Nmp-based ionic liquids: Recyclable catalysts for both hetero-Michael addition and Knoevenagel condensation in water

Article abstract of DOI:10.1080/00397911.2018.1434544

A series of novel N-methyl piperidine (Nmp)-based ionic liquids with 1,2-propanediol group are synthesized and used as catalysts for both hetero-Michael addition of α,β-unsaturated amides and Knoevenagel condensation at room temperature in water; and all the examined substrates could be transformed into corresponding products in good to excellent yields. Meanwhile IL-catalyzed hetero-Michael addition of α,β-unsaturated amides in water has not been reported in the previous literatures. Additionally, the catalyst is recyclable for the two reactions. This finding provides a green catalyst for both hetero-Michael addition of α,β-unsaturated amides and Knoevenagel condensation in water.

Full text of DOI:10.1080/00397911.2018.1434544

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Nmp-based ionic liquids: Recyclable catalysts for
both hetero-Michael addition and Knoevenagel
condensation in water
Pengkun Yang, Yawei Liu, Ling Chai, Zhenzhen Lai, Xiaomin Fang, Baoying
Liu, Wenkai Zhang, Minghua Lu, Yuanqing Xu & Hao Xu
To cite this article: Pengkun Yang, Yawei Liu, Ling Chai, Zhenzhen Lai, Xiaomin Fang, Baoying
Liu, Wenkai Zhang, Minghua Lu, Yuanqing Xu & Hao Xu (2018) Nmp-based ionic liquids:
Recyclable catalysts for both hetero-Michael addition and Knoevenagel condensation in water,
Synthetic Communications, 48:9, 1060-1067, DOI: 10.1080/00397911.2018.1434544
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 9, 1060–1067
https://doi.org/10.1080/00397911.2018.1434544
Nmp-based ionic liquids: Recyclable catalysts for both
hetero-Michael addition and Knoevenagel condensation
in water
Pengkun Yang, Yawei Liu, Ling Chai, Zhenzhen Lai, Xiaomin Fang, Baoying Liu,
Wenkai Zhang, Minghua Lu, Yuanqing Xu, and Hao Xu
College of Chemistry and Chemical Engineering, Henan University, Kaifeng, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 8 September 2017
A series of novel N-methyl piperidine (Nmp)-based ionic liquids with
1,2-propanediol group are synthesized and used as catalysts for both
hetero-Michael addition of α,β-unsaturated amides and Knoevenagel
condensation at room temperature in water; and all the examined
substrates could be transformed into corresponding products in good
to excellent yields. Meanwhile IL-catalyzed hetero-Michael addition
of α,β-unsaturated amides in water has not been reported in the
previous literatures. Additionally, the catalyst is recyclable for the
two reactions. This finding provides a green catalyst for both hetero-
Michael addition of α,β-unsaturated amides and Knoevenagel
condensation in water.
KEYWORDS
α,β-Unsaturated amide;
hetero-Michael addition; in
water; ionic liquid catalyzed;
Knoevenagel condensation
GRAPHICAL ABSTRACT
Introduction
It is well known that ionic liquids (ILs) are a green alternative to volatile organic solvents,
due to their unique features such as good dissolving capacity, negligible vapor pressure, and
ease of recyclability. In the past few years, ILs have also displayed promising applications in
the field of catalysis[1] because cations and anions of ILs can be engineered easily through
rational design and screen of various component ions, and the cations and anions in
well-designed ILs have positive synergetic effect in catalyzing organic reactions.[2] Hence,
CONTACT Hao Xu
xuhao@henu.edu.cn
College of Chemistry and Chemical Engineering, Henan University,
Kaifeng 475004, P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

SYNTHETIC COMMUNICATIONS®
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it is highly desirable to develop readily available and well-designed ILs as catalysts for
diverse reactions.
Water is a green solvent because it is safe, cheap, and nontoxic. One of the challenges
for organic reactions is to conduct the reaction in water. Hetero-Michael addition is an
important reaction for the formation of carbon–heteroatom bond and plays a key role
in the synthesis of many bioactive molecules.[3] But hetero-Michael addition performed
in water is rare, especially when using relatively inactive α,β-unsaturated amides as
Michael acceptors; despite the Michael adducts of various α,β-unsaturated amides have
wide bioactivities.[4] Furthermore, for the thio-Michael addition of α,β-unsaturated amides,
only the unsubstituted acrylamide could be transformed into the relevant thio-Michael
adduct in water by previous methods[5] because of less steric hindrance and better
solubility than substituted acrylamides; meanwhile IL-catalyzed hetero-Michael addition
of α,β-unsaturated amides in water has not been reported in the previous literatures. In
our previous work, several morpholine-based ionic liquids with 1,2-propanediol group
were synthesized and applied in the Knoevenagel condensation successfully.[6] In continu-
ation of our endeavors to develop simple and efficient methods for organic synthesis,[7]
herein four basic ionic liquids based on N-methyl piperidine (Nmp) and 3-chloro-1,2-
propanediol were successfully synthesized and developed as catalysts in hetero-Michael
addition, including thio-Michael addition and aza-Michael addition. Meanwhile the novel
Nmp-based ILs were also applied in the Knoevenagel condensation, and all the examined
substrates provided good yields in water.
Results and discussion
Four novel Nmp-based ionic liquids were synthesized (Scheme 1); the preparation of
[Nmp-PDO][OH], [Nmp-PDO][OAc], [Nmp-PDO][BF4], and [Nmp-PDO][Gly] were
described detailly in electronic supplementary material.
Initially, Michael addition of thiophenol (1c) with acrylamide (2a) leading to
3-(phenylthio)propanamide (3c) was chosen as the model to optimize conditions including
catalysts and solvents. As indicated in Table 1, five Nmp-based IL catalysts were screened
using water as the solvent at room temperature (entries 1–5), and [Nmp-PDO][OAc]
provided the highest yields (entry 3). Notably, the Michael addition could not proceed
in the absence of IL catalysts (entry 6). When the reaction was performed under sol-
vent-free conditions, a good yield of product 3c could be obtained as well (entry 7). The
effect of catalyst dosage on the model reaction was also investigated; product 3c was still
generated in moderate to good yields when the amount of catalyst was decreased (entries
8–10). However, more reaction time was needed. Therefore, the optimized IL-catalyzed
conditions were as follows: [Nmp-PDO][OAc] (10 mol%) as the catalyst and water as
the solvent at room temperature (Table 1).
Scheme 1. Synthesis of ionic liquids of [Nmp-PDO][X].

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P. YANG ET AL.
Table 1. Michael addition of benzenethiol (1c) with acrylamide (2a) catalyzed by Nmp-based ionic
liquids: Optimization of conditions.a
Entry
Catalysts
Solvent
Time (h)
Yieldb (%)
1
2
[Nmp-PDO][Cl]
[Nmp-PDO][OH]
[Nmp-PDO][OAc]
[Nmp-PDO][BF4]
[Nmp-PDO][Gly]
Catalyst free
[Nmp-PDO][OAc]
[Nmp-PDO][OAc]
[Nmp-PDO][OAc]
[Nmp-PDO][OAc]
H2O
H2O
H2O
H2O
H2O
H2O
Neat
H2O
H2O
H2O
6
6
57
88
3
6
90
4
6
6
24
6
24
48
60
64
86
5
6
Trace
89
7
8c
9d
10e
85
76
52
aReaction conditions: benzenethiol (0.5 mmol, 47 mg), acrylamide (0.5 mmol, 36 mg), catalyst (10 mol%), solvent (1 mL),
room temperature.
bIsolated yield.
cCatalyst 5 mol%.
dCatalyst 1 mol%.
eCatalyst 0.5 mol%.
As shown in Table 2, the scope of IL-catalyzed hetero-Michael addition of
α,β-unsaturated amides was investigated under the optimized conditions above. All the
examined substrates showed good reactivity in water. For the thio-Michael addition, their
reactivity was affected by the steric hindrance; the substrates with bigger group provided
lower yields (entries 1, 2, 6, and 8). Meanwhile thiophenols could also react with
α,β-unsaturated amides easily although the steric hindrance of phenyl groups was relatively
larger (Table 2, entries 3–5, 7, 9, and 10); it might be because the proton (Hþ) of thiophe-
nols could be removed more easily than thiols under the catalysis of basic Nmp-based ILs.
Furthermore, the aza-Michael addition of α,β-unsaturated amides could proceed smoothly
as well under the optimized condition (Table 2, entries 11–13).
Encouraged by the above results, the Nmp-based IL catalysts were also attempted to
catalyze the Knoevenagel condensation in water. First, Knoevenagel condensation of
malononitrile (4a) with 2-methylbenzaldehyde (5b) was chosen as the model reaction to
optimize conditions including catalysts and solvents (Table S1 in the supporting infor-
mation). Under the optimized conditions ([Nmp-PDO][OAC] (10 mol%) as the catalyst,
water as the solvent at room temperature), aryl/heteroaryl/α,β-unsaturated aldehydes
as well as aliphatic ketone were completely tolerated in the reaction (Table 3). Compared
with aldehydes, aliphatic ketone needed more time to react with activated methylene
compounds for its higher steric hindrance (Table 3, entry 12). Moreover, for the different
activated methylene compounds, Knoevenagel condensation of cyanoacetates needs more
time than malononitrile, because the electron-withdrawing ability of the cyano group is
stronger than ester group (Table 3, entries 13–17).
The model reactions in Tables 1 and S1 (please see Table S1 in the supporting info.)
were also chosen to examine the catalyst’s recyclability. The Nmp-based IL catalyst showed
good recyclability for both hetero-Michael addition and Knoevenagel condensation (please
see Tables S2 and S3 in the supporting info.).

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Table 2. The hetero-Michael addition of α,β-unsaturated amides catalyzed by [Nmp-PDO][OAc].a
Entry
1
1
2
3
t/h
Yieldb/%
6
94
2
2a
6
83
3
4
2a
2a
6
6
90
80
5
6
2a
6
6
82
85
1a
1c
7
2b
6
90
8
9
10
10
10
73
81
87
1c
2c
2c
10
1d
11
12
13
2a
2c
2c
8
10
8
98
92
82
1g
aReaction conditions: nucleophile 1 (0.5 mmol), α,β-unsaturated amides 2 (0.5 mmol), catalyst [Nmp-PDO][OAc] (10 mol%),
water (1 mL), room temperature.
bIsolated yield.

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P. YANG ET AL.
Table 3. Knoevenagel condensations catalyzed by [Nmp-PDO][OAc].a
Entry
1
4
5
6
t/min
Yieldb/%
95
10
2
3
4a
4a
10
10
94
93
4
5
6
4a
4a
4a
10
10
10
91
98
91
7
8
4a
4a
10
10
89
88
9
4a
4a
15
10
95
93
10
11
12
4a
4a
15
92
90
1200
13
5a
1200
96
14
15
4b
4b
5d
5h
1200
1200
90
88
(Continued)

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Table 3. Continued.
Entry
16
4
5
6
t/min
Yieldb/%
5d
1200
92
17
4c
5j
1200
91
aReaction conditions: activated methylene compound 4 (0.5 mmol), carbonyl compound 5 (0.5 mmol), catalyst [Nmp-PDO]
[OAc] (10 mol%), water (1 mL), room temperature.
bIsolated yield.
IL-catalyzed mechanisms for both hetero-Michael addition and Knoevenagel conden-
sation are proposed in Scheme 2. First, the hydrogen bonding interactions between the
hydroxyl groups of [Nmp-PDO][OAc] and the carbonyl group of 2 or 5 can be formed,
which making 2 or 5 more vulnerable. Then nucleophilic attack of 1 on 2 leads to the
hetero-Michael adduct 3, or nucleophilic attack of 4 on 5 leads to the Knoevenagel
condensation product 6 (Scheme 2).
Scheme 2. Possible mechanisms for both hetero-Michael addition and Knoevenagel condensations
catalyzed by [Nmp-PDO][OAc].
Figure 1. FTIR comparison of benzaldehyde, [Nmp-PDO][OAc], and benzaldehyde-[Nmp-PDO][OAc] mixture.

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P. YANG ET AL.
Controlled FTIR experiments were performed to verify the proposed mechanism, the
FTIR spectrums of benzaldehyde, [Nmp-PDO][OAc], and benzaldehyde-[Nmp-PDO]
[OAc] mixture were compared, and the results are shown in Figure 1. The absorption peak
of carbonyl group in benzaldehyde was at 1698 cm−1, while it was redshifted to 1660 cm−1
in the mixture (Fig. 1). Furthermore, the 13C NMR spectrums of benzaldehyde and benzal-
dehyde-[Nmp-PDO][OAc] mixture were also compared (Figures S3, S4 in Supplementary
data); the chemical shift of carbonyl group in benzaldehyde was 193.23, while it was 193.44
in mixture. These results above hinted the existence of hydrogen bonding interactions
between the carbonyl group of aldehyde and hydroxyl groups in [Nmp-PDO][OAc].
Additionally, thermal gravimetric analysis (TGA) of [Nmp-PDO][OAc] and
[Nmp-PDO][Gly] was also studied at the range of 25–650 °C, with a temperature ramp rate
of 10 °C/min under nitrogen atmosphere (Figures S1,S2. see supporting info.). As TG
diagram indicates, [Nmp-PDO][OAc] showed a stable structure up to 210 °C (initial
thermal decomposition temperature) and [Nmp-PDO][Gly] up to 200 °C.
Conclusion
Readily available and eco-friendly Nmp-based ILs are developed as the efficient and
recyclable catalysts for both hetero-Michael addition of α,β-unsaturated amides and
Knoevenagel condensation in water; and all the examined substrates can be transformed into
corresponding products in good to excellent yields. Meanwhile the hetero-Michael addition
performed in water is rare, especially when using relatively inactive α,β-unsaturated amides
as Michael acceptors; and IL-catalyzed hetero-Michael addition of α,β-unsaturated amides in
water has not been reported in the previous literatures. Moreover, several N-substituted
acrylamides are successfully used as the Michael acceptors in the IL-catalyzed thio-Michael
addition; only the unsubstituted acrylamide could be transformed into the relevant
thio-Michael adduct in water by previous methods. Additionally, the catalyst is recyclable
for the two reactions. All the results thus represent a green catalyst for both hetero-Michael
addition of α,β-unsaturated amides and Knoevenagel condensation in water.
Experimental section
General procedure for Michael condensation
Sulfur or nitrogen nucleophile 1 (0.5 mmol), α,β-unsaturated amides 2 (0.5 mmol),
[Nmp-PDO][OAc] (10 mol %), and water (1 mL) were added into a 25-mL Schlenk tube
and stirred at room temperature. Upon completion of the reaction (monitored by TLC),
the reaction mixture was extracted with ethyl acetate (3 � 5 mL), the organic and aqueous
layers were separated, and the aqueous layer was extracted with EtOAc (2 � 5 mL). The
combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified
by column chromatography on silica gel using petroleum ether/ethyl acetate as eluent to
afford target product 3.
3-(Phenylthio)propanamide (3c)
Eluent: petroleum ether/ethyl acetate (6:1). Yield 81 mg (90%). White solid, mp 116–118 °C.
1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.37 (d, J ¼ 7.3 Hz, 2H), 7.33–7.27 (m,2H), 7.21
(t, J ¼ 7.3 Hz, 1H), 5.57 (s, 2H), 3.21 (t, J ¼ 7.3 Hz, 2H), 2.52 (t, J ¼ 7.3 Hz, 2H).

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13C NMR (CDCl3, 100 MHz, 25 °C) δ 173.2, 135.3, 129.8, 129.1, 126.5, 35.3, 29.2. ESI-MS
[M þH]þ m/z 182.18; [M þ Na]þ 204.15.
General procedure for Knoevenagel condensation
A mixture of activated methylene compound 4 (0.5 mmol), carbonyl compound 5
(0.5 mmol), IL catalyst (10 mol%), and water (1 mL) was stirred at room temperature in
a 25-mL round-bottomed flask. Upon completion of the reaction (monitored by TLC),
the reaction mixture always solidified in the round-bottomed flask, then the solidified mix-
ture was filtered and washed with cold water (5 mL) to remove IL catalyst, and evaporated
under reduced pressure to obtain the target products 6. The product of 6l was purified by
column chromatography on silica gel using petroleum ether/ethyl acetate (8:1) as the eluent
and got pure product after the solvent was removed under reduced pressure.
2-Benzylidenemalononitrile (6a)
Yield 73 mg (95%). White solid, mp 84–85 °C. 1H NMR (CDCl3, 400 MHz, 25 °C) δ 7.94–7.88
(d, 2H), 7.79 (s, 1H), 7.67–7.61 (t, 1H), 7.59–7.51 (m, 2H). 13C NMR (CDCl3, 100 MHz, 25 °C)
δ 160.0, 134.7, 131.0, 130.8, 129.7, 113.7, 112.6, 82.9. APCI-MS [M − H]− m/z 154.03.
Funding
This work was supported by National Natural Science Foundation of China (Grant Nos. 21502042,
51403051, 21477033), Scientific Research Key Project Fund of Henan Provincial Education Depart-
ment (Grant Nos. 15A150041, 16A150003), Scientific Research Fund of Henan University (No.
2013YBZR008).
ORCID
Hao Xu
http://orcid.org/0000-0002-6069-3246
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