Microwave-assisted synthesis of α-aminophosphine oxides by the Kabachnik-Fields reaction applying amides as the starting materials

Abstract

A series of acylated α-aminophosphine oxides were synthesized by the microwave-assisted Kabachnik-Fields reaction of a series of carboxylic acid amides, formaldehyde and secondary phosphine oxides. To compensate the lower reactivity of the -NH₂ reagents, they had to be used in an excess. The solvolytic condensations furnished the α-aminophosphine oxides in yields of 58-93% after purification by chromatography.

Graphical Abstract

Keywords:

• α-Aminophosphine oxides
• carboxylic acid amides
• Kabachnik-Fields reaction
• microwave

Introduction

The Kabachnik-Fields reaction comprising the condensation of amines, oxo compounds and >P(O)H reagents, e.g. dialkyl phosphites is an important tool towards α-aminophosphonic derivatives ^[1-3] due to their potential as biologically active substrates.^[4-7] Numerous methods were described for the synthesis of α-aminophosphonates, however, the major part of the protocols reported applied a catalyst.^[8-16] The senior author of this article, together with a coworker, was who proposed that using the microwave (MW)-assisted solvent-free protocol, there is no need for any catalyst.^[17] Hence, cost and environmental burdens may be saved. The green chemical approaches deserve special attention. In this line, the ionic liquid catalyzed or catalyst-free, solvent-free and MW-promoted procedures should be mentioned.^[18-26] The authors of this paper belong to those, who tried to extend the scope of the phospha-Mannich reaction to obtain α-aminophosphine oxides.^[17,26-28] The “bis” Kabachnik-Fields reaction leading to ZN(CH₂P(O)Y₂)₂ (Z = alkyl or aryl, Y = alkoxy or alkyl/aryl) type of species are also of interest.^[25-31]

It was a challenge for us to try the phospha-Mannich condensation using a different kind of carboxylic amides as the -NH₂ component (Scheme 1A). The literature survey showed that mostly urethanes were applied as starting materials in the synthesis of acyl-aminophosphonates.^[32-40] These preparations requested the use of acetic acid, acetic anhydride or acetyl chloride as the solvent at 25 °C to afford the products in yields of 22-95%. There are three examples, when acetamide or urea derivatives were the starting materials of the Kabachnik-Fields reaction.^[41-43] These condensations were performed in toluene, acetic anhydride or acetyl chloride at 40-120 °C. As a matter of fact, the acylated α-aminophosphonates could also be prepared by the acylation of -NH₂ derivatives (Scheme 1B). However, the synthesis of the starting materials, unsubstituted α-aminophosphonates by the Kabachnik-Fields reaction utilizing ammonia or its precursors is not easy.^[44-46]

Scheme 1. Synthetic protocols for acylated α-aminophosphonates.

It was also obvious for us that the amides exhibit a lower reactivity in the phospha-Mannich condensation than amines.

Results and discussion

We wished to perform the Kabachnik-Fields reaction of a series of carboxylic acid amides (acetamide, propionic acid amide, as well as benzoic acid amide), paraformaldehyde and secondary phosphine oxides under MW conditions. The phospha-Mannich condensation of acetamide, paraformaldehyde and diphenylphosphine oxide served as the model reaction to find the optimum conditions. As earlier, we aimed at the catalyst- and solvent-free protocol.^[17] Experimental data were collected in Table 1. Reacting the three components at a 1:1:1 molar ratio at 150 °C, there was no reaction after a 2 h’s irradiation (Table 1, entry 1). Increasing the amount of acetamide to 5 equivalents, a low conversion of 2% was attained (Table 1, entry 2). A further increase to 10 equivalents led to a conversion of 11% (Table 1, entry 3). An increase in the temperature and reaction time to 180 °C and 3.5 h, respectively, brought the real breakthrough, as in this case the conversion was 61% (Table 1, entry 4). Following this line, applying a temperature of 200 and 220 °C, the conversion was 93 and 99%, respectively (Table 1, entries 5 and 6). One can see that practically a solvolytic-like accomplishment using acetamide in a 10-fold quantity at a relatively high temperature could compensate the lower reactivity of the amide. For comparison purpose, the last reaction was also carried out on conventional heating. A conversion of only 57% could be detected (Table 1, entry 7). In the realistic temperature range, the proceeding of the condensation was monitored by ³¹P NMR measurements. The curves obtained for 180, 200 and 220 °C can be seen in Figure 1. Our experiments also revealed that there were no side products, the corresponding α-aminophosphine oxide (1a) was formed in a neat reaction. After the work-up procedure including chromatography, product 1a was isolated in a yield of 72%.

Figure 1. Time dependence of the conversion of acetamide, paraformaldehyde, and Ph₂P(O)H to α-aminophosphine oxide (1a) at a 10:1:1 molar ratio.

Table 1. Optimization of the Kabachnik-Fields reaction of acetamide, paraformaldehyde, and diphenylphosphine oxide.

Entry	Quantity of aceatamide (eq.)	T (°C)	t (h)	Conversion^a (%)
1	1	150	2	-
2	5	150	2	2
3	10	150	2	11
4	10	180	3.5	61
5	10	200	3.5	93
6	10	220	3.5	99
7^b	10	220	3.5	57

^a Based on ³¹P NMR relative intensities.

^b Thermal control experiment in an oil bath.

In the next stage of our work, acetamide was also reacted in Kabachnik-Fields reactions utilizing other secondary phosphine oxides, such as bis(4-metylphenyl)phosphine oxide, bis(3,5-dimetylphenyl)phosphine oxide and dibenzylphosphine oxide at the conditions elaborated above. The corresponding α-aminophosphine oxides (1a-d) were obtained in yields of 72-93% (Table 2, entries 1-4). Then, propionic acid amide and benzamide were also converted to the corresponding α-aminophosphine oxides, 2a-d and 3a-d, respectively (Table 2, entries 5-8 and 9-12, respectively). As can be seen, the yields fell in the range of 57-91%, and the phopha-Mannich condensation of benzoic acid amide required a somewhat higher temperature of 240 °C. All compounds prepared are new, and were characterized by ³¹P, ¹³C and ¹H NMR spectral data, as well as HRMS.

Table 2. Kabachnik-Fields reaction of amides, paraformaldehyde, and secondary phosphine oxides.

Entry	Y	Z	T (°C)	Yield (%)
1	Me	Ph	220	72 (1a)
2		4-MeC6H4	220	85 (1b)
3		3,5-Me2C6H3	220	75 (1c)
4		Bn	220	93 (1d)
5	Et	Ph	220	91 (2a)
6		4-MeC6H4	220	89 (2b)
7		3,5-Me2C6H3	220	66 (2d)
8		Bn	220	62 (2d)
9	Ph	Ph	240	78 (3a)
10		4-MeC6H4	240	78 (3b)
11		3,5-Me2C6H3	240	58 (3c)
12		Bn	240	64 (3d)

Conclusions

In summary, an efficient, catalyst-free MW-assisted method was developed for the selective synthesis of acylated α-aminophosphine oxides by the phospha-Mannich reaction of carboxylic acid amides, paraformaldehyde and secondary phosphine oxides. All together, 12 new derivatives were prepared in good to high yields, which form a new family of compounds.

Experimental

General procedure for the synthesis of acylated α-aminophosphine oxides(1a-d, 2a-d and 3a-d)

A mixture of 5.0 mmol of the amide (0.29 g of acetamide, 0.37 g of propionamide or 0.61 g of benzamide), 0.50 mmol (0.02 g) of paraformaldehyde and 0.50 mmol of the secondary phosphine oxide (0.11 g of diphenylphosphine oxide, 0.12 g of di(p-tolyl)phosphine oxide, 0.13 g of bis(3,5-dimetylphenyl)phosphine oxide or 0.12 g of dibenzylphosphine oxide) was heated at 220 °C or 240 °C in a closed vial in a CEM Discover microwave reactor equipped with a pressure controller for 3.5 h. The crude product so obtained was dissolved in dichloromethane, and the excess of amide was removed by extraction with 3 × 15 mL of water.

The combined organic phases were dried (Na₂SO₄). Evaporation of the solvent left a residue that was passed through a 1 cm silica gel layer using 10% methanol in dichloromethane as the eluent to provide products 1a-d, 2a-d and 3a-d as white crystals. Most of the aminophosphine oxides were recrystallized from acetone. Characterization data and copies of ³¹P, ¹H, and ¹³C NMR spectra for the compounds synthesized were collected in the Supporting Information.

Additional information

Funding

The authors are indebted to the National Research, Development and Innovation Fund [No K119202] for financial support.