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

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.

Key words

bicyclic compounds - α-cyano enones - double Michael addition - annulation - Nazarov reagent

• References and Notes

• 1a Kung LR, Tu CH, Shia KS, Liu HJ. Chem. Commun. 2003; 2490
• 1b Chou HH, Wu HM, Wu JD, Ly TW, Jan NW, Shia KS, Liu HJ. Org. Lett. 2008; 10: 121
• 1c Hsieh MT, Chou HH, Liu HJ, Wu HM, Ly TW, Wu YK, Shia KS. Org. Lett. 2009; 11: 1673
• 1d Hsieh MT, Liu HJ, Ly TW, Shia KS. Org. Biomol. Chem. 2009; 7: 3285
• 1e Chin CL, Liao CF, Liu HJ, Wong YC, Hsieh MT, Amancha PK, Chang CP, Shia KS. Org. Biomol. Chem. 2011; 9: 4778
• 1f Wong YC, Hsieh MT, Amancha PK, Chin CL, Liao CF, Kuo CW, Shia KS. Org. Lett. 2011; 13: 896
• 1g Hsieh MT, Shia KS, Liu HJ, Kuo SC. Org. Biomol. Chem. 2012; 10: 4609
• 1h Tu CH, Shia KS, Kuo SC, Liu HJ, Hsieh MT. Synlett 2012; 23: 1653
• 1i For an account, see: Wu YK, Ly TW, Shia KS. Curr. Org. Synth. 2010; 7: 78

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 selected recent examples, see:
• 3a Gassama A, d’Angelo J, Cavé C, Mahuteau J, Riche C. Eur. J. Org. Chem. 2000; 3165
• 3b Ling T, Chowdhury C, Kramer BA, Vong BG, Palladino MA, Theodorakis EA. J. Org. Chem. 2001; 66: 8843
• 3c Beauhaire J, Ducrot PH. Tetrahedron Lett. 2002; 43: 4637
• 3d Ghosh S, Rivas F, Fischer D, González MA, Theodorakis EA. Org. Lett. 2004; 6: 941
• 3e Nagata K, Sekishiro Y, Itoh T. Heterocycles 2007; 72: 175

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
• 5a Lavallée J.-F, Deslongchamps P. Tetrahedron Lett. 1988; 29: 5117
• 5b Lavallée J.-F, Deslongchamps P. Tetrahedron Lett. 1988; 29: 6033
• 5c Ruel R, Hogan KT, Deslongchamps P. Synlett 1990; 516
• 5d Ruel R, Deslongchamps P. Tetrahedron Lett. 1990; 28: 3961
• 5e Lavallée J.-F, Spino C, Ruel R, Hogan K, Deslongchamps P. Can. J. Chem. 1992; 70: 1406
• 5f Ruel R, Deslongchamps P. Can. J. Chem. 1992; 70: 1939
• 5g Chapdelaine D, Belzile J, Deslongchamps P. J. Org. Chem. 2002; 67: 5669
• 5h Lepage O, Stone C, Deslongchamps P. Org. Lett. 2002; 4: 1091
• 5i Yang Z, Shannon D, Truong V.-L, Deslongchamps P. Org. Lett. 2002; 4: 4693
• 5j Rouillard A, Deslongchamps P. Tetrahedron 2002; 58: 6555
• 5k Lepage O, Deslongchamps P. J. Org. Chem. 2003; 68: 2183
• 5l Guay B, Deslongchamps P. J. Org. Chem. 2003; 68: 6140
• 5m Rouillard A, Bonin MA, Deslongchamps P. Helv. Chim. Acta 2003; 86: 3730
• 5n Trudeau S, Deslongchamps P. J. Org. Chem. 2004; 69: 832
• 5o Chen L, Deslongchamps P. Can. J. Chem. 2005; 83: 728
• 5p The Deslongchamps group disclosed the first Cs₂CO₃-induced annulation of a bicyclic α-cyano enone with modified Nazarov reagents in their synthetic endeavor toward quassinoids, see: Caron P.-Y, Deslongchamps P. Org. Lett. 2010; 12: 508

For selected recent examples, see:
• 6a Hoashi Y, Yabuta T, Takemoto Y. Tetrahedron Lett. 2004; 45: 9185
• 6b Tricotet T, Brückner R. Tetrahedron Lett. 2006; 47: 8499
• 6c Tricotet T, Brückner R. Eur. J. Org. Chem. 2007; 1069
• 6d Wei Q, Gong L.-Z. Org. Lett. 2010; 12: 1008
• 6e He P, Liu X, Shi J, Lin L, Feng X. Org. Lett. 2011; 13: 936
• 6f Petrović D, Brückner R. Org. Lett. 2011; 13: 6524
• 7a Zhang H, Reddy MS, Phoenix S, Deslongchamps P. Angew. Chem. Int. Ed. 2008; 47: 1272
• 7b Reddy MS, Zhang H, Phoenix S, Deslongchamps P. Chem. Asian J. 2009; 4: 725
• 7c Hoashi Y, Yabuta T, Yuan P, Miyabe H, Takemoto Y. Tetrahedron 2006; 62: 365
• 7d Barrero AF, Arseniyadis S, Quílez del Moral JF, Herrador MM, Rosellón A. Synlett 2005; 789
• 7e Takahata H, Yamabe K, Suzuki T, Yamazaki T. Heterocycles 1986; 24: 37
• 8 Wu YK, Ly TW, Shia KS In Advances in Organic Synthesis . Atta-ur-Rahman; Vol. 5. Bentham Science; New Jersey: 2013: 235-278
• 9a Zhu JL, Shia KS, Liu HJ. Chem. Commun. 2000; 1599
• 9b Zhu JL, Ko YC, Kuo CW, Shia KS. Synlett 2007; 1274
• 9c Zhu JL, Ko YC. Synthesis 2007; 3659
• 9d Lee FY, Zhu JL. J. Chin. Chem. Soc. 2008; 55: 659
• 9e Amancha PK, Lai YC, Liu HJ, Zhu JL. Tetrahedron 2010; 66: 871
• 9f Chu KC, Liu HJ, Zhu JL. Synlett 2010; 3061
• 9g Zhu JL, Huang PW, You RY, Lee FY, Tsao SW, Chen IC. Synthesis 2011; 715
• 9h For a Spotlight, see: Gao J.-W. Synlett 2012; 23: 317
• 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
• 12a Trost BM, Kunz RA. J. Org. Chem. 1974; 39: 2648
• 12b Enders D, Von Berg S, Jandeleit B. Org. Synth. 2002; 78: 169
• 13 Double Michael Addition Reaction; Typical Procedure for the Synthesis of Compounds 3a–i
  (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.