Technical articles
Experimental Decision-Making for Cross-Coupling Reactions: Target Bond Type, Substrate Combination, and Catalytic System Selection
Experimental Decision-Making for Cross-Coupling Reactions: Target Bond Type, Substrate Combination, and Catalytic System Selection
1. What Is Cross-Coupling?
Cross-coupling refers to the connection of two molecular fragments under the action of a metal catalyst to form a new chemical bond. In organic synthesis, these reactions are most commonly used to construct carbon–carbon bonds, and they have also been widely extended to carbon–nitrogen and carbon–oxygen bond formation. The importance of cross-coupling lies in its ability to directly join two pre-existing fragments, which gives it a central role in the synthesis of pharmaceutical molecules, natural products, and functional materials.
The 2010 Nobel Prize in Chemistry recognized the development of palladium-catalyzed cross-coupling in organic synthesis. Representative reactions include the Heck reaction, Negishi coupling, and Suzuki coupling. The core of these reactions is the palladium-catalyzed connection of two originally separate organic fragments to form a new carbon–carbon bond.
2. What Do Names Such as Suzuki–Miyaura Coupling, Negishi Coupling, and Sonogashira Coupling Mean?
These names refer to reactions named after researchers. In Chinese, they are usually transliterated from the corresponding chemists’ surnames and followed by a reaction-type term such as “coupling” or “amination.” They are standard names that have long been used in the international literature. The table below summarizes several common names, their naming origins, and the corresponding reactions.
Common name | Naming origin | Typical substrate combination | Main bond formed |
Heck reaction | Named after Heck; the Heck reaction is also commonly written as the Mizoroki–Heck reaction. | Halogenated substrates or triflates with alkenes | Carbon–carbon bond |
Negishi coupling | Named after Ei-ichi Negishi | Halogenated substrates or triflates with organozinc reagents | Carbon–carbon bond |
Suzuki–Miyaura coupling | Named after Akira Suzuki and Norio Miyaura | Halogenated substrates or triflates with organoboron compounds | Carbon–carbon bond |
Sonogashira coupling | Named after Kenkichi Sonogashira | Halogenated substrates or triflates with terminal alkynes | Carbon–carbon bond |
Buchwald–Hartwig amination | Named after Buchwald and Hartwig | Aryl halides or related leaving-group substrates with amines | Carbon–nitrogen bond |
3. When Should Cross-Coupling Be Prioritized?
Cross-coupling is usually a preferred option when the target molecule requires direct connection of two pre-existing fragments and the substrates already contain sites that can directly enter the reaction. Common reaction entry points can be divided into two types: one type includes electrophilic substrates such as aryl or alkenyl iodides, bromides, chlorides, and triflates; the other type includes coupling partners such as organoboron compounds, organozinc compounds, organotin compounds, terminal alkynes, amines, alcohols, phenols, and alkenes.
If these reactive sites are already present in the route design, cross-coupling can often directly serve as the “fragment-connection” step. If additional steps are needed to install and later remove reactive sites, the overall route length, substrate availability, and condition complexity should be re-evaluated.
4. Choosing the Reaction Type Based on the Target Bond
The first step in planning a cross-coupling experiment is to determine what bond needs to be formed. Carbon–carbon, carbon–nitrogen, and carbon–oxygen bonds differ in commonly used reaction types, substrate combinations, and key catalytic-condition requirements. The table below lists common types of cross-coupling reactions classified by target bond formation.
Target bond | Reaction type to consider first | Typical coupling partner | Common product direction |
Carbon–carbon bond | Suzuki–Miyaura coupling | Organoboron compounds | Aryl–aryl and aryl–alkenyl connections |
Carbon–carbon bond | Negishi coupling | Organozinc reagents | Carbon–carbon connections requiring relatively fast transmetalation |
Carbon–carbon bond | Sonogashira coupling | Terminal alkynes | Introduction of alkynyl fragments |
Carbon–carbon bond | Heck reaction | Alkenes | Construction of substituted alkenes |
Carbon–carbon bond | Stille coupling | Organotin reagents | Aryl–aryl and aryl–alkenyl connections; because organotin reagents pose toxicity and waste-treatment concerns, they should be selected cautiously in experiments |
Carbon–nitrogen bond | Buchwald–Hartwig amination | Amines | Formation of aryl carbon–nitrogen bonds |
Carbon–oxygen bond | Palladium-catalyzed carbon–oxygen coupling | Alcohols or phenols | Formation of aryl ethers and related structures |
5. Choosing a Specific Route Based on the Existing Substrate Combination
After the target bond has been identified, the next step is to examine what reaction entry points are already present in the substrates. The experimental entry point is determined by the type of substrate combination already available: one side is usually an electrophilic substrate such as an aryl or alkenyl halide, or an aryl or alkenyl triflate; the other side is a coupling partner such as an organoboron compound, organozinc reagent, terminal alkyne, alkene, or amine.
Existing substrate combination | Route to consider first | Basis for judgment |
Aryl or alkenyl halide, aryl or alkenyl triflate + organoboron compound | Suzuki–Miyaura coupling | Organoboron substrates are stable and widely available, making this a common starting point for carbon–carbon bond construction |
Aryl or alkenyl halide, aryl or alkenyl triflate + organozinc reagent | Negishi coupling | Organozinc reagents undergo relatively fast transmetalation and are suitable for routes designed around organozinc intermediates |
Aryl or alkenyl halide, aryl or alkenyl triflate + terminal alkyne | Sonogashira coupling | Enables direct introduction of alkynyl fragments; classic systems often contain a palladium catalyst and a copper co-catalyst |
Aryl or alkenyl halide, aryl or alkenyl triflate + alkene | Heck reaction | Suitable for forming substituted alkenes and commonly used for arylation or alkenylation of alkene structures |
Aryl or heteroaryl halide, aryl or heteroaryl triflate + amine | Buchwald–Hartwig amination | An important method for forming aryl or heteroaryl carbon–nitrogen bonds |
Among these routes, Suzuki–Miyaura coupling is often used as the starting point for carbon–carbon bond construction mainly because organoboron substrates are stable and broadly applicable. Negishi coupling is more suitable for routes already designed around organozinc intermediates. Sonogashira coupling is advantageous for direct alkynyl fragment introduction, while Buchwald–Hartwig amination specifically targets aryl carbon–nitrogen bond formation.
6. Which Aspects Should Be Considered When Evaluating a Cross-Coupling Catalytic System?
A cross-coupling catalytic system should be evaluated by considering the metal, leaving group, precatalyst, ligand, base, and solvent together. The table below summarizes several key factors that should be considered when judging a cross-coupling catalytic system.
Factor | What to examine | Impact on the experiment |
Metal system | Whether palladium or nickel matches the current transformation | Palladium and nickel are the most common metals in commercialized systems; different metals require different starting conditions and apply to different substrate types |
Leaving group | Whether it is iodine, bromine, chlorine, or triflate | The leaving group affects the ease of oxidative addition, so the starting conditions should be reassessed according to substrate type |
Precatalyst and ligand | Whether they can reliably generate the active catalytic species | Directly affects reaction initiation, substrate scope, and operational stability |
Base | Whether base strength matches substrate stability | Affects deprotonation, transmetalation, and side reactions |
Solvent | Whether it can balance solubility and catalytic state | Affects mass transfer, substrate stability, and catalytic efficiency |
7. First-Round Condition Screening for New Substrates
For a new substrate without available literature conditions, the first round of screening should examine the catalytic system, base, and solvent at the same time. It is not advisable to change only a single catalyst. The purpose of the first round is to identify a condition range that can initiate the reaction and generate the desired product, and then further refine the conditions based on conversion and side-reaction behavior. The table below can be used as a simplified framework for first-round condition screening.
First-round screening dimension | Recommended approach | Purpose |
Catalyst or precatalyst | Compare two to three representative systems in parallel | First determine whether the reaction can be initiated |
Base | Compare at least one relatively mild base and one relatively strong base | Determine whether deprotonation, transmetalation, and substrate stability are matched |
Solvent | Compare at least two representative solvent types | Evaluate solubility, mass transfer, and catalytic state |
Reaction scale | Start with small-scale parallel experiments | First identify conditions that give product and are reproducible |
Reproducibility confirmation | After product formation is observed, repeat the experiment first | Confirm condition reliability before considering scale-up and substrate-scope expansion |
Before scale-up, air and moisture sensitivity should be assessed according to the reaction type. Suzuki–Miyaura coupling can often use aqueous systems; Negishi coupling, organozinc reagents, zero-valent nickel systems, and reactions involving low-valent palladium or nickel active species usually require anhydrous, degassed, and inert-atmosphere conditions. During scale-up, the solvent water content, degassing method, order of addition, stirring efficiency, and heat-transfer conditions should be rechecked rather than simply reusing small-scale conditions.
8. Troubleshooting Order for Common Problems in Cross-Coupling
When problems occur in cross-coupling, the substrate and reactive-site compatibility should be checked first, followed by the suitability of the base and solvent. The final checks should focus on whether the catalyst is effectively activated and whether the system is affected by air and moisture. This troubleshooting order helps determine whether the problem comes from the substrate itself, the reaction conditions, or the catalytic system. The table below lists priority troubleshooting directions for several common problems.
Problem observed | Priority checks | Common causes |
No conversion | Substrate purity, reactive site, base, solvent | The reactive site has insufficient activity, or starting conditions capable of initiating the reaction have not yet been identified |
Low conversion | Catalytic system, base strength, concentration | Insufficient formation of the active catalytic species, or mismatch between the substrate and key steps such as transmetalation or deprotonation |
Many side reactions | Substrate stability, base, solvent | The substrate is unstable under the current conditions, or the base and solvent are not suitable |
Small-scale reaction works, but scale-up fails | Atmosphere, drying, order of addition, stirring | The activated catalytic system is more susceptible to air and moisture; differences in stirring and mass transfer are also amplified during scale-up |
9. Navigation Table for Representative Chemicals Related to Cross-Coupling Catalytic Systems：Select Tables 1–6 According to Research or Experimental Goals
Research or experimental goal | Recommended table to review first | Why start with this table | Suggested table(s) to cross-reference | Navigation notes |
Establish an initial screening system for conventional Suzuki–Miyaura coupling | Table 1 | Table 1 lists palladium sources, zero-valent palladium precatalysts, and biarylphosphine palladium precatalysts, making it useful for first identifying the starting catalytic system | Tables 4 and 6 | First select the palladium system according to the reactivity of the electrophilic substrate, then combine it with the organoboron type, base, and solvent to build the first-round conditions |
Compare the reactivity of aryl chlorides, aryl bromides, aryl iodides, and aryl triflates | Table 5 | Table 5 lists several typical electrophilic substrates, making it useful for first judging reaction difficulty based on leaving-group reactivity | Tables 1, 3, and 6 | First determine which leaving-group class the substrate belongs to, then return to the palladium precatalyst, ligand, and base system to adjust the conditions |
Develop conditions for Buchwald–Hartwig amination | Table 1 | The biarylphosphine palladium precatalysts in Table 1 are directly related to aryl amination and can serve as starting points for amination screening | Tables 3, 5, and 6 | First determine the palladium precatalyst, then screen based on the amine substrate type, ligand framework, and base strength |
Study aryl etherification with phenolic substrates | Table 1 | Aryl carbon–oxygen bond formation usually starts with palladium precatalyst systems, and Table 1 helps identify the catalytic framework first | Tables 3, 5, and 6 | Focus on cross-referencing phenolic substrates, diaryl monophosphine ligands, and base systems, while paying attention to leaving-group reactivity and substrate tolerance |
Screen Sonogashira coupling or alkynylation reactions | Table 5 | Table 5 lists terminal alkynes, protected alkynes, and common electrophilic substrates, making it useful for first determining whether the substrate combination is suitable | Tables 2 and 6 | First determine the alkyne source and electrophilic substrate type, then combine copper(I) iodide, base, and solvent to set up Sonogashira coupling conditions |
Evaluate Negishi coupling routes involving organozinc reagents | Table 5 | Table 5 lists dimethylzinc, diethylzinc, and typical electrophilic substrates, making it useful for judging whether an organozinc route is feasible | Tables 2 and 6 | First confirm the alkyl fragment to be introduced and the electrophilic substrate type, then conduct experiments with nickel or palladium systems and anhydrous solvent conditions |
Explore nickel-catalyzed cross-coupling or cross-electrophile coupling | Table 2 | Table 2 lists a zero-valent nickel source, a divalent nickel precursor, and a copper co-catalyst, making it useful for first establishing a nickel-system starting point | Tables 3, 5, and 6 | Start with nickel precursor selection, then screen the reaction conditions based on substrate type, ligand, and solvent |
Compare in situ assembled catalytic systems with precatalyst systems | Table 1 | Table 1 includes palladium acetate, a zero-valent palladium precatalyst, and multiple biarylphosphine palladium precatalysts, making direct comparison possible | Tables 3 and 6 | Compare in situ palladium source plus ligand systems with precatalyst systems in parallel, then observe initiation efficiency and reproducibility in combination with base and solvent |
Select ligand frameworks such as biaryl monophosphines and diphosphines | Table 3 | Table 3 is organized by ligand framework, making it convenient to start from three approaches: monodentate phosphines, diphosphines, and diaryl monophosphines | Tables 1 and 5 | First choose the ligand direction according to substrate type and bond-forming task, then return to palladium or nickel sources to assemble the specific catalytic system |
Design a two-step route of “borylation followed by coupling” | Table 4 | Table 4 lists arylboronic acids, boronate esters, trifluoroborates, MIDA boronates, and diboron reagents | Tables 5 and 6 | First determine which type of organoboron intermediate is needed, then plan the subsequent Suzuki-type coupling in combination with the electrophilic substrate and reaction medium |
Recheck variables when substrate conversion is low or conditions are unstable | Table 6 | Table 6 lists common bases and reaction solvents, making it useful for first checking whether base strength, medium polarity, and anhydrous conditions are matched | Tables 1, 3, and 5 | First recheck the base and solvent, then evaluate whether the problem originates from the conditions or from the substrate itself in combination with the catalytic system and substrate type |
Establish cross-coupling methodology starting from model substrates | Table 5 | Model substrates such as bromobenzene, iodobenzene, phenylacetylene, aniline, morpholine, and styrene in Table 5 are suitable as starting points for method development | Tables 1, 3, and 6 | First establish baseline conditions with model substrates, then gradually move to more complex substrates to evaluate the applicability of the catalytic system |
Table 1 | Palladium Catalysts, Palladium Precatalysts, and Biarylphosphine Palladium Precatalysts
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
General palladium precatalyst | 3375-31-3 | Palladium(II) acetate (47% Pd) | Suitable for synthesis | A commonly used palladium source that can be combined with phosphine ligands to assemble catalytic systems in situ; useful for condition screening in Suzuki–Miyaura coupling, the Heck reaction, and Buchwald–Hartwig amination | |
Pre-coordinated zero-valent palladium catalyst | 14221-01-3 | Tetrakis(triphenylphosphine)palladium(0) | Pd ≥8.9% | A ready-to-use zero-valent palladium catalyst suitable for reaction-starting experiments; useful for establishing cross-coupling conditions with aryl bromide and aryl iodide substrates | |
Zero-valent palladium precatalyst | 51364-51-3 | Tris(dibenzylideneacetone)dipalladium(0) | ≥99.95% metals basis | Often used together with diaryl monophosphine or diphosphine ligands to construct palladium-catalyzed cross-coupling systems with relatively broad substrate applicability | |
Pre-coordinated palladium complex | 95464-05-4 | 1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct | ≥99.3% metals basis | A pre-coordinated palladium complex containing a ferrocene-based diphosphine framework; commonly used in Suzuki–Miyaura coupling, Negishi coupling, and related aryl coupling reactions | |
Biarylphosphine palladium precatalyst | 1445085-82-4 | SPhos Pd G3 | ≥99.95% metals basis | Suitable for screening cross-coupling reactions of aryl chloride and aryl bromide substrates; applicable to carbon–carbon, carbon–nitrogen, and carbon–oxygen bond-forming reactions | |
Biarylphosphine palladium precatalyst | 1447963-75-8 | tBuXPhos Pd G3 | ≥99.95% metals basis | Suitable for Buchwald–Hartwig amination and related aryl coupling reactions; useful for exploring conditions with relatively reactive base systems | |
RuPhos palladium precatalyst | 1599466-85-9 | Methanesulfonato(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-methylamino-1,1′-biphenyl-2-yl)palladium(II) | ≥98% | Useful for screening aryl amination, aryl etherification, and some arylboron coupling conditions; suitable for method development around diaryl monophosphine palladium systems | |
Biarylphosphine palladium precatalyst | 1599466-81-5 | XPhos Pd G4 | ≥95% | Suitable for cross-coupling studies involving electrophilic substrates such as aryl chlorides and aryl triflates; useful for establishing aryl amination and Suzuki–Miyaura coupling systems |
Table 2 | Nickel Catalysts and Copper Co-Catalyst
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Copper co-catalyst | 7681-65-4 | Copper(I) iodide | Anhydrous grade, ≥99.995% metals basis | A common copper co-catalyst for Sonogashira coupling; can promote formation of copper acetylide intermediates from terminal alkynes and participate in alkynyl transfer | |
Zero-valent nickel precatalyst | 1295-35-8 | Bis(1,5-cyclooctadiene)nickel(0) | ≥96% | A commonly used zero-valent nickel source; useful for constructing nickel-catalyzed cross-coupling, cross-electrophile coupling, and reductive coupling systems; sensitive to air and moisture, and typically requires anhydrous conditions, an inert atmosphere, and small-scale controlled operation | |
Nickel precatalyst | 3264-82-2 | Nickel acetylacetonate | ≥95% | A stable divalent nickel precursor that can be used for initial condition screening in nickel-catalyzed carbon–carbon bond formation and cross-electrophile coupling |
Table 3 | Common Phosphine Ligands for Cross-Coupling
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
General monodentate phosphine ligand | 603-35-0 | Triphenylphosphine | ≥99% (GC) | Commonly used to generate palladium–phosphine catalytic systems in situ; useful for establishing basic conditions for classic palladium-catalyzed cross-coupling | |
Ferrocene-based diphosphine ligand | 12150-46-8 | 1,1′-Bis(diphenylphosphino)ferrocene (DPPF) | ≥99% | Commonly used in ligand screening for palladium and nickel catalytic systems; suitable for carbon–carbon bond formation involving aryl halides | |
Binaphthyl diphosphine ligand | 98327-87-8 | 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene | ≥98% | Useful for screening diphosphine ligand frameworks and comparing palladium-catalyzed coupling systems; if used for asymmetric catalysis, a single enantiomer of BINAP should be selected | |
Diaryl monophosphine ligand | 657408-07-6 | 2-Dicyclohexylphosphino-2′,6′-dimethoxybiphenyl | ≥98% | Suitable for condition screening in Suzuki–Miyaura coupling of aryl chloride substrates, aryl amination, and aryl etherification | |
Diaryl monophosphine ligand | 787618-22-8 | 2-Dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl | ≥98% | Useful for building palladium-catalyzed coupling systems involving substrates such as aryl chlorides and aryl triflates | |
Diaryl monophosphine ligand | 564483-18-7 | 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) | ≥97% | Commonly used in Buchwald–Hartwig amination, Suzuki–Miyaura coupling, and coupling reactions involving aryl triflates | |
Diaryl monophosphine ligand | 1070663-78-3 | Dicyclohexyl(2′,4′,6′-triisopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine | ≥97% | Suitable for aryl amination and aryl etherification systems; useful for screening palladium-catalyzed conditions with sterically hindered substrates |
Table 4 | Organoboron Coupling Partners and Borylation Reagents
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Arylboronic acid coupling partner | 98-80-6 | Phenylboronic acid (PBA) (contains varying amounts of Anhydride) | ≥99.5% | A commonly used arylboron source for Suzuki–Miyaura coupling; useful for establishing initial conditions for aryl–aryl bond formation | |
Substituted arylboronic acid coupling partner | 5720-07-0 | 4-Methoxybenzeneboronic Acid (contains varying amounts of Anhydride) | ≥95% | Useful for introducing aryl fragments bearing electron-donating substituents and for evaluating electronic effects in Suzuki–Miyaura coupling | |
Arylboronate ester coupling partner | 24388-23-6 | Phenylboronic Acid Pinacol Ester | ≥98% | A stable organoboron coupling partner that can undergo coupling with aryl halides or aryl triflates | |
Trifluoroborate coupling partner | 153766-81-5 | Potassium Phenyltrifluoroborate | ≥98% | A stable arylboron reagent suitable for Suzuki-type coupling and experimental systems requiring improved storage stability | |
MIDA boronate coupling partner | 109737-57-7 | Phenylboronic acid MIDA ester | ≥95% | Suitable for route design involving stepwise release of organoboron fragments and for Suzuki-type coupling studies in multistep sequential synthesis | |
Diboron reagent | 73183-34-3 | Bis(pinacolato)diboron | ≥99% | Commonly used for borylation of substrates such as aryl halides and alkenes; an important boron source for preparing substrates for subsequent Suzuki–Miyaura coupling | |
Hydroboration reagent | 25015-63-8 | 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane | ≥97% | Useful in transition-metal-catalyzed borylation and hydroboration reactions to prepare pinacol boronate-type coupling intermediates |
Table 5 | Typical Electrophilic Substrates and Coupling Partners
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Aryl chloride electrophilic substrate | 108-90-7 | C431386 | Chlorobenzene | Anhydrous grade, ≥99.8% | Can serve as an aryl chloride model substrate for evaluating how well ligands and precatalysts adapt to less reactive leaving groups |
Aryl bromide electrophilic substrate | 108-86-1 | Bromobenzene | Standard for GC, ≥99.5% (GC) | A common model substrate useful for initial experiments in Suzuki–Miyaura coupling, Sonogashira coupling, and aryl amination | |
Aryl iodide electrophilic substrate | 591-50-4 | Iodobenzene | ≥99% | Relatively high reactivity; suitable for establishing baseline cross-coupling conditions and comparing initiation activity across different catalytic systems | |
Aryl triflate electrophilic substrate | 17763-67-6 | Phenyl Trifluoromethanesulfonate | ≥98% (GC) | Can serve as an activated electrophilic substrate analogous to aryl halides for investigating coupling reactions involving aryl triflates | |
Aromatic amine coupling partner | 62-53-3 | Aniline | Standard for GC, ≥99.9% (GC) | Can serve as a model substrate for aryl amination and for evaluating the compatibility of different palladium catalytic systems with aromatic amine coupling | |
Secondary amine coupling partner | 110-91-8 | Morpholine | Distilled grade, ≥99.5% | Commonly used in model aryl amination reactions; useful for comparing the amination activity of different palladium precatalysts and ligands | |
Phenolic coupling partner | 108-95-2 | Phenol | ≥99.5% (GC) | Represents the phenolic oxygen nucleophile type required for aryl etherification and can be used as a substrate reference for aryl carbon–oxygen bond formation | |
Alkene coupling partner | 100-42-5 | Styrene | Standard for GC, ≥99.5% (GC), contains 10–15 ppm TBC stabilizer | A common alkene substrate for the Heck reaction; useful for establishing arylation conditions for alkenes; when used in model reactions, the effect of the stabilizer on reaction rate and purification should be considered | |
Electron-deficient alkene coupling partner | 96-33-3 | Methyl acrylate | Standard for GC, ≥99.5% (GC) | Commonly used in Heck reaction model systems and useful for comparing the effects of different bases and ligands on alkene coupling | |
Terminal alkyne coupling partner | 536-74-3 | Phenylacetylene | ≥97% | A commonly used alkyne substrate in Sonogashira coupling; useful for optimizing aryl alkynylation conditions | |
Protected alkyne coupling partner | 1066-54-2 | (Trimethylsilyl)acetylene | ≥98% | Can be used as a protected alkyne source for alkynyl fragment introduction and is suitable for subsequent deprotection or multistep alkynylation routes | |
Organozinc coupling partner | 557-20-0 | D684313 | Diethylzinc solution | 2 M in toluene | A common organozinc reagent for Negishi coupling; useful for ethyl fragment introduction and organozinc-system activity evaluation; requires anhydrous and inert-atmosphere operation, presents safety risks in the presence of water and air, and is suitable for small-scale controlled experiments |
Organozinc coupling partner | 544-97-8 | Dimethylzinc solution | 2.0 M in toluene | Useful for methylation-type Negishi coupling studies and for comparing the transmetalation behavior of different organozinc reagents; requires anhydrous conditions, an inert atmosphere, and small-scale controlled operation | |
Organotin coupling partner | 960-16-7 | Tributylphenylstannane | ≥95% | A representative organotin reagent for Stille coupling; useful for studies of aryl transfer reactions |
Table 6 | Common Bases and Reaction Solvents
Category | CAS No. | Aladdin Catalog No. | Name | Specification or Purity | Product Features and Applications |
Inorganic base | 584-08-7 | P485463 | Potassium carbonate | Anhydrous grade, high-purity, reagent grade, ≥99% | A common base for Suzuki–Miyaura coupling, the Heck reaction, and some aryl amination reactions; useful for basic condition screening |
Inorganic base | 7778-53-2 | Potassium phosphate tribasic | Anhydrous grade, ≥98% | Commonly used in organoboron coupling and aryl amination systems; can balance basicity with substrate tolerance | |
Inorganic base | 534-17-8 | Cesium carbonate | purum p.a., ≥98% (T) | Combines solubility and basicity; commonly used in aryl amination, aryl etherification, and some coupling reactions involving sterically hindered substrates | |
Strong base | 865-48-5 | S109392 | Sodium tert-butoxide | ≥98% | Commonly used in Buchwald–Hartwig amination and some palladium-catalyzed coupling systems; can promote amine deprotonation and progression of the catalytic cycle |
Anhydrous ether solvent | 109-99-9 | Tetrahydrofuran (THF) | Anhydrous grade, ≥99.9%, unstabilized | Suitable for organozinc reagents, nickel catalytic systems, and some borylation reactions; commonly used for systems sensitive to air and moisture | |
Anhydrous ether solvent | 123-91-1 | 1,4-Dioxane | Anhydrous grade, ≥99.8% | Commonly used in Suzuki–Miyaura coupling and aryl amination condition screening; can be combined with water or alcohols | |
Polar amide solvent | 127-19-5 | N,N-Dimethylacetamide (DMAC) | Anhydrous grade, ≥99.8% | Suitable for high-boiling coupling systems and useful for cross-coupling studies involving poorly soluble substrates or relatively high-temperature conditions | |
Aromatic hydrocarbon solvent | 108-88-3 | T399633 | Toluene | Anhydrous grade, ≥99.8% | Commonly used in organozinc reagent solution systems and some palladium-catalyzed coupling reactions; can serve as a nonpolar reaction medium |
Note: The products listed above are representative Aladdin products. More product specifications can be searched on the Aladdin website by product name, CAS number, or catalog number.
References
[1] Royal Swedish Academy of Sciences. Palladium-Catalyzed Cross Couplings in Organic Synthesis. 2010.
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[3] Seechurn C C C J, Kitching M O, Colacot T J, Snieckus V. Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angewandte Chemie International Edition, 2012, 51(21): 5062–5085.
[4] Dorel R, Grugel C P, Haydl A M. The Buchwald–Hartwig Amination After 25 Years. Angewandte Chemie International Edition, 2019, 58(48): 17118–17129.
[5] Mohajer F, Heravi M M, Zadsirjan V, Poormohammad N. Copper-free Sonogashira Cross-Coupling Reactions: An Overview. RSC Advances, 2021, 11(12): 6885–6925.
[6] Sigma-Aldrich. Cross-Coupling Reaction Manual: Desk Reference.
[7] Sigma-Aldrich. Cross-Coupling.
[8] Sigma-Aldrich. Scale-Up Guide: Suzuki–Miyaura Cross-Coupling Reaction.
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