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Site-selective Ru-catalysed saturation of unactivated arenes via directed 6π activation

10 September 2025

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On August 28, 2025, the Guangbin Dong group at the University of Chicago unveiled a new strategy for arene hydrogenation! For the first time, directed-group-controlled, site-selective saturation of unactivated arenes has been realized: under Ru catalysis, the arene adjacent to the directing group is hydrogenated with exceptional precision, tolerating 20+ sensitive functional groups—including alkenes and aryl bromides—with exclusive cis-selectivity of >20:1 and gram-scale yields, up to 85%. The method has already enabled a streamlined synthesis of the antimalarial agent cis-atovaquone (obtained in a single step from commercial starting material), providing a powerful tool for “escaping from flatland” in drug molecules.

Introduction

In modern organic synthesis, site-selective control has remained a central challenge. Strategies based on directing groups (DGs) have provided a reliable means to achieve site-selective transformations at proximate sites through non-bonding interactions between substrate substituents and reagents or catalysts. However, although this approach has been widely successful in the activation of 2π systems such as alkenes and carbonyls, as well as in the functionalization of C–H and C–C bonds, it has not yet been applied to achieve site-selective dearomatization of unactivated aromatic 6π systems.

Arene hydrogenation reactions can convert planar aromatic hydrocarbons into saturated three-dimensional cyclic structures, significantly enhancing the stereochemical complexity and introducing sp3-rich structural motifs, thereby improving the biological activity, metabolic stability, and solubility of pharmaceutical compounds. Nevertheless, current methods primarily rely on electronic or steric differences among the aromatic rings. Achieving site-selective hydrogenation of electronically and sterically unbiased benzene derivatives remains extremely challenging.

This Work

Design of Catalytic Systems

To achieve site-selective hydrogenation of arenes, the Guangbin Dong group has developed a ruthenium-catalysed arene saturation strategy that integrates a directing-group approach. This method employs di-tert-butylphosphinite as the directing group; coordination between this DG and the Ru catalyst enables highly selective hydrogenation of the adjacent arene ring (Fig. 1).
Under the optimised conditions—[Ru(p-cymene)Cl₂]₂ (5 mol %) as the catalyst, toluene/CH₃CN (3:1) as co-solvents, 50 psi H₂, 130 °C, 16 h—the model substrate undergoes hydrogenation of the targeted arene in up to 97 % yield, furnishing exclusively the cis-configured cyclohexane product with excellent stereoselectivity (Fig. 2).

Figure 1. Site-selective hydrogenation of arenes.[from Nature Catalysis]

Reaction Condition Optimization and Catalyst Characteristics

Through systematic optimization of the reaction conditions, the authors found that the uniqueness of the ruthenium catalyst and the specific reaction conditions are crucial for the successful implementation of directed hydrogenation (Fig. 2). Other transition metals (such as Rh and Pd) cannot replace the ruthenium catalyst; acetonitrile as a co-solvent has a significant impact on the reaction efficiency; the tert-butyl-substituted phosphinite directing group plays a key role in promoting the reaction, whereas the less bulky substituents (for example, isopropyl groups) are ineffective in directing the reaction.

Figure 2. Selected optimization of the reaction conditions.[from Nature Catalysis]

Key Reagent

CAS: 52462-29-0

Substrate Scope Study

This method demonstrates broad substrate scope and excellent functional-group tolerance (Fig. 3). In addition to simple phenyl group, para-, ortho- and meta-substituted arenes all gave the corresponding cis-hydrogenated products in excellent yield. A variety of functional groups—including trifluoromethyl, silyl, ketone, ester, phenyl, furyl and alkenyl—are tolerated. Notably, readily reducible functional groups such as benzyl ether, benzimidazole, nitrile, quinoline, naphthalene and aryl bromide remain intact, and the reaction retains high selectivity. The authors also examined the influence of different substituents and substitution patterns on the phenol ring (Fig. 4). They found that the C6-methyl group on the phenol with a small fluorine atom still afforded the desired products in excellent yields, and the C6-ethyl-substituted or C5, C6-disubstituted phenols also worked well. Furthermore, the strategy can be extended to α- and β-naphthol derivatives as well as to ortho furyl-substituted phenols.

Figure 3. Scope of the phenol substrates for the directed site-selective saturation.[from Nature Catalysis]

Figure 4. Additional examples for the directed site-selective saturation.[from Nature Catalysis]

Synthetic Applications

The synthetic utility of this method is fully demonstrated through three applications (Fig. 5): first, a streamlined synthesis of the cis-analogue of the antimicrobial agent atovaquone was achieved—starting from commercially available materials, the key precursor can be accessed in a single step, significantly shortening the conventional synthetic route that requires 6–9 steps; second, the reaction is scalable using normal Parr reactors, and good yields on three examples were obtained on gram scale; finally, owing to its high chemoselectivity, the method was successfully applied to the late-stage modification of two bioactive molecules—a thyroid hormone receptor inhibitor and a leukotriene B4 receptor 1 antagonist/phospholipase A2 inhibitor—selectively converting the phenyl group adjacent to the phenol OH into a cyclohexyl ring to afford sp³-enriched analogues.

Figure 5. Synthetic utilities.[from Nature Catalysis]

Conclusion

This study develops a directing group-enabled, ruthenium-catalyzed site-selective arene hydrogenation method, achieving efficient and highly selective saturation of unactivated aromatic rings. The outstanding features of this method include broad functional-group compatibility and excellent chemoselectivity, offering a powerful tool for the late-stage modification of complex bioactive molecules.

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Product Information

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References

[1]Yu, C., Yiu, L., Zhang, Z. et al. Site-selective Ru-catalysed saturation of unactivated arenes via directed 6π activation. Nat Catal 2025.

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