Synthesis of Unsymmetrical Methylenebisphenol Derivatives

Abstract

A simple and efficient route towards unsymmetrical methylenebisphenol derivatives is reported. This straightforward strategy avoids the use of harmful or dangerous chemicals, allowing the synthesis of highly functionalized bisphenyls with no need of protecting groups. The alkylation of the phenyl ring is selective for the para position of the hydroxyl substituent. All methylenebisphenols were obtained in a completely regioselective manner and isolated in high yields.

Key words

benzylation - phenols - regioselectivity - methylene­bisphenyls

• References and Notes

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• 14 Typical Experimental Procedure: A catalytic amount of concd H₂SO₄ (0.1 mL) was slowly added to a solution of 4 or 5 (2.0 mmol) and the desired substituted phenol (2.0 mmol) in glacial AcOH (5 mL) at r.t., and the solution was stirred at 90 °C during 2 h. The reaction mixture was then poured on ice (5 mL) and extracted with CH₂Cl₂ (3 × 10 mL). The organic layer was washed with sat. NaHCO₃, dried over MgSO₄, filtrated over silica gel and concentrated under reduced pressure to afford the pure products 3, and 6–9.
• 15 Physical Data of 5-(3-Acetyl-4-hydroxybenzyl)-2-hydroxybenzaldehyde (6): white solid; mp 130–132 °C. ¹H NMR (300.13 MHz, CDCl₃, 25 °C): δ = 12.18 (s, 1 H, OH), 10.92 (s, 1 H, OH), 9.84 (s, 1 H, CHO), 7.51 (d, ⁴ J _H–H = 2.1 Hz, 1 H, aromatic CH), 7.34 (dd, ⁴ J _H–H = 2.1 Hz, ³ J _H–H = 8.4 Hz, 1 H, aromatic CH), 7.31 (d, ⁴ J _H–H = 2.1 Hz, 1 H, aromatic CH), 7.28 (dd, ⁴ J _H–H = 2.1 Hz, ³ J _H–H = 8.4 Hz, 1 H, aromatic CH), 6.94 (d, ³ J _H–H = 8.4 Hz, 1 H, aromatic CH), 6.93 (d, ³ J _H–H = 8.4 Hz, 1 H, aromatic CH), 3.93 (s, 2 H, CH₂), 2.60 (s, 3 H, Me). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 204.3 (C=O), 196.4 (C=O), 161.0 (COH), 160.1 (COH), 137.5 (CH), 137.1 (CH), 133.1 (CH), 132.2 (C_q), 130.7 (C_q), 130.4 (CH), 120.4 (C_q), 119.5 (C_q), 118.7 (CH), 117.9 (CH), 39.6 (CH₂), 26.6 (Me). ESI–MS: m/z = 271.1 [M + H]⁺. Anal. Calcd for C₁₆H₁₄O₄: C, 71.10; H, 5.22. Found: C, 71.23; H, 5.36.
• 16 Crystal data: C₁₆H₁₄O₄, M = 270.27, triclinic, space group P-1, Z = 2, a = 6.9901(6) Å, b = 8.2805(7) Å, c = 11.7324 (9) Å, α = 93.845(4)°, β = 105.754(4)°, γ = 93.618 (4)°, V = 649.77(9) ų, yellow block with crystal size of 0.40 × 0.20 × 0.06 mm³. Of a total of 3526 reflections collected, 2959 were independent (R _int = 0.0540). Final R1 = 0.0627 [I >2σ(I)] and wR2 = 0.1607 (all data). CCDC 923073 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.