Enantioselective α‐Etherification of Branched Aldehydes via an Oxidative Umpolung Strategy

Abstract

Saturated carbonyl compounds are, via their enolate analogues, inherently nucleophilic at the α‐position. In the presence of a benzoquinone oxidant, the polarity of the α‐position of racemic α‐branched aldehydes is inverted, allowing for an enantioselective etherification using readily available oxygen‐based nucleophiles and an amino acid‐derived primary amine catalyst. A survey of benzoquinone oxidants identified p‐fluoranil and DDQ as suitable reaction partners. p‐Fluoranil enables the preparation of α‐aryloxylated aldehydes using phenol nucleophiles in up to 91 % ee, following either a one‐step or a two‐step, one‐pot protocol. DDQ allows for a more general etherification protocol in combination with a broader range of alcohol nucleophiles with enantioselectivities up to 95 % ee. Control experiments and isolation of a key quinol intermediate supports a mechanism proceeding via an SN2 dynamic‐kinetic resolution. These studies provide the basis for an aminocatalytic umpolung concept that allows for the asymmetric construction of tertiary ethers in the α‐position of aldehydes.

Branching out: redox strategies towards the synthesis of acyclic α-tertiary ethers

“…302 Although the original method was not amenable to the synthesis of a-tertiary ethers, in 2021, the authors employed modified conditions to achieve a-aryloxylation and a-alkoxylation of a,a-disubstituted aldehydes (Scheme 77B). 303 Similar to List's report, the a-alkoxylation could be rendered enantioselective by employing readily available primary amine organocatalysts (such as diamine B). This journal is © The Royal Society of Chemistry 2022…”

Intermolecular C–O Bond Formation with Alkoxyl Radicals: Photoredox-Catalyzed α-Alkoxylation of Carbonyl Compounds

“…Also, given the harsh oxidative conditions of umpolung strategies, aldehydes are quite challenging substrates for C−H α-alkoxylation. 14 We were therefore pleased to see that Nalkoxypyridinium 8 reacted smoothly under our mild photoredox conditions to furnish α-alkoxylated aldehyde 9 in 52% yield (Scheme 3c). 15 As the formation of α-alkoxylated ketones 4 was inhibited in the presence of radical scavengers such as TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) or in the absence of either photocatalyst or light (see Table 1), we presumed that a radical process was involved.…”

“…To our delight, we found that the same reaction conditions could be applied to afford an array of functionalized α-alkoxy amides 7a – g in good yields (Scheme b). Also, given the harsh oxidative conditions of umpolung strategies, aldehydes are quite challenging substrates for C–H α-alkoxylation . We were therefore pleased to see that N -alkoxypyridinium 8 reacted smoothly under our mild photoredox conditions to furnish α-alkoxylated aldehyde 9 in 52% yield (Scheme c)…”

Formal dual C(sp2)–H cross-dehydrogenative C–O bond formation to construct highly functionalized diaryl ethers with O2

“…10–12 Disregarding the cyclization reaction, nucleophilic addition to the oxygen of CO, especially of o -quinones, to afford the C–O bond is rare and limited to sp 3 C–O formation. 11 b ,13 However, this also shed light on diaryl ether synthesis with o -quinone using nucleophilic aromatic carbon. On the other hand, copper-catalyzed aerobic oxidation of phenol into o -quinone has been developed by the Lumb group in recent years.…”