Light Driven Chemistry

Novel Manufacturing Process for Pharmaceuticals and Specialty or Bulk Chemicals
Opportunity

Available for Licensing

IP Status

US Utility Patent Pending

Inventors

Garret Miyake
Chem-Hooi Lim
Max Kudisch
Bin Liu

At A Glance

We introduce a carbon-nitrogen (C-N) cross-coupling method that operates at room temperature using an inexpensive nickel (Ni) source while being tolerant to oxygen and proceeds through direct irradiation of the Ni complex without added photoredox catalyst, ligand, or base.

C-N cross-coupling is an important class of reactions with far-reaching impacts across chemistry, materials science, biology, and medicine. Transition metal complexes can elegantly orchestrate diverse aminations but typically require demanding reaction conditions, precious metal catalysts, or oxygen sensitive procedures.

Aryl C-N bonds are ubiquitous across a wide range of natural products and medicinally-relevant compounds, making aminations one of the most important and frequently used reactions in medicinal chemistry.

Licensing Director

Steve Foster
Steve.Foster@colostate.edu
970-491-7100

Reference No.: 18-036

Background

Copper-catalyzed Ullmann condensations constitute one of the oldest methods to construct an aryl C-N bond, but commonly require elevated temperatures that can limit reaction scope.  In the past two decades, however, there has been renewed interest in Ullmann-type cross-coupling reactions, largely due to significant advances in new Cu/ligand systems.  Since these developments, the field of transition metal-catalyzed C-N bond formation has evolved to provide a plethora of approaches for efficient aminations.  Notably, palladium-catalyzed C-N coupling has been the predominant method for constructing aryl C-N bonds.  However, not only is palladium a precious metal that raises sustainability and cost concerns, but also palladium catalysis typically utilizes strong base, high temperature and specialized ligands that post limitations in some applications.

As such, the potential to use abundant nickel catalysts has received significant interest.  The widespread use of Ni is, however, hampered by the required use of high temperatures, strong alkoxide bases, and air-sensitive Ni compounds.  In recent years a new paradigm has arisen in aryl C-N bond formation as methods have emerged that are driven by light.  And although these additions introduce a significant advancement in the field, the reactions typically require a strong alkoxide base, high energy UV irradiation, and have a limited reaction scope.  More recently, dual photoredox systems driven by light through a union of photoredox catalysts (PCs) and Ni catalysis have been reported.  But again, the use of these precious metal-base PCs raises sustainability and cost concerns for the proliferation of such technology.

Technology Overview

The light driven Ni-catalyzed C-N cross-coupling methodology created here does not use any added ligands, bases or photoredox catalysts.  By irradiating a solution containing an amine, an aryl halide, and a catalytic amount of NiBr2•3H2O by LED at room temperature, this operationally simple process is successful at coupling secondary, primary alkyl, or primary (hetero)aryl amines and aryl halides with diverse electronics – with 40 examples available!  The effectiveness of this method is highlighted by the successive use of light-driven C-N cross-coupling to synthesize complex structures, such as those found in pharmaceutical drugs.

This work establishes that the catalytically active Ni state for C-N cross-coupling can be efficiently accessed through electronic excitation of a nickel-amine complex without the aid of any supplementary PC to effect electron or energy transfer.  By eliminating the need for a PC, this work not only contributes to the mechanistic understanding of Ni-catalyzed cross-coupling chemistry, but also improves the potential and sustainability of this technology.

Benefits
  • No Photredox Catalysts
  • Low Temperatures
  • No Added Bases or Ligands
  • Cost Effective
  • Synthesizes Complex Structures
  • Sustainable
Relevant Publications

Lim, Chern-Hooi, et al. “C-N Cross-Coupling via Photoexcitation of Nickel-Amine Complexes.” Journal of the American Chemical Society, U.S. National Library of Medicine, 20 June 2018, www.ncbi.nlm.nih.gov/pubmed/29787252.

Last updated on October 7, 2019.