Ionic amino acids: Application as organocatalysts in the aza-Michael reaction

Article abstract of DOI:10.1016/j.molcata.2012.11.012

The ethyl methyl imidazolium salts of amino acids, [emim][AA], have been used as catalysts in the aza-Michael reaction. Furthermore, when chiral amino acids were used, a stereoselective reaction was achieved. The mechanism of the transformation was verified by the detection of a key intermediate by electrospray ionization mass spectroscopy (ESI-MS).

Full text of DOI:10.1016/j.molcata.2012.11.012

Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
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Journal of Molecular Catalysis A: Chemical
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Ionic amino acids: Application as organocatalysts in the aza-Michael reaction
Naoki Morimotoa, Yasuo Takeuchia, Yuta Nishinab,∗
a Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Division of Pharmaceutical Sciences, Okayama University, Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
b Research Core for Interdisciplinary Sciences, Okayama University, Tsushima, Kita-ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The ethyl methyl imidazolium salts of amino acids, [emim][AA], have been used as catalysts in the
aza-Michael reaction. Furthermore, when chiral amino acids were used, a stereoselective reaction was
achieved. The mechanism of the transformation was verified by the detection of a key intermediate by
electrospray ionization mass spectroscopy (ESI-MS).
Received 4 September 2012
Received in revised form
12 November 2012
Accepted 17 November 2012
Available online 27 November 2012
© 2012 Elsevier B.V. All rights reserved.
Keywords:
Amino acid
aza-Michael reaction
Asymmetric reaction
Organocatalyst
ESI-MS
1. Introduction
study, we have focused on readily available ionic amino acids pos-
sessing diverse functional groups and an asymmetric center with
Research focused on the development of organic reactions
using amino acid derivatives as organocatalysts [1] has progressed
dramatically since the work of List et al., which described the
proline-catalyzed aldol reaction of acetone with aromatic and
aliphatic aldehydes [1a]. In many cases, however, the direct use of
an amino acid as a catalyst has not promoted the reaction effec-
tively because of the limited solubility of many amino acids in
common organic solvents. Furthermore, the nucleophilicity of the
amino group in the amino acid, which is an active site of the cataly-
sis, is decreased by the neighboring carboxyl group. The direct use
of amino acids as catalysts has therefore been limited to only a few
applications [2]. Significant efforts have been focused on improving
the effectiveness of amino acids as organocatalysts and proline-
based systems in particular have attracted considerable attention,
with multiple catalysts having been proposed involving modifica-
tions to the carboxyl [2a, 2b, 3] and pyrrolidine [2c, 4] moieties.
Complex and skillful molecular design processes are invariably
required to develop high-performance catalysts and the result-
ing catalytic systems are invariably quite far removed from their
parent amino acid frameworks. Nevertheless, catalysts designed
and synthesized through multistep transformations of the specific
amino acids, such as proline, have been reported with greater fre-
quency than those utilizing simple amino acids. For the current
the goal of developing novel amino acid-derived organocatalysts
for use in organic reactions.
2. Experimental
2.1. Materials and methods
All solvents used in the catalytic test were of analytical grade
and were used as received from Ardrich, Wako Chemical, and TCI.
Purification of reaction products was carried out by flash chro-
matography using 100–200 mesh silica gel, and a mixture of ethyl
acetate and petroleum ether as the eluting agent. All the prod-
ucts were characterized by 1H NMR spectroscopy. 1H (400 MHz)
and 13C (100 MHz) NMR spectra were recorded using a JEOL JNM-
LA400, Varian 400-MR, and Varian Mercury300 spectrometers.
Proton chemical shifts are relative to solvent peaks [chloroform:
7.27 (1H), 77.00 (13C); deuterium oxide: 4.79 (1H)]. IR (ATR) spectra
were measured with JASCO ATR PRO450-S with Ge. High-resolution
mass spectra were measured by JEOL JMS-700. Ionic amino acids
([emim][AA]s) were prepared from corresponding amino acids and
[emim][OH] by literature procedure [5a]. HPLC was carried out
with LC-20AD, SPD-20A and CTO-20A. The ees of the Michael
product were determined by chiral-phase HPLC analysis using a
TCI Chiral BP-S column and Chiralcel OD column with the indi-
cated eluent systems. LCMS was carried out with LCMS-2020
systems.
∗
Corresponding author. Tel.: +81 86 251 8718; fax: +81 86 251 8718.
E-mail address: nisina-y@cc.okayama-u.ac.jp (Y. Nishina).
1381-1169/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molcata.2012.11.012

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N. Morimoto et al. / Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
2.2. General procedure for the synthesis of ionic amino acids
A reaction time of 5 h was found to be optimal, and when the
reaction was stopped after 3 h, the yield of 3a was reduced to
66% (Table 1, entry 5). Furthermore, ambient temperature was
found to be the optimal reaction temperature. When the reac-
tion was conducted at 50 and 0 ◦C, the yields of 3a were reduced
to 58% and 8%, respectively (Table 1, entries 6 and 7). Alco-
hols were found to be suitable solvents for the transformation
(MeOH: 69%, n-PrOH: 66%, i-PrOH: 68%, t-BuOH: 71%), whereas
aprotic solvents (THF, DMF and DMSO) and water inhibited the
reaction.
1-Ethyl-3-methylimidazolium hydroxide ([emim][OH]) aque-
ous solution was prepared from 1-ethyl-3-methylimidazolium
bromide using anion exchange resin (AMBERLITE IRA 400 OH). An
[emim][OH] aqueous solution was added dropwise to a slightly
excess equimolar amino acid aqueous solution. The mixture was
stirred under room temperature for 12 h. Then water was evapo-
rated, and then 90 mL of acetonitrile and 10 mL of methanol. The
mixture was then filtered to remove excess amino acid. Filtrate was
evaporated to remove solvents. The product was dried in vacuo.
3.2. Scope of the reaction
2.3. Typical procedure for aza-Michael reaction of chalcone and
aniline
With the optimum reaction conditions in hand, we next exam-
ined the substrate scope for the [emim][Gly]-catalyzed aza-Michael
reaction. The enone component of the reaction was fixed as chal-
cone (1a) and the scope for introducing functional groups on the
benzene ring of the aniline 2 was investigated. When anilines
bearing electron donating methyl or methoxy groups at the para-
position (2b and 2c) were used, the corresponding products (3b and
3c) were obtained in good yields (Table 2, entries 1–3). Halogenated
anilines (2d and 2e) also underwent the aza-Michael reaction
(Table 2, entries 4 and 5), whereas p-trifluoromethylaniline (2f)
gave only a low yield of the corresponding product 3f, even fol-
lowing a longer reaction time (Table 2, entries 6 and 7). Similarly,
p-nitroaniline performed poorly in this catalytic system (not listed
in Table 2). These results indicate that electron withdrawing sub-
stituents on the phenyl ring of the aniline component were not
well tolerated in the transformation. The substituents on enone
1 also affected the product yield. For example, the presence of
electron donating methyl or 4-methoxyphenyl groups at the ␣ posi-
tion of a carbonyl moiety suppressed the reaction (Table 2, entries
8–10). In contrast, the presence of a methyl group at the termi-
nal alkene position did not inhibit the reaction (Table 2, entry 11).
The corresponding cyclic enone systems were not well tolerated
under the reaction conditions, with cyclohexen-1-one (1e) pro-
viding product 3j in only 35% yield (Table 2, entry 12). When a
substrate containing a nucleophilic OH group at the ortho-position
was used (1f), we found that an intramolecular conjugate addition
occurred as opposed to the desired aza-Michael reaction to give 3-
phenylchroman-4-one (3k) as the only product (Table 2, entry 13)
[7]. In addition, the reaction did not progress at all when alkylamine,
which is more nucleophilic than aniline, was used as a substrate
[8].
To a solution of ethanol was added catalyst (10 mol%) in the
presence of chalcone (62.5 mg, 0.300 mmol) and aniline (13.7 ␮L,
0.150 mmol) at room temperature. After being stirred at the same
temperature for 5 h, diluted with water (2 mL), the precipitated
solid collected by filtration, and washed with water. The crude
product was purified via recrystallization from ethanol to afford a
1,3-diphenyl-3-(phenylamino)propan-1-one (3a) as a white solid.
3. Results and discussion
3.1. Investigations on catalysts and reaction conditions
Although amino acids are poorly soluble in organic solvents
because of the polarized carboxyl and amino groups, they can be
effectively solubilized in organic solvents when the carboxyl group
is neutralized with an imidazolium cation [5]. In the current study,
ethyl methyl imidazolium [emim] has been as a counter cation for
the carboxyl group, and the resulting ethyl methyl imidazolium
salts of amino acid ([emim][AA]) were evaluated as organocatalysts
in a variety of different organic reaction. As a result [emim][Gly]
was established as an effective catalyst in the aza-Michael reac-
tion of chalcone (1a) with aniline (2a) to give amino ketone 3a
(Table 1, entry 1) [6]. The glycine moiety was found to be important
to the catalytic activity, and the reaction did not proceed effectively
when [Gly] was replaced with [Br] or [OH] (Table 1, entries 2 and
3). In addition, the [emim] moiety was also found to be necessary,
in that glycine itself did not promote the reaction (Table 1, entry 4).
Table 1
Investigation of catalysts in aza-Michael reaction.a
The reusability of the [emim][Gly] catalyst was also exam-
ined. Following the reaction of chalcone (1a) with p-anisidine
(2c) in the presence of catalytic [emim][Gly], CH2Cl2 and water
were added, and the unreacted materials and product 3c were
extracted with CH2Cl2. The aqueous phase was then collected and
evaporated to dryness to give a residue that was dried in a vac-
uum at ambient temperature for 6 h. This technique provided at
least 98% recovery of the catalyst and allowed the catalyst to be
used for the next reaction. The catalyst could be reused at least 3
times without decrease of the product yield (see Supplementary
Data).
Entry
Catalyst
Yield (%)b
1
2
3
4
[emim][Gly]
[emim][Br]
[emim][OH]
Glycine
[emim][Gly]
[emim][Gly]
[emim][Gly]
97(90)c
0
0
0
3.3. Application for stereoselective reaction
5d
6e
7f
66
58
8
It was envisaged that the use of a chiral amino acid would
provide a catalytic asymmetric aza-Michael reaction [9,10]. We
prepared a series of [emim][AA] catalysts from 20 natural amino
acids and evaluated them as catalysts in the aza-Michael reaction
(Fig. 1). The [emim][l-Pro] catalyst gave the desired product in the
highest yield, whereas [emim][l-Phe] provided the highest enan-
tiomeric excess of (S)-3a [11]. An schematic explanation for the
stereospecific formation of the (S)-isomer of 3a has been shown in
a
Reactions performed using 1a (0.3 mmol), 2a (0.15 mmol), catalyst
(0.015 mmol), and EtOH (0.3 mL).
b
Yield determined by NMR using CHCl2CHCl2 as an internal standard.
Reactions performed using 1a (3.0 mmol), 2a (1.5 mmol), catalyst (0.15 mmol),
c
and EtOH (3 mL). Isolated yield after recrystallization.
d
Reaction performed for 3 h.
e
Reaction performed at 50 ◦C.
f
Reaction performed at 0 ◦C.

N. Morimoto et al. / Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
33
Table 2
Scope of substrates.a
Entry
1
1
R1
R2
2
R3
3
Yield (%)b
1a
Ph
Ph
2b
4-CH3
92
2c
3
1a
1a
Ph
Ph
Ph
Ph
2b
2c
4-CH3
3b
63
91
4-OCH3
4
5
1a
1a
Ph
Ph
Ph
Ph
2d
2e
4-Cl
4-I
52
77
6
1a
1a
Ph
Ph
Ph
Ph
2f
2f
4-CF3
4-CF3
Trace
15
7d
3f
8d
1b
CH3
Ph
2a
H
0
9
1c
(4-OCH3)C6H4
Ph
2a
H
Trace
10e
11
1c
(4-OCH3)C6H4
Ph
2a
2a
H
H
3h
21
91
1d
Ph
CH3
12
2a
H
35

34
N. Morimoto et al. / Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
Table 2 (Continued)
Entry
1
R1
R2
2
R3
H
3
Yield (%)b
13
1f
(2-OH)C6H4
Ph
2a
0f
a
Reactions performed using 1a (0.3 mmol), 2a (0.15 mmol), catalyst (0.015 mmol), and EtOH (0.3 mL).
Isolated yield after recrystallization.
Reaction performed for 3 h.
Reaction performed for 24 h.
Reaction performed for 48 h.
b
c
d
e
f
Intramolecular cyclization of 1 h gave 3-phenylchroman-4-one (3k) as a sole product in 52% yield.
Fig. 2. The attack of the aniline (2a) on the Si face of chalcone (1a)
3.4. Mechanistic investigations
was inhibited by the benzyl group of l-phenylalanine.
The stereochemistry of the product could be effectively con-
trolled by carefully selecting the appropriate l- or d-amino acid.
Thus, the opposite enantiomers were formed when [emim][l-
Phe] and [emim][d-Phe] were used (HPLC spectra were shown in
Supplementary Data) [12].
We attempted to confirm the presence of the reaction inter-
mediate by electrospray ionization mass spectroscopy (ESI-MS)
and therefore validate the proposed reaction mechanism because
it was suggested that the reaction mechanism in this case was
different from that previously reported for general examples of
Fig. 1. Evaluation of [emim][l-AA] catalysts in the enantioselective aza-Michael reaction.

N. Morimoto et al. / Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
35
organocatalysts [13]. Amine-type organocatalysts can typically
control the reactivity and stereoselectivity of the reaction by gen-
erating the corresponding iminium ion or enamine [14]. When we
mixed chalcone (1a) and the general amino acid organocatalyst l-
proline, a peak with an m/z value of 306 was detected by ESI(+)-MS
that corresponded to the iminium ion formed between l-proline
and chalcone (Fig. 3(a)). An equivalent mass pattern for the iminium
ion was not detected, however, when 1a was mixed with [emim][l-
Pro] or [emim][l-Phe], suggesting that the [emim][AA]-catalyzed
reaction would not proceed through an iminium ion intermediate
(Fig. 3(b-1)). In contrast, when [emim][l-Phe] and aniline (2a) were
mixed, a peak with an m/z value of 351 was detected by ESI(−)-MS
that corresponded to an intermediate consisting of [l-Phe]− and
two molecule of 2a (Fig. 3(c)) [15]. Furthermore, the subsequent
addition of chalcone (1a) led the detection of a peak by ESI(−)-MS
Fig. 2. Rationale for the observed stereoselectivity. Aniline attacks from the Si face
of the chalcone (as indicated by the dashed arrow).
Fig. 3. (a) Formation of iminium ion by the reaction of 1a with proline. (b) No interaction between 1a with [emim][AA]. (c) Complex formation of [emim][AA] with 2a. (d)
No interaction between 3a with [emim][AA].
Fig. 4. ESI(−)-MS analysis of the reaction of aniline (2a), [emim][l-Phe], and chalcone (1a).

36
N. Morimoto et al. / Journal of Molecular Catalysis A: Chemical 368–369 (2013) 31–37
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Scheme 1. Reaction mechanism.
with an m/z value of 465 that corresponded to a complex com-
prised of 1a, 2a, and [l-Phe]− (Fig. 4). In contrast, a complex of
[l-Phe]− and 1a (m/z = 372) was not detected (Fig. 3(b-2)). These
results would suggest that [emim][AA] and aniline (2a) initially
reacted to give [emim][AA]-2a, and that the subsequent reaction
of this two component intermediate with chalcone (1a) led to
the formation of a three component intermediate 1a-[emim][AA]-
2a, which existed like a supramolecular system (Scheme 1). We
were not able to observe the composite (m/z = 465) when a mix-
ture of [emim][l-Phe] and isolated 3a were analysed by ESI(−)-MS
(Fig. 3(d)).
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1059–1064.
[7] The [emim][Gly] is necessary in this reaction, that is, glycine and [emim][Br]
did not promote the reaction.
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4. Conclusions
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In conclusion, we have successfully demonstrated that ionic
amino acids can catalyze the aza-Michael reaction of ␣,␤-
unsaturated ketones and aromatic amines. Weak interactions, such
as hydrogen bonding interactions, triggered the expression of the
catalytic activity and enantioselectivity, and these factors could
be effectively controlled using different types of amino acids. The
precise design and selection of the cation (e.g., imidazole) and
anion moieties (e.g., amino acid) could lead to the development
of additional organocatalysts with enhanced levels of activity and
selectivity.
[10] Metal-catalyzed stereoselective aza-Micahel reaction:
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Acknowledgments
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The absolute configuration of 3a has been determined by chiral HPLC using
Chiralcel OD-H column (Daisel). See.
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This study was financially supported by Funds for the Devel-
opment of Human Resources in Science and Technology, and
Hatakeyama Culture Foundation, and the foundation for the pro-
motion of ion engineering.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2012.11.012.
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