A one-pot procedure for the synthesis of novel pyran-fused dicyanoanilines via a triethylamine/aqueous mediated pseudo four-component reaction

A facile pseudo four-component process was developed for the synthesis of dicyanoaniline derivatives fused to pyran ring. Reactions took place in the presence of triethylamine via a one-pot combination of pyran-4-one 1 with various aldehydes and two equivalents of malononitrile in water. Thus, novel products 4 were obtained in high yields after 5-7 h mixing at 40 ° C. After completion of the reactions, products solidified in the mixture spontaneously. This allowed an easy separation of the products and avoided costly chromatographic purifications.


Introduction
7] Dicyanoanilines demonstrate high quantum yield optical activities [8][9] due to having acceptor-donor-acceptor (A-D-A) sequence of functionalities.][14] In addition, the fluorescence features of dicyanoanilines make them attractive and as a result continuous efforts are devoted by synthetic chemists in recent years to prepare diverse groups of dicyanoanilines [15][16][17][18][19][20] and more studies are underway.
Pyran-4-one 1 is an important six-membered heterocyclic compound which is used in the synthesis of various heterocycles containing the pyran unit, 21 possessing diverse biological features, 22 and being part of the structure of several natural products. 23herefore, there is always demands for developing new procedures to prepare various structures containing the pyran unit as the key fragment.We are interested in the chemistry of pyran-4-one.5][26][27][28] In continuation, now we present a convenient and practical procedure by which ketone 1 undergoes a one-pot combination with aldehydes 2 and malononitrile 3. It should be noted that malononitrile is a very convenient reagent for many MCRs due to having a reactive methylene and two cyano groups to build several carbon-carbon and carbon-heteroatom bonds simoltaneously. 29Thus, a pseudo four-component process takes place and a new series of dicyanoanilines 4 is obtained (Scheme 1).Although there is a few reports on the synthesis of benzochromene based dicyanoanilines, 13,30 as far as we know, this is the first general report on the synthesis of isochroman containing dicyanoanilines.The products are expected to have fluorescence properties to be explored in continuation of our investigations in the near future.Scheme 1. One-pot synthesis of 4.

Results and Discussion
We first optimized the process by studying the reaction of 1 with benzaldehyde 2a and 3 under various sets of conditions (Table 1).In the presence of H2O and Et3N, an equimolar mixture of 1 and the aldehyde and two folds of 3 produced 4a in 94% yield after 6 h at 40 °C (entry 1).In the absence of water (entry 2) or the amine (entry 3), either very low yield of 4a was obtained or the reaction was stopped completely after the same time.Alternatively, it was shown that lower temperatures gave lower quantities of 4a even after a prolonged time period (entry 4).Similarly, the reaction was not complete when Et3N was used less than the optimized amounts (entries 5-7).Again, lower yields of the product was obtained when secondary (entries 8-9) or primary (entry 10) amines were used.The results supported that the optimum reaction is attainable when a tertiary amine is employed, as was further confimed by the use of DABCO in the reaction producing comparable amounts of 4a (entry 11).We next studied the diversity of the method by using the best conditions (Table 1, entry 1) for the reactions of 1 with 3 and different aldehydes (Table 2).Thus, not only benzaldehyde (entry 1), but also other aldehydes bearing electron donating-(entries 2-4) and electron attracting (entries 5-6) substituents combined with 1 and 3 to produce 85-95% of the respective products within 5-7 h.Similarly, furan-2-carbaldehyde (entry 7) and formaldehyde (entry 8) produced 4g-h efficiently.In all case, products precipitated in the reaction mixtures spontaneously upon cooling.This allowed an easy separation of the products by a simple filtration.
The structure of the products was elucidated based on spectroscopic methods.In the IR spectra, two peaks appearing at about 2200 and 3300 cm -1 were in favor of the existence of the nitrile and amine groups in the final structure, respectively.In addition, in NMR spectra (both 1 H and 13 C), three signals attributing to chemically different methylene groups confirmed the participation of the pyran ring in the structure of the target products.It is usual for aqueous conditioned organic reactions to be boosted by either hydrophobic 31 or hydrogen bonding 32 interactions.In order to see if such forces have effect on the progress of the present procedure, we conducted a group of experiments for the combination of ketone 1 with benzaldehyde and 3 (Table 3).All experiments were stopped earlier after 2 h so that the results can be meaningfully compared with those obtained under the optimized conditions.Entry 1 shows that when the H2O/Et2NH conditions are used only 55% of 4a is Without water, the reaction rate is dramatically decreased illustrating that the aqueous medium clearly enhances the reaction (entry 2).When aqueous solutions of NaCl (entries 3-4) and LiCl (entries 5-6) were used, again reduction in the yield of 4a was observed.

Entry
Additive Time (h) Yield (%) This descending pattern which is directly proportional to the concentrations of the salts exclude the intermediacy of a "salt-out" 33 effect and thus hydrophobic interactions can not have a major effect in catalyzing the process.In contrast, when LiClO 4 (entries 7-8) or guanidinium chloride (entries 9-10) were used as additives, the efficiency of the reaction was increased and higher yields of 4a were obtained after the 2 h time period.Finally, it took only 4 h for the reaction to reach to 96% yield in the presence of LiClO4 solution (entry 11).This enhancement would suggest the presence of a promoting hydrogen-bonded interaction between the reactants with water to ease up the energy barrier of the process similar to what occurs in a Lewis acid mediated reaction.
Based on our study, we propose an organocatalyzed cycle, as shown in Figure 1 for the combination of 1 with benzaldehyde 2a and 3.In the first step, via two parallel Knoevenagel pathways, the ketone and the aldehyde undergo condensation with 3 to produce the alkene intermediates 13 and 23.Then, the amine facilitates nucleophilic combination of 13 and 23 to cause two Michael additions in a row and form intermediate 4a'.Tautomerization of this imine to the corresponding enamine 4a'' and finally elimination step gives the desired product 4a.To support the mechanism, intermediates 13 and 23 were prepared separately and when reacted together under the optimized conditions 4a was obtained in high yield after the expected time.

Conclusions
In summary, we succeeded in presenting an efficient one-pot procedure for the synthesis of a novel series of dicyanoanilines fused to pyran ring.Reactions took place rapidly and high yields of isochroman derivatives were obtained under very mild conditions.The extension of the method to other heterocyclic systems and the study of the optical properties of the products are underway in the near future in our laboratory.

Table 1 .
Optimization of the synthesis of 4a (Ar = Ph) a yields determined by GC. b room temperature.