Benzylic amines are commonly found in current drug candidates and FDA approved drugs. The direct installation of a nitrogen into a benzylic C?H bond, generating a benzylic amine, would be significant as aromatics are ubiquitous in bioactive molecules. Additionally, direct functionalization of a prevalent C?H bond eliminates the need for pre-installed functionalities, eliminating synthetic overhead and accelerating drug-diversification. A highly site- and chemoselective, inexpensive first row transition metal-catalyzed benzylic C?H amination is proposed for the rapid diversification of topologically complex and functionally diverse molecules. The method will be optimized and the catalyst reactivity will be evaluated in a variety of common organic scaffolds used in drug design. Selectivity trends will be elaborated in more complex commercially available pharmaceuticals. Once reactivity and selectivity trends are established, the method will be used to diversify complex drug scaffolds and natural products. Nitrogen is abundant in pharmaceuticals and natural products, making nitrogen tolerance under the reaction conditions necessary to significantly broaden the applications of the proposed method. Bioactive molecules containing a tertiary amine or pyridine will undergo complexation to the quaternary salt, to quell unwanted side reactions from detrimental nitrogen binding to reaction intermediates in the benzylic C?H amination reaction. If the proposed research is achieved, many new small molecule drug candidates will be accessible in only one step from existing small molecules, pharmaceuticals, and natural products. Such a method would broadly impact human health and the field of medicine as rapid and inexpensive access to new drug candidates will be possible with an earth-abundant, non-toxic, first-row transition metal catalyst.
The aging human population and increasing drug resistance of many diseases will continue to create a high demand for the development of novel, potent bioactive molecules. The research proposed herein describes a new method for bioactive molecule diversification to provide rapid access to new drug targets.
| Clark, Joseph R; Feng, Kaibo; Sookezian, Anasheh et al. (2018) Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalization. Nat Chem 10:583-591 |
