A convenient one-pot synthesis of 4-hydroxycoumarin, 4-hydroxythiocoumarin, and 4-hydroxyquinolin-2(1H)-one

Article abstract of DOI:10.1081/SCC-100104003

An improved one-pot synthesis of 4-hydroxycoumarin, 4-hydroxythiocoumarin, and 4-hydroxyquinolin-2(1H)-one from 2-hydroxyacetophenone, 2-mercaptoacetophenone, and 2-aminoacetophenone, respectively, is described. The synthetic strategies involve the acylation and internal ring cyclization. This method is readily amenable to large-scale synthesis of 4-hydroxycoumarin, 4-hydroxythiocoumarin, and 4-hydroxyquinolin-2(1H)-one derivatives in high yields.

Full text of DOI:10.1081/SCC-100104003

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A CONVENIENT ONE-
POT SYNTHESIS OF 4-
HYDROXYCOUMARIN, 4-
HYDROXYTHIOCOUMARIN,
AND 4-
HYDROXYQUINOLIN-2(1H)-
ONE
a
a
Jae-Chul Jung , Young-Jo Jung & Oee-Sook Park
b
a
Department of Chemistry, College of Natural
Sciences, Chungbuk National University, Cheongju,
Chungbuk, 361-763, Korea
b
Department of Chemistry, College of Natural
Sciences, Chungbuk National University, Cheongju,
Chungbuk, 361-763, Korea
Version of record first published: 09 Nov 2006.
To cite this article: Jae-Chul Jung , Young-Jo Jung & Oee-Sook Park
2001): A CONVENIENT ONE-POT SYNTHESIS OF 4-HYDROXYCOUMARIN, 4-
(
HYDROXYTHIOCOUMARIN, AND 4-HYDROXYQUINOLIN-2(1H)-ONE, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:8, 1195-1200
To link to this article: http://dx.doi.org/10.1081/SCC-100104003

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SYNTHETIC COMMUNICATIONS, 31(8), 1195–1200 (2001)
A CONVENIENT ONE-POT SYNTHESIS
OF 4-HYDROXYCOUMARIN,
4
4
-HYDROXYTHIOCOUMARIN, AND
-HYDROXYQUINOLIN-2(1H)-ONE
Jae-Chul Jung, Young-Jo Jung, and Oee-Sook Park*
Department of Chemistry, College of Natural Sciences,
Chungbuk National University, Cheongju 361-763,
Chungbuk, Korea
ABSTRACT
An improved one-pot synthesis of 4-hydroxycoumarin,
-hydroxythiocoumarin,
4
and
4-hydroxyquinolin-2(1H)-
one from 2-hydroxyacetophenone, 2-mercaptoacetophenone,
and 2-aminoacetophenone, respectively, is described. The syn-
thetic strategies involve the acylation and internal ring
cyclization. This method is readily amenable to large-scale
synthesis of 4-hydroxycoumarin, 4-hydroxythiocoumarin,
and 4-hydroxyquinolin-2(1H)-one derivatives in high yields.
4
-Hydroxycoumarin, 4-hydroxythiocoumarin, and 4-hydroxyquino-
,2
1
lone derivatives are naturally occurring biologically active compounds,
useful intermediates for many industrial products such as dye stuffs,
herbicides,
quinolone derivatives, i.e., 4-hydroxy-3-arylquinolin-2(1H)-one and
3
,4
5
–7
8
and anticancer agents. Recent reports show 4-hydroxy-
*
Corresponding author.
1
195
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1
196
JUNG, JUNG, AND PARK
4-hydroxy-3-nitroquinolin-2(1H)-one, are selective glycine site antagonists
related to several central nervous system disorders including stroke, epi-
9
–14
lepsy, schizophrenia, Parkinson’s disease, and Alzheimer’s disease.
Scheme.
1
6
As part of our synthetic program directed toward the synthesis of
1
-hydroxycoumarin derivatives, we have recently reported an efficient
7
4
method for the preparation of 4-hydroxycoumarin and 4-hydroxythiocou-
marin. As an extension to our previous work, we found a convenient
one-pot synthesis of 4-hydroxycoumarin, 4-hydroxythiocoumarin, and 4-
hydroxyquinolin-2(1H)-one, reacting 2-hydroxyacetophenone, 2-mercap-
toacetophenone, and 2-aminoacetophenone with acylating agents such as
phosgene, dimethylcarbonate, or diethylcarbonate in the presence of stoi-
chiometric amount of base (Scheme). An evaluation of several acylating
agents was undertaken and the results of those experiments are shown in
the Table. In this reaction, we found that sodium hydride was the most
effective base among sodium ethoxide, sodium hydride, freshly prepared
sodium 3-aminopropylamide (NAPA), and potassium 3-aminopropylamide
(
KAPA).
In summary, an efficient one-pot synthesis of 4-hydroxycoumarin
3a), 4-hydroxythiocoumarin (3b), and 4-hydroxyquinolin-2(1H)-one (3c)
(
has been developed. This procedure seems to be amenable to large-scale
application.
EXPERIMENTAL
Reactions requiring anhydrous conditions were performed with the
usual precautions for rigorous exclusion of air and moisture.
Tetrahydrofuran and diethyl ether were distilled from sodium benzophe-
none ketyl prior to use. Thin layer chromatography (TLC) was performed
on precoated silica gel 60 F254 plates from EM reagents and visualized with

4
-HYDROXYCOUMARIN DERIVATIVES
1197
Table. Reaction of 2-Hydroxyacetophenone, 2-Mercaptoacetophenone, or 2-
Aminoacetophenone with Acylating Reagent
a
Compound
1
X
O
2(R1 ¼ R2)
Base
Yield (%)
Product
a
b
c
Cl
NaOEt
NaH
NaOEt
NaH
NAPA
KAPA
NaOEt
NaH
66
69
71
84
60
55
80
85
51
63
3a
OMe
OEt
b
c
NAPA
KAPA
1
S
Cl
NaOEt
NaH
NaOEt
NaH
NAPA
KAPA
NaOEt
NaH
NAPA
KAPA
62
66
74
81
61
58
81
86
55
62
3b
OMe
OEt
1
NH
Cl
NaOEt
NaH
NaOEt
NaH
NaOEt
NaH
61
65
76
79
76
81
3c
OMe
OEt
a
b
Isolated yields; Sodium 3-aminopropylamide ; Potassium 3-aminopropylamide.
15
c
15
254-nm UV light or ceric sulfate-ammoniummolybdate-sulfuric acid spray.
Flash chromatography was carried out on silica gel 60 (E. M. Merck, par-
1
13
ticle size 0.040 ꢀ 0.063 mm, 230 ꢀ 400 mesh ASTM). H NMR and
C
NMR spectra were recorded on a Brucker DPX 300 at 300 MHz and
7
(
6 MHz, respectively. The chemical shifts were reported in parts per million
ppm) downfield from tetramethylsilane, and J-values were in hertz. IR
spectra were obtained on a Jasco FT/IR-300E spectrometer. Mass spectra
were recorded on a Shimadzu-LKB 900 GC/MS system. All m.p. were
uncorrected. When necessary, chemicals were purified according to the
1
8
reported procedure.

1
198
JUNG, JUNG, AND PARK
General Procedure for the Preparation of 4-Hydroxycoumarin (3a)
To a stirred suspension at room temperature sodium hydride (60% in
mineral oil, 60 mmol) in anhydrous toluene (30 mL) was added dropwise
a solution of 2-hydroxyacetophenone (12 mmol) and acylating reagent
(
18 mmol) in anhydrous toluene (6 mL). The reaction mixture was heated
ꢁ
at 100 C for 3 h. After cooling, the solvent was evaporated and the residue
was treated with water (10 mL). The resulting solid was filtered, washed with
water, and then recrystallized from methanol or ethanol to give 4-hydroxy-
coumarin as a pale yellow crystal. R ¼ 0.30 (ethyl acetate, neat); m.p.
f
ꢁ
ꢁ
ꢁ
19
ꢁ
20
2
1
11 ꢀ 213 C (lit. m.p. 205.1 C and 206 C ); IR (ꢀ , KBr) 3387–2583,
À1
6
max
1
658, 1599, 1323 cm ; H NMR DMSO-d ) ꢁ 12.48 (br s, 1H), 7.82 (d,
1
3
J ¼ 7.20, 1H), 7.67ꢀ7.58 (m, 1H), 7.38ꢀ7.30 (m, 2H), 5.88 (s, 1H);
C
NMR (DMSO-d ) ꢁ 169.26, 164.97, 156.02, 134.76, 126.15, 125.53, 118.47,
6
þ
1
18.20, 92.72; MS (m/e) 162 (M ).
General Procedure for the Preparation of
-Hydroxythiocoumarin (3b)
4
To a stirred suspension at room temperature of sodium hydride (60%
in mineral oil, 50 mmol) in anhydrous toluene (25 mL) was added dropwise a
solution of 2-mercaptoacetophenone (10 mmol) and acylating reagent
(
15 mmol) in anhydrous toluene (5 mL). The reaction mixture was heated
ꢁ
at 100 C for 3 h. After cooling, the solvent was evaporated and the residue
was treated with water (8 mL). The resulting solid was filtered, washed with
water, and then recrystallized from methanol or ethanol to give 4-hydro-
xythiocoumarin as a pale yellow crystal. R ¼ 0.33 (ethyl acetate, neat); m.p.
f
ꢁ
ꢁ
21
ꢁ
1
2
09 ꢀ210 C (lit. m.p. 207 C); IR (ꢀ , KBr) 3061–2550, 1519, 1265; H
3
max
NMR (CDCl ) ꢁ 12.46 (br s, 1H), 8.32 (d, J ¼ 7.83 Hz, 1H), 7.83ꢀ7.63 (m,
1
3
3
H), 6.26 (s, 1H); C NMR (CDCl ) ꢁ 182.45, 166.93, 136.88, 131.48,
3
þ
126.84, 126.38, 126.09, 123.79, 103.26; MS (m/e) 178 (M ), 150, 136 (base
peak), 108, 69.
General Procedure for the Preparation of
-Hydroxyquinolin-2(1H)-one (3c)
4
To a stirred suspensions at room temperature of sodium hydride
60% in mineral oil, 125 mmol) in anhydrous toluene (60 mL) was added
(
dropwise a solution of 2-aminoacetophenone (50 mmol) and acylating
reagent (75 mmol) in anhydrous toluene (20 mL). The reaction mixture

4
-HYDROXYCOUMARIN DERIVATIVES
1199
ꢁ
was heated at 100 C for 2 h. After cooling, the solvent was evaporated and
the residue was treated with water (26 mL). The resulting solid was filtered,
washed with water, and then recrystallized from methanol or ethanol to give
4
-hydroxyquinolin-2(1H)-one as a pale yellow crystal. R ¼ 0.33 (10%
ꢁ ꢁ
max
f
22
methanol in chloroform); m.p. 320 C (dec, lit. m.p. >320 C); IR (ꢀ
KBr) 3276, 2867, 1647, 1559, 1261; H NMR (DMSO-d ) ꢁ 13.42 (br s, 1H),
,
1
6
1
0.27 (br s, 1H), 8.73 (d, J ¼ 8.44 Hz, 1H), 7.76ꢀ7.32 (m, 3H), 6.33 (s, 1H);
1
3
C NMR (DMSO-d ) ꢁ 162.46, 160.80, 155.52, 138.09, 130.47, 125.70,
6
þ
1
19.03, 115.41, 87.67; MS (m/e) 161 (M ), 133, 105, 91, 43 (base peak).
ACKNOWLEDGMENTS
This work has been supported by the Basic Science Research Institute
Program (BSRI-99-3433), Ministry of Education, Republic of Korea.
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Received May 1, 2000