Synlett 2014; 25(4): 543-546
DOI: 10.1055/s-0033-1340299
letter
© Georg Thieme Verlag Stuttgart · New York

Double Michael Addition Reactions of the Nazarov Reagent with 2-Cyano-2-Cycloalkenones: An Alternative Approach to cis-Fused Bicyclic Systems

Che-Hao Tu
a   Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, R.O.C.
,
Yen-Ku Wu
a   Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, R.O.C.
,
Kak-Shan Shia
b   Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan, R.O.C.
,
Sheng-Chu Kuo
c   Graduate Institute of Pharmaceutical Chemistry, China Medical University, Taichung 40402, Taiwan, R.O.C.
,
Hsing-Jang Liu*
a   Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan, R.O.C.
,
Min-Tsang Hsieh*
d   Chinese Medicinal Research and Development Center, China Medical University Hospital, 2 Yude Road, Taichung 40447, Taiwan, R.O.C.
e   School of Pharmacy, China Medical University, Taichung 404, Taiwan, R.O.C.   Fax: +886(4)22030760   eMail: d917410@alumni.nthu.edu.tw
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Publikationsverlauf

Received: 03. Oktober 2013

Accepted after revision: 26. Oktober 2013

Publikationsdatum:
04. Dezember 2013 (online)


Abstract

A highly stereoselective annulation reaction of 2-cyano-2-cycloalkenones with the Nazarov reagent catalyzed by 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU), leading to densely functionalized bicyclic systems, is developed.

Supporting Information

 
  • References and Notes


    • For the original report, see:
    • 2a Nazarov IN, Zauyalou SI. Zh. Obshch. Khim. 1953; 23: 1703

    • For general reviews of the Nazarov reagents, see:
    • 2b Zibuck R. Methyl 3-Oxo-4-pentenoate . In Encyclopedia of Reagents for Organic Synthesis . Vol. 5. Paquette L. A., Wiley; Chichester: 1995: 3558-3559
    • 2c Kaur T. Synlett 2006; 2853
    • 2d Audran G, Brémond P, Feuerstein M, Marque SR. A, Santelli M. Tetrahedron 2013; 69: 8325

      For elegant demonstrations of a synthon for the original Nazarov reagent, see:
    • 4a Amat M, Arioli F, Pérez M, Molins E, Bosch J. Org. Lett. 2013; 15: 2470
    • 4b Benetti S, Carli S, De Risi C, Pollini GP, Veronese AC, Zanirato V. Synlett 2008; 2609
  • 8 Wu YK, Ly TW, Shia KS In Advances in Organic Synthesis . Atta-ur-Rahman; Vol. 5. Bentham Science; New Jersey: 2013: 235-278
  • 10 For the preparation of 2-cyano-2-cyclohexanones, see: Liu HJ, Zhu JL, Shia KS. Tetrahedron Lett. 1998; 39: 4183
  • 11 Liotta D, Barnum RP, Zima G, Bayer C, Kezar HS. III. J. Org. Chem. 1981; 46: 2920
  • 13 Double Michael Addition Reaction; Typical Procedure for the Synthesis of Compounds 3ai
    (4aS*,8aS*)-4a-Cyano-2-hydroxy-5-oxo-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic Acid Methyl Ester (3a)
    Under an N2 atmosphere, DBU (0.5 equiv, 0.6 mmol) was added slowly to a solution of Nazarov reagent 1 (1.5 equiv, 1.8 mmol) and cycloalkenone 2a (1.2 mmol) in anhydrous THF (0.2 M in 2a) at –78 °C. After 2 h, the reaction was quenched with H2O (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL) and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, providing a crude residue that was purified flash column chromatography (silica gel; EtOAc–hexane, 1:4) to provide the desired product 3a as a white solid; mp 115.0–116.0 °C. IR (CH2Cl2 cast): 3405 (br), 2955, 2244, 1722, 1660, 1652, 1615 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 12.36 (s, 1 H), 3.72 (s, 3 H), 2.74 (dd, J = 12.0, 4.0 Hz, 1 H), 2.71–2.62 (m, 1 H), 2.50–2.36 (m, 3 H), 2.28 (td, J = 13.2, 6.4 Hz, 1 H), 2.17–2.12 (m, 1 H), 2.02–1.96 (m, 1 H), 1.90 (dd, J = 13.2, 6.0 Hz, 1 H), 1.67 (ddt, J = 13.6, 8.0, 4.4 Hz, 1 H), 1.62–1.40 (m, 1 H). 13C NMR (CDCl3, 100 MHz): δ = 202.8 (C), 171.5 (C), 170.7 (C), 118.3 (C), 99.5 (C), 52.2 (C), 51.8 (CH3), 40.1 (CH), 37.1 (CH2), 28.6 (CH2), 26.2 (CH2), 24.0 (CH2), 23.7 (CH2). HRMS (EI): m/z calcd for C13H15NO4: 249.1001; found: 249.1002.
  • 14 Crystallographic data for compounds 3c (CCDC 870142), 3e (CCDC 870141), 3g (CCDC 870138), 3h (CCDC 870139), and 3i (CCDC 870140) have been deposited with the Cambridge Crystallographic Data Centre.
  • 15 Crystallographic data for compounds 4a (CCDC 870143), 4b (CCDC 870144), 4d (CCDC 870145), and 4f (CCDC 870146) have been deposited with the Cambridge Crystallographic Data Centre.