A facile one-pot, three-component synthesis of 3,3′-(4-arylpyridine- 2,6-diyl)bis(2H-chromen-2-one) derivatives under microwave irradiation

Article abstract of DOI:10.1007/s11164-012-0696-5

A series of 3,3′-(4-arylpyridine-2,6-diyl)bis(2H-chromen-2-one) derivatives have been synthesized by the one-pot, three-component reaction of 3-acetylcoumarin, an aromatic aldehyde, and ammonium acetate in acetic acid under microwave irradiation. This procedure has the major advantages of short reaction time, good yields, low energy consumption, easy operation, and environmental friendliness. All of the products were characterized by IR and NMR spectroscopy, MS, and elemental analysis.

Full text of DOI:10.1007/s11164-012-0696-5

Res Chem Intermed (2013) 39:1401–1408
DOI 10.1007/s11164-012-0696-5
A facile one-pot, three-component synthesis of 3,
30-(4-arylpyridine-2,6-diyl)bis(2H-chromen-2-one)
derivatives under microwave irradiation
•
Jian-Feng Zhou Xiao-Jun Sun Feng-Wen Lou
•
•
•
Meng Lv Lu-Lu Zhang
Received: 5 February 2012 / Accepted: 18 June 2012 / Published online: 4 July 2012
Ó The Author(s) 2012. This article is published with open access at Springerlink.com
Abstract A series of 3,30-(4-arylpyridine-2,6-diyl)bis(2H-chromen-2-one) deriv-
atives have been synthesized by the one-pot, three-component reaction of 3-ace-
tylcoumarin, an aromatic aldehyde, and ammonium acetate in acetic acid under
microwave irradiation. This procedure has the major advantages of short reaction
time, good yields, low energy consumption, easy operation, and environmental
friendliness. All of the products were characterized by IR and NMR spectroscopy,
MS, and elemental analysis.
Keywords 3,30-(4-Arylpyridine-2,6-diyl)bis(2H-chromen-2-one) ꢀ
3-Acetylcoumarin ꢀ Multicomponent reaction ꢀ Microwave irradiation
Introduction
Substituted pyridines and condensed pyridines are highly reactive reagents that have
been extensively used in heterocyclic synthesis and have biological and pharma-
cological activity [1]. Pyridine ring systems, especially 2,4,6-triarylpyridines, are of
immense interest because of their unique position in medicinal chemistry [2–6].
Therefore, recent studies have highlighted the biological activity of triarylpyridines,
providing impetus for further studies in utilizing this structure in new therapeutic
drug classes [7–10].
Coumarin is also a biologically active substance, with numerous metabolites, and
is widespread in nature [11]. Coumarin derivatives constitute an important class of
J.-F. Zhou (&) ꢀ X.-J. Sun ꢀ F.-W. Lou
Jiangsu Key Laboratory for Chemistry of Low-Dimensional Materials, School of Chemistry and
Chemical Engineering, Huaiyin Normal University, Huaian 223300, China
e-mail: jfchow@sohu.com
M. Lv ꢀ L.-L. Zhang
School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021, China
123

1402
J.-F. Zhou et al.
heterocyclic compounds that have attracted significant attention in recent years
[12–14]. Hence, it would be interesting to combine the coumarin and pyridine ring
systems.
One method developed for synthesis of 3,30-(4-arylpyridine-2,6-diyl)bis
(2H-chromen-2-one) derivatives involves reaction of 3-coumarin methyl pyridinium
salts with appropriate 1-(2H-1-benzopyran-2-on-3-yl)-3-arylprop-2-en-1-ones in the
¨
presence of ammonium acetate and acetic acid under Krohnke reaction conditions
[15].
Verma et al. [16] synthesized a variety of 4-aryl-2,6-dicoumarinyl pyridines by
condensation of 1-(2H-1-benzopyran-2-on-3-yl)-3-aryl-prop-2-en-1-ones with urea
or amide derivatives using bismuth(III) nitrate–Al2O3 as catalyst. However, these
methods suffer from disadvantages such as long reaction time, critical product
isolation procedures, and harsh reaction conditions, which limit their use as
environmentally benign processes. For example the reaction mixture was further
stirred for 1 h and then heated for 8 h at 140 °C [15]), substrates were absorbed on
Bi(III) nitrate–Al2O3–ZnCl2 [16].
For the past few years, in our laboratory, because of continuing interest in the
synthesis of organic compounds by multi-component reactions under microwave
irradiation conditions, we have synthesized quinoxaline derivatives containing the
coumarin moiety [17], 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-carboni-
triles [18], and double coumarin derivatives [19] from coumarin compounds as
substrates. Herein, we report the synthesis of 3,30-(4-arylpyridine-2,6-diyl)bis(2H-
chromen-2-one) by one-pot, multi-component reaction of 3-acetylcoumarin,
aromatic aldehydes, and ammonium acetate in acetic acid under microwave
Ar: a: C6H5 b: 4-ClC6H4 c: 2-ClC6H4 d: 4-CH3OC6H4 e: 4-CH3C6H4
f: 4-(CH3)2NC6H4 g: 4- O2NC6H5 h: 3,4-OCH2OC6H3 i: Furyl
Scheme 1 Synthesis of 3,30-(4-arylpyridine-2,6-diyl)bis(2H-chromen-2-one) derivatives
123

A facile one-pot three-component synthesis
1403
irradiation conditions (Scheme 1). The reactions were completed in 5–8 min, with
60–86 % yields, low energy consumption, and easy work-up.
Experimental
Mps were determined by use of an XT-5 digital melting point instrument and
uncorrected. IR spectra were recorded on a Nicolet Avatar360FT-IR instrument. 1H
NMR were measured on a Burke 400-MHz spectrometer in CDCl3 with TMS as
internal standard. Mass spectra were recorded on an LCQ Advantage instrument.
Elemental analysis was performed with a Perkin-Elmer 240C elemental analyzer.
Reactions under microwave conditions were performed in a CEM Discover
monomode microwave reactor. All the reagents are commercially available.
General procedure for preparation of 3,30-(4-arylpyridine-2,6-diyl)bis
(2H-chromen-2-one) derivatives (5a–5i)
A mixture of the aromatic aldehyde (1 mmol), 3-acetylcoumarin (2 mmol) [20], and
ammonium acetate (4 mmol), in acetic acid (5 mL) was sealed in a vial with a cap
containing a septum. The loaded vial was then placed into the cavity of the microwave
reactor and heated at 150 W and 150 °C for 5–8 min (monitored by TLC). The
reaction mixture was left to stand at room temperature to solidify. The crude product
was collected, washed with ethanol, and recrystallized from 95 % ethanol.
3,30-(4-Phenylpyridine-2,6-diyl)bis(2H-chromen-2-one) (5a)
1
M.p 252–253 °C (253–254 °C) [15]; H NMR (CDCl3, 400 MHz) d: 7.39–7.78
(13H, m, Ar–H), 8.27, 8.29 (2H, s, 3-H and 5-H of pyridine ring), 9.19, 9.23 (2H, s,
40-H and 400-H of coumarin rings); IR (KBr) m: 3017, 1721, 1610, 1577, 1532,
761 cm-1; LC–MS (ESI): m/z = 444.7 (M ? H); Anal. Calcd. for C29H17NO4: C,
78.55; H, 3.86; N, 3.16 %. Found: C, 78.46; H, 3.94; N, 3.25 %.
3,30-(4-(4-Chlorophenyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5b)
1
M.p 268–269 °C; H NMR (CDCl3, 400 MHz) d: 7.39–7.84 (8H, m, Ar–H), 8.13
(2H, d, J = 7.60, Ar–H), 8.29 (2H, d, J = 7.60, Ar–H), 8.84 (2H, s, 3-H and 5-H of
pyridine ring), 9.20 (2H, s, 40-H and 400-H of coumarin rings); IR (KBr) m: 3111,
1726, 1608, 1577, 1534, 756 cm-1; LC–MS (ESI): m/z = 478.7 (M ? H); Anal.
Calcd. for C29H16ClNO4: C, 72.88; H, 3.37; N, 2.93 %. Found: C, 72.79; H, 3.44; N,
3.01 %.
3,30-(4-(2-Chlorophenyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5c)
1
M.p 233–234 °C; H NMR (CDCl3, 400 MHz) d: 7.37–7.84 (12H, m, Ar–H), 8.82
(2H, s, 3-H and 5-H of pyridine ring), 9.21 (2H, s, 40-H and 400-H of coumarin rings);
IR (KBr) m: 3111, 1732, 1609, 1576, 1534, 754 cm-1; LC–MS (ESI): m/z = 478.7
123

1404
J.-F. Zhou et al.
(M ? H); Anal. Calcd. for C29H16ClNO4: C, 72.88; H, 3.37; N, 2.93 %. Found: C,
72.79; H, 3.44; N, 3.01 %.
3,30-(4-(4-Methoxyphenyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5d)
1
M.p 275–276 °C (277–278 °C) [15]; H NMR (CDCl3, 400 MHz) d: 3.91 (3H, s,
OCH3), 7.32–7.80 (8H, m, Ar–H), 8.13 (2H, d, J = 7.60, Ar–H), 8.32 (2H, d,
J = 7.60, Ar–H), 8.62 (2H, s, 3-H and 5-H of pyridine ring), 8.88 (2H, s, 40-H and
400-H of coumarin rings); IR (KBr) m: 3108, 1725, 1607, 1569, 1510, 756 cm-1
LC–MS (ESI): m/z = 474.7 (M ? H); Anal. Calcd. for C30H19NO5: C, 76.10; H,
4.04; N, 2.96 %. Found: C, 76.01; H, 4.12; N, 3.04 %.
;
3,30-(4-(p-Tolyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5e)
1
M.p 267–268 °C (269–270 °C) [15]; H NMR (CDCl3, 400 MHz) d: 2.44 (3H, s,
CH3), 7.41–7.70 (12H, m, Ar–H), 8.11 (2H, d, J = 7.60, Ar–H), 8.27 (2H, d,
J = 7.60, Ar–H), 8.81 (2H, s, 3-H and 5-H of pyridine ring), 9.20 (2H, s, 40-H and
400-H of coumarin rings); IR (KBr) m: 3110, 1727, 1608, 1574, 1532, 756 cm-1
LC–MS (ESI): m/z = 458.7 (M ? H); Anal. Calcd. for C30H19NO4: C, 78.76; H,
4.19; N, 3.06 %. Found: C, 78.67; H, 4.28; N, 3.15 %.
;
3,30-(4-(4-(Dimethylamino)phenyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5f)
1
M.p 261–262 °C; H NMR (CDCl3, 400 MHz) d: 3.08 (6H, s, CH3), 7.40–7.65
(12H, m, Ar–H), 8.28 (2H, s, 3-H and 5-H of pyridine ring), 9.22 (2H, s, 40-H and
400-H of coumarin rings); IR (KBr) m: 3120, 1725, 1609, 1578, 1525, 755 cm-1
LC–MS (ESI): m/z = 487.8 (M ? H); Anal. Calcd. for C31H22N2O4: C, 76.53; H,
4.56; N, 5.76 %. Found: C, 76.44; H, 4.65; N, 5.92 %.
;
3,30-(4-(4-Nitrophenyl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5g)
1
M.p 248–250 °C; H NMR (CDCl3, 400 MHz) d: 7.40–7.86 (8H, m, Ar–H), 8.16
(2H, d, J = 7.60, Ar–H), 8.35 (2H, d, J = 7.60, Ar–H), 8.86 (2H, s, 3-H and 5-H of
pyridine ring), 9.24 (2H, s, 40-H and 400-H of coumarin rings); IR (KBr) m: 3124, 1726,
1608, 1575, 1512, 757 cm-1; LC–MS (ESI): m/z = 489.55 (M ? H); Anal. Calcd.
for C29H16N2O6: C, 71.31; H, 3.30; N, 5.74 %. Found: C, 71.23; H, 3.37; N, 5.90 %.
3,30-(4-(Benzo[d][1,3]dioxol-5-yl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5h)
1
M.p 249–250 °C; H NMR (CDCl3, 400 MHz) d: 6.06 (2H, s, CH2), 7.74–7.64
(12H, m, Ar–H), 8.67 (2H, s, 3-H and 5-H of pyridine ring), 9.20 (2H, s, 40-H and
400-H of coumarin rings); IR (KBr) m: 3104, 1725, 1608, 1578, 1532, 756 cm-1
LC–MS (ESI): m/z = 488.6 (M ? H); Anal. Calcd. for C30H17NO6: C, 73.92; H,
3.52; N, 2.87 %. Found: C, 73.84; H, 3.59; N, 2.95 %.
;
123

A facile one-pot three-component synthesis
1405
3,30-(4-(furan-2-yl)pyridine-2,6-diyl)bis(2H-chromen-2-one) (5i)
1
M.p 208–209 °C; H NMR (CDCl3, 400 MHz) d: 7.39–7.82 (11H, m, Ar–H), 8.78
(2H, s, 3-H and 5-H of pyridine ring), 8.89 (2H, s, 40-H and 400-H of coumarin rings);
IR (KBr) m: 3110, 1726, 1609, 1576, 1533, 754 cm-1; LC–MS (ESI): m/z = 434.6
(M ? H); Anal. Calcd. for C27H15NO5: C, 74.82; H, 3.49; N, 3.23 %. Found: C,
74.73; H, 3.56; N, 3.32 %.
Table 1 Effect of microwave
power on the yield of product 5b
Entry
Microwave
power (W)a
Yield
(%)b
1
2
3
4
5
6
80
100
120
150
180
200
56
65
80
86
79
60
a
Reaction conditions:
irradiation temperature, 150 °C;
irradiation time, 8 min
b
Yields of the isolated products
Table 2 Effect of microwave
irradiation temperature on the
yield of product 5b
Entry
Reaction
temperature
(°C)a
Yield
(%)b
1
2
3
4
100
120
150
180
65
76
86
60
a
Reaction conditions:
microwave power, 150 W;
irradiation time, 8 min
b
Yields of the isolated products
Table 3 Results of synthesis of
3,30-(4-arylpyridine-2,6-
diyl)bis(2H-chromen-2-one)
derivatives
Product
Ar
Irradiation
time (min)a
Yield
(%)b
5a
5b
5c
5d
5e
5f
C6H5
8
8
8
5
7
6
8
8
5
75
86
80
61
62
68
82
65
60
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
4-CH3C6H4
4-(CH3)2NC6H4
4-O2NC6H5
3,4-OCH2OC6H3
Furyl
a
5g
5h
5i
Reaction conditions:
microwave power, 150 W;
irradiation temperature 150 °C
b
Yields of the isolated products
123

1406
J.-F. Zhou et al.
Results and discussion
In this work, we initially investigated the effect of different microwave power
settings on the yield of product 5b when the microwave temperature and irradiation
time were fixed. It was observed that irradiation at 150 W gives better results
(Table 1, entry 4). Moreover, we also found that the yield of this reaction was
affected by the irradiation temperature. Synthesis of 5b was tested at different
irradiation temperatures in the range 80–150 °C. The results showed 150 °C was the
optimum irradiation temperature because it generated the highest yield of 5b
(Table 2, entry 4).
Scheme 2 Probable mechanism of formation of 3,30-(4-arylpyridine-2,6-diyl)bis(2H-chromen-2-one)
derivatives
123

A facile one-pot three-component synthesis
1407
Under these optimized reaction conditions, a series of 3,30-(4-arylpyridine-2,
6-diyl)bis(2H-chromen-2-one) derivatives 5 were synthesized under microwave
irradiation; the results are summarized in Table 3. As is shown in Table 3, when a
mixture of 3-acetylcoumarin 3, aromatic aldehyde 4, and ammonium acetate in acetic
acid were irradiated at 150 W and 150 °C, the reactions were almost complete in
5–8 min. The reaction mixtures were then washed with a small amount of ethanol. The
crude products were purified by recrystallization from 95 % ethanol to afford products
in 60–86 %yields. The structures of all the synthesized compounds were established
on the basis of their spectroscopic data and results from elemental analysis.
The IR spectra of compounds 3a–3i contained a very strong band between 1,721
and 1,732 cm-1 from the d-lactone carbonyl (C=O) stretching vibration. Strong
bands from aromatic C=C and C=N stretching vibrations were observed between
1,608 and 1,575 cm-1. The aromatic C–H stretching vibrations were observed as a
medium band between 3,017 and 3,124 cm-1. In the 1H NMR spectra of
compounds 3a–3i, the aromatic protons appeared in the form of multiplets between
d 7.32 and 7.86. The signals of the pyridine 3-H and 5-H protons were downfield of
the coumarin ring protons, with the 40-H and 400-H signals the most downfield. For
compounds with identical coumarin substitution at the 2 and 6-positions of the
pyridine, the 3-H and 5-H appeared as a singlets. Similarly in these compounds, the
coumarin ring 40-H and 400-H also gave singlets.
The reaction may proceed via imine 7 formed from 3-acetylcoumarin and
ammonium acetate; imine 7 reacts with coumarin chalcone 6 (from condensation of
the aromatic aldehyde with 3-acetylcoumarin) to give 9, followed by cycloaddition,
dehydration, and aromatization to afford the 3,30-(4-arylpyridine-2,6-diyl)bis(2H-
chromen-2-one) 5 (Scheme 2).
Conclusions
In conclusion, under microwave irradiation, an efficient one-pot, multi-component
reaction has been developed for synthesis of 3,30-(4-arylpyridine-2,6-diyl)bis
(2H-chromen-2-one) derivatives from 3-acetylcoumarin, the corresponding aromatic
aldehydes, and ammonium acetate. This facile procedure is not only an economical
and efficient synthetic strategy for synthesis of this class of significant compounds
but also enriches investigations on microwave-assisted multi-component reactions.
Moreover, this procedure has the major advantages of short reaction time, good
yields, low energy consumption, easy operation, and environmental friendliness.
Open Access This article is distributed under the terms of the Creative Commons Attribution License
which permits any use, distribution, and reproduction in any medium, provided the original author(s) and
the source are credited.
References
1. T. Yu, S. Yang, Y. Zhao, P. Zhang, Z. Lv, D. Fan, Z. Geng, Res. Chem. Intermed. 38, 215 (2012)
2. M. Balasubramanian, J.G. Keay, in Comprehensive Heterocyclic Chemistry II, vol. 5, eds. by A.R.
Katritzky, C.W. Rees, E.V.F. Scriven (Pergamon Press, London, 1996) and references cited therein
123

1408
J.-F. Zhou et al.
3. V. Klimesova, M. Svoboda, K. Waisser, M. Pour, J. Kaustova, IL Farmaco 54, 666 (1999)
4. I.J. Enyedy, S. Sakamuri, W.A. Zaman, K.M. Johnson, S. Wang, Bioorg. Med. Chem. Lett. 13, 513
(2003)
5. A.D. Pillai, P.D. Rathod, P.X. Franklin, M. Patel, M. Nivsarkar, K.K. Vasu, H. Padh, V. Sudarsanam,
Biochem. Biophys. Res. Commun. 301, 183 (2003)
6. B.Y. Kim, J.B. Ahn, H.W. Lee, S.K. Kang, J.H. Lee, J.S. Shin, S.K. Ahn, C.I. Hong, S.S. Yoon, Eur.
J. Med. Chem. 39, 433 (2004)
7. G. Lowe, A.S. Droz, T. Vilaivan, G.W. Weaver, L. Tweedale, J.M. Pratt, P. Rock, V. Yardley, S.L.
Croft, J. Med. Chem. 42, 999 (1999)
8. S. Bonse, J.M. Richards, S.A. Ross, G. Lowe, R.L. Krauth-Siegel, J. Med. Chem. 43, 4812 (2000)
9. L.-X. Zhao, T.S. Kim, S.-H. Ahn, T.-H. Kim, E. Kim, W.-J. Cho, H. Choi, C.-S. Lee, J.-A. Kim, T.C.
Jeong, C. Chang, E.-S. Lee, Bioorg. Med. Chem. Lett. 11, 2659 (2001)
10. L.-X. Zhao, Y.-S. Moon, A. Basnet, E. Kim, Y. Jahng, J.G. Park, T.C. Jeong, W.-J. Cho, S.-U. Choi,
C.O. Lee, S.-Y. Lee, C.-S. Lee, E.-S. Lee, Bioorg. Med. Chem. Lett. 14, 1333 (2004)
11. R. O’Kennedy, R.D. Thornes, Coumarins: Biology, Applications and Mode of Actions (John Wiley,
England, 1997)
12. A.A. Al-Amiery, R.I.H. Al-Bayati, K.Y. Saour, M.F. Radi, Res. Chem. Intermed. 38, 559 (2012)
13. W.-H. Zhan, J.-L. Hua, Y.-H. Jin, X. Teng, H. Tian, Res. Chem. Intermed. 34, 229 (2008)
14. A. Kotali, I.S. Lafazanis, P.A. Harris, Tetrahedron Lett. 48, 7181 (2007)
15. A.K. Patel, N.H. Patel, M. Patel, A.D.I. Brahmbhatt, ARKIVOC xi, 28 (2010)
16. A.K. Verma, S. Koul, K.K. Kapoor, T.K. Razdan, Aust. J. Chem. 60, 883 (2007)
17. J.-F. Zhou, G.-X. Gong, L.-T. An, Synlett 20, 3163 (2008)
18. J.-F. Zhou, Y-Zh Song, J-Sh Lv, Synth. Commun. 39, 1443 (2009)
19. G.X. Gong, J.F. Zhou, L.T. An, X.L. Duan, S.J. Ji, Synth. Commun. 39, 497 (2009)
20. O.A. Olayinka, C.N. Obinn, J. Heter, Chem. 47, 181 (2010)
123