Regiospecific synthesis of new fatty N-acyl trihalomethylated pyrazoline derivatives from fatty acid methyl esters (FAMEs)

Article abstract of DOI:10.1590/S0103-50532012005000071

A series of new fatty N-acyl trihalomethylated pyrazoline derivatives from fatty acid methyl esters was synthesized by the cyclocondensation of respective fatty hydrazides with 4-alkoxy-1,1,1-trialomethyl-3-alquen-2-ones. Efficient and regiospecific cyclizations catalyzed by BF₃·MeOH gave the desired products in good to excellent yields and at high purity.

Full text of DOI:10.1590/S0103-50532012005000071

J. Braz. Chem. Soc., Vol. 23, No. 11, 2122-2127, 2012.
Printed in Brazil - ©2012 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Short Report
S
Regiospecific Synthesis of New Fatty N-Acyl Trihalomethylated Pyrazoline
Derivatives from Fatty Acid Methyl Esters (FAMEs)
Paulo Beck,#,a Juliane M. dos Santos,a Bruna L. Kuhn,b Dayse N. Moreira,b
Alex F. C. Flores,b Marcos A. P. Martins,b Marcelo G. M. D’Ocaa and
Luciana A. Piovesan*,#, a
aEscola de Química e Alimentos, Universidade Federal do Rio Grande,
CP 474 , 96201-900 Rio Grande-RS, Brazil
bDepartamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria-RS, Brazil
Uma série de novas pirazolinas N-acil trialometiladas derivadas de ésteres metílicos de
ácidos graxos foi sintetizada por reação de ciclocondensação entre hidrazidas graxas e 4-alcóxi-
1,1,1-trialometil-3-alquen-2-onas. Ciclizações eficientes e regioespecíficas catalisadas por
BF3·MeOH levaram aos produtos desejados em rendimentos de bons a excelentes e alto grau de
pureza.
A series of new fatty N-acyl trihalomethylated pyrazoline derivatives from fatty acid methyl
esters was synthesized by the cyclocondensation of respective fatty hydrazides with 4-alkoxy-
1,1,1-trialomethyl-3-alquen-2-ones. Efficient and regiospecific cyclizations catalyzed by
BF3·MeOH gave the desired products in good to excellent yields and at high purity.
Keywords: N-acyl hydrazine, FAMEs, 4-alkoxy-1,1,1-trialomethyl-3-alquen-2-ones, N-acyl
trialomethylated pyrazoline
Introduction
and for a variety of halomethyl-substituted heterocyclic
compounds.10,11 The main synthetic method for preparing
pyrazole involves [3 + 2] cyclization, as in the classical
β-diketone with hydrazines.12,13
Trihalomethylated pyrazoline derivatives has been
described for its inflammatory, antioxidative, hypothermic,
antipyretic, analgesic, antinoceptive and a number of
other properties.1-8 Since the introduction of halogens
and halogenated groups into organic molecules often
confers significant and useful changes in their chemical,
physical and biological properties,9 the development of
new methods for synthesizing halogenated compounds
recently has attracted considerable interest. Among the
most convenient of these methods is the use of starting
materials containing halogens, including halogenated
1,3-dieletrophiles in the form of trihalomethylated
β-diketones and trihalomethylated α-β-unsaturated ketones
(as 4-alkoxy-1,1,1-trihalo-3-alken-2-ones), which are
regiospecific synthons for 5-trihalomethyl-1H-pyrazoles
Similarly, the introduction of fatty chains into organic
molecules also can produce important changes in their
chemical and physical properties. In this context, to study
the influence of fatty chains on the biologic activity of
organic compounds, our research group has developed
methodologies for synthesizing new nitrogen molecules
of pharmacological and technological interest. These
molecules are structurally simple, low in cost and
because of the inclusion of fatty chains have increased
lipophilicity.14-16
This paper describes a synthetic method for preparing
new fatty N-acyl trihalomethylated pyrazoline derivatives
from C16:0, 18:0 and 18:1 fatty acid families. It aimed
at the study of fatty molecules with biological potential,
bearing in mind the synthesis of pyrazole compounds from
4-alkoxy-1,1,1-trihalo-3-alken-2-ones in close connection
with this research.
*e-mail: lpiovesan@gmail.com
#These authors contributed equally to the work.

Vol. 23, No. 11, 2012
Beck et al.
2123
R1
O
R1
X3C
OCH3
O
O
HO
O
N
4-9
ii
iii
or
i
N
X3C
R
OH
R
OCH3
R
NHNH2
iv
R
1a-c
2a-c
O
3a-c
10-14a-c, 15a
R =
( )14
( )7
( )7
( )16
a
b
c
X/R1
4-Br-Ph
4-F-Ph
4-CH3-Ph
4-Cl-Ph
4-OCH3-Ph
CH3
Cl
F
4, 10
–
5, 11
–
6, 12
–
7, 13
–
–
9, 15
–
8, 14
Scheme 1. Synthesis of the new pyrazoline derivatives 10-14a-c, 15a. Reagents and conditions: (i) H2SO4/MeOH, 65 °C, 4 h. (ii) NH2NH2.2HCl, NaOCH3,
MeOH, 65 °C, 24 h. (iii) NH2NH2.HCl, NaOH, MeOH, 65 °C, 48 h. (iv) BF3.MeOH, 25 °C, 30 min, then MeOH, 65 °C, 24 h.
Results and Discussion
hydrazines 3a-c in the presence of methanol under reflux
for 24 h (entries 5-7).
The synthetic route for the preparation of compounds
10-15 is summarized in Scheme 1 and starts from the
esterification reaction of the corresponding fatty acid 1a-c,
in acid medium. The progress of the esterification was
monitored by silica gel thin layer chromatography (TLC)
and fatty acid methyl esters (FAMEs) 2a-c were obtained
with yields of 85-94%.15
The most convenient method for preparing fatty
hydrazides (fatty N-acyl hydrazines) from FAMEs
is through a hydrazinolysis reaction using hydrazine
monohydrate.17-20 Because the sale of this reagent be
controlled, it was tested methods using less reactive
hydrazines such as hydrazine monohydrochloridrate and
hydrazine dihydrochloridrate (Table 1). The FAMEs 2a-c
hydrazinolysis reaction for producing fatty N-acyl
hydrazines 3a-c was tested in the presence of two strong
bases, sodium hydroxide and sodium methoxide, which
release hydrazine into the reaction medium to act as
a nucleophile front of the FAME.
The hydrazinolysis reactions of FAMEs 2a-c were
first tested with hydrazine dihydrochloridrate. The use
of pyridine, triethylamine or sodium hydroxide as a base
did not result in the release of hydrazine into the medium
reaction, even with an increased molar ratio of base and/or
a longer reaction time. So, it was tested the use of sodium
methoxide as the base. As indicated in Table 1, after a few
attempts, reactions of FAME with a 3 mol equivalent of
hydrazine dihydrochloridrate and a 9 mol equivalent of
sodium methoxide produced pure samples of fatty N-acyl
Similarly, the use of pyridine or triethylamine as base
for hydrazine monohydrochloridrate did not produce
the desired products. Reactions of FAME with a 3 mol
equivalent of hydrazine monohydrochloridrate and a 3 mol
equivalent of sodium hydroxide as bases in the presence
of methanol under reflux for 48 h yielded pure samples of
fatty N-acyl hydrazines 3a-c (Table 1, entries 11-13). In
this case, the use of sodium methoxide did not lead to the
desired products, regardless of the molar ratio or reaction
time used (entries 14-19). The progress of all reactions
was monitored by silica gel TLC. The raw products did not
require purification and were analyzed by melting point, gas
chromatography/mass spectrometry (GC/MS) and infrared
(IR) spectrometry.
Cyclocondensation reactions
The 4-methoxy-1,1,1-trihalo-3-alken-2-ones 4-9 were
synthesized from the reaction of appropriate enol ether
or acetal with trichloroacetyl chloride or trifluoroacetic
anhydride, according to the literature.12,13
In previous reports, which related the cyclocondensation
reactions between 4-alkoxy-1,1,1-trihalo-3-alken-2-ones
and no-fatty N-acyl hydrazines, e.g., semicarbazide or
tiossemicarbazide, the pyrazoline derivatives were obtained
under mild conditions, methanol refluxing, with good to
excellent yields (71-96%).21,22 Initially, to prepare fatty
N-acyl trihalomethylated pyrazoline derivatives 10-15,
the cyclocondensation reactions were performed from

2124
Regiospecific Synthesis of New Fatty N-Acyl Trihalomethylated Pyrazoline Derivatives from FAMEs
J. Braz. Chem. Soc.
Table 1. Hydrazinolysis of fatty acid methyl esters 2a-c in methanol at 65 ºC
entry
FAME
Hydrazine
Base
FAME:hydrazine:basea
time / h
Result
1
2c
2c
2c
2c
2a
2b
2c
2c
2c
2c
2a
2b
2c
2c
2c
2c
2c
2c
2c
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.2HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NH2NH2.HCl
NaOH
NaOH
1:3:1
1:3:1
1:3:3
1:3:3
1:3:9
1:3:9
1:3:9
1:3:1
1:3:1
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:6
1:3:9
1:3:3
1:3:6
1:3:9
24
24
24
24
24
24
24
24
48
24
48
48
48
24
24
24
48
48
48
n.r.
n.r.
2
3
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOH
n.r.
4
2c + 3c
3a, 80%
3b, 80%
3c, 69%
n.r.
5
6
7
8
9
NaOH
n.r.
10
11
12
13
14
15
16
17
18
19
NaOH
n.r.
NaOH
3a, 80%
3b, 80%
3c, 69%
n.r.
NaOH
NaOH
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
n.r.
n.r.
n.r.
n.r.
2c + 3c
aStoichiometric ratio; n.r.: no reaction.
fatty N-acyl hydrazines 3a-c and enones 4-9 through
mild conditions in refluxing methanol with a reaction
time of 12 h. However, the presence of a strong electron-
withdrawing substituent at the N1 of 1,2-dinucleophile
makes it less reactive. This is because the electron pairs of
nitrogen atoms are in resonance with the carbonyl group
and demand more specific reaction conditions. When
inorganic acids such as H2SO4 and HCl were used as
catalysts, it was observed substrates even after a reaction
time of 72 h. Therefore, BF3·MeOH was tested as a Lewis
acid catalyst. It was first added a catalyst into a solution of
enone in methanol and immediately added the fatty N-acyl
hydrazine; no product was formed even after a reaction time
of 24 h. When fatty N-acyl hydrazine was added after 15
min, the product did form, and substrates were observed
by TLC. When fatty N-acyl hydrazine was added at 30 min
after the addition of catalyst, pure samples of 10-14a-c and
15a were recovered after a reaction time of 24 h.
This behavior demonstrates the presence of a stereogenic
center (C5) neighboring C4 and confirms that the structures
are 4,5-dihydropyrazoles. Previous studies demonstrated
that the doublet with greater deshielding corresponds to the
hydrogen at C4, which is cis relative to OH at C5.23,24 In
addition, the spectral data showed typical chemical shifts
for the alkyl substituent at C3 (15a) or aryl substituent (10-
14a-c) and for fatty-chain hydrogens.
Asobservedinotherstudiesusinghydrazidestosynthesize
pyrazoles from 4-alkoxy-1,1,1-trihalo-3-alken-2-ones, the
chain derived from the fatty acid linked to the N1 of the
pyrazoline ring acts as a protecting group for its electron-
withdrawing effect, preventing water elimination and the
subsequent aromatization of the pyrazoline ring, producing
a pyrazole.21,22,25-27Also, the presence of a trihalomethylated
group at the vinyl ketone and the chain derived from
the fatty acid at the dinucleophile were crucial for the
regiochemistry of the reactions, which produced only the
5-trihalomethylated isomers. The suggested pathway to the
cyclocondensation reaction is shown in Scheme 2. Whereas
the precursors 4-alkoxy-1,1,1-trihalo-3-alken-2-ones are
molecules composed by a block CCC with two eletrofilic
centers with distinguished reactivity, and the hydrazines are
very reactive front to sp2 carbon atoms, the first step is the
nucleophilic attack of unsubstituted nitrogen of hydrazine
The structures of the new fatty N-acyl trihalomethylated
pyrazoline derivatives were confirmed by IR and 1H and 13C
nuclear magnetic resonance (NMR) spectral data. The 1H and
13C NMR spectra of products 10-14a-c and 15a showed one
set of signals corresponding to the proposed structures.12,13
1H NMR showed signals for the diastereotopic protons H4a
and H4b of C4 as two doublets at 3.3-3.5 ppm (J ca. 19 Hz).

Vol. 23, No. 11, 2012
Beck et al.
2125
R1
O
R1
OH R1
HN
O
X3C
OCH3
X3C
OCH3
X3C
OCH3
H2N
NHCOR
NHCOR
H2N NHCOR
−CH3OH
R1
ROCHN
NHCOR
R1
HO
OH NH
O
HN
NH
N
X3C
X3C
R1
X3C
O
R
R1
HO
N
N
X3C
R
O
Scheme 2. Mechanism proposed to the pyrazoline derivative synthesis.
Table 2. Synthesis of new fatty N-acyl trihalomethylated pyrazoline derivatives
4-alkoxy-
4-alkoxy-
entry
N-Acyl hydrazine
1,1,1-trialomethyl- Product / %
3-alquen-2-ones
entry
N-Acyl hydrazine
1,1,1-trialomethyl- Product / %
3-alquen-2-ones
Br
CH3
O
O
5
11b, 85
1
10a, 87
( )16
3b
( )14
NHNH2
NHNH2
O
O
3a
Cl3C
Cl3C
Cl3C
Cl3C
OCH3
OCH3
OCH3
OCH3
Cl3C
Cl3C
Cl3C
Cl3C
OCH3
5
5
6
6
4
4
4
5
Br
Cl
Cl
CH3
O
O
6
7
8
11c, 80
12a, 87
12b, 85
2
3
4
10b, 87
10c, 82
11a, 85
( )7
3c
( )16
( )7
NHNH2
NHNH2
O
O
O
O
O
O
3b
OCH3
CH3
O
O
( )14
( )7
( )7
NHNH2
NHNH2
3a
3c
OCH3
Br
O
O
( )16
3b
( )14
3a
NHNH2
NHNH2
OCH3

2126
Regiospecific Synthesis of New Fatty N-Acyl Trihalomethylated Pyrazoline Derivatives from FAMEs
J. Braz. Chem. Soc.
Table 2. continuation
Conclusions
4-alkoxy-
entry
N-Acyl hydrazine
1,1,1-trialomethyl- Product / %
3-alquen-2-ones
In conclusion, this work demonstrates the synthesis
of fatty hydrazides from FAMEs. The new methodology
produces hydrazide derivatives from C16:0, 18:0
and 18:1 fatty acids with high yields and purity; the
compounds used as 1,2-dinucleophile precursors in
regiospecific cyclocondensation reactions with several
4-alkoxy-1,1,1-trihalo-3-alken-2-ones give rise to fatty
N-acyl trihalomethylated pyrazoline derivatives. The new
compounds were synthesized through efficient catalysis
with BF3·MeOH with good to excellent yields (80-90%)
and high purity.
Cl
O
9
12c, 80
13a, 88
13b, 85
13c, 80
14a, 85
14b, 85
( )7
( )7
( )7
( )7
NHNH2
O
3c
Cl3C
Cl3C
Cl3C
Cl3C
F3C
OCH3
OCH3
OCH3
OCH3
6
7
7
7
F
F
F
O
10
11
12
13
14
( )14
NHNH2
O
O
O
3a
Supplementary Information
O
Experimental procedures, data spectra and spectra of
synthesized compounds are available free of charge at
http://jbcs.sbq.org.br as a PDF file.
( )16
3b
NHNH2
Acknowledgments
O
( )7
3c
NHNH2
The authors are thankful for the financial support
from the Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior (CAPES), Fundação de Apoio à
Pesquisa do Estado do Rio Grande do Sul (FAPERGS)
and the Conselho Nacional de Desenvolvimento Científico
e Tecnológico (CNPq). Fellowships from CAPES
(P. Beck, J. M. dos Santos and L. A. Piovesan) are also
acknowledged.
OCH3
O
( )14
NHNH2
O
3a
OCH3
8
OCH3
O
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( )16
3b
NHNH2
O
F3C
OCH3
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Published online: November 6, 2012