Catalyst and Solvent-Free Microwave Assisted Expeditious Synthesis of 3-Indolyl-3-hydroxy Oxindoles and Unsymmetrical 3 , 3-Di ( indolyl ) indolin-2-ones

A simple and efficient method for the synthesis of 3-indolyl-3-hydroxy oxindoles and unsymmetrical 3,3-di(indolyl)indolin-2-ones using microwave irradiation without catalyst and solvent is described. A series of 3-indolyl-3-hydroxy oxindoles and unsymmetrical 3,3-di(indolyl)indolin-2ones have been synthesized in very short reaction times of 5 and 10 minutes and in yields ranging from 31% to 98% and from 53% to 78% respectively. This method offers a significant advantage over the conventional methods in terms of simplicity and shorter reaction time. To the best of our knowledge compounds N-allyl-3-hydroxy-3-(1-methyl-indol-3-yl)indolin-2-one (6c), N-allyl-3hydroxy-3-(5-methoxy-indol-3-yl)indolin-2-one (8c), N-benzyl-3-hydroxy-3-(1-methyl-indol-3-yl) indolin-2-one (10c), N-propargyl-3-hydroxy-3-(1-methyl-indol-3-yl)indolin-2-one (13c), N-propargyl3-hydroxy-3-(5-methoxy-indol-3-yl)indolin-2-one (14c), 3-(5-methoxy-1H-indol-3-yl)-3-(1H-indol3-yl)indolin-2-one (1e), 3-1-methyl(5-methoxy-1H-indol-3-yl)-3-(1H-indol-3-yl)indolin-2-one (2e), 3-1-allyl(5-methoxy-1H-indol-3-yl)-3-(1H-indol-3-yl)indolin-2-one (3e), 3-1-benzyl(5-methoxy-1H-indol-3-yl)-3-(1H-indol-3-yl)indolin-2-one (4e) and 3-1-(prop-2-ynyl)(5-methoxy-1H-indol-3-yl)-3(1Hindol-3-yl)indolin-2-one (5e) are reported here for the first time. All the compounds are characterized by IR, 1H, 13C NMR and HRMS. Corresponding author.

The synthesis of symmetrical 3,3-di(indolyl)indolin-2-ones has been reported [8]- [22], while in the case of unsymmetrical 3,3-di(indolyl)indolin-2-ones, so far only three reports are available in the literature to the best of our knowledge.The synthesis involves a stepwise process.Wang and Ji reported an ultrasound irradiation method in the presence of ceric ammonium nitrate (CAN) for 1 to 5 h [23]; Moghadam and co-workers reported the reaction in the ionic-liquid N,N,N,N-tetramethylguanidinium trifluoroacetate (TMGT) for 1 h [24] and Nikpassand and co-workers reported it with a montmorillonite in 30 -35 minutes [25].
In the case of 3-indolyl-3-hydroxy oxindoles, Kumar and co-workers reported the synthesis of various 3-indolyl-3-hydroxy oxindoles by supramolecular catalysis (β-Cyclodextrin) in 45 -190 minutes [7]; Shanthi and co-workers reported a time of 60 -120 minutes using K 2 CO 3 as a catalyst [26]; Meshram and co-workers reported a time of 15 minutes in the presence of Triton B [27]; Hosseini and Tavakolian reported a reaction time of 2.5 h using ZnO nanorods in aqueous medium [28].EtOH and water medium (60:40) in the presence of Lewis acid (FeCl 3 •6H 2 O) and ultrasonic irradiation in 5 -25 minutes was reported by Khorshidi and Tabatabaeian [29] while Makarem and co-workers reported an electrochemical method using EtOH/Propanol (60 -240 minutes) [30].Srihari and Murthy reported a heterogeneous catalyst (Kaolin/KOH) in the presence of MeOH as a solvent in 138 -470 minutes [31].Using various ionic-liquids, Moghadam and co-workers reported a reaction time of 10 -20 minutes [24].Jing Deng and coworkers reported an enantioselective version by using cupreine [32].Nadine and coworkers also reported the reaction using chiral scandium(III) and indium(III) pybox complexes [33].Recently, Pravathaneni Sai Prathima and co-workers reported the synthesis in aqueous medium using a base catalyst-diethanolamine [34].The focus of our lab is to develop "green" methods for organic synthesis.In addition to using biocatalysts for organic transformations, we have now used microwave irradiation for organic synthesis as reported in the present study.Use of solvent-free and catalyst-free reaction conditions is an attractive proposition as seen in numerous microwave-assisted reactions.To the best of our knowledge, this is the first report for catalyst and solvent-free synthesis of 3-indolyl-3-hydroxy oxindoles and unsymmetrical 3,3di(indolyl)indolin-2-ones under microwave irradiation in 5 and 10 minutes respectively.

, Scheme 3).
All the compounds were characterized by IR, 1 H, 13 C NMR and HRMS.To the best of our knowledge com- Proposed mechanism for the formation of 3-indolyl-3-hydroxy oxindole.

Material and Methods
Chemicals were obtained from Spectrochem, and used without further purification.All known products were identified by comparison of their physical and spectral data with those of authentic samples. 1 H and 13 C NMR spectra were recorded on a Bruker AV-400 spectrometer operating at 400 and 100 MHz, respectively.The spectra were calibrated on the solvent residual peak (DMSO-d6: δ = 2.50 ppm for 1 H and δ = 39.52 ppm for 13 C; CDCl 3 : δ = 7.26 ppm for 1 H and δ = 77.0ppm for 13 C).Analytical thin layer chromatography (TLC) was performed on Kieselgel 60 F254 aluminum sheets (Merck 1.05554).Column chromatography was performed on silica gel (100 -200 mesh).FT-IR spectra were recorded on a Nicolet-6700.High-resolution mass spectra were recorded with Thermo Scientific-Orbitrap Elite (Electro spray Ionization).Anton Paar microwave synthesizer was used at 600 rpm and temperature was kept constant at 70˚C and 150˚C.

General Procedure for the Synthesis of 3-Indolyl-3-hydroxy Oxindoles (1c to 15c)
A mixture of the isatin (0.6797 mmol, 100 mg) and indole (0.8156 mmol, 96 mg) was added to a microwave-oven reaction vial then irradiated for 5 minutes at 70˚C.After completion of the reaction (as indicated by TLC) the residue was washed with 2 mL of DCM and mixed with silica gel and then evaporated the solvent under reduced pressure, and the mixture was purified by column chromatography using EtOAc in hexanes.All the known products have spectral and physical data consistent with those reported in literatures.

General Procedure for the Synthesis of Unsymmetrical 3,3Di(indolyl)indolin-2-ones (1e to 5e)
A mixture of 3-indolyl-3-hydroxy oxindoles (0.3400 mmol, 100 mg) and indole (0.4100 mmol, 48 mg) was added to a microwave-oven reaction vial, and then irradiated for 10 minutes at 150˚C.Then the residue as washed with 2 mL of EtOAc and mixed with silicagel and then evaporated the solvent under reduced pressure,