Article pubs.acs.org/joc
Tunable Diastereoselective Desymmetrization of Cyclohexadienones Triggered by Copper-Catalyzed Three-Component Coupling Reaction Raghunath Reddy Anugu and Rambabu Chegondi* CSIR-Indian Institute of Chemical Technology (CSIR-IICT), Division of Natural Product Chemistry, Hyderabad 500007, India Academy of Scientific and Innovative Research (AcSIR), New Delhi 110020, India S Supporting Information *
ABSTRACT: Catalytic tandem diastereoselective desymmetrization of cyclohexadienone-containing 1,6-enynes has been achieved through copper-catalyzed [3 + 2]-cycloaddition followed by ketenimine formation and subsequent intramolecular conjugate addition. The cascade reaction provides cis-hydrobenzofurans in good yields with excellent diastereoselectivity. The exo- or endo-selectivity of bicyclic scaffolds depends on the selection of the base in the reaction. In addition, N-tethered bicyclic products further transformed into tricyclic compounds via intramolecular Michael addition.
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INTRODUCTION Tether-mediated desymmetrization of symmetric molecules is one of the powerful tools en route to efficient diastereo- and enantioselective syntheses of biologically active complex targets.1 In this context, a number of efficient synthetic methods have been developed for the desymmetrization of meso-cyclohexa-2,5dienones2 which are readily prepared from the oxidative dearomatization of the corresponding phenolic precursors.3 In the past decade, Hayashi et al. and Gaunt et al. developed a highly enantioselective desymmetrization strategy via an organocatalytic intramolecular Michael reaction (Scheme 1a).4 Recently, many research groups reported transition-metal-catalyzed desymmetrization of cyclohexadienones (Scheme 1b).5−7 Very recently, our group demonstrated the palladium-catalyzed regioselective domino cyclization of alkyne-tethered cyclohexadienones using boronic acids.8 Transition-metal-catalyzed multicomponent reactions (MCR) have been found to be an attractive synthetic strategy and have gained considerable attention in drug discovery due to rapid access to complex molecules in a single operation.9 In the past decade, Chang et al. developed highly efficient synthesis of N-sulfonylimidates by a copper catalyzed three-component coupling of sulfonyl azides, terminal alkynes, and alcohols.10 In 2010, the same research group extended the scope of the above reaction to four-component coupling by addition of nitrostyrenes via the Michael reaction, which is limited to arylacetylenes.11 During our continuous efforts in exploring the desymmetrization of C2-symmetric molecules,8,12 we envisioned that coppercatalyzed three-component coupling/conjugate addition reaction of alkyne-tethered cyclohexadienones would provide a potential route for the synthesis of cis-hydrobenzofurans (Scheme 1c). © 2017 American Chemical Society
Scheme 1. Previous and Present Desymmetrization Approaches
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RESULTS AND DISCUSSION The meso-1,6-dienyne 1a was selected as a model substrate and was reacted with tosylazide and methanol in the presence of 10 mol % CuI and Et3N in CH2Cl2 (Table 1, entry 1). Gratifyingly, the reaction proceeded to afford the required product as a mixture Received: April 19, 2017 Published: June 11, 2017 6786
DOI: 10.1021/acs.joc.7b00936 J. Org. Chem. 2017, 82, 6786−6794
Article
The Journal of Organic Chemistry Table 1. Reaction Optimizationa−c
Table 2. Copper-Catalyzed Three-Component Coupling Reaction with Na2CO3a−c
entry
catalyst
base
solvent
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
CuI CuCl [Cu(CH3CN)]4PF6 CuBr·Me2S Cu(OAc)2 Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O Cu(TFA)2·xH2O
Et3N Et3N Et3N Et3N Et3N Et3N DBU K2CO3 Na2CO3 DABCO quinine Na2CO3 Na2CO3 Na2CO3 Na2CO3 DABCO DABCO DABCO
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2CI2 THF Et2O 1,4-dioxane CH3CN THF Et2O CH3CN
82 86 71 74 80 91
