Ionic liquid and Lewis acid combination in the synthesis of novel (E)-1-(benzylideneamino)-3-cyano-6-(trifluoromethyl)-1H-2-pyridones

Article abstract of DOI:10.1007/s00706-011-0563-x

In this work, a new catalytic system to synthesize a series of new (E)-1-(benzylideneamino)-3-cyano-6-(trifluoromethyl)-1H-2-pyridones from the cyclo-condensation reaction of benzylidene cyanoacetohydrazide with 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF₃C(O)C (R²) = C(R¹)(OR), where R = Me, Et; R¹ = H, Me, Pr, Bu, Ph, 4-Me-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph; R² = H, Me and R ¹,R² = -(CH₂)_4-] is presented. The products were obtained at room temperature in moderate to good yields (42-87%). Comparison of the catalytic system with a conventional method was not possible, because the products were obtained only when the new catalyst system - consisting of triethylamine and Lewis acid in ionic liquid [BMIM][BF ₄] - was used. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0563-x

Monatsh Chem (2011) 142:1265–1270
DOI 10.1007/s00706-011-0563-x
ORIGINAL PAPER
Ionic liquid and Lewis acid combination in the synthesis of novel
(E)-1-(benzylideneamino)-3-cyano-6-(trifluoromethyl)-1H-2-
pyridones
•
Dayse N. Moreira Clarissa P. Frizzo Kelvis Longhi Aline B. Soares
•
•
•
•
Mara R. B. Marzari Lilian Buriol Sergio Brondani Nilo Zanatta
•
•
•
•
Helio G. Bonacorso Marcos A. P. Martins
Received: 17 March 2011 / Accepted: 26 June 2011 / Published online: 16 August 2011
Ó Springer-Verlag 2011
Abstract In this work, a new catalytic system to
synthesize a series of new (E)-1-(benzylideneamino)-3-
cyano-6-(trifluoromethyl)-1H-2-pyridones from the cyclo-
condensation reaction of benzylidene cyanoacetohydrazide
with 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones [CF3C(O)C
(R2) = C(R1)(OR), where R = Me, Et; R1 = H, Me, Pr,
Bu, Ph, 4-Me-Ph, 4-F-Ph, 4-Cl-Ph, 4-Br-Ph; R2 = H, Me
and R1,R2 = –(CH2)4–] is presented. The products were
obtained at room temperature in moderate to good yields
(42–87%). Comparison of the catalytic system with a
conventional method was not possible, because the prod-
ucts were obtained only when the new catalyst system—
consisting of triethylamine and Lewis acid in ionic liquid
[BMIM][BF4]—was used.
while milrinone, amrinone [3, 4], and their analogs [5–7]
have been shown to be cardiotonic agents for the treatment
of heart failure (Fig. 1). In addition, 2-pyridones can be
used as starting materials for synthesizing more complex
molecules, such as dienes in the Diels–Alder reaction [8],
and also as intermediates for the preparation of arylazo
dyes [9].
The main synthetic route to 2-pyridones involves the
reaction of cyanoacetamide or cyanoacetohydrazide and 1,3-
dielectrophilic reactants, such as 1,3-dicarbonyl compounds
[10, 11], a,b-unsaturated ketones [12–14], ketene dithio-
acetals [15], malonitrile [16] and its derivatives, and
2-arylvinamidinium salts [17]. The preparation of 2-pyri-
dones in this way involves a base-catalyzed reaction, and a
few protocols for this are reported in the literature [10–17].
In earlier methods, the use of polar and toxic solvents such as
acetonitrile as well as high reaction temperatures was
required. Most of these base-catalyzed reactions, especially
those involving cyanoacetohydrazide, furnished a limited
scope of products. There is still a lack of reports on 2-pyri-
dones that possess a trifluoromethyl group attached to their
structure, for example. Data from the literature have dem-
onstrated that the most convenient method to construct
trifluoromethylated heterocycles is from trifluoromethyl-
containing building blocks used as starting reactants
[18–20]. Our research group has systematically synthesized
4-alkoxy-1,1,1-trihalo-3-alken-2-ones and demonstrated
their importance as versatile building blocks in the
construction of trifluoromethyl-heterocyclic rings (e.g.,
isoxazoles, pyrazoles, pyrazolium chlorides, pyrrolidinones,
pyrimidines, pyrimidinones, pyrazolo[1,5-a]pyrimidines,
pyridines, thiazolopyrimidinones, selenazoles, quinolines,
and diazepines) [18–20].
Keywords 2-Pyridones Á Enones Á
Benzylidene cyanoacetohydrazide Á
Ionic liquid Á Catalysis
Introduction
Many naturally occurring and synthetic compounds con-
taining the 2-pyridone [1] scaffold possess interesting
pharmacological properties. Pyridone L-697,661 has been
identified as a specific non-nucleoside reverse transcriptase
inhibitor of human immunodeficiency virus-1 (HIV-1) [2],
D. N. Moreira Á C. P. Frizzo (&) Á K. Longhi Á
A. B. Soares Á M. R. B. Marzari Á L. Buriol Á S. Brondani Á
N. Zanatta Á H. G. Bonacorso Á M. A. P. Martins
´
Departamento de Quımica, Universidade Federal de Santa
For these applications, synthetic chemistry relies heavily
on the use of molecular solvents. Many of these solvents
Maria, Santa Maria, RS 97105-900, Brazil
e-mail: clarissa.frizzo@yahoo.com.br; mmartins@base.ufsm.br
123

1266
D. N. Moreira et al.
Fig. 1 2-Pyridones possessing
pharmacological properties
Scheme 1
R1
R2
CN
O
O
R1
O
i
Ph
+
F3C
OR
N N
H
F3C
N
N
R2
1a-1k
CN
6
Ph
7a-7k
i: Et3N (10 mol%), BF3·OEt2, [BMIM][BF ] (1 equiv), r.t., 24-48 h
4
have been found to be environmentally unfriendly, which
has generated interest in alternative reaction media [21].
One potential answer to these problems lies in the use of
ionic liquids (ILs). Ionic liquids have earned themselves a
reputation as excellent reaction media [22, 23]. Further-
more, ionic liquids have the potential to be recycled and re-
used many times [24, 25], greatly reducing waste and
environmental impacts. Therefore, it is desirable to find
novel catalytic procedures, especially ones that avoid the
use of molecular and toxic solvents, that represent efficient
routes to such highly useful organic products as 2-pyri-
dones. The combination of a classical base-catalyzed route
and ionic liquids could afford a new green methodology to
synthesize 2-pyridones. In this context, and in connection
with our ongoing interest in the synthesis and evaluation of
new trifluoromethylated heterocyclic compounds, we
report herein an environmentally friendly and efficient
reaction of 4-alkoxy-1,1,1-trihalo-3-alken-2-ones and cya-
noacetohydrazide using a new and interesting catalytic
system of base/Lewis acid and [BMIM][BF4] as a recy-
clable solvent (Scheme 1).
ethyl acetate under reflux for 5 h, and furnished the desired
product acylcyanoacetohydrazide 2 in excellent yield
(90%). The mixture of acylcyanoacetohydrazide 2 and
enone 1a was submitted to different reaction conditions,
using various basic catalysts and ethanol as solvent
(Table 1).
Unfortunately, all attempts to produce the desired
product failed; only 1-cyanoacetyl-4,5-dihydro-1H-pyra-
zole 4a, NH-pyrazole 5a, or a mixture of these was
attained. These products form due to a deprotection reac-
tion that occurred with acylcyanoacetohydrazide 2, which
freed both nitrogen atoms to react with the enone, leading
to the pyrazole derivatives.
In a second attempt, we performed another protection
reaction on cyanoacetohydrazine, converting it to a
hydrazone (a stronger protection group) in 96% yield.
This was obtained from the reaction of benzaldehyde and
cyanoacetohydrazide in ethanol for 16 h with stirring at
room temperature. Benzylidene cyanoacetohydrazide (6)
was submitted to different reaction conditions with enone
1a in order to find the best conditions for the synthesis of
2-pyridones. Initially, we evaluated the same conditions
that were used with acylcyanoacetohydrazide 2. However,
in all cases, only the starting material was recovered,
together with by-products that have not been identified.
Due to its special properties, the ionic liquid [BMIM][BF4]
was used in these cyclocondensation reactions, since it has
been demonstrated to be an excellent alternative medium
for heterocyclic synthesis [22]. In a first attempt, enone 1a
was reacted with 6 in the presence of triethylamine in
[BMIM][BF4] at room temperature for 24 h. From the
Results and discussion
Recently, we reported that the reaction of cyanoacetohyd-
razide under basic conditions led to the formation of a
mixture of 1-cyanoacetyl-4,5-dihydro-1H-pyrazole and a
dehydro-pyrazole [26]. Thus, we first performed a protec-
tion reaction in order to block one of the nitrogens of
cyanoacetohydrazide. The N-acylation was performed in
123

Ionic liquid and Lewis acid combination in the synthesis
1267
Table 1 Reaction conditions of enone 1a with acylcyanoacetohydrazide 2
Entry
T/°C
Base
Product molar ratio 4a:5a
Yield/%
1
2
3
4
r.t.
KOH
5:1
1:2
1:3
0:1
14
51
40
34
r.t.
Piperidine
Piperidine
Et3N
-78 to r.t.
Reflux
All reactions were carried out in ethanol for 16 h
Table 2 Reaction conditions of
enones 1a–1k with 6
Enone
R
R2
R1
Product
BF3ÁOEt2/equiv.
Time/h
Yield/%a
1a
1b
1c
1d
1e
1f
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
H
H
H
H
H
H
Me
Me
7a
7b
7c
7d
7e
7f
1.2
1.2
1.2
0.6
–
48
30
27
24
24
24
24
24
24
24
27
50
47
42
79
80
70
86
87
68
73
63
Pr
Bu
2-MeO-PhCH2
Ph
4-Me-Ph
4-F-Ph
4-Cl-Ph
4-Br-Ph
H
–
1g
1h
1i
7g
7h
7i
–
–
–
1j
7j
1.2
2.4
a
Yield of isolated compounds
after column chromatography
1k
Me
–(CH2)4–
7k
NMR spectroscopy and GC-MS data, we observed the
formation of the 2-pyridone 7a. However, this was
obtained as a mixture of products (hydroxyl, dehydrated,
and/or deprotected 2-pyridones). Thus, we rationalized that
the enone activation could require a Lewis acid, and a basic
catalyst may be required for anion formation in 6. We
therefore decided to use a catalytic system consisting of
BF3ÁOEt2, triethylamine, and [BMIM][BF4], which gave
the desired product 7a in moderate yield. The Lewis acid
BF3ÁOEt2 was chosen because it allowed activation under
mild conditions; stronger catalysts can cause the depro-
tection reaction of the starting material 6. In order to show
the efficacy of this new synthetic route, other trifluorom-
ethylated enones were submitted to these reaction
conditions with 6, as shown in Scheme 1. The reaction
time and amount of BF3ÁOEt2 were specific to each enone,
as demonstrated in Table 2. Considering the results, we can
see that aryl enones were more reactive than alkyl enones,
since the reactions of aryl enones did not require the
addition of a Lewis acid catalyst. All products were
obtained in moderate-to-good yields after purification by
column chromatography. This purification step was
required to remove any remaining starting material.
All isolated products were well characterized by their
1
melting points, H and 13C NMR, and MS data. In some
cases, the 2-pyridones were barely soluble in any deu-
terated solvents, so it was necessary to analyze them via
13C CPMAS-NMR. 2-Pyridone 7e was also identified by
123

1268
D. N. Moreira et al.
Experimental
Unless otherwise indicated, all common reactants and solvents
were used as obtained from commercial suppliers without
further purifications. 1Hand13C NMR spectra were recorded on
a Bruker DPX 400 (1H at 400.13 MHz and13C at 100.62 MHz)
in 5 mm sample tubes at 298 K (digital resolution
0.01 ppm) in CDCl3/TMS solutions. CPMAS-NMR spectra
have been obtained with a Bruker WB-400 spectrometer at
300 K with a wide-bore 4-mm DVT probehead. Samples were
carefully packed in ZrO2 rotors. 13C spectra were originally
referenced to a glycine sample and then the chemical shifts were
recalculated to the TMS [for the carbonyl atom d (glycine)1/4
176.1 ppm]. Mass spectra were registered on a HP 5973 MSD
connected to a HP 6890 GC and interfaced with a Pentium PC.
The GC was equipped with a split-splitless injector and auto-
sampler, crosslinked to a HP-5 capillary column (30 m,
0.32 mm internal diameter), and helium was used as the carrier
gas. Elementalanalyses were performed on a PerkinElmer 2400
CHN elemental analyzer. Melting points were determined on a
Fig. 2 Crystal structure of (E)-1-(benzylideneamino)-1,2-dihydro-2-
oxo-4-phenyl-6-(trifluoromethyl)-3-pyridinecarbonitrile (7e) obtained
using ORTEP
´
Microquımica MQAPF-302 melting point apparatus.
Typical procedure for the synthesis
of benzylideneamino-2-pyridones 7a-7k
X-ray diffraction. Using these data, the double-bond
configurations for the pyridones 7a-7k were determined.
ORTEP (Fig. 2) demonstrated that the benzylidene group
[C(6)-C(61-66)] is trans in relation to the 1-amino-
2-pyridone ring [N(2)-N(1)], and that the compound has
the E configuration.
In a round-bottomed flask, benzylidene cyanoacetohyd-
razide (6, 1.2 mmol), [BMIM][BF4] (1 mmol), and
triethylamine (10 mol%) were mixed. The mixture was
kept at room temperature under magnetic stirring until
complete homogenization. Then, a mixture of enones 1a–
1k (1 mmol) and BF3ÁOEt2 was added dropwise. The
amount of BF3ÁOEt2 used was different for each enone, as
detailed in Table 2. The mixture was maintained at room
temperature under magnetic stirring for 24–48 h. After this
period, dichloromethane was added and the reaction mix-
ture was washed with 10% hydrochloric acid solution
(3 9 10 cm3). Then the organic phase was dried over
anhydrous Na2SO4 and the solvent was evaporated under
reduced pressure. The products 7a-7k were purified by CC
using 10% hexane/ethyl acetate as eluent.
A probable mechanism for the formation of benzylidene-
amino-2-pyridones 7a-7k involves a Guareschi–Thorpe
reaction [27] that begins with the removal of a proton from
the benzylidene cyanoacetohydrazide, promoted by the
base, which leads to carbanion formation. This carbanion
attacks the b-carbon atom of the enone, which is activated
by the Lewis acid, resulting in the elimination of the OR
group. In the next step, the enaminoketone intermediate
formed undergoes cyclization through the addition of the
sp3 nitrogen of the benzylidene cyanoacetohydrazide to the
carbonyl carbon, giving the benzylideneamino-2-pyridones
7a-7k . Due to the neutral nature of the ionic liquid used in
this reaction [28], its role is probably to stabilize the
carbanion intermediate [29]. Because of the polar nature of
the ionic liquid, it is also generally accepted that the acti-
vation barrier to the reactions can be reduced by stabilizing
the polar transition states or reaction intermediate in polar
ionic liquids [30].
(E)-1-(Benzylideneamino)-1,2-dihydro-4-methyl-
2-oxo-6-(trifluoromethyl)-3-pyridinecarbonitrile
(7a, C15H10F3N3O)
Yield 50%; m.p.: 154–156 °C; 1H NMR (400 MHz,
CDCl3): d = 2.56 (s, 3H, Me), 6.69 (s, 1H, H5),
7.47–7.57 (m, 3H, Ar–H), 7.84–7.86 (m, 2H, Ar–H), 9.18
(m, 1H, H8) ppm; 13C NMR (100 MHz, CDCl3): d = 21.4
3
In summary, we have developed an efficient synthetic
route to a series of eleven new trifluoromethyl-2-pyridones
based on the cyclocondensation reaction of enones and
benzylidene cyanoacetohydrazide using the catalytic sys-
tem BF3ÁOEt2/triethylamine/[BMIM][BF4].
(Me), 107.6 (q, J = 5.4 Hz, C5), 109.3 (C3), 113.6 (CN),
1
118.9 (q, J = 286 Hz, CF3), 129.1, 129.3, 131.9, 133.1
(C–Ar), 137.2 (q, 2J = 34 Hz, C6), 156.7 (C4), 157.0 (C8),
?
167.6 (C=O) ppm; GC/MS (CI): m/z = 334 (M ? C2H7
7), 306 (MH?, 63), 243 (14), 203 (28), 104 (100).
,
123

Ionic liquid and Lewis acid combination in the synthesis
1269
2
(E)-1-(Benzylideneamino)-1,2-dihydro-2-oxo-4-propyl-6-
(trifluoromethyl)-3-pyridinecarbonitrile
(7b, C17H14F3N3O)
137.6 (q, J = 34 Hz, C6), 156.8 (C4), 157.4 (C8), 167.6
(C=O) ppm; GC/MS (CI): m/z = 367 (M?, 100), 297 (5).
Crystallographic data for 7e have been deposited with
the Cambridge Crystallographic Data Center (CCDC
767836). Copies of the data can be obtained, free of
charge, on application to CCDC 12 Union Road, Cam-
bridge CB2 1EZ, UK (fax: ?44-1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
1
Yield 47%; oil; H NMR (400 MHz, CDCl3): d = 1.06 (t,
3H, Me), 1.76 (sex, 2H, CH2), 2.79 (t, 2H, CH2), 6.68 (s,
1H, H5), 7.47–7.57 (m, 3H, H–Ar), 7.84–7.87 (m, 2H, H–
Ar), 9.20 (s, 1H, H8) ppm; 13C NMR (100 MHz, CDCl3):
d = 13.7 (C11), 22.6 (C10), 37.1 (C9), 106.6 (q,
3J = 5.4 Hz, C5), 109.2 (C3), 113.6 (CN), 119.1 (q,
1J = 286 Hz, CF3), 129.0, 129.3, 132.2, 133.1 (C–Ar),
(E)-1-(Benzylideneamino)-1,2-dihydro-4-
(4-methylphenyl)-2-oxo-6-(trifluoromethyl)-3-
2
137.6 (q, J = 34 Hz, C6), 157.0 (C4), 161.1 (C8), 167.4
(C=O) ppm; GC/MS (CI): m/z = 334 (MH?, 2), 259 (14),
231 (57), 104 (100).
pyridinecarbonitrile (7f, C21H14F3N3O)
Yield 70%; m.p.: 213–215 °C; 1H NMR (400 MHz,
CDCl3): d = 2.46 (s, 1H, Me), 6.89 (s, 1H, H5),
7.50–7.63 (m, 7H, Ar–H), 7.87–7.90 (m, 2H, Ar–H), 9.28
(s, 1H, H8) ppm; 13C NMR (100 MHz, CDCl3): d = 21.5
(E)-1-(Benzylideneamino)-4-butyl-1,2-dihydro-2-oxo-6-
(trifluoromethyl)-3-pyridinecarbonitrile
3
(Me), 106.3 (C3), 106.7 (q, J = 5.7 Hz, C5), 114.5 (CN),
1
119.1 (q, J = 286 Hz, CF3), 125.5, 126.8, 128.1, 129.0,
(7c, C18H16F3N3O)
Yield 42%; m.p.: 98–100 °C; 1H NMR (400 MHz, CDCl3):
d = 0.90–0.97 (t, 3H, Me), 1.36–1.47 (m, 2H, CH2),
1.63–1.71 (m, 2H, CH2), 2.81–2.88 (t, 2H, CH2), 6.41 (s,
1H, H5), 7.52–7.58 (m, 3H, H–Ar), 7.86–7.90 (m, 2H,
H–Ar), 8.90 (s, 1H, H8) ppm; 13C NMR (100 MHz, CDCl3):
d = 13.6 (CH3), 22.3 (C11), 29.4 (C10), 33.4 (C9), 99.2
129.2, 130.0, 131.4, 132.1, 133.1 (C–Ar), 137.5 (q,
2J = 34 Hz, C6), 156.7 (C4), 157.6 (C8), 167.3 (C=O)
ppm; GC/MS (CI): m/z = 381 (M?, 3), 285 (100).
(E)-1-(Benzylideneamino)-4-(4-fluorophenyl)-1,2-dihydro-
2-oxo-6-(trifluoromethyl)-3-pyridinecarbonitrile
(7g, C20H11F4N3O)
3
(C3), 100.8 (q, J = 5.4 Hz, C5), 112.4 (CN), 120.8 (q,
1J = 286 Hz, CF3), 129.1, 129.4, 131.5, 133.5 (C–Ar),
Yield 86%; m.p.: 211–214 °C; 1H NMR (400 MHz,
CDCl3): d = 6.86 (s, 1H, H5), 7.24–7.27 (m, 2H, H–Ar),
7.49–7.61 (m, 3H, H–Ar), 7.69–7.72 (m, 2H, H–Ar),
7.86–7.89 (m, 2H, H–Ar), 9.26 (s, 1H, H8) ppm; 13C
CPMAS-NMR (100 MHz): d = 104.9 (C5), 113.8 (C3),
115.5 (CN), 127.8, 132.9, 130.4, 135.3, 162.6 (C–Ar),
135.3 (C6), 154.4 (C8), 165.3 (C4), 165.3 (C=O) ppm;
GC/MS (CI): m/z = 298 (M? - CF3 - F, 11), 104 (22), 57
(100).
2
144.2 (q, J = 34 Hz, C6), 157.3 (C4), 157.6 (C8), 169.9
(C=O) ppm; GC/MS (CI): m/z = 392 (M? ? CH5
?
?
C2H7?, 14), 374 (MH? ? CH5, 29), 332 (100), 273 (40),
236 (91), 196 (25).
(E)-1-(Benzylideneamino)-1,2-dihydro-4-
(2-methoxybenzyl)-2-oxo-6-(trifluoromethyl)-3-
pyridinecarbonitrile (7d, C22H16F3N3O2)
Yield 69%; m.p.: 147–149 °C; 1H NMR (400 MHz,
CDCl3): d = 3.85 (s, 3H, OMe), 4.11 (s, 2H, CH2), 6.69
(s, 1H, H5), 6.90–6.98 (m, 3H, H–Ar), 7.47–7.62 (m, 3H,
H–Ar), 7.82–7.89 (m, 3H, H–Ar), 9.18 (s, 1H, H8) ppm;
13C CPMAS-NMR (100 MHz): d = 35.3 (CH2), 55.7
(MeO), 106.4 (C5), 107.7 (C3), 113.3 (CN), 114.7, 121.7,
124.0, 126.7, 128.8, 129.2, 131.2, 156.5 (C–Ar), 134.6
(C6), 154.6 (C4), 159.4 (C8), 166.8 (C=O) ppm.
(E)-1-(Benzylideneamino)-4-(4-chlorophenyl)-1,2-dihydro-
2-oxo-6-(trifluoromethyl)-3-pyridinecarbonitrile
(7h, C20H11ClF3N3O)
Yield 87%; m.p.: 209–212 °C; 1H NMR (400 MHz,
CDCl3): d = 6.86 (s, 1H, H5), 7.51–7.62 (m, 7H, H–Ar),
7.87–7.90 (m, 2H, H–Ar), 9.25 (s, 1H, H8) ppm; 13C
CPMAS-NMR (100 MHz): d = 104.1 (C5), 105.7 (C3),
107.4 (CN), 119.0, 129.0, 131.1, 132.1, 141.9 (C–Ar),
137.1 (C6), 155.0 (C8), 156.9 (C4), 168.6 (C=O) ppm;
GC/MS (CI): m/z = 132 (M? - 2Ph - CF3, 5), 104 (53),
57 (100).
(E)-1-(Benzylideneamino)-1,2-dihydro-2-oxo-4-phenyl-6-
(trifluoromethyl)-3-pyridinecarbonitrile
(7e, C20H12F3N3O)
Yield 80%; m.p.: 198–201 °C; 1H NMR (400 MHz,
CDCl3): d = 6.91 (s, 1H, H5), 7.51–7.69 (m, 8H, Ar–H),
7.87–7.91 (m, 2H, Ar–H), 9.28 (s, 1H, H8) ppm; 13C NMR
(100 MHz, CDCl3): d = 106.8 (q, 3J = 5.4 Hz, C5), 114.4
(C3), 114.9 (CN), 118.9 (q, 1J = 276 Hz, CF3), 128.1,
129.0, 129.2, 129.3, 131.5, 132.0, 133.2, 134.3 (Ar–C),
(E)-1-(Benzylideneamino)-4-(4-bromophenyl)-1,2-dihydro-
2-oxo-6-(trifluoromethyl)-3-pyridinecarbonitrile
(7i, C20H11BrF3N3O)
Yield 68%; m.p.: 208–210 °C; 1H NMR (400 MHz,
CDCl3): d = 6.85 (s, 1H, H5), 7.49–7.58 (m, 5H, H-Ar),
7.70–7.87 (m, 2H, H–Ar), 7.87–7.90 (m, 2H, H–Ar), 9.25
123

1270
D. N. Moreira et al.
(s, 1H, H8) ppm; 13C CPMAS-NMR (100 MHz): d =
103.4 (C5), 105.2 (C3), 107.0 (CN), 117.3, 131.5, 136.7
(C–Ar), 136.7 (C6), 155.5 (C4), 156.5 (C8), 167.1 (C=O)
ppm; GC/MS (CI): m/z = 207 (M? - Ph - Br - CF3, 5),
149 (31), 57 (100).
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8. Afarinkia K, Vinader V, Nelson TD, Posner GH (1992) Tetra-
hedron 48:9111
(E)-1-(Benzylideneamino)-1,2-dihydro-5-methyl-2-oxo-6-
(trifluoromethyl)-3-pyridinecarbonitrile
(7j, C15H10F3N3O)
Yield 73%; m.p.: 147–151 °C; 1H NMR (400 MHz,
CDCl3): d = 2.39 (q, 3H, 5J = 4.4 Hz, Me), 7.45–7.58
(m, 3H, H–Ar), 7.69 (s, 1H, H4), 7.85–7.88 (m, 2H, H–Ar),
8.89 (s, 1H, H8) ppm; 13C NMR (100 MHz, CDCl3):
ˇ´
´
ˇ ´ ´
9. Mijin DZ, Uscumlic GS, Perisic-Janjic NU, Valentic NV (2006)
Chem Phys Lett 418:223
10. Yang Y, Sun L, Dong S, Wang X, Yang L, Wu X, Bai H, Zhao Y
(2008) Mendeleev Commun 18:186
11. Yi H, Song L, Wang W, Liu J, Zhu S, Deng H, Shao M (2010)
Chem Commun 46:6941
12. Carles L, Narkunan K, Penlou S, Rousset L, Bouchu D, Ciufolini
MA (2002) J Org Chem 67:4304
13. Gorobets NY, Yousefi BH, Belaj F, Kappe CO (2004) Tetrahe-
dron 60:8633
4
d = 18.8 (q, J = 5.0 Hz, Me), 109.7 (C5), 116.1 (CN),
114.0 (C3), 120.2 (q, 1J = 274 Hz, CF3), 129.1, 129.4,
2
131.8, 133.3 (C–Ar), 135.9 (q, J = 32.7 Hz, C6), 149.6
(C4), 155.3 (C8), 169.4 (C=O) ppm; GC/MS (CI): m/z =
306 (MH?, 1), 264 (5), 202 (100).
14. Mathews A, Anabha ER, Sasikala KA, Lathesh KC, Krishnaraj
KU, Sreedevi KN, Prasanth M, Devaky KS, Asokan CV (2008)
Tetrahedron 64:1671
(E)-2-(Benzylideneamino)-2,3,5,6,7,8-hexahydro-3-oxo-1-
(trifluoromethyl)-4-isoquinolinecarbonitrile
15. Litvinov VP (1999) Russ Chem Rev 68:737
16. Ismail MMF, Noaman E (2005) Med Chem Res 14:382
17. Zhang XH, Zhong W, Li XZ, Li S (2009) Chin Chem Lett 20:771
18. Colla A, Clar G, Martins MAP, Krimmer S, Fischer P (1991)
Synthesis 483
19. Martins MAP, Cunico W, Pereira CMP, Sinhorin AP, Flores
AFC, Bonacorso HG, Zanatta N (2004) Curr Org Chem 1:391
20. Druzhinin SV, Balenkova ES, Nenajdenko VG (2007) Tetrahe-
dron 63:7753
21. Chiappe C, Malvaldi M, Pomelli CS (2010) Green Chem 12:1330
22. Martins MAP, Frizzo CP, Moreira DN, Zanatta N, Bonacorso HG
(2008) Chem Rev 108:2015
23. Chiappe C, Pieraccini D (2005) J Phys Org Chem 18:275
24. Valderrama JO, Robles PA (2007) Ind Eng Chem Res 46:1338
25. Harper JB, Kobrak MN (2006) Mini Rev Org Chem 3:253
26. Martins MAP, Moreira DN, Frizzo CP, Longhi K, Zanatta N,
Bonacorso HG (2008) J Braz Chem Soc 19:1361
(7k, C18H14F3N3O)
Yield 63%; m.p.: 176–179 °C; 1H NMR (400 MHz,
CDCl3): d = 1.74–1.79 (m, 2H, CH2), 1.82–1.88 (m, 2H,
CH2), 2.72 (t, 2H, CH2), 2.88 (t, 2H, CH2), 7.47–7.51 (m,
2H, H–Ar), 7.56–7.61 (m, 1H, H–Ar), 7.86–7.88 (m, 2H,
H–Ar), 8.83 (s, 1H, H8) ppm; 13C NMR (100 MHz,
4
CDCl3): d = 20.9 (C6), 21.3 (C5), 24.3 (q, J = 4.4 Hz,
C8), 28.3 (C7), 100.3 (C4), 112.0 (C8a), 113.0 (CN), 121.5
1
(q, J = 278 Hz, CF3), 128.1, 129.0, 129.4, 131.5, 133.3
(C–Ar), 142.6 (q, 2J = 35 Hz, C1), 153.3 (C4a), 156
(C10), 170.1 (C=O) ppm; GC/MS (CI): m/z = 419 (M?
?
CH5 ? 2C2H7?, 21), 392 (M? ? CH5 ? C2H7?, 100),
?
?
243 (29), 104 (38).
ˇ ´
´
´ ˇ
27. Misic-Vukovic M, Radojkovic-Velickovic M (1992) J Chem Soc
´
Acknowledgments The authors thank the Conselho Nacional de
Perkin Trans 2 1965
28. MacFarlane DR, Pringle JM, Johansson KM, Forsyth SA, Forsyth
M (2006) Chem Commun 18:1905
29. Oliver-Bourbigou H, Magna L, Morvan D (2010) Appl Catal A
Gen 373:1
´
Desenvolvimento Cientıfico e Tecnologico—CNPq (Universal/Proc.
485893/2007-0; Universal/Proc. 471519/2009-0; MAPA/Proc. 578426/
´
`
2008-0) and the Fundac¸a˜o de Amparo a Pesquisa do Estado do Rio
Grande do Sul—FAPERGS (PRONEX/Proc. 10/0037-8) for financial
support. The fellowships from CNPq (M.A.P.M., N.Z., H.G.B.,
P.T.C., M.R.B.M., D.N.M., K.L.), CAPES (C.P.F., PRODOC/Proc.
2684-32/2010, and L.B.), and FAPERGS are also acknowledged. The
30. Lee JW, Shin JY, Chun YS, Jang HB, Song CE, Lee S (2010)
Acc Chem Res 7:985
´
´
authors also thank Maria Angeles Garcıa and Rosa M. Claramunt
(UNED, Madrid, Spain) for the 13C CPMAS-NMR analysis.
References
1. Rigby JH (2000) Synlett 1
2. De Clerep E (1999) Farmaco 54:26
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