New Catalytic Methods for Atom-Efficient Synthesis of Nitrogen-Containing Compounds

Zhao, Pinjing

Abstract

Nitrogen-containing molecular moieties are among the most important subunits of biologically active compounds. In particular, a majority of drug molecules and drug candidates contain amine or nitrogen heterocycle (N-heterocycle) functionality. In spite of many synthetic routes towards nitrogen-containing compounds from classic organic chemistry and more recent catalysis development, there remains a significant need for efficient and cost-effective synthesis of amines and N-heterocycles in biomedical research and drug development. The primary goal of this proposed research is to develop new and atom- efficient transition metal-catalyzed synthetic methods for several classes of 5- and 6-membered N- heterocycles and other nitrogen-containing compounds such as ?-branched amines. The overall research strategy emphasizes on in-depth mechanism understanding and catalytic application of transition metal- mediated C-H bond activation and migratory insertion processes for C-C and C-N bond formation.
Three specific aims for this research are developed based on mechanistic insights from model catalytic couplings between N-H aromatic ketimines and alkynes previously studied by the PI's group.
Specific Aim 1 focuses on the development of catalytic N-heterocyclization processes by intramolecular hydroarylation of organic ?-systems to synthesize oxindole derivatives. The envisioned key steps of tandem C-H activation and ring-closure by intramolecular migratory insertion are mechanistically related to the model reaction of ruthenium-catalyzed [3+2] imine/alkyne annulation for indenamine synthesis. These reactions will provide efficient construction of oxindole structures including and isatins.
Specific Aim 2 focuses on redox-neutral annulation between alkynes and aromatic compounds with N-H moiety-based directing groups to synthesize several classes of 5- and 6-membered benzo-N-heterocycles with controlled chemoselectivity and stereoselectivity. Feasibility of this strategy was demonstrated with a model reaction of rhodium-catalyzed [4+2] imine/alkyne annulation to synthesize 3,4-dihydroisoquinolines, which proceeded by a proposed tandem sequence of C-H alkenylation and intramolecular alkene hydroamination.
Specific Aim 3 focuses on the development of nickel/N-heterocyclic carbene (NHC) catalysts for alkyne hydroamination with a broad scope of N-H nucleophiles. This study derives from a model reaction of Ni/NHC-catalyzed alkyne ?hydroimination? via a proposed anti-attack on Ni-coordinated alkynes by N-H imine nucleophiles. Mechanism-driven catalyst improvement will enable mild and cost-effective synthesis of imine- and enamine-type hydroamination products, which will be explored for novel N-heterocyclization procedures as well as a one-pot transfer hydrogenation protocol towards ?-branched amine synthesis. Successful completion of the proposed research will result in the development of several new catalytic reactions for atom-efficient synthesis of biomedically important amine and N-heterocycle structures from readily available building blocks. With the synergy between reaction mechanism understanding and catalyst development, results from our studies will advance the fundamental knowledge on organometallic chemistry and guide future developments of mechanistically related catalytic methods for applications in medicinal chemistry and drug synthesis.

Public Health Relevance

This proposed research aims to develop new, transition metal-based catalysts for efficient synthesis of nitrogen-containing small molecules that are important subunits of biologically active compounds. The catalyst design is guided by in-depth reaction mechanism understanding and focuses on new strategies of metal-mediated activation of carbon-hydrogen bonds and formation of carbon-carbon and carbon-nitrogen bonds. This work will contribute to the advancement of fundamental organometallic chemistry and catalysis, and provide new synthetic tools for biomedical research and drug development.