Synthesis and characterization of novel triazol compounds containing a thiophen ring as potential antifungal agents and the structure of 2-(2-hydroxy-2-p-tolyethyl)-5-(thiophen-2-ylmethyl)-4-(4H-1, 2, 4-triazol-4-yl)-2H-1, 2, 4-triazol-3(4H)-one

Article abstract of DOI:10.3906/kim-0904-11

A series of new 4-(3, 5-disubstitue-4H-1, 2, 4-triazol-4-yl)-5-(thiophen-2- yl-methyl)-2H-1, 2, 4-triazol-3(4H)-ones (3a-c) were obtained by reaction N'-1-ethoxy-2-thiophen-2-yl-ethylydene hydrazino carboxylic acid ethyl ester (1) and 4-amino-4H-1, 2, 4-triazoles (2). 4-(3, 5-disubstitue-4H-1, 2, 4-triazol-4-yl)-2-(2-oxo-2-arylethyl)-5-(thiophen-2-yl-methyl)-2H-1, 2, 4-triazol-3(4H)-ones (4a-e) and ethyl 2-(4-(3, 5-disubstitue-4H-1, 2, 4-triazol-4-yl)-5-oxo-3-(thiophen-2-ylmethyl)-4, 5-dihydro-1, 2, 4-triazol-1-yl)acetates (6a-c) were obtained by reaction of compounds 3 and bromoacetophenon derivatives and bromo ethylacetate, respectively. Compounds 5a-e were synthesized from the reaction of corresponding compounds 4a-e with NaBH₄. Compounds 7a-c were obtained by the reaction compounds 6 and LiAlH₄. Seventeen new compounds were synthesized and characterized by elemental analyses, IR, 1H-NMR, and 13 C-NMR spectral data. The structure of compound 5d was inferred through IR, 1H-, 13 C-NMR, elemental analyses, and X-ray spectral techniques. In addition, the newly synthesized chemicals were screened for their antibacterial and antifungal properties. Among the chemicals tested, 6a and 6b exhibited the highest degree of antifungal activity. tuebitak.

Full text of DOI:10.3906/kim-0904-11

Turk J Chem
34 (2010) , 551 – 563.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-0904-11
Synthesis and characterization of novel triazol
compounds containing a thiophen ring as potential
antifungal agents and the structure of
2-(2-hydroxy-2-p-tolyethyl)-5-(thiophen-2-ylmethyl)-4-
(4H-1,2,4-triazol-4-yl)-2H-1,2,4-triazol-3(4H)-one
1,∗
1
1
¨
¨ ˘
¨
Yasemin UNVER , Esra DUGDU , Kemal SANCAK
Mustafa ER2, Re¸sat USTABAS¸3
1Department of Chemistry, Karadeniz Technical University, 61080 Trabzon-TURKEY
e-mail: unver.yasemin@hotmail.com
2Department of Chemistry, Karabu¨k University, 78200 Karabu¨k-TURKEY
3Department of Middle Education, Educational Faculty, Ondokuz Mayıs University
55200-Atakum-Samsun, TURKEY
Received 08.04.2009
A series of new 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-
ones (3a-c) were obtained by reaction N’-1-ethoxy-2-thiophen-2-yl-ethylydene hydrazino carboxylic acid
ethyl ester (1) and 4-amino-4H-1,2,4-triazoles (2). 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-2-(2-oxo-2-arylethyl)-
5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-ones (4a-e) and ethyl 2-(4-(3,5-disubstitue-4H-1,2,4-triazol-
4-yl)-5-oxo-3-(thiophen-2-ylmethyl)-4,5-dihydro-1,2,4-triazol-1-yl)acetates (6a-c) were obtained by reaction
of compounds 3 and bromoacetophenon derivatives and bromo ethylacetate, respectively. Compounds 5a-e
were synthesized from the reaction of corresponding compounds 4a-e with NaBH4 . Compounds 7a-c were
obtained by the reaction compounds 6 and LiAlH4 . Seventeen new compounds were synthesized and char-
acterized by elemental analyses, IR, 1 H-NMR, and 13 C-NMR spectral data. The structure of compound 5d
was inferred through IR, 1 H-, 13 C-NMR, elemental analyses, and X-ray spectral techniques. In addition,
the newly synthesized chemicals were screened for their antibacterial and antifungal properties. Among the
chemicals tested, 6a and 6b exhibited the highest degree of antifungal activity.
Key Words: Synthesis, 1,2,4-triazole-3-one, NaBH4 , LiAlH4 , antimicrobial activity, X-ray
∗Corresponding author
551

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
Introduction
The 1,2,4-triazol compounds possess important pharmacology activities such as antifungal and antiviral ac-
tivities. Examples of such compounds bearing the 1,2,4-triazol residues are fluconazole,1 the powerful azole
antifungal agent, as well as the potent antiviral N- nucleoside ribavirin.2 Furthermore, various 1,2,4-triazole
derivatives have been reported to have fungicidal,3 insecticidal,4 and antimicrobial activity,5 and some showed
antitumor activity6 as well as anticonvulsant,7 antidepressant,8 and plant growth regulator anticoagulant
activities.9 It was reported that compounds having triazole moieties such as vorozole, anastrozole, and letrozole
appear to be very effective aromatase inhibitors very useful for preventing breast cancer.10−12
It is known that 1,2,4- triazol moieties interact strongly with heme iron, and aromatic substituents on
the triazoles are very effective for interacting with the active site aromatase.13
In recent years, there has been an increasing interest in the chemistry of thiophenes because of their
biological significance. Many of them have been widely investigated for therapeutic uses, especially as antifungal,
antibacterial, antiinflammatory, anticonvulsant, antiasthmatic, and analgesic agents. They are also known to
show anti-HIV, antiproliferative, germicidal, and D2 dopaminergic activities.14
Antimicrobial agents having different structures are frequently used in the treatment of microbial in-
fections. However, there is an increasing resistance to these drugs. Moreover, some azole derivatives used
as common antibiotics such as Amphotericin B have a toxic effect on humans as well as their antimicrobial
effects.15 To overcome the development of drug resistance, it is crucial to synthesize a new class of antimicro-
bials possessing different chemical properties from those of used commonly.
In view of these facts, the aim of this present study was to obtain triazol derivatives containing thiophen
(Scheme) to be used as antimicrobial agents. For years, several articles have been devoted to the synthesis and
pharmacological investigation of certain chemicals.16−20 We investigated the possible antimicrobial activity of
some 3a, 3b, 3c, 4a, 4b, 6a, 6b, and 6c to 12 standard organisms including bacterial and fungal strains. In
addition, the crystal data for compound 5d, Orthorhombic, space group Pbca, a = 11.2122 (5), b = 15.2298
3
˚
˚
(6), c = 22.4200 (9) (A), V=3828.4(3) (A ), Z = 8, are given in Experimental section.
Experimental
Chemistry
Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected. 1 H-NMR
and 13 C-NMR spectra were recorded on a Varian-Mercury 200 MHz spectrometer. The IR spectra were
measured as potassium bromide pellets using a Perkin-Elmer 1600 series FTIR spectrometer. Elemental analyses
were performed on a Hewlett-Packard 185 CHN analyzer; their values agreed with the calculated ones. All
the chemicals were obtained from Fluka Chemie AG Buchs (Switzerland). Compounds 1, 3a, and 4b were
synthesized by published methods,21−23 respectively.
General method for the synthesis of 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-5-(thiophen-2-
yl-methyl)-2H-1,2,4-triazol-3(4H)-ones (3a-c): Compound 1 (0.01 mol) and 3,5-disubstitue-4-amino-4H-
1,2,4-triazol (2) (0.01 mol) were heated at 165-170 ◦ C in an oil bath for 2 h. After cooling to room temperature,
a solid appeared. It was recrystallized from an appropriate solvent to afford the desired compound.
552

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Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
Synthesis of 4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-
3(4H)-one (3b): Following the general procedure above, a white solid was obtained. It was recrystallized from
ethanol/water (1:1) (yield 64%) to afford the desired compound. Mp 220-221 ◦ C. IR (KBr) (ν , cm−1) 3152
(NH), 1738 (C=O), 1605 (C=N); 1 H-NMR (DMSOd6)δ 3.84 (s,2H,CH2), 6.59-6.61 (m, 3H, thiophen H),
12.20 (s, NH); 13 C-NMR (DMSOd6) δ 25.76 (thiophen-CH2), thiophen C:[125.76 (CH), 127.65 (CH), 127.71
(CH), 135.63 (C)], 143.76 (C=N triazol-3-one), 144.02 (C=N triazol), 150.92 (C=O triazol-3-one); Analysis
(%Calculated/found) for C11 H12 N6 SO C:47.81/47.83, H:4.38/4.39, N:30.41/30.43.
Synthesis of 4-(3,5-ethyl-4H-1,2,4-triazol-4-yl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-
3(4H)-one (3c): Following the general procedure above, a white solid was obtained. It was recrystallized
from ethanol/water (1:1) (yield 671%) to afford the desired compound. Mp 231-232 ◦ C. IR (KBr) (ν , cm−1
)
3095 (NH), 1744 (C=O), 1598 (C=N); 1 H-NMR (DMSOd6)δ 3.87 (s, 2H, CH2), 6.81-6.85 (m, 3H, thiophen
H), 11.68 (s, NH); 13 C-NMR (200 MHz, DMSOd6)δ 26.64 (thiophen-CH2), thiophen C:[126.55 (CH), 127.70
(CH), 127.71 (CH), 135.40 (C)], 138.28 (C=N triazol-3-one), 144.12 (C=N triazol), 154.86 (C=O triazol-3-one);
Analysis (%Calculated/found) for C13 H16 N6 SO C:51.30/51.32, H:5.30/5.31, N:27.61/27.63.
General method for the synthesis of 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-2-(2-oxo-2-
arylethyl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-ones (4a-e): The corresponding 4-(3,5-
disubstitue-4H-1,2,4-triazol-4-yl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-ones (3a-c) (0.01 mol) were
refluxed with an equivalent amount of natrium in absolute ethanol for 1 h. Then bromoacetophenon derivatives
(0.01 mol) were added and refluxed for an additional 5 h. The precipitate was filtered off, washed with H2 O,
and recrystallized from an appropriate solvent to afford the desired compound.
2-(2-oxo-2-phenylethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-triazol-
3(4H)-one (4a): Following the general procedure above, a white solid was obtained. It was recrystallized
from benzene/petroleum ether (1:1) (yield 70%) to afford the desired compound. Mp 109-110 ◦ C. Analysis
(%Calculated/found) for C17 H14 N6 SO2 C:55.73/55.74, H:3.85/3.87, N:22.94/22.96; IR (KBr) (ν , cm−1) 1658
(acetophenon C=O), 1746 (triazol-3-one C=O), 1597 (C=N); 1 H-NMR (DMSO-d6)δ 4.02 (s, 2H, thiophen-
CH2), 5.27 (s, 2H, NCH2), 6.62-6.91 (m, 3H, thiophen+arom.H), 7.46-7.50 (m, 2H, thiophen+arom.H), 7.57-
7.68 (m, 2H, thiophen+arom.H), 8.05 (s, 2H, triazol H); 13 C-NMR (DMSO-d6) δ (ppm) 26.49 (thiophen-CH2),
52.29 (NCH2), thiophen C:[126.33 (CH), 127.27 (CH), 127.74 (CH), 133.91 (C)], arom. C: [128.06 (CH), 129.07
(CH), 133.90 (CH), 134.47 (C)], 143.30 (C=N triazol-3-one), 144.65 (C=N triazol) 167.60 (C=O triazol-3-one),
191.07 (C=O acetophenon); Analysis (%Calculated/found) for C17 H14 N6 SO2 C:55.73/55.74, H:3.85/3.87,
N:22.94/22.96.
4-(3,5-diethyl-4H-1,2,4-triazol-4-yl)-2-(2-oxo-2-phenylethyl)-5-(thiophen-2-yl-methyl)-2H-
1,2,4-triazol-3(4H)-one (4c): Following the general procedure above, a white solid was obtained. It was
recrystallized from benzene/petroleum ether (1:1) (yield 70%) to afford the desired compound. Mp 115-116 ◦ C.
Analysis (%Calculated/found) for C21 H22 N6 SO2 C:59.70/59.71, H:5.25/5.27, N:19.89/19.90; IR (KBr) (ν ,
cm−1) 1659 (acetophenon C=O), 1748 (triazol-3-one C=O), 1600 (C=N); 1 H-NMR (DMSO-d6)δ 1.24 (t, 6H,
J=3.4 Hz, CH3), 2.5 (q, 4H, J=3.4 Hz, CH2), 4.05 (s, 2H, thiophen-CH2), 5.35 (s, 2H, NCH2), 6.66-6.98 (m,
3H, thiophen+arom.H), 7.45-7.50 (m, 2H, thiophen+arom.H), 7.59-7.78 (m, 2H, thiophen+arom.H), 8.01 (s, 2H,
triazolH); 13 C-NMR (DMSO-d6) δ (ppm) 13.70 (CH2), 15.80 (CH3), 25.90 (thiophen-CH2), 60.10 (NCH2),
thiophen C:[123.40 (CH), 125.00 (CH), 126.50 (CH), 139.40 (C)], ar C: [128.45 (CH), 128.65 (CH), 132.90
553

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Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
(CH),137.40 (C)], 155.20 (C=N triazol-3-one), 160.45 (C=N triazol), 162.65 (C=O triazol-3-one), 192.07 (C=O
acetophenon); Analysis (%Calculated/found) for C21 H22 N6 SO2 C:59.70/59.71, H:5.25/5.27, N:19.89/19.90.
2-(2-oxo-2-p-tolylethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-triazol-
3(4H)-one (4d): Following the general procedure above, a white solid was obtained. It was recrystallized
from ethanol/water (1:1) (yield 70%) to afford the desired compound. Mp 210-211 ◦ C. IR (KBr) (ν , cm−1
)
1691 (acetophenon-C=O), 1715 (triazol-3-one C=O), 1597 (C=N); 1 H-NMR (DMSO-d6)δ 2.41 (s, 6H, CH3),
4.18 (s, 2H, thiophen-CH2), 5.48 (s, 2H, NCH2), 6.73-6.95 (m, 2H, thiophen+arom.H), 7.39-7.45 (m, 4H,
thiophen+arom.H), 7.94-7.98 (m, 2H, triazol H); 13 C-NMR (DMSO-d6)δ (ppm) 21.17 (CH3), 25.08 (thiophen-
CH2), 52.15 (NCH2), thiophen C:[126.00 (CH), 127.00 (CH), 128.23 (CH), 134.22 (C)], ar C: [129.37 (CH),
131.44 (CH), 136.92 (CH), 142.81 (C)], 143.35 (C=N triazol-3-one), 144.70 (C=N triazol), 150.14 (C=O
triazol-3-one), 191.79 (C=O acetophenon); Analysis (%Calculated/found) for C18 H16 N6 SO2 C:56.83/56.84,
H:4.24/4.25, N:22.09/22.00.
2-(2-(4-nitrophenyl)-2-oxoethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-
triazol-3(4H)-one (4e): Following the general procedure above, a white solid was obtained. It was recrys-
tallized from ethanol/water (1:1) (yield 65%) to afford the desired compound. Mp 185-186 ◦ C. IR (KBr)
(ν , cm−1) 1711 (acetophenon C=O), 1737 (triazol-3-one C=O), 1602 (-C=N) ; 1 H-NMR (DMSO-d6)δ 4.14
(s, 2H, thiophen-CH2), 5.51 (s, 2H, NCH2), 6.70-6.94 (m, 2H, thiophen + arom.H), 7.30-7.83 (m, 2H, thio-
phen+arom.H), 8.26-8.41 (m, 3H, thiophen + arom. H); 13 C-NMR (DMSO-d6)δ (ppm) 25.93 (thiophen-CH2),
52.73 (NCH2), thiophen C:[125.83 (CH), 127.06 (CH), 127.25 (CH), 134.04 (C)], ar C: [119.36 (CH), 123.93
(CH), 129.53 (CH), 138.56 (C)], 142.44 (C=N triazol-3-one), 143.76 (C=N triazol), 150.59 (C=O triazol-3-one),
190.80 (C=O acetophenon); Analysis (%Calculated/found) for C17 H13 N7 SO4 C:49.63/49.65, H:3.19/3.20,
N:23.83/23.84.
General method for the synthesis of 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-2-(2-hydroxy-
2-arylethyl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-ones (5a-e): A mixture of correspond-
ing compound 4 (0.01 mol) and NaBH4 (0.04 mol) in absolute ethanol (50 mL) was refluxed for 4 h. After
cooling to room temperature ice water was added to it with vigorous stirring. The solid obtained was filtered
off and recrystallized from an appropriate solvent to afford the desired compound.
2-(2-hydroxy-2-phenylethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-
triazol-3(4H)-one (5a): Following the general procedure above, a white solid was obtained. It was recrystal-
lized from ethanol/water (1:1) (yield 60%) to afford the desired compound. Mp 186-187 ◦ C. Analysis (%Calcu-
lated/found) for C17 H16 N6 SO2 C:55.42/55.48, H:4.38/4.42, N:22.81/22.82; IR (KBr) (ν , cm−1) 3434 (OH),
1746 (triazol-3-one C=O), 1635 (C=N); 1 H-NMR (DMSO-d6)δ 3.41-3.78 (m, 2H, NCH2), 4.17 (s, 2H, thiophen-
CH2), 4.95 (bs, 1H, CH-OH), 5.79 (d, 1H, OH, J= 5 Hz), 6.80-6.98 (m, 8H, thiophen+arom.H), 8.79 (s, 2H,
triazol H); 13 C-NMR (DMSO-d6)δ 25.13 (thiophen-CH2), 52.90 (N-CH2), 69.88 (CH-OH); thiophen-C:[125.97
(CH), 127.00 (CH), 127.43 (CH), 134.42 (C)], ar-C: [127.32 (CH), 128.15 (CH), 129.00 (CH), 131.00 (C)],
142.08 (C=N triazol-3-one), 142.70 (triazol C=N), 149.47 (C=O triazol-3-one); Analysis (%Calculated/found)
for C17 H16 N6 SO2 C:55.42/55.48, H:4.38/4.42, N:22.81/22.82.
4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-(2-hydroxy-2-phenylethyl)-5-(thiophen-2-yl-
methyl)-2H-1,2,4-triazol-3(4H)-one (5b): Following the general procedure above, a white solid was ob-
tained. It was recrystallized from ethanol/water (1:1) (yield 60%) to afford the desired compound. Mp 195-196
554

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Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
◦ C. IR (KBr) (ν , cm−1) 3412 (OH), 1746 (triazol-3-one C=O), 1637 (C=N); 1 H-NMR (DMSO-d6)δ 1.65
(s, 3H, CH3), 1.91 (s, 3H, CH3), 3.81-3.95 (m, 2H, NCH2), 4.19 (s, 2H, thiophen-CH2), 4.95 (bs, 1H, CH-
OH), 5.80 (d, 1H, OH, J= 5 Hz), 6.98-7.06 (m, 2H, thiophen+arom.H), 7.27-7.47 (m, 6H, thiophen+arom.H);
13 C-NMR (DMSO-d6)δ (ppm) 8.21 (CH3), 8.45(CH3), 25.08 (thiophen-CH2), 52.17 (N-CH2), 70.04 (CH-
OH); thiophen-C:[126.14 (CH), 127.28 (CH), 127.42 (CH), 134.74 (C)], ar-C: [126.46 (CH), 128.15 (CH), 128.35
(CH), 131.15(C)], 141.94 (C=N triazol-3-one), 142.55 (triazol C=N), 150.19 (C=O triazol-3-one); Analysis
(Calculated/found) for C19 H20 N6 SO2 C:57.56/57.58, H:5.08/5.10, N:21.20/21.24.
4-(3,5-diethyl-4H-1,2,4-triazol-4-yl)-2-(2-hydroxy-2-phenylethyl)-5-(thiophen-2-yl-methyl)-
2H-1,2,4-triazol-3(4H)-one (5c): Following the general procedure above, a white solid was obtained. It was
recrystallized from ethanol/water (1:1) (yield 58%) to afford the desired compound. Mp 200-201 ◦ C. IR (KBr)
(ν , cm−1) 3445 (OH), 1747 (triazol-3-one C=O), 1687 (-C=N); 1 H-NMR (DMSO-d6)δ 1.26 (q, 6H, J=3.6 Hz,
CH3), 2.59 (t, 4H, J=3.6 Hz, CH2), 3.78-3.90 (m, 2H, NCH2), 4.14 (s, 2H, thiophen-CH2), 4.96 (bs, 1H, CH-
OH), 5.83 (d, 1H, OH, J= 5 Hz), 6.95-6.97 (m, 2H, thiophen+arom.H), 7.35-7.44 (m, 6H, thiophen+arom.H).
13 C-NMR (DMSO-d6)δ 13.68 (CH2), 15.82 (CH3), 25.10 (thiophen-CH2), 52.15 (N-CH2), 70.10 (CH-OH);
thiophen-C: [126.17 (CH), 127.31 (CH), 127.46 (CH), 134.79 (C)], ar-C: [126.49 (CH), 128.21 (CH), 128.39
(CH), 131.17 (C)], 141.98 (C=N triazol-3-one), 142.58 (triazol C=N), 150.21 (C=O triazol-3-one); Analysis
(%Calculated/found) for C21 H24 N6 SO2 C:59.41/59.43, H:5.70/5.72, N:19.80/19.83.
2-(2-hydroxy-2-p-tolylethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-
triazol-3(4H)-one (5d): Following the general procedure above, a white solid was obtained. It was recrys-
tallized from ethanol/water (1:1) (yield 78%) to afford the desired compound. Mp 197-198 ◦ C. IR (KBr) (ν ,
cm−1) 3360 (OH), 1748 (triazol-3-one C=O), 1595 (C=N); 1 H-NMR (DMSO-d6)δ 2.29 (s, 3H, CH3), 3.66-3.94
(m, 2H, NCH2), 4.15 (s, 2H, thiophen-CH2), 4.90 (bs, 1H, CH-OH), 5.60 (d, 1H, OH, J= 5.6 Hz), 6.65-6.83 (m,
3H, thiophen+arom.H), 7.14-7.29 (m, 2H, thiophen+arom.H), 7.42-7.44 (m, 2H, thiophen+arom.H), 8.75 (s,
2H, triazolH); 13 C-NMR (DMSO-d6)δ 20.62 (CH3), 25.08 (thiophen-CH2), 52.08 (N-CH2), 69.76 (CH-OH);
thiophen-C:[125.92 (CH), 126.91 (CH), 127.00 (CH), 134.40 (C)], ar-C: [128.71 (CH), 136.50 (CH), 138.79 (CH),
139.79(C)], 142.59 (C=N triazol-3-one), 142.69 (triazol C=N), 149.67 (C=O); Analysis (%Calculated/found)
for C18 H18 N6 SO2 C:56.53/56.55, H:4.74/4.73, N:21.97/21.98.
2-(2-hydroxy-2-(4-nitrophenyl)ethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-
1,2,4-triazol-3(4H)-one (5e): Following the general procedure above, a white solid was obtained. It was
recrystallized from ethanol/water (1:1) (yield 78%) to afford the desired compound. Mp 188-189 ◦ C. IR (KBr)
(ν , cm−1) 3350 (OH), 1738 (triazol-3-one C=O), 1600 (C=N); 1 H-NMR (DMSO-d6)δ 3.85-3.94 (m, 2H,
NCH2), 4.01 (s, 2H, thiophen-CH2), 5.05 (bs, 1H, CH-OH), 6.05 (d, 1H, OH, J= 5.4 Hz), 6.66-6.89 (s, 2H,
thiophen+arom.H), 7.41-7.64 (m, 3H, thiophen+arom.H), 8.20 (s, 2H, triazol H); 13 C-NMR (DMSO-d6) δ
25.00 (thiophen-CH2), 52.50 (N-CH2), 70.00 (CH-OH); thiophen-C:[125.37 (CH), 126.97 (CH), 127.39 (CH),
134.31 (C)], ar-C: [123.34 (CH), 129.63 (CH), 132.82 (CH), 133.79 (C)], 142.73 (C=N triazol-3-one), 146.82
(triazol C=N), 149.82 (C=O); Analysis (%Calculated/found) for C17 H15 N7 SO4 C:49.39/49.41, H:3.66/3.68,
N:23.72/23.73.
General method for the synthesis of ethyl 2-(4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-5-
oxo-3-(thiophen-2-yl-methyl)-4,5-dihydro-1,2,4-triazol-1-yl) acetates (6a-c): The corresponding com-
pound 3 (0.01 mol) was refluxed with an equivalent amount of natrium in absolute ethanol for 1 h. Then ethyl
555

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Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
bromoacetate (0.01 mol) was added and refluxed for an additional 5 h. The precipitate was filtered off, washed
with H2 O, and recrystallized from appropriate solvent to afford the desired compound.
Ethyl 2-(5-oxo-3-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-4,5-dihydro-1,2,4-triazol-1-
yl) acetate (6a): Following the general procedure above, a white solid was obtained. It was recrystallized
from ethyl acetate/petroleum ether (1:2) (yield 67.78%) to afford the desired compound. Mp 123-124 ◦ C. IR
(KBr) (ν , cm−1) 1763 (ester C=O), 1732 (triazol-3-one C=O), 1595 (C=N), 1220 (C-O); 1 H-NMR (DMSO-d6)
δ 1.65 (t, 6H,J = 7.0 Hz, OCH2 CH3 ,), 4.36 (s, 2H, thiophen-CH2), 4.62 (q, 4H, J = 7.0 Hz, OCH2 CH3 ,),
4.92 (s, 2H, NCH2), 7.25 (s, 2H, thiophen H), 7.38 (s, 1H, thiophen H), 8.38 (s, 2H, triazol H); 13 C-NMR
(DMSO-d6) δ (ppm) 14.10 (-OCH2 CH3), 26.42 (thiophen-CH2), 47.16 (-OCH2 CH3), 62.28 (NCH2), thio-
phen C:[126.35 (CH), 127.31 (CH), 127.73 (CH), 133.68 (C)], 143.29 (C=N triazol), 150.07 (C=N triazol-
3-one), 157.07 (C=O triazol-3-one), 167.01 (C=O ester); Analysis (%Calculated/found) for C13 H14 N6 SO3
C:46.70/46.71, H:4.22/4.23, N:25.14/25.15.
Ethyl 2-(4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-5-oxo-3-(thiophen-2-yl-methyl)-4,5-dihydro-
1,2,4-triazol-1-yl) acetate (6b): Following the general procedure above, a white solid was obtained. It
was recrystallized from ethyl acetate/petroleum ether (1:2) (yield 66.78%) to afford the desired compound.
Mp 155-156 ◦ C IR (KBr) (ν , cm−1) 1759 (ester C=O), 1735 (triazol-3-one C=O), 1597 (C=N), 1240 (C-
O); 1 H-NMR (DMSO-d6) δ 1.31 (t, 3H, J = 7.2 Hz, OCH2 CH3), 2.08 (s, 6H, triazol-CH3), 3.98 (s, 2H,
thiophen-CH2), 4.26 (q, 2H, J = 7.2 Hz, OCH2 CH3), 4.63 (s, 2H, NCH2), 6.57 (s, 2H, thiophenH), 6.91
(s, 1H, thiophenH); 13 C-NMR (DMSO-d6)δ 9.07 (CH3 triazole), 14.12 (OCH2 CH3), 26.57 (thiophen-CH2),
47.43(OCH2 CH3), 62.27 (NCH2), thiophen-C:[126.56 (CH),127.56 (CH), 127.74 (CH), 133.40(C)], 143.63
(C=N triazol), 150.63 (C=N triazol-3-one), 150.64 (C=O triazol-3-one), 166.84 (C=O ester); Analysis (%Cal-
culated/found) for C15 H18 N6 SO3 C:49.71/49.72, H:5.01/5.04, N:23.19/23.20.
Ethyl 2-(4-(3,5-diethyl-4H-1,2,4-triazol-4-yl)-5-oxo-3-(thiophen-2-yl-methyl)-4,5- dihydro-
1,2,4-triazol-1-yl) acetate (6c): Following the general procedure above, a white solid was obtained. It was
recrystallized from ethyl acetate/petroleum ether (1:2) (yield 72.78%) to afford the desired compound. Mp 143-
144 ◦ C. IR (KBr) (ν , cm−1) 1754 (ester C=O), 1734 (triazol-3-one C=O), 1595 (C=N), 1240 (C-O); 1 H-NMR
(DMSO-d6)δ 1.56-1.59 (m, 9H, -OCH2 CH3+ triazol-CH2 CH3), 2.56-2.60 (m, 4H, triazol-CH2), 4.27 (s, 2H,
thiophen-CH2), 4.58 (q, 4H, J = 7.0 Hz, OCH2 CH3), 4.94 (s, 2H, NCH2), 6.88 (s, 2H, thiophen H), 7.56 (s,
1H, thiophen H); 13 C-NMR (DMSO-d6)δ 10.56, 14.05 (OCH2 CH3 +triazolCH3), 15.22 (triazol-CH2), 26.47
(thiophen-CH2), 47.32 (OCH2 CH3), 62.18 (N-CH2), thiophen-C:[126.91 (CH), 126.60 (CH), 127.53 (CH),
133.32(C)], 143.56 (C=N triazol), 150.25 (C=N triazol-3-one), 154.77 (C=O triazol-3-one), 167.79 (C=O ester);
Analysis (%Calculated/found) for C17 H22 N6 SO3 C:52.29/52.30, H:5.68/5.67, N:21.52/21.53.
General method for the synthesis of 4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-2-(2- hydrox-
yethyl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3(4H)-ones7(a-c): A mixture of corresponding com-
pound 6 (0.01 mol) and LiAlH4 (0.04 mol) in absolute ethanol (50 mL) was refluxed for 4 h. After cooling
to room temperature ice water was added to it with vigorous stirring. The solid obtained was filtered off and
recrystallized from an appropriate solvent to afford the desired compound.
2-(2-hydroxyethyl)-5-(thiophen-2-yl-methyl)-4-(4H-1,2,4-triazol-4-yl)-2H-1,2,4-triazol-3(4H)-
one (7a): Following the general procedure above, a white solid was obtained. It was recrystallized from ethyl
acetate/petroleum ether (1:2) (yield 65.80%) to afford the desired compound. Mp 111-112 ◦ C. IR (KBr) (ν ,
556

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
cm−1) 3348 (OH), 1735 (triazol-3-one C=O), 1594 (C=N); 1 H-NMR (DMSO-d6)δ 3.35-3.42 (m, 2H, NCH2),
4.44 (s, 2H, thiophen-CH2), 3.79-3.85 (m, 2H, CH2 -OH), 4.78 (bs, 1H, OH), 6.60-6.72 (m, 2H, thiophen),
6.91 (s, 1H, thiophen), 8.30 (s, 2H, triazol H); 13 C-NMR (DMSO-d6)δ 25.90 (thiophen-CH2), 42.75 (N-CH2),
56.80 (CH2 -OH); thiophen-C:[126.87 (CH), 126.65 (CH), 127.55 (CH), 133.38 (C)], 144.47 (triazol C=N),
155.08 (C=N triazol-3-one), 162.18 (C=O triazol-3-one); Analysis (%Calculated/found) for C11 H12 N6 SO2
C:45.20/45.23, H:4.14/4.12, N:28.75/28.75.
4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-2-(2-ethoxy-2-hydroxyethyl)-5-(thiophen-2-yl-methyl)-
2H-1,2,4-triazol-3(4H)-one (7b): Following the general procedure above, a white solid was obtained. It was
recrystallized from ethyl acetate/petroleum ether (1:2) (yield 63.06%) to afford the desired compound. Mp
135-136 ◦ C. IR (KBr) (ν , cm−1) 3346 (OH), 1738 (triazol-3-one C=O), 1595 (C=N); 1 H-NMR (DMSO-d6)δ
1.55-1.64 (m, 6H, triazol-CH2 CH3), 2.57-2.63 (m, 4H, triazol-CH2), 3.35-3.42 (m, 2H, NCH2), 4.43 (s, 2H,
thiophen-CH2), 3.79-3.88 (m, 2H, CH2 -OH), 4.78 (bs, OH), 6.60-6.76 (m, 2H, thiophen), 6.96 (s, 1H, thio-
phen); 13 C-NMR (DMSO-d6)δ 25.87 (thiophen-CH2), 42.75 (N-CH2), 56.88 (CH2 -OH); thiophen-C: [126.58
(CH),127.66 (CH), 127.78 (CH), 133.40(C)], 144.49 (triazol C=N), 155.07 (C=N triazol-3-one), 162.21 (C=O
triazol-3-one); Analysis (%Calculated/found) for C13 H16 N6 SO2 C:48.74/48.74, H:5.03/5.05, N:26.23/26.24.
4-(3,5-diethyl-4H-1,2,4-triazol-4-yl)-2-(2-ethoxy-2-hydroxyethyl)-5-(thiophen-2-yl- methyl)-
2H-1,2,4-triazol-3(4H)-one (7c): Following the general procedure above, a white solid was obtained. It was
recrystallized from ethyl acetate/petroleum ether (1:2) (yield 62.58%) to afford the desired compound. Mp
128-129 ◦ C. IR (KBr) (ν , cm−1) 3345 (OH), 1737 (triazol-3-one C=O), 1595 (C=N); 1 H-NMR (DMSO-d6)δ
2.10 (s, 6H, triazol-CH3), 3.35-3.42 (m, NCH2), 4.43 (s, thiophen-CH2), 3.79-3.85 (m, 2H, CH2 -OH), 4.81
(bs, OH), 6.60-6.72 (m, 2H, thiophen), 6.91(s, 1H, thiophen); 13 C-NMR (DMSO-d6) δ 25.86 (thiophen-CH2),
42.74 (N-CH2), 56.86 (CH2 -OH); thiophen-C: [126.95 (CH), 126.67 (CH), 127.55 (CH), 133.36 (C)], 144.48
(triazol C=N), 155.07 (C=N triazol-3-one), 162.17 (C=O triazol-3-one); Analysis (%Calculated/found) for
C15 H20 N6 SO2 C:51.71/51.70, H:5.79/5.78, N:24.12/24.14.
Microbiology: All test microorganisms except for Penicillum spp. and Aspergillus spp. were obtained
from the Refik Saydam Hıfzıssıhha Institute (Ankara, Turkey) and were as follows: Escherichia coli ATCC
35218, Pseudomonas aeruginosa ATCC 10145, Yersinia pseudotuberculosis ATCC 911, Klebsiella pneumoniae
ATCC 13883, Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, Bacillus subtilis ATCC
6633, Candida albicans ATCC 60193, Candida tropicalis ATCC 13803, and Candida glabrata ATCC 66032.
Penicillum spp. and Aspergillus spp. were isolated from soil. The chemicals were dissolved in ethanol to
prepare chemical stock solutions of 1 mg/mL.
Agar well diffusion method: A simple susceptibility screening test using the agar-well diffusion
method24 as adapted earlier25 was used. Microorganisms were suspended in Brain Heart Infusion (BHI)
(Difco, Detroit, MI, USA) broth and diluted approximately 106 colony forming unit (cfu) per mL. They were
“flood-inoculated” onto the surface of BHI agar and Sabouraud Dextrose agar (SDA) (Difco) and then dried.
For C. albicans, C. tropicalis, C. glabrata, Penicillum spp., and Aspergillus spp., SDA was used. Five-millimeter
diameter wells were cut from the agar by using a sterile cork-borer, and filled with 500 μg/50 μL of the chemical
substances. The plates were incubated for 18 h at 35 ◦ C. Antimicrobial activity was evaluated by measuring
the inhibition zones against the test organisms. The tests were carried out in duplicate. Ceftazidime (10 μg)
557

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
and fluconazole (5 μg) were the standard drugs. Ethanol was used as the solved control. The data are not
shown.
NH2
O
N
S
C
NNH
OC2H5
+
R
R
OC2H5
1
N
N
2
S
O
C
N
N
S
Ar
C
N
N
O
O
N
Ar
NH
O
R
CH2
Br
O
OCH2CH3
S
Br
C
N
N
O
CH2
N
N
N
R
OCH2CH3
R
R
O
N
N
N
N
N
R
R
3 (a-c)
(a-e)
4
N
6
N
(a-c)
NaBH4
LiAlH4
OH
S
C
N
OH
H
CH2
Ar
N
S
C
N
N
N
N
N
CH2
H
H
O
R
R
O
R
N
N
N
R
(a-e)
N
N
5
7 (a-c)
3,4,5,6,7
a
R
Ar
-H
-CH3
-C2H5
-H
b
c
CH3
NO2
d
e
-H
Scheme. Synthetic pathway for the preparation of target compounds (3, 4, 5, 6, and 7).
558

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
Mycelial growth inhibition test: Mycelial growth inhibition was tested by the agar diffusion met-
hod.26−28 Five-millimeter diameter mycelial agar disks were placed on PDA plates containing test chemicals.
The final concentration in the medium was adjusted to 1 mg/mL. The plates were incubated at 25 ◦ C for 3
days, and diameters of the mycelium colonies were then measured to examine the effects of the chemicals on
fungal growth. The tests were carried out in triplicate. The results are shown in Table 1.
Table 1.
Microorganisms (Colony diameters, mm)
Chemicals no
Penicillum spp.
Aspergillus spp.
3a
20
20
22
18
18
8
15
13
11
12
12
8
3b
3c
4a
4b
6a
6b
20
12
17
20
20
8
6c
8
Fluconazole
With ethanol
Untreated control
9
17
17
Crystallographic structure determination of compound 5d
The crystal structure of compound 5d (C18 H18 N6 O2 S) with dimensions of 0.29 mm × 0.16 mm × 0.12 mm
was determined by single crystal X-ray diffraction. X-ray data for compound 5d were collected with a Bruker
˚
Smart Area-CCD diffractometer by w-scan mode using Cu-Kα radiation(λ = 1.54178 A). For compound 5d cell
refinement: Bruker SMART 29 ; data reduction: Bruker SMART 29 ; program used to solve structure: SHELXS-
97 30 ; program used to refine structure: SHELXL-97 30 ; molecular graphics: ORTEP-3 for Windows 31 ; software
used to prepare material for publication: WinGX 32 . The geometrical parameters are given in Table 2.
Crystal data for C18 H18 N6 O2 S: M r = 382.44, Orthorhombic, space group Pbca, T =293(2)K, μ(a=
3
˚
˚
11.2122 (5), b = 15.2298 (6), c = 22.4200 (9) (A), V=3828.4(3) (A ), Z = 8. 17,746 measured reflections, 3424
were unique (Rint = 0.066), R1 , GOF = 1.05, largest peak and hole in final Fourier difference map were 0.38
−3
˚
and –0.29 e. A
.
Supplementary material
The compound 5d consists of two triazole, one benzene and one thiophene ring. The thiophene ring of compound
5d is disordered over 2 positions.The length of N1-N2 and the length of N42-N43 bonds in the triazole rings
˚
˚
are [1.405 (4) A] and [1.371 (4) A], respectively. Because of the substituents connected to N1 atom, the N1-N2
˚
bond is longer than N42-N43 bond and these lengths are compatible to the values in the literature [1.404 (4) A
559

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
Table 2. Crystallographic data for compound 5d.
ev10552s
Crystal data
Chemical formula
Mr
C18H18N6O2S
382.44
Cell setting, space group
Temperature (K)
Orthorhombic, Pbca
293 (2)
˚
a, b, c (A)
11.2122 (5), 15.2298 (6), 22.4200 (9)
3
˚
V (A )
3828.4 (3)
Z
8
Dx (Mg m−3
)
1.327
Radiation type
Cu K
Crystal form, colour
Crystal size (mm)
Prism, colourless
0.29 × 0.16 × 0.12
Data collection
Diffractometer
Bruker CCD 6000 area detector
Data collection method
Absorption correction
No. of measured, independent
and observed reflections
phi and scans
None
17,746, 3424, 2004
Criterion for observed reflections I > 2(I)
Rint
0.066
Refinement
Refinement on
No. of relections
No. of parameters
H-atom treatment
Weighting scheme
F 2
3424 reflections
301
Constrained to parent site
Calculated w = 1/[(Fo2) + (0.1756P )2]
where P = (Fo2 + 2Fc2)/3
33−34
˚
˚
in C18 H14 Cl2 N4 O2 ; 1.378 (3) A in C18 H12 ClN5 ]. The C5= O51 [1.202 (4) A ]
bond length has nearly
the same value with the C= O [1.209 (2) A in C12 H11 ClN4 O2 ]35 double bond length in the triazole rings.
The dihedral angle between the triazole rings is 87,88 (12)o and this points, that the triazole rings are nearly
perpendicular to each other.
˚
560

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
The crystal structure is stabilized by C-H. . .N, O-H. . .N and C-H. . .O intra- and intermolecular
hydrogen bonds.
Results and discussion
In the first part of this study, the synthesis of compounds 3a-c was performed from condensation of compound
1 with compound 2 in reasonably good yields (Scheme).
Analytical and spectroscopic data of compounds 3a-c confirmed the success of the cyclization reaction.
The IR data indicated the formation of compounds 3a-c by the disappearance of COCH2 (esteric) band of
compound 1 at 1247 cm−1 , and the new band at 1738- 1744 cm−1 belonging to triazole C=O.
In the 1 H-NMR spectra of compounds 3a-c, the existence of 3 was revealed by the disappearance the
chemical shifts belonging to esteric methylenes (4.18-4.24 ppm) in the precursor 1 after the cyclization and the
appearance of a new peak at 11.68-12.20 ppm integrating for one proton (exchangeable with D2 O) belonging
to N-H. 13 C-NMR spectra data were also in agreement with the proposed structures.
4-(3,5-disubstitue-4H-1,2,4-triazol-4-yl)-2-(2-oxo-2-arylethyl)-5-(thiophen-2-yl-methyl)-2H-1,2,4-triazol-3
(4H)-ones 4a-e were obtained from the reaction compounds 3a-c with bromo acetophenon derivatives in
reasonable good yields (Scheme).
The IR spectra of compounds 4a-e showed 2 sharp absorption bands, one of which, appearing at 1715-
1748 cm−1 , was attributed to the carbonyl function of 1,2,4-triazol-3-one ring and the other, observed 1658-
1691 cm−1 , at was assigned to C=O stretching frequency corresponding to ketone carbonyl. The NH signal
disappeared in the 1 H-NMR and IR spectra of compounds 4a-e.
In the 1 H NMR spectra of compounds 4a-e, a new additional signal belonging to methylene protons
of acetophenon was recorded at 4.95-5.51 ppm integrating for one proton. The signals belonging to carbonyl
carbon of ketone group were seen at 190.80-191.75 ppm in the 13 C-NMR spectra of compounds 4.
The synthesis of compounds 5a-e was performed by the reaction of compounds 4 with NaBH4 at the
reflux temperature in the presence of absolute ethanol (Scheme).
In the IR spectra of compounds 5, only one carbonyl function (C=O) belonging to 1,2,4-triazol-3-one
ring was observed at 1738-1748 cm−1 . While a C=O carbon signal belonging to acetophenon derivatives of
561

¨
Synthesis and characterization of novel triazol compounds..., Y. UNVER, et al.,
compounds 4 was recorded, these signals disappeared and new signals at 4.95-5.05 and 5.60-6.05 ppm belonging
to -CH and -OH protons of -CH-OH group of compounds 5 were seen. The signals of reduced (-CH-OH) carbon
atom of compounds 5 were observed at 69.88-70.04 ppm in the 13 C-NMR spectra respectively. New compounds
6 were obtained synthesized via the nucleophilic attack of N-1 on 5-oxo-[1,2,4] triazol ring to bromine-bearing
C atom of ethyl bromoacetate (Scheme).
In the 1 H-NMR spectra of compounds 6a-c additional signals derived from the ester group were observed
at 1.31-1.56 ppm (OCH2 CH3) and 4.26-4.62 ppm (OCH2 CH3) integrating for 2 protons and 3 protons,
respectively. In the 13 C-NMR spectra of these compounds, the signals belonging to the same groups were
recorded at 14.05-14.12 and 47.16-47.43 ppm, respectively.
The synthesis of compounds 7a-c was performed by the reaction of compounds 6 with LiAlH4 at the
reflux temperature in the presence of absolute ethanol (Scheme).
In the IR spectra of compounds 7, only one carbonyl function (C=O) belonging to 1,2,4-triazol-3-one
ring was observed at 1735-1738 cm−1 . While a C=O carbon signal belonging to the ester group of compounds
6 was recorded, these signals disappeared and new signals at 3.79-3.85 and 4.78-4.81 ppm belonging to CH2
and OH protons of the CH2 -OH group of compounds 7 were seen. The signals of reduced (-CH2 -OH) carbon
atom of compounds 7 were observed at 56.80-56.88 ppm in the 13 C-NMR spectra.
The chemical compositions of synthesized compounds were confirmed by IR, 1 H-NMR, 13 C-NMR, and
elemental analyses. All spectral data were presented in experimental section. In addition, only the 5d crystal
was suitable for single-crystal X-ray structure determination and a summary of crystallographic data and details
of the structure refinement are listed in Table 2. The X-ray crystal structure data of compound 5d verified the
structure of the compound besides IR, 1 H-NMR, 13 C-NMR, and elemental analyses.
The chemicals were found to be inactive against gram-positive and gram-negative bacteria and the yeast-
like fungi. However, the test chemicals showed antifungal activity against Penicillum spp. and Aspergillus spp.
Chemicals 4 and 6 showed very potent in vitro antifungal activity against Penicillum spp. (Table 1). Chemicals
4, 5, and 6 also showed antifungal activity against Aspergillus spp.
Acknowledgements
This work was supported by the Research Fund of Karadeniz Technical University. The authors thank Dr.
S¸engu¨l A. Karaog˘lu (Department of Chemistry, Rize University) for microbial studies.
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