Microwave-assisted, methanesulfonic acid-catalyzed synthesis of 3,3'-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones)

Article abstract of DOI:10.1007/s11164-013-1031-5

Efficient synthesis of 3,3'-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) has been achieved by methanesulfonic acid-catalyzed, microwave-assisted reaction of 4-hydroxycoumarin and aromatic aldehydes in ethanol. The procedure has the advantages of high y

Full text of DOI:10.1007/s11164-013-1031-5

Res Chem Intermed
DOI 10.1007/s11164-013-1031-5
Microwave-assisted, methanesulfonic acid-catalyzed
synthesis of 3,30-(arylmethylene)bis(4-hydroxy-2H-
chromen-2-ones)
•
•
•
•
Xan Qi Meng-Wei Xue Xiao-Jun Sun Yin Zhi
Jian-Feng Zhou
Received: 18 July 2012 / Accepted: 8 January 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Efficient synthesis of 3,30-(arylmethylene)bis(4-hydroxy-2H-chromen-
2-ones) has been achieved by methanesulfonic acid-catalyzed, microwave-assisted
reaction of 4-hydroxycoumarin and aromatic aldehydes in ethanol. The procedure
has the advantages of high yield, short reaction time, low energy consumption, and
1
convenient work-up. Compound structures were confirmed by IR, H NMR, and
13C NMR spectroscopy and by elemental analysis.
Keywords 3,30-(Arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) ꢀ
4-Hydroxycoumarin ꢀ Methanesulfonic acid ꢀ Microwave irradiation
Introduction
Coumarin derivatives are widespread in nature and have a variety of biological
activity, for example anticoagulant, insecticidal, antihelminthic, hypnotic, anti-
fungal, phytoalexin, and HIV protease inhibition [1–3]. It has been found that the
minimum active pharmacophore comprises a coumarin dimer containing an aryl
substituent on the central linker methylene [3, 4]. Addition of 4 and 7-hydroxy
substituents to the coumarin rings improves the potency of the compounds. Among
the systems studied, 3,30-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) have
been tested as a HIV integrase inhibitors, and have significant activity [3]. The
compound is a 4-hydroxycoumarin (4-hc) dimer, consisting of two monomeric
building blocks of 4-hc and a phenyl ring on the central methylene linker [5].
X. Qi ꢀ X.-J. Sun ꢀ Y. Zhi ꢀ J.-F. Zhou (&)
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.-W. Xue
Department of Chemistry, Nanjing Xiaozhuang University, Nanjing 211171, China
123

X. Qi et al.
However, 3,30-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) are usually pre-
pared by condensation of carbonyl compounds with 4-hydroxycoumarin in organic
solvents [3, 6–9], which uses large amounts of hazardous and toxic solvents
associated with such catalysts as piperidine [10], ethylene diammonium diace-
tate [11], glacial acetic acid, and acetic anhydride [6].
Recently, several methods using 4-hydroxycoumarin for preparation of 3,30-
(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) in aqueous media have been
reported. Although these methods are effective and ecofriendly, usually they not
only need TEBA [10] or I2 [11] as catalyst, but also reaction time is long. Thus, the
introduction of efficient new methods based on green methodology is still in great
demand. Methanesulfonic acid (CH3SO3H) has been widely used for the catalysis of
a variety of syntheses [12–16], because of the high purity of the product, rapid
reaction, no byproducts, and low molecular weight, and, therefore, low cost per acid
functionality. However, use of CH3SO3H as a catalyst in the synthesis of 3,30-
(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) has not yet been reported.
As part of our group’s continuing interest in microwave-assisted synthesis of
organic compounds [17–22], in this paper, we report a general and practical method
for microwave-assisted synthesis of 3,30-(arylmethylene)bis(4-hydroxy-2H-chro-
men-2-ones), 3, from 4-hydroxycoumarin, 1, and aromatic aldehydes, 2, with
CH3SO3H as catalyst, in ethanol (Scheme 1). The reactions were completed in short
reaction times of 6–9 min with high yields of 80–90 %, low energy consumption,
and convenient work-up.
Experimental
Melting points were determined with a WRS-1B digital melting-point apparatus
and are uncorrected. IR spectra were recorded on a Nicolet Avatar 360 FT-IR
instrument. 1H NMR spectra were measured on a Bruker 400-MHz spectrometer, in
CDCl3 or DMSO-d6 as solvent, with TMS as internal standard. Elemental analysis
was performed with a Perkin–Elmer 240 C elemental analyzer. Microwave-assisted
reactions were performed in a CEM Discover monomode microwave reactor. All
the reagents are commercially available.
OH Ar OH
OH
O
CH SO H
3
3
+
ArCHO
2
O
O
O
mwi
O
O
2
1
3
Ar: a: C6H5 b: 4-CH3C6H4 c: 4-ClC6H4 d: 4-O2NC6H5 e: 4-CH3OC6H4
f: 3,4-(CH3O)2C6H3 g: 4-(CH3)2NC6H4 h: 3,4-OCH2OC6H3
Scheme 1 Synthesis of 3,30-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones)
123

Methanesulfonic acid-catalyzed synthesis
General procedure for preparation of 3,30-(arylmethylene)bis(4-hydroxy-2H-
chromen-2-ones) (3a–h)
4-Hydroxycoumarin, 1, (2 mmol) and aromatic aldehyde, 2, (1 mmol) were mixed
with 3 mL ethanol. Methanesulfonic acid (0.05 g) was added and the reaction vial
was sealed with a cap containing a septum. The loaded vial was then placed in the
cavity of the microwave reactor and heated at 120 W and 120 °C for 6–9 min. After
completion of the reaction (as indicated by thin-layer chromatography, TLC), the
reaction mixture was left to cool to room temperature, resulting in precipitation of
the solid product. The product was isolated by filtration, then washed with water and
ethanol. The products were dried and recrystallized from a mixture of CHCl3 and
EtOH to afford the pure products 3a–h.
3,30-(Phenylmethylene)bis(4-hydroxy-2H-chromen-2-one) (3a)
1H NMR (CDCl3) d: 6.12 (s, 1H, CH), 7.24–8.10 (m, 13H, 13 9 CH), 11.33 (s, 1H,
OH), 11.56 (s, 1H, OH); 13C NMR (CDCl3) d: 36.21,105.68, 116.64, 124.41,
124.87, 126.49, 126.88, 128.64, 132.84, 135.22, 152.54; IR (KBr) m: 3427, 3035,
1675, 1611, 1562, 1493, 1445, 1349, 759 cm-1. Anal. calcd. for C25H16O6: C 72.81,
H 3.91; found C 72.61, H 3.79 %.
3,30-((4-Chlorophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3b)
1H NMR (CDCl3) d: 2.36 (s, 3H, CH3), 6.09 (s, 1H, CH), 7.11–8.08 (m, 12H,
12 9 CH), 11.32 (s, 1H, OH), 11.55 (s, 1H, OH); 13C NMR (CDCl3) d: 20.96,
35.90, 104.15, 116.62, 124.39, 124.83, 126.38, 129.34, 132.77, 136.42, 152.31; IR
(KBr) m: 3450, 3075, 1670, 1614, 1563, 1510, 1413, 1350, 1308, 764 cm-1. Anal.
calcd. for C26H18O6: C 73.23, H 4.25; found C 73.15, H 4.43 %.
3,30-((4-Nitrophenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3c)
1H NMR (CDCl3) d: 6.14 (s, 1H, CH), 7.28–8.22 (m, 12H, 12 9 CH), 11.40 (s, 1H,
OH), 11.59 (s, 1H, OH); 13C NMR (CDCl3) d: 36.55, 103.30, 104.80, 116.26,
123.87, 124.52, 125.15, 127.58, 133.35, 143.36, 146.93, 152.40, 164.84, 166.42,
169.10; IR (KBr) m: 3450, 3078, 1657, 1611, 1560, 14517, 1465, 1345, 761 cm-1
.
Anal. calcd. for C25H15NO8: C 65.65, H 3.31, N 3.06; found C 65.73, H 3.24, N
2.89 %.
3,30-(p-Tolylmethylene)bis(4-hydroxy-2H-chromen-2-one) (3d)
1H NMR (CDCl3) d: 6.06 (s, 1H, CH), 7.17–8.10 (m, 12H, 12 9 CH), 11.34 (s, 1H,
OH), 11.56 (s, 1H, OH); 13C NMR (CDCl3) d: 35.85, 103.74, 105.30, 116.64,
124.42, 124.97, 127.98, 128.77, 132.75, 133.90, 152.57, 164.62, 166.84, 169.19; IR
(KBr) m: 3427, 3075, 1675, 1615, 1561, 1492, 1444, 1349, 1270, 1212 cm-1. Anal.
calcd. for C25H15ClO6: C 67.20, H 3.38; found C 66.98, H 3.27 %.
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X. Qi et al.
3,30-((4-Methoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3e)
1H NMR (CDCl3) d: 3.82 (s, 3H, CH3O), 6.07(s, 1H, CH), 6.87–8.08 (m, 12H,
12 9 CH), 11.32(s, 1H, OH), 11.54 (s, 1H, OH); 13C NMR (CDCl3) d: 35.54, 55.27,
114.05, 116.62, 124.38, 124.84, 126.96, 127.63, 132.79, 158.46. IR (KBr) m: 3452,
3073, 1671, 1611, 1562, 1507, 1452, 1351, 1306, 1257, 768 cm-1. Anal. calcd. for
C26H18O7: C 70.58, H 4.10; found C 70.82, H 3.94 %.
3,30-((3,4-Dimethoxyphenyl)methylene)bis(4-hydroxy-2H-chromen-2-one) (3f)
1H NMR (CDCl3) d: 3.76 (s, 3H, CH3O), 3.89 (s, 3H, CH3O), 6.10 (s, 1H, CH),
6.73–8.09 (m, 11H, 11 9 CH), 11.32 (s, 1H, OH), 11.55(s, 1H, OH); 13C NMR
(CDCl3) d: 35.78, 55.90, 56.13, 110.48, 111.32, 116.64, 118.95, 124.36, 124.89,
127.57, 132.83, 148.10, 149.17, 152.41; IR (KBr) m: 3435, 3073, 1670, 1614, 1562,
1512, 1451, 1351, 1308, 1259, 765 cm-1. Anal. calcd. for C27H20O8: C 68.43, H
4.25; found C 68.21, H 4.12 %.
3,30-(Benzo[d][1, 3]dioxol-5-ylmethylene)bis(4-hydroxy-2H-chromen-2-one)
(3g)
1H NMR (DMSO-d6) d: 3.2 (s, 6H, 2CH3), 6.31 (s, 1H, CH),7.23–7.84 (m, 12H,
12 9 CH); 13C NMR (DMSO-d6) d: 36.45, 103.56, 116.05, 120.10, 123.49, 124.58,
128.68, 131.62, 141.21, 153.00, 164.94, 168.00; IR (KBr) m: 3428, 3083, 1662,
1610, 1563, 1523, 1448, 1349, 1309, 765 cm-1. Anal. calcd. for C27H21NO8: C
66.53, H 4.34, N 2.87; found C 65.29, H 3.24, N 2.98 %.
3,30-((4-(Dimethylamino)phenyl)methylene)bis(4-hydroxy-2H-chromen-2-one)
(3h)
1H NMR (CDCl3) d: 5.97 (s, 2H, OCH2O), 6.04 (s, 1H, CH), 6.69–8.07(m, 11H,
11 9 CH), 11.29(s, 1H, OH), 11.62 (s, 1H, OH); 13C NMR (CDCl3) d: 35.93,
101.18, 107.22, 108.23, 116.62, 119.61, 124.40, 124.87, 128.97, 132.86, 146.86,
148.09; IR (KBr) m: 3425, 3078, 1670, 1563, 1494, 1440, 1343, 1308, 1234,
763 cm-1. Anal. calcd. for C26H16O8: C 68.25, H 3.77; found C 68.48, H 3.68 %.
Results and discussion
To determine the optimum reaction conditions, 4-chlorobenzaldehyde and
4-hydroxycoumarin were chosen as starting substrates. We investigated the effect
of different microwave power and reaction temperature on the yield of product 3c
when reaction time was fixed. It was observed that irradiation at 120 W and reaction
at 120 °C gave the best result (Table 1, entry 3).
Under these optimized reaction conditions, a series of 3,30-(arylmethylene)bis
(4-hydroxy-2H-chromen-2-ones) 3a–h were synthesized; the results are summarized
in Table 2. As shown in Table 2, when mixtures of 4-hydroxycoumarin and an
123

Methanesulfonic acid-catalyzed synthesis
Table 1 Effect of microwave power and reaction temperature on the yield of product 3c
Entry
Microwave power (W)
Reaction temperature (°C)
Reaction time (min)
Yield (%)a
1
2
3
4
5
6
a
100
100
120
120
150
150
100
120
120
150
120
150
8
8
8
8
8
8
65
78
89
85
80
62
Yields of the isolated products
Table 2 Microwave-assisted synthesis of 3,30-(arylmethylene)bis(4-hydroxy-2H-chromen-2-ones) 3a–h
catalyzed by methanesulfonic acid
Product
Ar
Time (min)a
Yield (%)b
Mp (°C) (lit. mp)
3a
3b
3c
3d
3e
3f
3g
3h
a
C6H5
8
8
6
8
8
8
9
9
86
90
85
89
88
87
89
80
232–233 (228–230) [23]
270–271 (271–272) [24]
236–237 (232–234) [23]
259–260 (259–261) [24]
248–249 (245–247) [24]
267–268 (265–267) [24]
217–218 (216–217) [21]
254–255 (255–257) [24]
4-CH3C6H4
4-NO2C6H4
4-ClC6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
4-(CH3)2NC6H4
3,4-(OCH2O)C6H3
Microwave power, 120 W; reaction temperature, 120 °C
Yields of the isolated products
b
aromatic aldehyde in ethanol, with methanesulfonic acid as catalyst, were irradiated at
120 W and 120 °C, the reactions were almost complete in 6–9 min. After completion
of the reaction, the reaction mixture was left to cool to room temperature, resulting in
precipitation of the solid product. The crude solids were purified by recrystallization
from CHCl3–ethanol to afford the products in 80–90 % yield. The structures of all the
synthesized compounds were established on the basis of their spectroscopic data and
elemental analysis.
Conclusions
We have developed a novel, efficient method for microwave-assisted synthesis of
3,30-arylmethylene-)bis(4-hydroxy-2H-chromen-2-ones), using CH3SO3H as cata-
lyst, in ethanol. Short reaction times, good yields, low energy consumption, and
convenient work-up are advantages of this method.
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