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Advances in Transitional Metal Catalyzed Bond-Forming Reactions via Aqueous Micellar Catalysis

  • Author(s): Jin, Bo;
  • Advisor(s): Lipshutz, Bruce H;
  • et al.
Abstract

Traditional Sonogashira coupling reactions require high loadings of both palladium(II) and copper(I) catalysts. A copper-free, ppm palladium approach was discovered by using a combination of novel ligand and palladium pre-catalyst. A wide range of (hetero)aryl bromides and terminal alkynes can be tolerated under standard reaction condition in water at 45 oC without any organic solvent. In many cases solid crude products can be obtained by simple filtration, and the filtrate can be recycled. No more than 1 ppm of palladium residue was detected in ICP-MS analysis. A key internal alkyne precursor of commercially available tyrosine-kinase inhibitor ponatinib (Iclusig®) was prepared by using this methodology. This reaction is efficient, greener and cost-effective compared with currently used ones.

Fe/ppm Pd nanoparticles are highly useful catalysts used in Suzuki-Miyaura coupling reactions. However, the relatively long reaction time at 45 oC limits their applications in time-sensitive reactions. Modifications of the original nanoparticles were conducted by adding another earth abundant metal (Ni, Co, Mn) and screening different types of ligands. The original nanoparticles were used in a newly designed continuous flow reactor to synthesize key pharmaceutical intermediates. The sartan precursor, JAK inhibitor precursor and BRAF inhibitor precursor were prepared in this continuous flow platform. This approach gives an idea of how to perform large scale Suzuki-Miyaura coupling reactions in water using Fe/ppm Pd nanoparticles.

Diaryl ethers are common structures in drugs. These compounds are usually prepared by copper catalyzed Ullmann-type reactions under harsh conditions in organic solvents. Different types of ligands were tested with copper(I) or palladium(II) salts in water. These reactions give a hint of ligands and co-solvents used under aqueous micellar condition.

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