Substitutions of fluorine atoms and phenoxy groups in the synthesis of quinoxaline 1,4-di-N-oxide derivatives

Article abstract of DOI:10.3390/molecules13010086

The unexpected substitution of fluorine atoms and phenoxy groups attached to quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction

Full text of DOI:10.3390/molecules13010086

Molecules 2008, 13, 86-95
molecules
ISSN 1420-3049
2008 by MDPI
www.mdpi.org/molecules
©
Full Paper
Substitutions of Fluorine Atoms and Phenoxy Groups in the
†
Synthesis of Quinoxaline 1,4-di-N-oxide Derivatives
Esther Vicente, Raquel Villar, Asunción Burguete, Beatriz Solano, Saioa Ancizu,
Silvia Pérez-Silanes, Ignacio Aldana* and Antonio Monge
Unidad de Investigación y Desarrollo de Medicamentos, Centro de Investigación en Farmacobiología
Aplicada (CIFA), University of Navarra, 31080 Pamplona, Spain
†
th
Initial data presented at the 11 International Electronic Conference on Synthetic Organic Chemistry,
ECSOC-11, http://www.usc.es/congresos/ecsoc/11/ECSOC11.htm, 1-30 November 2007, paper
a035
*
Author to whom correspondence should be addressed. E-mail: ialdana@unav.es (for I. Aldana)
Received: 18 December 2007; in revised form: 16 January 2008 / Accepted: 16 January 2008 /
Published: 18 January 2008
Abstract: The unexpected substitution of fluorine atoms and phenoxy groups attached to
quinoxaline or benzofuroxan rings is described. The synthesis of 2-benzyl- and 2-phenoxy-
3
-methylquinoxaline 1,4-di-N-oxide derivatives was based on the classical Beirut reaction.
The tendency of fluorine atoms linked to quinoxaline or benzofuroxan rings to be replaced
by a methoxy group when dissolved in an ammonia saturated solution of methanol was
clearly demonstrated. In addition, 2-phenoxyquinoxaline 1,4-di-N-oxide derivatives
became 2-aminoquinoxaline 1,4-di-N-oxide derivatives in the presence of gaseous
ammonia.
Keywords: Quinoxaline, N-oxides, Beirut reaction, gaseous ammonia.
Introduction
Quinoxaline and quinoxaline-1,4-di-N-oxide are heterocycles that are frequently used in the
synthesis of biologically active compounds [1-4]. The quinoxaline moiety is described as a bioisoster

Molecules 2008, 13
87
of the quinoline, naphthyl, benzothienyl and other aromatic rings [5], and the widespread activity of
quinoxaline-1,4-di-N-oxide derivatives can be associated with the generation of free radicals [6]. In
our continuing efforts to find quinoxaline-1,4-di-N-oxide derivatives with antimycobacterial [7-9]
antiprotozoal [10-16] and anti-cancer activity [17, 18], a series of 2-benzyl-3-methylquinoxaline 1,4-
di-N-oxide derivatives was proposed. With regards to work carried out by our research team, this
series involves the analogues of 2-benzoyl-3-methylquinoxaline 1,4-di-N-oxide derivatives in which
the carbonyl group has been reduced [7]. In addition, with regards to Carta’s paper [19], this series,
together with a series of 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives, could complete
the bioisosterism replacements based on Grimm’s Hydride Displacement Law (Scheme 1). This law
states that the addition of a hydrogen atom with a pair of electrons (i.e. hydride) to an atom belonging
to groups 4A, 5A, 6A, 7A on the Periodic Table, produces an isoelectronic pseudoatom, showing the
same physical properties as those present in the column immediately behind the initial atom on the
Periodic Table of the Elements [5]. The aim of this work was to obtain 2-benzyl- and 2-phenoxy-3-
methylquinoxaline 1,4-di-N-oxide derivatives as potential antitubercular drug candidates.
Scheme 1. Design of new quinoxaline-1,4-di-N-oxide derivatives with antimycobacterial activity.
Carta et al. 2002
Jaso et al. 2003
O+
N
O+
N
O
R7
R6
S
R7
R6
+
N
+
N
O
O
Bioisosterism
[reduction]
Carta et al. 2004
O+
N
O+
H
O+
N
R7
R6
O
R7
R6
N
N
R7
R6
+
N
+
N
+
N
O
O
O
Grimm's Hydride Displacement Law: -O-, -NH-, -CH2-
Results and Discussion
In a continuing effort to obtain new antitubercular drug candidates, the synthesis of 2-benzyl- and
2
-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives was proposed. The synthesis of each of
these compounds was based on the classical Beirut reaction and, in this case, methanol and gaseous
ammonia were chosen as reaction solvent and catalyst, respectively.
After workup, all the compounds obtained were chemically characterized by thin layer
1
chromatography (TLC), infrared (IR) and nuclear magnetic resonance ( H-NMR) spectra, as well as by
elemental microanalysis. From these analyses, it was realised that the reaction with phenoxyacetone
had failed to give the functionalized 2-phenoxy derivatives; surprisingly, this reaction gave other
quinoxaline 1,4-di-N-oxide derivatives 10-12, with an amino group, instead of the phenoxy moiety,
linked to C2 of the quinoxaline ring (analytical data in the Experimental section). It is well known that

Molecules 2008, 13
88
the phenoxy scaffold is a good leaving group and that the ammonia gas is a potent base; the curious
part is that first the quinoxaline is formed and later, the substitution occurs (the events could not have
occurred in any other way due to the products obtained) (Scheme 2).
Scheme 2. Possible mechanism of reaction for 2-amino-3-methylquinoxaline
1
,4-di-N-oxide derivatives.
O
N
O
.
.
O
H
H
+
N
-
exc.
H
NH4+
:
N
O+
N
O+
N
O+
N
O
O
R7
R6
R7
R6
O
R7
R6
O
+
-
+
+
N
N
N
NH
NH2
O
O
O+
N
O+
N
R7
R6
NH2
R7
R6
O
.
.
H
H
+
δ+
N
N
+
N
H
O
O
O
The experimental conditions (reaction solvent and catalyst) were explored with the aim of obtaining
the target compounds. In an attempt to synthesize the 2-phenoxy derivatives, the catalyst and the
solvent were substituted by piperidine and dichloromethane, respectively. In this case, the 2-phenoxy-
3
-methylquinoxaline 1,4-di-N-oxide (13) was obtained (Scheme 3).
Scheme 3. Synthesis of 2-benzyl- and 2-phenoxy-3-methylquinoxaline 1,4-di-N-oxide derivatives.
O+
N
O+
N
O
R7
R6
R7
R6
NH3
(g)
+
O
+
N
N
CH OH
3
O
(1-9)
O+
N
O+
N
O+
N
O
O
R7
R6
R7
R6
O
O
R7
R6
NH2
O
O
NH3
(g)
+
+
O
+
N
+
N
N
CH OH
3
O
O
(
10-12)
O+
N
O+
N
R7
R6
R7
R6
piperidine
O
+
N
N
2
CH Cl2
O
(13)

Molecules 2008, 13
89
The formation of isomeric quinoxaline 1,4-di-N-oxide was observed in the case of monosubstituted
benzofuroxans. According to previous reports [20], we have observed that 7-substituted quinoxaline
1
,4-di-N-oxide derivatives prevailed over the 6-isomer, or in the case of the methoxy substituent, only
the 7-isomer was formed (NOESY data, not shown). In practice, the workup and purification permitted
isolation of the 7-isomer [21].
On the other hand, it was also observed that the reaction of difluorobenzofuroxan with
benzylacetone in methanol failed to give 2-benzyl-6,7-difluoro-3-methylquinoxaline 1,4-di-N-oxide
1
(
7); the H-NMR spectra of the obtained compound showed the presence of a methoxy group in the
structure and that it corresponded to a 6,7-disubstituted quinoxaline; we consequently thought that,
under these conditions, the fluorine atom in position 6 was being substituted by a methoxy group from
the solvent (compound 6). Such a displacement of the fluorine atom in position 6 has been observed on
other occasions [22]. In an attempt to obtain the 6,7-difluoro derivative, the solvent was changed but
keeping the remainder of the reaction conditions constant. In this case, using dichloromethane as
reaction solvent, 2-benzyl-6,7-difluoro-3-methyl-quinoxaline 1,4-di-N-oxide (7) was obtained
(
Scheme 4).
Scheme 4. Synthesis of 2-benzyl-7-fluoro-6-methoxy- and 2-benzyl-6,7-difluoro-3-
methylquinoxaline 1,4-dioxides.
O+
N
O+
N
O
F
F
F
NH3 (g)
+
O
(6)
+
N
N
CH OH
3
O
O
O+
N
O+
N
O
F
F
F
F
NH3 (g)
+
O
(7)
+
N
N
CH Cl
2 2
O
Finally, we observed another curiosity arising from the use of fluorinated compounds. When we
attempted to prepare R7(R6)-fluorobenzofuroxan by oxidation of the corresponding fluoronitroaniline,
as previously described [23], the compound obtained was actually R7(R6)-methoxybenzofuroxan.
Once again, methanol was present in the reaction as solvent. Therefore R7(R6)-fluorobenzofuroxan
was prepared by thermal decomposition as reported [22, 23, 24].
Scheme 5. Synthesis of 5(6)-fluorobenzofuroxan from the corresponding o-nitroaniline.
O+
N
O+
N
O
F
NO
2
F
NO2
F
NaOH, NaClO
MeOH
reflux
O
O
CH COOH
N
NH2
3
N
N3
Conclusions
Summarizing, this work clearly demonstrates the tendency of fluorine atoms linked to quinoxaline
or benzofuroxan rings to leave their positions and be replaced by a methoxy group when dissolving in
an ammonia saturated solution of methanol. In addition, the 2-phenoxyquinoxaline 1,4-di-N-oxide

Molecules 2008, 13
90
derivatives, in the presence of gaseous ammonia, become 2-aminoquinoxaline 1,4-di-N-oxide
derivatives.
Experimental
General
All the synthesized compounds were chemically characterized by thin layer chromatography (TLC),
1
infrared (IR), nuclear magnetic resonance ( H-NMR), mass spectra (MS) and elemental microanalysis
(
CHN). Alugram SIL G/UV254 (Layer: 0.2 mm) (Macherey-Nagel GmbH & Co. KG., Düren,
Germany) was used for TLC and Silica gel 60 (0.040-0.063 mm, Merck) for Flash Column
1
Chromatography. The H-NMR spectra were recorded on a Bruker 400 Ultrashield instrument (400
MHz), using TMS as the internal standard and with DMSO-d or CDCl as the solvents; the chemical
6
3
shifts are reported in ppm (δ) and coupling constants (J) values are given in Hertz (Hz). Signal
multiplicities are represented by: s (singlet), d (doublet), t (triplet), q (quadruplet), dd (double doublet)
and m (multiplet). The IR spectra were recorded on a Nicolet Nexus FTIR (Thermo, Madison, USA) in
KBr pellets. Mass spectra were measured on a MSD/DS 5973N mod. G2577A mass spectrometer
(
Agilent Technologies, Waldbronn, Germany) equipped with a direct insertion probe (DIP) and the
ionization method was electron impact (EI, 70 eV). Elemental microanalyses were obtained on an
CHN-900 Elemental Analyzer (Leco, Tres Cantos, Spain) from vacuum-dried samples. The analytical
results for C, H, and N, were within ± 0.4 of the theoretical values. Chemicals were purchased from
Panreac Química S.A. (Barcelona, Spain), Sigma-Aldrich Química, S.A. (Alcobendas, Spain), Acros
Organics (Janssen Pharmaceuticalaan, Geel, Belgium) and Lancaster (Bischheim-Strasbourg, France).
General synthesis of 2-benzyl-3-methylquinoxaline 1,4-di-N-oxide derivatives 1-9 [11, 19]
Equimolar amounts (3.0–10.0 mmol) of the appropriate benzofuroxan and benzylacetone were
added to methanol (20 mL) [or dichloromethane (20 mL) for the 6,7-difluoro derivative]. Gaseous
ammonia gas was bubbled for 10 minutes through the mixture, which was then stirred at room
temperature for 4 hours. After evaporating to dryness under reduced pressure, a crude solid was
obtained, which was then washed by adding diethyl ether and purified by recrystallization from a
mixture of methanol/dichloromethane.
-1
1
2
-Benzyl-3-methylquinoxaline 1,4-di-N-oxide (1). IR ν/cm : 1320, 1074, 713; H-NMR (CDCl
δ/ppm: 2.76 (s, 3H, C3-CH ), 4.62 (s, 2H, C2-CH -Ph), 7.29 (m, 5H, CH -C ), 7.85 (m, 2H,
+H ), 8.67 (m, 2H, H +H ).
3
)
3
2
2
6 5
H
H
6
7
5
8
-1
1
2
-Benzyl-7-fluoro-3-methylquinoxaline 1,4-di-N-oxide (2). IR ν/cm : 1321, 1077, 712; H-NMR
CDCl ) δ/ppm: 2.75 (s, 3H, C3-CH ), 4.60 (s, 2H, C2-CH -Ph), 7.30 (m, 5H, CH -C ), 7.58 (ddd,
J=2.74, 7.39, 9.52 Hz, 1H, H ), 8.33 (dd, J= 2.69, 8.75 Hz, 1H, H ), 8.68 (dd, J=5.10, 9.48 Hz, 1H,
).
(
3
3
2
2
6 5
H
6
8
H
5

Molecules 2008, 13
91
-1
1
2
-Benzyl-7-chloro-3-methylquinoxaline 1,4-di-N-oxide (3). IR ν/cm : 1323, 1076, 713; H-NMR
(CDCl
3
) δ/ppm: 2.74 (s, 3H, C3-CH
3
), 4.59 (s, 2H, C2-CH
2
-Ph), 7.30 (m, 5H, CH
2
-C
6
H
5
), 7.77 (dd,
J=2.21, 9.17 Hz, 1H, H ), 8.60 (d, J=9.16 Hz, 1H, H ), 8.69 (d, J=2.20 Hz, 1H, H ).
6
5
8
-1
1
2
-Benzyl-3,7-dimethylquinoxaline 1,4-di-N-oxide (4). IR ν/cm : 1322, 1080, 704; H-NMR (CDCl
3
2
)
-
3 3 2
δ/ppm: 2.63 (s, 3H, C7-CH ), 2.77 (s, 3H, C3-CH ), 4.62 (s, 2H, C2-CH -Ph), 7.30 (m, 5H, CH
C H ), 7.85 (m, 2H, H +H ), 8.67 (m, 2H, H +H ), 7.68 (d, J=8.91 Hz, 1H, H ), 8.47 (s, 1H, H ), 8.54
6
5
6
7
5
8
6
8
(
d, J=8.78 Hz, 1H, H
5
).
-1
1
2
-Benzyl-7-methoxy-3-methylquinoxaline 1,4-di-N-oxide (5). IR ν/cm : 1322, 1071, 707; H-NMR
). δ/ppm: 2.74 (s, 3H, C3-CH ), 4.02 (s, 3H, C7-OCH ), 4.61 (s, 2H, C2-CH -Ph), 7.25 (m, 5H,
(CDCl
3
3
3
2
CH -C H ), 7.43 (dd, J=2.72, 9.49 Hz, 1H, H ), 7.98 (d, J=2.71 Hz, 1H, H ), 8.54 (d, J=9.46 Hz, 1H,
2
6
5
6
8
H
5
).
-1
1
2
-Benzyl-7-fluoro-6-methoxy-3-methylquinoxaline 1,4-di-N-oxide (6). IR ν/cm : 1321, 1078, 703; H-
NMR (CDCl
3
) δ/ppm: 2.75 (s, 3H, C3-CH
3
), 4.11 (s, 3H, C6-OCH
3
), 4.58 (s, 2H, C2-CH
2
-Ph), 7.29
(
m, 5H, CH -C H ), 8.07 (d, J=7.85 Hz, 1H, H ), 8.33 (d, J=10.72 Hz, 1H, H ).
2
6
5
5
8
-1
1
2
-Benzyl-6,7-difluoro-3-methylquinoxaline 1,4-di-N-oxide (7). IR ν/cm : 1322, 1080; H-NMR
(
CDCl
3
) δ/ppm: 2.75 (s, 3H, C3-CH
+H ).
3
), 4.58 (s, 2H, C2-CH
2
-Ph), 7.30 (m, 5H, CH
2
-C
6
H
5
), 8.47 (dd,
J=9.28, 16.80 Hz, 2H, H
5
8
-1
1
2
-Benzyl-6,7-dichloro-3-methylquinoxaline 1,4-di-N-oxide (8). IR ν/cm : 1320, 1074, 713; H-NMR
(CDCl
3
) δ/ppm: 2.74 (s, 3H, C3-CH
3 2 2 6 5
), 4.56 (s, 2H, C2-CH -Ph), 7.33 (m, 5H, CH -C H ), 8.75 (s, 1H,
H
5
); 8.78 (s, 1H, H ).
8
-1
1
2
-Benzyl-3,6,7-trimethylquinoxaline 1,4-di-N-oxide (9). IR ν/cm : 1327, 1082, 706; H-NMR (CDCl
3
)
δ/ppm: 2.52 (s, 6H, C6-CH +C7-CH ), 2.73 (s, 3H, C3-CH ), 4.59 (s, 2H, C2-CH -Ph), 7.27 (m, 5H,
3
3
3
2
2 6 5 8 5
CH -C H ), 8.39 (s, 1H, H ), 8.42 (s, 1H, H ).
General synthesis of 2-amino-3-methylquinoxaline 1,4-di-N-oxide derivatives 10-12.
Equimolar amounts (3.0–10.0 mmol) of the appropriate benzofuroxan and phenoxyacetone were
added to methanol (20 mL). Gaseous ammonia was bubbled through the mixture for 10 minutes and
then it was stirred at room temperature for 4 hours. After evaporating to dryness under reduced
pressure, a crude solid was obtained. This was then washed by adding diethyl ether and purified by
recrystallization from a mixture of methanol/dichloromethane.
-1
1
2
-Amino-3-methylquinoxaline 1,4-di-N-oxide (10). IR ν/cm : 3400, 3290, 1616, 1329; H-NMR
DMSO-d ) δ/ppm: 2.57 (s, 3H, C3-CH ), 7.61 (m, 3H, NH +H ), 7.81 (t, J=7.78 Hz, 1H, H ), 8.31
dd, J=0.72, 8.53 Hz, 1H, H ), 8.37 (dd, J=0.73, 8.53 Hz, 1H, H ).
(
(
6
3
2
6
7
5
8

Molecules 2008, 13
92
-1
1
2
-Amino-7-chloro-3-methylquinoxaline 1,4-di-N-oxide (11). IR ν/cm : 3385, 3262, 1623, 1327; H-
NMR (DMSO-d ). δ/ppm: 2.55 (s, 3H, C3-CH ), 7.61 (dd, J=1.58, 9.07 Hz, 1H, H ), 7.77 (s, 2H,
NH ), 8.26 (d, J=2.23 Hz, 1H, H ), 8.36 (d, J=9.12 Hz, 1H, H ).
6
3
6
2
8
5
-
1
2
-Amino-6,7-dichloro-3-methylquinoxaline 1,4-di-N-oxide (12). IR ν/cm : 3416, 3299, 1617, 1325;
1
H-NMR (DMSO-d
6
3 2 5
). δ/ppm: 2.55 (s, 3H, C3-CH ), 7.86 (s, 2H, NH ), 8.42 (s, 1H, H ), 8.50 (s, 1H,
8
H )
Synthesis of 3-methyl-2-phenoxyquinoxaline 1,4-di-N-oxide (13).
An equimolar amount of phenoxyacetone was added to a solution of the appropriate benzofuroxan
3.0-10.0 mmol) in dry dichloromethane (35 mL). The mixture was allowed to stand at 0 ºC. Piperidine
1 mL) was added dropwise and the reaction mixture was stirred at room temperature in darkness for 4
(
(
hours. After evaporating to dryness under reduced pressure, a crude solid was obtained, which was
then washed by adding diethyl ether (or n-hexane), affording the target compound. The precipitate
-1
obtained was purified by recrystallization from a mixture of methanol/dichloromethane. IR ν/cm :
1
1
7
326, 1093, 760; H-NMR (CDCl
3
) δ/ppm: 2.72 (s, 3H, C3-CH
3
), 6.98 (d, J=7.72 Hz, 2H, H2’+H6’),
+H ); 8.63 (m, 1H,
.19 (t, J= 7.42 Hz, 1H, H4’), 7.39 (dd, J=7.57 Hz, 2H, H3’+H5’); 7.87 (m, 2H, H
6
7
5 8
H ); 8.69 (m, 1H, H ).
Table 1. Structure, analytical data (C, H, N) and MS of the synthesized compounds
O+
N
R7
R6
R2
+
N
CH3
O
Calc. C Calc. H Calc. N
found) (found) (found)
MS (EI, 70
eV): m/z
ID
R2
R6
R7
Formula
MW
(
·
+
7
2.17
71.78)
7.60
67.34)
3.90
64.01)
2.84
72.45)
8.91
68.59)
4.96
65.01)
3.58
63.61)
5.30
(5.27)
4.61
10.52 266 ([M ] ), 249,
(10.24) 232
9.85 284 ([M ] ), 267,
(10.19) 250
9.31 300 ([M ] ), 283,
(9.42) 266
9.99 280 ([M ] ), 263,
(10.30) 246, 230
9.45 296 ([M ] ), 279,
(9.58) 262, 247, 219
8.91 314 ([M ] ), 297,
(8.69) 280, 265, 237
9.27 302 ([M ] ), 285,
(9.00) 268
1
2
3
4
5
6
7
CH
2
2
2
2
2
2
2
-Ph
H
H
H
H
H
F
H
F
C
16
H
14
N
2
O
2
266.30
284.29
300.75
280.33
296.33
314.32
302.28
(
(
(
(
(
(
(
·
+
6
CH
CH
CH
CH
CH
CH
-Ph
-Ph
-Ph
-Ph
-Ph
-Ph
16 2 2
C H13FN O
(4.52)
4.36
·
+
6
Cl
16 2 2
C H13ClN O
(4.30)
5.75
·
+
7
CH
OCH
OCH
3
3
3
C
17
H
H
16
N
N
2
2
O
O
2
3
(5.66)
5.44
·
+
6
C
17
16
(5.34)
4.81
·
+
6
17 2 3
C H15FN O
(4.83)
4.00
·
+
6
F
F
16 12 2 2 2
C H F N O
(3.70)

Molecules 2008, 13
93
Table 1. Cont.
335.19
·
+
5
7.33
57.04)
3.45
73.16)
1.67
51.61)
6.03
46.40)
1.56
41.90)
7.16
66.81)
3.61
(3.52)
6.16
8.36 334 ([M ] ), 317,
(7.99) 300, 285
9.52 294 ([M ] ), 277,
(9.41) 260, 245
20.09 191 ([M ] ), 173,
(19.77) 145
17.90 225 ([M ] ), 208,
(17.51) 191
16.16 259 ([M ] ), 243,
(15.78) 226
10.44 268 ([M ] ), 251,
(10.05) 234, 175
8
9
0
1
2
3
CH
CH
2
2
-Ph
Cl
Cl
16 2 2 4
C H12Cl N O
(
(
(
(
(
(
·
+
7
-Ph CH
3
CH
3
18
C H
18
N
2
O
2
294.36
(6.16)
5.30
·
+
5
1
1
1
1
NH
NH
NH
2
2
2
H
H
9
C H
9
N
3
O
2
·H
2
O
191.19+18.02
225.64+9.01
260.08
(5.52)
3.83
·
+
4
H
Cl
H
Cl
Cl
H
9 8 3 2 2
C H ClN O ·½H O
(3.63)
2.71
·
+
4
9 7 2 3 2
C H Cl N O
(2.72)
4.51
·
+
6
O-Ph
C H
15
12
N
O
268.27
2
3
(4.52)
Acknowledgements
This work has been carried out with the financial support of the FIS project (1051005, October
005), the Instituto de Salud Carlos III: Red de centros de cancer RTICCC (C03/10) and the PiUNA
2
project (University of Navarra). We also thank the Ministerio de Educación y Ciencia for the grant
AP2003-2175) to Esther Vicente.
(
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