Novel traceless liquid-phase synthesis of coumarin derivatives on poly(ethylene glycol) support

Article abstract of DOI:10.1080/00397910600908868

Coumarin derivatives were prepared by the von Pechmann reaction of PEG-bound acetoacetate reagent with phenols in the presence of TiCl₄ in excellent yield and purity with a facile workup procedure. The polymer reagent could be recycled two to four times without diminishing the yield or purity. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600908868

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Novel Traceless Liquid‐Phase Synthesis of
Coumarin Derivatives on Poly(Ethylene
Glycol) Support
a
a
a
a
Shou‐Ri Sheng , Pei‐Gang Huang , Qiong Wang , Ren Huang & Xiao‐Ling
a
Liu
a
College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang, China
Published online: 24 Nov 2006.
To cite this article: ShouRi Sheng , PeiGang Huang , Qiong Wang , Ren Huang & XiaoLing Liu (2006) Novel
Traceless Liquid‐Phase Synthesis of Coumarin Derivatives on Poly(Ethylene Glycol) Support, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:21,
3175-3181
To link to this article: http://dx.doi.org/10.1080/00397910600908868
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Synthetic Communications , 36: 3175–3181, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600908868
Novel Traceless Liquid-Phase Synthesis of
Coumarin Derivatives on Poly(Ethylene
Glycol) Support
Shou-Ri Sheng, Pei-Gang Huang, Qiong Wang, Ren Huang,
and Xiao-Ling Liu
College of Chemistry and Chemical Engineering, Jiangxi Normal
University, Nanchang, China
Abstract: Coumarin derivatives were prepared by the von Pechmann reaction of
4
PEG-bound acetoacetate reagent with phenols in the presence of TiCl in excellent
yield and purity with a facile workup procedure. The polymer reagent could be
recycled two to four times without diminishing the yield or purity.
Keywords: Coumarins, liquid-phase synthesis, PEG-bound acetoacetate, von
Pechmann reaction
Solid-phase organic synthesis (SPOS) and high-throughput screening have
emerged as powerful tools for acceleration of drug discovery, allowing the
[1]
preparation of highly diverse compound libraries. However, SPOS suffers
from various problems such as the heterogeneous nature of the reaction
condition, reduced rate of reactions, and mass transport of reagents.
Recently, organic synthesis of small molecular compounds on soluble
polymers [i.e., liquid-phase organic synthesis (LPOS)] has been a focus of
[
2]
intense research activity. Unlike an insoluble matrix, the soluble polymer
support couples the advantages of homogeneous solution chemistry (high
reactivity, lack of diffusion phenomena, and ease of analysis without the
cleavage-and-check procedure) with those of solid-phase chemistry (use of
Received in Japan February 19, 2006
Address correspondence to Shou-Ri Sheng, College of Chemistry and Chemical
Engineering, Jiangxi Normal University, Nanchang 330027, China. E-mail:
shengsr@163.com
3
175

3
176
S.-R. Sheng et al.
excessive reagents and easy isolation and purification of product). Among the
various soluble polymers, polyethylene glycol (PEG) has increasingly become
[
3]
an attractive support. Coumarins, as one of the most important chemicals in
the cosmetics, argricultural, pharmaceutical, and material industries for its
[4]
bioactivity and photodynamic effects, have been both widely studied and
widely used but still generate much interest. Many methods have been
developed for preparing coumarins. Among these methods, the von
[
5]
Pechmann reaction has been the most widely used method because it
proceeds from very simple starting materials and gives good yields of
[6]
variously substituted coumarins. Until now, protic or Lewis acids have
been used as condensing reagents to promote the condensation of substituted
phenols with b-keto esters. Recently, improved methods have been developed
[
7a]
[7b,7c]
utilizing cation exchange resins,
[
solid acid catalyst,
[7e]
solvent-free
[7f]
7d]
methods catalyzed by InCl ,
3
sulfamic acid,
[7h]
p-TsOH,
and even use of ionic liquids and
Wells–
[7i]
[
7g]
Dawson heteropolyacid,
microwave irradiation for accelerated synthesis of different coumarins.
or TiCl4,
[7j]
However, most of these methods involve difficulties such as higher reaction
temperatures, long reaction times, laborious manipulation, and low overall
yields, or in some cases some reagents are not readily available. Several
[8]
solid-phase synthetic methods for coumarins using polymer reagents have
[9]
also been reported. More recently, Tocco et al. reported a liquid-phase
synthesis of 4-methyl coumarins by reaction of modified PEG-supported
phenol with ethyl acetoacetate using sulfuric acid. Herein, we report
another novel traceless route to the liquid-phase synthesis of substituted
coumarins using PEG-supported b-keto ester as shown in Scheme 1.
The PEG 4000–linked acetoacetate 2 was prepared by reaction of PEG
4000 (1) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (i.e., diketene acetone
adduct, TKD)
[
10]
in anhydrous toluene under reflux for 5 h. The conversion
1
of terminal hydroxyl groups on PEG was determined by H NMR analysis
to be quantitative. The FT-IR spectrum of the loaded resin 2 showed
complete disappearance of the hydroxyl OH stretch and the appearance of
2
1
C 55 O absorptions at 1743 and 1718 cm , which corresponds to ester and
ketone carbonyl group, respectively. With the PEG-bound acetoacetate 2 in
hand, we switched our attention to its application in liquid-phase combinator-
ial synthesis of substituted coumarins by the von Pechmann reaction, which is
one of the most simple and straightforward methods. Ordinarily, many
.
Brønsted and Lewis acids such as H SO , POCl , AlCl , ZnCl , BF Et O,
2
4
3
3
2
3
2
Scheme 1.

Novel Traceless Liquid-Phase Synthesis of Coumarin
3177
CH SO H, etc. have been used as condensing reagents. Here, we examined
3
3
several different acids including H SO , p-TsOH, ZnCl , AlCl , and TiCl .
4
2
4
2
3
After a series of experiments, we found that TiCl gave the best results. For
4
example, an excess amount of PEG-bound acetoacetate 2 was treated with
resorcinol (3a) in the presence of a catalytic amount of TiCl in THF at
4
room temperature for 30 min, and then the polymer reagent was removed
by precipitation with cold diethyl ether followed by filtration. The filtrate-
contaminated TiCl was poured into crushed ice, and the organic layer was
4
washed with water, dried, and concentrated in vacuo to afford the crude
1
product, which was directly analyzed by H NMR without further purification.
1
The H NMR measurement showed perfect conversion to 7-hydroxy-4-
methylcoumarin (4a) in 96% yield and high purity (.95%).
Using this procedure, a variety of substituted coumarins were syn-
thesized. As show in Table 1, the yields are excellent and purities are satis-
factory for most of the substrates. It is obvious that those substrates
containing electron-donating group give better results, but the phenols contain-
ing electron-withdrawing groups such as NO did not work (Entry 10). Phenol
2
(
3h), as a substrate with no electron-donating group, gave the desired coumarin
4h) only with 61% yield (Entry 8) even with enhanced reaction temperature or
(
prolonged reaction time. In some cases, a trace amount of the PEG residue
might contaminate the final products 4, but this problem could be easily
solved by recrystallization from ethanol or passing the crude product
through a silica gel column (10–15% ethyl acetate in hexane).
Finally, the recycling of PEG-bound ester 2 was investigated. The
recovered polymer, whose terminal functional group was a mixture of
hydroxyl and acetoacetyl groups, was reacted again with 2,2,6-trimethyl-
4
H-1,3-dioxin-4-one (TKD) to regenerate PEG-bound ester 2 cleanly.
Table 1. Synthesis of substituted coumarins using PEG-supported acetoacetate 2
a
b
Entry
R (Phenol 3)
Product
Time (min)
Yield (%)
Purity (%)
1
2
3
4
5
6
7
8
9
3-OH (3a)
3,5-Di OH (3b)
3-OCH (3c)
3-CH (3d)
4a
4b
4c
4d
4e
4f
35
40
96
96
96
92
90
94
94
61
91
—
.95
.95
.95
.95
.95
.95
.95
.95
.95
—
3
40
3
35
3-OCH CO Et (3e)
2
50
30
2
3-OCH
3-OH-5-CH
2
COC
6
H
5
(3f)
3
(3h)
4h
4h
4i
35
30
H (3h)
(1-Naphthol 3i)
4-NO (3j)
50
No reaction
1
0
2
4j
a
Isolated yield based on loading of original HO-PEG-OH. The products were charac-
1
terized from their spectra ( H NMR and IR) and comparison with authentic samples.
b 1
Purity was determined by integration of H NMR spectra.

3
178
S.-R. Sheng et al.
We found this could react with resorcinol (3a) without any trouble and
produce 7-hydroxy-4-methylcoumarin (4a), keeping nearly quantitative
yield and with excellent purity for one to four times. It showed that
synthesis of substituted coumarins using PEG-bound ester 2 not only gives
high yield and purity but also is a facile, speedy, cheap, and environmentally
friendly method throughout the course of the reaction.
In conclusion, we have developed a novel liquid-phase synthesis of
substituted coumarins using PEG-bound acetoacetate with advantages
of excellent yield, purity, and recyclability of the polymer reagent.
EXPERIMENTAL
Melting points were determined on an X melting-point apparatus and are
4
1
uncorrected. H NMR (400 MHz) spectra were recorded on a Bruker
Avance (400-MHz) spectrometer. FT-IR spectra were taken on a Perkin-
Elmer SP One FT-IR spectrophotometer. Mass spectra (EI, 70eV) were
recorded on a HP5989B mass spectrometer. All the chemicals were used
without further purification.
General Procedure for the Preparation of PEG-Bound
Acetoacetate 2
PEG 4000 (1) (4.0 g, 2 mmol terminal hydroxyl groups) and 2,2,6-trimethyl-
4
H-1,3-dioxin-4-one (5.0 mmol) were added to anhydrous toluene (20 mL)
under a nitrogen atmosphere. The resulted mixture was refluxed under
stirring for 5 h. After cooling to room temperature, anhydrous ether
(100 mL) was poured into the mixture to precipitate the yellow solid, which
was washed with Et O and AcOEt several times and dried in vacuo to
2
1
afford the PEG-bound acetoacetate 2. H NMR (CDCl ) d ¼ 2.27 (s, 3H,
3
CH ), 3.49 (s, 2H, COCH CO), 3.53–3.78 (m, PEG backbone,
3
2
OCH OCH O), 4.30 (t, J ¼ 5.00 Hz, 2H, PEG-OCH CH OCO); IR (KBr) n
2
2
2
2
2
9
885, 1743, 1718, 1646, 1467, 1360, 1344, 1280, 1242, 1147, 1115, 1061,
64, 842 cm
2
1
.
General Procedure for the Preparation of Substituted
Coumarins 4a–4i
Titanium (IV) chloride (0.5 mmol) was added to a solution of phenol 3
(
(
1.0 mmol) and PEG-bound acetoacetate 2 (1.5 mmol) in anhydrous THF
15 mL) under a nitrogen atmosphere at r.t. and stirred for 30–50 min, and
then the polymer was precipitated by addition of diethyl ether (100 mL) to
the mixture. For completion of the precipitation, the suspension was left at

Novel Traceless Liquid-Phase Synthesis of Coumarin
3179
08C for another 30 min. The white precipitate was collected and washed several
times with diethyl ether (2 ꢀ 5 mL) and dried in vacuo for regeneration. The
filtrate was poured into crushed ice and stirred until the ice melted, and the
organic phase was washed with water, dried over magnesium sulfate, and
concentrated to give crude products 4, which were further purified by recrystal-
lization from hot ethanol or passing the crude product through a silica-gel
column (10–15% ethyl acetate in hexane), if necessary.
Data
[11]
1
7
-Hydroxy-4-methylcoumarin (4a): mp 185–1878C (lit.
mp 1858C); H
NMR (DMSO-d ): d ¼ 9.45 (s, 1H), 7.62 (d, J ¼ 8.8 Hz, 1H), 6.86 (dd,
6
J ¼ 8.8, 2.4 Hz, 1H), 6.75 (d, J ¼ 2.4 Hz, 1H), 6.10 (s, 1H), 2.43 (s, 3H);
IR (KBr): 3270, 2925, 1680, 1606, 1565, 1393, 1320, 1269, 1140, 1069,
9
2
1
þ
82, 690 cm ; EIMS: m/z: 176 (M ).
[
11]
5
,7-Dihydroxy-4-methylcoumarin (4b): mp 283-2858C (lit.
mp 283–
1
2
858C); H NMR (DMSO-d ): d ¼ 8.71 (s, 1H), 8.56 (s, 1H), 7.14
6
(
d, J ¼ 8.6 Hz, 1H), 6.84 (d, J ¼ 8.6 Hz, 1H), 6.05 (s, 1H), 2.40 (s, 3H); IR
(
KBr): 3260, 2927, 1672, 1611, 1566, 1380, 1322, 1270, 1141, 1070, 974,
2
1
þ
6
90 cm ; EIMS: m/z: 192 (M ).
[
7h]
7
-Methoxy-4-methylcoumarin (4c): mp 156–1578C (lit.
mp 156–1588C);
1
H NMR (CDCl ): d ¼ 7.58 (d, J ¼ 8.7 Hz, 1H), 6.84 (d, J ¼ 8.7 Hz, 1H),
3
6
.72 (s, 1H), 6.08 (s, 1H), 2.56 (s, 3H), 2.40 (s, 3H); IR (KBr): 3010, 2927,
2
1
1
685, 1610, 1555, 1378, 1259, 1145, 1065, 978, 690 cm ; EIMS: m/z: 190
þ
(M ).
[
7h]
1
4
,7-Dimethylcoumarin (4d): mp 131–1328C (lit. mp 131-1328C); H NMR
(
CDCl ): d ¼ 7.50 (d, J ¼ 8.6 Hz, 1H), 6.82 (d, J ¼ 8.6 Hz, 1H), 6.70 (s, 1H),
3
6
1
.08 (s, 1H), 2.85 (s, 3H), 2.61 (s, 3H); IR (KBr): 3008, 2925, 1686, 1610,
2
1
þ
560, 1375, 1256, 1150, 1060, 980, 691 cm ; EIMS: m/z: 174 (M ).
[
7h]
7
-Ethoxycarbonylmethoxyl-4-methylcoumarin (4e): mp 99–1018C (lit.
mp
1
9
8–1008C); H NMR (CDCl ): d ¼ 7.78 (d, J ¼ 8.8 Hz, 1H), 7.34
3
(
d, J ¼ 8.8 Hz, 1H), 7.18 (s, 1H), 6.12 (s, 1H), 5.36 (s, 2H), 4.31
q, J ¼ 7.0 Hz, 2H), 2.65 (s, 3H), 1.71 (t, J ¼ 7.0 Hz, 3H); IR (KBr): 2920,
(
21
732, 1652, 1600, 1550, 1375, 1250, 1145, 1056, 981, 690 cm ; EIMS:
1
m/z: 262 (M ).
þ
[
7h]
7
-Benzoylmethoxyl-4-methylcoumarin (4f): mp 174–1758C (lit.
mp 173–
1
1
748C); H NMR (CDCl ): d ¼ 8.20–7.02 (m, 8H), 6.15 (s, 1H), 5.48
3

3
180
S.-R. Sheng et al.
(
s, 2H), 2.66 (s, 3H); IR (KBr): 3020, 2920, 1700, 1632, 1600, 1548, 1377,
2
1
þ
1
250, 1144, 1055, 983, 690 cm ; EIMS: m/z: 294 (M ).
[
7h]
7
2
6
1
-Hydroxy-4,5-dimethycoumarin (4g): mp 243–2448C (lit.
mp 243–
1
458C); H NMR (DMSO-d ): d ¼ 9.43 (s, 1H), 6.35 (s, 1H), 6.22 (s, 1H),
6
.12 (s, 1H), 2.95 (s, 3H), 2.64 (s, 3H); IR (KBr): 3160, 2926, 1668, 1605,
2
1
þ
565, 1395, 1321, 1270, 1141, 1069, 981, 690 cm ; EIMS: m/z: 190 (M ).
[7h]
1
4-Methylcoumarin (4h): mp 83-848C (lit.
mp 83–848C); H NMR
(
CDCl ): d ¼ 7.65–7.28 (m, 4H), 6.18 (s, 1H), 2.61 (s, 3H); IR (KBr):
3
3
6
010, 2930, 1665, 1610, 1500, 1450, 1401, 1375, 1269, 1140, 1065,
2
1
þ
92 cm ; EIMS: m/z: 160 (M ).
[
11]
1
4
-Methylbenzo[h]coumarin (4i): mp 155–1568C (lit. mp 1558C); H NMR
(
CDCl ): d ¼ 7.51–8.85 (m, 6H), 6.21 (s, 1H), 2.68 (s, 3H); IR (KBr): 3010,
3
2
1
2930, 1675, 1600, 1495, 1455, 1405, 1372, 1269, 1142, 1060, 690 cm
EIMS: m/z: 210 (M ).
;
þ
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the National Natural
Science Foundation (NSF) of China (No. 20562005) and NSF of Jiangxi
Province (No. 0620021).
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