Direct Intermolecular Azidation and Amination of Ketone Enolates via Umpolung¹

The α-amination of ketones is an important reaction in organic and medicinal chemistry. This poster discloses recent efforts from our group in preparing α-aminated ketones via enolonium species. These enolonium species are umpoled enolates i.e. electrophiles. Our recent discovery that it is possible to prepare enolonium species as discrete intermediates² makes it possible to add a variety of amine nucleophiles to the enolonium species to afford α-amino ketones. In previous work the amine nucleophile either had to be a ligand of the hypervalent iodine³ or otherwise tethered to the enolate⁴ in order to be compatible with the hypervalent iodine reagents. This ruled out amine nucleophiles that undergo oxidation processes or added extra steps to the overall process. The new direct reaction allows for the introduction of both N-heterocycles, aliphatic amines and azides in yields up to 83%. Some examples are shown below.

1) Atul A. More, Gulab Pathe, Keshaba N. Parida, Yuriy Lipisa, Shimon Maksymenko, Alex M. Szpilman, Submitted for publication, 2017

2) (a) S. Arava, J. N. Kumar, S. Maksymenko, M. A. Iron, K. N. Parida, P. Fristrup, A. M. Szpilman, Angew. Chem. Int. Ed. 2017, 56, 2599-2603 (b) Shimon Maksymenko, Keshaba N. Parida, Gulab Pathe, Yuriy Lipisa, Atul A. More, Alex M. Szpilman* Org. Lett. 2017, In Press

3) V. V. Zhdankin, Hypervalent Iodine Chemistry: Preparation, Structure, and Synthetic Applications of Polyvalent Iodine Compounds, Wiley, 2013
4) P. Mizar, T. Wirth, Angew. Chem. Int. Ed. 2014, 53, 5993-5997