The Morita-Baylis-Hillman reaction in aqueous-organic solvent system

Article abstract of DOI:10.1016/j.tetlet.2008.07.140

We have found that water and organic solvents mixed at different proportions can give good to excellent yields and short reaction times for the Morita-Baylis-Hillman reaction. The present Letter details our findings in the Morita-Baylis-Hillman reaction b

Full text of DOI:10.1016/j.tetlet.2008.07.140

Tetrahedron Letters 49 (2008) 5902–5905
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Tetrahedron Letters
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The Morita–Baylis–Hillman reaction in aqueous–organic solvent system
a
b
c
Rodrigo O. M. A. de Souza a, , Vera L. P. Pereira , Pierre M. Esteves , Mario L. A. A. Vasconcellos
*
a Núcleo de Pesquisas de Produtos Naturais, Universidade Federal do Rio de Janeiro, Bloco H, CCS, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil
b Instituto de Química, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Bloco A, Lab-622, Brazil
c Departamento de Química, Universidade Federal da Paraíba, Campus I, João Pessoa, PB 58059-900, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
We have found that water and organic solvents mixed at different proportions can give good to excellent
yields and short reaction times for the Morita–Baylis–Hillman reaction. The present Letter details our
findings in the Morita–Baylis–Hillman reaction between several aromatic aldehydes and methyl acrylate
or acrylonitrile. The selection of the catalyst was also evaluated and DABCO affored the best results when
compared to DBU, DMAP, HMT, Imidazole and Triethylamine.
Received 15 May 2008
Revised 22 July 2008
Accepted 24 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Morita–Baylis–Hillman reaction
DABCO
Catalysis
Water and biological active adducts
1. Introduction
This present Letter details our findings in the Morita–baylis–Hill-
man reaction between several aldehydes and methyl acrylate or
acrylonitrile.
The Morita–Baylis–Hillman1–4 reaction is an important way for
C–C bond formation. It involves the coupling of alkenes containing
electron-withdrawing groups (EWG) with aldehydes, ketones or
imines, among others. Tertiary amines are used as nucleophilic
catalysts where 1,4-diazabicyclo[2.2.2]octane (DABCO) is the most
First, the reaction between p-nitrobenzaldehyde (1a), acrylo-
nitrile (2a) and DABCO was examined in polar protic solvents
(Table 1, entries 1–3), where the best result was obtained in tert-
butanol (Table 1, entry 3). Following this initial study, we investi-
gated different proportions of a tert-butanol/water system (Table 1,
entries 4–11), as the presence of water is known to accelerate the
Morita–Baylis–Hillman.22,23 The effect of DABCO concentration
was also evaluated.
The result obtained in entry 7 (Table 1) shows a great improve-
ment on reaction time for the reaction carried in tert-butanol/
water (60:40) in comparison with entry 3 (Table 1). This study also
shows the dependence of reaction time on DABCO concentration
(Table 1, entries 7–9). With an increased amount of DABCO, the
reaction time can be greatly reduced and furnished on excellent
yield of product.
5,6
widely used (Scheme 1).
The Morita–Baylis–Hillman adducts have been extensively used
as intermediates in organic synthesis for a variety of applications,
many of which have biologically activity.7–14 Due to their synthetic
potential, several protocols have been proposed to accelerate this
reaction, such as the use of microwaves,15 ultrasound,16 addition
of salts,17 high pressure,18 protic media19 and ionic liquids.20
In our continuous search for efficient methodologies for the
Morita–Baylis–Hillman reaction,11–14,20,21 we have found that
aqueous organic solvents give good yields and short reaction times.
Given the interesting results, we have explored the use of other
nucleophilic catalyst for the Morita–Baylis–Hillman reaction on
tert-butanol/water system (Table 2, entries 1–6). In addition, the
use of a less reactive Michael acceptor, methyl acrylate (2b) and
less reactive electrophile, benzaldehyde (1b) and anisaldehyde
(1c) were evaluated. The results are summarized in Table 2 (entries
7–11).
HO R2
R1
X
NR3
EWG
+
EWG
R1
R2
R1,
R2 = alkyl, aryl, H.
X
= O, N
EWG = CN, CO2R, COR, NO2
The use of DABCO (Table 2, entry 1) gave better results than the
use of other tertiary amines such as triethylamine, imidazole,
DMAP, HMT and DBU (Table 2, entries 2–6). These results lead us
to use DABCO in the reactions between different Michael acceptors
and aromatic aldehydes increasing the scope of this reaction
Scheme 1. The Morita–Baylis–Hillman reaction.
* Corresponding author. Tel.: +55 2125627248; fax: +55 2125627559.
E-mail address: rodrigosouza@iq.ufrj.br (R. O. M. A. de Souza).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.140

R. O. M. A. de Souza et al. / Tetrahedron Letters 49 (2008) 5902–5905
5903
Table 1
Table 3
Reaction between p-nitrobenzaldehyde (1a), acrylonitrile (2a) and DABCO (X mol %)
Reaction between p-nitrobenzaldehyde (1a) and methyl acrylate (2b) under DABCO
in different polar protic solvents and water systems
catalysis (X mol %)
OH
OH
O
O
CN
CO2Me
H
+
H
+
Solvent
Solvent
CN
2a
CO2Me
X%mol DABCO
X%mol DABCO
O2N
O2N
O2
Entry
N
O2N
r. t.
r. t.
3
2b
4
1a
Solventa
1a
.
DABCO (mol %)
Time
Yieldb (%)
.
Entry
Solventa
DABCO (mol %)
Time
Yieldb (%)
1
2
3
4
5
6
7
8
9
MeOH
i-PrOH
tert-BuOH
100
100
100
100
50
10
100
50
24 h
24 h
6 h
1 h
3 h
4 h
20 min
2 h
12 h
2 h
6 h
55
67
81
94
82
1
2
3
4
5
6
7
8
MeOH
THF
DMSO
DMSO
DMSO
DMF
100
100
100
50
24 h
48 h
5 h 30 min
9 h
15 h
5 h 30 min
5 h 30 min
24 h
66
63
96
85
85
86
90
15
tert-BuOH/water (90:10)
tert-BuOH/water (90:10)
tert-BuOH/water (90:10)
tert-BuOH/water (60:40)
tert-BuOH/water (60:40)
tert-BuOH/water (60:40)
tert-BuOH/water (50:50)
tert-BuOH/water (40:60)
10
77
100
100
100
>99
>99
85
87
62
MeCN
CH2Cl2
10
100
100
a
10
11
Five millilitres of solvent were used.
Isolated yields.
b
a
Five millilitres of solvent were used.
Isolated yields.
b
p-nitrobenzaldehyde (1a) and methyl acrylate (2b). Once again,
100 mol % of DABCO results in a 60% reduction of the reaction time
and gives better yields (Table 3, entry 3).
Table 2
Given the beneficial effect of water, the following aqueous sys-
tems were evaluated: DMSO/water, DMF/water and MeCN/water
for the reaction between aromatic aldehydes (1a–e) and methyl
acrylate (2b), under DABCO catalysis (100 mol %) (Table 4).
Table 4 shows that DMSO/water, DMF/water and MeCN/water
systems promote a small improvement on reaction time for more
reactive aldehydes (Table 4, entries 1–3). However, the DMSO/
water system showed a large reduction in reaction time for less
reactive aldehydes that also gave better yields of products (Table
4, entries 4–7).
Different proportions of the DMSO/water, DMF/water and
MeCN/water systems were also evaluated in the reaction of less
activated aldehydes, and the results are summarized in Table 5.
Table 5 shows that different proportions of DMSO/water, DMF/
water and MeCN/water systems in the reaction between piperonal
(1d) and methyl acrylate (2b) under DABCO catalysis do not lead to
improvement on reaction time and yield when compared with
entry 6, Table 4.
Reaction between aromatic aldehydes (1a–h), Michael acceptors (2a–b) and catalyst
(100 mol %) in tert-butanol/water (60:40) system
O
OH
tert-butanol/water
(60:40)
EWG
H
+
EWG
Catalyst 100%mol
R
R
r. t.
1a R=NO2
1b R=H
2a EWG=CN
3-8
2b EWG=CO2Me
1c R=OMe
.
R
EWG
Catalyst
Time
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NO2 (1a)
NO2 (1a)
NO2 (1a)
NO2 (1a)
NO2 (1a)
NO2 (1a)
NO2 (1a)
H (1b)
CN (2a)
CN (2a)
CN (2a)
CN (2a)
CN (2a)
CN (2a)
DABCO
Triethylamine
Imidazole
DMAP
HMT
DBU
20 min
3 h
3, >99
3, >99
3, 22
3, 51
3, 60
3, 37
4, 92
5, 92
6, 79
24 h
24 h
24 h
24 h
9 h
24 h
24 h
24 h
48 h
48 h
48 h
48 h
48 h
48 h
CO2Me (2b)
CN (2a)
CO2Me (2b)
CN (2a)
CO2Me (2b)
CN (2a)
CO2Me (2b)
CN (2a)
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
H (1b)
The role of water in the Morita–Baylis–Hillman mechanism can
be rationalized as suggested by Aggarwal and co-workers24 in their
results on the theoretical calculations of the Morita–Baylis–
Hillman mechanism. They predict that in the absence of protic
OMe (1c)
OMe (1c)
F (1f)
7, 76
8, 55
11, 66
12, 57
13, 70
14, 61
15, 78
F (1f)
OH (1g)
OH (1g)
CF3 (1h)
solvents deprotonation of the
a-position is the rate-determining
CO2Me (2b)
CN (2a)
step and occurs through a cyclic transition state, with proton
a
Isolated yields.
Table 4
Reaction between aromatic aldehydes (1a–e), methyl acrylate (2b) and DABCO in
solvent/water (60:40) system
methodology (Table 2, entries 7–16). Table 2 shows that less reac-
tive aromatic aldehydes can give moderated to good yields (entries
8–11) in shortened reaction times.
OH
O
CO2Me
4, 6, 8-10
Time
Solvent
Ar
CO2Me
Ar
1a-e
H
100%mol DABCO
The reaction time observed for the reaction between p-nitro-
benzaldehyde (1a) and methyl acrylate (2b) under DABCO catalysis
in the tert-butanol/water (60:40) system (Table 2, entry 7) was
much longer to that observed for the reaction between p-nitro-
benzaldehyde (1a) and acrylonitrile (2a) under the same condi-
tions (Table 2, entry 1). These results prompted us to search for
alternative reaction media for the reaction between p-nitrobenz-
aldehyde (1a) and methyl acrylate (2b) (Table 3).
In Table 3, it is shown that solvents of higher dielectric con-
stants afforded better yields and shorter reaction times (entries
3, 6 and 7). DMSO was chosen solvent to investigate the effect of
DABCO concentration on the reaction time, for the reaction of
+
r. t.
2b
.
Entry
Aldehyde
Solventa
Yieldb (%)
1
2
3
4
5
6
7
p-Nitrobenzaldehyde (1a)
p-Nitrobenzaldehyde (1a)
p-Nitrobenzaldehyde (1a)
Benzaldehyde (1b)
Anisaldehyde (1c)
Piperonal (1d)
DMSO/water
DMF/water
2 h 30 min
3 h 30 min
5 h
3 h 30 min
8 h
4, 90
4, 91
4, 86
6, 95
8, 66
9, 85
10, 95
MeCN/water
DMSO/water
DMSO/water
DMSO/water
DMSO/water
15 h
12 h
Naftaldehyde (1e)
a
Five millilitres of solvent were used.
Isolated yields.
b

5904
R. O. M. A. de Souza et al. / Tetrahedron Letters 49 (2008) 5902–5905
3-Hydroxy-2-methylene-3-phenyl propanenitrile (5): 1H NMR
(CDCl3, 200 MHz): d = 7.4–7.2 (m, 5H) 6.15 (s, 1H), 5.95 (s, 1H),
5.3 (s, 1H).
Table 5
Reaction between piperonal (1d), methyl acrylate (2b) and DABCO in solvent/water
system
Methyl-3-hydroxy-2-methylene-3-phenyl propanoate (6): 1H
NMR (CDCl3, 200 MHz): d = 7.4–7.2 (m, 5H), 6.30 (s, 1H), 5.90 (s,
1H), 5.45 (s, 1H), 3.70 (s, 3H), 3.15 (s, 1H).
O
OH
O
solvent
O
O
O
O
O
+
CO2Me
100%mol DABCO
r. t.
3-Hydroxy-2-methylene-3-(4-metoxi-phenyl propanenitrile ð7):
1H NMR (CDCl3, 200 MHz): d = 7.5–7.2 (m, 4H) 6.22 (s, 1H), 5.98
(s, 1H), 5.42 (s, 1H), 3.85 (s, 3H).
.
Entry
Solventa
Timeb
Yieldc (%)
1
2
3
4
5
6
7
8
9
DMSO/water (90:10)
DMF/water (90:10)
MeCN/water (90:10)
DMSO/water (70:30)
DMF/water (70:30)
MeCN/water (70:30)
DMSO/water (50:50)
DMF/water (50:50)
MeCN/water (50:50)
32 h
38 h
48 h
24 h
36 h
36 h
18 h
36 h
36 h
73
70
70
82
72
80
62
66
42
Methyl-3-hydroxy-2-methylene-3-(4-metoxi-phenyl propanoate
(8): 1H NMR (CDCl3, 200 MHz): d = 7.6–7.3 (m, 4H), 6.32 (s, 1H),
5.95 (s, 1H), 5.45 (s, 1H), 4.1 (s, 3H), 3.75 (s, 3H), 3.15 (s, 1H).
3-Hydroxy-2-methylene-3-(3,4-methylenedioxyphenyl) propano-
ate ð9): 1H NMR (CDCl3, 200 MHz): d = 7.1–6.8 (m, 3H), 6.3 (d,
J = 1.43 Hz, 1H), 6.1 (d, J = 1.43 Hz, 1H) 5.82 (s, 2H), 5.40 (s, 1H),
3.66 (s, 3H), 2.2 (s, 1H, exchangeable with D2O).
Methyl-3-hydroxy-2-methylene-3-(2-naphthyl)propanoate (10):
1H NMR (CDCl3, 200 MHz): d = 7.9–7.3 (m, 7H), 6.31 (s, 1H), 6.36
(s, 1H), 5.19 (m, 1H), 3.74 (s, 3H).
a
Five millilitres of solvent were used.
No further improvement was observed.
Isolated yields.
b
c
3-Hydroxy-2-methylene-3-(4-fluoro) propanenitrile ð11): 1H NMR
(CDCl3, 200 MHz): d = 8.24 (d, 2H, J = 7.6 Hz), 7.86 (d, 2H,
J = 7.55 Hz), 6.23 (s, 1H), 5.90 (s, 1H), 5.40 (d, 1H, J = 5.81 Hz),
1.85 (s, 1H, exchangeable with D2O).
Methyl-3-Hydroxy-2-methylene-3-(4-fluoro) propanoate (12): 1H
NMR (CDCl3, 200 MHz): d = 8.20 (d, 2H, J = 7.90 Hz), 7.93 (d, 2H,
J = 7.33 Hz), 6.30 (s, 1H),5.90 (s, 1H), 5.45 (s, 1H), 3.70 (s, 3H).
3-Hydroxy-2-methylene-3-(4-hydroxi)propanenitrile (13): 1H
NMR (CDCl3, 200 MHz): d = 7.75 (d, 2 H, J = 7.0 Hz), 7.30 (d, 2H,
J = 6.95 Hz), 6.15 (s, 1H), 5.78 (s, 1H), 5.05 (d, 1H, J = 5.51 Hz).
Methyl-3-hydroxy-2-methylene-3-(4-hydroxi) propanoate (14):
1H NMR (CDCl3, 200 MHz): d = 7.66 (d, 2H, J = 6.95 Hz), 7.28 (d,
2H, J = 6.70 Hz), 6.15 (s, 1H),5.88 (s, 1H), 5.40 (s, 1H), 3.66 (s, 3H).
R2
H O
O
H
EWG
R1
R3N
Figure 1. Transition state proposed by Aggarwal and co-workers.
transfer to a hemiacetal alkoxide formed by addition of a second
equivalent of aldehyde to the intermediate alkoxide. As first
suggested by McQuade, this mechanism explains the observed
secondorder kinetics with respect to aldehyde concentration in
the absence of protic solvent. In contrast, in the presence of protic
solvents, they find a slightly lower energy pathway, in which the
protic solvent serves as a shuttle to transfer the proton from carbon
to oxygen (Fig. 1).
In conclusion, we have developed two different efficient reac-
tion conditions depending on the Michael aceptor used. For acrylo-
nitrile (2a), tert-butanol/water (60:40) was the system of choice,
while for methyl acrylate (2b), DMSO/water (60:40) gave better
results. In comparison with other tertiary amines, DABCO was
the catalyst of choice and quantitative proportions gave the best
yields.
3-Hydroxy-2-methylene-3-(4-trifluoromethane)
propanenitrile
ð15): 1H NMR (CDCl3, 200 MHz): d = 8.55 (d, 2H, J = 7.1 Hz), 8.3
(d, 2H, J = 7.01 Hz), 6.15 (s, 1H), 5.82 (s, 1H), 5.45 (d, 1H,
J = 5.81 Hz), 2.0 (s, 1H, exchangeable with D2O).
Acknowledgment
Financial support from CNPq, CAPES and FAPERJ, Brazilian
Governmental Financing Agencies, is gratefully acknowledged.
References and notes
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