K₂CO₃/NaI-Induced Cyclization of ω-Bromo α-Cyano Ketones: A New Annulation Approach for the Formation of Carbalkoxycyclohexane Ring System

Abstract

An operationally simple and highly effective annulation process, making use of ZnCl₂-catalyzed Michael addition and K₂CO₃/NaI-induced cyclization as key manipulations, has been developed to construct various bicyclic systems with a high level of functionalization valuable for further synthetic elaboration.

Key words

bicyclic compounds - α-cyano ketones - Michael addition - annulation - cyclization

• References and Notes

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• 8 Procedure for the Preparation of Lithium Enolate 9 To a stirred solution of ethyl 5-bromovalerate (0.58 mL, 3.64 mmol) in THF (4.5 mL) at –78 °C was added LDA (2 M in THF, 2.5 mL, 5.04 mmol) dropwise under nitrogen. The reaction mixture was stirred at the same temperature for 30 min, and the resulting stock solution (7 mL, 0.52 M) was used directly for subsequent 1,4-addition
• 9 5-Bromo-2-(2-cyano-3-oxocyclohexyl)pentanoic Acid Ethyl Ester (11) IR (CH₂Cl₂ cast): ν_max = 3431, 2946, 2249, 1731 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 4.23–4.14 (m, 2 H), 3.69 (d, J = 12.3 Hz, 0.4 H), 3.52 (d, J = 12.0 Hz, 0.6 H), 3.50–3.46 (m, 1 H), 3.43–3.34 (m, 2 H), 2.77–2.73 (m, 0.6 H), 2.67 (dt, J = 7.6, 3.3 Hz, 0.4 H), 2.61–2.56 (m, 1 H), 2.47–2.25 (m, 2 H), 2.21–2.01 (m, 2 H), 1.97–1.86 (m, 2 H), 1.85–1.76 (m, 2 H), 1.75–1.58 (m, 1 H), 1.29–1.20 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 200.4 (C), 199.8 (C), 172.9 (C), 172.1 (C), 116.5 (C), 115.5 (C), 61.1 (CH₂), 61.0 (CH₂), 48.2 (CH), 47.7 (CH), 47.4 (CH), 45.1 (CH), 44.2 (CH), 43.3 (CH), 40.4 (CH₂), 40.2 (CH₂), 33.1 (CH₂), 32.0 (CH₂), 30.7 (CH₂), 29.5 (CH₂), 28.7 (CH₂), 26.7 (CH₂), 26.0 (CH₂), 25.1 (CH₂), 24.5 (CH₂), 23.6 (CH₂), 14.3 (CH₃), 14.1 (CH₃). HRMS (EI): m/z calcd for C₁₄H₂₀NO₃Br: 329.0627; found: 329.0625
• 10 Gilman H, Jones RG, Woods LA. J. Org. Chem. 1952; 17: 1630
• 11 Takai K, Heathcock CH. J. Org. Chem. 1985; 50: 3247
• 12 Wojtasiewicz A, Barbasiewicz M, Makosza M. Eur. J. Org. Chem. 2010; 1885
• 13 (1S*,4aS*,8aR*)-4a-Cyano-5-oxodecahydronaphthalene-1-carboxylic Acid Ethyl Ester (19a) IR (CH₂Cl₂ cast): ν_max = 2950, 2233, 1731, 1715 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 4.10 (q, J = 7.1 Hz, 2 H), 2.78 (ddd, J = 13.4, 13.0, 7.1 Hz, 1 H), 2.61 (dt, J = 8.6, 3.1 Hz, 1 H), 2.48–2.41 (m, 2 H), 2.30–2.19 (m, 2 H), 1.98–1.83 (m, 3 H), 1.73–1.64 (m, 2 H), 1.59–1.46 (m, 3 H), 1.20 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 201.8 (C), 173.3 (C), 120.1 (C), 61.7 (CH₂), 48.9 (C), 44.8 (CH), 42.6 (CH), 38.9 (CH₂), 30.0 (CH₂), 28.4 (CH₂), 25.5 (CH₂), 21.7 (CH₂), 20.3 (CH₂), 14.1 (CH₃). HRMS (EI): m/z calcd for C₁₄H₁₉NO₃: 249.1365; found: 249.1383
• 14 (1R*,4aS*,8aR*)-4a-Cyano-5-oxodecahydro-naphthalene-1-carboxylic Acid Ethyl Ester (19b) IR (CH₂Cl₂ cast): ν_max = 2947, 2240, 1737, 1722 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 4.08 (m, 2 H), 2.81 (dt, J = 8.5, 4.1 Hz, 1 H), 2.65 (dt, J = 8.7, 4.0 Hz, 1 H), 2.49–2.38 (m, 2 H), 2.07–2.03 (m, 1 H), 1.95–1.89 (m, 2 H), 1.85–1.82 (m, 1 H), 1.80–1.75 (m, 1 H), 1.73–1.65 (m, 3 H), 1.64–1.59 (m, 1 H), 1.52–1.48 (m, 1 H), 1.19 (t, J = 7.1 Hz, 3 H). ¹³C NMR (150 MHz, CDCl₃): δ = 202.8 (C), 172.6 (C), 118.7 (C), 60.6 (CH₂), 55.1 (C), 42.9 (CH), 42.1 (CH), 36.6 (CH₂), 27.5 (CH₂), 23.9 (CH₂), 21.7 (CH₂), 20.9 (CH₂), 20.5 (CH₂), 14.0 (CH₃). HRMS (EI): m/z calcd for C₁₄H₁₉NO₃: 249.1365; found: 249.1380. Anal. Calcd for C₁₄H₁₉NO₃: C, 67.45; H, 7.68; N, 5.62. Found: C, 67.49; H, 7.67; N, 5.30
• 15 Crystallographic data have been deposited with Cambridge Crystallographic Data Centre (CCDC 845718)
• 16 To a stirred solution of 19a (10 mg, 0.04 mmol) in EtOH (5 mL) was added NaOEt (8.8 mg, 0.13 mmol) in one portion. The reaction mixture was stirred at r.t. for 2 d and quenched with H₂O (5 mL). The aqueous layer was separated and extracted with CH₂Cl₂ (3 × 5 mL). The combined organic extracts were washed with brine, dried over MgSO₄, filtered, and concentrated to give the crude residue, which was purified by flash chromatography on silica gel with EtOAc–n-hexane (1:4) to afford 19a (4.5 mg) and 19b (4.5 mg) in a combination of 90% yield
• 17 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845716)
• 18 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845720)
• 19 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845714)
• 20 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845715)
• 21 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845717)
• 22 Crystallographic data has been deposited with Cambridge Crystallographic Data Centre (CCDC 845719)