Synthesis and reactivity of ethyl 7-amino-3-tert-butyl-4-thioxo- 4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate

Article abstract of DOI:10.1134/S1070428012090138

Treatment of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1, 2,4]triazine-8-carboxylate with P₂S₅ in pyridine gave ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine- 8-carboxylate which was

Full text of DOI:10.1134/S1070428012090138

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2012, Vol. 48, No. 9, pp. 1226–1228. © Pleiades Publishing, Ltd., 2012.
Original Russian Text © L.M. Mironovich, M.V. Kostina, A.V. Bozhok, 2012, published in Zhurnal Organicheskoi Khimii, 2012, Vol. 48, No. 9,
pp. 1227–1229.
Synthesis and Reactivity of Ethyl 7-Amino-3-tert-butyl-4-thioxo-
4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carboxylate
L. M. Mironovich, M. V. Kostina, and A. V. Bozhok
Southwest State University, ul. 50 let Oktyabrya 94, Kursk, 305040 Russia
e-mail: myronovych@ua.fm
Received February 16, 2012
Abstract—Treatment of ethyl 7-amino-3-tert-butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbox-
ylate with P2S5 in pyridine gave ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-
8-carboxylate which was subjected to acylation, decarboxylation, and hydrazinolysis.
DOI: 10.1134/S1070428012090138
Bicyclic systems based on 1,2,4-triazines attract
interest from the synthetic viewpoint. In particular,
pyrazolo[1,2,4]triazine derivatives exhibit various
kinds of pharmacological activity, e.g., antiviral [1, 2].
We previously [3] synthesized ethyl 7-amino-3-tert-
butyl-4-oxo-4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-
8-carboxylate (I) by reaction of 4-amino-6-tert-butyl-
3-methylsulfonyl-4H-1,2,4-triazin-5-one with ethyl
cyanoacetate in pyridine. The goal of the present work
was to synthesize ethyl 7-amino-3-tert-butyl-4-thioxo-
4,6-dihydropyrazolo[5,1-c][1,2,4]triazine-8-carbox-
ylate (II) and examine its reactivity.
4-oxo group by thioxo with formation of ethyl
7-amino-3-tert-butyl-4-thioxo-4,6-dihydropyrazolo-
[5,1-c][1,2,4]triazine-8-carboxylate (II). The presence
of a thioxo group in the bicyclic system did not affect
its reactivity. Compound II reacted with excess 100%
hydrazine in methanol on heating to afford 7-amino-3-
tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]-
triazine-8-carbohydrazide (III) (Scheme 1). 7-Amino-
3-tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c]-
[1,2,4]triazine-8-carboxylic acid (IV) was synthesized
by heating ester II in boiling propan-1-ol in the pres-
ence of potassium hydroxide. Decarboxylation of IV
on heating in DMF afforded 7-amino-3-tert-butyl-6H-
pyrazolo[5,1-c][1,2,4]triazine-4-thione (VI).
Heating of compound I in pyridine with excess
phosphorus pentasulfide resulted in replacement of the
Scheme 1.
O
N
S
S
N
H
H
H
t-Bu
t-Bu
t-Bu
N
N
N
P2S5
N2H4
N
N
N
NH2
NH2
NH2
N
N
N
N
COOEt
COOEt
C(O)NHNH2
I
II
III
PhC(O)Cl, H+
KOH
S
N
S
N
S
H
H
N
H
t-Bu
t-Bu
t-Bu
N
N
Δ
N
N
N
NHR
NH2
NHC(O)R
R = H
N
N
N
N
COOH
C(O)NHNH2
VII, VIII
V, VI
IV
V, R = PhC(O); VI, R = H; VII, R = Me; VIII, R = Ph.
1226

SYNTHESIS AND REACTIVITY OF ETHYL 7-AMINO-3-tert-BUTYL-4-THIOXO-...
1227
By acylation of II with benzoyl chloride in ethyl
acetate in the presence of a catalytic amount of hydro-
chloric acid we obtained N-(3-tert-butyl-4-thioxo-4,6-
dihydropyrazolo[5,1-c][1,2,4]triazin-7-yl)benzamide
(V). The reaction was accompanied by hydrolysis of
the ester group and subsequent decarboxylation. Acyla-
tion of IV with acetic anhydride under solvent-free
conditions led to the formation of 7-acetylamino-3-
tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]-
triazine-8-carboxylic acid (VII), while the reaction of
IV with benzoyl chloride produced 7-benzoylamino-3-
tert-butyl-4-thioxo-4,6-dihydropyrazolo[5,1-c][1,2,4]-
triazine-8-carboxylic acid (VIII) (Scheme 1).
diluted with distilled water (1:1), the solvent was re-
moved, the residue was dissolved in DMF, the solution
was diluted with distilled water (1:1), and the precip-
itate was filtered off, dried in air, and recrystallized
from dioxane. Yield 0.257 g (87%), yellow crystals,
mp 145–150°C (with tarring). IR spectrum, ν, cm–1:
3433 (NH2), 2956, 2927, 1665 (C=O), 1630, 1606,
1540, 1480, 1457, 1389, 1362, 1230 (C=S), 1144,
1
1008, 973, 941, 831, 745, 661. H NMR spectrum, δ,
ppm: 1.27 t (3H, CH2CH3, J = 7.2 Hz), 1.35 s (9H,
t-Bu), 4.27 q (2H, CH2CH3, J = 7.0 Hz), 6.25 s (2H,
NH2), 13.20 s (1H, NH). Mass spectrum, m/z (Irel, %):
295 (100) [M]+, 293 (12), 256 (17), 234 (10), 213 (61),
211 (12), 160 (15), 128 (24), 109 (16), 97 (23), 96
(40), 76 (45), 73 (20), 72 (24), 69 (15), 62 (26), 59
(15), 44 (18), 41 (28). Found, %: C 48.82; H 5.79;
N 23.73. C12H17N5O2S. Calculated, %: C 48.80;
H 5.80; N 23.71.
The structure of compounds II–VIII was deter-
mined on the basis of their elemental compositions and
1
IR, H NMR, and mass spectra. Unlike initial com-
pound I, the IR spectra of II–VIII contained an ab-
sorption band at 1215–1238 cm–1 due to stretching
vibrations of the thioxo group. Carbonyl absorption in
the region 1660–1689 cm–1 was conserved in the IR
spectra of II–IV, VII, VIII, while compounds V, VI,
and VIII displayed a new carbonyl absorption band at
1697–1717 cm–1 (C=O) due to acyl group on the nitro-
7-Amino-3-tert-butyl-4-thioxo-4,6-dihydropyr-
azolo[5,1-c][1,2,4]triazine-8-carbohydrazide (III).
A mixture of 0.279 g (1 mmol) of compound II and
0.096 g (3 mmol) of 100% hydrazine in methanol was
heated for 10 h under reflux. The mixture was filtered
while hot, the filtrate was evaporated to dryness, the
residue was dissolved in DMF, the solution was diluted
with distilled water (1:2), and the precipitate was
filtered off, dried in air, and purified by reprecipitation
from dioxane with water (1:1). Yield 0.230 g (82%),
yellow crystals, mp 188–193°C (decomp.). IR spec-
trum, ν, cm–1: 3435, 2921, 1660 (C=O), 1630, 1540,
1490, 1458, 1390, 1352, 1215 (C=S), 1144, 1100, 960,
1
gen. The H NMR spectra of II–VIII also confirmed
the assumed structure. All compounds were character-
ized by a singlet at δ 1.19–1.38 ppm from protons in
the tert-butyl group, and the 8-H proton resonated in
the spectrum of VI at δ 8.2 ppm.
The obtained compounds showed selective anti-
microbial activity against Gram-positive bacteria
(Staphylococcus aureus, Micrococcus luteus).
1
740, 666. H NMR spectrum, δ, ppm: 1.36 s (9H,
t-Bu), 5.57 s (2H, NHNH2), 6.60 s (2H, NH2), 8.79 s
(1H, NHNH2), 12.86 s (1H, NH). Found, %: C 42.71;
H 5.40; N 34.89. C10H15N7OS. Calculated, %: C 42.69;
H 5.37; N 34.85.
EXPERIMENTAL
The IR spectra were recorded in KBr on a UR-10
1
spectrometer. The H NMR spectra were measured on
a Varian Mercury VX-200 instrument at 200 MHz
from solutions in DMSO-d6 using hexamethyldisil-
oxane as internal reference. The mass spectra were run
on an MS-1302 mass spectrometer. The purity of the
products was checked by TLC on Silufol UV-254
plates using chloroform–methanol (9 :1) as eluent.
Compound I was synthesized according to the proce-
dure reported in [3]; mp 242–244°C (decomp.).
7-Amino-3-tert-butyl-4-thioxo-4,6-dihydropyr-
azolo[5,1-c][1,2,4]triazine-8-carboxylic acid (IV).
A mixture of 0.279 g (1 mmol) of ester II and 0.112 g
(2 mmol) of potassium hydroxide in 10 ml of propan-
2-ol was heated for 6 h under reflux. The mixture was
evaporated to dryness, the residue was dissolved in
15 ml of distilled water, the solution was filtered, the
filtrate was acidified with 5% aqueous HCl to pH 5–6,
and the precipitate was filtered off and recrystallized
from methanol. Yield 0.229 g (86%), brown crystals,
mp >300°C (decomp.). IR spectrum, ν, cm–1: 3419,
2965, 2927, 1680 (C=O), 1622, 1538, 1479, 1460,
Ethyl 7-amino-3-tert-butyl-4-thioxo-4,6-dihydro-
pyrazolo[5,1-c][1,2,4]triazine-8-carboxylate (II).
A mixture of 0.279 g (1 mmol) of ethyl 7-amino-3-tert-
butyl-4-oxo-4,6-dihydropyrazolo[5,1-c]triazine-8-car-
boxylic acid (I) and 0.695 g (3.5 mmol) of phosphorus
pentasulfide in 10 ml of pyridine was heated for 3.5 h
under reflux. The mixture was filtered while hot and
1
1393, 1363, 1220 (C=S), 1129, 1034, 745. H NMR
spectrum, δ, ppm: 1.27 s (9H, t-Bu), 6.15 s (2H, NH2),
12.80 s (1H, COOH), 13.25 br.s (1H, NH). Found, %:
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012

MIRONOVICH et al.
1228
C 44.95; H 4.92; N 26.17. C10H13N5O2S. Calculated,
%: C 44.93; H 4.90; N 26.20.
reflux. The mixture was cooled, the solvent was
removed, the residue was dissolved in methanol, the
solution was diluted with distilled water (1:1), and the
precipitate was filtered off and dried in air. The
product was chromatographically pure. Yield 0.181 g
(59%), yellow crystals, mp 120–125°C (decomp.). IR
spectrum, ν, cm–1: 3448, 3199, 3094, 2960, 2930,
2880, 1717 (C=O), 1689 (C=O), 1598, 1549, 1483,
1451, 1393, 1367, 1273, 1243, 1226 (C=S), 1151,
N-(3-tert-Butyl-4-thioxo-4,6-dihydropyrazolo-
[5,1-c][1,2,4]triazin-7-yl)benzamide (V). A mixture
of 0.279 g (1 mmol) of compound II, 0.562 g
(4 mmol) of benzoyl chloride, and 2–3 drops of hydro-
chloric acid in 10 ml of ethyl acetate was heated for
18 h under reflux. The mixture was cooled, the solvent
was removed, the residue was dissolved in DMF, the
solution was diluted with distilled water (1:1), and the
precipitate was filtered off and dried in air. The
product was chromatographically pure. Yield 0.268 g
(82%), brown crystals, mp 207–210°C (decomp.). IR
spectrum, ν, cm–1: 3457, 3170, 3088, 2958, 2934,
2887, 1697 (C=O), 1583, 1547, 1484, 1476, 1393,
1386, 1297, 1279, 1238 (C=S), 1224, 1195, 1152,
1095, 1026, 937, 887, 853, 788, 776, 734, 714, 688,
661, 537, 485. 1H NMR spectrum, δ, ppm: 1.38 s (9H,
t-Bu), 7.44–7.67 m (3H, m-H, p-H), 7.93 d.d (2H, o-H,
J = 8.2 Hz), 8.20 s (1H, CH), 13.77 s (1H, NH). Mass
spectrum, m/z (Irel, %): 324 (3) [M]+, 203 (11), 202
(14), 201 (98), 200 (23), 168 (14), 142 (13), 141 (9),
110 (5), 109 (12), 105 (100), 85 (56), 84 (9), 83 (83),
82 (26), 77 (31), 60 (7), 57 (20), 56 (12), 55 (15), 51
(7), 41 (13). Found, %: C 58.72; H 5.21; N 21.40.
C16H17N5OS. Calculated, %: C 58.70; H 5.23; N 21.39.
1
1039, 897, 778, 661, 592, 545, 471. H NMR spec-
trum, δ, ppm: 1.20 s (3H, CH3), 1.40 s (9H, t-Bu),
13.0 s (1H, NH), 13.32 s (1H, OH). Mass spectrum,
m/z (Irel, %): 307 (4) [M]+, 294 (2), 291 (2), 258 (16),
256 (41), 249 (12), 225 (10), 224 (100), 201 (28), 200
(12), 192 (29), 186 (14), 185 (83), 184 (18), 183 (12),
170 (36), 162 (13), 160 (70), 130 (19), 128 (67), 127
(23), 126 (18), 115 (7), 98 (10), 97 (13), 96 (46), 83
(17), 69 (10), 68 (13), 66 (11), 64 (100), 60 (25), 59
(16), 57 (20), 43 (44), 41 (14). Found, %: C 46.58;
H 4.90; N 22.62. C12H15N5O3S. Calculated, %:
C 46.59; H 4.89; N 22.64.
7-Benzoylamino-3-tert-butyl-4-thioxo-4,6-dihy-
dropyrazolo[5,1-c][1,2,4]triazine-8-carboxylic acid
(VIII). A mixture of 0.267 g (1 mmol) of compound
IV, 0.422 g (3 mmol) of benzoyl chloride, and one
drop of hydrochloric acid in 10 ml of ethyl acetate was
heated for 6 h under reflux. The mixture was cooled,
the solvent was removed, the residue was dissolved in
propan-2-ol, the solution was diluted with distilled
water (1:5), and the precipitate was filtered off and
dried in air. The product was chromatographically
pure. Yield 0.241 g (65%), mp 265–267°C (decomp.).
IR spectrum, ν, cm–1: 3437, 3269, 3080, 2968, 2932,
2892, 1700 (C=O), 1665 (C=O), 1630, 1595, 1547,
1481, 1393, 1363, 1276, 1226 (C=S), 1140, 1107, 959,
7-Amino-3-tert-butyl-6H-pyrazolo[5,1-c][1,2,4]-
triazine-4-thione (VI). A mixture of 0.267 g (1 mmol)
of acid IV and 10 ml of DMF was heated for 6 h under
reflux. The solvent was removed, the precipitate was
dissolved in methanol, the solution was diluted with
distilled water (1:1), and the precipitate was filtered
off, dried in air, and purified by reprecipitation from
propan-2-ol with water (1:1). Yield 0.163 g (73%),
brown crystals, mp 139–143°C (with tarring). IR spec-
trum, ν, cm–1: 3447 (NH2), 2969, 2932, 2891, 2806,
1635, 1543, 1533, 1480, 1475, 1393, 1365, 1334,
1273, 1235 (C=S), 1206, 1196, 1144, 1127, 1072,
1049, 1040, 1007, 958, 937, 897, 778, 743, 666, 620.
1H NMR spectrum, δ, ppm: 1.38 s (9H, t-Bu), 5.62 s
(2H, NH2), 8.41 s (1H, CH), 13.77 s (1H, NH). Mass
spectrum, m/z (Irel, %): 223 (3) [M]+, 202 (13), 201
(100), 200 (32), 170 (17), 168 (20), 141 (9), 128 (11),
109 (17), 100 (9), 99 (14), 83 (25), 82 (11), 72 (10), 69
(15), 68 (17), 67 (9), 45 (14), 44 (16), 41 (25). Found,
%: C 48.43; H 5.89; N 31.39. C9H13N5S. Calculated,
%: C 48.41; H 5.87; N 31.36.
1
765, 713, 553, 520. H NMR spectrum, δ, ppm: 1.29 s
(9H, t-Bu), 7.24 t (2H, m-H, p-H, J = 6.9 Hz), 7.43 d
(3H, o-H, J = 7.4 Hz), 7.93 s (1H, NH), 10.61 s (1H,
NH), 13.45 s (1H, OH). Found, %: C 54.96; H 4.63;
N 18.87. C17H17N5O3S. Calculated, %: C 54.97;
H 4.61; N 18.86.
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1. Mironovich, L.M. and Promonenkov, V.K., Itogi Nauki
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Ibrahem, Y.M., Phosphorus, Sulfur Silicon Relat. Elem.,
2006, vol. 181, p. 1087.
7-Acetylamino-3-tert-butyl-4-thioxo-4,6-dihydro-
pyrazolo[5,1-c][1,2,4]triazine-8-carboxylic acid
(VII). A mixture of 0.267 g (1 mmol) of compound IV
and 5 ml of acetic anhydride was heated for 6 h under
3. Mironovich, L.M. and Kostina, M.V., Russ. J. Org.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 9 2012