The presence of amines in biologically active molecules, active pharmaceutical ingredients, and their building blocks is widespread. The alkene hydroamination reaction, formally the addition of an N-H bond across an unsaturated carbon-carbon bond, represents an efficient, practical and atom-economical method for the synthesis of amines from simple alkene starting materials. Significant advances have been made over the past few decades in developing this reaction;however, a general and dependable method for the intermolecular hydroamination of unactivated alkenes with broad functional group tolerance remains elusive. The proposed study outlines a strategy toward the development of rhodium catalysts for the hydroamination of unactivated alkenes.
The specific aims are: 1) To synthesize, isolate, and characterize rhodium catalysts containing an ?6-arene tethered to a phosphorus or nitrogen donor. A series of phosphinoalkylarene and pyridylalkylarene ligands will be synthesized and converted to the corresponding rhodium complexes for evaluation in subsequent hydroamination studies. 2) To test the catalysts prepared as part of Specific Aim 1 for intra- and intermolecular hydroaminations that current systems do not catalyze. Substrates that will be investigated include 1,1- and 1,2-disubstituted aminoalkenes that lack gem-disubstitution on the alkyl chain for intramolecular hydroaminations and unactivated olefins, such as 1- pentene, for intermolecular reactions. 3) To reveal mechanistic information about hydroaminations catalyzed by the rhodium complexes of Aim 1. It is difficult to predict whether the turnover-limiting step in reactions catalyzed by complexes of Aim 1 will be nucleophilic attack on the coordinated olefin or protonolysis of the alkylrhodium intermediate. To address this question, mechanistic studies will be focused on the identification and isolation of the key alkylrhodium intermediate from addition of amine to the coordinated olefin, and to study the reactivity of this intermediate toward protic acids. 4) To develop enantioselective hydroaminations, which represents a long-term objective. Chiral rhodium complexes containing the structural core of the complexes of Aim 1 will be investigated for the development of enantioselective hydroaminations.
For every drug on the market, thousands of compounds were synthesized as part of a drug discovery program. With the development of novel and efficient methods for the synthesis of biologically active molecules, new drugs will be discovered more rapidly for the treatment of disease.
| Julian, Lisa D; Hartwig, John F (2010) Intramolecular hydroamination of unbiased and functionalized primary aminoalkenes catalyzed by a rhodium aminophosphine complex. J Am Chem Soc 132:13813-22 |
