Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from isovanillin via 2-aroyl-3-methylchroman intermediates

Article abstract of DOI:10.1016/j.tet.2009.08.043

The synthesis of substituted 2-aroyl-3-methylchromen-4-one from isovanillin is described. O-Allylphenol (2) prepared from isovanillin (1) was allowed to react with various α-bromoacetophenone (3) to produce 2-(2-allyl-3,4-dimethoxy)phenoxy-1-aroylethanone

Full text of DOI:10.1016/j.tet.2009.08.043

Tetrahedron 65 (2009) 8702–8707
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from isovanillin
via 2-aroyl-3-methylchroman intermediates
,
,
*
Sie-Rong Li a, Chung-Jung Shu a, Liang-Yeu Chen a b, Hsing-Ming Chen c, Po-Yuan Chen a, Eng-Chi Wang a
a Faculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
b Graduate Institute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC
c Department of Nutrition and Health science, Fooyin University, Kaohsiung 831, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2009
Received in revised form 18 August 2009
Accepted 18 August 2009
Available online 21 August 2009
The synthesis of substituted 2-aroyl-3-methylchromen-4-one from isovanillin is described. O-Allylphenol
(2) prepared from isovanillin (1) was allowed to react with various -bromoacetophenone (3) to produce
a
2-(2-allyl-3,4-dimethoxy)phenoxy-1-aroylethanones (4). The resultant 4 were treated with 2 equiv of
potassium tert-butoxide to afford the substituted 2-aroyl-3-methylchromans (5) through an isomerization
of an allylic double bond and a carbanion–olefin intramolecular 6-endo-trig cyclization reaction. Sub-
sequently, resultant 5 were oxidized with DDQ to yield the title compound 6, in good over-all yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carbanion–olefin intramolecular cyclization
3,4-Dihydro-2H-benzopyrans
DDQ
2-Aroyl-3-methylchromen-4-ones
Isovanillin
1. Introduction
by the cyclization of the common intermediate 1-(2-hydroxy-
phenyl)-3-aryl-1,3-propanediones and followed by the dehydration
1-Chromen-4-one (4H-1-benzopyran-4-one) is a core and com-
mon framework of naturally occurring bioactive flavones, flavonols,
and isoflavones, which are closely related oxygen benzoheterocyclic
compounds.1 Because they exhibit diverse biological activities, the
studies of these compounds either from nature products or from
synthetic methods are still an attractive topic. The major biological
activities of flavones including anti-aggregatory and anti-
inflammatory activities,2 cytostatic activity,3 antibacterial and
antiviral activity,4 anti-allergic activity,5 estrogenic activity,6 hepato-
protective activity,7 aldose reductase inhibitory activity,8 as well as
other activities9 have been disclosed. Furthermore, it have been
reported that flavanol derivatives exhibit cardioprotective activity,10
antioxidative activity,11 and antiplatelet activity.12 Moreover, the
major biological activities of isoflavones reported are estrogenic
activity,13 antiviral activity,14 and aldose reductase inhibitory activ-
ity.15 In addition, certain synthetic chromen-4-one derivatives have
been reported to possess antimicrobial activity,16 anti-breast cancer
activity,17 and nonsteroidal antiestrogens activity,18 as well as other
activities. Even various synthetic chromen-4-ones were developed,
but their major strategies were derived from the traditional method
with diverse conditions.19 In addition, certain unique methods for
the preparation of chromen-4-ones include the carbonylation cou-
pling of o-iodophenols with terminal acetylenes,20 the coupling of
acid chlorides with terminal alkynes,21 the Pd-catalyzed carbonyl-
ation of o-iodophenols in the presence of acetylenes,22 and the
cyclization of a
-oxoketene and phenylacetylene.23 However, some
disadvantages still exist on those reported methods including
the tedious reaction condition, multi-synthetic steps, and lowyields.
Moreover 2-aroylchromen-4-ones exhibiting potential biological
activities were disclosed in previous studies.24 Therefore, to develop
a unique, concise, and high yield approaches for substituted chro-
men-4-ones are requisite and significant from both chemical and
biological viewpoints. In continuing our previous studies on
benzoheterocyclic and benzocarbocyclic compounds utilizing iso-
vanillin as starting material,25 herein we disclose a new synthetic
method for substituted 1-chromen-4-ones (Scheme 1). Our strategy
involves the utilization of isovanillin (1) as starting material, and
through a sequence of an O-allylation, Claisen rearrangement,
O-methylation, and H2O2 oxidation to give 2-allyl-3,4-dimethoxy-
phenol (2).26 Followed by the reaction of resultant phenol with
various a-bromoacetophenones (3a–e), 2-(2-allyl-3,4-dimethoxy)-
phenolxy-1-aryloylethanones (4a–e) were produced. Then, the
resultant ethanones were treated with 2 equiv of potassium tert-
butoxide to undergo a series of reactions including the formation of
* Corresponding author.
E-mail address: enchwa@kmu.edu.tw (E.-C. Wang).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.043

S.-R. Li et al. / Tetrahedron 65 (2009) 8702–8707
8703
O
Br
, K2CO3
OCH3
OCH3
3
R
OH
R
R
ref. 26
CH3O
CH3O
acetone, reflux, 3 hr
CH3O
OH
O
93~97%
CHO
O
O
1
4
2
OCH3
CH3O
CH3O
O
O
CH3O
R
tert-BuOK
DDQ
O
THF, reflux, 30 min
79~89%
1,4-dioxane, reflux, 3 d
60~62%
O
5
6
a. R = H, b. R = OCH3 , c. R = CH3, d. R = Cl, e. R = Br
Scheme 1. Synthesis of substituted 2-aroyl-3-methylchromen-4-ones from vanillin.
OCH3
dianions, isomerization of an allylic double bond, and a carbanion–
te
rt
-B
Cl
Cl
u
O
K
H3CO
H3CO
olefinic intra-molecular 6-endo-trig cyclization reaction to generate
substituted 2-aroyl-3-methyl-1-chroman (2-aroyl-3-methyl-3,4-
dihydro-2H-benzopyrans) (5a–e) in diasteromeric mixtures as key
intermediate. With separation or without separation of diastero-
meric mixtures, 5 was oxidized with DDQ (2,3-dichloro-5,6-
dicyano-1,4-benzoquinone) to yield the title compounds,
substituted 2-aroyl-3-methylchromen-4-ones (6a–e) in one pot.
OCH3
THF
, 0
°C,
O
4f
Cl
H3CO
1 h
O
r
O
4d
O
OCH3
2 x tert-BuOK
CH3
O
THF,reflux,
30 min
O
5d
Scheme 2. The formation of 4f or 5d from the reaction of 4d with one or 2 equiv of
potassium tert-butoxide.
2. Results and discussion
2-Allyl-3,4-dimethoxyphenol (2), which was prepared from iso-
vanillin through 3 steps,26 was allowed to react with various
The discrimination of trans-5d and cis-5d isomers was briefly
achieved by examining the coupling constant of H-2, which coupled
with H-3 in 1H NMR spectrum. For instance, the signal of H-2
a-bromoacetophenones (3a–d) in the presence of dried K2CO3 in the
refluxing acetone for 3 h to produce 2-(2-allyl-3,4-dimethoxy)-
(doublet) at
the trans-isomer of 5d. On the other hand, the signal of H-2 (dou-
blet) at
5.35 with coupling constant J¼2.0 Hz indicates that is the
d
4.96 with coupling constant J¼7.2 Hz indicates that is
phenoxy-1-aroylethanones (4a–d) in 93–97% yield. The formation of
–OCH2C(]O)– bond where singlet signal appeared at
d 5.12–5.19 in
1H NMR spectrum, briefly proved the success of the formation of 4a–
d. Subsequently, in the model reaction, while treatment of 4d with
potassium tert-butoxide at 0 ꢀC inTHF for 1 h, the product with lower
Rf value than that of starting material was obtained. The resultant
product (4f), in which double bond of allyl group was isomerized and
migrated to the position to conjugate with the benzene ring, was
proven by physical and spectral data.27 Nevertheless, at the same
reaction condition but using 2 equiv of potassium tert-butoxide and
elevation of the reaction temperature to the reflux for 30 min, the
products with higher Rf value than that of starting material were
afforded. The products, which were cyclized to give a diastereomeric
mixture, were carefully separated into trans-5d, and cis-5d isomers in
the ratio of 1.7:1 by silica gel column chromatography (ethyl acetate/
n-hexane¼1:20). The given result showed this intramolecular carb-
anion–olefin cyclization which is stereo-specific to 6-endo-trig cy-
clization and is favor to the stable trans-product. The reaction
described above was depicted in Scheme 2.
d
cis-isomer of 5d. Thereby, the mechanism for the generation of
compound 5 is rationally proposed and shown below. The allylic
proton and proton near the carbonyl group of 4 are abstracted by
2 equiv of potassium tert-butoxide to isomerize the double bond of
allyl group to form a more stable one and to generate a carbanion
which is subsequently isomerized to the initial enolate I. The initial
enolate subsequently undergoes the intramolecular carbanion–
olefinic 6-endo-trig cyclization reaction to give an unstable and
transient intermediate II. Because of thermodynamic controlled
reaction, II is isomerized to the cyclized carbanion III via a pro-
tonation–deprotonation with t-BuOH/t-BuOK. Then, the stable
enolate IV, which has resonance with III, is formed and sub-
sequently picks up a proton from a-carbon to produce the mixture
of trans- and cis-2-aroyl-3-methyl-3,4-dihydro-2H-benzopyran
(chroman) 5 (Scheme 3). The reaction condition for the formation of
5d is applied to the preparation of other chromans 5a–e from 4. The
MeO
MeO
MeO
MeO
MeO
2 tert-BuOK
CH3
O
CH3
O
MeO
4
Ar
Ar
Ar
O
O
O
O
I
II
III
MeO
MeO
CH3
Ar
H
O
u
B
-
t
cis-5
MeO
O
CH3
MeO
K
O
u
B
O
-
t
Ar
O
t
-
B
u
MeO
MeO
O
O
H
CH3
t
-
B
IV
u
O
Ar trans-5
K
O
O
Scheme 3. The mechanism for the formation of trans-5 and cis-5 from 4.

8704
S.-R. Li et al. / Tetrahedron 65 (2009) 8702–8707
1H NMR spectra, ESI-HRMS data, and elemental analyses (EA) of
2-aroyl-3-methylchromen-4-ones (6a–e) are depicted in Table 2.
Table 1
The ratio of trans- and cis-isomer, % yield, and typical protons of 5a–e obtained from
4a–e
H
CH3O
CH3O
a. R = H,
CH3
3
3. Conclusion
R
4
b. R = OCH3,
c. R = CH3,
d. R = Cl,
2
7
O
8
We have established a novel synthetic route for 2-aroyl-5,6-
dimethoxy-3-methylchromen-4-ones through the DDQ oxidation of
2-aroyl-3-methyl-1-chroman, which prepared from isovanillin via
a 6-endo-trig carbanion–olefin cyclization reaction. The screening of
biological activities of the resultant 2-aroyl-3-methyl-1-benzo-
pyran-4-ones is in progress under the cooperation with other
laboratories.
1
O
H
5
e. R = Br
Compound
cis/trans
Yieldb (%)
H-2 (
trans-
cis-
d
)
CH3-3 (d)
trans-
cis-
Ratioa
5a
5b
5c
5d
5e
1/2.2
1/3.2
1/2.7
1/1.7
1/2.8
86
84
89
79
80
4.96 (d, J¼7.2 Hz)
5.35 (d, J¼2.0 Hz)
4.88 (d, J¼7.2 Hz)
5.29 (d, J¼2.0 Hz)
4.93 (d, J¼7.6 Hz)
5.33 (d, J¼2.4 Hz)
4.84 (d, J¼7.6 Hz)
5.24 (d, J¼2.4 Hz)
4.84 (d, J¼7.6 Hz)
5.23 (d, J¼2.0 Hz)
1.09 (d, J¼6.4 Hz)
0.92 (d, J¼6.8 Hz)
1.07 (d, J¼6.4 Hz)
0.93 (d, J¼6.8 Hz)
1.07 (d, J¼6.0 Hz)
0.91 (d, J¼6.8 Hz)
1.08 (d, J¼6.4 Hz)
0.93 (d, J¼6.8 Hz)
1.08 (d, J¼6.0 Hz)
0.93 (d, J¼7.2 Hz)
4. Experimental
4.1. General
Melting points (Yanaco micro melting point apparatus) were
uncorrected. 1H NMR and 13C NMR spectra were obtained on a Var-
ian Gemini-200 or Varian Unity plus 400 Spectrometer. Chemical
shifts are indicated in parts per million with respect to TMS. Ele-
mental analyses were recorded on a Heraeus CHN-O Rapid analyzer.
Mass spectra were recorded on a Chem/hp/middle spectrometer
connected to a Hewlett Packard series II model gas–liquid chro-
matography. HRMS spectra were performed on a JEOL JMS SX/SX
102A instrument. Silica gel (230–400 mesh) for column chroma-
tography and precoated silica gel plates (60 F-254) for TLC was
purchased from E. Merck Co. UV light (254 nm) was used to detect
spots on TLC plates after development.
a
The ratio of cis/trans is determined by the isolated yield, which is separated from
column chromatography.
b
% Yield of 5 are the diastereomeric mixture obtained.
ratio of the resultant diasteromeric mixtures, % yield, and typical
protons in 1H NMR spectra are summarized in Table 1. Besides our
preliminary study,28 the cyclization of enolate to the non-activated
C]C double bond was also reported by other groups.29
Because of the thermodynamic driving force of this cyclization,
the ratio of cis-5/trans-5 is determined by the stability of these iso-
mers. This can be verified by heating pure cis-5b with t-BuOK in
t-BuOH for 4 h to yield the mixture of cis-5b and trans-5b in ratio of
1:2.7 by GC–MS analysis. Then, the diastereomeric mixtures 5a–e
were, respectively, oxidized by DDQ (2,3-dichloro-5,6-dicyano
p-benzoquinone) in refluxing dioxane for 3 days to yield the desired
chromen-4-ones (6a–e) in one pot. Besides the disappearance of
H-2, H-3, and H-4 signals from 1H NMR spectra and the appearance
of carbonyl groups at 1631–1649 cmꢁ1 in IR spectra, other data such
as EIMS and EA, which are the correct connectivity required for
compound 6a–e. The % yield, melting point (mp), selected signals of
4.2. General procedure for the preparation of 2-(2-allyl-
3,4-dimethoxyphenoxy)-1-arylethanones (4a–e)
As the general procedure, the mixture of 2-allyl-3,4-dimethoxy-
phenol (2) (1.9 g, 10.0 mmol) and K2CO3 (2.1 g, 15 mmol) in anhy-
drous acetone (20 mL) was stirred and heated to the reflux. To the
refluxing mixture,
a-bromoacetophenones (3a–e) (10 mmol) was
added in drops. The reaction mixture was continually heated to the
reflux for 3 h. At the end of reaction, which was monitored by TLC,
the mixture was cooled down to room temperature and was filtered.
The resultant filtrate, which was concentrated in vacuo to remove the
solvent was further purified from silica gel chromatography (ethyl
acetate/n-hexane¼1:20) to give pure 4a–e in yield of 93–98%,
respectively.
Table 2
The % yield, melting point (mp), selected signals of 1H NMR, EIMS, and elemental
analysis (EA) of 2-aroyl chroman-4-ones (6a–e)
CH3O
CH3O
O
4
a. R = H,
CH3
3
R
b. R = OCH3,
c. R = CH3,
d. R = Cl,
7
4.2.1. 2-(2-Allyl-3,4-dimethoxyphenoxy)-1-phenylethan-one (4a).
Compound 4a (2.93 g, 94%) was obtained as yellow liquid, Rf¼0.58
2 O
O
1
8
6
e. R = Br
(ethyl acetate/n-hexane¼1:4), IR (KBr) cmꢁ1
, nmax: 3067, 2936, 2832,
1702, 1636, 1595, 1485, 1446, 1254, 1222, 1128, 1086, 1035, 983, 913,
Compound
Yield (%)
Mp (ꢀC)
1H NMRa
CH3-3,
H-7,
EA
ESI-HRMS
calcd
found
791, 757, 728, 691; 1H NMR (CDCl3, 400 MHz)
d
3.49 (dt, J¼6.4,1.6 Hz,
calcd.
found
(C%, H%)
2H, ArCH2CH]CH2), 3.81, 3.82 (each s, 2ꢂ3H, 2ꢂOCH3), 4.96 (ddt,
J¼10.0,1.6,1.6 Hz,1H, ArCH2CH]CHaHb), 4.98 (ddt, J¼16.8,1.6,1.6 Hz,
1H, ArCH2CH]CHaHb), 5.19 (s, 2H, ArOCH2COAr0), 5.99 (ddt, J¼16.8,
10.0, 6.4 Hz, 1H, ArCH2CH]CH2), 6.51 (d, J¼8.8 Hz, 1H, ArH), 6.69 (d,
J¼8.8 Hz, 1H, ArH), 7.47–7.50 (m, 2H, ArH), 7.59–7.63 (m, 1H, ArH),
H-8
6a
6b
6c
6d
6e
62
57
60
60
69
118–120
171–173
153–155
161–162
178–180
2.02
7.31,
7.15
1.99
7.31,
7.16
2.00
7.31,
7.16
2.04
7.32,
7.14
2.04
7.32,
7.14
70.36, 4.97
70.12, 5.01
C19H16O5Na
347.0895
347.0897
67.79, 5.12
67.74, 5.12
C20H18O6Na
377.1001
8.00 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 28.3, 56.1, 60.9, 72.1,
377.1002
107.1, 110.0, 114.7, 123.8, 128.3, 128.7, 133.7, 134.7, 137.0, 147.9, 148.1,
150.6,195.2; EIMS (70 eV) m/z (rel intensity, %): 312 (Mþ,19), 294 (31),
193 (21), 192 (100), 191 (33), 178 (21), 177 (38), 105 (17); HRMS (ESI)
calcd for C19H20O4Na [MþNa]þ: 335.1259. Found: 335.1260.
70.99, 5.36
70.85, 5.35
C20H18O5Na
361.1052
361.1050
63.61, 4.21
63.27, 4.29
C19H15ClO5Na
381.0506
381.0503
4.2.2. 2-(2-Allyl-3,4-dimethoxyphenoxy)-1-(4-methoxyphenyl)-
56.59, 3.75
56.44, 3.77
C19H15BrO5Na
425.0001
ethanone (4b). Compound 4b (3.34 g, 98%) was obtained as yellow
liquid, Rf¼0.43 (ethyl acetate/n-hexane¼1:4), IR (KBr) cmꢁ1
, nmax:
424.9999
3057, 2926, 2836,1694,1560,1476,1246,1115,1024, 797, 592; 1H NMR
a
The chemical shift of proton H-7, which links with the signal of CH3O at the
position 6 in the structure of 6, is determined by NOESY technique.
(CDCl3, 400 MHz)
d
3.49 (dt, J¼6.4, 1.6 Hz, 2H, ArCH2CH]CH2), 3.80,

S.-R. Li et al. / Tetrahedron 65 (2009) 8702–8707
8705
3.81, 3.88 (each s, 3ꢂ3H, 3ꢂOCH3), 4.96 (ddt, J¼10.0, 1.6, 1.6 Hz, 1H,
ArCH2CH]CHaHb), 4.99 (ddt, J¼16.8, 1.6, 1.6 Hz, 1H, ArCH2CH]
CHaHb), 5.12 (s, 2H, ArO–CH2COAr), 6.00 (ddt, J¼16.8,10.0, 6.4 Hz,1H,
ArCH2CH]CH2), 6.51 (d, J¼9.2 Hz, 1H, ArH), 6.68 (d, J¼9.2 Hz, 1H,
ArH), 6.94 (d, J¼9.2 Hz, 2H, ArH), 8.00 (d, J¼9.2 Hz, 2H, ArH); 13C NMR
solution, potassium tert-butoxide (2.3 g, 20.5 mmol) in THF (20 mL)
was added in drops. The reaction mixture was continually kept at
the reflux for 30 min until TLC analysis showed complete con-
sumption of the starting material. After cooling to room tempera-
ture, the reaction mixture was quenched with an aqueous saturated
NH4Cl solution (25 mL), and concentrated in vacuo to remove THF.
The water suspension that was obtained was extracted with CH2Cl2
(20 mLꢂ3). The organic extracts were combined, washed with
brine (10 mLꢂ2), and dried with anhydrous MgSO4. After filtration,
the filtrate was concentrated in vacuo to remove the solvent.
The residue was purified by silica gel column (ethyl acetate/
n-hexane¼1:5) to obtain a diasteromeric mixture 5a–e, which was
directly used for next oxidation reaction. For spectrometric data
and the ratio of resultant isomers, a batch of diasteromeric mixture
was further subjected to silica gel column chromatography (ethyl
acetate/n-hexane¼1:20) to give trans-5a–e as major and cis-5a–e
as minor compounds, respectively.
(CDCl3, 100 MHz) d 28.4, 55.5, 56.1, 60.9, 72.1, 107.1, 110.2, 113.9, 114.7,
123.8, 127.8, 130.8, 137.1, 147.9, 148.2, 150.8, 164.0, 193.8; EIMS (70 eV)
m/z (rel intensity, %) 342 (Mþ, 15), 324 (51), 193 (29), 192 (100), 191
(24), 177 (34), 135 (66); ESI-HRMS calcd for C20H22O5Na [MþNa]þ:
365.1365. Found: 165.1363.
4.2.3. 2-(2-Allyl-3,4-dimethoxyphenoxy)-1-(p-tolyl)-ethanone (4c).
(3.03 g, 93%) was obtained as yellow liquid, Rf¼0.58 (ethyl ace-
tate: n-hexane¼1: 4), IR (KBr) cmꢁ1
, nmax: 3065, 2934, 2830, 1698,
1604, 1484, 1254, 1127, 1037, 991, 911, 790; 1H NMR (CDCl3,
400 MHz)
d
2.42 (s, 3H, CH3), 3.50 (dt, J¼6.0, 1.6 Hz, 2H,
ArCH2CH]CH2), 3.80, 3.81 (each s, 2ꢂ3H, 2ꢂOCH3), 4.96 (ddt,
J¼10.0, 1.6, 1.6 Hz, 1H, ArCH2CH]CHaHb), 4.99 (ddt, J¼16.8, 1.6,
1.6 Hz, 1H, ArCH2CH]CHaHb), 5.16 (s, 2H, ArOCH2COAr), 6.00
(ddt, J¼16.8, 10.0, 6.0 Hz, 1H, ArCH2CH]CH2), 6.50 (d, J¼9.0 Hz,
1H, ArH), 6.68 (d, J¼9.0 Hz, 1H, ArH), 7.27 (d, J¼8.0 Hz, 2H, ArH),
4.3.1. The diasteromeric mixture of 2-benzoyl-5,6-dimethoxy-3-
methylchroman (5a). Compound 5a (2.69 g, 86%) was obtained as
yellow liquid. trans-2-Benzoyl-5,6-dimethoxy-3-methylchroman
(trans-5a) (1.85 g, 59%) was obtained as yellow liquid, Rf¼0.61 (ethyl
7.90 (d, J¼8.0 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 21.7, 28.3,
56.1, 60.9, 72.1, 107.2, 110.1, 114.7, 123.8, 128.4, 129.4, 132.2, 137.0,
144.7, 147.9, 148.1, 150.7, 194.8; EIMS (70 eV) m/z (rel intensity, %)
326 (Mþ, 33), 308 (33), 193 (24), 192 (100), 191 (27), 177 (35), 119
(30); HRMS (ESI) Calcd for C20H22O4Na [MþNa]þ: 349.1417.
Found: 349.1416.
acetate/n-hexane¼1:4),1H NMR (CDCl3, 400 MHz)
1.09 (d, J¼6.4 Hz,
d
3H, CH3), 2.44–2.52 (m, 1H, H-3), 2.44–2.52 (m, 1H, H-4a), 2.89 (dd,
J¼19.6, 8.4 Hz, 1H, H-4b), 3.82, 3.83 (each s, 2ꢂ3H, 2ꢂOCH3), 4.96 (d,
J¼7.2 Hz, 1H, H-2), 6.62 (d, J¼9.0 Hz, 1H, ArH), 6.74 (d, J¼9.0 Hz, 1H,
ArH), 7.47 (t, J¼9.2 Hz, 2H, ArH), 7.59 (t, J¼7.2 Hz, 1H, ArH), 8.04 (d,
J¼8.0 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 17.7, 26.3, 28.4, 56.3,
4.2.4. 2-(2-Allyl-3,4-dimethoxyphenoxy)-1-(4-chloro-phenyl)-
ethanone (4d). Compound 4d (3.25 g, 94%) was obtained as colorless
crystal, mp 78–79 ꢀC, Rf¼0.61 (ethyl acetate/n-hexane¼1:4), IR (KBr)
60.2, 82.0, 110.9, 111.6, 115.9, 128.6, 129.0, 133.5, 135.2, 146.6, 146.9,
147.6, 197.2; cis-5a (0.84 g, 27%) was obtained as yellow liquid,
Rf¼0.56 (ethyl acetate/n-hexane¼1:4), 1H NMR (CDCl3, 400 MHz)
cmꢁ1
,
nmax: 3086, 2933, 2836,1705,1590,1486,1486,1258,1090, 987,
d
0.92 (d, J¼6.8 Hz, 3H, CH3), 2.59–2.68 (m, 1H, H-3), 2.74 (dd, J¼17.2,
956, 926, 826, 799, 742; 1H NMR (CDCl3, 400 MHz)
d
3.47 (dt, J¼6.0,
2.8 Hz,1H, H-4a), 3.08 (dd, J¼17.2, 6.0 Hz,1H, H-4b), 3.84, 3.84 (each s,
2ꢂ3H, 2ꢂOCH3), 5.35 (d, J¼2.0 Hz, 1H, H-2), 6.72 (d, J¼8.8 Hz, 1H,
ArH), 6.76 (d, J¼8.8 Hz, 1H, ArH), 7.49 (t, J¼7.6 Hz, 2H, ArH), 7.61
(t, J¼7.2 Hz, 1H, ArH), 7.97 (d, J¼7.6 Hz, 2H, ArH), 13C NMR (CDCl3,
1.6 Hz, 2H, ArCH2CH]CH2), 3.81, 3.81 (each s, 2ꢂ3H, 2ꢂOCH3), 4.93–
4.98 (m, 2H, ArCH2CH]CH2), 5.12 (s, 2H, ArOCH2COAr), 5.97 (ddt,
J¼15.6, 9.6, 6.0 Hz, 1H, ArCH2CH]CH2), 6.49 (d, J¼8.8 Hz, 1H, ArH),
6.69 (d, J¼8.8 Hz, 1H, ArH), 7.45 (d, J¼8.4 Hz, 2H, ArH), 7.95 (d,
100 MHz) d 13.5, 28.0, 28.5, 56.3, 60.2, 79.5, 111.5, 111.6, 115.6, 128.5,
J¼8.4 Hz, 2H, ArH); 13C NMR (CDCl3,100 MHz)
d
28.3, 56.1, 60.9, 72.2,
128.7, 133.4, 135.6, 147.8, 147.9, 196.9; EIMS (70 eV) m/z (rel intensity,
%) 312 (Mþ, 36), 207 (100), 192 (26), 179 (18), 176 (16), 151 (25); ESI-
HRMS calcd for C19H20O4Na [MþNa]þ: 335.1259. Found: 335.1261.
107.0, 110.0, 114.7, 123.7, 129.1, 129.9, 133.0, 136.9, 140.2, 148.0, 148.2,
150.4, 194.4; EIMS (70 eV) m/z (rel intensity, %) 348 ([Mþ2]þ, 8), 346
(Mþ, 21), 193 (20), 192 (100), 191 (27), 178 (20), 177 (38); HRMS (ESI)
calcd for C19H19ClO4Na [MþNa]þ: 369.0870. Found: 369.0873. Anal.
Calcd for C19H19ClO4: C, 65.80%; H, 5.52%. Found: C, 65.74%; H, 5.51%.
4.3.2. The diasteromeric mixture of 2-(4-methoxyl-benzoyl)-5,6-di-
methoxy-3-methylchroman (5b). Compound 5b (2.88 g, 84%) was
obtained as yellow viscous liquid. trans-2-(4-Methoxylbenzoyl)-5,6-
dimethoxy-3-methylchroman (trans-5b) (2.18 g, 64%) was obtained
as yellowish crystal, mp 109–111 ꢀC, Rf¼0.51 (ethyl acetate/
4.2.5. 2-(2-Allyl-3,4-dimethoxyphenoxy)-1-(4-bromo-phenyl)-
ethanone (4e). Compound 4e (3.80 g, 97%) was obtained as colorless
crystal, mp 80–81 ꢀC, Rf¼0.59 (ethyl acetate/n-hexane¼1:4), IR (KBr)
n-hexane¼1:4), 1H NMR (CDCl3, 400 MHz)
d
1.07 (d, J¼6.4 Hz, 3H,
cmꢁ1
,
nmax: 3085, 2933, 2836, 1705, 1587, 1486, 1255, 1224, 1127,
CH3-3), 2.42–2.49 (m, 1H, H-3), 2.42–2.49 (m, 1H, Ha-4), 2.91 (dd,
J¼20.0, 8.8 Hz, 1H, Hb-4), 3.82, 3.83, 3.87 (each s, 3ꢂ3H, 3ꢂOCH3),
4.88 (d, J¼7.6 Hz, 1H, H-2), 6.62 (d, J¼9.2 Hz, 1H, ArH), 6.74 (d,
J¼9.2 Hz, 1H, ArH), 7.94 (d, J¼8.8 Hz, 2H, ArH), 8.05 (d, J¼8.8 Hz, 2H,
1073, 986, 956, 925, 821; 1H NMR (CDCl3, 400 MHz)
d
3.47 (dt, J¼6.0,
1.6 Hz, 2H, ArCH2CH]CH2), 3.81, 3.81 (each s, 2ꢂ3H, 2ꢂOCH3), 4.93–
4.98 (m, 2H, ArCH2CH]CH2), 5.12 (s, 2H, ArOCH2COAr), 5.97 (ddt,
J¼15.6, 9.6, 6.0 Hz, 1H, ArCH2CH]CH2), 6.49 (d, J¼8.8 Hz, 1H, ArH),
6.69 (d, J¼8.8 Hz, 1H, ArH), 7.62 (d, J¼9.0 Hz, 2H, ArH), 7.87 (d,
ArH); 13C NMR (CDCl3, 100 MHz)
d 17.7, 26.7, 28.6, 55.5, 56.4, 60.2,
82.1, 110.9, 111.7, 113.8, 116.1, 128.2, 131.5, 146.5, 146.9, 147.8, 163.8,
195.5; cis-5b (0.70 g, 20%) was obtained as brownish liquid, 0.93 (d,
J¼9.0 Hz, 2H, ArH); 13C NMR (CDCl3,100 MHz)
d
28.3, 56.1, 60.9, 72.2,
d
107.0, 110.0, 114.7, 123.7, 129.0, 130.0, 132.0, 133.4, 136.9, 148.0, 148.2,
150.4, 194.7; EIMS (70 eV) m/z (rel intensity, %) 392 ([Mþ2]þ, 8), 390
(Mþ,11), 374 (12), 372 (12), 207 (19),193 (20),192 (100),191 (24),178
(18), 177 (35); HRMS (ESI) calcd for C19H19BrO4Na [MþNa]þ:
413.0364. Found: 413.0363. Anal. Calcd for C19H19BrO4: C, 58.33%; H,
4.89%. Found: C, 58.19%; H, 4.85%.
J¼6.8 Hz, 3H, CH3-3), 2.59–2.66 (m, 1H, H-3), 2.73 (dd, J¼17.2, 2.8 Hz,
1H, Ha-4), 3.07 (dd, J¼17.2, 6.4 Hz, 1H, Hb-4), 3.82, 3.83, 3.88 (each s,
3ꢂ3H, 3ꢂOCH3), 5.29 (d, J¼2.0 Hz, 1H, H-2), 6.71 (d, J¼8.8 Hz, 1H,
ArH), 6.75 (d, J¼8.8 Hz, 1H, ArH), 6.96 (d, J¼8.8 Hz, 2H, ArH), 7.99 (d,
J¼8.8 Hz, 2H, ArH); 13C NMR (CDCl3,100 MHz)
d 13.5, 28.0, 29.7, 55.5,
56.4, 60.2, 79.3, 111.5, 111.6, 113.8, 115.7, 128.4, 131.0, 146.7, 147.4,
148.0, 163.7, 195.2; EIMS (70 eV) m/z (rel intensity, %) 342 (Mþ, 37),
207 (100),192 (59),179 (25),176 (22),151 (33),136 (26),135 (76); ESI-
HRMS calcd for CH18O3Na [MþNa]þ: 365.1365. Found: 365.1363.
4.3. General procedure for the preparation of trans- and
cis-2-aryloyl-5,6-dimethoxy-3-methylchroman (5a–e)
Under the protection of N2, 4a–e (10.0 mmol) dissolved in THF
4.3.3. The diasteromeric mixture of 2-(4-methyl-benzoyl)-5,6-dime-
(20.0 mL) was stirred and heated to the reflux. To this refluxing
thoxy-3-methylchroman (5c). Compound 5c (2.90 g, 89%) was

8706
S.-R. Li et al. / Tetrahedron 65 (2009) 8702–8707
obtained as viscous yellow liquid. trans-2-(4-methylbenzoyl)-5,6-
dimethoxy-3-methylchroman (trans-5c) (2.1 g, 64%) was obtained
as yellowish crystal, mp 120–121 ꢀC, Rf¼0.61 (ethyl acetate/
111.4, 111.6, 115.7, 128.6, 130.2, 132.0, 134.4, 146.9, 147.4, 147.7, 196.2;
EIMS (70 eV) m/z (rel intensity, %) 392 ([Mþ2]þ,15), 390 (Mþ, 21), 207
(100), 192 (23), 179 (14), 151 (18); ESI-HRMS calcd for C19H19BrO4Na
[MþNa]þ: 413.0364. Found: 413.0362.
n-hexane¼1:4), 1H NMR (CDCl3, 400 MHz)
d
1.07 (d, J¼6.0 Hz, 3H,
CH3-3), 2.42 (s, 3H, CH3-40), 2.43–2.50 (m, 1H, H-3), 2.47 (dd,
J¼20.0 Hz, 8.4 Hz, 1H, Ha-4), 2.89 (dd, J¼20.0 Hz, 8.4 Hz, 1H, Hb-4),
3.82, 3.82 (each s, 2ꢂ3H, 2ꢂOCH3), 4.93 (d, J¼7.6 Hz, 1H, H-2), 6.62
(d, J¼8.8 Hz, 1H, ArH), 6.74 (d, J¼8.8 Hz, 1H, ArH), 7.27 (d, J¼8.4 Hz,
2H, ArH), 7.95 (d, J¼8.4 Hz, 2H, ArH), 13C NMR (CDCl3, 100 MHz)
4.4. General procedure for the preparation of 2-benzoyl-
5,6-dimethoxy-3-methylchromen-4-ones (6a–e)
The diastereomeric mixture of 5a–e (5.0 mmol) dissolved in 1,4-
dioxane (10.0 mL) was stirred and added DDQ (3.4 g, 15.0 mmol).
The resultant mixture was heated to the reflux for 3 days until TLC
analysis showed the consumption of the starting material. The re-
sultant mixture, which was cooled to room temperature was added
water (30 mL) and extracted with dichloromethane (20 mLꢂ3). The
organic extracts were combined, washed with brine (10 mLꢂ2),
and dried with anhydrous MgSO4. After filtration, the filtrate was
concentrated in vacuo to remove the solvent. The residue was
purified by silica gel column chromatography (ethyl acetate/
n-hexane¼1:5) to give 6a–e.
d
17.7, 21.7, 26.4, 28.5, 56.4, 60.2, 81.9, 110.9, 111.7, 116.0, 129.2, 129.3,
132.7, 144.4, 146.5, 146.9, 147.7, 196.7; cis-5c (0.81 g, 25%) was
obtained as yellow liquid, Rf¼0.56 (ethyl acetate/n-hexane¼1:4), 1H
NMR (CDCl3, 400 MHz)
d
0.91 (d, J¼6.8 Hz, 3H, CH3-3), 2.43 (s, 3H,
CH3-40), 2.59–2.66 (m, 1H, H-3, H-3), 2.73 (dd, J¼17.2, 2.8 Hz, 1H,
Ha-4), 3.01 (dd, J¼17.2, 6.4 Hz, 1H, Hb-4), 3.82, 3.84 (each s, 2ꢂ3H,
2ꢂOCH3), 5.33 (d, J¼2.4 Hz, 1H, H-2), 6.72 (d, J¼9.0 Hz, 1H, ArH),
6.76 (d, J¼9.0 Hz, 1H, ArH), 7.28 (d, J¼8.8 Hz, 2H, ArH), 7.87 (d,
J¼8.8 Hz, 2H, ArH); 13C NMR (CDCl3, 100 MHz)
d 13.5, 21.7, 28.0,
28.5, 56.3, 60.2, 79.5, 111.5, 111.6, 115.6, 128.5, 128.7, 133.4, 135.6,
147.8,147.4,147.9,196.9; EIMS (70 eV) m/z (rel intensity, %) 326 (Mþ,
71), 207 (100), 192 (38), 179 (21), 176 (18), 151 (28), 119 (17); ESI-
HRMS calcd for C20H22O4Na [MþNa]þ: 349.1416. Found: 349.1414.
4.4.1. 2-Benzoyl-5,6-dimethoxy-3-methyl-1-chromen-4-one (6a). Pure
6a (1.0 g, 62%) was obtained as yellow crystal, mp 118–120 ꢀC, Rf¼0.44
(ethyl acetate/n-hexane¼1:2), IR (KBr) cmꢁ1
, nmax: 2932, 1646, 1482,
4.3.4. Thediasteromericmixtureof2-(4-chlorobenzoyl)-5,6-dimethoxy-
3-methylchroman (5d). Compound 5d (2.74 g, 79%) was obtained as
viscous yellow liquid. trans-2-(4-chloro-benzoyl)-5,6-dimethoxy-3-
methylchroman (trans-5d) (1.73 g, 50%) was obtained as orange color
crystal, mp 101–102 ꢀC, Rf¼0.62 (ethyl acetate/n-hexane¼1:4), 1H
1368, 1260, 1168, 1095, 1054, 1012, 936, 800, 716; 1H NMR (CDCl3,
400 MHz)
d
2.03 (s, 3H, CH3), 3.93, 3.99 (each s, 2ꢂ3H, 2ꢂOCH3), 7.15
(d, J¼9.6 Hz, 1H, H-8), 7.31 (d, J¼9.6 Hz, 1H, H-7), 7.51–7.56 (m, 2H,
H-30), 7.66–7.70 (m, 1H, H-40), 7.91–7.94 (m, 2H, H-20); 13C NMR
(CDCl3, 100 MHz)
d 10.1, 57.1, 61.8, 113.5, 118.4, 119.4, 119.5, 129.0,
NMR (CDCl3, 400 MHz)
d
1.08 (d, J¼6.4 Hz, 3H, CH3-3), 2.43–2.50 (m,
130.0, 134.7, 134.9, 147.6, 150.1, 150.6, 154.1, 177.8, 188.9; EIMS (70 eV)
m/z (rel intensity, %) 324 (Mþ, 49), 310 (21), 309 (100), 295 (34), 281
(36), 105 (43), 77 (19); ESI-HRMS calcd for C19H16O5Na [MþNa]þ:
347.0895. Found: 347.0897. Anal. Calcd for C19H16O5: C, 70.36%; H,
4.97%. Found: C, 70.12%; H, 5.01%.
1H, H-3), 2.46 (dd, J¼20.4, 8.8 Hz, 1H, Ha-4), 2.88 (dd, J¼20.4, 8.8 Hz,
1H, Hb-4), 3.82, 3.83 (each s, 2ꢂ3H, 2ꢂOCH3), 4.84 (d, J¼7.6 Hz,1H, H-
2), 6.60 (d, J¼8.8 Hz, 1H, ArH), 6.74 (d, J¼8.8 Hz, 1H, ArH), 7.44 (d,
J¼8.4 Hz, 2H, ArH), 8.01 (d, J¼8.8 Hz, 2H, ArH); 13C NMR (CDCl3,
100 MHz)
d 17.6, 26.6, 28.3, 56.4, 60.2, 82.5, 110.9, 111.8, 116.0, 128.9,
130.6, 133.6, 140.0, 146.7, 146.9, 147.4, 196.1; cis-5d (1.01 g, 29%) was
4.4.2. 5,6-Dimethoxy-2-(4-methoxybenzoyl)-3-methyl-1-chromen-4-
obtained as yellow liquid, Rf¼0.57 (ethyl acetate/n-hexane¼1:4), 1H
one (6b). Pure 6b (1.01 g, 57%) was obtained as yellow crystal, mp
NMR (CDCl3, 400 MHz)
d
0.93 (d, J¼6.8 Hz, 3H, CH3-3), 2.60–2.65 (m,
171–173 ꢀC, Rf¼0.24 (ethyl acetate/n-hexane¼1:2), IR (KBr) cmꢁ1
,
1H, H-3), 2.74 (dd, J¼16.8, 2.8 Hz, 1H, Ha-4), 3.06 (dd, J¼16.8, 6.0 Hz,
1H, Hb-4), 3.82, 3.84 (each s, 2ꢂ3H, 2ꢂOCH3), 5.24 (d, J¼2.4 Hz, 1H,
H-2), 6.69 (d, J¼9.2 Hz, 1H, ArH), 6.75 (d, J¼9.2 Hz, 1H, ArH), 7.46 (d,
J¼8.6 Hz, 2H, ArH), 7.94 (d, J¼8.6 Hz, 2H, ArH); 13C NMR (CDCl3,
nmax: 2931, 2837, 1652, 1599, 1479, 1429, 1367, 1256, 1168, 1096, 1052,
1012, 934, 837, 799; 1H NMR (CDCl3, 400 MHz)
d 1.99 (s, 3H, CH3),
3.91, 3.93, 3.99 (each s, 3ꢂ3H, 3ꢂOCH3), 6.99 (d, J¼8.8 Hz, 2H, H-30),
7.16 (d, J¼8.8 Hz, 1H, H-8), 7.31(d, J¼8.8 Hz, 1H, H-7), 7.91 (d,
100 MHz)
d
13.6, 27.9, 28.4, 56.4, 60.2, 79.7, 111.4, 111.7, 115.7, 129.0,
J¼8.8 Hz, 2H, H-20); 13C NMR (CDCl3,100 MHz)
d 10.4, 55.9, 57.3, 62.0,
130.2, 133.9, 139.8, 146.9, 147.4, 147.7, 196.0; EIMS (70 eV) m/z (rel
intensity, %) 348 ([Mþ2]þ, 9), 346 (Mþ, 26), 207 (100), 192 (22), 179
(17), 151 (20); ESI-HRMS calcd for C19H19ClO4Na [MþNa]þ: 369.0870.
Found: 369.0871.
113.8, 114.5, 114.6, 118.7, 119.0, 119.5, 128.0, 132.8, 147.8, 150.3, 151.0,
155.0, 165.2, 187.5; EIMS (70 eV) m/z (rel intensity, %) 354 (Mþ, 51),
340 (21), 339 (100), 325 (18), 311 (28), 135 (76), 77 (14); ESI-HRMS
calcd for C20H18O6Na [MþNa]þ: 377.1001. Found: 377.1002. Anal.
Calcd for C20H18O6: C, 67.79%; H, 5.12%. Found: C, 67.74%; H, 5.12%.
4.3.5. The diasteromeric mixture of 2-(4-bromo-benzoyl)-5,6-dime-
thoxy-3-methylchroman (5e). Compound 5e (3.12 g, 80%) was
obtained as viscous yellow liquid. trans-2-(4-bromobenzoyl)-5,6-
dimethoxy-3-methylchroman (trans-5e) (2.29 g, 59%) was obtained
as orange color crystal, mp 99–100 ꢀC, Rf¼0.59 (ethyl acetate/
4.4.3. 5,6-Dimethoxy-3-methyl-2-(4-methylbenzoyl)-1-chromen-4-
one (6c). Pure 6c (1.02 g, 60%) was obtained as brown crystal, mp
153–155 ꢀC, Rf¼0.40 (ethyl acetate/n-hexane¼1:2), IR (KBr) cmꢁ1
,
nmax: 2933, 1631, 1478, 1425, 1368, 1264, 1163, 1095, 1054, 1003, 931,
n-hexane¼1:4), 1H NMR (CDCl3, 400 MHz)
d
1.08 (d, J¼6.0 Hz, 3H,
799, 764, 616; 1H NMR (CDCl3, 400 MHz)
d 2.00 (s, 3H, CH3-3), 2.46
CH3-3), 2.43–2.50 (m, 1H, H-3), 2.46 (dd, J¼20.4, 8.4 Hz, 1H, Ha-4),
2.93 (dd, J¼20.4, 8.4 Hz,1H, Hb-4), 3.82, 3.83 (each s, 2ꢂ3H, 2ꢂOCH3),
4.84 (d, J¼7.6 Hz, 1H, H-2), 6.60 (d, J¼9.0 Hz, 1H, ArH), 6.74 (d,
J¼9.0 Hz, 1H, ArH), 7.61 (d, J¼8.6 Hz, 2H, ArH), 7.93 (d, J¼8.6 Hz, 2H,
(s, 3H, CH3-40), 3.94, 4.00 (each s, 2ꢂ3H, 2ꢂOCH3), 7.16 (d, J¼9.2 Hz,
1H, H-8), 7.32 (d, J¼9.2 Hz, 1H, H-7), 7.33 (d, J¼8.0 Hz, 2H, H-30),
7.83 (d, J¼8.4 Hz, 2H, H-20); 13C NMR (CDCl3, 100 MHz)
d 10.1, 21.9,
57.0, 61.7, 113.5, 118.4, 119.1, 119.3, 129.70, 130.1, 132.3, 146.0, 147.6,
150.0, 150.6, 154.4, 177.8, 188.4; EIMS (70 eV) m/z (rel intensity, %)
338 (Mþ, 35), 324 (20), 323 (100), 309 (15) 295 (29), 119 (41), 91
(19); ESI-HRMS calcd for C20H18O5Na [MþNa]þ: 361.1052. Found:
361.1050. Anal. Calcd for C20H18O5: C, 70.99%; H, 5.36%. Found: C,
70.85%; H, 5.35%.
ArH); 13C NMR (CDCl3, 100 MHz)
d 17.6, 26.5, 28.3, 56.4, 60.2, 82.5,
110.9, 111.7, 116.0, 128.7, 130.7, 131.9, 133.9, 146.7, 146.9, 147.3, 196.3;
cis-5e (0.83 g, 21%) was obtained as yellow liquid, Rf¼0.55 (ethyl
acetate/n-hexane¼1:4),1H NMR (CDCl3, 400 MHz)
0.93 (d, J¼7.2 Hz,
d
3H, CH3-3), 2.60–2.65 (m,1H, H-3), 2.74 (dd, J¼16.8, 2.8 Hz,1H, Ha-4),
3.06 (dd, J¼16.8, 6.4 Hz,1H, Hb-4), 3.82, 3.84 (each s, 2ꢂ3H, 2ꢂOCH3),
5.23 (d, J¼2.0 Hz, 1H, H-2), 6.69 (d, J¼8.6 Hz, 1H, ArH), 6.75 (d,
J¼8.6 Hz, 1H, ArH), 7.63 (d, J¼8.8 Hz, 2H, ArH), 7.86 (d, J¼8.8 Hz, 2H,
4.4.4. 2-(4-Chlorobenzoyl)-5,6-dimethoxy-3-methyl-1-chromen-4-
one (6d). Pure 6d (1.08 g, 60%) was obtained as yellow crystal, mp
ArH); 13C NMR (CDCl3, 100 MHz)
d
13.6, 27.9, 28.4, 56.3, 60.2, 79.7,
161–162 ꢀC, Rf¼0.46 (ethyl acetate/n-hexane¼1:2), IR (KBr) cmꢁ1
,

S.-R. Li et al. / Tetrahedron 65 (2009) 8702–8707
8707
Li, J.; Jiang, Z. Y.; Dong, T. T. X.; Tsim, K. W. K. J. Agric. Food Chem. 2007, 55,
2438–2445.
nmax: 2943, 1646, 1579, 1581, 1481, 1366, 1236, 1167, 1087, 1050,
1001, 927, 844, 799, 769, 1H NMR (CDCl3, 400 MHz)
2.04 (s, 3H,
d
7. (a) Yoo, Y.-M.; Nam, J.-H.; Kim, M.-Y.; Choi, J.; Park, H.-J. Biol. Pharm. Bull. 2008,
31, 760–764; (b) Kim, K. H.; Kim, Y. H.; Lee, K. R. Bioorg. Med. Chem. Lett. 2007, 17,
6739–6743; (c) Han, H.-J.; Kim, T.-J.; Jin, Y.-R.; Hong, S.-S.; Hwang, J.-H.; Hwang,
B.-Y.; Lee, K.-H.; Park, T.-K.; Yun, Y.-P. Planta Med. 2007, 73, 1163–1168.
8. Fernandez, M.; Caballero, J.; Helguera, A. M.; Castro, E. A.; Gonzalez, M. P.
Bioorg. Med. Chem. 2005, 13, 3269–3277.
9. Brahmachari, G.; Gorai, D. Curr. Org. Chem. 2006, 10, 873–898 and literatures
cited therein.
10. Qin, C. X.; Chen, X.; Hughes, R. A.; Williams, S. J.; Woodman, O. L. J. Med. Chem.
2008, 51, 1874–1884.
11. (a) Zhou, B.; Miao, Q.; Yang, L.; Liu, Z.-L. Chem.dEur. J. 2005, 11, 680–691;
(b) Kim, M.-Y.; Kim, Y.-C.; Chung, S.-K. J. Sci. Food Agric. 2005, 85, 633–640;
(c) Woodman, O. L.; Meeker, W. F.; Boujaoude, M. J. Cardiovasc. Pharmacol.
2005, 46, 302–309; (d) Bao, J.; Cai, Y.; Sun, M.; Wang, G.; Corke, H. J. Agric.
Food Chem. 2005, 53, 2327–2332.
CH3), 3.93, 3.99 (each s, 2ꢂ3H, 2ꢂOCH3), 7.14 (d, J¼9.2 Hz, 1H, H-8),
7.32 (d, J¼9.2 Hz, 1H, H-7), 7.51 (d, J¼8.4 Hz, 2H, H-30), 7.86 (d,
J¼8.4 Hz, 2H, H-20); 13C NMR (CDCl3, 100 MHz)
d 10.1, 57.0, 61.8,
113.4, 118.4, 119.4, 120.0, 129.4, 131.3, 133.3, 141.3, 147.6, 150.1, 150.5,
153.5, 177.7, 187.7; EIMS (70 eV) m/z (rel intensity, %) 360 ([Mþ2]þ,
16), 358 (Mþ, 44), 345 (33), 343 (100), 329 (24), 315 (36), 139 (45);
ESI-HRMS calcd for C19H15ClO5Na [MþNa]þ: 381.0506. Found:
381.0503. Anal. Calcd for C19H15ClO5: C, 63.61%; H, 4.21%. Found: C,
63.27%; H, 4.29%.
4.4.5. 2-(4-Bromobenzoyl)-5,6-dimethoxy-3-methyl-1-chromen-4-
12. Sheu, J.-R.; Hsiao, G.; Chou, P.-H.; Shen, M.-Y.; Chou, D.-S. J. J. Agric. Food Chem.
2004, 52, 4414–4418.
one (6e). Pure 6e (1.39 g, 69%) was obtained as yellow crystal, mp
178–180 ꢀC, Rf¼0.47 (ethyl acetate/n-hexane¼1:2), IR (KBr) cmꢁ1
,
13. Stark, A.; Madar, Z. J. Pediatr. Endocrinol. Metabol. 2002, 15, 561–572.
14. (a) Andres, A.; Donovan, S. M.; Kuhlenschmidt, T. B.; Kuhlenschmidt, M. S. J. Nutr.
2007, 137, 2068–2073; (b) Phrutivorapongkul, A.; Lipipun, V.; Ruangrungsi, N.;
Watanabe, T.; Ishikawa, T. Chem. Pharm. Bull. 2002, 50, 534–537; (c) De Rodriguez,
D. J.; Chulia, J.; Simoes, C. M. O.; Amoros, M.; Mariotte, A. M.; Girre, L. Planta Med.
1990, 56, 59–62.
15. Moon, H.-I.; Jung, J.-C.; Lee, J. Bioorg. Med. Chem. 2006, 14, 7592–7594.
16. Goeker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005, 13, 1707–1714.
17. Brueggemeier, R.; Kim, Y.-W. Patent WO 2,004,012,682, 2004.
18. Ismail, K. A.; Abd El Aziem, T. Eur. J. Med. Chem. 2001, 36, 243–253.
19. (a) Nishinaga, A.; Maruyama, K.; Ando, H.; Sato, R.; Mashino, T.; Inada, A.;
Nakanishi, T. Tetrahedron Lett. 1990, 31, 3171–3174; (b) Zembower, D. E.; Zhang,
H. J. Org. Chem. 1998, 63, 9300–9305; (c) Kabalka, G. W.; Mereddy, A. R.
Tetrahedron Lett. 2005, 46, 6315–6317; (d) Rao, V. M.; Damu, G. L. V.; Sudhakar,
D.; Siddaiah, V.; Rao, C. V. ARKIVOC 2008, 11, 285–294.
nmax: 2953, 1649, 1579, 1478, 1368, 1236, 1167, 1058, 1004, 932, 806,
770; 1H NMR (CDCl3, 400 MHz)
d 2.04 (s, 3H, CH3), 3.93, 3.99 (each s,
2ꢂ3H, 2ꢂOCH3), 7.14 (d, J¼9.6 Hz, 1H, H-8), 7.32 (d, J¼9.2 Hz, 1H, H-
7), 7.68 (d, J¼8.4 Hz, 2H, H-30), 7.78 (d, J¼8.4 Hz, 2H, H-20); 13C NMR
(CDCl3, 100 MHz)
d 10.1, 57.0, 61.8, 113.4, 118.4, 119.4, 120.0, 130.1,
131.3, 132.4, 133.7, 147.6, 150.1, 150.4, 153.4, 177.7, 182.0; EIMS (70 eV)
m/z (rel intensity, %) 404 ([Mþ2]þ, 39), 402 (Mþ, 40), 389 (97), 387
(100), 361 (31), 359 (33), 185 (46), 183 (46); ESI-HRMS calcd for
C19H15BrO5Na [MþNa]þ: 425.0001. Found: 424.9999. Anal. Calcd for
C19H15BrO5: C, 56.59%; H, 3.75%. Found: C, 56.44%; H, 3.77%.
20. Kalinin, V. N.; Shostakovskii, M. V.; Ponomarev, A. B. Tetrahedron Lett. 1990, 31,
4073–4076.
Acknowledgements
21. Likhar, P. R.; Subhas, M. S.; Roy, M.; Roy, S.; Kantam, M. L. Helv. Chim. Acta 2008,
91, 259–264.
22. Torii, S.; Okumoto, H.; Xu, L. H.; Sadakane, M.; Shostakovsky, M. V.; Ponomaryov,
A. B.; Kalinin, V. N. Tetrahedron 1993, 49, 6773–6784.
The financial support from NSC (NSC 97-2113-M-037-001-MY2)
Taiwan is grateful.
23. Sergio de Carvalho, P.; Nachtigall, F. M.; Eberlin, M. N.; Moraes, L. A. B. J. Org.
Chem. 2007, 72, 5986–5993.
24. Payard, M.; Tronche, P.; Bastide, J.; Bastide, P.; Chavernac, G. Eur. J. Med. Chem.
1981, 16, 453–470.
References and notes
25. (a) Huang, K. S.; Wang, E. C. Tetrahedron Lett. 2001, 42, 6155–6157; (b) Tsai, T. W.;
Wang, E. C.; Huang, K. S.; Li, S. R.; Wang, Y. F.; Lin, Y. L.; Chen, Y. H. Heterocycles
2004, 63,1771–1781; (c) Chen, P. Y.; Chen, H. M.; Chen, L. Y.; Tzeng, J. Y.; Tsai, J. C.;
Chi, P. C.; Li, S. R.; Wang, E. C. Tetrahedron 2007, 63, 2824–2828.
26. Wang, E. C.; Hsu, M. K.; Lin, Y. L.; Huang, K. S. Heterocycles 2002, 57, 1997–2010.
27. Pure 4f (1.5 g, 87.6%) was obtained as colorless crystal, mp 137–139 ꢀC, Rf¼0.60
1. Harborne, J. B.; Williams, C. A. Phytochemistry 2000, 55, 481–504.
2. (a) Huang, W. H.; Lee, A. R.; Chien, P. Y.; Chou, T. C. J. Pharm. Pharmacol. 2005, 57,
219–225; (b) Kim, J. Y.; Lim, H. J.; Ryu, J.-H. Bioorg. Med. Chem. Lett. 2008, 18,
1511–1514.
3. (a) Hodek, P.; Trefil, P.; Stiborova, M. Chem. Biol. Interact. 2002, 139, 1–21;
(b) Hakimuddin, F.; Paliyath, G.; Meckling, K. Breast Cancer Res. Treat 2004, 85,
65–79; (c) Li, Y.; Fang, H.; Xu, W. Mini-Rev. Med. Chem. 2007, 7, 663–678.
4. (a) Orhan, I.; Ozcelik, B.; Kartal, M.; Ozdeveci, B.; Duman, H. Chromatographia
2007, 66, S153–S157; (b) Goyal, B. R.; Goyal, R. K.; Mehta, A. A. Pharmacog. Rev.
2007, 1, 143–150; (c) Friedman, M. Mol. Nutr. Food Res. 2007, 51, 116–134.
5. (a) Quan, W.; Lee, H. J.; Kim, C. Y.; Noh, C. W.; Um, B. H.; Oak, M.-H.; Kim, K.-M.
Planta Med. 2008, 74, 168–170; (b) Kawai, M.; Hirano, T.; Higa, S.; Arimitsu, J.;
Maruta, M.; Kuwahara, Y.; Ohkawara, T.; Hagihara, K.; Yamadori, T.; Shima, Y.;
Ogata, A.; Kawase, I.; Tanaka, T. Allergol. Int. 2007, 56, 113–123; (c) Hirano, T.;
Arimitsu, J.; Higa, S.; Naka, T.; Ogata, A.; Shima, Y.; Fujimoto, M.; Yamadori, T.;
Ohkawara, T.; Kuwabara, Y.; Kawai, M.; Kawase, I.; Tanaka, T. Int. Arch. Allergy
Immunol. 2006, 140, 150–156.
(ethyl acetate/n-hexane¼1:4), IR (KBr) cmꢁ1
,
nmax: 2957, 2932, 2838, 1704, 1590,
1.89 (dd,
1486, 1263, 1289, 1129, 1035, 983, 795; 1H NMR (CDCl3, 400 MHz)
d
J¼6.4 Hz, 1.6 Hz, 3H, ArCH]CHCH3), 3.77, 3.81 (each s, 2ꢂ3H, 2ꢂOCH3), 5.16
(s, 2H, ArOCHCOAr), 6.53 (d, J¼8.8 Hz, 1H, ArH), 6.57 (dq, J¼16.2 Hz, 2.0 Hz, 1H,
ArCH]CHCH3), 6.66 (d, J¼8.8 Hz, 1H, ArH), 6.71 (dq, J¼16.0 Hz, 6.4 Hz, 1H,
ArCH]CHCH3), 7.46 (d, J¼8.8 Hz, 2H, ArH), 7.94 (d, J¼8.8 Hz, 2H, ArH); 13C NMR
(CDCl3, 100 MHz) d 20.08, 56.18, 60.23, 72.26, 108.16, 110.04, 121.03, 122.28, 129.
07, 12.68, 132.15, 132.98, 140.21, 147.75, 148.27, 150.26, 193.94; EIMS (70 eV) m/z
(rel intensity, %) 348 ([Mþ2]þ, 15), 346 (Mþ, 42), 328 (18), 193 (27), 192 (100),
178 (12), 177 (30), 165 (20), 162 (21), 150 (11); Anal. Calcd for C19H19ClO4: C, 65.
80%; H, 5.52%. Found: C, 65.82%; H, 5.50%.
28. Chen, L. Y.; Li, S. R.; Chen, P. Y.; Tsai, I. L.; Hsu, C. L.; Lin, H. P.; Wang, T. P.; Wang,
E. C. Tetrahedron Lett. 2009, 50, 5748–5750.
29. (a) Mothes, C.; Lavielle, S.; Karoyan, P. J. Org. Chem. 2008, 73, 6706–6710;
(b) P0erez-Luna, A.; Botuha, C.; Ferreira, F.; Chemla, F. New J. Chem. 2008,
32, 594–606.
6. (a) Pinto, B.; Bertoli, A.; Noccioli, C.; Garritano, S.; Reali, D.; Pistelli, L. Phytother.
Res. 2008, 22, 362–366; (b) Choi, S. Y.; Ha, T. Y.; Ahn, J. Y.; Kim, S. R.; Kang, K. S.;
Hwang, I. K.; Kim, S. Planta Med. 2008, 74, 25–32; (c) Ahmed, N.; Dubuc, C.;
Rousseau, J.; Benard, F.; van Lier, J. E. Bioorg. Med. Chem. Lett. 2007, 17, 3212–
3216; (d) Zhu, J. T. T.; Choi, R. C. Y.; Chu, G. K. Y.; Cheung, A. W. H.; Gao, Q. T.;