Synthesis, Structure, and Spectroscopic Properties of Isotianil as a Bactericide

Article abstract of DOI:10.1134/S107042802010022X

Abstract: Isotianil [N-(2-cyanophenyl)-3,4-dichloro-1,2-thiazole-5-carboxamide] has beensynthesized in a good yield with high purity by reaction of the key intermediateproduct, N-(2-carbamoylphenyl)-3,4-dichloro-1,2-thiazole-5-carboxamide, withthionyl chloride in N,N-dimethylformamide at 60°C. The structure of isotianil wasstudied by X-ray analysis. It crystallized in triclinic space group P1 with a =11.459(3), b = 12.632(3), c = 22.528(5) ?, α = 78.897(3), β = 81.730(3), γ =71.493(3)°, Z = 10.

Full text of DOI:10.1134/S107042802010022X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2020, Vol. 56, No. 10, pp. 1801–1805. © Pleiades Publishing, Ltd., 2020.
Synthesis, Structure, and Spectroscopic Properties
of Isotianil as a Bactericide
J. Zhanga, J. Jia, B. Wanga, A.-Q. Jiaa, and Q.-F. Zhanga,*
a Institute of Molecular Engineering and Applied Chemistry, Anhui University of Technology, Anhui, 243002 China
*e-mail: zhangqf@ahut.edu.cn
Received May 31, 2020; revised June 9, 2020; accepted June 25, 2020
Abstract—Isotianil [N-(2-cyanophenyl)-3,4-dichloro-1,2-thiazole-5-carboxamide] has been synthesized in
a good yield with high purity by reaction of the key intermediate product, N-(2-carbamoylphenyl)-3,4-dichloro-
1,2-thiazole-5-carboxamide, with thionyl chloride in N,N-dimethylformamide at 60°C. The structure of isotianil
‾
was studied by X-ray analysis. It crystallized in triclinic space group P1 with a = 11.459(3), b = 12.632(3), c =
22.528(5) Å, α = 78.897(3), β = 81.730(3), γ = 71.493(3)°, Z = 10.
Keywords: bactericide, isotianil, intermediate, organic synthesis, X-ray analysis
DOI: 10.1134/S107042802010022X
INTRODUCTION
thionyl chloride in DMF afforded intermediate 3,4-di-
chloro-1,2-thiazole-5-carbonyl chloride (2) which
reacted with 2-aminobenzamide in DMF at 60°C to
give the key intermediate product, N-(2-carbamoyl-
phenyl)-3,4-dichloro-1,2-thiazole-5-carboxamide (3),
in a good yield. The target isotianil (4) was readily
obtained by treatment of 3 with thionyl chloride in
Isotianil is an environmentally friendly bactericide
that is used mainly for the prevention and control of
rice blast by stimulating the natural defense mechanism
of rice itself [1–4]. In 2002, Himmler reported a syn-
thetic route to isotianil via a one-pot reaction starting
from isatoic anhydride [5]. Treatment of isatoic anhy-
dride with ammonia in the presence of N,N-dimethyl-
formamide gave 2-aminobenzamide, which was
directly reacted with 3,4-dichloro-1,2-thiazole-5-car-
bonyl chloride to obtain N-(2-carbamoylphenyl)-3,4-
dichloro-1,2-thiazole-5-carboxamide, and the latter
was treated with thionyl chloride to afford the target
isotianil. The reaction of 2-cyanobenzylamine with
3,4-dichloro-1,2-thiazole-5-carbonyl chloride in the
presence of pyridine or 4-dimethylaminopyridine also
afforded isotianil [3, 6]. However, the reported syn-
theses of isotianil have problems such as low yields
along with low purity. Herein, we report a synthetic
route to isotianil with high purity and high yield and its
molecular structure according to single-crystal X-ray
diffraction data.
1
DMF. In the H NMR spectrum of 3, the signal at
δ 7.20–7.15 ppm was assigned to protons of the NH2
group, and signals in the region δ 7.52−8.26 ppm were
attributed to aromatic protons. The 13C NMR spectrum
of isotianil showed two signals at δC 157.35 and
116.89 ppm due to C=O and C≡N carbons, respec-
1
tively. In the H NMR spectrum of 4, the peaks in the
range δ 7.49–7.92 ppm were attributed to aromatic
protons, and the singlet at δ 11.04 ppm was assigned
to the NH proton, similar to that in compound 3
(δ 10.56 ppm). The IR spectrum of 4 showed absorp-
tion bands at 3321 (N–H), 1650 (C=O), and 2224 cm–1
(C≡N). The UV–Vis absorption spectra of 3 and 4 in
acetonitrile at room temperature showed strong bands
at λ 210 (4) and ~270 nm (3) due to π→π* transition
and at λ 283 (4) and 382 nm (3) due to n→π* transition
(see Supplementary Materials).
RESULTS AND DISCUSSION
The molecular structure of compound 4 was further
confirmed by X-ray crystallography (Fig. 1). Selected
bond lengths and angles are accordingly given in
Table 1, and the hydrogen bond parameters are listed in
Table 2. The C4–O1 bond length [1.220(10) Å] in-
dicates double-bond character of the carbon–oxygen
As shown in Scheme 1, the starting material was
3,4-dichloro-1,2-thiazole-5-carbonitrile which was
converted to 3,4-dichloro-1,2-thiazole-5-carboxylic
acid (1) in quantitative yield by hydrolysis in aqueous
sodium hydroxide. Treatment of compound 1 with
1801

ZHANG et al.
1802
Scheme 1.
Cl
Cl
Cl
Cl
Cl
Cl
NaOH, H2O
SOCl2, DMF
O
CN
COOH
N
N
O
N
S
S
S
Cl
1
2
O
NH2
H2N
HN
NC
NH2
Et3N/DMF
Cl
Cl
SOCl2, DMF
Cl
Cl
HN
N
S
N
S
O
O
3
4
bond, in agreement with the data for structurally
related N-arylbenzamides and 2-aminobenzophenones
{1.226(2) Å [7, 8]}. The C11–N3 bond length is
1.180(12) Å, which indicates the triple-bond character,
as in the structure of 2-acetamidobenzonitrile
{1.138(3) Å [9]}. The C1–Cl1 and C2–Cl2 bond
lengths are 1.720(10) and 1.708(9) Å, respectively. The
C10C11N3 bond angle is 177.3(13)° which is typical of
a C–C≡N group. The dihedral angle between the ben-
zene and isothiazole ring planes is 5.1(10)°, and the
torsion angle C3C4N2C5 is 178.2(10)°, i.e., the isothia-
zole and benzene rings are nearly coplanar.
nitrobenzamide (2.29 Å) [10]. The bond angles
N–H···O and N–H···Cl are in the range 127.2–134.0°.
Furthermore, classical N–H···Cl (H···Cl ~2.61 Å)
hydrogen bonds also contribute to stabilization of the
crystal structure of 4.
EXPERIMENTAL
All solvents were purified by routine procedures
and distilled under dry nitrogen before use. Sodium
hydroxide, thionyl chloride, and 2-aminobenzamide
were purchased from Alfa Aesar and were used without
The packing view of compound 4 is shown in
Fig. 2. The crystal packing of 4 is governed by weak
intermolecular N–H···O and N–H···Cl hydrogen-
bonding interactions (Table 2). The H···O distances
range from 2.28 to 2.38 Å, as in N-(4-chlorophenyl)-4-
Cl1
N3
C11
C10
Cl2
C1
C2
C3
N1
N2
C9
C8
C4
C5
C6
S1
C7
O1
Fig. 1. Structure of the molecule of N-(2-cyanophenyl)-3,4-
dichloro-1,2-thiazole-5-carboxamide (4) according to the
X-ray diffraction data. One molecule in the asymmetric unit
is shown with non-hydrogen atoms represented as thermal
displacement ellipsoids with a probability of 50%.
Fig. 2. Crystal packing of isotianil (4) viewed along the
a axis. Dashed lines indicate N–H···O and N–H···Cl hydro-
gen bonds.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

SYNTHESIS, STRUCTURE, AND SPECTROSCOPIC PROPERTIES OF ISOTIANIL
1803
Table 1. Selected bond lengths (d) and bond angles (ω) for compound 4
Bond
d, Å
Bond angle
N1S1C3
C1N1S1
C4N2C5
N1C1Cl1
C3C2Cl2
O1C4N2
O1C4C3
N3C11C10
ω, deg
S1–N1
S1–C3
O1–C4
N3–C11
N2–C4
N2–C5
Cl1–C1
Cl2–C2
1.653(8)
1.710(9)
1.220(10)
1.180(12)
1.350(10)
1.404(11)
1.720(10)
1.708(9)
95.7(4)
108.1(7)
127.6(8)
118.2(8)
128.0(8)
125.2(9)
118.8(9)
177.3(13)
Table 2. Parameters of hydrogen bonds in the crystal structure of isotianil (4)
D–H···A
D–H, Å
H···A, Å
D···A, Å
Angle DHA, deg
N2–H2···O5
N2–H2···Cl5
N5–H5···O1
N5–H5···Cl4
N8–H8···O4 a
N8–H8···Cl6
N11–H11···O3 b
N11–H11···Cl8
N14–H14···O4
N14–H14···Cl10
0.86
0.86
0.86
0.86
0.86
0.86
0.86
0.86
0.86
0.86
2.38
2.59
2.28
2.63
2.33
2.61
2.31
2.62
2.36
2.59
2.983(11)
3.238(8)
2.938(11)
3.236(8)
2.964(12)
3.240(8)
2.948(12)
3.235(8)
2.961(11)
3.225(8)
127.2
133.3
134.0
128.0
130.9
130.5
131.5
129.7
127.7
131.3
Symmetry operation: a x, y, z + 1; b x – 1, y, z.
Table 3. Crystallographic data for isotianil (4) and details of X-ray diffraction experiment
Formula
C11H5Cl2N3OS
298.14
dcalc, g/cm3
1.638
296(2)
Molecular weight
Temperature, K
Crystal system
Triclinic
F(000)
1500
‾
Space group
P1
μ(Mo Kα), mm–1
Total number of reflections
Number of independent reflections
Rint
0.698
a, Å
b, Å
c, Å
α
11.459(3)
12.632(3)
22.528(5)
78.897(3)
81.730(3)
71.493(3)
3022.4(12)
10
19220
13313
0.0301
Number of parameters
R1,a wR2b [I > 2σ(I)]
R1, wR2 (all reflections)
GoFc
812
β
0.0556, 0.1472
0.2555, 0.2795
0.852
γ
V, Å3
Z
a
b
c
R1 = ||Fo| – |Fc||/|Fo|.
wR2 = [w(|Fo | – |Fc |)2/w|Fo | ]
.
2
2
2 2 1/2
GoF = [w(|Fo| – |Fc|)2/(Nobs – Nparam)]2.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

ZHANG et al.
1804
further purification. 3,4-Dichloro-1,2-thiazole-5-carbo-
nitrile was purchased from Jiangsu Furun Chem. Co.
Ltd. and used after recrystallization. The melting points
were determined in capillaries using an X4 digital
melting-point apparatus and are uncorrected. The NMR
spectra were recorded on a Bruker ALX 400 spec-
trometer operating at 400 and 101 MHz for 1H and 13C,
respectively; the chemical shifts are given with refer-
ence to tetramethylsilane. The infrared spectra were
recorded on a Perkin-Elmer 16 PC FT-IR spectro-
photometer. Elemental analyses were carried out using
a Perkin Elmer 2400 CHN analyzer. Electronic absorp-
tion spectra were obtained on a Shimadzu UV-2600
spectrophotometer.
NH). IR spectrum (KBr), ν, cm–1: 3428 (N−H), 1725
(C=O), 1387 (C=N). Found, %: C 41.77; H 2.24;
N 13.26. C11H7Cl2N3O2S. Calculated, %: C 41.79;
H 2.23; N 13.29.
N-(2-Cyanophenyl)-3,4-dichloro-1,2-thiazole-5-
carboxamide (4, isotianil). Thionyl chloride (3 mL)
was added dropwise with vigorous stirring to a solution
of 3 (5.0 g, 0.015 mol) in DMF (5 mL). The mixture
was stirred at 60°C for 2 h (TLC), and distilled water
(20 mL) was added with stirring over a period of 1 h.
The gray solid was filtered off and washed with
distilled water (3×15 mL) and petroleum ether (3×
15 mL). An additional amount of the product was
isolated from the filtrate by extraction with ethyl
acetate (15 mL). The extract was washed with brine
(2×15 mL), dried with anhydrous MgSO4, filtered, and
concentrated under reduced pressure. Yield 6.03 g
3,4-Dichloro-1,2-thiazole-5-carboxylic acid (1).
3,4-Dichloro-1,2-thiazole-5-carbonitrile (5.0 g,
0.028 mol) was added to a solution of sodium hydrox-
ide (2.8 g, 0.070 mol) in distilled water (10 mL). The
mixture was stirred under reflux, and the progress of
reaction was monitored by TLC. After 6 h, the mixture
was acidified with dilute aqueous HCl (2 M) to pH ~3.
The product (a creamy-white solid) was filtered off,
thoroughly washed with distilled water, and dried
under reduced pressure in a desiccator. Yield 5.25 g
(95%), mp 177–179°C. 13C NMR spectrum
(DMSO-d6), δC, ppm: 165.32 s, 160.07 s, 148.95 s,
113.88 s. Found, %: C 26.57; H 0.63; N 15.57.
C4HCl2N2O2S. Calculated, %: C 26.81; H 0.56;
N 15.64.
1
(83%). H NMR spectrum (DMSO-d6), δ, ppm: 7.49 t
(1H, Harom, J = 7.6 Hz), 7.71 d (1H, Harom, J = 8.0 Hz),
7.82–7.75 m (1H, Harom), 7.92 d (1H, Harom, J =
7.8 Hz), 11.04 s (1H, NH). 13C NMR spectrum
(DMSO-d6), δC, ppm: 157.35 s, 156.16 s, 148.10 s,
139.06 s, 134.59 s, 133.91 s, 127.67 s, 126.72 s,
121.50 s, 116.89 s, 108.87 s. IR spectrum (KBr), ν,
cm–1: 3321 (N−H), 2224 (C≡N), 1650 (C=O).
Found, %: C 44.33; H 1.67; N 14.12. C11H5Cl2N3OS.
Calculated, %: C 44.31; H 1.69; N 14.09.
X-Ray diffraction data. The crystallographic data
for isotianil (4) and experimental details are sum-
marized in Table 3. The X-ray reflection intensities
were measured on a Bruker SMART APEX 2000 CCD
diffractometer at 293(2) K (Mo Kα radiation, graphite
monochromator, λ 0.71073 Å). The collected frames
were processed with SAINT software [11]. The data
were corrected for absorption using SADABS [12].
The structure was solved by the direct method and was
refined against F2 by the full-matrix least-squares
method using SHELXTL software package [13, 14].
All non-hydrogen atoms were refined anisotropically.
The positions of all hydrogen atoms were generated
geometrically (Csp3––H 0.96, Csp2–H 0.93 Å), assigned
isotropic thermal parameters, and allowed to ride on
their respective parent carbon atoms before the final
cycle of least-squares refinement. The crystallographic
data were deposited to the Cambridge Crystallographic
Data Centre (CCDC entry no. 1973435) and are avail-
able at https://www.ccdc.cam.ac.uk/.
3,4-Dichloro-1,2-thiazole-5-carbonyl chloride
(2). 3,4-Dichloro-1,2-thiazole-5-carboxylic acid (1,
5.0 g, 0.025 mol) was slowly added in portions with
stirring to thionyl chloride (5.1 mL, 0.070 mol).
N,N-Dimethylformamide was then added, and the mix-
ture was refluxed with stirring for 2 h. After completion
of the reaction (TLC), the mixture was cooled to room
temperature and evaporated under reduced pressure to
afford light yellow powder. Found, %: C 20.83;
N 12.12. C4Cl3N2OS. Calculated, %: C 20.85; N 12.16.
N-(2-Carbamoylphenyl)-3,4-dichloro-1,2-thia-
zole-5-carboxamide (3). A solution of 2-aminobenz-
amide (3.4 g, 0.025 mol) in triethylamine (5 mL) was
added dropwise to a solution of 2 (2.8 g, 0.070 mol) in
DMF (2 mL). The mixture was stirred at 60°C for 3 h
(TLC), ethyl acetate and distilled water were added,
and the organic phase was separated, dried with anhy-
drous MgSO4, filtered, and concentrated under reduced
pressure. The residue was recrystallized from dichloro-
methane. Yield: 6.03 g (83%). yellow powder.
1H NMR spectrum (DMSO-d6), δ, ppm: 7.20–7.15 m
(2H, NH2), 7.52 d (1H, Harom, J = 7.5 Hz), 7.75 d (2H,
FUNDING
This project was supported by the National Natural
Science Foundation of China (project no. 21372007).
H
arom, J = 11.5 Hz), 8.26 s (1H, Harom), 10.56 s (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020

SYNTHESIS, STRUCTURE, AND SPECTROSCOPIC PROPERTIES OF ISOTIANIL
1805
6. Chen, X.-Y., Liu, X.-P., Fan, Z.-J., Liang, X.-W.,
Li, Y.-D., Mao, W.-T., Li, J.-J., Wan, D., Wang, S.-H.,
Zhou, L.-F, Ji, X.-T., Hua, X.-W., and Huang, L.-W.,
CN Patent no. 102942565.
7. Zhu, J., Li, M., Wei, H., Wang, J., and Guo, C., Acta
Crystallogr., Sect. E, 2012, vol. 68, p. o843.
https://doi.org/10.1107/S1600536812007556
8. Cortez-Maya, S., Cortes, E.C., Hernández-Ortega, S.,
Apan, T.R., and Martínez-García, M., Synth. Commun.,
2012, vol. 42, p. 46.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
SUPPLEMENTARY MATERIALS
Supplementary materials are available for this article at
https://doi.org/10.1134/S107042802010022X and are acces-
sible for authorized users.
https://doi.org/10.1080/00397911.2010.521435
9. Arslan, B., Kazak, C., Kirilmis, C., Koca, M., and
Büyükgüngör, O., Acta. Crystallogr., Sect. E, 2005,
vol. 61, p. o1652.
https://doi.org/10.1107/S1600536805013152
10. Waris, G., Siddiqi, H.M., Flörke, U., Butt, M.S., and
Hussain, R., Acta Crystallogr., Sect. E, 2012, vol. 68,
p. o2768.
https://doi.org/10.1107/S1600536812036082
11. SMART and SAINT+ for Windows NT Version 6.02a,
Bruker Analytical X-ray Instruments, Madison,
Wisconsin, USA, 1998.
12. Sheldrick, G.M., SADABS, University of Göttingen:
Göttingen, Germany, 1996.
REFERENCES
1. Maienfisch, P. and Edmunds, A.J.F., Adv. Heterocycl.
Chem., 2012, vol. 121, p. 35.
https://doi.org/10.1016/bs.aihch.2016.04.010
2. Vicini, P., Incerti, M., Colla, P.L., and Loddo, R., Eur. J.
Med. Chem., 2009, vol. 44, p. 1801.
https://doi.org/10.1016/j.ejmech.2008.05.03
3. Assmann, L., Kuhnt, D., Elbe, H.-L., Erdelen, C.,
Dutzmann, S., Hänssler, G., Stenzel, K., Mauler-
Machnik, A., Kitagawa, Y., Sawada, H., and Sakuma, H.,
Int. Patent Appl. no. WO99/24413.
13. Sheldrick, G.M., SHELXTL Software Reference Manual
(Version 5.1), Bruker AXS, Madison, WI, 1997.
14. Sheldrick, G.M., Acta Crystallogr., Sect. A, 2008,
vol. 64, p. 112.
4. Arkai, K., Sato, Y., Shirakura, Sh., Endo, K., Naka-
mura, Sh., Ukawa, S., and Ueno, Ch., Int. Patent Appl.
Pub. no. WO2009/024251.
5. Himmler, T., Int. Patent Appl. no. WO2004/002969.
https://doi.org/10.1107/S0108767307043930
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 56 No. 10 2020