Sulfur–Fluoride Exchange (SuFEx)-Mediated Synthesis of Sterically Hindered and Electron-Deficient Secondary and Tertiary Amides via Acyl Fluoride Intermediates

5 years ago

Sulfur–Fluoride Exchange (SuFEx)-Mediated Synthesis of Sterically Hindered and Electron-Deficient Secondary and Tertiary Amides via Acyl Fluoride Intermediates

Marie-Claire Giel, John E. Moses, Christopher J. Smedley, Christian Spiteri, Andrew S. Barrow, Pallavi Sharma

Amide bond formation is one of the most executed reactions in chemistry and biology. This is largely due to the ubiquity of the amide functional group in biological molecules, natural products and pharmaceutically important drugs. We report here the development of “SuFExAmide”: a new sulfur–fluoride exchange (SuFEx) click chemistry based protocol for the efficient amidation of carboxylic acids via acyl fluoride intermediates. We have developed benzene-1,3-disulfonyl fluoride as a cost effective, powerful and versatile coupling agent, which delivers challenging secondary and tertiary amides in excellent yields from sterically hindered and electron-deficient amines. The straightforward method offers significant benefits over existing protocols in terms of substrate scope, efficiency and ease of operation and is demonstrated by the synthesis of 44 amides, including GNF6702, an antiprotozoal drug candidate. In the majority of cases, the amide products are obtained in high yield without the need for excess reagents or chromatographic purification. The perfect couple: A new SuFEx (sulfur–fluoride exchange) click chemistry based protocol for the efficient amidation of carboxylic acids via acyl fluoride intermediates, using benzene-1,3-disulfonyl fluoride as a condensing reagent. SuFExAmide has broad substrate scope and is well suited for the synthesis of challenging, sterically hindered and electron-deficient secondary and tertiary amides. The majority of the 44 examples of amide products described here were obtained in high yield without the need for excess reagents or chromatographic purification.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201701552