Synthesis, crystal structure, and fungicidal activity of a novel 1,2,3-thiadiazole compound

Article abstract of DOI:10.1080/10426507.2012.664219

A new 1,2,3-thiadiazole compound, C¹⁸H¹⁸Cl ²N⁴O²S, has been synthesized and the crystal structure was determined by single crystal X-ray diffraction study. The fungicidal activity of the title compound was determined and the results showed that it displays moderate fungicidal activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.

Full text of DOI:10.1080/10426507.2012.664219

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Synthesis, Crystal Structure, and
Fungicidal Activity of a Novel 1,2,3-
Thiadiazole Compound
Cheng-Xia Tan a , Jian-Quan Weng a , Zheng-Xiao Liu b , Xing-Hai Liu
a & Wei-Guang Zhao b
a College of Chemical Engineering and Materials Science , Zhejiang
University of Technology , Hangzhou , Zhejiang , China
b State-Key Laboratory of Elemento-Organic Chemistry, National
Pesticidal Engineering Centre (Tianjin) , Nankai University , Tianjin ,
China
Accepted author version posted online: 13 Feb 2012.Published
online: 07 Jun 2012.
To cite this article: Cheng-Xia Tan , Jian-Quan Weng , Zheng-Xiao Liu , Xing-Hai Liu & Wei-Guang
Zhao (2012) Synthesis, Crystal Structure, and Fungicidal Activity of a Novel 1,2,3-Thiadiazole
Compound, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:8, 990-996, DOI:
10.1080/10426507.2012.664219
To link to this article: http://dx.doi.org/10.1080/10426507.2012.664219
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Phosphorus, Sulfur, and Silicon, 187:990–996, 2012
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.664219
SYNTHESIS, CRYSTAL STRUCTURE, AND FUNGICIDAL
ACTIVITY OF A NOVEL 1,2,3-THIADIAZOLE COMPOUND
Cheng-Xia Tan,1 Jian-Quan Weng,1 Zheng-Xiao Liu,2
Xing-Hai Liu,1 and Wei-Guang Zhao2
1College of Chemical Engineering and Materials Science, Zhejiang University
of Technology, Hangzhou, Zhejiang, China
2State-Key Laboratory of Elemento-Organic Chemistry, National Pesticidal
Engineering Centre (Tianjin), Nankai University, Tianjin, China
GRAPHICAL ABSTRACT
Abstract A new 1,2,3-thiadiazole compound, C18H18Cl2N4O2S, has been synthesized and
the crystal structure was determined by single crystal X-ray diffraction study. The fungicidal
activity of the title compound was determined and the results showed that it displays moderate
fungicidal activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Crystal structure; synthesis; 1,2,3-thiadiazole; fungicidal activity
Received 25 November 2011; accepted 24 January 2012.
This work was supported financially by National Natural Science Foundation of China (No. 21002090),
Scientific Research Fund of Zhejiang Education Department (Y201018479).
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; Wei-Guang Zhao,
State-Key Laboratory of Elemento-Organic Chemistry, National Pesticidal Engineering Centre (Tianjin), Nankai
University, Tianjin, 300071, China. E-mail: zwg@nankai.edu.cn
990

SYNTHESIS, CRYSTAL STRUCTURE, AND FUNGICIDAL ACTIVITY
991
INTRODUCTION
In recent years, sulfur and nitro linked heterocycles has received considerable at-
tention in medicinal and pesticidal fields,1–5 because of their various activities, such as
KARI,6 herbicidal,7 fungicidal,8 antiviral,9 and antitubercular activities.10 It is reported
that 1,2,3-thiadiazole has beneficial medicinal and agricultural applications. Due to its
good bioactivity and usefulness as intermediates in organic synthesis, the chemistry of
the 1,2,3-thiadiazole ring has been widely studied. For example, many 1,2,3-thiadiazoles
exhibited plant inducer activity,11 anti-HBV activity,12 fungicidal activity,13 and insectici-
dal activity.14 1,2,3-Thiadiazoles as examples of pesticide precursors have become one of
the area of focus of developing agrochemicals in academia and industry. The piperidine
ring also exhibited excellent biological properties, such as antifungal,15 antimalarial16 and
antileukemic activities,17 GABA inhibitors,18 VLA-4 inhibitors,19 and herbicidal activity.20
A large variety of piperidine derivatives were successfully applied to commercial medicine
or pesticide, such as mepiquat chloride,21 acetamiprid,22 droperidol,23 haloperidol,24 and
fentanyl citrate.25
In view of these facts, and also as a part of our work on the development of bioactive
heterocyclic compounds, herein a 1,2,3-thiadiazole compound was synthesized and its
single crystal structure was determined.
RESULTS AND DISCUSSION
Chemistry
The synthesis procedure for title compound 8 is shown in Scheme 1. The intermediates
1, 2, 3, 4, 5weresynthesizedaccordingtoourreportedreference.12 Accordingtoourmethod,
the title compound 8 cannot be obtained. On the other hand, if the reaction temperature
◦
was under 0 C, the mono chloro compound was obtained. In the process of optimizing
the reaction, the reaction temperature was changed to room temperature or reflux. The title
compound 8 was obtained at room temperature. The proposed reaction procedure is shown
Scheme 1 The synthetic route of title compound.

992
C.-X. TAN ET AL.
1
in Scheme 2. The compound was also identified by H NMR. The measured elemental
analyses were also consistent with the corresponding calculated ones.
Scheme 2 The proposed reaction route.
Crystal Structure
The selected bond lengths and bond angles in Table 2. The selected dihedral angles
are shown in Table S1. The molecular structure of the title compound is shown in Figure 1.
The molecular packing of the molecule is shown in Figure S1. The π-π stacking is shown
in Figure S2.
Generally, the average bond lengths and bond angles of ring systems (phenyl and
1,2,3-thiadiazole) are normal ranges. The C6 N1 bond [1.33 Å] is shorter than a normal
C N single bond (1.47 Å), which shows that C6 N1 is conjugated with the O6 C1 double
bond. However, the C7 N2 bond [1.25 Å] is similar with the general C N double bond
length of 1.27 Å.
Table 1 Crystal structure and data refinement parameters
Compound
8
Empirical formula
Formula weight
C18H18Cl2N4O2S
425.32
Crystal system/Space group
a/Å
Triclinic, P-1
8.285 (3) Å
b/Å
10.072 (3) Å
11.828 (4) Å
99.094 (5)◦
c/Å
α/◦
β/◦
105.839 (5)◦
92.507 (5)◦
γ /◦
V/Å3
933.7 (5) Å3
2
1.513 Mg m−3
0.4800
Z
Dcalc (g/cm3)
µ (mm−1
)
Crystal size (mm)
Color/Shape
Temp (K)
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)
0.32 × 0.30 × 0.26
Colorless, prism
293(2)
3.4–26.4◦
5446
3794 [R(int) = 0.0148]
3794/0/244
1.070
R1 = 0.0324, wR2 = 0.0831
R1 = 0.0478, wR2 = 0.0912
0.250 and −0.211 e A−3
Largest difference peak/hole

SYNTHESIS, CRYSTAL STRUCTURE, AND FUNGICIDAL ACTIVITY
993
Table 2 Selected bond lengths (Å) and angles (◦) for the title compound
Bond lengths
Å
Bond angles
(◦)
Cl(1) C(15)
Cl(2) C(15)
S(1) N(4)
S(1) C(16)
O(1) C(6)
O(2) C(8)
N(1) C(6)
N(1) C(1)
N(1) C(5)
N(2) C(7)
N(2) C(8)
N(3) N(4)
N(3) C(17)
C(1) C(2)
C(15) C(16)
C(16) C(17)
C(17) C(18)
1.7875(1)
1.7672(1
1.650(2)
1.6774(1)
1.218(2)
1.195(3)
1.327(2)
1.461(2)
1.462(2)
1.251(2)
1.413(3)
1.287(3)
1.357(3)
1.505(3)
1.490(2)
1.360(3)
1.481(3)
N(4) S(1) C(16)
C(6) N(1) C(1)
C(6) N(1) C(5)
N(1) C(5) C(4)
C(10) C(9) C(8)
N(4) N(3) C(17)
N(1) C(1) C(2)
N(3) C(17) C(18)
C(16) C(17) C(18)
N(3) N(4) S(1)
O(1) C(6) N(1)
O(1) C(6) C(7)
N(1) C(6) C(7)
N(2) C(7) C(6)
O(2) C(8) N(2)
O(2) C(8) C(9)
N(2) C(8) C(9)
93.07(10)
118.77(16)
123.06(15)
111.35(16)
118.18(19)
113.98(18)
110.88(16)
118.11(19)
128.76(19)
111.71(14)
125.52(18)
116.41(17)
117.99(16)
124.18(17)
119.98(19)
124.53(19)
115.40(18)
As shown in Figure 1, the 1,2,3-thiadiazole rings (N3, N4, S1, C16, C17) and phenyl
rings (C9, C10, C11, C12, C13, C16) are fairly planars with plane equation 1.421x +
−5.365y +9.836z = 7.4185 (−1.347x + −4.201y + 11.354z = 9.4842), and the largest
deviation from the least squares plane is 0.0029 nm (0.0056 nm). Meanwhile, the 1,2,3-
thiadiazole ring is parallel with the phenyl ring (C1∼C6) with the angles of 20.4◦. From
the molecular structure, it can be seen that both groups on the N atoms of piperidine
ring are in the e-bond positions of chair conformation in the six-member ring. The X-
ray analysis also reveals that, in this compound, the benzene ring and 1,2,3-thiadiazole
ring are on the opposite sides of the C N double bond (Figure 1). The torsion angle of
Figure 1 Molecular structure of the title compound, showing displacement ellipsoids drawn at the 30% probability
level.

994
C.-X. TAN ET AL.
C(15) C(7) N(2) C(8) is 173.68◦, which indicates that the C N double bond is in the
(E)-configuration.
The intermolecular edge-to-face π-π stacking appears between the piperidine ring
and the phenyl ring C9∼C14 in another adjacent molecule (Figure S4), in which the distance
of H4B and the centroid of phenyl ring C9∼C14 is 2.839 Å. These interactions can help to
further stabilize the crystal structure.
Fungicidal Activity
The primary bioassay shows the title compound exhibits a moderate inhibiting ac-
tivity toward Alternaria solani, Gibberella sanbinetti, Phytophthora infestans (Mont.) de
Bary, Botrytis cinerea, Rhizoctonia solanii, Phytophthora capsici Leonian, Fusarium oxys-
porum, Physalospora piricola Nose, and Cercospora arachidiaola Hori. Its inhibition rates
to Alternaria solani, Gibberella sanbinetti, Phytophthora infestans (Mont.) de Bary, Botrytis
cinerea, Rhizoctonia solanii, Phytophthora capsici Leonian, Fusarium oxysporum, Physa-
lospora piricola Nose, and Cercospora arachidiaola Hori reach 17.4%, 32.3%, 32.3%,
43.5%, 30.3%, 36.1%, 26.9%, 25.8%, and 15.8% at 50 µg/mL respectively.
EXPERIMENTAL
Materials and Methods
All the reagents were of analytical grade. Melting points were determined using an
1
X-4 apparatus and uncorrected. H NMR spectra were measured on a Bruker AC-P500
(300 Hz) instrument using tetramethylsilane (TMS) as an internal standard and CDCl3 as
solvent. Elemental analyses were performed on a Vario EL elemental analyzer. Crystallo-
graphicdataof thecompoundwerecollectedon a Bruker SMART 1000CCDdiffractometer.
4-methyl-1,2,3-thiadiazole-5-carbaldehyde (5). Compound 5 was prepared
as a white solid using commercially available acetyl ethyl acetate as the starting material
according to the literature.12
(E)-4-((4-methyl-1,2,3-thiadiazol-5-yl)methylene)-2-phenyloxazol-5(4H)-
one (6). To a 50-mL three-necked round-bottomed flask equipped with a reflux condenser
bearing a calcium chloride tube were placed benzoylglycine (3.36 g, 17.9 mmol), 5 (2.32 g,
17.9 mmol), anhydrous sodium acetate (1.54 g, 17.9 mmol), and acetic anhydride (5.47 g,
53.6 mmol). The mixture was heated at 138 ◦C for 10 min, then lowered to 95 ◦C–100 ◦C
◦
for an additional 2 h. After being cooled to 80 C, the reaction mixture was treated with
ethanol (3 mL) and cooled to room temperature. The product precipitated out of solution,
and after standing overnight, the solid was collected, washed with ethanol (2 × 10 mL)
and hot water (3 × 5 mL), and dried to obtain 6 (2.81g, 57% yield) as a red solid, m.p.
◦
◦
1
233 C–235 C; H NMR (300 MHz, CDCl3) δ: 2.90 (s, 3H, 4-methyl-thiadiazole), 7.40
(s, 1H, CH ), 7.57–8.30 (m, 5H, Ph).
(E)-N-(1-(4-methyl-1,2,3-thiadiazol-5-yl)-3-oxo-3-(piperidin-1-yl)prop-1-en-
2-yl)benzamide (7). To a solution of 6 (1.4 g, 5.1 mmol) in CHCl3 (20 mL) was
stirred under an ice bath. A solution of piperidine (5.6 mmol) in CHCl3 (10 mL) were
added dropwise, the mixture was allowed to stir at room temperature for 1.5 h. After
standing overnight, the resulting solution was filtered, the filtered solution was evaporated
◦
◦
under reduced pressure to afford 7, as a yellow solid, yield 69%, m.p. 175 C–177 C;
1H NMR (300 MHz, CDCl3) δ: 0.92-1.75 (m, 6H, CH2 CH2 CH2 ), 2.59 (s, 3H,

SYNTHESIS, CRYSTAL STRUCTURE, AND FUNGICIDAL ACTIVITY
995
4-methyl-thiadiazole), 3.29–3.72 (m, 4H, CH2 N CH2 ), 7.24–7.81 (m, 5H, Ph+1H,
CH ), 9.15(s, 1H, NH ). Anal. calcd for C18H20N4O2S: C, 60.65; H, 5.66; N, 15.72;
found: C,60.76; H, 5.45; N, 15.76.
(E)-N-(1,1-dichloro-1-(4-methyl-1,2,3-thiadiazol-5-yl)-3-oxo-3-(piperidin-
1-yl)propan-2-ylidene)benzamide (8). To a solution of 7 (0.5 g, 1.39 mmol) in
CHCl3 (10 mL) was added chlorine (0.32 g, 2.0 mmol) in CCl4 (20 mL) at room
temperature. The mixture was stirred at room temperature for 2 h and then CaCO3 (0.07
g, 0.7 mmol) was added, the resulting solution was stirred for 5 h at room temperature.
The residue was subjected to silica gel column chromatography to afford compound 8,
◦
◦
1
white solid, yield 71%, m.p. 122 C–123 C; H NMR (300 MHz, CDCl3) δ: 0.79–1.68
(m, 6H, CH2 CH2 CH2 ), 2.96 (s, 3H, 4-methyl-thiadiazole), 3.65–3.87 (m, 4H,
CH2 N CH2 ), 7.22–7.85 (m, 5H, Ph). Anal. calcd for C18H18Cl2N4O2S: C, 50.83;
H, 4.27; N, 13.17; found: C,50.79; H, 4.39; N, 13.10.
Crystal Structure Determination
The prism-shaped single crystal of the title compound was obtained by recrystal-
lization from EtOH. The crystal with dimensions of 0.32 mm × 0.30 mm × 0.26 mm
was mounted on a Bruker SMART 1000 CCD area-detector diffractometer with a graphite-
monochromated MoKα radiation (λ = 0.71073 Å) by using a Phi scan modes at 293(2) K in
the range of 1.82◦ ≤ θ ≤ 26.43◦. A total of 5546 reflections were collected, of which 3794
were independent (Rint = 0.118) and 2973 were observed with I > 2σ(I). The calculations
were performed with SHELXS-97 program26 and the empirical absorption corrections were
applied to all intensity data. The nonhydrogen atoms were refined anisotropically. The hy-
drogen atoms were determined with theoretical calculations and refined isotropically. The
final full-matrix least squares refinement gave R1 = 0.0324 and wR2 = 0.0831 (w =
1/[σ2(Fo ) + (0.039P)2 + 0.2892P] where P = (Fo + 2Fc )/3, S = 1.07, ( /σ)max
=
2
2
2
0.001, ρmax = 0.25 and ρmin = −0.21 e Å−3. Atomic scattering factors and anomalous
dispersion corrections were taken from International Table for X-Ray Crystallography.27 A
summary of the key crystallgraphic information were given in Table 1.
Bioassay of Fungicidal Activities
The method for testing the primary biological activities was performed in an isolated
culture and the details are reported in the supplemental materials.
Supplementary material, CCDC-832172, contains the supplementary crystallo-
graphic 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.
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