Office of Technology Transfer – University of Michigan

Selective Fluorination of Aromatic and Heteroaromatic Systems

Technology #5499

This technology provides cheap and safe fluorination of aromatic and heteroaromatic systems for small and large scale syntheses. This method uses organometallic chemistry to form carbon-fluorine bonds under mild conditions, it is selective, general and suitable for a broad range of substrates. Addition of fluorine molecule(s) can enhance both drug pharmacokinetics by making it more bioavailable, lipophilic, and metabolically stable, as well as pharmacodynamics by increasing its affinity for the target protein. It has been noted that introducing a fluorine into a lead structure enhances the probability of development success by almost 10-fold. It is therefore not surprising that 20% of all drugs, and 30% of best-selling drugs in 2011, contain fluorine. However, formation of carbon-fluorine bonds remains a challenge where harsh conditions and hazardous reagents are often required, limiting synthetic diversity of fluorinated compounds and increasing development time and cost. Thus, a cheap, safe, and broadly applicable methodology for aromatic fluorination is needed.

Copper-Catalyzed Electrophilic Fluorination Under Mild Conditions

Researchers in the Department of Chemistry at the University of Michigan developed a new synthetic route for selective fluorination of aromatic and heteroaromatic systems. This method uses a copper-based catalyst and an electrophilic fluorine source to produce an aryl fluoride in high yield. An arylboronic acid is used as a substrate where C–B bond is replaced by C–F bond. Reaction proceeds under mild conditions and thus can be utilized with a broad range of substrates. This synthetic methodology can be used by pharmaceutical companies both in research and development and large scale manufacturing. It can be used to add fluorine groups to diverse collections of compounds, and utilize a common intermediate to make sets of fluorinated analogs for structure-activity relationship studies. Agrochemical and radiochemical companies can also benefit from this methodology.

Applications

  • Fluorination of aromatic and heteroaromatic compounds
  • R&D and process scales

Advantages

  • Cheaper and safer alternative to current methods
  • Performed under mild conditions
  • Obtain product in high yield
  • Wide substrate scope