A convenient new synthesis of fused 1,2,4-triazoles: The oxidation of heterocyclic hydrazones using copper dichloride

Article abstract of DOI:10.1016/j.tet.2005.01.111

A series of 1,2,4-triazoles have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with copper dichloride. General applicability of this simple transformation was confirmed by the synthesis of moderate to high yields of 1,2,

Full text of DOI:10.1016/j.tet.2005.01.111

Tetrahedron 61 (2005) 5942–5947
A convenient new synthesis of fused 1,2,4-triazoles: the oxidation
of heterocyclic hydrazones using copper dichloride
*
¨
Michael Ciesielski, Daniela Pufky and Manfred Doring
Institute for Technical Chemistry (ITC-CPV), Forschungszentrum Karslruhe, PO BOX 3640, 76021 Karlsruhe, Germany
Received 13 October 2004; revised 26 January 2005; accepted 27 January 2005
Available online 10 May 2005
Abstract—A series of 1,2,4-triazoles have been prepared by oxidative intramolecular cyclization of heterocyclic hydrazones with copper
dichloride. General applicability of this simple transformation was confirmed by the synthesis of moderate to high yields of 1,2,4-
triazolo[4,3-a]pyridines, 1,2,4-triazolo[4,3-a]pyrimidines, 1,2,4-triazolo[4,3-b]pyridazines, 1,2,4-triazolo[4,3-a]phthalazines, and 1,2,4-
triazolo[4,3-a]quinoxalines. A 1,2,4-triazolo[4,3-e]purine-6,8(7H)-dione was obtained in a lower yield.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Triazoles are an important class of heterocyclic compounds.
In particular, fused 1,2,4-triazoles 1–5 (Fig. 1) express
antifungal,1 bactericidal,1,2 anxiolytic,3,4 anticonvulsant5 or
herbicidal6 activities or can act as antidepressants.7 There-
fore, versatile and widely applicable methods for the
synthesis of 1–5 are of considerable interest. Most methods
for the preparation of 1–5 are based on heterocyclic
hydrazones or hydrazides as precursors. However, these
methods have some restrictions as regards their applicability
and the use of toxic reagents like lead tetraacetate,8,9
bromine9,10 or phosphorus oxychloride.8 In order to over-
come these limitations, the oxidant chloramine T11 and
(diacetoxy)iodobenzene12,13 as well as an electrochemical
method14 have been introduced.
Figure 1.
Recently, we have shown that heterocyclic substituted
imines undergo copper-catalyzed oxidation, thus forming
imidazo[1,5-a]pyridines, imidazo[1,5-a]imidazoles, and
imidazo[1,5-a]isochinolines using the nonhazardous, less
toxic, and inexpensive reagent copper dichloride.15,16
As part of our ongoing studies dealing with copper(II) in
synthesis, we now describe a novel copper-mediated
oxidative heterocyclization of hydrazones yielding the
corresponding 1,2,4-triazoles (Scheme 1).
Scheme 1.
2. Results and discussion
The synthesis of 1,2,4-triazolo derivatives from hydrazones
has a remarkably wide scope of application. Hydrazones of
aromatic and aliphatic aldehydes 7–11 (Fig. 2) with both
electron-withdrawing and electron-donating substituents
Keywords: Oxidation; Copper; Hydrazones; 1,2,4-Triazoles.
* Corresponding author. Tel.: C49 7247 82 4385; fax: C49 7247 82 2244;
e-mail: manfred.doering@itc-cpv.fzk.de
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.111

M. Ciesielski et al. / Tetrahedron 61 (2005) 5942–5947
5943
those reported in the literature except for 1d and 2a.
Nevertheless, spectroscopic data of these compounds
confirm the structure proposed and are listed in the
experimental section. The conditions applied for the
synthesis of each compound are listed in Table 1.
Comparison of the reactivities of the tested hydrazones
indicates that the cyclization is not strongly affected by the
substituent R. The reactivity to copper dichloride remains
unchanged when the phenyl group in the hydrazones is
replaced by an n-alkyl residue. In addition, hydrazones of
donor-substituted benzaldehydes (RZ2,3-dimethoxy-
phenyl and 4-hydroxy-phenyl) and those bearing an
acceptor substituent (RZ2-chloro-phenyl and 4-nitro-
phenyl) yielded triazoles under similar conditions.
Functionalities of the substrate are maintained, even when
substituents susceptible to oxidation, e.g. a hydroxy group,
are considered. On the other hand, the influence of the
nature of the heterocyclic moiety is more significant. If the
–NH–N]CH group is attached to a six-membered nitrogen-
containing ring, the triazoles are obtained in a smooth
reaction. The lower selectivity in the oxidation of 12
indicates that a five-membered ring is less favorable.
However, the difficulties of the heterocyclization of 12
could also be caused by the sterically demanding effect of
the methyl group at position 5 or by a stabilized
intermediate of the radical-based reaction. Investigations
concerning mechanistical studies are still in progress.
Figure 2.
were oxidized to give the corresponding 1,2,4-triazolo[4,3-
a]pyridines 1, 1,2,4-triazolo[4,3-a]pyrimidines 2, 1,2,4-
triazolo[4,3-b]pyridazines 3, 1,2,4-triazolo[4,3-a]phthala-
zines 4, and 1,2,4-triazolo[4,3-a]quinoxalines 5 in high
yields (Table 1). Heterocyclization of 12a was achieved in
the same way, but the yield of the 1,2,4-triazolo[4,3-
e]purine-6,8(7H)-dione 6a was rather poor.
The required hydrazones 7–12 were obtained by treating the
corresponding hydrazino heterocycles with aldehydes.
Unlike heterocyclic aldimines,15 the hydrazones 7–12 could
not be oxidized by atmospheric oxygen in the presence of
catalytic amounts of copper(II)chloride. Copper(I)com-
plexes of substituted hydrazones are not able to coordinate
oxygen in order to form copper(II)species and are likely to
decompose. Thus, reactive intermediates for a copper-
catalyzed oxidative cyclization are not generated.
Heterocyclization was carried out in absolute DMF under
argon. After the hydrazone had been dissolved, a solution of
two equivalents of copper dichloride was added and then,
the mixture was heated. The reaction had been completed
when its initially brown color turned to yellow due to
reduction of the copper(II) ions to copper(I). Isolation of the
1,2,4-triazolo compounds 1–5 was easily carried out. The
solvent was distilled off in vacuum, and the residue was
treated with an aqueous solution of ammonia in order to
remove the copper ions as a water-soluble complex. Then,
the precipitated crude products were filtered off and pure
1,2,4-triazolo compounds 1–5 were obtained by recrystalli-
zation. Only 1,2,4-triazolo[4,3-e]purine-6,8(7H)-dione 6a
had to be separated from impurities by column
chromatography.
3. Conclusion
In conclusion, we have developed a convenient and simple
method for the preparation of a wide variety of 1,2,4-
triazolo compounds by oxidation of heterocyclic substituted
hydrazones using copper dichloride as oxidation agent.
Besides, the presence of several functionalities in the
substrate is tolerated and does not influence the yield of the
resulting 1,2,4-triazole. Our current studies are directed to
Triazoles 1a,17 1b,17 1d14, 2a,18,19 3a20, and 5b21 have
already been described. Their melting points agree with
Table 1. Triazolo (1–6) compounds from the reaction of heterocyclic hydrazones (7–12) with copper dichloride
Hydrazone
R
Time (h)
Temp. (8C)
Triazole
Yield (%)
mp (8C)
7a
7b
7c
7d
8a
8b
9a
9b
10a
11a
11b
11c
12a
4-Chloro-phenyl
2-Chloro-phenyl
4-Hydroxy-phenyl
4-Nitro-phenyl
4-Chloro-phenyl
3,4-Dimethoxy-phenyl
4-Chloro-phenyl
3,4-Dimethoxy-phenyl
2-Chloro-phenyl
4-Chloro-phenyl
n-Propyl
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
0.5
1.0
0.75
0.5
0.75
90
90
90
1a
1b
1c
1d
2a
2b
3a
3b
4a
5a
5b
5c
6a
60
57
71
59
63
43
72
62
74
72
61
84
15
198–199
130–132
249–250
312–314
244–245
207–209
197–198
235–237
214–216
192–194
149–153
262–263
205–208 (dec.)
100
110
110
130
120
140
100
100
90
3,4-Dimethoxy-phenyl
n-Propyl
100

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M. Ciesielski et al. / Tetrahedron 61 (2005) 5942–5947
extend the scope of the method to cover additional
heterocyclic systems.
ambient temperature, the solution was concentrated in
vacuum and 70 ml 10% ammonia solution were added to the
residue. After stirring for 20 min at 40 8C in the presence of
air, the precipitated solid was filtered off and suspended
again in 70 ml 10% ammonia solution. Then, the solid was
filtered off, washed with water, and dried. The mixed
ammonia solutions were extracted with ethyl acetate twice.
The solid was boiled in 100 ml ethyl acetate. An insoluble
impurity was removed by filtration of the hot mixture. All
organic solutions were combined and the solvent was
distilled off in vacuum. Then, the crude product was
dissolved in 100 ml boiling ethanol, 50 ml water were added
and a small amount of a dark impurity was removed by
filtration of the hot solution. Pure 1a crystallized upon slow
cooling of the filtrate; yield 60%; mp 198–199 8C (lit.
192 8C17).
4. Experimental
4.1. General
Melting points were measured using the Bu¨chi melting point
apparatus B-545 and are uncorrected. The 1H and 13C NMR
spectra were recorded with a Bruker AC 250 spectrometer at
250 and 63 MHz, respectively. Mass spectra were recorded
on a Hewlett Packard 1100 MSD using the electrospray
ionization (ES) technique and on a Micromass GCT
spectrometer using an electron impact source (EI).
Elemental analysis was made by a Vario EL III from
Elementar Analysensysteme GmbH.
4.2.8. 3-(2-Chlorophenyl)-1,2,4-triazolo[4,3-a]pyridine
1b. 2.31 g (10 mmol) 7b17 and 2.69 g (20 mmol) CuCl2
were dissolved at 50 8C each in 30 ml absolute DMF Both
solutions were combined and the mixture was stirred under
argon at 50 8C for 20 min and afterwards at 90 8C for 1 h.
After cooling to ambient temperature, the solution was
concentrated in vacuum to approximately 10 ml. Then,
100 ml of 10% ammonia solution and 100 ml of ethyl
acetate were added and the mixture was stirred at 40 8C for
30 min in the presence of air. The organic layer was
separated and the ammoniacal solution was extracted with
ethyl acetate twice. All organic solutions were combined,
extracted with water, and dried over sodium sulfate. Then,
the solvent was removed. The viscous oil obtained was
dissolved in 60 ml of boiling toluene/n-hexane (1/1). A
small amount of impurity remained undissolved and was
removed by filtration of the hot solution. Pure 1b crystal-
lized upon slow cooling of the solution down to K20 8C;
yield 57%, mp 130–132 8C (lit. 132 8C17).
The references of the hydrazones 7a, 7b, 7c, 7d, 8a, 9a and
12a which have already been described in the literature are
noted in the experimental description of the corresponding
triazolo compounds. Preparation and experimental data of
8b, 9b, 10a, 11a, 11b and 11c are described in Section 4.2.
4.2. General procedure for the preparation of
hydrazones 8b, 9b, 10a, 11a, 11b, 11c
The hydrazine (25 mmol) was dissolved in a sufficient
amount of boiling ethanol and the aldehyd (25 mmol),
dissolved in 20 ml ethanol, was added dropwise. After that,
the solution was stirred and heated under reflux for 20 min.
The formed hydrazone was filtered from the cooled solution
and used in the next reaction without any purification.
4.2.1. 3,4-Dimethoxybenzaldehyde-pyrimidin-2-yl-
hydrazone 8b. H NMR (DMSO-D6) d 11.19, 8.49, 8.13,
1
7.33, 7.16, 7.04, 6.85, 3.56, 3.84; MS (EI) m/zZ258 (MC).
4.2.9. 3-(4-Hydroxyphenyl)-1,2,4-triazolo[4,3-a]pyridine
1c. A solution of 1.62 g (12.0 mmol) CuCl2 in 20 ml
absolute DMF was added to 1.28 g (6.0 mmol) 7c22 which
was dissolved in 10 ml absolute DMF and heated to 50 8C.
After stirring for 1 h at 90 8C, the solvent was removed in
vacuum and the residue treated for 30 min with 30 ml warm
10% ammonia solution and 5 g NaCl. The formed
precipitate was filtered out, whereas the aqueous solution
was extracted with ethyl acetate. The solvent was distilled
off and the solid obtained was combined with the former
one. Recrystallization from ethanol gave pure 1c as white
crystals; yield 71%; mp 249–250 8C; 1H NMR (DMSO-D6)
d 10.04, 8.46, 7.79, 7.70, 7.36, 6.99; 13C NMR (DMSO-D6)
d 159.45, 130.16, 127.96, 124.25, 117.57, 116.49, 116.06,
114.56; MS (EI) m/zZ211 (MC); calcd. (%) for C12H9N3O
(211.22) C 68.24, H 4.29, N 19.89; found (%) C 68.00, H
4.40, N 20.32.
4.2.2. 3,4-Dimethoxybenzaldehyde-(5-chloropyridin-2-
yl)-hydrazone 9b. H NMR (DMSO-D6) d 11.66, 8.11,
1
7.71, 7.41, 7.20, 7.04, 3.89, 3.85; MS (EI) m/zZ292 (MC).
4.2.3. 2-Chlorobenzaldehyde-phthalazin-1-ylhydrazone
10a. H NMR (DMSO-D6) d 12.26, 8.74, 8.65, 8.33, 8.15,
1
7.73, 7.43; MS (EI) m/zZ282 (MCKH).
4.2.4. 4-Chlorobenzaldehyde-quinoxalin-2-ylhydrazone
11a. H NMR (DMSO-D6) d 9.12, 8.76, 8.33, 7.94, 7.36,
1
7.60; MS (EI) m/zZ282 (MC).
1
4.2.5. Butanal-quinoxalin-2-ylhydrazone 11b. H NMR
(DMSO-D6) d 11.16, 8.86, 7.83, 7.58, 7.41, 2.19, 1.46, 0.86;
MS (EI) m/zZ214 (MC).
4.2.6. 3,4-Dimethoxybenzaldehyde-quinoxalin-2-yl-
hydrazone 11c. H NMR (DMSO-D6) d 11.59, 9.12, 8.05,
1
4.2.10. 3-(4-Nitrophenyl)-1,2,4-triazolo[4,3-a]pyridine
1d. 1.35 g (10.0 mmol) CuCl2 dissolved in 20 ml absolute
DMF were added to a heated (50 8C) suspension of 1.21 g
(5.0 mmol) 7d22 in 10 ml absolute DMF The solution
was stirred for 1 h at 100 8C and concentrated after cooling
to room temperature. Then, a solution of 30 ml 10%
ammonia and 10 g NaCl was added, and the mixture was
stirred at 45 8C for 15 min in the presence of air. A
7.88, 7.66, 7.41, 7.18, 7.00; MS (EI) m/zZ308 (MC).
4.2.7. 3-(4-Chlorophenyl)-1,2,4-triazolo[4,3-a]pyridine
1a. 1.85 g (8.0 mmol) 7a17 and 2.15 g (16.0 mmol) CuCl2
were dissolved each in 25 ml absolute DMF Both solutions
were combined and the mixture was stirred under argon at
50 8C for 20 min and then at 90 8C for 1 h. After cooling to

M. Ciesielski et al. / Tetrahedron 61 (2005) 5942–5947
5945
precipitate was formed, filtered out, dissolved in boiling
acetone and filtered again. Ocher-colored 1d crystallized
upon cooling of the solution; yield 59%; mp 312–314 8C
(lit. 296–298 8C14), 1H NMR (DMSO-D6) d 8.73, 8.43, 8.24,
7.93, 7.50, 7.12; 13C NMR (DMSO-D6) d 148.18, 148.09,
129.39, 128.97, 125.54, 123,54, 116.09; MS (EI) m/zZ240
(MC); calcd. (%) for C12H8N4O2 (240.22) C 60.00, H 3.36,
N 23.32; found (%) C 59.41, H 3.38, N 24.05.
mixture was stirred at 60 8C for 20 min and then heated at
120 8C for 1.5 h under argon. After cooling to approxi-
mately 30 8C, the volume of the mixture was reduced to
7 ml in vacuum. A solution of 100 ml water, 50 ml
concentrated ammonia, and 20 g NaCl was added and the
mixture was stirred for 20 min at 40 8C in the presence of
air. The precipitate was filtered off and treated again with
70 ml of 10% ammonia solution in the same manner. The
solid obtained was washed with water and dried on air. It
was dissolved in 200 ml of boiling xylene and a small
amount of an impurity was separated by filtration of the hot
solution. The filtrate was cooled down slowly, with 3b being
obtained in the form of small crystals; yield 62%; mp 235–
4.2.11. 3-(4-Chlorophenyl)-1,2,4-triazolo[4,3-a]pyrimi-
dine 2a. 1.51 g (6.5 mmol) 8a19 were dissolved in 25 ml
absolute DMF at 50 8C and a solution of 1.75 g (13 mmol)
CuCl2 in 25 ml warm absolute DMF was added. The
reaction mixture was stirred under argon at 50 8C for
20 min and then heated at 110 8C for 1 h. After cooling to
approximately 30 8C, the mixture was concentrated to 5 ml
in vacuum. Then, a mixture of 100 ml water, 50 ml
concentrated ammonia solution, and 10 g NaCl was
added. After stirring for 20 min at 40 8C in the presence
of air the precipitate was filtered off. Treatment with diluted
ammonia solution was repeated, the precipitate was filtered
off, washed with water, and dried. The crude product was
first recrystallized from ethanol/water (200 ml, 70/30) and
then from ethyl acetate; yield 63%; mp 244–245 8C (lit.
284–286 8C,18 278–280 8C19), 1H NMR (DMSO-D6) d 9.36,
8.87, 8.21, 7.60, 7.34; 13C NMR (DMSO-D6) d 164.20,
156.06, 137.65, 135.91, 129.67, 129.54, 129.10, 111.55; MS
(EI) m/zZ230 (MC); calcd. (%) for C11H7N4Cl (230.66) C
57.27, H 3.06, N 24.29; found (%) C 57.27, H 3.00, N 24.54.
1
237 8C; H NMR (CDCl3) d 8.12, 8.07, 7.94, 7.07, 6.97,
6.94, 3.93, 3.89; 13C NMR (CDCl3) d 151.44, 149.52,
127.00, 121.08, 118.71, 111.38, 110.96, 56.44, 56.40; MS
(EI) m/zZ290 (MC); calcd. (%) for C13H11ClN4O2
(290.71) C 53.71, H 3.81, N 19.27; found (%) C 53.58, H
3.64, N 19.46.
4.2.15. 3-(2-Chlorophenyl)-1,2,4-triazolo[3,4-a]phthala-
zine 4a. 1.61 g (12 mmol) CuCl2 dissolved in 20 ml DMF
were added to a suspension of 1.70 g (6 mmol) 10a in 20 ml
DMF at 70 8C The mixture was stirred at 80 8C for 20 min
and then heated at 140 8C for 30 min under argon. After
cooling, the yellow-brown solution was concentrated in
vacuum. A solution of 100 ml water, 50 ml concentrated
ammonia solution, and 20 g NaCl was added. This mixture
was stirred for 20 min at 40 8C in air and a solid
precipitated. It was filtered off and suspended again in
70 ml diluted ammonia solution. After stirring in air
(15 min), the solid was separated by filtration, washed
with water, and dried. The crude product was dissolved in
80 ml of boiling ethanol and the hot ethanolic solution was
filtered. After addition of water (40 ml), the solution was
cooled down slowly and 4a was obtained as brass-colored
crystals. The product was isolated by filtration. The filtrate
was heated again and treated with a solution of 5 g NaCl in
50 ml water. A brown impurity precipitated. It was removed
by filtration of the boiling solution. The filtrate was cooled
down slowly and a second fraction of the product was
obtained; yield 74%; mp 214–216 8C; 1H NMR (DMSO-D6)
d 9.07, 8.60–8.56, 8.25–8.21, 8.13–8.06, 7.99–7.92, 7.77–
7.54; 13C NMR (DMSO-D6) d 148.49, 134.39, 133.63,
132.82, 132.20, 131.21, 129.71, 128.99, 127.25, 125.61,
123.00, 122.50, 122.12; MS (EI) m/zZ280 (MC); calcd.
(%) for C15H9ClN4 (280.72) C 64.18, H 3.23, N 19.96;
found (%) C 63.98, H 3.07, N 20.01.
4.2.12. 3-(3,4-Dimethoxyphenyl)-1,2,4-triazolo[4,3-a]-
pyrimidine 2b. 2b was prepared from 8b in analogy to
the synthesis of 2a; yield 43%; mp 207–209 8C; H NMR
1
(CDCl3) d 8.82–8.72, 7.92–7.84, 7.80, 7.03–6.96, 6.93–
6.85, 3.94, 3.88; 13C NMR (CDCl3) d 154.46, 151.69,
149.53, 135.61, 123.33, 121.07, 111.49, 110.65, 110.10,
56.33, 56.34; MS (EI) m/zZ256 (MC); calcd (%) for
C13H12N4O2 (256.27) C 60.93, H 4.72, N 21.86; found (%)
C 60.80, H 4.46, N 21.86.
4.2.13. 6-Chloro-3-(4-chlorophenyl)-1,2,4-triazolo[4,3-
b]pyridazine 3a. A solution of 2.02 g (15 mmol) CuCl2 in
30 ml warm absolute DMF was added to a suspension of
1.53 g (7.22 mmol) 9a20 in 40 ml absolute DMF. The
reaction mixture was stirred at 50 8C for 20 min and then
heated at 130 8C for 1 h under argon. After cooling to
ambient temperature, the mixture was concentrated in
vacuum. The residue obtained was stirred with a mixture
of 150 ml 10% ammonia solution and 20 g NaCl for 20 min
at 40 8C in the presence of air. The solid precipitated from
the deep blue solution was filtered off. Treatment with
diluted ammonia solution was repeated, the crude product
was filtered off and dried on air. The crude product was
refluxed in 150 ml ethyl acetate, with a small amount of
impurity remaining undissolved. Then, it was filtered from
the hot solution and the solvent was removed in vacuum.
The pure compound was obtained by recrystallization from
ethanol; yield 72%; mp 197–198 8C (lit. 193–194 8C20).
4.2.16. 1-(4-Chlorophenyl)-1,2,4-triazolo[4,3-a]quinoxa-
line 5a. 1.27g (4.5 mmol) 11a were dissolved in 20 ml
absolute DMF at 50 8C and a warm solution of 1.21 g
(9 mmol) CuCl2 was added The mixture was stirred at 50 8C
for 20 min and then heated at 100 8C for 1 h under argon.
After the reaction mixture had been cooled to approximately
30 8C, it was concentrated to 5 ml in vacuum. Then, a
solution of 100 ml water, 50 ml concentrated ammonia, and
20 g NaCl was added and the mixture was stirred at 40 8C
for 20 min in the presence of air. After cooling to room
temperature, the precipitated solid was filtered off and
treated again with diluted ammonia solution (70 ml,
15 min). The solid obtained was washed with water and
dissolved in 60 ml of boiling ethanol. Small amounts of a
4.2.14. 6-Chloro-3-(3,4-dimethoxyphenyl)-1,2,4-tria-
zolo[4,3-b]pyridazine 3b. Both 2.18 g (7.4 mmol) 9b and
2.02 g (15 mmol) CuCl2 were dissolved in 35 ml warm
absolute DMF. The solutions were mixed at 50 8C. The

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M. Ciesielski et al. / Tetrahedron 61 (2005) 5942–5947
brown precipitate were filtrated from the solution and the
filtrate was cooled down slowly. The product was collected
by filtration. After the volume of the filtrate had been
reduced to 25 ml, a second fraction of 5a was obtained;
yield 72%; mp 192–194 8C; 1H NMR (CDCl3) d 9.27–9.20,
8.09–8.05, 7.65–7.50, 7.42–7.34; 13C NMR (CDCl3) d
144.09, 137.90, 137.09, 131.69, 129.97, 129.88, 128.27,
126.46, 126.96, 116.26; MS (ES) m/zZ281 (MCHC);
calcd. (%) for C15H9ClN4 (280.72) C 64.18, H 3.23, N
19.96; found (%) C 64.03, H 3.11, N 19.90.
argon at 50 8C. The reaction mixture was stirred at 50 8C for
20 min and then heated at 100 8C for 45 min under argon.
After cooling of the clear yellow-brown solution, its volume
was reduced to approximately 5 m. Then, 150 ml of an
ammonia solution (10%) containing 20 g NaCl was added.
The mixture was stirred for 30 min at room temperature, the
precipitated solid was filtered off, and treated again with a
diluted ammonia solution (50 ml). The ammoniacal filtrates
were extracted with ethyl acetate. The solid was refluxed
with 150 ml ethyl acetate. Small amounts of a substance
remained unsolved and were removed by filtration from the
boiling mixture. All organic solutions were mixed and dried
over Na2SO4. After the solvent had been removed in
vacuum, a brown solid was obtained. 6a was isolated by
flash chromatography on alumina (eluent: chloroform). The
crude product was dissolved in 20ml hot ethyl acetate, the
boiling mixture was filtrated, and 15 ml hot n-hexane were
added. While slowly cooling, 6a was obtained as sand-
colored crystals; yield 15%; mp 205–208 8C (dec.); 1H
NMR (CDCl3) d 3.89, 3.77, 3.05–2.90, 2.00–1.80, 1.08–
0.98; 13C NMR (CDCl3) d 155.90, 150.19, 128.39, 110.61,
34.31, 32.05, 31.02, 29.03, 21.06, 14.12; MS (EI) m/zZ276
(MC); calcd. (%) for C12H16N6O2 (276.30) C 52.16, H 5.84,
N 30.42; found (%) C 51.98, H 5.76, N 30.55.
4.2.17. 1-Propyl-1,2,4-triazolo[4,3-a]quinoxaline 5b. A
warm solution of 1.34 g (10 mmol) CuCl2 in 25 ml absolute
DMF and a solution of 1.07 g (5 mmol) 11b in 20 ml
absolute DMF were mixed and stirred for 20 min at 50 8C.
Then, the reaction mixture was heated at 100 8C for 45 min
under argon. After the solution had been cooled to 30 8C, it
was concentrated to 5 ml in vacuum. Then, a solution of
80 ml water, 40 ml concentrated ammonia solution, and
20 g NaCl was added and the mixture was stirred for 20 min
at 40 8C in the presence of air. A solid substance separated,
which was collected by filtration. The solid was treated
again with diluted ammonia solution (10%, 50 ml, 15 min).
The crude product was washed with water and then
dissolved in a boiling mixture of 80 ml water and 20 ml
ethanol. Small amounts of a dark impurity were removed by
filtration of the boiling solution and the filtrate was cooled
down slowly. 5a crystallized as large needles. A second
fraction of the product was obtained after adding NaCl to
the filtrate; yield 61%; mp 149–153 8C (lit. 150 8C21).
Acknowledgements
We are grateful to the Deutsche Forschungsgemeinschaft
(SFB 436) for financial support.
4.2.18. 1-(3,4-Dimethoxyphenyl)-1,2,4-triazolo[4,3-
a]quinoxaline 5c. 1.23 g (4 mmol) 11c and 1.08 g
(8 mmol) CuCl2 were dissolved each in 25 ml warm
absolute DMF Both solutions were mixed. The brown
reaction mixture was stirred at 50 8C for 20 min and heated
at 90 8C for 30 min under argon. While cooling, a pale
yellow solid precipitated. After the main part of the solvent
had been removed in vacuum, 50 ml water, 50 ml
concentrated ammonia solution, and 20 g NaCl were
added to the residue. The mixture was stirred for 20 min
at 40 8C in the presence of air, cooled to room temperature,
and the precipitated substance was collected by filtration. It
was suspended again in diluted ammonia solution (50 ml).
After stirring in air (15 min), the crude product was
collected by filtration, washed with water, and dried.
Then, it was dissolved in 200 ml of boiling xylene. Small
amounts of a dark substance had been filtered from the
boiling mixture and the solution was cooled down slowly,
whereby the product was obtained as sand-colored crystals;
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