A New Multicomponent Domino Transformation of 1,3-Dicarbonyl Compounds: One-Pot Regio-, Chemo- and Stereoselective Access to Valuable α,γ-Difunctionalized α-Ketoesters and Amides

Abstract

A new multi-component transformation between 1,3-dicarbonyls 1, aldehydes 2, and allylic, propargylic or benzylic halides 3 is described. It provides a regio-, chemo- and stereoselective one-pot access to α,γ-difunctionalized α-ketoesters and amides 4, bearing a quaternary center valuable for further synthetic transformations via ring-closing metathesis to give azaspiro systems found in bioactive natural products.

Key words

multi-component reaction - β-ketoesters - β-ketoamides - α,γ-difunctionalization - azaspiro derivatives

References

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20

General Experimental Procedure: To a solution of 1,3-dicarbonyl 1 (1 mmol) and DBU (3 mmol) in dry THF (8 mL) containing 10% dry MeOH in the case of β-ketoesters and MeOH alone (8 mL) in the case of β-ketoamides was added the corresponding aldehyde 2 (1 mmol) and halide 3 (2 mmol). The resulting solution was stirred under nitrogen at r.t. or under reflux for the indicated time (Table [1] ). After completion and evaporation of most of the solvent under reduced pressure, water (50 mL) was added to the oily residue. Extraction with Et₂O (3 × 40 mL) followed by successive washing with distilled water (2 × 20 mL) and brine (20 mL) gave, after drying (MgSO₄) and evaporation of the solvent, the crude compounds which were purified by flash chromatography on silica gel.

23

All new compounds showed correct mass spectra or elemental analyses (C, H, N); for example, 4d: yellow crystals, mp 52-54 °C, R_f = 0.55 (Et₂O/pentane, 30/70). IR(neat): ν = 2923, 1734, 1706, 1617, 1430, 1265 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 2.01 (m, 1 H), 2.54 (dd, broad, J = 13.6, 7.1 Hz, 1 H), 2.64 (m, 1 H), 2.86 (dd, broad, J = 13.6, 7.2 Hz, 1 H), 3.03 (m, 2 H), 3.74 (s, 3 H), 5.15 (m, 2 H), 5.73 (m, 1 H), 6.56 (dd, J = 3.4, 1.8 Hz, 1 H), 6.74 (d, J = 3.4 Hz, 1 H), 7.28 (t, J = 3.2 Hz, 1 H), 7.62 (d, J = 1.4 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.7, 29.5, 39.0, 53.0, 60.9, 113.1, 117.3, 119.3, 121.5, 132.8, 133.6, 145.8, 152.5, 171.9, 172.2, 202.8. Anal. Calcd for C₁₅H₁₆O₄: C, 69.22; H, 6.20. Found: C, 68.98; H, 6.21.