Novel approaches to synthesis of nitrogen containing heterocycles

In Chapter one, a modified approach for mercury promoted synthesis of mono-, di- and tri-substituted 5-aminotetrazoles, and 5-oxo-tetrazoles is reported. This mild protocol is applied to one pot synthesis of a number of amino acid tert-butyl ester- and peptide tert-butyl ester-tetrazole conjugates. It allows for incorporation of a tetrazole moiety into peptide structures. Finally, a solid phase synthetic protocol to incorporate tetrazole heterocycles at the N-terminus of a peptide, using HgCl2, DIC, or Mukaiyama's reagents was achieved. Chapter three describes the synthesis of 2-aminobenzimidazoles via intramolecular C-N bond formation between an aryl halide and a guanidine moiety using either copper or palladium catalysis. Inexpensive copper salts, such as CuI, are generally superior to the use of palladium catalysts. Regioselective cyclizations can also be achieved in high yield under CuI/1,10-phenanthroline catalyzed conditions, whereas palladium catalysis results in the formation of regioisomeric products. Copper- and palladium-catalyzed intramolecular C-S bond formation by cross-coupling between an aryl halide and thiourea functionality is also demonstrated for the synthesis of 2-aminobenzothiazoles. The copper-catalyzed reaction further expands the recent studies exploring the utility of copper salts as replacements for palladium in carbon-heteroatom bond forming reactions. This methodology is applied to the synthesis of the histamine H1-receptor antagonist astemizole (Hismanal) and its highly active metabolite norastemizole. This work is the first serious study of metal catalyzed arylation of guanidines, and is one of a handful of examples of copper catalyzed cyclizations involving C-N bond formation. Chapter two describes a modified Edman degradation procedure to provide an effective means of introducing a heterocycle at the N-terminus of an amino acid amide or peptide. Reaction of a peptide with an isothiocyanate, followed by dehydrothiolative trapping of the intermediate thiourea by intramolecular cyclization of the weakly nucleophilic adjacent amide nitrogen, generates an iminohydantoin. Solution-phase parallel synthesis of iminohydantoins and polymer-supported synthesis of dipeptide and tripeptide derived iminohydantoins were also achieved. Chapter four describes the formation of various benzoxazoles and a handful of benzthiazoles via intramolecular C-O cross-coupling between an aryl halide and an amide oxygen/sulfur using a catalytic amount of copper. Investigation of various ligands revealed 1,10-phenanthroline to be a superior ligand in benzoxazole formation. This protocol allowed for aryl, alky, vinyl, and hetero-aromatic substitutions at position 2-oxazole. A number of substitutions on the phenyl ring of benzoxazole were also well tolerated. An intermolecular approach has also been investigated. The developed intramolecular protocol is applied to total synthesis of antitumor agent UK-1 46 and its analog Me-UK-1 47. Also, a new protocol for the formation of substituted aminothiatriazoles from thiocarbamoylimidazolium salts is outlined. Thiocarbamoylimidazolium salts are synthesized from the corresponding amines by treatment with thiocarbonyldiimidazole (TCDI) followed by methylation with iodomethane. Thiocarbamoylimidazolium salts are shown to act as thiocarbamoyl cation equivalents. Substitution of the salts by azide anion followed by electrocyclization affords substituted aminothiatriazoles in good to excellent yields.