3-Amino-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]furazan –a multifunctional synthon for the synthesis of 1,2,5-oxadiazole derivatives

Article abstract of DOI:10.1007/s10593-019-02607-1

[Figure not available: see fulltext.] The chemical properties of 3-amino-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]furazan were scrutinized: acylation of the amino group and its oxidation to azo and nitro groups, reactions of the chloromethyl group with N-

Full text of DOI:10.1007/s10593-019-02607-1

DOI 10.1007/s10593-019-02607-1
Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
3-Amino-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]furazan –
a multifunctional synthon for the synthesis
of 1,2,5-oxadiazole derivatives
Andrei I. Stepanov1*, Dmitry V. Dashko1, Elena V. Stepanova2
1 Special Design and Technology Bureau ''Technolog'',
33a Sovetsky Ave., Saint Petersburg 192076, Russia;
е-mail: stepanoffai@yandex.ru, ddv65@bk.ru
2 North-Western State Medical University named after I. I. Mechnikov,
41 Kirochnaya St., Saint Petersburg 191015, Russia; е-mail: stepanoffev@yandex.ru
Submitted January 19, 2019
Accepted after revision October 21, 2019
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(12), 1233–1244
The chemical properties of 3-amino-4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]furazan were scrutinized: acylation of the amino group and
its oxidation to azo and nitro groups, reactions of the chloromethyl group with N- and S-nucleophilic reagents, as well as reactions of
transformation of the 1,2,4-oxadiazole ring.
Keywords: chloromethyl, furazan, 1,2,4-oxadiazole, 1,2,5-oxadiazole, oxidation.
Scheme 1
Oxadiazole derivatives are widely utilized in various
fields of chemistry: organic synthesis,1 medicinal
chemistry,2–8 in design of new materials.5,9 4-Aminofurazan-
3-carboxylic acid amidoxime (1) is widely used in the
synthesis of polyfunctional derivatives of furazan (1,2,5-
oxadiazole), which was the subject of a special review.10
A
number of studies were devoted to cyclization of the
amidoxime moiety of compound 1 into 1,2,4-oxadiazole
ring (Scheme 1).11–17 Some derivatives of substituted
3-amino-4-(1,2,4-oxadiazol-3-yl)furazan 2 exhibit antimyco-
bacterial activity against Mycobacterium tuberculosis18 and
are PI3K phosphoinositide 3-kinase inhibitors.19 Based on
the 4-(1,2,4-oxadiazol-3-yl)furazan skeleton, a number of
energetic compounds were also synthesized.7,16,17, 20–24
In continuation of our studies of derivatives of com-
pound 2,14,25 this work describes the reactivity of
4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-
3-amine (4)26 which we previously obtained from
4-aminofurazan-3-carboxylic acid amidoxime (1) via
chloroacetamide intermediate 3 (Scheme 2). There are
three potential reaction centers in furazan 4: amino group,
chloromethyl group, and 1,2,4-oxadiazole ring. The latter
can enter into both the ring opening reactions and reactions
of transformation into other heterocyclic systems8,29,30 due
to the reduced aromaticity,11,13,27 as well as the small ''π''
0009-3122/19/55(12)-1233©2019 Springer Science+Business Media, LLC
1233

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
character of the N–O bond of the 1,2,4-oxadiazole ring.28
Scheme 3
Based on this, we studied some reactions involving the
Method I
Ac2O–H2SO4
35–45°C, 15 min
92%
indicated reaction centers of compound 4.
N
Scheme 2
N
O
N
O
O
N
CH2Cl
Method II
Ac2O, NaOAc
NHAc
5
, 5 min
46%

N O
N
N
N
H2N
O
N
H2O2–H2SO4
N
CH2Cl
O
N
N
55–65°C, 30 min
87%
NO2
O
CH2Cl
6
4
CH2Cl
N
N
N
Compound 4 enters into a number of amino group-
specific reactions for aminofurazan derivatives. The
acylation reaction of compound 4 in the presence of Ac2O
and a catalytic amount of concentrated H2SO4 proceeds
under mild conditions with the formation of the
corresponding N-acetyl derivative 5. Using NaOAc as a
catalyst requires harsher reaction conditions (heating under
reflux) and leads to a lower yield of product 5. Oxidation of
the amino group of aminofurazans with H2O2-based
mixtures is the main method for the synthesis of
3-nitrofurazans.31,32 We used one of the most accessible
and effective mixtures, H2O2–H2SO4 (at temperatures
above 45°С), to obtain 4-[5-(chloromethyl)-1,2,4-oxadiazol-
3-yl]-3-nitrofurazan (6).14,25,33 It is known that the oxidation
of aminofurazans with KMnO4 in the presence of HCl is
used in the synthesis of azofurazans.1 Similar to the
oxidative dimerization of other 3-amino-4-(1,2,4-oxadiazol-
3-yl)furazans to the corresponding azo derivatives,14,25
oxidation of compound 4 with KMnO4 in an AcOH–HCl
mixture at 50°C leads to the formation of azo derivative 7
in 74% yield (Scheme 3).
KMnO4
AcOH–HCl
O
N
N
N
N
O
50°C, 20 min
74%
N
N
N
O
CH2Cl
7
It is well known that the chlorine atom in 1,2,4-oxa-
diazole chloromethyl derivatives can be substituted by N-,
O-, and S-nucleophiles.34 Indeed, the reaction of compound
4 with reagents such as NaN3 and KSCN leads to the
formation of the corresponding azides 8 and thiocyanates
9. Substitution of chlorine also occurs when reacting with a
number of primary and secondary amines and heterocyclic
thiols (Scheme 4).
It should be noted that, while the 13C NMR spectra of
compounds 8, 9, 10a–f, 11a–e, in particular, the signals of
the C–3 and C–4 atoms of the furazan ring at 155.7–155.9
and 137.3–140.1 ppm, respectively, and the signals of C-3'
and C-5' atoms of the 1,2,4-oxadiazole ring at 155.9–159.8
and 177.1–181.7 ppm, respectively, are consistent with the
spectra of compounds 2–7 and with literature data,35–37 for
Scheme 4
1234

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
Scheme 7
the product isolated as a result of the reaction of furazan 4
with MeNH2, the signal of the carbon atom C-5' of the
starting 1,2,4-oxadiazole ring is significantly shifted
upfield (177.0 → 155.6 ppm), and the signal of methylene
group experiences downfield shift (33.9 → 61.5 ppm).
Thus, the reaction with MeNH2 affects not only the
chloromethyl group, but also leads to the transformation
of the 1,2,4-oxadiazole ring. In this case, the formation of
3-(4-amino-1,2,5-oxadiazol-3-yl)-N-methyl-6H-1,2,4-oxadi-
azin-5-amine (12) is observed (Scheme 5). A similar
transformation was previously observed when studying the
properties of 5-chloromethyl-3-(5-nitrofuran-2-yl)-1,2,4-oxa-
diazole.38
1. AcOCH2COCl, PhMe
, 8 h
2. MeOH, H2O, HCl
, 2 h
N
O
N
N
N
N
OH
NH2
O
N
O
N
68%
CH2OH
NH2
NH2
1
14
The acylation of compounds 12 and 13 by Ac2O in the
presence of H2SO4 proceeds at the amino group of the
furazan ring, which leads to the formation of the cor-
responding 3-acetylaminofurazans 15 and 16 (Scheme 8).
Scheme 8
Scheme 5
N O
N
N
N O
N
N
O
N
O
N
Ac2O, H2SO4
rt, 24 h
73%
NH2
NHMe
NHAc
NHMe
12
15
N O
HN
N
N O
N
O
N
O
N
Ac2O, H2SO4
HN
NHAc
16
45–50°C, 30 min
56%
NH2
O
O
13
Under more severe conditions (K2CO3, MeOH–H2O
upon heating; KOH–MeOH, KOH–H2O at room
temperature) hydrolysis of chloromethyl derivative 4 leads
to the opening of the 1,2,4-oxadiazole ring. The final hydro-
lysis product was identified by us as ({[amino(4-amino-
1,2,5-oxadiazol-3-yl)methylidene]amino}oxy)acetic acid
(17). A probable reaction mechanism is shown in Scheme 9.
The acylation of compound 17 by Ac2O to give
diacetylamine 18 confirms the presence of two amino
Hydrolysis of 3-amino-4-[5-(chloromethyl)-1,2,4-oxa-
diazol-3-yl]furazan (4) under mild conditions (K2CO3,
EtOH, 30°С) produces 1,2,4-oxadiazine 13, the product of
the transformation of the 1,2,4-oxadiazole ring, instead of
the expected hydroxymethyl compound 14 (Scheme 6).
The structure of the obtained compound was established on
the basis of 13C NMR spectroscopy data. In the 13C NMR
spectrum of compound 13, the signal of the C-5' carbon
atom of the starting 1,2,4-oxadiazole ring is significantly
shifted upfield (177.0 → 144.4 ppm), and the signal of the
methylene group of the side chain experiences downfield
shift (33.9 → 67.7 ppm), which corresponds to the
previously described NMR spectra of 1,2,4-oxadiazin-
6(5H)-ones.39
To prove the direction of the hydrolysis reaction of
compound 4 toward the formation of oxadiazine 13, we
synthesized hydroxymethyl derivative 14 via the reaction
of amidoxime 1 with an excess of acetoxyacetyl chloride
and subsequent hydrolysis (Scheme 7). The main
difference between the 13C NMR spectra of the obtained
compound 14 and 1,2,4-oxadiazine 13 is the location of the
signal of the C-5' carbon atom, 180.9 and 144.4 ppm,
respectively.
1
groups in the starting substrate. The IR and H and 13C
NMR spectra of compound 17 are identical to the spectra
of the compound obtained by alkylation of amidoxime 1 in
the presence of ethyl chloroacetate followed by hydrolysis
(Scheme 10).
We previously showed that the reaction of compound 4
with hydrazine leads to a very uncharacteristic oxidation of
the chloromethyl group to the azomethine group resulting
in the formation of hydrazone 19 (Scheme 11).26 Several
cases are described in the literature when such reactions
were observed only for 6-chloromethylpurine,40 derivatives
of phenacyl bromide,41 and 4-chloro-2-chloromethyl-
6-pyrimidones;42 a possible mechanism of this reaction was
proposed.35–37 We have now shown that treatment of
compound
4
with phenylhydrazine also produces
Scheme 6
N
N
O
N
N O
N
O
N
O
N
HN
N
N
NH2
O
NH2
OH
O
N
O
13
K2CO3, EtOH
N
CH2Cl
30°C, 14 h
69%
N
N
NH2
O
N
O
4
N
CH2OH
NH2
14
1235

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
Scheme 9
H+
O–
CH2Cl
O
N
O
O
N
O
N
N
N
N
N
N
O
N
O–
OH
– Cl–
56%
NH2
NH2
HN
NH2
O
O
NH2
NH2
EtOH–H2O, 1:1
17
O
N
O
N
N
N
N
N
N
O–
40°C, 3 h
O
O
N
Ac2O, H2SO4
45–50°C, 30 min
74%
–OH
CH2Cl
–OH
CH2Cl
NH2
NH2
HO
– Cl–
–OH
N
N
4
O
N
O
OH
NHAc
O
N O
N O
N
N
O
N
O
N
NHAc
18
HN
NH2
N
O
OH
NH2
13
Cхема 10
Scheme 12
1. ClCH2CO2Et, K2CO3
DMF, 60°C, 5 h
2. NaOH, MeOH–H2O
40°C, 15 min
N
O
N
N
N
N
OH
O
N
OCH2COOH
NH2
NH2
82%
NH
NH2
2 1
17
Scheme 11
N
N
O
N
O
N2H4, MeOH
well as compound 21) with aqueous NaOH, the opening of
the 1,2,4-oxadiazole ring and the formation of amidoxime 1
took place (Scheme 12).
Prolonged heating of hydrazone 19 with HCl leads to a
very unusual version of the Wolff–Kishner43 reduction of
the carbonyl group with the formation of 4-(5-methyl-1,2,4-
oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (2b) (Scheme 13).
N
35–40°C
30 min
82%
NH2
N
19
NH2
N
N
PhNHNH2
MeOH
O
N
O
N
N
N
4
O
N
O
N
CH2Cl
, 30 min
44%
NH2
N
N
NH2
20
Scheme 13
NHPh
OH
N
N
N
N
N
N
O
N
O
O
N
O
NH2OH·HCl
NaHCO
HCl
– N2
42%
N
O
O
MeOH3
19
Me
N
, 18 h
N
NH2
NH2
N
NH
40–45°C, 8 h
83%
2b
NH2
N
21
Acylation of compounds 19 and 21 under mild
hydrazone 20, and the reaction of compound 4 with
hydroxylamine leads to a similar result, the formation of
oxime 21 (Scheme 11).
conditions (Ac2O, H+, 20–25°C) occurs at the amino group
of the furazan ring and leads to the formation of acylamines
23 and 24 (Scheme 14). Heating the reaction mixture to its
boiling point leads to resinification and the formation of a
complex mixture of unidentified products. The oxime
1H and 13C NMR spectra of compounds 19–21 confirm
their structures. Chemical shifts of the signals of carbon
atoms in the 13C NMR spectra of the obtained compounds
indicate the retention of the linked furazan (C-3, 155.9 ppm;
C-4, 137.4–137.6 ppm) and 1,2,4-oxadiazole rings (C-3',
159.3–159.7 ppm; C-5', 172.1–174.7 ppm). 1H NMR spectra
demonstrate the absence of a methylene group and the
presence of an azomethine fragment (7.67, 7.91, 8.47 ppm).
Despite the presence of an amino group, compounds 19 and
21 proved to be inert in the reaction with carbonyl
compounds (Me2CO or PhCHO in EtOH–AcOH). Under
more severe conditions in the presence of H2SO4, attempts
to condense compound 19 with carbonyl compounds (as
well as in their absence) led to the formation of
bishydrazone (azine) 22, which was insoluble in the
reaction medium. As a result of treating compound 19 (as
Scheme 14
N
N
N
N
N
N
Ac2O
H2SO4
O
N
O
N
O
O
45–50°C
30 min
NH2
NHAc
N
N
R
R
19 R = NH2
21 R = OH
23 R = NH2 (76%)
24 R = OH (71%)
N
N
O
Me2SO4
K2CO3
O
N
N
21
DMF, rt, 2 h
68%
NH2
N
OMe
25
1236

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
group of compound 21 is alkylated at the oxygen atom with
dimethyl sulfate to form methoxyimine 25.
Experimental
The oxidation of the furazan amino group of compound
19 to the nitro group with H2O2–H2SO4 is accompanied by
oxidative hydrolysis of the hydrazonomethyl fragment
followed by decarboxylation to form 3-nitro-4-(1,2,4-oxa-
diazol-3-yl)furazan (26) (Scheme 15). The presence of the
azomethine fragment in compounds 19 and 21 is also
confirmed by their transamination reactions with
semicarbazide and thiosemicarbazide leading to the
formation of the corresponding products 27, 28.
IR spectra were registered on an FSM-1201 FT
spectrometer in KBr pellets. 1H and 13C NMR spectra were
acquired on a Bruker DRX-400 spectrometer (400 and
100 MHz, respectively) in DMSO-d6, using residual
solvent signals (2.51 ppm for 1H nuclei, 39.96 ppm for 13
C
nuclei) to assign chemical shifts. The assignment of signals
in the 13C NMR spectra was based on the spectra of similar
compounds. Mass spectra were recorded on a Finnigan
MAT Incos 50 spectrometer (EI ionization, 70 eV). High-
resolution mass spectra were recorded on a Bruker
micrOTOF II mass spectrometer (electrospray ionization).
Elemental analysis was performed on a PerkinElmer Series
II 2400 Elemental analyzer. Melting points were
determined in an open capillary. Monitoring of the reaction
progress and assessment of the purity of synthesized
compounds were done by HPLC on a Shimadzu Series 20
chromatograph with a diode array detector (column Luna
С18(2) 250 × 4.6 mm, particle size 5 μm), mobile phase
MeOH–H2O, 3:1, thermostat and detector temperature
40°С, detection at 209, 230, and 254 nm.
Scheme 15
Compounds 2a,10 2b,14 3,26 426 were synthesized accord-
ing to literature methods.
4-(1,2,4-Oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (2a).10
IR spectrum, ν, cm–1: 3438, 2971, 2918, 2743, 2682, 1636,
1603, 1483, 1470, 1429, 1417, 1320, 1223, 1170, 1092,
1078, 1056, 1011, 997, 860, 704, 626, 611. 1H NMR
spectrum, δ, ppm: 6.50 (2H, s, NH2); 10.00 (1H, s, CH).
13C NMR spectrum, δ, ppm: 137.4 (С-4); 156.0 (С-3);
158.6 (С-3'); 168.7 (С-5'). Mass spectrum, m/z (Irel, %): 154
[M+1]+ (3), 153 [M]+ (100), 123 [M–NO]+ (23), 96 (94), 69
(19), 58 [NHCNOH]+ (90), 53 (28), 42 (15), 30 [NO]+ (55),
29 [CHO]+ (41).
The reaction of 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-
3-nitrofurazan (6) with hydrazine is accompanied not only
by the substitution of the nitro group for hydrazine group,
but also similar to the above-described conversion of the
chloromethyl group to form hydrazone 29. In this case, the
condensation of the obtained compound with Me2CO
affects only the more nucleophilic furazan hydrazine group
to form product 30 (Scheme 16).
4-(5-Methyl-1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-
3-amine (2b).14 IR spectrum, ν, cm–1: 3469, 3362, 2922, 2852,
2362, 1804, 1630, 1584, 1547, 1480, 1463, 1429, 1385, 1260,
1150, 1087, 1044, 1016, 978, 956, 925, 911, 862, 768, 737,
713, 693, 654, 577, 515, 458, 403. 1H NMR spectrum, δ, ppm:
2.74 (3H, s, CH3); 6.44 (2H, s, NH2). 13C NMR spectrum,
δ, ppm: 12.4 (CH3); 137.4 (С-4); 155.8 (С-3); 155.9 (С-3');
179.0 (С-5'). Mass spectrum, m/z (Irel, %): 167 [M]+ (19),
110 (14), 43 (100), 42 [CNO]+ (14), 32 (19), 30 [NO] (21)+.
3-Chloro-N-{4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-
1,2,5-oxadiazol-3-yl}acetamide (3).26 IR spectrum, ν, cm–1:
3340, 3005, 2950, 1704 (С=O), 1619, 1587, 1555, 1538,
1429, 1404, 1328, 1310, 1302, 1275, 1229, 1153, 1014,
970, 930, 906, 869, 820, 784, 770, 636, 619, 599, 566, 490.
1H NMR spectrum, δ, ppm: 11.4 (1H, s, NH); 5.27 (2H, s,
CH2); 4.46 (2H, s, CH2). 13C NMR spectrum, δ, ppm: 33.9
(CH2); 42.9 (CH2); 141.5 (С-4); 150.0 (С-3); 159.1 (С-3');
177.1 (С-5'); 166.3 (C=O). Mass spectrum, m/z (Irel, %):
279 [M(37Cl)]+ (2), 277 [M(35Cl)]+ (4), 230 (14), 228
[M–CH2Cl]+ (43), 201 [M–COCH2Cl]+ (15), 144 (13), 79
[COCH237Cl)]+ (25), 77 [COCH235Cl)]+ (83), 51 [CH237Cl)]+ (35),
49 [CH235Cl)]+ (100), 42 [CH2CO]+ (43), 30 [NO]+ (64).
4-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadi-
azol-3-amine (4).26 IR spectrum, ν, cm–1: 3469, 3013,
2963, 2921, 1629, 1605, 1587, 1551, 1465, 1428, 1388,
Scheme 16
Our studies of the chemical properties of 3-amino-
4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]furazan show that
the compound under consideration is
a promising
multifunctional synthon for the preparation of previously
inaccessible furazan derivatives. It was shown that the
reactivity of the amino group of the furazan ring is
predictable, while the behavior of the chloromethyl
substituent is less clear and may be accompanied by
transformation of the 1,2,4-oxadiazole ring.
1237

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
1294, 1273, 1145, 1014, 977, 943, 905, 763, 703, 641, 575,
3,3'-[Diazene-1,2-diyldi-(1,2,5-oxadiazole-4,3-diyl)]bis-
[5-(chloromethyl)-1,2,4-oxadiazole] (7). Compound 4
(2.00 g, 10 mmol) was added to a mixture of AcOH
(25 ml) and 35% HCl (25 ml), and the whole was heated to
30–35°С. KMnO4 (1.38 g, 10 mmol) was added to the
resulting suspension with stirring. The reaction mixture
was heated to 50°C and stirred for 20 min, then cooled to
room temperature, the KMnO4 residue was neutralized by
the addition of a small amount of a 30% aqueous H2O2.
The reaction mixture was diluted with H2O (50 ml), the
precipitate formed was filtered off and recrystallized from
AcOH. Yield 1.78 g (74%), orange-yellow crystals, mp 116–
117°С. IR spectrum, ν, cm–1: 3042, 3018, 2970, 1584,
1451, 1432, 1423, 1349, 1277, 1245, 1143, 1032, 1014,
969, 922, 903, 871, 788, 773, 767, 760, 710, 698, 648, 596,
486. 1H NMR spectrum, δ, ppm: 5.26 (4H, s, 2CH2).
13C NMR spectrum, δ, ppm: 33.9 (СН2); 141.5 (С-4); 162.2
(С-3); 158.6 (С-3'); 177.5 (С-5'). Mass spectrum, m/z
(Irel, %): 402 [M(37Cl)]+ (2), 401 (2), 400 [M(35Cl,37Cl)]+
(13), 399 (3), 398 [M(35Cl)]+ (21), 351 (34), 349 (100), 213
(35), 49 (22), 30 [NO]+ (85). Found, m/z: 398.9859 [M+H]+.
C10H5Cl2N10O4. Calculated, m/z: 398.9867.
4-[5-(Azidomethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadi-
azol-3-amine (8). NaN3 (0.90 g, 14 mmol) was added to a
solution of compound 4 (2.00 g, 10 mmol) in MeCN
(25 ml), and the mixture was stirred at 50–55°С for 5 h.
Then the reaction mixture was poured into H2O (50 ml),
the precipitate formed was filtered off and recrystallized
from MeOH. Yield 1.45 g (70%), white crystals, mp 118–
119°С. IR spectrum, ν, cm–1: 3468, 2921, 2853, 2216 (N3),
2121 (N3), 1627, 1603, 1558, 1469, 1389, 1340, 1306,
1282, 1191, 1149, 1014, 973, 909, 796, 569, 448, 413.
1H NMR spectrum, δ, ppm: 5.08 (2H, s, CH2); 6.49 (2H, s,
NH2). 13C NMR spectrum, δ, ppm: 47.8 (СН2); 137.7 (С-4);
155.9 (С-3); 156.0 (С-3'); 177.1 (С-5'). Mass spectrum, m/z
(Irel, %): 210 [M+2]+ (1), 209 [M+1]+ (9), 208 [M]+ (100),
151 (50), 96 (20), 69 (37), 58 (46), 54 (20), 53 (44), 42
(28), 30 [NO]+ (81), 28 [N2]+ (97). Found, m/z: 209.0522
[M+H]+. C5H5N8O2. Calculated, m/z: 209.0530.
1
567, 441, 413, 402. H NMR spectrum, δ, ppm: 5.26 (2H,
s, CH2); 6.40 (2H, br. s, CH2). 13C NMR spectrum, δ, ppm:
33.9 (CH2); 137.3 (С-4); 155.9 (С-3); 159.8 (С-3'); 177.0
(С-5'). Mass spectrum, m/z (Irel, %): 203 [M(37Cl)]+ (11),
201 [M(35Cl)]+ (35), 146 (30), 144 [M–NHCNO]+ (100), 77
(34), 69 (37), 58 [NHCNOH]+ (95), 54 (18), 53 (40), 51
(22), 49 (57), 42 (32), 30 [NO]+ (79).
N-{4-[5-(Chloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxa-
diazol-3-yl}acetamide (5). Method I. Concentrated H2SO4
(1 drop, ~0.03 ml) was added to a solution of compound 4
(1.00 g, 5.00 mmol) in Ac2O (5 ml, 0.46 mol). An
exothermic reaction was observed with the formation of a
precipitate. The reaction mixture was stirred at 35–45°С for
15 min, then MeOH (20 ml) was added, and the solvent
was evaporated under reduced pressure. The residue was
recrystallized from MeOH. Yield 1.10 g (92%), white
crystals, mp 99−100°С.
Method II. Anhydrous NaOAc (0.10 g, 1.20 mmol) was
added to a solution of compound 4 (1.00 g, 5.00 mmol) in
Ac2O (5 ml, 0.46 mol). The reaction mixture was brought
to a boil and heated under reflux for 5 min (longer heating
led to resinification of the reaction mixture). Then it was
cooled to room temperature, H2O (20 ml) was added, and
left overnight. The formed precipitate was filtered off and
recrystallized from MeOH. Yield 0.55 g (46%), light-
brown crystals, mp 98−99.5°С. IR spectrum, ν, cm–1: 3318,
3032, 2974, 2857, 1742 (C=O), 1713, 1614, 1589, 1551,
1518, 1372, 1324, 1244, 1220, 1157, 1147, 1043, 1018,
971, 905, 760, 752, 606, 598, 575, 509. 1H NMR spectrum,
δ, ppm: 2.12 (3H, s, CH3); 5.27 (2H, s, CH2); 11.20 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 23.2 (CH3); 33.9 (CH2);
141.8 (С-4); 150.5 (С-3); 159.3 (С-3'); 169.8 (C=O); 176.9
(С-5'). Mass spectrum, m/z (Irel, %): 245 [M(37Cl)]+ (4), 243
[M(35Cl)]+ (10), 215 (18), 203 (33), 201 [M–CH2CO]+
(100), 144 (19), 43 [CH3CO]+ (46). Found, %: C 34.23;
H 2.75; N 28.47. C7H6ClN5O3. Calculated, %: C 34.51;
H 2.48; N 28.75.
5-(Chloromethyl)-3-(4-nitro-1,2,5-oxadiazol-3-yl)-
1,2,4-oxadiazole (6). Compound 4 (20 g, 0.10 mol) was
added in 4–5-g portions to an oxidizing mixture prepared
from 36% aqueous H2O2 (30 ml, ~0.30 mol) and 94−96%
H2SO4 (40 ml, ~0.75 mol), keeping the temperature of the
reaction mixture at 55−65°С. At the end of the exothermic
reaction, the mixture was stirred at the same temperature
for 30 min. After cooling to room temperature, H2O
(500 ml) was added, and the mixture was extracted with
CH2Cl2 (2×50 ml). The organic layer was washed with H2O
(4×100 ml), dried over MgSO4, and evaporated under
reduced pressure. Yield 20.1 g (87%), light-yellow oil,
nD 1.524. IR spectrum, ν, cm–1: 3036, 2974, 1603, 1568,
1441, 1369, 1312, 1295, 1117, 1038, 1016, 970, 934, 891,
[3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5-yl]-
methyl thiocyanate (9). Finely ground KSCN (1.26 g,
13.00 mmol) was added to a solution of compound 4
(2.00 g, 10.00 mmol) in MeCN (25 ml). The mixture was
stirred at 50–55°С for 5 h, then poured into H2O (50 ml);
the precipitate formed was filtered off and recrystallized
from MeOH. Yield 1.84 g (82%), light-beige amorphous
powder, mp 97–98°С. IR spectrum, ν, cm–1: 3464, 3329,
3014, 2922, 2853, 2157 (CN), 1631, 1603, 1585, 1560,
1462, 1292, 1241, 1140, 1007, 965, 935, 875, 576.
1H NMR spectrum, δ, ppm: 4.93 (2H, s, CH2); 6.51 (2H, s,
NH2). 13C NMR spectrum, δ, ppm: 27.4 (CH2); 112.4
(SCN); 137.3 (С-4); 155.9 (С-3); 159.8 (С-3'); 177.2
(С-5'). Mass spectrum, m/z (Irel, %): 224 [M]+ (13), 194
[M–NO]+ (12), 165 [M–HSCN]+ (70), 109 (31), 108 (23),
72 [CH2SCN]+ (45), 69 (15), 58 [SCN]+ (100), 52 (33), 45
(21), 42 [CNO]+ (25), 30 [NO]+ (50). Found, m/z: 225.0180
[M+H]+. C6H5N6O2S. Calculated, m/z: 225.0189.
1
825, 756. H NMR spectrum, δ, ppm: 4.89 (2H, s, CH2).
13C NMR spectrum, δ, ppm: 32.9 (СН2); 139.1 (С-4); 158.5
(С-3); 156.9 (С-3'); 176.9 (С-5'). Mass spectrum, m/z
(Irel, %): 234 [M(37Cl)+1]+ (1), 233 [M(37Cl)]+ (17), 232
[M(35Сl)+1]+ (5), 231 [M(35Cl)]+ (48), 51 (10), 49 (28), 46
[NO2]+ (100), 30 [NO]+ (88). Found, m/z: 231.9861 [M+H]+.
C5H3ClN5O4. Calculated, m/z: 231.9868.
Synthesis of compounds 10a–f and 12 in the reaction
of 4-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-oxadi-
1238

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
azol-3-amine (4) with amines (General method). The
m, 2CH2); 2.45–2.55 (4H, m, N(CH2)2); 4.00 (2H, s, CH2);
6.47 (2H, s, NH2). 13C NMR spectrum, δ, ppm: 23.8 (CH2);
25.9 (CH2); 53.2 (NCH2); 55.8 (N(CH2)2); 137.5 (С-4);
155.9 (С-3); 159.2 (С-3'); 178.6 (С-5'). Mass spectrum, m/z
(Irel, %): 249 [M–1]+ (2), 137 (12), 98 [(CH2)5NCH2]+ (28),
97 (24), 96 (18), 84 [(CH2)5N]+ (100), 42 (21), 41 (18).
Found, m/z: 251.1259 [M+H]+. C10H15N6O2. Calculated,
m/z: 251.1251.
4-[5-(Pyrrolidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-
oxadiazol-3-amine (10e) was obtained in the reaction of
compound 4 with pyrrolidine. Yield 1.53 g (65%), beige
crystals, mp 87–88°С. IR spectrum, ν, cm–1: 3448, 2921,
2802, 1627, 1461, 1420, 1394, 1350, 1171, 1116, 1043,
1003, 968, 905, 879, 572. 1H NMR spectrum, δ, ppm: 1.71
(4H, s, (CH2)2); 2.62 (4H, s, N(CH2)2); 4.11 (2H, s, CH2);
6.46 (2H, s, NH2). 13C NMR spectrum, δ, ppm: 23.8 ((CH2)2);
49.6 (NCH2); 53.5 (N(CH2)2); 137.4 (С-4); 155.9 (С-3);
159.3 (С-3'); 179.0 (С-5'). Mass spectrum, m/z (Irel, %): 235
[M–1]+ (<1), 193 (1), 84 [CH2N(CH2)4]+ (42), 83 (40), 70
[N(CH2)4]+ (100), 55 (22), 42 [CH2NCH2]+ (46). Found,
m/z: 237.1088 [M+H]+. C9H13N6O2. Calculated, m/z:
237.1095.
4-{5-[(Benzylamino)methyl]-1,2,4-oxadiazol-3-yl}-1,2,5-
oxadiazol-3-amine (10f) was obtained in the reaction of
compound 4 with BnNH2. Yield 1.93 g (71%), beige
crystals, mp 102–103°С. IR spectrum, ν, cm–1: 3467, 3332,
3308, 2920, 2857, 163, 1551, 1455, 1153, 1115, 1023,
1005, 967, 901, 806, 737, 696, 580, 522. 1H NMR
spectrum, δ, ppm: 3.82 (2H, s, CH2); 4.13 (2H, s, CH2);
6.51 (2H, s, NH2); 7.22–7.37 (5H, m, H Ph). 13C NMR
spectrum, δ, ppm: 43.9; 55.5; 127.3 (C-4 Ph); 128.5 (C-3,5
Ph); 128.6 (C-2,6 Ph); 137.4 (C-1 Ph); 140.1 (С-4); 155.9
(С-3); 159.2 (С-3'); 180.7 (С-5'). Mass spectrum, m/z
(Irel, %): 271 [M–1]+ (1), 137 (10), 118 [PhCH=NCH2]+
(39), 117 (16), 106 [C7H7NH]+ (100), 91 [C7H7]+ (78), 70
(21). Found, m/z: 273.1102 [M+H]+. C12H13N6O2.
Calculated, m/z: 273.1095
3-(4-Amino-1,2,5-oxadiazol-3-yl)-N-methyl-6Н-1,2,4-
oxadiazin-5-amine (12) was obtained in the reaction of
compound 4 with MeNH2. Yield 1.14 g (58%), white
crystals, mp 195–196°С. IR spectrum, ν, cm–1: 3432, 3327,
3163, 3108, 2920, 2884, 1619, 1517, 1406, 1189, 1086,
993, 947, 906, 860, 570. 1H NMR spectrum, δ, ppm
(J, Hz): 2.91 (3H, d, J = 4.8, CH3); 4.26 (2H, s, CH2); 6.29
(2H, s, NH2); 8.51 (1H, br. s, NH). 13C NMR spectrum,
δ, ppm: 27.3 (СН3); 61.5 (C-6'); 142.6 (С-4); 153.7 (С-3);
159.3 (С-3'); 155.6 (С-5'). Mass spectrum, m/z (Irel, %): 197
[M+1]+ (5), 196 [M]+ (63), 139 [M–CH2=CHNO]+ (90), 82
(11), 68 (14), 58 (13), 57 (40), 56 [CH2CNO]+ (100), 55
(33), 54 (20), 53 (29), 42 [CNO]+ (57), 41 (33), 30 [NO]+
(48). Found, m/z: 197.0774 [M+H]+. C6H9N6O2.
Calculated, m/z: 197.0782.
corresponding amine (22 mmol) (Me2NH was used as a
30% aqueous solution) was added to a solution of com-
pound 4 (2.00 g, 10.00 mmol) in MeCN (25 ml), and the
mixture was stirred at 35–40°С for 1 h. The solvent and
excess amine were distilled off under reduced pressure.
H2O (50 ml) was added to the obtained residue, the insoluble
precipitate was filtered off and recrystallized from MeOH.
4-{5-[(tert-Butylamino)methyl]-1,2,4-oxadiazol-3-yl}-
1,2,5-oxadiazol-3-amine (10a) was obtained in the
reaction of compound 4 with t-BuNH2. Yield 1.21 g (51%),
small irregularly shaped plates, mp 113–114°С. IR spect-
rum, ν, cm–1: 3388, 3309, 3122, 2966, 1640, 1585, 1558,
1467, 1459, 1392, 1372, 1231, 1146, 1118, 1015, 975, 926,
1
907, 840, 785, 765, 580, 423. H NMR spectrum, δ, ppm:
1.07 (9H, s, С(CH3)3); 4.11 (2H, s, CH2); 6.49 (2H, s,
NH2). 13C NMR spectrum, δ, ppm: 28.9 (CH3); 39.1
(С(CH3)3); 51.0 (CH2); 137.5 (С-4); 155.9 (С-3); 159.2
(С-3'); 181.7 (С-5'). Mass spectrum, m/z (Irel, %): 238 [M]+
(<1), 224 [M–CH2]+ (17), 223 [M–CH3]+ (100), 165 (16),
70 (74), 57 (16), 41 (16), 30 [NO]+ (28). Found, m/z:
239.1259 [M+H]+. C9H15N6O2. Calculated, m/z: 239.1251.
4-{5-[(Dimethylamino)methyl]-1,2,4-oxadiazol-3-yl}-
1,2,5-oxadiazol-3-amine (10b) was obtained in the
reaction of compound 4 with Me2NH. Yield 1.13 g (54%),
light-beige amorphous powder, mp 98–99°С. IR spectrum,
ν, cm–1: 3470, 3451, 3310. 3156, 1630, 1587, 1557, 1467,
1
1360, 1146, 1013, 968, 854, 576, 402. H NMR spectrum,
δ, ppm: 6.48 (2H, s, NH2); 4.07 (2H, s, CH2); 2.36 (6H, s,
2CH3). 13C NMR spectrum, δ, ppm: 44.8 (CH3); 53.1
(СH2); 137.5 (С-4); 155.9 (С-3); 159.2 (С-3'); 181.7 (С-5').
Mass spectrum, m/z (Irel, %): 210 [M]+ (3), 167
[M–CH2=NCH3]+ (20), 151 (23), 137 (32), 110 (23), 58
[HNCNOH]+ (100), 44 [NMe2]+ (50), 42 [CNO]+ (38).
Found, m/z: 211.0943 [M+H]+. C7H11N6O2. Calculated,
m/z: 211.0938.
4-[5-(Morpholin-4-ylmethyl)-1,2,4-oxadiazol-3-yl]-
1,2,5-oxadiazol-3-amine (10c) was obtained in the
reaction of compound 4 with morpholine. Yield 1.74 g
(69%), white crystals, mp 184–185°С. IR spectrum, ν, cm–1:
3444, 3285, 3154, 2973, 2920, 2873, 2837, 1628, 1583,
1561, 1459, 1415, 1348, 1333, 1308, 1205, 1170, 1107,
1067, 1041, 1005, 973, 967, 921, 907, 863, 818, 712, 682,
617, 578, 524, 478, 446. 1H NMR spectrum, δ, ppm: 2.53–
2.61 (4H, m, (CH2)2O); 3.57–3.63 (4H, m, (CH2)2N); 4.06
(2H, s, CH2); 6.48 (2H, s, NH2). 13C NMR spectrum,
δ, ppm: 52.6 ((СН2)2N); 52.9 (CH2); 66.5 ((СН2)2О); 137.5
(С-4); 155.9 (С-3); 159.3 (С-3'); 178.2 (С-5'). Mass
spectrum, m/z (Irel, %): 252 [M]+ (1), 222 [M–NO]+ (1),
137 (64), 109 (21), 56 (32), 42 (40), 41 (19), 30 [NO]+
(25). Found, m/z: 253.1036 [M+H]+. C9H13N6O3.
Calculated, m/z: 253.1044.
4-[5-(Piperidin-1-ylmethyl)-1,2,4-oxadiazol-3-yl]-1,2,5-
oxadiazol-3-amine (10d) was obtained in the reaction of
compound 4 with piperidine. Yield 1.74 g (69%), white
crystals, mp 121–122°С. IR spectrum, ν, cm–1: 3469, 2922,
2853, 1726, 1638, 1543, 1506, 1315, 1144, 1112, 1038,
1001, 963, 899, 862, 764, 570, 433, 405. 1H NMR
spectrum, δ, ppm: 1.32–1.40 (2H, m, CH2); 1.49–1.54 (4H,
Synthesis of compounds 11a–e (General method).
NaHCO3 (1.68 g, 20 mmol) and the corresponding thiol
(11 mmol) were added to a solution of compound 4 (2.00 g,
10 mmol) in MeOH (35 ml). The mixture was stirred at
45–50°С for 5 h, then poured into H2O (50 ml); the
precipitate formed was filtered off and recrystallized from
AcOH.
1239

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
5-({[3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-
124.4 (CH); 129.4 (CH); 138.7 (С-4); 139.5; 155.7 (С-3);
155.9 (С-3'); 177.2 (С-5'). Mass spectrum, m/z (Irel, %): 279
[M]+ (1), 278 [M–1]+ (9), 221 [M–SCN]+ (40), 115 (11),
114 [1-methylimidazole-2-thiol]+ (100), 72 (11). Found, m/z:
280.0608 [M+H]+. C9H10N7O2S. Calculated, m/z: 280.0611.
4-(5-{[(1-tert-Butyl-1H-tetrazol-5-yl)sulfanyl]methyl}-
1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (11e) was
obtained in the reaction of compound 4 with 1-tert-butyl-
5-yl]methyl}sulfanyl)-1,3,4-thiadiazole-2-thiol (11а) was
obtained in the reaction of compound 4 with 1,3,4-
thiadiazole-2,5-dithiol. Yield 2.39 g (76%), white crystals,
mp 215–216°С. IR spectrum, ν, cm–1: 3438, 3339, 2921,
2853, 1630, 1603, 1585, 1490, 1443, 1380, 1254, 1238,
1
1145, 1114 (C=S), 1047, 715, 479. H NMR spectrum,
δ, ppm: 4.95 (2H, s, CH2); 6.47 (2H, br. s, NH2); 14.70
(1H, br. s, SH). 13C NMR spectrum, δ, ppm: 27.7 (СН2);
137.3 (С-4); 155.9 (С-3); 159.7 (С-3'); 177.9 (С-5'); 189.2
(C=S). Mass spectrum, m/z (Irel, %): 315 [M]+ (23), 258
(18), 150 (14), 109 (10), 77 (16), 76 (35), 73 (28), 64 (35),
60 (24), 59 (64), 58 (54), 53 (39), 46 (54), 45 [CHS]+
(100), 44 (21), 43 [CHNO]+ (37), 42 [CNO]+ (45), 30 (67),
29 (71). Found, m/z: 315.9748 [M+H]+. C7H6N7O2S3.
Calculated, m/z: 315.9740. According to the 13C NMR
spectrum, the compound is in the thione form.
tetrazole-5-thiol. Yield 2.3
g
(71%), light-brown
amorphous powder, mp 124–125°С. IR spectrum, ν, cm–1:
3469, 3461, 3355, 3316, 2981, 2923, 1626, 1603, 1583,
1550, 1397, 1377, 1220, 1145, 1137, 1106, 973, 929, 595,
1
581. H NMR spectrum, δ, ppm: 1.69 (9H, s, C(CH3)3);
5.13 (2H, s, CH2); 6.46 (2H, s, NH2). 13C NMR spectrum,
δ, ppm: 28.5 (CH2); 28.7 (CH3); 61.9 (C(CH3)3); 137.3
(С-4); 151.2 (tetrazole); 155.8 (С-3); 159.6 (С-3'); 178.0
(С-5'). Mass spectrum, m/z (Irel, %): 323 [M]+ (22), 268
(20), 267 [M–C4H8]+ (26), 210 (24), 167 (92), 137 (20),
109 (17), 57 [CMe3]+ (100), 41 (23). Found, m/z: 324.0980
[M+H]+. C10H14N9O2S. Calculated, m/z: 324.0986.
4-(5-{[(4-Methyl-4H-1,2,4-triazol-3-yl)sulfanyl]methyl}-
1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (11b) was
obtained in the reaction of compound 4 with 4-methyl-
1,2,4-triazole-3-thiol. Yield 2.02 g (72%), white needles,
mp 210–211°С. IR spectrum, ν, cm–1: 3449, 3269, 3238,
3119, 2972, 2929, 1633, 1585, 1554, 1519, 1466, 1429,
1395, 1333, 1244, 1212, 1172, 1148, 1011, 969, 929, 911,
880, 692, 644, 413. 1H NMR spectrum, δ, ppm: 3.62 (3H,
s, CH3); 4.82 (2H, s, CH2); 6.44 (2H, s, NH2); 8.59 (1H, s,
CH). 13C NMR spectrum, δ, ppm: 28.0 (СН3); 31.5 (СН2);
137.3 (С-4); 147.2; 147.6; 155.9 (С-3); 159.6 (С-3'); 178.3
(С-5'). Mass spectrum, m/z (Irel, %): 281 [M+1]+ (1), 280
[M]+ (4), 223 (44), 129 (13), 115 (98), 84 (14), 58 (15), 56
(16), 55 (30), 42 [CNO]+ (100), 30 [NO]+ (26). Found, m/z:
281.0571 [M+H]+. C8H9N8O2S. Calculated, m/z: 281.0564.
4-(5-{[(4-Amino-4H-1,2,4-triazol-3-yl)sulfanyl]methyl}-
1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (11с) was
obtained in the reaction of compound 4 with 5-amino-1,2,4-
triazole-3-thiol. Yield 1.94 g (69%), orange crystals,
mp 187–188°С. IR spectrum, ν, cm–1: 3471, 3400, 3380,
3316, 3178, 3128, 2954, 2919, 1649, 1633, 1608, 1583,
1558, 1498, 1472, 1382, 1347, 1275, 1236, 1159, 1119,
1077, 1057, 1017, 975, 910, 870, 766, 739, 711, 654, 569,
3-(4-Amino-1,2,5-oxadiazol-3-yl)-6H-1,2,4-oxadiazin-
5-ol (13). Chloromethyl derivative of compound 4 (1.0 g,
5.0 mmol) was added to a mixture of K2CO3 (1.5 g,
10.9 mmol) and EtOH (30 ml). The reaction mixture was
stirred at 30°С for 14 h, then it was filtered from inorganic
salts. The filtrate was acidified with concentrated HCl
(pH 1), H2O (30 ml) was added, and evaporated under
reduced pressure to 1/2 of the initial volume. The
precipitate was filtered off and recrystallized from MeOH–
H2O, 1:1 mixture. Yield 0.63 g (69%), white amorphous
powder, mp 225–226°С. IR spectrum, ν, cm–1: 3456, 3410,
3320, 3208, 3142, 1727, 1642, 1547, 1467, 1363, 1344,
1312, 1049, 1001, 971, 952, 917, 862, 774, 571, 517, 467.
1H NMR spectrum, δ, ppm: 4.53 (2H, s, CH2); 6.40 (2H, s,
NH2); 11.90 (1H, s, OH). 13C NMR spectrum, δ, ppm: 67.7
(C-6'); 138.6 (С-4); 144.4 (С-5'); 155.2 (С-3); 164.8 (С-3').
Mass spectrum, m/z (Irel, %): 184 [M+1]+ (1), 183 [M]+
(38), 126 (57), 98 (56), 96 (100), 71 (20), 69 (27), 68 (16),
54 (41), 53 (60), 43 [HCNO]+ (21), 42 [CNO]+ (55), 30
[NO]+ (91). Found, m/z: 184.0472 [M+H]+. C5H6N5O3.
Calculated, m/z: 184.0465.
1
542, 517, 498, 472, 410. H NMR spectrum, δ, ppm: 4.68
(2H, s, CH2); 6.14 (2H, s, NH2); 6.46 (2H, s, NH2); 12.10
(1H, s, NH). 13C NMR spectrum, δ, ppm: 26.1 (CH2); 137.4
(С-4); 154.4; 155.8 (С-3); 158.1; 159.6 (С-3'); 179.4 (С-5').
Mass spectrum, m/z (Irel, %): 282 [M+1]+ (1), 281 [M]+ (7),
224 (35), 129 (16), 128 (14), 116 (60), 86 (21), 85 (34), 70
(16), 58 (23), 45 (26), 43 [CHNO]+ (100), 42 [CNO]+ (25),
30 [NO]+ (35). Found, m/z: 282.0521 [M+H]+. C7H8N9O2S.
Calculated, m/z: 282.0516.
4-(5-{[(1-Methyl-1H-imidazol-2-yl)sulfanyl]methyl}-
1,2,4-oxadiazol-3-yl)-1,2,5-oxadiazol-3-amine (11d) was
obtained in the reaction of compound 4 with 1-methyl-
imidazole-2-thiol. Yield 1.92 g (69%), white amorphous
powder, mp 218–219°С. IR spectrum, ν, cm–1: 3463, 3353,
3178, 3135, 3112, 1854, 1627, 1595, 1462, 1407, 1283,
1175, 1132, 1028, 977, 862, 764, 746, 692, 490, 434.
1H NMR spectrum, δ, ppm: 3.52 (3H, s, CH3); 4.38 (2H, s,
CH2); 6.39 (2H, s, NH2); 6.97 (1H, s, CH); 7.26 (1H, s,
CH). 13C NMR spectrum, δ, ppm: 29.1 (CH2); 33.4 (CH3);
[3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5-yl]-
methanol (14). Amidoxime 1 (3.0 g, 21 mmol) was added
with stirring to PhMe (50 ml), then acetoxyacetyl chloride
(6.7 ml, 63 mmol) was added. The reaction mixture was
brought to a boil and heated under reflux for 8 h, then
cooled to room temperature, and evaporated under reduced
pressure. The residue was dissolved in MeOH (20 ml), H2O
(10 ml) and HCl (1 ml) were added, and the mixture was
heated under reflux for 2 h. The solvent was evaporated
under reduced pressure, the residue was recrystallized from
MeOH. Yield 2.6 g (68%), white powder, mp 161–162°С.
IR spectrum, ν, cm–1: 3468, 3382, 3321, 1642, 1583, 1557,
1467, 1434, 1400, 1376, 1243, 1211, 1155, 1090, 1028,
1019, 975, 906, 875, 766, 741, 579, 523, 465, 437.
1H NMR spectrum, δ, ppm: 4.88 (2H, s, CH2); 6.20 (1H, br. s,
ОН); 6.49 (2H, br. s, NH2). 13C NMR spectrum, δ, ppm:
55.6; 137.5 (С-4); 155.9 (С-3); 159.3 (С-3'); 180.9 (С-5').
Mass spectrum, m/z (Irel, %): 184 [M+1]+ (2), 183 [M]+
1240

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
(28), 126 (99), 69 [HNCNCO]+ (26), 58 [HNCNOH]+ (34),
3848, 3834, 3470, 3414, 3357, 3175, 2920, 2763, 2650,
2569, 1729, 1656, 1452, 1254, 1194, 1118, 972, 908, 875,
31 [CH2OH]+ (100), 30 [NO]+ (40), 28 [CHNH]+ (39).
Found, m/z: 184.0473 [M+H]+. C5H6N5O3. Calculated, m/z:
184.0465.
1
808, 726, 677, 538, 419. H NMR spectrum, δ, ppm: 4.67
(2H, s, CH2); 6.26 (2H, s, NH2); 6.57 (2H, s, NH2); 12.71
(1H, br. s, ОН). 13C NMR spectrum, δ, ppm: 70.9 (CH2);
140.0 (C-4); 144.5 (C=N); 154.9 (C-3); 171.5 (COOH).
Mass spectrum, m/z (Irel, %): 202 [M+1]+ (7), 201 [M]+
(89), 144 (40), 98 (100), 84 [H2NC2N2O]+ (18), 70 (26), 68
(40), 55 (52), 54 (36), 53 (38), 45 [COOH]+ (28), 43
[HNCNH2]+ (67), 42 [CNO]+ (26), 31 (21), 30 (67), 29
(30), 28 (55). Found, m/z: 202.0578 [M+H]+. C5H8N5O4.
Calculated, m/z: 202.0571.
Preparation of compound 17 from amidoxime 1. Ethyl
chloroacetate (2.60 g, 22 mmol) and K2CO3 (4.20 g,
30 mmol) were added to a solution of amidoxime 1 (2.86 g,
20 mmol) in DMF (20 ml). The reaction mixture was
stirred at 60°C for 5 h, then H2O (50 ml) was added. The
formed precipitate was filtered off, washed with H2O, and
dissolved in MeOH (20 ml). 5% Aqueous NaOH
(20 ml, 25 mmol) was added to the solution, the mixture
was heated to 40°C and stirred at this temperature for
15 min. The solvent was evaporated under reduced
pressure to 1/2 of the original volume and acidified with
concentrated HCl (pH 1). The formed precipitate was
filtered off and recrystallized from H2O. Yield 3.3 g (82%).
The analytical and spectral characteristics of compounds 17
obtained by different methods were identical.
N-{4-[5-(Methylamino)-6Н-1,2,4-oxadiazin-3-yl]-1,2,5-
oxadiazol-3-yl}acetamide (15). Concentrated H2SO4
(0.05 g, 1.0 mmol) was added to a solution of compound
12 (1.00 g, 5.1 mmol) in Ас2О (2 ml, 21.0 mmol). The
reaction mixture was stirred at room temperature for 24 h,
then MeOH (1 ml) was added. The formed precipitate was
filtered off and recrystallized from MeOH. Yield 0.89 g
(73%), white amorphous powder, mp 247–248°С.
IR spectrum, ν, cm–1: 3323, 3212, 2924, 1712, 1621, 1599,
1546, 1524, 1407, 1395, 1375, 1314, 1286, 1237, 1183,
1022, 996, 948, 898, 880, 847, 719, 681, 658, 605, 594,
1
533, 489. H NMR spectrum, δ, ppm (J, Hz): 2.17 (3H, s,
CH3); 2.92 (3H, d, J = 4.7, NHCH3); 4.28 (2H, s, CH2);
8.61 (1H, s, NH); 10.30 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 23.9 (COCH3); 27.4 (NHCH3); 61.5 (C-6'); 144.7
(С-4); 149.6 (С-3); 152.6 (С-5'); 159.4 (С-3'); 168.4
(C=O). Mass spectrum, m/z (Irel, %): 238 [M]+ (4), 139
(18), 57 (18), 56 (98), 55 (11), 53 (29), 46 (33), 44
[CH3NHCH2]+ (10), 43 [CH3CO]+ (40), 42 [CH2CO]+(54),
41 (24), 31 (34), 30 [NO]+ (100), 29 [CH2NH]+ (57), 27
[HCN]+ (24). Found, m/z: 239.0895 [M+H]+. C8H11N6O3.
Calculated, m/z: 239.0887.
N-[4-(5-Oxo-5,6-dihydro-4H-1,2,4-oxadiazin-3-yl)-1,2,5-
oxadiazol-3-yl]acetamide (16). Compound 13 (0.91 g,
5 mmol) and concentrated H2SO4 (0.05 g, 1 mmol) were
successively added with stirring to Ас2О (2 ml, 21 mmol).
The reaction mixture was stirred at 45–50°С for 30 min,
then MeOH (5 ml) was added, and the solvent was
evaporated under reduced pressure. The residue was
washed with H2O, hot (~60°C) MeOH (10 ml) was added,
followed by hot H2O dropwise (until crystallization
started), then cooled to room temperature. The precipitate
was filtered off and recrystallized from MeOH. Yield 0.63 g
(56%), white crystals, mp 231–232°С. IR spectrum, ν, cm–1:
3310, 3239, 3194, 3138, 3103, 1737, 1720, 1706, 1532,
1456, 1396, 1363, 1354, 1294, 1229, 1121, 1058, 1016,
999, 954, 914, 879, 852, 787, 664, 642, 602, 592, 583, 514.
1H NMR spectrum, δ, ppm: 2.14 (3H, s, CH3); 4.47 (2H, s,
CH2); 10.90 (1H, s, NH); 11.80 (1H, s, OH). 13C NMR
spectrum, δ, ppm: 23.4 (CH3); 67.2 (C-6'); 142.1 (С-4);
143.7 (С-5'); 149.9 (С-3); 165.3 (С-3'); 169.3 (C=O). Mass
spectrum, m/z (Irel, %): 225 [M]+ (2), 195 [M–NO]+ (29),
183 [M–CH2CO]+ (18), 153 (100), 126 (23), 96 (25),
43 [CH3CO]+ (26). Found, m/z: 226.0578 [M+H]+.
C7H8N5O4. Calculated, m/z: 226.0571.
({[Amino(4-amino-1,2,5-oxadiazol-3-yl)methylidene]-
amino}oxy)acetic acid (17). Compound 4 (2.0 g, 10 mmol)
was added to a solution of NaOH (1.2 g, 30 mmol) in
EtOH–H2O, 1:1 (50 ml). The reaction mixture was stirred
at 40°С for 3 h, then cooled to room temperature. The
solvent was evaporated under reduced pressure, the residue
was dissolved in H2O (10 ml) and acidified with
concentrated HCl (pH 1). The formed precipitate was
filtered off and recrystallized from H2O. Yield 0.63 g
(56%), white crystals, mp 191–192°С. IR spectrum, ν, cm–1:
[({(Acetylamino)[4-(acetylamino)-1,2,5-oxadiazol-3-yl]-
methylidene}amino)oxy]acetic acid (18). Compound 17
(1.00 g, 5 mmol) and concentrated H2SO4 (0.05 g, 1 mmol)
were successively added with stirring to Ас2О (2 ml, 2.16 g,
21 mmol). The reaction mixture was stirred at 45–50°С for
30 min, then H2O (5 ml) was added, and the solvent was
evaporated under reduced pressure. The residue was
washed with cold H2O (20 ml) and recrystallized from
MeOH. Yield 2.11 g (74%), white amorphous powder,
mp 210–211°С. IR spectrum, ν, cm–1: 3401, 3273, 2921,
2853, 1735, 1695, 1638, 1606, 1524, 1395, 1375, 1253,
1099, 1038, 903, 888, 747, 691, 674, 663, 588, 569, 502.
1H NMR spectrum, δ, ppm: 2.05 (3H, s, CH3); 2.08 (3H, s,
CH3); 3.35 (1H, br. s, COOH); 4.67 (2H, s, CH2); 10.64
(1H, s, NH); 10.91 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 23.0 (CH3); 23.1 (CH3); 71.3 (CH2); 136.5 (C-4);
145.0 (C=N); 150.3 (C-3); 169.1 (C=O); 169.2 (C=O);
170.8 (COOH). Mass spectrum, m/z (Irel, %): 285 [M]+ (2),
243 [M–CH2CO]+ (24), 154 (45), 153 (59), 126 (25), 98
(42), 96 (56), 70 (37), 69 (17), 55 (16), 54 (21), 53 (23), 43
[CH3CO]+ (100), 30 (38), 29 [CHO]+ (26). Found, m/z:
286.0790 [M+H]+. C9H12N5O6. Calculated, m/z: 286.0782.
4-[5-(Hydrazinylidenemethyl)-1,2,4-oxadiazol-3-yl]-
1,2,5-oxadiazol-3-amine (19). Hydrazine hydrate (9.2 g,
0.18 mol) was added with stirring at 35–40°С to a solution
of chloromethyl derivative 4 (16.0 g, 0.08 mol) in MeOH
(100 ml). After the exothermic reaction subsided, the
reaction mixture was stirred at 40°C for 30 min, then
evaporated under reduced pressure to 1/2 of the initial
volume. Hot (70–80°С) H2O (100 ml) was added and, with
stirring, cooled to room temperature. The precipitate was
filtered off, washed with H2O (2×50 ml) and recrystallized
1241

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
from AcOH. Yield 12.8 g (82%), white amorphous powder,
13C NMR spectrum, δ, ppm: 135.8; 137.4 (С-4); 155.9
(С-3); 159.7 (С-3'); 172.1 (С-5'). Mass spectrum, m/z
(Irel, %): 197 [M+1]+ (4), 196 [M]+ (35), 139 [M–NHCNO]+
(100), 30 [NO]+ (27). Found, m/z: 197.0427 [M+H]+.
C5H5N6O3. Calculated, m/z: 197.0418. Found, %: C 30.51;
H 2.14; N 42.71. C5H4N6O3. Calculated, %: C 30.62;
H 2.06; N 42.85.
mp 231–232°С. IR spectrum, ν, cm–1: 3469, 3367, 1633,
1599, 1553, 1465, 1385, 1367, 1309, 1262, 1151, 970, 928,
1
900, 862, 829, 769, 738, 575, 444. H NMR spectrum,
δ, ppm: 6.39 (2H, s, NH2); 7.67 (1H, s, СH); 8.93 (2H, s,
NH2). 13C NMR spectrum, δ, ppm: 117.3; 137.6 (С-4);
155.9 (С-3); 159.3 (С-3'); 174.9 (С-5'). Mass spectrum, m/z
(Irel, %): 196 [M+1]+ (1), 195 [M]+ (22), 138 (47), 69 (14),
53 (16), 43 [CH=NNH2]+ (100), 42 (30), 30 [NO]+ (26).
Found, m/z: 196.0585 [M+H]+. C5H6N7O2. Calculated, m/z:
196.0577. Found, %: C 30.62; H 2.64; N 50.43. C5H5N7O2.
Calculated, %: C 30.77; H 2.58; N 50.24.
4,4'-[1,2-Hydrazine-1,2-diylidenebis(methylylidene-
1,2,4-oxadiazole-5,3-diyl)]bis(1,2,5-oxadiazol-3-amine)
(22). Concentrated H2SO4 (0.05 g, 1 mmol) was added to a
solution of compound 19 (2.00 g, 10 mmol) in AcOH
(10 ml), and the mixture was heated under reflux for 2 h.
The reaction mixture was cooled to room temperature, the
precipitate was filtered off and recrystallized from AcOH.
Yield 0.93 g (52%), light-beige amorphous powder,
mp 286–287°С (decomp.). IR spectrum, ν, cm–1: 3454,
3326, 3296, 3216, 1630, 1535, 1519, 1424, 1387, 1373,
1351, 1303, 1236, 1175, 1153, 1006, 969, 810, 578, 561,
Synthesis of 4-(5-methyl-1,2,4-oxadiazol-3-yl)-1,2,5-
oxadiazol-3-amine (2b) from compound 19. Compound
19 (2.0 g, 10 mmol) was added to concentrated HCl
(10 ml). The reaction mixture was heated under reflux until
the starting compound was completely dissolved (about
18 h), then evaporated under reduced pressure. The residue
was dissolved in boiling H2O (20 ml). The solution was
cooled to 5°C, the precipitate was filtered off and
recrystallized from MeOH. Yield 0.7 g (42%). Analytical
and spectral characteristics were identical to those
described previously.14
1
467, 418. H NMR spectrum, δ, ppm: 6.51 (4H, s, 2NH2);
8.10 (2H, s, 2CH). 13C NMR spectrum, δ, ppm: 126.4;
137.3 (С-4); 155.9 (С-3); 159.9 (С-3'); 173.3 (С-5'). Mass
spectrum, m/z (Irel, %): 358 [M]+ (1), 328 [M–NO]+ (<1),
194 (60), 43 (100), 28 (30), 18 (25). Found, %: C 33.67;
H 1.95; N 46.75. C10H6N12O4. Calculated, %: C 33.53;
H 1.69; N 46.92.
4-{5-[(2-Phenylhydrazinylidene)methyl]-1,2,4-oxadiazol-
3-yl}-1,2,5-oxadiazol-3-amine (20). Phenylhydrazine
(3.4 g, 31 mmol) was added with stirring at room
temperature to a solution of chloromethyl derivative 4
(2.0 g, 10 mmol) in MeOH (100 ml). The reaction mixture
was brought to a boil and heated under reflux for 30 min,
then H2O (100 ml) was added, acidified with concentrated
HCl (pH 1) and left for 16 h. The formed precipitate was
filtered off, washed with H2O (2×50 ml), and recrystallized
from MeOH. Yield 1.2 g (44%), yellow amorphous
powder, mp 250–251°С. IR spectrum, ν, cm–1: 3465, 3344,
3272, 1638, 1588, 1556, 1512, 1497, 1446, 1397, 1359,
1338, 1262, 1197, 1176, 1156, 997, 969, 902, 891, 870,
N-{4-[5-(Hydrazinylidenemethyl)-1,2,4-oxadiazol-3-yl]-
1,2,5-oxadiazol-3-yl}acetamide (23). Compound 19 (1.00 g,
5 mmol) and concentrated H2SO4 (0.05 g, 1 mmol) were
successively added at room temperature to Ас2О (2 ml,
2.16 g, 21 mmol). The reaction was accompanied by a
noticeable exothermic effect, and a precipitate formed after
5 min. The reaction mixture was stirred at 45–50°С for
30 min, cooled to room temperature, the precipitate was
filtered off and recrystallized from MeOH. Yield 0.90 g
(76%), white amorphous powder, mp 226–227°С.
IR spectrum, ν, cm–1: 3398, 3222, 3166, 3033, 2934, 1698,
1592, 1531, 1369, 1315, 1254, 1158, 1129, 968, 910, 690,
1
785, 768, 758, 692, 643, 594, 506. H NMR spectrum,
1
δ, ppm: 6.50 (2H, s, NH2); 6.97–7.37 (5H, m, H Ph); 7.91
(1H, s, CH); 11.80 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 114.1 (С Ph); 118.7 (CH=N); 122.6 (С Ph); 130.0
(С Ph); 137.6 (С-4); 143.3 (С Ph); 155.9 (С-3); 159.6
(С-3'); 174.1 (С-5'). Mass spectrum, m/z (Irel, %): 273
[M+2]+ (1), 272 [M+1]+ (15), 271 [M]+ (96), 92 [C6H5NH]+
(26), 91 [C6H5N]+ (42), 77 [C6H5]+ (100), 65 (37), 39 (11).
Found, %: C 48.25; H 3.78; N 36.52. C11H9N7O2.
Calculated, %: C 48.71; H 3.34; N 36.15.
660, 596, 583. H NMR spectrum, δ, ppm: 2.12 (3H, s,
CH3); 8.08 (1H, s, CH); 11.20 (2H, s, NH2); 12.10 (1H, s,
NH). 13C NMR spectrum, δ, ppm: 23.2 (CH3); 126.3
(CH=N); 141.7 (С-4); 150.5 (С-3); 159.4 (С-3'); 169.8
(C=O); 173.3 (С-5'). Mass spectrum, m/z (Irel, %): 237 [M]+
(12), 236 [M–H]+ (100), 194 [M–CH3CO]+ (62), 167 (10),
111 (10), 43 (48) [CH3CO]+. Found, %: C 35.21; H 3.08;
N 41.62. C7H7N7O3. Calculated, %: C 35.45; H 2.97;
N 41.34.
4-{5-[(Hydroxyimino)methyl]-1,2,4-oxadiazol-3-yl}-
1,2,5-oxadiazol-3-amine (21). NH2OH·HCl (8.34 g,
0.12 mol) and NaHCO3 (12.60 g, 0.15 mol) were added to
a solution of compound 4 (10.00 g, 0.05 mol) in MeOH
(70 ml). The reaction mixture was stirred at 40–45°С for 8 h,
then H2O (100 ml) was added. The formed precipitate was
filtered off, washed with H2O (2×50 ml), and recrystallized
from AcOH. Yield 8.13 g (83%), white amorphous
powder, mp 182–183°С. IR spectrum, ν, cm–1: 3600, 3458,
3330, 3017, 2920, 2896, 1627, 1598, 1583, 1564, 1505,
1423, 1353, 1346, 1269, 1174, 1047, 998, 969, 912, 875,
N-(4-{5-[(Hydroxyimino)methyl]-1,2,4-oxadiazol-3-yl}-
1,2,5-oxadiazol-3-yl)acetamide (24) was obtained from
compound 21 (0.93 g, 5.3 mmol) by the method described
for furazan 23 synthesis at room temperature. Yield 0.85 g
(71%), light-yellow amorphous powder, mp 167–168°С.
IR spectrum, ν, cm–1: 3605, 3497, 3345, 3248, 1727, 1711,
1581, 1534, 1370, 1360, 1338, 1310, 1257, 1169, 1054,
1039, 1017, 1001, 970, 939, 826, 798, 768, 645, 596.
1H NMR spectrum, δ, ppm: 2.12 (3H, s, CH3); 8.48 (1H, s,
CH); 11.14 (1H, s, NH); 13.25 (1H, s, OH). 13C NMR
spectrum, δ, ppm: 23.2 (CH3); 135.9 (CH=N); 141.7 (С-4);
150.5 (С-3); 159.3 (С-3'); 169.8 (C=O); 172.1 (С-5'). Mass
spectrum, m/z (Irel, %): 239 [M+1]+ (2), 238 [M]+ (7), 210
1
822, 769, 580, 499, 447. H NMR spectrum, δ, ppm: 6.49
(2H, s, NH2); 8.47 (1H, s, CH); 13.30 (1H, s, OH).
1242

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
(17), 196 [M–CH2CO]+ (100), 139 (56), 72 (20), 43
2-{[3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-
5-yl]methylidene}hydrazinecarbothioamide (28) was
obtained from compound 19 (1.0 g, 5.0 mmol) and thio-
semicarbazide (0.6 g, 6.5 mmol) by the method described
for the synthesis of furazan 27. Yield 0.88 g (69%), light-
beige amorphous powder, mp 286–287°С (decomp.).
IR spectrum, ν, cm–1: 3445, 3394, 3320, 3279, 3173, 1633,
1615, 1597, 1511, 1469, 1428, 1355, 1275, 1176, 1127,
1061, 999, 968, 904, 875, 853, 788, 767, 629, 574, 482,
[CH3CO]+ (57), 30 [NO]+ (25). Found, m/z: 239.0515
[M+H]+. C7H7N6O4. Calculated, m/z: 239.0523.
4-{5-[(Methoxyimino)methyl]-1,2,4-oxadiazol-3-yl}-
1,2,5-oxadiazol-3-amine (25). Finely ground K2CO3 (1.40 g,
10 mol) was added to a solution of oxime 21 (1.00 g,
5 mmol) in DMF (40 ml), and Me2SO4 (0.88 g, 7 mmol)
was added with stirring at 15–20°С. The reaction mixture
was stirred at room temperature for 2 h and evaporated
under reduced pressure. H2O (50 ml) was added to the
residue, the formed precipitate was filtered off and
recrystallized from MeOH. Yield 0.81 g (68%), light-
yellow crystals, mp 118–119°С. IR spectrum, ν, cm–1:
3457, 3330, 3024, 2949, 1630, 1620, 1424, 1357, 1174,
1
403. H NMR spectrum, δ, ppm: 6.49 (2H, s, NH2); 8.16
(2H, s, NH2); 8.81 (1H, s, CH); 12.27 (1H, s, NH).
13C NMR spectrum, δ, ppm: 125.2 (N=CH); 137.3 (С-4);
156.0 (С-3); 159.8 (С-3'); 173.0 (С-5'); 179.6 (С=S). Mass
spectrum, m/z (Irel, %): 254 [M]+ (100), 199 (32), 194
[M–CNS]+ (45), 164 [M–CNS–NO]+ (26), 154 (20), 138
(29), 116 (40), 102 [H2NCSNHN=CH]+ (27), 85 (27), 60
(48), 53 (27), 42 [H2NCN]+ (15). Found, %: C 28.39;
H 2.53; N 43.97. C6H6N8O2S. Calculated, %: C 28.35;
H 2.38; N 44.08.
1
1063, 1003, 969, 936, 908, 873, 799, 578, 515. H NMR
spectrum, δ, ppm: 4.12 (3H, s, CH3); 6.50 (2H, s, NH2);
8.63 (1H, s, CH). 13C NMR spectrum, δ, ppm: 64.2
(OCH3); 136.4 (CH=N); 137.7 (С-4); 155.9 (С-3); 159.8
(С-3'); 172.1 (С-5'). Mass spectrum, m/z (Irel, %): 211
[M+1]+ (2), 210 [M]+ (15), 153 (100), 86 (25), 69 (14), 58
[HCNOMe]+ (29), 53 (14), 30 [NO]+ (24). Found,
m/z: 211.0581 [M+H]+. C6H7N6O3. Calculated, m/z:
211.0574.
5-(Hydrazinylidenemethyl)-3-(4-hydrazinyl-1,2,5-oxa-
diazol-3-yl)-1,2,4-oxadiazole (29). A solution of compound
6 (1.15 g, 5 mmol) in MeCN (5 ml) was added with stirring
at 20°С to a solution of hydrazine hydrate (1.20 g, 24 mmol)
in MeCN (30 ml). The reaction mixture was stirred at room
temperature for 1 h, diluted with H2O (50 ml). The precipitate
was filtered off and recrystallized from AcOH. Yield 0.87 g
(82%), white powder, mp 207–208°С (decomp.). IR spect-
rum, ν, cm–1: 3413, 3326, 3234, 2920, 2851, 1661, 1588,
1562, 1446, 1323, 1295, 1241, 1175, 1127, 995, 968, 948,
3-(4-Nitro-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazole (26)
was prepared using an oxidizing mixture, prepared from
36% aqueous H2O2 (4 ml, ~40 mmol) and 94−96% H2SO4
(5 ml, ~94 mmol), and 4-[5-(hydrazinylidenemethyl)-1,2,4-
oxadiazol-3-yl]-1,2,5-oxadiazol-3-amine (19) (2 g, 10 mmol)
by the method described for furazan 6 synthesis. Yield
0.98 g (54%), colorless roundish crystals. HPLC and
spectral characteristics of the compound match those
previously described.24 IR spectrum, ν, cm–1: 3430, 3138,
1609, 1564, 1539, 1505, 1422, 1408, 1307, 1270, 1116,
1035, 965, 910, 883, 823, 773, 742, 616, 586, 475, 418,
404. 1H NMR spectrum, δ, ppm: 10.1 (1H, s, CH).
13C NMR spectrum, δ, ppm: 141.1 (С-4); 156.5 (С-3');
160.0 (С-3); 169.2 (С-5'). Mass spectrum, m/z (Irel, %): 183
[M]+ (1), 137 [M–NO2]+ (2), 77 (22), 46 [NO2]+ (100), 38
(13), 30 [NO]+ (99).
2-{[3-(4-Amino-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-
5-yl]methylidene}hydrazinecarboxamide (27). Compound
19 (1.0 g, 5.0 mmol), semicarbazide hydrochloride (0.8 g,
7.2 mmol) were added to a mixture of АсОН (20 ml) and
concentrated HCl (10 ml). The reaction mixture was heated
under reflux for 8 h, H2O (50 ml) was added, and cooled to
room temperature. The precipitate was filtered off and
recrystallized from AcOH. Yield 0.8 g (62%), fine white
crystals, mp 282–283°С (decomp.). IR spectrum, ν, cm–1:
3488, 3438, 3373, 3287, 3231, 3194, 3103, 3013, 2921,
1707, 1639, 1619, 1586, 1439, 1421, 1356, 1307, 1192,
1000, 972, 919, 802, 736, 586, 508, 472. 1H NMR
spectrum, δ, ppm: 6.51 (2H, s, NH2); 6.80 (2H, s, NH2);
7.99 (1H, s, CH); 11.33 (1H, s, NH). 13C NMR spectrum,
δ, ppm: 123.0 (CH=N); 137.3 (С-4); 155.7 (C=O); 156.0
(С-3); 159.7 (С-3'); 173.2 (С-5'). Mass spectrum, m/z
(Irel, %): 238 [M]+ (4), 195 (13), 194 (100) [M–CONH2]+,
138 (26), 44 [H2NCO]+ (32), 43 [HNCO]+ (37), 42 (13).
Found, %: C 30.41; H 2.68; N 46.91. C6H6N8O3.
Calculated, %: C 30.26; H 2.54; N 47.05.
1
920, 882, 859, 825, 768, 429. H NMR spectrum, δ, ppm:
4.59 (2H, s, NH2); 7.31 (1H, s, NH); 7.68 (1H, s, NH); 8.97
(2H, s, NH2). 13C NMR spectrum, δ, ppm: 117.2 (C=N);
136.3 (С-4); 159.1 (С-3); 159.6 (С-3'); 174.9 (С-5'). Mass
spectrum, m/z (Irel, %): 210 [M]+ (2), 181 [M–NNH]+ (4),
138 [M–H2NNCNO]+ (12), 71 [HNN=CNO]+ (22), 69 (11),
43 [CH=NNH2]+ (100), 42 [CNO]+ (28), 31 [NHNH2]+
(18), 30 [NO]+ (42), 29 [CHO]+ (21), 28 (21). Found, m/z:
211.0693 [M+H]+. C5H7N8O2. Calculated, m/z: 211.0686.
5-(Hydrazinylidenemethyl)-3-{4-[2-(propan-2-ylidene)-
hydrazinyl]-1,2,5-oxadiazol-3-yl}-1,2,4-oxadiazole (30).
Compound 29 (0.7 g, 3.3 mol) was added to a mixture of
95% EtOH (10 ml), АсОН (1 ml), and acetone (1 ml,
9.0 mmol). The reaction mixture was stirred at 30–35°С for
5 h, then diluted with H2O (30 ml). The precipitate was
filtered off and recrystallized from MeOH. Yield 0.53 g
(64%), white amorphous powder, mp 213–214°С.
IR spectrum, ν, cm–1: 3414, 3313, 3216, 1619, 1586, 1571,
1430, 1369, 1311, 1229, 1156, 967, 921, 873, 768.
1H NMR spectrum, δ, ppm: 1.94 (3H, s, CH3); 1.98 (3H, s,
CH3); 7.69 (1H, s, N=CH); 8.69 (1H, NH); 9.01 (2H, s,
NH2). 13C NMR spectrum, δ, ppm: 16.7 (CH3); 29.0 (CH3);
117.1 (N=CH); 136.8 (С-4); 154.3 (N=CMe2); 155.0 (С-3);
159.1 (С-3'); 174.9 (С-5'). Mass spectrum, m/z (Irel, %): 251
[M+1]+ (12), 250 [M]+ (87), 221 (23), 220 (16), 191 (17),
176 (28), 138 (26), 98 (17), 83 (41), 71 [Me2CNNH]+ (21),
69 (16), 56 (87), 43 [CH=NNH2]+ (100), 42 [CNO]+ (72),
41 (43), 39 (23), 30 [NO]+ (51), 29 [CHO]+ (23), 28 (37).
Found, m/z: 251.1006 [M+H]+. C8H11N8O2. Calculated,
m/z: 251.0999.
1243

Chemistry of Heterocyclic Compounds 2019, 55(12), 1233–1244
22. Wang, B.; Xiong, H.; Cheng, G.; Zhang, Z.; Yang, H. New J.
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