Morita-baylis-hillman reaction on water without organic solvent, assisted by a 'catalytic' amount of amphiphilic imidazole derivatives

Article abstract of DOI:10.1055/s-0029-1216944

A Morita-Baylis-Hillman (MBH) reaction using water as a solvent without any organic solvent can be performed by using an amphiphilic N-alkylimidazole. This reaction is accelerated by the addition of water and is the first example of a 'catalytic' MBH reaction without organic solvent in the presence of water.

Full text of DOI:10.1055/s-0029-1216944

PAPER
3219
Morita–Baylis–Hillman Reaction on Water without Organic Solvent,
Assisted by a ‘Catalytic’ Amount of Amphiphilic Imidazole Derivatives
A
K
mphiphilic Imida
e
zole
A
ssis
i
tedMo
s
rita–Bayli
u
s–HillmanR
k
eactionsonW
e
ate
r
Asano, Seijiro Matsubara*
Department of Material Chemistry, Kyoto University, Kyoutodaigaku-katsura, Nishikyo, Kyoto 615-8510, Japan
Fax +81(75)3832459; E-mail: matsubar@orgrxn.mbox.media.kyoto-u.ac.jp
Received 24 April 2009; revised 25 May 2009
tor and organic solvents were also often used as a co-sol-
Abstract: A Morita–Baylis–Hillman (MBH) reaction using water
as a solvent without any organic solvent can be performed by using
an amphiphilic N-alkylimidazole. This reaction is accelerated by the
vent.7
h–l,8b
To solve this contradiction, we designed an
imidazole11 carrying a hydrophobic group,
6,7j,9
because
addition of water and is the first example of a ‘catalytic’ MBH re- aggregation of the amphiphilic compounds in water will
action without organic solvent in the presence of water.
form a hydrophobic phase, which may work as protection
for the nucleophilic catalyst from deactivation by water.
Key words: Morita–Baylis–Hillman reaction, organocatalyst,
water, imidazole, amphiphilic catalyst
We examined the reaction between benzaldehyde (2a)
and methyl vinyl ketone (3) using a stoichiometric amount
of an imidazole derivative and water as the solvent
The use of water as a solvent for organic reactions has (Scheme 2). Although N-methylimidazole 5a afforded
been important since the pioneering work by Breslow.1 only a trace amount of the product 4a, N-tetradecylimida-
Some practical reasons, such as cost, safety, and environ- zole 5b gave 4a in 37% yield. This suggests that the intro-
mental concerns, can be mentioned specially. Moreover, duction of a tetradecyl group to an imidazole will make
water as a solvent often benefits the organic reaction itself the reaction using water possible.
2
dynamically. The high polarity of water may stabilize an
3
ionic intermediate. In addition, the hydrophobicity of an
organic compound will give rise to cohesion of substrates,
O
OH
O
O
catalyst (0.5 mmol)
H2O (9.0 mmol)
4
H
which often enhances the reaction rate. The use of water
as a solvent has been expanded even to the areas of orga-
nometallic chemistry, which include air- and water-
sensitive species. As the chemistry of organocatalytic re-
actions has been developed in recent years, the arguments
about the contribution of water to these reactions have
been rekindled. In the reaction with an organocatalyst,
an ionic intermediate is inevitable, so the use of water may
+
2
5 °C, 12 h
2
a (0.5 mmol)
3 (1.0 mmol)
4
a
Yield (%) of 4a
<1
5
Catalyst
6
,7
N
N
(
5a)
N
N
Me
6
,7,8b
be effective.
(5b)
37
The Morita–Baylis–Hillman (MBH) reaction is a useful
method of C–C bond formation using an organocatalyst.8
The reaction is, however, notoriously slow and there have Scheme 2 MBH reaction between benzaldehyde and methyl vinyl
been many attempts to accelerate the reaction, some of
which have used water.
C14H29
–10
ketone using a stoichiometric amount of imidazole derivatives in the
presence of water
7
h–l,8b,9,10
The reaction is initialized
9
,10
by an amine or phosphine (Scheme 1) and the forma-
tion of a betaine intermediate 1 is a crucial step. In order To improve the yield, we examined the addition of a cat-
to stabilize such an ionic intermediate, one can use water alytic amount of Brønsted acid. As shown in Table 1,
as a solvent. However, the addition of water may depress Brønsted acids whose pK values are around 9 were effec-
a
the nucleophilicity of the amine. Actually, the reported tive in promoting this reaction (Table 1, entries 4–6, 8–
methods that show rate enhancements for MBH reactions 10). The added acid should activate methyl vinyl ketone
in the presence of water used excess nucleophilic media- without deactivation of the imidazole derivative. Among
R2
R2
OH
O
2
1
1
R CHO
R 3N
O
R 3N
O
1
+
O
R 3N
1
R 3N
O
1
Scheme 1 Schematic Morita–Baylis–Hillman reaction catalyzed by an amine
SYNTHESIS 2009, No. 19, pp 3219–3226
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216944; Art ID: F08809SS
Georg Thieme Verlag Stuttgart · New York
©

3
220
K. Asano, S. Matsubara
PAPER
Table 1 MBH Reaction between Benzaldehyde (2a) and Methyl Vinyl Ketone (3) in the Presence of a Brønsted Acida
N
N
C14H29 (5b, 100 mol%)
O
OH
O
O
additive
+
H
H2O, 25 °C, 12 h
2a
3
4a
b
Entry
Additive (mol%)
pK in H O
Yield (%)
a
2
1
2
3
4
5
6
7
8
9
0
TFA (20)
–0.25
39
49
37
51
54
52
46
61
64
63
Cl CCO H (20)
0.65
4.2
7.1
9.3
10
3
2
BzOH (20)
4-O NC H OH (20)
2
6
4
(CF ) CHOH (6) (20)
3
2
PhOH (20)
CF CH OH (20)
12
3
2
(CF ) CHOH (6) (40)
9.3
9.3
9.3
3
2
(CF ) CHOH (6) (60)
3
2
1
(CF ) CHOH (6) (100)
3 2
a
Benzaldehyde (2a, 0.5 mmol), methyl vinyl ketone (3, 1.0 mmol), N-tetradecylimidazole 5b (0.5 mmol), H O (9.0 mmol).
Isolated yield.
2
b
Table 2 MBH Reaction Between Benzaldehyde (2a) and Methyl
Vinyl Ketone (3) Using a Catalytic Amount of N-Tetradecylimida-
zole 5ba
use of 20 mol% of N-alkylimidazole 5b was shown to give
a reasonable yield of the product (Table 2, entry 5).
The amount of water was optimized under catalytic con-
ditions using 20 mol% of N-alkylimidazole 5b (Table 3).
It is noteworthy that without water the yield decreased to
N
N
OH
O
O
C14H29 (5b)
O
3
7%, while the reaction using 2.5 mmol of water afforded
(
CF3)2CHOH (6, 20 mol%)
H
+
4a in 67% yield (Table 3, entries 1 and 2). The amount of
water did not have a reasonable influence on the yield, and
in any case, water worked for the acceleration of the reac-
tion (Table 3, entries 2–10). Although a stoichiometric
H2O, 25 °C, 12 h
4
a
3
2a
b
Entry
Catalyst loading (mol%) Yield (%)
amount of nucleophile was required for acceleration by
water in reported MBH reactions,7
h–l,8b
we could construct
1
2
3
4
5
6
100
50
40
30
20
10
54
53
55
57
65
41
a ‘catalytic MBH reaction’ in the presence of water by us-
ing N-tetradecylimidazole 5b. This can be attributed to its
aggregation in water. The aggregation makes a hydropho-
bic space by the tetradecyl groups, in which nucleophilic
species are protected from deactivation by water, such as
protonation. In addition, the aggregation may also help the
reaction by placing organic substrates in close proximity.
1
,4-Diazabicyclo[2.2.2]octane and 4-(dimethylamino)py-
ridine, which have been regarded as efficient for MBH re-
actions, were also examined under our conditions; neither
of them were effective catalysts (Scheme 3). Nucleo-
philes should be endowed with amphiphilicity for MBH
a
Benzaldehyde (2a, 0.5 mmol), methyl vinyl ketone (3, 1.0 mmol),
1
,1,1,3,3,3-hexafluoropropan-2-ol (6, 0.1 mmol), H O (9.0 mmol).
2
b
Isolated yield.
them, 1,1,1,3,3,3-hexafluoropropan-2-ol (6) gave the best reactions using water.
results (Table 1, entry 5). The amount of acid was also op-
timized and the results revealed that 20 mol% was suffi-
cient for the reaction (Table 1, entries 5, 8–10).
Then we examined the effect created by modification of
the hydrophobic groups in the catalyst (Table 4). The
lengths of carbon chains were arranged from C1 to C16
We also tried to decrease the stoichiometric amount of the (Table 4, 5a–f, entries 1–6). Imidazoles with alkyl groups
imidazole derivative to a catalytic amount (Table 2). The more than C10 showed acceptable yields. No reasonable
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

PAPER
Amphiphilic Imidazole Assisted Morita–Baylis–Hillman Reactions on Water
3221
O
OH
O
nucleophile (20 mol%)
CF3)2CHOH (6, 20 mol%)
O
(
H
+
H2O (8.0 mmol), 25 °C, 12 h
2a (0.5 mmol)
3 (1.0 mmol)
4a
nucleophile: DABCO
DMAP
<1%
6%
Scheme 3 MBH reaction between benzaldehyde (2a) and methyl vinyl ketone (3) using DABCO and DMAP in the presence of water
Table 3 Optimization of the Amount of Water for MBH Reaction
Between Benzaldehyde (2a) and Methyl Vinyl Ketone (3) Catalyzed
by N-Tetradecylimidazole 5b
out stirring. The nonstirred reaction in a wider vial (i.d. 20
mm) gave the same yield of 4a as the vigorous stirred re-
action. However, if the nonstirred reaction was performed
in a narrower vial (i.d. 5 mm), the yield of 4a decreased to
50%.
a
N
N
OH
O
O
C14H29 (5b, 20 mol%)
O
These results showed that stirring was not necessary to
carry out the reaction under our conditions if there was
sufficient surface area where the water and organic phase
were contiguous. It seems to be important that the reaction
proceeded in the range of the organic phase that is close to
the surface of the water. In other words, this reaction can
(
CF3)2CHOH (6, 20 mol%)
H
+
H2O, 25 °C, 12 h
4
a
3
2a
b
Entry
H O (mmol)
Yield (%)
2
14
1
2
3
4
5
6
7
8
9
0
0
37
67
64
61
65
62
63
62
61
61
be classified as one of the reactions on water. We could
utilize the potential of water to promote an organic reac-
tion by forming a hydrophobic field for the reaction near
the boundary between water and organic compounds, not
by forming emulsions.
2.5
5.0
7.5
Under the optimized conditions, we examined MBH reac-
tions of methyl vinyl ketone (3) with various aldehydes 2
8.0
(
Table 5). The use of aryl aldehydes 2c–e carrying elec-
8.5
tron-withdrawing groups did not effect the yield (Table 5,
entries 2–4). Although the yields were not excellent, we
can show the possibility of MBH reactions that are cata-
lyzed by imidazole derivatives carrying a hydrophobic
group; such reactions are also accelerated by water.
9.0
9.5
10
1
56 (1 mL)
In conclusion, we have shown that some Morita–Baylis–
Hillman reactions in the presence of water are initiated by
a ‘catalytic’ amounts of N-alkylimidazoles; in this reac-
tion, the addition of water accelerated the reaction. The
‘catalytic’ reaction promoted by water was realized by the
amphiphilic imidazole derivatives carrying hydrophobic
groups. The amphiphilic catalyst forms a hydrophobic
field for an organic reaction near the boundary between
the water and the organic compounds by self-assembly.
These results show that such a reaction field constructed
by an amphiphilic organocatalyst near the surface of water
may be widely effective for the acceleration of organocat-
alytic reactions.
a
Benzaldehyde (2a, 0.5 mmol), methyl vinyl ketone (3, 1.0 mmol),
N-tetradecylimidazole 5b (0.1 mmol), 1,1,1,3,3,3-hexafluoropropan-
2
-ol (6, 0.1 mmol).
Isolated yield.
b
differences concerning the yield were observed among
these cases (Table 4, entries 2–6). We also introduced
1
2
fluorine atoms on the carbon chain, and it resulted in
only a slight increase in the yield (Table 4, 5g and 5h, en-
tries 7 and 8). We also tried an unsaturated carbon chain,
but the introduction of a (Z)-olefinic group in the middle
of the chain did not create any remarkable effect (Table 4,
5
i, entry 9).
1
NMR spectra were taken on a Varian Unity Inova 500 ( H, 500
In these reactions, vigorous stirring was not necessary, al-
though many reported reactions using water as a solvent
required it for the formation of emulsions or fine oil
1
3
1
MHz; C, 125.7 MHz) spectrometer using TMS ( H, d = 0) and
CDCl ( C, d = 77.0) as internal standards. F NMR spectra were
measured on a Varian Mercury 200 ( F, 188 MHz) spectrometer
with hexafluorobenzene as an internal standard (d = 0). GC-MS
analyses and HRMS spectra were obtained with a Jeol JMS-700
1
3
19
3
1
9
6
d,13
drops.
As shown in Scheme 4, the reactions of benzal-
dehyde (2a, 0.5 mmol) and methyl vinyl ketone (3, 1.0
mmol) in the presence of N-hexadecylimidazole 5f (0.1 spectrometer by electron ionization at 70 eV. IR spectra were deter-
mmol), 1,1,1,3,3,3-hexafluoropropan-2-ol (6, 0.1 mmol), mined on a Shimadzu FTIR-8200PC spectrophotometer. Melting
points were determined using a Yanako MP-500D. Optical rotations
and water (8.0 mmol) were examined both with and with-
were measured on a Jasco DIP-360.
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

3
222
K. Asano, S. Matsubara
PAPER
Table 4 MBH Reaction between Benzaldehyde (2a) and Methyl Vinyl Ketone (3) Catalyzed by Imidazole Derivatives 5 Having Various
Hydrophobic Groupsa
O
catalyst (20 mol%)
OH
O
O
(CF ) CHOH (6, 20 mol%)
3
2
+
H
H2O, 25 °C, 12 h
2a
3
4a
b
Entry
1
Catalyst
Yield (%)
5a
16
63
61
65
64
64
N
N
N
N
N
N
Me
2
3
4
5
6
5c
5d
5b
5e
5f
C10H21
C12H25
N
N
N
N
C14H29
C15H31
N
N
N
N
C16H33
7
8
5g
Me
F
65
F
F
F F
N
5h
5i
N
F
F
66
62
F
F
F
Me
9
N
N
a
Benzaldehyde (2a, 0.5 mmol), methyl vinyl ketone (3, 1.0 mmol), 1,1,1,3,3,3-hexafluoropropan-2-ol (6, 0.1 mmol), catalyst 5 (0.1 mmol),
H O (8.0 mmol).
2
b
Isolated yields.
Scheme 4 MBH reaction between benzaldehyde (2a) and methyl vinyl ketone (3) with/without stirring.
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

PAPER
Amphiphilic Imidazole Assisted Morita–Baylis–Hillman Reactions on Water
3223
Table 5 MBH Reaction between Various Aldehydes 2 and Methyl Vinyl Ketone (3) Catalyzed by N-Hexadecylimidazole 5f on Water without
Organic Solventa
N
N
C16H33 (5f, 20 mol%)
O
OH
O
O
(CF ) CHOH (6, 20 mol%)
3
2
+
R
H
R
H2O, 25 °C, time
2
3
4
b
Entry
1
Substrate 2
Product 4
Time (h)
Yield (%)
O
OH
O
H
12
37
67
2
b
c
4b
O
OH
O
2
3
4
H
12
12
F
F
2
4c
O
OH
O
H
64
O2N
O2N
2
d
4d
O
OH
O
H
12
12
61
65
N
N
2
e
4e
4f
O
O
OH
OH
O
5
6
H
H
2
2
f
O
24
24
62
63
g
4
4
g
OH
O
O
7
H
2
h
h
a
Aldehyde (2, 0.5 mmol), methyl vinyl ketone (3, 1.0 mmol), N-hexadecylimidazole 5f (0.1 mmol), 1,1,1,3,3,3-hexafluoropropan-2-ol (6, 0.1
mmol), H O (8.0 mmol).
2
b
Isolated yields.
Flash column chromatography was carried out using Kanto Chemi-
cal silica gel (spherical, 40–50 mm). Unless otherwise noted, com-
mercially available reagents were used without purification.
was extracted with EtOAc. The combined organic layers were
washed with brine, dried (Na SO ), and concentrated in vacuo. Pu-
rification by flash column chromatography (silica gel, EtOAc) gave
2
4
the corresponding N-alkylimidazoles in 64–78% yield. The NMR
1
13
N-Alkylimidazoles 5a–i
results ( H, C) are as below.
1
-Methyl-1H-imidazole (5a) was commercially available and used
without any purification.
1-Decyl-1H-imidazole (5c)
CAS [33529-02-1]. Yellow oil; yield: 64%.
N-Alkylimidazoles 5b–f;15 General Procedure
A mixture of imidazole (0.75 g, 11 mmol) and alkyl bromide (11
mmol) in toluene (20 mL) in the presence of TEAI (0.57 g, 2.2
mmol) and NaOH (1.3 g, 33 mmol) was refluxed for 10 h. The re-
1
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
3
(
t, J = 1.0 Hz, 1 H), 3.92 (t, J = 7.5 Hz, 2 H), 1.76 (tt, J = 7.0, 7.0
Hz, 2 H), 1.34–1.20 (m, 14 H), 0.87 (t, J = 7.0 Hz, 3 H).
sulting mixture was cooled to r.t., H O was added, and the mixture
2
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

3
224
K. Asano, S. Matsubara
PAPER
1
3
C NMR (CDCl ): d = 137.1, 129.4, 118.7, 47.0, 31.8, 31.1, 29.5,
1-(12,12,13,13,14,14,15,15,15-Nonafluoropentadecyl)-1H-imi-
dazole (5h)
3
1
6
2
9.4, 29.2, 29.0, 26.5, 22.6, 14.1.
NaH (60%, 0.15 g, 3.7 mmol) was washed with hexane and THF (3
mL) was added. To the soln, a soln of imidazole (0.23 g, 3.4 mmol)
in THF (3 mL) was added slowly at 0 °C. The mixture was stirred
1
-Dodecyl-1H-imidazole (5d)
CAS [4303-67-7]. Orange oil; yield: 66%.
1
at r.t. for 15 min. Then
a
soln of 1-bromo-
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.04 (t, J = 1.0 Hz, 1 H), 6.89
3
1
2,12,13,13,14,14,15,15,15-nonafluoropentadecane (1.5 g, 3.3
(
t, J = 1.0 Hz, 1 H), 3.91 (t, J = 7.0 Hz, 2 H), 1.76 (tt, J = 7.0, 7.0
mmol) in THF (4 mL) was added slowly to the mixture, and it was
stirred for 7 d. The mixture was filtered and the filtrate was concen-
trated in vacuo. Purification by flash column chromatography (sili-
ca gel, EtOAc) gave 5h (1.1 g, 79%) as a colorless oil.
Hz, 2 H), 1.32–1.20 (m, 18 H), 0.87 (t, J = 7.0 Hz, 3 H).
1
3
C NMR (CDCl ): d = 137.0, 129.3, 118.7, 47.0, 31.9, 31.1, 29.6,
3
2
9.5, 29.4, 29.3, 29.0, 26.5, 22.6, 14.1.
IR (neat): 2930, 2857, 1508, 1468, 1356, 1233, 1132, 1076, 1032,
1
-Tetradecyl-1H-imidazole (5b)
–
1
9
07, 880, 847, 812, 733, 719, 664, 625, 592, 532 cm .
1H NMR (CDCl
): d = 7.46 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
t, J = 1.0 Hz, 1 H), 3.92 (t, J = 7.5 Hz, 2 H), 2.04 (m, 2 H), 1.76 (tt,
J = 7.0, 7.0 Hz, 2 H), 1.59 (m, 2 H), 1.39–1.24 (m, 14 H).
19F NMR (CDCl
): d = 80.2 (3 F), 46.9 (2 F), 37.0 (2 F), 35.5 (2 F).
CAS [54004-47-6]. Pale yellow solid; yield: 68%.
1
3
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
t, J = 1.0 Hz, 1 H), 3.91 (t, J = 7.5 Hz, 2 H), 1.76 (tt, J = 7.0, 7.0
3
(
(
Hz, 2 H), 1.34–1.20 (m, 22 H), 0.88 (t, J = 7.0 Hz, 3 H).
1
3
3
C NMR (CDCl ): d = 137.1, 129.4, 118.7, 47.0, 31.9, 31.1, 29.7,
3
+
2
9.62, 29.58, 29.50, 29.4, 29.3, 29.1, 26.5, 22.7, 14.1.
HRMS: m/z [M] calcd for C H F N : 440.1874; found: 440.1874.
18 25 9 2
1
-Pentadecyl-1H-imidazole (5e)
(Z)-1-(Octadec-9-enyl)-1H-imidazole (5i)15
A mixture of imidazole (0.34 g, 5.0 mmol) and (Z)-1-bromoocta-
dec-9-ene (1.7 g, 5.0 mmol) in toluene (10 mL) in the presence of
TEAI (0.26 g, 1.0 mmol) and NaOH (0.60 g, 15 mmol) was refluxed
CAS [130482-55-2]. Pale yellow solid; yield: 70%.
1
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
t, J = 1.0 Hz, 1 H), 3.91 (t, J = 7.0 Hz, 2 H), 1.76 (tt, J = 7.0, 7.0
3
(
for 18.5 h. The resulting mixture was cooled to r.t., H O was added,
2
Hz, 2 H), 1.34–1.20 (m, 24 H), 0.87 (t, J = 7.0 Hz, 3 H).
and the mixture was extracted with EtOAc. The combined organic
layers were washed with brine, dried (Na SO ), and concentrated in
1
3
C NMR (CDCl ): d = 137.1, 129.4, 118.7, 47.0, 31.9, 31.1, 29.66,
3
2
4
2
9.65, 29.63, 29.62, 29.58, 29.50, 29.4, 29.3, 29.1, 26.5, 22.7, 14.1.
vacuo. Purification by flash column chromatography (silica gel,
EtOAc) gave 5i (1.2 g, 75%) as a yellow oil.
1
-Hexadecyl-1H-imidazole (5f)
CAS [90343-81-0].
CAS [58175-55-6]. White solid; yield: 78%.
1H NMR (CDCl
t, J = 1.0 Hz, 1 H), 5.34 (m, 2 H), 3.91 (t, J = 7.0 Hz, 2 H), 2.00 (dt,
J = 6.0, 7.0 Hz, 4 H), 1.76 (tt, J = 7.0, 7.0 Hz, 2 H), 1.36–1.22 (m,
2 H), 0.88 (t, J = 7.5 Hz, 3 H).
): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
1
3
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
3
(
(
t, J = 1.0 Hz, 1 H), 3.92 (t, J = 7.5 Hz, 2 H), 1.76 (tt, J = 7.0, 7.0
Hz, 2 H), 1.34–1.20 (m, 26 H), 0.87 (t, J = 7.0 Hz, 3 H).
1
2
3
C NMR (CDCl ): d = 137.1, 129.4, 118.7, 47.0, 31.9, 31.1, 29.67,
3
13
C NMR (CDCl ): d = 137.1, 130.0, 129.7, 129.4, 118.7, 47.0, 31.9,
3
2
2
9.66, 29.65, 29.64, 29.62, 29.58, 29.50, 29.4, 29.3, 29.1, 26.5,
2.7, 14.1.
3
2
1.1, 29.73, 29.66, 29.5, 29.4, 29.3, 29.1, 29.03, 29.01, 27.2, 27.1,
6.5, 22.7, 14.1.
(
R)-1-(13-Fluorotetradecyl)-1H-imidazole (5g)16
NaH (60%, 0.066 g, 1.65 mmol) was washed with hexane and THF
2 mL) was added. To the soln, a soln of imidazole (0.10 g, 1.5
MBH Reaction between Aldehydes and Methyl Vinyl Ketone;
General Procedure
To a 5-mL vial were added sequentially aldehyde 2 (0.5 mmol),
methyl vinyl ketone (3, 1.0 mmol), imidazole derivative 5 (0.1
(
mmol) in THF (2 mL) was added slowly at 0 °C. The mixture was
stirred at r.t. for 45 min, then a soln of (R)-1-bromo-13-fluoro-
tetradecane (0.44 g, 1.5 mmol) in THF (1 mL) was added slowly to
the mixture, and it was stirred for 7 d. The mixture was filtered and
the filtrate was concentrated in vacuo. Purification by flash column
chromatography (silica gel, EtOAc) gave 5g (0.30 g, 72%) as a
white solid; mp 32.6–32.8 °C.
mmol), 1,1,1,3,3,3-hexafluoropropan-2-ol (6, 0.1 mmol), and H O
2
(
1
8.0 mmol). The mixture was stirred in an oil bath kept at 25 °C for
2 h. The mixture was diluted with Et O, dried (anhyd Na SO ), and
2
2
4
concentrated in vacuo. Purification by flash column chromatogra-
phy (silica gel, hexane–EtOAc) gave the corresponding products.
[
a
]
2
8
–
6
.
7
(
c
4
.
4
6
,
C
H
C
l
)
.
D
3
4-Hydroxy-3-methylene-4-phenylbutan-2-one (4a)
CAS [73255-39-7]. Colorless oil.
IR (KBr) 2930, 2849, 2359, 1512, 1471, 1385, 1283, 1231, 1132,
107, 1082, 1057, 1036, 1007, 907, 837, 816, 750, 731, 665, 623
cm .
1
1
H NMR (CDCl ): d = 7.37–7.25 (m, 5 H), 6.20 (s, 1 H), 5.98 (d,
3
–
1
J = 1.0 Hz, 1 H), 5.62 (d, J = 5.0 Hz, 1 H), 3.13 (d, J = 5.0 Hz, 1 H),
1
2.34 (s, 3 H).
H NMR (CDCl ): d = 7.45 (s, 1 H), 7.05 (t, J = 1.0 Hz, 1 H), 6.90
3
(
t, J = 1.0 Hz, 1 H), 4.64 (m, 1 H), 3.92 (t, J = 7.5 Hz, 2 H), 1.76 (m,
13
C NMR (CDCl ): d = 200.4, 149.9, 141.4, 128.4, 127.7, 126.7,
3
2
1
H), 1.65 (m, 1 H), 1.56–1.38 (m, 2 H), 1.33 (t, J = 6.0 Hz, 3 H),
.36–1.22 (m, 17 H).
1
26.5, 72.9, 26.5.
1
3
4-Hydroxy-3-methylene-4-(2-naphthyl)butan-2-one (4b)
CAS [849900-45-4]. Colorless oil.
C NMR (CDCl ): d = 137.1, 129.4, 118.7, 91.1 (d, J = 164 Hz),
3
4
2
7.0, 36.9 (d, J = 21 Hz), 31.1, 29.52, 29.48, 29.47, 29.42, 29.40,
9.1, 26.5, 25.1, 25.0, 21.0 (d, J = 23 Hz).
1
H NMR (CDCl ): d = 7.86–7.79 (m, 4 H), 7.50–7.40 (m, 3 H), 6.23
3
1
9
(s, 1 H), 6.01 (d, J = 1.5 Hz, 1 H), 5.80 (d, J = 5.0 Hz, 1 H), 3.25
F NMR (CDCl ): d = –10.3.
3
(
dd, J = 5.0, 1.0 Hz, 1 H), 2.36 (s, 3 H).
+
HRMS: m/z [M] calcd for C H FN : 282.2471; found: 282.2472.
1
7
31
2
1
3
C NMR (CDCl ): d = 200.4, 149.8, 138.8, 133.2, 132.9, 128.12,
3
1
28.07, 127.6, 127.0, 126.1, 126.0, 125.4, 124.5, 72.9, 26.5.
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

PAPER
Amphiphilic Imidazole Assisted Morita–Baylis–Hillman Reactions on Water
3225
4
-(4-Fluorophenyl)-4-hydroxy-3-methylenebutan-2-one (4c)
References
CAS [888966-21-0]. Colorless oil.
(
1) (a) Rideout, D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102,
816. (b) Breslow, R. Acc. Chem. Res. 1991, 24, 159.
1
H NMR (CDCl ): d = 7.37–7.33 (m, 2 H), 7.06–7.01 (m, 2 H), 6.22
d, J = 0.5 Hz, 1 H), 5.99 (d, J = 1.5 Hz, 1 H), 5.61 (d, J = 5.0 Hz, 1
3
7
(
(
2) (a) Lubineau, A. Chem. Ind. 1996, 123. (b) Lindström, U.
M. Chem. Rev. 2002, 102, 2751. (c) Lubineau, A.; Augé, J.;
Queneau, Y. Synthesis 1994, 741. (d) Li, C.-J. Chem. Rev.
2005, 105, 3095.
H), 3.10 (d, J = 5.0 Hz, 1 H), 2.36 (s, 3 H).
1
3
C NMR (CDCl ): d = 200.3, 162.2 (d, J = 246 Hz), 149.8, 137.2,
3
1
28.2 (d, J = 7.7 Hz), 126.8, 115.2 (d, J = 21 Hz), 72.3, 26.5.
1
9
(3) (a) Dong, V. M.; Fiedler, D.; Carl, B.; Bergman, R. G.;
F NMR (CDCl ): d = 46.6.
3
Raymond, K. N. J. Am. Chem. Soc. 2006, 128, 14464.
(
2
b) Vaitheeswaran, S.; Thirumalai, D. J. Am. Chem. Soc.
006, 128, 13490.
4
-Hydroxy-3-methylene-4-(4-nitrophenyl)butan-2-one (4d)
CAS [203111-49-3]. Colorless oil.
(
4) (a) Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107,
1768. (b) Loncaric, C.; Manabe, K.; Kobayashi, S. Chem.
Commun. 2003, 574. (c) Ponaras, A. A. J. Org. Chem. 1983,
1
H NMR (CDCl ): d = 8.20 (dt, J = 9.0, 2.0 Hz, 2 H), 7.55 (ddt,
3
J = 9.0, 0.5, 2.0 Hz, 2 H), 6.27 (s, 1 H), 6.03 (d, J = 1.5 Hz, 1 H),
5
.68 (d, J = 5.5 Hz, 1 H), 3.29 (d, J = 5.5 Hz, 1 H), 2.36 (s, 3 H).
4
8, 3866. (d) Coates, R. M.; Roger, B. D.; Hobbs, S. J.;
Peck, D. R.; Curran, D. P. J. Am. Chem. Soc. 1987, 109,
160. (e) Gajewski, J. J.; Jurayj, J.; Kimbrough, D. R.;
1
3
C NMR (CDCl ): d = 200.1, 148.93, 148.86, 147.3, 127.8, 127.2,
3
1
1
23.6, 72.3, 26.4.
Gande, M. E.; Ganem, B.; Carpenter, B. K. J. Am. Chem.
Soc. 1987, 109, 1170. (f) Inoue, Y.; Araki, K.; Shiraishi, S.
Bull. Chem. Soc. Jpn. 1991, 64, 3079.
4
-Hydroxy-3-methylene-4-(3-pyridyl)butan-2-one (4e)
CAS [223393-88-2]. White solid.
(
5) (a) Runge, M. B.; Mwangi, M. T.; Miller, A. L. II.; Perring,
M.; Bowden, N. B. Angew. Chem. Int. Ed. 2008, 47, 935.
1
H NMR (CDCl ): d = 8.54 (d, J = 2.0 Hz, 1 H), 8.47 (dd, J = 5.0,
3
1
5
.5 Hz, 1 H), 7.72 (ddd, J = 8.0, 1.5, 0.5 Hz, 1 H), 7.26 (ddd, J = 8.0,
.0, 0.5 Hz, 1 H), 6.25 (d, J = 0.5 Hz, 1 H), 6.08 (d, J = 1.5 Hz, 1
(
b) Cornils, B.; Herrmann, W. A. In Aqueous-Phase
Organometallic Chemistry; Wiley-VCH: Weinheim, 1998.
c) Li, C.-J.; Chan, T.-H. In Organic Reactions in Aqueous
Media; John Wiley: New York, 1997.
(6) (a) Asano, K.; Matsubara, S. Org. Lett. 2009, 11, 1757.
b) Manabe, K.; Sun, X.-M.; Kobayashi, S. J. Am. Chem.
H), 5.64 (s, 1 H), 3.79 (br, 1 H), 2.35 (s, 3 H).
(
1
3
C NMR (CDCl ): d = 200.0, 149.3, 148.8, 148.3, 137.3, 134.3,
3
1
27.1, 123.3, 70.7, 26.4.
(
4
-Hydroxy-3-methylene-6-phenylhexan-2-one (4f)
Soc. 2001, 123, 10101. (c) Hayashi, Y.; Aratake, S.; Okano,
T.; Takahashi, J.; Sumiya, T.; Shoji, M. Angew. Chem. Int.
Ed. 2006, 45, 5527. (d) Mase, N.; Nakai, Y.; Ohara, N.;
Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C. F. III J. Am.
Chem. Soc. 2006, 128, 734. (e) Luo, S.; Mi, X.; Liu, S.; Xu,
H.; Cheng, J.-P. Chem. Commun. 2006, 3687.
CAS [108762-30-7]. Colorless oil.
1
H NMR (CDCl ): d = 7.30–7.26 (m, 2 H), 7.22–7.16 (m, 3 H), 6.11
s, 1 H), 6.01 (d, J = 1.0 Hz, 1 H), 4.45 (ddd, J = 6.5, 6.5, 6.5 Hz, 1
3
(
H), 2.82 (m, 1 H), 2.74 (d, J = 6.5 Hz, 1 H), 2.68 (m, 1 H), 2.35 (s,
H), 1.93 (m, 2 H).
3
(
7) (a) Pellissier, H. Tetrahedron 2007, 63, 9267.
1
3
C NMR (CDCl ): d = 200.9, 150.0, 141.7, 128.5, 128.4, 125.9,
3
(b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471. (c) Pan, C.; Wang, Z. Coord.
Chem. Rev. 2008, 252, 736. (d) Kočovský, P.; Malkov, A.
V. Pure Appl. Chem. 2008, 80, 953. (e) Gruttadauria, M.;
Giacalone, F.; Lo Meo, P.; Marculescu, A. M.; Riela, S.;
Noto, R. Eur. J. Org. Chem. 2008, 1589. (f) Brogan, A. P.;
Dickerson, T. J.; Janda, K. D. Angew. Chem. Int. Ed. 2006,
1
25.8, 71.0, 37.7, 32.1, 26.5.
4
-Hydroxy-3-methylenenonan-2-one (4g)
CAS [108762-27-2]. Colorless oil.
1
H NMR (CDCl ): d = 6.10 (s, 1 H), 5.99 (d, J = 1.0 Hz, 1 H), 4.40
ddd, J = 6.5, 6.5, 6.5 Hz, 1 H), 2.63 (d, J = 6.5 Hz, 1 H), 2.36 (s, 3
3
(
45, 8100. (g) Hayashi, Y. Angew. Chem. Int. Ed. 2006, 45,
H), 1.59 (m, 2 H), 1.42 (m, 1 H), 1.34–1.23 (m, 5 H), 0.88 (t, J = 7.0
Hz, 3 H).
8103. (h) Luo, S.; Zhang, B.; He, J.; Janczuk, A.; Wang, P.
G.; Cheng, J.-P. Tetrahedron Lett. 2002, 43, 7369. (i)Gatri,
R.; Gaïed, M. M. E. Tetrahedron Lett. 2002, 43, 7835.
1
3
C NMR (CDCl ): d = 200.8, 150.3, 125.6, 71.6, 36.2, 31.6, 26.5,
3
2
5.6, 22.6, 14.0.
(
8
j) Caumul, P.; Hailes, H. C. Tetrahedron Lett. 2005, 46,
125. (k) Davies, H. J.; Ruda, A. M.; Tomkinson, N. C. O.
4
-Hydroxy-3-methyleneundecan-2-one (4h)
Tetrahedron Lett. 2007, 48, 1461. (l) Hayashi, Y.; Okado,
K.; Ashimine, I.; Shoji, M. Tetrahedron Lett. 2002, 43,
8683.
CAS [108762-27-2]. Colorless oil.
1
H NMR (CDCl ): d = 6.10 (s, 1 H), 5.99 (d, J = 0.5 Hz, 1 H), 4.40
ddd, J = 6.5, 6.5, 6.5 Hz, 1 H), 2.63 (d, J = 6.5 Hz, 1 H), 2.36 (s, 3
3
(
(8) (a) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R.
J. Org. Chem. 1998, 63, 7183. (b) Aggarwal, V. K.; Dean,
D. K.; Mereu, A.; Williams, R. J. Org. Chem. 2002, 67, 510.
(9) Asano, K.; Matsubara, S. Synlett 2009, 35.
H), 1.59 (tt, J = 7.0, 7.0 Hz, 2 H), 1.42 (m, 1 H), 1.35–1.20 (m, 9 H),
0
.87 (t, J = 7.0 Hz, 3 H).
1
3
C NMR (CDCl ): d = 200.8, 150.3, 125.6, 71.6, 36.3, 31.8, 29.4,
3
(
10) (a) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. Rev.
2
9.2, 26.5, 25.9, 22.6, 14.1.
2007, 36, 1581. (b) Ciganek, E. Org. React. 1997, 51, 201.
(
(
c) Langer, P. Angew. Chem. Int. Ed. 2000, 39, 3049.
d) Cabrera, S.; Alemán, J.; Bolze, P.; Bertelsen, S.;
Acknowledgment
Jørgensen, K. A. Angew. Chem. Int. Ed. 2008, 47, 121.
e) Lin, Y.-S.; Liu, C.-W.; Tsai, T. Y. R. Tetrahedron Lett.
005, 46, 1859. (f) Tang, H.; Zhao, G.; Zhou, Z.; Gao, P.;
This work was supported financially by the Japanese Ministry of
Education, Culture, Sports, Science and Technology.
(
2
He, L.; Tang, C. Eur. J. Org. Chem. 2008, 126.
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York

3
226
K. Asano, S. Matsubara
PAPER
(
11) (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37,
34. (b) Nair, V.; Bindu, S.; Sreekumar, V. Angew. Chem.
(13) (a) Zhong, L.; Gao, Q.; Gao, J. B.; Xiao, J.; Li, C. J. Catal.
2007, 250, 360. (b) Li, J.; Zhang, Y.; Han, D.; Jia, G.; Gao,
J.; Zhong, L.; Li, C. Green Chem. 2008, 10, 608.
(14) Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb,
H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44,
3275.
5
Int. Ed. 2004, 43, 5130. (c) Suzuki, Y. J. Org. Synth. Chem.
Jpn. 2008, 66, 377. (d) Enders, D.; Niemeier, O.; Henseler,
A. Chem. Rev. 2007, 107, 5606.
(
12) (a) Kurihara, K.; Kunitake, T. J. Am. Chem. Soc. 1992, 114,
1
0927. (b) Matsubara, S.; Matsuda, H.; Hamatani, T.;
(15) Khabnadideh, S.; Rezaei, Z.; Khalafi-Nezhad, A.;
Bahrinajafi, R.; Mohamadi, R.; Farrokhroz, A. A. Bioorg.
Med. Chem. Lett. 2003, 13, 2863.
Schlosser, M. Tetrahedron 1988, 44, 2855.
(16) Vitz, J.; Mac, D. H.; Legoupy, S. Green Chem. 2007, 9, 431.
Synthesis 2009, No. 19, 3219–3226 © Thieme Stuttgart · New York