title: An investigation of imidazole and oxazole syntheses using aryl-substituted TosMIC reagents.
abstract: This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable regiochemistry. Employing chiral amines and aldehydes, particularly those derived from alpha-amino acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH(4)OH as the amine component in conjunction with a variety of aldehydes delivers 4, 5-disubstituted imidazoles in moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes is described.
authors.affiliation: SmithKline Beecham Pharmaceuticals, Synthetic Chemistry Department and Analytical Sciences Department, P.O. Box 1539, King of Prussia, Pennsylvania 19406, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sisko
authors.forename: A J
authors.initials: AJ
authors.lastname: Kassick
authors.forename: M
authors.initials: M
authors.lastname: Mellinger
authors.forename: J J
authors.initials: JJ
authors.lastname: Filan
authors.forename: A
authors.initials: A
authors.lastname: Allen
authors.forename: M A
authors.initials: MA
authors.lastname: Olsen
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D003486:Cyanides / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry; D014105:Tosyl Compounds / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000447:Aldehydes; D000596:Amino Acids; D003486:Cyanides; D007093:Imidazoles; D010080:Oxazoles; D014105:Tosyl Compounds