From Esters to Ketones via a Photoredox‐Assisted Reductive Acyl Cross‐Coupling Strategy

Abstract

A method was developed for ketone synthesis via a photoredox‐assisted reductive acyl cross‐coupling (PARAC) using a nickel/photoredox dual‐catalyzed cross‐electrophile coupling of two different carboxylic acid esters. A variety of aryl, 1°, 2°, 3°‐alkyl 2‐pyridyl esters can act as acyl electrophiles while N‐(acyloxy)phthalimides (NHPI esters) act as 1°, 2°, 3°‐radical precursors. Our PARAC strategy provides an alternative and reliable way to synthesize various sterically congested 3°‐3°, 3°‐2°, and aryl‐3° ketones under mild and highly unified conditions, which have been otherwise difficult to access. The combined experimental and computational studies identified a Ni0/NiI/NiIII pathway for ketone formation.

Photoinduced nickel-catalyzed reductive acyl cross-coupling: facile access to all carbon quaternary aliphatic ketones

“…14 A series of unactivated tertiary alkyl acid derived pyridin-2-yl esters can couple with primary, secondary, and tertiary radical precursors smoothly, affording a variety of sterically hindered dialkyl ketones including 3°–1°, 3°–2°, and 3°–3° unsymmetrical ketones with good functional group tolerance which have been otherwise difficult to access. As a step forward based on our previous work 12 and literature reports, 6 g ,9,10 b this catalytic protocol largely broadens the substrate scope of non-strained tertiary acyl electrophiles toward 2° and 3°-alkyl radicals. Particularly, α-tertiary amino acid derivatives are incorporated successfully to afford α-tertiary amino ketones for the first time.…”

“…encumbered 3°-1°dialkyl ketones in moderate to good yields (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Cyclic tertiary acyl electrophiles were also tolerated (7,8).…”

“…This result indicates that the acyl-Ni II species is unlikely to be involved in the catalytic cycle, which is consistent with our previous conclusion. 12 To examine the role of photoexcited HE*, fluorescence quenching experiments were performed (Scheme 3e). The Stern-Volmer relationship confirmed that neither 1a nor 2a quenched the excited HE*.…”

“…Recently, our group 12 reported a reductive acyl cross-coupling with two different carboxylic acid esters to access aryl/alkyl and dialkyl ketones in a highly chemoselective manner enabled by a dual nickel/photoredox catalyst. Despite an advance in the preparation of sterically hindered ketones, tertiary acyl electrophiles are largely limited to strained ring systems.…”

Expedient assembly of densely functionalized indanonesvianickel-catalyzed alkene hydroacylation with methyl esters

“…Accordingly, the direct conversion of the ester scaffold into other functional groups is extremely valuable in organic synthesis and late-stage functionalization of representative drugs. In clear contrast to frequently employed aldehydes and activated esters, 4 the direct cleavage of the C(acyl)–O bond of readily available and cheap methyl esters remains underdeveloped, despite their omnipresence in nature and industry. 5 The main hurdle in achieving useful reactivity is probably the non-ionizable nature and intrinsic chemical inertness of the C(acyl)–O bond arising from a favorable n O → π * CO conjugation effect (Fig.…”