Work

Practical and regioselective halonitrooxylation of olefins to access β-halonitrates

Year: 2024

Type: article

Abstract: Organic nitrates, as effective donors of the signaling molecule nitric oxide, are widely applied in the pharmaceutical industry. However, practical and efficient methods for accessing organic nitrates are still scarce, and achieving high regiocontrol in unactivated alkene difunctionalization remains challenging. Here we present a simple and practical method for highly regioselective halonitrooxylation of unactivated alkenes. The approach utilizes TMSX (X: Cl, Br, or I) and oxybis(aryl-λ3-iodanediyl) dinitrates (OAIDN) as sources of halogen and nitrooxy groups, with 0.5 mol % FeCl3 as the catalyst. Remarkably, high regioselectivity in the halonitrooxylation of aromatic alkenes can be achieved even without any catalyst. This protocol features easy scalability and excellent functional group compatibility, providing a range of β-halonitrates (127 examples, up to 99% yield, up to >20:1 rr). Notably, 2-iodoethyl nitrate, a potent synthon derived from ethylene, reacts smoothly with a variety of functional units to incorporate the nitrooxy group into the desired molecules. Organic nitrates have potential to enhance efficacy of bioactive molecules and in some cases can reduce side effects, but selective and efficient methods for their synthesis are generally scarce. Here, the authors present a methodology to difunctionalize alkenes, adding a nitrooxy and halogen in high regioselectivity via a hypervalent iodine reagent.

Source: Nature Communications

DOI: 10.1038/s41467-024-51655-5