Synthesis of pyrazolyl-2-pyrazolines by treatment of 3-(3-aryl-3- oxopropenyl)chromen-4-ones with hydrazine and their oxidation to bis(pyrazoles)

Article abstract of DOI:10.1002/ejoc.200400465

The synthesis of several 1-acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-4- yl]-2-pyrazolines 3a-3h has been accomplished by treatment of the 3-(3-aryl-3-oxopropenyl)chromen-4-ones 1a-h with hydrazine hydrate in hot acetic acid. The 1-acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines 2a-2f were also obtained as by-products. Oxidation of the 1-acetyl-4-pyrazolyl-2-pyrazolines 3a-3f with DDQ gave the 3(5)-aryl-5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl] pyrazoles 5a-5f. The oxidation of the 2-pyrazoline rings was accompanied by N-deacylation. The reaction mechanisms of both transformations are discussed, the first one being supported by experimental results. The structures of all new derivatives were established by NMR and the evidence of prototropic tautomerism is carefully discussed. Theoretical calculations of energies and of the ¹H and ¹³C NMR chemical shifts of the possible tautomeric forms of 5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3(5)-(4-methoxyphenyl)pyrazole (5c), by B3LYP and GIAO, showed that compounds of this type probably exist as mixtures of two tautomers. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400465

FULL PAPER
Synthesis of Pyrazolyl-2-pyrazolines by Treatment of 3-(3-Aryl-3-oxopropenyl)-
chromen-4-ones with Hydrazine and Their Oxidation to Bis(pyrazoles)
[a]
[b]
[b]
[b]
´
´
Albert Levai,* Artur M. S. Silva,* Diana C. G. A. Pinto, Jose A. S. Cavaleiro,
[c]
[c]
[d]
´
´
Ibon Alkorta, Jose Elguero, and Jozsef Jekö
´
Dedicated to Professor Dr. Karoly Lempert on the occasion of his 80th birthday
Keywords: B3LYP / Bispyrazoles / Chromones / GIAO / NMR spectroscopy / 4-Pyrazolyl-2-pyrazolines
The synthesis of several 1-acetyl-3-aryl-5-[3-(2-hydroxy- sults. The structures of all new derivatives were established
phenyl)pyrazol-4-yl]-2-pyrazolines 3a−3h has been accomp- by NMR and the evidence of prototropic tautomerism is care-
lished by treatment of the 3-(3-aryl-3-oxopropenyl)chromen-
4-ones 1a−h with hydrazine hydrate in hot acetic acid. The 1-
acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines 2a−2f were also
fully discussed. Theoretical calculations of energies and of
the 1H and 13C NMR chemical shifts of the possible tauto-
meric forms of 5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3(5)-
obtained as by-products. Oxidation of the 1-acetyl-4-pyrazo- (4-methoxyphenyl)pyrazole (5c), by B3LYP and GIAO,
lyl-2-pyrazolines 3a−3f with DDQ gave the 3(5)-aryl-5(3)-[3- showed that compounds of this type probably exist as mix-
(2-hydroxyphenyl)pyrazol-4-yl]pyrazoles 5a−5f. The oxida- tures of two tautomers.
tion of the 2-pyrazoline rings was accompanied by N-deacyl-
ation. The reaction mechanisms of both transformations are
discussed, the first one being supported by experimental re-
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
thiazoles under acetylating conditions.[2] Treatment with di-
azomethane provided 3-aroyl-4-(3-chromonyl)-2-pyrazol-
ines,[3] similarly to chalcones and related α,β-unsaturated
ketones.
The first representatives of 3-(3-aryl-3-oxopropenyl)chro-
men-4-ones 1 were described in the literature as early as
1976.[1] Although these chromones would appear to be con-
venient starting materials for the synthesis of a wide variety
of heterocyclic ring systems, their chemical transformations
have hitherto received relatively little attention, and for this
reason we decided to study their utility for the preparation
of nitrogen-containing heterocyclic compounds. In a first
series of experiments, 4-aryl-2-(3-chromonyl)-2,3-dihydro-
1,5-benzothiazepines were synthesized by treatment of com-
pounds 1 with 2-aminothiophenol.[2] These 1,5-benzothi-
azepines gave 2,2-disubstituted 3-acetyl-2,3-dihydrobenzo-
In continuation of these studies[2,3] and of our previous
work on the treatment of various chromone derivatives with
hydrazines,[4] investigation of the reactivity of 3-(3-aryl-3-
oxopropenyl)chromen-4-ones (1) towards hydrazines was
carried out. Since compounds 1 possess two moieties, a 3-
chromonyl group and an α,β-unsaturated ketone unit,
prone to reaction with hydrazines, their planned chemical
transformations seemed to be an especially challenging
task.
It is well established that treatment of α,β-unsaturated
ketones with hydrazines affords 3,5-disubstituted 2-pyrazol-
ines.[5] If it is also true for treatment of 3-(3-aryl-3-oxoprop-
enyl)chromen-4-ones with hydrazines, then the formation of
3-aryl-5-(3-chromonyl)-2-pyrazolines would be expected. It
has also been known for decades that treatment of various
chromone derivatives with hydrazines yields appropriately
substituted pyrazoles.[4,6] In this paper, the reaction of com-
pounds 1 with hydrazine hydrate and the structure eluci-
dation of the products obtained in this transformation are
described.
[a]
Department of Organic Chemistry, University of Debrecen,
P. O. Box 20, 4010 Debrecen, Hungary
Fax: (internat.) ϩ 36-52-453-836
E-mail: alevai@tigris.klte.hu
[b]
Department of Chemistry, University of Aveiro,
3810Ϫ193 Aveiro, Portugal
Fax: (internat.) ϩ 351-234-370-084
E-mail: arturs@dq.ua.pt
[c]
´
´
Instituto de Quımica Medica,
C/ Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ 34 91-5644853
E-mail: iqmbe17@iqm.csic.es
[d]
ICN Hungary Co., Ltd.,
´
4440 Tiszavasvari, Hungary
4672
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400465
Eur. J. Org. Chem. 2004, 4672Ϫ4679

Treatment of Chromones with Hydrazine
FULL PAPER
Results and Discussion
between the 3-chromonyl group and hydrazine might pre-
cede the reaction of the α,β-unsaturated ketone moiety,
yielding 3,4-disubstituted pyrazoles 4. Both intermediates
could then react with hydrazine to provide the pyrazolyl-2-
pyrazolines 3aϪ3h (Scheme 2).
Chemistry
In the study described here, 3-(3-aryl-3-oxopropenyl)-
chromen-4-ones (1aϪ1h) and hydrazine hydrate were
allowed to react in hot acetic acid, giving the 1-acetyl-3-
aryl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-pyrazolines
3aϪ3h (63Ϫ75%). The 1-acetyl-3-aryl-5-(3-chromonyl)-2-
pyrazolines 2aϪ2f (2Ϫ6%) were also obtained as by-
products (Scheme 1). Compounds 2aϪ2f and 3aϪ3f were
separated by column chromatography. In the cases of the
starting materials 1g and 1h, a minor component was also
detectable by thin-layer chromatography (TLC) in the crude
reaction mixtures, but we failed to isolate these minor com-
ponents by column chromatography. The structures of all
these new compounds (2aϪ2f and 3aϪ2h) were elucidated
by elemental analyses and by combined use of various spec-
troscopic methods.
For differentiation between the two possible formation
pathways of the pyrazolyl-2-pyrazolines 3aϪ3h an import-
ant consideration was that the 1-acetyl-3-aryl-5-(3-chro-
monyl)-2-pyrazolines 2aϪ2f were isolated as minor compo-
nents. The minor products 2b, 2c and 2f gave the appropri-
ate major products 3b, 3c and 3f on treatment with hydra-
zine hydrate in hot acetic acid (Scheme 3). It should also be
mentioned that the 3,4-disubstituted pyrazoles 4 shown in
Scheme 2 as other possible intermediates could not be de-
tected in the crude reaction mixtures (vide infra). In the
crude reaction mixtures only one kind of minor component
could be detected and in each case it was identified as the
1-acetyl-3-aryl-5-(3-chromonyl)-2-pyrazoline (2aϪ2f).
Scheme 3
The first attempt to oxidise the pyrazolyl-2-pyrazolines
3aϪ3f involved their treatment with chloranil in toluene or
dry dioxane at reflux. This oxidant proved to be weak, since
the pyrazolines 3aϪ3f were not oxidized, and could be
recovered, after several assays of different oxidation con-
ditions [e.g., different quantities of chloranil (2.5 to 4 equiv.)
and reaction times (3 to 8 days)]. As we had not obtained
the expected oxidation products we changed the oxidant to
DDQ. The oxidations of pyrazolines 3aϪ3f with DDQ in
toluene at reflux gave complex mixtures of compounds, but
in dry dioxane the bispyrazoles 5aϪ5f were obtained in
fairly good yields (51Ϫ60%). The oxidation of 2-pyrazoline
rings was accompanied by N-deacylation reactions. These
results can be envisaged to proceed by the DDQ dehydro-
genation mechanism.[7] In the present case one can postu-
late hydride transfer from the 5-positions of the 2-pyrazo-
line rings in 3aϪ3f, followed by an acylium cation transfer,
resulting in the formation of monoacetylated hydroquinone
and the bispyrazoles 5aϪ5f.
Scheme 1
The elemental analyses and mass spectra unequivocally
established the presence of two nitrogen atoms in the minor
products 2aϪ2f and four nitrogen atoms in the major prod-
ucts 3aϪ3h. In the IR spectra (see Exp. Sect.) of com-
pounds 2aϪ2f, two CϭO bands and one CϭN band were
assigned. The presence of NH, CϭO and CϭN bands in
the IR spectra of substances 3aϪ3h is consistent with pyr-
azolyl-2-pyrazoline structures. Structure elucidation of all
new compounds was completed by NMR spectroscopy.
The pyrazolyl-2-pyrazolines 3aϪ3h may be formed by re-
action between the starting materials 1aϪ1h and hydrazine
in two different ways, as shown in Scheme 2. As a first step,
the 1-acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines 2 may be
afforded, as in standard reactions between α,β-unsaturated
ketones and hydrazines.[5] As another possibility, reaction
NMR Spectroscopy
1
The H NMR spectra of the reaction mixtures of the 3-
(3-aryl-3-oxopropenyl)chromen-4-ones 1aϪ1h and hydra-
zine hydrate in [D6]DMSO each showed four broad singlets
at higher frequency values (at
δ
ϭ
9.78Ϫ10.15,
10.40Ϫ10.58, 12.61Ϫ12.73, 12.95Ϫ13.04 ppm), and the res-
onances of the 2-pyrazoline rings also appear as very broad
signals. After the addition of a few drops of trifluoroacetic
acid (TFA) the signals became narrow and it was possible
to identify the main compounds in these reaction mixtures
Scheme 2
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4673

´
A. Levai, A. M. S. Silva et al.
FULL PAPER
as the 1-acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]- peared as very broad signals. After the addition of a few
2-pyrazolines 3aϪ3f, together with the 1-acetyl-3-aryl-5-(3- drops of trifluoroacetic acid (TFA) the signals of those
chromonyl)-2-pyrazolines 2aϪ2f as by-products. These re- spectra became narrow and it was possible to assign all pro-
sults indicate that compounds 3aϪ3f exist in [D6]DMSO ton and carbon resonances of these compounds (5aϪ5f).
1
solution as mixtures of tautomers, the described high-reson-
The splitting of some signals in the H NMR spectra of
ance singlets being due to the NH and OH resonances with the bispyrazoles 5aϪ5f indicates a prototropic tautomerism
1
the prototropic rate increasing after the addition of TFA.
phenomenon. We carried out a more detailed H and 13C
For the structural characterisation of compounds 3aϪ3f NMR study of compound 5c (R ϭ OCH3), selected because
it is important to report the presence of three double dou- of its reasonable solubility in pure [D6]DMSO and its less
1
1
blets in their H NMR spectra (CDCl3 ϩ TFA), at δH
ϭ
complex H NMR spectrum. We also carried out theoreti-
3.08Ϫ3.15, 3.63Ϫ3.74 and 5.47Ϫ5.58 ppm, assigned to the cal calculations of both energies and shieldings. The ener-
resonances of 4-CH2 and H-5 in the 2-pyrazoline rings. The gies correspond to fully optimized geometries calculated at
resonances of the corresponding carbon atoms (δCH2
ϭ
the B3LYP/6-311ϩϩG** level as well as to absolute shield-
41.5Ϫ42.5, δC-5 ϭ 52.1Ϫ52.7 ppm), assigned by analysis of ings (σ, ppm) obtained by the GIAO approximation using
their HSQC spectra, and the presence of acetyl groups the same geometries on the parent compound 5a (R ϭ H).
(δH
ϭ
2.16Ϫ2.22 ppm and δC
ϭ
21.9Ϫ22.5 and Compound 5c could exist in four tautomeric forms corre-
167.9Ϫ169.5 ppm) supported the presence of acetylated 2- sponding to the two prototropic tautomers of each pyr-
pyrazoline rings. From the HMBC spectra of 3aϪ3f, corre- azole (Scheme 4).
lations between 4-CH2, H-5, H-2ЈЈ,6ЈЈ and C-3 (δC
ϭ
153.4Ϫ155.6 ppm) were established. These connectivities al-
lowed the complete assignment of the pyrazoline rings,
bearing aryl rings at their 3-positions and other substituents
at their 5-positions.
The 1H NMR spectra of compounds 3aϪ3f also each
presents a singlet at δH ϭ 7.91Ϫ8.11 ppm, corresponding
to the resonance of one proton, which correlates with the
carbon at δC ϭ 132.5Ϫ133.5 ppm in the HSQC spectra. In
the HMBC spectra, these proton signals present connec-
tivities with C-5 of the 2-pyrazoline ring and with two other
carbons appearing at δC
141.1Ϫ142.7 ppm. These data and the connectivities be-
tween H-6ЈЈЈ and the carbon appearing at δC
ϭ
121.7Ϫ124.2 and
ϭ
141.1Ϫ142.7 ppm supported the 1-acetyl-3-aryl-5-[3-(2-
hydroxyphenyl)pyrazol-4-yl]-2-pyrazoline (3aϪ3f) struc-
tures and the assignment of their C-3Ј and C-4Ј carbon res-
onances. The structural identification of compounds 3g and
3h was similar to that described for 3aϪ3f.
The most important features of the H and 13C NMR
spectra of compounds 2aϪ2f that allowed the establishment
of their structures are: i) the resonances of the acetyl
groups, δH ϭ 2.27Ϫ2.29 ppm (singlet) and δC ϭ 21.0Ϫ21.8
1
Scheme 4
The relative energies (absolute energy for 33: Ϫ988.81751
and 167.6Ϫ167.9 ppm, ii) resonances typical of H-2ЈЈ and Hartrees) show that the tautomerism of the first pyrazole
C-2ЈЈ of the chromone nucleus, δH ϭ 8.24Ϫ8.29 ppm ring should always be 3-substituted (i.e., the OϪH···N hy-
(singlet) and δC ϭ 154.4Ϫ154.8 ppm, iii) the resonances of drogen bond is preferred over the NϪH···O one). These two
the carbonyl groups of the chromone moieties, δC
167.6Ϫ167.9 ppm, and iv) the signals characteristic of a 2- 1 kJ/mol) and both should be present in solution.
pyrazoline ring, as three double doublet signals at δH
The 1H NMR spectrum (dilute solution: 5 mg in 0.5 mL)
ϭ
tautomers, 33 and 35, have very similar energies (less than
ϭ
3.22Ϫ3.27, 3.70Ϫ3.75 and 5.39Ϫ5.43 ppm, corresponding shows the well resolved signals of two compounds in a ratio
to the resonances of 2 ϫ H-4 and H-5. Some connectivities of about 55:45. When the concentration of 5c in [D6]DMSO
observed in their HMBC spectra (H-2ЈЈ Ǟ C-5, C-3ЈЈ, C- is increased (9 mg in 0.5 mL), the signals broaden but are
4ЈЈ and C-9ЈЈ; H-2Ј,6Ј Ǟ C-3) supported the structures of still resolved. Finally (at 12 mg in 0.5 mL of [D6]DMSO),
the 1-acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines (2aϪ2f) the coalescence of all signals belonging to 33 and 35 is ob-
and allowed the unequivocal assignment of some of their served. This corresponds to the well known fact that the
quaternary carbon resonances.
prototropic rate increases when the concentration
The 1H NMR spectra of the 3(5)-aryl-5(3)-[3-(2-hydroxy- increases.[8Ϫ10] To assign the signals to each tautomer (the
phenyl)pyrazol-4-yl]pyrazoles (5aϪ5f) in [D6]DMSO 55:45 difference is difficult to use for some signals), we cal-
showed some broad singlets at higher frequency values culated the σ values of the different protons of tautomers
(around 10 and 13 ppm) and the other resonances also ap- 33 (45%) and 35 (55%). The results are reported in Table 1.
4674
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4672Ϫ4679

Treatment of Chromones with Hydrazine
FULL PAPER
With the exception of C-5Ј of tautomer 33 (experimental
137.6, predicted 130.7 ppm) the remaining 19 points fitted
to Equation (2).
Table 1. Experimentally determined (5c, δ, ppm, [D6]DMSO) and
calculated (5a, σ, ppm) signals of tautomers 33 and 35 of com-
pound 5c
Signal
δ (5c, 33)
σ (5a, 33)
δ (5c, 35)
σ (5a, 35)
δ13C (ppm) ϭ (190Ϯ1) Ϫ (1.19Ϯ0.02) σ13C (ppm), n ϭ 19,
r2 ϭ 0.995
(2)
H-3Ј"
H-4Ј"
H-5Ј"
H-6Ј"
OH
NH-1Ј
H-5Ј
7.01
7.25
6.78
24.6103
24.5694
25.1315
24.6454
21.8024
22.8339
24.0408
22.7372
25.2166
7.01
7.25
6.78
7.25
13.33
10.28
7.85
9.90
6.36
24.7516
24.5666
25.1211
24.5952
21.7711
22.7655
24.2907
22.8646
25.0649
7.22
In summary, the complex case of the double tautomerism
of the bispyrazoles 5 has been solved by a combination of
NMR spectroscopy and theoretical calculations.
13.02
10.10
8.13
10.70
6.14
NH-1(or 2)
H-4
1
If the H and 13C NMR spectra (in CDCl3 ϩ TFA) of
the 1-acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-
pyrazolines 3aϪ3f are compared with those of compounds
5aϪ5f, the absence of the acetyl group and the oxidation
of the 2-pyrazoline ring into another pyrazole ring can be
deduced. The disappearance of the aliphatic region signals
is observed, together with the appearance of the signals at
If only the CH protons are used and account is taken
that the 3ЈЈЈ to 6ЈЈЈ signals have been estimated from 2D
spectra, Equation (1) relating experiment and calculations
is acceptable [Equation (1)].
δH
ϭ 6.50Ϫ6.52 ppm (as a singlet), and at δC ϭ
101.5Ϫ103.2, 141.6Ϫ142.3 and 147.0Ϫ148.0 ppm (in the
13C NMR spectra), attributed to the resonance of H-4, C-
4, C-5 and C-3, respectively, in the formed pyrazole ring.
Confirmation of these assignments was based on the con-
nectivities found in the HMBC spectra of the 3(5)-aryl-5(3)-
[3-(2-hydroxyphenyl)pyrazol-4-yl]pyrazoles (5aϪ5f) (H-
2ЈЈ,6ЈЈ Ǟ C-3; H-4 Ǟ C-3,C-5 and C-4Ј; H-5Ј Ǟ C-3Ј,C-4Ј
and C-5).
δ1H (ppm) ϭ (43 Ϯ 4) Ϫ (1.46 Ϯ 0.16) σ1H (ppm), n ϭ 12,
r2 ϭ 0.90
(1)
The OH and both NH signals of 5c disappear on ad-
dition of a drop of D2O to the [D6]DMSO solution, those
in the 10 ppm zone more quickly than those in the 13 ppm
zone. These last are the OH signals, protected from H/D
exchange by the hydrogen bond. If the signals follow the
order of the calculated σ, then the assignment in Table 1
should be correct.
Experimental Section
Although compound 5c was slightly soluble in
[D6]DMSO, its 13C NMR spectrum was difficult to obtain
(the reason why the solvent used in the Exp. Sect. is a mix-
ture of [D6]DMSO and TFA in a 99:1 ratio). The data re-
ported in Table 2 are a compromise between the decoupled
spectrum (considerable noise) and the HSQC experiment.
General Remarks: Melting points were measured in a Kofler hot-
stage apparatus and are uncorrected. IR (KBr) spectra were re-
corded on PerkinϪElmer 16 PC and MATTSON 7000 FTIR spec-
trometers. Mass spectra were recorded on VG Trio-2 and VG Auto-
spec Q instruments. Elemental analyses were obtained in a Carlo
Erba 1106 apparatus. NMR spectra were recorded on a Bruker
1
Avance 300 spectrometer (300.13 for H and 75.47 MHz for 13C),
with CDCl3 as a solvent, if not stated otherwise. Chemical shifts
(δ) are reported in ppm and coupling constants (J) in Hz. The
internal standard was TMS. 1H assignments were made by 2D
gCOSY and NOESY (mixing time of 800 ms) experiments, while
13C assignments were made with the aid of 2D gHSQC and
gHMBC (delays for one bond and long-range J C/H couplings
were optimised for 145 and 7 Hz, respectively) experiments. Thin-
layer chromatography (TLC) was performed with Merck silica gel
(60 F254) foils with 1,2-dichloroethane as eluent. The starting mate-
rials 1aϪ1h were synthesized by known procedures.[1]
Table 2. Experimentally determined (5c, δ, ppm, [D6]DMSO) and
calculated (5a, σ, ppm) signals of tautomers 33 and 35 of com-
pound 5c
Signal
δ (5c, 33)
σ (5a, 33)
δ (5c, 35)
σ (5a, 35)
C-3
C-4
C-5
C-3Ј
C-4Ј
C-5Ј
C-1Ј"
C-2Ј"
C-3Ј"
C-4Ј"
C-5Ј"
C-6Ј"
C-1"
C-2"/6"
C-3"/5"
C-4"
OMe
Ϫ
32.9632
74.6200
28.9739
26.4331
61.5873
49.8284
61.0735
17.7478
60.4585
47.4935
61.7179
48.8731
Ϫ
160.0
98.7
137.3
160.8
Ϫ
129.4
114.2
Ϫ
116.3
131.1
118.9
129.8
Ϫ
126.3
114.2
Ϫ
24.0707
77.2951
42.5235
26.2206
66.8172
49.7409
63.2599
17.7149
60.4585
47.4935
60.2312
50.2525
Ϫ
100.7
155.5
158.8
116.1
137.6
118.0
Ϫ
116.2
131.1
118.9
129.8
Ϫ
Computational Details: The structures of the molecules were in-
itially optimized at the B3LYP/6-31G* computational level[11,12] in
the GAUSSIAN98 package.[13] The conformations were confirmed
to be minima by frequency calculations at the same computational
level. Further optimization was carried out at the B3LYP/6-
311ϩϩG**[14] level and the geometries obtained at this level were
used to calculate the chemical shieldings by the GIAO method.[15]
126.3
114.2
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Treatment of the 3-(3-Aryl-3-oxopropenyl)chromen-4-ones with Hy-
drazine Hydrate: A mixture of the appropriate starting material
(1aϪ1h, 5.0 mmol), hydrazine hydrate (50.0 mmol) and acetic acid
(30 mL) was heated at reflux for 3 h, and then poured into water.
55.1
55.1
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´
A. Levai, A. M. S. Silva et al.
FULL PAPER
The precipitate was filtered off, washed with water and dried. The
minor products (2aϪ2f) and the major products (3aϪ3h) were
separated by silica gel column chromatography with 1,2-dichloro-
ethane as eluent and recrystallised from methanol.
J ϭ 3.0 Hz, C-1ЈЈ), 128.9 (d, J ϭ 8.5 Hz, C-2Ј,6Ј), 134.3 (C-7ЈЈ),
154.2 (C-3), 154.7 (C-2ЈЈ), 155.7 (C-9ЈЈ), 163.2 (d, J ϭ 248.1 Hz,
C-4Ј), 167.8 (COCH3), 175.3 (C-4ЈЈ) ppm. MS: m/z ϭ 350 [Mϩ].
C20H15FN2O3 (350.3): calcd. C 68.56, H 4.32, N 7.99; found C
68.52, H 4.34, N 7.96.
Minor Products
1-Acetyl-3-(4-chlorophenyl)-5-(3-chromonyl)-2-pyrazoline (2e): Yield
4%. M.p. 200Ϫ201 °C. IR (KBr): ν˜ ϭ 1666 (CϭO), 1644 (CϭO),
1610 (CϭN) cmϪ1. 1H NMR ([D6]DMSO): δ ϭ 2.27 (s, 3 H, CH3),
3.26 (dd, J ϭ 5.3, 17.8 Hz, 1 H, H-4trans), 3.71 (dd, J ϭ 12.2,
17.8 Hz, 1 H, H-4cis), 5.42 (dd, J ϭ 5.3, 12.2 Hz, 1 H, H-5),
7.47Ϫ7.52 (m, 1 H, H-6ЈЈ), 7.54 (d, J ϭ 8.5 Hz, 2 H, H-3Ј,5Ј), 7.65
(d, J ϭ 8.3 Hz, 1 H, H-8ЈЈ), 7.78 (d, J ϭ 8.5 Hz, 2 H, H-2Ј,6Ј),
7.79Ϫ7.83 (m, 1 H, H-7ЈЈ), 8.03 (d, 1 H, J ϭ 7.7 Hz, H-5ЈЈ), 8.29
(s, 1 H, H-2ЈЈ) ppm. 13C NMR ([D6]DMSO): δ ϭ 21.8 (CH3), 38.9
(C-4), 54.0 (C-5), 118.4 (C-8ЈЈ), 122.1 (C-3ЈЈ), 123.5 (C-10ЈЈ), 125.0
(C-5ЈЈ), 125.6 (C-6ЈЈ), 128.4 (C-2Ј,6Ј), 128.9 (C-3Ј,5Ј), 130.3 (C-1Ј),
134.4 (C-7ЈЈ), 134.7 (C-4Ј), 154.1 (C-3), 154.8 (C-2ЈЈ), 155.7 (C-
9ЈЈ), 167.9 (COCH3), 175.4 (C-4ЈЈ) ppm. MS: m/z ϭ 366 [Mϩ].
C20H15ClN2O3 (336.8): calcd. C 65.49, H 4.12, N 7.63; found C
65.45, H 4.14, N 7.66.
1-Acetyl-5-(3-chromonyl)-3-phenyl-2-pyrazoline (2a): Yield 5%.
M.p. 218Ϫ219 °C. IR (KBr): ν˜ ϭ 1662 (CϭO), 1640 (CϭO), 1607
(CϭN) cmϪ1. 1H NMR ([D6]DMSO): δ ϭ 2.29 (s, 3 H, CH3), 3.27
(dd, J ϭ 5.4, 17.8 Hz, 1 H, H-4trans), 3.75 (dd, J ϭ 12.2, 17.8 Hz,
1 H, H-4cis), 5.43 (dd, J ϭ 5.4, 12.2 Hz, 1 H, H-5), 7.46Ϫ7.53 (m,
4 H, H-6ЈЈ,3Ј,4Ј,5Ј), 7.67 (dd, J ϭ 8.4, 0.8 Hz, 1 H, H-8ЈЈ),
7.77Ϫ7.85 (m, 3 H, H-7ЈЈ,2Ј,6Ј), 8.05 (dd, J ϭ 8.0, 1.6 Hz, 1 H, H-
5ЈЈ), 8.29 (s, 1 H, H-2) ppm. 13C NMR ([D6]DMSO): δ ϭ 21.8
(CH3), 39.1 (C-4), 53.7 (C-5), 118.4 (C-8ЈЈ), 122.3 (C-3ЈЈ), 123.5 (C-
10ЈЈ), 124.9 (C-5ЈЈ), 125.6 (C-6ЈЈ), 126.6 (C-2Ј,6Ј), 128.8 (C-3Ј,5Ј),
130.2 (C-4Ј), 131.3 (C-1Ј), 134.3 (C-7ЈЈ), 154.6 (C-2ЈЈ), 155.1 (C-3),
155.7 (C-9ЈЈ), 167.8 (COCH3), 175.4 (C-4ЈЈ) ppm. MS: m/z ϭ 332
[Mϩ]. C20H16N2O3 (332.3): calcd. C 72.28, H 4.85, N 8.42; found
C 72.31, H 4.83, N 8.46.
1-Acetyl-5-(3-chromonyl)-3-(4-methylphenyl)-2-pyrazoline
(2b):
1-Acetyl-3-(4-bromophenyl)-5-(3-chromonyl)-2-pyrazoline (2f): Yield
6%. M.p. 206Ϫ207 °C. IR (KBr): ν˜ ϭ 1666 (CϭO), 1644 (CϭO),
1610 (CϭN) cmϪ1. 1H NMR ([D6]DMSO): δ ϭ 2.27 (s, 3 H, CH3),
3.26 (dd, J ϭ 5.4, 17.8 Hz, 1 H, H-4trans), 3.71 (dd, J ϭ 12.2,
17.8 Hz, 1 H, H-4cis), 5.42 (dd, J ϭ 5.4, 12.2 Hz, 1 H, H-5), 7.49
(ddd, J ϭ 1.0, 7.5, 7.9 Hz, 1 H, H-6ЈЈ), 7.63Ϫ7.73 (m, 5 H, H-
8ЈЈ,2Ј,3Ј,5Ј,6Ј), 7.81 (dt, J ϭ 1.5, 7.9 Hz, 1 H, H-7ЈЈ), 8.03 (dd, 1
H, J ϭ 1.5, 7.5 Hz, H-5ЈЈ), 8.29 (s, 1 H, H-2ЈЈ) ppm. 13C NMR
([D6]DMSO): δ ϭ 21.8 (CH3), 38.9 (C-4), 54.0 (C-5), 118.4 (C-8ЈЈ),
122.1 (C-3ЈЈ), 123.5 (C-4Ј,10ЈЈ), 124.9 (C-5ЈЈ), 125.6 (C-6ЈЈ), 128.5
(C-2Ј,6Ј), 130.6 (C-1Ј), 131.7 (C-3Ј,5Ј), 134.3 (C-7ЈЈ), 154.2 (C-3),
154.7 (C-2ЈЈ), 155.7 (C-9ЈЈ), 167.9 (COCH3), 175.3 (C-4ЈЈ) ppm.
MS: m/z ϭ 411 [Mϩ]. C20H15BrN2O3 (411.2): calcd. C 58.41, H
3.68, N 6.81; found C 58.44, H 3.66, N 6.84.
Yield 2%. M.p. 243Ϫ245 °C. IR (KBr): ν˜ ϭ 1658 (CϭO), 1642
1
(CϭO), 1610 (CϭN) cmϪ1. H NMR ([D6]DMSO): δ ϭ 2.28 (s, 3
H, CH3), 2.36 (s, 3 H, 4Ј-CH3), 3.24 (dd, J ϭ 5.2, 17.8 Hz, 1 H,
H-4trans), 3.71 (dd, J ϭ 12.2, 17.8 Hz, 1 H, H-4cis), 5.40 (dd, J ϭ
5.2, 12.2 Hz, 1 H, H-5), 7.29 (d, J ϭ 7.9 Hz, 2 H, H-3Ј,5Ј), 7.50
(dd, J ϭ 7.2, 7.6 Hz, 1 H, H-6ЈЈ), 7.67 (d, J ϭ 7.8 Hz, 1 H, H-8ЈЈ),
7.67 (d, J ϭ 7.9 Hz, 2 H, H-2Ј,6Ј), 7.82 (dd, J ϭ 7.2, 7.8 Hz, 1 H,
H-7ЈЈ), 8.04 (d, 1 H, J ϭ 7.6 Hz, H-5ЈЈ), 8.27 (s, 1 H, H-2ЈЈ) ppm.
13C NMR ([D6]DMSO): δ ϭ 21.0 (4Ј-CH3), 21.8 (CH3), 39.2 (C-
4), 53.6 (C-5), 118.4 (C-8ЈЈ), 122.3 (C-3ЈЈ), 123.5 (C-10ЈЈ), 124.9 (C-
5ЈЈ), 125.6 (C-6ЈЈ), 126.6 (C-2Ј,6Ј), 128.6 (C-1Ј), 129.3 (C-3Ј,5Ј),
134.3 (C-7ЈЈ), 140.0 (C-4Ј), 154.5 (C-2ЈЈ), 155.0 (C-3), 155.7 (C-
9ЈЈ), 167.7 (COCH3), 175.3 (C-4ЈЈ) ppm. MS: m/z ϭ 346 [Mϩ].
C21H18N2O3 (346.3): calcd. C 72.82, H 5.24, N 8.08; found C 72.86,
H 5.26, N 8.11.
Major Products
1-Acetyl-5-(3-chromonyl)-3-(4-methoxyphenyl)-2-pyrazoline
(2c):
1-Acetyl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3-phenyl-2-pyrazoline
Yield 4%. M.p. 214Ϫ215 °C. IR (KBr): ν˜ϭ 1658 (CϭO), 1640 (Cϭ
(3a): Yield 75%. M.p. 248Ϫ249 °C. IR (KBr): ν˜ ϭ 3216 (NH), 1624
1
O), 1608 (CϭN) cmϪ1. H NMR ([D6]DMSO): δ ϭ 2.28 (s, 3 H,
(CϭO), 1594 (CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA): δ ϭ
.
CH3), 3.22 (dd, J ϭ 5.2, 17.7 Hz, 1 H, H-4trans), 3.70 (dd, J ϭ 12.1, 2.16 (s, 3 H, CH3), 3.14 (dd, J ϭ 5.2, 17.9 Hz, 1 H, H-4trans), 3.69
17.7 Hz, 1 H, H-4cis), 3.81 (s, 3 H, OCH3), 5.39 (dd, J ϭ 5.2, (dd, J ϭ 11.9, 17.9 Hz, 1 H, H-4cis), 5.51 (dd, J ϭ 5.2, 11.9 Hz, 1
12.1 Hz, 1 H, H-5), 7.02 (d, J ϭ 8.4 Hz, 2 H, H-3Ј,5Ј), 7.50 (dd, H, H-5), 6.83 (t, J ϭ 7.5 Hz, 1 H, H-5ЈЈЈ), 6.94 (d, J ϭ 8.0 Hz, 1
J ϭ 7.5, 7.8 Hz, 1 H, H-6ЈЈ), 7.65 (d, J ϭ 8.2 Hz, 1 H, H-8ЈЈ), 7.71 H, H-3ЈЈЈ), 7.22 (ddd, J ϭ 1.4, 7.5, 8.0 Hz, 1 H, H-4ЈЈЈ), 7.30Ϫ7.34
(d, J ϭ 8.4 Hz, 2 H, H-2Ј,6Ј), 7.81 (dd, J ϭ 7.5, 8.2 Hz, 1 H, H-
7ЈЈ), 8.04 (d, 1 H, J ϭ 7.8 Hz, H-5ЈЈ), 8.24 (s, 1 H, H-2ЈЈ) ppm. 13
NMR ([D6]DMSO): δ ϭ 21.8 (CH3), 39.2 (C-4), 53.5 (C-5), 55.4
(m, 4 H, H-6ЈЈЈ,3ЈЈ,4ЈЈ,5ЈЈ), 7.58Ϫ7.61 (m, 2 H, H-2ЈЈ,6ЈЈ), 8.11 (s,
1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 22.4 (CH3),
42.2 (C-4), 52.6 (C-5), 114.7 (C-1ЈЈЈ), 117.4 (C-3ЈЈЈ), 120.4 (C-5ЈЈЈ),
C
(OCH3), 114.2 (C-3Ј,5Ј), 118.4 (C-8ЈЈ), 122.3 (C-3ЈЈ), 123.5 (C-10ЈЈ), 123.9 (C-4Ј), 127.7 (C-2ЈЈ,6ЈЈ), 129.7 (C-3ЈЈ,5ЈЈ), 131.3 (C-4ЈЈ), 132.0
123.8 (C-1Ј), 124.9 (C-5ЈЈ), 125.6 (C-6ЈЈ), 128.3 (C-2Ј,6Ј), 134.3 (C- (C-6ЈЈЈ), 132.4 (C-1ЈЈ), 132.9 (C-4ЈЈЈ), 133.3 (C-5Ј), 142.4 (C-3Ј),
7ЈЈ), 154.4 (C-2ЈЈ), 154.8 (C-3), 155.7 (C-9ЈЈ), 160.8 (C-4Ј), 167.6 155.4 (C-3), 156.8 (C-2ЈЈЈ), 169.3 (COCH3) ppm. MS: m/z ϭ 346
(COCH3), 175.4 (C-4ЈЈ) ppm. MS: m/z ϭ 362 [Mϩ]. C21H18N2O4 [Mϩ]. C20H18N4O2 (346.3): calcd. C 69.35, H 5.24, N 16.17; found
(362.4): calcd. C 69.60, H 5.01, N 7.73; found C 69.64, H 4.98, 7.77.
C 69.32, H 5.26, N 16.13.
1-Acetyl-5-(3-chromonyl)-3-(4-fluorophenyl)-2-pyrazoline (2d): Yield
1-Acetyl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3-(4-methylphenyl)-2-
2%. M.p. 226Ϫ227 °C. IR (KBr): ν˜ ϭ 1658 (CϭO), 1640 (CϭO), pyrazoline (3b): Yield 63%. M.p. 253Ϫ254 °C. IR (KBr): ν˜ ϭ 3216
1
1608 (CϭN) cmϪ1. 1H NMR ([D6]DMSO): δ ϭ 2.28 (s, 3 H, CH3), (NH), 1640 (CϭO), 1594 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
3.27 (dd, J ϭ 5.3, 17.8 Hz, 1 H, H-4trans), 3.73 (dd, J ϭ 12.2, TFA): δ ϭ 2.18 (s, 3 H, CH3), 2.27 (s, 3 H, 4ЈЈ-CH3), 3.13 (dd, J ϭ
17.8 Hz, 1 H, H-4cis), 5.42 (dd, J ϭ 5.3, 12.2 Hz, 1 H, H-5), 7.32
(t, JH,H and JH,F ϭ 8.9 Hz, 2 H, H-3Ј,5Ј), 7.50 (dd, J ϭ 7.1, 8.0 Hz, 4cis), 5.51 (dd, J ϭ 5.1, 11.9 Hz, 1 H, H-5), 6.86 (dd, J ϭ 7.1,
1 H, H-6ЈЈ), 7.67 (d, 1 H, J ϭ 8.4 Hz, H-8ЈЈ), 7.79Ϫ7.85 (m, 3 H, 7.6 Hz, 1 H, H-5ЈЈЈ), 6.97 (d, J ϭ 8.3 Hz, 1 H, H-3ЈЈЈ), 7.17 (d, J ϭ
5.1, 17.8 Hz, 1 H, H-4trans), 3.69 (dd, J ϭ 11.9, 17.8 Hz, 1 H, H-
H-7ЈЈ and H-2Ј,6Ј), 8.04 (dd, 1 H, J ϭ 1.6, 8.0 Hz, H-5ЈЈ), 8.29 (s, 8.1 Hz, 2 H, H-3ЈЈ,5ЈЈ), 7.26 (ddd, J ϭ 1.6, 7.1, 8.3 Hz, 1 H, H-
1 H, H-2ЈЈ) ppm. 13C NMR ([D6]DMSO): δ ϭ 21.8 (CH3), 39.1 4ЈЈЈ), 7.38 (dd, J ϭ 1.6, 7.6 Hz, 1 H, H-6ЈЈЈ), 7.52 (d, J ϭ 8.1 Hz,
(C-4), 53.8 (C-5), 115.8 (d, J ϭ 22.0 Hz, C-3Ј,5Ј), 118.4 (C-8ЈЈ), 2 H, H-2ЈЈ,6ЈЈ), 8.11 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ
122.2 (C-3ЈЈ), 123.5 (C-10ЈЈ), 124.9 (C-5ЈЈ), 125.6 (C-6ЈЈ), 128.0 (d, TFA): δ ϭ 21.5 (4ЈЈ-CH3), 22.2 (CH3), 42.0 (C-4), 52.2 (C-5), 114.6
4676
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4672Ϫ4679

Treatment of Chromones with Hydrazine
FULL PAPER
(C-1ЈЈЈ), 117.1 (C-3ЈЈЈ), 120.1 (C-5ЈЈЈ), 123.4 (C-4Ј), 127.4 (C- 8.0 Hz, 1 H, H-3ЈЈЈ), 7.24 (ddd, J ϭ 1.4, 7.5, 8.0 Hz, 1 H, H-4ЈЈЈ),
2ЈЈ,6ЈЈ), 129.3 (C-1ЈЈ), 130.0 (C-3ЈЈ,5ЈЈ), 131.7 (C-6ЈЈЈ), 132.4 (C- 7.34 (dd, J ϭ 1.4, 7.5 Hz, 1 H, H-6ЈЈЈ), 7.55 (s, 4 H, H-
4ЈЈЈ), 133.0 (C-5Ј), 141.1 (C-4ЈЈ), 142.0 (C-3Ј), 155.1 (C-3), 156.5 2ЈЈ,3ЈЈ,5ЈЈ,6ЈЈ), 8.10 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ
(C-2ЈЈЈ), 168.7 (COCH3) ppm. MS: m/z ϭ 360 [Mϩ]. C21H20N4O2
(360.4): calcd. C 69.98, H 5.59, N 15.54; found C 69.99, H 5.57,
N 15.52.
TFA): δ ϭ 22.1 (CH3), 41.6 (C-4), 52.4 (C-5), 114.7 (C-1ЈЈЈ), 116.9
(C-3ЈЈЈ), 120.0 (C-5ЈЈЈ), 123.0 (C-4Ј), 124.4 (C-4ЈЈ), 129.1 (C-
2ЈЈ,6ЈЈ), 131.2 (C-1ЈЈ), 131.5 (C-6ЈЈЈ), 132.2 (C-4ЈЈЈ), 132.4 (C-
3ЈЈ,5ЈЈ), 133.1 (C-5Ј), 141.9 (C-3Ј), 154.1 (C-3), 156.3 (C-2ЈЈЈ), 168.7
(COCH3) ppm. MS: m/z ϭ 425 [Mϩ]. C20H17BrN4O2 (425.2):
calcd. C 56.48, H 4.03, N 13.17; found C 56.44, H 4.04, N 13.14.
1-Acetyl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3-(4-methoxyphenyl)-
4-pyrazoline (3c): Yield 71%. M.p. 235Ϫ237 °C. IR (KBr): ν˜ ϭ 3232
1
(NH), 1644 (CϭO), 1608 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
TFA): δ ϭ 2.13 (s, 3 H, CH3), 3.08 (dd, J ϭ 5.0, 17.7 Hz, 1 H, H-
1-Acetyl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3-(1-naphthyl)-2-
4
trans), 3.63 (dd, J ϭ 11.7, 17.7 Hz, 1 H, H-4cis), 3.69 (s, 3 H, pyrazoline (3g): Yield 72%. M.p. 240Ϫ241 °C. IR (KBr): ν˜ ϭ 3216
1
OCH3), 5.47 (dd, J ϭ 5.0, 11.7 Hz, 1 H, H-5), 6.82 (t, J ϭ 7.3 Hz, (NH), 1644 (CϭO), 1594 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
1 H, H-5ЈЈЈ), 6.85 (d, J ϭ 8.7 Hz, 2 H, H-3ЈЈ,5ЈЈ), 6.94 (d, J ϭ TFA): δ ϭ 2.28 (s, 3 H, CH3), 3.34 (dd, J ϭ 5.1, 17.5 Hz, 1 H, H-
7.9 Hz, 1 H, H-3ЈЈЈ), 7.22 (dd, J ϭ 7.3, 7.9 Hz, 1 H, H-4ЈЈЈ), 7.30
4trans), 3.97 (dd, J ϭ 11.9, 17.5 Hz, 1 H, H-4cis), 5.56 (dd, J ϭ 5.1,
(d, J ϭ 7.3 Hz, 1 H, H-6ЈЈЈ), 7.51 (d, J ϭ 8.7 Hz, 2 H, H-2ЈЈ,6ЈЈ), 11.9 Hz, 1 H, H-5), 6.86 (t, J ϭ 7.4 Hz, 1 H, H-5ЈЈЈ), 6.94 (d, J ϭ
8.06 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 22.5 7.9 Hz, 1 H, H-3ЈЈЈ), 7.23 (dd, J ϭ 7.4, 7.9 Hz, 1 H, H-4ЈЈЈ), 7.41
(CH3), 42.5 (C-4), 52.7 (C-5), 56.2 (OCH3), 114.7 (C-1ЈЈЈ), 115.3
(C-3ЈЈ,5ЈЈ), 117.7 (C-3ЈЈЈ), 120.7 (C-5ЈЈЈ), 124.2 (C-4Ј), 125.1 (C- 7ЈЈ and H-8ЈЈ), 7.92Ϫ7.96 (m, 2 H, H-4ЈЈ and H-5ЈЈ), 8.12 (s, 1 H,
1ЈЈ), 129.6 (C-2ЈЈ,6ЈЈ), 132.3 (C-6ЈЈЈ), 133.2 (C-4ЈЈЈ), 133.5 (C-5Ј),
H-5Ј), 9.09 (d, J ϭ 8.4 Hz, 1 H, H-2ЈЈ) ppm. 13C NMR ([D6]DMSO
(d, J ϭ 7.4 Hz, 1 H, H-6ЈЈЈ), 7.45Ϫ7.61 (m, 4 H, H-3ЈЈ, H-6ЈЈ, H-
142.7 (C-3Ј), 155.6 (C-3), 157.1 (C-2ЈЈЈ), 162.7 (C-4ЈЈ), 169.5 ϩ TFA): δ ϭ 22.3 (CH3), 44.3 (C-4), 51.1 (C-5), 115.0 (C-1ЈЈЈ),
(COCH3) ppm. MS: m/z ϭ 376 [Mϩ]. C21H20N4O3 (376.4): calcd.
C 67.01, H 5.36, N 14.88; found C 66.96, H 5.38, N 14.84.
116.8 (C-3ЈЈЈ), 119.8 (C-5ЈЈЈ), 122.7 (C-4Ј), 125.7 and 128.0 (C-1ЈЈ,
C-6ЈЈ and C-7ЈЈ), 127.2 (C-2ЈЈ), 130.6 (C-10ЈЈ), 131.45 (C-4ЈЈ), 126.8
(C-3ЈЈ), 129.3 (C-5ЈЈ and C-8ЈЈ), 131.35 (C-6ЈЈЈ), 131.8 (C-4ЈЈЈ),
132.9 (C-5Ј), 134.3 (C-9ЈЈ), 141.7 (C-3Ј), 155.2 (C-3), 156.1 (C-2ЈЈЈ),
168.6 (COCH3) ppm. MS: m/z ϭ 396 [Mϩ]. C24H20N4O2 (396.4):
calcd. C 72.71, H 5.08, N 14.13; found C 72.76, H 5.05, N 14.09.
1-Acetyl-3-(4-fluorophenyl)-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-
pyrazoline (3d): Yield 64%. M.p. 247Ϫ248 °C. IR (KBr): ν˜ ϭ 3204
1
(NH), 1636 (CϭO), 1606 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
TFA): δ ϭ 2.16 (s, 3 H, CH3), 3.14 (dd, J ϭ 5.0, 17.9 Hz, 1 H, H-
4trans), 3.69 (dd, J ϭ 11.9, 17.9 Hz, 1 H, H-4cis), 5.53 (dd, J ϭ 5.0, 1-Acetyl-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-3-(2-naphthyl)-2-
11.9 Hz, 1 H, H-5), 6.83 (t, J ϭ 7.5 Hz, 1 H, H-5ЈЈЈ), 6.93 (d, J ϭ
pyrazoline (3h): Yield 69%. M.p. 261Ϫ262 °C. IR (KBr): ν˜ ϭ 3216
1
8.1 Hz, 1 H, H-3ЈЈЈ), 7.12 (t, JH,H ϭ JH,F ϭ 8.7 Hz, 2 H, H-3ЈЈ,5ЈЈ), (NH), 1640 (CϭO), 1588 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
7.22 (dd, J ϭ 7.5, 8.1 Hz, 1 H, H-4ЈЈЈ), 7.32 (d, J ϭ 7.5 Hz, 1 H, TFA): δ ϭ 2.18 (s, 3 H, CH3), 3.27 (dd, J ϭ 5.1, 17.8 Hz, 1 H, H-
H-6ЈЈЈ), 7.63 (dd, JH,F ϭ 5.5 and JH,H ϭ 8.7 Hz, 2 H, H-2ЈЈ,6ЈЈ), 4trans), 3.77 (dd, J ϭ 11.9, 17.8 Hz, 1 H, H-4cis), 5.55 (dd, J ϭ 5.1,
8.09 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 22.2
11.9 Hz, 1 H, H-5), 6.82 (t, J ϭ 7.4 Hz, 1 H, H-5ЈЈЈ), 6.91 (d, J ϭ
(CH3), 42.0 (C-4), 52.5 (C-5), 114.7 (C-1ЈЈЈ), 116.5 (d, J ϭ 22.0 Hz, 7.9 Hz, 1 H, H-3ЈЈЈ), 7.19 (dd, J ϭ 7.4, 7.9 Hz, 1 H, H-4ЈЈЈ), 7.32
C-3ЈЈ,5ЈЈ), 117.2 (C-3ЈЈЈ), 120.2 (C-5ЈЈЈ), 123.4 (C-4Ј), 128.7 (d, J ϭ (d, J ϭ 7.4 Hz, 1 H, H-6ЈЈЈ), 7.41Ϫ7.46 (m, 2 H, H-5ЈЈ and H-8ЈЈ),
3.1 Hz, C-1ЈЈ), 129.7 (d, J ϭ 8.5 Hz, C-2ЈЈ,6ЈЈ), 131.8 (C-6ЈЈЈ), 132.6
7.78Ϫ7.88 (m, 4 H, H-3ЈЈ, H-4ЈЈ, H-6ЈЈ and H-7ЈЈ), 7.89 (s, 1 H,
(C-4ЈЈЈ), 133.2 (C-5Ј), 142.2 (C-3Ј), 154.4 (C-3), 156.6 (C-2ЈЈЈ), H-1ЈЈ), 8.11 (s, 1 H, H-5Ј) ppm. NMR ([D6]DMSO ϩ TFA): δ ϭ
164.5 (d, J ϭ 248.7 Hz, C-4ЈЈ), 169.0 (COCH3) ppm. MS: m/z ϭ 22.4 (CH3), 42.2 (C-4), 52.8 (C-5), 114.7 (C-1ЈЈЈ), 117.5 (C-3ЈЈЈ),
364 [Mϩ]. C20H17FN4O2 (364.3): calcd. C 65.93, H 4.70, N 15.37;
found C 65.97, H 4.18, N 15.41.
120.5 (C-5ЈЈЈ), 124.0 (C-4Ј), 124.4 (C-3ЈЈ), 127.9 and 128.4 (C-1ЈЈ,
C-5ЈЈ and C-8ЈЈ), 128.9, 129.3 and 129.6 (C-4ЈЈ, C-6ЈЈ, C-7ЈЈ), 130.1
(C-2ЈЈ), 132.1 (C-6ЈЈЈ), 133.0 (C-4ЈЈЈ), 133.4 (C-5Ј), 134.1 (C-9Ј),
135.1 (C-10ЈЈ), 142.6 (C-3Ј), 155.6 (C-3), 156.9 (C-2ЈЈЈ), 169.5
(COCH3) ppm. MS: m/z ϭ 396 [Mϩ]. C24H20N4O2 (396.4): calcd.
C 72.71, H 5.08, N 14.13; found C 72.67, H 5.09, N 14.18.
1-Acetyl-3-(4-chlorophenyl)-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-
pyrazoline (3e): Yield 65%. M.p. 258Ϫ259 °C. IR (KBr): ν˜ ϭ 3224
1
(NH), 1640 (CϭO), 1596 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
TFA): δ ϭ 2.22 (s, 3 H, CH3), 3.14 (dd, J ϭ 4.9, 17.8 Hz, 1 H, H-
4trans), 3.74 (dd, J ϭ 11.9, 17.8 Hz, 1 H, H-4cis), 5.58 (dd, J ϭ 4.9, Transformation of the 1-Acetyl-3-aryl-5-(3-chromonyl)-2-pyrazolines
11.9 Hz, 1 H, H-5), 6.87 (t, J ϭ 7.5 Hz, 1 H, H-5ЈЈЈ), 6.94 (d, J ϭ 2b, 2c and 2f into the 1-Acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-
8.0 Hz, 1 H, H-3ЈЈЈ), 7.25 (ddd, J ϭ 1.5, 7.5, 8.0 Hz, 1 H, H-4ЈЈЈ), 4-yl]-2-pyrazolines 3b, 3c and 3f: A mixture of the appropriate 2-
7.39 (dd, J ϭ 1.5, 7.5 Hz, 1 H, H-6ЈЈЈ), 7.47 (d, 2 H, J ϭ 8.6 Hz, pyrazoline (2b, 2c, 2f, 1.0 mmol), hydrazine hydrate (0.5 mL,
H-3ЈЈ,5ЈЈ), 7.67 (d, 2 H, J ϭ 8.6 Hz, H-2ЈЈ,6ЈЈ), 7.91 (s, 1 H, H-5Ј) 10.0 mmol) and acetic acid (2.0 mL) was heated at reflux for 6 h,
ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 21.9 (CH3), 41.5 (C-4),
and then poured into water. The precipitate was separated by fil-
52.1 (C-5), 115.6 (C-1ЈЈЈ), 116.3 (C-3ЈЈЈ), 119.4 (C-5ЈЈЈ), 121.7 (C- tration, washed with water and dried to afford compounds 3b
4Ј), 128.5 (C-2ЈЈ,6ЈЈ), 129.0 (C-3ЈЈ,5ЈЈ), 130.4 (C-1ЈЈ), 130.8 (C-6ЈЈЈ), (81%), 3c (85%) and 3f (79%). The substances prepared in this way
130.9 (C-4ЈЈЈ), 132.5 (C-5Ј), 135.1 (C-4ЈЈ), 141.2 (C-3Ј), 153.4 (C-
were identical in every respect with those obtained as major prod-
3), 155.6 (C-2ЈЈЈ), 167.9 (COCH3) ppm. MS: m/z ϭ 380 [Mϩ]. ucts from treatment of 1b, 1c or 1f with hydrazine hydrate.
C20H17ClN4O2 (380.8): calcd. C 63.08, H 4.50, N 14.71; found C
63.04, H 4.54, N 14.73.
Synthesis of the 3(5)-Aryl-5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]py-
razoles 5aϪ5f: DDQ (159 mg, 0.7 mmol) was added to a solution
1-Acetyl-3-(4-bromophenyl)-5-[3-(2-hydroxyphenyl)pyrazol-4-yl]-2-
of the appropriate 1-acetyl-3-aryl-5-[3-(2-hydroxyphenyl)pyrazol-4-
pyrazoline (3f): Yield 70%. M.p. 262Ϫ263 °C. IR (KBr): ν˜ ؍ 3224 yl]-2-pyrazolines 3aϪ3f (0.7 mmol) in dry dioxane (30 mL). The
1
(NH), 1640 (CϭO), 1592 (CϭN) cmϪ1. H NMR ([D6]DMSO ϩ
mixture was heated at reflux under nitrogen until the consumption
TFA): δ ϭ 2.17 (s, 3 H, CH3), 3.15 (dd, J ϭ 5.1, 17.9 Hz, 1 H, H-
of the starting material was complete (ഠ10 hours). The solution
4trans), 3.71 (dd, J ϭ 12.0, 17.9 Hz, 1 H, H-4cis), 5.55 (dd, J ϭ 5.1, was then evaporated to dryness and the residue was dissolved in
12.0 Hz, 1 H, H-5), 6.85 (t, J ϭ 7.5 Hz, 1 H, H-5ЈЈЈ), 6.94 (d, J ϭ chloroform (40 mL) and washed with a saturated aqueous solution
Eur. J. Org. Chem. 2004, 4672Ϫ4679
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4677

´
A. Levai, A. M. S. Silva et al.
FULL PAPER
of potassium hydrogen carbonate (50 mL). The organic layer was
collected and dried with anhydrous sodium sulfate, and the solvent
was evaporated to dryness. The crude products were purified by
flash chromatography on silica gel (SDS type 60 A C.C., 40Ϫ63
µm); with chloroform as eluent a mixture of three unidentified
compounds was collected, while the bispyrazoles 5aϪf were eluted
with a 1:1 mixture of chloroform/ethyl acetate.
8.7 Hz, 2 H, H-3ЈЈ,5ЈЈ), 7.25 (ddd, J ϭ 1.5, 6.9, 8.3 Hz, 1 H, H-
4ЈЈЈ), 7.26 (dd, J ϭ 1.5, 7.5 Hz, 1 H, H-6ЈЈЈ), 7.69 (dd, JH,H
ϭ
8.7 Hz and JH,F ϭ 5.3 Hz, 2 H, H-2ЈЈ,6ЈЈ), 8.23 (s, 1 H, H-5Ј) ppm.
13C NMR ([D6]DMSO ϩ TFA): δ ϭ 102.6 (C-4), 110.8 (C-4Ј),
116.9 (d, J ϭ 18.2 Hz, C-3ЈЈ,5ЈЈ), 117.3 (C-1ЈЈЈ), 117.6 (C-3ЈЈЈ),
120.4 (C-5ЈЈЈ), 126.1 (d, J ϭ 2.9 Hz, C-1ЈЈ), 129.4 (d, J ϭ 8.4 Hz,
C-2ЈЈ,6ЈЈ), 132.0 (C-6ЈЈЈ), 132.3 (C-4ЈЈЈ), 135.4 (C-5Ј), 142.2 (C-5),
143.0 (C-3Ј), 147.1 (C-3), 156.7 (C-2ЈЈЈ), 164.3 (d, J ϭ 218.9 Hz,
C-4ЈЈ) ppm. EI-MS: m/z (rel. int.) ϭ 320 (62) [Mϩ·], 303 (100), 219
(7), 182 (6), 171 (5), 160 (5), 122 (4). C18H13FN4O (320.32): calcd.
C 67.49, H 4.09, N 17.49; found C 67.54, H 4.07, N 17.52.
5(3)-[3-(2-Hydroxyphenyl)pyrazol-4-yl]-3(5)-phenylpyrazole
(5a):
Yield 55% (116.3 mg). M.p. 218Ϫ219 °C (recrystallised from cyclo-
hexane/ethyl acetate). IR (KBr): ν˜ ϭ 3434 (OH), 3234 (NH), 1613
(CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA; 500.13 MHz): δ ϭ
.
3(5)-(4-Chlorophenyl)-5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]-
pyrazole (5e): Yield 54% (127.2 mg). M.p. 251Ϫ253 °C (recrystal-
lised from cyclohexane/ethyl acetate). IR (KBr): ν˜ϭ 3454 (OH),
6.55 (s, 1 H, H-4), 6.89 (t, J ϭ 7.6 Hz, 1 H, H-5ЈЈЈ), 7.00 (d, J ϭ
8.0 Hz, 1 H, H-3ЈЈЈ), 7.29 (dd, J ϭ 7.6, 8.0 Hz, 1 H, H-4ЈЈЈ), 7.34
(d, J ϭ 7.6 Hz, 1 H, H-6ЈЈЈ), 7.37 (t, J ϭ 7.6 Hz, 1 H, H-4ЈЈ), 7.44
(t, J ϭ 7.6 Hz, 2 H, H-3ЈЈ,5ЈЈ), 7.70 (d, J ϭ 7.6 Hz, 2 H, H-2ЈЈ,6ЈЈ),
8.25 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA;
125.8 MHz): δ ϭ 101.7 (C-4), 110.4 (C-4Ј), 116.8 (C-1ЈЈЈ,3ЈЈЈ), 119.7
(C-5ЈЈЈ), 126.4 (C-2ЈЈ,6ЈЈ), 129.55 (C-4ЈЈ), 129.61 (C-3ЈЈ,5ЈЈ), 129.7
(C-1ЈЈ), 131.38 and 131.41) C-4ЈЈЈ and C-6ЈЈЈ, 134.8 (C-5Ј), 141.6
(C-5), 142.1 (C-3Ј), 147.2 (C-3), 156.1 (C-2ЈЈЈ) ppm. EI-MS: m/z
(rel. int.) ϭ 302 (62) [Mϩ·], 285 (100), 182 (7), 171 (7), 151 (5), 115
(4). C18H14N4O (302.33): calcd. C 71.51, H 4.67, N 18.53; found C
71.61, H 4.65, N 18.56.
3236 (NH), 1624 (CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA):
.
δ ϭ 6.52 (s, 1 H, H-4), 6.85 (dd, J ϭ 7.3, 7.6 Hz, 1 H, H-5ЈЈЈ), 6.98
(d, J ϭ 8.1 Hz, 1 H, H-3ЈЈЈ), 7.26 (ddd, J ϭ 1.6, 7.3, 8.1 Hz, 1 H,
H-4ЈЈЈ), 7.30 (dd, J ϭ 1.6, 7.6 Hz, 1 H, H-6ЈЈЈ), 7.41 (d, J ϭ 8.5 Hz,
2 H, H-3ЈЈ,5ЈЈ), 7.65 (d, J ϭ 8.5 Hz, 2 H, H-2ЈЈ,6ЈЈ), 8.27 (s, 1 H,
H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 102.6 (C-4), 111.4
(C-4Ј), 116.6 (C-1ЈЈЈ), 117.5 (C-3ЈЈЈ), 120.3 (C-5ЈЈЈ), 128.6 (C-
2ЈЈ,6ЈЈ), 129.0 (C-1ЈЈ), 130.2 (C-3ЈЈ,5ЈЈ), 132.0 (C-6ЈЈЈ), 132.3 (C-
4ЈЈЈ), 135.1 (C-5Ј), 135.4 (C-4ЈЈ), 141.8 (C-5), 142.8 (C-3Ј), 147.0
(C-3), 156.7 (C-2ЈЈЈ) ppm. EI-MS: m/z (rel. int.) ϭ 338 (Mϩ·
,
37Cl,
25), 336 (Mϩ· 35Cl, 61), 321 (35), 319 (100), 284 (5), 252 (8), 171
,
5(3)-[3-(2-Hydroxyphenyl)pyrazol-4-yl]-3(5)-(4-methylphenyl)-
pyrazole (5b): Yield 60% (132.7 mg). M.p. 239Ϫ241 °C (recrystal-
lised from cyclohexane/ethyl acetate). IR (KBr): ν˜ ϭ 3388 (OH),
(11), 150 (27), 118 (10), 104 (12). C18H13ClN4O (336.77): calcd. C
64.19, H 3.89, N 16.64; found C 64.23, H 3.91, N 16.68.
3207 (NH), 1618 (CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA):
.
3(5)-(4-Bromophenyl)-5(3)-[3-(2-hydroxyphenyl)pyrazol-4-yl]-
pyrazole (5f): Yield 54% (144.0 mg). M.p. 253Ϫ254 °C (recrystal-
lised from cyclohexane/ethyl acetate). IR (KBr): ν˜ ϭ 3462 (OH),
δ ϭ 2.25 (s, 3 H, CH3), 6.51 (s, 1 H, H-4), 6.84 (dd, J ϭ 7.1, 7.8 Hz,
1 H, H-5ЈЈЈ), 6.95 (d, J ϭ 8.0 Hz, 1 H, H-3ЈЈЈ), 7.20 (d, J ϭ 8.0 Hz,
2 H, H-3ЈЈ,5ЈЈ), 7.22Ϫ7.26 (m, 1 H, H-4ЈЈЈ), 7.27 (dd, J ϭ 1.4,
7.8 Hz, 1 H, H-6ЈЈЈ), 7.54 (d, J ϭ 8.0 Hz, 2 H, H-2ЈЈ,6ЈЈ), 8.19 (s,
1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 21.6 (CH3),
102.6 (C-4), 109.9 (C-4Ј), 117.1 (C-1ЈЈЈ), 117.7 (C-3ЈЈЈ), 120.6 (C-
5ЈЈЈ), 125.8 (C-1ЈЈ), 127.5 (C-2ЈЈ,6ЈЈ), 131.0 (C-3ЈЈ,5ЈЈ), 132.1 (C-
6ЈЈЈ), 132.4 (C-4ЈЈЈ), 135.9 (C-5Ј), 141.7 (C-4ЈЈ), 142.8 (C-5), 143.5
(C-3Ј), 148.0 (C-3), 156.8 (C-2ЈЈЈ) ppm. EI-MS: m/z (rel. int.) ϭ 316
(56) [Mϩ·], 299 (100), 285 (6), 182 (6), 171 (7), 115 (6). C19H16N4O
(316.36): calcd. C 72.13, H 5.10, N 17.71; found C 72.17, H 5.08,
N 17.67.
3222 (NH), 1639 (CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA):
.
δ ϭ 6.50 (s, 1 H, H-4), 6.82 (t, J ϭ 7.5 Hz, 1 H, H-5ЈЈЈ), 6.95 (d,
J ϭ 7.9 Hz, 1 H, H-3ЈЈЈ), 7.20Ϫ7.27 (m, 2 H, H-4ЈЈЈ,6ЈЈЈ), 7.51 (d,
J ϭ 8.9 Hz, 2 H, H-3ЈЈ,5ЈЈ), 7.55 (d, J ϭ 8.9 Hz, 2 H, H-2ЈЈ,6ЈЈ),
8.23 (s, 1 H, H-5Ј) ppm. 13C NMR ([D6]DMSO ϩ TFA): δ ϭ 103.2
(C-4), 111.5 (C-4Ј), 116.7 (C-1ЈЈЈ), 118.0 (C-3ЈЈЈ), 120.8 (C-5ЈЈЈ),
124.5 (C-4ЈЈ), 129.3 (C-2ЈЈ,6ЈЈ), 129.3 (C-1ЈЈ), 132.3 (C-6ЈЈЈ), 132.9
(C-4ЈЈЈ), 133.6 (C-3ЈЈ,5ЈЈ), 135.5 (C-5Ј), 142.3 (C-5), 143.5 (C-3Ј),
147.4 (C-3), 157.1 (C-2ЈЈЈ) ppm. EI-MS: m/z (rel. int.) ϭ 382 (Mϩ·
81Br, 65), 380 (Mϩ· 79Br, 64), 365 (99), 363 (100), 332 (13), 315
,
,
5(3)-[3-(2-Hydroxyphenyl)pyrazol-4-yl]-3(5)-(4-methoxyphenyl)-
pyrazole (5c): Yield 58% (134.8 mg). M.p. 240Ϫ242 °C (recrystal-
lised from cyclohexane/ethyl acetate). IR (KBr): ν˜ ϭ 3462 (OH),
(18), 302 (8), 285 (19), 182 (14), 155 (6). C18H13BrN4O (381.23):
calcd. C 56.71, H 3.44, N 14.70; found C 56.74, H 3.42, N 14.73.
3241 (NH), 1624 (CϭN) cmϪ1 1H NMR ([D6]DMSO ϩ TFA):
.
δ ϭ 3.75 (s, 3 H, OCH3), 6.51 (s, 1 H, H-4), 6.87 (dt, J ϭ 0.9,
7.6 Hz, 1 H, H-5ЈЈЈ), 6.97 (dd, J ϭ 0.9, 8.1 Hz, 1 H, H-3ЈЈЈ), 7.01
(d, J ϭ 8.9 Hz, 2 H, H-3ЈЈ,5ЈЈ), 7.27 (ddd, J ϭ 1.6, 7.6, 8.1 Hz, 1
H, H-4ЈЈЈ), 7.31 (dd, J ϭ 1.6, 7.6 Hz, 1 H, H-6ЈЈЈ), 7.64 (d, J ϭ
8.9 Hz, 2 H, H-2ЈЈ,6ЈЈ), 8.19 (s, 1 H, H-5Ј) ppm. 13C NMR
([D6]DMSO ϩ TFA): δ ϭ 55.8 (OCH3), 101.5 (C-4), 109.2 (C-4Ј),
115.3 (C-3ЈЈ,5ЈЈ), 116.94 (C-1ЈЈЈ), 116.99 (C-3ЈЈЈ), 119.9 (C-5ЈЈЈ),
120.6 (C-1ЈЈ), 128.5 (C-2ЈЈ,6ЈЈ), 131.5 (C-4ЈЈЈ,6ЈЈЈ), 135.5 (C-5Ј),
142.3 (C-5), 142.6 (C-3Ј), 147.2 (C-3), 156.1 (C-2ЈЈЈ), 161.5 (C-4ЈЈ)
ppm. EI-MS: m/z (rel. int.) ϭ 332 (83) [Mϩ·], 315 (100), 300 (4),
272 (4), 182 (7), 171 (9), 115 (4). C19H16N4O2 (332.36): calcd. C
68.66, H 4.85, N 16.86; found C 68.59, H 4.87, N 16.83.
Acknowledgments
Thanks are due to the Hungarian National Research Foundation
(Grant No. OTKA T034123) and also to the University of Aveiro,
ˆ
‘‘Fundaca˜o para a Ciencia e Tecnologia’’ and FEDER for funding
¸
the Organic Chemistry Research Unit. The technical assistance of
Mrs. M. Nagy is highly appreciated.
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4672Ϫ4679

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FULL PAPER
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Received July 3, 2004
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