Expedited synthesis of benzofuran-2-carboxylic acids via microwave-assisted Perkin rearrangement reaction

Article abstract of DOI:10.1016/j.tetlet.2012.04.075

3-Halocoumarins are readily converted into benzofuran-2-carboxylic acids via a Perkin (coumarin-benzofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety. We explored this reaction under microwave reaction conditions and were able to significantly reduce reaction times as well as obtain very high yields of a series of benzofuran-2-carboxylic acid derivatives.

Full text of DOI:10.1016/j.tetlet.2012.04.075

Tetrahedron Letters 53 (2012) 3319–3321
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Tetrahedron Letters
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Expedited synthesis of benzofuran-2-carboxylic acids via microwave-assisted
Perkin rearrangement reaction
⇑
Karla-Sue C. Marriott , Rena Bartee, Andrew Z. Morrison, Leonard Stewart, Julian Wesby
Savannah State University, Department of Natural Sciences, College of Sciences and Technology, 3219 College Street, Savannah, GA 31404, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Halocoumarins are readily converted into benzofuran-2-carboxylic acids via a Perkin (coumarin–ben-
zofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring
fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety.
We explored this reaction under microwave reaction conditions and were able to significantly reduce
reaction times as well as obtain very high yields of a series of benzofuran-2-carboxylic acid derivatives.
Published by Elsevier Ltd.
Received 21 March 2012
Revised 11 April 2012
Accepted 17 April 2012
Available online 24 April 2012
Keywords:
Perkin rearrangement
Halocoumarin
Benzofuran-2-carboxylic acid
Microwave
Regioselective bromination
Syntheses of benzofuran-2-carboxylic acid derivatives are
important in the development of many biologically active mole-
cules for potential use in the treatment of cancer as well as central
nervous system disorders.1–4 Benzofuran-2-carboxylic acids are
produced from 3-halocoumarins quite readily via a Perkin (couma-
rin–benzofuran ring contraction) rearrangement reaction in the
presence of a base such as sodium hydroxide in ethanol or metha-
nol. This rearrangement reaction was first reported in 1870 by
Perkin5 and found to be general for 3-halocoumarins (Scheme 1).
The mechanism for the rearrangement has been proposed to in-
volve base-catalyzed ring fission of the 3-halocoumarin, resulting
in the corresponding dianion of the (E)-2-halo-3-(2-hydroxy-
phenyl)acrylic acid, followed by intramolecular nucleophilic attack
on the vinyl halide by the phenoxide anion yielding the benzofu-
ran-2-carboxylic acid as the final product. However, this proposal
does not account for the lack of activation for an SN reaction of
the vinyl halide. Investigations by Dalton and Newman6 led to an-
other mechanistic proposal, involving initial ring fission, followed
by Michael addition of methanol to the alkene, then intramolecular
SN cyclization of the alkyl halide with subsequent elimination of
methanol. The mechanism for the base-catalyzed ring fission of
coumarins has been studied extensively. Nucleophilic substitution
of vinyl halides can proceed by a number of mechanistic pathways,
more specifically those involving addition–elimination. Very
insightful reaction kinetics studies by Bowden and Battah7 sup-
ported by the determination of Hammett reaction constants
propose that the Perkin rearrangement occurs in two stages. The
first stage is a rapid first-order base-catalyzed ring fission that
appears to occur by rate-determining addition of hydroxide anion
to the carbonyl group. The Hammett reaction constant determined
for the ring fission at 30.0 °C was 2.34. The second stage is a
relatively slow first-order cyclization process for which the
Hammett reaction constant at 60.0 °C was À3.54. Bowden and
Battah went on to propose that the cyclization most likely
proceeds by rate-determining fission of the carbon–halogen bond,
following formation of an unstable carbanion intermediate formed
by an intramolecular nucleophilic attack on the vinyl group by the
phenoxide anion. This mechanistic pathway is summarized in
Scheme 2.
Traditionally 3-bromocoumarins (1) undergo Perkin rearrange-
ment in the presence of base at reflux for 3 h to give quantitative
yield of benzofuran-2-carboxylic acids (2).8 For our investigations
the required 3-bromocoumarins (1) were prepared via micro-
wave-assisted regioselective bromination in the presence of N-bro-
mosuccinimide (NBS) as brominating agent and acetonitrile as
solvent at 250 W for 5 min at 80 °C (Table 1).
We explored the Perkin rearrangement under microwave reac-
tion conditions with variation in Power/Watts (Table 2) to obtain
the best reaction conditions. We found that microwave-assisted
Perkin rearrangement of 3-bromo-4-methyl-6,7-dimethoxycoum-
arin (1a) in ethanol/sodium hydroxide at either 300 W or 400 W
for 5 min at 79 °C successfully yields 5,6-dimethoxy-3-methyl-
benzofuran-2-carboxylic acid (2a) in 99%. If the power was
decreased to 250 W, the reaction did not go to completion during
⇑
Corresponding author. Tel.: +1 912 358 4454.
E-mail address: marriottk@savannahstate.edu (K.-S.C. Marriot).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.04.075

3320
Karla-Sue C. Marriott et al. / Tetrahedron Letters 53 (2012) 3319–3321
Scheme 1. Perkin (coumarin–benzofuran ring contraction) rearrangement reaction reported in 1870 by W.H. Perkin.
the 5-min period. Alternately, if the power was increased to 500 W,
there was a slight decrease in product yield.
General experimental
Using the optimized parameters of 300 W for 5 min at 79 °C, we
went on to synthesize a series of benzofuran-2-carboxylic acids
(2a–d, Table 3) in very high yield. The microwave-assisted Perkin
rearrangement reaction presented here provides a more efficient
synthesis of benzofuran-2-carboxylic acids from 3-bromocouma-
rins with a reaction time of 5 min in comparison to the traditional
method with a reaction time of approximately 3 h. The rearrange-
ment proceeds in the presence of ethanol and sodium hydroxide.
During work-up hydrochloric acid was added to hydrolyze the
resultant sodium salt and produce the free acid form of the corre-
sponding benzofuran-2-carboxylic acids (2a–d) (Scheme 2).
3-Bromo-4-methyl-6,7-dimethoxycoumarin (1a)
4-Methyl-6,7-dimethoxycoumarin (0.05 g, 0.227 mmol) was
dissolved in acetonitrile (5 ml) in a microwave vessel. N-Bromo-
succinimide (0.06 g, 0.340 mmol) was added to the mixture and
the vessel inserted into the microwave at 250 W for 5 min at
80 °C. The reaction was monitored by thin layer chromatography
(silica gel, 3:1 CH2Cl2/EtOAc). Upon completion, the reaction mix-
ture was cooled and the resultant precipitate was collected by vac-
uum filtration. The crude product was then recrystallized from a
mixture of CH2Cl2/MeOH to yield 3-bromo-4-methyl-6,7-dimeth-
Scheme 2. Perkin rearrangement of 3-bromocoumarins (1) to benzofuran-2-carboxylic acids (2) based on the mechanistic pathway reported by Bowden and Battah.

Karla-Sue C. Marriott et al. / Tetrahedron Letters 53 (2012) 3319–3321
3321
Table 1
3:1 CH2Cl2/EtOAc). Upon completion of the reaction, the mixture
was concentrated on a rotary evaporator and the resultant crude
product obtained was dissolved in the minimum volume of water.
This solution was acidified with concentrated hydrochloric acid to
pH 1 resulting in precipitation of an off-white solid which was col-
lected by vacuum filtration and dried in an oven at 80 °C to yield 3-
methyl-5,6-dimethoxybenzofuran-2-carboxylic acid (2a, 0.039 g,
99%), sublimes at 227–228 °C (lit.,8 mp 228 °C); IR/cmÀ1 3308,
1702, 1623, 1577; 1H NMR (300 MHz, CDCl3): d 2.60 (3H, s,
–CH3), 3.95 and 4.00 (each 3H, s, –O–CH3), 6.98 (1H, s), 7.09 (1H, s).
Microwave-assisted preparation of 3-bromocoumarins (1a–d) in the presence of N-
bromosuccinimide (NBS) at 250 W for 5 minutes at 80 °C
Reactant
% Yield of (1)
4-Methyl-6,7-dimethoxycoumarin
4-Methyl-7-methoxycoumarin
6,7-Dimethoxycoumarin
(1a), 89%
(1b), 85%
(1c), 83%
(1d), 80%
7-Methoxycoumarin
Table 2
Microwave-assisted Perkin rearrangement of 3-bromo-4-methyl-6,7-dimethoxy-
coumarin (1a)
Conclusion
Temperature/°C
Power/Watts
Time/min
% Yield of (2a)
We have successfully performed microwave-assisted Perkin
rearrangement reactions to prepare benzofuran-2-carboxylic acids
(2) from 3-bromocoumarins (1) in very high yields. This expedited
synthetic protocol will serve as an efficient method for the synthe-
sis of benzofuran-2-carboxylic acids with very short reaction times
in high yields.
79
79
79
79
250
300
400
500
5
5
5
5
Incomplete
99
99
90
Table 3
Acknowledgment
Microwave-assisted Perkin rearrangement of 3-bromocoumarins (1a–d) at 79 °C,
300 W, 5 min
Karla-Sue C. Marriott received support for this work from the
National Institute of Health/National Institute on Drug Abuse
(NIH/NIDA) (DA027086).
Bromocoumarin (1)
Product (2)% Yield
(1a)
(1b)
(1c)
(1d)
(2a), 99%
(2b), 95%
(2c), 99%
(2d), 97%
References and notes
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vessel that was then sealed and inserted into the microwave for
5 min, at 300 W and at a temperature of 79 °C with stirring. The
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