Synthesis of mesoionic[1,2,3]triazolo[5,1-d][1,2,5]triazepines

Article abstract of DOI:10.1016/j.tet.2004.04.067

Intramolecular cyclization of 1-amino-3-phenacyl-4-carbohydrazido-1,2,3- triazolium-5-olates has been shown to take place via selective interaction of the carbonyl group with the terminal amino function of the hydrazido group to form a 1,2,5-triazepine ring. Minor products, resulting from the interaction of the α-nitrogen atom of the hydrazido group with the carbonyl function, having a N-amino-pyridazine structure were also detected and isolated. A general method for the synthesis of novel mesoionic 2-amino-7-aryl-4-oxo-2,4,5,8- tetrahydro[1,2,3]triazolo[5,1-d][1,2,5]triazepin-9-ium-3-olates was developed.

Full text of DOI:10.1016/j.tet.2004.04.067

Tetrahedron 60 (2004) 5367–5372
Synthesis of mesoionic[1,2,3]triazolo[5,1-d][1,2,5]triazepines
Elena A. Savel’eva,a Yury A. Rozin,a Mikhail I. Kodess,b Luc Van Meervelt,c Wim Dehaen,c
Yury Yu. Morzherina and Vasiliy A. Bakuleva
,
*
aDepartment of Technology and Organic Synthesis, The Urals State Technical University, 19 Mira str.,
620002 Ekaterinburg, Russian Federation
bInstitute of Organic Synthesis, Ural Division of Russian Academy of Sciences, 20 ul. Kovalevskoi, 620219 Ekaterinburg, Russian Federation
cDepartment of Chemistry, Laboratory of Organic Synthesis, University of Leuven, B-3001 Leuven, Belgium
Received 17 December 2003; revised 2 April 2004; accepted 23 April 2004
Abstract—Intramolecular cyclization of 1-amino-3-phenacyl-4-carbohydrazido-1,2,3-triazolium-5-olates has been shown to take place via
selective interaction of the carbonyl group with the terminal amino function of the hydrazido group to form a 1,2,5-triazepine ring. Minor
products, resulting from the interaction of the a-nitrogen atom of the hydrazido group with the carbonyl function, having a N-amino-
pyridazine structure were also detected and isolated. A general method for the synthesis of novel mesoionic 2-amino-7-aryl-4-oxo-2,4,5,8-
tetrahydro[1,2,3]triazolo[5,1-d][1,2,5]triazepin-9-ium-3-olates was developed.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
hydroxy-1H[1,2,3]triazoles with substituted phenacyl
bromides leads solely to N-3 alkylated products of type 1
(Scheme 1). We proposed that triazolotriazepines 4 could
be obtained in cyclization of mesoionic hydrazides of
3-phenacyl-1,2,3-triazolio-5-olate-4-carboxylic acid 3
(Scheme 1). However, it was found that the ester group at
the position 4 of the triazole ring did not react with
hydrazine hydrate. An attempt to obtain 1,2,3-triazole-4-
carbonyl chloride 2 starting from esters 1 completely failed.
Unfortunately, in both experiments the ethyl 1-substituted
5-hydroxy-1,2,3-triazole-4-carboxylate 1 was recovered
unchanged, demonstrating the low reactivity of the ester
group due to extensive conjugation with the olate function.
Fused 1,2,5-triazepines with a bridgehead nitrogen atom in
the molecule exhibit interesting biological properties.1 At
the same time, there are no examples of mesoionic
compounds among publications concerning the synthesis
of fused triazepines,2 although mesoionic 1,2,3-triazoles
fused to six-membered rings are known to exhibit various
biological effects.3 The latter prompted M. Furber and
colleagues4 to elaborate an efficient method to prepare
1,2,3-triazoles of mesoionic structure fused to quinazoline,
quinoxaline and benzotriazine rings. However, this method
did not give access to 1,2,3-triazoles fused to triazepine ring.
In this connection, we would like to report our recent results
of a new synthetic approach towards novel mesoionic
[1,2,3]triazolo[5,1-d][1,2,5]triazepines.
Therefore, the preparation of the desired hydrazide of type 3
was performed by a three-step synthesis starting from the
protected hydrazide 5 (Scheme 2). A diazo group transfer
reaction with hydrazide 5 allowed us prepare sodium 1H-
1,2,3-triazole-5-olate 6 in good yield by adapting a literature
protocol.5
2. Results and discussion
When the triazolate 6 was reacted with substituted phenacyl
bromides (Scheme 3), N-3 alkylated products 7 were
generated. After dilution with water, the hydrolysis of one of
the azomethine groups took place to form 1-amino-3-(p-R-
phenacyl)-4-(iso-propylidencarboxamido)-1,2,3-triazolium-
5-olate 8. We managed to isolate intermediate 7e (R¼CH3O),
in good yield and then transformed this compound to
1-aminotriazolium-5-olate 8e by subsequent hydrolysis.
The basic idea of our approach consists in the synthesis
of 3-phenacyl-4-carbohydrazido-1,2,3-triazolium-5-olates
which in subsequent cyclization of carbonyl and hydrazide
groups should form the 1,2,5-triazepine ring. Earlier we
have shown,5 that alkylation of 1-aryl- and 1-amino-5-
Keywords: Fused mesoionic heterocycles; 1-Amino-1,2,3-triazolium-5-
olate; [1,2,3]Triazolo[5,1-d][1,2,5]triazepine; [1,2,3]Triazolo[1,5-a]-
pyrazine; Diazo group transfer; Alkylation.
Heating of compounds 8a-e in a 0.1 N HCl solution leads to
the removal of the second isopropylidene group to result in
*
Corresponding author. Fax: þ7-3432-745483;
e-mail address: vasiliy.bakulev@toslab.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.04.067

5368
E. A. Savel’eva et al. / Tetrahedron 60 (2004) 5367–5372
Scheme 1.
Scheme 2.
Scheme 3. Reagents and conditions: (i), ArCOCH2Br, DMF, 70 8C, 5 h; (ii) H2O, rt, 1 h; (iii) 0.1 N HCl, 100 8C, 15 h.

E. A. Savel’eva et al. / Tetrahedron 60 (2004) 5367–5372
5369
Table 1. 13C NMR (at 100 MHz in DMSO-d6) chemical shifts (ppm) and coupling constants (J (Hz))
d (J (Hz))
Compound
4a
4b
4c
4d
4e
C3
153.9 d
3J¼1.2
109.9 t
3J¼2.8
156.5 s
152.5 quintet
2J¼4.2
153.8 br. s
153.9 d
3J¼1.2
153.9 d
3J¼1.3
109.9 dt
153.8 s
v1/2¼2.4 Hz
109.8 quintet
3J¼2.7
C3a
109.9 quintet
3J¼2.8
109.9 quintet
3J¼3.1
3J¼3.1, 3J¼3.5
C4
C7
156.5 s
156.4 s
151.3 quintet
156.3 s
151.3 quintet
2J¼3.6
156.6 s
152.6 quintet
152.5 quintet
2J¼4.5
2J¼4.2
2J¼4.0
C8
48.9 t
48.8 t
48.8 t
48.7
48.8 t
1J¼147.4 1J¼147.5 1J¼147.5 1J¼148 1J¼147.5
Arom.
Subs.
(CH3)
126.6, 128.9, 130.7, 133.9 126.5, 129.4, 131.0, 140.7 128.5, 128.9, 132.8, 135.5 128.6, 124.3, 124.3, 133.5 114.3, 126.0, 128.4, 161.4
—
—
20.8 qt
1J¼126.6
—
55.4 q
1J¼144.8
the triazolohydrazides 9, which undergo smooth cyclization
in situ to the desired 2-amino-7-aryl-4-oxo-2,4,5,8-tetra-
hydro-[1,2,3]triazolo[5,1-d][1,2,5]triazepinium-3-olates
4a-e in good yields. The 1H and 13C NMR spectral data for
compound 4 corroborate the formation of the triazepine ring
and are in a good accordance with its mesoionic structure6
(Table 1).
The shape of molecule 4d is determined by the boat
conformation of the 7-membered ring. The phenyl ring
makes an angle of 46.12(11)8 with the 5-membered ring.
The angle between the best planes through the 5- and
7-membered ring is 27.96(10)8. The asymmetric unit
consists of one molecule 4d, one DMF and one water
molecules. These solvent molecules are involved in a
hydrogen bond network with atoms N2, O8, N11, O12 and
N13 (as numbered in Fig. 1).
Thus, for compounds 4, splitting of signal C3a due to coupling
with protons of the methylene group C8 is observed. The
carbon signals for the methylene group C8 and C7 of the
triazepines 4 are shifted upfield in comparison with the signals
of similar atoms of precursors 8. The final structural proof for
the compounds 4 prepared was given by X-ray diffraction data
for crystals of 4d grown from DMF (Fig. 1).7
It should be noted that the reaction described here represents
the first example of the formation of the 1,2,5-triazepine
ring due to intramolecular interaction of carbohydrazide and
phenacyl functionalities.
It is known that both a- and b-nitrogen atoms of thio-
carbohydrazide group can react with the phenacyl moiety
leading to the formation of both seven- and six-membered
heterocyclic compounds.8 Careful study of the mother
liquid of the reaction of compound 8 with HCl allowed us
also to detect the presence of by-products, that were isolated
in two cases. On the basis of elemental analyses and 1H and
13C NMR data (Table 2) the structures of the minor products
were assigned as 2,5-diamino-6-aryl-4-oxo-4,5-dihydro-
[1,2,3]triazolo[1,5-a]pyrazinium-3-olates 10c and 10e.
It is known that 1,4-dihydro-5H-[1,3,4]-benzo- and
azolotriazepin-5-ones are capable of rearranging to
isomeric benzopyrimidin-4(3H)-ones.9 To determine the
formation mechanism of triazolo[1,5-a]pyrazinium-3-
olates 10, we have treated triazepines 4 with diluted
Figure 1. X-ray structure of 4d.
1
Table 2. H, 13C NMR (at 400 and 100 MHz in DMSO-d6) chemical shifts (ppm) and coupling constants (J (Hz))
Atom/group
13C
1H
10c
10e
10c
10e
C3
C3a
C4
C6
C7
Arom.
CH3
NH2
NH2
154.4 s
107.3 d, 3J¼5.3
154.4 s
—
—
—
—
—
—
—
—
3
107.2 d, J¼4.3
151.7 d, 3J¼0.8
151.7 br. s, v1/2¼2.4
139.9 dt, 2J¼6.3 3J¼3.2
139.1 dt, 2J¼6.8 3J¼3.4
104.5 d, 1J¼200.4
103.6 d, J¼200
7.61, s
7.53, d (J¼8.7), 7.6, d (J¼8.7)
7.52, s
1
127.7, 129.9, 131.6, 134.1
113.2, 123.2, 131.2, 160.1
7.01, d (J¼8.7), 7.53, d (J¼8.7)
1
—
—
—
55.3 q, J¼144.6
—
5.21, sa
3.81, s
5.23, sa
6.26, sa
—
—
6.28, sa
a
Disappeared after adding of D3CCOOD.

5370
E. A. Savel’eva et al. / Tetrahedron 60 (2004) 5367–5372
HCl. Triazepines 4 were found to be stable even after
prolonged heating at reflux in a solution of 0.1 N HCl, and
this confirms the formation of compounds 10 directly
from hydrazide 9 and rejects the rearrangement mechan-
ism for their formation.
1 h, the solid of 8a-d was filtered off, washed with water,
dried and crystallized from chloroform (8b), from toluene
(8c, d) or from ethanol (8a).
3.2.1. 1-Amino-4-{[2-(1-methylethylidene)hydrazino]-
carbonyl}-3-phenacyl-1H-1,2,3-triazol-3-ium-5-olate
(8a). Yield 2.28 g (45%); mp 234–236 8C; MS, m/z: 316
(54%, Mþ). [Found: C 53.10, H 4.97, N 26.55. C14H16N6O3.
requires: C 53.16, H 5.10, N 26.57]; 1H NMR (250 MHz) d:
1.92 (3H, s, CH3), 1.98 (3H, s, CH3), 6.2 (2H, s, COCH2),
6.4 (2H, s, NH2), 7.57 (2H, t, J¼7.3 Hz, Ph), 7.67 (1H, t,
J¼7.3 Hz, Ph), 8.04 (2H, d, J¼7.3 Hz, Ph), 10.89 (1H, s,
NH).
In conclusion, intramolecular cyclization of 1-amino-3-
phenacyl-4-carbohydrazido-1,2,3-triazolium-5-olates has
been shown to take place via selective interaction of the
carbonyl group with the terminal amino function of the
hydrazido group to form a 1,2,5-triazepine ring. Minor
products resulting from the interaction of the a-nitrogen
atom of the hydrazido group with the carbonyl function,
namely the N-amino-pyridazines were also detected. A
general method for the synthesis of novel mesoionic
2-amino-7-aryl-4-oxo-2,4,5,8-tetrahydro[1,2,3]triazolo
[5,1-d][1,2,5]triazepin-9-ium-3-olates was developed.
3.2.2. 1-Amino-4-{[2-(1-methylethylidene)hydrazino]-
carbonyl}-3-(4-methylphenacyl)-1H-1,2,3-triazol-3-ium-
5-olate (8b). Yield 2.96 g (56%); mp 225–228 8C; MS, m/z:
330 (16%, Mþ); n (cm21): 3272, 3175 (NH), 3060, 3030,
2990, 2940 (CH), 1660, 1640 (CO), 1600, 1550. [Found: C
54.27, H 5.38, N 25.64. C15H18N6O3. requires: C 54.53, H
3. Experimental
3.1. General
1
5.49, N 25.44]; H NMR (250 MHz) d: 1.90 (3H, s, CH3),
1.95 (3H, s, CH3), 2.43 (3H, s, CH3Ar), 6.22 (2H, s, CH2),
6.54 (2H, s, NH2), 7.42 (2H, d, J¼8.1 Hz, ArH), 7.94 (2H, d,
J¼8.1 Hz, ArH), 10.93 (1H, br. s., NH). 13C NMR
(100 MHz) d: 16.5 (qq, CH3, J¼127 Hz), 21.2 (q, CH3-p,
J¼131 Hz), 24.4 (qq, CH3, J¼127.5 Hz), 58.7 (t, CH2,
J¼144.9 Hz), 110.1 (quint, C(4), J¼1.7 Hz), 128.3 (dd,
Ar, J¼161.8 ,6.4 Hz), 129.4 (dm, Ar, J¼161.4, 5.8 Hz),
131.5 (t, Ar, J¼7.4 Hz), 144.9 (m, Ar), 153.6 (d, NCO,
J¼6.8 Hz), 154.2 (s, C(5)), 154.3 (m, CvN), 189.9 (d, CO,
J¼4.2 Hz).
Melting points are uncorrected. The 1H and 13C NMR
spectra were recorded in DMSO-d6 solution with Bruker
1
DRX-400, 400 MHz or Bruker WM-250, 250 MHz for H
and 100 MHz for 13C, using TMS as internal standard.
Infrared spectra were recorded in KBr on a UR-20
spectrometer. Mass spectra were recorded using Finnigan
MAT 8200 instrument.
3.1.1. Bis(1-methylethylidene)malonhydrazide (5). A
suspension of 10 g (0.76 mol) of malonhydrazide in
100 ml of acetone was refluxed for 2 h. The solid compound
5 was filtered off and washed with 15 ml of ethanol and
dried in vacuum. Yield 15.5 g (98%); mp 163–5 8C. [Found
C, 50.85, H, 7.53, N, 26.15. C9H16N4O2 requires: C, 50.93,
H, 7.60, N, 26.40].
3.2.3. 1-Amino-3-(4-chlorophenacyl)-4-{[2-(1-methyl-
ethylidene)hydrazino]-carbonyl}-1H-1,2,3-triazol-3-
ium-5-olate (8c). Yield 4.32 g (77%); MS, m/z: 350 (36%,
Mþ). [Found: C 47.90, H 5.08, N 23.88. C14H15ClN6O3.
1
requires: C 47.94, H 4.31, Cl 10.11, N 23.96]; H NMR
(250 MHz) d: 1.91 (3H, s, CH3), 1.97 (3H, s, CH3), 6.19
(2H, s, CH2), 6.46 (2H, s, NH2), 7.63 (2H, d, J¼8.5 Hz,
ArH), 8.05 (2H, d, J¼8.5 Hz, ArH), 10.88 (1H, br. s., NH).
13C NMR (100 MHz) d: 16.5 (q, CH3, J¼127.7, 3.1 Hz),
24.8 (q, CH3, J¼127.5, 2.9 Hz), 58.8 (t, CH2, J¼144.8 Hz),
109.9 (m, C(4), J¼1.4 Hz), 129.1 (dd, Ph, J¼169.1,
5.1 Hz), 130.1 (dd, Ph, J¼164.5, 6.9 Hz), 132.8 (t, Ph,
J¼7.4 Hz), 139.2 (t, Ar, J¼10.9, 3.03 Hz), 153.5 (d, NCO,
J¼7.1 Hz), 154.2 (s, C(5)), 154.3 (m, CvN, J¼6.6, 3.7 Hz),
189.8 (t, CO, J¼4.2 Hz).
3.1.2. Synthesis of sodium 1-[(1-methylethylidene)
amino]-4-{[2-(1-methylethylidene) hydrazino]carbonyl}-
1H-1,2,3-triazol-5-olate (6). The N01,N03-bis(1-methylethyl-
idene)-malonohydrazide 5 (9.96 g, 0.047 mol) was sus-
pended in a solution of sodium ethoxide (3.196 g,
0.047 mol) in 20 ml of dry ethanol, and tosyl azide
(9.26 g, 0.047 mol) was added in a dropwise manner at
0–5 8C. The reaction mixture was stirred for 2 h. After
cooling, the precipitate 6 was filtered off, washed with
chloroform and dried. Yield 11.45 g (75%); mp 202–
204 8C; n (cm21): 1650, 1610 (CO). [Found: C 40.17, H
5.33, N 32.84. C9H13N6NaO2. requires: C 41.54, H 5.04, N
32.29]; 1H NMR (250 MHz) d: 11.27 (1H, br. s, NH), 2.13
(3H, s, Me), 1.96 (3H, s, Me), 1.94 (3H, s, Me), 1.84 (3H, s,
Me).
3.2.4. 1-Amino-3-4-bromophenacyl)-4-{[2-(1-methyl-
ethylidene)hydrazino]-carbonyl}-1H-1,2,3-triazol-3-
ium-5-olate (8d). Yield 4.43 g (79%); MS, m/z: (%, Mþ).
[Found: C, 42.58, H, 3.84, N, 21.22. C14H15BrN6O3.
requires: C, 42.55, H, 3.83, N, 21.26]; 1H NMR
(250 MHz) d: 1.92 (3H, s, CH3), 1.97 (3H, s, CH3), 6.17
(2H, s, CH2), 6.45 (2H, s, NH2), 7.66 (2H, d, J¼8.3 Hz,
ArH), 8.12 (2H, d, J¼8.3 Hz, ArH), 10.87 (1H, br. s., NH).
13C NMR (100 MHz) d: 16.5 (q, CH3, J¼127.7, 3.1 Hz),
24.8 (q, CH3, J¼127.5, 2.9 Hz), 58.8 (t, CH2, J¼144.8 Hz),
109.9 (m, C(4), J¼1.4 Hz), 129.1 (dd, Ph, J¼169.1,
5.1 Hz), 130.1 (dd, Ph, J¼164.5, 6.9 Hz), 132.8 (t, Ph,
J¼7.4 Hz), 139.2 (t, Ar, J¼10.9, 3.03 Hz), 153.5 (d, NCO,
J¼7.1 Hz), 154.2 (s, C(5)), 154.3 (m, CvN, J¼6.6, 3.7 Hz),
189.8 (t, CO, J¼4.2 Hz).
3.2. Synthesis of 1-amino-3-(p-R-phenacyl)-4-
{[2-(1-methylethylidene)hydrazino]carbonyl}-[1,2,3]-
triazolium-5-olates (8a-d)
General procedure. A solution of sodium salt 6 (16 mmol)
and an equivalent amount of the corresponding phenacyl
bromide in 10 ml of DMF was heated at 708 for 3 h, cooled
to room temperature and diluted with 15 ml of water. After

E. A. Savel’eva et al. / Tetrahedron 60 (2004) 5367–5372
5371
3.3. Synthesis of 7e, 8e
(3H, s, CH3), 5.59 (2H, s, CH2), 6.16 (2H, s, NH2), 7.30 (2H,
d, J¼8.2 Hz, ArH), 7.77 (2H, d, J¼8.2 Hz, ArH), 11.04 (1H,
s, NH).
A solution of sodium salt 6 (9.03 g, 35 mmol) and
p-methoxyphenacyl bromide (8.15 g, 35 mmol) in DMF
(5 ml) was heated at 708 for 3 h, cooled to room temperature
and 7e was filtered off from the reaction mixture, washed
with DMF, dried and crystallized from ethanol. The filtrate
was mixed with of water (20 ml). After 1 h, the solid 8e was
filtered off, washed with water, dried and crystallized from
chloroform (Method A). Alternatively, a suspension of 7e
(6.02 g) in 50 ml water was heated at reflux for 0.5 h and
evaporated under reduced pressure (Method B). The crude
8e was purified as for method A.
3.4.3. 2-Amino-7-(4-chlorophenyl)-4-oxo-2,4,5,8-tetra-
hydro[1,2,3]triazolo[5,1-d][1,2,5]-triazepin-9-ium-3-
olate (4c). Yield 0.26 g (90%); mp 268–271 8C (decomp.);
MS, m/z: 292 (54%, Mþ). [Found: C, 45.08, H, 3.08, N,
28.68. C11H9ClN6O2 requires: C, 45.14, H, 3.10, N, 28.71];
1H NMR (250 MHz) d: 5.58 (2H, s, CH2), 6.09 (2H, s, NH2),
7.47 (2H, d, J¼8.5 Hz, ArH), 7.88 (2H, d, J¼8.5 Hz, ArH),
11.07 (1H, s, NH).
3.4.4. 2-Amino-7-(4-bromophenyl)-4-oxo-2,4,5,8-tetra-
hydro[1,2,3]triazolo[5,1-d][1,2,5]-triazepin-9-ium-3-
olate (4d). Yield 0.27 g (93%); mp 272–274 8C (decomp.);
MS, m/z: 336 (59%, M21), 338 (58%, Mþ1). [Found: C,
39.15, H, 2.66, N, 24.90. C11H9BrN6O2 requires: C, 39.19,
3.3.1. 3-[(3-Methoxyphenacyl)-1-[(1-methylethylidene)
amino]-4-{[2-(1-methylethylidene)hydrazino]carbonyl}-
1H-1,2,3-triazol-3-ium-5-olate (7e). Yield 6.62 g (49%);
mp 165–168 8C; MS, m/z: 386 (34%, Mþ.). [Found: C,
56.02, H, 5.56, N, 21.59. C18H22N6O4 requires: C, 55.96, H,
1
H, 2.69, N, 24.93]; H NMR (250 MHz) d: 5.57 (2H, s,
CH2), 6.07 (2H, br. s, NH2), 7.61 (2H, d, J¼8.8 Hz, ArH),
1
5.70, N, 21.76]; H NMR (250 MHz) d: 1.91 (3H, s, CH3),
1.98 (3H, s, CH3), 2.07 (3H, s, CH3), 2.31 (3H, s, CH3), 3.89
(3H, s, OCH3), 6.20 (2H, s, CH2), 7.06 (2H, d, ArH,
J¼8.8 Hz), 8.1 (2H, d, ArH, J¼8.8 Hz), 10.83 (1H, s, NH).
7.81 (2H, d, J¼8.8 Hz, ArH), 11.07 (1H, s, NH).
3.4.5. 2-Amino-7-(4-methoxyphenyl)-4-oxo-2,4,5,8-tetra-
hydro[1,2,3]triazolo[5,1-d][1,2,5]-triazepin-9-ium-3-
olate (4e). Yield 0.25 g (87%); mp 283–286 8C (decomp.);
MS, m/z: 288 (89%, Mþ). [Found: C, 49.98, H, 4.12, N,
29.13. C12H12N6O3 requires: C, 50.00, H, 4.20, N, 29.15];
1H NMR (250 MHz) d: 3.82 (3H, s, OCH3), 5.50 (2H, s,
CH2), 5.98 (2H, br. s, NH2), 6.97 (2H, d, J¼9.0 Hz, ArH),
7.80 (2H, d, J¼9.0 Hz, ArH), 10.71 (1H, s, NH).
3.3.2. 1-Amino-3-(4-methoxyphenacyl)-4-{[2-(1-methyl-
idene)hydrazino]-carbonyl}-1H-1,2,3-triazol-3-ium-5-
olate (8e). Yield 4.34 g (36%); mp 200–205 8C (subl.); MS,
m/z: 346 (32%, Mþ). [Found: C, 52.16, H, 5.06, N, 24.20.
C15H18N6O4 requires: C, 52.02, H, 5.20, N, 24.28]; 1H
NMR (250 MHz) d: 1.91 (3H, s, CH3), 1.97 (3H, s, CH3),
3.88 (3H, s, OCH3), 6.14 (2H, s, CH2), 6.40 (2H, s, NH),
7.04 (2H, d, ArH, J¼8.9 Hz), 7.95 (2H, d, ArH, J¼8.9 Hz),
10.90 (1H, s, NH). 13C NMR (100 MHz) d: 16.5 (q, CH3,
J¼127.5 Hz), 24.8 (q, CH3, J¼127.3 Hz), 55.7 (q, OCH3,
J¼145.6 Hz), 58.5 (t, CH2, J¼144.8 Hz), 110.2 (s, C(4)),
114.2 (dd, C(m), J¼162.8, 4.6 Hz), 126.8 (t, C(i),
J¼7.3 Hz), 130.6 (dd, C(o), J¼161.6, 7.1 Hz), 153.5 (d,
NCO, J¼6.9 Hz), 154.3 (m, CvN), 154.8 (s, C(5)), 188.7
(q, CO).
3.5. Isolation of triazolopyrazines 10c,e
The water filtrate from 4c,e was concentrated under reduced
pressure to yield crude 10c,e, which was than purified by
crystallization from ethanol.
3.5.1. 2,5-Diamino-6-(4-chlorophenyl)-4-oxo-4,5-di-
hydro-2H-[1,2,3]triazolo[1,5-a]pyrazin-8-ium-3-olate
(10c). Yield 0.022 g (7%); mp .250 8C (decomp.); MS, m/z:
292 (27%, Mþ). [Found: C, 45.17, H, 3.14, N, 28.64.
C11H9ClN6O2 requires: C, 45.14, H, 3.10, N, 28.71].
3.4. Synthesis of triazolotriazepines 4a-e
General procedure. A suspension of hydrazone 8 (1.0 mmol)
in diluted HCl (100 ml, 0.1 N) was heated at reflux for 15 h,
and then the reaction mixture was concentrated at reduced
pressure to 5 ml. After cooling, product 4 was filtered off and
washed with water up to neutral pH.
3.5.2. 2,5-Diamino-6-(4-methoxyphenyl)-4-oxo-4,5-di-
hydro-2H-[1,2,3]triazolo[1,5-a]pyrazin-8-ium-3-olate
(10e). Yield 0.015 g (5%); mp .250 8C (decomp.); MS,
m/z: 288 (30%, Mþ). [Found: C, 50.11, H, 4.29, N, 29.13.
C12H12N6O3 requires: C, 50.00, H, 4.20, N, 29.15].
3.4.1. 2-Amino-4-oxo-7-phenyl-2,4,5,8-tetrahydro[1,2,3]-
triazolo[5,1-d][1,2,5]triazepin-9-ium-3-olate (4a). Yield
0.24 g (93%); mp 273–276 8C (decomp.); MS, m/z: 258
(57%, Mþ). [Found: C, 51.13, H, 3.88, N, 32.52.
C11H10N6O2 requires: C, 51.16, H, 3.90, N, 32.54]; 1H
NMR (250 MHz) d: 5.57 (2H, s, CH2), 6.06 (2H, br. s, NH2),
7.45 (3H, m, Ph), 7.86 (2H, m, Ph), 11.01 (1H, s, NH).
Acknowledgements
We thank the Russian Foundation for Basic Research
(Grant 040332926), CRDF (Award No. RC1-2393-EK-02)
the K. U. Leuven, the Ministerie voor Wetenschapsbeleid
and INTAS for financial support of this work.
3.4.2. 2-Amino-7-(4-methylphenyl)-4-oxo-2,4,5,8-tetra-
hydro[1,2,3]triazolo[5,1-d][1,2,5]-triazepin-9-ium-3-
olate (4b). Yield 0.30 g (88%); mp 294–296 8C; MS, m/z:
272 (49%, Mþ); n (cm21): 3440, 3330, 3225, 3122 (NH),
3070, 3047, 3010, 2917 (CH), 1690, 1641 (CO), 1600.
[Found: C, 52.72, H, 4.53, N, 30.78. C15H18N6O4 requires:
References and notes
1. (a) Groszkowski, S.; Wrona, J. Pol. J. Pharmacol. Pharm. 1978,
´
5, 713–715. (b) Szadowska, A.; Mazur, M.; Kaminska, A.;
1
C, 52.94, H, 4.44, N, 30.87]; H NMR (250 MHz) d: 2.35

5372
E. A. Savel’eva et al. / Tetrahedron 60 (2004) 5367–5372
Kusowska, J.; Winer, A. Acta Pol. Pharm. 1982, 39, 463–467.
6. (a) Begtrup, M. Acta Chem. Scand. 1974, 28, 61. (b) Bocian,
W.; et al. Magn. Reson. Chem. 1996, 34, 453.
(c) Lenman, M.; Ingham, S.; Gani, D. J. Chem. Soc., Chem.
Commun. 1996, 1, 85–88. (d) Lenman, M.; Lewis, A.; Gani, D.
J. Chem. Soc., Perkin Trans. 1 1997, 16, 2297–2312.
7. Crystal structure determination of triazolotriazepine 4d. The
compound C11H9BrN6O2 was recrystallized from DMF. Crystal
data: crystal dimensions 0.30£0.20£0.10 mm, triclinic, P-1,
2. (a) Rossi, S.; Pirola, O.; Selva, F. Tetrahedron 1968, 21,
6395–6409. (b) Stefancich, G.; Artico, M.; Corelli, F.; Massa,
S. Synthesis 1983, 9, 757–759. (c) Peet, N. P.; Sunder, S.
Heterocycles 1986, 24, 3213–3221. (d) Hamer, R.; Effland, R.;
Klein, J.; Huger, F.; Wilker, J. J. Heterocycl. Chem. 1988, 25,
517–521. (e) Lancelot, J.-Ch.; Robba, M. Chem. Pharm. Bull.
1988, 7, 2381–2385. (f) Stefancich, G.; Silvestri, R.
J. Heterocycl. Chem. 1989, 26, 745–746. (g) Effland, R.;
Davis, L.; Kapples, K.; Olsen, G. J. Heterocycl. Chem. 1990,
27, 1015–1019. (h) Katritzky, A. R.; Fan, W.-Q.; Greenhill,
J. V. J. Org. Chem. 1991, 3, 1299–1301. (i) Bouteau, B.; Imbs,
J.-L.; Lancelot, J.-Ch.; Barthelmebs, M.; Robba, M. Chem.
Pharm. Bull. 1991, 39, 81–85. (j) Artico, M.; Massa, S.; Mai,
A.; Silvestri, R.; Stefancich, G. J. Heterocycl. Chem. 1992, 29,
241–245. (k) Kibal’nyi, A. V.; Nikolyukin, Yu. A.; Dulenko,
V. I. Chem. Heterocycl. Compd. (Engl. Transl.) 1994, 8,
895–900. (l) Marchalin, S.; Decroix, B. Heterocycles 1995, 41,
689–696. (m) El-Saghier, A. M. M.; Maihub, A. A.; Al-
Shirayda, H. Synth. Commun. 1997, 27, 142433–142444.
3. (a) Abu-El-Haj, M. J.; McFarland, J. W. 7 pp. US Patent
3933843, 1976. (b) Abu-El-Haj, M. J.; McFarland, J. W. 6 pp.
US Patent 4002636, 1977. (c) Nagano, E.; Yoshida, R. 17 pp.
EP 0116928, 1984.
˚
a¼6.6964(5), b¼9.0098(6), c¼15.6736(9) A, a¼78.936(4),
3
˚
b¼79.551(6), g¼76.967(6)8, V¼894.68(11) A , Z¼2,
rcalcd¼1.590 g cm23, 2umax¼142.28, m(Cu Ka)¼3.464 cm21
,
˚
Bruker SMART 6000 detector, CuKa (l¼1.54178 A), crossed
¨
Gobel mirrors, T¼100 K, 7789 measured reflections, 3242
independent reflections. The data were corrected for Lorentz
and polarization effects. Structure solved by direct methods,
asymmetric unit contains also one DMF and one water
molecule. Full-matrix least-squares refinement based on lF 2l,
252 parameters, OH and NH hydrogen atoms located from
difference density map, other hydrogen atoms placed at
calculated positions and refined in riding mode with tempera-
ture factors 20% higher than parent atom, R1¼0.0467 (for 2901
data with I.2s(I)), wR2¼0.1264, max./min. residual electron
density 0.61/20.84 e2
23. Crystallographic data (excluding
˚
A
structure factors) for the structure reported in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-227138.
Copies of the data can be obtained free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: þ44-
1223-336033; e-mail: deposit@ccdc.cam.ac.uk).
`
8. Molina, P.; Tarraga, A.; Serrano, C. Tetrahedron 1984, 40,
4901.
4. (a) Cooke, A.; Bonnert, R.; Cage, P.; Donald, D.; Furber, M.;
Withnall. J. PCT Int. Appl., 169 pp. WO 9902528, 1999. (b)
Abbott, P. A.; Bonnert, R. V.; Caffrey, M. V.; Cage, P. A.;
Cooke, A. J.; Donald, D. K.; Furber, M.; Hill, S.; Withnall, J.
Tetrahedron 2002, 58, 3185.
9. (a) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.; Pearson, Sh. A.;
Excellent, F.; Harper, A. P. J. Heterocycl. Chem. 1984, 21,
1817. (b) Scheiner, P.; Arwin, S.; Eliacin, M.; Tu, J.
J. Heterocycl. Chem. 1985, 22, 1435. (c) Raboisson, P.;
Norberg, B.; Casimir, J. R.; Bourguignon, J.-J. Synlett 2002,
3, 519.
5. Rozin, Yu. A.; Savel’eva, E. A.; Morzherin, Yu. Yu.; Dehaen,
W.; Toppet, S.; Van Meervelt, L.; Bakulev, V. A. J. Chem. Soc.,
Perkin Trans. 1 2002, 2, 211.