New 1,2,3-triazolo[1,5-a]quinoxalines: Synthesis and binding to benzodiazepine and adenosine receptors. II

Article abstract of DOI:10.1016/S0223-5234(02)01376-4

On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the benzodiazepine and A₁ and A_2A adenosine receptors, of a new series of derivatives, bearing some structural

Full text of DOI:10.1016/S0223-5234(02)01376-4

Eur. J. Med. Chem. 37 (2002) 565–571
www.elsevier.com/locate/ejmech
Original article
New 1,2,3-triazolo[1,5-a]quinoxalines: synthesis and binding to
benzodiazepine and adenosine receptors. II
Giuliana Biagi a, Irene Giorgi a, Oreste Livi a,*, Valerio Scartoni a, Laura Betti b,
Gino Giannaccini b, Maria Letizia Trincavelli b
a Dipartimento di Scienze Farmaceutiche, Uni6ersita` di Pisa, Via Bonanno, 6-56126 Pisa, Italy
b Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Uni6ersita` di Pisa, Via Bonanno, 6-56126 Pisa, Italy
Received 23 November 2001; received in revised form 25 March 2002; accepted 27 March 2002
Abstract
On pursuing research about 1,2,3-triazolo[1,5-a]quinoxalines, in this paper we report synthesis and binding assays toward the
benzodiazepine and A1 and A2A adenosine receptors, of a new series of derivatives, bearing some structural changes (introduction
of fluorine and trifluoromethyl in the seventh position, amino substituents in the fourth position, benzyl group in the fifth position
and aroyl substituents in the third position). The biological tests have shown that only the 7-fluorosubstituted compounds 3a and
4a and the N-benzyl derivative 7 have a good affinity toward the benzodiazepine receptors, while only the 7-trifluoromethyl
substituted compound 3b presents a moderate affinity with low selectivity toward the A1 adenosine receptors. The other structural
´
modifications strongly decreased biological activity. © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
Keywords: 1,2,3-triazolo[1,5-a]quinoxalines; Benzodiazepine receptor binding; Adenosine receptor binding
prevailing agonist activity for the N(5) methyl substi-
tuted compounds B. The best derivatives were A (R=
1. Introduction
Cl, Ki=53 nM) and B (R=Cl, Ki=54 nM) with
GABA ratios 1.2 and 1.6, respectively. Some deriva-
tives showed a good affinity also (KiB100 nM) to-
In a previous paper [1] we reported synthesis and
binding assays towards benzodiazepine and adenosine
A1 and A2A receptors of two series (A and B, Fig. 1) of
triazoloquinoxaline derivatives. The biological results
indicated that these compounds possessed a good
affinity towards the benzodiazepine receptors (Ki va-
lues included between 53 and 314 nM). The GABA
ratio values suggested a prevailing inverse agonist acti-
vity for the N(5) unsubstituted compounds A, and a
wards the A1 adenosine receptors, with
selectivity regarding the A2A receptor subtype.
a high
The best derivatives were A (R=OCH3, Ki=29
nM; R=CH3, Ki=49 nM).
The investigation on the 1,2,3-triazolo[1,5-a]-
quinoxalines was continued by the introduction of new
substituents on the tricyclic ring and the biological
evaluation of the new derivatives, to understand the
effect of the structural changes and, therefore, the
structure–activity relationships.
2. Chemistry
Fig. 1. Reference triazoloquinoxaline derivatives.
Two new substituents, a fluorine atom and a tri-
fluoromethyl group, were introduced in the seventh
position of the triazolo-quinoxaline ring. The fluorine
atom appeared interesting for the affinity towards the
* Correspondence and reprints
E-mail address: livi@farm.unipi.it (O. Livi).
´
0223-5234/02/$ - see front matter © 2002 Published by Editions scientifiques et me´dicales Elsevier SAS.
PII: S0223-5234(02)01376-4

566
G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
Fig. 4. Structure of compounds 6 and 7.
function had shown to increase the adenosine receptor
binding [3,4].
Thus starting from the 3-ethoxycarbonyl-1,2,3-tria-
zolo[1,5-a]quinoxalin-4-one (3c) [1], by a silylation–ami-
nation reaction with 3-pentylamine, (9)-a-methyl-
benzylamine and (9)-1-methyl-2-phenethylamine, the
corresponding 4-substituted compounds 5a–c were ob-
tained in very low yields (Fig. 3). An analogous reac-
tion between the fluoro substituted triazolo-quinoxaline
3a and (9)-a-methyl-benzylamine provided the deriva-
tive 5d in 18% yield.
The reaction of 3c with cyclohexylamine, carried out
also under different experimental conditions, allowed
isolation of the only disubstituted compound 6 (Fig. 4).
Besides, as an alternate structural pattern, to com-
pare with the previously examined N-methyl derivatives
[1], the N-benzylderivative 7 (Fig. 4) was prepared by
reaction of 3c with benzyl chloride in methylethylke-
tone, in the presence of anhydrous potassium carbo-
nate. The N-benzylsubstituted structure was confirmed
and discriminated from the O-benzyl isomer by the
chemical shift value (44.9 ppm) of the benzyl carbon in
the 13C-NMR spectrum of 7.
Finally, as a further structural change, triazolo-
quinoxaline derivatives bearing a lipophilic and bulky
substituent in the third position were prepared. In fact
a phenyl substituent in the third position of analogous
triazolo-quinazoline structures resulted effective for
binding towards the adenosine receptors [5] as well as a
furoyl substituent [6]. According to the acquired syn-
thetic procedure, 2-nitrophenylazide (1c) [7] and 2-ni-
tro-4-chlorophenylazide (1d) [8] were reacted with the
appropriate activated methylenic compound to obtain
the 4-aroyl-5-ethoxycarbonyl-1,2,3-triazoles, the key in-
termediates for the preparation of the corresponding
triazolo-quinoxaline derivatives.
Fig. 2. Synthetic route for the preparation of compounds 4a, b.
benzodiazepine receptors, because the structure of 3a
and 4a is comparable to the competitive antagonist
Ro.15-1788 (Flumazenil).
Thus starting from 2-nitro-4-fluoro-phenylazide (1a)
[2] or 2-nitro-4-trifluoromethyl-phenylazide (1b) [2]
(Fig. 2), by reaction with diethyl oxalacetate sodium
salt in anhydrous THF at 50 °C, a mixture consisting
of the expected triazole diester (2a or 2b) and triazole
byproducts together with the aniline corresponding to
the azide and the substituted benzofurazan-N-oxide
was obtained as previously described for analogous
reactions [1].
This mixture underwent a silica gel column flash-
chromatography and compounds 2a and 2b were iso-
lated in 25 and 16.5% yield, respectively. The
nitrogroup reduction of 2a and 2b, by catalytic hydro-
genation, induced intramolecular condensation between
the formed amino group and the ethoxycarbonyl func-
tion in the fifth position of the triazole ring, to give
directly the desired tricyclic derivatives 3a and 3b.
These compounds by treatment with dimethyl sulfate in
anhydrous acetone in the presence of anhydrous potas-
sium carbonate, provided the corresponding N-methyl
derivatives 4a and 4b. Their structure was confirmed by
spectroscopic data which agreed with those reported in
the literature [1] for analogous N-methyl compounds.
A further structural change concerned synthesis of
some new triazolo-quinoxaline derivatives bearing in
the fourth position an alkylamino or aralkylamino subs-
tituent. These lipophilic substituents bonded to a NH
Fig. 3. Synthesis of compounds 5a–d.

G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
567
Fig. 5. Synthetic route for the preparation of compounds 9a, b.
The reagents, ethyl benzoylpyruvate [9] and ethyl
2-furoylpyruvate [10] as sodium salts, were prepared
starting from acetophenone and 2-acetylfuran, respec-
tively, by a Claisen reaction with diethyl oxalate in
anhydrous ethanol, in the presence of sodium ethoxide.
The 1,3-dipolar cycloaddition reactions (Fig. 5) were
carried out in anhydrous THF, the azide solution was
added dropwise to the reagent solution at 40 °C and
the mixture was heated at 60 °C for 7 h, under stirring.
The expected triazolesters 8a and 8b were isolated in
moderate yield by flash-chromatography through a sil-
ica gel column, to separate them from large amounts of
2-nitroaniline and benzofurazan N-oxide. From the
alkaline aqueous layers little amounts of the corres-
ponding 5-carboxy acids were also isolated. The ni-
trogroup reduction by catalytic hydrogenation at room
temperature and pressure directly provided the 3-ben-
zoyl- (9a) and 3-furoyl- (9b) triazolo-quinoxalines, via
intramolecular cyclization with elimination of ethanol
between the formed aminogroup and the ethoxycar-
bonyl group in the fifth position of the triazole ring.
Under the same experimental conditions (Fig. 6), the
2-nitrophenylazide (1c) reacted with the 2-furoyl
reagent to give the expected triazolester 10, isolated by
flash chromatography, which was cyclized to the corres-
ponding 3-furoyl-triazolo-quinoxaline 11, by catalytic
hydrogenation.
The structures of all the new prepared compounds
were assigned according to their reaction mechanisms
and our previous evidence [1] and were confirmed by
analytical and spectroscopic data (Table 2 and Table 3).
3. Biological results and discussion
All the triazolo-quinoxaline derivatives underwent
binding assays either to benzodiazepine receptors or
adenosine A1 and A2A receptors. Their ability to inhibit
benzodiazepine receptor binding was measured by the
concentration which was able to displace [3H]-Ro 15-
1788 from bovine brain membranes. The inhibition of
binding towards adenosine receptors was measured by
the ability of compounds to displace [3H]-N6-cyclo-
hexyladenosine (CHA) from A1 adenosine receptors in
bovine cortical membranes and [3H]-2-[p-(2-car-
boxyethyl) - phenethylamino] - 5% - (N-ethylcarbamoyl)-
adenosine (CGS 21680) from A2A adenosine receptors
in bovine striatal membranes. The experimental details
of the receptor binding assays are reported in a pre-
vious paper [1].
The results of the binding assays toward the
adenosine receptors (Table 4) show that these triazolo-
quinoxaline derivatives have a low affinity towards the
two receptor subtypes. Only compound 3b, bearing the
trifluoromethyl group in the seventh position, shows a
good A1 receptor affinity (Ki=91 nM) and selectivity.
Fig. 6. Synthetic route for the preparation of compound 11.

568
G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
Table 1
Physico-chemical properties
In conclusion the structural changes introduced have
not induced an increase in biological activity with re-
gard to the previous derivatives [1]. However, the tri-
fluoromethyl group is the more effective substituent
towards the A1-adenosine receptors, whilst the fluorine
atom is better toward the benzodiazepine receptors. In
addition, introduction of a methyl or benzyl substituent
on the nitrogen in the fifth position induced a partial
agonist activity toward the benzodiazepine receptors.
Crystall.
solvent
Yield (%)
M.p. (°C)
Analysis C,H,N
a
2a
25
60
63
17
53
64
15
16
10
22
9
52
28
66
26
62
18
74
50–53
244–246
184–186
66–68
239–241
174–176
64–65
142–145
170–173
150–153
214–216
148–150
99–100
165–168
137–138
201–203
94–95
C14H13N4O6F
C12H9N4O3F
C13H11N4O3F
C15H13N4O6F3
C13H9N4O3F3
C14H11N4O3F3
C17H21N5O2
3a EtOH
4a EtOH
a
2b
3b EtOH
4b EtOH
5a EtOH
5b EtOAc
5c EtOAc
5d EtOAc
C
20H19N5O2
C21H21N5O2
20H18N5O2F
C22H28N6O
19H16N4O3
C18H14N4O5
16H10N4O2
C18H13N4O5Cl
16H9N4O2Cl
4. Experimental
C
4.1. Chemistry
6
EtOAc
7
8a
EtOH
C
a
Melting points were determined on a Kofler hot-
stage and are uncorrected. IR spectra in nujol mulls
were recorded on a Mattson Genesis series FTIR spec-
trometer. 1H-NMR and 13C-NMR spectra were
recorded with a Varian Gemini 200 spectrometer in
DMSO-d6 or CDCl3 in l units, using TMS as an
internal standard. Mass spectra were performed with a
Hewlett Packard MS/System 5988 A. Elemental analy-
ses (C, H, N) were within 90.4% of theoretical values
and were performed on a Carlo Erba Elemental Ana-
lyzer Mod. 1106 apparatus. TLC data were obtained
with Merck silica gel 60 F254, aluminium sheets.
Petroleum ether corresponds to fraction boiling at 40–
60 °C.
9a MeOH
C
a
8b
9b CHCl3
C
a
10
C16H12N4O6
C14H8N4O3
11 EtOAc
171–174
a Isolated by flash-chromatography
Table 2
Spectroscopic data
IR w (cm−1
)
Mass m/z
M+
Base
2a 1727 (COOEt), 1463 and 1342 (NO2)
3a 1740 (COOEt), 1674 (CON), 3417 (NH)
4a 1739 (COOEt), 1685 (CON)
2b 1730 (COOEt), 1470 and 1340 (NO2)
3b 1734 (COOEt), 1694 (CON), 3462 (NH)
4b 1736 (COOEt), 1680 (CON)
5a 1694 (COOEt), 3292 (NH)
5b 1694 (COOEt), 3246 (NH)
5c 1692 (COOEt), 3290 (NH)
5d 1693 (COOEt), 3265 (NH)
–
–
276
290
402
326
340
327
361
373
379
392
348
366
163
177
69
213
227
43
105
91
105
55
4.2. 1-(2-Nitro-4-fluoro-phenyl)-4,5-di-ethoxycarbonyl-
1H-1,2,3-triazole (2a)
To a suspension of 4.25 g (20.0 mmol) of diethyl
oxalacetate sodium salt in 60 mL of anhydrous THF,
heated at 35 °C, a solution of 2.50 g (13.7 mmol) of
2-nitro-4-fluoro-phenylazide [2] in 50 mL of anhydrous
THF was added dropwise. The reaction mixture was
stirred at 50 °C for a further 7 h, then the solvent was
evaporated in vacuo and the residue was treated with
H2O and extracted with CHCl3. The organic layer dried
(MgSO4) and evaporated in vacuo, gave a solid residue
(2.60 g) consisting of a mixture which was fractionated
by flash-chromatography through a silica gel column,
eluting with EtOAc–petroleum ether 1:2. The title com-
pound was isolated as a pure compound (Tables 1–3).
6
7
1650 (CON), 3390 and 3255 (NH)
1732 (COOEt), 1685 (CON)
91
105
8a 1725 (COOEt), 1669 (CO), 1464 and 1345
(NO2)
9a 1694 (CON, CO), 3425 (NH)
8b 1718 (COOEt), 1656 (CO), 1443 and 1340
(NO2)
9b 1678 (CON, CO), 3214
10 1736 (COOEt), 1658 (CO), 1462 and 1341
(NO2)
290
400
77
105
324
356
105
95
11 1684 (CON, CO), 3420 (NH)
280
95
4.3. 1-(2-Nitro-4-trifluoromethyl-phenyl)-
4,5-di-ethoxycarbonyl-1H-1,2,3-triazole (2b)
These new derivatives have generally shown a low
affinity towards the benzodiazepine receptors too
(Table 4). Only compounds 4a, 3a and 7 present a
moderate affinity with Ki values 80, 115 and 117 nM,
respectively; the GABA ratio values indicate a partial
agonist activity for 4a and 7 and an antagonist activity
for 3a.
To a suspension of 5.57 g (26.5 mmol) of diethyl
oxalacetate sodium salt in 60 mL of anhydrous THF,
heated at 35 °C, a solution of 4.12 g (20.0 mmol) of
2-nitro-4-trifluoromethyl-phenylazide [2] in 50 mL of
anhydrous THF was added dropwise and the reaction
mixture was worked up as described above. The solid

G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
569
Table 3
EtOAc–petroleum ether 1:4 gave the title compound as
a pure compound (Tables 1–3).
1H-NMR l (ppm) in DMSO-d6 or CDCl3*
2a
3a
4a
7.97 (m, 1H), 7.55 (m, 2H), 4.47 and 4.28 (2q, 4H), 1.44
and 1.25 (2t, 6H)
12.2 (br, 1H), 8.41 (m, 1H), 7.23 (m, 2H), 4.39 (q, 2H),
1.34 (t, 3H)
8.50 (m, 1H), 7.75 (m, 2H), 4.40 (q, 2H), 3.60 (s, 3H), 1.35
(t, 3H)
4.4. 3-Ethoxycarbonyl-7-fluoro-1,2,3-triazolo[1,5-a]-
quinoxalin-4-one (3a)
To a solution of 1.10 g (3.12 mmol) of the triazole
diester 2a in 70 mL of EtOH, 10% Pd/C (0.100 g) was
added and the mixture was hydrogenated at room
temperature (r.t.) and pressure. When the absorption of
the hydrogen volume was completed, the catalyst was
filtered off and washed with hot EtOH. Filtrate and
washings were combined and evaporated in vacuo to
give the title compound as a solid residue which was
purified by crystallisation (Tables 1–3).
2b* 8.56 (s, 1H), 8.13 (d, 2H), 7.79 (d, 1H), 4.51 and 4.32 (2q,
4H), 1.46 and 1.29 (2t, 6H)
12.4 (br, 1H), 8.55 (d, 1H), 7.71 (m, 2H), 4.41 (q, 2H), 1.35
(t, 3H)
8.66 (m, 1H), 7.98 (m, 2H), 4.42 (q, 2H), 3.69 (s, 3H), 1.36
(t, 3H)
8.85 (d, 1H), 8.20 (d, 1H), 7.80–7.25 (m, 3H), 4.50 (q, 2H),
4.15 (m, 1H), 1.85–1.20 (m, 10H), 1.21 (t, 3H)
9.40 (d, 1H), 8.44 (d, 1H), 7.63–7.25 (m, 8H), 5.50 (m, 1H),
4.51 (q, 2H), 1.61 (d, 3H), 1.41 (t, 3H)
8.90 (d, 1H), 8.40 (m, 1H), 7.80–7.10 (m, 8H), 4.50 (m,
1H), 4.45 (q, 2H), 2.80 (m, 2H), 1.30 (d, 3H), 1.26 (t, 3H)
9.55 (d, 1H), 8.42 (m, 1H), 7.55–7.42 (m, 7H), 5.50 (m,
1H), 4.51 (q, 2H), 1.61 (d, 3H), 1.41 (t, 3H)
9.89 (d, 1H), 8.45 (m, 1H), 7.45–7.28 (m, 3H), 4.15 (m,
2H), 2.17–1.30 (m, 20H)
3b
4b
5a
5b
5c
5d
6*
7
4.5. 3-Ethoxycarbonyl-7-trifluoromethyl-1,2,3-
triazolo[1,5-a]quinoxalin-4-one (3b)
To a solution of 1.32 g (3.28 mmol) of 2b in 200 mL
of EtOH, 10% Pd/C (0.100 g) was added and the
mixture was hydrogenated and worked up as described
above (Tables 1–3).
8.50 (d, 1H), 7.62–7.10 (m, 8H), 5.53 (s, 2H), 4.41 (q, 2H),
1.36 (t, 3H)
8a* 8.35 (m, 1H), 8.06 (m, 2H), 7.95–7.79 (m, 2H), 7.70–7.25
(m, 4H)
9a
12.2 (s, 1H), 8.32 (d, 1H), 7.60–7.18 (m, 8H)
4.6. 3-Ethoxycarbonyl-5-methyl-7-fluoro-1,2,3-triazolo-
[1,5-a]quinoxalin-4-one (4a) and 3-Ethoxycarbonyl-5-
methyl-7-trifluoromethyl-1,2,3-triazolo[1,5-a]-
quinoxalin-4-one (4b)
8b* 8.47 (m, 1H), 8.19–7.40 (m, 7H), 4.22 (q, 2H), 1.00 (t, 3H)
9b
12.0 (s, 1H), 8.38 (d, 1H), 7.74 (d, 1H), 7.60–7.41 (m, 3H),
7.41–7.20 (m, 3H)
10* 8.34 (d, 1H), 7.95–7.62 (m, 5H), 6.68 (m, 1H), 4.25 (q, 2H),
1.19 (t, 3H)
11
12.2 (s, 1H), 8.35 (d, 1H), 7.65–7.35 (m, 4H), 6.42–6.24 (m,
2H)
A mixture of 1.0 mmol of 3a or 3b, 0.60 mL (6.30
mmol) of dimethyl sulfate and 0.400 g (2.90 mmol) of
anhydrous potassium carbonate in 20 mL of anhydrous
acetone, was heated under reflux for 4.5 h. The inor-
ganic material was filtered off, washed with acetone and
the filtrates were combined and evaporated to give a
residue consisting of crude 4a or 4b, which was purified
by crystallisation (Tables 1–3).
residue from CHCl3 (3.0 g) underwent flash-chromato-
graphy through a silica gel column and elution with
Table 4
Results of the binding assays
Benzodiazepine
A1-adenosine
A2A-adenosine
Inhib.% (10 mM)
Ki (nM)
GABA ratio
Inhib.% (10 mM)
Ki (nM)
Inhib.% (10 mM)
Ki (nM)
3a
3b
4a
4b
5a
5b
5c
5d
6
97
67
98
72
55
0
26
24
0
99
78
36
0
115
2900
80
0.93
0.96
1.19
1.30
–
–
–
–
–
80
95
31
27
48
55
48
49
29
50
47
10
36
1131
91
\10 000
\10 000
7059
10.5
42
10
17
21
15
0
0
2
39
20
23
13
\10 000
\10 000
\10 000
\10 000
\10 000
\10 000
–
3900
\5000
\10 000
\10 000
\10 000
\10 000
117
3230
\10 000
\10 000
5139
5435
5387
–
\10 000
5692
7517
\10 000
\10 000
\10 000
\10 000
\10 000
\10 000
\10 000
7
1.20
1.20
–
9a
9b
11
–

570
G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
4.7. 3-Ethoxycarbonyl-4-(3-pentylamino)-1,2,3-
triazolo[1,5-a]quinoxaline (5a)
(0.44 mmol) of ammonium sulfate and 0.75 mL (6.50
mmol) of cyclohexylamine were added and heating
was continued for 20 h. The reaction mixture was
worked up as described to obtain 5a (Tables 1–3).
A suspension of 3-ethoxycarbonyl-1,2,3-triazolo[1,5-
a]quinoxalin-4-one (3c) [1] (0.350 g, 1.35 mmol) in 2.1
mL of hexamethyldisilazane (HMDS) was heated at
140 °C for 1 h; 0.132 g (1.00 mmol) of ammonium
sulfate and 0.87 mL (7.50 mmol) of 3-pentylamine
were added and heating was continued for 20 h. Af-
ter evaporation in vacuo, the residue was extracted
with CHCl3 and the organic layer was washed with
5% HCl, 10% NaOH and H2O, then dried on
MgSO4. Evaporation of the solvent gave a semisolid
residue (0.160 g) which was crystallised to obtain the
title compound (Tables 1–3).
4.12. 3-Ethoxycarbonyl-5-benzyl-1,2,3-triazolo[1,5-a]-
quinoxalin-4-one (7)
A mixture of 3c [1] (0.250 g, 0.97 mmol), benzyl
chloride (0.17 mL, 1.47 mmol) and anhydrous potas-
sium carbonate (0.400 g, 2.90 mmol) in 9 mL of
methyl ethyl ketone was heated under reflux for 4
days. The solvent was evaporated in vacuo and the
residue was treated with H2O. The insoluble material,
consisting of 7 as a white solid, was collected by
filtration and crystallised (Tables 1–3).
4.8. (9) 3-Ethoxycarbonyl-4-(1-phenylethyl)-1,2,3-
triazolo[1,5-a]quinoxaline (5b)
4.13. 1-(2-Nitrophenyl)-4-benzoyl-5-ethoxycarbonyl-
1H-1,2,3-triazole (8a) and 1-(4-chloro-2-nitrophenyl)-
4-benzoyl-5-ethoxycarbonyl-1H-1,2,3-triazole (8b)
A suspension of 3c [1] (0.250 g, 0.97 mmol) in 2.5
mL of HMDS was heated at 140 °C for 1 h; 0.044 g
(0.30 mmol) of ammonium sulfate and 0.60 mL (4.70
mmol) of (9)-a-methylbenzylamine were added and
heating was continued for 20 h. The reaction mixture
was worked up as described to obtain 5a (Tables 1–
3).
To 30 mL of anhydrous THF heated at 40 °C,
1.00 g (4.10 mmol) of ethyl benzoylpyruvate sodium
salt [9] was added and the mixture was stirred until
complete solution (ca. 1 h). A solution of 4.00 mmol
of 2-nitrophenylazide (1c) or 4-chloro-2-nitropheny-
lazide (1d) in 20 mL of anhydrous THF was added
dropwise. Temperature was raised to 60 °C and the
mixture was stirred for 7 h. The solvent was evapo-
rated in vacuo and the residue was treated with H2O
and extracted with CHCl3.
The organic layer, dried (MgSO4) and evaporated,
gave a solid residue consisting essentially of the ni-
troaniline corresponding to the azide (ca. 35%) and of
the expected triazole derivative 8a or 8b.
The mixture was fractionated by flash-chromatogra-
phy through a silica gel column, eluting with EtOAc–
petroleum ether 1:3, and the title compounds were
isolated as pure crystalline solids (Tables 1–3).
Acidification of the alkaline aqueous layers provided
the corresponding 1,2,3-triazole-5-carboxylic acids (ca.
14% yield).
4.9. (9) 3-Ethoxycarbonyl-4-(1-methyl-2-phenylethyl)-
1,2,3-triazolo[1,5-a]quinoxaline (5c)
A suspension of 3c [1] (0.250 g, 0.97 mmol) in 3.5
mL of HMDS was heated at 140 °C for 1 h; 0.044 g
(0.30 mmol) of ammonium sulfate and 0.70 mL (4.80
mmol) of (9)-a-methylphenethylamine were added
and heating was continued for 20 h. The reaction
mixture was worked up as described to obtain 5a
(Tables 1–3).
4.10. (9) 3-Ethoxycarbonyl-4-(1-phenylethyl)-7-
fluoro-1,2,3-triazolo[1,5-a]quinoxaline (5d)
A suspension of 3a (0.250 g, 0.90 mmol) in 5 mL
of HMDS was heated at 140 °C for 1 h; 0.044 g
(0.30 mmol) of ammonium sulfate and 0.58 mL (4.50
mmol) of (9)-a-methylbenzylamine were added and
heating was continued for 20 h. The reaction mixture
was worked up as described to obtain 5a (Tables 1–
3).
4.14. 1-(2-Nitrophenyl)-4-(2-furoyl)
-5-ethoxycarbonyl-1H-1,2,3-triazole (10)
To 30 mL of anhydrous THF heated at 40 °C,
1.00 g (4.30 mmol) of ethyl 2-furoylpyruvate sodium
salt [10] was added and the mixture was stirred until
complete solution (ca. 1 h). A solution of 2-nitro-
phenylazide (1c) (0.710 g, 4.30 mmol) in 20 mL of
anhydrous THF was added dropwise and the mixture
was worked up as described above. The separation by
flash-chromatography through a silica gel column,
4.11. 3-Cyclohexylaminocarbonyl-4-cyclohexylamino-
1,2,3-triazolo[1,5-a]quinoxaline (6)
A suspension of 3c [1] (0.350 g, 1.35 mmol) in 5
mL of HMDS was heated at 140 °C for 1 h; 0.058 g

G. Biagi et al. / European Journal of Medicinal Chemistry 37 (2002) 565–571
571
eluting with EtOAc–petroleum ether 1:2 provided the
title compound as a pure compound (Tables 1–3).
hydrogenated and worked up as described above (Ta-
bles 1–3).
4.15. 3-Benzoyl-1,2,3-triazolo[1,5-a]quinoxalin-4-one
(9a) and 3-(2-furoyl)-1,2,3-triazolo[1,5-a]-
References
quinoxalin-4-one (11)
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Chem. 33 (1998) 113–122.
[2] P.B. Ghosh, B. Ternai, M.W. Whitehouse, J. Med. Chem. 15
(1972) 255–260.
To a solution of 1.00 mmol of the triazolester 8a or
10 in 60 mL of EtOH, 30–40 mg of 10% Pd/C were
added and the mixture was hydrogenated at r.t. and
pressure. The catalyst was filtered off and washed with
hot EtOH. Filtrate and washings were combined and
evaporated in vacuo to give the title compounds as
solid residues which were purified by crystallisation
(Tables 1–3).
[3] G. Biagi, I. Giorgi, O. Livi, C. Manera, V. Scartoni, A. Lucacchini,
G. Senatore, Farmaco 51 (1996) 601–608.
[4] L. Betti, G. Biagi, G. Giannaccini, I. Giorgi, O. Livi, A. Lucac-
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[5] G. Biagi, I. Giorgi, O. Livi, V. Scartoni, S. Velo, A. Lucacchini,
G. Senatore, B. De Santis, A. Martinelli, Farmaco 51 (1996)
131–136.
4.16. 3-Benzoyl-7-chloro-1,2,3-triazolo[1,5-a]-
quinoxalin-4-one (9b)
[6] P.G. Baraldi, B. Cacciari, G. Spalluto, A. Borioni, M. Viziano,
S. Dionisotti, E. Ongini, Current Med. Chem. 2 (1995) 707–722.
[7] P.A.S. Smith, J.H. Boyer, in: R.S. Schreiber (Ed.), Organic
Syntheses, vol. 31, Wiley, New York, 1951, p. 14.
[8] L.K. Dyall, Austr. J. Chem. 39 (1986) 89–101.
[9] C. Beyer, L. Claisen, Ber. 20 (1887) 2078–2188.
[10] C. Musante, S. Fatutta, Gazz. Chim. Ital. 88 (1958) 879–898.
To a solution of the triazolester 8b (0.360 g, 1.10
mmol) in 60 mL of EtOH, ca. 100 mg of aqueous
Ni-Raney suspension were added and the mixture was