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Design and Scalable Synthesis of Novel N-Alkyl-Hydroxylamine Reagents for the Direct, Fe-Catalyzed Installation of Medicinally Relevant Amines

preprint
submitted on 29.05.2020 and posted on 01.06.2020 by Eric Falk, Szabolcs Makai, Tristan Delcaillau, Laura Gürtler, Bill Morandi

Secondary and tertiary alkylamines are privileged substance classes which are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of nine novel hydroxylamine-derived aminating reagents was designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The methodology displays an excellent functional group tolerance, and a broad scope of alkenes was converted to the corresponding products, including several drug-like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, is demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.

Funding

Swiss National Science Foundation (SNSF 184658)

History

Email Address of Submitting Author

morandib@ethz.ch

Institution

ETH Zurich

Country

Switzerland

ORCID For Submitting Author

0000-0003-3968-1424

Declaration of Conflict of Interest

N/A

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