Rapid Boulton–Katritzky rearrangement of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles upon exposure to water and HCl

Article abstract of DOI:10.1007/s10593-018-2321-z

[Figure not available: see fulltext.] Сhemical stability of 3-(2-aminoethyl)-5-substituted 1,2,4-oxadiazoles was studied with respect to Boulton–Katritzky rearrangement, which is known to produce planar pyrazolines and pyrazoles upon heating in DMF at 150°C or without solvent at 240°C. The reactivity of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles in one type of Boulton–Katritzky rearrangement was observed at room temperature in H₂O, DMF + H₂O, and in the presence of HCl. Hydrolysis of 3,5-disubstituted 1,2,4-oxadiazoles under the first two conditions gave 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium benzoates, while the action of HCl on 3,5-disubstituted 1,2,4-oxadiazoles produced their hydrochlorides along with 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium chloride hydrate. Thus, the reaction afforded spiropyrazoline compounds instead of products with a planar structure.

Full text of DOI:10.1007/s10593-018-2321-z

DOI 10.1007/s10593-018-2321-z
Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
Rapid Boulton–Katritzky rearrangement
of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles
upon exposure to water and HCl
Lyudmila A. Kayukova1*, Asem B. Uzakova1, Anna V. Vologzhanina2,
Kydyrmolla Akatan3, Esbol Shaymardan3, Sana K. Kabdrakhmanova3
1 A. B. Bekturov Institute of Chemical Sciences,
106 Shokan Ualikhanov St., Almaty 050010, Kazakhstan; е-mail: lkayukova@mail.ru
2 A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 Vavilov St., В-334, Moscow 119991, Russia; е-mail: vologzhanina@mail.ru
3 S. Amanzholov East Kazakhstan State University,
18/1 Amurskaya St., Ust-Kamenogorsk 070002, Kazakhstan; е-mail: ahnur.hj@mail.ru
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(6), 643–649
Submitted July 21, 2017
Accepted after revision March 1, 2018
Сhemical stability of 3-(2-aminoethyl)-5-substituted 1,2,4-oxadiazoles was studied with respect to Boulton–Katritzky rearrangement,
which is known to produce planar pyrazolines and pyrazoles upon heating in DMF at 150°C or without solvent at 240°C. The reactivity
of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles in one type of Boulton–Katritzky rearrangement was observed at room
temperature in H2O, DMF + H2O, and in the presence of HCl. Hydrolysis of 3,5-disubstituted 1,2,4-oxadiazoles under the first two
conditions gave 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium benzoates, while the action of HCl on 3,5-disubstituted 1,2,4-oxadiazoles
produced their hydrochlorides along with 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium chloride hydrate. Thus, the reaction afforded
spiropyrazoline compounds instead of products with a planar structure.
Keywords: 5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles, spiropyrazolines, Boulton–Katritzky rearrangement, hydrolysis, tendency
to regroup.
Scheme 1
Our recent interest in 3,5-substituted 1,2,4-oxadiazoles
has been motivated by their local anesthetic and
antituberculosis properties,1,2 as well as by some evidence
of their antidiabetic activity.3 Thus, the chemical stability
of 1,2,4-oxadiazoles is an area of increased interest. The
conversion of these heterocycles via Boulton–Katritzky
rearrangement, which depends on structural and external
factors, has been actively studied. Mononuclear hetero-
cyclic Boulton–Katritzky rearrangement occurs upon heating
according to the scheme ABD → XYZ (Scheme 1).4
Substituted 1,2,4-oxadiazoles undergo the Boulton–
Katritzky rearrangement under forcing conditions (in DMF
at 150°C or without solvent at 240°C), forming pyrazolines
and pyrazoles with planar structures.5 The electronic
A
X
A
B
B
D
X
Y
Y
Z
NH
N
H
H
D
Z
NHCOR2
N
O
R2
N
R1
NH
NH
N
N
R1
NHCOR2
N
O
R2
N
R1
N
N
R1
R1, R2 = H, alkyl, aryl
0009-3122/18/54(6)-0643©2018 Springer Science+Business Media, LLC
643

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
properties of aromatic substituents have been reported to
affect the Boulton–Katritzky rearrangement of 3-(2-amino-
aryl)-1,2,4-oxadiazoles to 3-(acylamino)-1H-indazoles to
the same extent as the thermal conditions. To avoid the
effects of thermal factors in the preparation of rearranged
3-(acylamino)-1H-indazoles, reaction conditions including
microwave irradiation have been used.6 Thermal
rearrangement of N-(1,2,4-oxadiazol-3-yl)hydrazones to
1,2,4-triazole derivatives provided the first example of a
triatomic side chain rearrangement involving the NNC
sequence of atoms attached to the C-3 atom of 1,2,4-oxa-
diazoles. The reactions were performed in the absence of
solvents and gave high yields of the final products.7
Conversion of the (Z)-hydrazone of 3-benzoyl-5-phenyl-
1,2,4-oxadiazole into the respective triazole was experi-
mentally investigated in aqueous dioxane over the pS+
range of 5.5(5)–13.9 (pS+ is an operational proton concen-
tration scale used in dioxane–water).8a The uncatalyzed
reaction was examined by quantum-chemical calculations
according to DFT, using a model system formed by the
(Z)-hydrazone of 3-formyl-1,2,4-oxadiazole and one or two
water molecules. The solvent effects were taken into
account by using COSMO (conductor-like screening
model) ‒ a continuum model approach for determining the
electrostatic interaction of a molecule with solvent.8b The
course of photochemical Boulton–Katritzky rearrangement
was examined depending on structural modifications in the
substrate molecules ((E)- or (Z)-isomers of the aryl-
hydrazones), the influence of substituents in the aryl-
hydrazone moiety, and the substituents at the C-5 atom of
the 1,2,4-oxadiazole ring.9
Figure 1. Series of 5-aryl-3-(2-amino)ethyl-1,2,4-oxadiazoles.
During our attempts to obtain hydrochlorides of 5-aryl-
3-[2-(thiomorpholin-1-yl)ethyl]-1,2,4-oxadiazoles and to
grow a single crystal for performing X-ray structural
analysis of 5-phenyl-3-[2-(4-phenylpiperazin-1-yl)ethyl]-
1,2,4-oxadiazole by prolonged keeping in 2-PrOH in the
presence of air moisture we occasionally observed the lability
of the investigated 1,2,4-oxadiazoles (Scheme 2).17,18 Thus,
3-(2-aminoethyl)-5-aryl-1,2,4-oxadiazoles having tertiary
amino groups at the β-position of substituent located at the
ring position 3 were capable of rearranging to spiro-
pyrazoline compounds. These transformations provided the
first examples of spiro compound formation through such
rearrangements and could be regarded as a variety of
Boulton–Katritzky rearrangement.
Scheme 2
The rearrangement rates of eleven (Z)-arylhydrazones
derived from 5-amino-3-benzoyl-1,2,4-oxadiazole into the
respective (2-aryl-5-phenyl-2H-1,2,3-triazol-4-yl)ureas were
determined in toluene and in aqueous dioxane in the
presence of trichloroacetic acid or piperidine at 40°C. The
results of acidic catalysis by trichloroacetic acid in both
solvents were correlated with the effects of aryl sub-
stituents according to the Ingold–Yukawa–Tsuno correla-
tion. When base catalysis by piperidine was used in toluene
or aqueous dioxane, a Hammet correlation was observed.10
A variation of the Boulton−Katritzky rearrangement
involving the use of a CNC side chain has been reported,
where 3-benzoyl-1,2,4-oxadiazole imines in the presence of
strong base afforded novel 4(5)-acylaminoimidazoles.11
Previously, we synthesized a series of 5-aryl-3-(2-amino-
ethyl)-1,2,4-oxadiazoles (Fig. 1). These compounds were
apparently stable during the isolation, purification, physico-
chemical and spectral characterization, as well as storage.12–15
The molecular structure of a representative member of this
series (3-(2-benzimidazol-1-yl)ethyl-5-phenyl-1,2,4-oxadi-
azole) was confirmed by X-ray structural analysis.16
In the present work, the Boulton–Katritzky rearrange-
ment of 3,5-disubstituted 1,2,4-oxadiazoles was performed
by using the example of 5-aryl-3-[2-(piperidin-1-yl)ethyl]-
1,2,4-oxadiazoles 4a‒e. 1,2,4-Oxadiazoles 4a‒e as crystal-
line precipitates were obtained by heating of О-aroyl-
(2-piperidin-1-yl)propioamidoximes 3a‒e in DMF at 70°C.
An additional amount of products 4a–e were isolated after
evaporating of the solvent under oil pump vacuum and
treating the residue with acetone (Scheme 3). The synthesis
of the starting compounds 1, 2a‒e, 3a‒e, and 1,2,4-oxa-
diazoles 4a–e has been described earlier, where compounds
4a–e were obtainted by dehydration of О-aroyl-(2-piperidin-
1-yl)propioamidoximes 3a‒e by heating in DMF in the
presence of molecular sieves.12
IR spectra of compounds 4a–e contained absorption
bands at 1595–1600 (C=C) and 1662–1664 cm–1 (C=N).
Compounds 4a–e also exhibited absorption at 1358–
Scheme 3
644

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
Scheme 4
1377 cm–1 (C‒O), which is a characteristic feature of
contained chloride as a counterion to the quaternary
ammonium cation (Scheme 4).
1
1,2,4-oxadiazoles. H NMR spectra of 1,2,4-oxadiazoles
4a–e showed peaks in the range of 3.12–3.14 and 3.82 ppm
(triplets of α- and β-methylene groups), as well as 3.30–3.36
and 3.42–3.50 ppm (multiplets of two methylene groups
bonded to the nitrogen atom of the piperidine heterocycle).
Each of the latter signals can be attributed to the axial and
equatorial protons of the heterocycle, differentiated by the
slow inversion of piperidine ring during the acquisition of
NMR spectra.
We investigated the behavior of 5-aryl-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazoles 4a–e in Boulton–Katritzky
rearrangement at 25°C in the following media: H2O, DMF–
H2O, 10:1, and HCl in ether. The transition from 1,2,4-oxa-
diazoles 4a‒c with electron-donating substituents or an
unsubstituted phenyl ring to 1,2,4-oxadiazoles 4d,e with
electron-withdrawing substituents occurs with a shortening
of the regrouping time from 2 weeks to 1 week in the
method I and from 10 to 6 h in the method II.
The physicochemical and spectral characteristics of the
obtained products, as well as the X-ray diffraction data (see
below) indicated that in H2O and DMF–H2O 1,2,4-oxa-
diazoles 4a–e were converted to spiropyrazolines 5a‒e, but
in ethereal HCl only compound 4e was converted to spiro-
pyrazoline 7, while 1,2,4-oxadiazoles 4a‒d were recovered
in the form of hydrochlorides 6a‒d. Spiropyrazolines 5a‒e
contained the respective benzoate anions, and compound 7
The formation of compounds 5a–e, 7 can be represented
as a series of protonation, proton transfer, and nucleophilic
attack steps, effectively constituting hydrolysis during the
reaction of 1,2,4-oxadiazoles 4a–e with water and wet HCl
(Scheme 5). The comparison of benzoates 5a‒e with 1,2,4-oxa-
diazoles 4a‒e revealed that the former have higher melting
points (mp 216–238°C) and Rf 0.58–0.78, compared to the
latter ‒ mp 206–230°C and Rf 0.47–0.65.
The main distinguishing feature in IR spectra of spiro
compounds 5a‒e and 7 compared to the IR spectra of
1,2,4-oxadiazoles 4a‒e was the presence of symmetric and
asymmetric ν(N‒H) stretching bands at 3300 and 3500 cm–1,
respectively. IR spectrum of chloride hydrate 7 did not
contain the characteristic ν(C‒O) absorption band of
1
1,2,4-oxadiazoles at 1358–1377 cm–1. H NMR spectra of
benzoates 5a‒e differed from the spectra of 1,2,4-oxa-
diazoles 4a‒e by the presence of NH2 proton signal with
1
the integral of 2H at 7.42–7.70 ppm. H NMR spectra of
1,2,4-oxadiazole hydrochlorides 6a‒d featured the NH+
1
proton signals at 12.63–13.20 ppm. H NMR spectrum of
spiro compound 7 contained the expected proton signals,
and no aromatic proton signals were observed. 3-Chloro-
benzoic acid (8) precipitated during the evaporation of
mother liquors obtained after chloride hydrate 7 was
collected by filtration.
Sсheme 5
645

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
were determined in glass capillaries on a PTP(M) apparatus
(Khimlabpribor, Russia). The reaction progress and purity
of the obtained products were controlled using Sorbfil
(Sorbpolymer, Russia) TLC plates coated with CTX-1A
silica gel, grain size 5‒17 μm, containing UV-254 indi-
cator. The eluent for TLC analysis was mixture benzene‒
EtOH, 1:3. The reagents were purchased from different
chemical suppliers and were purified before use. The
solvents for synthesis, recrystallization, and TLC analysis
(ethanol, 2-PrOH, benzene, DMF, acetone, diethyl ether)
were purified according to the standard techniques.
5-Aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles have
been synthesized earlier.12
Figure 2. Molecular structure of 2-amino-1,5-diazaspiro[4.5]dec-
1-en-5-ium 4-bromobenzoate (5d) with atoms represented by
thermal vibration ellipsoids of 50% probability.
After recrystallization of compounds 4a–e from 2-PrOH,
only in one case a crystal suitable for X-ray structural
analysis could be grown over 9 months. It turned out that a
rearrangement and the inclusion of one water molecule in
the structure of the resulting spiropyrazoline 4-bromo-
benzoate occurred, giving hydrate 5d (Fig. 2). The location
of all hydrogen atoms allowed to unambiguously confirm
that this structure is a salt, namely, 2-amino-1,5-diazaspiro-
[4.5]dec-1-en-5-ium 4-bromobenzoate. It crystallized in
chiral space group P21, and Flack 0.018(6) indicated the
correctness of its absolute configuration. The six- and five-
membered rings of this cation adopted the conformations of
chair and envelope, respectively. The deviation of the C(1)
atom from the mean plane of five-membered ring was
equal to 0.446(5) Å. The positive charge located on the N(1)
atom caused elongation of C(1)–N(1) and N(1)–N(2) bonds
compared to the average values for single bonds, which
was previously also observed for 2-amino-8-thia-1-aza-
5-azoniaspiro[4.5]dec-1-ene,17 for 1-(tert-butyl)-4,5-dihydro-
1H-pyrazol-1-ium,19 and for 1,1,3-trimethyl-Δ2-pyrazolin-
ium ions.20
It would be reasonable to assume that the high anti-
tuberculosis activity of water-soluble 5-aryl-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazoles 4a,b,d previously observed
during prolonged in vitro screening experiments was
actually due to the rearranged 2-amino-1,5-diazaspiro[4.5]-
dec-1-en-5-ium benzoates 5a,b,d.21
According to the obtained experimental data, the
following conclusions can be reached: electron-with-
drawing substituents in the phenyl ring accelerate the
rearrangement in the series of 5-aryl-3-[2-(piperidin-1-yl)-
ethyl]-1,2,4-oxadiazoles; hydrolysis in ethereal HCl occurs
immediately, while hydrolysis in DMF–H2O, 10:1, was
faster than in H2O. Finally, 5-aryl-3-[2-(piperidin-1-yl)ethyl]-
1,2,4-oxadiazoles are generally unstable in the presence of
acids and bases at room temperature. Thus, there is a
significant probability that rearranged products may be
present during biological screening experiments with the
compounds of this series.
Dehydration of N'-[(aryloxycarbonyl)oxy]-3-(piperidin-
1-yl)propanimidamides 3a‒e to 5-aryl-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazoles 4a‒e.
5-(4-Methoxyphenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4a). A solution of N'-{[(4-methoxyphenoxy)-
carbonyl]oxy}-3-(piperidin-1-yl)propanimidamide
(3a)
(1.04 g, 3.410 mmol) in dry DMF (10 ml) was heated on an
oil bath at 70°C for 1.5 h with TLC control. The obtained
crude precipitate of compound 4a (0.36 g, 1.183 mmol)
was filtered at room temperature, and the filtrate was
evaporated to dryness under oil pump vacuum at 50°C/
1 mmHg. The organic residue was treated with dry acetone
(10 ml). An additional quantity of 1,2,4-oxadiazole (4a)
(0.44 g, 1.531 mmol) was collected by filtration. The
combined portions of crude compound 4a were recrystal-
lized from 2-PrOH. Yield 0.50 g (51%), colorless solid,
mp 222‒224°C, Rf 0.60. IR spectrum, ν, cm–1: 1662 (C=N),
1598 (C=N), 1560 (C=C), 1363 (C–O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.49–1.60 (2H, m), 1.70–1.78 (2H, m), and
1.85–1.92 (2H, m, N(CH2)2(CH2)3); 3.13 (2H, t, J = 7.0,
CH2CH2N(CH2)2); 3.31–3.35 (2Heq, m) and 3.43–3.47
(2Hax, m, N(CH2)2); 3.72 (3H, s, p-CH3O); 3.82 (2H, t,
J = 7.0, CH2N(CH2)2); 6.75 (2H, d, J = 8.7, o-H Ar); 7.74
(2H, d, J = 8.7, m-H Ar). 13C NMR spectrum, δ, ppm: 21.0;
21.9; 31.4; 55.4; 60.7; 64.3; 112.4; 130.9; 135.1; 159.8;
168.6; 168.7. Found, %: C 66.53; H 7.42. C16H21N3O2.
Calculated, %: C 66.88; H 7.37.
3-[2-(Piperidin-1-yl)ethyl]-5-(p-tolyl)-1,2,4-oxadiazole
(4b) was obtained analogously to compound 4a from
3-(piperidin-1-yl)-N'-{[(p-tolyloxy)carbonyl]oxy}propanimid-
amide (3b) (1.30 g, 4.498 mmol) in dry DMF (10 ml).
Yield 0.86 g (71%), colorless solid, mp 219‒220°C, Rf 0.65.
IR spectrum, ν, cm–1: 1662 (C=N), 1595 (C=N), 1550
1
(C=C), 1359 (C–O). H NMR spectrum, δ, ppm (J, Hz):
1.49–1.60 (2H, m), 1.69–1.77 (2H, m), and 1.84–1.92 (2H,
m, N(CH2)2(CH2)3); 2.27 (3H, s, p-CH3); 3.14 (2H, t,
J = 7.0, CH2CH2N(CH2)2); 3.30–3.35 (2Heq, m) and 3.42–
3.50 (2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0 CH2N(CH2)2);
7.01 (2H, d, J = 8.0, o-H Ar); 7.70 (2H, d, J = 8.0, m-H Ar).
13C NMR spectrum, δ, ppm: 21.0; 21.3; 21.9; 31.5; 60.7;
64.3; 127.9; 129.5; 137.4; 139.7; 168.6; 168.9. Found:
C 70.53; H 7.42. C16H21N3O. Calculated, %: C 70.82; H 7.80.
5-Phenyl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazole (4c)
was obtained analogously to compound 4a from
N'-[(phenoxycarbonyl)oxy]-3-(piperidin-1-yl)propanimid-
amide (3c) (0.73 g, 2.652 mmol) in dry DMF (5 ml). Yield
Experimental
IR spectra were obtained on a Thermo Scientific Nicolet
1
5700 FTIR instrument in KBr pellets. H and 13C NMR
spectra were acquired on a Bruker Avance III 500 MHz
NMR spectrometer (500 and 126 MHz, respectively). The
signals of DMSO-d6 were used as internal reference for
1H NMR (2.50 ppm) and 13C NMR (39.5 ppm) spectra.
Elemental analysis was carried out on a CE440 elemental
analyzer (Exeter Analytical, Inc., China). Melting points
646

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
0.29 g (43%), colorless solid, mp 205‒206°C, Rf 0.63.
3.73 (3H, s, p-CH3O); 3.82 (2H, t, J = 7.0, CH2N(CH2)2);
6.75 (2H, d, J = 8.7, o-H Ar); 7.45 (2H, br. s, NH2); 7.74
(2H, d, J = 8.7, m-H Ar). 13C NMR spectrum, δ, ppm: 21.0;
22.0; 31.4; 55.4; 60.7; 64.3; 112.5; 130.9; 134.7; 160.0;
168.9. Found, %: C 63.11; H 7.30. C16H23N3O3. Calculated, %:
C 62.93; H 7.59.
Method II. 5-(4-Methoxyphenyl)-3-[2-(piperidin-1-yl)-
ethyl]-1,2,4-oxadiazole (4a) (0.5 g, 1.740 mmol) was
dissolved in DMF (5 ml) and distilled water (0.5 ml). The
solution was left at room temperature and checked by TLC
at the intervals of 1 h. After hydrolysis for 10 h, the
reaction solution was concentrated under water aspirator
vacuum and the organic residue was treated with diethyl
ether (10 ml). Product 5a was collected by filtration as a
white precipitate, then recrystallized from 2-PrOH. Yield
0.35 g (66%), colorless solid, mp 230‒232°C, Rf 0.78.
Found, %: C 63.25; H 7.80. C16H23N3O3. Calculated, %:
C 62.93; H 7.59.
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium 4-methyl-
benzoate (5b) was obtained analogously to compound 5a
from 3-[2-(piperidin-1-yl)ethyl]-5-(p-tolyl)-1,2,4-oxadiazole
(4b) (0.5 g, 1.843 mmol). Method I (2 weeks). Yield 0.34 g
(64%), colorless solid, mp 227‒228°C, Rf 0.75. IR spectrum,
ν, cm–1: 3500 (NH2 as), 3320 (NH2 sy), 1663 (C=N), 1599
(C=C), 1550 (COO– sy), 1368 (COO– as). 1H NMR
spectrum, δ, ppm (J, Hz): 1.50–1.60 (2H, m), 1.70–1.80
(2H, m), and 1.82–1.93 (2H, m, N(CH2)2(CH2)3); 3.13 (2H,
t, J = 7.0, CH2CH2N(CH2)2); 3.29–3.36 (2Heq, m) and 3.41–
3.48 (2Hax, m, N(CH2)2); 3.73 (3H, s, p-CH3); 3.82 (2H, t,
J = 7.0, CH2N(CH2)2); 6.75 (2H, d, J = 8.7, o-H Ar); 7.44
(2H, br. s, NH2); 7.70 (2H, d, J = 8.7, m-H Ar). 13C NMR
spectrum, δ, ppm: 20.1; 22.0; 31.6; 55.4; 60.2; 64.4; 112.6;
130.9; 134.7; 160.0; 168.3. Found, %: C 66.52; H 7.55.
C16H23N3O2. Calculated, %: C 66.41; H 8.01.
IR spectrum, ν, cm–1: 1663 (C=N), 1598 (C=N), 1553
1
(C=C), 1377 (C–O). H NMR spectrum, δ, ppm (J, Hz):
1.49–1.60 (2H, m), 1.70–1.78 (2H, m), and 1.85–1.92 (2H,
m, N(CH2)2(CH2)3); 3.12 (2H, t, J = 7.0, CH2CH2N(CH2)2);
3.31–3.36 (2Heq, m) and 3.43–3.48 (2Hax, m, N(CH2)2);
3.82 (2H, t, J = 7.0, CH2N(CH2)2); 7.23‒7.81 (5H, m,
C6H5). 13C NMR spectrum, δ, ppm: 21.0; 21.9; 31.6; 60.7;
127.4; 128.4; 129.4; 168.6; 168.9. Found, %: C 70.29;
H 7.39. C15H19N3O. Calculated: C 70.01; H 7.44.
5-(4-Bromophenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4d) was obtained analogously to compound 4a
from N'-{[(4-bromophenoxy)carbonyl]oxy}-3-(piperidin-
1-yl)propanimidamide (3d) (0.98 g, 2.770 mmol) in dry
DMF (10 ml). Yield 0.66 g (71%), colorless solid, mp 228‒
230°C, Rf 0.47. IR spectrum, ν, cm–1: 1662 (C=N), 1598
(C=N), 1547 (C=C), 1358 (C–O). 1H NMR spectrum, δ, ppm
(J, Hz): 1.50–1.61 (2H, m), 1.69–1.77 (2H, m), and 1.83–
1.92 (2H, m, N(CH2)2(CH2)3); 3.12 (2H, t, J = 7.0,
CH2CH2N(CH2)2); 3.31–3.35 (2Heq, m) and 3.42–3.49
(2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0, CH2N(CH2)2);
7.41 (2H, d, J = 8.0, o-H Ar); 7.74 (2H, d, J = 8.0, m-H Ar).
13C NMR spectrum, δ, ppm: 21.0; 22.0; 31.5; 60.7; 64.3;
122.1; 130.2; 131.6; 141.4; 167.7; 168.6. Found, %: C 53.71;
H 5.46. C15H18BrN3O. Calculated, %: C 53.58; H 5.40.
5-(3-Chlorophenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4e) was obtained analogously to compound 4a
from N'-{[(3-chlorophenoxy)carbonyl]oxy}-3-(piperidin-
1-yl)propanimidamide (3e) (3.94 g, 1.272 mmol) in dry
DMF (15 ml). Yield 2.97 g (80%), colorless solid, mp 207‒
208°C, Rf 0.56. IR spectrum, ν, cm–1: 1664 (C=N), 1600
(C=N), 1557 (C=C), 1360 (C–O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.49–1.61 (2H, m), 1.70–1.77 (2H, m), and
1.84–1.91 (2H, m, N(CH2)2(CH2)3); 3.12 (2H, t, J = 7.0,
CH2CH2N(CH2)2); 3.30–3.35 (2Heq, m) and 3.44–3.49
(2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0, CH2N(CH2)2);
7.25‒7.78 (4H, m, C6H4Cl-m). 13C NMR spectrum, δ, ppm:
21.0; 21.9; 31.5; 60.7; 64.3; 127.8; 128.2; 129.2; 129.3;
132.4; 144.6; 167.1; 168.6. Found, %: C 61.71; H 6.46.
C15H18ClN3O. Calculated, %: C 61.75; H 6.22.
Method II (10 h). Yield 0.30 g (56%), colorless solid,
mp 227‒228°C, Rf 0.75. Found, %: C 66.72; H 8.25.
C16H23N3O2. Calculated, %: C 66.41; H 8.01.
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium benzoate
(5c) was obtained analogously to compound 5a from
5-phenyl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazole (4c)
(0.5 g, 1.943 mmol). Method I (2 weeks). Yield 0.39 g
(73%), colorless solid, mp 220‒222°C, Rf 0.70. IR spectrum,
ν, cm–1: 3510 (NH2 as), 3436 (NH2 sy), 1663 (C=N), 1598
(C=C), 1554 (COO– sy), 1377 (COO– as). 1H NMR
spectrum, δ, ppm (J, Hz): 1.50–1.60 (2H, m), 168–1.77
(2H, m), and 1.83–1.92 (2H, m, N(CH2)2(CH2)3); 3.13 (2H,
t, J = 7.0, CH2CH2N(CH2)2); 3.30–3.35 (2Heq, m) and 3.43–
3.48 (2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0, CH2N(CH2)2);
7.45 (2H, br. s, NH2); 7.24‒7.82 (5H, m, C6H5). 13C NMR
spectrum, δ, ppm: 21.0; 22.0; 31.5; 60.7; 64.3; 127.4;
130.4; 131.8; 132.2; 167.0; 168.5. Found, %: C 64.95;
H 7.30. C15H21N3O2. Calculated, %: C 65.43; H 7.69.
Method II (10 h). Yield 0.30 g (56%), colorless solid,
mp 220‒222°C, Rf 0.70. Found, %: C 65.35; H 7.45.
C15H21N3O2. Calculated, %: C 65.43; H 7.69.
Hydrolysis of 5-aryl-3-[(2-piperidin-1-yl)ethyl]-1,2,4-
oxadiazoles 4a–e in H2O and in DMF–H2O to form
2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium benzoates 5a‒e.
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium 4-methoxy-
benzoate (5a). Method I. 5-(4-Methoxyphenyl)-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazole (4a) (0.5 g, 1.740 mmol) was
dissolved in distilled water (5 ml). The solution was left at
room temperature with daily TLC control. After hydrolysis
for 2 weeks, the aqueous solution was concentrated under
water aspirator vacuum. The organic residue was treated
with diethyl ether (10 ml). The hydrolysis product was
collected by filtration as a white precipitate, then recrystal-
lized from 2-PrOH. Yield 0.40 g (75%), colorless solid,
mp 230‒232°C, Rf 0.78. IR spectrum, ν, cm–1: 3500 (NH2
as), 3300 (NH2 sy), 1663 (C=N), 1599 (C=C), 1551 (COO–
1
sy), 1363 (COO– as). H NMR spectrum, δ, ppm (J, Hz):
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium 4-bromo-
benzoate (5d) was obtained analogously to compound 5a
from 5-(4-bromophenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4d) (0.5 g, 1.487 mmol). Method I (1 week).
1.50–1.60 (2H, m), 1.68–1.78 (2H, m), and 1.82–1.92 (2H,
m, N(CH2)2(CH2)3); 3.14 (2H, t, J = 7.0, CH2CH2N(CH2)2);
3.29–3.36 (2Heq, m) and 3.42–3.49 (2Hax, m, N(CH2)2);
647

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
Yield 0.39 g (74%), colorless solid, mp 237‒238°C,
12.63 (1H, br. s, HN+(CH2)2). 13C NMR spectrum, δ, ppm:
21.0; 21.9 (2C); 31.5 (2C); 55.9; 60.7; 64.3; 114.3, 123.4,
131.8, 163.5 (6С); 167.4; 168.5. Found, %: C 59.81;
H 7.30. С16H22ClN3O2. Calculated, %: C 59.35; H 6.85.
5-(4-Methylphenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole hydrochloride (6b) was obtained analogously
to compound 6a from 5-(4-methylphenyl)-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazole (4b) (0.3 g, 1.106 mmol).
Yield 0.19 g (56%), white opaque powder, mp 165‒168°C,
Rf 0.60. IR spectrum, ν, cm–1: 2800‒2480 (N+–H), 1664
(C=N), 1603 (C=C), 1320 (C–O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.48–1.63 (2H, m), 1.71–1.81 (2H, m), and
1.83–1.91 (2H, m, N(CH2)2(CH2)3); 3.12 (2H, t, J = 7.0,
CH2CH2N(CH2)2); 3.33–3.39 (4H, m, N(CH2)2); 3.47 (2H,
t, J = 7.0, CH2N(CH2)2); 7.70 (2H, d, J = 7.0, o-H Ar); 7.90
(2H, d, J = 7.0, m-H Ar); 13.20 (1H, br. s, HN+(CH2)2).
13C NMR spectrum, δ, ppm: 21.2; 22.0; 23.5; 31.6; 60.8;
64.5; 113.4; 123.5; 130.5; 163.5; 167.8; 169.2. Found, %:
C 62.72; H 7.45. С16H22ClN3O. Calculated, %: C 62.43;
H 7.20.
5-Phenyl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazole
hydrochloride (6c) was obtained analogously to com-
pound 6a from 5-phenyl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4c) (0.3 g, 1.167 mmol). Yield 0.19 g (55%),
white opaque powder, mp 237‒240°C, Rf 0.57. IR spectrum,
ν, cm–1: 2900‒2480 (N+–H), 1664 (C=N), 1603 (C=C),
1321 (C–O). 1H NMR spectrum, δ, ppm (J, Hz): 1.49–1.69
(2H, m), 1.72–1.82 (2H, m), and 1.83–1.91 (2H, m,
N(CH2)2(CH2)3); 2.35 (2H, t, J = 7.0, CH2CH2N(CH2)2);
3.32–3.38 (2Heq, m) and 3.43–3.48 (2Hax, m, N(CH2)2);
3.82 (2H, t, J = 7.0, CH2N(CH2)2); 7.25–7.83 (5H, m,
C6H5); 13.18 (1H, br. s, HN+(CH2)2). 13C NMR spectrum,
δ, ppm: 21.0; 21.9; 31.7; 60.9; 64.5; 127.4; 128.4; 129.6;
143.0; 168.7; 169.2. Found, %: C 61.55; H 6.98.
C15H20ClN3O. Calculated, %: C 61.32; H 6.86.
Rf 0.58. IR spectrum, ν, cm–1: 3480 (NH2 as), 3320 (NH2 sy),
1664 (C=N), 1595 (C=C), 1550 (COO– sy), 1359 (COO– as).
1H NMR spectrum, δ, ppm (J, Hz): 1.50–1.61 (2H, m),
1.70–1.80 (2H, m), and 1.82–1.92 (2H, m, N(CH2)2(CH2)3);
3.12 (2H, t, J = 7.0, CH2CH2N(CH2)2); 3.29–3.36 (2Heq, m)
and 3.41–3.48 (2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0,
CH2N(CH2)2); 7.41 (2H, d, J = 7.0, o-H Ar); 7.60 (2H, br. s,
NH2); 7.75 (2H, d, J = 7.0, m-H Ar). 13C NMR spectrum,
δ, ppm: 21.0; 21.9; 31.5; 60.7; 64.3; 122.2; 130.3; 131.6;
141.3; 167.8; 168.6. Found, %: C 50.78; H 5.31.
C15H20BrN3O2. Calculated, %: C 50.86; H 5.69.
Method II (6 h). Yield 0.30 g (57%), mp 237‒238°C,
Rf 0.58. Found, %: C 50.65; H 5.87. C15H20BrN3O2.
Calculated, %: C 50.86, H 5.69.
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium 3-chloro-
benzoate (5e) was obtained analogously to compound 5a
from 5-(3-chlorophenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole (4e) (0.5 g, 1.714 mmol). Method I (1 week).
Yield 0.41 g (77%), colorless solid, mp 214‒216°C,
Rf 0.68. IR spectrum, ν, cm–1: 3350 (NH2 as), 3340 (NH2 sy),
1664 (C=N), 1599 (C=C), 1557 (COO– sy), 1377 (COO–
as). 1H NMR spectrum, δ, ppm (J, Hz): 1.51–1.61 (2H, m),
1.70–1.79 (2H, m), and 1.83–1.92 (2H, m, N(CH2)2(CH2)3);
3.11 (2H, t, J = 7.0, CH2CH2N(CH2)2); 3.31–3.35 (2Heq, m)
and 3.43–3.47 (2Hax, m, N(CH2)2); 3.82 (2H, t, J = 7.0,
CH2N(CH2)2); 7.27‒7.77 (4H, m, C6H4Cl-m); 7.42 (2H, br. s,
NH2). 13C NMR spectrum, δ, ppm: 21.0; 22.0; 31.5; 60.7;
64.3; 127.8; 128.1; 129.2; 129.3; 132.4; 144.9; 166.9; 168.6.
Found, %: C 58.56; H 6.14. C15H20ClN3O2. Calculated, %:
C 58.16; H 6.51.
Method II (6 h). Yield 0.42 g (79%), colorless solid,
mp 214‒216°C, Rf 0.68. Found, %: C 58.55; H 6.35.
C15H20ClN3O2. Calculated, %: C 58.16; H 6.51.
Action of ethereal HCl solution on 5-aryl-3-[2-
(piperidin-1-yl)ethyl]-1,2,4-oxadiazoles 4a‒e to form
5-aryl-3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazole hydro-
chlorides 6a–d or 2-amino-1,5-diazaspiro[4.5]dec-1-en-
5-ium chloride hydrate (7) and 3-chlorobenzoic acid (8).
5-(4-Methoxyphenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole hydrochloride (6a). 5-(4-Methoxyphenyl)-
3-[2-(piperidin-1-yl)ethyl]-1,2,4-oxadiazole (4a) (0.3 g,
1.044 mmol) was dissolved in a minimum amount of
absolute ethanol. Then ethereal HCl solution was added
dropwise to pH 2. The resultant white precipitate was
triturated with a glass rod and filtered through a micro
funnel. Double volume of ether was added to the filtrate.
The white precipitate was collected by filtration and
combined with the first precipitate. After recrystallization
from 2-PrOH, 5-(4-methoxyphenyl)-3-[2-(piperidin-1-yl)-
ethyl]-1,2,4-oxadiazole hydrochloride (6a) was isolated.
Yield 0.23 g (68%), white opaque powder, mp 168‒170°C,
Rf 0.63. IR spectrum, ν, cm–1: 2850‒2450 (N+–H), 1685
(C=N), 1604 (С=С), 1261 (C–O). 1H NMR spectrum,
δ, ppm (J, Hz): 1.49–1.62 (2H, m), 1.70–1.80 (2H, m), and
1.84–1.92 (2H, m, N(CH2)2(CH2)3); 3.10 (2H, t, J = 7.0,
CH2CH2N(CH2)2); 3.32–3.38 (4H, m, N(CH2)2); 3.47 (2H,
t, J = 7.0, CH2CH2N(CH2)2); 3.82 (3H, s, p-CH3O); 7.01
(2H, d, J = 7.0, o-H Ar) and 7.89 (2H, d, J = 7.0, m-H Ar);
5-(4-Bromophenyl)-3-[2-(piperidin-1-yl)ethyl]-1,2,4-
oxadiazole hydrochloride (6d) was obtained analogously
to compound 6a from 5-(4-bromophenyl)-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazole (4d) (0.3 g, 0.892 mmol)
dissolved in absolute EtOH (0.5 ml). Yield 0.22 g (66%),
white opaque powder, mp 185‒186°C, Rf 0.81. IR spectrum,
ν, cm–1: 2900‒2554 (N+–H), 1678 (C=N), 1610 (C=C),
1296 (C–O). 1H NMR spectrum, δ, ppm (J, Hz): 1.50–1.61
(2H, m), 1.70–1.78 (2H, m), and 1.84–1.92 (2H, m,
N(CH2)2(CH2)3); 3.10 (2H, t, J = 7.0, CH2CH2N(CH2)2);
3.31–3.36 (2Heq, m) and 3.43–3.48 (2Hax, m, N(CH2)2);
3.82 (2H, t, J = 7.0, CH2N(CH2)2); 7.71 (2H, d, J = 7.0,
o-H Ar); 7.86 (2H, d, J = 7.0, m-H Ar); 13.19 (1H, br. s,
HN+(CH2)2). 13C NMR spectrum, δ, ppm: 21.0; 21.9; 31.5;
60.7; 64.3; 127.4; 130.4; 131.8; 132.2; 167.0; 168.5.
Found, %: C 48.78; H 5.31. C15H19BrClN3O. Calculated, %:
C 48.34, H 5.14.
2-Amino-1,5-diazaspiro[4.5]dec-1-en-5-ium chloride
hydrate (7). When ethereal HCl solution was added drop-
wise to a solution of 5-(3-chlorophenyl)-3-[2-(piperidin-
1-yl)ethyl]-1,2,4-oxadiazole (4e) (0.3 g, 1.028 mmol) in
EtOH (0.5 ml) to pH 2, white precipitate of 2-amino-
1,5-diazaspiro[4.5]dec-1-en-5-ium chloride hydrate (7) was
formed at once and collected by filtration. Yield 0.2 g
648

Chemistry of Heterocyclic Compounds 2018, 54(6), 643–649
5. Korbonits, D.; Kanzel-Szvoboda, I.; Horváth, K. J. Chem.
(94%), white opaque powder, mp 257‒260°C, Rf 0.21.
IR spectrum, cm–1: 3338 (NH2 ν as), 3260 (NH2 ν sy), 1678
(C=N ν), 1610 (NH2 δ). 1H NMR spectrum, δ, ppm (J, Hz):
1.49–1.61 (2H, m), 1.70–1.78 (2H, m), and 1.84–1.92 (2H,
m, N(CH2)2(CH2)3); 3.10 (2H, t, J = 7.0, CH2CH2N(CH2)2);
3.31–3.36 (2Heq, m) and 3.45–3.50 (2Hax, m, N(CH2)2);
3.83 (2H, t, J = 7.0, CH2CH2N(CH2)2); 7.34 (2H, br. s,
NH2). 13C NMR spectrum, δ, ppm: 21.0; 21.9; 31.5; 60.7;
64.3; 168.5. Found, %: C 46.56; H 8.54. C8H18ClN3O.
Calculated: C 46.26; H 8.74.
Soc., Perkin Trans. 1 1982, 759.
6. Ott, G. R.; Anzalone, A. V. Synlett 2011, 3018.
7. Piccionello, A. P.; Pace, A.; Buscemi, S.; Vivona, N. Org.
Lett. 2009, 11, 4018.
8. (a) Spinelli, D.; Corrao, A.; Frenna, V.; Vivona, N.; Ruccia, M.;
Cusmano, G. J. Heterocycl. Chem. 1976, 13, 357. (b) Bottoni, A.;
Frenna, V.; Lanza, C. Z.; Macaluso, G.; Spinelli, D. J. Phys.
Chem. A 2004, 108, 1731.
9. D'Auria, M.; Frenna, V.; Marullo, S.; Racioppi, R.; Spinelli, D.;
Viggiani, L. Photochem. Photobiol. Sci. 2012, 11, 1383.
10. D'Anna, F.; Frenna, V.; Ghelfi, F.; Marullo, S.; Spinelli, D.
J. Org. Chem. 2011, 76, 2672.
11. Piccionello, A. P.; Buscemi, S.; Vivona, N.; Pace, A. Org.
Lett. 2010, 12, 3491.
12. Kаyukova, L. A.; Zhumadildaeva, I. S.; Praliyev, K. D. Russ.
Chem. Bull., Int. Ed. 2002, 51, 2100. [Izv. Akad. Nauk, Ser.
Khim. 2002, 1945.]
13. Kаyukova, L. A. Chem. Heterocycl. Compd. 2003, 39, 223.
[Khim. Geterotsikl. Soedin. 2003, 253.]
14. Kayukova, L. A.; Akhelova, A. L.; Agzamova, R. A.;
Bismilda, V. L.; Kozhamkulov, U. A.; Cynamon, M.; Shoen, C. In
Poster Abstracts of 2006 NIAID Research Conference, Opatija,
Croatia, June 24‒30, 2006; Opatija, 2006, Abstr. No. 25, p. 25.
15. Kayukova, L. A.; Orazbaeva, M. A.; Petrov, A. A. In Russian
Conference on Organic Chemistry, Moscow, Russia, October
25‒30, 2009; Moscow, 2009, p. 215.
16. Kаyukova, L. A.; Beketov, K. М.; Аkhelova, А. L.;
Praliev, K. D. Chem. Heterocycl. Compd. 2006, 42, 914.
[Khim. Geterotsikl. Soedin. 2006, 1057.]
17. Kayukova, L. A.; Orazbaeva, M. A.; Gapparova, G. I.;
Beketov, K. M.; Espenbetov, A. A.; Faskhutdinov, M. F.;
Tashkhodjaev, B. T. Chem. Heterocycl. Compd. 2010, 46,
879. [Khim. Geterotsikl. Soedin. 2010, 1086.]
18. Kayukova, L. A.; Beketov, K. M.; Baitursynova, G. P. In:
International Сonference ''Catalysis in Organic Synthesis'',
September 15–20, 2012, Moscow, Russia, 2012, Abstr.
No. 122, p. 214.
19. Usachev, S. V.; Nikiforov, G. A.; Lyssenko, K. A.;
Nelubina, Y. V.; Levkin, P. A.; Kostyanovsky, R. G.
Tetrahedron: Asymmetry 2007, 18, 1540.
20. Yap, G. P. A.; Alkorta, I.; Elguero, J.; Jagerovic, N.
Spectroscopy Int. J. 2004, 18, 605.
3-Chlorobenzoic acid (8) was precipitated during the
evaporation of mother liquors obtained after the filtration
of choride hydrate 7. All characteristics of acid 8 cor-
responded to previously available data.22
X-ray diffraction analysis. Inclusion of one water
molecule in the structure of 1,2,4-oxadiazole 4d during its
crystallization from 2-PrOH over 9 months gave a single
crystal of 2-amino-1,5-diazaspiro[4.5]dec-1-en-5-ium
4-bromobenzoate (5d). The intensities of reflections were
measured on a Bruker Apex II CCD diffractometer with
MoKα radiation (λ 0.71073 Å, graphite monochromator).
The crystal (C15H20BrN3O2, Mr 354.25) was monoclinic,
space group P21, at 120.0 K: a 6.5058(5), b 7.9245(6),
c 15.1028(11) Å; β 98.2190(10)°; V 770.63(10) Å3; Z 2;
Dcalc 1.527 g·cm–3; μ 2.675 mm–1. A total of 9361 reflec-
tions were measured, 4012 independent (Rint 0.0561), final
R1 (I > 2σ(I)) 0.0259, wR(F2) 0.0547 (all data), GOF 0.897.
The structure was solved by direct method and refined by
full-matrix least-squares method against F2. Non-hydrogen
atoms were refined in anisotropic approximation. All
hydrogen atoms could be located on difference Fourier
maps. The H(C) atoms were included in the refinement by
the riding model with Uiso(H) = nUeq(C), where n = 1.5 for
methyl groups and 1.2 for the other atoms. All calculations
were performed using the SHELXL23 and OLEX224
software suites. The crystallographic dataset was deposited
at the Cambridge Crystallographic Data Center (deposit
CCDC 1496456).
21. Kayukova, L. A.; Praliev, K. Dzh.; Agzamova, R. A.;
Bismilda, V. L.; Kozhamkulov, U. A. KZ Patent 18598;
Inventor Bull. Rep. Kazakhstan 2010, No. 12. https://
gosreestr.kazpatent.kz/.
22. (a) Sigma-Aldrich Handbook of Fine Chemicals 2012–2014,
p. 652. (b) The Merck Index: An Encyclopedia of Chemicals,
Drugs, and Biologicals; Budavari, S., Ed.; Merck and Co.:
Rathway, 1989, p. 328. (c) NIST Chemistry WebBook, https://
webbook.nist.gov/cgi/cbook.cgi?ID=C937144&Mask=80.
(d) ChemicalBook Inc., https://www.chemicalbook.com/
SpectrumEN_937-14-4_1HNMR.htm.
References
1. Kayukova, L. A.; Praliev, K. D.;
Akhelova, A. L.;
Kemel'bekov, U. S.; Pichkhadze, G. M.; Mukhamedzhanova, G. S.;
Kadyrova, D. M.; Nasyrova, S. R. Pharm. Chem. J. 2011,
45(8), 468. [Khim.-Farm. Zh. 2011, 45(8), 29.]
2. Kаyukova, L. A.; Praliev, K. D.; Bismilda, V. L.; Chingisova, L. T.
In 48th International Conference on Medicinal Chemistry
(RICT 2012), Poitiers, France, July 4‒6, 2012; Poitiers, 2012,
Abstr. No. NA17, p. 117.
3. Fyfe, M. C. T.; Gardner, L. S.; King-Underwood, J.;
Procter, M. J.; Rasamison, C. M.; Schofield, K. L.;
Thomas, G. H. U. S. Patent 8207147.
4. Li, J. J. Name Reactions; Springer International Publishing:
Cham, 2014, 5th ed., p. 70.
23. Sheldrick, G. M. Acta Crystallogr., Sect. A: Found.
Crystallogr. 2008, A64, 112.
24. Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A. K.;
Puschmann, H. J. Appl. Crystallogr. 2009, (42), 339.
649