Electrochemical Dearomatizing Methoxylation of Phenols and Naphthols: Synthetic and Computational Studies

• Published in: Chemistry : a European journal Vol. 30; no. 20; pp. e202303916 - n/a
• Main Authors: Tomczyk, Ireneusz, Kalek, Marcin
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 05.04.2024; Wiley Subscription Services, Inc
• Subjects: Chemistry; Chemistry, Multidisciplinary; cyclohexadienones; Density functional theory; DFT calculations; Electrochemistry; electrosynthesis; Estrone; Instrumentation; Intermediates; Oxidants; Oxidizing agents; phenol dearomatization; Phenols; Physical Sciences; reaction mechanism; Science & Technology; Substitutes; Substrates; QUINOL ETHERS; ASYMMETRIC DEAROMATIZATION; electrosynthesis; NUCLEOPHILIC ADDITIONS; DENSITY-FUNCTIONAL THERMOCHEMISTRY; cyclohexadienones; DFT calculations; DESYMMETRIZATION; FITTING BASIS-SETS; reaction mechanism; phenol dearomatization; DERIVATIVES; ANODIC-OXIDATION; CONJUGATE ADDITION
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202303916

The electrochemical oxidative dearomatizing methoxylation of phenols and naphthols was developed. It provides an alternative route for the preparation of methoxycyclohexadienones, important and versatile synthetic intermediates, that eliminates the need for stoichiometric high‐energy chemical oxidants and generates hydrogen as a sole by‐product. The reaction proceeds in a simple constant current mode, in an undivided cell, and it employs standardized instrumentation. A collection of methoxycyclohexadienones derived from various 2,4,6‐tri‐substituted phenols and 1‐substituted‐2‐naphthols was obtained in moderate to excellent yields. These include a complex derivative of estrone, as well as methoxylated dearomatized 1,1′‐bi‐2‐naphthols (BINOLs). The mechanism of the reaction was subject to profound investigations using density functional theory calculations. In particular, the reactivity of two key intermediates, phenoxyl radical and phenoxenium ion, was carefully examined. The obtained results shed light on the pathway leading to the desired product and rationalize experimentally observed selectivities regarding a side benzylic methoxylation and the preference for the functionalization at the para over the ortho position. They also uncover the structure‐selectivity relationship, inversely correlating the steric bulk of the substrate with its propensity to undergo the side‐reaction. Moreover, the loss of stereochemical information from enantiopure BINOL substrates during the reaction is rationalized by the computations. Phenols and naphthols are dearomatized to methoxycyclohexadienones under simple and robust electrochemical conditions, in a green way without chemical oxidants. The mechanism of the reaction is established using density functional theory calculations, which also explain the chemo‐ and regioselectivity for differently‐substituted substrates.