Copper-Catalyzed Asymmetric Conjugate Addition to α-Alkylidene Cycloalkanones

Abstract

The asymmetric copper-catalyzed conjugate addition to α-alkylidene cycloalkanones, substituted at their terminal position with aromatic and aliphatic groups, is reported. While high enantioselectivity is reached using chiral phosphoramidite ligands, with R₃Al reagents, moderate diastereoselectivity was observed upon hydrolysis of the aluminium enolates. A Grignard reagent also react with high diastereo­selectivity.

Key words

α-alkylidene cycloalkanones - conjugate addition - copper - trialkylaluminium reagents - Grignard reagents

• References and Notes


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• 11 General Procedure In a Schlenk tube, to a solution of α-alkylidene cyclohexanone 1d (51.5 mg, 0.27 mmol), CuTc (2.5 mg, 0.013 mmol), L-2 (7.0 mg, 0.013 mmol) in Et₂O (3 mL) at –30 °C was added dropwise a solution of Me₃Al (2.0 M in heptane, 188 μL, 0.37 mmol), and the reaction was stirred for 2 h. At this point, an aliquot was taken and quenched with Ac₂O to determine the enantioselectivity. After addition of 2 mL of 1.2 M HCl in MeOH the reaction was stirred at r.t., and a saturated solution of Rochelle’s (or Seignette) salt was added (5 mL). After extraction of the aqueous phase with Et₂O, the combined organic phases were washed with brine, dried over MgSO₄, filtered, and concentrated in vacuo. GC analysis was used to determine the conversion and purification on silica gel (cyclohexane–EtOAc, 99:1) afforded 3e as colorless oil in 70% yield. Mixture of diastereomers = 3.1:1; dias indicates signals due to both. ¹H NMR (400 MHz, CDCl₃): δ = 1.14–1.23 (m, 4.5 H, 2 dias), 1.44–1.53 (m, 1.5 H, 2 dias), 1.59–1.73 (m, 3.1 H, 2 dias), 1.78–1.98 (m, 1.7 H, 2 dias), 2.15–2.38 (m, 3.1 H, 2 dias), 2.43–2.48 (m, 1 H, dia minor), 3.26–3.34 (m, 1 H, dia major), 3.47–3.53 (m, 1 H, dia minor), 6.86–6.89 (m, 2 H, 2 dias), 7.15–7.18 (m, 1 H, 2 dias). ¹³C NMR (100 MHz, CDCl₃): δ = 16.3, 20.7, 24.3, 24.9, 27.7, 28.2, 28.4, 31.9, 32.9, 34.2, 42.2, 42.3, 56.5, 57.7, 119.9, 120.6, 125.2, 125.4, 127.2, 127.5, 145.6, 146.9, 211.9, 213.3. IR (ATR): 3100, 2936, 2867, 1705, 1450, 1129, 785 cm^–1. HRMS (EI): m/z calcd for C₁₂H₁₆OS: 208.09164; found: 208.09173.
• 12 3i: Colourless oil. Mixture of diastereomers = 4.2:1. ¹H NMR (400 MHz, CD₂Cl₂): δ = 0.71 (d, J = 6.9 Hz, 1 H, dia minor), 0.81 (d, J = 6.8 Hz, 3 H, dia major), 0.85 (d, J = 6.8 Hz, 3 H, dia major), 0.90 (d, J = 6.7 Hz, 2 H, dia minor), 0.93 (d, J = 6.9 Hz, 3 H), 1.49–1.55 (m, 1.3 H, 2 dias), 1.61–1.81 (m, 4.3 H, 2 dias), 1.93–2.03 (m, 3.2 H, 2 dias), 2.05–2.13 (m, 1.9 H, 2 dias), 2.18–2.29 (m, 1.7 H, 2 dias). ¹³C NMR (100 MHz, CD₂Cl₂): δ = 13.4, 13.7, 18.3, 20.5, 21.1, 21.2, 21.3, 22.0, 24.7, 28.2, 30.4, 32.2, 38.8, 39.4, 39.6, 39.7, 52.6, 53.7, 220.0 (dia major), 221.7 (dia minor). IR (ATR): 2960, 2875, 1734, 1464, 1150 cm^–1. HRMS (EI): m/z calcd for C₁₀H₁₈O: 154.13522; found: 154.13513.
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Attempts to trap the transient enolate with allyl chloroformate to obtain a derivatizable allyl vinyl carbonate were unsuccessful. For recent leading references, see:
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