One-pot, three-component synthesis of pyranocoumarins containing an aroyl group

Introduction

Pyran, a well-known heterocyclic system, is a common and important moiety of a variety of natural products and medicinal agents [1, 2]. Besides, pyrano-fused heterocycles have attracted considerable synthetic interest because of their biological, pharmaceutical, and material properties [3–5]. In the last decades, some research groups have focused on pyranocoumarins and their heteroanalogous chemistry because they exhibit a variety of biological properties such as antifungal, insecticidal, anticancer, anti-HIV, anti-inflammatory, and antibacterial activities [6–8]. Among pyranocoumarins, the pyrano[3,2-c]coumarin compounds are the most synthetically accessible. Thus far, several methods have been developed for the preparation of pyrano[3,2-c]coumarins, but the most conventional approach to this class of compounds is the three-component condensation of a 4-hydroxycoumarin, an aromatic aldehyde, and malononitrile in the presence of weakly basic or acidic catalysts [9–13]. To the best of our knowledge, there is no report on the synthesis of pyrano[3,2-c]coumarins starting from arylglyoxals in a three-component reaction.

In recent years, we have been involved in the synthesis of new heterocycles containing a coumarin moiety [14–18]. Herein, we wish to report the synthesis of new pyrano[3,2-c]coumarins 4 by the one-pot, three-component reaction of 4-hydroxycoumarin (1) with arylglyoxals 2 and malononitrile (3) in good to excellent yields using Mohr’s salt as an efficient catalyst. Considering that there are many reports on the synthesis of pyranocoumarins employing aromatic aldehydes, in this report, some arylglyoxals are introduced as potential alternatives to produce molecules of type 4-containing aroyl groups.

Results and discussion

On the basis of our previous experience related to the synthesis of pyranocoumarins [19], the model reaction initially involved the solvent system EtOH/H₂O (1:1). After some optimizations including temperature and catalyst amounts, it was found that generally good yields of compound 4a were obtained when the mixture of the three starting components with Mohr’s salt (10 mol%) was initially stirred in EtOH/H₂O (1:1) at room temperature and then heated under reflux (Scheme 1). During the optimization of the reaction conditions, it was found that the Mohr’s salt is a more effective catalyst than common bases and acids. Table 1 shows the results obtained with other attempted catalysts in the synthesis of 4a.

Scheme 1

Synthesis of pyrano[3,2-c]coumarins.

The results illustrate the merit of Mohr’s salt in comparison with other catalysts in the aspects of yields. No product was obtained in the attempted reactions of entries 1–4 (Table 1). Product 4a was obtained in low yield in the presence of NH₄Cl (entry 5). The scope of this reaction was studied using a range of arylglyoxals 2. In all cases, derivatives of type 4 with high purity were obtained. It was also observed that the process tolerates both electron-donating and electron-withdrawing substituents on the aromatic ring. The reactions were completed after 100–150 min, and the products were separated by simple filtration of the precipitate. There was no evidence of the presumed compound 5 (Scheme 1) that would be derived by the reaction of two equivalents of 4-hydroxycoumarin with the arylglyoxal.

The structures of compounds 4 were assigned on the basis of comprehensive spectroscopic and elemental analyses. For example, the ¹H NMR spectrum of 4a exhibits two sharp singlets for methine (δ=5.42) and NH₂ (δ=7.69) protons. The signals at δ=7.53–8.16 correspond to aromatic protons. The proton decoupled ¹³C NMR spectrum of 4a shows 18 distinct resonances in agreement with the proposed structure. Characteristic signals at δ=198.1, 51.9, and 37.1 correspond to ketonic C=O, olefinic carbon, and carbon joined to nitrile group, respectively [20]. The IR spectrum of 4a shows characteristic bands at 3402–3292 cm^-1 (NH₂), 2201 cm^-1 (CN), 1708 cm^-1 (lactonic C=O), and 1678 cm^-1 (ketonic C=O).

The suggested mechanisms for the formation of 4 is shown in Scheme 2. The reaction is thought to take place in three steps. The initial event involves the generation of an intermediate aroylmethylene via the condensation of the arylglyoxal and malononitrile. In the next step, a Michael-type addition and subsequent intramolecular heterocyclization give the desired product 4.

Scheme 2

A plausible mechanism for the synthesis of 4 using Mohr’s salt.

Conclusion

Synthesis of new pyrano[3,2-c]coumarins via the three-component coupling reaction of 4-hydroxycoumarin with arylglyoxals and malononitrile is described. The advantages of the present method are high yields, short reaction times, excellent chemoselectivity, use of commercial Mohr’s salt as an extremely efficient catalyst, and ease of product isolation and purification.

Experimental

Chemicals were purchased from Merck and Aldrich chemical companies. Arylglyoxals were synthesized according to our previous reports [21, 22]. Melting points were measured on an electrothermal KSB1N apparatus. IR spectra were recorded by a JASCO FT-IR-680 plus spectrometer using KBr pellets. ¹H NMR and ¹³C NMR spectra were recorded on an FT-NMR Bruker Avance spectrometer at 300 and 75 MHz, respectively, in DMSO-d₆. TLC was performed on TLC-grade silica gel-G/UV 254-nm plates.