Synthesis and Antiproliferative Activity of Phosphorus Substituted 4-Cyanooxazolines, 2-Aminocyanooxazolines, 2-Iminocyanooxazolidines and 2-Aminocyanothiazolines by Rearrangement of Cyanoaziridines

• Main Authors: Victor Carramiñana, Ana M. Ochoa de Retana, Francisco Palacios, Jesús M. de los Santos
• Format: Article
• Language: English
• Published: MDPI AG 2021-07-01
• Series: Molecules
• Subjects: phosphorus substituted cyanoaziridines; 4-cyanooxazolines; 2-aminocyanooxazolines; 2-iminocyanooxazolidines; 2-aminocyanothiazolines; antiproliferative effect
• Online Access: https://www.mdpi.com/1420-3049/26/14/4265

Several phosphorus-substituted <i>N</i>-acylated cyanoaziridines <b>2</b> and <i>N</i>-carbamoylated cyanoziridines <b>5</b> were prepared in good to high yields. <i>N</i>-Acylated cyanoaziridines <b>2</b> were used, after ring expansion, in an efficient synthesis of oxazoline derivative <b>3a</b> and in a completely regio-controlled reaction in the presence of NaI. Conversely, <i>N</i>-carbamoyl cyanoaziridines <b>5</b> reacted with NaI to obtain a regioisomeric mixture of 2-aminocyanooxazolines <b>7</b>. Mild acidic conditions can be used for the isomerization of <i>N</i>-thiocarbamoyl cyanoaziridine <b>6a</b> into a 2-aminocyanothiazoline derivative <b>8a</b> by using BF₃·OEt₂ as a Lewis acid. Likewise, a one pot reaction of <i>N</i>H-cyanoaziridines <b>1</b> with isocyanates obtained 2-iminocyanooxazolidines <b>9</b> regioselectively. This synthetic methodology involves the addition of isocyanates to starting cyanoaziridines to obtain <i>N</i>-carbamoyl cyanoaziridines <b>5</b>, which after the ring opening, reacts with a second equivalent of isocyanate to give the final 2-imino cyanooxazolidines <b>9</b>. In addition, the cytotoxic effect on the cell lines derived from human lung adenocarcinoma (A549) was also screened. 2-Iminooxazolidines <b>9</b> exhibited moderate activity against the A549 cell line in vitro. Furthermore, a selectivity towards cancer cells (A549) over non-malignant cells (MCR-5) was detected.