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KEYWORDS
Multicomponent
reactions (MCRs);
Green chemistry;
4H-chromene
derivatives;
Resorcinol;
Malononitrile.
Abstract. A simple, efficient and one-pot method has been developed for the synthesis of densely functionalized aryl derivatives of 2-amino-3-cyano-7-hydroxy-4H-chromene by the domino Knoevenagel-Michael-cyclization reactions of aromatic aldehydes, resorcinol and malononitrile in the presence of a catalytic amount of Na^sub 2^CO^sub 3^ under grinding conditions.
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1. Introduction
4H-chromene and its derivatives constitute a major class of naturally occurring compounds [1,2]. They occur considerably in plants, including edible vegetables and fruits [3]. This moiety is widely found in natural alkaloids, avonoids, tocopherols and anthocyanins [4]. 4H-chromene derivatives demonstrate a wide range of biological activity and have received great interest as therapeutic agents, due to their low toxicity and use rates [5,6]. Some representative pharmaceutical applications include anticancer [7,8], antioxidant [9], antiproliferative [10], antibacterial, antiviral [11], and central nervous system active drugs [12]. The current interest in 2-amino-4H-chromene derivatives arises from their potential applications in the treatment of human in ammatory TNF-mediated diseases, such as rheumatoid and psoriatic arthritis, and in cancer therapy [13]. Widespread interest in the 4H-chromenecontaining structures has led to extensive study of their synthesis [14]. Along this line, several procedures have been reported for the synthesis of 2-amino-4H chromene derivatives using diverse enol components, malononitrile and the corresponding aldehydes in the presence of di erent catalysts. Amongst recent catalytic systems, DBU [15], DABCO [16], piperidine [17], morpholine [18], triethyl amine [19], hexamethylenetetramine [20], ionic liquid [21], cetyltrimethylammonium chloride (CTAC) [22], triethylbenzylammonium chloride (TEBC) [23], PEG-400 [24], Ca(OH)2 [25], and KF/Al2O3 [26] could be mentioned for this threecomponent reaction. Furthermore, Makerem et al. have reported an electro-chemically induced multicomponent condensation of resorcinol, malononitrile and aromatic aldehydes, in the presence of NaBr, as an electrolyte in propanol [27].
However, almost all these methods su er from long reaction time, high temperature, use of solvents or expensive and hazardous catalysts, and problems associated with the reusability of the catalysts. Therefore, the introduction of milder, faster and more environmentally benign methods resulting in higher yields is still in great demand. Furthermore, a solventfree technique represents a cost e ective, clean, rapid and safe procedure. Grinding is a useful tool to bring together di erent solid compounds...