Synthesis of 9-substituted xanthenes by the condensation of arynes with ortho-hydroxychalcones

Article abstract of DOI:10.1016/j.tetlet.2012.02.072

The reaction of o-(trimethylsilyl)aryl triflates, CsF, and o-hydroxychalcones affords a general and efficient way to prepare biologically interesting 9-substituted xanthenes. This chemistry presumably proceeds by the tandem intermolecular nucleophilic att

Full text of DOI:10.1016/j.tetlet.2012.02.072

Tetrahedron Letters 53 (2012) 2202–2205
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Tetrahedron Letters
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Synthesis of 9-substituted xanthenes by the condensation of arynes with
ortho-hydroxychalcones
⇑
Chun Lu, Anton V. Dubrovskiy, Richard C. Larock
Department of Chemistry, Iowa State University, Ames, IA 50011, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 12 July 2010
Revised 13 February 2012
Accepted 15 February 2012
Available online 25 February 2012
The reaction of o-(trimethylsilyl)aryl triflates, CsF, and o-hydroxychalcones affords a general and efficient
way to prepare biologically interesting 9-substituted xanthenes. This chemistry presumably proceeds by
the tandem intermolecular nucleophilic attack of the phenoxide of the chalcone on the aryne and subse-
quent intramolecular Michael addition. The introduction of an external base, Cs2CO3, has proven benefi-
cial in this reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Arynes
ortho-Hydroxychalcones
Nucleophilic
Michael addition
Cesium carbonate
Herein, we wish to present a novel route to 9-substituted
xanthenes in a simple one step process under mild reaction condi-
tions starting from readily available o-hydroxychalcones.1 During
the course of our work, related chemistry has been reported by
Huang et al.2 While the Huang protocol allows one to efficiently
obtain xanthenes and acridine derivatives, our work has focused
on the scope and limitations of this process. Also, our procedure al-
lows one to obtain the desired products in an operationally simpler
way using shorter reaction times.
most of these synthetic approaches involve either multistep proce-
dures or fairly harsh reaction conditions.
Since a convenient approach to aryne generation by the fluo-
ride-induced 1,2-elimination of o-(trimethylsilyl)aryl triflates was
first reported in 1983,12 the reactivity of arynes, especially their
electrophilicity, has been explored extensively. For example, in
our group, in situ generated benzyne has been coupled with simple
nucleophiles, such as amines, sulfonamides, phenols, and arene-
carboxylic acids,13 to generate monosubstituted arenes. Besides
those simple coupling reactions, insertion processes (Scheme 1)
have been reported for nucleophiles bearing neighboring electro-
philes, such as ureas,14 keto esters,15 amides,15 sulfonamides,16
and acid halides.17
We have been particularly interested in annulation processes,
which rapidly construct the biologically-interesting ring systems
by simple tandem processes. For example, we have reported that
salicylates and in situ generated arynes readily react to form het-
eroatom ring systems, such as xanthones, thioxanthones, and acri-
dones (Scheme 2).18
From some of the oldest known dyes3 to newly developed
agriculturally- and pharmaceutically-interesting intermediates,4
xanthenes have attracted attention for decades and continue to
be the focus of biological and material science studies today.
Many naturally-occurring and man-made xanthene derivatives
have been reported to exhibit extraordinary biological activities,
including anti-malarial,5 anti-trypanosomal,6 anti-leishmanial,6
and anti-tumor7 activities. More recently, the notable fluorescent
properties of xanthenes have received attention. For example, xan-
thene derivatives have been prepared as fluorescent probes,8 and
electrostatic sensors.9
Herein, we present
a novel coupling reaction between
The synthesis of xanthene derivatives has also been widely
studied. There are several well established approaches to xanthene
derivatives,10 which typically feature the formation of the central
heterocyclic ring, often by the combinations of Friedel–Crafts
methodology and C–O bond formation. Xanthenes can also be ob-
tained by reduction of the corresponding xanthones.11 However,
o-hydroxychalcones and o-(trimethylsilyl)aryl triflates, which pro-
vides a new method for the synthesis of 9-substituted xanthenes in
a simple one step process under very mild reaction conditions.
Nu
Nu
E
Nu
E
+
E
⇑
Corresponding author. Tel.: +1 515 294 4660; fax: +1 515 294 0105.
E-mail address: larock@iastate.edu (R.C. Larock).
Scheme 1. Aryne insertion reactions.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.072

C. Lu et al. / Tetrahedron Letters 53 (2012) 2202–2205
2203
O
X
CO2R2
XH
TfO
CsF
R3
TMS
R1
R1
R3
+
X = O, S, NR
Scheme 2. Synthesis of xanthones and analogues using arynes.
Table 1
Optimization studiesa
O
O
Ph
O
OTf
Ph
Ph
+
+
O
OH
1a
TMS
OPh
2a
3a
4a
Entry
CsF (equiv)
Solvent
Temp (oC)
Additive (equiv)
% Yieldb 3a (4a)
1
2
3
4
5
6
7
2.0
MeCN
THF
THF
THF
THF
THF
THF
rt
rt
rt
65
65
65
65
—
—
—
—
—
—
32 (68)
17 (65)
Traced
60 (17)
67
2.0 TBAFc
2.0
2.0
3.0
5.0
3.0
74
80
1.0 Cs2CO3
a
Reactions were conducted on a 0.25 mmol scale with 1.2 equiv of 2a in 10 ml of solvent for 24 h.
Yields of products isolated by column chromatography.
TBAF (1 M in THF).
b
c
d
Very low conversion.
Our optimization work was carried out using commercially
available o-hydroxychalcone 1a and o-(trimethylsilyl)phenyl
triflate (2a) under variety of different reaction conditions
phenoxide anions bearing electron-withdrawing groups can be
generated in substantial amounts when Cs2CO3 is present, which
favors the formation of the side product (see the mechanistic
discussion).
a
(Table 1). We first examined some commonly used benzyne reac-
tion conditions, namely MeCN with added CsF (entry 1), and THF
with TBAF19 (entry 2). Not surprisingly, our initial studies indicated
that significant amounts of the corresponding phenyl ether 4a
were generated alongside 3a, which was produced in only a low
yield. When employing CsF in THF (entry 3), although the reaction
proceeded in very low conversion, the desired product 3a was gen-
erated as the major product, which suggested that THF was able to
suppress proton abstraction.16 By raising the temperature to 65 °C
(entry 4), the reaction could be completed in 24 h and 60% yield
was produced. Interestingly, we observed that as the amount of
the base CsF added to the system was increased (entries 5 and
6), the yield improved. Finally, with the addition of 1 equiv of
Cs2CO3 (entry 7), the yield was improved to 80%. Other bases, such
as Li2CO3 and K2CO3, were also tested, but none of them was as
effective as Cs2CO3. Thus, the reaction conditions reported in entry
7 (3 equiv of CsF, 1 equiv of Cs2CO3 in THF solvent at 65 °C) were
chosen as our optimal conditions for further study.
We next examined a wide range of o-hydroxychalcones bearing
various functional groups (Table 2). Chalcones with electron-
donating methoxy (entry 2) and methyl (entry 3) substituents
provided decent yields, 74% and 64%, respectively. A fluoro-
substituted chalcone (entry 4) also afforded good results. Sub-
strates with other electron-withdrawing groups, such as I (entry
5), Br (entry 6), and NO2 (entry 7) groups, resulted in much lower
yields under our ‘optimal’ conditions. However, by simply remov-
ing the Cs2CO3 base (1.2 equiv of 2a, 3.0 equiv of CsF, THF, 65 °C),
the yields can be improved significantly. This is probably because
The effect of the group X on the carbon–carbon double bond has
also been examined. Decent yields were provided by substrates
with different acyl groups (entries 8–12). Aldehyde (entry 13)
and cyano (entry 14) groups are also tolerated. For the substrate
with an ester group (entry 15), an inseparable mixture of the de-
sired product and arylation side product was generated. For rea-
sons that are not obvious, a sulfonyl group does not activate the
Michael acceptor sufficiently in this chemistry to produce a good
yield. The use of additional benzyne precursor, a lower tempera-
ture, and a longer reaction time was necessary to get a decent yield
(entry 16).
The behavior of the aryne precursors 2b, 2c, and 2d (Table 3)
has also been examined in this reaction. All of these substrates
generated lower yields than benzyne itself, perhaps due to slower
aryne generation. We have observed that aryne precursor 2d af-
fords a single isomeric product 3s. This regioselectivity for 3-meth-
oxybenzyne has been seen previously in our group and by
others.11a,20
Based on the experimental results and previous studies,11,16 we
postulate that this coupling reaction proceeds in the following
manner (Scheme 3). The intermediate C generated from nucleo-
philic coupling of the aryne and the aryl oxide undergoes intramo-
lecular Michael addition to afford the desired xanthene B after
protonation.
However, well known proton abstraction by C could lead to dia-
ryl ether A, which has been observed by us as the major side prod-
uct for most of the substrates examined in this reaction. Since the

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C. Lu et al. / Tetrahedron Letters 53 (2012) 2202–2205
Table 2
Reaction scope with different chalcone derivativesa
X
3.0 CsF
R
R
X
TfO
1.0 Cs2CO3
+
1.2
65 º
O
OH
C, THF
TMS
1a
2a
3
Entry
Chalcone
R
X
Product/yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
H
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)C6H4(OMe)-p
C(O)C6H4I-p
C(O)Me
C(O)t-Bu
C(O)C6H11
CHO
CN
CO2t-Bu
SO2Ph
3a/80
3b/74
3c/64
3d/84
OMe
Me
F
I
3e/60 (78)c
3f/58 (75)c
3g/41 (70)c
3h/61
Br
NO2
H
H
H
H
H
H
H
3i/73
3j/71
3k/65
3l/64
3m/60
3n/70
H
H
3o/60d
3p/15 (51)e
a
b
c
Reactions were conducted on a 0.25 mmol scale for 24 h.
Yields of products isolated by column chromatography.
Reactions were conducted with 1.2 equiv of 2a, 3.0 equiv of CsF and THF (10 ml) at 65 oC.
1H NMR spectroscopic yield.
d
e
This reaction was conducted with 2.0 equiv of 2a, 3.0 equiv of CsF and THF (10 ml) at 45 oC for 30 h.
Table 3
Reaction with different benzyne precursorsa
O
O
Ph
3.0 CsF
1.0 Cs2CO3
TfO
Ph
R
R
+
OH
65 ºC, THF
TMS
O
2
3
1a
Entry
1
Aryne precursor
Product/yield (%)b
Me
OTf
2b
2c
3q/51
3r/46c
Me
MeO
TMS
OTf
2
3
MeO
OMe
TMS
O
TMS
OTf
OMe
Ph
2d
3s/57
O
a
b
c
Reactions were conducted on a 0.25 mmol scale for 24 h in 10 ml of THF.
Yields of products isolated by column chromatography.
The reaction time was 48 h.

C. Lu et al. / Tetrahedron Letters 53 (2012) 2202–2205
2205
O
Ph
O
O
TfO
CsF
Ph
Ph
+
+
O
OH
TMS
OPh
A
B
-
+
O
O Cs
O
+
Ph
Ph
Michael
Addition
Ph
+
-
+
-
O Cs
Cs
O
O
C
Scheme 3. Possible mechanism.
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proton abstraction of C is quite fast, a competition is present be-
tween intramolecular cyclization and intermolecular proton
abstraction. In order to suppress this side reaction, dry reaction
conditions and the addition of an extra base are necessary. This
helps to remove the acidic protons present before intermediate C
is able to react with the proton and generate the side product A.
In conclusion, we have demonstrated that o-hydroxychalcones
and related compounds undergo annulation reactions with o-(tri-
methylsilyl)aryl triflates through tandem nucleophilic coupling
and subsequent Michael addition. This reaction affords a general
one-pot approach to 9-substituted xanthenes from readily pre-
pared starting materials. Mild reaction conditions allow a variety
of functional groups to be tolerated in this reaction. With carbonyl
and other functionalities in the products, further elaboration can
easily be achieved.
Acknowledgments
We gratefully acknowledge the financial support of this work
by the Kansas University NIH Center of Excellence in Chemical
Methodology and Library Development (P50 GM069663).
Supplementary data
Supplementary data (experimental procedure and characteriza-
tion data) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2012.02.072.
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