Primary-Secondary Diamine Catalyzed Enantioselective Synthesis of Substituted Cyclohex-2-enones by Cascade Michael–Aldol–­Dehydration of Ketones with Chalcones

Abstract

A simple primary-secondary diamine organocatalyst catalyzes the cascade Michael–aldol–dehydration of chalcones and unmodified ketones to produce substituted cyclohex-2-enones under mild conditions with good yields and high enantio- and/or diastereoselectivities. The success of the catalyst system is possibly due to simultaneous activation of the electrophilic chalcone by iminium formation and the nu­cleophilic ketone by enamine formation with an overall intramolecular iminium–di-enamine mechanism.

Key words

cascade reaction - chalcone - chiral cyclohex-2-enone - organocatalysis

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• 18 A mixture of chalcone 4a (0.2 mmol), acetone (3 mmol), organocatalyst 3 (0.06 mmol), 3,5-dinitrobenzoic acid (0.08 mmol) in t-BuOH (500 μL) was stirred at r.t. for 96 h. After column chromatography (eluent: 95:5, hexane–EtOAc) a white solid was obtained (40 mg, 80%). The enantiomeric excess (ee) was determined by HPLC using a Chiralcel OJ-H column (hexane–i-PrOH = 90:10); flow rate 1.0 mL/min; t _R (major) = 18.3 min, t _R (minor) = 21.3 min (ee 89%); [α]_D ²⁶ +34.8 (c 0.5, CH₂Cl₂); mp 92–93 °C. IR (KBr): 1663 (CO), 1605, 1497, 1444, 1372, 1265, 761 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 2.69–2.82 (m, 2 H, CH₂), 2.95 (ddd, = 2.4, 11.2, 17.8 Hz, 1 H, CH_A H_BCO), 3.07 (dd, J = 4.4, 17.8 Hz, CH_A H_B CO, 1 H), 3.43–3.51 (m, 1 H, PhCH), 6.52 (d, J = 1.8 Hz, 1 H, C=CH), 7.29–7.46 (m, 8 H, Ar), 7.53–7.58 (m, 2 H, Ar). ¹³C NMR (50 MHz, CDCl₃): δ = 36.2, 40.9, 43.9, 125.0, 126.1 (2 C), 126.7 (2 C), 127.0, 128.8 (3 C), 130.1, 138.3, 143.1, 158.7 (2 C), 199.2 (CO).
• 19 The structures of 6c (CCDC 1041621) and 9b (CCDC 1041622) were confirmed by single-crystal X-ray data. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.