Improved synthesis of pyrylium salts leading to 2,4-disubstituted diarylfurans via novel mechanism

Article abstract of DOI:10.1016/j.tetlet.2003.10.069

Improved synthesis of pyrylium salts from either substituted benzoic acids or their methyl esters, and substituted acetophenone is reported en route to the synthesis of 2,4-diarylfurans. The mechanism involved in the formation of the pyrylium salt using t

Full text of DOI:10.1016/j.tetlet.2003.10.069

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 9271–9274
Improved synthesis of pyrylium salts leading to 2,4-disubstituted
diarylfurans via novel mechanismꢀ
Ange´lica M. Bello and Lakshmi P. Kotra*
Faculty of Pharmacy, Department of Chemistry and Molecular Design and Information Technology Center, 19 Russell Street,
University of Toronto, Toronto, Ontario, Canada M5S 2S2
Received 12 September 2003; revised 8 October 2003; accepted 13 October 2003
Abstract—Improved synthesis of pyrylium salts from either substituted benzoic acids or their methyl esters, and substituted
acetophenone is reported en route to the synthesis of 2,4-diarylfurans. The mechanism involved in the formation of the pyrylium
salt using these starting materials is proposed.
© 2003 Elsevier Ltd. All rights reserved.
Substituted furans, frequently found in Nature, exhibit
interesting biological and pharmacological properties.
Alkyl and aryl furans have shown antibacterial,1 fungi-
cidal,2 muscle relaxant,3 insecticidal4 and enzymatic
inhibition5 activities as well as nucleic acid binding
properties.6 Routes to synthesize substituted diaryl-
furans, however, are limited.7,8 Usually, they are syn-
thesized from either 1,4-diketones9 or the condensation
of acetophenone and various benzaldehydes,2a,10 a,b-
unsaturated ketones11 or pyrylium salts.12,13
Pyrylium salts have played an important role as inter-
mediates for the synthesis of various aryl furan deriva-
tives. As part of our strategic drug discovery program,
we were interested in exploring different pathways to
efficiently synthesize substituted furan derivatives dur-
ing the synthesis of some biologically interesting
molecules. In this report, we disclose an improved and
facile synthesis of pyrylium salts en route to 2-aroyl-
3,5-diarylfurans and 2,4-diarylfurans. We discovered
that the substituted pyrylium salts can be synthesized
Scheme 1.
ꢀ Supplementary data associated with this article can be found at doi:10.1016/j.tetlet.2003.10.069
* Corresponding author. Tel. +1-416-978-2882; fax +1-416-978-8511; e-mail: p.kotra@utoronto.ca
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.069

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A. M. Bello, L. P. Kotra / Tetrahedron Letters 44 (2003) 9271–9274
Table 1. Pyrylium salts obtained from substituted benz-
starting from either substituted benzoic acids or substi-
tuted benzoyl esters (Scheme 1). We propose a possible
mechanism involved in the formation of pyrylium salts
when either a carboxylic acid or an ester is used as a
starting material, instead of an aryl aldehyde.
aldehyde, benzoic acid and methyl benzoate
R1
R2 (% yield)
Published yields
(%)
-H
-OH
-OMe
Typically, condensation of 4-substituted benzaldehyde
with 4-substituted acetophenone mediated by the Lewis
acid catalyst, boron trifluoride etherate in benzene, was
reported many years ago for the synthesis of a large
number of 2,4,6-triarylpyrylium salts.14 This procedure
follows a mechanism of condensation-dehydrogenation
to provide pyrylium salts.
-H
-Br
-OMe
-NO2
42
22
42
45
37
28
51
53
55
31
61
65
38 (Ref. 14)
22 (Ref. 15)
(Ref. 12)
a
13 (Ref. 16)
a Yield for the pyrylium salt was not reported.
We used substituted benzoic acids/esters instead of
substituted aldehydes as the starting material because
of the availability of diverse analogs, the ease to handle
and store these starting materials. Furthermore, it
seemed possible to synthesize the pyrylium salts
through these alternate starting materials, considering
the mechanistic details involved in the formation of
pyrylium salts (vide infra).
These pyrylium salts were converted into 2,4-diaryl-
furans using
procedure previously described12
a
(Scheme 2). Briefly, 2,4,6-triarylpyrylium salts in ace-
tone were treated with an aqueous solution of Na2CO3,
and the mixture was stirred for 1 h at room tempera-
ture. Iodine was added, and the stirring was continued
for an additional 12 h. The resulting dark mixture was
poured into aqueous Na2S2O3 solution, and the
aqueous phase was extracted with CHCl3. The organic
layer was subjected to work-up followed by purification
to obtain 2-aroyl-3,5-diarylfurans (6a–c). In this reac-
tion, compounds 6a–c were purified by chromatogra-
phy if the starting material was benzaldehyde.
However, if the pyrylium salt was obtained from ben-
zoic acid or its ester, the purification was easier and a
precipitation in CHCl3–hexanes generated pure
product. In order to obtain the desired diarylfurans
such as 7a–c from the 2-aroyl-3,5-diarylfurans 6a–c, we
employed the Hallar–Bauer reaction.17,18
Thus, BF3·OEt2 (2 equiv.) was added to a solution of
benzaldehyde, benzoic acid, or methyl benzoate (1
equiv.) and 4-bromoacetophenone (2 equiv.) in anhy-
drous toluene. The clear solution was refluxed for 2 h.
After cooling to room temperature, acetone was added
and the dark red solution was poured into excess ether.
A yellow precipitate was formed which was then
filtered, washed with ether and dried under vacuum.
Analyses confirmed that the yellow precipitate was the
pyrylium salt, which was spectroscopically identical
whether the starting material was benzaldehyde, ben-
zoic acid, or methyl benzoate. Methyl benzoate pro-
duced higher yields of pyrylium salts than benzoic acid
and benzaldehyde (Table 1). Similar procedures were
used with substituted benzaldehydes, benzoic acids, or
methyl benzoates. The best yields were obtained with
p-nitro and p-methoxy substituted derivatives. Yields
reported in the literature using benzaldehydes to obtain
the respective pyrilium salts are in general lower than
those obtained using benzoic acids or their respective
esters in this study (Table 1).12,14–16
A mechanism for the formation of pyrylium salts from
esters or carboxylic acids is proposed herein (Scheme
3). We propose the formation of keto–enol equilibrium
of acetophenone 4, induced by the Lewis acid, boron
trifluoride etherate as the first step (Scheme 3, species
4A–B). The enol form of the acetophenone 4B initiates
a nucleophilic attack onto the activated carboxylic
functionality (2 or 3) followed by the elimination of
-OR moiety (either hydroxyl or alkoxy group) (8) gen-
erating the b-diketone 9. The latter species is then
proposed to undergo condensation with another enol
Scheme 2.

A. M. Bello, L. P. Kotra / Tetrahedron Letters 44 (2003) 9271–9274
9273
Scheme 3.
form of acetophenone (4B), forming the b-hydroxy-d-
diketone 10. This underscores the requirement for 2
equiv. of acetophenone 4 for the reaction to progress
and to obtain respectable yields. The elimination of the
hydroxyl group in the form of (OBF3)− will result in an
unsaturated d-diketone 11.
with the proposed mechanism, an electron-withdrawing
moiety such as nitro in the para position to the car-
boxyl group makes the latter to be more susceptible to
an electrophilic attack. The possibility to use various
substituted aryl carboxylic acids or esters opens the
door to a wide variety of diaryl furans, which perhaps
earlier had to be synthesized through a corresponding
aldehyde or some other means.
If the starting material was benzaldehyde instead of a
benzoic acid or its ester, the leaving group in species
similar to 10 is a hydride (in the form of hydrogen
molecule).14 This important difference of the elimina-
tion of (OBF3)− instead of a hydrogen molecule, in the
proposed scheme, makes the reported procedure using
aryl carboxylates or esters a facile reaction for the
formation of pyrylium salts. The d-diketone 11 is then
enolized to form the specie 12. Species 12 upon internal
cyclization through the elimination of a BF3 molecule
generates the six-membered ring 13, which is followed
by the elimination of (OBF3)− and is assisted by the
lone-pair electrons on oxygen atom, producing the
pyrylium salt 5 (Scheme 3).
In summary, we have presented the synthesis of
pyrylium salts from aromatic substituted carboxylic
acids and esters. A possible mechanism involved in the
formation of pyrylium salts starting from acetophe-
nones and either carboxylic acid or a methyl ester
mediated through a Lewis acid catalyst is proposed.
These findings are very useful for the synthesis of
biologically relevant diaryl furans from readily avail-
able and easily manageable aryl carboxylates and/or
their corresponding esters.
In our experiments, we observed that the isolated
pyrylium salts obtained from either benzoic acid or
methyl benzoate is cleaner than those obtained from
benzaldehyde (according to the TLC and NMR analy-
ses). The only by-product obtained from the reaction
using the benzoic acids or their methyl esters as starting
material is compound 14, which is a result of condensa-
tion of three molecules of acetophenone.19 Unlike dur-
ing the synthesis of pyrylium salts from benzaldehyde,
the procedure using benzoic acid or its methyl ester
does not involve any dehydrogenation in the last step of
salt formation (vide supra), which in turn avoids forma-
tion of reduced by-products. Furthermore, using the
p-nitro substituent required lower temperatures
(approximately at 80°C) than p-methoxy (approxi-
mately 140°C) to form the pyrylium salt. In agreement
Supplementary data
Syntheses of compound 5a–d, 6a–c and 7a–b, and X-
ray crystal structure of compound 14 and the corre-
sponding crystallographic data are provided. The
supplementary data is available online with the paper in
ScienceDirect.
Acknowledgements
A.M.B. acknowledges the postdoctoral grant received
from the Universidad Auto´noma del Estado de
Morelos. L.P.K. is a recipient of Rx&D HRF-CIHR
research career award.

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