have also been an active research area.6 General synthetic
methodologies may involve the condensation reactions between
ketones (or aldehydes) and a number of different forms of
nucleophiles, under acidic or basic conditions.7 Among the
reported synthetic strategies, the palladium-catalyzed heteroan-
nulation reaction of o-alkenyl or -alkynyl phenols under
relatively mild conditions has also been largely employed.8 Most
of them could not provide satisfactory results because of the
requirement of strongly acidic or basic conditions or difficulties
in the introduction of different substituent patterns starting from
readily available materials.
A Facile Approach to the Synthesis of Chiral
2-Substituted Benzofurans
Lidia De Luca, Giampaolo Giacomelli,* and
Giammario Nieddu
Dipartimento di Chimica, UniVersita` degli Studi di Sassari, Via
Vienna 2, I-07100 Sassari, Italy
Enantiomerically pure 2-substituted benzofurans might con-
stitute starting materials for the production of biologically active
compounds.9 Considering the real tendency directed toward the
development of enantiomerically pure drugs, there is a limited
number of papers related to the preparation of enantiomers of
benzofuran or more generally azole compounds, either by
steroselective synthesis10 or enantiomeric separation.11
Following our research on the synthesis of heterocyclic
derivatives starting from relatively available compounds, we
were therefore interested in the preparation of benzofurans and
indole substrates. In this work, we wish to report development
of a convenient method for the generation of 2-substituted
benzofuran that could be easily adapted to the synthesis of
homochiral derivatives.
The applied methodology starts from the improvement of an
old procedure that reported the use of triphenylphosphine
bromonium salt, triethyl amine, and acyl chloride under reflux-
ing toluene for 8 h,12 which was suitably modified to be cleanly
applicable to N-protected amino acids for obtaining chiral
enantiomerically pure R-alkyl-2-benzofuranmethanamines.
For our purposes, although acid chlorides could be used in
the formation of simple optically active 2-alkyl benzofurans,
such as, e.g., (R)-2-(1-phenylpropyl)benzofuran, this procedure
did not allow the use of optically active amino acids, as
racemization phenomena might be heavily involved.13 Moreover
many acid chlorides are dangerously toxic, irritating, and
ReceiVed January 24, 2007
An effective route to chiral optically active 2-substituted
benzofurans directly from carboxylic acids is reported. This
procedure, which allows the preparation of R-alkyl-2-
benzofuranmethanamines from N-protected R-amino acids
without sensible racemization phenomena, proceeds in good
yields under mild conditions with the help of microwave
irradiation.
The benzofuran ring system features in a large number of
naturally occurring biologically active compounds and in
potential synthetic pharmacologic agents. For example, a variety
of benzofuran derivatives have been investigated as estrogen
receptor (ER) ligands,1 H3 receptor antagonists,2 selective
ligands for the dopamine D3 receptor subtype,3 metalloprotein-
ase-13 inhibitors,4 and antifungal agents.5
For these reasons, many efforts have been directed for
developing synthetic strategies for this privileged structure, and
recently combinatorial approaches to this class of compounds
(6) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
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A. Tetrahedron Lett. 1997, 38, 2311-2314. (d) Boehm, T. L.; Showalter,
H. D. H. J. Org. Chem. 1996, 61, 6498-6499.
* To whom correspondence should be addressed. Fax: +39-079-212069.
(1) (a) Halabalaki, M.; Aligiannis, N.; Papoutsi, Z.; Mitakou, S.;
Moutsatsou, P.; Sekeris, C.; Skaltsounis, A.-L. J. Nat. Prod. 2000, 63, 1672-
1674. (b) Von Angerer, E.; Biberger, C.; Leitchtl, S. Ann. N.Y. Acad. Sci.
1995, 761, 176-191. (c) Teo, C. C.; Kon, O. L.; Sim, K. Y.; Ng, S. C. J.
Med. Chem. 1992, 35, 1330-1339. (d) Crenshaw, R. R.; Jeffries, A. T.;
Luke, G. M.; Cheney, L. C.; Bialy, G. J. Med. Chem. 1971, 14, 1185-
1190.
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Esbenshade, T. A.; Hancock, A. A.; Cowart, M. D. Bioorg. Med. Chem.
Lett. 2005, 15, 2559-2563. (b) Cowart, M.; Pratt, J. K.; Stewart, A. O.;
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(9) Yuan, Y.; Men, H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 14720-
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(4) Hu, Y.; Xiang, J. S.; Di Grandi, M. J.; Du, X.; Ipek, M.; Laakso, L.
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(5) (a) Khan, M. W.; Alam, M. J.; Rashid, M. A.; Chowdhury, R. Bioorg.
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10.1021/jo070142c CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/10/2007
J. Org. Chem. 2007, 72, 3955-3957
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