Table 3 Aldol reaction in CO2–PEG(OMe)2 system
under neat conditions before the autoclave was filled with CO2.
CO2 was cooled at 210 °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 was cooled
with ice and then the pressure was released. After hydrolytic
work-up 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 3 as
a pale yellow oil (113 mg, 72% yield).
In summary, we have found that use of PEGs as additives was
effective for Mannich and aldol reactions in scCO2. PEGs
would work as surfactants in the reaction media, and formation
of emulsions was observed in these cases. The PEGs media are,
as far as we know, the first example to accelerate reactions by
forming emulsions in a single scCO2 phase. Further investiga-
tions on the mechanism of these reactions as well as on
applications to other synthetic reactions in scCO2 are now in
progress.
Entry
1c,d,e
2c,e
Aldehyde
PhCHO 11
11
Silyl enol ether
Yield (%)
38
10
10
10
72 (52j)
93
3
4
5
10
89
90
11
The authors are grateful to Mr Takehiro Tsuchiya for his
technical support at the early stage of this work. This work was
partially supported by CREST and a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
6
7
12f
12f
89
78
8
9
10
11
11
11
11
11
8f,g
9f,h
6
82k
91l
84
7i
91m
a Poly(ethylene glycol) dimethyl ether (average Mw was 500). b PEG(OMe)2
(ca. 20 mg) was added in the 10 mL reaction vessel. c The reaction was
carried out at 15 MPa. d Poly(ethylene glycol) (average Mw was 400) was
added. e Additive (4 g L21). f 1.5 eq. was used. g E+Z = 87+13. h E+Z =
7+93. i E+Z = 3+97. j Without PEG(OMe)2. k Syn+anti = 33+67. l Syn+anti
= 31+69. m Syn+anti = 26+74.
Notes and references
† 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.8
‡ Poly(butylene oxide)-block-poly(ethylene oxide) was used as a surfactant
in a water–CO2 system.3c
§ Emulsions formed during 8 MPa to 15 MPa at 50 °C.
in scCO2 and that the catalyst and substrates would be packed
into the emulsions. The effects of pressure and average
molecular weight (Mw) of PEGs on yields were examined, and
the results are summarized in Table 1. The highest yield of the
adduct was obtained at 15 MPa using PEG of Mw = 400.
Several examples of Mannich reactions in the CO2–PEG system
are shown in Table 2. In most cases, the reaction proceeded
smoothly at 50 °C/15 MPa for 3 h to afford the corresponding
b-amino carbonyl derivatives in high yields. It is noteworthy
that various substrates including imines derived from aromatic
and heterocyclic as well as aliphatic aldehydes and silyl
enolates derived from esters, thioesters, and a ketone are
applicable in this system.
We also found that the CO2–PEG system was effective for
scandium-catalyzed aldol reactions of silyl enolates with
aldehydes.7 In this reaction, poly(ethylene glycol) dimethyl
ether (PEG(OMe)2, average Mw = 500) was more efficient than
PEG (Table 3, entries 1 and 2). We examined several examples
of the aldol reactions in the CO2–PEG(OMe)2 system. Not only
benzaldehyde, but also substituted aromatic, aliphatic, and a,b-
unsaturated aldehydes were applicable to this medium. In
addition, various silyl enolates derived from a ketone, esters,
and thioesters also worked well to afford the corresponding
aldol adducts in high yields. We also observed that the CO2–
PEG(OMe)2 medium formed emulsions in these aldol reac-
tions.
1 See for example: Supercritical Fluids, in Chem. Rev., ed. R. Noyori,
1999, 99, 353–634; Symposium on Supercritical Fluids in Ind. Eng.
Chem. Res., 2000, 39, 4441–4907.
2 M. J. Burk, S. Feng, M. F. Gross and W. Tumas, J. Am. Chem. Soc., 1995,
117, 8277; S. Kainz, D. Koch, W. Baumann and W. Leitner, Angew.
Chem., Int. Ed. Engl., 1997, 36, 1628; S. Kainz, A. Brinkmann, W.
Leitner and A. Pfaltz, J. Am. Chem. Soc., 1999, 121, 6421; G. Franciò and
W. Leitner, Chem. Commun., 1999, 1663; G. Franciò, K. Wittmann and
W. Leitner, J. Organomet. Chem., 2001, 621, 130.
3 (a) D. A. Canelas, D. E. Betts and J. M. DeSimone, Macromolecules,
1996, 29, 2818; (b) Y.-M. Yong, W. P. Hems, J. L. M. van Nunen, A. B.
Holmes, J. H. G. Steinke, P. L. Taylor, J. A. Segal and D. A. Griffin,
Chem. Commun., 1997, 1811; (c) G. B. Jacobson, C. T. Lee, Jr., K. P.
Johnston and W. Tumas, J. Am. Chem. Soc., 1999, 121, 11902; (d) M. R.
Giles, J. N. Hay, S. M. Howdlej and R. J. Winder, Polymer, 2000, 41,
6715; (e) S. L. Wells and J. DeSimone, Angew. Chem., Int. Ed., 2001, 40,
518.
4 See for example: S. Kobayashi, T. Wakabayashi, S. Nagayama and H.
Oyamada, Tetrahedron Lett., 1997, 38, 4559; S. Kobayashi, Y. Mori, S.
Nagayama and K. Manabe, Green Chem., 1999, 175; K. Manabe and S.
Kobayashi, Org. Lett., 1999, 1, 1965; K. Manabe and S. Kobayashi,
Tetrahedron Lett., 1999, 40, 3773; K. Manabe, Y. Mori and S.
Kobayashi, Tetrahedron, 1999, 55, 11203; K. Manabe, Y. Mori, T.
Wakabayashi, S. Nagayama and S. Kobayashi, J. Am. Chem. Soc., 2000,
122, 7202; S. Kobayashi, W. Lam and K. Manabe, Tetrahedron Lett.,
2000, 41, 6115; K. Manabe, N. Aoyama and S. Kobayashi, Adv. Synth.
Catal., 2001, 343, 174; Y. Mori, K. Manabe and S. Kobayashi, Angew.
Chem., Int. Ed., 2001, 40, 2815.
5 S. Kobayashi and H. Ishitani, J. Chem. Soc., Chem. Commun., 1995,
1379; S. Kobayashi, H. Ishitani, S. Komiyama, D. C. Oniciu and A. R.
Katritzky, Tetrahedron Lett., 1996, 37, 3731.
6 J. Matsuo, T. Tsuchiya, K. Odashima and S. Kobayashi, Chem. Lett.,
2000, 178.
7 S. Kobayashi, I. Hachiya, H. Ishitani and M. Araki, Synlett, 1993, 472.
8 K. Chandler, C. W. Culp, D. R. Lamb, C. L. Liotta and C. A. Eckert, Ind.
Eng. Chem. Res., 1998, 37, 3252.
A typical experimental procedure is described for the reaction
of imine 1 with silyl enolate 2: 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 1 (103 mg, 0.53
mmol), silyl enolate 2 (113 mg, 0.65 mmol) and poly(ethylene
glycol) (44 mg, average Mw = 400) were mixed in a small
ampoule and put in the autoclave separately to prevent reactions
Chem. Commun., 2001, 1842–1843
1843