A concise one-pot synthesis of 3,4-diaryl-1H-pyrazoles from natural isoflavones and hydrazine hydrate

Article abstract of DOI:10.1002/hlca.200790217

An efficient protocol has been developed for the preparation of a series of new 3,4-diaryl-1H-pyrazoles, potential pharmacological and agricultural targets, by the reaction of hydrazine hydrate with different natural isoflavones or their derivatives. The

Full text of DOI:10.1002/hlca.200790217

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Helvetica Chimica Acta – Vol. 90 (2007)
A Concise One-Pot Synthesis of 3,4-Diaryl-1H-pyrazoles from Natural
Isoflavones and Hydrazine Hydrate
by Zun-Ting Zhang*, Da-Jin Tan, and Dong Xue
Key Laboratory of Medicinal Plant Resources and Natural Pharmaceutical Chemistry
Shaanxi Normal University), Ministry of Education, and School of Chemistry and Materials Science,
Shaanxi Normal University, Xiꢀan 710062, P. R. China
(
(
phone: þ 86-29-85303940; fax: þ 86-29-85307774; e-mail: zhangzt@snnu.edu.cn)
An efficient protocol has been developed for the preparation of a series of new 3,4-diaryl-1H-
pyrazoles, potential pharmacological and agricultural targets, by the reaction of hydrazine hydrate with
different natural isoflavones or their derivatives. The target compounds were obtained in good-to-
excellent yields (80 – 95%; Table 2) under fairly mild reaction conditions (808) tolerating various
functional groups. The new compounds were fully characterized, and the single-crystal X-ray structures
of 3,5-diethoxy-2-[4-(4-ethoxyphenyl)-1H-pyrazol-3-yl]phenol (26) and of the peracetylated compound
2
-{1-acetyl-4-[4-acetoxy-3-(diacetylamino)phenyl]-1H-pyrazol-3-yl}-5-acetoxyphenyl acetate (35) were
solved (Figure).
Introduction. – The chemistry of 1H-pyrazoles is particularly interesting because of
their potential application in medicinal chemistry as analgesic [1][2], anti-inflamma-
tory [3][4], antitumor [5][6], antimicrobial [7][8], or therapeutic agents [9], as well as
based on their wide applications in agriculture as potent insecticides [10][11] and
herbicides [12][13], although scarcely found in nature [14]. Due to many promising
pharmacological, agrochemical, and analytical applications, 3,4-diarylpyrazoles are
being used as inhibitors of heat-shock protein 90 (HSP90) and as therapeutics of
cancer. Therefore, 3,4-diarylpyrazoles have been the focus of many synthetic targets
over the past decades [15].
Recently, Xie et al. [16] and Dymock et al. [17] reported the synthesis of some 3,4-
diarylpyrazoles by reacting hydrazine (NH ÀNH ) with synthetic isoflavones. It is well-
2
2
known that natural isoflavones display a wide range of biological activities [18]. For
instance, soybean isoflavones (daidzein and genistein) have antidysrhythmic [19],
antioxidant [20], and cardiovascular-inhibiting [21] properties. Ipriflavone is used in the
prevention and treatment of osteoporosis [22]; and irisolidone (¼ 5,7-dihydroxy-6,4’-
dimethoxyisoflavone) is an effective antidiabetic [23]. However, it is necessary to
modify the structure of natural isoflavones to increase their biological activities and
generally poor solubilities.
Recently, we reported the synthesis of several new water-soluble isoflavones [24].
In order to enhance their biological activity and to develop more-powerful new drugs,
we herein report the high-throughput synthesis of a series of new 3,4-diarylpyrazoles by
means of a one-pot procedure based on the reaction of hydrazine with natural
isoflavones.
ꢁ
2007 Verlag Helvetica Chimica Acta AG, Zürich

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2097
Results andDiscussion. – Initially, we screened several solvents, including MeOH,
EtOH, THF, MeCN, DMF, and BuOH, for the model reaction between ipriflavone
(
¼ 7-(1-methylethoxy)-3-phenyl-4H-1-benzopyran-4-one; 1 mmol) with hydrazine hy-
drate (5 mmol) at 808. The results of these studies are summarized in Table 1. EtOH
was found to be the best solvent in terms of reaction time (90 min) and yield (92%;
Entry 1). Reasonable results were also obtained with other solvents, but the conversion
of ipriflavone to the corresponding 3,4-diarylpyrazole appears to be sluggish at 808
(
Entries 2 – 6). Therefore, we decided to use EtOH for further studies.
Table 1. Solvent Effects on the Reaction of Ipriflavone with Hydrazine Hydrate
Entry
Solvent
Time [min]
Yield [%]a)
1
2
3
4
5
6
EtOH
MeOH
THF
MeCN
BuOH
DMF
90
150
160
120
140
130
92
85
60
72
78
55
a) Yields refer to the pure, recrystallized product.
With the optimized reaction conditions at hand, the structurally divergent
isoflavones 1 – 16 were reacted with hydrazine hydrate to illustrate the scope of this
1
type of synthesis of 3,4-diarylpyrazoles ). All substrates smoothly reacted within 0.75 –
6
h to afford the target compounds in excellent yields, as shown in Scheme 1 and
Table 2. Although the reaction solvent was the same as in the procedure elaborated by
Dymock et al. [17], the reaction time was nearly halved.
1
13
All products were characterized by IR, H- and C-NMR, and HR-MS (see Exper.
Part). The structures of compounds 26 and 35 were further established by single-crystal
X-ray diffraction (Fig. 1). In the crystal structure of 26, only one tautomer was found,
the one with the H-atom at the N(2)-atom (species B in Scheme 2 below).
As shown in Table 2, the synthesis of 3,4-diarylpyrazoles lacking OH groups in both
aromatic rings is accomplished in high yields. If the benzopyranone ring bears no OH
group at C(5) (Entries 2, 3, and 5), the products were formed in nearly quantitative
yields; otherwise, the yield was lower (Entries 8 and 9). These results are not surprising
because isoflavones with a 5-OH group react with more difficulty than those without
electron-donating substituents at this position, probably because their intermediate
benzene-1,3,5-triol is easily oxidized. The usefulness of this methodology lies in the fact
that the reactions are carried out rapidly under very mild conditions. Moreover, the
method is compatible with many functional groups such as MeO, NO , Br, i-Pr, etc.
2
1)
For systematic compound names, see Exper. Part (names in parentheses).

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Helvetica Chimica Acta – Vol. 90 (2007)
Scheme 1
Nitroisoflavone and hydrazine may either react directly or in the presence of FeCl3
as catalyst. In the latter case, simultaneous reduction of the NO group occurs, leading
2
to the corresponding amines 32 or 34 (Scheme 1). Because pyrazoles often exist in
tautomeric forms (Scheme 2) [25], the structures of compounds 20, 32, and 34 could not
1
13
be unambiguously determined by regular H- and C-NMR experiments performed in
2
(
D )DMSO. However, deuterium ( H)-exchange experiments simplified the spectra
6
and allowed us to assign the different signals (see Exper. Part).
A Michael-addition mechanism can be proposed for the reaction of hydrazine with
isoflavones (Scheme 3). Thus, nucleophilic attack of hydrazine at the C(2)-atom of an
isoflavone C gives rise to the intermediate D, whose benzopyranone ring opens to E.
The latter then attacks the C¼O group, which, upon loss of H O and protonation, leads
2
to the final pyrazole product F [26].
Conclusions. – We have further elaborated and optimized the reaction of hydrazine
hydrate with different natural isoflavones to access pharmacologically and agricultur-
ally interesting 3,4-diarylpyrazoles. The mild reaction condition, short reaction times,
simple workup, excellent yields, and the use of an environmentally benign solvent
(
EtOH) offer advantages over other procedures for the synthesis of these compounds.
On the basis of the present investigation, we are currently carrying out further research
on possible industrial, pharmacological, and agricultural applications of 3,4-diaryl-
pyrazoles.

Helvetica Chimica Acta – Vol. 90 (2007)
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Table 2. Synthesis of 3,4-Diaryl-1H-pyrazoles by Reaction of Various Isoflavones with Hydrazine
Hydrate at 808 in EtOH. For details, see Exper. Part.
Entry Substrate
Product
Time [h]
2.5
Yield [%]a)
85
1
2
3
4
5
6
7
2.0
1.5
2.0
0.75
1.0
2.5
93
95
89
93
93
80

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Helvetica Chimica Acta – Vol. 90 (2007)
Table 2 (cont.)
Entry Substrate
8
Product
Time [h] Yield [%]a)
2.5
82
9
2.0
84
1
1
1
1
0
1
2
3
1.5
1.5
1.5
2.0
90
93
90
94
1
4
1.5
92

Helvetica Chimica Acta – Vol. 90 (2007)
2101
Table 2 (cont.)
Entry Substrate
Product
Time [h] Yield [%]a)
1
5
2.0
94
1
6
6.0
89b)
1
7
8
1.0
6.0
90
1
91b)
1
9
1.0
95
a) Yields of pure, isolated products. b) Reaction carried out with FeCl · 6 H O/C as catalyst.
3
2
Experimental Part
General. Thin-layer chromatography (TLC): silica gel 60 GF254 plates; visualization under UV light
254 nm). Melting points (m.p.) are uncorrected. IR Spectra: Nicollet 170SX FT-IR spectrophotometer;
(
À1
1
13
as KBr pellets; in cm . H- and C-NMR Spectra: at 300/75 MHz, resp., in (D )DMSO, unless otherwise
6
indicated; chemical shifts d in ppm rel. to Me Si (¼0 ppm), coupling constants J in Hz. HR-ESI-MS:
4
Bruker Daltonics APEX-II 4.7E FT-ICR mass spectrometer; in m/z. X-Ray crystallography: Bruker
Smart-1000 CCD diffractometer.
General Procedure (GP1 ) for the Synthesis of 17 – 31 and 33. Hydrazine hydrate was added to an
EtOH soln. of the appropriate isoflavone at 60 – 858, and the mixture was stirred at 858 for the time
specified (Table 2). The progress of the reaction was monitored by TLC. After completion of the
reaction, the mixture was poured into H O, the precipitate was filtered, and washed with H O until the
2
2

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Helvetica Chimica Acta – Vol. 90 (2007)
Figure. Single-crystal X-ray structures of a) 26 and b) 35. Displacement ellipsoids are shown at the 30%-
probability level. In the case of 26, one Et group is disordered. For details, see Table 3 and Exper. Part.
filtrate was neutral. The precipitate was recrystallized from EtOH to afford the corresponding pure
products in yields of 80 – 95% (see Table 2).

Helvetica Chimica Acta – Vol. 90 (2007)
2103
Scheme 2. Alternative Tautomeric Forms of 3,4-Diarylpyrazoles
Scheme 3. Proposed Mechanism for the Reaction of Isoflavones with Hydrazine Hydrate
3
-(2,4-Dihydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole (¼4-[4-(4-Hydroxyphenyl)-1H-pyra-
zol-3-yl]benzene-1,3-diol; 17). Colorless solid. M.p. 179.6 – 181.48. IR: 3137, 1617, 1559, 1505, 1457,
1
1
(
1
2
387, 1250, 1177, 1055, 978, 834. H-NMR: 6.24 (d, J ¼ 8.4, 1 H); 6.41 (s, 1 H); 6.71 (d, J ¼ 8.4, 2 H); 6.93
13
d, J ¼ 8.4, 1 H); 7.12 (d, J ¼ 8.4, 2 H); 8.05 – 8.36 (m, 5 H). C-NMR: 103.4; 107.2; 107.9; 115.8; 120.1;
þ
þ
3
23.7; 129.1; 131.5; 133.4; 140.6; 156.7; 157.2; 159.7. HR-ESI-MS: 269.0926 ([M þ H] , C H N O ; calc.
15
13
2
69.0926).
3
-(4-Ethoxy-2-hydroxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole (¼ 5-Ethoxy-2-[4-(4-hydroxy-
phenyl)-1H-pyrazol-3-yl]phenol; 18). Colorless solid. M.p. 245.6 – 247.88. IR: 3306, 3024, 2973, 1628,
1
1
2
1
516, 1486, 1441, 1383, 1237, 1166, 1038, 987, 894, 832. H-NMR: 1.33 (t, J ¼ 6.7, 3 H); 3.99 (q, J ¼ 6.7,
13
H); 6.37 – 6.69 (m, 4 H); 7.08 (s, 3 H); 7.63 – 7.85 (m, 1 H). C-NMR: 15.1; 63.4; 102.4; 105.7; 115.6;
þ
19.4; 128.1; 128.9; 130.1; 132.6; 137.9; 142.2; 156.4; 156.9; 159.6. HR-ESI-MS: 297.1229 ([M þ H] ,
þ
C H N O ; calc. 297.1239).
17
17
2
3
3
-(4-Ethoxy-2-hydroxyphenyl)-4-(4-ethoxyphenyl)-1H-pyrazole (¼ 5-Ethoxy-2-[4-(4-ethoxyphenyl)-
1
1
3
1
1
H-pyrazol-3-yl]phenol; 19). Colorless crystals. M.p. 120.3 – 121.88. IR: 3364, 2979, 2871, 1634, 1586,
1
525, 1436, 1384, 1240, 1184, 1163, 1133, 1113, 1090, 1046, 987, 824, 784. H-NMR: 1.31 (t, J ¼ 6.3, 6 H);
.98 (m, 4 H); 6.30 – 6.46 (m, 2 H); 6.81 – 6.99 (m, 3 H); 7.17 (d, J ¼ 6.3, 2 H); 7.78 (m, 1 H); 10.10 (m,
13
H); 12.87 (m, 1 H). C-NMR: 15.2; 63.4; 102.5; 105.7; 114.8; 119.1; 126.7; 128.2; 129.8; 132.3; 138.1;
þ
þ
3
46.6; 157.2; 158.1; 160.5. HR-ESI-MS: 325.1548 ([M þ H] , C H N O ; calc. 325.1552).
19
21
2
3
-(2-Hydroxy-4-methoxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole ( ¼ 2-[4-(4-Hydroxyphenyl)-1H-
pyrazol-3-yl]-5-methoxyphenol; 20). Colorless crystals. M.p. 230.7 – 232.58. IR: 3370, 3282, 2608, 1621,
595, 1569, 1533, 1510, 1482, 1432, 1354, 1249, 1165, 1115, 1027, 953, 829. H-NMR ((D )DMSO): 3.72 (s,
1
1
3
1
2
6
H); 6.34 – 6.74 (m, 4 H); 7.11 (d, J ¼ 7.2, 3 H); 7.76 (m, 1 H); 9.33 (m, 1 H); 10.24 (m, 1 H); 12.87 (m,
1
H). H-NMR ((D )DMSO/D O): 3.78 (s, 3 H); 6.45 (d, J ¼ 7.8, 1 H); 6.58 (s, 1 H); 6.78 (d, J ¼ 8.4,
6
2
13
H); 7.10 (d, J ¼ 8.4, 2 H); 7.17 (d, J ¼ 8.4, 2 H); 7.80 (s, 1 H). C-NMR ((D )DMSO): 55.5; 102.0;
6

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Helvetica Chimica Acta – Vol. 90 (2007)
1
1
1
05.2; 110.8; 115.7; 119.4; 120.7; 125.2; 128.3; 129.5; 130.2; 132.3; 135.3; 138.0; 146.1; 155.9; 156.7; 157.3;
13
60.4; 161.0. C-NMR ((D )DMSO/D O): 55.4; 101.8; 105.5; 110.6; 115.7; 119.7; 125.0; 128.7; 131.4;
6
2
þ
þ
38.0; 146.5; 155.3; 156.5; 160.7. HR-ESI-MS: 283.1072 ([M þ H] , C H N O ; calc. 283.1083).
16
15
2
3
3
-(2-Hydroxy-4-methoxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole ( ¼ 5-Methoxy-2-[4-(4-methoxy-
phenyl)-1H-pyrazol-3-yl]phenol; 21). Colorless crystals. M.p. 150.5 – 151.68. IR: 3431, 2921, 2728, 2603,
1
1
621, 1597, 1564, 1534, 1507, 1480, 1434, 1386, 1323, 1202, 1172, 1100, 1062, 1033, 950, 833. H-NMR: 3.72
(
s, 6 H); 6.33 – 6.49 (m, 2 H); 6.84 – 7.21 (m, 5 H); 7.84 (m, 1 H); 10.14 (m, 1 H); 12.89 (m, 1 H).
13
C-NMR: 55.5; 102.0; 105.2; 114.3; 119.1; 125.9; 128.1; 129.9; 132.3; 138.2; 146.3; 156.2; 157.3; 161.3. HR-
þ
þ
ESI-MS: 297.1233 ([M þ H] , C H N O ; calc. 297.1239).
17
17
2
3
3-(2,4-Dihydroxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole ( ¼ 4-[4-(4-Methoxyphenyl)-1H-pyra-
zol-3-yl]benzene-1,3-diol; 22). Colorless crystals. M.p. 209.2 – 211.08. IR: 3334, 2933, 2540, 1729, 1611,
1
(
5
2
1
573, 1519, 1408, 1353, 1295, 1247, 1157, 1116, 1064, 1025, 956, 868, 814, 733. H-NMR: 3.72 (s, 3 H); 6.33
13
m, 2 H); 6.88 (m, 3 H); 7.22 (d, J ¼ 8.4, 2 H); 7.78 (m, 1 H); 9.92 (m, 2 H); 12.83 (m, 1 H). C-NMR:
5.5; 103.4; 107.0; 114.3; 118.9; 126.9; 129.9; 132.1; 136.1; 138.0; 146.4; 157.1; 158.0; 159.2. HR-ESI-MS:
þ
þ
3
83.1080 ([M þ H] , C H N O ; calc. 283.1083).
16
15
2
3
-(2,4-Dihydroxyphenyl)-4-(4-hydroxy-3,5-diisopropylphenyl)-1H-pyrazole (¼4-{4-[4-Hydroxy-3,5-
bis(1-methylethyl)phenyl]-1H-pyrazol-3-yl}benzene-1,3-diol; 23). Colorless solid. M.p. 232.0 – 233.28. IR:
3
1
429, 2963, 2621, 1612, 1563, 1496, 1466, 1383, 1316, 1255, 1177, 1104, 1058, 971, 954, 839. H-NMR: 1.08
(
d, J ¼ 6.0, 12 H); 3.26 (m, 2 H); 6.23 (s, 1 H); 6.42 (s, 1 H); 6.96 (s, 3 H); 7.75 (m, 1 H); 9.49 (s, 1 H).
13
C-NMR: 23.4; 26.5; 103.1; 106.6; 109.6; 119.9; 122.0; 125.6; 129.9; 132.1; 135.4; 137.6; 149.3; 157.0; 158.8.
þ
þ
HR-ESI-MS: 353.1863 ([M þ H] , C H N O ; calc. 353.1865).
21
25
2
3
3-(2,6-Dihydroxy-4-ethoxyphenyl)-4-(4-hydroxyphenyl)-1H-pyrazole (¼ 5-Ethoxy-2-[4-(4-hydroxy-
phenyl)-1H-pyrazol-3-yl]benzene-1,3-diol; 24). Pink crystals. M.p. 259.6 – 261.38. IR: 3274, 3155, 2984,
2
6
(
1
557, 1631, 1587, 1512, 1447, 1356, 1284, 1231, 1199, 1173, 1143, 1120, 1055, 958, 820. H-NMR: 1.31 (t, J ¼
.7, 3 H); 3.91 (q, J ¼ 6.7, 2 H); 5.95 (s, 2 H); 6.60 (d, J ¼ 8.1, 2 H); 7.11 (d, J ¼ 8.1, 2 H); 7.65 (s, 1 H); 9.21
13
m, 3 H); 12.37 (s, 1 H). C-NMR: 15.2; 63.2; 98.9; 114.6; 115.5; 120.1; 125.9; 127.3; 131.9; 137.2; 155.6;
þ
þ
4
1
58.3; 160.5. HR-ESI-MS: 313.1183 ([M þ H] , C H N O ; calc. 313.1188).
17
17
2
3
-(2,6-Dihydroxy-4-ethoxyphenyl)-4-(4-ethoxyphenyl)-1H-pyrazole (¼ 5-Ethoxy-2-[4-(4-ethoxy-
phenyl)-1H-pyrazol-3-yl]benzene-1,3-diol; 25). Pink crystals. M.p. 188.7 – 190.18. IR: 3395, 3339, 2977,
2
1
933, 2362, 1622, 1581, 1513, 1476, 1445, 1392, 1351, 1286, 1247, 1164, 1107, 1047, 949, 843, 813. H-NMR:
1
1
.29 (t, J ¼ 6.5, 6 H); 3.92 (q, J ¼ 6.5, 4 H); 5.97 (s, 2 H); 6.76 (d, J ¼ 7.8, 2 H); 7.23 (d, J ¼ 7.8, 2 H); 7.74 (s,
13
H). C-NMR: 14.7; 62.7; 62.8; 93.0; 98.9; 114.2; 119.3; 126.4; 127.0; 135.4; 156.3; 157.8; 160.0. HR-ESI-
þ
þ
4
MS: 341.1492 ([M þ H] , C H N O ; calc. 341.1501).
19
21
2
3-(2,4-Diethoxy-6-hydroxyphenyl)-4-(4-ethoxyphenyl)-1H-pyrazole (¼ 3,5-Diethoxy-2-[4-(4-ethoxy-
phenyl)-1H-pyrazol-3-yl]phenol; 26). Pink crystals. M.p. 168.4 – 169.68. IR: 3341, 3101, 2980, 2930, 2874,
1
624, 1586, 1526, 1507, 1478, 1440, 1393, 1355, 1287, 1239, 1172, 1116, 1092, 1046, 941, 828, 807, 706.
1
H-NMR: 0.92 (t, J ¼ 5.4, 3 H); 1.33 (m, 6 H); 3.79 (q, J ¼ 5.4, 2 H); 3.99 (q, J ¼ 5.8, 4 H); 6.10 (s, 1 H);
.15 (s, 1 H); 6.79 (d, J ¼ 7.8, 2 H); 7.19 (d, J ¼ 7.8, 2 H); 7.75 (s, 1 H); 9.52 (s, 1 H); 12.48 (s, 1 H).
3
6
1
C-NMR: 14.7; 15.1; 63.3; 63.4; 63.9; 91.8; 94.6; 100.7; 113.7; 114.6; 119.8; 127.2; 127.6; 137.2; 156.9; 158.0;
þ
þ
4
1
59.2; 160.8. HR-ESI-MS: 369.1804 ([M þ H] , C H N O ; calc. 369.1814).
21
25
2
3
-(6-Hydroxy-2,4-dimethoxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole ( ¼ 3,5-Dimethoxy-2-[4-(4-
methoxyphenyl)-1H-pyrazol-3-yl]phenol; 27). Colorless solid. M.p. 172.0 – 173.78. IR: 3439, 2973, 2939,
1
2
3
1
1
832, 2618, 1618, 1539, 1462, 1419, 1385, 1287, 1249, 1204, 1153, 1107, 1044, 955, 882, 832, 803. H-NMR:
.54 (s, 3 H); 3.68 (s, 3 H); 3.75 (s, 3 H); 6.14 (s, 2 H); 6.78 (d, J ¼ 8.4, 2 H); 7.19 (d, J ¼ 8.4, 2 H); 7.76 (s,
13
H). C-NMR: 55.4; 55.5; 55.9; 90.5; 94.1; 114.2; 119.9; 127.2; 127.3; 137.7; 142.3; 157.6; 157.9; 158.1;
þ
þ
4
60.2; 161.7. HR-ESI-MS: 327.1338 ([M þ H] , C H N O ; calc. 327.1345).
18
19
2
3-(6-Hydroxy-2,3,4-trimethoxyphenyl)-4-(4-methoxyphenyl)-1H-pyrazole (¼ 3,4,5-Trimethoxy-2-[4-
(
4-methoxyphenyl)-1H-pyrazol-3-yl]phenol; 28). Colorless solid. M.p. 106.5 – 107.28. IR: 3490, 3332,
1
2
3
936, 1612, 1559, 1510, 1464, 1409, 1338, 1287, 1245, 1177, 1111, 1074, 1021, 973, 823. H-NMR: 3.37 (s,
H); 3.65 (s, 3 H); 3.68 (s, 3 H); 3.78 (s, 3 H); 6.37 (s, 1 H); 6.80 (d, J ¼ 8.4, 2 H); 7.21 (d, J ¼ 8.4, 2 H);
13
7
1
3
.76 (s, 1 H); 9.41 (s, 1 H); 12.6 (s, 1 H). C-NMR: 55.4; 56.0; 60.8; 61.0; 96.2; 103.2; 114.3; 120.5; 127.1;
þ
þ
5
27.4; 135.0; 137.6; 142.3; 146.2; 153.1; 155.4; 157.7. HR-ESI-MS: 327.1439 ([M þ H] , C H N O ; calc.
19
21
2
57.1450).

Helvetica Chimica Acta – Vol. 90 (2007)
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3
-(3-Bromo-2-hydroxy-4-isopropoxyphenyl)-4-phenyl-1H-pyrazole
(¼2-Bromo-3-(1-methyl-
ethoxy)-6-(4-phenyl-1H-pyrazol-3-yl)phenol; 29). Colorless solid. M.p. 171.6 – 173.48. IR: 3379, 2974,
1
2
4
2
926, 1617, 1507, 1421, 1372, 1290, 1226, 1161, 1110, 1043, 766. H-NMR (CDCl ): 1.36 (d, J ¼ 6.0, 6 H);
3
13
.52 (m, 1 H); 6.27 (d, J ¼ 8.7, 1 H); 7.10 (d, J ¼ 8.7, 1 H); 7.37 (s, 4 H); 7.63 (s, 1 H). C-NMR (CDCl ):
3
2.1; 72.1; 105.7; 111.0; 120.3; 127.4; 128.6; 129.5; 130.4; 133.2; 139.6; 147.4; 155.0; 156.3; 157.0. HR-ESI-
þ
þ
2
MS: 373.0542 ([M þ H] , C H N BrO ; calc. 373.0552).
18
18
2
3
-(2-Hydroxy-4-isopropoxyphenyl)-4-phenyl-1H-pyrazole (¼ 5-(1-Methylethoxy)-2-(4-phenyl-1H-
pyrazol-3-yl)phenol; 30). Colorless crystals. M.p. 129.2 – 130.98. IR: 3262, 2973, 1624, 1577, 1514, 1443,
1
1
6
(
361, 1276, 1162, 983, 924, 843, 756. H-NMR (CDCl ): 1.32 (d, J ¼ 6.0, 6 H); 4.50 (m, 1 H); 6.21 (d, J ¼
3
13
.3, 1 H); 6.58 (s, 1 H); 7.09 (d, J ¼ 8.7, 1 H); 7.37 (s, 5 H); 8.13 (s, 1 H); 8.98 (m, 2 H). C-NMR
CDCl ): 22.1; 69.8; 102.6; 103.5; 107.3; 109.6; 120.2; 127.3; 128.6; 129.2; 129.5; 133.3; 147.1; 157.3; 158.9.
3
þ
þ
2
HR-ESI-MS: 295.1443 ([M þ H] , C H N O ; calc. 295.1447).
18
19
2
3
-(2,4-Dihydroxyphenyl)-4-(3-nitro-4-hydroxyphenyl)-1H-pyrazole (¼4-[4-(4-Hydroxy-3-nitro-
phenyl)-1H-pyrazol-3-yl]benzene-1,3-diol; 31). Red crystals. M.p. 240.6 – 242.98. IR: 3365, 3123, 2953,
1
2
1
1
1
843, 1637, 1593, 1531, 1477, 1439, 1386, 1349, 1269, 1193, 1094, 1009, 831. H-NMR: 6.28 (s, 1 H); 6.40 (s,
H); 6.94 (d, J ¼ 8.1, 2 H); 7.04 (d, J ¼ 8.7, 1 H); 7.46 (d, J ¼ 8.7, 1 H); 7.91 (d, J ¼ 8.1, 2 H); 9.77 (s, 2 H);
13
0.79 (s, 1 H); 12.90 (s, 1 H). C-NMR: 103.3; 107.2; 108.4; 117.2; 119.6; 122.5; 126.3; 132.2; 134.2; 137.0;
þ
þ
5
38.1; 143.2; 150.6; 156.9; 159.5. HR-ESI-MS: 314.0770 ([M þ H] , C H N O ; calc. 314.0777).
15
12
3
3
-(2-Hydroxy-4-methoxyphenyl)-4-(3-nitro-4-methoxyphenyl)-1H-pyrazole (¼ 5-Methoxy-2-[4-(4-
methoxy-3-nitrophenyl)-1H-pyrazol-3-yl]phenol; 33). Colorless crystals. M.p. 172.2 – 174.28. IR: 3554,
317, 3053, 1618, 1569, 1533, 1470, 1408, 1246, 1180, 1120, 1071, 950, 843. H-NMR: 3.75 (s, 3 H); 3.89 (s,
1
3
3
1
1
H); 6.46 (d, J ¼ 7.8, 1 H); 6.51 (s, 1 H); 7.09 (d, J ¼ 8.4, 1 H); 7.28 (d, J ¼ 8.7, 1 H); 7.51 (d, J ¼ 7.8,
13
H); 7.78 (s, 1 H); 7.93 (s, 1 H); 9.89 (s, 1 H); 12.92 (s, 1 H). C-NMR: 55.5; 57.1; 102.1; 105.4; 114.8;
þ
17.2; 122.9; 127.4; 131.8; 132.8; 138.5; 139.7; 150.5; 157.0; 160.5; 161.2. HR-ESI-MS: 342.1089 ([M þ H] ,
þ
C H N O ; calc. 342.1090).
17
16
3
5
General Procedure (GP2 ) for the Synthesis of Compounds 32 and 34. Hydrazine hydrate (5 mmol)
was added to a soln. of the corresponding isoflavone (1 mmol) in EtOH. Then, FeCl · 6 H O (0.2 g;
3
2
0
.0014 g/C) was added at 808, and the mixture was stirred at this temp. for 6 h. The mixture was filtered,
and the filtrate was kept overnight. The formed precipitate was filtered off and purified by
recrystallization from EtOH to afford the product.
3
-(2,4-Dihydroxyphenyl)-4-(3-amino-4-hydroxyphenyl)-1H-pyrazole (¼4-[4-(3-Amino-4-hydroxy-
phenyl)-1H-pyrazol-3-yl]benzene-1,3-diol; 32). Prepared according to GP2 . Colorless solid.
M.p. 290 – 292.38. IR: 3387, 3306, 3211, 3005, 2579, 1615, 1557, 1467, 1406, 1332, 1295, 1224, 1178, 1117,
1
9
53, 910, 819, 753, 707. H-NMR ((D )DMSO): 4.36 – 4.50 (m, 4 H); 6.09 – 6.84 (m, 10 H); 7.03 (s, 1 H);
6
7
.06 (s, 1 H); 7.46 (s, 1 H); 7.73 (s, 1 H); 8.81 – 9.07 (m, 2 H); 9.38 – 9.50 (m, 3 H); 10.91 (s, 1 H); 12.42 (s,
1
1
2
1
H); 12.99 (s, 1 H). H-NMR ((D )DMSO/D O): 4.49 (s, 2 H); 6.35 (d, J ¼ 7.8, 1 H); 6.47 – 6.51 (m,
6
2
13
H); 6.73 (m, 2 H); 7.10 (d, J ¼ 7.8, 1 H); 7.78 (s, 1 H). C-NMR: 103.2; 107.1; 109.8; 115.0; 115.2; 117.5;
þ
20.0; 125.6; 128.9; 131.3; 136.1; 143.2; 155.7; 156.7; 158.3. HR-ESI-MS: 284.1034 ([M þ H] ,
þ
C H N O ; calc. 284.1035).
15
14
3
3
3
-(2-Hydroxy-4-methoxyphenyl)-4-(3-amino-4-methoxyphenyl)-1H-pyrazole (¼2-[4-(3-Amino-4-
methoxyphenyl)-1H-pyrazol-3-yl]-5-methoxyphenol; 34). Prepared according to GP2 . Colorless solid.
M.p. 184.9 – 186.58. IR: 3426, 3296, 2932, 1626, 1543, 1510, 1466, 1439, 1370, 1256, 1182, 1112, 1063, 1028,
1
9
(
88, 820, 755. H-NMR ((D )DMSO): 3.71 (s, 12 H); 4.57 (s, 2 H); 4.71 (s, 2 H); 6.29 – 7.15 (m, 12 H); 7.52
6
1
s, 1 H); 7.80 (s, 1 H); 9.74 (s, 1 H); 10.97 (s, 1 H); 12.55 (s, 1 H); 13.10 (s, 1 H). H-NMR ((D )DMSO/
6
D O): 3.74 (s, 6 H); 4.04 (s, 2 H); 6.40 – 6.52 (m, 3 H); 6.67 – 6.74 (t, 2 H); 7.10 (s, 1 H); 7.70 (s, 1 H).
2
1
3
C-NMR: 55.5; 55.7; 101.8; 105.3; 111.1; 114.3; 116.5; 119.9; 125.5; 126.6; 130.2; 137.3; 145.8; 156.0;
þ
þ
1
56.8; 160.6. HR-ESI-MS: 312.1338 ([M þ H] , C H N O ; calc. 312.1348).
17
18
3
3
2-{4-[4-Acetoxy-3-(diacetylamino)phenyl]-1-acetyl-1H-pyrazol-3-yl}-5-acetoxyphenyl Acetate (35).
For X-ray diffraction, compound 32 (1 mmol) was peracetylated by exposure to Ac O (8 mmol) in anh.
2
pyridine (5 ml) at 808 for 1 h. The mixture was poured into ice-water. The precipitate was filtered off,
washed neutral with H O, and purified by recrystallization from EtOH. Yield of 35: 95%. Colorless
2
crystals. M.p. 205.4 – 207.38. IR: 3429, 3149, 3063, 2997, 2932, 1770, 1722, 1617, 1498, 1431, 1376, 1191, 1137,
1
1
013, 910, 838, 719. H-NMR (CDCl ): 1.99 (s, 3 H); 2.21 – 2.30 (m, 14 H); 2.74 (s, 3 H); 7.04 (d, J ¼ 6.3,
3

2
106
Helvetica Chimica Acta – Vol. 90 (2007)
1
3
3
1
5
H); 7.25 (d, J ¼ 8.4, 1 H); 7.41 (m, 2 H); 8.42 (s, 1 H). C-NMR (CDCl ): 20.7; 21.1; 21.5; 26.2; 116.9;
3
19.5; 122.3; 124.2; 126.7; 129.1; 129.6; 130.4; 131.9; 146.5; 149.0; 151.8; 168.3; 169.2; 172.3. HR-ESI-MS:
þ
þ
9
58.1479 ([M þ Na] , C H N NaO ; calc. 558.1488). X-Ray: see Figure and section below.
27
25
3
2
X-Ray Crystal Structures of Compounds 26 and 35 ). Diffraction data were collected on a Bruker
Smart-1000 CCD diffractometer with graphite-monochromated MoK radiation (l 0.71073 Š) using the
a
2
(
w À 2q) scan technique. The structures were solved by direct methods and refined on F by full matrix
least-squares with the SHELXL-97 program. All non-H-atoms were refined anisotropically. All H-atoms
were treated using a riding model. The crystals used for the diffraction study showed no decomposition
during data collection. In the crystal structure of 26, an Et group (C(18), C(19), C(18’), C(19’); Figure)
was disordered over 0.60 and 0.40 occupied positions, so the bond lengths C(18)ÀC(19) and
C(18’)ÀC(19’) were restraint in the refinement. The crystallographic data of the two compounds are
collected in Table 3.
Table 3. Crystallographic Data of 26 and 35
2
6
35
Empirical formula
Color, shape
M [g/mol]
r
C H N O
pink, block
368.42
C H N O
9
colorless, plate
535.50
21
24
2
4
27 25
3
Crystal size [mm]
Temperature [K]
Wavelength [Š]
0.39 ꢀ 0.30 ꢀ 0.20
0.37 ꢀ 0.28 ꢀ 0.27
296(2)
296(2)
0.71073
0.71073
Crystal system
monoclinic
monoclinic
Space group
P2 /n
1
P2 /c
1
Unit-cell parameters [Š, 8]:
a ¼ 8.3072(7)
b ¼ 17.8746(15)
c ¼ 13.5921(11)
b ¼ 106.0580(10)
1939.5(3)
a ¼ 13.676(3)
b ¼ 13.952(3)
c ¼ 14.091(3)
b ¼ 99.560(4)
2651.4(9)
Volume [Š3]
Z
4
4
3
Calculated density [g/cm ]
Absorption coefficient [mm
1.262
0.088
1.342
0.102
À1
]
q-Range [8] for data collection
Limiting indices
1.93 to 25.10
À 9 ꢁ h ꢁ 9
2.07 to 25.10
À 16 ꢁ h ꢁ 16
À 16 ꢁ k ꢁ 13
À 16 ꢁ l ꢁ 15
13,381
1
6 ꢁ k ꢁ 21
À 16 ꢁ l ꢁ 13
Reflections collected
Independent reflections
Absorption correction
Completeness to qmax
Data/restraints/parameters
9,634
3,447 [R(int) ¼ 0.0234]
multiscan
99.9%
3,447/2/268
1.071
4,720 [R(int) ¼ 0.0632]
multiscan
99.9%
4,720/0/359
1.012
2
Goodness-of-fit on F
Final R indices [I > 2s(I)]
R Indices (all data)
Largest diff. peak and hole [e/Š ]
R ¼ 0.0606, wR ¼ 0.1638
R ¼ 0.0513, wR ¼ 0.1073
1
2
1
2
R ¼ 0.0899, wR ¼ 0.1886
1
R ¼ 0.1537, wR ¼ 0.1271
1
2
2
3
0.260, À 0.221
0.301, À 0.205
2)
The crystallographic data of 26 and 35 have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers CCDC-641949 and -641950, resp. Copies of the
data can be obtained, free of charge, at http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 90 (2007)
2107
We thank the National Natural Science Foundation of China (No. 20772076) and the Ministry of
Education of the Peopleꢀs Republic of China for financial support (Science and Technology Key Project
No. 107138).
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Received June 18, 2007