Use of polyphosphoric acid in the hydrolysis of chromone esters

Article abstract of DOI:10.1081/SCC-120002508

Hydrolysis of esters was achieved in fairly high yield (59-98%) using polyphosphoric acid (PPA). The reagent was particularly useful for the hydrolysis of chromone side chain esters without ring opening.

Full text of DOI:10.1081/SCC-120002508

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USE OF POLYPHOSPHORIC ACID IN THE HYDROLYSIS
OF CHROMONE ESTERS
Xungui He a , Zhiyu Li a & Qidong You a
a Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009,
P.R. China
Version of record first published: 16 Aug 2006.
To cite this article: Xungui He, Zhiyu Li & Qidong You (2002): USE OF POLYPHOSPHORIC ACID IN THE HYDROLYSIS OF
CHROMONE ESTERS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 32:5, 709-714
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SYNTHETIC COMMUNICATIONS, 32(5), 709–714 (2002)
USE OF POLYPHOSPHORIC ACID IN THE
HYDROLYSIS OF CHROMONE ESTERS
Xungui He, Zhiyu Li, and Qidong You*
Department of Medicinal Chemistry, China
Pharmaceutical University, Nanjing 210009, P.R. China
ABSTRACT
Hydrolysis of esters was achieved in fairly high yield
(59–98%) using polyphosphoric acid (PPA). The reagent
was particularly useful for the hydrolysis of chromone side
chain esters without ring opening.
7-Methoxy-4-oxo-4H,1-benzopyran-2-carboxylic acid (1b) possesses
many important biological properties, including antimicrobial,1 antiviral,2,3
and aldose reductase inhibiting activities.4 Its salt was also formulated into
a transdermal preparation for melanin.5 Some of its salts with organic
bases have vitamin P activity and have been used in the treatment of circu-
latory disorders.6
Derivatives of chromone-2-carboxylic acids are mostly obtained
through hydrolysis of the corresponding methyl or ethyl esters under
either acidic or basic condition with the chromone ring intact. Acids used
include concentrated hydrochloric acid in acetic acid7 or 48% hydrobromic
acid in acetic acid,8 or a mixture of aqueous dioxan and hydrochloric
acid.9 Bases used include sodium hydroxide,10–12 sodium carbonate13 or
*Corresponding author. E-mail: qdyou@publicl.ptt.js.cn
709
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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HE, LI, AND YOU
sodium bicarbonate,14 even aqueous triethylamine15 in a solvent which is
inert to the reaction condition, for example, methanol,13,15 ethanol10,12,14
and acetone.11
During our research, we intended to introduce a benzimidazole
group to the 6-position of chromone using 2-ethoxycarbonyl-4-oxo-4H,
1-benzopyran-6-carboxylic acid as the starting material in PPA. We only
got a product with a free acid group attached to the 2-position of chromone
instead of the desired ethyl ester group on the position. The fact was that the
ethyl chromone-2-carboxylate was hydrolyzed by PPA leaving the labile
chromone ring intact. Then we successfully applied this procedure to the
hydrolysis of (1a) to (1b) (Scheme 1). Compared with this new procedures,
the authors treated (1a) with aqueous hydrochloric acid, sodium hydroxide,
or sodium carbonate, only ring-opening products (7) and (8) (Scheme 2)
were recovered.
Scheme 1. Hydrolysis of chromone ester (1a) with PPA.
Scheme 2. Hydrolysis of 1a with aqueous strong acid or base.
PPA is a reagent with a tendency to combine with water. In organic
synthesis, PPA has been used in dehydration and cyclization of aryl or
arylalkyl acid. Scholl and Meyer16 first effected ring closures with it and
soon after Koebner and Robinson17 realize its usefulness in cyclodehydra-
tion. In some reaction, PPA was more effective than concentrated sulfuric
acid, hydrochloric acid and even liquid hydrogen fluoride. Since PPA is a
medium–strong acid without oxidizing properties, fission,18 rearrange-
ment,19 isomerization,20,21 ether cleavage22 and transformation of nitriles

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Table 1. Hydrolysis of Esters in PPA
711

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HE, LI, AND YOU
to amides. However, to date, its use in the hydrolysis of esters to the corres-
ponding acids has not been evaluated.
In our research, we found that some esters also gave the corresponding
acids in good yield (59–98%) when heated in PPA for several hours
(Table 1). All products were verified by IR, 1H-NMR. This reaction
system was particularly useful for chromone ester hydrolysis where the
starting material is very sensitive to strong acids and bases and oxidizing
agents.
In our studies, we found that ethyl 2-furancarboxylate in PPA
become dark above 80ꢀC and L-phenylalanine methyl ester underwent
polymerization. Some compounds with hydroxyl or/and mercapto group
formed phosphoric esters.23
The mechanism of hydrolysis of esters by PPA may involve nucleo-
philic attack of the hydroxyl group of PPA on the carbonyl group of esters
produces carbonyl polyphosphates (9) which release carboxylic acids when
mixed with water (Scheme 3).
Scheme 3. The postulated mechanism of hydrolysis of esters by PPA.
GENERAL PROCEDURES
Esters (1 part) were mixed with a sufficient quantity of PPA (10–20
parts) to give a paste. The mixture was heated to about 145–160ꢀC for
3.5–5 h, permitted to cool to about 100ꢀC, and poured into a large
volume of rapidly stirred cold water in a thin stream and neutralized with
sodium hydroxide or sodium carbonate at low temperature. The precipitate
was collected by filtration and washed with water for several times.

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713
The filtrate was extracted with ethyl acetate. The products were recrystalized
from alcohol or chloroform.
ACKNOWLEDGMENT
This research work was financially supported by The Excellent
Backbone Younger Teacher Foundation of China Education Ministry.
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Received in the UK November 28, 2000

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