Facile construction of the benzofuran and chromene ring systems via Pd II-catalyzed oxidative cyclization

Article abstract of DOI:10.1021/ol051264z

(Chemical Equation Presented) We herein report the development of one-pot procedures for the conversion of allyl aryl ethers to 2-methylbenzofurans (via sequential Claisen rearrangement and oxidative cyclization) and for the conversion of aryl homoallyl e

Full text of DOI:10.1021/ol051264z

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3355-3358
Facile Construction of the Benzofuran
and Chromene Ring Systems via
PdII-Catalyzed Oxidative Cyclization
So Won Youn* and Jeong Im Eom
Department of Chemistry, Pukyong National UniVersity, Busan, 608-737, Korea
sowony@pknu.ac.kr
Received May 30, 2005
ABSTRACT
We herein report the development of one-pot procedures for the conversion of allyl aryl ethers to 2-methylbenzofurans (via sequential Claisen
rearrangement and oxidative cyclization) and for the conversion of aryl homoallyl ethers to chromenes (via direct oxidative cyclization). It is
likely that both reactions proceed via a common Pd-catalyzed pathway involving olefin activation, nucleophilic attack, and â-hydride elimination.
Benzofurans and chromenes have attracted considerable
attention due to their biological activity and their presence
in a variety of significant natural products.1 Consequently,
a number of synthetic strategies have been reported for the
construction of benzofurans2,3 and chromenes.4 A common
approach to the benzofuran ring system consists of Claisen
rearrangement5 of an allyl aryl ether followed by Pd-
catalyzed intramolecular oxidative cyclization3c-f of the
corresponding 2-allylphenol, accomplishing the overall trans-
formation in two discrete reactions (Scheme 1). Chromenes
are also constructed by a two-step sequence, typically
involving prefunctionalization of the arene (e.g., halogenation
at the 2-position) followed by Heck-type cyclization.4d-f We
were interested in developing a one-pot synthesis of benzo-
furans from allyl aryl ethers whereby a single catalytic system
would invoke sequential Claisen rearrangement and oxidative
cyclization.6 Similarly, we proposed that the direct oxidative
coupling of unactivated arene and olefin components of aryl
homoallyl ethers would be an efficient route to the chromene
core, obviating the need for prehalogenation. Herein we
report simple, convenient methods for the one-pot synthesis
(1) (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285. (b) Keay,
B. A. ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996; Vol. 2. p 395.
(c) Cagniant, P.; Cagniant, D. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Boulton, A. J., Eds.; Academic Press: New York, 1975;
Vol.18, p 337. (d) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao.
G. Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939.
(2) For recent examples, see: (a) Zhang, J.; Zhang, Y.; Zhang, Y.;
Herndon, J. W. Tetrahedron 2003, 59, 5609. (b) Cruz, M. del C.; Tamariz,
J. Tetrahedron Lett. 2004, 45, 2377. (c) Xie, X.; Chen, B.; Lu, J.; Han, J.;
She, X.; Pan, X. Tetrahedron Lett. 2004, 45, 6235. (d) Konno, T.; Chae,
J.; Ishihara, T.; Yamanaka, H. Tetrahedron 2004, 60, 11695. (e) Bellur,
E.; Freifeld, I.; Langer, P. Tetrahedron Lett. 2005, 46, 2185.
(3) For a review, see: (a) Cacchi, S.; Fabrizi, G.; Goggiomani, A.
Hetereocycles 2002, 56, 613. For intramolecular oxidative arene-olefin
cyclizations, see: (b) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew.
Chem., Int. Ed. 2004, 43, 6144 and references therein. For oxidative
cyclizations of 2-allylphenols, see: (c) Hosokawa, T.; Maeda, K.; Koga,
K.; Moritani, I. Tetrahedron Lett. 1973, 14, 739. (d) Hosokawa, T.; Ohkata,
H.; Moritani, I. Bull. Chem. Soc. Jpn. 1975, 48, 1533. (e) Hosokawa, T.;
Murahashi, S.-I. Acc. Chem. Res. 1990, 23, 49. (f) Roshchin, A. I.;
Kel’chevski, S. M.; Bumagin, N. A. J. Organomet. Chem. 1998, 560, 163
and references therein.
(4) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055.
(b) Youn, S. W.; Pastine, S. J.; Sames, D. Tetrahedron 2003, 59, 8859.
(c) Hardouin, C.; Burgaud, L.; Valleix, A.; Doris, E. Tetrahedron Lett. 2003,
44, 435. (d) Caddick, S.; Kofie, W. Tetrahedron Lett. 2002, 43, 9347.
(e) Shezad, N.; Clifford, A. A.; Rayner, C. M. Tetrahedron Lett. 2001, 42,
323. (f) Shi, L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. J.
Org. Chem. 1983, 48, 3894.
(5) For a review, see: (a) Castro, A. M. M. Chem. ReV. 2004, 104, 2939.
(b) Hiersemann, M.; Abraham, L. Eur. J. Org. Chem. 2002, 1461. For
Claisen rearrangement of allyl aryl ethers with catalytic amount of metal
catalysts, see: (c) (IrCl3/AgOTf) Grant, V. H.; Liu, B. Tetrahedron Lett.
2005, 46, 1237 and references therein. (d) (Yb(OTf)3) Sharma, G. V. M.;
Ilangovan, A.; Sreenivas, P.; Mahalingam, A. K. Synlett 2000, 615.
(e) (Pd(MeCN)2Cl2) Anjaneyulu, A. S. R.; Isaa, B. M. J. Chem. Soc., Perkin
Trans. 1 1991, 2089.
(6) For one-pot synthesis of benzofurans from â-haloallyl aryl ethers,
see: (a) Tao, Z.-F.; Qian, X.; Fan, M. Tetrahedron 1997, 53, 13329.
(b) Mali, R. S.; Pandhare, N. A.; Sindkhedkar, M. D. Tetrahedron Lett.
1995, 36, 7109. (c) Saisi, M. R. Hetereocycles 1982, 19, 1473.
10.1021/ol051264z CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/29/2005

1
of the crude reaction mixture by H NMR showed the
remainder of the material to be either products of ether
cleavage or uncyclized Claisen products, reaffirming our
initial worries that these side reactions would be problematic.
The formation of benzofuran instead of dihydrobenzofuran
suggested that â-hydride elimination had occurred, followed
by isomerization of the initially formed exocyclic olefin to
the thermodynamically preferred benzofuran. This indicated
that a stoichiometric oxidant would be required for the
catalytic conversion of 1 to 2. In accord with this hypothesis,
treatment of 1 with a catalytic amount of Pd(CH3CN)2Cl2
and a stoichiometric amount of 1,4-benzoquinone in
1,4-dioxane at room temperature for 5 h led to 2 in 54%
yield (Table 1, entry 3). In addition to Pd(CH3CN)2Cl2,
Pd(PhCN)2Cl2 served as an effective catalyst for this reaction
(Table 1, entry 4). Conversely, PtCl2, RuCl3, and other Pd-
(II) sources were not effective (Table 1, entries 5-9). It was
also found that 1,4-benzoquinone was the optimal oxidant
in this reaction system. We supposed that the addition of
base would promote the cyclization of the Claisen-derived
intermediate allylphenol, since the phenolic hydroxyl should
be deprotonated in order to act as nucleophile toward the
olefin fragment, either directly or through coordination to
Pd.3b-f,7 As expected, the inclusion of Na2CO3 provided
increased yield (Table 1, entry 10). Finally, increasing the
temperature to 65 °C led to the optimal result in the
presence of 5 mol % Pd(CH3CN)2Cl2, 1,4-benzoquinone, and
Na2CO3, providing benzofuran 2 in 66% yield (Table 1, entry
14).
Scheme 1. General Methods for Synthesis of Benzofurans and
Chromenes
of benzofurans by Claisen rearrangement and subsequent
oxidative cyclization of allyl aryl ethers and for the synthesis
of chromenes by direct oxidative cyclization of aryl homo-
allyl ethers.
We focused our initial efforts in this area on the one-pot
synthesis of benzofuran 2 from allyl aryl ether 1. Transition
metal complexes that were previously reported to either
promote Claisen rearrangement5 or facilitate the oxidative
cyclization of 2-allylphenols3c-f were included in the screen
(Table 1; for complete data, see Supporting Information).
Table 1. Optimization Studies for the Cyclization of
Compound 1a
With the establishment of a viable one-pot reaction system,
we set out to explore the scope of this sequential process.
As shown in Table 2, a variety of allyl aryl ethers underwent
tandem Claisen rearrangement/oxidative cyclization in the
presence of Pd(CH3CN)2Cl2 to form the corresponding
benzofurans.
en-
try
temp time yield
catalyst (mol %)
oxidant
base
(°C)
(h)
(%)b
1
2
3
4
5
6
7
8
9
Pd(MeCN)2Cl2 (100)
Pd(MeCN)2Cl2 (20)
Pd(MeCN)2Cl2 (20)
Pd(PhCN)2Cl2 (20)
Pd(OAc)2 (20)
Pd(PPh3)2Cl2 (20)
PdCl2 (20)
PtCl2 (20)
-
-
-
-
-
-
-
-
-
-
-
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
80
65
80
4
24
5
5
5
5
5
5
5
5
5
5
0.5
5
30
18
54
50
-
-
trace
-
-
60
trace
5
52
66
BQ
BQ
BQ
BQ
BQ
BQ
BQ
BQ
CuCl2
This method was compatible with functional groups such
as methoxy, methylenedioxy, and free hydroxyl. While
reactions of electron-rich arenes were facile, higher catalyst
loading and increased temperatures were required for rela-
tively electron-deficient arenes (Table 2, entry 2 and entries
4 and 5). It should be noted that in addition to producing
the desired benzofuran product 18, aryl crotyl ether 17
yielded a small amount of chromene product 19, which could
have formed through either direct oxidative coupling of the
arene to the alkene or 6-endo cyclization of the Claisen-
derived 2-(R-methylallyl)phenol. The former seems more
plausible, since 5-exo cyclization occurs predominantly over
6-endo in the PdII-catalyzed oxidative cyclization of
2-allylphenols.3c-f,8 This result prompted us to extend the
application of our catalytic system to the formation of
chromenes from aryl homoallyl ethers via direct oxidative
cyclization.
RuCl3 (20)
10 Pd(MeCN)2Cl2 (20)
11 Pd(MeCN)2Cl2 (20)
12 Pd(MeCN)2Cl2 (20)
13 Pd(MeCN)2Cl2 (10)
14 Pd(MeCN)2Cl2 (5)
15 Pd(MeCN)2Cl2 (2)
Na2CO3
Na2CO3
Cu(OAc)2 Na2CO3
BQ
BQ
BQ
Na2CO3
Na2CO3
Na2CO3
12
trace
a All reactions were carried out with catalyst, base (1 equiv), and oxidant
(1 equiv) in dioxane (0.015 M). b Determined by 1H NMR using trichloro-
ethylene as an internal standard.
Metal complexes were examined in a variety of solvents,
and the effects of oxidants and bases were studied. When
the reaction was carried out with a stoichiometric amount
of Pd(CH3CN)2Cl2 at room temperature, 1 was completely
consumed in 4 h and benzofuran 2 was formed in 30% yield,
presumably as a result of Pd-catalyzed Claisen rearrangement
followed by oxidative cyclization (Table 1, entry 1). Analysis
(7) (a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M.
Angew. Chem., Int. Ed. 2003, 42, 2892. (b) Beccalli, E. M.; Broggini, G.;
Paladino, G.; Pennoni, A.; Zoni, C. J. Org. Chem. 2004, 69, 5627.
(8) For a specific example of a 6-endo cyclization of 2-allylphenols,
see: Larock, R. C.; Wei, L.; Hightower, T. R. Synlett 1998, 522.
3356
Org. Lett., Vol. 7, No. 15, 2005

Scheme 2. Direct Oxidative Cyclization of 20a
Table 2. Pd-Catalyzed Benzofuran Synthesisa
a Pd(MeCN)2Cl2 (5 mol %), Na2CO3 (1 equiv), and BQ (1 equiv)
in dioxane (0.015 M) at room temperature. bDetermined by 1H NMR
using trichloroethylene as an internal standard.
We proceeded to explore the substrate scope of this new
method (Table 3). Several chromene derivatives could be
Table 3. Pd-Catalyzed Chromene Synthesisa
a All reactions were performed with Pd(MeCN)2Cl2, Na2CO3 (1 equiv),
and BQ (1 equiv) in dioxane (0.015 M) for 1-5 h. b Isolated yields.
c Performed with 5 mol % Pd(MeCN)2Cl2 at 65 °C. d Performed with
20 mol % Pd(MeCN)2Cl2 at 80 °C. e Performed with 25 mol %
Pd(MeCN)2Cl2 at 80 °C. f Performed with 10 mol % Pd(MeCN)2Cl2 at
80 °C. g Performed with 10 mol % Pd(MeCN)2Cl2 at 65 °C. h The ratios
1
were determined by H NMR of the mixture.
a All reactions were performed with Pd(MeCN)2Cl2, Na2CO3 (1 equiv),
and BQ (1 equiv) in dioxane (0.015 M) for 1-5 h. b Isolated yields.
c Performed with 5 mol % Pd(MeCN)2Cl2 at room temperature. d Performed
with 25 mol % Pd(MeCN)2Cl2 at 80 °C. e Performed with 20 mol %
Since palladium dichloride complexes are known to
catalyze olefin isomerization,9 we worried that, upon expo-
sure to the catalytic system we had developed for the tandem
Claisen rearrangement/oxidative cyclization, an aryl homo-
allyl ether such as 20 might simply isomerize to the aryl
crotyl ether 17 and then undergo conversion to a similar
mixture of products 18 and 19. To our delight, cyclization
of 20 at room temperature in the presence of Pd(CH3CN)2Cl2
gave chromene 19 in 77% yield without any detectable
amount of benzofuran 18 (Scheme 2).
1
Pd(MeCN)2Cl2 at 80 °C. f The ratios were determined by H NMR of the
mixture.
prepared from their corresponding aryl homoallyl ethers.
Higher catalyst loadings were required in similarly substituted
systems relative to the analogous benzofuran formation;
variations in the nucleophilicity of the arenes are reflected
in the catalytic demands, with less nucleophilic arenes
requiring higher catalyst loadings (Table 3, entries 2-6). The
(9) (a) Han, X.; Widenhoefer, R. A. J. Org. Chem. 2004, 69, 1738 and
references therein. (b) Reference 3d and references therein.
Org. Lett., Vol. 7, No. 15, 2005
3357

oxidative cyclization occurred with excellent regioselectivity
for unsymmetrically substituted substrates (Table 3, entries
2-5), and only the homoallyl naphthyl ether 27 gave a
significant amount of the regioisomeric exo-olefin.
Plausible mechanisms for both Pd-catalyzed cyclizations
presented herein are outlined in Scheme 3 and are based on
sequently, intramolecular cyclization proceeds via oxypalla-
dation.3c-f Coordination of the C-C π-bond by palladium
activates the olefin toward intramolecular nucleophilic attack3
by the phenolic oxygen, which is readily deprotonated by
the stoichiometric quantity of base.3b-f,7 Subsequent â-hy-
dride elimination produces Pd(H)Cl and the 2,3-dihydro-2-
methylene benzofuran, which isomerizes to the thermody-
namically stable 2-methylbenzofuran.3 Pd(H)Cl eliminates
HCl and forms Pd0, which is reoxidized by BQ to regenerate
the catalytically active Pd(II) species (Scheme 3a).
Scheme 3. Possible Mechanism for the Pd-Catalyzed
Cyclizations
Cyclization of the aryl homoallyl ether most likely
proceeds via carbopalladation, wherein activation of the
olefin by coordination to Pd(II) is followed by intramolecular
nucleophilic attack by the arene. Subsequent â-hydride
elimination forms Pd(H)Cl and the 4-methylenechromane,
which isomerizes to the thermodynamically favored 4-methyl-
chromene.4e Since no products derived from initial olefin
isomerization were detected in any of the reactions in Table
3, it is likely that attack of the arene on the Pd-complexed
olefin is fast relative to Pd-mediated olefin isomerization9
(Scheme 3b).
In summary, we have developed both a one-pot procedure
for the conversion of allyl aryl ethers to 2-methylbenzofurans
and a direct oxidative cyclization of aryl homoallyl ethers
to afford chromenes. Because a diverse range of allyl and
homoallyl aryl ethers can be easily prepared, these Pd-
catalyzed oxidative cyclizations represent an attractive means
for the facile construction of benzofuran and chromene ring
systems, which are pervasive motifs in biologically active
natural products and pharmaceutical drug targets. Although
the method is currently limited to electron-rich substrates,
we are exploring ways to broaden the scope of the reaction
to include other arenes, as well as acyclic substrates for the
synthesis of monocyclic heterocycles.
Acknowledgment. This work was supported by Korea
Research Foundation Grant (KRF-2004-003-C00118). We
acknowledge Professor Dalibor Sames of Columbia Univer-
sity for support of this work and intellectual contribution.
the Wacker oxidation mechanism.10 For allyl aryl ethers, the
Pd-complexed olefin first undergoes Claisen rearrangement5
to form the corresponding 2-allylphenol intermediate. Sub-
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(10) Ba¨ckvall, J. E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc.
1979, 101, 2411.
OL051264Z
3358
Org. Lett., Vol. 7, No. 15, 2005