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-ligand combinations.
- C—H activation
- late-stage functionalization
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 . Benzimidazoles have a central role in contemporary homogeneous catalysis, particularly as ligands in metal catalysis and as a source of
Substituted benzimidazoles are typically synthesized de novo using a range of methods . This is by far the most common approach, and new methods emerge steadily . 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 scaffold—so-called late-stage functionalization .
In this chapter the current catalytic strategies and methods for the intermolecular functionalization of benzimidazoles will be presented. These are surprisingly few, which illustrates the complexity involved when trying to selectively functionalize specific positions in the scaffold (Figure 1). The current strategies to solve this problem, and thus greatly streamline the synthesis of substituted benzimidazoles, will be presented herein with selected examples appearing since around 2003. We consider only
2. Catalytic functionalization chemistry
Functionalization at nitrogen is perhaps the most straightforward. Classical bimolecular substitution can be used to alkylate in the presence of suitable bases. Nucleophilic aromatic substitutions or Ullmann couplings give rise to a number of
A selectivity issue must be mentioned for unsymmetrical benzimidazoles with a free N—H. There is a rapid tautomeric equilibrium in which the proton shuffles between the two nitrogen sites. Thus, a particular tautomer must be “locked” in advance of the functionalization by substitution in order to obtain one distinct isomer.
Shieh and co-workers have reported an effective 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed N-benzylation reaction using dibenzyl carbonate (
Buchwald et al. have reported one of the most general catalytic systems for efficient and mild
The authors propose a mechanism for this transformation initiated by
Bao et al. have reported practical copper-catalyzed methods for
2.2 Functionalization at C-2
Catalytic functionalization at position C-2 is by far the most predominant in the literature. This is likely due to the more reactive nature of this particular C—H bond as it is situated between the two electron-withdrawing nitrogen sites. Although palladium, nickel, and rhodium play the major roles in this chemistry, some examples of copper-catalyzed C-2 functionalization exist. For example, copper(II) acetate in the presence of air has been employed for oxidative couplings of benzimidazoles at C-2 . Furthermore, one exciting example of a copper(I) iodide (10 mol%)-catalyzed arylation with iodobenzene at C-2 of
2.2.1 Arylation and vinylation
An early example of palladium-catalyzed C-2 arylation by Bellina and Rossi involves the coupling of aryl iodides
The contemporary power of palladium-catalyzed coupling chemistry lies in ligand design . The size and nature of the ligand play a crucial role in determining the possible pathways, selectivity, and kinetics, and, as such, optimization of ligand structure to suit the needs of the desired coupling reaction is key to modern catalytic reaction design. The number of ligands with vast spread in electronic and steric properties for palladium catalysis available today is large and expanding rapidly. This area lies at the forefront of modern catalysis research in organic chemistry .
A major step forward from the ligandless C-2 arylation reported above is the C—H arylation of
The first Ni-catalyzed C—H arylation and vinylation at C-2 of benzimidazoles were reported by Itami et al. in 2015 . A major advance in the chemistry was the use of carbamate derivatives of phenols (
The proposed mechanism for the nickel(II)-catalyzed approach involves reduction to a nickel(0) species by action of the bisphosphines or benzimidazole to initiate a Ni(0)–Ni(II) catalytic cycle . Oxidative addition of the carbamate aryl C—O bond onto the activated Ni(0)-bisphosphine complex followed by C—H nickelation assisted by departure of the corresponding carbamic acid generates a key intermediate for reductive elimination of the product and regeneration of the active Ni(0) species .
The ability of nickel to undergo C—O activation enables the use of a range of practical and available substrates for functionalization. Wang and co-workers have recently disclosed C-2 arylations of benzimidazoles using methoxyarenes as functionalization agents in the presence of Grignard reagents . Thus, the reaction system effects tandem C—O/C—H activation with subsequent coupling. The Grignard reagent was critical in order to minimize nonproductive couplings. A major demonstration of the applicability of this method is the reaction between steroidal hormone β-estradiol methoxy derivative
C-2 vinylation with alkynes as functionalization reagents has been reported, and these reactions occur under mild conditions with nickel or cobalt complexes in the presence of phosphine ligands. In a nickel-catalyzed process reported by Nakao et al.,
In the area of catalytic C-2 alkylations, rhodium(I) and nickel(0) complexes play a major role. Rhodium(I)-catalyzed
Obtaining branched selectivity in C-2 alkylations has been one of the major challenges in this chemistry, and the above example is the only report appearing before 2017 demonstrating this. As is often the case, fine-tuned selectivity control can be a matter of discovering fine-tuned ligand properties. Thus, Tran and Ellman recently reported a rhodium(I)-catalyzed C-2 alkylation of benzimidazoles
2.3 Functionalization at C-4/C-7
Catalytic functionalizations at positions 1–3 are rather common in benzimidazoles. The activated nature of these positions makes direct functionalization chemistry feasible with a variety of catalytic systems as surveyed in Sections 2.1 and 2.2. Selective catalytic functionalization at positions 4–7 is significantly more challenging since these positions are less activated and also less chemically distinguishable from each other. Benzimidazoles that are pre-functionalized with some reactive functional group (mostly halogens), generated by de novo synthesis, are commonly used to achieve selectivity in these cases.
In order to obtain a key monomer for the construction of crystalline covalent organic frameworks (COFs), Xu et al. reported the double functionalization of 4,7-dibromobenzimidazole
A great example of the utility of benzimidazole functionalization at C-4/C-7 in medicinal chemistry was reported by Auberson et al. in 2015 . The 4-bromo-6-carbomethoxybenzimidazole
Another powerful cross-coupling transformation of aryl halides is the Buchwald-Hartwig amination. The selective formation of C—N bonds clearly has numerous applications in medicinal chemistry. De la Fuente et al. have reported Buchwald-Hartwig functionalization with
2.4 Functionalization at C-5 and C-6
Although most reported halogenated benzimidazoles are generated by de novo synthesis, in which the halogen is pre-functionalized on the starting materials used for assembling the benzimidazole scaffold, some examples exist of selective catalytic halogenations directly onto benzimidazole.
A practical and selective monobromination at C-5 has been reported by Das et al. in which sulfonic-acid functionalized silica acts as a heterogeneous acid catalyst system . With only 13 wt% catalyst in the presence of an equivalent of N-bromosuccinimide (NBS), 77% yield of 5-bromobenzimidazole
Cui et al. report a strategy for iodination at C-6 of
The strategy of bromination/Pd-catalyzed coupling has been employed for installment of various groups at positions C-5/C-6 in benzimidazoles. However, many are described only in the patent literature which often presents little information about conditions and chemical yields. Notably, this strategy has been employed for regioselective cyanation and carboxylation , alkylation (Negishi coupling) , alkynylation (Hiyama coupling) , and heteroarylation (Suzuki-Miyaura coupling) , thus demonstrating that a variety of combinations of halogens and cross-coupling chemistries are possible for synthesis of diverse benzimidazoles.
The need for new benzimidazoles with unique appendages and well-defined regioselectivity is undeniable from the viewpoints of medicinal and materials chemistry. The numerous applications, some of which are described herein, warrant further studies into the synthesis of novel analogues. This chapter has described the role of state-of-the-art catalytic chemistry in intermolecular functionalization of de novo assembled benzimidazole scaffolds. Particularly well developed are functionalizations at nitrogen and at position C-2 in the scaffold.
JHH wishes to acknowledge funding for this work through the Research Council of Norway (grant no. 275043 CasCat) and the Department of Chemistry at UiT The Arctic University of Norway. RF acknowledges the Northern Norway Regional Health Authority (grant no. SFP1196-14). The publication charges for this article have been funded by a grant from the publication fund of UiT The Arctic University of Norway.
Conflict of interest
The authors declare no conflicts of interest.