Construction of All-Carbon Quaternary Stereocenters by Scandium-Catalyzed Intramolecular C–H Alkylation of Imidazoles with 1,1-Disubstituted Alkenes

Abstract

The exo-selective C–H cycloaddition of imidazoles to 1,1-disubstituted alkenes has been achieved for the first time by using half-sandwich scandium catalysts. A wide range of imidazole compounds bearing various 1,1-disubstituted aliphatic alkenes, styrenes, dienes, and enynes have been selectively converted in high yields to the corresponding bicyclic imidazole derivatives bearing β-all-carbon-substituted quaternary stereocenters. By using a chiral half-sandwich scandium catalyst, the asymmetric exo-selective cyclization has also been achieved with a high level of enantioselectivity.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…Therefore, as challenging as it seems to be, there is still a demand for applying this relevant methodology to obtain new compounds with known pharmacological properties. However, several molecules based on structural scaffolds related to important biological activities have been successfully achieved via scandium-catalyzed C-H activation [37][38][39][40][41]. Hou's group presented various studies on this theme [42,43], such as a notable work recently published in which they promoted a scandium-catalyzed intramolecular cyclization on benzimidazole substrates, via a C-H activation at the C-2 position (Scheme 2B).…”

“…Hou's group presented various studies on this theme [42,43], such as a notable work recently published in which they promoted a scandium-catalyzed intramolecular cyclization on benzimidazole substrates, via a C-H activation at the C-2 position (Scheme 2B). In this process, a scandium(III)/Cp* catalyst containing two units of an o-N,N-(dimethylamino)benzyl ligand [Sc-1] was applied, and several examples of cyclic benzimidazole compounds were obtained in excellent yields (Scheme 2C) [37]. Benzimidazole compounds bearing substituents in their C-2 position are present in several bioactive molecules.…”

Accessing C2‐Functionalized 1,3‐(Benz)azoles through Transition Metal‐Catalyzed C−H Activation

“…In 2018, Wang et al came up with a novel technique that exploited synergy between Ni and LA. Alike previously described Hou's method, [18] the group performed exo-selective annulation of benzimidazoles 25 with olefins but explored conventional NiÀ Al bimetallic synergistic catalysis for the creation of a designated β-stereocenter on 27 (Scheme 9). [19] γ-Stereocenters could be constructed with ease but the utter difficulty lied in sterically congested β-center creation as it needed much harsher and vigorous conditions.…”

“…Hou's group reported intramolecular cyclization of 4,5‐disubstituted imidazole ring 22 to prepare bicyclic imidazole 24 possessing an all‐carbon quaternary center, capitalizing on 1,1‐disubstituted alkene group present in the extended moiety (Scheme 8). [18] A half‐sandwich TBDPS‐Sc catalyst 23 was taken advantage of to perform the cycloaddition reaction in an exo ‐selective fashion. Also, trisubstituted alkenes participated in this annulation without much friction.…”

“…came up with a novel technique that exploited synergy between Ni and LA. Alike previously described Hou's method, [18] the group performed exo ‐selective annulation of benzimidazoles 25 with olefins but explored conventional Ni−Al bimetallic synergistic catalysis for the creation of a designated β ‐stereocenter on 27 (Scheme 9). [19] …”