An efficient and simple synthesis of α-amino phosphonates as ‘drug like’ molecules catalyzed by silica-supported perchloric acid (HClO₄–SiO₂)

1 Introduction

The synthesis and use of phosphonate-containing molecules as an important class of active compounds, have received increased attention during the last two decades (Engle and Cohen, 2003; Savignac and Iorga, 2003). In this relation, the utilities of α-amino phosphonates as HIV protease (Peyman et al., 1992, 1994), anti-therombotic agents (Meyer and Barlett, 1998), enzyme inhibitors (Allen et al., 1989), antibiotics (Atherton et al., 1986), peptid mimics (Kafarski and Leczak, 1991), herbicides, fungicides, insecticides (Maier and Spörri, 1990), as well as important role for antibody generation (SmithIII et al., 1994), are well documented. Because of their pharmacological and biological importance, many procedures for the synthesis of α-amino phosphonates have been developed. Among the numerous reported methods, the nucleophilic addition reaction of phosphites with imines is one of the most convenient of these methods, and usually catalyzed by base (Pudovik, 1952), Bronsted (Petrov et al., 1974), or Lewis acids such as BF₃–OEt₂ (Ha and Nam, 1992), SnCl₄ (Laschate and Kunz, 1992). However, these methods are not devoid of their limitation as many imines are hygroscopic and are not sufficiently stable for isolation. In the other hands, these reactions cannot be proceeded in a one-pot reaction involving a carbonyl compound, an amine and a trialkyl phosphite, because the amines and water exist during imine formation can decompose or deactivate the Lewis acid (Yokomatsu et al., 1994).

To overcome some of these problems, recently one-pot three-component synthesis of α-amino phosphonates has been developed. This conversion has been carried out by employing catalysts including lanthanide triflate (Qian and Huang, 1998), indium(Ш) chloride (Ranu et al., 1999) lithium perchlorate (Saidi and Azizi, 2002), magnesium perchlorate (Bhagat and Chakraborti, 2007), TaCl₅–SiO₂ (Chandrasekhar et al., 2001), PhNMe₃Cl (Heydari and Arefi, 2007), TiO₂ (Hosseini-Sarvari, 2008), sulfamic acid (Mitragotri et al., 2008), In(OTf)₃ (Ghosh et al., 2004) CF₃CO₂H (Akiyama et al., 2003), Amberlite-IR 120 (Bhattacharya and Rana, 2008), H₃PW₁₂O₄₀ (Heydari et al., 2007), Amberlyst-15 (Tajbakhsh et al., 2008), oxalic acid (Vahdat et al., 2008), trifluoroethanol (Heydari et al., 2009), Na₂CaP₂O₇ (Elmakssoudi et al., 2005),[emim]Br (Yavari and Hajinasiri, 2009). However, many of these methods have drawbacks: for instance, long reaction time, environmental pollution caused by means of organic solvents, and expensive catalyst. Therefore, there is a need to develop a facile one-pot synthesis of α-amino phosphonates without these problems. The use of solid acidic catalysts supported on silica has attracted much attention in organic synthesis due to their advantages such as, reusability, inexpensiveness, ease of preparation and handling, nontoxicity, operational simplicity and ease of isolation from the reaction mixture. Silica-supported perchloric acid (HClO₄–SiO₂) is well known as an efficient heterogeneous catalyst for various chemical reactions (Chakraborti and Gulhane, 2003; Kumar et al., 2007, 2006; Khan et al., 2006; Bigdeli et al., 2007; Das et al., 2007; Kantevari et al., 2007; Shaterian et al., 2007). In continuation of our research works in the synthesis of α-amino phosphonates (Maghsoodlou et al., 2009, 2010), herein, we employed the silica-supported perchloric acid as an efficient and reusable heterogeneous acid catalyst for one-pot three-component synthesis of α-amino phosphonates under solvent-free conditions at 80 °C (Scheme 1).

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Scheme 1

Synthesis of α-amino phosphonates.

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2 Experimental

Melting points and IR spectra of all compounds were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer, respectively. The ¹H, ¹³C and ³¹P NMR spectra were obtained on BRUKER DRX-250 AVANCE instruments with CDCl₃ as a solvent. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on Agilent Technology (HP) spectrometer operating at an ionization potential of 70 eV. All reagents and solvents obtained from Fluka and Merck were used without further purification.

3 Results and discussion

Silica-supported perchloric acid was prepared according to the literature procedure (Chakraborti and Gulhane, 2003). In order to find out the optimum quantity of silica-supported perchloric acid, a reaction between benzaldehyde, aniline and trimethyl phosphite was carried out under solvent-free conditions using different quantities of HClO₄–SiO₂ (Table 1 and Fig. 1). As seen in Fig. 1, silica-supported perchloric acid with 3 mol% gives excellent yield in 65 min at 80 °C.

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Figure 1

The reaction between benzaldehyde, aniline and Trimethyl phosphite in the presence of different mol% of HClO₄–SiO₂.

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Hence, a series of α-amino phosphonates were prepared in high to excellent yields from the reaction between aldehyde (1 mmol), amine (1.2 mmol) and trialkyl phosphites (1 mmol) in the presence of silica-supported perchloric acid (3 mol%). The results are summarized in Table 2.

As can be seen from Table 2, each benzaldehyde containing electron-deficient or electron-releasing groups reacts efficiently with aniline for generation of the corresponding α-amino phosphonates (Table 2, entries 1–13). Also the reactions between substituted aniline, substituted benzaldehyde and trimethyl/triethyl phosphite led to the desired α-amino phosphonate in good yield (Table 2, entries 16–23). In addition, this method is effective even with aliphatic aldehydes, which normally produce low yields due to their intrinsic lower reactivity (Table 2, entries 14 and 15). On the basis of experimental results, the rate of all the reactions in the presence of trimethyl phosphite was increased in comparison with triethyl phosphite under constant conditions. The wide applicability of the present method is evident from the fact that it is tolerant towards various functional groups including alkoxy, halides and nitro groups. We have also prepared five new analogues of these compounds in excellent yields (Table 2, entries 16–20). These new compounds characterized by melting point, IR, NMR (¹H, ¹³C and ³¹P), Mass spectroscopies and Elemental analyses.

The reusability of the catalysts is an important benefit in present method and makes it useful for commercial applications. Thus, the recyclability of the catalyst was checked for the reaction between benzaldehyde, aniline and trimethyl phosphite in the presence of HClO₄–SiO₂ (3 mol%). The separated catalyst can be reused after washing with MeOH and drying at 100 °C. The results indicate that the catalyst can be used five times without any loss of its activity (Table 3).

4 Conclusion

Thus, we have demonstrated that silica supported perchloric acid is an efficient and green catalyst for the synthesis of α-amino phosphonates. α-amino phosphonate derivatives were prepared via a one-pot three-component reaction between aryaldehyde, amine and trialkyl phosphite in the presence of catalytic silica-supported perchloric acid in solvent-free conditions. The thermal solvent-free green procedure offer advantages such as shorter reaction time, high yields, environmentally benign, simple work-up, cost effective recovery and the reusability of catalyst for a few times without a significant change in its activity.