Brønsted Acid or Lewis Acid Catalyzed [3+3] Cycloaddition of Azomethine Imines with N-Benzyl Azomethine Ylide: A Facile Access to Bicyclic N-Heterocycles

Abstract

1,3-Dipolar cycloaddition reactions are one of the most important methods to obtain diverse heterocycles with novel skeletons. We herein report the Brønsted acid or Lewis acid catalyzed [3+3] cycloaddition of azomethine imines with nonstabilized azomethine ylide generated in situ from an N-benzyl precursor, providing a clean and facile access to diverse bicyclic N-heterocycles in moderate to good yields for further biological testing. Also, the protocol developed achieved the formation of C–C and C–N bonds simultaneously in a single step.

Key words

cycloaddition - bicyclic N-heterocycles - azomethine imines - N-benzyl azomethine ylide - TFA - Zn(OTf)₂

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• 8 General Procedure for the [3+3] Annulation Reaction of N-Benzyl-Substituted Compound 1 and Azomethine Imines 3 To a solution of azomethine imines 3 (0.02 mmol) and N-benzyl-substituted compound 1 (0.03 mmol, 1.5 equiv) at 0 °C in CH₂Cl₂ (2 mL) was added acid catalyst (0.002 mmol, 0.1 equiv), the reaction mixture was stirred in refrigerated precision water baths at 10 °C for 72 h (depending on TLC monitor), N-benzyl-substituted compound 1 (0.05 mmol, 2.5 equiv) was added during this period. After the completion of the reaction, the reaction mixture was cooled to 0 °C, and was diluted with sat. NaHCO₃ solution. The filtrate was concentrated under vacuum and purified by flash column (hexane–EtOAc, 1:9) to give the product 4.
• 9 Selected Spectral Data for Compound 4a Yield 71% for TFA-catalyzed reaction [70% yield for Zn(OTf)₂-catalyzed reaction]; white solid. ¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.27 (m, 10 H), 4.91 (d, J = 11.3 Hz, 1 H), 3.78–3.68 (m, 4 H), 3.36–3.25 (m, 1 H), 2.96–2.89 (m, 1 H), 2.84–2.75 (m, 1 H), 2.69–2.60 (m, 2 H), 2.50–2.39 (m, 1 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.35, 138.03, 137.03, 129.04, 128.75, 128.52, 128.33, 127.74, 127.52, 66.99, 61.58, 58.68, 57.61, 47.96, 30.09. IR (film): ν_max = 3029, 2924, 2844, 1695, 1602, 1494, 1453, 1410, 1328, 1280, 1129, 1065, 1027, 929, 979, 758, 100, 633, 569, 529, 498, 466 cm^–1. HRMS (MALDI): m/z calcd for C₁₉H₂₂N₃O⁺ [M + H]⁺: 308.1757; found: 308.1763.