Solvent-free synthesis of α-aminophosphonates: Cellulose-SO₃H as an efficient catalyst

1 Introduction

α-Aminophosphonates are phosphorus structural analogs of α-amino acids (Sheridan, 2002). The medicinal importance and biological effects of α-aminophosphonate derivatives as antibiotics (Atherton et al., 1986), herbicides, fungicides, insecticides (Maier and Spoerri, 1991), enzyme inhibitors (Allen et al., 1989), HIV protease (Peyman et al., 1994), plant growth regulators (Emsley and Hall, 1976) anti-thrombotic agents (Meyer and Barlett, 1998), peptidases and proteases (Miller et al., 1998), had stimulated scientific research to develop many synthetic procedures for them. Based on this background over the last few years we have synthesized and reported (Prasad et al., 2007; Reddy et al., 2010) some bioactive, antimicrobial, anti cancer and anti oxidant phosphonates.

Among the various synthetic protocols described for the synthesis of α-aminophosphonates (Ordonez et al., 2009) nucleophilic addition of phosphites to imines i.e., Kabachnik-Fields reaction (Cherkasov and Galkin, 1998) proved to be a convenient route. For the efficient and capitulate oriented synthesis of α-aminophosphonates various other synthetic methodologies have been reported by using different catalysts. In such hierarchical reports Lewis acids such as lantanide triflate, (Manabe and Kobayashi, 2000) samarium diiodide, (Xu et al., 2003) indium (III) chloride, Lee et al., 2001 (bromodimethyl) sulfonium bromide, (Kudrimoti and Bommena, 2005) lithium perchlorate (Heydari et al., 2001), zirconium tetrachloride (Yadav et al., 2001), tin tetrachloride (Laschat and Kunz, 1992), bismuth nitrate pentahydrate (Bhattacharya and Kaur, 2007) and magnesium perchlorate (Bhagat and Chakraborti, 2007) were identified as efficient catalysts. Several metal complexes have also been used as effective catalysts for this reaction, (De Noronha et al., 2011) including ytterbium, boron, aluminium, zirconium and molybdenum complexes. As an alternative, the use of heteropoly acid (HPA) such as 12-tungstophosphoric acid as catalysts has also received considerable attention (Heydari et al., 2007). In yet another attempt phenyltrimethylammonium chloride (Heydari and Arefi, 2007) was used as a catalyst for obtaining new generation of α-aminophosphonates. The same applicability is not excluded for the natural phosphate alone or potassium fluoride doped natural phosphate (Zahouily et al., 2007). Recently, the organocatalysis has emerged as an important area of research over the last decade as it involved more stable, eco-friendly, readily available, less expensive catalyst and required less demanding reaction conditions in comparison to the metal catalyst. (Dalko and Moisan, 2001) In such sequence oxalic acid, (Vahdat et al., 2008) quinine, (Pettersen et al., 2006) and camphor sulfonic acid (Shinde et al., 2011) were used as potential catalysts. Similarly some solid supported catalysts (Chandrasekhar et al., 2001) like silica supported tantalum pentachloride and alumina-supported reagents were also exploited for accomplishing the same results. Later on Lewis salt boron trifluoride diethyl etherate, transition metal oxide titanium dioxide and some resins like amberlite-IR 120 and amberlyst-15 were explored as catalysts in the synthesis of α-aminophosphonates (Bhattacharya and Rana, 2008). Recently, the solid acid catalyst like montmorillonite KSF and sulfamic acid was employed for this purpose (Mitragotri et al., 2008).

However, these catalysts have various drawbacks like their non availability difficulties in preparation and requirement of long reaction times. Many of them when used with substrates containing aliphatic amino groups, uncharacterizable by products were formed. Due to significant potential biological activity of α-aminophosphonates the emphasis was focused on the development of an efficient and at the same time bio-friendly sustainable synthesis for them. In this context the search for efficient and green catalyst arose. Efforts in this direction led to the discovery of Cellulose-SO₃H that was already proved as promising solid acid catalyst for the synthesis of some important class of organic compounds (Shaabani et al., 2008) like α-amino nitriles, quinolines and imidazoazines. In this connection, now we wish to report the Cellulose-SO₃H as an efficient catalyst for the synthesis of α-aminophosphonates from an aldehyde, an amine and dialkylphosphite in one pot solvent free three component synthesis at room temperature.

2 Experimental

2.3

2.3 General procedure for the synthesis of α-aminophosphonates (4a–w)

A mixture of an aldehyde (1 mmole), an amine (1 mmole), diethylphosphite (1 mmole) and Cellulose-SO₃H (0.04 g) were stirred at room temperature for a particular period of time as given in Table 2 to produce the title compounds (Scheme 1). After completion of the reaction dichloromethane was added to the reaction mixture and stirred and then separated the Cellulose-SO₃H and collected by filtration. Dichloromethane layer was removed in a rota-evaporator. The residual product was purified by silica gel column chromatography. The collected Cellulose-SO₃H was reused for at least 3 to 4 runs without loss of product yield.

Table 2 Synthesis of α-aminophosphonates 4a.^a

Entry	Solvent	Time (min)	Yield (%)c
1	EtOH	120	nrd
2	CH2Cl2	120	nr
3	CH3CN	120	nr
4	Toluene	120	nr
5	Solvent-free	60	nr
6	EtOH + Cellulose-SO3Hb	60	66
7	CH2Cl2 + Cellulose-SO3H	60	70
8	CH3CN + Cellulose-SO3H	60	71
9	Toluene + Cellulose-SO3H	60	75
10	Solvent-free + Cellulose-SO3H	15	98

a Reaction conditions: room temperature, equimolar (1 mmol) ratio.

b Amount of catalyst (Cellulose-SO₃H) used in 0.04 g.

c Isolated yield calculated after purification.

d No reaction.

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Scheme 1

Cellulose-SO₃H catalyzed synthesis of α-aminophosphonates.

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3 Results and discussion

In continuation of our ongoing program in developing methods for the synthesis of α-aminophosphonates and identifying new catalysts (Reddy et al., 2007), we had performed the optimization of the efficiency of various catalysts on the synthesis of α-aminophosphonates at different concentrations to the select the best catalyst (Table 1) and finally we found Cellulose-SO₃H as an efficient catalyst for the present reaction.

Initially, the three component reaction involving benzaldehyde, aniline and diethylphosphite by using various solvents was performed for a period of 120 min at room temperature. The desired α-aminophosphonates (4a) were not obtained (Table 2, entries 1–4). The same reaction when run under the solvent-free condition the expected product 4a (Table 2, entry 5) was not formed even after stirring the reaction mixture for 60 min. When Cellulose-SO₃H catalyzed preparation of 4a was performed in various solvents on the same substrates for 60 min, the product formation (Table 2, entries 6–9) was observed in low yields (66–75%). Then finally in an effort to improve the yield further, the reaction was conducted without solvent in the presence of Cellulose-SO₃H as a catalyst. Surprisingly formation of the target product 4a was formed with 98% yield within 15 min (Table 2, entry 10).

The optimization studies of the catalyst required for the reaction of an aldehyde, aniline with phosphate in the presence of various amounts of catalyst ranging from 0.01–0.10 g showed that the best results in terms of yields and reaction time would be obtained with 0.04 g (Fig. 1).

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Figure 1

Optimization plot of Cellulose-SO₃H.

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When extended to variety of other substrates under the Cellulose-SO₃H catalyzed solvent-free conditions, the reaction proceeded smoothly at room temperature affording high yields (Table 3) of the desired products (4a–w) within 15–30 min without formation of any undesired by products (Scheme 1). Also analyzed the yield of the product 4a at different runs with the reused catalyst is represented in Fig. 2.

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Figure 2

Reusability of the Cellulose-SO₃H.

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The scope of reactivity in view of substrates has been found that this method is equally effective for both electron-rich as well as electron-deficient aldehydes and aniline. The reactivities of aromatic amines with heterocyclic aldehydes such as furfuraldehyde and 4-(4-pyridyl)benzaldehyde produced corresponding products (Table 3, entry 4u, 4v and 4w) in excellent yields. Even in the case of sterically hindered substrate trimethoxybenzaldehyde, the reaction resulted in good yields (Table 3, entry 4s and 4t).

Here the role of Cellulose-SO₃H in this method appears to be to take away the water formed during the formation of the imine intermediate in the first step of the reaction by itself converting into iminium salt of cellulose sulfate. Thus the main difficulty of the reversibility in the first step of Kabachnik-Fields reaction, where the backward reaction occurs to form the substrates is prevented. Subsequently, the cellulose sulfate abstracts a proton from the H-phosphonate and renders its phosphorus atom more nucleophilic and further catalyzes its nucleophilic addition at the electrophilic imine carbon atom. Thus the Cellulose-SO₃H catalyzes the total reaction in both the steps, first by removal of water and preventing reversibility in the first stage and rendering phosphorus more nucleophilic by abstraction of proton from H-phosphonate in the second step. During this reaction Cellulose-SO₃H catalyzes the reaction only by proton transfer and chemically remains as it is for recycling (Fig. 3). Thus the simplicity and efficiency of this reaction with applicability to a wide range of different substrates, this procedure becomes the choice for the commercial large scale industrial manufacture of α-aminophosphonates.

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Figure 3

Mechanistic pathway for the synthesis of α-aminophosphonates.

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4 Conclusion

The present communication reports an efficient green synthesis of α-aminophosphonates in high yield with short reaction times at room temperature using Cellulose-SO₃H as catalyst. This method is an elegant technique for C–P bond formation by nucleophilic addition of dialkylphosphites to in situ generated imines.