This review summarizes the latest trends and developments of isoxazole-enabled alkyne amination reactions and their applications in divergent heterocycle synthesis.

One-carbon ring expansion reaction of heteroarenes involving typical dearomative cyclopropanation has gained wide attention in the past decade because this method allows the facile synthesis of various valuable ring-expanded heterocycles. However, the related catalytic asymmetric exploration remains challenging with scarce reports. Herein, we disclose an enantioselective dearomative one-carbon ring expansion of benzofurans via vinyl cations formed by copper-catalyzed cyclization of diynes, leading to practical and atom-economic assembly of an array of valuable 2H-chromenes bearing a quaternary carbon stereocenter in generally good to excellent yields with excellent enantioselectivities (up to 96% ee). Notably, this protocol not only represents an asymmetric one-carbon ring expansion reaction of heteroarenes based on alkynes, but also constitutes an enantioselective dearomative single-atom skeletal editing of benzofurans. Additionally, this reaction also features a broad substrate scope, detailed mechanism studies strongly supported by theoretical calculations, and the biological activity of the products.

A copper-catalyzed Buchner reaction via diyne cyclization is disclosed, affording bicycle-fused cycloheptatrienes in high yields, while norcaradienes can be selectively produced by substrate control via a phenyl cyclopropanation reaction.

A copper-catalyzed intramolecular formal one-carbon insertion into esters via a cascade diyne cyclization/[1,2]-acyl shift pathway is disclosed, enabling the atom-economical and practical synthesis of various chromeno[3,4-c]pyrroles.

In contrast to ynamides, whose chemistry has been extensively explored, ynimines remain underutilized in organic synthesis despite their rich functionalities. Here we report a general strategy to access 2-imido-1,3-dienes, synthetically challenging building blocks, through the reaction of ynimines with carboxylic acids. Leveraging this transformation, we develop a three-component reaction of ynimines, carboxylic acids and electron-deficient alkenes that enables the efficient synthesis of 1-imido-3,4- trans -disubstituted cyclohex-1-enes. The sequence proceeds via regioselective hydroacyloxylation and Mumm rearrangement to generate 2-imido-1,3-dienes, which undergo Diels–Alder cycloadditions. An intramolecular variant furnishes trans -fused tricyclic architectures reminiscent of trans -Δ⁹-tetrahydrocannabinol. Chemoselective hydrolysis further converts 2-imido-1,3-dienes into 2-amido-1,3-dienes, enabling chiral squaramide-catalysed enantioselective Diels–Alder reactions to afford 1-amido-3,4- cis -disubstituted cyclohex-1-enes with high stereocontrol. Distinct concerted and stepwise cycloaddition pathways rationalize the observed stereodivergence.

Quinone methides and their aza -analogues represent the pivotal intermediates in asymmetric synthesis. However, catalytic enantioselective reactions of extended naphthalene-based analogues including naphthoquinone methides (Nap-QMs) and aza -naphthoquinone methides ( aza -Nap-QMs) remain underdeveloped and are limited to nucleophilic additions. Herein, we report an organocatalytic asymmetric [4 + 2] cycloaddition of enamides with Nap-QMs and aza -Nap-QMs, providing an efficient access to a diverse range of tricyclic phenalene derivatives bearing chiral tertiary amines with excellent remote stereocontrol. Furthermore, a CPA/Ag-catalyzed tandem cycloaddition/cyclization enables an asymmetric relay reaction, affording chiral dihydrobenzo[ e ]indoles and 1,2-dihydronaphtho[2,1- b ]furans with high enantioselectivities. This protocol not only represents the first asymmetric cycloaddition and relay cyclization of ( aza )-Nap-QMs, but also constitutes the first asymmetric synthesis of chiral dihydrophenalenes.