Green and Efficient Synthesis of Spiroheterocyclic Compounds from Reactions of Isatins, 3-Amino-1-phenyl-1H-pyrazol-5(4H)-one, and Monocyclic Ketones

Abstract The reactions of isatins, 3-amino-1-pheyl-1H-pyrazol-5(4H)-one, and monocyclic ketones, have been developed for preparation of spiro[indoline-3,4'-pyrazolo[3,4-b]quinoline]-2,3'(6'H)-dione, spiro[cyclohepta[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3-dione, spiro[cycloocta[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3(6H)-dione, and spiro[cyclo dodeca[b]pyrazolo[4,3-e]pyridine-4,3'-indoline]-2′,3(6H)-dione derivatives in aqueous and acetic acid mixed medium. Studies have shown that water was an excellent medium for this reaction. The significant features of this method are wide substrate scope, high yields, operational simplicity, and minimal environment impact.


Introduction
Pyrazole and its derivatives are the important structures in medicinal and organic chemistry, because these compounds have displayed broad spectrum of pharmacological and biological activities, such as anti-bacterial, anti-depressant, and anti-hyperglycemic. 1 Quinoline derivatives are also found with anti-malarial, anti-inflammatory, anti-tuberculosis, and anti-breast cancer activities, and they are the key structural units of many medicine and natural products. 2Because of the important activities of these kinds compounds, chemists wanted to synthesize some skeletons with both of them.In facts, pyrazolo [3,4-b]quinoline was the compound with different bioactivities, such as anti-viral, anti-microbial, and anti-malarials. 3Other research was reported that pyrazolo [3,4-b]quinoline derivatives could be used as highly fluorescent materials in the blue emission range (400-500 nm) as well as promising materials for electroluminescent applications. 4Owing to their importance, many methods have been reported to synthesize pyrazolo [3,4-b]quinoline derivatives.For example, Karnakar et al., 5 Sumesh et al., 6 and Quiroga et al., 7 reported to prepare pyrazolo [3,4-b]quinoline derivatives from the reactions of aldehyde, amino pyrazole, and 1,3cyclohexanedione or dimedone under different conditions.Ren et al., 8 and Karamthulla et al., 9 have synthesized benzo[h]pyrazolo [3,4-b]quinoline from the three component reactions of 2-hydroxy-1,4-naphthoquinone, aldehydes, and aminopyrazoles.Karthikeyan et al. reported to give corresponding pyrazolo [3,4-b]quinoline derivatives from acetanilide via multistep reactions. 10an also obtained pyrazolo [3,4-b]quinoline derivatives from multistep reactions used phenylhydrazine and b-ketoesters as starting materials. 11Hosseinjani-Pirdehi et al. reported a four-component reaction for the synthesis of pyrazolo [3,4-b]quinoline derivatives under solvent-free conditions. 12][15][16][17] Isatin and its derivatives are also a commonly used reagents in organic synthesis, especially in the construction of spiro compounds in multi-component reactions.For example, D. Basavaraja et al. reported an efficient multi-component reaction for the synthesis of spiro-dihydropyridine oxindoles via isatin, malononitrile, allenoate, and amines. 18A simple and efficient method for the synthesis of spirooxindole derivatives via a three-component reaction of isatin, 5-aminopyrazole, and 1,3-dicarbonylcompounds was reported by Wu and coauthors. 19A highly stereoselective three-component reaction of benzodioxole chalcones, isatins, and sarcosine has been developed to synthesize spirooxindole derivatives. 20In recent years, we have been working on simple and effective methods to construct heterocyclic compounds. 21Herein, we found that the monomonocyclic ketones were the efficient reagents for the preparation of spiroheterocyclic compounds with pyrazolo [3,4-b]quinolone and pyrazolo [4,3-e]pyridine skeletons from the reaction of isatins and 3-amino-1-phenyl-1H-pyrazol-5(4H)-one under green conditions.

Results and discussion
At the beginning of this synthesis, isatin 1a, 3-amino-1-phenyl-1H-pyrazol-5(4H)-one 2, and cyclohexanone 3 were chosen as starting material for the screening of optimum condition Scheme 1. Synthesis of 4a in model reaction.(Scheme 1).It could be found when reaction was conducted in EtOH used PTSAÁH 2 O (0.4 mmol) as a catalyst at 80 C for 7 h, the corresponding product 4a was obtained with 66% yield (entry 1).Then, the other solvents, such as MeOH, MeCN, and dimethylformamide (DMF) were used in the model reaction, and the different yields could be obtained (entries 2-4).Interestingly, when H 2 O was used as a solvent in the reaction, the product 4a was obtained with 25% yield (entry 5).When acetic acid replaced PTSAÁH 2 O in the reaction, the yield of 4a decreased sharply (entry 6).Considering the reported reaction of 1, 3-diketone in water and acetic acid, 22 as Table 2. Synthesis of pyrazolo [3,4- Cl Br   increasing the amount of glacial acetic acid in composition, it was found the yield was indeed improved (entries 7 and 8).We decided to use a mixture solvent of water and acetic acid to test the reaction.When the volume ratio of mixed solvent (H 2 O: HOAc) was 1:1, 2:1, and 3:1, the yields of the product were 65%, 77%, and 80%, respectively (entries 9-11).However, as the amount of water was further increased, the yield of the reaction decreased rapidly (entries 12 and 13).Therefore, the volume ratio of mixed solvent (H 2 O: HOAc) as 3:1 was chosen as preferred reaction medium.Subsequently, the reaction temperature was raised to 90 C, the yield could reach at 85% (entry 14).It also showed that the yield changed little under prolonging the time or increasing the temperature conditions (entries 15 and 16).Further studies found that the reaction did not perform at all in pure water (entry 17) or poor yield was gained in acetic acid condition (entry 18).The results are listed in Table 1.
Under preferred condition, we firstly carried out the reactions of the different isatins, 3-amino-1-phenyl-1H-pyrazol-5(4H)-one and cyclohexanone in mixed solvent (H 2 O:HOAc ¼ 3: 1), and a series of expected compounds (4a-4h) were gained with excellent yields.Then, 4-methylcyclohexanone was further used in this approach, and the reactions were performed smoothly to give the corresponding products 4i-4o with high yields.It could be found that the electronic properties of the substituent on isatins had little effect on the reactions.The results are summarized in Table 2.
The structures of all products were determined from their IR, 1 H NMR, 13 C NMR, and highresolution mass spectrometry (HRMS) spectra.The possible reaction process is shown in the Figure 1 (e.g. the synthesis of 4).Initially, in the presence of HOAc, isatins 1 and cyclohexanone 3 underwent condensation reaction to give intermediate A, and then A took a proton from HOAc to get the intermediate B. It could be seen that H 2 O played an important role in assisting proton transfer in the reaction process.Furthermore, in addition to providing proton to facilitate the completion of the reaction, acetic acid also acts as a solvent.This may be the reason why the H 2 O-HOAc mixed solvent could facilitate the successful completion of this synthesis strategy.

General information
All reagents were purchased from the Merck and Sigma-Aldrich chemical companies and used without further purification.Melting points were determined on XT-5 microscopic melting-point apparatus and were uncorrected.IR spectra were recorded on a FT Bruker Tensor 27 spectrometer. 1H NMR and 13 C NMR spectra were obtained from solution in DMSO-d 6 with Me 4 Si as internal standard using a Bruker-400 spectrometer.HRMS spectra were obtained with a Bruker microTOF-Q 134 instrument.

General procedure for the synthesis of spiroheterocyclic compounds
The mixture of isatin (1 mmol), 3-amino-1-phenyl-1H-pyrazol-5(4H)-one (1 mmol), and monomonocyclic ketones (1 mmol), H 2 O (6 mL), HOAc (2 mL) was put in a reaction flask under 90 C about 5-8 h (monitored by TLC).After the reaction was finished, the product was precipitated out of the mixed-solvent.The reaction mixture was cooled to room temperature and the products could be isolated out from solvent.Then, compounds 4 and 6 were recrystallized from DMF to obtain pure product.

Table 3 .
Synthesis of pyrazolo[4,3-e]pyridine derivative 6. a The addition reaction was taken place between 2 0 and B to form intermediate C. With the help of H 2 O, intermediate D was obtained, which further converted to its tautomer E. Promoted by HOAc, intermediate F was obtained.Subsequently, F performed intramolecular cyclization reaction to generate cyclization intermediate G, and G further transferred a proton to H 2 O and obtained the intermediate H. Finally, H removed a molecule of H 2 O under heating conditions to obtain the product 4.