Chinese Chemical Letters  2015, Vol.26 Issue (01):1-5   PDF    
Facile three-component synthesis and insecticidal evaluation of hexahydroimidazo[1,2-a]pyridine derivatives
Ye-Feng Fana, Wen-Wen Zhanga, Xu-Sheng Shaoa, Zhi-Ping Xua, Xiao-Yong Xua, Zhong Lia,b     
a Shanghai Key Lab of Chemistry Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;
b Shanghai Collaborative Innovation Center for Biomanufacturing Technology, Shanghai 200237, China
Abstract: A series of new hexahydroimidazo[1,2-a]pyridine derivatives were synthesized via convenient and practical three-component reactions. Preliminary bioassays showed that majority of the target compounds exhibited moderate to excellent insecticidal activity against cowpea aphids (Aphis craccivora). Among them, compound 9l demonstrated significant activity with LC50 value of 0.00918 mmol/L which was about 3.8-fold higher than that of imidacloprid (IMI). Furthermore, the study of stereostructure-activity relationship of four isomers of 9k indicated that configuration played a key role in insecticidal activity of these compounds.
Key words: Neonicotinoids     Hexahydroimidazo[1,2-a]pyridine     Three-component reaction     Configuration     Insecticidal activity    
1. Introduction

Neonicotinoids,synthetic agonists selectively acting on the nicotinic acetylcholine receptors (nAChRs) located in the insect central nervous system (CNS) [1, 2],are potent broad-spectrum insecticides that possess contact,stomach and systemic activity. By virtue of high efficiency,mammalian safety,low toxicity and unique mode of action,neonicotinoids have replaced those conventional and environmentally less-benign insecticides,such as organophosphorus,carbamates,and pyrethroids [3, 4, 5, 6]. In 2011, neonicotinoids accounted for 28.5% of the total global insecticide market which was topmost among all of insecticides [7]. However, an inevitable problem associated with the widespread and frequent use of these insecticides is the occurrence of resistance and cross-resistance [8, 9, 10, 11]. It was reported some species exhibited more than 100-fold resistance to imidacloprid (1, Fig. 1) [12, 13]. Therefore,concerted efforts have to be made to discover potential candidates for the pest controlling in the future.

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Fig. 1. Structures of neonicotinoids.

In previous work,our group reported an innovative neonicotinoid compound 2 that showed excellent insecticidal activity [14]. However,it was unstable and could lead to the formation of compound 3 via self-Diels-Alder reaction [15]. Inspired by the facts,a novel series of hexahyroimidazo[1,2-α]pyridine neonicotinoids 4 were constructed via aza-Diels-Alder cycloaddition reactions [16] and some of those compounds exhibited good insecticidal activity. Whereas the previous structural modifications were only focused on the variations in benzene ring (unit E), other units such as 6-chloropyridin-3-ylmethyl (unit A),five membered ring (unit B),five-membered heterocycle (unit C) and cyano group (unit D) have not been investigated yet. Therefore,as an extension of our previous study and part of ongoing effort to discover potential insecticides,a series of hexahydroimidazo[1,2- a]pyridine derivatives 5 with structural diversity at five fragments were envisaged (Fig. 2).

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Fig. 2. The molecular design of target compounds.

However,the previous method still utilized the step-by-step synthetic strategy which restrained the efficiency of synthesis and bioactivity screening. Therefore,the development of an efficient, convenient and practical protocol to access compounds 5 was also both desirable and valuable. In recent years,multi-component reactions (MCRs) have served as powerful tools for the combinatorial synthesis in organic chemistry [17, 18, 19, 20, 21, 22, 23, 24]. MCRs could offer access to large compound library with diverse functionalities with the avoidance purification steps for possible combinatorial surveying of structure variations [25]. Thus,in this paper,we reported the synthesis of hexahydroimidazo[1,2-α]pyridine derivatives via one-pot,three-component reactions and the insecticidal evaluation of title compounds. 2. Experimental

All melting points (mp) were obtained on Bu¨ chi Melting Point B540 and uncorrected.NMRspectra 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. 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)imidazolidine was consumed,triethylamine (4.5 mmol) was added to the solution and stirred for another 3 h. Then 2-(2-fluoro-4-methylbenzylidene) 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. 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 threecomponent 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-α]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.

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Scheme 1. General synthetic route for title compounds 9.

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 reinvestigated 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.

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Scheme 2. General synthetic route for title compounds 13.
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 91 (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 ethyl had no activity. The target compound 9a-9k (R2 = CO2Et) exhibited similar insecticidal activity compared with the reported compounds (R2 = CN) [16]. As for the substituent Ar,the introduction of a fluoro group at 2-position was beneficial for the increase of activity. In particular,the compound with 2-fluoro- 4-methyl group (9k) showed relatively higher insecticidal activity. The insecticidal activity of six-membered ring analogs 13g and 13h was higher than that of corresponding five-membered ring counterparts [16]. The replacement of furyl with thienyl (13i and 13j) could not improve the activity dramatically.

Table 1
Insecticidal activity of compounds 9a-9l,13a-13j and imidacloprid against cowpea aphids.
3.3. Stereostructure-activity relationship

To our knowledge,isomer chirality has an impact on the bioactivity [15, 27]. To explore the stereostructure-activity relationship of this kind of compounds,compound 9k was resolved by preparative chiral HPLC. The result showed that there were four isomers: 9k-1,9k-2,9k-3 and 9k-4. The percentage compositions of them were 27.61%,22.58%,20.93% and 28.88%,respectively. By comparing the spectroscopic data,it was found 9k-1 and 9k-4 were a pair of enantiomers and 9k-2 and 9k-3 were another. The establishment of the stereochemistry of four isomers was made possible by the combination of X-ray crystallographic analysis (Fig. 3),principle of enantiomers,cis-principle of Diels-Alder reaction [28, 29] and NOESY NMR analysis (Fig. 4). Then the insecticidal activity against cowpea aphids of four isomers was tested. The LC50 values of 9k-1,9k-2,9k-3 and 9k-4 were 0.27048,0.21819,0.03515 and 0.02273 mmol/L,respectively.Based on the contrast of the LC50 value and stereochemistry of 9k-1 and 9k-2 or 9k-3 and 9k-4,it was speculated that the configuration of stereocenter C(7) did not influence the insecticidal activity. While the discrepancies in activity and stereostructure between 9k-1 and 9k-3 or 9k-2 and 9k-4 illuminated that the configuration of stereogenic carbons C(5) and C(6) had a significant effect on the insecticidal activity. And the (5R,6R)-configuration was more beneficial to the activity. These results would increase our databank of insecticidal activity of hexahydroimizadol[1,2-α]pyridine derivatives for further studies.

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Fig. 3. Crystal structure of the compound 9k-3 (left) and 9k-4 (right).

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Fig. 4. Configuration of four stereoisomers.
4. Conclusion

In summary,a series of hexahydroimidazo[1,2-α]pyridine derivatives were conveniently synthesized via three-component reactions and screened for their insecticidal activity against cowpea aphids. Most of the title compounds exhibited good activities at 500 mg L-1. Among them,compounds 9j-9l and 13g-13j were as active as or more than imidacloprid. Especially,the activity of compound 9l was 3.8-fold higher than that of imidacloprid based on the value of LC50. The stereostructure-activity relation research of four isomers of 9k expounded that configuration of C(5) and C(6) playedmore crucial role in the insecticidal activity than that of C(7). Moreover,controlling the C(5) and C(6) of this kind of compounds as R configuration would avail to the activity. Further structure- activity relationship studies of the hexahydroimizadol[1,2-α]pyridine derivatives are in progress.

Acknowledgment

This work was supported by National Key Technology R&D Program of China (No. 2011BAE06B01).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2014.10.019.

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