Chinese Chemical Letters  2015, Vol.26 Issue (05):599-602   PDF    
Alumina-supported heteropoly acid: An effi cient catalyst for the synthesis of azaarene substituted 3-hydroxy-2-oxindole derivatives via C(sp3)H bond functionalization
Shuang-Hong Hao, Xue-Yan Zhang, Dao-Qing Dong, Zu-Li Wang     
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China
Abstract: A method of C(sp3)-H bond functionalization of methyl azaarenes catalyzed by alumina-supported heteropoly acid and addition to isatins was developed. This transformation could be used for the synthesis of biologically important 3-hydroxy-2-oxindole derivatives in good to excellent yields and the catalyst could be reused for six times without significant decrease in activity.
Key words: Alumina-supported heteropoly acid     C(sp3)-H functionalization     Azaarenes     3-Hydroxy-2-oxindoles     Isatin    
1. Introduction

The 3-hydroxy-2-oxindole nucleus is a core structure in various biological molecules,such as donaxaridine,welwitindolinone, convolutamydine-A,dioxibrassinine,SM-130686 and maremycin- B (Fig. 1) [1]. These compounds possess extremely potent biological,chemical and pharmaceutical activities. Consequently tremendous efforts have been made to access these compounds. One of the most efficient methods for obtaining these compounds is the direct C(sp3)-H functionalization [2] of alkyl-substituted azaarene and subsequent addition to isatins. In recent years, examples catalyzed by transition metal [3],Brønsted acids [4] and microwave [5] has been reported. Although these protocols represented the most straightforward and effective manner to construct this motif,the discovery of a new,less expensive,less toxic and more environmental method is urgently needed.

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Fig. 1. Biologically active 3-hydroxy-2-oxindole derivatives.

Heteropoly acids have several advantages,such as readily available,Brønsted acidity,easy to handle and nontoxic,which make them attract extensive attentions in organic synthesis [6]. For example,Friedel-Crafts [7],Diels-Alder [8],esterification [9], oxidation [10] reactions catalyzed by heteropoly acids have been realized. In continuation of our interest in C(sp3)-H bond functionalization,we present herein alumina-supported heteropoly acid-catalyzed [11] reactions of 2-alkyl azaarenes with isatins to afford 3-hydroxy-2-oxindole derivatives. 2. Experimental

All major chemicals were obtained from commercial sources and used without further purification. All reactions were monitored by TLC. Column chromatography was performed on silica gel. 2.1. General procedure for the preparation of H3O40PW2·xH2O/Al2O3

Catalyst was synthesized according to the literature [11]. H3O40PW2·xH2O (2 g) was dissolved in 8 mL of methanol, then 8 g alumina was added to this solution and stirred for 4 h. The performed catalyst was dried at 80 °C for removal of methanol and subsequently calcined at 100 °C for 3 h. 2.2. General procedure for C(sp3)-H functionalization of azaarenes

A 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with 2,6-lutidine (0.75 mmol,3 equiv.),1-methyl isatin (0.25 mmol),dioxane (0.5 mL) and H3O40PW2·xH2O/Al2O3 (0.03 equiv.). The tube was sealed and heated at 120 °C for 24 h. After completion of the reaction,the solution was extracted with ether (3× 10 mL). The organic layer was dried with anhydrous Na2SO4,and concentrated under vacuum. The residue was chromatographed on a silica gel column eluted with a mixture of petroleum ether and ethyl acetate (3:1) to give pure products. 3. Results and discussion

For optimization of conditions,the reaction of 2,6-lutidine (1a) with 1-methyl isatin (2a) was chosen as a model reaction. In our initial screening experiments,the effects of various aluminasupported heteropoly acids were examined. To our delight,all of the heteropoly acids catalyzed the reaction (Table 1,entries 1-3) and phosphotungstic acid (H3O40PW2·xH2O/Al2O3) afforded the desired products with the highest yield (85%). No desired product was obtained when not any catalysts was added (Table 1,entry 4). Encouraged by this result,we next investigated the effect of solvent on the reaction. When the reactions were conducted in ethylene glycol (EG),ethanol,dichloroethane,moderate to good yields of the desired products were obtained (Table 1,entries 8, 10 and 12). Other solvents such as N,N-dimethylformamide (DMF), dimethyl sulphoxide (DMSO),toluene,H2O,1,2-dimethoxyethane (DME) and THF lead to a lower yields (Table 1,entries 5-7,9, 11 and 13).

Table 1
Optimization of heteropoly acid catalyzed C(sp3)-H bond functionalization.a

It is worthwhile to note that when the loading of catalyst was reduced to 0.1,0.05 and even 0.03 equiv.,the yield of the product was remained unaffected (Table 1,entries 14-16). Reacting at 120 °C was essential for this reaction,either reducing or increasing the reaction temperature lead to a slightly decrease in the yield (Table 1,entries 18 and 19). Meanwhile,it was found that the yield was not proportional to the reaction time. When the reaction time was prolonged from 24 h to 48 h,the yield was almost unchanged (Table 1,entry 17).

Choosing the optimized reaction condition,a series of isatins and heteroarenes were tested to examine the scope of the substrates. The results are summarized in Table 2. In general,all of the reactions are effective for affording the 3-hydroxy-2- oxindole derivatives in good to excellent yields. Istain with methyl or phenyl group on the nitrogen atom could react with various 2- substituted azaarenes with good yields (Table 2,3a-3c,3q,3u). On the other hand,isatins without methyl or phenyl substituents on the nitrogen atom were also suitable for this system. For example, 2-methylpyridine,2,6-dimethylpyridine,2,4,6-trimethylpyridine and 2-methylquinoline derivatives could react smoothly with Nunprotected istains giving 75-88% yields (Table 2,3d,3f,3g,3r,3t). Substituted istains with electron-withdrawing or electron-donating group attached to benzene rings,such as 5-nitro isatin,5- bromo istain,5-methyl istain,5-methoxyl istain and 8-bromo istain,could react smoothly with azaarene to generate the corresponding products (Table 2,3e,3h-3p). It is worthwhile to note that 4-methylpyridine was also good substrates for this reaction,although lower yields were obtained (Table 2,3b,3l,3s).

Table 2
Synthesis of azaarene-substituted 3-hydroxy-2-oxindoles via C(sp3)-H functionalization of 2-methyl azaarenes with isatins.a

The proposed mechanism for the synthesis of 3-hydroxy-2- oxindole derivatives is described in Scheme 1. Initially,enamine A was formed with the assistance of H3O40PW2·xH2O. Then nucleophilic addition reaction between enamine A and isatins occurred to afford the desired products C via transition state B.

Finally,the recyclability of the alumina-supported heteropoly acid catalyst was investigated (Table 3). After the reaction was completed,the organic reaction solution was vacuum-filtered through a sintered glass funnel,which was washed successively with diethyl ether and dioxane. Then the catalyst can be reused directly without further purification. The recovered catalyst could be recovered and reused for six runs without loss of its activity.

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Scheme 1. Proposed mechanism of addition of C(sp3)-H bond to isatin.

Table 3
Recovery and reuse of catalyst alumina-supported heteropoly acid.a
4. Conclusion

In conclusion,an efficient system catalyzed by aluminasupported heteropoly acid has been developed for the synthesis of bioactive 3-hydroxy-2-oxindole derivatives in good to excellent yields. Several 2-methyl azaarenes and isatins could be tolerated in this reaction. The use of alumina-supported heteropoly acid permitted the product to be easily separated from the catalyst. Furthermore,the alumina-supported heteropoly acid could be recovered and recycled by a simple filtration of the reaction solution and reused for six consecutive trials without significant loss of activity. Further studies to expand this reaction to more substrates and asymmetric C(sp3)-H bond functionalization are ongoing in our lab. Acknowledgments

Financial support from the National Natural Science Foundation of China (No. 21402103),the research fund of Qingdao Agricultural University’s High-level Person (No. 631303),the Scientific Research Foundation of Shandong Province Outstanding Young Scientist Award (No. BS2013YY024) were gratefully acknowledged.

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