The synthesis of azole derivatives from 3-[(4-methylphenyl)amino]- propanehydrazide and its N'-phenylcarbamoyl derivatives, and their antibacterial activity

Article abstract of DOI:10.1007/s00706-012-0799-0

5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol- 2(3H)-thione, 5-[2-[(4-methylphenyl)amino]ethyl]- 1,3,4-oxadiazol-2(3H)-one, N-(2,5-dimethyl-1H-pyrrol-1-yl)- 3-[(4-methylphenyl)amino]propanamide, and a series of N-[(phenylcarbamoyl)amino]-3-[(4-methylphenyl)amino]- propanamides and 3-[(4-methylphenyl)(phenylcarbamoyl)- amino]-N-[(phenylcarbamoyl)amino] propanamides, and their thio analogues were synthesized from 3-[(4-methylphenyl)- amino]propanehydrazide. 1,3,4-Oxadiazole-2(3H)-thione was converted to 4-amino-2,4-dihydro-5-[2-[(4-methylphenyl)- amino]ethyl]-3H-1,2,4- triazole-3-thione, whereas cyclization of N'-phenylcarbamoyl derivatives provided thiazole, oxadiazoles, and thiadiazole, as well as triazole derivatives. Two of the synthesized compounds exhibited good antibacterial activity against Rhizobium radiobacter. Springer-Verlag 2012.

Full text of DOI:10.1007/s00706-012-0799-0

Monatsh Chem (2012) 143:1441–1450
DOI 10.1007/s00706-012-0799-0
ORIGINAL PAPER
The synthesis of azole derivatives from 3-[(4-methylphenyl)amino]-
propanehydrazide and its N0-phenylcarbamoyl derivatives, and their
antibacterial activity
•
Ingrida Tumosiene Ilona Jonuskiene
•
_
Kristina Kantminiene Zigmuntas Jonas Beresnevicius
ˇ
_
•
_
ˇ
Received: 5 March 2012 / Accepted: 18 May 2012 / Published online: 21 June 2012
Ó Springer-Verlag 2012
Abstract 5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxa-
diazol-2(3H)-thione, 5-[2-[(4-methylphenyl)amino]ethyl]-
1,3,4-oxadiazol-2(3H)-one, N-(2,5-dimethyl-1H-pyrrol-1-yl)-
3-[(4-methylphenyl)amino]propanamide, and a series of
N-[(phenylcarbamoyl)amino]-3-[(4-methylphenyl)amino]-
propanamides and 3-[(4-methylphenyl)(phenylcarbamoyl)-
amino]-N-[(phenylcarbamoyl)amino]propanamides, and their
thio analogues were synthesized from 3-[(4-methylphenyl)-
amino]propanehydrazide. 1,3,4-Oxadiazole-2(3H)-thione was
converted to 4-amino-2,4-dihydro-5-[2-[(4-methylphenyl)-
amino]ethyl]-3H-1,2,4-triazole-3-thione, whereas cyclization
of N0-phenylcarbamoyl derivatives provided thiazole, oxadi-
azoles, and thiadiazole, as well as triazole derivatives. Two of
the synthesized compounds exhibited good antibacterial
activity against Rhizobium radiobacter.
activity. They are also suitable compounds as synthons in
the synthesis of various heterocyclic compounds. Cycli-
zation of hydrazine derivatives is a well-known method for
azole synthesis [1]. The five-membered heterocyclic
nucleus plays a vital role in many biological activities;
thus, azole derivatives have been demonstrated to possess
antibacterial [2, 3], anti-inflammatory [4], antitumor [5],
antifungal [3], and antimicrobial [6–9] activities. 5-Mer-
capto-1,2,4-triazoles containing the furyl radical are
potential anti-HIV-1 agents [10], whereas substituted tria-
zole-3-thiones have demonstrated antidepressant activity
[11].
Previously, we described the cyclization of N-phenyl-b-
alanine hydrazide, N-phenyl- and N-(p-tolyl)-N-carboxy-
phenyl-b-alanine dihydrazides, N,N0-bis(hydrazinocarbo-
nylethyl)-1,4-phenylenediamine, and their semicarbazides
and thiosemicarbazides into compounds containing one or
several azole fragments [2, 12–14]. As a continuation of our
search for compounds possessing antibacterial and antifungal
activities, we report herein the synthesis of heterocyclic
compounds from 3-(4-methylphenylamino)propanehydraz-
ide (1) and its carbamoyl derivatives. Cyclization of
N0-phenylcarbamoyl derivatives to oxazole and thiazole,
oxadiazole andthiadiazole, as well as triazole derivatives was
carried out. Some of the synthesized compounds were tested
for antibacterial activity.
Keywords Amino acids ꢀ Biological activity ꢀ
Cyclization ꢀ Heterocycles ꢀ 1,3,4-Oxa(thia)diazoles ꢀ
1,2,4-Triazoles
Introduction
N-Substituted amino acids as well as their hydrazides,
amides, and hydrazones have continuously attracted
attention of researchers owing to their properties that are
useful in technological applications as well as biological
Results and discussion
_
ˇ
_
ˇ
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
N-(4-Methylphenyl)-b-alanine hydrazide (1) was obtained
from N-phenyl-b-alanine by heating at reflux with hydra-
zine in toluene as described elsewhere [15]. Reaction of 1
in a solution of ethyl xanthogenate in ethanol, with-
out isolation of the intermediate potassium salt of
_
K. Kantminiene
Department of General Chemistry, Kaunas University of
_
Technology, Radvilenu˛ pl. 19, 50254 Kaunas, Lithuania
123

_
I. Tumosiene et al.
1442
Scheme 1
CS2, KOH, EtOH
H
CDI
H
H
N
N
N
H
N
N
O
N
2
O
NH2
O
1
NH
4
NH
O
O
S
NH2NH2
O
H
H
N
N
H
N
N
O
N
N
H2N
NH
S
5
3
propanedithionate, and subsequent acidification of the
reaction mixture with hydrochloric acid provided 5-[2-[(4-
methylphenyl)amino]ethyl]-1,3,4-oxadiazol-2(3H)-thione (2)
(Scheme 1). Heating of oxadiazole-2-thione 2 at reflux with
hydrazine and subsequent acidification of the reaction mixture
with acetic acid resulted in formation of 4-amino-2,4-dihydro-
5-[2-[(4-methylphenyl)amino]ethyl]-3H-1,2,4-triazole-3-thi-
one (3). In our previous work [16], 3 was obtained by melting
N-(2-carboxyethyl)-N-(4-methylphenyl)-b-alanine with thio-
carbohydrazide.
The rates of reaction of propanehydrazide 1 with phenyl
isocyanates may be different. Its reaction with p-tolyl iso-
thiocyanate was very facile, e.g., after 15 min the crystals of
1
9 started precipitating from the reaction mixture. In the H
NMR spectra of semicarbazides 6–9, additional aromatic
proton resonances are present in comparison with the spec-
trum of 1, and two triplets attributed to two methylene CH2
group protons are shifted downfield by 0.13–0.41 and
0.05–0.67 ppm. The introduction of the second phenylcar-
bamoyl group into molecules of semicarbazides 6–9
markedly increased the solubility of the compounds
obtained. Semicarbazides 6–9 are soluble in DMSO and
DMF only, whereas their phenylcarbamoyl derivatives
10–12 are soluble in such organic solvents as aromatic
hydrocarbons, alcohols, dioxane, and tetrahydrofuran.
The direction of semicarbazide cyclization depends on
the reaction conditions. At room temperature on treatment
with phosphorus oxychloride or concentrated sulfuric acid,
semicarbazides undergo dehydration and cyclize to oxadi-
azole or thiadiazole derivatives [2], whereas triazolones
or triazolethiones are obtained under the action of alkali
[2, 6].
Oxadiazol-2-one 4 was synthesized by the reaction of 1
1
with 1,10-carbonyldiimidazole (CDI) in dioxane. In the H
NMR spectrum of 4, a singlet attributed to the NH proton
in the 1,3,4-oxadiazole moiety is observed at 10.30 ppm,
whereas the proton of the same group in its thio analogue 2
resonated at 13.99 ppm owing to the stronger deshielding
effect of the thioxo group.
Reaction of 1 with 2,5-hexanedione in propan-2-ol in the
presence of a catalytic amount of acetic acid provided N-(2,5-
dimethyl-1H-pyrrol-1-yl)-3-[(4-methylphenyl)amino]pro-
panamide (5). Carbon resonances ascribed to the CH3 groups
in the pyrrole moiety are observed at 10.86 ppm in the 13
C
NMR spectrum of 5, whereas resonances at 102.77 ppm and
126.65 ppm confirm the existence of a pyrrole ring in this
compound.
Reaction of 6–9 in aqueous solutions of KOH or
NH2NH2 at reflux temperature and subsequent acidification
of the reaction mixtures provided 2,4-dihydro-5-[2-[(4-
methylphenyl)amino]ethyl]-4-phenyl-3H-1,2,4-triazol-3-one
(13), dihydrotriazolone 14, 2,4-dihydro-5-[2-[(4-methyl-
phenyl)amino]ethyl]-4-phenyl-3H-1,2,4-triazole-3-thione
(15), and dihydrotriazolethione 16, accordingly (Scheme 3).
Carbamoyl groups attached to the secondary nitrogen atom
in dicarbamoyl derivatives 10–12 underwent hydrolysis on
treatment with alkali or hydrazine and, thus, triazole
derivatives 13–16 were obtained.
Acid semicarbazides and thiosemicarbazides are easily
synthesized from the respective hydrazides and organic
isocyanates. On cyclization, they produce oxadiazoles and
triazolones and their thio analogues [2, 13]. Depending on
the ratio of the reacting substances, reaction of 1 with
phenyl isocyanates resulted in formation of propanehyd-
razide phenylcarbamoyl derivatives
6
and
9
and
di(phenylcarbamoyl) derivative 10 (Scheme 2). In a similar
way, phenylthiocarbamoyl propanamides 7 and 8 and
di(phenylthiocarbamoyl) propanamides 11 and 12 were
synthesized when phenyl isothiocyanates were used.
In the 1H NMR spectra of 13–16, a deshielding effect of
the triazole ring on the adjacent methylene group is
observed. Its triplets are shifted downfield to the region of
123

The synthesis of azole derivatives and their antibacterial activity
1443
R
23
R'
22
20
21
R'
24
X
N
25
2
6
3
2
N
19
H
2 ArNCX
4
H
ArNCX
4
N
17
1
1
1
17
7
8
7
5
8
5
H
6
H
9
9
R'
13
X
N
R'
X
N
12
16
12
16
N
O
N
O
10
14
H
H
14
R
N
H
N
H
R
11
11
18
18
15
15
R'
R'
6 - 9
10 - 12
ArNCX
6
7
8
9
X = O, R = R' = H
X = O, R = H, R = CH3,
10 X = O,
R = R' = H
R = R' = H
11
X = S,
X = S,
R = R' = H
R' = H
12
X = S, R = CH3,
R' = H
X = S,
R = CH3,
Ar = C6H5; 4-CH3C6H4; 3,5-(CH3)2C6H3
Scheme 2
Scheme 3
H
N
X
N
13
14
15
16
N
X = O, R = R' = H
R'= CH3
a) KOH
b) NH2NH2
X = O, R = H,
X = S, R = R' = H
R= CH ,
R'
6 - 9
N
H
X = S,
R' = H
R
3
R'
13 -16
R'
R
KOH
R'
X
POCl
3 or
N
H
H2SO4
10 - 12
N
R'
R
X
N
X = O, R = R' = H
X = S, R = R' = H
17
18
19
R'
N
N
H
R = CH ,
X = S,
R' = H
17 - 19
3
2.57–2.64 ppm when compared with the chemical shifts of
methylene group protons in the spectra of 6–9.
oxadiazole moiety and are observed at 8.68 and
9.75 ppm. Singlets of the NHNH group protons, which
are present in the spectrum of phenylcarbamoyl semi-
carbazide 10 at 7.89 and 8.03 ppm, are absent. In a
At room temperature when dissolved in concentrated
sulfuric acid, semicarbazides 6, 7 and thiosemicarbazides 8,
1
9
underwent cyclization to 5-[2-[(4-methylphenyl)-
similar manner, in the H NMR spectrum of 18, proton
amino]ethyl]-N-phenyl-1,3,4-oxadiazol-2-amine (20), its
dimethyl homologue 21, and their thio analogues 5-[2-[(4-
methylphenyl)amino]ethyl]-N-phenyl-1,3,4-thiadiazol-2-
amine (22) and dihydrothiadiazol-2-amine 23 (Scheme 4).
resonances of NHAr and NHAr0 are shifted downfield in
comparison with the spectrum of 11 owing to the influ-
ence of the thiadiazole moiety and are observed at 8.71
and 10.29 ppm. Singlets of the NHNH group protons,
characteristic of phenylcarbamoyl semicarbazide 11 and
observed at 9.56 and 9.59 ppm, are absent in the spectrum
of 18. The proton in the NH group adjacent to Ar0
1
In the H NMR spectrum of 17, proton resonances of
NHAr and NHAr0 are shifted downfield in comparison
with the spectrum of 10 owing to the influence of the
123

_
I. Tumosiene et al.
1444
Scheme 4
H
N
H
N
N
R'
N
H
X
R'
X
N
R
O
N
H
H2SO4
R'
N
N
H
R
H
20 - 23
R'
R'
6 - 9
H
N
H
XH
N
N
O
X = O, R = R' = H,
6, 20
N
H
R
1.
2.
CH3COONa
R' = CH ,
X = O, R = H,
7, 21
8, 22
9, 23
24
3
C H COCH Br
6
4
2
X = S, R = R' = H,
R'
R'
R
R = CH ,
X = S,
R' = H
3
X = S, R = R' = H.
H
N
R
H
:
N
O
N
H
N
O
R
R'
X
H
N
R'
H
R
R'
N
N
X
H
R'
N
+
O
N
H
24
N
N
..
OH
N
O
X
H3O
+
H
R
R
R'
R'
H
N
R'
H
N
R'
H
H
N
N
X
N
N
OH2
N
+
O
N
O
+
..
OH2
X
:
H
1
resonates in the region of 9.79–10.35 ppm in the H NMR
spectra of 20–23.
As seen from the data presented in Table 1, R. radio-
bacter is sensitive to compounds 5, 18, 22, and 23;
furthermore, 1,3,4-thiadiazol-2-amines 22 and 23 are active
in a broader range of concentrations, whereas 2, 3, and 21
did not exhibit antibacterial activity against the tested
microorganism strain.
N-(3,4-Diphenyl-2(3H)-thiazolylidene)-3-[(4-methylphe-
nyl)amino]propanehydrazide (24) was synthesized by
heating 8 at reflux with phenacyl bromide. The formation
of 24 was supported by the presence of one resonance of an
NH group at 10.90 ppm, absence of two NH group spectral
signals, a new singlet at 7.99 ppm ascribed to the SCH
group, and new proton resonances attributed to the aro-
Experimental
1
matic moiety in the H NMR spectrum.
Some of the synthesized compounds were evaluated
for their antibacterial activity against a strain of Rhizo-
bium radiobacter (Agrobacterium tumefaciens) by the
diffusion technique [16, 17]. R. radiobacter is a soil-
borne, Gram-negative bacterium, which is a causative
agent of ‘‘crown gall’’ disease, an economically important
disease of many plants [18]. Activities of the tested
compounds were compared with the known antibacterial
agent ampicillin.
1H and 13C NMR spectra were recorded on a Varian Unity
Inova 300 spectrometer (300 and 75 MHz, respectively)
using TMS as an internal standard and DMSO-d6 as a
solvent. IR spectra were taken on a Perkin-Elmer Spectrum
Bx FT-IR spectrometer. Mass spectra were recorded on a
Waters Micromass ZQ 2000 instrument. Elemental analy-
ses (C, H, N) were performed on an Elemental Analyzer
CE-440, and their results were found to be in good
agreement ( 0.2 %) with the calculated values. Melting
123

The synthesis of azole derivatives and their antibacterial activity
1445
1,618 (C=N), 1,318 (C=S) cm-1; MS (ESI, 20 eV): m/z
(%) = 236 ([M?1]?, 100).
Table 1 Antibacterial activity of 2, 3, 5, 18, and 21–23 against
Rhizobium radiobacter determined by the diffusion method
Compound
Concentration/lg cm-3
4-Amino-2,4-dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-
3H-1,2,4-triazole-3-thione (3, C11H15N5S)
50
150
250
450
550
A mixture of 2.35 g 2 (10 mmol), 0.32 g NH2NH2
(10 mmol), and 30 cm3 dioxane was heated at reflux for
8 h, and then acidified with acetic acid to pH 3. The
precipitate was isolated by filtration and washed with H2O
until pH 7. Recrystallization from propan-2-ol afforded
1.39 g (56 %) 3. m.p.: 105–106 °C (Ref. [19], oily
a
2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
?
?
-
-
-
-
-
?
?
-
-
3
b
5
?
18
21
22
23
a
?
-
?
?
1
residue); H NMR, IR, and MS spectra were found to be
identical with the literature ones [19].
The compound did not exhibit antibacterial activity
b
5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol-
2(3H)-one (4, C11H13N3O2)
The compound exhibited antibacterial activity
A mixture of 1.93 g 1 (10 mmol) and 1.94 g 1,10-carbon-
yldiimidazole (12 mmol) in 40 cm3 dry dioxane was
heated at reflux for 12 h. H2O (30 cm3) was added and
the crystalline precipitate was isolated by filtration. Puri-
fication by column chromatography (acetone/hexane 1:1,
Rf = 0.8) afforded 1.34 g (61 %) 4. m.p.: 144–145 °C; 1H
NMR (300 MHz, DMSO-d6): d = 2.14 (s, 3H, CH3), 2.93–
2.99 (m, 2H, CH2CN), 3.18–3.27 (m, 2H, CH2NH), 5.25 (t,
J = 6.10 Hz, 1H, NHCH2), 6.49 (d, J = 8.10 Hz, 2H,
points were determined on an Auto probe analyzer APA 1.
Monitoring of the reaction course and purity of the com-
pounds prepared was carried out using TLC on silica gel
plates (Merck, F254). Silica gel (Acros Organics, New
Jersey, USA, 0.035–0.070 mm) was used for column
chromatography.
3-[(4-Methylphenyl)amino]propanehydrazide
(1, C10H15N3O)
A
mixture of 35.84 g N-(4-methylphenyl)-b-alanine
H
(2,6)Ar), 6.90 (d, J = 8.10 Hz, 2H, H(3,5)Ar), 10.29 (s, 1H,
(0.2 mol) and 10 g hydrazine (0.2 mol) in 100 cm3 toluene
was heated at reflux with complete azeotropic separation of
the formed water. The liquid fractions were concentrated in
vacuo. Recrystallization of the residue from propan-2-ol
afforded 26.63 g (69 %) 1. m.p.: 135–136 °C (Ref. [15]
m.p. 135–136 °C).
NNH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 19.99
(CH3), 32.97 (C-8), 43.53 (C-7), 112.33 (C-2, 6), 124.36
(C-4), 129.32 (C-3, 5), 146.07 (C-1), 150.98 (C-9), 169.63
ꢀ
(C-10) ppm; IR (KBr): m = 3,361, 2,975 (NH), 1,691
(C=O), 1,522 (C=N) cm-1; MS (ESI, 25 eV): m/z
(%) = 220 ([M?1]?, 50).
5-[2-[(4-Methylphenyl)amino]ethyl]-1,3,4-oxadiazol-
2(3H)-thione (2, C11H13N3OS)
N-(2,5-Dimethyl-1H-pyrrol-1-yl)-3-[(4-methyl-
To 1.68 g KOH (30 mmol) dissolved in 50 cm3 ethanol,
3 cm3 CS2 (3.8 g, 50 mmol) was added dropwise and the
mixture was stirred at room temperature for 15 min.
Afterwards 5.79 g 1 (30 mmol) dissolved in 50 cm3
ethanol was added and the reaction mixture was heated at
reflux for 24 h. The liquid fractions were concentrated in
vacuo and the residue was dissolved in 150 cm3 H2O and
acidified with HCl to pH 3–4. The precipitate was isolated
by filtration and washed with methanol. Recrystallization
from methanol afforded 5.01 g (71 %) 2. m.p.: 66–67 °C;
1H NMR (300 MHz, DMSO-d6): d = 2.14 (s, 3H, CH3),
2.93 (t, J = 6.60 Hz, 2H, CH2CN), 3.37 (t, J = 6.60 Hz,
2H, CH2N), 5.48 (br s, 1H, NHCH2), 6.49 (d, J = 8.40 Hz,
2H, H(2,6)Ar), 6.90 (d, J = 8.40 Hz, 2H, H(3,5)Ar), 13.99 (s,
1H, NNH) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 19.99 (CH3), 25.25 (C-8), 40.21 (C-7), 112.35 (C-2,
6), 124.58 (C-4), 129.36 (C-3, 5), 145.61 (C-1), 162.64 (C-
phenyl)amino]propanamide (5, C16H21N3O)
A mixture of 0.97 g 1 (5 mmol), 40 cm3 propan-2-ol,
0.46 g 2,5-hexanedione (10 mmol), and 1 cm3 acetic acid
was heated at reflux for 12 h. Afterwards 20 cm3 cold H2O
was added. Recrystallization of the precipitate from
1
ethanol afforded 0.85 g (63 %) 5. m.p.: 131–132 °C; H
NMR (300 MHz, DMSO-d6): d = 1.97 (s, 6H, 2 CH3),
2.14 (s, 3H, CH3), 2.54 (t, J = 6.90 Hz, 2H, COCH2), 3.32
(q, J = 6.6 Hz, J = 12.90 Hz, 2H, NHCH2), 5.38 (t,
J = 8.40 Hz, 1H, NH), 5.62 (s, 2H, 2 CH), 6.53 (d,
J = 8.40 Hz, 2H, H(2,6)Ar), 6.91 (d, J = 8.40 Hz, 2H,
H
(3,5)Ar), 10.59 (s, 1H, NH) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 10.86 (2 CH3), 19.99 (CH3), 33.18 (C-8),
39.70 (C-7), 102.77 (C-11, 12), 112.23 (C-2, 6), 124.18 (C-
4), 126.65 (C-10, 13), 129.31 (C-3, 5), 146.06 (C-1),
ꢀ
170.30 (C=O) ppm; IR (KBr): m = 3,360, 3,277 (NH),
1,663 (C=O), 1,524 (CN) cm-1; MS (ESI, 25 eV): m/z
(%) = 272 ([M?1]?, 70).
ꢀ
9), 177.68 (C-10) ppm; IR (KBr): m = 3,364, 3,276 (NH),
123

_
I. Tumosiene et al.
1446
3-[(4-Methylphenyl)amino]-N-[(phenylcarba-
(75 MHz, DMSO-d6): d = 20.65 (CH3), 30.85 (C-8), 50.45
(C-7), 112.22 (C-2, 6), 124.65 (C-4), 125.78 (C-14), 127.57
(C-12, 16), 127.79 (C-13, 15), 129.41 (C-3, 5), 139.70 (C-
11), 140.47 (C-1), 170.10 (C-9), 181.56 (C-10) ppm; IR
moyl)amino]propanamide (6, C17H20N4O2)
To 1.93 g 1 (10 mmol) dissolved in 20 cm3 methanol,
1.09 cm3 phenyl isocyanate (1.19 g, 10 mmol) was added
dropwise and heated at reflux for 1 h. The crystalline
precipitate was isolated by filtration and washed with
methanol. Recrystallization from DMF/H2O afforded
ꢀ
(KBr): m = 2,966–3,363 (NH), 1,702 (CO), 1,504 (O=C–
N), 1,330 (C=S) cm-1; MS (ESI, 20 eV): m/z (%) = 351
([M?Na]?, 60).
1
2.54 g (81 %) 6. m.p.: 132–133 °C; H NMR (300 MHz,
DMSO-d6): d = 2.14 (s, 3H, CH3), 2.27 (t, J = 7.20 Hz,
2H, CH2CO), 3.18 (q, J = 6.90 Hz, J = 13.20 Hz, 2H,
CH2NH), 4.18 (s, 2H, NHAr0), 5.28 (t, J = 5.55 Hz, 1H,
NHCH2), 6.47 (d, J = 8.40 Hz, 2H, H(2,6)Ar), 6.88 (d,
J = 8.40 Hz, 2H, H(3,5)Ar), 6.95 (t, J = 8.10 Hz, 1H,
3-[(4-Methylphenyl)amino]-N-[[(4-methylphenyl)car-
bamothioyl]amino]propanamide (9, C18H22N4OS)
Prepared from 1.93 g 1 (10 mmol) and 2.99 cm3 p-tolyl
isothiocyanate (1.49 g, 25 mmol) by following the same
procedure as for the synthesis of 6 except that the duration
of heating at reflux was 20 min. Yield 2.02 g (59 %); m.p.:
184–185 °C (from DMF/H2O); 1H NMR (300 MHz,
DMSO-d6): d = 2.15 (s, 3H, CH3), 2.29 (s, 3H, CH3),
2.46 (t, J = 6.90 Hz, 2H, CH2CO), 3.26 (t, J = 6.90 Hz,
2H, CH2NH), 5.34 (s, 1H, NH), 6.50 (d, J = 8.40 Hz, 2H,
H
(4)Ar0), 7.25 (t, J = 8.10 Hz, 2H, H(3,5)Ar0), 7.49 (d,
J = 8.10 Hz, 2H, H
Ar0), 8.78, 9.02 (2 s, 2H,
(2,6)
NHNHCO) ppm; 13C NMR (75 MHz, DMSO-d6):
d = 19.99 (C-17), 33.38 (C-8), 39.71 (C-7), 112.16 (C-2,
6), 118.37 (C-12, 16), 121.74 (C-14), 124.03 (C-4), 128.53
(C-13, 15), 129.27 (C-3, 5), 139.61 (C-11), 146.23 (C-1),
H
(2,6)Ar), 6.90 (d, J = 8.40 Hz, 2H, H(3,5)Ar), 7.09–7.17
ꢀ
155.95 (C-10), 170.13 (C-9) ppm; IR (KBr): m = 2,829–
(m, 2H, H(3,5) Ar0), 7.25–7.33 (m, 2H, H(2,6) Ar0), 9.51 (s,
2H, 2 NH), 9.96 (s, 1H, NHAr0) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 20.05 (CH3-Ar0), 20.52 (CH3-Ar), 33.29
(C-8), 39.28 (C-7), 112.29 (C-2, 6), 124.25 (C-4), 125.80
(C-11), 128.50 (C-12, 16), 129.34 (C-3, 5), 134.22 (C-13,
15), 136.42 (C-14), 146.27 (C-1), 170.74 (C-9), 180.95 (C-
3,311 (NH), 1,669, 1,643 (CO), 1,525 (O=C–N) cm-1; MS
(APCI?, 25 eV): m/z (%) = 335 ([M?Na]?, 100).
N-[[(3,5-Dimethylphenyl)carbamoyl]amino]-3-[(4-methyl-
phenyl)amino]propanamide (7, C19H24N4O2)
Prepared from 1.93 g 1 (10 mmol) and 1.045 cm3 3,5-
dimethylphenyl isocyanate (1.41 g, 10 mmol) by following
the same procedure as for the synthesis of 6 except that the
duration of heating at reflux was 3 h. Yield 1.33 g (39 %);
ꢀ
10) ppm; IR (KBr): m = 3,360, 3,270, 3,138, 2,969 (NH),
1,684 (CO), 1,512 (O=C–N), 1,378 (C=S) cm-1; MS (ESI,
25 eV): m/z (%) = 365 ([M?Na]?, 100).
1
m.p.: 145–146 °C (from DMF/H2O); H NMR (300 MHz,
3-[(4-Methylphenyl)(phenylcarbamoyl)amino]-N-
[(phenylcarbamoyl)amino]propanamide (10, C24H25N5O3)
Method A. Prepared from 1.93 g 1 (10 mmol) and 2.7 cm3
phenyl isocyanate (2.97 g, 25 mmol) by following the
same procedure as for the synthesis of 6 except that the
duration of heating at reflux was 4 h. Yield 3.23 g (75 %)
(from propan-2-ol).
DMSO-d6): d = 2.13 (s, 3H, CH3), 2.18 (s, 6H, 2 CH3),
2.40 (t, J = 7.05 Hz, 2H, CH2CO), 3.84 (t, J = 7.05 Hz,
2H, CH2NH), 6.57 (d, J = 9.30 Hz, 2H, H(2,6)Ar), 6.91–
7.10 (m, 5H, H(3,5)Ar ? HAr0), 7.63 (s, 1H, NH), 7.95 (s,
1H, NH), 8.55 (s, 1H, NH), 9.72 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 20.04 (CH3Ar), 21.05 (2
CH3), 32.24 (C-8), 46.08 (C-7), 112.36 (C-2, 6), 124.33
(C-4), 127.95 (C-12, 16), 129.34 (C-3, 5), 137.25 (C-14),
137.57 (C-11), 139.40 (C-13, 15), 146.31 (C-1), 155.38
Method B. A mixture of 0.78 g 6 (2.5 mmol), 10 cm3
DMF, and 0.27 cm3 phenyl isocyanate (0.30 g, 2.6 mmol)
was heated at reflux for 6 h. Afterwards 30 cm3 H2O was
added. The resin-like product formed was washed with
3 9 10 cm3 H2O. Twice repeated recrystallization from
propan-2-ol afforded 0.79 g (73 %) 10. m.p.: 145–146 °C;
1H NMR (300 MHz, DMSO-d6): d = 2.34 (s, 3H, CH3),
2.44 (t, J = 7.20 Hz, 2H, CH2CO), 3.88 (t, J = 7.20 Hz,
2H, CH2N), 6.89–7.01 (m, 4H, HAr), 7.16–7.29 (m, 5H,
HAr0), 7.37–7.51 (m, 5H, HAr00), 7.89 (s, 1H, NH), 8.03 (s,
1H, NH), 8.72 (s, 1H, NH), 9.78 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 20.63 (CH3), 32.19 (C-
8), 46.04 (C-7), 112.25, 118.54, 119.72, 121.84, 121.92,
127.81, 128.17, 128.54, 128.69, 139.05, 139.52, 139.88
(CAr), 154.47 (CO), 155.28 (CO), 170.51 (CS) ppm; IR
ꢀ
(C-9), 170.72 (C-10) ppm; IR (KBr): m = 2,861–3,275
(NH), 1,668, 1,616 (CO), 1,527 (O=C–N) cm-1; MS
(APCI?, 25 eV): m/z (%) = 341 ([M?1]?, 100).
3-[(4-Methylphenyl)amino]-N-[(phenylcarbamothioyl)-
amino]propanamide (8, C17H20N4OS)
Prepared from 1.93 g 1 (10 mmol) and 1.90 cm3 phenyl
isothiocyanate (1.35 g, 10 mmol) by following the same
procedure as for the synthesis of 6 except that the duration
of heating at reflux was 1.5 h. Yield 2.20 g (67 %); m.p.:
162–163 °C (from DMF/H2O); 1H NMR (300 MHz,
DMSO-d6): d = 2.33 (s, 3H, CH3), 2.63 (t, J = 7.80 Hz,
2H, CH2CO), 4.35 (t, J = 7.80 Hz, 2H, CH2NH), 7.21–
7.32 (m, 9H, HAr ? HAr0), 8.73 (s, 1H, NH), 9.52 (s, 1H,
NH), 9.58 (s, 1H, NH), 9.96 (s, 1H, NH) ppm; 13C NMR
ꢀ
(KBr): m = 2,924–3,422 (NH), 1,705, 1,656 (CO), 1,529
123

The synthesis of azole derivatives and their antibacterial activity
1447
(OCN) cm-1; MS (ESI, 25 eV): m/z (%) = 431 ([M?1]?,
100).
2,4-Dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-4-phe-
nyl-3H-1,2,4-triazol-3-one (13, C17H18N4O)
A mixture of 0.78 g 6 (2.5 mmol) and 25 cm3 20 %
aqueous KOH solution was heated at reflux for 4 h and
then cooled to room temperature. Afterwards conc. HCl
was added to pH 4. The crystalline precipitate was isolated
by filtration and washed with H2O. Recrystallization from
DMF/H2O afforded 0.35 g (48 %) 13. m.p.: 153–154 °C;
1H NMR (300 MHz, DMSO-d6): d = 2.12 (s, 3H, CH3-
Ar), 2.61 (t, J = 7.20 Hz, 2H, CH2C), 3.09–3.19 (m, 2H,
NHCH2), 5.37 (s, 1H, NHAr), 6.27 (d, J = 8.25 Hz, 2H,
3-[(4-Methylphenyl)(phenylcarbamothioyl)amino]-N-
[(phenylcarbamothioyl)amino]propanamide
(11, C24H25N5OS2)
Method A. Prepared from 1.93 g 1 (10 mmol) and 4.52 cm3
phenyl isothiocyanate (3.38 g, 25 mmol) by following the
same procedure as for the synthesis of 6. Yield 3.24 g
(70 %).
Method B. Prepared from 1.93 g 1 (10 mmol) and
0.47 cm3 phenyl isothiocyanate (0.34 g, 2.6 mmol) by
following the same procedure as for the synthesis of 10
(method B). Yield 0.79 g (68 %); m.p.: 157–158 °C (from
H
(2,6)Ar), 6.82 (d, J = 8.25 Hz, 2H, H(3,5)Ar), 7.38–7.45
(m, 2H, HAr0), 7.48–7.55 (m, 3H, HAr0), 11.70 (s, 1H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 19.96 (CH3),
25.75 (C-8), 39.60 (C-7), 111.98 (C-2, 6), 124.14 (C-4),
127.54 (C-12, 16), 128.60 (C-14), 129.28 (C-13, 15),
129.38 (C-3, 5), 132.87 (C-11), 145.21 (C-1), 145.71 (C-9),
1
propan-2-ol); H NMR (300 MHz, DMSO-d6): d = 2.33
(s, 3H, CH3), 2.64 (t, J = 7.80 Hz, 2H, CH2CO), 4.35 (t,
J = 7.80 Hz, 2H, CH2N), 7.06–7.48 (m, 14H, HAr, HAr0,
HAr00), 8.73 (s, 1H, NH), 9.56 (s, 1H, NH), 9.59 (s, 1H,
NH), 9.96 (s, 1H, NH) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 20.63 (CH3), 30.85 (C-8), 50.42 (C-7), 112.81,
119.78, 124.63, 125.75, 127.55, 127.76, 127.96, 130.46,
137.00, 139.03, 139.69, 140.44 (CAr), 170.15 (CO), 180.79
ꢀ
154.33 (C-10) ppm; IR (KBr): m = 3,326, 2,890 (NH),
1,670 (CO), 1,528 (C=N), 1,499 (C–N) cm-1; MS
(APCI?, 25 eV): m/z (%) = 295 ([M?1]?, 20), 317
([M?Na]?, 70).
4-(3,5-Dimethylphenyl)-2,4-dihydro-5-[2-[(4-methyl-
phenyl)amino]ethyl]-3H-1,2,4-triazol-3-one
(14, C19H22N4O)
ꢀ
(CS), 181.55 (CS) ppm; IR (KBr): m = 2,960–3,360 (NH),
1,709 (CO), 1,369 (CS) cm-1; MS (ESI, 25 eV): m/z
(%) = 464 ([M?1]?, 40).
Prepared from 0.68 g 7 (2 mmol) by following the same
procedure as for the synthesis of 13 to afford 0.42 g (65 %)
3-[(4-Methylphenyl)[(4-methylphenyl)car-
bamothioyl]amino]-N-[[(4-methylphenyl)car-
bamothioyl]amino]propanamide (12, C26H29N5OS2)
Method A. A mixture of 1.93 g 1 (10 mmol) and 2.29 cm3
p-tolyl isothiocyanate (3.73 g, 25 mmol) was heated at
reflux for 1 h. The crystalline precipitate was isolated by
filtration. Recrystallization from propan-2-ol afforded
3.83 g (78 %) 12.
1
14. m.p.: 202–203 °C; H NMR (300 MHz, DMSO-d6):
d = 2.11 (s, 3H, CH3), 2.28 (s, 6H, 2 CH3), 2.57 (t,
J = 7.20 Hz, 2H, CH2C), 3.15 (t, J = 7.20 Hz, 2H,
NHCH2), 5.41 (s, 1H, NHAr), 6.26 (d, J = 8.40 Hz, 2H,
H
(2,6)Ar), 6.81 (d, J = 8.40 Hz, 2H, H(3,5)Ar), 6.96 (d,
J = 0.60 Hz, 2H, H(2,6)Ar0), 7.10 (d, J = 0.60 Hz, 1H,
(4)Ar0), 11.75 (br s, 1H, NH) ppm; 13C NMR (75 MHz,
H
DMSO-d6): d = 20.09 (CH3), 20.71 (2 CH3), 25.77 (C-8),
39.90 (C-7), 112.11 (C-2, 6), 124.33 (C-4), 125.17 (C-12,
16), 129.43 (C-3, 5), 130.14 (C-14), 132.76 (C-11), 138.93
(C-13, 15), 145.46 (C-1), 145.81 (C-9), 154.58 (C-10) ppm;
Method B. Prepared from 0.86 g 9 (2.5 mmol) and
0.24 cm3 p-tolyl isothiocyanate (0.39 g, 2.6 mmol) by
following the same procedure as for the synthesis of 10
(method B). Yield 0.81 g (66 %); m.p.: 172–173 °C (pro-
1
ꢀ
IR (KBr): m = 3,355, 2,917 (NH), 1,698 (CO), 1,527
pan-2-ol); H NMR (300 MHz, DMSO-d6): d = 2.16 (s,
(C=N), 1,455 (C–N) cm-1; MS (APCI?, 25 eV): m/z
(%) = 323 ([M?1]?, 90).
3H, CH3), 2.28 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.46 (t,
J = 6.90 Hz, 2H, CH2CO), 3.25 (t, J = 6.90 Hz, 2H,
CH2N), 6.49 (d, J = 8.40 Hz, 2H, H(2,6)Ar), 6.90 (d,
J = 8.40 Hz, 2H, H(3,5)Ar), 7.02–7.08 (m, 4H, HAr0),
7.19–7.25 (m, 4H, HAr00), 9.50 (s, 2H, NH), 9.95 (s, 2H,
NH) ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.03,
20.47, 20.63 (CH3), 33.31 (C-8), 50.42 (C-7), 112.25 (C-2,
6), 123.82 (C-4), 125.87 (C-14, 21), 128.25, 128.80 (C-13,
15, 20, 22), 129.31 (C-3, 5), 133.53, 130.48 (C-12, 16, 19,
23), 136.42 (C-11), 136.78 (C-18), 146.26 (C-1), 169.43
2,4-Dihydro-5-[2-[(4-methylphenyl)amino]ethyl]-4-
phenyl-3H-1,2,4-triazole-3-thione (15, C17H18N4S)
Method A. A mixture of 1.57 g 8 (5 mmol) and 50 cm3
20 % aqueous KOH solution was heated at reflux for 3 h
and then cooled to room temperature. Afterwards conc.
HCl was added to pH 4. The crystals formed were isolated
by filtration and washed with H2O. Recrystallization from
DMF/H2O afforded 0.64 g (83 %) 15.
ꢀ
(CO), 171.23 (CS), 179.52 (CS) ppm; IR (KBr): m = 3,360,
3,271, 3,138, 2,969 (NH), 1,684 (CO), 1,513 (O=C–N),
Method B. A mixture of 0.66 g 7 (2 mmol), 0.064 g
NH2NH2 (2 mmol), and 10 cm3 methanol was heated at
50–60 °C for 4 h. Afterwards 40 cm3 cold H2O was added
1,378, 1,356 (C=S) cm-1
(%) = 492 ([M?1]?, 90).
; MS (ESI, 25 eV): m/z
123

_
I. Tumosiene et al.
1448
afforded 0.43 g (87 %) 17. m.p.: 98–99 °C; 1H NMR
(300 MHz, DMSO-d6): d = 2.34 (s, 3H, CH3), 2.43 (t,
J = 7.20 Hz, 2H, CH2CO), 3.87 (t, J = 7.20 Hz, 2H,
CH2N), 8.68, 9.75 (2 s, 2H, ArNH, Ar0NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 20.58 (CH3), 32.18 (C-8), 39.71
(C-7), 110.22, 118.50, 119.68, 121.78, 121.88, 127.76,
128.12, 128.49, 130.08, 136.07, 139.47, 139.83 (CAr),
154.42 (C-9), 155.21 (C-10), 170.44 (CS) ppm; IR (KBr):
to the reaction mixture. The precipitate was isolated by
filtration and purified by column chromatography (acetone/
hexane 1:1, Rf = 0.87). Recrystallization from DMF/H2O
afforded 0.31 g (50 %) 15.
Method C. A mixture of 0.93 g 11 (2 mmol) and 20 cm3
10 % aqueous KOH solution was heated at reflux for 4 h.
The crystalline precipitate was isolated by filtration.
Recrystallization from DMF/H2O afforded 0.61 g (98 %)
m = 3,360, 2,929 (NH), 1,512 (CN) cm-1; MS (ESI,
1
ꢀ
15. m.p.: 173–174 °C; H NMR (300 MHz, DMSO-d6):
25 eV): m/z (%) = 414 ([M?1]?, 100).
d = 2.11 (s, 3H, CH3), 2.63 (t, J = 7.20 Hz, 2H, CH2C),
3.16 (q, J = 7.20 Hz, J = 13.80 Hz, 2H, NHCH2), 5.43 (t,
J = 6.60 Hz, 1H, NHAr), 6.24 (d, J = 8.25 Hz, 2H,
3-(4-Methylphenyl)-1-phenyl-3-[2-[5-(phenylamino)-1,3,4-
thiadiazol-2-yl]ethyl]thiourea (18, C24H23N5S2)
H
(2,6)Ar), 6.79 (d, J = 8.25 Hz, 2H, H(3,5)Ar), 7.34–7.49
Prepared from 0.56 g 11 (1.2 mmol) by following the same
procedure as for the synthesis of 17 except that POCl3 was
used instead of conc. H2SO4 to afford 0.45 g (84 %) 18.
m.p.: 93–94 °C (ethanol); 1H NMR (300 MHz, DMSO-d6):
d = 2.32 (s, 3H, CH3), 3.28 (t, J = 7.35 Hz, 2H, CH2CN),
4.47 (t, J = 7.35 Hz, 2H, CH2NH), 6.96–7.58 (m, 14H,
HAr, HAr0, HAr00), 8.71 (s, 1H, NHAr0), 10.29 (s, 1H,
NHAr00) ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.60
(CH3), 27.66 (C-8), 53.57 (C-7), 117.22, 121.70, 124.76,
125.97, 127.43, 127.74, 128.98, 130.44, 137.07, 139.55,
140.39, 140.60 (CAr), 156.28 (C-9), 164.35 (C-10), 181.75
(m, 5H, HAr0), 13.76 (s, 1H, NH) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 19.99 (CH3), 25.30 (C-8), 39.71
(C-7), 111.98 (C-2, 6), 124.22 (C-4), 127.24 (C-12, 16),
128.38 (C-14), 128.55 (C-13, 15), 129.42 (C-3, 5), 133.66
(C-11), 145.58 (C-1), 150.52 (C-9), 167.54 (C-10) ppm; IR
ꢀ
(KBr): m = 3,310, 2,920 (NH), 1,525 (C=N), 1,497 (C–N),
1,298 (C=S) cm-1; MS (ESI, 20 eV): m/z (%) = 331
([M?Na]?, 100).
2,4-Dihydro-4-(4-methylphenyl)-5-[2-[(4-methylphenyl)-
amino]ethyl]-3H-1,2,4-triazole-3-thione
(16, C18H20N4S)
ꢀ
(C=S) ppm; IR (KBr): m = 3,367, 2,924 (NH), 1,510 (CN)
cm-1; MS (ESI, 25 eV): m/z (%) = 446 ([M?1]?, 100).
Method A. Prepared from 0.51 g 9 (45 mmol) by following
the same procedure as for the synthesis of 15 (method A) to
afford 0.64 g (83 %) 16.
1,3-Bis(4-methylphenyl)-3-(2-[5-[(4-methylphenyl)amino]-
1,3,4-thiadiazol-2-yl]ethyl)thiourea (19, C26H27N5S2)
Prepared from 0.49 g 12 (1 mmol) by following the same
procedure as for the synthesis of 17 to afford 0.21 g (44 %)
19. m.p.: 97–98 °C (propan-2-ol); 1H NMR (300 MHz,
DMSO-d6): d = 2.16 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.32
(s, 3H, CH3), 3.13 (t, J = 6.60 Hz, 2H, CH2CN), 3.36 (t,
J = 6.60 Hz, 2H, CH2N), 6.57 (d, J = 8.40 Hz, 2H,
Method B. Prepared from 0.34 g 9 (1 mmol) and
0.064 g NH2NH2 (2 mmol) by following the same proce-
dure as for the synthesis of 15 (method B) to afford 0.15 g
(50 %) 16. m.p.: 192–193 °C; 1H NMR (300 MHz,
DMSO-d6): d = 2.12 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.62
(t, J = 7.20 Hz, 2H, CH2C), 3.16 (q, J = 7.05 Hz,
J = 14.10 Hz, 2H, CH2NH), 5.42 (t, J = 6.00 Hz, 1H,
NHAr), 6.25 (d, J = 8.10 Hz, 2H, H(2,6)Ar), 6.81 (d,
J = 8.10 Hz, 2H, H(3,5)Ar), 7.26–7.38 (m, 4H, HAr0),
13.72 (s, 1H, NHAr0) ppm; 13C NMR (75 MHz, DMSO-
d6): d = 19.99 (CH3-Ar), 20.73 (CH3-Ar0), 25.26 (C-8),
39.71 (C-7), 112.00 (C-2, 6), 124.19 (C-4), 128.09 (C-14),
129.27 (C-12, 16), 129.87 (C-13, 15), 131.05 (C-3, 5),
139.11 (C-11), 145.58 (C-1), 150.61 (C-9), 167.59 (C-10)
H
(2,6)Ar), 6.93 (d, J = 8.40 Hz, 2H, H(3,5)Ar), 7.08–7.17
(m, 4H, HAr0), 7.42–7.54 (m, 4H, HAr00), 10.19 (s, 2H, NH)
ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.03, 20.26,
20.46 (CH3), 29.21 (C-8), 42.72 (C-7), 112.84, 117.20,
124.99, 126.07, 127.50, 128.24, 129.31, 129.39, 130.34,
130.48, 138.39, 145.33 (CAr), 157.02 (C-9), 164.42 (C-10),
ꢀ
181.75 (CS) ppm; IR (KBr): m = 3,358, 2,910 (NH), 1,515
(CN) cm-1; MS (ESI, 25 eV): m/z (%) = 474 ([M?1]?,
70).
ꢀ
ppm; IR (KBr): m = 3,392, 2,935 (NH), 1,524 (C = N),
1,494 (C–N), 1,338 (C=S) cm-1; MS (APCI?, 25 eV): m/z
(%) = 348 ([M?Na?1]?, 50).
5-[2-[(4-Methylphenyl)amino]ethyl]-N-phenyl-1,3,4-oxa-
diazol-2-amine (20, C17H18N4O)
A mixture of 0.62 g 6 (2 mmol) and 5 cm3 conc. H2SO4
was stirred at room temperature until fully dissolved
(approx. 20 min). The reaction mixture was added drop-
wise to an ice/water mixture. The crystalline precipitate
was isolated by filtration and washed with H2O. Recrys-
tallization from methanol afforded 0.57 g (98 %) 20. m.p.:
114–115 °C; 1H NMR (300 MHz, DMSO-d6): d = 2.23 (s,
3-(4-Methylphenyl)-1-phenyl-3-[2-[5-(phenylamino)-1,3,4-
oxadiazol-2-yl]ethyl]urea (17, C24H23N5O2)
To 5 cm3 conc. H2SO4 was added 0.52 g 10 (1.2 mmol) in
portions and the reaction mixture was stirred at room
temperature for 30 min. Afterwards, it was added drop-
wise into ice-water mixture. The crystalline precipitate
was isolated by filtration. Recrystallization from ethanol
123

The synthesis of azole derivatives and their antibacterial activity
1449
3H, CH3), 2.29 (t, J = 7.20 Hz, 2H, CH2CO), 3.47 (t,
J = 7.20 Hz, 2H, CH2NH), 6.89–6.99 (m, 2H, HAr), 7.15–
7.21 (m, 2H, HAr), 7.36–7.48 (m, 5H, HAr0), 8.76 (s, 1H,
NHAr), 9.78 (s, 1H, NHAr0) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 20.70 (CH3), 32.32 (C-8), 46.12 (C-7),
112.63 (C-2, 6), 119.85 (C-12, 16), 124.27 (C-4), 128.29
(C-14), 128.69 (C-13, 15), 130.24 (C-3, 5), 136.29 (C-11),
139.90 (C-1), 155.39 (C-9), 169.61 (C-10) ppm; IR (KBr):
7.18 (m, 4H, HAr), 7.44–7.56 (m, 4H, HAr0), 10.35 (s, 1H,
NHAr0) ppm; 13C NMR (75 MHz, DMSO-d6): d = 20.34
(CH3Ar0), 20.51 (CH3Ar), 27.30 (C-8), 46.51 (C-7), 112.29
(C-2, 6), 117.38 (C-12, 16), 121.96 (C-11), 123.09 (C-4),
129.38 (C-3, 5), 129.94 (C-13, 15), 138.37 (C-14), 155.56
(C-1), 157.42 (C-9), 164.67 (C-10) ppm; IR (KBr):
ꢀm = 3,232, 2,919 (NH), 1,514 (CN) cm-1; MS (ESI,
25 eV): m/z (%) = 325 ([M?1]?, 40).
m = 3,310, 2,919 (NH), 1,520 (CN) cm-1; MS (APCI?,
ꢀ
N-(3,4-Diphenyl-2(3H)-thiazolylidene)-3-[(4-methyl-
phenyl)amino]propanehydrazide (24, C25H24N4OS)
To 3.28 g 8 (10 mmol) dissolved in 40 cm3 ethanol, 1.98 g
phenacyl bromide (10 mmol) and 16.4 g sodium acetate
(200 mmol) were added and the reaction mixture was
heated at reflux for 10 h. Afterwards it was cooled to room
temperature, poured into ice-cold water while stirring and
left overnight in the cold. The precipitate formed was
isolated by filtration and washed with H2O three times.
Recrystallization from H2O afforded 1.19 g (55 %) 24.
m.p.: 126–127 °C; 1H NMR (300 MHz, DMSO-d6):
d = 2.13 (s, 3H, CH3), 2.32–2.45 (m, 2H, CH2CO), 3.14
(t, J = 7.05 Hz, 2H, CH2NH), 5.23 (s, 1H, NHAr), 6.36–
6.53 (m, 4H, HAr), 6.84–7.08 (m, 5H, HAr0), 7.31–7.48 (m,
5H, HAr00), 7.99 (s, 1H, SCH), 10.90 (s, 1H, NH) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 19.97, 33.31, 47.69,
112.34, 120.87, 123.07, 124.39, 127.57, 128.33, 128.70,
128.88, 129.26, 129.43, 129.69, 139.09, 145.82, 150.22,
156.77, 170.55 ppm; IR (KBr): ꢀm = 3,354, 2,916 (NH),
1,707 (CO), 1,580 (O=C–N) cm-1; MS (ESI, 25 eV):
m/z (%) = 468 ([M?K]?, 40).
25 eV): m/z (%) = 295 ([M?1]?, 90).
N-(3,5-Dimethylphenyl)-5-[2-[(4-methyl-
phenyl)amino]ethyl]-1,3,4-oxadiazol-2-amine
(21, C19H22N4O)
Prepared from 0.68 g 7 (2 mmol) by following the same
procedure as for the synthesis of 20 to afford 0.67 g (69 %)
21. m.p.: 191–192 °C (methanol); 1H NMR (300 MHz,
DMSO-d6): d = 2.19 (s, 3H, CH3), 2.29 (s, 6H, 2 CH3),
2.59 (t, J = 7.20 Hz, 2H, CH2CO), 3.51 (t, J = 7.20 Hz,
2H, CH2NH), 7.05–7.39 (m, 7H, HAr ? HAr0), 8.79 (s,
1H, NHAr), 9.87 (s, 1H, NHAr0) ppm; 13C NMR (75 MHz,
DMSO-d6): d = 20.65 (CH3), 23.16 (2 CH3), 29.37 (C-8),
46.54 (C-7), 111.70 (C-2, 6), 119.07 (C-12, 16), 122.25
(C-4), 130.54 (C-3, 5), 136.97 (C-14), 138.42 (C-11), 138.92
(C-13,15), 144.20 (C-1), 155.26 (C-9), 169.40 (C-10) ppm; IR
(KBr): m = 3,309, 2,920 (NH), 1,599 (CN) cm-1; MS
ꢀ
(APCI?, 25 eV): m/z (%) = 323 ([M?1]?, 70).
5-[2-[(4-Methylphenyl)amino]ethyl]-N-phenyl-1,3,4-thia-
diazol-2-amine (22, C17H18N4S)
Prepared from 0.66 g 8 (2 mmol) by following the same
procedure as for the synthesis of 20 to afford 0.58 g (94 %)
22. m.p.: 152–153 °C (methanol); 1H NMR (300 MHz,
DMSO-d6): d = 2.15 (s, 3H, CH3), 3.13 (t, J = 7.50 Hz,
2H, CH2CO), 3.35 (t, J = 7.50 Hz, 2H, CH2NH), 5.56 (s,
1H, NH), 6.53 (d, J = 8.40 Hz, 2H, HAr(2,6)), 6.91 (d,
J = 8.40 Hz, 2H, HAr(3,5)), 6.96 (t, J = 7.80 Hz, 1H,
HAr0(4)), 7.32 (t, J = 7.80 Hz, 2H, HAr0(3,5)), 7.59 (d,
J = 7.80 Hz, 2H, HAr0(2,6)), 10.21 (s, 1H, NHAr0) ppm;
13C NMR (75 MHz, DMSO-d6): d = 20.00 (CH3), 29.38
(C-8), 42.39 (C-7), 112.36 (C-2, 6), 117.07 (C-12, 16),
121.45 (C-14), 124.41 (C-4), 128.94 (C-13, 15), 129.35 (C-
3, 5), 140.76 (C-11), 145.90 (C-1), 157.53 (C-9), 164.25
Biology
Antibacterial activity was tested using the disk diffusion
technique. The microbial agent R. radiobacter was com-
mercially available from the German Collection of
Microorganisms and Cell Cultures (DSMZ). The zone of
inhibition of bacterial growth was investigated. The main
solution (1 mg/cm3) of synthesized compounds was pre-
pared in DMSO and was diluted at various concentrations
(50, 150, 250, 450, 550 lg/cm3) in DMSO. Cultures of
R. radiobacter were cultivated in petri dishes for 24 h at
37 °C on Luria–Bertani (LB) agar medium. A bacterial
suspension was prepared from cultivated bacterial cul-
tures and 100 mm3 inoculum containing bacterial cells
(108 CFU/cm3) was spread over LB agar medium. Filter
paper disks were prepared by adding 25 mm3 of each
compound solution and then disks were put on LB agar
medium. Ampicillin was used as the positive control, and
DMSO was used as a negative control. The petri dishes
were incubated for 24 h at 37 °C and zones of inhibition
were then ascertained for each sample.
ꢀ
(C-10) ppm; IR (KBr): m = 3,360, 2,923 (NH), 1,510 (CN)
cm-1; MS (APCI?, 25 eV): m/z (%) = 311 ([M?1]?, 70).
5-[2-(4-Methylphenylamino)ethyl]-N-phenyl-1,3,4-thia-
diazol-2-amine (23, C18H20N4S)
Prepared from 0.86 g 9 (2.5 mmol) by following the same
procedure as for the synthesis of 20 to afford 0.56 g (69 %)
23. m.p.: 105–106 °C (ethanol); 1H NMR (300 MHz,
DMSO-d6): d = 2.23 (s, 3H, CH3Ar0), 2.30 (s, 3H,
CH3Ar), 3.29 (t, J = 6.60 Hz, 2H, CH2CN), 3.55 (t,
J = 6.60 Hz, 2H, NHCH2), 5.61 (s, 1H, NHCH2), 7.05–
123

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I. Tumosiene et al.
1450
Acknowledgments The financial support of Research Council of
Lithuania (MIP-120/2011) is gratefully acknowledged.
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Med Chem 45:4726
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