Chemistry of modified flavonoids. 24. Synthesis of 4- aryloxy-3-(2-hydroxy- 4-hydroxy/alkoxyphenyl)pyrazoles

Article abstract of DOI:10.1023/B:COHC.0000027889.10448.c1

3-Aryloxychromones are recyclized under the action of hydrazine into derivatives of 4-aryloxy-3-(2,4-dihydroxyphenyl)pyrazole.

Full text of DOI:10.1023/B:COHC.0000027889.10448.c1

Chemistry of Heterocyclic Compounds, Vol. 40, No. 2, 2004
CHEMISTRY OF MODIFIED FLAVONOIDS.
24*. SYNTHESIS OF 4- ARYLOXY-3-(2-HYDROXY-
4-HYDROXY/ALKOXYPHENYL)PYRAZOLES
V. V. Arkhipov, M. M. Garazd, M. N. Smirnov, and V. P. Khilya
3-Aryloxychromones are recyclized under the action of hydrazine into derivatives of 4-aryloxy-3-(2,4-
dihydroxyphenyl)pyrazole.
Keywords: 3-aryloxychromones, 4-aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles, recycli-
zation.
The interaction of hydrazine and its derivatives with compounds containing the chromone system may
be effected in two main directions, with the formation of hydrazones or by recyclization of the chromone
fragment. It is known that isoflavones and 3-hetarylchromones are readily recyclized under the action of
hydrazine exclusively into 4-aryl- and 4-hetarylpyrazole derivatives [2-5].
In the present work we have studied the interaction of 7-hydroxy- and 7-alkoxy-3-aryloxychromones
1a-j with hydrazine. The synthesis of 3-phenoxychromones 1a-d by the heterocyclization of the corresponding
α-aryloxy-2,4-dihydroxyacetophenones under conditions of acid and base catalysis has been described
previously [6-7]. Like the preparation of chromone 1b [7], the use of the modified Kostanecki–Robinson method
and subsequent acid hydrolysis of the resulting acetate led to compound 1e. The 7-alkoxy derivatives 1f-j were
obtained by the alkylation of the corresponding 7-hydroxy derivatives with alkyl halides in acetone in the
presence of potassium carbonate by the known procedure of [7]. The physicochemical properties of the new
chromone derivatives 1e-j are given in Tables 1 and 2.
R2O
4
'
R2O
2
"
4
"
R1
R3
O
7
2
R3
NH2NH2
O
2
'
3
4
'
HO
O
2
5
'
5
N
R1
O
1a–j
N
1
H
2a–j
1, 2 a R1 = R2 = R3 = H, b R1 = Me, R2 = R3 = H, c R1 = CF3, R2 = R3 = H, d R1 = COOH,
R2 = R3 = H, e R1 = Me, R2 = H, R3 = OEt, f R1 = R2 = Me, R3 = H, g R1 = Me, R2 = Et, R3 = H,
h R1 = Me, R2 = Bu, R3 = H, i R1 = Me, R2 = CH2Ph, R3 = H, j R1 = R2 = Me, R3 = OEt
_______
* For Part 23 see [1].
__________________________________________________________________________________________
Kiev Taras Shevchenko University, Kiev 02033, Ukraine; e-mail: ishchenko@mail.univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 218-222, February, 2004. Original article
submitted November 27, 2001; revision submitted January 10, 2003.
0009-3122/04/4002-0183©2004 Plenum Publishing Corporation
183

TABLE 1. Physicochemical Properties of Compounds 1e-j and 2a-j
Found, %
——————
Calculated, %
Empirical
formula
Compound
mp, °С
Yield, %
C
H
N
1e
1f
C18H16O5
69.18
69.22
72.28
72.33
72.94
72.96
74.0
74.06
76.99
77.08
69.90
69.93
67.14
67.16
67.00
67.18
57.08
57.15
61.50
61.54
66.15
66.25
68.94
68.91
69.68
69.66
71.02
70.99
5.0
—
—
—
—
—
—
184
168
160
131
135
126
179
171
169
185
163
155
142
105
135
116
87
91
88
81
76
87
89
90
48
60
94
93
94
96
95
96
5.16
C17H14O4
4.92
5.00
5.38
5.44
6.18
6.21
5.0
5.06
5.52
5.56
4.47
4.51
4.85
5.00
3.27
3.30
3.90
3.87
5.52
5.56
5.48
5.44
5.90
5.85
6.57
6.55
5.35
5.41
1g
1h
1i
C18H16O4
C20H20O4
C23H18O4
1j
C19H18O5
2a
2b
2c
2d
2e
2f
С15H12N2O3
С16H14N2O3
С16H11F3N2O3
С16H12N2O5
С18H18N2O4
С17H16N2O3
С18H18N2O3
С20H22N2O3
С23H20N2O3
С19H20N2O4
10.21
10.44
9.98
9.92
8.19
8.33
8.82
8.97
8.51
8.58
9.35
9.45
9.17
9.03
8.28
8.48
2g
2h
2i
74.00
74.18
67.15
67.05
7.69
7.52
7.99
8.23
2j
5.98
5.92
As a result of brief heating of alcoholic solutions of compounds 1a-j with an excess of hydrazine,
opening of the pyrone ring occurs with subsequent cyclization into 4-aryloxy-3-(2-hydroxy-4-
hydroxy/alkoxyphenyl)pyrazoles 2a-j. Their structure was confirmed by the results of elemental analysis
(Table 1), data of 1H NMR spectra (Table 2) etc. The pyrazoles obtained were dissolved in dilute alkali and with
an alcoholic solution of ferric chloride they form blue-green chelate complexes by means of the phenolic
1
hydroxyl and a nitrogen atom of the pyrazole ring. In their H NMR spectra, measured in DMSO-d6, signals
characteristic of such structures were observed in the 9.4-13.2 ppm region. The protons of the pyrazole ring NH
group were displayed as strongly broadened peaks at lowest field (12.9-13.2 ppm). A singlet was observed for
the 2'-OH group proton at 10.8-11.3, and for the 4'-OH group proton at 9.1-9.6 ppm. In the case of compounds
2f-j in place of the singlet for the 4'-hydroxy group signals were present in the spectrum for the corresponding
alkoxy substituent. Displacement of the 6'-H proton signal in the spectra of pyrazoles 2 by 1.0-1.2 ppm towards
high field, compared with the position of the peak of the same proton in the spectra of the initial chromones 1
(found in position 5 in them), is explained by the formation of the chelate structure [8].
3-Phenoxychromones, like other isoflavones, are therefore readily cyclized in high yield into the
corresponding pyrazoles, which enables this reaction to be used for preparative purposes for the synthesis of
derivatives of 4-aryloxy-3-(2,4-dihydroxyphenyl)pyrazole unavailable by other methods.
184

TABLE 2. 1H NMR Spectra of 3-Aryloxychromones 1e-j
Signals of protons, δ, ppm, coupling constants (J, Hz)*
Com-
pound
5-H
(1H, d,
J = 8.0)
6-H
(1H, dd,
J = 2.0; 8.0)
8-H
(1H, d,
J = 2.0)
2'-H,
6'-H
3'-H,
5'-Н
(2H, m)
2-Me
(3H, s)
7-OR2
4'-R3
(2H, m)
1e*2
2.36
7.97
7.10
10.65 (1H, s, Н)
7.30
6.83 (s)
6.83 (s)
1.28 (3H, t, CH3);
3.93 (2H, q, CH2)
1f
2.39
2.39
8.00
8.00
7.10
7.10
3.97 (3H, s, CH3)
4.23 (2H, q CН2);
1.44 (3H, t, J = 7.0, CH3)
7.20
7.20
7.05
7.00
7.00
6.95
7.00 (1H, m, H)
6.95 (1H, m, H)
1g
1h
2.39
8.00
7.10
3.88 (2H, t, OCH2);
7.20
7.05
7.00
7.00 (1H, m, H)
1.59 (2H, m, OCH2CH2);
1.36 (2H, m, CH2CH3);
0.89 (3H, t, J = 7.0, CН3)
1i
1j
2.38
2.38
8.00
8.00
7.15
7.00
7.50 (5H, m, Ph);
5.33 (2H, s, CН2)
7.20
7.20
7.05
7.00
7.00 (1H, m, H)
3.95 (3H, s, CH3)
6.90 (s)
6.90 (s)
3.95 (2H, q CH2);
1.33 (3H, t, CH3)
_______
* In (CD3)2CO.
*2 In DMSO-d6.

TABLE 3. 1H NMR Spectra of Substituted Pyrazoles 2a-j
Signals of protons, δ, ppm, coupling constants (J, Hz)
Com-
pound
3'-H
(1H, d,
J = 2.0)
5'-H
6'-H
3''-H,
5''-H,
(2H, m)
Solvent
1-H
(1H, s)
2'-OH
(1H, s)
2''-H, 6''-H,
(2H, m)
5-R1 (s)
4'-OR2
4''-R3
(1H, dd,
(1H, d,
J = 2.0; 8.0) J = 8.0)
2a
2b
DMSO-d6
(CD3)2CO
12.90
12.09
7.78
2.17
10.76
11.11
6.36
6.38
9.15 (1H, s)
6.22
6.25
7.45
7.58
7.28
7.28
7.00
7.00
7.00 (1H, m)
7.00 (1H, m)
8.40 (1H, s)
(3H, CH3)
—
2c
2d
2e
DMSO-d6
(CD3)2CO
DMSO-d6
13.40
13.00
12.75
10.25
6.41
6.36
6.21
9.63 (1H, s)
9.49 (1H, s)
9.45 (1H, s)
6.17
6.18
6.18
7.28
7.28
7.38
7.20
7.28
6.84 (s)
6.90
6.84
6.84 (s)
6.90 (1H, m)
6.84 (1H, m)
1.29 (3H, t, CH3),
3.95 (2H, q, CH2)
13.00 (1H, COOH) 10.19
2.07 (3H, CH3)
10.95
2f
2g
(CD3)2CO
(CD3)2CO
12.13
12.13
2.19 (3H, CH3)
2.18 (3H, CH3)
11.18
11.15
6.48
6.43
3.74 (3H, s, CH3)
1.31 (3H, t, J = 7.0);
6.32
6.32
7.65
7.65
7.28
7.28
7.00
7.00
7.00 (1H, m)
7.00 (1H, m)
3.98 (2H, q, J = 7.0, CH2)
2h
(CD3)2CO
12.17
2.17 (3H, CH3)
11.14
6.45
3.88 (2H, t, J = 7.0,
OCH2); 1.59 (2H, m,
OCH2CH2); 1.36 (2H, m,
CH2CH3); 0.89 (3H, t,
J = 7.0, CH3)
6.31
7.65
7.28
7.00
7.00 (1H, m)
2i
2j
DMSO-d6
DMSO-d6
12.70
12.86
2.08 (3H, CH3)
2.07 (3H, CH3)
11.15
11.08
6.55
6.41
7.40 (5H, m, Ph);
5.05 (2H, s, CH2)
3.69 (3H, s, CH3)
6.43
6.36
7.48
7.51
7.28
7.00
7.00 (1H, m)
6.83 (s)
6.83 (s)
1.29 (3H, t, CH3),
3.95 (2H, q, CH2)

EXPERIMENTAL
The progress of reactions and the purity of compounds obtained were checked by TLC on Silufol UV
254 plates in the systems chloroform—methanol, 9 : 1 and
1
19 : 1. The H NMR spectra were measured on Bruker WP 100SY and Varian VXR 300 instruments (100 and
300 MHz respectively) in DMSO-D6 and (CD3)2CO relative to TMS (internal standard).
3-(4-Ethoxyphenoxy)-7-hydroxy-2-methylchromone (1e). A mixture of α-(4-ethoxyphenoxy)-2,4-
dihydroxyacetophenone (2.58 g, 10 mmol), acetic anhydride (4.7 ml: 50 mmole), and triethylamine (5.6 ml,
40 mmol) was maintained at 125-130°C for 4 h. After cooling, the reaction mixture was poured into cold water
(200 ml), the precipitated solid 7-acetoxy derivative was filtered off, washed thoroughly on the filter with water,
and crystallized from ethanol. The crystals obtained were dissolved in the minimum amount of ethanol,
concentrated hydrochloric acid (1 ml) was added to the solution, and the mixture boiled until disappearance of
the starting material (TLC). The crystals of product 1e, precipitated on cooling, were separated and crystallized
from ethanol.
7-Alkoxy-3-aryloxy-2-methylchromones (1f-j) (General Method). The appropriate alkyl halide
(5.5 mmol) was added to a solution of chromone 1b,e (5 mmol) in absolute acetone (50 ml) containing powdered
freshly calcined potassium carbonate (2.07 g, 15 mmol) with vigorous stirring and heating. The reaction mixture
was maintained at 50-60°C for 1-3 h (the end of the reaction was determined by TLC). After cooling, the
mixture was transferred to 1 N sulfuric acid solution (100 ml), the solid product was filtered off, and crystallized
from 2-propanol.
4-Aryloxy-3-(2-hydroxy-4-hydroxy/alkoxyphenyl)pyrazoles (2a-j) (General Procedure). A solution
of 85% hydrazine hydrate (0.5 ml) in ethanol (5 ml) was added to a hot solution or suspension of the appropriate
3-aryloxychromone 1a-j (4 mmol) in ethanol (20 ml). The reaction mixture was boiled for 5-30 min (the end of
the reaction was determined by TLC) and transferred to ice water (200 ml) (in the case of acid 2d the resulting
mixture was acidified with dilute hydrochloric acid to pH 6). The precipitate of product 2 was filtered off, and
crystallized from 50% ethanol.
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