Synthesis and crystal structure of novel sulfone derivatives containing 1,2,4-triazole moieties

Article abstract of DOI:10.3390/molecules15020766

Some 3-(Substituted methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2, 4-triazole derivatives were synthesized in six steps starting from easily accessible gallic acid. The resulting sulfides were then catalytically oxidized to the title sulfones with H₂O₂. The products were obtained in high yield under mild conditions and practically devoid of any by-products. The structures were confirmed by elemental analysis, IR, ¹H- and ¹³C-NMR spectral data. Furthermore, a detailed X-ray crystallography structural analysis of model triazole 7g was carried out.

Full text of DOI:10.3390/molecules15020766

Molecules 2010, 15, 766-779; doi:10.3390/molecules15020766
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Crystal Structure of Novel Sulfone Derivatives
Containing 1,2,4-Triazole Moieties
Weiming Xu, Baoan Song *, Pinaki Bhadury, Yang Song and Deyu Hu
Key Laboratory of Green Pesticide and Agriculture Bioengineering, Ministry of Education, Research
and Development Center for Fine Chemicals, Guizhou University, Guiyang 550025, China;
E-Mails: xuweiming2009@163.com (W.X.); bhadury@gzu.edu.cn (P.B.); yangsdqj@gmail.com
(Y.S.); fcc.dyhu@gzu.edu.cn (D.H.)
* Author to whom correspondence should be addressed; E-Mail: songbaoan22@yahoo.com;
Tel.: +86 851 362 0521; Fax: +86 851 362 2211.
Received: 5 November 2009; in revised form: 25 January 2010 / Accepted: 29 January 2010 /
Published: 3 February 2010
Abstract: Some 3-(Substituted methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-
1,2,4-triazole derivatives were synthesized in six steps starting from easily accessible
gallic acid. The resulting sulfides were then catalytically oxidized to the title sulfones with
H2O2. The products were obtained in high yield under mild conditions and practically
devoid of any by-products. The structures were confirmed by elemental analysis, IR,
13
1H- and C-NMR spectral data. Furthermore, a detailed X-ray crystallography structural
analysis of model triazole 7g was carried out.
Keywords: sulfone derivatives; 1,2,4-triazole; sodium tungstate; hydrogen peroxide;
synthesis; crystal structure
1. Introduction
Organic compounds incorporating heterocyclic ring systems continue to attract considerable
interest due to their wide range of biological activities. In this context, heterocyclic compounds
bearing 1,2,4-triazole scaffolds find wide application both in medicinal chemistry as antibacterial [1],
antimicrobial [2], antidepressant [3], antiinflammatory [4], antiviral [5], and human antifungal [6]
agents, and in agricultural science as potent fungicides [7], herbicides [8] and insecticides [9]. A large

Molecules 2010, 15
767
number of sulfur-containing 1,2,4-triazoles are known for their biological activities [10–12] and the
corresponding sulfone analogues are encountered in a large number of patents and chemical literature
describing extensive commercial applications [13]. Based on our earlier observation that certain
appropriately substituted 2-sulfonyl-5-(3,4,5-trimethoxyphenyl)-1,3,4-thiadiazole and 2-sulfonyl-5-
(3,4,5-trimethoxyphenyl)-1,3,4-oxadiazole derivatives possessed good bioactivity [14], we undertook
the synthesis of some additional triazole derivatives from naturally occurring gallic acid [15], and
evaluated them for their bioactivity profile after subtle structural modification. The synthetic routes to
the sulfides 6 and title sulfones 7 are depicted in Scheme 1. The structures of all the compounds were
verified by the IR, NMR, and elemental analysis. Furthermore, 3-(3-methoxybenzylsulfonyl)-4-
phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7g) was subjected to detailed investigation by
X-ray crystallography.
Scheme 1. Reagents and conditions: synthetic route to title compounds 6 and 7.
R = benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 4-bromobenzyl, 4-methylbenzyl, 2-fluorobenzyl, 3-
methoxybenzyl, allyl, methyl, ethyl.
2. Results and Discussion
2.1. Chemistry
3,4,5-Trimethoxybenzhydrazide (3) was synthesized from the starting material gallic acid through
etherification, esterification and hydrazidation. The compound 3 was then converted into 4 by reaction
with 1-isothiocyanatobenzene in ethanol. Cyclization of this intermediate with sodium hydroxide
under reflux conditions afforded 4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (5).
Subsequently, this triazole analogue was converted to the thioether derivatives 6 in a thioetherification
reaction with suitable halides (RX) catalyzed by indium or indium trichloride [16]. Treatment of the
sulfides with H2O2 catalyzed by sodium tungstate finally produced the title heterocyclic sulfone
derivatives 7. Although the electron rich thioether can be oxidized to sulfone by a variety of agents
such as m-CPBA [17], CH3CO3H [18], halogen derivatives NaClO [19], H5IO6 [20], transition metal

Molecules 2010, 15
768
derivatives e.g., manganese (iv) oxide [21] and KMnO4 [22], none of them seem to match the
advantages offered by aqueous hydrogen peroxide, which is an ideal environmentally-friendly waste-
avoiding oxidant with water being the only theoretical by-product of the reaction. Moreover, due to its
high solubility in water and many organic solvents, it is very attractive as an oxidant for solution-phase
reactions. Compared to other reagents, aqueous hydrogen peroxide is readily available, cheap, and is
associated with easy handling, storage and transportation. This prompted us to compare the efficacy of
H2O2 against other agents e.g. NaClO, KMnO4, m-CPBA, and the results are provided in Table 1.
Table 1. Effect of different oxidizing agents for the synthesis of 7a. *
Molar ratio
(Sub:Oxid)
Yield
(%)
28
0
0
45
48
Entry
Oxidant
Catalyst
Solvent
1
2
3
4
5
6
m-CPBA
KMnO4
NaClO
H2O2
H2O2
H2O2
(NH4)6Mo7O24
1:3
1:2
1:4
1:4
1:4
1:4
chloroform
glacial acetic acid
water
glacial acetic acid
glacial acetic acid
glacial acetic acid
-
-
Al2O3
-
Na2WO4·2H2O
55
* 0.43 mmol of intermediate 6a, 12 mL of solvent, the reaction time for entries 1-3 was 70 min, for
entries 4-6 was 40 min; all the reactions were conducted at 45 °C.
It could be easily observed that amongst all the oxidizing agents, H2O2 afforded the highest yield of
the product (Table 1, Entries 4–6). Since some Lewis acid metal catalysts possessing vacant orbitals
e.g. Sc(OTf)3 [23], Fe(III)-and Mn(III)-meso-tetraarylporphyrin [24], (NH4)2MoO4 [25] and
methyltrioxorhenium(VII) (CH3ReO3, abbreviated as MTO) [26] are known to catalyze certain
oxidative reactions, the role of catalysts Al2O3, (NH4)2MoO4, and Na2WO4·2H2O was studied in
selected cases. The yield of sulfone was found to be considerably lower with the oxidant m-CPBA in
the presence of the catalyst (NH4)2MoO4 (Entry 1) and practically negligible for the uncatalyzed
reactions using oxidants KMnO4 and NaClO, respectively (Entries 2 and 3). When the oxidation with
hydrogen peroxide was executed in the presence of catalysts Al2O3 and Na2WO4·2H2O, the later
exhibited much superior activity compared to the former (Entries 4 and 6). This is indeed in line with
the observation noted by Sato et al. [27] who reported an effective conversion of diaryl sulfides into
sulfones by the oxidant hydrogen peroxide in the presence of the catalyst sodium tungstate. Having
established the role of the oxidant H2O2 and the catalyst Na2WO4·2H2O, a systematic study of the
effect of reaction parameters e.g., reaction temperature, time, solvent, molar ratio (substrate: oxidant)
and the amount of catalyst was undertaken for optimization of the reaction. The results for the
synthesis of 7a are summarized in Table 2.
First, the effect of amount of the oxidant was studied. As the molar ratio of the reagents (substrate:
hydrogen peroxide) was varied at 55 °C (Table 2, Entries 1–4), a maximum yield of 88% was noticed
with a molar ratio of 1:6 (Table 2, Entry 2). On increasing the temperature from 45 °C to 50 °C and
then 55 °C, the corresponding yields obtained were 77.0%, 84% and 88% (Table 2, Entries 5, 6, and 2)
respectively. When the temperature was further increased to 60 °C and 70 °C, no improvement but
rather a slight lowering in the yield (Table 2, Entries 7–8) was observed.

Molecules 2010, 15
Table 2. Optimization of reaction conditions for the synthesis of 7a.*
769
Molar ratio
Sub:Oxi
1:5
Yield
Entry
T/°C
Time/min
Solvent
(%)
74
88
83
64
77
84
82
77
70
84
16
70
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
55
55
55
55
45
50
60
70
55
55
55
55
55
55
55
50
50
50
50
50
50
50
50
40
70
50
50
50
50
50
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
glacial acetic acid
acetonitrile
1:6
1:7
1:8
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
1:6
toluene
acetone
ethanol
DMF
0
41
* Reaction conditions: 0.43 mmol of intermediate 6a, 12 mL of solvent, oxidant was H2O2, catalyst
was Na2WO4·2H2O.
Next, in order to obtain ideal reaction time, the reaction was also carried out for 40 min and 70 min
(Entries 9 and 10), but the most suitable time was found to be 50 min (Entry 2). Amongst the different
solvents examined, yields were found to be significantly lower in N,N-dimethylformamide (DMF),
acetonitrile and toluene as compared to glacial acetic acid, while practically no product was observed
in acetone and ethanol (Table 2, Entries 2 and 11–15). The ability of glacial acetic acid to serve both
as a proton donor and a miscible cosolvent for organic/aqueous phase might account for this
observation. Based on these results, the optimal conditions for the synthesis of sulfone are established
with a molar ratio of (substrate:oxidant) 1:6 in glacial acetic acid at 55 °C for 50 min. As may be seen
from Table 3, using optimal conditions, the compounds 7a-7i were obtained in high yields (80–92%).
Table 3. Yields of compound 7 under optimized conditions.
Entry
Compound
R
Yield (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
benzyl
88
85
89
88
80
89
92
89
88
4-fluorobenzyl
4-methoxybenzyl
4-bromobenzyl
4-methylbenzyl
2-fluorobenzyl
3-methoxybenzyl
allyl
methyl

Molecules 2010, 15
770
2.2. Crystal Structure Analysis of 7g
The crystal data and summary of data collection and structure refinement of 7g are given in Table 4.
Selected bond lengths and angles are given in Table 5. The molecular structure of compound 7g is
shown in Figure 1 and the packing of the molecule in crystal lattice is illustrated in Figure 2.
Table 4. Crystal data and summary of data collection and structure refinement.
Compound
C25H25N3O6S
Formula weight
Crystal system, Space group
a(nm)
495.54
Triclinic, p-1
0.74510(10)
b(nm)
1.17850(16)
c(nm)
1.39007(19)
α(°)
80.593(5)
β(°)
89.492(5)
γ(°)
88.471(5)
1.2038(3)
2
1.367
520
Volume(nm3)
Formula units
Calculated density(Mg/m3)
F(000)
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices[I>2σ(I)]
Rindices(all data)
Semi-empirical frome quivalents
Full-matrix least-squares on F2
4536/0/316
1.062
R1 = 0.0426, ωR1 = 0.1103
R1 = 0.0574, ωR1 = 0.1192
Table 5. Crystal data and summary of data collection and structure refinement.
Length
(nm)
Angle
(°)
C(1)-O(1)
C(4)-O(1)
C(4)-C(9)
C(5)-O(2)
C(6)-C(7)
0.1429(3)
0.1362(2)
0.1395(2)
0.1374(2)
0.1383(2)
0.1480(2)
0.1312(2)
0.1376(2)
0.1304(2)
0.1367(2)
C(7)-C(8)-C(10)
N(1)-C(10)-N(3)
N(1)-C(10)-C(8)
N(3)-C(10)-C(8)
N(2)-C(11)-N(3)
N(2)-C(11)-S(1)
N(3)-C(11)-S(1)
C(17)-C(12)-C(13)
C(17)-C(12)-N(3)
C(13)-C(12)-N(3)
119.60(16)
110.30(14)
126.10(15)
123.59(15)
111.96(15)
125.30(13)
122.63(13)
121.50(17)
118.90(16)
119.59(16)
109.60(13)
120.28(17)
120.36(18)
119.35(17)
107.69(14)
106.23(14)
103.83(14)
127.11(14)
C(8)-C(10)
C(10)-N(1)
C(10)-N(3)
C(11)-N(2)
C(11)-N(3)
C(11)-S(1)
C(12)-C(17)
C(12)-C(13)
C(12)-N(3)
C(16)-C(17)
C(18)-C(19)
C(18)-S(1)
C(19)-C(20)
0.1785(17) C(19)-C(18)-S(1)
0.1376(3)
0.1377(3)
0.1453(2)
0.1382(3)
0.1514(2)
C(20)-C(19)-C(24)
C(20)-C(19)-C(18)
C(24)-C(19)-C(18)
C(10)-N(1)-N(2)
C(11)-N(2)-N(1)
0.1777(19) C(11)-N(3)-C(10)
0.1382(3) C(11)-N(3)-C(12)

Molecules 2010, 15
771
Table 5. Cont.
C(10)-N(3)-C(12)
C(20)-C(21)
0.1388(3)
0.1392(3)
0.1366(2)
0.1419(3)
0.1396(2)
129.06(14)
118.34(11)
110.62(10)
109.92(10)
106.08(9)
108.40(9)
102.14(8)
C(22)-C(23)
C(23)-O(6)
C(25)-O(6)
N(1)-N(2)
O(4)-S(1)
O(4)-S(1)-O(5)
O(4)-S(1)-C(18)
O(5)-S(1)-C(18)
O(4)-S(1)-C(11)
0.1425(16) O(5)-S(1)-C(11)
0.1427(16) C(18)-S(1)-C(11)
O(5)-S(1)
Figure 1. The molecular structure of 7g.
Figure 2. The packing of the molecule in crystal lattice of 7g.

Molecules 2010, 15
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From the bond length data it can be observed that the bond length of N(1)-N(2) is 0.1396 nm, which
is shorter than the normal single N-N bond length (0.1450 nm). The bond lengths of 0.1376 nm and
0.1367 nm for N(3)-C(10) and N(3)-C(11), respectively, are shorter than normal single N-C bond
length (0.1470 nm) and hence indicative of some double bond character. Again, the N(1)-C(10)
(0.1312 nm) and the N(2)-C(11) (0.1304 nm) bond lengths are significantly closer to that of a typical
C=N bond (0.134 nm). The N-C and N=C bonds near the phenyl ring are longer than the symmetrical
bonds present near the sulfone presumably due to the conjugation of the phenyl with the triazole ring.
The bond lengths observed in the 1,2,4-tirazole ring are in agreement with those found in other related
studies [28–29]. The bond angle of C(10)-N(1)-N(2) is 107.69(14)° and C(11)-N(2)-N(1) is
106.23(14)°. The bond angle values further confirm the presence of delocalization in the triazole ring.
In the title compound, three phenyl rings (p3) are situated at different orientations with the triazole
ring (p1). The dihedral angle between p1 and the 3,4,5-trimethoxyphenyl moiety (p2) is 42.53°, p1 and
p3 is 75.25°, p1 and 4-methoxyphenyl (p4) is 79.29°. p2, p3 and p4 are torsional leading to a steady
system. In the crystal structure, C-H⋯ π supramolecular interactions occur between adjacent molecules
with C(1)-H1B⋯ p4 angle of 155.30°, H1B⋯ p4 distance of 0.27375 nm, C(1)⋯ p4 distance of
0.3632(3) nm, C(3)-H3C⋯ p1 angle of 128.81°, H3C⋯ p1 distance of 0.30359 nm, C(3)⋯ p1 distance
of 0.3714(3) nm, C(14)-H14⋯ p2 angle of 155.46°, H14⋯ p4 distance of 0.26964 nm and C(14)⋯ p2
distance of 0.3563(2) nm. In the solid state, the above mentioned hydrogen bonds that connect the
molecules through a three dimensional network presumably stabilize the crystal structure.
3. Experimental
3.1. General
Unless otherwise stated, all the reagents and reactants were purchased from commercial suppliers;
melting points were determined on a XT-4 binocular microscope (Beijing Tech Instrument Co., China)
13
and are uncorrected; the 1H-NMR and C-NMR spectra were recorded on a JEOL ECX 500 NMR
1
13
spectrometer at room temperature operating at 500 MHz for H-NMR and 125 MHz for C-NMR by
using CDCl3 as the solvent and TMS as an internal standard; infrared spectra were recorded in KBr on
a Bruker VECTOR 22 spectrometer; elemental analysis was performed on an Elemental Vario-III
CHN analyzer. The course of the reactions was monitored by TLC; analytical TLC was performed on
silica gel GF254; column chromatographic purification was carried out using silica gel. The
carbothiamide (4) was prepared as described in the literature from gallic acid as the starting material
through esterification and hydrazidation [30].
3.2. Preparation of 4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (5) [16]
A solution of compound 4 (2.39 g, 6.62 mmol) in 2 mol/L aqueous sodium hydroxide (5 mL,
10.0 mmol) was heated under reflux for 8 h. After cooling to room temperature, the solution was
acidified with dilute hydrochloric acid. The precipitate was filtered off, washed with water, dried and
recrystallized from ethanol to afford a white solid; yield 70.0%; m.p. 185–186 °C.

Molecules 2010, 15
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3.3. Preparation of 3-(substituted methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazoles 6
A mixture of 4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole-3-thiol (5) (0.54 g,
1.57 mmol), 2.6% aqueous NaOH solution (1.57 mmol) and water (20 mL) was stirred at room
temperature for 5 min; then the appropriate halides (1.57 mmol) and InCl3 (0.34 g, 0.157 mmol) were
added and the solution was further stirred for an additional 5 h. The mixture was filtered and the
resulting crude solid was washed with 5% Na2CO3 solution and distilled water, dried under vacuum,
and recrystallized from methanol and water (v/v = 3:1) to afford the pure compounds 6.
3-(Benzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6a): This compound was
obtained as a white solid; yield 88%; m.p. 136–138 °C (lit [16] 139–141 °C); 1H-NMR: δ3.61 (s, 6H,
3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.47 (s, 2H, CH2S), 6.63 (s, 2H, 3,4,5-trimethoxybenzyl-H),
13
7.14-7.49 (m, 10H, Ar-H); C-NMR: δ 37.43, 55.91, 60.97, 105.16, 121.75, 127.66, 127.81, 128.72,
129.31, 129.97, 130.06, 134.59, 136.57, 139.08, 152.53, 153.09, 154.61.
3-(4-Fluorobenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6b): white solid, yield
85%; m.p. 88–90 °C; IR (KBr cm-1): ν 1587, 1521, 1487, 1462, 1431 (C=N and C=C of rings), 698 (C-
1
S-C); H-NMR: δ 3.59 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.43 (s, 2H, CH2S), 6.64 (s, 2H,
3,4,5-trimethoxybenzyl-H), 7.14-7.50 (m, 9H, Ar-H); 13C-NMR: δ 36.43, 55.91, 60.97, 105.25,
121.65, 127.61, 128.82, 130.01, 130.07, 130.68, 133.64, 134.53, 135.39, 139.22, 152.03, 153.11,
154.71; Anal. Calcd. for C24H22FN3O3S(451.51): C 63.84%, H 4.91%, N 9.31%. Found: C 63.68%, H
4.72%, N 9.26%.
3-(4-Methoxybenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6c): white solid,
yield 94%; m.p. 135-136 °C (lit [16] 140–142 °C); 1H-NMR: δ3.61 (s, 6H, 3,5-di-CH3O), 3.71 (s, 3H,
4-CH3O of 4-methoxybenzyl), 3.82 (s, 3H, 4-CH3O), 4.50 (s, 2H, CH2S), 6.64 (s, 2H, 3,4,5-
trimethoxy-benzyl-H), 7.28-7.56 (m, 9H, Ar-H); 13C-NMR: δ 35.33, 55.31, 55.87, 55.94, 105.25,
113.62, 114.72, 121.76, 128.83, 129.71, 130.02, 134.67, 138.09, 139.12, 152.41, 153.19, 154.65,
159.71;
3-(4-Bromobenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6d): white solid, yield
88%; m.p. 165–167 °C; IR (KB, cm-1): ν 1587, 1508, 1498, 1463, 1425 (C=N and C=C of rings), 705
1
(C-S-C); H-NMR: δ 3.60 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.42 (s, 2H, CH2S), 6.63 (s,
13
2H, 3,4,5-trimethoxybenzyl-H), 7.13–7.50 (m, 9H, Ar-H); C-NMR: δ 36.49, 55.91, 60.97, 105.26,
121.64, 121.76, 127.61, 130.01, 130.07, 131.02, 131.79, 134.53, 135.93, 139.24, 152.09, 153.11,
154.72; Calcd. for C24H22BrN3O3S(512.42): C 56.25%, H 4.33%, N 8.20%. Found: C 56.16%, H
4.39%, N 8.30%.
3-(4-Methylbenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6e): white solid, yield
91.2%; m.p. 150–152 °C; IR (KBr cm-1): ν 1587, 1512, 1487, 1458, 1429 (C=N and C=C of rings),
705 (C-S-C); 1H-NMR: δ 2.31 (s, 3H, 4-CH3 of 4-methylbenzyl), δ: 3.60 (s, 6H, 3,5-di-CH3O), 3.82 (s,
3H, 4-CH3O), 4.45 (s, 2H, CH2S)，6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.08-7.48 (m, 9H, Ar-H);
13C-NMR: δ 21.23, 37.10, 55.91, 60.97, 105.27, 121.80, 127.68, 129.22, 129.40, 129.90, 130.01,

Molecules 2010, 15
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133.43, 134.65, 137.59, 139.15, 152.71, 153.09, 154.56; Anal. Calcd. for C25H25N3O3S (447.55): C
67.09%, H 5.63%, N 9.39%. Found: C 67.20%, H 5.48%, N 9.42%.
3-(2-Fluorobenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6f): white solid, yield
89%; m.p. 88–90 °C; IR (KBr cm-1): ν 1587, 1521, 1487, 1462, 1431 (C=N and C=C of rings), 698 (C-
1
S-C); H-NMR: δ 3.60 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.51 (s, 2H, CH2S), 6.64 (s, 2H,
3,4,5-trimethoxybenzyl-H), 7.00-7.51 (m, 9H, Ar-H); 13C-NMR: δ 30.47, 55.91, 60.97, 105.26,
115.63, 121.73, 124.12, 124.29, 127.64, 129.99, 130.06, 131.65, 134.55, 139.20, 152.34, 153.10,
154.71, 160.10, 162.07; Anal. Calcd. for C24H22FN3O3S (451.51): C 63.84%, H 4.91%, N 9.31%.
Found: C 63,68%, H 4.72%, N 9.26%.
3-(3-Methoxybenzylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6g): white solid,
1
yield 78.0%; m.p. 140–141 °C (lit [16] 145–147 °C); H-NMR: δ 3.59 (s, 6H, 3,5-di-CH3O), 3.74 (s,
3H, 3-CH3O of 3-methoxybenzyl), 3.80 (s, 3H, 4-CH3O), 4.43 (s, 2H, CH2S), 6.64 (s, 2H, 3,4,5-
trimethoxy-benzyl-H), 7.28-7.48 (m, 9H, Ar-H); 13C-NMR: δ 37.43, 55.32, 55.87, 55.90, 105.23,
113.69, 114.72, 121.76, 127.63, 129.94, 130.02, 134.57, 138.00, 139.12, 152.45, 153.09, 154.65,
159.79.
3-(Allylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6h): white solid, yield 82.0%;
1
m.p. 97–98 °C (lit [16] 102–104 °C); H-NMR: δ 3.60 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O),
3.91 (s, 2H, CH2S), 5.14-5.32 (m, 2H, C=CH2), 5.96–5.60 (m, 1H, HC=C), 6.64 (s, 2H, 3,4,5-
trimethoxybenzyl-H), 7.27–7.56 (m, 5H, Ar-H); 13C-NMR: δ35.56, 55.88, 61.03, 105.23, 119.22,
121.76, 127.74, 130.00, 130.11, 132.65, 134.66, 139.07, 152.30, 153.05, 154.67.
3-(Methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (6i): white solid, yield 76.0%.
mp 102–104 °C (lit [16] 114–116 °C); 1H-NMR: δ 2.73 (s, 3H, CH3S), 3.60 (s, 6H, 3,5-di-CH3O), 3.82
(s, 3H, 4-CH3O), 6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.27-7.55 (m, 5H, Ar-H); 13C-NMR: δ 14.86,
55.94, 61.01, 105.26, 121.80, 127.55, 130.05, 130.14, 134.65, 139.08, 153.08, 153.83, 154.77.
3.4. General procedure for the preparation of title compounds 7
To a three-necked 100 mL flask equipped with a magnetic stirrer was added 3-(substituted
methylthio)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (0.43 mmol), acetic acid (10 mL)
and Na2WO4·2H2O (0.007 g, 0.022 mmol). The resulting mixture was stirred for 5 min, and then 30%
H2O2 (0.29 g, 2.58 mmol) was slowly added into the system, heated to 55 °C and the reaction was
continued for 50 min. After cooling to room temperature, the mixture was neutralized by 5% sodium
hydroxide to a pH of 7.0, extracted with chloroform (3 × 30 mL), dried over anhydrous magnesium
sulfate, and separated on silica column with ethyl acetate /petroleum ether (v/v = 1:3) to give pure
products 7.
3-(Benzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7a): white solid, yield
88.6%; m.p. 152–153 °C; IR (KBr cm-1): ν 1587, 1519, 1496, 1473, 1458 (C=N and C=C of rings),
1342, 1147 (SO2); 1H-NMR: δ 3.59 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.86 (s, 2H, CH2SO2),
13
6.62 (s, 2H, 3,4,5-trimethoxybenzyl-H), 6.99–7.49 (m, 10H, Ar-H); C-NMR: δ 55.91, 60.90, 61.73,

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105.88, 120.00, 125.95, 127.63, 128.92, 129.34, 129.58, 130.47, 131.76, 133.35, 139.92, 152.23,
153.11, 155.82; Anal. Calcd. for C24H23N3O5S (465.52): C 61.92%, H 4.98%, N 9.03%. Found: C
62.01%, H 4.51%, N 9.05%.
3-(4-Fluorobenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7b): white solid,
yield 85.0%; m.p. 152–153 °C; IR (KBr cm-1): ν 1585, 1521, 1496, 1473, 1458 (C=N and C=C of
1
rings), 1338, 1158 (SO2); H-NMR: δ 3.60 (s, 6H, 3,5-di-CH3O), 3.83 (s, 3H, 4-CH3O), 4.87 (s, 2H,
CH2SO2), 6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.15-7.52 (m, 9H, Ar-H); 13C-NMR: δ 56.00, 60.76,
61.00, 105.97, 119.93, 124.58, 127.69, 129.20, 129.81, 130.68, 133.15, 133.33, 135.80, 139.94,
152.27, 153.23, 156.05; Anal. Calcd. for C24H22FN3O5S (483.51): C 59.62%, H 4.59%, N 8.69%.
Found: C 59.91%, H 4.96%, N 8.86%.
3-(4-Methoxybenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7c): white solid,
yield 89.0%; m.p. 182–184 °C; IR (KBr cm-1): ν 1585, 1517, 1496, 1473, 1458 (C=N and C=C of
1
rings), 1334, 1147 (SO2); H-NMR: δ 3.61 (s, 6H, 3,5-di-CH3O), 3.71 (s, 3H, 4-CH3O of 4-
methoxybenzyl), 3.87 (s, 3H, 4-CH3O), 4.82 (s, 2H, CH2SO2), 6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H),
13
7.04-7.51 (m, 9H, Ar-H); C-NMR: δ 55.80, 60.45, 60.92, 105.94, 115.60, 120.85, 122.90, 127.91,
129.64, 130.04, 130.98, 131.70, 133.01, 135.01, 139.80, 153.26, 153.41, 160.64; Anal. Calcd. for
C25H25N3O6S (495.55): C 60.59%, H 5.08%, N 8.48%. Found: C 60.70%, H 5.04%, N 8.55%.
3-(4-Bromobenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7d): white solid,
yield 88.0%; m.p. 172–173 °C; IR (KBr cm-1): ν 1585, 1520, 1498, 1479, 1458 (C=N and C=C of
1
rings), 1332, 1145(SO2); H-NMR: δ 3.60 (s, 6H, 3,5-di-CH3O), 3.83 (s, 3H, 4-CH3O), 4.85 (s, 2H,
CH2SO2), 6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.14-7.52 (m, 9H, Ar-H); 13C-NMR: δ 55.91, 60.76,
60.91, 105.90, 119.84, 123.94, 125.04, 127.59, 129.72, 130.60, 132.10, 133.24, 133.35, 139.88,
152.16, 153.15, 155.98; Anal. Calcd. for C24H22BrN3O5S (544.42): C 52.95%, H 4.07%, N 7.72%.
Found: C 53.35%, H 4.29%, N 7.52%.
3-(4-Methylbenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7e): white solid,
yield 80.2%; m.p. 181–183 °C; IR (KBr cm-1): ν 1587, 1514, 1498, 1475, 1454 (C=N and C=C of
1
rings), 1334, 1143 (SO2); H-NMR: δ 2.35 (s, 3H, 4-CH3 of 4-methylbenzyl), 3.60 (s, 6H, 3,5-di-
CH3O), 3.82 (s, 3H, 4-CH3O), 4.83 (s, 2H, CH2SO2), 6.63 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.04-
13
7.51 (m, 9H, Ar-H); C-NMR: δ 21.35, 55.99, 61.00, 60.99, 61.48, 105.95, 120.14, 122.83, 127.75,
129.68, 130.53, 131.70, 133.48, 139.50, 140.04, 152.44, 153.18, 155.88; Anal. Calcd. for
C25H25N3O5S (479.55): C 62.61%, H 5.25%, N 8.76%; Found: C 62.61%, H 4.76%, N 8.52%.
3-(2-Fluorobenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7f): white solid.
yield 89.0%; m.p. 153–154 °C; IR (KBr cm-1): ν 1587, 1519, 1496, 1477, 1460 (C=N and C=C of
1
rings), 1323, 1153 (SO2); H-NMR: δ 3.61 (s, 6H, 3,5-di-CH3O), 3.83 (s, 3H, 4-CH3O), 4.97 (s, 2H,
CH2SO2), 6.67 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.09-7.54 (m, 9H, Ar-H); 13C-NMR: δ 54.94, 56.02,
60.99, 106.04, 113.71, 115.95, 116.12, 120.05, 124.62, 127.79, 130.70, 131.68, 133.44, 139.78,
152.52, 153.23, 156.16, 160.98, 162.97; Anal. Calcd. for C24H22FN3O5S (483.51): C 59.62%, H
4.59%, N 8.69%. Found: C 59.50%, H 4.54%, N 8.30%.

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3-(3-Methoxybenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7g): white solid,
yield 92.8%; m.p. 153–155 °C; IR (KBr cm-1): ν 1598, 1514, 1492, 1471, 1460(C=N and C=C of
1
rings), 1321, 1124(SO2); H NMR (CDCl3, 500 MHz): δ 3.59 (s, 6H, 3,5-di-CH3O), 3.73 (s, 3H, 3-
CH3O of 3- methoxybenzyl), 3.82 (d, 3H, 4-CH3O), 4.81 (s, 2H, CH2SO2)，6.62 (s, 2H, 3,4,5-
13
trimethoxy benzyl-H), 6.83-7.50 (m, 9H, Ar-H); C NMR (CDCl3, 125 MHz): δ 55.41, 55.99, 60.98,
61.96, 105.96, 115.76, 116.49, 120.10, 124.05, 127.74, 129.60, 129.97, 130.51, 133.42, 140.04,
153.18, 155.94, 159.96; Anal. Calcd. for C25H25N3O6S (495.55): C 60.59%, H 5.08%, N 8.48%.
Found: C 60.56%, H 5.43%, N 8.87%.
3-(Allylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7h): white solid, yield 89.5%;
m.p. 132–134 °C; IR (KBr cm-1): ν 1589, 1518, 1496, 1479, 1456 (C=N and C=C of rings), 1325, 1145
(SO2); 1H-NMR: δ 3.591 (s, 6H, 3,5-di-CH3O), 3.82 (s, 3H, 4-CH3O), 4.33 (s, 2H, CH2SO2), 5.51-5.55
(m, 2H, C=CH2), 5.89-5.95 (m, 1H, HC=C), 6.65 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.42-7.56 (m,
13
5H, Ar-H); C-NMR: δ 55.98, 59.52, 61.00, 105.94, 120.05, 122.90, 126.81, 127.87, 129.97, 130.79,
133.45, 140.00, 152.50, 153.19, 156.01; Anal. Calcd. for C20H21N3O5S (415.46): C 57.82%, H 5.09%,
N 10.11%. Found: C 57.52%, H 5.38%, N 10.45%.
3-(Methylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-triazole (7i): white solid, yield
80.2%; m.p. 141–143 °C, IR (KBr cm-1): ν 1587, 1514, 1498, 1475, 1454 (C=N and C=C of rings),
1
1334, 1143 (SO2), H-NMR: δ 3.49 (s, 3H, CH3-SO2), 3.59 (s, 6H, 3,5-di-CH3O), 3.81 (s, 3H, 4-
13
CH3O), 6.64 (s, 2H, 3,4,5-trimethoxybenzyl-H), 7.41-7.54 (m, 5H, Ar-H); C-NMR: δ 43.02, 55.99,
60.97, 106.01, 119.99, 127.81, 130.03, 130.81, 133.40, 140.09, 153.22, 153.60, 156.22; Anal Calcd.
for C18H19N3O5S (389.43): C 55.52%, H 4.92%, N 10.79%. Found: C 55.32%, H 4.61%, N 10.84%.
3.5. X-ray structure determination of 7g
A crystal of the title compound with dimensions of 0.20 mm × 0.22 mm × 0.18 mm was mounted
on a Bruker SM ART Apex area-detector diffractometer with a graphite-monochromated Mo-Ka
radiation(λ = 0.071073 nm) by using an φ-ω scan mode at 293(2) K in the range of 1.48 ≤ θ ≤ 25.99. A
total of 12566 reflections were collected, of which 4536 were independent (Rint = 0.0318) and 3543
were observed with I > 2σ(I). The calculations were performed with SHELXS-97 program [31] and the
empirical absorption corrections were applied to all intensity data. The non-hydrogen atoms were
refined anisotropically. The hydrogen atoms were determined with theoretical calculations and refined
isotropically. The final full-matrix least-squares refinement gave R = 0.0426 and ωR = 0.1103
(ω = l/[σ2(Fo2) + (0.0607P)2 + 0.0212P], where P = ( Fo2 + 2Fc2)/3). S = 1.033, (Δσ)max/(e.nm-3) = 174,
(Δσ)min/(e.nm-3) = -353. Crystallographic data (excluding structure factors) for the structure have been
deposited with the Cambridge Crystallographic Data Center as supplementary publication No. CCDC
703877. These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/
data_request/cif.

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4. Conclusions
In the present study, a mild and effective method for the preparation of novel sulfone derivatives
containing 1,2,4-triazole moieties was undertaken using gallic acid as the starting material. The key
step of the oxidation from thioether to the corresponding sulfone was optimized. The method has some
salient features such as faster reaction rates, high yields and environmental friendliness. The
13
synthesized compounds were characterized by spectral data (1H-NMR, C-NMR, IR) and elemental
analysis. Furthermore, 3-(3-methoxybenzylsulfonyl)-4-phenyl-5-(3,4,5-trimethoxyphenyl)-4H-1,2,4-
triazole (7g) was investigated by X-ray crystallographic analysis. In the solid state, a three dimensional
hydrogen bond network within the molecule presumably imparts stability to the crystal lattice.
Acknowledgements
We are grateful to the National Natural Science Foundation of China (Nos. 20962005, 20762002)
for supporting the project.
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© 2010 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).