Potassium salt of nitroacetonitrile in the synthesis of nitrogen heterocycles

Article abstract of DOI:10.1007/s10593-016-1819-5

Methods of synthesis of 3-nitroazolo[5,1-c][1,2,4]triazin-4-amines, their conversion to [1,2,4]triazolo[5,1-c][1,2,4]triazine-3,4-diamines, and cyclization of one of the latter to 8H-imidazo[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]triazine have been developed with stable potassium salt of nitroacetonitrile.

Full text of DOI:10.1007/s10593-016-1819-5

DOI 10.1007/s10593-016-1819-5
Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1057–1060
Potassium salt of nitroacetonitrile
in the synthesis of nitrogen heterocycles
Egor K. Voinkov1, Eugeny N. Ulomskiy1,2*, Vladimir L. Rusinov1,2,
Oleg N. Chupakhin1,2, Evgeny B. Gorbunov1,2, Roman A. Drokin1, Victor V. Fedotov1
1 Ural Federal University named after the first President of Russia B. N. Yeltsin,
19 Mira St., Yekaterinburg 620002, Russia; e-mail: ulomsky@yandex.ru
2 I. Ya. Postovskii Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
22 S. Kovalevskoi St. / 20 Akademicheskaya St., Yekaterinburg 620219, Russia
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2015, 51(11/12), 1057–1060
Submitted November 12, 2015
Accepted December 11, 2015
Methods of synthesis of 3-nitroazolo[5,1-с][1,2,4]triazin-4-amines, their conversion to [1,2,4]triazolo[5,1-c][1,2,4]triazine-3,4-diamines,
and cyclization of one of the latter to 8H-imidazo[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]triazine have been developed with stable potassium salt of
nitroacetonitrile.
Keywords: azolo triazines, nitroacetonitrile, nitrogen heterocycles, azo coupling, diazotation, stability.
One of the pressing problems of contemporary organic
synthesis is the instability of certain key intermediates for
the preparation of leading products. These unstable
compounds containing in the molecule simultaneously
nucleophilic and electrophilic reactive sites include a
number of nitro compounds: nitroacetaldehyde, metazonic
acid, and nitroacetonitrile (NAN). For all its obvious
potential as a synthetic "building" block nitroacetonitrile
undeservedly is rarely used in organic synthesis. The main
if not the only reason is the low thermodynamic stability of
this compound1 forcing researchers to work with extreme
caution or, more often, find an alternative, less dangerous
route. Therefore, most of the work with nitroacetonitrile is
limited to reactions such as azo coupling,2 Knoevenagel
condensation,3–11 and related processes.12–14 At the same
time, the use of NAN is known to offer vast opportunities
in ring closure reactions to form monocyclic structures
such as 4-nitropyrazol-3-amine,15 6-azauracils,16 4-nitro-
izoxazoles,17 2,4,6-tricyanopyridine N-oxide,18 as well as
polycondensed systems, chromenes19,20 and azolo[5,1-c]-
[1,2,4]triazines.21
accessible and user-friendly reagent. Preparation as well as
advantages of potassium salt of NAN were described in a
previous paper.*
The use of potassium salt of NAN 2 in reactions with
3-aminoazoles 1a–i allowed access to azolylhydrazones
3a–i which then have been converted with good yields into
3-nitroazolo[5,1-c][1,2,4]triazin-4-amines 4a–i (Scheme 1),
which are of interest as biologically active compounds.22
The advantage of the synthetic technique that we have
developed in comparison with previously published
methods21-22 is the stability, safety, and ease of work with
salt 2.
Using our proposed potassium salt of NAN 2 made
compounds 4, key intermediates in the synthesis of imid-
azo[4,5-e]azolo[5,1-c][1,2,4]triazines, structural analogs of
potential inhibitors of adenosine receptors,23 more readily
available.
Reduction of 3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-
4-amines 4b,e leads to [1,2,4]triazolo[5,1-c][1,2,4]triazine-
3,4-diamines 5a,b (Scheme 2).
In this work, we demonstrated for the first time the
possibility of synthesizing nitrogen heterocycles with
potassium salt of nitroacetonitrile (2) as an easily
* Voinkov, E. K.; Ulomskiy, E. N.; Rusinov, V. L.; Savateev, K. V.;
Fedotov, V. V.; Gorbunov, E. B.; Isenov, M. L.; Eltsov, O. S. Mendeleev
Commun. In press.
1057
0009-3122/15/51(11/12)-1057©2015 Springer Science+Business Media New York

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1057–1060
Scheme 1
NC
NC
CO2Et
K+
KOH
–
–
K+
K+
N–
H2O
rt, 20 h
NO2
NO2
NC
NC
2
N
X
N
40% H2SO4
1) KOAc, 5°C
2) rt, 1 h
NO2
NO2
NH
R
R
R
or AcOH
(for 3e)
N
N
X
N
N
N
N
X
Cl–
NaNO2, HCl
H
H
NH
NH
3a–i
R
R
H2O, EtOH
–5°C, 10 min
X
+
NH2
N2
DMF
, 3 h
NH2
1a–i
NO2
N
X
N
a R = H, X = N
b R = Me, X = N
c R = SMe, X = N
d R = CO2Et, X = N
e R = 3-Py, X = N
g R = SMe, X = C–CO2Et
h R = Ph, X = N
f R = SMe, X = C–CN i R = H, X = C–CO2Et
N
N
4a–i
Such reducing agents as zinc in acetic acid and
Potassium salt of ethyl nitrocyanoacetate was prepared
according to a known method.24
hydrochloric acid or sodium dithionite were not suitable for
reducing the nitro group of triazolotriazines 4b,e. The most
convenient way of reducing the nitro group was
hydrogenation in the presence of palladium on carbon in
DMF solution under a pressure of 10 atm.
Synthesis of 3-nitroazolo[5,1-с][1,2,4]triazin-4-amines 4a–i
(General method).
Solution А. A solution of KOH (0.56 g, 0.01 mol) and
potassium salt of ethyl nitrocyanoacetate (1.96 g, 0.01 mol) in
Н2О (8 ml) was stirred at room temperature for 3 h, then kept
overnight. 4 M aqueous KOAc (8 ml, 0.03 mol) was added to
the resulting solution, and the mixture cooled to 5°С.
Scheme 2
A mixture of 3-aminoazole 1a–i (0.010 mol), EtOH (10 ml),
H2O (10 ml), and concentrated HCl (2.5 ml, 0.030 mol)
was treated with a solution of NaNO2 (0.759 g, 0.011 mol)
in H2O (3 ml) at –5 °С. The reaction mixture was kept at this
temperature for 10 min, then added to the solution A. The
mixture was kept at room temperature for 1 h; the formed
precipitate was filtered, stirred with 40% aqueous H2SO4
(10 ml) (AcOH (10 ml) was used for compound 4e),
filtered, and dried. The obtained hydrazone 3a–i was
heated under reflux in DMF for 3 h. The solvent was
evaporated, the residue triturated in water, filtered, and dried.
3-Nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-4-amine (4а).
Yield 1.09 g (60%), orange-brown powder, mp >315°С. IR
spectrum, ν, cm–1: 772, 839, 1081, 1152, 1186, 1219, 1251,
1291, 1336, 1422, 1477, 1499, 1555, 1644, 1660, 3103,
The final stage of this work was cyclization of ortho-
diamine 5a to form imidazole ring. The reaction was
conducted by heating under reflux with triethyl
orthoformate to afford in 47% yield 2-methyl-8H-imidazo-
[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]triazine (6), which is related
to the unknown heterocyclic group of triazolo-6-azapurines
(Scheme 2). The structure of triazolotriazinediamines 5a,b
and imidazotriazolotriazine 6 was established on the basis
of IR, 1H NMR spectra as well as elemental analysis data.
To conclude, we have developed efficient methods for
the synthesis of azolo[5,1-c][1,2,4]triazines using potas-
sium salt of nitroacetonitrile as a stable and convenient key
intermediate.
1
3328. H NMR spectrum, δ, ppm: 8.73 (1H, s, H-7); 9.65
(1H, br. s) and 10.10 (1H, br. s, NH2). Found, %: C 26.27;
H 1.77; N 54.35. C4H3N7O2. Calculated, %: C 26.53;
H 1.67; N 54.14.
7-Methyl-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]triazin-4-amine
hydrate (4b). Yield 1.07 g (55%), light-yellow powder,
mp 214–215°С. IR spectrum, ν, cm–1: 766, 801, 848, 1217,
1248, 1258, 1319, 1347, 1405, 1440, 1503, 1553, 1622,
1
1680, 2998, 3377, 3626. H NMR spectrum, δ, ppm: 2.62
(3H, s, CH3); 9.43 (1H, br. s) and 10.01 (1H, br. s, NH2).
Found, %: C 28.64; H 3.19; N 45.97. C5H5N7O2·H2O.
Calculated, %: C 28.17; H 3.31; N 46.00.
Experimental
IR spectra were recorded on a Bruker Alpha spectrometer,
ZnSe (ATR). H and 13C NMR spectra were registered on a
1
7-(Methylsulfanyl)-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]-
triazin-4-amine (4с). Yield 1.09 g (48%), orange powder,
mp 283–285°С. IR spectrum, ν, cm–1: 627, 693, 702, 765,
842, 1199, 1242, 1300, 1325, 1361, 1410, 1475, 1503,
Bruker Avance II spectrometer (400 and 100 MHz,
respectively) in DMSO-d6, with TMS as internal standard.
Elemental analysis was performed on a Perkin Elmer 2400
CHN Elemental Analyzer. Sulfur content was determined by
bariummetric titration. Melting points were determined on a
Staffordshire, ST150SA. Monitoring of the reaction progress
was done by TLC on Silufol UV-254 plates (eluent EtOAc).
1
1540, 1645, 3069, 3382. H NMR spectrum, δ, ppm: 2.74
(3H, s, SCH3); 9.67 (2H, br. s, NH2). Found, %: C 26.49;
H 2.36; N 43.13; S 14.11. C5H5N7O2S. Calculated, %:
C 26.43; H 2.22; N 43.15; S 14.11.
1058

Chemistry of Heterocyclic Compounds 2015, 51(11/12), 1057–1060
Ethyl
4-amino-3-nitro[1,2,4]triazolo[5,1-c][1,2,4]tria-
Synthesis of [1,2,4]triazolo[5,1-c][1,2,4]triazine-
3,4-diamines 5a,b (General method). Nitro derivative 4b,e
(3.4 mmol) was dissolved in DMF (10 ml), and 5 % by
mass palladium on carbon (0.15 g) was added. The
reduction was done in the autoclave at 45°С and 10 atm H2
pressure for 4 h. The reaction mixture was then cooled to
room temperature and filtered. The filtered solid was
heated under reflux with DMSO (10 ml) and filtered while
hot. The filtrate was cooled to room temperature and
diluted with 3 volumes of water. The formed precipitate
was filtered, washed with water, and dried in air.
zine-7-carboxylate hydrate (4d). Yield 1.26 g (50%),
brown powder, mp 213–215°С (decomp.). IR spectrum, ν,
cm–1: 747, 771, 844, 1017, 1199, 1249, 1290, 1326, 1356,
1401, 1479, 1507, 1555, 1653, 1722, 1747, 2921, 3108,
3256, 3410, 3607. 1H NMR spectrum, δ, ppm (J, Hz): 1.45
(3H, t, J = 7.1, ОCH2CH3); 4.51 (2H, q, J = 7.1,
ОCH2CH3); 10.00 (2H, br. s, NH2). Found, %: C 31.37;
H 3.17; N 36.28. C7H7N7O4·H2O. Calculated, %: C 31.00;
H 3.35; N 36.15.
3-Nitro-7-(pyridin-3-yl)[1,2,4]triazolo[5,1-c][1,2,4]triazin-
4-amine (4е). Yield 1.42 g (55%), light-orange powder, mp
312–314°С. IR spectrum, ν, cm–1: 630, 666, 682, 703, 731,
770, 845, 962, 1026, 1081, 1121, 1139, 1218, 1325, 1349,
1392, 1426, 1450, 1495, 1512, 1543, 1582, 1599, 1660,
7-Methyl[1,2,4]triazolo[5,1-c][1,2,4]triazine-3,4-diamine
hydrate (5a). Yield 0.36 g (64%), grayish silver powder,
mp >300°С. IR spectrum, ν, cm–1: 636, 732, 766, 1148, 1204,
1316, 1362, 1409, 1472, 1497, 1603, 1651, 1660, 3037,
3182, 3334. 1H NMR spectrum, δ, ppm: 2.37 (3H, s, CH3);
5.77 (2H, br. s, NH2); 8.75 (2H, br. s, NH2). Found, %:
C 32.48; H 4.86; N 53.30. C5H7N7·H2O. Calculated, %:
C 32.79; H 4.95; N 53.53.
1
2570, 2719, 2846, 3074, 3369. H NMR spectrum, δ, ppm
(J, Hz): 7.63 (1H, dd, J = 7.9, J = 4.8, H Py); 8.59 (1H, dt,
J = 7.9, J = 1.9, H Py); 8.76 (1Н, dt, J = 4.8, J = 1.5, H Py);
9.44 (1H, d, J = 1.7, H Py); 9.68 (1H, br. s) and 10.13 (1H,
br. s, NH2). Found, %: C 41.58; H 2.55; N 43.58.
C9H6N8O2. Calculated, %: C 41.87; H 2.34; N 43.40.
7-(Pyridin-3-yl)[1,2,4]triazolo[5,1-c][1,2,4]triazine-
3,4-diamine (5b). Yield 0.62 g (81%), brown powder, mp
>300°С. IR spectrum, ν, cm–1: 649, 697, 735, 752, 818,
830, 963, 1029, 1115, 1139, 1158, 1304, 1351, 1414, 1431,
1454, 1490, 1575, 1593, 1645, 1681, 2948, 3196, 3253,
4-Amino-7-(methylsulfanyl)-3-nitropyrazolo[5,1-c][1,2,4]-
triazine-8-carbonitrile hemihydrate (4f). Yield 1.13 g
(45%), orange powder, mp >315°С. IR spectrum, ν, cm–1:
609, 655, 673, 690, 718, 762, 813, 865, 1089, 1197, 1222,
1279, 1325, 1362, 1407, 1500, 1559, 1651, 2232, 3128,
3180, 3232, 3338. 1H NMR spectrum, δ, ppm: 2.61 (3H, s,
SCH3); 10.60 (2H, br. s, NH2). Found, %: C 32.10; H 2.35;
N 37.71; S 12.04. C7H5N7O2S·0.5H2O. Calculated, %:
C 32.31; H 2.32; N 37.68; S 12.32.
1
3299, 3389. H NMR spectrum, δ, ppm (J, Hz): 5.91 (2H,
br. s, NH2); 7.50 (1H, dd, J = 7.8, J = 4.8, H Py); 8.44 (2H,
d, J = 7.0, 2H Py); 8.65 (1H, dd, J = 4.8, J = 1.6, H Py); 9.29
(1H, br. s) and 12.50 (1H, br. s, NH2). Found, %: C 47.15;
H 3.52; N 48.92. C9H8N8. Calculated, %: C 47.37; H 3.53;
N 49.10.
Ethyl 4-amino-7-(methylsulfanyl)-3-nitropyrazolo[5,1-c]-
[1,2,4]triazine-8-carboxylate (4g). Yield 1.25 g (42%),
light-brown powder, mp 302–304°С. IR spectrum, ν, cm–1:
783, 828, 1017, 1056, 1158, 1209, 1296, 1323, 1343, 1406,
1484, 1552, 1640, 1696, 1711, 3001, 3191, 3240, 3345.
1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.1,
ОCH2CH3); 2.68 (3H, s, SCH3); 4.39 (2H, q, J = 7.1,
ОCH2CH3); 9.51 (1H, br. s) and 9.65 (1H, br. s, NH2).
Found, %: C 36.41; H 3.17; N 28.11; S 10.52. C9H10N6O4S.
Calculated, %: C 36.24; H 3.38; N 28.17; S 10.75.
3-Nitro-7-phenyl[1,2,4]triazolo[5,1-c][1,2,4]triazin-4-amine
(4h). Yield 1.62 g (63%), brown powder, mp >315°С. IR
spectrum, ν, cm–1: 565, 624, 666, 692, 718, 747, 767, 845,
1025, 1065, 1124, 1178, 1214, 1247, 1278, 1327, 1347,
1398, 1441, 1504, 1519, 1537, 1646, 3122, 3170, 3369.
1H NMR spectrum, δ, ppm (J, Hz): 7.50–7.66 (3H, m,
Н Ph); 8.31 (2H, dd, J = 3.4, H Ph); 9.58 (1Н, br. s) and
10.04 (1H, br. s, NH2). Found, %: C 46.82; H 3.02; N 38.38.
C10H7N7O2. Calculated, %: C 46.70; H 2.74; N 38.12.
Ethyl 4-amino-3-nitropyrazolo[5,1-c][1,2,4]triazine-
8-carboxylate (4i). Yield 1.21 g (48%), pale-yellow
precipitate, mp 309–310°С. IR spectrum, ν, cm–1: 557, 630,
665, 688, 747, 781, 826, 860, 1035, 1093, 1138, 1183,
1210, 1252, 1286, 1304, 1330, 1344, 1368, 1393, 1424,
1452, 1503, 1566, 1644, 1707, 2984, 3058, 3400. 1H NMR
spectrum, δ, ppm (J, Hz): 1.41 (3H, t, J = 7.1, ОCH2CH3);
4.39 (2H, q, J = 7.1, ОCH2CH3); 8.69 (1H, s, H-7); 9.79
(2H, br. s, NH2). Found, %: C 38.29; H 3.56; N 33.28.
C8H8N6O4. Calculated, %: C 38.10; H 3.20; N 33.32.
2-Methyl-8H-imidazo[4,5-e][1,2,4]triazolo[5,1-c][1,2,4]-
triazine dihydrate (6). A mixture of compound 5a (50 mg,
0.3 mmol) and HC(OEt)3 (3 ml) was heated under reflux
for 3 h, and the solvent left to evaporate. The residue was
triturated with methyl tert-butyl ether, filtered, and dried.
Yield 25 mg (47%), brown powder, mp 259°С.
IR spectrum, ν, cm–1: 762, 838, 994, 1047, 1156, 1303,
1358, 1426, 1531, 1557, 1613, 1646, 1703, 2919, 3156,
3209, 3310, 3429. 1H NMR spectrum, δ, ppm: 2.69 (3H, s,
CH3); 8.95 (1H, s, H-7). Found, %: C 34.10; H 4.30;
N 46.81. C6H5N7·2H2O. Calculated, %: C 34.13; H 4.30;
N 46.43.
This work was carried out with funding from the Russian
Science Foundation (Grant 14-13-01301).
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