Palladium-catalyzed direct arylation of 4-hydroxycoumarins with arylboronic acids via C-OH bond activation

Article abstract of DOI:10.1016/j.tetlet.2009.02.116

Operationally simple PdCl₂-catalyzed direct arylation of 4-hydroxycoumarins with arylboronic acids via C-OH bond activation under mild conditions is described, which gave rise to the corresponding 4-arylcouamrins in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.02.116

Tetrahedron Letters 50 (2009) 2103–2105
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed direct arylation of 4-hydroxycoumarins
with arylboronic acids via C–OH bond activation
Yong Luo a, Jie Wu a,b,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Operationally simple PdCl2-catalyzed direct arylation of 4-hydroxycoumarins with arylboronic acids via
C–OH bond activation under mild conditions is described, which gave rise to the corresponding 4-aryl-
couamrins in good to excellent yields.
Received 18 December 2008
Revised 10 February 2009
Accepted 17 February 2009
Available online 21 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Arylboronic acid
4-Hydroxycoumarin
Palladium chloride
C–OH bond activation
The transition metal-catalyzed cross-coupling reactions are
known to be a powerful tool for C–C bond formations.1 Tradition-
ally, these cross-coupling reactions rely on the use of pre-activated
substrates, such as organic (pseudo)halides. Recently, the first
palladium-catalyzed cross-coupling reactions via C–OH bond
activation of tautomerizable heterocycles with arylboronic acids
utilizing phosphonium salts as activation reagent were reported.
In this Letter, Kang disclosed that the presence of phosphonium
salt enabled an in situ activation of tautomerizable heterocycle,
which then underwent the subsequent palladium-catalyzed
cross-coupling reactions with arylboronic acids.2 Usually, this
methodology required a separate pre-formation of the correspond-
ing heterocycle-phosphonium salt electrophile in the absence of
the palladium catalyst. In addition, high temperature was required
in the reaction process. Very recently, Ackermann reported that
phenols could be employed as proelectrophiles in ruthenium-cata-
lyzed dehydrative direct arylations, proceeding through chemo-
and regioselective functionalizations of C–H and C–OH bonds.3 As
part of a continuing effort in our laboratory toward the develop-
ment of new methods for cross-coupling reactions and their appli-
cation in the synthesis of natural product-like compounds,4 we
became interested in developing novel and efficient method to
construct the diverse coumarins and related heterocycles.5 It is
well known that coumarins as a privileged scaffold show interest-
ing biological properties.6,7 Continuous efforts toward their syn-
thesis have been reported due to the prominence of coumarins in
natural products and biologically active molecules.8–10 Recently,
we also discovered that 4-substituted coumarins showed good
anti-HCV (hepatitis C virus) activity.11 With a hope for finding
promising lead antivirus compounds by evaluations of analogous
structures, we developed an efficient method for rapid syntheses
of diverse coumarins. Herein, we would like to disclose our recent
efforts for the synthesis of 4-arylcouamrins via palladium-cata-
lyzed direct arylation of 4-hydroxycoumarins with arylboronic
acids. This C–OH bond activation is highly effective under mild
conditions.
At the outset, a set of experiments were carried out using 4-
hydroxycoumarin 1a and 4-methylphenylboronic acid 2a as model
substrates. We reasoned that the presence of arenesulfonyl chlo-
ride would enable an in situ activation of 4-hydroxycoumarin sub-
strates. Based on these considerations, the reactions were
performed in the presence of different palladium catalysts, base,
and p-toluenesulfonyl chloride (Scheme 1). Only a trace amount
of product 3a was detected when the reaction was catalyzed by
PdCl2(PPh3)2 (5 mol %) in the presence of Na2CO3 as base in THF
B(OH)2
OH
O
C6H4p-Me
[Pd] (5 mol %)
+
TsCl, solvent
base, 60 ºC
O
O
O
CH3
3a
1a
2a
* Corresponding author. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.116

2104
Y. Luo, J. Wu / Tetrahedron Letters 50 (2009) 2103–2105
Table 1
minary optimized conditions [PdCl2 (5 mol %), Na2CO3, TsCl, THF–
H2O, 60 °C]. The results are summarized in Table 1. To assess the
impact of the structural and functional motifs on the reaction,
we tested a range of linking units between 4-hydroxycoumarins
and arylboronic acids. For all cases, 4-hydroxycoumarin 1 reacted
with arylboronic acid 2 leading to the corresponding products 3
in good to excellent yields. For instance, reaction of 4-hydroxy-
coumarin 1a with 4-methoxyphenylboronic acid 2b under the
standard conditions gave rise to the desired product 3b in 98%
yield (Table 1, entry 2). Similar yield was obtained when phenylbo-
ronic acid 2c was utilized as coupling partner (Table 1, entry 3, 91%
yield). Reaction of 4-hydroxycoumarin 1a and arylboronic acid
with electron-withdrawing group attached on the aromatic ring
also proceeded well to afford the desired product in good yield (Ta-
ble 1, entries 4–7). It seems that the group attached on the aro-
matic ring of arylboronic acid 2 does not effect the reaction
markedly. Other 4-hydroxycoumarins were also examined. 4-Hy-
droxy-6-methylcouamrin 1b reacted with phenylboronic acid 2c
leading to the desired product 3h in 92% yield (Table 1, entry 8).
6,7-Dimethyl-4-hydroxycoumarin 1c was also good substrate in
the reaction of arylboronic acids, and the corresponding products
were generated in good yields (Table 1, entries 9–11). Reactions
of fluoro- or chloro-substituted 4-hydroxycoumarin with different
arylboronic acids proceeded well to give rise to the desired prod-
ucts in good yields (Table 1, entries 12–17).
Palladium-catalyzed direct arylation of 4-hydroxycoumarin 1 with arylboronic acid
212
OH
R2
O
PdCl2 (5 mol %)
R2 B(OH)2
R1
R1
+
O
THF-H2O, Na2CO3
TsCl, 60 ºC
O
1
O
2
3
Entry
Coumarin 1
R2
Yield (%)a
OH
1
2
3
4
5
6
7
8
4-MeC6H4 (2a)
4-MeOC6H4 (2b)
C6H5 (2c)
98 (3a)
98 (3b)
91 (3c)
88 (3d)
68 (3e)
90 (3f)
52 (3g)
92 (3h)
O
O 1a
1a
1a
1a
1a
1a
1a
2-ClC6H4 (2d)
3-NO2C6H4 (2e)
3-NCC6H4 (2f)
4-CF3C6H4 (2g)
C6H5 (2c)
In conclusion, we have described an efficient route for the syn-
thesis of 4-arylcouamrins via palladium-catalyzed direct arylation
of 4-hydroxycoumarins with arylboronic acids. This C–OH bond
activation is highly effective under mild conditions. The focused li-
brary generation and screening for biological activity of these small
molecules are under investigation in our laboratory, and the results
will be reported in due course.
OH
O
O
O
1b
1c
OH
9
10
11
12
13
14
15
16
4-MeOC6H4 (2b)
C6H5 (2c)
98 (3i)
94 (3j)
80 (3k)
97 (3l)
88 (3m)
54 (3n)
96 (3o)
87 (3p)
90 (3q)
Acknowledgments
O
1c
Financial support from National Natural Science Foundation of
China (20772018), Shanghai Pujiang Program, and Program for
New Century Excellent Talents in University (NCET-07-0208) is
gratefully acknowledged.
1c
2-ClC6H4 (2d)
4-MeOC6H4 (2b)
C6H5 (2c)
OH
Cl
References and notes
O
O
1d
1d
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a
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12. General experimental procedure for palladium-catalyzed direct arylation of 4-
hydroxycoumarin 1 with arylboronic acid 2: A solution of 4-hydroxycoumarin 1
(0.3 mmol), p-toluenesulfonyl chloride (0.33 mmol, 1.1 equiv), ArB(OH)2
(0.36 mmol, 1.2 equiv), Na2CO3 (0.9 mmol, 3.0 equiv), and PdCl2 (5 mol %) in
H2O/THF (1:20, 2.1 mL) was stirred at 60 °C for period of time. After
2
a
completion of the reaction as indicated by TLC, the solvent was diluted with
EtOAc (10 mL), washed with saturated NaCl (10 Â 2 mL), and dried by
anhydrous Na2SO4. Evaporation of the solvent followed by purification on
silica gel provided the corresponding compound 3. Selected example: 4-
phenylcoumarin (3c): 1H NMR (500 MHz, CDCl3) d (ppm) 6.41 (s, 1H), 7.20–
7.30 (m, 2H), 7.40–7.60 (m, 7H). 13C NMR (125.7 MHz) d (ppm) 161.0, 155.9,
154.5, 135.5, 132.2, 129.9, 129.1, 128.7, 127.3, 124.4, 119.3, 117.6, 115.5. m/z
(M++1): 223.