Radical C−H Acylation of Nitrogen Heterocycles Induced by an Aerobic Oxidation of Aldehydes

Abstract

An aerobic radical approach for the synthesis of unsymmetrical heteroaryl ketones is described herein. The reaction involves cross‐dehydrogenative coupling between aldehydes and heteroaromatic bases with molecular oxygen (O2). The key aspect of the method is the generation of reactive acyl radical via homolytic activation of aldehyde C−H bond using O2 as the sole oxidant. The reaction has a good substrate scope with respect to aldehydes and functionalized nitrogen heterocycles. Based on our mechanistic studies, a radical chain pathway is suggested for the reaction. A synthetic application of the method is demonstrated in the formal synthesis of natural alkaloid (±) angustureine.

Oxidase‐Type C−H/C−H Coupling Using an Isoquinoline‐Derived Organic Photocatalyst

“…Experiments were further conducted to explore the activation of aldehyde as the target C−H bond in this compound class is much weaker than in alkanes. The O 2 itself has been reported to activate aldehydes to give acyl radicals through aldehyde auto‐oxidation [20, 27] . Therefore, O 2 may work as a direct oxidant to generate an acyl radical.…”

“…The O 2 itself has been reported to activate aldehydes to give acyl radicals through aldehyde auto-oxidation. [20,27] Therefore, O 2 may work as a direct oxidant to generate an acyl radical. A hydroacylation reaction was carried out between fumarate 6 and aldehyde 3 n in the presence of 2.…”

Oxidase‐Type C−H/C−H Coupling Using an Isoquinoline‐Derived Organic Photocatalyst

“…Our reaction conditions, namely ambient temperature and air as the oxidant, improved substantially over previous conditions which involved high temperature ( � 100 °C) and pure O 2 for a similar type of Minisci reactions between aldehydes and heterocycles. [20] In the reaction with cyclopentanecarbaldehyde (4 p), 22 % of 5 p' which originated from decarbonylation was also obtained. Similar side products were not observed or formed in a trace amount for the reactions with substrates 4 l-4 o.…”

Aldehydes: magnificent acyl equivalents for direct acylation

“…In 2017 Maiti et al developed highly regioselective Pdcatalyzed direct ortho-mono and diacylation of carbazole at C1 and C8 positions using aldehydes as acylating agents via C-H bond activation. 90 Authors prepared 20 diacylatd and 4 mono acylated derivatives in 27-94% yields by coupling various aromatic and aliphatic aldehydes with N-pyridyl carbazoles (Scheme 58A). Aromatic aldehydes bearing electron withdrawing (Cl, COOMe) at para-positions provided higher yield of diacylated products in comparison of aldehydes having electron-releasing (Me, OMe) groups.…”