Chemistry of Benzimidazoles

*Chemistry and Applications of Benzimidazole and its Derivatives*

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**12**

**15**

**Chapter 2**

**Abstract**

ligand combinations.

functionalization

**1. Introduction**

properties to emerge.

scaffold—so-called late-stage functionalization [5].

Catalytic Intermolecular

This chapter describes contemporary strategies for selective catalytic intermolecular functionalization of the benzimidazole scaffold. Functionalization at nitrogen and position C-2 is well developed employing copper, palladium, rhodium, nickel, and cobalt catalysis. Direct CH activation is the predominant approach to C-2 functionalization. Nickel-based catalysts can activate C—O bonds in conjunction with C—H activation at benzimidazole which grants access to a very broad range of phenols and enols as convenient functionalization precursors in this chemistry. The remaining carbon positions of benzimidazoles are typically functionalized via a sequential halogenation/coupling strategy to ensure selectivity. A key success factor in enabling these chemistries has been the fine-tuning of catalyst-

**Keywords:** benzimidazoles, catalysis, C—H activation, cross-coupling, late-stage

Benzimidazoles are tremendously important heterocycles in chemistry. They play a vital part in modern medicinal chemistry due to the importance of the benzimidazole as a pharmacophore in natural products and pharmaceuticals [1]. Benzimidazoles have a central role in contemporary homogeneous catalysis, particularly as ligands in metal catalysis and as a source of *N*-heterocyclic carbenes [2]. Moreover, they are important components of organic materials, e.g., optoelectronic materials [3]. Thus, the generation of a broad range of structurally diverse benzimidazoles is of paramount importance for enabling novel applications and unique

Substituted benzimidazoles are typically synthesized de novo using a range of methods [1]. This is by far the most common approach, and new methods emerge steadily [4]. However, large libraries of benzimidazoles are needed in medicinal chemistry, catalysis, and materials science in order to discover fine-tuned properties and to optimize these. Thus, de novo synthesis makes for a rather inefficient approach since the benzimidazole scaffold must be constructed for each new analogue needed. A more powerful strategy would be to start with available benzimidazoles and be able to do functionalization with desired groups directly onto the

Functionalization of

*Jørn H. Hansen and Richard Fjellaksel*

Benzimidazoles

#### **Chapter 2**
