Iron-catalyzed, microwave-promoted, one-pot synthesis of 9-substituted xanthenes by a cascade benzylation-cyclization process

Article abstract of DOI:10.1021/ol902489a

"Chemical Equation Presented" An efficient iron-catalyzed, microwave-promoted cascade benzylation-cyclization of phenols is reported. Benzyl acetates, benzyl bromides, and benzyl carbonates are suitable benzylating reagents. The reactions proceed to afford both 9-aryl and 9-alkyl xanthene derivatives in good to high yields using FeCI3 as the catalyst under MW irradiation conditions

Full text of DOI:10.1021/ol902489a

ORGANIC
LETTERS
2010
Vol. 12, No. 1
100-103
Iron-Catalyzed, Microwave-Promoted,
One-Pot Synthesis of 9-Substituted
Xanthenes by a Cascade
Benzylation-Cyclization Process
Xiaobing Xu, Xiaolei Xu, Hongfeng Li, Xin Xie, and Yanzhong Li*
Institute of Medicinal Chemistry, Department of Chemistry, East China Normal
UniVersity, 3663 North Zhongshan Road, Shanghai 200062, P. R. China
yzli@chem.ecnu.edu.cn
Received October 28, 2009
ABSTRACT
An efficient iron-catalyzed, microwave-promoted cascade benzylation-cyclization of phenols is reported. Benzyl acetates, benzyl bromides,
and benzyl carbonates are suitable benzylating reagents. The reactions proceed to afford both 9-aryl and 9-alkyl xanthene derivatives in good
to high yields using FeCl3 as the catalyst under MW irradiation conditions.
Direct C-H functionalization catalyzed by transition metals
has become an important topic in organometallic chemistry.
This method represents one of the most effective and atom-
economical routes for C-C bond-forming reactions. The
catalysts employed in these processes are usually expensive
metals such as Ru, Rh, Pt, Pd, Au, etc.1,2 In recent years,
the development of sustainable, environmentally friendly, and
low-cost C-C bond-forming protocols attracted much at-
tention in synthetic organic chemistry. As a result, several
excellent works concerning direct C-C bond-forming reac-
tions catalyzed or mediated by iron have been reported, for
example, the benzylation of arenes and heteroarenes,3 the
arylation of 2-arylpyridines,4 and the direct functionalization
of a C-H bond adjacent to a heteroatom,5 as a result of the
unique properties of iron catalysts, such as low price, less
toxicity, and ease of synthesis. Our group6 and others7 reported
the iron-catalyzed C-H activation of terminal alkynes. During
the course of our ongoing study on the development of
transition-metal-mediated heterocycle-forming protocols,8 we
found that xanthenes could be efficiently prepared using iron
catalyst under microwave irradiation conditions.
Xanthenes are important classes of compounds as they are
useful biologically active molecules;9 they can also be used
as dyes and fluorescent materials.10 There have been various
(3) (a) Iovel, I.; Mertins, K.; Kischel, J.; Zapf, A.; Beller, M. Angew.
Chem., Int. Ed. 2005, 44, 3913. (b) Mertins, K.; Iovel, I.; Kischel, J.; Zapf,
A.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 238. (c) Mertins, K.; Iovel,
I.; Kischel, J.; Zapf, A.; Beller, M. AdV. Synth. Catal. 2006, 348, 691.
(4) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858.
(1) Dyker, G. Handbook of C-H Transformations; Wiley-VCH: Wein-
heim, 2005
.
(2) (a) Roesky, P. W. Angew. Chem., Int. Ed. 2009, 48, 2. (b) Li, C.-J.
Acc. Chem. Res. 2009, 42, 335. (c) Bergman, R. G. Nature 2007, 446, 391.
(d) Campos, K. R. Chem. Soc. ReV. 2007, 36, 1069. (e) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f) Alberico, D.; Scott,
M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (g) Godula, K.; Sames, D.
Science 2006, 312, 67. (h) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV.
2002, 102, 1731. (i) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (j)
(5) (a) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 1. (b) Li,
Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 6505.
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Lett. 2008, 10, 5341. (b) Kohno, K.; Nakagawa, K.; Yahagi, T.; Choi, J.-
C.; Yasuda, H.; Sakakura, T. J. Am. Chem. Soc. 2009, 131, 2784.
Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997, 97, 2879
.
10.1021/ol902489a  2010 American Chemical Society
Published on Web 11/25/2009

procedures for the synthesis of xanthenes;8f,11-14 elegant
examples include: inter- or intramolecular trapping of arynes
by phenols or aldehydes,11 Pd-catalyzed cyclization of
polycyclic aryltriflate esters,12 Yb-catalyzed reaction of
ꢀ-naphthol and aldehydes,13 and the reaction of 2-tetralone
and salicylaldehydes under acidic conditions.14a Although
these methods are efficient for the synthesis of xanthenes,
the application scope is limited to the synthesis of either
9-aryl- or 9-alkyl-substituted xanthenes. Therefore, the
development of a general procedure for the synthesis of both
9-aryl- and 9-alkyl-substituted xanthenes is highly desired.
In addition, the advantages of microwave-assisted synthesis
have been widely recognized,15 such as dramatically reducing
reaction times, less or no toxic waste generation and higher
yields. Herein we would like to present our results of the
iron-catalyzed, microwave-promoted cascade benzylation-
cyclization of phenols for the synthesis of 9-substituted
xanthenes.
We started our investigation with 1-(2-bromophenyl)ethyl
acetate (1a), which was synthesized according to the reported
method.16 The reaction of 1a with 4-methyl phenol (2a) was
selected as a model reaction to screen the experimental
conditions. Selected results are summarized in Table 1. First,
the reaction was carried out using 5 mol % of FeCl3 as
catalyst under microwave irradiation at 50 °C. We were
happy to see that the benzylation reaction was completed in
10 min. After the mixture cooled to room temperature, DMF
and Cs2CO3 (5.0 equiv) were added. The resulting reaction
mixture was kept for another 10 min under microwave
irradiation at 130 °C, and the desired xanthene 3a was formed
Table 1. Optimization of Reaction Conditions for the One-Pot
Synthesis of 3a
entry
catalyst (mol %)
base (equiv)
yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
FeCl3 (5)
FeCl3 (5)
FeCl3 (5)
Cs2CO3 (5.0)
Cs2CO3 (5.0)
Cs2CO3 (4.0)
Cs2CO3 (5.0)
Cs2CO3 (4.0)
Cs2CO3 (5.0)
K2CO3 (5.0)
KOH (5.0)
tBuOK (5.0)
Cs2CO3 (5.0)
Cs2CO3 (5.0)
Cs2CO3 (5.0)
Cs2CO3 (5.0)
Cs2CO3 (5.0)
75
46b
39
72
39
trace
c
trace
c
c,d
e
FeCl3 (10)
FeCl3 (10)
FeCl3 (2)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
FeCl3 (10)
BF3·Et2O (5)
HCl (5)
f
trace
10
TsOH·H2O (5)
a Yields were determined by GC after hydrolysis, and unless otherwise
noted, the benzylation reaction was carried out under solvent-free conditions.
b Reactions were carried out without the MW irradiation: benzylation at 50
°C for 1 h, then cyclization at 130 °C for 9 h. c Only benzylation product
was obtained. d Reactions were carried out in DCM. e Reactions were carried
out in DMF, and a trace amount of benzylation product was detected. f The
reaction system was complicated.
in 75% yield (Table 1, entry 1). Controlled experiments
without the microwave irradiation afforded xanthene 3a in
only 46% yield (Table 1, entry 2). Less Cs2CO3 (4.0 equiv)
gave much lower yield of the product (Table 1, entry 3).
When 10 mol % of FeCl3 was used, the product yield was
similar to that of 5 mol % (Table 1, entry 4). Two mole
percent of FeCl3 resulted in trace amount of the desired
product (Table 1, entry 6). Switching to other bases such as
K2CO3, KOH, and tBuOK gave only benzylation product or
very low yields of the xanthene (Table 1, entries 7-9). It is
interesting to note when solvents such as DCM or DMF were
used from the benzylation step, there was almost no
formation of xanthene 3a (Table 1, entries 10 and 11). In
the presence of catalytic amounts of various acids (BF3·Et2O,
HCl, TsOH·H2O) the desired product 3a was obtained in low
yields (Table 1, entries 12-14). It was clear that the
optimized reaction condition was to use 5 mol % of FeCl3
as the catalyst under microwave irradiation, followed by the
addition of Cs2CO3 as the base and DMF as the solvent for
the subsequent cyclization.
Having established an effective catalytic system for the
one-pot synthesis of xanthenes, we next examined the
reaction of a variety of benzyl acetates and phenols to explore
the scope of the cascade benzylation-cyclization reaction
under the optimized conditions. The representative results
are shown in Table 2. The reaction was applicable to various
benzyl acetates and phenols. Acetates with an alkyl group
at the benzylic position reacted smoothly with various
phenols to afford 9-alky-substituted xanthenes. For example,
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Liu, J.; Yan, B.; Li, Y. Tetrahedron Lett. 2009, 50, 2353. (f) Li, H.; Yang,
J.; Liu, Y.; Li, Y. J. Org. Chem. 2009, 74, 6797. (g) Li, E.; Xu, X.; Li, H.;
Zhang, H.; Xu, X.; Yuan, X.; Li, Y. Tetrahedron 2009, 65, 8961
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G.; Uchida-Ernouf, G.; Lacroix, R. Eur. J. Med. Chem. 1978, 13, 67. (b)
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M.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049. (d)
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Org. Lett., Vol. 12, No. 1, 2010
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Table 2. Synthesis of Xanthenes from the Reaction of Phenols
and Benzyl Acetates
Table 3. Synthesis of Xanthenes from the Reaction of Phenols
with Benzyl Bromides and Carbonates
a Isolated yields.
with various substitutes could also be employed in the
xanthene forming reaction. 2,4-Dimethyl phenol (2b) reacted
with 1a smoothly to produce 3e in 70% yield (Table 2, entry
5). Even deactivated phenols such as 4-chlorophenol (2d) and
4-bromophenol (2e) furnished the xanthenes in 77% (3g) and
60% (3h) yields, respectively (Table 2, entries 7 and 8).
Likewise, the reaction of naphthalen-2-ol (2c) with 1a led to
the expected xanthene 3f in 40% yield (Table 2, entry 6).
To further probe the scope and limitations of this process,
we also examined other benzylating reagents under the
optimized reaction conditions (Table 3). As shown in Table
3, in addition to benzyl acetates, benzyl bromides and benzyl
carbonates are also suitable for the benzylation-cyclization
reaction. Benzyl bromides with a methyl or a phenyl at the
benzylic position reacted with phenols to give good yields
of the desired xanthenes (Table 3, entries 1-4). When 1-(2-
bromophenyl)ethyl ethyl carbonate (5a) was used, in all cases
the corresponding products were obtained in good yields (60
-67%, Table 3, entries 5-7). (2-Bromophenyl)(phenyl)m-
ethyl ethyl carbonate (5b) yielded the desired 3d in 51%
yield (Table 3, entry 8). When benzyl alcohol such as 1-(2-
bromophenyl)ethanol was used as benzylating reagent, it
reacted with 4-methyl phenol (2a) to afford the desired
xanthene 3a in only 29% yield.
a Isolated yields. b Cy ) cyclohexyl.
benzylating agents such as 1-(2-bromophenyl)ethyl acetate
(1a), 2-bromobenzyl acetate (1b), and 1-(2-bromophenyl-
)propyl acetate (1c) reacted with 4-methylphenol (2a) to give
the corresponding 9-alkyl xanthene derivatives in good yields
(Table 2, entries 1-3). When acetates with a cyclohexyl
group at the benzylic position (1e) were used, the cyclized
product was obtained in 73% yield (Table 2, entry 10). More
interestingly, the reaction of 1e and deactivated phenol 2d
could also proceed to give the desired xanthene in moderated
yield (Table 2, entry 11). Acetates with an aryl group at the
benzylic position were also suitable substrates. Reaction of
(2-bromophenyl)(phenyl)methyl acetate (1d) and 2a fur-
nished the desired 3d in 66% yield (Table 2, entry 4). Acetate
bearing a p-tolyl group, 1f, reacted with 4-methylphenol (2a)
and halophenols 2d and 2e to afford the corresponding
xanthenes in good yields (Table 2, entries 12-14). Phenols
In summary, we have reported an efficient iron-catalyzed,
microwave-promoted cascade benzylation-cyclization of
phenols and a variety of benzylating reagents such as benzyl
102
Org. Lett., Vol. 12, No. 1, 2010

acetates, benzyl bromides, and benzyl carbonates. The
reactions proceed to afford both 9-aryl and 9-alkyl xanthene
derivatives in good to high yields using FeCl3 as the catalyst
with the assistance of MW irradiation. Further application
of this novel iron-catalyzed cascade benzylation-cyclization
procedure to extend the scope of synthetic utility of the
reaction are under progress in our group.
for financial support. We also thank the Laboratory of
Organic Functional Molecules, the Sino-French Institute of
ECNU for support.
Supporting Information Available: Experimental details
and spectroscopic characterization of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (nos. 20572025 and 20872037)
OL902489A
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