Spirooxindoles:Recent report of green synthesis approach

Spirooxindole is a compound with a unique framework and broad bioactivities in medicine.In this study,we have reviewed various approaches or methods in synthesizing spirooxindole derivatives focused on green synthesis.Synthesis of spirooxindoles is mainly carried out through multicomponent reactions combined with various green approaches such as the use of heterogeneous catalysts(nano-sized,magnetic,metal-complex,and metal-organic framework catalysts),deep eutectic solvent,solvent-free reactions,catalyst-free reactions,as well as the use of ultrasonic and microwaves irradiation.The green method is carried out in addition to obtaining high yields,it also offers reductions in the use of hazardous chemicals,energy use,purification processes,and waste generation.As a result,green synthesis methods in the synthesis of spirooxindole derivatives are more environmentally friendly.

Modular Assembly of Six-Membered Carbocyclic Spirooxindoles via Peterson Olefination/Michael Addition/C(sp^(3))Arylation Cascade

Concise assembly of spirooxindoles is of great significance but a challenging task in modern organic synthesis.Described herein is an unusual base-promoted[4+2]spiroannulation of rarely used isatin-derivedβ-silylcarbinols with o-halogen aromatic ketones,which enables rapid and modular synthesis of six-membered carbocyclic spirooxindoles in high yields with excellent functional group tolerance(>50 examples).Mechanistic experiments revealed that this reaction involved a Peterson olefination,Michael addition and intramolecular C(sp^(3))arylation cascade.The variegated synthetic derivatization of target products and successful construction of bioactive molecules further illustrate the synthetic potential in spirooxindole-related drug discovery.

[3＋3] Formal Cycloadditions of Nitrones from Isatins and Azaoxyallyl Cations for Construction of Spirooxindoles

A [3＋3] formal cycloaddition reaction between in situ formed azaoxyallyl cations and nitrones from isatins has been developed, furnishing a spectrum of spiro[1,2,4-oxadiazinan-5-one]oxindoles in good to excellent yields with excellent diastereoselectivity. This method provides direct and efficient access to potentially bioactive spirooxin- doles incorporating a six-membered heterocyclic scaffold.

Construction of polycyclic spirooxindoles through[3+2]annulations of Morita–Baylis–Hillman carbonates and 3-nitro-7-azaindoles

A mild and efficient dearomatic [3＋2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers in excellent yields（up to 96%） with high regio- and diastereoselectivity（dr 〉 19：1）. Moderate enantioselectivity（79% ee） was obtained by employing a chiral DMAP-type Lewis base catalyst.

AgF-Mediated Dialkylation of Activate Alkenes: An Efficient Access to Nitrile-Containing Spirooxindoles

A novel Ag-mediated dialkylation reaction of alkenes was disclosed,in which AgF was essential to activate C-H bond of acetonitrile.This reaction provided an efficient way to nitrile-containing spirooxindoles from readily available(1H-indol-3-yl)methanamine derivatives.

NHC-catalysed retro-aldol/aldol cascade reaction enabling solvent-controlled stereodivergent synthesis of spirooxindoles

An N-heterocyclic carbene(NHC)-catalysed retro-aldol/aldol cascade reaction of spirooxindole-basedβ-hydroxyaldehyde has been developed.The ring opening-closure process enables the diastereodivergent synthesis of spirocyclopentaneoxindole products with four consecutive stereocenters by simply changing the reaction solvents(THF or DCE).The Michael/aldol/retro-aldol/aldol sequential protocol allows the diastereodivergent synthesis of spirocyclopentaneoxindoles from 3-substituted oxindole andα,β-unsaturated aldehyde under the relay catalysis of a chiral secondary amine and an NHC catalyst.Moreover,four stereoisomers of the product can be selectively provided by using different combinations of a chiral secondary amine and a solvent.

Synthesis, Structure and Antimicrobial Activity of 9,9-Dimethyl-9,10-dihydrospiro[benzo[a]-xanthene-12,3'-indoline]-2',11(8H)-dione

One novel spiro-compound（C_（26）H_（21）NO_3） has been synthesized and characterized by means of NMR spectroscopy,elemental analyses and X-ray diffraction. The single crystal belongs to the monoclinic system,space group P21/c with a = 8.8039（7）,b = 24.123（2）,c = 10.0751（9） ？,β = 108.403（3）°,M3r = 395.44,V = 2030.3（3） ？~3,Z = 4,D_c = 1.294 g/cm,F（000） = 832.0,μ = 0.085 mm^（-1）,R = 0.0801 and wR = 0.2228. The title compound shows good activities against Micrococcus tetragenus,Bacillus cereus,Bacillus subtilis,Staphylococcus aureus,S.albus and Escherichia coli.

Construction of Spirooxindole Skeleton Through Intramolecular Dieckmann Cyclization

A highly efficient and direct approach was developed to construct the structurally diverse spirooxindole skeleton,which is an important basic motif in natural products.Both the 3,30-pyrrolidonyl spirooxindoles and spiroindolin-2-one dlactones were 2smoothly obtained by the intramolecular Dieckmann cyclization of oxindoles in excellent yield under mild conditions.

Alum （KAI（SO4）2·12H2O） Catalyzed Multicomponent Transformation： Simple, Efficient, and Green Route to Synthesis of Functional- ized Spiro[chromeno[2,3-d]pyrimidine-5,3＇-indoline]-tetraones in Ionic Liquid Media

The combination of isatin, barbituric acid, and cyclohexane-1,3-dione derivatives in the presence of alum （KAI（SO4）2· 12H2O） as a catalyst for 15 min was found to be a suitable and efficient method for the synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3＇-indoline]-tetraones.

A cesium fluoride promoted efficient and rapid multicomponent synthesis of functionalized 2-amino-3-cyano-4H-pyran and spirooxindole derivatives

A rapid, one-pot and highly efficient protocol for the synthesis of pharmaceutically interesting functionalized 2-amino-3-cyano-4H-pyran and spirooxindole derivatives has been developed using commercially available Cs F as a catalyst in the reaction of malononitrile and aryl aldehydes or isatins with 1,3-cyclohexanediones. The major advantages of this methodology are excellent yield at ambient temperature, very short reaction time（5–10 min）, and use of an inexpensive catalyst.

A highly efficient In(OTf)3-catalyzed[3+3]annulation of spirocyclopropyl oxindoles with 1,4-di-thiane-2,5-diol

Spirooxindoles play an important role in drug discove ry and development.The development of efficient methods for the synthesis of spirooxindoles from easily available sta rting materials is of curre nt interest Herein,we report in detail the In(OTf)3-catalyzed[3+3]annulation of spirocyclopropyl oxindoles and 1,4-di-thiane-2,5-diol,which allows the facile preparation of spiro[indoline-3,4'-thiopyran]-2-ones bearing(tetrahydro)thiopyran skeleton.

Protecting-Group-Free Total Synthesis and Biological Investigation of Cabucine Oxindole A

Owing to their challenging structures and promising biological profiles,spirooxindole alkaloids have long attracted much attention from the synthetic community.Herein,we wish to describe a concise,protecting-group-free total synthesis of cabucine oxindole A,a putative natural spirooxindole alkaloid and a possible biosynthetic congener of cabucine and palmirine.Key transformations of our approach include a one-step,organocatalytic and enantioselective construction of the spiro[pyrrolidine-3,3'-oxindole]moiety and a Korte rearrangement to furnish the final dihydropyran motif.Biological investigation of 1 and its synthetic intermediates revealed lactone 2 as a mild MOLT-4 and MCF7 cell line inhibitor.

Three-component reaction for synthesis of functionalized spiro[indoline-3,4'-pyrano[3,2-h]quinolines]

The functionalized spiro[indoline-3,40-pyrano[3,2-h]quinolines] were efficiently prepared in high yields from three-component reaction of 8-hydroxyquinoline, isatins and malononitrile or ethyl cyanoacetate in ethanol at room temperature for about 12 h in the presence of piperidine.

Discovery of spirooxindole-ferrocene hybrids as novel MDM2 inhibitors

A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis.In vitro protein binding and cellular proliferation assays suggested that compound 5 d was the most potent mouse double minute 2 homolog(MDM2)inhibitor.In addition,mechanistic studies indicated that compound 5 d suppressed MDM2-mediated p53 degradation,induced apoptosis and promoted oxidative damage.Molecular docking studies have suggested that 5 d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53.This work can provide a basis for the development of novel multifunctional MDM2 inhibitors.The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.

Three-Component Reaction for Construction of Spiro[indoline- 3,7＇-thiazolo[3,2-a]pyridines] and Spiro[benzo[4,5]- thiazolo[3,2-a]pyridine-3,3＇-indolines]

The three-component reaction of thiazole （benzothiazole）, dialkyl but-2-ynedioate, and isatinylidene malononi- triles in toluene at 110-120 ℃ in a sealed tube afforded a mixture of cis/trans-isomers of functionalized di- astereoisomeric spiro[indoline-3,7＇-thiazolo[3,2-a]pyridines] and spiro[benzo[4,5]thiazolo[3,2-a]pyridine-3,3＇-in- dolines] in good yields. Both cis-isomers and trans-isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three-component reaction con- taining 2-（1,3-dioxo-lH-inden-2（3H）-ylidene）malononitrile resulted in spiro[indene-2,7＇-thiazolo[3,2-a]pyridine] derivatives.

One-pot Two-Step Cycloaddition Reaction for Convenient Synthesis of Polycyclic Spirooxindole-fused [1,3]Oxazines

The novel spirooxindoline fused [1,3]oxazines were efficiently synthesized from Diels-Alder reaction of N-arylmaleimides with 1,2-dihydro-2-oxospiro[3H-indole-3,2＇-[2H,9aH-pyrido[2,1-b][l,3]oxazines], which were generated in situ from three-component reactions of substituted pyridines and isatins with methyl propiolate, or di- methyl acetylenedicarboxylate. The stereochemistry of the products was clearly clarified by the analysis of 1H NMR data and single crystal structures of the obtained polycyclic compounds.

An Efficient Synthesis of Spiroquinoxalinones via Tandem Reactions

A mild and efficient synthesis of spiroquinoxalinones via tandem condensation of chlorooxoindoline 1 with benzene-1,2-diamines 2 is described.And a plausible mechanism for the reaction is proposed.

Synthesis of Dispirocyclopentyl-3,3＇-bisoxindoles via Domino Cycloaddition Reactions of 4-Dimethylaminopyridinium Bromides with 3-Phenacylideneoxindoles

The base mediated cycloaddition reactions of 4-dimethylamino-l-phenacylpyridinium bromides with two mo- lecular 3-phenaeylideneoxindoles in methylene dichloride afforded functionalized dispirocyclopentyl-3,3＇-bisoxin- doles in good yields and with high diastereoselectivity. The similar cycloaddition reactions of 1-（N,N-dialkylcarba- moylmethyl） and 1-cyanomethyl 4-dimethylamino-pyridinium bromide in refluxing ethanol in the presence of triethylamine a/so resulted in dispirocyclopentyl-3,3＇-bisoxindoles with high diastereoselectivity. The stereochemis- try of dispirocyclopentyl-3,3＇-bisoxindoles was elucidated on the basis of ^1H NMR data and single crystal struc- tures.

One pot three component synthesis of spiro [indolo-3,10’-indeno[1,2-b]quinolin]-2,4,11’-triones as a new class of antifungal and antimicrobial agents

A simple and efficient three component procedure has been developed for the synthesis of highly substituted spiro[indolo-3,100-indeno[1,2-b]quinolin]-2,4,11＇-triones by one pot three component condensation of enaminones, isatin and indane-1,3-dione in ethanol：water（1：1） in presence of ceric ammonium nitrate（CAN） as catalyst. This method provides several advantages such as lesser reaction time, high yield of products and operational simplicity. The antimicrobial activity of some of the compounds has been investigated against six microbial strains, some of the tested compounds showed good antimicrobial activity.

Approach to 2′-(Dialkylamino)-1-alkyl-4′H-spiro[indoline-3,5′-oxazole]-2,4′-diones and 1,3-Oxazin-4-ones via Cyclization of Vilsmeier Salts withα-Hydroxy andβ-Carbonyl Amides

A straiglitforward and efficient synthetic method of 2′-(dialkylammo)-l-alkyl-4′H-spiro[indoline-3,5′-oxazole]-2,4′-diones and 2-(dialkylamino)-5,6-dihydro-4H-naphtho[2,1-e][1,3]oxazin-4-one-derivatives have been developed from a-hydroxy andβ-carbonyl amides and various Vilsmeier salts.A wide range of heterocyclic compounds were obtained in excellent yields(up to 97%),which will provide promising candidates lor chemical biology and drug discovery.