Water-Mediated Three-Component Wittig–S_NAr Reactions

Abstract

A novel one-pot, three-component Wittig–S_NAr approach to ethyl (E)-3-[4-(morpholino-1-yl)-3-nitrophenyl]acrylate, ethyl (E)-3-[3-cyano-4-(morpholino-1-yl)phenyl]acrylates, ethyl (E)-3-[2-(morpholino-1-yl)-5-nitrophenyl]acrylate, ethyl (E)-3-[5-(morpholino-1-yl)-4-nirtofuryl-2-yl]acrylates, and their analogues, which would be used as intermediates of aurora 2 kinase inhibitors ,etc. has been developed starting from readily available nitro- or cyano-group-activated haloaromatic aldehydes, secondary amines, quaternary phosphonium salts, and sodium hydroxide, using water as a solvent, with high stereoselectivity and in moderate to high yield. The noteworthy features of this one-pot, three-component process is highlighted by its rapid and highly efficient formation of a new C(sp²)–N bond and a new C(sp²)–C(sp²) double bond using water as a simple nontoxic convenient and environmentally benign solvent under metal-free mild reaction conditions.

Key words

three-component reaction - Wittig reaction - S_NAr - water

• References and Notes


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• 9 Typical Procedure for the Preparation of Compound 1 – Wittig–S_NAr Reaction To a 25 mL three-necked round-bottomed flask was added 4-fluoro-3-nitrobenzaldehyde (2b, 0.1691 g, 1.0 mmol), NaOH (0.0600 g, 1.5 mmol), (2-ethoxy-2-oxoethyl)triphenylphosphonium bromide (4a, 0.6440 g, 1.5 mmol), piperidine (3b, 0.2968 mL, 3.0 mmol), and H₂O (5 mL), then heated to 50 °C. The reaction progress was carefully monitored by TLC. After 10 min, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Ethyl (E)-3-(4-Morpholino-1-yl-3-nitrophenyl)acrylate (1a) Orange solid. HRMS: m/z calcd for C₁₅H₁₈N₂O₅ [M + H]: 307.1294; found: 307.1293. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 2.01 Hz, 1 H), 7.60–7.56 (m, 2 H), 7.09 (d, J = 8.61 Hz, 1 H), 6.36 (d, J = 15.96 Hz, 1 H), 4.25 (q, J = 7.12 Hz, 2 H), 3.85–3.82 (m, 4 H), 3.12–3.10 (m, 4 H), 1.33 (t, J = 7.13 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 166.5 (s, 1 C), 146.6 (s, 1 C), 142.0 (s, 1 C), 141.6 (s, 1 C), 132.6 (s, 1 C), 127.7 (s, 1 C), 126.0 (s, 1 C), 120.5 (s, 1 C), 118.5 (s, 1 C), 66.5 (s, 2 C), 60.6 (s, 1 C), 51.4 (s, 2 C), 14.3 (s, 1 C) ppm. Ethyl (E)-3-[3-Nitro-4-(piperidin-1-yl)phenyl]acrylate (1b) Orange solid. HRMS: m/z calcd for C₁₆H₂₀N₂O₄ [M + H]: 305.1501; found: 305.1499. ¹H NMR (400 MHz, CDCl₃): δ = 7.91 (d, J = 2.10 Hz, 1 H), 7.59–7.55 (m, 2 H), 7.08 (d, J = 12.06 Hz, 1 H), 6.33 (d, J = 15.93 Hz, 1 H), 4.26 (q, J = 7.12 Hz, 2 H), 3.12–3.09 (m, 4 H), 1.73–1.63 (m, 6 H), 1.34 (t, J = 7.13 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 166.7 (s, 1 C), 147.5 (s, 1 C), 142.1 (s, 1 C), 140.8 (s, 1 C), 132.3 (s, 1 C), 126.4 (s, 1 C), 125.7 (s, 1 C), 120.5 (s, 1 C), 117.4 (s, 1 C), 60.5 (s, 1 C), 52.2 (s, 2 C), 25.7 (s, 2 C), 23.9 (s, 1 C), 14.3 (s, 1 C) ppm. Ethyl (E)-3-[3-Nitro-4-(pyrrolidin-1-yl)phenyl]acrylate (1c) Yellow solid. HRMS: m/z calcd for C₁₅H₁₈N₂O₄ [M + H]: 291.1345; found: 291.1347. ¹H NMR (400 MHz, CDCl₃): δ = 7.88 (d, J = 2.09 Hz, 1 H), 7.57 (d, J = 15.92 Hz, 1 H),7.53 (dd, J = 8.97, 2.13 Hz, 1 H), 6.90 (d, J = 8.98 Hz, 1 H), 6.28 (d, J = 15.90 Hz, 1 H), 4.26 (q, J = 7.13 Hz, 2 H), 3.27 (t, J = 6.45 Hz, 4 H), 2.02–2.00 (m, 4 H), 1.34 (t, J = 7.13 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 167.1 (s, 1 C), 143.4 (s, 1 C), 142.6 (s, 1 C), 136.7 (s, 1 C), 131.6 (s, 1 C), 127.1 (s, 1 C), 122.0 (s, 1 C), 116.3 (s, 1 C), 115.7 (s, 1 C), 60.4 (s, 1 C), 50.6 (s, 2 C), 25.6 (s, 2 C), 14.3 (s, 1 C) ppm.