Catalytic Aerobic Synthesis of Aromatic Ethers from Non‐Aromatic Precursors

Abstract

Aryl ethers are ubiquitous compounds and intermediates widely used in the synthesis of dyes, cosmetics, materials, fragrances, plant protection agents, stabilizers for plastics, natural products, and pharmaceuticals. [1] Within these molecules, the ether functionality confers particular properties to the aromatic ring. The ability to synthesize aryl ethers with a wide range of aliphatic and aromatic moieties represents a challenge and has thus attracted constant interest throughout the history of organic chemistry. Nevertheless, all existing methods for the preparation of aromatic ethers are based on the same reaction schemes, starting from aromatic precursors, either with a pre-existing oxygen atom (phenols) or with a pre-installed reactive functionality (Scheme 1, left). For example, aryl alkyl ethers can be prepared by nucleophilic substitution reactions of either a phenol with an aliphatic substrate (Williamson reaction), [2,3] or of an alcohol with an aromatic precursor. [4] In the same manner, other approaches have been developed more recently, such as transition-metalcatalyzed allylic O alkylation reactions of phenols, electrophilic addition reactions of phenols to alkenes, [5] coupling reactions between alcohols and aryl halides through palladium (Buchwald-Hartwig reaction) [6] or copper (Ullmann ether synthesis) [7,8] catalysis, and copper-catalyzed coupling reactions of alcohols with arylboron (Chan-Lam type coupling) [9] or arylbismuth [10] compounds, but all these approaches still require aromatic substrates. In addition, stoichiometric amounts of unwanted by-products are gener-Scheme 1. General approaches for the preparation of aryl ethers [*] Dr.

Copper- versus palladium-catalyzed aromatization of 2-(methoxycarbonyl) tetralones: synthesis of methyl 1-hydroxy-2-naphthoates

“…27 We have proposed the initial formation of the O-palladium enolate in equilibrium with the Cpalladium enolate, which evolves by β-hydride elimination to the same unsaturated α-tetralone. In fact, aromatization processes of cyclohexanones and cyclohexenones catalyzed by CuCl 2 , 28 iodine, 29 vanadium oxides 30 or Pd 31,32 have been described. Final 1,6-tautomerization of this unsaturated α-tetralone would provide the corresponding naphthol.…”

Pd-Catalyzed Synthesis of Aryl Amines via Oxidative Aromatization of Cyclic Ketones and Amines with Molecular Oxygen

“…17 Among the tested precatalysts, 22 good yields of 61 and 66% had been obtained with Pd(OAc) 2 and [(PMePh 2 ) 2 PdCl 2 ], respectively (Table 1, entries 2 and 3). However, the reaction was accompanied by the formation of undefined polymeric decomposition products.…”

“…16 This year, our groups have independently developed the first intermolecular arylation reactions of heteroatom nucleophiles with cyclic ketones. Aliphatic alcohols have been arylated with 2-cyclohexen-1-ones in a Cu-catalyzed aerobic ether synthesis, 17 and aryl amines have been accessed from nitro arenes and cyclohexanones in a Pd-catalyzed cross-dehydrogenative arylation. 18 We envisaged that an aerobic aromatization of various cyclohexanone derivatives with both primary and secondary amines would introduce a direct and atom-economic access to various aryl amines.…”

C‐3β‐Tethered Functional Cholesterol Conjugates by Nitrile Oxide Alkyne Cycloaddition (NOAC)

“…Their synthesis is non-trivial and has attracted significant interest. [15] To validate NOAC chemistry as a vehicle for the assembly of cholesterol conjugates like 21, aldehyde-functionalised aryl ether 19 was required. It is known that MK-10-promoted aryl etherification of cholesterol in CHCl 3 at 50-70°C is suited to electron-rich, but not to electron-deficient phenols.…”