Enantioselective β-Alkylation of Aldehydes through an Organocatalyzed C–C Bond-Scission Reaction

Abstract

A novel organocatalyzed C–C bond-scission reaction of saturated aldehydes containing a suitable leaving group at the β-position was used for the in situ formation of iminium intermediates, which were then captured by nucleophiles to achieve a direct enantioselective β-alkylation of aldehydes. Within short reaction times, the corresponding β-alkylated aldehyde products were obtained in high yields (48–87%) and with excellent enantioselectivities (84–98%).

Key words

bond scission - alkylation - organocatalysis - aldehydes - ­enantioselectivity

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• 13 β-Alkylation Reaction; General Procedure A mixture of the appropriate malonate ester 8 (0.30 mmol, 3.0 equiv) and LiOH·H₂O (4.2 mg, 0.10 mmol, 1.0 equiv) in CH₂Cl₂ (0.4 mL) was stirred at r.t. for 5 min. Catalyst 4a (3.2 mg, 0.01 mmol, 10 mol%) and aldehyde 3 (0.1 mmol, 1.0 equiv) were then added, and the mixture was stirred at r.t. until the reaction was complete. The mixture was directly transferred onto a silica gel column and purified by column chromatography (hexane–EtOAc) to give the pure product 9. Diethyl [(1R)-3-Oxo-1-phenylpropyl]malonate (9a) Colorless oil; yield: 25.3 mg (87%); [α]_D ²⁴ –38.1 (c 1.0, CHCl₃; 96% ee). ¹H NMR (500 MHz, CDCl₃): δ = 9.60 (s, 1 H), 7.30–7.20 (m, 5 H), 4.21 (q, J = 7.0 Hz, 2 H), 4.03–3.99 (m, 1 H), 3.95 (q, J = 7.0 Hz, 2 H), 3.72 (d, J = 10 Hz, 1 H), 2.96–2.85 (m, 2 H), 1.26 (t, J = 7.0 Hz, 3 H), 1.00 (t, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 200.0, 168.0, 167.4, 139.8, 128.7, 128.1, 127.5, 61.8, 61.4, 57.5, 47.4, 39.5, 14.0, 13.7. The enantiomeric excess of 9a was determined by chiral-stationary-phase HPLC analysis using a ChiralPak AD-H column (80:20 hexanes–i-PrOH at 0.5 mL/min; λ = 220 nm), major enantiomer: t_R = 17.9 min; minor enantiomer: t_R = 22.3 min.
• 14 We thank one of the referees for pointing out this important aspect.