Michael addition reactions of acetoacetates and malonates with acrylates in water under strongly alkaline conditions

Article abstract of DOI:10.1016/j.tetlet.2005.07.045

Michael addition reactions of acetoacetates and malonates with acrylates in a 5 M KOH aqueous solution without using any other catalysts are described. When they are either tert-butyl or benzyl esters, the reaction proceeded very rapidly to afford moderate to high yields of the corresponding bis-Michael adducts that are unexpectedly stable under these conditions.

Full text of DOI:10.1016/j.tetlet.2005.07.045

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6275–6277
Michael addition reactions of acetoacetates and malonates with
acrylates in water under strongly alkaline conditions
Michiko Iwamura,* Yuka Gotoh, Tomoyuki Hashimoto and Reiko Sakurai
Department of Biomolecular Science, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan
Received 1 June 2005; revised 12 July 2005; accepted 13 July 2005
Available online 27 July 2005
Abstract—Michael addition reactions of acetoacetates and malonates with acrylates in a 5M KOH aqueous solution without using
any other catalysts are described. When they are either tert-butyl or benzyl esters, the reaction proceeded very rapidly to afford mod-
erate to high yields of the corresponding bis-Michael adducts that are unexpectedly stable under these conditions.
Ó 2005 Elsevier Ltd. All rights reserved.
Whereas water is an environmentally benign, non-toxic,
and cheaper solvent than any other organic solvents, its
use as the solvent for organic reactions has been quite
limited until the most recent decade. Since then, there
are numerous reports on the reactions successfully
carried out in water in the presence of newly developed
catalysts or surfactants.1,2 Many of these reports refer to
superior properties of water over organic solvents such
as the ability to increase reaction rate or yield, or to
decrease the steps of the workup procedure. Michael
addition reaction is one of the most frequently studied
reactions found to be suitable for the reaction in
water.3–6 However, there has been a limited number of
reports on the reactions in water under simply basic
conditions.7,8 In this letter, we report an efficient
Michael reaction of acetoacetates and malonates with
acrylates in KOH aqueous solution without any kind
of organometallic catalysts.
Although 1 was obtained in high yield, 1 was often
contaminated with yellowish substance (structure
unidentified), which required time-consuming column
chromatographic process for separation. However, 1
has to be supplied in bulk by the simple purification pro-
cess since it is the starting material for the synthesis of
our dendrimers. Looking for more efficient and by-prod-
uct-free reaction procedure, we found that the reaction
proceeded efficiently in 5–7 M KOH aqueous solution
within 2 h to give almost pure and colorless 1 in over
60% yield. In addition to the often referred advantages
of using water as a solvent, this procedure has the fol-
lowing remarkable features compared with other reac-
tions in water: (1) no organometallic or phase-transfer
catalyst used by many others is necessary, (2) although
both the starting materials and the product are esters,
hydrolysis is almost suppressed during the reaction, (3)
the reaction proceeded very rapidly. We then investi-
gated the optimum reaction conditions and the avail-
ability of this reaction medium to the Michael reaction
of other compounds.
In the course of our investigations to design and synthe-
size new polyester dendrimers, we found that the
Michael reaction of benzyl acetoacetate with tert-butyl
acrylate in the presence of t-BuOK in THF gave bis-
adduct 1 (see Eq. 1 in Table 1) in over 90% yield. The
new polyester dendrimers were successfully synthesized
using the AB2 type building block derived from subse-
quent hydrogenolysis and decarboxylation of 1.9
The dependency of the product yield on the concentra-
tion of KOH was first tested and the results are shown
in Table 1.10 The reaction in a 5M KOH solution at
room temperature gave the adduct 1 in the highest yield
(entry 4). Although the reaction at 40 °C also afforded 1
in good yield (entry 5), the reaction at 0 °C proceeded
very slowly to give a trace amount of 1. The reactions
in solutions of higher than 5M resulted in lower yields
(entries 6 and 7). While any kind of reaction products
was obtained from the organic extract from a 0.1 M
KOH solution, a very small amount of the organic
Keywords: Michael reactions; 5M KOH aqueous solution; Aceto-
acetate; Malonate; Acrylate.
*
Corresponding author. Tel.: +81 474727562; fax: +81 474751855;
e-mail: michiko@biomol.sci.toho-u.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.045

6276
M. Iwamura et al. / Tetrahedron Letters 46 (2005) 6275–6277
Table 1. Dependency of concentration of aqueous KOH and temperaturea
O
O
O
O
O
O
aq.KOH
2.5 h
O
O
2
+
ð1Þ
O
O
OBn
OBn
1
Entry
KOH aq (M)
T (°C)
Yield of 1 (%)
b
1
2
0.1
1
20
20
—
11
3
4
55
6
50
520
63
7
Trace
68
40
20
20
42
38c
7
10
a Benzyl acetoacetate (0.13 mmol) and tert-butyl acrylate (3.9 mmol) were reacted in a KOH aqueous solution (3 mL). After the reaction, the product
was isolated by chromatography.
b Almost no reaction took place.
c Yield after 24 h of reaction.
extract consisting of both 1 and mono-adduct 2 was
collected from a 1 M KOH solution suggesting that
hydrolysis of the esters is the major reaction.
same level thereafter up to 240 min, suggesting that 1 is
stable against hydrolysis under these conditions.
Although a small amount of mono-adduct 2 was found
in the organic extracts of the reactions for 15and 30 min
when enough acetoacetate remained unreacted in the
reaction medium, it was completely converted to 1 as
the reaction proceeded. The amount of benzyl alcohol
was increased during the first stage of the reaction and
stayed almost constant after 60 min. Since the increase
of benzyl alcohol is almost coincident with the decrease
of benzyl acetoacetate, benzyl alcohol is mainly derived
from the hydrolysis of the acetoacetate but not from 1.
We next examined the time dependency of the product
yield in a 5M KOH solution. The reaction was stopped
after certain intervals and the reaction mixture was
extracted with AcOEt. The total weight was measured
after washing and evaporation of the solvent under
reduced pressure. The amount (%) of constituents of
the organic extracts was calculated from the NMR spec-
tra that consisted of the signals assigned to 1, benzyl
alcohol, benzyl acetoacetate, and/or mono-adduct 2.
Although tert-butyl acrylate was detected by the HPLC
analysis of the organic extract before evaporation, it was
not found in NMR spectra taken after evaporation. As
shown in Figure 1, benzyl acetoacetate was almost con-
sumed and the yield of 1 reached over 80% after 90 min.
Contrary to our expectation, the yields of 1 stayed at the
Several examples of the Michael reactions in a KOH
solution are summarized in Table 2. While the reactions
of tert-butyl acetoacetate with benzyl or tert-butyl acryl-
ate proceeded as well (entries 1 and 2), the reaction of
ethyl acetoacetate with tert-butyl acrylate resulted in
hydrolysis of acetoacetate (entry 3). Therefore, the
100
O
O
AcCH2CO2Bn
80
O
O
O
O
1
OBn
60
40
1
O
O
O
BnOH
2
20
0
O
OBn
2
0
60
120
180
240
Time (min)
Figure 1. Change in amount (%) of constituents of organic extract with progress of the reaction (1).

M. Iwamura et al. / Tetrahedron Letters 46 (2005) 6275–6277
Table 2. Michael reactions in aqueous KOH solutiona
6277
Entry
R
R0
R00
Time (h)
Yieldb (%)
1
2
3
4
Me
Me
Me
BnO
Bn
t-Bu
t-Bu
Et
Bn
Bn
Bn
2.573
2.579
2.5Hydrolyzed
1.0
t-Bu
t-Bu
t-Bu
1.0
c
75
d
e
f
5BnO
—
6
7
8
t-BuO
t-BuO
MeO
t-Bu
t-Bu
Me
Bn
Bn
t-Bu
2.582
2.580
2.5Hydrolyzed
c
a Reactions were conducted on a dicarbonyl compound (0.13 mmol) and acrylate (0.39 mmol) in 3 mL of 5–7 M KOH solution.
b Isolated yields.
c The organic layer was disappeared.
d No reaction occurred.
e Mono-adduct was obtained.
f Bis-adduct obtained from the reaction in 7 M KOH.
presence of the protecting groups stable under strongly
basic conditions such as benzyl or tert-butyl is necessary
for the reaction. The similar situation was found for
malonates (entries 4–7). Dibenzyl and di-tert-butyl mal-
onate reacted with tert-butyl and benzyl acrylate,
respectively, to afford bis-adducts (entries 4 and 5),
which can be useful precursors of tricarboxylates having
one free and two protected carboxyl groups. Due to
lower acidity of a-hydrogen of 1,3-diester (pKa ꢀ 13)
than that of 1,3-ketoester (pKa ꢀ 11), the reaction of
dibenzyl malonate in a 5M KOH solution gave a
mono-adduct as a major product, and a 7 M KOH solu-
tion is necessary to obtain a satisfactory yield of bis-
adduct.
References and notes
1. (a) Grieco, P. A. Organic Synthesis in Water; Blackie
Academic and Professional: London, 1998; (b) Li, C.-J.;
Chan, T.-H. Organic Reactions in Aqueous Media; John
Wiley & Sons: New York, 1997.
2. Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35,
209–217.
3. Keller, E.; Feringa, B. L. Tetrahedron Lett. 1996, 37,
1879–1882.
4. Mori, Y.; Kakumoto, K.; Manabe, K.; Kobayashi, S.
Tetrahedron Lett. 2000, 41, 3107–3111.
5. Shimizu, S.; Shirakawa, S.; Suzuki, T.; Sasaki, Y. Tetra-
hedron 2001, 57, 6169–6173.
6. (a) Naidu, B. N.; Sorenson, M. E.; Connolly, T. P.; Ueda,
Y. J. Org. Chem. 2003, 68, 10098–10102; (b) Naidu, B. N.;
Li, W.; Sorenson, M. E.; Connolly, T. P.; Wichtowski, J.
A.; Zhang, Y.; Kim, O. K.; Matiskella, J. D.; Lam, K. S.;
Bronson, J. J.; Ueda, Y. Tetrahedron Lett. 2004, 45, 1059–
1063.
7. Elder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed.
Engl. 1971, 10, 496–497.
8. Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2003, 68,
9173–9176.
In summary, Michael reactions of acetoacetates and
malonates with acrylates proceeded smoothly to afford
bis-adducts in an aqueous 5–7 M KOH solution, when
they are the esters of benzyl or tert-butyl that are fairly
stable in strongly basic solution. As far as we know, this
is the first example of Michael reactions successfully car-
ried out in a strongly alkaline aqueous solution to afford
a bis-adduct without a noticeable amount of by-prod-
ucts. Although its application is rather limited for the
time being, it will offer a new concept for the reaction
in a strongly basic aqueous medium. Application of this
simple procedure to other reactions are now in progress
in our laboratory.
9. Hirayama, Y.; Nakamura, T.; Uehara, S.; Sakamoto, Y.;
Yamaguchi, K.; Sei, Y.; Iwamura, M. Org. Lett. 2005, 7,
525–529.
10. A typical experimental procedure for the Michael reaction
in a 5M KOH solution is described: To a mixture of
benzyl acetoacetate (25mmol) and tert-butyl acrylate
(75mmol), 40 mL of 5M KOH aqueous solution is
added. The emulsified reaction mixture is stirred at room
temperature for 2 h to give a clear organic layer separated
from the aqueous layer. Then the organic layer is
separated and the aqueous layer is extracted with ethyl
acetate. The combined organic extract is washed
with water, 1 M HCl, and brine successively and
dried over MgSO4. The solution is concentrated under
reduced pressure and chromotographed on silica-gel to
afford 1.
Supplementary data
Experimental procedure for the syntheses of 1, 1H NMR
of 1, 2, and bis-adducts made by the reactions in Table 2
are available. Supplementary data associated with this
article can be found, in the online version at
doi:10.1016/j.tetlet.2005.07.045.