A green and efficient synthesis of 3,3′-arylidenebis[4-hydroxy-6- methyl-2(1h)-3-pyridinone]s in water under microwave irradiation

Article abstract of DOI:10.1002/jhet.210

(Chemical Equation Presented) A series of 3,3′-arylidenebis[4- hydroxy-6-methyl-2(1H)-3-pyridinone]s were synthesized via threecomponent reactions of aromatic aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one, and ammonium acetate in water under microwave irra

Full text of DOI:10.1002/jhet.210

22
A Green and Efficient Synthesis of 3,30-Arylidenebis[4-hydroxy-
6-methyl-2(1h)-3-pyridinone]s in Water under
Microwave Irradiation
Vol 47
Feng Shi, Longji Cao, Ning Ma, Ge Zhang, Rongshun Chen, Yajie Zhang,
and Shujiang Tu*
School of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of
Biotechnology for Medicinal Plant, Xuzhou, Jiangsu 221116, People’s Republic of China
*E-mail: lautu2001@363.net
Received November 23, 2008
DOI 10.1002/jhet.210
Published online 21 December 2009 in Wiley InterScience (www.interscience.wiley.com).
A series of 3,30-arylidenebis[4-hydroxy-6-methyl-2(1H)-3-pyridinone]s were synthesized via three-
component reactions of aromatic aldehydes, 4-hydroxy-6-methyl-2H-pyran-2-one, and ammonium ace-
tate in water under microwave irradiation. This method has the advantages of environmental friendli-
ness, short reaction time, high yields, and easy operation. This efficient synthesis not only offers an
economical and green synthetic strategy to this class of significant compounds but also enriches the
investigations on microwave-assisted synthesis in water.
J. Heterocyclic Chem., 47, 22 (2010).
INTRODUCTION
synthesis of 3,30-arylidenebis[4-hydroxy-6-methyl-2(1H)-
3-pyridinone]s is of great significance.
The pyridinone ring is one of the most well-known
systems among the naturally occurring heterocycles.
Many members of this class of heterocycles have
antibacterial [1], antifungal [2], cardiotonic [3], antineo-
plastic [4], antiinflammatory and analgesic [5], and other
significant bioactivities [6]. Therefore, pyridinone deriva-
tives, especially bispyridinone derivatives, which contain
two skeletons of pyridinone in one molecular structure,
are of great importance in medicinal and organic
chemistry.
In recent years, microwave-assisted synthesis in water
as solvent has become a hotspot of investigation,
because it combines the two prominent green chemistry
principles of ‘‘safer solvents’’ and ‘‘energy efficiency’’
[9]. In addition to the general advantages of water as
solvent [10], several benefits for the reaction are
expected when using water as reaction medium for
microwave-superheated protocols [11].
As a continuation of our efforts on synthesizing het-
erocycles possessing significant bioactivities with green
and efficient method [12], we herein report the synthesis
of 3,30-arylidenebis[4-hydroxy-6-methyl-2(1H)-3-pyridi-
none]s through three-component reactions of 4-hydroxy-
6-methyl-2H-pyran-2-one 1, aromatic aldehydes 2, and
ammonium acetate in water under microwave irradiation
(MWI) (Scheme 1). This efficient synthesis not only
offers a green synthetic strategy to this class of signifi-
cant compounds but also enriches the investigations on
microwave-assisted synthesis in water.
However, survey of the literature only reveals two
typical methods on synthesizing 3,30-arylidenebis[4-
hydroxy-6-methyl-2(1H)-3-pyridinone]s. One method is
the condensation of 4-hydroxy-6-methyl-2-pyridone with
aromatic aldehydes catalyzed by triethylamine in ethanol
under traditional heating condition [7]. Unfortunately,
this method suffers from low yield (14–45%), long reac-
tion time (8–10 h), and use of toxic organic catalyst and
solvent.
Another method is the multicomponent reaction of tri-
acetic acid lactone, aromatic aldehydes, and ammonium
acetate in ethanol under traditional heating conditions
[8]. However, this approach still has disadvantages of
lower yield (11–45%), longer reaction time (26 h), and
being less environmental-unfriendly because ethanol, a
volatile and flammable organic solvent, is used. As a
result, developing a green and efficient approach to the
RESULTS AND DISCUSSION
Initially, to demonstrate the superiority of water as
solvent, despite its natural property of being harmless to
environment, we compared the synthesis of 3c in water
with other organic solvents including glycol, DMF,
C
V
2009 HeteroCorporation

January 2010
A Green and Efficient Synthesis of 3,30-Arylidenebis[4-hydroxy-6-methyl-
23
2(1H)-3-pyridinone]s in Water under Microwave Irradiation
Scheme 1
Table 2
Temperature optimization for the synthesis of 3c.
Entry
T (oC)
Time (min)
Yield (%)
1
2
3
4
5
6
60
70
15
12
10
8
44
65
74
83
81
80
80
90
glacial acetic acid, and ethanol. The mixture of 4-
hydroxy-6-methyl-2H-pyran-2-one 1 (2 mmol), 4-bro-
mophenyl aldehyde 2c (1 mmol), ammonium acetate
(2 mmol), and corresponding solvent (2 mL) was irradi-
ated under MWI at 100ꢀC and 150 W for a given time,
then the crude product was purified by recrystallization
from EtOH.
100
110
8
8
was then attacked by 1 to generate another intermediate
5. Finally, the ammonolysis, intermolecular cyclization
and dehydration of 5 gave rise to target product 3.
All the products were characterized by IR, H NMR,
and elemental analyses.
1
The results (Table 1) reveal that compared with the
solvents of glycol, DMF, and EtOH, water can not only
improve the yield but also shorten the time of this reac-
tion. Although the yield of the reaction in acetic acid is
a little higher than that in water, considering environ-
mental friendliness and avoidance of using toxic organic
reagents, water was preferred as solvent for all further
microwave-assisted reactions.
In conclusion, we have developed a green and effi-
cient approach to the synthesis of 3,30-arylidenebis[4-
hydroxy-6-methyl-2(1H)-3-pyridinone]s in water under
MWI. This method has the notable advantages over the
existing ones owing to its features of environmental
friendliness, short reaction time, high yield, low cost,
and easy operation. On the other hand, this reaction sup-
plies a good example of efficient microwave-assisted
synthesis in water as solvent.
Moreover, the same reaction of 1 (2 mmol), 2c (1
mmol), and ammonium acetate (2 mmol) in water (2
mL) under MWI (150 W) was used to optimize the
reaction temperature, and the results are shown in Table
2. It is obvious that 90ꢀC is the most suitable reaction
temperature.
EXPERIMENTAL
Under these optimized reaction conditions, a series
of 3,30-arylidenebis[4-hydroxy-6-methyl-2(1H)-3-pyridi-
none]s 3 were synthesized, and the results are given in
Table 3. As shown in Table 3, this protocol can be
applied not only to aromatic aldehydes with electron-
withdrawing groups but also to those with electron-
donating groups under the same conditions. Therefore,
the electronic nature of the substrate has no significant
effect on this reaction.
MWI was carried out in a monomodal Emrys Creator from
Personal Chemistry, Uppsala, Sweden. Melting points were
determined in XT5 apparatus and are uncorrected. IR spectra
were recorded on a FT-IR-Tensor 27 spectrometer. 1H NMR
spectra were measured on a DPX 400 spectrometer operating
at 400 MHz, using DMSO-d6 as solvent and TMS as internal
standard. Elemental analysis was determined by using a
Perkin-Elmer 240c elemental analysis instrument.
General procedure for the syntheses of compounds 3
with MWI. Typically, in a 10-mL Emrys reaction vial, 4-
hydroxy-6-methyl-2H-pyran-2-one 1 (2 mmol), aldehyde 2 (1
mmol), ammonium acetate (2 mmol), and water (2 mL) were
Although the detailed mechanism of the above reac-
tion remains to be fully clarified, the formation of 3,30-
arylidenebis[4-hydroxy-6-methyl-2(1H)-3-pyridinone]s 3
could be explained by a reaction sequence presented in
Scheme 2.
Table 3
Synthesis of 3 under MWI in water.
First, the condensation of aldehyde 2 and 4-hydroxy-
6-methyl-2H-pyran-2-one 1 gave intermediate 4, which
Time/ Yield /
min
Entry
3
Ar
%
Mp (lit.) / oC
>300
>300 (>300)[7]
>300
>300
>300 (>300)[8]
>300
>300 (>300) [7]
>300 (>300) [7]
>300
1
2
3a
3b
3c
4-FC6H4
4-ClC6H4
4-BrC6H4
8
10
8
85
81
83
83
82
85
86
82
84
81
75
Table 1
3
4
Solvent optimization for the synthesis of 3c.
3d 2,4-Cl2C6H3
3e
3f
8
5
6
3-NO2C6H4
4-NO2C6H4
C6H5
8
Entry
Solvent
Time (min)
Yield (%)
10
10
12
10
12
15
1
2
3
4
5
glycol
water
AcOH
DMF
12
8
76
81
83
73
78
7
8
3g
3h 4-OCH3C6H4
3i 4-CH3C6H4
3j 2-OCH3C6H4
3k Thiophen-2-yl
6
9
16
10
10
11
>300
>300
EtOH
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

24
F. Shi, L. Cao, N. Ma, G. Zhang, R. Chen, Y. Zhang, and S. Tu
Vol 47
0
C5 -H), 2.17 (s, 6H, 2CH3). Anal. Calcd. for C19H16Cl2N2O4:
C, 56.04; H, 3.96; N, 6.88; Found: C, 56.20; H, 3.93; N, 6.81.
3,30-(3-Nitrobenzylidene)bis[4-hydroxy-6-methylpyridin-2(1H)-
one] (3e). This compound was obtained according to above
general procedure; IR (KBr): m 3300–2500, 1634, 1526, 1455,
Scheme 2
1
1392, 1351, 1257, 1127, 1108, 1042, 820, 728, 676 cmꢁ1; H
NMR: d 12.22 (s, br, 2H, 2OH), 11.79 (s, 2H, 2NH), 8.06 (d,
1H, J ¼ 8.4 Hz, ArH), 7.93 (s, 1H, ArH), 7.55 (t, 1H, J ¼ 8.0
Hz, ArH), 7.46 (d, 1H0, J ¼ 7.6 Hz, ArH), 6.07 (s, 1H, CH),
5.96 (s, 2H, C5-H, C5 -H), 2.19 (s, 6H, 2CH3). Anal. Calcd.
for C19H17N3O6: C, 59.53; H, 4.47; N, 10.96; Found: C,
59.37; H, 4.50; N, 11.00;
3,30-(4-Nitrobenzylidene)bis[4-hydroxy-6-methylpyridin-2(1H)-
one] (3f). This compound was obtained according to above
general procedure; IR (KBr): m 3300–2600, 1636, 1518, 1460,
1
1385, 1347, 1293, 1192, 1008, 883, 921, 8249, 768 cmꢁ1; H
NMR: d 12.19 (s, br, 2H, 2OH), 11.78 (s, 2H, 2NH), 8.13 (d,
2H, J ¼ 8.4 Hz, ArH), 7.26 (d, 02H, J ¼ 8.4 Hz, ArH), 6.06 (s,
1H, CH), 5.94 (s, 2H, C5-H, C5 -H), 2.18 (s, 6H, 2CH3). Anal.
Calcd. for C19H17N3O6: C, 59.53; H, 4.47; N, 10.96; Found:
C, 59.41; H, 4.49; N, 11.01.
3,30-(Benzylidene)bis[4-hydroxy-6-methylpyridin-2(1H)-one]
(3g). This compound was obtained according to above general
procedure; IR (KBr): m3300–2600, 1629, 1494, 1453, 1396,
mixed and then capped. The mixture was irradiated at 150 W
and at 90ꢀC for a given time. The reaction mixture was cooled
to room temperature and poured into water (50 mL), filtered to
give the crude product, which was further purified by recrystal-
lization from EtOH.
1
1363, 1262, 1213, 1181, 1115, 1027, 896, 824, 772 cmꢁ1; H
NMR: d 12.43 (s, br, 2H, 2OH), 11.69 (s, 0 2H, 2NH), 6.92–
6.78 (m, 5H, ArH), 5.91 (s, 2H, C5-H, C5 -H), 5.82 (s, 1H,
CH), 2.17 (s, 6H, 2CH3). Anal. Calcd. for C19H18N2O4: C,
67.44; H, 5.36; N, 8.28. Found: C, 67.30; H, 5.38; N, 8.25.
3,30-(4-Methoxylbenzylidene)bis[4-hydroxy-6-methylpyri- din-
2(1H)-one] (3h). This compound was obtained according to
above general procedure; IR (KBr): m 3300–2600, 1633, 1509,
1459, 1418, 1388, 1302, 1248, 1178, 1035, 850, 832, 774
3,30-(4-Fluorobenzylidenebis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3a). This compound was obtained according to
above general procedure; IR (KBr): m 3433–2611, 1635, 1457,
1389, 1309, 1259, 1222, 1195, 1164, 1005, 932, 883, 848, 781
cmꢁ1 1H NMR: d 12.28 (s, br, 2H, 2OH), 11.71 (s, 2H,
;
2NH), 7.05–6.99 (m, 4H, ArH), 5.94(s, 1H, C5-H), 5.88 (s,
0
1H, C5 -H), 5.82 (s, 1H, CH), 2.17 (s, 6H, 2CH3). Anal. Calcd.
for C19H17FN2O4: C, 64.04; H, 4.81; N, 7.86. Found: C,
64.21; H, 4.83; N, 7.81.
cmꢁ1 1H NMR: d 12.41 (s, br, 2H, 2OH), 11.68 (s, 2H,
;
2NH), 6.91 (d, 2H, J ¼ 8.4 Hz, ArH), 6.79 (d, 2H, J ¼ 8.4
0
Hz, ArH), 5.90 (s, 2H, C5-H, C5 -H), 5.82 (s, 1H, CH), 3.70 (s,
3H, OCH3), 2.17 (s, 6H, 2CH3). Anal. Calcd. for C20H20N2O5:
C, 65.21; H, 5.47; N, 7.60. Found: C, 65.09; H, 5.45; N, 7.55.
3,30-(4-Methylbenzylidene)bis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3i). This compound was obtained according to
above general procedure; IR (KBr): m 3300–2600, 1634, 1512,
1460, 1387, 1302, 1308, 1127, 1105, 1041, 920, 887, 753
3,30-(4-Chlorobenzylidene)bis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3b). This compound was obtained according to
above general procedure; IR (KBr): 3600–2600, 1482, 1456,
1382, 1318, 1283, 1249, 1195, 1163, 1007, 883, 821, 753
cmꢁ1 1H NMR (400 MHz, DMSO-d6, 25ꢀC): d 12.20 (s, br,
;
2H, 2OH), 11.72 (s, 2H, 2NH), 7.28 (d, 2H, J ¼ 8.0 Hz,
0
ArH), 7.01 (d, 2H, J ¼ 8.0 Hz, ArH), 5.91 (s, 2H, C5-H, C5 -
H), 5.80 (s, 1H, CH), 2.17 (s, 6H, 2CH3). Anal. Calcd. for
C19H17ClN2O4: C, 61.21; H, 4.60; N, 7.51; Found: C, 61.08;
H, 4.62; N, 7.45.
cmꢁ1 1H NMR: d 12.50 (s, br, 2H, 2OH), 11.67 (s, 2H,
;
2NH), 7.03 (d, 2H, J ¼ 8.4 Hz, ArH), 6.90 (d, 2H, J ¼ 8.4
0
Hz, ArH), 5.91 (s, 2H, C5-H, C5 -H), 5.83 (s, 1H, CH), 2.25 (s,
3H, CH3), 2.17 (s, 6H, 2CH3). Anal. Calcd. for C20H20N2O4:
C, 68.17; H, 5.72; N, 7.95. Found: C, 68.23; H, 5.69; N, 7.89.
3,30-(2-Methoxylbenzylidene)bis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3j). This compound was obtained according to
above general procedure; IR (KBr): m 3300–2600, 1632, 1490,
1396, 1356, 1340, 1290, 1243, 1103, 1029, 888, 818, 769
3,30-(4-Bromobenzylidene)bis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3c). This compound was obtained according to
above general procedure; IR (KBr): m 3457–2583, 1631, 1486,
1459, 1386, 1314, 1285, 1255, 1191, 1074, 1010, 883, 815,
1
755 cmꢁ1; H NMR: d 12.22 (s, br, 2H, 2OH), 11.74 (s, 2H,
2NH), 7.42 (d, 2H, J ¼ 8.4 Hz, ArH), 6.95 (d, 2H, J ¼ 8.4
0
cmꢁ1 1H NMR: d 12.62 (s, br, 2H, 2OH), 11.47 (s, 2H,
;
Hz, ArH), 5.92 (s, 2H, C5-H, C5 -H), 5.87 (s, 1H, CH), 2.17 (s,
6H, 2CH3). Anal. Calcd. for C19H17BrN2O4: C, 54.69; H,
4.11; N, 6.71; Found: C, 54.45; H, 4.07; N, 6.75.
2NH), 7.15–7.08 (m, 2H, ArH), 6.86–6.80 (m, 2H, ArH), 6.02
0
(s, 1H, CH), 5.84 (s, 2H, C5-H, C5 -H), 3.52 (s, 3H, OCH3),
2.13 (s, 6H, 2CH3). Anal. Calcd. for C20H20N2O5: C, 65.21;
H, 5.47; N, 7.60. Found: C, 65.05; H, 5.45; N, 7.66.
3,30-(2,4-Dichlorobenzylidene)bis[4-hydroxy-6-methylpyr-idin-
2(1H)-one] (3d). This compound was obtained according to
above general procedure; IR (KBr): m 3600–2600, 1639, 1462,
1456, 1388, 1325, 1258, 1190, 1127, 1107, 1048, 887, 862,
3,30-(4-Thiophen-2-ylidene)bis[4-hydroxy-6-methylpyridin-
2(1H)-one] (3k). This compound was obtained according to
above general procedure; IR (KBr): m 3300–2600, 1633, 1556,
1537, 1514, 1504, 1486, 1455, 1393, 1360, 1253, 1200, 922,
1
772 cmꢁ1; H NMR: d 11.81 (s, br, 2H, 2OH), 11.44 (s, 2H,
2NH), 7.40 (s, 1H, ArH), 7.33–7.30 (m, 1H, ArH) 7.19 (d, 1H,
J ¼ 8.0 Hz, ArH), 6.18 (s, 1H, CH), 5.83 (s, 2H, C5-H,
1
887, 753 cmꢁ1; H NMR: d 12.92 (s, br, 2H, 2OH), 11.66 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

January 2010
A Green and Efficient Synthesis of 3,30-Arylidenebis[4-hydroxy-6-methyl-
25
2(1H)-3-pyridinone]s in Water under Microwave Irradiation
Rosenberg, S.; Sham, H. L. Bioorg Med Chem Lett 2003, 13, 4001.
2H, 2NH), 7.24 (d, 1H, J ¼ 5.2 Hz, ArH), 6.87–6.84 (m, 1H,
Ar0H), 6.57 (s, 1H, ArH), 6.09 (s, 1H, CH), 5.90 (s, 2H, C5-H,
C5 -H), 2.16 (s, 6H, 2CH3). Anal. Calcd. for C17H16N2O4S: C,
59.29; H, 4.68; N, 8.13. Found: C, 59.11; H, 4.71; N, 8.09.
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Acknowledgments. We thank the National Natural Science
Foundation of China (Nos. 20672090 and 200810102050), the
Preliminary Item of Xuzhou Normal University on Natural Sci-
ence Foundation of China (No. 08XLY04), the Science and Tech-
nology Foundation of Xuzhou City (No. XM08C027), the Qiang
Lan Project (08QLT001) and the Natural Science Foundation
(09KJB150011) of Jiangsu Education Committee for financial
supports.
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DOI 10.1002/jhet