Ethyl Nitroacetate in Aza-Henry Addition on Trifluoromethyl Aldimines: A Solvent-Free Procedure To Obtain Chiral Trifluoromethyl α,β-Diamino Esters

Abstract

A self-catalyzed aza-Henry addition of ethyl nitroacetate on N-alkyl trifluoromethyl aldimines was reported to synthesize β-amino α-nitro trifluoromethyl esters, precursors of α,β-diamino acid derivatives. In the presence of a resident chiral center on the imine nitrogen, the use of a suitable Lewis acid leads to a good stereofacial control, always resulting from a nucleophilic unlike attack. By starting from optically pure N-protected trifluoromethyl aldimines or directly from N-α-amino ester trifluoromethyl aldimines, small ψ[CH(CF3)NH]-peptidomimetic backbones can be achieved in which a new primary amine function represents a possible center for synthetic extension. Finally, a very interesting, and never observed before, palladium-catalyzed syn β-elimination occurred, leading to the selective nitro group reduction reaction on the syn-α-amino ester functionalized aza-Henry adducts and obtaining more stable optically pure trifluoromethyl conjugated imines.

Aza-Henry Reactions on C-Alkyl Substituted Aldimines

“…While only recently, C -CF 3 substituted aldimines [9,10,11] are reported in the aza-Henry reactions as interesting trifluoromethyl nitrogen-containing starting materials; the reactivity of C -aryl analogues has been well documented in the literature, while very few data are reported on the reactivity of C -alkyl substituted aldimines [2]. Classically, non-enantioselective nucleophilic addition of nitro alkanes to C -aryl substituted aldimines usually required the presence of a base as catalyst [12].…”

Synthesis of β-Aminoenones via Cross-Coupling of In-Situ-Generated Isocyanides with 1,3-Dicarbonyl Compounds

“…How do we find a suitable condition that is compatible with both the formation of isocyanide and the C–H insertion of a methylene group of 1,3-dicarbonyls? How do we suppress the formation of byproduct imine between carbonyl and amine? How do we control the overinsertion issue with two C–H bonds? To verify our hypothesis with these challenges, we then chose amine 1a , ethyl bromodifluoroacetate ( 2 ), and Co­(acac) 2 as a model the reaction, and we probed which reaction conditions could afford higher yield (see Table , as well as the Supporting Information (SI) for details).…”

Selective Synthesis of Trifluoromethyl β‐Lactams by a Zn‐Promoted 2‐Bromo Ester Addition on C‐CF3‐Substituted Aldimines

“…Indeed, an ester group in the nitrogen α position ( 1c ) may itself be involved in a coordination process with Zn, that induces an undesired aldimine molecular degradation, probably in a way similar to that which involves the α‐halogen‐esters.…”