An efficient synthesis of 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones catalyzed by sulfonated β-CD as a supramolecular catalyst in water

Graphical abstract

Abstract

Sulfonated-β-cyclodextrin (β-CD-SO₃H) promoted efficient and fast electrophilic substitution reaction of indoles with various isatins reflux in water is reported affording various 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones in good to excellent yields in short reaction time.

Indole derivatives are important compounds that are widespread in nature as well as exhibit significant biological activities.¹ 3-Substituted 3-hydroxyoxindoles are encountered in a large variety of natural products with a wide spectrum of biological activities.² 3,3-di(indolyl)indolin-2-one derivatives were assessed as anticancer,³ anti-HIV,⁴ antiviral,⁵ anti-tumor,⁶ antifungal,7, 8 anti-angiogenic,⁹ anticonvulsants,¹⁰ anti-Parkinson’s disease therapeutic,¹¹ and effective SARS corona virus 3CL protease inhibitor.¹² Furthermore, a large number of bis (indolyl) methanes have been isolated from natural sources,¹³ and some of these natural products, for example, vibrindole have shown promising biological activity.¹⁴

Recently a number of methods for the synthesis of 3-substituted-3-hydroxyoxindoles and 3,3-di(indolyl)indolin-2-ones have been reported in the literature involving the use of K₂CO₃,15a β-cyclodextrin,15b triton-B,15c ZnO nano-rods,15d LiClO₄,15e Sc/In (OTF),15f cupreine,15g ionic liquids,16a bismuth(III) triflate,16b indium(III) acetylacetonate,16c silica sulfuric acid,16d Bronsted acidic ionic liquid,16e ruthenium,16f ceric ammonium nitrate (CAN) under ultrasound irradiation,16g iodine,16h KSF,16i water–ethanol,16j and water16k at reflux temperature. These reported methodologies produce good results in many instances. However, some of the synthetic strategies suffer from metal catalyst, expensive reagents, long reaction time, environmentally hazardous, harsh reaction condition, tedious work-up procedure, unsatisfactory yield and use of homogeneous catalyst which are difficult to separate from the reaction mixture and reuse.

Aqueous phase organic synthesis has attracted the attention of chemists as it overcomes the harmful effects associated with the organic solvents and is environmentally benign. These reactions become more sophisticated if they can be performed under supramolecular catalysis. In view of the above, the development of a generally applicable and environmentally benign methodology for the synthesis of 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones derivatives is highly desirable. We report, herein, an aqueous phase synthesis of 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones from isatins and indoles in the presence of sulfonated-β-cyclodextrin (β-CD-SO₃H) (Fig. 1 and Scheme 1 ).

Figure 1.

Chemical structure of β-CD-SO₃H.

Scheme 1.

General scheme for the synthesis of 3-indolyl-3-hydroxy oxindoles and 3,3-di(indolyl)indolin-2-ones.

Supramolecular catalysis is a discipline in chemistry which involves intermolecular interactions where covalent bonds are not established between the interacting species which can be molecules, ions or radicals.¹⁷ The most accessible β-cyclodextrin (β-CD) is a cyclic oligosaccharide consisting of seven glucose units. The cavity size and the inner hydrophobicity are suitable for encapsulating a variety of guests such as aromatic compounds.¹⁸ The improvement of the reaction rate and selectivity with β-CD inclusion complexes has been reported in a number of organic reactions.¹⁹ β-cyclodextrin mediated reactions in water are very useful tool for economic as well as environmental points of view.20, 21 Sulfonated-β-cyclodextrin shows good results over β-cyclodextrin in the synthesis of 2,3-dihydroquinazolin-4(1H)-one²² and 3,4-dihydropyrimidine-2(1H)-one.²³

In continuation of our work on β-CD,²⁴ we envisioned β-CD-SO₃H as a supramolecular catalyst and study its application on the synthesis of 3-substituted 3-hydroxyoxindoles and 3,3-di(indolyl)indolin-2-ones to develop a simple and efficient method in aqueous media.

Initially, the β-CD-SO₃H was synthesized according to the method reported recently.22, 23 The –SO₃H content obtained was in agreement with the proposed method, the value was 0.52 mequiv g⁻¹, and it matches with the literature report22, 23 confirmed the sulfonation of β-CD. The catalytic role β-CD-SO₃H for the synthesis of 3-substituted 3-hydroxyoxindoles and 3,3-di(indolyl)indolin-2-ones has been compared with various reported catalysts and found fast conversion within 5 min with yield up to 96% (Table 1, Table 2 ).

Table 1.

Comparison for preparation methods of 3-substituted 3-hydroxyoxindoles with various reported catalysts

Entry	Catalyst	Reaction conditions	Time (h/min)	Yield (%)	Refs.
1	K2CO3	20 mol %, rt, in water	1 h	91	15a
2	Triton-B	7 mol %, rt, in water	15 min	94	15c
3	ZnO nano-rods	10 mol %, 80 °C, in water	1.5 h	95	15d
4	LiClO4	10 mol %, 60 °C, in ethanol	4 h	93	15e
5	β-Cyclodextrin	100 mol %, 40 °C, in water	1 h	93	15b
6	β-CD-SO3H	10 mol %, reflux in water	5 min	96	This work

Table 2.

Comparison of preparative methods of 3,3-di(indolyl)indolin-2-ones with various reported catalysts

Entry	Catalyst	Reaction conditions	Time (h/min)	Yield (%)	Refs.
1	Ionic liquid	60 mol % of ([BMIM][BF4]LiCl), rt	1 h	93	16a
2	Bismuth(III) Triflate	2 mol %, CH3CN, rt	3 h	92	16b
3	Indium(III) acetylacetonate	10 mol %,(H2O:CH3CN 4:1), rt	2.5 h	92	16c
4	Silica sulfuric acid	0.2 g, CH2Cl2, rt	2 h	92	16d
5	Ruthenium trichloride	5 mol %, MeOH, 50 °C	2 h	75	16f
6	Ceric ammonium nitrate (CAN)	10 mol %, US, EtOH, rt	3 h	95	16g
7	I2 (Iodine)	10 mol %, CH2Cl2, rt	14 h	82	16h
8	KSF	0.1 g, reflux in EtOH	0.5 h	90	16i
9	β-CD-SO3H	10 mol %, H2O, reflux	5 min	96	This work

In order to optimize the reaction conditions and the performance of β-CD-SO₃H as a catalyst for the synthesis of 3-substituted 3-hydroxyoxindoles, we studied 5-methoxy indole with isatin as a model reaction. The reaction proceeds in the absence of β-CD-SO₃H to give lower yield (60%) with longer reaction time and in presence of 100 mol % β-CD and required 60 min to get 93% of yield.15b The best result was obtained for 10 mol % of β-CD-SO₃H affording 96% of within 5 min (Table 3, Table 4 ). Encouraged by the initial success, we applied the optimal protocol to a variety of isatins and indoles (Table 5 ). Generally, the reactions were performed using 10 mol % of β-cyclodextrin-SO₃H in H₂O at reflux temperature for 5–15 min to give the desired products in good to excellent yields;²⁵ the results are summarized in Table 5.

Table 3.

Study of the effect of temperature on reaction time and yields for the synthesis of 3,3-bis(5-methoxy-1H-indol-3-yl)indolin-2-one^a

Entry	Temp (°C)	Time (min)	Yieldb (%)
1	Rt	300	40
2	40	240	60
3	60	120	80
4	80	30	84
5	100	5	96

^aReaction condition: isatin (1.0 mmol), 5-methoxy indole (2.0 mmol), β-CD-SO₃H (0.1 mmol) and water (2 mL).

^bIsolated yield.

Table 4.

Formation of 3,3-bis(5-methoxy-1H-indol-3-yl)indolin-2-one using different amounts of catalyst at reflux in aqueous media^a

Entry	Catalyst (mmol)	Time (min)	Yieldb (%)
1	β-CD-SO3H (0.00)	120	60
2	β-CD-SO3H (0.05)	20	90
3	β-CD-SO3H (0.10)	5	96
4	β-CD-SO3H (0.20)	5	94
5	β-CD-SO3H (0.30)	5	94

^aReaction condition: isatin (1.0 mmol), 5-methoxy indole (2.0 mmol), water (2 mL), refluxed.

^bIsolated yield.

Table 5.

Synthesis of 3-hydroxy-3-indolylindoline-2-ones in the presence of β-CD-SO₃H in water at reflux temp^a

Sr. No.	Isatin	Indole	Product	Time (min)	Yieldb (%)
3a				5	86
3b				5	92
3c				15	88
3d				5	96
3e				10	86
3f				5	88

^aReaction condition: isatin (1.0 mmol), indole (1.0 mmol), β-CD-SO₃H (0.1 mmol), water (2 mL).

^bIsolated yield.

In order to optimize the reaction condition and the performance of β-CD-SO₃H as a catalyst for this 3,3-di(1H-indol-3-yl)indolin-2-one the reaction between simple isatin and 5-methoxy indole was selected as a model reaction by using different reaction parameters and various amounts of catalyst (Table 3, Table 4). The reaction proceeds in the absence of β-CD-SO₃H to give less yield (60%). The best result was obtained for 10 mmol % of β-CD-SO₃H (Table 6 , entry 4c), affording 96% of 3,3-bis(5-methoxy-1H-indol-3-yl)indolin-2-one within 5 min. A further increase in the amount of catalyst has no significant effect on the yield and reaction time (Table 4, entries 4 and 5). The role of β-CD-SO₃H as the catalyst has been confirmed when a similar reaction was carried out in the absence of catalyst (Table 4, entry 1), giving only 60% yield with a longer reaction time 2 h. It indicates that β-CD-SO₃H not only improves the yield of the product but also accelerates the rate of reaction. The significant presence of β-CD-SO₃H has a great influence on the reaction time as well as the yield (Table 4, entry 3). Temperature plays an important role, as at low temperature there is only a trace amount of product formed and required longer reaction time and as the temperature increases from 40 °C to reflux the yields also increase with decrease in reaction time (Table 3).

Table 6.

β-CD-SO₃H catalyzed synthesis of 3,3-di(indolyl)indolin-2-ones^a

Sr. No.	Isatin	Indole	Product	Time (min)	Yieldb (%)
4a				10	95
4b				15	95
4c				5	96c, 94d, 92e
4d				45	94
4e				130	80
4f				30	91
4g				15	93
4h				30	93
4i				130	91
4j				30	85
4k				30	88
4l				45	87
4m				15	94
4n				10	95
4o				45	90

^aReaction condition: isatin (1.0 mmol), indole (1.0 mmol), β-CD-SO₃H (0.1 mmol), water (2 mL).

^bIsolated yield.

^c,d,eYield after I, II, and III recycle of catalyst.

A variety of structurally divergent isatins possessing different substituents were selected to understand the scope and generality of the β-CD-SO₃H promoted reaction to form 3,3-di(indolyl)indolin-2-ones.²⁶ The results obtained are summarized in Table 6. For all the entries water was used as the solvent and the reaction was conducted under reflux condition. In all cases, the conversion was completed within 5–45 min with good to excellent yields except for 5-nitroindole (Table 6 entry 4e, 80% and entry 4i, 91%). A further increase in reaction time had no significant effect on the yields. In addition, the substituent on the aromatic indoles showed slightly different effects on the yields, reactions of aromatic indoles with electron-donating groups afforded little better yields of products than those with the electron-withdrawing groups (Table 6 entry 4e, 80% and entry 4i, 91%).

β-CD-SO₃H was chosen as the catalyst since it is recyclable, environmentally benign, easily accessible and due to presence of the –SO₃H group it possesses greater solubility than β-CD in water which enhances the rate of reaction greater than β-CD and shows good results over β-CD. The supramolecular β-CD have tendency to form inclusion complex with isatin which is reported by Rama Rao15b similarly due to presence of the –SO₃H group in β-CD-SO₃H it possesses greater solubility than β-CD and also forms inclusion complex more effectively with isatin to enhance the rate of reaction.

The catalyst recovery and reusability²⁷ were studied by three cycles including the use of fresh catalyst for the synthesis of 3,3-bis(5-methoxy-1H-indol-3-yl)indolin-2-one (Table 6, entry 4c). In every cycle, the catalyst was almost quantitatively recovered and after second and third use of catalyst decrease in yield is not much more significant which is shown in Figure 2 . The FTIR spectra (Fig. 3 ) of fresh and recovered β-CD-SO₃H were also measured and no change was found in the functional group as well as in fingerprint region, indicating that no reaction occurs with β-CD-SO₃H.

Figure 2.

Catalyst β-CD-SO₃H recyclability data (for Table 6, entry 4c).

Figure 3.

FTIR of (a) fresh β-CD-SO₃H and (b) recovered β-CD-SO₃H (for Table 6, entry 4c).

In conclusion, we report β-CD-SO₃H as a highly efficient, reusable, environmentally benign catalyst for the synthesis of 3-substituted 3-hydroxyoxindoles and 3,3-di(indolyl)indolin-2-ones. The advantages of this catalyst are good to excellent yields of product, short reaction times, simple and clean work-up of the desired product without column chromatography, easy recovery and reuse of the catalyst.

Supplementary data

Supplementary data

Experimental procedures and spectral data.