Fluorous Alkoxyethyl Ether {AE, [4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-Heptadecafluoro-1-(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-heptadecafluorodecyl)undecyloxy]ethene}1

[240810-64-4]  · C23H12F34O  · (MW 950.29)

(reagent used to protect hydroxyl groups and aniline nitrogens; protected substrates are rendered fluorous-soluble and can be purified by fluorous liquid-liquid or solid phase extraction techniques; after cleavage fluorous label can be recycled)

Physical Data: mp 36-38 °C.

Solubility: soluble in tetrahydrofuran, diethyl ether, FC-72; insoluble in H2O.

Analysis of Reagent Purity: 1H and 13C NMR, IR, elemental analysis.

Handling, Storage, and Precautions: reagent is best stored under a nitrogen atmosphere in a dry environment.

Preparative Methods: the fluorous vinyl ether is prepared1 by a two-step reaction sequence involving Grignard reagent formation from commercially available 1H,1H,2H,2H-heptadecafluorodecyl iodide by sonication with magnesium powder and condensation with ethyl formate to give an intermediate secondary alcohol (1). Vinylation of this alcohol with ethyl vinyl ether and mercury (II) acetate in FC-72 (a commercially available (3M) fluorocarbon solvent which consists of perfluorohexane (C6H14) isomers, bp 56 °C) provides the vinyl ether in 51% yield (2).

Protection of Alcohols

Protection of alcohols as fluorous alkoxy ethyl acetals (AE) proceeds under mildly acidic conditions.1 Treatment of an ethereal solution of a primary alcohol and three equiv of fluorous vinyl ether with 5 mol % of 10-camphorsulfonic acid (CSA) for 3 h at room temperature provides the fluorous acetal in good yields (3). Secondary and tertiary alcohols can be protected using THF as solvent at 65 °C for 30-45 min (4).1

Although a three-fold excess of the fluorous vinyl ether is necessary for optimal yields, the majority of the unreacted vinyl ether is recoverable after the protection reaction via chromatography on SiO2. The fluorous acetals are stable to basic and nucleophilic reaction conditions.1

Protection of Aniline Nitrogen

A single example of N-protection of an aromatic amine has been reported, although the yield is low (5).1

Deprotection of Fluorous Acetals

Removal of fluorous acetals proceeds under mildly acidic conditions (6). Three-phase extraction2 of the reaction mixture (saturated NaHCO3/acetonitrile/FC-72) provides the deprotected alcohols (acetonitrile phase) in excellent yields as well as the fluorous alcohol (FC-72 layer) in quantitative yield. This fluorous alcohol can be vinylated to regenerate the vinyl ether (2), thus making the protecting group efficiently recyclable.

The fluorous AE and the fluorous THP3 are the only readily recyclable fluorous protecting groups.4

Purification of Fluorous AE-Protected Compounds

The techniques of fluorous liquid-liquid extraction and fluorous solid-phase extraction can be used to purify the fluorous AE-protected substrates after reactions.2 Due to the high fluorine content of the acetal, fluorous liquid-liquid extraction procedures need not be limited to acetonitrile as the organic solvent; diethyl ether, ethyl acetate, or dichloromethane may also be used. Solid phase extraction using fluorous reverse phase silica gel (FRP SiO2)5 is a purification option for large or highly polar substrates.6 The fluorous AE has higher fluorine content than the fluorous THP3 and the BPFOS7 protecting groups, but lower fluorine content than most tris(perfluoroalkyl) silyl ethers.2,8 The fluorous AE has been applied to a selective purification of a mixture of alcohols.9 Protection of a mixture of six alcohols resulting from addition of six different nucleophiles to a single aldehyde followed by extraction of the fluorous acetals with FC-72/acetonitrile was selective for the six fluorous AE-protected compounds (7). Subsequent deprotection in diethyl ether ether/methanol with catalytic acid followed by FC-72/acetonitrile extraction allowed separation of the fluorous solvolysis product from the now pure mixture of six alcohols (7).

Related Reagents.

Fluorous THP, BPFOS, tris(perfluoroalkyl)silyl bromides.

1. Wipf, P.; Reeves, J. T., Tetrahedron Lett. 1999, 40, 5139.
2. (a) Horváth, I. T., Acc. Chem. Res. 1998, 31, 641. (b) Curran, D. P., Angew. Chem., Int. Ed. 1998, 37, 1174. (c) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P., J. Org. Chem. 1997, 62, 2917. (d) Studer A.; Hadida, S.; Ferritto, R.; Kim, S. Y., Jeger, P.; Wipf, P.; Curran, D. P., Science 1997, 275, 823.
3. Wipf, P.; Reeves, J. T., Tetrahedron Lett. 1999, 40, 4649.
4. Jarowicki, K.; Kocienski, P., J. Chem. Soc., Perkin Trans 1 2000, 2495.
5. Curran, D. P.; Hadida, S.; He, M., J. Org. Chem. 1997, 62, 6714.
6. (a) Kainz, S.; Luo, Z.; Curran, D. P.; Leitner, W., Synthesis 1998, 1425. (b) Billiet, H. A. H.; Schoenmakers, P. J.; De Galan, L., J. Chromatography 1981, 218, 443.
7. Röver, S.; Wipf, P., Tetrahedron Lett. 1999, 40, 5667.
8. Boutevin, B.; Guida-Pietrasanta, F.; Ratsimihety, A.; Caporiccio, G.; Gornowicz, G. J., J. Fluorine Chem. 1993, 60, 211.
9. Wipf, P.; Reeves, J. T.; Balachandran, R.; Giuliano, K. A.; Hamel, E.; Day, B. W., J. Am. Chem. Soc. 2000, 122, 9391.

Jonathan T. Reeves

University of Pittsburgh, Pittsburgh, Pennsylvania, USA

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.