Efficient three-component one-pot synthesis of fully substituted pyridin-2(1H)-ones via tandem Knoevenagel condensation-ring-opening of cyclopropane-intramolecular cyclization

Article abstract of DOI:10.1039/b905742k

An efficient synthesis of fully substituted pyridin-2(1H)-ones was developed via three-component one-pot reactions of readily available 1-acetyl-1-carbamoyl cyclopropanes, malononitrile and cyclic secondary amines.

Full text of DOI:10.1039/b905742k

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Efficient three-component one-pot synthesis of fully substituted
pyridin-2(1H)-ones via tandem Knoevenagel condensation–ring-opening
of cyclopropane–intramolecular cyclizationw
Fushun Liang,* Xin Cheng, Jing Liu and Qun Liu
Received (in Cambridge, UK) 23rd March 2009, Accepted 24th April 2009
First published as an Advance Article on the web 13th May 2009
DOI: 10.1039/b905742k
An efficient synthesis of fully substituted pyridin-2(1H)-ones was
developed via three-component one-pot reactions of readily
available 1-acetyl-1-carbamoyl cyclopropanes, malononitrile
and cyclic secondary amines.
isolated after work-up and column chromatography gave
these in 32% and 28% yield, respectively. The structures of
2a and 2b were characterized as fully substituted pyridin-
2(1H)-ones on the basis of their spectra and analytical data
(Scheme 1). Clearly, both piperidine and malononitrile take
part in the ring-opening reaction of the cyclopropane, leading
to different pendant groups on the pyridin-2(1H)-one frame-
work. It was reasonable to believe that either 2a or 2b may
be achieved as the main product after optimization of the
reaction.
The utility of cyclopropane derivatives in organic synthesis
has been recognized due to their well-known ‘‘unsaturated’’
character, which can lead to a variety of ring-opening reactions
under the influence of a wide range of reactive species, such
as electrophiles, nucleophiles, and radicals.1 In our previous
work, the ring-opening/ring closure reactions of 1-acetyl-1-
carbamoyl cyclopropanes were developed for the synthesis
of furoquinolines2a under metal catalyst, and halogenated
pyridin-2(1H)-ones under Vilsmeier conditions.2b In conjunction
with these studies and our continued interest regarding the
synthetic potential of double EWGs (electron-withdrawing
groups) activated cyclopropanes towards various carbo- and
heterocycles,3 we explored the Knoevenagel reaction4 of
1-acetyl-1-carbamoyl cyclopropanes and malononitrile5 in
the presence of piperidine. As a result of the research, we
developed a straightforward and efficient synthesis of fully
functionalized pyridin-2(1H)-ones6 of types 2 and 3 via a
one-pot three-component tandem reaction. 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 The
development of three-component reactions on appropriately
substituted cyclopropanes has been reported by separate
groups.8 Herein, we wish to communicate our preliminary
results.
With this idea in mind, we modified the reaction in Scheme 1
by varying of the amount of malononitrile and piperidine in
the reaction system. Upon treatment of 1a with malononitrile
(1.1 equiv.) and piperidine (2.0 equiv.), the reaction exclusively
afforded 2a in 68% yield (Table 1, entry 1). In the following
work, a variety of 1-acetyl-1-carbamoyl cyclopropanes 1 were
subjected to the reactions under identical conditions (Table 1).
It was observed that cyclopropane substrates 1b–d bearing a
variety of amide groups were efficient for the three-component
reaction, giving the corresponding pyridin-2(1H)-ones 2b–d in
high yields (entries 2–4). When the R1 group on substrates 1
was changed to methyl, the desired cyclization product could
not be attained (entry 5). In the case of cyclopropane substrate
1e with a methyl substituent on the cyclopropyl ring, the
reaction proceeded smoothly to furnish pyridin-2(1H)-one 2f
as a single regioisomer in 58% yield (entry 6). Such a regio-
selective ring-opening is in accordance with the results
observed in similar ring-enlargement reactions.2,9 In order to
determine the scope with respect to the amine component, and
to prepare multisubstituted pyridin-2(1H)-ones with different
amine group, morpholine and pyrrolidine were selected. To
our delight, the reactions of 1a, 1d and 1g with morpholine
and malononitrile, under identical conditions afforded the
desired pyridin-2(1H)-ones 2g–i in 60–65% yield (entries 7–9).
Similarly, the reaction of 1d with pyrrolidine and
malononitrile also gave a satisfactory result and 2-amino-4-
methyl-6-oxo-1-phenyl-5-(2-(pyrrolidin-1-yl)ethyl)-1,6-dihydro-
pyridine-3-carbonitrile 2j was obtained in 66% yield
The substrates, 1-acetyl-1-carbamoyl cyclopropanes 1, were
prepared following the procedure described by our group.2
With substrates 1 in hand, we selected 1-acetyl-N-phenylcyclo-
propanecarboxamide 1a as the model compound to examine
the three-component reaction. The mixture comprising 1a,
malononitrile (2.0 equiv.) and piperidine (2.0 equiv.) was
stirred in anhydrous DMF solution (5.0 mL) at room
temperature. As indicated by TLC, the reaction proceeded
smoothly and the two products 2a and 3a were successfully
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: liangfs112@nenu.edu.cn;
Fax: +86 431-8509-9759
w Electronic supplementary information (ESI) available: Experimental
details and characterization for all new compounds. CCDC 714333
(4b). For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b905742k
Scheme 1 Reaction of 1a with malononitrile in the presence of
piperidine.
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Table
1
Three-component one-pot reactions leading to multi-
60–83% yield (entries 2–5). Likewise, other secondary amines
such as morpholine and pyrrolidine were also subjected to
reaction sequences. Consequently, in the reactions of 1a or 1g
with malononitrile and morpholine, pyridin-2(1H)-ones 3a
and 3f were obtained in 72 and 76% yield, respectively
(entries 6 and 7). Pyrrolidine also proved to be effective in the reac-
tions of 1a or 1d with malononitrile, giving 3a in 62% yield and
3d in 64% yield (entries 8 and 9). From the above one can see
that the formation of either 2 or 3 as the main product
was dependent on the feed ratio between the amine and
malononitrile used in the reaction. The pyridin-2(1H)-ones
of types 2 and 3 with molecular versatility and multi-
substitutions indicated the efficiency of the three-component
one-pot reaction. Furthermore, the functional groups on
the framework and the flexible placement of the latent
functionalities in these products make them extremely versatile
intermediates in further synthetic transformations.
substituted pyridin-2(1H)-ones 2a
Yieldb
(%)
Entry
1
R1
R2
X
Time/h
2
1
2
3
4
5
6
7
8
9
10
1a
1b
1c
1d
1e
1f
1a
1d
1g
1d
Ph
H
H
H
H
H
Me
H
H
H
H
CH2
CH2
CH2
CH2
CH2
CH2
O
O
O
nil
2.5
2.0
2.5
3.5
8.0
3.0
2.5
2.5
2.5
3.0
2a
2b
2c
2d
2e
2f
2g
2h
2i
68
78
65
64
n.r.
58
60
61
65
66
4-ClPh
4-MePh
2,4-Me2Ph
Me
Ph
Ph
2,4-Me2Ph
2-Cl
2,4-Me2Ph
To gain insight into the mechanism of the multi-component
reaction of 1-acetyl-1-carbamoyl cyclopropanes, malononitrile
and piperidine, reactions based on acetylacetamides containing
a 2,2-diethyl or cyclopentyl group2,3a with malononitrile and
piperidine were conducted under otherwise identical conditions
(Table 3). However, the reaction with 2,2-diethyl-3-oxo-N-
phenylbutanamide 1h gave none of the expected cyclization
product 4a. Instead, a Knoevenagel condensation product 5a
was obtained in high yield (entry 1). As for their cyclopentyl
counterparts 1i and 1j, the corresponding pyridin-2(1H)-ones
4b and 4c could be obtained, but in fairly low yield (18% for
4b and 20% for 4c, entries 2 and 3) and prolonged reaction
time (24 h).10 The structure of 4b was confirmed by single-
crystal X-ray analysis (Fig. 1). The Knoevenagal condensation
products 5b and 5c were demonstrated as the main products.11
On the basis of all the results mentioned above, a possible
mechanism for the synthesis of substituted pyridin-2(1H)-ones
of type 2 was proposed, as depicted in Scheme 2. The overall
transformation involves tandem Knoevenagel condensation of
1 and malononitrile with piperidine as the base, ring-opening
reaction of cyclopropane with piperidine as the nucleo-
phile and intramolecular cyclization sequences. Interestingly,
piperidine plays dual roles of both a base (twice) and a
nucleophile (once) in the explored reactions. Similarly, when
malononitrile acts as a nucleophile to fragment the cyclo-
propane moiety, the corresponding pyridin-2(1H)-ones 3
would be produced. The experimental results presented in
Tables 1–3 demonstrate that the formation of the allene-type
imino intermediate II via the ring-opening of cyclopropane, is
favorable for the formation of fully substituted pyridin-2(1H)-
ones.
2j
a
b
1 : malononitrile : amine = 1 : 1.1 : 2.0. Isolated yields after
purification by recrystallization in ethanol.
(entry 10). It is noteworthy that all the crude products 2 could
be purified simply by recrystallization from ethanol.
Next, with the aim to make product 3a in Scheme 1 to be the
main product, we increased the amount of malononitrile and
decreased that of piperidine simultaneously. After several
trials, we found that when the feed ratio of 1a–malononitrile–
piperidine was 1 : 2.1 : 0.2, product 3a could be obtained in a
yield of 64% (Table 2, entry 1). Further decrease in the
amount of piperidine to 0.1 equiv. was not enough to drive
the reaction to completion. Under the optimized conditions
mentioned above, a series of 1-acetyl-1-carbamoyl cyclo-
propanes 1b–d and 1f were reacted with malononitrile
(2.1 equiv.) in the presence of piperidine (0.2 equiv.). The
multi-component reactions proved to be efficient, affording the
corresponding highly substituted pyridin-2(1H)-ones 3b–e in
Table
2 Three-component one-pot reactions leading to multi-
substituted pyridin-2(1H)-ones 3a
Yieldb
(%)
Entry
1
R1
R2
X
Time/h
3
In summary, an efficient and divergent synthesis of fully
substituted pyridin-2(1H)-ones 2 and 3 has been developed
based on the three-component one-pot reaction of readily
available 1-acetyl-1-carbamoyl cyclopropanes 1, malononitrile
and secondary amines such as piperidine, morpholine or
pyrrolidine. The overall transformation involves tandem
Knoevenagel condensation of 1 with malononitrile, ring-
opening reaction of activated cyclopropane towards a C–N
nucleophile and intramolecular cyclization sequences. This
protocol is associated with readily available starting materials,
mild conditions, dense and flexible substitution patterns,
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1f
1a
1g
1a
1d
Ph
H
H
H
H
Me
H
H
H
H
CH2
CH2
CH2
CH2
CH2
O
O
nil
nil
2.5
2.5
3.5
3.5
2.5
3.0
3.0
3.5
4.0
3a
3b
3c
3d
3e
3a
3f
64
83
60
65
66
72
76
62
64
4-ClPh
4-MePh
2,4-Me2Ph
Ph
Ph
2-Cl
Ph
2,4-Me2Ph
3a
3d
a
b
1 : malononitrile : amine = 1 : 2.1 : 0.2. Isolated yields after
purification by recrystalization in ethanol.
ꢀc
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Table 3 Reactions of acetylacetamides containing a 2,2-diethyl or cyclopentyl group with malononitrile and piperidinea
Entry
1
R1
R3 or (R3,R3)
Time/h
4 (yield, %)b
5 (yield, %)b
1
2
3
1h
1i
1j
Ph
4-ClPh
4-OMePh
Et
(CH2)4
(CH2)4
24
24
24
4a (0%)
4b (18%)
4c (20%)
5a (85%)
5b (74%)
5c (70%)
a
b
Reagents and conditions: 1 (1.0 mmol), malononitrile (2.0 mmol), piperidine (2.0 mmol), room temperature. Isolated yields.
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231–293.
Fig. 1 ORTEP drawing of 4b.
7 For reviews on multi-component reactions, see: (a) G. H. Posner,
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potential synthetic utility of the final products, and easy
control of the reaction orientation by reaction conditions
selection. Further research is ongoing in our laboratory.
Financial support of this research by NENU’S Scientific
Innovation Project (NENU-STC08013 and NENU-STB07007),
analysis and test foundation of Northeast Normal Unicersity and
the Department of Science and Technology of Jilin Province
(20080421) is greatly acknowledged.
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ꢀc
This journal is The Royal Society of Chemistry 2009
3638 | Chem. Commun., 2009, 3636–3638