Process-Ready Nickel-Catalyzed Suzuki-Miyaura Coupling Enabled by tri-ProPhos

Area of Science:

• Organic Chemistry
• Catalysis
• Process Chemistry

Background:

• Palladium-catalyzed Suzuki-Miyaura coupling (Pd-SMC) is crucial for synthesizing active pharmaceutical ingredients (APIs) but is costly.
• Nickel-catalyzed SMC (Ni-SMC) is a cheaper alternative, yet faces challenges in catalyst loading and substrate scope.
• There's a need for sustainable synthesis methods using polar solvents like alcohols and water.

Purpose of the Study:

• To develop a novel catalyst for efficient Ni-SMC of heterocycles in polar solvents.
• To address limitations of existing Ni-SMC methods regarding catalyst loading and solvent compatibility.
• To provide a scalable and cost-effective alternative for API synthesis.

Main Methods:

• Development of a (tri-ProPhos)Ni catalyst featuring a phosphine moiety with hydroxyl groups.
• Application of the catalyst for Ni-SMC of various heterocycles in isopropanol (i-PrOH) and water.
• Validation of the catalytic system on a decagram scale.

Main Results:

• The (tri-ProPhos)Ni catalyst enables robust Ni-SMC of diverse heterocycles, including those found in APIs.
• Efficient catalysis was achieved in i-PrOH and pure water, demonstrating compatibility with polar solvents.
• Low catalyst loadings (0.03-0.1 mol %) were effective, and the method was successfully scaled to decagram quantities.

Conclusions:

• The (tri-ProPhos)Ni catalyst offers a sustainable and efficient platform for Ni-SMC in greener solvents.
• This method presents a viable alternative to Pd-SMC for commercial API synthesis, reducing costs and environmental impact.
• The catalyst's unique ligand structure enhances stability and facilitates transmetalation, broadening the scope of Ni-SMC.