Soluble polymer-supported synthesis of 4-methyl coumarin on modified poly(ethylene glycol)s

Article abstract of DOI:10.1055/s-2005-865231

A simple liquid phase synthetic method for the preparation of 4-methyl coumarin on modified poly(ethylene glycol)s by using the von Pechmann reaction is described.

Full text of DOI:10.1055/s-2005-865231

1296
LETTER
Soluble Polymer-Supported Synthesis of 4-Methyl Coumarin on Modified
Poly(ethylene glycol)s1
S
oluble Polymer-S
r
upported
a
S
ynthesis
z
of 4-Methy
i
l
C
oum
e
arin lla Tocco,* Michela Begala, Giovanna Delogu, Gabriele Meli, Carmen Picciau, Gianni Podda
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Cagliari, Via Ospedale 72, 09124 Cagliari, Italy
Fax +39(070)6758553; E-mail: toccog@unica.it
Received 11 February 2005
portant biological (anti-coagulant, anti-HIV, anti-hyper-
Abstract: A simple liquid phase synthetic method for the prepara-
tion of 4-methyl coumarin on modified poly(ethylene glycol)s by
using the von Pechmann reaction is described.
proliferative)11 and photophysical properties (fluorescent
tags).12–14
To date, many routes to coumarin derivatives have been
studied, including the Perkin,15 Knoevenagel,16,17 Refor-
matsky,18 and Wittig19–21 reactions as well as innovative
techniques such as microwave irradiation.22
Key words: von Pechmann condensation, multicomponent reac-
tion, liquid phase synthesis, heterocycles, coumarins
In recent years the synthesis of small organic molecules
on polymeric supports has become a significant field of
interest in particular its application in the field of combi-
natorial chemistry.2,3
Nevertheless, the von Pechmann reaction still remains the
most widely applied method to synthesize coumarins and
involves the condensation of phenolic substrates with b-
keto esters in the presence of condensing agents such as
protic or Lewis acids.23,24
Much attention is now focused on liquid-phase synthesis
because it combines the advantages of the classical homo-
geneous solution methodology (high reactivity and simple
analytical procedures) with those of solid-phase synthesis
(easy isolation and purification of the final products and
high stability of the system polymer-supported mole-
cule).4–6
In Schemes 1 and 2, we report the compounds synthesized
in our study and the related synthetic routes. The polymers
of choice were the mono methyl ether of PEG with
Mw = 5000 and the dihydroxy PEG with Mw = 4600, used
to obtain compounds 9–15 and 10–16, respectively. The
starting materials are the mesylates 3 and 4 which proved
to be very good activated intermediates.25
In particular, among the soluble supports, poly(ethylene
glycol)s (PEG) are the most interesting polymers because
they can be functionalized with different spacers or reac-
tive groups and are also commercially available, inexpen-
sive, non toxic, highly resistant to drastic physical and
chemical conditions, and are soluble in a wide variety of
solvents.6
The reaction involves 12 M sulfuric acid as acidic con-
densing agent (see typical procedure); if the reaction is
carried out using a Lewis acid such as indium(III) chloride
(for reaction conditions see reference23), the reaction does
not occur. In fact, due to the high complexing ability of
PEGs, indium(III) chloride is not free to act as catalyst.
Due to these features, PEG chemistry has shown broad-
based application over the last decade, which may be in
large part attributed to the use of PEG-conjugates.
In Scheme 1, we report in detail the synthesis of com-
pounds 9 and 10. The hydroxy derivative of choice is
resorcinol; in fact, it is well known that among all mono-,
di-, and tri-hydroxy phenols, resorcinol is the most reac-
tive and condenses rapidly with many b-ketoesters.26
In fact, polymer conjugation is a field of increasing inter-
est in pharmaceutical chemistry for delivering drugs with
simple structures as well as more complex ones such as
oligonucleotides or enzymes.7
The synthetic procedure starts by anchoring the mono al-
lylated resorcinol 2 to mesylates 3 or 4, to give the inter-
mediates 5 and 6 which were promptly deprotected using
palladium diacetate and triphenylphosphine in absolute
ethanol.27 The phenolic substrates 7 and 8 so obtained
were used to carry out the von Pechmann reaction with
ethyl acetoacetate in 12 M sulfuric acid. Compounds 9
and 10 were obtained as pure products following classical
precipitation–filtration technique typical for liquid-phase
synthesis.6,28
Encouraged by these very interesting results and on the
basis of some our previous experiences in PEG-supported
synthesis8 and in the characterization of coumarin deriva-
tives,9 we report herein the synthesis of the 4-methyl cou-
marin prepared, for the first time, by using the soluble
support approach applied to the von Pechmann reaction.10
Coumarins are a well known class of heterocycles, that are
very attractive due to their versatility in a large number of
applications and are mainly investigated due to their im-
Scheme 2 describes the synthesis of 15 and 16 from inter-
mediates 3 and 4, which were transformed in three steps25
into mesylates 11 and 12 which gave rise to derivatives 15
and 16, in a similar way as for compounds 9 and 10.
SYNLETT 2005, No. 8, pp 1296–1300
1
7.
0
5.
2
0
0
5
Advanced online publication: 14.04.2005
DOI: 10.1055/s-2005-865231; Art ID: G05405ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Soluble Polymer-Supported Synthesis of 4-Methyl Coumarin
1297
OMs
OH
MsCl, TOA
CH2Cl2
OH
HO
OMs
MsO
= MeO-PEG- (MW 5000 Da)
= -PEG- (MW 4600 Da)
OH
OH
Br
K2CO3, acetone, KI
OH
O
2
1
O
OMs
O
3
Cs2CO3, DMF
60 °C
5
+ 2
O
O
OMs
MsO
O
O
4
Pd(OAc)2
PPh3
EtOH
6
OH
HO
OH
O
or
O
O
7
8
O
O
H2SO4 12 M
C2H5
H3C
C
O
H2
CH3
CH3
H3C
O
O
O
or
O
O
O
O
O
O
10
9
Scheme 1
The overall yield from the commercially available un- 9, 10, 15, and 16 have been performed. The MALDI spec-
functionalized PEGs was ≥ 65% for 9 and 10 (4 steps), trum for compound 16, is shown in Figure 1 which con-
while yields ≥ 75% were observed for 15 and 16 (7 steps). sists of a wide distribution of peaks centred at about m/z
The presence of the spacer, in the synthesis of 15 and 16, 4800 and extending from m/z 4000 up to m/z 6000. These
which separates the reactive functionalities from the PEG data clearly reveal the absence of degradation of the poly-
core, could result in the higher yields.8c
meric support and show that it is resistant to the drastic
synthetic conditions. Indeed, the MALDI-MS methodolo-
gy is an important tool for a qualitative determination of
possible structural modifications of the polymers.
1
Analysis of the H NMR spectra of the obtained com-
pounds showed that the von Pechmann reaction gave rise
only to the linear coumarinic isomer, as expected. In fact,
under the general von Pechmann reaction conditions, us- In conclusion, we succeeded in developing an innovative
ing sulfuric acid as condensing agent, the formation of the method to synthesize the coumarin nucleus, with an im-
7-hydroxy derivative is always preferred to the 5-hydroxy provement in the yields30 through a very stable C–O bond
isomer.26 In the case of our synthetic approach, the 7- connection to the soluble support which was resistant to
PEG-supported derivative is the only product, probably the drastic operating conditions.
also as a result of steric hindrance related to the polymer
structure.
Moreover, PEG conjugation could almost certainly im-
prove the pharmacokinetics and bio-distribution, due to
1
Together with the H NMR investigations, a series of the efficient synthesis, stability and high water solubility
MALDI-MS analysis29 of the PEG-conjugate derivatives of the supported coumarin. Also the PEG-coumarin
Synlett 2005, No. 8, 1296–1300 © Thieme Stuttgart · New York

1298
G. Tocco et al.
LETTER
OMs
MsO
OMs
3
4
3 steps 25
O
OMs
O
OMs
MsO
O
11
12
2
O
O
O
13
O
O
O
O
O
O
14
2 steps
CH3
O
O
O
SPACER
15
or
O
CH3
H3C
O
O
O
O
O
O
16
SPACER
SPACER
O
O
Scheme 2
Figure 1 MALDI-MS spectrum of compound 16
Synlett 2005, No. 8, 1296–1300 © Thieme Stuttgart · New York

LETTER
Soluble Polymer-Supported Synthesis of 4-Methyl Coumarin
1299
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All PEG samples (Aldrich and Fluka) were melted in vacuum at
90 °C for about 45 min before use, to remove any trace of moisture.
After reaction, the crude mixture was concentrated in vacuum to
eliminate the solvent. CH2Cl2 (6–7 mL) was added to completely
dissolve the residue. Et2O (50 mL per g of polymer) was added to
the mixture, which was cooled to 0 °C. The suspension obtained
was filtered through a sintered glass filter and the residue was
washed repeatedly with Et2O. All the samples were crystallized
from i-PrOH. It is a well known fact, that PEGs, due to their helical
structure, show a strong propensity to crystallize.31 The yields of
PEG-supported compounds were determined by weight. The indi-
cated yields were for pure products after crystallization from i-
PrOH. Their purity was confirmed by 300 MHz 1H NMR
spectroscopy32 in CDCl3 with pre-saturation of the methylene sig-
nals of the polymeric support at 3.60 ppm; a relaxation delay of 6 s
and an acquisition time of 4 s were used to ensure complete relax-
ation and accuracy of integration. The integrals of the signals of the
PEG CH2OCH3 fragment at d = 3.30 and 3.36 ppm, were used as in-
ternal standards.
Matrix-assisted laser desorption/ionization (MALDI) measure-
ments were performed on a Reflex time-of-flight instrument (Bru-
ker-Franzen Analytik, Bremen, Germany), operating in positive ion
mode. Ions, formed by a pulsed UV laser beam (nitrogen laser,
l = 337 nm) were accelerated to 25 kV. Pulsed ion extraction (PIE)
was obtained applying a voltage of about 17 kV to the second grid
for 200 ns. Samples were dissolved in water at a concentration of 1
mg/mL. The matrix was dihydroxybenzoic acid, saturated with
aqueous 0.1% TFA; 5 mL samples of solution were mixed with the
same volume of matrix solution. About 1 mL of the resulting solu-
tion was deposited on the stainless steel multiprobe and allowed to
dry before being introduced into the mass spectrometer. Mass spec-
tra were obtained by averaging 100 laser shots.
PEG-Supported von Pechmann Reaction; Typical Procedure
(9)
To a solution of 7 (1 g, 0.196 mmol) in H2SO4 (12 M, 12 mL),
cooled at 0 °C, was added dropwise ethyl acetoacetate (0.1 g, 0.097
mL, 0.784 mmol) and the mixture was stirred at r.t. for 48 h. The
reaction mixture was poured into crushed ice (7 g) and stirred until
the ice melted. Then the mixture was extracted with CH2Cl2 (5 ×),
dried over Na2SO4, filtered, and then concentrated to a small vol-
ume.
The pure product 9 was obtained by precipitation with Et2O filtra-
tion technique and then crystallized from i-PrOH.
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Acknowledgment
We wish to thank Dr Maurizio Benaglia (Dip. Chimica Organica e
Industriale - University of Milan) for expert help in determining 1H
NMR spectra of the PEG compounds and Dr Roberta Seraglia and
Dr Elisa Basso (CNR-ISTM - Padua) for MALDI-MS measure-
ments.
This work was supported by Ministero dell’Università, dell’Istru-
zione e della Ricerca MIUR-PRIN 2003 and Progetto di Ricerca
Scientifica 2003 - Università di Cagliari.
References
(1) Presented at the 5th Spanish Italian Symposium on Organic
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September 2004.
Synlett 2005, No. 8, 1296–1300 © Thieme Stuttgart · New York

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G. Tocco et al.
LETTER
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(32) Analytical details for compounds 9 and 15. 9. 1H NMR (300
MHz, CDCl3): d = 2.40 (s, 3 H), 3.36 (s, 3 H), 6.20 (s, 1 H),
6.80 (s, 4J = 2.43 Hz, 1 H), 6.90 (d, 3J = 8.50 Hz, 4J = 2.43
Hz, 1 H), 7.60 (s, 3J = 8.50 Hz, 1 H). 15. 1H NMR (300 MHz,
CDCl3): d = 1.81 (m, 2 H), 2.40 (s, 3 H), 2.70 (t, 2 H), 3.36
(s, 3 H), 3.92 (t, 2 H), 6.18 (d, 3J = 8.50 Hz, 2 H), 6.30 (s,
1 H), 6.81 (d, 3J = 8.41, 1 H), 6.88 (s, 1 H), 6.98 (d, 3J = 8.50,
2 H), 7.50 (d, 3J = 8.41, 1 H).
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Synlett 2005, No. 8, 1296–1300 © Thieme Stuttgart · New York