Ionic liquid, [bmim]Br, as an efficient promoting medium for synthesis of 3-acetoacetylcoumarin derivatives without the use of any catalyst

Article abstract of DOI:10.1080/00397910902779306

A series of 3-acetoacetylcoumarin derivatives were synthesized via the reaction of substituted 2-hydroxybenzaldehydes and 4-hydroxy-6-methyl-2H-pyran- 2-one in ionic liquid. This method has the advantages of good yields, milder reaction conditions, easier workup, no catalyst, and environmentally benign procedure.

Full text of DOI:10.1080/00397910902779306

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Ionic Liquid, [bmim]Br,
as an Efficient Promoting
Medium for Synthesis of
3-Acetoacetylcoumarin
Derivatives Without the Use of
Any Catalyst
a b
b
b
Da-Qing Shi
, Yao Zhou & Shao-Feng Rong
a
College of Chemistry, Chemical Engineering
and Materials Science, Key Laboratory of Organic
Synthesis of Jiangsu Province, Suzhou University,
Suzhou, China
b
College of Chemistry and Chemical Engineering,
Xuzhou Normal University, Xuzhou, China
Published online: 04 Sep 2009.
To cite this article: Da-Qing Shi , Yao Zhou & Shao-Feng Rong (2009): Ionic Liquid,
[bmim]Br, as an Efficient Promoting Medium for Synthesis of 3-Acetoacetylcoumarin
Derivatives Without the Use of Any Catalyst, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:19,
3500-3508
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1
Synthetic Communications , 39: 3500–3508, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902779306
Ionic Liquid, [bmim]Br, as an Efficient Promoting
Medium for Synthesis of 3-Acetoacetylcoumarin
Derivatives Without the Use of Any Catalyst
1
Da-Qing Shi, Yao Zhou, and Shao-Feng Rong
College of Chemistry, Chemical Engineering and Materials Science,
Key Laboratory of Organic Synthesis of Jiangsu Province,
Suzhou University, Suzhou, China
,2
2
2
1
2
College of Chemistry and Chemical Engineering, Xuzhou
Normal University, Xuzhou, China
Abstract: A series of 3-acetoacetylcoumarin derivatives were synthesized via the
reaction of substituted 2-hydroxybenzaldehydes and 4-hydroxy-6-methyl-2H-
pyran-2-one in ionic liquid. This method has the advantages of good yields,
milder reaction conditions, easier workup, no catalyst, and environmentally
benign procedure.
Keywords: 3-Acetoacetylcoumarin,
methyl-2H-pyran-2-one, ionic liquid
2-hydroxybenzaldehyde,
4-hydroxy-6-
Coumarin and its derivatives are natural compounds and are important
chemicals in perfume, cosmetic, and pharmaceutical industrial
[
1]
production. Some coumarin derivatives have been reported to exhibit
biological properties, such as anti-oxidant, anti-inflammatory, antialler-
gic, hepatoprotective, antiviral, anticarcinogenic, and anticoagulant
[
2–10]
properties.
because of these diverse pharmacological properties.
coumarin derivatives are generally prepared by the reaction of
They have attracted considerable interest in recent years
[
11]
3-Acetoacetyl-
2
-hydroxybenzaldehydes and 4-hydroxy-6-methyl-2H-pyran-2-one in an
Received October 12, 2008.
Address correspondence to Da-Qing Shi, College of Chemistry, Chemical
Engineering and Materials Science, Suzhou University, Suzhou 215123, China.
E-mail: dqshi@suda.edu.cn
3
500

3
-Acetoacetylcoumarin Derivatives
3501
organic solvent (e.g., ethanol or toluene) in the presence of a base like
[
12]
[13]
triethylamine
by ammonium acetate.
and potassium fluoride (KF)–alumina
or catalyzed
[14]
Room-temperature ionic liquids, especially those based on 1-alkyl-3-
methylimidazolium cations, have shown great promise as an attractive
alterative to conventional organic solvents, and more attention has been
[
15]
currently focused on organic reactions promoted by ionic liquids. They
are nonvolatile, recyclable, nonexplosive, easily operable, and thermally
[
16]
robust.
liquids in organic reactions, such as Friedel–Crafts reactions,
There are many reports concerning the applications of ionic
[
17]
Diels–
[20]
Pechmann condensations,
[
18]
[19]
Alder reactions,
Biginelli reactions,
Heck reactions,
Beckmann rearrangements,
[21]
[22]
and other reac-
tions. As part of our current studies on the development of new routes
[
23]
[24]
to heterocyclic system in ionic liquids, we now report an efficient and
clean synthetic route to 3-acetoacetylcoumarin derivatives in ionic liquid
[
bmim]Br.
To get 3-acetoacetylcoumarin derivatives 3, we reported a facile
method consisting of substituted 2-hydroxybenzaldehyde and
1
4
9
-hydroxy-6-methyl-2H-pyran-2-one 2 in an ionic liquid [bmim]Br at
ꢀ
0 C for a few hours (Scheme 1).
It is well-known that choosing an appropriate solvent and reaction
temperature is crucially important for an efficient organic synthesis. To
search for the optimal reaction conditions, the reaction of salicylaldehyde
1
a and 4-hydroxy-6-methyl-2H-pyran-2-one 2 was examined using
different solvents and different reaction temperatures. The corresponding
results are summarized in Table 1.
It is shown in Table 1 that the ionic liquid [bmim]Br as solvent at
ꢀ
9
0 C resulted in the best yield and shortest reaction time. Therefore,
bmim]Br was chosen as the solvent for this reaction.
[
Under these optimized reaction conditions, a series of 3-acetoacetyl-
coumarin derivatives 3 were synthesized. The results are summarized
in Table 2.
The structure of 3a was based on the spectroscopic data and
high-resolution mass spectra (HRMS). It should be noted that the
ꢁ
1
infrared (IR) spectra exhibited broad bands at 3441 cm
(OH) and
Scheme 1. The synthetic route for the 3-acetoacetylcoumarin derivatives 3.

3502
D.-Q. Shi, Y. Zhou, and S.-F. Rong
Table 1. Solvent and reaction temperature optimization for the synthesis of 3a
Reaction
temperature ( C)
Time
(h)
Yield
(%)
ꢀ
Entry
Solvent
1
2
3
4
5
6
7
8
9
[bmim]Br
[bmim]BF
90
90
90
Rt
40
60
80
Reflux
Reflux
Reflux
Reflux
100
4
8
8
98
54
60
56
65
73
85
28
33
71
23
81
4
[bmim]PF6
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
30
21
12
8
29
25
18
30
7
CH
CH
3
3
COCH
CN
3
1
1
1
0
1
2
EtOH
CHCl
DMF
3
ꢁ
1
1
absence of the methylene (CH ) group and instead a singlet at 15.80 ppm
730 cm (C¼O), and the NMR spectra (in solvent CDCl ) showed the
2
3
(OH) and a singlet at 6.97 ppm (CH). We can see clearly that it was an
enol form, not a keto tautomerism, perhaps the large-conjugative-
system-stable enol moiety. The structures are the same as in our previous
[
13]
results.
On the basis of the structure of 3, the following mechanistic pathway
leading to the parent heterocycle 3a can be formulated. It starts with the
Knoevenagel condensation of pyranone 2 with salicylaldehyde (1a) in
ionic liquid to give 3-salicylidenepyrane-2,4-dione 4. This compound
ꢀ
Table 2. Synthesis of 3-acetoacetylcoumarin derivatives 3 in [bmim]Br at 90 C
1
2
3
Entry
Product
R
R
R
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
H
Br
H
H
Cl
H
H
H
H
H
H
H
H
Br
Cl
Br
Cl
H
4
4
4.5
4
3
4
3
3
2.5
3
98
99
85
92
90
88
56
80
93
86
CH O
3
3g
3h
3i
(CH ) C
3
(CH ) C
3 3
3
H
H
H
CH
3
O
H
H
H
CH
3
O
1
0
3j
CH3

3
-Acetoacetylcoumarin Derivatives
3503
Scheme 2. The mechanistic pathway leading to the 3-acetoacetylcoumarin.
was already described as produced from the same components and
sodium amide in liquid ammonia.
[25]
The functional pyrone unit in 4
undergoes a ring-opening reaction mediated by a nucleophic attack of
the phenolic group onto the lactone carbonyl, yielding 3-acetoacetylcou-
marin (3a). A plausible mechanism for the formation of 3a is outlined in
Scheme 2.
In conclusion, with good yields and mild conditions, we think that
the present work provides a useful method for the preparation of 3-acet-
oacetylcoumarin derivatives. Compared with other methods, this new
method has the advantages of easier workup, milder reaction conditions,
better yields, no catalyst, and a more environmentally benign procedure.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
IR spectra were recorded on a Tensor 27 spectrometer in KBr with
ꢁ
1
1
absorptions in centimeters
00-MHz spectrometer in CDCl with tetramethylsilane (TMS) as inter-
. H NMR was measured on an Inova
4
3
nal standard. High-resolution mass spectra (HRMS) were obtained using
a time-of-flight mass spectrometry (TOF-MS) instrument.
General Procedure for the Preparation of 3-Acetoacetylcoumarin
Derivatives (3)
A dry 50 mL flask was charged with substituted 2-hydroxybenzaldehyde
1
(1 mmol), 4-hydroxy-6-methyl-2H-pyran-2-one 2 (1 mmol), and 2 mL
ꢀ
[
Bmim]Br. The mixture was stirred at 90 C for 2.5–4.5 h, and the sticky

3504
D.-Q. Shi, Y. Zhou, and S.-F. Rong
liquor was poured into water. Then solid material was filtered off and
washed with water, and the crude product was purified by recrystalliza-
tion from ethanol to give pure 3.
SPECTRAL DATA
3
-Acetoacetylcoumarin (3a)
ꢀ
[14]
Mp: 144–145 C (lit. 148–150 C); IR (KBr) v: 3441, 3131, 3063, 1730,
ꢀ
ꢁ1 1
1
608, 1585, 1455, 1362, 1262, 1301, 1186, 1108, 820, 761 cm ; H NMR
(
CDCl ) d: 2.24 (3H, s, CH ), 6.97 (1H, s, CH), 7.25–7.32 (2H, m,
3
3
ArH), 7.54–7.59 (2H, m, ArH), 8.59 (1H, s, CH), 15.80 (1H, s, OH).
þ
HRMS calcd. for C H O , m=z: 230.0579 (M ); found, m=z:
1
3
10
4
2
30.0580.
6
,8-Dibromo-3-acetoacetylcoumarin (3b)
ꢀ
[13]
ꢀ
188–189 C); IR (KBr) v: 3457, 3121, 3065, 1757,
Mp: 186–187 C (lit.
619, 1575, 1450, 1363, 1208, 1187, 864, 826, 772 cm
CDCl ) d: 2.23 (3H, s, CH ), 6.93 (1H, s, CH), 7.66 (1H, d, J ¼ 2.0 Hz,
ꢁ1
1
1
(
; H NMR
3
3
ArH), 7.90 (1H, d, J ¼ 2.0 Hz, ArH), 8.45 (1H, s, CH), 15.67 (1H, s,
7
9
OH). HRMS calcd. for C H Br O , m=z: 385.8789 (M ); found,
þ
1
3
8
2
4
m=z: 385.8787.
6
-Chloro-3-acetoacetylcoumarin (3c)
ꢀ
[13]
ꢀ
Mp: 197–198 C (lit.
ꢁ
197–199 C); IR (KBr) v: 3437, 3064, 1737, 1613,
1 1
1
578, 1480 cm ; H NMR (CDCl ) d: 2.24 (3H, s, CH ), 7.01 (1H, s,
3
3
CH), 7.32 (1H, d, J ¼ 8.88, ArH), 7.56–7.59 (1H, m, ArH), 7.62 (1H, d,
J ¼ 2.0, ArH), 8.57 (1H, s, CH), 15.78 (1H, s, OH). HRMS calcd. for
3
C H ClO , m=z: 266.0160 (M ); found, m=z: 266.0165.
7
þ
1
3
9
4
6
-Bromo-3-acetoacetylcoumarin (3d)
ꢀ
[13]
ꢀ
211–212 C); IR (KBr) v: 3437, 3064, 1736, 1611,
Mp: 209–211 C (lit.
583, 1551, 1403, 1280, 1257, 1184, 1110, 1017, 885, 822, 781 cm ; H
NMR (CDCl ) d: 2.25 (3H, s, CH ), 6.97 (1H, s, CH), 7.23 (1H, d,
ꢁ1 1
1
3
3
J ¼ 8.8 Hz, ArH), 7.68 (1H, dd, J ¼ 8.8 Hz, J ¼ 2.4 Hz, ArH), 7.74
1
2

3
-Acetoacetylcoumarin Derivatives
3505
(
1H, d, J ¼ 2.4 Hz, ArH), 8.53 (1H, s, CH), 15.75 (1H, s, OH). HRMS
þ
13 9 4
7
9
calcd. for C H BrO , m=z: 307.9684 (M ); found, m=z: 307.9693.
6
,8-Dichloro-3-acetoacetylcoumarin (3e)
ꢀ
[13]
Mp: 198–200 C (lit. 200–202 C); IR (KBr) v: 3457, 3116, 3066, 1747,
614, 1576, 1417, 1365, 1274, 1225, 1183, 1097, 1011, 886, 830, 777,
ꢀ
1
7
ꢁ1
1
36, 704 cm ; H NMR (CDCl ) d: 2.25 (3H, s, CH ), 6.69 (1H, s,
3
3
CH), 7.50 (1H, s, ArH), 7.62 (1H, s, ArH), 8.50 (1H, s, CH), 15.70
3
5
þ
1H, s, OH). HRMS calcd. for C H Cl O , m=z: 297.9800 (M );
13 8 2 4
(
found, m=z: 297.9791.
8
-Methoxy-3-acetoacetylcoumarin (3f)
ꢀ
[14]
Mp: 170–172 C (lit.
605, 1575, 1474, 1441, 1278, 1185, 1124, 1098, 820, 789, 733 cm
ꢀ
172–173 C); IR (KBr) v: 3446, 2941, 2844, 1725,
ꢁ
1
1
;
1
H NMR (CDCl ) d: 2.21 (3H, s, CH ), 3.93 (3H, s, OCH ), 6.99 (1H,
3
3
3
s, CH), 7.12–7.17 (2H, m, ArH), 7.20–7.25 (1H, m, ArH), 8.58 (1H, s,
CH), 15.79 (1H, s, OH). HRMS calcd. for C H O , m=z: 260.0685
1
4
12
5
þ
(
M ); found, m=z: 260.0695.
6
,8-Di-tert-butyl-3-acetoacetylcoumarin (3g)
ꢀ
Mp: 163–165 C. IR (KBr) v: 3444, 3123, 3070, 1724, 1619, 1581, 1441,
ꢁ
1
;
1
396, 1363, 1332, 1283, 1252, 1188, 1107, 1012, 893, 835, 792, 711 cm
H NMR (CDCl ) d: 1.31 [9H, s, (CH ) C], 1.47 [9H, s, (CH ) C], 2.22
1
3
3 3
3 3
(
3H, s, CH ), 6.99 (1H, s, CH), 7.39 (1H, d, J ¼ 2.0 Hz, ArH), 7.62 (1H,
3
d, J ¼ 2.0 Hz, ArH), 8.59 (1H, s, CH), 15.83 (1H, s, OH). HRMS calcd.
þ
for C H O , m=z: 342.1831 (M ); found, m=z: 342.1831.
2
1
26
4
7
-Methoxy-3-acetoacetylcoumarin (3h)
ꢀ
[13]
Mp: 176–177 C (lit. 175–177 C); IR (KBr) v: 3447, 2937, 1728, 1609,
506, 1558, 1426, 1362, 1274, 1224, 1181, 1122, 1022, 843, 810,
ꢀ
1
7
6
ꢁ
1 1
72 cm ; H NMR (CDCl ) d: 2.18 (3H, s, CH ), 3.83 (3H, s, OCH ),
3
3
3
.76 (1H, d, J ¼ 2.4 Hz, ArH), 6.83 (1H, dd, J ¼ 8.8 Hz, J ¼ 2.4 Hz,
1
2
ArH), 6.91 (1H, s, CH), 7.46 (1H, d, J ¼ 8.8 Hz, ArH), 8.53 (1H, s,
CH), 15.92 (1H, s, OH). HRMS calcd. for C H O , m=z: 260.0685
1
4
12
5
þ
M ); found, m=z: 260.0694.
(

3506
D.-Q. Shi, Y. Zhou, and S.-F. Rong
6
-Methoxy-3-acetoacetylcoumarin (3i)
ꢀ
Mp: 170–171 C; IR (KBr) v: 3446, 3123, 1732, 1603, 1567, 1494, 1456,
1
ꢁ
1 1
419, 1361, 1293, 1269, 1184, 1108, 1031, 959, 856, 827, 808 cm ; H
NMR (CDCl ) d: 2.24 (3H, s, CH ), 3.84 (3H, s, OCH ), 7.01 (2H, s,
3
3
3
CH þ ArH), 7.19 (1H, dd, J ¼ 8.8 Hz, J ¼ 2.4 Hz, ArH), 7.27 (1H, d,
1
2
J ¼ 8.8 Hz, ArH), 8.58 (1H, s, CH), 15.82 (1H, s, OH). HRMS calcd.
þ
for C H O , m=z: 260.0685 (M ); found, m=z: 260.0695.
1
4
12
5
6
-Methyl-3-acetoacetylcoumarin (3j)
ꢀ
[13]
Mp: 176–178 C (lit.
570, 1489, 1419, 1293, 1261, 1221, 1180, 1137, 1014, 957, 809 cm
ꢀ
179–180 C); IR (KBr) v: 3441, 2925, 1733, 1615,
ꢁ
1
1
;
1
H NMR (CDCl ) d: 2.21 (3H, s, CH ), 2.37 (3H, s, CH ), 7.03 (1H, s,
3
3
3
CH), 7.26–7.28 (1H, m, ArH), 7.43–7.47 (2H, m, ArH), 8.61 (1H, s,
CH), 15.83 (1H, s, OH). HRMS calcd. for C H O , m=z: 244.0736
1
4
12
4
þ
M ); found, m=z: 244.0746.
(
ACKNOWLEDGMENTS
We are grateful to the Foundation of Key Laboratory of Organic Synth-
esis of Jiangsu Province and the Key Laboratory of Biotechnology on
Medical Plants of Jiangsu Province for financial support.
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