Catalyst-free four-component domino synthetic approach toward versatile multicyclic spirooxindole pyran scaffolds

Abstract

A new versatile strategy involving a sequential four-component reaction of the nitroketene dithioacetals, alkylamine/benzylamine, isatin and various enolizable active methylene structures (pyrazolone, barbituric acid, 1,3-indandione and 2-hydroxy-1,4-naphthoquinone) as precursors under mild and catalyst-free conditions results in the synthesis of new functionalized spirooxindole pyrans named spiro[indoline-3,4 0pyrano[2,3-c]pyrazol], spiro[indoline-3,5 0 -pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3 0indoline] and spiro[benzo[g]chromene-4,3 0 -indoline] in moderate to good yields. The use of various active methylene compounds affords a range of skeletally distinct spirooxindole-based heterocycles with potential biological properties. The present strategy has many advantages, such as convenient one-pot operation, simple workup procedures and straightforward isolation without using tedious purification steps such as column chromatography, progress under catalyst-free condition and high molecular diversity. ; Tel: +98 28 33780040 † Electronic supplementary information (ESI) available. See Scheme 1 Synthesis of spiro(indoline-3,4 0 -pyrano[2,3-c]pyrazol)-2-one derivatives catalyzed by indium trichloride. Scheme 2 The one-pot, multi-component synthesis of bis-spirooxindoles in PEG-400/K 2 CO 3 at room temperature. 16526 | RSC Adv., 2019, 9, 16525-16533 This journal is Scheme 3 Synthetic approaches for the formation of spiro[indoline-3,4 0 -pyrano[2,3-c]pyrazol], spiro[indoline-3,5 0 -pyrano[2,3-d]pyrimidine], spiro[indeno[1,2-b]pyran-4,3 0 -indoline] and spiro[benzo[g]chromene-4,3 0 -indoline] (5a-q).Scheme 4 A plausible mechanism for the formation of 5 in catalyst-free conditions.This journal is

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

“…The final intramolecular O ‐cyclization step allows the formation of the desired multicyclic spirooxindole pyran scaffolds. Despite moderate yields, this convenient one‐pot process comprises simple work‐up procedures and high molecular diversity (17 examples) [175] . Mohebat et al .…”

Recent Developments on Catalyst‐Free, Visible‐Light‐Triggered Synthesis of Heterocyclic Scaffolds and Their Mechanistic Study

“…Dihydropyrano [2,3-c]pyrazole and its derivatives are attractive and fruitful scaffolds in the field of synthetic as well as medicinal chemistry having diverse biological activities such as anti-inflammatory, anti-microbial activity, anti-cancer, analgesic and anti-oxidant etc. [62] Tripathi et al reported an eco-friendly and metal-free procedure for the synthesis of pyrano [2,3-c]pyrazoles (73) via a four-component reaction of ethylacetoacetate (69), hydrazine hydrate (70), aromatic aldehydes (71) and malononitrile (72) at room temperature (Scheme 38). [63] The reaction was carried out in solvent-free and catalyst-free conditions exploiting visible light as a promoter.…”

“…They also found that in the absence of visible light, the yield of the product was noticeably decreased to 30 % which specified the importance of light. The authors proposed that ethyl acetoacetate (69) and hydrazine hydrate (70) underwent nucleophilic addition reaction to form 39 A, which through keto-enol tautomerism led to 39 B. Then, malononitrile (72) tautomerized in presence of visible light and reacted with benzaldehyde (71) to form benzylidene malononitrile adduct 39 D which formed a radical 39 E by photochemical activation.…”

“…[69] These spirooxindole pyran derivatives increase synthetic chemists' attention due to their anti-fungal, anticancer, anti-bacterial, anti-HIV and anti-viral activities. [70] Zhang et al 2-hydroxynaphthalene-1,4-dione (84 a) or dimedone (84 b) or 4-hydroxycoumarin (84 c) at room temperature (Scheme 44). [71] This report displays considerable advantages such as environmentally friendly solvent, catalyst-free reaction conditions, large-scale application and chromatographic separation free.…”

Three‐component electrosynthesis of spirooxindole‐pyran derivatives through a simple and efficient method

“…Characterized by highly pronounced biological properties, spirocompounds are representatives of an important category of naturally occurring substances . The spirooxindole skeleton, as the core structure of many pharmacological agents and natural alkaloids with various functional groups taking position at C‐3 of oxindoles, often presents an enhancement in their biological activity . These substances also show diverse activities such as antiproliferative, anti‐inflammatory, antihuman immunodeficiency virus, antihuman respiratory syncytial virus, antidengue virus, anti‐influenza virus agents, and therapeutic value for several clinical illnesses such as obesity, diabetes, gastrointestinal, and urinary disease functioning via β3 adrenoceptor agonism …”