Synthesis and hydroxydeamination in the series of 6-aryl- and 6-benzoimidazolyl-7-aminoazolo[5,1-c]-1,2,4-triazines

Article abstract of DOI:10.1023/A:1021320025860

The replacement of the amino group with the hydroxy group was examined in the series of 6-aryl- and 6-benzoimidazolyl-7-aminoazolo[5, 1-c]-1,2,4-triazines. These reactions provide a convenient synthetic procedure for the preparation of fused azolo[5,1-c]-1,2,4-triazin-7-ones.

Full text of DOI:10.1023/A:1021320025860

Russian Chemical Bulletin, International Edition, Vol. 51, No. 9, pp. 1737—1743, September, 2002
1737
Synthesis and hydroxydeamination in the series of 6ꢀarylꢀ and
6ꢀbenzoimidazolylꢀ7ꢀaminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines
b
E. N. Ulomskii,a S. L. Deev,b T. S. Shestakova,a V. L. Rusinov,a and O. N. Chupakhin
ꢀ
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 0458. Eꢀmail: rusinov@htf.ustu.ru
bInstitute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 1189. Еꢀmail: chupakhin@ios.uran.ru
The replacement of the amino group with the hydroxy group was examined in the series of
6ꢀarylꢀ and 6ꢀbenzoimidazolylꢀ7ꢀaminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines. These reactions provide
a convenient synthetic procedure for the preparation of fused azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ
7ꢀones.
Key words: hydroxydeamination, hetarylamine, azo coupling, alkylation, cycloconꢀ
densation.
Scheme 1
Fused azoloazines attract continuing interest of chemꢀ
ists primarily because of their structural similarity to puꢀ
rines.1 Due to this structural feature, fused azoloazines
can serve as antimetabolites being efficient antiviral and
antitumor drugs.2—5 One line of investigation in this field
of chemistry of heterocyclic compounds involves the synꢀ
thesis of 6ꢀsubstituted azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines and
examination of their properties. In the present study, we
synthesized 6ꢀarylꢀ and 6ꢀbenzoimidazolylꢀ7ꢀaminoꢀ
azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines and examined their hydroxyꢀ
deamination with the aim of preparing 7ꢀoxo derivatives
of azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines. Some compounds of the
latter series proved to possess antiviral activity.3
Results and Discussion
It is known6,7 that the reactions of azolyldiazonium
salts (1) with 2ꢀcyanomethylbenzoimidazole afforded
6ꢀbenzoimidazolylꢀ7ꢀaminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines.
We applied procedures described previously6 in the synꢀ
thesis of hydrazone 2 and benzoimidazolylpyrazoloꢀ
triazine (3) starting from 4ꢀethoxycarbonylpyrazolꢀ3ꢀ
yldiazonium (Scheme 1).
However, an attempt to perform azo coupling of comꢀ
pounds 5a—c with arylacetonitrile derivatives failed. We
found that the preparation of 6ꢀphenylꢀ1,2,4ꢀtriazoꢀ
lo[5,1ꢀc]ꢀ1,2,4ꢀtriazines required the use of aryl(forꢀ
myl)acetonitriles activated with respect to the electroꢀ
philic attack. Thus the reactions of phenyl(formyl)acetoꢀ
nitrile with triazolyldiazonium salts 5a—c in the presꢀ
ence of sodium acetate afforded hydrazones 6a—c. Atꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1594—1600, September, 2002.
1066ꢀ5285/02/5109ꢀ1737 $27.00 © 2002 Plenum Publishing Corporation

1738
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
Ulomskii et al.
Table 1. Yields, melting points, IR spectroscopic data, and
molecular weights (according to the results of mass spectromꢀ
etry) of compounds 2—4, 6—9, and 10a
tempts to purify compounds 6a—c by crystallization led
to cyclization giving rise to compounds 7a—c even upon
heating for a short period, which did not allow us to
characterize hydrazones 6a—c by elemental analysis. A
more convenient procedure for the synthesis of 7ꢀaminoꢀ
6ꢀarylꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines 7a—c involves
refluxing of hydrazones 6a—c in DMF. The use of triꢀ
ethylamine instead of sodium acetate in the azo coupling
reactions made it possible to directly prepare 7ꢀaminoꢀ
6ꢀarylꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines. This proceꢀ
dure was used for the synthesis of compounds 7d—f
(Scheme 2).
Comꢀ M.p.a
pound /°С
Yield М+,
(%)b m/z
IR spectrum,
ν/cm–1
2
276
76
323
2215 (CN),
3320, 3390, 3400 (NH)
3120, 3150, 3460 (NH)
1650 (C=O),
1695 (C=O) (1615, 1640)c
2210 (СN), 3450 (NH)
2210 (CN), 3460 (NH)
2215(CN), 3450 (NH)
3290, 3230 (NH)
3400, 3270 (NH)
3280, 3190 (NH)
3310, 3200 (NH)
3210, 3100 (NH)
3
4
278
>300
63
323
70 (A), 324
50 (B)
6а
6b
6c
7а
7b
7c
7d
7e
7f
8а
8b
8c
8d
8e
8f
280—282
297
271
283—286
293
81
72
85
60
65
55
40
71
52
90
74
75
69
65
53
212
226
258
212
226
258
348
362
394
213
227
259
349
363
395
Scheme 2
297
220 d
230 d
240—242 d
232
3330, 3090 (NH)
1720 (C=O), 3300 (NH)
1700 (C=O), 3270 (NH)
1730(C=O), 3300 (NH)
1705 (C=O), 3250 (NH)
1690 (C=O), 3200 (NH)
1690 (C=O), 3120 (NH)
1720 (C=O)
245
220
221
210
232
130 d
9а
51 (A), 241
70 (B)
39
35
40
9b
9c
137 d
140 d
255
287
1710 (C=O)
1710 (C=O)
3190, 3300 (NH)
10а e 207—210
a After recrystallization from DMF.
b A synthesis procedure is indicated in parentheses.
c See Ref. 8.
d After recrystallization from EtOH.
e X = BF4.
In the IR spectra of compounds 3 and 7a—f, the amino
group is manifested as a broad band in the region of
3200—3400 cm–1 (Table 1). The 1H NMR spectra of
azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines 3 and 7a—f show resonances
assigned to the protons of the aryl and azole substituents.
The presence of the equivalent trifluoromethyl substituꢀ
ents in compounds 7d—f is confirmed by the presence of
singlets in their 19F NMR spectra (δ 100.29—100.46)
(Table 2).
5: R = H (a), Me (b), SMe (c)
The [5,1ꢀc]ꢀfusion of the rings is confirmed by the
presence of a singlet in the 13C NMR spectrum of comꢀ
pound 7a recorded without suppression of 13C—1H spinꢀ
spin coupling (Table 3).
We found that 7ꢀaminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines 3
and 7a—f underwent hydroxydeamination in dilute hydroꢀ
chloric acid to give azolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀones 4
and 8a—f, respectively, as evidenced by the fact that the
IR spectra of compounds 4 and 8a—f have absorption
bands in the region of 1690—1730 cm–1 corresponding
to the carbonyl group (see Table 1). It is worthy of note
6—8
R
H
Me
SMe
Ar
Ph
Ph
Ph
7, 8
R
H
Me
SMe
Ar
a
b
c
d
e
f
3,5ꢀ(CF3)2C6H3
3,5ꢀ(CF3)2C6H3
3,5ꢀ(CF3)2C6H3
The IR spectra of hydrazones 2 and 6a—c have a
strong absorption band in the region of 2210—2215 cm–1
corresponding to stretching vibrations of the nitrile group.

7ꢀAminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
1739
1
Table 2. Data from H and 19F NMR spectroscopy for compounds 2—4, 6—9, and 10a (Bruker WMꢀ250)
Comꢀ
pound
δ
1Н
19F
2
1.48 (t, 3 Н, OCH2Me); 4.59 (q, 2 Н, ОCH2Me); 7.40—7.70, 7.80—8.20 (both m, 2 H each, С6Н4);
8.76 (s, 1 Н, Н(2)); 10.76, 13.15, 14.50 (all br.s, 1 H each, NH)
1.36 (t, 3 Н, OCH2Me); 4.35 (q, 2 Н, ОCH2Me); 7.20—7.37, 7.60—7.78 (both m, 2 H each, С6Н4);
8.73 (s, 1 Н, Н(2)); 9.76, 10.15, 13.50 (all br.s, 1 H each, NH)
1.34 (1.37)a (t, 3 Н, OCH2Me); 4.35 (4.35)a (q, 2 Н, ОСН2Me); 7.41—7.57 (7.10—7.45)a,
7.73—7.89 (7.57—7.83)a (both m, 2 H each, С6Н4); 8.39 (8.70)a (s, 1 Н, Н(2))
7.30—7.52, 7.70—7.86 (both m, 2 H each, Ph); 7.88 (s, 0.7 Н, Н(2)); 8.51 (s, 0.3 Н, Н(2));
5.50—7.00 (br.s, 2 Н, NH)
—
—
—
—
3
4
6a
6b
6c
7а
7b
7c
7d
7e
7f
8а
8b
8c
8d
8e
8f
2.25 (s, 3 Н, СMe); 7.25—7.39 (m, 3 Н, Ph); 7.72—7.83 (m, 2 Н, Ph); 4.50—6.50 (br.s, 2 Н, NH)
2.59 (s, 3 H, SMe); 7.35—7.39 (m, 3 H, Ph); 7.86—7.90 (m, 2 H, Ph); 5.70—7.00 (br.s, 2 Н, NH)
7.49—7.59 (m, 3 H, Ph); 7.70—7.74 (m, 2 Н, Ph); 8.67 (s, 1 H, H(2)); 8.50 (br.s, 2 Н, NH2)
2.54 (s, 3 H, СMe); 7.46—7.58 (m, 3 Н, Ph); 7.64—7.80 (m, 2 Н, Ph); 8.44 (br.s, 2 Н, NH2)
2.72 (s, 3 H, SMe); 7.47—7.59 (m, 3 Н, Ph); 7.63—7.80 (m, 2 Н, Ph); 8.50 (br.s, 2 Н, NH2)
7.99 (s, 1 H, C6H3(CF3)2); 8.25 (s, 2 H, C6H3(CF3)2); 8.55 (s, 1 H, Н(2)); 8.90 (br.s, 2 H, NH2)
2.58 (s, 3 H, CMe); 7.98 (s, 1 H, C6H3(CF3)2); 8.25 (s, 2 H, C6H3(CF3)2); 8.73 (br.s, 2 H, NH2)
2.73 (s, 3 H, SMe); 8.19 (s, 1 H, C6H3(CF3)2); 8.30 (s, 2 H, C6H3(CF3)2); 8.79 (br.s, 2 H, NH2)
7.40—7.52 (m, 3 H, Ph); 8.02—8.07 (m, 2 Н, Ph); 8.29 (s, 1 Н, Н(2)); 13.00—14.00 (br.s, 1 Н, NH)
2.48 (s, 3 H, CMe); 7.44—7.52 (m, 3 H, Ph); 7.95—8.07 (m, 2 H, Ph); 13.00—14.00 (br.s, 1 Н, NH)
2.66 (s, 3 Н, SMe); 7.41—7.49 (m, 3 Н, Ph); 7.96—8.05 (m, 2 Н, Ph); 13.00—14.00 (br.s, 1 Н, NH)
8.03 (s, 1 H, C6H3(CF3)2); 8.30 (s, 1 H, Н(2)); 8.63 (s, 2 H, C6H3(CF3)2); 14.50 (br.s, 1 H, NH)
2.61 (s, 3 H, CMe); 8.04 (s, 1 H, C6H3(CF3)2); 8.25 (s, 2 H, C6H3(CF3)2)
2.75 (s, 3 H, SMe); 8.02 (s, 1 H, C6H3(CF3)2); 8.24 (s, 2 H, C6H3(CF3)2)
1.48 (t, 3 Н, NСH2Me); 4.44 (q, 2 Н, NCH2Me); 7.46—7.52 (m, 3 Н, Ph);
8.00—8.10 (m, 2 Н, Ph); 8.42 (s, 1 H, Н(2))
—
—
—
—
—
100.46 (s, CF3)
100.46 (s, CF3)
100.44 (s, CF3)
—
—
—
100.29 (s, CF3)
100.44 (s, CF3)
100.41 (s, CF3)
—
9а
9b
9c
1.46 (t, 3 Н, NСH2Me); 2.44 (s, 3 Н, CMe); 4.37 (q, 2 Н, NCH2Me); 7.44—7.50 (m, 3 Н, Ph);
7.99—8.02 (m, 2 Н, Ph)
1.46 (t, 3 Н, NСH2Me); 2.65 (s, 3 Н, SMe); 4.37 (q, 2 Н, NCH2Me); 7.47—7.50 (m, 3 Н, Ph);
8.00—8.03 (m, 2 Н, Ph)
1.53 (t, 3 H, NCH2Me); 4.48 (q, 2 Н, NCH2Me); 7.56—7.59 (m, 3 Н, Ph);
7.66—7.70 (m, 2 Н, Ph); 8.76 (s, 1 Н, Н(2))
—
—
—
b
10а
a See Ref. 8.
b X = BF4.
Table 3. Data from 13C NMR spectroscopy for compounds 7a, 8a, and 9a—c (Bruker DRXꢀ400)
Comꢀ
pound
δ (JC,H/Hz)
R
C(2)
C(3a)
C(6)
C(7)
NCH2
—
CMe
—
Ph
7а
8а
9а
—
155.88 d
(1J = 209)
153.53 d
155.25 d
(3J = 5.7)
151.22 d
(3J = 9.3)
150.73 dt
(3J = 9.3,
3J = 2.7)
133.89 t
(3J = 7.2)
139.14 t
139.94
128.50; 128.55;
128.90; 133.41
128.08; 128.36
129.34; 132.55
132.42 (C(1´));
s
—
—
149.47
—
—
(1J = 210)
153.24 d
(3J = 3.7)
138.64 t
s
149.03
s
49.40 tq
(1J = 143.0,
3J = 4.6)
13.0 qt
(1J = 128.4,
3J = 3.3)
(1J = 210.6)
(3J = 3.7)
128.13 (C(2´), C(6´));
128.40 (C(3´), C(5´));
129.45 (C(4´))
9b
9c
13.59 q
162.79 q
150.93 t
138.60 t
148.50
s
49.24 tq
(1J = 143.0,
3J = 4.6)
14.2 qt
(1J = 128.8,
3J = 3.9)
132.32 (C(1´));
(1J = 122.7) (2J = 7.2)
(3J = 2.7)
(3J = 3.6)
128.31 (C(2´), C(6´));
128.50 (C(3´), C(5´));
129.45 (C(4´))
13.43 q
(1J = 142.5) (3J = 4.7)
151.22 q
151.22 t
(3J = 2.6)
139.02 t
(3J = 3.6)
147.63
s
49.24 tq
(1J = 143.3,
3J = 4.5)
12.86 qt
(1J = 128.5,
3J = 3.24)
132.23 (C(1´));
128.13 (C(2´), C(6´));
128.45 (C(3´), C(5´));
129.44 (C(4´))

1740
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
Ulomskii et al.
1
that the aromatic protons in the H NMR spectrum of
benzoimidazole 4 are manifested as an AA´XX´ system
consisting of two symmetrical twoꢀproton multiplets.
The reactions of 7ꢀaminoꢀ6ꢀphenylꢀ1,2,4ꢀtriazoꢀ
lo[5,1ꢀc]ꢀ1,2,4ꢀtriazines (7a—c) with EtI or EtBr in DMF
followed by treatment of the reaction mixture with water
afforded 4ꢀethylꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀ
ones (9a—c), which represent simultaneously alkylation
and hydroxydeamination products (Scheme 3).
pounds 9b,c, resonances of the substituent R are also
observed (see Table 3).
1
The H NMR spectra of compounds 9a—c have sigꢀ
nals for the protons of both the azole and aryl substituꢀ
ents (δ 7.0—8.0). The signals of the Et groups are obꢀ
served at δ 1.30—4.40 (see Table 2).
The mechanisms A, B, and C can be proposed for the
reactions of hetarylamines 7a—c with EtI or EtBr
(Scheme 4).
The mechanism A involves hydroxydeamination as
the first step giving rise to triazolotriazines 8a—c, which
are strong NHꢀacids.9 These acids form salts 11a—c with
ammonia that liberated. Then, compounds 11a—c are
alkylated under standard conditions.10 The mechanism B
involves the formation of quaternary ammonium salts
12a—c. In this case, the triethylammonium group is
readily replaced giving rise to compounds 8a—c. The
latter react with triethylammonium hydrohalide and ethyl
halide. The mechanism C involves the formation of
triazinium cations 10a—c, which are readily transformed
into triazolo[5,1ꢀc]ꢀ1,2,4ꢀtrazinones 9a—c.
Scheme 3
To establish the reaction pathway, we carried out
additional experiments. We found that compound 8a did
not react with triethylammonium hydrobromide and EtBr
in DMF. The starting compound 8a was isolated from
the reaction mixture, which allowed us to exclude the
path B. Further examination of the resistance of hetarylꢀ
amine 7a to hydrolysis demonstrated that prolonged reꢀ
fluxing of compound 7a in water or aqueous DMF did
not afford triazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀone 8a. This
indicates that the reaction cannot follow the path A.
Hence, the reaction most probably proceeds through the
mechanism C.
R = H (a), Me (b), SMe (c); X = Hal, BF4
The position of the Nꢀethyl group in compounds 9a—c
was established by 13C NMR spectroscopy. The assignꢀ
ment of the signals in the spectra was made based on the
chemical shifts in the spectra measured with full 13C—1H
decoupling and taking into account the hyperfine strucꢀ
ture of the signals in the spectra measured with retention
of 13C—1H spinꢀspin coupling. In the spectrum of comꢀ
pound 9a, the C(2) atom gives a doublet with a large
spinꢀspin coupling constant (1JC,H = 210.6 Hz) without
additional splitting, which excludes the presence of the
Et substituent in the azole fragment of the molecule.
This conclusion was confirmed by the structure of the
resonance for the bridgehead C(3a) atom, which is maniꢀ
fested as a doublet of triplets with small spinꢀspin couꢀ
The 1H NMR spectrum of the reaction mixture which
was obtained by the reaction of hetarylamine 7a with
EtBr shows signals for the protons of the azole ring at
δ 8.1—8.9 corresponding to amine 7a, triazolotriazine
9a, and an unidentified alkyl derivative. The latter is,
apparently, salt 10a (X = Br). In addition, the spectrum
has overlapping signals of the Et groups, multiplets of
the Ph substituents of all the aboveꢀmentioned comꢀ
pounds, and a triplet corresponding to the ammonium
1
ion (δ 7.1, J = 49.95 Hz). The absence of the signals of
pling constants (3JC(3a),H(2) = 9.3 Hz and 3JC(3a),H(NCH )
2.7 Hz). In the spectra of compounds 9b,c, the signals
=
alkylammonium salts is additional evidence that the
path B is impossible.
2
for the C(2) atom are observed as quartets with small
With the aim of studying the reactions of hetarylamines
7a—c with alkyl halides, triazolotriazinium 10a was synꢀ
thesized from triazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazine 7a (X = BF4)
under the action of the Meerwein reagent and the specꢀ
troscopic characteristics of this salt were determined.
Thus the chemical shift of the H(2) atom (δ 8.76) correꢀ
sponds to the signal of the unidentified compound obꢀ
served in the 1H NMR spectrum of the reaction mixture.
In addition, brief refluxing of salt 10a (X = BF4) in
water afforded a compound whose physicochemical charꢀ
spinꢀspin coupling constants (2JC,H = 7.2 Hz and 3JC,H
=
4.7 Hz, respectively) and the signal for the bridgehead
C(3a) atom degenerates into a triplet (see Table 3). In
the spectra of compounds 9a—c, the lowꢀfield singlet
(δ 147.5—149.1) was assigned to the C(7) atom and the
triplet at δ 138—139 was attributed to the resonance for
the C(6) atom. The remaining lowꢀfield multiplets beꢀ
long to the Ph group. The highꢀfield region of the specꢀ
tra has signals of the Et group. In the spectra of comꢀ

7ꢀAminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
1741
Scheme 4
R = H (a), Me (b), SMe (c); Hal = Br, I
Scheme 5

1742
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
Ulomskii et al.
Table 4. Data from elemental analysis of compounds 3, 4,
7—9, and 10a
acteristics are identical with those of 6ꢀphenylꢀ1,2,4ꢀ
triazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀone (9a) prepared by the
reaction of amine 7a with EtI or EtBr in DMF. These
experiments demonstrate that the formation of triꢀ
azolo[5,1ꢀc]ꢀ1,2,4ꢀtrazinones 9a—c proceeds most likely
via the pathway C.
Comꢀ
pound
Found
Calculated
Molecular
formula
(%)
С
Н
N
Compound 4 can also be prepared by the reaction of
diethyl 7ꢀaminopyrazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinoꢀ3,6ꢀdiꢀ
carboxylate (13) with orthoꢀphenylenediamine dihydroꢀ
chloride in acetic acid (Scheme 5). Aminoheterocycle 3
generated in the first step of the reaction readily underꢀ
went hydroxydeamination under the action of hydrogen
chloride that has been liberated and water.
The results of our study are in contradiction with the
results of an earlier investigation8 in which the tetracyclic
structure (14) was assigned to the reaction product. The
authors established the structure of benzodiazepine 14
based on the data from IR spectroscopy, mass spectromꢀ
etry, elemental analysis, and 1H NMR spectroscopy,
which is insufficient because compounds 4 and 14 are
isomers.
We performed the independent synthesis of heteroꢀ
cycle 4 and demonstrated that tetracyclic structure 14
assigned to the condensation product8 is in error and
that benzoimidazole derivative 4 is in fact the reaction
product.
Hence, hydroxydeamination is a typical reaction of
7ꢀaminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines and provides a conꢀ
venient procedure for the synthesis of azolotriazinones.
3
55.49
55.73
55.30
55.55
56.60
56.60
58.61
58.41
51.26
51.15
41.21
41.38
43.00
43.09
39.63
39.59
56.33
56.34
58.30
58.15
50.90
50.96
41.36
41.26
42.68
42.98
39.75
39.49
59.55
59.74
61.04
61.17
54.34
54.34
44.24
44.04
4.00
4.02
3.81
3.70
3.92
3.80
4.42
4.46
4.01
3.90
1.89
1.72
2.11
2.21
2.05
2.03
3.10
3.31
3.91
3.99
3.33
3.50
1.47
1.43
2.02
1.93
1.77
1.77
4.60
4.60
5.21
5.13
4.55
4.56
4.03
3.97
30.22
30.34
25.45
25.91
39.41
39.60
37.60
37.15
32.09
32.54
23.86
24.14
23.24
23.20
21.26
21.32
32.96
32.85
30.35
30.82
27.07
27.01
20.01
20.06
18.85
19.28
17.29
17.72
28.95
29.03
26.98
27.43
24.66
24.37
26.10
25.69
С15Н13N7O2
C15H12N6O3
C10H8N6
4
7а
7b
7c
7d
7e
7f
C11H10N6
C11H10N6S
C12H6F6N6
C13H8F6N6
C13H8SF6N6
C10H7N5O
8а
8b
8c
8d
8e
8f
C11H9N5O
C11H9N5OS
C12H5F6N5O
C13H7F6N5O
C13H7F6N5OS
C12H11N5O
C13H13N5O
C13H13N5OS
C12H13BF4N6
Experimental
The IR spectra were recorded on a Specord IRꢀ75 specꢀ
trometer (KBr pellets). The 1H, 13C, and 19F NMR spectra
were measured on Bruker WMꢀ250 (250 MHz) and Bruker
DRXꢀ400 (400 MHz) spectrometers in DMSOꢀd6 with Me4Si,
9а
9b
9c
10а*
1
DMSOꢀd6, and C6F6 as the internal standards for the H, 13C,
and 19F NMR spectra, respectively. The mass spectra were
obtained on a VarianꢀMATꢀ311A instrument with direct inlet
of the sample into the ion source (energy of ionizing elecꢀ
trons was 70 eV, temperature of the ionization chamber was
100—300 °C). The melting points were determined on a Boetius
stage. The TLC analysis was carried out on Silufol UVꢀ254
plates in ethyl acetate; spots were visualized with UV light or
iodine vapor.
* X = BF4.
7ꢀAminoꢀ6ꢀbenzoimidazolylpyrazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazine (3)
was synthesized according to a procedure described previously.6
3ꢀRꢀ5ꢀAminoꢀ1,2,4ꢀtriazoles were prepared according to
known procedures.11—13 Triethyloxonium tetrafluoroborate was
synthesized according to a procedure described previously.14
Phenyl(formyl)acetonitrile and its bis(trifluoromethyl) derivaꢀ
tive, which were synthesized according to a known procedure,15
were kindly provided by P. V. Podsevalov (Scientific Developꢀ
ment Firm "Okta," Perm, Russia). Ethyl 3ꢀaminopyrazoleꢀ4ꢀ
carboxylate and benzoimidazolꢀ2ꢀylacetonitrile were purchased
from Aldrich. All other reagents and solvents were domestically
produced and used without additional purification.
Azolylhydrazones 2, 6a—c. Nitric acid (d = 1.4 g mL–1
,
7 mL, 0.1 mol) or concentrated HCl (11 mL, 0.1 mol) was
added to a solution of 5ꢀaminoꢀ1,2,4ꢀtriazole or ethyl 3ꢀaminoꢀ
pyrazoleꢀ4ꢀcarboxylate (0.05 mol), respectively, in water
(20 mL). The reaction mixture was cooled to 0 °C and then a
solution of NaNO2 (3.45 g, 0.05 mol) in water (5 mL) was
added at 0 °C. The reaction mixture was kept at 0 °C for 15 min
and added to a solution of phenyl(formyl)acetonitrile (7.25 g,
0.05 mol) or benzoimidazolꢀ2ꢀylacetonitrile (7.9 g, 0.05 mol)
and NaOAc (10 g) in 50% aqueous EtOH (40 mL) cooled to
5 °C. Then the reaction mixture was kept at ∼20 °C for 2 h. The
precipitate of hydrazone 2 or 6 that formed was filtered off,
washed with water and EtOH, and dried.
The yields of the reaction products and solvents used for
their crystallization are listed in Table 1. The results of elemenꢀ
tal analysis are given in Table 4.

7ꢀAminoazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines
Russ.Chem.Bull., Int.Ed., Vol. 51, No. 9, September, 2002
1743
Rꢀ7ꢀAminoꢀ6ꢀphenylꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines
(7a—c). A solution of hydrazone 6a—c (0.01 mol) in DMF
(5 mL) was refluxed for 10 min and cooled. The precipitate
that formed was filtered off and recrysallized.
References
1. R. K. Robins, G. R. Ravenkar, D. E. O´Brien, R. H.
Springer, T. Novinson, A. Albert, K. Senga, J. P. Miller,
and D. G. Streeter, J. Heterocycl. Chem., 1985, 22, 601.
2. Selective Toxicity, The PhysicoꢀChemical Basis of Therapy,
Ed. A. Albert, Chapman and Hall, London—New York,
1987, 1.
3. V. L. Rusinov, E. N. Ulomskii, O. N. Chupakhin, M. M.
Zubairov, A. B. Kapustin, N. I. Mitin, M. I. Zhiravetskii,
and I. A. Vinograd, Khim.ꢀfarm. Zh., 1990, 41, 24 [Pharm.
Chem. J., 1990, 41 (Engl. Transl.)].
4. K. L. Horspool, M. F. G. Stevens, G. G. Newton, E. Lunt,
R. J. A. Walsh, B. L. Pedgrift, G. U. Baig, F. Lavelle, and
C. Fizames, J. Med. Chem., 1990, 33, 1393.
5. M. J. Wanner, J. K. F. D. Künzel, A. P. Ijzerman,
and G.ꢀJ. Koomen, Bioorgan. Med. Chem. Lett., 2000,
10, 2141.
6. E. N. Ulomskii, S. L. Deev, V. L. Rusinov, and O. N.
Chupakhin, Zh. Org. Khim., 1999, 35, 1384 [Russ. J. Org.
Chem., 1999, 35 (Engl. Transl.)].
7. J. Slouka and V. Bekarek, Collect. Czech. Chem. Commun.,
1984, 49, 275.
8. Y. Kurasawa, Y. Okamoto, and A. Takada, J. Heterocycl.
Chem.,1987, 24,1799.
9. L. G. Egorova, A. Yu. Petrov, and V. L. Rusinov, Khim.
Geterotsikl. Soedin., 1984, 697 [Chem. Heterocycl. Compd.,
1984, 20 (Engl. Transl.)].
10. E. N. Ulomskii, V. L. Rusinov, O. N. Chupakhin, G. L.
Rusinov, A. V. Chernyshev, and G. G. Aleksandrov, Khim.
Geterotsikl. Soedin., 1987, 1543 [Chem. Heterocycl. Compd.,
1987, 23 (Engl. Transl.)].
11. Organic Synthesis, J. Wiley and Sons, New York; Chapman
and Hall, London, 1946, 26.
12. Beilsteins Handbuch der Organischen Chemie, Springer, Berꢀ
lin, 1936, 26, 145.
13. S. M. Desenko and V. D. Orlov, Azageterotsikly na osnove
aromaticheskikh nepredel´nykh ketonov [Azaheterocycles
Based on Aromatic Unsaturated Ketones], Folio, Kharkov,
1998, 148 pp. (in Russian).
Rꢀ7ꢀAminoꢀ6ꢀ[3,5ꢀbis(trifluoromethyl)phenyl]ꢀ1,2,4ꢀ
triazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazines (7d—f). Diazotization of
3ꢀRꢀ5ꢀaminoꢀ1,2,4ꢀtriazoles was carried out as described above.
The reaction mixture was kept at 0 °C for 15 min and then
added to a solution of formyl[3,5ꢀbis(trifluoromethyl)]acetoꢀ
nitrile (14.05 g, 0.05 mol) and Et3N (10 mL) in 50% aqueous
EtOH (40 mL) cooled to 5 °C. Then reaction mixture was kept
at ∼20 °C for 2 h. The precipitate of hetarylamine 7 that formed
was filtered off, washed with water, and recrystallized.
6ꢀBenzoimidazolylpyrazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀone (4).
Method A. A suspension of hetarylamine 3 (0.32 g, 1 mmol) in
23% HCl (d = 1.115 g mL–1; 5 mL) was refluxed for 0.5 h.
After cooling of the reaction mixture, the precipitate that formed
was filtered off and recrystallized.
Method B. Compound 4 was synthesized from pyrazoꢀ
lo[5,1ꢀc]ꢀ1,2,4ꢀtriazine (13) according to a procedure described
previously.8
6ꢀArylꢀ4,7ꢀdihydroꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriazinꢀ7ꢀ
ones (8a—f). A suspension of hetarylamine (7a—f) (1 mmol) in
23% HCl (d = 1.115 g mL–1; 5 mL) was refluxed for 0.5 h.
After cooling of the reaction mixture, the precipitate that formed
was filtered off and recrystallized.
2ꢀRꢀ4ꢀEthylꢀ6ꢀphenylꢀ4,7ꢀdihydroꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ
1,2,4ꢀtriazinꢀ7ꢀones (9a—c). Ethyl bromide or iodide
(0.012 mol) was added to a solution of hetarylamine 7a—c
(0.01 mol) in DMF (10 mL), the reaction mixture was heated
for 2 h at 100 °C, and water (20 mL) was added to the cooled
reaction mixture. The precipitate that formed was filtered off
and recrystallized.
4ꢀEthylꢀ6ꢀphenylꢀ4,7ꢀdihydroꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀ
triazinꢀ7ꢀone (9a). Method B. A suspension of compound 10a
(1 g, 3 mmol) in water (5 mL) was refluxed for 20 min. After
cooling of the reaction mixture, the precipitate that formed
was filtered off and recrystallized.
7ꢀAminoꢀ4ꢀethylꢀ6ꢀphenylꢀ1,2,4ꢀtriazolo[5,1ꢀc]ꢀ1,2,4ꢀtriꢀ
azinium tetrafluoroborate (10a) (X = BF4). Triethyloxonium
tetrafluoroborate (3.4 g, 1.8 mmol) was added to a suspension
of amine 6a (2 g, 1 mmol) in dichloroethane (15 mL). The
reaction mixture was kept at ∼20 °C for 24 h. The precipitate
that formed was filtered off.
14. L. E. Fieser and M. Fieser, Reagents for Organic Synthesis,
WileyꢀInterscience, New York—London—Sydney—Toronto,
1968, 3.
15. US Pat. 2,989,539, 20.06.1961.
This study was financially supported by the Russian
Foundation for Basic Research (Project Nos. 00ꢀ15ꢀ97390
and 99ꢀ03ꢀ32923) and the US Civilian Research and
Development Foundation (CRDF, Grant RECꢀ005).
Received July 20, 2001;
in revised form May 16, 2002