Synthesis of 2-amino-7-hydroxy-4H-chromene derivatives under ultrasound irradiation: A rapid procedure without catalyst

2.1 Chemical and apparatus

Chemical reagents in high purity were purchased from the Merck Chemical Company. All materials were of commercial reagent grade. Melting points were determined in open capillaries using an Electrothermal Mk3 apparatus and are uncorrected. Infrared (IR) spectra were recorded using a Perkin-Elmer FT-IR 550 Spectrometer. ¹H NMR and ¹³C NMR spectra were recorded with a Bruker DRX-400 spectrometer at 400 and 100 MHz, respectively. NMR spectra were obtained in DMSO-d₆ solutions. The element analyses (C, H, N) were obtained from a Carlo ERBA Model EA 1108 analyzer carried out on Perkin-Elmer 240c analyzer. Ultrasonication was performed in a EUROSONIC® 4D ultrasound cleaner with a frequency of 50 kHz and an output power of 200 W. The reaction ask was located in the maximum energy area in the cleaner, where the surface of reactants (reaction vessel) is slightly lower than the level of the water and the temperature of the water bath was controlled at 60 °C.

2.2 General procedure for the synthesis of 2-amino-7-hydroxy-4H-chromenes in water under ultrasound irradiation

A 50 mL flask was charged with aldehyde (1 mmol), malononitrile (1 mmol) and resorcinol (1 mmol) in water (2 mL). The mixture was sonicated under silent condition by ultrasound (50 kHz) at 60 °C for the appropriate time, as shown in Table 3. The temperature of reaction mixture was controlled by a water batch. After the completion of the reaction (monitored by TLC), the reaction was allowed to cool, the solvent was evaporated, then the solid residue was recrystallized from ethanol to afford the pure 2-amino-7-hydroxy-4H-chromene derivatives as white solid (Table 3).

2.3 Spectroscopic data for new compounds

3.1 Effects of the solvents under ultrasound irradiation

We examined the effect of various polar protic, aprotic and non polar solvents on a model reaction under ultrasound irradiation at room temperature (Table 1, entry 1–12). We did this experiment under solvent free condition but the reaction did not take place even after prolonged reaction time (Table 1, entry 1). The above results indicate that the solvent is required for the reaction. As could be seen in Table 1, in non polar solvents such as n-hexane, chloroform and dry diethyl ether, the reaction did not go in a forward direction, whereas in case of polar aprotic solvents such as DMSO, acetonitrile, THF, 1,4-dioxane and DMF, the yield of the reaction was found to be very low (15–30%, Table 1, entries 6–10) but in case of polar protic solvents such as ethanol (Table 1, entry 11), desire product was obtained in 62% yield. This observation revealed that, the present reaction required highly polar protic solvent system; thus we chose water as a greener and environmentally acceptable solvent for multicomponent reaction of benzaldehyde 1a, malononitrile 2, and resorcinol 3 for the synthesis of chromene derivatives (Table 1, entry 12).

3.2 Effects of reaction temperature and frequency under ultrasonic irradiation

Subsequent efforts were focused on optimizing conditions for the formation of 2-amino-7-hydroxy-4H-chromene by using different temperatures and frequencies of ultrasonic irradiation to determine their effects on the reaction (Table 2). At 60 °C the yield of the product is maximum. Due to the unavailability of activation energy, the rate of the reaction is very slow at a temperature below 60 °C and at a higher temperature there might be some sort of polymerization of the Knoevenagel condensation product which lowers the yield of the desired product. It was observed that the reaction in the presence of water and ultrasonic irradiation with power 200 W at 60 °C in frequency of 50 kHz afforded the best result as obtained product with 98% isolated yield during 1 min (Table 2, entry 8).

3.3 The effect of ultrasonic irradiation

To assess the efficiency of ultrasound irradiation in inducing this reaction, the reaction of aldehyde 1a with malononitrile 2 and resorcinol 3 as a model was investigated under high speed stirring conditions. We observed a small amount of solid in this system at first because of aldehyde and malononitrile insoluble or slightly soluble in water. The reaction failed to component (5a) in only 40% yield even after long hours of stirring (Table 1, entry 13).

The mechanism of this reaction can be seen as sequential reactions involving Knoevenagel reaction, Michael addition and an intra-molecular cyclization that may take place in the formation of the final product under ultrasound irradiation. The probable mechanism is given in Scheme 2 (Khaksar et al., 2012; Safari and Zarnegar, 2012). When the reaction was performed under sonication, the precipitates were observed disappearing gradually and forming again in great numbers. After filtration and analysis such as ¹H NMR, it was surprising to find that the product is the desired one. In this solid–liquid heterogeneous system, ultrasound was found to have a beneficent effect on the synthesis. Passage of ultrasound through liquid medium gives rise to sinusoidal variation in the bulk pressure. This variation gives rise to the phenomenon of cavitations, a physical process that creates, enlarges, and implodes gaseous and vaporous cavities in an irradiated liquid, thus enhancing the mass transfer and allowing chemical reactions to occur (Atchley et al., 1989; Koda et al., 2003; Wang et al., 2005). Possible nuclei for occurrence of cavitation events are gas pockets trapped in the walls and crevices of the solid and reactor wall, or they could be small bubbles already present in the medium. The physical effects of ultrasound and cavitations are several folds. These effects are mainly responsible for generating strong convection in the liquid medium through several mechanisms such as microstreaming, microturbulence, acoustic waves and microjets which lead to the acceleration of dissolution and heat and mass transformations (Safari et al., 2012). Thus, ultrasound irradiation activates the reaction mixture by inducing high local temperatures and pressure generated inside the cavitation bubble and its interfaces when it collapses and accelerates the reaction rate and shortens the reaction time. Furthermore, it is indicated that the application of ultrasound irradiation plays an increasingly important role on promoting the route 5–4 than route 1–5 (Safari et al., 2012).

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Scheme 2 Synthetic route to 2-amino-7-hydroxy-4H- chromenes.

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3.4 High efficiency synthesis by ultrasound irradiation

After optimizing the conditions, the generality of this method was examined by the reaction of several aldehydes, malononitrile and resorcinol in water under ultrasound irradiation. Interestingly, a variety of aldehydes including aryl aldehydes, aliphatic aldehydes and heterocyclic aldehydes participated well in this reaction (Table 3). As evident from the results, this procedure is uniformly effective for both aliphatic and aromatic aldehydes. It is noteworthy that the methodology worked well for spatially-hindered aldehydes (entries 6–11). Encouraged by this achievement, the versatility of the reaction was explored further by extending the methodology to the synthesis of bis-4H-chromene. When p-phthalaldehyde was treated with two equiv malononitrile and resorcinol under similar conditions, the reaction proceeded cleanly to give the corresponding bis-4H-chromene (4r) in 97% yield (Scheme 3). It can be concluded that the presence of the CHO functional group as the electron-withdrawing substituents on the aromatic ring can increase the yield .The order of yield of aldehydes is aryl-, heterocyclic- > aliphatic aldehydes. The activity of aldehydes with electron-withdrawing groups is higher than that with electron-donating groups. The position of substituent in the benzene rings of aldehyde influences this reaction. In fact, two para position structures (entry 2 and 3 of Table 3) have the highest, and o and m-positioned aldehydes have lower yields (due to similar yields.

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Scheme 3 Catalyst and base free synthesis of bis-4H-chromene in water under ultrasound irradiation.

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