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
1. Xiang, Y.; Hirth, B.; Asmussen, G.; Biemann, H. P.; Bishop, K. A.; Good, A.;
Fitzgerald, M.; Gladysheva, T.; Jain, A.; Jancsics, K.; Liu, J.; Metz, M.; Papoulis, A.;
Skerlj, R.; Stepp, J. D.; Wei, R. R. Bioorg. Med. Chem. Lett. 2011, 21, 3050–3056.
2. Campiani, G.; Butini, S.; Trotta, F.; Fattorusso, C.; Catalanotti, B.; Aiello, F.;
Gemma, S., et al J. Med. Chem. 2003, 46, 3822–3839.
oxycoumarin (1a, 0.060 g, 89%) as white crystals, mp 205–206 °C
(lit.,9 mp 205–206 °C).
3. Schlotter, K.; Boeckler, F.; Hübner, H.; Gmeiner, P. J. Med. Chem. 2006, 49, 3628–
3635.
4. Bettinetti, L.; Schlotter, K.; Hübner, H.; Gmeiner, P. J. Med. Chem. 2002, 45, 4594–
4597.
5,6-Dimethoxy-3-methyl-benzofuran-2-carboxylic acid (2a)
3-Bromo-4-methyl-6,7-dimethoxycoumarin (1a) (0.05 g, 0.167
mmol) was added to a microwave vessel. Ethanol (5 ml) and so-
dium hydroxide (0.0201 g, 0.503 mmol) were then added to the
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
reaction was monitored by thin layer chromatography (silica gel,
5. Perkin, W. H. J. Chem. Soc. 1870, 23, 368.
6. Newman, M. S.; Dalton, C. K. J. Org. Chem. 1965, 30, 4122–4126.
7. Bowden, K.; Battah, S. J. Chem. Soc., Perkin Trans. 2 1998, 1603.
8. Whalley, W. B. J. Chem. Soc. 1953, 3479.
9. Patel, M. G.; Sethna, S. J. Indian Chem. Soc. 1960, 37, 227.