Innovative regioselective synthesis of dispiro[fluorene-9,3'-pyrazole-5',4″-pyrazolidines]: experimental and...

A simple one-pot protocol is described for the synthesis of dispiro[fluorene-9,3'-pyrazole-5',4″-pyrazolidines] via a [3 + 2] cycloaddition reaction between 9-diazo-9H-fluorene (DF) and a series of (E/Z)-4-arylidene-1-phenylpyrazolidine-3,5-diones (APPs). In all cases, the cycloaddition proceeds with complete regioselectivity, affording a single regioisomeric framework as a pair of diastereomers through an endo approach. The structures and regiochemical outcomes of the cycloadducts were established by comprehensive 1D and 2D NMR spectroscopic analyses (¹H, ¹³C, DEPT-135, COSY, ¹H-HSQC, HMBC, and ROESY). The regiochemistry and mechanism of the cycloaddition reaction were investigated using density functional theory (DFT) calculations at the B3LYP/cc-pVTZ level of theory, supported by analysis of global and dual local electrophilicity and nucleophilicity descriptors. To rationalize the observed stereoselectivity, the relevant transition-state structures were located and optimized using a QST3-based transition-state search at the same level of theory. Global electron density transfer (GEDT) analysis revealed that the cycloaddition reactions are highly polar, with electron density flowing from 9-diazo-9H-fluorene (DF) toward the (E/Z)-4-arylidene-1-phenylpyrazolidine-3,5-dione (APP) framework. Consistently, molecular electrostatic potential surface (MESP) analysis showed that, in the energetically favored transition states, the reacting partners approach through regions of opposite electrostatic potential, leading to stabilizing electrostatic interactions between the two fragments. The computational results are consistent with the experimental observations and support a polar, synchronous one-step cycloaddition mechanism. The developed protocol affords the desired dispiro compounds in good to excellent yields (59-91%) with complete regioselectivity, providing a single regioisomeric framework as a pair of diastereomers. This work provides valuable insights into diazo-based cycloaddition chemistry and is expected to stimulate further research in the synthesis of structurally complex spiroheterocycles. Compared to previously reported approaches, the present method offers a simple one-pot strategy with high efficiency, complete regioselectivity, and operational simplicity.