Efficient routs to oxazolines and oxazolies through activation of amides

Oxazolines are nitrogen-containing heterocyclic compounds that are of a special interest due to their applications as active components in a broad range of pharmaceutical products. A challenging task remains in developing reliable and efficient methods that would allow expedient approach to these heterocycles from inexpensive and environmentally friendly substrates and reagents. During preliminary studies, it was unexpectedly found that oxazoline can be produced by reacting N,N dichlorobenzamide with styrene. The central goals of this thesis project were:

• to optimize the conditions for the formation of N,N dichlorobenzamide by chlorinating benzamide, and
• to optimize coupling of N,N-dichlorobenzamide with a representative alkene, styrene, leading to the formation of oxazoline. There are no prior literature reports of using chloro amides for the synthesis of these heterocycles. Trichloroisocyanuric acid (TCCA) belongs to the family of N-chloroamides, which are commonly used as bleaching agents and bactericides. In this study, TCCA was used as a chlorinating agent for the amide starting material, following a recent literature report. While a mixture of N,N dichlorobenzamide and N-monochlorobenzamide was produced initially in the reaction of benzamide with TCCA, screening of the reaction conditions (varying solvents, temperature, isolation procedure) revealed the set that results in clean formation of the dichloroamide. Following chlorination, reaction conditions for the coupling of N,N dichlorobenzamide with styrene were optimized. The results of the preliminary investigation confirmed that the oxazoline ring is indeed formed (a transformation not yet described in the literature), albeit with a concurrent formation of an acyclic side product, later assigned as N-(2-chloro-2-phenylethyl)benzamide. The two products are close in polarity and not easily separable using column chromatography. After considerable effort, two unique sets of conditions (base-mediated and MnO2-mediated) were discovered that convert N-(2-chloro-2-phenylethyl)-benzamide into the target oxazoline. A one-pot procedure for oxazoline formation starting from benzamide that does not require the purification of reaction intermediates was subsequently developed and rendered to yield 73% of the desired product, 2,5-diphenyl-2-oxazoline. In addition, applying this procedure to p-methylstyrene and p-toluamide resulted in formation of two homologous oxazoline products, which were both isolated in a 75% yield (2-(4-methylphenyl)-5-phenyloxazoline and 5-(4-methylphenyl)-2-phenyloxazoline.
  Finally, several oxidizing conditions were developed that allow to convert the formed oxazoline into oxazole, using DDQ and/or MnO2, with up to 65% efficiency. In summary, preparing oxazolines and oxazoles using the newly developed transition metal-free methods is very promising for future pharmaceutical applications.