Facile Two-Step Synthesis of Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate by Exploiting Garegg–Samuelsson Reaction Conditions

Abstract

A facile two-step synthesis of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (Still–Gennari reagent) has been developed by exploiting Garegg–Samuelsson reaction conditions. Starting from trimethyl phosphonoacetate, Still–Gennari reagent was prepared in 94% yield via methyl 2-{bis[(trimethylsilyl)oxy]phosphoryl}acetate intermediate. This synthetic procedure was also used to prepare some kinds of Horner–Wadsworth–Emmons reagents and related compounds.

Key words

Horner–Wadsworth–Emmons reagents - Still–Gennari reagent - phosphorus - Garegg–Samuelsson reaction conditions - 2,2,2-trifluoroethanol

• References and Notes

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• 13 Preparation of Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate (Still–Gennari Reagent, 1)^5,6 TMSBr (90 μL, 0.691 mmol) was added at r.t. to a solution of trimethyl phosphonoacetate (2; 50.3 mg, 0.276 mmol) in anhydrous CH₂Cl₂ (0.55 mL). After stirring at r.t. for 5 h under argon, evaporation of the reaction mixture in vacuo gave methyl 2-{bis[(trimethylsilyl)oxy]phosphoryl}acetate (4), which was used without further purification. Ph₃P (181 mg, 0.691 mmol) and I₂ (175 mg, 0.691 mmol) were added to a solution of 4 in anhydrous CHCl₃ (1.8 mL) at r.t. under argon. After stirring at r.t. for 15 min under argon, imidazole (188 mg, 2.76 mmol) was added. The reaction mixture was stirred for 15 min at r.t. and then for 30 min at 50 °C. Afterwards, 2,2,2-trifluoroethanol (79 μL, 1.10 mmol) was added, and the reaction mixture was stirred at 60 °C for 5 h. After filtration of the reaction mixture, the filtrate was evaporated in vacuo to give a crude product 1, which was purified by silica gel [Silica Gel PSQ 60B (Fuji Silysia Chemical)] column chromatography [n-hexane–EtOAc (2:1)] to afford 1 (82.3 mg, 94%) as a colorless oil. IR (neat): 1747, 1265, 1174, 1072, 963 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 4.51–4.42 (m, 4 H), 3.78 (s, 3 H), 3.17 (d, ² J _H,P = 21.1 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2 (d, ² J _C,P = 4.5 Hz), 122.5 (qd, ¹ J _C,F = 277.1 Hz, ³ J _C,P = 8.2 Hz), 62.7 (qd, ² J _C,F = 38.2 Hz, ² J _C,P = 5.5 Hz), 53.1, 33.8 (d, ¹ J _C,P = 145.1 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₇H₉F₆O₅PNa: 340.9990; found: 340.9982. Anal. Calcd for C₇H₉F₆O₅P: C, 26.43; H, 2.85. Found: C, 26.28; H, 2.89.
• 14 Methyl 2-[Bis(phenylthio)phosphoryl]acetate (7f)Colorless oil; yield 79.5 mg (85%). IR (neat): 3059, 2952, 1737, 1473, 1439, 1268, 1220, 1107, 1023, 1002 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.63–7.59 (m, 4 H), 7.45–7.36 (m, 6 H), 3,77 (s, 3 H), 3.30 (d, ² J _H,P = 16.2 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.1 (d, ² J _C,P = 4.6 Hz), 136.0 (d, ³ J _C,P = 4.4 Hz), 129.8 (d, ⁵ J _C,P = 2.8 Hz), 129.5 (d, ⁴ J _C,P = 2.1 Hz), 125.3 (d, ² J _C,P = 6.5 Hz), 52.8, 42.6 (d, ¹ J _C,P = 61.4 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₅O₃PS₂Na: 361.0098; found: 361.0069. Anal. Calcd for C₁₅H₁₅O₃PS₂: C, 53.24; H, 4.47. Found: C, 52.96; H, 4.67.Methyl 2-[Bis(phenylamino)phosphoryl]acetate (7g)Pale yellow columns (CHCl₃/n-hexane); mp 115.0–116.0 °C; yield 71.9 mg (86%). IR (KBr): 3330, 3185, 1731, 1602, 1502, 1434, 1397, 1282, 1268, 1242, 1207, 1181, 1106 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.23–7.17 (m, 4 H), 7.16–7.12 (m, 4 H), 6.99–6.93 (m, 2 H), 6.25 (br s, 2 H), 3.65 (s, 3 H), 3.17 (d, ² J _H,P = 19.3 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 168.4 (d, ² J _C,P = 4.5 Hz), 139.5, 129.3, 122.4, 118.9 (d, ² J _C,P = 6.4 Hz), 52.8, 35.9 (d, ¹ J _C,P = 103.8 Hz). HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₁₇N₂O₃PNa: 327.0874; found: 327.0858. Anal. Calcd for C₁₅H₁₇N₂O₃P: C, 59.21; H, 5.63; N, 9.21. Found: C, 59.18; H, 5.66; N, 8.98.
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• 20 Ethyl 2-[Bis(2,2,2-trifluoroethoxy)phosphoryl]-2-fluoroacetate (10)Colorless oil; yield 46.1 mg (49%). IR (neat): 2983, 2947, 1770, 1456, 1420, 1374, 1271, 1174, 1068, 1021, 963 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 5.34 (dd, ² J _H,F = 46.4 Hz, ² J _H,P = 12.8 Hz, 1 H), 4.60–4.43 (m, 4 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 163.4 (dd, ² J _C,F = 21.8 Hz, ² J _C,P = 1.9 Hz), 122.1 (qdd, ¹ J _C,F = 277.8 Hz, ³ J _C,P = 8.0 Hz, ⁵ J _C,F = 5.6 Hz), 84.3 (dd, ¹ J _C,F = 199.7 Hz, ¹ J _C,P = 168.0 Hz), 63.5 (qd, ² J _C,F = 38.8 Hz, ² J _C,P = 5.9 Hz), 63.3, 13.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₀F₇O₅PNa: 373.0052; found: 373.0046. Anal. Calcd for C₈H₁₀F₇O₅P: C, 27.44; H, 2.88. Found: C, 27.49; H, 3.10.