Synthesis of 1-phenyl-3-(chromon-3-YL)-2-propen-1-one derivatives: A new group of biologically active compounds

Full text of DOI:10.1023/A:1020828607049

Pharmaceutical Chemistry Journal
Vol. 36, No. 6, 2002
SYNTHESIS OF 1-PHENYL-3-(CHROMON-3-YL)-2-PROPEN-1-ONE
DERIVATIVES: A NEW GROUP OF BIOLOGICALLY ACTIVE COMPOUNDS
1
1
1
V. A. Tuskaev, É. T. Oganesyan, and S. Kh. Mutsueva
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 6, pp. 27 – 29, June, 2002.
Original article submitted January 8, 2002.
4
R
There are numerous published data showing evidence of
a broad spectrum of pharmacological activity inherent in
3
R
O
5
R
7
2
3
1
,3-diphenylpropenone (chalcone) derivatives [1]. By substi-
tuting the residues of various heterocycles for one or both
benzene nuclei in the chalcone molecule, it is possible not
only to introduce an additional pharmacophore into the base
structure, but to modify more significantly (as compared to
simple functionalization of the benzene nucleus) the charac-
ter of electron density distribution on the propenone frag-
ment. In our opinion, selection of the chromon-3- yl residue
can simultaneously increase the antiallergic activity and de-
crease the toxicity of chalcone derivatives [2 – 4].
2
R
H C
3
5
1
R
O
O
I –XVI
1
5
With substituents R – R listed in Table 1.
A conventional method for the synthesis of chalcones
employs the base-catalyzed Claisen – Schmidt condensation.
We have used an alternative variant of the reaction between
reagents offered by the acid catalysis. The synthesis was con-
ducted in anhydrous acetic acid in the presence of a catalytic
amount of perchloric acid (method A). Under these condi-
tions, the reactions of 3-formyl-6-methylchromone with sub-
stituted acetophenones yield chalcones I – XI (Table 1).
In accordance with this prognosis, we have synthesized a
series of 1-phenyl-3-(6-methylchromon-3-yl)-2-propen-1-one
derivatives (I – XVI) of the general structural formula
1
Pyatigorsk State Pharmaceutical Academy, Pyatigorsk, Russia.
TABLE 1. The Yields and Some Physicochemical Properties of 1-Phenyl-3-(6-methylchromon-3-yl)-2-propen-1-one Derivatives
1
2
3
4
5
IR spectrum
vaseline oil): n, cm
Compound
R
R
R
R
R
M.p., °C
Yield, %
– 1
(
I
H
CH
H
H
H
H
CH
Ph
H
H
H
H
163 – 164
181 – 182
193 – 195
239 – 240
205 – 207
176 – 177
159 – 161
195 – 197
225 – 226
204 – 205
253 – 254
196 – 197
208 – 209
211 – 213
243 – 244
131 – 132
73
75
62
54
48
62
76
71
85
78
82
63
65
68
73
58
1665, 1630, 1595, 1010
1666, 1640, 1600, 980
1670, 1630, 1590, 1005
1670, 1610, 1570, 985
1665, 1630, 1600, 990
1660, 1640, 1600, 990
1670, 1635, 1600, 990
1670, 1630.1600, 985
1665, 1640, 1605, 980
1670, 1595, 1530, 1010
1670, 1630, 1590, 985
1653, 1613, 987
II
3
3
III
H
H
H
IV
H
H
OH
OH
OCH
F
H
H
V
H
t-Bu
H
t-Bu
H
H
VI
H
3
H
VII
VIII
IX
H
H
H
H
H
H
Cl
H
H
H
Cl
H
Cl
H
H
X
H
Br
H
H
XI
H
H
NO
H
2
H
H
XII
XIII
XIV
XV
XVI
OH
OH
OH
OH
OH
H
H
H
H
H
CH
3
H
1653, 990
H
H
OCH
Cl
3
H
1626, 1600, 980
H
H
H
1640, 1627, 974
H
H
H
CH
3
1653, 1627, 1600
309
0
091-150X/02/3606-0309$27.00 © 2002 Plenum Publishing Corporation

3
10
V. A. Tuskaev et al.
Since the endocyclic carbonyl group of 3-formylchromo-
of the carbonyl group in the propenone fragment. As is
known, the introduction of electron donor substituents at po-
sitions 4 or 4¢ of the chalcone molecule leads to a shift of the
electron density toward the carbonyl group and decreases po-
larization of this group, which is accompanied by a decrease
in the frequency and integral intensity of the stretching vibra-
tions n(C=O); electron acceptors substituted at the same po-
sitions produce the opposite effect [8]. This behavior was ob-
served for the absorption band in the region of
1670 – 1650 cm 1.
ne is a stronger acceptor of proton than is the formyl group
occurring in the side chain [5], we may suggest that an active
intermediate in the acid-catalyzed reactions of chromone-
3
-carboxaldehyde with acetophenones is the pyrylium salts.
In connection with this, we have studied the interaction of
the reagents in a mixture of triethylorthoformate and 70%
perchloric acid. This reaction proceeds with the formation of
perchlorates of 3-(1-(R-benzoyl)-2-ethylene)-4-ethoxy-6-
methylchromylium salts, the hydrolysis of which leads with
a quantitative yield to the target products (method B). This
method was used for the synthesis of chalcones I, II, VI,
VIII, and XI.
–
The stretching vibrations of the carbonyl group in the
chromone cycle were manifested at 1640 – 1620 cm – 1. This
decrease in the n(C=O) frequency as compared to the value
–
1
Our attempts at conducting the condensation of
-formylchromone with ortho-hydroxyacetophenones by
(1660 cm ) in unsubstituted chromone can be explained by
the increase in contribution of the betaine pyrylium moiety to
the ground state of the chromone molecule.
3
method A were unsuccessful, apparently because of the de-
crease in the nucleophilicity of ketone as the result of forma-
tion of an intramolecular hydrogen bond. Using method B
leads to the formation of cyclization products, 2- (6-methyl-
chromon-3-yl)chromones. The method for the synthesis of
chromone analogs of ortho-hydroxychalcone described in [6]
is based on the dimerization of 2,3-unsubstituted chromones
in an alkaline medium. Unfortunately, this method is charac-
terized by the limited possibility of varying substituents
–
1
The intense band in the region of 1600 cm was attrib-
uted to the stretching vibrations of the vinylene group of the
propenone fragment. The medium-intensity band in the re-
–
1
gion of 1000 – 980 cm , characteristic of the out-of-plane
bending vibrations of disubstituted ethylene derivatives, is
evidence of the transoidal configuration of the synthesized
compounds. The intensity of the band due to the stretching
vibrations of an exocyclic double bond was significantly
greater as compared to the n(C=O) intensity, which is evi-
dence in favor of the s-cis arrangement of the carbonyl and
vinylene groups.
1
5
R – R , which is explained by certain features of the reac-
tion chemistry.
In this context, we decided to convert the initial
-hydroxyacetophenones into 2,2-difluoro-4-methylbenzo-
e]-1,3,2-dioxaborine derivatives [7]. Reactions of these de-
rivatives with 6-methylchromone-3-carboxaldehyde in acetic
acetic led to a quantitative yield of 1-(6-methylchromon-3-
yl)-2-(2,2-difluorobenzo-[e]-1,3,2-dioxaborin-4-yl)ethylene
derivatives. Treatment of the latter compounds with sodium
hydrocarbonate in ethanol allowed us to obtain the target
products XII – XVI (method C).
1
The H NMR spectra of the synthesized compounds con-
2
[
tain two doublets in the intervals of 8.6 – 8.7 and
7.4 – 7.5 ppm, which is a manifestation of the AB system of
vinylene protons. The value of the spin – spin coupling con-
stant, Jab = 15.5 ± 0.3 Hz (typical of the trans-disubstituted
ethylenes), is indicative of the E-configuration of the
chromone analogs of chalcone.
O
R 5
4
R
5
R
4
R
O
BF Et O
O
B
3
2
R
+
O
–
C H ONa
AcOH
F
F
2
5
OH
2
O
CH3
O
O
O
O
O
R
R
O
OC H
2
5
OC H5
O
2
R
O
O
5
R
R
AcOH/H+
C H O
O
2
5
4
R
C H O
O
2
5
O
B
+
O
–
F
O
O
O
F
R
R
O
O
4
OH
R
CH3
Me CO/NaHCO3
2
5
R
OH
In the IR spectra of the synthesized compounds, the
O
highest frequency band in the characteristic absorption range
of 1700 – 1500 cm – 1 was assigned to stretching vibrations
XII – XVI

Synthesis of 1-Phenyl-3-(chromon-3-yl)-2-propen-1-one derivatives
311
As is known, the chemical shifts of olefin protons in 4,4¢-
The initial acetophenones were synthesized by acylating
disubstituted chalcones depend linearly on the electron prop-
erties of subsitituents and are described by the Hammett
equation [1]. However, variation of substituents in the ben-
zene ring of compounds I – XI did not significantly influence
the chemical shifts of olefin protons, which is evidence of the
weak electron interaction in the 1-phenylpropenone frag-
ment. This can be explained by the phenyl ring being dis-
placed out of the plane of the molecule.
benzenes according to the Friedel – Crafts reaction [10];
6-methylchromone-3-carboxaldehyde was obtained as de-
scribed in [11].
1-Phenyl-3-(6-methylchromon-3-yl)-2-propen-1-one
derivatives (I – XI).
Method A. To a mixture of 1.88 g (10 mmole) of
6-methylchromone-3-carboxaldehyde and 10 mmole of the
corresponding acetophenone, dissolved on heating in 10 ml
of glacial acetic acid, was added 0.03 ml of a 70% perchloric
acid solution. The reaction mixture was heated for
30 – 60 min at 80 – 90°C and cooled. The precipitate was
separated by filtration and washed with 20 ml of hexane. The
obtained ketone was recrystallized from n-butanol or ben-
zene.
The proton in position 2 of the chromone nucleus shows
up as a narrow singlet in the region of 8.1 – 8.2 ppm. Such a
significant descreening can be explained by the localization
at C of a positive charge appearing due to the electron ac-
2
ceptor properties of the substituent in position 3.
The signal from proton at C is also shifted toward
5
Method B. To a mixture of 1.88 g (10 mmole) of 6-me-
thylchromone-3-carboxaldehyde and 10 mmole of the corre-
sponding acetophenone, dissolved in 10 ml of freshly dis-
tilled triethylorthoformate, was added 1 ml of a 70%
perchloric acid solution. The reaction mixture was heated for
weaker fields (d = 8.06 – 8.21 ppm), which is explained by
the character of the electron density distribution in the mole-
cule and by the magnetic anisotropy of the peri-carbonyl
group of the heterocycle. This signal has the form of a dou-
blet with meta constants J = 2.6 Hz.
Table 2 presents a computer-predicted pharmacological
activity spectrum of the synthesized compounds. The prog-
nosis was obtained using the PASS program (Version 4.2,
15 min on a water bath and allowed to stand for 1 – 3 h at
room temperature. The precipitate was separated by filtration
and washed with 30 ml of dry diethyl ether. The obtained
3-(1-(R-benzoyl)-2-ethylene)-4-ethoxy-6-methylchromylium
1
996). The high probability (79 – 92%) of antiallergic activ-
perchlorate was crystallized from glacial acetic acid. To 1.0 g
of this perchlorate dissolved on heating in 15 ml of acetone
was added dropwise 5 ml of a 20% aqueous solution of so-
dium acetate. The target chalcone, which precipitated on
cooling, was separated by filtration, washed with water,
dried, and recrystallized from toluene.
ity manifestations confirms the expediency of combining the
benz-g-pyrone and 1-phenylpropen-2-one fragments in the
same structure. The probability of manifestation of histamine
receptor blocking activity is much lower (26 – 51%). In our
opinion, of special interest is the prediction of GABAergic
and tranquilizer properties. Taking into account that the syn-
thesized compounds involve no nitrogen-containing substitu-
ents, numerical estimates of the probability of manifestation
of these activity types are rather high (67 – 73 and 30 – 47%,
respectively). The ability of flavones (chrysin, apigenin, and
related synthetic derivatives) to interact with benzodiazepine
receptors of the brain and produce an anxiolytic effect com-
parable with that of diazepam [9] is known. This is also in-
dicative of the promising search for new neurotropic agents
in the series of 1-phenyl-3-(6-methylchromon-3-yl)-2-pro-
pen-1-one derivatives.
1-(2-Hydroxyphenyl)-3-(6-methylchromon-3-yl)-2-pr
open-1-one derivatives (XII – XVI).
TABLE 2. Biological Activity Spectrum Predicted for 1-Phenyl-
3-(6-methylchromon-3-yl)-2-propen-1-one Derivatives
Probability of activity manifestations, %
Respira-
Antial- GABA- Antioxi- Analep- Tranquil- tory Antihis-
Com-
pound
lergic
ergic
dant
tic
izer
analep- tamine
tic
EXPERIMENTAL PART
I
II
III
IV
V
VI
VII
VIII
IX
92
92
85
87
88
90
84
86
77
81
86
88
88
84
79
71
72
72
66
67
63
68
75
68
70
70
73
69
69
65
67
64
51
51
51
63
65
49
33
36
27
39
46
64
64
63
39
46
65
65
55
66
61
65
58
58
51
54
59
61
61
58
48
67
42
42
30
28
28
40
47
35
36
36
35
25
25
–
60
60
50
60
55
62
53
54
44
49
55
55
55
54
39
59
51
51
31
42
43
49
36
42
28
37
35
40
40
36
26
27
The 1H NMR spectra were measured on a Bruker
WP-300 spectrometer with a working frequency of 300
MHz. The samples were studied as solutions in deuterated
chloroform with a concentration of 0.3 – 0.5 mole/liter; the
internal standard was HMDS or CDCl . The IR absorption
3
spectra in a 600 – 3600 cm – 1 range were recorded on
Specord 74-IR and Specord 75-IR spectrophotometers using
samples prepared as suspensions in Vaseline oil. The course
of reactions was monitored and the purity of the reaction
products was checked by TLC on Silufol UV-254 plates
eluted in toluene – hexane (9 : 1), butanol – acetic acid – wa-
ter (5 : 3 : 2), and toluene – ethanol (9 : 1) systems; the spots
were revealed under UV irradiation.
X
XI
XII
XIII
XIV
XV
XVI
30
–

3
12
V. A. Tuskaev et al.
Method C. To 1.88 g (10 mmole) of 6-methylchro-
2. É. T. Oganesyan, A. S. Saraf, A. V. Simonyan, et al.,
mone-3-carboxaldehyde dissolved on heating in 15 ml of
acetic acid was added 10 mmole of the corresponding
Khim.-Farm. Zh., 25(8), 18 – 24 (1991).
3
4
5
6
. V. V. Kulach,
N. I. Nikul’hsina,
and
V. I. Ishchenko,
2
,2-difluoro-4-methylbenzo-[e]-1,3,2-dioxaborine derivative
and the reaction mixture was heated for 30 – 60 min at
0 – 90°C and cooled. The precipitated 1-(6-methylchro-
Khim.-Farm. Zh., 22(8), 1018 – 1025 (1988).
. É. T. Oganesyan, V. A. Tuskaev, and L. S. Sarkisov, Khim.-
8
Farm. Zh., 28(12), 17 – 23 (1994).
mon-3-yl)-2-(2,2-difluoro-4-methylbenzo-[e]-1,3,2-dioxabor
in-4-yl)ethylene was separated by filtration, washed with
ether, and dissolved in 20 ml of ethanol. To the hot solution
was added dropwise 5 ml of a 20% aqueous solution of so-
dium hydrocarbonate. The target compound precipitating on
cooling was separated by filtration, washed with water, dried,
and recrystallized from ethanol.
. V. K. Polyakov, Yu. N. Surov, R. G. Shevtsova, et al., Zh.
Obshch. Khim., 48(10), 2273 – 2227 (1978).
. R. R. Soni and K. N. Trivedi, Indian J. of Chem., 27B (9),
8
11 – 813 (1988).
7. M. Yora, T. Hogwerg, and S. Drake, Acta Chem. Scand., 38(5),
59 – 366 (1984).
3
The biological activity spectrum was predicted using the
PASS 4.2 (1996) program developed by V. V. Poroikov and
D. A. Filimonov.
8
. S. V. Tsukerman, Yu. N. Surov, and V. F. Lavrushin, Zh. Org.
Khim., 31(3), 524 – 529 (1968).
9. A. C. Paladini, J. Pharm. Pharmacol., 50(21), 21 (1998).
1
0. C. Weygand and F. Hilgetag, Experimental Methods in Organic
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