b School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China
Multi-component reactions (MCRs) represent an attractive synthetic strategy to effectively build small-molecule libraries . The possibility of increasing yields,saving both reagents and solvents,and the simplification of the purification process are among the benefits in using MCRs in organic synthesis . MCRs have attracted much interest of synthetic chemists and been the focus of many synthetic efforts,especially in drug discovery and library synthesis. We have previously reported the application of MCRs to the synthesis of several types of heterocycles such as pyridine dicarbonitriles,thiazoles,and oxazoles .
Chromenopyridine derivatives 1,which can be sucessfully synthesized via a known MCR by refluxing salicylaldehyde,thiol and malononitrile (Scheme 1) in ethanol ,are of significant medicinal relevance. Structures bearing this motif display a diverse range of biological properties including glucocorticoid receptor (GR) agonists [5a],anti-tumor [5b],anti-bacterial [5b],anti-proliferative [5c],anti-myopic [5d],hypotensive [4a],anti-histaminic [5f],anti- rheumatic [5g],and anti-asthmatic activities [5h].
Chromene derivatives 2,which are widely present in plants including edible vegetables and fruits ,represent a significant class of compounds with broad and remarkable biological active, such as antimicrobial and antifungal ,antioxidant ,antileishmanial ,antitumor ,hypotensive ,antiproliferation ,local anesthetic ,antiallergenic ,central nervous system (CNS) activities ,as well as for the treatment of Alzheimer's disease  and schizophrenia disorders .
Several methods have been reported for the synthesis of new chromenopyridines and chromenes [4, 18]. Recently,in our study of the MCR to produce chromenopyridine,an interesting temperature- sensitivity phenomenon was observed. Chromenopyridine 1 was generated at reflux condition,while chromene 2 was obtained at room temperature condition (Scheme 1). Therefore,we conducted library synthesis and mechanistic study of the MCR. 2. Experimental
Melting point (mp) was measured on a microscopic melting point apparatus. The IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer with a KBr disk. 1H NMR and 13C NMR spectra were taken on a Bruker AV 300 or AV 500 MHz and 75 MHz or 125 MHz spectrometer in DMSO-d6 or CDCl3,chemical shift are given in part per million (ppm) relative to TMS as an internal standard. Mass spectra and high resolution mass spectra were performed on Agilent Q TOF 6520 mass spectrometer with electron spray ionization (ESI) as the ionization mode. Optical rotation was recorded using a sodium lamp with a Rudolph Autopol I automatic polarimeter with 1 dm tube.
General procedure for the synthesis of chromenopyridines 1: Salicylaldehyde (0.5 mmol),malononitrile (1.0 mmol),thiol (0.5 mmol) were dissolved in EtOH (2 mL) and pyridine (0.1 mmol) was added and stirred at reflux temperature for 2-6 h. The reaction mixture was cooled to room temperature,filtered,washed with water and redissolved in DMF (2 mL),the undissolved marerial in DMF was filtered off,and water (4 mL) was added to the filtrate. The resulting precipitate was filtered and dried in vacuum to afford chromenopyridine (1a-u) as an off-white powder.
General procedure for the synthesis of chromenes 2: Salicylaldehyde (0.5 mmol),malononitrile (1.0 mmol),thiophenol (0.5 mmol) were dissolved in EtOH (2 mL) and the piperidine (0.1 mmol) was added and stirred at room temperature for 1-3 h. The white solid which precipitated was filtered,washed with ethanol and dried in vacuum to afford chromenes (2a-q) as an offwhite powder. The structures of the synthesized compounds were characterized by their IR,1H NMR,13C NMR and HRMS spectra. The physical and spectral data of the products are given as Supporting information. 3. Results and discussion
Detailed results determined by the screening of reaction condition are summarized in Supporting information. Libraries of chromenopyridines (Table 1) and chromenes (Table 2) were synthesized to prove the general applicability of the optimal reaction conditions. It was observed that all reactions employing aromatic thiols generated the desired products in both libraries. On the other hand,aliphatic thiols showed a lower reactivity. Yields of 51% and 59% were observed with ethanethiol and propanethiol as nucleophiles in Table 1 (entries 5-6),however no reaction was observed with aliphatic thiols in Table 2. The lack of reactivity of aliphatic thiols in the MCR is potentially due to the pKa of the proton in aliphatic thiols is higher than in aromatic thiols,making deprotonation of aromatic thiols easier at the same temperature. A similar phenomenon was observed for different aromatic thiols. The thiols containing an electron-donating group (such as pmethoxy) have higher pKas also lead to lower yields (entries 4,10, 14 in Tables 1 and 2). Salicylaldehyde containing an electrondonating group and 2-hydroxy-1-naphthaldehyde afforded lower yields (entries 15-21 in Table 1 and entries 13-17 in Table 2). Clearly,this is due to 6-substitution in the salicylaldehyde building block leads to more steric hindrance than 5-substitution,which was also observed in our previous research into the synthesis of pyridine-3,5-dicarbonitriles [3a, b]. The structures of 1q and 2a (Fig. 1) were confirmed by X-ray crystallography.
Scheme 2 elucidates the stepwise mechanism of the MCR at both reflux condition and r.t. conditions in which a chromene intermediate 3 was generated from salicylaldehyde and malononitrile in the first stage . Interestingly,temperaturesensitivity selectivity was observed in the second stage of the MCR. Intermediates 4 and 6,which are 1,4-addition products of 3 with thiol and malononitrile at reflux and r.t. temperature reaction conditions respectively,were isolated. After manolonitrile was added to 4 and 4-methylthiophenol added to 6,products 1a and 2a were obtained. Hereby,the reaction of 4 and malononitrile was a synergistic ring-formed pathway at refluxing condition,while it was a nucleophilic addition between 6 and thiol at room temperature condition,resulting in different products at different temperatures. These results suggest that the reaction temperature is instrumental in controlling the precise order in which building blocks are added to the scaffold.
To further confirm the effect of temperature on formation of product,two sets of reactions were set up to explore the distribution of chromenopyridine and chromene products up to temperature in 1 h (Fig. 2). Both pyridine and piperidine were employed. In general, formation of chromenopyridine was enhanced with increasing temperature,while formation of chromene was inhibited at higher temperature,again proving that the MCR is a temperaturesensitivity reaction. Interestingly,the optimized catalyst not only improves the yield of the desired product,but also impedes formation of the other structure. Pyridine stops the formation of chromene product from 70 ?,while chromenopyridine was not formed at temperatures below 55 ? with piperidine as catalyst. In addition,the two products are not interconverted,when we subject 2a to reflux condition and find it cannot convert to 1a.
|Fig. 2. Distribution of compound 1a and 2a up to temperature in different catalysts. (a) Pyridine as catalyst; (b) piperidine as catalyst.|
DFT calculations using Gaussian 09  were performed using the B3LYP functional  to elucidate the experimental findings using 6-311++G (d,p) as the basis set . The polarizable continuum model  was used to model ethanol. The calculations focused on the bifurcation point in the MCR,given that both at reflux and at r.t. intermediate 3 is formed first. Starting from intermediate 3 our calculations show that initially protonating the imide group is crucial in forming a stable intermediate upon addition of either the malononitrile or thiolate anions.
Inspection of the electrostatic potential of the protonated intermediate shows that the positive charge is located on the imine group,therefore,forming either 4 or 6 (Fig. 3) from this requires shielding of this site by the solvent and,thereby rationalizing the need for a polar,hydrogen bonding solvent for the maximum yield. The consequence for our theoretical study is that explicit solvent molecules are needed,which gives complications which are outside the scope of this paper.
|Fig. 3. Intermediates in the MCR. Panel (a) intermediate 4; panel (b) intermediate 6.|
Analogous to the formation of 4 and 6,the subsequent formation of further intermediates in route to 1a or 2a can be rationalized by successive protonation of intermediates followed by reaction with either the malononitrile or thiolate anions, rationalizing the need for a base,which is neither too strong nor too weak. These steps were not studied in detail. Instead,the final products 1a and 2a were optimized. Our calculations show that the Gibbs energy of 1a is 126.2 kJ/mol below that of 2a,again confirming that it is the thermodynamically controlled product. 4. Conclusion
In summary,temperature-sensitivity MCRs for preparing chro- menopyridine at reflux and chromene at r.t. reaction condition were established. Libraries based on optimized reaction conditions for each structure were synthesized. Mechanistic studies proved that constructing order of building blocks was changed with different reaction temperature,which eventually lead to the formation of different products. Further investigation about biological activity of products is now underway and will be reported in due course. Acknowledgments
This work was financially supported by the National High Technology Research and Development Program of China (863 Program,No. 2012AA02A701),the National High Technology Research and Development Program of China (863 Program,No. 2013AA031901) and Program for Changjiang Scholars and Innovative Research Team in University (No. IRT1066). 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.2014.05.008.
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