C−H Bonds as Ubiquitous Functionality: A General Approach to Complex Arylated Imidazoles via Regioselective Sequential Arylation of All Three C−H Bonds and Regioselective N-Alkylation Enabled by SEM-Group Transposition

Abstract

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C–H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C–H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4–C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

Total synthesis and cytotoxicity of Leucetta alkaloids

“…While this was encouraging, this meant that an exchange of imidazole N-substituents was necessary and that this had to be accomplished in a position selective manner. Fortunately, Robiette, 30 Sames 31 and more recently Knochel 17b have demonstrated that the DMAS-protecting group can be removed with a methyl group via the intermediacy of an imidazolium salt formed by reaction with methyl triflate or Meerwein’s salt. Given this encouraging precedent, the corresponding DMAS-protected 4,5-diiodoimidazole was used as a starting material.…”

Lungenkrebs: EGFR‐Inhibitoren mit hoher Wirksamkeit gegen die therapieresistente L858R/T790M/C797S‐Mutante.

“…[15] Die elektrophile Bromierung des geschützten Imidazols konnte unter kontrollierten Bedingungen und in hohen Ausbeuten in MeCN mit NBS erreicht werden. Kommerziell erhältliches 4-Fluoracetophenon wurde in a-Stellung bromiert (6)u nd mit S-Methylthiopseudoharnstoff cyclisiert und ergab das Imidazol 7 in moderaten Ausbeuten.…”

Biaryl Synthesis through Metal‐Catalyzed C–H Arylation

“…Murai and Shibahara [123] also synthesized this target via sequential C-H arylation from a simple imidazole using their robust catalyst, [Pd(phen) 2 ](PF 6 ) 2 . Sames [125] also reported multiple arylations of simple imidazoles using his own catalytic system.…”