Highly effective synthetic methods for substituted 2-arylbenzofurans using [3,3]-sigmatropic rearrangement: Short syntheses of stemofuran A and eupomatenoid 6

Article abstract of DOI:10.1021/ol049564o

Matrix presented. A new and efficient synthesis of 2-arylbenzofurans has been achieved via a route involving acylation and subsequent [3,3]-sigmatropic rearrangement of oxime ethers. Its synthetic utility is demonstrated by a short synthesis of stemofuran

Full text of DOI:10.1021/ol049564o

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1761-1763
Highly Effective Synthetic Methods for
Substituted 2-Arylbenzofurans Using
[3,3]-Sigmatropic Rearrangement: Short
Syntheses of Stemofuran A and
Eupomatenoid 6
Okiko Miyata, Norihiko Takeda, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, Motoyamakita, Higashinada, Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received March 9, 2004
ABSTRACT
A new and efficient synthesis of 2-arylbenzofurans has been achieved via a route involving acylation and subsequent [3,3]-sigmatropic
rearrangement of oxime ethers. Its synthetic utility is demonstrated by a short synthesis of stemofuran A and eupomatenoid 6 in which no
procedure for protection of the phenolic hydroxyl groups is needed.
Benzo[b]furans carrying functional groups are attractive tar-
gets of organic synthesis because of their biological activity
and their wide occurrence in nature.1 As a consequence, there
has been growing interest in developing general and versatile
synthetic methods for benzofuran derivatives.2 Some 2-aryl-
benzofurans are inhibitors of cell proliferation and platelet-
activating factor, and some of them show good fungicidal,
insecticidal, and cytotoxic activities.1j-l Therefore, 2-aryl-
benzofurans have been a new subject of synthetic studies
for the development of biologically active compounds.3
We have now developed a new preparative route to
2-arylbenzofurans 1 using the successive reactions of oxime
ethers. The route involves acylation, [3,3]-sigmatropic rear-
rangement, and intramolecular cyclization reactions.4 Fur-
thermore, this method was successively applied to the short
synthesis of stemofuran A 25 and eupomatenoid 6 3,6 the
latter of which has shown antifungal, insecticidal, and anti-
oxidant activities (Figure 1).
We first investigated the substituent effects in the reaction
of oxime ethers 4, prepared by condensation of O-phenyl-
(2) (a) Friedrichsen, W. In ComprehensiVe Heterocyclic Chemistry II;
Bird, C. W., Katritzky, A. R., Rees, C. W, Scriven, E. F. V., Eds.;
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R.; Cases, M.; Keenan, M.; Lewis, R. A.; Tan, P. Tetrahedron Lett. 2003,
44, 2995-2999. (c) Dahle´n, A.; Petersson, A.; Hilmersson, G. Org. Biomol.
Chem. 2003, 1, 2423-2426. (d) McKiernan, G. J.; Hartley, R. C. Org. Lett.
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2282.
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Perkin Trans. 1 2002, 1115-1123. (c) Li, J.; Jeong, S.; Esser, L.; Harran,
P. G. Angew. Chem., Int. Ed. 2001, 40, 4765-4770. (d) Li, J.; Burgett, A.
W. G.; Esser, L.; Amezcua, C.; Harran, P. G. Angew. Chem., Int. Ed. 2001,
40, 4770-4773. (e) Hughes, C. C.; Trauner, D. Angew. Chem., Int. Ed.
2002, 41, 1569-1572. (f) Patil, A. D.; Freyer, A. J.; Killmer, L.; Offen, P.;
Carte, B.; Jurewicz, A. J.; Johnson, R. K. Tetrahedron 1997, 53, 5047-
5060. (g) Kurosawa, W.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2003,
125, 8112-8113. (h) Tamada, M.; Endo, K.; Hikino, H.; Kabuto, C.
Tetrahedron Lett. 1979, 873-876. (i) Muhammad, I.; Li, X.-C.; Jacob, M.
R. Tekwani, B. L.; Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66,
804-809. (j) Ward, R. S. Nat. Prod. Rep. 1993, 10, 1-28. (k) Ward R. S.
Nat. Prod. Rep. 1995, 12, 183-205. (l) Ward, R. S. Nat. Prod. Rep. 1997,
14, 43-74.
(4) Miyata, O.; Takeda, N.; Morikami, Y.; Naito, T. Org. Biomol. Chem.
2003, 1, 254-256.
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Greger, H. J. Nat. Prod. 2002, 65, 820-827.
10.1021/ol049564o CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/23/2004

2-arylbenzofurans 5b and 5c in good yields, respectively
(entries 2 and 3). Even when a phenolic hydroxyl group is
present as an electron-donating group at the para position,
the desired benzofuran 5d was obtained in 84% yield after
chromatograpy using silica gel (entry 4). Direct recrystalli-
zation of the crude product obtained from oxime ether 4d
gave benzofuran 5n having a p-trifluoroacetoxy group (entry
5). However, the oxime ether 4e with a p-methoxyl group
gave the benzofuran 5e only in low yield with a small amount
of starting material 4e (entry 6).
A similar trend was observed in the reaction of oxime
ethers 4f-i, prepared from propiophenones (entries 7-10).
The oxime ethers 4f-h were subjected to reaction with
TFAT to give the 2-aryl-3-methylbenzofurans 5f-h in good
to excellent yields while the oxime ether 4i having a
p-methoxyl group gave corresponding benzofuran 5i in 26%
yield.
Figure 1. 2-Arylbenzofurans.
hydroxylamine and various acetophenones, with trifluoro-
acetyl triflate (TFAT),7 which is a powerful acylating agent
(Table 1).8 When unsubstituted oxime ether 4a was treated
The next substrate of choice was oxime ethers 4j-m with
a meta-substituted phenyl group. Under similar reaction
conditions, the oxime ethers 4j-l were converted into the
desired benzofurans 5j-l in good yield (entries 11-13). The
reaction of substrate 4m with a m-methoxyl group also
proceeded smoothly to afford the desired benzofuran 5m in
excellent yield (entry 14).
Table 1. Conversion of Oxime Ethers into 2-Arylbenzofuransa
A plausible reaction pathway based on these results is
shown in Scheme 1. As shown in our previous studies,4 the
entry
4
R1
R2
time (h)
5
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4d
4e
4f
4g
4h
4i
H
H
H
H
H
H
Me
Me
Me
Me
H
H
H
H
H
p-Br
1
1.5
5
2
2
2
2
2
2
2
2
5
2
5a
5b
5c
5d
5n c
5e
5f
5g
5h
5i
99
96
85 (9)
84
92
15 (12)
82
91
86
26 (13)
94
Scheme 1
p-NO2
p-OH
p-OH
p-OMe
H
p-Br
p-OH
p-OMe
m-Br
m-NO2
m-OH
m-OMe
4j
4k
4l
5j
5k
5l
95
86
93
4m
1.5
5m
a TFAT (5 equiv) and DMAP (3 equiv) were used. b Yields in parentheses
are for the recovered starting material. c 5n (R2 ) p-OCOCF3).
oxime ethers 4 are acylated with TFAT to form the trifluoro-
acetylated compounds A. These would immediately rearrange
to give the dienones B, which are converted into the 2-aryl-
benzofurans 5 via cyclization followed by elimination of
trifluoroacetamide.
In the case of oxime ether 4d with the hydroxyl group,
the acylation proceeds at both the imine part and the hydroxyl
group to form diacylated enehydroxylamine C, which can
then rearrange to afford the acylated 2-arylbenzofuran 5n.
This labile benzofuran 5n was readily hydrolyzed during
column chromatograpy using silica gel to give the phenolic
benzofuran 5d (Scheme 2). Similarly, oxime ethers 4h and
4l would give the desired 2-arylbenzofurans 5h and 5l via
the corresponding diacylated intermediates.
with TFAT (5 equiv) in the presence of (dimethylamino)-
pyridine (DMAP) (3 equiv) at room temperature, the ex-
pected 2-phenylbenzofuran 5a was obtained in quantitative
yield (entry 1). Similarly, the reaction of oxime ethers 4b
and 4c having the p-bromo- and p-nitrophenyl groups which
are electron-withdrawing group proceeded smoothly to give
(6) (a) Bowden, B. F.; Ritchie, E.; Taylor, W. C. Aust. J. Chem. 1972,
25, 2659-2669. (b) Stahl, E.; Ittel, I. Planta Med. 1981, 42, 144-154. (c)
Freixa, B.; Vila, R.; Ferro, E. A.; Adzet, T.; Can˜igueral, S. Planta Med.
2001, 67, 873-875. (d) Carini, M.; Aldini, G.; Orioli, M.; Facino, R. M.
Planta Med. 2002, 68, 193-197. (e) Chauret, D. C.; Bernard, C. B.;
Arnason, J. T.; Durst, T. J. Nat. Prod. 1996, 59, 152-155.
(7) (a) Lee, J. S.; Fuchs, P. L. Org. Lett. 2003, 5, 3619-3622. (b) Forbus,
T. R., Jr.; Taylor, S. L.; Martin, J. C. J. Org. Chem. 1987, 52, 4156-4159.
(8) When trifluoroacetic anhydride, which is the usual trifluoroacetyl
agent, was used, the oxime ether could not give 2-arylbenzofuran.
As mentioned above, the series of reactions leading to the
formation of 2-arylbenzofurans proceeded smoothly except
for oxime ethers having a p-methoxyl group (4e and 4i). This
1762
Org. Lett., Vol. 6, No. 11, 2004

Scheme 2
Scheme 4
is due to the electron-donating ability of the p-methoxyl
group. The electron-donating ability lowers the reactivity of
the intermediates B formed from 4e and 4i toward nucleo-
philic attack of the carbonyl oxygen.
The high potential of this reaction for synthesis has been
proved by the practical synthesis of natural 2-arylbenzo-
furans. We chose stemofuran A 25 and eupomatenoid 6 36
as our targets which have a hydroxylphenyl group at the
2-position of the benzofuran skeleton. We succeeded in the
total synthesis of these natural products without a step for
protection of the phenolic hydroxyl groups.
Another target of our synthesis is eupomatenoid 6 36
(Scheme 4). Known syntheses of eupomatenoid 6 3 reported
by two groups11,12 include the protection and deprotection
reactions of the hydroxyl group.
The condensation of O-phenylhydroxylamine 10,10 pre-
pared from boronic acid 9, with propiophenone proceeded
effectively to give the oxime ether 11 in excellent yield,
which was then treated with TFAT to give the desired
benzofuran 12 in 92% yield.
At first, we examined the preparation of stemofuran A 2,
recently isolated from Stemona collinsae5 (Scheme 3). Al-
Finally, the introduction of a propenyl group was achieved
by using Suzuki coupling with propenyl boronic acid to give
eupomatenoid 6 3 in 52% overall yield from 9 in five steps.
Physical and spectral properties of 3 were identical with those
of natural eupomatenoid 6 3 reported in the literature.6 Our
synthesis is superior to those reported by both Bach’s12 and
Stevenson’s11 groups in both yield and number of steps.
In conclusion, we have now established a novel and po-
tential synthetic route to 2-arylbenzofurans. The reaction pro-
ceeds via sequential acylation, rearrangement, and cyclization
of oxime ethers under the mild conditions. Furthermore, we
have succeeded in the short synthesis of stemofuran A and
eupomatenoid 6.
Scheme 3
Acknowledgment. We are grateful for Grants-in-Aid for
Scientific Research on Priority Areas (A) from the Ministry
of Education, Culture, Sports, Science and Technology (T.N.)
and for Scientific Research (C) from the Japan Society for
the Promotion of Science (O.M.). We also acknowledge a
research grant from the Science Research Promotion Fund
of the Japan Private School Promotion Foundation.
though Pasturel et al.9 synthesized stemofuran A 2 in 44%
overall yield from 2-hydroxybenzaldehyde, the synthesis
includes many transformations involving protection and
deprotection of a hydroxyl group. O-Phenylhydroxyamine
7 was prepared from the phenylboronic acid 6 in two steps
acccording to the literature procedures.10 The condensation
of 7 with dihydroxyacetophenone gave the oxime ether 8,
which was subjected to our reaction conditions to give
stemofuran A 2 in 95% yield. The spectral data of this ben-
zofuran 2 are identical with those reported in the literature.5
Thus, we have succeeded in a four-step synthesis with 72%
overall yield.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL049564O
(9) Pasturel, J. Y.; Solladie, G.; Maignan, J. Fr. Demande FR 2833259,
2003; Chem. Abstr. 2003, 139, 36375.
(10) Petrassi, H. M.; Sharpless, K. B.; Kelly, J. W. Org Lett., 2001, 3,
139-142.
(11) McKittrick, B. A.; Stevenson, R. J. Chem. Soc., Perkin Trans. 1
1983, 475-482.
(12) Bach, T.; Bartels, M. Synthesis 2003, 925-939.
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