Copper-Catalyzed Three-Component Carboiminolactonization of Electron-Deficient Olefins.

Herein we report the three-component copper-catalyzed carboiminolactonization of α,ß-unsaturated carbonyl derivatives. In the presence of a Cu(I) catalyst, α-haloesters, electron-deficient alkenes, and primary amines couple to generate γ-iminolactones in a single step. The scope of the reaction is explored with respect to the three coupling partners. Nineteen examples are presented with yields of these hydrolytically labile heterocycles of up to 69%. Mechanistic investigations support the formation of an oxocarbenium by way of an atom transfer radical addition (ATRA) intermediate.

Cu-Catalyzed Three-Component Carboamination of Electron Deficient Olefins.

The copper-catalyzed three-component carboamination of atropates for the synthesis of α-aryl amino acid derivatives is presented. The scope of the reaction is explored with respect to all three coupling partners: the alkyl halide, the atropate, and the aryl amine. A total of 41 examples are included, with yields of ≤92%. Both primary and secondary aryl amines participate in the carboamination along with α-haloesters, nitriles, and perfluoroiodoalkanes. Mechanistic investigations support a radical mechanism involving Cu-mediated C-N bond formation with the radical adduct.

Energy Decomposition Analyses Reveal the Origins of Catalyst and Nucleophile Effects on Regioselectivity in Nucleopalladation of Alkenes.

Nucleopalladation is one of the most common mechanisms for Pd-catalyzed hydro- and oxidative functionalization of alkenes. Due to the electronic bias of the π-alkene-palladium complexes, nucleopalladations with terminal aliphatic alkenes typically deliver the nucleophile to the more substituted sp2 carbon to form the Markovnikov-selective products. The selective formation of the anti-Markovnikov nucleopalladation products requires the inherent electronic effects to be overridden, which is still a significant challenge for reactions with simple aliphatic alkenes. Because the interactions between the nucleophile and the alkene substrate are influenced by a complex combination of multiple types of steric and electronic effects, a thorough understanding of the interplay of these underlying interactions is needed to rationalize and predict the regioselectivity. Here, we employ an energy decomposition approach to quantitatively separate the different types of nucleophile-substrate interactions, including steric, electrostatic, orbital interactions, and dispersion effects, and to predict the impacts of each factor on regioselectivity. We demonstrate the use of this approach on the origins of catalyst-controlled anti-Markovnikov-selectivity in Hull's Pd-catalyzed oxidative amination reactions. In addition, we evaluated the regioselectivity in a series of nucleopalladation reactions with different neutral and anionic Pd catalysts and N- and O-nucleophiles with different steric and electronic properties. On the basis of these computational analyses, a generalized scheme is established to identify the dominant nucleophile-substrate interaction affecting the regioselectivity of nucleopalladations with different Pd catalysts and nucleophiles.

Palladium-catalysed anti-Markovnikov selective oxidative amination.

In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep approach and require one reactant to be activated prior to the carbon-nitrogen bond formation. This leads to a reaction inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond, in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations are reported.