A Regioselective Synthesis of Multi-Substituted 2-Imino-1,3-oxazolines by One-Pot Reaction

Abstract

Heterocycles are significant chemical entities for research on small molecule drugs and their development in the pharmaceutical industry. Attention until now has focused on synthetic methods for forming heterocycles. However, new and efficient synthetic methods for the construction of heterocyclic molecules are now being researched continuously. In our previous papers, we reported the construction of two different combinatorial libraries, including novel 2imino-1,3-thiazolines 1, that show T-type calcium channel inhibitory activity and fungicidal property. Recently, a number of reports examined the significant biological activities of the 2-imino-1,3-thiazoline derivatives. As an extension of our efforts to investigate the biological activities of their analogues, we synthesized 2-imino-1,3-oxazolines 2, which are isosteres of 2-imino-1,3-thiazolines 1 (Figure 1). In the present study we investigate a method for synthesizing multi-substituted 2-imino-1,3-oxazolines 2 with the aim of increasing the diversity in chemical structures. A comparison of the biological activity of 1 and 2 promises to increase our understanding of the structure-activity relationship of this series. A literature survey revealed few reports on the synthetic methods of 2-imino-1,3-oxazolines. The synthetic methodologies of 2-imino-1,3-oxazolines reported over the past three decades were classified into four categories. First, a condensation of α-haloketone and symmetrical diphenylurea in presence of bromine as the condensing agent gave 2-arylimino-3-aryl-1,3-oxazolines. Second, electrochemical synthesis of substituted phenylmonoimine with N-acylcarbonimidoyl dichloride resulted in tetraaryliminooxazolines. Third, the reaction of ketenimine with hydroxylamino derivatives gave 2-imino-1,3-oxazolines through 3-iminoisoxazolines. Fourth, the reaction of alkyl diazoacetates with carbodiimides in presence of transition metal salts gave 2-imino-1,3-oxazoline derivatives. Unfortunately, all these reported methods suffered the limitations of low yield, harsh reaction conditions, and lack of regioselectivity and chemical structural diversity of the products. Therefore, we herein report a very simple and convenient synthetic method for the preparation of multi-substituted 2-imino-1,3-oxazolines derivatives with the aim of increasing the product diversity and production yield, by reacting α-hydroxyketone and carbodiimide in the presence of copper salts as a catalyst.