The synthesis of S-substituted derivatives of 3-[2-[(4-methylphenyl)amino] ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones and their antioxidative activity

Article abstract of DOI:10.1007/s00706-013-1096-2

A series of novel S-substituted derivatives of 3-[2-[(4-methylphenyl)amino] ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones was synthesized by the reaction of 1,2,4-triazole-5-thiones with alkyl, benzyl, and phenacyl halides as well as halogen-containing esters or amides. The reactions were carried out in DMF in the presence of KOH, K₂CO₃, or triethylamine, or in dioxane in the presence of NaH. The synthesized compounds were screened for their free radical scavenging activity. N-[2-[5-(Butylsulfanyl)-4-phenyl-4H-1,2, 4-triazol-3-yl]ethyl]-4-methylaniline showed excellent antioxidant activity, 2.5 times higher than that of the antibiotic control (cefazolin). Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-013-1096-2

Monatsh Chem (2014) 145:319–327
DOI 10.1007/s00706-013-1096-2
ORIGINAL PAPER
The synthesis of S-substituted derivatives of 3-[2-[(4-
methylphenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-
triazole-5-thiones and their antioxidative activity
•
Ingrida Tumosiene Ilona Jonuskiene
•
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Kristina Kantminiene Zigmuntas Jonas Beresnevicius
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•
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Received: 14 June 2013 / Accepted: 29 September 2013 / Published online: 25 October 2013
Ó Springer-Verlag Wien 2013
Abstract AseriesofnovelS-substitutedderivativesof3-[2-
[(4-methylphenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1H-
1,2,4-triazole-5-thiones was synthesized by the reaction of
1,2,4-triazole-5-thiones with alkyl, benzyl, and phenacyl
halides as well as halogen-containing esters or amides. The
reactions were carried out in DMF in the presence of KOH,
K2CO3, or triethylamine, or in dioxane in the presence of
NaH. The synthesized compounds were screened for their
free radical scavenging activity. N-[2-[5-(Butylsulfa-
nyl)-4-phenyl-4H-1,2,4-triazol-3-yl]ethyl]-4-methylaniline
showed excellent antioxidant activity, 2.5 times higher than
that of the antibiotic control (cefazolin).
synthesis of novel compounds possessing useful properties.
For example, triazolethiones containing 3-benzofuranyl [1],
3-benzoimidazolylethyl [2], and 3-indolyl [3] moieties show
antimicrobial activity. 1,4-Dimethyl-3-(dichlorophenyl)-2,4-
dihydro-3H-1,2,4-triazol-5-thiones exhibit strong antide-
pressantactivityandlow toxicity[4]. 1,2,4-Triazole-3-thiones
containing methylphenyl and chlorophenyl or nitrophenyl
groups showed antioxidative and urease inhibitory activities
[5]. Triazolethiones containing substituents at two or three
nitrogens in the heterocycle have been identified as antibac-
terial and antifungal agents [6]. 4-Amino-(substituted
benzamidoalkyl)-1,2,4-triazole-5(1H)-thiones showed anti-
cancer activity against a human tumor cell line, leukemia
(K-562) [7]. Plant growthregulation[8] activitywas exhibited
by 3-(3-hydroxybutyl)-4-substituted benzylidene)amino-1H-
1,2,4-triazole-5-thiones, the strength of which depends on the
substituents in the phenyl group.
Keywords Alkylations ꢀ Heterocycles ꢀ
Antioxidant activity
Introduction
Thione–thiol tautomerism is characteristic of triazol-
ethiones; therefore, they easily form S-alkyl (or
S-substituted) derivatives which elicit a broad spectrum of
biological activities as well. 3-Bromophenylsulfonylphenyl
5-ethyl (or phenacyl, or ethoxycarbonylmethyl) thio-1,2,4-
triazoles possess antibacterial properties [9], whereas
3-phenyl-5-pyridazinylthio-1,2,4-triazole derivatives exhi-
bit insecticidal activity [10]. 3-Naphthoxymethyl-5-
ethylthio-1,2,4-triazole derivatives have shown good hyp-
olipidemic activity [11]. 4-Amino-3-furyl-5-phenyl (or
ethoxycarbonylmethyl) thio-1,2,4-triazoles possess anti-
HIV activity [12]. S-Alkyl-1,2,4-thiazole derivatives con-
taining the tetrahydrobenzothiophenyl moiety as well as
bis-compounds obtained by alkylation of these compounds
with diiodomethane have displayed anti-Alzheimer activity
[13].
Heterocyclic compounds form a significant group of biolog-
ically active compounds. Among them, compounds
containing the triazolethione moiety deserve special attention
owing to their wide array of biological activities. The bio-
logical activity of 1,2,4-triazolethiones depends on the nature
of the substituents; therefore, the chemical functionalization
of the triazole ring is a promising and facile approach to the
_
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I. Tumosiene ꢀ I. Jonuskiene ꢀ Z. J. Beresnevicius (&)
Department of Organic Chemistry, Kaunas University of
_
Technology, Radvilenu˛ pl. 19, 50254 Kaunas, Lithuania
e-mail: zigmuntas.beresnevicius@ktu.lt
_
K. Kantminiene
Department of General Chemistry, Kaunas University of
_
Technology, Radvilenu˛ pl. 19, 50254 Kaunas, Lithuania
As a continuation of our search for biologically
active compounds [14], we report herein the synthesis of
123

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I. Tumosiene et al.
320
S-substituted derivatives of 3-[2-[(4-methylphenyl)amino]-
ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-triazole-5-thiones, and
the investigation of the structure–activity relationship and
influence of S-substituents on the biological activity of the
synthesized compounds. Depending on the pH of the med-
ium, triazolethiones can exist in the thione or thiole form. In
alkylation reactions, their oxo analogues, triazolones, form
N-substituted derivatives under acidic conditions and
S-substituted derivatives in basic medium. To the best of our
knowledge, the products of triazolethione alkylation and
acylation reactions have been isolated from the reaction
mixtures only under basic conditions when the thione–thiol
equilibrium of 1,2,4-triazole-5-thiones is shifted towards the
formation of thioles.
aqueous potassium hydroxide solution and subsequently
acidifying the reaction mixture [15] (Scheme 1).
Alkylation reactions of 1 were performed using three
methods (A, B, C). Alkylation employing haloalkanes and
chloroacetamide was carried out in the presence of KOH
and K2CO3 (method A). Method B was used for alkylation
with chloroacetate and phenacyl bromides in the presence
of triethylamine. The reaction products were isolated in
63–85 % yield after diluting the reaction mixture with
water. Alkylation reaction of 1a with (chloromethyl)ben-
zene according to method A provided the target product 7a
in only 41 % yield, therefore the other methods were tes-
ted. The yield of the S-benzyl derivative according to the
conditions of method B was 59 %, whereas alkylation
reaction in the presence of NaH (method C) gave 7a in
78 % yield. The starting compounds 1a and 1b are only
slightly soluble, whereas S-alkyl derivatives dissolve well
in common organic solvents.
1,2,4-Triazole-5-thiones were alkylated with alkyl,
benzyl, and phenacyl halides as well as halo-carboxylic
acids, their amides, and esters. The synthesized compounds
were tested for antioxidative activity; their activity was
compared to that of non-alkylated compounds.
In the 1H NMR spectra of the S-substituted deriva-
tives, the singlet of the NH group proton in the
heterocyclic moiety is absent in comparison with the
Results and discussion
spectra of the starting triazolethiones
1
(approx.
13.7 ppm), whereas signals of the protons at the
a-position of the S-substituent are observed in the range
of 2.95–4.90 ppm. In the spectra of S-alkyl derivatives
2–6, these resonances are shifted upfield and are found at
approx. 3.00 ppm, and in the spectra of the derivatives
3-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1
H-1,2,4-triazole-5-thione (1a) and its 4-(4-methylphenyl)
homologue 1b were synthesized from N-(4-methylphenyl)-b-
alanines via semicarbazides by heating the latter at reflux in
Scheme 1
H
3
N
N
N
N
N 10
N
N
N
2
SH
S
R'
S
4
7
N
9
N
N
H
5
1
N
1'
8
6
2'
H
H
6'
3'
4'
5'
R
R
R
2 - 12
1 a, b
R
R'
1a
1b
H
CH3
-
-
2a
2b
3a
H
CH3
H
CH3CH2-
CH3CH2-
(CH3)2CH
4a
4b
5a
6a
7a
H
CH3
H
H
H
CH3CH2CH2CH2-
CH3CH2CH2CH2-
(CH3)2CHCH2-
(CH3)2CHCH2CH2-
C6H5CH2-
8a
8b
9a
H
CH3
H
C2H5OCOCH2-
C2H5OCOCH2-
NH2COCH2-
10a
10b
11a
12a
H
CH3
H
C6H5COCH2-
C6H5COCH2-
4-ClC6H4COCH2-
4-NO2C6H4COCH2-
H
123

The synthesis of S-substituted derivatives
321
containing a benzyl group (7a) or carbonylmethyl group
(8–12) the respective proton resonances are in the range
of 4.01–4.90 ppm.
acetamide (16) were also synthesized from S-alkyl com-
pounds 2a, 4a, and 7a (Scheme 2). Under the influence of
the electron-withdrawing ethanoyl group, the proton signals
of the p-tolyl and NCH2 groups are shifted downfield by
Compounds 8a and 8b were characterized by the pre-
sence of additional signals derived from the ester group,
1
which are observed in the H NMR spectrum at 1.17 and
1
0.27–0.54 ppm in the H NMR spectrum for 16 in com-
parison with the corresponding proton signals in the
spectrum for the non-acylated compound 4a.
1.15 ppm (–OCH2CH3), and 4.09 and 4.10 (–OCH2CH3)
ppm, respectively. The resonance of the NH group proton
is shifted downfield in comparison with the spectrum of the
starting compound 1. The carbons of the ester groups res-
onated at 14.0 and 13.9, and 61.3 and 61.1 ppm,
respectively, in the 13C NMR spectrum. The signal of the
CO carbon is observed at 154 ppm.
Ester 8a on treatment with hydrazine hydrate was con-
verted to the corresponding hydrazide 17 [16, 17]
(Scheme 3). The signals that originated from the ester
functionality in 8a disappeared; instead, new signals due to
the hydrazide structure were recorded at 5.41 and
9.37 ppm, respectively. Further support for the formation
of the hydrazide structure is the appearance of strong
absorption vibrations indicating the presence of NHNH2 at
3,397–2,860 cm-1 in the FTIR spectrum.
Introduction of the acetyl group usually increases or
enhances the biological activity of the compound. There-
fore, 1a was heated at reflux with acetic anhydride to
provide N-(4-methylphenyl)-N-[2-(4-phenyl-5-sulfanyli-
dene-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]acetamide (13),
which on treatment with iodoethane or (chloro-
methyl)benzene gave S-alkyl derivatives 14 and 15. In
comparison with the spectra of non-acylated compounds,
the protons of the benzene ring resonated at lower field in
The antioxidative activity of the synthesized compounds
was evaluated by 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hy-
drazyl (DPPH) radical scavenging method. Cefazolin, a
widely used first-generation cephalosporin antibiotic, with
high antioxidative action, was used as a control. As seen
from the results presented in Table 1, 3-[2-[(4-methyl-
phenyl)amino]ethyl]-4-phenyl-4,5-dihydro-1H-1,2,4-tria-
zole-5-thione (1a) showed a very high scavenging ability
which surpassed that of cefazolin. Among the S-substituted
triazole derivatives, butyl derivative 4a showed approx.
80 % scavenging action, whereas when an isopentyl group
was introduced, the scavenging property disappeared (6a).
The presence of the methyl group in the phenyl ring of
the heterocyclic moiety diminished the scavenging activity
(2a, 2b, 4a, and 4b) or had no influence on it (8a and 8b).
1
the H NMR spectra of 14 and 15 because of the deshiel-
ding effect of the acyl group. In the same manner, the
NCH2 group is strongly deshielded by the acyl group and
its proton resonances are shifted downfield. The resonances
of Ar0 protons are shifted upfield. The NH group proton
singlet is absent, whereas there is a singlet ascribed to the
CH3 group protons.
Compounds 14 and 15 as well as N-[2-[5-(butylsulfanyl)-
4-phenyl-4H-1,2,4-triazol-3-yl]ethyl]-N-(4-methylphenyl)-
Scheme 2
H
N
N
N
N
S
R'
S
N
2 a, 4a, 7 a
N
1a
N
N
O
O
14 - 16
13
CH3CH2-
2a R' =
4a R' =
7a R' =
CH3CH2CH2CH2-
C6H5CH2-
Scheme 3
N
N
N
N
S
S
O
O
N
N
N
N
H
N NH2
H
O
H
8a
17
123

_
I. Tumosiene et al.
322
(Merck, F254). Silica gel (Acros Organics, New Jersey, USA,
0.035–0.070 mm) was used for column chromatography.
3-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4,5-dihy-
dro-1H-1,2,4-triazole-5-thione (1a) and 3-[2-[(4-methyl
phenyl)amino]ethyl]-4-(4-methylphenyl)-4,5-dihydro-1H-
1,2,4-triazole-5-thione (1b) were prepared as described
Table 1 Antioxidant activity of compounds 1–17
Compound
R
R0
DPPH scavenging/%
Cefazolin
1a
32.06
67.10
49.08
44.13
39.27
40.28
80.73
53.88
35.25
0.0
H
–
1b
CH3
H
–
1
2a
CH3CH2–
earlier [15]; their H NMR spectra were identical to those
2b
CH3
H
CH3CH2–
described in Ref. [15].
3a
(CH3)2CH–
4a
H
CH3CH2CH2CH2–
CH3CH2CH2CH2–
(CH3)2CHCH2–
(CH3)2CHCH2CH2–
C6H5CH2–
General procedure for synthesis of N-[2-(5-substituted
sulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]ethyl]-4-
methylanilines 2–12
4b
CH3
H
5a
6a
H
Method A. To 1.24 g 1a (4 mmol) or 1.3 g 1b (4 mmol)
dissolved in 5 cm3 DMF, 0.15 g KOH powder (4 mmol),
0.5 g K2CO3, and 5 mmol alkyl halide were added. The
reaction mixture was stirred at 35–40 °C for 3–8 h.
Afterwards 30 cm3 cold water was added; the precipitate
formed was isolated by filtration and recrystallized from
propan-2-ol (unless indicated otherwise).
7a
H
39.27
33.38
34.56
30.46
0.0
8a
H
C2H5OCOCH2–
C2H5OCOCH2–
NH2COCH2–
C6H5COCH2–
C6H5COCH2–
4-ClC6H4COCH2–
4-NO2C6H4COCH2–
–
8b
CH3
H
9a
10a
10b
11a
12a
13
H
CH3
H
33.50
32.86
52.93
54.10
42.66
Method B. To 1.24 g 1a (4 mmol) or 1.3 g 1b (4 mmol)
dissolved in 5 cm3 DMF, 0.51 g triethylamine (0.70 cm3,
5 mmol) and alkyl halide (5 mmol) were added. The
reaction mixture was stirred at room temperature for 2–6 h.
Afterwards 30 cm3 cold water was added; the precipitate
formed was isolated by filtration and recrystallized from
propan-2-ol.
H
H
17
H
NH2NHCOCH2–
The presence of the methyl group in the compounds con-
taining a phenacyl fragment had a positive influence on the
activity (10a and 10b). A similar effect was observed for
the chloro and nitro substituents—compound 10a had no
scavenging ability, whereas the activity of the chloro (11a)
and nitro (12a) derivatives was close to that of cefazolin or
even surpassed it.
N-[2-[5-(Ethylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-4-methylaniline (2a, C19H22N4S)
Prepared according to method A from 1a and 0.78 g
(0.4 cm3) iodoethane by stirring for 3 h. Yield 0.93 g
(69 %); m.p.: 85–86 °C; TLC: Rf = 0.28 (acetone/hex-
1
ane = 1:1); H NMR (400 MHz, DMSO-d6): d = 1.27 (t,
J = 7.2 Hz, 3H, CH3), 2.12 (s, 3H, CH3), 2.76 (t,
J = 7.2 Hz, 2H, CH2-C), 3.05 (q, J = 7.2 Hz, 2H,
CH3CH2), 3.26 (t, J = 7.2 Hz, 2H, NHCH2), 5.47 (s, 1H,
NH), 6.28 (d, J = 8.4 Hz, 2H, H(2,6)Ar), 6.81 (d,
J = 8.4 Hz, 2H, H(3,5)Ar), 7.41–7.47 (m, 2H, H(3,5)Ar0),
7.54–7.62 (m, 3H, H(2,4,6)Ar0) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 14.8 (CH3CH2), 20.0 (Ar–CH3), 24.7 (C-
8), 26.5 (CH3CH2), 40.7 (C-7), 112.0 (C-2,6), 124.1 (C-4),
127.4 (C-30,50), 129.3 (C-40), 129.7 (C-20,60), 129.8 (C-3,5),
133.0 (C-10), 145.6 (C-1), 149.7 (C-9), 153.9 (C-10) ppm; IR
(KBr): m = 3,305 (NH), 1,513, 1,498 (C=N), 1,267 (C–S–C)
cm-1; MS (ESI, 25 eV): m/z (%) = 339 ([M?H]?, 100).
Experimental
1H and 13C NMR spectra were recorded on a Avance III 400
spectrometer (400 and 100 MHz, respectively) using TMS as
an internal standard and DMSO-d6 as a solvent. The following
abbreviations are used to explain the multiplicities: s = sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet,
quin = quintuplet, sext = sextet, sep = septet, b = broad.
IR spectra were taken on a Perkin-Elmer Spectrum Bx FT-IR
spectrometer. Mass spectra were recorded on a Waters Mi-
cromass ZQ 2000 instrument. Elemental analyses (C, H, N)
were performed on an elemental analyzer (CE-440, Exeter
Analytical) and their results were found to be in good agree-
ment ( 0.2 %) with the calculated values. Melting points
were determined on a Mel-Temp melting point apparatus
(Electrothermal, A Bibby Scientific Company, USA). Moni-
toring of the reaction course and purity of the compounds
prepared was carried out using TLC on silica gel plates
N-[2-[5-(Ethylsulfanyl)-4-(4-methylphenyl)-4H-1,2,4-
triazol-3-yl]ethyl]-4-methylaniline (2b, C20H24N4S)
Prepared according to method A from 1b and 0.78 g
(0.4 cm3) iodoethane. Yield 1.41 g (62 %); m.p.:
96–97 °C; TLC: Rf = 0.26 (acetone/hexane = 1:1); 1H
NMR (400 MHz, DMSO-d6): d = 1.27 (t, J = 7.2 Hz, 3H,
CH3), 2.12 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.73 (t,
123

The synthesis of S-substituted derivatives
323
J = 7.2 Hz, 2H, CH2-C), 3.04 (q, J = 7.2 Hz, 2H,
CH3CH2), 3.23 (t, J = 7.2 Hz, 2H, NHCH2), 5.45 (s, 1H,
NH), 6.27 (d, J = 8.1 Hz, 2H, H(2,6)Ar), 6.80 (d,
J = 8.1 Hz, 2H, H(3,5)Ar), 7.29 (d, J = 8.1 Hz, 2H, H(3,5)
Ar0), 7.37 (d, J = 8.1 Hz, 3H, H(2,6)Ar0) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 14.7 (CH3), 20.0 (Ar-CH3),
20.7 (Ar0-CH3), 24.7 (C-8), 26.4 (CH3CH2), 40.7 (C-7),
112.0 (C-2,6), 124.1 (C-4), 127.1 (C-30,50), 129.2 (C-40),
130.2 (C-20,60), 130.4 (C-3,5), 139.6 (C-10), 145.6 (C-1),
149.8 (C-9), 153.9 (C-10) ppm; IR (KBr): m = 3,304 (NH),
1,514, 1,499 (C=N), 1,268 (C–S–C) cm-1; MS (ESI,
25 eV): m/z (%) = 353 ([M?H]?, 100).
N-[2-[5-(Butylsulfanyl)-4-(4-methylphenyl)-4H-1,2,4-
triazol-3-yl]ethyl]-4-methylaniline (4b, C22H28N4S)
Prepared according to method A from 1b and 0.92 g
(0.57 cm3) 1-iodobutane. Isolation by column chromatog-
raphy (acetone/hexane 1:1, Rf = 0.44) afforded 0.98 g
(64 %) 4b. M.p.: 124–125 °C; 1H NMR (400 MHz,
DMSO-d6): d = 0.84 (t, J = 7.2 Hz, 3H, CH3), 1.32 (sext,
J = 7.2 Hz, 3H, CH2), 1.59 (quin, J = 7.2 Hz, 2H, CH2),
2.11 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.72 (t, J = 7.2 Hz,
2H, CH2-C), 3.03 (t, J = 7.2 Hz, 2H, CH2), 3.21 (t,
J = 7.2 Hz, 2H, NHCH2), 5.44 (s, 1H, NH), 6.25 (d,
J = 8.0 Hz, 2H, H(2,6)Ar), 6.80 (d, J = 8.0 Hz, 2H,
H
(3,5)Ar), 7.30 (d, J = 8.0 Hz, 2H, H(3,5)Ar0), 7.37 (d,
4-Methyl-N-[2-[4-phenyl-5-(propan-2-ylsulfanyl)-4H-
1,2,4-triazol-3-yl]ethyl]aniline (3a, C20H24N4S)
J = 8.0 Hz, 2H, H(2,6)Ar0) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 13.3 (CH3), 20.0 (Ar-CH3), 20.7 (Ar0-
CH3), 21.0 (CH3CH2CH2CH2), 24.7 (C-8), 30.9
(CH3CH2CH2CH2), 31.7 (CH3CH2CH2CH2), 40.7 (C-7),
112.0 (C-2,6), 124.1 (C-4), 127.1 (C-30,50), 129.3 (C-40),
130.3 (C-20,60), 130.5 (C-3,5), 139.6 (C-10), 145.7 (C-1),
149.9 (C-9), 154.0 (C-10) ppm; IR (KBr): m = 3,284 (NH),
1,515, 1,497 (C=N), 1,261 (C–S–C) cm-1; MS (ESI,
25 eV): m/z (%) = 381 ([M?H]?, 100).
Prepared according to method A from 1a and 0.85 g
(0.50 cm3) 2-iodopropane. Yield 1.05 g (75 %); m.p.:
1
103–104 °C; TLC: Rf = 0.32 (acetone/hexane = 1:1); H
NMR (400 MHz, DMSO-d6): d = 1.27 (d, J = 6.9 Hz,
6H, 2CH3), 2.11 (s, 3H, CH3), 2.75 (t, J = 7.2 Hz, 2H,
CH2-C), 3.24 (t, J = 7.2 Hz, 2H, NHCH2), 3.59 (sep,
J = 6.9 Hz, 1H, CH), 5.45 (s, 1H, NH), 6.26 (d,
J = 8.4 Hz, 2H, H(2,6)Ar), 6.80 (d, J = 8.4 Hz, 2H,
H
(3,5)Ar), 7.39–7.44 (m, 2H, H(3,5)Ar0), 7.53–7.60 (m,
4-Methyl-N-(2-[5-[(2-methylpropyl)sulfanyl]-4-phenyl-4H-
1,2,4-triazol-3-yl]ethyl)aniline (5a, C21H26N4S)
3H, H(2,4,6)Ar0) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 20.0 (Ar-CH3), 23.0 (CH3), 24.8 (C-8), 38.3 (CH),
40.6 (C-7), 112.0 (C-2,6), 124.1 (C-4), 127.5 (C-30,50),
129.2 (C-40), 129.7 (C-20,50), 129.7 (C-3,5), 133.2 (C-10),
145.6 (C-1), 149.07 (C-9), 153.8 (C-10) ppm; IR
(KBr): m = 3,290 (NH), 1,514, 1,497 (C=N), 1,262
Prepared according to method A from 1a and 0.69 g
(0.54 cm3) 1-bromo-2-methylpropane. Yield 1.02 g
(70 %); m.p.: 139–140 °C; TLC: Rf = 0.67 (acetone/
hexane = 1:1); 1H NMR (400 MHz, DMSO-d6):
d = 0.90 (d, J = 6.6 Hz, 6H,
2 CH3), 1.86 (sep,
(C–S–C) cm-1
([M?H]?, 90).
;
MS (ESI, 25 eV): m/z (%) = 353
J = 6.6 Hz, 1H, CH), 2.11 (s, 3H, CH3), 2.73 (t,
J = 6.9 Hz, 2H, CH2-C), 2.95 (d, J = 6.9 Hz, 2H, CH2),
3.21 (q, J = 6.9 Hz, J = 13.8 Hz, 2H, NHCH2), 5.44 (t,
J = 6.3 Hz, 1H, NH), 6.24 (d, J = 8.4 Hz, 2H, H(2,6)Ar),
6.80 (d, J = 8.4 Hz, 2H, H(3,5)Ar), 7.40–7.46 (m, 2H,
N-[2-[5-(Butylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-4-methylaniline (4a, C21H26N4S)
Prepared according to method A from 1a and 0.92 g
(0.57 cm3) 1-iodobutane. Isolation by column chromatog-
raphy (acetone/hexane 1:1, Rf = 0.37) afforded 1.01 g
(69 %) 4a. M.p.: 113–114 °C; 1H NMR (DMSO-d6):
d = 0.84 (t, J = 7.5 Hz, 3H, CH3), 1.32 (sext,
J = 7.5 Hz, 3H, CH2), 1.59 (quin, J = 7.5 Hz, 2H, CH2),
2.12 (s, 3H, CH3), 2.78 (t, J = 7.2 Hz, 2H, CH2-C), 3.05 (t,
J = 7.2 Hz, 2H, CH2), 3.33 (t, J = 7.2 Hz, 2H, NHCH2),
4.91 (s, 1H, NH), 6.51 (d, J = 8.1 Hz, 2H, H(2,6)Ar), 6.93
(d, J = 8.1 Hz, 2H, H(3,5)Ar), 7.42–7.47 (m, 2H, H(3,5)Ar0),
7.56–7.62 (m, 3H, H(2,4,6)Ar0) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 13.3 (CH3), 20.1 (Ar-CH3), 21.0
(CH3CH2CH2CH2), 23.9 (C-8), 30.9 (CH3CH2CH2CH2),
31.7 (CH3CH2CH2CH2), 42.3 (C-7), 114.6 (C-2,6), 127.4
(C-4), 127.8 (C-30,50), 129.5 (C-40), 129.9 (C-20,60), 130.0
(C-3,5), 132.8 (C-10), 142.5 (C-1), 150.2 (C-9), 153.4 (C-
10) ppm; IR (KBr): m = 3,283 (NH), 1,514, 1,496 (C=N),
1,260 (C–S–C) cm-1; MS (ESI, 25 eV): m/z (%) = 367
([M?H]?, 80).
H
(3,5)Ar0), 7.55–7.61 (m, 3H, H(2,4,6)Ar0) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 20.0 (Ar-CH3), 21.3 (CH3),
24.7 (C-8), 27.8 (CH), 40.5 (CH2), 40.6 (C-7), 112.0 (C-
2,6), 124.1 (C-4), 127.5 (C-30,50), 129.3 (C-40), 129.8 (C-
20,60), 129.9 (C-3,5), 133.1 (C-10), 145.7 (C-1), 149.9 (C-9),
153.9 (C-10) ppm; IR (KBr): m = 3,289 (NH), 1,515,
1,496 (C=N), 1,262 (C–S–C) cm-1; MS (ESI, 25 eV):
m/z (%) = 367 ([M?H]?, 70).
4-Methyl-N-(2-[5-[(3-methylbutyl)sulfanyl]-4-phenyl-4H-
1,2,4-triazol-3-yl]ethyl)aniline (6a, C22H28N4S)
Prepared according to method A from 1a and 0.99 g
(0.65 cm3) 1-iodo-3-methylbutane. Yield 1.17 g (77 %);
m.p.: 109–110 °C; TLC: Rf = 0.64 (acetone/hex-
ane = 1:1); 1H NMR (400 MHz, DMSO-d6): d = 0.84
(d, J = 6.3 Hz, 6H, 2 CH3), 1.51 (q, J = 7.2 Hz, 2H,
CH2), 1.59 (sep, J = 6.6 Hz, 1H, CH), 2.11 (s, 3H, CH3),
2.74 (t, J = 7.2 Hz, 2H, CH2-C), 3.04 (t, J = 7.2 Hz, 2H,
CH2), 3.23 (q, J = 7.2 Hz, 2H, NHCH2), 5.45 (t,
123

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I. Tumosiene et al.
324
J = 6.3 Hz, 1H, NH), 6.25 (d, J = 8.4 Hz, 2H, H(2,6)Ar),
6.80 (d, J = 8.4 Hz, 2H, H(3,5)Ar), 7.40–7.46 (m, 2H,
H(2,6)Ar), 6.80 (d, J = 8.1 Hz, 2H, H(3,5)Ar), 7.42–7.48 (m,
2H, H(3,5)Ar0), 7.57–7.65 (m, 3H, H(2,4,6)Ar0) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 14.0 (CH3CH2), 20.0
(Ar-CH3), 24.6 (C-8), 33.9 (CH2), 40.7 (C-7), 61.3
(CH3CH2), 112.1 (C-2,6), 124.3 (C-4), 127.3 (C-30,50),
129.3 (C-40), 130.0 (C-20), 130.1 (C-3), 132.8 (C-10), 145.7
(C-1), 149.1 (C-9), 154.2 (C=O), 168.1 (C-10 C–S–) ppm;
IR (KBr): m = 3,301 (NH), 1,744 (C=O), 1,521, 1,448
(C=N), 1,309 (C–S–C), 1,165 (C–O–C) cm-1; MS (ESI,
25 eV): m/z (%) = 397 ([M?H]?, 90).
H
(3,5)Ar0), 7.54–7.61 (m, 3H, H(2,4,6)Ar0) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 20.0 (Ar-CH3), 21.9 (CH3),
24.7 (C-8), 26.6 (CH), 30.2 (CH2CH2), 37.8 (CH2CH2),
40.6 (C-7), 112.0 (C-2,6), 124.1 (C-4), 127.4 (C-30,50),
129.3 (C-40), 129.8 (C-20,60), 129.3 (C-3,5), 133.1 (C-10),
145.7 (C-1), 149.8 (C-9), 153.9 (C-10) ppm; IR (KBr):
m = 3,292 (NH), 1,513, 1,498 (C=N), 1,264 (C–S–C)
cm-1; MS (ESI, 25 eV): m/z (%) = 381 ([M?H]?, 100).
N-[2-[5-(Benzylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-4-methylaniline (7a, C24H24N4S)
Ethyl 2-[[4-(4-methylphenyl)-5-[2-[(4-methylphenyl)-
amino]ethyl]-4H-1,2,4-triazol-3-yl]sulfanyl]acetate
(8b, C22H26N4O2S)
Method A. Prepared from 1a and 0.63 g (0.58 cm3)
(chloromethyl)benzene. Yield 0.66 g (41 %).
Prepared according to method B from 1b and 0.61 g
(0.54 cm3) ethyl chloroacetate except that the reaction
mixture was stirred for 30 min at 35 °C. Yield 1.39 g
(85 %); m.p.: 134–135 °C; TLC: Rf = 0.44 (acetone/
hexane = 1:1); 1H NMR (400 MHz, DMSO-d6):
d = 1.15 (t, J = 7.2 Hz, 3H, CH3CH2), 2.12 (s, 3H,
CH3), 2.73 (t, J = 7.2 Hz, 2H, CH2-C), 2.41 (s, 3H, CH3),
3.21 (t, J = 7.2 Hz, 2H, NHCH2), 4.01 (s, 2H, CH2), 4.10
(q, J = 7.2 Hz, 2H, CH3CH2), 5.45 (s, 1H, NH), 6.26 (d,
J = 8.1 Hz, 2H, H(2,6) Ar), 6.81 (d, J = 8.1 Hz, 2H,
Method B. Prepared from 1a and 0.63 g (0.58 cm3)
(chloromethyl)benzene. Yield 0.94 g (59 %).
Method C. To 1.24 g 1a (4 mmol) dissolved in 5 cm3
DMF, 0.12 g NaH (5 mmol) was added. The reaction
mixture was stirred at room temperature until evolution of
hydrogen stopped (approx. 10 min), and 0.63 g (chloro-
methyl)benzene (0.58 cm3, 5 mmol) dissolved in 5 cm3
dioxane was then added dropwise. The reaction mixture
was stirred at 50 °C for 2 h. Afterwards 30 cm3 cold water
was added and the precipitate formed was isolated by
filtration. Recrystallization from propan-2-ol afforded
1.25 g (78 %) 7a; m.p.: 134–135 °C; TLC: Rf = 0.44
H
(3,5)Ar), 7.33 (d, J = 8.1 Hz, 2H, H(3,5)Ar0), 7.40 (d,
J = 8.1 Hz, 3H, H(2,6)Ar0) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 13.9 (CH3CH2), 20.0 (Ar-CH3), 20.7 (Ar0-
CH3), 24.5 (C-8), 33.8 (CH2), 40.7 (C-7), 61.1 (CH3CH2),
112.1 (C-2,6), 124.2 (C-4), 127.0 (C-30), 129.2 (C-40),
130.1 (C-20), 130.4 (C-3), 139.8 (C-10), 145.6 (C-1), 149.1
(C-9), 154.2 (C=O), 168.0 (C-10) ppm; IR (KBr):
m = 3,300 (NH), 1,746 (C=O), 1,522, 1,449 (C=N), 1,309
(C–S–C), 1,164 (C–O–C) cm-1; MS (ESI, 25 eV):
m/z (%) = 411 ([M?H]?, 90).
1
(acetone/hexane = 1:1); H NMR (400 MHz, DMSO-d6):
d = 2.11 (s, 3H, CH3), 2.74 (t, J = 7.2 Hz, 2H, CH2-C),
3.23 (t, J = 7.2 Hz, 2H, NHCH2), 4.32 (s, 2H, CH2), 5.45
(s, 1H, NH), 6.26 (d, J = 8.4 Hz, 2H, H(2,6)Ar), 6.82 (d,
J = 8.4 Hz, 2H,
H(3,5)Ar), 7.17–7.44 (m, 7H,
HAr0 ? HAr00), 7.46–7.67 (m, 3H, HAr0) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 20.0 (Ar-CH3), 24.7 (C-8),
36.3 (CH2), 40.7 (C-7), 112.0 (C-2,6), 124.1 (C-4), 127.3
(C-30,50), 128.3 (C-300,500), 128.8 (C-400), 129.3 (C-40), 129.7
(C-20,60), 129.8 (C-3,5), 132.9 (C-10), 134.4 (C-100), 137.0
(C-200,600), 145.6 (C-1), 149.4 (C-9), 154.0 (C-10) ppm; IR
(KBr): m = 3,318 (NH), 1,520, 1,497 (C=N), 1,288 (C–S–C)
cm-1; MS (ESI, 25 eV): m/z (%) = 401 ([M?H]?, 100).
2-[[5-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4H-
1,2,4-triazol-3-yl]sulfanyl]acetamide (9a, C19H21N5OS)
Prepared according to method A from 1a and 0.47 g
2-chloroacetamide.
147–148 °C; TLC:
Yield
1.14 g
(78 %);
m.p.:
Rf = 0.54
(acetone/hexane/
CH3OH = 1:1:1); 1H NMR (400 MHz, DMSO-d6):
d = 2.11 (s, 3H, CH3), 2.74 (t, J = 7.2 Hz, 2H, CH2-C),
3.22 (q, J = 7.2 Hz, 2H, NHCH2), 3.37 (s, 2H, CH2), 5.44
(t, J = 6.3 Hz, 1H, NH), 6.25 (d, J = 8.1 Hz, 2H,
Ethyl 2-[(5-[2-[(4-methylphenyl)amino]ethyl]-4-phenyl-
4H-1,2,4-triazol-3-yl)sulfanyl]acetate (8a, C21H24N4O2S)
Prepared according to method B from 1a and 0.61 g
(0.54 cm3) ethyl chloroacetate except that the reaction
mixture was stirred for 20 min at 35 °C. Yield 2.38 g
(86 %); m.p.: 84–85 °C; TLC: Rf = 0.33 (acetone/hex-
H
(2,6)Ar), 6.81 (d, J = 8.1 Hz, 2H, H(3,5)Ar), 7.25 (s, 1H,
NH2), 7.44–7.51 (m, 2H, H(3,5)Ar0), 7.56–7.63 (m, 3H,
(2,4,6)Ar0), 7.68 (s, 1H, NH2) ppm; 13C NMR (100 MHz,
H
1
ane = 1:1); H NMR (400 MHz, DMSO-d6): d = 1.17 (t,
DMSO-d6): d = 20.0 (Ar-CH3), 24.6 (C-8), 35.9 (CH2),
40.7 (C-7), 112.0 (C-2,6), 124.2 (C-4), 127.4 (C-30,50),
129.3 (C-40), 129.9 (C-20,60), 130.0 (C-3,5), 132.9 (C-10),
145.7 (C-1), 149.8 (C-9), 153.9 (C=O), 168.6 (C-10) ppm;
IR (KBr): m = 3,366–2,860 (NH, NH2), 1,693 (C=O),
J = 7.2 Hz, 3H, CH3CH2), 2.11 (s, 3H, CH3), 2.74 (t,
J = 7.2 Hz, 2H, CH2-C), 3.21 (t, J = 7.2 Hz, 2H,
NHCH2), 4.01 (s, 2H, CH2), 4.09 (q, J = 7.2 Hz, 2H,
CH3CH2), 5.43 (s, 1H, NH), 6.25 (d, J = 8.1 Hz, 2H,
123

The synthesis of S-substituted derivatives
325
1,523, 1,498 (C=N), 1,268 (C–S–C) cm-1; MS (ESI,
Prepared according to method B from 0.93 g 1a and 1.17 g
2-bromo-1-(4-chlorophenyl)ethanone. Yield 0.96 g (52 %);
m.p.: 149–150 °C; TLC: Rf = 0.76 (acetone/hexane = 1:1);
1H NMR (400 MHz, DMSO-d6): d = 2.11 (s, 3H, CH3), 2.73
(t, J = 7.2 Hz, 2H, CH2-C), 3.20 (t, J = 7.2 Hz, 2H,
NHCH2), 4.83 (s, 2H, CH2), 5.44 (s, 1H, NH), 6.24 (d,
J = 8.1 Hz, 2H, H(2,6)Ar), 6.80 (d, J = 8.1 Hz, 2H, H(3,5)Ar),
25 eV): m/z (%) = 368 ([M?H]?, 100).
2-[[5-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4H-
1,2,4-triazol-3-yl]sulfanyl]-1-phenylethan-1-one
(10a, C25H24N4OS)
Prepared according to method B from 0.93 g 1a (3 mmol)
and 0.594 g 2-bromo-1-phenylethanone (3 mmol). Yield
0.81 g (63 %); m.p.: 138–139 °C; TLC: Rf = 0.38 (ace-
tone/hexane = 1:1); 1H NMR (400 MHz, DMSO-d6):
d = 2.11 (s, 3H, CH3), 2.75 (t, J = 7.2 Hz, 2H, CH2-C),
3.22 (t, J = 7.2 Hz, 2H, NHCH2), 4.87 (s, 2H, CH2), 5.45
(s, 1H, NH), 6.26 (d, J = 8.1 Hz, 2H, H(2,6)Ar), 6.81 (d,
J = 8.1 Hz, 2H, H(3,5)Ar), 7.45–7.51 (m, 2H, H(3,5)Ar0),
7.44–7.51 (m, 2H,
(2,4,6)Ar0 ? HAr00), 7.44–7.51 (d, J = 8.7 Hz, 2H, HAr00)
H
(3,5)Ar0), 7.57–7.66 (m, 5H,
H
ppm; 13C NMR (100 MHz, DMSO-d6): d = 19.9 (Ar-CH3),
24.6(C-8), 39.9 (CH2), 40.6 (C-7), 112.0 (C-2,6), 124.2 (C-4),
127.3 (C-30,50), 128.8 (C-400), 129.3 (C-40), 129.9 (C-300,500),
130.0 (C-3,5), 130.2 (C-20,60), 132.8 (C-10), 133.9 (C-100),
138.5 (C-200,600), 145.6 (C-1), 149.2 (C-9), 154.0 (C-10), 192.2
(C=O) ppm; IR (KBr): m = 3,290 (NH), 1,695 (C=O), 1,517,
1,450 (C=N), 1,326 (C–S–C) cm-1; MS (ESI, 25 eV): m/
z (%) = 464 ([M?H]?, 100).
7.52–7.63 (m, 5H,
J = 7.2 Hz, 1H, H(4)Ar00), 8.01 (d, J = 6.9 Hz, 2H,
(2,6)Ar00) ppm; 13C NMR (100 MHz, DMSO-d6):
H
(2,4,6)Ar0 ? H(3,5)Ar00), 7.68 (t,
H
d = 20.0 (Ar-CH3), 24.6 (C-8), 40.0 (CH2), 40.6 (C-7),
112.0 (C-2,6), 124.2 (C-4), 127.3 (C-30,50), 128.3 (C-
300,500), 128.7 (C-400), 129.3 (C-40), 129.9 (C-20,60), 130.0
(C-3,5), 132.9 (C-10), 133.6 (C-100), 135.2 (C-200,600), 145.6
(C-1), 149.3 (C-9), 154.0 (C-10), 193.0 (C=O) ppm; IR
(KBr): m = 3,289 (NH), 1,692 (C=O), 1,514, 1,447 (C=N),
1,326 (C–S–C) cm-1; MS (ESI, 25 eV): m/z (%) = 429
([M?H]?, 100).
2-[[5-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4H-
1,2,4-triazol-3-yl]sulfanyl]-1-(4-nitrophenyl)ethan-1-one
(12a, C25H23N5O3S)
Prepared according to method B from 1a and 1.0 g 2-bromo-
1-(4-nitrophenyl)ethanone. Yield 1.01 g (71 %); m.p.:
1
182–183 °C; TLC: Rf = 0.68 (acetone/hexane = 1:1); H
NMR (400 MHz, DMSO-d6): d = 2.11 (s, 3H, CH3), 2.74 (t,
J = 7.2 Hz, 2H, CH2-C), 3.20 (t, J = 7.2 Hz, 2H, NHCH2),
4.90 (s, 2H, CH2), 5.43 (s, 1H, NH), 6.24 (d, J = 8.4 Hz, 2H,
2-[[4-(4-Methylphenyl)-5-[2-[(4-methylphenyl)-
amino]ethyl]-4H-1,2,4-triazol-3-yl]sulfanyl]-1-
phenylethan-1-one (10b, C26H26N4OS)
H
(2,6)Ar), 6.80 (d, J = 8.4 Hz, 2H, H(3,5)Ar), 7.45–7.51 (m,
2H, H(3,5)Ar0), 7.57–7.64 (m, 3H, H(2,4,6)Ar0), 8.23 (d,
J = 8.4 Hz, 2H, HAr00), 8.36 (d, J = 8.4 Hz, 2H, HAr00)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 20.0 (Ar-CH3),
24.6 (C-8), 40.1 (CH2), 40.6 (C-7), 112.0 (C-2,6), 123.8 (C-
400), 00124.2 (C-4), 127.3 (C-30,50), 129.3 (C-40), 129.8 (C-
300,5 ), 129.9 (C-3,5), 130.0 (C-20), 132.8 (C-10), 140.0 (C-
200,600), 145.6 (C-1), 150.0 (C-9), 154.1 (C-10), 192.6 (C=O)
ppm; IR (KBr): m = 3,288 (NH), 1,690 (C=O), 1,515,
1,450 (C=N), 1,298 (C–S–C) cm-1; MS (ESI, 25 eV):
m/z (%) = 474 ([M?H]?, 90).
Prepared according to method B from 1b and 1.0 g
2-bromo-1-phenylethanone. Yield 0.72 g (81 %); m.p.:
1
141–142 °C; TLC: Rf = 0.76 (acetone/hexane = 1:1); H
NMR (400 MHz, DMSO-d6): d = 2.12 (s, 3H, CH3), 2.41
(s, 3H, Ar0-CH3), 2.72 (t, J = 7.2 Hz, 2H, CH2-C), 3.20 (t,
J = 7.2 Hz, 2H, NHCH2), 4.85 (s, 2H, CH2), 5.42 (s, 1H,
NH), 6.25 (d, J = 8.1 Hz, 2H, H(2,6)Ar), 6.80 (d,
J = 8.1 Hz, 2H, H(3,5)Ar), 7.31–7.42 (m, 4H, HAr0), 7.55
(t, J = 7.5 Hz, 2H, H(3,5)Ar00), 7.68 (t, J = 7.5 Hz, 2H,
H
(4)Ar00), 8.00 (d, J = 7.5 Hz, 2H, H(2,6)Ar00) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 20.0 (Ar-CH3), 20.7
(Ar0-CH3), 24.6 (C-8), 40.0 (CH2), 40.7 (C-7), 112.0 (C-
2,6),00124.2 (C-4), 127.1 (C-30,50), 128.3 (C-300,500), 128.7
(C-4 ), 129.2 (C-40), 130.2 (C-20,60), 130.4 (C-3,5), 133.6
(C-100), 135.2 (C-200,600), 139.8 (C-10), 145.6 (C-1), 149.4
(C-9), 154.1 (C-10), 193.1 (C=O) ppm; IR (KBr):
m = 3,290 (NH), 1,694 (C=O), 1,513, 1,446 (C=N), 1,327
N-(4-Methylphenyl)-N-[2-(4-phenyl-5-sulfanylidene-4,5-
dihydro-1H-1,2,4-triazol-3-yl)ethyl]acetamide
(13, C19H20N4OS)
A mixture of 1.24 g 1 (4 mmol) in 10 cm3 acetic anhydride
was heated at reflux for 6 h. To the reaction mixture
30 cm3 water was added and the mixture was kept at 4 °C
for 24 h. The aqueous solution was decanted and the
residue was crystallized from a propan-2-ol/water mixture
to afford 0.98 g (70 %) 13. M.p.: 191–192 °C; TLC:
Rf = 0.6 (acetone/hexane = 1:1); 1H NMR (400 MHz,
DMSO-d6): d = 1.63 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.61
(t, J = 6.9 Hz, 2H, CH2C), 3.64 (t, J = 6.9 Hz, 2H,
(C–S–C) cm-1
; MS (ESI, 25 eV): m/z (%) = 443
([M?H]?, 70).
1-(4-Chlorophenyl)-2-[[5-[2-[(4-methylphenyl)-
amino]ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl]-
ethan-1-one (11a, C25H23ClN4OS)
123

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I. Tumosiene et al.
326
NHCH2), 7.04 (d, J = 8.1 Hz, 2H, H(2,6)Ar), 7.21 (d,
J = 8.1 Hz, 2H, H(3,5)Ar), 7.32–7.37 (m, 2H, H(3,5)Ar0),
7.47–7.53 (m, 3H, H(2,4,6)Ar0), 13.72 (s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 20.5 (Ar-CH3), 22.2
(CH3), 23.8 (C-8), 45.3 (C-7), 127.7 (C-2,6), 128.2 (C-4),
129.3 (C-30,50), 129.4 (C-40), 130.0 (C-20,60), 133.5 (C-3,5),
137.2 (C-10), 139.6 (C-1), 149.7 (C-9), 167.6 (C=O), 169.1
(C=S) ppm; IR (KBr): m = 2,920 (NH), 1,660 (C=O),
1,509 (C=N), 1,497 (C–N), 1,340 (C=S) cm-1; MS (ESI,
25 eV): m/z (%) = 353 ([M?H]?, 80).
CH3), 3.67 (t, J = 7.2 Hz, 2H, NCH2), 7.05 (d,
J = 8.0 Hz, 2H, H(2,6)Ar), 7.20 (d, J = 8.0 Hz, 2H,
H
(3,5)Ar), 7.27–7.31 (m, 2H, H(3,5)Ar0), 7.50–7.56 (m,
3H, H(2,4,6)Ar0) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 13.3 (CH3), 20.5 (Ar-CH3), 21.0 (CH2), 22.2
(COCH3), 23.2 (C-8), 30.9 (CH3CH2CH2CH2), 31.8
(CH3CH2CH2CH2), 46.1 (C-7), 127.2 (C-2,6), 127.8 (C-
30,50), 129.7 (C-4), 129.8 (C-40), 130.0 (C-20,60), 132.9
(C-3,5), 137.1 (C-10), 139.9 (C-1), 149.9 (C-9), 152.9 (C-
10), 169.0 (C=O) ppm; IR (KBr): m = 1,648 (C=O),
1,516, 1,500 (C=N), 1,293 (C–S–C) cm-1; MS (ESI,
25 eV): m/z (%) = 409 ([M?H]?, 100).
N-[2-[5-(Ethylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-N-(4-methylphenyl)acetamide (14, C21H24N4OS)
Method A. To 0.35 g 13 (1 mmol) dissolved in 10 cm3
methanol, 0.1 g triethylamine (0.14 cm3, 1 mmol) was
added and the reaction mixture was stirred at room
temperature for 10 min. Afterwards 0.16 g iodoethane
(0.08 cm3, 1 mmol) was added dropwise and the reaction
mixture was stirred at 35 °C for 4 h. The liquid fractions
were concentrated in vacuo. Recrystallization of the
residue from hexane afforded 0.19 g (51 %) 14.
Method B. A mixture of 0.34 g 2a (1 mmol) in 5 cm3
acetic anhydride was heated at reflux for 2 h. Afterwards
the liquid fractions were concentrated in vacuo and the
residue was crystallized from hexane to afford 0.28 g
(70 %) 14. M.p.: 138–139 °C; TLC: Rf = 0.23 (acetone/
hexane = 1:1); 1H NMR (400 MHz, DMSO-d6): d = 1.25
(t, J = 7.2 Hz, CH3CH2), 1.62 (s, 3H, CH3), 2.32 (s, 3H,
CH3), 2.73 (t, 2H, J = 6.8 Hz, 3H, CH2-C), 3.02 (q,
J = 7.2 Hz, 2H, CH3CH2), 3.67 (t, J = 6.8 Hz, 2H,
NCH2), 7.05 (d, J = 7.6 Hz, 2H, H(2,6)Ar), 7.20 (d,
J = 7.6 Hz, 2H, H(3,5)Ar), 7.26–7.36 (m, 2H, H(3,5)Ar’),
7.47–7.61 (m, 3H, H(2,4,6)Ar0) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 14.7 (CH3), 20.5 (Ar-CH3), 22.2 (CH3),
23.2 (C-8), 26.4 (CH3CH2), 46.1 (C-7), 127.2 (C-2,6),
127.8 (C-30,50), 129.7 (C-4), 129.8 (C-40), 130.0 (C-20,60),
132.9 (C-3,5), 137.1 (C-10), 139.9 (C-1),149.8 (C-9), 153.0
(C-10), 169.0 (C=O) ppm; IR (KBr): m = 1,660 (C=O),
1,509, 1,498 (C=N), 1,301 (C–S–C) cm-1; MS (ESI,
25 eV): m/z (%) = 381 ([M?H]?, 100).
N-[2-[5-(Benzylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-N-(4-methylphenyl)acetamide (16, C26H26N4OS)
Method A. To 0.35 g 13 (1 mmol) dissolved in 10 cm3
methanol, 0.1 g triethylamine (0.14 cm3, 1 mmol) was
added and the mixture was stirred at room temperature for
10 min. Afterwards 0.13 g (chloromethyl)benzene
(0.12 cm3, 1 mmol) was added dropwise and the reaction
mixture was stirred at 35 °C for 4 h. The liquid fractions
were concentrated in vacuo and the residue was crystal-
lized from hexane to afford 0.30 g (69 %) 16.
Method B. A mixture of 0.4 g 7a (1 mmol) and 5 cm3
acetic anhydride was heated at reflux for 2 h. The liquid
fractions were concentrated in vacuo and the residue was
crystallized from hexane to afford 0.32 g (72 %) 16.
M.p.: 135–136 °C; TLC: Rf = 0.41 (acetone/hex-
ane = 1:1); 1H NMR (400 MHz, DMSO-d6): d = 1.62
(s, 3H, CH3), 2.31 (s, 3H, CH3), 2.72 (t, J = 7.2 Hz, 2H,
CH2-C), 3.66 (t, J = 7.2 Hz, 2H, NCH2), 4.29 (s, 2H,
CH2), 7.03 (d, J = 8.4 Hz, 2H, H(2,6)Ar), 7.14-7.34 (m,
9H, HAr ? HAr0 ? HAr00), 7.44–7.56 (m, 3H, HAr0)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 20.6 (Ar-
CH3), 22.2 (CH3), 23.2 (C-8), 36.2 (CH2), 46.1 (C-7),
127.1 (C-2,6), 127.4 (C-4), 127.8 (C-30,50), 128.4 (C-
300,500), 128.9 (C-400), 129.7 (C-40), 129.8 (C-20,60), 130.0
(C-3,5), 132.8 (C-100), 137.1 (C-10), 137.1 (C-200,600),
139.9 (C-1), 149.5 (C-9), 153.1 (C-10), 168.9 (C=O)
ppm; IR (KBr): m = 1,655 (C=O), 1,495, 1,397 (C=N),
1,303 (C–S–C) cm-1; MS (ESI, 25 eV): m/z (%) = 443
([M?H]?, 90).
N-[2-[5-(Butylsulfanyl)-4-phenyl-4H-1,2,4-triazol-3-yl]-
ethyl]-N-(4-methylphenyl)acetamide (15, C23H28N4OS)
A mixture of 0.73 g 4a (2 mmol) and 5 cm3 acetyl
chloride was stirred at room temperature for 4 h.
Afterwards 20 cm3 distilled water was added to the
reaction mixture. The precipitate formed was isolated by
filtration and recrystallization from hexane afforded
0.68 g (84 %) 15. M.p.: 122–123 °C; TLC: Rf = 0.36
2-[[3-[2-[(4-Methylphenyl)amino]ethyl]-4-phenyl-4,5-
dihydro-1H-1,2,4-triazol-5-yl]sulfanyl]acetohydrazide
(17, C19H24N6OS)
To 1.98 g 8a (5 mmol) dissolved in 40 cm3 methanol,
0.48 g hydrazine hydrate (15 mmol) was added and the
reaction mixture was stirred at room temperature for 6 h.
Afterwards 40 cm3 H2O was added and the mixture was
kept at 4 °C for 24 h. The precipitate was isolated by
filtration and recrystallization from ethanol afforded 1.1 g
(57 %) 17. M.p.: 98–99 °C; TLC: Rf = 0.74 (acetone/
hexane = 1:1); 1H NMR (400 MHz, DMSO-d6): d = 2.11
1
(acetone/hexane = 1:1); H NMR (400 MHz, DMSO-d6):
d = 0.84 (t, J = 7.2 Hz, 3H, CH3), 1.31 (sext,
J = 7.2 Hz, 2H, CH2), 1.57 (quin, J = 7.2 Hz, 2H,
CH2), 2.32 (s, 3H, CH3), 2.72 (t, J = 7.2 Hz, 2H,
CH2-C), 3.01 (t, J = 7.2 Hz, 2H, CH2), 3.34 (s, 3H,
123

The synthesis of S-substituted derivatives
327
(s, 3H, CH3), 2.73 (t, J = 7.2 Hz, 2H, CH2-C), 3.24 (t,
J = 7.2 Hz, 2H, NHCH2), 3.85 (s, 2H, CH2), 4.43 (s, 1H,
NH), 5.41 (s, 2H, NH2), 6.27 (d, J = 8.1 Hz, 2H, H(2,6)Ar),
6.81 (d, J = 8.1 Hz, 2H, H(3,5)Ar), 7.42–7.51 (m, 2H,
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123