Multicomponent reaction of chalcones, malononitrile and DMF leading to γ-ketoamides

Article abstract of DOI:10.1039/c4ob00971a

An efficient synthesis of γ-ketoamides was developed by the one-pot multicomponent reaction of chalcones, malononitrile and DMF (as both the reactant and solvent) in the presence of NaOH (3.0 equiv.). The reaction features high atom economy, easily availa

Full text of DOI:10.1039/c4ob00971a

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Biomolecular Chemistry
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Multicomponent reaction of chalcones,
malononitrile and DMF leading to γ-ketoamides†
Enxiang Wei,a Bing Liu,a Shaoxia Lina and Fushun Liang*a,b
Cite this: Org. Biomol. Chem., 2014,
12, 6389
Received 11th May 2014,
Accepted 27th June 2014
An efficient synthesis of γ-ketoamides was developed by the one-pot multicomponent reaction of chal-
cones, malononitrile and DMF (as both the reactant and solvent) in the presence of NaOH (3.0 equiv.).
The reaction features high atom economy, easily available starting materials, operational simplicity, and
good tolerance with diverse functional groups.
DOI: 10.1039/c4ob00971a
www.rsc.org/obc
source in organic transformation. On the other hand, the mul-
ticomponent protocol provides a new and efficient entry to
Introduction
4-Oxobutanamides1 constitute the core structure of quite a lot γ-ketoamide derivatives.
of naturally occurring and unnatural compounds, which
display important pharmacological and biological pro-
perties.2,3 In this context, development of convenient and
Results and discussion
efficient methods toward such types of products is of great sig-
nificance. Recently, we reported the reaction of chalcones and
malononitrile4 with K2CO3 as the base, affording 4-oxo-butane-
nitrile derivatives,5 in which malononitrile is used as an
organic cyanide source6 (Scheme 1). In continuation of this
research, we found that, in the presence of excess base and
under otherwise identical conditions, 4-oxobutanamides could
be assembled via a multicomponent process. Multicomponent
reactions (MCRs) have been refined in recent years as powerful
and useful tools in synthetic chemistry and have attracted
increasing attention due to the advantages of greater
efficiency, atom economy and structural complexity.7 On one
hand, the present result further demonstrates the feasibility
and validity of using malononitrile as an organic cyanide
Initially, the model reaction of chalcone 1h with malononitrile
was examined under basic conditions (Table 1). For the reac-
tion system in DMF with 3.3 equiv. of K2CO3 as the base,
N,N-dimethyl-4-oxo-2,4-diphenylbutanamide (3h) was isolated
in 26% yield after 72 h (entry 1). To our delight, when NaOH
(3.3 equiv.) was used as the base, the product 3h was obtained
in 92% yield within 48 h (entry 2). However, a stronger base
like t-BuOK gave slightly lower yield (entry 3). By comparison,
in the case of using organic bases such as piperidine, DABCO
and DBU, no target product was observed (entries 4–6).
With the optimal conditions established above (Table 1,
entry 1), a range of reactions was carried out with various sub-
strates
1 and malononitrile in the presence of NaOH
(3.3 equiv.) in DMF (Table 2). The scope of the substitutes on
Table 1 Optimization of the reaction conditionsa
Entry
Base (3.3 equiv.)
Time (h)
Yieldb (%)
Scheme 1
1
2
3
4
5
6
K2CO3
NaOH
t-BuOK
Piperidine
DABCO
DBU
72
48
48
72
72
72
26
92
88
n.d.
n.d.
n.d.
aDepartment of Chemistry, Northeast Normal University, Changchun 130024, China.
E-mail: liangfs112@nenu.edu.cn; Fax: (+86) 431-85099759
bKey Laboratory for UV-Emitting Materials and Technology of Ministry of Education,
Northeast Normal University, Changchun 130024, China
†Electronic supplementary information (ESI) available. CCDC 996425 (3p). For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4ob00971a
a Reactions were carried out with 1h (1.0 mmol) and malononitrile
(1.1 equiv.) in DMF (4.0 mL) at rt. b Isolated yield. n.d. = not detected.
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Table 2 Scope of substratesa
Entry
Ar1
Ar2
3
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
84
91
92
71
78
84
89
92
86
87
63
78
79
72
71
73
68
74
67
83
Fig. 2 X-ray crystal structure of 3p.
2-Naphthyl
2-Furyl
2-Thienyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-Me2NC6H4
3,4-O2CH2Ph
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
3-NO2C6H4
1-Naphthyl
2-Furyl
2-Thienyl
9
10
11
12
13
14
15
16
17
18
19
20
Scheme 2 Control experiment.
3s
3t
a Reactions were carried out with
1 (1.0 mmol), malononitrile
(1.1 equiv.), NaOH (3.3 equiv.) in DMF (4.0 mL) at rt for 48 h. b Isolated
yield.
the enone substrates 1 was investigated. Substituent Ar1 may
be phenyl (Table 2, entry 2), electron-rich aryls (Table 2,
entries 1 and 3), electron-deficient aryl (Table 2, entry 4),
2-naphthyl (Table 2, entry 5) and heteroaryl (Table 2, entries 6
and 7). The Ar2 substituents include electron-rich aryls
(Table 2, entries 8–12), halogen-substituted phenyl (Table 2,
entries 13–16), 3-nitrophenyl (Table 2, entry 17), 1-naphthyl
(Table 2, entry 18) and heteroaryl groups (Table 2, entries 19
and 20). The scope of the reaction was further explored in
regard to α,β-unsaturated carbonyl compounds as the sub-
strates (Fig. 1). Nevertheless, 4-(4-bromophenyl)-3-buten-2-one
and 4,4-dimethyl-1-phenylpent-1-en-3-one gave only a trace
amount of the target products. Ethyl cinnamate and cinnamal-
dehyde gave no desired products, when subjected to otherwise
identical conditions. The structure of 3p was confirmed by
X-ray single crystal diffraction (Fig. 2). All the above results
indicated the efficiency of the reactions which could proceed
smoothly to afford the corresponding γ-ketoamides in moder-
ate to excellent yields (63–92%).
Scheme 3 Plausible mechanism for the formation of γ-ketoamides.
from separately isolated intermediate, 4-oxo-2,4-diphenylbutane-
nitrile (2a), product 3a could be obtained in 91% yield with
NaOH (2.2 equiv.) as the base and DMF as the solvent in
0.5 h.8
Although the exact mechanism was still unclear, a plausible
mechanism for the formation of 4-oxobutanamides 3 was ten-
tatively proposed in Scheme 3. Cyanated intermediate 2 5,9 is
generated first, which further reacts with dimethylamine10 lib-
erated in situ from DMF under a strong alkaline environ-
ment,11 to give almidine intermediate II.12 Hydrolysis of the
intermediate II delivers the final γ-ketoamide product 3.13
Conclusion
In order to elucidate the possible mechanism for the reac-
tion, a control experiment was carried out (Scheme 2). Starting
In summary, we have developed a convenient and efficient
method for the synthesis of functionalized 4-oxobutanamides
from simple α,β-unsaturated enones and malononitrile in
DMF. The one-pot multicomponent reaction features readily
available starting materials, broad substrate scope, mild con-
ditions and high efficiency. Ongoing studies are focused on
applying this reaction to more complex molecules as well as
gaining detailed insights into the reaction mechanism.
Fig. 1 Further exploration on the substrate scope.
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Experimental
General procedure for the preparation of 3. Synthesis of 3h
General procedure for the preparation of 3 (3h as an example):
to
a mixture of (E)-1-phenyl-3-(p-tolyl)prop-2-en-1-one 1h
(1 mmol, 0.2221 g) in 4 mL of DMF was added NaOH
(3.3 mmol, 0.1320 g). The reaction mixture was stirred at room
temperature for 48 h. After the reaction was completed (moni-
tored by TLC), the resulting mixture was concentrated under
reduced pressure and the residue was purified through
column chromatography on silica gel (eluent, petroleum
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yellow oil in 92% yield.
N,N-Dimethyl-4-oxo-4-phenyl-2-(p-tolyl)butanamide (3h)
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2.95 (s, 3H), 3.03 (s, 3H), 3.05 (d, J = 3.5 Hz, 1H), 4.08–4.14 (m,
1H), 4.49–4.52 (m, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.25 (t, J =
7.5 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.53 (t, J = 7.5 Hz, 1H), 7.97
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Acknowledgements
Financial support from the National Natural Science Foun-
dation of China (21172034 and 21372039) and Program for
New Century Excellent Talents in University (NCET-11-0611) is
gratefully acknowledged.
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