Rhodium(III)-Catalyzed Directing Group-Enabled Unsymmetrical Three-Component Diamination of Alkenes

Abstract

Substituted 1,2-diamines are common structural motifs in natural products and bioactive molecules, and their regioselective synthesis remains a pivotal challenge in organic chemistry. Herein, we report a Rh(III)-catalyzed directing group enabled unsymmetrical three- component diamination of alkenes (bearing thioether or amide directing groups), anilines, and dioxazolones for the efficient construction of 1,3-diamine derivatives. Under the optimized conditions, a broad range of anilines bearing electron-withdrawing substituents (e.g., –NO₂, –CF₃, –COOMe) are well tolerated, affording the desired products in moderate to excellent yields (61%–92%) with excellent regioselectivities (>20 : 1). Notably, anilines with electron-donating groups exhibit low reactivity, furnishing the desired products in poor yields. In contrast, the aryl ring of the thioether substrate can accommodate both electron-withdrawing and electron-donating groups without compromising reaction efficiency and selectivity. Additionally, both thioether and amide directed alkenes are compatible with the catalytic system. Mechanistic studies, including radical trapping experiments, control reactions, and high-resolution mass spectrometry analysis, reveal that the reaction proceeds through a sulfur- or amide-directed rhodacycle intermediate rather than an aziridine pathway. The directing group plays a key role in controlling both reactivity and regioselectivity by facilitating the formation of a stable five- or six-membered metallacycle intermediates. The synthetic utility of this methodology is further demonstrated by gram-scale synthesis and versatile derivatizations of the products, enabling the rapid construction of unsymmetrical diamine compound libraries. In summary, we have developed a Rh(III)-catalyzed protocol for the regioselective synthesis of unsymmetrical 1,2-diamines. This method features high regioselectivity, operational simplicity, and broad substrate scope, providing a practical and robust entry to structurally diverse diamines for applications in complex molecule synthesis and medicinal chemistry.