Synthesis of Ethers via Reaction of Carbanions and Monoperoxyacetals

Abstract

Although transfer of electrophilic alkoxyl (“RO+”) from organic peroxides to organometallics offers a complement to traditional methods for etherification, application has been limited by constraints associated with peroxide reactivity and stability. We now demonstrate that readily prepared tetrahydropyranyl monoperoxyacetals react with sp3 and sp2 organolithium and organomagnesium reagents to furnish moderate to high yields of ethers. The method is successfully applied to the synthesis of alkyl, alkenyl, aryl, heteroaryl, and cyclopropyl ethers, mixed O,O-acetals, and S,S,O-orthoesters. In contrast to reactions of dialkyl and alkyl/silyl peroxides, the displacements of monoperoxyacetals provide no evidence for alkoxy radical intermediates. At the same time, the high yields observed for transfer of primary, secondary, or tertiary alkoxides, the latter involving attack on neopentyl oxygen, are inconsistent with an SN2 mechanism. Theoretical studies suggest a mechanism involving Lewis acid promoted insertion of organometallics into the O–O bond.

A Heteroarylamine Library: Indium‐Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines

“…2‐( n ‐Decyloxy)thiophene (7 aa) : The title compound was synthesized using the following reagents and conditions: 5 a (158 mg, 1.00 mmol), 2 a (28.5 mg, 0.250 mmol), In(NTf 2 ) 3 (23.9 mg, 25.0 μmol), PhCl (1.0 mL), 50 °C, 4 h, and was isolated by column chromatography on silica gel (hexane). Compound 7 aa has already appeared in the literature, and its spectral and analytical data are in good agreement with those reported. Accordingly, 13 C NMR data are omitted here.…”

Copper‐Catalyzed Electrophilic Etherification of Arylboronic Esters with Isoxazolidines

“…To develop electrophilic etherification of organometallic compounds, the selection of an appropriate leaving group on the oxygen atom is crucial because the electrophilic oxygen atom could also serve as the leaving group (Scheme A, etherification: 1 → 2 vs. amination: 1 → 3 ). The Dussault group reported the electrophilic etherification of an organolithium compound through cleavage of the weak oxygen−oxygen bond (Scheme B) . The Orentas group documented the electrophilic etherification of carbanion 6 (M=Li, MgBr) with 1,2‐oxazetidine 7 .…”

The Chemistry of Peresters

“…This is especially interesting as anionic attack onto the oxygen would be most closely compared to S N 2‐type attack on a neopentyl center, which is generally forbidden. Peroxyacetals, which also activate the attached peroxide towards attack on hindered oxygen atoms, have been suggested to react via insertion of organometallics (RLi, RMgX) into the peroxide bond …”

“…The acyl group of peresters provides significant and directional activation of the neighboring O‐O, enabling selective transfer of tertiary alkoxy subunits to a variety of alkyl and aryl organometallics (see Figure ); reactivity is much poorer towards stabilized carbanions . Although no mechanism has been proven, the neopentyl‐like steric buttressing around the electrophilic oxygen of a tertiary perester would seemingly disfavor in‐line S N 2‐type displacement relative to insertion into the O‐O bond, a mechanism described for analogous attack on peroxyacetals and dialkyl peroxides . Transfer of primary or secondary oxygen groups is usually precluded by the facility of base‐promoted fragmentation (see section “Reactions: Heterolytic fragmentation”).…”