Abstract
Straightforward regio- and diastereoselective synthesis of bi-spirooxindole-engrafted rhodanine analogs 5a–d were achieved by one-pot multicomponent [3 + 2] cycloaddition (32CA) reaction of stabilized azomethine ylide (AYs 3a–d) generated in situ by condensation of L-thioproline and 6-chloro-isatin with (E)-2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)-N-(2-morpholinoethyl)acetamide. The bi-spirooxindole-engrafted rhodanine analogs were constructed with excellent diastereo- and regioselectivity along with high chemical yield. X-ray crystallographic investigations for hybrid 5a revealed the presence of four contiguous stereocenters related to C11, C12, C19 and C22 of the spiro structure. Hirshfeld calculations indicated the presence of many short intermolecular contacts such as Cl...C, S...S, S...H, O...H, N...H, H...C, C...C and H...H interactions. These contacts played a very important role in the crystal stability. The polar nature of the 32CA reaction was studied by analysis of the conceptual DFT reactivity indices. Theoretical study of this 32CA reaction indicated that it takes place through a non-concerted two-stage one-step mechanism associated with the nucleophilic attack of AY 3a to the electrophilic ethylene derivative.
Highlights
Rhodanines (2-thioxothiazolidin-4-ones) privileged structure has attracted much attention in pharmaceutical and medicinal chemistry [1,2]
The key step of this strategy is the generation of azomethine ylides (AYs) which react with electron-deficient ethylene to produce pyrrolidinespirooxindole with contiguous stereocenters
Based on the findings above and continuing in the contribution to the synthesis of new spiro-heterocycle hybrids, in this study we report the straightforward synthesis of rhodanine-substituted spiro[pyrrolidine-oxindole]-carboxamide/morpholine derivatives 5a–d using the 32CA reaction methodology
Summary
Rhodanines (2-thioxothiazolidin-4-ones) privileged structure has attracted much attention in pharmaceutical and medicinal chemistry [1,2]. The key step of this strategy is the generation of azomethine ylides (AYs) which react with electron-deficient ethylene to produce pyrrolidinespirooxindole with contiguous stereocenters. These pyrrolidine-spirooxindole molecules in particular have shown a panoply of significant pharmaceutical targets and applications, such as MDM2 inhibitors [20,21,22], anti-cancer treatment [7,23], AChE inhibitors [24,25,26] and prospective activity against SARS-CoV-2 [27]. Structural modifications have emerged as attractive synthetic targets for researchers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
