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Modular Arene Functionalization by Differential 1,2-Diborylation

14 July 2025

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Aromatic ring compounds are the most common ring structures in small molecule drugs, and half of them have vicinal substitution patterns [1] (Figure 1a). Traditional synthesis methods for such molecules usually rely on aromatic substrates that already carry one functional group and gradually introduce the second one at the vicinal position step-by-step (Figure 1b).

Figure 1. Background

Recently, Dong Guangbin's team at the University of Chicago reported a nickel-catalyzed vicinal diborylation method that was published in Nature [2]. This method can directly install two chemically differentiated boryl groups in a regio- and site-selective manner using readily available aryl triflates or chlorides as substrates. This reaction operates under mild reaction conditions and shows a broad substrate scope and excellent functional group tolerance. Each boryl group can be independently transformed into various groups, providing an efficient modular, regioselective, and divergent approach to access diverse vicinal difunctionalized arenes, showing promise for constructing analogue libraries (Figure 2).

Figure 2. This work

Reaction innovation

For the first time, the highly selective simultaneous introduction of two different boryl groups (Bpin and Bdan) at the ortho position of aromatics was achieved, breaking through the limitations of traditional methods for differential substitution at the ortho position.

The reaction does not require directing groups or precious metals (such as palladium), uses cheap nickel catalysts, and can be scaled up to gram scale.

Reaction discovery and optimization

The authors initially adopted the Pd/NBE catalysis to realize diborylation with Bpin-Bdan as the reagent (Figure 3a). The optimal reaction conditions were determined: Ni(cod)₂/PPhCy₂ as catalyst, DABCO as base, and cyclohexane as solvent (Figure 3b). Further studies found that aromatic halides need to add triflate (such as Zn(OTf)₂ or TIPS-OTf) to effectively participate in the reaction (Figure 3c), confirming that triflate plays a key role in this Ni catalytic system.

Figure 3. Reaction discovery and optimization

Scope investigation

It is compatible with various aryl triflates and chlorides (including complex drug molecules such as estrone, acetaminophen, etc.), and tolerates sensitive functional groups such as fluorinated, ester, and pyridine (Figure 4). It is also suitable for substrates containing fused rings, heterocyclic rings (such as indole, thiophene), and free hydroxyl and carboxyl groups.

Figure 4. Scope investigation

Synthetic utility exploration

Scale-up reaction: Use cheap nickel catalyst and can be scaled up to gram scale (Figure 5a).

Modular: Through the "two-step method" to convert Bpin and Bdan separately, 1,2-difunctionalized aromatics.

Drug molecule construction: Rapidly construct a library of 2-arylpropionic acid bioactive molecules (such as AKR1C3 inhibitors), and the steps are significantly simplified compared with traditional methods (Figure 5b).

Figure 5. Synthetic utility exploration

Mechanistic studies

The combined experimental and computational mechanistic studies reveal ahighly unusual reaction pathway, involving the formation of a dearomatized gem-diboryl species and 1,2-boron migration. The site- and regioselectivity of this reaction are proposed to be controlled by steric interactions of the boryl groups with the nickel catalyst.

AmBeed Featured Product Lines

Nickel catalysts, organoboron compounds, phosphine ligands, and aryl triflates and aryl chlorides raw materials used in the above studies. At AmBeed, we offer a diverse catalog of high-purity reagents to support your research in this field:

·Nickel catalysts (100+) - widely used in the construction of C-C bonds and C-X bonds in organic synthesis, with advantages such as low cost and good selectivity.

·Boronic acids/esters (7000+) - widely used in transition metal catalytic reactions such as Suzuki coupling and Chan-Lam coupling, with mild reaction conditions and good functional group compatibility.

·Phosphine ligands (1200+) - widely used in transition metal catalytic reactions to regulate activity and selectivity through coordination between phosphorus atoms and metal centers.

·Aryl chlorides (3000+)- as important synthetic intermediates, widely used in coupling reactions and functional group transformations.

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References

[1]Sherer, E. C., Stuart, D. R. et al. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. J. Med. Chem. 2020, 63, 13389−13396.

[2]Guangbin D. et al. Modular arene functionalization by differential 1,2-diborylation. Nature, 2025.

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