Nickel-Mediated Photoreductive Cross Coupling of Carboxylic Acid Derivatives for Ketone Synthesis

Abstract

A simple photochemical, nickel-catalyzed synthesis of ketones starting from carboxylic acids is presented. Hantzsch-ester (HE) functions as a cheap, green and strong photoreductant upon visible-light excitation to facilitate radical generation and also engages in the Ni-catalytic cycle to restore the reactive species. With this dual role, HE allows for the coupling of a large variety of radicals (1°,2°, benzylic, α-oxy & α-amino) with aroyl and alkanoyl moieties, a new feature in the synthesis of ketones through dual nickel photoredox catalysis. With both precursors deriving from abundant carboxylic acids, this protocol is a welcome addition to the organic chemistry toolbox. The reaction proceeds under mild conditions without the need for toxic metal reagents or bases and shows a wide scope, including pharmaceuticals and complex molecular architectures.

A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry

“…Recent studies have proposed that, when used in excess (2 equiv), photoexcited Hantzsch ester [E red (HE*/HE •+ ) = −2.28 V vs SCE in DMF] 68 reduces NHP esters (2 equiv) and Ni I (10 mol %) [E red (Ni I /Ni 0 ) = −1.17 V vs. SCE in THF] 69 to form an alkyl radical and regenerate Ni 0 , respectively. 42,70 Under the modified conditions, where only 1.25 equiv of Hantzsch ester was used, it is unlikely that photoexcited HE reduces the NHP (1.0 equiv) and turns over Ni I (10 mol %) for multiple catalytic cycles. Based on these new conditions and insight from related experimental data and computational studies, we propose an alternative mechanism wherein Hantzsch ester behaves as a two-electron reductant proceeding via an electron−proton−electron transfer mechanism (Figure 4d).…”

Photoinduced Nickel-Catalyzed Reductive Acyl Cross-Coupling: Facile Access to All Carbon Quaternary Aliphatic Ketones

“…Here, we disclose a photoinduced nickelcatalyzed reductive acyl coupling reaction without the necessary to add photocatalyst. 52,53 A series of unactivated tertiary alkyl acids 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 o -1 o , 3 o -2 o , and 3 o -3 o unsymmetrical ketones with good functional group tolerance, which have been otherwise di cult to access. A step forward based on our previous work 50 and literature reports 31,[37][38][39]41 , this catalytic protocol largely broadens the substrate scope of non-strained tertiary acyl electrophiles toward 2 o and 3 o -alkyl radicals, To the best of our knowledge, there are two isolated reports regarding the coupling of unstrained tertiary acyl electrophiles with secondary radical precursors, and in both cases, only one or two substrate examples were shown 54,55 .…”