Metal-free reductive amination of carboxylic acids by Brønsted acid activation Milly Stoneley 1 , Dr Alex Scollan 1 , Dr Huiling Shao 2 , Dr Yike Zhou 2 , Professor Ken Houk 2 and Professor Ross Denton 1* 1 University of Nottingham, UK, 2 University of California, USA Amines and their derivatives are fundamental functional groups that are present in a wide range of bioactive and commercially important molecules and as a result, new methods for the construction of amines are of significant interest. 1,2 Reductive amination plays a paramount role in the construction of these amine motifs and accounts for 25% of all C-N bond formation, however, this method has significant drawbacks as the handling of aldehyde starting materials can be difficult due to aldol dimerization and autooxidation. 2 We report a metal-free reductive amination reaction using carboxylic acids as nominal electrophiles. Carboxylic acids are both more abundant and easier to handle, presenting an advantage over reductions containing aldehyde substrates. Although reductive amination methodologies using carboxylic acids are not a new concept, these often include metal catalysts, 4,5 high excesses of reagents 6 or specialised glassware. 7 This method utilises the dual reactivity of phenylsilane to both activate the carboxylic acid towards amide formation, and the subsequent reduction to the amine in conjunction with a cheap Brønsted acid. A wide range of amines were obtained from this method, including substrates with potentially reducible groups, those with a handle for further reaction and unsymmetrical diamines, as well as pharmaceutical targets. In addition, this reaction can be conducted without rigorous exclusion of air and moisture in standard laboratory glassware. Mechanistic investigations show that Brønsted acid-mediated silane activation, occurs to generate silylbenzenesulfonates, which demonstrate enhanced reactivity compared to the parent silane.
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