Next Article in Journal
Fluorescent Polystyrene Films for the Detection of Volatile Organic Compounds Using the Twisted Intramolecular Charge Transfer Mechanism
Next Article in Special Issue
Spiropyran-Isoquinoline Dyad as a Dual Chemosensor for Co(II) and In(III) Detection
Previous Article in Journal
γ-Tocotrienol Inhibits Proliferation and Induces Apoptosis via the Mitochondrial Pathway in Human Cervical Cancer HeLa Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 22
Issue 8
10.3390/molecules22081295
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

An Efficient Synthesis of Spiro[indoline-3,9′-xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate

by
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
2
Zhejiang Medicine Co., Ltd., Shaoxing 312000, Zhejiang, China
*
Authors to whom correspondence should be addressed.
Molecules 2017, 22(8), 1295; https://doi.org/10.3390/molecules22081295
Submission received: 19 July 2017 / Revised: 31 July 2017 / Accepted: 1 August 2017 / Published: 4 August 2017
(This article belongs to the Special Issue Advances in Spiro Compounds)
Browse Figures
Versions Notes

Abstract

:
A simple and efficient method for the synthesis of spiro[indoline-3,9′-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.

Graphical Abstract

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 [4,5,6]. 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-3,3′-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 [8,9,10,11].Spiro[indoline-3,9′-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 [21,22,23,24,25]. Our previous work on the catalytic synthesis of spiro[4H-pyran-oxindole] derivatives was carried out smoothly in the presence of magnesium perchlorate [26]. The handling, storage, and precautionary information of the oxidative Mg(ClO4)2 can be found in the literature, and it is relatively safe when used as a Lewis acid catalyst [27,28].
In continuance of our research on the synthesis of spiro compounds and the application of perchlorate, we herein investigated the synthesis of a series of spiro[indoline-3,9′-xanthene]trione via the condensation of isatin and 1,3-cyclohexanedione in the presence of green catalyst magnesium perchlorate in aqueous ethanol medium (Scheme 1).

2. Results and Discussion

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 synthesis of spiro[indoline-3,9′-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 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 Table 1.
As shown in Table 2, it was found that this procedure works with a wide variety of substrates. Nine types of substituted isatins as well as 1,3-cyclohexanedione were used in this reaction (Scheme 1). After the reaction was over monitored by the thin layer chromatography (TLC), the resulting solid was filtered and washed with aqueous ethanol solution to yield a crude product, which was then recrystallized from ethanol to afford pure substituted spiro[indoline-3,9′-xanthene]trione 3a–3m. All of the products were crystalline and characterized based on their melting points, elemental analysis, and spectral data (IR, 1H-NMR, 13C-NMR).
The mechanism for the synthesis of spiro[indoline-3,9′-xanthene]trione was via the intermediate 4, followed by the removal of a molecule of water (Figure 1), which can be proved by the following process. 6-Fuloro-isatine and dimedone were stirred for 24 h at room temperature and then catalyzed by magnesium perchlorate in the aqueous ethanol. Then the precipitate was filtered, washed and dried. The 1H-NMR spectra data of the obtained solid showed that there was a strong peak in the shift of 11.68, which was assigned to the hydroxyl hydrogen of the compound 4. Finally, the solid was stirred at 80 °C for another 10 h to afford the product 3m. This proposed mechanism is in consistent with that reported in References [15,29,30].

3. Experimental Section

All chemicals used were obtained from commercial suppliers and used without further purifications. IR spectra were recorded on a Nicolet-6700 spectrometer (Thermo Scientific, MMAS, Waltham, MA, USA). 1H-NMR spectra were determined on a Bruker AVANCE DMX III 400 M spectrometer (Bruker, Fallanden, Switzerland) and 13C-NMR spectra were obtained on the same instrument. Samples were dissolved in deuterated DMSO, which provided the deuterium lock for the spectrometers. Elemental microanalysis was carried out on a Euro vector EA 3000 CHN analyzer (Milan, Italy). Melting points were measured using a BUCHI M-560 melting point apparatus (Buchi labortechnik AG, Flawil, Switzerland). HRMS measurements were performed on a Waters Micromass GCT Premier (Waters, MMAS, New York, NY, USA). Reactions were monitored by thin-layer chromatography (TLC), carried out on 0.25 mm silica gel plates and visualized with UV light.

General Procedure for the Synthesis of Spiro[indoline-3,9′-xanthene]trione (3)

Mg(ClO4)2 (0.1 g) was added to a mixture of isatin (2 mmol), and dimedone (4 mmol) in aqueous ethanol solution (50%, v/v, 5 mL), and the resulting mixture was stirred at 80 °C for 10–12 h. Upon completion of the reaction (TLC, Ethyl acetate/Petroleum ether = 1:4), the mixture was allowed to cool to room temperature. The resulting solid was filtered and washed successively with water (2 × 30 mL) and cold aqueous ethanol (2 × 1 mL) to afford a crude product, which was recrystallized from EtOH to afford the pure product 3. Some insolubility could be observed in the refluxing ethanol during the recrystallization process, which should be filtered when hot.
3′,3′,6′,6′-Tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3a). White powder; m.p.: 306–307 °C (305 °C) [15]; IR (KBr) cm−1: 3431, 2957, 1733, 1666, 1616, 1469, 1345, 1222, 1168. 1H-NMR (400 MHz, CDCl3): δH (ppm) 1.04 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.11 and 2.25 (4H, AB system, J = 16 Hz, 2CH2), 2.44 and 2.56 (4H, J = 17.6Hz, 2CH2), 6.83–6.90 (3H, m, H-Ar), 7.13–7.17 (1H, m, H-Ar), 7.62 (1H, s, NH); 13C-NMR (100 MHz, CDCl3): δC (ppm) 27.2, 29.0, 32.0, 41.2, 45.7, 50.9, 109.4, 113.6, 121.9, 122.3, 128.5, 133.6, 142.3, 163.5, 178.8, 195.3; Anal. Calcd. for C24H25NO4: C, 73.64; H, 6.44; N, 3.58%. Found: C, 73.67; H, 6.36; N, 3.52%.
5,3′,3′,6′,6′-Pentamethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3b). White powder; m.p.: 294–295 °C (310 °C) [16]; IR (KBr) cm−1: 3314, 2959, 1745, 1670, 1618, 1349, 1315, 1168. 1H-NMR (CDCl3): δH (ppm) 1.04 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.13 and 2.24 (4H, AB system, J = 16.4 Hz, 2CH2), 2.21 (3H, s, CH3), 2.45 and 2.55 (4H, AB system, J = 17.6 Hz, 2CH2), 6.66 (1H, s, H-Ar), 6.73 (1H, d, J = 8.0 Hz, H-Ar), 6.95 (1H, d, J = 7.6 Hz, H-Ar), 7.46 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 21.2, 27.4, 28.9, 31.9, 41.2, 45.7, 50.9, 108.9, 113.7, 123.2, 128.9, 132.2, 133.7, 139.8, 163.4, 178.7, 195.3. Anal. Calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45%. Found: C, 73.58; H, 6.41; N, 3.48%.
5-Chloro-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3c). White powder; m.p.: 309–310 °C; IR (KBr) cm−1: 3457, 2958, 1739, 1665, 1616, 1509, 1349, 1224, 1120. 1H-NMR (CDCl3): δH (ppm) 1.06 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.16 and 2.26 (4H, AB system, J = 16.4 Hz, 2CH2), 2.48 and 2.56 (4H, J = 17.6 Hz, 2CH2), 6.76 (1H, d, J = 8.4 Hz, H-Ar), 6.83 (1H, d, J = 1.6 Hz, H-Ar), 7.12 (1H, dd, J = 1.6 Hz, J = 8.4 Hz, H-Ar), 7.89 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.5, 28.7, 31.9, 41.2, 45.8, 50.9, 110.3, 113.2, 122.6, 126.9, 128.3, 135.2, 141.2, 163.8, 178.3, 195.4. Anal. Calcd. for C24H24ClNO4: C, 67.68; H, 5.68; N, 3.29%. Found: C, 67.59; H, 5.62; N, 3.37%. HRMS (ESI): m/z [M + H]+ calcd. for C24H24ClNO4: 425.9047; found: 425.9041.
5-Nitro-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3d). Pale yellow powder; m.p.: 276–277 °C (278 °C) [15]; IR (KBr) cm−1: 3452, 2958, 1745, 1667, 1629, 1346, 1225, 1169. 1H-NMR (CDCl3): δH (ppm) 1.00 (6H, s, 2CH3), 1.11 (6H, s, 2CH3), 2.17 and 2.26 (4H, AB system, J = 16 Hz, 2CH2), 2.53 and 2.59 (4H, AB system, J = 18 Hz, 2CH2), 6.89 (1H, d, J = 8.8 Hz, H-Ar), 7.80 (1H, d, J = 2.0 Hz, H-Ar), 8.14 (1H, dd, J = 2.0 Hz, J = 8.8 Hz, H-Ar), 8.37 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.7, 28.5, 32.1, 41.1, 45.5, 50.8, 108.9, 112.8, 118.1, 125.9, 134.5, 143.0, 148.6, 164.5, 178.6, 195.8. Anal. Calcd. for C24H24N2O6: C, 66.04; H, 5.54; N, 6.42%. Found: C, 65.91; H, 5.47; N, 6.29%.
7,3′,3′,6′,6′-Pentamethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3e). White powder; m.p.: 287–289 °C; IR (KBr) cm−1: 3336, 2955, 1731, 1671, 1618, 1348, 1224, 1168. 1H-NMR (CDCl3): δH (ppm) 1.04 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.15 and 2.25 (4H, AB system, J = 17.2 Hz, 2CH2), 2.27 (3H, s, CH3), 2.45 and 2.56 (4H, AB system, J = 17.6 Hz, 2CH2), 6.70 (1H, d, J = 7.2 Hz, H-Ar), 6.80 (1H, J = 7.2 Hz, J = 7.6 Hz, H-Ar), 6.97 (1H, d, J = 7.6 Hz, H-Ar), 7.48 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 16.3, 27.1, 29.0, 33.6, 41.2, 54.8, 111.9, 113.7, 118.0, 120.0, 121.9, 140.8, 163.4, 168.7, 179.0, 181.6, 195.4, 202.3. Anal. Calcd. for C25H27NO4: C, 74.05; H, 6.71; N, 3.45%. Found: C, 73.53; H, 6.53; N, 3.37%. HRMS (ESI): m/z [M + H]+ calcd for C25H27NO4: 405.4862; found: 405.4857.
7-Chloro-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3f). White powder; m.p.: 270–271 °C; IR (KBr) cm−1: 3451, 2959, 1738, 1666, 1623, 1348, 1224, 1131. 1H-NMR (CDCl3): δH (ppm) 1.02 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.14 and 2.26 (4H, AB system, J = 16.0 Hz, 2CH2), 2.45 and 2.56 (4H, AB system, J = 17.6 Hz, 2CH2), 6.75 (1H, d, J = 7.2 Hz, H-Ar), 6.80 (1H, J = 7.2 Hz, J = 8.0 Hz, H-Ar), 7.14 (1H, d, J = 8.0 Hz, H-Ar), 7.48 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.2, 28.9, 32.0, 46.7, 50.8, 113.3, 114.7, 120.5, 122.7, 128.4, 134.7, 140.1, 163.7, 177.9, 195.3. Anal. Calcd forC24H24ClNO4: C, 67.68; H, 5.68; N, 3.29%. Found: C, 67.53; H, 5.61; N, 3.18%. HRMS (ESI): m/z [M + H]+ calcd. for C24H24ClNO4: 425.1394; found: 425.1391.
3′,4′,6′,7′-Tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3g). White powder; m.p.: 336–337 °C (m.p. 336 °C) [31]; 1H-NMR (CDCl3): δH(ppm) 1.60–2.09 (4H, m, CH2), 2.25–2.62 (4H, m, CH2), 2.64 (4H, t, J = 6.4 Hz, CH2), 6.83–6.89 (3H, m, H-Ar), 7.13–7.18 (1H, m, H-Ar), 7.59 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 20.0, 27.6, 37.2, 45.8, 109.1, 114.8, 121.9, 122.7, 128.5, 133.8, 142.2, 164.9, 178.9, 195.4. Anal. Calcd. for C20H17NO4: C, 71.63; H, 5.11; N, 4.18%. Found: C, 71.52; H, 5.03; N, 4.35%.
5-Methyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3h). White powder; m.p.: 287–288 °C; IR (KBr) cm−1: 3312, 2957, 1743, 1668, 1618, 1350, 1314, 1167. 1H-NMR (CDCl3): δH (ppm) 1.83–2.10 (4H, m, CH2), 2.23 (3H, s, CH3), 2.26–2.66 (4H, m, CH2), 2.64 (4H, t, J = 6.8 Hz, CH2), 6.67 (1H, s, H-Ar), 6.72 (1H, d, J = 8.0 Hz, H-Ar), 6.95 (1H, d, J = 7.6 Hz, H-Ar), 7.59 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 20.0, 21.2, 27.6, 37.2, 45.9, 108.8, 114.9, 123.7, 128.9, 131.2, 133.7, 139.7, 167.9, 178.9, 195.5. Anal. Calcd. for C21H19NO4: C, 72.19; H, 5.48; N, 4.01%. Found: C, 71.67; H, 5.33; N, 4.15%. HRMS (ESI): m/z [M + H]+ calcd. for C21H19NO4: 349.1314; found: 349.1310.
5-Chloro-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3i). White powder; m.p.: 364–365 °C; IR (KBr) cm−1: 3455, 2959, 1747, 1670, 1637, 1349, 1228, 1175. 1H-NMR (CDCl3): δH (ppm) 1.97–2.10 (4H, m, CH2), 2.23 (3H, s, CH3), 2.29–2.37 (4H, m, CH2), 2.65 (4H, t, J = 6.4Hz, CH2), 6.77 (1H, d, J = 8.0 Hz, H-Ar), 6.84 (1H, d, J = 2.0 Hz, H-Ar), 7.13 (1H, dd, J = 2.0 Hz, J = 8.0 Hz, H-Ar), 7.60 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 19.9, 27.5, 37.1, 46.0, 110.0, 114.4, 123.2, 127.0, 128.3, 135.3, 140.9, 165.3, 178.4, 195.4. Anal. Calcd for C20H16ClNO4: C, 64.96; H, 4.36; N, 3.79%. Found: C, 64.87; H, 4.28; N, 3.61%. HRMS (ESI): m/z [M + H]+ calcd. for C20H16ClNO4: 369.0768; found: 369.0764.
5-Fuloro-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,′H)-trione (3j). White powder; m.p.: 302–303 °C; IR (KBr) cm−1: 3457, 2958, 1732, 1667, 1618, 1492, 1349, 1222, 1167. 1H-NMR (CDCl3): δH (ppm) 1.04 (6H, s, 2CH3), 1.12 (6H, s, 2CH3), 2.15 and 2.27 (4H, AB system, J = 16.0 Hz, 2CH2), 2.45 and 2.57 (4H, AB system, J = 17.6 Hz, 2CH2), 6.60 (1H, dd, J = 2.0 Hz, J = 7.6 Hz, H-Ar), 6.72 (1H, J = 4.4 Hz, J = 8.4 Hz, H-Ar), 6.80–6.85 (1H, m, H-Ar), 8.16 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.3, 28.9, 32.0, 41.2, 46.2, 50.9, 110.1, 113.3, 114.6, 134.9, 138.6, 157.7, 160.1, 163.8, 178.7, 195.4. Anal. Calcd. for C24H24FNO4: C, 70.40; H, 5.91; N, 3.42%. Found: C, 69.93; H, 5.86; N, 3.35%. HRMS (ESI): m/z [M + H]+ calcd. for C24H24FNO4: 409.1689; found: 409.1685.
5-Bromo-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3k). White powder; m.p.: 288–289 °C; IR (KBr) cm−1: 3447, 2959, 1733, 1668, 1619, 1495, 1349, 1224, 1169. 1H-NMR (CDCl3): δH (ppm) 1.98–2.10 (4H, m, 2CH2), 2.29–2.37 (4H, m, 2CH2), 2.65 (4H, t, J = 6.4 Hz, 2CH2), 6.72 (1H, d, J = 8.4 Hz, H-Ar), 6.97 (1H, d, J = 1.6 Hz, H-Ar), 7.25–7.28 (1H, m, H-Ar), 7.71 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 19.9, 27.5, 37.1, 45.9, 110.5, 114.3, 114.4, 125.9, 131.2, 135.7, 141.4, 165.3, 178.3, 195.4. Anal. Calcd. for C20H16BrNO4: C, 57.99; H, 3.89; N, 3.38%. Found: C, 57.71; H, 3.81; N, 3.42%. HRMS (ESI): m/z [M + H]+ calcd. for C20H16BrNO4: 413.0263; found: 413.0259.
5-Bromo-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3l). White powder; m.p.: 290 °C (290 °C) [15]; IR (KBr) cm−1: 3449, 2958, 1731, 1665, 1617, 1347, 1223, 1165. 1H-NMR (CDCl3): δH (ppm) 1.05 (6H, s, 2CH3), 1.11 (6H, s, 2CH3), 2.15 and 2.25 (4H, AB system, J = 16.4 Hz, 2CH2), 2.47 and 2.56 (4H, AB system, J = 17.6 Hz, 2CH2), 6.72 (1H, d, J = 8.4 Hz, H-Ar), 6.95 (1H, d, J = 2.0 Hz, H-Ar), 7.26(1H, m, H-Ar), 7.98 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.5, 28.7, 32.0, 41.2, 45.8, 50.9, 110.9, 113.2, 114.3, 125.5, 131.3, 135.6, 141.5, 164.0, 178.4, 195.6. Anal. Calcd. for C24H24BrNO4: C, 61.28; H, 5.14%; N, 2.98%. Found: C, 61.03; H, 5.17; N, 2.92%.
6-Fuloro-3′,3′,6′,6′-tetramethyl-3′,4′,6′,7′-tetrahydrospiro[indoline-3,9′-xanthene]-1′,2,8′(2′H,5′H)-trione (3m). White powder; m.p.: 281–283 °C; IR (KBr) cm−1: 3453, 2959, 1739, 1664, 1619, 1347, 1223, 1130. 1H-NMR (CDCl3): δH (ppm) 1.04 (6H, s, 2CH3), 1.13 (6H, s, 2CH3), 2.15 and 2.28 (4H, AB system, J = 16.4 Hz, 2CH2), 2.46 and 2.58 (4H, AB system, J = 17.6 Hz, 2CH2), 6.74 (1H, d, J = 6.8 Hz, H-Ar), 6.70–7.03 (1H, m, H-Ar), 8.03 (1H, s, NH). 13C-NMR (CDCl3): δC (ppm) 27.2, 28.9, 32.0, 41.2, 45.4, 50.9, 112.9, 113.2, 121.9, 123.4, 124.8, 132.6, 143.6, 163.8, 178.6, 195.5. Anal. Calcd. for C24H24FNO4: C, 70.40; H, 5.91; N, 3.42%. Found: C, 69.99; H, 5.85; N, 3.47%. HRMS (ESI): m/z [M + H]+ calcd for C24H24FNO4: 409.1689; found: 409.1685.

4. Conclusions

The present report describes the synthesis of spiro[indoline-3,9′-xanthene]trione derivatives in good yields, catalyzed by Mg(ClO4)2 at 80 °C in aqueous ethanol media. This protocol is efficient, simple, mild, eco-friendly, and also advantageous in terms of short reaction time and easy workup procedure.

Supplementary Materials

Supplementary materials are available online.

Acknowledgments

We gratefully acknowledge the financial support from Public Projects of Zhejiang Province of China (No. 2016C31032, NO. 2015C31147) and the National Natural Science Foundation of China (No. 51402195).

Author Contributions

R.S. and C.W. conceived and designed the experiments; C.C., C.L., J.L. and J.J. performed the experiments; L.W. analyzed the data; C.W. wrote the paper

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Zhang, M.-Z.; Chen, Q.; Yang, G.-F. A review on recent developments of indole-containing antiviral agents. Eur. J. Med. Chem. 2015, 89, 421–441. [Google Scholar] [CrossRef] [PubMed]
  2. Zhou, J.; Feng, J.-H.; Fang, L. A novel monoterpenoidindole alkaloid with anticancer activity from Melodinuskhasianus. Bioorg. Med. Chem. Lett. 2017, 27, 893–896. [Google Scholar] [CrossRef] [PubMed]
  3. Perron, F.; Albizati, K.F. Chemistry of spiroketals. Chem. Rev. 1989, 89, 1617–1661. [Google Scholar] [CrossRef]
  4. Santos, M.M.M. Recent advances in the synthesis of biologically active spirooxindoles. Tetrahedron 2014, 70, 9735–9757. [Google Scholar] [CrossRef]
  5. Creasey, W.A. Pharmacology, Biochemistry, and Clinical Applications of the Monoterpenoid Alkaloids. In Chemistry of Heterocyclic Compounds; Saxton, J.E., Ed.; John Wiley & Sons Inc.: Hoboken, NJ, USA, 1983; Volume 25. [Google Scholar] [CrossRef]
  6. Kang, T.H.; Matsumoto, K.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Pteropodine and isopteropodine positively modulate the function of rat muscarinic M1 and 5-HT2 receptors expressed in Xenopus oocyte. Eur. J. Pharmacol. 2002, 444, 39–45. [Google Scholar] [CrossRef]
  7. Yu, S.; Qin, D.; Shangary, S.; Chen, J.; Wang, G.; Ding, K.; McEachern, D.; Qiu, S.; Nikolovska-Coleska, Z.; Miller, R.; et al. Potent and orally active small molecule inhibitors of the MDM2-P53 interaction. J. Med. Chem. 2009, 52, 7970–7973. [Google Scholar] [CrossRef] [PubMed]
  8. Kasralikar, H.M.; Jadhavar, S.C.; Bhusare, S.R. Synthesis and molecular docking studies of oxochromenylxanthenone and indolylxanthenone derivatives as anti-HIV-1 RT inhibitors. Bioorg. Med. Chem. Lett. 2015, 25, 3882–3886. [Google Scholar] [CrossRef] [PubMed]
  9. Evangelinou, O.; Hatzidimitriou, A.G.; Velali, E. Mixed-ligand copper (I) halide complexes bearing 4,5-bis(diphenylphosphano)-9,9-dimethyl-xanthene and N-methylbenzothiazole-2-thione: Synthesis, structures, luminescence and antibacterial activity mediated by DNA and membrane damage. Polyhedron 2014, 72, 122–129. [Google Scholar] [CrossRef]
  10. Jamison, J.M.; Krabill, K.; Hatwalkar, A.; Jamison, E.; Tsai, C. Potentiation of the antiviral activity of poly r(A-U) by xanthene dyes. Cell Biol. Int. Rep. 1990, 14, 1075–1084. [Google Scholar] [CrossRef]
  11. Ion, R.M.; Frackowiak, D.; Planner, A.; Wiktorowicz, K. The incorporation of various porphyrins into blood cells measured via flow cytometry, absorption and emission spectroscopy. Acta Biochim. Pol. 1998, 45, 833–845. [Google Scholar] [PubMed]
  12. Stefanović, G.; Pavičić-Woss, M.; Lorenc, L.; Mihailović, M.L. Condensation of isatin with diketones. Tetrahedron 1959, 6, 97–102. [Google Scholar] [CrossRef]
  13. Sarkar, P.; Mukhopadhyay, C. p-tert-Butylcalix[8]arene: An effective nano-ranged organocatalyst for the syntheses of xanthenes and acridines. Curr. Organocatal. 2016, 3, 205–215. [Google Scholar] [CrossRef]
  14. Baradarani, M.M.; Khoshsirat, S.; Moharampour, M.; Ebrahimisaatlo, B.; Rashidi, A.; Różycka-Sokołowska, E.; Joule, J.A. Spiro[4H-pyran-3,3′-oxindoles] derived from 1,2,3,4-tetrahydroquinoline-Part 2. J. Heterocycl. Chem. 2017, 54, 944–951. [Google Scholar] [CrossRef]
  15. Ahadi, S.; Khavast, H.R.; Bazgir, A. A clean synthesis of spiro[indoline-3,9′-xanthene]trione derivatives. Chem. Pharm. Bull. 2008, 56, 1328–1330. [Google Scholar] [CrossRef] [PubMed]
  16. Kothandapani, J.; Ganesan, A.; Mani, G.K.; Kulandaisamy, A.J.; Rayappan, J.B.; Ganesan, S.S. Zinc oxide surface: A versatile nanoplatform for solvent-free synthesis of diverse isatin derivatives. Tetrahedron Lett. 2016, 57, 3472–3475. [Google Scholar] [CrossRef]
  17. Das, P.; Dutta, A.; Bhaumik, A.; Mukhopadhyay, C. Heterogeneous ditopic ZnFe2O4 catalyzed synthesis of 4H-pyrans: Further conversion to 1,4-DHPs and report of functional group interconversion from amide to ester. Green Chem. 2014, 16, 1426–1435. [Google Scholar] [CrossRef]
  18. Karimi-Jaberi, Z.; Jaafarizadeh, A. One-pot, three-component reaction of dimedone, amines, and isatin in the presence of tris(hydrogensulfato) boron: Synthesis of pyrroloacridine derivatives. Res. Chem. Intermed. 2015, 41, 4913–4918. [Google Scholar] [CrossRef]
  19. Suman, R.; Bhaumik, A.; Pramanik, M.; Butcher, R.J.; Yildirim, S.O. Binary conjugate Bronsted-Lewis acid supported on mesoporous silica nanoparticles for the domino addition/elimination/addition and addition/elimination/addition/cyclization cascade. Catal. Commun. 2014, 43, 173–178. [Google Scholar]
  20. Liang, B.; Kalidindi, S.; Porco, J.A., Jr.; Stephenson, C.R.J. Multicomponent reaction discovery: Three-component synthesis of spirooxindoles. Org. Lett. 2010, 12, 572–575. [Google Scholar] [CrossRef] [PubMed]
  21. Bhagat, S.; Chakraborti, A.K. An extremely efficient three-component reaction of aldehydes/ketones, amines, and phosphites (Kabachnik-Fields Reaction) for the synthesis of α-aminophosphonates catalyzed by magnesium perchlorate. J. Org. Chem. 2007, 72, 1263–1270. [Google Scholar] [CrossRef] [PubMed]
  22. Jafari, A.A.; Moradgholi. Mg(ClO4)2, an efficient catalyst for synthesis of β-amino alcohols by ring opening of epoxides with amines under solvent-free conditions. Synth. Commun. 2011, 41, 594–602. [Google Scholar] [CrossRef]
  23. Khatik, G.L.; Kumar, R.; Chakraborti, A.K. Magnesium perchlorate as a new and highly efficient catalyst for the synthesis of 2,3-dihydro-1,5-benzothiazepines. Synthesis 2007, 4, 541–546. [Google Scholar] [CrossRef]
  24. Kamble, V.T.; Ekhe, V.R.; Joshi, N.S.; Biradar, A.V. Magnesium perchlorate: An efficient catalyst for one-pot synthesis of pyrano- and furanoquinolines. Synlett 2007, 9, 1379–1382. [Google Scholar] [CrossRef]
  25. Alinezhad, H.; Tajbakhsh, M.; Tehrani, S.S. Selective monobromination of 1,3-diones with N-bromosaccharin/Mg(ClO4)2 system in solution and under solvent-free conditions. Bull. Korean Chem. Soc. 2011, 32, 1543–1546. [Google Scholar] [CrossRef]
  26. Wu, C.-L.; Shen, R.-P.; Chen, J.-H.; Hu, C.Q. An efficient method for multicomponent synthesis of spiro[4H-pyran-oxindole] derivatives catalyzed by magnesium perchlorate. Bull. Korean Chem. Soc. 2013, 34, 2431–2435. [Google Scholar] [CrossRef]
  27. Chakraborti, A.K.; Chankeshwara, S.V. Magnesium perchlorate. In e-EROS Encyclopedia of Reagents for Organic Synthesis; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2009. [Google Scholar] [CrossRef]
  28. Mendiratta, S.K.; Dotson, R.L.; Brooker, R.T. Perchloric acid and perchlorates. In Kirk-Othmer Encyclopedia of Chemical Technology; John Wiley & Sons, Inc.: Hoboken, NJ, USA, 2005. [Google Scholar] [CrossRef]
  29. Poriel, C.; Cocherel, N.; Rault-Berthelot, J.; Vignau, L.; Jeannin, O. Incorporation of Spiroxantheneunits in blue-emitting oligophenyleneframeworks: Anew molecular design for OLED applications. Chem. Eur. J. 2011, 17, 12631–12645. [Google Scholar] [CrossRef] [PubMed]
  30. Cocherel, N.; Poriel, C.; Vignau, L.; Bergamini, J.F.; Rault-Berthelot, J. DiSpiroXanthene-IndenoFluorene: A new blue emitter for nondopedorganiclight emitting diode applications. Org. Lett. 2010, 12, 452–455. [Google Scholar] [CrossRef] [PubMed]
  31. Joshi, K.C.; Jain, R.; Arora, S. Synthesis and mass fragmentation of fluorinated spiro[3H-indole-3,9′-9H-Xanthene]-1′,2,8′-(1H,2′H,5′H)-triones. J. Fluor. Chem. 1989, 42, 149–162. [Google Scholar] [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
Molecules 22 01295 sch001 550
Scheme 1. Synthesis of spiro[indoline-3,9′-xanthene]trione.
Scheme 1. Synthesis of spiro[indoline-3,9′-xanthene]trione.
Molecules 22 01295 sch001
Molecules 22 01295 g001 550
Figure 1. Proposed mechanism for the synthesis of spiro[indoline-3,9′-xanthene]trione.
Figure 1. Proposed mechanism for the synthesis of spiro[indoline-3,9′-xanthene]trione.
Molecules 22 01295 g001
Table
Table 1. Solvent effects on the reaction of isatin and dimedone, in the presence of 10 mol % magnesium perchlorate a.
Table 1. Solvent effects on the reaction of isatin and dimedone, in the presence of 10 mol % magnesium perchlorate a.
EntrySolvent/T (°C)Time (h)Yield b (%)
1PhCH3(reflux)24Trace
2CH2Cl2(reflux)24Trace
3CH3OH(reflux)1264
4C2H5OH(reflux)1271
5C2H5OH/H2O(1/1)(80)1083
6H2O(80)1277
7CH3CN(reflux)1260
8THF(reflux)1258
a Isatin (2 mmol), dimedone (4 mmol); solvent (5 mL), Mg(ClO4)2 (10%mol). b Isolated yield.
Table
Table 2. Synthesis of spiro[indoline-3,9′-xanthene]trione 3.
Table 2. Synthesis of spiro[indoline-3,9′-xanthene]trione 3.
ProductR1R2Time (h)Yield a (%)
3aHCH31083
3b5-MeCH31275
3c5-ClCH31079
3d5-NO2CH31081
3e7-MeCH31271
3f7-ClCH31078
3gHH1080
3h5-MeH1269
3i5-ClH1082
3j5-FCH31083
3k5-BrH1071
3l5-BrCH31078
3m6-FCH31085
a Isolated yield.

Share and Cite

MDPI and ACS Style

Chen, C.; Lv, C.; Liang, J.; Jin, J.; Wang, L.; Wu, C.; Shen, R. An Efficient Synthesis of Spiro[indoline-3,9′-xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate. Molecules 2017, 22, 1295. https://doi.org/10.3390/molecules22081295

AMA Style

Chen C, Lv C, Liang J, Jin J, Wang L, Wu C, Shen R. An Efficient Synthesis of Spiro[indoline-3,9′-xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate. Molecules. 2017; 22(8):1295. https://doi.org/10.3390/molecules22081295

Chicago/Turabian Style

Chen, Chunfeng, Chunlei Lv, Jianfeng Liang, Jianqing Jin, Lijun Wang, Chunlei Wu, and Runpu Shen. 2017. "An Efficient Synthesis of Spiro[indoline-3,9′-xanthene]trione Derivatives Catalyzed by Magnesium Perchlorate" Molecules 22, no. 8: 1295. https://doi.org/10.3390/molecules22081295

Article Metrics

Back to TopTop