Microwave-assisted aqueous synthesis of 6-ferrocenyl pyridin-2(1H)-one derivative

Article abstract of DOI:10.1002/jhet.995

A clean and green method for synthesizing a series of new ferrocenyl pyridin-2(1H)-one derivative was developed via the one-pot reactions of aldehydes, Meldrum's acid, acetylferrocene, and ammonium acetate using high-temperature water as a solvent and microwave heating. This method had several advantages such as good yields, reduced environmental impact, and convenient procedure.

Full text of DOI:10.1002/jhet.995

66
Microwave-Assisted Aqueous Synthesis of 6-Ferrocenyl Pyridin-2(1H)-one
Vol 50
Derivative
a
b
b
b
a
b
*
Jin-Peng Zhang, Jie Ding, Ning Ma, Bo Jiang, Li-Chun Xu, and Shu-Jiang Tu
aDepartment of Public Health, Xuzhou Medical College, Jiangsu, 221000, People’s Republic of China
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Jiangsu, 221116, People’s Republic of China
*
E-mail: laotu2001@263.net
Received March 26, 2011
DOI 10.1002/jhet.995
View this article online at wileyonlinelibrary.com.
A clean and green method for synthesizing a series of new ferrocenyl pyridin-2(1H)-one derivative was
developed via the one-pot reactions of aldehydes, Meldrum’s acid, acetylferrocene, and ammonium acetate
using high-temperature water as a solvent and microwave heating. This method had several advantages such
as good yields, reduced environmental impact, and convenient procedure.
J. Heterocyclic Chem., 50, 66 (2013).
INTRODUCTION
derivatives were reported to display antimalarial [10],
antitumor [11], and DNA cleaving [12] activities. For
these reasons, the synthesis of these molecules containing
ferrocene unit has attracted considerable attention [13].
On the other hand, the pyridin-2(1H)-one ring system
and the corresponding dihydro and tetrahydro derivatives
possess structural features found in a wide variety of
naturally occurring alkaloids [14]. The pyridin-2(1H)-one
derivatives have been found to exhibit interesting biological
activities such as kappa opioid receptor agonists [15],
antitumor agents [16], farnesyltransferase inhibitors [17],
and cardiotonic agents [18]. It is now well established that
the incorporation of ferrocene units in organic molecules
introduces significant and new properties in these materials
[19]. The introduction of ferrocenyl group on the 2(1H)-
pyridone ring may lead to novel biological activities.
However, the synthesis of these compounds with both
ferrocene motif and pyridin-2(1H)-one motif was neglected
all the time. Therefore, the synthesis of these compounds
and development of more rapid and efficient entry to these
heterocycles are strongly desired. Herein, we would like to
report a rapid and efficient method for synthesizing ferroce-
nyl pyridin-2-one derivatives in high-temperature water
using inexpensive reagents as starting materials and MW
heating (Scheme 1).
The similar polarity of classic organic solvents and high-
temperature water has encouraged chemists to investigate
the organic transformations in aqueous media [1]. In addition
to being a safe, readily available, and environmentally
friendly solvent, water has also been recognized as an effec-
tive reaction medium with unique properties and possibilities
for many organic reactions [2]. Simultaneously, high density
microwave (MW) irradiation has matured into a reliable and
useful methodology for accelerated processing of small-scale
reactions [3]. Thus, it has become clear that the combined
approach of MW superheating and aqueous conditions
offers a nearly synergistic strategy in the sense that the
combination in itself offers greater potential than the two
parts in isolation [4].
In modern drug discovery, a number of solutions to
increase the output of unique chemical entities have been
presented, for example, combinatorial synthesis, parallel
synthesis, and automated library production [5]. Even
though many of these small-scale techniques in themselves
are productive, they generate significant quantities of chem-
ical waste [6]. Overall, the development of new methods that
reduce the environmental impact is of increasing importance,
not only for pharmaceutical production but also in the
medicinal or combinatorial chemistry research laboratory.
The use of water as a nontoxic reaction medium, together
with the employment of energy-efficient MW heating [7],
must be considered to be both promising and enabling
green alternatives.
RESULTS AND DISCUSSION
To explore the full scope and versatility of this method,
various reaction conditions were investigated, including
solvent, temperature, and volume of water variations.
Highlighted in Table 1 for compound 4a, for example, is
the influence of solvents on the reaction yield. The MW
Metallocenes are known to exhibit a wide range of biolog-
ical activity [8]. Among them, ferrocene has attracted special
attention because it is neutral, chemically stable, nontoxic,
and able to cross cell membranes [9]. Recently, ferrocenyl
© 2013 HeteroCorporation

January 2013
Microwave-Assisted Aqueous Synthesis of 6-Ferrocenyl Pyridin-2(1H)-one Derivative
67
Table 2
Optimization of the temperatures in the synthesis of compound 4a in water.
Scheme 1
Entry
T/ꢀC
Time/min
Yield/%
1
2
3
4
5
6
80
90
100
110
120
130
12
11
8
6
6
45
50
64
68
73
70
6
Table 1
Optimization of the solvents in the synthesis of compound 4a at 100ꢀC.
(100ꢀC). When the temperature was increased from 100ꢀC
to 120ꢀC (Table 2, entries 3–5), the yield of product 4a
was further increased. However, no significant increase in
the yield of product 4a was observed as the reaction temper-
ature was raised to 130ꢀC (Table 2, entry 6). Therefore,
120ꢀC was chosen as the reaction temperature for all further
MW-assisted reactions. Furthermore, the volume of water
was found to be important in this reaction as well. When
1.0À1.5 mL of water was used as solvent, the reaction gave
the best result.
These optimization results prompted us to select water
as reaction solvent for further study. At the beginning of
the search for the aldehyde substrate scope, Meldrum’s
acid and acetylferrocene were used as model substrates
(Table 3, entries 1–9), and the results indicated that
aromatic aldehydes bearing such functional groups as
nitro, fluoro, chloro, bromo, or methoxyl were able to
effect the synthesis of compound 4. We have also observed
delicate electronic effects, that is, aryl aldehydes with
electron-withdrawing groups (Table 3, entries 1–5) reacted
rapidly, whereas substitution of electron-rich groups
(Table 3, entries 7–8) on the benzene ring decreased the
reactivity, requiring longer reaction times. Moreover, the
heterocyclic aldehyde such as thiophene-2-carbaldehyde
(Table 3, entry 9) still displayed high reactivity and clean
reaction under this standard condition.
Entry
Solvent
Power (W)
Time (min)
Yield (%)
1
2
3
4
5
Glycol
Water
HOAc
DMF
200
200
200
200
200
14
8
12
15
14
Trace
64
Trace
42
None
56
assisted reaction of 4-chlorobenzaldehyde (1a, 1.0 mmol),
Meldrum’s acid (2, 1.0 mmol), and acetylferrocene
(3, 1.0 mmol) in the present of ammonium acetate
(3.0 mmol) was examined using glycol, water, glacial
acetic acid, and DMF as solvents (1.0 mL) and solvent-free
at 100ꢀC, respectively (Scheme 2). All the reactions were
carried out at the maximum power of 200 W. The results
were summarized in Table 1.
It was shown in Table 1 that the reaction using water as
solvent resulted in good yield (Table 1, entry 2), whereas
glycol, HOAc, DMF, or solvent-free did not give satisfactory
result (Table 1, entries 1, 3, 4, and 5). So water was chosen as
the reaction solvent.
To optimize the reaction temperature, the earlier reaction
was carried out in water at temperatures ranging from 80ꢀC
to 130ꢀC, with an increment of 10ꢀC each time, using the
maximum power of 200 W. (Table 2).
From Table 2, we found that the yield of product 4a was
improved and the reaction time was shortened as the
temperature was increased from 80ꢀC to 100ꢀC (Table 2,
entries 1–3). Because the reactions were carried out in a
sealed tube under a pressurized atmosphere, the temperature
could be increased beyond the boiling point of water
For comparison, when the four-component reaction was
carried out in a 10 mL sealed tube in water (1.0 mL) with
Table 3
Synthesis of 4 under microwave irradiation at 120ꢀC in water.
Mp/ꢀC
Scheme 2
Entry
4
R
Time/min Yield/%
Cl
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-ClC6H4
4-BrC6H4
4-FC6H4
3,4-Cl2C6H3
4-NO2C6H4
C6H5
4-CH3OC6H4
3,4-OCH2OC6H3
2-thiophenyl
6
6
8
6
4
8
10
9
73
80
75
79
81
68
70
74
72
274–276
254–256
250–252
189–191
217–218
247–249
210–211
206–207
200–202
Cl
O
O
O
O
O
NH4OAc / water
MWI
+
Fe
+
N
O
H
Fe
CHO
10
4a
3
1a
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

68
J.-P. Zhang, J. Ding, N. Ma, B. Jiang, L.-C. Xu, and S.-J. Tu
Vol 50
Scheme 4
1a (1.0 mmol), 2 (1.0 mmol), and 3 (1.0 mmol) in the
present of ammonium acetate (3.0 mmol) under classical
heating conditions at 120ꢀC, the product 4a failed to be
obtained after 2 h. The results indicated (Table 3, entry 1)
that there is a clear advantage in terms of reaction time
and yield when working under MW conditions. Therefore,
the reaction was efficiently promoted by MW irradiation.
All these new products were characterized by IR spectra,
1H NMR data, and elemental analyses. In the IR spectra of
compound 4g showed strong absorptions at 3204 cmÀ1
because of NH group, and at 1682 cmÀ1 because of C═O
Br
Br
O
O
O
O
O
NH4OAc
+
Fc
- CH3COCH3
- CO2
Fc
N
H
O
3
8b
4
Yield 80%
1
which was followed by reaction with Meldrum’s acid 2 and
ammonium acetate, product 4b was given in 45% yield
(Scheme 5). The fact was further supported proposed
mechanism.
group. The H NMR spectrum of 4g showed a singlet at
d 3.73 because of OCH3, a singlet at d 4.18 and 4.28
because of ferrocenyl-H, and a singlet at d 9.12 because
of NH proton (exchanged with D2O).
In summary, we have accomplished the synthesis
of highly functionalized ferrocenyl pyridin-2(1H)-one
derivatives of potentially biological importance using
high-temperature water as a solvent and MW heating. It
is availably expanded the scope of the class of organic
synthesis in aqueous media. In addition, it is possible to
apply the tenets of green chemistry to the generation of
interesting products using aqueous media methods that
are less expensive and less toxic than those with organic
solvents. Moreover, the procedure offers several advantages
including operational simplicity, clean reactions, increased
safety for small-scale high-speed synthesis, and minimal
environmental impact that make it a useful and attractive
process for the synthesis of these compounds.
It is well known that the pKa value of Meldrum’s acid is
lower than those of acetylferrocene, so the aldehydes were
first condensed with Meldrum’s acid. Although the detailed
mechanism of the earlier reaction remains to be fully clari-
fied, the formation of 4 was expected to proceed via initial
condensation of acetylferrocene 2 with amine from ammo-
nium acetate to afford 1-ferrocenylethenamine 7, which
further underwent in situ Michael addition reaction with
compound 8 to yield intermediate 9. The intermediate 9 then
cyclized and subsequently lost a carbon dioxide and an
acetone molecule to afford the product 4 (Scheme 3).
In order to support the proposed mechanism, the
compound 8b was prepared independently from
p-bromobenzaldehyde 1b and Meldrum’s acid 2 and then
employed in a three-component reaction with acetylferro-
cene 3 and ammonium acetate to afford product 4b in 80%
yield (Scheme 4). When p-bromobenzaldehyde 1b was first
condensed with acetylferrocene 3 to afford chalcones 9,
EXPERIMENTAL
Microwave syntheses were carried out on MW oven EmrysTM
Creator from Personal Chemistry, Uppsala, Sweden. Melting
points were determined in open capillaries and are uncorrected.
IR spectra were recorded on a FTIR-tensor 27 spectrometer
in KBr. 1H NMR spectra were measured on a DPX 400 MHz
spectrometer using TMS as an internal standard and DMSO-d6
as solvent. Elemental analyses were determined by using a
Perkin–Elmer 240c elemental analysis instrument.
Scheme 3
O
NH3
NH
NH2
Fc
Fc
Fc
7
3
Sample experimental. All MW-assisted reactions were
performed in EmrysTM Creator from Personal Chemistry,
Uppsala, Sweden. Typically, in a 10-mL EmrysTM reaction
vial, aromatic aldehyde (1.0mmol), acetylferrocene (1.0mmol),
O
O
O
O
2
O
Ar CHO
+
ArHC
O
O
O
8
1
NH2
Scheme 5
Ar
O
O
Ar
O
O
O
Fc
O
O
Br
O
O
ArHC
7
Fc
N
H
Fc
NH2
O
O
O
O
O
O
O
NH4OAc
8
9
R
+
Fc
- CH3COCH3
- CO2
- CH3COCH3
- CO2
Br
O
Fc
N
O
H
Fc
O
N
H
9
2
4
4
Yield 45%
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2013
Microwave-Assisted Aqueous Synthesis of 6-Ferrocenyl Pyridin-2(1H)-one Derivative
69
Meldrum’s acid (1.0mmol), ammonium acetate (3.0mmol), and
water (1.0 mL) were mixed and then capped. The mixture was
irradiated by MW at 200W and at 120ꢀC for a given time. The
automatic mode stirring helped the mixing and uniform heating
of the reactants. Upon completion, monitored by TLC, the
reaction mixture was cooled to room temperature and washed
with 2 mL ether, filtered to give the crude products, which were
further purified by recrystallization from 95% EtOH. The
analytical data of new products are the following:
(d, J = 4.4 Hz, 1H, CH), 4.73 (d, J = 7.6 Hz, 2H, ferrocenyl),
4.29 (s, 2H, ferrocenyl), 4.18 (s, 5H, ferrocenyl), 3.78–3.75
(m, 1H, CH), 2.76 (dd, J1 = 16.0 Hz, J2 = 7.6 Hz, 1H, CH2),
2.49 (dd, J1 = 16.0 Hz, J2 = 7.2 Hz, 1H, CH2); Anal. Calcd for
C21H19FeNO, C, 70.61; H, 5.36; N, 3.92; found C, 70.84;
H, 5.39; N, 3.79%.
4-(4-Methoxyphenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-
one (4g). Red solid; IR (KBr): n 3204, 3102, 3028, 1682, 1596,
1519, 1346, 854, 753 cmÀ1 1H NMR (400 MHz, DMSO-d6) d
;
4-(4-Chlorophenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one
(4a). Brown solid; IR (KBr): n 3208, 3097, 1673, 1644, 1498,
9.12 (s, 1H, NH), 7.21 (d, J= 8.4 Hz, 2H, ArH), 7.04 (d, J=8.4Hz,
2H, ArH), 5.38 (d, J= 4.4 Hz, 1H, CH), 4.72 (d, J=7.6Hz, 2H,
ferrocenyl), 4.28 (s, 2H, ferrocenyl), 4.18 (s, 5H, ferrocenyl), 3.73
(s, 3H, OCH3), 3.70 3.68 (m, 1H, CH), 2.73 (dd, J1 =16.0Hz,
J2 = 6.8 Hz, 1H, CH2), 2.44 (dd, J1 =16.0Hz, J2 = 7.2 Hz, 1H,
CH2); Anal. Calcd for C22H21FeNO2: C, 68.23; H, 5.47; N, 3.62;
Found C, 68.41; H, 5.39; N, 3.58%.
;
1375, 1091, 817cmÀ1 1H NMR (400MHz, DMSO-d6)
d 9.20 (s, 1H, NH), 7.41 (d, J = 8.4Hz, 2H, ArH), 7.32
(d, J = 8.4 Hz, 2H, ArH), 5.38 (d, J = 4.4 Hz, 1H, CH), 4.72
(d, J = 7.6 Hz, 2H, ferrocenyl), 4.29 (s, 2H, ferrocenyl), 4.18
(s, 5H, ferrocenyl), 3.79–3.76 (m, 1H, CH), 2.73 (dd,
J1 = 16.0 Hz, J2 = 7.6 Hz, 1H, CH2), 2.48 (dd, J1 = 16.0 Hz,
J2 = 7.2 Hz, 1H, CH2); Anal. Calc. for C21H18ClFeNO: C,
64.40; H, 4.63; N, 3.58; found C, 64.56; H, 4.54; N, 3.49 %.
4-(4-Bromophenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one
(4b). Brown solid; IR (KBr): n 3208, 3099, 1672, 1647, 1482, 1376,
4-(Benzo[d][1,3]dioxol-5-yl)-6-ferrocenyl-3,4-dihydropyridin-2
(1H)-one (4h). Red solid; IR (KBr): n 3230, 3084, 2901,
1665, 1488, 1440, 1374, 1036, 813cmÀ1 1H NMR (400 MHz,
;
DMSO-d6) d 9.14 (s, 1H, NH), 6.88–6.86 (m, 2H, ArH), 6.76 (dd,
J1 =8.0Hz, J2 = 1.6 Hz, 1H, ArH), 5.97 (s, 2H, CH2), 5.37
(d, J= 4.4 Hz, 1H, CH), 4.72 (d, J= 10.0 Hz, 2H, ferrocenyl), 4.28
(s, 2H, ferrocenyl), 4.18 (s, 5H, ferrocenyl), 3.69–3.67 (m, 1H, CH),
2.72 (dd, J1 = 16.0 Hz, J2 = 6.8 Hz, 1H, CH2), 2.47 (dd, J1 = 16.0 Hz,
J2 = 7.2 Hz, 1H, CH2); Anal. Calcd for C22H19FeNO3: C, 65.86; H,
4.77; N, 3.49; found C, 65.67; H, 4.84; N, 3.56%.
1
1074, 914, 816 cmÀ1; H NMR (400 MHz, DMSO-d6) d 9.12 (s,
1H, NH), 7.54 (d, J= 8.4 Hz, 2H, ArH), 7.27 (d, J= 8.4 Hz, 2H, ArH),
5.38 (d, J= 4.4 Hz, 1H, CH), 4.73 (d, J= 7.6 Hz, 2H, ferrocenyl), 4.28
(s, 2H, ferrocenyl), 4.18 (s, 5H, ferrocenyl), 3.77–3.76 (m, 1H, CH),
2.76 (dd, J1 =16.0 Hz, J2 = 7.6 Hz, 1H, CH2), 2.47 (dd, J1 = 16.0 Hz,
J2 = 7.2 Hz, 1H, CH2); Anal. Calc. for C21H18BrFeNO: C, 57.83; H,
4.16; N, 3.21; found: C, 57.74; H, 3.31; N, 3.14 %.
4-(4-Fluorophenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one
(4c). Brown solid; IR (KBr): n 3205, 3098, 1671, 1647, 1508, 1370,
1223, 1075, 1007, 821, 793 cmÀ1; 1H NMR (400 MHz, DMSO-d6)
d 9.12 (s, 1H, NH), 7.35–7.32 (m, 2H, ArH), 7.20–7.153
(m, 2H, ArH), 5.39 (d, J= 4.0 Hz, 1H, CH), 4.73 (d, J=9.6Hz,
2H, ferrocenyl), 4.29 (s, 2H, ferrocenyl), 4.18 (s, 5H, ferrocenyl),
3.81–3.76 (m, 1H, CH), 3.70–3.68 (m, 1H, CH), 2.78–2.72
(m, 1H, CH2), 2.49–2.46 (m, 1H, CH2); Anal. Calcd for
C21H18FFeNO: C, 67.22; H, 4.84; N, 3.73; found C, 67.35; H,
4.68; N, 3.65%.
4-(Thiophen-2-yl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one
(4i). Red solid; IR (KBr): n 3208, 3098, 1669, 1645, 1447, 1368,
1257, 997, 819, 698 cmÀ1 1H NMR (400MHz, DMSO-d6) d
;
9.13 (s, 1H, NH), 7.37 (d, J = 4.8 Hz, 1H, thiophenyl-H),
7.00 6.95 (m, 2H, thiophenyl-H), 5.49 (d, J = 4.8 Hz, 1H, CH),
4.72 (d, J = 6.0 Hz, 2H, ferrocenyl), 4.29 (s, 2H, ferrocenyl), 4.18
(s, 5H, ferrocenyl), 4.06 4.02 (m, 1H, CH), 2.85 (dd, J1 = 16.0Hz,
J2 = 6.8 Hz, 1H, CH2), 2.52 (dd, J1 = 16.0Hz, J2 = 7.2 Hz, 1H,
CH2); Anal. Calcd for C19H17FeNOS, C, 62.82; H, 4.72; N, 3.86;
S, 8.83 found C, 62.74; H, 4.64; N, 3.97; S, 8.94%.
4-(3,4-Dichlorophenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-
one (4d). Brown solid; IR (KBr): n 3205, 3096, 1673, 1650, 1467,
Acknowledgments. We are grateful for financial support from the
NSFC (Nos, 81273103 and 30872143), the Foundation of Xuzhou
Medical College (Grant No. 201022), the Sci. Foundation in
Interdisciplinary Maj. Res. Project of XZNU (No. 09XKXK01),
and the PAPD of Jiangsu Higher Education Institutions.
1366, 1007, 817 cmÀ1 1H NMR (400 MHz, DMSO-d6) d 9.23
;
(s, 1H, NH), 7.63 (d, J= 8.4 Hz, 1H, ArH), 7.55 (s, 1H, ArH), 7.32
(dd, J1 =8.4Hz, J2 = 1.6 Hz, 1H, ArH), 5.41 (d, J=4.8Hz, 1H,
CH), 4.75 (d, J= 7.6 Hz, 2H, ferrocenyl), 4.30 (s, 2H, ferrocenyl),
4.18 (s, 5H, ferrocenyl), 3.83–3.73 (m, 1H, CH), 2.79 (dd,
J1 = 16.0 Hz, J2 = 7.6 Hz, 1H, CH2), 2.48 (dd, J1 =16.0Hz,
J2 =7.2Hz, 1H, CH2); Anal. Calcd for C21H17Cl2FeNO: C, 59.19;
H, 4.02; N, 3.29; found C, 59.08; H, 3.94; N, 3.37%.
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4-(4-Nitrophenyl)-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one
(4e). Red solid; IR (KBr): n 3203, 3107, 1682, 1651, 1596, 1520,
1346, 1104, 855, 812, 754 cmÀ1; 1H NMR (400 MHz, DMSO-d6)
d 9.27 (s, 1H, NH), 8.23 (d, J = 8.4 Hz, 2H, ArH), 7.58
(d, J = 8.4 Hz, 2H, ArH), 5.42 (d, J = 4.4 Hz, 1H, CH), 4.75
(d, J = 7.6 Hz, 2H, ferrocenyl), 4.30 (s, 2H, ferrocenyl), 4.19
(s, 5H, ferrocenyl), 3.97–3.95 (m, 1H, CH), 2.84 (dd,
J1 = 16.0 Hz, J2 = 7.6 Hz, 1H, CH2), 2.51 (dd, J1 = 16.0 Hz,
J2 = 7.2 Hz, 1H, CH2); Anal. Calcd for C21H18FeN2O3:
C, 62.71; H, 4.51; N, 6.96; found C, 62.91; H, 4.60; N, 6.87%.
4-Phenyl-6-ferrocenyl-3,4-dihydropyridin-2(1H)-one (4f). Red
solid; IR (KBr): n 3201, 3080, 1668, 1650, 1371, 1075, 820,
1
763 cmÀ1; H NMR (400MHz, DMSO-d6) d 9.17 (s, 1H, NH),
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Journal of Heterocyclic Chemistry
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J.-P. Zhang, J. Ding, N. Ma, B. Jiang, L.-C. Xu, and S.-J. Tu
Vol 50
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet