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

Che-Hao Tu; Kak-Shan Shia; Sheng-Chu Kuo; Hsing-Jang Liu; Min-Tsang Hsieh

doi:10.1055/s-0031-1290386

Synlett, Table of Contents

Synlett 2012; 23(11): 1653-1656
DOI: 10.1055/s-0031-1290386

letter

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

Che-Hao Tu

^aDepartment of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan

,

Kak-Shan Shia

^bInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan

,

Sheng-Chu Kuo

^cGraduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan

,

Hsing-Jang Liu*

^aDepartment of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan

,

Min-Tsang Hsieh*

^dChinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan, Fax: +886(4)22030760 Email: d917410@alumni.nthu.edu.tw

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Abstract

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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

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References

References and Notes

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7 Demailly G, Solladie G. J. Org. Chem. 1981; 46: 3102
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)