Synthesis of some novel 1,2,3-triazole derivatives containing kojic acid moiety and evaluation for their antioxidant activity

Article abstract of DOI:10.1007/s00706-016-1844-1

Abstract: A series of novel 1,2,3-triazole derivatives containing kojic acid moiety were synthesized by 1,3-dipolar cycloaddition reaction of 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one and 2-(azidomethyl)-5-benzyloxy-4H-pyran-4-one with different alkynes in

Full text of DOI:10.1007/s00706-016-1844-1

Monatsh Chem
DOI 10.1007/s00706-016-1844-1
ORIGINAL PAPER
Synthesis of some novel 1,2,3-triazole derivatives containing kojic
acid moiety and evaluation for their antioxidant activity
Mahnaz Saraei1 Zarrin Ghasemi2 Gholamreza Dehghan3
•
•
•
Marhamat Hormati1 Khadijeh Ojaghi1
•
Received: 5 June 2016 / Accepted: 1 September 2016
Ó Springer-Verlag Wien 2016
Abstract A series of novel 1,2,3-triazole derivatives con-
taining kojic acid moiety were synthesized by 1,3-dipolar
cycloaddition reaction of 2-(azidomethyl)-5-hydroxy-4H-
pyran-4-one and 2-(azidomethyl)-5-benzyloxy-4H-pyran-
4-one with different alkynes in 41–99% yields. In the case
of terminal alkynes, the reactions occurred in the presence
of Cu(I) catalyst. The antioxidant activity of the synthe-
sized compounds containing 5-hydroxyl group was
evaluated by 1,1-diphenyl-2-picrylhydrazyl method.
Graphical abstract
Introduction
1,2,3-Triazoles are an important class of five-membered
heterocycles containing nitrogen atoms that have attracted
much attention due to their diverse biological activities,
such as antifungal [1], antibacterial [2], anticancer [3],
antiallergic [4], anti-HIV [5], and antitubercular [6]. In
addition, a number of compounds containing 1,2,3-triazole
moiety have found industrial applications as dyes, agro-
chemicals, photostabilizers, and corrosion inhibitors [7].
Several methods have been reported for the synthesis of
1,2,3-triazoles in the literature [8–10]. One of the most
important and useful methods for the synthesis of 1,2,3-
triazoles is 1,3-dipolar cycloaddition of azides with alkynes
pioneered by Huisgen et al. [11]. Because of poor regios-
electivity of this method for terminal alkynes, Sharpless
et al. [12] and Meldal et al. [13] improved the regioselec-
tivity of the reaction of azide with terminal alkynes in the
presence of Cu(I) salts as catalyst.
On the other hand, 4H-pyran-4-one derivatives are an
important class of heterocyclic compounds that have
been studied due to their wide range biological activities
and their presence in many natural materials [14–18].
Kojic acid (5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-
one) is a natural substance produced from carbohydrate
sources in an aerobic process by various fungi and bac-
teria, such as, Aspergillus and Penicillium [19, 20]. Kojic
acid and some of its derivatives have shown antimicro-
bial, antibacterial, and antifungal activities [21–23]. In
addition, kojic acid and its derivatives are used in the
food industry as an additive to prevent the browning of
food materials and as a skin-lightening agent in cosmetic
products, because it inhibits tyrosinase [24, 25]. There
are many reports on the synthesis of 1,2,3-triazoles
containing different heterocyclic moieties [26, 27]. As
Keywords Kojic acid Á Azidomethyl derivatives Á
1,2,3-Triazole Á 1,3-Dipolar cycloaddition Á
Antioxidant activity
& Mahnaz Saraei
m_saraei@pnu.ac.ir;
mahnaz_saraii@yahoo.com
1
Department of Chemistry, Payame Noor University,
PO BOX 19395-3697, Tehran, Iran
2
Department of Organic and Biochemistry, Faculty of
Chemistry, University of Tabriz, Tabriz, Iran
3
Department of Biology, Faculty of Natural Sciences,
University of Tabriz, Tabriz, Iran
123

M. Saraei et al.
Scheme 1
the best of our knowledge, the synthesis of 1,2,3-triazoles
containing 4H-pyran-4-one moiety has not been reported.
Recently, we have reported a new class of hybrid
molecules possessing 4H-pyran-4-one coupled to 1,2,3-
triazole [28]. In this study, we became interested in the
use of the commercially available kojic acid as a starting
material for the synthesis of new 1,2,3-triazole deriva-
tives possessing kojic acid moiety. In addition, the
synthesized derivatives of kojic acid containing 5-hy-
droxyl group were evaluated for their radical scavenging
activities using the 1,1-diphenyl-2-picrylhydrazyl (DPPH)
radical scavenging method.
triazoles were synthesized from 2-(azidomethyl)-5-benzy-
loxy-4H-pyran-4-one (3b) with various alkynes.
Kojic acid (1a) was reacted with benzyl chloride in the
presence of sodium hydroxide to afford 5-benzyloxy-2-
(hydroxymethyl)-4H-pyran-4-one (1b) according to the
literature [31]. The reaction of kojic acid (1a) and 5-ben-
zyloxy-2-(hydroxymethyl)-4H-pyran-4-one (1b) with
thionyl chloride at room temperature produced 2-(chloro-
methyl)-5-hydroxy-4H-pyran-4-one (chlorokojic acid, 2a)
and 5-benzyloxy-2-(chloromethyl)-4H-pyran-4-one (2b),
respectively, which are converted to 2-(azidomethyl)-5-
hydroxy-4H-pyran-4-one (3a) and 2-(azidomethyl)-5-ben-
zyloxy-4H-pyran-4-one (3b) using sodium azide in dry
DMF at room temperature [32, 33]. The structure of azide
compounds 3a and 3b was in accordance with their spec-
troscopic data. The FT-IR spectra of the azide compounds
3a and 3b showed a strong absorption band at 2109 and
2098 cm-1 corresponding to the azide groups, respectively.
As shown in Scheme 1, the azide compounds 3a and 3b
were reacted with internal alkynes, such as dimethyl and
diethyl acetylenedicarboxylate, in dry toluene that resulted
in the corresponding of 1,4,5-trisubstituted-1,2,3-triazoles
4a–4d in moderate-to-excellent yields.
Results and discussion
In connection with our interest in the synthesis of hetero-
cyclic compounds [29, 30], we have synthesized a series of
novel 1,2,3-triazole derivatives containing kojic acid moi-
ety from the reaction of 2-(azidomethyl)-5-hydroxy-4H-
pyran-4-one (azidokojic acid, 3a) and 2-(azidomethyl)-5-
benzyloxy-4H-pyran-4-one (3b) with different alkynes
under the reflux conditions.
Kojic acid (1a) was selected as starting material for the
synthesis of 1,2,3-triazole analoges. First, we turned our
attention to the formation of the corresponding 1,2,3-tria-
zoles from the reaction of azidokojic acid (3a) with various
alkynes. Then, we protected the 5-hydroxyl group of kojic
acid using benzyl chloride and the corresponding 1,2,3-
1,4-Disubstituted 1,2,3-triazoles 5a–5j were synthesized
in moderate-to-excellent yields by the reaction of azide
compounds 3a and 3b with terminal alkynes, such as
methyl acetylenecarboxylate, ethyl acetylenecarboxylate,
phenylacetylene, propargyl alcohol, and 3-butyn-1-ol, in
the presence of CuI as a catalyst in dry acetonitrile under
123

Synthesis of some novel 1,2,3-triazole derivatives containing kojic acid moiety and…
Scheme 2
Conclusions
Table 1 Results of antioxidant activity of 3a, 4a–4c, 5a, 5c, 5e, and
5g compounds
In this study, we have reported a new class of 1,2,3-
triazole derivatives containing kojic acid moiety by the
1,3-dipolar cycloaddition reaction of 2-(azidomethyl)-5-
hydroxy-4H-pyran-4-one and 2-(azidomethyl)-5-benzy-
loxy-4H-pyran-4-one with different alkynes in moderate-
to-excellent yields. The synthesized compounds contain-
ing 5- hydroxyl group were evaluated for antioxidant
activity. Among these compounds, 4a, 4c and 5a, 5c, 5e
showed the most potent scavenging activity, while the
compounds 5g and 4b showed very weak antioxidant
activity in DPPH assay.
Compd. No.
DPPH (IC50)/lg cm-3
RSA % (80 lg cm-3
)
3a
4a
4b
4c
5a
5c
5e
5g
347
263
348
270
251
204
213
489
19.1
32.4
18.4
30.2
38.1
41.6
40.2
11.3
the reflux conditions (Scheme 2). In the case of terminal
alkynes, the use of Cu(I) salts is essential. In the absence of
Cu(I), the products were obtained in a mixture of 1,4- and
1,5-regioisomers that were difficult to separation. The
structures of the synthesized compounds were established
Experimental
All reagents were purchased from Merck or Fluka com-
panies and were used without further purification. All
reactions were followed by thin-layer chromatography
(TLC) on silica gel 60 HF254, with detection by UV light.
Crude products were recrystallized or purified by prepar-
1
on the basis of FT-IR, H NMR, 13C NMR, MS, and ele-
mental analysis.
The nitrogen centered stable radical 1,1-diphenyl-2-
picrylhydrazyl (DPPH) has been often used to characterize
antioxidants. In the DPPH assay, the ability of synthesized
compounds to act as donors of hydrogen atoms or electrons
in transforming DPPH radical (violet color) into its reduced
form, DPPH-H (yellow color), was measured by the
spectrophotometric method. Kojic acid exhibited antioxi-
dant activity [34, 35]. In this study, we investigated the
antioxidant activity of 1,2,3-triazoles 4a and 4b for the first
time. Compound 4a showed much stronger antioxidant
activity than compound 4b. Thus, we evaluated the
antioxidant activity of the synthesized derivatives con-
taining 5-hydroxyl group 3a, 4a–4c and 5a, 5c, 5e, 5g
using the DPPH assay. The results, expressed as IC50
values and RSA%, are shown in Table 1. All compounds
3a, 4a–4c, and 5a, 5c, 5e, 5g showed antioxidant activity.
ative layer chromatography (PLC; silica gel 60 F254
,
Merck, CAMAG, Switzerland) using acetone: n-hexane
(1:1) as eluent. All solvents were dried and distilled prior to
use. Melting points were determined on an Electrothermal
Barnstead 9200 apparatus (Barnstead, UK). FT-IR spectra
were obtained using KBr pellets on a tensor 27-Bruker
spectrometer (Shimadzu, Japan). H NMR and 13C NMR
1
spectra were recorded with a FT-NMR-Bruker spectrom-
eter (Germany), at 400 and 100 MHz, respectively, in
CDCl3 and DMSO-d6. Mass spectra were recorded on
direct insert probe Agilent technologies 5975c with triple
axis detector. Elemental analyses were carried out on
Perkin-Elmer CHNS-O Analyzer, Model 2400 Series II.
Spectrophotometric measurements were done at 517 nm
using a T-60 spectrophotometer (PG-Instrument, UK).
123

M. Saraei et al.
2-(Azidomethyl)-5-benzyloxy-4H-pyran-4-one
6.28 (s, 1H,pyrone-H), 7.30–7.34 (m, 5H, Ar–H), 7.49 (s,
1H, pyrone-H) ppm; 13C NMR (100 MHz, CDCl3):
d = 50.6, 53.0, 53.7, 71.7, 115.0, 127.7, 128.6, 128.8,
129.4, 135.3, 140.7, 141.1, 147.4, 158.3, 158.7, 160.1, 173.8
(pyrone-CO) ppm; and MS: m/z (%) = 399 (M?, 25), 83
(100).
(3b, C13H11N3O3)
To a suspension of 0.39 g sodium azide (6 mmol) in 8 cm3
dry DMF, 1 g 5-benzyloxy-2-(chloromethyl)-4H-pyran-4-
one (2b, 4 mmol) was added and the mixture was stirred at
room temperature for 24 h. The reaction mixture was
poured into cold water. The resulting precipitates were
filtered off, washed with water, and dried in vacuum. The
crude product was recrystallized from ethanol: chloroform
(1:1) to give azide compound 3b as yellow solid, in 0.85 g
(83%) yield. M.p.: 101–102 °C; FT-IR (KBr): m = 3126,
3060, 2923, 2869, 2098 (N3), 1643 (pyrone-CO), 1608,
Diethyl 1-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]-1,2,3-
triazole-4,5-dicarboxylate (4c, C14H15N3O7)
Recrystallized from EtOH. Orange solid; yield 0.168 g
(99%); m.p.: 149–151 °C; FT-IR (KBr): m = 3294, 3032,
2923, 2856, 1745 (ester-CO), 1645 (pyrone-CO), 1566,
1515, 1450, 1377, 1255, 1164, 1103, 1020, 856, 630 cm-1
;
1427, 1371, 1263, 1193, 1153, 981, 865, 759 cm-1; H
1
1H NMR (400 MHz, CDCl3): d = 1.36–1.43 (m, 6H, –
CH3), 4.40–4.48 (m, 4H, –CO2CH2–), 5.76 (s, 2H, –CH2N–
), 6.36 (s, 1H, pyrone-H), 7.07 (br, 1H, –OH), 7.82 (s, 1H,
pyrone-H) ppm; 13C NMR (100 MHz, CDCl3): d = 12.7,
13.0, 49.5, 61.1, 62.2, 111.0, 128.2, 137.5, 140.0, 145.0,
156.8, 158.7, 158.9, 172.6 (pyrone-CO) ppm; and MS: m/z
(%) = 337 (M?, 6), 125 (100).
NMR (400 MHz, CDCl3): d = 4.07 (s, 2H, –CH2N–), 5.00
(s, 2H, –CH2O–), 6.34 (s, 1H, pyrone-H), 7.24-7.31 (m,
5H, Ar–H), 7.48 (s, 1H, pyrone-H) ppm; 13C NMR
(100 MHz, CDCl3): d = 50.0, 70.8, 113.3, 126.7, 127.5,
127.7, 134.4, 140.4, 146.2, 160.2, 173.2 (pyrone-CO) ppm;
and MS: m/z (%) = 257 (M?, 6), 91 (100).
General procedure for the synthesis of 1,4,5-trisubstituted
1,2,3-triazoles 4a–4d
Diethyl 1-[[5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methyl]-
1,2,3-triazole-4,5-dicarboxylate (4d, C21H21N3O7)
To a solution of 2-(azidomethyl)-5-hydroxy-4H-pyran-4-
one (3a) or 2-(azidomethyl)-5-benzyloxy-4H-pyran-4-one
(3b) (0.5 mmol) in 5 cm3 dry toluene, dimethyl or diethyl
acetylenedicarboxylate (2 mmol) was added and the mix-
ture was heated under reflux for 24–48 h (monitored by
TLC). After the completion of the reaction, the resulting
precipitate was collected by filtration and dried under
reduced pressure to give crude product which was purified
by recrystallization from EtOH or preparative layer chro-
matography (PLC) on silica gel.
Purified by PLC on silica gel using n-hexane: acetone (1:1)
as eluent to produce the title compound. Brown oil; yield
0.087 g (41%); FT-IR (KBr): m = 3083, 2983, 2937, 1731
(ester-CO), 1654 (pyrone-CO), 1554, 1461, 1377, 1271,
1207, 1153, 1060, 1008, 852, 744 cm-1
;
1H NMR
(400 MHz, CDCl3): d = 1.38 (t, 3H, J = 7.2 Hz, –CH3),
1.43 (t, 3H, J = 7.2 Hz, –CH3), 4.40–4.49 (m, 4H, –
CO2CH2–), 5.05 (s, 2H, –CH2N–), 5.69 (s, 2H, –CH2O–),
6.29 (s, 1H,pyrone-H), 7.33–7.38 (m, 5H, Ar–H), 7.50 (s,
1H, pyrone-H) ppm; and 13C NMR (100 MHz, CDCl3):
d = 13.9, 14.2, 50.4, 62.3, 63.3, 71.9, 114.9, 127.7, 128.6,
128.8, 129.3, 135.3, 141.1, 141.2, 147.4, 157.9, 158.8,
159.9, 173.8 (pyrone-CO) ppm.
Dimethyl 1-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]-
1,2,3-triazole-4,5-dicarboxylate (4a, C12H11N3O7)
Recrystallized from EtOH. White solid; yield 0.15 g
(97%); m.p.: 161–163 °C; FT-IR (KBr): m = 3249, 3033,
2964, 1731 (ester-CO), 1656 (pyrone-CO), 1558, 1460,
General procedure for the synthesis of 1,4-disubstituted
1,2,3-triazoles 5a–5j
1
1384, 1334, 1220, 1143, 1060, 823, 684 cm-1; H NMR
To a solution of azide compound 3a or 3b (0.5 mmol) and
terminal alkyne (2 mmol) in 6 cm3 dry acetonitrile, 10 mol
% (CuI) was added. The mixture was heated under reflux
for 5–48 h, and progress of the reaction was monitored by
TLC. After the completion of the reaction, the resulting
precipitate was collected by filtration, dried under reduced
pressure, and purified by recrystallization or preparative
layer chromatography (PLC) on silica gel.
(400 MHz, CDCl3): d = 3.98 (s, 3H, –CH3), 3.99 (s, 3H, –
CH3), 5.74 (s, 2H, –CH2N–), 6.35 (s, 2H (1H, pyrone-H)
and (1H, –OH)), 7.79 (s, 1H, pyrone-H) ppm; 13C NMR
(100 MHz, CDCl3): d = 49.8, 52.0, 52.7, 110.9, 137.0,
145.0, 159.0, 172.4 (pyrone-CO) ppm; and MS: m/
z (%) = 309 (M?, 10), 125 (100).
Dimethyl 1-[[5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methyl]-
1,2,3-triazole-4,5-dicarboxylate (4b, C19H17N3O7)
Methyl 1-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]-1,2,3-
triazole-4-carboxylate (5a, C10H9N3O5)
Recrystallized from EtOH. White solid; yield 0.15 g
(75%); m.p.: 128–129 °C; FT-IR (KBr): m = 3082, 3010,
2954, 2885, 1753 (ester-CO), 1652 (pyrone-CO), 1556,
Recrystallized from EtOH. Light yellow solid; yield 0.12 g
(95%); m.p.: 190–192 °C; FT-IR (KBr): m = 3226, 3089,
2960, 1730 (ester-CO), 1652 (pyrone-CO), 1616, 1579,
1460, 1353, 1272, 1215, 1149, 1062, 979, 827, 769 cm-1
;
1H NMR (400 MHz, CDCl3): d = 3.94 (s, 3H, –CH3), 3.96
(s, 3H, –CH3), 5.00 (s, 2H, –CH2N–), 5.67 (s, 2H, –CH2O–),
1
1539, 1450, 1379, 1226, 1134, 869, 682 cm-1; H NMR
(400 MHz, DMSO-d6): d = 3.82 (s, 3H, –CH3), 5.65 (s,
123

Synthesis of some novel 1,2,3-triazole derivatives containing kojic acid moiety and…
1
2H, –CH2N–), 6.46 (s, 1H,pyrone-H), 8.02 (s, 1H, pyrone-
H), 8.89 (s, 1H, triazole-H) 9.35 (br, 1H, –OH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 50.4, 52.1, 113,5, 130.2,
139.1, 140.3, 146.2, 160.0, 160.7, 173.8 (pyrone-CO) ppm;
and MS: m/z (%) = 251 (M?, 27), 166 (100).
1587, 1452, 1388, 1263, 1218, 1151, 767 cm-1; H NMR
(400 MHz, DMSO-d6): d = 5.64 (s, 2H, –CH2N–), 6.49 (s,
1H, pyrone-H), 7.32–7.36 (m, 1H, Ph-H), 7.43–7.47 (m,
2H, Ph-H), 7.86 (d, 2H, J = 7.6 Hz, Ph-H), 8.07 (s, 1H,
triazole-H), 8.67 (s, 1H, pyrone-H), 9.32 (br, 1H, –OH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 50.7, 113.8,
122.6, 125.7, 128.6, 129.4, 130.8, 140.6, 146.7, 147.2,
161.0, 174.3 (pyrone-CO) ppm; and MS: m/z (%) = 269
(M?, 22), 116 (100).
Methyl 1-[[5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methyl]-
1,2,3-triazole-4-carboxylate (5b, C17H15N3O5)
Recrystallized from EtOH. White solid; yield 0.11 g
(64%); m.p.: 178–179 °C; FT-IR (KBr): m = 3078, 2952,
2887, 1728 (ester-CO), 1645 (pyrone-CO), 1550, 1442,
5-Benzyloxy-2-[(4-phenyl-1,2,3-triazole-1-yl)methyl]-4H-
pyran-4-one (5f, C21H17N3O3)
1
1348, 1274, 1222, 1149, 1047, 977, 862, 769 cm-1; H
NMR (400 MHz, CDCl3): d = 3.99 (s, 3H, –CH3), 5.07 (s,
2H, –CH2N–), 5.44 (s, 2H, –CH2O–), 6.41 (s, 1H,pyrone-
H), 7.35–7.40 (m, 5H, Ar–H), 7.53 (s, 1H, pyrone-H), 8.22
(s, 1H, triazole-H) ppm; 13C NMR (100 MHz, CDCl3):
d = 51.0, 52.5, 72.0, 115.5, 127.8, 128.1, 128.7, 128.9,
135.2, 140.8, 141.3, 147.5, 158.2, 160.7, 173.7 (pyrone-
CO) ppm; and MS: m/z (%) = 341 (M?, 5), 91(100).
Recrystallized from EtOH. Cream solid; yield 0.16 g
(89%); m.p.: 135–137 °C; FT-IR (KBr): m = 3087,
3043, 2940, 1652 (pyrone-CO), 1620, 1600, 1429, 1220,
989, 761, 690 cm-1
;
1H NMR (400 MHz, CDCl3):
d = 5.07 (s, 2H,-CH2N-), 5.42 (s, 2H,-CH2O-), 6.39 (s,
1H,pyrone-H), 7.36-7.40 (m, 6H, Ar–H), 7.44-7.48 (m, 2H,
Ar–H), 7.54 (s, 1H, pyrone-H), 7.84 (d, 2H, J = 7.2 Hz,
Ar–H), 7.86 (s, 1H, triazole-H) ppm; 13C NMR (100 MHz,
CDCl3): d = 51.0, 71.9, 115.0, 120.0, 125.8, 127.8, 128.6,
128.7, 128.8, 129.0, 129.9, 135.3, 141.3, 147.4, 148.8,
159.4, 174.0 (pyrone-CO) ppm; and MS: m/z (%) = 359
(M?, 75), 91 (100).
Ethyl 1-[(5-hydroxy-4-oxo-4H-pyran-2-yl)methyl]-1,2,3-
triazole-4-carboxylate (5c, C11H11N3O5)
Recrystallized from EtOH. Orange solid; yield 0.13 g
(96%); m.p.: 200–202 °C; FT-IR (KBr): m = 3137, 3001,
2956, 2865, 1722 (ester-CO), 1631 (pyrone-CO), 1550,
1446, 1380, 1334, 1242, 1218, 1147, 1051, 1020, 869,
5-Hydroxy-2-[[4-(hydroxymethyl)-1,2,3-triazol-1-yl]me-
thyl]-4H-pyran-4-one (5 g, C9H9N3O4)
1
769 cm-1; H NMR (400 MHz, CDCl3): d = 1.42 (t, 3H,
J = 7.1 Hz, –CH3), 4.44 (q, 2H, J = 7.1 Hz, –CO2CH2–),
5.47 (s, 2H, –CH2N–), 6.22 (br, 1H, –OH), 6.43 (s, 1H,
pyrone-H), 7.83 (s, 1H, pyrone-H), 8.20 (s, 1H, triazole-H)
ppm; 13C NMR (100 MHz, CDCl3): d = 13.3, 50.2, 60.7,
111.3, 127.0, 136.9, 145.0, 158.6, 172.3 (pyrone-CO) ppm;
and MS: m/z (%) = 265 (M?, 11), 125 (100).
Recrystallized from methanol: acetonitrile (2:1); Light
yellow solid; yield 0.11 g (98%); m.p.: 157–159 °C; FT-IR
(KBr): m = 3263, 3137, 2940, 1647 (pyrone-CO), 1622,
1
1585, 1423, 1382, 1231, 1147, 1002, 908, 782 cm-1; H
NMR (400 MHz, DMSO-d6): d = 4.53 (s, 2H, –CH2N–),
5.26 (br, 1H, –OH), 5.58 (s, 2H, –CH2O–), 6.38 (s, 1H,
pyrone-H), 8.06 (s, 1H, pyrone-H), 8.09 (s, 1H, triazole-H),
9.33 (s, 1H, –OH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 50.0, 55.0, 113.0, 124.0, 140.1, 146.1, 161.0, 173.7,
173.9 (pyrone-CO) ppm; and MS: m/z (%) = 223 (M?,
32), 149 (100).
Ethyl
1-[[5-(benzyloxy)-4-oxo-4H-pyran-2-yl]methyl]-
1,2,3-triazole-4-carboxylate (5d, C18H17N3O5)
Recrystallized from EtOH. White solid; yield 0.13 g
(73%); m.p.: 119–120 °C; FT-IR (KBr): m = 3076, 2989,
1724 (ester-CO), 1641 (pyrone-CO), 1527, 1450, 1386,
1
1272, 1218, 1012, 871, 767 cm-1; H NMR (400 MHz,
5-Benzyloxy-2-[[4-(hydroxymethyl)-1,2,3-triazole-1-yl]me-
thyl]-4H-pyran-4-one (5h, C16H15N3O4)
CDCl3): d = 1.43 (t, 3H, J = 7.2 Hz, –CH3), 4.45 (q, 2H,
J = 7.2 Hz, –CO2CH2–), 5.06 (s, 2H, –CH2N–), 5.44 (s,
2H, –CH2O–), 6.39 (s, 1H, pyrone-H), 7.33-7.43 (m, 5H,
Ar–H), 7.54 (s, 1H, pyrone-H), 8.22 (s, 1H, triazole-H)
ppm; 13C NMR (100 MHz, CDCl3): d = 14.3, 51.0, 61.6,
72.0, 115.4, 127.8, 128.1, 128.7, 128.8, 135.2, 141.1,
141.3, 147.5, 158.4, 160.3, 173.8 (pyrone-CO) ppm; and
MS: m/z (%) = 355 (M?, 7), 91(100).
Recrystallized from chloroform. White solid; yield 0.086 g
(55%); m.p.: 141–142 °C; FT-IR (KBr): m = 3446, 3087,
2877, 1647 (pyrone-CO), 1556, 1456, 1377, 1284, 1218,
1
1161, 1014, 676 cm-1; H NMR (400 MHz, DMSO-d6):
d = 4.52 (d, 2H, J = 5.6 Hz, –CH2OH), 4.91 (s, 2H, –
CH2N–), 5.22 (t, 1H, J = 5.6 Hz, –OH), 5.58 (s, 2H, –
CH2O–), 6.37 (s, 1H, pyrone-H), 7.34–7.40 (m, 5H, Ar–H),
8.07 (s, 1H, pyrone-H), 8.21 (s, 1H, triazole-H) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 49.7, 55.0, 70.5, 114.1,
123.6, 128.1, 128.2, 128.4, 136.0, 141.4, 146.9, 148.5,
161.0, 173.0 (pyrone-CO) ppm; and MS: m/z (%) = 313
(M?, 14), 91(100).
5-Hydroxy-2-[(4-phenyl-1,2,3-triazol-1-yl)methyl]-4H-
pyran-4-one (5e, C14H11N3O3)
Recrystallized from methanol: acetonitrile (1:1). Yellow
solid; yield 0.13 g (96%); m.p.: 217–219 °C; FT-IR (KBr):
m = 3261, 3091, 3031, 2960, 2854, 1622 (pyrone-CO),
123

M. Saraei et al.
5-Hydroxy-2-[[4-(2-hydroxyethyl)-1,2,3-triazol-1-yl]me-
thyl]-4H-pyran-4-one (5i, C10H11N3O4)
References
1. Aher NG, Pore VS, Mishra NN, Kumar A, Shukla PK, Sharma A,
Bhat MK (2009) Bioorg Med Chem Lett 19:759
2. Phillips OA, Udo EE, Abdel-Hamid ME, Varghese R (2009) Eur
J Med Chem 44:3217
3. Khazir J, Hyder I, Gayatri JL, Yandrati LP, Nalla N, Chasoo G,
Mahajan A, Saxena AK, Alam MS, Qazi GN, Sampath Kumar
HM (2014) Eur J Med Chem 82:255
4. Buckle DR, Rockell CJM, Smith H, Spicer BA (1986) J Med
Chem 29:2262
5. Giffin MJ, Heaslet H, Birk A, Lin YC, Cauvi G, Wong CH,
McRee DE, Elder JH, Stout CD, Torbett BE (2008) J Med Chem
51:6263
Recrystallized from methanol: acetonitrile (2:1); Light
yellow solid; yield 0.117 g (98%); m.p.: 155–157 °C; FT-
IR (KBr): m = 3379, 3080, 2926, 2892, 1642 (pyrone-CO),
1609, 1582, 1425, 1322, 1299, 1216, 1075, 844, 672 cm-1
;
1H NMR (400 MHz, DMSO-d6): d = 2.76 (t, 2H,
J = 6.4 Hz, –CH2CH2OH), 3.50 (s, 2H, –OH), 3.61–3.64
(m, 2H, –CH2CH2OH), 5.52 (s, 2H, –CH2N–), 6.36 (s, 1H,
pyrone-H), 7.95 (s, 1H, pyrone-H), 8.04 (s, 1H, triazole-H)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 29.1, 50.0,
60.2, 113.1, 123.6, 140.2, 146.0, 161.1, 173.8 (pyrone-CO)
ppm; and MS: m/z (%) = 237 (M?, 31), 125 (100).
6. Tripathi RP, Yadav AK, Ajay A, Bisht SS, Chaturvedi V, Sinha
SK (2010) Eur J Med Chem 45:142
7. Fan WQ, Katritzky AR (1996) In: Katritzky AR, Rees CW,
Scriven EFV (eds) Comprehensive heterocyclic chemistry II, vol
4. Elsevier Science, Oxford, p 1
5-Benzyloxy-2-[[4-(2-hydroxyethyl)-1,2,3-triazole-1-
yl]methyl]-4H-pyran-4-one (5j, C17H17N3O4)
8. Kristin O, Edmund AH, Trond VH (2007) Tetrahedron Lett
48:2097
9. Evans WJ, Montalvo E, Champagne TM, Ziller JW, DiPasquale
AG, Rheingold AL (2008) J Am Chem Soc 130:16
10. Amantini D, Fringuelli F, Piermatti O, Pizzo F, Zunino E, Vac-
caro L (2005) J Org Chem 70:6526
Purified by PLC on silica gel using n-hexane: acetone (1:1)
as eluent to produce the title compound. Brown oil; yield
0.13 g (79%); FT-IR (KBr): m = 3373, 3082, 2925, 2862,
1650 (pyrone-CO), 1502, 1448, 1429, 1267, 1213, 1156,
1053, 981, 750 cm-1 1H NMR (400 MHz, DMSO-d6):
;
11. Huisgen R (1984) In: Padwa A (ed) 1,3-Dipolar cycloaddition
chemistry, vol 1. Wiley-Interscience, New York, p 1
12. Rostovtsev VV, Green LG, Fokin VV, Sharpless KB (2002)
Angew Chem Int Ed 41:2596
13. Tornøe CW, Christensen C, Meldal M (2002) J Org Chem
67:3057
14. Kamino T, Kuramochi K, Kobayashi S (2003) Tetrahedron Lett
44:7349
15. Caturla F, Amat M, Reinoso RF, Calaf E, Warrellow G (2006)
Bioorg Med Chem Lett 16:3605
d = 2.78 (t, 2H, J = 6.6 Hz, –CH2CH2OH), 3.35 (br, 1H,
–OH), 3.63–3.65 (m, 2H, –CH2CH2OH), 4.91 (s, 2H, –
CH2N–), 5.56 (s, 2H, –CH2O–), 6.37 (s, 1H, pyrone-H),
7.35–7.40 (m, 5H, Ar–H), 7.97 (s, 1H, pyrone-H), 8.21 (s,
1H, triazole-H) ppm; and 13C NMR (100 MHz, DMSO-
d6): d = 29.0, 49.7, 60.1, 70.5, 114.1, 123.4, 128.1, 128.2,
128.4, 136.0, 141.4, 145.2, 146.9, 161.0, 173.0 (pyrone-
CO) ppm.
16. Kanazawa T, Ohkawa Y, Kuda T, Minobe Y, Tani T, Nishizawa
M (1997) Chem Pharm Bull 45:1046
17. Garey D, Ramirez MI, Gonzales S, Wertsching A, Tith S, Keefe
K, Pen˜a MR (1996) J Org Chem 61:4853
Measurement of antioxidant activity of 1,2,3-triazoles by
DPPH method
Antioxidant activity of compounds 3a, 4a–4c, and 5a, 5c,
5e, 5g was measured by DPPH according to the method
described before by Dehghan and Khoshkam [36]. The
various concentrations (39.70–199.99 lg cm-3) of the
samples solution in DMSO were added to 1 cm3 of 0.1 mM
DPPH in methanol and the mixture was shaken vigorously.
The reduction of DPPH was measured at 517 nm using a
spectrophotometer after 10 min (As). As a control, the
absorbance of the blank solution of DPPH (1 cm3) was also
determined at 517 nm (Ac). The percentage of radical
scavenging activity (RSA %) was calculated using the
following equation:
18. Matsumura Y, Shirai K, Maki T, Itakura Y, Kodera Y (1998)
Tetrahedron Lett 39:2339
19. Kwak MY, Rhee JS (1992) Biotechnol Bioeng 39:903
20. Parrish FW, Wiley BJ, Simmons EG, Long L Jr (1996) Appl
Microbiol 14:136
˘
21. Aytemir MD, Hider RC, Erol DD, Ozalp M, Ekizoglu M (2003)
Turk J Chem 27:445
22. Kotani T, Ichimoto I, Tatsumi C, Fujita T (1976) Agric Biol
Chem 40:765
23. Kayahara H, Shibata N, Tadasa K, Maeda H, Kotani T, Ichimoto
I (1990) Agric Biol Chem 54:2441
24. Burdock GA, Soni MG, Garabin IG (2001) Regul Toxicol Pharm
33:80
25. Noh JM, Kwak SY, Kim DH, Lee YS (2007) Biopolymers 88:300
26. Beena Kumar N, Rohilla RK, Roy N, Rawat DS (2009) Bioorg
Med Chem Lett 19:1396
27. Kumar KK, Seenivasan SP, Kumar V, Das TM (2011) Carbohydr
Res 346:2084
RSA% ¼ 100 ðAc À AsÞ=Ac
IC50 values (the concentration of the tested compound in
the reaction mixture which causes 50% of RSA) were
determined by the linear regression analysis from the
obtained RSA values.
28. Saraei M, Eftekhari-Sis B, Faramarzi M, Hossienzadeh R (2014)
J Heterocycl Chem 51:1500
29. Shahrisa A, Saraei M (2009) J Heterocycl Chem 46:268
30. Shahrisa A, Miri R, Esmati S, Saraei M, Mehdipour AR, Sharifi
M (2012) Med Chem Res 21:284
31. Masateru M, Shone RL (1987) Aralkoxy and aryloxyalkoxy kojic
acid derivatives. US patent 4,705,871, Nov 10, 1987. Chem Abstr
106:156276
Acknowledgements The authors thank the Research Council of
Payame Noor University for financial support.
123

Synthesis of some novel 1,2,3-triazole derivatives containing kojic acid moiety and…
32. Fakih S, Podinovskaia M, Kong X, Collins HL, Schaible UE,
Hider RC (2008) J Med Chem 51:4539
33. Durden JA, Stansbury HA, Catlette WH (1964) J Chem Eng Data
9:228
34. Niwa Y, Akamatsu H (1991) Inflammation 15:303
35. Lajis AFB, Hamid M, Ariff AB (2012) J Biomed Biotechnol.
Article ID 952452
36. Dehghan G, Khoshkam Z (2012) Food Chem 131:422
123