Nickel-Mediated Aerobic C(sp2)–Nucleophile Coupling Reactions for Late-Stage Diversification of Aryl Electrophiles

In the field of medicinal chemistry, molecular diversification is a crucial step in the discovery of new drugs. However, existing catalytic methods often face challenges when dealing with complex drug molecules, as these molecules are typically more complex than simple substrates. In particular, the formation of carbon-heteroatom (C–X) bonds is an important tool for the late-stage functionalization of drug molecules, but traditional catalytic methods have limitations in reaction scope and substrate applicability. Therefore, developing a general strategy for C–X bond formation that is widely applicable to complex drug molecules is of great significance.

In recent years, nickel-catalyzed reactions have garnered attention due to their low cost and unique redox activity. Compared to palladium, nickel can generate high-valent nickel intermediates (such as Ni(III)) through single-electron redox events, enabling C–X bond formation. However, existing nickel-catalyzed reactions are often limited to activated aryl or heteroaryl halides and a narrow range of nucleophiles. To address these issues, this study proposes a new strategy based on nickel-mediated oxidative addition complexes (OACs), achieving broad C–X bond formation under simple aerobic oxidation conditions.

Source of the Paper

This paper was co-authored by Dipankar Das, Long P. Dinh, Ryan E. Smith, Dipannita Kalyani, and Christo S. Sevov, from The Ohio State University and Merck & Co. Inc. The paper was published in April 2025 in the journal Nature Synthesis, with the DOI 10.1038/s44160-024-00721-3.

Research Process and Results

1. Synthesis of Nickel Complexes and Oxidative Coupling Reactions

The study first synthesized nickel-based oxidative addition complexes (OACs) through electrochemical reduction conditions. These complexes were generated via oxidative addition reactions between inexpensive nickel precursors and aryl or heteroaryl halides. Experiments showed that the oxidative coupling of these complexes with nucleophiles under electrochemical conditions was limited, with only thiol nucleophiles yielding high yields of thioether products (2d). Other nucleophiles (such as water, pentanol, and aniline) primarily produced biaryl or demetallated by-products.

2. Exploration of the Oxidative Coupling Mechanism

Using cyclic voltammetry (CV), the authors proposed two possible reaction mechanisms: the nucleophile-first pathway and the oxidation-first pathway. The study found that nickel complexes with tridentate ligands (such as 1) preferentially follow the oxidation-first pathway, where the complex is first oxidized to form an unstable Ni(III) intermediate, which then coordinates with the nucleophile before undergoing reductive elimination. This mechanism explains why only highly reactive nucleophiles (such as thiols) can effectively participate in the reaction.

3. C–X Bond Formation Under Aerobic Oxidation Conditions

To overcome the limitations of electrochemical oxidation, the authors developed a simple aerobic oxidation method. The study found that exposing nickel complexes to air generates a high-valent (peroxo)Ni(III) intermediate, which can undergo substitution reactions with various nucleophiles (such as nitrogen, oxygen, sulfur, carbon, phosphorus, and halides) to form C–X bonds. Using electron paramagnetic resonance (EPR) spectroscopy, the authors confirmed the existence of this intermediate and further investigated its reactivity with different nucleophiles.

4. Optimization of Reaction Conditions and Substrate Scope

After optimizing the reaction conditions, the authors applied this method to a range of drug-like substrates, including aryl chlorides, heteroaryl halides, and small peptides. Through a two-step, one-pot procedure, the authors successfully achieved various C–X bond-forming reactions, such as hydroxylation, thioetherification, and amination, demonstrating the broad applicability of this method in the late-stage diversification of drug molecules.

5. High-Throughput Experimentation Validation

To further validate the generality of this method, the authors conducted high-throughput experimentation (HTE), testing reactions between various drug-like aryl halides and nucleophiles on a 5 µmol scale. The results showed high success rates for reactions such as cyanation, thioetherification, and phosphination, further proving the practical value of this method in medicinal chemistry.

Research Conclusions and Significance

This study developed a general strategy based on nickel-mediated oxidative addition complexes, achieving broad C–X bond formation under simple aerobic oxidation conditions. This method is not only applicable to traditional aryl halides but can also handle drug-like substrates, providing a new tool for the late-stage diversification of drug molecules. Additionally, this study revealed the unique mechanism of nickel complexes in oxidative coupling reactions, offering important insights for future catalyst design.

Research Highlights

1. Broad Applicability: This method is applicable to a wide range of nucleophiles and complex substrates, overcoming the limitations of traditional nickel-catalyzed reactions.
2. Simple Reaction Conditions: C–X bond formation is achieved through aerobic oxidation, avoiding complex electrochemical or photochemical conditions.
3. In-Depth Mechanistic Studies: Using techniques such as CV and EPR, the detailed mechanism of nickel complexes in oxidative coupling reactions was elucidated.
4. High-Throughput Validation: HTE experiments demonstrated the practicality and generality of this method in medicinal chemistry.

Other Valuable Information

This study also showcased the application of this method in peptide modification, particularly the rapid construction of macrocyclic peptides through C–S bond formation, providing new avenues for the development of macrocyclic peptide drugs. Additionally, the authors provided detailed experimental procedures and data analysis, facilitating the replication and extension of this method by other researchers.