A quick and advantageous synthesis of 2H-1-benzopyran-2-ones unsubstituted on the pyranic nucleus

Article abstract of DOI:10.1055/s-2008-1067238

The synthesis of 2H-1-benzopyran-2-ones (coumarins) unsubstituted on the pyranic nucleus was realized by condensation of malic acid and phenols under mild conditions. A short reaction time, improved yields, good purity of the products, and an easy clean experimental protocol are the advantages of this procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067238

SHORT PAPER
2871
A Quick and Advantageous Synthesis of 2H-1-Benzopyran-2-ones
Unsubstituted on the Pyranic Nucleus
Synthesis of
2
H
-1-
e
Benzopyra
o
n-2-ones rge Bratulescu*
Faculty of Chemistry, University of Craiova, 13 A.I. Cuza, 200396 Craiova, Romania
E-mail: georgebratulescu@yahoo.com
Received 5 October 2007; revised 30 May 2008
R4
R4
Abstract: The synthesis of 2H-1-benzopyran-2-ones (coumarins)
unsubstituted on the pyranic nucleus was realized by condensation
of malic acid and phenols under mild conditions. A short reaction
time, improved yields, good purity of the products, and an easy
clean experimental protocol are the advantages of this procedure.
COOH
CHOH
CH2
R3
R3
R2
+
– 3H2O
– CO
R2
COOH
OH
O
O
R1
R1
Key words: coumarin, 2H-1-benzopyran-2-one, malic acid, phe-
1
2
nols, condensation
Scheme 1
A large number of natural products bear a 2H-1-benzopy-
ran-2-one (coumarin) as part of in their structure.1 2H-1-
Benzopyran-2-ones show wide biological activity, e.g. as
antioxidants,2 anticoagulants,3 antifungal agents,4 anthel-
mintic, hypnotic, and cytotoxic agents,1,5 They are widely
used as agrochemicals,6 additives in cosmetics and food,5
optical brighteners, and dispersed fluorescent and tunable
laser dyes optical agents.7–10 Therefore, the synthesis of
these heterocyclic compounds is of current interest.
Table 1 Synthesis of 2H-1-Benzopyran-2-ones
Entry R1
R2
R3 R4
Temp Time Product Yield
(°C) (min)
(%)
68
71
70
69
84
62
70
72
73
79
90
93
1
2
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
103
106
114
111
117
3
3
2a
2b
2c
2d
2e
2f
H
H
Me
H
3
Cl
Br
H
H
2.5
2.5
2.5
3
4
H
H
2H-1-Benzopyran-2-one have been synthesized by sever-
al routes, including Perkin,11,12 von Pechman,13 Knoeve-
nagel,14,15 Reformatsky,16 Wittig,17 and combined Claisen
rearrangement, ring-closing metathesis, and Diels–
Alder18 reactions. These methods all require specific or-
ganic or inorganic catalysts, organic solvents, long reac-
tion times, or extensive purification operations to separate
the products, which leads to extensive amounts of waste.2
5
H
Cl
6
H
H
NO2 118
7
H
Me
H
H
101
106
104
119
3
2g
2h
2i
8
Me
H
Me
Me
H
3
9
Me
OMe
H
3
Previously, we realized the synthesis of several organic
compounds using a chemical paste medium and micro-
wave irradiation.19,20 In this medium, during microwave
irradiation, hot points are created that function like cata-
lytic centers and, hence, chemical reactions take place
rapidly.20
10
11
12
H
3
2j
H
OMe 121
OH 123
3
2k
2l
H
Me
2.5
a Satisfactory microanalysis obtained: C 0.04, H 0.03; 2f N +0.01.
The synthesis of 2H-1-benzopyran-2-ones unsubstituted
on the pyranic heterocyclic nucleus constitutes a chemis-
try challenge because poor yields are frequently ob-
tained.5,15 Herein we report a new microwave-assisted
synthesis of 2H-1-benzopyran-2-ones 2 from phenol de-
rivatives 1 and malic acid (Scheme 1, Table 1).
ventional methods; the products were obtained with high
purity. Moreover, the workup procedure is simple, the
products only need to be recrystallized. These benefits
make this method one of the cleanest for 2H-1-benzopyr-
an-2-one synthesis.
The paste medium like chemical medium was obtained
adding a few drops of pyridine. By this method the syn-
thesis of 2H-1-benzopyran-2-ones 2a–l was completed in
a shorter time and with improved yields compared to con-
Malic acid, phenol derivatives, TsOH, and pyridine are commer-
cially available reagents. The synthesized products were identified
by TLC (silica gel, MeOH), elemental analysis, H NMR, and IR
1
spectra. The melting points were measured using a Böetius melting
point apparatus. IR spectra were recorded on KBr disks using a
1
Perkin-Elmer 1600 spectrophotometer. H and 13C NMR spectra
SYNTHESIS 2008, No. 18, pp 2871–2873
x
x.
x
x
.
2
0
0
8
were obtained in CDCl3 solns with TMS as internal standard on a
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1067238; Art ID: Z23607SS
Bruker ARX 300 MHz spectrometer at 300 MHz (1H) and 100 MHz
© Georg Thieme Verlag Stuttgart · New York

2872
G. Bratulescu
SHORT PAPER
s
(13C). Elemental analyses were carried out with a Carlo Erba model
1106 apparatus. An Optiquick Y71 microwave device operating at
650 W was employed. The temperature during the microwave irra-
diation was determined with the help of a Novo Quick digital ther-
mometer.
IR: 1741 (vs) (C=O), 1524 (s) (NO2as), 1327 (vs) (NO2 ), 1277 (s)
(C–Oas), 1119 cm–1 (s) (C–Os).
1H NMR: d = 6.28 (d, J = 9.6 Hz, 1 H, H3), 7.62 (dd, J = 7.8, 6.9
Hz, 1 H, H7), 7.71 (dd, J = 7.8, 0.9 Hz, 1 H, H8), 7.92 (d, J = 9.6
Hz, 1 H, H4), 8.12 (dd, J = 6.9, 0.9 Hz, 1 H, H6).
13C NMR: d = 116.7, 118.6, 123.8, 128.3, 130.7, 143.9, 147.9,
2H-1-Benzopyran-2-one Derivatives 2a–l; General Procedure
To a mixture of malic acid (2 mmol) and phenol derivatives 1 (2
mmol) was added 98% H2SO4 (0.7 mmol) in a 25-mL Erlenmeyer
flask. A few drops of pyridine were added and the resulting paste
was irradiated in a microwave oven (l = 12.2 cm) for the required
time. The resulting residue was purified by recrystallization (EtOH)
to give the 2H-1-benzopyran-2-one derivatives.
152.1, 160.7.
6,7-Dimethyl-2H-1-benzopyran-2-one (2g)
Mp 147 °C.
IR: 1721 (vs) (C=O), 1239 (s) (C–Oas), 1110 cm–1 (s) (C–Os).
1H NMR: d = 2.39 (s, 3 H, CH3), 2.48 (s, 3 H, CH3), 6.19 (d, J = 9.4
Hz, 1 H, H3), 6.98 (s, 1 H, H8), 7.12 (s, 1 H, H5), 7.63 (d, J = 9.4
Hz, 1 H).
13C NMR: d = 16.2 (7-Me), 18.4 (6-Me), 115.9, 119.8, 120.3, 128.1,
134.2, 137.3, 143.7, 148.2, 160.2.
2H-1-Benzopyran-2-one (2a)
Mp 70 °C (Lit.21 69–70 °C).
IR: 1729 (vs) (C=O), 1260 (s) (C–Oas), 1108 cm–1 (s) (C–Os).
1H NMR: d = 6.38 (d, J = 9.5 Hz, 1 H, H3), 7.24 (ddd, J = 7.7, 7.4,
1.1 Hz, 1 H, H6), 7.31 (dd, J = 8.3, 1.1 Hz, 1 H, H8), 7.46 (dd,
J = 7.7, 1.6 Hz, 1 H, H5), 7.52 (ddd, J = 8.3, 7.4, 1.6 Hz, 1 H, H7),
7.71 (d, J = 9.5 Hz, 1 H, H3).
13C NMR: d = 116.5, 116.8, 118.8, 124.4, 127.9, 131.7, 143.4,
153.9, 160.6.
5,8-Dimethyl-2H-1-benzopyran-2-one (2h)
Mp 121 °C.
IR: 1719 (vs) (C=O), 1246 (s) (C–Oas), 1106 cm–1 (s) (C–Os).
1H NMR: d = 2.49 (s, 3 H, CH3), 2.31 (s, 3 H, CH3), 6.23 (d, J = 9.4
Hz, 1 H, H3), 7.09 (d, J = 7.3 Hz, 1 H, H6), 7.28 (d, J = 7.3 Hz, 1
H, H7), 7.63 (d, J = 9.4 Hz, 1 H, H4).
13C NMR: d = 14.3 (8-Me), 18.7 (5-Me), 115.9, 124.9, 128.2, 128.9,
130.2, 133.8, 142.8, 152.5, 160.4.
5-Methyl-2H-1-benzopyran-2-one (2b)
Mp 82 °C.
IR: 1722 (vs) (C=O), 1254 (s) (C–Oas), 1101 cm–1 (s) (C–Os).
1H NMR: d = 2.51 (s, 3 H, CH3), 6.22 (d, J = 9.3 Hz, 1 H, H3), 6.83
(dd, J = 8.1, 1.2 Hz, 1 H, H8), 7.08 (dd, J = 7.4, 1.2 Hz, 1 H, H6),
7.28 (dd, J = 8.1, 7.4 Hz, 1 H, H7), 7.61 (d, J = 9.3 Hz, 1 H, H4).
13C NMR: d = 18.1 (MeO), 114.8, 116, 117.8, 125.9, 131.8, 136.4,
140.5, 154.9, 160.5.
5,7-Dimethyl-2H-1-benzopyran-2-one (2i)
Mp 132 °C.
IR: 1722 (vs) (C=O), 1257 (s) (C–Oas), 1103 cm–1 (s) (C–Os).
1H NMR: d = 2.50 (s, 3 H, CH3), 2.67 (s, 3 H, CH3), 6.22 (d, J = 9.3
Hz, 1 H, H3), 6.87 (d, J = 1.1 Hz, 1 H, H6), 7.92 (d, J = 1.1 Hz, 1
H, H8), 7.59 (d, J = 9.3 Hz, 1 H, H4).
13C NMR: d = 18.6 (5-Me), 24.4 (7-Me), 115.9, 116.9, 128.1, 128.3,
136.1, 137.2, 143.7, 150.7, 160.8.
8-Chloro-2H-1-benzopyran-2-one (2c)
Mp 146 °C.
IR: 1702 (vs) (C=O), 1221 (s) (C–Oas), 1005 cm–1 (s) (C–Os).
1H NMR: d = 6.31 (d, J = 9.4 Hz, 1 H, H3), 7.19 (dd, J = 7.7, 7.2
Hz, 1 H, H6), 7.47 (dd, J = 7.7, 1.2 Hz, 1 H, H5), 7.38 (dd, J = 7.2,
1.2 Hz, 1 H, H7), 7.65 (dd, J = 9.4 Hz, 1 H, H4).
13C NMR: d = 113.8, 120.2, 123.9, 125.6, 127.8, 132.1, 143.7,
147.3, 159.5.
7-Methoxy-2H-1-benzopyran-2-one (2j)
Mp 117 °C.
IR: 1706 (vs) (C=O), 1233 (vs) (C–Oas), 1025 cm–1 (vs) (C–Os).
1H NMR: d = 3.87 (s, 3 H, CH3), 6.24 (d, J = 9.4 Hz, 1 H, H3), 6.80
(d, J = 1.4 Hz, 1 H, H8), 6.84 (dd, J = 5.8, 1.4 Hz, 1 H, H6), 7.37 (d,
J = 5.8 Hz, 1 H, H5), 7.64 (d, J = 9.4 Hz, 1 H, H4).
13C NMR: d = 56 (MeO), 104.7, 112.5, 113.1, 114.9, 132.1, 138.2,
154.5, 156.0, 160.6.
8-Bromo-2H-1-benzopyran-2-one (2d)
Mp 135 °C.
IR: 1719 (vs) (C=O), 1247 (s) (C–Oas), 1024 cm–1 (s) (C–Os).
1H NMR: d = 6.37 (d, J = 9.4 Hz, 1 H, H3), 7.24 (dd, J = 7.8, 7.2
Hz, 1 H, H6), 7.52 (dd, J = 7.8, 1.3 Hz, 1 H, H5), 7.61 (dd, J = 7.2,
1.3 Hz, 1 H, H7), 7.72 (d, J = 9.4 Hz, 1 H, H4).
13C NMR: d = 113.5, 124.2, 124.6, 126.1, 129.2, 130.3, 143.4,
146.1, 160.2.
5-Methoxy-2H-1-benzopyran-2-one (2k)
Mp 82 °C.
IR: 1712 (vs) (C=O), 1240 (s) (C–Oas), 1019 cm–1 (vs) (C–Os).
1H NMR: d = 3.82 (s, 3 H, CH3), 6.23 (d, J = 9.3 Hz, 1 H, H3), 6.69
(dd, J = 6.9, 1 Hz, 1 H, H6), 6.73 (dd, J = 8.1, 1 Hz, 1 H, H8), 7.19
(dd, J = 8.1, 6.9 Hz, 1 H, H7), 7.60 (d, J = 9.3 Hz, 1 H, H4).
13C NMR: d = 56.1 (MeO), 104.5, 109.3, 109.9, 114.2, 132.4, 138.9,
154.5, 156.1, 161.6.
5-Chloro-2H-1-benzopyran-2-one (2e)
Mp 91 °C.
IR: 1710 (vs) (C=O), 1239 (s) (C–Oas), 1019 cm–1 (s) (C–Os).
1H NMR: d = 6.31 (d, J = 9.5 Hz, 1 H, H3), 6.87 (dd, J = 8.2, 1.2
Hz, 1 H, H8), 6.94 (dd, J = 7.1, 1.2 Hz, 1 H, H6), 7.13 (dd, J = 8.2,
7.1 Hz, 1 H, H7), 7.55 (d, J = 9.5 Hz, 1 H, H4).
13C NMR: d = 115.9, 120.6, 125.1, 129.1, 130.8, 132.4, 142.8,
152.3, 160.3.
5-Hydroxy-7-methyl-2H-1-benzopyran-2-one (2l)
Mp 217 °C.
IR: 3154 (m) (OH), 1712 (vs) (C=O), 1251 (s) (C–Oas), 1067 cm–1
(s) (C–Os).
1H NMR: d = 2.71 (s, 3 H, CH3), 6.27 (d, J = 9.2 Hz, 1 H, H3), 6.58
(d, J = 1.3 Hz, 1 H, H6), 6.67 (d, J = 1.3 Hz, 1 H, H8), 7.57 (d,
J = 9.2 Hz, 1 H, H4), 10.04 (br s, 1 H, OH).
5-Nitro-2H-1-benzopyran-2-one (2f)
Mp 178 °C.
Synthesis 2008, No. 18, 2871–2873 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 2H-1-Benzopyran-2-ones
2873
13C NMR: d = 25.8 (7-Me), 112.7, 113.1, 116.2, 116.8, 140.2,
143.7, 152.6, 159.2, 160.1.
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Synthesis 2008, No. 18, 2871–2873 © Thieme Stuttgart · New York