One-pot synthesis of pyrano[3,2-c ]pyran derivatives catalyzed by KF/Al 2 O 3

A series of pyrano[3,2-c ]pyran derivatives have been synthesized by the reaction of aromatic aldehyde, malononitrile or cyanoacetate and 4-hydroxy-5-methylpyran-2-one in EtOH at room temperature catalyzed by KF/Al 2 O 3 . The structures of the products were characterized by IR, 1 H NMR and elemental analysis, and 4a was further confirmed by X-ray diffraction analysis


Introduction
It is known that many pyran derivatives exhibit a wide spectrum of pharmacological activities and biological activities at melanocortin receptors being used in the design of peptidomimetics relating to a tripeptide structure, 1 such as fungicidal, insecticidal and acaricidal activity, 2 antiviral activity, 3 miticidal activity, 4 stimulant activity, 5 and anticonvulsant activity. 6These promoted us to synthesis these compounds via a new way.Particularly, we focused our attention on the use of KF-alumina as catalyst, because the utility of fluoride salts as potential base in a variety of synthetic reactions has been recognized in recent years, 7 resulting in their higher selectivity, milder reaction conditions and easier work-up.Especially alumina coated with potassium fluoride (KF-alumina) has been a versatile solid-supported reagent developed by Ando et al. for alkylation. 8Over the years the reagent has been found application in a large number of organic reactions. 9In order to further enlarge the application of the reagent of KF-alumina, in this paper, we would like to report one pot synthesis these potential active pyrano [3,2-c]pyran derivatives by the reaction of aromatic aldehyde, malononitrile or cyanoacetate and 4-hydroxy-6methylpyran-2-one catalyzed by KF-alumina at room temperature.
When aromatic aldehyde (1), malononitrile, or cyanoacetate (2) and 4-hydroxy-6-methylpyran-2one (3) were treated with KF-Al 2 O 3 in ethyl alcohol at room temperature, 2-amino-4-aryl-4H, 5H-pyrano[3,2-c]pyran-5-one derivatives (4) were obtained in slightly high yields (75-98%) (Scheme 1).In order to demonstrate the efficiency and the applicability of the present method, we performed the reaction of a variety of aromatic aldehyde with malononitrile or cyanoacetate and 3 in EtOH at room temperature and in the presence of KF-Al 2 O 3 .As shown in Table 1, we can see a series of 1 reacted with 2 and 3 to give the corresponding products 4 in good yields under same reaction conditions.
The isolated pyrano[3,2-c]pyran derivatives 4 were completely characterized by IR, 1 H NMR and elemental analyses.The analyses were in agreement with their structures.The melting points of known compounds were conformed to those of the references reported.The IR spectra for 4a exhibited sharp bands at 3400, 3327 cm -1 (NH 2 ), 2199 cm -1 (CN), 1716 cm -1 (C=O).The 1 H NMR spectrum of 4a exhibited a singlet identified as methyl (2.24), two singlets exhibited at 4.57 and 6.32 ppm identified as two methines (CH and CH=), respectively, and along with multiplets (7.64-8.14)for aromatic protons.The NH proton resonance at 7.35 disappeared after addition of D 2 O to the DMSO-d 6 solution of 4a.In order to further confirm the structure of the product, the X-ray analysis 10 of 4a was carried out.The crystal structure of 4a was shown in Figure 1.Although the detailed mechanism of the above reaction has not been clarified yet, the formation of 4 can be explained by the possible mechanism presented in Scheme 2.
In conclusion, we find a novel one-pot method available for the synthesis of pyrano[3,2c]pyran derivatives.Meanwhile, the new method also further expands the application of the catalyst of KF-Al 2 O 3 in organic synthesis.Compared with other methods, 11 this method has the advantage of one-step, easy work-up, milder reaction conditions and good yields in synthesis these potential active compounds.

Experimental Section
General Procedures.Melting points were determined in open capillaries and are uncorrected.IR spectra were recorded on a TENSOR 27 spectrometer in KBr. 1 H NMR spectra were obtained for solutions in DMSO-d 6 with Me 4 Si as internal standard using a Bruker-400 spectrometer.Elemental analyses were carried out using Carlo Erba 1110 analyzer.X-ray diffraction was measured on a Siemens P4 diffractometer.

Scheme 1 Table 1 .
The reaction time and the yields of the products 4