St. Xaviers College, Ahmedabad
Radical cross-electrophile coupling (XEC) has emerged as a powerful alternative to classical cross-coupling for C–C bond formation in drug discovery. Using single-electron transfer pathways, XEC avoids prefunctionalized reagents and expands functional group tolerance. Key advances include nickel catalysis, dual photoredox/Ni systems, electrochemical methods, and metal-free photocatalysis. These strategies enable late-stage diversification, library synthesis, and bioactive molecule modification. Challenges in scalability, selectivity, and asymmetric control remain, but progress in ligand design, green catalysis, and machine learning points to XEC as a promising frontier in medicinal chemistry.
Making carbon–carbon (C–C) bonds is one of the most important tasks in chemistry, because it allows scientists to build the frameworks of drugs and other biologically active molecules. Classical cross-coupling reactions such as the Suzuki–Miyaura, Negishi, and Stille reactions have been extremely powerful for constructing complex structures [1–3]. However, these methods usually require specially prepared organometallic reagents, can be sensitive to functional groups, and rely on expensive transition metals. These drawbacks often limit their use in medicinal chemistry, especially when modifying advanced molecules late in a synthesis.
To overcome these issues, radical cross-electrophile coupling (XEC) has emerged over the past decade as an exciting alternative. Instead of relying on two-electron processes, XEC uses single-electron transfer (SET) pathways to directly join two electrophiles, often under reductive or photocatalytic conditions. The early breakthroughs came from Weix and co-workers, who showed that nickel catalysts could couple aryl halides with alkyl halides in reductive conditions [4–6]. This was a turning point, since it avoided the need for organometallic precursors and opened the door to radical-based bond-forming strategies.
The field quickly grew with the Introduction of dual catalysis. In a landmark study, MacMillan and Doyle demonstrated that combining nickel catalysis with photoredox catalysis could enable the coupling of α-carboxyl sp³-carbons with aryl halides [7]. Around the same time, Molander and co-workers introduced redox-active esters and Katritzky salts as radical precursors, making it much easier to connect sp³ fragments relevant to drug molecules [8–11]. These developments gave chemists new ways to assemble fragments and to modify molecules late in a synthesis — exactly what is needed in medicinal chemistry.
Radical approaches also allow new types of bond disconnections. For example, Xu and co-workers used aldehyde hydrazones as radical precursors for C–H transformations [12]. Doyle’s group developed methods using catalytic chlorine radicals to directly functionalize sp³–H bonds [13],and later explained the mechanistic role of chlorine photoelimination in nickel/photoredox systems [14]. These studies illustrate how radical strategies can achieve reactivity that would be very difficult with traditional methods.
Newer approaches have pushed sustainability and simplicity. Bonciolini et al. developed a metal-free photocatalytic method that uses visible light to perform C1 homologation and alkylation of carboxylic acids with aldehydes — a mild and practical reaction with direct relevance to drug discovery [15]. Baran and co-workers pioneered electrochemical XEC, using electricity instead of stoichiometric reductants, which made the reactions greener and more scalable [16-18].
The value of XEC in medicinal chemistry is becoming clearer. Dombrowski et al. compared seven different C(sp²)–C(sp³) cross-coupling methods in library synthesis and provided guidance on which methods are most effective for pharmaceutical research [19]. Zhang et al. studied photoredox-mediated C(sp³)–C(sp²) couplings across drug-like molecules, showing how they can be applied to late-stage diversification [23]. Such studies demonstrate how methodological progress is now directly feeding into medicinal chemistry workflows.
The scope of XEC continues to expand. Aggarwal’s group developed stereocontrolled radical couplings of boronic esters [24], while Reisman and Baran applied reductive couplings in complex natural product synthesis [25]. Weix and Fu extended XEC to asymmetric couplings [26]. Meanwhile, cobalt-, copper-, and nickel-based systems have diversified the available mechanisms [28-30]. Alongside these advances, computational chemistry, high-throughput experimentation, and machine learning are helping predict reactivity and accelerate method discovery [31-33].
Taken together, these advances show that radical cross-electrophile coupling has moved beyond a niche method and is becoming a mainstream tool for C–C bond formation. For medicinal chemists, XEC offers a way to streamline syntheses, expand chemical space, and enable late-stage diversification — making it a new frontier for drug discovery. In this review, we will highlight the key methodological innovations, mechanistic insights, and applications of radical XEC in medicinal chemistry, while also discussing the challenges that remain, such as scalability, selectivity, and controlling complex mechanisms.
Here is the general reaction of XEC:
Figure 1: General reaction mechanism of XEC
Timeline of breakthroughs in Radical Cross-Electrophile Coupling (XEC)
The growth of radical cross-electrophile coupling (XEC) can be traced through several important breakthroughs that steadily expanded what the reaction can achieve. The journey began in 2010, when Weix showed that nickel catalysis could directly join two different electrophiles—aryl and alkyl halides—without needing pre-activated partners, proving the concept of reductive XEC [6]. In 2014, MacMillan and Doyle brought a major leap forward by combining photoredox and nickel catalysis, using visible light to generate radicals and thereby opening the door to a much wider range of substrates [7,8]. Soon after, Molander introduced redox-active esters as reliable radical precursors, allowing simple carboxylic acids to be converted into useful building blocks for sp³–sp² couplings [9]. Baran then advanced the field with electrochemical methods, replacing chemical reductants with electricity to make the process cleaner and more sustainable [16]. Most recently, Bonciolini and co-workers showed that even metal-free photocatalysis can drive XEC efficiently, pointing toward greener, minimal-metal systems [15]. Taken together, these milestones illustrate how quickly XEC has moved from a proof-of-concept to a powerful and versatile tool for making carbon–carbon
GENERAL MECHANISTIC OVERVIEW
Ni-Catalyzed Reductive Cycle
This mechanism involves a nickel(0) catalyst that enters a reductive catalytic cycle. It typically starts with oxidative addition (Ni? to Ni²?), then proceeds to single-electron transfer (SET) steps which generate and intercept radicals, enabling bond formation via reductive coupling.
Dual Photoredox/Ni Catalysis
A photoredox and nickel catalyst work synergistically in this process. The photoredox catalyst absorbs light and generates a radical via SET, which is then intercepted by the nickel catalyst. The nickel center facilitates subsequent bond formation steps, expanding the scope of accessible transformations.
Metal-Free Photocatalysis
In this platform, an organic photocatalyst is directly photoexcited. Upon irradiation, it generates a radical species through SET without the use of transition metals. This pathway is attractive for its sustainability and metal-free character.
Electrochemical Pathway
Electrochemistry can provide a controlled means of radical generation. Cathodic reduction at the electrode surface directly produces radical species from suitable precursors, allowing precise control of the redox environment and avoiding stoichiometric chemical reductants.
REACTION SCOPES:
Here is a comparative summary table of seven C(sp²)–C(sp³) coupling strategies based on Dombrowski et al. (2020), organized by method, scope, advantages, limitations, and drug discovery relevance, as described in the paper provided.
|
Method no. |
Method |
Scope |
Advantages |
Limitations |
Drug Discovery Relevance |
|
1. |
Suzuki(BF3K salts) |
Primary alkyl groups, broad functionality |
Reliable, good for primary alkyls, broad reagent access |
Poor for secondary/tertiary, limited diversity for some substrates |
Widely used,efficient, broad substrate base |
|
2. |
Suzuki (MIDA boronates) |
Select alkyl groups, limited reagents |
Some stable reagents, air stable |
Poor for secondary/ tertiary, limited diversity for some substrates |
Less relevant due to Narrow scope |
|
3. |
Negishi coupling |
Primary/secondary/benzylic alkyl groups |
High yield for available reagents, rebust |
Availability/ stability of organozincs, diversity limited |
Suitable for specific cases,Strong for benzylic |
|
4. |
Ni-catalyzed reductive CEC |
Primary/secondary alkyl bromides |
Broad building block access, scalable |
Poor for tertiary/benzylic/ basic amines |
High relevance, especially in flow or process |
|
5. |
Ni/photoredox BF3K coupling |
Secondary alkyl groups,α- oxo/amino |
Good for secondary / functional groups, novel applications |
Poor for primary alkyls with e-withdrawing groups/tertiary/ benzyl |
Expand chemical diversity, Growing toolbox |
|
6. |
Ni/photoredox decarboxylative coupling |
α-oxy/ α-amino acid groups |
Unique substrates, potential for SAR |
Generally low yields outside Stabilised acids, Regioisomers risks |
Useful for SAR ,novel functionalities |
|
7. |
Ni/photoredox CEC |
Primary/ secondary alkyl bromides |
General monomer scope,library amenable |
Not compatible with tertiary/ benzylic/ Basic amines |
Amenable to parallel and flow synthesis |
Method 1: Suzuki Cross-coupling (BF3K salts)
Figure:2 proposed mechanism of Suzuki Cross-Coupling (BF3K salts) [19]
Figure 3: Suzuki Cross-Coupling of cyclopropyltrifluoroborate
Method:2 Suzuki Cross-Coupling (MIDA BORONATES)
Proposed BMIDA allylation to expand scope to generating new bonds to sp3-hybridized carbons.
Reaction mechanism is same as Suzuki Cross-Coupling (BF3K salts).
Figure 4: Suzuki Cross-Coupling reaction of MIDA boronates (BMIDA allylation)[20]
Figure 5: synthesis of ibuprofen using BMIDA allylation [20]
Method 3: Negishi coupling
Reaction mechanism:
Figure 6: Proposed mechanism of Negishi coupling reaction
Figure 7: Synthesis of Indazole [21]
Method 4: Ni-Catalyzed Reductive CEC
(A)
(B)
(C)
Figure 8: (A) A model reaction , (B)The origin of cross selectivity, (C) Catalytic cycle of mechanism of Ni-Catalyzed Reductive CEC [22]
Method 5: Ni/photoredox BF3K Coupling
Figure 9: Photoredox cross-coupling as a general manifold for cross-coupling of diverse Csp3 derived radicals; proposed catalytic cycle for photoredox cross-coupling [8]
Method 6: Ni/photoredox Decarboxylative coupling
Figure 10: Proposed catalytic cycle of mechanism of Ni/photoredox Decarboxylative coupling [7]
Figure 11: (A)Amino acid coupling partners and (B) Csp3–H, C–X cross-coupling [7]
Method 7:Ni/photoredox CEC
Figure 12:Csp3–Csp3 cross-coupling reaction of alkyl bromides with Ethers (Paixão and König’s work in 2020) [27]
APPLICATIONS IN MEDICINAL CHEMISTRY
Library Synthesis
In the 2020 study by Dombrowski et al.,XEC was used to quickly make many different drug-like molecules by attaching various alkyl groups onto common starting materials called aryl halides. They used automated tools and purification techniques to speed up creating large, diverse libraries of compounds useful for drug research. XEC can work with many types of molecules, including ones with rings and nitrogen atoms, helping chemists build many new molecules for testing how changes affect activity (SAR studies).[19]
Late-Stage Diversification of Drug Scaffolds
Zhang et al. showed that XEC is useful for making changes late in the process of making complex drug molecules.They used XEC with special catalysts to add different alkyl groups onto advanced drug structures without remaking the whole molecule. This helps scientists quickly explore how changes in structure affect drug properties like solubility and stability.[23]
Real-World Bioactive Molecule Modification
XEC has been used to modify real drugs and natural products safely under gentle conditions. It allows chemists to add alkyl groups directly to important parts of these molecules, helping make new versions for testing. This speeds up the process of improving drugs and finding better medicines.[24-26]
Challenges and future aspects
Cross-electrophile coupling (XEC) in medicinal chemistry faces several important challenges that are being actively addressed with promising future directions. One key challenge is scalability, where recent advances in electrochemistry [16-18] and flow chemistry have improved reaction efficiency and scalability, with ongoing efforts to further integrate these methods for large-scale pharmaceutical manufacturing. Selectivity also remains a critical focus; improved ligand design has enhanced regio- and stereoselectivity, and the emerging application of machine learning holds promise for optimizing reaction conditions and guiding ligand development to achieve even greater selectivity for complex molecules.[26] Functional group tolerance is another area of progress, as newer catalyst systems have shown better compatibility with diverse functional groups. Future developments aim at creating greener catalysts and exploring non-metal catalytic pathways to expand functional group compatibility while improving sustainability.[15,28-30] Additionally, the development of asymmetric XEC variants is at an early stage, with initial successes in enantioselective reactions, and continued research is expected to provide robust asymmetric methods. These advancements collectively aim to broaden the utility of XEC, making it a more powerful, selective, sustainable, and versatile tool for drug discovery and development.
CONCLUSION :
Radical cross-electrophile coupling (XEC) has quickly grown from a new idea into a powerful tool for medicinal chemistry. Starting with nickel-catalyzed reactions, the field has expanded to include photoredox–nickel systems, electrochemical methods, and even metal-free photocatalysis. These advances go beyond academic interest—they are now helping chemists build drug-like molecules faster, modify complex scaffolds at late stages, and explore new chemical space. While challenges remain in scaling up, improving selectivity, and achieving asymmetric control, new approaches such as better ligands, computational design, and machine learning are already showing promise. Overall, XEC is not just an alternative to classical methods but a game-changing strategy that can speed up drug discovery and open the door to more sustainable and diverse chemistry.
ACKNOWLEDGEMENT:
I sincerely thank my mentors and colleagues for their guidance and support and I am really thankful to Department of St Xavier’s College Ahmedabad.
REFERENCES
Diya Panchal, Radical Cross-Electrophile Coupling in Medicinal Chemistry: A New Frontier for C-C Bond Construction, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 10, 995-1009. https://doi.org/10.5281/zenodo.17324301
10.5281/zenodo.17324301
