Friedel±Crafts-Type Conjugate Addition of Indoles Using a Lewis Acid±Surfactant-Combined Catalyst in Water Kei Manabe, Naohiro Aoyama, Shu Å Kobayashi* Graduate School of Pharmaceutical Sciences, The University of Tokyo, CREST, Japan Science and Technology Corporation (JST), Hongo, Bunkyo-ku, Tokyo 113±0033, Japan Fax: (+81) 35684 0634; e-mail: sgobayas@mol.fu-tokyo.ac.jp Received October 25, 2000; Accepted November 26, 2000 Organic reactions in aqueous media have at- tracted much attention, [1] firstly because water in- duces unique reactivities and selectivities which are not observed for reactions in organic media, and secondly because the use of water as a solvent reduces the use of harmful organic solvents and leads to the development of environ- mentally friendly chemical processes. Since the dis- covery of water-tolerant Lewis acids, Lewis acid-cat- alyzed reactions have become feasible in aqueous media. [2] However, in spite of the fact that various types of Lewis acid-catalyzed reactions in aqueous media have been developed so far, Friedel±Crafts re- actions of aromatic compounds in such media have not yet been reported. Since Friedel±Crafts reactions are one of the most important Lewis acid-mediated reactions, [3] the development of catalytic Friedel± Crafts reactions in aqueous media should greatly con- tribute to the realization of ``green'' chemical pro- cesses. In the course of our research on Lewis acid cataly- sis, we have found that Lewis acid±surfactant-com- bined catalysts (LASCs) were effective catalysts in water without using any organic co-solvents. [4] LASCs are composed of Lewis acidic metal cations and anio- nic surfactants, both of which are essential for effi- cient catalysis in water. Quite recently, we realized LASC-catalyzed Michael reactions of b-ketoesters to enones in water. [4d] These results prompted us to ap- ply LASCs to the Friedel±Crafts-type conjugate addi- tion of aromatic compounds in water. Among the aro- matic compounds, we selected indoles as substrates because of their biological importance and high reac- tivity. Herein, we report that scandium tris(dodecyl sulfate), Sc(DS) 3 , a representative LASC, can be used for conjugate addition of indoles to electron-deficient olefins in water. The reaction of indole with methyl vinyl ketone was carried out as a model (Scheme 1). [5] Indeed, Sc(DS) 3 was found to be an effi- cient catalyst in water. The reaction was com- pleted in 1 h to give the desired product in 98% yield (Table 1, entry 1). It should be mentioned that this reaction time is shorter than that reported for Yb(OTf) 3 [5c,5d] and clay [5a,5e] catalyzed reactions in or- ganic solvents. [6] It is also noted that only 2.5 mol % of the catalyst was sufficient, and that low temperature to control the reaction was not necessary, in contrast to the BF 3 ´ Et 2 O-catalyzed reaction for the same sub- strates. [5b,6] Scheme 1. When scandium triflate, Sc(OTf) 3 , was used as a cata- lyst in water, the reaction was slow, and the product was obtained in only 28% yield (Table 1, entry 2). An anionic surfactant (sodium dodecyl sulfate, SDS) alone also gave the product in a low yield (entry 3). These results indicate that both the Lewis acidic scandium cation and the anionic surfactant moiety in Sc(DS) 3 are indispensable for efficient catalysis in water, suggesting that the formation of colloidal par- ticles by a LASC with organic substrates is a key to the catalysis in other LASC-catalyzed reactions. [4f] 174 Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001 1615-4150/01/34301-174±176 $ 17.50-.50/0 Adv. Synth. Catal. 2001, 343, No. 2 COMMUNICATIONS Keywords: Friedel±Crafts reactions; Lewis acids; surfactants; indoles; aqueous reactions Table 1. Reaction of indole with methyl vinyl ketone in water (Scheme 1)