Palladium-Catalyzed Regioselective Synthesis of Oxygenated Biphenyls

Abstract

Palladium-catalyst-mediated Michael addition reaction of arylboronic acids to cyclohexa-2,4-dienones followed by aromatization sequence in one-pot furnished several oxygenated biphenyl derivatives. Application of the developed methodology was successfully applied to the synthesis of biphenyl natural products aucuparin and 2′-hydroxy-3,4,5-trimethoxybiphenyl.

Key words

biphenyls - cyclohexa-2,4-dienones - arylboronic acid - tandem reactions - natural products

• References and Notes

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• 21 General Procedure for the Synthesis of Biphenyl Derivatives
  Method A To a reaction vessel, arylboronic acid (3.0 equiv), cyclohexa-2,4-dienone (1.0 equiv), Pd(OAc)₂ (0.1 equiv), 2,2′-bipyridine (0.4 equiv) and THF–AcOH (3 mL, 2:1) were added. The reaction vessel was sealed and heated to 60 °C for 4 h. During this time TLC analysis indicated the disappearance of cyclohexa-2,4-dienone. The crude product was then purified by silica gel flash chromatography using EtOAc–hexanes as eluent system to give biphenyl derivatives. Method B To a reaction vessel, Pd₂(dba)₃·CHCl₃ (0.03 equiv), Ph₃P (0.06 equiv), cyclohexa-2,4-dienone (1.0 equiv), methoxy arylboronic acid (2.0 equiv), Cs₂CO₃ (1.0 equiv), and toluene (2 mL) were added. The reaction vessel was sealed and stirred at 60 °C for 4 h. After the aqueous workup, the product was extracted with CH₂Cl₂. All the organic extracts were combined, dried over Na₂SO₄, filtered, and concentrated to give a residue. The residue was either purified at this step or is diluted with dioxane (8 mL) followed by addition of 4 M HCl in dioxane (2 mL for 0.5 mmol of cyclohexa-2,4-dienone). The reaction mixture was stirred for 2 h at r.t., solvents evaporated, and the crude residue was subjected to silica gel flash chromatography using EtOAc–hexanes to give biphenyl derivatives. 4,5-Dimethoxybiphenyl-3-ol (1a) ¹H NMR (300 MHz, CDCl₃): δ = 7.59–7.51 (m, 2 H), 7.47–7.38 (m, 2 H), 7.36–7.30 (m, 1 H), 6.86 (d, J = 1.8 Hz, 1H), 6.70 (d, J = 1.8 Hz, 1 H), 5.92 (s, 1 H), 3.95 (s, 3 H), 3.93 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.4 (C), 149.4 (C), 140.9 (C), 137.5 (C), 135.0 (C), 128.6 (2 × CH), 127.2 (CH), 126.9 (2 × CH), 106.9 (CH), 103.3 (CH), 61.0 (CH₃), 55.9 (CH₃). HRMS (ESI⁺): m/z calcd for C₁₄H₁₅O₃ [M + H]: 231.1016; found: 231.1011; 3,5-Dimethoxybiphenyl-4-ol (Aucuparin, 15) ¹H NMR (300 MHz, CDCl₃): δ = 7.58–7.51 (m, 2 H), 7.46–7.37 (m, 2 H), 7.36–7.28 (m, 1 H), 6.80 (s, 2 H), 5.53 (br s, 1 H), 3.95 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 147.3 (2 × C), 141.4 (C), 134.5 (C), 132.9 (C), 128.7 (2 × CH), 126.9 (3 × CH), 104.2 (2 × CH), 56.4 (2 × CH₃). HRMS (ESI⁺): m/z calcd for C₁₄H₁₅O₃ [M + H]: 231.1016; found: 231.1010; 2′-(Benzyloxy)-4,5-dimethoxybiphenyl-3-ol (17) ¹H NMR (300 MHz, CDCl₃): δ = 7.44–7.28 (m, 7 H), 7.08–7.00 (m, 2 H), 6.82 (d, J = 1.8 Hz, 2 H), 6.76 (d, J = 1.8 Hz,1 H), 5.75 (s, 1 H), 5.08 (s, 2 H), 3.94 (s, 3 H), 3.76 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 155.6 (C), 151.6 (C), 148.8 (C), 137.1 (C), 134.6 (C), 134.5 (C), 130.9 (C), 130.8 (CH), 128.5 (CH), 128.4 (2 × CH), 127.7 (CH), 127.2 (2 × CH), 121.4 (CH), 113.5 (CH), 109.3 (CH), 106.1 (CH), 70.6 (CH₂), 61.0 (CH₃), 55.7 (CH₃). HRMS (ESI⁺): m/z calcd for C₂₁H₂₁O₄ [M + H]: 337.1434; found: 337.1434; 2′-Hydroxy-3,4,5-trimethoxy-biphenyl (19) ¹H NMR (300 MHz, CDCl₃): δ = 7.30–7.27 (m, 1 H), 7.26–7.23 (m, 1 H), 7.01–6.98 (m, 2 H), 6.65 (s, 2 H), 5.31 (s, 1 H), 3.91 (s, 3 H), 3.89 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 154.0 (2 × C), 152.4 (C), 137.7 (C), 132.4 (C), 129.9 CH), 129.2 (CH), 128.1 (C), 120.7 (CH), 115.7 (CH), 106.1 (2 × CH), 60.9 (CH₃), 56.2 (2 × CH₃). HRMS (ESI⁺): m/z calcd for C₁₅H₁₇O₄ [M + H]: 261.1121; found: 261.1120.