2-R-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones

Article abstract of DOI:10.1007/s10593-005-0102-y

α-(5-Phenyl-1,3,4-thiadiazolyl-2)-6-ethyl-2,4-dihydroxyacetophenone was synthesized by the condensation of 4-ethylresorcinol with 2-cyanomethyl-5-phenyl-1,3,4-thiadiazole. Interaction of the former with carboxylic acid anhydrides and halides and subsequen

Full text of DOI:10.1007/s10593-005-0102-y

Chemistry of Heterocyclic Compounds, Vol. 40, No. 12, 2004
2-R-6-ETHYL-7-HYDROXY-3-(5-PHENYL-
1,3,4-THIADIAZOLYL-2)CHROMONES
T. V. Shokol, V. V. Semenyuchenko, and V. P. Khilya
α-(5-Phenyl-1,3,4-thiadiazolyl-2)-6-ethyl-2,4-dihydroxyacetophenone was synthesized by the
condensation of 4-ethylresorcinol with 2-cyanomethyl-5-phenyl-1,3,4-thiadiazole. Interaction of the
former with carboxylic acid anhydrides and halides and subsequent hydrolysis gave 2-R-6-ethyl-7-
hydroxy-3-(5-phenyl-1,3,4-thiadiazoyl)chromones.
Keywords: 2-R-7-acyloxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones, 2-R-6-ethyl-7-hydroxy-
3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones, α-(5-phenyl-1,3,4-thiadiazolyl-2)-6-ethyl-2,4-dihydroxy-
acetophenone.
3-Hetarylchromones, the synthetic analogs of natural isoflavones, possess a wide range of biological
effects [1-3]. Derivatives of 3-thiazolylchromones have anticancer activity which is increased by the introduction
of a phenyl group into the thiazole ring [4]. It seemed of interest to follow the change in activity on substituting a
carbon atom in the thiazole ring by a heteroatom, in particular nitrogen, i.e., to synthesize the thiadiazole analogs
of isoflavone with a phenyl radical in the thiadiazole ring and to investigate their properties.
2-Cyanomethyl-5-phenyl-1,3,4-thiadiazole (1) was chosen as the starting material for this objective [5].
The 7-dialkylamino-3-(5-phenyl-1,3,4-thiadiazolyl-2)coumarines, isomeric to chromones, were synthesized by
condensation of the starting nitrile 1 with 4-dialkylamino-2-hydroxybenzaldehyde and have found use as yellow-
green fluorescent materials in textiles and plastics [6]. However 3-(5-phenyl-1,3,4-thiadiazolyl-2)-chromones
have not been obtained. An attempt to synthesize 7-hydroxy-3-(-5-phenyl-1,3,4-thiadiazolyl-2)-chromone from
the corresponding 2-hydroxyacetophenone using acetoformic anhydride was reported in the literature, but the
reaction was only carried out qualitatively and the reaction products were not isolated [7].
With the objective of synthesizing the previously unknown 2-R-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-
thiadiazolyl-2)chromones nitrile 1 was used in the Hess reaction with 4-ethylresorcinol and boron trifluoride
etherate to give, after hydrolysis, the key product – α-(5-phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxy-
acetophenone (2) in 55% yield. It should be noted that, in contrast to the thiazole analogs [8,9] the reaction was
carried out at room temperature because heating the reaction mixture led to a considerable decrease in the yield
of the required product (Scheme 1).
1
Compound 2 can exist in keto and enol forms. The presence in the H NMR spectrum, recorded in
deuteroacetone (and also CDCl3 and CD3OD), of a two proton singlet for the methylene group at 5.05 ppm and
only two weak field singlets for the hydroxy groups at 12.13 and 9.75 ppm indicates that compound 2 exists
exclusively in the keto form in these solvents. Of the two hydroxy groups 2-OH, which can form a hydrogen
bond with the oxygen atom of the carbonyl group, absorbs at weaker field, whereas the 4-OH group cannot
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: vikhilya@mail.univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, 1840-1847, December, 2004. Original article
submitted July 11, 2002; revision submitted September 29, 2004.
1588
0009-3122/04/4012-1588©2004 Springer Science+Business Media, Inc.

undergo such an interaction but underwent deuterium exchange on the addition of D2O. The product 2 also exists
1
as the keto form in CDCl3 and CD3OD. When the H NMR spectrum of 2 was recorded in DMSO-d6 both
tautomers were observed as demonstrated by the appearance of a singlet for the methylene group at 6.60 ppm in
addition to the singlet at 4.96 ppm and of a weak field singlet for the enol proton at 13.79 ppm. Doubling of the
signals of the hydroxy groups and the aromatic protons were also observed. According to the integrated
intensities, the tautomeric equilibrium consists of 85% ketone and 15% enol.
Scheme 1
HO
Et
OH
, Et2O · BF3 /HCl
1.
N
N
Ph
CH2CN
S
2. H2O
1
Et
HO
HO
Et
OH
OH
S
S
Ph
Ph
OH
O
N
N
N
2
N
NH2OH HCl
·
Ac2O/Py
(MeO)2SO2/K2CO3
O
Me
C
O
OH
HO
Et
OH
S
Et
S
Ph
OH
N
Ph
N
N
N
N
3
OH
MeO
Et
OMe
5
S
Ph
OH
N
N
4
On acetylation of compound 2 with an equimolar mixture of acetic anhydride and pyridine in the cold
1
the monoacetylated derivative 3 was formed as indicated by the presence in the H NMR spectrum, recorded in
DMSO-d6, along with the signals of the ethyl and aromatic protons, of a three proton singlet of the acetyl group
at 2.71 ppm and a signal of only one OH group (10.29 ppm) in position 2. The weak field singlet of the enolic
proton at 12.76 ppm and the singlet of the methine proton 6.28 ppm, together with the absence of a signal in the
region for methylene protons indicates that the acetoxy derivative 3 in DMSO-d6 solutions exists only in the enol
form in contrast to the starting material 2.
The monomethyl derivative was not obtained when compound 2 was alkylated with an equimolar
amount of dimethyl sulfate in the presence of potassium carbonate in either acetone or benzene solution. In both
cases the reaction went further and the dimethoxy derivative 4 was obtained on the addition of a further mole of
1
dimethyl sulfate. This was confirmed by the appearance in the H NMR spectrum, recorded in deuteroacetone,
1589

of two three proton singlets at 3.87 (CH3O-4) and 4.00 ppm (CH3O-2) and just one weak field singlet at
13.90 ppm which we ascribe to the enol proton. Two singlets at 6.69 and 6.40 ppm were observed in the 6 ppm
region, one of which belongs the methyne proton of the enol and the other to proton H-3. On addition of D2O to
the sample, the signals of the enol and methyne protons are extinguished as a result of deuterium exchange,
while the singlet of the H-3 proton is unaffected (6.42 ppm). Thus, in contrast to the ketone starting material 2,
the dimethoxy derivative 4 exists as the enol form in deuteroacetone.
The oxime 5 was obtained by reaction of the ketone 2 with hydroxylamine hydrochloride in pyridine.
The H NMR spectrum of 5 has three monoprotonic weak field singlets at 11.67 (N-OH), 10.92 (2-OH), and
1
9.45 ppm (4-OH) and a two proton singlet for the methylene group at 4.63 ppm.
Compounds 2, 3, and 5 form chelate complexes with iron(III) chloride with green, blue, and violet colors
respectively.
Reaction of ketone 2 with an excess of trifluoroacetic anhydride or ethyl oxalyl chloride in pyridine did
not stop at the stage of the diacyl derivative but was accompanied by cyclodehydration to give condensation
products. After treatment of the reaction mixture with water 2-trifluoromethyl- or 2-ethoxycarbonyl-6-ethyl-7-
hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (6a,b) respectively were isolated.
TABLE 1. Characteristics of Compounds 2-7
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Recrystallization
solvent
Yield,
%
mp, °С
N
S
2
С18H16N2O3S
C20H18N2O4S
C20H20N2O3S
C18H15N3O3S
C20H13F3N2O3S
C22H18N2O3S
C22H18N2O5S
C20H16N2O3S
C21H18N2O3S
C19H14N2O3S
C22H15F3N2O4S
C24H20N2O6S
C22H18N2O4S
C24H22N2O4S
C21H16N2O4S
C22H16Cl2N2O4S
8.50
8.23
7.58
7.33
7.57
7.62
8.12
7.93
6.53
6.70
6.79
6.63
6.85
6.63
7.85
7.69
7.66
7.40
8.07
8.00
6.22
6.09
6.11
6.03
7.09
6.89
6.53
6.45
7.33
7.14
6.12
5.89
9.64
9.42
8.60
8.38
8.63
8.73
9.19
9.07
7.87
7.66
7.89
7.59
7.83
7.59
8.90
8.80
8.75
8.47
9.30
9.15
7.26
6.93
7.19
6.90
8.06
7.89
7.52
7.38
8.32
8.17
6.97
6.75
239
333
185
222
256
261
282
317
272
316
155
199
188
167
197
193
Ethanol
Ethanol
50
85
63
58
86
82
72
95
84
—*
75
89
86
89
81
89
3
4
Ethyl acetate
Ethyl acetate
Dioxane
5
6a
6b
6c
6d
6e
6f
7a
7b
7d
7e
7f
7g
Dioxane
Ethanol
DMF
DMF
DMF
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
Ethyl acetate
Acetonitrile
_______
* Yield 46 (A) and 71% (B).
1590

For the reaction of compound 2 with succinic anhydride to form 2-(β-carboxyethyl)-6-ethyl-7-hydroxy-
3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6c) only a brief heating until the reagents had dissolved was
necessary. For the condensation of compound 2 with acetic and propionic anhydrides in triethylamine only
heating for solution of 2 is necessary, further heating (in contrast to the thiazole analogs) leads only to
blackening of the product and a decrease in yield. In these cases, in contrast to products 6a-c, treatment of the
reaction mixture with water did not lead to removal of the acyl group at position 7; instead 2-methyl- or 2-ethyl-
substituted 7-acyloxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (7d,e) were formed. The required
7-hydroxy derivatives 6d,e were obtained refluxing the 7-acyloxy derivatives 7d,e for a short time with dilute
sodium hydroxide.
The interaction of ketone 2 with chloracetyl chloride in pyridine occurred extremely vigorously even in
the cold to give a tarry product. Chromatographically pure 7-chloracetoxy-2-chloromethyl-6-ethyl-3-(5-phenyl-
1,3,4-thiadiazolyl-2)chromone (7g) was formed in high yield by refluxing compound 2 with a two fold excess of
chloroacetyl chloride and pyridine in dioxane.
6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6f) was synthesized by two methods: by
heating the initial ketone with ethyl orthoformate and pyridine in the presence of a catalytic amount of piperidine
and by Wilsmeier formylation in the presence of boron trifluoride etherate. In the latter case the reaction goes
practically at room temperature and the product obtained is purer and in much higher yield.
O
R
HO
Et
6'
5'
1.
2.
S
4'
N
N
O
2' 3'
6a–f
2
Ac2O/Py
5 % NaOH
O
1
C
O
R
O
R
N
3.
S
Et
Ph
O
N
7a,b,d–g
O
.
;
(CF3CO)2O
or DMF,
PCl5, BF3 Et2O;
1.
O ; ClCCO Et CH(OEt)3 / Py
;
2
O
O
2.
3.
;
H2O
O
O
,
Ac2O (EtCO)2O/Et3N or
ClCH2COCl, Py /
6 a R = CF3, b R = CO2Et, c R = CH2CH2COOH, d R = Me, e R = Et, f R = H; 7a R = CF3,
R1 = Me; b R = CO2Et, R1 = Me; d R = R1 = Me; e R = R1 = Et; f R = H, R1 = Me;
g R = R1 = CH2Cl
The 7-hydroxychromones 6a,b,f are easily acylated with acetic anhydride in pyridine in the cold to give
the 7-acetoxy derivatives 7a, b, f in high yield. However acylation of product 6c under the same conditions was
unsuccessful.
1591

TABLE 2. 1H NMR Spectra of Compounds 2-7
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
2
1.25 (3H, t, J = 7, CH3); 2.65 (2H, q, J = 7, CH2CH3); 5.06 (2H, s, CH2C(O));
6.43 (1H, s, H-3); 7.57 (3H, m, HPh-3',4',5'); 7.93 (1H, s, 6-H); 8.04 (2H, m, HPh-2',6');
9.75 (1H, s, OH-4); 12.13 (1H, s, OH-2)
3
4
5
1.18 (3H, t, J = 7, CH3CH2); 2.53 (2H, q, J = 7, CH2CH3); 2.71 (3H, s, CH3C(O)O);
6.28 (1H, s, =CH); 7.39 (1H, s, H-3); 7.57 (3H, m, HPh-3',4',5'); 7.89 (2H, d, J = 7,
HPh-2',6'); 8.31 (1H, s, H-6); 10.29 (1H, s, OH-2); 12.76 (1H, s, HO–C=)
1.16 (3H, t, J = 7, CH3CH2); 2.54 (2H, q, J = 7, CH2CH3); 3.87 (3H, s, CH3O-4);
4.00 (3H, s, CH3O-2); 6.40 (1H, s, H-3); 6.69 (1H, s, =CH); 7.56 (3H, m, HPh-3',4',5');
7.73 (1H, s, H-6); 7.89 (2H, m, HPh-2',6'); 13.90 (1H, s, HO–C=)
1.14 (3H, t, J = 7, CH3); 2.54 (2H, q, J = 7, CH2CH3); 4.63 (2H, s, CH2–C=NOH);
6.28 (1H, s, H-3); 7.29 (1H, s, H-6); 7.49 (3H, m, HPh-3',4',5'); 7.89 (2H, m, HPh-2',6');
9.45 (1H, s, OH-4); 10.92 (1H, s, OH-2); 11.67 (1H, s, N–OH)
6a
6b
1.24 (3H, t, J = 7, CH3); 2.69 (2H, q, J = 7, CH2); 6.99 (1H, s, H-8);
7.57 (3H, m, HPh-3',4',5'); 7.84 (1H, s, H-5); 8.06 (2H, m, HPh-2',6'); 11.25 (1H, s, OH)
1.26 (3H, t, J = 7, CH2CH3-6); 1.32 (3H, t, J = 7, CO2CH2CH3-2);
2.71 (2H, q, J = 7, CH2CH3-6); 4.24 (2H, q, J = 7, CO2CH2CH3-2); 6.99 (1H, s, H-8);
7.56 (3H, m, HPh-3',4',5'); 7.89 (1H, s, H-5); 8.04 (2H, m, HPh-2',6'); 11.12 (1H, s, OH)
6c
1.25 (3H, t, J = 7, CH2CH3-6); 2.70 (2H, q, J = 7, CH2CH3-6); 2.83 (2H, t, J = 7,
CH2CH2–COOH-2); 3.66 (2H, t, J = 7, CH2CH2COOH-2); 6.90 (1H, s, H-8);
7.53 (3H, m, HPh-3',4',5'); 7.84 (1H, s, H-5); 8.03 (2H, m, HPh-2',6'); 10.88 (1H, s, OH);
12.27 (1H, br. s, COOH)
6d
6e
6f
1.26 (3H, t, J = 7, CH2CH3-6); 2.67 (2H, q, J = 7, CH2CH3-6); 3.04 (3H, s, CH3-2);
6.92 (1H, s, H-8); 7.52 (3H, m, HPh-3',4',5'); 7.84 (1H, s, H-5); 8.02 (2H, m, HPh-2',6');
10.82 (1H, s, OH)
1.25 (3H, t, J = 7, CH2CH3-6); 1.46 (3H, t, J = 7, CH2CH3-2); 2.67 (2H, q, J = 7,
CH2CH3-6); 3.44 (2H, q, J = 7, CH2CH3-2); 6.92 (1H, s, H-8);
7.52 (3H, m, HPh-3',4',5'); 7.83 (1H, s, H-5); 8.03 (2H, m, HPh-2',6'); 10.85 (1H, s, OH)
1.25 (3H, t, J = 7, CH3); 2.67 (2H, q, J = 7, CH2); 6.98 (1H, s, H-8);
7.53 (3H, m, HPh-3',4',5'); 7.89 (1H, s, H-5); 8.02 (2H, m, HPh-2',6'); 9.29 (1H, s, H-2);
10.94 (1H, s, OH)
7a
7b
1.25 (3H, t, J = 7, CH2CH3-6); 2.39 (3H, s, CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6);
7.58 (3H, m, HPh-3',4',5'); 7.68 (1H, s, H-8); 8.07 (3H, m, H-5 and HPh-2',6')
1.26 (3H, t, J = 7, CH2CH3-6); 1.32 (3H, t, J = 7, CO2CH2CH3-2); 2.39 (3H, s,
CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6); 4.45 (2H, q, J = 7, CO2CH2CH3-2);
7.56 (3H, m, HPh-3',4',5'); 7.63 (1H, s, H-8); 8.06 (2H, m, HPh-2',6'); 8.12 (1H, s, H-5)
7d
7e
7f
1.26 (3H, t, J = 7, CH2CH3-6); 2.38 (3H, s, CH3C(O)O-7); 2.69 (2H, q, J = 7, CH2CH3-6);
3.06 (3H, s, CH3-2); 7.51 (1H, s, H-8); 7.55 (3H, m, HPh-3',4',5'); 8.04 (2H, m, HPh-2',6');
8.08 (1H, s, H-5)
1.25 (6H, t, J = 7, CH2CH3-6 and CH3CH2C(O)O-7); 1.46 (3H, t, J = 7, CH2CH3-2);
2.70 (4H, m, CH2CH3-6 and CH3CH2C(O)O-7); 3.46 (2H, q, J = 7, CH2CH3-2);
7.51 (1H, s, H-8); 7.55 (3H, m, HPh-3',4',5'); 8.02 (2H, m, HPh-2',6'); 8.07 (1H, s, H-5)
1.27 (3H, t, J = 7, CH2CH3-6); 2.38 (3H, s, CH3C(O)O-7); 2.68 (2H, q, J = 7, CH2CH3-6);
7.53 (3H, m, HPh-3',4',5'); 7.59 (1H, s, H-8); 8.03 (2H, m, HPh-2',6'); 8.13 (1H, s, H-5);
9.44 (1H, s, H-2)
7g
1.28 (3H, t, J = 7, CH2CH3-6); 2.73 (2H, q, J = 7, CH2CH3-6); 4.70 (2H, s,
ClCH2C(O)O-7); 5.51 (2H, s, CH2Cl-2); 7.56 (3H, m, HPh-3',4',5'); 7.72 (1H, s, H-8);
8.07 (2H, m, HPh-2',6'); 8.14 (1H, s, H-5)
_______
* Spectra were recorded in deuteroacetone (compounds 2 and 4) and DMSO-
d6 (the rest).
The chromones 6 are colorless high melting compounds. In their 1H NMR spectra there are signals of the
ethyl group protons at position 6, signals of the aromatic protons of the phenyl groups, singlets of the aromatic
protons of chromone H-8 (6.90-6.99 ppm and H-5 (7.83-7.89 ppm), a weak field singlet of the 7-OH group in
the 10.82-11.25 ppm range, and also for the corresponding substituents at position 2 (Table 2).
1592

The stretching vibrations of the C=O groups of the chromone ring were observed in the range 1635-1610
cm-1 in their IR spectra.
In the 1H NMR spectra of the 7-acetoxy derivatives 7a,b,d,f the weak field singlet s missing and a three
proton singlet of the acetoxy groups appears in the 2.38-2.39 ppm range. In the spectrum of the 7-propionyl
derivative 7e the signals of this group and of the ethyl group in position 6 overlap, but the signals of the
2-CH2CH3 group appear at weaker field. The 1H NMR spectrum of compound 7g is characterised by two singlets
for the methylene groups of the 7-chloracetoxy group at 4.70 ppm and of the 2-CH2Cl group at 5.51 ppm. In the
IR spectra of the 7-acyloxy compounds 7 the C=O stretch of the chromone ring occurs at 1640-1650 cm-1 and
that for the acyl groups in the 1750-1770 cm-1 region.
Thus starting from α-(5-phenyl-1,3,4-thiadiazolyl-2)-2,4-dihydroxy-5-acetophenone a series of
7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)-6-ethylchromones with different positions at position 2 and their
7-acyloxy derivatives have been synthesized.
EXPERIMENTAL
The purity of the compounds synthesized was monitored by TLC on Silufol UV-254 strips with 9:1
1
chloroform as eluant. H NMR spectra were recorded on a Mercury 400 (Varian) (400 MHz) machine and IR
spectra of KBr discs on a Pye-Unicam SP 3-300 spectrophotometer.
1
The characteristics of compounds are given in Table 1 and their H NMR spectra in Table 2.
α-(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxyacetophenone (2). A stream of dry hydrogen
chloride was passed through a stirred suspension of 2-cyanomethyl-5-phenyl-1,3,4-thiadiazole (1) (20.1 g,
100 mmol) in borontrifluoride etherate (100 ml) for 6 h at room temperature. After 1 day the reaction mixture
was added in portions to hot water (700 ml) and was refluxed for 3 h with 1 ml of sulphuric acid.. The precipitate
which formed was filtered hot. The crude product was reprecipitated from 5% sodium hydroxide solution with
20% acetic acid and was then refluxed in ethanol.
α-(5-Phenyl-1,3,4-thiadiazolyl-2)-4-acetoxy-5-ethyl-2-hydroxyacetophenone (3). Acetic anhydride
(0.2 g, 2 mmol) was added to a solution of ketone 2 (0.68 g, 2 mmol) in pyridine (4 ml). The mixture was kept in
a refrigerator for 48 h and the precipitate which formed was filtered off.
α-(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dimethoxyacetophenone (4). A mixture of ketone 2
(0.34 g, 1 mmol), freshly dried potassium carbonate (0.7 g, 4.5 mmol), and dimethyl sulfate (0.14 g, 1.1 mmol)
was refluxed for 6 h in benzene or acetone. More dimethyl sulfate (0.14 g, 1.1 mol) was then added and the
mixture was refluxed for further hour. The course of the reaction was monitored by TLC. The potassium
carbonate was filtered off and the mother liquor evaporated.
α-(5-Phenyl-1,3,4-thiadiazolyl-2)-5-ethyl-2,4-dihydroxyacetophenone oxime (5). A solution of
ketone 2 (1.02 g, 3 mmol) and hydroxylamine hydrochloride (0.63 g, 9 mmol)in absolute pyridine was refluxed
for 1 h and was then kept at room temperature for 12 h. Th reaction mixture was poured into water (100 ml) and
the water was changed until the oil formed did not crystallize and the residue was then filtered.
6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)-2-trifluoromethylchromone (6a). Trifluoro-
acetic anhydride (4.2 g, 20 mmol) was added dropwise to a solution of ketone (2) (1.7 g, 5 mmol) in pyridine (10
ml) cooled to 0°C. The mixture was kept at room temperature for 48 h, poured into ice water (100 ml), and the
precipitate was filtered off.
2-Ethoxy-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6b) was synthesized
analogously from ketone 2 (1.7 g, 5 mmol) and ethyl oxalyl chloride (1.56 g, 11.4 mmol).
2-(β-Carboxyethyl)-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6c). A mixture of
ketone 2 (1.7 g, 5 mmol) and succinic anhydride (3.5 g, 30 mmol) in pyridine (5 ml, 60 mmol) was heated
rapidly until all had dissolved and was then kept at room temperature. After 12 h the precipitate was filtered off,
washed with methanol, transferred into water (50 ml), filtered, and washed with water and methanol.
1593

2-Alkyl-7-alkoxy-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (7d,e). A mixture of ketone 2
(1.7 g, 5 mmol), triethylamine (2.52 g, 25 mmol), and acetic or propionic anhydride (25 mmol) was rapidly
heated until all had dissolved and was then kept at room temperature for 12 h. The product was isolated as for
6c.
2-Alkyl-6-ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromones (6d,e). A 5% solution of
sodium hydroxide (1 ml) and water (25 ml) were added to a solution of the corresponding 7-alkoxy derivative
7d,e (1 mmol) in ethanol (50 ml). The mixture was refluxed for 5 min, more water (25 ml) was added, the
mixture was cooled, neutralized to pH 7 with hydrochloric acid, and the precipitate was filtered off.
6-Ethyl-7-hydroxy-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (6f). A. Piperidine (3 drops) was
added to a solution ketone 2 (0.68 g, 2 mmol) and ethyl orthoformate (2.1g, 12 mmol) in pyridine (4 ml) and the
mixture was heated at 100°C for 45 min. . The mixture was cooled , the precipitate was filtered off an washed
with water. Yield 0.32 g (46%).
B. Boron trifluoride etherate (4.23 g, 30 mmol) was added dropwise to a stirred suspension of ketone 2
(1.7 g, 5 mmol) in DMF (7.3 g, 0.1 mmol), then phosphorus pentachloride (1.25 g, 6 mmol) was added in
portions, and the mixture was kept at 50°C for 15 min.. The mixture was poured into water (10 ml), refluxed for
15 min, cooled and the precipitate was filtered off. Yield 1.24 g (71%).
2-R-7-Acetoxy-6-ethyl-3-(5-phenyl-1,2,4-thiadiazolyl-2)chromones (7a,b,f). The corresponding
7-hydroxyproduct 6a,b,f (2 mmol) was dissolved in a mixture of pyridine (2 ml) and acetic anhydride (0.82 g,
8 mmol) and kept at room temperature for 24 h. The precipitate was filtered off and washed with methanol and
water.
7-Chloracetoxy-2-chloromethyl-6-ethyl-3-(5-phenyl-1,3,4-thiadiazolyl-2)chromone (7g). Pyridine
(0.34 g ,4.4 mmol) and chloroacetyl chloride (0.5 g, 4.4 mmol) were added to a solution of ketone 2 (0.68 g,
2 mmol) in absolute dioxane (15 ml) and the mixture was refluxed for 6 h. The mixture was cooled, the
precipitate was filtered off, the mother liquor was evaporated, treated with water and an additional amount of
product was filtered off.
REFERENCES
1.
A. L. Kazakov, V. P. Khilya, V. V. Mezheritskii, and Yu. Litkei, Natural and Modified Isoflavonoids [in
Russian]. Izd-vo Rost. Un-ta, (1985).
2.
3.
4.
5.
6.
7.
8.
N. V. Gorbulenko and V. P. Khilya, Ukr. Khim. Zhurn., 60, No. 1, 79 (1994).
M. S. Frasinyuk and V. P. Khilya, Khim. Geterotsikl. Soedin. 3 (1999).
V. P. Khilya, L. G. Grishko, and D. V. Vikhman, Khim.-Pharm. Zhurn., 10, No. 8, 74 (1976).
H. Eilingsfeld, Chem. Ber., 98, 1308 (1965).
M. Patsch and C. Vamvakaris, Ger. Offen., 2529434; Chem. Abstr., 86, 122953 (1977).
V. G. Pivovarenko and V. P, Khilya, Khim. Geterotsikl. Soedin., 625 (1991).
V. P. Khilya, V. Sabo, L. G. Grishko, D. V. Vikhman, and F. S. Babichev, Zh. Org. Khim., 9, 2561
(1973).
9.
V. P. Khilya, T. M. Tkachuk, I. P. Kupchevskaya, and G. M. Golubushina, DAN UkrSSR, Ser B., No. 5,
61 (1980).
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