Modern medicine is reliant on the preparation of complex organic molecules. These compounds comprise the active ingredients of most pharmaceutical agents. As the need for more selective, more potent, and more effective medicines increases, there is an ever-growing need to develop new methods for efficient chemical synthesis of complex organic molecules. Alkyl amines are a common structural element in many major pharmaceutical agents. Although numerous methods exist for their construction, many of these methods rely on common chemical intermediates (carbonyl compounds) as starting materials. This common chemical feedstock limits the ways in which alkyl amines can be prepared. Thus, there is need for new methods to prepare such molecules from other precursors. This proposal outlines two new methods to prepare complex alkyl amines using non-carbonyl starting materials. The thematic linkage of the proposed methods is the utilization of transition metal-based catalysts to develop new approaches to amine synthesis using nitroalkane starting materials.
In Aim 1, a new approach to the carbon-centered alkylation of nitroalkanes using simple copper catalysts is proposed. The products from these reactions are readily converted into alkyl amines. Previous methods to achieve this transformation relied on experimentally demanding reaction conditions or on the use of either complex or highly toxic reagents. Based on our preliminary discovery of mild reaction conditions for the C-alkylation of nitroalkanes using abundant alkyl halides, a general method to prepare complex nitroalkanes is proposed.
Aim 2 outlines plans for the development of a method for the catalytic conversion of nitroalkanes into enantioenriched amines using ruthenium catalysis. This new method promises to provide a new route into enantioenriched amines that is highly complementary to existing methods and can be broadly leveraged against the products from Aim 1, as well as nitroalkanes prepared by existing methods. In total, the proposed methodology is expected to provide improved access to complex alkyl amines using non-traditional starting materials. This effort will directly benefit the preparation of complex nitrogen-bearing organic molecules and aid in the discovery of the next generation of pharmaceutical agents.
Alkyl amines are common structural elements in many major pharmaceutical agents but are often difficult to prepare due to lack of synthetic methods. This proposal outlines two new methods to prepare complex alkyl amines using non-traditional starting materials. This effort will increase the means by which complex nitrogen- bearing organic molecules can be prepared, which will likely aid in the discovery of the next generation of medicines for the treatment of human disease.
| Rezazadeh, Sina; Devannah, Vijayarajan; Watson, Donald A (2017) Nickel-Catalyzed C-Alkylation of Nitroalkanes with Unactivated Alkyl Iodides. J Am Chem Soc 139:8110-8113 |
| Gietter-Burch, Amber A S; Devannah, Vijayarajan; Watson, Donald A (2017) Trifluoromethylation of Secondary Nitroalkanes. Org Lett 19:2957-2960 |
| Shimkin, Kirk W; Gildner, Peter G; Watson, Donald A (2016) Copper-Catalyzed Alkylation of Nitroalkanes with ?-Bromonitriles: Synthesis of ?-Cyanonitroalkanes. Org Lett 18:988-91 |
| Gietter-Burch, Amber A S; Mitrut, Roxana E; Watson, Donald A (2015) Highly Diastereoselective Michael Reactions Using ?-Nitrocarbonyl Nucleophiles. Org Lett 17:5468-71 |
| Shimkin, Kirk W; Watson, Donald A (2015) Recent developments in copper-catalyzed radical alkylations of electron-rich ?-systems. Beilstein J Org Chem 11:2278-88 |
| Gietter, Amber A S; Gildner, Peter G; Cinderella, Andrew P et al. (2014) General route for preparing ?-nitrocarbonyl compounds using copper thermal redox catalysis. Org Lett 16:3166-9 |
