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 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)imidazolidin-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 trifluoromethyl 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.

Fig. 1
figure 1

Strategy to synthesis dihydro-pyridine-fused neonicotinoids with a trifluoromethyl group

Full size image

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 uncorrected. 1HNMR 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 δ (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-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- oxobutaneanilides (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 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): δ 8.58 (s, 1H), 8.34 (d, 1H, J = 1.6 Hz, Py–H), 8.11 (s, 1H), 7.80 (dd, 1H, J 1 = 2.0 Hz, J 2 = 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) σ(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): δ 8.50 (s, 1H), 8.33 (d, 1H, J = 1.6 Hz, Py–H), 8.09 (s, 1H), 7.78 (dd, 1H, J 1 = 2.0 Hz, J 2 = 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) σ (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): δ 8.44 (s, 1H), 8.34 (d, 1H, J = 1.6 Hz, Py–H), 8.08 (s, 1H), 7.79 (dd, 1H, J 1 = 2.8 Hz, J 2 = 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) σ(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): δ 8.47 (s, 1H), 8.34 (d, 1 H, J = 2.0 Hz, Py–H), 8.09 (s, 1H), 7.80 (dd, 1 H, J 1  = 2.4 Hz, J 2  = 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) σ(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.

6e

Yield, 70 %, Yellow solid; mp, 176–177 °C; 1H NMR (CDCl3): δ 8.35 (d, 1H, J = 2.4 Hz, Py–H), 8.32 (s, 1H), 8.09 (s, 1H), 7.79 (dd, 1H, J 1 = 2.4 Hz, J 2 = 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) σ(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 C21H16Cl2F3N5O4: 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): δ 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, J 1  = 2.4 Hz, J 2  = 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) σ (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): δ 8.59 (s, 1H), 8.35 (d, 1H, J = 2.0 Hz, Py–H), 8.09 (s, 1H), 7.80 (dd, 1H, J 1  = 2.2 Hz, J 2  = 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) σ(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

Yield, 73 %, Yellow solid; mp, 190–191 °C; 1H NMR (CDCl3): δ 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, J 1  = 2.4 Hz, J 2  = 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) σ (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 C23H21ClF3N5O5: 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): δ 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, 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) σ (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

Yield, 73 %, Yellow solid; mp, 147–148 °C; 1H NMR (CDCl3): δ 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, J 1 = 2.4 Hz, J 2 = 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) σ (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): δ 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, J 1  = 2.4 Hz, J 2  = 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) σ (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): δ 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, J 1 = 2.4 Hz, J 2 = 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) σ (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): δ 8.44 (s, 1H), 8.36 (d, 1H, J = 2.0 Hz, Py–H), 8.20 (dd, 1H, J 1 = 1.2 Hz, J 2 = 8.0 Hz, Py–H), 8.09 (s, 1H), 7.84 (dd, 1H, J 1  = 2.8 Hz, J 2  = 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) σ (cm−1): 3,353, 3,079, 2,929, 2,843, 1,635, 1,547, 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

Yield, 77 %, Yellow solid; mp, 178–179 °C; 1H NMR(DMSO–d6): δ 9.99 (s, 1H), 9.79 (s, 1H), 8.34 (m, 3H), 7.82 (dd, 1H, J 1 = 2.4 Hz, J 2 = 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) σ (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

Yield, 70 %, Yellow solid; mp, 183–184 °C; 1H NMR (DMSO–d6): δ 8.35 (d, 1H, J = 2.0 Hz, Py–H), 8.25 (s, 1H), 8.14 (s, 1H), 7.81 (dd, 1H, J 1  = 2.4 Hz, J 2  = 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) σ (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

Yield, 73 %, Yellow solid; mp, 128–129 °C; 1H NMR (CDCl3): δ, 8.37 (d, 1H, J = 2.4 Hz, Py–H), 8.11 (s, 1H), 7.98 (s, 1H), 7.84 (dd, 1H, J 1 = 2.4 Hz, J 2 = 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) σ (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

Yield, 65 %, Yellow solid; mp, 182–183 °C; 1H NMR (CDCl3): δ 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, J 1 = 2.8 Hz, J 2 = 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) σ (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.

6r

Yield, 80 %, Yellow solid; mp, 185–186 °C; 1H NMR (CDCl3): δ 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, J 1 = 2.6 Hz, J 2 = 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) σ (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): δ 10.10 (s, 1H), 9.96 (s, 1H), 8.37 (m, 3H), 7.83 (dd, 1H, J 1 = 2.4 Hz, J 2 = 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, J 1  = 2.8 Hz, J 2  = 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) σ (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 Scheme 1, and their structures were confirmed by 1H NMR, IR and elemental analyses.

Scheme 1
scheme 1

General synthetic route for title compounds 6

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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.

Scheme 2
scheme 2

Presumed mechanism for the multicomponent reaction

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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.

Fig. 2
figure 2

Crystal structures of compound 6b

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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.

Table 1 Insecticidal activity results of the synthetic compounds 6a–s
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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.