Advantages and Challenges of Cross-Coupling Reactions and Recent Progress in Suzuki–Miyaura Reactions
1. Introduction
Cross-coupling reactions have revolutionized synthetic chemistry by enabling the precise and efficient construction of carbon–carbon bonds, with the Suzuki–Miyaura reaction in particular becoming indispensable in pharmaceuticals, materials science, and natural product synthesis due to its broad substrate scope and mild reaction conditions (Figure 1).
While their advantage lies in allowing researchers to construct reaction systems with excellent performance, the field also faces significant challenges: the sheer number of reported experimental protocols makes identifying suitable reaction conditions for specific substrates a cumbersome and time-consuming task.
In theory, modern chemistry should be able to accelerate reaction optimization through high-throughput experimental technologies that enable rapid, parallel testing of many reaction conditions. However, despite these advances, a recent SciFinder analysis shows that over 80% of current Suzuki–Miyaura reactions still rely on pre-2003 conditions.
The limited adoption of newer methodologies highlights the urgent need for systematic optimization strategies and exploration of alternative catalytic systems. Recent studies have provided crucial mechanistic insights, expanded substrate and electrophile scope, improved reagent stability, and developed strategies for tuning bases, solvents, and ligands.
Notably, the review by J. W. Meringdal and D. Menche [1] synthesizes key findings since 2016, focusing on the widely used palladium–phosphine catalyzed (hetero)aryl bond formation reaction. The authors analyze major reaction parameters, identify underexplored areas, and propose clear strategies for designing high-performance Suzuki–Miyaura coupling reactions tailored to specific substrates.
2. Mechanistic Insights & Transmetalation Pathways
From the earlier period (2016-2022), it was well established that transmetalation is typically the rate-deterring step, and that pathways (Pd–OH (oxo-palladium) vs. boronate/boron-mediated) are strongly influenced by ligand electronics & geometry, base, solvent polarity, and halide effects (Figure 2) [1].
The review by J. W. Meringdal and D. Menche highlights evidence favoring the boronate pathway involving monodentate ligand intermediates. Notably, TMSOK (potassium trimethylsilanolate) was found to enhance palladium–boronic acid coordination. The Denmark group first identified the key monodentatepre-transmetalation intermediate via NMR in 2016, and the Bissember groupconfirmed its crystal structure by X-ray diffraction in 2021 [1].
2.1 New Findings (2024-2025):
In addition to the aforementioned review, recent studies provide further mechanistic insights into the Suzuki–Miyaura reaction, as summarized in Table 1.
Table 1. Recent Mechanistic Insights into Suzuki–Miyaura Cross-Coupling (2024–2025)
2.2 Implications/Integration with older understanding:
The requirement for base in transmetalation is not universal; under appropriate catalyst design (ligand, metal, intermediate oxidation state) one can bypass or reduce dependence on exogenous base.
Steric hindrance, ligand coordination geometry, and the metal oxidation state (for example, Fe(I) in iron/NHC systems) again matter strongly in determining which pathway is operative.
These findings suggest new levers (cationic intermediates, base-free or low-base systems) to optimize especially for base-sensitive or complex substrates.
3. Research on the Influence of Ligands on the Reaction
The review by J. W. Meringdal and D. Menche noted that, compared to the electron-rich triisopropylphosphine (PᵢPr₃), the electron-deficient triphenylphosphine (PPh₃) ligand accelerates transmetallation, while the bidentate ferrocenylbis (diphenylphosphine) (dppf) greatly slows it. The fastest transmetallation occurs with one equivalent of an electron-deficient monophosphine ligand, supporting the conclusion that transmetallation is the rate-determining step.
In 2021, Doyle, Sigman, and co-workers expanded on Sigman’s earlier statistical analysis by evaluating geometric ligand volumes for reactivity. Comparing reaction yields across ligands and substrates, they found halides require PdL1-type complexes, while triflates favor PdL2-type catalysts. Mechanistically, halides react faster with PdL1, whereas triflates may need a second ligand for oxidative addition. Overall, electron-deficient PdL1 species transmetallate fastest, with PdL1 and PdL2 complexes preferred for halide and triflate substrates, respectively [1].
From earlier work, ligand electronics/sterics, monodentate vs. bidentate, and ligand dissociation had been known to strongly affect each step: oxidative addition, stability of Pd(0), transmetallation, and reductive elimination. Recent findings sharpen this understanding [5-10].
3.1 Recent Findings:
Table 2. Recent Advances in Ligand Design and Selection for Suzuki–Miyaura Cross-Coupling (2024–2025)
3.2 Implications / Adjustments:
Ligand tuning must consider not just one step (often oxidative addition) but the balance: a ligand good for OA that prevents facile transmetallation may be worse for overall rate.
Bulky, electron-rich ligands remain beneficial for challenging electrophiles (like aryl chlorides), but one must ensure they can allow or facilitate the downstream steps (e.g., via flexible conformations or partial ligand dissociation).
Non-phosphine ligands (like NHCs) are increasingly important, especially for non-Pd metals (Fe, Ni) or when cost / sustainability is a concern.
4. Boron Sources are Either Reactive or Stable (Trade-Offs & New Types)
As seen from the review [1], boron sources are classified into reactive and stable types. Researchers deepened the analysis of boron source stability by studying the protodeboronation mechanism and found that 2-pyridyl boronates exhibit the highest stability even at high pH. Notably, some boronates become more labile at the pKa of the corresponding boronic acid due to autocatalytic deborylation, and boronates from heterocycles can vary in protodeboronation rate by a factor of ten because of multiple mechanisms.
The Denmark group studied transmetallation rates of various boronic esters, finding the glycol boronic ester about 100× faster than the least reactive pinacol ester. They widely adopted neopentyl glycol boronic ester as the optimal balance of stability and reactivity; even as an additive, it accelerates reactions using boronic acids.
In 2020, Yoshida & Tsuchimoto and Mutoh & Saito achieved efficient coupling of highly stable and inert boronic acids with KOtBu as the base, extending to 2-pyridyl and ortho-fluoro arene boronates as well as sterically hindered substrates.
Meanwhile, Akai & Ikawa observed that pinacol-based boronic esters improve yields with labile substrates. Converting such substrates to pinacol esters before coupling enhances performance. Later, in 2022, they introduced 1,1,2,2-tetraethylethylene glycol boronic esters (“ethyl pinacol”) for labile boron sources.
Overall, these studies show boron source choice strongly influences both reactivity and stability, with pH-dependent behavior varying by substrate type.
Historically, boronic acids, boronic esters, organotrifluoroborates, MIDA boronates, etc., each have trade-offs: reactivity vs stability, proneness to protodeboronation, ease of handling vs requirement for activation. Recent work adds new reagents and revises how to think about this trade-off.
4.1 Recent Findings (2023-2025):
Table 3. Recent Advances in Boron Reagent Development for Suzuki–Miyaura Couplings (2023–2025)
4.2 Implications / Adjustments:
For substrates sensitive to protodeboronation (e.g., heteroaryl borons, vinyl or glycal boronates), using “stable” boron sources like glycal boronates or BF₂ boracycles helps preserve material and reduce side products.
“Reactive” boron sources may still be needed when fast transmetallation is required; but the newer stable ones narrow the gap: often only modest increases in catalyst loading or mild heating are needed to compensate.
When scaling up, or for process work, stable boron sources improve reproducibility, handling, and storage.
5. The Issue of To Dissolve or Not to Dissolve (Solvent / Media / Dissolution Effects)
In 2019, Düfert, Milner, and co-workers studied halide inhibition and ways to overcome it. Stoichiometric transmetallation experiments showed that replacing a chloro- with an iodo-substituted complex drastically slowed the reaction; conversion remained incomplete even after one day. In catalytic cross-coupling of chlorobenzene, adding potassium iodide reduced conversion and slowed the rate. They linked this inhibition to halide salt solubility in the organic phase: higher solubility gave stronger inhibition. Switching the solvent from THF to toluene (lower polarity) eliminated the inhibition and restored full conversion [1].
For polar substrates, the organic phase can become too hydrophobic. Using 2-methyl-THF (less miscible with water) limits halide salt dissolution and improves outcomes. Triflate salts had no negative effect on conversion. Using an iodo- instead of a bromo-substrate sometimes required higher temperature or more electron-deficient catalysts for similar conversion [1].
In 2021, Denmark and co-workers used Lewis acid additive trimethyl borate to enhance rate and selectivity. Replacing the inorganic base with potassium trimethylsilanolate (TMSOK) in anhydrous conditions improved reaction rates, as the less polar boronate had better solubility in the organic phase. However, the nucleophilicity of TMSOK limits solvent choice [1].
Recently, Hein and co-workers found soluble halide salts (TBACl > TBABr > TBAI) can improve reaction outcomes, offering a solution to acidic catalyst poisoning and insoluble boronates [1].
The aforementioned literature emphasized solvent polarity, water content, co-solvent versus organic solvent, and the handling of insoluble salts/phases. Recent research more clearly defines when the dissolution state influences the mechanism or rate.
5.1 Recent Findings (2024-2025):
Table 3. Recent Advances in Boron Reagent Development for Suzuki–Miyaura Couplings (2023–2025)
4.2 Implications / Adjustments:
For substrates sensitive to protodeboronation (e.g., heteroaryl borons, vinyl or glycal boronates), using “stable” boron sources like glycal boronates or BF₂ boracycles helps preserve material and reduce side products.
“Reactive” boron sources may still be needed when fast transmetallation is required; but the newer stable ones narrow the gap: often only modest increases in catalyst loading or mild heating are needed to compensate.
When scaling up, or for process work, stable boron sources improve reproducibility, handling, and storage.
5. The Issue of To Dissolve or Not to Dissolve (Solvent / Media / Dissolution Effects)
In 2019, Düfert, Milner, and co-workers studied halide inhibition and ways to overcome it. Stoichiometric transmetallation experiments showed that replacing a chloro- with an iodo-substituted complex drastically slowed the reaction; conversion remained incomplete even after one day. In catalytic cross-coupling of chlorobenzene, adding potassium iodide reduced conversion and slowed the rate. They linked this inhibition to halide salt solubility in the organic phase: higher solubility gave stronger inhibition. Switching the solvent from THF to toluene (lower polarity) eliminated the inhibition and restored full conversion [1].
For polar substrates, the organic phase can become too hydrophobic. Using 2-methyl-THF (less miscible with water) limits halide salt dissolution and improves outcomes. Triflate salts had no negative effect on conversion. Using an iodo- instead of a bromo-substrate sometimes required higher temperature or more electron-deficient catalysts for similar conversion [1].
In 2021, Denmark and co-workers used Lewis acid additive trimethyl borate to enhance rate and selectivity. Replacing the inorganic base with potassium trimethylsilanolate (TMSOK) in anhydrous conditions improved reaction rates, as the less polar boronate had better solubility in the organic phase. However, the nucleophilicity of TMSOK limits solvent choice [1].
Recently, Hein and co-workers found soluble halide salts (TBACl > TBABr > TBAI) can improve reaction outcomes, offering a solution to acidic catalyst poisoning and insoluble boronates [1].
The aforementioned literature emphasized solvent polarity, water content, co-solvent versus organic solvent, and the handling of insoluble salts/phases. Recent research more clearly defines when the dissolution state influences the mechanism or rate.
5.1 Recent Findings (2024-2025):
Table 4. Advances in Reaction Media, Catalysis, and Scale-Up for Suzuki–Miyaura Couplings (2024–2025)
5.2 Implications / Adjustments:
When designing reactions, don’t assume that more water or more polar solvent always helps. There is a “sweet spot” for aqueous/organic proportions; excess aqueous phase can dilute reactive species, complicate phase transfer or slow parts of cycle.
Phase transfer catalysts are powerful levers: they can change which transmetalation path is operative, drastically affecting rate and lowering of catalyst loading.
For scale and reproducibility, ensure good dissolution or at least good dispersion of all reagents (bases, boron sources, catalysts). Poor solubility of any component can become limiting. Using co-solvents or surfactants / micelles (when compatible) helps.
6. Conclusion and Practical Guidelines
The recent literature shows that many of the constraints long thought to be inherent in Suzuki–Miyaura cross-coupling can be mitigated or bypassed: base requirement, metal type, sensitivity of boron reagents, and substrate scope. Mechanistic understanding has deepened (especially with respect to the transmetalation step and the stabilization of intermediates), allowing more rational design of catalyst systems.
Thus, while the older frameworks still hold value (ligand electronics/geometry, solvent effects, halide inhibition), they now sit alongside newer levers: base-free or low-base pathways, earth-abundant catalysts, one-pot / tandem workflows, and more meticulous choice of boron reagents.
Key Takeaways for Reaction Design:
Catalyst and Ligand Selection
For challenging electrophiles (e.g., aryl chlorides, heteroaryl substrates), electron-rich, bulky ligands or NHC-based systems often enhance oxidative addition but must allow facile transmetallation and reductive elimination.
Use cationic Pd(II)/Ni(II) intermediates or base-free systems for substrates sensitive to strongly basic conditions.
Boron Reagent Choice
Stable reagents (e.g., glycal boronates, BF₂ boracycles) minimize protodeboronation and aid scale-up reproducibility, while reactive esters (e.g., glycol esters) enable faster transmetallation when speed dominates over stability.
For labile boronic acids, pre-conversion to pinacol or ethyl pinacol esters improves yields and handling.
Solvent and Dissolution Control
Optimal aqueous/organic balance matters: too much water can dilute reactants or impede mass transfer; biphasic systems with phase-transfer catalysts (PTCs) enable rate acceleration and even pathway switching.
Ensure complete dissolution or effective dispersion of all components; use co-solvents, micelles, or mechanical stirring at scale to prevent precipitation bottlenecks.
Green and Scalable Approaches
Micellar catalysis reduces organic solvent usage while maintaining high turnover and heteroaryl tolerance.
Electrochemical variants integrate oxidative steps under milder conditions, reducing stoichiometric oxidants and waste.
Data-Driven Optimization
Machine learning-guided ligand and condition prediction accelerates discovery by integrating reactivity descriptors with high-throughput data, reducing empirical trial-and-error.
References
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