Phenylphosphonic Acid as Efficient and Recyclable Catalyst in the Synthesis of α-Aminophosphonates under Solvent-Free Conditions

Abstract

Phenylphosphonic acid is an efficient, friendly and reusable heterogeneous catalyst for the synthesis of α-aminophosphonates through a ‘one-pot’ three-component reaction of amines, carbonyl compounds and dialkyl phosphites under solvent-free conditions. This methodology illustrates a very simple procedure, with wide applicability, extending the scope to aliphatic and aromatic amines, aliphatic and aromatic aldehydes and aliphatic ketones. It also enabled the synthesis of α-aminophosphonates in large scale, clean conversion, easy workup and purification. Excellent results were obtained in each case obtaining the desire compounds in moderate to good yields.

Key words

α-aminophosphonates - phenylphosphonic acid catalyst - solvent-free conditions - heterogeneous catalysis

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• 24 In a typical experiment, to a mixture of aldehyde or ketone (2.0 mmol) and benzylamine (2.0 mmol) was added the phenylphosphonic acid (5; 10 mol%). The reaction mixture was stirred at r.t. for 20 min. After this time, dimethyl phosphite (2.1 mmol) was added and the reaction mixture was stirred at 50 °C for the specific period of time (see Tables 1–3), and the progress of the reaction was monitored by TLC. The crude was directly subjected to silica gel flash chromatography eluting with EtOAc, obtaining the pure α-aminophosphonates. ¹H NMR, ¹³C NMR, ³¹P NMR, and HRMS data for some newly obtained α-aminophosphonates are as follows. Compound 6g: yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 3.48 [d, J = 10.5 Hz, 3 H, (MeO)₂P], 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.78 (AB system, J = 13.3 Hz, 1 H, Bn), 3.79 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.89 (d, J = 20.1 Hz, 1 H, CHP), 6.63 (ddd, J = 8.0, 2.0, 2.0 Hz, 1 H, H_Ar), 6.77 (d, J = 8.0 Hz, 1 H, H_Ar), 7.11 (dd, J = 2.0, 2.0 Hz, 1 H, H_Ar), 7.20–7.31 (m, 5 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 50.8 (d, J = 17.6 Hz, Bn), 53.8 [d, J = 7.1 Hz, (MeO)₂P], 54.1 [d, J = 7.6 Hz, (MeO)₂P], 58.2 (d, J = 157.8 Hz, CHP), 114.7 (d, J = 5.0 Hz), 115.1, 121.0 (d, J = 8.1 Hz), 126.0, 127.2, 128.4 (2 × C), 139.0, 145.0 (2 × C). ³¹P NMR (161.9 MHz, CDCl₃): δ = 26.62. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₆H₂₁NO₅P: 338.1157; found: 338.1159. Compound 6k: white solid; mp 94–96 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.44 (br s, 1 H, NH), 3.58 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.5 Hz, 3 H, (MeO)₂P], 3.75 [d, J _HP = 10.6 Hz, 3 H, (MeO)₂P], 3.84 (AB system, J = 13.3 Hz, 1 H, Bn), 4.10 (d, J = 20.2 Hz, 1 H, CHP), 7.22–7.36 (m, 6 H, H_Ar), 7.40–7.52 (m, 4 H, H_Ar), 7.59–7.64 (m, 4 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 51.3 (d, J = 17.4 Hz, Bn), 53.6 [d, J = 6.6 Hz, (MeO)₂P], 53.9 [d, J = 6.6 Hz, (MeO)₂P], 59.1 (d, J = 154.3 Hz, CHP), 127.1, 127.3, 127.4, 127.5, 128.5 (d, J = 6.7 Hz), 128.9, 129.1 (d, J = 5.5 Hz), 134.6, 139.3, 140.7, 140.9, 141.0. ³¹P NMR (161.9 MHz, CDCl₃): δ = 23.05. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₂₂H₂₅NO₃P: 382.1572; found: 382.1588. Compound 6l: colorless liquid. ¹H NMR (400 MHz, CDCl₃): δ = 2.17 (br s, 1 H, NH), 3.52 (AB system, J = 13.3 Hz, 1 H, Bn), 3.58 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.80 (AB system, J = 13.3 Hz, 1 H, Bn), 3.93 (s, 3 H, MeO), 4.13 (d, J = 20.7 Hz, 1 H, CHP), 7.21–7.36 (m, 5 H, H_Ar), 7.52 (AA′BB′ system, J = 8.3, 2.2 Hz, 2 H, H_Ar), 8.06 (AA′BB′ system, J = 8.3 Hz, 2 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 51.5 (d, J = 17.3 Hz, Bn), 52.3 (MeO₂C), 53.7 [d, J = 6.9 Hz, (MeO)₂P], 54.0 [d, J = 6.9 Hz, (MeO)₂P], 59.4 (d, J = 152.8 Hz, CHP), 127.5, 128.5, 128.7, 128.8 (d, J = 5.9 Hz), 130.0, 130.1, 138.9, 141.1, 166.9. ³¹P NMR (161.9 MHz, CDCl₃): δ = 22.15. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₈H₂₃NO₅P: 364.1314; found: 364.1322. Compound 6n: white solid; mp 59–62 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.35 (br s, 1 H, NH), 3.52 (AB system, J = 13.2 Hz, 1 H, CH₂Ph), 3.61 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.74 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.79 (AB system, J = 13.2 Hz, 1 H, CH₂Ph), 4.12 (d, J = 20.6 Hz, 1 H, CHP), 7.21–7.35 (m, 5 H, H_Ar), 7.55 (AA′BB′ system, J = 8.1, 1.4 Hz, 2 H, H_Ar), 7.64 (AA′BB′ system, J = 8.1 Hz, 2 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 51.5 (d, J = 17.1 Hz, CH₂Ph), 53.7 [d, J = 6.9 Hz, (MeO)₂P], 54.0 [d, J = 7.0 Hz, (MeO)₂P], 59.3 (d, J = 153.0 Hz, CHP), 124.3 (q, J = 275.0, CF₃), 125.7 (dq, J = 3.6, 3.6 Hz), 127.6, 128.5, 128.7, 129.1 (d, J = 5.9 Hz), 130.4 (dq, J = 32.2, 2.9 Hz), 138.9, 140.1 (d, J = 3.5 Hz). ³¹P NMR (161.9 MHz, CDCl₃): δ = 24.78 (q, J = 2.5 Hz). HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₇H₂₀F₃NO₃P: 374.1133; found: 374.1035. Compound 6p: yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 2.56 (br s, 1 H, NH), 3.43 [d, J = 10.4 Hz, 3 H, (MeO)₂P], 3.60 (AB system, J = 13.4 Hz, 1 H, CH₂Ph), 3.74 [d, J = 10.5 Hz, 3 H, (MeO)₂P], 3.82 (AB system, J = 13.4 Hz, 1 H, CH₂Ph), 4.09 (d, J = 20.2 Hz, 1 H, CHP), 6.10–6.17 (m, 2 H, H_Ar), 6.78 (ddd, J = 4.3, 2.6, 1.8 Hz, 1 H, H_Ar), 7.18–7.35 (m, 5 H, H_Ar), 9.71 (br s, 1 H, NH-pyrrole). ¹³C NMR (100 MHz, CDCl₃): δ = 51.2 (d, J = 16.9 Hz, CH₂Ph), 52.5 (d, J = 160.4 Hz, CHP), 53.5 [d, J = 6.9 Hz, (MeO)₂P], 53.9 [d, J = 7.0 Hz, (MeO)₂P], 108.1, 109.5 (d, J = 9.4 Hz), 119.0, 124.8 (d, J = 5.4 Hz), 127.2, 128.4, 128.5, 139.5. ³¹P NMR (161.9 MHz, CDCl₃): δ = 22.70. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₄H₂₀N₂O₃P: 295.1212; found: 295.1224. Compound 6q: yellow liquid. ¹H NMR (200 MHz, CDCl₃): δ = 1.94 (br s, 1 H, NH), 3.60 (AB system, J = 13.3 Hz, 1 H, Bn), 3.64 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.81 [d, J = 10.6 Hz, 3 H, (MeO)₂P], 3.87 (AB system, J = 13.3 Hz, 1 H, Bn), 4.12 (d, J = 22.2 Hz, 1 H, CHP), 6.36–6.42 (m, 2 H, H_Ar), 7.22–7.35 (m, 5 H, H_Ar), 7.46 (ddd, J = 2.5, 1.8, 0.8 Hz, 1 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 51.3 (d, J = 16.4 Hz, CH₂Ph), 52.7 (d, J = 162.5 Hz, CHP), 53.4 [d, J = 6.9 Hz, (MeO)₂P], 53.9 [d, J = 6.8 Hz, (MeO)₂P], 109.5 (d, J = 7.5 Hz), 110.6, 127.2, 128.4 (2 × C), 138.8, 142.7 (2 × C). ³¹P NMR (81 MHz, CDCl₃): δ = 23.36. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₄H₁₉NO₄P: 296.1052; found: 296.1039. Compound 6r: colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 7.3 Hz, 3 H, Me), 1.31–1.43 (m, 1 H, CH₂), 1.49–1.64 (m, 3 H, NH, CH₂), 1.68–1.81 (m, 1 H, CH₂), 2.91 (ddd, J = 12.2, 8.5, 4.6 Hz, 1 H, CHP), 3.77 [d, J = 9.9 Hz, 3 H, (MeO)₂P], 3.80 [d, J = 9.9 Hz, 3 H, (MeO)₂P], 3.87 (AB system, J = 13.1, 1.8 Hz, 1 H, Bn), 3.96 (AB system, J = 13.1 Hz, 1 H, Bn), 7.20–7.37 (m, 5 H, H_Ar). ¹³C NMR (100 MHz, CDCl₃): δ = 14.0 (Me), 19.4 (d, J = 10.9 Hz, CH₂), 32.1 (CH₂), 52.3 (d, J = 5.0 Hz, CH₂Ph), 52.8 [d, J = 7.6 Hz, (MeO)₂P], 53.0 [d, J = 6.4 Hz, (MeO)₂P], 53.7 (d, J = 149.4 Hz, CHP), 127.2, 128.5 (2 × C), 140.1. ³¹P NMR (161.9 MHz, CDCl₃): δ = 28.35. HRMS (FAB⁺): m/z [M + H]⁺ calcd for C₁₃H₂₃NO₃P: 272.1416; found: 272.1415.
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