Summary The scope and utility of fluorous (perfluorinated) fluids as reaction media for Lewis acid catalyzed Friedel–Crafts reaction are described. Introduction The Friedel–Crafts reaction is one of the most important synthetic reactions, especially in industrial production.1 Usually, this reaction is carried out in toxic and/or harmful organic reaction media like CH2Cl2, CS2, etc.2 Ogawa and Curran reported that benzotrifluoride (BTF) is a useful alternative solvent to CH2Cl2 and can be used in Friedel–Crafts acylation.3 However, BTF reacts with AlCl3 which is typically used in Friedel–Crafts reactions (Scheme 1).4 In addition, BTF is sensitive to some reducing Scheme 1 conditions and hydrolyzed by aqueous acid at high temperature.5 These reactivities clearly limit its utility as a reaction medium.Recent studies of fluorous (perfluorinated) fluids as new alternative reaction media are having an important impact on organic reactions.6 These fluids all have very unusual properties, such as high density and high stability, low solvent strength, and extremely low solublity in water and organic materials.6 However, the scope and limitations of the utility of fluorous media are still unclear.In our previous paper,7 we reported the ease of handling and re-use of fluorous fluids. In this paper, we describe the utility of fluorous fluids as the reaction medium for Friedel–Crafts reactions. Results and discussion As shown in Table 1, acetylation proceeds smoothly in every fluorous reaction medium tested as well as in CH2Cl2, and negligible differences in solvent effect were observed.The catalyzed acetylation of benzene and p-xylene using an equimolar amount CF3 + AlCl3 CCl3 + AlF3 Friedel–Crafts reaction in fluorous fluids Hirofumi Nakano and Tomoya Kitazume* Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku Yokohama 226- 8501, Japan. E-mail: tkitazum@bio.titech.ac.jp Received 4th May 1999 of AlCl3 was performed at room temperature by employing perfluorotriethylamine as the solvent, resulting in 89 and/or 55% yields, respectively; however the reaction in hexane did not proceed.We have reported that fluorous solvents can be more than 90% recovered by three phase extraction,7 and it is possible to reuse them in the same reaction system.These results show that fluorous liquids possess the possibility to be good reaction media, especially for Friedel–Crafts reaction. Common problems in the use of stoichiometric amounts of AlCl3 are its instability and the disposal of the stoichiometric amount of Al(OH)3 after aqueous work-up. In view of ‘Atom Economy’,8 catalytic reactions are preferable. Hence, catalytic acylation with ZnCl2 was next investigated (Table 2).This benzoylation was performed at reflux temperature in highly toxic sym-tetrachloroethane (entry 11).9 The same reaction was carried out in perfluoro-2-butyltetrahydrofuran under the same conditions (entry 12) and the benzoylated product was isolated in comparable yield. In entry 13, the same reaction was successfully carried out in perfluorotriethylamine at a lower reflux temperature. These results show that fluorous media with lower reflux temperatures and non-flammability are good substitutes in Friedel–Crafts acylation for conventional organic liquids.For economical and environmental reasons, recycling of catalysts is favorable. Thus far, the use of catalysts bearing perfluorinated ligands and their recovery after reaction using a fluorous biphase system6 has been of great concern to chemists.However, such ‘fluorous catalysts’ are not commercially available and their synthesis often requires tedious steps and expensive starting materials. Therefore, before pursuing perfluorinated catalysts, we Green Chemistry August 1999 179 C G One of the main issues in green chemistry is the choice of solvent.Many solvents such as benzene and carbon tetrachloride are now considered as unusable due to toxicity problems, and others such as hydrocarbons are problematic due to difficulties with flammability and volatility. Ionic liquids and supercritical fluids are some of the newer choices available to the chemist (see e.g. Green Chemistry, 1999, 1 23, 65 and 91). A third class of solvents which may be of some benefit are the fluorous materials —highly fluorinated molecules with exceptional stability.The work in this paper describes the use of these solvents in the Friedel–Crafts reaction, a particularly aggressive reaction medium, involving strong Lewis acids such as aluminium chloride, and also a very important reaction industrially. DJM Green Contexttried to utilize commercially available catalysts which can be recycled easily.Sc(OTf)3 has been shown to be a good Friedel–Crafts catalyst and can be recovered quantitatively after extractive work-up in an aqueous phase separated from the organic products.10 As shown in Scheme 2, Sc(OTf)3 effectively catalyzes the acetylation of anisole in perfluorinated solvents and only the p-adduct was obtained in 69%, 3 times the average isolated yield.Moreover, benzaldehyde dimethylacetal was also reacted with anisole to produce a disubstituted material in 57% yield (Scheme 3). Further, Sc(OTf)3 can be recovered free from organic products by simple extractive work-up. Successive reuse of the recovered Sc(OTf)3 and solvent in the same reaction without further purification yielded the product in 40% yield (Fig. 1). In conclusion, we have shown that perfluorinated liquids are good alternative reaction media for use in the Lewis acid catalyzed Friedel–Crafts reaction. 180 Green Chemistry August 1999 Table 1 Acetylation reactions using different solvents Entry Arene Solvent Product Yield (%)a 1 Benzene Perfluorotriethylamine 89 2 Perfluorotri-n-butylamine 81 3 Perfluoro-2-butyltetrahydrofuran 87 4 p-Xylene Perfluorotriethylamine 55 5 Perfluorotri-n-butylamine 57 6 Perfluoro-2-butyltetrahydrofuran 46 7 Perfluoro-n-hexane 63 8 CH2Cl2 78 9 Anisole Perfluorotriethylamine 89b 10 Mesitylene Quantitative a Isolated yield.b Only p-adduct was obtained.O MeO O O O R O Cl + R O rt, overnight AlCl3 (1.0 eq.) Table 2 Catalytic acylation with ZnCl2 Reflux Yield Entry Solvent temp./°Ca (%)b 11 sym-Tetrachloroethane 138 66c 12 Perfluoro-2-butyltetrahydrofuran 99–107 62 13 Perfluorotriethylamine 70 64 a Bath temperature.b Isolated yield. c Ref. 9. OMe But O Ph Cl + OMe But Ph O reflux, 40 h ZnCl2 (10 mol %) Scheme 2 OMe Ac2O + OMe O Sc(OTf)3 (20 mol %) perfluorotriethylamine rt, 4 h cycle 1: 69% cycle 2: 40%Scheme 3 Fig. 1 Notes and references 1 G.A. Olah, Friedel–Crafts Chemistry, Wiley, New York, 1973. 2 Review: P. H. Gore, Chem. Rev., 1955, 55, 229. 3 A. Ogawa and D. P. Curran, J. Org. Chem., 1997, 62, 450. 4 A. L. Henne and M. S. Newman, J. Am. Chem. Soc., 1938, 60, 1697; R. K. Ramchandani, R. D. Wakharkar and A. Sudalai, Tetrahedron Lett., 1996, 37, 4063. 5 R. E. Banks, B.E. Smart and J. C. Tatlow, Organofluorine Chemistry, Plenum, New York, 1994. 6 Selected examples: I. T. Horváth and J. Rábai, Science, 1994, 266, 72; S. G. DiMagno, P. H. Dussault and J. A. Schultz, J. Am. Chem. Soc., 1996, 118, 5312; A. Studer, S. Hadida, R. Ferritto, S.-Y. Kim, P. Jeger, P. Wipf and D. P. Curran, Science, 1997, 275, 823; I. Klement, H. Lütjens and P. Knochel, Angew.Chem., Int. Ed. Engl., 1997, 36, 1454. 7 H. Nakano and T. Kitazume, Green Chemistry, 1999, 1, 21. 8 B. M. Trost, Angew. Chem., Int. Ed. Engl., 1995, 34, 259. 9 M. Kulka, J. Am. Chem. Soc., 1954, 76, 5469. 10 A. Kawada, S. Mitamura and S. Kobayashi, Synlett, 1994, 545; T. Tsuchimoto, K. Tobita, T. Hiyama and S. Fukuzawa, Synlett, 1996, 557; T. Tsuchimoto, T. Hiyama and S.Fukuzawa, Chem. Commun., 1996, 2345; T. Tsuchimoto, K. Tobita, T. Hiyama and S. Fukuzawa, J. Org. Chem., 1997, 62, 6997; H. Kotsuki, T. Oshisi and M. Inoue, Synlett, 1998, 255. 11 Typical procedure is as follows. To a solution of acetyl chloride (0.356 ml, 5 mmol), aluminium chloride (667 mg, 5 mmol) and perfluorotriethylamine (3 ml) at 0 °C, benzene (0.444 ml, 4 mmol) was added. After completion of the addition, the ice bath was removed and the reaction mixture was three-phase extraction aqueous layer organic layer fluorous reaction medium Sc(OTf)3 organic product recycle recycle OMe OMe Ph Sc(OTf)3 (20 mol %) perfluorotriethylamine rt, overnight 57 % OMe Ph OMe + OMe stirred overnight at room temperature. The reaction was quenched with 4 ml of water, and stirred for a few minutes. Then, the fluorous solvent was recovered by three phase extraction, and the organic layer was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography afforded the product. Paper 9/03544C Green Chemistry August 1999 181