Discovery and development of copper catalysts for the C-alkylation of nitroalkanes

Date
2014
Authors
Gildner, Peter G.
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Publisher
University of Delaware
Abstract
Nitroalkanes are useful reagents for building complex molecules in organic synthesis by acting as powerful intermediates for forming new carbon-carbon (C-C) bonds, and serving as precursors for a variety of functional groups. Despite this wealth of established reactivity, the carbon alkylation of nitroalkanes with alkyl electrophiles remains undeveloped. Despite the seeming simplicity and high value of this potential transformation, general conditions for this reaction are not known. The discovery and development of catalytic conditions to promote the C -alkylation of nitroalkanes with several classes of alkyl electrophiles are reported. The success of this newly developed C -alkylation methodology is dependent on copper bromide together with diketoimine (nacnac) ligands to catalyze the alkylation of nitroalkanes in a thermal redox pathway. The utility of this method is first demonstrated with the C -alkylation of various functionalized nitroalkanes with a variety of functional group bearing benzyl bromides. It is proposed that a stabilized radical intermediate is generated by single electron transfer (SET) or atom transfer (AT) from an electron-rich Cu(I)-nacnac complex. Subsequent radical-anion coupling, followed by the transfer of an electron back to the copper catalyst, leads to the observed product. The broad application of this C -alkylation method for nitroalkanes is further established by the successful coupling of several additional radical-stabilizing substrate classes including α-bromocarbonyls, α-bromonitroalkanes, α-bromocyanoalkanes, and a trifluoromethyl radical source. Detailed accounts of the optimization and scope of each of these substrate classes are described herein. Given the synthetic utility of nitroalkanes as intermediates for building molecular complexity, the value of the functional group dense nitrogen-containing products obtained, and the importance of enantioselective methods, detailed investigations into an asymmetric C -alkylation method are also reported. While the development of several potential strategies are described, the success of this challenging goal is ultimately realized using either copper or nickel catalysts formed from chiral diamine ligands. Promising yields and enantioselectivities are reported using α-bromoamide electrophiles. The enantioenriched nitroalkane products also serve successfully as intermediates to incorporate asymmetry into even more complex products.
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