Acidic ionic liquid [NMP]H2PO4 as dual solvent-catalyst for synthesis of β-alkoxyketones by the oxa-Michael addition reactions

Article abstract of DOI:10.1016/j.tet.2010.08.017

Acidic ionic liquid N-methyl-2-pyrrolidonium dihydrogen phosphate [NMP]H₂PO₄ was prepared and used as efficient catalyst and reaction medium to synthesize β-alkoxyketones by the oxa-Michael addition reactions for the first time. The

Full text of DOI:10.1016/j.tet.2010.08.017

Tetrahedron 66 (2010) 8300e8303
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Tetrahedron
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Acidic ionic liquid [NMP]H2PO4 as dual solvent-catalyst for synthesis
of
b-alkoxyketones by the oxa-Michael addition reactions
*
Hui Guo, Xia Li, Jun-Liang Wang, Xiao-Han Jin, Xian-Fu Lin
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2010
Received in revised form 2 August 2010
Accepted 10 August 2010
Available online 13 August 2010
Acidic ionic liquid N-methyl-2-pyrrolidonium dihydrogen phosphate [NMP]H2PO4 was prepared and
used as efficient catalyst and reaction medium to synthesize
b-alkoxyketones by the oxa-Michael
addition reactions for the first time. The effect of anions and cations, amount of ionic liquid on the re-
action was investigated. Various alcohols and phenols proceeded smoothly and led to corresponding
b
-alkoxyketones with high yields under mild reaction conditions, O-selectivity addition of amino-
ethanols was also achieved in this paper. Compared with traditional imidazolium ionic liquids, [NMP]
H2PO4 gave the better results. The ionic liquid was stable and could be reused at least five times with
a slight loss of activity.
Keywords:
N-Methyl-2-pyrrolidonium
dihydrogen phosphate
oxa-Michael addition
Alcohols
Ó 2010 Published by Elsevier Ltd.
Phenols
N-Substituted aminoethanols
1. Introduction
Beckmann rearrangement,15 Mannich reaction,16 SaucyeMarbet re-
action,17 selective alkylation of phenol,18 and arene carbonylation.19
The synthesis of
b
-alkoxyketones has attracted a great deal of
Although there are many publications utilizing basic and chiral ionic
liquids in Michael addition reactions,20e23 relevant reports about
oxa-Michael addition reactions using acidic ionic liquids as catalysts
are relatively scarce. Furthermore, imidazolium ionic liquids are the
most frequently used among these reports. But the application of
imidazolium ionic liquids is restricted due to the expensive cost and
high toxicity.24 Recently, some non-imidazolium ionic liquids have
been prepared and applied in heck reaction, esterification, prepara-
tion of azides, oxidative desulfurization, and biodiesel synthesis.25
However, preparation and application of novel acidic ionic liquids
for oxa-Michael addition reactions are still highly desirable.
With a wish to establish more simple and practical reaction
conditions, we have prepared and applied a series of acidic ionic
liquids in the oxa-Michael addition reactions, satisfactory results
were obtained when [NMP]H2PO4 was used (Scheme 1). To the best
of our knowledge, we represent the first example of oxa-Michael
reactions in acidic ionic liquid. The acidic ionic liquid [NMP]H2PO4
was used as a novel, recyclable, and efficient catalyst as well as
reaction medium for oxa-Michael addition reactions.
attention from both academia and industry since they are building
blocks and structural motifs of many natural products. The oxa-
Michael addition reactions of alcohols to
a
,
b
-unsaturated com-
pounds provide a direct protocol to construct
b
-alkoxyketones.1
However, the reaction proceeds less efficiently because of the low
reactivity and reversibility.2 Strong bases or acids, red mercury
oxide, boron trifluoride etherate, and a few transition metals (e.g.,
Pd, Cu, V) have been used as catalysts, but these synthetic methods
are limited due to their drawbacks, such as violent reaction con-
ditions and hazardous results to environment.3e5 A lot of effort
have been made and a new strategy with chiral phosphoric acid as
catalyst to perform enantioselective oxa-Michael addition reaction
was developed recently.6
Room-temperature ionic liquids (RTIL) have been applied in many
areas because of their unique physical and chemical properties, such
as good solvating ability, variable polarity, negligible vapor pressure,
and ease of recyclability in recent years.7e10 Some acidic ionic liquids
have been successfully used in esterification reaction,11 cleavages of
ethers,12 FriedeleCrafts alkylation reaction,13 hydrolytic reaction,14
[NMP]H2PO4
R
W
HO
W=COCH3,CHO
Scheme 1. The oxa-Michael addition reactions promoted by [NMP]H2PO4.
R
W
+
O
* Corresponding author. Fax: þ86 571 87952618; e-mail address: llc123@zju.edu.cn
(X.-F. Lin).
0040-4020/$ e see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2010.08.017

H. Guo et al. / Tetrahedron 66 (2010) 8300e8303
8301
Table 3
2. Results and discussion
Initial studies were carried out using the addition of
a
The oxa-Michael addition promoted by [NMP]H2PO4
Yieldb (%)
b-phenyl-
Entry
1
Substrate
Product
ethanol to methyl vinyl ketone (MVK) as a model reaction. Table 1
showed the effect of different ionic liquids on the reaction. It was
clear that the conversion was heavily influenced by the anions and
cations of ionic liquids. In a first set of experiments, ionic liquids of the
general [cation][BF4] and [DMIM]Cl, [BMIM]PF6 were tested as cata-
lyst and reaction medium (entries 1e5, Table 1). For ionic liquids of
the general [cation][BF4], the conversion decreased as the volume of
the cation increased (entries 1e3, Table 1). The [BMIM]PF6 ionic liquid
was less efficient and gave only 33% conversion (entry 4, Table 1).
Furthermore, [DMIM]Cl produced the oxa-adduct with lower con-
version than [BMIM]BF4 (entry 5, Table 1). However, the best con-
versionwas still lower than 50% (entry 1, Table 1). In the second set of
experiments, two acidic imidazole ionic liquid [BMIM]HSO4 and
[HMIM]HSO4 were tested (entries 6 and 7, Table 1). Although both
imidazolium ionic liquids gave higher conversions, the results still
could not meet our needs. In order to obtain higher conversion, some
non-imidazolium ionic liquids were prepared and applied in the re-
action. Compared with traditional imidazolium ionic liquids,
N-methyl-2-pyrrolidonium ionic liquid [NMP]HSO4 produced the
oxa-adduct with the better result (entry 8, Table 1). It was found that
the conversiondecreased slightly when theanionwasPTSAꢀ (entry 9,
Table 1). To our delight, a promising result (95% conversion) was
achieved when [NMP]H2PO4 was employed (entry 10, Table 1). The
order of catalytic activity could be related to the solvating ability of
N-methyl-2-pyrrolidonium ionic liquids.
OH
O
90
O
NO
2
OH
O
2
3
81
71
O2N
O
OH
O
O
O
4
5
6
78
86
83
HO
O
O
OH
OH
O
O
O
O
O
O
O
N
N
N
N
N
7
92
O
N
OH
O
O
8
82
63
57
OH
O
O
9
HO
Table 1
O
The effect of ionic liquids on the oxa-Michael addition reactiona
O
Entry
Catalyst
Conversionb (%)
10
HO
O
1
2
3
4
5
6
7
8
9
[BMIM]BF4
[OMIM]BF4
[Bupy]BF4
[BMIM]PF6
[DMIM]Cl
[BMIM]HSO4
[HMIM]HSO4
[NMP]HSO4
[NMP]PTSA
[NMP]H2PO4
47
27
38
33
43
54
71
87
84
95
O
11
67
OH
O
O
12
13
61
54
HO
Cl
O
O
OH
Cl
10
O
a
Reactions were carried out on 0.5 mmol scale of
b
-phenylethanol with 2 equiv of
MVK (entries 1e10, Table 1) in 2 mmol ionic liquid at room temperature for 24 h.
OH
O
b
14
15
92c
48d
Conversion determined by HPLC.
O
Cl
It should be noted that the amount of ionic liquid has an impor-
tant impact on the reaction. As indicated in Table 2, the conversion
was very low when the amount of ionic liquid was 0.1 mmol. After
the screening, the optimal amount of ionic liquid was about 2 mmol.
O
Cl
OH
O
NO2
O
16
17
43d
59e
HO
NO2
OH
O
Table 2
The effect of amount of ionic liquid on the oxa-Michael addition reactiona
O
H
Conversionb (%)
O
Entry
Catalyst
Amount of catalyst (mmol)
1
2
3
4
[NMP]H2PO4
[NMP]H2PO4
[NMP]H2PO4
[NMP]H2PO4
2
1
0.5
0.1
95
90
82
30
OH
O
H
18
19
48e
O
a
Reactions were carried out on 0.5 mmol scale of b-phenylethanol with 2 equiv of
OH
OH
MVK (entries 1e4, Table 2) in ionic liquid at room temperature for 24 h.
df
b
Conversion determined by HPLC.
O
O
With the optimized reaction conditions in hand, we then ex-
amined the scope and limitations of this strategy for other struc-
turally diverse substrates, the results were summarized in Table 3.
df
O
20
21
O
b
-Phenylethanol produced the oxa-adduct with high yield (entry 1,
Table 3). The reactivity of 4-nitrobenzyl alcohol (entry 2, Table 3)
was lower due to the effect of substituted group. Sterically hin-
dered secondary alcohols, such as dl-sec-phenethyl alcohol and
O
H
H
93
N
N
OH
O
(continued on next page)

8302
Table 3 (continued)
H. Guo et al. / Tetrahedron 66 (2010) 8300e8303
other entries) under the same reaction conditions. As shown in
Table 3, 92% conversion was obtained, this result revealed this
catalyst was practical even for large scale reaction. Acrylaldehyde
could also be used as acceptor and reacted with b-phenylethanol
and dl-sec-phenethyl alcohol to give the corresponding oxa-
adducts with moderate yields (entries 17 and 18, Table 3). Cyclo-
hex-2-enone and chalcone were examined under the same re-
action conditions (entries 19 and 20, Table 3), but there were no
reaction for both substrates. Elevating the reaction temperature to
50 ꢁC still did not make the oxa-Michael addition happen. This
might be due to the nature of their poor activity.
Entry
Substrate
Product
Yieldb (%)
56
22
O
OH
HN
HN
HO
O
O
O
23
47
N
H
N
H
a
The Michael addition reaction of N-substituted aminoethanols
was an important reaction to synthesize many useful compounds.
Zhang reported that the addition selectivity of aminoethanols
depended on the polarity of the solvent.30 Aminoethanols could
undergo oxa-Michael addition in polar solvents such as DMSO.
There was no report about oxa-Michael addition of N-substituted
aminoethanols with environmentally friendly methodologies. We
investigated the reaction of N-Benzylethanolamine (entry 21, Table
3) in [NMP]H2PO4 and the corresponding oxa-adduct was obtained
with 93% yield. The result accounted for the first example of oxa-
Michael addition of N-substituted aminoethanol as the oxygen
nucleophile to a Michael acceptor using ionic liquid as catalyst.
Other structurally diverse N-substituted aminoethanol derivatives
were also examined and the corresponding oxa-adducts were
produced with moderate yields (entries 22 and 23, Table 3).
The remaining [NMP]H2PO4 could be reused without any addi-
Reactions were carried out on 0.5 mmol scale of substracts with 2 equiv of MVK
(entries 1e13, 21e23, Table 3) in 2 mmol ionic liquid at room temperature for 24 h.
b
Yield of isolated product.
Reactions were carried out on 5 mmol scale of b-phenylethanol with 2 equiv of
c
MVK (entry 14, Table 3) in 2 mmol ionic liquid at room temperature for 24 h.
Conversion determined by HPLC.
d
Reactions were carried out on 0.5 mmol scale of substracts with 2 equiv of MVK
(entries 15 and 16, Table 3) in 2 mmol ionic liquid at 50 ꢁC for 24 h.
e
Reactions were carried out on 0.5 mmol scale of substracts with 2 equiv of
acrylaldehyde (entries 17 and 18, Table 3) in 2 mmol ionic liquid at room temper-
ature for 24 h.
f
No reaction.
2-indanol alcohol (entries 3 and 4, Table 3) showed relatively lower
activities compared to b-phenylethanol. Interesting, cinnamyl al-
cohol provided the oxa-adduct exclusively with good yield under
the same reaction conditions (entry 5, Table 3). More complicated
heteroaromatic alcohols, such as 3,4-(methylenedioxy) benzyl al-
cohol and 1-hydroxybenzotrizole could also be used as substrates
to obtain the corresponding oxa-Michael adducts with moderate
to high yields (entries 6 and 7, Table 3). Aliphatic alcohols were also
tested in the reaction. As the carbon chain length of the alcohol
moiety increased, the reactivity decreased (entries 8e10, Table 3).
Sterically hindered alcohols, such as propan-2-ol and 3-methyl-
butan-1-ol (entries 11 and 12, Table 3) gave only moderate yields
under the same reaction conditions. But the result of propan-2-ol
was still superior to the known base-catalysed (12e20%),26
BF3$OEt2-catalysed (34%)27 and Tsoh-catalysed reaction (45%).28
The reactivity of 2-chloroethanol (entry 13, Table 3) was lower
than ethanol because of the effect of substituted group. Further-
more, 4-chlorophenol and 4-nitrophenol could also give the cor-
responding oxa-adducts with moderate yields in higher reaction
temperature (entries 15 and 16, Table 3). While they could not
undergo oxa-Michael addition reactions in the presence of strong
acid Tf2NH due to the competitive interference of FriedeleCrafts-
type reaction.29 A large scale reaction was attempted with 5 mmol
tional operation. The addition reaction of b-phenylethanol to MVK
was repeated five times and the results were shown in Table 4. It
could be seen that the ionic liquid [NMP]H2PO4 remained consis-
tent activity and high conversions were obtained.
Table 4
Recycling of [NMP]H2PO4 in the Michael addition of
b
-phenylethanol to MVKa
Conversionb (%)
Run
1
2
3
4
5
95
91
91
92
91
a
Reactions were carried out on 0.5 mmol scale of b-phenylethanol with 2 equiv of
MVK (entries 1e5, Table 4) in 2 mmol ionic liquid at room temperature for 24 h.
b
Conversion determined by HPLC.
The high activity of ionic liquid with [NMP]cation could be
rationalized by a proposed mechanism (Scheme 2). On the one side,
the anion could give proton to activate the MVK. On the other side,
the carbonyl moiety of cation could interact with the hydroxyl
of
b
-phenylethanol and 10 mmol of MVK (ten times larger than
N
H2PO4
OH
N
O
H
N
O
O
OH+
O
N
O
H
O
O
H
O
OH
OH
O
N
H2PO4
O
O
Scheme 2. Proposed mechanism for the oxa-Michael addition reaction promoted by [NMP]H2PO4.

H. Guo et al. / Tetrahedron 66 (2010) 8300e8303
8303
group via H-bond to increase its nucleophilicity. It is expected that
such synergistic activation delivers high activity, as demonstrated
experimentally.
2.67 (t, 2H), 2.78 (t, 2H), 3.56(t, 2H), 3.69 (t, 2H), 3.80 (s, 2H),
7.31e7.32 (m, 5H).
Supplementary data
3. Conclusion
Supplementary data for this article can be found in the online
version, at doi:10.1016/j.tet.2010.08.017. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
In summary, a simple and efficient method for oxa-Michael
addition reaction was developed using novel acidic ionic liquid
[NMP]H2PO4 as catalyst and reaction medium. Compared with tra-
ditional imidazolium ionic liquids, [NMP]H2PO4 produced the better
results. A series of b-alkoxyketones were obtained with high yields
References and notes
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4.4. Typical procedure for Michael addition of N-substituted
aminoethanols to methyl vinyl ketone
To a mixture of N-Benzylethanolamine (0.5 mmol, 75 mg) in
[NMP]H2PO4 (2 mmol), MVK (1 mmol, 70 mg) was added. After
addition, the reaction was stirred for 24 h at room temperature.
Then the mixture was neutralized with saturated NaHCO3 solution,
extracted with ethyl acetate, dried over anhydrous sodium sulfate.
The solvent was evaporated and the product was isolated by col-
umn chromatography. IR (neat): 2926, 1712, 1453, 1360, 1261, 1170,
1041, 799, 735, 700 cmꢀ1; 1H NMR (400 MHz, CDCl3):
d
¼2.17 (s, 3H),