New bis(chalcones) and their transformation into bis(pyrazoline) and bis(pyrazole) derivatives

Article abstract of DOI:10.1002/ejoc.200390117

The reaction of bis(chalcones) 1a-d and bis(chalcone) tetrabromo derivatives 3a-d with hydrazine hydrate gave bis(pyrazolines) 4a-d and bis(pyrazoles) 5a-d, respectively. Bis(pyrazoles) 5e,f bearing hydroxyphenyl substituents have been prepared from the r

Full text of DOI:10.1002/ejoc.200390117

FULL PAPER
New Bis(chalcones) and Their Transformation into Bis(pyrazoline) and
Bis(pyrazole) Derivatives
[a]
[a]
[a]
[b]
´
´
Diana C. G. A. Pinto, Artur M. S. Silva,* Jose A. S. Cavaleiro, and Jose Elguero
Keywords: Nitrogen heterocycles / NMR spectroscopy / Natural products
The reaction of bis(chalcones) 1a−d and bis(chalcone) tetra-
bromo derivatives 3a−d with hydrazine hydrate gave bis(pyr-
ponding benzyloxy-substituted 5c,d gave very poor yields.
The structures of all new compounds have been established
azolines) 4a−d and bis(pyrazoles) 5a−d, respectively. Bis(pyr- by extensive NMR spectroscopic studies.
azoles) 5e,f bearing hydroxyphenyl substituents have been
prepared from the reaction of bis(chromones) 6c,d with hy- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
drazine hydrate, because their synthesis from the corres- Germany, 2003)
various procedures have been developed for their syn-
Introduction
theses.[12] As a result, a wide variety of pyrazoles and pyra-
zolines have hitherto been described in the literature.[12,13]
Chalconoids constitute an important class of naturally
This interest of scientists in such compounds has been
stimulated by their promising pharmacological, agrochem-
ical, and analytical applications. For instance, in the last
decade 2-(hydroxyphenyl)pyrazoles have been used as ultra-
violet stabilisers,[14] as analytical reagents in the com-
plexation of transition metal ions,[15] and also as analgesic
agents and as platelet aggregation inhibitors.[16] These ap-
plications — especially their ability to form complexes with
a variety of metal ions[15] and our interest in the prepara-
tion and molecular structure of 2-(hydroxyphenyl)-
pyrazoles[17Ϫ19] — have prompted us to devote our atten-
tion to new types of these compounds, the 3-aryl-5-[3- and
4-(3-arylpyrazol-5-yl)phenyl]pyrazoles, and some other de-
rivatives.
The most common method for the synthesis of 2-(hydro-
xyphenyl)pyrazoles involves the treatment of β-diketones
with hydrazine hydrate.[12] Our recent studies indicate, how-
ever, that these pyrazoles can be obtained in good overall
yields from the reaction of hydrazine hydrate with
chromones.[18Ϫ19] There are, however, reports indicating
that the treatment of 2-hydroxychalcones or 2-hydroxychal-
cone dibromides with phenylhydrazine in an alkaline me-
dium affords pyrazoline derivatives.[20] Here we report the
synthesis of 3-aryl-5-[3- and 4-(3-aryl-2-pyrazolin-5-yl)-
phenyl]-2-pyrazolines 4aϪd and 3-aryl-5-[3- and 4-(3-aryl-
pyrazol-5-yl)phenyl]pyrazoles 5aϪf from bis(chalcones)
1aϪf and bis(chalcone) tetrabromo derivatives 3aϪf.[21]
occurring flavonoid compounds exhibiting a wide spectrum
of biological activities, which include potential applications
as artificial sweeteners, new drugs, and agrochemicals.[1Ϫ10]
The term chalconoid has been used to designate the whole
family of compounds possessing a 1,3-diarylpropane skel-
eton, which can be functionalised in the propane chain by
the presence of olefinic, keto and/or hydroxy groups. The
most common and widespread compounds of the chal-
conoid group are the chalcones, which possess a 1,3-diaryl-
2-propen-1-one carbon framework,[1,3,5] but there are also
other important derivatives of this family, such as the dihy-
drochalcones.[2,4,9]
Chalcones, one class of the anthochlor pigments, usually
give yellow to orange colours to the tissues in which they
are located. Although these compounds are not responsible
for pigmentation in the most-yellow-coloured flowers, they
are still attractive to insects and in such a way they contrib-
ute to the flowers’ pollination.[11] The importance of these
compounds is due not only to their colours, but also to
their biological activities and the fact that they are interme-
diates in the synthesis and biosynthesis of other
flavonoids.[1Ϫ3,5Ϫ10] Following our interest in the chemistry
of flavonoid-type compounds we have synthesised new chal-
cone derivatives 1 and studied their transformations into
new bis(2-pyrazolines) 4 and bis(pyrazoles) 5.
Pyrazoles and their reduced forms pyrazolines are well-
known nitrogen-containing heterocyclic compounds and
[a]
Department of Chemistry, University of Aveiro,
3810-193 Aveiro, Portugal
Results and Discussion
Fax: (internat.) ϩ 351-234/370084
E-mail: arturs@dq.ua.pt
[b]
Chemistry
´
´
Instituto de Quımica Medica,
C/ Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ 34-91/5644853
E-mail: iqm17@iqm.csic.es
Bis(chalcones) 1aϪd were obtained in moderate yields
(42Ϫ56%) from the base-catalysed aldol reaction of 2Ј-hy-
Eur. J. Org. Chem. 2003, 747Ϫ755  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0747 $ 20.00ϩ.50/0
747

D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Elguero
FULL PAPER
droxyacetophenone and appropriate phthaldicarboxal- (Scheme 2, B). Following our previous work on the bromin-
dehydes (Scheme 1, A). In this synthesis the desired chal- ation of 2-styrylchromones,[23] we used a similar procedure
cones resulted from the condensation of two molecules of for the bromination of bis(chalcones) 1e,f, which proved
2Ј-hydroxyacetophenone with the appropriate dialdehyde. It also to be a convenient method for these substrates because
seems, however, that the second condensation competes the corresponding tetrabromo derivatives 3c,d were ob-
with a Cannizzaro reaction, since an amount of 2Ј-hydroxy- tained in good yields (Scheme 2, B).
chalcones bearing carboxyl or hydroxymethyl groups in the
B ring were obtained (see Exp. Sect.). The former of these
derivatives could also have been obtained by the oxidation
of the second carboxaldehyde. The formation of these by-
products is responsible for the moderate yields of the bi-
s(chalcones). The reaction of 2Ј-hydroxyacetophenone with
ortho-phthaldicarboxaldehyde, under the same conditions,
gave the products of the Cannizzaro reaction and a new
compound 2 in a poor yield. Some changes in the experi-
mental procedure, such as protection from daylight and
adding the ortho-phthaldicarboxaldehyde after degassing
the reaction mixture, allowed the synthesis of compound 2
to proceed in good yield, but still we could not obtain the
desired chalcone. This result indicates that, under our ex-
perimental conditions, oxidation of the second carboxal-
Scheme 2
dehyde group is easier in ortho-phthaldicarboxaldehyde
than in the meta- or para-phthaldicarboxaldehydes. Thus,
after the aldol intermediate has formed a cyclisation reac-
tion occurs to give lactone 2 (Scheme 1, B). The presence
of this compound is concluded from its NMR spectroscopic
data, such as the carbonyl carbon atoms at δ ϭ 169.9 ppm
(lactone) and δ ϭ 201.6 ppm (ketone), the hydroxy group
Our first approach to the synthesis of bis(pyrazoles)
5aϪd began with the reaction in methanol under reflux of
the bis(chalcones) 1aϪd with an excess of hydrazine hydrate
(Scheme 3). These reactions yielded the corresponding
bis(2-pyrazolines) 4aϪd, which precipitated in the reaction
medium and were removed by filtration and washed with
ethanol. Next, we attempted to oxidise these bis(2-pyrazol-
ines) 4aϪd into pyrazole derivatives by treatment with chlo-
ranil in toluene at reflux. This oxidant proved to be too
strong, causing the pyrazoline ring to be destroyed and the
isolation of the bis(chalcones) 1aϪd. Several other oxida-
tion methods (MnO2, O2, S8) were tested, but similar results
were obtained.
involved in an intramolecular hydrogen bond (δ
ϭ
12.02 ppm) and an ABX spin system (2 ϫ 1Ј-H and 3-H).
Scheme 1
Scheme 3
The bis(chalcone) tetrabromo derivatives 3a,b were ob-
To circumvent the oxidation step for the conversion of
tained in good yields by treatment of a carbon tetrachloride bis(pyrazolines) 4aϪd into the corresponding bis(pyrazoles)
solution of the appropriate bis(chalcones) 1a,b with brom- 5aϪd, we decided to use the bis(chalcone) tetrabromo de-
ine (Scheme 2, A). We did not apply the same procedure to rivatives 3aϪd. Treatment of compounds 3aϪd with an ex-
bis(chalcones) 1c,d since their A ring is activated and there cess of hydrazine hydrate, in methanol under reflux, af-
was the possibility that halogenation could occur in this forded the desired pyrazoles 5aϪd in good overall yields
ring. Generally the bromination of 2Ј-hydroxychalcones (50Ϫ61%, Scheme 4). This synthetic approach constitutes a
gives poor yields, but if the hydroxy group is protected the new method for the preparation of these types of pyrazoles.
reaction gives the corresponding dibromo derivatives in The debenzylation of pyrazoles 5c,d was carried out with
good yields.[22] Taking this feature into account, the bi- hydrogen bromide in glacial acetic acid (33%), but the cor-
s(chalcones) 1e,f were obtained in very good yields by treat- responding bis[3-(2-hydroxyphenyl)pyrazoles] 5e,f were ob-
ing the appropriate bis(chalcones) 1c,d with benzyl chloride tained in poor yields and their purification was difficult.
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Eur. J. Org. Chem. 2003, 747Ϫ755

Bis(chalcones) and Their Transformation into Bis(pyrazoline) and Bis(pyrazole) Derivatives
FULL PAPER
Recalling our previous work on pyrazoles from 2-substi- addition to the other, or by the superposition of the NMR
tuted chromones,[18,19] we tried to prepare these bis[3-(2- spectra of the possible two diastereoisomers.
hydroxyphenyl)pyrazoles] 5e,f from chromones 6c,d. This
The main characteristics in the structural characteris-
method proved to be a suitable one since the desired pyra- ation of bis(chromones) 6c,d are the resonances of the 3-H
zoles 5eϪf were obtained in good overall yields (Scheme 4). (s, δ ഠ 6.9 ppm) and C-3 (δ ഠ 108 ppm) atoms, the reson-
Chromones 6c,d were obtained by oxidative cyclisation of ance of 2,3,5,6-H appearing as a singlet at δ ϭ 8.11 ppm in
chalcone derivatives 1cϪd with a catalytic amount of iodine the case of 6d, and the resonance of 2-H appearing as a
in refluxing DMSO.
triplet at δ ϭ 8.49 ppm in the case of 6c.
The reaction of bis(chalcones) 1aϪd with hydrazine hy-
drate afforded solid products. The TLC analysis of these
solids revealed the presence, in each case, of a single spot
1
and their H NMR spectra seem to indicate that they are
constituted by pure bis(2-pyrazolines) 4aϪd (two inequiva-
lent protons of a methylene group coupled with a methine
proton, and an NH proton at δ ϭ 7.86 ppm). These reac-
tions may give rise to a mixture of two diastereoisomers
(one being a pair of enantiomers and the other a meso
1
structure), but the H NMR spectra of the products sug-
gested, in each case, the presence of a single compound. In
the 13C NMR spectra of these products, however, there are
duplications of some carbon resonances, supporting the ex-
pected mixture of two isomers. Separating these mixtures
by using a chiral HPLC column, or by using a lanthanide
shift reagent {europium tris[3-(trifluoromethylhydroxyme-
thylene)-(ϩ)-camphorate]}, proved unsuccessful as were all
attempts to grow single crystals of pyrazolines 4aϪd.
The detailed analysis of the 13C NMR spectra of bis(2-
pyrazolines) 4aϪc allowed us to identify two sets of reson-
ances, one being less intense than the other (Table 1 shows
Scheme 4
NMR Spectroscopy
1
The most important features of the H and 13C NMR these two sets for compounds 4a, the resonances in brackets
spectra of bis(chalcones) 1aϪf are: i) the coupling constants correspond to the less-intense ones). These data suggest
JHα-Hβ ഠ 16 Hz indicating the presence of a trans config- that one of the diastereomers, either the meso or the d,l pair,
uration of the double bond; ii) the C-β carbon atom reson- was formed with slight selectively. AM1 calculations for the
ances (δ ϭ 141.6Ϫ146.6 ppm) appeared downfield of those two isomers of bis(2-pyrazoline) 4d indicate that the meso
of the C-α atoms (δ ϭ 121.4Ϫ128.0 ppm), because of the diastereomer is the most stable (∆Hf ϭ 2 kcal molϪ1) (Fig-
mesomeric deshielding effect of the carbonyl group; iii) the ure 1). Thus, we assume tentatively that the most-abundant
singlets at δ ϭ 12.51Ϫ12.77 ppm and 5.15Ϫ5.18 ppm, as- isomer is the meso one. Taking these data into account, we
signed to the resonances of the hydroxy groups of 1c,d and can consider that the mechanism of formation of bis(2-pyr-
the benzylic CH2 units of 1e,f, respectively; iv) the carbonyl azolines) 4aϪd involves two steps: i) First there is the reac-
carbon atom resonances at δ ϭ 190.2Ϫ196.3 ppm; v) the tion of each bis(chalcone) with one molecule of hydrazine
singlet in the range δ ϭ 7.28Ϫ7.75 ppm in the cases of giving a racemic mixture of a compound bearing one pyra-
1b,d,f, corresponding to the 2,3,5,6-H protons resonance, zoline ring and a chalcone moiety; ii) secondly, there is the
arising because of the symmetry of the molecule; vi) the reaction of these compounds with a second molecule of hy-
broad singlet in the range δ ϭ 7.39Ϫ8.47 ppm for 1a,c,e, drazine. The 13C NMR and AM1 data suggest that in this
which is assigned to the resonance of protons 2-H.
second step there is a small chiral induction, leading to the
1
From the H and 13C NMR spectra of bis(chalcone) di- mixture of diastereoisomers, of which the meso form is the
bromides 3aϪd, it is important to note the doublets at δ ϭ more stable. One can rationalise that the chiral induction is
5.51Ϫ5.68 and 5.82Ϫ6.34 ppm corresponding to the reson- minor because there is a great distance between the re-
ances of H-β and H-α, respectively, and also the resonances sulting stereogenic centres.
of C-β (δ ഠ 49 ppm) and C-α (δ ഠ 47 ppm). The coupling
J
Hα-Hβ ϭ 11.2Ϫ11.5 Hz indicates a trans diaxial orientation
Table 1. 13C NMR chemical shifts of the two diastereoisomers of
bis(2-pyrazoline) 4a
of these protons, which confirms the expected anti addition
of bromine to the two vinylic moieties of bis(chalcones)
1a,b,e,f. These two additions must give rise to the formation
of two diastereoisomers of bis(chalcone) dibromides 3aϪd,
but the NMR spectroscopic data suggests the presence of
only one compound. This apparent diastereoselectivity
might arise from a chiral induction from the first bromine
C-1,3 137.0 (136.8) C-3Ј 170.6 (171.0) C-1ЈЈ
129.8 (129.9)
C-2 127.7 C-4Ј 41.7 (41.9) C-2ЈЈ,6ЈЈ 128.44 (128.41)
C-4,6 128.7 (129.0) C-5Ј 61.5
C-5 128.0
C-3ЈЈ,5ЈЈ 129.4
C-4ЈЈ 132.5 (135.6)
Eur. J. Org. Chem. 2003, 747Ϫ755
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D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Elguero
FULL PAPER
Conclusion
We have synthesised the bis(pyrazoles) 5aϪf from the re-
actions of bis(chalcones) 1aϪd and bis(chalcone) tetra-
bromo derivatives 3aϪd with hydrazine hydrate. The former
reaction gave the corresponding bis(2-pyrazolines) 4aϪd,
but attempts at their oxidation were unsuccessful; the reac-
tion, however, starting with bis(chalcone) tetrabromo deriv-
atives 3aϪd gave the corresponding bis(pyrazoles) 5aϪd in
good yields. Since the preparation of bis(pyrazoles) 5e,f
bearing hydroxyphenyl substituents from the corresponding
benzyloxy-substituted compounds 5c,d gave very poor
yields, these compounds were instead synthesised in good
yields by the reaction of bis(chromones) 6c,d with hydrazine
hydrate. All of these reactions allowed us to establish new
synthetic methods for the preparation of novel bis(pyra-
zoles) 5aϪf.
Experimental Section
General Remarks: Melting points were measured in a Reichert
Thermovar apparatus fitted with a microscope and are uncorrec-
ted. NMR spectra were recorded on Bruker AMX and DRX 300
spectrometers (300.13 for 1H and 75.47 MHz for 13C), with CDCl3
as solvent if not stated otherwise. Chemical shifts (δ) are reported
in ppm and coupling constants (J) in Hz. The internal standard
was TMS. Unequivocal 13C assignments were made with the aid of
2D gHSQC (or HETCOR) and gHMBC (delays for one bond and
long-range J C/H couplings were optimised for 145 and 7 Hz, re-
spectively) experiments. Electron impact (EI, 70 eV) MS were re-
corded on VG Autospec Q and M spectrometers. Elemental Ana-
lyses were obtained with a CHNS 932 Leco analyser (University of
Aveiro). Preparative thin-layer chromatography was performed
with Merck silica gel 60 DGF254. Column chromatography was
performed with Merck silica gel 60, 70Ϫ230 mesh. All other chem-
icals and solvents used were obtained from commercial sources and
used as received or dried using standard procedures.
Figure 1. a. Compound 4d, meso isomer; b. compound 4d, d,l iso-
mer
1
The H NMR spectra of 4aϪd revealed other character-
istic signals such as: i) the 2ЈЈ-OH proton resonances ap-
pearing as sharp singlets at δ ϭ 11.17 ppm in pyrazolines
4c,d, indicating the presence of an intramolecular hydrogen
bond; ii) the 2,3,5,6-H resonances at δ ϭ 7.39Ϫ7.60 ppm in
pyrazolines 4b,d appearing as singlets because of the sym-
metry of the molecules; iii) the 2-H resonances at δ ϭ
7.50 ppm in pyrazolines 4a,c appearing as broad singlets
because of small coupling with 4,6-H.
Because of the symmetry of bis(pyrazoles) 5aϪf their
NMR spectra are simple. The most characteristic 1H NMR
resonances of bis(pyrazoles) 5aϪf are those attributable to
the NH and 4Ј-H protons, which appear, respectively, in the
ranges δ ϭ 13.12Ϫ13.75 and 7.21Ϫ7.52 ppm. It is worth
noting the singlets at δ ϭ 5.31 ppm attributable to the res-
onance of the CH2 protons of the 2ЈЈ-OCH2C6H5 groups in
the cases of pyrazoles 5c,d, as well as the broad singlets at
δ ϭ 10.70Ϫ10.90 ppm for the resonance of 2ЈЈ-OH pro-
tons in the cases of pyrazoles 5e,f. The assignment of the
resonances of the protonated carbon atoms in the 13C
NMR spectra of pyrazoles 5aϪf was based on the analysis
of HSQC spectra, whereas those of the quaternary carbon
atoms were based on the connectivities found in HMBC
spectra (Figure 2 shows the most important ones).
Synthesis of Bis(chalcones) (1aϪd): An aqueous solution of sodium
hydroxide (60%, 150 mL) was added slowly to a methanolic solu-
tion (200 mL) of the appropriate acetophenone (33 mmol). After
cooling the solution to room temperature, a methanolic suspension
(50 mL) of isophthaldialdehyde or terephthaldialdehyde (2.2 g,
16.4 mmol) was added. The reaction mixture was stirred at room
temperature for 20 h, and then it was poured into a mixture of ice
and commercial hydrochloric acid (pH was adjusted to about 2).
The resulting solid was filtered, dissolved in dichloromethane
(150 mL), and washed with a saturated solution of sodium hydro-
gen carbonate (2 ϫ 100 mL). The solvent was evaporated to dry-
ness and the residue was purified by column chromatography using
dichloromethane as eluent. The compounds eluted in this order:
hydroxymethylchalcone derivatives, bis(chalcones) 1aϪd, then car-
boxychalcones. Finally, each of these compounds was crystallised
from ethanol. We describe here as examples the characterisation of
only one hydroxymethylchalcone and one carboxychalcone.
3-(3-Oxo-3-phenylpropenyl)chalcone (1a): Yield 50% (5.58 g). M.p.
141Ϫ143 °C (recrystallised from ethanol). 1H NMR:
δ ϭ
7.47Ϫ7.56 (m, 5 H, 2 ϫ 3Ј,5Ј-H and 5-H), 7.59 (d, J ϭ 15.7 Hz,
H-α), 7.59Ϫ7.64 (m, 2 H, 2 ϫ 4Ј-H), 7.70 (dd, J ϭ 7.7, 1.5 Hz, 2
H, 4,6-H), 7.84 (d, J ϭ 15.7 Hz, H-β), 7.89 (s br, 1 H, 2-H), 8.05
Figure 2. Main connectivities found in the HMBC spectra of pyra-
zoles 5aϪf
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Eur. J. Org. Chem. 2003, 747Ϫ755

Bis(chalcones) and Their Transformation into Bis(pyrazoline) and Bis(pyrazole) Derivatives
FULL PAPER
(d, J ϭ 8.1 Hz, 4 H, 2 ϫ 2Ј,6Ј-H) ppm. 13C NMR: δ ϭ 122.9 (2 ϫ
3-Carboxy-2Ј-hydroxychalcone: Yield 25% (2.21 g). M.p. 212Ϫ214
C-α), 128.2 (C-2), 128.5 (2 ϫ C-2Ј,6Ј), 128.7 (2 ϫ C-3Ј,5Ј), 129.6 °C (recrystallised from ethanol). 1H NMR ([D6]DMSO): δ ϭ
(C-5), 130.1 (C-4,6), 133.0 (2 ϫ C-4Ј), 137.9 (2 ϫ C-1Ј), 135.7 (C- 6.90Ϫ7.02 (m, 2 H, 3Ј-H and 5Ј-H), 7.54Ϫ7.65 (m, 2 H, 4-H and
1,3), 143.8 (2 ϫ C-β), 190.3 (2 ϫ CϭO) ppm. EI-MS: m/z (rel.
5-H), 8.01Ϫ8.13 (m, 2 H, 4Ј-H and 6-H), 8.39 (s broad, 1 H, 2-H),
int.) ϭ 338 (99) [Mϩ·], 337 (41), 309 (10), 233 (100), 215 (6), 207 7.88 (d, J ϭ 15.6 Hz, 1 H, H-β), 8.10 (d, J ϭ 15.6 Hz, 1 H, H-α),
(23), 178 (7), 155 (8), 127 (11), 105 (72), 77 (68). C24H18O2 (338.13):
calcd. C 85.18, H 5.36; found C 85.15, H 5.60.
8.26 (d, J ϭ 7.8 Hz, 1 H, 6Ј-H), 12.45 (s broad, 1 H, 2Ј-OH) ppm.
13C NMR ([D6]DMSO): δ ϭ 117.8 (C-3Ј), 119.4 (C-1Ј and C-5Ј),
121.0 (C-α), 123.1 (C-2), 129.4 (C-5), 129.8 (C-1), 131.1 (C-6Ј),
132.9 (C-4), 134.9 (C-6), 131.6 (C-3), 136.5 (C-4Ј), 143.9 (C-β),
161.8 (C-2Ј), 167.5 (3-CO2H), 193.6 (CϭO) ppm. EI-MS: m/z (rel.
int.) ϭ 268 (90) [Mϩ·], 267 (74), 251 (31), 222 (27), 194 (17), 165
(32), 147 (100), 131 (22), 121 (59), 92 (13), 77 (13), 65 (14).
4-(3-Oxo-3-phenylpropenyl)chalcone (1b): Yield 56% (6.25 g). M.p.
196Ϫ197 °C (recrystallised from ethanol). 1H NMR: δ ϭ 7.52 (dd,
J ϭ 7.5, 6.5 Hz, 4 H, 2 ϫ 3Ј,5Ј-H), 7.59 (d, J ϭ 15.7 Hz, 2 ϫ H-
α), 7.61 (t, J ϭ 7.5 Hz, 2 H, 2 ϫ 4Ј-H), 7.70 (s, 4 H, 2,3,5,6-H),
7.82 (d, J ϭ 15.7 Hz, 2 ϫ H-β), 8.04 (d, J ϭ 6.5 Hz, 4 H, 2 ϫ
2Ј,6Ј-H) ppm. 13C NMR: δ ϭ 123.0 (2 ϫ C-α), 128.5 (2 ϫ C-2Ј,6Ј),
128.7 (2 ϫ C-3Ј,5Ј), 128.9 (C-2,3,5,6), 133.0 (2 ϫ C-4Ј), 136.8 (2 ϫ
C-1Ј), 138.0 (C-1,4), 143.5 (2 ϫ C-β), 190.2 (2 ϫ CϭO) ppm. EI-
MS: m/z (rel. int.) ϭ 338 (100) [Mϩ·], 337 (29), 309 (11), 261 (8),
233 (86), 207 (11), 178 (10), 127 (11), 105 (41), 77 (54). EI-HRMS
(C24H18O2 [Mϩ·]): calcd. 338.1306, found 338.1305.
Synthesis of Lactone 2: An aqueous solution of sodium hydroxide
(60%, 150 mL) was added slowly to a degassed methanolic solution
(200 mL) of 2Ј-hydroxyacetophenone (4.0 mL, 33 mmol) that was
protected from daylight. After cooling the solution to room tem-
perature, a methanolic suspension (50 mL) of ortho-phthaldicar-
boxaldehyde (2.2 g, 16.4 mmol) was added. The reaction mixture
was stirred at room temperature for 20 h, and then it was poured
into a mixture of ice and commercial hydrochloric acid (pH was
adjusted to ഠ2). The resulting solid was filtered, dissolved in
dichloromethane (150 mL), and then washed with a saturated solu-
tion of sodium hydrogen carbonate (2 ϫ 100 mL). The solvent was
evaporated to dryness and the residue was purified by column chro-
matography using dichloromethane as eluent to yield 3-[2-(2-hydro-
xyphenyl)-2-oxoethyl]-2-benzofuran-1(3H)-one (2) (6.16 g, 70%),
which was crystallised from ethanol. M.p. 134Ϫ136 °C (recrys-
2Ј-Hydroxy-3-[3-(2-hydroxyphenyl)-3-oxopropenyl]chalcone
(1c):
Yield 42% (5.13 g). M.p. 180Ϫ181 °C (recrystallised from ethanol).
1H NMR ([D6]DMSO): δ ϭ 7.02 (d, J ϭ 8.4 Hz, 2 H, 2 ϫ 3Ј-H),
7.03 (t, J ϭ 8.1 Hz, 2 H, 2 ϫ 5Ј-H), 7.55Ϫ7.61 (m, 3 H, 2 ϫ 4Ј-H
and 5-H), 7.88 (d, J ϭ 15.6 Hz, 2 H, 2 ϫ H-β), 8.00 (dd, J ϭ 7.8,
1.2 Hz, 2 H, 4,6-H), 8.14 (d, J ϭ 15.6 Hz, 2 H, 2 ϫ H-α), 8.28 (dd,
J ϭ 8.1, 1.2 Hz, 2 H, 2 ϫ 6Ј-H), 8.47 (s br, 1 H, 2-H), 12.51 (s, 2
H, 2 ϫ 2Ј-OH) ppm. 13C NMR ([D6]DMSO): δ ϭ 117.8 (2 ϫ C-
3Ј), 119.3 (2 ϫ C-5Ј), 120.8 (2 ϫ C-1Ј), 122.7 (2 ϫ C-α), 129.5 (C-
2), 129.7 (C-5), 131.0 (2 ϫ C-6Ј), 131.4 (C-4,6), 135.2 (C-1,3), 136.5
(2 ϫ C-4Ј), 144.1 (2 ϫ C-β), 161.9 (2 ϫ C-2Ј), 193.7 (2 ϫ CϭO)
ppm. EI-MS: m/z (rel. int.) ϭ 370 (79) [Mϩ·], 369 (25), 249 (50),
236 (13), 223 (10), 202 (7), 165 (8), 147 (85), 128 (13), 121 (100),
102 (12), 93 (29), 77 (15), 65 (57). C24H18O4 (370.40): calcd. C
77.82, H 4.90; found C 78.08, H 4.66.
1
tallised from ethanol). H NMR: δ ϭ 3.46 (dd, J ϭ 17.7, 6.5 Hz,
1 H, 1Јcis-H), 3.79 (dd, J ϭ 17.7, 6.5 Hz, 1 H, 1Јtrans-H), 6.17 (t,
J ϭ 6.5 Hz, 1 H, 3-H), 6.91 (dd, J ϭ 8.0, 7.4 Hz, 1 H, 5ЈЈ-H), 7.02
(d, J ϭ 8.8 Hz, 1 H, 3ЈЈ-H), 7.52 (dd, J ϭ 8.8, 7.4 Hz, 1 H, 4ЈЈ-H),
7.55Ϫ7.60 (m, 2 H, 4-H and 6-H), 7.65 (d, J ϭ 8.0 Hz, 1 H, 6ЈЈ-
H), 7.70 (t, J ϭ 7.5 Hz, 1 H, 5-H), 7.93 (d, J ϭ 7.9 Hz, 1 H, 7-H),
12.02 (s, 1 H, 2ЈЈ-OH) ppm. 13C NMR: δ ϭ 43.2 (C-1Ј), 76.6 (C-
3), 118.7 (C-3ЈЈ), 119.0 (C-1ЈЈ), 119.3 (C-5ЈЈ), 122.6 (C-6), 125.9 (C-
7 and C-8), 129.6 (C-4), 129.8 (C-6ЈЈ), 134.4 (C-5), 137.2 (C-4ЈЈ),
149.2 (C-9), 162.5 (C-2ЈЈ), 169.9 (C-1), 201.6 (C-2Ј) ppm. EIMS:
m/z (rel. int.) ϭ 268 (48) [Mϩ·], 267 (7), 250 (25), 223 (27), 222 (14),
194 (7), 147 (100), 133 (58), 121 (61), 120 (38), 105 (19), 77 (23),
65 (19). EI-HRMS (C16H12O4 [Mϩ·]): calcd. 268.0736, found
268.0730.
2Ј-Hydroxy-4-[3-(2-hydroxyphenyl)-3-oxopropenyl]chalcone
(1d):
Yield 51% (6.23 g). M.p. 259Ϫ261 °C (recrystallised from ethanol).
1H NMR: δ ϭ 6.98 (t, J ϭ 7.7 Hz, 2 H, 2 ϫ 5Ј-H), 7.06 (d, J ϭ
7.7 Hz, 2 H, 2 ϫ 3Ј-H), 7.54 (t, J ϭ 7.7 Hz, 2 H, 2 ϫ 4Ј-H), 7.73
(d, J ϭ 15.3 Hz, 2 H, H-α), 7.75 (s, 4 H, 2,3,5,6-H), 7.94 (d, J ϭ
15.3 Hz, 2 H, 2 ϫ H-β), 7.95 (d, J ϭ 7.7 Hz, 2 H, 2 ϫ 6Ј-H), 12.77
(s, 2 H, 2 ϫ 2Ј-OH) ppm. 13C NMR: δ ϭ 118.7 (2 ϫ C-3Ј), 119.9
(2 ϫ C-1Ј), 121.1 (2 ϫ C-5Ј), 121.4 (2 ϫ C-α), 129.9 (C-2,3,5,6),
130.8 (2 ϫ C-6Ј), 137.2 (C-1,4), 138.6 (2 ϫ C-4Ј), 146.6 (2 ϫ C-β),
162.0 (2 ϫ C-2Ј), 196.3 (2 ϫ CϭO) ppm. EI-MS: m/z (rel. int.) ϭ
370 (100) [Mϩ·], 369 (47), 353 (9), 249 (63), 236 (16), 223 (12), 202
(9), 165 (8), 147 (64), 130 (19), 121 (76), 102 (8), 93 (24), 77 (13),
65 (42). EI-HRMS (C24H18O4 [Mϩ·]): calcd. 370.1205, found
370.1195.
Benzylation of Bis(chalcones) 1c,d. Synthesis of 2Ј-Benzyloxychal-
cones 1e,f: Potassium carbonate (32.4 mmol, 4.47 g), potassium
iodide (2.69 g, 16.2 mmol) and benzyl chloride (1.5 mL,
12.96 mmol) were added to a solution of chalcones 1c,d (5.4 mmol)
in acetone (100 mL). The mixture was heated under reflux for 12 h
and then the inorganic solids were removed by filtration and
washed with acetone (2 ϫ 20 mL). The solvent was evaporated to
dryness and the residue was purified by column chromatography
using dichloromethane as eluent. Finally, the 2Ј-benzyloxychal-
cones 1e,f were crystallised from ethanol.
2Ј-Hydroxy-3-hydroxymethylchalcone: Yield 20% (1.68 g). M.p.
192Ϫ194 °C (recrystallised from ethanol). 1H NMR ([D6]acetone):
δ ϭ 5.15 (s, 2 H, 3-CH2OH), 7.42Ϫ7.47 (m, 2 H, 3Ј-H and 5Ј-H),
7.86Ϫ7.95 (m, 2 H, 4-H and 5-H), 8.02 (dt, J ϭ 7.8, 1.7 Hz, 1 H, 2Ј-Benzyloxy-3-[3-(2-benzyloxyphenyl)-3-oxopropenyl]chalcone (1e):
4Ј-H), 8.20 (d, J ϭ 6.9 Hz, 1 H, 6-H), 8.31 (s broad, 1 H, 2-H), Yield 71% (2.11 g). M.p. 136Ϫ137 °C (recrystallised from ethanol).
8.39 (d, J ϭ 15.5 Hz, 1 H, H-β), 8.51 (d, J ϭ 15.5 Hz, 1 H, α), 8.72 1H NMR: δ ϭ 5.15 (s, 4 H, 2Ј-OCH2C6H5), 7.06Ϫ7.11 (m, 4 H, 2
(dd, J ϭ 8.4, 1.7 Hz, 1 H, 6Ј-H), 13.38 (s, 1 H, 2Ј-OH) ppm. 13C
NMR ([D6]acetone): δ ϭ 64.2 (3-CH2OH), 118.7 (C-3Ј), 119.8 (C-
ϫ 3Ј-H and 2 ϫ 5Ј-H), 7.20Ϫ7.26 (m, 7 H, 5-H and 3,4,5-H of 2Ј-
OCH2C6H5), 7.32Ϫ7.41 (m, 7 H, 2,4,6-H and 2 ϫ 2,6-H of 2Ј-
5Ј), 120.8 (C-1Ј), 121.2 (C-α), 127.7 (C-2), 128.5 (C-6), 129.7 (C-5), OCH2C6H5), 7.50 (ddd, J ϭ 8.0, 7.7, 1.8 Hz, 2 H, 2 ϫ 4Ј-H), 7.57
131.3 (C-6Ј), 130.0 (C-4), 135.4 (C-1), 144.3 (C-3), 137.4 (C-4Ј), (AB, J ϭ 15.9 Hz, 2 H, 2 ϫ H-α), 7.74 (AB, J ϭ 15.9 Hz, 2 H, 2
146.3 (C-β), 164.4 (C-2Ј), 194.9 (CϭO) ppm. EI-MS: m/z (rel. ϫ H-β), 7.77 (dd, J ϭ 7.8, 1.8 Hz, 2 H, 2 ϫ 6Ј-H) ppm. 13C NMR:
int.) ϭ 254 (100) [Mϩ·], 253 (71), 236 (56), 223 (42), 207 (18), 178 δ ϭ 70.6 (2 ϫ 2Ј-OCH2C6H5), 112.8 (2 ϫ C-3Ј), 121.2 (2 ϫ C-5Ј),
(14), 165 (17), 147 (63), 131 (15), 121 (45), 115 (17), 92 (17), 77
(20), 65 (21).
127.4 (2 ϫ C-2,6 of 2Ј-OCH2C6H5), 127.8 (2 ϫ C-α), 128.2 (2 ϫ
C-4 of 2Ј-OCH2C6H5), 128.3 (C-2), 128.6 (2 ϫ C-1Ј and 2 ϫ C-3,5
Eur. J. Org. Chem. 2003, 747Ϫ755
751

D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Elguero
material was complete. After 4 h the mixture was poured into ice
FULL PAPER
of 2Ј-OCH2C6H5), 129.1 (C-5), 129.5 (C-4,6), 130.9 (2 ϫ C-6Ј),
133.4 (2 ϫ C-4Ј), 135.6 (C-1,3), 136.0 (2 ϫ C-1 of 2Ј-OCH2C6H5), and the bis(chalcone) tetrabromo derivatives 3c,d were removed by
141.7 (2 ϫ C-β), 157.6 (2 ϫ C-2Ј), 191.8 (2 ϫ CϭO) ppm. EIMS: filtration, washed with water, and recrystallised from carbon tetra-
m/z (rel. int.) ϭ 550 (3) [Mϩ·], 459 (10), 339 (12), 236 (13), 211 (11),
121 (24), 91 (100), 65 (7). C38H30O40 (550.64): calcd. C 82.89, H
5.49; found C 82.65, H 5.36.
chloride.
2Ј-Benzyloxy-3-[3-(2-benzyloxyphenyl)-1,2-dibromo-3-oxopropenyl]-
α,β-dibromo-α,β-dihydrochalcone (3c): Yield 72% (3.76 g). M.p.
179Ϫ180 °C (recrystallised from carbon tetrachloride). H NMR:
1
2Ј-Benzyloxy-4-[3-(2-benzyloxyphenyl)-3-oxopropenyl]chalcone (1f):
Yield 77% (2.29 g). M.p. 179Ϫ180 °C (recrystallised from ethanol).
1H NMR: δ ϭ 5.18 (s, 4 H, 2Ј-OCH2C6H5), 7.09 (dd, J ϭ 7.9,
7.2 Hz, 2 H, 2 ϫ 5Ј-H), 7.10 (d, J ϭ 7.8 Hz, 2 H, 2 ϫ 3Ј-H),
7.25Ϫ7.29 (m, 6 H, 2 ϫ 3,4,5-H of 2Ј-OCH2C6H5), 7.28 (s, 4 H,
2,3,5,6-H), 7.41Ϫ7.49 (m, 4 H, 2 ϫ 2,6-H of 2Ј-OCH2C6H5), 7.50
(ddd, J ϭ 7.8, 7.2, 1.8 Hz, 2 H, 2 ϫ 4Ј-H), 7.53 (AB, J ϭ 15.9 Hz,
2 H, 2 ϫ H-α), 7.63 (AB, J ϭ 15.9 Hz, 2 H, 2 ϫ H-β), 7.76 (dd,
J ϭ 7.9, 1.8 Hz, 2 H, 2 ϫ 6Ј-H) ppm. 13C NMR: δ ϭ 70.7 (2 ϫ
2Ј-OCH2C6H5), 112.9 (2 ϫ C-3Ј), 121.2 (2 ϫ C-5Ј), 127.5 (2 ϫ
C-2,6 of 2Ј-OCH2C6H5), 128.0 (2 ϫ C-α), 128.1 (2 ϫ C-4 of 2Ј-
OCH2C6H5), 128.7 (C-2,3,5,6 and 2 ϫ C-3,5 of 2Ј-OCH2C6H5),
129.1 (2 ϫ C-1Ј), 131.0 (2 ϫ C-6Ј), 133.4 (2 ϫ C-4Ј), 136.1 (C-1
and C-4), 136.7 (2 ϫ C-1 of 2Ј-OCH2C6H5), 141.6 (2 ϫ C-β), 157.6
(2 ϫ C-2Ј), 191.8 (2 ϫ CϭO) ppm. EIMS: m/z (rel. int.) ϭ 550 (5)
[Mϩ·], 459 (8), 369 (5), 339 (5), 235 (5), 223 (5), 211 (5), 121 (17),
91 (100), 65 (11). C38H30O4 (550.64): calcd. C 82.89, H 5.49; found
C 82.73, H 5.20.
δ ϭ 5.21 (s, 4 H, 2 ϫ 2Ј-OCH2C6H5), 5.42 (d, J ϭ 11.5 Hz, 2 H, 2
ϫ H-β), 6.25 (d, J ϭ 11.5 Hz, 2 H, 2 ϫ H-α), 6.77Ϫ6.86 (m, 3 H,
2-H and 4,6-H), 7.05Ϫ7.16 (m, 5 H, 5-H and 2 ϫ 3Ј,5Ј-H),
7.52Ϫ7.62 (m, 12 H, 2 ϫ 4Ј-H and 2 ϫ 2,3,4,5,6-H of 2Ј-
OCH2C6H5), 8.04Ϫ8.06 (m, 2 H, 2 ϫ 6Ј-H) ppm. 13C NMR: δ ϭ
49.3 (2 ϫ C-β), 51.4 (2 ϫ C-α), 71.3 (2 ϫ 2Ј-OCH2C6H5), 112.8 (2
ϫ C-3Ј), 121.4 (2 ϫ C-5Ј), 124.2 (2 ϫ C-1Ј), 128.1 (C-2), 128.4 (C-
4,6), 128.9 (2 ϫ C-2,6 of 2Ј-OCH2C6H5), 129.1 (2 ϫ C-3,5 of 2Ј-
OCH2C6H5), 129.2 (2 ϫ C-4 of 2Ј-OCH2C6H5), 129.0 (C-5), 132.8
(2 ϫ C-4Ј), 135.2 (2 ϫ C-6Ј), 135.3 (2 ϫ C-1 of 2Ј-OCH2C6H5),
139.0 (C-1,3), 158.2 (2 ϫ C-2Ј), 191.8 (2 ϫ CϭO) ppm. FAB-MS:
m/z (rel. int.) ϭ 875 (0.5) [[M ϩ H]ϩ, 81Br], 713 (3), 663 (24), 647
(11), 555 (16), 316 (11), 288 (17), 211 (100), 165 (7), 154 (51) 91
(35). C38H30O4Br4 (870.26): C 52.44, H 3.47, found: C 52.15, H
3.17.
2Ј-Benzyloxy-4-[3-(2-benzyloxyphenyl)-1,2-dibromo-3-oxopropenyl]-
α,β-dibromo-α,β-dihydrochalcone (3d): Yield 70% (3.65 g). M.p.
217Ϫ219 °C (recrystallised from carbon tetrachloride). 1H NMR
(CDCl3/TFA): δ ϭ 5.27 (s, 4 H, 2 ϫ 2Ј-OCH2C6H5), 5.51 (d, J ϭ
11.5 Hz, 2 H, 2 ϫ H-β), 6.34 (d, J ϭ 11.5 Hz, 2 H, 2 ϫ H-α), 6.92
(s, 4 H, 2,3,5,6-H), 7.17 (t, J ϭ 7.9 Hz, 2 H, 2 ϫ 5Ј-H), 7.21 (d,
J ϭ 8.2 Hz, 2 H, 2 ϫ 3Ј-H), 7.47Ϫ7.52 (m, 6 H, 2 ϫ 3,4,5-H of
2Ј-OCH2C6H5), 7.58Ϫ7.62 (m, 4 H, 2 ϫ 2,6-H of 2Ј-OCH2C6H5),
7.67 (dd, J ϭ 8.2, 7.9 Hz, 2 H, 2 ϫ 4Ј-H), 8.03 (d, J ϭ 7.9 Hz, 2
H, 2 ϫ 6Ј-H) ppm. 13C NMR (CDCl3/TFA): δ ϭ 48.8 (2 ϫ C-β),
51.0 (2 ϫ C-α), 71.7 (2 ϫ 2Ј-OCH2C6H5), 113.4 (2 ϫ C-3Ј), 121.8
(2 ϫ C-5Ј), 123.8 (2 ϫ C-1Ј), 128.6 (2 ϫ C-2,6 of 2Ј-OCH2C6H5),
Synthesis of Bis(chalcone) Tetrabromides 3a,b: Bromine was added
slowly to a solution of bis(chalcones) 1a,b (5.9 mmol) in carbon
tetrachloride (80 mL) until the reaction mixture became red, and
then the mixture was stirred at room temperature until the con-
sumption of the starting material was complete. The resulting bi-
s(chalcone) tetrabromo derivatives 3a,b were removed by filtration,
washed with carbon tetrachloride (2 ϫ 10 mL), and then recrys-
tallised from carbon tetrachloride.
α,β-Dibromo-3-(1,2-dibromo-3-oxo-3-phenylpropenyl)-α,β-dihydro-
chalcone (3a): Yield 80% (3.11 g). M.p. 205Ϫ206 °C (recrystallised
129.0 (C-5), 129.1 (C-2,3,5,6), 129.2 (2
ϫ C-3,4,5 of 2Ј-
1
from carbon tetrachloride). H NMR: δ ϭ 5.69 (d, J ϭ 11.2 Hz, 2
OCH2C6H5), 132.9 (2 ϫ C-6Ј), 135.1 (2 ϫ C-1 of 2Ј-OCH2C6H5),
136.9 (2 ϫ C-4Ј), 138.5 (C-1,3), 159.1 (2 ϫ C-2Ј), 196.6 (2 ϫ Cϭ
O) ppm. EIMS: m/z (rel. int.) ϭ 660 (3) [M Ϫ 2OBn]ϩ·, 441 (5)
331 (5), 281 (5), 181 (44), 131 (59), 91 (30). C38H30O4Br4 (870.26):
C 52.44, H 3.47, found: C 52.40, H 3.27.
H, 2 ϫ β), 5.82 (d, J ϭ 11.2 Hz, 2 H, 2 ϫ α), 7.49Ϫ7.53 (m, 1 H,
5-H), 7.57 (d, J ϭ 6.7 Hz, 2 H, 4,6-H), 7.58 (dd, J ϭ 7.7, 7.3 Hz,
4 H, 2 ϫ 3Ј,5Ј-H), 7.65 (s br, 1 H, 2-H), 7.69 (t, J ϭ 7.3 Hz, 2 H,
2 ϫ 4Ј-H), 8.13 (d, J ϭ 7.7 Hz, 4 H, 2 ϫ 2Ј,6Ј-H) ppm. 13C NMR:
δ ϭ 46.8 (2 ϫ C-α), 49.0 (2 ϫ C-β), 128.7 (C-2), 128.9 (2 ϫ C-
2Ј,6Ј), 129.0 (2 ϫ C-3Ј,5Ј), 129.2 (C-4,6), 129.5 (C-5), 134.3 (2 ϫ
C-4Ј and C-1,3), 139.0 (2 ϫ C-1Ј), 191.0 (2 ϫ CϭO) ppm. EIMS:
m/z (rel. int.) ϭ 662 (Mϩ·, 0.01), 577 (0.4), 429 (2), 417 (3), 393 (2),
338 (43), 233 (44), 207 (12), 105 (100), 77 (45). C24H18Br4O2
(658.01): calcd. C 43.81, H 2.76; found C 43.90, H 2.46.
Synthesis of Bis(2-pyrazolines) 4aϪd: Hydrazine hydrate (22 mmol)
was added to a methanolic suspension (100 mL) of bis(chalcones)
1aϪd (1.35 mmol). The reaction mixture was then heated under
reflux for 24 h under nitrogen. The bis(2-pyrazolines) 4aϪd were
removed by filtration, washed with ethanol, and precipitated from
methanolic solutions.
α,β-Dibromo-4-(1,2-dibromo-3-oxo-3-phenylpropenyl)-α,β-dihydro-
chalcone (3b): Yield 83% (3.22 g). M.p. 237Ϫ238 °C (recrystallised
from carbon tetrachloride). H NMR (CDCl3/TFA): δ ϭ 5.68 (d,
3-Phenyl-5-[3-(3-phenyl-2-pyrazolin-5-yl)phenyl]-2-pyrazoline (4a):
Yield 59% (292 mg). M.p. 138Ϫ140 °C. 1H NMR ([D6]DMSO/
TFA): δ ϭ 3.56 (dd, J ϭ 17.8, 9.3 Hz, 2 H, 2 ϫ 4Ј-Htrans), 3.90 (dd,
J ϭ 17.8, 9.9 Hz, 2 H, 2 ϫ 4Јcis-H), 5.22 (dd, J ϭ 9.9, 9.3 Hz, 2 H,
2 ϫ 5Ј-H), 7.45Ϫ7.67 (m, 9 H, 4,5,6-H and 2 ϫ 3ЈЈ,4ЈЈ,5ЈЈ-H), 7.66
(s br, 1 H, 2-H), 7.84 (d, J ϭ 7.0 Hz, 4 H, 2 ϫ 2ЈЈ,6ЈЈ-H) ppm. 13C
NMR ([D6]DMSO/TFA): δ ϭ 41.7 and 41.9 (2 ϫ C-4Ј), 61.5 (2 ϫ
C-5Ј), 127.7 (C-2), 128.0 (C-5), 128.41 and 128.44 (2 ϫ C-2ЈЈ,6ЈЈ),
128.7 and 129.0 (C-4,6), 129.4 (2 ϫ C-3ЈЈ,5ЈЈ), 129.8 and 129.9 (2
ϫ C-1ЈЈ), 132.5 and 132.6 (2 ϫ C-4ЈЈ), 136.8 and 137.0 (C-1,3),
170.6 and 171.0 (2 ϫ C-3Ј) ppm. EIMS: m/z (rel. int.) ϭ 366 (100)
[Mϩ·], 337 (10), 320 (8), 248 (8), 222 (18), 192 (15), 145 (50), 119
(20), 104 (15), 91 (20), 77 (28). FAB-HRMS (C24H23N4 [M ϩ H]ϩ):
calcd. 367.1923, found 367.1924.
1
J ϭ 11.4 Hz, 2 H, 2 ϫ H-β), 5.93 (d, J ϭ 11.4 Hz, 2 H, 2 ϫ H-α),
7.64 (dd, J ϭ 7.9, 7.4 Hz, 4 H, 2 ϫ 3Ј,5Ј-H), 7.66 (s, 4 H, 2,3,5,6-
H), 7.79 (t, J ϭ 7.4 Hz, 2 H, 2 ϫ 4Ј-H), 8.16 (d, J ϭ 7.9 Hz, 4 H,
2 ϫ 2Ј,6Ј-H) ppm. 13C NMR: δ ϭ 47.0 (2 ϫ C-α), 48.5 (2 ϫ C-β),
129.3 (C-2,3,5,6), 129.7 (2 ϫ C-2Ј,3Ј,5Ј,6Ј), 134.3 (2 ϫ C-1Ј), 135.9
(2 ϫ C-4Ј), 139.4 (C-1,3), 196.7 (2 ϫ CϭO) ppm. EIMS: m/z (rel.
int.) ϭ 662 (2) [Mϩ· 81Br], 338 (27) 233 (29), 181 (44), 131 (59),
,
105 (100), 69 (100). C24H18Br4O2 (658.01): calcd. C 43.81, H 2.76;
found C 43.70, H 2.50.
Synthesis of Bis(chalcone) Tetrabromo Derivatives 3c,d: Pyridinium
tribromide (3.84 mg, 12 mmol) was added to a solution of bis(chal-
cones) 1e,f (6 mmol) in acetic acid (100 mL). The mixture then 3-Phenyl-5-[4-(3-phenyl-2-pyrazolin-5-yl)phenyl]-2-pyrazoline (4b):
stood at room temperature until the consumption of the starting Yield 68% (336 mg). M.p. 190Ϫ192 °C. 1H NMR ([D6]DMSO/
752
Eur. J. Org. Chem. 2003, 747Ϫ755

Bis(chalcones) and Their Transformation into Bis(pyrazoline) and Bis(pyrazole) Derivatives
FULL PAPER
TFA): δ ϭ 3.65 (dd, J ϭ 17.1, 8.4 Hz, 2 H, 2 ϫ 4Ј-Htrans), 3.90 (dd,
(C-4,6), 129.9 (C-5), 132.9 (C-1,3), 134.1 (2 ϫ C-7Ј), 156.2 (2 ϫ C-
J ϭ 17.1, 9.1 Hz, 2 H, 2 ϫ 4Ј-Hcis), 5.21 (dd, J ϭ 9.1, 8.4 Hz, 2 H, 9Ј), 162.1 (2 ϫ C-2Ј), 178.2 (2 ϫ C-4Ј). EIMS: m/z (rel. int.) ϭ 366
2 ϫ 5Ј-H), 7.40 (dd, J ϭ 7.3, 7.0 Hz, 4 H, 2 ϫ 3ЈЈ,5ЈЈ-H), 7.43Ϫ7.50
(100) [Mϩ·], 367 (11), 338 (24), 246 (6), 218 (13), 189 (6), 155 (5),
(m, 2 H, 2 ϫ 4ЈЈ-H), 7.50 (s, 4 H, 2,3,5,6-H), 7.81 (d, J ϭ 7.3 Hz, 120 (56), 92 (40), 64 (10). EI-HRMS (C24H14O4 [Mϩ·]): calcd.
4 H, 2 ϫ 2ЈЈ,6ЈЈ-H) ppm. 13C NMR ([D6]DMSO/TFA): δ ϭ 41.7 366.0892, found 366.0889.
(2 ϫ C-4Ј), 61.3 (2 ϫ C-5Ј), 128.6 (2 ϫ C-2ЈЈ,6ЈЈ), 129.1 (2 ϫ C-
4Ј-(2-Chromonyl)flavone (6d): Yield 84% (769 mg). M.p. 298Ϫ299
3ЈЈ,5ЈЈ), 129.5 (C-2,3,5,6), 129.6 (2 ϫ C-1ЈЈ), 132.9 (2 ϫ C-4ЈЈ),
1
°C (recrystallised from ethanol). H NMR: δ ϭ 6.91 (s, 2 H, 2 ϫ
136.6 (2C, C-1,4), 172.3 and 172.4 (2 ϫ C-3Ј) ppm. EIMS: m/z (rel.
3Ј-H), 7.45 (dd, J ϭ 7.9, 7.4 Hz, 2 H, 0.9 Hz, 2 ϫ 6Ј-H), 7.61 (dd,
int.) ϭ 366 (100) [Mϩ·], 247 (11), 222 (15), 191 (10), 145 (50), 118
J ϭ 8.1, 0.9 Hz, 2 H, 2 ϫ 8Ј-H), 7.73 (ddd, J ϭ 8.1, 7.4, 1.7 Hz, 2
(17), 104 (14), 91 (23), 77 (30). FAB-HRMS (C24H23N4 [M ϩ H]ϩ):
H, 2 ϫ 7Ј-H), 8.09 (s, 4 H, 2,3,5,6-H), 8.26 (dd, J ϭ 7.9, 1.7 Hz, 2
calcd. 367.1923, found 367.1940.
H, 2 ϫ 5Ј-H) ppm. 13C NMR: δ ϭ 108.6 (2 ϫ C-3Ј), 118.1 (2 ϫ
C-8Ј), 124.2 (2 ϫ C-10Ј), 125.5 (2 ϫ C-6Ј), 125.9 (2 ϫ C-5Ј), 126.9
(C-2,3,5,6), 134.0 (2 ϫ C-7Ј), 134.7 (C-1,4), 156.4 (2 ϫ C-9Ј), 161.9
(2 ϫ C-2Ј), 178.1 (2 ϫ C-4Ј) ppm. EIMS: m/z (rel. int.) ϭ 366 (100)
[Mϩ·], 367 (12), 338 (16), 246 (14), 218 (15), 189 (7), 155 (10), 126
(10), 120 (42), 92 (32), 64 (9). EI-HRMS (C24H14O4 [Mϩ·]): calcd.
366.0892, found 366.0890.
3-Hydroxyphenyl-5-{3-[3-(2-hydroxyphenyl)-2-pyrazolin-5-yl]-
phenyl}-2-pyrazoline (4c): Yield 65% (349 mg). M.p. 147Ϫ149 °C.
1H NMR ([D6]DMSO): δ ϭ 2.99 (ddd, J ϭ 16.4, 11.4, 3.6 Hz, 2
H, 2 ϫ 4Ј-Htrans), 3.64 (dd, J ϭ 16.4, 10.8 Hz, 2 H, 2 ϫ 4Ј-Hcis),
4.86 (ddd, J ϭ 11.4, 10.8, 3.6 Hz, 2 H, 2 ϫ 5Ј-H), 6.88 (dt, J ϭ
7.7, 0.8 Hz, 2 H, 2 ϫ 5ЈЈ-H), 6.91 (d, J ϭ 8.0 Hz, 2 H, 2 ϫ 3ЈЈ-H),
7.23 (ddd, J ϭ 8.0, 7.7, 1.4 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.29 (dd, J ϭ 7.7,
1.4 Hz, 2 H, 2 ϫ 6ЈЈ-H), 7.31Ϫ7.34 (m, 3 H, 4,5,6-H), 7.50 (s, 1 H,
2-H), 7.86 (d, J ϭ 3.6 Hz, 2 H, 2 ϫ NH), 11.17 (s, 2 H, 2 ϫ 2ЈЈ-
OH) ppm. 13C NMR: δ ϭ 41.0 and 41.1 (2 ϫ C-4Ј), 62.18 and
62.21 (2 ϫ C-5Ј), 115.8 (2 ϫ C-3ЈЈ), 116.8 (2 ϫ C-1ЈЈ), 119.2 (2 ϫ
C-5ЈЈ), 125.3 and 125.5 (C-2), 125.9 (C-4,6), 127.9 (2 ϫ C-6ЈЈ),
128.8 (C-5), 129.9 (2 ϫ C-4ЈЈ), 142.57 and 142.61 (C-1,3), 152.7 (2
ϫ C-3Ј), 156.8 (2 ϫ C-2ЈЈ) ppm. EIMS: m/z (rel. int.) ϭ 398 (47)
[Mϩ·], 384 (26), 292 (35), 264 (25), 246 (53), 238 (57), 218 (14), 189
(22), 161 (100), 135 (56), 121 (67), 105 (34), 91 (52),77 (67), 65 (48).
FAB-HRMS (C24H23N4O2 [M ϩ H]ϩ): calcd. 399.1821, found
399.1836.
Synthesis of Bis(pyrazoles) 5aϪd: Hydrazine hydrate (15 mmol) was
added to a methanolic suspension (100 mL) of tetrabromochal-
cones 3aϪd (1.0 mmol). The reaction mixture was heated under
reflux for 24 h under nitrogen. The solvent was evaporated and the
residue was washed with water and extracted with chloroform (3
ϫ 30 mL). The solvent was evaporated to dryness and the residue
purified by thin-layer chromatography, using a mixture of chloro-
form and acetone (9:1) as eluent. The main spot in each case was
identified as bis(pyrazoles) 5aϪd.
3-Phenyl-5-[3-(3-phenylpyrazol-5-yl)phenyl]pyrazole (5a): Yield 53%
(192 mg). Yellow oil. 1H NMR ([D6]DMSO/TFA): δ ϭ 7.31 (s, 2
H, 2 ϫ 4Ј-H), 7.36 (t, J ϭ 7.3 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.47 (dd, J ϭ
7.8, 7.3 Hz, 4 H, 2 ϫ 3ЈЈ,5ЈЈ-H), 7.54 (t, J ϭ 7.5 Hz, 1 H, 5-H),
7.83 (dd, J ϭ 7.5, 1.6 Hz, 2 H, 4,6-H), 7.87 (d, J ϭ 7.8 Hz, 4 H, 2
ϫ 2ЈЈ,6ЈЈ-H), 8.35 (t, J ϭ 1.6 Hz, 1 H, 2-H), 13.46 (s, 2 H, 2 ϫ
NH) ppm. 13C NMR ([D6]DMSO/TFA): δ ϭ 100.4 (2 ϫ C-4Ј),
122.6 (C-2), 125.0 (C-4,6), 125.6 (2 ϫ C-2ЈЈ,6ЈЈ), 128.4 (2 ϫ C-4ЈЈ),
129.2 (2 ϫ C3ЈЈ,5ЈЈ), 129.7 (C-5), 131.2 (2 ϫ C-1ЈЈ), 132.2 (C-1,3),
147.4 (2 ϫ C-3Ј), 147.8 (2 ϫ C-5Ј) ppm. EIMS: m/z (rel. int.) ϭ
362 (100) [Mϩ·], 333 (5), 247 (6), 189 (6), 181 (10), 105 (10), 84
(34), 77 (12), 66 (41). EI-HRMS (C24H18N4 [Mϩ·]): calcd. 362.1531,
found 362.1540.
3-Hydroxyphenyl-5-{4-[3-(2-hydroxyphenyl)-2-pyrazolin-5-yl]-
phenyl}-2-pyrazoline (4d): Yield 72% (387 mg). M.p. 197Ϫ199 °C.
1H NMR: ([D6]DMSO): δ ϭ 2.98 (dd, J ϭ 16.6, 10.8 Hz, 2 H, 2
ϫ 4Ј-Htrans), 3.61 (dd, J ϭ 16.6, 10.7 Hz, 2 H, 2 ϫ 4Ј-Hcis), 4.85
(dd, J ϭ 10.8, 10.7 Hz, 2 H, 2 ϫ 5Ј-H), 6.88 (t, J ϭ 7.5 Hz, 2 H,
2 ϫ 5ЈЈ-H), 6.91 (d, J ϭ 8.0 Hz, 2 H, 2 ϫ 3ЈЈ-H), 7.23 (ddd, J ϭ
8.0, 7.5, 1.4 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.29 (dd, J ϭ 7.5, 1.4 Hz, 2 H, 2
ϫ 6ЈЈ-H), 7.39 (s, 4 H, 2,3,5,6-H), 7.86 (s, 2 H, 2 ϫ NH), 11.17 (s,
2 H, 2 ϫ 2ЈЈ-OH) ppm. 13C NMR: δ ϭ 40.9 (2 ϫ C-4Ј), 61.9 (2 ϫ
C-5Ј), 115.8 (2 ϫ C-3ЈЈ), 116.8 (2 ϫ C-1ЈЈ), 119.2 (2 ϫ C-5ЈЈ), 126.9
(2 ϫ C-2,3,56), 127.8 (2 ϫ C-6ЈЈ), 129.8 (2 ϫ C-4ЈЈ), 141.4 (2 ϫ C-
1,4), 152.5 (2 ϫ C-3Ј), 156.8 (2 ϫ C-2ЈЈ) ppm. EIMS: m/z (rel.
int.) ϭ 398 (100) [Mϩ·], 369 (6), 263 (8), 238 (75), 207 (8), 178 (6),
161 (77), 134 (21), 120 (17), 105 (17), 91 (27), 77 (25), 65 (15). FAB-
HRMS (C24H23N4O2 [M ϩ H]ϩ): calcd. 399.1821, found 399.1834.
3-Phenyl-5-[4-(3-phenylpyrazol-5-yl)phenyl]pyrazole (5b): Yield 57%
(206 mg). Yellow oil. 1H NMR ([D6]DMSO/TFA): δ ϭ 7.30 (s, 2
H, 2 ϫ 4Ј-H), 7.34 (t, J ϭ 7.4 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.44 (dd, J ϭ
7.8, 7.4 Hz, 4 H, 2 ϫ 3ЈЈ,5ЈЈ-H), 7.85 (d, J ϭ 7.8 Hz, 4 H, 2 ϫ
2ЈЈ,6ЈЈ-H), 7.96 (s, 4 H, 2,3,5,6-H), 13.42 (s, 2 H, 2 ϫ NH) ppm.
13C NMR ([D6]DMSO/TFA): δ ϭ 101.2 (2 ϫ C-4Ј), 126.4 (2 ϫ C-
2ЈЈ,6ЈЈ), 126.9 (C-2,3,5,6), 129.4 (2 ϫ C-4ЈЈ), 129.7 (2 ϫ C-3ЈЈ,5ЈЈ),
130.8 (2 ϫ C-1ЈЈ), 131.2 (C-1,4), 148.0 and 148.1 (2 ϫ C-3Ј and 2
ϫ C-5Ј) ppm. EIMS: m/z (rel. int.) ϭ 362 (46) [Mϩ·], 247 (5), 181
(5), 105 (15), 91 (8), 84 (82), 77 (16), 66 (100). EI-HRMS
(C24H18N4 [Mϩ·]): calcd. 362.1531, found 362.1516.
Synthesis of Bis(chromones) 6c,d: Iodine (0.3 g, 1.2 mmol) was ad-
ded to a solution of chalcones 1c,d (2.5 mmol) in DMSO (8 mL).
The mixture was heated under reflux for 1 h, and then was poured
into ice (100 g) and water (100 mL) to precipitate the product. The
solid was removed by filtration, dissolved in chloroform (80 mL),
and washed with a 20% aqueous solution of sodium thiosulfate (2
ϫ 100 mL). The organic layer was dried with anhydrous sodium
sulfate and the solvent evaporated to dryness. Finally, each com-
pound was recrystallised from ethanol.
3-(2-Benzyloxyphenyl)-5-{3-[3-(2-benzyloxyphenyl)pyrazol-5-yl]-
phenyl}pyrazole (5c): Yield 52% (299 mg). M.p. 240Ϫ241 °C
(recrystallised from methanol). 1H NMR ([D6]DMSO/TFA): δ ϭ
5.26 (s, 4 H, 2 ϫ 2ЈЈ-OCH2C6H5), 7.04 (dd, J ϭ 7.8, 7.1 Hz, 2 H,
3Ј-(2-Chromonyl)flavone 6c: Yield 76% (695 mg). M.p. 249Ϫ250 °C
1
(recrystallised from ethanol). H NMR: δ ϭ 6.94 (s, 2 H, 2 ϫ 3Ј- 2 ϫ 5ЈЈ-H), 7.19 (d, J ϭ 7.8 Hz, 2 H, 2 ϫ 3ЈЈ-H), 7.18Ϫ7.22 (m, 2
H), 7.47 (dt, J ϭ 7.8, 1.0 Hz, 2 H, 2 ϫ 6Ј-H), 7.65 (dd, J ϭ 8.3, H, 2 ϫ 4-H of 2ЈЈ-OCH2C6H5), 7.25 (s, 2 H, 2 ϫ 4Ј-H), 7.29Ϫ7.34
1.0 Hz, 2 H, 2 ϫ 8Ј-H), 7.72 (t, J ϭ 7.8 Hz, 1 H, 5-H), 7.76 (ddd, (m, 4 H, 2 ϫ 3,5-H of 2ЈЈ-OCH2C6H5), 7.31Ϫ7.36 (m, 2 H, 2 ϫ
J ϭ 8.3, 7.8, 1.5 Hz, 2 H, 2 ϫ 7Ј-H), 8.09 (dd, J ϭ 7.8, 1.8 Hz, 2
4ЈЈ-H), 7.46 (d, J ϭ 7.2 Hz, 4 H, 2 ϫ 2,6-H of 2ЈЈ-OCH2C6H5),
H, 4,6-H), 8.26 (dd, J ϭ 7.8, 1.5 Hz, 2 H, 2 ϫ 5Ј-H), 8.49 (t, J ϭ 7.47Ϫ7.53 (m, 1 H, 5-H), 7.75 (dd, J ϭ 7.3, 1.5 Hz, 2 H, 4,6-H),
1.8 Hz, 1 H, 2-H). 13C NMR: δ ϭ 108.3 (2 ϫ C-3Ј), 118.1 (2 ϫ C- 7.79 (dd, J ϭ 7.1, 1.5 Hz, 2 H, 2 ϫ 6ЈЈ-H), 8.22 (s br, 1 H, 2-H)
8Ј), 123.9 (2 ϫ C-10Ј), 125.5 (2 ϫ C-6Ј), 125.8 (2 ϫ C-5Ј), 129.0 ppm 13C NMR ([D6]DMSO/TFA): δ ϭ 70.1 (2 ϫ 2ЈЈ-OCH2C6H5),
Eur. J. Org. Chem. 2003, 747Ϫ755
753

D. C. G. A. Pinto, A. M. S. Silva, J. A. S. Cavaleiro, J. Elguero
103.7 (2 ϫ C-4Ј), 113.7 (2 ϫ C-3ЈЈ), 118.3 (2 ϫ C-1ЈЈ), 121.3 (2 ϫ (2 ϫ C-2ЈЈ) ppm. EIMS: m/z (rel. int.) ϭ 394 (5) [Mϩ·], 380 (100),
FULL PAPER
C-5ЈЈ), 123.1 (C-2), 125.9 (C-4,6), 127.8 (2 ϫ C-2,6 of 2ЈЈ-
366 (47), 338 (11), 218 (5), 176 (5), 128 (5), 120 (25), 92 (15). EI-
OCH2C6H5), 128.1 (2 ϫ C-4 of 2ЈЈ-OCH2C6H5), 128.7 (2 ϫ C-6ЈЈ HRSM (C24H18N4O2 [Mϩ·]): calcd.394.1430, found 394.1425.
and 2 ϫ C-3,5 of 2ЈЈ-OCH2C6H5), 129.8 (C-5), 130.5 (2 ϫ C-4ЈЈ),
3-(2-Hydroxyphenyl)-5-{4-[3-(2-hydroxyphenyl)pyrazol-5-yl]phenyl}-
131.8 (C-1,3), 137.2 (2 ϫ C-1 of 2ЈЈ-OCH2C6H5), 143.2 (2 ϫ C-3Ј),
pyrazole (5f): M.p. Ͼ 300 °C (recrystallised from methanol). 1H
147.9 (2 ϫ C-5Ј), 155.5 (2 ϫ C-2ЈЈ). ) ppm. FABMS: m/z (rel.
NMR ([D6]DMSO/TFA): δ ϭ 6.91 (dd, J ϭ 7.9, 7.6 Hz, 2 H, 2 ϫ
int.) ϭ 575 (27), 369 (15), 221 (13), 219 (10), 203 (11), 191 (13),
5ЈЈ-H), 6.99 (d, J ϭ 8.0 Hz, 2 H, 2 ϫ 3ЈЈ-H), 7.22 (ddd, J ϭ 8.0,
187 (11), 177 (12), 165 (17), 161 (24), 159 (27), 154 (90), 91 (100).
7.6, 1.6 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.41 (s, 2 H, 2 ϫ 4Ј-H), 7.75 (dd, J ϭ
FAB-HRMS (C38H31N4O2 [M ϩ H]ϩ): calcd. 575.2447, found
7.9, 1.6 Hz, 2 H, 2 ϫ 6ЈЈ-H), 8.00 (s, 4 H, 2,3,5,6-H), 10.90 (s br, 2
575.2468.
H, 2 ϫ 2ЈЈ-OH), 13.75 (s br, 2 H, 2 ϫ NH) ppm. 13C NMR
3-(2-Benzyloxyphenyl)-5-{4-[3-(2-benzyloxyphenyl)pyrazol-5-yl]-
phenyl}pyrazole (5d): Yield 61% (350 mg). M.p. 265Ϫ266 °C
(recrystallised from methanol). 1H NMR ([D6]DMSO/TFA): δ ϭ
5.31 (s, 4 H, 2 ϫ 2ЈЈ-OCH2C6H5), 7.06 (t, J ϭ 7.5 Hz, 2 H, 2 ϫ
5ЈЈ-H), 7.21 (s, 2 H, 2 ϫ 4Ј-H), 7.22 (d, J ϭ 7.3 Hz, 2 H, 2 ϫ 3ЈЈ-
H), 7.31Ϫ7.37 (m, 4 H, 2 ϫ 4ЈЈ-H and 2 ϫ 4-H of 2ЈЈ-OCH2C6H5),
7.42 (dd, J ϭ 7.7, 6.9 Hz, 4 H, 2 ϫ 3,5-H of 2ЈЈ-OCH2C6H5), 7.55
(d, J ϭ 6.9 Hz, 4 H, 2 ϫ 2,6-H of 2ЈЈ-OCH2C6H5), 7.82 (s, 4 H,
2,3,5,6-H), 7.83 (dd, J ϭ 7.5, 1.5 Hz, 2 H, 2 ϫ 6ЈЈ-H), 13.12 (s br,
2 H, 2 ϫ NH) ppm. 13C NMR ([D6]DMSO/TFA): δ ϭ 69.9 (2 ϫ
2ЈЈ-OCH2C6H5), 103.1 (2 ϫ C-4Ј), 113.6 (2 ϫ C-3ЈЈ), 119.3 (2 ϫ
C-1ЈЈ), 121.1 (2 ϫ C-5ЈЈ), 125.7 (C-2,3,5,6), 127.9 (2 ϫ C-2,6 of 2ЈЈ-
OCH2C6H5), 128.1 (2 ϫ C-6ЈЈ and 2 ϫ C-4 of 2ЈЈ-OCH2C6H5),
128.7 (2 ϫ C-3,5 of 2ЈЈ-OCH2C6H5), 129.6 (2 ϫ C-4ЈЈ), 131.4 (C-
1,4), 137.3 (2 ϫ C-1 of 2ЈЈ-OCH2C6H5), 142.9 (2 ϫ C-3Ј), 147.6 (2
ϫ C-5Ј), 155.1 (2 ϫ C-2ЈЈ) ppm. EIMS: m/z (rel. int.) ϭ 574 (16)
[Mϩ·], 484 (16), 394 (10), 314 (10), 132 (9), 105 (9), 91 (100). FAB-
HRMS (C38H31N4O2 [M ϩ H]ϩ): calcd. 575.2447, found 575.2425.
([D6]DMSO/TFA): δ ϭ 102.0 (2 ϫ C-4Ј), 116.2 (2 ϫ C-1ЈЈ), 117.1
(2 ϫ C-3ЈЈ), 119.9 (2 ϫ C-5ЈЈ), 126.9 (C-2,3,5,6), 128.2 (2 ϫ C-6ЈЈ),
130.4 (2 ϫ C-4ЈЈ and C-1,4), 146.2 (2 ϫ C-5Ј), 147.3 (2 ϫ C-3Ј),
155.6 (2 ϫ C-2ЈЈ) ppm. EIMS: m/z (rel. int.) ϭ 394 (100) [Mϩ·],
267 (7), 197 (10), 131 (7), 120 (5), 91 (5), 78 (15), 63 (16). EI-HRMS
(C24H18N4O2 [Mϩ·]): calcd. 394.1430, found 394.1421.
Acknowledgments
Thanks are due to the University of Aveiro and ‘‘Fundac¸a˜o para a
ˆ
Ciencia e Tecnologia’’ for funding the Organic Chemistry Re-
search Unit.
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P. M. Dey, J. B. Harborne), Academic Press, London, 1989,
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B. A. Bohm in Methods in Plant Biochemistry, vol. 1 (Eds.:
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Method A. Debenzylation of Bis(pyrazoles) 5c,d: A suspension of
bis(pyrazoles) 5c,d (0.5 mmol) in a solution of hydrobromic acid in
acetic acid (33%, 10 mL) was refluxed for 1.5 h, and then the mix-
ture was poured into ice (100 g) and water (100 mL). The aqueous
phase was extracted with ethyl acetate (3 ϫ 100 mL) and the com-
bined organic layers washed with water (2 ϫ 100 mL). The solvent
was evaporated to dryness and the residue purified by thin-layer
chromatography using a mixture of chloroform and acetone (8:2)
as eluent. The main eluted spot from the base line was identified
as the expected bis(pyrazoles) 5e,f (ഠ 5% yield), which were recrys-
tallised from methanol.
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A. Krutosikova, M. Uher in Natural and Synthetic Sweet
Substances (Translation, Ed.: J. Hudec), Ellis Horwood, New
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V. S. Parmar, K. S. Bisht, R. Jain, S. Singh, S. K. Sharma, S.
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Method B. From Bis(chromones) 6c,d: Hydrazine hydrate (0.74 mL,
15.3 mmol) was added to a methanolic suspension (100 mL) of
bis(chromones) 6c,d (1.91 mmol). The reaction mixture was heated
under reflux for 24 h under nitrogen. The solvent was evaporated
and the residue was washed with water and extracted with chloro-
form (3 ϫ 30 mL). The 3,5-diphenylpyrazoles 5e,f were purified
by thin-layer chromatography using a mixture of chloroform and
acetone (8:2) as eluent. The main spot was identified as the ex-
pected bis(pyrazoles) [5e, 74% (557 mg); 5f, 76% (572 mg)], which
were recrystallised from methanol.
[8] [8a]
[8b]
D. A. Lewis, Chem. Br. 1992, 141Ϫ144.
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J. Pincemail, C. Deby, K. Drieu, R. Anton, Goutier R.,
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in Biology and Medicine, Singapore, 1989, pp. 161Ϫ179. [10b]S.
3-(2-Hydroxyphenyl)-5-{3-[3-(2-hydroxyphenyl)pyrazol-5-yl]phenyl}-
pyrazole (5e): M.p. Ͼ 300 °C (recrystallised from methanol). 1H
NMR ([D6]DMSO/TFA): δ ϭ 6.90 (dd, J ϭ 7.8, 7.2 Hz, 2 H, 2 ϫ
5ЈЈ-H), 6.99 (d, J ϭ 7.6 Hz, 2 H, 2 ϫ 3ЈЈ-H), 7.21 (ddd, J ϭ 7.6,
7.2, 1.6 Hz, 2 H, 2 ϫ 4ЈЈ-H), 7.45 (dt, J ϭ 7.4, 2.2 Hz, 1 H, 5-H),
7.52 (s, 2 H, 4Ј-H), 7.75 (dd, J ϭ 7.8, 1.6 Hz, 2 H, 6ЈЈ-H), 8.08 (t,
J ϭ 7.4 Hz, 2 H, 1.6 Hz, 4,6-H), 8.57 (s br, 1 H, 2-H), 10.70 (s br,
2 H, 2 ϫ 2ЈЈ-OH) ppm. 13C NMR ([D6]DMSO/TFA): δ ϭ 102.0
(2 ϫ C-4Ј), 116.8 (2 ϫ C-3ЈЈ), 118.8 (2 ϫ C-1ЈЈ), 119.7 (2 ϫ C-5ЈЈ),
123.8 (C-2), 125.2 (C-4,6), 125.8 (C-5), 128.0 (2 ϫ C-6ЈЈ), 129.1 (C-
1,3), 130.1 (2 ϫ C-4ЈЈ), 145.6 (2 ϫ C-5Ј), 147.1 (2 ϫ C-3Ј), 155.4
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