Project Summary Amines and their derivatives are ubiquitous substances since they are present in the overwhelming majority of drug molecules, agrochemicals, functional materials as well as many compounds that are produced by living organisms (i.e., natural products). Notably, there are, on average, 2.8 nitrogen atoms in each of the 200 best- selling small molecule drugs and, of these drugs, 80% contain at least one N-heterocyclic fragment. It is also estimated that 45% of drug candidates contain a chiral amine moiety. Among these nitrogen-containing compounds, aromatic and heteroaromatic amines (i.e., anilines) appear as core structures in more than one third of drug candidates while aziridines, the three-membered and equally highly-strained nitrogen analogues of epoxides, are important synthetic intermediates en route to structurally complex molecules due to their versatility in myriad regio- and stereoselective transformations. Not surprisingly, organic chemists invest a considerable amount of effort devising better strategies for synthesis of amines that serve as key chemical building blocks for the preparation of biologically active compounds, especially in medicinal chemistry. These strategies can also be used for late-stage functionalization of complex molecules that enables the exploration of new chemical space for biological studies. Consequently, new and powerful synthetic strategies and methods for the rapid and direct introduction of nitrogen into readily available and inexpensive precursors such as alkanes, alkenes, arenes, heteroarenes as well as carbonyl compounds are expected to have a far-reaching impact upon how organic synthesis, medicinal chemistry, biochemistry and chemical biology are practiced. In particular, the introduction of unprotected nitrogen and other heteroatoms in a single step and under mild conditions will result in processes that are more efficient and “greener” than currently used multi-step routes and ultimately will lead to the faster development of new medicines. During the course of the proposed project novel metal-catalyzed and organocatalytic amination processes will be developed that will take advantage of both catalytically and stoichiometrically generated electrophilic aminating agents. Thus, the direct synthesis of chiral as well as achiral primary and secondary anilines from aromatic and heteroaromatic compounds, of alpha-aminated carbonyl compounds from ketones and carboxylic acid derivatives, of fully-substituted amines from ketimines, ketoximes and ketiminoesters and of NH- as well as N-alkylaziridines from isolated/unactivated olefins will be achieved. The proposed catalytic amination processes will be thoroughly investigated to uncover and understand their mechanistic underpinnings. Emphasis will be given to the development of reactions that can utilize abundant and inexpensive starting materials and convert these to structurally complex/value added products under operationally simple and mild reaction conditions.

Project Narrative This project brings together the complementary expertise of two laboratories to tackle the challenges of developing a wide variety of organo- and metal-catalyzed amination reactions to prepare structurally diverse chiral amines. Olefins will be directly converted to enantiomerically enriched NH- and N-alkylaziridines via catalytically-generated N-electrophilic oxaziridines, ketimines and ketiminoesters will furnish fully-substituted amines upon catalytic asymmetric allylation, while arenes will be converted to the corresponding chiral and sterically hindered N-alkylanilines via catalytic C-H amination and using novel electrophilic aminating agents with previously inaccessible structural complexity. The resulting unprotected amine products are highly prized by the synthetic/medicinal chemistry communities and the new environmentally friendly chemical transformations (i.e., green chemistry) that emerge will expedite synthetic access to and reduce the production cost of highly functionalized nitrogen-containing materials and ultimately will lead to the faster development of new medicines.