Synthesis of 4-aryl-3(5)-(2-hydroxyphenyl)pyrazoles by reaction of isoflavones and their 4-thio analogues with hydrazine derivatives

Article abstract of DOI:10.1071/CH07268

4-Aryl-3(5)-2-(hydroxyphenyl)pyrazoles have been prepared by the reaction of isoflavones and their 4-thio analogues with hydrazine hydrate and phenylhydrazine in hot pyridine. The reaction mechanism for the formation of these pyrazoles is discussed. All t

Full text of DOI:10.1071/CH07268

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 905–914
Synthesis of 4-Aryl-3(5)-(2-hydroxyphenyl)pyrazoles
by Reaction of Isoflavones and their 4-Thio Analogues
with Hydrazine Derivatives∗
Albert Lévai,A,E Artur M. S. Silva,B,E José A. S. Cavaleiro,B José Elguero,C
Ibon Alkorta,C and József Jeko˝ D
ADepartment of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary.
BDepartment of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
CInstituto de Química Médica, C/ Juan de la Cierva, 3, E-28006 Madrid, Spain.
DDepartment of Chemistry, College of Nyíregyháza, Sóstói u. 31/b, H-4400 Nyíregyháza, Hungary.
ECorresponding authors. Email: alevai@puma.unideb.hu; artur.silva@ua.pt
4-Aryl-3(5)-2-(hydroxyphenyl)pyrazoles have been prepared by the reaction of isoflavones and their 4-thio analogues
with hydrazine hydrate and phenylhydrazine in hot pyridine. The reaction mechanism for the formation of these pyra-
1
zoles is discussed. All the new compounds have been fully characterized by NMR spectroscopy. In [D6]DMSO, a H
NMR study allows observation of the presence of both pyrazole annular tautomers, due to the presence of intramolecular
hydrogen bonds in each tautomer (OH· · ·N and NH· · ·O). Theoretical calculations have been carried out on tautomers
and conformers of compounds 20 (3(5)-(2-hydroxy-4-methoxyphenyl)-5(3)-methyl-4-phenylpyrazole) and 21 (3(5)-
(2-hydroxy-4-methoxyphenyl)-4-(2-methoxyphenyl)-5(3)-methylpyrazole), including the absolute shieldings (GIAO/B3
LYP/6–311++G∗∗) of 21.
Manuscript received: 30 July 2007.
Final version: 13 September 2007.
Introduction
as a mixture of tautomers in [D6]DMSO solution. The proto-
tropic exchange is slow owing to the presence of intramolecular
hydrogen bonds OH· · ·N and NH· · ·O, allowing observation of
the signals of both tautomers. However, in CDCl3, the proton
exchange is too fast and only average signals were observed.[18]
In the present study, we have also observed annular tautomers
of the obtained pyrazoles in [D6]DMSO solutions, and studied
the steric effect of the 5-aryl group (using the numbering of
the OH· · ·N tautomer). These experimental results were com-
plemented by a theoretical study that suggests that the in solid
state, these compounds exist as the OH· · ·N tautomer and in
[D6]DMSO solutions as a mixture of both tautomers, with the
OH· · ·N being predominant.
Pyrazoles are well-known and widely investigated five-
membered nitrogen-containing heterocyclic compounds and
theirsyntheseshavebeensummarizedinprincipaltextbooks.[1,2]
Owing to the wide variety of their bioactivities, these com-
pounds are useful materials in drug research[3] and in the
development of agricultural chemicals.[4] Recently, it was
demonstrated that ortho-hydroxyphenylpyrazoles possess anal-
gesic activity, are platelet aggregation inhibitors[5] and potent
inhibitors of Hsp90 ATPase activity (in particular, those derived
from isoflavones)[6–10] and can act as analytical reagents.[11]
Concerning their potential application, an interesting example
is the application of N-(2-hydroxyphenyl)pyrazoles as photopro-
tectors of polystyrene.[12,13] All these features have stimulated
the synthesis of numerous pyrazole-type compounds.
Formerly, we investigated the synthesis of ortho-hydroxy-
phenylpyrazoles by the reaction of several groups of chromones
with hydrazines.[14–18] As a consequence, we developed sim-
ple and convenient procedures for the preparation of 3,4,5-
trisubstituted pyrazoles. The experience gained in the course of
the above-mentioned studies has prompted us to study the syn-
thesis of new ortho-hydroxyphenylpyrazoles by the reaction of
isoflavone analogues with several different hydrazines, which
will be described in the present paper.
Results and Discussion
Chemistry
Although the synthesis of pyrazoles by the reaction of iso-
flavonesandhydrazineshasreceivedsomeattention,[9,10,13,19–21]
nosystematicstudieshavebeenaccomplishedtoassesstheinflu-
ence of some structural substituents of the isoflavones on their
reactivity with hydrazines. It is well known that the reaction of
chromones with hydrazines starts with a nucleophilic attack of
the nitrogen atom of the hydrazine at C2 of the chromone skele-
ton. Therefore, the substituents at this position can be a decisive
factor on this chemical transformation. For this reason, one of
the aims of our present study was to investigate the influence of
Recently, we demonstrated, using NMR spectroscopy, that 4-
benzyl-3(5)-(ortho-hydroxyphenyl)-5(3)-phenylpyrazolesexists
∗Dedicated to Professor Gábor Tóth on the occasion of his 65th birthday.
© CSIRO 2007
10.1071/CH07268
0004-9425/07/120905

906
A. Lévai et al.
5
8
5
R1
4
HO
MeO
HO
O
R1
9 2
O
6
R2
2؅
R2
R
7
6
2؅
10
3
3
3؅
4؅
B
3؅
4؅
A
4
2
O
OH
O
O
6؅
6؅
5؅
5؅
1: R ꢀ H
2: R ꢀ OMe
3–5
12,13,15
3,12: R1 ꢀ Pr, R2 ꢀ H
A: (1) Butyric or isobutyric anhydride, NEt3
(2) NaOH, MeOH
B: MeI, K2CO3, acetone
4,13: R1 ꢀ Pr, R2 ꢀ OMe
5,15: R1 ꢀ iPr, R2 ꢀ OMe
Scheme 1. Synthesis of isoflavones 12, 13, and 15.
4؆
3؆
2؆
5؆
6؅
5؅
8
5
R1
MeO 4؅
3؅
MeO
O
2
9
R2
R2
2؅
MeO
R2
R1
7
6
4
10
3
R1
5
NH2NH2·H2O
Pyridine
3؅
4؅
4
2؅
O
3
O
N
N
1
N
O
6؅
N
H
2
H
H
H
5؅
6–17
OH···N
NH···O
18–29
6,18: R1 ꢀ R2 ꢀ H
12,24: R1 ꢀ Pr, R2 ꢀ H
13,25: R1 ꢀ Pr, R2 ꢀ OMe
14,26: R1 ꢀ iPr, R2 ꢀ H
15,27: R1 ꢀ iPr, R2 ꢀ OMe
16,28: R1 ꢀ Ph, R2 ꢀ H
17,29: R1 ꢀ Ph, R2 ꢀ OMe
7,19: R1 ꢀ H, R2 ꢀ OMe
8,20: R1 ꢀ Me, R2 ꢀ H
9,21: R1 ꢀ Me, R2 ꢀ OMe
10,22: R1 ꢀ Et, R2 ꢀ H
11,23: R1 ꢀ Et, R2 ꢀ OMe
Scheme 2. Synthesis of 4-aryl-3(5)-(2-hydroxyphenyl)pyrazoles 18–29.
R1
MeO
MeO
O
R2
R1
R2
MeO
R2
R1
NH2NH2·H2O
Pyridine
S
N
N
O
N
O
N
H
H
H
H
30–32
OH···N
NH···O
30: R1 ꢀ Me, R2 ꢀ H
31: R1 ꢀ Me, R2 ꢀ OMe
32: R1 ꢀ Ph, R2 ꢀ H
20,21,28
Scheme 3. Synthesis of 4-aryl-3(5)-(2-hydroxyphenyl)pyrazoles 20, 21, and 28.
the steric demand of the substituents attached to C2 of
isoflavones on their reaction with hydrazines. Substituents cho-
sen for the present study were hydrogen, methyl, ethyl, propyl,
isopropyl, and phenyl groups. As the presence of a substituent
in the ortho-position of the 3-phenyl group can also hinder the
attack of a reagent at C2 of the isoflavone molecule, the influence
of a C2ꢀ methoxy group was also investigated.
Starting materials 6–11, 14, 16, and 17 are known compounds
and were synthesized according to literature methods.[22–31]
However, isoflavones 12, 13, and 15 are new compounds being
synthesized by the first time in the current study. Ring closure
of 2,4-dihydroxyphenyl benzyl ketones 1 and 2 by treatment
with butyric or isobutyric anhydride in triethylamine followed by
sodium hydroxide in methanol afforded 7-hydroxyisoflavones
3–5. Methylation of compounds 3–5 with methyl iodide under
basic conditions provided 7-methoxyisoflavones 12, 13, and 15
(Scheme 1).
be used as a convenient solvent for this reaction. Compounds 6–
17 and hydrazine hydrate were allowed to react in hot pyridine
and pyrazoles 18–29 were obtained in good yields (69–87%;
Scheme 2).
To investigate the influence of the replacement of the oxy-
gen atom at C4 for a sulfur atom, 4-thioisoflavones 30–32 were
treated with hydrazine hydrate in hot pyridine and the same
pyrazoles (20, 21, and 28) were formed as in the case of their
isoflavone congeners (8, 9, and 16) in similarly good yields (79–
84%; Scheme 3). These results show that isoflavones and their
4-thio analogues react similarly with hydrazine, providing the
same pyrazoles.
The effect of the steric demand of the C2 substituents of
isoflavones was only an increase in the reaction time from 4
to 16 h (see Experimental). The presence of a 2ꢀ-methoxy group
was almost without influence on this transformation. The reason
for these findings may originate from the high nucleophilicity
of the hydrazine, which makes possible an effective nucleophilic
attack even at a crowded carbon atom.
We also studied the reaction of isoflavones 6–9, 11, 14, and
16 with phenylhydrazine in hot pyridine. It was found that only
the 7-methoxyisoflavone 6 and the 7,2ꢀ-dimethoxyisoflavone 7
reacted with phenylhydrazine to afford pyrazoles 33 and 34,
Reactions of isoflavones 6–17 and hydrazine hydrate have
been investigated in various solvents. If acetic acid, which
proved to be a convenient solvent for the reaction of 3-(3-aryl-
3-oxopropenyl)chromones,[17] was used, the starting material
was recovered in each case. The reaction was too slow in hot
methanol. Ourpreliminaryexperimentsshowedthatpyridinecan

Synthesis of Hydroxyphenylpyrazoles
907
MeO
R2
MeO
O
O
R2
R2
MeO
OH
N
PhNHNH2
Pyridine
O
N
N
N
H
6,7
6,33,35: R2 ꢀ H
7,34,36: R1 ꢀ Me, R2 ꢀ OMe
35,36
33,34
Scheme 4. Synthesis of 4-aryl-3(5)-(2-hydroxyphenyl)-1-phenylpyrazoles 33 and 34.
H2N NHR3
NHR3
R1
R2
R3HN NH
HN
R1
R2
R1
MeO
MeO
O
MeO
O
X
R2
O
X
OH
6–17
38
37
X ꢀ O, S
R3 ꢀ H or Ph
R2
R1
MeO
MeO
OH
R2
R1
When R3 ꢀ H
N
O
N
N
N
H
R3
R3
18–29: R3 ꢀ H
18–29: R3 ꢀ H
33,34: R3 ꢀ Ph
Scheme 5. Proposal of mechanism for the synthesis of pyrazoles 18–29 and 33, 34.
under longer reaction time (48 h) and in lower yields (29 and
25%; Scheme 4). The reaction was regioselective as the cor-
responding isomers 35 and 36 were not detected. Isoflavones
substituted with a methyl (8, 9), ethyl (11), isopropyl (14), or
phenyl (16) group at their C2 carbon atom did not react with
phenylhydrazine and were recovered unchanged even after such
a long reaction time.These observations prove that a less nucleo-
philic hydrazine derivative cannot effectively attack the C2 car-
bon atom of an isoflavone substituted with an alkyl or a phenyl
group at this position. Isoflavones 6 and 7 were allowed to react
with 2-hydrazinopyridine under the same reaction conditions,
but the starting materials were recovered in both cases. It appears
that this less nucleophilic hydrazine derivative cannot cleave the
isoflavone ring even with a hydrogen atom at position 2.
The structures of all newly synthesized pyrazoles (18–29,
33, and 34) were elucidated by elemental analyses and by spec-
troscopic methods. Both the elemental analyses and the mass
spectra unambiguously proved the presence of two nitrogen
atoms in each compound. In their infrared (IR) spectra (see
Experimental) C=N and NH bands characteristic for a pyra-
zole ring were assigned in all cases. Structure elucidation of all
new pyrazoles was completed by various NMR techniques (see
below).
the reaction of isoflavones with phenylhydrazine gives only
4-aryl-1-phenyl-5-(2-hydroxyphenyl)pyrazoles 33, 34.
NMR Study of the Tautomerism of Pyrazoles 18–29
and 33, 34
The 1H NMR spectra of compounds 18−29 in [D6]DMSO
show four broad singlets at higher frequency values (Table 1),
indicating that under such conditions they exist as a mixture
of tautomers (OH· · ·N and NH· · ·O; Schemes 2 and 3). The
assignment of the signals (because the ratio is not 50:50, those
belonging to the same tautomer are easily identified) is based on
our previous work on related compounds.[18]
TheOHsignalisalmostinvariant(9.85 0.10 ppm), OH· · ·N
and NH· · ·O signals are quite regular for compounds 18–
27 (13.08 0.11 ppm and 12.38 0.29 ppm, respectively), and
they increase significantly when R1 = Ph, compounds 28 and
29 (13.58 ppm and 12.83 ppm, respectively). The NH signal of
the OH· · ·N tautomer shows a clear dependence on the nature
of R2, from 11.0 ppm on average for R2 = H to 11.6 ppm on
average for R2 = OMe. Table 1 also reports the percentages
of both tautomers (ratio = [OH· · ·N]/[NH· · ·O]) as well as the
corresponding equilibrium constant.
A plausible reaction mechanism is shown in Scheme 5.
The first step is a nucleophilic attack of the most nucleophilic
hydrazine nitrogen atom at the C2 carbon atom of the chromone
nucleus, followed by ring opening affording structure 38. The
hydrazine moiety of the intermediate 38 can react with the car-
bonyl (X=O) or with the thiocarbonyl group (X=S) of this
molecule to give rise to the pyrazole ring. Pyrazoles formed
from the reaction of isoflavones with hydrazine hydrate may
exist in a mixture of tautomers OH· · ·N and NH· · ·O. However,
To fully characterize the structures of pyrazoles 18–29, some
drops of trifluoroacetic acid (TFA) were added to the [D6]DMSO
solution to increase the prototropy. In the discussion of the struc-
tural characterization of pyrazoles 18–29, the numbering system
of isomers OH· · ·N will be used. The main features of the NMR
data of these pyrazoles are the resonances of the pyrazole pro-
ton H5 for the 3,4-disubstituted pyrazoles 18 and 19 (δH 8.30,
8.44)andthoseofthealkylgroupsof5-alkyl-3,4-diarylpyrazoles
20–27, whereas the spectra of triarylpyrazoles 28 and 29 are

908
A. Lévai et al.
Table 1. Chemical shifts (δ) of the OH and NH protons of pyrazoles 18–29 in [D6]DMSO, percentages of tautomers, and ꢀG293 values in kJ mol−1
Compound
δ OH [OH· · ·N]
δ NH [OH· · ·N]
δ NH [NH· · ·O]
δ OH [NH· · ·O]
Ratio
[%]
ꢀG293
[kJ mol−1
]
[ppm]
[ppm]
[ppm]
[ppm]
18, R1 = R2 = H
13.15
13.22
13.04
13.01
13.07
13.05
13.07
13.03
13.10
13.04
13.58
13.60
10.33
11.27
11.09
11.62
11.21
11.69
11.27
11.70
11.35
11.73
10.94
11.47
12.77
12.63
12.39
12.20
12.38
12.22
12.37
12.22
12.37
12.20
12.91
12.76
9.81
9.81
9.76
9.84
9.78
9.89
9.80
9.90
9.84
9.92
9.90
9.95
39/61
68/32
76/24
89/11
80/20
91/09
80/20
92/08
82/18
92/08
45/55
66/34
1.1
−1.8
−2.8
−5.1
−3.4
−5.6
−3.4
−5.9
−3.7
−5.9
0.5
19, R1 = H, R2 = OMe
20, R1 = Me, R2 = H
21, R1 = Me, R2 = OMe
22, R1 = Et, R2 = H
23, R1 = Et, R2 = OMe
24, R1 = Pr, R2 = H
25, R1 = Pr, R2 = OMe
i
26, R1 = Pr, R2 = H
i
27, R1 = Pr, R2 = OMe
28, R1 = Ph, R2 = H
29, R1 = Ph, R2 = OMe
−1.6
R1
R1
R1
H3CO
H
H3CO
H3CO
H
H
H
H
CH2R
H
N
OH
N
N
NH
OH
OH
NH
NH
H
Fig. 1. Main connectivities found in the heteronuclear multiple bond coherence spectra of pyrazoles 18–29.
characterized by the complex aromatic region.The resonances of
the quaternary carbons, especially those of C3 (δC 141.6–143.5),
C5 (δC 143.6–152.5, save for compounds 18 and 19 where they
are methinic carbons and appear at δC 133.6, 134.8), C4 (δC
115.7–122.1), C2ꢀ (δC 157.2–158.3) and C4ꢀ (δC 162.3–163.5),
have been assigned based on the connectivities found in hetero-
nuclear multiple bond coherence (HMBC) spectra (Fig. 1). As
expected, the resonances of C3 are similar in all pyrazoles 18–
29, but those of C4 and C5 are very sensitive to the substituents
of those positions; those of C5 are shifted to high frequency val-
ues with the increase of steric hindrance of the substituents. The
1H and 13C NMR spectra of pyrazole 21 were also acquired in
CDCl3 and [D6]DMSO (see Experimental) and the signals of
the labile OH and NH protons appear as two broad singlets (δNH
10.03 and 11.64; δOH 11.36 and 13.00), those of the [D6]DMSO
solution appearing at higher frequency values. The carbon
resonances of C3 and C5 have also been assigned by the connec-
tivities found in the HMBC spectra and appear at δC 138.5 and
147.2 in the [D6]DMSO solution and at δC 138.6 and 148.9 in the
CDCl3 solution. These 1H and 13C NMR data seem to indicate
that in CDCl3 and [D6]DMSO solutions, the prototropy equilib-
rium is taking place, being almost oriented towards the OH· · · N
isomers. The same conclusion could be found from the NMR
data of pyrazole 22 in a CDCl3 solution (see Experimental).
In the case of pyrazoles 33 and 34, there is no prototropy
and the main features of their NMR data are the resonances
of the: (i) H5 and OH protons, which appear as narrow sin-
glets at δH 7.90–8.08 and 9.71–9.83, respectively; (ii) C3 and
C5 carbons appearing at δC 136.5–137.1 and 138.9–140.7,
respectively; and (iii) C2ꢀ and C4ꢀ, which appear at δC 157.0–
157.2 and 160.8–161.1, respectively. The assignment of the
quaternary carbon resonances of compounds 33 and 34 were
based on the connectivities found in the HMBC spectra: C2ꢀ-
OH → C1ꢀ, C2ꢀ and C3ꢀ; H5 → C4 and C3; H6ꢀ → C2ꢀ, C4ꢀ and
C3; H2ꢀꢀ → C4. The 1H and 13C NMR spectra of pyrazoles 33
and 34 acquired in [D6]DMSO with some drops of TFA (see
Experimental) led us to show that in these cases, the NMR spec-
tra are not solvent-dependent, except for the resonances of the
labile protons.
The ꢀG293 values of Table 1 can be analyzed using a
presence or absence matrix (1 when the substituent is present, 0
when the substituent is absent) with the following results (all val-
ues in kJ mol−1): H 0.8, Me −2.8, Et −3.3, Pr −3.5, iPr −3.6, Ph
0.6, and OMe −2.4. The six first coefficients correspond to R1
and the last one to R2. Excluding the phenyl group, the influence
of the tautomerism, as measured by ꢀG293, is linearly related
(r2 = 0.97, slope = 2.8) to the Taft steric parameter Es.[32] The
steric effect (negative coefficients) increases the amount of tau-
tomer OH· · ·N. The effect of the phenyl group is not only steric
like the others, but also electronic, and it slightly favours the
NH· · ·O tautomer, i.e. when R1 = Ph, it prefers to be at posi-
tion 3, a fact established for simple pyrazoles.[33] It has to be
mentioned that the OMe group stabilizes the OH· · ·N tautomer.
Experimental and Theoretical NMR Study of the
Tautomerism of Pyrazoles 20 and 21: the Effect of the
ortho-Methoxy Group at Position 2ꢀꢀ (R2 = OMe)
We have studied in detail compound 21 including the solid-state
13C cross-polarization magic angle spinning (CPMAS) NMR
spectrum (Table 2). A first observation is that the addition of a
small amount ofTFA, which was used to narrow the [D6]DMSO
13C signals by increasing the tautomerization rate, produces sig-
nificant modifications of the chemical shifts, in particular, on C1ꢀ
(ꢀδ 3.6), C4ꢀ (ꢀδ −3.3), C6ꢀ (ꢀδ −4.5), C3 (ꢀδ 4.6), C4 (ꢀδ
−4.1), and C5 (ꢀδ −5.5 ppm) as a result of a partial protonation
at the pyrazole N2 position. This forbade the use of data in these
conditions (see Experimental) for calculating tautomerism.
We have represented in Scheme 6 the different tautomeric
forms of pyrazoles 21 and 20 with their associated differences
in energy in kJ mol−1 (in bold, calculated at the B3 LYP/6–
311++G∗∗ level). According to the DFT calculations, in the gas

Synthesis of Hydroxyphenylpyrazoles
909
Table 2. 13C chemical shifts (δ) and absolute shieldings (σ, ppm) of pyrazole 21
Carbon
atom
δ [D6]DMSO
solution [ppm]
δ [D6]DMSO +TFA
δ Solid
state [ppm]
δ OH· · ·N
21a [ppm]
δ NH· · ·O
21b [ppm]
δ 89% 21a
11% 21b [ppm]
solution [ppm]
C1ꢀ
C2ꢀ
C3ꢀ
C4ꢀ
C5ꢀ
C6ꢀ
C3
110.9
157.4
101.4
159.5
104.7
127.2
147.2
112.5
138.5
122.4
157.2
111.6
129.2
120.7
132.0
9.6
107.3
157.6
102.2
162.8
106.1
131.7
142.6
116.6
144.0
119.5
158.0
112.4
130.9
121.4
132.4
10.5
110.2
157.2
98.9
110.7
160.0
97.3
112.9
153.2
102.3
158.7
100.0
129.5
136.3
114.3
147.6
124.7
156.8
107.6
128.8
120.7
133.2
15.3
111.0
159.3
97.8
160.6
108.4
129.7
148.2
112.0
138.9
123.6
158.9
112.4
127.0
123.6
132.4
7.5
160.6
107.0
126.9
151.6
116.5
136.5
125.5
158.1
108.2
128.7
119.8
133.5
10.3
160.4
106.2
127.2
149.9
116.3
137.7
125.5
157.9
108.2
128.7
119.9
133.5
10.9
C4
C5
C1ꢀ
C2ꢀ
C3ꢀ
C4ꢀ
C5ꢀ
C6ꢀ
Me
OMe
OMe
55.0
55.3
55.6
55.8
54.7
56.1
53.5
53.8
53.6
53.1
53.5
53.8
H3C
H3C
that is, the methoxy group slightly destabilizes the NH· · ·O
tautomer (20b, 21b).
H3C
O
H3C
O
O
O
We compared the experimental chemical shifts of compound
21 in [D6]DMSO and in the solid state (CPMAS spectrum)
with the calculated absolute shieldings of the four tautomers
of Table 2. We used all the carbon atoms (including those of
TMS) and also the four most sensitive to tautomerism (C2ꢀ,
C6ꢀ, C3, and C5), the results being the same. In the solid state,
the best fit is obtained with 21a (OH· · ·N) (n = 19, r2 = 0.997,
see below). In DMSO solution, the best fit is obtained with a
mixture of 89% of 21a and 11% of 21b or 21d, but for the rea-
sons explained above, 21b seems to be more appropriate (n = 19,
r2 = 0.998). The calculated δ values for tautomers 21a and 21b
were obtained from the absolute shieldings σ through the fol-
lowing equation: δ(CPMAS) = 174.9 − 0.947σ (21a), n = 19,
r2 = 0.977. The 89/11 ratio was calculated from these values.
Table 2 values correspond obviously in the case of CPMAS/21a
to a slope of 1.000 and an r2 value of 1.000 and in the case
of DMSO/89% 21a:11% 21b mixture to a slope of 0.99 and
r2 = 0.998
CH3
CH3
N N
N N
H
O
O
H
H
H
21a) OH···N
tautomer
21b) NH···O
tautomer
22.8
0.0
3-aryl-5-methyl
5-aryl-3-methyl
H3C
H
H3C
H
O
O
O
O
H3C
O
H3C
O
CH3
CH3
N
N
N N
H
H
21c) OH···O
tautomer
20.4
21d) OH···O
tautomer
11.1
3-aryl-5-methyl
5-aryl-3-methyl
H3C
O
H3C
O
Conclusions
CH3
CH3
The reaction of isoflavones and their thio analogues with
hydrazine hydrate in hot pyridine gave new 4-aryl-3(5)-(2-
hydroxyphenyl)-4-pyrazoles 18–29. However, these compounds
reacted in the same conditions with the less nucleophilic phenyl-
hydrazine only when they did not have 2-substituents, giving rise
to 4,5-diaryl-1-phenylpyrazoles (33 and 34). The present study
showed that both annular tautomers of pyrazoles (18–29) exist
in [D6]DMSO solutions, owing to the presence of intramolec-
ular hydrogen bonds (IMHBs) in each tautomer (OH· · ·N and
NH· · ·O). The NMR data of pyrazoles (18–29) in [D6]DMSO
solutions also showed that the steric effect of a 5-substituent
increased the amount of the tautomer OH· · ·N. It is notice-
able that the IMHBs are maintained in a solvent like DMSO,
known to cleave HBs, thus proving how strong they are. A
theoretical study with 3(5)-(2-hydroxy-4-methoxyphenyl)-4-(2-
methoxyphenyl)-5(3)-methylpyrazole 21 suggests that, in solid
state, this compound exist as the OH· · ·N tautomer and in
N
N
N N
H
O
O
H
H
H
20b) NH···O
tautomer
5-aryl-3-methyl
20.0
20a) OH···N
tautomer
3-aryl-5-methyl
0.0
Scheme 6. Tautomeric forms of pyrazoles 21 and 20 with their associated
differences in energy in kJ mol−1
.
phase, for compound 21 there are two tautomers (21c and 21d)
that involve OH· · ·O hydrogen bonds (HBs). One of them, 21d,
is the second most stable tautomer (11.1 kJ mol−1 above 21a).
Presumably in DMSO the OH· · ·O HBs are not weaker than the
NH· · ·O HBs of 21b (and all other pyrazoles). Therefore, from
20a/20b (20.0 kJ mol−1) to 21a/21b (22.8 kJ mol−1), there is a
difference of −2.8 kJ mol−1, comparable with −2.4 kJ mol−1
deduced from the analysis of Table 1 results (see above);

910
A. Lévai et al.
[D6]DMSO solutions as a mixture of both tautomers, with the
7-Hydroxy-2ꢀ-methoxy-2-propylflavone 4
(4.03 g, 65%), mp 153–154◦C. δH (CDCl3) 0.88 (3H, t, J 7.4,
CH3), 1.68 (2H, sextet, J 7.4, CH2CH2CH3), 2.36–2.53 (2H,
m, CH2CH2CH3), 3.70 (3H, s, 2ꢀ-OCH3), 6.76–6.80 (2H, m,
H6 and H8), 6.91 (1H, d, J 8.0, H3ꢀ), 6.99 (1H, dt, J 0.9 and
7.4, H5ꢀ), 7.15 (1H, dd, J 1.8 and 7.4, H6ꢀ), 7.32 (1H, ddd, J
1.8, 7.4 and 8.0, H4ꢀ), 7.98 (1H, d, J 9.2, H5), 9.74 (1H, br
s, 7-OH). δC (CDCl3) 13.7 (CH3), 20.4 (CH2CH2CH3), 34.5
(CH2CH2CH3), 55.3 (2ꢀ-OCH3), 102.4 (C8), 110.9 (C3ꢀ), 115.4
(C6), 115.7 (C10), 119.4 (C3), 120.6 (C5ꢀ), 121.9 (C1ꢀ), 127.2
(C5), 129.7 (C4ꢀ), 131.9 (C6ꢀ), 157.4 (C2ꢀ), 158.1 (C9), 162.9
(C7), 167.4 (C2), 177.8 (C4). m/z 310 (M+•, 11), 279 (100), 267
(48), 250 (23). νmax/cm−1 3276, 1625, 1590, 1570, 1495, 1461,
1394, 1243, 1218, 1163, 1117, 1007, 853, 754, 704, 592 (Found:
C 73.6, H 5.9. C19H18O4 requires C 73.5, H 5.8%).
OH· · · N being the predominant.
Experimental
Melting points were measured in a Kofler hot-stage appa-
ratus and are uncorrected. IR (KBr) spectra were recorded
on a Perkin–Elmer 16 PC spectrometer. Mass spectra were
recorded on a VG Trio-2 instrument. Elemental analyses were
obtained on a Carlo Erba 1106 apparatus. H and 13C NMR
1
spectra were recorded on Bruker Avance 300 spectrometer (at
300.13 and 75.47 MHz, respectively) unless stated otherwise;
chemical shifts are reported in ppm (δ) using TMS as inter-
nal reference, and coupling constants (J) are given in Hz. The
1H unequivocal assignments were made using two-dimensional
gradient-selected COSY correlation spectroscopy (gCOSY)
experiments, while 13C assignments were made with the aid of
two-dimensional gradient-selected heteronuclear single quan-
tum coherence (gHSQC) and gHMBC (delays for one-bond
and long-range J C/H couplings were optimized for 145 and
7 Hz, respectively) experiments. 13C CPMAS NMR spectra were
recorded at 100.62 MHz on a Bruker Avance 400 spectrometer
with the following conditions: 5 s of recycle delay, 1.5 ms of time
contact, 90◦ pulse of 5 µs and acquisition time (AQ) of 33.8 ms.
Column chromatography was performed with Merck silica gel
60, using 4:1 v/v toluene/ethyl acetate as eluent. Starting mate-
rials 6–11, 14, 16, 17, and 30–32 were synthesized according
to known procedures.[22–31] Calculations were carried out with
the Gaussian 03 package[34] at the B3 LYP/6–311++G∗∗ lev-
els; frequency calculations were carried out to confirm that the
obtained structures corresponded to energy minima.[35,36] Abso-
lute shieldings were calculated with the GIAO approximation[37]
based on the B3 LYP/6–311++G∗∗ calculations.
7-Hydroxy-2-isopropyl-2ꢀ-methoxyisoflavone 5
(4.16 g, 67%), mp 275–276◦C. δH (500 MHz, [D6]DMSO)
1.149 (3H, d, J 6.9, CH3), 1.152 (3H, d, J 6.9, CH3), 2.62 (1H,
septet, J 6.9, CH(CH3)2), 3.70 (3H, s, 2ꢀ-OCH3), 6.87 (1H, d, J
2.2, H8), 6.91 (1H, dd, J 2.2 and 8.7, H6), 7.00 (1H, t, J 7.5,
H5ꢀ), 7.08 (1H, d, J 8.2, H3ꢀ), 7.10 (1H, dd, J 1.8 and 7.5,
H6ꢀ), 7.37 (1H, ddd, J 1.8, 7.5 and 8.2, H4ꢀ), 7.85 (1H, d, J 8.7,
H5). δC (125 MHz, [D6]DMSO) 19.3 and 19.8 (2 × CH3), 31.0
(CH(CH3)2), 55.3 (2ꢀ-OCH3), 102.0 (C8), 111.2 (C3ꢀ), 114.6
(C6), 115.6 (C10), 117.3 (C3), 120.3 (C5ꢀ), 122.0 (C1ꢀ), 127.0
(C5), 129.4 (C4ꢀ), 131.7 (C6ꢀ), 157.1 (C2ꢀ), 157.3 (C9), 162.5
(C7), 168.6 (C2), 175.2 (C4). m/z 310 (M+•, 6), 295 (3), 279
(100), 267 (44). νmax/cm−1 3125, 1624, 1566, 1494, 1459, 1402,
1375, 1284, 1247, 1170, 1111, 989, 852, 761 (Found: C 73.5,
H 5.8. C19H18O4 requires C 73.5, H 5.8%).
General Procedures for the Preparation of
7-Methoxyisoflavones 12, 13, and 15
General Procedures for the Preparation of
7-Hydroxyisoflavones 3–5
A mixture of the particular 7-hydroxyisoflavone (3–5, 2.8 or
3.1 g, 10.0 mmol), CH3I (1.0 mL, 20.0 mmol), anhydrous ace-
tone (150 mL), and K2CO3 (5.0 g) was refluxed for 6 h, and then
the inorganic salts were filtered off. The solvent was evaporated
under reduced pressure and the residue was crystallized from
methanol to obtain 7-methoxyisoflavones 12, 13, and 15.
A
mixture of 2,4-dihydroxydeoxybenzoin
1
(4.56 g,
20.0 mmol) or 2,4-dihydroxy-2ꢀ-methoxydeoxybenzoin
2
(5.16 g, 20.0 mmol), butyric anhydride (100 mL) or isobutyric
anhydride (100 mL), and Et3N (50 mL) was refluxed for 5 h, then
poured onto crushed ice, and acidified with dilute HCl. The oily
precipitate was extracted with CHCl3, the solution was washed
with brine, dried with CaCl2, and the solvent was evaporated
under reduced pressure. The residue was refluxed for 10 min in
a mixture of MeOH (100 mL) and 2 M NaOH (50 mL), cooled
to room temperature, and acidified with dilute HCl. The pre-
cipitate was separated by filtration, washed free of acid, and
recrystallized from MeOH to afford 7-hydroxyisoflavones 3–5.
7-Methoxy-2-propylisoflavone 12
(4.18 g, 71%), mp 97–98◦C. δH (CDCl3) 0.91 (3H, t, J 7.4,
CH3), 1.69–1.76 (2H, m, CH2CH2CH3), 2.49–2.54 (2H, m,
CH2CH2CH3), 3.92 (3H, s, 7-OCH3), 6.86 (1H, d, J 2.3, H8),
6.96 (1H, dd, J 2.3 and 8.9, H6), 7.23–7.27 (2H, m, H2ꢀ,6ꢀ), 7.33–
7.46 (3H, m, H3ꢀ,4ꢀ,5ꢀ), 8.03 (1H, d, J 8.9, H5). δC (CDCl3) 13.7
(CH3), 20.8 (CH2CH2CH3), 34.2 (CH2CH2CH3), 57.7 (OCH3),
99.8 (C8), 114.1 (C6), 117.3 (C10), 123.4 (C3), 127.6 (C5 and
C4ꢀ), 128.3 (C3ꢀ,5ꢀ), 130.4 (C2ꢀ,6ꢀ), 133.2 (C1ꢀ), 157.6 (C9),
163.8 (C7), 165.8 (C2), 176.6 (C4). m/z 294 (M+•, 40), 279
(100), 265 (43), 251 (5). νmax/cm−1 1628, 1601, 1568, 1502,
1439, 1389, 1361, 1266, 1206, 1119, 1021, 1066, 947, 838, 756,
705, 601 (Found: C 77.6, H 6.1. C19H18O3 requires C 77.5,
H 6.2%).
7-Hydroxy-2-propylisoflavone 3
(3.31 g, 59%), mp 129–130◦C. δH (CDCl3) 0.91 (3H, t, J
7.4, CH3), 1.71 (2H, sextet, J 7.4, CH2CH2CH3), 2.53 (2H, t,
J 7.4, CH2CH2CH3), 6.77 (1, d, J 2.2, H8), 6.80 (1H, dd, J 2.2
and 8.7, H6), 7.27 (2H, dd, J 1.5 and 8.2, H2ꢀ,6ꢀ), 7.31–7.44
(3H, m, H3ꢀ,4ꢀ,5ꢀ), 8.00 (1H, d, J 8.7, H5). δC (CDCl3) 13.7
(CH3), 20.8 (CH2CH2CH3), 34.4 (CH2CH2CH3), 102.5 (C8),
115.6 (C6), 115.8 (C10), 122.9 (C3), 127.3 (C5), 127.8 (C4ꢀ),
128.5 (C3ꢀ,5ꢀ), 130.5 (C2ꢀ,6ꢀ), 133.0 (C1ꢀ), 158.0 (C9), 162.9
(C7), 167.1 (C2), 177.0 (C4). m/z 280 (M+•, 42), 265 (100),
251 (15), 237 (3). νmax/cm−1 3157, 1616, 1562, 1494, 1458,
1396, 1269, 1234, 1174, 1112, 1007, 852, 759, 704, 600 (Found:
C 77.2, H 5.7. C18H16O3 requires C 77.1, H 5.8%).
7,2ꢀ-Dimethoxy-2-propylisoflavone 13
(4.80 g, 74%), mp 117–118◦C. δH (CDCl3) 0.89 (3H, t, J 7.4,
CH3), 1.70 (2H, septet, J 7.4, CH2CH2CH3), 2.35–2.52 (2H, m,
CH2CH2CH3), 3.75 (3H, s, 2ꢀ-OCH3), 3.91 (3H, s, 7-OCH3),
6.85 (1H, d, J 2.4, H8), 6.94 (1H, dd, J 2.4 and 9.0, H6), 6.95–
7.04 (2H, m, H3ꢀ and H5ꢀ), 7.14 (1H, dd, J 1.8 and 7.4, H6ꢀ),

Synthesis of Hydroxyphenylpyrazoles
911
7.36 (1H, ddd, J 1.8, 7.5 and 8.2, H4ꢀ), 8.13 (1H, d, J 9.0, H5). δC
(CDCl3) 13.7 (CH3), 20.4 (CH2CH2CH3), 34.4 (CH2CH2CH3),
55.5 (2ꢀ-OCH3), 55.7 (7-OCH3), 99.8 (C8), 111.0 (C3ꢀ), 113.9
(C6), 117.3 (C10), 119.8 (C3), 120.5 (C5ꢀ), 122.2 (C1ꢀ), 127.6
(C5), 129.4 (C4ꢀ), 131.9 (C6ꢀ), 157.4 (C2ꢀ), 157.7 (C9), 163.6
(C7), 166.0 (C2), 176.3 (C4). m/z 324 (M+•, 10), 293 (100), 281
(45), 264 (14). νmax/cm−1 1633, 1609, 1573, 1496, 1441, 1388,
1243, 1206, 1164, 1110, 1022, 846, 762 (Found: C 74.0, H 6.1.
C20H20O4 requires C 74.1, H 6.2%).
m/z 296 (M+•, 100), 281 (4), 265 (10), 253 (7). νmax/cm−1 3247,
1627, 1581, 1500, 1459, 1427, 1346, 1251, 1199, 1162, 1112,
1022, 950, 836, 809, 755, 547 (Found: C 68.8, H 5.5, N 9.5.
C17H16N2O3 requires C 68.9, H 5.4, N 9.5%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-5(3)-methyl-
4-phenylpyrazole 20
(1.14 g, 81% from 8, and 1.18 g, 84% from 30, reaction time
6 h), mp 182–183◦C. δH ([D6]DMSO + drops TFA) 2.28 (3H,
s, CH3), 3.63 (3H, s, 4ꢀ-OCH3), 6.27 (1H, dd, J 2.4 and 8.6,
H5ꢀ), 6.49 (1H, d, J 2.4, H3ꢀ), 6.87 (1H, d, J 8.6, H6ꢀ), 7.14 (2H,
dd, J 1.7 and 7.9, H2ꢀꢀ,6ꢀꢀ), 7.21–7.31 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ). δC
([D6]DMSO + drops TFA) 10.8 (CH3), 55.9 (4ꢀ-OCH3), 102.7
(C3ꢀ), 106.6 (C5ꢀ), 107.2 (C1ꢀ), 120.7 (C4), 128.9 (C4ꢀꢀ), 129.9
(C3ꢀꢀ,5ꢀꢀ), 130.6 (C2ꢀꢀ,6ꢀꢀ), 131.6 (C1ꢀꢀ), 132.9 (C6ꢀ), 142.6 (C3),
143.6 (C5), 158.3 (C2ꢀ), 163.5 (C4ꢀ). m/z 280 (M+•, 100), 265
(3), 251 (5), 237 (15). νmax/cm−1 3264, 1627, 1573, 1515, 1432,
1332, 1251, 1164, 1043, 950, 856, 800, 777, 698, 630, 601
(Found: C 73.0, H 5.7, N 9.9. C17H16N2O2 requires C 72.8,
H 5.8, N 10.0%).
7,2ꢀ-Dimethoxy-2-isopropylisoflavone 15
(5.44 g, 84%), mp 173–174◦C. δH (500 MHz, [D6]DMSO)
1.179 (3H, d, J 6.8, CH3), 1.182 (3H, d, J 6.8, CH3), 2.66 (1H,
septet, J 6.8, CH(CH3)2), 3.70 (3H, s, 2ꢀ-OCH3), 3.92 (3H, s,
7-OCH3), 7.01 (1H, dt, J 1.0 and 7.5, H5ꢀ), 7.04 (1H, dd, J 2.4
and 8.8, H6), 7.09 (1H, dd, J 1.0 and 7.9, H3ꢀ), 7.12 (1H, dd,
J 1.8 and 7.5, H6ꢀ), 7.16 (1H, d, J 2.4, H8), 7.38 (1H, ddd, J
1.8, 7.5 and 7.9, H4ꢀ), 7.91 (1H, d, J 8.8, H5). δC (125 MHz,
[D6]DMSO) 19.3 and 19.7 (2 × CH3), 31.0 (CH(CH3)2), 55.3
(2ꢀ-OCH3), 56.1 (7-OCH3), 100.2 (C8), 111.2 (C3ꢀ), 114.6 (C6),
116.5 (C10), 117.6 (C3), 120.3 (C5ꢀꢀ), 122.0 (C1ꢀ), 126.6 (C5),
129.4 (C4ꢀ), 131.7 (C6ꢀ), 157.1 (C2 ), 157.3 (C9), 163.7 (C7),
168.9 (C2), 175.1 (C4). m/z 324 (M+•, 4), 309 (3), 293 (100),
281 (53). νmax/cm−1 1633, 1609, 1494, 1440, 1278, 1201, 1167,
1122, 1028, 858, 790, 763 (Found: C 74.2, H 6.3. C20H20O4
requires C 74.1, H 6.2%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(2-
methoxyphenyl)-5(3)-methylpyrazole 21
(1.33 g, 86% from 9, and 1.27 g, 82% from 31, reaction time
6 h), mp 177–178◦C. δH ([D6]DMSO + drops TFA) 2.17 (3H, s,
CH3), 3.58 and 3.64 (2 × 3H, 2s, 2 × OCH3), 6.24 (1H, dd,
J 2.5 and 8.7, H5ꢀ), 6.50 (1H, d, J 2.5, H3ꢀ), 6.82 (1H, d,
J 8.7, H6ꢀ), 6.88 (1H, dt, J 0.9 and 7.4, H5ꢀꢀ), 6.99–7.03
(2H, m, H3ꢀꢀ and H6ꢀꢀ), 7.30 (1H, ddd, J 1.7, 7.4 and 8.4,
H4ꢀꢀ). δC ([D6]DMSO + drops TFA) 10.5 (CH3), 55.6 and 55.8
(2 × OCH3), 102.2 (C3ꢀ), 106.1 (C5ꢀ), 107.3 (C1ꢀ), 112.4 (C3ꢀꢀ),
116.6 (C4), 119.5 (C1ꢀꢀ), 121.4 (C5ꢀꢀ), 130.9 (C4ꢀꢀ), 131.7 (C6ꢀ),
132.4 (C6ꢀꢀ), 142.6 (C3), 144.0 (C5), 157.6 (C2ꢀ), 158.0 (C2ꢀꢀ),
162.8 (C4ꢀ). m/z 310 (M+•, 100), 296 (16), 279 (23), 251 (8).
νmax/cm−1 3334, 1625, 1589, 1523, 1438, 1374, 1270, 1205,
1168, 1122, 1093, 1014, 848, 759, 590 (Found: C 69.6, H 5.9,
N 9.1. C18H18N2O3 requires C 69.7, H 5.8, N 9.0%).
δH ([D6]DMSO) 2.05 (3H, s, CH3), 3.63 and 3.66 (2 × 3H,
2s, 2 × OCH3), 6.14 (1 H, dd, J 2.6 and 8.7, H5ꢀ), 6.41 (1H, d, J
2.6, H3ꢀ), 6.81 (1H, d, J 8.7, H6ꢀ), 6.99 (1H, t, J 7.4, H5ꢀꢀ), 7.05
(2H, d, J 7.4, H3ꢀꢀ and H6ꢀꢀ), 7.38 (1H, t, J 7.4, H4ꢀꢀ), 11.64 (1H,
br s, NH), 13.00 (1H, br s, 2ꢀ-OH). δC ([D6]DMSO) 9.6 (CH3),
55.0 and 55.3 (2 × OCH3), 101.4 (C3ꢀ), 104.7 (C5ꢀ), 110.9 (C1ꢀ),
111.6 (C3ꢀꢀ), 112.5 (C4), 120.7 (C5ꢀꢀ), 122.4 (C1ꢀꢀ), 127.2 (C6ꢀ),
129.2 (C4ꢀꢀ), 132.0 (C6ꢀꢀ), 138.5 (C5), 147.2 (C3), 157.2 (C2ꢀꢀ),
157.4 (C2ꢀ), 159.5 (C4ꢀ).
General Procedure for the Treatment of Isoflavones 6–17
and 4-Thioisoflavones 30–32 with Hydrazine Hydrate
A mixture of the appropriate isoflavone (6–17 or 30–32,
5.0 mmol), hydrazine hydrate (50.0 mmol), and pyridine (40 mL)
was refluxed for 4–16 h, and poured into H2O. The precipi-
tate was separated by filtration, washed with water, dried, and
recrystallized from methanol to afford pyrazoles 18–19.
3(5)-(2-Hydroxy-4-methoxyphenyl)-
4-phenylpyrazole 18
(985 mg, 74%; reaction time 4 h), mp 187–188◦C. δH
([D6]DMSO + drops TFA) 3.69 (3H, s, OCH3), 6.40 (1H, dd,
J 2.4 and 8.6, H5ꢀ), 6.54 (1H, d, J 2.4, H3ꢀ), 6.73 (1H, d, J
8.6, H6ꢀ), 7.18–7.30 (5H, m, H2ꢀꢀ,3ꢀꢀ,4ꢀꢀ,5ꢀꢀ,6ꢀꢀ), 8.44 (1H, s,
H5). δC ([D6]DMSO drops TFA) 55.8 (4ꢀ-OCH3), 102.6 (C3ꢀ),
106.4 (C5ꢀ), 107.4 (C1ꢀ), 122.1 (C4), 128.5 (C3ꢀꢀ,4ꢀꢀ,5ꢀꢀ), 129.6
(C2ꢀꢀ,6ꢀꢀ), 131.8 (C1ꢀꢀ),ꢀ 132.8 (C6ꢀ), 133.6 (C5), 141.6 (C3),
158.1 (C2ꢀ), 163.3 (C4 ). m/z 266 (M+•, 100), 235 (10), 223
(10), 161 (12). νmax/cm−1 3434, 1617, 1597, 1532, 1496, 1479,
1431, 1386, 1322, 1273, 1173, 1105, 1065, 1035, 952, 861, 823,
765, 702, 675, 564 (Found: C 72.3, H 5.3, N 10.6. C16H14N2O2
requires C 72.2, H 5.3, N 10.5%).
δH (CDCl3) 2.13 (3H, s, CH3), 3.67 (3H, s, 2ꢀꢀ-OCH3), 3.74
(3H, s, 4ꢀ-OCH3), 6.16 (1H, dd, J 2.6 and 8.8, H5ꢀ), 6.55 (1H,
d, J 2.6, H3ꢀ), 6.91 (1H, d, J 8.8, H6ꢀ), 6.97–7.03 (2H, m, H3ꢀꢀ
and H5ꢀꢀ), 7.16 (1H, dd, J 1.7 and 7.5, H6ꢀꢀ), 7.38 (1H, t, J 7.5,
H4ꢀꢀ), 10.03 (1H, br s, NH), 11.36 (1H, br s, 2ꢀ-OH). δC (CDCl3)
9.8 (CH3), 55.1 and 55.4 (2 × OCH3), 101.4 (C3ꢀ), 105.3 (C5ꢀ),
110.8 (C1ꢀ), 111.2 (C3ꢀꢀ), 113.1 (C4), 120.8 (C5ꢀꢀ), 122.2 (C1ꢀꢀ),
127.8 (C6ꢀ), 129.2 (C4ꢀꢀ), 132.4 (C6ꢀꢀ), 138.6 (C5), 148.9 (C3),
157.6 (C2ꢀ and C2ꢀꢀ), 159.9 (C4ꢀ).
3(5)-(2-Hydroxy-4-methoxyphenyl)-
4-(2-methoxyphenyl)pyrazole 19
(1.16 g, 78%; reaction time 4 h), mp 143–144◦C. δH
([D6]DMSO + drops TFA) 3.67 and 3.76 (2 × 3H, 2s,
2 × OCH3), 6.42 (1H, dd, J 2.4 and 8.7, H5ꢀ), 6.63 (1H, d, J
2.4, H3ꢀ), 6.93 (1H, dt, J 0.8 and 7.5, H5ꢀꢀ), 7.04 (1H, d, J
8.7, H6ꢀ), 7.06 (1H, d, J 7.9, H3ꢀꢀ), 7.19 (1H, dd, J 1.7 and 7.6,
H6ꢀꢀ), 7.34 (1H, ddd, J 1.7, 7.5 and 7.9, H4ꢀꢀ), 8.41 (1H, s, H5).
δC ([D6]DMSO + drops TFA) 55.8 and 56.0 (2 × OCH3), 102.6
(C3ꢀ), 106.4 (C5ꢀ), 108.0 (C1ꢀ), 112.5 (C3ꢀꢀ), 118.2 (C4), 120.3
(C1ꢀꢀ), 121.5 (C5ꢀꢀ), 130.6 (C4ꢀꢀ), 131.5 (C6ꢀꢀ), 132.1 (C6ꢀ), 134.8
(C5), 142.7 (C3), 157.7 and 157.8 (C2ꢀ and C2ꢀꢀ), 163.2 (C4ꢀ).
5(3)-Ethyl-3(5)-(2-hydroxy-4-methoxyphenyl)-
4-phenylpyrazole 22
(1.28 g, 87%, reaction time 6 h), mp 165–166◦C. δH
([D6]DMSO + drops TFA) 1.13 (3H, t, J 7.6, CH3), 2.71 (2H,
q, J 7.6, CH2), 3.66 (3H, s, 4ꢀ-OCH3), 6.30 (1H, dd, J 2.3 and
8.6, H5ꢀ), 6.50 (1H, d, J 2.3, H3ꢀ), 6.89 (1H, d, J 8.6, H6ꢀ), 7.17
(2H, dd, J 1.5 and 7.8, H2ꢀꢀ,6ꢀꢀ), 7.26–7.36 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ).

912
A. Lévai et al.
δC ([D6]DMSO + drops TFA) 13.2 (CH3), 18.4 (CH2), 55.6 (4ꢀ-
OCH3), 102.3 (C3ꢀ), 106.1 (C5ꢀ), 106.8 (C1ꢀ), 119.7 (C4), 128.6
(C4ꢀꢀ), 129.5 (C3ꢀꢀ,5ꢀꢀ), 130.4 (C2ꢀꢀ,6ꢀꢀ), 131.2 (C1ꢀꢀ), 132.5 (C6ꢀ),
121.3 (C5ꢀꢀ), 130.8 (C4ꢀꢀ), 131.6 (C6ꢀ), 132.6 (C6ꢀꢀ), 142.7 (C3),
152.5 (C5), 157.5 (C2ꢀ), 158.1 (C2ꢀꢀ), 162.5 (C4ꢀ). m/z 338 (M+•
,
100), 323 (16), 307 (12), 295 (20). νmax/cm−1 3300, 1632, 1590,
1524, 1436, 1382, 1319, 1256, 1203, 1168, 1030, 954, 842, 810,
748, 591 (Found: C 70.9, H 6.6, N 8.4. C20H22N2O3 requires C
71.0, H 6.6, N 8.3%).
142.4 (C3), 148.2 (C5), 157.8 (C2ꢀ), 162.9 (C4ꢀ). m/z 294 (M+•
,
100), 279 (3), 265 (5), 237 (10). νmax/cm−1 3266, 1625, 1587,
1519, 1438, 1363, 1255, 1203, 1170, 1128, 1095, 1037, 952,
817, 773, 701, 588 (Found: C 73.5, H 6.2, N 9.6. C18H18N2O2
requires C 73. 5, H 6.2, N 9.5%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-5(3)-isopropyl-
4-phenylpyrazole 26
δH (CDCl3) 1.19 (3H, t, J 7.6, CH3), 2.62 (2H, q, J 7.6, CH2),
3.74 (3H, s, 4ꢀ-OCH3), 6.16 (1H, dd, J 2.6 and 8.8, H5ꢀ), 6.56
(1H, d, J 2.6, H3ꢀ), 6.90 (1H, d, J 8.8, H6ꢀ), 7.27 (2H, dd, J 1.9
and 7.3, H2ꢀꢀ,6ꢀꢀ), 7.37–7.44 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ). δC (CDCl3)
13.4 (CH3), 17.7 (CH2), 55.1 (4ꢀ-OCH3), 101.6 (C3ꢀ), 105.3
(C5ꢀ), 110.1 (C1ꢀ), 116.7 (C4), 127.3 (C4ꢀꢀ), 128.6 (C6ꢀ), 128.7
(C3ꢀꢀ,5ꢀꢀ), 130.5 (C2ꢀꢀ,6ꢀꢀ), 133.6 (C1ꢀꢀ), 143.6 (C5), 148.5 (C3),
157.7 (C2ꢀ), 160.1 (C4ꢀ).
(1.14 g, 74%, reaction time 12 h), mp 176–177◦C. δH
([D6]DMSO + drops TFA) 1.22 (6H, d, J 6.9, CH3), 3.07 (1H,
septet, J 6.9, CH), 3.66 (3H, s, 4ꢀ-OCH3), 6.29 (1H, dd, J 1.8
and 8.6, H5ꢀ), 6.51 (1H, d, J 1.8, H3ꢀ), 6.88 (1H, d, J 8.6, H6ꢀ),
7.18 (2 H, d, J 6.5, H2ꢀꢀ,6ꢀꢀ), 7.30–7.36 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ).
δC ([D6]DMSO + drops TFA) 21.9 (CH3), 25.5 (CH), 55.5 (4ꢀ-
OCH3), 102.1 (C3ꢀ), 105.9 (C5ꢀ), 106.9 (C1ꢀ), 119.0 (C4), 128.5
(C4ꢀꢀ), 129.3 (C3ꢀꢀ,5ꢀꢀ), 130.3 (C2ꢀꢀ,6ꢀꢀ), 131.3 (C1ꢀꢀ), 132.2 (C6ꢀ),
142.5 (C3), 151.8 (C5), 157.7 (C2ꢀ), 162.5 (C4ꢀ). m/z 308 (M+•
,
5(3)-Ethyl-3(5)-(2-hydroxy-4-methoxyphenyl)-
4-(2-methoxyphenyl)pyrazole 23
100), 293 (9), 279 (7), 265 (12). νmax/cm−1 3386, 1629, 1586,
1522, 1439, 1367, 1318, 1257, 1202, 1167, 1124, 1034, 952,
830, 774, 699, 589 (Found: C 73.9, H 6.6, N 9.0. C19H20N2O2
requires C 74.0, H 6.5, N 9.1%).
(1.18 g, 69%, reaction time 6 h), mp 98–99◦C. δH
([D6]DMSO4 + drops TFA) 1.06 (3H, t, J 7.6, CH3), 2.52 (2H,
q, J 7.6, CH2), 3.52 and 3.55 (2 × 3H, 2s, 2 × OCH3), 6.22 (1H,
dd, J 2.4 and 8.7, H5ꢀ), 6.50 (1H, d, J 2.4, H3ꢀ), 6.81 (1H, d, J 8.7,
H6ꢀ), 6.87 (1H, t, J 7.6, H5ꢀꢀ), 6.99 (1H, d, J 8.4, H3ꢀꢀ), 7.01 (1H,
dd, J 1.7 and 7.6, H6ꢀꢀ), 7.30 (1H, ddd, J 1.7, 7.6 and 8.4, H4ꢀꢀ).
δC ([D6]DMSO + drops TFA) 13.0 (CH3), 18.8 (CH2), 55.7 and
55.9 (2 × OCH3), 102.3 (C3ꢀ), 106.2 (C5ꢀ), 107.4 (C1ꢀ), 112.3
(C3ꢀꢀꢀ), 116.2 (C4), 119.7 (C1ꢀꢀ), 121.5 (C5ꢀꢀ), 131.0 (C4ꢀꢀ), 131.8
(C6 ), 132.6 (C6ꢀꢀ), 142.8 (C3), 149.1 (C5), 157.7 (C2ꢀ), 158.2
(C2ꢀꢀ), 162.9 (C4ꢀ). m/z 324 (M+•, 100), 309 (3), 295 (25), 267
(6). νmax/cm−1 3330, 1623, 1596, 1517, 1457, 1436, 1369, 1319,
1243, 1199, 1162, 1124, 1027, 950, 840, 755, 588 (Found: C
70.3, H 6.2, N 8.7. C19H20N2O3 requires C 70.4, H 6.2, N 8.6%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-5(3)-isopropyl-
4-(2-methoxyphenyl)pyrazole 27
(1.30 mg, 77%, reaction time 16 h), mp 178–179◦C. δH
([D6]DMSO + drops TFA) 1.17 (6H, d, J 7.0, CH3), 2.86 (1H,
septet, J 7.0, CH), 3.62 (3H, s, 2ꢀꢀ-OCH3), 3.66 (3H, s, 4ꢀ-OCH3),
6.25 (1H, dd, J 2.2 and 8.7, H5ꢀ), 6.51 (1H, d, J 2.3, H3ꢀ), 6.82
(1H, d, J 8.7, H6ꢀ), 6.90 (1H, dd, J 7.4 and 7.6, H5ꢀꢀ), 7.02–7.04
(2H, m, H3ꢀꢀ and H6ꢀꢀ), 7.33 (1 H, ddd, J 1.5, 7.6 and 7.8, H4ꢀꢀ). δC
([D6]DMSO + dropsTFA) 21.6 (CH3), 25.9 (CH), 55.5 and 55.7
(2 × OCH3), 102.0 (C3ꢀ), 105.9 (C5ꢀ), 107.2 (C1ꢀ), 112.2 (C3ꢀꢀ),
116.1 (C4), 119.5 (C1ꢀꢀ), 121.3 (C5ꢀꢀ), 131.8 (C4ꢀꢀ), 131.4 (C6ꢀ),
132.3 (C6ꢀꢀ), 142.5 (C3), 147.3 (C5), 157.4 (C2ꢀ), 157.9 (C2ꢀꢀ),
162.5 (C4ꢀ). m/z 338 (M+•, 100), 323 (11), 307 (8), 295 (40).
νmax/cm−1 3380, 1636, 1589, 1527, 1464, 1437, 1386, 1294,
1242, 1160, 1137, 1031, 973, 843, 769, 603 (Found: C 71.1,
H 6.5, N 8.2. C20H22N2O3 requires C 71.0, H 6.6, N 8.3%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-4-phenyl-
5(3)-propylpyrazole 24
(1.26 g, 82%, reaction time 12 h), mp 153–154◦C. δH
([D6]DMSO + drops TFA) 0.66 (3H, t, J 7.5, CH3), 1.41 (2H,
sextet, J 7.5, CH2CH2CH3), 2.53 (2H, t, J 7.5, CH2CH2CH3),
3.64(3H, s, 4ꢀ-OCH3), 6.16(1H, dd, J2.5and8.6, H5ꢀ), 6.38(1H,
d, J 2.5, H3ꢀ), 6.76 (1H, d, J 8.6, H6ꢀ), 7.04 (2H, dd, J 1.8 and 7.6,
H2ꢀꢀ,6ꢀꢀ), 6.95–7.29 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ). δC ([D6]DMSO + drops
TFA) 14.0 (CH3), 22.3 (CH2CH2CH3), 26.9 (CH2CH2CH3),
55.8 (4ꢀ-OCH3), 102.5 (C3ꢀ), 106.3 (C5ꢀ), 107.0 (C1ꢀ), 120.4
(C4), 128.8 (C4ꢀꢀ), 129.7 (C3ꢀꢀ,5ꢀꢀ), 130.6 (C2ꢀꢀ,6ꢀꢀ), 131.5 (C1ꢀꢀꢀ),
132.7 (C6ꢀ), 142.5 (C3), 147.1 (C5), 158.1 (C2ꢀ), 163.1 (C4 ).
m/z 308 (M+•, 100), 293 (11), 279 (21), 265 (6). νmax/cm−1
3300, 1627, 1586, 1519, 1375, 1317, 1253, 1203, 1162, 1132,
1027, 950, 833, 755, 702, 588 (Found: C 74.1, H 6.5, N 9.2.
C19H20N2O2 requires C 74.0, H 6.5, N 9.1%).
4,5(3)-Diphenyl-3(5)-(2-hydroxy-
4-methoxyphenyl)pyrazole 28
(1.47 g, 86% from 16, and 1.35 g, 79% from 32, reaction
time 16 h), mp 213–214◦C. δH ([D6]DMSO + drops TFA) 3.56
(3H, s, 4ꢀ-OCH3), 6.18 (1H, dd, J 2.4 and 8.6, H5ꢀ), 6.41
(1H, d, J 2.4, H3ꢀ), 6.81 (1H, d, J 8.6, H6ꢀ), 6.99–7.03 (2H,
m, H2ꢀꢀ,6ꢀꢀ), 7.13–7.15 (3H, m, H3ꢀꢀ,4ꢀꢀ,5ꢀꢀ), 7.22–7.28 (5H, m,
Ph). δC ([D6]DMSO + dropsTFA) 55.6 (4ꢀ-OCH3), 102.3 (C3ꢀ),
105.9 (C5ꢀ), 108.1 (C1ꢀ), 119.2 (C4), 128.4 (C1ꢀꢀ), 129.1 (C4ꢀꢀ),
129.2, 129.4 and 129.5 (C3ꢀꢀ,5ꢀꢀ, and 5-Ph), 130.2 (C4ꢀꢀꢀ), 131.0
(C2ꢀꢀ,6ꢀꢀ), 132.1 and 132.2 (C6ꢀ and C1ꢀꢀꢀ), 143.5 (C3), 144.8
(C5), 158.0 (C2ꢀ), 162.3 (C4ꢀ). m/z 342 (M+•, 100), 313 (5),
237 (6), 165 (13). νmax/cm−1 3381, 1631, 1577, 1524, 1446,
1386, 1318, 1284, 1260, 1202, 1163, 1035, 953, 832, 771, 598
(Found: C 77.3, H 5.3, N 8.1. C22H18N2O2 requires C 77.2,
H 5.3, N 8.2%).
3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(2-
methoxyphenyl)-5(3)-propylpyrazole 25
(1.25 g, 74%, reaction time 16 h), mp 135–136◦C. δH
([D6]DMSO + drops TFA) 0.76 (3H, t, J 7.4, CH3), 1.48 (2H,
sextet, J 7.4, CH2CH2CH3), 2.51 (2H, t, J 7.4, CH2CH2CH3),
3.60 (3H, s, 2ꢀꢀ-OCH3), 3.65 (3H, s, 4ꢀ-OCH3), 6.25 (1H, dd,
J 2.4 and 8.7, H5ꢀ), 6.51 (1H, d, J 2.4, H3ꢀ), 6.83 (1H, d, J
8.7, H6ꢀ), 6.91 (1H, dd, J 7.2 and 7.6, H5ꢀꢀ), 7.01–7.05 (2H,
m, H3ꢀꢀ and H6ꢀꢀ), 7.33 (1H, ddd, J 1.6, 7.6 and 7.9, H4ꢀꢀ).
δC ([D6]DMSO + drops TFA) 13.8 (CH3), 21.6 (CH2CH2CH3),
26.8 (CH2CH2CH3), 55.5 and 55.7 (2 × OCH3), 102.1 (C3ꢀ),
105.8 (C5ꢀ), 107.2 (C1ꢀ), 112.1 (C3ꢀꢀ), 115.2 (C4), 119.6 (C1ꢀꢀ),
3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(2-
methoxyphenyl)-5(3)-phenylpyrazole 29
(1.32 g, 71%, reaction time 16 h), mp 179–180◦C. δH
([D6]DMSO + drops TFA) 3.30 (3H, s, 2ꢀꢀ-OCH3), 3.54 (3H,
s, 4ꢀ-OCH3), 6.14 (1H, dd, J 1.7 and 8.6, H5ꢀ), 6.40 (1H, d, J 1.7,
H3ꢀ), 6.81–6.88 (2H, m, H6ꢀ and H5ꢀꢀ), 6.84 (1H, d, J 8.4, H3ꢀꢀ),

Synthesis of Hydroxyphenylpyrazoles
913
6.91 (1H, dd, J 1.3 and 7.3, H6ꢀꢀ), 7.21–7.36 (6H, m, H4ꢀꢀ and 5-
Ph). δC ([D6]DMSO + dropsTFA) 55.66 and 55.73 (2 × OCH3),
102.3 (C3ꢀ), 106.0 (C5ꢀ), 108.1 (C1ꢀ), 112.5 (C3ꢀꢀ), 115.7 (C4),
120.6 (C1ꢀꢀ), 121.7 (C5ꢀꢀ), 128.6, 129.0, 129.5, and 130.5 (Ph5),
131.0 (C4ꢀꢀ), 131.5 (C6ꢀ), 132.8 (C6ꢀꢀ), 144.3 (C3), 145.1 (C5),
157.9 (C2ꢀ), 158.5 (C2ꢀꢀ), 162.5 (C4ꢀ). m/z 372 (M+•, 15), 358
(14), 340 (6), 327 (100). νmax/cm−1 3386, 1630, 1584, 1522,
1484, 1462, 1435, 1365, 1283, 1158, 1123, 1030, 971, 862, 754,
689, 624 (Found: C 74.1, H 5.5, N 7.6. C23H20N2O3 requires
C 74.2, H 5.4, N 7.5%).
(1H, d, J 7.9, H3ꢀꢀ), 7.01 (2H, dd, J 1.4 and 7.5, H6ꢀꢀ), 7.13 (1H,
dt, J 1.4, 7.5 and 7.9, H4ꢀꢀ), 7.19–7.33 (5H, m, 1-Ph), 7.91 (1H,
s, H5). δC ([D6]DMSO + drops TFA) 55.2 (2ꢀꢀ-OCH3), 55.5 (4ꢀ-
OCH3), 101.7(C3ꢀ), 105.3(C5ꢀ), 110.7(C1ꢀ), 111.7(C3ꢀꢀ), 119.3
(C4), 120.6 (C5ꢀꢀ), 122.2 (C1ꢀꢀ), 124.3 (C2ꢀꢀꢀ,6ꢀꢀꢀ), 127.2 (C4ꢀꢀꢀ),
128.2 (C4ꢀꢀ), 129.0 (C3ꢀꢀꢀ,5ꢀꢀꢀ), 130.4 (C6ꢀ), 132.9 (C6ꢀ), 137.9
(C3), 141.06 (C1ꢀꢀꢀ), 141.13 (C5), 157.1 (C2ꢀꢀ), 157.5 (C2ꢀ),
161.4 (C4ꢀ).
Acknowledgements
Thanks are due to the Hungarian Scientific Research Fund (grant no. OTKA
T049468) and also to the University of Aveiro, ‘Fundação para a Ciência
e a Tecnologia,’ and FEDER for funding the Organic Chemistry Research
Unit. The technical assistance of Mrs M. Nagy and Mr L. Szabó is highly
appreciated.
General Procedure for the Reaction of Isoflavones
6–9, 11, 14, and 16 with Phenylhydrazine
A mixture of the appropriate starting material (6–9, 11, 14,
and 16, 5.0 mmol), phenylhydrazine (50.0 mmol) and pyridine
(40 mL) was refluxed for 48 h and then poured into H2O. The
precipitate was separated by filtration, washed with H2O, dried,
and recrystallized from MeOH to obtain pyrazoles 33 and 34.
Isoflavones 8, 9, 11, 14, and 16 were recovered unchanged.
References
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1,4-Diphenyl-3(5)-(2-hydroxy-
4-methoxyphenyl)pyrazole 33
(1.32 g, 77%), mp 176–177◦C. δH ([D6]DMSO) 3.70 (3H,
s, 4ꢀ-OCH3), 6.38 (1H, br d, J 8.3, H5ꢀ), 6.43 (1H, br s, H3ꢀ),
6.92 (1H, d, J 8.3, H6ꢀ), 7.13–7.34 (10H, m, 1-Ph and 4-Ph),
8.08 (1H, s, H5), 9.83 (1H, s, 2ꢀ-OH). δC ([D6]DMSO) 55.0 (4ꢀ-
OCH3), 101.3 (C3ꢀ), 105.2 (C5ꢀ), 109.9 (C1ꢀ), 122.1 (C4), 123.9
(C2ꢀꢀꢀ,6ꢀꢀꢀ), 126.1 (C4ꢀꢀꢀ), 126.5 (C3ꢀꢀꢀ,5ꢀꢀꢀ), 127.0 (C4ꢀꢀ), 128.5
and 128.7 (C2ꢀꢀ,3ꢀꢀ,5ꢀꢀ,6ꢀꢀ), 132.6 (C6ꢀ), 133.0 (C1ꢀꢀ), 136.4 (C3),
138.9 (C5), 140.3 (C1ꢀꢀꢀ), 157.2(C2ꢀ), 161.1(C4ꢀ). m/z 342 (M+•
,
100), 327 (5), 251 (6), 77 (42). νmax/cm−1 3343, 1629, 1594,
1573, 1517, 1495, 1430, 1372, 1296, 1147, 1032, 954, 768, 697,
658 (Found: C 77.3, H 5.3, N 8.3. C22H18N2O2 requires C 77.2,
H 5.3, N 8.2%).
δH ([D6]DMSO + drops TFA) 3.68 (3H, s, 4ꢀ-OCH3), 6.36
(1H, br d, J 8.4, H5ꢀ), 6.44 (1H, br s, H3ꢀ), 6.91 (1H, d, J 8.4,
H6ꢀ), 7.09–7.32 (10H, m, 1-Ph and 4-Ph), 8.04 (1H, s, H5). δC
([D6]DMSO + drops TFA) 55.2 (4ꢀ-OCH3), 101.8 (C3ꢀ), 105.6
(C5ꢀ), 110.3 (C1ꢀ), 122.7 (C4), 124.4 (C2ꢀꢀꢀ,6ꢀꢀꢀ), 126.5 (C4ꢀꢀ),
127.0 (C3ꢀꢀꢀ,5ꢀꢀꢀ), 127.4 (C4ꢀꢀ), 128.8 and 129.1 (C2ꢀꢀ,3ꢀꢀ,5ꢀꢀ,6ꢀꢀ),
133.0 (C6ꢀ), 133.5 (C1ꢀ), 137.0 (C3), 139.2 (C5), 140.8 (C1ꢀꢀꢀ),
157.7 (C2ꢀ), 161.6 (C4ꢀ).
3(5)-(2-Hydroxy-4-methoxyphenyl)-4-(2-
methoxyphenyl)-1-phenylpyrazole 34
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(465 mg, 25%), mp 214–215◦C. δH ([D6]DMSO) 3.66 (3H,
s, 2ꢀꢀ-OCH3), 3.70 (3H, s, 4ꢀ-OCH3), 6.31 (1H, br d, J 8.4, H5ꢀ),
6.35 (1H, s, H3ꢀ), 6.75 (1H, t, J 7.5, H5ꢀꢀ), 6.83 (1H, d, J 8.4,
H6ꢀ), 6.99 (2H, d, J 7.5, H3ꢀꢀ and H6ꢀꢀ), 7.16 (1H, t, J 7.5, H4ꢀꢀ),
7.21–7.36 (5H, m, 1-Ph), 7.90 (1H, s, H5), 9.71 (1H, s, 2ꢀ-OH).
δC ([D6]DMSO) 54.9 (2ꢀꢀ-OCH3), 55.2 (4ꢀ-OCH3), 101.1 (C3ꢀ),
104.8 (C5ꢀ), 110.2 (C1ꢀ), 111.3 (C3ꢀꢀ), 118.7 (C4), 120.1 (C5ꢀꢀ),
121.6 (C1ꢀꢀ), 123.7 (C2ꢀꢀꢀ,6ꢀꢀꢀ), 126.7 (C4ꢀꢀꢀ), 127.8 (C4ꢀꢀ), 128.6
(C3ꢀꢀꢀ,5ꢀꢀꢀ), 129.8 (C6ꢀꢀ), 132.4 (C6ꢀ), 137.1 (C3), 140.6 (C1ꢀꢀꢀ),
140.7 (C5), 156.5 (C2ꢀꢀ), 157.0 (C2ꢀ), 160.8 (C4ꢀ). m/z 372 (M+•
,
100), 357 (5), 250 (23), 77 (55). νmax/cm−1 3190, 1621, 1594,
1526, 1498, 1432, 1379, 1297, 1244, 1166, 1130, 1027, 960,
836, 752, 691, 666 (Found: C 74.1, H 5.5, N 7.5. C23H20N2O3
requires C 74.2, H 5.4, N 7.5%).
δH ([D6]DMSO + drops TFA) 3.65 (3H, s, 2ꢀꢀ-OCH3), 3.70
(3H, s, 4ꢀ-OCH3), 6.29 (1H, dd, J 2.3 and 8.44, H5ꢀ), 6.35 (1H, d,
J 2.3, H3ꢀ), 6.74 (1H, t, J 7.5, H5ꢀꢀ), 6.83 (1H, d, J 8.4, H6ꢀ), 6.95

914
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