Synthesis of Multifunctional 2-Aminobenzimidazoles on DNA via Iodine-Promoted Cyclization

Abstract

2-Aminobenzimidazole cores are among the most common structural components in medicinal chemistry and can be found in many biologically active molecules. Herein, we report a mild protocol for the synthesis of multifunctional 2-aminobenzimidazoles on-DNA with broad substrate scopes. The reaction conditions expand our ability to design and synthesize 2-aminobenzimidazole core-focused DNA-encoded libraries.

DNA-encoded libraries (DELs): a review of on-DNA chemistries and their output

“…A year later, Liu's team and their coworkers successfully synthesized the multifunctional 2-aminobenzimidazoles on DNA via the iodine-promoted cyclization. 74 2-Aminobenzimidazoles were synthesized through the thiourea formation and the I 2 -promoted cyclodesulfurization ( Table 6 entry 5). The conditions for the two steps were optimized with broad substrate scopes, and the average conversion achieved 73%.…”

Transition‐Metal‐Free Base‐Controlled C−N Coupling Reactions: Selective Mono Versus Diarylation of Primary Amines with 2‐Chlorobenzimidazoles

“…Benzimidazole and its derivatives are an important class of N‐heterocyclic compounds which are widely distributed in pharmaceuticals, metal ligands, polymers and materials [1] . More specifically, 2‐aminobenzimidazoles such as astemizole, [2] mizolastine [3] and oxbendazole [4] are vital structural units which demonstrate versatile biological and pharmaceutical activity [5] . In addition, these compounds have been used as ligands for organometallic compounds or materials.…”

Universal encoding of next generation DNA-encoded chemical libraries

“…[4][5][6][7][8] However, obtaining ligands for "difficult" targetse.g., protein-protein interactionsmay remain challenging when using Lipinski's rule of ve compliant single-pharmacophore DELs, displaying typically compounds consisting of two or three sets of diversity elements. [9][10][11][12] While some approaches are currently explored to create better performing single-pharmacophore DELs, for example by developing new DNA-compatible reactions, [13][14][15] adopting diverse scaffolds and building blocks, [16][17][18] or exploring different spatial building block arrangements, 10,19,20 another promising option to tackle difficult targets may be exploring larger binding surfaces. 21 This has been attempted, for instance, by generating macrocyclic DELs, 16,[22][23][24][25] but large libraries in general will require the introduction of several sets of building blocks, thereby lowering DEL library quality.…”