Design, synthesis and insecticidal activities of dihydropyridine-fused neonicotinoids compounds with trifluoromethyl group

Article abstract of DOI:10.1007/s11164-014-1835-y

A series of novel neonicotinoids containing a dihydro-pyridine ring and a trifluoromethyl group were designed and synthesized by multicomponent reactions of 6-Cl-PMNI, triethoxymethane and 4,4,4-trifluoro-3-oxobutaneanilides (9) under solvent-free and cat

Full text of DOI:10.1007/s11164-014-1835-y

Res Chem Intermed
DOI 10.1007/s11164-014-1835-y
Design, synthesis and insecticidal activities
of dihydropyridine-fused neonicotinoids compounds
with trifluoromethyl group
•
•
•
Zhongzhen Tian Shuxia Cui Li Dongmei
Zhiping Xu
Received: 18 August 2014 / Accepted: 24 September 2014
Ó Springer Science+Business Media Dordrecht 2015
Abstract A series of novel neonicotinoids containing a dihydro-pyridine ring and
a trifluoromethyl group were designed and synthesized by multicomponent reac-
tions of 6-Cl-PMNI, triethoxymethane and 4,4,4-trifluoro-3-oxobutaneanilides (9)
under solvent-free and catalyst-free conditions. The trifluoromethyl group plays an
important role as an electron-withdrawing group in enhancing the reaction activity
1
of compound 9. The target compounds were characterized by H NMR, IR and
elemental analysis. Bioassays indicated that most of the synthesized compounds
exhibited moderate insecticidal activities against Aphis craccivora.
Keywords cis-Neonicotinoid Á Dihydro-pyridine Á Trifluoromethyl group Á
Insecticidal activity
Introduction
Neonicotinoids are natural product-derived pesticides and the most important new
class of insecticides in the last two decades, and have a large impact on worldwide
insecticide use [1, 2]. Neonicotinoids include Imidacloprid, Acetamiprid,
Clothianidin, Dinotefuran, Nitenpyram, Thiacloprid, and Thiamethoxam [3, 4].
Neonicotinoids act selectively on the insect central nervous system (CNS) as
agonists of the postsynaptic nicotinic acetylcholine receptors (nAChRs) [5]. The
Z. Tian (&) Á S. Cui Á L. Dongmei
Shandong Provincial Key Laboratory of Fluorine Chemistry and Chemical Materials, School of
Chemistry and Chemical Engineering, University of Jinan, No. 336, West Road of Nan Xinzhuang,
Jinan 250022, People’s Republic of China
e-mail: chm_tianzz@ujn.edu.cn
Z. Xu
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of
Science and Technology, Shanghai 200237, People’s Republic of China
123

Z. Tian et al.
greatest attributes of neonicotinoids are their novel mode of action, low mammalian
toxicity, broad insecticidal spectrum, and good systemic properties [6, 7]. They are
now registered globally in more than 120 countries and extensively used in seed
treatment and soil treatment, or directly applied to plant foliage for crop protection
[8].
However, it remains essential to continually explore novel neonicotinoid
candidates because significant increases in resistance and cross-resistance have
been observed in various insect species after frequent field applications.
Nitromethylene analogue 6-Cl-PMNI {2-chloro-5-[(2-(nitromethylene)imidazolid-
in-1-yl) methyl]pyridine, 1} exhibits remarkably higher receptor binding activity [9,
10] compared with Imidacloprid; however, its use has been limited owing to its
photoinstability [11] and weak hydrophobicity [12]. In recent years, a large amount
of modification of the structures has been invested in the development of 6-Cl-
PMNI. These modification strategies include the cis-neonicotinoids family by
introducing a ring into the lead compound to fix the nitro moiety in the cis position
[13]. It is well established that trans/cis isomers may differ significantly in
biological activity, toxicity, and metabolic properties in medicinal chemistry.
Dicyclic neonicotinoid analogue 3 containing a tetrahydro-pyrimidine ring was
discovered by Bayer, in which the nitro group is in cis to the chloropyridinylmethyl
moiety, and also showing high biological activity [14]. Li et al. developed a series of
systematic studies on moderating the neonicotinoids with fused tetrahydropyridine 4
[15] and dihydropyrrole 5 [16], which exhibited satisfactory insecticidal activity,
and LC50 value of 5 was tenfold higher than imidacloprid against the cowpea aphid,
Aphis craccivora.
On the other hand, the trifluoromethyl group is a very important substituent in
medicinal chemistry, due to its unique stereoelectronic properties, and usually
increases the lipophilicity of a molecule [17]. In order to find the diversity of
nitromethylene neonicotinoids with cis nitro configuration, we have designed a
novel neonicotinoids family by introducing a dihydro-pyridine ring and tri-
fluoromethyl group into the lead compound to fix the nitro moiety in the cis position
(6 in Fig. 1). We expected that the new structure could not only overcome its
photoinstability but also improve hydrophobicity by the trifluoromethyl group. This
paper describes the synthesis and biological activities of a number of nitromethylene
derivatives containing dihydro-pyridine and the trifluoromethyl group.
Experimental
All starting materials and reagents were commercially available and used without
further purification otherwise stated. Melting points were obtained with a digital
melting point WRS-1B (Shen Guang Instrument, Shanghai, China) and were
1
uncorrected. HNMR spectra were recorded on a Bruker Avaace III (400 MHz)
spectrometer with DMSO-d6 or CDCl3 as the solvent and TMS as the internal
standard. Chemical shifts are reported in d (parts per million) values. Elemental
analyses were determined on a Yanaco MT-3CHN elemental analyzer. IR spectra
were recorded on a PE Spectrum with dried KBr as the adjuvant. Analytical thin-
123

Dihydropyridine-fused neonicotinoids compounds
O2N
N
N
N
H
NO2
NH
Cl
N
3 cis
N
O
O2N
N
Ph
O2N
N
Cl
N
N
6-Cl-PMNI (1)
trans
H
N
O
O
OH
N
CF3
Cl
N
NO2
N
4 cis
Cl
N
6 cis
O
NH
N
O2N
Cl
N
N
N
Imidacloprid (2)
trans
Cl
N
5 cis
Fig. 1 Strategy to synthesis dihydro-pyridine-fused neonicotinoids with a trifluoromethyl group
layer chromatography (TLC) was carried out on precoated plates (silica gel GF254),
and spots were visualized with ultraviolet (UV) light.
The activities of insecticidal compounds against A. craccivora were tested by the
leaf-dip method. All bioassays were performed on representative test organisms
reared in the laboratory. All compounds were dissolved in dimethyl sulfoxide
(DMSO) and diluted with distilled water containing Triton X-100 (0.1 mg/L) to
obtain series concentrations of 500 and 100 mg/L and others for bioassays. For
comparative purposes, imidacloprid was tested under the same conditions.
Horsebean plant leaves with 40–60 apterous adults were dipped in diluted
solutions of the chemicals containing Triton X-100 (0.1 mg/L) for 5 s, and the
excess dilution was sucked out with filter paper; the burgeons were placed in the
conditioned room (25 1 °C, 50 % RH). Water containing Triton X-100 (0.1 mg/L)
was used as control. The mortality rates were evaluated 24 h after treatment. Each
treatment had three repetitions, and the data were adjusted and subjected to probit
analysis.
Synthetic procedures
Unless otherwise noted, reagents and solvents were used as received from
commercial suppliers. Yields were not optimized. The raw materials nine were
synthesized according to the literature [18].
General synthetic procedure 6a–s
6-Cl-PMNI (2.5 mmol), triethoxymethane (3 mmol) and 4,4,4-trifluoro-3- oxobu-
taneanilides (3 mmol) were placed into a 25 mL round-bottom flask and the mixture
was refluxed. The resulting solution was stirred for 1–3 h, and the reaction progress
was monitored by TLC. On completion of the reaction, the mixture was cooled to
room temperature, and then a small amount of dichloromethane was added to
123

Z. Tian et al.
dissolve the mixture. The residue was purified by silica gel column chromatography
to give the pure products.
Data for 6a
Yield, 85 %, Yellow solid; mp, 184–185 °C; 1H NMR (CDCl3): d 8.58 (s, 1H), 8.34
(d, 1H, J = 1.6 Hz, Py–H), 8.11 (s, 1H), 7.80 (dd, 1H, J1 = 2.0 Hz, J2 = 8.0 Hz,
Py–H), 7.54 (s, 1H, Py–H), 7.53 (s, 1H, Ph–H), 7.35 (m, 3H, Ph–H), 7.17 (t, 1H,
J = 7.2 Hz, Ph–H), 5.09 (d, 1H, J = 15.2 Hz, Py–CH2), 4.42 (d, 1H, J = 15.2 Hz,
Py–CH2), 4.21–3.63 (m, 4H, N–CH2–CH2–N); IR (KBr) r(cm-1) : 3,270, 3,195,
3,133, 3,073, 2,893, 1,643, 1,545, 1,451, 1,347, 1,267, 1,177, 955, 755; Anal. Calcd
for C21H17ClF3N5O4: C, 50.87; H, 3.46; N, 14.12. Found: C, 50.97; H, 3.57; N,
14.23.
6b
Yield, 88 %, Yellow solid; mp, 148–149 °C; 1H NMR (CDCl3): d 8.50 (s, 1H), 8.33
(d, 1H, J = 1.6 Hz, Py–H), 8.09 (s, 1H), 7.78 (dd, 1H, J1 = 2.0 Hz, J2 = 8.0 Hz,
Py–H), 7.39 (d, 2H, J = 8.4 Hz, Ph–H), 7.35 (d, 1H, J = 8.0 Hz, Ph–H), 7.13 (m,
2H, Ph–H), 5.08 (d, 1H, J = 15.2 Hz, Py–CH2–), 4.41 (d, 1H, J = 15.2 Hz, Py–
CH2–), 4.16-3.62 (m, 4H, N–CH2–CH2–N), 2.32 (s, 3H, –CH3); IR(KBr) r (cm-1):
3,281, 3,079, 2,905, 1,645, 1,547, 1,449, 1,253, 1,175, 815; Anal. Calcd for
C22H19ClF3N5O4: C, 51.82; H, 3.76; N, 11.18. Found: C, 51.94; H, 3.70; N, 11.23.
6c
Yield, 68 %, Yellow solid; mp, 164–165 °C; 1H NMR (CDCl3): d 8.44 (s, 1H), 8.34
(d, 1H, J = 1.6 Hz, Py–H), 8.08 (s, 1H), 7.79 (dd, 1H, J1 = 2.8 Hz, J2 = 8.0 Hz,
Py–H), 7.44 (m, 2H, Ph–H), 7.38 (d, 1H, J = 8.8 Hz, Py–H), 6.86 (d, 2H,
J = 8.8 Hz, Ph–H), 5.08 (d, 1H, J = 15.2 Hz, Py–CH2–), 4.40 (d, 1H,
J = 15.2 Hz, Py–CH2–), 4.16–3.61 (m, 4H, N–CH2–CH2–N), 3.84 (s, 3H,
–OCH3); IR (KBr) r(cm-1): 3,285, 3,015, 2,979, 2,911, 1,647, 1,555, 1,457,
1,263, 1,173, 951, 779; Anal. Calcd for C22H19ClF3N5O5: C, 50.25; H, 3.64; N,
13.32. Found: C, 50.43; H, 3.51; N, 13.23.
6d
Yield, 72 %, Yellow solid; mp, 123–124 °C; 1H NMR (CDCl3): d 8.47 (s, 1H), 8.34
(d, 1 H, J = 2.0 Hz, Py–H), 8.09 (s, 1H), 7.80 (dd, 1 H, J1 = 2.4 Hz, J2 = 8.4 Hz,
Py–H), 7.42 (d, 2H, J = 8.4 Hz, Ph–H), 7.36 (d, 1H, J = 8.4 Hz, Py–H), 7.16 (d,
2H, J = 8.4 Hz, Ph–H), 5.10 (d, 1 H, J = 15.2 Hz, Py–CH2), 4.41 (d, 1 H,
J = 15.6 Hz, Py–CH2), 4.17–3.49 (m, 4H, N–CH2–CH2–N), 2.63 (m, 2H, Ph–CH2),
1.23 (m, 3H, CH3); IR (KBr) r(cm-1): 3,280, 3,062, 2,968, 2,826, 1,636, 1,566,
1,266, 1,176, 952, 828; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H, 4.04; N,
13.37. Found: C, 52.97; H, 4.16; N, 13.57.
123

Dihydropyridine-fused neonicotinoids compounds
6e
1
Yield, 70 %, Yellow solid; mp, 176–177 °C; H NMR (CDCl3): d 8.35 (d, 1H,
J = 2.4 Hz, Py–H), 8.32 (s, 1H), 8.09 (s, 1H), 7.79 (dd, 1H, J1 = 2.4 Hz,
J2 = 8.8 Hz, Py–H), 7.51 (m, 2H, Ph–H), 7.39 (d, 1H, J = 8.4 Hz, Py–H), 7.26 (m,
2H, Ph–H), 5.12 (d, 1H, J = 15.2 Hz, Py–CH2–), 4.46 (d, 1H, J = 15.6 Hz, Py–CH2–),
4.17–3.63 (m, 4H, –N–CH2–CH2–N–); IR(KBr) r(cm-1): 3,259, 3,199, 3,125, 3,061,
2,909, 1,641, 1,573, 1,539, 1,495, 1,251, 1,175, 955, 825; Anal. Calcd for C21H16Cl2
F3N5O4: C, 47.56; H, 3.04; N, 13.21. Found: C, 47.73; H, 3.16; N, 13.37.
6f
Yield, 65 %, Yellow solid; mp, 149–150 °C; 1H NMR (CDCl3): d 8.48 (s, 1H), 8.38
(d, 1H, J = 2.0 Hz, Py–H), 8.24 (s, 1H, Py-H), 7.85 (dd, 1 H, J1 = 2.4 Hz,
J2 = 8.4 Hz, Py–H), 7.48 (m, 1H, Ph–H), 7.14(m, 2H, Ph–H), 4.87 (d, 1H,
J = 16.0 Hz, Py–CH2), 4.64 (d, 1H, J = 16.4 Hz, Py–CH2), 4.04–3.84 (m, 4H,
N–CH2–CH2–N), 2.54 (t, 2H, J = 7.6 Hz), 1.52 (m, 2H, CH2), 1.27 (m, 2H, CH2),
0.89 (t, 3H, J = 7.2 Hz, CH3); IR (KBr) r (cm-1): 3,291, 3,061, 2,921, 2,861,
1,633, 1,561, 1,353, 1,237, 1,169, 829; Anal. Calcd for C25H25ClF3N5O4: C, 54.40;
H, 4.57; N, 12.69. Found: C, 54.72; H, 4.34; N, 12.76.
6g
Yield, 86 %, Yellow solid; mp, 192–193 °C; 1H NMR (CDCl3): d 8.59 (s, 1H), 8.35
(d, 1H, J = 2.0 Hz, Py–H), 8.09 (s, 1H), 7.80 (dd, 1H, J1 = 2.2 Hz, J2 = 8.2 Hz,
Py–H), 7.51 (m, 2H, Ph–H), 7.37 (d, 1 H, J = 8.4 Hz, Py–H), 7.05 (m, 2H, Ph–H),
5.09 (d, 1H, J = 15.6 Hz, Py–CH2), 4.43 (d, 1H, J = 15.2 Hz, Py–CH2), (m, 4H,
N–CH2–CH2–N); IR (KBr) r(cm-1): 3,263, 3,212, 3,057, 2,903, 1,637, 1,555,
1,513, 1,347, 1,245, 1,175, 959, 831; Anal. Calcd for C21H16ClF4N5O4: C, 49.09; H,
3.14; N, 13.63. Found: C, 49.21; H, 3.98; N, 13.79.
6h
1
Yield, 73 %, Yellow solid; mp, 190–191 °C; H NMR (CDCl3): d 10.18 (s, 1H),
9.82 (s, 1H), 8.38 (d, 1H, J = 2.4 Hz, Py–H), 8.23 (s, 1H), 7.85 (dd, 1H,
J1 = 2.4 Hz, J2 = 8.4 Hz, Py–H), 7.54 (d, 1H, J = 8.4 Hz, Py–H), 7.49 (d, 2H,
J = 8.8 Hz, Ph–H), 6.91 (m, 2H, Ph–H), 4.87 (d, 1H, J = 16.4 Hz, Py–CH2–), 4.63
(d, 1H, J = 16.0 Hz, Py–CH2–), 4.08–3.80 (m, 6H, N–CH2–CH2–N and –O–CH2–),
1.31 (t, 3H, J = 7.2 Hz –CH3). IR (KBr) r (cm-1) : 3,445, 3,275, 3,065, 2,979,
2,919, 1,629, 1,573, 1,505, 1,353, 1,237, 1,169, 837; Anal. Calcd for C23H21ClF3-
N5O5: C, 51.17; H, 3.92; N, 12.97. Found: C, 51.37; H, 3.86; N, 13.05.
6i
Yield, 69 %, Yellow solid; mp, 202–203 °C; 1H NMR (CDCl3): d 9.99 (s, 1H), 8.39
(s, 1H), 8.30 (s, 1H, Py–H), 7.86 (d, 1H, J = 8.4 Hz, Py–H), 7.84 (d, 1H,
123

Z. Tian et al.
J = 8.4 Hz, Py–H), 7.10 (s, 3H, Ph–H), 4.88 (d, 1H, J = 16.0 Hz, Py–CH2), 4.56
(d, 1H, J = 16.4 Hz, Py–CH2), 4.03-3.57 (m, 4H, N–CH2–CH2–N), 2.13 (s, 6H,
CH3); IR (KBr) r (cm-1): 3,295, 3,029, 2,975, 2,913, 1,647, 1,557, 1,469, 1,333,
1,267, 1,185, 959, 775; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H, 4.04; N,
13.37. Found: C, 52.92; H, 3.93; N, 13.56.
6j
1
Yield, 73 %, Yellow solid; mp, 147–148 °C; H NMR (CDCl3): d 10.07 (s, 1H),
9.77 (s, 1H), 8.38 (d, 1H, J = 2.4 Hz, Py–H), 8.26 (s, 1H), 7.85 (dd, 1H,
J1 = 2.4 Hz, J2 = 8.4 Hz, Py–H), 7.55 (d, 1H, J = 8.4 Hz, Py–H), 7.24 (s, 2H,
Ph–H), 6.76 (s, 1H, Ph–H), 4.87 (d, 1H, J = 16.0 Hz, Py–CH2–), 4.64 (d, 1H,
J = 16.0 Hz, Py–CH2–), 4.07–3.81 (m, 4H, –N–CH2–CH2–N–), 2.25 (s, 6H,
–CH3); IR (KBr) r (cm-1): 3,433, 3,316, 3,087, 2,919, 2,777, 1,677, 1,575, 1,517,
1,303, 1,217, 1,191, 951, 827; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H, 4.04;
N, 13.37. Found: C, 52.89; H, 4.01; N, 13.46.
6k
Yield, 78 %, Yellow solid; mp, 135–136 °C; 1H NMR (DMSO–d6): d 8.83 (s, 1H),
8.41 (s, 1H), 8.38 (d, 1H, J = 2.4 Hz, Py–H), 8.17(s, 1H), 8.06 (m, 1H), 7.80 (dd,
1H, J1 = 2.4 Hz, J2 = 8.4 Hz, Py–H), 7.37 (d, 1H, J = 8.0 Hz, Py–H), 7.08 (m,
3H, Ph–H), 5.08 (d, 1H, J = 15.6 Hz, Py–CH2–), 4.42 (d, 1H, J = 15.6 Hz,
Py–CH2–), 4.22–3.62 (m, 4H, N–CH2–CH2–N); IR (KBr) r (cm-1): 3,661, 3,361,
3,055, 2,893, 1,649, 1,533, 1,453, 1,313, 1,257, 1,179, 753; Anal. Calcd for
C21H16ClF4N5O4: C, 49.09; H, 3.14; N, 13.63. Found: C, 49.33; H, 3.04; N, 13.56.
6l
Yield, 68 %, Yellow solid; mp, 163–164 °C; 1H NMR (CDCl3): d 8.49 (s, 1H), 8.37
(d, 1H, J = 2.0 Hz, Py-H), 8.19 (d, 1H, J = 6.8 Hz, Ph-H), 8.10 (s, 1H), 7.85 (dd,
1H, J1 = 2.4 Hz, J2 = 8.4 Hz, Py-H), 7.40 (d, 1H, J = 8 Hz, Py-H), 7.11 (t, 1H,
J = 8 Hz, Ph-H), 6.97 (t, 1H, J = 7.8 Hz, Ph-H), 6.90 (d, 1H, J = 8 Hz, Ph-H),
5.13 (d, 1H, J = 15.2 Hz, Py-CH2-), 4.43 (d, 1H, J = 15.6 Hz, Py-CH2-), 4.21-3.63
(m, 4H, -N-CH2-CH2-N-). IR (KBr) r (cm-1): 3,363, 3,099, 2,955, 2,835, 1,641,
1,551, 1,457, 1,223, 1,183, 1,019, 949, 755; Anal. Calcd for C21H16Cl2F3N5O4: C,
47.56; H, 3.04; N, 13.21. Found: C, 47.76; H, 3.11; N, 13.38.
6m
Yield, 73 %, Yellow solid; mp, 146–147 °C; 1H NMR(CDCl3): d 8.44 (s, 1H), 8.36
(d, 1H, J = 2.0 Hz, Py–H), 8.20 (dd, 1H, J1 = 1.2 Hz, J2 = 8.0 Hz, Py–H), 8.09 (s,
1H), 7.84 (dd, 1H, J1 = 2.8 Hz, J2 = 8.4 Hz, Py–H), 7.39 (d, 1H, J = 8.4 Hz,
Ph–H), 7.11 (m, 1H, Ph–H), 6.97 (m, 2H, Ph–H), 5.10 (d, 1H, J = 15.6 Hz,
Py–CH2–), 4.42 (d, 1H, J = 15.2 Hz, Py–CH2–), 4.19–3.62 (m, 4H, N–CH2–CH2–N),
3.96 (s, 3H, –OCH3); IR (KBr) r (cm-1): 3,353, 3,079, 2,929, 2,843, 1,635, 1,547,
123

Dihydropyridine-fused neonicotinoids compounds
1,461, 1,325, 1,229, 1,189, 1,177, 1,109, 1,019, 951, 755; Anal. Calcd for
C22H19ClF3N5O5: C, 50.25; H, 3.64; N, 13.32. Found: C, 50.46; H, 3.57; N, 13.23.
6n
1
Yield, 77 %, Yellow solid; mp, 178–179 °C; H NMR(DMSO–d6): d 9.99 (s, 1H),
9.79 (s, 1H), 8.34 (m, 3H), 7.82 (dd, 1H, J1 = 2.4 Hz, J2 = 8.4 Hz, Py–H), 7.55 (d,
1H, J = 8.0 Hz, Py–H), 6.93 (m, 1H, Ph–H), 4.89 (d, 1H, J = 16.0 Hz, Py–CH2–),
4.72 (d, 1H, J = 16.4 Hz, Py–CH2–), 4.12–3.86 (m, 6H, N–CH2–CH2–N and –O–
CH2–), 1.36 (t, 1H, J = 6.8 Hz, –CH3); IR (KBr) r (cm-1): 3,446, 3,352, 3,066,
2,988, 2,930, 1,658, 1,534, 1,452, 1,348, 1,238, 1,194, 968, 750; Anal. Calcd for
C23H21ClF3N5O5: C, 51.17; H, 3.92; N, 12.97. Found: C, 51.26; H, 4.09; N, 13.23.
6o
1
Yield, 70 %, Yellow solid; mp, 183–184 °C; H NMR (DMSO–d6): d 8.35 (d, 1H,
J = 2.0 Hz, Py–H), 8.25 (s, 1H), 8.14 (s, 1H), 7.81 (dd, 1H, J1 = 2.4 Hz,
J2 = 8.0 Hz, Py–H), 7.36 (d, 1H, J = 8.4 Hz, Py–H), 7.27 (m, 2H, Ph–H), 7.07 (m,
2H, Ph–H), 5.06 (d, 1H, J = 15.6 Hz, Py–CH2–), 4.42 (d, 1H, J = 15.6 Hz, Py–
CH2–), 4.20–3.62 (m, 4H, N–CH2–CH2–N), 2.27 (m, 3H, –CH3), 2.10 (s, 3H,
–CH3). IR (KBr) r (cm-1): 3,383, 3,245, 3,069, 2,933, 1,645, 1,567, 1,451, 1,345,
1,255, 1,169, 949, 779; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H, 4.04; N,
13.37. Found: C, 52.68; H, 4.14; N, 13.55.
6p
1
Yield, 73 %, Yellow solid; mp, 128–129 °C; H NMR (CDCl3): d, 8.37 (d, 1H,
J = 2.4 Hz, Py–H), 8.11 (s, 1H), 7.98 (s, 1H), 7.84 (dd, 1H, J1 = 2.4 Hz,
J2 = 8.4 Hz, Py–H), 7.39 (d, 1H, J = 8.4 Hz, Py–H), 7.34 (d, 1H, J = 7.6 Hz, Py–
H), 7.01 (d, 2H, J = 8.4 Hz, Ph–H), 5.08 (d, 1H, J = 15.6 Hz, Py–CH2), 4.45 (d,
1H, J = 15.6 Hz, Py–CH2), 4.18– 3.89 (m, 4H, N–CH2–CH2–N), 2.31 (s, 3H, CH3),
2.21 (s, 3H, CH3). IR (KBr) r (cm-1): 3,400, 3,242, 2,952, 1,652, 1,560, 1,530,
1,458, 1,266, 1,174, 820, 742, 646; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H,
4.04; N, 13.37. Found: C, 52.93; H, 3.93; N, 13.45.
6q
1
Yield, 65 %, Yellow solid; mp, 182–183 °C; H NMR (CDCl3): d 10.06 (s, 1H),
9.82 (s, 1H), 8.39 (d, 1H, J = 2.4 Hz, Py–H), 8.38 (s, 1H), 7.85 (dd, 1H,
J1 = 2.8 Hz, J2 = 8.4 Hz, Py–H), 7.59 (s, 1H, Ph–H), 7.57 (d, 1H, J = 8.0 Hz,
Py–H), 7.10 (d, 1H, J = 3.6 Hz, Ph–H), 6.90 (d, 1H, J = 7.2 Hz, Ph–H), 4.89 (d,
1H, J = 16 Hz, Py–CH2–), 4.66 (d, 1H, J = 16.0 Hz, Py–CH2–), 4.08–3.81 (m, 4H,
–N–CH2–CH2–N–), 2.26 (s, 3H, –CH3), 2.15 (s, 3H, –CH3). IR (KBr) r (cm-1) :
3,241, 3,083, 3,013, 2,943, 2,921, 2,857, 1,651, 1,567, 1,343, 1,275, 1,177, 1,001,
807; Anal. Calcd for C23H21ClF3N5O4: C, 52.73; H, 4.04; N, 13.37. Found: C,
52.89; H, 4.23; N, 13.49.
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Z. Tian et al.
6r
Yield, 80 %, Yellow solid; mp, 185–186 °C; 1H NMR (CDCl3): d 9.98 (s, 1H), 9.94
(s, 1H), 8.41 (d, 1H, J = 2.0 Hz, Py–H), 8.31 (s, 1H), 7.89 (dd, 1H, J1 = 2.6 Hz,
J2 = 8.2 Hz, Py–H), 7.56 (d, 1H, J = 8.4 Hz, Py–H), 6.91 (s, 2H, Ph–H), 4.89 (d,
1H, J = 16.0 Hz, Py–CH2), 4.57 (d, 1H, J = 16.4 Hz, Py–CH2), 4.06–3.81 (m, 4H,
N–CH2–CH2–N), 2.11 (s, 3H, CH3), 2.10 (s, 6H, CH3). IR (KBr) r (cm-1) : 3,211,
2,977, 2,917, 2,871, 1,645, 1,563, 1,507, 1,337, 1,247, 1,173, 1,011, 955, 735; Anal.
Calcd for C24H23ClF3N5O4: C, 52.73; H, 4.04; N, 13.37. Found: C, 52.86; H, 4.11;
N, 13.48.
6s
Yield, 85 %, Yellow solid; mp, 146–147 °C; 1H NMR (DMSO–d6): d 10.10 (s, 1H),
9.96 (s, 1H), 8.37 (m, 3H), 7.83 (dd, 1H, J1 = 2.4 Hz, J2 = 8.4 Hz, Py–H), 7.71 (d,
1H, J = 2.4 Hz, Ph–H), 7.55 (d, 1H, J = 8.0 Hz, Py–H), 7.45 (dd, 1H,
J1 = 2.8 Hz, J2 = 9.2 Hz, Ph–H), 4.89 (d, 1H, J = 16.0 Hz, Py–CH2–), 4.70 (d,
1H, J = 16.4 Hz, Py–CH2–), 4.12–3.86 (m, 4H, N–CH2–CH2–N). IR (KBr) r
(cm-1): 3,453, 3,329, 3,085, 2,925, 2,845, 1,677, 1,577, 1,427, 1,465, 1,303, 1,215,
1,183, 827. Anal. Calcd for C21H15Cl3F3N5O4: C, 44.66; H, 2.68; N, 12.40. Found:
C, 44.59; H, 2.77; N, 12.56.
Results and discussion
Synthesis
Starting from ethyl 4,4,4-trifluoro-3-oxobutanoate (7), condensates with anilines
afforded the corresponding intermediate 4,4,4-trifluoro-3-oxobutaneanilides (9)
according to reported methods [16]. The title compounds (6) were prepared in
65–88 % yield by reacting 6-Cl-PMNI, triethoxymethane and 4,4,4-trifluoro-3-
oxobutaneanilides (9) in one-pot, under solvent-free and catalyst-free conditions.
Trifluoromethyl group plays an important role as an electron-withdrawing group in
enhancing the reaction activity of compound 9. If the trifluoromethyl group was
replaced by a methyl group, the expected compound was not found in the reaction
process. This method offered several advantages, such as short reaction time,
relatively good yield and simple post-processing. The synthetic route is illustrated in
1
Scheme 1, and their structures were confirmed by H NMR, IR and elemental
analyses.
The plausible mechanism was presumed in Scheme 2. The assembly of 6 can be
explained via the initial Michael addition of 10 to the ylidenic bond in 1, leading to
the formation of an acyclic intermediate 11, which cyclized into the intermediate 12
via nucleophilic attack of an NH group on a carbonyl carbon. Then, intermediate 12
removed the ethanol to give the final product 6. The formation of 10 is via the
condensation reaction of triethoxymethane 8 and appropriate 4,4,4-trifluoro-3-
oxobutaneanilides 9.
123

Dihydropyridine-fused neonicotinoids compounds
O
O
F3C
O
7
130 o
C
PhNH2
O
NO2
Ph
O2N
N
N
O
O
H
OH
O
O
O
Ph
reflux
NH
N
N
+
+
N
H
F3C
CF3
Cl
N
Cl
N
8
9
6
6-Cl-PMNI
Me
EtO
Me
Cl
F
Et
Me
MeO
Bu
Ph =
Me
Me
6c
6b
6g
6a
6e
6f
6h
6i
6j
6d
Me
Me
Me
Me
Me
Cl
Me
OMe
Me
OEt
F
Cl
Cl
Me
Me
6r
6k
6s
6l
6q
6m
6o
6n
6p
Scheme 1 General synthetic route for title compounds 6
O2N
O
O
Ph
NH
6-Cl-PMNI
N
O2N
N
N
H
O
O
O
O
O
H
Cl
N
O
Ph
F3C
NH
N
+
N
F3C
O
Ph
H
F3C
O
O
Cl
N
11
8
9
10
O
O
N
O
O
Ph
Ph
O2N
N
O2N
N
H
N
H
-EtOH
OH
OH
CF3
N
N
CF3
Cl
N
Cl
N
12
6
Scheme 2 Presumed mechanism for the multicomponent reaction
To verify the structure of the product dihydro-pyridine, 6 was selected as a
representative compound and characterized by X-ray crystallography as shown in
Fig. 2.
Insecticidal activities
Insecticidal activities of compounds 6 against Aphis craccivora are shown in
Table 1. In general, most of the compounds showed moderate insecticidal activity at
500 mg/L. The insecticidal activities of compounds 6f, 6j, and 6k displayed[90 %
at 500 mg/L, and showed [50 % at 100 mg/L. The insecticidal activity of
compounds 6i, 6l, 6m, 6n, 6o, and 6p were over 70 % at 500 mg/L.
123

Z. Tian et al.
Fig. 2 Crystal structures of compound 6b
Table 1 Insecticidal activity results of the synthetic compounds 6a–s
Compounds
–Ph
Mortality (%)
500 mg/L-1
100 mg/L-1
6a
6b
6c
6d
6e
6f
Aniline
15
35
32
41
10
93
18
32
88
92
91
76
79
65
83
70
33
45
56
nta
nt
nt
nt
nt
56
nt
nt
20
62
51
nt
nt
nt
26
nt
nt
nt
nt
4-CH3-aniline
4-OCH3-aniline
4-Et-aniline
4-Cl-aniline
4-Bu-aniline
6g
6h
6i
4-F-aniline
4-OEt-aniline
2,6-Dimethylaniline
3,5-Dimethylaniline
2-F-Aniline
6j
6k
6l
2-Cl-Aniline
6m
6n
6o
6p
6q
6r
6s
2-OCH3-Aniline
2-OEt-Aniline
2,3-Dimethylaniline
2,4-Dimethylaniline
2,5-Dimethylaniline
2,4,6-Trimethylaniline
2,4-Dichloroaniline
a
Not tested
123

Dihydropyridine-fused neonicotinoids compounds
Conclusions
To summarize, we have achieved the one-pot, three-component synthesis of a
highly functional dihydro-pyridine ring and containing a trifluoromethyl group
under solvent-free and catalyst-free conditions. The trifluoromethyl group plays an
important role as an electron-withdrawing group in enhancing the reaction activity
of compound 9. Bioassays indicated that most of the synthesized compounds
exhibited moderate insecticidal activities against A. craccivora.
Acknowledgment This work was financial supported by the National Science Foundation China
Program (Grant 20902037), the Opening Project of Shanghai Key Laboratory of Chemical Biology.
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