3-(4-Phenyl-1,2,4-triazol-3-yl)chromones

Article abstract of DOI:10.1007/s10593-006-0011-8

The condensation of 4-phenyl-1,2,4-triazol-3-ylacetonitrile with 2-methyl-, 4-ethylresorcinol, and with pyrogallol gave α-(4-phenyl-1,2,4-triazol-3- yl)-2,4-dihydroxyacetophenones. Upon treatment with acid anhydrides and chlorides and subsequent hydrolysi

Full text of DOI:10.1007/s10593-006-0011-8

Chemistry of Heterocyclic Compounds, Vol. 41, No. 11, 2005
3-(4-PHENYL-1,2,4-TRIAZOL-3-YL)CHROMONES
T. V. Shokol, V. A. Turov, A. V. Turov, N. V. Krivokhizha, V. V. Semenyuchenko,
and V. P. Khilya
The condensation of 4-phenyl-1,2,4-triazol-3-ylacetonitrile with 2-methyl-, 4-ethylresorcinol, and with
pyrogallol gave α-(4-phenyl-1,2,4-triazol-3-yl)-2,4-dihydroxyacetophenones. Upon treatment with acid
anhydrides and chlorides and subsequent hydrolysis these form 7-hydroxy-3-(4-phenyl)-1,2,4-triazol-3-
yl)chromones with different substituents in both the benzene and the pyrone rings.
Keywords: 8-R1-6-R2-2-R3-7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones, α-(4-phenyl-1,2,4-
triazol-3-yl)-3-R1-5-R2-2,4-dihydroxyacetophenones.
3-Hetarylchromones are now a rather broad class of compounds having different biological activity
[1-3]. However, only isolated examples of triazole analogs of isoflavones are known (3-(4H-1,2,4-triazol-3-yl)-
[4, 5], 3-(2H-1,2,3-triazol-4-yl)chromones [6], and 2,3-dihydro-3-(1H-1,2,4-triazol-1-yl)chromones [7]), with
the latter patented as fungicides. The starting materials for their synthesis are the corresponding α-triazolyl-2-
hydroxyacetophenones. 3-(4,5-Dihydro-1H-1,2,4-triazol-5-yl)chromones have been isolated amongst the
products of the 1,3-dipolar cycloaddition of 3-(aryliminomethyl)chromones and C-acetylhydrazinoyl bromides
[8].
With the aim of broadening the scope of triazole analogs of isoflavones we have synthesized a series of
starting α-(4-phenyl-1,2,4-triazol-3-yl)-2,4-dihydroxyacetophenones (1a-c) with different substituents in the
phenyl ring via condensation of 4-phenyl-1,2,4-triazol-3-ylacetonitrile with 2-methyl- and 4-ethylresorcinol and
with pyrogallol. Modified Hoesch reaction conditions were used with boron trifluoride etherate as solvent and
catalyst.
It should be noted that the products 1a,b are obtained in chromatographically pure form and in high
yields (78-80%) (as was found in the case of the condensation with the resorcinol (1d)) but the pyrogallol
derivative 1c was obtained in only 22% yield, very likely due to tarring of the reaction product.
Compounds 1 can exist in the ketone (A) and enolic (B) forms. Rapid recrystallization of compound 1b
1
from ethanol gave a 50% yield of a colorless product, the H NMR spectrum of which (DMSO-d6 solvent)
showed the presence of a two-proton methylene singlet at 4.53 ppm and two low field singlets at 10.49 and
11.68 ppm which are assigned to the hydroxyl groups in the positions 4 and 2 of phenolic ring respectively. Thus
the sample exists in the ketone form A only. After two weeks a light-yellow product is precipitated from the
mother liquor whose 1H NMR spectrum (DMSO-d6) shows both the signal for the methylene group of ketone A
at 4.53 ppm and also signals for a methine proton at 5.29 ppm and enolic proton at 14.09 ppm for the enol form
(B) together with a double set of the remaining signals. Thus, in this case, we have shown the presence of keto-
enol tautomerism with an isomer ratio of 84% (A) to 16% (B) as judged by the integrated intensities of the
signals. With
a
more prolonged crystallization process the enol content of the sample is
__________________________________________________________________________________________
Taras Shevchenko Kiev National University, Kiev 01033, Ukraine; e-mail: vkhilya@mail.univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1676-1684, November, 2005. Original
article submitted December 11, 2003.
0009-3122/05/4111-1411©2005 Springer Science+Business Media, Inc.
1411

R1
HO
R2
OH
1.
,
.
N
N
Et2O BF3 / HCl
CH2CN
N
2. H2O
Ph
R1
R2
HO
OH
OH
HO
R1
Ph
Ph
R2
N
N
N
N
N
OH
O
N
1a–d
B
A
.
NH2–NH2 H2O
.
NH2OH HCl
Et
Et
HO
HO
Ph
Ph
N
N
N
OH
N
N
OH
N
N
OH
N
NH2
3
2
a R1 = Me, R2 = H; b R1 = H, R2 = Et; c R1 = OH, R2 = H; d R1 = R2 = H
increased, 1H NMR showing that 1b exists in DMSO-d6 solution as 32% ketone A and 68% enol B. The isomer
ratio is virtually equal in the less polar deuteroacetone (49% A to 51% B) but in the nonpolar chloroform it is
present only in the keto form A (δCH = 4.28 ppm). In this sample an increase in temperature when recording the
2
1H NMR spectrum in DMSO-d6 from 0°C to 90°C causes the content of the keto form A to increase from 32% to
54% whereas the spectrum of the pure ketone A remains unchanged.
The presence of the keto-enol tautomerism is also observed in the 1H NMR spectra of compounds 1a,c,d
recorded in DMSO-d6. In this solution the products 1a and 1d, recrystallized respectively from ethanol and ethyl
acetate, exist principally in the enol B form (94%) and contain only 6% of the ketone A. The yellow coloring of
these samples is also evidence for the large enol content, in which a greater degree of conjugation of the phenol
and triazole rings is achieved.
1
The H NMR spectrum in DMSO-d6 of the colorless pyrogallol derivative 1c (recrystallized from
aqueous DMF) shows principally the keto form A (87%) and 13% of the enol B. The given data points to a
greater solubility of the enol form B of compounds 1a-d. The rate of interconversion of the tautomers proved to
be quite low and this allowed the isolation of the pure keto form A in the case of the product 1b.
Thus the ratio of the tautomers A and B depends on the temperature, the solvent polarity, and on
duration of the crystallization time.
The IR spectra of compounds 1a-d show strong absorption bands at 3080-3139 cm-1 (stretching
vibrations of the 4-OH) group, 1627-1630 cm-1 (stretching of the carbonyl group), and 1505-1510 cm-1 (triazole
ring).
Compounds 1 undergo typical reactions at the carbonyl group. Treatment of the product 1b with
hydroxylamine hydrochloride in pyridine gives the oxime 2 and with hydrazine hydrate in alcohol the hydrazone
3. The spectra of these compounds were recorded in DMSO-d6 and showed signals for the ethyl group and
1412

aromatic protons (Table 2) together with a typical methylene singlet at 4.16 ppm (oxime 2) to 4.08 ppm
(hydrazone 3). The hydroxyl group protons of the oxime 2 absorb at low field at 9.41 (4-OH), 10.97 (2-OH), and
11.17 ppm (N–OH). In the spectrum of the hydrazone 3 the lowest field signal is the singlet for the 2-OH group
proton at 12.65 ppm together with a two-proton amino group singlet at 6.62 ppm.
The ketones 1a-c react with trifluoroacetic anhydride or ethoxalyl chloride in pyridine in the cold and
cyclize to 6-R2-8-R1-7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones with trifluromethyl (4a,b) or
carbethoxy substituents (5a-c) at position 2 of the molecule.
Treatment of the ketone 1b with acetic anhydride in triethylamine at 130°C and subsequent work up of
the reaction mixture with water gave 7-acetoxy-6-ethyl-2-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone (6b)
which readily hydrolyzed using aqueous alcoholic base to give the target 7-hydroxy derivative 7b. It was not
possible to prepare the pure 7-acetoxy derivatives of 2-methylchromones under the same conditions (A) or in
pyridine at 90-95°C [4] (B) from the ketones 1a,b due to partial hydrolysis when treated with water hence the
dry products underwent acid or base hydrolysis to give the 7-hydroxy-2-methylchromones 7a,d. It should be
noted that change of base or increase in temperature did not affect the yield of compound 7d which was 57%, as
in the study [4].
Ac2O / Py
5% NaOH or HCl
R1
R1
R3
AcO
R2
O
O
R3
HO
O
O
Ph
Ph
Ac2O / Py
1
N
N
R2
N
N
N
N
6b, 9a,b,d, 10b
4a,b, 5a–c, 7a,b,d, 8a–d
O
.
/ Py; DMF, BF3 Et2O, PCl5
1. (CF3CO)2O,
Cl
CO2Et
2. H2O
4a, 5a, 7a–9a R1 = Me, R2 = H; 4b–10b R1 = H, R2 = Et; 5c, 8c R1 = OH, R2 = H;
4a,b R3 = CF3, 5a–c, 10b R3 = CO2Et, 6b, 7a,b,d R3 = Me, 8a–d, 9a,b R3 = H
The 7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones unsubstituted at the position 2 had been
prepared before using the Venkataraman method by refluxing the starting ketone 1d with ethyl orthoformate in
pyridine [4] or by treatment with acetoformic anhydride without a catalyst at room temperature [5]. Since the
chromone 8b prepared by us using the Venkataraman method could not be prepared in the pure state we have
used a Vilsmeier formylation. This method allows the synthesis of the 7-hydroxychromones 8a,c, unsubstituted
in the position 2, and the previously obtained product 8d [4, 5] in good yields over 1 h.
The existence of several functional groups in the target chromones leads to their modification. When
treated with acetic anhydride in pyridine in the cold the 7-hydroxychromones 8a,b,d and 5b form the
corresponding 7-acetoxy derivatives 9a,b,d and 10b. Acid hydrolysis of the ester group in the molecule 5a gave
the 7-hydroxy-8-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone-2-carboxylic acid 11a (Table 1).
Me
COOH
HO
O
Ph
N
H2SO4, AcOH
5a
O
N
N
11a
1413

TABLE 1. Characteristics of Compounds 1-11*
Com-
pound
Empirical
formula
Found, %
Calculated, % N
——————
mp, °С
Yield, %
1a
1b
1c
2
С17H15N3O3
13.77
13.59
12.80
13.00
13.34
13.50
16.67
16.56
20.97
20.76
10.76
10.85
10.73
10.47
10.95
10.74
10.51
10.37
10.77
10.68
11.10
10.79
12.79
12.61
182
244-245
198
78
80
22
91
75
82
60
52
71
86
58
C18H17N3O3
C16H13N3O4
C18H18N4O3
C18H19N5O2
C19H12F3N3O3
C20H14F3N3O3
C21H17N3O5
C22H19N3O5
C20H15N3O6
C22H19N3O4
C19H15N3O3
249-250
187-188
217
3
4a
4b
5a
5b
5c
6b
7a
>300
138
200-201
212
190
206
40 (A),
72 (B)
7b
8a
C20H17N3O3
C18H13N3O3
C19H15N3O3
C17H11N3O4
C20H15N3O4
C21H17N3O4
C24H21N3O6
C19H13N3O5
12.33
12.10
13.11
13.16
12.52
12.61
13.24
13.08
11.81
11.63
11.48
11.19
9.42
9.39
11.36
11.57
>300
147
96
57
68
40
65
59
52
43
8b
8c
225
243
9a
184
9b
10b
11a
196
197-198
242
_______
* Characteristics of compounds 1d, 7d-9d (R1 = R2 = R3 = H) were reported
in [4]. Compounds 1a,b, 3, 5c, 7b-9b were recrystallized from ethanol; 1c,
8a from aqueous DMF; 2 from dioxane; 4a from aqueous ethanol; 4b-5b
from acetonitrile; 5a, 7a from methanol; 8c from 2-propanol; 9a from ether;
10b from ethyl acetate; 11a from acetic acid.
The 8-R1-6-R2-2-R 3-7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones and their acetyl derivatives are
colorless, crystalline materials. Typical features of their 1H NMR spectra are a one-proton triazole 5-H singlet at
8.76-9.29, a five-proton phenyl multiplet in the range 7.38-7.71 ppm, and a low field one-proton 7-OH singlet at
10.31-11.21 ppm for the products 4, 5, 7, 8, 11 and three-proton acetoxy group singlet at 2.30-2.36 ppm for
acetoxy derivatives 6 and 9. The substituents at the position 2 in the synthesized chromones show the following
signals: a singlet H-2 proton in 8 and 9 at 8.53-8.63 and 8.72-8.78 ppm respectively, a three-proton
2-methylchromone singlet at 2.30-2.39 ppm in 7b and 6b, and a three-proton triplet at 1.11-1.14 and two-proton
quartet at 4.21-4.25 ppm corresponding to the ethyl group protons in the 2-carbethoxychromones 5b and 10b.
1414

TABLE 2. 1H NMR Spectroscopic Characteristics of Compounds 1-11*
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1
2
1a
6% A + 94% B: 1.94 (s, 3-CH3) A, 1.97 (s, 3-CH3) B, 4.55 (s, CH2) A, 5.32 (s, CH) B,
6.31 (d, J = 8, H-5) B, 6.40 (d, J = 8, H-5) A, 6.98 (d, J = 8, H-6) B, 7.45 (m, C6H5) A,
7.58 (d, J = 8, H-6) A, 7.65 (m, C6H5) B, 8.61 (s, Htriazole-5) A, 8.80 (s, Htriazole-5) B,
9.69 (s, 4-OH) B, 10.41 (s, 4-OH) A, 12.31 (s, 2-OH) A, 14.12 (br. s, HO–C=) B,
2-OH B exchanged with D2O
1b
A: 1.13 (3H, t, J = 7.5, 5-CH3CH2); 2.47 (2H, q, J = 7.5, 5-CH3CH2);
4.53 (2H, s, CH2C(O)); 6.25 (1H, s, H-3); 7.44 (5H, m, C6H5); 7.52 (1H, s, H-6);
8.58 (1H, s, 5-CHtriazole); 10.49 (1H, s, 4-OH); 11.68 (1H, s, 2-OH)
32% A + 68% B: 1.05 (t, J = 7.5, 5-CH3CH2) B, 1.13 (t, J = 7.5, 5-CH3CH2) A,
2.38 (q, J = 7.5, 5-CH3CH2) B, 2.47 (q, J = 7.5, 5-CH3CH2) A, 4.53 (s, CH2C(O)) A,
5.29 (s, CH) B, 6.19 (s, H-3) B, 6.24 (s, H-3) A, 6.90 (s, H-6) B, 7.47 (m, C6H5) A,
7.51 (s, H-6) A, 7.66 (m, C6H5) B, 8.59 (s, Htriazole-5) A, 8.84 (s, Htriazole-5) B,
9.90 (s, 4-OH) B, 10.47 (s, 4-OH) A, 11.67 (s, 2-OH) A, 14.09 (br. s, HO–C=) B,
2-OH B exchanged with D2O
1c
87% A + 13% B: 4.56 (s, CH2CO) A, 5.34 (s, CH) B, 6.21 (d, J = 8, H-5) B
6.37 (d, J = 8, H-5) A, 6.68 (d, J = 8, H-6) B, 7.27 (d, J = 8, H-6) A, 7.46 (m, C6H5) A,
7.67 (m, C6H5) B, 8.63 (s, 5-CHtriazole) A, 8.85 (s, 5-CHtriazole) B, 10.01 (br. s, 4-OH) A,
11.79 (s, 2-OH) A, remaining protons exchanged with D2O
1d
6% A + 94 % B: 4.53 (s, CH2C(O)) A, 5.32 (s, CH) B, 6.10 (d, J = 1.5, H-3) A,
6.14 (d, J = 1.5, H-3) B, 6.21 (dd, J3,5 = 1.5, J5,6 = 8, H-5) B, 6.35 (dd, J3,5 = 1.5, J5,6 = 8,
H-5) A, 7.13 (d, J = 8, H-6) B, 7.45 (d, J = 8, H-6) A, 7.47 (m, C6H5) A, 7.65 (m, C6H5) B,
8.61 (s, 5-CHtriazole) A, 8.85 (s, 5-CHtriazole) B, 9.89 (br. s, 4-OH) B, 10.50 (br. s, 4-OH) A,
11.75 (s, 2-OH) A, 14.14 (br. s, HO–C=) B, 2-OH exchanged with D2O
2
1.07 (3H, t, J = 7.5, 5-CH3CH2); 2.43 (2H, q, J = 7.5, CH3CH2); 4.16 (2H, s, CH2C(O));
6.26 (1H, s, H-3); 6.99 (1H, s, H-6); 7.53 (5H, s, C6H5); 8.49 (1H, s, 5-CHtriazole);
9.41 (1H, s, 4-OH); 10.97 (1H, s, 2-OH); 11.17 (1H, s, N–OH)
3
0.90 (3H, t, J = 7.5, 5-CH3CH2); 2.16 (2H, q, J = 7.5, 5-CH3CH2); 4.08 (2H, s, CH2C(O));
6.15 (1H, s, H-3); 6.27 (1H, s, H-6); 6.62 (2H, br. s, NH2); 7.59 (5H, m, C6H5);
8.55 (1H, s, 5-CHtriazole); 12.65 (1H, br. s, 2-OH); 4-OH exchanged with D2O
4a
4b
5a
5b
5c
6b
2.25 (3H, s, 8-CH3); 7.06 (1H, d, J = 8, H-6); 7.33 (2H, m, HPh-2',6');
7.73 (3H, m, HPh-3',4',5'); 7.71 (1H, d, J = 8, H-5); 8.91 (1H, s, Htriazole-5);
11.02 (1H, s, 7-OH)
1.20 (3H, t, J = 7.5, 6-CH3CH2); 2.64 (2H, q, J = 7.5, 6-CH3CH2); 6.92 (1H, s, H-8);
7.32 (2H, s, HPh-2',6'); 7.43 (3H, s, HPh-3',4',5'); 7.71 (1H, s, H-5); 8.88 (1H, s, 5-CHtriazole);
11.21 (1H, s, 7-OH)
1.16 (3H, t, J = 7.5, 2-CH3CH2O); 2.27 (3H, s, 8-CH3); 4.24 (2H, q, J = 7.5, 2-CH3CH2O);
7.41 (1H, d, J = 8, H-6); 7.43 (5H, m, C6H5); 7.65 (1H, d, J = 8, H-5);
8.81 (1H, s, Htriazole-5); 10.85 (1H, s, 7-OH)
1.11 (3H, t, J = 7.5, 2-CO2CH2CH3); 1.18 (3H, t, J = 7.5, 6-CH3CH2); 2.62 (2H, q, J = 7.5,
6-CH3CH2); 4.21 (2H, q, J = 7.5, 2-CO2CH2CH3); 6.92 (1H, s, H-8); 7.39 (5H, m, C6H5);
7.64 (1H, s, H-5); 8.87 (1H, s, 5-CHtriazole); 11.10 (1H, s, 7-OH)
1.07 (3H, t, J = 7.5, 2-CO2CH2CH3); 4.21 (2H, q, 2-CO2CH2CH3);
7.08 (1H, d, J = 8, H-6); 7.29 (1H, d, J = 8, H-5); 7.44 (5H, m, C6H5);
9.29 (1H, s, 5-CHtriazole); 7-OH and 8-OH exchanged with D2O
1.17 (3H, t, J = 7.5 6-CH3CH2); 2.35 (3H, s, 7-CH3C(O)O); 2.39 (3H, s, 2-CH3);
2.59 (2H, q, J = 7.5, 6-CH3CH2); 7.38 (1H, s, H-8); 7.42 (5H, m, C6H5); 7.80 (1H, s, H-5);
8.87 (1H, s, 5-CHtriazole
)
7a
7b
2.23 (3H, s, 8-CH3); 2.35 (3H, s, 2-CH3); 6.91 (1H, d, J = 8, H-6); 7.39 (5H, m, C6H5);
7.59 (1H, d, J = 8, H-5); 8.81 (1H, s, 5-CHtriazole); 10.54 (1H, s, 7-OH)
1.19 (3H, t, J = 7.5, 6-CH3CH2); 2.30 (3H, s, 2-CH3); 2.59 (2H, q, J = 7.5, 6-CH3CH2);
6.81 (1H, s, H-8); 7.35 (5H, m, C6H5); 7.57 (1H, s, H-5); 8.77 (1H, s, 5-CHtriazole);
10.66 (1H, s, 7-OH)
7d
8a
2.32 (3H, s, 2-CH3); 6.78 (1H, s, H-8); 6.84 (1H, d, J = 8, H-6); 7.39 (5H, m, C6H5);
7.71 (1H, d, J = 8, H-5); 8.80 (1H, s, 5-CHtriazole); 10.67 (1H, s, 7-OH)
2.25 (3H, s, 8-CH3); 6.91 (1H, d, J = 8, H-6); 7.38 (5H, m, C6H5); 7.59 (1H, d, J = 8, H-5);
8.58 (1H, s, H-2); 8.76 (1H, s, 5-CHtriazole); 10.58 (1H, s, 7-OH)
1415

TABLE 2 (continued)
1
2
8b
1.17 (3H, t, J = 7.5, 6-CH3CH2); 2.60 (2H, q, J = 7.5, 6-CH3CH2); 6.89 (1H, s, H-8);
7.40 (5H, s, C6H5); 7.56 (1H, s, H-5); 8.53 (1H, s, H-2); 8.79 (1H, s, 5-CHtriazole);
10.58 (1H, s, 7-OH)
8c
8d
9a
9b
6.90 (1H, d, J = 8, H-6); 7.23 (1H, d, J = 8, H-5); 7.40 (5H, m, C6H5); 8.63 (1H, s, H-2);
8.81 (1H, s, 5-CHtriazole); 9.48 (1H, s, 8-OH); 10.31 (1H, s, 7-OH)
6.84 (2H, m, H-6 + H-8); 7.39 (5H, m, C6H5); 7.73 (1H, d, J = 8, H-5); 8.54 (1H, s, H-2);
8.76 (1H, s, 5-CHtriazole); 10.71 (1H, s, 7-OH)
2.30 (3H, s, 7-CH3C(O)O); 2.35 (3H, s, 8-CH3); 7.18 (1H, d, J = 8, H-6);
7.42 (5H, m, C6H5); 7.80 (1H, d, H-5); 8.78 (1H, s, H-2); 8.81 (1H, s, 5-CHtriazole
)
1.17 (3H, t, J = 7.5, 6-CH3CH2); 2.35 (3H, s, 7-CH3C(O)O); 2.57 (2H, q, J = 7.5,
6-CH3CH2); 7.41 (5H, m, C6H5); 7.46 (1H, s, H-8); 7.81 (1H, s, H-5); 8.72 (1H, s, H-2);
8.80 (1H, s, 5-CHtriazole
2.32 (3H, s, 7-CH3C(O)O); 7.19 (1H, d, J = 8, H-6); 7.40 (5H, m, C6H5); 7.48 (1H, s, H-8);
7.95 (1H, d, J = 8, H-5); 8.74 (1H, s, H-2); 8.81 (1H, s, 5-CHtriazole
)
9d
)
10b
1.14 (3H, t, J = 7.5, 2-CH3CH2OC(O)); 1.20 (3H, t, J = 7.5, 6-CH3CH2); 2.36 (3H, s,
7-CH3C(O)O); 2.61 (2H, q, J = 7.5, 6-CH3CH2); 4.25 (2H, q, J = 7.5, 2-CH3CH2OC(O));
7.41 (5H, s, C6H5); 7.58 (1H, s, H-8); 7.88 (1H, s, H-5); 8.83 (1H, s, 5-CHtriazole
)
11a
2.27 (3H, s, 8-CH3); 7.00 (1H, d, J = 8, H-6); 7.40 (5H, m, C6H5); 7.66 (1H, d, J = 8, H-5);
8.98 (1H, s, 5-CHtriazole); 10.89 (1H, s, 7-OH); COOH exchanged with D2O
_______
* Spectra recorded in DMSO-d6.
The IR spectra of the target chromones show absorption stretching bands for the cyclic carbonyl group at
1640-1660, the 7-OH group at 3420-3480, and the triazole ring at 1505-1510 cm-1. The strong absorption band at
1770 cm-1 in the IR spectra of the 7-acetoxy derivatives are due to the stretching vibrations of the carbonyl
group.
Hence, based on α-(4-phenyl-1,2,4-triazol-3-yl)-3-R1-5-R2-2,4-dihydroxyacetophenones, we have
synthesized a series of 7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones with differing substituents both in
the benzene and pyrone rings
EXPERIMENTAL
The purity of the synthesized compounds was monitored using TLC on Silufol UV-254 plates eluting
with a mixture of chloroform and methanol (9:1). 1H NMR spectra were recorded using CDCl3 or DMSO-d6 on
a Varian Mercury 400 spectrometer (400 MHz) using TMS as internal standard. IR Spectra were taken for KBr
tablets on a Nexus 475 spectrometer.
α-(4-Phenyl-1,2,4-triazol-3-yl)-3-R1-5-R2-2,4-dihydroxyacetophenones 1a-d. A stream of dry
hydrogen chloride was passed through a stirred solution of 4-phenyl-1,2,4-triazol-3-ylacetonitrile [9] (17 g,
0.1 mol) and resorcinol, 2-methylresorcinol, 4-ethylresorcinol, or pyrogallol (0.1 mol) in boron trifluoride
etherate (100 ml) for 6 h at 50-60°C. After 12 h the mixture was transferred in portions into hot water (0.5 l) and
refluxed for 2 h with 1 ml of sulfuric acid. It was then cooled, neutralized with ammonia solution to pH 4-5, and
the precipitate was filtered off.
α-(Phenyl-1,2,4-triazol-3-yl)-5-ethyl-2,4-dihydroxy-acetophenone Oxime (2). A solution of the
substituted ethylacetophenone 1b (0.97 g, 3 mmol) and hydroxylamine hydrochloride (0.63 g, 9 mmol) was
refluxed for 1 h in pyridine (4 ml). After 12 h it was poured into water (100 ml), triturated, and the crystallized
precipitate was filtered off.
1416

α-(Phenyl-1,2,4-triazol-3-yl)-5-ethyl-2,4-dihydroxyacetophenone Hydrazone (3). A solution of the
ketone 1b (0.97 g, 3 mmol) and hydrazine hydrate (0.5 g, 15 mmol) was refluxed for 1 h in ethanol (5 ml). The
product was cooled and the precipitate was filtered off.
8-R1-6-R2-7-Hydroxy-2-(4-phenyl-1,2,4-triazol-3-yl)-2-trifluoromethylchromones (4a,b). Trifluoro-
acetic anhydride (8.4 g, 40 mmol) was added dropwise with stirring to a solution of the ketone 1a,b (10 mmol)
in pyridine (10 ml) cooled to 0°C. The product was held at room temperature for 48 h, poured into iced water
(100 ml), and the precipitate was filtered off.
8-R1-6-R2-2-Carbethoxy-7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones
(5a-c)
were
synthesized by the preceding method from the corresponding ketones 1a-c (10 mmol) and ethoxalyl chloride
(3 g, 22 mmol) (for compounds 1a,b) or 33 mmol (for compound 1c).
7-Acetoxy-6-ethyl-2-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone (6b).
A
solution of the
substituted ethylacetophenone (3.23 g, 10 mmol), acetic anhydride (5.1 g, 50 mmol) and triethylamine (5 g,
50 mmol) was heated at 130-140°C for 2 h. After cooling the solution was poured into water (100 ml) and the
precipitate was filtered off.
6-Ethyl-7-hydroxy-2-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone (7b). A 5% solution of sodium
hydroxide (1.5 ml) and water (5 ml) were added to a solution of the 7-acetoxy derivative 6b (0.6 g, 1.5 mmol) in
ethanol (10 ml). The mixture was refluxed for 5 min, poured into water (100 ml), neutralized with hydrochloric
acid to pH 7, and the precipitate was filtered off.
7-Hydroxy-2,8-dimethyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone (7a). A.
A mixture of the
substituted methylacetophenone 1a (4.63 g, 15 mmol), acetic anhydride (7.1 g, 70 mmol) and triethylamine
(8.3 g, 60 mmol) was heated at 130-140°C on an oil bath while the reaction was monitored by TLC. The cooled
reaction mixture was poured into a mixture of water (100 ml) and hydrochloric acid (5 ml) and the precipitate
was filtered off. It was transferred to a mixture of methanol (20 ml) and sulfuric acid (1 ml) and refluxed with
the reaction monitored chromatographically, cooled, and the precipitate was filtered off.
B. A mixture of compound 1a (4.5 g, 14.6 mmol) and acetic anhydride (8.2 g, 80 mmol) in pyridine
(25 ml) was heated at 90-95°C for 5 h and then cooled and poured into ice. The tar was triturated in water until
formation of a precipitate which was filtered off, dissolved in a minimum amount of alcohol, and refluxed for
30 s with 5% sodium hydroxide solution (3 ml). The product was diluted with water (50 ml), acidified with
hydrochloric acid to pH 4-5, and the precipitate was filtered off.
7-Hydroxy-2-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone (7d) was prepared similarly to
compound 7a using method A in 57% yield.
8-R1-6-R2-7-Hydroxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones (8a-d). Boron trifluoride etherate
(8.46 g, 60 mmol) was added dropwise with stirring to a solution of the corresponding dihydroxyacetophenone
1a-d (10 mmol) in DMF (15 ml, 0.2 mol). Phosphorus pentachloride (2.3 g, 11 mmol) was added portionwise
and the product was held for 30 min at 70-80°C. The mixture was poured into water (100 ml), refluxed for
30 min, cooled, and the precipitate was filtered off. The yield of 7-hydroxy-3-(4-phenyl-1,2,4-triazol-3-
yl)chromone (8d, R1 = R2 = R3 = H) was 57%.
2-R3-6-R2-8-R1-7-Acetoxy-3-(4-phenyl-1,2,4-triazol-3-yl)chromones (9a,b,d, 10b). A solution of the
corresponding 7-hydroxy product 8a,b,d or 5b (1.5 mmol) in a mixture of acetic anhydride (0.61 g, 6 mmol) and
pyridine (0.5 g, 6 mmol) was held at room temperature for 24 h. The precipitated product was filtered off (in the
case of the products 9a,d) or poured into water (50 ml) and filtered to give the precipitated 7-acetoxy-3-(4-
phenyl-1,2,4-triazol-3-yl)chromone (9b) and compound 10b.
7-Hydroxy-8-methyl-3-(4-phenyl-1,2,4-triazol-3-yl)chromone-2-carboxylic Acid (11a). A solution of
the carbethoxychromone 5a was refluxed in a mixture of acetic acid (2.3 ml) and conc. H2SO4 (0.75 ml) for 15
min, held for 12 h, and the precipitate was filtered off.
1417

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