An efficient route to 4-aryloxycoumarins via one-pot reactions of 4-hydroxycoumarins with hypervalent iodine reagents

Article abstract of DOI:10.1016/j.tetlet.2017.09.021

Highly efficient reactions of 4-hydroxycoumarin with hypervalent iodine reagents under mild conditions are described, which give rise to 4-aryloxycoumarins in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2017.09.021

Accepted Manuscript
An efficient route to 4-aryloxycoumarins via one-pot reactions of 4-hydroxy-
coumarins with hypervalent iodine reagents
Wei Gao, Linchu Xu, Chun Gong, Qiuping Ding, Yiyuan Peng
PII:
S0040-4039(17)31138-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.09.021
TETL 49291
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
8 August 2017
10 September 2017
12 September 2017
Please cite this article as: Gao, W., Xu, L., Gong, C., Ding, Q., Peng, Y., An efficient route to 4-aryloxycoumarins
via one-pot reactions of 4-hydroxycoumarins with hypervalent iodine reagents, Tetrahedron Letters (2017), doi:
http://dx.doi.org/10.1016/j.tetlet.2017.09.021
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Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
An efficient route to 4-aryloxycoumarins via one-pot reactions of
4-hydroxycoumarins with hypervalent iodine reagents
Wei Gao,a, b Linchu Xu,b Chun Gong,b Qiuping Ding,a Yiyuan Peng*a
aKey Laboratory of Functional Small Organic Molecules, Ministry of Education, Jiangxi Province’s Key Laboratory of Green
Chemistry, and Jiangxi Normal University, Nanchang, Jiangxi 330022, China.
bJiangxi academy of forestry, Nanchang, Jiangxi 330013, China.
Abstract—Highly efficient reactions of 4-hydroxycoumarin with hypervalent iodine reagents under mild conditions are described, which
give rise to 4-aryloxycoumarins in good to excellent yields. © 2017 Elsevier Science. All rights reserved
Aryl ethers is one of the most prevalent heterocyclic
compounds.1 It is present as key element of numerous
drugs, designed cosmetics and natural products.2 The
formation of aryl-O bond is an challenging task in synthetic
chemistry.3 Traditionally, the nucleophilic substitution
reactions of phenols with aryl halides are the straight
forward ways to form aryl-O bond. However, these
reactions suffer from harsh reaction conditions such as the
requirement of stoichiometric amount of copper catalyst,
high reaction temperature, and long reaction time with low
yield.4 Therefore, many efforts have been devoted to
prepare these aryl ethers starting from simple precursors.5,6
Concurrently, various readily accessible reagents such as
N-donors, N- and O-donors and P-based ligands have been
used to carry out in Cu-catalyzed Ullmann coupling
reactions.7 These protocols proceeded well, but again, the
high cost of ligands and the use of a strong base are still the
main problems to be overcome. Thus, the development of
milder reaction conditions with base- and ligand-free
catalytic systems for this transformation is highly desirable.
It is well-known that (diacetoxyiodo)benzene as an
hypervalent iodine reagent has been widely used for
organic synthesis due to its replacement of toxic heavy-
metal reagents.17 These hypervalent iodine reagents could
be synthesized via the reaction of substituted iodobenzenes
with sodium perborate in acetic acid in the presence of
triflic acid.18a In 2011, a novel Heck coupling reaction was
reported by Mao in which (diacetoxy)iodobenzene was
directly used instead of iodobenzene under mild
conditions.19a
An
efficient
route to 3-iodo-4-
aryloxycoumarins between 4-hydroxycoumarins and aryl
hypervalent iodine reagents has been well documented.19b
Moreover, 3-iodo-4-aryloxycoumarins could be reduced by
zinc in acetic acids.19c Therefore, we assumed that the
desired 4-aryloxycoumarins could be obtained via one-pot
reactions of 4-hydroxycoumarins with hypervalent iodine
reagents in the presence of metal (Scheme 1c).
Scheme 1 Works on 4-aryloxycoumarins.18b,18c
R
OH
Cu(OAc)2
CH2Cl2
HO
OH
Coumarin core structures as widespread structural units in
naturally products8-10 are known to exhibit various
important potential biological activities such as anti-HIV,11
enzyme inhibitor,12 antifungal,13 and antioxidant.14 In the
long run, we have focused on facilitating the generation of
coumarin derivatives. For example, our group reported an
efficient route to 4-substituted coumarin derivatives via
palladium-catalyzed couplings of alkenyl tosylates with
organoindium reagents15 and direct sulfanylation of 4-
hydroxycoumarins with thiols in water.16 Also, Asish
developed a protocol for the cross-coupling of arylboronic
acids with 4-hydroxycoumarins (Scheme 1a).18b Alizadeh
employed the reaction of Phenols with 4-tosylcoumarins to
O
O
B
+
+
a:
Et3N, 4A0 MS
N2, 24h, r.t.
R
O
O
O
R
ΟΤs
Cu(ΟΑc)2
O
R
OH
b:
c:
Na2CO3
DMF
O
O
O
O
O
R
OH
O
Metal
DMF
R
+
I(OAc)2
O
O
O
afford the desired 4-aryloxycoumarins (Scheme 1b).18c
-------------------------------------
The initial studies were carried out for the reaction of 4-
hydroxycoumarin 1a with 1-(diacetoxyiodo)-4-
methylbenzene 2a, with an expectation to develop an
Corresponding author. Tel.: +86-791-88120388; fax: +86-791-88120388;
e-mail: yiyuanpeng@jxnu.edu.cn
Keywords: 4-hydroxycoumarin, hypervalent iodine reagent, 4-
aryloxycoumarins.

2
Tetrahedron Letters
efficient route to 4-aryloxycoumarins (Table 1). At the
outset, to optimize conditions for this transformation, the
reaction was performed in the presence of CuI (50 mol %)
as catalyst with Na2CO3 (0.5 eq) in DMSO at 110℃. To our
delight, the desired product 3a was observed although this
transformation was still not completed after 12h (Table 1,
entry 1). A worse result was displayed when Cu(OAc)2 was
used as a replacement (Table 1, entry 2). The screening of
solvents indicated that DMF was the best choice (Table 1,
entry 3-6). A base-free experiment suggested that the
reaction was highly efficient with almost quantitative yield
(93% yield) (Table 1, entry 7). Other metals such as Mg, Al,
Fe and Zn were also investigated, but the results were less
effective than copper powder (Table 1, entry 8-11). Thus,
copper powder was used to promote in the subsequent
investigation. When reaction temperature was lowered to
80 ℃, the efficiency of the reaction was a little bit
decreased, giving the desired product 3a in 91% yield
(Table 1, entry 12). However, the amount of copper
powder plays an important role regard with the yield of
the reaction. When reducing the amount of copper
powder to 20 mol % (Table 1, entry 13), the product
yield decreased gradually. Compared with other
protocols,18b,18c our access avoided the use of base and
ligand. Thus, this methodology gives a supplement rout to
the 4-aryloxycoumarins.
(diacetoxyiodo)benzenes. All reactions went to completion
with good to excellent yields. For example, the reaction of
4-hydroxycoumarin 1a with 1-(diacetoxyiodo)-3-
methylbenzene 2b provided the desired product 3b in 90%
yield (Table 2, entry 2). When (diacetoxyiodo)benzene 2c
was examined, the corresponding products 3c was isolated
in 88% yield (Table 2, entry 3).
Table
2
Reactions of 4-hydroxycoumarins with
hypervalent iodine reagentsa,19
OH
OAr
Copper powder
(0.5 eq)
DMF, 80 oC
+
Ar Ι(ΟΑc)2
1.2eq
O
O
O
O
1
2
3
Entry
1
Substrate 1
ΟΗ
Ar
4-MeC6H4 (2a)
Yield(%)b
91 (3a)
O
1a
1a
1a
1a
O
2
3
4
5
3-MeC6H4 (2b)
C6H5 (2c)
4-FC6H4 (2d)
4-MeC6H4 (2a)
90 (3b)
88 (3c)
78 (3d)
92 (3e)
ΟΗ
Table 1 Condition screening for the reaction of 4-
1a
hydroxycoumarin
methylbenzene 2a
with
1-(diacetoxyiodo)-4-
O
O
1b
6
7
8
9
1b
1b
1b
3-MeC6H4 (2b)
C6H5 (2c)
4-FC6H4 (2d)
4-MeC6H4 (2a)
88 (3f)
87 (3g)
75 (3h)
95 (3i)
ΟΗ
OC6H4p-Me
Metal
+
Ι(ΟΑc)2
solvent,
ΟΗ
O
O
O
O
1a
2a
3a
O
O
O
Ent
ry
1
Catalyst
(eq)
CuI (0.5)
Cu(OAc)2
(0.5)
Cu (0.5)
Cu (0.5)
Cu (0.5)
Cu (0.5)
Cu (0.5)
Mg (0.5)
Al (0.5)
Fe (0.5)
Zn (0.5)
Cu (0.5)
Cu (0.2)
Solven
t
T
( )
Yield 3a
(%)a
20
base
1c
1c
1c
1c
10
11
12
13
3-MeC6H4 (2b)
C6H5 (2c)
4-FC6H4 (2d)
4-MeC6H4 (2a)
96 (3j)
90 (3k)
86 (3l)
81 (3m)
Na2CO3
Na2CO3
DMSO 110
DMSO 110
DMSO 110
2
Trace
ΟΗ
3
4
5
Na2CO3
Na2CO3
Na2CO3
Na2CO3
53
Trace
Trace
73
93
35
NR
55
76
91
F
THF
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
110
110
110
110
110
110
110
110
80
O
O
6
7
8
9
10
11
12
13
1d
1d
1d
-
-
-
-
-
-
-
14
15
16
3-MeC6H4 (2b)
C6H5 (2c)
4-MeC6H4 (2a)
82 (3n)
80 (3o)
95 (3p)
OH
H3C
O
O
1e
1e
1e
80
41
a Yields based on isolation.
17
18
3-MeC6H4 (2b)
C6H5 (2c)
97 (3q)
93 (3r)
a Reaction conditions: 4-hydroxycoumarins 1 (0.3 mmol), hypervalent
iodine reagents 2 (0.36 mmol), Cu (50 mol %), DMF (3.0 mL), 80 ℃.
b Isolated yield based on 4-hydroxycoumarins 1.
Subsequently, we started to explore the generality of the
reaction. Thus, various 4-hydroxycoumarins were
employed in the reactions of (diacetoxyiodo)benzenes
under the standard conditions [Cu (50 mol %), DMF, 80℃]
(Table 2). It was noteworthy that this 4-aryloxycoumarins
formation was found to be workable with different
1
Similarly, 1-(diacetoxyiodo)-4- fluobenzene 2d was also a
suitable substrate in the reaction, which afforded the

Tetrahedron Letters
3
product 3d in 78% yield (Table 2, entry 4). This condition
was also workable for other 4-hydroxycoumarins 1b-1e
bearing methyl, methoxy group, and fluoro functionality on
the aromatic ring. For instance, 4-hydroxy-6-
methylcoumarin 1b reacted with 1-(diacetoxyiodo)-4-
methylbenzene 2a resulting in the desired coumarin 3e in
92% yield (Table 2, entry 5). Reactions of hypervalent
iodine reagent 2b or 2c with 4-hydroxy-6-methylcoumarin
1b proceeded well to generate the desired product 3f or 3g
in 88% and 87% yield, respectively (Table 2, entries 6-7).
Again, 1-(diacetoxyiodo)-4-fluobenzene 2d reacted with 4-
hydroxy-6-methylcoumarin 1b, production the 4-(4-
fluorophenoxy)-6-methylcoumarin 3h in 75% yield (Table
2, entry 8). It seems that (diacetoxyiodo)benzenes bearing
strong electron withdrawing groups were unfavorable for
the route to 4-aryloxycoumarins. For example, no desired
product was observed, when hypervalent iodine reagent
such as 1-(diacetoxyiodo)-4-nitrobenzene was used (not
shown in table 2). Due to the strong electron-withdrawing
effect of nitro group, the hypervalent iodine reagent could
not react with 4-hydroxycoumarin to form the key iodide
intermediate smoothly.
avoid the use of base? In order to find the possible answer,
four control experiments were performed (Scheme 2).
When iodobenzene was reacted with 4-hydroxycoumarin
under the standard conditions, no reaction occurred,
which suggested that the presence of hypervalent iodine
reagent might be very important (Scheme 2a). The reaction
proceeded smoothly when (diacetoxyiodo)benzene reacted
with 4-hydroxycoumarin in the absence of copper powder,
providing the product 3s (Scheme 2b) in almost quantitative
yield, which could also be transformed to 3c by Cu powder
in the presence of acetic acid (Scheme 2c). However, in the
absence of acetic acid, 3s could not be reduced to 3c by Cu
powder (Scheme 2d). All these indicated that the iodide
product 3s and the presence of acetic acid might be the key
intermediates during the reaction. Based on the control
experiments, the mechanistic pathway is very obvious.
Firstly, the key iodide intermediate is formed via a simple
coupling
hypervalent iodine reagents, production acetic acid,
simultaneously. Secondly, the coordination of
reaction
of
4-hydroxycoumarins
with
coumariniodide undergoes reductive reactions in the
presence of copper powder and acetic acid to give the final
product 3 (Scheme 3).
The reactions of 4-hydroxy-7-methoxycoumarin 1c, 6-
fluoro-4-hydroxycoumarin 1d with hypervalent iodine
reagents 2 also generate the desired products smoothly in
good to excellent yields (Table 2, entries 9-15). On the
whole, 4-hydroxy-7-methoxycoumarin 1c afforded the
desired product with 86%-96% yields (Table 2, entries 9-
12) are higher than 6-fluoro-4-hydroxycoumarin 1d with
80%-82% yields respectively (Table 2, entries 12-15). And,
all these results indicated that 4-hydroxycoumarins bearing
electron donating groups could have better results than
those bearing electron withdrawing ones. The similar
structure 4-hydroxy-6-methyl-2H-pyran-2-one 1e was
examined as well. As expected, all reactions worked well to
facilitate the generation of the corresponding products in
high yields (Table 2, entries 16-18).
Scheme 3 Proposed pathway
OH
OAr
Copper powder
DMF, 80 oC
+
Ar Ι(ΟΑc)2
1.2eq
O
O
O
O
1
2
3
DMF
O
OAr
80 oC
DMF
I
I
Ar
Scheme 2 Mechanistic studies.
ΟΗ
O
O
O
+
O
Copper powder
(0.5 eq)
+
CH3COOH
Copper powder
DMF
a:
b:
NR
DMF, 80 o
C
+
+
I
H2
O
O
ΟΗ
OC6H5
I
80 oC
DMF
Ι(ΟΑc)2
In summary, we have provided an efficient and facile one-
pot route to 4-aryloxycoumarins via reactions of 4-
hydroxycoumarin with hypervalent iodine reagents. The
transformation is highly efficient under mild conditions
without base.
O
O
O
O
3s
OC6H5
I
OC6H5
Copper powder
(0.5 eq)
c:
CH3COOH(1.0 eq)
DMF, 80 oC
O
O
O
O
Acknowledgments
3s
3c
OC6H5
I
Financial support from National Natural Science
Foundation of China (No. 21162012 and 21362014), key
laboratory of Functional Small Organic Molecule, Ministry
of Education, Jiangxi Normal University (NO.KLFS-KF-
201407) is gratefully acknowledged.
Copper powder
(0.5 eq)
DMF, 80 oC
d:
NR
O
O
3s
Traditional Ullmann coupling reactions were carried out
with base. This raises the question: Why did our access

4
Tetrahedron Letters
10. Lipshutz, B. H. Chem. Rev. 1986, 86, 795.
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20. General procedure for Cu-catalyzed reactions of 4-
hydroxycoumarin with hypervalentiodine reagents: 4-
hydroxycoumarins 1 (0.3 mmol), hypervalent iodine reagents
2 (0.36 mmol) in DMF (3.0 mL), and Cu (50 mol %) was
added at 80 ℃. After completion of the reaction as indicated
by TLC, the reaction mixture was cooled to room
temperature and water (20 mL) was added. The mixture was
extracted with CH2Cl2 (3 × 10 mL) and dried over anhydrous
Na2SO4. The solution was filtered, concentrated, and the
residue was purified by column chromatography to afford the
product 3. Data of selected example: 4-(p-tolyloxy)coumarin
(3a)18b, Yield: 91%; 1H NMR (400 MHz, CDCl3) δ 8.03 (dd,
J = 8.0, 1.2 Hz, 1H), 7.64-7.58 (m, 1H), 7.38-7.32 (m, 2H),
7.29-7.25 (m, 2H), 7.08-7.02 (m, 2H), 5.42 (s, 1H), 2.40 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 166.5, 162.6, 153.6,
150.1, 136.6, 132.7, 130.8, 124.0, 123.0, 120.9, 116.8, 115.5,
93.3, 20.9. (For details, please see Supporting Information)
9. (a) Kirilmis, C.; Ahmedzade, M.; Servi, S.; Koca, M.;
Kizirgil, A.; Kazaz, C. Eur. J. Med. Chem. 2008, 43, 300. (b)
Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002,
45, 2670. (c) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.;
Veitch, N. C.; Hall, D. R. Tetrahedron 2006, 62, 4214.

Tetrahedron Letters
5
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An efficient route to 4-aryloxycoumarins via
one-pot reactions of 4-hydroxycoumarins with
hypervalent iodine reagents
Wei Gao, Linchu Xu, Chun Gong, Qiuping Ding, Yiyuan Peng*
OH
OAr
Copper powder
(0.5 eq)
DMF, 80 oC
+
Ar Ι(ΟΑc)2
1.2eq
O
O
O
O
1
2
3
1. 4-aryloxycoumarins were obtained by one-pot
reactions from 4-hydroxycoumarins.
2. The reaction exhibited good functional group
tolerance.
3. The reaction avoided the use of base and
ligant.
4. The targeted heterocycle is a structure with a
broad range of biological activities.