Iridium-catalyzed reductive Ugi-type reactions of tertiary amides

Abstract

Amides are ubiquitous in the fine chemical, agrochemical and pharmaceutical industries, but are rarely exploited as substrates for homologous amine synthesis. By virtue of their high chemical stability, they are essentially inert to all but the harshest of chemical reagents and to the majority of chemical transformations routinely used in organic synthesis. Accordingly, the development of chemoselective carbon−carbon bond-forming methodologies arising from the functionalization of the amide functionality should find widespread use across academia and industry. We herein present our findings on a series of Ugi-type reactions of tertiary amides enabled by an initial chemoselective iridium-catalyzed partial reduction, followed by reaction with isocyanide and (thio)acetic acid or trimethylsilyl azide, thus providing a multicomponent synthesis of α-amino (thio)amide or α-amino tetrazole derivatives. The reductive Ugi-type reactions are amenable to a broad range of amides and isocyanides, and are applicable to late-stage functionalization of various bioactive molecules and pharmaceutical compounds.

A practical catalytic reductive amination of carboxylic acids

“…1B) is based upon the dual reactivity of hydrosilanes, which mediate direct amide coupling [23][24][25][26] and amide reduction in the presence of a metal catalyst. [27][28][29][30] Combining these processes gives a reductive amination reaction in which carbon-nitrogen bond formation is complete before reduction begins, thereby avoiding unwanted reduction of the carboxylic acid, leading to alcohol by-products. Although we had established proof-of-concept for this general approach using iridium catalysis, 18 the synthesis of secondary amines was complicated by relatively high iridium loadings and the fact that different silanes were required for the amidation and reduction step.…”

Homogeneous and heterogeneous catalytic reduction of amides and related compounds using molecular hydrogen

“…These transformations afford α-branched alkanamines from amides through the formation of a hemiaminal-type intermediate. Normally, this reaction works by employing metal hydrides or silanes as reducing agents in combination with an iridium homogeneous catalyst to afford amines α-substituted with nitrile 164 , amide 165 , or alkyl groups 166 . Clearly, performing this kind of reductive functionalization employing H 2 is a very attractive research line that will be more exploited in the future.…”

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

“…Quite recently Xie and Dixon showed that it is possible to synthesize α-tetrazolylamines from simple and linear tertiary amides using an iridium-based catalytic protocol [ 19 ]. They have, however, only reported one example of lactam functionalization which only proceeded with moderate efficiency (1- tert -butylazepan-2-one, 41% yield of the desired product).…”