Synthesis of 1,2-Fused Bicyclic Imidazolidin-4-ones by Redox-Neutral Cyclization Reaction of Cyclic Amines and α-Ketoamides

Abstract

A redox annulation reaction of cyclic amines and α-ketoamides was developed. A variety of 1,2-fused bicyclic imidazolidin-4-ones were synthesized in moderate to good yields from cyclic amines by ­redox-neutral α-C–H functionalization.

Key words

redox annulation - cyclic amine - α-ketoamide - bicyclic imidazolidin-4-one - α-C–H functionalization

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• 8 The nitrogen-attached proton of N-alkyl-substituted α-ketoamide is less acidic than that of N-aryl-substituted α-ketoamide. The addition of acetic acid was believed to facilitate the intramolecular proton transfer of the azomethine ylide generated from the reaction of N-alkyl-substituted α-ketoamide and pyrrolidine (see ref. 4r).
• 9 Typical Procedure for the Synthesis of 3aAn oven-dried reaction vessel was charged with α-ketoamide 1a (112.6 mg, 0.5 mmol), pyrrolidine (2a) (62.0 μL, 0.75 mmol,), and toluene (1.5 mL) under argon. The vessel was sealed and heated to 130 °C for 10 h. The reaction solution was cooled to room temperature and the volatiles were removed under vacuum. Purification by flash column chromatography (petroleum ether/ethyl acetate, 8:1) afforded the desired bicyclic imidazolidin-4-one product 3a (112.7 mg, 81%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.59 (d, J = 7.0 Hz, 2 H), 7.53–7.47 (m, 2 H), 7.40–7.32 (m, 4 H), 7.31–7.24 (m, 1 H), 7.20–7.14 (m, 1 H), 5.53 (dd, J = 6.3, 3.8 Hz, 1 H), 4.55 (s, 1 H), 3.35–3.45 (m, 1 H), 2.98–2.85 (m, 1 H), 2.37–2.26 (m, 1 H), 2.06–1.79 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.6, 138.1, 137.2, 129.0, 128.5, 127.7, 126.8, 125.2, 121.2, 79.9, 70.8, 55.5, 31.4, 24.1.