Study on the Synthesis of Some (Un)Substituted 2-Amino-4-aryl-7-hydroxy-4 H -chromene-3-carbonitriles in the Water Medium †

: An efficient and simple synthesis of substituted 2-amino-4 H -chromene-3-carbonitriles was developed by the one-pot and three-component reaction of a mixture of corresponding substituted benzaldehydes, resorcinol, and malononitrile in the presence of sodium carbonate solution as a catalyst at room temperature.


Introduction
Recently, multi-component coupling reactions (MCRs) have received interest in organic synthesis due to their conveniences and benefits [1]. In these reactions, three or more starting materials react with each other to form a product, where all or most of the atoms contribute to the newly formed product. Essentially, in an MCR, a product is created by putting components or members together according to a cascade of elementary chemical reactions [1]. Histologically, the MCRs were discovered by Adolph Strecker in 1860 [2] with the synthesis of α-amino acid, involving the reaction of potassium cyanide, ammonium chloride, and an aldehyde to make an alpha amino acid, and nowadays are continuously developed organically and synthetically in laboratories [3,4].
The organic reactions that are carried out in an aqueous medium and at room temperature are of great interest to synthetic chemists [5,6]. Water is an environmental, nonflammable, nonhazardous, inexpensive, and naturally available solvent. Water also gives the benefits of simple workup and purification by simple phase separation techniques. Therefore, organic reactions carried out in aqueous media are an attractive and interesting area of green chemistry [7,8]. Additionally, the performance of the organic reactions at room temperature helps mitigate the decomposition of the product (if available) or the formation of unwanted products [9]. 4H-Chromene derivatives and compounds with chromene moiety have notable usage in organic synthesis due to their biological activities [10]. These compounds function as the important pharmacophores, which are associated with a broad range of pharmacological activities. They are antimicrobial [11], hypolipidemic [12], anti-inflammatory [13,14], anti-proliferative [15], antioxidant [11,16], anticoagulant [17], and anti-leishmanial [18], antitumor [15], anti-diabetic [19], cytotoxicity [10,20], and anticancer [16,20] agents.

Results and discussion
For the purpose of applying an environmental and cheap solvent, we used water as a solvent in the synthesis of compounds of (un)substituted 2-amino-7-hydroxy-4-aryl-4H-chromene-3carbonitriles (Scheme 1). The model reaction was made with unsubstituted benzaldehyde 1a ( Table  1). The base, reaction time, and reaction temperature optimizations for yields are listed in Table 1. The different inorganic and organic basic catalysts were used in the catalyst surveys, such as NaOH, NaHCO3, Na2CO3, K2CO3, ammonium acetate, 4-dimethylaminopyridine (DMAP), triethylamine, and piperidine, and the reactions were examined in water at room temperature. In general, the inorganic bases gave the product 4a in higher yields (Entries 1-4), while the organic bases gave the product 4a in lower yields (Entries 5-8). We found that sodium carbonate (with 0.1 equivalent amount, Entries 3) in 10 mL of water provided the target product 4a in 90% yield. Therefore, sodium carbonate was chosen for further investigations in water at different times and temperatures (Entries 8-15). a Reaction conditions: The reaction was performed by using 2 mmol of 1, 2 mmol of 2, and 2 mmol of 3, in the presence of 10 mol% or 5 mol% of basic additive in 10 mL of water under different temperature conditions. b Isolated yields.
When the concentration of this catalyst was half reduced, the yield of 4a did not change (in 90% yield in Entry 9). We found that increasing amounts of this catalyst, from 0.1 equiv. (Entry 3) to 0.15 equiv. (Entry 10) to 0.2 equiv. (Entry 11), resulting in the slight reduction of reaction yields (88% in Entry 10 and 87% in the Entry 11). On the other hand, raising the temperature of the reaction from 25 °C (Entry 3) to 70 °C (Entry 12) in the reflux-heating method (Entry 13) lead to reduced product yields of 4a, to 80% and 70%, respectively. The reaction time did not significantly change the yields of the products. For example, in Entries 14 and 15, the yields of 4a were 91% (for 180 min) and 90% (for 240 min), respectively. Hence, sodium carbonate in the amount of 0.05 equiv. in 10 mL of water was used in the synthesis of all the other chromenes 4b−l ( Table 2).
The absorption band that appeared in regions at ν = 3500-3450 cm −1 belonged to the hydroxyl group, and two other absorption bands that appeared in regions 3420-3250 cm −1 in IR spectra of 4Hchromenes 4a-l confirmed the presence of the amino group in these molecules. The nitrile functional group had the absorption band at 2203-2188 cm −1 . All 1 H NMR spectra of chromenes 4a-l had characteristic signals at δ = 4.95-4.50 ppm, with an integral height of one proton; this signal belongs to a proton on position 4 and could be used as the identification sign for 4H-pyrans and 4Hchromenes. In addition, the chemical shift appearing at δ = 9.70-9.60 ppm confirmed the presence of a hydroxyl group on position 7 of the chromene ring. The amino group on position 2 of chromenes 4a-l had a resonance signal at δ = 6.84-6.83 ppm. The carbon atom at position 2 had a chemical shift downfield at δ = 161.4-160.1 ppm, due to the electron-withdrawing influence of an oxygen atom in the chromene ring. The carbon atom in the nitrile group showed a resonance signal at δ = 121.2-119.6 ppm. This evidence proved that chromenes 4a-l were formed through three component reactions between substituted benzaldehydes 1a-l, malononitrile 2, and resorcinol 3, in the presence of sodium carbonate as a catalyst. a Reaction conditions: The reaction was performed by using 2 mmol of 1a-l, 2 mmol of 2, and 2 mmol of 3, in the presence of 5 mol% of sodium carbonate in 10 mL of water at room temperature conditions. b Isolated yields.

Experimental
Melting points were determined by open capillary method on STUART SMP3 instrument (BIBBY STERILIN, UK) and were uncorrected. IR spectra (KBr disc) were recorded on an Impact 410 FT-IR Spectrometer (Nicolet, USA). 1 H and 13 C NMR spectra were recorded on Avance Spectrometer AV500 (Bruker, Germany) at 500.13 and 125.77 MHz, respectively, using DMSO-d6 as solvent and TMS as an internal standard. All analytical thin-layer chromatography (TLC) was performed on silica gel 60 WF254S aluminum sheets (Merck, Germany) and was visualized with UV light. Chemical reagents in high purity were purchased from the Merck Chemical Company. All materials were of commercial reagent grade.

Conclusions
The use of sodium carbonate, as a catalyst in water, as the reaction medium in the synthesis of 2-amino-7-hydroxy-4H-chromene-3-carbonitriles 4a-l opens a new direction in chromene chemistry. This synthetic procedure for these chromene-3-carbonitrile rings is a cheap, efficient, and simple method.