Arenes and heteroarenes are omnipresent in both nature and society, and can be found throughout the human body and in other organisms, as well as in vitamins, drugs, dyes, pesticides, polymers and literally all other aspects of life. As these molecular frameworks form the backbones of some of the most important compounds in both biological systems and industrial applications, the need for methods for their functionalization and derivatization is of the utmost importance. Of particular interest are methods for the direct formation of carbon-carbon bonds through the introduction of alkyl and fluorinated alkyl groups. Alkyl groups serve medicinal chemists by improving pharmacokinetic profiles as well as providing functional handles, and fluoroalkyl appendages are widely utilized as they can serve as attenuated bioisoteres of more reactive and labile functionalities. The proposed research aims to expand upon a recently developed method in our laboratory for the direct, site-selective incorporation of alkyl and fluoroalkyl motifs into heteroarenes. Building on initial proof of concept studies, a "tool kit" of reagents will be synthesized and screened for ther ability to functionalize simple heteroarenes. Once synthesized, a method for sequential addition of multiple groups in a one-pot, site-selective fashion will be developed, taking advantage of the inherent nucleophilic or electrophilic character of each alkyl radical species. Finally, the long-term goal for this research is the application of this novel methodology to complex heteroarene backbones of biologically relevant compounds. Success in these goals would have an immediate impact on the medical community, giving medicinal chemists a new avenue for the rapid generation of interesting and diverse lead compounds for biological evaluation.
The proposed research focuses on the development of a novel, radical-mediated method for the direct, site-selective alkylation and fluoroalkylation of biologically relevant heteroarene scaffolds. These appendages are of significance to medical chemistry as they can improve pharmacokinetics, provide functional handles and act as bioisosteres for more labile and sensitive functionalities. Therefore, the development of a robust method for the site-selective incorporation of these motifs into pharmaceutically relevant scaffolds would have an immediate impact on the medical community as it would allow for the synthesis of libraries of novel lead compounds for biological evaluation.
|Wengryniuk, Sarah E; Weickgenannt, Andreas; Reiher, Christopher et al. (2013) Regioselective bromination of fused heterocyclic N-oxides. Org Lett 15:792-5|