Translate this page into:
Magnetite nanoparticles catalyzed preparation of isatin ketals under solvent free conditions promoted by ultrasound irradiation
⁎Corresponding author. Tel.: +98 911 339 759; fax: +98 131 322 00 66. khorshidi@guilan.ac.ir (Alireza Khorshidi)
-
Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
Reasonable yields of the desired ketals. Easy recycling of the catalyst. Solvent free conditions. Application of sonic waves in promotion of the reaction.
Abstract
Fe3O4 magnetic nanoparticles (MNPs) were synthesized via chemical precipitation method and used as an efficient and recyclable catalyst in ketalization of isatins. It was found that a solvent free process, under irradiation of sonic waves provides good to excellent yields of the desired ketals.
Keywords
Iron
Nanostructure
Protecting group
Ultrasound
Isatin
Ketal
1 Introduction
Isatins are well known for their biological activities (Pandeya et al., 2005; Tozawa et al., 1998; Igosheva et al., 2005; Ogata et al., 2003; Hamaue et al., 2002). These are also, precursor to many pharmacologically active compounds such as oxindoles (da Silva et al., 2001) and isatin ketals, which have anticonvulsant (Rajopadhye and Popp, 1988), anxiolytic (Geronikaki et al., 2004) psychotropic (Zhunghietu, 2002) and sedative-hypnotic (Zapata-Sudo et al., 2007) activities. Ketalization of the more electrophilic carbonyl (C3) of isatin, also, allows selective chemical transformation of the other parts of molecule (Vine et al., 2007). In the literature, ketalization of isatins has been reported using different methods such as organic and inorganic acid catalysis (Sato et al., 1996), acid activated clays and microwave irradiation (Ribeiro et al., 2007) and heteropolycompounds as catalysts (Santos et al., 2008), which have their own drawbacks such as inorganic waste (Sato et al., 1996), need of Brazilian native clays and instruments (Ribeiro et al., 2007), and use of toxic solvents (Santos et al., 2008). As a result, development of new synthetic methods leading to isatin ketals is still an important issue.
In the last decade, the use of nano-sized magnetic particles in the manufacture of fine chemicals has attracted increasing attention, owing to the special features such as unique electrical and magnetic properties, selectivity, stability and above all, reusability, which are most sought after green chemistry, drug delivery and biosensors (Leslie-Pelecky and Rieke, 1996; Elliott and Zhang, 2001).
Ultrasound irradiation, on the other hand, has emerged as an efficient technique for reagent activation in organic synthesis (Wang et al., 2012; Heravi, 2010). In continuation of our recent works on indole and oxindole derivatives (Khorshidi, 2012; Khorshidi and Tabatabaeian, 2011), we now describe our study of magnetite nanoparticles catalyzed ketalization of isatins under ultrasound irradiation.
2 Experimental
Fe3O4 MNPs were synthesized with higher efficiency by using a five-necked reactor. A stock solution of FeCl3·6H2O (10.4 g), FeCl2·4H2O (4.0 g) and HCl (1.7 mL, 12 mol L−1) in 50 mL of deionized water which was degassed with nitrogen gas for 20 min before use, added dropwise (by using a dropping funnel connected to one neck) into 500 mL of degassed NaOH solution (1.5 mol L−1) at 80 °C during 30 min. Central neck was connected to a home-made condenser allowing circulation of cold water to prevent vaporization of solution. A glassware stirrer rotating at 1000 rpm, was passed through the condenser and central neck. Third neck was used to sparge nitrogen gas during the synthesis. The other necks were used for temperature monitoring and sampling. After completion, the obtained Fe3O4 nanoparticles were separated from the reaction medium by a magnetic field (1.4 T strength), and washed with 500 mL deionized water four times. The obtained MNPs were characterized by using XRD and SEM. Fig. 1 shows the XRD pattern of the synthesized MNPs, which matched well with library patterns (JCPDS No. 19-629), indicating that the sample has a cubic crystal system.
SEM and TEM images of the prepared MNPs were obtained as shown in Fig. 2. Fe3O4 surface morphology analysis by SEM demonstrated the agglomeration of many ultrafine particles, in which their diameter ranged from 10 to 40 nm as it is obvious from TEM.
IR spectra were recorded on a Shimadzu FTIR-8400S spectrometer. 1H NMR and 13C NMR spectra were obtained on a Bruker DRX-400 (or DRX-100) Avance spectrometer. Analytical GC evaluations of product mixtures were carried out on a Varian CP-3800 chromatograph (using a split/splitless injector, CP Sil 8CB column, FID assembly). X-ray powder diffraction (XRD) measurements were performed using a Philips diffractometer with monochromatized Cu kα radiation. The morphology of synthesized samples was characterized with a scanning electron microscope (SEM) from Philips Company (XL30 ESEM). Elemental analyses were made by a Carlo-Erba EA1110 CNNO-S analyzer and agreed with the calculated values. The ultrasonic device used was a UP 400 S instrument, emitting 24 kHz ultrasound at tunable intensity levels (up to a maximum of 460 W cm−2). 5-chloro, 7-chloro and 5-bromo isatins were prepared according to the literature (Sadler and Warren, 1956; Lindwall et al., 1931). All other materials were purchased from Merck and used without further purification.
Isatin (1 mmol) and nano-sized Fe3O4 (0.15 g) were added to an open vial (containing 5 mL of diol, excess) located in a thermostatic bath at 75 °C, and the reaction mixture was sonicated (3 mm sonotrode, 24 kHz, 460 W cm−2) for 1 h. After completion of the reaction (as indicated by TLC or GC), a magnetic field of 1.4 T was applied to collect MNPs and the supernatant liquid was decanted. The catalyst washed thoroughly with ethyl acetate (3 × 5 mL) and then treated with acetone (5 mL). The combined washings and decanted liquid were treated with water to remove the excess diol. The organic layer was dried over anhydrous sodium sulfate, and then concentrated in vacuum. The crude product was purified by preparative TLC (n-hexane/ethyl acetate: 10/3). The recovered catalyst was reactivated at 80 °C overnight and characterized by XRD and TEM to ensure that its structure has been preserved.
2.1 Characterization data
2.1.1 Spiro[1,3-dioxolane-2,3′-indolin]-2′-one, 3aa
m.p. 130–132 °C, IR (KBr): υ (cm−1); 760, 1085, 1218, 1475, 1622, 1741, 2848, 2894, 3115, 3215, 3430. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.29–4.40 (2H, m), 4.50–4.60 (2H, m), 6.82 (1H, d, 3JHH = 7.6 Hz), 7.04 (1H, t, 3JHH = 7.6 Hz), 7.27 (1H, t, 3JHH = 7.6 Hz), 7.38 (1H, d, 3JHH = 7.6 Hz), 8.67 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 66.0, 102.6, 110.9, 123.4, 124.6, 125.2, 131.8, 142.0, 175.9 ppm. Anal. Calcd for C10H9NO3: C, 62.82; H, 4.74; N, 7.33; found: C, 62.77; H, 4.72; N, 7.32.
2.1.2 5′-Chloro-spiro[1,3-dioxolane-2,3′-indolin]-2′-one, 3ba
m.p. 173–175 °C, IR (KBr): υ (cm−1); 756, 815, 950, 995, 1030, 1101, 1218, 1481, 1624, 1746, 2880, 3059, 3140, 3184, 3426. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.28–4.46 (2H, m), 4.52–4.61 (2H, m), 6.95 (1H, d, 3JHH = 7.6 Hz), 7.27 (1H, s), 7.35 (1H, d, 3JHH = 7.6 Hz), 9.66 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 66.7, 102.6, 112.9, 126.0, 127.9, 128.1, 132.2, 142.7, 175.3 ppm. Anal. Calcd for C10H8ClNO3: C, 53.23; H, 3.57; N, 6.21; found: C, 53.29; H, 3.61; N, 6.22.
2.1.3 5′-Bromo-spiro[1,3-dioxolane-2,3′-indolin]-2′-one, 3ca
m.p. 188–190 °C, IR (KBr): υ (cm−1); 822, 943, 1088, 1210, 1468, 1620, 1738, 2907, 2986, 3055, 3315, 3434. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.24–4.40 (2H, m), 4.40–4.55 (2H, m), 6.70 (1H, d, 3JHH = 8.0 Hz), 7.24 (1H, s), 7.38 (1H, d, 3JHH = 8.0 Hz), 9.28 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 66.1, 66.1, 102.1, 112.4, 115.7, 126.6, 128.4, 134.5, 141.2, 175.4 ppm. Anal. Calcd for C10H8BrNO3: C, 44.47; H, 2.99; N, 5.19; found: C, 44.44; H, 3.00; N, 5.19.
2.1.4 7′-chloro-spiro[1,3-dioxolane-2,3′-indolin]-2′-one, 3da
m.p. 175–177 °C, IR (KBr): υ (cm−1); 756, 815, 950, 1030, 1101, 1220, 1480, 1624, 1748, 2884, 3063, 3425. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.27–4.38 (2H, m), 4.43–4.55 (2H, m), 7.04 (1H, t, 3JHH = 7.6 Hz), 7.24 (1H, d, 3JHH = 7.6 Hz), 7.34 (1H, d, 3JHH = 7.6 Hz), 9.87 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 66.6, 66.7, 103.0, 116.1, 124.4, 124.7, 127.8, 132.3, 141.6, 175.2 ppm. Anal. Calcd for C10H8ClNO3: C, 53.23; H, 3.57; N, 6.21; found: C, 53.19; H, 3.62; N, 6.20.
2.1.5 Spiro[1,3-dioxane-2,3′-indolin]-2′-one, 3ab
m.p. 152–154 °C, IR (KBr): υ (cm−1); 744, 754, 1028, 1085, 1118, 1216, 1470, 1624, 1710, 2840, 2898, 2978, 3091, 3155, 3183, 3384. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.66 (1H, dt, J = 13.2, 2.0 Hz), 2.26–2.48 (1H, m), 3.96–4.04 (2H, m), 4.95–5.04 (2H, m), 6.76 (1H, d, 3JHH = 7.6 Hz), 7.04 (1H, dt, J = 7.6, 1.2 Hz), 7.26 (1H, dt, J = 7.6, 1.2 Hz), 7.42 (1H, d, 3JHH = 7.6 Hz), 8.35 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.4, 61.3, 94.0, 110.3, 123.3, 124.5, 127.9, 131.0, 140.3, 174.0 ppm. Anal. Calcd for C11H11NO3: C, 64.38; H, 5.40; N, 6.83; found: C, 64.32; H, 5.35; N, 6.85.
2.1.6 5′-Chloro-spiro[1,3-dioxane-2,3′-indolin]-2′-one, 3bb
m.p. 184–186 °C, IR (KBr): υ (cm−1); 754, 820, 1030, 1130, 1264, 1472, 1485, 1626, 1733, 2918, 2990, 3060, 3301, 3445. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.64 (1H, dt, J = 13.2, 2.0 Hz), 2.18–2.42 (1H, m), 3.93–4.01 (2H, m), 4.88–5.02 (2H, m), 6.72 (1H, d, 3JHH = 8.0 Hz), 7.22 (1H, d, 3JHH = 8.0 Hz), 7.33 (1H, s), 8.89 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.8, 61.7, 94.3, 111.9, 125.2, 128.6, 129.8, 131.3, 140.2, 174.3 ppm. Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84; found: C, 55.07; H, 4.19; N, 5.88.
2.1.7 5′-Bromo-spiro[1,3-dioxane-2,3′-indolin]-2′-one, 3cb
m.p. 204–206 °C, IR (KBr): υ (cm−1); 754, 820, 1029, 1198, 1264, 1473, 1485, 1621, 1737, 2916, 2986, 3310, 3448. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.62 (1H, dt, J = 13.2, 2.0 Hz), 2.20–2.39 (1H, m), 3.91–3.98 (2H, m), 4.87–5.01 (2H, m), 6.68 (1H, d, 3JHH = 7.9 Hz), 7.34 (1H, d, 3JHH = 8.0 Hz), 7.53 (1H, s), 9.05 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.3, 61.3, 93.7, 111.8, 115.6, 127.7, 129.6, 133.8, 139.5, 173.7 ppm. Anal. Calcd for C11H10BrNO3: C, 46.50; H, 3.55; N, 4.93; found: C, 46.57; H, 3.58; N, 4.92.
2.1.8 7′-Chloro-spiro[1,3-dioxane-2,3′-indolin]-2′-one, 3db
m.p. 164–166 °C, IR (KBr): υ (cm−1); 780, 925, 1030, 1188, 1322, 1460, 1475, 1623, 1717, 2978, 3095, 3253, 3408. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.58 (1H, dt, J = 13.3, 2.1 Hz), 2.18–2.38 (1H, m), 3.83–3.91 (2H, m), 4.84–5.03 (2H, m), 6.92 (1H, t, 3JHH = 8.0 Hz), 7.18 (1H, d, 3JHH = 8.0 Hz), 7.23 (1H, d, 3JHH = 8.0 Hz), 8.84 (1H, br) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 25.8, 61.7, 94.7, 115.9, 123.0, 124.3, 129.8, 131.4, 139.3, 174.0 ppm. Anal. Calcd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84; found: C, 55.11; H, 4.25; N, 5.79.
3 Results and discussion
Scheme 1 summarizes the optimized details of the ultrasound promoted ketalization reaction of isatins, under catalysis of Fe3O4 MNPs. In order to optimize the reaction conditions with respect to catalyst type, catalyst loading, solvent, and to examine the effect of temperature on the reaction yield, Isatin and ethylene glycol were selected as model substrates and progress of the reaction was monitored by GC technique. The results are summarized in Table 1. As it is shown, in the absence of catalyst at room temperature, no formation of the desired product was observed (entry 1), and the best catalyst was found to be Fe3O4 nanoparticles, in an optimum loading of 0.150 g per mmol of isatin (entry 4). It seemed that the reaction yield was proportional to the catalyst loading. For example, increasing the catalyst amount from 0.050 g per mmol of isatin (entry 2) to 0.150 g/mmol, improved the yield (entry 4). Eventually, it was found that temperature had a significant effect on the reaction, and the best result was obtained at 75 °C (entry 6). Commercial granular Fe3O4 in the presence and in the absence of ultrasound irradiation, on the other hand, resulted in unsatisfactory yields (12% and less than 3%). BET analysis of the Fe3O4 MNPs showed that the surface area of our catalyst was 79.95 m2/g, which corresponds to more available active sites. This observation also showed that the magnetic character of the catalyst is not essential for the ketalization reaction, but significantly facilitates the reaction workup and catalyst recovery. It is noteworthy that the yield of the product was solvent dependent and the best solvent was found to be ethylene glycol itself. This may be due to the fact that excess of alcohol can shift the chemical equilibrium toward the production of ketals.
| Entrya | Catalyst | Solvent | Catalyst loading (g per mmol of isatin) | Temperature (°C) | Yieldb,% |
|---|---|---|---|---|---|
| 1 | No catalyst | Ethylene glycol | 0 | 25 | 0 |
| 2 | Fe3O4 | Ethylene glycol | 0.050 | 25 | 15 |
| 3 | Fe3O4 | Ethylene glycol | 0.100 | 25 | 34 |
| 4 | Fe3O4 | Ethylene glycol | 0.150 | 25 | 67 |
| 5 | Fe3O4 | Ethylene glycol | 0.150 | 50 | 52 |
| 6 | Fe3O4 | Ethylene glycol | 0.150 | 75 | 98 |
| 7 | Fe3O4 | Ethylene glycol | 0.150 | 100 | 94 |
| 8 | Granular Fe3O4 | Ethylene glycol | 0.150 | 75 | 12c |
| 9 | Granular Fe3O4 | Ethylene glycol | 0.150 | 75 | <3d |
| 10 | Fe3O4 | Dioxane | 0.150 | 75 | 45e |
| 11 | Fe3O4 | 1,2-DCE | 0.150 | 75 | 11e |
The effect of irradiation and its intensity on the reaction yield was also tested. Table 2, summarizes the effect of irradiation intensity on the reaction yield. As it is shown, increase in the rated power of the ultrasonic horn from 20% to 100% (92–460 W cm−2, respectively), resulted in increase of reaction yield. This could be due to maximization of cavitation and effective distribution of the reactants throughout the reaction mixture. In order to investigate the effect of the irradiation frequency, an ultrasonic cleaner with a frequency of 50–60 kHz and a normal power of 250 W was also, used. Running in the same conditions, the ultrasonic cleaner produced much lower noise, but the yield of the isolated product was only 69%. Thermal conditions in the absence of ultrasound irradiation, however, resulted in an unsatisfactory yield (21%). This may be due to the fact that a magnetic stirrer could not be used, and mechanical stirring did not effectively distribute the reactants throughout the reaction mixture. With the optimized conditions in hand (Scheme 1), various isatins and diols were used and indicated the generality and scope of the reaction. Typical results are shown in Table 3. Treatment of isatin (1 mmol, 147 mg) with ethylene glycol (5 mL) in the presence of Fe3O4 MNPs at 75 °C for 1 h under ultrasonic irradiation gave spiro[1,3-dioxolane-2,3′-indolin]-2′-one in 97% isolated yield (entry 1). The reaction can be used for ketalization of substituted isatins with either ethylene glycol or 1,3-propanediol (entries 2–8). The same chemoselectivity toward ketalization of C3 carbonyl was observed in each case. To further investigate the diversity of substrates, simple ketones such as acetophenone, propiophenone and cyclohexanone were also tested, and the results were satisfying (entries 9–11).
| Entrya | Isatin | Diol | Product | Time (h) | Yieldb (%) |
|---|---|---|---|---|---|
| 1 | Isatin | Ethylene glycol |
|
1 | 97 |
| 2 | 5-Chloroisatin | Ethylene glycol | 3ba | 1 | 88 |
| 3 | 5-Bromoisatin | Ethylene glycol | 3ca | 1 | 85 |
| 4 | 7-chloroisatin | Ethylene glycol | 3da | 1 | 94 |
| 5 | Isatin | 1,3-Propanediol |
|
1 | 95 |
| 6 | 5-Chloroisatin | 1,3-Propanediol | 3bb | 1 | 83 |
| 7 | 5-Bromoisatin | 1,3-Propanediol | 3cb | 1 | 81 |
| 8 | 7-chloroisatin | 1,3-Propanediol | 3db | 1 | 83 |
| 9 | Cyclohexanone | Ethylene glycol |
|
0.5 | 90 |
| 10 | Acetophenone | Ethylene glycol |
|
0.75 | 78 |
| 11 | Propiophenone | Ethylene glycol |
|
0.75 | 71 |
In order to evaluate reusability of the solid catalyst, the reaction of isatin and ethylene glycol was carried out in the presence of the recycled catalyst in successive runs. The yields were 97, 97, 93, 88 and 85 for runs 1–5. Only 12% loss of efficiency in terms of the product yield was observed after five runs, which promises minimization of the waste. In order to ensure that the catalyst has preserved its structure during the course of reaction, the recycled catalyst of the third run was characterized by XRD and TEM techniques. As it is obvious from Fig. 3, XRD pattern of the recycled MNPs matched well with library patterns (JCPDS No. 19-629). TEM imaging on the other hand, showed that the size and morphology of the recycled MNPs were almost preserved (Fig. 4).
4 Conclusions
In conclusion, we have developed a convenient method for ketalization of isatins in the presence of Fe3O4 magnetic nanoparticles (MNPs) as catalyst.
Acknowledgment
Support of this study by the Research Council of University of Guilan is gratefully acknowledged.
References
- J. Braz. Chem. Soc.. 2001;12:273.
- Environ. Sci. Technol.. 2001;35:4922.
- Bioorg. Med. Chem.. 2004;12:6559.
- Jpn. J. Pharmacol.. 2002;88:95.
- Chin. Chem. Lett.. 2010;21:1399.
- Neurochem. Int.. 2005;47:216.
- Ultson. Sonochem.. 2012;19:570.
- J. Serb. Chem. Soc.. 2011;76:1347.
- Chem. Mater.. 1996;8:1770.
- J. Am. Chem. Soc.. 1931;53:317.
- J. Neurol. Sci.. 2003;206:79.
- Acta Pharm.. 2005;55:27.
- J. Med. Chem.. 1988;31:1001.
- Catal. Commun.. 2007;8:2130.
- J. Am. Chem. Soc.. 1956;78:1251.
- J. Mol. Catal. A: Chem.. 2008;295:18.
- J. Mol. Catal. A: Chem.. 1996;114:209.
- Biochem. Pharmacol.. 1998;56:1041.
- Bioorg. Med. Chem.. 2007;15:931.
- Chin. Chem. Lett.. 2012;23:561.
- Pharmacol. Biochem. Be.. 2007;86:678.
- Chem. Inform.. 2002;33:111.