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3. Results and discussion
3.1. Synthesis
It was designed that the dienophiles generated by the
Knoevenagel condensation of cyano compounds 7 with aromatic
aldehydes 8 in the presence of catalyst reacted in situ with the
diene compounds 6 to yield the target compounds via three-
component reactions. The diene compounds 6 were synthesized
according to the reported procedure [14]. Then the reaction
condition was investigated to realized the one-pot preparation of
hexahydroimidazo[1,2-a]pyridine derivatives. The examination
of catalyst, solvent and temperature led to the following
informative observations: (i) piperidine was the optimal catalyst;
(ii) dichloromethane was the suitable solvent; (iii) the product
yield was highest at room temperature. Finally, the target
compounds 9 were furnished in moderate to good yields catalyzed
by piperidine in dichloromethane at room temperature as showed
in Scheme 1.
When R1 was replaced by benzyl, phenyl, or ethyl and n = 1
(Fig. 2), the analogs of compounds 6 were very difficult to be
isolated and unstable. Thus, an alternative approach was proposed
based on an aza-hydro-allyl addition of compounds 10 on the
five-membered aromatic heterocyclic aldehydes 11, followed by
aza-Diels–Alder cycloaddition with the prepared electrondeficient
dienophiles 12 [16] in situ. The reaction condition was reinves-
tigated to come true the draft. The beneficial results were
concluded after the research: (i) acetonitrile was the suitable
solvent; (ii) low temperature was necessary to the good yield of
products. Then the title compounds 13 were generated from
compounds 10, 11 and 12 in acetonitrile at 0 8C in one-pot as
depicted in Scheme 2.
Fig. 1. Structures of neonicotinoids.
2. Experimental
All melting points (mp) were obtained on Bu¨chi Melting Point
B540 and uncorrected. NMR spectra were recorded in DMSO-d6 (1H
at 400 MHz and 13C at 100 MHz) using TMS as the internal
standard on a Bruker AM-400 spectrometer. High-resolution mass
spectra were recorded under electron impact (70 eV) condition
using a MicroMass GCT CA 055 instrument. Analytical thin-layer
chromatography (TLC) was carried out on precoated plates (silica
gel 60 F254), and spots were visualized with ultraviolet (UV) light.
All other solvents and reagents were used as obtained from
commercial sources without further purification.
2.1. General procedure for preparation of 9a–9l
A solution of ethyl 2-cyanoacetate (3.0 mmol), benzaldehyde
(3.0 mmol) and piperidine (0.3 mmol) in 20 mL dichloromethane
was stirred for 2 h at room temperature. Then 2-chloro-5-((2-(2-
(furan-2-yl)-1-nitrovinyl)-4,5-dihydro-1H-imidazol-1-yl)methyl)-
pyridine (2.0 mmol) was added to the mixture. The reaction
progress was monitored by TLC. On completion of the reaction,
the mixture was concentrated under reduced pressure and the
crude product was subjected to chromatography on silica gel to
afford the pure product 9a. Compounds 9b–9l were synthesized
analogously.
3.2. Insecticidal activity
The insecticidal activity of target compounds against cowpea
aphid [26] was evaluated using imidacloprid as control (Table 1).
Most of the target compounds exhibited moderate to excellent
insecticidal activity. The LC50 values of some compounds were
approximately equal to that of imidacloprid. In particular, the
bioactivity of compound 9l (LC50 = 0.00918 mmol/L) was 3.8-fold
more active than that of imidacloprid (LC50 = 0.03502 mmol/L).
The insecticidal activity varied depending upon R1, R2, Ar, the size
of ring (n) and the patterns of five-membered heterocycle. For the
effect of R1, it was observed that 6-chloropyridine-3-ylmethyl and
2-chlorothiazol-5-ylmethyl units were favorable to the insecticidal
activity, whereas compounds 13a–13f bearing benzyl, phenyl or
2.2. General procedure for preparation of 13a–13j
The solution of 1-benzyl-2-(nitromethylene)imidazolidine
(3.0 mmol), furan-2-carbaldehyde (3.6 mmol) and concentrated
hydrochloric acid (4.5 mmol) in 30 mL acetonitrile was stirred in
ice-bath for 4 h. When the 1-benzyl-2-(nitromethylene)imidazo-
lidine was consumed, triethylamine (4.5 mmol) was added to the
solution and stirred for another 3 h. Then 2-(2-fluoro-4-methyl-
benzylidene)malononitrile was added to the mixture. The reaction
progress was monitored by TLC. On completion of the reaction, the
mixture was concentrated under reduced pressure the crude
product was subjected to chromatography on silica gel to afford
the pure product 13a. Compounds 13b–13j were synthesized
analogously.
Physical and spectroscopic characterization data of compounds
9a–9l and 13a–13j were given in Supporting information.
Scheme 1. General synthetic route for title compounds 9.
Fig. 2. The molecular design of target compounds.
Scheme 2. General synthetic route for title compounds 13.
Please cite this article in press as: Y.-F. Fan, et al., Facile three-component synthesis and insecticidal evaluation of
Fan, Ye-Feng
