Novel Method for the Synthesis of α-Amino-α′-hydroxyalkylphosphinic Acids and Bis(α-aminoalkyl)phosphinic Acids: Nuclephilic Addition of α-Hydroxy-H-phosphinic Acids to Diimines

Abstract

We report here a novel and simple method for the synthesis of α-amino-α′-hydroxyalkylphosphinic acids in good yields in two simple steps without any protection–deprotection steps. We have developed an efficient method for the synthesis of α-amino-α′-hydroxyalkylphosphinic acids via the reaction of easily available α-hydroxyalkylphosphinic acids with diimines. Treatment of α-­hydroxyalkylphosphinic acids with diimines in the presence of ­trimethylsilyl chloride (TMSCl) gives α-amino-α′-hydroxyalkylphosphinic acids in good yields. The reaction gave a mixture of two diastereomeric forms of α-amino-α′-hydroxyalkylphosphinic acids. The difference in solubility in organic solvents allowed us to readily separate the diastereoisomers.

Key words

phosphinic acids - hydroxyalkylphosphinic acid - amino-α′-hydroxyalkylphosphinic acid - diimines - bis(α-aminoalkyl)phosphinic acid

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• 23 General Procedure for the Preparation of α-(Amino-alkyl)-α′-(hydroxyalkyl)phosphinic Acid (3) Trimethylsilyl chloride (6 mmol, 0.75 mL) was added dropwise to a suspension of 1-hydroxy-H-phosphinic acid (2 mmol) in anhyd toluene (10 mL) under argon, and the mixture was stirred at 0 °C for 30 min. A solution of diimine (3 mmol) in toluene (5 mL) was added to the reaction mixture, and the mixture was stirred at reflux for 4 h. EtOH (5 mL) was added to this mixture, and the mixture was stirred at reflux for 1 h, during which time a white solid precipitated. This was collected by filtration, washed with EtOH (2 mL), and air drying to give a mixture of diastereo-isomers of α-amino-α′-hydroxyphosphinic acid in 41–83% yield. All products gave satisfactory spectral data in accordance with the assigned structures. α-Amino(phenyl)methyl[α′-hydroxy(phenyl)methyl]-phosphinic Acid (3a) White solid, mixture of two diastereoisomers. ¹H NMR (400 MHz, D₂O): δ = 4.02 (d, 1 H, J = 12.4 Hz), 4.08 (d, 1 H, J = 8.8 Hz), 4.60 (d, 1 H, J = 4.8 Hz), 4.85 (d, 1 H, overlap with D₂O signal), 7.19–7.45 (m, 20 H) ppm. ¹³C NMR (100 MHz, D₂O–TMS): δ = 54.0 (d, J _PC = 89.0 Hz), 54.2 (d, J _PC = 88.0 Hz), 72.2 (d, J _PC = 101.0 Hz), 72.4 (d, J _PC = 102.0 Hz), 127.0–127.5 (Ar), 127.6 (d, J _PC = 4.0 Hz), 127.7 (d, J _PC = 4.0 Hz), 128.1 (d, J _PC = 1.0 Hz), 128.3 (d, J _PC = 2.0 Hz), 128.4 (d, J _PC = 1.0 Hz), 138.6 (d, J _PC = 3.0 Hz), 138.8 (d, J _PC = 2.0 Hz), 139.1 (d, J _PC = 2.0 Hz) ppm. ³¹P NMR (162 MHz, D₂O–H₃PO₄): δ = 32.90, 33.37 ppm. HRMS: m/z calcd for C₁₄H₁₅NO₃PNa₂ [M + 2Na⁺]: 322.0585; found: 322.0581.