The chromene moiety is an important structural component in both biologically active and natural compounds. The basic structural framework of chromenes is a common feature of many tannins and polyphenols  found in tea, fruits, vegetables and red wine. These compounds are of special important, due to their biological effects. Fused chromenes are biologically active compounds with various activities such as antimicrobial,  mutagenicitical,  antiviral, [4, 5] antiproliferative,  antitumoral,  and central nervous system activities . These moieties are also present in natural alkaloids, flavonoids, tocopherols, and anthocyanins. Functionalized chromenes have recently played an ever-increasing role in the synthetic approaches to promising compounds in the field of medicinal chemistry. Among the different types of chromene systems, 2-amino-4H-chromenes (or 2-amino-4H-benzo[b]pyrans) are of particular utility as they belong to privileged medicinal scaffolds serving for the generation of small-molecule ligands with highly pronounced spasmolytic, diuretic, anticoagulant, and antianaphylactic activities. 
Multicomponent reactions (MCRs), in which three or more reactants are combined together in a single reaction flask to generate a product incorporating most of the atoms contained in the starting materials  is a promising approach for the preparation of compound libraries in the field of modern medicinal and combinatorial chemistry. The rapid assembly of molecular diversity utilizing MCRs has received a great deal of attention. For example, the Hantzsch, [14a] Ugi, [14b, c] and Biginelli [14d] multicomponent reactions are the methods of choice to prepare functionalized 1,4-dihydropyridine, benzodiazepinedione, and dihydropyrimidine privileged scaffolds, respectively. Combinations of solvent-free and MCR one-pot multicomponent condensations represent very powerful green chemical technology procedures from both the economical and synthetic point of view and represent a possible instrument to perform a near ideal synthesis because they enhance the rate of many organic reactions and afford quantitative yields.
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2-Amino-4H-chromenes are generally prepared by refluxing active methylene compounds (mostly malononitrile), with an aldehyde and an activated phenol in the presence of hazardous organic bases like piperidine in organic solvents such as ethanol and acetonitrile for several hours . Recently, relatively benign catalysts such as cetyltrimethylammonium chloride (CTACl),  cetyltrimethylammonium bromide,  KSF clay,  KF/Al2O3,  TiCl4,  triethylamine,  basic alumina,  MgO,  heteropolyacids,  basic ionic liquids,  iodine/K2CO3,  and DABCO have been used in this reaction. However, some of these catalysts such as MgO and basic alumina can only catalyze the condensation reaction of aromatic aldehydes and malononitrile with active α-naphthol, and are not suitable for less active β-naphthols, whereas other catalysts require longer reaction times, laborious workup procedures and afford only moderate yields. For these reasons the development of an environmentally benign and simple procedure for synthesis of 2-amino-4H-chromenes has thus become particularly fascinating and remains a great challenge.
In continuation of our interests on developing environmentally benign protocols for solvent-free multi-component reactions , we report herein our results for synthesis of 2-amino-4H-chromenes with sodium carbonate that efficiently catalyzed three-component condensation of an aldehyde, malononitrile and an activated phenol with excellent yields under solvent-free condition. This method has many advantages, such as no need to toxic organic solvents and toxic catalysts, its lower cost, high yields, and simplicity in processing which are beneficial to the industry and to the environment. Other benefits are no need for isolation of any intermediate, thus reducing overall reaction time, saving money, energy and raw materials.
Results and Discussion
The model reaction was carried out simply by mixing of p-chlorobenzaldehyde (1), malononitrile (2) and β-naphthol (3b) (1.0 mmol each) and various basic or acidic catalysts (0.1 mmol) in a mortar and pestle (Scheme 1). The resulting mixture was heated in a drying oven at the temperature and for the given time in Table 1.
In the absence of any catalyst no reaction was observed at room temperature and all starting materials remained unchanged, whereas after raising the temperature to 125 °C aldehyde and malononitrile were disappeared. Below this temperature the yield of 4 (Ar=p-ClC6H4) is negligible and therefore there is no remarkable yield of 6, even in the presence of Na2CO3 catalyst.
The process represents a typical condensation in which the benzylidenemalononitrile 4 (Scheme 2), containing the electron-poor C-C double bond is fast and quantitatively produced by Knoevenagel condensation of malononitrile and the aromatic aldehyde and subsequent water elimination. As we have previously reported [28b], this step of the reaction easily occurs under solvent-free condition and without adding any catalyst, but is incomplete at lower temperatures. The formation of this intermediate was secured by mp and NMR of the product 4 after 4 hours. By increasing the temperature to 150 °C the product 6b was formed with reasonable yield. As it is shown in Table 1, among the various basic or acidic catalysts, sodium carbonate was found to be the best one for this synthesis affording quantitative yields of 6b under solvent-free condition in one hour. This is of special interest, because Na2CO3 is a very cheap, environmentally friendly and available catalyst.
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The second step represents a typical cascade reaction  and presumably involves ortho C-alkylation of α- or β-naphthol giving the intermediate 5. Nucleophilic addition of the phenolic OH group to the CN moiety producing the final 2-amino-4H-chromenes 6 requires the intervention of the catalyst, as the uncatalyzed reaction afforded no remarkable product at 125°C.
Table 1. Effect of various catalysts on preparation of 6b
Yield (%) of 6
a 0.1 mmol each for 1.0 mmol of 1.
The scope and the generality of the present method were then further demonstrated by the reaction of various aromatic aldehydes with malononitrile and α- or β-naphthol. In all cases up to quantitative yields in reasonable reaction times were obtained. Both a- and b-naphthol are enough active to give the corresponding products in high yield. Contrary to that has been reported previously , no remarkable decrease in the yields was observed for the ortho-substituted benzaldehyde derivatives.
The reactions of p-hydroxybenzaldehyde with 2 and 4-chloro-1-naphthol, and 1 and 2 with 4-hydroxycumarine proceed also smoothly to yield 6q and 6s respectively, however with moderate yields, possibly due to their lower activity against a- and b-naphthols.
The structures of all products were determined on the basis of their analytical and/or spectral data. The 1H NMR spectra of the products show a characteristic single peak at 4.90-5.90 ppm for H-4 and the 13C NMR spectra exhibit a specific peak in the region of 54-60 ppm that is related to C-4.
Table 2. Synthesis of 2-amino-4H-chromenes under solvent-free condition catalyzed by sodium carbonate a
M P (°C)
a mmol ratio of aldehyde/malononitrile/naphthol/Na2CO3 is 1.0/1.0/1.0/0.1.
In summary, we have reported a new and effective methodology for the eco-compatible preparation of 2-amino-4H-chromenes via one-pot three component reaction of aromatic aldehydes, malononitrile and active naphthols using a catalytic amount of Na2CO3 under solvent-free conditions. The use of commercially available and inexpensive catalyst, avoiding use of hazardous organic bases and organic solvents, easy workup, short reaction times, and mild reaction conditions make this method very attractive and practical.
Material and methods
All of the chemical materials used in this work were purchased from Merck or Fluka and used without further purification. Melting points were determined with an Electrothermal melting point apparatus and are uncorrected. Infrared (IR) spectra were recorded with a Shimadzu 8400s FT-IR spectrometer using potassium bromide pellets. 500MHz 1HNMR spectra were recorded on a DRX-500 Advance Bruker spectrometer. The chemical shifts are reported in ppm (δ-scale) relative to internal TMS and coupling constants are reported in DMSO-d6. Products are all known compounds and were identified by comparing of their physical and spectra data with those reported in the literature.
General procedure for preparation of 2-Amino-4H-Chromenes
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In a typical experiment, a stoichiometric mixture of an aldehyde (1), malononitrile (2), naphthol (1.0 mmol each) and sodium carbonate (0.1 mmol) mixed together using a mortar and pestle. The result mixture was heated in a drying oven at 125°C. After cooling, the mixture was washed with hot water and purified by recrystallization from hot ethanol, if necessary. The results are summarized in Table 2.
Selected characterization data:
Compound 6a: 4H-Naphtho[1,2-b]pyran-3-carbonitrile,2-amino-4-(4-chlorophenyl)
IR (KBr), ν (cm-1): 3408, 3326 , 2190, 1649, 1590; 1H NMR (DMSO-d6, 500 MHz), δ (ppm): 5.36 (s, 1H, CH), 7.0 (s, 2H, NH2), 7.20 (d, 2H, J=8.2 Hz, ArH), 7.33-7.38 (m, 3H, ArH), 7.41-7. 47 (m, 2H, ArH), 7.81 (d, 1H, J=8.02 Hz, ArH), 7.91-7.96 (m, 2H, ArH).
Compound 6b: 1H-Naphtho[2,1-b]pyran-2-carbonitrile,3-amino-1-(4-chlorophenyl)
IR (KBr), ν (cm-1): 3452, 3334, 2190, 1666, 1590, 1409; 1H NMR (DMSO-d6, 500 MHz), δ (ppm): 4.95 (s, 1H, CH), 7.09 (d, 1H, J=8.53 Hz ArH), 7.19 (s, 2H, NH2), 7.27 (d, 2H, J=8.37 Hz, ArH), 7.36 (d, 2H, J=8.35 Hz, ArH), 7.57-7.66 (m, 3H, ArH), 7.89 (d, 1H, J=8.02 Hz, ArH), 8.24 (d, 1H, J=8.31 Hz, ArH).
Compound 6j: 1H-Naphtho[2,1-b]pyran-2-carbonitrile,3-amino-1-(3-nitrophenyl)
IR (KBr), ν (cm-1): 3462, 3356, 2190, 1654, 1589; 1H NMR (DMSO-d6, 500 MHz), δ (ppm): 5.63 (s, 1H, CH), 7.17 (s, 2H, NH2), 7.38 (d, 1H, J=8.9 Hz, ArH), 7.42-7.48 (m, 2H, ArH), 7. 57 (t, 1H, J=7.8 Hz, ArH), 7.67 (d, 1H, J=7.7 Hz, ArH), 7.86 (d, 1H, J=8. 2 Hz, ArH), 7.93 (d, 1H, J=7.6 Hz, ArH), 7.98 (d, 1H, J=8.9 Hz, ArH), 8.03 (d, 1H, J=8.07 Hz, ArH), 8.08 (s, 1H, ArH), 13C NMR (DMSO-d6, 125 MHz), 57.82, 115.47, 117.74, 121.04, 122.18,122.72, 124.36, 126.03, 128.28, 129.48, 130.78, 130.95, 131.33, 131.73, 134.59, 147.84, 148.75, 148.86, 160.84.
Compound 6o: 4H-Naphtho[1,2-b]pyran-3-carbonitrile,2-amino-4-(2-nitrophenyl)
IR (KBr), ν (cm-1): 3419, 3326, 2192, 1651, 1590; 1H NMR (DMSO-d6, 500 MHz), δ (ppm): 4.94 (s, 1H, CH), 7.09 (d, 1H, J=7.9 Hz, ArH), 7.19 (s, 2H, NH2), 7.21-7.23 (d, 2H, J=7.6 Hz, ArH), 7.51 (d, 2H, J=7.33 Hz, ArH), 7.59-7.65 (m, 3H, ArH), 7.89 (d, 1H, J=7.7 Hz, ArH), 8.23 (d, 1H, J=7.9 Hz, ArH). 13C NMR (DMSO-d6, 125 MHz), 56.62, 118.19, 120.95, 121.24, 121.58, 123.59, 124.89, 126.94, 127.62,1 27.75, 128.57, 130.82, 132.48, 133.62, 143.61, 145.95, 161.02.
We acknowledge Iran University of Science and Technology (IUST) for partial financial support of this work.