Overview of Suzuki coupling reaction
In the entire Suzuki-coupling reaction cycle, the oxidation-addition reaction of Pd(0) with halogenated aromatics to produce the Pd(II) complex is considered to be the decisive step.
The relative activity of the departing group in the substrate halogenated aromatics is as follows: I– >Otf– >Br– >>Cl–. If there are groups on aryl and alkenyl, the auxo-action of the electron-absorbing group on oxidation-addition is stronger than that of the electron-donating group. In the steps of reducing and eliminating complexes of Pd(II)) to obtain the coupled product, the relative rate is aryl-aryl>alkyl-aryl>n-propyl-n-propyl>ethyl-ethyl>methyl-methyl.
The most classic catalyst used in the Suzuki reaction is Pd(PPh3)4. Others are PdCl2, PdCl2(dppf), Pd(OAc)2, Pd(PPh3)2Cl2, NiCl2(dppf), etc. These catalysts feature some characteristics such as easy post-processing and low air sensitivity and have mature applications in specific reactions. Some reactions may require other highly catalytically active ligands that are characterized by strong electronegativity and high steric hindrance. This is because more electronegative ligands are favorable for oxidation-addition reactions and high steric hindrance ligands benefit to reduction-elimination. Therefore, the development of efficient and inexpensive new catalysts and ligands is a research direction.
Suzuki coupling reaction with common aryl halide and aryl boronic acid
This kind of reaction is the most common. Procedures include: under the presence of water, add a catalyst, alkali, and organic solvent; heat reflux for a reasonable period to complete the reaction. Please note that the reaction system must be strictly controlled under the anaerobic environment. Usually, if the reaction is feasible, the production rate will be high. K2CO3, K3PO4, Na2CO3, CsF, Cs2CO3, t-Bu-Na, and other alkalis are recommended to use while NaHCO3 is not on the recommendation list. The effect of alkali strength on the coupling of 2, 4, 6-trimethylboric acid with large steric resistance is shown as follows: Ba (OH)2>NaOH>K3PO4>Na2CO3>NaHCO3. However, reactions with a weak alkali tend to be cleaner than with a strong alkali. Solvent systems generally utilize toluene/EtOH/H2O, CH3CN/H2O, or dioxane/H2O.
Suzuki coupling reaction with large steric aryl boric acid
The steric effect of aryl boric acid on the Suzuki coupling reaction is much greater than that of aryl halide. When the ortho of aryl boronic acid is a substituent, the reaction rate is slow and the yield is low. Adding strong alkali aqueous solutions such as NaOH or Ba(OH)2, and taking benzene and DME as solvents can accelerate the reaction significantly.
Sometimes large hindrance aryl boronic acid can be converted into borate ester with satisfactory results.
Suzuki coupling reaction with aryl boronic acid (ester) containing sensitive functional groups
The yield of 2-aldehyde phenylboronic acid and 2-iodotoluene is only 39% in aqueous Na2CO3 solution and DME at 80℃. One way to increase the yield is to substitute the corresponding aryl borate for aryl boronic acid, using anhydrous K3PO4 as the alkali and DMF as the solvent to increase the yield to 89%.
If aryl boric acid or aryl halide itself with other water-sensitive groups, such as easy hydrolysis of ester groups (especially methyl ester and ethyl ester) and cyanogen, this method can also be applied. Experiments have proved that in the absence of water, even if the alkali is not dissolved, the Suzuki coupling reaction can also be carried out with many substrates.
What if the substrate contains both ester groups and can only react in the water? One way to do this is to add trace amounts of water. If the substrate itself contains methyl ester, it won’t react in toluene/EtOH/H2O because of transesterification. Researchers can simply replace the EtOH with MeOH to solve the problem. Another way is to obtain carboxylic acid products and then esterify.
Suzuki coupling reaction with heterocyclic aryl boronic acid
Good results can also be obtained when heterocyclic aryl boronic acid participates in the Suzuki coupling reaction.
3-pyridinyl diethyl borane is an air- and water-stable compound that can be used for heterocyclic aromatic reactions.
Generally speaking, the results of Suzuki coupling using 2-thiophenboric acid and 3-pyridine boric acid are not ideal.
Suzuki coupling reaction with alkyl boric acid
The yield of the Suzuki reaction involving aryl halide and methyl boric acid (ester) is generally low. An improved method is to use highly toxic TlOH or Tl2CO3 as an alkali. It has been reported recently that potassium methyl trifluoroborate has been used instead of methyl boric acid to obtain better results. The outstanding advantages of this method are that the reagent is easy to prepare and stable to air.
Suzuki coupling reaction with alkenyl boric acid
Suzuki coupling reaction with triflate
Because trifluoromethyl sulfonate can be easily prepared from the corresponding phenol or ketone, the participation of this reagent in the Suzuki coupling reaction has attracted more and more scientific researchers’ interest.
In the coupling reaction of trifluoromethyl sulfonate and aryl boric acid, sometimes the catalyst ligand PPh3 is easy to react with triflate at the initial stage of the reaction, resulting in the decomposition of the catalyst into palladium black. If LiBr or KBr equivalent to catalyst is added to the reaction system, it can prevent the decomposition reaction.
Suzuki coupling reaction with aryl chloride
Mitchell et al. reported that using dppb as a palladium ligand can effectively catalyze the Suzuki reaction of chloro-aryl-hetero-aryl boronic acid, with a yield of up to 98%. Later, Wang Shen et al. used tricyclohexylphosphorus (PCy3) as a palladium ligand and found that this ligand catalyst could activate aryl chloride bond most effectively, which may be because tricyclohexylphosphorus has more electrons than triphenyl phosphorus, thus increasing the ability of palladium oxidation to insert aryl chloride bond. Meanwhile, it was also found that under the catalysis of Pd(PCy3)Cl2, ortho aryl chloride was more efficient than aryl chloride.
Suzuki coupling reaction with nickel-catalyzed system
Syun Satio et al. found that chlorinated aromatic hydrocarbons and aryl boric acid could be coupled at a high yield at 80℃ under the catalysis of zero-valent nickel. Zero-valent nickel was prepared from NiCl2(dppf) (10 mol%) and n-BuLi (40 mol%) in a “one-pot” reaction, and chlorinated aromatic hydrocarbons could carry various electron-sucking or electron-donating genes. In this method, the cost of nickel catalyst is low, and chlorinated aromatic hydrocarbons used as reactants are cheap, therefore, it has high industrial application value. NiCl2(PPh3)2 has also been studied to catalyze the substitution of borates and brominates by alkyls, resulting in the synthesis of bioactive compounds at room temperature with a high yield of 80%.
Other Methods
Studies have found that for certain iodide substitutes, some non-phosphorus ligand catalysts can catalyze the reaction efficiently under relatively mild conditions, such as PdCl2, Pd(OAc)2, Pd/C, etc. At the same time, the impurity formed by ligands in the reaction can avoid the trouble of the product separation process.
- Direct Pd/C for Suzuki coupling reaction
Hiroa et al. used water as the solvent and Pd/C catalyzed the Suzuki coupling reaction between iodophenol and aryl boric acid at room temperature and achieved very good results. This method has great significance for mass production because it is called clean production.
D. S. Ennis et al. used Pd/C as the catalyst to carry out a large-scale Suzuki coupling reaction to produce an antidepressant drug, SB-245570.
- Direct Pd(OAc)2 is used for the Suzuki coupling reaction
