Hydrazides and hydrazones as versatile Michael-Donors for iminium-catalyzed conjugate addition reactions

Abstract

In the work compiled in this thesis is presented a series of strategies that have been studied and have lead to the asymmetric synthesis of useful building blocks in high yields and stereochemical control. These are reliant on the use of chiral secondary amines as the element that induces stereocontrol, where the activation of the substrate is based on the formation of an iminium ion intermediate within the catalytic cycle. In this sense, it has been demonstrated that, under this type of activation, hydrazides and hydrazones are efficient and versatile reagents that can be used as Michael donors in conjugate addition reactions.Thus, the performance of these hydrazide and hydrazone reagents as N-donors has been initially tested. In this context, two different aza-Michael initiated cascade reactions have been studied, using either N,N¿-disubstituted hydrazides or hydrazones derived from pyruvaldehyde in the reaction with -unsaturated aldehydes. Furthermore, the synthetic versatility of the products obtained has allowed a series of transformations to be performed, which is highlighted in the synthesis of valuable adducts (e.g. pyrazolines, pyrazolidinones or 1,3-diamines).On the other hand, the ability of hydrazones to act C-pro-nucleophiles for the same type of reaction has also been demonstrated. In this sense, the conjugate addition reaction between N-monosubstituted hydrazones and various enals via iminium activation has been studied, confirming that hydrazones containing an electron-withdrawing group at the azomethine position undergo this process in a highly efficient manner. Moreover, the importance of this methodology has been highlighted by the synthesis of a series of 1,4-dicarbonyl compounds, verifying that hydrazones can behave as acyl anion equivalents.