Mechanochemical‐ (Hand‐Grinding‐) Assisted Domino Synthesis of Fused Pyran‐Spirooxindoles under Solvent‐ and Catalyst‐Free Condition

Abstract

An efficient and green strategy is developed to synthesize 2‐amino‐2‐oxospiro [indoline‐3, 4′‐pyran]‐3′‐carbonitriles. The method encompasses a domino multicomponent reaction using isatin or acetanaphthelenequinone, malononitrile or ethylcyanoacetate and enolizable 1, 3‐dicarbonyl compounds without any promoter and catalyst in one pot through hand grinding in excellent yields within minutes.

Catalyst-free mechanochemistry as a versatile tool in synthetic chemistry: a review

“…Pyran-spirooxindoles are structural motifs in several natural products which display a wide range of bioactivities including anti-microbial, anti-cancer, anti-Alzheimer's, anti-HIV, anti-tubercular and anti-inflammatory properties. 75 Due to the biological importance and complexity of these structures they have become a special interest in organic synthesis, and in this regard a variety of catalysts under different conditions have been reported for their preparation. 75 More importantly, Hussen et al developed a catalyst, solvent-free mechanochemical (grinding) synthesis of fused pyran-spirooxindoles ( 78 ) via a domino multicomponent reaction from isatins ( 77 ), malononitrile/ethyl cyanoacetate/cyano acetamide ( 21 / 55 / 56 ), and cyclic 1,3-dicarbonyl compounds ( 76 ) at rt (Scheme 31).…”

“…75 Due to the biological importance and complexity of these structures they have become a special interest in organic synthesis, and in this regard a variety of catalysts under different conditions have been reported for their preparation. 75 More importantly, Hussen et al developed a catalyst, solvent-free mechanochemical (grinding) synthesis of fused pyran-spirooxindoles ( 78 ) via a domino multicomponent reaction from isatins ( 77 ), malononitrile/ethyl cyanoacetate/cyano acetamide ( 21 / 55 / 56 ), and cyclic 1,3-dicarbonyl compounds ( 76 ) at rt (Scheme 31). 75 a These reactions provide high yields (87–95%) of products in 25 min involving easy workup, non-chromatography purifications and large-scale feasibility.…”

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

“…With the disappearance of the starting materials from TLC, the third component (dimedone) was added (Michael addition) and grinding continued in the same manner until the reaction is finished. This green protocol based on mechanochemical activation proved to be highly efficient with good reaction scope and short reaction times (Scheme 69C), with simple work‐up procedure and suitable for multigram scale (up to 92 % yield of the desired compound) [139] …”

A Facile and Green Pathway for One‐Pot Multicomponent Synthesis of Functionalized Spiroxyindoles using Caffeinium Hydrogen Sulfate as a Catalyst.

“…To achieve this domino Knoevenagel‐Michael‐cyclization product a large number of catalytic approaches have been reported such as InCl 3 in refluxing acetonitrile, L‐proline‐melamine, triethylbenzyl ammonium chloride (TEBA), pTSA, β‐Cyclodextrin, SDS, ZnFe 2 O 4 , butyl methyl imidazolium tetrafluoroborate [BMIm] [BF 4 ], glucose‐water organocatalytic system and nanocrystalline MgO . These compounds have also been synthesized by catalyst free mechanochemical methods . In fact many of these methodologies are effective for the preparation of targeted products but many of them suffer from serious drawbacks such as use of expensive and carcinogenic organic solvents, technical intricacy, generation of byproducts involving mixture of compounds, non‐recyclability of the catalysts, long reaction times and tedious workup and product isolation processes.…”

“…[23] These compounds have also been synthesized by catalyst free mechanochemical methods. [24] In fact many of these methodologies are effective for the preparation of targeted products but many of them suffer from serious drawbacks such as use of expensive and carcinogenic organic solvents, technical intricacy, generation of byproducts involving mixture of compounds, non-recyclability of the catalysts, long reaction times and tedious workup and product isolation processes.…”