Lewis Acid Catalysis in Supercritical Carbon Dioxide. Use of Poly(ethylene glycol) Derivatives and Perfluoroalkylbenzenes As Surfactant Molecules Which Enable Efficient Catalysis in ScCO2

Article abstract of DOI:10.1021/jo0353177

Lewis acid catalysis in supercritical carbon dioxide (CO₂) was investigated. While solubility of most organic materials is low in scCO ₂, poly(ethylene glycol) derivatives or perfluoroalkylbenzenes were found to work as surfactants to dissolve organic materials in scCO₂. In the presence of these molecules, Lewis acid catalyzed organic reactions such as aldol-, Mannich-, and Friedel-Crafts-type reactions proceeded smoothly in scCO₂. Formation of emulsions was observed in these reactions, and the systems were studied in detail.

Full text of DOI:10.1021/jo0353177

Lew is Acid Ca ta lysis in Su p er cr itica l Ca r bon Dioxid e. Use of
P oly(eth ylen e glycol) Der iva tives a n d P er flu or oa lk ylben zen es a s
Su r fa cta n t Molecu les Wh ich En a ble Efficien t Ca ta lysis in ScCO2
Ichiro Komoto and Shuj Kobayashi*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-Ku,
Tokyo 113-0033, J apan
skobayas@mol.f.u-tokyo.ac.jp
Received September 7, 2003
Lewis acid catalysis in supercritical carbon dioxide (CO2) was investigated. While solubility of most
organic materials is low in scCO2, poly(ethylene glycol) derivatives or perfluoroalkylbenzenes were
found to work as surfactants to dissolve organic materials in scCO2. In the presence of these
molecules, Lewis acid catalyzed organic reactions such as aldol-, Mannich-, and Friedel-Crafts-
type reactions proceeded smoothly in scCO2. Formation of emulsions was observed in these reactions,
and the systems were studied in detail.
In tr od u ction
thesis, successful dispersion polymerization reactions of
methyl methacrylate and others in CO2 with fluorinated
polymer surfactants were reported by DeSimone et al.5
Hay et al. used polysiloxane instead of fluorinated
polymers in poly(methyl methacrylate) synthesis.6 How-
ever, these reaction systems have not been applied to
other organic reactions, and more simple reaction sys-
tems are desired to dissolve many reactants or catalysts
and, thus, to accelerate the reactions in scCO2.
On the other hand, we have recently developed several
Lewis acid catalyzed organic reactions in water. In these
reactions, surfactant molecules which create colloidal
particles with organic compounds accelerated the reac-
tions by concentrating substrates and catalysts inside the
particles.7 For example, scandium triflate catalyzed aldol
reactions of aldehydes with silicon enolates proceeded
smoothly in water with sodium dodecyl sulfate (SDS) as
a surfactant. In this reaction, emulsions were formed in
water, and the reactions proceeded faster in water than
in organic solvents.7c
Bearing these experimental results in mind, we thought
that some specific molecules might work as surfactants
and accelerate organic reactions in scCO2 by forming
concentrated colloidal dispersions. We now report that
poly(ethylene glycol) (PEG) derivatives or 1-dodecyloxyl-
4-perfluoroalkylbenzenes work as surfactants in several
organic reactions such as aldol-, Mannich-, and Friedel-
Crafts-type reactions in scCO2.8 Formation of emulsions
was observed in these scCO2/surfactant systems. The use
Supercritical fluids (SCF) are an attractive alternative
to conventional solvents and are becoming more impor-
tant in organic chemistry and related industries.1 In
particular, supercritical carbon dioxide (scCO2) is cur-
rently well investigated as an environmentally friendly
solvent and is widely used due to its low cost, nontoxicity
and nonflammability, ease of recovery and reuse, and
moderate critical conditions (Tc ) 31.1 °C, Pc ) 7.4 MPa),
etc. On the other hand, a drawback is that CO2 behaves
like a hydrocarbon solvent and that reactants and/or
catalysts have often only low solubility in CO2. Addition
of small quantities of co-solvents was attempted in part
to improve the solubility in scCO2. Introduction of per-
fluorinated side chains in reactants and/or ligands was
also investigated to increase the solubility in scCO2.2
Alternatively, dispersion systems such as water-SCF
biphasic media with several kinds of surfactants were
investigated in organic synthesis including hydrogenation
reactions. For example, Tumus and co-workers studied
hydrogenation reactions of alkenes in a water-CO2
biphasic system, which formed microemulsions with ionic
-
perfluoropolyether ammonium carboxylate (PEPE CO2
-
NH4+).3 J essop and co-workers used tetraalkylammonium
sulfate as a surfactant in hydrogenation reactions of
arenes in water-supercritical ethane.4 In polymer syn-
(1) See, for example: (a) Noyori, R., Ed. Supercritical Fluids. In
Chem. Rev. 1999, 99, 353-634. (b) Symposium on supercritical fluids
in 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. Engl. 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.
(3) J acobson, G. B.; Lee J r., C. T.; J ohnston, K. P.; Tumas, W. J .
Am. Chem. Soc. 1999, 121, 11902.
(4) Bonilla, R. J .; J ames, B. R.; J essop, P. G. Chem. Commun. 2000,
941.
(5) Canelas, D. A.; Betts, D. E.; DeSimone, J . M. Macromolecules
1996, 29, 2818.
(6) Giles, M. R.; Hay, J . N.; Howdle, S. M.; Winder, R. J . Polymer
2000, 41, 6715.
(7) See, for example: (a) Kobayashi, S.; Wakabayashi, T.; Na-
gayama, S.; Oyamada, H. Tetrahedron Lett. 1997, 38, 4559. (b)
Kobayashi, S.; Mori, Y.; Nagayama, S.; Manabe, K. Green Chem. 1999,
175. (c) Manabe, K.; Mori, Y.; Wakabayashi, T.; Nagayama, S.;
Kobayashi, S. J . Am. Chem. Soc. 2000, 122, 7202. (d) Manabe, K.;
Aoyama, N.; Kobayashi, S. Adv. Synth. Catal. 2001, 343, 174. (e)
Manabe, K.; Mori, Y.; Kobayashi, S. Tetrahedron 2001, 57, 2537.
10.1021/jo0353177 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/07/2004
680
J . Org. Chem. 2004, 69, 680-688

Lewis Acid Catalysis in Supercritical Carbon Dioxide
TABLE 1. Effects of Ca ta lysts a n d Ad d itives in ScCO2
TABLE 2. Effect of P r essu r e of CO2 a n d Molecu la r
Weigh t of P EG
entry
catalyst
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
Yb(OSO2C4F9)3
additive
yield (%)
b
entry
pressure (MPa)a
Mw
yield (%)
1
2
3
4
5
6
7
8
9
none
10
72
36
35
58
26
47
62
64
40
PEGa
1
2
3
4
5
6
7
10
15
20
25
15
15
15
400
400
400
400
200
39
72
46
39
39
52
20
CH2Cl2
CH3CN
c
CH2Cl2
hexaned
none
600
1000
Yb(OSO2C8F17
Yb(OSO2C4F9)3
Yb(OSO2C8F17
)
none
3
PEGa
PEGa
a
b
Pressure of CO2. Molecular weight of PEG. PEG (ca. 40 mg)
was added in a 10 mL reaction vessel.
10
)
3
a
Poly(ethylene glycol) (average molecular weight was 400).
b
Additive (ca. 40 mg) was added in a 10 mL reaction vessel.
Yb(OTf)3-PEG system was higher than that in the Yb-
(OSO2C4F9)3-PEG or Yb(OSO2C8F17)3-PEG system (Table
1, entries 2, 9, and 10). The formation of emulsions was
observed in the presence of PEG (Figure 1, right), while
substrates attached to the wall of the reaction vessel and
did not spread out during the reaction without the
additive (Figure 1, left). These facts indicated that PEG
acted as a surfactant in scCO2 and that the catalyst and
substrates would be packed into the emulsion, and
therefore, the reaction proceeded rapidly. The effect of
pressure of CO2 and average molecular weight (Mw) of
PEG on the yield of the product is summarized in Table
2. The highest yield was obtained at 15 MPa using PEG
of Mw ) 400. This system was applicable to various
substrates including imines derived from aromatic and
heterocyclic as well as aliphatic aldehydes and silicon
enolates derived from esters, thioesters, and a ketone
(Table 3).
We also found that the CO2-PEG system was effective
for scandium-catalyzed aldol reactions.13 Interestingly,
in this reaction, poly(ethylene glycol) dimethyl ether
(PEG(OMe)2, Mw ) 500) was more effective than PEG.
The effects of pressure of CO2 and concentration of PEG-
(OMe)2 on yields were examined, and the results are
summarized in Chart 1. From these results, it was shown
that lower pressure was better for the aldol reaction to
obtain high yields in comparison to the Mannich-type
reaction. Although the precise mechanism is not clear, a
certain extent of CO2 pressure might be necessary in the
case of Mannich-type reactions to regenerate the catalyst
from the catalyst-product complex at the surface or the
inside of the particles.14 On the other hand, in the
correlation of the yields of the aldol adduct with the
concentration of the additive, high yields of the aldol
adduct were obtained at concentrations from 1 to 8 g/L,
while the yield decreased at the concentration of 0.5 g/L.
We also observed that the CO2-PEG(OMe)2 medium
formed emulsions when the concentration of the additive
was 1 g/L. The reaction state was a little cloudy in the
c Reaction was carried out in CH2Cl2. Reaction was carried out
d
in hexane.
of surfactants to facilitate the formation of emulsions in
a single scCO2 phase is a novel approach to synthesize
small organic molecules.
Resu lts a n d Discu ssion
Ln (OTf)3-Ca ta lyzed Ald ol- a n d Ma n n ich -Typ e Re-
a ction s in th e CO2-P EG Der iva tive System . Aldol
and Mannich reactions provide useful methods for con-
struction of carbon-carbon bonds. Among them, Lewis
acid mediated aldol reactions of silicon enolates with
aldehydes and Mannich-type reactions of silicon enolates
with imines (Mukaiyama-type reactions) have several
advantages over conventional methods.9
In an initial trial, Yb(OTf)3-catalyzed Mannich-type
reaction10 of imine 1a with silicon enolate 2a was
conducted in scCO2. The reaction proceeded very slowly,
and the desired product was obtained in only 10% yield
after 3 h. It was assumed that the low solubility of 1a
and 2a in scCO2 caused the low yield. We then tested
several compounds which might work as surfactants to
dissolve the substrates in scCO2. While normal organic
solvents such as dichloromethane or acetonitrile slightly
improved the yield, poly(ethylene glycol) (PEG) was found
to be much more effective (Table 1).11 We also confirmed
that in the absence of PEG the longer the perfluoroalkyl
chains of ytterbium catalysts were, the higher the yields
of the desired products (Table 1, entries 1, 7, and 8).12
On the other hand, a reverse tendency was observed in
the PEG-CO2 system. The yield of the product in the
(8) Preliminary communications: (a) Komoto, I.; Kobayashi, S.
Chem. Commun. 2001, 1842. (b) Komoto, I.; Kobayashi, S. Org. Lett.
2002, 4, 1115. Quite recently, PEG was used as an organic solvent in
a biphasic catalytic system in scCO2. Heldebrant, D. J .; J essop, P. G.
J . Am. Chem. Soc. 2003, 125, 5600.
(9) (a) Mukaiyama, T.; Banno, K.; Narasaka, K. Chem. Lett. 1973,
1011. (b) Ojima, I.; Inaba, S.-I.; Yoshida, K. Tetrahedron Lett. 1977,
3643.
(10) (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. (c) Kobayashi, S.; Ishitani, H.;
Komiyama, S.; Oniciu, D. C.; Katritzky, A. R. Tetrahedron Lett. 1996,
37, 3731.
(11) An example using PEG as a phase-transfer catalyst between a
scCO2 phase and a solid KCl salt phase in the cyanation reaction of
benzyl chloride was reported: Chandler, K.; Culp, C. W.; Lamb, D. R.;
Liotta, C. L.; Eckert, C. A. Ind. Eng. Chem. Res. 1998, 37, 3252.
(12) We have already reported 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.
(13) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993,
472.
(14) Fu¨rstner, A.; Ackermann, L.; Beck, K.; Hori, H.; Koch, D.;
Langemann, K.; Liebl, M.; Six, C.; Leitner, W. J . Am. Chem. Soc. 2001,
123, 9000.
J . Org. Chem, Vol. 69, No. 3, 2004 681

Komoto and Kobayashi
F IGURE 1. Reaction vessels of the Yb(OTf)3-catalyzed Mannich reaction of imine 1a with silicon enolate 2a in CO2: no additive
(left); PEG added (right). The black lump is a stirring bar.
TABLE 3. Ma n n ich -Typ e Rea ction s in th e CO2-P EG System
entry
R1
R2
imine
R3
R4
R5
SiR6R7R8
enolate
product
yield (%)
syn/anti
1
2
3
4
5
6
7
8
9
10
11
12
13c
Ph
Ph
Ph
Ph
Ph
Ph
1b
1b
1c
1d
1e
1e
1e
1e
1e
1f
Me
Me
Me
Me
H
H
Me
H
Me
H
H
Me
H
Me
Me
Me
Me
H
Me
Me
Me
H
H
H
Me
H
OMe
OMe
OMe
OMe
SEt
SiMe3
2a
3b
3b
3c
3d
3e
3f
3g
3h
3h
3i
85
97
74
75
91
95
39
68
63
89
67
44
78h
SitBuMe2
SitBuMe2
SiMe3
2b
2b
2a
PhCHdCH-
2-furyl
Ph
Ph
Ph
Ph
Ph
cyclohexyl
cyclohexyl
cyclohexyl
Ph
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
o-MeOC6H4
Ph
Ph
Ph
Ph
SiMe3
SiMe3
2c
SEt
SEt
2d d
2e
57/43
SiMe3
OMe
OMe
SEt
OEt
OMe
Ph
SitBuMe2
SitBuMe2
SiMe3
2fe
2gf
2c
38/62
31/69
1f
1f
1b
SitBuMe2
SitBuMe2
SiMe3
2h
2b
2ig
3j
3k
3l
a
b
Poly(ethylene glycol) (average molecular weight was 400). PEG (ca. 40 mg) was added in a 10 mL reaction vessel. c The reaction
was carried out at 8 MPa. E/Z ) 3/97. e E/Z ) 87/13. f E/Z ) 7/93. g 1.5 equiv was used. The yield was determined by 1H NMR analysis.
d
h
CHART 1. Effects of P r essu r e of CO2 a n d Con cen tr a tion of P EG(OMe)2 in th e Ald ol Rea ction of Ald eh yd e
4a w ith Silicon En ola te 2i a t 50 °C for 3 h in th e CO2-P EG(OMe)2 System (Con d ition s: 2 g/L (Left); 8 MP a
(Righ t))
case of 0.5 g/L. It seemed that the critical micelle
concentration (cmc) of this reaction system was between
0.5 and 1 g/L. We examined several examples of the aldol
reactions in the CO2-PEG(OMe)2 system (Table 4). Not
only benzaldehyde but also substituted aromatics, ali-
phatic, and R,â-unsaturated aldehydes reacted smoothly,
and various silicon enolates derived from a ketone, esters,
and thioesters also reacted well to afford the correspond-
ing aldol adducts in high yields.
Ald ol a n d F r ied el-Cr a fts Rea ction s in scCO2
Usin g 1-Dod ecyloxy-4-p er flu or oa lk ylb en zen es a s
Su r fa cta n ts. PEG derivatives were found to work well
as surfactants for the reactions in scCO2. We then
continued to search for more efficiently tuned molecules
682 J . Org. Chem., Vol. 69, No. 3, 2004

Lewis Acid Catalysis in Supercritical Carbon Dioxide
TABLE 4. Ald ol Rea ction s in th e CO2-P EG System
entry
R1
aldehyde
R3
R4
R5
Ph
Ph
Ph
SiR6R7R8
enolate
product
yield (%)
syn/anti
1c-e
2c,e
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
Ph
4a
4a
4b
4c
4a
4d
4e
4a
4a
4a
4a
4a
4a
4a
4a
4a
H
H
H
H
H
H
H
H
Me
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
SiMe3
SiMe3
SiMe3
SiMe3
2i
2i
2i
2i
5a
5a
5b
5c
5d
5e
5f
5g
5g
5h
5i
5j
5k
5l
5l
5m
38
72 (52n)
93
p-ClC6H4
p-MeC6H4
Ph
89
90
89
78
82
91
84
91
51
48
77
96
Ph
OEt
OEt
OEt
OMe
OMe
SEt
SEt
SEt
OtBu
OiPr
OiPr
OPh
SitBuMe2
SitBuMe2
SitBuMe2
SitBuMe2
SitBuMe2
SiMe3
2h f
2h d
2h f
2ff,g
2gf,h
2c
PhCHdCH-
PhCH2CH2-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
33/67
31/69
H
Me
Me
Me
Me
H
SiMe3
SiMe3
2d i
2e
26/74
SiMe3
2jj
29/71
45/55
37/63
34/66
SitBuMe2
SitBuMe2
SitBuMe2
2k k
2ll
Me
H
Me
2m m
62
a
b
Poly(ethylene glycol) dimethyl ether (average molecular weight was 500). PEG(OMe)2 (ca. 20 mg) was added in a 10 mL reaction
vessel. c The reaction was carried out at 15 MPa. Poly(ethylene glycol) (average molecular weight was 400) was added. e Additive (4
d
g/L). f 1.5 equiv was used. E/Z ) 87/13. E/Z ) 7/93. E/Z ) 3/93. E/Z ) 96/4. E/Z ) 88/12. E/Z ) 12/88. E/Z ) 96/4. Without
g
h
i
j
k
l
m
n
PEG(OMe)2.
TABLE 5. Effect of Ad d itives a n d Ca ta lysts
of the perfluoroalkyl chains of the additives, interesting
results were observed in the CO2-fluorosurfactant sys-
tems. Namely, lower yields of the product were obtained
when additive 6b with a shorter perfluoroalkyl chain 6b
and one without a perfluoroalkyl chain (6c) were used.
Also, the alkyl chain of the ether part effected the yields
of the product. The longer the alkyl chain, the higher the
yields of the aldol adduct were (Table 5, entries 4 and
5). While the formation of emulsions such as in the CO2-
PEG system was observed using 6a (Figure 2, right), no
emulsions were observed without the additive (Figure 2,
left). When additive 6c was used, the reaction mixture
became slightly cloudy. These observations indicated that
perfluoroalkylbenzenes acted as surfactants and that
both the perfluoroalkyl and the alkyl chains of the ether
domains were necessary to form the emulsions.
Several examples of the Sc(OTf)3-catalyzed aldol type
reactions of aldehydes with silicon enolates and Yb(OTf)3-
catalyzed Mannich-type reactions of imines with silicon
enolates in the presence of 6a in scCO2 are shown in
Tables 6 and 7, respectively. It is noted in most cases
that the yields using 6a are better than those using PEGs
as an additive in scCO2. Fluorosurfactant 6a was recov-
ered quantitatively from the reaction mixture by simple
extraction with a fluorous solvent (FC-72), and the Lewis
acid catalyst was also recovered and reused without loss
of activity (see the Experimental Section).
entry
cat.
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OSO2C4F9)3
Sc(OSO2C8F17
additive
yield (%)
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6a
6a
80
61
48
75
69
73
51
)
3
a
Additive (ca. 20 mg) was added in a 10 mL reaction vessel.
which act as surfactants in scCO2. We designed a
fluorosurfactant as an alternative and fixed a perfluoro-
alkyl chain as a CO2-philic domain and an alkyl chain
as a lipophilic domain. Based on this consideration, we
prepared 1-dodecyloxy-4-heptadecafluorooctylbenzene (6a),
which was tested in the Sc(OTf)3-catalyzed aldol reaction
of 1-trimethylsiloxy-1-phenylethene 2i with benzaldehyde
4a in scCO2. It was found that the reaction proceeded
smoothly in the presence of a small amount of 6a to afford
the corresponding aldol adduct in 80% yield (Table 5,
entry 1). It should be noted that the yield was better than
that obtained using PEG(OMe)2 as an additive (Table 4,
entry 2). In this system, we observed a tendency similar
to that in the CO2-PEG system regarding yields of the
aldol reaction in that the longer the perfluoroalkylsul-
fonyl chains of the scandium catalysts were, the lower
the yields of the desired product. In regard to the length
The CO2-fluorosurfactant system was successfully
applied to other organic reactions. We found that fluo-
rosurfactant 6a was also effective for Friedel-Crafts
alkylation and acylation reactions. We tested Friedel-
Crafts alkylation of indoles, and several examples are
shown in Table 8.7d,15 This system gave alkylated indoles
in higher yields than the system without the fluoro-
(15) (a) Iqbal, Z.; J acson, 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.
J . Org. Chem, Vol. 69, No. 3, 2004 683

Komoto and Kobayashi
F IGURE 2. Reaction vessels of the Sc(OTf)3-catalyzed aldol reaction of aldehyde 4a with silicon enolate 2i in CO2: 6a added
(right); no additive (left). The black lump is a stirring bar.
TABLE 6. Ald ol Rea ction s in th e CO2-6a System
TABLE 8. F r ied el-Cr a fts Alk yla tion of In d ol
Der iva tives in th e CO2-6a System
yield (syn/anti)
entry aldehyde enolate product
6a
PEG(OMe)2
1
2
3
4
5
6
4a
4a
4a
4a
4d
4e
2h
5d
5h
5g
5g
5e
5f
90 (-)
90 (-)
2cb
2fc
2gd
2h
87 (-)
84 (-)
97 (40/60)
98 (50/50)
99 (-)
82 (33/67)
91 (31/69)
89 (-)
2h
92 (-)
78 (-)
a
Additive (ca. 20 mg) was added in a 10 mL reaction vessel.
1.2 equiv was used. c E/Z ) 87/13. E/Z ) 7/93.
b
d
TABLE 7. Ma n n ich -Typ e Rea ction s in th e CO2-6a
System
a
Product yields without the additive are shown in parentheses.
b
6a (ca. 40 mg) was added in a 10 mL reaction vessel.
yield (syn/anti)
entry
imine
enolate
product
6a
PEG
perform Friedel-Crafts acylation by catalytic quantities,
but in halogenated solvents, acetonitrile, or nitro-
methane.17 It is noted that Friedel-Crafts acylation
proceeded smoothly in nonpolar scCO2.
1
1b
1b
1e
1e
1f
2a
3b
3l
3h
3h
3i
97 (-)
61 (-)
85f (-)
78 (-)
2b
3
2ic
2fd
2ge
2c
82 (31/69)
73 (-)
68f (38/62)
63f (-)
89f (-)
4
5
90 (-)
Con clu sion
a
Additive (ca. 20 mg) was added in a 10 mL reaction vessel.
Reaction was carried out at 8 MPa. c 1.5 equiv was used. E/Z
b
d
We have developed unique new media, scCO2-surfac-
tant systems. Among several molecules tested, poly-
(ethylene glycol) derivatives and perfluoroalkylbenzenes
were found to work as efficient surfactant molecules in
scCO2. In these media, reactants and catalysts were
homogenized to form emulsions, and Lewis acid-catalyzed
fundamental carbon-carbon bond-forming reactions such
as aldol, Mannich, and Friedel-Crafts alkylation and
acylation reactions proceeded smoothly. The length of the
) 87/13. e E/Z ) 7/93. f PEG (ca. 40 mg) was added in a 10 mL
reaction vessel.
surfactant or with PEGs. We also confirmed the forma-
tion of emulsions in these reactions. We conducted
further examinations of Friedel-Crafts acylation, and the
results are summarized in Table 9. Not only acetylation
but also benzoylation products were obtained in good
yields. Moreover, an acid anhydride as well as acyl
chlorides also worked well to give the corresponding
aromatic ketones. In conventional methods, Friedel-
Crafts acylation has been carried out in halogenated
solvents (e.g., dichloromethane, dichloroethane) with a
stoichiometric amount of a Lewis acid (e.g., AlCl3, FeCl3,
SnCl4).16 Several metal triflates have been used to
(16) (a) Friedel-Crafts and Related Reactions; Olah, G. A., Ed.; New
York, 1963-64; Vols. I-IV. (b) Olah, G. A. Friedel-Crafts Chemistry;
Wiley-Interscience: New York, 1973. (c) Heaney, H. Comprehensive
Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford, 1991;
Vol. 2, pp 733-752.
(17) For recent examples, see: Kobayashi, S.; Komoto, I.; Matsuo,
J .-i. Adv. Synth. Cat. 2001, 343, 71 and references therein.
684 J . Org. Chem., Vol. 69, No. 3, 2004

Lewis Acid Catalysis in Supercritical Carbon Dioxide
TABLE 9. F r ied el-Cr a fts Acyla tion in th e CO2-6a System
a
b
Products yield without the additive are shown in parentheses. 6a (ca. 20 mg) was added in a 10 mL reaction vessel.
1 H), 3.66 (d, J ) 13.2 Hz, 1 H), 3.89 (s, 1 H), 7.19-7.38 (m,
10 H); 13C NMR (CDCl3) δ 19.4, 24.1, 47.4, 51.4, 51.8, 67.7,
126.8, 127.4, 127.9, 128.1, 128.2, 129.0, 139.1, 140.5, 177.7.
Met h yl 2,2-d im et h yl-3-p h en yl-3-p h en yla m in op r op i-
on a te (3b):19 1H NMR (CDCl3) δ 1.16 (s, 3 H), 1.27 (s, 3 H),
3.64 (s, 3 H), 4.49 (s, 1 H), 6.45-6.62 (m, 3 H), 6.99-7.07 (m,
2 H), 7.18-7.28 (m, 5 H); 13C NMR (CDCl3) δ 20.7, 24.5, 47.0,
52.0, 64.9, 113.4, 117.3, 127.4, 128.0, 128.3, 129.0, 139.2, 146.9,
177.0.
perfluoroalkyl chains of the catalysts and the surfactants
influenced the yields of the products, and it was assumed
that the reactants were packed in the media under highly
concentrated conditions. This methodology provides a key
to address the low reactivity issue of organic reactions
in scCO2 due to low solubility in CO2.
Exp er im en ta l Section
Meth yl 2,2-d im eth yl-5-p h en yl-3-p h en yla m in o-4-p en -
ten oa te (3c):19 1H NMR (CDCl3) δ 1.29 (s, 3 H), 1.32 (s, 3 H),
3.67 (s, 3 H), 4.13 (d, J ) 7.1 Hz, 1 H), 6.09 (dd, J ) 7.2, 15.8
Hz, 1 H), 6.55 (d, J ) 15.8 Hz, 1 H), 6.63-6.70 (m, 3 H), 7.10-
7.17 (m, 2 H), 7.19-7.34 (m, 5 H); 13C NMR (CDCl3) δ 21.6,
23.5, 47.0, 52.0, 62.6, 113.7, 117.6, 126.5, 127.2, 127.6, 128.5,
129.2, 132.9, 136.7, 147.3, 177.0.
Meth yl 3-(2′-fu r yl)-2,2-d im eth yl-3-p h en yla m in op r op i-
on a te (3d ):20 1H NMR (CDCl3) δ 1.26 (s, 3 H), 1.27 (s, 3 H),
3.68 (s, 3 H), 4.71 (s, 1 H), 6.15 (d, J ) 3.2 Hz, 1 H), 6.25 (dd,
J ) 1.8, 3.2 Hz, 1 H), 6.61-6.72 (m, 3 H), 7.09-7.15 (m, 2 H),
7.30 (dd, J ) 0.9, 1.8 Hz, 1 H); 13C NMR (CDCl3) δ 19.9, 23.6,
47.3, 51.6, 51.8, 61.5, 108.9, 109.9, 126.9, 128.1, 128.3, 140.2,
141.8, 153.6, 177.3.
S-Eth yl 3-(2′-m eth oxyp h en yla m in o)-3-p h en ylp r op a n e-
th ioa te (3e):7e 1H NMR (CDCl3) δ 1.26 (s, 3 H), 1.27 (s, 3 H),
3.68 (s, 3 H), 4.71 (s, 1 H), 6.15 (d, J ) 3.2 Hz, 1 H), 6.25 (dd,
J ) 1.8, 3.2 Hz, 1 H), 6.61-6.72 (m, 3 H), 7.09-7.15 (m, 2 H),
7.30 (dd, J ) 0.9, 1.8 Hz, 1 H); 13C NMR (CDCl3) δ 14.5, 23.5,
51.8, 55.4, 55.5, 109.4, 111.2, 116.9, 121.1, 126.3, 127.4, 128.7,
136.5, 142.0, 146.9, 197.0.
S-Eth yl 3-(2′-m eth oxyp h en yla m in o)-2-m eth yl-3-p h en -
ylp r op a n eth ioa te (3f) (syn/anti ) 57/43):21 1H NMR (CDCl3)
δ 1.09 (t, J ) 7.3 Hz, 3 H), 1.11 (d, J ) 7.3 Hz, 1.29 H), 1.16
(t, J ) 7.4 Hz, 1.29 H), 1.22 (d, J ) 7.0 Hz, 1.71 H), 1.22 (t, J
) 7.2 Hz, 1.29 H), 2.72-2.89 (m, 2 H), 2.94-3.10 (m, 1 H),
3.83 (s, 1.29 H), 3.85 (s, 1.71 H), 4.50 (d, J ) 7.7 Hz, 0.43 H),
4.70 (d, J ) 5.7 Hz, 0.57 H), 5.31 (brs, 1 H), 6.30 (dd, J ) 1.5,
Gen er a l Meth od s. Tetramethylsilane (TMS) served as
internal standard (δ ) 0) for 1H NMR, CDCl3 was used as
internal standard (δ ) 77) for 13C NMR, and CF3COOH was
used as internal standard (δ ) -76.5) for 19F NMR. Column
chromatography was performed on silica gel 60 (Merck), and
preparative thin-layer chromatography was carried out using
Wakogel B-5F.
Ma ter ia ls. The perfluorobenzenes surfactants were pre-
pared by the method described below. All reagents and
solvents were used after purification according to usual
methods.
Typ ica l Exp er im en ta l P r oced u r e for th e Ald ol-Typ e
Rea ction in scCO2-P EG System . Syn th esis of Meth yl
3-Ben zyla m in o-2,2-d im eth yl-3-p h en ylp r op ion a te (3a ).18
Yb(OTf)3 (16 mg, 0.026 mmol) and a small stirring bar were
placed in a 10 mL stainless steel autoclave under argon
atmosphere. Imine 1a (103 mg, 0.53 mmol), silicon enolate 2a
(113 mg, 0.65 mmol), and poly(ethylene glycol) (44 mg, average
Mw ) 400) were mixed in a small ampule and put in the
autoclave separately to prevent reactions under neat condi-
tions before the autoclave was filled with CO2. CO2 was cooled
at -10 °C and charged with an 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, the reactor was cooled
with ice, and then the pressure was released. After hydrolytic
workup with aqueous NaHCO3 and ethyl ether, the organic
layer was dried with anhydrous Na2SO4. After being concen-
trated, the residue was subjected to preparative TLC to give
3a as a pale yellow oil (113 mg, 72% yield): 1H NMR (CDCl3)
δ 1.03 (s, 3 H), 1.12 (s, 3 H), 3.64 (s, 3 H), 3.40 (d, J ) 13.2 Hz,
(19) Akiyama, T.; Takaya, J .; Kagoshima, H. Adv. Synth. Catal.
2002, 344, 338.
(20) Ojima, I.; Inaba, S.; Nagai, M. Synthesis 1981, 546.
(21) The configuration of the major diastereomer was assigned by
transformation into the methyl ester derivative.
(18) Ipaktschi, J .; Heydari, A. Chem. Ber. 1993, 126, 1905.
J . Org. Chem, Vol. 69, No. 3, 2004 685

Komoto and Kobayashi
7.6 Hz, 0.57 H), 6.34 (dd, J ) 1.5, 7.8 Hz, 0.43 H), 6.50-6.74
(m, 3 H), 7.14-7.32 (m, 5 H); 13C NMR (CDCl3) δ 12.4, 14.2,
14.5, 14.6, 15.9, 21.0, 23.3, 23.4, 54.75, 54.80, 55.57, 55.59, 60.0,
60.4, 60.9, 109.4, 109.5, 111.0, 111.3, 116.5, 116.8, 121.01,
121.04, 127.02, 127.03, 127.1, 127.2, 127.3, 127.4, 128.38,
128.44, 128.6, 136.7, 136.8, 140.9, 141.1, 146.9, 147.0, 201.5,
202.1; IR (neat) 3409, 2966, 2931, 1677, 1603, 1513, 1455,
5.33 (dd, J ) 4.3, 7.6 Hz, 1 H), 7.23-7.59 (m, 8 H), 7.91-7.94
(m, 2 H); 13C NMR (CDCl3) δ 47.4, 70.0, 125.7, 127.7, 128.1,
128.6, 128.7, 128.8, 133.7, 142.9, 200.2.
3-(4′-Ch lor op h e n yl)-3-h yd r oxy-1-p h e n yl-1-p r op a n -
on e (5b):23 1H NMR (CDCl3) δ 3.34 (d, J ) 5.8 Hz, 2 H), 3.63
(brs, 1 H), 5.32 (t, J ) 5.8 Hz, 1 H), 7.26-7.43 (m, 4 H), 7.44-
7.52 (m, 2 H), 7.56-7.63 (m, 1 H), 7.94 (d, J ) 8.3 Hz, 2 H);
13C NMR (CDCl3) δ 47.2, 69.4, 127.1, 128.1, 128.66, 128.72,
133.3, 133.7, 136.4, 141.4, 199.9.
1223, 1028, 963, 737, 702 cm-1; HRMS (m/z) calcd for C19H23
-
NO2S (M+) 329.1450, found 329.1425.
3-H yd r oxy-1-p h e n yl-3-(4′-m e t h ylp h e n yl)-1-p r op a n -
on e (5c):23 1H NMR (CDCl3) δ 2.36 (s, 3 H), 3.34-3.38 (m, 2
H), 3.51 (brs, 1 H), 5.32 (t, J ) 5.9 Hz, 1 H), 7.19 (d, J ) 7.9
Hz, 2 H), 7.33 (d, J ) 7.9 Hz, 2 H), 7.43-7.50 (m, 2 H), 7.55-
7.62 (m, 1 H), 7.93-7.98 (m, 2 H); 13C NMR (CDCl3) δ 21.1,
47.4, 69.9, 125.7, 128.1, 128.7, 129.2, 133.6, 136.6, 137.4, 140.0,
200.2.
S-E t h yl 3-(2′-m et h oxyp h en yla m in o)-2,2-d im et h yl-3-
p h en ylth iop r op a n e th ioa te (3g): 1H NMR (CDCl3) δ 1.17
(t, J ) 7.4 Hz, 3 H), 1.23 (s, 3 H), 1.27 (s, 3 H), 2.83 (q, J ) 7.4
Hz, 2 H), 3.85 (s, 3 H), 4.59 (s, 1 H), 5.29 (brs, 1 H), 6.28 (dd,
J ) 1.5, 7.6 Hz, 1 H), 6.55 (ddd, J ) 1.5, 7.6, 7.6 Hz, 1 H), 6.62
(ddd, J ) 1.5, 7.6, 7.6 Hz, 1 H), 6.70 (dd, J ) 1.5, 7.6 Hz, 1 H),
7.18-7.33 (m, 5 H); 13C NMR (CDCl3) δ 14.4, 19.9, 23.3, 24.8,
53.5, 55.6, 64.6, 109.4, 110.9, 116.3, 121.1, 127.3, 127.9, 128.6,
137.0, 139.2, 146.9, 205.7; IR (neat) 3414, 2971, 2933, 1674,
1603, 1512, 1455, 1252, 1223, 947, 735, 706 cm-1; HRMS (m/
z) calcd for C20H25NO2S (M+) 343.1606, found 343.1599.
Meth yl 3-(2′-m eth oxyp h en yla m in o)-2-m eth yl-3-p h en -
ylp r op ion a te (3h )22 (syn/anti ) 38/62 at Table 3, entry 8):
1H NMR (CDCl3) δ 1.14 (d, J ) 7.1 Hz, 1.86 H), 1.21 (d, J )
7.3 Hz, 1.14 H), 2.83-2.92 (m, 0.62 H), 2.94-3.02 (m, 0.38 H),
3.59 (s, 1.14 H), 3.65 (s, 1.86 H), 3.86 (s, 1.86 H), 3.88 (s, 1.14
H), 4.51 (d, J ) 7.8 Hz, 0.62 H), 4.73 (d, J ) 5.4 Hz, 0.38 H),
5.04 (brs, 0.38 H), 5.28 (brs, 0.62 H), 6.33 (dd, J ) 1.5, 7.8 Hz,
0.38 H), 6.40 (dd, J ) 1.5, 8.0 Hz, 0.62 H), 6.57 (ddd, J ) 1.5,
7.8, 7.9 Hz, 0.38 H), 6.59 (ddd, J ) 1.5, 7.9, 8.0 Hz, 0.62 H),
6.65-6.76 (m, 2 H), 7.17-7.35 (m, 5 H); 13C NMR (CDCl3) δ
12.1, 15.0, 46.5, 46.7, 51.75, 51.78, 55.6, 59.4, 60.5, 109.4, 109.5,
111.0, 111.1, 116.5, 116.6, 121.1, 126.8, 126.9, 127.2, 127.4,
128.4, 128.5, 136.79, 136.84, 140.9, 141.2, 146.9, 174.5, 175.3.
S-E t h yl 3-cycloh exyl-3-p h en yla m in op r op a n et h ioa t e
(3i): 1H NMR (CDCl3) δ 0.95-1.29 (m, 2 H), 1.19 (t, J ) 7.4
Hz, 3 H), 1.50-1.92 (m, 9 H), 2.72 (dd, J ) 6.7, 15.0 Hz, 1 H),
2.77 (dd, J ) 5.6, 14.9 Hz, 1 H), 2.84 (q, J ) 7.4 Hz, 2 H),
3.70-3.76 (m, 1 H), 6.61 (d, J ) 8.1 Hz, 2 H), 6.66 (d, J ) 7.3
Hz, 1 H), 7.14 (dd, J ) 7.3, 8.1 Hz, 2 H); 13C NMR (CDCl3) δ
14.6, 23.5, 26.2, 26.4, 29.1, 29.6, 41.9, 46.1, 55.8, 113.3, 117.3,
129.3, 147.4, 198.3; IR (neat) 3402, 3054, 3024, 2926, 2853,
1680, 1601, 1505, 1449, 1319, 1259, 745, 690 cm-1; HRMS (m/
z) calcd for C17H25NOS (M+) 291.1657, found 291.1645.
Eth yl 3-cycloh exyl-3-p h en yla m in op r op ion a te (3j): 1H
NMR (CDCl3) δ 0.96-1.30 (m, 5 H), 1.18 (t, J ) 7.1 Hz, 3 H),
1.47-1.93 (m, 6 H), 2.45 (dd, J ) 7.0, 14.9 Hz, 1 H), 2.55 (dd,
J ) 5.2, 14.9 Hz, 1 H), 3.65-3.72 (m, 1 H), 4.06 (q, J ) 7.1
Hz, 2 H), 6.59-6.69 (m, 3 H), 7.11-7.17 (m, 2 H); 13C NMR
(CDCl3) δ 14.1, 26.2, 26.4, 29.3, 29.4, 37.1, 42.1, 55.3, 60.4,
113.3, 117.1, 129.2, 129.2, 147.7, 172.3; IR (neat) 3393, 2926,
2851, 1732, 1602, 1509, 1280, 1187, 748, 692 cm-1; MS (m/z)
275 (M+). Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N,
5.09. Found: C, 74.05; H, 9.08; N, 5.07.
Eth yl 3-h yd r oxy-3-p h en ylp r op ion a te (5d ):24 1H NMR
(CDCl3) δ 1.26 (t, J ) 7.2 Hz, 3 H), 2.70-2.80 (m, 2 H), 3.26
(brs, 1 H), 4.18 (q, J ) 7.2 Hz, 2 H), 5.13 (dd, J ) 4.4, 8.2 Hz,
1 H), 7.24-7.52 (m, 5 H), 7.25-7.33 (m, 2 H); 13C NMR (CDCl3)
δ 14.1, 43.3, 60.8, 70.3, 125.7, 127.8, 128.5, 142.5, 172.4.
Eth yl 3-h yd r oxy-5-p h en yl-1-p en t-4-en oa te (5e):25 1H
NMR (CDCl3) δ 1.28 (t, J ) 7.1 Hz, 3 H), 2.57-2.71 (m, 2 H),
3.06 (brs, 1 H), 4.19 (q, J ) 7.1 Hz, 2 H), 4.72 (m, 1 H), 6.22
(dd, J ) 6.2, 15.9 Hz, 1 H), 6.66 (d, J ) 15.9 Hz, 1 H), 7.21-
7.43 (m, 5 H); 13C NMR (CDCl3) δ 14.2, 41.5, 60.8, 68.9, 126.5,
127.8, 128.6, 129.9, 130.8, 136.4, 172.2.
Eth yl 3-h yd r oxy-5-p h en yl-1-p en ta n oa te (5f):25 1H NMR
(CDCl3) δ 1.27 (t, J ) 7.2 Hz, 3 H), 1.64-1.92 (m, 2 H), 2.38-
2.56 (m, 2 H), 2.64-2.88 (m, 2 H), 3.05 (d, J ) 3.9 Hz, 1 H),
3.96-4.04 (m, 1 H), 4.17 (q, J ) 7.2 Hz, 2 H), 7.15-7.32 (m, 5
H); 13C NMR (CDCl3) δ 14.1, 31.7, 38.1, 41.3, 60.7, 67.2, 125.9,
128.40, 128.43, 141.7, 173.0.
Meth yl 3-h yd r oxy-2-m eth yl-3-p h en ylp r op ion a te (5g):26
1H NMR (CDCl3) syn isomer δ 1.12 (d, J ) 7.1 Hz, 3 H), 2.79
(dq, J ) 7.1, 4.1 Hz, 1 H), 3.67 (s, 3 H), 5.10 (d, J ) 4.1 Hz, 1
H), 7.22-7.48 (m, 5 H), anti isomer δ 1.01 (d, J ) 7.1 Hz, 3
H), 2.79 (dq, J ) 8.4, 7.1 Hz, 1 H), 3.73 (s, 3 H), 4.75 (d, J )
8.4 Hz, 1 H), 7.20-7.48 (m, 5 H); 13C NMR (CDCl3) syn isomer
δ 10.7, 46.3, 51.9, 73.6, 125.9, 127.5, 128.2, 141.4, 176.2, anti
isomer δ 14.5, 47.1, 51.9, 76.4, 126.7, 128.1, 128.5, 141.5, 176.2.
S-Eth yl 3-h yd r oxy-3-p h en ylp r op a n eth ioa te (5h ):27 1H
NMR (CDCl3) δ 1.27 (t, J ) 7.4 Hz, 3 H), 2.89-3.05 (m, 5 H),
5.19 (d, J ) 8.4 Hz, 1 H), 7.27-7.42 (m, 5 H); 13C NMR (CDCl3)
δ 14.6, 23.5, 52.5, 70.9, 125.6, 127.9, 128.6, 142.3, 199.1.
S-Eth yl 3-h yd r oxy-2-m eth yl-3-p h en ylp r op a n eth ioa te
(5i)28 (syn/anti ) 26/74): 1H NMR (CDCl3) δ 1.02 (d, J ) 7.2
Hz, 2.22 H), 1.16 (d, J ) 7.2 Hz, 0.78 H), 1.22 (t, J ) 7.4 Hz,
0.78 H), 1.26 (t, J ) 7.4 Hz, 2.22 H), 2.82-3.04 (m, 3 H), 4.81
(d, J ) 8.3 Hz, 0.74 H), 5.11 (d, J ) 4.0 Hz, 0.26 H), 7.26-
7.40 (m, 5 H); 13C NMR (CDCl3) δ 11.3, 14.6, 15.5, 23.2, 23.3,
54.9, 55.4, 73.7, 76.6, 126.0, 126.6, 127.5, 128.1, 128.2, 128.5,
141.2, 141.6, 203.7, 204.1.
S-Eth yl 3-h yd r oxy-2,2-d im eth yl-3-p h en ylp r op a n eth -
ioa te (5j):29 1H NMR (CDCl3) δ 1.11 (s, 3 H), 1.21 (s, 3 H),
1.25 (t, J ) 7.4 Hz, 3 H), 2.87 (q, J ) 7.4 Hz, 2 H), 4.93 (s, 1
H), 7.25-7.34 (m, 5 H); 13C NMR (CDCl3) δ 14.4, 19.0, 23.3,
23.6, 54.3, 78.9, 127.7, 127.8, 139.9, 207.9.
ter t-Bu t yl 3-h yd r oxy-2-m et h yl-3-p h en ylp r op ion a t e
(5k )30 (syn/anti ) 29/71): 1H NMR (CDCl3) δ 1.02 (d, J ) 7.1
Hz, 2.13 H), 1.13 (d, J ) 7.1 Hz, 0.87 H), 1.43 (s, 2.61 H), 1.47
Meth yl 3-cycloh exyl-2,2-d im eth yl-3-p h en yla m in op r o-
p a n oa te (3k ):19 1H NMR (CDCl3) δ 1.00-1.26 (m, 4 H), 1.19
(s, 3 H), 1.23 (s, 3 H), 1.48-1.73 (m, 7 H), 3.50 (d, J ) 3.9 Hz,
1 H), 3.65 (s, 3 H), 4.06 (brs, 1 H), 6.59-6.65 (m, 3 H), 7.10-
7.16 (m, 2 H); 13C NMR (CDCl3) δ 22.6, 24.3, 26.1, 26.4, 26.8,
28.5, 32.9, 41.3, 47.3, 51.8, 64.0, 112.5, 116.4, 129.3, 149.7,
178.1.
1,3-Dip h en yl-3-p h en yla m in op r op a n -1-on e (3l):19 1H
NMR (CDCl3) δ 3.41 (dd, J ) 7.5, 16.1 Hz, 1 H), 3.50 (dd, J )
5.4, 16.1 Hz, 1 H), 5.00 (dd, J ) 5.4, 7.5 Hz, 1 H), 6.54-6.58
(m, 2 H), 6.63-6.70 (m, 1 H), 7.06-7.11 (m, 2 H), 7.20-7.35
(m, 3 H), 7.40-7.58 (m, 5 H), 7.88-7.92 (m, 2 H); 13C NMR
(CDCl3) δ 46.2, 54.9, 113.9, 117.9, 126.4, 127.4, 128.2, 128.7,
128.8, 129.1, 133.4, 136.6, 142.8, 146.7, 198.2.
(23) Hasegawa, E.; Ishiyama, K.; Horaguchi, T.; Shimizu, T. J . Org.
Chem. 1991, 56, 1631.
(24) Huang, Y-. Z.; Liao, Y. J . Org. Chem. 1991, 56, 1381.
(25) Carreira, E. M.; Singer, R. A.; Lee, W. J . Am. Chem. Soc. 1994,
116, 8837.
(26) Kobayashi, S.; Hachiya, I.; Takahori, T. Synthesis 1993, 371.
(27) Kobayashi, S.; Ishitani, H.; Yamashita, Y.; Ueno, M.; Shimizu,
H. Tetrahedron 2001, 57, 861.
(28) Kobayashi, S.; Horibe, M. Tetrahedron 1996, 52, 7277.
(29) Kobayashi, S.; Hachiya, I. J . Org. Chem. 1994, 59, 3590.
(30) Kamimura, A.; Mitsudera, H.; Asano, S.; Kidera, S.; Kakehi,
A. J . Org. Chem. 1999, 64, 6353.
3-Hyd r oxy-1,3-d ip h en yl-1-p r op a n on e (5a ):23 1H NMR
(CDCl3) δ 3.34 (d, J ) 4.3 Hz, 1 H), 3.35 (d, J ) 7.6 Hz, 1 H),
(22) Muraoka, T.; kamiya, S.; Matsuda, I.; Itoh, K. Chem. Commun.
2002, 1284.
686 J . Org. Chem., Vol. 69, No. 3, 2004

Lewis Acid Catalysis in Supercritical Carbon Dioxide
(s, 6.39 H), 2.76 (m, 0.71 H), 2.78-2.92 (m, 1 H), 2.97 (m, 0.29
H), 4.78 (dd, J ) 3.8, 7.9 Hz, 0.71 H), 5.07-5.09 (m, 0.29 H),
7.23-7.37 (m, 5 H); 13C NMR (CDCl3) δ 11.4, 15.5, 29.66, 29.70,
48.25, 48.35, 55.0, 55.6, 73.8, 76.7, 126.1, 126.6, 127.4, 128.0,
128.2, 128.4, 141.8, 175.3.
Isopr opyl 3-h ydr oxy-2-m eth yl-3-ph en ylpr opion ate (5l)31
(syn/anti ) 37/63 in Table 4, entry 15): 1H NMR (CDCl3) δ
1.03 (d, J ) 7.1 Hz, 1.89 H), 1.12 (d, J ) 7.1 Hz, 1.11 H), 1.16
(d, J ) 6.2 Hz, 1.11 H), 1.21 (d, J ) 6.2 Hz, 1.11 H), 1.21 (d,
J ) 6.2 Hz, 1.89 H), 1.24 (d, J ) 6.2 Hz, 1.89 H), 2.70-2.82
(m, 1 H), 3.04 (brs, 1 H), 4.74 (d, J ) 8.2 Hz, 0.63 H), 5.00 (dq,
J ) 6.2, 6.2 Hz, 0.37 H), 5.06 (dq, J ) 6.2, 6.2 Hz, 0.63 H),
5.07 (d, J ) 4.2 Hz, 0.37 H), 7.24-7.38 (m, 5 H); 13C NMR
(CDCl3) δ 11.0, 14.5, 21.61, 21.63, 21.66, 21.7, 46.5, 47.2, 68.07,
68.13, 73.7, 76.3, 126.1, 126.6, 127.4, 127.9, 128.2, 128.4, 141.4,
141.7, 175.4.
29.4, 29.57, 29.59, 29.62, 29.65, 31.9, 67.8, 114.4, 120.4, 129.4,
159.1; IR (KBr) 2925, 2845, 1600, 1497, 1466, 1248, 1085, 1040,
750, 697 cm-1
.
1-Hexyloxy-4-h ep ta d eca flu or ooctylben zen e (6d ): mp
28-29 °C; 1H NMR (CDCl3) δ 0.91 (t, J ) 9.0 Hz, 3 H), 1.30-
1.53 (m, 6 H), 1.80 (dq, J ) 7.0, 7.0 Hz, 2 H), 4.00 (t, J ) 6.5
Hz, 2 H), 6.97 (d, J ) 9.0 Hz, 2 H), 7.49 (d, J ) 9.0 Hz, 2 H);
13C NMR (CDCl3) δ 14.0, 22.6, 25.7, 29.1, 31.5, 68.2, 107.0-
116.8 (m), 114.4, 118.6 (t, J ) 33.0 Hz), 120.5 (t, J ) 24.8 Hz),
128.4 (t, J ) 6.2 Hz), 161.9; 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 ) 14.8 Hz, 2 F), -81.1 (t, J ) 10.0 Hz, 3 F); IR (KBr)
2941, 2869, 1615, 1521, 1473, 1202, 1155, 1105, 845, 652, 559
cm-1; MS (m/z) 596 (M+). Anal. Calcd for C20H17F17O: C, 40.28;
H, 2.87. Found: C, 40.00; H, 2.96.
1-Meth oxy-4-h ep ta d eca flu or ooctylben zen e (6e):35 mp
1
P h en yl 3-h yd r oxy-2-m eth yl-3-p h en ylp r op ion a te (5m )32
(syn/anti ) 34/66): 1H NMR (CDCl3) δ 1.14 (d, J ) 7.1 Hz,
1.98 H), 1.29 (d, J ) 7.1 Hz, 1.02 H), 2.96-3.08 (m, 1 H), 4.83
(d, J ) 8.6 Hz, 0.66 H), 5.13 (d, J ) 5.0 Hz, 0.34 H), 6.84-
6.89 (m, 1 H), 6.99-7.04 (m, 1 H), 7.13-7.22 (m, 1 H), 7.26-
7.40 (m, 7 H); 13C NMR (CDCl3) δ 11.5, 14.4, 46.9, 47.4, 74.1,
76.4, 121.4, 121.5, 125.9, 126.2, 126.7, 127.8, 128.2, 128.4,
128.6, 129.37, 129.41, 141.4, 150.4, 150.5, 174.0, 174.3.
P r ep a r a tion of 1-Dod ecyloxy-4-h ep ta d eca flu or ooctyl-
ben zen e (6a ).33,34 Into a 50 mL glass autoclave were added
0.30 g of 4-dodecyloxyiodobenzene (0.8 mmol), 5.54 g of
1-iodononafluorobutane (16 mmol), 1.02 g of activated copper
(16 mmol), and 8 mL of pyridine, and the mixture was heated
at 150 °C, 48 h. After being cooled to room temperature, 10
mL of water and 2 mL of 1 N aq HCl were added, and then
the mixture was filtered with Celite and eluted with hexane.
The filtrate was washed with 1 N aq HCl (30 mL × 5) and
water (30 mL × 3). After drying with sodium sulfate, the
mixture was purified by column chromatography (hexane) to
give 139 mg of 6a (0.29 mmol, 36% yield) as a white solid:
28-30 °C; H NMR (CDCl3) δ 3.86 (s, 3 H), 6.99 (d, J ) 8.9
Hz, 2 H), 7.51 (d, J ) 8.9 Hz, 2 H); 13C NMR (CDCl3) δ 55.3,
107.5-119.0 (m), 114.0, 120.9 (t, J ) 24.8 Hz), 128.5 (t, J )
6.2 Hz), 137.7, 142.3, 162.4; 19F NMR (CDCl3) δ -126.4 (s, 2
F), -123.0 (s, 2 F), -122.2 (s, 6 F), -110.0 (t, J ) 14.1 Hz, 2
H), -81.1 (t, J ) 10.0 Hz, 3 F); IR (KBr) 2970, 2844, 1615,
1519, 1205, 1146, 1027, 842, 651, 560 cm-1
.
Typ ica l Exp er im en ta l P r oced u r e for th e Ald ol-Typ e
Rea ction in scCO2-P er flu or oa lk ylben zen e System . Sc-
(OTf)3 (13 mg, 0.026 mmol), 1-dodecyloxy-4-heptadecafluoro-
octylbenzene 6a (20 mg), and a small stirring bar were placed
in a 10 mL stainless steel autoclave under argon atmosphere.
Aldehyde 4a (54 mg, 0.51 mmol) and silicon enolate 2i (116
mg, 0.60 mmol) were mixed in a small ampule and put in the
autoclave separately to prevent reactions under neat condi-
tions 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, the reactor 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 con-
centrated in vacuo to give a crystalline residue, which was
dried under reduced pressure at 200 °C for 4 h to afford 13
mg (quantitive recovery) of Sc(OTf)3 as colorless crystals. The
organic layer was concentrated, and the residue was treated
with an aq HCl/THF solution (10 mL, 1 N aq HCl/THF ) 1:9)
at 0 °C for 1 h. After addition of water, the mixture was
extracted with dichloromethane and the organic layer was
dried with anhydrous Na2SO4. After filtration and concentra-
tion, 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 6a (20 mg,
quantitative recovery). The dichloromethane layer was con-
centrated, and the residue was subjected to preparative TLC
to give the aldol adduct 5a as a pale yellow oil (92 mg, 80%
yield).
1
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 (KBr) 2921, 2853, 1615, 1518, 1475, 1370, 1257, 1211,
1144, 1112, 1090, 1051, 1017, 952, 845, 661, 559 cm-1; MS (m/
z) 680 (M+). Anal. Calcd for C26H29F17O: C, 45.89; H, 4.30.
Found: C, 46.04; H, 4.60. After column chromatography, 150
mg of p-dodecyloxyiodobenzene was recovered (48% recovery).
1-Dodecyloxy-4-n on aflu or obu tylben zen e (6b): 1H NMR
(CDCl3) δ 0.88 (t, J ) 7.0 Hz, 3 H), 1.24-1.50 (m, 18 H), 1.80
(dq, J ) 7.0, 7.0 Hz, 2 H), 3.99 (t, J ) 6.6 Hz, 2 H), 6.97 (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, 28.9, 29.4, 29.57, 29.60, 29.6, 29.7, 31.9, 68.3,
106-120 (m), 114.4, 120.5 (t, J ) 24.8 Hz), 128.4, 161.9; 19F
NMR (CDCl3) δ -125.8- -126.1 (m, 2 F), -123.1- -123.3 (m, 2
F), -110.2 (dt, J ) 2.8, 13.3 Hz, 2 F), -81.4 (ddt, J ) 2.7, 2.7,
9.8 Hz, 3 F); IR (neat) 2927, 2853, 1614, 1519, 1466, 1349,
1232, 1135, 869, 826, 742, 686, 594, 526 cm-1; HRMS (m/z)
calcd for C22H29F9O (M+) 480.2075, found 480.2058.
4-(3′-In d olyl)-2-bu ta n on e (7a ):7d 1H NMR (CDCl3) δ 2.05
(s, 3 H), 2.76 (t, J ) 7.4 Hz, 2 H), 2.94-3.00 (m, 2 H), 6.86-
6.89 (m, 1 H), 7.00-7.07 (m, 1 H), 7.08-7.14 (m, 1 H), 7.23-
7.27 (m, 1 H), 7.48-7.53 (m, 1 H), 7.94 (brs, 1 H); 13C NMR
(CDCl3) δ 19.3, 30.0, 44.1, 111.1, 115.1, 118.6, 119.2, 121.4,
122.0, 127.1, 136.3, 208.8.
3-(3′-In d olyl)-1,3-d ip h en yl-1-p r op a n on e (7b):7d 1H NMR
(CDCl3) δ 3.71 (dd, J ) 7.5, 16.7 Hz, 1 H), 3.81 (dd, J ) 7.5,
16.7 Hz, 1 H), 5.06 (t, J ) 7.1 Hz, 1 H), 6.94-7.02 (m, 2 H),
7.10-7.17 (m, 2 H), 7.21-7.44 (m, 8 H), 7.49-7.55 (m, 1 H),
7.90-7.94 (m, 2 H), 7.98 (brs, 1 H); 13C NMR (CDCl3) δ 38.2,
45.2, 111.1, 119.2, 119.4, 119.5, 121.4, 122.1, 126.3, 126.6,
127.8, 128.1, 128.4, 128.6, 133.0, 136.6, 137.1, 144.2, 198.6.
4-{3′-(1′-Meth ylin d olyl)}-2-bu ta n on e (7c):7d 1H NMR
(CDCl3) δ 2.13-2.17 (m, 3 H), 2.80-2.87 (m, 2 H), 3.01-3.08
(m, 2 H), 3.71-3.75 (m, 3 H), 6.82-6.86 (m, 1 H), 7.08-7.15
1-Dod ecyloxyben zen e (6c): 1H NMR (CDCl3) δ 0.88 (t, J
) 6.7 Hz, 3 H), 1.24-1.50 (m, 18 H), 1.80 (dq, J ) 6.7, 6.7 Hz,
2 H), 3.95 (t, J ) 6.6 Hz, 2 H), 6.86-6.96 (m, 3 H), 7.25-7.33
(m, 2 H); 13C NMR (CDCl3) δ 14.1, 22.7, 26.0, 29.27, 29.34,
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Y. J . Org. Chem. 1993, 58, 4771.
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2001, 1959.
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C. H. Angew. Chem., Int. Ed. 1999, 38, 3748.
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J . Org. Chem, Vol. 69, No. 3, 2004 687

Komoto and Kobayashi
(m, 1 H), 7.20-7.32 (m, 2 H), 7.55-7.61 (m, 1 H); 13C NMR
(CDCl3) δ 19.2, 30.0, 32.5, 44.3, 109.2, 113.6, 118.65, 118.68,
121.5, 126.3, 127.5, 136.9, 208.7.
H), 7.24 (d, J ) 7.8 Hz, 1 H), 7.41-7.47 (m, 2 H), 7.54-7.60
(m, 1 H), 7.77-7.81 (m, 2 H); 13C NMR (CDCl3) δ 20.1, 21.4,
125.7, 128.3, 129.2, 130.1, 131.9, 132.8, 135.6, 137.3, 138.2,
140.6, 198.5.
2-(3′-In d olyl)-2-p h en yl-1-n it r oet h a n e (7d ):7d 1H NMR
(CDCl3) δ 4.92 (dd, J ) 8.3, 12.3 Hz, 1 H), 5.04 (dd, J ) 7.5,
12.3 Hz, 1 H), 5.17 (dd, J ) 7.5, 8.4 Hz, 1 H), 6.96-7.00 (m, 1
H), 7.06 (ddd, J ) 1.0, 7.1, 8.0 Hz, 1 H), 7.18 (ddd, J ) 1.0,
7.1, 8.2 Hz, 1 H), 7.21-7.35 (m, 7 H), 7.43 (d, J ) 8.0 Hz, 1
H), 8.04 (brs, 1 H); 13C NMR (CDCl3) δ 41.5, 79.5, 111.3, 114.3,
118.9, 119.9, 121.6, 122.6, 126.0, 127.5, 127.7, 128.9, 136.4,
139.1.
1-P h en ylsu lfon yla cetylp yr r ole (8d ):39 1H NMR (CDCl3)
2-isomer δ 2.35 (s, 3 H), 6.36 (dd, J ) 3.2, 3.4 Hz, 1 H), 7.06
(dd, J ) 1.7, 3.4 Hz, 1 H), 7.48-7.56 (m, 2 H), 7.57-7.64 (m,
1 H), 7.83 (dd, J ) 1.7, 3.2 Hz, 1 H), 7.96-8.00 (m, 1 H), 8.00-
8.03 (m, 1 H), 3-isomer δ 2.41 (s, 3 H), 6.69 (dd, J ) 1.7, 3.3
Hz, 1 H), 7.16 (dd, J ) 2.2, 3.3 Hz, 1 H), 7.64-7.70 (m, 1 H),
7.52-7.60 (m, 2 H), 7.75 (dd, J ) 1.7, 2.2 Hz, 1 H), 7.90-7.93
(m, 1 H), 7.93-7.96 (m, 1 H); 13C NMR (CDCl3) 2- isomer δ
26.9, 110.4, 124.4, 128.1, 128.6, 130.4, 133.3, 133.6, 138.9,
185.7, 3-isomer δ 27.2, 112.4, 121.6, 124.5, 127.1, 129.4, 129.7,
134.6, 138.0, 192.8.
1′-Hyd r oxy-2′-a ceton a p h th on e (8a ):36 1H NMR (CDCl3)
δ 2.69 (s, 3 H), 7.26 (d, J ) 8.4 Hz, 1 H), 7.53 (ddd, J ) 1.3,
7.0, 8.3 Hz, 1 H), 7.58-7.66 (m, 1 H), 7.63 (d, J ) 8.3 Hz, 1
H), 7.75 (d, J ) 8.0 Hz, 1 H), 8.46 (d, J ) 8.3 Hz, 1 H), 14.02
(s, 1 H); 13C NMR (CDCl3) δ 26.9, 113.2, 118.3, 124.4, 124.9,
125.2, 125.9, 127.4, 130.0, 137.3, 162.5, 204.3.
2′,4′,6′-Tr im eth yla cetop h en on e (8e):38 1H NMR (CDCl3)
δ 2.21 (s, 6 H), 2.27 (s, 3 H), 2.45 (s, 3 H), 6.83 (s, 2 H); 13C
NMR (CDCl3) δ 19.1, 21.0, 128.4, 132.3, 138.3, 139.8, 208.6.
2′-Meth oxy-1′-a ceton a p h th on e (8b):37 1H NMR (CDCl3)
δ 7.89 (d, J ) 9.2 Hz, 1 H), 7.80 (d, J ) 8.1 Hz, 1 H), 7.76 (d,
J ) 8.1 Hz, 1 H), 7.48 (ddd, J ) 1.5, 6.9, 8.1 Hz, 1 H), 7.37
(ddd, J ) 1.2, 6.9, 8.1 Hz, 1 H), 7.29 (d, J ) 9.2 Hz, 1 H), 3.98
(s, 3 H), 2.65 (s, 3 H); 13C NMR (CDCl3) δ 32.7, 56.4, 112.8,
123.6, 124.1, 125.1, 127.7, 128.1, 128.8, 130.3, 131.4, 153.9,
205.2.
Ack n ow led gm en t. This work was partially sup-
ported by CREST and SORST, J apan Science and
Technology Corporation (J ST), and a Grant-in-Aid for
Scientific Research from J apan Society of the Promotion
of Science.
2,4-Dim eth ylben zop h en on e (8c):38 1H NMR (CDCl3) δ
2.33 (s, 3 H), 2.39 (s, 3 H), 7.05 (d, J ) 7.8 Hz, 1 H), 7.11 (s, 1
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, experimental details, and spectral data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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