R.O.C.
bSchool of Medical and Health Sciences, Fooyin University, Kaohsiung 831, Taiwan, R.O.C.
cFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan, R.O.C.
dInstitute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.
The synthesis of neoflavene and neoflavenes with methoxy substituents at different positions are de-
scribed. As starting materials, various salicylaldehydes were run through sequential reactions such as
O-allylation, Grignard reaction, oxidation, Wittig reaction, and ring-closing metathesis to yield the target
neoflavenes in good yield. Among the prepared neoflavenes, 7-methoxy-4¢-methoxyneoflavene (6e) and
8-methoxy-4¢-methoxyneoflavene (6f) exhibiting potential cell toxicities against various cells were dis-
closed. In particular, 6f which exhibited an IC50 value of 6.5 ± 2.0 and 5.1 ± 1.1 mM against gastric carci-
noma and lung carcinoma cells in vitro was found, respectively. Meanwhile, the structure and activity rela-
tionship of our synthesized neoflavenes is further discussed briefly.
Keywords: Neoflavenes; Ring-closing metathesis; Cytotoxicities.
INTRODUCTION
Neoflavenes, which chemically belong to 4-phenyl-
the cytotoxic activities of the prepared neoflavenes against
various cells such as human esophageal carcinoma cells,
cervical carcinoma cells, etc., are also investigated (Table
1).
2H-chromenes or 4-phenyl-2H-1-benzopyrans, were origi-
nally isolated from natural sources1 and were only paid lit-
tle attention about their biological activities in current re-
search.2 Moreover, even some strategies for the syntheses
of neoflavenes have been developed,3-7 but their drawbacks
include tedious reaction conditions, low yield, and com-
mercially unavailable starting materials. Since the Grubbs’
catalyst was discovered in 1995, the ring-closing metathe-
sis (RCM) has been widely employed in various aspects in
organic synthesis.8 In particular, some heterocyclic com-
pounds which were difficult to prepare, can be synthesized
by RCM.
Furthermore, before our previous study,9 the syn-
thesis of neoflavenes which utilized RCM, has never
been reported in current literature reports. In this our ex-
tended study, we would like to report a brief, efficient, and
straightforward synthetic approach to the neoflavene skel-
eton and neoflavenes with methoxy substituents at various
positions from commercially available salicylaldehydes.
Our synthetic strategy is depicted in Scheme I. In addition,
RESULTS AND DISCUSSION
As in the general procedure, a mixture of salicylalde-
hydes (1) and allyl bromide in acetonitrile in the presence
of K2CO3 was heated to reflux to give 1-allyloxybenzalde-
hydes (2a-g) in 95-98% yields. Subsequently, 2a-g were
respectively reacted with arylmagnesium chloride to give
(2-allyloxyphenyl)arylmethanol 3a-g in 91-96% yields.
Compound 3a was used as a model for the oxidation under
various conditions, such as Dess-Martin oxidation,10 Swern
oxidation,11 and MnO2 to give 4a in 89%, 92% and 90%
yield, respectively. For the reason of easy handling and
economic concerns, MnO2 was chosen for oxidizing 3a-g
to give compounds 4a-g in 90-96% yields. Then, com-
pounds 4 were reacted with methylenetriphenylphosphane
which had been generated from methyltriphenylphospho-
nium bromide and potassium tert-butoxide in situ, to un-
dergo the Wittig reaction to give dienes 5a-g in 92-98%
* Corresponding author. Fax: +886-7-3125339 (E. C. Wang); +886-6-3028162 (P. J. Lu);
E-mail: enchwa@kmu.edu.tw; pjlu2190@mail.ncku.edu.tw

924 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Li et al.
Scheme I Synthetic strategy of neoflavenes from salicylaldehydes
yields. Subsequently, the dienes which were obtained were
respectively subjected to RCM using Grubbs’ catalyst (II)
to produce the desired neoflavenes (6a-g) in 90-93% yields.
The structure elucidation of neoflavenes (6a-g) was con-
6e and 6f exhibited inhibitory effects on various cells and
had significant activity in human esophageal carcinoma
(CE81T), cervical carcinoma (Hela), oral squamous carci-
noma (SAS), gastric carcinoma (AGS), lung carcinoma
(A549), hepatocellular carcinoma (SKHep) and prostate
cancer (PC3). Conversely, compound 6a-d, and 6g did not
have conspicuous signals in this test. In the present studies,
regarding the activity against individual cell lines, com-
pound 6f exhibited the highest cytotoxic activity among
our synthesized neoflavenes. The IC50 (mM) of 6f toward
CE81T, Hela, SAS, AGS, A549, RCC 786-O SKHep and
PC3 are 10.8 ± 1.6, 10.7 ± 4.2, 13.2 ± 4.3, 6.5 ± 2.0, 5.1 ±
1.1, 10.6 ± 2.2, 9.9 ± 2.0, and 15.4 ± 5.4, respectively. Com-
pared to 6f, the second potent compound was compound 6e
which showed similar cytotoxicities in seven examined
1
firmed by spectral data such as H-NMR, 13C-NMR, EI-
MS, and HRMS. Furthermore, the cytotoxicity studies of
the prepared neoflavenes were investigated and depicted as
follows. Eight cell lines including human esophageal carci-
noma (CE81T), cervical carcinoma (Hela), oral squamous
carcinoma (SAS), gastric carcinoma (AGS), lung carci-
noma (A549), renal cell carcinoma (786-O), hepatocellular
carcinoma (SKHep) and prostate cancer (PC3) were used
for cytotoxicity screening in vitro. The IC50 results are sum-
marized in Table 1.
As shown in Table 1, two of the prepared compounds
Table 1. The cytotoxicities of neoflavene analogues
Cell lines CE 81T
IC50
Hela
SAS
AGS
A549 RCC 786-O SKHep
PC-3
IC50
IC50
IC50
IC50
IC50
IC50
IC50
Compds
(mM)
(mM)
(mM)
(mM)
(mM)
(mM)
(mM)
(mM)
6a
6b
6c
6d
6e
6f
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
15.9 ± 4.2
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
12.4 ± 0.7
09.8 ± 1.8 11.0 ± 3.6 13.2 ± 1.6 9.1 ± 2.7 08.9 ± 0.8
9.6 ± 1.7 15.8 ± 3.9
10.8 ± 1.6 10.7 ± 4.2 13.2 ± 4.3 6.5 ± 2.0 05.1 ± 1.1 10.6 ± 2.2 9.9 ± 2.0 15.4 ± 5.4
ND ND ND ND 25.5 ± 3.8 ND ND ND
6g
* ND: Not Detected

Synthesis and Evaluation of the Cytotoxicities of Neoflavenes
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 925
cancer cell lines, but no cytotoxicity to the renal carcinoma
RCC786-O cells.
0.16 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3,
400 MHz) d 4.65 (dt, J = 5.2 Hz, 1.2 Hz, 2H, OCH2CH=CH2),
5.34 (ddt, J = 10.4 Hz, 1.2 Hz, 1.2 Hz, 1H, OCH2CH=CHaHb),
5.45 (ddt, J = 17.2 Hz, 1.2 Hz, 1.2 Hz, 1H, OCH2CH=CHaHb),
6.01 (ddt, J = 17.2 Hz, 10.4 Hz, 5.2 Hz, 1H, OCH2CH=CH2),
6.97 (dd, J = 8.8 Hz, 0.8 Hz, 1H, ArH), 7.02 (td, J = 8.8 Hz,
0.8 Hz, 1H, ArH), 7.52 (td, J = 7.6 Hz, 1.6 Hz, 1H, ArH),
7.83 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 10.53 (s, 1H, CHO);
13C-NMR (CDCl3, 100 MHz) d 69.04, 112.76, 117.93,
120.73, 124.96, 128.27, 132.28, 135.75, 160.83, 189.62;
EI-MS (70 eV) m/z (rel. intensity, %) 163 ([M+1]+, 100),
162 (M+, 24), 161 (54), 133 (24), 121 (76), 120 (19), 105
(18), 92 (26); HRMS calcd for C10H10O2: 162.0681. Found:
162.0680.
CONCLUSION
Mainly based on RCM, neoflavene and neoflavenes
with methoxy substituents at different positions were syn-
thesized. The prepared neoflavenes 6a, 6b, 6c, and 6g,
which all have no methoxy group at the 4¢-position in the
structure, exhibited almost no cytotoxicity to the examined
cancer cell lines. The neoflavene derivative 6d, which has a
4¢-methoxy group but no methoxy group at the 7-position,
or 8-position, showed cytotoxicity to A549 but no cyto-
toxicity to the other cancer cell lines examined. Thus, the
basic requirement for common cyctoxic activities must
have a methoxy group at the 4¢-position on the structure of
neoflavenes (6e-f). In addition, the methoxy group pre-
sented at 8- and 7-positions (compound 6f, 6e) enhanced
the cytotoxic activities, respectively.
2-Allyloxy-4-methoxybenzaldehyde (2b)13
(18.24 g, 95%) was obtained as colorless crystal, mp
1
37-38 °C, Rf = 0.33 (ethyl acetate: n-hexane = 1: 6), H-
NMR (CDCl3, 200 MHz) d 3.85 (s, 3H, OCH3), 4.62 (dt, J
= 5.2, 1.4 Hz, 2H, OCH2CH=CH2), 5.33 (dd, J = 10.6, 1.4
Hz, 1H, OCH2CH=CH2), 5.45 (dd, J = 17.4, 1.2 Hz, 1H,
OCH2CH=CH2), 6.04 (ddt, J = 17.4, 10.6, 5.2 Hz, 1H,
OCH2CH=CH2), 6.43 (d, J = 2.0 Hz, 1H, ArH), 6.54 (dd, J
= 8.8, 2.0 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 1H, ArH),
10.35 (s, 1H, CHO); 13C-NMR (CDCl3, 100 MHz) d 55.56,
69.11, 98.97, 106.00, 118.06, 119.20, 130.44, 132.23,
162.62, 165.99, 188.24; EI-MS (70 eV) m/z (rel. intensity,
%) 193 ([M+1]+, 30), 192 (M+, 35), 164 (28), 163 (54), 151
(100), 150 (91), 135 (45), 122 (27) , 95 (28); HRMS calcd
for C11H12O3: 192.0786. Found: 192.0784.
EXPERIMENTAL
Melting points (Yanaco micro melting-point appara-
tus) were uncorrected. 1H-NMR and 13C-NMR spectra were
obtained on a Varian Gemini-200 or Varian Unity plus 400
Spectrometer. Chemical shifts are indicated in parts per
million with respect to TMS. Elemental analyses were re-
corded on a Heraeus CHN-O rapid analyzer. Mass spectra
were recorded on a Chem/hp/middle spectrometer con-
nected to a Hewlett Packard series II model gas-liquid
chromatograph. HRMS spectra were performed on a JEOL
JMS SX/SX 102A instrument. Silica gel (230-400 mesh)
for column chromatography and precoated silica gel plates
(60 F-254) for TLC were purchased from E. Merck Co. UV
light (254 nm) was used to detect spots on TLC plates after
development.
2-Allyloxy-3-methoxybenzaldehyde (2c)14
(18.82 g, 98%) was obtained as colorless liquid, Rf =
0.26 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 200
MHz) d 3.86 (s, 3H, OCH3), 4.62 (dt, J = 6, 1.2 Hz, 2H,
OCH2CH=CH2), 5.33 (dd, J = 10.2, 1.2 Hz, 1H, OCH2CH=CH2),
5.45 (dd, J = 17.4, 1.2 Hz, 1H, OCH2CH=CH2), 6.04 (ddt, J
= 17.4, 10.2, 6 Hz, 1H, OCH2CH=CH2), 7.10 (m, 2H,
ArH), 7.37 (dd, J = 6.2 ,3.2 Hz, 1H, ArH), 10.41 (s, 1H,
CHO); 13C-NMR (CDCl3, 100 MHz) d 55.89, 75.03,
113.34, 117.87, 118.86, 123.99, 129.97, 133.01, 151.05,
152.85, 190.18; EI-MS (70 eV) m/z (rel. intensity, %) 193
([M+1]+, 100), 192 (M+, 54), 175 (17), 166 (20), 164 (29),
163 (55), 151 (83), 136 (17), 131 (20), 122 (20); HRMS
calcd for C11H12O3: 192.0781. Found: 192.0783.
General procedure for the preparation of 2-allyloxy-
benzaldehydes (2a-c)
As a general procedure, the solution of 2-hydroxy-
benzaldehyde (1a-c) (100 mmol) in dry acetonitrile (80
mL) was stirred and anhydrous K2CO3 (16.59 g, 120 mmol),
allyl bromide (14.52 g, 120 mmol) in sequence were added,
under dry nitrogen. The reaction mixture which was ob-
tained was heated to reflux for 4 hr. Work-up as in the usual
procedure, and purified by silica-gel column chromatogra-
phy with ethyl acetate/n-hexane (1/15) as eluent, to yield
pure 2a-c, respectively.
General procedure for the preparation of (2-allyloxy-
phenyl)aryl methanol (3a-g)
2-Allyloxybenzaldehyde (2a)12
To a stirred solution of 1-allyloxybenzaldehyde (2)
(30 mmol) in THF (100 mL) was added phenyl-magnesium
(15.40 g, 95%) was obtained as colorless liquid, Rf =

926 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Li et al.
chloride (2.0 M in THF) (36 mmol) in drops. And then the
reaction mixture was continually stirred for 2 hr at room
temperature. The resulting solution was concentrated in
vacuo, and the residue which was obtained was purified by
column chromatography on silica gel (ethyl acetate: n-hex-
ane = 1: 15) to give pure 3a-g.
(dd, J = 17.2, 1.2 Hz, 1H, OCH2CH=CHHtrans-gem), 5.89
(ddt, J = 17.2, 10.2, 5.8 Hz, 1H, OCH2CH=CH2), 6.03 (d, J
= 4.6 Hz, 1H, ArCH(OH)Ph), 6.83 (dd, J = 7.8, 1.8 Hz,
1Hz, ArH), 6.99 (m, 2H, ArH), 7.28 (m, 5H, ArH); 13C-
NMR (CDCl3, 50 MHz) d 55.63, 71.99, 73.46, 111.75,
117.50, 119.67, 123.91, 126.31, 127.01, 128.02, 133.89,
137.62, 143.74, 144.99, 152.45; EI-MS (70 eV) m/z (rel.
intensity, %) 271 ([M+1]+, 3), 270 (M+, 14), 251 (18), 229
(52), 212 (39), 211 (100), 170 (23), 196 (83), 152 (18), 151
(21), 141 (49), 115 (17), 105 (30), 77 (25); HRMS calcd for
C17H18O3: 270.1250. Found: 270.1253.
(2-Allyloxyphenyl)phenylmethanol (3a)
(6.62 g, 92%) was obtained as colorless crystals, mp
50-51 °C, Rf = 0.10 (ethyl acetate: n-hexane = 1: 15), 1H-
NMR (CDCl3, 400 MHz) d 3.30 (br d, J = 5.6 Hz, 1H, OH),
4.49 (dt, J = 5.2 Hz, 1.2 Hz, 2H, OCH2CH=CH2), 5.12 (ddt,
J = 10.4 Hz, 1.2 Hz, 1.2 Hz, 1H, OCH2CH=CHaHb), 5.28
(ddt, J = 17.2 Hz, 1.2 Hz, 1.2 Hz, 1H, OCH2CH=CHaHb),
5.92 (ddt, J = 17.2 Hz, 10.4 Hz, 5.2 Hz, 1H, OCH2CH=CH2),
6.07 (d, J = 5.6 Hz, 1H, ArCH(OH)Ph), 6.84 (d, J = 8.4 Hz,
1H, ArH), 6.93 (d, J = 7.4 Hz, 1H, ArH), 7.18-7.48 (m, 7H,
ArH); 13C-NMR (CDCl3, 100 MHz) d 69.00, 72.28, 112.11,
117.54, 120.99, 126.50, 127.07, 127.86, 128.07, 128.55,
132.44, 132.91, 143.44, 155.68; EI-MS (70 eV) m/z (rel.
intensity, %) 240 (M+, 12), 200 (13), 199 (100), 197 (10),
194 (10), 182 (13), 181 (83), 153 (13), 152 (27), 121 (90),
107 (11), 105 (30), 77 (37); HRMS calcd for C16H16O2:
240.1145. Found: 240.1147.
(2¢-Allyloxyphenyl)-(4²-methoxyphenyl)methanol (3d)
(7.77 g, 96%) was obtained as colorless liquids, Rf =
0.30 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.19 (br d, J = 5.2 Hz, 1H, OH), 3.71 (s, 3H,
OCH3), 4.44 (dt, J = 5.2 Hz, 1.6 Hz, 2H, OCH2CH=CHaHb),
5.18 (ddt, J = 10.4 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CCHaHb),
5.28 (ddt, J = 17.2 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb),
5.91 (ddt, J = 17.2 Hz, 10.4 Hz, 5.2 Hz, 1H, OCH2CH=CH2),
6.00 (d, J = 5.2 Hz, 1H, ArCH(OH)Ph), 6.80 (d, J = 8.8 Hz,
2H, ArH), 6.80 (dd, J = 7.6, 1.2 Hz, 1H, ArH), 6.92 (td, J =
7.2, 1.2 Hz, 1H, ArH), 7.18 (ddd, J = 7.6, 7.2, 1.6 Hz, 1H,
ArH), 7.26 (d, J = 8.8 Hz, 2H, ArH), 7.30 (dd, J = 7.2, 1.6
Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.01,
68.66, 71.36, 111.74, 113.33, 117.31, 120.76, 127.32,
127.69, 128.24, 132.46, 132.84, 135.55, 155.31, 158.50;
EI-MS (70 eV) m/z (rel. intensity, %) 270 (M+, 1), 230 (16),
229 ([M-41]+, 100), 224 (18), 211 (19), 168 (13), 135 (26),
122 (24), 121 (79); ESI-HRMS calcd for C17H18O3Na
[M+Na]+: 293.1154. Found: 293.1155.
(2-Allyloxy-4-methoxyphenyl)phenylmethanol (3b)
(7.73 g, 95%) was obtained as colorless liquids, Rf =
0.08 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
200 MHz) d 3.10 (br d, J = 3.6 Hz, 1H, OH), 3.73 (s, 3H,
OCH3), 4.44 (dt, J = 5.2, 1.4 Hz, 2H, OCH2CH=CH2), 5.21
(ddt, J = 10.2, 1.4, 1.4 Hz, 1H, OCH2CH=CHaHb), 5.29
(ddt, J = 17.2, 1.4, 1.4 Hz, 1H, OCH2CH=CHaHb), 5.91
(ddt, J = 17.2, 10.2, 5.2 Hz, 1H, OCH2CH=CCHaHb), 5.99
(d, J = 5.6 Hz, 1H, ArCH(OH)Ph), 6.41 (s, 1H, ArH), 6.42
(m, 1H, ArH), 7.22 (m, 6H, ArH); 13C-NMR (CDCl3, 50
MHz) d 55.21, 68.79, 71.54, 99.80, 104.38, 117.47,
125.03, 126.32, 126.83, 127.93, 128.38, 132.66, 143.59,
156.47, 160.01; EI-MS (70 eV) m/z (rel. intensity, %) 271
([M+1]+, 3), 270 (M+, 12), 229 (35), 227 (12), 211 (43),
168 (15), 165 (53), 164 (100), 152 (25), 151 (56), 137 (22),
106 (37), 77 (15); HRMS calcd for C17H18O3: 270.1250.
Found: 270.1253.
(2¢-Allyloxy-4¢-methoxyphenyl)-(4²-methoxyphenyl)-
methanol (3e)
(8.54 g, 95%) was obtained as colorless crystal, mp
1
46-47 °C, Rf = 0.14 (ethyl acetate: n-hexane = 1: 6), H-
NMR (CDCl3, 400 MHz) d 2.95 (br d, J = 4.0 Hz, 1H, OH),
3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.48 (dt, J = 5.2,
1.6 Hz, 2H, OCH2CH=CH2), 5.24 (ddt, J = 10.4, 1.6, 1.6
Hz, 1H, OCH2CH=CCHaHb), 5.31 (ddt, J = 17.2, 1.6, 1.6
Hz, 1H, OCH2CH=CHaHb), 5.94 (ddt, J = 17.2, 10.4, 5.2
Hz, 1H, OCH2-CH=CH2), 5.86 (br d, J = 4.0 Hz, 1H,
ArCH(OH)Ph), 6.43 (d, J = 2.4 Hz, 1H, ArH), 6.45 (dd, J =
8.0, 2.4 Hz, 1H, ArH), 6.84 (d, J = 8.8 Hz, 2H, ArH), 7.13
(d, J = 8.0 Hz, 1H, ArH), 7.28 (d, J = 8.8 Hz, 2H, ArH);
13C-NMR (CDCl3, 100 MHz) d 55.16, 55.28, 68.83, 71.32,
99.82, 104.32, 113.41, 117.58, 125.23, 127.66, 128.27,
132.73, 135.77, 156.53, 158.56, 160.03; EI-MS (70 eV)
m/z (rel. intensity, %) 300 (M+, 25), 259 (94), 241 (23), 198
2-Allyloxy-3-methoxy-phenyl)phenylmethanol (3c)
(7.81 g, 96%) was obtained as colorless liquids, Rf =
0.27 (ethy lacetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 200
MHz) d 3.16 (br d, J = 4.6 Hz, 1H, OH), 3.80 (s, 3H, OCH3),
4.21 (ddt, J = 11.8, 5.8, 1.2 Hz, 1H, OCHaHbCH=CH2),
4.35 (ddt, J = 11.8, 5.8, 1.2 Hz, 1H, OCHaHbCH=CH2),
5.15 (dd, J = 10.2, 1.2 Hz, 1H, OCH2CH=CHcis-gemH), 5.22

Synthesis and Evaluation of the Cytotoxicities of Neoflavenes
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 927
(16), 191 (23), 164 (22), 152 (30), 151 (100), 137 (26), 135
(55); ESI-HRMS calcd for C18H20O4Na [M+Na]+:
323.1259. Found: 323.1256.
was added MnO2 (17.39 g, 200 mmol) and stirred at room
temperature for 5 hr. After the end of reaction, the mixture
was filtered, and the filtration was concentrated in vacuo.
The residue which was obtained was purified from sil-
ica-gel column chromatography to give pure 4a-g.
(2¢-Allyloxy-3¢-methoxyphenyl)-(4²-methoxyphenyl)-
methanol (3f)
(8.36 g, 93%) was obtained as colorless liquid, Rf =
0.17 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.02 (br s, 1H, OH), 3.76 (s, 3H, OCH3), 3.82 (s, 3H,
OCH3), 4.27 (ddt, J = 12.0, 5.6, 1.6 Hz, 1H, OCHaHbCH=CH2),
4.33 (ddt, J = 12.0, 5.6, 1.6 Hz, 1H, OCHaHbCH=CH2),
5.16 (ddt, J = 10.4, 1.6, 1.6 Hz, 1H, OCH2CH= CHaHb),
5.25 (ddt, J = 17.2, 1.6, 1.6 Hz, 1H, OCH2CH=CHaHb),
5.92 (ddt, J = 17.2, 10.4, 5.6 Hz, 1H, OCH2CH=CH2), 6.00
(br s, 1H, ArCH(OH)Ph), 6.83 (d, J = 8.4 Hz, 2H, ArH),
6.84 (dd, J = 8.0, 1.6 Hz, 1H, ArH), 6.96 (dd, J = 8.0, 1.6
Hz, 1H, ArH) 7.04 (t, J = 8.0 Hz, 1H, ArH), 7.27 (d, J = 8.4
Hz, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.15, 55.64,
71.61, 73.46, 111.60, 113.46, 117.53, 119.44, 123.97,
127.67, 133.97, 135.97, 137.83, 144.91, 152.50, 158.66;
EI-MS (70 eV) m/z (rel. intensity, %) 300 (M+, 1), 284 (14),
283 ([M-17]+, 100), 282 (8), 260 (6), 242 (6), 151 (7);
ESI-HRMS calcd for C18H20O4Na [M+Na]+: 323.1259.
Found: 323.1261.
2-Allyloxybenzophenone (4a)15
(4.31 g, 90%) was obtained as colorless liquid, Rf =
0.15 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3,
200 MHz) d 4.44 (dt, J = 5.2 Hz, 1.2 Hz, 2H, OCH2CH=
CH2), 4.98 (ddt, J = 10.4 Hz, 1.2 Hz, 1.2 Hz, 1H, OCH2CH=
CHaHb), 5.04 (ddt, J = 17.2 Hz, 1.2 Hz, 1.2 Hz, 1H,
OCH2CH=CHaHb), 5.70 (ddt, J = 17.2 Hz, 10.4 Hz, 5.2 Hz,
1H, OCH2CH=CH2), 6.96 (d, J = 8.0 Hz, 1H, ArH), 7.05
(td, J = 7.6 Hz, 0.8 Hz, 1H, ArH), 7.36-7.57 (m, 5H, ArH),
7.78-7.83 (m, 2H, ArH); 13C-NMR (CDCl3, 50 MHz) d
68.92, 112.76, 116.81, 120.79, 128.10, 129.22, 129.57,
129.74, 131.86, 132.32, 132.68, 138.11, 156.34, 196.50;
EI-MS (70 eV) m/z (rel. intensity, %) 239 ([M+1]+, 54),
238 (M+, 21), 223 (35), 209 (45), 197 (67), 195 (35), 194
(71), 181 (76), 121 (66), 115 (45), 106 (40), 105 (100), 77
(95); HRMS calcd for C16H14O2: 238.0988. Found:
238.0990.
(2-Allyloxy-4-methoxyphenyl)phenylmethanone (4b)16
(4.86 g, 91%) was obtained as colorless liquid, Rf =
0.17 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
200 MHz) d 3.85 (s, 3H, OCH3), 4.12 (dt, J = 5.6, 1.8 Hz,
2H, OCH2CH=CH2), 4.97 (ddt, J = 17.2, 1.8, 1.8 Hz, 1H,
OCH2CH=CHaHb), 5.03 (ddt, J = 10.8, 1.8, 1.8 Hz, 1H,
OCH2CH=CHaHb), 5.69 (ddt, J = 17.2, 10.8, 5 Hz, 1H,
OCH2CH=CH2), 6.48 (d, J = 2.2 Hz, 1H, ArH), 6.57 (dd, J
= 8.4, 2.2 Hz, 1H, ArH), 7.46 (m, 4H, ArH), 7.71 (m, 2H,
ArH); 13C-NMR (CDCl3, 50 MHz) d 55.45, 68.88, 99.81,
105.09, 116.85, 121.84, 127.94, 129.44, 132.08, 132.16,
132.23, 139.14, 158.48, 163.31, 195.73; EI-MS (70 eV)
m/z (rel. intensity, %) 269 ([M+1]+, 56), 268 (M+, 98), 267
(28), 254 (12), 253 (60), 211 (19), 191 (15), 175 (16), 163
(23), 105 (100), 77 (22); HRMS calcd for C17H16O3:
268.1094. Found: 268.1096.
(2¢-Allyloxy-3¢-methoxyphenyl)-(2²-methoxyphenyl)-
methanol (3g)
(8.17 g, 91%) was obtained as colorless crystal, mp
121-122 °C, Rf = 0.20 (ethyl acetate: n-hexane = 1: 6),
1H-NMR (CDCl3, 400 MHz) d 3.22 (d, J = 4.8 Hz, 1H,
OH), 3.78 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.07 (ddt, J =
12.4, 5.6, 1.2 Hz, 1H, OCHaHbCH=CH2), 4.50 (ddt, J =
12.4, 5.6, 1.2 Hz, 1H, OCHaHbCH=CH2), 5.16 (ddt, J =
10.4, 1.6, 1.2 Hz, 1H, OCH2CH=CHcis-gemH), 5.27 (ddt, J =
17.2, 1.6, 1.2 Hz, 1H, OCH2CH=CHHtrans-gem), 5.99 (ddt, J
= 17.2, 10.4, 5.6 Hz, 1H, OCH2CH=CH2), 6.42 (d, J = 4.8
Hz, 1H, ArCH(OH)Ph), 6.83-6.93 (m, 4H, ArH), 7.02 (t, J
= 7.6 Hz, 1H, ArH), 7.21-7.25 (m, 2H, ArH); 13C-NMR
(CDCl3, 100 MHz) d 55.27, 55.67, 66.79, 73.59, 110.36,
111.49, 117.17, 119.64, 120.47, 123.71, 127.74, 128.42,
131.32, 134.25, 136.88, 145.24, 152.38, 156.65; EI-MS
(70 eV) m/z (rel. intensity, %) 301 ([M+1]+, 3), 300 (M+,
21), 284 (17), 283 (100), 251 (5), 241 (6), 211 (9), 147 (6);
ESI-HRMS calcd for C18H20O4Na [M+Na]+: 323.1259.
Found: 323.1256.
(2-Allyloxy-3-methoxyphenyl)phenylmethanone (4c)
(4.81 g, 90%) was obtained as colorless liquid, Rf =
0.21 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
200 MHz) d 3.86 (s, 3H, OCH3), 4.41 (d, J = 5.8 Hz, 2H,
OCH2CH=CH2), 4.98 (dd, J = 10.2, 1.0 Hz, 1H, OCH2CH=
CHaHb), 5.03 (dd, J = 17.2, 1.0 Hz, 1H, OCH2CH=CHaHb),
5.72 (ddt, J = 17.2, 10.2, 5.8 Hz, 1H, OCH2CH=CH2), 6.93
(dd, J = 2.2, 1.8 Hz, 1H, ArH), 7.03 (dd, J = 7.8, 1.8 Hz, 1H,
ArH), 7.11 (t, J = 7.8 Hz, 1H, ArH), 7.46 (m, 3H, ArH),
General procedure for the preparation of 2-allyloxy-
benzophenones (4a-g)
To (2-allyloxyphenyl)phenylmethanol (3a-g) (20
mmol) dissolved in anhydrous dichloromethane (85 mL)

928 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Li et al.
7.81 (m, 2H, ArH); 13C-NMR (CDCl3, 50 MHz) d 55.68,
74.41, 114.18, 117.06, 120.25, 123.87, 127.99, 129.58,
132.78, 133.38, 134.26, 137.51, 145.40, 152.59, 195.99;
EI-MS (70 eV) m/z (rel. intensity, %) 269 ([M+1]+, 38),
268 (M+, 69), 267 (22), 253 (33), 240 (21), 239 (30), 227
(69), 225 (40), 222 (20), 213 (32), 212 (100), 184 (57), 151
(34), 105 (34), 77 (36); HRMS calcd for C17H16O3:
268.1094. Found: 268.1096.
0.26 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.83 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.43 (dt, J
= 6.0 Hz, 1.6 Hz, 2H, OCH2CH=CH2), 5.02 (ddt, J = 10.4
Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.08 (ddt, J =
17.2 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.78 (ddt,
J = 17.2 Hz, 10.4 Hz, 6.0 Hz, 1H, OCH2CH=CH2), 6.90 (d,
J = 8.8 Hz, 2H, ArH), 6.90 (dd, J = 8.0 Hz, 1.6 Hz, 1H,
ArH), 7.02 (dd, J = 8.0 Hz, 1.6 Hz, 1H, ArH), 7.12 (t, J =
8.0 Hz, 1H, ArH), 7.81 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR
(CDCl3, 100 MHz) d 55.29, 55.72, 74.60, 113.35, 113.73,
117.21, 120.16, 123.98, 130.38, 132.20, 133.59, 134.79,
145.14, 152.66, 163.51, 194.68; EI-MS (70 eV) m/z (rel.
intensity, %) 299 ([M+1]+, 100), 298 (M+, 14), 257 (29),
242 (46), 239 (26), 214 (61), 151 (63), 135 (94), 122 (39),
77 (57); ESI-HRMS calcd for C18H18O4Na [M+Na]+:
321.1103. Found: 321.1101.
(2¢-Allyloxyphenyl)-(4²-methoxyphenyl)methanone
(4d)
(5.09 g, 95%) was obtained as colorless liquid, Rf =
0.32 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.83 (s, 3H, CH3), 4.47 (dt, J = 4.8 Hz, 1.6 Hz, 2H,
OCH2CH=CH2), 5.07 (ddt, J = 10.8 Hz, 1.6 Hz, 1.6 Hz, 1H,
OCH2CH=CHaHb), 5.08 (ddt, J = 17.2 Hz, 1.6 Hz, 1.6 Hz,
1H, OCH2CH=CHaHb), 5.79 (ddt, J = 17.2 Hz, 10.8 Hz, 4.8
Hz, 1H, OCH2CH=CH2), 6.89 (d, J = 8.8 Hz, 2H, ArH),
6.95 (d, J = 8.0 Hz, 1H, ArH), 7.02 (t, J = 7.6 Hz, 1H, ArH),
7.35 (dd, J = 7.6, 1.6 Hz, 1H, ArH), 7.41 (ddd, J = 8.0, 7.6,
1.6 Hz, 1H, ArH), 7.80 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR
(CDCl3, 100 MHz) d 55.32, 68.84, 112.65, 113.30, 116.78,
120.66, 129.27, 129.55, 130.74, 131.30, 132.04, 132.42,
155.86, 163.36, 195.01; EI-MS (70 eV) m/z (rel. intensity,
%) 269 ([M+1]+, 100), 268 (M+, 8), 238 (8), 224 (16), 161
(8), 148 (19), 147 (7), 135 (31), 77 (8); ESI-HRMS calcd
for C17H17O3 [M+H]+: 269.1178. Found: 269.1177.
(2¢-Allyloxy-4¢-methoxyphenyl)-(4²-methoxyphenyl)-
methanone (4e)17
(2¢-Allyloxy-3¢-methoxyphenyl)-(2²-methoxyphenyl)-
methanone (4g)
(5.73 g, 96%) was obtained as colorless liquid, Rf =
0.25 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.68 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.30 (dt, J
= 6, 1.6 Hz, 2H, OCH2CH=CH2), 5.00 (ddt, J = 10.4 Hz, 1.6
Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.04 (ddt, J = 17.2 Hz,
1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.66 (ddt, J = 17.2,
10.4, 6.0 Hz, 1H, OCH2CH=CH2), 6.91 (d, J = 8.4 Hz, 1H,
ArH), 6.97 (t, J = 7.6 Hz, 1H, ArH), 7.01-7.10 (m, 3H,
ArH), 7.43 (td, J = 8.4, 2, Hz, 1H, ArH), 7.50 (dd, J = 7.6, 2
Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.67,
55.89, 74.54, 111.57, 114.85, 117.08, 120.10, 121.13,
123.89, 129.75, 130.55, 132.84, 133.62, 135.90, 146.34,
152.67, 158.49, 195.49; EI-MS (70 eV) m/z (rel. intensity,
%) 299 ([M+1]+, 42), 298 (M+, 19), 267 (38), 257 (38), 242
(56), 151 (96), 135 (100), 122 (30), 92 (34), 77 (59); ESI-
HRMS calcd for C18H19O4 [M+H]+: 299.1283. Found:
299.1285.
(5.66 g, 95%) was obtained as colorless liquid, Rf =
0.22 (ethyl acetate: n-hexane = 1: 6), 1H-NMR (CDCl3, 400
MHz) d 3.81 (s, 6H, 2 ´ OCH3), 4.42 (dt, J = 4.8, 1.6, 2H,
OCH2CH=CH2), 5.03 (ddt, J = 16.8, 1.6, 1.6 Hz, 1H,
OCH2CH=CHaHb), 5.04 (ddt, J = 10.8, 1.6, 1.6 Hz, 1H,
OCH2CH=CHaHb), 5.74 (ddt, J = 16.8, 10.8, 4.8 Hz, 1H,
OCH2CH=CH2), 6.47 (d, J = 2.4 Hz, 1H, ArH), 6.53 (dd, J
= 8.4, 2.4 Hz, 1H, ArH), 6.87 (d, J = 8.8 Hz, 2H, ArH), 7.36
(d, J = 8.4 Hz, 1H, ArH), 7.75 (d, J = 8.8 Hz, 2H, ArH);
13C-NMR (CDCl3, 100 MHz) d 55.27, 55.31, 68.82, 99.76,
104.87, 113.09, 116.78, 122.17, 131.51, 131.62, 131.86,
132.19, 157.86, 162.70, 162.97, 194.26; EI-MS (70 eV)
m/z (rel. intensity, %) 299 ([M+1]+, 38), 298 (M+, 19), 268
(64), 254 (100), 253 (51), 241 (53), 214 (54), 211 (75), 148
(79), 135 (79); ESI-HRMS calcd for C18H19O4 [M+H]+:
299.1283. Found: 299.1285.
General procedure for the preparation of 1-allyloxy-
2-(phenylvinyl)benzene (5a-g)
Under the protection of dried nitrogen, to methyltri-
phenylphosphonium bromide (7.15 g, 20 mmol) dissolved
in anhydrous THF (50 mL) and cooled at 0 °C was added
potassium tert-butoxide (2.25 g, 20 mmol) in portion. The
resulting mixture was stirred at 0 °C for 15 min. Then, the
reaction solution turned yellow and was added in drops to
the solution of 2-allylbenzophenones (4a-g) (15 mmol) in
THF (5 mL). The resulting solution was stirred for 3 hr at 0
°C. Finally, the solution was quenched with saturated
NH4Cl aq. solution. After concentration in vacuo to remove
(2¢-Allyloxy-3¢-methoxyphenyl)-(4²-methoxyphenyl)-
methanone (4f)
(5.67 g, 95%) was obtained as colorless liquid, Rf =

Synthesis and Evaluation of the Cytotoxicities of Neoflavenes
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 929
THF, the mixture which was obtained was extracted with
EtOAc (20 mL ´ 5). The organic layer was combined and
washed with brine and then dried with anhydrous MgSO4.
After filtration, the filtrate was concentrated in vacuo. The
obtained residue was purified by silica-gel column chroma-
tography (ethyl acetate: n-hexane = 1: 15) to give pure
5a-g.
Hz, 1H, OCH2CH=CHaHb), 5.32, 5.67 (each d, J = 1.6 Hz,
1H, Ar(Ph)C=CH2), 5.66 (ddt, J = 17.2 Hz, 10.4 Hz, 5.6
Hz, 1H, OCH2CH=CH2), 6.86 (dd, J = 7.6 Hz, 1.6 Hz, 1H,
ArH), 6.90 (dd, J = 8.4 Hz, 1.6 Hz, 1H, ArH), 7.04 (dd, J =
8.4 Hz, 7.6 Hz, 1H, ArH), 7.27 (m, 5H, ArH); 13C-NMR
(CDCl3, 100 MHz) d 55.68, 73.54, 111.83, 115.69, 116.77,
122.99, 123.65, 126.60, 127.29, 127.96, 134.15, 136.51,
141.33, 145.46, 146.81, 152.91; EI-MS (70 eV) m/z (rel.
intensity, %) 267 ([M+1]+, 1), 266 (M+, 4), 265 (4), 251
(10), 248 (12), 238 (12), 235 (12), 226 (17), 225 (100), 219
(21), 198 (13), 197 (43), 183 (13), 182 (34), 181 (18), 169
(13), 166 (25), 165 (44), 154 (21), 153 (26), 152 (20), 145
(22); HRMS calcd for C18H18O2: 266.1301. Found:
266.1304.
1-Allyloxy-2-(phenylvinyl)benzene (5a)
(3.25 g, 92%) was obtained as colorless liquid, Rf =
0.65 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3,
400 MHz) d 4.33 (dt, J = 5.2 Hz, 1.6 Hz, 2H, OCH2CH=
CH2), 4.97-5.03 (m, 2H, OCH2CH=CH2), 5.33, 5.68 (each
d, J = 1.6 Hz, 1H, Ar(Ph)C=CH2), 5.62 (ddt, J = 17.2 Hz,
10.4 Hz, 5.2 Hz, 1H, OCH2CH=CH2), 6.86 (dd, J = 8.0 Hz,
0.8 Hz, 1H, ArH), 6.99 (td, J = 8.0 Hz, 0.8 Hz, 1H, ArH),
7.20-7.31 (m, 7H, ArH); 13C-NMR (CDCl3, 100 MHz) d
68.96, 112.79, 115.47, 116.44, 120.85, 126.43, 127.18,
127.94, 128.90, 131.30, 131.55, 132.97, 141.45, 147.33,
156.04; EI-MS (70 eV) m/z (rel. intensity, %) 237 ([M+1]+,
7), 236 (M+, 3), 221 (25), 208 (20), 207 (20), 195 (67), 168
(25), 167 (93), 166 (31), 165 (74), 152 (33), 145 (100), 115
(17); HRMS calcd for C17H16O: 236.1196. Found:
236.1198.
1-(Allyloxy)-2-[1-(4-methoxyphenyl)vinyl]benzene (5d)
(3.83 g, 96%) was obtained as colorless crystal, mp
1
41-42 °C, Rf = 0.59 (ethyl acetate: n-hexane = 1: 9), H-
NMR (CDCl3, 400 MHz) d 3.77 (s, 3H, OCH3), 4.35 (dt, J
= 4.8 Hz, 1.6 Hz, 2H, OCH2CH=CH2), 5.02 (ddt, J = 10.4
Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.05 (ddt, J =
17.2 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.22, 5.60
(each d, J = 1.6 Hz, 1H, Ar(Ph)C=CH2), 5.67 (ddt, J = 17.2
Hz, 10.4 Hz, 4.8 Hz, 1H, OCH2CH=CH2), 6.79 (d, J = 8.8
Hz, 2H, ArH), 6.87 (d, J = 7.6 Hz, 1H, ArH), 6.97 (t, J = 7.6
Hz Hz, 1H, ArH), 7.23 (d, J = 8.8 Hz, 2H, ArH), 7.20-7.30
(m, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.18,
68.93, 112.78, 113.29, 113.74, 116.43, 120.81, 127.54,
128.77, 131.24, 131.74, 133.04, 133.97, 146.55, 155.99,
158.96; EI-MS (70 eV) m/z (rel. intensity, %) 267 ([M+1]+,
31), 266 (M+, 26), 251 (14), 238 (15), 237 (21), 225 (15),
197 (29), 176 (19), 175 (100), 147 (37). HRMS calcd for
C18H18O2: 266.1307. Found: 266.1306.
2-Allyloxy-4-methoxy-1-(1-phenylvinyl)benzene (5b)
(3.80 g, 95%) was obtained as colorless liquid, Rf =
0.60 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
400 MHz) d 3.79 (s, 3H, OCH3), 4.30 (dt, J = 4.8, 1.6 Hz,
1H, OCH2CH=CH2), 4.98 (ddt, J = 18.0 Hz, 1.6 Hz, 1.6 Hz,
1H, OCH2CH=CHaHb), 4.99 (ddt, J = 11.2 Hz, 1.6 Hz, 1.6
Hz, 1H, OCH2CH=CHaHb), 5.30, 5.60 (each d, J = 1.6 Hz,
1H, Ar(Ph)C=CH2), 5.60 (ddt, J = 18.0 Hz, 11.2 Hz, 4.8
Hz, 1H, OCH2CH=CH2), 6.45 (d, J = 2.4 Hz, 1H, ArH),
6.51 (dd, J = 8.4 Hz, 2.4 Hz, 1H, ArH), 7.25 (m, 6H, ArH);
13C-NMR (CDCl3, 50 MHz) d 55.26, 68.83, 100.27,
104.57, 115.05, 116.45, 124.16, 126.47, 127.07, 127.86,
131.68, 132.73, 141.81, 146.97, 156.96, 160.48; EI-MS
(70 eV) m/z (rel. intensity, %) 267 ([M+1]+, 33), 266 (M+,
99), 265 (100), 252 (12), 251 (46), 238 (14), 237 (27), 236
(71), 235 (16), 225 (12), 223 (10), 197 (20), 165 (11);
HRMS calcd for C18H18O2: 266.1307. Found: 266.1305.
2-Allyloxy-1-methoxy-3-(1-phenylvinyl)benzene (5c)
(3.84 g, 96%) was obtained as colorless liquid, Rf =
0.44 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
400 MHz) d 3.83 (s, 3H, OCH3), 4.21 (dt, J = 5.6, 1.6 Hz,
1H, OCH2CH=CH2), 4.97 (ddt, J = 10.4 Hz, 1.2 Hz, 1.2 Hz,
1H, OCH2CH=CHaHb), 5.02 (ddt, J = 17.2 Hz, 1.2 Hz, 1.2
2-Allyloxy-4-methoxy-1-[1-(4-methoxyphenyl)vinyl]-
benzene (5e)
(4.36 g, 98%) was obtained as colorless liquid, Rf =
0.57 (ethylacetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400
MHz) d 3.79 (s, 3H, OCH3), 3.82 (s, 3H, OCH3), 4.35 (dt, J
= 4.8 Hz, 2.0 Hz, 1H, OCH2CH=CH2), 5.04 (ddt, J =10.4
Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.04 (ddt, J =
17.6 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.20, 5.54
(each d, J = 1.6 Hz, 1H, Ar(Ph)C=CH2), 5.63 (ddt, J = 17.6,
10.4, 4.8 Hz, 1H, OCH2CH=CH2), 6.46 (d, J = 2.4 Hz, 1H,
ArH), 6.52 (dd, J = 8.0, 2.4 Hz, 1H, ArH), 6.80 (d, J = 8.8
Hz, 2H, ArH), 7.18 (d, J = 8.0 Hz, 1H, ArH), 7.24 (d, J =
8.8 Hz, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.24,
55.32, 68.95, 100.38, 104.59, 113.26, 113.46, 116.54,

930 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Li et al.
124.45, 127.63, 131.67, 132.89, 134.41, 146.23, 156.99,
158.92, 160.39; EI-MS (70 eV) m/z (rel. intensity, %) 297
([M+1]+, 22), 296 (M+, 45), 281 (47), 267 (38), 266 (100),
253 (21), 227 (55), 212 (24), 175 (28), 169 (23);
ESI-HRMS calcd for C19H21O3 [M+H]+: 297.1491. Found:
297.1489.
Found: 319.1307.
General procedure for the preparation of neoflavenes
(6a-g)
To 1-allyloxy-2-(arylvinyl)benzenes (5a-g) (5 mmol)
dissolved in dichloromethane (100 mL) was added Grubbs’
catalyst (5% mol), and the reaction mixture was stirred at
room temperature for 4 hr. Then, the mixture was concen-
trated in vacuo to remove the solvent. The residue was puri-
fied by silica gel column chromatography (ethyl acetate:
n-hexane = 1: 15) to give pure 6a-g.
2-Allyloxy-3-methoxy-1-[1-(4-methoxyphenyl)vinyl]-
benzene (5f)
(4.27 g, 96%) was obtained as colorless liquid, Rf =
0.46 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400
MHz) d 3.77 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 4.24 (dt, J
= 5.6 Hz, 1.6 Hz, 1H, OCH2CH=CH2), 4.99 (ddt, J = 10.4
Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.06 (ddt, J =
17.2 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.21, 5.60
(each d, J = 1.6 Hz, 1H, Ar(Ph)C=CH2), 5.72 (ddt, J = 17.2
Hz, 10.4 Hz, 6.0 Hz, 1H, OCH2CH=CH2), 6.80 (d, J = 8.8
Hz, 2H, ArH), 6.85 (dd, J = 8.0 Hz, 1.6 Hz, 1H, ArH), 6.89
(dd, J = 8.4 Hz, 1.6 Hz, 1H, ArH), 7.04 (dd, J = 8.0 Hz, 1H,
ArH), 7.24 (d, J = 8.8 Hz, 2H, ArH); 13C-NMR (CDCl3,
100 MHz) d 55.14, 55.71, 73.63, 111.73, 113.33, 113.90,
116.72, 122.97, 123.62, 127.74, 133.88, 134.27, 136.76,
145.52, 146.10, 152.92, 159.04; EI-MS (70 eV) m/z (rel.
intensity, %) 297 ([M+1]+, 44), 296 (M+, 100), 295 (52),
282 (17), 281 (49), 267 (17), 266 (38), 265 (54), 255 (18),
175 (21); ESI-HRMS calcd for C19H20O3Na [M+Na]+:
319.1310. Found: 319.1307.
Neoflavene (4-Phenyl-2H-chromene) (6a)18
(0.95 g, 91%) was obtained as colorless liquid, Rf =
0.62 (ethyl acetate: n-hexane = 1: 15), 1H-NMR (CDCl3,
400 MHz) d 4.86 (d, J = 4.0 Hz, 2H, H-2), 5.80 (t, J = 4.0
Hz, 1H, H-3), 6.84 (td, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 6.90
(dd, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 7.00 (dd, J = 8.0 Hz, 1.6
Hz, 1H, ArH), 7.15 (td, J = 8.0 Hz, 1.6 Hz, 1H, ArH ), 7.37
(m, 5H, ArH); 13C-NMR (CDCl3, 100 MHz) d 65.24,
116.16, 119.89, 121.12, 125.80, 127.74, 128.33, 128.58,
129.19, 130.03, 137.11, 154.68, 186.22; EI-MS (70 eV)
m/z (rel. intensity, %) 208 (M+, 75), 207 (100), 179 (21),
178 (32), 152 (15), 132 (11), 131 (33); HRMS calcd for
C15H12O1: 208.0888. Found: 208.0886.
7-Methoxyneoflavene (7-Methoxy-4-phenyl-2H-
chromene) (6b)19
(1.07 g, 90%) was obtained as colorless liquid, Rf =
0.61 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
400 MHz) d 3.76 (s, 3H, OCH3), 4.81 (d, J = 4.0 Hz, 2H,
H-2), 5.63 (t, J = 4.0 Hz, 1H, H-3), 6.40 (dd, J = 8.4 Hz, 2.4,
1H, ArH), 6.48 (d, J = 2.4 Hz, 1H, ArH), 6.92 (d, J = 8.4
Hz, 1H, ArH), 7.34 (m, 5H, ArH); 13C-NMR (CDCl3, 100
MHz) d 55.26, 65.46, 101.88, 106.81, 116.81, 116.90,
126.63, 127.65, 128.28, 128.50, 136.93, 138.43, 156.01,
160.52; EI-MS (70 eV) m/z (rel. intensity, %) 239 ([M+1]+,
16), 238 (M+, 96), 237 (100), 223 (32), 194 (22), 165 (17),
161 (26); HRMS calcd for C16H14O2: 238.0994. Found:
238.0991.
2-Allyloxy-1-methoxy-3-[1-(2-methoxy-phenyl)vinyl]-
benzene (5g)
(4.31 g, 97%) was obtained as colorless liquid, Rf =
0.52 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400
MHz) d 3.62 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.22 (dt, J
= 5.6 Hz, 1.6 Hz, 1H, OCH2CH=CH2), 5.04 (ddt, J = 10.4
Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.12 (ddt, J =
17.2 Hz, 1.6 Hz, 1.6 Hz, 1H, OCH2CH=CHaHb), 5.59, 5.62
(each d, J = 2.0 Hz, 1H, Ar(Ph)C=CH2), 5.80 (ddt, J = 17.2
Hz, 10.4 Hz, 6.0 Hz, 1H, OCH2CH=CH2), 6.80-6.84 (m,
2H, ArH), 6.81 (d, J = 7.2 Hz, 1H, ArH), 6.89 (td, J = 7.2
Hz, 0.8 Hz, 1H, ArH), 6.96 (dd, J = 8.4 Hz, 7.2 Hz, 1H,
ArH), 7.21 (d, J = 7.2 Hz, 1H, ArH), 7.22 (td, J = 7.2 Hz,
1.6 Hz, 1H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.37,
55.73, 73.14, 111.21, 111.22, 116.47, 119.31, 120.33,
122.23, 123.31, 128.33, 130.39, 131.74, 134.58, 137.31,
143.82, 145.14, 152.79, 156.81; EI-MS (70 eV) m/z (rel.
intensity, %) 297 ([M+1]+, 1), 296 (M+, 3), 265 (21), 256
(18), 255 (100), 225 (14), 175 (27), 152 (12), 122 (24), 121
(70); ESI-HRMS calcd for C19H20O3Na [M+Na]+: 319.1310.
8-Methoxyneoflavene (8-Methoxy-4-phenyl-2H-
chromene) (6c)
(1.10 g, 92%) was obtained as colorless crystal, mp
66-68 °C (n-hexane + ethyl acetate) [lit.20 70-71 °C], Rf =
0.24 (ethyl acetate: n-hexane = 1: 19), 1H-NMR (CDCl3,
400 MHz) d 3.92 (s, 3H, OCH3), 4.92 (d, J = 4.0 Hz, 2H,
H-2), 5.83 (t, J = 4.0 Hz, 1H, H-3), 6.66 (dd, J = 7.2 Hz, 2.0
Hz, 1H, ArH), 6.83 (m, 2H, ArH), 7.35-7.42 (m, 5H, ArH);
13C-NMR (CDCl3, 100 MHz) d 55.97, 65.36, 111.97,

Synthesis and Evaluation of the Cytotoxicities of Neoflavenes
J. Chin. Chem. Soc., Vol. 55, No. 4, 2008 931
118.20, 119.89, 120.45, 124.35, 127.66, 128.21, 128.52,
137.08, 138.28, 143.53, 148.00; EI-MS (70 eV) m/z (rel.
intensity, %) 239 ([M+1]+, 17), 238 (M+, 100), 237 (57),
223 (20), 207 (17), 195 (17), 167 (16), 165 (28), 161 (20);
HRMS calcd for C16H14O2: 238.0988. Found: 238.0991.
4¢-Methoxyneoflavene (4-(4-Methoxyphenyl)-2H-
chromene) (6d)
1H, ArH), 7.24 (d, J = 8.8 Hz, 1H, ArH); 13C-NMR (CDCl3,
100 MHz) d 55.03, 55.85, 65.24, 111.82, 113.51, 118.12,
119.02, 120.32, 124.51, 129.55, 130.53, 136.50, 143.55,
147.91, 159.09; EI-MS (70 eV) m/z (rel. intensity, %) 269
([M+1]+, 19), 268 (M+, 100), 267 (33), 253 (45), 238 (12),
237 (17), 235 (12), 225 (14), 210 (13) , 165 (16);
ESI-HRMS calcd for C17H17O3 [M+H]+: 269.1178. Found:
269.1177.
(1.09 g, 92%) was obtained as colorless crystal, mp
93-94 °C (n-hexane + ethyl acetate) [lit.3 89-92 °C], Rf =
0.58 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400
MHz) d 3.84 (s, 3H, OCH3), 4.82 (d, J = 4.0 Hz, 2H, H-2),
5.75 (t, J = 4.0 Hz, 1H, H-3), 6.85 (td, J = 7.6 Hz, 1.2 Hz,
1H, ArH), 6.89 (dd, J = 8.0 Hz, 1.2 Hz, 1H, ArH), 6.93 (d, J
= 8.8 Hz, 2H, ArH), 7.02 (dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH),
7.15 (ddd, J = 8.0 Hz, 7.6 Hz, 1.6 Hz, 1H, ArH), 7.27 (d, J =
8.8 Hz, 2H, ArH); 13C-NMR (CDCl3, 100 MHz) d 55.28,
65.21, 113.73, 116.15, 119.17, 121.10, 123.90, 125.82,
129.11, 129.72, 130.59, 136.61, 154.78, 159.25; EI-MS
(70 eV) m/z (rel. intensity, %) 239 ([M+1]+, 16), 238 (100),
237 (66), 223 (31), 207 (39), 195 (20), 194 (18), 167 (16),
165 (35), 152 (14). HRMS calcd for C16H14O2: 238.0994.
Found: 238.0996.
8-Methoxy-2¢-methoxyneoflavene (8-Methoxy-4-(2-
methoxyphenyl)-2H-chromene) (6g)
(1.21 g, 90%) was obtained as colorless crystal, mp
123-124 °C (n-hexane + ethyl acetate), Rf = 0.30 (ethyl ace-
tate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400 MHz) d 3.70
(s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.96 (d, J = 4.0 Hz, 2H,
H-2), 5.75 (t, J = 4.0 Hz, 1H, H-3), 6.34 (dd, J = 7.6 Hz, 1.6
Hz, 1H, ArH), 6.71 (t, J = 7.6 Hz, 1H, ArH), 6.77 (dd, J =
8.0 Hz, 1.6 Hz, 1H, ArH), 6.93 (d, J = 8.0 Hz, 1H, ArH),
6.97 (t, J = 7.6 Hz, 1H, ArH), 7.17 (dd, J = 7.6 Hz, 1.6 Hz,
1H, ArH), 7.33 (td, J = 8.0 Hz, 1.6 Hz, 1H, ArH);13C-NMR
(CDCl3, 100 MHz) d 55.38, 55.93, 65.61, 110.81, 111.62,
117.97, 120.19, 120.52, 121.00, 124.35, 127.28, 129.13,
130.84, 134.07, 142.71, 147.74, 157.08; EI-MS (70 eV)
m/z (rel. intensity, %) 269 ([M+1]+, 18), 268 (M+, 100), 267
(11), 254 (11), 253 (43), 238 (18), 237 (48), 221 (9), 206
(9), 165 (13); ESI-HRMS calcd for C17H16O3Na [M+Na]+:
291.0997. Found: 291.1000.
7-Methoxyneoflavene (7-Methoxy-4-(4-methoxy-
phenyl)-2H-chromene) (6e)
(1.25 g, 93%) was obtained as colorless crystal, mp
102-104 °C (n-hexane + ethyl acetate) [lit.3 101-103 °C], Rf
= 0.58 (ethyl acetate: n-hexane = 1: 9), 1H-NMR (CDCl3,
200 MHz) d 3.79 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.82
(d, J = 4.0 Hz, 2H, H-2), 5.62 (t, J = 4.0 Hz, 1H, H-3), 6.42
(dd, J = 8.4 Hz, 2.6 Hz, 1H, ArH), 6.49 (d, J = 2.6 Hz, 1H,
ArH), 6.92 (d, J = 8.8 Hz, 2H, ArH), 6.96 (d, J = 8.4 Hz,
1H, ArH), 7.27 (d, J = 8.8 Hz, 2H, ArH);13C-NMR (CDCl3,
50 MHz) d 55.27, 55.33, 65.53, 101.92, 106.85, 113.74,
116.19, 117.13, 126.69, 129.68, 130.88, 136.53, 156.15,
159.26, 160.53; EI-MS (70 eV) m/z (rel. intensity, %) 269
([M+1]+, 18), 268 (M+, 100), 267 (74), 253 (32), 237 (17),
225 (15), 165 (22), 161 (16), 153 (19), 152 (19). HRMS
calcd for C17H16O3: 268.1099. Found: 268.1099.
Cytotoxic assays
The cytotoxic potential of all synthesized neoflavenes
was evaluated against a panel of human cancer cell lines us-
ing an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte-
trazolium bromide) assay.21 Cancer cells were treated as in-
dicated for 48 hr in medium containing 10% FBS. Then, 20
ml MTT (2 mg/mL) was added to the cultures and incubated
during the final 1.5 hr. The resultant tetrazolium salt was
then dissolved by the addition of dimethyl sulfoxide. Color
was measured spectrophotometrically in a microtitter plate
reader at 570 nm and used as a relative measure of viable
cell number. The number of viable cells following treat-
ment was compared to solvent and untreated control cells
and used to determine the percent of control growth as
(Abtreaded/Abcontrol) ´ 100, where Ab represents the mean
absorbance (n = 6). The concentration that killed 50% of
cells (IC50) was determined from the linear portion of the
curve by calculating the concentration of agent that re-
duced absorbance in treated cells, compared to control
cells, by 50%.
8-Methoxy-4¢-methoxyneoflavene (8-Methoxy-4-(2-
methoxy-phenyl)-2H-chromene) (6f)
(1.21 g, 90%) was obtained as colorless crystal, mp
68-69 °C (n-hexane + ethyl acetate), Rf = 0.26 (ethyl ace-
tate: n-hexane = 1: 9), 1H-NMR (CDCl3, 400 MHz) d 3.80
(s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.85 (d, J = 4.0 Hz, 2H,
H-2), 5.75 (t, J = 4.0 Hz, 1H, H-3), 6.65 (dd, J = 6.8 Hz, 2.4
Hz, 1H, ArH), 6.76-6.82 (m, 2H, ArH), 6.89 (d, J = 8.8 Hz,

932 J. Chin. Chem. Soc., Vol. 55, No. 4, 2008
Li et al.
R. H. Org. Lett. 1999, 1, 953-956. (f) Saito, N.; Sato, Y.;
Mori, M. Org. Lett. 2002, 4, 803-805. (g) Huang, K. S.;
Wang, E. C. Tetrahedron Lett. 2001, 42, 6155-6157.
9. Li, S. R.; Chen, L. Y.; Tsai, J. C.; Tzeng, J. Y.; Tsai, I. L.;
Wang, E. C. Tetrahedron Lett. 2007, 48, 2139-2141.
10. Caddick, S.; Khan, S.; Frost, L. M.; Smith, N. J.; Cheung, S.;
Pairaudeau, G. Tetrahedron 2000, 56, 8953-8958.
11. Ohsugi, S. I.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka,
M.; Kodama, S. Tetrahedron 2003, 59, 8393-8398.
12. Pradhan, P. K.; Jaisankar, P.; Pal, B.; Dey, S.; Giri, V. S.
Synth. Communs. 2004, 34, 2863-2872.
ACKNOWLEDGEMENT
We are grateful to NSC Taiwan for financial support.
Received February 19, 2008.
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