An Efficient Synthesis of Spiro[Indoline-3,9'-Xanthene]

molecules Article An Efficient Synthesis of Spiro[indoline-3,90- xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate Chunfeng Chen 1,2, Chunlei Lv 2, Jianfeng Liang 2, Jianqing Jin 2, Lijun Wang 1, Chunlei Wu 1,* and Runpu Shen 1,* 1 Department of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, Zhejiang, China; [email protected] 2 Zhejiang Medicine Co., Ltd., Shaoxing 312000, Zhejiang, China; [email protected] (C.C.); [email protected] (C.L.); [email protected] (J.L.); [email protected] (J.J.) * Correspondence: [email protected] (C.W.); [email protected] (R.S.); Tel.: +86-575-8834-8939 (C.W.) Received: 19 July 2017; Accepted: 1 August 2017; Published: 4 August 2017 Abstract: A simple and efficient method for the synthesis of spiro[indoline-3,90-xanthene]trione derivatives by means of condensation between isatins and 1,3-cyclohexanedione in the presence of a catalytic amount of magnesium perchlorate at 80 ◦C in 50% aqueous ethanol medium has been described. Notably, the present method offers desirable advantages of good yields, simplicity of workup procedure, easy purification, and reduced reaction times. Keywords: aqueous; isatin; spiro[indoline-3,90-xanthene]trione; magnesium perchlorate 1. Introduction Heterocyclic compounds play important roles in the drug discovery process. The indole moiety is probably the most well-known heterocycle, which occurs in many important natural products, pharmaceuticals, and other synthetic materials exhibiting a variety of biological activities and other properties [1,2]. Spiro compounds represent an important class of naturally occurring substances characterized by highly pronounced biological properties [3]. The spirooxindole system is the core structure of many pharmacological agents and natural alkaloids [4–6]. The key structural characteristic of these compounds is the spiro ring fused at the 3-carbon position of the oxindole core with varied heterocyclic motifs. These spirooxindoles seem to be promising candidates for drug discovery, since they incorporate both oxindoles and other heterocyclic moieties simultaneously. For example, MI-219, a spiroindoline-3,30-pyrrolidine, was described by Wang et al. as a potent MDM2 inhibitor [7]. Xanthenes have been reported to possess pharmacological activities such as antiviral, antibacterial, and anti-inflammatory properties, and are also known as sensitizers in photodynamic therapy (PDT) for abolishing tumor cells [8–11].Spiro[indoline-3,90-xanthene]trione, as a member of spiro compounds, has attracted researchers’ attentions for its unique structure and biological effects since the first report by Lorenc in 1959 [12], and various catalysts for its synthesis have been developed such as p-tert-Butylcalix[8]arene [13], p-TSA [14,15], ZnO [16], ZnFe2O4 [17], B(HSO4)3 [18], HBF4 supported on silica nanoparticles [19], and SnCl4 [20]. Although these reported protocols have their eligibilities, they also suffer from one or more drawbacks. So, the development of novel, efficient methods is still a valid goal. In recent years, magnesium perchlorate has received considerable attention as an inexpensive, nontoxic, readily available catalyst for various transformations under mild and convenient conditions, affording the corresponding products in excellent yields with high selectivity [21–25]. Our previous Molecules 2017, 22, 1295; doi:10.3390/molecules22081295 www.mdpi.com/journal/molecules Molecules 2017, 22, 1295 2 of 7 Molecules 2017, 22, 1295 2 of 7 work on the catalytic synthesis of spiro[4H-pyran-oxindole] derivatives was carried out smoothly in the presencepresence ofof magnesiummagnesium perchlorate perchlorate [ 26[26].]. The The handling, handling, storage, storage, and and precautionary precautionary information information of theof the oxidative oxidative Mg(ClO Mg(ClO4)2 can4)2 can be foundbe found in the in literature,the literature, and itand is relativelyit is relatively safe when safe when used asused a Lewis as a acidLewis catalyst acid catalyst [27,28]. [27,28]. InIn continuancecontinuance of ourour researchresearch onon thethe synthesissynthesis ofof spirospiro compoundscompounds andand thethe applicationapplication of 0 perchlorate, wewe hereinherein investigated investigated the the synthesis synthesis of of a series a series of spiro[indoline-3,9of spiro[indoline-3,9-xanthene]trione′-xanthene]trione via thevia the condensation condensation of isatinof isatin and and 1,3-cyclohexanedione 1,3-cyclohexanedione in in the the presence presence of of green green catalystcatalyst magnesiummagnesium perchlorate inin aqueousaqueous ethanolethanol mediummedium (Scheme(Scheme1 1).). R2 R2 O O O O R2 Mg(ClO4)2, 10mol% 2 O R O + EtOH/H O R 1 2 , 12h 2 N (v/ v = 1:1) H R 2 R2 R1 O N O 1 2 H 3 R1 = H; 5-CH3; 5-Cl; 5-NO2; 5-F; R2=H;CH3 5-Br; 6-F; 7-CH3; 7-Cl Scheme 1.1. Synthesis of spiro[indoline-3,90′-xanthene]trione. 2. Results and Discussion 2. Results and Discussion In our initial study, the reaction of isatin 1a and dimedone 2 was used as a simple model substrate In our initial study, the reaction of isatin 1a and dimedone 2 was used as a simple model substrate in different solvents in the presence of magnesium perchlorate to achieve suitable conditions for the in different solvents in the presence of magnesium perchlorate to achieve suitable conditions for synthesis of spiro[indoline-3,9′-xanthene]trione. After screening, we found that the reaction can the synthesis of spiro[indoline-3,90-xanthene]trione. After screening, we found that the reaction can proceed smoothly in good yield in aqueous ethanol solution (50%, v/v). The reaction mixture was proceed smoothly in good yield in aqueous ethanol solution (50%, v/v). The reaction mixture was presented as a suspension state throughout all the process. The color of the reaction mixture changed presented as a suspension state throughout all the process. The color of the reaction mixture changed from pale red to pale yellow along with the reaction proceeding. The results are summarized in from pale red to pale yellow along with the reaction proceeding. The results are summarized in Table1. Table 1. Table 1. Solvent effects on the reaction of isatin and dimedone, in the presence of 10 mol % magnesium perchlorateTable 1. Solventa. effects on the reaction of isatin and dimedone, in the presence of 10 mol % magnesium perchlorate a. ◦ b EntryEntry Solvent/T Solvent/T(°C) ( C) Time Time (h) (h) Yieldb Yield(%) (%) 11 PhCHPhCH3(reflux)3(reflux) 24 24 Trace Trace 2 CH Cl (reflux) 24 Trace 2 CH2 2Cl2 2(reflux) 24 Trace 3 CH3OH(reflux) 12 64 3 CH3OH(reflux) 12 64 4 C2H5OH(reflux) 12 71 2 5 54 C2H5COH/HH OH(reflux)2O(1/1)(80) 12 10 71 83 65 C2H5OH/H H2O(80)2O(1/1)(80) 10 12 83 77 76 CH3CN(reflux)H2O(80) 12 12 77 60 8 THF(reflux) 12 58 7 CH3CN(reflux) 12 60 a b Isatin (28 mmol), dimedoneTHF(reflux) (4 mmol); solvent (5 mL), Mg(ClO12 4)2 (10%mol).58Isolated yield. a Isatin (2 mmol), dimedone (4 mmol); solvent (5 mL), Mg(ClO4)2 (10%mol). b Isolated yield. As shown in Table2, it was found that this procedure works with a wide variety of substrates. NineAs types shown of substitutedin Table 2, isatinsit was asfound well that as 1,3-cyclohexanedione this procedure works were with used a wide in this variety reaction of (Schemesubstrates.1). AfterNine types the reaction of substituted was over isatins monitored as well as by 1,3-cyclohexanedione the thin layer chromatography were used in (TLC), this reaction the resulting (Scheme solid 1). wasAfter filtered the reaction and washed was over with monitored aqueous by ethanol the thin solution layer chromatography to yield a crude product,(TLC), the which resulting was solid then 0 recrystallizedwas filtered and from washed ethanol with to afford aqueous pure ethanol substituted solu spiro[indoline-3,9tion to yield a crude-xanthene]trione product, which3a– 3mwas. All then of therecrystallized products were from crystalline ethanol andto afford characterized pure substituted based on theirspiro[indoline-3,9 melting points,′-xanthene]trione elemental analysis, 3a– and3m. 1 13 spectralAll of the data products (IR, H-NMR, were crystallineC-NMR). and characterized based on their melting points, elemental analysis, and spectral data (IR, 1H-NMR, 13C-NMR). Molecules 2017, 22, 1295 3 of 7 Molecules 2017, 22, 1295 3 of 7 Table 2. Synthesis of spiro[indoline-3,9′-xanthene]trione 3. Table 2. Synthesis of spiro[indoline-3,90-xanthene]trione 3. Product R1 R2 Time (h) Yield a (%) 3a H CH3 10 83 a Product R1 R2 Time (h) Yield (%) 3b 5-Me CH3 12 75 3a H CH3 10 83 3c 5-Cl CH3 10 79 3b 5-Me CH3 12 75 3c3d 5-NO5-Cl2 CH3 CH3 10 1081 79 3d3e 7-Me5-NO 2 CH3 CH3 12 1071 81 3e 7-Me CH 12 71 3f 7-Cl CH3 3 10 78 3f 7-Cl CH 10 78 3g 3 3g H HH H10 1080 80 3h3h 5-Me5-Me H H12 1269 69 3i 3i 5-Cl5-Cl H H10 1082 82 3j 3j 5-F5-F CH3 CH3 10 1083 83 3k 3k 5-Br5-Br H H10 1071 71 3l 5-Br CH3 10 78 3l 5-Br CH3 10 78 3m 6-F CH3 10 85 3m 6-F CHa Isolated3 yield. 10 85 a Isolated yield. 0 The mechanism for thethe synthesissynthesis ofof spiro[indoline-3,9spiro[indoline-3,9′-xanthene]trione was was via the intermediate 4,, followed by the removal of a moleculemolecule of waterwater (Figure(Figure1 1),), whichwhich cancan bebe provedproved byby thethe following following process. 6-Fuloro-isatine 6-Fuloro-isatine and and dimedo dimedonene were were stirred stirred for for 24 24 h hat atroom room temperature temperature and and then then catalyzed catalyzed by bymagnesium magnesium perchlorate perchlorate in the in aqueous the aqueous ethanol.

Load more