Oxidative aromatic C-O bond formation: synthesis of 3-functionalized benzo[b]furans by FeCl3-mediated ring closure of a-Aryl ketones

Article abstract of DOI:10.1021/ol902157c

A variety of 3-functionalized benzo[b]furans were achieved by way of a FeCl₃-medlated Intramolecular cyclization of electron-rich a-aryl ketones. The alkoxy substituent on the benzene ring In the substrates was essential for an efficient cyclization to occur. This novel method allows the construction of benzo[b]furan rings by joining the O-atom on the side chain to the benzene ring via direct oxidative aromatic C-O bond formation.

Full text of DOI:10.1021/ol902157c

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4978-4981
Oxidative Aromatic C-O Bond Formation:
Synthesis of 3-Functionalized
Benzo[b]furans by FeCl3-Mediated Ring
Closure of r-Aryl Ketones
Zhidan Liang, Weizhe Hou, Yunfei Du,* Yongliang Zhang, Yan Pan, Deng Mao,
and Kang Zhao*
Tianjin Key Laboratory for Modern Drug DeliVery & High-Efficiency, School of
Pharmaceutical Science and Technology, Tianjin UniVersity, Tianjin 300072, China
duyunfeier@tju.edu.cn; combinology@yahoo.com
Received September 17, 2009
ABSTRACT
A variety of 3-functionalized benzo[b]furans were achieved by way of a FeCl3-mediated intramolecular cyclization of electron-rich r-aryl ketones.
The alkoxy substituent on the benzene ring in the substrates was essential for an efficient cyclization to occur. This novel method allows the
construction of benzo[b]furan rings by joining the O-atom on the side chain to the benzene ring via direct oxidative aromatic C-O bond
formation.
Benzo[b]furan derivatives have drawn extensive and endur-
ing attention for their wide occurrence in natural products,
broad range of biological activities, and significant pharma-
ceutical potentials.1 It is not surprising therefore that great
efforts have been directed toward developing synthetic
approaches for the construction of this privileged structure.2
The predominant strategy involves the formation of an
annulated furan ring from the benzene derivatives. On the
basis of the bond formation patterns, the methods of this
strategy can be generalized into the following types:2f (1)
The O-atom of the benzo[b]furan ring is introduced by
utilizing O-containing arenes as starting materials in the early
synthetic stage (a, b, and c in Figure 1). (2) The O-atom is
connected to the benzene ring by the transition-metal-
catalyzed O-arylation of o-halobenzyl ketones (d in Figure
1). (3) The O-moiety on the side chain is joined to the
benzene ring without any substituent in the ortho position,
through the direct formation of a bond between the oxygen
(1) (a) ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996; Vol. 2, pp
259-287. (b) Hou, X. L.; Yang, Z.; Yeung, K. S.; Wong, H. N. C. Prog.
Heterocycl. Chem. 2008, 19, 176. For selected papers on the biological
activities and pharmacological interest of benzofurans, see: (c) Ziegert, R. E.;
Toraeng, J.; Knepper, K.; Braese, S. J. Comb. Chem. 2005, 7, 147. (d)
Hou, X.-L.; Yang, Z.; Yeung, K.-S.; Wong, H. N. C. Prog. Heterocycl.
Chem. 2005, 17, 142. (e) Carlsson, B.; Singh, B. N.; Temciuc, M.; Nilsson,
S.; Li, Y.-L.; Mellin, C.; Malm, J. J. Med. Chem. 2002, 45, 623. (f) Flynn,
B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670.
Figure 1
. General bond formation patterns for the construction of
benzo[b]furan skeletons from benzene derivatives.
10.1021/ol902157c CCC: $40.75
Published on Web 10/05/2009
 2009 American Chemical Society

Table 1. Synthesis of 3-Functionalized Benzo[b]furans by FeCl3-Mediated Ring Closure of R-Aryl Ketonesa
a Optimal conditions: 1 equiv of 1, 2.5 equiv of anhydrous FeCl3 in DCE at rt unless otherwise stated. b Isolated yields after silica gel chromatography.
c Reaction occurred at 40 °C. d Reaction occurred at reflux temperature. e With the concomitant formation of other unidentified byproducts.
and an aryl sp2 carbon (e in Figure 1). This last strategy
provides a unique access to benzo[b]furan compounds since
such a method would avoid using the “privileged” phenol
drivatives as starting materials and postpone the introduction
of the oxygen atom to a later synthetic step. Furthermore,
there is no need to install a halogen atom in the ortho position
of the benzene ring since such a substituent is not indispen-
sable by this approach. To our knowledge, a methodology
of constructing benzo[b]furans in such a way has rarely been
exploited, and only a photoinduced approach falls into this
category.3 In this communication, we describe such an
intramolecular cyclization pathway for the construction of
3-functionalized benzo[b]furans by direct C-H functional-
ization of an electron-rich aromatic ring with a side chain
O-moiety.
(2) For selected reviews on synthetic approaches to benzo[b]furans, see:
(a) Dell, C. P. Sci. Synth. 2001, 10, 11. (b) Steel, P. G. Sci. Synth. 2001,
10, 87. (c) Greve, S.; Friedrichsen, W. Prog. Heterocycl. Chem. 1999, 11,
144. (d) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. (e) Brown, R. C. D.
Angew. Chem., Int. Ed. 2005, 44, 850. (f) Kadieva, M. G.; Oganesyan,
E. T. Chem. Hetercycl. Compd. 1997, 33, 1245. (g) Hou, X.-L.; Yang, Z.;
Wong, H. N. C. Prog. Heterocycl. Chem. 2003, 15, 167. (h) McCallion,
G. D. Curr. Org. Chem. 1999, 3, 67. (i) Zeni, G.; Larock, R. C. Chem.
ReV. 2006, 106, 4644. For recent selected papers on synthesis of benzo[b-
]furans, see: (a) Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. J. Org. Chem.
2007, 72, 10283. (b) Zhao, B.; Lu, X. Org. Lett. 2006, 8, 5987. (c) Farago,
J.; Kotschy, A. Synthesis 2009, 85. (d) Huang, X.-C.; Liu, Y.-L.; Liang,
Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525. (e) Lu, B.;
Wang, B.; Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337. (f) Carril, M.;
SanMartin, R.; Tellitu, I.; Dominguez, E. Org. Lett. 2006, 8, 1467. (g)
Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung, R. P.; Yao, P.-Y.;
Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361. (h) Nagamochi, M.; Fang, Y.-
Q.; Lautens, M. Org. Lett. 2007, 9, 2955. De Luca, L.; Giacomelli, G.;
Nieddu, G. J. Org. Chem. 2007, 72, 3955. (i) Mattson, A. E.; Scheidt, K. A.
J. Am. Chem. Soc. 2007, 129, 4508. (j) Martinex, C.; lvarez, R. A.;
Aurrecoechea, J. M. Org. Lett. 2009, 11, 1083. (k) Nakamura, I.; Mizushima,
Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022. (l) Zhang, H.;
Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed. 2004, 43, 6144.
In recent decades, the development of novel methodologies
that directly functionalize aromatic C-H bonds to construct
C-N/O bonds using transition-metal catalysis has received
considerable attention.4 In our previous work, we realized
(3) (a) Pandey, G.; Krishna, A.; Bhalerao, U. T. Tetrahedron Lett. 1989,
30, 1867.
Org. Lett., Vol. 11, No. 21, 2009
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1h, with a methylenedioxy substitution on the benzene ring,
could afford the benzo[b]furan product 2h in an excellent
94% yield by the method. By replacing the meta-methoxy
group with a bromo group in 1a, we found that substrate 1i
could also give the desired 2i in good yield. However, we
were disappointed to find that substrate 4a (Figure 2), an
analogue of 1i by exchanging the position of the methoxy
and the bromo group, yielded no benzo[b]furan product under
the same conditions. Gratifyingly, substrate 1j, structurely
differing from compound 4a by replacing the methyl group
with a phenyl group, gave the cyclized product 2j in
relatively lower yield, with the cost of a longer reaction time
and a higher reaction temperature. Further reducing one
methoxy group on the benzene ring in substrate 1a led us to
discover that the solely para-methoxy-substituted 1k fur-
nished the desired 2k in a poor 30% yield after the reaction
mixture was refluxed for 5 h, while the meta-methoxy-
substituted compound 4b (Figure 2) was unreactive under
the same conditions. Interestingly, when the methyl group
in 1k was replaced with a phenyl group, we were pleased to
see that benzo[b]furan 2l could be obtained in moderate yield,
although at the expense of a higher reaction temperature and
a longer reaction time. On the basis of the above experimental
facts, we tentatively conclude that a para-methoxy group is
more determinant than a meta-methoxy group in the substrate
for the ring closure to occur. Furthermore, when R1 was a
Figure 2. Other models that failed to afford benzo[b]furans.
the formation of a series of N-alkoxyindole-3-carbonitriles
via a novel FeCl3-mediated intramolecular aromatic C-N
bond formation.5 Inspired by this finding, we were interested
in investigating the construction of benzo[b]furan skeletons
by a similar intramolecular oxidative C-O coupling of R-aryl
ketonitriles 1, which are readily available by the condensation
of substituted benzyl cyanides with carboxylic esters. To
initiate our study, the unsubstituted R-aryl ketonitrile 3a
(Figure 2) was chosen to test the feasibility of the ring closure
mediated by FeCl3. However, it was found that substrate 3a
was inert, and no desired benzo[b]furan compound was
achieved when applying various oxidants under many
conditions.6 A further screen of the substrate pattern led us
to discover that substrate 1a, with 3,4-dimethoxy substituted
on the benzene ring, could be conveniently converted to the
desired benzo[b]furan 2a in 70% yield when oxidized by
FeCl3 in DCE at room temperature (entry 1, Table 1). This
result implies that the presence of electron-donating methoxy
groups on the benzene ring of the substrate was crucial for
the oxidative intramolecular cyclization to occur.
Table 2. Further Variations of E groups in Substrate 1a
Since the importance of an electron-rich substrate is
obvious, we first sought to probe the substrate scope of this
FeCl3-mediated oxidative reaction by changing the R1 groups
while keeping the 3,4-dimethoxy benzene moiety intact. The
results listed in Table 1 demonstrated that when R1 was a
relatively long-chained propyl group (entry 2, Table 1), a
bulkier tert-butyl group (entry 3, Table 1), or benzyl group
(entry 4, Table 1), the substrates could undergo ring closure
to give the desired corresponding benzo[b]furan products in
moderate yields, although these substrates needed relatively
longer reaction times. For the substrates with R1 being an
aryl group, the reactions also furnished the desired cyclized
products in acceptable yields, with shorter reaction times
(entries 5-7, Table 1).
Next, we decided to investigate the substitution variations
of the electron-rich substrates. It was observed that substrate
(4) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932. (b) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (c) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto,
T.; Hiroya, K. Org. Lett. 2007, 9, 2931. (d) Thu, H.-Y.; Yu, W.-Y.; Che,
C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (e) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (f) Ueda, S.;
Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411.
(5) Du, Y.; Chang, J.; Reiner, J.; Zhao, K. J. Org. Chem. 2008, 73,
2007.
(6) (a) No desired product achieved when using FeCl3 as oxidant and
carrying out the reaction in DCE at rt to reflux. (b) Other oxidative
conditions: K3Fe(CN)6/MeCN, Cu(OAc)2/AcOH, Mn(OAc)3/AcOH, CAN/
CH3CN, and MnO2/CH2Cl2 were also ineffective for this conversion, since
substrate 3a would dimerize under these conditions. For such homocoupling
reactions, see: De Jongh, H. A. P.; De Jonge, C. R. H. I.; Mijs, W. J J.
Org. Chem. 1971, 36, 3160, and references cited therein.
a Conditions: See Table 1. b Isolated yields after silica gel chromatography.
c Reaction occurred at 40 °C. d Complex mixture, 30% of 1t recovered.
4980
Org. Lett., Vol. 11, No. 21, 2009

phenyl group, the cyclization process was somewhat en-
hanced compared to in the cases when it was a methyl group.
The reaction proceeded equally well with substrates 1m,n,
in which the naphthyl ring could be taken as an electron-
rich benzene ring. Thus, two furan-fused heterocycles 2m,n
could be obtained by the approach (entries 13 and 14, Table
2).
Scheme 2. Proposed Mechanistic Pathway
To further extend the substrate scope, we finally came to
change the benzylic cyano group in the substrates into other
electron-withdrawing groups. To our delight, substrates
1o-r, bearing an ethoxycarbonyl or alkyl acyl group, also
successfully rendered the corresponding benzo[b]furan prod-
ucts in moderate yields (entries 1-4, Figure 2). When the
substrate was solely substituted with a para-methoxy group
in the benzene ring (1s,t, in which E represents an alkyl acyl
group), we found that the desired benzo[b]furan products
2s,t were obtained in relatively low yields. However, for
susbtrate 5a, differing from 1l by changing the cyano group
into an ethoxycarbonyl group, no desired cyclized product
was separated under the same conditions. Similarly, we found
that when the two methoxy groups were both removed from
the benzene ring in the substrate compounds 3b and 3c
(Figure 2) failed to provide any cyclized products under the
same conditions.
the process, based on the fact that compound 5b, without an
electron-withdrawing group (E ) H) at the benzylic position,
failed to provide the desired cyclized product under the
described conditions. Next, a conjugated cycloaddition
process would occur to transform B into the carbocation
intermediate C, which would be greatly stabilized if R1
represents a phenyl group. Further tautomerization of C
would lead to the stable D, or even the more stable E, if R
was an electron-donating group, e.g., a methoxy or bromo
group. Finally, rearomatization of C-E by loss of a proton
would give the title compound 2.
It is worth mentioning that when compound 6, differing
from 1o by one more methylene group, was subjected to
the same reaction conditions an unexpected indene 7 was
achieved in 45% yield,7 with no formation of the desired
chromene-3-carboxylate derivative (Scheme 1).
In summary, we demonstrated herein a novel synthetic
approach to 3-functionalized benzo[b]furan derivatives start-
ing from readily available R-aryl ketones. The underpinning
strategy is the FeCl3-mediated ring closure of the electron-
rich R-aryl ketones, which realized the construction of
benzo[b]furan rings by joining the O-atom on the side chain
to the benzene ring via direct oxidative aromatic C-O bond
formation. Efforts toward the development of proper oxida-
tive conditions for the R-aryl ketones without alkoxy
substituents on the aromatic ring, as well as the application
of the current reaction in organic synthesis, are in progress
in our laboratory.
Scheme 1. Formation of Indene Derivatives 10 from Compound 9
All the structures of the cyclized products were determined
by detailed study of the spectroscopic data. Furthermore,
product 2p was unambiguously confirmed through X-ray
crystallographic analysis (see Supporting Information).
A tentative mechanistic pathway is shown in Scheme 2.
Initially, one electron would be abstracted from the electron-
rich aromatic ring 1 by ferric chloride, which acts as a single
electron oxidant, to afford the aromatic radical cation A.
Mediated by ferric chloride, a second single-electron transfer
(SET) process would convert the radical cation A to the
oxonium intermediate B. The benzylic electron-withdrawing
group is thought to promote the loss of the acidic proton in
Acknowledgment. Y. Du acknowledges the National
Natural Science Foudation of China (#20802048) and
Cultivation Foundation (B) for New Faculty of Tianjin
University (TJU-YFF-08B68) for financial support. We also
thank Miss Xiling Zhao, University of California, San Diego,
for revising our English text.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds (PDF)
and X-ray structural data of 2p (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) For formation of such indene compounds catalyzed by H3PO4, see:
Koo, J. J. Am. Chem. Soc. 1953, 75, 1891.
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