1-Dodecyloxy-4-perfluoroalkylbenzene as a Novel Efficient Additive in Aldol Reactions and Friedel-Crafts Alkylation in Supercritical Carbon Dioxide

Article abstract of DOI:10.1021/ol0173127

matrix presented 1-Dodecyloxy-4-perfluoroalkylbenzenes accelerated organic reactions such as aldol-type reactions and Friedel-Crafts alkylation in supercritical carbon dioxide. The perfluoroalkylbenzene worked as a surfactant in the system, and formation of emulsions during the reactions was observed.

Full text of DOI:10.1021/ol0173127

ORGANIC
LETTERS
2002
Vol. 4, No. 7
1115-1118
1-Dodecyloxy-4-perfluoroalkylbenzene as
a Novel Efficient Additive in Aldol
Reactions and Friedel−Crafts Alkylation
in Supercritical Carbon Dioxide
Ichiro Komoto and Shu¯ Kobayashi*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
skobayas@mol.f.u-tokyo.ac.jp
Received December 31, 2001
ABSTRACT
1-Dodecyloxy-4-perfluoroalkylbenzenes accelerated organic reactions such as aldol-type reactions and Friedel−Crafts alkylation in supercritical
carbon dioxide. The perfluoroalkylbenzene worked as a surfactant in the system, and formation of emulsions during the reactions was observed.
Supercritical carbon dioxide (scCO2)1 is rapidly becoming
attractive as a solvent due to its low cost, moderate critical
conditions (Tc ) 31 °C, Pc ) 7.4 MPa), and environmentally
benign nature. However, a problem is that catalysts or
reactants are only sparingly soluble in scCO2 and that they
would not have sufficient reactivity and selectivity in many
cases. Introduction of perfluorinated side chains in reactants
and/or ligands or addition of liquid solvents was investigated
to increase the solubility in scCO2.2 On the other hand,
several reactions using water-CO2 biphasic dispersions or
surfactant-containing dispersion polymerization reactions
have been studied.3 Quite recently, we have developed
Mannich and aldol reactions in a scCO2/poly(ethylene glycol)
derivatives (PEGs) system.4 PEGs worked as surfactants in
scCO2, and reactants and catalysts were spread out in the
reaction vessels to form emulsions. The reactions proceeded
smoothly in this system to give improved product yields
compared to those obtained under no additive conditions.
In this paper, we report an alternative additive, 1-dodecyloxy-
4-perfluoroalkylbenzene, which works as an efficient surf-
actant to accelerate several organic reactions in scCO2.
Our finding that PEGs work as surfactants in scCO2 was
unexpected. We then started to design an alternative surfac-
tant: a molecule that has a CO2-philic unit and a lipophilic
unit in the same molecule. We fixed a perfluoroalkyl chain
(3) (a) Canelas, D. A.; Betts, D. E.; DeSimone, J. M. Macromolecules
1996, 29, 2818. (b) Yong, Y.-M.; Hems, W. P.; van Nunen, J. L.; Holmes,
M. A. B.; Steinke, J. H. G.; Taylor, P. L.; Segal, J. A.; Griffin, D. A. Chem.
Commun. 1997, 1811. (c) Jacobsen, G. B.; Lee, Jr., C. T.; Johnston, K. P.
J. Org. Chem. 1999, 64, 1201. (d) Jacobsen, G. B.; Lee, Jr., C. T.; Johnston,
K. P.; Tumas, W. J. Am. Chem. Soc. 1999, 121, 11902. (e) Bonilla, R. J.;
James, B. R.; Jessop, P. G. Chem. Commun. 2000, 941. (f) Giles, M. R.;
Hay, J. N.; Howdle, S. M.; Winder, R. J. Polymer 2000, 41, 6715. (g) Wells,
S. L.; Desimone, J. Angew. Chem., Int. Ed. 2001, 40, 518. (h) Shim, J.-J.;
Yates, M. Z.; Johnston, K. P. Ind. Eng. Chem. Res. 2001, 40, 536.
(4) Komoto, I.; Kobayashi, S. Chem. Commun. 2001, 1842.
(1) See, for example: (a) Noyori, R., Ed. Supercritical Fluids. Chem.
ReV. 1999, 99, 353-634. (b) Symposium on supercritical fluids. Ind. Eng.
Chem. Res. 2000, 39, 4441-4907.
(2) (a) Burk, M. J.; Feng, S.; Gross, M. F.; Tumas, W. J. Am. Chem.
Soc. 1995, 117, 8277. (b) Kainz, S.; Koch, D.; Baumann, W.; Leitner, W.
Angew. Chem., Int. Ed. Eng. 1997, 36, 1628. (c) Kainz, S.; Brinkmann, A.;
Leitner, W.; Pfaltz, A. J. Am. Chem. Soc. 1999, 121, 6421. (d) Francio, G.;
Leitner, W. Chem. Commun. 1999, 1663. (e) Francio, G.; Wittmann, K.;
Leitner, W. J. Organomet. Chem. 2001, 621, 130.
10.1021/ol0173127 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/14/2002

as a CO2-philic domain, while an alkyl chain was thought
to be suitable as a lipophlic domain. Based on this consid-
eration, we synthesized 1-dodecyloxy-4-heptadecafluoro-
octylbenzene (1a), which was tested in the scandium triflate
(Sc(OTf)3)-catalyzed aldol reaction5 of 1-trimethylsiloxy-1-
phenylethene (3) with benzaldehyde in scCO2. It was found
that the reaction proceeded smoothly in the presence of a
small amount of 1a to afford the corresponding aldol adduct
in 80% yield. It should be noted that the yield was better
than that obtained using poly(ethylene glycol) dimethyl ether
(PEG(OMe)2) as an additive. In addition, lower yields were
obtained when shorter perfluoroalkylbenzene 1b and 1-do-
decyloxybenzene (1c) were used (Table 1). We also observed
Figure 1. Aldol reaction in a CO2/1a system. In b, the black lump
is a stirring bar.
Table 1. Effect of Additives and Catalysts
reactions proceeded smoothly to afford the aldol adducts in
excellent yields. Aromatic as well as aliphatic and R,â-
unsaturated aldehydes worked well. It is noted that the yields
using 1a are mostly better than those using PEG(OMe)2 as
an additive in scCO2. Perfluorobenzene 1a could be recov-
ered quantitatively from the reaction mixture by simple
extraction with a fluorous solvent (FC-72) (see below), and
the Lewis acid catalyst (Sc(OTf)3) was also recovered and
reused without loss of activity. Furthermore, the Yb(OTf)3-
catalyzed Mannich-type reactions (imino aldol reactions) of
imines with silicon enolates7 also proceeded in the presence
of a small amount of 1a in scCO2. The desired â-amino-
carbonyl compounds were obtained in high yields in all cases
under the conditions.
The present system was successively applied to other
organic reactions. We also found that the CO2/1a system
was effective for Friedel-Crafts alkylation reaction of
indoles.8 Several examples are shown in Table 3, and in all
cases, the alkylated indoles were obtained in high yields.
We could confirm the formation of emulsions in the reaction
of N-methylindole with MVK (Table 3, entry 3).
a Additive (ca. 20 mg) was added in a 10 mL reaction vessel. b PEG
(ca. 40 mg) was added in 10 mL reaction vessel.
A typical experimental procedure is described for the
reaction of aldehyde 2 with silicon enolate 5: Sc(OTf)3 (13
mg, 0.026 mmol), 1-dodecyloxy-4-heptadecafluorooctyl-
benzene 1a (20 mg), and a small stirring bar were placed in
a 10 mL stainless steel autoclave under argon atmosphere.
Aldehyde 1 (54 mg, 0.51 mmol) and silicon enolate 5 (116
mg, 0.60 mmol) were mixed in a small ampule and put in
the autoclave separately to prevent reaction under neat
conditions before the autoclave was filled with CO2. CO2
was cooled at -10 °C and charged with a HPLC pump.
During the introduction of CO2, the autoclave was heated,
and then pressure and temperature were adjusted to 15 MPa
and 50 °C. The mixture was stirred for 3 h, and the reactor
an interesting tendency that the longer the perfluoroalkyl-
sulfonyl chains of the scandium catalysts were, the lower
the yields of the desired product in the presence of 1a (Table
1, entries 6 and 7).6 While the formation of emulsions was
observed using 1a (Figure 1a), substrates attached to the wall
of the reaction vessel and did not spread out during the
reaction without the additives (Figure 1b). These facts
indicated that perfluoroalkylbenzenes acted as surfactants and
that the catalysts and substrates would be packed into the
emulsions.
Several examples of the Sc(OTf)3-catalyzed aldol reaction
of aldehydes with silicon enolates in the presence of 1a in
scCO2 are shown in Table 2, entries 1-6. In all cases, the
(7) (a) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.; Hachiya,
I. Synlett 1995, 233. (b) Kobayashi, S.; Ishitani, H. J. Chem. Soc., Chem.
Commun. 1995, 1379.
(5) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993, 472.
(6) We also confirmed that the longer perfluoroalkyl chains of the
scandium catalysts were, the higher the yields of the desired products.
Matsuo, J.; Tsuchiya, T.; Odashima, K.; Kobayashi, S. Chem. Lett. 2000,
178.
(8) (a) Iqbal, Z.; Jacson, A. H.; Rao, K. R. N. Tetrahedron Lett. 1988,
29, 2577. (b) Dujardin, G.; Poirier, J.-M. Bull. Soc. Chim. Fr. 1994, 131,
900. (c) Harrington, P.; Kerr, M. A. Synlett 1996, 1047. (d) Poupaert, J.
H.; Bukuru, J.; Gozzo, A. Monatsh. Chem. 1999, 130, 929. (e) Manabe,
K.; Aoyama, N. Kobayashi, S. AdV. Synth. Catal. 2001, 343, 174.
1116
Org. Lett., Vol. 4, No. 7, 2002

Table 2. Aldol and Mannich Reactions in a CO2/1a System
a Parentheses are the product yields in the case using PEGs. b Additive (ca. 20 mg) was added in a 10 mL reaction vessel. c 1.2 equiv was used. d E/Z )
87/13. e E/Z ) 93/7. f Syn/anti ) 40/60. g Syn/anti ) 33/67. h Syn/anti ) 50/50. i Syn/anti ) 31/69. j PEG (ca. 40 mg) was added in a 10 mL reaction
vessel. k Reaction was carried out at 15 Mpa. l Syn/anti ) 40/60. m Syn/anti ) 31/69.
was cooled with ice and then the pressure was released. After
hydrolytic workup with water and dichloromethane, the
organic layer was dried with anhydrous Na2SO4. The aqueous
layer was concentrated in vacuo to give a crystalline residue,
which was dried under reduced pressure at 200 °C for 4 h
to afford 13 mg (quantitative recovery) of Sc(OTf)3 as
colorless crystals. The organic layer was concentrated, and
the residue was treated with an aqueous HCl/THF solution
(10 mL, 1 N aqueous HCl/THF ) 1:9) at 0 °C for 1 h. After
addition of water, the mixture was extracted with dichloro-
methane and the organic layer was dried with anhydrous
Na2SO4. After filtration and concentration, dichloromethane
(5 mL) was added to the residue and extracted with
perfluorohexanes (FC-72, 15 mL) several times. The fluorous
layer was concentrated to give 1a (20 mg, quantitative
recovery). The dichloromethane layer was concentrated, and
the residue was subjected to preparative TLC (hexane/ethyl
acetate) to give the aldol adduct as a pale yellow oil (92
mg, 80% yield).
1-bromododecane (2.28 g, 9.2 mmol), DMF (5 mL), and
K2CO3 (1.28 g, 9.2 mmol) were mixed and stirred at 150 °C
for 2 h. After aqueous workup with aqaqueous HCl and
dichloromethane (to adjust under pH 7), the organic layer
was washed with water and then dried with anhydrous
Na2SO4. After removal of the solvents, the residue was
purified by column chromatography (silica gel) to give
4-dodecyloxy iodobenzene (1.72 g, 97% yield) as a white
solid. 4-Dodecyloxyiodobenzene (0.15 mg, 0.40 mmol),
1-iodoheptadecafluorooctane (4.37 g, 8.0 mmol), activated
copper (0.51 g, 8.0 mmol), and pyridine (4 mL) were mixed
in a glass autoclave, and the mixture was stirred at 150 °C
for 48 h.9 A small amount of aqueous 1 N HCl was added
after cooling to room temperature, and the mixture was
treated with Celite filtration eluted by ethyl ether. After being
washed with aqueous 1 N HCl (five times) and water (five
times), the mixture was dried with anhydrous Na2SO4 and
(9) (a) McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(b) Kobayashi, Y.; Kumadaki, I.; Sato, S.; Hara, N.; Chikami, E. Chem.
Pharm. Bull. 1970, 18, 2334. (c) Wiedenfeld, D.; Niyogi, S.; Charkrabarti,
D. J. Fluorine Chem. 2000, 104, 303.
1-Dodecyloxy-4-heptadecafluorooctylbenzene 1a was syn-
thesized as follows: 4-iodophenol (1.00 g, 4.6 mmol),
Org. Lett., Vol. 4, No. 7, 2002
1117

as a white solid.10 4-Dodecyloxyiodobenzene (55%) was
recovered.
Table 3. Friedel-Crafts Alkylation of Indol Derivatives in a
In summary, we have found that fundamental carbon-
carbon bond-forming reactions such as aldol-type reactions
and Friedel-Crafts alkylation proceed smoothly in the
presence of a small amount of perfluoroalkylbenzene 1a in
scCO2. In scCO2, 1a works as a surfactant to form emulsions.
In most cases, perfluoroalkylbenzene 1a is more effective
than PEGs, which also work as surfactants as we have
previously found. Further investigations to apply this new
system to other synthetic reactions are now in progress.
CO2/1a System
Acknowledgment. This work was partially supported by
CREST, Japan Science and Technology Corporation (JST),
and a Grant-in-Aid for Scientific Research from the Japan
Society of the Promotion of Science.
OL0173127
1
(10) Experimental data: mp 54-55 °C; H NMR (CDCl3) δ 0.88 (t, J
) 6.9 Hz, 3 H), 1.24-1.50 (m, 18 H), 1.80 (dq, J ) 6.9, 6.9 Hz, 2 H), 3.99
(t, J ) 6.5 Hz, 2 H), 6.96 (d, J ) 8.8 Hz, 2 H), 7.48 (d, J ) 8.8 Hz, 2 H);
13C NMR (CDCl3) δ 14.1, 22.7, 26.0, 29.1, 29.4, 29.59, 29.63, 29.68, 29.71,
32.0, 68.3, 105-119 (m), 114.5, 120.6 (t, J ) 24.8 Hz), 128.4 (t, J ) 6.2
Hz), 162.0; 19F NMR (CDCl3) δ -126.4 (bs, 2 F), -123.0 (bs, 2 F), -122.2
(bs, 6 F), -121.6 (bs, 2 F), -110.0 (t, J ) 14.6 Hz, 2 F), -81.1 (t, J )
10.0 Hz, 3 F); IR (cm-1) (KBr) 2921, 2853, 1615, 1518, 1475, 1370, 1257,
1211, 1144, 1112, 1090, 1051, 1017, 952, 845, 661, 559; MS (m/z) 680
(M+). Anal. Calcd for C26H29F17O: C, 45.89; H, 4.30. Found: C, 46.04; H,
4.60.
a Parentheses are the product yields without the additive. b 1a (ca. 20
mg) was added in a 10 mL reaction vessel.
then concentrated. The residue was subjected to column
chromatography (silica gel) to give 1a (85 mg, 32% yield)
1118
Org. Lett., Vol. 4, No. 7, 2002