Breaking the aliphatic wall: iridium-catalyzed direct reductive amination of ketones and secondary amines

The direct reductive amination reaction is highly important for medicinal chemistry and process chemistry research since it is 100% atom-economy and delivers water as the only side-product. Its applicability for purely aliphatic amines and purely aliphatic ketones remained elusive until this recent collaboration from the ISCR and Janssen Pharmaceutica.
Breaking the aliphatic wall: iridium-catalyzed direct reductive amination of ketones and secondary amines

The sustainable production of active pharmaceutical ingredients (API) is fundamental for the progress of our society. In this respect, efforts devoted to apply green technologies and reducing the number of steps as well as the use of more benign processes is appealing. The current synthesis of APIs typically rely on catalytic methodologies. From the many ones available, those involving transition metal catalysts are highly attractive because they enable to explore efficient and less demanding retrosynthetic schemes. In this scenario, aliphatic amines are prevalent motifs found in a myriad number of APIs. The most sustainable synthesis from an industrial point of view is the direct reductive amination reaction which consist on combining ketones and amines in the presence of tiny amounts of a metal catalyst under hydrogen pressure. This process delivers the desired alkylated amine with water as the solely side-product with full atom-economy. However, the existing methodologies fail to employ both aliphatic coupling partners. In the present contribution, we have disclosed such an unprecedented transformation by means of a unique iridium-catalyzed process compatible with a broad range of biologically relevant motifs (see image). This is the very first collaboration between the ISCR and Janssen Pharmaceutica (a Johnson & Johnson company) and the results have been published in Chemistry – a European Journal: https://doi.org/10.1002/chem.202201078.

Contact

Rafael Gramage-Doria, Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France
rafael [dot] gramage-doriaatuniv-rennes1 [dot] fr

 

Published May 06, 2022