Microwave-assisted synthesis of N,N-bis(phosphinoylmethyl)amines and N,N,N-tris(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms

A family of N,N-bis(phosphinoylmethyl)amines bearing different substituents on the phosphorus atoms was synthesized by the microwave-assisted and catalyst-free Kabachnik–Fields reaction of (aminomethyl)phosphine oxides with paraformaldehyde and diphenylphosphine oxide. The three-component condensation of N,N-bis(phosphinoylmethyl)amine, paraformaldehyde and a secondary phosphine oxide affording N,N,N-tris(phosphinoylmethyl)amine derivatives was also elaborated. This method is a novel approach for the synthesis of the target products.


General information
The 31 P, 13 C, 1 H NMR spectra were recorded in CDCl 3 solution on a Bruker AV-300 or DRX-500 spectrometer operating at 121.5,75.5 and 300 or 202.4,125.7 and 500 MHz, respectively. Chemical shifts are reported downfield relative to 85% H 3 PO 4 and TMS. The coupling constants are given in Hz. Mass spectrometric measurements were performed using a Q-TOF Premier mass spectrometer in positive electrospray mode and a Shimadzu LCMS-ITTOF mass spectrometer. The reactions were carried out in a 300 W CEM Discover microwave reactor (CEM Microwave Technology Ltd., Buckingham, UK) equipped with a pressure controller applying 30-80 W under isothermal conditions.

General procedure for the synthesis of (aminomethyl)dibenzyl-, (aminomethyl)di(ptolyl)-or (aminomethyl)diphenylphosphine oxides
A mixture of 1.0 mmol amine (0.10 mL of butylamine, 0.12 mL of cyclohexylamine or 0.11 mL benzylamine), 1.0 mmol (0.03 g) of paraformaldehyde, and 1.0 mmol of the secondary phosphine oxide (0.24 g of di(p-tolyl)phosphine oxide, 0.24 g of dibenzylphosphine oxide or 0.20 g of diphenylphosphine oxide) and 1.5 mL of acetonitrile was heated at 100 °C in a closed vial in a CEM Discover microwave reactor equipped with a pressure controller for 1 h. Acetonitrile and the water formed during reaction were removed in vacuum. The crude product so obtained was passed through a 1 cm silica gel layer using ethyl acetate. After evaporating the solvent, the products 5a,b, 6a,b, 7a,b and 8 were obtained as crystals or oils. The following products were thus prepared: (Butylaminomethyl)di(p-tolyl)phosphine oxide (5a) Yield: 97% (0.31 g) of compound 5a as pale yellow oil; 31

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Hydrogenation of (benzylaminomethyl)diphenylphosphine oxide To 1.6 g (5.00 mmol) of (benzylaminomethyl)diphenylphosphine oxide (8) in 100 mL of methanol was added 0.50 g of 10% palladium on carbon (Selcat Q) and the suspension was then hydrogenated in a stainless steel autoclave at 12 bar and 75 °C for 3 h. The mixture was filtered, and the catalyst was washed with methanol. After evaporating the solvent and column chromatography 0.54 g (47%) of 9 was obtained as a white crystal.

General procedure for the synthesis of N,N-bis(phosphinoylmethyl)amines containing different Y 2 P=O groups
A mixture of 0.12 g (0.50 mmol) of (aminomethyl)diphenylphosphine oxide (9), 0.015 g (0.5 mmol) of paraformaldehyde, and 0.10 g (0.50 mmol) of 0.5 mmol of the secondary phosphine oxide (0.10 g of diphenylphosphine oxide, 0.12 g of di(p-tolyl)phosphine oxide or 0.12 g of dibenzylphosphine oxide) and 1.5 mL of acetonitrile was heated at 100 °C in a closed vial in a CEM Discover microwave reactor equipped with a pressure controller for 40 min. Acetonitrile and the water formed during the reaction were removed in vacuum. The crude product so obtained was passed through a 1 cm silica gel layer using ethyl acetate. After evaporating the solvent, the products 13a-c were obtained as crystals or oils. The following products were thus prepared:

General procedure for the synthesis of N,N,N-tris(phosphinoylmethyl)amines
A mixture of 0.50 mmol of N,N-bis(phosphinoylmethyl)amines (0.22 g of N,Nbis(diphenylphosphinoylmethyl)amine or 0.24 g of N,N-(diphenylphosphinoylmethyl)(di-ptolylphosphinoylmethyl)amine), 0.015 g (0.50 mmol) of paraformaldehyde, and 0.50 mmol of the secondary phosphine oxide (0.12 g of dibenzylphosphine oxide, 0.12 g of di(ptolyl)phosphine oxide or 0.10 g of diphenylphosphine oxide) and 1.5 mL of acetonitrile was heated at 100 °C in a closed vial in a CEM Discover microwave reactor equipped with a pressure controller for 2 h. Acetonitrile and the water formed during the reaction were S10 removed in vacuum. The crude product so obtained was passed through a 1 cm silica gel layer using ethyl acetate. After column chromatography, the products 14-17 were obtained as crystals. The following products were thus prepared: