Synthesis of Diethyl α-(o-Nitroaryl)phosphoglycines via Oxidative Nucleophilic Substitution of Hydrogen in Nitroarenes

Abstract

The carbanion of protected diethyl phosphoglycinate adds to nitroarenes in liquid ammonia in ortho position to the nitro group. Subsequent oxidation of the resulting adduct σ^H with potassium permanganate gave N-protected diethyl α-(o-nitroaryl)phosphoglycinates.

Key words

amino acids - carbanions - oxidation - arylation

References and Notes

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• 16b

  Modified Literature Procedure ^¹6c
  To the solution of diethyl phosphoglycinate (4.55 g, 27.2 mmol) in CHCl₃ (100 mL) Et₃N (3 equiv, 81.6 mmol, 12.5 mL) was added followed by CS₂ (1.5 equiv, 40.8 mmol, 2.43 mL). The resulting mixture was stirred at r.t. for 24 h, and then ethylene bromide (1.2 equiv, 32.6 mmol, 6.07 g) was added. The solution was stirred for further 24 h at 60 ˚C. After cooling to r.t., the mixture was washed with H₂O, dried with anhyd Na₂SO₄, and evaporated. The residue was purified by column chromatography (CHCl₃-MeOH, 30:1, v/v). The N-protected phosphoglycinate was obtained as an oil, 3.73 g, 51% yield.

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General Procedure
To liquid NH₃ (15 mL) at -78 ˚C a solution of nitroarene (2.0 mmol) and 1b (269 mg, 1.0 mmol) was added followed by dropwise addition of KOt-Bu in THF (1.05 mL, 1.00 M, 1.05 mmol) over 5 min. The reaction mixture was stirred at this temperature for 30 min and then solid KMNO₄ (156 mg, 1.0 mmol) was added. After 5 min reaction was quenched by addition of NH₄Cl (500 mg), and the mixture was left to evaporation of NH₃. The residue was treated with H₂O (50 mL) and EtOAc (50 mL) and filtered through a pad of Celite. The organic layer was separated, dried, and evaporated. Products were isolated by column chromatography (EtOAc-hexane).

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Selected Analytical Data
Diethyl N -(1,3-Ditiholan-2-ylidene)-α-(2-nitrophenyl)-phosphoglycinate (2a)
Solidifying oil. IR (film, CH₂Cl₂): ν_max = 2986, 2905, 1589, 1534, 1355, 1245, 1026, 572 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.00 (m, 1 H), 7.90 (m, 1 H), 7.61 (m, 1 H), 7.41 (m, 1 H), 4.50 (s, 1 H), 5.96 (d, J = 18.8 Hz), 4.11-4.00 (m, 4 H), 3.64-3.40 (m, 4 H), 1.26-1.21 (m, 6 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 175.6 (d, J = 19 Hz), 148.4 (d, J = 7 Hz), 132.9 (d, J = 4 Hz), 130.9 (d, J = 7 Hz), 130.7 (d, J = 4 Hz), 128.1 (d, J = 4 Hz), 124 (d, J = 3 Hz), 65.9 (d, J = 156 Hz), 63.4 (d, J = 15 Hz), 63.3 (d, J = 15 Hz), 38.1, 35.0, 16.3 (d, J = 10 Hz), 16.2 (d, J = 10 Hz). ^³¹P NMR (162 MHz, CDCl₃): δ = 18.1. ESI-LRMS (+): m/z 391 [M + H]⁺. Anal. Calcd for C₁₄H₁₉N₂O₅S₂P: C, 43.07; H, 4.91; N, 7.18; S, 16.43. Found: C, 42.85; H, 4.90; N, 7.17; S, 16.55.
Diethyl N -(1,3-Dithiolan-2-ylidene)-α-(1-nitro-2-naphthyl)-phosphoglycinate (9b)
Oil. IR (film, CH₂Cl₂): ν_max = 2983, 1581, 1528, 1254, 1049, 1020, 563 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.05-7.95 (m, 2 H), 7.90-7.85 (m, 1 H), 7.76-7.71 (m, 1 H), 7.63-7.54 (m, 2 H), 5.15 (d, J = 18.0 Hz), 4.20-4.00 (m, 4 H), 3.65-3.51 (m, 2 H), 3.49-3.35 (m, 2 H), 1.28 (dt, J = 0.4, 7.1 Hz, 3 H), 1.22 (dt, J = 0.4, 7.1 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 175.7 (d, J = 19 Hz), 146.8 (d, J = 9 Hz), 133.0 (d, J = 2 Hz), 130.6 (d, J = 3 Hz), 128.4, 127.9 (d, J = 2 Hz), 127.4, 126.2 (d, J = 4 Hz), 126.0 (d, J = 6 Hz), 124.2 (d, J = 2 Hz), 121.8, 66.9 (d, J = 161 Hz), 63.6 (d, J = 8 Hz), 63.5 (d, J = 8 Hz), 38.2, 34.9, 16.2 (d, J = 6 Hz), 16.1 (d, J = 6 Hz). ^³¹P NMR (162 MHz, CDCl₃): δ = 17.6. ESI-LRMS (+): m/z 463 [M + H]⁺. Anal. Calcd for C₁₈H₂₁N₂O₅S₂P: C, 49.08; H, 4.91; N, 6.36; S, 14.56. Found: C, 48.62; H, 4.93; N, 6.34; S, 14.45.

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The hydrolysis reactions were performed according to literature procedure, see ref. 15a.
Selected Analytical Data
Diethyl α-(5-Fluoro-2-nitrophenyl)phosphoglycinate (3c)
Oil. IR (film, CH₂Cl₂): ν_max = 3250, 2987, 1689, 1589, 1532, 1351, 1236 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.27 (s, 1 H), 8.00 (ddd, J = 0.4, 5.1, 9.0 Hz, 1 H), 7.64 (dt, J = 2.7, 9.5 Hz, 1 H), 7.13-7.09 (m, 1 H), 5.52 (d, J = 21.5 Hz), 4.26-4.00 (m, 4 H), 2.95 (br s, 1 H), 1.29 (t, J = 7.0 Hz, 3 H), 1.17 (t, J = 7.0 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 164.9 (d, J = 204 Hz), 160.9 (d, J = 7.4 Hz), 144.7 (dd, J = 2.3, 5.0 Hz), 137.0 (d, J = 6.6 Hz), 127.9 (dd, J = 1.6, 7.8 Hz), 116.5 (dd, J = 2.4, 3.5 Hz), 115.4 (dd, J = 2.3, 18.6 Hz), 63.6 (d, J = 5.5 Hz), 63.5 (d, J = 5.5 Hz), 47.8 (d, J = 118 Hz), 16.3 (d, J = 2.5 Hz), 16.2 (d, J = 2.5 Hz). ^³¹P NMR (162 MHz, CDCl₃): δ = 22.0. ESI-LRMS (+): 357 [M + Na]⁺. Anal. Calcd for C₁₂H₁₆N₂O₆PF: C, 43.12; H, 4.83; N, 8.38. Found: C, 43.16; H, 4.83; N, 8.30.