As it was shown in our previous report that addition of phosphorous acid to the reaction medium could enable stubborn steric-restricted annulations, we also decided to attempt to stimulate the reactivity using this trick. Again, the reactions did not proceed, and the starting amine 1a remained intact in both cases (entries 3, 4). Next, a mixture of 86% orthophosphoric acid and 87% polyphosphoric acids (approximately corresponding to anhydrous H 3PO 4) or molten 87% polyphosphoric acid (PPA) were employed as the media for the reactions carried out at 120 ☌. However, the reaction did not proceed under these conditions. In the initial experiment, a mixture of these reagents was heated in 86% orthophosphoric acid at 110 ☌ ( Table 1, entry 1) or 120 ☌ (entry 2). With this idea in mind, we attempted to carry out reactions between 2-(1-amino ethyl)aniline ( 1a) and 1-nitropropane ( 4c) in a molar ratio of 1:2. Employing strategically placed second nucleophilic functionality (carbon or heteroatom-based), the resulting amidinium species ( 7) can be transformed into a variety of heterocyclic compounds, such as benzoxazoles ( 8) or benzimidazoles ( 9), perimidines ( 10), 6,7-dihydro-1 H-cyclopentaperimidines ( 11), 1,3,4-oxa-di-azoles ( 12), imidazolines ( 13), 3,4-dihydro-iso-quinolines ( 14), imidazo pyridines ( 15), and triazolopyridines ( 16) ( Scheme 2). Furthermore, it was found that nitrogen-based nucleophiles ( 6), such as aliphatic amines, anilines, or hydrazines, can be utilized instead of water in a process mechanistically related to the classical Nef reaction. These phosphorylated nitronates tend to react with various carbon-based nucleophiles, for instance electron-rich arenes, allowing for Friedel–Crafts-type C–H functionalization reactions, often with subsequent accompanying rearrangements. Results and DiscussionĪlthough nitroalkanes ( 4) normally behave as pronucleophilic species in a polyphosphoric acid medium they are stabilized in a form of phosphorylated nitronates ( 5) with profound electrophilic properties. Herein, we wish to disclose an account of our recent progress towards preparation of these important heterocycles via annulation involving electrophilically activated nitroalkanes. Still, elaboration of novel synthetic methods allowing for the efficient assembly of the 3,4-dihydroquinazoline core is exceedingly desired. Due to their highly unusual polycyclic scaffolds and newly discovered anti-cancer and antiviral activities, these trigoliimines are in focus of multiple synthetic exercises. Additionally, a family of trigonoliimine alkaloids were isolated from the leaves of tropical plants from the genus Trigonostemon. Among them are cytotoxic alkaloid chaetominine isolated from endophytic fungi of the Chaetomium genus and 3-hydroxyfumiquinazoline A isolated from the fungus Aspergillus fumigatus, which has demonstrated promising antifungal and insecticidal activities ( Figure 1). This structural fragment is found in thousands of natural products and synthetic medicinal agents, including many alkaloids with valuable biological activities. 3,4-Dihydroquinazolines belong to privileged scaffolds widely used in drug design, with their importance in medicinal chemistry being difficult to overstate.
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