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Efficient and Selective Palladium‐Catalysed C‐3 Urea Couplings to 3,5‐Dichloro‐2(1 H )‐pyrazinones
Author(s) -
Belfrage Anna Karin,
Gising Johan,
Svensson Fredrik,
Åkerblom Eva,
Sköld Christian,
Sandström Anja
Publication year - 2015
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201403405
Subject(s) - chemistry , palladium , combinatorial chemistry , peptidomimetic , urea , aryl , denticity , catalysis , xantphos , amide , stereochemistry , medicinal chemistry , organic chemistry , peptide , biochemistry , alkyl , crystal structure
The development of a robust palladium‐catalysed urea N ‐arylation protocol to install various ureas at the 3‐position of the 2(1 H )‐pyrazinone scaffold is described. The method involves Pd(OAc) 2 in combination with bidentate ligands, xantphos [4,5‐bis(diphenylphosphino)‐9,9‐dimethylxanthene] in particular, and resulted in good to excellent coupling yields of aliphatic, aromatic, and sterically hindered ureas. Furthermore, the C‐3 chlorine was shown to be selectively displaced in the presence of aryl halide ureas, and this finding was supported by density functional theory (DFT) calculations. This allows further diversification of the scaffold for the production of compound libraries. Overall, the protocol facilitates further exploitation of pyrazinones as beta‐sheet‐inducing scaffolds in the development of sophisticated peptidomimetics/protease inhibitors. This is exemplified here by the synthesis of a new pyrazinone‐based hepatitis C virus (HCV) NS3 protease inhibitor.