Efficient liquid-phase synthesis of 2′-hydroxychalcones

Article abstract of DOI:10.1016/S0960-894X(02)00553-X

The condensation of 2′-hydroxyacetophenone (1) with aromatic aldehydes (2) in a well closed vessel using microwave irradiation or classical heating at 132 °C, provides a fast and simple method for the liquid-phase synthesis of 2′-hydroxychalcones without formation of by-products. Antiproliferative activity of these compounds were evaluated using MCF-7 cells.

Full text of DOI:10.1016/S0960-894X(02)00553-X

Bioorganic & Medicinal Chemistry Letters 12 (2002) 2685–2687
0
Efficient Liquid-Phase Synthesis of 2 -Hydroxychalcones
a,
b
c
c
Edmont V. Stoyanov, * Yves Champavier, Alain Simon and Jean-Philippe Basly
aDepartment of Industrial Pharmacy, Faculty of Pharmacy, Dunav 2, Sofia 1000, Bulgaria
bService Commun de RMN, Facult e´ de Pharmacie, 2 rue du Docteur Marcland, 87025 Limoges cedex, France
cUPRES EA 1085, ‘Biomole´cules et cibles tumorales’, Faculte´ de Pharmacie, 2 rue du Docteur Marcland,
8
7025 Limoges cedex, France
Received 7December 2001; revised 29 May 2002; accepted 11 July 2002
0
Abstract—The condensation of 2 -hydroxyacetophenone (1) with aromatic aldehydes (2) in a well closed vessel using microwave
0
ꢀ
irradiation or classical heating at 132 C, provides a fast and simple method for the liquid-phase synthesis of 2 -hydroxychalcones
without formation of by-products. Antiproliferative activity of these compounds were evaluated using MCF-7cells.
#
2002 Elsevier Science Ltd. All rights reserved.
Natural chalcones and related synthetic analogues
mediate a broad spectrum of biological responses
including those that might be able to influence pro-
trials to reproduce some of them, which present the
9
aldolic condensation between 1 and 2, gave a mixture
of products and large amount of starting compounds.
Obviously, the reaction conditions under mW needed
more detailed investigation.
1
,2
cesses dysregulated during cancer development. Many
synthetic methods have been described to obtain 2 -
0
hydroxychalcones. Nevertheless, the Claisen–Schmidt
3
condensation stays the most common method in homo-
geneous phase or in interfacial solid-liquid conditions
In this paper, we report convenient reaction procedure
for the synthesis of 2 -hydroxychalcones with very good
0
yields without formation of by-products (Scheme 1).
4
using barium hydroxide catalyst (C-200). Unfortunately
2
0
5,6
One synthetic pathway to avoid this undesirable reac-
-hydroxychalcones always cyclized to flavanones.
We applied successful microwave irradiation for the
preparation of target molecules 3a–j. The reaction took
place in well closed pressure tube for 2 min with high
7
tion is using protective group or the Friedel–Crafts
8
reaction of phenols with acyl halides. This method
request long reaction time and anhydrous conditions
which limits the scope of its application.
1
2
yields (Table 1). It is noteworthy to mention that all
our trials to carry out the reaction in open vessel failed.
A mixture of two products (3 and 4) and starting com-
pounds was obtained in this case. Obviously, the well
closed tube affords to reach temperatures much higher
than boiling point of ethanol. The measured temperature
in the reaction tube immediately after the irradiation was
In the last few years were published some microwave
assisted methods for the synthesis of various
9ꢁ11
chalcones.
table for the preparation of 2 -hydroxychalcones. Our
These reaction procedures were not sui-
0
Scheme 1.
*
0
Corresponding author. Tel.: +359-2-988-3142; fax: +359-2-987-9874; e-mail: estoyanov@yahoo.com
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00553-X

2686
E. V. Stoyanov et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2685–2687
0
Table 1. Substituted 2 -hydroxychalcones prepared in this study
Acknowledgements
Entry
R1
R2
R3
Observed MSa
Yield (%)
E. V. Stoyanov thanks Hertie Foundation and Alex-
ander von Humboldt Foundation for the award of a
‘Roman Herzog Research Fellowship’.
3
3
3
3
3
3
3
3
a
b
c
d
e
f
H
H
H
H
H
H
OMe
H
H
H
H
H
H
OMe
OMe
H
H
F
Br
Me
OMe
OMe
OMe
N(Me)
223
241
301, 303
23790
253
283
313
266
93
93
94
89
91
87
93
References and Notes
g
h
2
1
. Dimmock, J. R.; Elias, D. W.; Beazely, M. A.; Kandepu,
Products show satisfactory H NMR13 and MS data.
N. M. Curr. Med. Chem. 1999, 6, 1125.
2. Middleton, E.; Kandaswami, C.; Theoharides, T. C. Phar-
macol. Rev. 2000, 52, 673.
a
(Mꢁ1) peak. Negative electrospray experiments were conducted on
Waters LCZ 2000 platform.
3
. Dhar, D. N. The Chemistry of Chalcones and Related
Compounds; John Wiley and Sons: New York, 1981; p 213.
4. Alcantara, A. R.; Marinas, J. M.; Sinisterra, J. V. Tetra-
hedron Lett. 1987, 28, 1515.
ꢀ
repeat the same experiments in the same vessel in oil
bath at 132 C. In these conditions reaction was com-
1
32 C. To prove the microwave effect in this case we
5
2
6
1
. Hoshino, Y.; Takeno, N. Bull. Chem. Soc. Jpn. 1986, 59,
ꢀ
903.
. Barry, K. O.; Main, L. J. Chem. Soc., Perkin Trans. 2 1982,
309.
plete for 3 min and also no by-products were detected,
which means that the microwave irradiation is not
important and could be replaced with classical heating
7. Rall, G. J.; Oberholzer, M. E.; Ferreria, D.; Roux, D. G.
Tetrahedron Lett. 1976, 17, 1023.
8. Bigi, F.; Casiraghi, G.; Casnati, G.; Marchesi, S.; Sartori,
G.; Vignali, C. Tetrahedron 1984, 40, 4081.
9. Gupta, R.; Gupta, A.; Paul, Satya; Kachroo, P. L. Indian J.
Chem. Sect. B 1995, 34, 161.
ꢀ
at 132 C for practically the same reaction time with the
same yields. Longer irradiation as well as longer heating
(
more than 6 min) gave already a mixture of 3 and 4.
In order to establish the general behaviour of this reac-
tion under these conditions, several types of aromatic
aldehydes 2 were studied (Table 1). We found out that
both aldehydes with electon-withdrawing and electron-
1
1
1
1
0. Babu, G.; Perumal, P. T. Synth. Commun. 1997, 27, 3677.
1. Gall, E.; Texier-Boullet, F.; Hamelin, J. Synth. Commun.
999, 29, 3651.
0
2. In
a
typical procedure
a
mixture of 2 -hydroxy-
0
donating substituents react smoothly with 2 -hydroxy-
acetophenone (1). Secondary reactions, for example
acetophenone (1) (1.36 g, 10 mmol) and the corresponding
aromatic aldehyde 2 (10 mmol) in 20% KOH/EtOH (10 g) was
filled into a 15-mL pressure tube (ALDRICH, with threaded
type A plug, length 10.2 cm and additionally provided with a
teflon ring) and placed in a beaker (200 mL). After irradiation
in an ordinary domestic microwave oven (Moulinex CK3 with
0
cyclisation of 2 -hydroxychalcone to flavanone, were
not observed. This affords to avoid phenolic group
protection as well as the use of interfacial solid-liquid
catalyst such as barium hydroxide (C-200).
rotating plate) at 70 W for 2 min, or heating in oil bath at
ꢀ
132 C for 3 min, the reaction mixture was cooled and poured
into crushed ice water (100 mL). Then concd HCl (10 mL) was
The growth inhibitory activity of the compounds was
determined in the MCF-7human breast cancer cell line
ꢀ
added and the reaction mixture was left to stay at 2–3 C
overnight. The separated solid was collected by filtration and
1
4
using the MTT assay as described by Denizot et al.
and are reported in Figure. 1.
recrystallized from methanol.
1
1
400 MHz spectrometer and Me
pound 3a: 6.95 (1H, ddd, 5 -H, J50,60
3. H NMR spectra were recorded in CDCl using a Bruker
3
Compound 3c showed interesting cytotoxic activity
IC =12.3 mM).
4
Si as internal standard. Com-
0
0
0
=7.8 Hz,
=8.4 Hz,
(
=8.1 Hz, J
0
5 ,4
5
0
J5
0
0
0
0
0
0
=1.0 Hz); 7.04 (1H, dd, 3 -H,
J
0
0
,3
,5
,3
3 ,4
0
J
J
3
=1.0 Hz); 7.44 (3H, m, 3-, 4-, 5-H); 7.50 (1H, ddd, 4 -H,
=8.4 Hz, J =7.8 Hz, J =1.5 Hz); 7.67 (2H, m, 2- 6-
Our synthetic approach constitutes a simple and high
yielding way for the development of flavonoid structu-
0
0
0 0
4 ,6
4
4
,5
1
5,16
H); 7.67 (1H, d, a-H, Ja,b=15.4 Hz); 7.93 (1H, d, b-H,
rally-related compounds as pharmacological agents.
0
Ja,b=15.4 Hz); 7.93 (1H, dd, 6 -H,
0
J
0
0
=8.1 Hz,
J =1.5 Hz); 12.81 (1H, s, 2 -OH). Compound 3b: 6.93 (1H,
6 ,5
0 0
6 ,4
0
ddd, 5 -H, J
(
5
0
,6
0
=7.9 Hz, J
5
0
,4
0
=7.7 Hz, J
5
0
,3
0
=0.8 Hz); 6.94
0
2H, d, 3- 5-H, J3,2=J5,6=8.7Hz); 7.02 (1H, dd, 3 -H,
0
J3
0
0
=8.0 Hz,
=8.0 Hz, J
J
0
0
0
=0.8 Hz); 7.49 (1H, ddd, 4 -H,
0
,4
,3
3 ,5
,5
J
J
6
4
0
0
4
0
=7.7 Hz, J
4
0
,6
=1.2 Hz); 7.54 (1H, d, a-H,
a,b=15.5 Hz); 7.90 (1H, d, b-H, Ja,b=15.5 Hz); 7.92 (1H, dd,
0
0
0
=1.2 Hz); 12.94 (1H, s, 2 -OH).
6 ,4
-H, J6
0
0
=7.9 Hz, J
0
,5
0
Compound 3c: 6.95 (1H, ddd, 5 -H, J5
0
0
0
0
0
0
=8.1 Hz,
=8.4 Hz,
=8.4 Hz,
,6
,4
,3
0
J
J
J4
5
0
0
0
,4
,5
,5
0
0
0
=7.6 Hz, J
=0.8 Hz); 7.51 (1H, ddd, 4 -H,
=7.6 Hz,
5
0
,3
0
=0.8 Hz); 7.04 (1H, dd, 3 -H, J
3
0
3
J
4
J
0
0
=1.3 Hz); 7.52 (2H, d, 2- 6-H,
4 ,6
J
7
J
J6
2,3=J6,5=8.5 Hz); 7.58 (2H, d, 3-, 5-H, J3,2=J5,6=8.5 Hz);
.64 (1H, d, a-H, a,b=15.5 Hz); 7.85 (1H, d, b-H,
a,b=15.5 Hz); 7.90 (1H, dd, 6 -H,
J
0
J
6
0
,5
0
=8.1 Hz,
0
=1.3 Hz); 12.73 (1H, s, 2 -OH). Compound 3d: 2.40 (3H,
,4
Figure 1. Antiproliferative activity: MCF-7were incubated with chal-
cones at 20 mM for 6 days. Data points represent the mean values of
three independent experiments and are expressed as percentage of
control (untreated cells).
0
0
0
s, 4-CH
0
3
); 6.94 (1H, ddd, 5 -H, J
=1.0 Hz); 7.02 (1H, dd, 3 -H,
5
0
,6
0
=7.9 Hz, J
0
5
0
,4
,4
0
=7.7 Hz,
=8.4 Hz,
J
5
0
,3
J
3
0
0

E. V. Stoyanov et al. / Bioorg. Med. Chem. Lett. 12 (2002) 2685–2687
2687
);
J
(
3
0
,5
0
=1.0 Hz); 7.24 (2H, d, 3-, 5-H, J3,2=J5,6=8.1 Hz); 7.49
pound 3g: 3.90* (3H, s, 3-OCH
3
); 3.93* (3H, s, 4-OCH
3
0
1H, ddd, 4 -H, J4
0
0
=8.4 Hz, J
0
0
=7.7 Hz, J
0
0
=1.4 Hz);
3.98* (3H, s, 2-OCH ); 6.74 (1H, d, 5-H, J5,6=8.8 Hz); 6.94
3
,3
4 ,5
4 ,6
0
7
J
6
.56 (2H, d, 2-, 6-H, J2,3=J6,5=8.1 Hz); 7.62 (1H, d, a-H,
a,b=15.5 Hz); 7.91 (1H, d, b-H, Ja,b=15.5 Hz); 7.92 (1H, dd,
(1H, ddd, 5 -H, J
0
5
0
,6
0
=8.1 Hz, J =7.7 Hz, J
0 0
=8.4 Hz, J =0.9 Hz); 7.40 (1H, d,
3 ,5
5
0
,4
0
5 ,3
0 0
=0.9 Hz);
7.02 (1H, dd, 3 -H, J
3
0
,4
0
0
0
0
-H, J6
0
0
=7.9 Hz, J
0
0
=1.4 Hz); 12.87(1H, s, 2 -OH).
6-H, J6,5=8.8 Hz); 7.49 (1H, ddd, 4 -H,
0
J
0
0
=8.4 Hz,
,5
6 ,4
4 ,3
0
Compound 3e: 3.87(3H, s, 4-OCH 3); 6.93 (1H, ddd, 5 -H,
=8.0 Hz, J =7.8 Hz, J =0.8 Hz); 6.95 (2H, d, 3-, 5-
H, J3,2=J5,6=8.8 Hz); 7.02 (1H, dd, 3 -H, J
J
4 ,5
7.92 (1H, dd, 6 -H, J =8.1 Hz, J =1.4 Hz); 8.10 (1H, d,
0
=7.7 Hz, J =1.4 Hz); 7.72 (1H, d, a-H, Ja,b=15.5 Hz);
0
0
4 ,6
0
J
5
0
,6
0
5
0
,4
0
5
0
,3
0
6 ,5 6 ,4
0
0
0
0
0
0
0
0
0
0
=8.4 Hz,
=8.4 Hz,
b-H, Ja,b=15.5 Hz); 12.97(1H, s, 2 -OH); (* HMBC data were
used to assign proton resonances). Compound 3h: 3.06 (6H, s,
3
,4
0
J3
0
0
=0.8 Hz); 7.49 (1H, ddd, 4 -H,
0
J
,5
,5
4 ,3
J
7
J
4
0
0
=7.8 Hz, J
4
,6
0
=1.4 Hz); 7.54 (1H, d, a-H, Ja,b=15.4 Hz);
4-N(CH
3 2
) ); 6.70 (2H, d, 3-, 5-H, J3,2=J5,6=8.8 Hz); 6.92
0
.63 (2H, d, 2-, 6-H, J2,3=J6,5=8.8 Hz); 7.90 (1H, d, b-H,
a,b=15.4 Hz); 7.92 (1H, dd, 6 -H, =8.0 Hz,
=1.4 Hz); 12.93 (1H, s, 2 -OH). Compound 3f: 3.94* (3H,
(1H, ddd, 5 -H, J
5
0
,6
0
=8.6 Hz, J
7.00 (1H, dd, 3 -H, J =8.4 Hz, J
=8.4 Hz, J =7.6 Hz, J
5
0
,4
0
=7.6 Hz, J
=0.9 Hz); 7.46 (1H,
=1.2 Hz); 7.46
5 ,3
0 0
=0.9 Hz);
0
0
J
6
0
,5
0
3
0
,4
0
0 0
3 ,5
0
0
J6
0
0
ddd, 4 -H, J
0
0
0
0
0
0
,4
4 ,3
4 ,5
4 ,6
s, 4-OCH
3
); 3.97* (3H, s, 3-OCH
3
); 6.92 (1H, d, 5-H,
0
(1H, d, a-H,
Ja,b=15.2 Hz); 7.57 (2H, d, 2- 6-H,
J
J5
J3
5,6=8.3 Hz); 6.94 (1H, ddd, 5 -H,
J
5
0
,6
0
=8.0 Hz,
=8.3 Hz,
=0.9 Hz); 7.17 (1H, d, 2-H, J2,6=1.9 Hz); 7.27 (1H, dd, 6-
J2,3=J6,5=8.8 Hz); 7.92 (1H, d, b-H, Ja,b=15.2 Hz); 7.93
0
0
0
0
=1.2 Hz); 13.19 (1H, s, 2 -
6 ,4
0
0
0
=7.7 Hz, J
0
0
=0.9 Hz); 7.02 (1H, dd, 3 -H, J
0
0
(1H, dd, 6 -H, J
OH).
0
0
=8.6 Hz, J
0
,4
,5
5 ,3
3 ,4
6 ,5
0
0
H,
J6,5=8.3 Hz,J6,2=1.9 Hz ); 7.49 (1H, ddd, 4 -H,
14. Denizot, F.; Lang, R. J. Immunol. Meth. 1986, 89, 271.
15. Le Bail, J. C.; Laroche, T.; Marre-Fournier, F.; Habrioux,
G. Cancer Lett. 1998, 133, 101.
16. Le Bail, J. C.; Pouget, C.; Fagnere, C.; Basly, J. P.; Chu-
lia, A. J.; Habrioux, G. Life Sci. 2001, 68, 751.
J
J
6
4
0
,3
0
4 ,5 4 ,6
=8.3 Hz, J =7.7 Hz, J =1.4 Hz); 7.52 (1H, d, a-H,
0 0 0 0
=15.4 Hz); 7.89 (1H, d, b-H, J =15.4 Hz); 7.93 (1H, dd,
a,b
-H, J
a,b
=1.4 Hz); 12.92 (1H, s, 2 -OH); [*
0
0
0
0
=8.0 Hz, J
0
0
6
,5
6
,4
HMBC data were used to assign proton resonances]. Com-