Nitroalkanes are very useful intermediates in organic synthesis. Despite their wide-ranging reactivity as nucleophiles via the addition to carbonyls, conjugate addition, allylation, and arylation, a general method for the C-alkylation of nitroalkanes with simple electrophiles has remained an open challenge in organic synthesis for more than seventy years. Bridging this gap in reactivity would provide a valuable new method for incorporating nitrogen atoms in the synthesis of biologically relevant molecules.Our group has discovered a simple solution to this long-standing problem in copper-based homogeneous catalysts that allow for the high-yielding alkylation of nitronate-anions with simple radical stabilizing electrophiles to furnish two distinct pharmacophore classes. Functionalized �-nitroarenes are synthesized using mild conditions from commercially available benzylic bromides and simple nitroalkanes. Phenethylamines, easily obtained upon reduction of �-nitroarenes, are a potent class of medicinal agents for treating obesity and other metabolic diseases. Additionally, a-bromocarbonyls serve as excellent coupling partners for C-alkylation of nitroalkanes providing ready access to 1,3-nitrocarbonyls, a class not easily accessed with previously known methods. The resultant 1,3-nitroesters, -amides, -ketones, and -aldehydes can serve as intermediates for additional reactivity. Notably, reduction of the 1,3-nitroesters provides direct access to �-amino acids, a class of molecules displaying remarkable biological reactivity with increased proteolytic stability. The scope and limitations of this method, as well as the future directions of this research program, will be discussed.

<i>C</i>-Alkylation of nitroalkanes: Methods to prepare unique intermediates useful in the synthesis of biologically active amines

247th National Meeting (2014)

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C-Alkylation of nitroalkanes: Methods to prepare unique intermediates useful in the synthesis of biologically active amines