Synthesis of tetrahydrobenzo[b]pyran under catalysis of NH₄Al(SO₄)₂·12H₂O (Alum)

1 Introduction

Multi-component reactions (MCRs) are emerging as important tools for efficient synthesis of a wide variety of organic molecules (Domling and Ugi, 2000). Such reactions offer a number of practical, environmental, and economical advantages for construction of complex molecular architectures over the more traditional approaches. While numerous MCRs have been devised, relatively few processes that result in the formation of two or more intermolecular carbon–carbon bonds are known.

4H-pyrans belong to an important class of heterocyclic compounds having important biological activities (Green et al., 1995). They are reported to have diverse pharmacological activities such as anti-coagulant, anti-cancer, spasmolytic, diuretic, anti-ancaphylactia (Weber et al., 1999), Alzheimer’s disease, AIDs associated dementia and myoclonus (Konkoy et al., 2001). They are also reported to serve as an important regulator for potassium cation channel (Sun et al., 1997) and photochemical activities (Armetso et al., 1989).

Because of the intense interest in the biological activity of these compounds, several improved procedures for the synthesis of pyrans were reported. One of the most important methods for the synthesis of these compounds is one-pot condensation of an aldehyde, dimedone and malononitrile. Various catalysts such as acetic acid (Kamaljit et al., 1996), CeMgxZr₁-xO₂ (Rathod et al., 2010), HTMAB (Jin et al., 2004), TEBA (Shi et al., 2003), DBSA (Jin et al., 2004), basic quaternary ammonium salt (Zhao et al., 2010), RE(PFO)₃ Wang et al., 2006, and s-proline (Balalaie et al., 2006) have been used for this reaction. Some of them are very fascinating from a synthetic chemist’s point of view. Despite their tremendous success, some drawbacks still remain for example, reacting at high temperature, expensive catalysts, etc. In order to circumvent these obstacles, we decided to reconsider developed new synthetic routes. The results are represented in the following section.

2 Results and discussion

Very recently, we reported the preparation of quinazolinediones (Azizian et al., 2003a), γ-spiroiminolactiones (Azizian et al., 2003b), pyroles (Azizian et al., 2003c), and cis-isoquinolonic acid (Azizian et al., 2005) via the respective multi-component reactions. Along this line, we designed a new method for the three-component synthesis of tetrahydrobenzo[b]pyrans in one step. In this direction, the use of relatively heterogeneous, nontoxic and inexpensive NH₄Al(SO₄)₂·12H₂O (Alum) was taken as the center of our study (Azizian et al., 2005; Mohammadi et al., 2008). In the course of our research on the application of heterogeneous catalysts in organic reactions, we have found that alum is an effective promoter for the preparation of tetrahydrobenzo[b]pyrans.

In addition, we have found that the one-pot condensation of dimedone 1, aldehydes 2a-t, and active methylene compounds (meldrum’s acid, malononitrile, ethyl and methyl cyanoacetate and indandione) in the presence of a catalytic amount of Alum results in a rapid formation of the corresponding tetrahydrobenzo[b]pyran 4a-t when the reaction mixtures were heated with stirring at 80 °C (Schemes 1 and 2) (Table 1).

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Scheme 1 Synthesis of tetrahydrobenzo[b]pyrans 4a-t.

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Scheme 2 Proposed mechanism for the formation of products 4a-t.

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Furthermore, it is remarkable to note that the condensation proceeds with a slight amount of catalyst concentration (20 mol%, Alum) at ambient conditions and gives tetrahydrobenzo[b]pyrans in good yields. Interestingly, the heterogeneous catalyst was not deactivated and could be reused several times. Five consecutive runs of the reaction of dimedone, benzaldehyde and malononitrile with Alum were carried out (Fig. 1). The results demonstrate that there is almost no significant change in the activity of the catalyst, so, it could be used for at least five times successfully leading to high turn-over numbers (TONs).

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Figure 1 Five consecutive runs of the reaction of dimedone, benzaldehyde and malononitryl with Alum.

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3 Conclusions

We described a successful strategy including, an efficient and convenient green synthesis, for the preparation of tetrahydrobenzo[b]pyran derivatives via a three-component reaction between dimedone, aldehydes, and active methylene compounds using NH₄Al(SO₄)₂·12H₂O (Alum) as catalyst at 80 °C. The method offers several advantages including high yield of products, using the inexpensive, reusable, nontoxic, and easily available NH₄Al(SO₄)₂·12H₂O catalyst, and an easy experimental workup procedure that makes it a useful process for the synthesis of tetrahydrobenzo[b]pyrans.

4 Experimental

Melting points were measured on the Electrothermal 9100 apparatus and are uncorrected. IR spectra were measured on a Shimadzu IR-470 Spectrophotometer. ¹H NMR and ¹³C NMR spectra were determined on Bruker 300 DRX Avance instrument at 300 and 75 MHz, respectively. MS spectra were recorded on a Shimadzu QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were performed using a Heracus CHN–O-Rapid analyzer.