Application of high pressure induced by water-freezing to the Michael reaction of alcohols with α,β-enones

Article abstract of DOI:10.1246/cl.2002.296

High pressure (about 200MPa), which was realized by freezing water in a sealed autoclave, has been successfully applied to a high-yield Michael reaction of alcohols and α,β-unsaturated ketones in the presence of a catalytic amount of DMAP and LiClO₄. Only a moderate yield was obtained under atmospheric pressure.

Full text of DOI:10.1246/cl.2002.296

296
Chemistry Letters 2002
Application of High Pressure Induced by Water-freezing to
the Michael Reaction of Alcohols with ꢀ,ꢁ-Enones
Yujiro Hayashiꢀ and Koichi Nishimura
Department of Industrial Chemistry, Faculty of Engineering, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received December 21, 2001; CL-011282)
High pressure (about 200 MPa), which was realized by
freezing water in a sealed autoclave, has been successfully
applied to a high-yield Michael reaction of alcohols and ꢀ,ꢁ-
unsaturated ketones in the presence of a catalytic amount of
DMAP and LiClO4. Only a moderate yield was obtained under
atmospheric pressure.
tetramethylguanidine and NaOMe13 was investigated. Among the
bases examined, DMAP gave the best result but the yield was not
satisfactory (ꢃ30%).14 To improve the yield, various metal
salts15 were screened as additives. Lithium salts, especially
LiClO4 (52%) and LiBF4 (53%), were found to give good results.
Further investigation of the reaction conditions including molar
ratio of the reagents and reaction time revealed that the reaction of
2-cyclohexen-1-one with 3equiv of BnOH in the presence of
10 mol% of each DMAP and LiClO416 under the pressure induced
by water-freezing for 85 h17 gave the desired Michael adduct
nearly quantitatively (97%, Table 1, entry 1).
Pressure is one of the important factors affecting the rate of
organic reactions, especially many reactions with a large,
negative volume of activation.1 High pressure technology has
become an indispensable tool in organic synthesis, though
specialized, expensive apparatus is necessary to carry out
reactions under high pressure. Hence the development of more
convenient techniques for performing high pressure reactions is
desirable.
Scheme 1.
The volume of water increases about 10% on freezing. When
water is frozen in a sealed autoclave, a high pressure of up to about
200 MPa can be realized. Recently, this pressure has been
elegantly utilized for the inactivation of microorganisms by
Hayakawa et al.2 This paper describes the first application of the
pressure induced by water-freezing to accelerate organic reac-
tions.
Table 1. The effect of pressure and temperature on yielda
Entry
Pressure/atm
Temp./ꢂC
Yield/%b
1
2
3
4
2000
ꢁ20
ꢁ20
20
97
55
56
18
1
1
1
50
The Michael reaction of alcohols and ꢀ,ꢁ-enones under basic
conditions is one of the hardest synthetic transformations to
achieve efficiently, because the product ꢁ-alkoxy ketones easily
revert to the starting materials via the retro Michael reaction. To
overcome this, a large excess of Michael donor is generally
employed.3 There are, however, successful examples of this
reaction under strong basic conditions employing the reactive
Michael acceptor4 and non-basic conditions using Pd(II)
catalyst.5 As the Michael reaction is known to be accelerated by
the high pressure owing to the large negative volume of
activation6 and the product ꢁ-alkoxy ketones are useful
intermediates for natural product synthesis, the pressure induced
by water-freezing was first applied to this reaction.
aReaction conditions: molar ratio; 2-cyclohexen-1-one : BnOH :
DMAP : LiClO4 ¼ 1 : 3 : 0:1 : 0:1. bIsolated yield.
To confirm the effect of pressure, the same reaction was
performed at atmospheric pressure at ꢁ20, 20, and 50 ꢂC without
changing the other reaction parameters. The results are shown in
Table 1. Under atmospheric pressure, the product was isolated in
about 55%yield bothat ꢁ20 and 20 ꢂC. This yield didnotincrease
further with longer reaction times. On the other hand, the yield
decreased at higher temperature because of the side reactions
(50 ꢂC). When the purified Michael product and 2 equiv of BnOH
were treated with 10 mol% of DMAP and LiClO4 for 85 h at
20 ꢂC, the Michael product was recovered in 70% yield along with
2-cyclohexen-1-one in 25%. This result clearly indicates that the
present Michael reaction is an equilibrium, and that high pressure
shifts this equilibrium towards the formation of the Michael
adduct, giving the product in good yield.
Next, the present method was applied to other ꢀ,ꢁ-
unsaturated ketones, the results being summarized in Table 2.
Though 2-cyclopenten-1-one gave a poor result, other cyclic
enones such as 2-cyclohepten-1-one and 2-cycloocten-1-one
were found to react effectively to afford the Michael products in
good yields. Not only cyclic enones, but also acyclic enones are
suitable acceptors. Moreover the latter are found to react much
faster than the former. 1-Phenyl-2-buten-1-one, 3-nonen-2-one
and 3-hepten-2-one gave the Michael products in good yields
after 13 h. In contrast to these successful results, ꢀ-substituted
ꢀ,ꢁ-unsaturated ketones such as 3-methyl-3-penten-2-one and
The reaction of benzyl alcohol (BnOH) with 2-cyclohexen-1-
one was selected as a model. It was performed as follows: To a
1 mL Teflon tube7 was added BnOH, 2-cyclohexen-1-one, base
and additive (vide infra), and the tube was capped with exclusion
of air. This tube was placed in an autoclave(capacity about
100 mL),8 and equipped with a pressure monitor.9 The autoclave
was completely filled with water, sealed tightly, and left in a
household electric refrigerator at ꢁ20 ꢂC.10 It was found that the
internal pressure reached about 200 MPa after 12 h. After a given
time, the autoclave was taken out of the refrigerator, and the
Teflon tube was removed from the autoclave. Volatile organic
materials were removed under reduced pressure, after which
purification by column chromatography on Florisil afforded the
Michael product.11
First, the use of bases such as DMAP,12 DBU,12 DABCO,12
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
297
carvone, and ꢀ,ꢁ-unsaturated esters such as tert-butyl crotonate
and dibenzyl fumarate did not react with BnOH under the present
high pressure conditions.
pressure induced by water-freezing has several noteworthy
features: Only an autoclave and a household electric refrigerator
are required to achieve the high pressure, no specialized or
expensive apparatus is needed, which makes this high pressure
technology easily available to the average laboratory. Scale-up
would be easy compared to the usual high pressure technology.
Further studies of the application of the pressure induced by
water-freezing to organic synthesis are under way.
Table 2. Michael reaction of ꢀ,ꢁ-enone and BnOH under the pressure
induced by water-freezinga
This work was supported by the Iwatani Naoji foundation and
Grants-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, of Japan.
The authors thank Dr. Kiyoshi Hayakawa of the Kyoto
Prefectural Comprehensive Center for Small and Medium
Enterprises for instruction concerning the pressure induced by
water-freezing and a generous gift of autoclaves.
This paper is dedicated to Professor T. Mukaiyama on the
occasion of his 75th birthday.
References and Notes
1
Review, see: K. Matsumoto, M. Kaneko, H. Katsura, N. Hayashi, T.
Uchida, and R. M. Acheson, Heterocycles, 47, 1135 (1998); M. Ciobanu
and K. Matsumoto, Liebigs Ann. Recueil, 1997, 623; K. Matsumoto, A.
Sera, and T. Uchida, Synthesis, 1985, 1; K. Matsumoto and A. Sera,
Synthesis, 1985, 999; R. J. Giguere, in ‘‘Organic Synthesis Theory and
Applications,’’ ed. by T. Hudlicky, JAI Press Inc., London (1989),
Vol. 1.
2
3
K. Hayakawa, Y. Ueno, S. Kawamura, T. Kato, and R. Hayashi, Appl.
Microbiol. Biotechnol., 50, 415 (1998).
A. Bernardi, S. Cardani, C. Scolastico, and R. Villa, Tetrahedron, 46,
1987 (1990); C. Fehr and O. Guntern, Helv. Chim. Acta, 75, 1023
(1992). Because of the difficulty of the Michael reaction of an alcohol or
alkoxide with ꢀ,ꢁ-unsaturated carbonyl compounds, a two step
sequence of alkoxymercuration-demercuriation is generally employed,
see; S. Thaisrivongs and D. Seebach, J. Am. Chem. Soc., 105, 7407
(1983).
The generality of this reaction with respect to the Michael
donor, alcohol, was examined as summarized in Table 3. The
lower yield observed for 4-methoxybenzyl alcohol is due to the
high viscosity of the reaction media at ꢁ20 ꢂC with this alcohol
which melts at 24 ꢂC. Though 1-phenyl-1-ethanol did not react
with 2-cyclohexen-1-one, probably owing to steric effects, other
alcohols such as MeOH, EtOH, and allyl alcohol were found to be
good Michael donors, reacting with 2-cyclohexen-1-one to afford
the products in good yields. As BnOH and allyl alcohol, which are
both masked water equivalents,18 are good Michael donors, their
reactions are equivalent to hydroxylation of water to ꢀ,ꢁ-
unsaturated carbonyl compounds, water itself being a poor
Michael donor.
4
5
T. Mikami, T. Iwaoka, M. Kato, H. Watanabe, and N. Kubodera, Synth.
Commun., 27, 2363 (1997).
T. Hosokawa, T. Shinohara, Y. Ooka, and S. Murahashi, Chem. Lett.,
1989, 2001.
G. Jenner, NewJ. Chem., 23, 525(1999), and seereviewsinReference1.
The Teflon tube is made by Hikari Koatu Kiki Co. Ltd. Hiroshima,
Japan.
6
7
8The autoclave is made by Atlas Co. Ltd. Tokyo, Japan and its size is as
follows; 78mm outside diameter, 340 mm height, 25 mm inside
diameter, and 200 mm depth.
9 KH78, Naganokeiki Co. Ltd., Tokyo, Japan.
10 Occasional stirring is not necessary.
11 When the Michaelproduct, 3-benzyloxycyclohexan-1-one, waspurified
by column chromatography on silica gel, the retro Michael reaction
proceeded in part with a concomitant decrease in yield.
12 DMAP ¼ 4-(N,N-dimethylamino)pyridine,
DBU ¼ 1,8-diazabicy-
Table 3. The Michael reaction of various alcohols and of water with 2-
cyclohexen-1-one under the pressure induced by water-freezinga
clo[5.4.0]undec-7-ene, DABCO ¼ 1,4-diazabicyclo[2.2.2]octane.
13 In the case of NaOMe, MeOH was used as the Michael donor instead of
BnOH.
Alcohols
Yield/%b
Alcohols
Yield/%b
14 Reaction conditions are as follows; molar ratio; 2-cyclohexen-1-
one : BnOH : DMAP ¼ 1 : 1:7 : 0:1, reaction time is 15 h.
15 The amount of additive is 10 mol%. The yields for the other additives
examined are as follows; LiCl 41%, LiBr 41%, LiI 43%, LiOHꢄH2O
25%, LiNO2 39%, NaCl 33%, NaI 29%, KCl 14%, K2CO3 41%, MgCl2
0%, NH4Cl 16%, BaOHꢄ8H2O 34%, Yb(OSO2CF3)3 25%,
Sc(OSO2CF3)3 18%.
16 Without DMAP, the reaction did not proceed at all even in the presence
of LiClO4.
17 The yields for other reaction times are as follows; 61% (15 h), 79%
(35 h).
PhCH2OH
MeOH
EtOH
97
93
86
CH2 ¼ CHCH2OH
p ꢁ CH3OPhCH2OH
H2O
72
57
3–10
aReaction conditions: molar ratio; 2-cyclohexen-1-one : alcohol :
DMAP : LiClO4 ¼ 1 : 3 : 0:1 : 0:1, reaction time is 85 h. bIsolated
yield.
In summary, we have successfully applied the high pressure
induced by water-freezing to the Michael addition of alcohols to
ꢀ,ꢁ-unsaturated ketones. The combined use of a catalytic amount
of DMAP and LiClO4 is a key to the success of this reaction. The
18T. W. Greene and P. G. M. Wuts, ‘‘Protective Groups in Organic
Synthesis,’’ 3rd ed., John Wiley & Sons, New York (1999).