Four-Component Reaction of Trialkyl Phosphites, Amines, and Electron-Deficient Acetylenic Compounds: Synthesis of Phosphonate Derivatives in Water

Abstract

An effective route for the synthesis of phosphonate derivatives is described. This procedure involves the reaction of a trialkyl phosphites and dialkyl acetylenedicarboxylate in the presence of amines in water as the solvent at room temperature.

Key words

water - primary amines - trialkyl phosphites - four-component reactions - dialkyl acetylenedicarboxylate

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• 31 General Procedure for the Preparation of Compounds 5 A mixture of trialkyl phosphites 1 (2 mmol) and dialkyl acetylenedicarboxylate 2 (2 mmol) in H₂O (5 mL) was stirred for 45 min and then added to a mixture of dimethyl acetylenedicarboxylate 4 (2 mmol) and primary amine 3 (2 mmol) in H₂O that had been previously stirred for 30 min (5 mL). The reaction mixture was then stirred for a further 6 h at r.t. After completion of the reaction [6 h; TLC monitoring (EtOAc–hexane, 1:7)], the solid residue was filtered and washed with cold Et₂O to give pure product 5. Representative Analytical Data for Compound 5a Yellow powder, yield 0.72 g (92%), mp 152–154 °C. IR (KBr): ν_max = 3142, 1742, 1740, 1735, 1729, 1527, 1457, 1287cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 3.27 (3 H, s, NMe), 3.41 (3 H, d, ³ J _HP = 11 Hz, MeO), 3.45 (3 H, d, ³ J _HP = 11 Hz, MeO), 3.52 (3 H, s, MeO), 3.72 (3 H, s, MeO), 3.78 (3 H, s, MeO), 4.22 (1 H, d, ³ J _HP = 8 Hz, CH), 12.35 (1 H, br s, NH) ppm.¹³C NMR (125.7 MHz, CDCl₃): δ = 38.6 (NMe), 51.3 (d, ² J _CP = 9 Hz, CH), 51.8 (MeO), 52.2 (MeO), 53.2 (d, ² J _PC = 7 Hz, MeO), 53.7 (MeO), 54.2 (d, ² J _PC = 7 Hz, MeO), 62.8 (d ¹ J _PC = 135 Hz, C), 117.2 (d, ³ J _PC = 21.6 Hz, C), 142.8 (d, ³ J _PC = 21 Hz, C), 161.7 (C=O), 162.8 (d, ² J _PC = 6 Hz, C=O), 167.5 (d, ³ J _PC = 21 Hz, C=O), 189.4 (d, ² J _PC = 9 Hz, C=O) ppm. ³¹P NMR (202 MHz, CDCl₃): δ = 25.7. MS (EI): m/z (%) = 393 (15) [M⁺], 362 (82), 77 (56), 31 (100). Anal. Calcd for C₁₄H₂₀NO₁₀P (393.28): C, 42.76; H, 5.13; N, 3.56. Found: C, 42.63; H, 5.02; N, 3.44.