Brominated trihalomethylenones as versatile precursors to 3-ethoxy, -formyl, -azidomethyl, -triazolyl, and 3-aminomethyl pyrazoles

Article abstract of DOI:10.1002/jhet.996

5-Bromo[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones are explored as precursors to the synthesis of 3-ethoxymethyl-5-trifluoromethyl-1H- pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3-Ethoxymethyl-carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3-acetal-pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3-azidomethyl-5- ethoxycarbonyl-1H-pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3-[4(5)-phenyl-1,2,3-triazolyl]5- ethoxycarbonyl-1H-pyrazoles and to reduction conditions resulting in 3-aminomethyl-1H-pyrazole-5-carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.

Full text of DOI:10.1002/jhet.996

January 2013
Brominated Trihalomethylenones as Versatile Precursors to 3-Ethoxy,
-Formyl, -Azidomethyl, -Triazolyl, and 3-Aminomethyl Pyrazoles
71
a
b
a
a
c
a
*
Marcos A. P. Martins, Adilson P. Sinhorin, Clarissa P. Frizzo, Lilian Buriol, Elisandra Scapin, Nilo Zanatta, and
Helio G. Bonacorsoa
aNúcleo de Química de Heterociclos, Departamento de Química, Universidade Federal de Santa Maria, 97105-900,
Santa Maria, Rio Grande do Sul, Brazil
bInstituto Universitário Norte Mato Grossense, Universidade Federal de Mato Grosso, 78550000, Sinop, Mato Grosso, Brazil
cLaboratório de Química, Coordenação de Engenharia Ambiental, Universidade Federal do Tocantins,
Av. NS 15 ALC NO 14, Bloco II,109 Norte, Palmas, Tocantins, Brazil
*
E-mail: mmartins@base.ufsm.br
Received March 23, 2011
DOI 10.1002/jhet.996
View this article online at wileyonlinelibrary.com.
5-Bromo[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones are explored as precursors to the
synthesis of 3-ethoxymethyl-5-trifluoromethyl-1H-pyrazoles from a cyclocondensation reaction with hydrazine
monohydrate in ethanol. 3-Ethoxymethyl-carboxyethyl ester pyrazoles were formed as a result of a substitution
reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3-acetal-pyrazole that was
easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic
substitution reaction with sodium azide to synthesize the 3-azidomethyl-5-ethoxycarbonyl-1H-pyrazole
from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction
with phenyl acetylene furnishing the 3-[4(5)-phenyl-1,2,3-triazolyl]5- ethoxycarbonyl-1H-pyrazoles and to
reduction conditions resulting in 3-aminomethyl-1H-pyrazole-5-carboxyethyl ester. The products were
obtained by a simple methodology and in moderate to good yields.
J. Heterocyclic Chem., 50, 71 (2013).
INTRODUCTION
received considerable interest [1]. The most convenient
method to construct halogenated compounds is to use
halogen-containing building blocks as starting material [2].
During the last 20 years, we have developed a general
synthesis of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones [3,4],
an important halogen-containing building block, and
The introduction of halogens and halogenated groups into
organic molecules often confers significant and useful
changes in their chemical and physical properties. Therefore,
methods for the synthesis of halogenated compounds have
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M. A. P. Martins, A. P. Sinhorin, C. P. Frizzo, L. Buriol, E. Scapin,
D. N. Moreira, N. Zanatta, and H. G. Bonacorso
Vol 50
demonstrated its usefulness in heterocyclic preparations,
for example, isoxazoles [3,5,6], pyrazoles[7], pyrazolium
chlorides [8], pyrrolidinones [9], pyrimidines [10],
pyridines [11], thiazines [12], and diazepines[13].
Despite extensive studies on applications of 4-alkoxy-1,1,
1-trihalo-3-alken-2-ones in heterocyclic chemistry [4,6–15],
5-heteroalkyl substituted 4-alkoxy-1,1,1-trihalo-3-alken-
2-ones and their usefulness in the synthesis of heterocycles
have been less explored. These compounds are highly
functionalized intermediates, which may be useful for
further synthetic conversions. In a previous work [6], we
reported the synthesis of 5-bromo-1,1,1-trichloro-4-methoxy-
3-penten[hexen]-2-ones, in high purity, from the reaction
of 1,1,1-trichloro-4-methoxy-3-penten[hexen]-2-ones with
bromine in the presence of pyridine. The use of these
important 1,3,4-trielectrophiles in the synthesis of other
1,1,1-trichloro-5-heteroalkyl-4-methoxy-3-penten[hexen]-2-
ones by nucleophilic substitution of bromine and their
application in the synthesis of isoxazole heterocyclic systems
was also reported [6] (Scheme 1). In another work, we
reported a general and efficient synthetic approach for the
preparation of a series of 5-bromo[5,5-dibromo]-1,1,1-
trihalo-4-methoxy-3-alken-2-ones in high purity and good
yields and the use of 5-bromo-1,1,1-trichloro-4-methoxy-
3-penten[hexen]-2-ones in the synthesis of several
heterocycles, such as pyrazolium [8], 4,5-dihydropyrazoles
[6], isoxazoles[6], andtiopyrimidines [6] (Scheme1). Herein,
we report the use of mono- and dibrominated 5-bromo
[5,5-dibromo]-1,1,1-trihalo-4-methoxy-3-alken-2-ones as
building blocks in the synthesis of 3(5)-ethoxymethyl-5
(3)trihalomethyl-1H-pyrazoles from cyclocondensation
reactions of these brominated precursors with hydrazine
monohydrate and with subsequent easy acetalhydrolyzation
leading to the formyl group. We also demonstrate the
synthesis of 3-triazolemethyl-5-halomethyl[ethoxycarbonyl]-
1H-pyrazoles by a set of reactions of the brominated
precursors with sodium azide, followed by a cycloconden-
sation reaction with hydrazine monohydrate and then a
cycloaddition reaction with phenyl acetylene. Finally,
we show a reduction reaction where the azide group
present in the compound 3-azidomethyl-1H-pyrazole-5-
ethoxycarbonyl ester is reduced to amine.
RESULTS AND DISCUSSION
Firstly, the 4-alkoxy-1,1,1-trihalo-3-alken-2-ones, 1a–c,
2a–c, were obtained from the acylation reaction of enol ether
or acetal with trifluoroacetic anhydride or trichloroacetic acid
in accordance with the methodology developed in our
laboratory [3]. Subsequently, the 5-bromo[5,5-dibromo]-1,1,1-
trihalo-4-methoxy-3-penten[hexen]-2-ones, 3a–c, 4a–c,
were synthesized from the reaction of 4-alkoxy-1,1,
1-trihalo-3-alken-2-ones, 1a–c, 2a–c, with bromine in
the presence of pyridine [6b]. The 5-bromo-1,1,1-
trihalo-3-hexen-2-ones, 3a, 4a, were also submitted to the
allylnucleophilic substitution of bromine by sodium azide
Scheme 1
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3-Ethoxy, -Formyl, -Azidomethyl, -Triazolyl, and 3-Aminomethyl Pyrazoles
Scheme 2
to synthesize 5-azido-1,1,1-trihalo-3-hexen-2-ones, 3d, 4d,
using the reaction conditions previously determined by
Martins et al. [6]. Scheme 2 shows the synthetic route to ob-
tain the building block used in this work, which furnished
the heterocyclic compounds.
We started our study from the cyclocondensation reaction
of 5-bromo[5,5-dibromo]-1,1,1-trichloro-4-methoxy-3-
penten-2-ones, 4c (1 mmol), with hydrazine monohydrate
(1.1 mmol), by evaluating the best reaction conditions
for the formation of compound 6c. The first test was
performed in ethanol as solvent at 65ꢀC for 4 h, on the basis
of a work previously published by us [14]. However,
the product was not identified using these reactionconditions.
Therefore, the optimization of the reaction was carried
out, varying the time and reaction conditions to obtain the
desired product in high yields and purity. The optimization
of this reaction is described in Scheme 3.
attention on the optimization of the reaction conditions
of 3-[1(1-di)ethoxy]-5-trihalomethylpyrazoles, 5a–c, 6a–c.
This reaction was performed between 5-bromo[5,5-
dibromo]-1,1,1-trihalo-4-methoxy-3-penten[hexen]-2-ones,
3a–c, 4a–c, and hydrazine monohydrate, using EtOH
as solvent at 65ꢀC for 24h. According to Scheme 4, the
products 5a–c, 6a–c, were obtained in good yields
65–85%.
In the reaction of monobrominated enones, 3a–b, 4a–b, with
hydrazine monohydrate, substitution of the bromine by
ethanol took place, and products 3-[1-ethoxy]-5-trihalomethyl-
1H-pyrazoles 5a–b,6a–b were formed. Likewise, the
reaction of dibrominated enones 3c, 4c with hydrazine
monohydrate led to the disubstitution of both bromines by
ethanol, resulting to acetal 3-[1-(diethoxy]-5-trifluoromethyl-
1H-pyrazoles, 5c, 6c. The substitution of bromine by
ethanol probably occurred by an SN2 mechanism, where
the solvent acted as nucleophile. Elucidation of the
The best reaction condition to furnish product 6c entailed
the reaction time of 24 h under neat conditions, that is, without
the presence of pyridine or HCl. Later, we focused our
1
structure was carried out by assignments of H and 13C
NMR and GC–MS analysis.
Scheme 3
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M. A. P. Martins, A. P. Sinhorin, C. P. Frizzo, L. Buriol, E. Scapin,
D. N. Moreira, N. Zanatta, and H. G. Bonacorso
Vol 50
Scheme 4
Although mild conditions were used, we believed that the
It is interesting to mention that the acetal product 6c can
be hydrolyzed and easily forms the formyl group in the
presence of the HCl (15%) under heating at 65ꢀC for 6 h
as shown in Scheme 5.
conversion of group CCl3 into CO2Et can occur through
a mechanism similar to those of neighboring assistance
reported for the reaction of a-haloketones with alkoxide
groups [16]. Through this mechanism, during ring closure,
the carbonyl oxygen of the b-alkoxyvinyltrichloromethyl
begins the chlorine substitutions with attack on the carbon
atom of the trichloromethyl group.
In a continuation, herein, we present, for the first time,
the application of 5-azido-1,1,1-trihalo-3-hexen-2-ones,
3d, 4d, as precursors in the synthesis of pyrazoles 5d, 6d
by the cyclocondensation reaction with hydrazine monohy-
drate in EtOH at 65ꢀC for 24 h as shown in Scheme 6. The
reaction conditions were the same as those used in the syn-
thesis of pyrazoles 5a–c, 6a–c. The products 5d and 6d
were obtained in good yields (X = F, 68%; X = Cl, 73%).
Our research group has demonstrated the use of
5-azido-1,1,1-trichloro-3-hexen-2-ones as precursors to 4,
5-dihydroisoxazoles and their stability in dehydration reac-
tion in acid media [6]. Therefore, it seemed that the
azide function as a pyrazole substituent could be explored
as a precursor to triazole synthesis. 1,2,3-Triazoles are
Scheme 5
Scheme 6
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Brominated Trifluoromethylenones as Versatile Precursors to
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3-Ethoxy, -Formyl, -Azidomethyl, -Triazolyl, and 3-Aminomethyl Pyrazoles
nitrogen heteroarenes that have a range of important applica-
tions in the pharmaceutical and agricultural industries [17].
The most widely used method for the synthesis of 1,2,
3-triazoles, pioneered by Huisgen, involves the thermal
1,3-dipolar cycloaddition of organic azides with alkynes
[18]. In connection with our ongoing investigation
into the synthesis of trihalomethyl compounds, we were
interested in exploring this cycloaddition reaction, where
some of the key building blocks contained halomethyl
groups. To the best of our knowledge, there is only one
example of a 1,3-dipolar cycloaddition of heterocyclic
methylene azides with alkynes [19].
Initially, we performed the reaction between compound 6d
and phenyl acetylene according to the literature [20] to obtain
the 1,4-substituted 1,2,3-triazoles 8d and 1,5-substituted 9d.
Then, we tested other reaction conditions to optimize the
reaction as shown in Scheme 7. The best condition was
obtained using toluene at 110ꢀC for 24 h. The mixture of
isomers was obtained in excellent yield (85%). The propor-
tion of isomers was determinate by 1H and 13C NMR. Assign-
ment of 8d and 9d isomers was possible by comparison
of chemical shift of methylene group with the similar
compounds in literature [19].
We first used LiAlH4 as a reducing agent; however, the
product was not identified. In a second attempt, we used
the method developed by Friguelli et al. [21], which uses
NaBH /CoCl 6H O, and once again, we were unsuc-
•
4
2
2
cessful. Finally, we used the technique developed by
Zwierzaki [22], via the Staudinger reaction, which
makes use of triethylphosphite and gaseous hydrochloric
acid as reducing agents, and this method reduced the
azide group to amine. The first step of the reaction was
carried out using benzene as a solvent and the mixture
of compound 6d with triethylphosphite, in a molar ratio
of 1:2, respectively, at room temperature for 12 h. In the
second step, gaseous HCl was added, and the mixture
was left under stirring for 12 h at room temperature.
The product 10d was obtained in moderate yield, 50%
(Scheme 8).
In summary, we have demonstrated the versatility of
brominated trihalomethylated building blocks in the
Scheme 8
Another interesting point to mention here is the useful-
ness of compound 6d as a precursor because the azide
group can be reduced to amine. We started our study
evaluating the best reaction conditions for products 10d.
Scheme 7
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M. A. P. Martins, A. P. Sinhorin, C. P. Frizzo, L. Buriol, E. Scapin,
D. N. Moreira, N. Zanatta, and H. G. Bonacorso
Vol 50
the residue was dissolved in dichloromethane (5 mL), washed with
H2O (3 Â 5 mL), dried (MgSO4), filtered, and the solvent was
removed under reduced pressure.
generation of both new precursors and heterocyclic com-
pounds. In a set of reactions, we showed their synthetic po-
tential, where it was demonstrated that 5-bromo-1,1,1-
trihalo-4-methoxy-3-penten-2-one underwent a sequence of
reactions including nucleophilic substitution, cycloconden-
sation, cycloaddition, and reducing reactions.
1
3-(1-Ethoxyethyl)-5-trifluoromethyl-1H-pyrazole (5a). Oil. H
NMR (200MHz, CDCl3) d 6.39 (s, 1H, H4), 4.52 (s, 2H, H6),
3.51 (q, 2H, H7), 1.16 (t, 3H, H8). 13C NMR (400MHz, CDCl3)
d 142.3 (C3), 102.7 (C4), 142.5 (q, 2J = 34 Hz, C5), 66.5
1
(C6), 62.9 (C7), 14.6 (C8), 121.1(q, J = 287Hz, CF3). GC–MS
(m/z, %) 194 (M+, 4), 149 (100), 101 (23).
1
3-(1-Ethoxyethyl)-5-trifluoromethyl-1H-pyrazole (5b). Oil. H
EXPERIMENTAL
NMR (200 MHz, CDCl3) d 9.06 (s, 1H, NH), 6.45 (s, 1H, H4),
4.70 (q, 1H, H6), 3.50 (q, 2H, H7), 1.20 (t, 3H, H8), 1.52 (d, 3H,
CH3). 13C NMR (400MHz, CDCl3) d 143.7 (C3), 101.3 (C4),
Unless otherwise indicated, all common reagents and solvents
were used as obtained from commercial suppliers without further
purification. 13C NMR spectra were recorded on a Bruker DPX
400 spectrometer (13C at 100.61 MHz) and 1H spectra were
recorded on a Bruker DPX 200 spectrometer (1H at 200.13 MHz)
at 300 K, in CDCl3 as solvent, containing TMS as internal
standard. All spectra were acquired in a 5-mm tube at natural
abundance. Mass spectra were registered in an HP 5973 MSD
2
139.1 (q, J = 34Hz, C5), 68.5 (C6), 65.3 (C7), 15.0 (C8), 120.5
1
(q, J = 287 Hz, CF3), 20.6 (C10), 20.6 (CH3). GC–MS (m/z, %)
208 (M+, 2), 193 (67), 179 (3), 165 (100).
1
3-Diethoxymethyl-5-trifluoromethyl-1H-pyrazole (5c). Oil. H
NMR (200MHz, CDCl3) d 6.60 (s, 1H, H4), 6.82 (s, 1H, H6),
3.86 (2q, 4H, H7, OCH2), 1.22 (2t, 6H, H8, CH3). 13C NMR
(400MHz, CDCl3) d 137.7 (C3), 104.5 (C4), 143.7 (q, 2J = 34 Hz,
C5), 80.3 (C6), 64.5 (C7, OCH2), 14.6 (C8, CH3), 120.6(q,
1J = 287 Hz, CF3). GC–MS (m/z, %) 238 (M+, 100).
connected to an HP 6890 GC and interfaced by
a
Pentium PC. The GC was equipped with a split-splitless, injector,
cross-linked HP-5 capillary column (30m, 0.32 mm of internal
diameter), and helium was used as the carrier gas.
3-Azidomethyl-5-trifluoromethyl-1H-pyrazole (5d). Oil. 1H
NMR (200MHz, CDCl3) d 6.62 (s, 1H, H4), 4.45 (s, 2H, H6).
13C NMR (400MHz, CDCl3) d 140.4 (C3), 103.4 (C4), 142.8
(q, 2J = 38Hz, C5), 44.8 (C6), 120.9 (q, 1J = 280 Hz, CF3).
GC–MS (m/z, %) 191 (M+, 50), 172 (25), 149 (100), 101 (80),
67 (100).
Typical procedure for the synthesis of compounds 5a–c, 6a–c.
The hydrazine monohydrate (1.1 mmol) was readily added to the
5-bromo-1,1,1-trihalo-4-methoxy-3-penten-2-ona (1mmol) and
dissolved in ethanol (3 mL). The reaction mixture was heated at
65ꢀC for 24h. Then, the solvent was evaporated at reduced
pressure, and the residue was dissolved in dichloromethane
(5 mL), washed with H2O (2 Â 5 mL), dried (MgSO4), filtered,
and the solvent was removed under reduced pressure.
Typical procedure for the synthesis of compound 7c. The
aqueous HCl solution (15%) (3mL) was added to the compounds
6c, and the reaction mixture was heated at 65ꢀC for 6 h. Then, the
solvent was evaporated at reduced pressure, and the residue was
dissolved in dichloromethane (5 mL), washed with H2O
(2 Â 5 mL), dried (MgSO4), filtered, and the solvent was removed
under reduced pressure.
3-Ethoxymethyl-1H-pyrazole-5-carboxyethyl ester (6a). Oil. 1H
NMR (200 MHz, CDCl3) d 11.01 (s, 1H, NH), 6.79 (s, 1H, H4),
4.52 (s, 2H, H6), 3.45 (q, 2H, H7), 1.12 (t, 3H, H8), 4.28 (q, 2H,
H10), 1.26 (q, 2H, H10); 13C NMR (400MHz, CDCl3) d 145.4
(C3), 107.3 (C4), 140.1 (C5), 65.8 (C6), 60.7 (C7), 14.8 (C8),
161.2 (C9), 61.1 (C10), 14.8 (C11); GC–MS (m/z, %) 198 (M+,
2), 154 (70), 108 (100), 79 (40).
3-(1-Ethoxylethyl-1H-pyrazole-5-carboxyethyl ester (6b). Oil.
1H NMR (200MHz, CDCl3) d 9.51 (s, 1H, NH), 6.77 (s, 1H,
H4), 4.65 (q, 1H, H6), 3.43 (q, 2H, H7), 1.19 (t, 3H, H8), 4.39
(q, 2H, H10), 1.27 (t, 3H, H10), 1.44 (d, 3H, CH3); 13C NMR
(400MHz, CDCl3) d 150.9 (C3), 105.6 (C4), 139.9 (C5), 70.4
(C6), 60.8 (C7), 14.1 (C8), 161.2 (C9), 64.1 (C10), 15.1 (C11),
21.6 (CH3); GC–MS (m/z, %) 212 (M+, 1), 197 (40), 168 (85),
123 (100), 65 (20).
Typical procedure for the synthesis of compounds 5d,
6d.
The hydrazine (1.1 mmol) was readily added to the
5-azido-1,1,1-trihalo-4-methoxy-3-penten-2-one (1 mmol) and
dissolved in ethanol (3 mL). The reaction mixture was heated at
65ꢀC for 24 h. Then, the solvent was evaporated at reduced
pressure, and the residue was dissolved in dichloromethane
(5 mL), washed with H2O (3 Â 5 mL), dried (MgSO4), filtered,
and the solvent was removed under reduced pressure.
Typical procedure for the synthesis of compounds 8d, 9d.
Phenylacetylene (1 mmol) was readily added to 3-azidomethyl-
5-trichloromethyl-1H-pyrazoles (1 mmol) and dissolved in toluene
(3 mL). The reaction mixture was heated at 110ꢀC for 24h. Then,
the solvent was evaporated at reduced pressure and the residue
was dissolved in dichloromethane (5 mL), washed with H2O
(3 Â 5 mL), dried (MgSO4), filtered, and the solvent was removed
under reduced pressure.
Typical procedure for the synthesis of compound 10d.
3-Azidomethyl-5-trichloromethyl-1H-pyrazoles (1mmol) were
readily added to triethylphosphite (2mmol) and dissolved in
benzene (2 mL). The reaction mixture was heated at room
temperature for 12 h. Then, HCl gaseous was added, and the
mixture was left under stirring for 12 h at room temperature.
Subsequently, the solvent was evaporated at reduced pressure, and
3-Diethoxymethyl-1H-pyrazole-5-carboxyethyl ester (6c). Oil.
1H NMR (200MHz, CDCl3) d 6.88 (s, 1H, H4), 7.10 (s, 1H, H6),
4.40 (q, 2H, H7), 1.40 (t, 3H, H8), 4.18 (q, 2H, H10), 1.53 (t, 3H,
H11); 13C NMR (400 MHz, CDCl3) d 152.3 (C3), 107.1 (C4)
(C4), 136.1 (C5), 66.7 (C6), 61.7 (C7), 13.5 (C8), 159.2 (C9),
64.1 (C10), 14.1 (C11); GC–MS (m/z, %) 199 (M[ÀOEt] 2), 169
(100), 153 (4), 137 (50), 123 (5).
1
3-Azidomethyl-1H-pyrazole-5-carboxyethyl ester (6d). Oil. H
NMR (200MHz, CDCl3) d 6.82 (s, 1H, H4), 4.42 (s, 2H, H6),
4.28 (q, 2H, H8), 1.28 (t, 3H, H9); 13C NMR (400MHz, CDCl3)
d 145.2 (C3), 107.7 (C4), 137.8 (C5), 46.2 (C6), 159.8 (C7), 60.7
(C8), 13.5 (C9); GC–MS (m/z, %) 195 (M+, 8), 167 (6), 153
(100), 120 (22), 107(30).
3-Formyl-1H-pyrazole-5-carboxyethyl ester (7c). Oil. 1H NMR
(200MHz, CDCl3) d 7.23 (s, 1H, H4), 9.99 (s, 2H, H6), 3.57 (q, 2H,
H7), 1.12 (t, 3H, H8). 13C NMR (400 MHz, CDCl3) d 152.5 (C3),
107.3 (C4), 137.0 (C5), 185.5 (C6), 159.9 (C9), 61.4 (C10), 14.4
(C11). GC–MS (m/z, %) 169 (M+, 1), 154 (100), 121 (80), 67 (100).
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3-Ethoxy, -Formyl, -Azidomethyl, -Triazolyl, and 3-Aminomethyl Pyrazoles
[6] (a) Martins, M. A. P.; Sinhorin, A. P.; Zimmermann, N. E. K.;
Zanatta, N.; Bonacorso, H. G.; Bastos, G. P. Synthesis 2001, 1959; (b)
Martins, M. A. P.; Sinhorin, A. P.; Rosa, A.; Flores, A. F. C.; Wastowski,
A. D.; Pereira, C. M. P.; Flores, D. C.; Beck, P.; Freitag, R. A.; Brondani,
S.; Cunico, W.; Bonacorso, H. G.; Zanatta, N. Synthesis 2002, 2353.
[7] (a) Braibante, M. E. F.; Martins, M. A. P.; Clar, G. J
Heterocycl Chem 1993, 30, 1159; (b) Bonacorso, H. G.; Wastowski, A.
D.; Zanatta, N.; Martins, M. A. P.; Naue, J. A. J Fluorine Chem 1998,
92, 23; (c) Bonacorso, H. G.; Oliveira, M. R.; Wentz, A. P.; Wastowski,
1-[1H-Pyrazol-3-yl-5-carboxyethyl ester]-methyl-4-phenyl-1,2,3-
triazole (8d). Oil. H NMR (200 MHz, CDCl3) d 6.85(s, 1H, H4),
1
4.45 (s, 2H, H6), 5.64 (s, 1H, H10), 5.71 (s, 1H, H11), 4.37 (q,
2H, H13), 1.38 (q, 3H, H14), 7.33–7.88 (m, 5H); 13C NMR
(400 MHz, CDCl3) d 145.2 (C3), 107.9 (C4), 138.2 (C5), 46.0
(C6), 130.1 (C10), 126.2 (C11), 160.3 (C12), 61.4 (C13), 14.0
(C14), 128–130 (Ph). GC–MS (m/z, %) 297 M+ (22), 269 (15),
252 (9), 223 (23), 196(42), 153(100), 107 (25).
A. D.; Oliveira, A. B.; Hörner, M.; Zanatta, N.; Martins, M. A. P.
Tetrahedron 1999, 55, 345; (d) Bonacorso, H. G.; Wastowski, A. D.;
1-[1H-Pyrazole-3-yl-5-carboxyethyl ester]-methyl-5-phenyl-
1,2,3-triazole (9d). Oil. 1H NMR (200MHz, CDCl3) d 6.7 (s, 1H,
H4), 4.67 (s, 2H, H6), 5.64 (s, 1H, H10), 5.71 (s, 1H, H11), 4.37
(q, 2H, H13), 1.38 (q, 3H, H14), 7.33–7.88 (m, 5H); 13C NMR
(400 MHz, CDCl3) d 148.0 (C3), 108.2(C4), 137.6(C5), 45.0
(C6), 132.8 (C10), 120.1 (C11), 160.0 (C12), 61.4 (C13), 14.0
(C14), 128–130 (Ph). GC–MS (m/z, %) 297 M+ (13), 269 (16),
252 (25), 223 (100), 196 (22), 153 (40), 107 (70).
Zanatta, N.; Martins, M. A. P. Synthetic Commun 2000, 30, 1457; (e)
Bonacorso, H. G.; Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Synthesis
2001, 1505. (f) Flores, A. F. C.; Rosa, A.; Flores, D. C.; Zanatta, N.;
Bonacorso, H. G.; Martins, M. A. P. Synthetic Commun 2002, 32, 1585.
[8] Martins, M. A. P.; Pereira, C. M. P.; Sinhorin, A. P.; Bastos, G.
P.; Zimmermann, N. E. K.; Rosa, A.; Bonacorso, H. G.; Zanatta, N.
Synthetic Commun 2002, 32, 419.
[9] Zanatta, N.; Rosa, L. S.; Loro, E.; Bonacorso, H. G.; Martins,
M. A. P. J Fluorine Chem 2001, 107, 149.
3-Aminomethyl-1H-pyrazole-5-carboxyethyl ester (10d). Oil. 1H
NMR (200 MHz, CDCl3) d12.49 (s, NH2), 6.87 (s, 1H, H4), 4.51
(s, 2H, H6), 4.39 (q, 2H, OCH2), 1.43 (t, 3H, CH3). 13C NMR
(400 MHz, CDCl3) d 142.4 (C3), 108.5 (C4), 138.8 (C5), 36.0
(C6), 163.6 (C7), 61.4 (OCH2), 12.4 (CH3). GC–MS (m/z, %) 169
(M+, 100), 170 (6%).
[10] (a) Pacholski, I. L.; Blanco, I.; Zanatta, N.; Martins, M. A. P. J
Braz Chem Soc 1991, 1, 118; Chem Abstr 1994, 120, 323443n; (b)
Madruga, C. C.; Clerici, E.; Martins, M. A. P.; Zanatta, N. J Heterocycl
Chem 1995, 32, 735; (c) Zanatta, N.; Cortelini, M. F. M.; Carpes, M. J.
S.; Bonacorso, H. G.; Martins, M. A. P. J Heterocycl Chem 1997, 34,
509; (d) Zanatta, N.; Fagundes, M. B.; Ellenshon, R.; Marques, M.;
Bonacorso, H. G.; Martins, M. A. P. J Heterocycl Chem 1998, 35, 451;
(e) Zanatta, N.; Madruga, C. C.; Marisco, P. C.; Flores, D. C.; Bonacorso,
H. G.; Martins, M. A. P. J Heterocycl Chem 2000, 37, 1213; (f) Zanatta,
N.; Pacholski, I. L.; Faoro, D.; Bonacorso, H. G.; Martins, M. A. P.
Synthetic Commun 2001, 31, 2855.
Acknowledgments. The authors thank the Conselho Nacional de
Desenvolvimento Científico e Tecnológico em Pesquisa (CNPq/
PADCT), Fundação de Amparo à Pesquisa do Estado do Rio
Grande do Sul (FAPERGS) for financial support. The fellowships
from CNPq, CAPES, and FATEC are also acknowledged.
[11] Zanatta, N.; Barichello, R.; Bonacorso, H. G.; Martins, M. A.
P. Synthesis 1999, 765.
[12] Bonacorso, H. G.; Bittencourt, S. R. T.; Lourega, R. V.; Flores,
A. F. C.; Zanatta, N.; Martins, M. A. P. Synthesis 2000, 1431.
[13] (a) Bonacorso, H. G.; Bittencourt, S. R. T.; Wastowski, A. D.;
Wentz, A. P.; Zanatta, N.; Martins, M. A. P. Tetrahedron Lett 1996, 37,
9155; (b) Bonacorso, H. G.; Bittencourt, S. R. T.; Wastowski, A. D.; Wentz,
A. P.; Zanatta, N.; Martins, M. A. P. J Heterocycl Chem 1999, 36, 45.
[14] (a) Martins, M. A. P.; Freitag, R. A.; Flores, A. F. C.;
Zanatta, N. Synthesis 1995, 1491; (b) Martins, M. A. P.; Freitag, R. A.;
Rosa, A.; Flores, A. F. C.; Zanatta, N.; Bonacorso, H. G. J Heterocycl
Chem 1999, 36, 217.
[15] Martins, M. A. P.; Flores, A. F. C.; Bastos, G. P.; Sinhorin, A.
P.; Bonacorso, H. G.; Zanatta, N. Tetrahedron Lett 2000, 41, 293.
[16] (a) Martins, M. A. P.; Freitag, R. A.; Flores, A. F. C.; Zanatta, N.
Synthesis 1995, 1491; (b) Martins, M. A. P.; Freitag, R. A.; Rosa, A.; Flores,
A. F. C.; Zanatta, N.; Bonacorso, H. G. J Heterocycl Chem 1999, 36, 217; (c)
Henery-Logan, K. R.; Fridinger, T. L. Chem Commun 1968, 130.
[17] (a) Fan, W.-Q.; Katrizky, A. R. In Comprehensive Heterocyclic
Chemistry II; Katrizky, A. R.; Rees, C. W.; Scriven, E. F. V. Eds; Pergamon
Press: Oxford, 1996; (b) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.;
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[18] L’Abbe, G. Chem Rev 1969, 69, 345
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet