From renewable levulinic acid to a diversity of 3-(Azol-3-yl)propanoates

Article abstract of DOI:10.1002/jhet.1774

Efficient heterocyclization of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4- heptenoate and methyl 7,7,7-trichloro-4-methoxy-6-oxo-4-heptenoate into isoxazole and pyrazole derivatives that represent a new type of glutamate-like 3-(trihalomethylated-1,2-azol-3-yl)propanoate is reported. Preparation of the key methyl 7,7,7-trihalo-4-methoxy-6-oxohept-4-enoate precursors from levulinic acid is also described. The synthetic potential of this synthetic protocol was indicated by the production of several methyl and ethyl 3-(isoxazol-3-yl) propanoates and 3-(1H-pyrazol-3-yl)propanoates, and the respective acid derivatives, in good (70-95%) yields. The crystal structure for ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3-carboxylate (10c) has been determined by monocrystal X-ray diffraction analysis. The N-H^...H intermolecular hydrogen bonds join the molecules into catamer.

Full text of DOI:10.1002/jhet.1774

May 2014
From Renewable Levulinic Acid to a Diversity of 3-(Azol-3-yl)
Propanoates
733
a
b
c
a
a
*
Alex F. C. Flores, Luciana A. Piovesan, Lucas Pizzuti, Darlene C. Flores, Juliana L. Malavolta, and
Marcos A. P. Martinsa
aChemistry Department, Federal University of Santa Maria, 97105-900 Santa Maria, Rio Grande do Sul, Brazil
bEscola de Química e Alimentos, Lab. Kolbe de Síntese Orgânica (LKSO), Federal University of Rio Grande, 96201-900
Rio Grande, Rio Grande do Sul, Brazil
cFederal University of Grande Dourados, 79804-970 Dourados, Mato Grosso do Sul, Brazil
*
E-mail: alex.fcf@ufsm.br
Received March 21, 2012
DOI 10.1002/jhet.1774
Published online 3 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
O
O
CX3
O
RO
RO
CX3
N
N
Y
Y
HO
MeO
O
O
OMe O
X = F, Cl
Y = O, NH, NPh, NCONH2, NCSNH2, NCOCH3
R = H, Me, Et
OR
Efficient heterocyclization of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-heptenoate and methyl 7,7,7-
trichloro-4-methoxy-6-oxo-4-heptenoate into isoxazole and pyrazole derivatives that represent a new type
of glutamate-like 3-(trihalomethylated-1,2-azol-3-yl)propanoate is reported. Preparation of the key methyl
7,7,7-trihalo-4-methoxy-6-oxohept-4-enoate precursors from levulinic acid is also described. The synthetic
potential of this synthetic protocol was indicated by the production of several methyl and ethyl 3-(isoxazol-3-yl)
propanoates and 3-(1H-pyrazol-3-yl)propanoates, and the respective acid derivatives, in good (70–95%) yields.
The crystal structure for ethyl 5-(3-ethoxy-3-oxopropyl)-1H-pyrazole-3-carboxylate (10c) has been determined
by monocrystal X-ray diffraction analysis. The N–H.. .H intermolecular hydrogen bonds join the molecules
into catamer.
J. Heterocyclic Chem., 51, 733 (2014).
INTRODUCTION
fine organic material from renewable sources and presents
us with an attractive acetyl group [18–22]. Our continuing
interest in functionalized 1,3-dielectrophilic compounds
led us to study a new aspect of the application of the acetal
acylation method for producing methyl 7,7,7-trifluoro-
4-methoxy-6-oxo-4-heptenoate (1) and methyl 7,7,7-
trichloro-4-methoxy-6-oxo-4-heptenoate (2) [23].
With this in mind, we designed and synthesized a series
of new 3-(azol-3-yl)propanoates from precursors 1 and 2,
which were obtained by the trihaloacylation of methyl
4,4-dimethoxypentanoate derived from levulinic acid.
The azole rings are an important framework in pharma-
ceuticals and agricultural chemicals and for the develop-
ment of new functional materials [1–6]. For example,
(S)-a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) is a classic AMPA receptor agonist, and a large
number of heterocyclic Glu analogs, most of which are
derived from AMPA, are potent and selective agonists at
AMPA receptors. The 3-heteroaryl-propanoates are impor-
tant targets for the development of potent and selective
AMPA antagonists and represent potential drugs for cerebral
ischemia or epilepsy. Good results were observed for
ethyl 3-(2-ethoxycarbonyl-1H-imidazol-4-yl) propenoate
and its saturated derivative at micromolar concentrations
(Fig. 1)[7]. The synthesis of new drugs targeting the
glutamatergic system is also important for the treatment of
mood disorders [8–10].
We have systematically used the acetal acylation method
for the synthesis of a wide range of 4-alkoxy-1,1,1-
trihalo-3-alken-2-ones [11–13]. These 1,3-dielectrophilic
precursors have proved to be important building blocks
for the regiospecific synthesis of heterocyclic compounds
bearing trihalo methyl/carboxyl groups with important
pharmacological and synthetic applications [14–17].
Levulinic acid (4-oxopentanoic acid, LA) is an important
RESULTS AND DISCUSSION
Methyl 7,7,7-trihalo-4-methoxy-6-oxo-4-heptenoates (1, 2)
were synthesized, according with previous publications,
from the reaction of methyl 4,4-dimethoxypentanoate
with trifluoroacetic anhydride or trichloroacetyl chloride
(Scheme 1) [11].
To prepare isoxazole derivatives, precursors 1 and 2 were
reacted with hydroxylamine hydrochloride in different reac-
tion conditions. When the reaction was performed in pyridine
in a molar ratio of 1:1.2:1.2 using methanol or ethanol
under reflux, we obtained the methyl (5-trihalomethyl-5-
hydroxy-4,5-dihydroisoxazol-3-yl) propanoates 3b and 4b
© 2013 HeteroCorporation

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A. F. C. Flores, L. A. Piovesan, L. Pizzuti, D. C. Flores, J. L. Malavolta, and M. A. P. Martins
Vol 51
CO2Et
CO2Et
signals assignable to diastereotopic hydrogens at the 4-C
position of the isoxazole, with typical chemical shift
values (3b, d 3.1–3.37ppm and a JH–H coupling constant
of 18.3 Hz; 4b, d 3.23–3.66 ppm, JH–H = 18.5 Hz). Interest-
ingly, the two methylenes of the propanoate chain
were characterized as a broad singlet signal at d 2.7 ppm.
Compounds 3b and 4b were reacted with sulfuric acid
for dehydration/aromatization of the isoxazole ring. After
4-h stirring at 40ꢀC, we isolated the aromatic derivatives
5a and 6a, both resulting from dehydration at the isoxazole
ring and hydrolysis of the ester function of the acid. The
3-(5-trihalomethylisoxazol-3-yl) propanoic acids (5a, 6a)
were obtained as colorless solids after purification by
CO2Et
N
N
N
N
H
H
N
N
H
CO2Et
CO2Et
Figure 1. 3-(Imidazol-4-yl)propanoates and propenoates as a-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid antagonists.
Scheme 1. Process to acylate exclusively methyl site.
O
MeO OMe
OH
i
OMe
1
recrystallization from acetone. The H NMR spectrum of
O
O
5a exhibits a singlet at d 6.63 ppm for the aromatic isoxazole
4-H. The aromatic isoxazole was also confirmed by observa-
tion of 13C NMR signals at d 162.6, d 105.5, and d 159 ppm
for 3-C, 4-C, and 5-C, respectively. Assignment of 5-C was
easy because it resonates as a quartet, with a characteristic
2JCF = 42.6 Hz [13,24,25].
LA
methyl 4,4-dimethoxypentanoate
ii
i. 3 HC(OCH3)3, p-TosOH,
25°C, 24 h, 93%
OMe
O
OMe
X3C
Reacting 1 with hydroxylamine hydrochloride in
aqueous medium to obtain propanoic acid 5a in one step
was successful; after 24 h under reflux, pure propanoic acid
5a (Scheme 2) was isolated. However, the same reaction
conditions for precursor 2 lead to the propanoic acid 7a,
which is derived from three steps: the aromatization of the
isoxazole ring, the hydrolysis of ester function, and finally
the hydrolysis of trichloromethyl to a carboxylic moiety.
-
ii. X3CCOZ (X= F, Z= F3CO2
or X= Cl, Z= Cl), pyridine,
0 to 25°C, 16 h. 1 87%, 2 94%
O
1, 2
X = F, Cl
Scheme 2. Synthesis of isoxazole derivatives.
CO2Me
1
This was confirmed by a H NMR spectrum in DMSO,
i
which exhibits a singlet signal at d 7.08 ppm representing
the aromatic isoxazole 4-H and a broad singlet at
10.58 ppm representing the carboxyl group at the 5-C posi-
tion of the isoxazole ring. A 13C NMR spectrum exhibits
two signals at d 164.2 and d 173.7 ppm, both for carboxyl
groups [26,27].
HO
N
X3C
O
3b, 4b
ii
(X = Cl)
CO2H
O
OMe CO2Me
iii
X = F
The cyclocondensation of 1 with hydrazine monohydrate
was performed in a molar ratio of 1:1.2 using water,
methanol, or ethanol as the solvent [28–30]. All mixtures
were stirred at 65ꢀC for 12 h; the solvent was evaporated
under reduced pressure; and the products were dissolved in
CHCl3, dried with Na2SO4, and isolated. When these
reactions were performed in acid medium, pyrazole 8 was
obtained. When the reaction was conducted in ethanol, 9
promoted the transesterification of the methyl ester (CO2Me)
into ethyl ester (CO2Et); when the reaction was conducted
in water, 9 promoted the hydrolysis of the methyl ester to
carboxylic acid. The 3-(5-trifluoromethyl pyrazol-3-yl)
propanoic acid (8a) was obtained in pure form as a colorless
solid; alkyl 3-(5-trifluoromethylpyrazol-3-yl)propanoates
(8b, c) were obtained in pure form as yellow-red oils.
The 1H NMR spectra of 8a–c exhibit a singlet around
d 6.4–6.6 ppm for the aromatic pyrazole 4-H. The aromatic
pyrazole also was confirmed by the observation of 13C
NMR signals at d 144, d 101, and d 141 ppm for 3-C, 4-C,
X3C
N
X3C
O
1, 2
5a, 6a
Compound
X
CO2H
1, 3, 5
2, 4, 6
F
Cl
iii
N
HO2C
X = Cl
O
i. NH2OH. HCl, Pyridine, MeOH
65°C, 8 h. 70-95% yield.
7a
ii. H2SO4, 40 °C, 4 h. 60-75% yield..
iii. NH2OH.HCl, H2O, 100 °C, 12 h. 68-75% yield.
in 90–95% yields (Scheme 2). These compounds were
obtained as colorless crystalline solids, after purification by
recrystallization from hexane.
Compounds 3b and 4b were characterized as
dihydroisoxazoles by 1H/13C NMR spectra in CDCl3.
1
The H NMR spectra of 3b and 4b exhibit two doublet
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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From Renewable Levulinic Acid to a Diversity of 3-(Azol-3-yl)propanoates
735
and 5-C, respectively. The assignment of 5-C was
easy because it resonates as a quartet, with a characteristic
However, despite our best efforts to retain CCl3, all
reactions of 2 and RNHNH2 (R═H or Ph) produced
some proportion of 1H-pyrazole-5-carboxylate. Even using
aprotic solvent at low temperature, we obtained a mixture
of trichloromethylpyrazole and its respective carboxyl
derivatives. The 1H-pyrazole-5-carboxylates 11b and c were
prepared pure in water or alcoholic (MeOH or EtOH) solvent
at 70ꢀC (Scheme 4). Products 10a–c and 11b and c were
isolated as colorless crystalline solids. The structures of
isolated compounds were assigned by MS and 1H/13C
NMR spectroscopy data. X-ray diffraction enabled us to
observe that compound 10c exists as tautomer ethyl 5-(3-
methoxy-3-oxopropyl)-1H-pyrazole-3-carboxylate, which
is crystallized as a catemer along the ab plane [33] (Fig. 2).
Condensation of 2 with phenylhydrazine in water at 70ꢀC
produced a mixture of the 1,5- and 1,3-regioisomers 11a
and 12a.
To expand sampling diversity from LA, we conducted
condensations between precursors 1 and 2 and semicarbazide
hydrochloride, thiosemicarbazide, and methyl hydrazine
carboxylate (Scheme 5). These reactions proceeded
smoothly in MeOH to produce the respective methyl 3-(5-
hydroxy-5-trihalomethyl-4,5-dihydro-1H-pyrazol-3-yl)
propanoates (13b–18b). The acyl substituent at the N1-
position guarantees the stability of 5-trihalomethyl-5-
hydroxy-4,5-dihydro-1H-pyrazole products because of the
electron-withdrawing effect of the amide carbonyl group.
Dehydration of propanoates 13b–18b could not be achieved
without the parallel hydrolysis of the N1carboxyls. The
1H NMR spectra of 13b–18b exhibit two doublet signals
assignable to diastereotopic hydrogens at the 4-C position
of the 1H-pyrazole, with values typical of chemical shifts,
d 3.2–3.7 ppm, and the coupling constant JH–H = 19 Hz.
2JCF = 33.7 Hz. Reactions between
1 and hydrazine
hydrochloride produced 1H-pyrazoles 8a–c in low yields
and used the large excess amount of hydrazine only under
pyridine assistance.
Cyclocondensations between precursor 1 and free
phenylhydrazine to form pyrazoles were performed in a
molar ratio of 1:1.2 using water, methanol, or ethanol as
the solvent [31]. All mixtures were initially stirred for 1 h at
0–5ꢀC and after for 12 h at 25ꢀC, and the solvent was
evaporated under vacuum. The residue was dissolved in
chloroform and washed with water two times, and methyl
3-(5-trifluoromethyl-1-phenyl-1H-pyrazol-3-yl)propanoate
(9b) was obtained in pure form as red-brown oil. At this
condition, transesterification did not occur; to obtain
pyrazoles 9a and 9c, the cyclization reaction between 1
and phenylhydrazine hydrochloride was performed in
water or ethanol. The mixtures were stirred at reflux for
8 h. This led to the formation of ethyl 3-(5-trifluoromethyl-
1-phenylpyrazol-3-yl)propanoate (9c) in a good (68%) yield.
This cyclocondensation in water to obtain 9a creates a
complex mixture of products with proposed structures
supported by mass and 1H/13C NMR spectra. The 1H NMR
spectra of 9b and c exhibit a singlet at 6.4–6.6 ppm represent-
ing the aromatic pyrazole 4-H and multiplet signals at
high field 2.7–3.0 ppm for propanoate methylenes. Aromatic
pyrazoles are also confirmed through 13C NMR signals at
d 151, d 108, and d 132 ppm for 3-C, 4-C, and 5-C, respec-
tively. Assignment of 5-C was straightforward because it
2
resonates as a quartet, with characteristic JCF = 38 Hz.
Similarly, the use of free phenyl hydrazine improved the
yield compared with the phenylhydrazine hydrochloride
previously tested (Scheme 3).
The cyclocondensations between 2 and hydrazines were
conducted in two ways. First, our goal was to retain the
trichloromethyl group allowing us to obtain trichloromethyl-
1H-pyrazoles; second, we conducted one-pot cyclocondensa-
tion and hydrolysis of trichloromethyl to the carboxyl group
and obtained 1H-pyrazole carboxylates [32].
Scheme 4. Synthesis of 1H-pyrazole-5-carboxylate.
CO2R
O
OMe CO2Me
i, ii
Cl3C
N
N
Cl3C
N
2
1
R
Scheme 3. Synthesis of aromatic trifluoromethyl-1H-pyrazoles.
i. NH2NH2. H2O, ROH (R =H, Me, Et)
CO2R
CO2R
65°C, 8 h.
O
OMe CO2Me
ii. a) NH2NHPh, ROH ( R = Me, Et),
i, ii, iii
25 °C, 30 min., then reflux, 8 h.
F3C
N
RO2C
F3C
N
N
1
1
1
R
R
Compound R1
R
yield (%)
Compound R1
R
H
yield (%)
93
i. NH2NHR1. H2O, ROH (R =H, Me, Et)
65°C, 8-12 h.
10a
10b
10c
11b
11c
H
H
H
H
93
94
77
94
68
8a
H
Me
Et
ii. NH2NHPh, MeOH 0 to 5 °C, 30 min.
then reflux °C, 8 h (9b).
8b
8c
9b
9c
H
H
Me
Et
94
77
94
68
Ph Me
Ph Et
Ph Me
Ph Et
iii. NH2NHPh.HCl, EtOH 0 to 5 °C, 30 min.
then reflux °C, 8 h (9c).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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A. F. C. Flores, L. A. Piovesan, L. Pizzuti, D. C. Flores, J. L. Malavolta, and M. A. P. Martins
Vol 51
Figure 2. X-ray structure of 10c. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 5. 5-Trihalomethyl-5-hydroxy-4,5-dihydro-1H-pyrazoles.
CO2Me
Finally, precursor 1 was reacted with tetraelectrophilic
aminoguanidine hydrochloride [34,35]. Several conditions
were tested for obtaining methyl 3-(1-carboxyamidino-5-
trifluoromethyl-5-hydroxy-4,5-dihydro-1H-pyrazol-3-yl)
propanoate, and even under large excess of
aminoguanidine, we always obtained pyrazolyl–pyrimidine
19b. Then, we allowed precursor 1 to react with
aminoguanidine in a 2:1 molar proportion between 1 and
aminoguanidine hydrochloride in MeCN and, after purifica-
tion by recrystallization from hexane, obtained 19b as a
pure colorless solid in 65% yield (Scheme 6). The structure
O
OMe CO2Me
HO
i, ii
X3C
N
X3C
N
1, 2
Y
R1
13b-18b
i. NH2NHCONH2.HCl, Py, MeOH/H2O,
65 °C, 18 h.
X
F
Y
R1
ii. NH2NHC(=Y)R1, MeOH, 50 °C, 18 h.
1
of 19b was determined by MS and H/13C NMR spectral
13b
O
O
S
NH2
NH2
NH2
NH2
OMe
OMe
14b Cl
15b
16b Cl
17b
18b Cl
data. The product methyl 3-{2-[5-hydroxy-3-(3-methoxy-3-
oxopropyl)-5-trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl]-
6-trifluoromethyl pyrimidin-4-yl}propanoate (19b) was
dehydrated to its respective bis-aromatic pyrazolyl–
pyrimidine, 20b, using H2SO4 98%. The methyl 3-{2-[3-(3-
methoxy-3-oxopropyl)-5-trifluoromethyl-1H-pyrazol-1-
yl]-6-(trifluoromethyl)pyrimidin-4-yl}propanoate (20b) was
obtained as a colorless solid when precipitated from cooled
diluted acid solution. We were unable to obtain some product
from precursor 2 and aminoguanidine hydrochloride.
F
S
F
O
O
Again, as in 4,5-dihydroisoxazole, the two methylenes of the
propanoate chain were characterized as a broad singlet signal
at d 2.7 ppm. The structure of the 5-trihalomethyl-5-
hydroxy-4,5-dihydro-1H-pyrazole was also supported by
MS and 13C NMR data.
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From Renewable Levulinic Acid to a Diversity of 3-(Azol-3-yl)propanoates
737
Scheme 6. Synthesis of pyrazolyl–pyrimidine derivatives.
CO2Me
Methyl 3-(5-hydroxy-5-trihalomethyl-4,5-dihydroisoxazol-3-yl)
propanoates (3b and 4b). A solution of methyl 7,7,7-trihalo-
4-methoxy-6-oxo-4-heptenoate 1 or 2 (5 mmol), hydroxylamine
hydrochloride (7.5mmol), and pyridine (7.5mmol) in MeOH
or EtOH (10 mL) was stirred for 8 h at 65ꢀC. The solvent
was removed, and the residue was dissolved in CHCl3 (20 mL)
and washed with HCl 10% (10mL). The solution was dried
over Na2SO4, and the solvent was evaporated, producing 3b or
4b. The products were purified by recrystallization in hexane. 3b
O
OMe CO2Me
i
HO
F3C
N
F3C
N
1
H2N
NH
1
(850mg, 70%), mp 78–79ꢀC, H NMR (CDCl3, 400 MHz) d 2.7
1
(large s, 4H, 2CH2), 3.1 (d, J = 18.2Hz, 1H, H4), 3.37
(d, J = 18.2Hz, 1H, H4), 3.72 (s, 3H, OMe). 13C NMR
(CDCl3, 100 MHz) d 23.2 (CH2), 30.4 (CH2), 45.6 (C-4), 52.6
(OMe), 103.3 (q, JC–F = 34.3 Hz, C-5), 122.3 (q, JC–F = 283.8 Hz,
CF3), 158.8 (C-3), 173.5 (C═O). MS [m/z(%)] 241 (M+, <5),
224 (–OH, 14), 210 (–OMe, 100), 182 (–C(O)OMe, 55), 172
(–CF3, 39), 164 (26), 140 (74), 112 (40), 68 (CF3, 46), 59 (78).
C8H10F3NO4: C, 39.80; H, 4.07; N, 5.64; found C, 39.50;
H, 4.17; N, 5.74. 4b (1.4g, 95%), mp 80–82ꢀC, 1H NMR
CO2Me
CO2Me
HO
N
N
N
N
F3C
F3C
ii
F3C
N
N
N
N
F3C
CO2Me
CO2Me
(CDCl3, 400MHz)
d 2.71 (large s, 4H, 2CH2), 3.23
20b
19b
(d, J = 18.5 Hz, 1H, H4), 3.66 (d, J = 18.5Hz, 1H, H4), 3.71
(s, 3H, OMe). 13C NMR (CDCl3, 100 MHz) d 23.1 (CH2), 30.1
(CH2), 46.5 (C4), 52.1 (CH3), 100.8 (CCl3), 110.8 (C5), 159 (C3),
172.8 (C═O). MS [m/z(%)] 289 (M+, <5), 274 (–OH, 5), 258
(–OMe, 18), 172 (–CCl3, 28), 140 (100), 87 (28), 59 (61). Anal.
Calcd for C8H10Cl3NO4: C, 33.07; H, 3.47; N, 4.82; found
C, 33.17; H, 3.48; N, 4.79.
i. NH2NH(C=NH)NH2.HCl, Py, MeOH, 65 °C, 18 h.
ii. H2SO4 98%, 40 °C, 4 h.
EXPERIMENTAL
1H and 13C NMR spectra were collected at 300 K using a 5-mm
dual probe on a Bruker DPX 400 spectrometer (1H at 400.13 MHz
and 13C at 100.62 MHz (UFSM, Santa Maria, RS, Brazil)).
Chemical shifts (d) are quoted in parts per million (ppm) from
TMS, and coupling constants (J) are given in Hz. Melting points
were determined using open capillaries on an Electrothermal
Mel-Temp 3.0 apparatus (Barnstead Thermoline, Dubuque, IA).
Mass spectra were registered in an Agilent HP 5973 MSD
connected to a HP 6890 GC and interfaced using a Pentium PC
(Agilent Technologies, Santa Clara, CA). The GC was equipped
with a split–splitless injector, cross-linked to an HP-5 capillary
column (30 m, 0.32 mm i.d.), and helium was used as the carrier
gas. The CHN elemental analyses were performed on a Perkin-Elmer
2400 CHN elemental analyzer (São Paulo University, USP/Brazil).
The diffraction measurements were performed by graphite mono-
chromatized Mo Ka radiation with k= 0.71073 Å on a Bruker
SMART CCD diffractometer [36]. The structure was solved with
direct methods using the SHELXS-97 program [37] and refined on
F2 by full-matrix least-squares using the SHELXL-97 package
[38]. The absorption correction was performed by Gaussian methods
[39]. Anisotropic displacement parameters for nonhydrogen atoms
were applied. The hydrogen atoms were placed at calculated
positions with 0.96 Å (methyl CH3), 0.97 Å (methylene CH2),
0.98 Å (methine CH), 0.93 Å (aromatic CH), and 0.82 Å (OH) using
a riding model. The hydrogen 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 109.5ꢀ, and the H atoms
were allowed to rotate around the C–C bond. The molecular graph
was prepared using ORTEP3 for Windows [40]. Crystallographic
data for the structure of 10c have been deposited with the
Cambridge Crystallographic Data Centre and allocated deposition
number CCDC 849417. 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).
3-(5-Trifluoromethylisoxazol-3-yl)propanoic acid (5a).
A
solution of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-heptenoate 1
(5 mmol) and hydroxylamine hydrochloride (7.5 mmol) in H2O
(10 mL) was stirred for 12h at reflux. The solution was extracted
with CHCl3 (3 ꢁ 10 mL). The organic solution was dried with
Na2SO4, and the solvent was evaporated, which gave the pure
propanoic acid 5a (750 mg, 72%). Decomposed at >180ꢀC,
1H NMR (DMSO-d6, 400 MHz) d 2.86 (t, J = 6.9 Hz, 2H, CH2),
3.08 (t, J = 7.0 Hz, 2H, CH2), 6.63 (s, 1H, H4). 13C NMR
(DMSO-d6, 100 MHz) d 21.3 (CH2), 31.7 (CH2), 105.5 (C4), 118.0
(q, JC–F =270Hz, CF3), 159 (q, JC–F = 43 Hz, C5), 162.6 (C3), 178.0
(C═O). MS [m/z(%)] 191 (ꢂOH, 25), 163 (ꢂC(O)OH, 15), 140
(ꢂCF3, <5), 94 (53), 68 (CF3, 100). Anal. Calcd for C7H6F3NO3:
C, 40.2; H, 2.89; N, 6.70; found C, 40.17; H, 3.00; N, 6.65.
3-(5-Trichloromethylisoxazol-3-yl)propanoic acid (6a). To
the respective 4,5-dihydroisoxazole 4b (1 mmol) was added H2SO4
98% (2.5 mL) at 50ꢀC. The mixture was stirred for 4 h. After the
acidic solution was diluted with cooled water, the precipitated solid
was filtered and dried over CaCl2 under vacuum, which gave the
pure propanoic acid 6a (200 mg, 69%). Decomposed at >180ꢀC, 1H
NMR (D2O, 400 MHz) d 2.65 (t, J= 7.2 Hz, 2H, CH2), 2.91
(t, J= 7.2 Hz, 2H, CH2), 7.1 (s, 1H, H-4). 13C NMR (D2O, 100 MHz):
d 21.7 (CH2), 31.4 (CH2), 110.1 (C-4), 108.2 (CCl3), 160.6 (C-5),
160.5 (C-3), 173 (C═O). MS [m/z(%)] 258 (M+, <5), 239 (ꢂOH,
10), 221 (ꢂCl, 100), 68 (23), 55 (14). Anal. Calcd for C7H6Cl3NO3:
C, 32.53; H, 2.34; N, 5.42; found C, 32.45; H, 2.50; N, 5.4.
3-(2-Carboxyethyl)isoxazole-5-carboxylic acid (7a).
A
solution of methyl 7,7,7-trichloro-4-methoxy-6-oxo-4-heptenoate
2 (5mmol) and hydroxylamine hydrochloride (7.5mmol) in H2O
(10 mL) was stirred for 12 h at reflux. The solution was extracted
with CHCl3 (3ꢁ 10mL). The organic solution was dried with
Na2SO4, and the solvent was evaporated, which gave the pure
propanoic acid 7a (785 mg, 85%). Decomposed at >200ꢀC,
1H NMR (DMSO-d6, 400MHz): d 2.65 (s, 2H, CH2), 2.89
(s, 2H, CH2), 7.08 (s, 1H, H4), 10.32 (bulky s, OH). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

738
A. F. C. Flores, L. A. Piovesan, L. Pizzuti, D. C. Flores, J. L. Malavolta, and M. A. P. Martins
Vol 51
(DMSO-d6, 100MHz) d 21.7 (CH2), 31 (CH2), 109.6 (C4), 158.4
(C5), 161.3 (C3), 164.3 (C═O), 173.8 (C═O). Anal. Calcd
for C7H7NO5: C, 48.25; H, 3.81; N, 7.57; found C, 48.2; H, 3.95; N, 7.45.
7.45 (m, 5H, Ph). 13C NMR (CDCl3, 100 MHz) d 14 (Me), 21.4
(CH2), 32.7 (CH2), 60.8 (OCH2), 103.4 (C4), 121.3 (q, JC–F =269Hz,
CF3), 142.7 (q, JC–F = 38 Hz, C-5), 125.3–138.6 (m, 5H, Ph), 143.8
(C3), 171.6 (C═O). MS [m/z(%)] 312 (M+, 64), 267 (–OEt, 25), 239
(–C(O)OEt, 100), 77 (Ph, 35).C15H15F3N2O2: C, 56.38; H, 4.39; N,
9.39; found C, 56.6; H, 4.57; N, 9.3.
3-(5-Trifluoromethyl-1H-pyrazol-3-yl)propanoic acid (8a).
A
solution of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-heptenoate 1
(5 mmol) and hydrazine monohydrate (5 mmol) in H2O (10mL) was
stirred for 12 h at reflux. The solution was extracted with CHCl3
(3 ꢁ 10 mL). The organic solution was dried with Na2SO4, and the
solvent was evaporated, which gave the pure propanoic acid 8a
(975 mg, 93%). mp 88–89ꢀC, 1H NMR (DMSO-d6, 400 MHz)
d 2.61 (t, J= 7.5 Hz, 2H, CH2), 2.87 (t, J= 7.5 Hz, 2H, CH2), 6.46
(s, 1H, H-4), 12.27 (s, OH), 13.35 (s, NH). 13C NMR (DMSO-d6,
100 MHz) d 20.3 (CH2), 32.7 (CH2), 101.5 (C4), 121 (q,
JC–F = 268 Hz, CF3), 141 (q, JC–F = 34 Hz, C5), 144.3 (C3), 173.3
(C═O). MS [m/z(%)] 208 (M+ 57), 191 (ꢂOH, <5), 163 (ꢂCOOH,
100), 143 (ꢂCF3, 41), 101 (32), 75 (CH2CH2C(O)OH, 39), 69
(CF3, 12), 67 (11), 55 (<5). Anal. Calcd for C7H7F3N2O2: C, 40.39;
H, 3.39; N, 13.46; found C, 40.4; H, 3.45; N, 13.15.
3-(2-Carboxyethyl)-1H-pyrazole-5-carboxylic acid (10a).
A
solution of methyl 7,7,7-trichloro-4-methoxy-6-oxo-4-heptenoate 2
(5 mmol) and hydrazine monohydrate (6 mmol) in H2O (5mL) was
stirred for 8 h at reflux. The solution was extracted with CHCl3
(3 ꢁ 10 mL). The organic solution was dried with Na2SO4, and the
solvent was evaporated, which gave the pure propanoic acid 10a
(625 mg, 68%). Decomposed at >150ꢀC. 1H NMR (DMSO-d6,
400 MHz) d 2.59 (t, J= 7.5 Hz, 2H), 2.83 (t, J=7.5Hz, 2H), 6.5
(s, 1H, H4), 11.2 (bulky s, 3H, NH, OH). 13C NMR (DMSO-d6,
100 MHz) d 21.3 (CH2), 33.1 (CH2), 106.2 (C4), 140.6 (C5), 146.4
(C3), 162.4 (C═O), 173.4 (C═O). Anal. Calcd for C7H8N2O4:
C, 45.66; H, 4.38; N, 15.21; found C, 45.45; H, 4.64; N, 15.5.
Alkyl 3-(5-trifluoromethyl-1H-pyrazol-3-yl)propanoates 8b
Alkyl
3(5)-(3-alkoxy-3-oxopropyl)-1H-pyrazole-5(3)-
A solution of methyl 7,7,7-
and 8c.
A solution of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-
carboxylates 10b and 10c.
heptenoate 1 (5 mmol) and hydrazine monohydrate (5 mmol) in
MeOH (10 mL, 8b) or EtOH (10mL, 8c) was stirred for 8 h at 65ꢀC.
The solvent was removed, and the residue was dissolved in CHCl3
(20mL) and washed with H2O (10 mL). The solution was dried with
Na2SO4, and the solvent was evaporated, which gave the pure
trichloro-4-methoxy-6-oxo-4-heptenoate 2 (5mmol) and hydrazine
monohydrate (5 mmol) in MeOH (10mL, 10b) or EtOH
(10 mL, 10c) was stirred for 8 h at reflux. The solvent was
removed, and the residue was dissolved in CHCl3 (20mL) and
washed with H2O (10mL). The solution was dried with Na2SO4,
and the solvent was evaporated, which gave the respective
alkyl carboxylate. The products were purified by recrystallization
in hexane. 10b (985mg, 93%). mp 60–61ꢀC, 1H NMR
(CDCl3, 400MHz) d 2.7 (t, J = 7 Hz, 2H, CH2), 3.03 (t, J = 7.1Hz,
2H, CH2), 3.7 (s, 3H, OMe), 3.88 (s, 3H, OMe), 6.62 (s, 1H, H4).
13C NMR (CDCl3, 100MHz) d 21.7 (CH2), 33.7 (CH2), 52.4
(2OMe), 107.1 (C4), 141.4 (C5), 146.5 (C3), 162.6 (C═O), 173.6
(C═O). MS [m/z(%)] 212 (M+, 20), 181 (–OMe, 22), 152 (–C(O)
OMe, 29), 121 (–OMe, 100), 94 (–C(O)OMe, 5), 79 (17), 66 (23).
Anal. Calcd for C9H12N2O4: C, 50.94; H, 5.70; N, 13.20;
found C, 50.92; H, 5.73; N, 13.15.
1
respective alkyl propanoate 8b (1.0 g, 94%), as red-yellow oil. H
NMR (CDCl3, 400 MHz) d 2.7 (t, J= 6.8 Hz, 2H, CH2), 3.02 (t,
J= 6.8 Hz, 2H, CH2), 3.72 (s, OMe), 6.35 (s, 1H, H4). 13C NMR
(CDCl3, 100 MHz) d 20.6 (CH2), 33.27 (CH2), 52.3 (OMe), 102.3
(C4), 121.4 (q, JC–F = 268 Hz, CF3), 143.1 (q, JC–F =38Hz, C5),
144.1 (C3), 173.6 (C═O). MS [m/z(%)] 222 (M+, 14), 163 (ꢂC(O)
OCH3, 100), 69 (CF3, <5). Anal. Calcd for C8H9F3N2O2: C, 43.25;
H, 4.08; N, 12.61; found C, 43.4; H, 4.15; N, 12.35.
8c (1.1 g, 77%), as red-yellow oil. 1H NMR (CDCl3, 400 MHz)
d 1.26 (t, J = 7.1 Hz, 3H, Me), 2.68 (t, J = 6.8 Hz, 2H, CH2), 3.01
(t, J = 6.8 Hz, 2H, CH2), 4.17 (q, 2H, OCH2), 6.35 (s, 1H, H4).
13C NMR (CDCl3, 100 MHz) d 14.2 (Me), 20.6 (CH2), 33.5
(CH2), 61.4 (OCH2), 102.3 (C4), 121.5 (q, JC–F = 268 Hz, CF3),
143.1 (q, JC–F = 37 Hz, C5), 144.1 (C3), 173.3 (C═O). MS
[m/z(%)] 236 (M+, 43), 191 (–OEt, 14), 162 (–C(O)OEt, 100),
149 (32), 69 (CF3, <5). Anal. Calcd for C9H11F3N2O2:
C, 45.77; H, 3.81; N, 11.86; found C, 45.85; H, 3.95; N, 11.55.
10c (1.05 g, 87%). mp 87–88ꢀC, 1H NMR (CDCl3, 400 MHz)
d 1.16 (t, 3H, J = 7.1 Hz, Me), 1.28 (t, 3H, J = 7.1 Hz, Me), 2.61
(t, 2H, J = 7.1 Hz, CH2), 2.96 (t, 2H, J = 7.1 Hz, CH2), 4.07
(t, 2H, J = 7.1Hz, OCH2), 4.28 (q, 2H, J =7.1 Hz, OCH2), 6.55
(s, 1H, H4), 10.03 (bulky s, 1H, NH). 13C NMR (CDCl3,
100 MHz) d 14.1 (Me), 14.2 (CH3), 21.5 (CH2), 33.5 (CH2),
60.8 (OCH2), 61.0 (OCH2), 106.7 (C-4), 140.7 (C-5), 146.7 (C-3),
161.4 (C═O), 172.9 (C═O). MS [m/z(%)] 240 (M+ 11), 195
(–OEt), 167 (–CO2Et, 33), 149 (53), 121 (100), 79 (23), 66 (24),
53 (24). Anal. Calcd for C11H16N2O4: C, 54.99; H, 6.71;
N, 11.66; found C, 55.17; H, 6.77; N, 11.60.
Alkyl
3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)
propanoates 9b and 9c. To a stirred solution of methyl 7,7,7-
fluoro-4-methoxy-6-oxo-4-heptenoate 1 (5 mmol) in MeOH (5 mL)
was added a solution of phenylhydrazine (5 mmol) in MeOH (5 mL)
at 0–5ꢀC. Then, the mixture was stirred for 8 h at reflux. After that,
the solution was dried with Na2SO4 and filtered, and the solvent was
removed, which gave the pure respective alkyl propanoate 9b (1.4 g,
94%) as yellow oil. 1H NMR (CDCl3, 400 MHz) d 2.73 (t,
J= 7.2 Hz, 2H, CH2), 3.02 (t, J= 7.2 Hz, 2H, CH2), 3.68 (s, 3H,
OMe), 6.62 (s, 1H, H4), 7.44 (m, 5H, Ph). 13C NMR (CDCl3,
100 MHz) d 23.6 (CH2), 33.6 (CH2), 52.1 (Me), 108.3 (C4), 120.1
(q, JC–F = 269 Hz, CF3), 127.5 (q, JC–F = 39 Hz, C-5), 152 (C3), 173
(C═O). MS [m/z(%)] 298 (M+, 28), 267 (–OMe, 16), 239 (–C(O)
OMe, 100), 77 (Ph, 47). Anal. Calcd for C14H13F3N2O2: C, 57.69;
H, 4.84; N, 8.97; found C, 57.83; H, 4.97; N, 8.8.
Alkyl 3-(3-methoxy-3-oxopropyl)-1-phenyl-1H-pyrazole-5-
carboxylates 11b and 11c. A solution of methyl 7,7,7-trichloro-
4-methoxy-6-oxo-4-heptenoate
2
(5 mmol) phenylhydrazine
hydrochloride (5 mmol) in MeOH (10 mL, 11b) or EtOH (10mL,
11c) was stirred for 30 min at 25ꢀC and after for 8 h at reflux. The
solvent was removed, and the residue was dissolved in CHCl3
(20 mL) and washed with H2O (10 mL). The solution was dried
with Na2SO4, and the solvent was evaporated, which gave the
respective alkyl carboxylate. The products were purified by
recrystallization in hexane. 11b (1,4g, 94%). mp 44–45ꢀC, 1H
NMR (CDCl3, 400 MHz) d 2.75 (t, J = 7.5Hz, 2, CH2), 3.05
(t, J = 7.5 Hz, 2H, CH2), 3.71 (s, 3H, OMe), 3.78 (s, 3H, OMe),
6.85 (s, 1H, H4), 7.43 (m, 5H, Ph). 13C NMR (CDCl3, 100MHz):
d 23.5 (CH2), 33.6 (CH2), 51.9 (OMe), 52.1 (OMe), 111.5 (C4),
126–140.3 (Ph), 133.6 (C5), 151.7 (C3), 159.7 (C═O), 173.4
For 9a and 9c was used a solution of phenylhydrazine
hydrochloride (5 mmol) in water or EtOH repeating the same
procedure. 9c (1.1 g, 68%) as yellow oil. 1H NMR
(CDCl3, 400 MHz) d 1.2 (t, 3H, Me), 2.58 (t, J= 7.5 Hz, 2H, CH2),
2.96 (t, J= 7.4 Hz, 2H, CH2), 4.1 (q, 2H, OCH2), 6.45 (s, 1H, H4),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
From Renewable Levulinic Acid to a Diversity of 3-(Azol-3-yl)propanoates
739
(C═O). MS [m/z(%)] 288 (M+, 32), 257 (–OMe, 14), 229 (–C(O)
OMe, 100), 77 (Ph, 23). Anal. Calcd for C15H16N2O4: C, 62.49;
H, 5.59; N, 9.72; found C, 62.55; H, 5.75; N, 9.85.
16b (1.30 g, 73%). mp 131–132ꢀC,
1H NMR (CDCl3,
400 MHz): d 2.7 (m, 4H), 3.36 (d, J = 19 Hz, 1H, H-4), 3.62
(d, J = 19 Hz, 1, H4), 3.69 (s, 3H, OMe), 9.0 (s, 1H). 13C NMR
(CDCl3, 100 MHz): d 25.3 (CH2), 30.0 (CH2), 50.0 (C-4), 52.2
(OMe), 102.4 (C5), 104.3 (CCl3), 159.4 (C3), 172.4 (C═O),
179.2 (C═S). Anal. Calcd for C9H12Cl3N3O3S: C, 31.01; H,
3.47; N, 12.05; found C, 31.06; H, 3.54; N, 12.05.
11c (1.47 g, 93%). mp 59–60ꢀC, 1H NMR (CDCl3, 400 MHz)
d 1.2 (t, 3H, Me), 1.36 (t, 3H, Me), 2.58 (t, J = 7.5, 2H, CH2), 2.93
(t, J = 7.5 Hz, 2H, CH2), 4.08 (q, J = 7.2 Hz, 2H, OCH2), 4.38
(q, J= 7.2 Hz, 2H, OCH2), 6.73 (s, 1H, H4), 7.43 (m, 5H, Ph). 13
C
NMR (CDCl3, 100 MHz): d 14.3 (Me), 14.6 (Me), 21.7 (CH2),
33.6 (CH2), 61.0 (OCH2), 61.2 (OCH2), 107.9 (C4), 126.1–143.9
(Ph), 139.1 (C5), 144.2 (C3), 162.7 (C═O), 171.9 (C═O). MS [m/z
(%)] 316 (M+, 53), 271 (–OEt, 50), 243 (–CO2 Et, 49), 197 (100),
171 (57), 77 (Ph, 48). Anal. Calcd for C17H20N2O4: C, 64.54; H,
6.37; N, 8.85; found C, 64.55; H, 6.45; N, 8.75.
Methyl 3-(3-methoxy-3-oxopropyl)-5-trifluoro[chloro] methyl-
1H-pyrazole-1-carboxylate 17b, 18b. A solution of methyl 7,7,7-
trihalo-4-methoxy-6-oxo-4-heptenoate 1 or 2 (2 mmol) and hydrazine
methyl carboxylate (2.4 mmol) in methanol (10 mL) was stirred for
18 h at 25ꢀC. The solvent was removed, and the residue was
dissolved in CHCl3 (10 mL) and washed with water (10 mL). The
solution was dried with Na2SO4, and the solvent was evaporated,
which gave the pure respective methyl propanoate 17b (480 mg,
Methyl 3-(1-carbamoyl-5-hydroxy-5-trifluoro [chloro]methyl-
4,5-dihydro-1H-pyrazol-3-yl)propanoates 13b and 14b.
A
1
79%). mp 81–82ꢀC, H NMR (CDCl3, 400 MHz) d 2.68 (s, 4H,
solution of methyl 7,7,7-trihalo-4-methoxy-6-oxo-4-heptenoates 1
or 2 (5 mmol), semicarbazide hydrochloride (6 mmol), and pyridine
(6 mmol) in MeOH (3 mL) : H2O (9 mL) was stirred for 18 h at
65ꢀC. MeOH was removed, and aqueous residue was extracted
with CHCl3 (3 ꢁ 10 mL) and washed with HCl 10% solution
(10 mL). The solution was dried with Na2SO4, and the solvent
was evaporated, which gave the respective alkyl propanoates
13b and 14b. The products were purified by recrystallization in hexane.
13b (1.4 g, 98%). mp 106–107ꢀC, 1H NMR (CDCl3, 400MHz) d 2.66
(bulky s, 4H, 2CH2), 3.13 (d, J= 19 Hz, 1H, H4), 3.3 (d, J=19Hz, 1H,
H4), 3.7 (s, 3H, OMe), 5.95 (s, 2H, NH2), 6.32 (s, 1H, OH).
13C NMR (CDCl3, 100 MHz) d 24.93 (CH2), 30.05 (CH2),
46.59 (C4), 52.01 (Me), 90.73 (q, J = 34 Hz, C-5), 123.25 (q,
J = 286 Hz, CF3), 154.98 (C3), 156.75 (CONH2), 172.66
(CO2Me). MS [m/z(%)] 283 (M+, 6), 239 (–CONH2, <44), 222
(–OH, 17), 209 (OMe, 17), 191 (-CO2 Me), 171 (–CF3, 76), 162
(52), 139 (100), 111 (61), 97 (57), 69 (CF3, 12), 55 (19). Anal.
Calcd for C9H12F3N3O4: C, 38.17; H, 4.27; N, 14.84; found
C, 38.37; H, 4.18; N, 14.45.
2CH2), 3.16 (d, JH–H = 19.1 Hz, 1H, H4), 3.30 (d, JH–H = 19.1 Hz,
1H, H4), 3.70 (s, 3H, OMe), 3.89 (s, 3H, OMe). 13C NMR (CDCl3,
100 MHz) d 24.7 (CH2), 30.3 (CH2), 45.6 (C4), 51.9 (OMe), 53.8
2
(OMe), 90.7(q, JC–F = 34 Hz, C5), 123 (q, JC–F = 286.5 Hz, CF3),
153.8 (C3), 156.2 (NCO2Me), 172.4 (CO2Me). MS [m/z(%)] 298
(M+, <5), 280 (40), 221 (49), 177 (100), 125 (90), 69 (CF3, 15), 59
(37). Anal. Calcd for C10H13F3N2O5: C, 40.28; H, 4.39; N, 9.39;
found C, 40.4; H, 4.5; N, 9.65.
1
18b (485 g, 70%). mp 73–74ꢀC, H NMR (CDCl3, 400 MHz)
d 2.70 (s, 4H, 2CH2), 3.28 (d, JH–H =19.11Hz, 1H, H4), 3.56
(d, JH–H = 19.11Hz, 1H, H4), 3.70 (s, 3H, OMe), 3.88 (s, 3H,
OMe), 6.84 (s, 1H, OH). 13C NMR (CDCl3, 100 MHz) d 25.1
(CH2), 30.3 (CH2), 48.5 (C4), 51.9 (OMe), 53.7 (OMe), 100.2
(C5), 103.5 (CCl3), 155.0 (C3), 158.3 (NCO2Me), 172.3 (CO2Me).
MS [m/z(%)] 348 (M+, <5), 319 (M+ + 4-Cl, <5), 317 (M+ + 2-Cl,
11), 315, (M+ ꢂ Cl, 11), 283 (<5), 229 (60), 197 (42), 153 (66),
111 (100), 59 (26). Anal. Calcd for C10H13Cl3N2O5: C, 34.56;
H, 3.77; N, 8.06; found C, 34.4; H, 3.90; N, 8.22.
14b (1.58 g, 95%). mp 114–115ꢀC, 1H NMR
(CDCl3, 400 MHz) d 2.68 (s, 4H, 2CH2), 3.28 (d, J = 19 Hz, 1H,
H4), 3.56 (d, J = 19 Hz, 1H, H4), 3.7 (s, 3, OMe), 7.60 (s, 1H)
13C NMR (CDCl3, 100 MHz): d 25.0 (CH2), 30.0 (CH2), 49.2
(C4), 51.9 (OMe), 100.6 (C5), 104.2 (CCl3), 157.3 (C3), 157.8
(CONH2), 172.3 (CO2Me). Anal. Calcd for C9H12Cl3N3O4:
C, 32.50; H, 3.64; N, 12.64; found C, 31.88; H, 3.54; N, 12.85.
Methyl 3-(1-carbamothioyl-5-hydroxy-5-(trihalome thyl)-4,5-
Methyl
trifluoromethyl-4,5-dihydro-1H-pyrazol-1-yl]-6-(tri fluo romethyl)
pyrimidin-4-yl)propanoate (19b). A solution of methyl 7,
7,7-fluoro-4-methoxy-6-oxo-4-heptenoate (4mmol) and
3-{2-[5-hydroxi-3-(3-metoxy-3-oxopropyl)-5-
1
aminoguanidine hydrochloride (2mmol) in acetonitrile (10 mL)
was stirred for 24 h at 80ꢀC. After the solvent was removed and
the residue was dissolved in chloroform (20mL) and washed with
water (2 ꢁ 10mL), the organic solution was dried with Na2SO4,
and the solvent was evaporated, which gave the bismethyl
dihydro-1H-pyrazol-3-yl)propanoates 15b, 16b.
A solution
of methyl 7,7,7-trihalo-4-methoxy-6-oxo- 4-heptenoate 1 or 2
(5 mmol) and thiosemicarbazide (6 mmol) in MeOH (10 mL) was
stirred for 18 h at 65ꢀC. The solvent was removed, and the residue
was dissolved in CHCl3 (20 mL) and washed with H2O (10mL).
The solution was dried with Na2SO4, and the solvent was
evaporated, which gave the methyl propanoates 15b and 16b.
The products were purified by recrystallization in hexane. 15b
(1.15 g, 76%). mp 111–112ꢀC, 1H NMR (CDCl3, 400 MHz),
d 2.68 (s, 4H, 2CH2), 3.28 (d, J= 19 Hz, 1H, H4), 3.37
(d, J= 19 Hz, 1H, H4), 3.7 (s, 3H, OMe), 6.27 (s, OH), 7.08
(s, NH2), 7.93 (s, NH2). 13C NMR (CDCl3, 100 MHz) d 25.1
(CH2), 29.8 (CH2), 47.1 (C4), 52.1 (Me), 92.5 (q, J=34Hz, C5),
123.2 (q, J=290Hz, CF3), 157.3 (C3), 172.2 (C═O), 177.1
(C═S). MS [m/z(%)] 299 (M+, 91), 282 (–NH2, <5), 268 (–S, 14),
238 (–CSNH2), 222 (–H2O, <5), 208 (–OMe, 22), 180 (–
HCO2Me), 171 (–CF3, 71), 139 (100), 97 (45), 69 (CF3, 17), 60
(52), 55 (17). Anal. Calcd for C9H12F3N3O3S: C, 36.12; H, 4.27;
N, 14.84; found C, 38.37; H, 4.18; N, 14.45.
propanoate 19b. The product was purified by recrystallization
1
in hexane. 19b (530 mg, 56%). mp 89–90ꢀC,
NMR
(CDCl3, 400 MHz) d 2.74 (m, 6H, 3CH2), 3.09 (m, 2H, CH2), 3.22
(d, JH–H = 19.0 Hz, 1H, H4), 3.37 (d, JH–H = 19.0 Hz, 1H, H4), 3.65
(s, 3H, OMe), 3.66 (s, 3H, OMe), 7.0 (s, 1H, H pyrimidine). 13C
NMR (CDCl3, 100 MHz) d 25.1 (CH2), 30.4 (CH2), 31.1 (CH2),
32.3 (CH2), 46.4 (C-4), 51.9 (2 OMe), 92.0 (q, 2JC–F = 33.7 Hz, C-5),
3
1
108.4 (q, JC–F =2.6Hz, C40), 120.1 (q, JC–F = 275.0 Hz, CF3),
1
2
123.4 (q, JC–F = 288.0 Hz, CF3), 155.0 (q, JC–F =36.4Hz, C-50),
156.0 (C-3), 158.8 (C-10), 172.5 (C═O), 172.6 (C═O), 172.9 (C-30).
MS [m/z(%)] 472 (M+, 42), 441 (–OCH3, 39), 403 (–CF3, 95), 363
(71), 339 (100), 190 (57). Anal. Calcd for C17H18F6N4O5: C, 43.23;
H, 3.84; N, 11.86; found C, 43.4; H, 3.92; N, 11.72.
Methyl 3-{2-[3-(3-metoxy-3-oxopropyl)-5-trifluoromethyl-1H-
pyrazol-1-yl]-6-(trifluoro methyl)pyrimidin-4-yl)propanoate (20b).
To the product 19b (1 mmol) was added concentrated sulfuric acid
98% (3mL). The mixture was stirred for 4 h at 40ꢀC, the acidic
solution was diluted with cooled water, and the precipitate was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

740
A. F. C. Flores, L. A. Piovesan, L. Pizzuti, D. C. Flores, J. L. Malavolta, and M. A. P. Martins
Vol 51
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Zanatta, N.; Bonacorso, H. G.; Flores, D. C. Synthesis 2005, 2744.
[14] Martins, M. A. P.; Machado, P.; Piovesan, L. A.; Flores, A. F. C.;
Campos, M. M. A.; Scheidt, C.; Bonacorso, H. G.; Zanatta, N. Monatsh
Chem 2008, 139, 985.
filtered and dried over calcium chloride under vacuum, which gave
the pure methyl propanoate 20b (390 mg, 86%). mp 98ꢀC, 1H NMR
(CDCl3, 400MHz) d 2.78 (t, 2H, JH–H =7.4 Hz, CH2), 2.96 (t, 2H,
JH–H = 7.4Hz, CH2), 3.11 (t, 2H, JH–H = 7.4Hz, CH2), 3.26 (t, 2H,
JH–H = 7.0Hz, CH2), 3.68 (s, 3H, OMe), 3.72 (s, 3H, OMe), 6.82
(s, 1H, H4, pyraz), 7.53 (s, 1H, H4 pyrym). 13C NMR (CDCl3,
100 MHz) d 23.4 (CH2), 31.0 (CH2), 32.5 (CH2), 32.9 (CH2),
1
51.8 (OMe), 51.9 (OMe), 114.8 (C-4), 114.8 (C4), 119.2 (q, JC–
1
F =268.0Hz, CF3), 120.0 (q, JC–F = 275.0Hz, CF3), 134.5 (q,
2
2JC–F = 40.0 Hz, C-5), 154.3 (C3), 155.7 (C-1), 156.6 (q, JC–
F = 37.0 Hz, C-5), 172.5 (C═O), 172.9 (2C=O), 174.7 (C-3). MS [m/
z(%)] 454 (M+, 30), 423 (–OCH3, 33), 395 (–C(O)OCH3, 39), 383
(–CF3, 100), 335 (68), 315 (34), 289 (24), 173 (13), 78 (13), 59 (42).
Anal. Calcd for C17H16F6N4O4: C, 44.94; H, 3.55; N, 12.33; found
C, 45.15; H, 3.70; N, 12.42.
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A. F. C.; Bonacorso, H. G.; Zanatta, N.; Martins, M. A. P. J Mol Struct
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CONCLUSIONS
This work presents a convenient method for obtaining
novel glutamate-like 3-(azolyl)propanoates from renewable
precursor LA and demonstrates that methyl 1,1,1-trihalo-4-
methoxy-6-oxo-4-heptenoate compounds are versatile sub-
strates in heterocyclic chemistry. The high synthetic potential
of these accessible reagents has numerous applications in
the synthesis of heterocyclic products, with structures that
have been determined by NMR experiments and X-ray
diffraction analysis. Furthermore, we obtained important
dicarboxyl derivatives from cyclocondensation between
methyl 1,1,1-trichloro-4-methoxy-6-oxo-4-heptenoate and
1,2-dinucleophilic hydroxylamine and hydrazine. These
derivatives show interesting nootropic activity in rats.
Acknowledgments. Financial support from Conselho Nacional de
Desenvolvimento Científico e Tecnológico (CNPq) and Fundação
de Amparo à Pesquisa do Estado do Rio Grande do Sul
(FAPERGS grant PqG 06/2010 no 1016236) is acknowledged.
The Bruker X-ray diffractometer was funded by infrastructure
grant from the Financiadora de Estudos e Projetos (CT-INFRA/
FINEP). We thank CNPq for fellowships.
[30] Wang, D.-J.; Fan, L.; Zheng, C.-Y.; Fang, Z.-D. J Fluorine
Chem 131, 2010, 584.
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Chem 2006, 43, 1003.
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Zanatta, N.; Bonacorso, H. G. Synth Commun 2000, 32, 1585.
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R.; Samat, A.; Lokshin, V.; Valés, M.; Elguero, J. J Org Chem 2006, 71, 6881.
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Pinto, E.; Flores, A. F. C.; Venzke, D.; Pereira, C. M. P. Ultrason Sono-
chem 2010, 17, 34.
[36] Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS
(Version 2.0.1.9), SAINT (Version 7.3A) and SADABS (Version 2004/
1) and XPREP (Version 2005/4), Bruker AXS Inc., Madison, Wisconsin,
USA, 2006.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet