Highly Regioselective Introduction of Aryl Substituents via Asymmetric 1,4-Addition of Boronic Acids to Linear α,β,γ,δ-Unsaturated Ketones

Abstract

An efficient palladium(II)-catalyzed regioselective asymmetric 1,4-conjugate addition of arylboronic acids to linear α,β,γ,δ-unsaturated ketones is developed using phosphapalladacycle catalysts. The relevant 1,4-products were obtained exclusively with perfect regioselectivity, appreciable yields, and enantioselectivities. A wide range of dienone substrates as well as substituted arylboronic acids are tolerated in this protocol which proceeds at room temperature.

Key words

asymmetric catalysis - regioselectivity - phosphapallada­cycle - boronic acid - conjugate addition

• References and Notes


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• 13 Synthesis of Compound 3 Arylboronic acid (0.5 mmol, 5 equiv) and α,β,γ,δ-unsaturated ketone (0.1 mmol, 1 equiv) were added to a solution of catalyst (0.015 mmol, 3 mol%) in toluene (0.5 mL). K₃PO₄ (0.1 mmol, 1 equiv) was subsequently added, and the solution left to stir for 48 h. The crude adduct was then purified via silica gel chromatography (n-hexanes–EtOAc = 10:1 or n-hexanes–CH₂Cl₂ = 1:1). (R)-1,3,5-Triphenylpent-4-en-1-one (3a) Light yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 3.51 (m, 2 H, CH₂), 4.31 (m, 1 H, CHAr), 6.40 (m, 2 H), 7.18–7.56 (m, 13 H), 7.94 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 44.0, 44.6, 126.3, 126.7, 127.3, 127.8, 128.1, 128.5, 128.7, 128.7, 130.1, 132.7, 133.1, 137.2, 137.2, 143.4, 198.2. ESI-HRMS: m/z calcd for C₂₃H₂₁O [M + H]⁺: 313.1592; found: 313.1591. [α]_D 3.01 (c 0.7, CHCl₃). The er were determined via HPLC using a chiral column (Daicel Chiralpak IC), n-hexanes–i-PrOH = 98:2, 0.5 mL/min, 254 nm: t _R (major) = 22.1 min; t _R (minor) = 25.3 min. (+)-3,5-Diphenyl-1-(p-tolyl)pent-4-en-1-one (3e) Light yellow oil. ¹H NMR (500 MHz, CDCl₃): δ = 2.39 (s, 3 H, ArMe), 3.46 (m, 2 H, CH₂), 4.29 (m, 1 H, CHAr), 6.39 (m, 2 H), 7.16–7.31 (m, 12 H), 7.84 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.7, 44.0, 44.4, 126.3, 126.6, 127.2, 127.8, 127.9, 128.3, 128.5, 128.5, 128.7, 129.3, 130.0, 132.7, 134.7, 137.3, 143.4, 143.9, 197.8. ESI-HRMS: m/z calcd for C₂₄H₂₃O [M + H]⁺: 327.1749; found: 327.1744. [α]_D 0.8 (c 0.4, CH₂Cl₂). The er were determined via HPLC using a chiral column (Daicel Chiralpak IC), n-hexanes–i-PrOH = 98:2, 0.5 mL/min, 280 nm: t _R (major) = 21.4 min; t _R (minor) = 23.2 min. (+)-1,5-Diphenyl-3-(p-tolyl)pent-4-en-1-one (3n) Light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 2.31 (s, 3 H, ArMe), 3.47 (m, 2 H, CH₂), 4.26 (m, 1 H, CHAr), 6.38 (m, 2 H), 7.10–7.56 (m, 12 H), 7.94 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 21.2, 43.7, 44.7, 126.2, 127.6, 128.1, 128.4, 128.6, 129.4, 132.8, 133.0, 136.2, 137.3, 140.3, 198.4. ESI-HRMS: m/z calcd for C₂₄H₂₃O [M + H]⁺: 327.1749; found: 327.1750. [α]_D 5.2 (c 0.2, CH₂Cl₂). The er was determined via HPLC using a chiral column (Daicel Chiralpak IC), n-hexanes–i-PrOH = 99:1, 0.5 mL/min, 210 nm: t _R (major) = 26.5 min (major); t _R (minor) = 29.9 min.