Strategies toward the Difunctionalizations of Enamide Derivatives for Synthesizing α,β-Substituted Amines

CONSPECTUS: Enamide and enecarbamate derivatives containing a nucleophilic center at the beta-position from their nitrogen atom as well as a latent electrophilic site at their alpha-position are interesting motifs in organic chemistry. This dual reactivity- analogous that of the enamines-enables difunctionalization and increased structural complexity. Furthermore, an electron-withdrawing group on nitrogen drastically increases their stability. In that respect, enamides and enecarbamates are excellent partners for multicomponent transformations, and our research primarily focuses on these compounds in particular. Difunctionalization generally occurs through the nucleophilic addition of the enecarbamate on an electrophile to form iminium, which can subsequently react with a nucleophilic species. Although potent, such an approach is highly challenging due to the low stability of the intermediate iminium, leading to undesired hydrolysis or oligomerization. Epimerization, competitivity, and compatibility issues between the reaction partners are additional hindrances to developing these methodologies. To overcome these limitations, we described many complementary strategies. To control the enantioselectivity of these transformations, chiral phosphoric acids were found to be particularly well-suited to activate multiple reactants due to the formation of a hydrogen bonds network, allowing for an organized transition state in a chiral pocket. Interestingly, when deprotonated as phosphates, they can also play the role of ligands for Lewis acidic metals. To avoid iminium oligomerization, we successfully used stabilized alpha-arylated enamides. However, this approach was restricted to a simple nucleophilic addition at the beta-position. To achieve the difunctionalizations of alpha-unsubstituted derivatives, we explored reversibly linked nucleophile and electrophile to address their compatibility problem. Alternatively, we devised a sequential methodology for resolving the stability issue of the N-acyl iminium based on its intermediate trapping using a temporary nucleophile (alcohol or thiol). Interestingly, the trapping agent could further be displaced by the desired final alpha-substituent under Lewis acidic or photocatalytic activation. This led us to design new chiral and bifunctional phosphoric acid catalysts bearing chromophores to merge asymmetric organocatalysis and photochemistry. These photocatalysis studies incited us to focus on radical processes to manage original functionalizations that would not be feasible otherwise. beta-Alkylation and beta-trifluoromethylation of enecarbamates via visible-light-promoted atom transfer radical additions were successfully performed. As beta-allylations remained unattainable with the precedent methods, we eventually turned our attention to cerium(IV)-mediated oxidative single electron transfers. It allowed for singly occupied molecular orbital activation of these substrates to elicit their umpolung reactivity. Thus, the functionalization of enecarbamate derivatives appears as a valid synthetic strategy for obtaining important building blocks for agrochemical, pharmaceutical, and cosmetic industries, including diamines, haloamines, aminotryptamines, and less accessible trifluoromethylated or allylic compounds.

Automated summary

Enamide and enecarbamate derivatives with nucleophilic and electrophilic centers have dual reactivity, enabling difunctionalization and increased structural complexity. Strategies such as using chiral phosphoric acids and visible-light-promoted atom transfer radical additions have been employed to overcome stability, competititveness, and compatibility issues. The functionalization of these derivatives is a valid synthetic strategy for obtaining important building blocks.