Cux2 (x =cl, br) as catalysts for pechmann reaction: Synthesis of 4-substituted coumarins

Article abstract of DOI:10.3184/030823409X447745

CuX₂ (X=Cl, Br) are found to be efficient catalysts (10 mol%) for the Pechmann condensation reaction of phenols and b-ketoesters to give 4-substituted coumarins under solvent-free conditions. The yields of coumarin derivatives obtained via this

Full text of DOI:10.3184/030823409X447745

JOURNAL OF CHEMICAL RESEARCH 2009
JUNE, 339–341
RESEARCH PAPER 339
CuX2 (X =Cl, Br) as catalysts for Pechmann reaction: synthesis of
4-substituted coumarins
Yi Wang, Feng Xu*, You-Ping Tian, Hui-Li Li and Jian-Jun Wang
Key Laboratory of Macromolecular Science of Shaanxi Province, School of Chemistry & Materials Science, Shaanxi Normal
University, Xi'an, Shaanxi, 710062, P. R. China
CuX2 (X=Cl, Br) are found to be efficient catalysts (10 mol%) for the Pechmann condensation reaction of phenols
and b-ketoesters to give 4-substituted coumarins under solvent-free conditions. The yields of coumarin derivatives
obtained via this new protocol, were equal or higher than those using the conventional method and the reaction
time was reduced to a few minutes.
Keywords: coumarins, Pechmann reaction, CuX2, catalysis, heterocycles
Coumarins (2H-1-benzopyran-2-one) and their derivatives
are important natural products. In addition, they have a
broad range of applications in the pharmaceutical, perfume,
and cosmetic industries. They have been used successfully
as additives to food, optical brightening agents, and as
dispersed fluorescent and tunable laser dyes. They have
varied bioactivities, for example, inhibition of platelet
aggregation,1 anti-cancer agents,2 steroid 5a-reductase
inhibitiors.3 Coumarins also act as intermediates for the
synthesis of fluorocoumarins, chromenes, coumarones,
and 2-acylresorcinols.4 Consequently, coumarins and their
derivatives are interesting targets for organic chemists.
acid CuX2 catalysts under solvent-free condition to produce
the 4-substituted coumarins in excellent yields (Scheme 1).
This is novel, one-pot condensation not only preserves
the simplicity of the Pechmann condensation reaction but
also consistently produces excellent yields of the coumarin
derivatives and greatly decreases environmental pollution.
In the presence of CuX2 (X =Cl, Br) (10 mol%), the reaction
of ethyl acetoacetate (6 mmol) and phloroglucinol (5 mmol)
was carried out under solvent-free condition for 5 min at
80°C, and gave 5,7-dihydroxy-4-methylcoumarin (5) in 96%
(X =Cl) and 98% (X = Br) yields. Similarly, phloroglucinol
was treated with ethyl benzoylacetate in the presence of CuX2
(X =Cl, Br) (10 mol%) for 10 min to furnish coumarins (6) in
89% yields for CuCl2 and 91% yields for CuBr2 respectively
(Table 1, entries 1 and 2). The melting point of these products
(in Table 1) was in good agreement with the corresponding
literature values.
Encouraged by the above results, other phenolic substrates
were subjected to the Pechmann reaction using CuX2 (X =Cl,
Br) as catalysts. Resorcinol, 5-methylresorcinol, a-naphthol
and pyrogallol were subjected to the reaction with different
b-ketoesters as shown in Table 1 to give the corresponding
coumarin derivatives. The reaction was found to be adaptable
to a variety of substrates and the yields, in general, were high
(80–98%). Short reaction times were observed (5–20 min)
regardless of structural variations in the phenols or b-ketoesters.
Different substitution patterns on the aromatic ring could be
introduced with high efficiency. For most of the substrates,
the reaction time was reduced substantially even under mild
reaction conditions in contrast to reported procedures24,25 and
gave an excellent yield of the coumarin derivatives.
Coumarinshavebeensynthesisedbyseveralroutesincluding
the Pechmann,5 Perkin,6 Knoevenagel,7 Reformatsky,8 and
Wittig reactions9 and by flash vacuum pyrolysis.10 The
Pechmann reaction is a simple procedure for the synthesis of
4-substituted coumarins in good yields by reacting phenols
and b-ketoesters in the presence of acidic catalyst. Various
acidic catalysts including H2SO4, HClO4, CF3COOH, PPA,
•
ZrOCl2, Sm(NO3)3 6H2O, FeCl3, ZnCl2, AlCl3, TiCl4, InCl3,
ZrCl4, Montmorillonite, cation exchange resins, microwave
irradiation, ionic liquids and a polyaniline supported acid
catalyst, are known to affect this condensation.11-22 However,
some of these catalysts have to be used in large amounts.
Moreover, in some cases, long reaction times were needed,
undesired side products were isolated and often high reaction
temperatures up to 150°C were required.
Recently, CuX2 has emerged as a powerful Lewis acid
catalyst for various chemical transformations. The new
interest in CuX2 is easily justified by its favourable ecological
properties. Recently considerable emphasis has been placed
on improvement in the environmental impact of industrial
chemical processes. Cupric halides are relatively nontoxic,
inexpensive, insensitive to air and no special care is required in
handling them. In connection with our research on developing
new methods using CuX2 as catalyst,23 we have studied their
use in the Pechmann condensation, to produce the coumarins
derivatives.
In conclusion, we have demonstrated an efficient and simple
alternative for the preparation of substituted coumarins via the
CuX2 (X =Cl, Br) catalysed Pechmann reaction in solvent-
free conditions. Prominent among the advantages of this new
method are operational simplicity, good yields, short reaction
times and an easy work-up.
Experimental
Staring materials were obtained from commercial suppliers and were
used without further purification. Melting points were determined
with X-5 apparatus in open glass capillaries and were uncorrected.
IR spectra were recorded on EQUINX 55 FT-IR spectrometer using
Result and discussion
The substituted phenols and ethyl acetoacetate or ethyl
benzoylacetate undergo condensation in the presence of Lewis
R1
O
O
CuX2 (X=Cl, Br)
Solvent-free, 80°C
+
R
R
R1
OEt
R1=CH3, Ph
OH
O
O
Scheme 1 Preparation of coumarins catalysed by CuX2 under solvent free conditions.
* Correspondent. E-mail: fengxu@snnu.edu.cn

340 JOURNAL OF CHEMICAL RESEARCH 2009
Table 1 CuX2 (X=Cl, Br) catalysed synthesis of 4-substituted coumarin
Entry
Phenol
Ethyl acetoacetate
Producta
Time c/min
5
Yield b/%
CH3
1
Resorcinol
1
CH3COCH2CO2Et
92 (CuCl2) 94 (CuBr2)
HO
OH
HO
2
O
O
O
O
Ph
2
3
PhCOCH2CO2Et
CH3COCH2CO2Et
10
10
88 (CuCl2) 87 (CuBr2)
90 (CuCl2) 93 (CuBr2)
HO
3
O
OH CH3
5-methylresorcinol
CH3
H3C
4
O
OH Ph
HO
OH
4
PhCOCH2CO2Et
20
86 (CuCl2) 97 (CuBr2)
H3C
5
O
O
OH CH3
Phloroglucinol
5
6
CH3COCH2CO2Et
PhCOCH2CO2Et
10
15
96 (CuCl2) 98 (CuBr2)
89 (CuCl2) 81 (CuBr2)
OH
HO
6
O
O
O
OH Ph
HO
OH
HO
7
O
CH3
1-naphthol
7
8
CH3COCH2CO2Et
PhCOCH2CO2Et
15
30
86 (CuCl2) 87 (CuBr2)
No product
O
O
O
OH
Ph
8
O
CH3
9
Pyrogallol
9
CH3COCH2CO2Et
PhCOCH2CO2Et
15
20
85 (CuCl2) 89 (CuBr2)
80 (CuCl2) 83 (CuBr2)
HO
O
O
O
OH
OH
HO
OH
Ph
10
10
HO
O
OH
aAll products were characterised by comparison of their m.p., IR, and 1H NMR spectra with those of authentic samples.
bIsolated yields.
cAll reactions were carried out at 80°C.
KBr pellets. NMR spectral data were collected on an AVANCF 300
MHz spectrometer in DMSO-d6 with TMS as an internal standard.
Elemental analyses were performed with a Vario ELIII instrument.
7-hydroxy-4-phenyl-2H-chromen-2-one (2): Solid; m.p. 256–
258°C (Lit.12, 256–257°C), IR: υmax 3157, 2983, 2806, 1680, 1588,
1433, 1389, 1263, 1241, 1150, 1108 cm−1
.
5-hydroxy-4,7-dimethyl-2H-chromen-2-one (3): Solid; m.p.259–
260°C (Lit.27, 257–258°C), IR: υmax 3440, 3047, 2929, 1658, 1612,
Gerenal experimental procedure
1513, 1448, 1409, 1380, 1339, 1295, 1252, 1150, 1099 cm−1
.
The CuX2 (X=Cl, Br) (0.5 mol) was added to the phenol
(5 mmol) and b-ketoester (6 mmol), in a 50 mL round bottom flask
and the contents were stirred in a pre-heated oil-bath at 80°C. After
completion of the reaction (monitored by TLC, the time indicated in
Table 1), the reaction mixture was cooled to room temperature and the
viscous contents were poured into water. The products were collected
by filtration, washed with water and dried. They were further purified
by silica column chromatography for analysis.
All the coumarin derivatives are well-known. Compound (1) was
selected as the representative product and was fully characterised
(melting point, IR, 1H NMR and elemental analysis). Other
compounds were identified by their melting point and IR and by
comparison of their physical and spectral data with literature.
7-hydroxy-4-methyl-2H-chromen-2-one (1): Solid; m.p. 186–187°C
(Lit.26, 182–184°C), IR: υmax 3500, 3156, 2807, 1677, 1598, 1449, 1390,
1273, 1239, 1156, 1131, 1065 cm−1. 1H NMR: d 2.36 (s, 3H, –CH3), 6.08(s,
1H, C=CH), 6.75(d, 2H, ArH), 7.57(s, 1H, ArH), 10.52(s, H, –OH). Anal.
Calcd for C8H10O3: C, 68.18%; H, 4.58. Found: C, 68.15%; H, 4.56%.
5-hydroxy-7-methyl-4-phenyl-2H-chromen-2-one (4): Solid; m.p.
225–226°C (Lit.12, 226°C), IR: υmax 3439, 3064, 2983, 1674, 1657,
1611, 1450, 1369, 1339, 1313, 1276, 1174, 1106, 1070 cm−1
.
5,7-dihydroxy-4-methyl-2H-chromen-2-one (5): Solid; m.p. 281–
283°C (Lit.26, 284–285°C), IR: υmax 3449, 2926, 2686, 1667, 1622,
1587, 1552, 1473, 1388, 1362, 1301, 1237, 1159, 1099, 1076 cm−1
.
5,7-dihydroxy-4-phenyl-2H-chromen-2-one (6): Solid; m.p. 245–
246°C (Lit.12, 246–247°C), IR: υmax 3416, 3163, 2983, 1688, 1670,
1587, 1552, 1450, 1389, 1364, 1276, 1161, 1074, 1027 cm−1
.
4-methyl-2H-benzo[h]chromen-2-one (7): Solid; m.p. 154–155°C
(Lit.26, 153–154°C), IR: υmax 3436, 3197, 1683, 1628, 1572, 1554,
1469, 1380, 1271, 1147, 1082 cm−1
.
7,8-dihydroxy-4-methyl-2H-chromen-2-one (9): Solid; m.p.
240–241°C (Lit.15, 241–243°C), IR: υmax 3413, 3232, 2984, 1646,
1727, 1619, 1596, 1513, 1448, 1389, 1335, 1307, 1230, 1138, 1061,
1007 cm−1
.

JOURNAL OF CHEMICAL RESEARCH 2009 341
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This workwas financially supported by the Scientific Research
Foundation for Chinese Scholars Returned from Overseas
(ROCS-2007), State Education Ministry of China, NSFC
(20872085) and the Natural Science Foundation of Shaanxi
Province (No. SJ08B22).
Received 3 Feburary 2009; accepted 19 March 2009
Paper 09/0425 doi: 10.3184/030823409X447745
Published online: 22 June 2009
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