One-Pot Synthesis of 3,5-Disubstituted and Polysubstituted Phenols from Acyclic Precursors

Abstract

A new strategy for the synthesis of 3,5-disubstituted phenols is established through one-pot Robinson annulation of α,β-unsaturated ketones with α-fluoro-β-ketoesters followed by in situ dehydrofluorination and tautomerization. This method has been extended to the synthesis of polysubstituted phenols and applied in the preparation of biologically active compounds.

One-pot Fluorination and Organocatalytic Robinson Annulation for Asymmetric Synthesis of Mono- and Difluorinated Cyclohexenones

“…We have recently reported a one-pot Robinson annulation/dehydrofluorination/aromtization sequence for fluorinated phenols 2 using α-fluoro-β-ketoesters and α-fluoro-α,β-unsaturated ketones as substrates [ 24 ]. We envisioned that α-fluoro-α,β-unsaturated ketones 6 could be used for asymmetric synthesis of 4,6-difluorocyclohexanones 4 under organocatalytic conditions.…”

“…However, all of these reactions afforded 4a – c as decarboxylated products, even at low reaction temperatures (−30–0 °C). No aromatization products were observed under the reaction temperature without heating [ 24 ]. The products 4a – c were found not to be stable during the workup and rotary vapor concentration of the crude product.…”

“…As part of our recent effort on the synthesis of organofluorine compounds using α-fluoro-β-keto esters [ 23 , 24 , 25 ], we have reported a one-pot fluorination/Robinson annulation sequence for fluorinated cyclohexenones 1 ( Scheme 1 A) [ 23 ], Robinson annulation/dehydrofluorination/aromatization sequence for phenols 2 ( Scheme 1 B) [ 24 ], and pyridines [ 25 ]. We envisioned that in the presence of an organocatalyst, such as cinchona alkaloid primary amine cat-1 , the one-pot asymmetric synthesis could be developed for the preparation of monofluorocyclohexenones 3 and difluorocyclohexenones 4 ( Scheme 1 C).…”

Recent Progress in Transition‐Metal‐Free, Base‐Mediated Benzannulation Reactions for the Synthesis of a Diverse Range of Aromatic and Heteroaromatic Compounds

“…A Cs 2 CO 3 ‐mediated [3+3] cyclocondensation method for the construction of 3,5‐disubstituted phenols has recently been exploited by Zhang, Yi, and co‐workers (Scheme ) . Their treatment of readily available α,β‐unsaturated ketones 38 and α‐fluoro‐β‐ketoesters 39 with one equivalent of Cs 2 CO 3 in MeCN at 70 °C afforded a range of diversely substituted α‐hydroxybenzoates 40 in moderate‐to‐excellent yields.…”

Regioselective Multicomponent Synthesis of 2,4,6‐Trisubstituted Phenols from Fischer Alkynyl Carbene Complexes

“…[19] Some of the more representative pathways for obtaining the phenol core are illustrated in Scheme 1. These include benzannulation reactions of carbene complexes (a), [20] photochemical insertion of the CO ligand into aryl and alkenyl carbenes (b), [21] metal-catalyzed reactions using palladium (c), [22,23] copper (d), [24] rhodium (e), [25] and rhenium (f ), [26] one-pot processes involving adducts derived from the Robinson annulation (g), [27] selective nucleophilic aromatic substitution of aryl halides (h), [28] and oxidation of aryl hydrosilanes (i).…”