An unusual cyclization leading to functionalized isoxazolines was discovered at ZIOC
Isoxazolines are important representatives of five-membered nitrogen-oxygen heterocycles widely used in organic and medicinal chemistry. The isoxazoline ring is a key structural fragment of various biologically active compounds, such as the herbicide methiozolin, the insecticides afoxolaner and fluralaner, and the herbicide antidote isoxadifen-ethyl. In addition, isoxazolines are useful intermediates in organic synthesis and can be transformed through N–O bond cleavage into such important compounds as 1,3-amino alcohols and β hydroxy ketones.
It was found at the Laboratory of Organic and Metal-Organic Nitrogen-Oxygen Systems of the Zelinsky Institute, that nitroalkyl-substituted malonic esters undergo cyclization to isoxazolines under acylation conditions. Based on the discovered transformation, an approach was developed for the rapid assembly of polysubstituted isoxazolines from available precursors. In contrast to many literature analogues, in this case, the closure of the isoxazoline ring does not require the use of an external oxidizing agent or reducing agent, but is the formal elimination of water from the substrate molecule. The transformation is of a general nature and leads to high yields of target products under mild conditions using available reagents. It is important that there is no loss of optical purity, which makes it possible to carry out the asymmetric synthesis of isoxazolines. A number of mechanistic experiments carried out made it possible to propose the most probable ways of the found cyclization, and further transformations into pyrrolidine and furan derivatives demonstrated the value of the obtained products for targeted organic synthesis.
Yulia A. Antonova, Yulia V. Nelyubina, Sema L. Ioffe, Alexey Yu. Sukhorukov, Andrey A. Tabolin, Ring Closure of Nitroalkylmalonates for the Synthesis of Isoxazolines under the Acylation Conditions, Adv. Synth. Catal. 2022, 364, 2606-2612. DOI: 10.1002/adsc.202200420