A One-Pot Two-Step Three-Component Stereoselective Mechanosynthesis of Ester-Functionalized Multisubstituted Δ²-Pyrazolines and Their Application in the Detection of Fluoride Ions

A stereo-, regio-, and chemoselective one-pot, three-component reaction involving alkylidene Meldrum’s acids, nitrile imines, and alcohols/phenols, promoted by Cs2CO3, was developed under ball milling conditions. This method provides trans ester-functionalized multisubstituted Δ2-pyrazolines (>40 examples) with moderate-to-good yields (up to 90%) and excellent diastereoselectivity (up to 98%), introducing three bonds (C–C, C–N, and C–O) and installing four different substituents in a single synthetic operation in just 90 min. Leveraging the chemoselective nature of the protocol, we exploited it to prepare a fluorogenic Δ2-pyrazoline tag for molecules with isocyanate functionality and to synthesize a hybrid molecule, combining Δ2-pyrazoline and 1,2,3-triazole scaffolds, showcasing its versatility. In addition, the sustainability of the procedure was assessed through various green chemistry metrics, revealing ball milling’s superior reaction mass efficiency (RME) and EcoScale, lower E factor, and higher molar efficiency, emphasizing its environmentally favorable characteristics. Given the significance of fluoride anion (F–) in environmental and biological contexts, the described protocol was employed to prepare an acid-functionalized Δ2-pyrazoline and further used for detecting fluoride ions in competitive media, demonstrating a “turn-on” fluorescence response to fluoride in a 50% water/acetonitrile mixture.