Modular Synthesis of α-Substituted Alkenyl Acetals by a Palladium-Catalyzed Suzuki Reaction of α-Haloalkenyl Acetals with Organoboranes

Abstract

A modular and straightforward synthetic strategy for the preparation of α-substituted alkenyl acetals has been developed. α-Haloalkenyl acetals react smoothly with (het)aryl boronic acids, aryl boronates, or B-alkyl-9-borabicyclo[3.3.1]nonanes through Pd-catalyzed Suzuki cross-coupling under mild conditions with good to high yields. This protocol features a broad substrate scope and good functional-group compatibility, and is easily scaled up.

Key words

alkenyl acetals - palladium catalysis - Suzuki reaction - cross-coupling - arylboronic acids - arylation

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• 16 (3,3-Diethoxyprop-1-en-2-yl)benzene (3a): Typical Procedure A Schlenk tube equipped with a magnetic stirrer bar was charged with Pd(OAc)₂ (0.9 mg, 0.004 mmol, 2 mol%), XPhos (3.8 mg, 0.008 mmol, 4 mol%), Cs₂CO₃ (163 mg, 0.5 mmol, 2.5 equiv), and PhB(OH)₂ (2a; 48.8 mg, 0.4 mmol, 2 equiv). The tube was then sealed with a cap and degassed by alternating vacuum evacuation and N₂ backfill. A 0.2 M solution of 2-bromo-3,3-diethoxyprop-1-ene (1a; 41.6 mg, 0.2 mmol) in 1,4-dioxane (1 mL) was added to the tube under nitrogen, and the mixture was stirred at 40 °C for 3 h. When the reaction was complete (TLC), the mixture was cooled to r.t., diluted with EtOAc (2 mL), and pushed through a plug of silica gel with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography [silica gel (300-400 mesh), EtOAc-petroleum ether (1:100)] to give a light-yellow oil; yield: 34.6 mg (84%). ¹H NMR (500 MHz, CDCl₃): δ = 7.53–7.52 (m, 2 H), 7.34–7.28 (m, 3 H), 5.56 (s, 1 H), 5.55 (s, 1 H), 5.25 (s, 1 H), 3.68–3.62 (m, 2 H), 3.58–3.52 (m, 2 H), 1.21 (t, J = 7.1 Hz, 6 H). ¹³C NMR (125 MHz, CDCl₃): δ = 144.9, 138.5, 128.1, 127.6, 126.7, 115.7, 101.8, 61.4, 15.1.