Azines, such as pyridines, quinolines, pyrimidines, and pyridazines, are widespread components of pharmaceuticals. Their occurrence derives from a suite of physiochemical properties that match key criteria in drug design and is tunable by varying their substituents. Developments in synthetic chemistry, therefore, directly impact these efforts, and methods that can install various groups from azine C−H bonds are particularly valuable. Furthermore, there is a growing interest in late-stage functionalization (LSF) reactions that focus on advanced candidate compounds that are often complex structures with multiple heterocycles, functional groups, and reactive sites. Because of factors such as their electron-deficient nature and the effects of the Lewis basic N atom, azine C−H functionalization reactions are often distinct from their arene counterparts, and the application of these reactions in LSF contexts is difficult. However, there have been many significant advances in azine LSF reactions, and this review will describe this progress, much of which has occurred over the past decade. It is possible to categorize these reactions as radical addition processes, metal-catalyzed C−H activation reactions, and transformations occurring via dearomatized intermediates. Substantial variation in reaction design within each category indicates both the rich reactivity of these heterocycles and the creativity of the approaches involved.

We report ad ynamic kinetic resolution (DKR) of chiral 4-pentenals by olefin hydroacylation. Ap rimary amine racemizes the aldehyde substrate via enamine formation and hydrolysis.Then, acationic rhodium catalyst promotes hydroacylation to generate a,g-disubstituted cyclopentanones with high enantio-and diastereoselectivities.Bymerging epimerization with asymmetric catalysis,chemists have developed powerful ways to convert racemic reagents into enantiopure precursors,i ncluding those used for making natural products and medicinal targets. [1] While most dynamic kinetic resolutions (DKRs) feature hydrogenation [2a-c] or acylation, [2d,e] variants that exploit CÀCb ond formation remain rare. [3] Olefin hydroacylation is an atomeconomical [4] route to ketones that achieves both C À Hb ond activation and C À Cb ond formation. [5] Herein, we disclose aDKR strategy to prepare a,g-disubstituted cyclopentanones by intramolecular hydroacylation.Thef irst kinetic resolution of an a-chiral aldehyde was fortuitously discovered by James and Young in 1983. While attempting to develop an enantioselective decarbonylation, the authors observed that 2-methyl-2-phenylpent-4-enal underwent intramolecular hydroacylation to furnish the corresponding cyclopentanone in up to 69 % ee (Figure 1a). [6a,b] Fu and Tanaka described ap arallel kinetic resolution of racemic 4-alkynals to generate am ixture of enantioenriched cyclopentenones and cyclobutanones. [6c] Most recently,W illis and co-workers disclosed ak inetic resolution of b-thio aldehydes by intermolecular alkyne hydroacylation. [6d] Aldehydes bearing either a-o rb-stereocenters undergo kinetic resolution. These early studies contributed to emerging kinetic resolutions that occur by CÀHb ond activation, [7] but the theoretical yield for the enantiopure ketone products is limited to 50 %. Despite the first resolution being reported over three decades ago,t he DKR of aldehydes by hydroacylation had yet to be achieved. In light of this challenge,w ei magined combining aldehyde racemization with formyl CÀHb ond functionalization to invent DKRs that proceed by hydroacylation. [8] Figure 1. Resolutions of chiral aldehydes by hydroacylation.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

We report ad ynamic kinetic resolution (DKR) of chiral 4-pentenals by olefin hydroacylation. Ap rimary amine racemizes the aldehyde substrate via enamine formation and hydrolysis.Then, acationic rhodium catalyst promotes hydroacylation to generate a,g-disubstituted cyclopentanones with high enantio-and diastereoselectivities. Figure 1. Resolutions of chiral aldehydes by hydroacylation. Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.