Synthesis, biological activity and crystal structure of ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,8-tetrahydropyrido[2,1b][1,3] thiazine-7-carboxylate

Article abstract of DOI:10.1007/s11164-012-0769-5

The compound ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,8- tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate (C₁₄H ₂₂N₄O₄S₂) has been synthesized by multicomponent reactions, and characterized by ¹H NMR, IR, and X-ray diffraction. The crystal structure analysis shows that the thiazinane ring displays a half-chair conformation. The benzene ring is almost vertical to the tetrahydro-pyridine ring. Intramolecular H-bonding of N- H···O type exists and completes an S (6) ring. In the crystal, the molecules are connected into a 3D network by a N- H···O and C-H···O intermolecular hydrogen bond. The bioassay indicates that the compound shows moderate insecticidal activity against Aphis craccivora.

Full text of DOI:10.1007/s11164-012-0769-5

Res Chem Intermed (2013) 39:2435–2443
DOI 10.1007/s11164-012-0769-5
Synthesis, biological activity and crystal structure
of ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,
8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate
•
Dongmei Li Zhongzhen Tian Gaolei Wang
•
Received: 15 July 2012 / Accepted: 13 August 2012 / Published online: 25 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract The compound ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,
8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate (C14H22N4O4S2) has been
1
synthesized by multicomponent reactions, and characterized by H NMR, IR, and
X-ray diffraction. The crystal structure analysis shows that the thiazinane ring
displays a half-chair conformation. The benzene ring is almost vertical to the tet-
rahydro-pyridine ring. Intramolecular H-bonding of N–HÁÁÁO type exists and com-
pletes an S (6) ring. In the crystal, the molecules are connected into a 3D network by
a N–HÁÁÁO and C–HÁÁÁO intermolecular hydrogen bond. The bioassay indicates that
the compound shows moderate insecticidal activity against Aphis craccivora.
Keywords Cis-neonicotinoid insecticide Á Tetrahydropyrido Á Intramolecular
H-bonding Á Thiazinane ring
Introduction
Neonicotinoid insecticide acts on the insect nicotinic acetylcholine receptor [1, 2],
and is one of the most important insecticide classes, used for crop protection and
pethygiene. In the 1990s, imidacloprid led to the booming and prosperous devel-
opment of neonicotinoids owing to the characteristics of high efficiency, mamma-
lian safety, low toxicity, no cross-resistance, and unique mode of action [3–6].
Replacing organophosphorus, carbamate, and pyrethroid compounds, neonicoti-
noids have taken the share of 25 % in the insecticidal market and have been used for
insect control worldwide [7].
D. Li Á Z. Tian (&) Á G. Wang
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School
of Chemistry and Chemical Engineering, University of Jinan, 106 Jiwei Road, Jinan 250022,
People’s Republic of China
e-mail: chm_tianzz@ujn.edu.cn
123

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D. Li et al.
Nithiazine, developed by Shell in the late 1970s [8], is a potent insecticide. It
exhibits better biological activities against Lepidoptera pests compared with
imidacloprid, but has not been used extensively as a commercial product, due in part
to its photoinstability [9].
In recent years, neonicotinoids have tremendous development in cis-configuration
yield, which may effectively improve photostability and liposoluble [10–15]. Here,
in order to improve the photoinstability of nithiazine, we design a novel structure
family by introducing a tetrahydro-pyridine ring into the lead compound to fix the
nitro moiety in the cis position and synthesize the new nitromethylene compound.
This paper describes its synthesis, biological activities, and crystal structure.
NO2
O2N
R
N
N
NH
N
N
Cl
N
Cl
N
imidazolidine
cis
trans
O2N
O2N
HN
R
?
HN
S
S
Nithiazine 2
Experimental
Physical measurements
All melting points (m.p.) were obtained with Bu¨chi Melting Point B540 and are
uncorrected. 1H NMR spectra were recorded on a Bruker AV-400 (400 MHz)
spectrometer with TMS as an internal reference, and CDCl3 was used as the solvent
for all NMR spectra and Infrared spectra. Chemical shifts are reported in d (parts per
million) values. Combustion analyses for elemental composition were made with an
OCH3
O2N
HN
NO2
S
NC
COOEt
CHO
HS
NH2
EtOOC
H2N
NO2
S
S
S
EtOH
H3CO
N
1
2
3
Scheme 1 Synthetic route to the title compound
123

Synthesis, biological activity and crystal structure
2437
Elementar vario EL III. Infrared spectra were measured on a Nicolet FT-IR-20SX
instrument in potassium bromide (KBr) disk. All chemicals or reagents were
purchased from standard commercial supplies (Scheme 1).
Synthesis
2-(Nitromethylene)-1,3-thiazinane (2)
A mixture of 3-aminopropanethiol (15.0 g, 0.16 mol) and compound 1 (23.1 g,
0.14 mol) in anhydrous ethanol (350 mL) was stirred for 18 h at room temperature.
The solvent, CH2Cl2 (150 mL) and distilled water (350 mL), was evaporated under
vacuum, and the mixture was stirred for 30 min. The phases were separated and the
aqueous phase was extracted twice with CH2Cl2. The combined CH2Cl2 solutions
were washed with saturated NaCl solution, dried with MgSO4, the solvent was
evaporated, and the residue was recrystallized from anhydrous ethanol. A pale
Table 1 Crystal data and structure refinements for ethyl 6-amino-8-(4-methoxy phenyl)-9-nitro-2,3,4,
8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate
Empirical formula
Formula weight
Temperature(K)
Crystal system
Space group
C18H21N3O5S
390.70
293(2)
Triclinic
P -1
˚
a (A)
13.1550(15)
10.5441(14)
13.3623(17)
90.000(14)
91.825(11)
90.000
˚
b (A)
˚
c (A)
a (°)
b(°)
c (°)
3
˚
Volume (A )
1,852.5(4)
Z
4
Density (calc.) (g cm-3
)
1.430
Absorption coefficient (nm-1
)
0.333
F (000)
Crystal size (nm3)
396
0.25 9 0.23 9 0.14
2.97–26.0
Theta range for data collection (°)
h/k/l
-9, 9/-12, 12/-15, 15
9,842
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
3,400[R(int) = 0.030]
3,400/0/212
1.065
R = 0.0538; wR(F2) = 0.1407
R = 0.0846;wR = 0.1529
0.75 and -0.50
3
Largest different peak and hole (e A )
˚
123

2438
D. Li et al.
yellow crystalline powder was obtained. Yield, 76 %; m.p. 74.6–75.3 °C; 1H NMR
(400 MHz, CDCl3): d (ppm) 2.21–2.27(m, 2H, NCH2CH2CH2S), 3.12 (t, J =
6.0 Hz, 2H, NCHCH2CH2S), 3.60 (t, J = 5.4 Hz, 2H, NCH2CH2CH2S), 6.63 (s,
1H, = CH–NO2), 8.14 (s, 1H, NH); IR (KBr cm-1) r: 3,436, 3,110, 2,947, 2,908,
2,864, 1,531, 1,355; Anal. Calcd for C5H8N2O2S: C, 37.49; H, 5.03; N, 17.49,
Found: C, 37.50; H, 5.10; N, 17.50.
Ethyl 6-amino-8-(4-methoxyphenyl)-9-nitro-2,3,4,
8-tetrahydropyrido[2,1b][1,3]thiazine-7-carboxylate (3)
A solution of ethyl cyanoacetate (0.64 g, 5.66 mmol) in anhydrous ethanol (15 mL)
was added dropwise to a solution of p-methoxybenzaldehyde (0.77 g, 5.66 mmol)
in anhydrous ethanol (10 mL) at room temperature. After 3 min of stirring at room
temperature, piperidine (0.1 mmol) used as catalyst was added dropwise. The
resulting mixture was stirred for another 3 h, then 2-(nitromethylene)-1,3-thiazinane
(0.60 g, 3.75 mmol) was added to the reaction mixture, refluxed for 20 h, and
cooled to room temperature. Solid crystal product was filtered, washed with
CH2Cl2, and recrystallized from anhydrous ethanol. An orange-yellow powder was
obtained. Yield, 61 %; m.p. 173.9–175.4 °C; 1H NMR (400 MHz, CDCl3): d (ppm)
1.26 (t, J = 7.0 Hz, 3H, CH3), 2.17–2.25 (m, 1H, CH2CH2CH2S), 2.39–2.48 (m,
1H, NCH2CH2CH2S), 2.84–2.97 (m, 2H, NCH2–CH2CH2S), 3.67–3.74 (m, 1H,
NCH2CH2CH2S), 3.75 (s, 3H, OCH3), 3.98–4.04 (m, 1H, NCH2CH2CH2S), 4.14 (q,
J = 7.2 Hz, 2H, CH2OCO), 5.51 (s, 1H, PhCH), 6.20 (s, 2H, NH2), 6.77 (d,
J = 8.8 Hz, 2H, PhH), 7.11 (d, J = 8.8 Hz, 2H, PhH); IR(KBr cm-1) r: 3,438,
Fig. 1 The molecular structure of the title compound with atom numbering scheme. Dotted lines indicate
intramolecular N–HÁÁÁO interactions
123

Synthesis, biological activity and crystal structure
2439
3,290, 3,039, 2,983, 2,933, 2,898, 2,835, 1,672, 1,639, 1,504, 1,432, 1,245, 1,108,
829; Anal. Calcd for C18H21N3O5S: C, 55.23; H, 5.41; N, 10.73, Found: C, 55.27;
H, 5.42; N, 10.77.
Crystal structure determination
Crystals were obtained by slow evaporation from CH2Cl2–EtOH (1:2) solutions of
the pure compound 4. A colorless single crystal of suitable size, 0.25 9 0.1 9
Table 2 Selected geometric parameters for the title compound
˚
Bond lengths (A)
C9–C10
1.381(3)
1.387(3)
1.529(3)
1.386(3)
1.404(3)
1.505(3)
1.506(3)
1.368(3)
1.741(2)
1.377(3)
1.431(3)
1.407(3)
O3–C16
O3–C17
N2–C1
1.338(3)
1.450(3)
1.350(3)
1.230(3)
1.240(2)
1.383(3)
1.374(3)
1.377(3)
1.359(3)
1.443(3)
1.212(3)
1.372(3)
C9–C14
C9–C3
N1–C5
N3–O5
N1–C1
N3–O4
C3–C4
C14–C13
C12–C13
C12–C11
C2–C1
C3–C2
C5–C4
C5–S1
O1–C12
C2–C16
O2–C16
C10–C11
O1–C15
C4–N3
Angles (°)
C10–C9–C14
C10–C9–C3
C14–C9–C3
C5–N1–C1
C4–C3–C2
C4–C3–C9
C2–C3–C9
C4–C5–N1
C4–C5–S1
Torsion angles (°)
C10–C9–C3–C4
C14–C9–C3–C4
C10–C9–C3–C2
C14–N1–C5–C4
C1–N1–C5–S1
N1–C5–C4–C3
S1–C5–C4–C3
C2–C3–C4–C5
117.0(2)
121.01(19)
122.00(19)
113.4(4)
N1–C5–S1
C5–C4–N
119.37(16)
121.01(19)
122.59(19)
116.40(18)
120.28(18)
118.3(2)
C5–C4–C3
N3–C4–C3
C1–C2–C3
C16–C2–C3
N2–C1–C2
N2–C1–N1
C2–C1–N1
108.34(17)
113.47(16)
112.65(17)
117.92(19)
122.71(16)
124.8(2)
114.8(2)
120.38(19)
101.9(2)
-79.0(2)
-134.5(2)
-169.2(8)
39.7(4)
C9–C3–C4–C5
C2–C3–C4–N3
C9–C3–C4–N3
C4–C3–C2–C1
C9–C3–C2–C1
C3–C2–C1–N1
C5–N1–C1–C2
95.5(2)
149.23(19)
-84.9(2)
28.9(3)
-97.5(2)
-5.3(3)
7.3(3)
-173.40(15)
-30.4(3)
138.3(4)
123

2440
D. Li et al.
0.1 mm3, was selected for X-ray diffraction analysis. Data were collected on a
Bruker Smart 1000 CCD area diffractometer equipped with graphite monochromatic
˚
Mo Ka radiation (k = 0.71073 A) at 293 K (2). The unit cell dimensions were
obtained by least-squares refinement and the structure was solved by direct methods
with SHELXTL-97 software [16]. The final refinement was performed by full-matrix
least-squares techniques with anisotropic thermal data for the non-hydrogen atoms
on F2. All the non-H atoms were refined anisotropically, and the H atoms were
placed in the calculated positions and refined isotropically. The crystallographic data
and refinement information are summarized in Table 1.
Biology assay
The resultant compound was dissolved in acetone and diluted with water containing
Triton X-100 (0.1 mL L-1) to obtain a concentration of 500.0 mg L-1 and others
for bioassays.
Fig. 2 Packing of the title molecules in the crystal structure. Dotted lines indicate intermolecular
N–HÁÁÁO interactions
123

Synthesis, biological activity and crystal structure
2441
Fig. 3 Packing of the title molecules in the crystal structure. Dotted lines indicate intermolecular
C–HÁÁÁO interactions
Pea aphids (Aphis craccivora) were dipped according to a slightly modified FAO
dip test. Tender shoots of soybean with 40–60 healthy apterous adults were dipped
in diluted solutions of the chemicals containing Triton X-100 (0.1 mL L-1) for 5 s,
the superfluous fluid was removed, and the shoots were placed in the conditioned
room (23 1 °C, RH 50 %). Water containing Triton X-100 (0.1 mL L-1) was
used as control. Mortality was assessed after 24 h, and data were corrected and
subjected to probit analysis as before.
123

2442
D. Li et al.
˚
Table 3 Hydrogen-bonding geometry for the title compound (A, °)
D–HÁÁÁA
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
N2–H2BÁÁÁO2
0.87
0.85
0.96
0.96
0.97
0.97
0.96
0.97
0.97
0.97
0.97
2.05
3.26
3.18
3.86
3.19
3.12
3.69
3.05
3.93
3.24
3.32
2.7218
3.0418
3.9097
3.9097
3.5122
3.5122
4.5449
3.8525
3.9977
3.9637
3.8926
134.2
67.9
N2–H2AÁÁÁO2a
C15–H15AÁÁÁO2a
C15–H15BÁÁÁO2a
C17–H17AÁÁÁO1b
C17–H17BÁÁÁO1b
C18–H18AÁÁÁO3c
C7–H7BÁÁÁO4d
C8–H8AÁÁÁO4d
C7–H7BÁÁÁO5e
C8–H8AÁÁÁO5e
133.7
86.0
101.3
105.8
150.3
140.6
86.8
132.5
119.3
Symmetry codes:
a
1 - x, 1 - y, 1 - z
b
x, 1.5 - y, 0.5 ? z
c
x, -1 ? y, z
d
1 - x, y, z
e
1 - x, y, z
Results and discussion
The crystal structure of the title compound is shown in Fig. 1. This structure shows
that the thiazinane ring displays a half-chair conformation. The methoxyl occupies a
position coplanar to the benzene ring [C15–O1–C12–C13 torsion angle =
171.3(7)°], which is vertical to the tetrahydro-pyridine ring. The carbonyl oxygen
(O2) and a hydrogen atom of the amino group (N2) form a six-ring structure to lock
the molecular conformation. The nitro group is cis to the S atom. Some selected
bond lengths, bond angles, and torsion angles are listed in Table 2.
Figures 2 and 3 depict the packing of the title molecules in a unit cell. It can be
seen from Fig. 2 that the title molecules are connected into supramolecular layers of
two molecules thick in the ac plane by N–HÁÁÁO intermolecular hydrogen bonds. In
addition, a complex network of C–HÁÁÁO interactions connect the title molecules into
a 3D architecture. The crystal structure of the title compound is stabilized by the
combination of N–HÁÁÁO and C–HÁÁÁO intermolecular bonds. The H-bonding
interactions are listed in Table 3.
The title compound was screened for its insecticidal activities against
A. craccivora; the result exhibited 56 % insecticidal activities at 500 mg L-1
.
Conclusion
In conclusion, a new neonicotinoid insecticide ethyl 6-amino-8-(4-methoxy-
phenyl)-9-nitro-2,3,4,8-tetrahydropyrido[2,1-b][1,3]thiazine-7-carboxylate has been
123

Synthesis, biological activity and crystal structure
1
2443
synthesized and characterized by H NMR, IR, and X-ray diffraction. The crystal
structure analysis shows that the nitro is cis to that S atom and shows 56 %
insecticidal activity at 500 mg L-1 against A. craccivora. This result will contribute
to the structural change required to improve the bioactivity of cis-neonicotinoid
insecticide.
Acknowledgments We thank the National Science Foundation China Program (grants 20902037), the
Promotive Research Fund for Excellent Young and Middle-aged Scientists of Shandong Province (grants
BS2010NY001), and the Opening Fund of Shanghai Key Laboratory of Chemical Biology (grants
SKLCB-2008-08).
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