Synthesis, crystal structure, and antioxidant properties of novel 1,2,4-triazol-5-ones containing 3,4-dimethoxyphenyl and 3,4-dihydroxyphenyl moiety

Article abstract of DOI:10.3906/kim-1006-707

A series of new 4-(3,4-dimethoxyphenethyl)-5-akyl/aryl-2H-1,2,4-triazol- 3(4H)-ones (3a-g) was obtained by the reaction of ethyl 2-(ethoxy) (alkylidene/arylidene) hydrazinecarboxylate (1) and 2-(3,4-dimethoxyphenyl) ethanamine (2). Compounds 4a-f and 5 we

Full text of DOI:10.3906/kim-1006-707

Turk J Chem
35 (2011) , 265 – 277.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1006-707
Synthesis, crystal structure, and antioxidant properties
of novel 1,2,4-triazol-5-ones containing
3,4-dimethoxyphenyl and 3,4-dihydroxyphenyl moiety
1,∗
1
1
1
¨
¨
¨
Yasemin UNVER , Sevgi MEYDANAL , Kemal SANCAK , Dilek UNLUER ,
2
1
¨
¨
Re¸sat USTABAS¸ , Esra DUGDU
1Department of Chemistry, Karadeniz Technical University, 61080 Trabzon-TURKEY
e-mail: unver.yasemin@hotmail.com
2Department of Middle Education, Educational Faculty, Ondokuz Mayıs University,
55200, Atakum, Samsun-TURKEY
Received 22.06.2010
A series of new 4-(3,4-dimethoxyphenethyl)-5-akyl/aryl-2H-1,2,4-triazol-3(4H)-ones (3a-g) was obtained
by the reaction of ethyl 2-(ethoxy)(alkylidene/arylidene)hydrazinecarboxylate (1) and 2-(3,4-dimethoxyphen-
yl)ethanamine (2). Compounds 4a-f and 5 were synthesized from the reaction of corresponding compounds
3a-f and 3g with BBr3 , respectively. With elemental analysis, IR, 1 H-NMR, and 13 C-NMR spectral data,
14 newly synthesized compounds were characterized. The structure of compound 3a was inferred through
IR, 1 H- and 13 C-NMR, elemental analysis, and X-ray spectral techniques. In addition, the newly synthe-
sized chemicals were screened for their antioxidant properties. Among the chemicals tested, 4a, 4c, 4d, 4f,
and 5 exhibited the highest degree of antioxidant activity.
Key Words: Synthesis, 1,2,4-triazole-3-one, antioxidant activity, X-ray
Introduction
The synthesis of 1,2,4-triazole derivatives has been attracting widespread attention due to their diverse biolog-
ical activities, such as antimicrobial, antiinflammatory, anti-TB, and antiproliferative and analgesic antitumor
activities.1−8 There are some antimicrobial drugs containing a triazole moiety. For instance, fluconazole and
itraconazole are used in medical therapy.9−10 In addition, vorozole, letrozole, fadrozole, and anastrozole are
∗Corresponding author
265

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Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
nonsteroidal drugs used for the treatment of estrogen-dependent breast cancer.11 It is known that 1,2,4-triazole
moieties strongly interact with the heme iron and aromatic substituents of the active site of aromatase.12 2,4-
Dihydro-3H -1,2,4-triazol-3-one derivatives (1) have been found to be the basic skeleton of several biologically
active compounds, such as angiotensin II antagonists, anticonvulsant agents, and the phytotoxic natural prod-
ucts (3) isolated from Actinomadura, and 3-thione derivatives (2) have also been reported to have antidepressant
activity (Figure 1).13
R2
X
R3
N
N
NH
N
N
N
HO
O
R1
OH
HO
1:X=O
2:X=S
3
Figure 1.
Antioxidants are widely studied for their capacity to protect organisms and cells from damage induced
by oxidative stress during metabolism. Active components preventing or reducing the impact of oxidative
stress on cells is a recent research field. Exogenous chemicals in food systems and endogenous metabolic
processes in the human body produce highly reactive free radicals, particularly oxygen-derived free radicals.
Because they are capable of oxidizing biomolecules, they cause cell death, thus leading to tissue damage. Free
radical oxidative processes also play a significant pathological role in causing human diseases. Many disease
manifestations, such as cancer, emphysema, cirrhosis, atherosclerosis, and arthritis, have been correlated with
oxidative tissue damage. In addition, excessive generation of reactive oxygen species (ROS) induced by various
stimuli leads to a variety of pathophysiological abnormalities such as inflammation, diabetes, genotoxicity, and
cancer. Antioxidants are highly important for the potential treatment of these kinds of diseases, for they
scavenge and prevent the formation of free radicals, and so in recent years there has been a growing interest in
finding new antioxidant compounds.14−15
Hydroxytyrosol, or 2-(3,4-dihydroxyphenyl)ethanol, is a simple phenol extracted from olive oil and wine,
which is now used in integrators and cosmetics. Studies on the consumption of antioxidants in foods and in
vitro studies on cells have shown that hydroxytyrosol might contribute to the prevention of human diseases.
Interestingly, at high molecular concentrations, hydroxytyrosol inhibits or delays the rate of growth of a range
of bacteria and fungi. Thus, this simple phenol, like other molecules characterized by a catechol ring, shows
both antioxidant and prooxidant activities.16
In view of these facts, the aim of the present study was to synthesize the compounds containing catechol
and triazole rings that have radical scavenging properties and interact with the stable free radical DPPH.
Experimental section
All chemicals were obtained from Fluka Chemie AG (Buchs, Switzerland). 1 H-NMR and 13 C-NMR spectra were
recorded on a Varian XL-200 NMR spectrophotometer in DMSO-d6 . IR spectra were recorded on a PerkinElmer
266

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Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
Spectrum One FT-IR spectrometer in KBr pellets. The MS spectra were measured with a Micromass Quattro
LC/ULTIMA LC-MS/MS spectrometer with EtOH as a solvent. The experiment was performed in the positive
ion mode. Elemental analyses were performed on a Hewlett-Packard 185 CHN analyzer. Melting points were
measured on an electrothermal apparatus and are uncorrected. Compound (1) was prepared as described by
Ikizler and Sancak.17
General procedure for the preparation of 4-(3,4-dimethoxyphenethyl)-5-alkyl/aryl-
2H-1,2,4-triazol-3(4H)-ones (3a-g):
Ethyl 2-(ethoxy)(alkylidene/arylidene)hydrazinecarboxylate (1) (10 mmol), together with 2-(3,4-dimethoxy
phenyl)ethanamine (2) (1.25 g, 10 mmol), was heated without solvent in a sealed tube for 2 h at 160-180 ◦ C.
The mixture was then cooled to room temperature and a solid formed. The crude product was recrystallized
using acetone/petroleum ether (1:2) to afford the desired compound.
4-(3,4-dimethoxyphenethyl)-5-methyl-2H-1,2,4-triazol-3(4H)-one (3a): Yield: 1.95 g (74.14%);
colorless crystals, mp 108 ◦ C. IR (KBr, ν , cm−1): 3314 (NH), 1714 (C=O), 1590 (C=N), 1262 (C-O-C);
1 H-NMR (DMSO-d6 , δ, ppm): 1.76 (s, 3H, CH3), 2.92 (t, 2H, Ar–CH2), 3.83-3.86 (m, 6H, OCH3), 3.78 (t,
2H, N-CH2), 6.60-6.69 (m, 2H, arom. H), 6.78-6.82 (m, 1H, arom. H), 10.28 (s, 1H, NH); 13 C-NMR (DMSO-
d6 , δ, ppm): 11.48 (CH3), 34.49 (Ar-CH2), 43.29 (CH2), 55.86 and 55.89 (OCH3), arom. C [111.28 (CH),
111.88 (CH), 120.90 (CH), 130.18 (C), 147.91(C), 149.01(C)], 145.28 (C=N), 155.79(C=O). Anal. Calc. for
C13 H17 N3 O3 M+ : (264.06) C, 59.30; H, 6.51; N, 15.90. Found: C, 59.36; H, 6.48; N, 15.97%.
4-(3,4-dimethoxyphenethyl)-5-ethyl-2H-1,2,4-triazol-3(4H)-one (3b): Yield: 2.16 g (78.22%),
colorless crystals, mp 120 ◦ C. IR (KBr, ν , cm−1): 3321 (NH), 1704 (C=O), 1584 (C=N), 1259 (C-O-C);
1 H-NMR (DMSO-d6 , δ, ppm): 1.02 (t, 3H, CH3), 2.40 (q, 2H, CH2), 2.80 (t, 2H, Ar–CH2), 3.74-3.79 (s, 6H,
OCH3), 3.65 (t, 2H, N-CH2), 6.66-6.70 (m, 2H, arom. H), 6.85-6.87 (m, 1H, arom. H), 11.38 (s, 1H, NH);
13 C-NMR (DMSO-d6 , δ, ppm): 9.40 (CH3), 18.01 (CH2), 33.58 (Ar-CH2), 41.65 (N-CH2), 55.31 and 55.16
(OCH3), arom. C [111.59 (CH), 112.29 (CH), 120.60 (CH), 130.29 (C), 148.17 (C), 148.47(C)], 147.33 (C=N),
154.92 (C=O). Anal. Calc. for C14 H19 N3 O3 M+ : (277.92) C, 60.63; H, 6.91; N, 15.54. Found: C, 60.69; H,
6.96; N, 15.62%.
4-(3,4-dimethoxyphenethyl)-5-propyl-2H-1,2,4-triazol-3(4H)-one (3c): Yield: 2.23 g (76.70%),
colorless crystals, mp 124 ◦ C. IR (KBr, ν , cm−1): 3329 (NH), 1698 (C=O), 1593 (C=N), 1260 (C-O-C);
1 H-NMR (DMSO-d6 , δ, ppm): 0.88 (t, 3H, CH3), 1.50-1.62 (m, 2H, CH3 -CH2 -CH2), 2.04 (q, 2H, CH3 -
CH2 -CH2), 2.94 (t, 2H, Ar–CH2), 3.77-3.84 (s, 6H, OCH3), 3.84 (t, 2H, N-CH2), 6.62-6.66 (m, 2H, arom.
H), 6.77-6.81 (m, 1H, arom. H), 10.87 (s, 1H, NH); 13 C-NMR (DMSO-d6 , δ, ppm): 13.61 (CH3), 19.00
(CH3− CH2), 27.22 (CH3− CH2− CH2), 34.47 (Ar-CH2), 43.03 (N-CH2), 55.86 and 55.89 (OCH3), arom. C
[111.43 (CH), 112.03 (CH), 120.83 (CH), 130.28 (C), 148.07 (C), 149.06 (C)], 147.94 (C=N), 155.96 (C=O).
Anal. Calc. for C15 H21 N3 O3 M+ : (291.98) C, 61.84; H, 7.27; N, 14.42. Found: C, 61.80; H, 7.34; N, 14.48%.
4-(3,4-dimethoxyphenethyl)-5-phenyl-2H-1,2,4-triazol-3(4H)-one (3d): Yield: 2.27 g (70.05%),
colorless crystals, mp 148 ˚C. IR (KBr, ν , cm−1): 3434 (NH), 1710 (C=O), 1592 (C=N), 1265 (C-O-C); 1 H-
NMR (DMSO-d6 , δ, ppm): 2.68 (t, 2H, Ar–CH2), 3.59-3.69 (s, 6H, OCH3), 3.91 (t, 2H, N-CH2), 6.39-6.44
(m, 2H, arom. H), 6.72-6.76 (m, 1H, arom. H), 7.34-7.58 (m, 5H, arom. H), 11.88 (s, 1H, NH); 13 C-NMR
267

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Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
(DMSO-d6 , δ, ppm): 33.16 (Ar-CH2), 42.38 (N-CH2), 54.93 and 55.29 (OCH3), arom. C [111.53 (CH), 111.81
(CH), 120.32 (CH), 127.30 (C), 145.30 (C), 148.40 (C), phenyl H 127.68 (CH), 128.52 (CH), 129.66 (CH), 129.78
(C)], 146.63 (C=N), 154.95 (C=O). Anal. Calc. for C18 H19 N3 O3 M+1 : (326.20) C, 66.45; H, 5.89; N, 12.91.
Found: C, 66.40; H, 5.94; N, 12.95%.
4-(3,4-dimethoxyphenethyl)-5-p-tolyl-2H-1,2,4-triazol-3(4H)-one (3e): Yield: 2.65 g (68.91%),
colorless crystals, mp 135 ◦ C. IR (KBr, ν , cm−1): 3427 (NH), 1681 (C=O), 1618 (C=N), 1277 (C-O-C); 1 H-
NMR (DMSO-d6 , δ, ppm): 2.43 (s, 3H, CH3), 2.86 (t, 2H, Ar–CH2), 3.86 and 3.91 (s, 6H, OCH3), 3.60-3.66
(t, 2H, N-CH2), 6.71-7.75 (m, 7H, arom. H), 10.17 (s, 1H, NH); 13 C-NMR (DMSO-d6 , δ, ppm): 21.41 (CH3),
36.10 (Ar-CH2), 41.18 (N-CH2), 55.74 and 55.87 (OCH3), arom. C [111.26 (CH), 111.99 (CH), 120.73 (CH),
131.84 (C), 148.17(C), 148.90 (C), phenyl C [127.34 (C), 127.63 (CH), 129.30 (CH), 140.24 (C)], 147.52 (C=N),
155.80 (C=O). Anal. Calc. for C19 H21 N3 O3 M+ : (339.39) C, 67.24; H, 6.24; N, 12.38. Found: C, 67.29; H,
6.18; N, 12.34%.
4-(3,4-dimethoxyphenethyl)-5(thiophen-2ylmethyl)-2H-1,2,4-triazol-3(4H)-one (3f): Yield:
2.25 g (65.21%), colorless crystals, mp 138 ◦ C. IR (KBr, ν , cm−1): 3329 (NH), 1715 (C=O), 1593 (C=N), 1262
(C-O-C); 1 H-NMR (DMSO-d6 , δ, ppm): 2.58 (t, 2H, Ar–CH2), 3.85 (s, 2H, thiophene CH2), 3.73 and 3.78
(s, 6H, OCH3), 3.65 (t, 2H, N-CH2), 6.55-7.46 (m, 6H, arom. H), 11.59 (s, 1H, NH); 13 C-NMR (DMSO-d6 ,
δ, ppm): 26.75 (thiophene CH2), 34.30 (Ar-CH2), 42.87 (N-CH2), 56.03 and 56.12 (OCH3), arom. C [111.49
(CH), 113.03 (CH), 121.34 (CH), 130.88 (C), 148.18 (C), 149.32 (C), thiophene C [126.34 (C), 127.30 (CH),
127.76 (CH), 138.18 (C)], 146.49 (C=N), 155.60 (C=O). Anal. Calc. for C17 H19 N3 O3 S M+ : (346.01) C,
59.11; H, 5.54; N, 12.17. Found: C, 59.17; H, 5.59; N, 12.11%.
5-(3,4-dimethoxybenzyl)-4(3,4-dimethoxyphenethyl)-2H-1,2,4-triazol-3(4H)-one (3g): Yield:
2.44 g (61.06%), colorless crystals, mp 130 ◦ C. IR (KBr, ν , cm−1): 3336 (NH), 1710 (C=O), 1592 (C=N),
1265 (C-O-C); 1 H-NMR (DMSO-d6 , δ, ppm): 2.52 (t, 2H, Ar–CH2), 3.37 (s, 2H, 3,4-dimethoxy-CH2), 3.71
(bs, 6H, OCH3), 3.58 (t, 2H, N-CH2), 6.59-7.92 (m, 6H, arom. H), 11.51 (s, 1H, NH); 13 C-NMR (DMSO-d6 ,
δ, ppm): 30.84 (3,4-dimethoxy-CH2), 33.46 (Ar-CH2), 42.00 (N-CH2), 55.17, 55.22, 55.32 (OCH3), arom. C
[111.69 (CH), 111.71 (CH), 112.21 (CH), 120.42 (CH), 120.53 (CH), 127.35 (C), 130.14 (C), 147.39 (C), 148.49
(C), 148.62 (C)], 146.44 (C=N), 154.94 (C=O). Anal. Calc. for C21 H25 N3 O5 M+ : (400.14) C, 63.14; H, 6.31;
N, 10.52. Found: C, 63.19; H, 6.26; N, 10.59%.
General procedure for the preparation of 4-(3,4-dihydroxyphenethyl)-5-alkyl/aryl-2H-1,2,4-
triazol-3(4H)-ones (4a-f):
A solution of 4-(3,4-dimethoxyphenethyl)-5-akyl/aryl-2H-1,2,4-triazol-3(4H)-ones (3a-f) (10 mmol) in
chloroform (100 mL) was added to a solution of boron tribromide (10 mmol) in chloroform (200 mL) at 0 ◦ C.
The reaction mixture was then stirred under a nitrogen atmosphere at ambient temperature for 1 h, and was
poured into ice containing sufficient 50% sodium hydroxide to attain a pH of 10. The addition of concentrated
sulfuric acid provided a precipitate that was extracted into ether. The combined organic extract was washed
with water and brine, and then dried and concentrated in a vacuum to obtain compounds 4a-f. The crude
product was recrystallized using ethyl acetate and petroleum ether (1:4) to afford the desired compound (Scheme
1).
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Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
OCH3
OCH3
O
C
NNH
OC2H5
(Ar)R
+
3,4 R/Ar
H2N
OC2H5
2
CH3
a
1
160-1800C
oil bath
CH2CH3
CH2CH2CH3
b
c
N
NH
d
N
NH
O
(Ar)R
O
(Ar)R
CH3
e
f
N
N
BBr3
S
OCH3
g
OH
OCH3
OCH3
OH
4(a-f)
OCH3
3(a-g)
Scheme 1. Synthesis of compounds 3 and 4.
4-(3,4-dihydroxyphenethyl)-5-methyl-2H-1,2,4-triazol-3(4H)-one (4a): Yield: 1.32 g (56.32%),
colorless crystals, mp 223 ◦ C. IR (KBr, ν , cm−1): 3217 (OH), 1694 (C=O), 1587 (C=N); 1 H-NMR (DMSO-
d6 , δ, ppm): 1.78 (s, 3H, CH3), 2.64 (t, 2H, Ar-CH2), 3.60 (t, 2H, N-CH2), 6.33-6.52 (m, 2H, arom. H),
6.60-6.64 (m, 1H, arom. H), 8.75 (bs, 2H, OH), 11.31 (s, 1H, NH); 13 C-NMR (DMSO-d6δ, ppm): 11.05 (CH3),
33.64 (Ar-CH2), 42.19 (N-CH2), arom. C [115.51 (CH), 116.15 (CH), 119.45 (CH), 128.85 (C), 144.49 (C),
145.11 (C)], 143.78 (C=N), 154.80 (C=O). Anal. Calc. for C11 H13 N3 O3 M+ : (236.00) C, 56.16; H, 5.57; N,
17.86. Found: C, 56.21; H, 5.51; N, 17.81%.
4-(3,4-dihydroxyphenethyl)-5-ethyl-2H-1,2,4-triazol-3(4H)-one (4b): Yield: 1.29 g (55.76%),
colorless crystals, mp 134 ◦ C. IR (KBr, ν , cm−1): 3222 (OH), 1698 (C=O), 1593 (C=N); 1 H-NMR (DMSO-
d6 , δ, ppm): 1.36 (s, 3H, CH3), 2.13 (s, 2H, CH2), 2.66 (t, 2H, Ar-CH2), 3.68 (t, 2H, N-CH2), 6.35-6.58 (m,
2H, arom. H), 6.65-6.69 (m, 1H, arom. H), 8.78 (bs, 2H, OH), 11.36 (s, 1H, NH); 13 C-NMR (DMSO-d6 , δ,
ppm): 16.25 (CH3), 26.33 (CH2), 33.71 (Ar-CH2), 42.22 (N-CH2), arom. C [115.53 (CH), 116.18 (CH), 119.49
(CH), 128.88 (C), 144.55 (C), 145.16 (C)], 143.80 (C=N), 154.86 (C=O). Anal. Calc. for C12 H15 N3 O3 M+ :
(249.27) C, 57.82; H, 6.07; N, 16.86. Found: C, 57.88; H, 6.12; N, 16.81%.
4-(3,4-dihydroxyphenethyl)-5-propyl-2H-1,2,4-triazol-3(4H)-one (4c): Yield: 1.29 g (46.0%),
colorless crystals, mp 175 ◦ C. IR (KBr, ν , cm−1): 3227 (OH), 1710 (C=O), 1605 (C=N); 1 H-NMR (DMSO-
d6 , δ, ppm): 0.84 (t, 3H, CH3), 1.41-1.52 (m, 2H, CH3 -CH2), 2.08 (t, 2H, CH2 -CH2), 2.66 (t, 2H, Ar-CH2),
3.63 (t, 2H, N-CH2), 6.35-6.58 (m, 2H, arom. H), 6.53-6.64 (m, 1H, arom. H), 8.67 (bs, 2H, OH), 11.33 (s,
1H, NH); 13 C-NMR (DMSO-d6 , δ, ppm): 13.39 (CH3), 18.27 (CH3 CH2), 26.33 (CH2 CH2), 33.56 (Ar-CH2),
42.05 (N-CH2), arom. C [115.42 (CH), 116.04 (CH), 119.35 (CH), 128.77 (C), 143.76 (C), 147.18(C)], 143.76
269

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Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
(C=N), 154.89 (C=O). Anal. Calc. for C13 H17 N3 O3 M+ : (264.00) C, 59.30; H, 6.51; N, 15.96. Found: C,
59.34; H, 6.57; N, 15.91%.
4-(3,4-dihydroxyphenethyl)-5-phenyl-2H-1,2,4-triazol-3(4H)-one (4d): Yield: 1.36 g (46%),
colorless crystals, mp 175 ◦ C. IR (KBr, ν , cm−1): 3256 (OH), 1692 (C=O), 1595 (C=N); 1 H-NMR (DMSO-
d6 , δ, ppm): 2.53 (t, 2H, Ar-CH2), 3.76 (t, 2H, N-CH2), 6.18-6.36 (m, 2H, arom. H), 6.37-6.57 (m, 1H, arom.
H), 7.46-7.52 (m, 5H, arom. H), 8.75 (bs, 2H, OH), 11.89 (s, 1H, NH); 13 C-NMR (DMSO-d6δ, ppm): 33.25
(Ar-CH2), 42.69 (N-CH2), arom. C [115.40 (CH), 115.78 (CH), 119.04 (CH), 127.76 (CH), 128.69 (CH), 128.14
(C), 129.14 (CH), 145.30 (C), 146.51 (C)], 143.75 (C=N), 154.95 (C=O). Anal. Calc. for C16 H15 N3 O3 M+ :
(298.00) C, 64.64; H, 5.09; N, 14.13. Found: C, 64.69; H, 5.14; N, 14.18%.
4-(3,4-dihydroxyphenethyl)-5-p-toly-2H-1,2,4-triazol-3(4H)-one (4e): Yield: 1.41 g (46.87%),
colorless crystals, mp 186 ◦ C. IR (KBr, ν , cm−1): 3258 (OH), 1699 (C=O), 1597 (C=N); 1 H-NMR (DMSO-d6 ,
δ, ppm): 2.41 (s, 3H, CH3), 2.56 (t, 2H, Ar-CH2), 3.82 (t, 2H, N-CH2), 6.21-6.45 (m, 2H, arom. H), 6.54-6.59
(m, 1H, arom. H), 7.61-7.67 (m, 5H, arom. H), 8.78 (bs, 2H, OH), 11.88 (s, 1H, NH); 13 C-NMR (DMSO-d6 ,
δ, ppm): 24.03 (CH3), 33.27 (Ar-CH2), 42.70 (N-CH2), arom. C [115.42 (CH), 115.79 (CH), 119.10 (CH),
127.84 (CH), 128.70 (CH), 128.18 (C), 129.17 (CH), 145.33 (C), 146.55 (C)], 143.78 (C=N), 154.91 (C=O).
Anal. Calc. for C17 H17 N3 O3 M+ : (311.34) C, 65.58; H, 5.50; N, 13.50. Found: C, 65.62; H, 5.56; N, 13.58%.
4-(3,4-dihydroxyphenethyl)-5-(thiophen-2-ylmethyl)-2H-1,2,4-triazol-3(4H)-one (4f): Yield:
1.53 g (48.28%), colorless crystals, mp 189 ◦ C. IR (KBr, ν , cm−1): 3216 (OH), 1694 (C=O), 1583 (C=N);
1 H-NMR (DMSO-d6 , δ, ppm) 2.55 (t, 2H, Ar-CH2), 3.84 (t, 2H, thiophene CH2), 3.68 (t, 2H, N-CH2),
6.36-6.70 (m, 3H, arom. H), 6.90-7.49 (m, 3H, arom. H), 8.83 (bs, 2H, OH), 11.57 (s, 1H, NH); 13 C-NMR
(DMSO-d6δ, ppm): 25.96 (thiophene CH2), 33.46 (Ar-CH2), 42.34 (N-CH2), arom. C [115.50 (CH), 116.00
(CH), 119.28 (CH), 128.58 (C), 145.13 (C), 146.65 (C)], thiophene C [125.51 (CH), 126.50 (C), 126.97 (CH),
137.39 (C)], 143.83 (C=N), 154.77 (C=O). Anal. Calc. for C15 H15 N3 O3 S M+ : (318.00) C, 56.77; H, 4.76; N,
13.24. Found: C, 56.70; H, 4.82; N, 13.28%.
The synthesis of 4-(3,4-dihydroxyphenethyl)-5-(3,4-dimethoxyphenethyl)-2H-1,2,4-
triazol-3(4H)-one (5):
A solution of 4-(3,4-dimethoxyphenethyl)-5-(3,4-dimethoxyphenethyl)-2H-1,2,4-triazol-3(4H)-one (3g) (10 mmol)
in chloroform (100 mL) was added to a solution of boron tribromide (40 mmol) in chloroform (300 mL) at 0
◦ C. The reaction mixture was then stirred under a nitrogen atmosphere at ambient temperature for 1 h and
poured into ice containing sufficient 50% sodium hydroxide to attain a pH of 10. The addition of concentrated
sulfuric acid provided a precipitate that was extracted into ether. The combined organic extract was washed
with water and brine, dried, and concentrated in a vacuum to obtain compound 5. The crude product was
recrystallized using ethyl acetate and petroleum ether (1:4) to afford the desired compound.
4-(3,4-dihydroxyphenethyl)-5-(3,4-dimethoxyphenethyl)-2H-1,2,4-triazol-3(4H)-one (5):
Yield: 2.44 g (61.06%), colorless crystals, mp 130 ◦ C. IR (KBr, ν , cm−1): 3293 (OH), 1693 (C=O), 1687
(C=N); 1 H-NMR (DMSO-d6 , δ, ppm): 2.38 (t, 2H, Ar-CH2), 3.38 (t, 2H, Ar-CH2), 3.40 (t, 2H, N-CH2),
6.22-6.75 (m, 6H, arom. H), 8.75-9.00 (m, 4H, OH), 11.45 (s, 1H, NH); 13 C-NMR (DMSO-d6 , δ, ppm): 31.25
(Ar-CH2), 33.98 (Ar-CH2), 43.15 (N-CH2), arom. C [116.25 (CH), 116.71 (CH), 120.30 (CH), 126.46 (C),
270

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
126.47 (CH), 144.18(C), 144.53 (C), 145.44 (C), 145.68 (C)], 147.99 (C=N), 155.82 (C=O). Anal. Calc. for
C
17 H17 N3 O5 M+ : (344.00) C, 59.47; H, 4.99; N, 12.24. Found: C, 59.53; H, 4.91; N, 12.28%.
Results and discussion
In the first part of this study, compounds 3a-g were synthesized via the reaction of compound 1 with compound
2 (Scheme 1). Analytical and spectroscopic data of 3 confirmed the success of the cyclization reaction.
The synthesis of 4-(3,4-dihydroxyphenethyl)-5-akyl/aryl-2H-1,2,4-triazol-3(4H)-ones(4a-f) was performed
by the reaction of 3 with BBr3 at reflux temperature in the presence of chloroform. The compounds were char-
acterized by elemental analyses, mass spectral data, and 1 H- and 13 C-NMR and IR spectra.
Compound 5 was synthesized via the reaction of compound 3g with BBr3 (Scheme 2).
N
NH
N
NH
HO
HO
H3CO
H3CO
O
O
N
N
BBr3
OH
OCH3
OCH3
OH
5
3g
Scheme 2. Synthesis of compound 5.
Some of synthesized compounds were investigated for antioxidant activity, and compounds 4a, 4c, 4d,
4f, and 5 were found to be active. As a result, the data obtained from our research could guide us toward the
development of novel antioxidant compounds.
Antioxidant activity
DPPH assay: The radical scavenging activity of the synthesized compounds against stable free radical 2.2-
diphenyl-2-picrylhydrazyl hydrate (DPPH, Sigma-Aldrich Chemie, Steinheim, Germany) was determined spec-
trophotometrically. When DPPH reacts with antioxidant compounds, which can donate hydrogen, it is reduced.
Following the reduction, its deep violet color in methanol bleached to yellow, showing a significant absorption
decrease at 517 nm (18). Then 50 μL of various concentrations of the compounds dissolved in methanol were
added to 5 mL of a 0.004% methanol solution of DPPH. After a 30 min incubation period at room tem-
perature, the absorbance was read against a blank at 517 nm (ATI-UnicamUV-2 UV-Vis spectrophotometer,
Cambridge, UK). Free radical DPPH inhibition in percentage (I%) was calculated as follows: I% = (Ablank
–
Asample /Ablank)× 100, where Ablank is the absorbance of the control reaction (containing all reagents except
the test compound) and Asample is the absorbance of the test compound. Compound concentrations providing
50% inhibition (IC50) were calculated from a graph plotted as inhibition percentage against compound con-
centration. Tests were carried out in triplicate, and butylated hydroxytoluene (BHT) was used as a positive
control (Figures 2 and 3).18
271

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
8
7.0
6.5
7
110
6
5
4
3
2
1
0
100
90
80
70
60
50
40
30
20
10
0
4.4
3.6
4a
4c
4d
4f
2.0
5
0
2
4
6
8
10 12 14 16 18 20
4a
4c
4d
4f
5
Concentration (µg/mL)
Figure 2. I% values of compounds 4a, 4c, 4d, 4f, and 5.
Figure 3. IC50 values of compounds 4a, 4c, 4d, 4f, and
5.
Crystal structure determination of 3a
Data collection
The crystal structure of compound 3a (C13 H17 N3 O3 .H2 O), with crystal dimensions of 0.49 × 0.45 × 0.43
mm, was determined by single crystal X-ray diffraction. The data collection was performed on a Bruker Smart
˚
Area-CCD diffractometer with Mo Kα radiation (λ = 0.71073 A) at 293(2) K. The systematic absences and
intensity symmetries indicated the monoclinic P 2(1)/c space group. A total of 9002 reflections (3430 unique)
within the θ range of [1.58◦ < θ < 28◦ ] were collected in the rotation mode with Rint = 0.022. The data
collection method was φ and ω scans with κ offsets. The program used for cell refinement and data collection
was Bruker SMART.19 The structure was solved with direct methods by using SHELXS-9720 and was refined by
full-matrix least square techniques on F 2 using SHELXL-97.20 A molecular plot was prepared with ORTEPIII
for Windows.21 WinGX software22 was used to prepare material for publication.
Figure 4. ORTEPIII diagram of compound 3a.
272

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
The crystal structure of compound 3a, C13 H17 N3 O3·H2 O, was determined by single crystal X-ray
diffraction technique (Figures 4 and 5). Compound 3a crystallizes in the triclinic space group in the asym-
˚
˚
˚
metric unit, with the following unit-cell parameters: a = 13.302(3) A, b = 6.8441(15) A, c = 16.390(4) A,
◦
◦
3
˚
β =103.611(4) , γ =1450.2(6) , and V = 1450.2(6) A , with Z = 4; crystallographic data are shown in Table
1. The structure of compound 3a consists of one triazole ring and one benzene ring. Nonhydrogen fractional
atomic coordinates and isotropic or equivalent isotropic displacement parameters are listed in Table 2. Hydro-
gen bond geometries are given in Table 3. The 1,2,4-triazole ring and the benzene ring are planar, with the
˚
˚
maximum deviation from the least squares planes being 0.0097(16) A for atom C11 and -0.0119(17) A for atom
˚
C3. Atom N1 has a substituent. Therefore, the C12—N1 and C11—N1 bond distances [1.3725(18) A] are longer
Figure 5. Packing diagram of compound 3a.
273

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
˚
˚
than C11—N2 [1.3415(19) A]. The N3-N2 bond length [1.3775(18) A] agrees with the values reported in the
23
24
˚
˚
˚
literature [1.3823(17) A, 1.398(4) A ]. The N3=C12 bond length [1.296(2) A] is longer than some values
reported in the literature.25,26 However, it is close to other reported values.27,28 In the 1-, 2-, and 4-triazole ring,
˚
atoms N2 and N3 have no substituents, and the N2—N3 bond length, 1.3776(18) A, is close to values reported
30,31
in the literature.29 The O3—C11 bond length of 1.238(18) A lies within the range previously reported.
˚
The dihedral angle between the benzene and triazole rings is 55.25(5)◦ .
Table 1. Crystal and experimental data.
Chemical formula
Mr
C13H17N3O3.H2O
281.31
Cell setting, space group
Temperature (K)
Monoclinic, P 2(1)/c
293(2)
˚
a, b, c (A)
13.302 (3), 6.8441(15), 16.390(4)
3
˚
V (A )
1450.2(6)
Z
4
Dx (mg/cm3)
Radiation type
1.288
Mo K
μ (mm−1
)
0.10
Crystal form, color
Crystal size (mm3)
Data collection
Prism, colorless
0.49 × 0.45 × 0.43
Diffractometer
CCD area detector
No. of measured independent 9002, 3430, 2325
and observed reflections
Criterion for observed
reflections
I > 2σ(I)
Rint
0.022
28.0
θmax
Refinement
Refinement on
No. of reflections
No. of parameters
(Δ/σmax
F 2
3430
191
< 0.0001
0.24, -0.20
SHELXL
0.016 (2)
−3
˚
(Δρ)max , (Δρ)min (e A
Extinction method
)
Extinction coefficient
274

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
Table 2. Nonhydrogen fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters.
Atom
C1
x
y
z
Ui∗so/Ueq
0.5147(2)
-0.2298(4)
0.3800(3)
-0.0753(3)
0.0842(2)
0.0937(2)
-0.2152(3)
-0.2021(3)
-0.0501(2)
-0.0348(2)
-0.0889(2)
-0.3522(2)
-0.4551(2)
-0.4517(3)
0.43692(13) 0.1008(9)
0.31609(12) 0.0726(6)
C2
0.26410(18)
0.40713(12)
0.34313(11)
0.29715(11)
0.42567(14)
0.37943(13)
0.31448(11)
0.26236(11)
0.14760(11)
0.09050(12)
0.14547(12)
0.18530(17)
C3
0.31778(9)
0.28652(9)
0.20180(9)
0.0512(4)
0.0447(4)
0.0438(3)
C4
C5
C6
0.26334(11) 0.0598(5)
0.17766(10) 0.0554(4)
C7
C8
0.14621(9)
0.05421(9)
0.03348(9)
0.11927(9)
0.0435(3)
0.0455(4)
0.0411(3)
0.0437(3)
C9
C10
C11
C12
C13
N1
0.00939(10) 0.0465(4)
-0.06812(12) 0.0679(5)
0.13011(9) -0.29154(16)
0.08680(11) -0.54737(18)
0.11974(11) -0.61303(19)
0.05338(7)
0.11189(8)
0.04310(9)
0.40274(7)
0.34433(7)
0.17240(7)
0.19067(9)
0.0397(3)
0.0513(3)
0.0552(4)
0.0698(4)
0.0570(3)
0.0644(4)
0.0798(5)
N2
N3
O1
O2
O3
0.44746(10)
0.33325(9)
-0.0743(2)
0.22234(17)
0.06365(11) -0.24874(17)
O1W 0.00840(14) -0.85485(19)
Table 3. Hydrogen-bonding geometry (A, ◦ ) for (I).
˚
D-H. . . A
D–H H. . . A
D. . . A
D–H. . . A
160
N2-H2. . . O1W
C1-H1A. . . O1i
O1W-H1W. . . O3ii
0.86
0.96
0.82
1.971 2.796(2)
2.550 3.297(2)
1.932 2.738(2)
2.030 2.829(2)
135
168
O1W-H2W. . . O3iii 0.80
178
D: donor, A: acceptor. Symmetry transformations used to generate equivalent atoms. i -x+1, -y, -z+1; ii -x, y-1/2,
-z+1/2; iii x, y-1, z.
Supplementary data: CCDC, 698179.
The crystal structure is stabilized by intra- and intermolecular interactions, C-H...π , and π − π stacking
interactions. There are 3 intermolecular and 1 intramolecular hydrogen bonds in the structure (Table 3).
˚
In the N-H. . . O-type N2-H2. . . O1W intramolecular hydrogen bond, the N2. . . O1W distance is 2.796(2) A
and the intramolecular strong interaction is of the D-H. . . type. It has an angle of 160◦ (Figure 4). The
intramolecular hydrogen bond supplies a leading contribution to the stabilization of the crystallographically
275

¨
Synthesis, crystal structure, and antioxidant properties of..., Y. UNVER, et al.,
observed conformation of compound 3a. In the intermolecular hydrogen bonds, 1 C-H. . . O-type (C1-H1A. . . O1)
and 2 O-H. . . O-type (O1W-H1W.. . O3 and O1W-H2W. . . O3) C1-H1A. . . O1 intermolecular hydrogen bonds
are weaker than others. The O-H. . . O-type intermolecular hydrogen bonds, O1W-H1W. . . O3 and O1W-
˚
˚
H2W. . . O3, have short hydrogen-acceptor distances (1.932 A and 2.030 A, respectively). Both of these hydrogen
bonds, O1W-H1W.. . O3 and O1W-H2W. . . O3, are nearly linear (168◦ and 178◦ , respectively) and fairly
strong. In addition, there is one remarkable intermolecular π − π stacking interaction between the triazole
˚
rings [Cg1. . . Cg1 = 3.3810(12) A; symmetry code: -x, 1-y, -z]. Since the perpendicular distance between the
˚
interacting π -rings is smaller than 3.8 A, this stacking interaction supplies a considerable contribution to the
stabilization of the crystal structure. On the other hand, the crystal structure also has an intermolecular C-
H...π contact involving the benzene ring of a symmetry-related molecule at (1-x, -1/2+y, 1/2-z) [C6...Cg2 =
◦
˚
˚
3.680(2) A, H6...Cg2 = 2.86 A, and C6-H6...Cg2 = 148 ].
Acknowledgements
This study was funded by the Research Fund of Karadeniz Technical University. The authors thank Dr.
Mu¨nevver So¨kmen for antioxidant studies.
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277

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