An efficient and regioselective synthesis of 1,1′-oxalylbis [3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles] from 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones

Article abstract of DOI:10.1007/s00706-011-0455-0

This work describes the regioselective synthesis of two new series of 1,10-oxalylbis[3-(alkyl/aryl/ heteroaryl)-4,5-dihydro-5-hydroxy-5- (trihalomethyl)-1Hpyrazoles], where the 3-substituents are H, Me, C ₆H₅,4-FC₆H_4<

Full text of DOI:10.1007/s00706-011-0455-0

Monatsh Chem (2011) 142:277–285
DOI 10.1007/s00706-011-0455-0
ORIGINAL PAPER
An efficient and regioselective synthesis of 1,10-oxalylbis
[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles]
from 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones
•
Helio G. Bonacorso Cleber A. Cechinel
•
•
Jussara Navarini Rosalia Andrighetto
•
´
•
Marcos A. P. Martins Nilo Zanatta
Received: 10 March 2010 / Accepted: 2 February 2011 / Published online: 26 February 2011
Ó Springer-Verlag 2011
Abstract This work describes the regioselective synthe-
sis of two new series of 1,10-oxalylbis[3-(alkyl/aryl/
heteroaryl)-4,5-dihydro-5-hydroxy-5-(trihalomethyl)-1H-
pyrazoles], where the 3-substituents are H, Me, C6H5,
4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-NO2C6H4, 4,40-BiPh, and
2-furyl, in a one-pot methodology with ethanol as solvent,
from the reaction of 4-alkoxy-4-(alkyl/aryl/heteroaryl)-
1,1,1-trihaloalk-3-en-2-ones with oxalyldihydrazide (51–
89%). Complementarily, the dehydration reactions of five
examples of the described oxalylbispyrazolines are also
reported, which furnished the respective 1,10-oxalylbis
[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles] in
53–78% yields without the two C(O)–N bond cleavages.
showing that a carbonyl function attached to a pyrazole
nucleus was a promising structure.
In 1972, Lotti and Vezzosi synthesized 13 1-(alka-
noyl)aroyl-substituted 3,5-dimethylpyrazoles from the
reaction of 3,5-dimethyl-1H-pyrazoles with an appropriate
acid chloride in diethylether as solvent and in the presence of
triethylamine. As a result, most of these compounds showed
hypoglycemic activity greater than that of 1-butyl-3-(4-tol-
ylsulfonyl)urea (tolbutamide). In the same paper 1,10-
oxalylbis(3,5-dimethylpyrazole) was also synthesized and
evaluated, showing interesting hypoglycemic activity [6].
In 1975, some 1,10-adipyl- and 1,10-oxalylbis(3,5-di-
methylpyrazoles) and the respective 2-pyrazolin-5-ones were
prepared by the reaction of adipyl/oxalylhydrazine with
1,3-dicarbonyl compounds and evaluated as potential
antidiabetics [7].
Keywords Oxalyldihydrazide ꢀ Ketones ꢀ Pyrazolines ꢀ
Pyrazoles ꢀ Bispyrazoles
In 1988, a study on tautomerism in a series of conden-
sation products of 1,3-dicarbonyl compounds and
dihydrazides of dicarboxylic acids was reported [8]. This
study demonstrated the crystalline state of 1,10-malonyl-
and 1,10-oxalylbispyrazolines. The authors also observed
1,10-oxalylbis[5-(t-butyl)-4,5-dihydro-5-hydroxy-1H-pyr-
azole] as a diastereomeric mixture in solution. Later
the synthesis, electron spin resonance (ESR) spectra, and
magnetic susceptibility of binuclear copper(II) complexes
based on some 1,10-dicarbonyl-linked bispyrazolines were
reported in 1989 [9].
Introduction
Since 1967, it has been estimated that the incidence of
people with diabetogenic genes is one in four and that the
rate of increase of diabetes is approximately three times
that of the population in general [1]. Moreover, Grunwald
[2] stated that there is still hope and need for oral hypo-
glycemic agents with mechanisms of action other than
those of the compounds presently available. The first works
on animals revealed that 5-methylpyrazole-3-carboxylic
acid derivatives very nearly approached this goal [3–5],
In 1998, a series of a-keto esters was prepared in good
yields by the formation of N-acylpyrazoles, followed by the
appropriate Grignard reactions [10]. In the first step, 1,10-
oxalylbis(3,5-dimethylpyrazole) was obtained in 64% yield
when the reaction of 3,5-dimethyl-1H-pyrazole with oxalyl
chloride was carried out in toluene as solvent and also in
the presence of triethylamine. In a recent work, El-Sayed
et al. [11] reported the N-acylation of 5(3)-hydroxy-3(5)-
H. G. Bonacorso (&) ꢀ C. A. Cechinel ꢀ J. Navarini ꢀ
R. Andrighetto ꢀ M. A. P. Martins ꢀ N. Zanatta
´
´
Nucleo de Quımica de Heterociclos, NUQUIMHE,
Departamento de Quımica, Universidade Federal de Santa
´
Maria, 97105-900 Santa Maria, RS, Brazil
e-mail: heliogb@base.ufsm.br
123

278
H. G. Bonacorso et al.
substituted-1H-pyrazoles, on average in 75% yields,
employing different acyl halides.
Thus, considering the biological importance of 2-pyr-
azolines and the fact that trifluoro(chloro)methylated
analogs, such as 1,10-oxalylbispyrazoles 2, 3, 5, 6 have not
yet been produced, it would be of interest to demonstrate a
simple and environmentally benign method to obtain these
heterocycles. Herein, we report results of the reaction
of these b-alkoxyvinyl trihalomethyl ketones with oxa-
lyldihydrazide in ethanol as solvent, which was expected to
deliver the new bis[4,5-dihydro-5-hydroxy-5-(trihalometh-
yl)-1H-pyrazoles] bearing an oxalyl moiety on the newly
formed ring system, thus offering opportunities for struc-
tural variations due to the presence of the uncommon
trihalomethyl group at position 5 and alkyl, aryl or het-
eroaryl substituents at position 3 of the bispyrazolines and
the respective bispyrazoles (Schemes 1, 2).
In 2009, we reported a one-step and regioselective
procedure for the synthesis of a novel series of 1,10-car-
bonylbis[3-(alkyl/aryl/heteroaryl)-4,5-dihydro-5-hydroxy-
5-(trifluoromethyl)-1H-pyrazoles] [12–14] from the
cyclocondensation reactions of 4-alkoxy-4-(aryl/hetero-
aryl)-1,1,1-trifluoroalk-3-en-2-ones with carbohydrazide.
As a synthetic alternative, in 2010, two new series of
1,10-carbonylbis[3-(aryl/heteroaryl)-5-(trihalomethyl)-1H-
pyrazoles] [15] were synthesized by us in a one-pot
methodology from the reaction of 4-methoxy-4-(aryl/-
heteroaryl)-1,1,1-trihalobut-3-en-2-ones with 1,3-diamino-
guanidine monohydrochloride. The heterocycles were
obtained regioselectively in good yields (62–86%) and
short reaction time.
In the course of our ongoing interest in new heterocyclic
scaffolds which present promising pharmacological activ-
ity, we have explored the application of 4-alkoxy-4-(alkyl/-
aryl/heteroaryl)-1,1,1-trihaloalk-3-en-2-ones 1, 4 in the
synthesis of novel 1,10-oxalylbis[4,5-dihydro-5-hydroxy-5-
(trihalomethyl)-1H-pyrazoles] 2, 5 and the respective
dehydrated bispyrazole systems 3, 6.
Results and discussion
4-Alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-trihaloalk-3-en-2-
ones 1a, 1b, 4a, 4b [16], 1c–1f, 4c–4f [17], 1g [18], and 1h
[19] are readily available CCC synthetic blocks and were
prepared from trifluoroacetylation [20] or trichloroacetylation
R
R
CF3
OH
O
F3C
O
N
N
O
OMe(Et)
R
ii
i
N
N
N
N
66 - 72%
51 - 83%
F3C
N
O
N
O
CF3
CF3
HO
R
R
1a-1h (2.0 equiv.)
2a-2h
3c, 3f
1-3
a
b
c
d
e
f
g
h
R
H
Me Ph 4-FC6H4 4-ClC6H4 4-NO2C6H4 BiPh-4-yl 2-Furyl
i:(NH 2NHCO)2 (1.0 equiv.), EtOH/H2O, 2-5h, 80oC; ii:SOCl2, Pyridine, Benzene, 0-80ºC, 1h
Scheme 1
R
R
CCl3
OH
O
O
Cl3C
O
N
N
O
OMe(Et)
R
ii
i
N
N
N
N
53 - 78%
63 - 89%
Cl3C
N
N
O
CCl3
CCl3
HO
R
R
4a 4f
-
5a 5f
-
6c 6e 6f
, ,
(2.0 equiv.)
4-6
a
b
c
d
e
f
__________________________________________
R
H
Me Ph 4-FC6H4 4-ClC6H4 4-BrC6H4
i :(NH2NHCO)2 (1.0 equiv.), EtOH/H2O, 2-5h, 80oC; ii:SOCl2, Pyridine, Benzene, 0-80º C, 1h
Scheme 2
123

Synthesis of 1,10-oxalylbis[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles]
279
reactions [21] of enol ethers commercially available or gen-
erated in situ from the respective aryl- or heteroaryl methyl
ketone acetals with trifluoroacetic anhydride or with trichlo-
roacetyl chloride, respectively, in the presence of pyridine, as
described in [16–19].
sensitive groups are lost during the dehydration reaction
due to the acidic conditions and temperature.
In 2001, Zhu et al. [23] performed the dehydration
of 4,5-dihydro-5-hydroxy-4-(2-hydroxyethyl)-5-(trifluoro-
methyl)-1-(pentafluorophenyl)- and -1-(tetrafluorophenyl)-
1H-pyrazoles by treatment with P2O5 to obtain the
respective pyrazoles. However, in the same study, under
the same reaction condition, 4,5-dihydro-1-(heptafluoro-
butanoyl)-5-hydroxy-4-(2-hydroxyethyl)-5-(trifluoromethyl)-
1H-pyrazole did not furnish the aromatic compound, and it
was necessary to employ thionyl chloride and pyridine in
chloroform as dehydration medium to obtain the respective
pyrazole, which was purified only by column chromatog-
raphy. In contrast to the use of P2O5, no experimental
details were reported for the employment of thionyl chlo-
ride in the cited work.
Subsequently, we reacted pure ketones 1 and 4 with
oxalyldihydrazide, regioselectively obtaining in a one-step
reaction novel 1,10-oxalylbis[4,5-dihydro-5-hydroxy-5-
(trihalomethyl)-1H-pyrazoles] 2 and 5 and subsequently
the respective dehydrated bispyrazole systems 3 and 6.
The reactions of 4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-
trihaloalk-3-en-2-ones 1, 4 with oxalyldihydrazide in 2:1
molar ratio using a mixture of ethanol/water (20:1 v/v) as
an ecofriendly solvent were carried out under mild condi-
tions under reflux (80 °C) for 2–5 h.
After stirring under these conditions, thin-layer chro-
matography (TLC) showed that the reactions proceeded
smoothly and gave the products in 51–83% yields for the
trifluoromethyl-substituted system 2 (Scheme 1) and in
63–89% yields for the trichloromethylated bispyrazolines 5
(Scheme 2). Compounds 2 and 5 were isolated as stable
white solids by crystallization from the original reac-
tion solvent, but only after reducing the volume to half,
following mild refrigeration at approximately 5 °C for
1–2 days.
After a review of the literature and in an attempt to
obtain aromatic pyrazoles for further biological assays, we
chose thionyl chloride/pyridine [24–26] as the dehydration
agent and report here the conditions required to accomplish
the dehydration of 2 and 5, which present a hydroxy and
trihalomethyl, aryl, and oxalyl group attached directly to
the C-5, C-3, and N-1 atom of the bispyrazoline rings,
respectively (Schemes 1, 2). In spite of the relative diffi-
culty of this elimination, because of the presence of these
substituents, 2c, 2f, 5c, 5e, and 5f were dehydrated to give
the respective bispyrazole derivatives 3c, 3f, 6c, 6e, and 6f
in 66–72% yields for the trifluoromethyl-substituted system
3 (Scheme 1) and in 53–78% yields for the trichlorome-
thylated bispyrazolines 6 (Scheme 2), only by stirring a
mixture of 2 and 5, thionyl chloride, and pyridine at 80 °C
for about 1 h in benzene as solvent, according to similar
procedures described in the literature [24–26]. Compounds
3 and 6 were easily isolated as stable white or yellow solids
and were recrystallized from ethanol.
Presumably, the reactions start with the Michael addi-
tion of the amino groups of oxalyldihydrazide at the
b-carbon atom of the enones 1 and 4 furnishing addi-
tion products. The aminoether functions are unstable in
alcohol/water (reaction solvent), and the alkoxy groups are
eliminated as methanol (R = H) or ethanol (R = H).
Subsequently, two intramolecular cyclization reactions
occur involving the carbonyl functions of the nonisolated
bis-b-enaminones and the second nitrogens of the dinu-
cleophile reagent. In addition, the elimination of two water
molecules is not likely to occur in the bispyrazoline
structures 2 and 5 due to the electron-withdrawing effect of
the hydroxy and trihalomethyl groups, the weak acid
reaction condition employed (ethanol/water), and also
due to the electronic effect of the carbonyl substituent of
the oxalyl moiety at the N-1 position of both rings.
This structural feature allowed the isolation of the new
1,10-oxalylbis[4,5-dihydro-5-hydroxy-5-(trihalomethyl)-1H-
pyrazoles] in accordance with results and mechanisms
(Fig. 1) obtained previously for reactions of similar enones
with carbohydrazide [12] and cyanoacetohydrazide [13,
14], but not with diaminoguanidine [15].
The structures of 1,10-oxalylbis[4,5-dihydro-5-hydroxy-
5-(trifluoromethyl)-1H-pyrazoles] 2a–2h were deduced
from nuclear magnetic resonance (NMR) experiments and
by comparison with NMR data of other 2-pyrazolines
formerly synthesized in our laboratory [12–23].
Due to the symmetry, compounds 2 showed only one set
1
of peaks and presented H NMR chemical shifts in dime-
thyl sulfoxide (DMSO)-d6 for the hydroxy protons in the
range of d = 8.59 ppm, and the four methylene protons
(H4) are shown as typical AB systems as two doublets; one
of them is on average at d = 3.89 and the other at
3.50 ppm, with a geminal coupling constant of 19 Hz.
The 13C{1H} NMR spectra also exhibited only one set
of peaks, despite the fact that two stereogenic carbons are
present in each molecule. The oxalyl derivatives 2 also
presented the typical 13C NMR chemical shifts of both
pyrazoline rings at d = 149.8 ppm (C3) and 44.7 ppm
(C4). Due to the presence of the CF3 group, both C5
In recent years, the treatment of 2-pyrazolines in an
acidic medium using either pure sulfuric acid, P2O5, mix-
tures of sulfuric acid in boiling acetic acid, acetic acid in
boiling ethanol, hydrochloric acid/ethanol, acetic anhy-
dride, or acetic acid have been the most employed methods
for dehydration [22]. However, in many cases, acid-
123

280
H. G. Bonacorso et al.
O
OR1
OR1
O
O
H2NHN
X3C
R
NHNH2
R
R
CX3
1, 4
1, 4
O
EtOH/H2O
H
H
R1
O
R1
O
O
R
O
O
- R1OH
X3C
NHN
H
NHN
H
O
O
O
R
O
H
N
H
N
CX3
X3C
N
H
N
H
R
O
O
R
O
H
N
N
CX3
X3C
N
N
H
O
R
O
R
R
N
N
H
O
N
O
O
HO
CX3
CX3
H
N
N
N
N
X3C
X3C
O
OH
N
O
O
2, 5
R
R
R = H, Me, Aryl, 2-Furyl; R1 = Et, Me; X = F, Cl
Fig. 1 Proposed mechanism for the synthesis of 2a–2h and 5a–5f
carbons presented a characteristic quartet at 90.8 ppm with
2JCF = 35 Hz. Also, both CF3 groups showed a typical
carbonyl carbons showed only one singlet in the range of
158.7 ppm.
1
quartet at 121.9 ppm with JCF = 286 Hz, and the two
In contrast to the trifluoromethyl-substituted bispyrazo-
lines 2a–2h, 1,10-oxalylbis[4,5-dihydro-5-hydroxy-5-(trichloro-
methyl)-1H-pyrazoles] 5a–5f showed two sets of NMR
signals. Thus, as expected, the 13C{1H} NMR spectra also
exhibited two peaks for each carbon of the pyrazoline rings
as well as for the oxalyl moiety.
carbonyl carbons (oxalyl moiety) showed one NMR signal
on average at 159.4 ppm. All signals are consistent with 1H
and 13C NMR chemical shifts of the 2-pyrazolines and the
oxalyl moiety for this symmetrical system.
The dehydrated trifluoromethylated compounds 3, being
a symmetrical system, presented one set of signals in both
1H and 13C NMR spectra and, in comparison with 2,
showed typical chemical shifts of the pyrazole ring for both
H-4 on average at 8.17 ppm as singlet peaks. The 13C{1H}
NMR spectra exhibited chemical shifts for both pyrazole
ring carbons on average at 151.2 (C3), 101.7 (C4), 137.6
The chemical shifts of the four diastereotopic methylene
protons (H4) appeared as two multiplets in the narrow ranges
of 4.37–3.42 and 4.05–3.27 ppm. The hydroxy protons, as
two singlets, are shown in the 1H NMR spectra in the range of
8.72–8.01 ppm. Compounds 5 also presented the typical
13C{1H} NMR spectra where the chemical shifts for non-
symmetrical structures showed separate signals for each
2
1
(C5, JCF = 38), and 122.1 ppm (CF3, JCF = 289). Both
123

Synthesis of 1,10-oxalylbis[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles]
281
pyrazoline ring carbon in the narrow ranges of 156.7–152.1
(C3), 50.3–46.6 (C4), 102.8–101.0 (C5), and 103.0–
102.5 ppm (CCl3). Both carbonyl carbons of the oxalyl
moiety appeared as two singlets in the range of 162.3–
156.7 ppm, which is consistent with NMR chemical shift
assignmentswhencompared with compounds2 andliterature
data for trichloromethyl-substituted 2-pyrazolines [21, 27].
The trichloromethylated bispyrazoles 6, also a sym-
metrical system, presented one set of signals in both 1H and
13C NMR spectra and in comparison with 5 showed typical
chemical shifts of the pyrazole rings for both H-4 on
average at 8.07 ppm as one singlet peak. The 13C{1H}
NMR spectra exhibited chemical shifts for both pyrazole
ring carbons on average at 154.4 (C3), 84.6 (C4), 147.0
(C5), and 112.5 ppm (CCl3). Both carbonyl carbons
showed only one singlet on average at 158.3 ppm.
center but also can vary with the solvent used in the anal-
ysis. Unfortunately, compounds 2–3 and 5–6 are weakly
soluble in nonpolar solvents to give more conclusions.
Complementarily, we also performed X-ray diffraction
measurements (Fig. 2) for a monocrystal of compound 5c
(5S*, 50R*/5R*, 50S*—meso). The crystallographic data of
5c showed relevant information for the structural deter-
mination of this compound. Briefly, molecule 5c shows
that the five-membered 2-pyrazolines are planar, and the
phenyl ring is attached to the C-3 of each pyrazoline. The
torsion angles of N(2)–N(1)–C(1)–O(1), N(2a)–N(1a)–
C(2)–O(2), and O(1)–C(1)–C(2)–O(2) are 171.5(4)°,
-164.7(4)°, and 75.6(6)°, respectively, demonstrating that
each carbonyl group is almost coplanar in relation to the
2-pyrazoline rings, but not to each other. It was also
observed that both phenyl rings are almost coplanar to the
respective attached pyrazolines and present torsion angles
of -178.9(4)° for N(2)–C(3)–C(31)–C(32) and -10.1(6)°
for N(2a)–C(3a)–C(31a)–C(32a).
To explain the spectroscopic behavior differences of the
trihalomethyl-substituted bispyrazoline series 2 and 5 by
NMR spectral data, the following considerations should be
mentioned. Initially, it appears that each molecule of the
series 2 and 5 has two chiral centers at carbons-5, which are
separated byan oxalyl moiety. This fact suggests the possible
presence of two pairs of diastereomers: 5S*, 50S*/5R*, 50R*
(racemate) and 5S*, 50R*/5R*, 50S* (meso) for both series.
However, the analysis of 1H and 13C NMR spectra showed
that only one pair of diastereomers was isolated for the tri-
fluoromethyl-substituted series 2 and that two pairs were
obtained for the trichloromethylated series 5, since only one
set of signals was obtained for 2 and two sets were observed
for 5. However, there is no apparent reason to explain the
diastereoselectivity found for series 2 and 5. Thus, we were
surprised to observe that the NMR chemical shifts for the two
pairs of diastereomers in 2 are isochronous and for com-
pounds 5 anisochronous. Second, it was also interesting to
observe the magnetic behavior of the dehydrated systems 3
and 6, where there are no chiral centers. In this case, for both
series no anisochrony was observed, demonstrating that the
magnetic anisochrony for the series 2–3 and 5–6 depends on
the presence of the stereogenic carbons and the trihalomethyl
groups. Third, a similar effect was observed previously by
Yusupov et al. [8] for 1,10-oxalylbis[5-(t-butyl)-4,5-dihy-
dro-5-hydroxy-1H-pyrazole], wherethet-butylgroupinduced
the formation of diastereomers.
In conclusion, we consider the regioselective reaction
reported here to be a useful, simple, and convenient
method, which employs commercially available reagents,
an environmentally benign method (ethanol as solvent),
and mild conventional conditions to obtain the novel and
interesting trihalomethylated series of 1,10-oxalylbis
(3-substituted-2-pyrazolines). On the other hand, the dehy-
drated 1,10-oxalylbis(1H-pyrazoles) could be obtained only
in presence of an aromatic solvent (benzene or toluene).
Experimental
Unless otherwise indicated all common reagents and sol-
vents were used from commercial suppliers without further
purification. Oxalyldihydrazide was obtained commercially
from Aldrich (ACS grade). All melting points were deter-
mined using open capillaries on an Electrothermal Mel-
Temp 3.0 apparatus. 1H and 13C NMR spectra were
acquired on a Bruker DPX 200 spectrometer (1H at
200 MHz and 13C at 50 MHz), 5 mm sample tubes, 298 K,
digital resolution 0.01 ppm, in DMSO-d6 for 2, 3, 5, 6
using tetramethylsilane (TMS) as internal reference or
fluorobenzene as external reference (19F NMR). The dif-
fraction measurements were carried out by graphite-
Thus, we suggest that CCl3, a bulky group in comparison
with CF3, induces the appearance of different sets of signals
for compounds 5a–5f due to their magnetic anisotropy,
which is stronger than that of the CF3 group. On the other
hand, a CF3 group presents a weaker magnetic anisotropy
than a CCl3 group and its magnetic influence is less
observable in the bispyrazoline system 2 also due, in part, to
the distance between the two chiral centers. It is noteworthy
that, according to the literature [33], the degree of aniso-
chrony is not only a function of the distance from a chiral
˚
monochromatized Mo Ka radiation with k = 0.71073 A on
a Bruker SMART CCD diffractometer [28]. The structure
of 5c was solved with direct methods using SHELXS-97
program [29], and refined on F2 by full-matrix least-
squares using the SHELXL-97 package [30]. The absorp-
tion correction was performed by Gaussian methods [31].
Anisotropic displacement parameters for nonhydrogen
atoms were applied. The hydrogen atoms were placed at
˚
calculated positions with 0.96 A (methyl CH3), 0.97 A
˚
123

282
H. G. Bonacorso et al.
Fig. 2 A view of the compound 5c [(5S*, 50R*/5R*, 50S*)—(meso)] with atomic labeling. Displacement ellipsoids are drawn at the 50%
probability level. H atoms are represented by circles of arbitrary radii
˚
(methylene CH2), 0.98 A (methine CH), 0.93 A (aromatic
˚
CH), and 0.82 A (OH) using a riding model. The hydrogen
˚
evaporator under reduced pressure. After cooling (B5 °C)
for 1–2 days the compounds 2a–2h and 5a–5f were
obtained pure directly by filtration, washed with cold eth-
anol/water (20:1 v/v), and dried under vacuum.
isotropic thermal parameters were kept equal to
Uiso(H) = vUeq (carrier C atom), with v = 1.5 for methyl
groups and v = 1.2 otherwise. The valence angles C–C–H
and H–C–H of methyl groups were set to 109.5°, and the H
atoms were allowed to rotate around the C–C bond. The
molecular graph was prepared using ORTEP3 for Windows
[32]. Crystallographic data for the structure of 5c (meso)
have been deposited with the Cambridge Crystallographic
Data Centre and allocated deposition number CCDC
711243. Copies of the data can be obtained free of charge,
on application to CCDC 12 Union Road, Cambridge CB2
1EZ, UK (Fax ?44-1223-336033 or via http://www.ccdc.
cam.ac.uk/conts/retrieving.html).
1,10-Oxalylbis[4,5-dihydro-5-(trifluoromethyl)-1H-pyrazol-
5-ol] (2a, C10H8F6N4O4)
White solid, yield 72%; m.p.: 172–174 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.36 (s, 2H, 2OH), 7.28 (s, 2H,
2H-3), 3.44 (d, J = 19 Hz, 2H, H-4, H-40), 3.15 (d, J = 19 Hz,
2H, H-4, H-40) ppm; 13C NMR (50 MHz, DMSO-d6):
1
d = 159.7 (2C=O), 147.1 (2C-3), 122.7 (q, J = 285 Hz,
2CF3), 89.0 (q, 2J = 34 Hz, 2C-5), 45.6 (2C-4) ppm; 19F NMR
(376 MHz, DMSO-d6): d = -76.5 (s, 2CF3) ppm.
1,10-Oxalylbis[4,5-dihydro-3-methyl-5-(trifluoromethyl)-
1H-pyrazol-5-ol] (2b, C12H12F6N4O4)
General procedure for the synthesis of 1,10-
oxalylbis[4,5-dihydro-5-hydroxy-5-(trihalomethyl)-1H-
pyrazoles] 2a–2h and 5a–5f
White solid, yield 77%; m.p.: 212–213 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.24 (s, 2H, 2OH), 3.45 (d,
2H, J = 20 Hz, H-4, H-40), 3.09 (d, 2H, J = 20 Hz, H-4,
H-40), 1.93 (s, 6H, 2Me) ppm; 13C NMR (50 MHz, DMSO-
d6): d = 160.5 (2C=O), 155.4 (2C-3), 122.5 (q,
1J = 285 Hz, 2CF3), 90.3 (q, J = 34 Hz, 2C-5), 47.5
(2C-4), 15.2 (2Me) ppm; 19F NMR (376 MHz, DMSO-d6):
d = -76.5 (s, 2CF3) ppm.
A solution of 4-substituted 4-methoxy-1,1,1-trihaloalk-3-
en-2-ones 1a–1h (10 mmol) and oxalyldihydrazide
(5 mmol) in 20 cm3 ethanol and 1 cm3 distilled water was
stirred at 80 °C for 2–5 h. After the reaction time the
solvent was evaporated to half its volume on a rotatory
123

Synthesis of 1,10-oxalylbis[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles]
283
1,10-Oxalylbis[4,5-dihydro-3-phenyl-5-(trifluoromethyl)-
1H-pyrazol-5-ol] (2c, C22H16F6N4O4)
J = 18 Hz, H-4, H-40), 3.68 (d, 2H, J = 18 Hz, H-4, H-40)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 152.9 (2C=O),
142.2 (2C-3), 138.7, 129.9, 129.7, 128.6, 128.5, 128.4,
White solid, yield 54%; m.p.: 224–225 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.67 (s, 2H, 2OH), 7.72–7.77
(m, 4H, 2 Ar), 7.45–7.56 (m, 6H, 2Ar), 4.03 (d, 2H,
J = 19 Hz, H-4, H-40), 3.65 (d, 2H, J = 19 Hz, H-4, H-40)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 161.4 (2C=O),
154.1 (2C-3), 131.5, 130.0, 129.1, 127.0 (12C, 2Ar), 120.6
1
126.6, 126.3 (24C, 2biPh), 120.1 (q, J = 287 Hz, 2CF3),
2
91.1 (q, J = 35 Hz, 2C-5), 44.0 (2C-4) ppm; 19F NMR
(376 MHz, DMSO-d6): d = -76.5 (s, 2CF3) ppm.
1,10-Oxalylbis[3-(2-furyl)-4,5-dihydro-5-(trifluoromethyl)-
1H-pyrazol-5-ol] (2h, C18H12F6N4O)
1
2
(q, J = 286 Hz, 2CF3), 91.7 (q, J = 35 Hz, 2C-5), 44.7
(2C-4) ppm; 19F NMR (376 MHz, DMSO-d6): d = -76.6
(s, 2CF3) ppm.
White solid, yield 58%; m.p.: 118–120 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.63 (s, 2H, 2OH), 7.90 (s,
2H, 2Fur), 6.98–7.01 (m, 2H, 2Fur), 6.67–6.68 (m, 2H, 2
Fur), 3.89 (d, 2H, J = 18 Hz, H-4, H-40), 3.50 (d, 2H,
J = 18 Hz, H-4, H-40) ppm; 13C NMR (50 MHz, DMSO-
d6): d = 160.5 (2C=O), 146.1 (2C-3), 145.0, 144.9, 114.7,
1,10-Oxalylbis[3-(4-fluorophenyl)-4,5-dihydro-5-
(trifluoromethyl)-1H-pyrazol-5-ol] (2d, C22H14F8N4O4)
White solid, yield 51%; m.p.: 204–205 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.63 (s, 2H, 2OH), 7.69–7.76
(m, 4H, 2Ar), 7.28–7.37 (m, 4H, 2Ar), 4.03 (d, 2H,
J = 19 Hz, H-4, H-40), 3.62 (d, 2H, J = 19 Hz, H-4, H-40)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 163.2 (d,
1J = 253 Hz, 2C, 2 Ar), 161.0 (2C=O), 152.9 (2C-3),
1
112.3 (8C, 2Fur), 122.2 (q, J = 287 Hz, 2CF3), 90.6 (q,
2J = 35 Hz, 2C-5), 43.9 (2C-4) ppm; 19F NMR (376 MHz,
DMSO-d6): d = -75.6 (s, 2CF3) ppm.
1,10-Oxalylbis[4,5-dihydro-5-(trichloromethyl)-1H-
pyrazol-5-ol] (5a, C10H8Cl6N4O4)
4
3
129.0 (d, J = 3 Hz, 2C, 2 Ar), 127.9 (d, J = 9 Hz, 4C,
2Ar), 116.0 (d, 2J = 22 Hz, 4C, 2Ar), 122.7 (q,
1J = 286 Hz, 2CF3), 90.9 (q, 2J = 35 Hz, 2C-5), 44.2
(2C-4) ppm; 19F NMR (376 MHz, DMSO-d6): d = -76.5
(s, 2CF3), -107.9 (s, 2F-Ph) ppm.
Yellow solid, yield 89%; m.p.: 197–198 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.21 (s, 2H, 2OH), 8.01 (d,
2H, J = 2 Hz, 2H-3), 3.48–3.55 (m, 2H, H-4, H-40), 3.27–
3.38 (m, 2H, H-4, H-40) ppm; 13C NMR (50 MHz, DMSO-
d6): d = 161.8 (C=O), 160.9 (C=O0), 156.7 (C-3), 155.8
1,10-Oxalylbis[3-(4-chlorophenyl)-4,5-dihydro-5-(trifluo-
romethyl)-1H-pyrazol-5-ol] (2e, C22H14Cl2F6N4O4)
(C-30), 103.0 (CCl3), 102.8 (CCl3 ), 101.2 (C-5), 101.1
0
(C-50), 50.3 (C-4), 50.2 (C-40) ppm.
White solid, yield 64%; m.p.: 223–225 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.66 (s, 2H, 2OH), 7.66–7.76
(m, 4H, 2 Ar), 7.53–7.55 (m, 4H, 2 Ar), 4.03 (d, 2H,
J = 19 Hz, H-4, H-40), 3.62 (d, 2H, J = 19 Hz, H-4, H-40)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 167.3 (2C=O),
152.6 (2C-3), 135.5, 128.7, 128.6, 128.4 (12C, 2Ar), 122.5
1,1’-Oxalylbis[4,5-dihydro-3-methyl-5-(trichloromethyl)-
1H-pyrazol-5-ol] (5b, C12H12Cl6N4O4)
Yellow solid, yield 63%; m.p.: 190–191 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.03 (s, 2H, 2OH), 3.58–3.42
(m, 2H, H-4, H-40), 3.38–3.25 (m, 2H, H-4, H-40), 1.96–
1.92 (m, 6H, 2Me) ppm; 13C NMR (50 MHz, DMSO-d6):
d = 157.2 (C=O), 156.7 (C=O0), 152.1 (2C-3), 102.8
1
2
(q, J = 283 Hz, 2CF3), 91.0 (q, J = 35 Hz, 2C-5), 44.0
(2C-4) ppm; 19F NMR (376 MHz, DMSO-d6): d = -76.6
(s, 2CF3) ppm.
0
(CCl3), 102.6 (CCl3 ), 101.0 (2C-5), 50.2 (2C-4), 18.3
(2Me) ppm.
1,10-Oxalylbis[4,5-dihydro-3-(4-nitrophenyl)-5-
1,10-Oxalylbis[4,5-dihydro-3-phenyl-5-(trichloromethyl)-
1H-pyrazol-5-ol] (5c, C22H16Cl6N4O4)
(trifluoromethyl)-1H-pyrazol-5-ol] (2f, C22H14F6N6O8)
White solid, yield 83%; m.p.: 307–308 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.79 (s, 2H, 2OH), 8.29–8.35
(m, 4H, 2Ar), 7.89–7.97 (m, 4H, 2Ar), 4.15 (d, 2H,
J = 19 Hz, H-4, H-40), 3.71 (d, 2H, J = 19 Hz, H-4, H-40)
ppm; 13C NMR (50 MHz, DMSO-d6): d = 152.2 (2C=O),
148.4 (2C-3), 135.3, 127.7, 123.7, 123.6 (12C, 2 Ar), 122.1
Yellow solid, yield 69%; m.p.: 210–211 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.69 (s, 1H, OH), 8.64 (s, 1H,
OH0), 7.77–7.85 (m, 4H, 2Ar), 7.33–7.66 (m, 6H, 2Ar), 3.93–
4.13 (m, 2H, H-4, H-40), 3.63–3.88 (m, 2H, H-4, H-40) ppm;
13C NMR (50 MHz, DMSO-d6): d = 162.1 (C=O), 161.3
(C=O0), 154.2 (C-3), 154.1 (C-30), 130.9, 129.7, 129.3, 128.6,
128.5, 126.8, 126.6, 126.4 (12C, 2 Ar), 102.8 (CCl3), 102.6
1
2
(q, J = 286 Hz, 2CF3), 91.6 (q, J = 35 Hz, 2C-5), 43.8
(2C-4) ppm; 19F NMR (376 MHz, DMSO-d6): d = -76.5
(s, 2CF3) ppm.
0
(CCl3 ),102.1(C-5),101.9(C-50),47.0(C-4),46.7(C-40)ppm.
1,10-Oxalylbis[3-(4-fluorophenyl)-4,5-dihydro-5-(trichlo-
romethyl)-1H-pyrazol-5-ol] (5d, C22H14Cl6F2N4O4)
Yellow solid, yield 72%; m.p.: 178–180 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.72 (s, 1H, OH), 8.56 (s, 1H,
OH0), 7.83–7.90 (m, 4H, 2Ar), 7.25–7.32 (m, 4H, 2Ar),
1,10-Oxalylbis[3-(1,10-biphenyl-4-yl)-4,5-dihydro-5-
(trifluoromethyl)-1H-pyrazol-5-ol] (2g, C34H24F6N4O4)
White solid, yield 63%; m.p.: 200–202 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.67 (s, 2H, 2OH), 7.70–7.78
(m, 12H, 2biPh), 7.38–7.50 (m, 6H, 2 biPh), 4.08 (d, 2H,
123

284
H. G. Bonacorso et al.
4.13–4.37 (m, 2H, H-4, H-40), 3.69–4.05 (m, 2H, H-4,
H-40) ppm; 13C NMR (50 MHz, DMSO-d6): d = 162.3 (d,
1J = 253 Hz, 2C, 2 Ar), 161.2 (C=O), 160.6 (C=O0), 153.5
7.81–7.83 (m, 4H, 2Ar), 7.48–7.49 (m, 6H, 2Ar) ppm;
13C NMR (50 MHz, DMSO-d6): d = 156.7 (2C=O), 155.4
(2C-3), 133.2 (q, J = 38 Hz, 2C-5), 128.9, 128.7, 128.5,
2
4
1
126.0 (12C, 2Ar), 122.8 (q, J = 294 Hz, 2CF3), 100.5
(C-3), 153.4 (C-30), 129.3 (d, J = 3 Hz, 2C, 2 Ar), 127.5
3
1
(d, J = 9 Hz, 4C, 2Ar), 115.7 (d, J = 22 Hz, 4C, 2 Ar),
(2C-4) ppm; 19F NMR (376 MHz, DMSO-d6): d = -60.4
(s, 2CF3) ppm.
0
102.9 (CCl3), 102.7 (CCl3 ), 102.2 (C-5), 102.1 (C-50), 47.0
(C-4), 46.8 (C-40) ppm.
1,10-Oxalylbis[3-(4-nitrophenyl)-5-(trifluoromethyl)-1H-
pyrazole] (3f, C22H10F6N6O6)
1,10-Oxalylbis[3-(4-chlorophenyl)-4,5-dihydro-5-
(trichloromethyl)-1H-pyrazol-5-ol] (5e, C22H14Cl8N4O4)
Yellow solid, yield 77%; m.p.: 255–256 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.70 (s, 2H, 2OH), 7.81–7.87
(m, 4H, 2Ar), 7.50–7.55 (m, 4H, 2Ar), 4.00–4.14 (m, 2H,
H-4, H-40), 3.71–3.95 (m, 2H, H-4, H-40) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 162.1 (C=O), 161.2 (C=O0),
153.7 (C-3), 153.3 (C-30), 135.6, 135.5, 128.7, 128.6, 128.5.
Yellow solid, yield 66%; m.p.: 203–204 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.07 (s, 2H, H-4, H-40), 7.89–
7.92 (m, 4H, 2Ar), 7.28–7.37 (m, 4H, 2 Ar) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 160.8 (2C=O), 147.0 (2C-3),
142.1 (q, J = 38 Hz, 2C-5), 133.9, 128.1, 126.4, 124.3
1
(12C, 2Ar), 121.5 (q, J = 285 Hz, 2CF3), 103.0 (2C-4)
ppm; 19F NMR (376 MHz, DMSO-d6): d = -60.5 (s,
2CF3) ppm.
2
0
128.4, 128.3, 128.2 (12C, 2Ar), 102.8 (CCl3), 102.5 (CCl3 ),
102.3 (C-5), 102.2 (C-50), 46.8 (C-4), 46.6 (C-40) ppm.
1,10-Oxalylbis[3-phenyl-5-(trichloromethyl)-1H-pyrazole]
(6c, C22H12Cl6N4O2)
1,10-Oxalylbis[3-(4-bromophenyl)-4,5-dihydro-
5-(trichloromethyl)-1H-pyrazol-5-ol]
White solid, yield 54%; m.p.: 195–196 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.05 (s, 2H, H-4, H-40), 7.84–
7.86 (m, 4H, 2Ar), 7.37–7.45 (m, 4H, 2Ar) ppm; 13C NMR
(50 MHz, DMSO-d6): d = 157.0 (2C=O), 153.5 (2C-3),
146.9 (2C-5), 130.1, 128.6, 127.8, 125.9 (12C, 2Ar), 112.3
(2CCl3), 84.6 (2C-4) ppm.
(5f, C22H14Br2Cl6N4O4)
Yellow solid, yield 80%; m.p.: 262–263 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.71 (s, 1H, OH), 8.59 (s, 1H,
OH0), 7.73–7.80 (m, 4H, 2Ar), 7.66–7.69 (m, 4H, 2Ar),
3.93–4.15 (m, 2H, H-4, H-40), 3.61–3.81 (m, 2H, H-4,
H-40) ppm; 13C NMR (50 MHz, DMSO-d6): d = 162.2
(C=O), 161.4 (C=O0), 153.9 (C-3), 153.7 (C-30), 131.8,
129.1, 128.9, 128.8, 128.4, 128.2, 124.7, 124.6 (12C, 2Ar),
1,10-Oxalylbis[3-(4-chlorophenyl)-5-(trichloromethyl)-1H-
pyrazole] (6e, C22H10Cl8N4O2)
White solid, yield 78%; m.p.: 227–229 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.07 (s, 2H, H-4, H-40), 7.76
(d, 4H, J = 8 Hz, 2Ar), 7.64 (d, 4H, J = 8 Hz, 2Ar) ppm;
13C NMR (50 MHz, DMSO-d6): d = 156.9 (2C=O), 152.8
(2C-3), 147.0 (2C-5), 131.8, 128.0, 127.6, 124.0 (12C,
2Ar), 112.5 (2CCl3), 84.5 (2C-4) ppm.
0
102.9 (CCl3), 102.8 (CCl3 ), 102.4 (C-5), 102.3 (C-50), 46.9
(C-4), 46.7 (C-40) ppm.
General procedure for the synthesis of 1,10-oxalylbis
[5-(trihalomethyl)-1H-pyrazoles] 3c, 3f, 6c, 6e, 6f
A solution of the respective bispyrazolines 2 or 5
(2.8 mmol) and 3 cm3 pyridine (37.1 mmol) in 50 cm3
benzene was cooled to 0 °C, and 1.22 cm3 thionyl chloride
(16.8 mmol) diluted in 25 cm3 benzene was added drop-
wise over 10 min. The solution was stirred for additional
30 min, during which time the temperature was allowed to
rise to 20 °C. The mixture was then heated under reflux
(bath temperature 80 °C) for 1 h and then filtered to remove
the pyridine hydrochloride at room temperature. The solu-
tion was extracted twice with benzene (2 9 50 cm3) and
dried over sodium sulfate. Evaporation of the solvent under
reduced pressure on a rotatory evaporator left 3c, 3f, 6c, 6e,
6f as white or yellow solid products, which were purified by
recrystallization from ethanol.
1,10-Oxalylbis[3-(4-bromophenyl)-5-(trichloromethyl)-1H-
pyrazole] (6f, C22H10Br2Cl6N4O2)
White solid, yield 53%; m.p.: 197–198 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.09 (s, 2H, H-4, H-40), 7.85
(d, 4H, J = 8 Hz, 2Ar), 7.52 (d, 4H, J = 8 Hz, 2Ar) ppm;
13C NMR (50 MHz, DMSO-d6): d = 161.0 (2C=O), 157.0
(2C-3), 147.1 (2C-5), 135.3, 128.9, 128.5, 126.8 (12C,
2Ar), 112.6 (2CCl3), 84.6 (2C-4) ppm.
Acknowledgments The authors acknowledge the financial support
´
from Conselho Nacional de Desenvolvimento Cientıfico e Tec-
nologico—CNPq (Proc. 303.296/2008-9). Fellowships from CAPES
´
and CNPq are also acknowledged.
References
1,10-Oxalylbis[3-phenyl-5-(trifluoromethyl)-1H-pyrazole]
(3c, C22H12F6N4O2)
1. McKendry JBR (1967) Appl Ther 9:531
2. Grundwald FA (1971) In: Burger A (ed) Medicinal chemistry, 3rd
edn. Wiley, New York
White solid, yield 72%; m.p.: 163–164 °C; 1H NMR
(200 MHz, DMSO-d6): d = 8.27 (s, 2H, H-4, H-40),
123

Synthesis of 1,10-oxalylbis[3-(alkyl/aryl/heteroaryl)-5-(trihalomethyl)-1H-pyrazoles]
285
3. White P (1965) Med Clin North Am 49:857
4. Smith DL, Forist AA, Dulin WE (1965) J Med Chem 8:350
5. Gerritsen GC, Dulin WE (1965) J Pharmacol Exp Ther 150:491
6. Lotti B, Vezzosi O (1972) Farmaco 27:313
7. Ram VJ, Pandey HN (1975) Chem Pharm Bull 23:751
8. Yusupov VG, Yakimovich SI, Umarov BB, Zerova IV, Parpiev
NA (1988) Zh Org Khim 24:1823
9. Parpiev NA, Yusupov VG, Umarov BB, Larin GM, Minin VV
(1989) Dokl Akad Nauk 4:44
10. Kashima C, Shirahata Y, Tsukamoto Y (1998) Heterocycles
49:459
20. Druzhinin SV, Balenkova ES, Nenajdenko VG (2007) Tetrahe-
dron 63:7753
21. Martins MAP, Cunico W, Pereira CMP, Sinhorin AP, Flores
AFC, Bonacorso HG, Zanatta N (2004) Curr Org Chem 1:391
22. Singh SP, Kumar D, Jones BG, Threadgill MD (1999) J Fluor
Chem 107:107
23. Song L-P, Zhu S-Z (2001) J Fluor Chem 111:201
24. Padwa A (1968) J Org Chem 30:1274
25. Bonacorso HG, Paim GR, Guerra CZ, Sehnem RC, Cechinel CA,
Porte LMF, Martins MAP, Zanatta N (2009) J Braz Chem Soc
20:509
11. Khalil AK, Hassan MA, Mohamed MM, El-Sayed AM (2006)
Indian J Chem Sect B 45B:2485
12. Bonacorso HG, Cechinel CA, Deon ED, Sehnem RC, Luz FM,
Martins MAP, Zanatta N (2009) ARKIVOC ii:174
13. Moreira DN, Frizzo CP, Longhi K, Zanatta N, Bonacorso HG,
Martins MAP (2008) Monatsh Chem 139:1049
26. Bonacorso HG, Wentz AP, Lourega RV, Cechinel CA, Moraes
TS, Flores AFC, Martins MAP, Zanatta N (2007) J Heterocycl
Chem 44:223
27. Bonacorso HG, Oliveira MR, Wentz AP, Wastowski AD, de
Oliveira AB, Hoerner M, Zanatta N, Martins MAP (1999) Tet-
rahedron 55:345
14. Martins MAP, Moreira DN, Frizzo CP, Longhi K, Zanatta N,
Bonacorso HG (2008) J Braz Chem Soc 19:1361
15. Bonacorso HG, Cechinel CA, Porte LMF, Navarini J, Cavinatto
S, Sehnem RC, Martins DB, Zanatta N, Martins MAP (2010)
J Heterocycl Chem 47:1073
28. Bruker APEX2 (version 2.1), COSMO (version 1.56), BIS (ver-
sion 2.0.1.9), SAINT (version 7.3A), SADABS (version 2004/1),
and XPREP 9 version 2005/4), Bruker AXS (2006) Madison,
USA
29. Sheldrick GM, SHELXS-97 (1997) Program for crystal structure
¨
16. Colla A, Martins MAP, Clar G, Krimmer S, Fischer P (1991)
Synthesis 6:483
solution, University of Gottingen, Germany
30. Sheldrick GM, SHELXL-97 (1997) Program for crystal structure
¨
17. Martins MAP, Siqueira GM, Flores AFC, Clar G, Zanatta N
(1994) Quim Nova 17:24
18. Bonacorso HG, Cechinel CA, Oliveira MR, Costa MB, Martins
MAP, Zanatta N, Flores AFC (2005) J Heterocycl Chem 42:1055
19. Flores AFC, Brondani S, Zanatta N, Rosa A, Martins MAP
(2002) Tetrahedr Lett 43:8701
refinement, University of Gottingen, Germany
31. Coppens P, Leiserowitz L, Rabinovich D (1965) Acta Crystallogr
18:1035
32. Farrugia LJJ (1997) Appl Crystallogr 30:565
33. Almy J, Alveres RM, Fernadez AH, Vasquez ASJ (1997) J Chem
Educ 74:1479
123