The synthesis and antimicrobial activity of some new methyl N-arylthiocarbamates, dimethyl N-aryldithiocarbonimidates and 2-arylamino-2-imidazolines

Article abstract of DOI:10.1016/j.ejmech.2005.02.002

Methyl N-arylthiocarbamates (2a-d) and dimethyl N-aryldithiocarbonimidates (2e-i) were synthesized from the reaction of aromatic amines with carbon disulfide and methyl iodide and NaOH in various quantitative amounts. 2-Arylamino-2-imidazolines (3a-i) wer

Full text of DOI:10.1016/j.ejmech.2005.02.002

European Journal of Medicinal Chemistry 40 (2005) 687–693
www.elsevier.com/locate/ejmech
The synthesis and antimicrobial activity of some new methyl
N-arylthiocarbamates, dimethyl N-aryldithiocarbonimidates
and 2-arylamino-2-imidazolines
Süleyman Servi a,*, Murat Genc a, Seher Gür b, Murat Koca a
a Department of Chemistry, Faculty Science–Art, Firat University, 23169 Elazig, Turkey
b Department of Biology, Faculty Science–Art, Firat University, 23169 Elazig, Turkey
Received 21 October 2004; revised and accepted 16 February 2005
Available online 01 April 2005
Abstract
Methyl N-arylthiocarbamates (2a–d) and dimethyl N-aryldithiocarbonimidates (2e–i) were synthesized from the reaction of aromatic
amines with carbon disulfide and methyl iodide and NaOH in various quantitative amounts. 2-Arylamino-2-imidazolines (3a–i) were pre-
pared by heating both methyl N-arylthiocarbamates (2a–d) and dimethyl N-aryldithiocarbonimidates (2e–i) with 1,2-diaminoethane under
reflux. o-chlorobenzyl derivatives of [1,3,4]-thiadiazole-2-yl substituted aminoimidazoline compounds were synthesized by treatment of
[1,3,4]-thiadiazole-2-yl substituted aminoimidazolines (3h–i) with 2-benzyl chloride in basic medium and DMSO. Some of the synthesized
compounds were tested in vitro for their antimicrobial activity. All of the selected compounds showed some antimicrobial activity against test
microorganisms. Compounds 2f and 3f which have 1,3-benzothiazol ring exhibited a weak activity against Candida globrata.
© 2005 Elsevier SAS. All rights reserved.
Keywords: Antimicrobial activity; Methyl N-arylthiocarbamates; Dimethyl N-aryldithiocarbonimidates; 2-Arylamino-2-imidazolines
1. Introduction
dithiocarbonimidates have allowed to synthesis of
2-arylamino-2-imidazolines. 2-Arylamino-2-imidazolines
have an interesting chemistry [2–5] and they are effective
pharmacophores in medicinal chemistry. 2-Arylamino-2-
imidazolines, in particular 2,6-dichlorophenylamino-2-
imidazoline (clonidine) have a pronounced, hypotensive
action, which is coupled with a sedative action. Moreover,
some of these compounds also have a more or less pro-
N-mono and N,N-disubstituted dithiocarbamate deriva-
tives have showed antibacterial, antiviral and antifungal activi-
ties [1]. Methyl N-arylthiocarbamates and dimethyl N-aryl
* Corresponding author. Tel.: +90 424 237 0000; fax: +90 424 233 0062.
E-mail address: sservi@firat.edu.tr (S. Servi).
0223-5234/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2005.02.002

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S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
nounced analgesic action which, however, because of the
simultaneous existence of the hypotensive action and the
depressant action on the central nervous system, was consid-
ered unexploitable. A hypotensive action has also been
described for benzoyl derivatives of 2-arylamino-2-
imidazoline, especially for the compound 1-benzoyl-2-(2′,6′-
dichlorophenyl amino)-2-imidazoline, in the depressant action
on the central nervous system and thus the sedative action
being substantially less pronounced with this compound [6].
2. Chemistry
The reaction of CS2 and CH3I with aromatic amine in the
presence concentrated aqueous NaOH lead to the formation
of methyl N-arylthiocarbamates (2a–d) and dimethyl
N-aryldithiocarbonimidates (2e–i) which on treatment with
bisnucleophile such as DAE give N-aryl substituted aminoimi-
dazoline.
In the first part of the study, compounds 2a–i were synthe-
sized by the treatment of CS2 and CH3I with aromatic (or
hetero-aromatic) amines in basic medium. In this reaction,
different compounds can be synthesized by using various
amount of reactive. 2a–d compounds were synthesized when
1 mol CS2, 1 mol CH3I with 1 mol aromatic amine were used.
On the other hand, 2e–i compounds were obtained when 2 mol
CS2, 2 mol CH3I with 1 mol aromatic amine were used.
The synthesis of compounds 2a–i, 3a–i, 4g, h are pre-
sented in Schemes 2,3. Compounds 3a–i were synthesized
by refluxing of 2a–i with DAE in DMF for 8 h. To strengthen
nucleophilic attack of NH2 on DAE was used excess amount
of DAE.Yields of 3h, i compounds were obtained lower than
other 3 compounds.
The most recognized of the 2-arylamino-2-imidazolines
are clonidine and moxonidine compounds. These com-
pounds have been shown a1 and a2 adrenoceptor activities
and more specially, phentolamine, which contains an imida-
zoline ring, is a known a1-adrenergic antagonist (Scheme 1).
Imidazoline I2 receptors are widely distributed in the body
and brain of different species including humans. Function-
ally these receptors have been implicated in a variety of dis-
ease states such as psychiatric disorders, opiate withdrawal
Parkinson’s andAlzheimer’s disease as well as Huntington’s
chorea [7–10].
[1,3,4]-Thiadiazoles and their derivatives exhibit diverse
biological activities possibly due to the presence of =N–C–S
moiety [11]. Various phenyl substituted [1,3,4]-thiadiazole-
2-amines and their derivatives have recently received signifi-
cant importance because of their diverse biological proper-
ties [12,13]. Prompted by these observations and in
continuation of our work on the synthesis of 2-arylamino-2-
imidazolines, we thought it worthwhile to synthesis new com-
pounds of 2-arylamino-2-imidazolines having [1,3,4]-
thiadizole moiety, with the objective of obtaining new
biologically active compounds.
In this study, methyl N-arylthiocarbamates (2a–d) and di-
methyl N-aryldithiocarbonimi dates (2e–i) were synthesized
by reaction of aromatic amines with carbon disulfide (CS2)
and methyl iodide (CH3I). 2-arylamino-2-imidazolines (3a–i)
were obtained by treatment 1,2-diaminoethane (DAE) with
2a–i compounds at 120 °C for 8 h.
This article reports the first synthesis of compounds 2a–e,
2g–i, 3e, 3g–i. Also reported are synthesis of o-chlorobenzyl
derivatives of [1,3,4]-thiadiazole-2-yl substituted aminoimi-
dazolines (3h–i), which have not been synthesized previ-
ously. So far, antimicrobial activity of 2-arylamino-2-
imidazolines and their derivatives which having o-chloro
benzyl group has not been investigated.
5-Aryl substituted-[1,3,4]-thiadizole amines (1h, i) were
synthesized by cyclization of aryl carboxylic acids and thio-
semicarbazide in phosphorous oxychloride [11–14]. The reac-
tion of compounds 1h, i with CS2 and CH3I and NaOH led to
the formation dimethyl N-[1,3,4]-thiadiazole-2-yl substi-
tuted dithiocarbonimidates (2h, i). The treatment of com-
pounds 2h, i with DAE resulted in the formation of [1,3,4]-
thiadiazole-2-yl substituted aminoimidazolines 3h, i (Scheme
3). Compounds 4h, i were synthesized via nücleophilic attack
of N on imidazoline ring (endocyclic nitrogen atom) to
chloride-bearing C atom of 2-benzyl chloride compound. Syn-
thesis of o-chlorobenzyl derivatives of compounds 3h, i were
carried out by treatment [1,3,4]-thiadiazole-2-yl aminoimi-
dazolines (3h, i) with 2-benzyl chloride in DMSO and basic
medium (Scheme 3).
2a–i, 3e, 3g–i and 4h, i were synthesized and character-
ized for the first time in this present study. The synthesized
some compounds were tested in vitro for their antimicrobial
activity.
3. Result and discussion
Compounds 2a–d have showed thioimidate–thioamide tau-
tomerization. Thioamide form is more dominant according
Scheme 1. Imidazoline derivatives containing a 2-aminoimidazoline or an imidazoline ring which are known to interact with a-adrenergic receptors.

S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
689
Scheme 2
.
Synthesis of methyl N-arylthiocarbamates, dimethyl N-heteroaryldithioimidocarbonates and 2-arylamino-2-imidazolines.
Scheme 3. Synthesis of 2-chloro substituted benzyl derivatives of compounds 3h, i.
to IR, 1H-NMR and 13C-NMR data at room temperature. In
the 1H-NMR spectrum of compounds 2a–d were observed at
2.46–2.62 (SCH3) and 8.91–9.95 ppm (SH, controlled by
changing with D2O) integrating for three proton and one pro-
ton, respectively. The IR spectra of compounds 2a–i showed
SCH3 absorption between 830 and 726 cm–1. In addition, the
IR spectra of compounds 2a–d displayed SH absorption
between 3214 and 3110 cm–1. Besides the IR spectra of com-
pounds 2e and 2h showed to two different NO2 absorption
peak both 1530 and 1350 cm–1. The 1H-NMR spectra of com-
pounds 2e–i displayed no signals belonging to SH group;
instead, SCH3 signal appeared between 2.48 and 2.65 inte-
grating for six protons. In the 13C-NMR spectra of com-
pounds 2a–i, S–CH3 and C=N signals appeared d 16.2 and
142.5 ppm, respectively.
Compounds 3a–i have showed imine–enamine tautomer-
ization. The imine–enamine tautomerization of 2-arylamino-
2-imidazolines was investigated by means of 1H-NMR spec-
troscopy. In the 1H-NMR (200 and 90 MHz) spectra of 3a–i
singlets integrating for four hydrogens were observed at d
3.78–3.76 ppm, respectively. These compounds are effec-
tively symmetrical because of imine–enamine dynamic tau-
tomerization, which makes the CH2 protons equivalent. At
the same time this effect causes lowering of the order of the
spectra (Dt/J = 0). In the IR spectra of compounds 3a–i dis-
played two different NH absorption (stretching) 3450–
3250 cm–1.
1
In the H-NMR spectra of compounds 4h, i the signals
belonging to 2-benzyl chloride (aliphatic CH2) were observed
at 4.70 ppm while the signals belonging to endocyclic imida-

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S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
zoline NH disappeared. The signals belonging to exocyclic
NH were appeared at 5.49 ppm for 4h and 8.19 ppm for 4i
compounds. The IR spectra at 4h, i compounds showed addi-
tional peaks at 750 and 1140 cm–1 due to o-substituted phe-
nyl group.
nyl group were found to be the most active compounds against
the Gram-positive bacteria S. aureus ATCC 6538, while
the compound 2a which bearing a phenyl group showed
poor activity towards S. aureus ATCC 6538 and B. subtilis
ATCC 6633. Dimethyl N-heteroaryldithioimidocarbonates
bearing5-substitutedthiazolering(2eand2g),dimethylN-hetero-
aryldithioimidocarbonates having benzothiazole ring (2f) and
2-arylamino-2-imidazoline bearing thiazole ring (3e) exhib-
ited promising activity against S. aureus. In addition, com-
pounds 2f and 3e showed poor antifungal activity towards C.
globrata. Also, all of the other compounds exhibited poor
activity against S. aureus, E. coli, B. subtilis and C. glo-
brata.
The compounds 2h, i and 3h which have [1,3,4]-thiadiazole
ring showed a poor antimicrobial effect against test orga-
nisms (256 µg ml–1). Similarly, compounds 4h and i which
contain o-chlorobenzyl group on endocyclic nitrogen atom
of [1,3,4]-thiadiazol-2-yl amino-2-imidazolins showed the
same weak effect against test organisms (256 µg ml–1).
Compounds 2g, 3g which have 2,4,6-trimethyl benzyl
group and 3i exhibited poor antifungal activity towards C.
tropicalis. Likewise, compounds 2f and 2g indicated poor anti-
bacterial effect against E. coli.
3.1. Biological evaluation
We have designed and synthesized novel compounds of
2-arylamino-2-imidazolines class, in order to investigate the
relationships between antimicrobial activity and structure. The
minimum inhibitory concentration (MIC) of the synthesized
compounds was determined against the Gram-positive Bacil-
lus subtilis, Staphylococcus aureus, the Gram-negative
Escherichia coli, Salmonella typhimurium and the yeast Can-
dida globrata and Candida tropicalis using a standard broth
dilution technique. Their antimicrobial activity was com-
pared to ampicillin and fluconazol as standard drugs. All the
MIC results are presented in Table 1.
The obtained data reported that compounds were able to
inhibit the growth of the selected microorganisms in vitro
showing MIC values between 512 and 8 µg ml–1.
All the synthesized compounds showed some degree of
antimicrobial activities against test microorganisms. Among
the synthesized compounds, methyl N-4-chlorophenyl-
thiocarbamate 2b was found the most active derivative at an
MIC value of 8 µg ml–1 against S. aureus. Compounds 2a–c,
2e–g, 3e and 3f might be slightly more active than others
against some of the test microorganisms.
These results indicated that the standard antibiotic was only
active by an extra fourfold and eightfold in comparison to 2b
and c, respectively, which demonstrates the potential effi-
cacy.
4. Experimental
Compounds 2b and c which having electron withdrawing
substituents such as, chloride or bromide, respectively, on phe-
4.1. Chemistry
Table 1
Antimicrobial activity results (MIC values in µg ml–1) of synthesized com-
pounds with the standard drugs
Aromatic and hetero-aromatic amines were obtained from
commercial sources, except for hetero-aromatic amines (1g–i)
which were used to synthesis of 2g–i and 3g–i compounds.
1h, i compounds were prepared following literature proce-
dures [12–14]. Melting points (uncorrected) were deter-
mined with a Gallenkamp apparatus. IR spectra were mea-
sured on a Mattson model FT-IR spectrometer (potassium
bromide disks), and 1H spectrum were recorded on FX 90Q
JEOL and 200 MHz Bruker AC instruments. Chemical shift
values are reported in parts per million (d) relative to tetram-
ethyl silane as an internal standard. Elemental analyses were
performed on a LECO model 932 instrument.
Sample
S.t
256
E.c
256
256
256
256
256
512
512
256
256
256
256
256
256
256
256
256
256
2
B.s
S.a
128
8
C.g
256
256
256
256
256
128
256
256
256
256
256
128
256
256
256
256
256
–
C.t
2a
2b
2c
2d
2e
2f
2g
2h
2i
3b
3e
3f
3g
3h
3i
4h
128
256
256
256
256
256
256
256
256
256
256
256
512
256
256
256
256
2
256
256
256
256
256
256
512
256
256
256
256
256
512
256
512
256
256
–
256
256
256
256
256
256
256
256
256
256
256
256
256
256
256
256
2
16
256
64
64
64
256
256
256
64
4.1.1. General method for the synthesis of compounds
(2a–d)
256
256
256
256
256
256
2
To a well-stirred cold solution of aromatic amines
(0.04 mol) in DMF (20 ml) were added aqueous NaOH (20 M,
4 ml), carbon disulfide (3.0 ml, d: 1.26 g cm–3, 0.05 mol),
and methyl iodide (3.1 ml, d: 2.28 g cm–3, 0.05 mol) in
sequence at intervals of 30 min and stirring was continued
for 2–4 h. The mixture was then poured into cold water and
the resulting solid was washed with water and recrystallized
from ethanol solvent to afford the desired compound (Scheme
2). The following products were obtained.
4i
Ampicilin
Fluconazol
8
8
In vitro activity of the selected compounds and the reference drugs (MIC
values in µg ml–1). B.s: B. subtilis ATCC 6633, S.a: S. aureus ATCC 6538 P,
E.c: E. coli ATCC 25922, S.t: S. typhimurium NRRL B 4420, C.g: C. glo-
brata ATTC 66032, C.t: C. tropicalis ATCC 13803.

S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
691
4.1.1.1. Methyl N-phenylthiocarbamate (2a). (Yield 57%),
yellow powder, m.p. 92–93 °C. Analysis (Calc./found %):
for C8H9NS2 C: 2.42/51.94, H: 4.95/4.79, N: 7.64/7.35, S:
34.99/34.53; IR (KBr) (t, cm–1), 3110 (S–H stretching), 2920
(aliphatic C–H stretching), 1600 (C=N stretching), 775 (SCH3
C: 28.90/28.39, H: 2.83/3.06, N: 16.85/15.34, S: 38.58/38.79;
IR (KBr) (t, cm–1), 3095 (aromatic C–H stretching), 2979–
2930 (aliphatic C–H stretching), 1678 (C=C stretching), 1621
(C=N stretching), 1530 (Ar–NO2 asymmetric stretching) and
1350 (symmetric stretching), 841 (S–CH3 stretching); H-
NMR (CHCl3-d, 90 MHz) d (ppm) 2.65 (s, 6H, SCH3), 8.36
1
1
stretching); H-NMR (CHCl3-d, 90 MHz) d (ppm) 2.46 (s,
3H, SCH3), 7.4 (s, 5H, Ar–H), 9.40 (1H, SH).
(s, 1H, thiazole ring proton).
4.1.2.2. Dimethyl N-(1,3-benzothiazol-2-yl) dithioimidocar-
bonate (2f). (Yield 69%), yellowish powder, m.p. 101–
102 °C (ethanol). Analysis (Calc./found %): for C10H10N2S3
C: 47.21/48.39, H: 3.96/4.06, N: 11.01/11.34, S: 37.81/38.77;
IR (KBr) (t, cm–1), 2995 (aliphatic C–H stretching), 1592
(C=C stretching), 1510 (C=N stretching), 833 (S–CH3 stretch-
4.1.1.2. Methyl N-4-chlorophenylthiocarbamate (2b). (Yield
64%), orange powder, m.p. 112–114 °C. Analysis
(Calc./found %): for C8H8ClNS2 C: 44.13/44.24, H:
3.70/3.50, N: 6.43/6.27, S: 29.45/28.06; IR (KBr) (t, cm–1),
2932 (aliphatic C–H stretching), 1617 (C=N stretching), 507
(C–Cl); 1H-NMR (CHCl3-d, 90 MHz) d: 2.66 (s, 3H, SCH3),
7.40–7.60 (m, 4H, Ar–H), 9.85 (1H, SH).
1
ing); H-NMR (CHCl3-d, 90 MHz) d (ppm) 2.59 (s, 6H,
SCH3), 6.90–7.30 (m, 2H, Ar–H), 7.50–7.86 (2H, m, Ar–H).
4.1.1.3. Methyl N-4-bromophenylthiocarbamate (2c). (Yield
65%), brown powder, m.p. 133–135 °C.Analysis (Calc./found
%): for C8H8BrNS2 C: 36.65/36.12, H: 3.08/3.45, N:
5.34/4.98, S: 24.46/24.58; IR (KBr) (t, cm–1), 3214 (S–H
stretching), 2971 (aliphatic C–H stretching), 1643 (C=C
stretching), 1585 (C=N stretching) 726 (SCH3 stretching);
1H-NMR (CHCl3-d, 90 MHz) d: 2.62 (s, 3H, SCH3), 7.44–
7.60 (m, 4H, Ar–H), 8.91 (1H, SH).
4.1.2.3. Dimethyl N-[5-(2,4,6-trimethylbenzyl)thiazole-2-yl]
dithioimidocarbonate (2g). (Yield 74%), orange power, m.p.
91–92 °C (ethanol). Analysis (Calc./found %): for
C16H20N2S3 C: 57.10/58.12, H: 5.99/5.19, N: 8.32/8.45, S:
28.58/28.97; IR (KBr) (t, cm–1), 2920 and 2855 (aliphatic
C–H stretching), 1612 (C=C stretching), 1523 (C=N stretch-
ing), 756 (S–CH3 stretching); 1H-NMR (CHCl3-d, 90 MHz)
d (ppm) 2.26 (s, 9H, mesitylene CH3), 2,58 (s, 6H, SCH3),
3,92 (s, 2H, aliphatic CH2), 6,21 (s, 1H, thiazole ring pro-
ton), 6.87–7.26 (m, 2H, Ar–H).
4.1.1.4. Methyl N-4-methoxyphenylthiocarbamate (2d). (Yield
63%), light brown crystal, m.p. 109–111 °C. Analysis
(Calc./found %): for C9H11NOS2 C: 50.67/50.08, H:
5.20/5.37, N: 6.57/6.54, S: 30.06/30.56; IR (KBr) (t, cm–1),
3158 (S–H stretching), 3078 (aromatic C–H stretching),
2962–2921 (aliphatic C–H stretching), 1607 (C=C stretch-
ing), 1589 (C=N stretching), 1253 (OCH3 stretching), 830
(S–CH3 stretching); 1H-NMR (CHCl3-d, 90 MHz) d: 2.62 (s,
3H, SCH3), 3.81 (s, 3H, OCH3), 6.95–7.26 (m, 4H, aromatic
protons) 9.17 (1H, SH).
4.1.2.4. Dimethyl N-{5-phenyl- [1,3,4]-thiadiazol-2-yl}
dithioimidocarbonate (2h). (Yield 62%), orange powder, m.p.
111–113 °C (ethanol). Analysis (Calc./found %): for
C11H11N3S3 C: 46.95/46.65, H: 3.94/3.38, N: 14.93/14.23,
S:34.18/ 34.37; IR (KBr) (t, cm–1), 2968 (aliphatic C–H
stretching), 1619 (C=C stretching), 1578 and 1537 (C=N
1
stretching), 751 (S–CH3 stretching); H-NMR (CHCl3-d,
90 MHz) d (ppm) 2.64 (s, 6H, SCH3), 7.47–7.99 (m, 5H,
Ar–H).
4.1.2. General method for the synthesis of compounds
(2e–i)
4.1.2.5. Dimethyl N-{5-(4-nitrophenyl) [1,3,4]-thiadiazol-2-
yl} dithioimidocarbonate (2i). (Yield 55%); orange powder,
m.p. 250–251 °C (ethanol). Analysis (Calc./found %): for
C11H10N4O2S3 C: 40.48/39.56, H: 3.09/3.32, N: 17.16/17.19,
S: 27.47/28.09; IR (KBr) (t, cm–1), 2930–2900 (aliphatic C–H
stretching), 1633 (C=C stretching), 1592 (C=N stretching),
1510 (Ar–NO2 asymmetric stretching) and 1349 (symmetric
stretching), 846 (S–CH3 stretching); H-NMR (CHCl3-d,
90 MHz) d (ppm) 2.48 (s, 6H, SCH3), 8.31–8.52 (m, 4H,
Ar–H).
To a solution of aromatic (or heteroaromatic) amine
(0.1 mol) in DMF (75 ml), aqueous 20 M sodium hydroxide
(5.5 ml, 0.11 mol) was added with stirring at room tempera-
ture. After 10 min carbon disulfide (3.3 ml, d: 1.26 g cm–3,
0.055 mol) was added and stirring was continued for 30 min.
Then aqueous 20 M sodium hydroxide (3 ml, 0.06 mol) and
carbon disulfide (1.8 ml, 0.0275 mol) were added. This opera-
tion was finally repeated 10 min later. After 30 min the reac-
tion was placed in an ice bath, methyl iodide (12.5 ml, d:
2.28 g cm–3, 0.2 mol) was added drop wise and stirring was
continued for 2 h. The mixture was then poured into ice cooled
water and the precipitate thus obtained was filtered, washed
with water, dried and recrystallized from ethanol. The follow-
ing products were obtained.
1
4.1.3. Synthesis of 2-arylamino-2-imidazolines (3a–i)
A solution of 2a–i (0.04 mol) in DMF (15 ml) was added
to a solution of 1,2-diaminoethane (0.08 mol) in DMF (15 ml)
with stirring at room temperature. The reaction mixture was
maintained at 120 °C for 8 h. Then the mixture was cooled
and added to ice-cold water. The resulting solid was washed
with water, dried and recrystallized from appropriate sol-
vent.
4.1.2.1. Dimethyl N-(5-nitro-1,3-thiazol-2-yl) dithioimido-
carbonate (2e). (Yield 59%), yellow powder, m.p. 174–
175 °C (ethanol).Analysis (Calc./found %): for C6H7N3O2S3

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S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
4.1.3.1.
N-(Phenyl)-N-(4,5-dihydro-1H-imidazol-2-yl)
C11H11N5S C: 53.86/54.03, H: 4.52/4.66, N: 28.56/28.41, S:
13.07/13.65. IR (KBr) (t, cm–1), 3317 and 3297 (N–H stretch-
ing), 1614 (C=C stretching), 1528 (C=N stretching), 1443
(N–H bending); 1H-NMR (DMSO-d6, 90 MHz) d (ppm) 3.76
(s, 4H, imidazoline CH2), 7.45 (s, 5H, Ar–H); 7.55 (s, 2H,
NH).
amine (3a). (Yield 63%), white powder, m.p. 115–116 °C
(ethanol). Analysis (Calc./found %): for C9H11N3 C:
67.06/68.11, H: 6.88/7.24, N: 26.07/26.83; IR (KBr) (t, cm–1),
3277 (imidazoline N–H stretching), 3257 (N–H stretching),
1
1660 (C=N stretching), 1537 (N–H bending); H-NMR
(DMSO-d6, 200 MHz) d (ppm): 3.48 (s, 1H, NH), 3.73 (s,
4H, imidazoline CH2), 6.30 (broad peak, 1H, imidazoline
NH), 7.12–8.20 (m, 5H, Ar–H).
4.1.3.7. N-{5-(4-Nitrophenyl)-[1.3.4]-thiadiazole-2-yl}-N-
(4,5-dihydro-1H-imidazol-2-yl) amine (3i). (Yield 44%), yel-
low powder, m.p. 239–240 °C (ethanol).Analysis (Calc./found
%): for C11H10N6O2S C: 45.51/45.11, H: 3.47/3.70, N:
28.95/28.56, S: IR (KBr) (t, cm–1), 3396 and 3218 (N–H
stretching), 1626 (C=C stretching), 1538 (C=N stretching),
1508 (Ar–NO2 asymmetric stretching), 1465 (N–H bending)
1350 (Ar–NO2 symmetric stretching); 1H-NMR (DMSO-d6,
90 MHz) d (ppm) 3.58 (s, 4H, imidazoline CH2), 7.53–8.29
(m, 4H, Ar–H), 8.09 (s, 2H, NH).
4.1.3.2. N-(4-Chlorophenyl)-N-(4,5-dihydro-1H-imidazol-2-
yl) amine (3b). (Yield 71%); white powder, m.p. 147–148 °C
(ethanol). Analysis (Calc./found %): for C9H10Cl N3 C:
55.25/56.13, H: 5.15/5.74, N: 21.48/22.05; IR (KBr) (t, cm–1),
3284 (imidazoline N–H stretching), 3245 (N–H stretching),
1
1681 (C=N stretching), 1594 (N–H bending); H-NMR
(DMSO-d6, 200 MHz): d (ppm) 3.67 (s, 1H, NH), 3.76 (s,
4H, imidazoline CH2), 6.24 (broad peak, 1H, imidazoline
NH), 7.05–7.40 (m, 4H, Ar–H).
4.1.4. Synthesis of 2-benzyl chloride derivatives
of compounds 3h, i
To a mixture of N-[5-(4-nitrophenyl)-1.3.4-thiadiazole-2-
yl)-N-(4,5-dihydro-1H-imidazol-2-yl) amine (0.91 g,
3.14 mmol) and finely powdered NaOH (0.5 g, 12.5 mmol)
in DMSO (7 ml) was added drop wise 2-benzyl chloride
(0.35 ml, 3.45 mmol). The resulting solution was stirred at
35–40 °C for 1 h. Then water was added to the reaction mix-
ture, and the solid that precipitated was collected crystalliza-
tion from ethanol.
4.1.3.3. N-(5-Nitro-1,3-thiazol-2-yl)-N-(4,5-dihydro-1H-
imidazol-2-yl) amine (3e). (Yield 46%), white powder, m.p.
133–135 °C (chloroform). Analysis (Calc./found %): for
C6H7N3O2S C: 33.80/34.19, H: 3.31/3.59, N: 32.85/33.21,
S: 15.04/15.19; IR (KBr) (t, cm–1), 3358 and 3317 (N–H
stretching), 1681 (C=C stretching), 1619 (C=N stretching),
1544 (Ar–NO2 asymmetric stretching), 1465 (N–H bending)
1359 (Ar–NO2 symmetric stretching); 1H-NMR (DMSO-d6,
90 MHz) d (ppm) 3.66 (s, 4H, imidazoline CH2), 8.19 (s, 2H,
NH), 8.35 (s, 1H, thiazole ring proton).
4.1.4.1. [1-(2-Chlorobenzyl)-4,5-dihydro-1H-imidazole-2-
yl]-[5-phenyl-[1,3,5]-thiadiazol-2-yl] amine (4h). (Yield
64%), orange powder, m.p. 153 °C (ethanol). Analysis
(Calc./found %): for C18H16ClN5S C: 58.45/58.65, H:
4.36/3.28, N: 18.93/19.08, S: 8.67/7.93. IR (KBr) (t, cm–1),
3314 (N–H stretching), 3075 (aromatic C–H stretching),
2954–2858 (C–H stretching), 1676 (C=C stretching), 1592
(C=N stretching), 507 (C–Cl); 1H-NMR (DMSO-d6,
90 MHz,) d (ppm) 3.27 (s, 4H, imidazoline CH2), 4.67 (s,
2H, aliphatic CH2), 5.49 (s, 1H, NH), 7.50–7.82 (m, 9H,
Ar–H).
4.1.3.4. N-(1,3-Benzothiazol-2-yl)-N-(4,5-dihydro-1H-
imidazol-2-yl) amine (3f). (Yield 66%), white powder, m.p.
131–132 °C (ethanol). Analysis (Calc./found %): for
C10H10N4S C: 55.02/55.63, H: 4.62/4.96, N: 25.37/26.41, S:
14.69/15.19. IR (KBr) (t, cm–1), 3281 (imidazoline N–H
stretching), 3220 (N–H stretching), 1611 (C=N stretching),
1528 (N–H bending); 1H-NMR (DMSO-d6, 200 MHz): d 1.74
(s, 1H, NH), 3.78 (s, 4H, imidazoline CH2), 7.09–7.64 (m,
4H, Ar–H), 8.01 (broad peak, 1H, imidazoline NH).
4.1.4.2. [1-(2-Chlorobenzyl)-4,5-dihydro-1H-imidazole-2-
yl]-[5-(4-nitrophenyl)[1,3,5]thiadiazol-2yl] amine (4i). (Yield
58%), orange powder, m.p. > 300 °C (THF, toluene). Analy-
sis (Calc./found %): for C18H15ClN6O2S C: 52.11/52.78, H:
3.64/3.62, N: 20.26/20.19, S: 7.73/7.89. IR (KBr) (t, cm–1),
3331 (N–H stretching), 3067 (aromatic C–H stretching),
2930–2872 (C–H stretching), 1674 (C=C stretching), 1592
(C=N stretching), 1516 (Ar–NO2 asymmetric stretching),
1455 (N–H bending), 1349 (Ar–NO2 symmetric stretching);
1H-NMR (DMSO-d6, 90 MHz,) d (ppm) 3.30 (s, 4H, imida-
zoline CH2), 4.73 (s, 2H, aliphatic CH2), 7.45 (m, 8H,Ar–H),
8.39 (s, 1H, NH).
4.1.3.5. N-[5-(2,4,6-Trimethylbenzyl) thiazole-2-yl]-N-(4,5-
dihydro-1H-imidazole-2-yl) amine (3g). (Yield 66%), light
gray powder, m.p. 172–174 °C (toluene). Analysis
(Calc./found %): for C16H20N4S C: 63.97/63.85, H: 6.71/6.56,
N: 18.65/18.34, S: 10.67/10.07. IR (KBr) (t, cm–1), 3382 and
3372 (N–H stretching), 2923 (C–H stretching), 1626 (C=C
stretching), 1532 (C=N stretching), 1471 (N–H bending);
1H-NMR (DMSO-d6, 90 MHz) d (ppm) 2.15 (s, 2H, NH),
2.26 (s, 9H, 3 × CH3), 3.66 (s, 4H, imidazoline CH2), 3.91 (s,
2H, aliphatic CH2), 5.76 (s, 1H, thiazole ring proton), 6.87
(m, 2H, Ar–H).
4.2. Microbiology
4.1.3.6. N-(5-Phenyl-[1,3,4]-thiadiazol-2-yl)-N-(4,5-dihydro-
1H-imidazol-2-yl) amine (3h). (Yield 57%), yellowish crys-
tal, m.p. 192–194 °C (toluene).Analysis (Calc./found %): for
For determining both antibacterial and antifungal activity,
the synthesized compounds and the control drugs were dis-

S. Servi et al. / European Journal of Medicinal Chemistry 40 (2005) 687–693
693
solved in absolute dimethylsulfoxide (DMSO). Further dilu-
References
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Acknowledgements
We are indebted to the Firat University Research Founda-
tion (FÜBAP 755) for financial support of this work.