Stereoselective Synthesis of β-Branched Baylis-Hillman Adducts via ­Organozinc Species

Abstract

An efficient one-pot, three-component coupling reaction for the synthesis of unusual β-branched Baylis-Hillman adducts has been developed. Organozinc species CF₃CO₂ZnEt added to α,β-acetylenic ketones in a 1,4-fashion to yield allenolates, which reacted with aldehydes providing highly functionalized trisubstituted olefins in good to excellent yields with stereoselectivity.

Baylis-Hillman adducts - organozinc species - acetylenic ketones - aldehydes

References

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<A NAME="RU07405ST-13">13</A>

Typical Procedure for Reaction of α,β-Acetylenic Ketones with CF ₃ CO ₂ ZnEt and Aldehydes.
To a solution of Et₂Zn (78.5 µL, 0.75 mmol) in 2 mL CH₂Cl₂ at 0 °C was added dropwise CF₃COOH (58 µL, 0.75 mmol) slowly via syringe under N₂. After stirring for 30 min at 0 °C, aldehyde (0.5 mmol) was added, and then acetylenic ketone (0.75 mmol) was added. The mixture was stirred for 5 h at r.t. until TLC indicated complete consumption of the starting aldehyde. The reaction was quenched by sat. aq NH₄Cl and extracted with Et₂O (3 × 10 mL). The combined organic extracts was washed with brine, dried over MgSO₄ and concentrated under reduced pressure to an oil residue. The desired product was isolated by silica gel chromatography with petroleum ether-EtOAc (10:1 to 5:1). Data for compound 2a: ¹H NMR (300 MHz, CDCl₃): δ = 7.18 (d, J = 8.5 Hz, 2 H), 6.80 (d, J = 8.5 Hz, 2 H), 5.80 (t, J = 7.5 Hz, 1 H), 5.32 (d, J = 4.9 Hz, 1 H), 3.72 (s, 3 H), 2.75 (d, J = 4.9 Hz, 1 H), 2.22 (dq J = 7.5, 7.5 Hz, 2 H), 2.10 (s, 3 H), 0.99 (t, J = 7.5 Hz, 3 H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 204.63, 159.18, 142.98, 138.67, 133.96, 127.81, 113.92, 75.07, 55.31, 31.67, 22.87, 14.01 ppm. IR (neat):
ν = 3435, 2966, 2838, 1683, 1611, 1585, 1512, 1249, 1174, 1033, 837 cm^-1. HRMS (CI): m/z calcd for C₁₄H₁₉O₃ [MH⁺]: 235.1334; found: 235.1336.

<A NAME="RU07405ST-14">14</A>

Crystal data of 2f: C₁₃H₁₅NO₄, crystal system, orthorhombic; space group, Pbca; unit cell dimensions, a = 11.403 (2) Å, α = 90°; b = 8.844 (1) Å, β = 90°; c = 25.584 (4) Å, γ = 90°; volume, Z = 2580.14 (52) ų; D _cald = 1.283 g/cm³; Z = 8; µ = 0.096 mm^-1; F ₀₀₀ = 1056; full-matrix least-squares refinement on F²; final R indices [I>2σ(I)], R1 = 0.0385, wR2 = 0.0831; R indices (all data), R1 = 0.0922, wR2 = 0.0927.

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