Brønsted Base Catalyzed Conjugate Addition of β-Acylvinyl Anion Equivalents to α,β-Unsaturated Ketones

Abstract

A Brønsted base catalyzed addition reaction of allyl sulfones having a diethoxyphosphoryloxy group, which are new precursors of β-acylvinyl anion equivalents, with α,β-unsaturated ketones was developed. The reaction proceeded efficiently under the influence of a phosphazene base as the catalyst. This is a rare example of a catalytic addition reaction of β-acylvinyl anion equivalents. A preliminary study on an asymmetric variant was also conducted with a chiral bis(guanidino)iminophosphorane catalyst.

Key words

Brønsted base catalysis - conjugate addition - umpolung - phosphazenes - organocatalysis - asymmetric catalysis

Publication History

Received: 27 January 2022

Accepted after revision: 16 April 2022

Accepted Manuscript online:
16 April 2022

Article published online:
09 June 2022

• References and Notes


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• 8 Diethyl (1Z)-6-Oxo-1,4,6-triphenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (1aa): Typical Procedure for the Brønsted Base Catalyzed Addition of Allyl Sulfones 1 to Chalcone Derivatives 2nChalcone (2a, 25 mg, 0.12 mmol) and a 2.0 M solution of P2-tBu in THF (5.0 μL, 0.010 mmol) were sequentially added to a solution of 1a (41 mg, 0.10 mmol) in toluene (0.50 mL), and the mixture was stirred at rt for 3 h. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (1:1)] to give a yellow oil; yield: 57 mg (0.092 mmol, 92%; dr = 55:45).nIR (ATR): 2981, 1681, 1594, 1448, 1273, 1141, 1087, 1080, 1022, 975, 744, 690 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 0.98 (td, J = 7.2, 0.6 Hz, 3 H), 1.15 (td, J = 7.2, 0.6 Hz, 3 H), 3.51 (dd, J = 17.4, 9.0 Hz, 1 H), 3.58–3.93 (m, 4 H), 3.96 (dd, J = 17.4, 4.8 Hz, 1 H), 4.43 (m, 1 H), 4.96 (dd, J = 10.8, 6.6 Hz, 1 H), 5.72 (dd, J = 10.8, 1.2 Hz, 1 H), 7.19–7.57 (m, 16 H), 7.78 (d, J = 7.2 Hz, 2 H), 7.91 (d, J = 7.2 Hz, 2 H); δ (minor diastereomer) = 0.96 (td, J = 7.2, 0.6 Hz, 3 H), 1.17 (td, J = 7.2, 0.6 Hz, 3 H), 3.58–3.93 (m, 5 H), 4.06 (dd, J = 17.4, 5.4 Hz, 1 H), 4.56 (m, 1 H), 4.92 (dd, J = 10.8, 6.6 Hz, 1 H), 5.14 (dd, J = 10.8, 1.2 Hz, 1 H), 6.96 (d, J = 7.2 Hz, 2 H), 7.14 (t, J = 7.2 Hz, 1 H), 7.19–7.57 (m, 12 H), 7.62 (t, J = 7.2 Hz, 1 H), 7.88 (d, J = 7.2 Hz, 2 H), 7.97 (d, J = 7.2 Hz, 2 H).¹³C NMR (150 MHz, CDCl₃): δ = 15.70 (d, J = 7.2 Hz), 15.75 (d, J = 7.2 Hz), 15.9 (d, J = 7.2 Hz), 39.4, 40.1, 42.0, 43.8, 64.4 (d, J = 5.7 Hz), 64.6 (d, J = 5.7 Hz), 65.7, 67.3, 107.3 (d, J = 7.2 Hz), 108.9 (d, J = 7.2 Hz), 125.9, 126.9, 127.1, 128.06, 128.08, 128.12, 128.2, 128.3, 128.37, 128.41, 128.6, 128.7, 129.3, 129.4, 129.6, 132.86, 132.94, 133.2, 133.3, 134.2, 134.3, 136.8, 136.9, 138.8, 139.1, 139.8, 141.3, 150.6 (d, J = 8.6 Hz), 151.8 (d, J = 8.7 Hz), 197.5, 197.6; ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = –6.8; δ (minor diastereomer) = –6.5; HRMS (ESI): m/z [M⁺] calcd for C₃₄H₃₅O₇PS: 618.1841; found 618.1841.
• 9 (2E)-1,4,6-Triphenylhex-2-ene-1,6-dionenTo a flask containing KF (15 mg, 0.25 mmol) was added a solution of 3aa (31 mg, 0.050 mmol) in EtOH (0.5 mL). The resulting mixture was warmed to 40 °C, stirred for 17 h, and then cooled to rt. The reaction was quenched with sat. aq NH₄Cl, and the product was extracted with CH₂Cl₂. The combined organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude mixture was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give a white solid: 13 mg (0.037 mmol, 73%); mp 139.0–141.0 °C.nIR (ATR): 3082, 3059, 3025, 2883, 1678, 1668, 1611, 1488, 1448, 1371, 1252, 1187, 1001, 748, 697 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 3.52 (dd, J = 17.4, 6.0 Hz, 1 H), 3.58 (dd, J = 17.4, 7.8 Hz, 1 H), 4.43 (ddd, J = 7.8, 7.2, 6.0 Hz, 1 H), 6.88 (dd, J = 15.0, 1.2 Hz, 1 H), 7.21 (dd, J = 15.0, 7.2 Hz, 1 H), 7.24–7.27 (m, 1 H), 7.31–7.36 (m, 4 H), 7.44 (dd, J = 7.8, 7.8 Hz, 2 H), 7.47 (dd, J = 7.8, 7.8 Hz, 2 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.85 (dd, J = 7.8, 1.8 Hz, 2 H), 7.95 (dd, J = 7.8, 1.2 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ = 44.4, 45.5, 64.1, 64.6, 109.7, 124.6, 125.7, 126.6, 127.7, 128.1, 128.2, 128.4, 128.6, 128.7, 132.5, 138.0, 142.4, 142.9, 153.1, 191.3. HRMS (ESI): m/z [M⁺] calcd for C₂₄H₂₀O₂: 340.1463; found: 340.1463.
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• 11 The pK _BH ⁺ of an achiral bis(guanidino)iminophosphorane possessing a backbone similar to (M)-5 was reported to be 26.8 in THF, see: Kolomeitsev, A. A; Koppel, I. A.; Rodima, T.; Barten, J.; Lork, E.; Röschenthaler, G.-V.; Kaljurand, I.; Kütt, A.; Koppel, I.; Mäemets, V.; Leito, I. J. Am. Chem. Soc. 2005, 127, 17656.
• 12 Diethyl (1Z)-4-Methyl-6-(1-methyl-1H-imidazol-2-yl)-6-oxo-1-phenyl-3-(phenylsulfonyl)hex-1-en-1-yl phosphate (7)nA 0.50 M solution of KHMDS in toluene (40 μL, 0.020 mmol), 1a (41 mg, 0.10 mmol), and 6 (18 mg, 0.12 mmol) were sequentially added at one-minute intervals to a solution of (M)-5·HCl (10 mg, 0.011 mmol) in toluene (1.0 mL), and the mixture was stirred for 1 h at rt. The reaction was then quenched with sat. aq NH₄Cl, and the product was extracted with EtOAc. The combined organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was initially purified by column chromatography [silica gel, hexane–EtOAc (1:2 to 1:3)] then further purified by preparative HPLC to give the major diastereomer as a yellow oil; yield: 36 mg (0.065 mmol, 65%; dr 94:6; 56% ee); [α]_D ²².⁰ +20.9 (c 1.82, CHCl₃).HPLC: DAICEL Chiralcel OD-3, 2.1 × 150 mm (hexane–i-PrOH, 85:15, 1.0 mL/min, λ = 254 nm, 30 °C): T _r = 12.7 min (major), 14.5 min (minor). IR (ATR): 2971, 1680, 1443, 1410, 1258, 1145, 1013, 980, 912, 724, 693 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ (major diastereomer) = 1.13 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 1.19 (d, J = 6.0 Hz, 3 H), 3.34–3.41 (m, 2 H), 3.69–3.74 (m, 1 H), 3.81–3.97 (m, 4 H), 3.99 (s, 3 H), 4.51 (dd, J = 10.8, 3.0 Hz, 1 H), 5.68 (d, J = 10.8 Hz, 1 H), 7.02 (s, 1 H), 7.12 (s, 1 H), 7.32–7.37 (m, 5 H), 7.51 (dd, J = 7.8, 7.8 Hz, 2 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 2 H). ¹³C NMR (150 MHz, CDCl₃): δ (major diastereomer) = 15.88 (d, J = 5.7 Hz), 15.90 (d, J = 7.2 Hz), 19.8, 28.6, 36.1, 41.7, 64.4 (d, J = 5.9 Hz), 64.6 (d, J = 5.7 Hz), 66.5, 106.5 (d, J = 7.2 Hz), 126.1, 126.9, 128.3, 128.7, 128.87, 128.93, 129.5, 133.3, 134.3, 139.0, 143.1, 152.3 (d, J = 8.7 Hz), 190.8. ³¹P NMR (243 MHz, CDCl₃): δ (major diastereomer) = 6.5; δ (minor diastereomer) = 6.6. HRMS (ESI): m/z [M⁺] calcd for C₂₇H₃₃N₂O₇PS: 560.1746; found: 560.1744.
• 13 The reaction of 1a with 2a was attempted, but 3aa was obtained in only a low enantiomeric excess (~20% ee).