Iridium-Catalyzed Regio- and Diastereoselective Synthesis of C-Substituted Piperazines

Abstract

Piperazine rings are essential motifs frequently found in commercial drugs. However, synthetic methodologies are mainly limited to N-substituted piperazines, preventing structural diversity. Disclosed herein is a straightforward catalytic method for the synthesis of complex C-substituted piperazines based on an uncommon head-to-head coupling of easily prepared imines. This 100% atom-economic process allows the selective formation of a sole diastereoisomer, a broad substrate scope, and a good functional group tolerance employing a bench-stable iridium catalyst under mild reaction conditions. Key to the success is the addition of N-oxides to the reaction mixture, as they notably enhance the catalytic activity and selectivity.

Redox–Transmetalation Reactions: Easy Access to Homo- and Heterodimetallic d8,d10 Complexes

“…Notably, the bpi released in the mixtures containing iridium undergoes an unusual [3 + 3]-cycloaddition reaction, resulting in tetrapyridiyl-piperazine in ca. 12 h …”

Heterocyclic Merging of Stereochemically Diverse Chiral Piperazines and Morpholines with Indazoles

“…Hence, synthetic approaches targeting the effective and stereoselective generation of carbon-substituted piperazine and morpholine compounds hold significant practical value. [9][10][11][12][13][14] We have previously reported methods leading to the systematic preparation of diverse enantiomerically pure piperazines and morpholines. [15][16][17][18][19][20][21] These studies led us to consider that a structurally unique collection of compounds could be achieved in the context of merging these stereodiverse ring systems with other biologically valuable heterocycles (Scheme 1).…”

“…The addition of substituents on the carbon atoms might also lead to greater target selectivity. Hence, synthetic approaches targeting the effective and stereoselective generation of carbon‐substituted piperazine and morpholine compounds hold significant practical value [9–14] . We have previously reported methods leading to the systematic preparation of diverse enantiomerically pure piperazines and morpholines [15–21] .…”