Sonochemistry as a General Procedure for the Synthesis of Coumarins, Including Multigram Synthesis

Article abstract of DOI:10.1055/s-0036-1590201

This study describes a general procedure for the synthesis of different coumarins via sonochemistry using active methylene compounds and 2-hydroxybenzaldehydes or resorcinol. The application of sonochemistry for the synthesis of these compounds was also very effective on a multigram scale with a higher yield, higher amount of crystalline compound, and shorter reaction time compared with the compounds obtained using the classical procedures.

Full text of DOI:10.1055/s-0036-1590201

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–F
A
paper
Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
Sonochemistry as a General Procedure for the Synthesis of
Coumarins, Including Multigram Synthesis
ULTRASOUND
Ligia S. da Silveira Pintoa
Marcus V. N. de Souza*a,b
IRRADIATION
a
Universidade Federal do Rio de Janeiro, Instituto de Química,
Departamento de Química Orgânica, CP 68563, 21945-970
Rio de Janeiro, Brazil
FioCruz-Fundação Oswaldo Cruz, Instituto de Tecnologia em
O
b
CO2Et
CO2Et
Fármacos-Far-Manguinhos, Rua Sizenando Nabuco, 100,
Manguinhos, 21041-250 Rio de Janeiro, Brazil
marcos_souza@far.fiocruz.br
H
CO2Et
. 11 examples
. 49–90% yield
O
possible on multigram scale
+
OH
O
.
88%
Received: 13.12.2016
Accepted after revision: 28.02.2017
Published online: 24.03.2017
DOI: 10.1055/s-0036-1590201; Art ID: ss-2016-m0753-op
Abstract This study describes a general procedure for the synthesis of
different coumarins via sonochemistry using active methylene com-
pounds and 2-hydroxybenzaldehydes or resorcinol. The application of
sonochemistry for the synthesis of these compounds was also very ef-
fective on a multigram scale with a higher yield, higher amount of crys-
talline compound, and shorter reaction time compared with the com-
pounds obtained using the classical procedures.
Key words coumarins, sonochemistry, synthesis, multigram scale,
Figure 1 Applications of coumarin nucleus
smaller scale
por cavities, and implosive collapse of bubbles in a liq-
uid).1
2,13
It is important to note that there are previously re-
Coumarins are a class of natural products that are found
in many plant species belonging to the benzopyrone family.
This class and its derivatives are important compounds in
the drug development and natural product fields because
they possess a wide range of pharmacological activities, in-
cluding anti-HIV, antibacterial, antifungal, anti-inflamma-
tory, antileishmanial, antimalarial, antitumor, and antide-
ported examples of using ultrasound in synthesizing other
coumarin analogues.1
4–16
In some cases, compared with the
classical procedures, sonochemistry has several advantages
17
such as higher yields, greater amount of crystalline com-
pounds,18 and a reduced reaction time.17 Considering these
advantages, this study describes sonochemistry as a general
procedure for the synthesis of different coumarins using ac-
tive methylene compounds and 2-hydroxybenzaldehydes
or resorcinol. The application of sonochemistry for the syn-
thesis of these compounds was also very effective on a mul-
tigram scale and produced a higher yield and a crystalline
compound with a shorter reaction time compared with the
compounds obtained using classical procedures.
1,2
pressant activities. Coumarins also have applications in
cosmetics an can be used as optical brightening agents, la-
ser dyes, and fluorescence markers (Figure 1).3–6 The syn-
thesis of the coumarin nucleus was first described in 1868
by the great English chemist Willian Henry Perkin using sa-
7
licylaldehyde, acetic anhydride, and sodium acetate. Other
synthetic methods such as Pechmann and Knoevenagel9
condensations are also effective for the preparation of this
nucleus, and owing to the recent increase in its importance,
new synthetic methodologies are still being developed.10,11
Ultrasound also has a wide range of applications and is
used in sonochemistry, which is a field that studies the ef-
fect of ultrasonic waves in chemical reactions because of
acoustic cavitation (defined as the formation, growth of va-
8
Multigram Synthesis
The multigram synthesis of 3-ethoxycarbonylcoumarin
(1) by Knoevenagel condensation involved a procedure that
used ultrasonic irradiation and reflux with vigorous mag-
netic stirring in absolute ethanol (Scheme 1). The workup
procedure for both the ultrasonic and reflux reactions in-
volved washing the solid with a mixture of ethanol and wa-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

B
Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
ter. The advantage of using the ultrasonic procedure over
the reflux temperature method is a significantly reduced
reaction time (40 min compared with 7 h) and an increased
yield (88% compared with 80%). Moreover, it produces more
crystalline coumarin 1. These advantages are useful for in-
dustrial applications (Figure 2).
CO2Et
CO2Et
CO2Et
a
R
O
O
O
O
2–7
O
COOH
O
O
O
b
O
O
CO2Et
CO2Et
CO2Et
piperidine, AcOH, EtOH
)), 675 W, 40 min, 88%
8
H
H
+
)
2
CO Et
OH
O
O
80 °C, 7 h, 80%
1
R
OH
CN
O
CN
c
Scheme 1 Reagents and conditions for synthesis of coumarins and
comparison of the ultrasonic and reflux procedure
MeO
O
9
COMe
COMe
OH
COMe
d
O
0
1
EtO2C
HO
OH
MeOC
e
HO
O
O
11
Scheme 2 Reagents and conditions: ultrasound and reflux; a) piperi-
dine, AcOH, EtOH; b) H O; c) piperidine, EtOH; d) piperidine, AcOH,
2
EtOH; e) H SO (70%).
2
4
Characterization of the compounds synthesized in this
study was achieved using IR and NMR spectra and HRMS
data. For compounds 2–7, the general spectral findings are
as follows: (i) the chemical shifts of the =CH, CH , and CH
Figure 2 Coumarin 1 furnished by 1) ultrasonic irradiation and 2) re-
flux with vigorous magnetic stirring
2
3
1
protons in the H NMR spectra occurred in the ranges of
.94–8.67, 4.29–4.33, and 1.31–1.33 ppm, respectively, and
ii) the C=O (ester) and C=O (lactone) stretching vibrations
in the IR spectra occurred in the ranges of 1737–1756 and
8
(
General Procedure for Coumarins by Using Ultrasonic
Irradiation
–1
1687–1710 cm , respectively. For compound 8, (i) the
1
A variety of coumarins were also prepared using ultra-
sonic irradiation (at a frequency of 20 kHz with 90% of the
maximum power output without pulsing) (Scheme 2).
Comparisons of the yields and reaction times for the two
processes are listed in Table 1. Compounds 2–7 were ob-
tained with reaction times between 5–30 minutes and
yields of 60–88%. Comparable yields using the reflux meth-
od were obtained only after 240–1440 minutes of the reac-
tion because of the ultrasonic cavitation effects. The advan-
tage in the preparation of compound 8 using the ultrasonic
method was the reduced reaction time, that is, 30 minutes
compared to 120 minutes. Compound 9 was obtained with
a comparable reaction time and yield for both the ultrason-
ic and reflux procedures. The chromene 10 was obtained in
a significantly reduced reaction time (5 min compared to
chemical shifts of the OH and =CH protons in the H NMR
spectra were at 13.26 and 8.75 ppm, respectively, and (ii)
the C=O (carboxylic acid) and C=O (lactone) stretching vi-
–1
brations in the IR spectrum occurred at 1737 and 1671 cm ,
respectively. For compound 9, (i) the chemical shift of the
1
=CH proton in the H NMR spectra occurred at 8.84 ppm,
and (ii) C≡N and C=O (lactone) stretching vibrations in the
–1
IR spectra occurred at 2229 and 1712 cm , respectively. For
compound 10, (i) the chemical shifts of the =CH, COCH , and
3
1
CH protons in the H NMR spectra occurred at 7.71, 2.40,
3
and 1.83 ppm, respectively, and (ii) the O–H and C=O (ester)
stretching vibrations in the IR spectra occurred at 3430 and
–1
1648 cm , respectively. For compound 11 (i) the chemical
1
shifts of the =CH and CH protons in the H NMR spectra oc-
3
curred at 6.81 and 2.37 ppm, respectively, and (ii) the C=O
(lactone) stretching vibrations in the IR spectra occurred at
360 min) and an increased yield (90% compared to 66%).
–1
Compound 11 was obtained with a 2-minute reaction time
and an 87% yield. A comparable yield using the reflux meth-
od was only obtained after 60 minutes of the reaction.
1666 cm .
In this study, the use of ultrasound in combination with
organic synthesis proves that sonochemistry is effective as
a tool for preparing coumarin nucleus and its derivatives on
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

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Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
Table 1 Comparisons of Heating and Ultrasound Methods for Coumarins
Product
Structure
Heating method
Time (min)
Ultrasound method
Time (min)
Yield (%)
6419
Yield (%)
60
O2N
CO2Et
O
2
3
108019
300
30
5
O
CO2Et
82
78
O
O
CO2Et
4
5
240
48
5
5
82
88
O
O
O
CO2Et
36020
8220
O
CO2Et
6
7
8
9
96021
1440
12022
85
5
80
83
80
O
O
OMe
CO2Et
84
5
MeO
O
O
O
OH
9522
30
O
MeO
O
O
CN
O
30
50
66
20
5
49
90
O
COMe
OH
1
1
0
1
360
6023
8923
2
87
HO
O
O
a multigram scale. Coumarins are an important class of nat-
ural products with a wide range of applications in different
fields. In drug discovery, for example, this class plays a criti-
cal role against a wide range of diseases, which will be ex-
plored by our medicinal chemistry group in the future.
3-Ethoxycarbonylcoumarin (1); Ultrasonic Procedure
A 2-L flask was charged with salicylaldehyde (200 g, 1.6 mol), diethyl
malonate (288 g, 1.8 mol), and absolute EtOH (500 mL). To this mix-
ture were added piperidine (21 mL, 0.2 mol) and glacial AcOH (2.1
mL, 0.04 mol) and ultrasonic irradiation was performed for 40 min
(frequency = 20 kHz, amplitude = 90% of the maximum power output)
without a pulse. Then, hot H O (60 °C) (500 mL) was added to the
2
flask, and after cooling at r.t., the mixture was stored overnight in a
refrigerator. The product was collected by filtration and washed with
Chemical reagents and solvents were obtained from Merck and Al-
drich and used without further purification. A multiwave Eco-sonics
QR750 ultrasonic generator (20 kHz, 750 W) equipped with a con-
verter/transducer and titanium oscillator (horn, diameter = 4 mm and
a solution of EtOH (200 mL) and distilled H O (300 mL). After washing
2
with distilled H O (1 L), the coumarin 1 was obtained as a white solid;
2
yield: 313 g (1.4 mol, 88%); mp 87.5–88.9 °C (Lit.24 mp 91–93 °C).
13 mm) was used for the ultrasonic irradiation. Melting points were
IR (KBr): 3065 (C–H arom), 2979, 2930, 2865 (C–H aliphatic), 1780
determined using a MQAPF-302 Micro Química apparatus and are un-
corrected. IR spectra were recorded using a Thermo Nicolet Nexus
–1
(
C=O ester), 1763 (C=O lactone), 1607 cm (C=C).
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.76 (1 H, s, H-4), 7.93 (1 H,
670 spectrometer as KBr discs. HRMS was performed using a Bruker
6
dd J = 7.7, 1.6 Hz, H-5), 7.77–7.73 (1 H, m, H-7), 7.46–7.40 (2 H, m, H-
Compact QTOF mass spectrometer system. Solution NMR spectra
6
, 8), 4.30 (2 H, q, J = 7.1 Hz, CH ), 1.32 (3 H, t, J = 7.1 Hz, CH ).
were recorded in DMSO-d6 using a Bruker Avance 500 spectrometer
2
3
1
13
13
operating at 400 and 500 MHz ( H) and 100 and 125 MHz ( C) at r.t.
C NMR (100 MHz, DMSO-d ): δ = 162.5, 155.9, 154.4, 148.6, 134.4,
6
130.2, 124.8, 117.7, 117.6, 116.1, 61.1, 14.0.
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Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
HRMS: m/z [M + Na]+ calcd for C12H10O Na: 241.0579; found:
3-Ethoxycarbonyl-7-methylcoumarin (4)
4
241.0474
Yield: 699 mg (3.0 mmol, 82%); white solid; mp 97.6–98.3 °C.
IR (KBr): 3041 (C–H arom), 2985 (CH ), 1745 (C=O ester), 1710 (C=O
lactone), 1611, 1557, 1481 cm (C=C).
3
3-Ethoxycarbonylcoumarin (1); Thermal Procedure
–1
A 2-L flask was charged with salicylaldehyde (200 g, 1.6 mol), diethyl
malonate (288 g, 1.8 mol), and absolute EtOH (500 mL). To this mix-
ture, piperidine (21 mL, 0.2 mol) and glacial AcOH (2.1 mL, 0.04 mol)
were added, and the solution was heated under reflux for 7 h. After
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.72 (1 H, s, H-4), 7.80 (1 H, d,
6
J = 7.9 Hz, H-5), 7.27–7.23 (2 H, m, H-6, H-8), 4.29 (2 H, q, J = 7.1 Hz,
CH ), 2.44 (1 H, s, ArCH ), 1.31 (3 H, t, J = 7.1 Hz, CH ).
2
3
3
13
C NMR (100 MHz, DMSO-d ): δ = 162.6, 156.0, 154.6, 148.7, 145.9,
this period of time, hot H O (60 °C) (500 mL) was added. After cooling
6
2
1
29.9, 125.9, 116.2, 116.0, 115.4, 61.0, 21.4, 14.0.
the reaction mixture at r.t., it was stored overnight in a refrigerator.
The product was collected by filtration and washed with a solution of
HRMS: m/z [M + Na]+ calcd for C13H12O Na: 255.0736; found:
4
EtOH (200 mL) and distilled H O (300 mL). After washing with dis-
255.0638.
2
tilled H O (1 L), the coumarin 1 was obtained as a yellow solid; yield:
2
24
2
86 g (1.3 mol, 80%); mp 89.4–90.7 °C (Lit. mp 91–93 °C).
3-Ethoxycarbonyl-6-methylcoumarin (5)
Yield: 751 mg (3.2 mmol, 88%); white solid; mp 99.0–100.1 °C (Lit.20
mp 105 °C).
The spectral data were identical with the sample prepared above by
ultrasonic procedure.
IR (KBr): 3055 (C–H arom), 2989 (CH ), 1756 (C=O ester), 1705 (C=O
lactone), 1619, 1574, 1493 cm (C=C).
3
Ultrasound Irradiation for the Synthesis of Coumarin Derivatives
–1
2–9, 11, and Chromene Derivative 10; General Procedures
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.67 (1 H, s, H-4), 7.69 (1 H, d,
6
J = 1.7 Hz, H-5), 7.56 (1 H, dd, J = 8.5, 1.7 Hz, H-7), 7.34 (1 H, d, J = 8.5
Hz, H-8), 4.30 (2 H, q, J = 7.1 Hz, CH ), 2.37 (1 H, s, ArCH ), 1.32 (3 H, t,
J = 7.1 Hz, CH3).
3
-Ethoxycarbonylcoumarins 2–7; General Ultrasonic Procedure
2
3
The 3-ethoxycarbonylcoumarin derivatives were prepared from a
:1.1 mol ratio of the appropriate salicylaldehyde (500 mg, 4.1 mmol)
1
13
C NMR (100 MHz, DMSO-d ): δ = 162.6, 156.0, 152.6, 148.4, 135.3,
6
and diethyl malonate (722 mg, 4.51 mmol) in absolute EtOH (2 mL).
To this mixture, piperidine (34.5 mg, 0.4 mmol) and a catalytic
amount of glacial AcOH were added. Ultrasonic irradiation was per-
formed (frequency = 20 kHz, amplitude = 90% of the maximum power
output) without a pulse for 5–30 min. After this period of time, hot
134.0, 130.0, 117.5, 117.4, 115.8, 61.1, 20.1, 14.0.
HRMS: m/z [M + Na]+ calcd for C13H12O Na: 255.0736; found:
4
255.0639.
H O (60 °C) (3 mL) was added, and after cooling the mixture at r.t., it
3-Ethoxycarbonyl-8-methoxycoumarin (6)
2
Yield: 653 mg (2.6 mmol, 80%); white solid; mp 91.9–92.2 °C (Lit.25
was stored overnight in a refrigerator. The product was collected by
filtration and washed with a solution of EtOH (1 mL) and distilled H O
mp 88–90 °C).
2
(
2 mL). Finally, the product was washed with distilled H O (20 mL).
2
IR (KBr): 3086, 3041 (C–H arom), 2983 (OCH ), 1737 (C=O ester),
3
–1
1702 (C=O lactone), 1610, 1577, 1479 (C=C), 1242 cm (Ar–O–CH3).
3
-Ethoxycarbonyl-6-nitrocoumarin (2)
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.73 (1 H, s, H-4), 7.47–7.41 (2
6
Yield: 477 mg (1.8 mmol, 60%); white solid; mp 190.4–190.5 °C (Lit.19
mp 195.5–196.5 °C).
H, m, H-5, H-6), 7.36–7.32 (1 H, m, H-7), 4.30 (2 H, q, J = 7.1 Hz, CH2),
3
.92 (1 H, s, OCH ), 1.32 (3 H, t, J = 7.1 Hz, CH ).
3
3
IR (KBr): 3090, 3057 (C–H arom), 1756 (C=O ester), 1687 (C=O lac-
13
C NMR (100 MHz, DMSO-d ): δ = 162.5, 155.6, 148.8, 146.1, 143.8,
6
tone), 1615 (C=C), 1524, 1343 cm–1 (NO2).
124.7, 121.1, 118.2, 117.7, 116.3, 61.2, 56.1, 14.0.
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.94–8.93 (2 H, m, H-4, H-5),
+
6
HRMS: m/z [M + H] calcd for C13H13O : 249.0685; found: 249.0757.
5
8.51 (1 H, dd, J = 9.2, 2.8 Hz, H-7), 7.66 (1 H, d, J = 9.2 Hz, H-8), 4.33 (2
H, q, J = 7.1 Hz, CH ), 1.33 (3 H, t, J = 7.1 Hz, CH ).
2
3
3
-Ethoxycarbonyl-7-methoxycoumarin (7)
13
C NMR (100 MHz, DMSO-d ): δ = 162.0, 158.0, 155.0, 147.6, 143.6,
Yield: 677 mg (2.7 mmol, 83%); white solid; mp 127.7–130.2 °C (Lit.26
mp 135–137 °C).
6
128.4, 126.0, 119.4, 118.1, 117.6, 61.4, 14.0.
HRMS: m/z [M + Na]+ calcd for C12H NO Na: 286.0430; found:
9
6
IR (KBr): 3054 (C–H arom), 2983 (OCH ), 1745 (C=O ester), 1694 (C=O
lactone), 1606, 1563, 1508 (C=C), 1212 cm (Ar–O–CH3).
3
286.0331.
–1
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.72 (1 H, s, H-4), 7.84 (1 H, d,
6
3
-Ethoxycarbonyl-8-methylcoumarin (3)
J = 8.6 Hz, H-5), 7.04–6.99 (1 H, m, H-6, H-8), 4.28 (2 H, q, J = 7.1 Hz,
CH ), 3.90 (1 H, s, OCH ), 1.31 (3 H, t, J = 7.1 Hz, CH ).
Yield: 665 mg (2.9 mmol, 78%); white solid; mp 79.4–80.7 °C.
2
3
3
IR (KBr): 3052 (C–H arom), 2984 (CH ), 1741 (C=O ester), 1700 (C=O
lactone), 1602, 1574, 1461 cm (C=C).
13
3
C NMR (100 MHz, DMSO-d ): δ = 164.6, 162.7, 156.9, 156.1, 149.1,
6
–1
131.5, 113.2, 111.3, 100.2, 60.8, 56.2, 14.0.
1
H NMR (400 MHz, DMSO-d /TMS): δ = 8.72 (1 H, s, H-4), 7.74 (1 H,
+
6
HRMS: m/z [M + H] calcd for C13H13O : 249.0685; found: 249.0765.
5
dd, J = 7.6, 0.8 Hz, H-5 or H-7), 7.61 (1 H, dd, J = 7.6, 0.8 Hz, H-7 or H-
5
), 7.30 (1 H, t, J = 7.6 Hz, H-6), 4.31 (2 H, q, J = 7.1 Hz, CH ), 2.37 (1 H,
2
Coumarin-3-carboxylic Acid (8); Ultrasonic Procedure
s, ArCH ), 1.32 (3 H, t, J = 7.1 Hz, CH ).
3
3
A 10 mL round-bottomed flask was charged with H O (2 mL), salicyl-
2
13
C NMR (100 MHz, DMSO-d ): δ = 162.5, 156.0, 152.7, 148.9, 135.4,
6
aldehyde (93.2 mg, 7.6 mol), and Meldrum’s acid (100 mg, 6.9 mol).
Ultrasonic irradiation was applied for 30 min (frequency = 20 kHz,
amplitude = 90% of the maximum power output) without a pulse. The
127.9, 125.0, 124.3, 117.4, 117.2, 61.1, 14.7, 14.0.
+
HRMS: m/z [M + H] calcd for C13H13O : 233.0736; found: 233.0814.
4
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Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
product was collected by filtration and washed with distilled H O to
out a pulse for 2 min. The reaction mixture was poured over ice water,
the separated solid was collected by filtration, and purified via recrys-
tallization from MeOH; yield: 493 mg (2.8 mmol, 87%); white solid;
2
afford 8 as a white solid; yield: 105.6 mg (0.5 mmol, 80%); mp 181.2–
22
1
82.5 °C (Lit. mp 188.0–188.8 °C).
23
mp 182.1–184.4 °C (Lit. mp 184–186 °C).
IR (KBr): 3058 (C–H arom), 2819 (CH ), 1737 (C=O carboxylic acid),
3
–1
1671 (C=O lactone), 1607, 1567 cm (C=C).
IR (KBr): 3481, 3437 (OH), 3123 (C–H arom), 2819 (CH ), 1666 (C=O
3
–1
1
lactone), 1602, 1565 cm (C=C).
H NMR (400 MHz, DMSO-d /TMS): δ = 13.26 (1 H, s, OH), 8.75 (1 H, s,
6
1
H-4), 7.92 (1 H, dd, J = 7.7, 1.6 Hz, H-5), 7.76–7.72 (1 H, m, H-7), 7.46–
H NMR (500 MHz, DMSO-d /TMS): δ = 10.53 (1 H, s, OH), 7.59 (1 H, d,
6
7.39 (2 H, m, H-6, H-8).
J = 8.5 Hz, H-5), 6.81 (1 H, dd, J = 8.5, 2.5 Hz, H-6), 6.71 (1 H, d, J = 2.5
1
3
Hz, H-8), 6.13 (1 H, s, H-3), 2.37 (1 H, s, CH
3
).
C NMR (100 MHz, DMSO-d ): δ = 163.9, 156.5, 154.4, 148.3, 134.2,
6
13
1
30.1, 124.7, 118.3, 117.9, 116.0.
C NMR (125 MHz, DMSO-d ): δ = 161.2, 160.3, 154.8, 153.5, 126.6,
6
–
112.8, 112.0, 110.2, 102.2, 18.1.
HRMS: m/z [M – H] calcd for C H O : 189.0266; found: 189.0195.
10
5
4
–
HRMS: m/z [M – H] calcd for C H O : 176.0473; found: 175.0403.
1
0
7
3
3-Cyano-7-methoxycoumarin (9); Ultrasonic Procedure
A mixture of 4-methoxysalicylaldehyde (500 mg, 3.3 mmol) and ethyl
cyanoacetate (373 mg, 3.3 mmol) in absolute EtOH (2 mL) and piperi-
dine (34.5 mg, 0.4 mmol) was irradiated with ultrasound for 20 min
Acknowledgment
The authors are grateful to the Brazilian agencies Capes, CNPq, and
FAPERJ for financial support.
(frequency = 20 kHz, amplitude = 90% of the maximum power output)
without a pulse. After cooling the reaction mixture, the resulting pre-
cipitate was recrystallized from EtOH to furnish 9 as a yellow solid;
27
yield: 324 mg (1.6 mmol, 49%); mp 214.7–216.1 °C (Lit. mp 217–
18 °C).
IR (KBr): 3084 (C–H arom), 2955 (OCH ), 2229 (C≡N), 1712 (C=O lac-
References
2
3
(1) Costa, M.; Dias, T. A.; Brito, A.; Proença, F. Eur. J. Med. Chem.
2016, 123, 487.
–1
tone), 1617, 1599 (C=C), 1254 cm (Ar–O–CH3).
1
(2) Venugopala, K. N.; Rashmi, V.; Odhav, B. Biomed. Res. Int. 2013,
H NMR (400 MHz, DMSO-d /TMS): δ = 8.84 (1 H, s, H-4), 7.73 (1 H, d,
6
1.
J = 8.8 Hz, H-5), 7.12 (1 H, d, J = 2.4 Hz, H-8), 7.07 (1 H, dd, J = 8.8, 2.4
Hz, H-6), 3.91 (1 H, s, OCH3).
(
(
3) Yourick, J. J.; Bronaugh, R. L. J. Appl. Toxicol. 1997, 17, 153.
4) Zahradnik, M. The Production and Application of Fluorescent
Brightening Agents; Wiley: New York, 1992.
13
C NMR (100 MHz, DMSO-d ): δ = 165.3, 157.3, 156.4, 153.1, 131.2,
6
1
15.0, 113.8, 111.2, 100.9, 97.4, 56.4.
(5) Trenor, S. R.; Shultz, A. R.; Love, B. J.; Long, T. E. Chem. Rev. 2004,
104, 3059.
HRMS: m/z [M + Na]+ calcd for C11H NO Na: 224.0426; found:
2
7
3
24.0320.
(
6) Murray, R. D. H.; Mendez, J.; Brown, S. A. The Natural Couma-
rins: Occurrence, Chemistry and Biochemistry; Wiley: New York,
1982.
1
-(2-Hydroxy-2-methyl-2H-chromen-3-yl)ethanone (10); Ultra-
sonic Procedure
(7) Perkin, W. H. J. Chem. Soc. 1868, 21, 181.
(
(
8) Pechmann, H.; Duisberg, C. Ber. Dtsch. Chem. Ges. 1884, 17, 929.
9) Knoevenagel, E. Ber. Dtsch. Chem. Ges. 1904, 37, 4461.
A mixture of salicylaldehyde (500 mg, 4.1 mmol), pentane-2,4-dione
(451 mg, 4.5 mmol), absolute EtOH (2 mL), piperidine (34.5 mg, 0.4
(
(
(
(
(
10) Harkiss, A. H. Org. Biomol. Chem. 2016, 14, 8911.
11) Priyanka, P.; Sharma, R. K.; Katiyar, D. Synthesis 2016, 48, 2303.
12) Suslick, K. S. Sci. Am. 1989, 260, 80.
13) Mason, T. J. Chem. Soc. Rev. 1997, 26, 443.
14) Kanchithalaivan, S.; Sumesh, R. V.; Kumar, R. R. ACS Comb. Sci.
2014, 16, 566.
mmol), and a catalytic amount of glacial AcOH was irradiated with ul-
trasound (frequency = 20 kHz, amplitude = 90% of the maximum
power output) without a pulse for 5 min. After solvent removal, the
residue was purified by column chromatography over a silica gel col-
umn (eluent: hexane/EtOAc 85:15) to afford 10 as a yellow solid;
28
yield: 754 mg (3.7 mmol, 90%); mp 83.5–84.8 °C (Lit. mp 135–
36 °C).
IR (KBr): 3430 (OH), 3065, 3038 (C–H arom), 2994 (CH ), 1648 (C=O
(
(
15) Sripathi, S. K.; Logeeswari, K. Int. J. Org. Chem. 2013, 3, 42.
16) Prousis, K. C.; Avlonitis, N.; Heropoulos, G. A.; Calogeropoulou,
T. Ultrason. Sonochem. 2014, 21, 937.
1
3
–1
ester), 1624, 1603, 1567 cm (C=C).
(17) Sadjadi, S.; Eskandari, M. Ultrason. Sonochem. 2013, 20, 640.
1
H NMR (400 MHz, DMSO-d /TMS): δ = 7.71 (1 H, s, H-4), 7.43 (1 H,
6
(18) Rabiei, K.; Naeimi, H. Ultrason. Sonochem. 2015, 24, 150.
dd, J = 7.5, 1.4 Hz, H-5), 7.36–7.32 (1 H, m, H-7), 7.00 (1 H, td, J = 7.5,
(
19) Kempen, I.; Hemmer, M.; Counerotte, S.; Pochet, L.; de Tullio, P.;
Foidart, J-M.; Blacher, S.; Noël, A.; Frankenne, F.; Pirotte, B. Eur.
J. Med. Chem. 2008, 43, 2735.
1.4 Hz, H-6), 6.94 (1 H, s, OH), 6.91 (1 H, d, J = 7.5 Hz, H-8), 2.40 (1 H, s,
COCH ), 1.83 (1 H, s, CH ).
3
3
13
C NMR (100 MHz, DMSO-d ): δ = 196.2, 152.8, 134.2, 133.8, 132.0,
(20) Suljic, S.; Pietruszka, J. Adv. Synth. Catal. 2014, 356, 1007.
(21) Ghanei-Nasab, S.; Khoobi, M.; Hadizadeh, F.; Marjani, A.;
Moradi, A.; Nadri, H.; Emami, S.; Foroumadi, A.; Shafiee, A. Eur. J.
Med. Chem. 2016, 121, 40.
6
128.8, 121.0, 119.5, 116.1, 97.6, 27.2, 27.0.
HRMS: m/z [M + Na]+ calcd for C12H12O Na: 227.0786; found:
3
227.0681.
(
(
(
22) Cunha, S.; Iunes, C. E. M.; Oliveira, C. C.; de Santana, L. L. B.
Quim. Nova 2015, 38, 1125.
7-Hydroxy-4-methylcoumarin (11); Ultrasonic Procedure
23) Elgogary, S. R.; Hashem, N. M.; Khodeir, M. N. J. Heterocycl.
Chem. 2015, 52, 506.
24) Horning, E. C.; Horning, M. G.; Dimming, D. A. Org. Synth. 1948,
H SO (70%, 4.5 mL) was added dropwise over 3 min to a stirred mix-
2
4
ture of resorcinol (500 mg, 4.5 mmol) and ethyl acetoacetate (582 mg,
.5 mmol) in an ice bath. Ultrasonic irradiation was applied (frequen-
cy = 20 kHz, amplitude = 90% of the maximum power output) with-
4
28, 24.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F

F
Synthesis
L. S. da Silveira Pinto, M. V. N. de Souza
Paper
(
25) Karade, N. N.; Gampawar, S. V.; Shinde, S. V.; Jadhav, W. N. Chin.
J. Chem. 2007, 25, 1686.
(27) Fringuelli, F.; Piermatti, O.; Pizzo, F. Synthesis 2003, 2331.
(28) Zonouzi, A.; Googheri, M. S.; Miralinaghi, P. S. Org. Prep. Proced.
Int. 2008, 40, 471.
(26) Ma, Y.; Luo, W.; Quinn, P. J.; Liu, Z.; Hider, R. C. J. Med. Chem.
2004, 47, 6349.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–F