New palladium-catalyzed domino reaction with intramolecular ring closure of an N-(2-chloro-3-heteroaryl)arylamide: First synthesis of oxazolo[4,5-b] pyrazines

Article abstract of DOI:10.1002/adsc.201300845

The synthesis of novel planar heterocycles is at the heart of basic research as such scaffolds constitute key building blocks in important diverse areas of research: drug discovery, material sciences, and pesticides. The well-known benzoxazole is often contained in drug candidates but tweaking its lipophilicity and target interaction points are often desired. In this respect, the oxazolo[4,5-b]pyrazine is an attractive heterocyclic scaffold as it possesses increased water solubility as well as two additional hydrogen bonding acceptors. We here report a new Pd(II)-catalyzed domino reaction comprising the first Pd(II)-assisted intramolecular cyclization of an N-(2-chloro-3-heteroaryl) arylamide and validate its value by application to the first synthesis of 2-substituted oxazolo[4,5-b]pyrazines. We demonstrate that a bidentate phosphorus ligand as well as the presence of an aromatic nitrogen atom is required for the domino reaction to proceed. The robustness of the methodology is confirmed by the synthesis of 23 2-substituted oxazolo[4,5-b]pyrazine analogues in good-to-high yields and containing both electron-withdrawing as well as electron-donating substituents on the reacting arylamide.

Full text of DOI:10.1002/adsc.201300845

Supporting Information
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Supporting Information
New Palladium-Catalyzed Domino Reaction with Intramolecular Ring Closure of an N-(2-Chloro-3-
heteroaryl)arylamide: First Access to Oxazolo[4,5-b]pyrazines
Charles S. Demmer[1], Jacob C. Hansen[1], Jan Kehler[2], and Lennart Bunch[1],*
[1]Chemical Neuroscience Group, Department of Drug Design and Pharmacology, Faculty of Health and
Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
[2]Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, 2500 Valby, Denmark, Fax: (+45)ꢀ36433965
*To whom correspondence should be addressed. Phone: +45 35336244. Fax: +45 35336041. E-mail:
lebu@sund.ku.dk
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