Bismuthtriflate-catalyzed Reaction of N-Alkylisatins with Allyltrimethylsilane Harhadas M. Meshram,* Palakuri Ramesh, B. Chennakesava Reddy, and G. Santosh Kumar Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India (Received February 1, 2011; CL-110090; E-mail: meshram@iict.res.in) An efficient and general method has been described for the synthesisof 3-allyl-3-hydroxyoxindole by the reaction ofisatins with allyltrimethylsilane in the presence of Bi(OTf) 3 ¢4H 2 O. The method is catalytic and suitable for the preparation of functionalized 3-allyl-3-hydroxyoxindoles. 3-Substituted 3-hydroxyoxindoles are the core constituents of naturally occurring alkaloids and potent bioactive mole- cules. 1,2 Some of the bioactive molecules like convolutamy- dines, 3 diazonamide A, 4a leptosin D, 4b 30-hydroxyglucoisati- sin, 4c witindolinone C, 4d TMC-95s, 5 celogentin K, 6 dioxi- brassinine 7 as well as several other pharmaceutically active compounds 8 have a stereogenic center at the C-3 position. Particularly, chiral 3-substituted 3-hydroxyindolin-2-ones are found to be usefulin medicinal chemistry as antibacterial, anti-inflammatory, 9a laxative, 9b growth-hormone secretagogue agents, 9c and new targets for cancer chemotherapy. 9d The hydroxyindolines are also usefulin the synthesisof chiral ligands which are used to obtainhigh enantioselectivities in numerous catalytic reactions. 10 Due to theirdistinct biological and chemical properties, their construction has stimulated synthetic chemists, 4a for the search of simple and efficient approaches. 5 Because of the important medicinal value of 3- hydroxyindolines, an efficient and general protocolfor the synthesisof these molecules is desirable. The synthesisof 3- allyl-3-hydroxyoxindole derivatives has been reported by the reaction ofisatinwith allylorganometallics and allyl alcohols with palladium catalysts. 1b,11 Unfortunately, these reagents do have limitations. Since allylorganometallics are extremely strong bases as well as potent nucleophiles, their use with base-sensitive substrates is precluded. Organometallic carbon nucleophile reagents are incompatiblewith halo, nitro, and cyano functionalities, whileallyl bromide and allylorganome- tallics are corrosive and toxic. In view of this, there is still need to develop a general and efficient method for the synthesisof allyloxindole derivatives. Recentlybismuth compounds have attracted attention due to their low toxicity, low cost, and high stability. 12 Bismuth salts have been reported as catalysts for opening of epoxides, 13 Mannich type reactions, 14 deprotection of acetals, 15 Friedel- Crafts reactions, 16 Fries and Claisen rearrangements, 17 and Sakurai reactions. 18 Bi(OTf) 3 is particularly attractive because it is commercially available or can be easily prepared from commercially available starting materials. 19 Bismuth triflate has been reported by Dubac as an efficient catalyst for the Mukaiyama aldol reaction with silyl enol ethers 20 and was recently used with a chiral ligand as reported by Kobayashiin an elegant enantioselective method. 21 Mukaiyama aldol reactions have been studied with dioxinone-derived silyl dienol ethers which proceeds regioselectively. 22 To the best of our knowledge allyltrimethylsilane has not been used for the allylation ofisatin. As a part of our ongoing research in the development of new methodologies, 23 herein we wish to report the efficient syn- thesisof 3-allyl-3-hydroxyoxindoles by the reaction ofisatin with allyltrimethylsilane in the presence of Bi(OTf) 3 ¢4H 2 O (Scheme 1). Initially, we explored various Lewis acids such as BF 3 ¢OEt 2 , InBr 3 ,Bi(OTf) 3 ¢4H 2 O, TiCl 4 ,I 2 , SnCl 4 , and SnCl 2 for the allyloxindole reaction. Among these, Bi(OTf) 3 ¢4H 2 O was found to provide optimum conversion with good yield (Table 1). The reaction ofisatin 1 with allyltrimethylsilane 2 was studied in the presence of 5 mol% of Bi(OTf) 3 ¢4H 2 O in different solvents such as DMF, toluene, THF, acetonitrile, and dichloromethane. The reaction proceeded inall the solvents with different degrees of conversion. However, THF was the solvent of choice in terms of reaction time and yield. Further, during optimization of the mole ratioof catalyst, it was noticed that the lower catalyst loading (1 mol%)did not allow the reaction to proceed; where as the higher catalyst loading (10 mol%) afforded the product in decreased yields. Encouraged by these results, we further studied the scope and limitations of this reaction with respect to the isatin (Table 2). Generally, excellent yields of 3-allyl-3-hydroxyoxindoles were obtained with 1.5 equivof allyltrimethylsilane 2 and 5 mol% of Bi(OTf) 3 ¢4H 2 O at ¹78 °C in THF. The addition of allyltrimethylsilane 2 to various isatins 1 proceeded readily and N O O R R 1 R 2 SiMe 3 R 3 N O R R 1 R 2 HO R 3 + 1 R = H, CH 3 , Et, Bn R1 = H, CH 3 , F, Cl, Br, NO 2 , OCH 3 R2 = H, Br R3 = H, CH 3 5 mol% Bi(OTf) 3 ·4H 2 O THF, -78°C - 20°C 3 R 5 R4 = R5 = H, CH 3 R 4 R 5 R 4 2 Scheme 1. Table 1. 3-Allyl-3-hydroxyoxindoles formation in different Lewis acid conditions a Entry Lewis acid (5 mol%) Time/h Yield/% 1 BF 3 ¢OEt 2 7.4 72 2 InBr 3 6 65 3 Bi(OTf) 3 ¢4H 2 O 4 92 4 TiCl 4 6.5 82 5 I 2 10 55 6 SnCl 4 8.9 58 7 SnCl 2 8.0 69 a All the reactions were carried out at ¹78-20 °C. Published on the web March 2, 2011 357 doi:10.1246/cl.2011.357 © 2011 The Chemical Society of Japan Chem. Lett. 2011, 40, 357-359 www.csj.jp/journals/chem-lett/