Synthesis and study of novel 1,2,4-triazolylacetic acid derivatives

Article abstract of DOI:10.1007/s10593-016-1901-z

[Figure not available: see fulltext.] A range of 1,2,4-triazolylacetic acids and their derivatives with various substituents at the triazole ring position 3 have been synthesized. The properties of the obtained compounds were studied, showing that: 1) triazolylacetic esters are strong acylating agents; 2) all the obtained triazolylacetic acids underwent decarboxylation when heated to the melting point; 3) the CH2 group in the acetyl moiety can react as methylene component in condensation reactions.

Full text of DOI:10.1007/s10593-016-1901-z

DOI 10.1007/s10593-016-1901-z
Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
Synthesis and study of novel
1,2,4-triazolylacetic acid derivatives
Dmitro M. Khomenko1*, Roman O. Doroshchuk1,
Oleksandr V. Vashchenko1, Rostyslav D. Lampeka1
1 Kyiv Taras Shevchenko National University,
64 Volodymirska St., Kyiv 01601, Ukraine; e-mail: dkhomenko@ukr.net
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2016, 52(6), 402–408
Submitted March 15, 2016
Accepted June 6, 2016
A range of 1,2,4-triazolylacetic acids and their derivatives with various substituents at the triazole ring position 3 have been synthesized.
The properties of the obtained compounds were studied, showing that: 1) triazolylacetic esters are strong acylating agents; 2) all the
obtained triazolylacetic acids underwent decarboxylation when heated to the melting point; 3) the СН2 group in the acetyl moiety can
react as methylene component in condensation reactions.
Keywords: 1,2,4-triazole, triazolylacetic acid, acylation, decarboxylation, intramolecular condensation.
1,2,4-Triazole rings are found in many compounds that
possess various types of biological activity. For example,
some triazole-containing compounds have valuable
pharmacological properties, such as anti-inflammatory,
antifungal, and antiviral activity.1 For this reason, it is
important to pursue the synthesis of polyfunctional
compounds containing 1,2,4-triazole ring, including 1,2,4-tri-
azolylacetic acids and their derivatives, which can be
further transformed through common chemical reactions.
The versatility of such synthetic intermediates originates
from the presence of three functional groups in their
molecules: carboxyl group,2 methylene group,3 and,
specifically, the 1,2,4-triazole ring,4 which can react with other
compounds of various types. It should be noted that
polyfunctional compounds containing 1,2,4-triazole ring
have been studied as potential anticancer drugs5 and are
also of interest as starting materials for the synthesis of
explosives,6 herbicides,7 various amino acid derivatives and
pseudopeptides,8 as well as other biologically active
compounds.9
by intramolecular cyclization of the obtained amidra-
zones.3a,10 Such method provides an opportunity for the
synthesis of 3-substituted 1,2,4-triazolylacetic acids from
the corresponding hydrazides, which are more readily available
than the starting materials used in the majority of other
reactions leading to 1,2,4-triazoles.11–13
Despite the fairly large number of known derivatives of
1,2,4-triazolylacetic acids, no comprehensive synthetic
studies and characterization of these compounds has been
performed yet. The goal of this work therefore was to
obtain 1,2,4-triazolylacetic acids with various types of
substituents at position 3 of the 1,2,4-triazole ring and to
describe the spectra and other properties of these
compounds.
We used hydrazides of various carboxylic acids as the
starting materials (Scheme 1), including the aliphatic
compounds 1a–d,f, aromatic compounds 1g,h, and
heterocyclic compounds 1i,j. Among the aliphatic
hydrazides, we should point to compounds that may be
considered as derivatives of glycolic (compounds 1b,d)
and aminoacetic (compounds 1c,f) acids. Aminoacetic acid
hydrazide (1е) itself was not used in this study, with the
N-benzyloxycarbonyl-protected analog 1f used instead.
In order to prepare derivatives of triazolylacetic acids,
we used a method based on acylation of carboxylic acid
hydrazides with ethyl malonate monoimidoester, followed
0009-3122/16/52(6)-0402©2016 Springer Science+Business Media New York
402

Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
Scheme 1
Acylation of hydrazides 1a–d,f–j with ethyl malonate
ring, similarly to p-nitrophenyl substituent, has a
monoimidoester was performed by heating in ethanol. In
considerable electron-withdrawing ability. Based on this,
we consider that the key role in stabilizing one of the
tautomers of compound 3h was played by the formation of
associates with dimethyl sulfoxide, because the formation
of intramolecular hydrogen bonds in the case of R = Ar
was possible only with the oxygen atom of ester group.
Compounds with aliphatic substituent R lacking any
heteroatoms able to form hydrogen bonds (for example,
compound 3a) gave 1Н NMR signals that were not doubled
or significantly broadened. At the same time, derivatives of
glycolic and aminoacetic acids (except compound 3e),
which also can be considered as compounds with aliphatic
substituents, gave proton signals that were all clearly
doubled, due to the possibility of intramolecular hydrogen
bond formation both with the oxygen atom of ester group,
and with the heteroatom of substituent R. The amino ester
3e existed as a zwitterion, confirmed by the absence of
the case of hydrazides 1b,c,f–j, precipitates formed in the
1
solutions, which were identified by Н NMR spectra and
literature data13 as the respective amidrazones 2b,c,f–j.
Compounds 2b,c,f–j were used in the next step of synthesis
without additional purification. Heating of amidrazones
2b,c,f–j to the melting point resulted in intramolecular
condensation, producing the triazoles 3b,c,f–j. Triazoles
3а,d were obtained by prolonged refluxing of the starting
hydrazides 1а,d with ethyl malonate monoimidoester in
ethanol without isolation of the intermediate amidrazones.
Triazole 3е, containing an aminomethyl group, was
obtained from compound 3f by catalytic hydrogenolysis of
the benzyloxycarbonyl protecting group.
1
A characteristic Н NMR spectral feature for some of
compounds 3 in DMSO-d6 solution was doubling or
significant broadening of signals due to the protons
separated by 2–4 bonds from the triazole heterocycle,
1
triazole proton signal in its Н NMR spectrum and the
1
which was not the case for H NMR spectra acquired in
presence of a protonated amino group signal.
CDCl3 solutions (Fig. 1). This may be caused by the
stabilization of tautomeric forms I and II of the studied
compounds14 not only due to the formation of
intramolecular hydrogen bonds, but also through
association with dimethyl sulfoxide molecules, which
slowed the interconversion of tautomers. This phenomenon
was also observed in the spectra of carboxylic acid
hydrazides, which have certain structural similarity to 1,2,4-
triazoles.15
It should be noted that for compounds with aromatic
substituent R, the stability of tautomers apparently is
determined by the total electronic effect ( I and M) of the
aromatic ring in the substituent. For example, the spectrum
of compound 3g contained only a single set of signals
corresponding to one molecular species, while the proton
signals were doubled in the spectrum of compound 3h (the
1
ratio of tautomeric forms was 1:2 according to H NMR
spectrum). The acceleration of the tautomerization process
could be explained by the increased acidity of the triazole
proton when changing from p-hydroxy- to p-nitrophenyl
substituent. This explanation was also indirectly supported
1
1
by the absence of a double set of Н NMR signals in the
Figure 1. Н NMR spectra of compound 3d in a) CDCl3
spectra of compounds 3i,j (R = Het), because the pyridine
and b) DMSO-d6.
403

Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
Scheme 2
Based on the aforementioned facts, we conclude that the
probability of these compounds existing in several
tautomeric forms decreases in the following series of
substituents R: CH2OAr > CH2NHAr > Ar > Alk.
The existence of several tautomeric forms of the studied
compounds is the reason why triazole ring carbon atoms
were not observed in 13С NMR spectra of all studied
compounds, except for compound 3е. This fact was easily
explained by the significant broadening of these carbon
signals, formed as superposition of signals from several
tautomeric forms and transition states. This hypothesis was
supported by the appearance of these signals in the
spectrum when sulfuric acid was added, which accelerated
proton exchange processes. An additional confirmation was
obtained from the presence of triazole ring carbon signals
in the spectrum of compound 3е even without added acid,
because compound 3е existed in zwitterionic form
containing a deprotonated triazole ring.
Scheme 3
Alkaline hydrolysis of triazolylacetic acid esters 3a–j
followed by acidification of the reaction medium led to the
formation of compounds 4a–j, which in the majority of
cases were acids insoluble in water. However, compounds
4d,e could not be isolated in pure form due to their
significant solubility in water and the associated problems
with reaction mixture work-up, and mainly because of the
decarboxylation of the obtained carboxylic acids. Only
eight carboxylic acids 4a–c,f–j were isolated in pure form.
As already mentioned above, 3-substituted (1H-1,2,4-
triazol-5-yl)acetic acids are readily decarboxylated. We
established that in the case of carboxylic acids 4b,c,f–j this
decarboxylation reaction proceeded smoothly upon melting
of neat compounds and led to the formation of methyltriazoles
5b,c,f–j (Scheme 2). It is likely that this process, similarly
to the case of pyridinecarboxylic acids,15 proceeded
through the zwitterionic tautomeric form.
Scheme 4
Compounds 3, similarly to other esters of carboxylic acids,
can act as acylating agents (Scheme 3). This approach was
used for obtaining a range of amides and hydrazides by using
aniline, benzylamine, ammonia, and hydrazine as nucleophiles.
We should also note that the methylene group in
compounds 3 is sufficiently active and can participate in
condensation reactions with aldehydes (Scheme 4).
Thus, we have obtained a series of triazolylacetic acids
with various substituents at position 3 of the triazole ring.
A tautomeric equilibrium was observed in ethyl esters of
triazolylacetic acids in DMSO solutions. The ratio of
tautomeric forms depended on the nature of substituent at
position 3 of the triazole heterocycle. It was established
that triazolylacetic acids underwent decarboxylation upon
heating to the melting point. Esters of triazolylacetic acids
were shown to act as active acylating agents that may
participate in condensation reactions in the role of
methylene components, and thus can serve as intermediates
in the synthesis of triazole derivatives.
X
X
O
3g,i
N
R
OEt
Piperidine (cat.)
EtOH, , 36 h
N NH
10, 11
O
54–56%
10 R = 3-Py, X = O; 11 R = 4-O2NC6H4, X = S
Varian Mercury 400 (400 MHz, the rest of the compounds)
spectrometers. The solvents were DMSO-d6 (compounds
3c,h, 4a,c–j, 5h, 6–11) and CDCl3 (the rest of the
compounds), internal standard – signal of residual solvent
protons (DMSO-d6 – 2.50 ppm, CDCl3 – 7.26 ppm). 13С
NMR spectra were acquired on a Varian Mercury 400
spectrometer (100 MHz) in 0.1 М solution of H2SO4 in
CDCl3 (compounds 3b,e–g,i, 5c) and in 0.1 М solution of
H2SO4 in DMSO-d6 (the rest of the compounds), internal
standard – signal of solvent carbon atoms (CDCl3 – 76.2 ppm,
DMSO-d6 – 39.5 ppm). 13С NMR spectrum of compound
4j could not be acquired due to the low solubility of this
material in DMSO-d6. LC-MS analysis was performed on an
Agilent 1100 LC/MSD SL instrument in gradient elution
mode. The mobile phase: A – H2O + 0.1% HCOOH; B –
Experimental
1Н NMR spectra were acquired on Bruker Avance DRX
500 (500 MHz, compounds 3a–c,g,i,j, 5b,c,g,i,j) and
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Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
MeCN + 0.1% HCOOH. Column: Zorbax SB C-18 (30 × 4.6 mm,
%: С 59.76; Н 5.79; N 16.08. C13H15N3O3. Calculated, %:
particle size 1.8 μm), the temperature was 40°C. A diode
matrix was used for quantitative detection at 215 nm
wavelength. The chromatographic peaks were identified by
a single quadrupole mass spectrometer with chemical
ionization at atmospheric pressure. Elemental analysis was
performed on a Perkin Elmer C,H,N-analyzer. Melting
points were determined on a Stuart Scientific SMP3
apparatus.
С 59.71; Н 5.82; N 16.09.
Ethyl (3-phenylaminomethyl-1Н-1,2,4-triazol-5-yl)-
acetate (3c). Yield 19.50 g (75%). White powder. Mp 136–
1
138°С. H NMR spectrum, δ, ppm (J, Hz): 1.30 (3Н, t,
J = 6.5, OCH2CН3); 3.88 (2H, s, CH2CO); 4.24 (2Н, q,
J = 6.5, OCH2СН3); 4.45 (2Н, s, CН2Ph); 6.65 (2H, d,
J = 6.5, H-2,6 Ph); 6.75 (1H, t, J= 6.5, H-4 Ph); 7.17
(2H, t, J = 5.2, H-3,5 Ph). 13C NMR spectrum, δ, ppm: 14.0;
32.7; 40.3; 60.9; 113.8; 118.2; 120.0; 146.5; 152.6; 156.8;
168.1. Mass spectrum, m/z (Irel, %): 261 [M+H]+ (100).
Found, %: С 60.03; Н 6.24; N 21.47. C13H16N4O2.
Calculated, %: C 59.99; Н 6.20; N 21.52.
The solvents were purified and dried according to
standard procedures16 prior to use. The starting hydrazides
1a–d,f–j17 and ethyl malonate monoimidoester18 were
obtained by standard procedures.
Synthesis of 3-substituted ethyl (1H-1,2,4-triazol-5-yl)-
acetates 3a,d (General method). Hydrazide 1a,d (0.10 mol)
was added to a solution of ethyl malonate monoimidoester
(18.40 g, 0.12 mol) in EtOH (200 ml). The mixture was
refluxed for 24 h, the solvent was removed by distillation,
the obtained residue was recrystallized from toluene.
Ethyl (3-methyl-1Н-1,2,4-triazol-5-yl)acetate (3a).
Yield 14.03 g (83%). White crystals. Mp 97–98°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3Н, t, J = 7.5,
OCH2CН3); 2.43 (3H, s, 3-CH3); 3.84 (2H, s, CH2CO);
4.22 (2Н, q, J = 7.5, OCH2СН3); 10.11 (1Н, br. s, NН).
13C NMR spectrum, δ, ppm: 10.2; 14.0; 31.4; 61.9; 149.6;
152.7; 167.2. Mass spectrum, m/z (Irel, %): 170 [M+H]+
(100). Found, %: С 49.75; Н 6.54; N 24.82. C7H11N3O2.
Calculated, %: C 49.70; Н 6.55; N 24.84.
Ethyl (3-hydroxymethyl-1Н-1,2,4-triazol-5-yl)acetate
(3d). Yield 14.62 g (79%). White crystals. Mp 87–89°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.28 (3Н, t, J = 7.2,
OCH2CН3); 3.88 (2H, s, CH2CO); 4.20 (2Н, q, J = 7.2,
OCH2СН3); 4.77 (2H, s, CH2OH); 6.01 (1H, br. s, CH2OH).
13C NMR spectrum, δ, ppm: 13.0; 32.5; 55.4; 60.8; 153.8;
158.2; 168.8. Mass spectrum, m/z (Irel, %): 186 [M+H]+
(100). Found, %: С 45.42; Н 5.96; N 22.72. C7H11N3O3.
Calculated, %: C 45.40; Н 5.99; N 22.69.
Ethyl {3-[(N-benzyloxycarbonylamino)methyl]-1Н-1,2,4-
triazol-5-yl}acetate (3f). Yield 20.35 g (64%). White powder.
1
Mp 115–117°С. H NMR spectrum, δ, ppm (J, Hz): 1.25
(3Н, t, J = 6.8, OCH2CН3); 3.85 (2H, s, CH2CO); 4.17 (2Н,
q, J = 6.8, OCH2СН3); 4.46 (2H, d, J = 6.0, CH2NH); 5.07
(2H, s, OCH2Ph); 6.18 (1H, br. s, CH2NH); 7.30 (5H, s,
H Ph); 10.47 (1Н, br. s, NН triazole). 13C NMR spectrum,
δ, ppm: 13.1; 31.9; 36.1; 60.8; 66.1; 127.1; 127.2; 127.5;
135.2; 152.3; 155.8; 156.1; 167.9. Mass spectrum, m/z (Irel,
%): 319 [M+H]+ (100). Found, %: С 56.60; Н 5.70;
N 17.60. C15H18N4O4. Calculated, %: C 56.62; Н 5.74; N 17.56.
Ethyl [3-(4-nitrophenyl)-1Н-1,2,4-triazol-5-yl]acetate (3g).
1
Yield 23.18 g (84%). Beige powder. Mp 178–179°С. H
NMR spectrum, δ, ppm (J, Hz): 1.36 (3Н, t, J = 7.5,
OCH2CН3); 4.07 (2H, s, CH2CO); 4.32 (2Н, q, J = 7.5,
OCH2СН3); 8.26 (2H, d, J = 9.0, H-3,5 Ar); 8.31 (2H, d,
J = 9.0, H-2,6 Ar); 11.80 (1Н, br. s, NН triazole). 13C NMR
spectrum, δ, ppm (J, Hz): 13.2; 31.6; 61.5; 123.1; 126.2;
135.7; 147.4; 150.3; 159.4; 168.4. Mass spectrum, m/z (Irel,
%): 277 [M+H]+ (100). Found, %: С 52.17; Н 4.38; N 20.28.
C12H12N4O4. Calculated, %: С 52.20; Н 4.44; N 20.27.
Ethyl [3-(4-hydroxyphenyl)-1Н-1,2,4-triazol-5-yl]ace-
tate (3h). Yield 12.15 g (49%). White powder. Mp 213–
1
214°С. H NMR spectrum, δ, ppm (J, Hz): 1.19 (3Н, t,
J = 6.2, OCH2CН3); 3.71 (0.70H, s) and 3.91 (1.30H, s,
CH2CO); 4.11 (2Н, q, J = 6.2, OCH2СН3); 6.80 (0.70H, d,
J = 8.0) and 6.87 (1.30H, d, J = 8.0, H-2,6 Ar); 7.78 (2H, d,
J = 7.2, H-3,5 Ar); 9.65 (0.35H, s) and 9.96 (0.65H, s, ArOH);
13.71 (0.35Н, br. s) and 13.79 (0.65Н, br. s, NН). 13C NMR
spectrum, δ, ppm (J, Hz): 14.1; 32.9; 61.1; 116.0; 128.2;
153.1; 155.0; 160.0; 168.5. Mass spectrum, m/z (Irel, %): 248
[M+H]+ (100). Found, %: С 58.29; Н 5.30; N 16.99.
C13H12N3O3. Calculated, %: C 58.33; Н 5.31; N 16.98.
Ethyl [3-(pyridin-3-yl)-1Н-1,2,4-triazol-5-yl]acetate
(3i). Yield 20.65 g (89%). Beige powder. Mp 111–114°С. 1H
NMR spectrum, δ, ppm (J, Hz): 1.34 (3Н, t, J = 7.0,
OCH2СН3); 4.04 (2H, s, CH2CO); 4.30 (2Н, q, J = 7.0,
OСH2СН3); 7.39 (1H, dd, J = 7.5, J = 4.5, H-5 Py); 8.37 (1H,
d, J = 7.5, H-4 Py); 8.66 (1H, d, J = 4.5, H-6 Py); 9.33 (1H,
s, H-2 Py); 12.09 (1Н, br. s, NН triazole). 13C NMR spectrum, δ,
ppm: 13.1; 32.0; 60.9; 123.2; 126.3; 134.3; 145.4; 147.8;
151.5; 157.0; 168.1. Mass spectrum, m/z (Irel, %): 233 [M+H]+
(100). Found, %: С 56.89; Н 5.24; N 24.08. C11H12N4O2.
Calculated, %: С 56.89; Н 5.21; N 24.12.
Synthesis of 3-substituted ethyl (1H-1,2,4-triazol-5-yl)-
acetates 3b,c,f–j (General method). Hydrazide 1b,c,f–j
(0.10 mol) was added to a solution of ethyl malonate
monoimidoester (18.40 g, 0.12 mol) in EtOH (200 ml), and
the mixture was heated at reflux. A precipitate of
amidrazone 2b,c,f–j started to form after 30 min. Refluxing
was continued until complete dissolution of the starting
hydrazide (1 h), then the solution was cooled. The obtained
precipitate was filtered off, washed with EtOH, air-dried,
and used without additional purification in the next step.
Heating of amidrazones 2b,c,f–j to melting point (120–
240°C) led to the formation of triazoles 3b,c,f–j. The
obtained melts can be recrystallized from EtOH.
Ethyl (3-phenoxymethyl-1Н-1,2,4-triazol-5-yl)acetate
(3b). Yield 19.30 g (74%). White powder. Mp 81–82°С.
1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3Н, t, J = 7.0,
OCH2CН3); 3.95 (2H, s, CH2CO); 4.22 (2Н, q, J = 7.0,
OCH2СН3); 5.19 (2Н, s, CН2OPh); 6.98 (1H, t, J = 8.0, H-4
Ph); 7.00 (2H, d, J = 8.0, H-2,6 Ph); 7.29 (2H, t, J = 8.0, H-3,5
Ph); 10.63 (1Н, br. s, NН). 13C NMR spectrum, δ, ppm: 13.1;
31.2; 60.8; 61.7; 113.6; 120.5; 128.5; 152.4; 156.3; 156.9;
168.2. Mass spectrum, m/z (Irel, %): 262 [M+H]+ (100). Found,
Ethyl [3-(pyridin-4-yl)-1Н-1,2,4-triazol-5-yl]acetate (3j).
Yield 20.42 g (88%). Beige powder. Mp 118–119°С.
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Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
1H NMR spectrum, δ, ppm (J, Hz): 1.34 (3Н, t, J = 7.0,
{3-[(N-Benzyloxycarbonylamino)methyl]-1Н-1,2,4-tri-
azol-5-yl}acetic acid (4f). Yield 5.84 g (64%). White
powder. Mp 159–161°С (decomp., H2O). 1H NMR
spectrum, δ, ppm (J, Hz): 3.67 (2H, s, CH2CO); 4.23 (2H,
s, CH2NHCO); 5.04 (2H, s, OCH2Ph); 7.36 (5H, s, H Ph);
7.72 (1H, br. s, CH2NHCO); 12.73 (1Н, br. s, NН triazole);
13.39 (1H, br. s, COOH). 13C NMR spectrum, δ, ppm:
32.2; 36.5; 66.0; 128.0; 128.1; 128.5; 136.8; 151.6; 155.7;
156.5; 169.8. Mass spectrum, m/z (Irel, %): 291 [M+H]+
(100). Found, %: С 53.64; Н 4.82; N 19.23. C13H14N4O4.
Calculated, %: C 53.79; H 4.86; N 19.30.
OCH2СН3); 4.05 (2H, s, CH2CO); 4.30 (2Н, q, J = 7.0,
OСH2СН3); 7.99 (2H, d, J = 5.0, H-3,5 Py); 8.72 (2H, d,
J = 5.0, H-2,6 Py); 12.41 (1Н, br. s, NН). 13C NMR
spectrum, δ, ppm: 14.1; 32.6; 61.2; 121.8; 143.0; 145.7;
153.1; 157.1; 168.2. Mass spectrum, m/z (Irel, %): 233
[M+H]+ (100). Found, %: C 56.94; Н 5.18; N 24.13.
C11H12N4O2. Calculated, %: С 56.89; Н 5.21; N 24.12.
Ethyl (3-aminomethyl-1Н-1,2,4-triazol-5-yl)acetate
(3e). Pd/C (10%) catalyst (0.10 g) was added to a solution
of ester 3f (1.00 g, 3.14 mmol) in EtOH (20 ml), and the
mixture was stirred under hydrogen atmosphere at room
temperature for 20 h. The reaction mixture was filtered and
the filtrate was evaporated to dryness. The white crystalline
residue was suspended in Et2O (15 ml), stirred for 24 h, the
precipitate of compound 3e was filtered off and air-dried.
Yield 0.47 g (81%). White powder. Mp 108–109°С (Et2O).
1H NMR spectrum, δ, ppm (J, Hz): 1.26 (3Н, t, J = 5.6,
[3-(4-Nitrophenyl)-1Н-1,2,4-triazol-5-yl]acetic
acid
(4g). Yield 6.11 g (68%). White powder. Mp 111–113°С
(decomp., H2O). 1H NMR spectrum, δ, ppm (J, Hz): 3.88 (2H,
s, CH2CO); 8.23 (2H, d, J = 8.8, H-3,5 Ar); 8.30 (2H, d,
J = 8.8, H-2,6 Ar); 14.04 (1Н, br. s, NН). 13C NMR
spectrum, δ, ppm: 32.8; 124.4; 127.1; 136.2; 147.9; 153.0;
157.8; 169.8. Mass spectrum, m/z (Irel, %): 249 [M+H]+
(100). Found, %: C 48.33; H 3.29; N 22.48. C10H8N4O4.
Calculated, %: C 48.39; H 3.25; N 22.57.
+
OCH2CН3); 3.84 (2H, s, CH2CO); 4.02 (2H, s, CH2NH3+);
4.18 (2Н, q, J = 5.6, OCH2СН3); 5.32 (3H, s, CH2NH3 ).
13C NMR spectrum, δ, ppm: 13.1; 32.8; 37.5; 60.6; 153.8;
159.3; 168.7. Mass spectrum, m/z (Irel, %): 185 [M+H]+
(100). Found, %: С 45.68; Н 6.54; N 30.43. C7H12N4O2.
Calculated, %: C 45.65; H 6.57; N 30.42.
[3-(4-Hydroxyphenyl)-1Н-1,2,4-triazol-5-yl]acetic acid
(4h). Yield 6.47 g (73%). Light-brown powder. Mp 143–
1
145°С (decomp., H2O). H NMR spectrum, δ, ppm (J, Hz):
3.73 (2H, s, CH2CO); 6.85 (2H, d, J = 8.4, H-2,6 Ar); 7.79
(2H, d, J = 8.4, H-3,5 Ar); 9.88 (1H, br. s, ArOH); 12.74
(1Н, br. s, NН). 13C NMR spectrum, δ, ppm: 32.6; 116.0;
116.3; 128.6; 152.4; 155.0; 160.5; 169.6. Mass spectrum, m/z
(Irel, %): 220 [M+H]+ (100). Found, %: С 54.89; Н 4.16;
N 19.13. C10H9N3O3. Calculated, %: С 54.80; Н 4.14;
N 19.17.
Synthesis of 3-substituted (1H-1,2,4-triazol-5-yl)-
acetic acids 4a–c,f–j (General method). Ester 3a–c,f–j
(10 g) was treated by the addition of 3 equiv of 1 N NaOH
solution. The hydrolysis occurred at room temperature over
10 h. The reaction mixture was then acidified with an
equimolar amount of HCl, and crystalline precipitate of
acid 4a–c,f–j was obtained.
[3-(Pyridin-3-yl)-1Н-1,2,4-triazol-5-yl]acetic acid (4i).
Yield 5.19 g (59%). Beige powder. Mp 211–212°С
(3-Methyl-1Н-1,2,4-triazol-5-yl)acetic acid (4a). Yield
6.50 g (78%). White powder. Mp 193–195°С (decomp.,
1
(decomp., H2O). H NMR spectrum, δ, ppm (J, Hz): 3.88
1
H2O). H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s,
(2H, s, CH2CO); 7.52 (1H, dd, J = 8.4, J = 5.2, H-5 Py);
8.32 (1H, d, J = 8.4, H-4 Py); 8.64 (1H, d, J = 5.2, H-6 Py);
9.17 (1H, s, H-2 Py); 12.84 (1H, br. s, СООН); 14.04 (1Н,
br. s, NН). 13C NMR spectrum, δ, ppm: 32.1; 125.5; 127.8;
136.5; 144.1; 147.2; 153.2; 156.7; 170.0. Mass spectrum,
m/z (Irel, %): 205 [M+H]+ (100). Found, %: C 52.88;
H 4.01; N 27.39. C9H8N4O2. Calculated, %: C 52.94;
H 3.95; N 27.44.
CH3); 3.59 (2H, s, CH2CO); 13.32 (1Н, br. s, NН triazole).
13C NMR spectrum, δ, ppm: 10.2; 31.5; 150.0; 152.6;
168.7. Mass spectrum, m/z (Irel, %): 142 [M+H]+ (100).
Found, %: С 42.61; H 4.99; N 29.72. C5H7N3O2.
Calculated, %: C 42.55; H 5.00; N 29.77.
(3-Phenoxymethyl-1Н-1,2,4-triazol-5-yl)acetic acid
(4b). Yield 6.07 g (71%). White powder. Mp 122–123°С.
1H NMR spectrum, δ, ppm (J, Hz): 3.75 (2H, s, CH2CO);
5.08 (2Н, s, CН2OPh); 6.95 (1H, t, J = 8.0, H-4 Ph); 7.03
(2H, d, J = 8.0, H-2,6 Ph); 7.29 (2H, t, J = 8.0, H-3,5 Ph);
13.81 (1Н, br. s, NН). 13C NMR spectrum, δ, ppm: 34.5; 61.6;
114.8; 121.5; 129.8; 152.2; 155.2; 157.9; 163.4. Mass
spectrum, m/z (Irel, %): 234 [M+H]+ (100). Found, %:
С 56.68; Н 4.71; N 18.00. C11H11N3O3. Calculated, %:
С 56.65; Н 4.75; N 18.02.
[3-(Pyridin-4-yl)-1Н-1,2,4-triazol-5-yl]acetic acid (4j).
Yield 6.51 g (74%). Beige powder. Mp 238–239°С (decomp.,
H2O). 1H NMR spectrum, δ, ppm (J, Hz): 3.87 (2H, s, CH2CO);
7.90 (2H, d, J = 5.4, H-3,5 Py); 8.67 (2H, d, J = 5.4, H-2,6 Py);
14.02 (1Н, br. s, NН). Mass spectrum, m/z (Irel, %): 205
[M+H]+ (100). Found, %: С 52.92; Н 4.01; N 27.39.
C9H8N4O2. Calculated, %: C 52.94; H 3.95; N 27.44.
Synthesis of 3-substituted 5-methyl-1H-1,2,4-triazoles
5b,с,f–j (General method). The appropriate carboxylic acid
4b,с,f–j (1 g) was heated to the melting point. The process
of melting was accompanied by vigorous evolution of
carbon dioxide. The obtained amorphous melts were pure
methyltriazoles 5b,c,f–j according to spectral data.
(3-Phenylaminomethyl-1Н-1,2,4-triazol-5-yl)acetic acid
(4с). Yield 5.62 g (63%). White powder. Mp 197–198°С
1
(decomp., H2O). H NMR spectrum, δ, ppm (J, Hz): 3.65
(2H, s, CH2CO); 4.25 (2Н, s, CН2NHPh); 6.09 (1Н, br. s,
СН2NHPh); 6.54 (1H, t, J = 8.0, H-4 Ph); 6.62 (2H, d,
J = 7.2, H-2,6 Ph); 7.05 (2H, t, J = 7.2, H-3,5 Ph); 13.16 (1Н,
br. s, NН). 13C NMR spectrum, δ, ppm: 32.7; 40.2; 113.7;
118.3; 129.2; 146.8; 152.4; 156.9; 169.6. Mass spectrum, m/z
(Irel, %): 233 [M+H]+ (100). Found, %: C 56.97; H 5.26; N 24.22.
C11H12N4O2. Calculated, %: C 56.89; H 5.21; N 24.19.
5-Methyl-3-phenoxymethyl-1Н-1,2,4-triazole
(5b).
1
Yield 0.80 g (94%). Beige powder. H NMR spectrum, δ,
ppm (J, Hz): 2.49 (3H, s, CH3); 5.17 (2Н, s, CН2OPh); 6.98
(2H, d, J = 6.0, H-2,6 Ph); 6.99 (1H, t, J = 8.0, H-4 Ph);
7.29 (2H, t, J = 8.0, H-3,5 Ph); 8.89 (1Н, br. s, NН).
406

Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
13C NMR spectrum, δ, ppm: 10.8; 60.9; 114.9; 121.7;
aniline (1.40 g, 0.015 mol) was heated to 120°С. The
obtained melt was crystallized from EtOH. Yield 1.85 g
(66%). White crystals. Mp 184–185°С. 1H NMR spectrum,
δ, ppm (J, Hz): 3.99 (2Н, s, CH2CO); 7.06 (1Н, t, J = 7.6,
H-4 Ph); 7.32 (2H, d, J = 7.6, H-3,5 Ph); 7.61 (2Н, d,
J=7.6, H-2,6 Ph); 7.90 (2H, d, J = 5.6, H-3,5 Py); 8.65 (2Н,
d, J = 5.6, H-2,6 Py); 10.39 (1Н, s, CONHPh); 14.25 (1Н,
br. s, NН triazole). 13C NMR spectrum, δ, ppm: 34.7;
119.3; 122.8; 123.8; 129.0; 138.9; 142.9; 146.6; 154.1;
156.8; 165.5. Mass spectrum, m/z (Irel, %): 280 [M+H]+
(100). Found, %: С 64.58; Н 4.49; N 25.08. C15H13N5O.
Calculated, %: C 64.51; H 4.69; N 25.07.
N-Benzyl[3-(4-nitrophenyl)-1Н-1,2,4-triazol-5-yl]acet-
amide (7). A solution of ester 3g (2.76 g, 0.010 mol) and
benzylamine (1.40 g, 0.015 mol) in toluene (50 ml) was
refluxed for 24 h. The precipitate that formed was filtered
off, washed with toluene, and dried. Yield 2.40 g (71%).
White crystals. Mp 233–235°С (PhMe). 1H NMR
spectrum, δ, ppm (J, Hz): 3.82 (2H, s, CH2CO); 4.34 (2H,
d, J = 6.0, NHСН2Ph); 7.24–7.36 (5Н, m, H Ph); 8.25 (2Н,
d, J = 8.8, H Ar); 8.36 (2Н, d, J = 8.8, H Ar); 8.79 (1Н, t,
J = 6.0, NHСН2Ph); 14.25 (1Н, br. s, NН triazole). 13C
NMR spectrum, δ, ppm: 33.7; 42.6; 124.4; 127.0; 127.1;
127.5; 128.5; 136.1; 139.2; 147.9; 153.5; 157.6; 166.7.
Mass spectrum, m/z (Irel, %): 338 [M+H]+ (100). Found, %:
С 60.53; Н 4.44; N 20.71. C17H15N5O3. Calculated, %:
C 60.53; H 4.48; N 20.76.
[3-(Pyridin-3-yl)-1Н-1,2,4-triazol-5-yl]acetamide (8). A
mixture of ester 3i (2.32 g, 0.01 mol) and 25% aqueous
ammonia (10 ml) was refluxed for 10 h. The obtained
solution was evaporated to dryness, the residue was
recrystallized from EtOH. Yield 1.70 g (78%). Beige
crystals. Mp 241–243°С. 1H NMR spectrum, δ, ppm (J, Hz):
3.68 (2H, s, СH2CO); 7.18 (1H, br. s) and 7.67 (1H, br. s,
CONH2); 7.50 (1H, dd, J = 7.6, J = 5.2, H-5 Py); 8.29 (1H,
d, J = 7.6, H-4 Py); 8.61 (1H, d, J = 5.2, H-6 Py); 9.15 (1Н,
s, H-2 Py); 14.04 (1H, br. s, NH triazole). 13C NMR
spectrum, δ, ppm: 33.4; 127.9; 130.3; 139.3; 142.0; 142.3;
153.8; 155.7; 168.7. Mass spectrum, m/z (Irel, %): 204 [M+H]+
(100). Found, %: C 53.24; H 4.43; N 34.48. C9H9N5O.
Calculated, %: C 53.20; H 4.46; N 34.46.
129.8; 153.6; 153.8; 157.6. Mass spectrum, m/z (Irel, %):
190 [M+H]+ (100). Found, %: С 63.55; Н 5.82; N 22.23.
C10H11N3O. Calculated, %: C 63.48; Н 5.86; N 22.21.
N-[(5-Methyl-1Н-1,2,4-triazol-3-yl)methyl]aniline (5с).
1
Yield 0.78 g (96%). White powder. H NMR spectrum, δ,
ppm (J, Hz): 2.44 (3H, s, CH3); 4.45 (2Н, s, CН2NHPh);
6.66 (2H, d, J = 7.5, H-2,6 Ph); 6.76 (1H, t, J = 7.5, H-4
Ph); 7.18 (2H, t, J = 7.5, H-3,5 Ph). 13С NMR spectrum, δ,
ppm: 11.8; 40.8; 112.5; 117.6; 128.7; 146.8; 155.4; 159.3.
Mass spectrum, m/z (Irel, %): 189 [M+H]+ (100). Found, %:
С 63.76; Н 6.42; N 29.82. C10H12N4. Calculated, %:
С 63.81; Н 6.43; N 29.76.
Benzyl [(5-methyl-1H-1,2,4-triazol-3-yl)methyl]carba-
1
mate (5f). Yield 0.77 g (91%). White powder. H NMR
spectrum, δ, ppm (J, Hz): 2.39 (3H, s, CH3); 4.44 (2H, d,
CH2NH); 5.07 (2H, s, OCH2Ph); 6.11 (1H, br. s, NHCH2CO);
7.30 (5H, s, H Ph); 12.39 (1Н, br. s, NН triazole). 13C NMR
spectrum, δ, ppm: 11.3; 37.0; 65.6; 127.8; 127.9; 128.3;
136.9; 153.8; 156.3; 156.9. Mass spectrum, m/z (Irel, %): 247
[M+H]+ (100). Found, %: С 58.51; Н 5.79; N 22.74.
C12H14N4O2. Calculated, %: С 58.53; Н 5.73; N 22.75.
5-Methyl-3-(4-nitrophenyl)-1Н-1,2,4-triazole
(5g).
1
Yield 0.80 g (97%). Beige powder. H NMR spectrum, δ,
ppm (J, Hz): 2.61 (3H, s, CH3); 8.26 (2H, d, J = 9.0, H-3,5
Ar); 8.31 (2H, d, J = 9.0, H-2,6 Ar). 13C NMR spectrum, δ,
ppm: 11.3; 124.3; 127.1; 134.9; 148.0; 154.6; 156.3. Mass
spectrum, m/z (Irel, %): 205 [M+H]+ (100). Found, %:
С 52.88; Н 3.90; N 27.47. C9H8N4O2. Calculated, %:
C 52.94; H 3.95; N 27.44.
4-(5-Methyl-1Н-1,2,4-triazol-3-yl)phenol (5h). Yield
1
0.78 g (98%). White powder. H NMR spectrum, δ, ppm
(J, Hz): 2.26 (1.05H, s) and 2.36 (1.95H, s, CH3); 6.79
(0.70H, d, J = 7.6) and 6.85 (1.30H, d, J = 7.6, H-2,6 Ar);
7.77 (2H, d, J = 7.6, H-3,5 Ar); 9.61 (0.35H, br. s) and 9.91
(0.65H, br. s, OH); 13.79 (0.65Н, br. s) and 14.43 (0.35Н,
br. s, NН). 13C NMR spectrum, δ, ppm: 11.1; 116.1; 116.3;
128.4; 153.6; 154.8; 160.3. Mass spectrum, m/z (Irel, %):
176 [M+H]+ (100). Found, %: С 61.78; Н 5.17; N 23.96.
C9H9N3O. Calculated, %: С 61.70; Н 5.18; N 23.99.
5-Methyl-3-(pyridin-3-yl)-1Н-1,2,4-triazole (5i). Yield
1
0.74 g (94%). Beige powder. H NMR spectrum, δ, ppm
Hydrazide of [3-(pyridin-3-yl)-1Н-1,2,4-triazol-5-yl]-
acetic acid (9). A solution of ester 3i (2.32 g, 0.010 mol)
and N2H4·H2O (0.55 g, 0.011 mol) in EtOH (50 ml) was
refluxed for 1 h. The precipitate that formed was filtered off,
washed with EtOH, and dried. Yield 2.00 g (92%). White
(J, Hz): 2.58 (3H, s, CH3); 7.41 (1H, dd, J = 8.0, J = 5.0,
H-5 Py); 8.39 (1H, d, J = 8.0, H-4 Py); 8.66 (1H, d, J = 5.0,
H-6 Py); 9.35 (1H, s, H-2 Py); 11.69 (1Н, br. s, NН).
13C NMR spectrum, δ, ppm: 11.8; 125.4; 128.2; 136.5;
143.8; 146.7; 154.9; 157.0. Mass spectrum, m/z (Irel, %):
161 [M+H]+ (100). Found, %: С 59.98; Н 5.09; N 35.01.
C8H8N4. Calculated, %: C 59.99; H 5.03; N 34.98.
1
crystals. Mp 218–219°С (EtOH). H NMR spectrum, δ,
ppm (J, Hz): 3.64 (2H, s, CH2CO); 4.32 (2H, br. s,
NHNH2); 7.49 (1H, dd, J = 8.0, J = 4.4, H-5 Py); 8.28 (1H,
d, J = 8.0, H-4 Py); 8.61 (1H, d, J = 4.4, H-6 Py); 9.14 (1Н,
s, H-2 Py); 9.37 (1H, br. s, NHNH2); 13.93 (1H, br. s, NH
triazole). 13C NMR spectrum, δ, ppm: 32.3; 124.2; 126.4;
133.4; 146.8; 157.1; 153.6; 157.3; 166.7. Mass spectrum,
m/z (Irel, %): 219 [M+H]+ (100). Found, %: С 49.55;
Н 4.58; N 38.56. C9H10N6O. Calculated, %: C 49.54;
H 4.62; N 38.51.
5-Methyl-3-(pyridin-4-yl)-1Н-1,2,4-triazole (5j). Yield
1
0.75 g (96%). Beige powder. H NMR spectrum, δ, ppm
(J, Hz): 2.58 (3H, s, CH3); 7.99 (2H, d, J = 7.5, H-3,5 Py);
8.71(2H, d, J = 7.5, H-2,6 Py); 11.69 (1Н, br. s,
NН triazole). 13C NMR spectrum, δ, ppm: 11.8; 121.3;
142.6; 146.7; 155.4; 157.6. Mass spectrum, m/z (Irel, %):
161 [M+H]+ (100). Found, %: С 59.97; Н 4.99; N 34.94.
C8H8N4. Calculated, %: C 59.99; H 5.03; N 34.98.
Ethyl 3-(furan-2-yl)-2-[3-(pyridin-3-yl)-1H-1,2,4-tria-
zol-5-yl]prop-2-enoate (10). A solution of ester 3i (2.32 g,
0.010 mol), furfurol (1.15 g, 0.012 mol), and piperidine
[3-(Pyridin-4-yl)-1Н-1,2,4-triazol-5-yl]-N-phenylacet-
amide (6). A mixture of ester 3j (2.32 g, 0.01 mol) and
407

Chemistry of Heterocyclic Compounds 2016, 52(6), 402–408
2. (a) Chernyshev, V. M.; Chernysheva, A. V.; Taranushich, V. A.
(0.1 ml) in EtOH (50 ml) was refluxed for 36 h. The
obtained solution was evaporated to dryness, the residue
was recrystallized from toluene. Yield 1.73 g (56%).
Russ. J. Appl. Chem. 2006, 79, 783. [Zh. Prikl. Khim. 2006,
79, 792.] (b) Nara, H.; Kaieda, A.; Sato, K.; Terauchi, J. Eur.
Patent 1953148.
1
Brown crystals. Mp 170–174°С. H NMR spectrum, δ,
3. (a) Kiselyov, A. S.; Piatnitski Chekler, E. L.; Chernisheva, N. B.;
Salamandra, L. K.; Semenov, V. V. Tetrahedron Lett. 2009,
50, 3809. (b) Moderhack, D.; Schneider, J.-C. J. Heterocycl.
Chem. 2007, 44, 393.
ppm (J, Hz): 1.22 (3Н, t, J = 6.8, OCH2СН3); 4.22 (2Н, q,
J = 6.8, OСH2СН3); 6.60 (1Н, s, H Fur); 6.92 (1Н, br. s,
H Fur); 7.52 (1H, d, J = 6.0, J = 3.6, H-5 Py); 7.78 (1Н, s,
H Fur); 7.87 (1Н, s, С=СН); 8.36 (1H, d, J = 6.0, H-4 Py);
8.63 (1H, d, J = 3.6, H-6 Py); 9.21 (1Н, s, H-2 Py); 14.31
(1Н, br. s, NН). 13C NMR spectrum, δ, ppm (J, Hz): 14.2;
61.5; 113.3; 114.7; 120.3; 126.6; 128.9; 132.0; 139.1;
142.0; 145.0; 148.0; 149.0; 151.9; 156.8; 165.0. Mass
spectrum, m/z (Irel, %): 311 [M+H]+ (100). Found, %:
С 61.91; Н 4.62; N 17.97. C16H14N4O3. Calculated, %:
C 61.93; H 4.55; N 18.05.
4. (a) Abdel-Megeed, A. M.; Abdel-Rahman, H. M.;
Alkaramany, G.-E. S.; El-Gendy, M. A. Eur. J. Med. Chem.
2009, 44, 117. (b) Kofman, T. P.; Uvarova, T. A.; Kartseva, G. Y.;
Uspenskaya, T. L. Russ. J. Org. Chem. 1997, 33, 1784. [Zh.
Org. Khim. 1997, 33, 1876.]
5. Al-Soud, Y. A.; Al-Masoudi, N. A.; Ferwanah, A. El-R. S.
Bioorg. Med. Chem. 2003, 11, 1701.
6. (a) Thottempudi, V.; Gao, H.; Shreeve, J. M. J. Am. Chem.
Soc. 2011, 133, 6464. (b) Thottempudi, V.; Shreeve, J. M.
Synthesis 2012, 44, 1253.
7. Gienckle, W.; Lehr, S.; Fischer, R.; Lindell, D. S.; Haeuser-
Hahn, I.; Heinemann, I.; Gatzweiler, E.; Rosinger, C. H.;
Becker, A.; Voerste, A.; Goergens, U. D. I. US Patent
20140302988.
Ethyl 2-[3-(4-nitrophenyl)-1H-1,2,4-triazol-5-yl]-3-(thio-
phen-2-yl)prop-2-enoate (11). A solution of ester 3g (2.76 g,
0.010 mol), thiophene-2-carbaldehyde (1.35 g, 0.012 mol),
and piperidine (0.1 ml) in EtOH (50 ml) was refluxed for
36 h. The obtained solution was evaporated to dryness, the
residue was recrystallized from toluene. Yield 2.00 g
8. (a) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42, 4331.
(b) Blayo, A.-L.; Brunel, F.; Martinez, J.; Fehrentz, J.-A. Eur.
J. Org. Chem. 2011, 23, 4293.
9. (a) Adams, A. D.; Green, A. I.; Szewczyk J. W. WO Patent
2007064553. (b) Maruyama, T.; Onda, K.; Hayakawa, M.;
Suzuki, T.; Kimizuka, T.; Matsui, T.; Takasu, T.; Nagase, I.;
Hamada, N.; Ohta, M. Chem. Pharm. Bull. 2010, 58, 533. (c)
Gonzalez, A. Z.; Li, Z.; Beck, H. P.; Canon, J.; Chen, A.;
Chow, D.; Duquette, J.; Eksterowicz, J.; Fox, B. M.; Fu, J.;
Huang, X.; Houze, J.; Jin, L.; Li, Y.; Ling, Y.; Lo, M.-C.;
Long, A. M.; McGee, L. R.; McIntosh, J.; Oliner, J. D.;
Osgood, T.; Rew, Y.; Saiki, A. Y.; Shaffer, P.; Wortman, S.;
Yakowec, P.; Yan, X.; Ye, Q.; Yu, D.; Zhao, X.; Zhou, J.;
Olson, S. H.; Sun, D.; Medina, J. C. J. Med. Chem. 2014, 57, 2963.
10. (a) Woodard, S. S.; Jerome, K. D. Comb. Chem. High
Throughput Screening 2011, 14(2), 132. (b) Khomenko, D. N.;
Doroschuk, R. A.; Lampeka, R. D. Ukr. Khim. Zh. 2009, 75(7),
30. (c) Khomenko, D. M.; Doroschuk, R. O.; Vaschenko, O. V.;
Lampeka, R. D. Ukr. Khim. Zh. 2014, 80(12), 83.
1
(54%). Light-brown crystals. Mp 231–233°С. H NMR
spectrum, δ, ppm (J, Hz): 1.23 (3Н, t, J = 7.2, OCH2СН3);
4.23 (2Н, q, J = 7.2, OСH2СН3); 7.12 (1Н, dd, J = 4.8,
J = 3.6, H thiophene); 7.68 (1Н, d, J = 3.6, H thiophene);
7.74 (1Н, d, J = 4.8, H thiophene); 8.31 (1Н, s, С=СН);
8.32 (2Н, d, J = 8.0, H-3,5 Ar); 8.36 (2Н, d, J = 8.0, H-2,6
Ar); 14.59 (1Н, br. s, NН). 13C NMR spectrum, δ, ppm
(J, Hz): 14.3; 61.4; 116.0; 124.5; 127.0; 127.8; 134.3;
136.4; 136.6; 137.4; 139.3; 147.8; 151.4; 159.2; 165.1.
Mass spectrum, m/z (Irel, %): 371 [M+H]+ (100). Found, %:
С 55.10; Н 3.84; N 15.13. C17H14N4O4S. Calculated, %:
C 55.13; H 3.81; N 15.13.
11. (a) Ainsworth, C.; Jones, R. G. J. Am. Chem. Soc., 1954, 76,
5651. (b) Danagulyan, G. G.; Panosyan, G. A.; Sahakyan, L. G.
Chem. Heterocycl. Compd. 2007, 43, 996. [Khim. Geterotsikl.
Soedin. 2007, 1175.]
Supplementary information file containing 1Н and 13С NMR
spectra of the obtained compounds is available online at
http://link.springer.com/journal/10593.
12. Gilchrist, T. L. Heterocyclic Chemistry [Russian translation];
Mir: Moscow, 1996, p. 351.
13. (a) Cocco, M. T.; Congiu, C.; Maccioni, A.; Onnis, V. J.
Heterocycl. Chem. 1992, 29, 1631. (b) Neilson, D. G.; Roger, R.;
Heatlie, J. W. M.; Newlands, L. R. Chem. Rev. 1970, 80, 151.
14. Begtrup, M. J. Chem. Soc., Perkin Trans. 2, 1976, 736.
15. (a) Brown, B. R. Q. Rev., Chem. Soc. 1951, 5, 131.
(b) Volovenko, Yu. M.; Kartsev, V. G.; Komarov, I. V.;
Turov, A. V.; Khilya, V. P. Nuclear Magnetic Resonance
Spectroscopy for Chemists [in Russian]; MBFNP, 2011, p. 135.
16. Gordon, A. J.; Ford, R. A. Chemist’s Companion: Practical
Data, Techniques, References [Russian translation]; Mir:
Moscow, 1976, p. 437.
References
1. (a) Al-Masoudi, I. A.; Al-Soud, Y. A.; Al-Salihi, N. J.;
Al-Masoudi, N. A. Chem. Heterocycl. Compd. 2006, 42,
1377. [Khim. Geterotsikl. Soedin. 2006, 1605.] (b) Johnson, E. M.;
Szekely, A.; Warnock, D. W. Antimicrob. Agents Chemother.
1999, 43, 1260. (c) Tsukuda, T.; Shiratori, Y.; Watanabe, M.;
Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N. Bioorg.
Med. Chem. Lett. 1998, 8, 1819. (d) Roberts, J.; Schock, K.;
Marino, S.; Andriole V. T. Antimicrob. Agents Chemother.
2000, 44, 3381. (e) Neikova, N.; Simonov, D.; Galunska, G.;
Velichkova, A.; Gulubov, A.; Karparov, A. Arzeim. Forsch.
1981, 31, 747.
17. Volovel'skii, L. N.; Knorozova, G. V. J. Gen. Chem. USSR
(Engl. Transl.) 1964, 34, 341. [Zh. Obsch. Khim. 1964, 34, 343.]
18. Clickman, S. A.; Cope, A. C. J. Am. Chem. Soc. 1945, 67, 1012.
408