Palladium-catalyzed alkene carboamination reactions for the synthesis of substituted piperazines.

Tetrahedron
Josephine S NakhlaJohn P Wolfe

Abstract

A strategy for the stereoselective preparation of enantiomerically enriched cis-2,6-disubstituted piperazines from amino acid precursors is described. The target compounds are generated in 95-99% ee with good to excellent levels of diastereoselectivity (usually 14:1 to >20:1) using Pd-catalyzed carboamination reactions between aryl or alkenyl halides and substituted ethylenediamine derivatives to form the heterocyclic rings. The synthesis requires only 4-5 steps from commercially available amino acids, and allows for the modular construction of piperazines bearing different substituents at N(1), N(4), C(2), and C(6). The use of this strategy for the construction of 2,3-disubstituted piperazines, fused bicyclic piperazines, and tetrahydroquinoxalines is also reported. In addition, the mechanism of the key carboamination reactions are discussed, and new models that predict and explain the stereochemical outcome of these transformations are presented.

References


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Citations

Jul 6, 2014·Organic & Biomolecular Chemistry·Priyanka SinghGautam Panda
Mar 31, 2011·Organic Letters·Joshua D NeukomJohn P Wolfe
Mar 21, 2012·Angewandte Chemie·Nicholas R Babij, John P Wolfe
Nov 19, 2013·Drug Discovery Today·Richard DovestonAdam Nelson
Jun 3, 2017·The Journal of Organic Chemistry·James D FirthLeigh Ferris
Jan 17, 2013·Chemical Communications : Chem Comm·Paul MacLellan, Adam Nelson
Mar 20, 2010·The Journal of Organic Chemistry·Brandon R RosenJohn P Wolfe
Jun 2, 2009·The Journal of Organic Chemistry·Matthew L LeathenJohn P Wolfe
Feb 23, 2010·The Journal of Organic Chemistry·Luana BagnoliMarcello Tiecco

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