Synthesis, Crystal Structure, and Biological Activity of Some Novel Sulfoxide Compounds Containing 1,2,3-Thiadiazole Moiety

Article abstract of DOI:10.1080/10426507.2015.1031755

Some new sulfoxide compounds containing 1,2,3-thiadiazole moiety were synthesized from diethyl carbonate and hydrazine hydrate by multi-step reactions. Their structures were confirmed by NMR, MS, and elemental analysis. One of the title compounds, 5-(4-cyclopropyl-5-((3-fluorobenzyl)sulfinyl)-4H-1,2,4-triazol-3-yl)-4-methyl-1,2,3-thiadiazole (C₁₅H₁₄FN₅OS₂), was structurally determined by a single crystal X-ray diffraction study. The biological activity of the title compound was determined, and the results showed that it displays moderate biological activities.

Full text of DOI:10.1080/10426507.2015.1031755

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Synthesis, Crystal Structure and Biological Activity
of Some Novel Sulfoxide Compounds Containing
1,2,3-thiadiazole Moiety
Li-Jing Min, Ming-Yan Yang, Jin-Xia Mu, Zhao-Hui Sun, Cheng-Xia Tan, Jian-
Quan Weng, Xing-Hai Liu & Yong-Gang Zhang
To cite this article: Li-Jing Min, Ming-Yan Yang, Jin-Xia Mu, Zhao-Hui Sun, Cheng-Xia Tan, Jian-
Quan Weng, Xing-Hai Liu & Yong-Gang Zhang (2015): Synthesis, Crystal Structure and Biological
Activity of Some Novel Sulfoxide Compounds Containing 1,2,3-thiadiazole Moiety, Phosphorus,
Sulfur, and Silicon and the Related Elements, DOI: 10.1080/10426507.2015.1031755
To link to this article: http://dx.doi.org/10.1080/10426507.2015.1031755
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ACCEPTED MANUSCRIPT
Synthesis, Crystal Structure and Biological Activity of Some Novel Sulfoxide Compounds
Containing 1,2,3-thiadiazole Moiety
Li-Jing Min1, Ming-Yan Yang2, Jin-Xia Mu4, Zhao-Hui Sun2, Cheng-Xia Tan2, Jian-Quan Weng2,
Xing-Hai Liu2,* , Yong-Gang Zhang3,*
1College of Life Science, Huzhou University, Huzhou, 313000, Zhejiang, China
2College of Chemical Engineering, Zhejiang University of Technology, Hangzhou, 310014,
Zhejiang, China
3Biology Institute of Shandong Academy of Science, Jinan, 250014, China
4College of Quality & Safety Engineering, China Jiliang University, Hangzhou, 310018,
Zhejiang, China
*Address correspondence to Xing-Hai Liu, College of Chemical Engineering and Materials
Science, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China. E-mail:
xhliu@zjut.edu.cn
**Address correspondence Biology Institute of Shandong Academy of Science, Jinan, 250014,
China, email: zhangyg@sdas.org
Abstract
Some new sulfoxide compounds containing 1,2,3-thiadiazole moiety were synthesized from
diethyl carbonate and hydrazine hydrate by multi-step reactions. Their structures were
confirmed by NMR, MS and elemental analysis. One of the title compounds,
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5-(4-cyclopropyl-5-((3-fluorobenzyl)sulfinyl)-4H-1,2,4-triazol-3-yl)-4-methyl-1,2,3-thiadiazole
(C15H14FN5OS2), was structurally determined by a single crystal X-ray diffraction study. The
biological activity of the title compound was determined and the results showed that it displays
moderate biological activities.
Keywords
crystal structure, synthesis, 1,2,3-thiadiazole, sulfoxide, herbicidal activity
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INTRODUCTION
Research in heterocyclic compounds is an active area because of their medicinal and
pesticidal importance [1-3], such as Keto-Acid Reducto-Isomerase activities [4], antifungal
activities [5], anticancer activity[6], and antibacterial activity[7]. In recent years, 1,2,4-triazole
compounds were shown to exhibit excellent activities[8]. For example, some of them have been
developed as commercial drugs or pesticides (Figure 1). Due to their diverse properties,
1,2,4-triazole fungicides become one of the foci in drug research. As well as 1,2,4-triazole,
1,2,3-thiadiazole derivatives have also displayed a wide spectrum of remarkable biological
activities (Figure 1), such as fungicidal activities [9-10], anti-HBV [11], and as neuroprotective
agents [12]. Furthermore, the sulfoxide group is a key group in many biological molecules,
perhaps the SO group is a hydrogen bond receptor. In the past years, many active compounds
containing the sulfoxide group were discovered[13].
In view of these facts mentioned above, and also as a part of our work[14-20] on the
synthesis of bioactive lead compounds, the title compounds were designed, synthesized and
1
characterized by H NMR, MS and elemental analysis. The crystal structure of title compound
was determined. The biological activity of title compound was also tested.
RESULTS AND DISCUSSION
Chemistry and Activity
The presented research work illustrates the synthesis of new sulfoxides as outlined in
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Scheme
4-cyclopropyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazole-3-thiol (8) was synthesized
by the reaction of N-cyclopropyl-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)
1.
The
parent
molecule,
the
key
intermediate
hydrazinecarbothioamide (7) under basic conditions. The product thioether (9) was obtained
from 4-cyclopropyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazole-3-thiol (8) with halides.
The target compounds were obtained via oxidation. In the process of the oxidation, KMnO4,
K2S2O8, m-CPBA or H2O2/HOAc were used as oxidizing agents. When we used KMnO4, K2S2O8,
H2O2/HOAc as oxidation agents, the final product was a sulfone, indicating that the oxidation is
too strong, while the use of m-CPBA as oxidation agent, afforded the sulfoxide, although the
sulfone product was also found (Table 1).
The final product was collected by the addition of cold water and filtration/solvent
extraction depending upon the conditions of the products. The structures of the new compounds
were verified by 1H-NMR and mass spectral data, elemental analysis data and the X-ray data as
illustrated above in the experimental section.
Compound 10a was obtained as a white power having the molecular formula C15H14FN5OS2.
In its ESI-MS spectrum, molecule 10a showed a 2M+Na peak(m/z 748.78) and M+Na peak(m/z
1
386.10) respectively. In the H-NMR spectrum, the signals of CH2 nearby sulfonyl group
resonated at 4.77 ppm and 5.10 ppm as two doublets with J coupling of 12.96 and 12.93 Hz. The
signals of cyclopropane group appeared at 0.93-1.16 and 1.25-1.37 as two multi-peaks
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respectively. The signal of CH3 of 1,2,3-thaidiazole appeared at 3.03 ppm. The elemental
analysis results are in accord with the theoretical value.
To investigate the KARI inhibitory activity and herbicidal activity of these synthesized title
compounds, cyclopropane-1,1-dicarboxylic acid (CPD), a potent inhibitor of KARI in vitro, was
used as the control. We found that title compound 10a showed moderate inhibition abilities on
rape root than the control CPD at 100 μg/mL (41.7%). It displayed only weak activity against
Echinochloa crusgalli (31.7%) and KARI (18.76%) at 100 μg/mL.
Crystal Structure
Selected bond lengths, bond angles and torsion angles are shown in Table 2. The molecular
structure of the title compound is shown in Figure 2. The molecular packing of the molecule is
shown in Figure S 1 (Supplemental Materials).
Generally, the average bond lengths and bond angles of ring system (phenyl, cyclopropane,
triazole and 1,2,3-thiadiazole) are in the observed normal ranges [20-26]. However, the C2=N2
bond [1.357(3) Å] and C3=N4 [1.326(3) Å] are longer than the general C=N double bond length
of 1.27 Å [27]. As shown in Figure 2, the 1,2,3-thiadiazole ring is nearly planar with
1,2,4-triazole ring with a small dihedral angle (θ) of 24.9º. The triazole ring (N3, N4, C5, N5, C4)
and thiadiazole ring (N1, N2, S1, C3, C2) is essentially planar, with plane equation -1.264x +
1.117y + 11.170z = 8.2129 and -0.332x + 6.591y + 9.665z = 7.8466 respectively, and the largest
deviation from the least squares plane is 0.00066 Å and 0.00020 Å. Meanwhile, the phenyl ring
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is parallel with both the 1,2,3-thiadiazole ring and the 1,2,4-triazole ring with the respective
dihedral angles of 25.6 º and 26.5 º. The cyclopropane ring is nearly vertical with
1,2,3-thiadiazole ring(123.7º), 1,2,4-triazole ring(99.2º) and phenyl ring(104.9º) respectively.
The S1=O1 bond length is 1.4822(17) Å. It is larger than that bond of SO2. The torsion angle of
thioether group C5–S1–C9–C10 is 60.48(19)°.
In the intermolecular edge-to-face π-π stacking pattern of the title compound, it is worth
mentioning that the two molecules of each stacking unit are centrosymmetric, which can be
proven by the relative position of the CH3 of H and thiadiazole rings of the two molecules: the
centroid separation of them is 3.411 Å, and their dihedral angle is 76.35º. Another intramolecular
edge-to-face π-π stacking pattern of the title compound can be proved by the relative position of
the H of cyclopropane and phenyl ring of the title molecule: the centroid separation of them is
2.759 Å, and their dihedral angle is 92.33º.
The title compound has an extensive network of hydrogen bonding. In the ab plane, they are
linked together by C-H···O hydrogen bonds to form a one-dimensional chain. The slight
discrepancy of crystal structures is probably the consequence of the weakness of this hydrogen
bond and van der Waals interactions in the solid-state structure.
EXPERIMENTAL
Materials and Methods
1
Melting points were determined using an X-4 apparatus and uncorrected. H NMR spectra were
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measured on a Bruker AV-400 instrument using TMS as an internal standard and CDCl3 as the
solvent. Elemental analyses were performed on a Vario EL elemental analyzer. Crystallographic
data of the compound were collected on a Rigaku Saturn Diffractometer. All the reagents are of
analytical grade or freshly prepared before use.
Synthesis
The title compounds were synthesized according to the route shown in Scheme 1, and the yields
were not optimized.
Intermediate 4-methyl-1,2,3-thiadiazole-5-carboxylic acid hydrazide (5~9) was synthesized
according to the literature [4]. A mixture of acylhydrazine (5) with isothiocyanatocyclopropane
(6) (1.5 g) was refluxed for 3 h in ethanol. After cooling down to room temperature, the products
were obtained and recrystallized from methanol to give 7, yellow crystals, yield 88.5%, m.p.
1
117-118 oC, H NMR (400 MHz, CDCl3): 0.40-0.79(m, 4H, CH2), 2.78(m, 1H, CH), 3.31(s, 3H,
Me). A mixture of compound (7) (10 mmol) in aqueous NaOH solution (5 mL, 2N) was refluxed
for 4 h. After cooling down to room temperature, HCl aqueous solution (4N) was added to afford
a large amount of precipitate. The solid was filtered, dried and recrystallized from methanol to
give intermediate (8), yellow crystal, yield 85.6%, m.p. 205-209 oC, 1H NMR (400 MHz, CDCl3):
1.13-1.25(m, 4H, CH2), 2.42(s, 3H, CH3), 2.91-2.97(m, 1H, CH), 10.86(br, 1H, SH). To a stirred
solution of 8 (5.1 mmol) and K2CO3 (0.2 g, 5.6 mmol) in DMF (15 mL), a mixture of a
substituted benzyl chloride or alkyl halide (5.6 mmol) was added dropwise. The resulting
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mixture was stirred at room temperature for overnight. The mixture was poured into water, The
precipitate formed was filtered off and recrystallized from petroleum ether/acetone to give (9) in
good yields. To a stirred solution of compound 9 (2 mmol) in CH2Cl2 (8 mL) was added m-CPBA
(1.1 mmol). The reaction was monitored by TLC. When the reaction was complete, the solvent
was removed under reduced pressure vacuum. The crude product was purified by
chromatography over silica gel to give 10. (PE : EA = 5 : 1). The Supplemental Materials
contains representative 1H NMR spectra for 10a-10d (Figures S 2 – S 5).
5-(4-cyclopropyl-5-((3-fluorobenzyl)sulfinyl)-4H-1,2,4-triazol-3-yl)-4-methyl-1,2,3-thiadiazo
le (10a) white crystal, yield, 37.0%; m.p., 117-118 oC; 1H NMR (400 MHz, CDCl3), 0.93-1.16(m,
2H, CH2), 1.25-1.37(m, 2H, CH2), 3.03(s, 3H, Het-CH3), 3.21-3.27(m, 1H, cyclopropane-CH),
4.77(d, J = 12.96 Hz, 1H, CH2), 5.10(d, J = 12.93 Hz, 1H, CH2), 7.06-7.59(m, 4H, Ph-H);
ESI-MS: 748.78[2M+Na]+, 386.10[M+Na]+; Anal. Calcd for C15H14FN5OS2 (%): C, 49.57; H,
3.88; N, 19.27. Found: C, 49.40; H, 4.17; N, 18.82.
4-(((4-cyclopropyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)sulfinyl)methyl)b
enzonitrile (10b) white yellow crystal, yield 36%, m.p.152-155◦C;1H NMR (CDCl3, 500 MHz),
δ:1.06(m, 2H, CH2), 1.32(m, 2H, CH2), 3.04(s, 3H, CH3), 3.36(m, 1H, CH), 4.90(d, J=13.05Hz,
1H, SCH2), 5.12(d, J=13.05Hz, 1H, SCH2), 7.62(d, J=8.25Hz, 2H, ArH), 7.70(d, J=8.25Hz, 2H,
ArH). MS (ESI), m/z: 371.07 (M+1) +. Elemental anal. (%), calculated: C, 51.87; H, 3.81; N,
22.69; found: C, 51.65; H, 3.76; N, 22.71.
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5-(4-cyclopropyl-5-((2-methylbenzyl)sulfinyl)-4H-1,2,4-triazol-3-yl)-4-methyl-1,2,3-thiadiaz
1
ole (10c) white yellow crystal, yield 28%, m.p.176-179◦C; H NMR (CDCl3, 500 MHz),
δ:1.00(m, 2H, CH2), 1.24(m, 2H, CH2), 2.48(s, 3H, CH3), 2.96(m, 1H, CH), 3.03(s, 3H, CH3),
4.86(d, J=12.85Hz, 1H, SCH2), 5.13(d, J=12.85Hz, 1H, SCH2), 7.16-7.31(m, 4H, ArH). MS
(ESI), m/z: 360.09 (M+1) +. Elemental anal. (%), calculated: C, 53.46; H, 4.77; N, 19.48; found:
C, 53.44; H, 4.81; N, 19.69.
2-((4-cyclopropyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-4H-1,2,4-triazol-3-yl)sulfinyl)acetonitril
e (10d)
white yellow crystal, yield 33%, m.p.152-154◦C; 1H NMR (CDCl3, 500 MHz), δ:1.10-1.18(m,
2H, CH2), 1.41-1.53(m, 2H, CH2), 3.07(s, 3H, CH3), 3.51-3.53(m, 1H, CH), 4.43 (d, J=15.55Hz,
1H, SCH2), 4.90(d, J=15.55Hz, 1H, SCH2). MS (ESI), m/z: 295.04 (M+1) +. Elemental anal. (%),
calculated: C, 40.80; H, 3.42; N, 28.55; found: C, 41.23; H, 3.81; N, 28.71.
Bioassay
The herbicidal activity and KARI activity are determined according the references[27-29].
Crystal Structure Determination
The cube-shaped single crystal of the title compound was obtained by recrystallization from
EtOH. The crystal with dimensions of 0.20mm ×0.16mm × 0.10mm was mounted on a Rigaku
Saturn Diffractometer with a graphite-monochromated MoKα radiation (λ = 0.71073Å) by using
a Phi scan modes at 113(2) K in the range of 3.02°≤θ≤25.02°. A total of 10549 reflections were
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collected, of which 2766 were independent (Rint = 0.0728) and 2155 were observed with I > 2σ(I).
The calculations were performed with SHELXS-97 program[30] 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 = 0.0428 and wR = 0.1017 (w
2
2
= 1/[σ2(Fo ) + (0.0519P)2] where P = (Fo + 2Fc2)/3), S = 1.04, (Δ/σ)max < 0.0001, Δρmax = 0.31
and Δρmin = -0.31 e Å-3. Atomic scattering factors and anomalous dispersion corrections were
taken from International Table for X-Ray Crystallography[31]. A summary of the key
crystallographic information were given in Table 3. CCDC 1051855 contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK; fax: +44-1223-336033; e-mail:
deposit@ccdc.cam.ac.uk.
Acknowledgment
This work was supported financially by National Natural Science Foundation of China
(No.21002090, 31000008, 21205109), The Key Innovation Team of Science and Technology in
Zhejiang Province (2010R50018-06) and the National Key Technologies R&D Program
(2011BAE06B03-01).
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Table 1. The Effects of Oxidant and Temperature on the Oxidation of Thioether
condition
H2O2/HOAc/r.t.
H2O2/HOAc/reflux
KMnO4/ r.t.
sulfoxide
no.
no.
no.
m-CPBA/ r.t.
K2S2O4/ r.t.
yes/ 1 h
no.
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Table 2. Selected Bond Lengths (Å) and Bond Angles (°)
Bond
Dist.
1.4822(17)
1.798(3)
1.831(2)
1.671(2)
1.701(2)
1.309(3)
1.310(3)
1.357(3)
1.326(3)
1.391(3)
1.315(3)
1.361(3)
1.449(3)
1.503(3)
1.383(4)
1.454(3)
1.494(3)
1.501(3)
1.400(3)
1.401(3)
Angle
(°)
S(1)-O(1)
S(1)-C(5)
S(1)-C(9)
S(2)-N(1)
S(2)-C(3)
F(1)-C(14)
N(1)-N(2)
N(2)-C(2)
N(3)-C(4)
N(3)-N(4)
N(4)-C(5)
N(5)-C(5)
N(5)-C(6)
C(1)-C(2)
C(2)-C(3)
C(3)-C(4)
C(6)-C(7)
C(9)-C(10)
C(10)-C(15)
C(10)-C(11)
O(1)-S(1)-C(5)
C(5)-S(1)-C(9)
N(1)-S(2)-C(3)
N(2)-N(1)-S(2)
C(4)-N(3)-N(4)
C(5)-N(5)-C(4)
C(5)-N(5)-C(6)
N(2)-C(2)-C(1)
C(3)-C(2)-C(1)
N(4)-C(5)-N(5)
N(3)-C(4)-C(3)
C(6)-C(7)-C(8)
C(15)-C(10)-C(9)
F(1)-C(14)-C(13)
N(4)-C(5)-S(1)
N(5)-C(5)-S(1)
N(5)-C(6)-C(7)
N(5)-C(6)-C(8)
C(7)-C(6)-C(8)
N(3)-C(4)-N(5)
106.34(11)
94.51(11)
93.35(13)
111.12(18)
106.9(2)
104.14(19)
129.0(2)
118.5(2)
128.0(2)
111.6(2)
123.7(2)
60.35(16)
120.6(2)
119.7(2)
123.34(19)
125.03(18)
120.08(19)
117.23(19)
59.96(16)
110.6(2)
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Table 3 Crystal Structure and Data Refinement Parameters
Compound
Empirical Formula
Formula Weight
C15H14FN5OS2
379.43
Crystal System / Space Group Monoclinic, P2(1)/n
a / Å
10.597(2)
b / Å
13.487(3)
c / Å
11.261(2)
90
α / °
β / °
102.41(3)
γ / °
V / Å3
90
1572.0(5)
Z
4
D calc (g/cm3)
μ (mm-1)
1.536
0.36
Crystal size (mm)
Color / Shape
Temp (K)
0.20 x 0.16 x 0.10
Colorless/Cube
113(2)
Theta range for collection
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness of fit on F2
Final R indices [I > 2σ(I)]
R indices (all data)
Largest difference peak/hole
3.02 to 25.02
10549
2766
2766 / 0 / 228
1.045
R1 = 0.0428, wR2 = 0.1017
R1 = 0.0580, wR2 = 0.1075
0.309 and -0.315 e.A^-3
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Figure 1. The commercial pesticides contain 1,2,3-thiadiazole or 1,2,4-triazole group
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Figure 2 The molecular structure of the title compound
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O
O
O
O
N
O
O
80% NH2NH2 H2O
r.t.
O
HN
NH2
O
O
N
O
O
H
EtOH, r.t.
O
2
3
N
N
80% NH2NH2 H2O
Ref.
SOCl2, CH2Cl2
r.t.
H
N
N
N
O
S
S
NH2
S
O
5
O
4
N
N
N
H
NCS
1. NaOH, Ref.
K2CO3, RX
DMF, r.t.
N
N
N
SH
N
S
N
H
N
N
S
EtOH, Ref.
H
2. HCl
O
7
8
N
N
N
N
m-CPBA
R
N
R
N
S
S
N
N
N
N
S
S
O
10a-10d
9a-9d
Scheme 1 The synthetic route of title compound
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