Catalyst-free synthesis of α,α-bis(4-hydroxycoumarin-3-yl) toluene in aqueous media under microwave irradiation

Article abstract of DOI:10.1080/00397910802398272

An efficient catalyst-free synthesis of α,α-bis(4- hydroxycoumarin-3-yl)toluene was performed by the reaction of 4-hydroxycoumarin with aromatic aldehydes in aqueous media under microwave irradiation. The reaction was completed in short reaction time of 8

Full text of DOI:10.1080/00397910802398272

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Catalyst-Free Synthesis of α,α-
bis(4-Hydroxycoumarin-3-
yl)toluene in Aqueous Media
Under Microwave Irradiation
a
a b
b
Gui-Xia Gong , Jian-Feng Zhou , Li-Tao An
,
b
a
Xiu-Li Duan & Shun-Jun Ji
a
School of Chemistry and Chemical Engineering, Key
Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou University, Suzhou, China
b
Department of Chemistry, Jiangsu Key Laboratory
for Chemistry of Low-Dimensional Materials, Huaiyin
Teachers College, Huaian, China
Published online: 08 Jan 2009.
To cite this article: Gui-Xia Gong , Jian-Feng Zhou , Li-Tao An , Xiu-Li Duan & Shun-
Jun Ji (2009): Catalyst-Free Synthesis of α,α-bis(4-Hydroxycoumarin-3-yl)toluene
in Aqueous Media Under Microwave Irradiation, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:3,
497-505
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1
Synthetic Communications , 39: 497–505, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802398272
Catalyst-Free Synthesis of a,a-
bis(4-Hydroxycoumarin-3-yl)toluene in
Aqueous Media Under Microwave Irradiation
1
Gui-Xia Gong, Jian-Feng Zhou, Li-Tao An, Xiu-Li Duan,
1,2
2
2
1
and Shun-Jun Ji
1
School of Chemistry and Chemical Engineering, Key Laboratory of Organic
Synthesis of Jiangsu Province, Suzhou University, Suzhou, China
2
Department of Chemistry, Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials, Huaiyin Teachers College, Huaian, China
Abstract: An efficient catalyst-free synthesis of a,a-bis(4-hydroxycoumarin-
-yl)toluene was performed by the reaction of 4-hydroxycoumarin with aromatic
3
aldehydes in aqueous media under microwave irradiation. The reaction was com-
pleted in short reaction time of 8–10 min with high yields of 76–94, was environ-
mental benign, and had easy workup. Their structures were confirmed by IR
1
13
spectra, H NMR, C NMR, and elemental analysis.
Keywords: Aqueous media, aromatic aldehyde, a,a-bis(4-hydroxycoumarin-
3
-yl)toluene, 4-hydroxycoumarin, microwave irradiation
Coumarin derivatives are widespread in nature and have various biological
activities such as anticoagulant, insecticidal, antihelminthic, hypnotic,
[
1–3]
antifungal, phytoalexin, and HIV protease inhibition.
the minimum active harmacophore consisted of a coumarin dimer contain-
It was found that
[
3,4]
ing an aryl substituent on the central linker methylene.
The addition
of 4- and 7-hydroxy substituents in the coumarin rings improved the
potency of the compounds. Among the systems studied, the a,a-benzyli-
dene bis(4-hydroxycoumarin-3-yl)toluene has been tested as a HIV inte-
[
3]
grase inhibitor and has shown significant activity. The compound is a
Received May 21, 2008.
Address correspondence to Jian-Feng Zhou, Department of Chemistry,
Huaiyin Teachers College, 223300 Huaian, China. E-mail: orgjfzhou@yahoo.
com.cn
4
97

498
G.-X. Gong et al.
4
blocks of 4-hc and a phenyl ring on the central methylene linker.
-hydroxycoumarin (4-hc) dimer, consisting of two monomeric building
[
5]
However, a,a-benzylidene bis(4-hydroxycoumarin-3-yl)toluene is usually
prepared by the condensation of carbonyl compounds with 4-hydroxycou-
[
3,6a–d]
marin in organic solvents,
and toxic solvents associated with catalysts, such as piperidine, ethylene-
which employs large amounts of hazardous
7]
[
[
8]
[6a]
diammonium diacetate, glacial acetic acid, and acetic anhydride.
In today’s world, synthetic chemists in both academia and industry are
constantly challenged to consider more environmentally benign methods
for generation of the desired target molecules. Among the 12 principles
of green chemistry, the desire for to utilize ‘‘safer solvents’’ and to ‘‘design
for energy efficiency’’ can be considered 2 key principles of relevance to
[9]
synthetic chemists. Because of the toxic and volatile nature of many
organic solvents, water as a reaction medium was considered a very prom-
ising and attractive substitute for volatile organic solvents and was widely
[
10]
used in the green chemistry area since Breslow, who showed that hydro-
phobic effects could strongly enhance the rate of several organic reactions,
rediscovered the use of water as a solvent in organic chemistry in 1980s.
There has been growing recognition that water is an attractive medium
for many organic reactions, resulting in less expensive, less dangerous,
[
11]
and environmentally friendly reactions, such as Diels–Alder reactions,
[12]
[13]
Claisen rearrangement reactions,
Reformatsky reactions,
It is known that microwave irradiation
has been utilized as one of the most convenient and efficient ways to pro-
and
[14]
pinacol-coupling reactions.
[15–17]
mote organic reactions.
In particular, the use of microwave energy to
directly heat chemical reactions has become an increasingly popular tech-
nique in the scientific community. Therefore, in recent years, the combi-
nation of these two prominent green chemistry principles, microwaves
and water, has become very popular and received substantial interest
[18]
due to the work of Leadbeater
and others who demonstrated that a
great variety of synthetic organic transformations can be carried out very
efficiently and rapidly under these environmentally benign conditions.
Recently, several methods of synthesis using 4-hydroxycoumarin for
preparation of a,a-bis(4-hydroxycoumarin-3-yl)toluene in aqueous media
have been reported. Despite effectiveness and ecofriendliness of these
[
19]
[20]
methods, they use catalysts such as TEBA
and I2
and have long
reaction times. Thus, the introduction of efficient new methods based
on green methodology is still in great demand. In our laboratory, con-
tinuing our interest in the synthesis of organic compounds by microwave
[
21–24]
irradiation,
we report an efficient, simple, and practical method for
the catalyst-free synthesis of a,a-bis (4-hydroxycoumarin-3-yl)toluene 3
using aromatic aldehydes 1 and 4-hydroxy-coumarin 2 in aqueous media
under microwave irradiation (Scheme 1). The reactions were completed

a,a-bis(4-Hydroxycoumarin-3-yl)toluene
499
Scheme 1. a: Ar ¼ C
CH
e: Ar ¼ 4-CH
OCH OC H , h: Ar ¼ 4-N(CH ) C H , and i: Ar ¼ 4-OHCC H .
6
H
5
, b: Ar ¼ 4-ClC
6
H
4
, c: Ar ¼ 4-NO
2
C
6
H
,
4
, d: Ar ¼ 4-
3
C
6
H
4
,
3
OC
6
H
4
,
f: Ar ¼ 3,4-(CH
3
O)
2
C
6
H
3
g: Ar ¼ 3,4-
2
6
3
3 2
6
4
6
4
in short reaction times of 8–10 min with high yields of 76–94%, were
environmental benign, and had easy workup.
RESULTS AND DISCUSSION
As is shown in Table 1, the catalyst-free reaction of aromatic aldehyde
and 4-hydroxycoumarin needs only 8–10 min in aqueous media under
ꢀ
microwave irradiation at 150 W and 150 C. It had other advantages such
as only filteration, easy operation, high yield, and less pollution. Further-
more, the reaction has been found to be applicable to dialdehyde as
exemplified by using 1,4-benzenedialdehyde. Two carbonyl groups from
the dialdehyde were reacted with four molecules of 4-hydroxycoumarin
to afford the product 4 in 86% yield (Scheme 2). The structures of these
compounds were established by spectroscopic and analytical data. The
Table 1. Catslyst-free synthesis of 3a–h, and 4 in aqueous media under microwave
irradiation
Time
(min)
Yield
b
(%)
lit.
[19,20,25,6a]
mp
a
ꢀ
Compounds
Ar
Mp ( C)
3
3
3
3
3
3
3
3
4
a
b
c
d
e
f
C H
6
9
9
8
9
8
8
9
9
10
85
92
91
94
76
84
85
95
86
233–234
258–259
238–239
269–270
249–250
269–270
264–265
216–217
307–309
228–230
259–261
232–234
271–272
245–247
265–267
255–257
210
5
4-ClC
4-NO
4-CH C H
6 4
H
2
C
6
H
4
3
6
4
4-CH
3,4-(CH
3
OC
6
H
4
3
O)
2
C
3,4-OCH OC H
6
H
3
g
h
2
6
3
4-N(CH
4-OHCC
3
)
2
C
6
H
4
6
H
4
313–315
a
b
ꢀ
Microwave power: 150 W; reactive temperature: 150 C.
Yields of the isolated products.

500
G.-X. Gong et al.
0
00 000
Scheme 2. Catalyst-free synthesis of 1,4(a,a ,a ,a )teter (4-hydroxycoumarin-
-yl)toluene in aqueous media under microwave irradiation.
3
ꢀ
1
IR spectra of compounds show the OH stretching at 3400 cm region
ꢀ1
1
and a strong absorption at 1670 cm , due to the C=O group. The H
NMR spectra of compound 3a–3g show the OH proton absorption at
1
ous DMSO-d in exchange, the OH proton absorption of 3h and 4 disap-
1.30 and 11.50 ppm in CDCl . However, because of the OH and aque-
3
6
peared in DMSO-d6.
[
19]
The reaction may proceed via addition, elimination, and addition
i.e., benzylidene is formed by nucleophilic addition of 4-hydroxycou-
marin to the benzaldehyde followed by dehydration, in the Michael
(
[
20]
addition fashion, to give a,a-bis(4-hydroxycoumarin-3-yl)toluene).
In conclusion, an efficient, simple, and practical method for the
catalyst-free synthesis of a,a-bis(4-hydroxycoumarin-3-yl)toluene from
the corresponding aromatic aldehydes and 4-hydroxycoumarin in aque-
ous media under microwave irradiation has been developed.
EXPERIMENTAL
Melting points were determined with an WRS-1B digital melting-point
apparatus and are uncorrected. IR spectra were recorded on a Nicolet
1
Avatar 360 FT-IR instrument. H NMR spectra were measured on a
Burke 400-MHz spectrometer in CDCl or DMSO-d using TMS as an
3
6
internal standard. Elemental analyses were determined using a Perkin-
Elmer 240 C elemental analyzer. Reactions under microwaves were per-
1
formed in a CEM Discover monomode microwave reactor. All the
reagents are commercially available.
General Procedure for the a,a-bis(4-Hydroxycoumarin-3-yl)toluene
(3a–h, 4)
Aromatic aldehyde (1 mmol) and 4-hydroxycoumarin (2 mmol) were
mixed in 2 mL water and sealed with a cap containing a septum. The

a,a-bis(4-Hydroxycoumarin-3-yl)toluene
501
loaded vial was then placed into the cavity of the microwave reactor and
ꢀ
heated at 150 W, 150 C, for 8–10 min (as indicated by thin-layer chroma-
tography, (TLC). After completion of the reaction, the reaction mixture
was then allowed to cool to room temperature, resulting in the precipi-
tation of the solid product. The product was filtered off and dried. The
isolated products were subjected to crystallization (mixture of CHCl3
and EtOH) to afford the pure product.
Data
Compound 3a
ꢁ
1 1
IR (KBr) n: 3427, 3035, 1675, 1611, 1562, 1493, 1445, 1349, 759 cm ; H
NMR (CDCl ) d: 6.12 (s, 1H, CH), 7.24–8.10 (m, 13H, 13 ꢂ CH), 11.33
3
1
3
(
s, 1H, OH), 11.56 (s, 1H, OH); C NMR (CDCl ) d: 36.21, 105.68,
3
116.64, 124.41, 124.87, 126.49, 126.88, 128.64, 132.84, 135.22, 152.54.
Anal. calcd. for C H O : C, 72.81; H, 3.91. Found: C, 72.61; H, 3.79.
2
5
16
6
Compound 3b
IR (KBr) n: 3427, 3075, 1675, 1615, 1561, 1492, 1444, 1349, 1270,
ꢁ
1 1
1
1
3
1
6
212 cm ; H NMR (CDCl ) d: 6.06 (s, 1H, CH), 7.17–8.10 (m, 12H,
3
1
3
2 ꢂ CH), 11.34 (s, 1H, OH), 11.56 (s, 1H, OH); C NMR (CDCl ) d:
3
5.85, 103.74, 105.30, 116.64, 124.42, 124.97, 127.98, 128.77, 132.75,
33.90, 152.57, 164.62, 166.84, 169.19. Anal. calcd. for C H ClO : C,
7.20; H, 3.38. Found: C, 66.98; H, 3.27.
2
5
15
6
Compound 3c
IR (KBr) n: 3450, 3078, 1657, 1611, 1560, 14517, 1465, 1345, 761 cm
ꢁ
1
;
1
H NMR (CDCl ) d: 6.14 (s, 1H, CH), 7.28–8.22 (m, 12H, 12 ꢂ CH),
3
1
3
1
1
1
6
1.40 (s, 1H, OH), 11.59 (s, 1H, OH); C NMR (CDCl ) d: 36.55,
3
03.30, 104.80, 116.26, 123.87, 124.52, 125.15, 127.58, 133.35, 143.36,
46.93, 152.40, 164.84, 166.42, 169.10. Anal. calcd. for C H NO : C,
5.65; H, 3.31; N, 3.06. Found: C, 65.73; H, 3.24; N, 2.89.
2
5
15
8
Compound 3d
IR (KBr) n: 3450, 3075, 1670, 1614, 1563, 1510, 1413, 1350, 1308,
ꢁ
1 1
7
64 cm ; H NMR (CDCl ) d: 2.36 (s, 3H, CH ), 6.09 (s, 1H, CH),
3 3
7
.11–8.08 (m, 12H, 12 ꢂ CH), 11.32 (s, 1H, OH), 11.55 (s, 1H, OH);

502
G.-X. Gong et al.
1
3
C NMR (CDCl ) d: 20.96, 35.90, 104.15, 116.62, 124.39, 124.83, 126.38,
3
1
4
29.34, 132.77, 136.42, 152.31. Anal. calcd. for C H O : C, 73.23; H,
.25. Found: C, 73.15; H, 4.43.
26 18 6
Compound 3e
IR (KBr) n: 3452, 3073, 1671, 1611, 1562, 1507, 1452, 1351, 1306, 1257,
ꢁ
1 1
7
68 cm ; H NMR (CDCl ) d: 3.82 (s, 3H, CH O), 6.07 (s, 1H, CH),
3 3
6
.87–8.08 (m, 12H, 12 ꢂ CH), 11.32 (s, 1H, OH), 11.54 (s, 1H, OH);
1
3
C NMR (CDCl ) d: 35.54, 55.27, 114.05, 116.62, 124.38, 124.84,
3
1
26.96, 127.63, 132.79, 158.46. Anal. calcd. for C H O : C, 70.58; H,
2
6
18
7
4
.10. Found: C, 70.82; H, 3.94.
Compound 3f
IR (KBr) n: 3435, 3073, 1670, 1614, 1562, 1512, 1451, 1351, 1308, 1259,
ꢁ
1 1
7
65 cm ; H NMR (CDCl ) d: 3.76 (s, 3H, CH O), 3.89 (s, 3H, CH O),
3 3 3
6
.10 (s, 1H, CH), 6.73–8.09 (m, 11H, 11 ꢂ CH), 11.32 (s, 1H, OH), 11.55
1
3
(s, 1H, OH); C NMR (CDCl ) d: 35.78, 55.90, 56.13, 110.48, 111.32,
3
116.64, 118.95, 124.36, 124.89, 127.57, 132.83, 148.10, 149.17, 152.41.
Anal. calcd. for C H O : C, 68.43; H, 4.25. Found: C, 68.21; H, 4.12.
2
7
20
8
Compound 3g
IR (KBr) n: 3425, 3078, 1670, 1563, 1494, 1440, 1343, 1308, 1234,
ꢁ
; H NMR (CDCl ) d: 5.97 (s, 2H, OCH O), 6.04 (s, 1H,
3 2
1
1
7
63 cm
CH), 6.69–8.07 (m, 11H, 11 ꢂ CH), 11.29 (s, 1H, OH), 11.62 (s, 1H,
1
3
OH); C NMR (CDCl ) d: 35.93, 101.18, 107.22, 108.23, 116.62,
3
1
19.61, 124.40, 124.87, 128.97, 132.86, 146.86, 148.09. Anal. calcd. for
C H O : C, 68.25; H, 3.77. Found: C, 68.48; H, 3.68.
2
6
16
8
Compound 3h
IR (KBr) n: 3428, 3083, 1662, 1610, 1563, 1523, 1448, 1349, 1309,
ꢁ
1 1
7
7
1
1
65 cm ; H NMR (DMSO-d ) d: 3.2 (s, 6H, 2CH ), 6.31 (s, 1H, CH),
6 3
1
3
.23–7.84 (m, 12H, 12 ꢂ CH); C NMR (DMSO-d ) d: 36.45, 103.56,
6
16.05, 120.10, 123.49, 124.58, 128.68, 131.62, 141.21, 153.00, 164.94,
68.00. Anal. calcd. for C H NO : C, 66.53; H, 4.34; N, 2.87. Found:
2
7
21
8
C, 65.29; H, 3.24; N, 2.98.

a,a-bis(4-Hydroxycoumarin-3-yl)toluene
Compound 4
503
IR (KBr) n: 3436, 3074, 1662, 1603, 1564, 1502, 1449, 1347, 1309,
ꢁ
1
1
7
2
1
62 cm ; H NMR (DMSO-d ) d: 6.35 (s, 2H, 2CH), 7.05–7.92 (m,
6
1
3
0H, 20 ꢂ CH); C NMR (DMSO-d ) d: 36.12, 104.70, 116.43, 118.13,
6
24.27, 124.35, 127.05, 132.42, 137.27, 152.61, 165.29, 165.32. Anal.
calcd. for C H O : C, 70.60; H, 3.75. Found: C, 70.35; H, 3.66.
4
4
26 12
ACKNOWLEDGMENT
We thank the Jiangsu Key Laboratory for Chemistry of
Low-Dimensional Materials for financial support.
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