Tethering for Selective Synthesis of 2,2′-Biphenols: The Acetal Method

• Published in: Chemistry : a European journal 2013-12, Vol.19 (52), p.17827-17835
• Main Authors: Masters , Kye-Simeon, Bihlmeier, Angela, Klopper, Wim, Bräse , Stefan
• Format: Article
• Language: English
• Subjects: acetals; Acetals - chemical synthesis; Acetals - chemistry; Activation analysis; aromatic substitution; biaryls; Chemistry; Cleavage; Dimerization; dioxepines; Ligands; Mathematical analysis; Molecular Structure; Oxidation-Reduction; Phenols; Phenols - chemical synthesis; Phenols - chemistry; Stereoisomerism; Strategy; Synthesis; Tethering; tethers
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201301969

2,2'‐Biphenols are a large and diverse group of compounds with exceptional properties both as ligands and bioactive agents. Traditional methods for their synthesis by oxidative dimerisation are often problematic and lead to mixtures of ortho‐ and para‐connected regioisomers. To compound these issues, an intermolecular dimerisation strategy is often inappropriate for the synthesis of heterodimers. The ‘acetal method’ provides a solution for these problems: stepwise tethering of two monomeric phenols enables heterodimer synthesis, enforces ortho regioselectivity and allows relatively facile and selective intramolecular reactions to take place. The resulting dibenzo[1,3]dioxepines have been analysed by quantum chemical calculations to obtain information about the activation barrier for ring flip between the enantiomers. Hydrolytic removal of the dioxepine acetal unit revealed the 2,2′‐biphenol target. All tied up! Oxidative dimerisation of phenols often results in regioisomeric mixtures. One solution is the use of an acetal tether to impart ortho reactivity to the hydroxyarenes in a 1:1 ratio. Cyclisation forms dibenzo[1,3]dioxepine intermediates, then cleavage of the acetal linker delivers the unmasked biphenol (see scheme).