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Copper-mediated Functionalization of Aryl C-H Bonds


New ways to produce drug leads - Part III

The Situation: Current methods for selective introduction of functional groups to organic molecules are costly due to the use of rare transition metal catalysts.

Our Solution: We developed a novel strategy for selective functionalization of organic molecules using readily available copper(II)-catalysts. This technology allows tremendous savings for organic synthesis of pharmacologically important compounds, and will revolutionize pharmaceutical manufacturing in the near future.

Background

Selective functionalization of C−H bonds of organic molecules is an important tool for producing new class of compounds useful as drug leads for bio-pharmaceutical research. Controlled C−H bond functionalization is one of the most challenging processes in chemistry, generally requiring either a stoichiometeric amount of a heavy-metal salt or a catalyst containing a transition metal. A wide range of transition metal catalysts, including ruthenium (Ru), rhodium (Rh), platinum (Pt), and palladium (Pd), have been used in C−H activation reactions with varying degrees of success; however, the ever-increasing cost of these metals detracts from the allure of their use. Consequently, a need exists for an efficient method for functionalization aryl C−H bonds based on a strategy that does not comprise a rare, costly transition metal. Likewise, a need also exists for a general oxidation method in which the oxidant is safe and cost-effective.

Applications

  1. To customize or modify pharmacologically important molecules with desired functional groups.
  2. To generate previously unattainable compounds as candidates for drug screening (creating new combinational libraries).

Advantages

  • Offers unconventional short-cuts in synthetic processes, hence dramatically cuts cost in manufacturing pharmaceuticals and other fine chemicals.
  • Readily available catalysts and oxidants are used for safety and cost-effectiveness.
  • Functionalized products obtained by this technology can be used as building blocks for further synthetic transformations to yield biologically active small molecules.

Technology

Figure

This invention provides a cost-cutting improvement for direct functionalization of pyridyl-substituted aromatic compounds, using copper-containing catalysts in place of palladium-containing catalysts. In this technology, 2-arylpyridine substrates are reacted with anionic nucleophiles in the presence of copper(II) to furnish substituted arylpyridines by regioselective functionalization at the ortho position of the aryl ring. Also, the present invention allows for both mono- and di-functionalizations of aromatic compounds by manipulating the reaction conditions. Within the last decade, bulk palladium has sold on the international metal market for roughly 5000 times the cost of bulk copper. Therefore, based on catalyst cost alone, this technology offers tremendous savings in manufacturing costs comparing to traditional methods that require expensive transition metal-catalysts. Moreover, oxygen can be utilized efficaciously along with this invention as a stoichiometric oxidant, further cutting down operational costs for manufacturing pharmaceuticals and other fine chemicals.

Patent Status

  • Patent pending in United States

Inventors

Jin-Quan Yu

To discuss this technology with a licensing officer, please call Irene Abrams at (781)-736-2176 or email iabrams@brandeis.edu and ask about record ID: 2006-0301.