Comparative use of solvent-free KF-Al2O3 and K 2CO3 in acetone in the synthesis of quinoxaline 1,4-dioxide derivatives designed as antimalarial drug candidates

Article abstract of DOI:10.1002/jhet.5570420718

In this paper we describe two new basic conditions for the synthesis of quinoxaline 1,4-dioxide derivatives in moderate to good yields. These conditions, exemplified by the use of K₂CO₃ in acetone or KF/Al₂O₃ in

Full text of DOI:10.1002/jhet.5570420718

Nov-Dec 2005
1381
Comparative Use of Solvent-free KF-Al O and K CO in Acetone
2
3
2
3
in the Synthesis of Quinoxaline 1,4-Dioxide Derivatives Designed
as Antimalarial Drug Candidates
1,2
1
1
1
1
1
L. M. Lima , B. Zarranz , A. Marin , B. Solano , E. Vicente , S. Pérez Silanes ,
1*
1
I. Aldana and A. Monge
1*
Unidad en Investigación y Desarrollo de Medicamentos,
Centro de Investigación en Farmacobiología Aplicada (CIFA),
University of Navarra, 31080 Pamplona, Spain
2
Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio),
Faculdade de Farmácia, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro,
PO Box 68024, RJ 21944-970, Brazil
Received April 14, 2005
In this paper we describe two new basic conditions for the synthesis of quinoxaline 1,4-dioxide deriva-
tives in moderate to good yields. These conditions, exemplified by the use of K CO in acetone or KF/Al O
2
3
2 3
in the absence of an organic solvent, were reproducible and applicable to the synthesis of 2-(carboethoxy)-3-
phenylquinoxaline 1,4-dioxide derivatives substituted in position 4 with electron-donating or electron-with-
drawing groups.
J. Heterocyclic Chem., 42, 1381 (2005).
Introduction.
was carried out in order to evaluate their antimalarial pro-
file (Chart 1). This paper describes the systematic study of
base and acid catalyst condensation of benzofurazan oxide
(12) with ethyl benzoylacetate, as well as the comparative
Interest in the preparation and reactions of quinoxaline
1,4-dioxides remains high partly due to the diverse biolog-
ical activity observed in this type of heterocyclic com-
pounds [1-3]. Our research group has recently described
the preparation and pharmacological evaluation of various
quinoxaline 1,4-dioxides derivatives with antichagas, anti-
malarial, anticancer and antituberculosis activities [4-10].
For example, we reported that compound, 3-amino-2-
quinoxalinecarbonitrile 1,4-dioxide (1), displays a
hypoxia-selective cytotoxicity in cell culture which is sim-
ilar to that observed for tirapazamine (TZP, 2), a clinically
promising anticancer agent that selectively kills the
hypoxic cells [4-5].
use of solvent free KF-Al O and K CO in acetone in the
2
3
2
3
synthesis of the target esters (4-11) (Tables 1 and 2).
Results and Discussion.
Benzofurazan oxide (12) reacts with enamines that are
generated in situ and also with enolates in order to form
quinoxaline di-N-oxide in good yield [12-13]. This reac-
tion, which has been given the name of Beirut reaction, is
an excellent method for preparing a variety of heterocyclic
compounds.
In an attempt to optimize the pharmacological activity of
compound (3), a prototype of an antimalarial drug candi-
date [11], the synthesis of 2-(carboethoxy)-3-phenyl-
quinoxaline 1,4-dioxide funcionalized derivatives (4-11)
However, contrary to the condensation of benzofurazan
oxide (12) with enamines, the use of β-keto-esters in a
basic medium give quinoxaline di-N-oxide in low yields.
For instance, the preparation of 2-methyl-3-car-

1382
L. M. Lima, B. Zarranz, A. Marin, B. Solano, E. Vicente, S. Pérez Silanes, I. Aldana and A. Monge
Vol. 42
boethoxyquinoxaline di-N-oxide, using triethylamine as
the base and solvent, resulted in the formation of the
desired product in 22% yield [13]. Nevertheless, some
exceptions were found, as exemplified by the work of
Kluge and coworkers, which describes the synthesis of 2-
(carboethoxy)-3-phenylquinoxaline 1,4-dioxide (4) in
47% of yield, using calcium hydroxide as base and 2-
propanol as solvent [14].
In a continuing effort to synthesize new antimalarial
drug candidates, a proposal was made to substitute the
nitrile group, present in lead-compound 3, with a car-
boethoxy moiety (Chart 1). A decision was made to vary
the electronic profile of phenyl moiety and to correlate
these modifications with the antimalarial profile of targets
esters (4-11) (Chart 1).
The synthetic strategy was initiated by a systematic study
carried out on the condensation of benzofurazan oxide (12)
with ethyl benzoylacetate in order to identify a new
methodology for the synthesis of 2-(carboethoxy)-3-
phenylquinoxaline 1,4-dioxide (4), previously described by
Kluge and coworkers [14], followed by subsequent use of
the selected methodology in the preparation of the target
esters (5-11). Thus, 12 was condensed with ethyl benzoy-
lacetate in triethylamine and chloroform (as base and sol-
vent, respectively) at room temperature [11]. Surprisingly,
after seven days of reaction, the desired product, 2-(car-
boethoxy)-3-phenylquinoxaline 1,4-dioxide (4), was
obtained in very low yield (Table 1). In an attempt to signif-
icantly improve this yield, triethylamine was substituted for
morpholine or piperidine but without success (Table 1). The
attempts to change the solvent and the reaction temperature
failed to give (4) in good yields (Table 1). Therefore, the
use of sodium ethoxide in ethanol for the formation of (4)
was studied [15]; the results obtained were unexpected. In
fact, using this methodology, it was impossible to isolate
the desired derivative (4). After acidification of the aqueous
phase, a complex mixture of compounds was obtained but
the separation of these compounds by silica gel column
chromatography was not possible.
The next step taken was to investigate the use of an inor-
ganic base as catalyst for the aforementioned chemical
transformation. Condensation of benzofurazan oxide (12)
with ethyl benzoylacetate was carried out in the presence
of potassium carbonate at room temperature, using acetone
as the solvent. The result was the formation of (4) in 50%
yield (Table 1). With this promising result, an attempt was
made to improve the yield using a more polar solvent, such
as N,N-dimethylformamide (DMF). No significant differ-
ences were observed in the reactions carried out in the
presence of acetone or DMF (Table 1).
Considering the versatility of potassium fluoride on alu-
mina (KF/Al O ), as an agent for inducing different chem-
2
3
ical transformations [16], the use of KF/Al O as a base
2
3
and solid support, in the absence of an organic solvent, in
the condensation of 12 with ethyl benzoylacetate was stud-
ied. Interestingly, the condensation step was carried out
spontaneously, resulting in the formation of derivative (4)
in 38% yield (Table 1).
In the condensation of 12 with ethyl benzoylacetate in an
acid catalytic version, ammonium acetate in a mixture of
Table 1
Different Conditions for the Synthesis of 2-(Carboethoxy)-3-phenylquinoxaline 1,4-Dioxide
W
Reagent
Solvent
Temperature
Time
Yield (%)
H
H
H
H
H
H
H
H
H
H
H
Et N
Morpholine
Piperidine
CHCl
CHCl
CHCl
CHCl
EtOH
EtOH
EtOH
acetone
DMF
r.t.
r.t.
r.t.
reflux
reflux
reflux
r.t.
r.t.
r.t.
r.t.
reflux
7 days
7 days
7 days
30 h
30 h
30 h
1 h
2 h
2 h
5
7
5
0*
8
3
3
3
3
3
3
Et N
3
Et N
3
Morpholine
NaOEt
0
K CO
50
53
38
13
2
3
K CO
2
3
KF-Al O
XX
spontaneous
7 days
2
3
Ac(NH )
toluene/AcOH
4 2
*complex mixture of product soluble in aqueous basic phase

Nov-Dec 2005
Comparative Use of Solvent-free KF-Al O and K CO
3
1383
2
3
2
toluene and acetic acid [17], under reflux for seven days,
resulted in the formation of (4) in only 13% yield.
Once the systematic study of the condensation of benzo-
furazan oxide (12) with ethyl benzoylacetate under differ-
The assignment of gross structural features for each 2-
(carboethoxy)-3-phenylquinoxaline 1,4-dioxide derivative
was unequivocally determined by H-NMR, C-NMR,
IR, mass spectra and elemental analyses.
1
13
Table 2
Synthesis of 2-(Carboethoxy)-3-phenylquinoxaline 1,4-Dioxide Derivatives Applying Methods A and B. Method A: 12+ Functionalized
Ethyl Benzoylacetate/K CO /acetone/r.t.; Method B: 12 + Functionalized Ethyl Benzoylacetate//KF-Al O 40% w/t; r.t
2
3
2 3
Compounds
W
s
Method
Time (hr)
Yield (%)
Method
Time (hr)
Yield (%)
p
4
5
6
7
8
9
10
11
H
F
Cl
Br
CH
CF
NO
OCH
0
A
A
A
A
A
A
A
A
2
2
2
2
2
2
2
2
50
35
34
64
46
60
60
15
B
B
B
B
B
B
B
B
spontaneous
spontaneous
spontaneous
spontaneous
spontaneous
spontaneous
No reaction
spontaneous
38
34
48
40
36
31
0
0.15
0.24
0.26
-0.14
0.53
0.81
-0,28
3
3
2
33
3
Conclusions.
ent conditions was concluded, the methodologies that had
led to better yields of 4 were selected. A study in which
the electronic character of the β-keto esters was varied
was then carried out (Table 2). As shown in Table 2, the
condensation of benzofurazan oxide (12) with para-sub-
This study permitted the identification of two new basic
conditions for the synthesis of quinoxaline 1,4-dioxide
derivatives in moderate to good yields. These conditions,
exemplified by the use of K CO in acetone or by the use
2
3
stituted ethyl benzoylacetate, using K CO in acetone at
2
3
of KF/Al O , in the absence of an organic solvent, were
2
3
room temperature for two hours, resulted in the formation
of the corresponding quinoxaline di-N-oxides (4-11) in
moderate to good yields. These results appear to indicate
that the condensation step was influenced by the electronic
profile of the β-keto-ester because significant differences
were found upon comparing the condensation of 12 with
reproducible and applicable to the synthesis of 2-(car-
boethoxy)-3-phenylquinoxaline 1,4-dioxide derivatives
substituted in position 4 with electron-donating or elec-
tron-withdrawing groups. In terms of simplicity, cost, and
availability of reagents, the use of potassium carbonate in
acetone appeared to be the method of choice for large-
scale applications. The reaction which was carried out
using 73.4 mmol of benzofurazan oxide (12) and 73.4
mmol of β-keto-ester resulted in the formation of the
desired product without a significant loss of yield.
that of ethyl-(4-nitrobenzoyl)acetate (σ = 0.81) and with
p
that of ethyl-(4-methoxylbenzoyl) acetate (σ = -0.28)].
p
These results suggest that β-keto-ester attaches to an elec-
tron-withdrawing group (positive value of σ ), facilitating
p
the condensation step with benzofurazan oxide (12) and
resulting in the formation of quinoxaline 1,4-dioxide in
superior yields. In contrast, no significative differences
EXPERIMENTAL
Chemistry.
were observed for the condensation when using KF/Al O
2
3
as the catalyst, in the absence of organic solvent.
However, this transformation seemed to depend on the
physical state of the β-keto-ester. In other words, it
appears that at least one of the reagents used in this trans-
formation step must be a liquid in order for the chemical
conversion to be a success; no reaction was found when a
solid β-keto-ester, such as (4-nitrobenzoyl)acetate, was
used (Table 2).
Melting points were determined with a Mettler FP82+FP80
apparatus (Greifense, Switzerland) and have not been corrected.
1
The H NMR spectra were recorded on a Bruker AC-200E
instrument (200 MHz) and Bruker 400 Ultrashield (400 MHz),
using TMS as the internal standard and with DMSO-d and
6
CDCl as the solvent; the chemical shifts are reported in ppm (δ)
3
and coupling constants (J) values are given in Hertz (Hz). Signal
multiplicities are represented by: s (singlet), d (doublet), t

1384
L. M. Lima, B. Zarranz, A. Marin, B. Solano, E. Vicente, S. Pérez Silanes, I. Aldana and A. Monge
Vol. 42
(triplet), q (quadruplet), dd (double doublet) and m (multiplet).
The IR spectra were performed on a Perkin Elmer 1600 FTIR
(Norwalk, CT, USA) in KBr pellets; the frequencies are
expressed in cm . Elemental microanalyses were obtained on an
Elemental Analyzer (Carlo Erba 1106, Milan, Italy) from vac-
uum-dried samples. The analytical results for C, H, and N, were
Anal. Calcd. for C H N O : C, 65.80; H, 4.52; N, 9.03.
17 14 2 4
Found: C, 65.65; H, 4.57; N, 8.98.
2-(Carboethoxy)-3-(4'-fluoro)phenylquinoxaline 1,4-Dioxide
(5).
-1
The derivative (5) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-fluorobenzoyl)acetate as yellow
powder (Methods A and B: 35% and 34% yields, respectively).
within 0.4 of the theoretical values.

Alugram SIL G/UV
(Layer: 0.2 mm) (Macherey-Nagel
254
1
H NMR (DMSOd ): δ 1.15 (t, J= 7.2 Hz, OCH CH ); 4.30 (t,
GmbH & Co. KG. Postfach 101352. D-52313 Düren, Germany)
was used for Thin Layer Chromatography and Silica gel 60
(0.040-0.063 mm) for Column flash Chromatography (Merck).
HPLC conditions: Column Nova Pack C18 60 A 4 µm (3.9x150
mm); mobile phase: acetonitrile/water (60:40); flux: 1 mL/min.
Chemicals were purchased from E. Merck (Darmstadt,
Germany), Scharlau (F.E.R.O.S.A., Barcelona, Spain), Panreac
Química S.A. (Montcada i Reixac, Barcelona, Spain), Sigma-
Aldrich Química, S.A., (Alcobendas, Madrid), Acros Organics
(Janssen Pharmaceuticalaan 3a, 2440 Geel, België) and
Lancaster (Bischheim-Strasbourg, France).
6
2
3
J= 7.2 Hz, OCH CH ); 7.21 (t, J= 8.6 Hz, H3' and H5'); 7.64 (m,
2
3
H6 and H7); 7.93 (dd, J= 8.6 Hz and 4.0 Hz, H2' and H6'); 8.66
13
(m, H5 and H8) ppm. C NMR (CDCl ): δ 14.07 (OCH CH ),
3
2
3
63.81 (OCH CH ), 116.41 (C3' and C5'), 120.93 (C5), 121.18
2
3
(C8), 125.77 (C1'), 132.53 (C6), 132.63 (C2' and C6'), 133.24
(C7), 136.46 (C2), 137.78 (C10), 138.76 (C3), 139.13 (C9),
159.65 (CO Et), 163.11 (C4') ppm. Ir (KBr): 3036 (ArC-H),
2
1741 (C=O), 1348 (N-oxide), 1319 (C-F), 771 and 834 (p-substi-
-1
+
tuted phenyl) cm . Mass: 328 (m/z, 100%), 312 (M , 7%), 267
+
+
+
(M , 54%), 239 (M , 62%), 95 (M , 29%).
Anal. Calcd. for C H N O F: C, 62.19; H, 3.96; N, 8.54.
Benzofurazan oxide (12) was prepared as reported [4].
17 13
2 4
Found: C, 62.15; H, 3.82; N, 8.37.
General Procedure for the Preparation of 2-(Carboethoxy)-3-
phenylquinoxaline 1,4-Dioxide 4'-Functionalized Derivatives (4-
11).
2-(Carboethoxy)-3-(4'-chloro)phenylquinoxaline 1,4-Dioxide
(6).
The derivative (6) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-chlorobenzoyl)acetate as yellow
powder (Methods A and B: 34% and 48% yields, respectively).
Metho d A.
The corresponding functionalized ethyl benzoylacetate (7.34
mmol) and 9.55 mmol of potassium carbonate were added to a
solution of 7.34 mmol of benzofurazan oxide (12) in 50 mL of
acetone. The suspension was stirred at room temperature for two
hours. The quinoxaline 1,4-dioxide derivatives (4-11) were iso-
lated by adding 50 mL of water, followed by extraction with
dichlorometane (5 x 40 mL). The organic layer was dried
1
H NMR (CDCl ): δ 1.18 (t, J= 7.2 Hz, OCH CH ); 4.32 (t, J=
3
2
3
7.2 Hz, OCH CH ); 7.53 (dd, J= 8.8 Hz and 1.6 Hz, H3' and
2
3
H5'); 7.58 (dd, J= 8.8 Hz and 1.6 Hz, H2' and H6'); 7.95 (m, H6
13
and H7); 8.68 (m, H5 and H8) ppm. C NMR (CDCl ): δ 14.07
3
(OCH CH ), 63.86 (OCH CH ), 120.94 (C5), 121.18 (C8),
2
3
2
3
126.19 (C1'), 129.54 (C2' and C6'), 131.19 (C3' and C5'), 132.69
(C6), 133.26 (C7), 136.59 (C2), 137.61 (C4'), 137.82 (C10),
(Na SO ), filtered, and evaporated to dryness. The residue was
2
4
purified by recrystallization from a mixture of methanol/ether/n-
hexane (2:4:4). Yields 15-64%.
138.76 (C3), 139.01 (C9), 159.59 (CO Et) ppm. Ir (KBr): 3029
2
(ArC-H), 1745 (C=O), 1341 (N-oxide), 1090 (C-Cl), 771 and 822
-1
+
(p-substituted phenyl) cm . Mass: 344 (m/z, 6%), 328 (M , 2%),
Method B.
+
+
+
151 (M , 10%), 139 (M , 100%), 111 (M , 19%).
Anal. Calcd. for C H N O Cl: C, 59.30; H, 3.78; N, 8.14.
Appropriate stoichometric quantities of benzofurazan oxide
(12) (7.34 mmol) and of functionalized ethyl benzoylacetate (7.34
mmol) with 1 g of KF-Al O (40% w/t) were thoroughly mixed in
17 13
2 4
Found: C, 58.99; H, 3.83; N, 8.17.
2
3
an agate mortar; an instantaneous change of color was observed in
the mixture. The quinoxaline 1,4-dioxide derivatives (4-11) were
isolated by adding 100 mL of dichoromethane, followed by filtra-
tion and evaporation of the organic layer under reduced pressure.
The residue was purified by recrystallization from a mixture of
methanol/ether/n-hexane (2:4:4). Yields 31-48%.
2-(Carboethoxy)-3-(4'-bromo)phenylquinoxaline 1,4-Dioxide
(7).
The derivative (7) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-bromobenzoyl)acetate as yellow
powder (Methods A and B: 64% and 40% yields, respectively).
1
H NMR (CDCl ): δ 1.18 (t, J= 7.2 Hz, OCH CH ); 4.31 (t, J=
3
2
3
7.2 Hz, OCH CH ); 7.52 (dd, J= 8.4 Hz and 1.6 Hz, H3' and
2-(Carboethoxy)-3-phenylquinoxaline 1,4-Dioxide (4).
2
3
H5'); 7.69 (dd, J= 8.4 Hz and 1.6 Hz, H2' and H6'); 7.94 (m, H6
The derivative (4) was obtained by condensation of benzofu-
razan oxide (12) with ethyl benzoylacetate as yellow powder
13
and H7); 8.66 (m, H5 and H8) ppm. C NMR (CDCl ): δ 14.08
3
(OCH CH ), 63.89 (OCH CH ), 120.96 (C5), 121.19 (C8),
2
3
2
3
1
(Methods A and B: 50% and 38% yields, respectively). H NMR
126.00 (C4'), 126.67 (C1'), 131.84 (C2' and C6'), 132.51 (C3' and
C5'), 132.70 (C6), 133.27 (C7), 136.28 (C2), 137.83 (C10),
(CDCl ): δ 1.08 (t, J= 7.2 Hz, OCH CH ); 4.25 (t, J= 7.2 Hz,
3
2
3
OCH CH ); 7.53 (m, H3'-H5'); 7.61 (m, H2' and H6'); 7.91 (m,
2
3
138.78 (C3), 139.05 (C9), 159.58 (CO Et) ppm. Ir (KBr): 2985
2
13
H6 and H7); 8.65 (m, H5 and H8) ppm. C NMR (CDCl ): δ
13.98 (OCH CH ), 63.65 (OCH CH ), 120.89 (C5), 121.08
3
(ArC-H), 1742 (C=O), 1349 (N-oxide), 1013 (C-Br), 779 and
2
3
2
3
-1
+
821 (p-substituted phenyl) cm . Mass: 390 (m/z, 25%), 325 (M ,
(C8), 127.84 (C1'), 129.16 (C3' and C5'), 130.15 (C2' and C6'),
131.26 (C4'), 132.51 (C6), 132.53 (C7), 136.53 (C2), 137.73
+
+
26%), 220 (M , 53%), 91 (M , 95%).
Anal. Calcd. for C H N O Br: C, 52.44; H, 3.34; N, 7.20.
17 13
2 4
(C10), 138.81 (C3), 140.08 (C9), 159.66 (CO Et) ppm. Ir (KBr):
2
Found: C, 52.28; H, 3.37; N, 7.13.
2978 (ArC-H), 1746 (C=O), 1352 (N-oxide), 701 and 666
-1
(mono-substituted phenyl) cm . Mass: 310 (m/z, 100%), 294
2-(Carboethoxy)-3-(4'-methyl)phenylquinoxaline 1,4-Dioxide
(8).
+
+
+
+
(M , 6%), 249 (M , 51%), 221 (M , 46%), 77 (M , 46%).

Nov-Dec 2005
Comparative Use of Solvent-free KF-Al O and K CO
3
1385
2
3
2
The derivative (8) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-methylbenzoyl)acetate as yellow
powder (Methods A and B: 46% and 36% yields, respectively).
NMR (CDCl ): δ 1.17 (t, J= 7.2 Hz, OCH CH ); 3.89 (s, OCH );
3 2 3 3
4.31 (t, J= 7.2 Hz, OCH CH ); 7.05 (dd, J= 8.8 Hz and 1.6 Hz, H3'
2
3
and H5'); 7.60 (dd, J= 8.8 Hz and 1.6 Hz, H2' and H6'); 7.91 (m, H6
1
13
H NMR (CDCl ): δ 1.15 (t, J= 7.2 Hz, OCH CH ); 2, 47 (s,
and H7); 8.66 (m, H5 and H8) ppm. C NMR (CDCl ): δ 14.13
3
2
3
3
ArCH ); 4.30 (t, J= 7.2 Hz, OCH CH ); 7.35 (d, J= 8.0 Hz, H3'
(OCH CH ), 55.84 (ArOCH ), 63.66 (OCH CH ), 114.63 (C3'
3
2
3
2 3 3 2 3
and H5'); 7.52 (d, J= 8.0 Hz, H2' and H6'); 7.91 (m, H6 and H7);
and C5'), 119.71 (C1'), 120.86 (C5), 121.17 (C8), 131.83 (C2' and
C6'), 132.89 (C6), 133.06 (C7), 136.62 (C2), 137.53 (C10), 138.78
13
8.69 (m, H5 and H8) ppm. C NMR (CDCl ): δ 14.03
3
(OCH CH ), 22.02 (ArCH ), 63.64 (OCH CH ), 120.89 (C5),
(C3), 139.97 (C9), 159.89 (CO Et), 161.82 (C4') ppm. Ir (KBr):
2
3
3
2
3
2
121.21 (C8), 124.83 (C1'), 129.88 (C3' and C5'), 130.01 (C2' and
C6'), 132.07 (C6), 132.39 (C7), 136.60 (C2), 137.64 (C10),
3090 (ArC-H), 1740 (C=O), 1343 (N-oxide), 1261 (C-O-C), 777
-1
and 829 (p-substituted phenyl) cm . Mass: 340 (m/z, 100%), 324
+
+
+
+
138.83 (C3), 140.26 (C9), 141.65 (C4'), 159.79 (CO Et) ppm. Ir
(M , 15%), 262 (M , 39%), 235 (M , 31%), 179 (M , 96%).
Anal. Calcd. for C H N O : C, 63.53; H, 4.71; N, 8.23.
2
(KBr): 3023 (ArC-H), 1745 (C=O), 1349 (N-oxide), 777 and 818
18 16
2 5
-1
+
(p-substituted phenyl) cm . Mass: 324 (m/z, 100%), 308 (M ,
Found: C, 63.37; H, 4.72; N, 8.13.
+
+
+
7%), 263 (M , 40%), 235 (M , 30%), 105 (M , 44%).
Anal. Calcd. for C H N O : C, 66.66; H, 4.94; N, 8.64.
Acknowledgements.
18 16
2 4
Found: C, 66.39; H, 4.96; N, 8.52.
We wish to thank the "Ministerio Español de Ciencia y
Tecnología" (Project SAF 2002-00073) for their financial contri-
bution to this research project and also thank the "Coordenação
de Aperfeiçoamento de Pessoal de Nível Superior" (CAPES; BR)
for the fellowship (to LML; BEX0520/04-7) received.
2-(Carboethoxy)-3-(4'-trifluoromethyl)phenylquinoxaline 1,4-
Dioxide (9).
The derivative (9) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-trifluoromethylbenzoyl)acetate as
orange crystals (Methods A and B: 60% and 31% yields, respec-
1
REFERENCES AND NOTES
tively). H NMR (DMSOd ): δ 1.12 (t, J= 7.2 Hz, OCH CH );
6
2
3
4.29 (t, J= 7.2 Hz, OCH CH ); 7.77 (d, J= 8.8 Hz, H2' and H6');
2
3
7.82 (dd, J= 8.8 Hz, H3' and H5'); 7.94 (m, H6 and H7); 8.67 (m,
[1] J. P. Dirlan and J. E. Presslitz, J. Med. Chem., 21, 483 (1978).
[2] J. P Dirlan, L. J Czuba, B. W.Dominy, R. B. James, R. M
Pezzullo, J. E. Presslitz and W. W. Windisch, J. Med. Chem., 22, 1118
(1979).
[3] A. Carta, M. Loriga, G. Paglietti, A. Mattana, P. L. Fiori, P.
Mollicotti, L. Sechi and S. Zanetti, Eur. J. Med. Chem., 39, 195 (2004).
[4] A. Monge, J. A. Palop, A. D. de Ceráin, V. Senador, F. J.
Martínez-Crespo, Y. Sainz, S. Narro, E. García, C. de Miguel, M.
González, E. Hamilton, A. J. Barker, E. D. Clarke and D. T Greenhow, J.
Med. Chem., 38, 1786 (1995).
13
H5 and H8) ppm. C NMR (CDCl ): δ 13.94 (OCH CH ),
3
2
3
63.92 (OCH CH ), 120.60 (ArCF ), 120.99 (C5), 121.19 (C8),
2
3
3
125.31 (C4'), 126.14 (C3' and C5'), 130.85 (C2' and C6'), 131.48
(C1'), 132.87 (C6), 133.36 (C7), 136.23 (C2), 137.99 (C10),
138.66 (C9), 138.77 (C3), 159.42 (CO Et) ppm. Ir (KBr): 2955
2
(ArC-H), 1747 (C=O), 1350 (N-oxide), 1319 (C-F), 771 and 834
-1
+
(p-substituted phenyl) cm . Mass: 378 (m/z, 64%), 362 (M ,
+
+
+
5%), 317 (M , 39%), 289 (M , 57%), 179 (M , 100%).
Anal. Calcd. for C H N O F : C, 57.14; H, 3.44; N, 7.41.
[5] A. Monge, F. J. Martinez-Crespo, A. Lopez de Cerain, J. A.
Palop, S. Narro, V. Senador, A. Marin, Y. Sainz, M. Gonzalez, E.
Hamilton, A. J. Barker, E. D. Clarke and D. T. Greenhow, J. Med. Chem.,
38, 4488 (1995).
18 13
2 4 3
Found: C, 57.12; H, 3.36; N, 7.29.
2-(Carboethoxy)-3-(4'-nitro)phenylquinoxaline 1,4-dioxide (10).
[6] G. Aguirre, H. Cerecetto, R. Di Maio, M. González, M. E. M.
Alfaro, A. Jaso, B. Zarranz, M. A. Ortega, I. Aldana and A. Monge,
Bioorg. Med. Chem. Lett., 14, 3835 (2004).
[7] B. Zarranz, A. Jaso, I. Aldana and A. Monge, Bioorg. Med.
Chem., 11, 2149 (2003).
[8] A. Jaso, B. Zarranz, I. Aldana and A. Monge, Eur. J. Med.
Chem., 38, 791 (2003).
[9] M. A. Ortega, M. J. Morancho, F. J. Martinez-Crespo, Y.
Sainz, M. E. Montoya, A. D. de Ceráin and A. Monge, Eur. J. Med.
Chem., 35, 21 (2000).
[10] I. Aldana, M. A. Ortega, A. Jaso, B. Zarranz, P. Oporto, A.
Jiménez, A. Monge and E. Deharo, Die Pharmazie, 58, 68 (2002).
[11] B. Zarranz, A. Jaso, I. Aldana, A. Monge, S. Maurel, V.
Jullian and M. Sauvain, Arzneim-Forsch./Drug Res. (2005), in press.
[12] M. J. Haddadin and C. H. Issidorides, Tetrahedron Lett., 6,
3253 (1965).
The derivative (10) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-nitrobenzoyl)acetate as yellow
powder (Methods A and B: 60% and 0% yields, respectively). H
1
NMR (DMSOd ): δ 1.17 (t, J= 7.2 Hz, OCH CH ); 4.30 (t, J=
6
2
3
7.2 Hz, OCH CH ); 7.85 (dd, J= 8.8 Hz and 1.6 Hz, H2' and
2
3
H6'); 7.97 (m, H6 and H7); 8.40 (dd, J= 8.8 Hz and 1.6 Hz, H3'
13
and H5'); 8.68 (m, H5 and H8) ppm. C NMR (CDCl ): δ 14.09
3
(OCH CH ), 64.11 (OCH CH ), 121.03 (C5), 121.18 (C8),
2
3
2
3
124.25 (C2' and C6'), 131.77 (C1'), 131.79 (C3' and C5'), 133.13
(C6), 133.52 (C7), 135.99 (C2), 137.92 (C10), 138.11 (C3),
138.75 (C9), 149.41 (C4'), 159.34 (CO Et) ppm. Ir (KBr): 2981
2
(ArC-H), 1740 (C=O), 1521 (C-NO ), 1342 (N-oxide), 777 and
2
-1
+
851 (p-substituted phenyl) cm . Mass: 355 (m/z, 26%), 339 (M ,
4%), 294 (M , 10%), 179 (M , 100%), 144 (M , 33%).
Anal. Calcd. for C H N O : C, 57.46; H, 3.66; N, 11.83.
+
+
+
17 13
3 6
[13] M. J. Haddadin and C. H. Issidorides, J. Org. Chem., 31, 4067
(1966).
Found: C, 57.38; H, 3.72; N, 11.74.
[14] A. F. Kluge, M. L. Maddox and G. S. Lewis, J. Org. Chem.,
45, 1909 (1980).
[15] W. Yu and Z. Jin, Tetrahedron Lett., 42, 369 (2001).
[16] B. E. Blass, Tetrahedron, 58, 9301 (2002).
[17] F. Risitano, G. Grassi, F. Foti and C. Bilardo, Tetrahedron, 56,
9669 (2000).
2-(Carboethoxy)-3-(4'-methoxy)phenylquinoxaline 1,4-Dioxide
(11).
The derivative (11) was obtained by condensation of benzofu-
razan oxide (12) with ethyl (4-methoxybenzoyl)acetate as yellow
1
powder (Methods A and B: 15% and 33% yields, respectively). H