[BPy]HSO4 as an Efficient and Recyclable Catalyst for One-Pot Synthesis of α-Aminophosphonates under Solvent-Free Conditions

α-Aminophosphonates are an important class of compounds because they are considered to be used as phosphorous analogs of the corresponding α-amino acids. Their diverse applications include as enzyme inhibitors [1], HIV protease [2], antibiotics [3], herbicides, fungicides, insecticides [4], as well as antithrombotic agents [5]. Various methods have been developed for the synthesis of α-aminophosphonates [6]. Recently, the synthesis of α-aminophosphonates by the one-pot three-component condensation of aldehydes, amines, and diethylphosphite or triethylphosphite has been explored in the presence of a variety of catalysts such as Cd(ClO4)2·xH2O [7], KH2PO4 [8], choline chloride·2ZnCl2 [9], H3PW12O40 [10], Zn(OAc)2·2H2O [11], [Cu(3,4tmtppa)](MeSO4)4 [12], sulfamic acid [13], HClO4-SiO2 [14], NbCl5 [15], ytterbium perfluorooctanoate [16], nanoCeO2 [17], alum [18], Al(OTf)3 [19], thiamine hydrochloride (VB1) [20], CeCl3·7H2O [21], xanthan sulfuric acid [22], and silica sulfuric acid [23, 24]. However, some of these methods suffer from one or more drawbacks such as use of toxic catalysts which are usually nonrecoverable and organic solvents, tedious workup procedures, and the requirement of heating conditions. Thus, the development of simple, efficient, and environmentally friendly methods under mild conditions using recyclable catalysts for the synthesis of α-aminophosphonates is of current interest. Acidic ionic liquids have emerged as promising acid catalysts in replacement of conventional homogeneous and heterogeneous acidic catalysts because they are flexible, nonvolatile, noncorrosive, of low toxicity, immiscible with many organic solvents, and reusable [25]. Ionic liquids’ ([bnmim][HSO4] [26], [psmim][HSO4] [27]) catalyzed synthesis of α-aminophosphonates has also been reported. Solvent-free organic reactions make procedures simpler and prevent solvent wastes, hazards, and toxicity [28]. We report herein the acidic ionic liquid [BPy]HSO4 catalyzed onepot synthesis of α-aminophosphonates at room temperature under solvent-free conditions.


Results and Discussion
We herein report, a simplified and benign procedure for the preparation of the ionic liquid [BPy]HSO 4 using sodium bisulphate (Scheme 1), in place of sulphuric acid [29].The significant advantages of using sodium bisulphate in place of sulphuric acid in the preparation of [BPy]HSO 4 over the previous method is to avoid the release of corrosive hydrogen bromide and reduction in processing time from 48 h to 1 h.The acidic nature of [BPy]HSO 4 has been exploited in the preparation of 1,5-benzodiazepine derivatives by the reaction of o-phenylenediamine with chalcones [29].We now report a clean and efficient method for the one-pot three-component synthesis of α-aminophosphonates using [BPy]HSO 4 as recyclable catalyst at room temperature under solvent-free conditions (Scheme 2).
In the initial experiments, in order to evaluate the catalytic efficiency of [BPy]HSO 4 in this three-component reaction, the reaction of benzaldehyde with aniline and triethyl phosphite was selected as model.The experimental procedure is very simple.A mixture of benzaldehyde, aniline, triethyl phosphite, and [BPy]HSO 4 was stirred at room temperature.After completion of the reaction, the product was purified by crystallization with ethanol.To optimize the amount of a catalyst under solvent-free conditions, we examined the effects of catalyst loading on the synthesis of α-aminophosphonate.The results are summarized in Table 1.It is important to note that the synthesis of αaminophosphonate could not be achieved in the absence of catalyst (Table 1, entry 1) [8].The optimum catalyst loading for [BPy]HSO 4 was found to be about 30 mol %.When the amount of the catalyst decreased to 20 mol% from 30 mol% relative to the substrates, the yield was not reduced but longer time was required to complete the reaction (Table 1, entries 4 and 5).However, the use of 40 mol% of the catalyst showed almost the same yield and the same time was required (Table 1, entry 6).
After optimizing the conditions, we examined the scope of the reaction by condensing several substituted aromatic aldehydes with amines and triethyl phosphite using 30 mol% of [BPy]HSO 4 as catalyst under solvent-free conditions at room temperature.The examples studied covered electronrich and electron-deficient aromatic aldehydes with aniline derivatives containing electron-donating and electronwithdrawing groups.As shown in Table 2, the presence of electron-donating groups on the aldehyde produced the corresponding α-aminophosphonates in good yields and the reaction was sluggish (Table 2, entries 2, 3, and 11).The presence of electron-donating groups on the aldehyde resulted in increased electron density on the nitrogen atom of the imine.This makes the iminium ion a bad electrophilic center which is subsequently attacked by the nucleophilic phosphite species to give the α-aminophosphonates.The steric hindrance of the aromatic ring had some influence on the rate and yield of the reaction.
A proposed mechanism for the synthesis of α-aminophosphonates catalyzed by [BPy]HSO 4 is shown in Scheme 3. The mechanism of this reaction is believed to involve formation of an activated imine by the acidic ionic liquid so that addition of the phosphite is facilitated to give a phosphonium intermediate, which then undergoes reaction with the water generated during formation of the imine to give the α-aminophosphonate and ethanol [17].
From both an environmental and an economic standpoint, it is highly desirable that the catalyst can be recovered and reused.The reusability of the [BPy]HSO 4 catalyst Organic Chemistry International Scheme 3: Proposed mechanism for the synthesis of α-aminophosphonates catalyzed by [BPy]HSO 4 .was also examined.For this purpose, the same model reaction was again studied under optimized conditions.After completion of the reaction, the product was purified by crystallization with ethanol.The mother liquor containing the catalyst was rotary evaporated to remove solvent and the resulting catalyst was reused directly for the next run.As shown in Table 3, the recovered catalyst can be reused at least four additional times in subsequent reactions without any loss in catalytic activity, more than 90% yield of αaminophosphonate could be obtained in each recycle.Finally, the efficiency of [BPy]HSO 4 was compared with that of other ionic liquids reported earlier in the synthesis of α-aminophosphonates via condensation of aniline and benzaldehyde with triethyl phosphite.The data summarized in Table 4 clearly demonstrate that [BPy]HSO 4 is an effective ionic liquid for the synthesis of α-aminophosphonates.

Conclusion
In summary, we have demonstrated that a readily available ionic liquid [BPy]HSO 4 can be used as a recyclable catalyst for the synthesis of α-aminophosphonates by the one-pot reaction of an aldehyde, an amine, and triethyl phosphite at room temperature under solvent-free conditions.The operational simplicity together with the use of recyclable and environmentally benign catalyst are remarkable features of the procedure.

Typical
Procedure for the Synthesis of α-Aminophosphonates.A mixture of aldehyde (10 mmol), amine (10 mmol), triethyl phosphite (12 mmol), and [BPy]HSO 4 (30 mol%) was stirred at room temperature for the appropriate time (Table 2).After completion of the reaction, as indicated by thin-layer chromatography, the reaction mixture was purified by crystallization with ethanol.The mother liquor containing the catalyst was rotary evaporated to remove solvent and the resulting catalyst was reused directly for the next run.

Table 1 :
Effects of the amount of [BPy]HSO 4 on the synthesis of α-aminophosphonate a .
a Isolated yield.

Table 4 :
Comparison of ionic liquids used for the synthesis of α-aminophosphonate.