Synthesis of 2-cyanoacrylamides through Pd-catalyzed monohydration of methylenemalononitriles

Article abstract of DOI:10.1080/00397911.2018.1542496

A straightforward and efficient method has been developed for the synthesis of 2-cyanoacrylamide from 2-methylenemalononitriles through monohydration. A series of methylenemalononitriles underwent the reaction under mild and simple reaction conditions wit

Full text of DOI:10.1080/00397911.2018.1542496

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis of 2-cyanoacrylamides
through Pd-catalyzed monohydration of
methylenemalononitriles
Yingtian Liu, Xinxin Dang, Yu He, Hudong Bai, Xuehong Chen, Jun-Long Li,
Junting Fan, Hezhong Jiang & Jiahong Li
To cite this article: Yingtian Liu, Xinxin Dang, Yu He, Hudong Bai, Xuehong Chen, Jun-Long
Li, Junting Fan, Hezhong Jiang & Jiahong Li (2019): Synthesis of 2-cyanoacrylamides through
Pd-catalyzed monohydration of methylenemalononitriles, Synthetic Communications, DOI:
10.1080/00397911.2018.1542496
To link to this article: https://doi.org/10.1080/00397911.2018.1542496
Published online: 12 Feb 2019.
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https://doi.org/10.1080/00397911.2018.1542496
Synthesis of 2-cyanoacrylamides through Pd-catalyzed
monohydration of methylenemalononitriles
Yingtian Liua, Xinxin Danga, Yu Hea, Hudong Baia, Xuehong Chena, Jun-Long Lib,
Junting Fanc, Hezhong Jianga, and Jiahong Lia
aDepartment School of Life Science and Engineering Institution, Southwest Jiaotong University,
b
Chengdu, China; Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan
c
Industrial Institute of Antibiotics, Chengdu University, Chengdu, China; Department of Pharmaceutical
Analysis School of Pharmacy, Nanjing Medical University, Nanjing, China
ABSTRACT
ARTICLE HISTORY
Received 29 June 2018
A straightforward and efficient method has been developed for the
synthesis of 2-cyanoacrylamide from 2-methylenemalononitriles
through monohydration. A series of methylenemalononitriles under-
went the reaction under mild and simple reaction conditions with
good to excellent yield.
KEYWORDS
Methylenemalononitriles;
mild condition;
monohydration; palladium
acetate catalyzed;
2-cyanoacrylamides
GRAPHICAL ABSTRACT
Introduction
The hydration of nitriles is a significant reaction for synthesis of functionalized amides,
which not only exhibits chemical and pharmacological interest but also serves as versa-
tile building blocks.[1] Traditionally, hydration of nitrile through various strong acids or
bases have been widely explored and demonstrated as a versatile and powerful tool for
construction of amide.[2] However, under these conditions, starting nitriles and amides
are possible to form carboxylic acids, which decreases the selectivity. Moreover, sensitive
functional groups might not withstand such harsh conditions. In this context, much
effort has been directed toward the search, and the main approaches for alternative
catalyst fall into enzymes[3] and a broad spectrum of transition metals.[4] For example,
the monohydration of b-hydroxyglutarodinitrile with MnO2/SiO2 was reported by
Breuilles and coworkers.[5] Grigg et al. investigated the monohydration of a series of
CONTACT Hezhong Jiang
jianghz10@sina.com; Jiahong Li
jiahongljh@163.com
Department School of Life
Science and Engineering Institution, Southwest Jiaotong University, Chengdu, 610041, China.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis

2
Y. LIU ET AL.
Dong's work:
NC
R
CONH
NC
R
CN
2
Cu(OAc)
2
(1)
R
2
R
2
1
1
Foucaud's work:
NC
CONH
2
O
O
base
+
NH
2
(2)
R
R
CN
Xie's work:
NC
CN
NC
R
CONH
2
pH=9~10
pH=1~3
+
H N
2
OH HCl
(3)
R
1
R
2
R
2
1
Rode's work:
O
CN
CN
NC
CONH
2
Fe3O4/PVP-PWA
+
(4)
R
1
R
1
this work:
NC
R
CN
NC
CONH
2
Pd(OAc)
2
R
2
R
R
2
1
1
Scheme 1. “Different approaches for the synthesis of 2-cyanoacrylamides.”
malononitriles with KF ꢀ Al2O3 in t-BuOH.[6] Kiss revealed that the mixture of mono-
and diamides could be formed by the modification of molecular sieves with
copper(II).[7] Garca-Garrido and Rajender S. Varma reported the hydration of nitriles
under microwave irradiation conditions.[8] Hydration of methylenemalononitriles with
oximes catalyzed by MnO2 was revealed by Ashfaq.[9]
2-Cyanoacrylamide scaffolds have potential bioactivities such as reversible cysteine-tar-
geted Michael acceptors to inhibit RSK2, MSK1 kinases.[10] They also inhibit dengue
and West Nile virus serine proteases (NS2B–NS3).[11] It is recognized that methoxy-sub-
stituted aryl 2-cyanoacrylamides are reversible thiol conjugate addition acceptors in
dynamic combinatorial chemistry.[12] Therefore, the development of novel and efficient
methods for synthesis of 2-cyanoacrylamides remain highly desirable. In 2013, Dong’s
group investigated the monohydration of 2-benzylidenemalononitrile with copper(II)
acetate catalysts (Scheme 1. Eq. (1)).[13] Direct Knoevenagel condensation reactions of
aldehydes with cyanoacetamides have also been reported (Scheme 1. Eq. (2)).[14] Xie’s
group used tandem reaction, starting with NH2OHꢁHCl and methylenemalononitriles in
alkaline environment followed by acidizing to pH of 1–3 (Scheme 1. Eq (3)).[15] In 2016,
Chandrashekhar V.Rode reported a tandem reaction to synthesize 2-cyanoacrylamides
with a ferrite-based solid acid composite of Fe3O4, poly(vinylpyrrolidone), and

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SYNTHETIC COMMUNICATIONSV
3
Table 1. Hydration of substrates under different conditions.
entry
1c
catalyst
Pd(OAc)2
solvent
H2O
time
20 h
yieldb(%)
0
2
3
4
5
Pd(OAc)2
Pd(PPh3)4
PdCl2COD
PdCl2(Amphos)
PdCl2
AcOH
AcOH
AcOH
AcOH
2 h
2 h
2 h
2 h
81
64
Trace
21
9
6
AcOH
2 h
7
8
9
PdCl2(PPh3)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AcOH
DCE
1,4-dioxane
EtOH
DMSO
toluene
DCE
AcOH
CH3CH2COOH
HCOOH
TFA
4M H2SO4
4M HCl
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
2 h
2 h
2 h
2 h
2 h
2 h
2 h
10 min
Trace
n.r.
n.r.
n.r.
n.r.
n.r.
19
31
69
74
11
24
n.r.
9
87
81
65
84
91
89
10
11
12
13d
14
15
16
17
18
19
20
21e
22f
23g
24f,h
25f,i
26f,j
2 h
10 min
10 min
10 min
10 min
20 h
10 min
10 min
10 min
10 min
10 min
10 min
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
aReaction conditions unless otherwise specified: 1a (0.325 mmol), solvent (2 mL), 80 ꢂC.
bIsolated yield.
cAdditional 0.2 equivalent CTAB.
dAdditional 4 equivalent AcOH was added.
e5 mol% of catalyst.
f2.5 mol% of catalyst.
g1 mol% of catalyst.
h60 ꢂC.
i40 ꢂC.
jRoom temperature.
phosphotungstic acid (Scheme 1. Eq (4)).[16] Although a number of modified methods
under improved conditions have been reported, many of them suffer from a drawback
that the reaction cannot complete in short time under mild conditions. Herein, we
report an efficient protocol for the synthesis of 2-cyanoacrylamides from the Pd-
catalyzed monohydration of methylenemalononitrile at room temperature in 10 revised
Scheme 1.
Result and discussion
In an initial study, substrate 1a was subjected to water in the presence of 20 mol%
ꢂ
CTAB and 10 mol% palladium acetate at 80 C (Table 1, entry 1), but no monoamide

4
Y. LIU ET AL.
was observed. To our delight, the monohydration product 2a was obtained in 81% iso-
lated yield when the solvent was switched to acetic acid (Table 1, entry 2). Variations
on the catalysts showed that the use of palladium acetate gave the best yield, while the
lower yield of products was detected by using other catalysts, such as Pd(PPh3)4,
PdCl2COD, PdCl2(Amphos), PdCl2, and PdCl2(PPh3)2 (Table 1, entries 3–7). In terms
of solvent effect, no product was found in DCE, 1,4-dioxane, EtOH, DMSO, or
toluene (Table 1, entries 8–12). The addition of 4 equivalent of acetic acid in DCE
gave 19% yield of product (Table 1, entry 13). This result suggests that the acid is
necessary. Acid screening showed that formic acid dramatically increased the reaction
rate as well as yield, such that good yield was obtained only after 10 min (Table 1,
entry 16). Propionic acid, trifluoroacetate acid, and other inorganic acids
gave inferior results (Table 1, entry 15, 17–19). Interestingly, without any catalyst,
the hydration of 1a could hardly proceed in the formic acid (Table 1, entry 20).
Upon a decrease of the amount of Pd(OAc)2 to 2.5 mol%, the reaction of 1a
provided the product in 81% yield (Table 1, entry 22). Further decrease of
the amount of Pd(OAc)2 would lead to the incomplete reaction (Table 1, entry
23). Lowering the reaction temperature had no significant influence on the
reaction, and it could give excellent results even at room temperature
(Table 1, entry 26).
With the optimal reaction condition in hand, we moved on to explore the scope of
the substrate. The results are constructed in Table 2. Overall, benzylidenemalononitriles
with electron-withdrawing or electron-donating groups, such as Cl, NO2, MeO, and
Me were compatible with the reaction conditions and gave corresponding
amides with good to excellent yield (Table 2, entries 1–11). Ortho-, meta- and
para-substituted benzylidenemalononitriles also exhibited high conversions. The
high yields and short reaction time of these substrates suggest that the rates were
barely influenced by the electronic effects. Heteroaromatic nitriles were also found to
participate smoothly in the reaction and formed monoamides in 92% and 77%
yield, respectively (Table 2, entries 14–15). It also displayed high activity for
alkenyl nitrile as well as aliphatic nitrile (Table 2, entries 16–17), which again
demonstrated its wide substrate scope. Notably, the methylenemalononitriles
1b–q were hydrated to pure (E)-monoamides 2b–q, which were verified by
1H-NMR.[16,17]
Having 2-monosubstituted methylenemalononitriles been investigated, more
experiments were conducted to test the substrate scope of the 2,2-disubstituted
methylenemalononitriles, which proceeded smoothly to afford amide products in mod-
erate yields. As shown in Table 2, 2-cyclohexylidenemalononitrile 1 s was hydrated to
corresponding amide in prolonged reaction time and 78% yield (Table 2, entry 18). It
was worth noting that 1t–w could give a mixture of (E)- and (Z)-2-cyanoacrylamide
2t–w (Table 2, entry 19), which may due to the steric hindrance of 2-substituent group.
2, 2-Diphenylsubstituted 1x gave monoamide 2x in 78% yield (Table 2, entry 23).
Different kinds of 2-substituent groups could give moderate yield of monoamides,
which demonstrated that the mild reaction condition is compatible for a wide scope
of substrates

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SYNTHETIC COMMUNICATIONSV
5
Table 2. Monohydration of 2-methylenemalononitriles 1 to 2-cyanoacrylamides 2.
entry
1
substrate
product
yieldb(%)
89
1b
1c
2b
2c
2d
2
3
4
5
6
92
92
90
92
84
1d
1e
2e
1f
2f
1g
2g
7
8
9
70
93
80
1h
1i
2h
2i
1j
2j
10
11
92
85
1k
1l
2k
2l
(Continued)

6
Y. LIU ET AL.
Table 2. (Continued).
12
90
57
1m
2m
13
1n
1o
2n
2o
14
15
92
77
1p
1q
2p
2q
2r
16
17
86
80
1r
1s
18c
19c
78
89
2s
1t
2t
20c
21d
22e
72
67
45
1u
1v
2u
2v
1w
1x
2w
23d
78
2x
aReaction conditions unless otherwise specified: 1 (0.325 mmol), Pd(OAc)2 (2.5 mol%), HCOOH (2 mL), room tempera-
ture, 10 min.
bIsolated yield.
cReact for 7 h.
dReact for 4 h.
eReact for 2 h.

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7
Experimental section
General methods
Unless otherwise noted, all reagents were obtained from commercial suppliers and used
without further purification. Pd(OAc)2 was purchased from Xiya reagent.
Methylenemalononitriles were prepared according to the literature procedures. The
products were purified by column chromatography over silica gel (300–400 mesh). TLC
was performed on glass-backed silica plates. NMR spectra were obtained on a JNM-
1
ECZ600R/S1 spectrometer. NMR data were obtained for H at 600 MHz and for 13C at
1
150 MHz. The H NMR (600 MHz) chemical shifts were measured relative to CDCl3 or
DMSO-d6 as the internal references (CDCl3: d = 7.26, DMSO-d6: d = 2.50). The 13C
NMR (150 MHz) chemical shifts were given using DMSO-d6 as the internal references
(DMSO-d6: d = 39.52). ESI HRMS was recorded on a Waters SYNAPT G2 and Water
XEVO G2 Q-ToF.
General procedure for synthesis of monoamides 2
A mixture of 2-substituted methylenemalononitrile (0.325 mmol) and Pd(OAc)2 (1.82
mg, 2.5 mol%) in HCOOH (2.0 mL) was stirred at room temperature for 10 min and
then diluted with water. The mixture was saturated with sodium carbonate until the pH
= 7–8, followed by extraction with dichloromethane (3 ꢃ 20 mL). The combined
organic phase was washed with saturated brine (3 ꢃ 20 mL), dried over Na2SO4, fil-
tered, and concentrated in vacuo. The crude product was purified by flash chromatog-
raphy (silica gel, petroleum ether:ethyl acetate = 2:1) to give (E)- Monoamides.
General procedure for synthesis of methylenemalononitriles
Malononitrile (9.5 mmol) and the aldehyde (9.5 mmol) were dissolved in 5 mL of
EtOH in a 50 mL flask, followed by adding one drop of triethylamine. After stirring at
room temperature for 2 h, filtrate the solid to give the crude products. Further purifica-
tion was completed by flash chromatography.
Conclusion
In conclusion, we have developed a concise method comprising Pd(OAc)2-catalyzed,
HCOOH-promoted monohydration of 2-methylenemalononitriles. This protocol pro-
vided a variety of cyanoamides in good to excellent yield, which have shown tolerance
of functional groups, mild condition and fast reaction rate, and thereby would be poten-
tially useful for practical applications
Funding
This work was supported by the Fund of Science and Technology Agency of Chengdu under
Grant No. 2015-HM01-00311-SF; the Administration of Traditional Chinese Medicine of Sichuan
under Grant No. 2016Q037; the fund of Antibiotics Research and Re-evaluation Key Laboratory
of Sichuan Province, Sichuan Industrial Institute of Antibiotics, Chengdu University under Grant

8
Y. LIU ET AL.
No. ARRLKF17-09, ARRLKF17-10; and the Fundamental Research Funds for the Central
Universities under Grant No. 2682017CX091.
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