Succinic acid dihydrazide: A convenient N,N-double block for the synthesis of symmetrical and non-symmetrical succinyl-bis[5-trifluoro(chloro)methyl-1H- pyrazoles]

Article abstract of DOI:10.1590/S0103-50532010000900009

This paper describes the conventional regioselective synthesis of a series of new succinyl spacer bis-(3,5-substituted 2-pyrazolines and 1H-pyrazoles), namely; 1,4-bis[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl] butane-1,4-diones (46-88percent) and the respective dehydrated system (60-78percent), new 1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutane hydrazides (52-81percent) and the non-symmetrical 2-pyrazolines derivatives thereof as 1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-4-(5- (trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones (75-91percent). All succinyl substituted bispyrazoles were obtained from the cyclocondensation reactions of 4-substituted 4-alkoxy-1,1,1-trihaloalk-3-en-2- ones, where the 4-substituents are H, Me, Ph, 4-FC₆H₄, 4-ClC₆H₄, 4-OMeC₆H₄, 4-NO ₂C₆H₄, 1-naphthyl and 2-furyl, with succinic acid dihydrazide in ethanol as solvent under controlled reaction conditions. -

Full text of DOI:10.1590/S0103-50532010000900009

J. Braz. Chem. Soc., Vol. 21, No. 9, 1656-1663, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Succinic Acid Dihydrazide: a Convenient N,N-Double Block for the Synthesis of
Symmetrical and non-Symmetrical Succinyl-bis[5-trifluoro(chloro)methyl-1H-pyrazoles]
Helio G. Bonacorso,* Cleber A. Cechinel, Everton P. Pittaluga, Adriana Ferla,
Liliane M. F. Porte, Marcos A. P. Martins and Nilo Zanatta
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Este trabalho apresenta a síntese regiosseletiva de séries de bis-2-pirazolinas e bis-1H-
pirazóis succinil intercalados inéditas, denominadas 1,4-bis[5-(trifluormetil)-5-hidróxi-4,5-
diidro-1H-pirazol-1-il]butano-1,4-dionas (46-88%), o respectivo sistema desidratado (60-78%),
1-[5-(trifluormetil)-5-hidróxi-4,5-diidro-1H-pirazol-1-il]-4-oxabutano hidrazidas (52-81%) e
2-pyrazolinas derivadas não simétricas, como 1-[5-(trifluormetil)-5-hidróxi-4,5-diidro-1H-pirazol-
1-il)-4-(5-(triclorometil)-5-hidróxi-4,5-diidro-1H-pirazol-1-il]butano-1,4-dionas (75-91%). Todos
os bis-pirazóis succinil substituídos foram obtidos a partir de reações de ciclocondensação de
4-alcóxi-1,1,1-trialo-3-alquen-2-onas 4-substituídas (4-substituinte = H, Me, fenil, 4-FC6H4,
4-ClC6H4, 4-OMeC6H4, 4-NO2C6H4, 1-naftil and 2-furil), com dihidrazida succínica, em etanol
como solvente, sob condições reacionais convencionais controladas.
This paper describes the conventional regioselective synthesis of a series of new succinyl
spacer bis-(3,5-substituted 2-pyrazolines and 1H-pyrazoles), namely; 1,4-bis[5-(trifluoromethyl)-5-
hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones (46-88%) and the respective dehydrated
system (60-78%), new 1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-4-
oxobutane hydrazides (52-81%) and the non-symmetrical 2-pyrazolines derivatives thereof as
1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)-4-(5-(trichloromethyl)-5-hydroxy-
4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones (75-91%). All succinyl substituted bispyrazoles
were obtained from the cyclocondensation reactions of 4-substituted 4-alkoxy-1,1,1-trihaloalk-3-
en-2-ones, where the 4-substituents are H, Me, Ph, 4-FC6H4, 4-ClC6H4, 4-OMeC6H4,4-NO2C6H4,
1-naphthyl and 2-furyl, with succinic acid dihydrazide in ethanol as solvent under controlled
reaction conditions.
Keywords: succinic acid dihydrazide, vinyl ketones, 2-pyrazolines, bis-pyrazoles, butanediones
Introduction
Moreover, bis-pyrazolyl containing acyl spacer
groups are rare in the literature and new synthetic routes
to obtain these compounds and studies of their potential
as pharmaceuticals and agrochemicals, such as herbicidal
agents, have been relatively little explored.8-11
A review of the literature showed few publications about
the construction of a succinyl spacer bis-(3,5-substituted
1H-pyrazoles) system. In 1961, according to a US patent,
Wright8 reported the systematic synthesis and a biological
activity study of a series of bis-(4-nitropyrazol-1-yl) spacer
compounds, where the linker moiety was an aliphatic
hydrocarbon chain [-(CH2)n-] containing 1 to 12 carbon
atoms, saturated or unsaturated, and substituted by one
or more lower alkyl (not more than 4 carbon atoms) or
Bis-pyrazolyl ketones and similar chemical structures
have been most commonly synthesized by substitution
reactions involving phosgene, esters or alkyl- and acyl-
dihalides with 1H-pyrazoles.1-7 However, this synthetic
procedure is efficient for this synthesis starting only from
symmetric substituted or non-substituted 1H-pyrazoles
because non-symmetric 3- or 5-substituted 1H-pyrazoles
existing in two tautomeric structures, in solution, and
their N1-substitution reactions lead to three possible bis-
pyrazolyl spacer isomers.
*e-mail: heliogb@base.ufsm.br

Vol. 21, No. 9, 2010
Bonacorso et al.
1657
hydroxyl groups. In the same patent, diacyl group spacers
[-CO-(CH2)n-CO-] with n being an integer from 1 to 12, or
an ether group of the formula [-(CH2)x-O-(CH2)y-], where x
and y are identical or different integers from 1 to 10; or even
a divalent cycloalkyl group such as 1,4-cyclohexylene, were
synthesizedandbiologicallytested.Thesenewbis-pyrazolyl
compounds showed useful activity as antiprotozoal agents,
especially in the treatment of trichomoniasis (e.g., that
caused by T. vaginalis). The 1,7-di-(4-nitropyrazol-1-yl)
n-heptane and their respective n-pentane analogue were
of outstanding activity and low toxicity. Specifically, only
1,1’-succinylbis(3,5-dimethyl-4-nitropyrazole) and the
non-substituted 1,1’-succinyl bis-(4-nitropyrazole) were
prepared using the appropriate 1H-pyrazole and succinyl
chloride. In 2005, Shi et al.12 reported the synthesis of
N,N’-butanedioylbis(5-ferrocenyl-3-methyl-1H-pyrazole)
from the reaction of ferrocenoylacetone and succinic acid
dihydrazide. In the same year, Al-Talib et al.13 reported
that the reaction of oxalic, malonic and succinic acid
dihydrazide with 2,4-pentanedione gave smoothly the
corresponding oxalyl-, malonyl- and succinyl-N,N’-bis(3,5-
dimethyl-1H-pyrazole). It is also important to mention
that aroyl and heteroaroyl spacer bispyrazoles have been
synthesized employing 1,3-dicarbonyl compounds or
derivatives thereof and, for example, isophthalic acid
dihydrazide14 or 1,3,4-thiadiazole-2,5-dithioglycolic acid
dihydrazide,15 respectively.
More recently, pyrazolylcarbohydrazides have been
cited as new and promising antitumor drugs and have
been synthesized and studied mostly as a potential lung
cancer cell growth suppressant. In 2007,16 a series of
1-arylmethyl-3-aryl-1H-pyrazole-5-carbohydrazide
derivatives was synthesized and their effects on A549
cell growth and apoptosis were evaluated. The structure-
activity relationships and prediction of lipophilicity of the
compounds were also studied. Later, in 2008,17 a new series
of 1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-
carbohydrazide derivatives was synthesized. All of the
1-(2′-hydroxy-3′-aroxypropyl)-3-aryl-1H-pyrazole-5-
carbohydrazide derivatives inhibited the growth of A549
cells in dosage- and time-dependent manners. Typically,
any compounds inducedA549 and H460 cells to autophagy,
but did not inhibit the growth of human umbilical vein
endothelial cells (HUVEC). Thus, one can see that not
only the bis-(pyrazolyl) spacer compounds, but also the
pyrazolylcarbohydrazide intermediates are important.
Recently, our laboratory reported the regioselective
synthesis of seven examples of 3-(alkyl/aryl/heteroaryl)-
5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazolyl-
1-carbohydrazides (44-86%) and four examples of bis-(3-
aryl-5-trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-
1-yl)methanones (73-89%) from cyclocondensation
reactions of 4-substituted 4-alkoxy-1,1,1-trifluoroalk-3-
en-2-ones, where the substituents were H, alkyl, aryl and
heteroaryl with carbohydrazide, and symmetrical bis-
pyrazolylmethanones were obtained, where the substituents
at the 3 and 5 positions of the pyrazoles could be different
from each other.18 In the same work, bis-(5-trifluoromethyl-
5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)
methanone was subjected to dehydration under various
reaction conditions, but in all attempts the aromatized
1H-pyrazole was obtained with the simultaneous removal
of the carbonyl function due to the cleavage of both C(O)–N
bonds.
On the other hand, it is well-known that the introduction
of a trifluoromethyl group into heterocyclic compounds
may have a significant influence on their biological and
physical properties and the simple replacement of a
hydrogen atom by a fluorine atom is a strategy widely
used in drug development to alter biological functions. The
resulting change in the electron distribution of a molecule
following this replacement can alter the pKa, the dipole
moments, and even the chemical reactivity and stability of
neighboring functional groups. In terms of drug design, the
employment of fluorinated molecules can be used to alter
the rate of drug metabolism and thereby the production of
a longer duration of action.19
The most convenient method to construct trifluoro and
trichloromethylated heterocycles, including trihalomethyl
substituted 2-pyrazolines and many pyrazoles, is to use
fluorine- and chlorine-containing building blocks as starting
reagents. Thus, 4-alkoxy-4-(alkyl/aryl/heteroaryl)-1,1,1-
trifluoro(chloro)alk-3-en-2-ones are versatile precursors
for the heterocyclic synthesis and direct construction of
this type of heterocycles.20-23
In this context and in an attempt to develop synthetic
methods to obtain acyl spacer heterocycles and new
fluorinated molecules, herein we report a practical and
regioselective methodology for the preparation of a
series of 1,4-bis(5-(trifluoromethyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl)butane-1,4-diones (2) and
the respective dehydrated bis-pyrazole systems (3),
new 1-(5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl)-4-oxobutane hydrazide intermediates
(4) and the non-symmetrical 2-pyrazoline derivatives
thereof as 1-(5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl)-4-(5-(trichloromethyl)-5-hydroxy-
4,5-dihydro-1H-pyrazol-1-yl)butane-1,4-diones (5)
from the cyclocondensation reactions of 4-substituted
1,1,1-trifluoro(chloro)alk-3-en-2-ones (1) with succinic
acid dihydrazide in ethanol as solvent under conventional
and controlled reaction conditions (Schemes 1 and 2).

1658
Succinic Acid Dihydrazide: a Convenient N,N-Double Block
J. Braz. Chem. Soc.
Results and Discussion
the carbonyl function at positions 5 and 1 of these two
succinyl-bispyrazolines, 2c and 2e were dehydrated
to give the respective 3-aryl-substituted 1,4-bis(5-
(trifluoromethyl)-1H-pyrazol-1-yl)butane-1,4-diones 3c
and 3e in 78 and 60% yields, only by stirring the mixtures
of 2c or 2e, thionyl chloride and pyridineat 80 ºC for about
1 h in benzene as solvent, according to similar procedures
described in the literature.24
Since the 1970s, according to previous publications,20-23
research groups have reported the systematic synthesis
of 4-substituted 4-alkoxy-1,1,1-trihaloalk-3-en-2-ones
(1) from the trihaloacetylation reaction of the respective
enolethers (1a, 1b) or acetals (1c-i) with trifluoracetic
anhydride or trichloroacetyl chloride, respectively.
According to the literature,8 1,1’-succinyl-bis(3,5-
dimethyl-4-nitropyrazole) and the non-substituted
1,1’-succinyl-bis(4-nitropyrazole) were prepared using
the appropriate 1H-pyrazole and succinyl chloride in the
presence of anhydrous sodium carbonate when the reactions
were carried out in dry acetone as solvent for 20 h at 20 ºC,
but no yields were reported.
In this work, we initially carried out the reaction of
4-methoxy-4-phenyl-1,1,1-trifluoro-3-alken-2-one (1c)
with succinic acid dihydrazide in a 2:1 molar ratio, in
ethanol as solvent at room temperature, however when
monitored by TLC no reaction was observed. Subsequently,
when the mixture was heated to reflux, after stirring for
6 h, TLC showed that the reaction proceeded smoothly and
gave the product 2c in 79% yield (Scheme 1). The most
satisfactory results for the synthesis of the other compounds
2 were obtained from the reaction condition described
above and were isolated as stable solids by recrystallization
from ethanol.
Subsequently, after a review of the literature
and attempting to obtain aromatic pyrazoles for
further biological assays, we chose thionyl chloride/
pyridine as the dehydration agent and report here the
conditions required to accomplish the dehydration of two
representative examples of compounds 2, which present a
hydroxyl- and a trifluoromethyl-group, a phenyl (for 2c)
or 4-fluorophenyl (for 2e) and a succinyl 2-pyrazoline
attached directly to the C-5, C-3 and N-1 atom of each
pyrazoline ring, respectively (Scheme 1). Because of the
relative difficulty to perform the dehydration reaction,
due to the presence of a trifluoromethyl substituent and
Motivated by the importance of some
pyrazolylcarbohydrazides already described in the
literature,12,13 we attempted to synthesize some examples
of new 1-(5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-
pyrazol-1-yl)-4-oxobutane hydrazides (4). We investigated
this reaction employing 4-substituted 4-methoxy-1,1,1-
trifluorobut-3-en-2-ones with two substituents with
opposite electronic effects (4-methoxyphenyl and
4-nitrophenyl) and the neutral substituent 4-phenyl.
Initially, we carried out the reaction of 4-methoxy-4-
phenyl-1,1,1-trifluorobut-3-en-2-one (1c) with succinic
acid dihydrazide in a 1:1 molar ratio in ethanol as solvent
at room temperature from 4 to 24 h, however when
monitored by TLC no reaction was observed and the
starting materials were recovered. Surprisingly, when the
mixture was heated to 50-55 ºC, after stirring for 3 h, TLC
showed that the reaction proceeded smoothly and gave
product 4c in 81% yield (Scheme 2). The most satisfactory
results for the synthesis of the other compounds 4 were
obtained from the reaction condition described above and
the compounds were isolated as stable white powders
after the reaction time by simple filtration under reduced
pressure in 52-81% yields.
Finally, aiming to obtain examples of non-symmetrical
succinyl spacer bis-pyrazoles, the reaction of 1-(3-phenyl-
5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-
yl)-4-oxobutane hydrazides 4c with two trichlorometylated
vinyl ketones (4-methoxy-1,1,1-trichloropent-3-en-2-one
and 4-methoxy-4-phenyl-1,1,1-trichlorobut-3-en-2-one)
was performed. In these cases, the desired products 5b
and 5c were isolated in 91 and 75% yields, respectively,
R
R
O
OMe(Et)
R
R
O
O
N
R
N
O
O
N
N
i
ii
N
N
46-88%
60-78%
N
N
F3C
(CH2)2
(CH2)2
3c, 3e
OH
F3C
HO
CF3
CF3
F3C
1a-i (2.0 equiv.)
2a-f, 2h-i
a
b
c
d
e
f
g
i
1-3
h
4-NO2Ph 2-Naphthyl 2-Furyl
Me Ph 4-OMePh 4-FPh 4-ClPh
R
H
Scheme 1. Reagents and conditions: (i) (NH2NHCOCH2)2 (1.0 equiv.), EtOH, 5-10 h, 80 ºC; (ii) SOCl2, pyridine, benzene, 1 h, 0-80 ºC.

Vol. 21, No. 9, 2010
Bonacorso et al.
1659
R
Ph
O
OMe
R
N
O
O
O
N
O
(CH2)2
5b-c
N
i
ii
N
NHNH2
N
N
52-81%
75-91%
F3C
R
(CH2)2
OH
F3C
HO
CF3
OH
Cl3C
1c-d, 1g (1.0 equiv.)
4c-d, 4g
4,5
b
c
d
g
4-NO2Ph
Me Ph 4-OMePh
R
Scheme 2. Reagents and conditions: (i) (NH2NHCOCH2)2 (1.0 equiv.), EtOH, 4 h, 0-50 ºC; (ii) CCl3C(O)CH=C(OMe)R (1.0 equiv.), EtOH, 16 h, 50 ºC.
showing an interesting and promising employment of
pyrazolyl substituted succinic acid hydrazides such as
4 (Scheme 2). Compounds 5 were obtained when the
reactions of pure 4c and 4-methoxy-1,1,1-trichloroalk-3-
en-2-ones were carried out in a molar ratio of 1:1 at 50 ºC
for about 16 h also in ethanol as solvent.A complex mixture
of products was obtained when the reactions were carried
out under refluxing ethanol for 1 to 2 h.
spectra exhibited chemical shifts, in DMSO-d6, for both
pyrazole ring carbons on average at 152.6 (C3), 111.7 (C4),
2
1
134.1 (C5, JCF 41) and 119.1 ppm (CF3, JCF 268). Both
carbonyl and ethylene carbons showed signals in the range
of d 169.8 ppm and 29.5 ppm, respectively.
For the pyrazolyl-succinic acid hydrazides (4), the OH,
1
NH and NH2 groups showed H NMR chemical shifts in
DMSO-d6 in the range of d 7.97 ppm, d 8.97 ppm and
d 4.15 ppm, respectively. Now, due to the non-symmetry
of compounds 4, the four methylene protons of the succinyl
moiety appeared as broad peaks on average at 3.07 and
2.24 ppm.As expected, the 13C{1H} NMR spectra exhibited
only one peak for each carbon of the pyrazoline ring and
the hydrazinosuccinyl moiety.
The structures of 1,4-bis[5-(trifluoromethyl)-5-
hydroxy-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-diones
(2a-f, 2h-i) were deduced from NMR experiments and by
comparison with NMR data of other 2-pyrazolines formerly
synthesized in our laboratory.18,22,23 Compounds 2 showed
the 1H NMR chemical shifts in DMSO-d6 of the hydroxy
protons in the range of d 8.04 ppm and the four methylene
protons (H4) are shown as a typical AB system as two
doublets, in which, one of them is on average at d 3.79 and
the other at d 3.44 ppm, with a geminal coupling constant
of 19-20 Hz. Due to the symmetry of compounds 2, the
four ethylene protons (succinyl moiety) appeared as one
singlet peak on average at 3.06 ppm. The 13C{1H}NMR
spectra exhibited only one set of peaks, despite the fact that
two stereogenic carbons are present in each molecule. The
succinyl derivatives 2 also presented the typical 13C NMR
chemical shifts of the both pyrazoline rings at d 149.8 ppm
(C3) and d 45.2 ppm (C4). Due to the presence of the CF3
group, both C5 carbons presented a characteristic quartet at
d 90.3 ppm with 2JCF 33 Hz. Also, both CF3 groups showed
a typical quartet at d 123.4 ppm with 1JCF 285 Hz and the
two carbonyl and ethylene carbons showed NMR signals
in the range of d 170.1 ppm and 29.3 ppm, respectively.All
the signals are consistent with 1H and 13C NMR chemical
shifts of the pyrazoline and the succinyl moiety for this
symmetrical system.
1
The unambiguous H and 13C NMR chemical shift
assignments of non-symmetrical 1-[5-(trifluoromethyl)-
5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl]-4-[5-
(trichloromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-
1-yl]butane-1,4-diones (5b-c), in DMSO-d6 as solvent,
were made by comparison with NMR data of other
trifluoro(chloro)methyl substituted 2-pyrazolines formerly
obtained in our laboratory.18,22,23 In contrast to compounds
2, molecules 5 showed two sets of NMR signals. The
chemical shifts of the four diasterotopic methylene
protons (H4) appeared, as typical AB systems, as four
doublets with a geminal coupling constant on average at
19 Hz. The hydroxy protons, as two singlets, are shown
in the 1H NMR spectra in the range of d 7.72-8.05 and the
four methylene protons of the succinyl moiety appeared
as broad peaks on average at 3.09 ppm and 2.97 ppm.
Compounds 5 also presented the typical 13C{1H}NMR
spectra where the chemical shifts for non-symmetrical
structures showed separate signals for each pyrazoline
ring carbons. Also, due to the non-symmetry of 5b-c, the
two carbonyl carbon methylene groups of the succinyl
moiety appeared as four peaks which is consistent with
NMR chemical shift assignments when compared with
compounds 2 and literature data for trichloromethyl
substituted 2-pyrazolines.23
Thedehydratedcompounds3cand3f,beingsymmetrical
1
systems, presented one set of signals in both H and
13C NMR spectra and, in comparison with 2c and 2f showed
typical chemical shifts of the pyrazole ring for both H-4
on average at 7.5 ppm as singlet peaks. The 13C{1H} NMR

1660
Succinic Acid Dihydrazide: a Convenient N,N-Double Block
J. Braz. Chem. Soc.
Conclusions
(d, J 20, 2H, 2H-4), 2.90 (s, 4H, 2CH2). 13C NMR: d 170.3
(2C=O), 144.9 (2C-3), 122.8 (q, J 285, 2CF3), 88.9 (q,
1
In conclusion, in this study we showed that the
conventional cyclocondensation reaction between 4-alkoxy-
4-(alkyl/aryl/heteroaryl)-1,1,1-trifluoro(chloro)alk-3-en-
2-ones and succinic acid dihydrazide under controlled
reaction conditions is a useful, simple and convenient
procedure to obtain new succinyl spacer bis-(3,5-substituted
2-pyrazolines and 1H-pyrazoles), namely 1,4-bis(5-
(trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-pyrazol-1-yl)
butane-1,4-diones (46-88%) and the respective dehydrated
system (60-78%), new 4-(5-(trifluoromethyl)-5-hydroxy-
4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutane hydrazides (52-
81%) and the non-symmetrical 2-pyrazolines derivatives
thereof as 1-(5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl)-4-(5-(trichloromethyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl)butane-1,4-diones (75-91%).
2J 34, 2C-5), 46.0 (2C-4), 29.3 (2CH2). Anal. Calc. for
C12H12F6N4O4 (390.08): C, 36.93; H, 3.10; N, 14.36%.
Found: C, 37.05; H, 3.01; N, 14.62%.
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-3-methyl-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2b)
1
Yield 57%, mp 141-142 ºC. H NMR: d 7.65 (s, 1H,
OH), 7.62 (s, 1H, OH), 3.39 (d, J 19, 2H, 2H-4), 3.05 (d,
J 19, 2H, 2H-4,), 2.84 (s, 4H, 2CH2), 2.00 (s, 6H, 2CH3).
13C NMR: d 169.9 (2C=O), 153.6 (2C-3), 123.3 (q, 1J 285,
2CF3), 90.3 (q, 2J 33, 2C-5), 47.8 (2C-4), 29.3 (2CH2), 15.2
(2CH3). Anal. Calc. for C14H16F6N4O4 (418.11): C, 40.20;
H, 3.86; N, 13.39%. Found: C, 40.16; H, 3.92; N, 13.55%.
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-3-phenyl-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2c)
1
Experimental
Yield 79%, mp 265-266 ºC. H NMR: d 8.02 (s, 1H,
OH), 8.00 (s, 1H, OH), 7.79-7.81 (m, 4H, 2Ar), 7.49 (s,
6H, 2Ar), 3.89 (d, J 19, 2H, 2H-4,), 3.55 (d, J 19, 2H,
2H-4), 3.07 (s, 4H, 2CH2). 13C NMR: d 170.3 (2C=O),
151.4 (2C-3), 130.6, 130.8, 128.8, 126.5 (12C, 2Ar), 122.6
(q, 1J 285, 2CF3), 91.1 (q, 2J 33, 2C-5), 44.4 (2C-4), 29.4
(2CH2). Anal. Calc. for C24H20F6N4O4 (542.14): C, 53.14;
H, 3.72; N, 10.33%. Found: C, 53.63; H, 3.01; N, 10.11%.
General procedures
Unless otherwise indicated all common reagents and
solvents were used from commercial suppliers without
further purification. All melting points were determined
using open capillaries on an Electrothermal Mel-Temp 3.0
1
13
apparatus and are uncorrected. H and C NMR spectra
were acquired on a Bruker DPX 200 spectrometer (1H at
200.13 MHz and 13C at 50.32 MHz), 5 mm sample tubes,
298 K, digital resolution 0.01 ppm, in DMSO-d6 for 2-5
using TMS as internal reference and all coupling constants
(J) are given in Hertz (Hz). The CHN elemental analyses
were performed on a Perkin-Elmer 2400 CHN elemental
analyzer (São Paulo University, USP/Brazil).
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-3-(4-
methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl]butane-
1,4-dione (2d)
Yield 78%, mp 219-221 ºC. H NMR: d 7.92 (s, 1H,
OH), 7.90 (s, 1H, OH), 7.73-7.75 (m, 4H, 2Ar), 7.03-7.04
1
(m, 4H, 2Ar), 3.82 (s, 6H, 2OCH3), 3.83 (d, J 19, 2H, 2H-4),
13
3.51 (d, J 19, 2H, 2H-4), 3.19 (s, 4H, 2CH2). C NMR:
d 170.1 (2C=O), 161.1 (2C, 2Ar), 151.1 (2C-3), 131.8,
122.7, 114.2 (10C, 2Ar), 122.8 (q, 1J 285, 2CF3), 90.8 (q,
2J 33, 2C-5), 55.3 (2OCH3), 44.5 (2C-4), 29.3 (2CH2).
Anal. Calc. for C26H24F6N4O6 (602.16): C, 51.83; H, 4.02;
N, 9.30%. Found: C, 51.84; H, 3.91; N, 9.58%.
Synthesis of 1,4-bis[5-(trifluoromethyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-diones (2a-f, 2h-i)
A solution of 4-substituted 4-alkoxy-1,1,1-trifluoro-
3-alken-2-ones (1a-f, 1h-i) (10 mmol), succinic acid
dihydrazide (5 mmol), ethanol (20 mL) and distilled
o
water (1 mL) was stirred at 80 C for 5-10 h. After the
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-3-(4-fluorophenyl)-
4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2e)
Yield 74%, mp 219-220 ºC. 1H NMR: d 7.68-7.75 (m,
4H, Ar), 7.26 (s, 2H, 2OH), 7.09-7.17 (m, 4H, 2Ar), 3.70
(d, J 18, 2H, 2H-4,), 3.50 (d, J 18, 2H, 2H-4), 3.23 (s, 4H,
2CH2). 13C NMR: d 170.0 (2C=O), 163.4 (d, 1J 248, 2C-F,
2Ar), 150.3 (2C-3), 128.5, 126.5, 115.4 (10C, 2Ar), 91.0
(q, 2J 33, 2C-5), 123.2 (q, 1J 285, 2CF3), 44.2 (2C-4), 29.2
(2CH2). Anal. Calc. for C24H18F8N4O4 (578.12): C, 49.84;
H, 3.14; N, 9.69 %. Found: C, 49.59; H, 3.25; N, 9.89%.
reaction time the solvent was evaporated to half by rotatory
evaporator under reduced pressure. After cooling (≤ 8 ºC)
for 1-2 days the compounds 2a-f, 2h-i were obtained pure
directly by filtration, washed with cold ethanol and dried
under vacuum apparatus.
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-4,5-dihydro-1H-
pyrazol-1-yl]butane-1,4-dione (2a)
1
Yield 46%, mp 160-161 ºC. H NMR: d 7.76 (s, 2H,
2OH), 7.21 (s, 2H, 2H-3), 3.40 (d, J 20, 2H, 2H-4,), 3.10

Vol. 21, No. 9, 2010
Bonacorso et al.
1661
1,4-bis[3-(4-Chlorophenyl)-5-(trifluoromethyl)-5-hydroxy-
as solid products which were purified by recrystallization
from ethanol.
4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2f)
1
Yield 63%, mp 189-191 ºC. H NMR: d 8.03 (s, 1H,
OH), 8.01 (s, 1H, OH), 7.81-7.83 (m, 4H, 2Ar), 7.54-7.56
(m, 4H, 2Ar), 3.89 (d, J 19, 2H, 2H-4), 3.55 (d, J 19, 2H,
2H-4), 3.07 (s, 4H, 2CH2). 13C NMR: d 170.1 (C=O), 169.8
(C=O), 153.6 (2C, 2Ar), 150.4 (2C-3), 135.1, 129.1, 127.3
(10C, 2Ar), 123.1 (q, 1J 285, 2CF3), 90.6 (q, 2J 33, 2C-5),
44.2 (2C-4), 29.3 (2CH2). Anal. Calc. for C24H18Cl2F6N4O4
(610.06): C, 47.15; H, 2.97; N, 9.16 %. Found: C, 47.21;
H, 3.01; N, 9.11%.
1,4-bis[5-(Trifluoromethyl)-3-phenyl-1H-pyrazol-1-yl]
butane-1,4-dione (3c)
Yield 78%, mp 180-181 ºC. 1H NMR: d 7.86-7.88 (m,
4H, 2Ar), 7.45-7.47 (m, 6H, 2Ar), 7.21 (s, 2H, 2H-4), 3.79
(s, 4H, 2CH2). 13C NMR: d 169.6 (2C=O), 153.4 (2C-3),
2
135.0 (q, J 41, 2C-5), 130.4, 129.9, 128.9, 126.3 (12C,
2Ar), 119.3 (q, 1J 269, 2CF3), 111.2 (2C-4), 29.7 (2CH2).
Anal. Calc. for C24H16F6N4O2 (506.12): C, 56.92; H, 3.18;
N, 11.06%. Found: C, 56.98; H, 3.34; N, 10.92%.
1,4-bis[5-(Trifluoromethyl)-5-hydroxy-3-(1-naphthyl)-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2h)
1,4-bis[5-(Trifluoromethyl)-3-(fluorophenyl)1H-pyrazol-1-
yl]butane-1,4-dione (3f)
Yield84%, mp224-226ºC. 1HNMR:d9.18(s, 1H, OH),
9.14 (s, 1H, OH), 8.01-8.13 (m, 6H, 2Ar), 7.87-7.91 (m,
2H, 2Ar), 7.56-7.66 (m, 6H, 2Ar), 4.14 (d, J 19, 2H, 2H-4,),
3.80 (d, J 19, 2H, 2H-4,), 3.23 (s, 4H, 2CH2). 13C NMR: d
170.1 (2C=O), 151.1 (2C-3), 133.4, 130.9, 129.5, 128.9,
128.5, 127.4, 126.2, 125.7, 124.8, 124.5 (20C, 2Ar), 126.7
(q, 1J 286, 2CF3), 89.9 (q, 2J 34, 2C-5), 46.6 (2C-4), 29.5
(2CH2). Anal. Calc. for C32H24F6N4O4 (642.17): C, 59.82;
H, 3.76; N, 8.72%. Found: C, 59.26; H, 3.91; N, 8.98%.
Yield 60%, mp 189-190 ºC. 1H NMR: d 8.06-8.11 (m,
4H, 2Ar), 7.95 (s, 2H, 2H-4), 7.33-7.42 (m, 4H, 2Ar),
3.73 (s, 4H, 2CH2). 13C NMR: d 170.1 (2C=O), 163.1 (d,
2
1J 246, 2C-F, 2Ar), 151.8 (2C-3), 133.3 (q, J 41, 2C-5),
1
128.7, 128.3, 116.2 (10C, 2Ar), 119.2 (q, J 268, 2CF3),
112.3 (2C-4), 29.3 (2CH2). Anal. Calc. for C24H14F8N4O2
(542.10): C, 53.15; H, 2.60; N, 10.33%. Found: C, 53.34;
H, 2.86; N, 10.03%.
1,4-bis[3-(Fur-2-yl)-5-(trifluoromethyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-dione (2i)
Synthesis of 1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl]-4-oxobutane hydrazides (4c-d, 4g)
Yield 88%, mp 213-214 ºC. 1H NMR: d 8.10 (s, 1H, OH),
8.07 (s, 1H, OH), 7.91 (d, 2H, 2Fur), 7.07 (d, 2H, 2Fur), 6.68
(dd, 2H, 2Fur), 3.79 (d, J 19, 2H, 2H-4), 3.43 (d, J 19, 2H,
2H-4), 2.97 (s, 4H, 2CH2). 13C NMR: d 170.0 (2C=O), 145.7
(2C-3), 145.2, 142.8, 114.4, 112.1 (8C, 2Fur), 122.6 (q, 1J
286, 2CF3), 90.1 (q, 2J 33, 2C-5), 44.1 (2C-4), 29.3 (2CH2).
Anal. Calc. for C20H16F6N4O6 (522.10): C, 45.99; H, 3.09;
N, 10.73%. Found: C, 45.39; H, 3.44; N, 10.78%.
General procedure
To an ice-cold stirred mixture of 4-substituted
4-alkoxy-1,1,1-trifluoro-3-alken-2-ones 1c-d (10 mmol)
diluted in ethanol (15 mL) another mixture of succinic
acid dihydrazide (10 mmol) and ethanol (10 mL) was
added at room temperature. The resulting new mixture
o
was stirred for 4 h at 50 C. After the reaction time the
solvent was evaporated to half by rotatory evaporator
under reduced pressure and after cooling (≤ 8 ºC) for 1-2
days the compounds 4c-d, 4g were obtained pure directly
by filtration, washed with cold ethanol and dried under
vacuum apparatus.
Synthesis of 1,4-bis[5-(trifluoromethyl)-1H-pyrazol-1-yl]
butane-1,4-diones (3c, 3f)
General procedure
A solution of bis-pyrazoline butane-1,4-diones (2c,
2f) (2.8 mmol) and pyridine (33.8 mmol, 3 mL) in 50 mL
of benzene was cooled to 0 ºC and thionyl chloride
(16.8 mmol, 1.22 mL) diluted in 25 mL of benzene was
added dropwise over 10 min. The solution was stirred for an
additional 30 min, during which time the temperature was
allowed to rise to 20 ºC. The mixture was then heated under
reflux (bath temperature 80 ºC) for 1 h and then filtered to
remove the pyridine hydrochloride at room temperature.
The solution was extracted twice with benzene (2 × 50 mL)
and dried over sodium sulfate. Evaporation of the solvent
under reduced pressure by rotatory evaporator left 3c, 3f
1-[5-(Trifluoromethyl)-5-hydroxy-3-phenyl-4,5-dihydro-
1H-pyrazol-1-yl]-4-oxobutane hydrazide (4c)
1
Yield 81%, mp 240-241 ºC. H NMR: d 8.97 (s, 1H,
NH), 8.01 (s, OH), 7.79-7.82 (m, 2H, Ar), 7.48-7.50 (m,
3H, Ar), 4.16 (s, 2H, NH2), 3.9 (d, 1H, H-4, J 19), 3.55 (d,
1H, H-4, J 19), 3.07 (s, 2H, CH2), 2.24 (s, 2H, CH2). 13C
NMR: d 170.7 (C=O), 170.1 (C=O), 151.4 (C-3), 128.2,
127.8, 122.6, 114.2 (4C, Ar), 122.7 (q, 1J 289, CF3), 90.8
(q, 2J 34, C-5), 44.4 (C-4), 29.3 (CH2), 28.9 (CH2). Anal.
Calc. for C14H15F3N4O3 (344.11): C, 48.84; H, 4.39; N,
16.27%. Found: C, 48.5; H, 4.01; N, 16.34%.

1662
Succinic Acid Dihydrazide: a Convenient N,N-Double Block
J. Braz. Chem. Soc.
1-[5-(Trifluoromethyl)-5-hydroxy-3-(4-methoxyphenyl)-
(CH2). Anal. Calc. for C19H18Cl3F3N4O4 (374.12): C, 43.08;
H, 3.42; N, 10.58%. Found: C, 43.41; H, 3.85; N, 10.75%.
4,5-dihydro-1H-pyrazol-1-yl]-4-oxobutane hydrazide (4d)
1
Yield 77%, mp 194-195 ºC. H NMR: d 8.98 (s, 1H,
NH), 7.94 (s, OH), 7.74 (d, 2H, Ar), 7.00 (d, 2H, Ar), 4.15
(s, 2H, NH2), 3.85 (d, 1H, H-4, J 19), 3.51 (d, 1H, H-4, J
19), 3.81 (s, 3H, OMe), 3.04 (s, 2H, CH2), 2.24 (s, 2H, CH2).
13C NMR: d 174.7 (C=O), 170.0 (C=O), 150.9 (C-3), 161.0,
130.1, 122.5, 114.9 (4C, Ar), 125.7 (q, 1J 284, CF3), 90.7
(q, 2J 32, C-5), 55.1 (OCH3), 44.2 (C-4), 29.3 (CH2), 26.0
(CH2). Anal. Calc. for C15H17F3N4O4 (374.12): C, 48.13;
H, 4.58; N, 14.97%. Found: C, 48.29; H, 4.51; N, 14.73%.
1-[5-(Trifluoromethyl)-5-hydroxy-3-phenyl-4,5-dihydro-
1H-pyrazol-1-yl]-4-[5-(trichloromethyl)-5-hydroxy-3-
phenyl-4,5-dihydro-1H-pyrazol-1-yl]butane-1,4-dione (5c)
1
Yield 75%, mp 214-215 ºC. H NMR: d 7.99 (s, 1H,
OH’), 7.92 (s, 1H, OH), 7.79-7.83 (m, 4H, Ar), 7.48-7.49
(m, 6H, Ar), 3.98 (d, J 19, 1H, H-4’), 3.89 (d, J 19, 1H,
H-4), 3.78 (d, J 19, 1H, H-4’), 3.56 (d, J 19, 1H, H-4),
3.11 (s, 2H, CH2’), 3.07 (s, 2H, CH2). 13C NMR: d 172.5
(C=O’), 170.0 (C=O), 153.5 (C-3’), 151.1 (C-3), 130.5,
130.2, 129.7, 129.3, 128.5, 128.4, 126.3, 126.2 (12C, 2Ar),
1-[5-(Trifluoromethyl)-5-hydroxy-3-(4-nitrophenyl)-4,5-
1
dihydro-1H-pyrazol-1-yl]-4-oxobutane hydrazide (4g)
103.3 (CCl3), 101.4 (C-5’), 125.6 (q, J 285, CF3), 90.9
1
Yield 52%, mp 239-240 ºC. H NMR: d 8.96 (s, 1H,
(q, 2J 34, C-5), 46.5 (C-4’), 44.1 (C-4), 29.7 (CH2’), 29.2
(CH2). Anal. Calc. for C24H20Cl3F3N4O4 (590.05): C, 48.71;
H, 3.41; N, 9.47%. Found: C, 49.11; H, 3.74; N, 9.42%.
NH), 8.30-8.33 (d, 2H, Ar), 8.05-8.07 (m, 2H, Ar), 4.15
(s, 2H, NH2), 4.06 (d, 1H, H-4, J 19), 3.63 (d, 1H, H-4,
13
J 19), 3.12 (s, 2H, CH2), 2.24 (s, 2H, CH2). C NMR: d
170.7 (C=O), 170.2 (C=O), 149.8 (C-3), 148.1, 136.2,
Acknowledgments
1
2
127.9, 127.3 (4C, Ar), 122.4 (q, J 289, CF3), 91.5 (q, J
32, C-5), 44.1 (C-4), 29.3 (CH2), 28.9 (CH2). Anal. Calc.
for C14H14F3N4O5 (389.09): C, 43.19; H, 3.62; N, 17.99%.
Found: C, 43.24; H, 3.61; N, 18.03%.
The authors are thankful for the financial support
from Conselho Nacional de Desenvolvimento Científico
e Tecnológico - CNPq (Proc. No. 303296/2008-9).
Fellowships from Coordenação de Aperfeiçoamento de
Pessoal de Nível Superior - CAPES (Cechinel, C. A.) and
CNPq (Porte, L. M. F.) are also acknowledged.
Synthesis of 1-[5-(trifluoromethyl)-5-hydroxy-4,5-dihydro-
1H-pyrazol-1-yl]-4-[5-(trichloromethyl)-5-hydroxy-4,5-
dihydro-1H-pyrazol-1-yl]butane-1,4-diones (5b-c)
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solvent was evaporated to half by rotatory evaporator
under reduced pressure and after cooling (≤ 8 ºC) for 1-2
days the compounds 5b-c were obtained pure directly
by filtration, washed with cold ethanol and dried under
vacuum apparatus.
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