Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav
Selective Functionalization of Aliphatic Amines and Derivatives
Aliphatic amines are ubiquitous among pharmaceutical compounds, driving significant research into the
synthesis and functionalization of molecules bearing nitrogen atoms. Traditional strategies use functional group
handles to synthesize amines. We have been engaged in a research program that uses resident C-H bonds
and transforms them directly into the functionality of interest. The central challenge to derivatizing amines,
thus, was one of positional selectivity. A number of strategies were advanced in the previous funding period
with broad success.
In the next funding period, we will expand the repertoire of reactions, the positions of activation and the
complementarity to existing methods. We will develop methods to arylate C-H bonds in aliphatic amines, to
difunctionalize vicinal C-H bonds in analogy to olefin difunctionalization, again with complete positional
selectivity and to use earth abundant metal salts to activate distal C-H bonds of amines. Complementary
approaches will be aimed at providing a method to functionalize inaccessible C-H bonds on tertiary amines,
common components of many FDA approved drugs. These will allow structural diversification of complex
molecules as well as a structural editing approach to provide homologous scaffolds to bioactive molecules.
Lastly, primary amines are surprisingly widely available, far more so than alkyl halides or even carboxylic
acids, no doubt due to the ubiquity and importance of amide bond constructions. We will develop a
complementary strategy that will use the C-N bond as a functional group handle in cross-coupling chemistry.
All of these methods are designed to facilitate drug design and discovery in the pursuit of more efficacious
treatments for human diseases.
The specific goals of this research are as follows:
1) Site-Selective Remote Functionalization of Aliphatic Amines
2) Selective a-Functionalization of Tertiary Alkylamines
3) Deaminative Functionalization of Primary Amines
PHS 398/2590 (Rev. 09/04) Page Continuation Format Page