New Facile Synthesis of 7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones

Article abstract of DOI:10.1081/SCC-200036639

A new facile synthesis of 6-amino-7-hydroxy-4-substituted benzopyranones is described through the von Pechmann reaction. The yields obtained were high, and the proposed methodology leads to pure products. The selectivity of formation of the desired products can be attributed to the formation of an intramolecular hydrogen bond, which leads to reduced reactivity of the 2-hydroxyl group.

Full text of DOI:10.1081/SCC-200036639

This article was downloaded by: [University of Cambridge]
On: 08 October 2014, At: 17:49
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T
3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
New Facile Synthesis of
7‐Hydroxy‐6‐amino‐4‐substituted
Benzopyran‐2‐ones
b a
a
Gikas Evagelos
, Parissi‐Poulou Maria , Kazanis
a
a
Michael & Vavagianis Andreas
a
University of Athens, Department of Pharmacy,
Division of Pharmaceutical Chemistry , Athens,
Greece
b
GAIA Research Center , The Goulandris Natural
History Museum , 13 Levidou Str., Kifissia, 14562,
Greece
Published online: 10 Jan 2011.
To cite this article: Gikas Evagelos , Parissi‐Poulou Maria , Kazanis Michael &
Vavagianis Andreas (2004) New Facile Synthesis of 7‐Hydroxy‐6‐amino‐4‐substituted
Benzopyran‐2‐ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:22, 4233-4242, DOI: 10.1081/
SCC-200036639
To link to this article: http://dx.doi.org/10.1081/SCC-200036639
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our
platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,

completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 22, pp. 4233–4242, 2004
New Facile Synthesis of 7-Hydroxy-6-amino-
4
-substituted Benzopyran-2-ones
2,1,* 1
1
Gikas Evagelos,
Parissi-Poulou Maria, Kazanis Michael,
and Vavagianis Andreas
1
1
University of Athens, Department of Pharmacy, Division of
Pharmaceutical Chemistry, Athens, Greece
2
GAIA Research Center, The Goulandris Natural History
Museum, Kifissia, Greece
ABSTRACT
A new facile synthesis of 6-amino-7-hydroxy-4-substituted benzopyra-
nones is described through the von Pechmann reaction. The yields
obtained were high, and the proposed methodology leads to pure
products. The selectivity of formation of the desired products can be
attributed to the formation of an intramolecular hydrogen bond, which
leads to reduced reactivity of the 2-hydroxyl group.
Key Words: Coumarin; 7-hydroxy-6-amino-4-substituted benzopyran-
2-ones; von Pechmann reaction.
*
Correspondence: Gikas Evagelos, GAIA Research Center, The Goulandris Natural
History Museum, 13 Levidou Str., Kifissia 14562, Greece; E-mail: vgigas@otenet.gr
or bioan@gnhm.gr.
4
233
DOI: 10.1081/SCC-200036639
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4
234
Evagelos et al.
Benzopyran-2-ones, also known as coumarins, represent one of the most
widely used chemical categories. They occur widely in natural products, but
they are also substances of high commercial interest because they have
[
1]
[2]
been used as antibiotics (novoviokin, coumermycin),
[4–6]
antibacterials,
(dicoumarol, warfarin,
[
3]
[7,8]
antitumor, antiviral
agents, anticoagulants
[
9]
acenocoumarin), against psoriasis (psoralen, aggelikin), as aldose reductase
inhibitors, etc. They have been also found significant commercial exploitation
[
10]
due to their physicochemical behavior as optical brighteners, lasing dyes,
and enzymatic reaction substrates.
Many methods have been used for their synthesis such as the Perkin
reaction, the Knoevenagel reaction, the Wittig reaction, the Claisen rearrange-
ment, the Michael addition, the Costanecki acylation, etc. However, the most
used reaction for coumarin synthesis is the von Pechmann reaction, where a
b-ketoester is condensed with a phenol in the presence of an acidic catalyst
giving the desired products usually in high yield and pure form. The most
widely used catalyst is H SO (usually 70% aqueous) followed by PCl ,
2
4
5
POCl , AlCl , etc. When PCl is used, there is also the possibility of formation
3
3
5
benzopyran-4-ones known as chromones (Simmonis reaction). Many phenols
have been used for the preparation of coumarins, the most widely used being
resorcinol. Nevertheless, the yield of the reaction is heavily dependent on the
nature of the phenol substituents. Accordingly phenols with þR substituents
facilitate the reaction, whereas 2R retard it. The reactivity of the conden-
sation can be realized with the nitroresorcinols where the 2-nitroresorcinol
undergoes condensation with high yield, whereas 4-nitroresorcinol does not.
In an extensive program of synthesizing fluorescent coumarin-based
probes in our laboratory, we tried to synthesize 7-hydroxy-6-amino-4-substi-
tuted coumarins as synthons for obtaining the desired targets. A literature
search revealed that these compounds were synthesized by nitration of the
7
reduction of the nitro products.
-hydroxy-4-substituted coumarin molecule with various nitration agents and
[
11,12]
The usage of the nitration mixture
HNO /H SO produces a mixture of the 6 and 8 isomers in low yield
3
2
4
13,14]
[
(
ꢀ30%).
Another way leading to the desired products is the nitration
of the 7-hydroxycoumarin nucleus with NO BF and its subsequent
2
4
[15,16]
reduction.
ethyl)-4-methyl-chromen-2-one affords the acetamidocoumarin which can be
[17]
hydrolyzed to the target molecule but again in low yield.
A Beckman rearrangement of 7-hydroxy-6-(1-hydroxyimino-
An alternative
method involving the Pechmann condensation of nitroresorcinol with a-ethyl-
acetoacetate did not afford a coumarin in our hands.
An alternative way could be the synthesis the target molecule from
4
-aminoresorcinol and a b-ketoester, but the phenol is extremely sensitive
and undergoes rapid oxidation. To avoid this, the amine moiety had to be
protected, and an easy way of accomplishing this its transformation to an

Synthesis of 7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones
4235
acetamide. Thus, compound I is expected to be a synthon that could undergo a
Pechmann condensation. The other main problem was the possibility of the
formation of isomers because the 4-hydroxy group could give I or II, and
the 2-hydroxy group could lead to the formation of III (Scheme 1). The IR
spectrum of the molecule revealed the existence of an intramolecular hydrogen
bond. In an effort to elucidate this observation, a molecular modeling exper-
iment has been performed on the conformation of the molecule using a semi-
empirical approach with the AM1 Hamiltonian. It was found that the hydroxyl
of the 2 position forms a hydrogen bond with the amide oxygen (Fig. 1), and it
is not thus available for reaction with a b-ketoester. Another reason for the
selectivity of the aforementioned reaction is the possibility of stereochemical
hindrance of the acetamido group to the phenolic group of the 2-position
Figure 1.
The condensation with a b-ketoester in the presence of H SO (the Von
2
4
Pechmann reaction) gave only the product I. This could be easily be confirmed
1
by the H-NMR spectrum where there is no coupling between the aromatic
protons of the benzene nucleus, indicating that they are isolated. The synthesis
was performed with three b-ketoesters, namely, ethyl acetoacetate, ethyl
v-bromoacetoacetate, and acetonedicarboxylic acid in the presence of sulfuric
acid as the catalyst. In all three cases, the reaction yield was excellent.
Subsequently, the amine function was deprotected by acidic hydrolysis. It is
of interest that neutralization of the amine hydrochloric salt with NH OH
4
yielded the anion of the presumably very acidic phenol. So a crucial step in
Scheme 1. Possible products from the application of the von Pechmann reaction on III.

4
236
Evagelos et al.
Figure 1. Electrostatic potential and molecular conformation of (3). A hydrogen
bond is formed between the hydrogen of the phenol at position 2 and the carbonyl
oxygen of the amide group.
the isolation procedure of the free base of the phenol was the careful neutraliza-
tion of the amine to pH ꢀ 7 with solid potassium bicarbonate. In the acid, no
neutralization was attempted, because the compound exists in zwiterionic form.
EXPERIMENTAL
All solvents were purchased from LabScan Ireland. All reagents were
obtained from Merck Darmstad Germany and were used without any further

Synthesis of 7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones
4237
Scheme 2. Synthetic route for the products (6), (9), (11).

4
238
Evagelos et al.
purification. Melting points were obtained with a B u¨ chi apparatus and are
uncorrected. The IR spectra were recorded on Perkin–Elmer Model 883
1
apparatus as nujol mulls. The H-NMR spectra were obtained on a 200 MHz
Bruker Model AC-200, and results were processed by the Win-NMR v1
Software using d -DMSO as the solvent.
6
N-(2,4-Dimethoxyphenyl)acetamide (2)
In a solution of 2,4-dimethoxyaniline (23 g) (1) dissolved in 50 mL CHCl3,
a sodium carbonate solution (20 g) in 77 mL of water was added. The biphasic
system was vigorously stirred, and a mixture of CH COCl (11.78 g) in 20 mL
3
CHCl was added dropwise. The stirring continued for an additional 30 min,
3
the two phases are separated, the aqueous was washed with CHCl , and all
3
the organic solvent was combined, washed twice with brine, and the solvent
was removed in vacuo. The residue was recrystalized from absolute ethanol,
[18]
giving white crystals in quantitative yield m.p. 1178C (bibl. 1178C ).
N-(2,4-Dihydroxyphenyl)-acetamide (3)
(
2) (20.3 g) and AlCl (125.5 g) are heated in an preheated oil bath (1408C)
3
along with 50 g of NaCl. The reaction continues until the evolution of gas ceases.
The melt is poured in a water-ice mixture, and the resulting solution is extracted
with ethyl acetate. The solvent is removed in vacuo, and the resulting solid is
[19]
recrystallized from water in quantitative yield m.p. 1808C (bibl 1658C ).
2
1
IR (nujol mull): 3369 cm
groups with a hydrogen bond) 1638 cm (NH-CO).
(sharp-NH), 3528-2539 (wide-2hydroxyl
2
1
1
H-NMR (ppm)(dmso-d ): 2 ppm (s, 3H, -CO-CH ), 6.1–6.2 ppm
3
6
(
dd, 1H, aromatic), 6.3 (d, 1H, aromatic), 7.1–7.2 ppm (d, 1H, aromatic),
.2 ppm (s, 2H, OH), 9.6 ppm (s, 1H, NHCO).
9
N-(4-Bomomethyl-7-hydroxy-2-oxo-2H-chromen-6-yl)
acetamide (4)
(3) (6.4 g) are mixed with ethyl v-bromoacetoacetate (5.1 g), the uniform
paste formed is cooled to 08C by means of an ice bath and 10 mL of aq. H SO
2
4
(
70% v/v) are added dropwise. The solution formed is left refrigerated (58C)
overnight. Subsequently, the resulting green solution is poured in an ice-
water mixture, the precipitate is collected by suction filtration and washed
with cold water until the washings became neutral, and a small quantity of

Synthesis of 7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones
4239
cold aqueous ethanol. The solid was recrystalized from DMF giving a white
solid m.p. 250–2528C.
2
1
IR (cm )(nujol): 3523–2812 (hydroxyl), 3420 (amide), 1712 (lactone),
652 (amide carbonyl).
NMR (ppm)(dmso-d ): 2.1 (s, 3H, CH -CO), 4.7 (s, 2H, -CH -Br), 6.15
1
6
3
2
(s, 1H, 55 C-CH-), 6.83 (s, 1H, aromatic), 8.31 (s, 1H, aromatic), 9.38 (s, 1H,
OH), 11.18 (s, 1H, NH).
Hydrochloride of 6-Amino-4-bromomethyl-7-
hydroxychromen-2-one (5)
In a fine suspension of (4) (2 g) in ethanol (40 mL), 15 mL of HCl are
added, and the mixture is refluxed for 2 hr. During the reaction, a clear solution
is formed. Subsequently, the solution is filtered, and the solvent is partly
removed in vacuo. The remainder is left to cool at room temperature and
a white solid is formed. The solid is washed with absolute ethanol
m.p. . 2708C yield 70%.
6
-Amino-4-bromomethyl-7-hydroxychromen-2-one (6)
A suspension of (5) (1.2 g) suspended in deionized water (50 mL) was
neutralized with solid NaHCO to pH 7. The yellow precipitate is collected
3
by suction filtration. m.p. . 2708C.
2
1
IR (cm )(nujol): 2453–2831 (hydroxyl and amine connected with
hydrogen bond), 1715 (lactone).
NMR (ppm)(dmso-d ): 4.9 (s, 2H, -CH Br), 6.5 (s, 1H, 55 CH-CO), 7.0
6
2
(s, 1H, aromatic), 7.6 (s, 1H, aromatic), 8.5–10.5 (2H, -NH , wide), 11–12.5
2
(1H, -OH, wide) elemental analysis for C H BrNO : calc. C 44.47%
H 2.29%. Found C 44.6% H 2.35%.
1
0
8
3
N-(7-Hydroxy-4-methyl-2-oxo-2H-chromen-6-yl)acetamide (7)
(3) (17.5 g) are mixed with an equimolar amount of ethyl acetoacetate
13.65 g), and the homogenous mixture is cooled by means of an ice-salt
(
bath below 08C. 31 mL of aq H SO (70% v/v) are added dropwise, and
2
4
the mixture is refrigerated at 58C overnight. Subsequently, the mixture
is poured in an ice-water mixture. The precipitate is collected washed with
cold water and acetone. Recrystallization from DMF afforded yellow crystals.
Yield 67.6% m.p. . 2808C.
2
1
IR (cm )(nujol): 3410 (amide), 1735 (lactone), 1665 (amide).

4
240
Evagelos et al.
NMR (ppm)(dmso-d ): 2.1 (s, 1H, CH -CO), 2.3 (s, 3H, -C(CH ) 55 ),
6
3
3
6
.2 (s, 1H, -CH 55 CO-), 6.8 (s, 1H, aromatic), 8.1 (s, 1H, aromatic), 9.4
s, 1H, -OH-), 11 (s, 1H, -NH-).
(
6
-Amino-7-hydroxy-4-methylchromen-2-one
hydrochloride (8)
This was prepared by using the same procedure as described for (5). Yield
0.4%.
9
2
6
-Amino-7-hydroxy-4-methylchromen-2-one
This was prepared by using the same procedure as described for (6) m.p.
[
17]
58–2608C (bibl 273–2748C ).
(6-Acetylamino-7-hydroxy-2-oxo-2H-chromen-
4-yl)acetic acid (10)
Citric acid (15.5 g) is mixed with 20mL of H SO , and the mixing is con-
2
4
tinued for 30min until a uniform paste is obtained. Then the mixture is heated
slowly to 658C, and the heating is continued until the evolution of gas has been
ceased. The mixture is then brought to room temperature and then cooled down
to 2158C by means of an ice-salt bath. Subsequently, (3) (10 g) is added so that
the temperature is maintained low and a portion of 20mL of sulfuric acid is
added dropwise. The solution is refrigerated overnight and then poured into a
mixture of ice-water. A yellow precipitate is formed, which is collected by
suction filtration and recrystallized from MeOH. Yield 85% m.p. 219–2208C.
2
1
IR (cm )(nujol): 3550–2800 (carboxylic acid and phenolic hydroxyl),
760 (lactone), 1710 (caboxylic acid), 1675 (amide).
NMR (ppm)(dmso-d ): 2.1 (s, 3H, CH -CONH), 3.7 (s, 2H, -CH -COOH),
1
6
3
2
6
.3 (s, 1H, -CH 55 CO), 6.8 (s, 1H, aromatic), 8.1 (s, 1H, aromatic), 11.0 (s, 1H,
COOH), 11.1 (s, 1H, -CO-NH).
Elemental analysis for C H NO 1/2 H O calc: C 54.54% H 3.91%.
Found: C 54.81% H 4.5%.
.
1
3
11
6
2
Hydrochloride of (6-amino-7-hydroxy-2-oxo-2H-chromen-
-yl)acetic acid (11)
4
This was prepared by using the same procedure as described for (5).
White solid Yield 82.4% m.p. . 2708C.

Synthesis of 7-Hydroxy-6-amino-4-substituted Benzopyran-2-ones
4241
2
IR (cm )(nujol): 2870–2465 (w, hydroxyl and NH with itramolecular
1
þ
3
hydrogen bond), 1705 (lactone), 1690 (carboxylic acid).
NMR (ppm)(dmso-d ): 4 (s, 2H, CH -COOH), 6.3 (s, 1H, 55 CH-CO),
6
2
7
.1 (s, 1H, aromatic), 7.6 (s, 1H, aromatic), 8.5–10.5 (2H, -NH2), 11–12.5
1H, -OH).
Elemental analysis for C H ClNO 1.5 H O calc: C 46.86% H 3.9%.
(
.
1
1
10
5
2
Found: C 46.51%, H 3.5%.
REFERENCES
. Maxwell, A. Mol Microbiol. 1993, 9 (4), 681.
. Musicki, B.; Periers, A.M.; Laurin, P.; Ferroud, D.; Benedetti, Y.;
Lachaud, S.; Chatreaux, F.; Haesslein, J.L.; Iltis, A.; Pierre, C.;
Khider, J.; Tessot, N.; Airault, M.; Demassey, J.; Dupuis-
Hamelin, C.; Lassaigne, P.; Bonnefoy, A.; Vicat, P.; Klich, M.
Bioorg. Med. Chem. Lett. 2000, 10 (15), 1695.
1
2
3
4
. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Viola, G.; Vedaldi, D.;
Dall’Acqua, F. Tetrahedron Lett. 2002, 43 (42), 7473.
. Yoakim, C.; Bonneau, P.R.; D e´ ziel, R.; Doyon, L.; Duan, J.; Guse, I.;
Landry, S.; Malenfant, E.; Naud, J.; Ogilvie, W.W.; O’Meara, J.A.;
Plante, R.; Simoneau, B.; Thavonekham, B.; B o¨ s, M.; Cordingley, M.G.
Bioorg. Med. Chem. Let. 2004, 14 (3), 739.
5
6
. Uchiumi, F.; Hatano, T.; Ito, H.; Yoshida, T.; Tanuma, S. Antiviral Res.
2
003, 58 (1), 89.
. Yu, D.; Suzuki, M.; Xie, L.; Morris-Natschke, S.L.; Lee, K.H. Med. Res. Rev.
003, 23 (3), 322.
2
7. Jeddy, A.S.; Gleason, B.L. Ann. Pharmacother. 2003, 37 (10), 1502.
8. Pineo, G.; Hull, R.D. Hematol. Oncol. Clin. North Am. 2003, 17 (1), 201.
9. Guiotto, A.; Chilin, A.; Manzini, P.; Dall’Acqua, F.; Bordin, F.;
Rodighiero, P. Farmaco 1995, 50 (6), 479.
1
1
1
0. Sharma, V.K.; Saharo, P.D.; Sharma, N.; Rastogi, R.C.; Ghoshal, S.K.;
Mohan, D. Spectrochim. Acta A 2003, 59 (6), 1161.
1. Shah, N.M.; Metha, D.H. J. Ind. Chem. Soc. 1954, 31, 784; Chem. Abtr.
1
956, 325.
2. Chakravarti, D.; Ghosh, B. J. Ind. Chem. Soc. 1935, 12, 791Chem. Abstr.
936, 3802.
1
1
3. Pecmann; Obermiller. Ber. Dtsch. Chem. Ges. 1901, 34, 666.
4. Naik, A.R.; Jadhav, G.V. J. Ind. Chem. Soc. 1948, 25, 171; Chem. Abstr.
1
1
949, 2621.
5. Kozlova, I.K. Khim. Geterotsikl. Soedin. 1985, 7, 906; Chem. Abstr.
986, 104, 5699k.
1
1

4
242
Evagelos et al.
1
1
1
1
6. Kozlova, I.K U.S.S.R. SU 1.106.812; Chem. Abstr. 1985, 102, 24482j.
7. Metha, R.H.; Sethna, S. J. Indian Chem. Soc. 1964, 41 (2), 122.
8. Heidelberger, M.; Jacobs, W.A. J. Am. Chem. Soc. 1919, 41, 1469.
9. Vorozhtzov, N.N.; Gorkov, A.M. J. Gen. Chem. (USSR) 1933, 2, 421;
Chem Abstr. 1933, 17, 968.
Received in the UK March 30, 2004