Nef–Perkow–Mumm Cascade towards Imido Phosphate Derivatives

Abstract

A one-pot, four-component synthesis of imido phosphates has been achieved using a Nef–Perkow sequence followed by addition of carboxylic acid derivatives. The final imido moiety is formed via a Mumm rearrangement of an intermediate imidate.

Key words

vinyl phosphate - keteneimine - isocyanide - Nef reaction - Perkow reaction - Mumm rearrangement

• References and Notes


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• 15 Nef–Perkow–Mumm Product 4a – Typical Procedure Under an argon atmosphere, a mixture of chloroacetyl chloride (80 μL, 1.0 mmol) and cyclohexyl isocyanide (124 μL, 1.0 mmol) was stirred at rt for 5 min. Then trimethyl phosphite (118 μL, 1.0 mmol) was added, and the mixture was stirred at rt for 5 min to afford the imidoyl chloride intermediate. To a 1.0 M solution of benzoic acid (122 mg, 1.0 mmol) in MeCN were added Na₂CO₃ (106 mg, 1.0 mmol) and the imidoyl chloride intermediate (formed in situ), and the mixture was stirred at 40 °C for 1 h. The resulting mixture was dissolved in DCM and washed with H₂O. The organic layer was extracted, dried over MgSO₄, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (EtOAc/ DCM, 10:90) to afford 4a as yellow oil in 73% yield (278 mg, 0.73 mmol). R_f = 0.59 (DCM/EtOAc, 5:5). ¹H NMR (400 MHz, CDCl₃): δ = 7.63 (d, J_HH = 8.1 Hz, 2 H), 7.52 (t, J_HH = 7.3 Hz, 1 H), 7.41 (dd, J_HH = 8.1, 7.3 Hz, 2 H), 5.43 (dd, J_HH,HP = 3.0, 2.0 Hz, 1 H), 5.22 (dd, J_HH,HP = 3.0, 2.0 Hz, 1 H), 4.42–4.34 (m, 1 H), 3.70 (d, J_HP = 11.4 Hz, 6 H), 2.11–2.02 (m, 2 H), 1.84–1.81 (m, 4 H), 1.66–1.63 (m, 1 H), 1.39–1.18 (m, 3 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 173.6, 166.8 (d, J_CP = 8.1 Hz), 147.7 (d, J_CP = 8.1 Hz), 136.7, 132.7, 129.3, 128.7, 108.4 (d, J_CP = 3.7 Hz), 58.8, 55.1 (d, J_CP = 6.6 Hz), 30.3, 26.2, 25.2 ppm. ³¹P NMR (161.9 MHz, H₃PO₄): δ = –4.8 ppm. HRMS: m/z calcd for C₁₈H₂₄NO₆P: 381.1341; found: 381.1326. IR (neat): 3033, 2960, 2936, 2859, 1707, 1659, 1631, 1450, 1329, 1280, 1187, 1044 cm^–1. Nef–Perkow–Mumm Product 6a – Typical Procedure Under an argon atmosphere, a mixture of p-chlorobenzoyl chloride (128 μL, 1.0 mmol) and cyclohexyl isocyanide (124 μL, 1.0 mmol) was stirred at 60 °C for 2 h. Then trimethyl phosphite (118 μL, 1.0 mmol) was added, and the mixture was stirred at rt for 5 min to afford the ketenimine intermediate. To a 1.0 M solution of the keteneimine (formed in situ) in MeCN was added p-nitrobenzoic acid (167 mg, 1.0 mmol), and the mixture was stirred at 40 °C for 1 h. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel (EtOAc/DCM, 5:95) to afford 6a as yellow oil in 56% yield (292 mg, 0.56 mmol). R_f = 0.71 (DCM/EtOAc, 7:3). ¹H NMR (400 MHz, CDCl₃): δ = 8.26 (d, J_HH = 9.1 Hz, 2 H), 7.67 (d, J_HH = 9.1 Hz, 2 H), 7.38–7.33 (m, 4 H), 6.09 (d, J_HP = 7.8 Hz, 1 H), 3.80 (d, J_HP = 11.4 Hz, 3 H), 3.73–3.66 (m, 1 H), 3.58 (d, J_HP = 11.4 Hz, 3 H), 2.15–2.06 (m, 1 H), 2.01–1.92 (m, 1 H), 1.77–1.72 (m, 3 H), 1.55–1.44 (m, 2 H), 1.09–1.04 (m, 3 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 172.9, 171.6 (d, J_CP = 5.1 Hz), 150.0, 140.6, 135.7, 133.1 (d, J_CP = 5.9 Hz), 129.3, 129.3, 129.1, 124.0, 77.2 (d, J_CP = 4.4 Hz), 60.5, 54.9 (d, J_CP = 5.9 Hz), 54.5 (d, J_CP  = 5.9 Hz), 30.4, 29.2, 26.2, 26.1, 24.8 ppm. ³¹P NMR (161.9 MHz, H₃PO₄): δ = 0.3 ppm. IR (neat): 2938, 2859, 1716, 1688, 1530, 1348, 1300, 1044, 909, 855 cm^–1.