The following dissertation deals with two research projects. The first project describes an efficient metal-free synthesis of 1H-indazoles. Indazoles exhibit a diverse range of pharmacological properties and are used as anti-cancer, -inflammatory, -microbial agents. The synthesis of 1H-indazoles is achieved from o-aminobenzoximes by the selective activation of the oxime in the presence of the aminogroup. The reaction occurs with a variety of substituted o-aminobenzoximes using a slight excess of methanesulfonyl chloride and triethylamine at 0-23 °C and is amenable to scale-up. The reaction also works well with o-aminobenzaldoximes and several N-substituted aminobenzoximes. The mechanism was investigated and it was determined that the reaction proceeds via an addition-elimination pathway. The synthesis of 1H-indazoles under these conditions is extremely mild compared with previous synthetic approaches and affords the desired compounds in good to excellent yields.
The second project detailed in this thesis describes strategies to functionalize oxazoles from readily available starting materials. Oxazoles are an important class of heterocycle that exhibit a diverse range of biological activities. The synthesis of 2-substituted oxazoles is achieved via nickel-catalyzed cross-coupling reaction of 2-methylthio-oxazole and various organozinc reagents. The reaction works well with electron-withdrawing, electron-donating, and heteroaryl substrates. An extension of this method is demonstrated with a chemoselective, one-pot synthesis of unsymmetrical 2,5-disubstituted oxazoles. This synthesis of 2- and 2,5-substituted oxazoles using this method provides great advantages over previous methods for these compounds and is highly complementary to current cyclodehydration strategies.
The synthesis of a variety 2,4- and 2,5 –disubstituted oxazoles was achieved from either 2-(butylthio)-5-iodooxazole or 2-(butylthio)-4-iodooxazoles. The reaction commenced with either a Suzuki-Miyaura or Sonogashira reaction at the iodide followed by a nickel- or palladium-catalyzed cross-coupling reaction of the thiobutyl group with various organozinc reagents. This reaction sequence leads to a variety of di-substituted oxazoles using this iterative cross-coupling method.