Suzuki and Related Cross-Coupling Reactions

Cross-coupling reactions, and the Suzuki reaction in particular, are among the widely used synthetic methods for creating new C-C bonds to form more complex molecules from smaller molecules.  In the Suzuki reaction, or Suzuki–Miyaura reaction, an organoboron compound, and an organohalide are cross-coupled in the presence of a base using a palladium complex as a catalyst. The reaction is used in the pharmaceutical industry to link, for example, aromatic ring structures to create more complex intermediate compounds used in API synthesis. Related coupling reactions include Negishi and Heck, which also use transition metal complexes as catalysts in cross-coupled reactions.  The Negishi reaction couples organohalides with organozinc compounds to form C-C bonds, while the Heck reaction uses a palladium catalyst to couple an unsaturated halide with an alkene, forming a substituted alkene. 

There are a number of other reactions that form C-C bonds in cross-coupled products.  In Kumada-Corriu coupling, a Grignard reagent, and an organic halide are coupled using palladium or nickel. The Sonogashira reaction uses a palladium catalyst and a copper co-catalyst to cross-couple an alkyne and an aryl or vinyl halide.  

Generally, commonly used cross-coupling reactions can be classified as either catalyzed reactions or non-catalyzed.  Catalyzed cross-coupling reactions typically use a transition metal such as palladium, zinc, nickel complexed with a variety of ligands. The Grignard reaction is an example of a non-catalyzed C-C bond forming synthesis.

Catalyzed cross-coupling reactions include:

• Suzuki–Miyaura – Couples boronic acids, boron esters, borane with alkyl or aryl halides
• Negishi – Couples organozinc compounds with organohalides
• Heck – Couples unsaturated halide with an alkene
• Kumada-Corriu – Couples Grignard reagent with organohalides
• Stille – Couples organic halides with organotin compounds 
• Sonogashira – Couples terminal alkyne and an aryl or vinyl halide.
• Hayashi-Miyaura - couples bis(pinacolato)diboron (B2pin2) with aryl halides and vinyl halides

In the Suzuki - or Suzuki–Miyaura - reaction, an organoboronic acid and an organohalide are cross-coupled using a palladium complex as a catalyst in the presence of a base. The reaction is used in the pharmaceutical industry to link, for example, aromatic ring structures to create more complex intermediate compounds used in API synthesis.

There are three basic processes that occur in a Suzuki coupling reaction. In the first step, a Pd(II) intermediate compound is formed via oxidative addition of a Pd(0) complex by an aryl halide species. Next, in the presence of a base, the organoborane compound reacts with the Pd(II) intermediate species and forms a second intermediate complex via transmetalation. Finally, the product is formed via reductive elimination and the original Pd(0) complex is reestablished. 

Cross-coupling reactions are among the most prolifically used methods to achieve C-C bonding as well as C-H, C-N, C-O, etc bond formation.  For this reason, cross-coupling reactions are important in pharmaceutical, polymer, and natural synthesis applications. In the case of the widely adapted Suzuki reaction, there are numerous advantages of this synthesis method:

• Mild reaction conditions with good yields
• Stable in air and water
• Low toxicity; supports green chemistry
• Useful with a broad range of functional groups
• High reaction stereoselectivity
• Can readily be used in telescoped reactions 
• Wide diversity of available organoboron compounds
• Palladium complexes available with an array of ligands 

The Heck reaction is important in commercial applications as well. For example, the pharmaceuticals montelukast (Asthma), naproxen (NSAID), eletriptan (migraines), and rilpivirine (HIV) all used Heck reactions in their synthesis. The Sonogashira reactions were used in the synthesis of terbinafine (fungicide). The Negishi reaction is not typically used for large-scale synthesis due to the toxicity associated with stannanes and water/oxygen sensitivity, but it has proven very useful in natural product synthesis. 

Part of the reason for the ever-widening scope of Suzuki coupling and related reactions is the expanding research, development, and availability of novel organoboron compounds and transition metal catalyst complexes. In situ vibrational is providing important information in the synthesis of these reagents and catalysts with regard to activity and structure, such as how ligands are bonded. Furthermore intermediates that form during coupling reactions are observed and identified by in-situ vibrational spectroscopy. In chemical process development and scale-up,  investigating the effect of reaction variables such as temperature, dosing rate, and stirring on coupling reactions leads to optimized syntheses.

For these reasons, ReactIR and ReactRaman in-situ vibrational spectroscopy are valuable tools in the study of Suzuki and related coupling reactions. Also, to ensure process safety and to support studies on the effect of reaction variables, EasyMax and EasyMax HFCal are important in quantifying reaction kinetics and thermodynamics. In situations where reaction samples are required for offline testing, EasySampler provides unattended, automated sample removal, and dilution - without disturbing the reaction.

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