Suzuki reaction

The Suzuki reaction or Suzuki coupling is an

, allowing for rapid generation of molecular complexity.

${\displaystyle {\begin{array}{c}\\{\color {Red}{\ce {R^{1}}}}{\ce {-X}}+{\color {Blue}{\ce {R^{2}-BY2}}}\ {\ce {->[{\text{[Pd] cat., base}}]}}\ {\color {Red}{\ce {R^{1}}}}{\ce {-}}{\color {Blue}{\ce {R^{2}}}}\\\end{array}}}$

General scheme of Suzuki reaction

Several reviews have been published describing advancements and the development of the Suzuki reaction.[5]^[6][7]

The

The Suzuki coupling takes place in the presence of a base and for a long time the role of the base was not fully understood. The base was first believed to form a trialkyl borate (R₃B-OR), in the case of a reaction of a trialkylborane (BR₃) and

In most cases the oxidative addition is the

Oxidative addition proceeds with retention of

The Suzuki coupling occurs with retention of configuration on the double bonds for both the organoboron reagent or the halide.

Transmetalation is an

The final step is the reductive elimination step where the palladium(II) complex (E) eliminates the product (3) and regenerates the palladium(0) catalyst (A). Using

The ligand plays an important role in the Suzuki reaction. Typically, the phosphine ligand is used in the Suzuki reaction. Phosphine ligand increases the electron density at the metal center of the complex and therefore helps in the oxidative addition step. In addition, the bulkiness of substitution of the phosphine ligand helps in the reductive elimination step. However, N-heterocyclic carbene ligands have recently been used in this cross coupling, due to the instability of the phosphine ligand under Suzuki reaction conditions.^[17] N-Heterocyclic carbenes are more electron rich and bulky than the phosphine ligand. Therefore, both the steric and electronic factors of the N-heterocyclic carbene ligand help to stabilize active Pd(0) catalyst.^[18]

The advantages of Suzuki coupling over other similar reactions include availability of common boronic acids, mild reaction conditions, and its less toxic nature.

Another example is the coupling of 3-pyridylborane and 1-bromo-3-(methylsulfonyl)benzene that formed an intermediate that was used in the synthesis of a potential central nervous system agent. The coupling reaction to form the intermediate produced 278 kilograms in a 92.5% yield.[15]^[23]

Significant efforts have been put into the development of heterogeneous catalysts for the Suzuki CC reaction, motivated by the performance gains in the industrial process (eliminating the catalyst separation from the substrate), and recently a Pd single atom heterogeneous catalyst has been shown to outperform the industry default homogeneous Pd(PPh₃)₄ catalyst.^[25]

The Suzuki coupling has been frequently used in syntheses of complex compounds.^[26][27] The Suzuki coupling has been used on a citronellal derivative for the synthesis of caparratriene, a natural product that is highly active against leukemia:^[28]

Various catalytic uses of metals other than palladium (especially nickel) have been developed.

Investigation into the nickel catalyzed cross-coupling continued and increased the scope of the reaction after these first examples were shown and the research interest grew. Miyaura and Inada reported in 2000 that a cheaper nickel catalyst could be utilized for the

It was also reported by Wu and co-workers in 2011 that a highly active nickel catalyst for the cross-coupling of aryl chlorides could be used that only required 0.01-0.1 mol% of nickel catalyst. They also showed that the catalyst could be recycled up to six times with virtually no loss in catalytic activity.^[33] The catalyst was recyclable because it was a phosphine nickel nanoparticle catalyst (G₃DenP-Ni) that was made from dendrimers.

Advantages and disadvantages apply to both the palladium and nickel-catalyzed Suzuki coupling reactions. Apart from Pd and Ni catalyst system, cheap and non-toxic metal sources like iron and copper^[34] have been used in Suzuki coupling reaction. The Bedford research group^[35] and the Nakamura research group^[36] have extensively worked on developing the methodology of iron catalyzed Suzuki coupling reaction. Ruthenium is another metal source that has been used in Suzuki coupling reaction.^[37]

Nickel catalysis can construct C-C bonds from amides. Despite the inherently inert nature of amides as synthons, the following methodology can be used to prepare C-C bonds. The coupling procedure is mild and tolerant of myriad functional groups, including: amines, ketones, heterocycles, groups with acidic protons. This technique can also be used to prepare bioactive molecules and to unite heterocycles in controlled ways through shrewd sequential cross-couplings. A general review of the reaction scheme is given below.^[38]

The synthesis of a tubulin-binding compound (antiproliferative agent) was carried out using a trimethoxybenzamide and an indolyl pinacolatoboron coupling partner on a gram scale.^[38]

Aryl

• Chan-Lam coupling
• Heck reaction
• Hiyama coupling
• Kumada coupling
• Negishi coupling
• Petasis reaction
• Sonogashira coupling
• Stille reaction
• List of organic reactions