Herein, we report a directing-group-enabled Huisgen cycloaddition of azides and alkynes for the synthesis of functionalized triazoles in which the triazene group could act as a directing group to enable this regioselective [3 + 2] cycloaddition and further replacement by diverse groups, including amino, amide, halogen, and heterocycle substituents. This method represents a general and practical synthesis of triazoles under mild reaction conditions and broad substrate scope.

A novel iridium-catalyzed hydroxyl-enabled cycloaddition of azides and alkynes has been developed. In the presence of catalytic amount (2 mol%) of [Ir(cod)Cl] 2 , the 2-alkynyl phenols would engage in a regioselective cycloaddition with various azides for rapid access to diverse triazoles, and the hydroxyl group acts as directing group to enable this reaction. The process is featured mild and biocompatible reaction condition with the achievement of brevity and diversity. Furthermore, the hydroxyl group offers ample opportunity for late-stage divergent transformations of the products.

Alkylamines are ubiquitous in pharmaceuticals, materials and agrochemicals. The Mannich reaction is a well-known three-component reaction for preparing alkylamines and has been widely used in academic research and industry. However, the nucleophilic components in this process rely on C(sp2)−H and activated C(sp3)−H bonds while the unactivated C(sp3)−H bonds involved Mannich alkylamination is a long-standing challenge. Here, we report an unprecedented multicomponent double Mannich alkylamination for both C(sp2)−H and unactivated benzylic C(sp3)−H bonds. In this process, various 3-alkylbenzofurans, formaldehyde and alkylamine hydrochlorides assemble efficiently to furnish benzofuran-fused piperidines. Mechanistic studies and density functional theory (DFT) calculations revealed a distinctive pathway that a multiple Mannich reaction and retro-Mannich reaction of benzofuran and dehydrogenation of benzylic C(sp3)−H bonds were key steps to constitute the alkylamination. This protocol furnishes a Mannich alkylamine synthesis from unusual C–H inputs to access benzofuran-fused piperidines with exceptional structural diversity, molecular complexity and drug-likeness. Therefore, this work opens a distinctive vision for the alkylamination of unactivated C(sp3)−H bonds, and provides a powerful tool in diversity-oriented synthesis (DOS) and drug discovery.

Multicomponent reactions (MCRs) are powerful tool for the construction of polyfunctional molecules in an operationally simple and atom-economic manner, and the discovery of novel MCRs requests various building blocks. Herein, triazenyl alkynes were disclosed as versatile building blocks in a multicomponent reaction with carboxylic acids, aldehydes and anilines to furnish b-amino amides with the achievement of high diastereoselectivity and structural diversity. In this process, triazenyl alkynes were bifunctional so that the alkyne moiety acts as C2 fragment and triazene serves as directing group to modulate the transition state thus achieving high diastereoselectivity, in consistence with DFT calculations. Furthermore, the triazenyl group also enables diverse late-stage transformation. This protocol opens a new vision for the discovery of building block and rational design of MCRs.

An one-pot reaction of carboxylic acids and ynol ethers for the synthesis of β-keto esters has been developed. Under promotion of Ag 2 O, various carboxylic acids and ynol ethers could transform to α-acyloxy enol esters, which undergo a following DMAP-catalyzed rearrangement to deliver β-keto esters rapidly. This method provides a direct approach to β-keto esters from carboxylic acids without any preactivation. The protocol features mild reaction conditions, broad substrate scope, and the products could be transformed to an array of compounds.