SCHEME 1. Retrosynthetic Analysis of
2-Aryl-3-Substituted Benzo[b]furans
New Synthesis of 2-Aryl-3-Substituted
Benzo[b]furans from Benzyl 2-Halophenyl
Ethers†
Roberto Sanz,* Delia Miguel, Alberto Mart´ınez, and
Antonio Pe´rez
of furan rings from various arene derivatives by formation of
one O-C, one C-C or one O-C, and one C-C bonds,4 there
are a limited number of methodologies available based on
simultaneous two C-C bond formations, that is, C2-C3 and
C3-C3a bonds.5 In this context, we envisaged that if we were
able to prepare R-lithiobenzyl 2-lithiophenyl ethers, the subse-
quent reaction with carboxylic esters6 and further dehydration
would provide us the corresponding 2-aryl-3-substituted benzo-
[b]furans (Scheme 1). We believe that this disconnection would
represent one efficient strategy for benzo[b]furan formation,
because starting benzyl ethers are readily accessible, and the
C3 substituent could be easily selected from the huge pool of
available esters.
Departamento de Qu´ımica, AÄ rea de Qu´ımica Orga´nica,
Facultad de Ciencias, UniVersidad de Burgos,
Pza. Misael Ban˜uelos s/n, 09001-Burgos, Spain
ReceiVed February 9, 2006
However, whereas 3-substituted benzo[b]thiophene deriva-
tives have been synthesized by reaction of acyl chlorides with
the dianion of thioanisole,7 it is well-known that R-oxygen
carbanions are unstable and usually undergo protophilic cleavage
(elimination) or [1,2]-Wittig rearrangement.8 In our studies on
the reactivity of o-lithioaryl ethers, we have found that benzyl
o-lithioaryl ethers, generated by halogen-lithium exchange with
t-BuLi (2 equiv), undergo in THF a tandem anion translocation/
Wittig rearrangement to afford diarylcarbinols.9 We reasoned
that if a benzylic hydrogen atom is removed in that process by
an aryllithium moiety, an excess of base could give rise to an
R-lithiobenzyl o-lithiophenyl ether. Although this kind of
organolithium could undergo the Wittig rearrangement, the high
anionic character of the o-lithiophenoxy ring could inhibit the
rearrangement.10
Treatment of benzyl 2-halophenyl ethers with 3 equiv of
t-BuLi results in Li-halogen exchange and lithiation at
benzylic methylene simultaneously. These dianions do not
undergo Wittig rearrangement and can be trapped with
electrophiles. Their reactions with carboxylic esters afford
the corresponding 2-aryl-3-hydroxy-2,3-dihydrobenzo[b]-
furans as a mixture of diastereoisomers. Subsequent acid-
catalyzed or mediated dehydration gives moderate to good
overall yield of a variety of 2-aryl-3-substituted benzo[b]-
furans.
In this paper, we wish to report a novel one-step synthesis
of 2-aryl-3-substituted benzo[b]furans by condensation of car-
boxylic esters with the dianions generated from benzyl 2-halo-
phenyl ethers.
Benzo[b]furans have attracted considerable attention as a
result of their biological activity and their presence in a variety
of significant natural products.1 So, there is a growing interest
in developing general and versatile synthetic methods for the
preparation of this kind of compound.2 In this area, we have
recently reported a practical and efficient route to 4-halo and
4-functionalized benzo[b]furans from 3-halophenols based on
a tandem Sonogashira coupling/5-endo-dig cyclization of 3-halo-
2-iodophenols with alkynes.3 In contrast to the vast array of
methods for benzo[b]furan synthesis based on the construction
(3) Sanz, R.; Castroviejo, M. P.; Ferna´ndez, Y.; Fan˜ana´s, F. J. J. Org.
Chem. 2005, 70, 6548-6551.
(4) 3-Arylbenzofurans have been prepared by the formation of the C3-
C3a bond through a halogen-metal exchange/cyclization process from
iodoketones: (a) Kraus, G. A.; Kim, I. Org. Lett. 2003, 5, 1191-1192. (b)
Kraus, G. A.; Schroeder, J. D. Synlett 2005, 2504-2506.
(5) Katritzky has designed a one-pot, four-step preparation of benzofurans
using benzotriazole chemistry: Katritzky, A. R.; Serdyuk, L.; Xie, L. J.
Chem. Soc., Perkin Trans. 1 1998, 1059-1064.
† Dedicated to Professor Francisco J. Arna´iz on the occasion of his 60th
birthday.
(6) We have reported that 1,4-dianions, like 3,4-bis(lithiomethyl)-
dihydropyrroles, efficiently react with carboxylic esters to afford hydroxy
cyclic derivatives: Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.; Ignacio, J. M.
Eur. J. Org. Chem. 2003, 771-783. Also, 2-substituted 6-azaindoles have
been synthesized by the condensation of the dianion derived from 3-amino-
4-picoline with carboxylic esters: Song, J. J.; Tan, Z.; Gallou, F.; Xu, J.;
Yee, N. K.; Senanayake, C. H. J. Org. Chem. 2005, 70, 6512-6514.
(7) (a) Campaigne, E.; Rogers, R. B.; Donelson, A.; Bosin, T. R. J.
Heterocycl. Chem. 1973, 10, 979-981. (b) Campaigne, E.; Homfeld, R.;
Mais, D. E. J. Heterocycl. Chem. 1978, 15, 1351-1359. (c) Cabiddu, S.;
Cancelu, D.; Floris, C.; Gelli, G.; Melis, S. Synthesis 1988, 888-890.
(8) (a) Wittig, G.; Lo¨hmann, L. Justus Liebigs Ann. Chem. 1942, 550,
260-268. (b) Marshall, J. A. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp 975-
1014. (c) Tomooka, K.; Yamamoto, H.; Nakai, T. Liebigs Ann./Recl. 1997,
1275-1281.
(1) (a) Keay, B. A.; Dibble, P. W. Furans and their Benzo Derivatives:
Applications. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2,
pp 395-436. (b) Hou, X.-L.; Yang, Z.; Wong, H. N. C. Furans and
Benzofurans. In Progress in Heterocyclic Chemistry; Gribble, G. W.,
Gilchrist, T. L., Eds.; Pergamon: Oxford, 2002; Vol. 14, pp 139-179. Some
2-arylbenzo[b]furans are inhibitors of cell proliferation and the platelet-
activating factor, and some of them show fungicidal and cytotoxic
activities: Ward, R. S. Nat. Prod. Rep. 1997, 14, 43-74.
(2) For recent reports on the synthesis of 2,3-disubstituted benzo[b]furans,
see: (a) Miyata, O.; Takeda, N.; Naito, T. Org. Lett. 2004, 6, 1761-1763.
(b) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004,
43, 6144-6148. (c) Kim, K.-O.; Tae, J. Synthesis 2005, 387-390. (d)
Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem. 2005, 3334-
3341. (e) Liao, Y.; Smith, J.; Fathi, R.; Yang, Z. Org. Lett. 2005, 7, 2707-
2709. (f) Chen, C.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964-6967.
(9) Barluenga, J.; Fan˜ana´s, F. J.; Sanz, R.; Marcos, C.; Trabada, M. Org.
Lett. 2002, 4, 1587-1590.
10.1021/jo060271d CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/07/2006
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J. Org. Chem. 2006, 71, 4024-4027