Task‐specific Ionic Liquid Mediated Eco‐compatible Approach for the Synthesis of Spirooxindole Derivatives and Their DNA Cleavage Activity

Abstract

Guanidine‐based task‐specific ionic liquid 1,1,3,3‐tetramethylguanidine acetate [TMG][Ac]was found to be a very effective solvent for the synthesis of pharmaceutically important spirooxindole derivatives through one‐pot multicomponent reaction of substituted isatin, thiazolidine‐4‐carboxylic acid and naphthoquinone followed by the spontaneous dehydrogenation in excellent yields without using any reagent and catalyst. The TMG‐based ionic liquid could be recovered and used at least four times without considerable reduction in its activity. The advantageous features of the developed synthetic protocol are high atom economy, operational simplicity, shorter reaction time, easily handling, and environmentally benign. The structure and relative stereochemistry of final products was established by single crystal X‐ray structure and spectroscopic techniques. The synthesized compounds were subjected for DNA cleavage activity.

The application of isatin-based multicomponent-reactions in the quest for new bioactive and druglike molecules

“…Dandia, Jain and co-workers proposed that the design of hybrid heterocyclic systems with spirooxindole fused pyrrolo [1,2c]thiazole skeletons and naphthoquinone units could increase their biological activities. Consequently they reported the synthesis of a new family of spiroheterocyclic compounds, incorporating those three pharmacophoric components using a guanidium based ionic liquid (IL) (1,1,3,3-tetramethylguanidine acetate [TMG][Ac]) as green solvent [64]. Decarboxylative condensation of the substituted isatin derivative with L-thioproline affords the corresponding azomethine ylide which subsequently undergoes a 1,3-dipolar cycloaddition reaction with the 1,4-naphthoquinone and subsequent tautomerization and rapid oxidation under atmospheric conditions resulting in the formation of the described spiro[benzo[f]thiazolo [4,3-a]isoindole-5,3 0 -indoline]-2 0 ,6,11-trione derivatives (Scheme 6).…”

Engaging Isatins in Multicomponent Reactions (MCRs) – Easy Access to Structural Diversity

“…This strategy allows the reaction to proceed under mild conditions, with easy work‐up (no chromatographic purification) and short reaction times (Scheme 8B). Good yields of the desired cycloadducts were obtained and the [TMG][Ac] ionic liquid could be used at least four times without considerable loss of activity [26] . The authors suspected that the azomethine ylide formed by decarboxylative condensation, undergoes 1,3‐dipolar cycloaddition reaction with the naphthoquinone affording the cycloadduct intermediate which is tautomerized to the corresponding hydronaphtoquinone derivative resulting in the desired product due to rapid oxidation under atmospheric air conditions (see Scheme 8B, mechanistic insight).…”

“…[Bmim]Br [19] [Bmim]BF 4 [20] [TMG][Ac] [26] DABCO−H]Cl [84] [Bmim]OH [103] [Cmpy]I [104] MOACS [106] ([DB‐18‐C‐6K + ][OH − ] nIL [186] …”

Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles

“…To date, several powerful dipole-controlled multicomponent 1,3-dipolar cycloadditions have been explored selectively to access N -fused pyrrolidinyl spirooxindoles by using diverse α -amino acids as precursors to furnish isatin-derived azomethine ylides [ 40 , 56 , 57 , 58 , 59 ] ( Scheme 1 b). Noticeably, 1,4-enedione derivatives [ 60 , 61 , 62 ], such as maleimides [ 63 , 64 ], methylene indolinones [ 65 , 66 , 67 ], 1,4-naphthoquinone [ 68 , 69 , 70 , 71 ], maleic anhydride, etc., can be activated by two carbonyl groups, which can enhance the flexibility and diversity of cyclization in synthetic chemistry. To the best of our knowledge, only individual multicomponent dipolarophile-controlled methods have been elegantly developed to synthesize N -fused pyrrolidinyl spirooxindoles, while designated catalysts are necessary for this synthetic strategy [ 72 ].…”