New heterocycles with a 3-aminofurazanyl substituent

Article abstract of DOI:10.1023/A:1021668216426

New 3-aminofurazans containing 1,2,4- and 1,3,4-oxadiazole, pyridine, and 1,2,4-triazole substituents in the 4-position were synthesized.

Full text of DOI:10.1023/A:1021668216426

Russian Journal of Organic Chemistry, Vol. 38, No. 9, 2002, pp. 1351 1355. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 9, 2002,
pp. 1405 1408.
Original Russian Text Copyright
2002 by Shaposhnikov, Korobov, Sergievskii, Pirogov, Mel’nikova, Tselinskii.
Dedicated to Full Member of the Russian Academy of Sciences
V.A. Tartakovskii on the 70th Anniversary of His Birth
New Heterocycles with a 3-Aminofurazanyl Substituent
S. D. Shaposhnikov, N. V. Korobov, A. V. Sergievskii, S. V. Pirogov,
S. F. Mel’nikova, and I. V. Tselinskii
St. Petersburg State Institute of Technology, Moskovskii pr. 26, St. Petersburg, 198013 Russia
e-mail: sfm@tu.spb.ru
Received December 26, 2001
Abstract New 3-aminofurazans containing 1,2,4- and 1,3,4-oxadiazole, pyridine, and 1,2,4-triazole substit-
uents in the 4-position were synthesized.
Polyheterocyclic compounds having an oxadiazole
fragment are potential biologically active compounds.
Among isomeric oxadiazoles, 1,2,3- and 1,2,4-oxadi-
azoles were studied in sufficient detail. Interest in
pounds. Scheme 1 shows the structures of presently
known aminopolyazoles I which contain an amino-
furazanyl moiety [2 10].
As initial compounds we selected 3-aminofurazan-
1,2,5-oxadiazole derivatives as biologically active
4
-carboxamide oxime (VII), 3-aminofurazan-4-carbo-
substances has arisen relatively recently, and some
representatives of this series have been found, which
exhibit a wide spectrum of biological properties: anti-
microbial, antituberculous, spasmolytic, and muscle
relaxant activity, etc. [1].
From the viewpoint of synthesis of new biologic-
ally active compounds in the series of heteryl-sub-
stituted 1,2,5-oxadiazoles, the corresponding amino
derivatives attract specific attention as starting com-
hydrazide (VIII), and 3-aminofurazan-4-carboxamide
hydrazone (IX), which were synthesized previously
[11]. The 1,2,4-oxadiazole fragment in position 4 of
the furazan ring in compound VII was built up via
reaction with nitriles and carboxamides (Scheme 2).
Products X XIII were obtained by fusion of amide
oxime VII with carboxamides and nitriles at elevated
temperature. Compound XIV was synthesized by
reaction with cyanogen bromide in aqueous alcohol
Scheme 1.
R =
[2, 3],
,
[4],
[4],
[5],
[
6],
[8],
[9],
[10].
_
___________
*
This study was financially supported by the Ministry of
Education of the Russian Federation (project no. 2000 T00-
9
.3-2076).
1
070-4280/02/3809-1351$27.00 2002 MAIK Nauka/Interperiodica

1
352
SHAPOSHNIKOV et al.
Scheme 2.
XIII, R‘ = 2-pyridyl; X, R = CH , XI, R = 4-pyridyl; XII, R = 4-aminofurazan-3-yl.
3
Scheme 3.
The reaction of amide oxime VII with methyl
-aminofurazan-4-carboxylate or methyl 3-amino-
ring almost does not depend on the substituent in
position 4; the corresponding signal appears at 6.4
6.7 ppm, i.e., in the region typical of aminofurazans.
3
furazan-4-carboximidate afforded product XII. It
should be noted that fusion of 3-aminofurazan-4-car-
boxamide oxime VII with carboxamides and nitriles
occurs in a fairly narrow temperature range. The
yields of compounds X XII do not exceed 50%
because of thermal decomposition of the reactants.
The NH signals in the spectra of isomeric 1,2,4- and
2
1,3,4-oxadiazoles XIV and XV and 1,2,4-triazole
XVI are located in a weaker field: 8.35, 7.75, and
12.70 ppm, respectively. These data suggest higher
reactivity of the amino group attached to furazan ring.
In fact, treatment of 3-amino-4-(5-amino-1,2,4-oxadi-
azol-3-yl)-1,2,5-oxadiazole (XIV) with potassium
permanganate in acid medium gave azo derivative
XVII as a result of oxidative dimerization at the
furazan amino groups. The amino group in the furazan
ring of XIV is selectively diazotized, and subsequent
reaction of the diazo compound with sodium azide
yields azidofurazan derivative XVIII (Scheme 4).
Likewise, 3-amino-4-(5-methyl-1,2,4-oxadiazol-3-yl)-
The reactions of 3-aminofurazan-4-carbohydrazide
VIII) and amidrazone IX with cyanogen bromide
(
resulted in formation of bicyclic 3-amino-4-(amino-
azolyl)furazan derivatives, 2-amino-5-(3-amino-1,2,5-
oxadiazol-4-yl)-1,3,4-oxadiazole (XV) and 3-amino-
4
-(5-amino-1H-1,2,4-triazol-3-yl)-1,2,5-oxadiazole
(XVI) (Scheme 3).
1
In the H NMR spectra of the products, the chem-
ical shift of protons of the amino group in the furazan
Scheme 4.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

NEW HETEROCYCLES WITH A 3-AMINOFURAZANYL SUBSTITUENT
1353
Scheme 5.
1
,2,5-oxadiazole (X) is readily oxidized at the amino
3-aminofurazan-4-carboxamide was heated for 1 h
at 170 C and was then poured into 100 ml of water.
The resulting suspension was heated under stirring
to the boiling point, filtered while hot, and cooled.
The precipitate was filtered off and dried at 50 C.
group with trifluoroperoxyacetic acid to give 60% of
the corresponding nitro derivative XIX (Scheme 5).
EXPERIMENTAL
1
Yield 37%, mp 238 C. IR spectrum, , cm : 3468,
The IR spectra were recorded on a Perkin Elmer
Spectrum 1000 instrument from samples prepared as
thin films on a KBr support. The H and C NMR
spectra were obtained on a Bruker AC-200 spectrom-
eter in DMSO using the solvent signals as reference.
The mass spectra (70 eV) were run on a Varian CH-6
mass spectrometer.
3
1
359, 1633, 1556, 1499, 1420, 1390, 1157, 1101,
1
026, 976. H NMR spectrum (DMSO-d ), , ppm:
6
1
13
13
6.70 (2H, NH ), 6.86 s (2H, NH ). C NMR spec-
2
2
trum (DMSO-d6), C, ppm: 166.64, 159.60, 155.76,
155.59, 136.30, 135.06. Found, %: C 30.15; H 2.43;
N 47.81. C H N O . Calculated, %: C 30.52; H 1.71;
6
4
8
3
N 47.45.
The initial compounds, 4-aminofurazan-3-carbox-
amide oxime (VII) [11], 4-aminofurazan-3-carbo-
hydrazide (VIII) [6], methyl 4-aminofurazan-3-car-
boximidate [6], 4-aminofurazan-3-carboxamide hydra-
zone (IX) [7], and methyl 4-aminofurazan-3-car-
boxylate [11] were synthesized by known methods.
b. A mixture of 0.5 g (3.5 mmol) of methyl
3-aminofurazan-4-carboximidate and 0.5 g (3.5 mmol)
of amide oxime VII was heated for 1 2 min at 220
230 C. It was then cooled, and 25 ml of water was
added. The suspension was heated to the boiling
point, kept boiling for 5 min, and filtered while hot.
The precipitate was dissolved in 3 ml of DMF, the
solution was poured into 30 ml of water, and the
product was filtered off and dried in air. Yield
0.16 g (19%).
c. A solution of 0.4 g (7.14 mmol) of potassium
hydroxide in a minimal volume of water was poured
into 40 ml of 1-butanol. The mixture was heated to
the boiling point and was kept boiling until the
temperature reached 115 118 C. A solution of
1 g (6.9 mmol) of amide oxime VII and 2.0 g
3
-Amino-4-(5-methyl-1,2,4-oxadiazol-3-yl)fura-
zan (X). A mixture of 2 g (14 mmol) of amide oxime
VII and 1.66 g (28.14 mmol) of acetamide was heated
for 7 h at 180 C and was then poured into 100 ml
of water. The resulting suspension was heated to the
boiling point, filtered while hot, and cooled. The
precipitate was filtered off and dried at 50 C. Yield
1
1
2
.27 g (54%), mp 160 C. H NMR spectrum, , ppm:
.73 s (3H, CH ), 6.40 s (2H, NH ). Found, %:
3
2
C 36.00; H 2.54; N 50.02. C H N O . Calculated, %:
5
5
5
2
C 35.93; H 3.02; N 41.90.
-Amino-4-[5-(3-pyridyl)-1,2,4-oxadiazol-3-yl]-
,2,5-oxadiazole (XI). A mixture of 2 g (14 mmol)
(0.14 mmol) of methyl 3-aminofurazan-4-carboxylate
3
in 20 ml of butanol was added, and a solid began to
separate from the solution almost immediately. The
mixture was boiled for 6 h and cooled, and the precip-
itate was filtered off, washed with a small amount
of butanol and 25 ml of hot water, and dried at 60 C.
Yield 1.0 g (60%).
1
of amide oxime VII and 3.42 (28 mmol) of nicotin-
amide was heated for 8 h at 160 165 C. It was then
cooled, and the solid material thus obtained was
washed with 20 ml of ether, dried in air, washed with
2
5 ml of hot water, and again dried in air. Yield 1 g
3
-Amino-4-[5-(4-pyridyl)-1,2,4-oxadiazol-3-yl]-
1
(
31%), mp 195 C (decomp.). H NMR spectrum, ,
ppm: 9.44 s (1H, pyridine), 8.931 (1H, pyridine),
.65 d (1H, pyridine), 7.73 t (1H, pyridine), 6.64 s
2H, NH ). Found, %: C 47.22; H 3.08; N 36.33.
1
2
(
,2,5-oxadiazole (XIII) was synthesized by fusion of
g (13.9 mmol) of amide oxime VII with 2.9 g
28 mmol) of 4-cyanopyridine at 130 C. Yield 32%,
mp 210 212 C (decomp.). H NMR spectrum,
ppm: 8.90 s (1H, pyridine), 8.45 d (1H, pyridine),
8
(
1
2
,
C H N O . Calculated, %: C 46.96; H 2.63; N 36.51.
9
6
6
2
3
-Amino-4-[5-(4-amino-1,2,5-oxadiazol-3-yl)-
,2,4-oxadiazol-3-yl]-1,2,5-oxadiazole (XII).
a. An equimolar mixture of amide oxime VII and
8.15 t (1H, pyridine), 7.75 t (2H, NH ). Found, %:
2
1
C 47.21; H 3.07; N 36.95. C H N O . Calculated, %:
9
6
6
2
C 46.96; H 2.63; N 36.51.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

1
354
SHAPOSHNIKOV et al.
3
-Amino-4-(5-amino-1,2,4-oxadiazol-3-yl)fura-
itate was filtered off and dispersed in 50 ml of aceto-
nitrile, and the suspension was heated to the boiling
point and filtered. The product was dried in air. Yield
zan (XIV). A solution of 8 g (80 mmol) of KHCO3
in 30 ml of water was added to a suspension of 10 g
70 mmol) of amide oxime VII in 50 ml of alcohol,
and 7.42 g (70 mmol) of cyanogen bromide was then
added in portions. The mixture was stirred for 24 h
at 15 20 C, and the precipitate was filtered off,
washed with water, and dried. Yield 10.5 g (89%),
1
(
2.5 g (63%), mp >250 C. H NMR spectrum, , ppm:
13
8
1
.37 s (NH2). C NMR spectrum, C, ppm: 173.66,
63.11, 158.33, 142.52. Found, %: C 28.89; H 1.27;
N 50.39. C H N O . Calculated, %: C 28.93; H 1.21;
8
4
12
4
N 50.60.
1
mp >275 C (decomp.; from water). H NMR spec-
5
-Amino-3-(4-azido-1,2,5-oxadiazol-3-yl)-1,2,4-
trum (DMSO-d ), , ppm: 8.35 s (2H, NH ), 6.34 s
6
2
oxadiazole (XVIII). Diamine XIV, 1 g (5.95 mmol),
was added at 0 5 C to a solution of 0.41 g
(
1
2H, NH2). 13C NMR spectrum (DMSO-d6), C, ppm:
73.2, 160.0, 156.19, 138.4. Found, %: C 28.51;
H 2.48; N 50.08. C H N O . Calculated, %: C 28.58;
(
6.00 mmol) of sodium nitrite in 50 ml of sulfuric
4
4
6
2
acid. The mixture was stirred for 15 min, and 30 ml
of acetic acid was added, maintaining the temperature
at 0 5 C. The mixture was stirred for 30 min, a solu-
tion of 0.78 g (12.0 mmol) of sodium azide in 40 ml
of acetic acid was added, and the mixture was stirred
for 15 min, poured into 100 ml of water, and extracted
with diethyl ether (3 50 ml). The extracts were
washed with water until neutral reaction, dried, and
evaporated under reduced pressure. Yield 0.7 g (61%),
H 2.40; N 5.00.
3
-Amino-4-(5-amino-1,3,4-oxadiazol-2-yl)fura-
zan (XV). A solution of 8 g (80 mmol) of potassium
hydrogen carbonate in 30 ml of water was added to
a suspension of 10 g (70 mmol) of hydrazide VIII in
50 ml of alcohol, and 7.42 g (70 mmol) of cyanogen
bromide was added in portions. The mixture was
stirred for 24 h at 15 20 C, and the precipitate was
filtered off, washed with water, and dried. Yield 9.9 g
mp 174 175 C (decomp.; from CHCl ). IR spectrum,
1
3
(84%), mp 225 C (decomp.; from water). H NMR
1
,
cm : 3401, 3332, 3149, 2159, 2135, 1686, 1673,
spectrum (DMSO-d ), , ppm: 7.78 s (2H, NH2);
1
6
1
1587, 1523, 1493, 1418, 1351, 1206, 972. H NMR
spectrum, , ppm: 8.3 s (NH2). 13C NMR spectrum,
C, ppm: 173.43, 158.45, 153.32, 140.96. Found, %:
C 24.81; H 1.12; N 57.67. C H N O . Calculated, %:
3
6
.49 s (2H, NH2).
C NMR spectrum (DMSO-d6),
C, ppm: 165.38, 155.56, 143.12, 135.57. Found, %:
C 28.53; H 2.44; N 50.03. C H N O . Calculated, %:
4
4
6
2
4
2
8
2
C 28.58; H 2.40; N 50.00.
-Amino-4-(5-amino-1,2,4-triazol-3-yl)furazan
XVI). A suspension of 1 g (7 mmol) of amidrazone
IX in 20 ml of water was heated until it became
homogeneous, 0.75 g (7 mmol) of cyanogen bromide
was added in portions, and 0.7 g (7 mmol) of potas-
sium hydrogen carbonate was then added. The mixture
was stirred for 24 h at 15 20 C, and the precipitate
C 24.75; H 1.04; N 57.73.
3
4-(5-Methyl-1,2,4-oxadiazol-3-yl)-3-nitro-1,2,5-
oxadiazole (XIX). Trifluoroacetic anhydride, 90 ml,
was slowly added (dropwise) at 50 C to 34 g (1 mol)
of 30% hydrogen peroxide, and a solution of 5 g
(0.03 mol) of oxadiazole X in 60 ml of acetonitrile
was then added. The mixture was kept for 1 h at 50 C
and cooled, and volatile components were evaporated
in the cold. Compound XIX was isolated as a light
brown oily substance. Yield 4 g (60%). H NMR
spectrum, , ppm: 2.81 s (CH3). C NMR spectrum,
C, ppm: 180.04, 160.53, 157.51, 141.62, 12.85.
Found, %: C 30.92; H 1.21; N 35.82. C H N O .
Calculated, %:C 30.47; H 1.53; N 35.53.
(
was filtered off, washed with water, and dried. Yield
1
1
0
.5 g (43%), mp 270 C (decomp.; from water). H
NMR spectrum (DMSO-d6), , ppm: 12.70 s (1H,
13
1
3
NH), 6.38 s (2H, NH ), 6.44 s (2H, NH ). C NMR
2
2
spectrum (DMSO-d6),
C, ppm: 158.40, 156.04,
5
3
5
4
1
50.07, 140.60. Found, %: C 28.78; H 3.11; N 58.56.
C H N O. Calculated, %: C 28.75; H 3.02; N 58.67.
4
5
7
3
,3 -Azobis[4-(5-amino-1,2,4-oxadiazol-3-yl)-
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dispersed in a mixture of 80 ml of acetonitrile and
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002

NEW HETEROCYCLES WITH A 3-AMINOFURAZANYL SUBSTITUENT
1355
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 9 2002