Synthesis and reactions of thioamides of 5-amino-2-aryl-2H-1,2,3-triazole- 4-carboxylic acid

Article abstract of DOI:10.1007/s10593-009-0348-x

A method has been developed for obtaining thioamides of 5-amino-2-aryl-2H-1,2,3-triazole-4-carboxylic acid. Their heterocyclization reactions with bifunctional reagents has been studied. New heterocyclic polycyclic ensembles have been synthesized containi

Full text of DOI:10.1007/s10593-009-0348-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
SYNTHESIS AND REACTIONS
OF THIOAMIDES OF 5-AMINO-
2-ARYL-2H-1,2,3-TRIAZOLE-
4-CARBOXYLIC ACID
N. P. Belskaya1**, S. G. Sapozhnikova1, V. A. Bakulev1,
O. S. Eltsov, P. A. Slepukhin2, and Z.-J. Fan3
A method has been developed for obtaining thioamides of 5-amino-2-aryl-2H-1,2,3-triazole-
4-carboxylic acid. Their heterocyclization reactions with bifunctional reagents has been studied. New
heterocyclic polycyclic ensembles have been synthesized containing a 1,2,3-triazole fragment, a
thiazole, and a residue of the natural alkaloid cytisine.
Keywords: aminoimidazoles, α-halo ketones, thiazoles, thioamides, thioimidinium salts, 1,2,3-tria-
zoles, 1,2,4-triazoles.
We previously developed a procedure for the synthesis of arylhydrazonoacetamidines containing
fragments of natural compounds and pharmacophoric groups, and also substituents differing in spatial and
electronic effects at the nitrogen atom of the amidine group [1]. A broad series of 5-amino-2-aryl-2H-1,2,3-
triazole-4-carbonitriles was obtained by the oxidative cyclization reaction of the synthesized
arylhydrazonoacetamidines. The new compounds showed good fungicidal activity at concn. = 50 µg/ml in
experiments in vitro [1]. It should be noted that the synthesized 2H-1,2,3-triazoles contain a cyano group at the
C-5 atom of the heterocycle and are of interest as building blocks for obtaining new heterocyclic compounds and
for studying their biological activity. Its transformation into a thioamide function is the most widespread
direction of modification of the cyano group. Such a transformation is of undoubted interest, since thioamides,
although being a long established and widely known class of compounds, and up to the present time continue to
be the focus of intensive investigations in organic, and especially heterocyclic chemistry. The main reason for
such steady attention is the large variety of chemical reactions of thioamides [2-4].
_______
* Dedicated to Academician of the Russian Academy of Sciences O. N. Chupakhin on his 75th jubilee.
** To whom correspondence should be addressed, e-mail: belska@mail.ustu.ru.
1Ural State Technological University named of the First President of Russia B. N. Yeltsin, Ekaterinburg 620002,
Russia.
2I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences, Ekaterinburg
620041, Russia.
3State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, China.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1061-1071, July, 2009. Original
article submitted June 1, 2009.
844
0009-3122/09/4507-0844©2009 Springer Science+Business Media, Inc.

The present work is devoted to the synthesis and investigation of the reactions of thioamides of
5-amino-2-aryl-2H-1,2,3-triazole-4-carboxylic acid for constructing new polyheterocycles and the study of their
biological action.
Various methods are proposed in the literature for obtaining thioamides [5, 6]. Of them the most
convenient methods are based on the reaction of nitriles with hydrogen sulfide, the important special feature of
which is the possibility of carrying it out without the formation of side products. Thioamides 2 were obtained in
good yield on passing hydrogen sulfide through a cooled solution of 2H-1,2,3-triazole-4-carbonitriles 1a-f in
pyridine in the presence of triethylamine. The structure of compounds 2a-f was confirmed by spectral data and
by data of elemental analysis.
S
NH2
CN
N
H2S
N
N
pyridine
Ar
NRR1
N
N
NRR1
Ar
N
2a–f
55–95%
1a–f
1, 2 a–e Ar = 4-MeOC6H4, a NRR1 = NHMe, b NRR1 = NHC6H11-cyclo,
c NRR1 = piperidino,, d NRR1 = morpholino, e NRR1 = 4-(pyrimidin-2-yl)piperazin-1-yl;
O
N
N
f Ar = 4-FC6H4, NRR1 =
Transformation of the nitrile group of triazoles 1 into a thioamide allows the introduction of two
additional nucleophilic centers into position 4 of the triazole ring and an electrophilic center associated with the
thiocarbonyl carbon atom. Thanks to the presence of these reactive centers, and also the amino group in the
ortho position in compounds 2a,b the reaction of triazoles 2 with various bifunctional reagents becomes
practicable.
O
a
S
Br
NH
S
R2
N
Ar
N
N
N
NH2
3
R2
Ar
N
N
–HBr
NRR1
NRR1
O
2a–f
4a–f
R1 = H
HN
–H2O
–H2O
R2
S
N
N
Ar
N
N
S
N
R2
N
N
N
Ar
NRR1
R
6a,b
5a–f 52–74%
3 a R2 = 4-ClC6H4, b R2 = 4-MeOC6H4, c R2 = pyridin-3-yl; 4, 5 a–e Ar = 4-MeOC6H4,
a NRR1 = HNMe, R2 = 4-ClC6H4; b NRR1 = HNC6H11-cyclo, R2 = 4-ClC6H4;
c NRR1 = piperidino, R2 = pyridin-3-yl; d NRR1 = morpholino, R2 = 4-ClC6H4;
e NRR1 = 4-(pyrimidin-2-yl)piperazin-1-yl, R2 = pyridin-3-yl; f Ar = 4-FC6H4,
O
N
N
NRR1 =
, R2 = 4-ClC6H4; 6 a, b Ar = 4-MeOC6H4, R2 = 4-ClC6H4,
a R = Me, b R = C6H11-cyclo
845

One of the most convenient and widespread methods of heterocyclization of thioamides is their
interaction with α-halo ketones (Hantzsch reaction) [7, 8]. The interaction usually occurs on boiling the initial
reactants in an organic solvent.
Reaction of thioamides 2 with α-halo ketones was carried out on heating in ethyl alcohol for 5-6 h. The
1
crystalline product was separated by filtration. Signals appeared in the H NMR spectra of 5-amino-2-aryl-
4-(thiazol-2-yl)-2H-1,2,3-triazoles 5a-f corresponding to the proton-containing group in position 4 of the
thiazole ring and a singlet for the proton in position 5 of the thiazole ring at 7.14-8.64 ppm.
The structure of compound 5d was investigated by X-ray crystallography (Fig. 1). The overall
organization of the molecule, bond lengths, and valence angles were close to usual for such a system. The
heterocycles form a planar conjugated system, with deviation of atoms from the mean square plane no more than
0.04 Å. The plane of the 4-methoxyphenyl substituent is twisted relative to the conjugation plane of the
heterocycles by 14.0o, the 4-chlorophenyl substituent forms an angle of 3.8o with the conjugation plane of the
heterocycles, which shows its participation in the conjugation system of the heterocyclic system.
Fig. 1. Overall shape of the 5d molecule according to data of X-ray structural analysis.
It must be noted that in this reaction for thioamides 2a,b containing a secondary amino group in position
5 of the heterocycle, an alternative direction is possible for cyclization to 2,4-dihydro-1,2,3-triazolo[4,5-e]-
1
1,4-thiazepines 6a,b. However on measuring the H NMR spectrum of product 6a in CDCl3 the signal of the
protons of the methyl group of the methylamino fragment was fixed as a doublet at 3.14 ppm (J = 4.8 Hz),
which confirms the formation of a thiazole and not a thiazepine ring.
Esters of acetylenedicarboxylic acid are convenient biselectrophilic reagents, the reaction of which with
thioamides is used for the synthesis of various heterocyclic systems due to their high reactivity and the
possibility of obtaining new compounds with various sizes of heterocyclic fragment depending on the structure
of the reacting substances [9, 10].
Interaction of 1,2,3-triazole-4-thioamides 2 with the dimethyl ester of acetylenedicarboxylic acid
(DMAD) was carried out in methanol at room temperature. The reaction was completed 5-10 min after mixing
the reactants. It should be noted that on interacting thioamides with DMAD the formation is possible of several
heterocyclic products by an addition–elimination mechanism (routes A, B, C) and also by addition and
cyclization (D).
1
The reaction products were isolated in 63-70% yield. Their structure was identified with the aid of H,
13C NMR, mass spectra and data of elemental analysis. Mass spectral data enabled exclusion of the formation of
2,4,5,7-tetrahydro-1,2,3-triazolo[4,5-d]-1,3-thiazines 10, since the molecular ion peak in the mass spectrum of
the obtained products corresponded to the mass of cyclization products with elimination of a molecule of
846

NH
E
E
N
N
S
D
R1 = H
Ar
N
E
2a–c
+
E = COOMe
N
R
E
C
А
B
10a,b
R2=H
– MeOH
NH
N
– MeOH
– MeOH
S
E
N
N
7
E
Ar
N
Ar
6
N
7
4
E
N
S
5
4
2
O
6
N
S
Ar
R
9a,b
N
2
O
5
N
N
N
NRR1
N
O
7a–c
NRR1
8a–c
7, 8 a–c, 9, 10 a,b Ar = 4-MeOC6H4, 7, 8 a NRR1 = NHMe, b NRR1 = NHC6H11-cyclo,
c NRR1 = piperidino; 9, 10 a R = Me, b R = C6H11-cyclo
methanol. In addition signals were absent from the 1H NMR spectra for CH2 group protons. The multiplicity of
the NHR group signals (quartet for compound 7a with J = 4.8 and a doublet for compound 7b with J = 7.6 Hz)
indicates that this nucleophilic center does not participate in the heterocyclization and excludes the formation of
2,4,5,8-tetrahydro-1,2,3-triazolo[4,5-e][1,4]thiazepinones 9a,b. The position of the vinylic proton H-6 in the
6.87-6.97 ppm region and the absence of an interaction of this atom with the C-4 carbonyl atom in the 13C NMR
spectrum are characteristic differences of thiazoles with an exocyclic double bond. The interaction with DMAD
therefore occurs exclusively with the participation of the thioamide fragment and leads to the formation of the
methyl esters of [2-(5-amino-2-aryl-2H-1,2,3-triazol-4-yl-4-oxo-4H-thiazol-5-ylidene]acetic acids 7a-c, and not
2H-(1,2,3-triazol-4-yl)-4H-1,3-thiazines 8a-c.
CONHNH2
NH2
H
N
N
N
Ar
N
– H2S
N
2c–e
+
N
O
N
NR1R2
11a–c
– H2O
H
Ar
Ar
H
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NRR1
NRR1
B
A
12a–c
11, 12a–c Ar = 4-MeOC6H4, a NRR1 = piperidino, b NRR1 = morpholino,
c NRR1 = 4-( pyrimidin-2-yl)piperazin-1-yl
847

Of interest in the special features of the structure of the thioamide group is the presence not only of
nucleophilic centers (nitrogen and sulfur atoms) but also of an electrophilic carbon atom, which permits these
compounds to react with nucleophilic reagents [2, 3]. Heating thioamides 2 with nicotinic acid hydrazide leads
to the formation of new 1,2,3-triazoles 12a-c with a 1,2,4-triazole ring in position 4, probably through the
intermediate amidrazones 11a-c. Triazoles 12 were obtained in 55-94% yield.
1
Signals were present in the H NMR spectra of compounds 12 for the proton-containing groups of the
pyridine ring at the C-3 atom of the 1,2,4-triazole ring. The signal of the NH proton of the heterocycle is
displaced to a significant extent towards low field (up to 14.5 ppm) and is displayed as two broad singlets. This
may be the result of the existence of an equilibrium between forms A and B of compounds 12.
It is known that alkylation of the sulfur atom in the thiocarbamoyl fragment leads to an increase in the
reactivity of thioamides in relation to nucleophilic reagents, and also blocks the sulfur atom in heterocyclization
reactions [12]. Alkylation of thioamides was carried out in acetone using an excess of alkylating agent. The
thioimidium salt 13 was isolated in good yield. However the interaction of the obtained salt 13 with primary and
secondary amines did not lead to the preparation of amidino derivatives 15. The sole product of this reaction was
in all cases the cyanotriazole 1c.
Me
I
S
NH
N
+
S
–
N
N
N
NH2
N
N
X
NH
Ar
Ar
N
HN
N
MeI
+
X
Ar
N
N
N
N
14a,b
N
2c
15a,b
13
CN
– MeSH
N
N
N
Ar
N
1c
13, 15a,b Ar = 4-MeOC6H4; 14, 15 a X = CH2, b X = (CH2)2; Ar = 4-MeOC6H4
The use in the reaction of the ethyl ester of aminocyanoacetic acid lead to the preparation of
aminoimidazole 17, probably as a result of cyclization of amidine 16 formed in the first stage.
Ar
N
N
COOEt
NH2
N
COOEt
CN
H
N
Ar
N
N
N
N
N
H2N
COOEt
CN
H
+
13
N
NH
– MeSH
N
17
40%
16
13, 16, 17 Ar = 4-MeOC6H4
As a result of the investigations carried out we have shown that 5-amino-2H-1,2,3-triazole-
4-carbonitriles 1 are convenient starting materials for the synthesis of the corresponding thioamides. The latter
interact with a wide circle of cyclizing agents differing in nature and reactivity, leading to the formation of
polyheterocyclic ensembles containing not only new, but also in certain cases a unique combination of
heterocycles. These include the 1,2,3-triazole fragment, thiazole, imidazole, 1,2,4-triazole, and various tertiary
cycloalkylamines, including substituted piperazines or a residue of the natural alkaloid cytisine.
848

EXPERIMENTAL
1
The H and 13C NMR spectra were obtained on a Bruker DRX-400 instrument (400 and 100 MHz
respectively) in DMSO-d6, internal standard was TMS. A check on the progress of reactions and the
homogeneity of the obtained substances was effected by TLC on Sorbfil UV-254 plates in the system ethyl
acetate–hexane, 1:1. The mass spectra were recorded on a Varian MAT 311A instrument, accelerating voltage
was 3 kV, ionization energy 70eV.
The X-ray structural investigations of a crystal of compound 5d (from acetone) were carried out by
the standard procedure on an automatic four-circle X-ray Xcalibur 3 diffractometer with a CCD detector
(λMoK, graphite monochromator, ω-scanning). The analysis used a fragment of a colorless laminar crystal of
size 0.47×0.36×0.09 mm. The structure was solved by the direct method with the SHELXS97 program [13] and
was refined with the SHELXL97 program [14] by the least squares method in an anisotropic approximation for
the non-hydrogen atoms. The hydrogen atoms were located by the peaks of electron density distribution and
were included in the refinement in the isotropic approximation in the "rider" model. No corrections for
absorption were introduced.
5-Amino-2H-1,2,3-triazole-4-carbonitriles 1 were obtained by the method of [1] developed previously.
Preparation of Thioamides 2a-f (General Method). A solution of 5-amino-2H-1,2,3-triazole-
4-carbonitrile 1 and triethylamine (0.3 ml, 0.002 mmol) in dry pyridine (50 ml) was saturated with hydrogen
sulfide for 2 h. After leaving for 8-10 h the reaction mixture was poured onto ice. The solid was filtered off and
thoroughly washed with water.
2-(4-Methoxyphenyl)-5-methylamino-2H-1,2,3-triazole-4-thiocarboxamide (2a). Yield was 96%;
o
1
mp 149-150 C. H NMR spectrum, δ, ppm (J, Hz): 2.97 (3H, br. s, CH3); 3.84 (3H, s, OCH3); 7.05 (1H, br. s,
NH); 7.00 and 7.94 (4H, J = 9.5, AA'XX', H Ar); 8.92 (H, s, CSNH); 9.23 (H, s, CSNH). 13C NMR spectrum, δ,
ppm: 30.3; 56.0; 115.1; 120.1; 128.6; 132.9; 156.7; 159.1; 187.0. Mass spectrum, m/z (Irel, %): 263 [M]+ (56).
Found, %: C 50.35; H 5.18; N 26.83; S 12.31. C11H13N5OS. Calculated, %: C 50.18; H 4.98; N 26.60; S 12.18.
5-Cyclohexylamino-2-(4-methoxyphenyl-2H-1,2,3-triazole-4-thiocarboxamide (2b). Yield was 94%;
1
mp 129-130oC. H NMR spectrum, δ, ppm (J, Hz): 1.32-1.42 (5H, m, 2CH2 + CH); 1.43-1.45 (1H, m, CH);
1.59-1.62 (2H, m, CH2); 2.03-2.04 (2H, m, CH2); 3.59-3.61 (1H, m, CH); 3.83 (3H, s, OCH3); 6.91 (1H, br. s,
CSNH); 6.99 and 7.91 (4H, J = 9.0, AA'XX', H Ar); 7.3 (1H, d, J = 7.5, NH); 9.0 (2H, br. s, CSNH). 13C NMR
spectrum, δ, ppm: 23.8; 25.2; 32.1; 51.4; 55.4; 114.5; 119.6; 127.9; 132.3; 154.5; 158.6; 186.5. Mass spectrum,
m/z (Irel, %): 331 [M]+ (73). Found, %: C 58.16; H 6.55; N 21.35; S 9.78. C16H21N5OS. Calculated, %: C 57.98;
H 6.39; N 21.13; S 9.67.
2-(4-Methoxyphenyl)-5-piperidino-2H-1,2,3-triazole-4-thiocarboxamide (2c). Yield was 94%; mp
145-146oC. 1H NMR spectrum, δ, ppm (J, Hz): 1.60-1.70 (6H, m, 3CH2); 3.25-3.29 (4H, m, 2CH2); 3.83 (3H, s,
OCH3); 6.98 and 7.88 (4H, J = 7.1, AA'XX', H Ar); 9.15 (1H, br. s, CSNH); 9.48 (1H, br. s, CSNH). 13C NMR
spectrum, δ, ppm: 23.6; 24.8; 50.6; 55.5; 114.8; 120.2; 132.5; 135.2; 155.1; 158.4; 190.0. Mass spectrum, m/z
(Irel, %): 317 [M]+ (65). Found, %: C 56.81; H 6.15; N 22.31; S 10.25. C15H19N5OS. Calculated, %: C 56.76;
H 6.03; N 22.06; S 10.10.
2-(4-Methoxyphenyl)-5-morpholino-2H-1,2,3-triazole-4-thiocarboxamide (2d). Yield was 66%; mp
153-154oC. 1H NMR spectrum, δ, ppm (J, Hz): 3.33-3.36 (4H, m, 2CH2); 3.75-3.77 (4H, m, 2CH2); 3.81 (3H, s,
OCH3); 7.0 and 7.89 (4H, J = 9.0, AA'XX', H Ar); 9.3 (2H, br. s, CSNH); 9.7 (2H, br. s, CSNH). 13C NMR
spectrum, δ, ppm: 114.7; 119.53; 132.4; 135.1; 154.6; 158.6; 189.5. Mass spectrum, m/z (Irel, %): 319 [M]+
(70.4). Found. %: C 52.76; H 5.45; N 21.7; S 10.34. C14H17N5O2S. Calculated, %: C 52.65; H 5.37; N 21.93;
S 10.04.
2-(4-Methoxyphenyl)-5-[4-(pyrimidin-2-yl)piperazin-1-yl]-2H-1,2,3-triazole-4-thiocarboxamide (2e).
Yield was 94%; mp 190-191oC. 1H NMR spectrum, δ, ppm (J, Hz): 3.40-3.50 (4H, m, CH2); 3.55-3.60 (2H, m,
CH2); 3.83 (3H, s, OCH3); 3.90-4.00 (4H, m, 2CH2); 6.55 (1H, t, J = 4.8, H Pyr); 7.0 and 7.9 (4H, J = 9.0,
849

AA'XX', H Ar); 8.30 (2H, d, J = 4.8, H Pyr); 9.2 (2H, br. s, CSNH); 9.6 (2H, br. s, CSNH). Mass spectrum, m/z
(Irel, %): 396 [M]+ (65.4). Found, %: C 54.18, H 5.00; N 28.48; S 8.25. C18H20N8OS. Calculated, %: C 54.53;
H 5.08; N 28.26; S 8.09.
2-(4-Fluorophenyl)-5-(8-oxo-1,5,6,8-tetrahydro-2H,4H-1,5-methanopyrido[1,2-a][1,5]diazocin-3-yl)-
2H-1,2,3-triazole-4-thiocarboxamide (2f). Yield was 95%; mp 159-160oC. 1H NMR spectrum, δ, ppm (J, Hz):
1.91 (2H, br. s, CH2); 2.55 (1H, br. s, CH); 3.00 (1H, d, J = 10.8, CH); 3.14 (1H, dd, J = 11.6, J = 2.0, CH); 3.21
(1H, s, CH); 3.73 (1H, dd, J = 15.6, J = 6.3, CH); 3.79 (1H, d, J = 11.6, CH); 4.10 (1H, d, J = 11.2, CH); 4.23
(1H, d, J = 15.6, CH); 6.16 (1H, d, J = 7.0, H Ar); 6.18 (1H, d, J = 8.8, H Ar); 7.29 (1H, dd, J = 7.8, J = 8.8, H
Ar); 7.40 (1H, t, J = 8.80, H Ar); 7.90 (2H, dd, J = 8.30, J = 4.8, H Ar); 9.57 (1H, br. s, NH); 9.94 (1H, br. s,
NH). Mass spectrum, m/z (Irel, %): 410 [M]+ (52.2). Found, %: C 58.15; H 4.37; N 20.72; S 7.93. C20H19FN6OS.
Calculated, %: C 58.52; H 4.67; N 20.47; S 7.81.
Synthesis of Compounds 5a-f (General Method). A solution of thiocarboxamide 2 (0.5 mmol) and
bromoacetophenone (0.5 mmol) in ethyl alcohol (50 ml) was boiled for 3-6 h. The solvent was evaporated under
vacuum, and the residue recrystallized from ethyl alcohol.
{5-[4-(4-Chlorophenyl)thiazol-2-yl]-2-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl}methylamine (5a).
Yield was 77%; mp 179-181oC. 1H NMR spectrum, δ, ppm (J, Hz): 3.18 (3H, d, J = 4.0, NHCH3); 3.86 (3H, s,
OCH3); 5.89 (1H, br. s, NH); 6.93 and 7.83 (4H, J = 8.9, AA'XX', H Ar); 7.40 (1H, s, CH); 7.43 and 7.97 (4H,
J = 8.0, AA'XX', H Ar). 13C NMR spectrum, δ, ppm: 30.5; 55.5; 113.8; 114.6 (2C); 119.0 (2C); 127.3; 128.2
(2C); 128.8 (2C); 132.4; 132.7; 132.8; 152.6; 153.5; 158.1; 158.7. Mass spectrum, m/z (Irel, %): 397 [M]+ (73).
Found, %: C 57.54; H 4.17; Cl 9.01; N 17.83; S 8.15. C19H16ClN5OS. Calculated, %: C 57.36; H 4.05; Cl 8.91;
N 17.60; S 8.06.
{5-[4-(4-Chlorophenyl)thiazol-2-yl]-2-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl}cyclohexylamine (5b).
1
Yield was 83%; mp 149-151oC. H NMR spectrum, δ, ppm (J, Hz): 1.29-1.55 (5H, m, 2CH2 + CH); 1.60-1.70
(1H, m, CH); 1.74-1.85 (2H, m, CH2); 2.10-2.18 (2H, m, CH2); 3.62-3.72 (1H, m, CH); 3.84 (3H, s, OCH3);
6.14 (1H, br. s, NH); 6.99 and 7.88 (4H, J = 9.0, AA'XX', H Ar); 7.45 and 7.96 (4H, J = 8.8, AA'XX', H Ar);
13
7.98 (1H, s, CH). C NMR spectrum, δ, ppm: 23.9 (2C); 25.3; 32.2 (2C); 51.6; 55.4; 114.0; 114.7 (2C); 119.1
(2C); 127.4; 127.6; 128.9 (2C); 132.3; 132.6; 132.8; 150.9; 153.1; 158.1; 158.8. Mass spectrum, m/z (Irel, %):
465 [M]+ (77). Found, %: C 61.98; H 5.25; Cl 7.43; N 15.36; S 6.95. C24H24ClN5OS. Calculated, %: C 61.86;
H 5.19; Cl 7.61; N 15.03; S 6.88.
3-{2-[2-(4-Methoxyphenyl)-5-piperidino-2H-1,2,3-triazol-4-yl]thiazol-4-yl}pyridine (5c). Yield was
1
78%; mp 250-251oC. H NMR spectrum, δ, ppm (J, Hz): 1.63-1.69 (2H, m, CH2); 3.45-3.65 (4H, m, 2CH2);
3.83 (3H, s, OCH3); 7.12 and 7.88 (4H, J = 9.2, AA'XX', H Ar); 8.05 (1H, t, J = 7.6, H Py); 8.64 (1H, s, CH);
8.85 (1H, br. s, H Py); 8.90 (1H, d, J = 8.0, H Py); 9.40 (1H, br. s, H Py). Mass spectrum, m/z (Irel, %): 418 [M]+
(60.1). Found, %: C 63.35; H 5.46; N 20.51; S 7.47. C22H22N6OS. Calculated, %: C 63.14; H 5.30; N 20.08;
S 7.66.
1-{5-[4-(4-Chlorophenyl)thiazol-2-yl]-2-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl}morpholine (5d).
1
Yield was 66%; mp 189-190oC. H NMR spectrum, δ, ppm (J, Hz): 3.49-3.54 (4H, m, 2CH2); 3.83 (3H, s,
OCH3); 3.84-3.89 (4H, m, 2CH2); 7.12 and 7.89 (4H, J = 9.1, AA'XX', H Ar); 7.57 and 8.05 (4H, J = 8.6,
AA'XX', H Ar); 8.29 (1H, s, CH). Mass spectrum, m/z (Irel, %): 453 [M]+ (43.1). Found, %: C 58.21; H 4.44;
Cl 7.81; N 15.43; S 7.06. C22H20ClN5O2S. Calculated, %: C 58.20; H 4.40; Cl 7.80; N 15.40; S 7.00.
2-{4-[2-(4-Methoxyphenyl)-5-(4-pyridin-3-yl)thiazol-2-yl]-2H-1,2,3-triazol-4-yl}piperazin-1-ylpyrimi-
1
dine (5e). Yield was 94%; mp 210-211oC. H NMR spectrum, δ, ppm (J, Hz): 3.50-3.65 (4H, m, 2CH2); 3.84
(3H, s, OCH3); 3.85-4.50 (4H, m, 2CH2); 6.55-6.65 (1H, m, H Pyr); 7.05 and 7.91 (4H, J = 8.8, AA'XX', H Ar);
7.43 (1H, dd, J = 4.3, J = 5.0, H Py); 8.19 (1H, s, CH); 8.25-8.30 (1H, m, H Py); 8.33 (2H, d, J = 4.3, H Py);
8.53 (1H, d, J = 5.0, H Py); 9.2 (1H, br. s, Py). Mass spectrum, m/z (Irel, %): 497 [M]+ (43.6). Found, %:
C 60.31; H 5.00; N 25.42; S 6.24. C25H25N9OS. Calculated, %: C 60.35; H 4.66; N 25.33; S 6.44.
850

3-{5-[4-(4-Chlorophenyl)thiazol-2-yl]-2-(4-fluorophenyl)--2H-1,2,3-triazol-4-yl}-1,2,3,4,5,6-hexahydro-
1,5-methanopyrido[1,2-a][1,5]diazocin-8-one (5f). Yield was 41%, mp 219-221oC. 1H NMR spectrum, δ, ppm
(J, Hz): 2.0 (2H, br. s, CH2); 2.57 (1H, br. s, CH); 2.93 (1H, d, J = 11.0, CH); 3.22 (1H, br. s, CH); 3.32 (1H, d,
J = 12.10, CH); 3.82-3.94 (2H, m, CH2); 4.45 (2H, d, J = 14.9, CH2); 6.08 (1H, d, J = 6.8, H Ar); 6.21 (1H, d,
J = 9.2, H Ar); 7.22 (1H, dd, J = 6.8, J = 9.2, H Ar); 7.23 (2H, dd, J = 8.8, J = 8.4, H Ar); 7.53 and 8.04 (4H,
J = 8.8, AA'XX',H Ar); 7.96 (2H, dd, J = 4.4, J = 8.8, H Ar); 8.03 (1H, s, CH). Mass spectrum, m/z (Irel, %): 544
[M]+ (43.6). Found, %: C 61.50; H 4.00; Cl 6.00; N 15.00; S 5.50. C28H22ClFN6OS. Calculated, %: C 61.70;
H 4.07; Cl 6.50; N 15.42; S 5.88.
Synthesis of Methyl Esters of [2-(5-Amino-2-aryl-2H-1,2,3-triazol-4-yl)-4-oxo-4H-thiazol-
5-ylidene]acetic Acid 7a-c (General Method). The dimethyl ester of acetylenedicarboxylic acid (DMAD)
(0.061 ml, 0.5 mmol) was added to a solution of thioamide 2 (0.5 mmol) in methanol at room temperature. After
the reaction was complete (TLC) the solid was filtered off.
Methyl Ester of {2-[2-(4-Methoxyphenyl)-5-methylamino-2H-1,2,3-triazol-4-yl]-4-oxo-4H-thiazol-
1
5-ylidene}acetic Acid (7a). Yield was 71%; mp 229-230oC. H NMR spectrum, δ, ppm (J, Hz): 3.08 (3H, d,
J = 5.2, CH3); 3.86 (3H, s, OCH3); 3.87 (3H, s, OCH3); 6.68 (1H, q, J = 5.2, NH); 7.06 and 8.02 (4H, J = 9.3,
13
AA'XX', H Ar); 6.92 (1H, s, CH). C NMR spectrum, δ, ppm: 30.1; 52.8; 55.7; 100.0; 114.5 (2C); 120.9 (2C);
126.6; 132.7; 143.6; 156.8; 160.2; 166.3; 179.8; 181.4. Mass spectrum, m/z (Irel, %): 373 [M]+ (43.5). Found, %:
C 51.22; H 4.31; N 18.41; S 8.36. C16H15N5O4S. Calculated, %: C 51.47; H 4.05; N 18.76; S 8.59.
{2-[5-Cyclohexylamino-2-(4-methoxyphenyl)-2H-1,2,3-triazol-4-yl]-4-oxo-4H-thiazol-5-ylidene}-
1
acetic Acid Methyl Ester (7b). Yield was 64%; mp 189-190oC. H NMR spectrum, δ, ppm (J, Hz): 1.23-1.36
(1H, m, CH); 1.38-1.51 (4H, m, 2CH2); 1.61-1.70 (1H, m, CH); 1.74-1.83 (2H, m, CH2); 2.05-2.14 (2H, m,
CH2); 3.63-3.74 (1H, m, CH); 3.86 (3H, s, CH3); 3.87 (3H, s, OCH3); 6.36 (1H, d, J = 7.6, NH); 6.94 (1H, s,
CH); 7.06 and 8.00 (4H, J = 9.2, AA'XX', H Ar). 13C NMR spectrum, δ, ppm: 24.9 (2C); 25.6; 33.0 (2C); 52.7;
55.6; 100.0; 114.5 (2C); 120.8; 120.9 (2C); 126.6; 132.7; 143.8; 155.1; 160.1; 166.4; 179.6; 181.4. Mass
spectrum, m/z (Irel, %): 441 [M]+ (74.5). Found, %: C 57.22; H 5.31; N 15.41; S 7.36. C21H23N5O4S. Calculated,
%: C 57.13; H 5.25; N 15.86; S 7.26.
Methyl Ester of {2-[2-(4-Methoxyphenyl)-5-piperidino-2H-1,2,3-triazol-4-yl]-4-oxo-4H-thiazol-
5-ylidene}acetic Acid (7c). Yield was 65%; mp 147-149oC. 1H NMR spectrum, δ, ppm (J, Hz): 1.6-1.8 (6H, m,
3CH2); 3.5-3.67 (4H, m, 2CH2); 3.86 (3H, s, OCH3); 3.87 (3H, s, OCH3); 6.90 (1H, s, CH); 7.05 and 7.98 (4H,
J = 9.1, AA'XX', H Ar). Mass spectrum, m/z (Irel, %): 427 [M]+ (65.1). Found, %: C 55.85; H 4.65; N 16.21;
S 7.63. C20H21N5O4S. Calculated, %: C 56.19; H 4.90; N 16.38; S 7.50.
Synthesis of 5-(2H-1,2,3-Triazol-4-yl)-4H-1,2,4-triazoles 12a-c (General Method). A mixture of
thioamide 2 (0.5 mmol) and nicotinic acid hydrazide (0.123 g, 1.0 mmol) was heated at 200oC for 3 h.
Separation and purification of the obtained product was carried out with the aid of column chromatography
(chloroform–ethanol, 30:1). Yields were 55-94%.
3-{5-[2-(4-Methoxyphenyl)-(5-piperidin-1-yl)-2H-1,2,3-triazol-4-yl]-4H-1,2,4-triazol-3-yl}pyridine
(12a). Yield was 64%; mp 153-155oC. 1H NMR spectrum, δ, ppm (J, Hz): 1.62 (2H, br. s, CH2); 1.67 (4H, br. s,
2CH2); 3.45 (4H, br. s, 2CH2); 3.84 (3H, s, OCH3); 7.00 and 7.90 (4H, J = 9.0, AA'XX', H Ar); 7.47 (1H, br. s,
H Py); 8.58 (1H, d, J = 7.0, H Py); 8.60 (1H, br. s, H Py); 9.26 (1H, s, H Py); 14.20 (1H, br. s, NH). Mass
spectrum, m/z (Irel, %): 402 [M]+ (56.1). Found, %: C 62.59; H 5.83; N 27.69. C21H22N8O. Calculated, %:
C 62.67; H 5.51; N 27.84.
3-{5-[2-(4-Methoxyphenyl)-(5-morpholin-1-yl)-2H-1,2,3-triazol-4-yl]-4H-1,2,4-triazol-3-yl}pyri-
1
dine (12b). Yield was 94%, mp 169-170oC. H NMR spectrum, δ, ppm (J, Hz): 3.35-3.60 (4H, m, 2CH2);
3.65-3.95 (4H, br. s, 2CH2); 3.85 (3H, s, OCH3); 7.00 and 7.93 (4H, J = 8.8, AA'XX', H Ar); 7.46 (1H, br. s,
H Py); 7.45 (1H, d, J = 7.0, H Py); 8.58 (1H, br. s, H Py); 8.57 (1H, br. s, H Py); 9.24 (1H, s, H Py); 14.57 and
14.65 (1H, br. s + br. s, NH). Mass spectrum, m/z (Irel, %): 404 [M]+ (65.1). Found, %: C 59.21; H 4.71;
N 27.95. C20H20N8O2. Calculated, %: C 59.40; H 4.98; N 27.71.
851

2-{4-[2-(4-Methoxyphenyl)-5-(5-pyridin-3-yl-1H-1,2,4-triazol-3-yl)-2H-1,2,3-triazol-4-yl]piperazin-
1
1-yl}pyrimidine (12c). Yield was 55%; mp 229-230oC. H NMR spectrum, δ, ppm (J, Hz): 3.40-3.65 (4H, m,
2CH2); 3.84 (3H, s, OCH3); 3.90-4.11 (4H, m, 2CH2); 6.55-6.60 (1H, m, H Py); 6.80-7.05 (3H, m, H Ar + H
Pyr); 7.85 (2H, d, J = 8.8, H Ar); 7.94 (1H, d, J = 5.4, H Py); 8.30-8.34 (3H, m, H Pyr and H Py); 8.8 (1H, br. s,
Py); 14.55 (1H, br. s, NH). Mass spectrum, m/z (Irel, %): 481 [M]+ (51.6). Found, %: C 60.01; H 4.95; N 31.76.
C24H23N11O. Calculated, %: C 59.87; H 4.81; N 32.00.
{[2-(4-Methoxyphenyl)-5-piperidino-2H-1,2,3-triazol-4-yl]iminomethyl}methylsulfonium
Iodide
(13). A solution of thioamide 2c (0.160 g, 0.5 mmol) and methyl iodide (0.3 ml, 5 mmol) in acetone (30 ml) was
boiled for 5 h. The reaction mixture was cooled, and the solid filtered off. Yield 75%, mp 105-106oC. 1H NMR
spectrum, δ, ppm (J, Hz): 1.71 (2H, br. s, CH2); 1.73 (4H, br. s, 2CH2); 2.77 (3H, s, SCH3); 3.60 (4H, m, 2CH2);
3.86 (3H, s, OCH3); 7.05 and 7.92 (4H, J = 8.8, AA'XX', H Ar). Mass spectrum, m/z (Irel, %): 316 [M-142]+
(55.4). Found, %: C 41.61; H 4.74; N 15.53. C16H21IN5OS. Calculated, %: C 41.92; H 4.59; N 15.28.
Ethyl Ester of 5-Amino-2-[2-(4-methoxyphenyl)-5-piperidino-2H-(1,2,3-triazol-4-yl)-1H-imida-
zole-4-carboxylic Acid (17). A solution of compound 13 (0.215 g, 0.5 mmol) and aminocyanoacetic acid ethyl
ester (0.46 g, 3.6 mmol) in chloroform was boiled. The reaction mixture was cooled, and the solid filtered off.
1
Yield 40%; mp 83-85oC. H NMR spectrum, δ, ppm (J, Hz): 1.33 (3H, t, J = 7.0, CH3); 1.60-1.73 (6H, m,
3CH2); 3.35 (4H, br. s, 2CH2); 3.82 (3H, s, OCH3); 4.23 (2H, q, J = 7.1, CH2); 5.51 (2H, s, NH2); 7.00 and 7.87
(4H, J = 8.8, AA'XX', H Ar). Mass spectrum, m/z (Irel, %): 411 [M]+ (45.1). Found, %: C 58.44; H 5.95;
N 24.03. C20H25N7O3. Calculated, %: C 58.38; H 6.12; N 23.83.
The work was carried out with the financial support of the RFFI (grant 08-03-00376_a and grant 08-03-
92208 of the GFEN_a), the National Natural Science Foundation of China (No. 20672062, No. 20872071), and
the International Collaboration Program of the National Natural Science Foundation of China (No.
20911120069).
REFERENCES
1.
N. P. Belskaya, M. A. Demina, S. G. Sapognikova, Z.-J. Fan, H.-Ke Zhang, W. Dehaen, and
V. A. Bakulev, ARKIVOC, (xvi), 9 (2008).
2.
3.
4.
5.
6.
7.
8.
T. S. Jagodzinski, Chem. Rev., 103, 197 (2003).
H. Takahata and T. Yamazaki, Heterocycles, 27, 1953 (1988).
E. Abdel-latif, and S. Bondok, Heteroatom. Chem., 17, 299 (2006).
R. N. Hurd and G. De LaMater, Chem. Rev., 61, 45 (1961).
K. A. Petrov and L. N. Andreev, Usp. Khim., 38, 41 (1969).
C. J. J. Goddart, J. Heterocycl. Chem., 28, 1607 (1991).
I. Yavari, S. Z. Sayeed-Alangi, R. Hajinasiri, and H. Sajjadi-Ghotbabadi, Monatsh. Chem., 140, 209
(2009).
9.
10.
11.
12.
A. Darehkordi, K. Saidi, and M. R. Islami, ARKIVOC, (i), 180 (2007).
N. A. Danilkina, L. E. Mikhailov, and B. A. Ivin, Russ. J. Org. Chem., 42, 783 (2006).
R. M. Acheson and J. D. Wallis, J. Chem. Soc., Perkin Trans. 1, 415 (1981).
O. V. Solod, K. N. Zelenin, and V. V. Pinson, Khim. Geterotsikl. Soedin., 3 (1996). [Chem. Heterocycl.
Comp., 32, 1 (1996)].
13.
14.
G. M. Sheldrick, SHELXS97. Program for the Solution of Crystal Structures, Göttingen Univ.,
Göttingen (1997).
G. M. Sheldrick, SHELXL97. Program for the Refinement of Crystal Structures, Univ. of Göttingen,
Göttingen (1997).
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