Chemically catalyzed amide bond formation under mild reaction conditions.
- Enables amide bond formation under mild reaction conditions.
- Organocatalyst are easily synthesized.
- Avoids the use and disposal of hazardous chemicals.
Amide bonds are very frequently incorporated into active pharmaceutical ingredients (API). Amide bond formation is one of the most prevalent transformations in the pharmaceutical industry, accounting for 16% of all reactions carried out in medicinal chemistry laboratories. However, the ideal method for amide synthesis (i.e., the direct condensation of a carboxylic acid and an amine) has some challenges and requires use of either forcing conditions or an additional step to complete the transformation. The development of safe and efficient processes for amide formation on industrial scale is of paramount importance. The ideal reagent is inexpensive, safe, simple to handle, easy to purge from reaction mixtures, and contributes only minimally to waste streams.
Emory researchers have developed a new aerobic, catalytic oxidation−reduction condensation system for efficient acylative bond formations. It is based upon the use of benzoisothiazolones (BITs) as easily prepared and modified S−N bond-derived organocatalytic oxidants. Carboxylic acids and amine/amino acid reactants can be converted to amides and peptides at neutral pH within 5−36 hours at 50°C using catalytic quantities of a redox-active BIT and a copper complex. These catalytic "oxidation−reduction condensation" reactions are carried out open to dry air using oxygen gas as the terminal oxidant and a slight excess of triethylphosphite as the reductant. Triethylphosphate is an easily removed byproduct. These simple-to-run catalytic reactions provide practical and economical procedures for the acylative construction of C−N bonds.
This method has been tested in small scale production of compounds.
Publication: Gangireddy, P. et al. (2017). Journal of Organic Chemistry, 82(7), 3513–3529.