GC

Organic reactions without an organic medium

Utilization of perfluorotriethylamine as a reaction medium
Hirofumi Nakano and Tomoya Kitazume* Department of Bioengineering, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama 2268501, Japan. E-mail: tkitazum@bio.titech.ac.jp Received 5th October 1998 Summary
Perfluorotriethylamine is a good alternative reaction medium for Lewis acid catalyzed reactions and it can be easily recycled by simple extractive workup. superior to perfluorotri-n-butylamine (entry 3 vs. 4) presumably due to higher lipid solubility derived from the shorter perfluoroalkyl chains, and turned out to be as appropriate a solvent as CH2Cl2 which is commonly used in this reaction (entry 4 vs. 5). Only modest yields were obtained when the reaction was carried out in nonpolar hexanes (entry 6) or without solvent (entry 7). These results clearly show that some solvent effects of perfluorotriethylamine promoted the reaction. Some comments are worth noting, e.g. (1) the basicity of perfluorotrialkylamine is so low that the amine does not interact with a strong Lewis acid like TiCl4,5 (2) however, the amines polarity might be retained to some extent,6 which might be as important a factor in the promotion of reaction as lipophilicity. Althogh the lipid solubility of perfluorotri-n-butylamine is lower than that of perfluorohexane, perfluoro-2-butyltetrahydrofuran (critical solution temperatures in mixtures with n-hexane are 59 C for perfluorotributylamine, 20 C for perfluorohexane and 29 C for perfluoro-2-butyltetrahydrofuran)7 and hexanes, it was found to be a better reaction medium. Among fluorous amines, perfluorotriethylamine, which exhibits relatively high lipophilicity due to its short perfluoroalkyl chains and suitable boiling point, could be an ideal alternative solvent. To the best of our knowledge, this is the first application of perfluorotriethylamine as a reaction medium. The catalytic version of this reaction8 using acetal in place of aldehyde also proceeded smoothly (Fig. 1). Furthermore, recyOMe + Ph OMe TMS
TMSOTf (10 mol %) (C2F5)3N 0 C, then rt. 1h.

Introduction
One of the most important issues in scientific society is the environmental problem. Thus far, there have been increasing demands for substitutes for toxic and/or harmful solvents like CH2Cl2.1 Recently, inert and less toxic fluorous (perfluorinated) fluids have been recognized and are attracting attention as new alternative solvents.2 However, it is still not clear what kind of reactions to run in these solvents and how to run them. This fact allowed us to survey the scope and limitations of the utility of fluorous liquids as alternative reaction media for Lewis acid catalyzed reactions, which are of great current interest due to their unique reactivities and selectivities. We examined the HosomiSakurai reaction3 as a model reaction, and the results are summarized in Table 1. Table 1 Results of the HosomiSakurai allylation in various solvents

OMe Ph quant.

Entry R 1 2 n-C5H11

Solvent

Yield (%)a 67 57 78 90 92 63 67 98 Quantitative

Perfluorohexane Perfluoro-2-butyltetrahydrofuran 3 Perfluorotributylamine 4 Perfluorotriethylamine 5 CH2Cl2 6 Hexanes 7 Neat 8 CH2CH2Ph Perfluorotriethylamine 9 c-C6H11 a Isolated yield.

Fig. 1 Catalytic allylation in perfluorotriethylamine. cling of the solvents is under investigation from both environmental and economical points of view. While perfluorotriethyl-

Green Context
The search for replacements for halogenated solvents is a key area for investigation, with many of these solvents due to be phased out or banned completely. This report describes the use of perfluorinated amines as an alternative medium for reactions involving Lewis acid catalysts. The solvent may be readily recovered and reused. SJT

Results and discussion

As shown in Table 1, perfluorotrialkylamines were better reaction media than perfluorohexane4 and perfluoro-2-butyltetrahydrofuran (entries 14). In addition, perfluorotriethylamine was

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amine shows some miscibility with organic materials, extractive workup with ethyl acetate/water resulted in high recovery of the reaction medium (90%). Successive reuse of the recovered solvent in the same reaction without further purification yielded amounts of product as high as in the first cycle (Fig. 2). This
O + TMS
TiCl4 (1.0 eq.) (C2F5)3N

organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel chromatography afforded the homoallyl alcohol. Paper 8/08193J

OH

n-C5H11

n-C5H11
cycle 1: 90 % cycle 2: 92 %

Fig. 2 Recycling perfluorotriethylamine without purification. result clearly shows that the highly hydrophobic character of the perfluorinated material allows us to recycle directly the reaction medium for highly moisture-sensitive reactions. This is another merit of fluorous reaction media. In conclusion, we have shown that perfluorotriethylamine is a promising alternative reaction medium. Further studies to clarify the scope and limitation of fluorous reaction media are actively in progress in our group.

Notes and references

1 For example: S. Kobayashi, T. Wakabayashi, S. Nagayama and H. Oyamada, Tetrahedron Lett., 1997, 38, 4559; J. M. Tanko and J. F. Blackert, Science, 1994, 263, 203; A. Ogawa and D. Curran, J. Org. Chem., 1997, 62, 450. 2 D.-W. Zhu, Synthesis, 1993, 953; I. T. Horvth and J. Rbai, Science, 1994, 266, 72; S. Halida and D. P. Curran, J. Am. Chem. Soc., 1996, 118, 2531; S. G. DiMagno, P. H. Dussault and J. A. Schultz, J. Am. Chem. Soc., 1996, 118, 5312; A. Studer, S. Halida, R. Ferritto, S.-Y. Kim, P. Jeger, P. Wipf and D. P. Curran, Science, 1997, 275, 823; A. Studer, P. Jeger, P. Wipf and D. P. Curran, J. Org. Chem., 1997, 62, 2917; I. Klement, H. Ltjens and P. Knochel, Angew. Chem., Int. Ed. Engl., 1997, 36, 1454; J. J. J. Juliette, I. T. Horvth and J. A. Gladysz, ibid., 1997, 36, 1610; M.-A. Guillevic, A. M. Arif, I. T. Horvth and J. A. Gladysz, ibid., 1997, 36, 1612; J.-M. Vincent, A. Rabion, V. K. Yachandra and R. H. Fish, ibid., 1997, 36, 2346; B. Betzemeier and P. Knochel, ibid., 1997, 36, 2623; M. Hoshino, P. Degenkolb and D. P. Curran, J. Org. Chem., 1997, 62, 8341. 3 For reviews, see: A. Hosomi, Acc. Chem. Res., 1988, 21, 200; I. Fleming, J. Dunogues and R. Smithers, Org. React., 1989, 37, 57. 4 99%; 85% n-isomer; bp = 57 C. 5 M. Gaensslen, U. Gross, H. Oberhammer and S. Rdiger, Angew. Chem., Int. Ed. Engl., 1992, 31, 1467. 6 B. E. Smart, in Organofluorine Chemistry: Principles and Commercial Applications, ed. R. E. Banks, B. E. Smart and J. C. Tatlow, Plenum Press, New York, 1994. 7 U. Gross, G. Paske and S. Rdiger, J. Fluorine Chem., 1993, 61, 11. 8 T. Tsunoda, M. Suzuki and R. Noyori, Tetrahedron Lett., 1980, 21, 71. 9 Typical procedure is as follows. Under a nitrogen atmosphere, titanium tetrachloride (0.220 ml, 2 mmol) was added dropwise to aldehyde (2 mmol) and allyltrimethylsilane (0.333 ml, 2.1 ml) in perfluorotriethylamine (4 ml) at 278 C. After completion of the addition, the dry iceacetone bath was removed and the reaction mixture was stirred for 15 min at rt. The reaction was quenched with 4 ml of water, and stirred for a few minutes. Then, 3.6 ml of fluorous solvent was recovered by three phase extraction (organic layer: 4 ml of ethyl acetate). The

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