Synthesis and some transformations of 2-[(4-aminofurazan-3-yl)-1H-1,2,4-triazol-5-yl]acetic acid derivatives

Article abstract of DOI:10.1007/s11172-018-2325-y

Two methods for the synthesis of 1,2,4-triazolylacetic ester bearing an aminofurazanyl substituent at the position 5 were developed. The triazole cycle was formed via the cyclocondensation of 3-aminofurazanecarboxylic acid hydrazide or amidrazone with ethoxycarbonylethyl acetimidate hydrochloride.

Full text of DOI:10.1007/s11172-018-2325-y

Russian Chemical Bulletin, International Edition, Vol. 67, No. 11, pp. 2035—2043, November, 2018
2035
Synthesis and some transformations of
2-[(4-aminofurazan-3-yl)-1H-1,2,4-triazol-5-yl]acetic acid derivatives*
N. S. Aleksandrova,a S. S. Semyakin,a A. A. Anisimov,b M. I. Struchkova,a and A. B. Sheremeteva
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: sab@ioc.ac.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation
Two methods for the synthesis of 1,2,4-triazolylacetic ester bearing an aminofurazanyl
substituent at the position 5 were developed. The triazole cycle was formed via the cyclocon-
densation of 3-aminofurazanecarboxylic acid hydrazide or amidrazone with ethoxycarbonyl-
ethyl acetimidate hydrochloride.
Key words: 1,2,4-triazole, furazan, cyclocondensation, single crystal X-ray diffraction.
The 1,2,4-triazole ring is widely applied as a structural
unit in the development of pharmaceuticals, herbicides,
and materials.1—4 A design of the new derivatives is usually
based on the functionalized molecules, the so-called build-
ing blocks, which possess several reaction centers. An
opportunity to involve these blocks in various reactions is
employed in the directed synthesis. The derivatives of
2-(3-R-1,2,4-triazol-5-yl)acetic acid are fairly efficient
building blocks.5—12 However, there was only the one such
compound reported, wherein the substituent R is an azolyl,
3,3´-bi(1,2,4-triazol-5-yl)-5,5´-diacetic acid.5
To continue our ongoing research on the synthesis of
1,2,4-triazoles linked with 1,2,5-oxadiazole (furazan)
ring,13 herein we report on the possible methods for
preparation of 2-[(3-furazan-3-yl)-1H-1,2,4-triazol-5-yl]-
acetic acids and some of their transformations, as well as
single crystal X-ray diffraction studies of the intermediate
and target products.
The reaction of hydrazide 1 with available ethoxycarbon-
ylacetimidate ethyl ester hydrochloride 2 in a boiling al-
cohol, i.e. under the conditions used for condensations of
2 earlier,5 led to a mixture of products (according to TLC
control, there were seven spots of similar intensity).
Fusion14 of hydrazide 1 with iminoester 2 resulted in an
inseparable resinified mixture. Our studies revealed that
the cyclocondensation between compounds 1 and 2 pro-
ceeds smoothly in the presence of triethylamine and
acetic acid in boiling acetonitrile. At the optimal ratio
between the reactants, triazolylacetic ester 3 was prepared
in the yield of 85% (Scheme 1). It should be noted that
the formation of side product 4 containing an 1,3,4-oxa-
diazole cycle was not observed under the found conditions.
The structure of triazole 3 was confirmed by spectral
methods and also unambiguously proved by the single
crystal X-ray diffraction. Compound 3 crystallized in the
form of four symmetrically independent molecules (A, A´,
A´´, and AA). Figure 1 shows a general view for one of the
independent molecules (A). In all the molecules, both
heterocycles are located at the same plane, and a relatively
weak intramolecular bond N(3)—H(3)…N(4) is formed
(Table 1). The carboxyl moiety is rotated with respect to
In 1959, it was shown that a convenient pathway to
1,2,4-triazole ring formation is the cyclocondensation
reaction of imino esters with acid hydrazides.14 However,
it was reported that this reaction in some cases resulted in
either 1,3,4-oxadiazoles instead of triazoles,15 or stopped
at the step of formation of linear products of the con-
densation, or was accompanied by an resinification.5
Amidrazones can be used as the alternative of acid hydr-
azides in the cyclization reaction with iminoesters, giving
the expected 1,2,4-triazoles.5 The both approaches were
utilized in this work.
O(1)
N(2)
N(6)
C(3)
C(8)
O(3)
C(5)
C(4)
C(6)
O(2)
N(1)
C(2)
C(7)
C(1)
The starting 3-aminofurazancarboxylic acid hydrazide
N(5)
(1) can be readily obtained from methyl ester of this acid.16
N(4)
N(3)
* Dedicated to Academician of the Russian Academy of Sciences
B. A. Trofimov on the occasion of his 80th birthday.
Fig. 1. Molecular structure of compound 3 with thermal ellip-
soids drawn at 50% probability level.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2035—2043, November, 2018.
1066-5285/18/6711-2035 © 2018 Springer Science+Business Media, Inc.

2036 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
Aleksandrova et al.
Scheme 1
Table 1. Parameters of intra- (IntraM) and intermolecular (InterM) hydrogen bonds (HB) in the structure of compound 3
Moiety
d/Å
ω/deg
N—H—N(O)
Symmetry
operation
HB
N—H
H…N(O)
N…N(O)
N(5)—H(5)…N(6″)
0.85(4)
0.75(4)
1.02(4)
0.92(4)
0.77(4)
0.81(4)
0.98(4)
0.80(4)
0.87(4)
0.99(4)
0.81(4)
0.87(4)
2.04(4)
2.51(4)
2.15(4)
1.90(4)
2.52(4)
2.32(4)
1.88(4)
2.51(4)
2.35(4)
1.86(4)
2.54(4)
2.11(4)
2.870(5)
3.016(5)
3.137(6)
2.812(5)
3.048(5)
3.098(6)
2.854(5)
3.024(6)
3.170(6)
2.831(5)
3.072(5)
2.977(5)
165(3)
127(3)
164(3)
171(3)
127(3)
161(3)
171(3)
124(3)
157(3)
164(3)
124(3)
175(3)
1 – x,1 – y,–z
x, y, z
InterM (A, A″)
IntraM
InterM (A, A)
InterM (A´, AA)
IntraM
InterM (A´, A″)
InterM (A″, A)
IntraM
N(3)—H(3A)…N(4)
N(3)—H(3B)…N(1)
1 – x, 2 – y,1 – z
x, y, z
N(5´)—H(5´)…N(6A)
N(3´)—H(3´A)…N(4´)
N(3´)—H(3´B)…N(1″)
N(5″)—H(5″)…N(6)
N(3″)—H(3″A)…N(4″)
N(3″)—H(3″)B…N(1´)
N(5A)—H(5A)…N(6´)
N(3A)—H(3AA)…N(4A)
N(3A)—H(3AB)…O(2´)
x, y, z
1 – x,1 – y,1 – z
2 – x, 1 – y, –z
x, y, z
1 – x,1 – y,1 – z
x + 1, y, z
x, y, z
2 – x,1 – y,–z
InterM (A″, A´)
InterM (AA, A´)
IntraM
InterM (AA, A´)
the plane of heterocycles so that the expected intramo-
lecular hydrogen bond N(5)—H(5)…O(2) is not formed.
Differences in O—N bond lengths of the furazan ring
obey the tendency discovered previously:17—19 the N—O
bond at a donor substituent is longer (Table 2).
Differences in the molecular structure of independent
molecules are due mainly to the orientation of carboxyl
moiety relative to the plane containing the heterocycles
(see Table 2).
In the each of four molecules, the hydrogen atom is
located at the N(5) atom of the triazole ring. Calculations
for three possible tautomers (the hydrogen atom at N(5),
N(4), or N(6) atoms)* demonstrated that the N(5)—H
tautomer is more favorable by 0.7 and 2.6 kcal mol–1 than
the N(4)—H and N(6)—H tautomers, respectively, which
* The numbering of nitrogen atoms corresponds to that shown
in Fig. 1.
Table 2. Selected bond lengths (d) and torsion angles (ϕ) of symmetrically independent molecules in the crystal
structure of compound 3
Molecule
d/Å
ϕ/deg
N(5)—C(4)—C(5)—C(6)
N(1)—O(1)
N(2)—O(1)
C(4)—C(5)—C(6)—O(2)
A
1.400(4)
1.400(4)
1.409(4)
1.404(4)
1.383(4)
1.379(4)
1.374(4)
1.374(4)
–50.8(5)
–67.6(5)
–79.4(4)
–90.7(15)
7.2(5)
163.8(4)
–19.2(5)
8(3)
A´
A″
AA*
* The angle values are given only for the major component of disordered moiety (see Experimental).

3-Aminofurazanyl-1,2,4-triazolylacetic acid
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
2037
could be due to the formation of the intramolecular
N(5)—H(5)…O(2) bond in the isolated molecule. However,
there was no such bond in the real crystal. Probably, the
formation of N(5)—H tautomer in the crystal is related to
its stabilization by a system of intermolecular hydrogen
bonds (see Table 1). It is important that the strongest
intermolecular H-bonds are formed between the sym-
metrically independent molecules, which can apparently
explain their formation. A similar situation is usually ob-
served in cocrystals, crystalline solvates, and crystals with
Z´ > 1 (see Refs 20—26).
C(6)
C(5)
O(2)
C(4)
N(5)
N(6)
C(3)
N(4)
N(2)
C(2)
C(7)
C(8)
O(3)
N(3)
O(1)
O(4)
C(10)
C(1)
N(1)
C(9)
Fig. 2. Molecular structure of compound 6 with thermal ellip-
soids drawn at 50% probability level.
of linear product (Scheme 2),27,28 whose yield depends
marginally on the heating time (1—4 h) and the concentra-
tion of reactants in the solvent, being of 31—37%. Accord-
ing to data reported in the literature, the reaction of
iminoesters with hydrazides can produce two types of
linear products as a result of substitution of (i) the imino
group in the iminoether,5 the product of type 6, or (ii)
ethoxy groups,12,14,29 the product of type 6´.
1
According to H and 13C NMR spectra, the product
contained two ethoxy groups, i.e. it was compound 6,
whose structure was also confirmed by the single crystal
X-ray diffraction. Compound 6 crystallized in the form of
two symmetrically independent molecules (A and A´)
possessing the similar structure (Fig. 2).
As in the case of compound 3, molecule 6 can hypo-
thetically be existed in the form of three tautomers. The
two most probable forms are shown below.
The condensation of amidrazone 5 with iminoester 2
in DMF or DMSO at ∼100 °C is stopped at the formation
Scheme 2

2038 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
Aleksandrova et al.
efficiency giving amide 8. N-Methylation of compound 3
with dimethyl sulfate in the presence of KOH occurred at
the N(1) and N(2) atoms of triazole ring (see Scheme 2)
providing a mixture of two isomeric products 9 and 10
(∼1 : 1) in the yield of 82%, which were separated chro-
matographically. While this reaction was carried out in the
presence of NaOH, the yield of methylation products was
almost two times decreased, but their ratio did not change.
The structure of isomers 9 and 10 was unambiguously
confirmed by 2D correlation spectroscopy of 1H—13C
HMBC NMR. The spectrum of compound 9 contains
a cross-peak of the hydrogen atoms of Me group with the
carbon atom of triazole ring at the furazanyl substituent,
while there was that with the carbon atom C—CH2CO2Et
in the case of compound 10.
The oxidation of amino group in compound 3 by the
KMnO4—HCl system used traditionally for the synthesis
of azofurazans30 led to the formation of azo compound 11
in the yield of 87%. It should be noted that during the
saponification of azo compound 11, there was observed
not only the expected reaction, but also a reduction of the
azo group. Thus, the azo group was reduced to an amino
group upon the treatment with an aqueous alkali, which
led to the formation of acid 7. In the case of hydrolysis by
aqueous HBr, the azo group was reduced to a hydrazo
group giving diacid 12 in the yield of 73% (see Scheme 3).
In conclusion, the condensation of aminofurazanecarb-
oxylic acid hydrazide with ethoxycarbonylethyl acetimid-
ate hydrochloride was demonstrated as the efficient
preparative method for 1,2,4-triazole-3-ethyl ester bearing
the aminofurazanyl substituent at the position 5. This
compound containing several reaction sites is the conve-
nient precursor for a target-oriented synthesis. More op-
portunities of its applications will be published in our
upcoming reports. It should be noted that in the last decade
there has been an intense growth of interest in compounds,
the framework of which is constructed from an ensemble
of azoles, including the furazan ring, which has in 2016
become the subject of comprehensive review.31 Since the
publication of this review, a number of furazan derivatives
combined with pyrazole,32 various oxadiazoles,33—37
triazole,38 and tetrazole39—43 rings has been obtained.
Compounds incorporating these structural combinations
According to the quantum chemical calculations, there
are two intramolecular H-bonds in the both forms (in the
crystal, only the N(3)—H(3A)…N(4) bond is observed)
(Table 3). While in the isolated state, the tautomer bearing
the amino group at the C=NN bond, the NH2-tautomer
(observed experimentally), is more energetically favorable
by 10.1 kcal mol–1 than the tautomer in which the proton
is located at the hydrazine nitrogen atom, the NH—N-
tautomer. As in compound 3, the N(1)—O(1) bond at the
NH2 group in the both independent molecules of com-
pound 6 is significantly longer (N(1)—O(1): 1.404(3),
N(2)—O(1): 1.372(3) Å in molecule A; N(1´)—O(1´):
1.409(3), N(2´)—O(1´): 1.377(3) Å in molecule A´). The
most strongly bound dimer in the crystal (due to the two
N(3)—H(1)…N(1´) and N(3´)—H(1´)…N(1) H-bonds)
is precisely formed between the symmetrically independent
molecules (see Table 3). At the same time, fairly strong
H-bonds were also observed for symmetrically dependent
molecules.
A reflux of the solution of compound 6 in acetic acid
for 8—10 h was accompanied by the cyclocondensation
leading to the formation of same triazole 3 in the yield of
28—30%. It should be noted that triazole 3 can be directly
prepared via the interaction of compound 5 with 2 in re-
fluxed acetic acid (see Scheme 2). The yield of triazole 3
did not exceed 20%, but it is greater than that of overall
reaction 5→6→3 (9—11%).
The saponification of ester 3 under both alkaline and
acidic conditions led smoothly to the formation of acid 7
in a practically quantitative yield (Scheme 3). The treat-
ment of ester 3 with aqueous ammonia was of the same
Table 3. Parameters of intra- (IntraM) and intermolecular (InterM) hydrogen bonds (HB) in the structure of compound 6
Moiety
d/Å
ω/deg
N—H—N(O)
Symmetry
operation
HB
N—H
H…N(O)
N…N(O)
N(3)—H(1)…N(1´)
N(3´)—H(1´)…N(1)
N(6)—H(3)…O(3)
N(6´)—H(3´)…O(3´)
N(3)—H(2)...N(4)
N(3´)—H(2´)...N(4´)
0.85(4)
0.95(4)
0.87(4)
0.87(4)
0.83(4)
0.85(4)
2.31(4)
2.23(4)
2.12(3)
2.26(3)
2.23(4)
2.32(4)
3.150(5)
3.114(5)
2.951(4)
3.048(4)
2.877(5)
2.894(5)
170(3)
154(3)
160(3)
151(3)
136(3)
125(3)
x, y – 1, z
x, y + 1, z
InterM (A, A´)
InterM (A´, A)
InterM (A, A)
InterM (A´, A´)
IntraM
2 – x,–y,1 – z
2 – x, 1 – y,2 – z
x, y, z
x, y, z
IntraM

3-Aminofurazanyl-1,2,4-triazolylacetic acid
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
2039
Scheme 3
temperature to a solution of methyl 3-amino-furazancarboxylate
(6.3 g, 0.044 mol) in methanol (150 mL). The reaction mixture
was stirred for 1 h and stored for 16 h, then evaporated to dryness.
The residue was recrystallized from water. Colorless crystalline
product 1 was isolated in the yield of 5.37 g (85%), m.p.
170 —171 °C. IR, ν/cm–1: 3426, 3355, 3333, 3158, 2962, 2887,
1699, 1683, 1630, 1559, 1536, 1491, 1427, 1361, 1328, 1217, 1124,
1004, 984, 952. 1H NMR (CDCl3), δ: 4.7 (br.s, 2 H, NNH2);
6.32 (s, 2 H, CNH2); 10.31 (br.s, 1 H, NH). 13C NMR (DMSO-d6),
δ: 140.0, 156.1, 157.1. MS (EI, 70 eV), m/z (Irel (%)): 143 [M]+
(113). Found (%): C, 25.26; H, 3.57; N, 48.88. C3H5N5O2
(143.11). Calculated (%): C, 25.18; H, 3.52; N, 48.94.
are considered promising materials. The design of more
advanced materials requires the development of new
methods and building blocks appropriate for their synthe-
sis. The compounds reported in this work will expand the
opportunities in the design of future materials.
Experimental
IR spectra were recorded on a Bruker ALPHA spectrometer
in KBr pellets. 1H, 13C, and 15N NMR spectra were recorded on
a Bruker AM-300 spectrometer (300, 75, and 51 MHz, respec-
tively) in DMSO-d6 or CDCl3. Chemical shifts in the NMR
spectra were determined with respect to solvent residual signals
(2.50 ppm for 1H and 39.5 ppm for 13C) or to the external stan-
dard, MeNO2, for 15N. Mass spectra were recorded on a Finnigan
MATINCOS 50 spectrometer (direct input, EI ionization, 70 eV).
High-resolution mass spectra (HRMS) were obtained using on
a Bruker MicroOTOFII instrument with electrospray ionization.
Elemental analysis was performed on a PerkinElmer Series II
2400 instrument. Melting points were determined in a Gallen-
kamp melting block without any corrections. The reaction
progress and purity of obtained compounds were monitored by
TLC on Sorbfil 60 F254 plates. The starting methyl ester and
amidrazone of 4-aminofurazan-3-carboxylic acid (5) were pre-
pared according to the known procedures.16,27,28
Ethyl 3-(4-aminoufurazan-3-yl)-1,2,4-triazol-5-acetate (3).
A. NEt3 (6.4 mL, 44.8 mmol) was added to a suspension of
iminoester hydrochloride 2 (9 g, 46 mmol) in acetonitrile (52 mL)
at 25 °C under stirring, and 30 min later, hydrazide 1 (5.44 g,
38 mmol) and acetic acid (1.15 mL, 20 mmol) were added to the
mixture. The resulting mixture was refluxed for 5 h, cooled, and
evaporated on a rotary evaporator. The dry residue was crystal-
lized from water to give colorless crystals of product 3 (7.7 g,
85%), Rf 0.3 (CCl4—MeCN, 3 : 1), m.p. 188—189 °C. IR, ν/cm–1
:
3508, 3466, 3406, 2989, 2943, 2818, 2755, 2704, 1733, 1626, 1597,
1465, 1395, 1369, 1324, 1220, 1183, 1063, 1026, 984, 874. 1H NMR
(DMSO-d6), δ: 1.19 (t, 3 H, Me, J = 6.7 Hz); 4.04 (s, 2 H,
CH2CO); 4.13 (m, 2 H, CH2Me); 6.43 (s, 2 H, NH2); 14.66
(s, 1 H, NH). 13C NMR (DMSO-d6), δ: 13.8, 32.1, 61.0, 139.2,
151.2, 151.5, 155.1, 167.8. MS (EI, 70 eV), m/z: 238 [M]+ 193,
181, 165, 153, 135, 107, 83. Found (%): C, 40.42; H, 4.27;
Hydrazide of 4-aminofurazan-3-carboxylic acid (1). Hydr-
azine hydrate (2.2 g, 0.044 mol) was added dropwise at room

2040 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
Aleksandrova et al.
N, 35.22. C8H10N6O3 (238.08). Calculated (%): C, 40.34;
H, 4.23; N, 35.28.
B. A solution of compound 6 (0.16 g, 0.56 mmol) in acetic
acid (3 mL) was refluxed for 8 h. The solvent was evaporated, the
residue was washed with water (0.5 mL) and crystallized from
water. Product 3 was isolated in the yield of 0.04 g (30%), m.p.
188—189 °C.
C. Similarly to method A, product 3 (0.11 g, 19%) identical
to the known sample was prepared from amidrazone 5 (0.36 g,
2.53 mmol) and iminoester 2 (0.5 g, 2.55 mol) in acetic acid
(5 mL).
in the yield of 0.16 g (52%), and then crystallized from water,
m.p. 264—265 °C. The product was identical to compound 7
obtained according to method A.
3-(3-Aminofurazan-4-yl)-1,2,4-triazole-5-acetamide (8).
Ester 3 (0.238 g, 1 mmol) was added to an aqueous solution of
ammonia (24%, 5 mL). The resulting suspension was stirred at
50 °C until the solution was formed (∼1 h). The reaction mixture
was evaporated on a rotary evaporator, and the dry residue was
recrystallized from water. Colorless amorphous product 8 was
obtained in the yield of 0.195 g (93%), m.p. 294—295 °C (de-
comp.). IR, ν/cm–1: 3459, 3346, 3305, 3202, 3051, 2975, 2934,
2812, 2755, 2909, 1677, 1636, 1594, 1560, 1471, 1428, 1393, 1332,
1270, 1176, 1131, 1064, 1014, 983, 866. 1H NMR (CDCl3), δ:
3.79 (s, 2 H, CH2); 6.41 (s, 2 H, NH2); 7.23 (s, 1 H, CONH);
7.72 (s, 1 H, CONH); 14.55 (br.s, 1 H, NH). 13C NMR
(DMSO-d6), δ: 33.3, 139.4, 150.5, 152.9, 155.2, 168.6. Found (%):
C, 34.52; H, 3.39; N, 46.82. C6H7N7O2 (209.17). Calculated (%):
C, 34.45; H, 3.37; N, 46.88.
Methylation of compound 3. A solution of KOH (0.56 g,
10 mmol) in abs. ethanol (17 mL) was added to a suspension of
triazole 3 (2 g, 8.4 mmol) in abs. ethanol (17 mL) under stirring.
Dimethyl sulfate (1.59 g, 12.6 mmol) was added to the resulting
solution. The reaction mixture was stirred under reflux for 3.5 h,
cooled, and poured into methylene chloride (400 mL). The re-
sulting solution was washed with brine (3×100 mL), dried over
MgSO4, and evaporated. The mixture of isomers 9 and 10 was
obtained in the yield of 1.74 g (82%). The isomers were sepa-
rated by column chromatography (SiO2 40/100, eluent was
CHCl3—CCl4, 1 : 1). Isomer 9 was eluted first from the column,
then 10.
Ethyl 3-[3-(4-aminofurazan-3-yl)-3-aminomethylidenehydr-
azono]-3-ethoxypropanoate (6). A mixture of iminoester 2 (0.59 g,
3 mmol) and amidrazone 5 (0.43 g, 3 mol) in DMSO (5 mL) was
heated at 100—105 °C for 2 h. The reaction mixture was cooled
and diluted with water (10 mL). The precipitate was filtered,
washed with water, dried in air, and recrystallized from ethanol.
Light cream product 6 was obtained in the yield of 0.27 g (31%),
Rf = 0.7 (CCl4—MeCN, 3 : 1), m.p. 102—103 °C. IR, ν/cm–1
:
3492, 3376, 2955, 1708, 1637, 1572, 1533, 1372, 1331, 1288, 1275,
1179, 1052, 1034, 1002. 1H NMR (DMSO-d6), δ: 1.14 (t, 3 H,
Me, J = 6.7 Hz); 1.26 (t, 3 H, Me, J = 6.8 Hz); 3.55 (s, 2 H,
CH2CO); 4.05 (d, 2 H, CH2Me, J = 6.9 Hz); 4.28 (d, 2 H,
CH2Me, J = 6.9 Hz); 6.41 (s, 2 H, NH2); 6.76 (s, 2 H, NH2).
13C NMR (DMSO-d6), δ: 13.7, 13.9, 36.2, 60.5, 62.4, 140.5,
147.5, 154.9, 161.0, 167.6. 15N NMR (DMSO-d6), δ: 33.6, –11.2,
–99.5, –114.7, –297.9, –328.2. Found (%): C, 42.31; H, 5.69;
N, 35.22. C8H10N6O3 (284.28). Calculated (%): C, 42.25;
H, 5.67; N, 35.16.
3-(3-Aminofurazan-4-yl)-1,2,4-triazole-5-acetic acid (7).
A. A suspension of ester 3 (2 g, 8.4 mmol) in aqueous (18 mL)
solution of NaOH (0.7 g, 17.5 mmol) was stirred at 70 °C for
1 h. The reaction mixture was cooled to 10 °C and acidified to
pH 3 with H2SO4 (20%). The formed precipitate was filtered off,
washed with water (2×5 mL), and dried in air. Product 7 was
isolated as a colorless amorphous solid in the yield of 1.69 g
(96%), m.p. 258—264 °C. After recrystallization from water, m.p.
was 264—265 °C. IR, ν/cm–1: 3478, 3461, 3342, 2938, 2706,
1742, 1706, 1632, 1596, 1468, 1421, 1396, 1332, 1278, 1237, 1189,
1128, 1064, 1016, 986, 935, 900, 872. 1H NMR (CDCl3), δ: 3.95
(s, 2 H, CH2); 6.41 (s, 2 H, NH2); 14.5 (br.s, 1 H, NH). 13C NMR
(DMSO-d6), δ: 32.4, 139.2, 150.5, 152.4, 155.2, 169.4. MS (EI,
70 eV), m/z (Irel (%)): 210 [M]+ (5), 166 (8), 153 (30), 135 (19),
109 (75), 44 (100). Found (%): C, 34.34; H, 2.90; N, 39.91.
C6H6N6O3 (210.15). Calculated (%): C, 34.29; H, 2.88; N, 39.99.
B. Ester 3 (0.5 g, 2.1 mmol) was suspended in aqueous HBr
(48%, 5 mL) and stirred with stirbar at room temperature. After
1 h, a homogeneous solution was formed, which was addition-
ally stirred for 24 h; this resulted in a suspension. Then the pH
of reaction mixture was adjusted to 3 with NaOH (10%) at 5 °C.
The formed precipitate was filtered off, washed with water
(3×5 mL), and dried in air. Product 7 was isolated in the yield of
0.42 g (96%), m.p. 259—260 °C. After recrystallization from
water, m.p. was 264—265 °C. The compound was identical to
the product obtained according to method A.
Ethyl {2-[5-(4-aminofurazan-3-yl)-1-methyl-1H-1,2,4-tri-
azol-3-yl]}acetate (9) was recrystallized from CHCl3/CCl4 to
give colorless amorphous solid (0.8 g, 37.8%), m.p.122—123 °C.
IR, ν/cm–1: 3402, 3292, 3247, 3214, 3187, 2957, 1737, 1636, 1572,
1500, 1446, 1409, 1402, 1371, 1336, 1286, 1211, 1185, 1095, 1079,
1055, 1040, 1022, 993, 907, 881, 861. 1H NMR (DMSO-d6),
δ: 1.19 (t, 3 H, Me, J = 7.0 Hz); 3.83 (s, 2 H, CH2CO); 4.11 (q,
2 H, OCH2Me, J = 7.0 Hz); 4.13 (s, 3 H, NCH3); 6.58 (s, 2 H,
NH2). 13C NMR (DMSO-d6), δ: 14.0, 33.9, 37.8, 60.8, 136.5,
142.9, 155.4, 156.9, 168.9. 15N NMR (DMSO-d6), δ: 32.5, –12.4,
–71.4, –122.6, –166.2, –329.0. MS (EI, 70 eV), m/z (Irel (%)):
252 [M]+ (3), 195 (12), 179 (5), 167 (3), 149 (19), 121 (100).
Found (%): C, 42.91; H, 4.82; N, 33.24. C9H12N6O3 (252.23).
Calculated (%): C, 42.86; H, 4.80; N, 33.32.
Ethyl {2-[3-(4-aminofurazan-3-yl)-5-methyl-5H-1,2,4-tri-
azol-5-yl]}acetate (10) was crystallized from CHCl3/CCl4 to give
colorless amorphous solid (0.82 g, 38.7%), m.p. 120—121 °C.
IR, ν/cm–1: 3476, 3311, 2989, 1706, 1627, 1598, 1525, 1483, 1457,
1399, 1375, 1335, 1214, 1157, 1094, 1021, 980, 901, 876, 869.
1H NMR (DMSO-d6), δ: 1.20 (t, 3 H, Me, J = 12.0 Hz); 3.94
(s, 3 H, NCH3); 4.14 (q, 2 H, OCH2Me, J = 12.0 Hz); 4.18
(s, 2 H, CH2CO); 6.40 (s, 2 H, NH2). 13C NMR (DMSO-d6), δ:
13.8, 31.7, 35.9, 61.2, 139.0, 149.7, 151.2, 155.2, 167.5. 15N NMR
(DMSO-d6), δ: 32.7, –11.6, –74.5, –121.7, –163.0, –329.9.
Found (%): C, 42.89; H, 4.84; N, 33.27. C9H12N6O3 (252.23).
Calculated (%): C, 42.86; H, 4.80; N, 33.32.
C. A suspension of azo compound 11 (0.348 g, 0.7 mmol) in
aqueous (3.1 mL) solution of NaOH (0.12 g, 3 mmol) was
heated to 70 °C and stirred at this temperature for 2 h. The reac-
tion mixture was cooled to 10 °C and acidified to pH 3 with H2SO4
(20%). The formed precipitate was filtered off, washed with
water, and dried in air. A colorless amorphous solid was isolated
4,4´-Bis(3-ethoxycarbonylmethyl-1,2,4-triazol-5-yl)azofur-
azan (11). A solution of KMnO4 (1.26 g, 8 mmol) in water (50 mL)
was added dropwise at room temperature and under vigorous
stirring to a suspension of compound 3 (2.4 g, 10 mmol) in
a mixture of conc. HCl (10 mL) and water (20 mL). The reaction

3-Aminofurazanyl-1,2,4-triazolylacetic acid
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
2041
Table 4. Crystallographic data and X-ray diffraction experiment parameters for compounds 3 and 6
Parameter
Compound 3
Compound 6
Formula
C8H10N6O3
238.22
C10H16N6O4
284.29
Molecular weight
Crystal system
Tricl–inic
Tricl–inic
Space group
P1
P1
a/Å
9.692(4)
14.133(6)
16.144(6)
85.798(9)
75.141(9)
88.914(9)
2131.8(15)
8
7.9614(14)
9.5073(17)
19.959(4)
82.080(3)
78.880(3)
65.541(3)
1346.5(4)
4
b/Å
c/Å
α/deg
β/deg
γ/deg
V/Å3
Z
dcalc/g cm–3
1.484
1.402
Absorption coefficient μ/mm–1
F(000)
0.118
0.111
992
600
θ range for the data collection/deg
The number of reflections
measured
independent (Rint
with I ≥ 2σ(I)
1.88—27.00
1.04—26.19
20807
9299 (0.1026)
4089
4898
4898 (0.1028)
2965
)
The number of refined parameters
Completeness of a dataset (%)
736
99.9
0.949
0.0691
0.1720
394
96.1
1.085
0.0889
0.1862
GOOF
Convergent reliability index (R1(F))a [I ≥ 2σ(I)]
Convergent reliability index (wR2(F2)b [all data]b
Residual electron density (ρmax/ρmin)/e Å3
0.489/–0.332
0.309/–0.345
a R1 = ∑ |Fo – |Fc||/∑(Fo); b wR2 = (∑[w(Fo2 – Fc2)2]/∑[w(Fo2)2 ]1/2
.
mixture after 2 h was discolored with oxalic acid and extracted
with ethyl acetate (5×50 mL). The combined extracts were washed
with brine (2×25 mL), dried over MgSO4, and evaporated. The
residue was recrystallized from MeCN to give yellow product 11
(2 g, 86%), m.p. 203—204 °C. Rf 0.3 (CCl4 : MeCN, 3 : 1). IR,
ν/cm–1: 3128, 2991, 1738, 1726, 1439, 1372, 1335, 1299, 1216,
1138, 1032, 990, 982, 933, 844. 1H NMR (CDCl3), δ: 1.18 (br.s,
3 H, Me); 4.05 (br.s, 2 H, CH2); 4.13 (br.m, 2 H, CH2); 14.76
(br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 13.8, 32.3, 61.2, 143.9,
148.4, 152.9, 161.9, 168.0. HRMS: found, m/z 473.1381 [M + H]+;
C16H16N12O6; calculated, m/z 473.1394. Found (%): C, 40.75;
H, 3.44, N, 35.49. C16H16N12O6 (472.38). Calculated (%):
C, 40.68; H, 3.41; N, 35.58.
1,2-Bis(3-(1H-3-carboxymethyl-1,2,4-triazol-5-yl)furazan-
4-yl)hydrazine (12). Azo compound 11 (0.4 g, 0.84 mol) was
stirred in aqueous HBr (48%, 5 mL) at 30—40 °C. The solution
was being gradually formed. The reaction mixture was stirred for
3 days and cooled to 5 °C; the precipitate was filtered off, washed
with water, and dried in air. Product 12 was obtained in the yield
of 0.26 g (73%), m.p. 154—155 °C. IR, ν/cm–1: 3449, 3281, 3229,
3088, 1717, 1582, 1551, 1290, 1221, 1190, 1056, 1030, 948, 915.
1H NMR (CDCl3), δ: 3.97 (s, 3 H, CH2); 6.2 (br.s, NH + H2O);
8.74 (br.s, 1 H, NH). 13C NMR (DMSO-d6), δ: 32.4, 138.7,
149.9, 152.6, 156.3, 169.3. HRMS: found, m/z: 419.0919 [M + H]+;
X-ray diffraction analysis of compounds 3 and 6 was perform-
ed on an APEX II CCD diffractometer (λ(Mo-Kα) = 0.71073 Å,
graphite monochromator, ω-scan) at 120 K. The structures were
solved by the direct method and refined using the full-matrix
least-squares on F2hkl in the anisotropic approximation for non-
hydrogen atoms. Hydrogens at the N atoms were located in
a difference electron density maps and refined in the isotropic
approximation. The other hydrogen atoms were added geo-
metrically. The major parameters of crystal structure are given
in Table 4. The ester moiety of compound 3 in all the four sym-
metrically independent molecules is partially or completely
disordered. The detailed information is provided in the CIF file.
The both structures are deposited with the Cambridge Crystallo-
graphic Data Centre CCDC 1861870 and 1861871 for compounds
3 and 6, respectively, and available at www.ccdc.cam.ac.uk.
Calculation procedure. The molecules of compounds 3 and
6 were optimized using GAUSSIAN03 software package44 at the
M052X/6-311G(df,pd) approximation. The adequacy of this
approximation for the calculation of structure and energy of
various nitrogenous heterocycles was reported in a number of
works.45—48 The calculated electron density distribution was
analyzed within the framework of theory of R. Bader "Atoms in
molecules"49 using the AIMALL program.50 To estimate the
energy of contacts, its correlation with the potential energy den-
sity V(r) at the critical point of bond (Eint = ½V(r))51,52 was used,
which is useful for the analysis of various types of interac-
tions.53—56
C
12H11N12O6; calculated, m/z 419.0924. Found (%): C, 34.52;
H, 2.47; N, 40.11. C12H10N12O6 (418.29). Calculated (%):
C, 34.46; H, 2.41; N, 40.18.

2042 Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
Aleksandrova et al.
24. K. Yu. Suponitsky, N. I. Burakov, A. L. Kanibolotsky, V. A.
Mikhailov, J. Phys. Chem. A, 2016, 120, 4179.
25. A. A. Gidaspov, V. A. Zalomlenkov, V. V. Bakharev, V. E.
Parfenov, E. V. Yurtaev, M. I. Struchkova, N. V. Palysaeva,
K. Yu. Suponitsky, D. B. Lempertd, A. B. Sheremetev, RSC
Adv., 2016, 6, 34921.
26. A. B. Sheremetev, V. L. Korolev, A. A. Potemkin, N. S.
Aleksandrova, N. V. Palysaeva, T. H. Hoang, V. P. Sinditskii,
K. Yu. Suponitsky, Asian J. Org. Chem., 2016, 5, 1388.
27. V. G. Andrianov, A. V. Eremeev, Chem. Heterocycl. Compd.
(Engl. Transl.), 1994, 30, 608.
This work was financially supported by the Russian
Science Foundation (Project No. 14-13-01153). The
authors are grateful to the Center of Structural Research
at the A. N. Nesmeyanov Institute of Organoelement
Compounds of the Russian Academy of Sciences for the
provided equipment for X-ray investigations of compounds
3 and 6.
References
28. A. I. Stepanov, V. S. Sannikov, D. V. Dashko, A. G. Roslya-
kov, A. A. Astrat´ev, E. V. Stepanova, Chem. Heterocycl.
Compd. (Engl. Transl.), 2015, 51, 350.
29. N. Y. Khromova, M. M. Fedorov, S. I. Malekin, F. V. Kutkin,
Russ. J. Org. Chem., 2016, 52, 1490.
30. Y. Qu, S. P. Babailov, J. Mater. Chem. A, 2018, 6, 1915.
31. L. L. Fershtat, N. N. Makhova, Russ. Chem. Rev., 2016,
85, 1097.
1. V. A. Ostrovskii, M. S. Pevzner, T. P. Kofman, M. B.
Shcherbinin, I. V. Tselinskii, Targets Heterocycl. Syst., 1999,
3, 467.
2. A. Moulin, M. Bibian, A.-L. Blayo, S. El Habnouni, J. Mart-
inez, J.-A. Fehrentz, Chem. Rev., 2010, 110, 1809.
3. A. Diaz-Ortiz, P. Prieto, J. R. Carrillo, R. Martin, I. Torres,
Curr. Org. Chem., 2015, 19, 568.
4. A. Ayati, S. Emami, A. Foroumadi, Eur. J. Med. Chem., 2016,
109, 380.
5. V. V. Kiseleva, A. A. Gakh, A. A. Faynzil´berg, Bull. Acad.
Sci. USSR, Div. Chem. Sci., 1990, 39, 1888.
6. T. P. Kofman, T. A. Uvarova, G. Y. Kartseva, Russ. J. Org.
Chem., 1995, 31.
32. A. V. Kormanov, D. L. Lipilin, T. K. Shkineva, I. A. Vatsadze,
A. M. Kozeev, I. L. Dalinger, Chem. Heterocycl. Compd.
(Engl. Transl.), 2017, 53, 876.
33. P. F. Pagoria, M.-X. Zhang, N. B. Zuckerman, A. J. DeHope,
D. A. Parrish, Chem. Heterocycl. Compd. (Engl. Transl.), 2017,
53, 760.
7. V. Chernyshev, A. Chernysheva, V. Taranushich, Russ. J. Appl.
Chem., 2009, 82, 276.
8. A. S. Kiselyov, E. L. P. Chekler, N. B. Chernisheva, L. K.
Salamandra, V. V. Semenov, Tetrahedron Lett., 2009, 50, 3809.
9. A. A. Dippold, T. M. Klapotke, Z. Anorg. Allg. Chem., 2011,
637, 1453.
34. L. L. Fershtat, I. V. Ovchinnikov, M. A. Epishina, A. A.
Romanova, D. B. Lempert, N. V. Muravyev, N. N. Makhova,
ChemPlusChem, 2017, 82, 1315.
35. N. A. Troitskaya-Markova, O. G. Vlasova, T. I. Godovikova,
S. G. Zlotin, O. A. Rakitin, Mendeleev Commun., 2017,
27, 448.
10. A. A. Dippold, T. M. Klapotke, Chem. Eur. J., 2012, 18, 16742.
11. J. Zhang, S. Dharavath, L. A. Mitchell, D. A. Parrish, J. M.
Shreeve, J. Am. Chem. Soc., 2016, 138, 7500.
12. D. M. Khomenko, R. O. Doroshchuk, O. V. Vashchenko,
R. D. Lampeka, Chem. Heterocycl. Compd. (Engl. Transl.),
2016, 52, 402.
13. S. S. Semyakin, M. I. Struchkova, A. B. Sheremetev, Chem.
Heterocycl. Compd. (Engl. Transl.), 2016, 52, 346.
14. I. Ya. Postovskii, N. N. Vereshchagina, J. Gen. Chem. USSR,
1959, 29.
15. H. Weidinger, J. Kranz, Chem. Ber., 1963, 96, 1049.
16. A. B. Sheremetev, N. S. Aleksandrova, D. E. Dmitriev, B. B.
Averkiev, M. Yu. Antipin, J. Heterocycl. Chem., 2005, 42, 519.
17. K. Yu. Suponitsky, K. A. Lyssenko, M. Yu. Antipin, N. S.
Aleksandrova, A. B. Sheremetev, T. S. Novikova, Russ. Chem.
Bull., 2009, 58, 2129.
36. R. Duddu, J. Hoare, P. Sanchez, R. Damavarapu, D. Parrish,
J. Heterocyclic Chem., 2017, 54, 3087.
37. Q. Sun, C. Shen, X. Li, Q. Lin, M. Lu, J. Mater. Chem. A,
2017, 5, 11063.
38. Z. Xu, G. Cheng, H. Yang, X. Ju, P. Yin, J. Zhang, J. M.
Shreeve, Angew. Chem., Int. Ed., 2017, 56, 5877.
39. V. N. Kizhnyaev, T. V. Golobokova, F. A. Pokatilov,
L. I. Vereshchagin, Y. I. Estrin, Chem. Heterocycl. Compd.
(Engl. Transl.), 2017, 53, 682.
40. B.-D. Wu, X.-Y. Li, J. Liang, X.-H. Geng, H.-S. Huang,
H. Huang, J.-Y. Wang, W.-H. Hu, Polyhedron, 2018, 139, 148.
41. A. I. Stepanov, V. S. Sannikov, D. V. Dashko, A. G. Roslya-
kov, A. A. Astrat´ev, E. V. Stepanova, Chem. Heterocycl.
Compd. (Engl. Transl.), 2017, 53, 746.
42. A. I. Stepanov, V. S. Sannikov, D. V. Dashko, A. G. Roslyakov,
A. A. Astrat´ev, E. V. Stepanova, Z. G. Aliev, T. K. Goncha-
rov, S. M. Aldoshin, Chem. Heterocycl. Compd. (Engl. Transl.),
2017, 53, 779.
43. V. V. Parakhin, N. I. Shlykova, O. A. Luk´yanov, Russ. Chem.
Bull., 2017, 66, 320.
44. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery, K. N.
Kudin, Jr., J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jara-
millo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Moro-
kuma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G.
18. A. B. Sheremetev, N. S. Aleksandrova, N. V. Palysaeva, M. I.
Struchkova, V. A. Tartakovsky, K. Y. Suponitsky, Chem. Eur.
J., 2013, 19, 12446.
19. A. B. Sheremetev, B. V. Lyalin, A. M. Kozeev, N. V. Palysaeva,
M. I. Struchkova, K. Y. Suponitsky, RSC Adv., 2015, 5, 37617.
20. C. B. Aakeröy, J. Desper, M. Fasulo, I. Hussain, B. Levin,
N. Schultheiss, CrystEngComm, 2008, 10, 1816.
21. A. B. Sheremetev, N. V. Palysaeva, M. I. Struchkova, K. Yu.
Suponitsky, M. Yu. Antipin, Eur. J. Org. Chem., 2012, 2266.
22. K. Y. Suponitsky, K. A. Lyssenko, I. V. Ananyev, A. M.
Kozeev, A. B. Sheremetev, Cryst. Growth Des., 2014, 14, 4439.
23. I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, A. V. Korma-
nov, M. I. Struchkova, K. Yu. Suponitsky, A. A. Bragin, K. A.
Monogarov, V. P. Sinditskii, A. B. Sheremetev, Chem. Asian
J., 2015, 10, 1987.

3-Aminofurazanyl-1,2,4-triazolylacetic acid
Russ. Chem. Bull., Int. Ed., Vol. 67, No. 11, November, 2018
2043
Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Pis-
korz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A.
Al-Laham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gon-
zalez, J. A. Pople, Gaussian 03, Revision E.01, Gaussian, Inc.,
Wallingford, 2004.
50. T. A. Keith, AIMAll, Version 14.11.23. TK Gristmill Software,
Overland Park KS, USA, 2014 (http://aim.tkgristmill.com).
51. E. Espinosa, I. Alkorta, I. Rozas, J. Elguero, E. Molins, Chem.
Phys. Lett., 2001, 336, 457.
52. E. Espinosa, E. Molins, C. Lecomte, Chem. Phys. Lett., 1998,
285, 170.
53. K. A. Lyssenko, Mendeleev Commun., 2012, 22, 1.
54. A. O. Dmitrienko, V. A. Karnoukhova, A. A. Potemkin, M. I.
Struchkova, I. A. Kryazhevskikh, K. Yu. Suponitsky, Chem.
Heterocycl. Compd. (Engl. Transl.), 2017, 53, 532.
55. K. Yu. Suponitsky, A. E. Masunov, M. Yu. Antipin, Mende-
leev. Commun., 2008, 18, 265.
45. J. Sponer, K. E. Riley, P. Hobza, PCCP, 2008, 10, 2595.
46. K. Y. Suponitsky, A. E. Masunov, M. Y. Antipin, Mendeleev
Commun., 2009, 311.
47. I. L. Dalinger, A. Kh. Shakhnes, K. A. Monogarov, K. Yu.
Suponitsky, A. B. Sheremetev, Mendeleev Commun., 2015,
25, 429.
56. I. L. Dalinger, K. Yu. Suponitsky, T. K. Shkineva, O. B.
Lempert, A. B. Sheremetev, J. Mater. Chem. A, 2018, 6, 14780.
48. I. L. Dalinger, A. V. Kormanov, K. Yu. Suponitsky, N. V.
Muravyev, A. B. Sheremetev, Chem. Asian J., 2018, 13, 1165.
49. R. F. W. Bader, Atoms in Molecules. A Quantum Theory,
Clarendon Press, Oxford, 1990.
Received July 31, 2018;
in revised form August 28, 2018;
accepted September 2, 2018