Synthesis and biological evaluation of some novel 4H-benzopyran-4-one derivatives as nonsteroidal antiestrogens

Article abstract of DOI:10.1016/S0223-5234(01)01218-1

The preparation and characterization of some novel 2- and 3-substituted-7-methoxy-4H-1-benzopyran-4-one are presented. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic and antiimplantation activities in mature female albino rats. 3-Benzyl-7-methoxy-4H-1-benzopyran-4-one (14) showed the highest uterotrophic activity (87%) based on dry uterine weight gain. The antifertility activity, as assessed by the post-coital antiimplantation activity test, was of weak potency for most compounds (14-29%). Among the products, the 2-(4′-methoxyphenyl)-7-methoxy-4H-1-benzopyran-4-one (19) exhibited the highest antiestrogenic activity of 65%. It also elicited 31% of the uterotrophic activity of estradiol.

Full text of DOI:10.1016/S0223-5234(01)01218-1

Eur. J. Med. Chem. 36 (2001) 243–253
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01218-1/SCO
Short Communication
Synthesis and biological evaluation of some novel 4H-benzopyran-4-one
derivatives as nonsteroidal antiestrogens
Khadiga Ahmed Ismaila*, Tarek Abd El Aziemb
aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt
bDepartment of Pharmacology and Drug Toxicology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
Received 19 June 2000; revised 7 December 2000; accepted 4 January 2001
Abstract – The preparation and characterization of some novel 2- and 3-substituted-7-methoxy-4H-1-benzopyran-4-one are pre-
sented. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic and antiimplantation activities in mature
female albino rats. 3-Benzyl-7-methoxy-4H-1-benzopyran-4-one (14) showed the highest uterotrophic activity (87%) based on dry
uterine weight gain. The antifertility activity, as assessed by the post-coital antiimplantation activity test, was of weak potency for
most compounds (14–29%). Among the products, the 2-(4%-methoxyphenyl)-7-methoxy-4H-1-benzopyran-4-one (19) exhibited the
´
highest antiestrogenic activity of 65%. It also elicited 31% of the uterotrophic activity of estradiol. © 2001 Editions scientifiques et
me´dicales Elsevier SAS
4H-1-benzopyran-4-one / antiestrogens / uterotrophic activity / antiimplantation activity
1. Introduction
for epidemiological findings [15]. High intake of phy-
toestrogens through soybeans and their products is
thought to be associated with low incidences of
prostate cancer in Asian countries [15], while the
incidence is much higher in black men in the USA
The phytoestrogens formononetin, daidzein,
biochanin A and genistein as well as the coumestan
coumestrol (figure 1) are known to be present in
various plant species, and particularly in soybean
extracts and in vegetable dietary compounds like al-
falfa [1–3]. They have been considered as responsible
[16].
One of the interesting findings about flavonoids is
the influence they have on the incidence of cancer by
for the depression of fertility observed in sheep graz-
modulating the cytochrome p-450 monoxygenase sys-
ing clover pasture by acting on progesterone levels [4]
tem [17] and inhibition of the effects of tumor pro-
or on pituitary luteinising hormone release [5, 6].
moters [18]. Flavonoids may also influence the
Their estrogenic activity has been assessed in biologi-
incidence of breast cancer by acting as antiestrogens
cal assays such as the increase in the uterine weight of
[10, 19] or as aromatase inhibitors [20].
sheep [7], mouse [8] or rat [9] and by biochemical tests
like binding to estrogen receptors [10, 11]. Several
studies have shown a possible effect of these com-
pounds on the synthesis of sex hormone-binding glob-
ulins (SHBG) by the liver, as well as on sex steroid
metabolism [12–14]. Genistin and daidzein possess
anticancer effects at relatively early stages of prostate
cancer development, providing experimental support
Moreover, a series of flavones has been prepared
which were variously substituted [21], for evaluation
of their cytotoxicity to ANN-1 cells which contain a
tyrosine kinase. 3-Amino-4-methoxyflavone was the
most cytotoxic compound.
In this report, we describe the synthesis of two
series of flavones substituted at the 2- or 3-position
(figure 2) to study the effect of structural modulation
around the flavone nucleus on its estrogenic and
antifertility activities.
* Correspondence and reprints
E-mail address: kadiga99@yahoo.com (K.A. Ismail).

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K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
Fig. 1. Structure of several phytoestrogens.
On the other hand, acylation of 2-(t-
butyldimethylsilyloxy)-4-methoxyacetophenone (2)
2. Chemistry
A number of synthetic methods for the preparation
of the 3-substituted flavones have been developed [22,
23] but these require several sequential reactions in-
volving the application of the Hoesch reaction [24] on
the 2-hydroxyacetophenone derivatives using different
substituted nitriles.
with acyl chloride using lithium diisopropylamide
(LDA) at −78°C [28] (figure 4) gave 1-[2%-(t-
butyldimethylsilyloxy) - 4% - methoxyphenyl] - 3 - sub-
stituted propane-1,3-dione (15–18) as viscous residue
which was dried under reduced pressure. The 1H
NMR spectra of the crude products showed that they
exist as a tautomer mixture [29–31] and they were
used as such in subsequent reactions without any
further purification. Treatment of the propane-1,3-
dione derivatives (15–18) with glacial acetic acid con-
taining 0.5% H2SO4 at 95–100°C for 3 h resulted in
cleavage of the silyl protecting group followed by
cyclization to provide 2-substituted-7-methoxy-4H-1-
benzopyran-4-one (19–22) as a yellow precipitate, in
moderate yields, which were crystallized from
EtOAc–hexane.
Herein we report the synthesis of the new 3-substi-
tuted-7-methoxy-4H-1-benzopyran-4-ones
(11–14)
starting from 2-hydroxy-4-methoxyacetophenone (1)
according to figure 3. The key step in this synthesis
involved the alkylation with alkyl halide using potas-
sium tertiary butoxide of 2-(t-butyldimethylsilyloxy)-
4-methoxyacetophenone (2) which was prepared by
the protection of the hydroxyl group of 1 using t-
butyldimethylsilylchloride. The t-butyldimethylsilyl
protecting group has been utilized due to its easy
introduction and subsequent cleavage in high yield
[25, 26]. The O-silyl protected alkylacetophenone
derivatives (3–6) were therefore treated with tetra-n-
butylammonium fluoride [27] to produce the corre-
sponding 2%-alkyl-2-hydroxy-4-methoxyacetophenone
(7–10) in good yield. Cyclization of the alkyl deriva-
tives (7–10) was achieved via methanesulfonylchlo-
ride using boron trifluoride diethyl etherate at 0°C
[23] to give the desired 3-substituted-7-methoxy-4H-1-
benzopyran-4-ones (11–14) which were purified by
crystallisation from ethanol to produce yellow crys-
tals in moderate yields.
Fig. 2. General structure of designed compounds.

K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
245
Fig. 3. Reactions and conditions: (a) TBSCl, Et3N, DMAP, CH2Cl2, room temperature overnight; (b) RBr, t-BuOK, DMF, 0°C,
8 h; (c) (n-Bu)4 NF, THF, 0°C, 45 min; (d) BF3-Et2O, MeSO2Cl, DMF, heat on water bath, 2 h.
Fig. 4. Reactions and conditions: (a) RCOCl, LDA, THF, −78°C; (b) HOAc, H2SO4, heat at 95–100°C, 3 h.
In addition, the 2-(3-pyridyl)-7-methoxy-4H-1-ben-
zopyran-4-one (24) [32] was prepared in 70.5% yield
by a modified condensation reaction involving the
treatment of 2-(t-butyldimethylsilyloxy)-4-methoxy-
acetophenone (2) with methyl nicotinate using lithium
hexamethyldisilylamide (LiHMDS) at −78°C to ob-
phenyl]-3-(3-pyridyl)-propane-1,3-dione (23) as a yel-
low precipitate which crystallized from methanol and
1
was identified by IR, H NMR and 13C NMR. Com-
pound 23 was cyclized into 2-(3-pyridyl)-7-methoxy-
4H-1-benzo-pyran-4-one (24) using glacial acetic acid
containing 0.5% H2SO4 at 95–100°C for 3 h (figure
5).
tain
1-[2%-(t-butyldimethylsilyloxy)-4%-methoxy-

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K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
“ The first group received the vehicle (DMSO) and
served as a control.
“ The second group received a standard daily dose of
estradiol (0.16 mg kg−1) subcutaneously dissolved in
the vehicle.
“ The remaining groups were injected with the com-
pounds under investigation subcutaneously once
daily over the 3-day period in 0.1 mL DMSO (0.09
mmol day−1 rat−1).
The rats were weighed 24 h after the last dose and
vaginal smears were taken and examined under the
microscope. The rats were sacrificed by cervical disloca-
tion. The uteri were removed, freed from extraneous
tissues, blotted between a filter paper and weighed (wet
weight). The uteri were dried in an oven at 60°C for 48
h and then weighed (dry weight). The gain in uterine
weight calculated as mg uterine weight/100 g body
weight and the percentage of dry/wet weight are shown
in table I. The agonistic activity (%) estimated by the
following formula [35] (table I).
Fig. 5. Reactions and conditions: (a) LiHMDS, THF, −78°C;
(b) (i) HOAc, H2SO4, heat at 95–100°C, 3 h; (ii) Na2CO3.
3. Biological activity
3.1. Uterotrophic activity
The uterotrophic activity [33, 34] of the synthesized
compounds was evaluated by determining the uterine
weight gain in mature ovariectomized female albino rats
(about 150 g) (obtained from the animal house of the
Faculty of Pharmacy, Alexandria). The animals were
divided into 13 groups, each with six rats. The rats were
ovariectomized 2–4 days before starting the injection
and then injected subcutaneously for three consecutive
days as follows:
(WT−WV)
(WS−WV)
% Agonistic activity=
×100
where WT is the relative dry uterine weight of animals
treated with test compound, WS the relative dry uterine
weight of animals treated with a standard dose of
estradiol (0.16 mg kg−1), and WV the relative dry uterine
weight of control animals.
Table I. Estrogenic potencies and post-coital antiimplantation efficacies of the synthesized compounds in ovariectomized mature
female rats.
Comp.
Wet uterine
Dry uterine
Dry weight/wet
% Uterotrophic
Antiimplantation
%
weight (mg/100 g) weight (mg/100 g) weight % (n)a
activity based on activityc (no. of
Antiimplantation
dry weight
implants)
activityc
Controlb
Estradiol
11.2290.64
3.8290.66
34.1892.28 (6)
35.8691.18
34.7191.72
31.5291.12
38.9890.72*
35.1190.96
37.4890.82
38.6890.64*
36.1690.48
31.1890.52
30.4290.71
8.0090.7
0
0
100
29
19
14
24
15
14
21
15
23
20.1692.82**
19.4892.56**
18.3591.43**
11.1690.86
7.4291.72**
6.8290.96**
5.9690.82**
4.2290.37*
6.9690.88**
4.9491.55*
4.8290.58*
4.5691.26*
4.1291.26
100
83
59
11
87
31
28
21
8
11
12
13
14
19
20
21
22
24
3.5091.19
5.290.912
7.0191.50
4.2091.50
7.1891.55
7.0093.50
4.091.65
7.2093.50
4.591.50
19.5691.82**
13.2592.16*
12.5490.89
12.4690.81
13.6691.87*
16.2890.92**
5.1490.73*
37
a Number of animals in each group=5.
b Rats received vehicle (DMSO) and served as control.
c Minimum effect dose for prevention of pregnancy (0.05 mg kg−1 body weight for estradiol). Doses of the tested compounds were
calculated on a molar ratio basis. Results are expressed as mean9SEM. Data were analyzed by one-way variance. Student’s t-test
for unpaired observations was used. Differences between means were considered significant if *PB0.05; **PB0.001.

K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
247
Fig. 6. Uterotrophic activity of estradiol and compound 14 in ovariectomized mature female rats.
The previous procedure was repeated using different
doses of compound 14 (0.039, 0.079, 0.159, 0.319
mg kg−1) (figure 6).
dry uterine weight of animals treated with a standard
dose of estradiol, and WV the relative dry uterine weight
of control animals.
The previous procedure was repeated using different
doses of compound 19 (0.029, 0.053, 0.106, 0.213
mg kg−1) (figure 7).
3.2. Antiuterotrophic activity
The antiuterotrophic activity [36, 37] of the synthe-
sized compounds was assessed in mature ovariectomized
albino female rats (about 250 g). The compounds were
administered subcutaneously in 0.1 mL DMSO along
with of E2-17b (0.098 mg kg−1 in 0.1 mL DMSO) at two
different sites for three consecutive days. Inhibition was
expressed as percent inhibition from the formula of
Hatmann et al. [37] (table II).
3.3. Antiimplantation activity
Mature female cycling albino rats (150–200 g) were
mated with active males during the night after the day
of proestrus. Animals with evidence of positive mating
(presence of sperm in the vaginal smears) received the
test compound dissolved in 0.1 mL DMSO subcuta-
neously on days 1–7 post-coitum [34, 36–38]. The ani-
mals were examined by laparatomy on day 10 of
pregnancy for the number of implantation sites. Results
were compared with those obtained on administration
of the standard estradiol (table I).
(WS,T−WV)
ꢀ
n
% Inhibition =100−
×100
(WS−WV
where WS,T is the relative dry uterine weight of animals
treated with estradiol+test compounds, WS the relative

248
K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
4. Results and discussion
ited a postcoital antifertility activity of 24% relative to
estradiol and was almost (15%) devoid of antiutero-
trophic activity.
On the other hand, introduction of various p-sub-
stituted phenyl groups (compounds 19 and 20),
phenethyl group (compound 22) and pyridyl group
(compound 24) at the 2-position of flavone induced a
weak uterotrophic activity. Compound 19, having a
p-methoxyphenyl moiety, elicited the highest (65%)
antiuterotrophic activity (table II).
Summing up the results, compounds 14 and 19 are
the most active among the series. The former pro-
duced the highest uterotrophic (87%) and the latter
produced the highest (65%) antiuterotrophic
response.
The results of biological screening (tables I and II)
showed that the 3-allyl flavone derivative 11, at a dose
of 0.09 mmol rat−1 day−1, produced an 83% increase in
uterine weight and reduced the postcoital antiimplan-
tation activity to 29% relative to estradiol (table I). It
also produced weak (38%) antiuterotrophic activity
(table II). Replacement of the allyl group by the
isopropyl group (compound 12) decreased the utero-
trophic activity to 59% and replacement by octyl
group notably decreased the uterotrophic activity to
11%. In contrast, the 3-benzylflavone derivative 14,
increased the uterotrophic activity to 87% and exhib-
Table II. Antiuterotrophic activity of the synthesized com-
pounds in ovariectomized mature female rats (number of
animals in each group=6; doses of the tested compounds
were calculated on a molar ratio basis; results were expressed
as mean9S.E.M.; data are analyzed by one-way variance.
Student’s t-test for unpaired observations was used; Differ-
ences between means were considered significant if *PB0.005;
**PB0.001).
A more precise assessment of the uterotrophic ac-
tivity of 14 and antiuterotrophic activity of 19 is
illustrated in figures 6 and 7, respectively. The utero-
trophic effect in response to different doses (0.0225–
0.18 mmol rat−1 day−1) of 3-benzyl-7-methoxy-4H-
1-benzopyran-4-one (14) was compared to that of
similar doses of estradiol. Compound 14 at a dose of
0.0225, 0.045 and 0.09 mmol rat−1 day−1 caused a 15,
53 and 78% uterotrophic effect, respectively (figure 6).
At a higher dose (0.18 mmol rat−1 day−1), compound
14 did not produce a greater uterotrophic response.
On the other hand, the antiuterotrophic activity of
2-(4%-methoxyphenyl)-7-methoxy-4H-1-benzopyran-
4-one 19 was studied by simultaneous administration
of various doses (0.0225–0.18 mmol rat−1 day−1) of
this compound and a standard dose of estradiol (0.09
mmol rat−1 day−1). Compound 19 at 0.0225–0.045
mmol rat−1 day−1 caused a dose-related inhibition of
estradiol-induced increase in uterine weight (figure 7).
A maximal inhibition (65%) was attained at a dose of
0.18 mmol rat−1 day−1, indicating its partial but sig-
nificant antiestrogenic effect.
Compound Dry uterine weight
mg rat−1
% Antiuterotrophic
activity
Controla
Estradiol
4.6890.54
49.2693.62**
32.4192.12**
29.6891.43**
26.5290.92**
42.5390.86*
20.1690.76
11
12
13
14
19
20
21
22
24
38
44
51
15
65
14
24
21
35
43.2191.28*
38.6590.88**
40.1191.16*
33.6891.15**
a Rats received vehicle (DMSO) and served as control.
The results obtained in this study have indicated
that these newly synthesized compounds should be
useful for seeking novel chemical approach to the
discovery of potent nonsteroidal antiestrogens.
5. Experimental protocols
5.1. Chemistry
Materials: Chemical reagents were bought from
Aldrich. Thin layer chromatography (TLC) was per-
formed on Whatman precoated silica gel F254 aluminum
Fig. 7. Dose–response curve of the antiuterotrophic activity
of compound 19 in ovariectomized mature female rats. Results
are expressed as mean S.E.M.

K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
249
foils. Visualization was accomplished with UV light/or
5.1.2. General procedure for the alkylation of
phosphomolybdic acid solution followed by heating.
Purification of the reaction products was carried out by
flash column chromatography using glass column dry
packed with neutral alumina a grade I or silica gel
(230–400 mesh). Organic solutions were dried over an-
hydrous MgSO4; evaporation refers to removal of sol-
vent on a rotary evaporator under reduced pressure.
Melting point were determined using a Thomas Hoover
capillary melting point apparatus and are uncorrected.
IR spectra were obtained on salt plates in KBr, pellet or
in CCl4, using a Nicolet Protege 460 model spectrome-
2-(t-butyldimethylsilyloxy)-4-methoxyacetophenone (2)
(synthesis of compounds 3–6)
Potassium t-butoxide (0.5 g, 4.5 mmol) was added to
a solution of 2-(t-butyldimethylsilyloxy)-4-methoxyace-
tophenone (2, 0.84 g, 3 mmol) in anhydrous DMF (10
mL) under argon atmosphere at 0°C. The mixture was
stirred at 0°C for 1 h. A solution of freshly distilled
alkyl bromide (6 mmol) in anhydrous DMF (3 mL) was
added via a cannula to the reaction mixture with stirring
at 0°C. The stirring was continued at 0°C for 8 h. The
solution was quenched with saturated solution of
NH4Cl, extracted with EtOAc (3×30 mL), dried over
MgSO4, filtered and evaporated under reduced pressure
to produce sticky mass, which was purified by flash
chromatography on neutral alumina (eluent: 25%
EtOAc in hexanes).
1
ter. Peaks were reported in cm−1. H NMR spectra were
recorded on a Bruker 250 MHz spectrometer with TMS
as internal standard in CDCl3 unless otherwise noted.
Mass spectral data were determined at the Ohio State
University Chemical Instrument center with a Kratos
MS-30 mass spectrometer. Elemental analyses were per-
formed by the Microanalytical Unit, Faculty of Science,
Cairo University, Egypt. Analyses indicated by the sym-
bols of elements were within 0.4% of the theoretical
values. All reactions were carried out under an argon
atmosphere, unless otherwise noted.
5.1.2.1. 2%-Allyl-2-(t-butyldimethylsilyloxy)-4-
methoxyacetophenone (3)
White solid (0.65 g, 68%): m.p. 95–92°C. IR (cm−1
,
1
KBr) 3100 (CHꢀCH2). 1637 (CꢀO), 1302 (SiꢁCH3). H
NMR (CHCl3-d) l 7.65 (d, J=10 Hz, 1H, H5), 6.55
(dd, J=10 and 2 Hz, 1H, H6), 6.4 (d, J=2 Hz, 1H,
H3), 5.6–5.95 (m, 1H, CHꢀ), 4.9–5.15 (m, 2H, CH2ꢀ),
3.8 (s, 3H, OCH3), 3–3.15 (m, 2H, CH2), 2.4–2.6 (t, 2H,
CH2), 1.02 (s, 9H, (CH3)3), 0.3 (s, 6H, (CH3)2). 13C
NMR (CHCl3-d) l 199 (CꢀO), 164.2, 158, 132.4, 124.5,
107.5 and 106.2 (aromatic C), 105.7 (CHꢀ), 91.2 (CH2ꢀ),
55.6 (OCH3), 44.5 (COCH2), 33.5 (Cꢁ(CH3)3), 33.1
5.1.1. 2-(t-Butyldimethylsilyloxy)-4-
methoxyacetophenone (2)
Et3N (6.29 mL, 45.13 mmol) was added to a cooled
(0°C) solution of 2-hydroxy-4-methoxyacetophenone (1)
(5 g, 30.08 mmol) and DMAP (0.36 g, 3 mmol) in
CH2Cl2 (40 mL). A solution of t-butyldimethylsilylchlo-
ride (TBSCl) (5 g, 33.09 mmol) in CH2Cl2 (10 mL) was
added to the reaction mixture dropwise over 10 min and
the mixture was stirred at r.t. overnight. The reaction
mixture was poured into ice water (500 mL) and ex-
tracted with CH2Cl2 (3×50 mL). The combined extracts
were washed with brine (3×50 mL) and dried over
MgSO4, filtered and evaporated under reduced pressure
to produce a yellow oil which was purified by flash
chromatography on neutral alumina (eluent: 10%
EtOAc in hexanes) to give a colorless oil (yield: 7 g,
(CH2), 26.1, 25.4 and 18.4 (CH3 groups). MS m/z
’
(relative intensity, %): 320 ([M] +, 15), 205 ([M−
’
C6H15Si] +, 100). Anal. Found: C, 67.45; H, 8.85. Calc.
for C18H28O3Si: C, 67.46; H, 8.80%.
5.1.2.2. 2-(t-Butyldimethylsilyloxy)-2%-
isopropyl-4-methoxyacetophenone (4)
White solid (0.67 g, 69%): m.p. 110–112°C. IR (cm−1
,
1
KBr) 1639 (CꢀO), 1300 (SiꢁCH3). H NMR (CHCl3-d)
l 7.71 (d, J=10 Hz, 1H, H5), 6.59–6.5 (m, 2H, H6+
H3), 3.8 (s, 3H, OCH3), 2.75 (d, J=8 Hz, 2H, COCH2),
2.44–2.3 (m, 1H, CH), 1.4 (d, J=9.75 Hz, 6H, (CH3)2),
1.05 (s, 9H, (CH3)3), 0.32 (s, 6H, Si(CH3)2). 13C NMR
(CHCl3-d) l 198.2 (CꢀO), 166.4, 165.5, 164.7, 159.6,
132.9 and 122.3 (aromatic C), 55.7 (OCH3), 42.2
(COCH2), 32.5 (Cꢁ(CH3)3), 26.4 (CH), 25.6, 22.3 and
18.2 (CH3 groups). MS m/z (relative intensity, %): 322
1
83%). H NMR (CHCl3-d) l 7.69 (d, J=10.6 Hz, 1H,
H5), 6.5 (dd, J=10.6 and 2 Hz, 1H, H6), 6.35 (d, J=2
Hz, 1H, H3), 3.79 (s, 3H, OCH3), 2.51 (s, 3H, COCH3),
1 (s, 9H, (CH3)3), 0.24 (s, 6H, (CH3)2). 13C NMR
(CHCl3-d) l 198.7 (CꢀO), 164, 157.3, 132.5, 124.2, 107.1
and 106.1 (aromatic C), 55.7 (OCH3), 31.65 (Cꢁ(CH3)3),
26.3, 25.1 and 18.3 (CH3 groups). MS m/z (relative
intensity, %): 281 ([MH]+, 65), 165 ([M−C6H15Si]+, 100).
Anal. Found: C, 64.22; H, 8.66. Calc. for C15H24O3Si:
C, 64.25; H, 8.62%.
’
’
([M] +, 30), 208 ([MH−C6H15Si] +, 100), 165([MH−
’
C9H22Si] +, 97). Anal. Found: C, 67.08; H, 9.39. Calc.
for C18H30O3Si: C, 67.04; H, 9.37%.

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K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
5.1.2.3. 2-(t-Butyldimethylsilyloxy)-4-
methoxy-2%-octylacetophenone (5)
(aromatic C), 107.9 (CHꢀ), 99.7 (CH2), 55.8 (OCH3),
43.2 COCH2), 32.4 (CH2). Anal. Found: C, 69.90; H,
6.88. Calc. for C12H14O3: C, 69.89; H, 6.84%.
White solid (0.75 g, 64%): m.p. 129–131°C. IR (cm−1
,
1
KBr) 1636 (CꢀO), 1305 (SiꢁCH3). H NMR (CHCl3-d)
l 7.79 (d, J=10 Hz, 1H, H5), 6.45 (dd, J=10 and 2 Hz,
1H, H6), 6.36 (s, 1H, H3), 3.1–2.9 (m, 2H, COCH2),
1.95–1.75 (m, 2H, CH2), 1.45–1.2 (m, 12H, (CH2)6),
1–0.85 (m, 12H, CH3 of octyl+(CH3)3), 0.3 (s, 6H,
Si(CH3)2. 13C NMR (CHCl3-d) l 198.0 (CꢀO), 164.8,
161.0, 152.2, 132.9, 121.4, 105.3 (aromatic C), 55.8
(OCH3), 43.1 (COCH2), 32.5 (Cꢁ(CH3)3, 30.2, 29.6 and
29.5 (CH2) 26.6, 23.0 and 14.4 (CH3 groups). Anal.
Found: C, 70.38; H, 10.25. Calc. for C23H40O3Si: C,
70.36; H, 10.26%.
5.1.3.2. 2-Hydroxy-2%-isopropyl-4-methoxyacetophenone
(8)
Yield: 82%. m.p. 125–127°C. IR (cm−1, KBr) 3435
1
(OH), 1640 (CꢀO). H NMR (CHCl3-d) l 12.6 (s, 1H,
phenolic OH), 7.83 (d, J=10 Hz, 1H, H5), 6.56–6.3 (m,
2H, H3+H6), 3.88 (s, 3H, OCH3), 3.55–3.48 (m, 2H,
COCH2), 2.4–2.25 (m, 1H, CH(CH3)2), 1.23 (d, J=10
Hz, 6H, (CH3)2). 13C NMR (CHCl3-d) l 198.9 (C=O),
166.4, 164.7, 159.6, 132.9, 122.3 and 105.3 (aromatic C),
55.8 (OCH3), 40.2 (COCH2), 26.4 (CH), 22.9 (CH3). MS
’
m/z (relative intensity, %): 208 ([M] +, 100). Anal.
Found: C, 69.22; H, 7.76. Calc. for C12H16O3: C, 69.21;
H, 7.74%.
5.1.2.4. 2%-Benzyl-2-(t-butyldimethylsilyloxy)-4-
methoxyacetophenone (6)
White solid (0.6 g, 54.5%): m.p. 97–99°C. IR (cm−1
,
1
KBr) 1639 (CꢀO), 1301 (SiꢁCH3). H NMR (CHCl3-d)
l 7.8 (d, J=10 Hz, 1H, H5), 7.5–7.3 (m, 5H, phenyl-H),
6.55–6.49 (m, 2H, H3+H6), 3.86 (s, 3H, OCH3), 2.95 (t,
2H, COCH2), 2.6–2.45 (m, 2H, CH2), 1.03 (s, 9H
Cꢁ(CH3)3), 0.3 (s, 6H, Si(CH3)2). 13C NMR (CHCl3-d) l
198.1 (CꢀO), 166.5, 165.6, 136.4, 133.1, 129.1, 128.6,
128.0, 121.8, 108.0, 105.7 and 101.2 (aromatic C) 55.9
(OCH3), 40.28 (COCH2), 32.5 (Cꢁ(CH3)3), 29.44 (CH2),
26.5, 19.4 and 18.9 (CH3 groups). MS m/z (relative
5.1.3.3. 2-Hydroxy-4-methoxy-2%-octylacetophenone (9)
Yield: 79%. m.p. 151–153°C. IR (cm−1, KBr) 3440
1
(OH), 1638 (CꢀO). H NMR (CHCl3-d) l 12.6 (s, 1H,
phenolic OH), 7.88 (d, J=10 Hz, 1H, H5), 6.64–6.43
(m, 2H, H3+H6), 3.89 (s, 3H, OCH3), 3.5 (t, 2H,
COCH2), 1.95–1.75 (m, 2H, CH2), 1.59–1.28 (m,
12H,(CH2)6, 0.9 (t, 3H, CH3). 13C NMR (CHCl3-d) l
199.3 (CꢀO), 164.5, 161.2, 132.6, 129.3, 128.9, 105.2
(aromatic C), 55.5 (OCH3), 43.3 (COCH2) 32.2, 29.5,
23.0 and 22.6 (CH2), 14.4 (CH3). Anal. Found: C, 73.36;
H, 9.42. Calc. for C17H26O3: C, 73.35; H, 9.41%.
’
’
intensity, %): 370 ([M +], 11), 165 ([MH−C13H22Si] +,
100). Anal. Found: C, 71.35; H, 8.15. Calc. for
C22H30O3Si: C, 71.31; H, 8.16%.
5.1.3.4. 2%-Benzyl-2-hydroxy-4-methoxyacetophenone
(10)
5.1.3. 2%-Alkyl-2-hydroxy-4-methoxyacetophenone
(7–10)
Yield: 79%. m.p. 119–121°C. IR (cm−1, KBr) 3436
1
A solution of t-n-butylammonium fluoride in THF (1
M, 15 mL, 15 mmol) was added to a solution of
2% - alkyl - 2 - (t - butyldimethylsilyloxy) - 4 - methoxyaceto-
phenone (3–6, 5 mmol) in THF (30 mL) at 0°C and
stirring was continued for 45 min. THF was distilled off
at reduced pressure and the residue was treated with
water (100 mL). The precipitate was filtered, washed
with water, dried and crystallized from ethanol.
(OH), 1637 (CꢀO). H NMR (CHCl3-d) l 12.5 (s, 1H,
phenolic OH), 7.9 (d, J=10 Hz, 1H, H5), 7.55–7.3 (m,
5H, phenyl H), 6.6–6.45 (m, 2H, H3+H6), 3.85 (s, 3H,
(OCH3), 3.3 (t, 2H, COCH2), 2.82 (t, 2H, CH2). 13C
NMR (CHCl3-d) l 201.7 (CꢀO), 156.5, 147.6, 140.5,
136.4, 133.1, 132.7, 129.1, 128.8, 128.3, 124.8, 119.7,
114.2 (aromatic C), 55.9 (OCH3), 40.0 (COCH2), 29.2
’
(CH2). MS m/z (relative intensity, %): 256 ([M] +, 100).
Anal. Found: C, 75.01; H, 6.30. Calc. for C16H16O3: C,
74.98; H, 6.29%.
5.1.3.1. 2%-Allyl-2-hydroxy-4-methoxyacetophenone (7)
Yield: 85%. m.p. 115–117°C. IR (cm−1, KBr) 3439
(OH), 1640 (CꢀO). H NMR (CHCl3-d) l 12.8 (s, 1H,
phenolic OH), 7.85 (d, J=10 Hz, 1H, H5), 6.65–6.41
(m, 2H, H3+H6), 6.2–6 (m, 1H, CHꢀ), 5.61–5.32 (m,
2H, CH2ꢀ), 3.9 (s, 3H, OCH3) 3.63–3.52 (m, 2H,
COCH2), 2.5–2.36 (m, 2H, CH2). 13C NMR (CHCl3-d)
l 200.0 (CꢀO), 164.7, 160.6, 133.9, 133.3, 121.7, 119.6
1
5.1.4. 3-Substituted-7-methoxy-4H-1-benzopyran-4-ones
(11–14)
A solution of 2%-alkyl-2-hydroxy-4-methoxyacetophe-
none (7–10, 0.9 mmol) in anhydrous DMF (6 mL) was
treated cautiously with freshly distilled BF3·Et2O (4
equiv.) at 0°C. A solution of MeSO2Cl (3 equiv.) in

K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
251
DMF (4 mL) was added to the mixture. The mixture
was heated on a steam bath for 2 h. The cooled product
was poured with stirring into water. The initial oil
quickly solidified to give the chromone (11–14) as yel-
low solid which was purified by crystallization from
ethanol.
7.31 (m, 5H, phenyl H), 7.12–7 (m, 2H, H5+H8), 3.95
(s, 3H, OCH3), 3.91 (s, 2H, CH2-Ar). 13C NMR (CHCl3-
d) l 179.6 (CꢀO), 166.5 (C9), 164.7 (C7), 146.4 (C2),
133.1 (C3), 132.7, 129.1, 128.6, 125.8, 124.9, 124.7,
121.2, 119.8 (aromatic C), 55.9 (OCH3), 30.1 (CH2). MS
’
m/z (relative intensity, %): 266 ([M] +, 100). Anal.
Found: C, 76.70; H, 8.09. Calc. for C17H14O3: C, 76.68;
H, 8.38%.
5.1.4.1. 3-Allyl-7-methoxy-4H-1-benzopyran-4-one (11)
Yield: 75%. m.p. 150–152°C. IR (cm−1, KBr) 1639
(CꢀO). H NMR (CHCl3-d) l 8.1 (s, 1H, H2), 8.0–7.85
(m, 1H, H6), 7.51–7.3 (m, 2H, H5+H8), 6.3–6.13 (m,
1H, CHꢀ), 5.7–5.52 (m, 2H, CH2ꢀ), 3.91 (s, 3H, OCH3),
2.63–2.5 (m, 2H, CH2). 13C NMR (CHCl3-d) l 179.7
(CꢀO), 165.0 (C9), 160.5 (C7), 156.0 (C2), 144.9 (C3),
127.8, 126.9, 125.5, 124.5, 118.3, 99.3 (C5, C6, C8, C10,
1
5.1.5. 2-Substituted-7-methoxy-4H-1-benzopyran-4-one
(19–22)
n-BuLi (4.34 mL, 10 mmol, from 2.3 M in hexanes)
was added dropwise to a solution of diisopropylamine
(1.41 mL, 10 mmol) in anhydrous THF (50 mL) with
stirring at −78°C under argon atmosphere. The mixture
was stirred at −78°C for 30 min. A solution of 2-(t-bu-
tyl-dimethylsilyloxy)-4-methoxyacetophenone (2, 4.75
mmol) in THF (10 mL) was added via a cannula to the
stirred LDA solution at −78°C. The mixture was
warmed to −25°C and stirred for 1 h at this tempera-
ture, then cooled to −78°C and a solution of freshly
distilled acid chloride (5 mmol) in THF (10 mL) was
added via a cannula. Stirring was continued at −78°C
for 3 h then at r.t. overnight. The reaction mixture was
diluted with EtOAc (50 mL) and acidified to pH 3 with
1 N HCl. The organic layer was separated, dried over
MgSO4, filtered and evaporated to give a viscous residue
of 1-[2%-(t-butyldimethyl-silyloxy)-4%-methoxyphenyl]-3-
substituted propane-1,3-dione (15–18) which was dried
CHꢀ and CH2ꢀ), 54.0 (OCH3), 32.5 (CH2). MS m/z
’
(relative intensity, %): 216 ([M] +, 100). Anal. Found: C,
72.23; H, 5.61. Calc. for C13H12O3: C, 72.21; H, 5.59%.
5.1.4.2. 3-Isopropyl-7-methoxy-4H-1-benzopyran-4-one
(12)
Yield: 79%. m.p. 133–135°C. IR (cm−1, KBr) 1637
1
(CꢀO). H NMR (CHCl3-d) l 8.15 (s, 1H, H2), 7.91–
7.85 (m, 1H, H6), 7.58–7.35 (m, 2H, H5+H8), 3.85 (s,
3H, OCH3), 2.55 (m, 1H, CH(CH3)2), 1.4 (d, J=8 Hz,
6H, (CH3)2). 13C NMR (CHCl3-d) l 179.8 (CꢀO), 165.5
(C9), 159.6 (C7), 149.6 (C2), 140.2 (C3), 138.2, 132.9,
124.6, 120.8 (C5, C6, C8 and C10), 56.3 (OCH3), 29.3
(CH), 22.7, 22.3 (CH3)2. MS m/z (relative intensity, %):
’
1
218 ([M] +, 100). Anal. Found: C, 71.57; H, 6.50. Calc.
under reduced pressure for 24 h (identified by crude H
NMR). It was mixed with glacial acetic acid (20 mL)
and H2SO4 (0.1 mL) and heated at 95–100°C under
argon atmosphere for 3 h. Acetic acid was distilled off
at reduced pressure and the residue was quenched with
water (50 mL). It was extracted with CHCl3 (3×20 mL)
and the combined extracts were dried over MgSO4,
filtered and evaporated to give yellow solid of 2-substi-
tuted-7-methoxy-4H-1-benzopyran-4-one (19–22) which
was crystallized from EtOAc–hexanes.
for C13H14O3: C, 71.55; H, 6.46%.
5.1.4.3. 7-Methoxy-3-octyl-4H-1-benzopyran-4-one (13)
Yield: 70.5%. m.p. 175–177°C. IR (cm−1, KBr) 1638
1
(CꢀO). H NMR (CHCl3-d) l 8.17 (s, 1H, H2), 7.88–
7.84 (m, 1H, H6), 7.56–7.4 (m, 2H, H5+H8), 3.87 (s, 3H,
OCH3), 1.95–1.77 (t, 2H, CH2), 1.7–1.2 (m, 12H,
(CH2)6), 0.9 (br t, 3H, CH3). 13C NMR (CHCl3-d) l
179.5 (CꢀO), 166.3 (C9), 161.05 (C7), 158.3 (C2), 149.6
(C3), 138.1, 127.6, 124.6, 118.3 (C5, C6, C8, C10), 55.8
(OCH3), 32.5, 32.1, 29.6, 29.5, 26.3, 23.0 (CH2 groups),
5.1.5.1. 2-(4%-Methoxyphenyl)-7-methoxy-4H-
1-benzopyran-4-one (19)
’
14.5 (CH3). MS m/z (relative intensity, %): 288 ([M] +,
100), Anal. Found: C, 75.01; H, 8.09. Calc. for
C18H24O3: C, 74.97; H, 8.38%.
Yield 88%, m.p. 146–148°C (reported m.p. 144°C)
[28].
5.1.4.4.
(14) [39]
3-Benzyl-7-methoxy-4H-1-benzopyran-4-one
5.1.5.2. 7-Methoxy-2-(4%-nitrophenyl)-4H-1-
benzopyran-4-one (20)
Yield: 77% m.p. 129–131°C (reported m.p. 131°C)
Yield: 89% m.p. 169–171°C. IR (cm−1, KBr) 1647
[39] IR (cm−1, KBr) 1639 (CꢀO). H NMR (CHCl3-d) l
(CꢀO). H NMR (CHCl3-d) l 8.35 (d, J=12 Hz, 2H,
1
1
8.2 (s, 1H, H2), 7.87–7.83 (d, J=8 Hz, 1H, H6), 7.5–
H3%+H5%), 8.17–8 (m, 3H, H2%+H6%+H6), 7.07–6.97 (m,

252
K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
2H, H5+H8), 6.81 (s, 1H, H3), 3.95 (s, 3H, OCH3). 13C
NMR (CHCl3-d) l 177.7 (CꢀO), 165.0 (C9), 160.5 (C7),
158.3 (C2), 149.6 (C4%), 138.5, 133.1, 127.6, 127.4, 124.6,
NH4Cl, dried over MgSO4, filtered and evaporated to
give a yellow precipitate which was crystallized from
MeOH (0.97 g, 70.5%): m.p. 172–174°C. IR (cm−1
,
118.1, 115.3, 112.2, 110.0, 100.8 (aromatic C), 56.3
KBr,) 1680 and 1640 (free and associated CꢀO). 1H
NMR (CHCl3-d) l 12.3 (s, 0.88H, enol OH), 9.18 (s,
1H), 8.75 (br s, 1H), 8.15 (m, 1H), 7.65 (d, J=10.6
Hz, 1H), for pyridine H2, H6, H5 and H4, respectively,
7.5–7.4 (m, 1H, H5%), 6.7 (s, 0.88 H, vinylic proton of
the enol form), 6.55–6.4 (m, 2H, H3%+H6%), 4.57 (s,
0.2H, the methylene protons of the keto form), 3.91 (s,
3H, OCH3), 1.08 (s, 9H, (CH3)3); 0.25 (s, 6H,
Si(CH3)2). 13C NMR (CHCl3-d) l 195.0 (CꢀO), 166.6
(ꢀCꢁOH), 165.9 (C4%), 152.7 (C2%), 148.2 (pyridine C2),
146.9 (pyridine C6), 138.9, 134.4, 130.6, 123.9, 119.6,
118.7, 113.1 (pyridine C3, C4, C5 and C1%, C3%, C5%, C6%),
93.1 (CHꢀ), 56.1 (OCH3), 26.5, 26.3, 18.9, 18.3 (CH3
groups).
’
(OCH3). MS m/z (relative intensity, %): 297 ([M] +,
100). Anal. Found: C, 64.66; H, 3.75; N, 4.78. Calc. for
C16H11NO5: C, 64.65; H, 3.73; N, 4.71%.
5.1.5.3. 7-Methoxy-2-(4%-trifluoromethylphenyl)-4H-
1-benzopyran-4-one (21)
Yield: 76% m.p. 156–158°C. IR (cm−1, KBr) 1645
1
(CꢀO). H NMR (CHCl3-d) l 8.12–8.04 (d, J=10 Hz,
2H, H3%+H5%), 7.91–7.8 (m, 3H, H2+H6%+H6), 6.8 (s,
1H, H3), 6.72–6.65 (m, 2H, H5+H8), 3.85 (s, 3H,
OCH3). 13C NMR (CHCl3-d) l 178.1 (CꢀO), 164.1
(C9), 160.2 (C7), 151.5 (C2) 140.2 (C4%), 138.5 (C6), 135
(C3), 132.9 (CF3), 131.8, 131.1, 127.4, 125.8, 121.8,
112.9, 109.8 (aromatic C), 56.2 (OCH3). MS m/z (rela-
’
tive intensity, %): 320 ([M] +, 100). Anal. Found: C,
63.75; H, 3.50; F, 17.81. Calc. for C17H11O3F3: C,
63.75; H, 3.46; F, 17.79%.
5.1.7. 2-(3-Pyridyl)-7-methoxy-4H-1-benzopyran-4-one
(24) [32]
1-[2%-(t-Butyldimethylsilyloxy)-4%-methoxyphenyl]-3-
(3-pyridyl) propane-1,3-dione (23, 1 g, 2.6 mmol) was
mixed with glacial HOAc (15 mL) and H2SO4 (0.1 mL)
and heated at 95–100°C under anhydrous condition
for 3 h. Acetic acid was distilled off at reduced pres-
sure and the residue was quenched with saturated
Na2CO3 solution (20 mL) to give gray precipitate
which was crystallized from MeOH to give a shiny buff
5.1.5.4. 2-(i-Phenethyl)-7-methoxy-4H-1-
benzopyran-4-one (22)
Yield: 61%. m.p. 166–167°C. IR (cm−1, KBr) 1640
1
(CꢀO). H NMR (CHCl3-d) l 8.1 (d, J=12 Hz, 1H,
H6), 7.2-7.03 (m, 5H, phenyl H), 6.95–6.80 (m, 2H,
H5+H8), 6.78 (s, 1H, H3), 3.8 (s, 3H, OCH3), 2.98 (t,
2H, CH2), 2.75 (t, 2H, CH2). 13C NMR (CHCl3-d) l
177.7 (CꢀO), 163.6 (C9), 157.6 (C7), 147.3 (C2), 134.2
(C3), 129.9, 128.7, 127.9, 127.7, 126.9, 126.6, 126.3,
124.5, 118.7, 115.1 (aromatic C), 56.2 (OCH3), 42.5
precipitate (0.45 g, 69%), m.p. 182–184°C. IR (cm−1
,
KBr) 1658 (CꢀO), 1610 (CꢀN), 1595, 1565 (g-pyrone
1
ring). H NMR (CHCl3-d) l 9.14 (s, 1H,), 8.75 (br s,
1H) and 8.13 (m, 2H) for pyridine H2, H6, H4 and H5,
respectively, 7.45 (br s, 1H, H6), 7.1-6.95 (m, 2H, H5+
H8), 6.72 (s, 1H, H3), 3.89 (s, 3H, OCH3). 13C NMR
(CDCl3) d 177.6 (C=O),166.1 (C9) 164.7 (C7), 161.3,
160.9, 158.3, 152.4, 147.8, 135.8, 133.7, 128.2, 127.5,
124.0, 118.1 (pyridine C and C1, C2, C5, C6, C8, C10),
56.3 (OCH3). Anal. Found: C, 71.16; H, 4.40; N, 5.55.
Calc. for C15H11NO3: C, 71.14; H, 4.37; N, 5.53%.
and 29.8 (CH2)2. MS m/z (relative intensity, %): 280
’
([M] +, 100). Anal. Found: C, 77.12; H, 5.75. Calc. for
C18H16O3: C, 77.13; H, 5.75%.
5.1.6. 1-[2%-(t-Butyldimethylsilyloxy)-4%-
methoxyphenyl]-3-(3-pyridyl)-propane-1,3-dione (23)
A solution of Li HMDS in THF (7.14 mL, 7.14
mmol, 1 M solution in THF) was added to a well
stirred solution of 2-[(t-butyldimethylsilyl)-oxy]-4-
methoxyacetophenone (2, 1 g, 3.5 mmol) in THF (10
mL) under argon at −78°C in 15 min. After 30 min, a
solution of methyl nicotinate (0.5 g, 3.5 mmol) in THF
(2 mL) was added dropwise. The reaction mixture was
stirred at −78°C for 1 h then at r.t. for 18 h. The
solution was quenched with water (15 mL), the THF
was evaporated, EtOAc (10 mL) was added, the or-
ganic layer was washed with saturated solution of
Acknowledgements
The authors thank Dr Stephen Bergemieir for helpful
discussions and financial support for this work, par-
tially done in his laboratory at Ohio State University,
Columbus, OH, USA.

K.A. Ismail, T. Abd El Aziem / European Journal of Medicinal Chemistry 36 (2001) 243–253
253
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