Synthesis of zwitterionic salts of pyridinium-meldrum acid and barbiturate through unique four-component reactions

Article abstract of DOI:10.1021/cc900161z

An efficient synthetic procedure for the preparation of the unusual charge-separated pyridinium-Meldrum acid and N,N-dimethylbarbiturate acid zwitterionic salts was developed though a unique one-pot fourcomponent reaction involving pyridine, aromatic aldehyde, Meldrum acid or N,N-dimethylbarbituric acid, and p-nitrobenzyl bromide in acetonitrile. By varying combinations of four components involving nitrogencontaining heterocycles, we conveniently established reactiveα-halomethylene compounds, aldehydes and β-dicarbonyl compounds a library of zwitterionic salts.

Full text of DOI:10.1021/cc900161z

260
J. Comb. Chem. 2010, 12, 260–265
Synthesis of Zwitterionic Salts of Pyridinium-Meldrum Acid and
Barbiturate through Unique Four-component Reactions
Qi-Fang Wang, Li Hui, Hong Hou, and Chao-Guo Yan*
College of Chemistry & Chemical Engineering, Yangzhou UniVersity, Yangzhou 225002, China
ReceiVed October 14, 2009
An efficient synthetic procedure for the preparation of the unusual charge-separated pyridinium-Meldrum
acid and N,N-dimethylbarbiturate acid zwitterionic salts was developed though a unique one-pot four-
component reaction involving pyridine, aromatic aldehyde, Meldrum acid or N,N-dimethylbarbituric acid,
and p-nitrobenzyl bromide in acetonitrile. By varying combinations of four components involving nitrogen-
containing heterocycles, we conveniently established reactive R-halomethylene compounds, aldehydes and
ꢀ-dicarbonyl compounds a library of zwitterionic salts.
Introduction
involves pyridine, p-nitrobenzyl bromide, aromatic aldehydes
and Meldrum acid or barbituric acid.
As one kind of heterocyclic ammonium salts, the special
nature of pyridinium salts allows them to be used in a great
variety of synthetic reactions.1,2 Because of the aromatic
character of the pyridine heterocycle, its basicity, and the
electron-attracting influence of the nitrogen atom, pyridinium
cations in combination with strongly electron-withdrawing
substituent like carbonyl, cyano, or nitro groups increase the
activity and, hence, the synthetic utility of methylene groups.3
Pyridinium salts derived from R-halogenocarbonyl compounds
are easily deprotonated to give pyridium ylide, which are prone
to be high potential synthons and undergo versatile reactions.4,5
The most known reaction is Michael addition of active
methylene groups in pyridinium salts onto suitable acceptor
compounds to give polysubstituted pyridines and terpyridines,
in which the pyridyl unit is split off.6,7 The second widely used
reaction is 1,3-dipolar cycloaddition of pyridinium salt with
acetylene and activated alkenes to give indolizine derivatives,
in which the pyridyl unit is remained.8–11 The third kind of
reaction is tandem reaction of pyridinium salts with alkenes
bearing with electron-withdrawing groups to give the cor-
responding cyclopropanes12 and 2,3-dihydrofurans.13 Re-
cently, we realized that the versatile reactivity and very easily
in situ formation of pyridinium salts can be used to develop
multicomponent reactions and found some interesting
results. Polysubstituted pyridines,14 cyclopropanes,15 dihy-
drofuranes,16 and pyrido[1,2-a]benzimidazole derivatives17
could be produced efficiently from one-pot multicomponent
cyclization reaction involving pyridinium salts in situ. In
continuation of our efforts to investigate new one-pot
multicomponent reactions, we develop this kind of reaction
to other reactive methylene compounds. Here we wish to
report the formation of the unusual charge-separated pyri-
dinium-Meldrum acid and N,N-dimethylbarbituric acid zwit-
terionic salts via new four-component reactions which
Results and Discussion
The first R-halomethyl substrate we examined was p-
nitrobenzyl bromide. When a mixture of benzaldehyde,
Meldrum acid, p-nitrobenzyl bromide, and an excess of
pyridine in acetonitrile was stirred at room temperature for
two hours, TLC analysis clearly showed that p-nitroben-
zylpyridinium salt was formed in situ from the substitution
reaction of p-nitrobenzyl bromide to pyridine, and ben-
zylidene Meldrum acid was also formed in situ by Knoev-
enagel condensation of aromatic aldehyde with Meldrum acid
catalyzed by pyridine. But the reaction could not go further
even the mixture was stirred for additional two days. We
thought that the basicity of pyridine might too weak to
deprotonate the pyridinium salt to form pyridium ylide. One
stronger base triethylamine was added to the system. After
the mixture was stirred overnight, a lot of yellow precipitates
were formed. After carefully analysis it is found that an
unexpected zwitterionic salt 1a was produced in 78% yield.
1a has high polarity and high melting point, in which the
positive charge is on the pyridium nitrogen atom and the
negative charge is on methylene carbon atom, which is
further delocalized onto the two carbonyl groups of Meldrum
acid. This pyridinium-Meldrum acid zwitterion obviously
results from the reaction of N-p-nitrobenzylpyridium bromide
with arylidene Meldrum Acid which are both formed in situ.
Similarly, various aromatic aldehydes were tested under the
same conditions and the corresponding pyridinium-Meldrum
acid zwitterions 1b-1k were obtained in high yields (Table
1). This result demonstrated that aromatic aldehydes carrying
either electron-donating or electron-withdrawing substituents
showed similar reactivity and reacted efficiently to yield the
final products. As shown in Table 1, other pyridine deriva-
tives such as 3-picoline also gave the corresponding zwit-
terionic salts 2a-2f in very high yields (72-91%).
The structures of zwitterionic salts were fully characterized
* To whom correspondence should be addressed. E-mail: cgyan@
yzu.edu.cn.
1
by H and 13C NMR, MS, and IR spectra and elemental
10.1021/cc900161z  2010 American Chemical Society
Published on Web 01/21/2010

Synthesis of Zwitterionic Salts
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 261
Table 1. Zwitterionic Salts of Pyridinium-Meldrum Acid from
Reaction of p-Nitrobenzyl Bromide
Table 2. Zwitterionic Salts of Pyridinium-Meldrum Acid from
R-Phenacyl Bromide
entry
compd
Ar
R
yield (%)
entry
compd
Ar
R
yield (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
78
74
72
78
75
72
80
64
69
82
67
83
82
73
91
72
89
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
H
H
H
H
H
H
H
H
H
H
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
3-CH3
4-CH3
4-CH3
91
85
71
94
88
83
78
85
91
82
89
95
84
94
83
88
73
70
88
86
94
96
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-BrC6H4
p-EtC6H4
p-i-PrC6H4
m-PhOC6H4
m-CH3C6H4
m-ClC6H4
m-NO2C6H4
Ph
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-BrC6H4
p-EtC6H4
p-i-PrC6H4
m-PhOC6H4
m-ClC6H4
m-NO2C6H4
Ph
p-CH3C6H4
p-CH3OC6H4
p-ClC6H4
p-NO2C6H4
m-ClC6H4
Ph
9
9
10
11
12
13
14
15
16
17
1j
10
11
12
13
14
15
16
17
18
19
20
21
22
3j
3k
3l
1k
2a
2b
2c
2d
2e
2f
3m
3n
3o
3p
3q
3r
4a
4b
4c
4d
p-NO2C6H4
m-ClC6H4
p-CH3OC6H4
Ph
p-CH3C6H4
p-BrC6H4
m-NO2C6H4
analysis. This unprecedented result is of value to us not only
because we are interested in the design of the new multi-
comonent reaction, but also because we are unable to find
examples of other methods allowing for such convenient
synthesis in related literature. Pyridinium zwitterions are
usually very reactive species, which should be kept at low
temperature and in an inert atmosphere. The majority of these
zwitterions are synthesized by first preparing the pyridinium
salt, followed by the elimination of an acid in the reaction
with a base.18 A literarure survey reveals that very early the
addition product from benzylpyridinium bromide and chal-
cone can be isolated sometimes as cyclimonium chloride or
perchlorate.19a Recently a similar charge-separated pyri-
dinium barbiturate zwitterion was successfully prepared from
1,3-dimethylbarbituric acid and 2-pyridinecarbaldehyde in
methanol.19b Some other stable pyridinium zwitterions have
also been synthesized from pyridine participated multicom-
ponent reactions.20,21 The addition of nucleophiles such as
triphenyl phosphine, pyridine, tertiary amine, dimethyl
sulfoxide to activated alkynes like dimethyl acetylenedicar-
boxylate has been known to generate zwitterionic species.
These reactive intermediates can be captured by suitable
substrates to give versatile compounds.22 Very recently the
synthesis of stable charge-separated pyridinium-tetronic acid
zwitterions from the three-component reaction of pyridine,
isoquinoline, quinoline, or N-methylimidazole with dialkyl
acetylenedicarboxylates and 3-chlorotetronic acid was de-
scribed.23 Here the stable pyridinium-Meldrum acid zwitte-
rions can be successfully separated as the main products,
which might the result of the negative charge on the carbon
atom is greatly delocalized onto two carbonyl group.24
To evaluate the scope of this four-component reaction
further, other reactive R-halomethyl compounds such as
R-phenacyl bromide were also tested under the standard
reaction conditions, and the results are summarized in Table
2. When pyridine was used in the reaction we are satisfied
to find that analogy pyridinium-Meldrum acid zwitterions
with benzoyl group (3a-3j) were obtained in very good
yields (71-94%). When 3-picoline and 4-picoline was used
in the reaction the zwitterionic salts (3k-3r) were also
produced. However 4-picoline gave the zwitterionic salts in
little lower yields (Entry 17, 18). When isoquinoline was
used in the reaction the zwitterionic salts (4a-4d) were also
produced in high yields (Entry 19-22). The structures of
the products were fully characterized by H and 13C NMR,
1
MS, and IR spectra and were further confirmed by single
X-ray diffraction study performed for an representative
compound 3a (Figure 1). From the figure it is clearly seen
that the formed zwitterionic salt came from all four com-
ponents of the reaction. The pyridyl group and Meldrum acid
unit exist in the same side of molecule, which cause the
positive charge and negative charge in the shortest distance.
The methylene carbon atom in Meldrum acid unit adopts a
sp2 hybrid and the negative charge is delocalized to two
carbonyl groups.
To continue the investigation, the behavior of another
active methylene compound, N,N-dimethylbarbituric acid,
which has very similar structure and reactivity with that of
Meldrum acid, was envisaged in this four-component reac-
tion. When four-component reactions of aromatic aldehyde,
N,N-dimethylbarbituric acid, p-nitrobenzyl bromide or R-phen-
acyl bromide and pyridine in acetonitrile were carried out
at the standard conditions, the pyridinium-N,N-dimethylbar-
biturate zwitterionic salts 5a-5h were formed in moderate
yields (43-81%, Table 3). This result clearly demonstrated
that this four-component reaction has great generality and

262 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Wang et al.
Figure 1. Molecular structure of zwitterionc salt 3a.
Table 3. Zwitterionic Salts of Pyridinium and Imidazolium
N,N-Dimethylbarbituric Acid
Scheme 1. Molecular Structures of Zwitterionic Salts 5j-5o
entry
compd
Ar
R
yield (%)
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
H
H
3-CH3
H
66
68
43
69
79
65
81
43
43
p-CH3C6H4
Ph
Ph
p-CH3C6H4
Ph
Ph
H
2-CH3
3-CH3
4-CH3
p-CH3C6H4
Ph
more component combinations involving 4-(dimethylami-
no)pyridine and barbiturate or thiobarbiturate have been used
in the reaction, which demonstrated that this four-component
reaction has very potential generality. The single crystal
structure of 5k was also determined by X-ray diffraction
(Figure 2). The pyridinium group and N,N-dimethylbarbi-
turate unit also exist in the same side of molecule, which
cause the positive charge and negative charge are in the
shortest distance.
can be developed to other active methylene compounds. This
kind of pyridinium-N,N-dimethylbarbiturate zwitterionic salt
has very similar structure with the zwitterion prepared by
Jursic’s group.19b It is interesting to find that N-methylimi-
dazole can take part in the reaction to yield the zwitterionic
salt 5i in moderate yield (entry 9). In zwitterionic salts 5a-5i,
the positive charge is on the nitrogen atom of pyridine or
imidazole. The negative charge is on the methylene carbon
of barbituric acid and is also delocalized onto the two
electron-withdrawing carbonyl groups, which improves the
stability of the zwitterionic salts.
Finally, to further explore the potential of this protocol
for synthesis versatile zwitterionic salts, we investigated the
reactions involving ethyl R-bromoacetate and N-chloro-
acetylmorphiline. The four-component reaction also proceeds
very smoothly and more zwitterionic salts 5j-5o were
obtained in satisfied yields (Scheme 1). It can be seen that
Encouraged by these results, we turned our attention to
attempt to study the reactivity of the obtained zwitterionic
salts. When four-component reactions of aromatic aldehyde,
N,N-dimethylbarbituric acid, p-benzyl bromide and pyridine
in acetonitrile were carried out at refluxed condition for 24 h,
it is very interesting to find that a mixture of cyclopropanes
6a-6c and 2,3-dihydrofuran 7a-7d were formed in lower
yields which were successfully separated by the TLC (Table.
4). The structures of cyclopropanes and 2,3-dihydrofurans
1
were characterized with spectroscopy. H NMR analysis

Synthesis of Zwitterionic Salts
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 263
Figure 2. Molecular structure of zwitterionc salt 5k.
Table 4. Synthesis of Cyclopropanes and 2,3-Dihydrofurans
from Four Component Reactions
Scheme 2. Proposed Mechanism of the Four Component
Reaction
entry
Ar
6
yield (%)
33
7
yield (%, cis/trans)
1
2
3
4
Ph
6a
7a
7b
7c
7d
36 (1:8)
31 (1:11)
35 (2:5)
33 (2:5)
p-CH3C6H4
p-ClC6H4
p-BrC6H4
6b
6c
30
28
revealed that the cyclopropanes 6a-6c were found to be in
the thermodynamically stable trans orientation on the basis
of the comparison of the coupling constants of two protons
on 2,3-position. On the other hand 2,3-dihydrofuranes 7a-7d
were found to have cis and trans isomers in different ratios
also based on the 1H NMR analysis. This preliminary result
clearly indicates that the above prepared zwitterionic salts
have potential application in organic synthesis.
To explain the mechanism of this one-pot multicomponent
reaction, we propose a plausible reaction course, which is
illustrated in Scheme 2. This mechanism is based on the our
previously established for the synthesis of cyclopropanes and
dihydrofurans via the tandem reaction of pyridinium salt.15,16
The first step is the formation of the two reaction intermedi-
ates already identified by the experiments described in the
preceding paragraph, namely the N-p-nitrobenzylpyridinium
bromide (A) formed from the substitution of p-nitrobenzyl
bromide to pyridine and the arylidene N,N-dimethylbarbituric
acid (B) formed by the Knoevenagel condensation of
aromatic aldehyde with N,N-dimethylbarbituric acid. The
second step is a Michael addition of a pyridinium ylide (C)
which is formed by deprotonation of the N-p-nitrobenzylpy-
ridinium species (A) by triethylamine to (B) to afford the
zwitterion salt 5. On heating this zwitterion salt proceeds
further according to two different paths to give different
products. In the first path the intramolecular substitution of
the carbanion replaces pyridine with formation of the
cyclopropane 6. In the second path the carbanion transfers
to resonance-stabilized enolate through the keto-enol tau-
tomerism, which in turn substitutes pyridine to give the 2,3-

264 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Wang et al.
dihydrofuran 7. In this proposed reaction mechanism pyridine
acts as a nucleophilic tertiary amine to form pyridinium
cation and zwitterionic salt, as a base to catalyze Knoev-
enagel condensation and as a good leaving group to finish
the intramolecular substitution reaction.
8.10 (d, J ) 8.4 Hz, 2H, p-NO2C6H4), 7.98 (t, J ) 7.2 Hz,
1H, PyH), 7.54 (d, J ) 8.4 Hz, 2H, p-NO2C6H4), 7.45 (d, J
) 7.2 Hz, 2H, C6H5), 7.41 (d, J ) 12.6 Hz, 1H, CH), 7.14
(t, J ) 7.2 Hz, 2H, C6H5), 7.09 (t, J ) 7.2 Hz, 1H, C6H5),
5.18 (d, J ) 12.0 Hz, 1H, CH), 2.57 (s, 3H, CH3), 1.45 (s,
3H, CH3), 1.42 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3)
δ(ppm): 148.3, 145.8, 144.1, 143.2, 141.7, 140.5, 139.1,
129.3, 128.5, 126.8, 126.7, 124.4, 101.5, 74.0, 45.9, 27.7,
23.8, 18.9. MS(ESI-): m/z ) 459.63. Anal. Calcd for
C26H24N2O6: C 67.82, H 5.25, N 6.08; found C 67.69, H
5.56, N 5.70.
Typical Procedure for the Preparation Pyridinium-
N,N-dimethylbarbituric Acid Zwitterionic Salt (Entry 1
in Table 3). A mixture of benzaldehyde (2.0 mmol), N,N-
dimethylbarbituric acid (2.0 mmol), p-nitrobenzyl bromide
(2.0 mmol), and an excess of pyridine (4.0 mmol) in
acetonitrile was stirred at room temperature for two hours,
then triethylamine (2.0 mmol) was added to the system. After
the mixture was stirred overnight, the yellow precipitates
were formed, which were collected by filtration and washed
with ethanol and petroleum ether to give the pure product
5a. Yield: 65.6%. mp: 156-158 °C. IR (KBr): 3425(s),
1661(s), 1571(vs), 1525(s), 1430(s), 1384(m), 1351(s),
1264(w), 1148(w), 1039(w), 840(vw), 816(w), 775(m),
703(m), 671(m) cm-1. 1H NMR (600 MHz, CDCl3) δ(ppm):
9.03 (d, J ) 6.0 Hz, 2H, PyH), 8.35 (t, J ) 7.8 Hz, 1H,
PyH), 8.14 (d, J ) 8.4 Hz, 2H, p-NO2C6H4), 7.88 (t, J )
7.2 Hz, 2H, PyH), 7.67 (d, J ) 6.6 Hz, 1H, CH), 7.62 (d, J
) 9.0 Hz, 2H, p-NO2C6H4), 7.57 (d, J ) 7.8 Hz, 2H, C6H5),
7.16 (t, J ) 7.8 Hz, 2H, C6H5), 7.10 (t, J ) 7.2 Hz, 1H,
C6H5), 5.46 (d, J ) 12.6 Hz, 1H, CH), 3.20 (s, 3H, CH3),
3.10 (s, 3H, CH3). 13C NMR (150 MHz, CDCl3) δ(ppm):
163.9, 153.3, 148.4, 145.3, 144.4, 142.9, 140.0, 129.3, 128.8,
128.4, 127.3, 127.0, 124.6, 84.9, 45.9, 27.8, 27.1. MS(ESI-):
m/z ) 457.65. Anal. Calcd for C25H22N4O5: C 65.49, H 4.84,
N 12.22; found C 65.27, H 5.20, N 11.85.
Conclusions
In conclusion, we described here an unexpected and
interesting four-component reaction including pyridine,
aromatic aldehyde, Meldrum acid or N,N-dimethylbarbituric
acid and p-nitrobenzyl bromide. A series of unusual charge-
separated pyridinium-Meldrum acid and barbituric acid
zwitterionic salts are prepared in high yields in very
convenient manner. Prominent among the advantages of this
new method are novelty, operational simplicity, and good
yields. The stability, reactivity and the formation mechanism
of this kind of zwitterionic salts are also investigated. Further
expansion of the reaction scope and synthetic applications
of this methodology are in progress in our laboratory.
Experimental Section
Typical Procedure for the Preparation Pyridinium-
Meldrum Acid Zwitterionic Salt from Reaction of p-
Nitrobenzyl Bromide (Entry 1 in Table 1). A mixture of
benzaldehyde (2.0 mmol), Meldrum acid (2.0 mmol), p-
nitrobenzyl bromide (2.0 mmol), and an excess of pyridine
(4.0 mmol) in acetonitrile was stirred at room temperature
for two hours; then triethylamine (2.0 mmol) was added to
the system. After the mixture was stirred over night, the
yellow precipitates formed and were collected by filtration
and washed with ethanol and petroleum ether to give the
pure product 1a. Yield: 78.4%. mp: 216-218 °C. IR (KBr):
3432(w), 3061(w), 1581(vs), 1523(m), 1491(w), 1389(m),
1350(m), 1259(w), 1205(w), 1106(w), 1047(vw), 926(vw),
1
740(w) cm-1. H NMR (600 MHz, CDCl3) δ(ppm): 9.05
(d, J ) 6.0 Hz, 2H, PyH), 8.38 (t, J ) 7.8 Hz, 1H, PyH),
8.13 (d, J ) 8.4 Hz, 2H, p-NO2C6H4), 7.93 (t, J ) 7.8 Hz,
2H, PyH), 7.54 (d, J ) 8.4 Hz, 2H, p-NO2C6H4), 7.46-7.43
(m, 3H, C6H5, CH), 7.17-7.11 (m, 3H, C6H5), 5.19 (d, J )
Acknowledgment. This work was financially supported
by the National Natural Science Foundation of China (Grant
No. 20672091 and 20972132).
12.0 Hz, 1H, CH), 1.44 (s, 3H, CH3), 1.42 (s, 3H, CH3). 13
C
Supporting Information Available. Experimental details
and characterization data including IR, MS, 1H, and 13C NMR
spectra, as well as X-ray crystallographic data for new
compounds. This information is available free of charge via
the Internet at http://pubs.acs.org.
NMR (150 MHz, CDCl3) δ(ppm): 142.6, 129.3, 128.6, 128.4,
127.4, 124.5, 109.4, 65.9, 58.5, 45.9, 18.5, 15.3. MS(ESI-):
m/z ) 445.98. Anal. Calcd for C25H22N2O6: C 67.26, H 4.97,
N 6.27; found C 67.35, H 5.20, N 5.97.
Typical Procedure for the Preparation Pyridinium-
Meldrum Acid Zwitterionic Salt from Reaction of r-Phen-
acyl Bromide (Entry 1 in Table 2). A mixture of benzal-
dehyde (2.0 mmol), Meldrum acid (2.0 mmol), R-phenacyl
bromide (2.0 mmol), and an excess of pyridine (4.0 mmol)
in acetonitrile was stirred at room temperature for two hours;
then triethylamine (2.0 mmol) was added to the system. After
the mixture was stirred overnight, the yellow precipitates
were collected by filtration and washed with ethanol and
petroleum ether to give the pure product 3a. Yield: 83.2%.
mp: 204-206 °C. IR (KBr): 3437(w), 3035(w), 1579(vs),
1523(m), 1387(m), 1349(m), 1260(w), 1205(w), 1108(w),
References and Notes
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Synthesis of Zwitterionic Salts
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