A convenient and efficient synthesis of coumarin-containing phthalides and derivatives

Article abstract of DOI:10.1055/s-0032-1316871

A highly efficient and convenient procedure to access a series of coumarin-containing phthalides and derivatives is developed. The novel bis-heterocyclic products are obtained via reactions between 4-hydroxycoumarins (or 4-hydroxy-2-quinolones) with different 2-formylbenzoic acids in water as an environmentally friendly solvent. 4-Aryl substituted derivatives of 3-(4-hydroxy)coumarinylphthalide are obtained in excellent yields by initial conversion into the corresponding triflate and subsequent palladium-catalyzed Suzuki-Miyaura coupling with arylboronic acids. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1316871

PAPER
▌1181
paper
A Convenient and Efficient Synthesis of Coumarin-Containing Phthalides and
Derivatives
Efficient Synthesis of Coumarin-Containing Phthalides
Shao-Chun Shen,a Xing-Wen Sun,*a Guoqiang Lin*a,b
a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax +86(21)65642406; E-mail: sunxingwen@fudan.edu.cn
b
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
E-mail: lingq@mail.sioc.ac.cn
Received: 13.01.2013; Accepted after revision: 01.03.2013
However, there are few reports that describe the synthesis
Abstract: A highly efficient and convenient procedure to access a
of such of bis-heterocyclic compounds containing both
series of coumarin-containing phthalides and derivatives is devel-
coumarin and phthalide units.4
oped. The novel bis-heterocyclic products are obtained via reactions
between 4-hydroxycoumarins (or 4-hydroxy-2-quinolones) with
different 2-formylbenzoic acids in water as an environmentally
friendly solvent. 4-Aryl substituted derivatives of 3-(4-hy-
significant attention. A large number of scientists are in-
droxy)coumarinylphthalide are obtained in excellent yields by ini-
tial conversion into the corresponding triflate and subsequent
The development of new, clean and environmentally be-
nign synthetic methods in organic synthesis has gained
volved in the study of water as a reaction medium, due to
the fact that it can undoubtedly be considered as the safest
solvent available to chemists.5 Hence, the development of
an effective and general method for the synthesis of 3-
coumarinylphthalides in water represents an interesting
and important challenge.
palladium-catalyzed Suzuki–Miyaura coupling with arylboronic
acids.
Key words: coumarins, phthalides, bis-heterocyclic, water, Suzuki–
Miyaura coupling
Our research group has been interested in the synthesis of
phthalides and their analogues.6 In 2008, we reported syn-
theses of the bis-heterocyclic compounds, 3-indolyl-sub-
stituted phthalides, which displayed in vitro activity
against Alzheimer’s disease, via Friedel–Crafts reactions
in water.6d Inspired by these results, and in continuation of
our interest in medicinal and green chemistry, herein, we
report our development of a convenient and highly effi-
cient method for the synthesis of coumarin-containing
phthalides and their derivatives.
Coumarins are an important class of benzopyrones which
are present in a wide variety of natural products, as well
as in numerous pharmaceutically important compounds.1
As a privileged scaffold, coumarins show a broad spec-
trum of biological activity.2 For example, novobiocin and
clorobiocin are coumarin-derived antibiotics, which are
used as competitive inhibitors of the bacterial adenosine-
5′-triphosphate (ATP) binding gyrase B subunit, blocking
negative supercoiling of relaxed DNA.2a,d Another exam-
ple, wedelolactone, is a natural coumarin-containing
product used as an antidote of venomous snake-bites.1h
On the other hand, phthalide frameworks are found as
structural subunits in a large number of natural products,
many of which demonstrate a wide range of biological ac-
tivity.3 Accordingly, the combination of coumarin and
phthalide moieties may potentially provide a class of nov-
el drug candidates with unusual biological activities.
Initially, the reaction between 4-hydroxycoumarin (1a)
and 2-formylbenzoic acid (2a) (1.5 equiv) was investigat-
ed in pure water at 40 °C (Scheme 1). To our delight, the
reaction proceeded smoothly to give the desired coupled
product 3a in 94% yield (Table 1, entry 1). While the
structure was confirmed from NMR spectroscopic data,
the fortuitous crystallization of 3a provided additional un-
ambiguous support for the structure (Figure 1).7
O
OH
O
O
OH
O
O
H
H2O
+
OH
40 °C, 10 h
94%
O
O
O
1a
2a
3a
Scheme 1 Synthesis of 3-(4-hydroxy)coumarinylphthalide (3a)
SYNTHESIS 2013, 45, 1181–1190
Advanced online publication: 27.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316871; Art ID: SS-2013-H0044-OP
© Georg Thieme Verlag Stuttgart · New York

1182
S.-C. Shen et al.
PAPER
However, the reaction between 6-methyl-4-hydroxycou-
marin (1b) and 2-formylbenzoic acid (2a) did not occur at
40 °C. When the reaction temperature was raised to 60 °C
and the reaction time increased to 24 hours, only a trace
amount of product 3b was obtained. Further optimization
of the reaction conditions led to the finding that the reac-
tion proceeded smoothly at 80 °C, over 24 hours, to afford
the desired product 3b in 86% yield (Table 1, entry 2). Un-
der the optimized reaction conditions [coumarin (1 equiv),
2-formylbenzoic acid (1.5 equiv), pure water (1 mL), 24
h, 80 °C], the scope of this protocol was investigated us-
ing a range of substituted coumarins and 2-formylbenzoic
acid (2a) (Table 1, entries 1–7).
Figure 1 X-ray ORTEP illustration of fused compound 3d (50%
probability ellipsoids)
Table 1 Synthesis of Substituted Phthalides in Watera
O
OH
O
OH
X
O
H2O
H
+
OH
80 °C
R2
R1
R2
X
O
O
R1
O
1
2
3
Entry
Heterocycle
Acid
Time (h)
10
Product
Yield (%)b
O
OH
O
O
O
R1 = H, X = O
1a
R2 = H
2a
1c
3a
94
O
OH
O
O
O
R1 = 6-Me, X = O
1b
R2 = H
2a
2
3
4
5
6
24
24
24
24
24
3b
3c
3d
3e
3f
86
84d
89
96
91
O
OH
O
O
R1 = 6-Br, X = O
1c
R2 = H
2a
Br
O
O
O
OH
O
R1 = 6-OMe, X = O
1d
R2 = H
2a
MeO
O
O
OH
O
R1 = 7-OMe, X = O
1e
R2 = H
2a
MeO
O
O
O
OH
O
R1 = 6,7-naphthyl, X = O
1f
R2 = H
2a
O
O
Synthesis 2013, 45, 1181–1190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of Coumarin-Containing Phthalides
1183
Table 1 Synthesis of Substituted Phthalides in Watera (continued)
O
OH
O
OH
O
O
H2O
H
+
OH
80 °C
R2
R1
R2
X
O
X
R1
O
1
2
3
Entry
Heterocycle
Acid
Time (h)
24
Product
Yield (%)b
O
OH
O
O
O
R1 = 5,6-naphthyl, X = O
1g
R2 = H
2a
7
8
3g
3h
75
16
O
OH
O
R1 = H, X = NH
1h
R2 = H
2a
48
24
N
H
O
O
O
OH
R1 = H, X = NMe
1i
R2 = H
2a
9
3i
87
N
O
O
Me
O
O
O
OH
OMe
R1 = H, X = O
1a
R2 = 5,6-(OMe)2
2b
10
11
24
24
3j
94
92
OMe
O
O
O
OH
O
R1 = H, X = O
1a
R2 = 5,6-(OCH2O)-
2c
3k
O
O
O
O
OH
R1 = H, X = O
1a
R2 = 4-Br
2d
12
24
3l
81
O
O
Br
a All reactions were performed with compound 1 (0.3 mmol) and acid 2 (0.45 mmol) in water (1 mL).
b Yield of isolated product after chromatographic purification.
c The reaction was carried out at 40 °C.
d Yield of isolated product after trituration with Et2O.
Coumarins bearing different substituents reacted smooth- Subsequently, the reactions between coumarin 1a and
ly with 2-formylbenzoic acid (2a) to afford the desired substituted 2-formylbenzoic acids 2b–d were examined.
phthalides 3 in good to excellent yields (Table 1, entries Substrates with electron-donating or electron-withdraw-
1–7). In contrast, the reaction between 4-hydroxy-2-qui- ing groups reacted smoothly under the present conditions
nolone (1h) and 2-formylbenzoic acid (2a) gave only a to afford the corresponding coumarin-containing
16% yield of the corresponding phthalide due to poor con- phthalides in good to excellent yields (81–94%, Table 1,
version (Table 1, entry 8). However, the reaction of 4-hy- entries 10–12).
droxy-1-methyl-2-quinolone (1i) with acid 2a gave the
expected product 3i in a high 87% yield (Table 1, entry 9).
With this general and convenient method in hand, and in
order to introduce additional diversity to the coumarin
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1181–1190

1184
S.-C. Shen et al.
PAPER
scaffold, we initiated an investigation to prepare 3-(3-oxo- minutes on increasing the reaction temperature to 50 °C,
1,3-dihydroisobenzofuran-1-yl)-4-substituted-2H-chro- with the desired product 6a obtained in 86% yield (Table
men-2-ones 6 starting from 4-hydroxy-3-(3-oxo-1,3-dihy- 2, entry 5). On the basis of these results, the optimized
droisobenzofuran-1-yl)-2H-chromen-2-one (3a). It is conditions [50 °C, PdCl2(PPh3)2 (10.5 mg, 5 mol%) as
worth noting that 4-substituted coumarins show good ac- catalyst, 2 M Na2CO3 (aq) (0.9 mmol, 3 equiv) as base,
tivity against the hepatitis C virus (HCV).8
and THF as the solvent] were employed to investigate the
reactions of triflate 4 with a series of arylboronic acids 5
(Table 3).
Transition metal catalyzed cross-coupling reactions are
powerful and effective methods for carbon–carbon (C–C)
bond formation.9 Among these reactions, the Suzuki– In general, this protocol proved to have wide applicability
Miyaura coupling is widely used due to its excellent func- for a variety of arylboronic acids. It was found that aryl-
tional group tolerance and the mild nature of the arylbo- boronic acids possessing electron-withdrawing or elec-
ronic acid coupling partners.10 Therefore, we initially tron-donating substituents were tolerated under these
prepared triflate 4 from 3a, in a straightforward manner, conditions, affording the desired coupled products 6 in
and then examined its reaction with phenylboronic acid good to excellent yields (86-98%, Table 3, entries 1–7). It
(5a) via the palladium-catalyzed Suzuki–Miyaura cou- was worth noting that even heterocyclic boronic acids, in-
pling (Table 2).
cluding furan-2-ylboronic acid, thien-2-ylboronic acid
and thien-3-ylboronic acid, underwent the coupling reac-
tion under the optimized conditions to afford good yields
of the corresponding products (Table 3, entries 8–10).
Treatment of a mixture of triflate 4 (128 mg, 0.3 mmol),
phenylboronic acid (5a) (41 mg, 0.33mmol), bis(triphe-
nylphosphine)palladium(II) chloride [PdCl2(PPh3)2] (10.5
mg, 0.015 mmol), and sodium bicarbonate (76 mg, 0.9 In summary, we have developed a highly efficient method
mmol) in methanol (2 mL), at room temperature under an for the synthesis of 3-(4-hydroxy)coumarinylphthalides
inert nitrogen atmosphere for one hour, produced the de- 3a–g,j–l and 3-(4-hydroxy)quinolinylphthalides 3h,i,
sired product 6a in only 25% yield. The use of sodium car- along with a simple and convenient process for the prepa-
bonate or potassium carbonate as the base also resulted in ration of 3-(4-aryl substituted)coumarinylphthalides 6a–j.
poor yields (Table 2, entries 1–3). In an attempt to im- The initial coupling reaction to give phthalides 3 has the
prove the yield, we investigated the effects of commonly advantage of occurring in water as an environmentally
used organic and inorganic bases in tetrahydrofuran. Grat- friendly solvent, whilst both methods are attractive in
ifyingly, the reaction was found to proceed efficiently in terms of their simplicity and the typically high yields of
tetrahydrofuran (r.t., 5 h) when using an aqueous solution products obtained. The introduction of additional diversi-
of sodium carbonate (2 mol/L, 3.0 equiv) as the base, to ty into the present scaffold, and screening of these small
give the desired product 6a in 86% yield (Table 2, entry molecules for biological activity are currently under in-
4).10e The reaction was found to be complete within 15 vestigation in our laboratory.
Table 2 Synthesis of 3-(4-Phenyl)Coumarinylphthalide (6a)
O
O
O
OH
O
O
Ph
O
O
O
OTf
O
O
O
PhB(OH)2 (5a)
Tf2O, Et3N
CH2Cl2
PdCl2(PPh3)2, base
solvent
O
3a
4
6a
Entry
Base
Solvent
Temp (°C)
Time (h)
Yield (%)a
1
2
3
4
5
NaHCO3
Na2CO3
K2CO3
MeOH
MeOH
MeOH
THF
r.t.
r.t.
r.t.
r.t.
50
1
25
20
20
86
86
3
3
Na2CO3 (aq)b
Na2CO3 (aq)b
5
THF
0.25
a Yield of isolated product.
b Na2CO3 (aq) = 2 mol/L.
Synthesis 2013, 45, 1181–1190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of Coumarin-Containing Phthalides
1185
Table 3 Synthesis of 3-(4-Substituted)Coumarinylphthalides
O
O
R3
O
O
OTf
O
O
R3B(OH)2 (5)
PdCl2(PPh3)2
Na2CO3 (aq)
THF, 50 °C
O
O
4
6
Entry
Boronic acid 5
Time (min)
Product
Yield (%)a
O
O
O
1
15
6a
86
B(OH)2
O
O
O
O
B(OH)2
2
15
6b
87
O
O
O
O
O
O
B(OH)2
3
4
5
6
15
15
15
20
6c
6d
6e
6f
89
87
86
94
O
OMe
O
O
O
MeO
B(OH)2
O
O
O
CF3
F3C
B(OH)2
O
O
O
F
F
B(OH)2
O
O
O
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1181–1190

1186
S.-C. Shen et al.
PAPER
Table 3 Synthesis of 3-(4-Substituted)Coumarinylphthalides (continued)
O
O
R3
O
O
O
OTf
O
O
O
R3B(OH)2 (5)
PdCl2(PPh3)2
Na2CO3 (aq)
THF, 50 °C
4
6
Entry
Boronic acid 5
Time (min)
Product
Yield (%)a
O
O
O
7
25
6g
98
B(OH)2
O
O
O
O
O
O
O
S
B(OH)2
O
8
9
30
35
6h
6i
58
82
O
O
B(OH)2
S
O
O
S
O
B(OH)2
S
10
50
6j
93
O
O
a Yield of isolated product.
and concentrated. The residue was purified by flash column chro-
matography on silica gel to give the corresponding product 3, apart
from compound 3c, which was obtained as described below.
Commercial reagents and solvents were used as received. Unless
otherwise stated, all reactions were performed in test tubes. Flash
column chromatography was performed using HuangHai silica gel
(60 Å pore size, 32–63 μm, standard grade). Analytical thin-layer
chromatography was performed using HuangHai glass plates pre-
coated with silica gel (0.25 mm, 230–400 mesh), impregnated with
a fluorescent indicator (254 nm). Thin-layer chromatography plates
were made visual by exposure to UV light. Organic solutions were
concentrated on a rotary evaporator at ~20 Torr (house vacuum) at
25–35 °C.Melting points were measured on a Mel-Temp apparatus
and are uncorrected. The majority of the 4-hydroxy-3-(3-oxo-1,3-
dihydroisobenzofuran-1-yl)-2H-chromen-2-ones (3a–l) were ther-
mally unstable above 120 °C, except for product 3i. FT-IR spectra
were obtained using a Nicolet AV-360 spectrophotometer. 1H
NMR, 13C NMR and 19F NMR spectra were recorded on an ECA
(400 MHz) or a DMX (500 MHz) spectrometer using TMS as the
internal standard; chemical shifts (δ) are quoted in ppm. HRMS was
performed using a Waters Micromass GCT Premier spectrometer.
4-Hydroxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-2H-chro-
men-2-one (3a)
Yield: 83 mg (94%); white solid.
IR (KBr): 3496, 3383, 1735, 1677, 1609, 1561, 1350, 1291, 1067,
975, 762, 726 cm–1.
1H NMR (400 MHz, acetone-d6): δ = 10.39 (s, 1 H), 8.11–8.09 (m,
1 H), 7.79 (d, J = 7.3 Hz, 1 H), 7.57–7.55 (m, 1 H), 7.47 (s, 2 H),
7.37 (d, J = 6.4 Hz, 1 H), 7.27 (d, J = 8.2 Hz, 1 H), 7.15 (s, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 176.2, 173.4, 154.1, 152.0,
133.6, 131.2, 127.7, 127.2, 124.7, 124.1, 122.8, 122.1, 121.4, 115.9,
93.8, 78.8.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H10O5: 294.0528; found:
294.0536.
3-(4-Hydroxy)coumarinylphthalides 3; General Procedure
A mixture of 4-hydroxycoumarin 1 (0.3 mmol) and 2-formylbenzo-
ic acid 2 (0.45 mmol, 1.5 equiv) in H2O (1.0 mL) was stirred at the
appropriate temperature and stated period of time (see Table 1). The
mixture was diluted with MeOH, dried over anhyd Na2SO4, filtered
4-Hydroxy-6-methyl-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-
2H-chromen-2-one (3b)
Yield: 79 mg (86%); white solid.
IR (KBr): 3427, 2921, 1776, 1725, 1678, 1631, 1617, 1535, 1456,
1350, 1298, 1221, 1118, 723 cm–1.
Synthesis 2013, 45, 1181–1190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of Coumarin-Containing Phthalides
1187
1H NMR (400 MHz, acetone-d6): δ = 7.75–7.71 (m, 2 H), 7.59 (t,
J = 7.8 Hz, 1 H), 7.47 (t, J = 7.4 Hz, 1 H), 7.25–7.22 (m, 2 H), 7.03–
6.99 (m, 2 H), 2.29 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 173.3, 171.7, 152.5, 133.8,
132.2, 131.6, 128.1, 127.7, 125.3, 124.5, 122.0, 116.1, 93.0, 78.7,
21.0.
1H NMR (500 MHz, acetone-d6): δ = 8.37 (d, J = 8.0 Hz, 1 H), 8.20
(d, J = 8.7 Hz, 1 H), 7.95 (d, J = 7.9 Hz, 1 H), 7.76 (d, J = 7.6 Hz,
1 H), 7.71 (d, J = 8.7 Hz, 1 H), 7.66–7.60 (m, 2 H), 7.53–7.51 (m,
1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.17 (s, 1
H).
13C NMR (100 MHz, DMSO-d6): δ = 172.8, 171.6, 152.1, 150.8,
135.1, 134.0, 128.3, 127.7, 127.0, 124.6, 123.3, 122.4, 122.3, 122.2,
122.0, 116.7, 93.8, 78.4, 49.1.
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H12O5: 308.0685; found:
308.0683.
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H12O5: 344.0685; found:
344.0687.
6-Bromo-4-hydroxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-
2H-chromen-2-one (3c)
A mixture of 6-bromo-4-hydroxycoumarin (1c) (0.3 mmol) and 2-
formylbenzoic acid (2a) (0.45 mmol, 1.5 equiv) in H2O (1.0 mL)
was stirred at 80 °C for 24 h. The solvent was removed and the res-
idue triturated with Et2O, filtered, washed with Et2O (3 × 5.0 mL),
and the resulting solid dried under vacuum to give the desired prod-
uct 3c.
1-Hydroxy-2-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-3H-ben-
zo[f]chromen-3-one (3g)
Yield: 77 mg (75%); yellow solid.
IR (KBr): 3431, 3049, 1735, 1626, 1580, 1518, 1454, 1438, 1420,
1344, 1293, 1211, 1108, 1072, 1016, 821, 723 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 10.17 (d, J = 8.6 Hz, 1 H),
7.81 (d, J = 8.9 Hz, 1 H), 7.75 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 7.4
Hz, 1 H), 7.41 (t, J = 7.5 Hz, 1 H), 7.33–7.20 (m, 4 H), 7.13 (d,
J = 8.9 Hz, 1 H), 7.08 (d, J = 7.2 Hz, 1 H).
Yield: 94 mg (84%); white solid.
IR (KBr): 3433, 1744, 1642, 1596, 1533, 1450, 1350, 1288, 1118,
728 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.90 (s, 1 H), 7.75–7.73 (m, 1
H), 7.59–7.53 (m, 2 H), 7.47–7.43 (m, 1 H), 7.27 (d, J = 7.8 Hz, 1
H), 7.09 (d, J = 7.8 Hz, 1 H), 6.93 (s, 1 H).
13C NMR (125 MHz, acetone-d6): δ = 177.7, 172.0, 163.6, 154.4,
152.3, 132.8, 127.7, 127.1, 127.0, 124.4, 121.5, 117.3, 114.2, 92.0,
78.8.
13C NMR (100 MHz, DMSO-d6): δ = 172.5, 171.6, 153.6, 152.6,
133.8, 133.5, 128.0, 127.8, 127.7, 125.2, 124.5, 122.0, 118.8, 114.6,
91.5, 78.9, 49.1.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H9BrO5: 371.9633;
found: 371.9628.
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H12O5: 344.0685; found:
344.0688.
4-Hydroxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)quinolin-
2(1H)-one (3h)
Yield: 14 mg (16%); white solid.
IR (KBr): 3430, 3162, 2930, 1738, 1649, 1617, 1596, 1499, 1406,
1206, 1077, 728 cm–1.
1H NMR (400 MHz, acetone-d6): δ = 8.11 (d, J = 8.3 Hz, 1 H), 7.86
(d, J = 8.3 Hz, 1 H), 7.73–7.67 (m, 2 H), 7.59–7.53 (m, 2 H), 7.44
(t, J = 7.3 Hz, 1 H), 7.36 (d, J = 8.2 Hz, 1 H), 6.95 (s, 1 H).
4-Hydroxy-6-methoxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-
yl)-2H-chromen-2-one (3d)
Yield: 86 mg (89%); white solid.
IR (KBr): 3437, 2911, 2849, 1771, 1724, 1672, 1637, 1534, 1466,
1438, 1380, 1278, 1180, 1115, 1047, 733, 625 cm–1.
1H NMR (400 MHz, acetone-d6): δ = 7.75 (d, J = 7.3 Hz, 1 H),
7.59–7.55 (m, 1 H), 7.45–7.42 (m, 2 H), 7.29 (d, J = 7.3 Hz, 1 H),
7.10–7.06 (m, 2 H), 6.96 (s, 1 H), 3.72 (s, 3 H).
13C NMR (100 MHz, acetone-d6): δ = 174.7, 172.1, 164.3, 155.1,
152.7, 148.7, 133.1, 127.8, 127.4, 124.0, 123.5, 121.7, 118.3, 116.9,
107.4, 92.5, 79.0, 55.1.
13C NMR (100 MHz, DMSO-d6): δ = 171.4, 162.6, 150.9, 139.4,
134.4, 132.0, 128.9, 127.4, 124.9, 123.8, 122.2, 121.8, 115.9, 76.0.
HRMS (EI, 70 eV): m/z [M]+ calcd for C17H11NO4: 293.0688;
found: 293.0694.
4-Hydroxy-1-methyl-3-(3-oxo-1,3-dihydroisobenzofuran-1-
yl)quinolin-2(1H)-one (3i)
Yield: 80 mg (87%); white solid; mp 242–243 °C.
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H12O6: 324.0634; found:
324.0632.
IR (KBr): 3427, 2957, 1723, 1642, 1627, 1622, 1601, 1576, 1509,
1468, 1413, 1397, 1324, 1309, 1286, 1242, 1206, 1159, 1080, 965,
929, 757, 748, 693, 688 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 11.39 (s, 1 H), 8.09 (d, J = 6.8
Hz, 1 H), 7.86 (dd, J1 = 7.2 Hz, J2 = 1.8 Hz, 1 H), 7.72–7.63 (m, 2
H), 7.59–7.48 (m, 2 H), 7.40 (d, J = 7.2 Hz, 1 H), 7.30 (t, J = 7.4 Hz,
1 H), 7.07 (s, 1 H), 3.49 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 170.8, 161.0, 160.4, 150.1,
139.6, 133.9, 132.1, 128.4, 127.0, 124.4, 123.8, 121.6, 115.6, 114.9,
105.3, 75.6, 28.9.
4-Hydroxy-7-methoxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-
yl)-2H-chromen-2-one (3e)
Yield: 93 mg (96%); white solid.
IR (KBr): 3440, 2910, 2848, 1773, 1725, 1675, 1638, 1535, 1450,
1118, 1047, 735 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 7.95 (d, J = 8.3 Hz, 1 H), 7.68
(d, J = 7.5 Hz, 1 H), 7.47 (t, J = 7.3 Hz, 1 H), 7.37 (t, J = 7.4 Hz, 1
H), 7.20 (d, J = 7.3 Hz, 1 H), 7.14 (s, 1 H), 6.60 (d, J = 8.6 Hz, 1 H),
6.51 (s, 1 H), 3.78 (s, 3 H).
13C NMR (125 MHz, acetone-d6): δ = 175.5, 172.5, 164.5, 162.8,
156.8, 153.7, 133.6, 128.8, 127.9, 127.5, 124.6, 122.6, 117.3, 110.4,
100.4, 92.1, 79.7, 55.8.
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H12O6: 324.0634; found:
324.0636.
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H13NO4: 307.0845;
found: 307.0842.
3-(4,5-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-hy-
droxy-2H-chromen-2-one (3j)
Yield: 100 mg (94%); white solid.
IR (KBr): 3435, 2936, 2839, 1735, 1655, 1601, 1530, 1498, 1459,
1426, 1355, 1270, 1051, 970, 903, 761, 708 cm–1.
1H NMR (400 MHz, acetone-d6): δ = 7.80 (d, J = 6.9 Hz, 1 H), 7.38
(t, J = 8.3 Hz, 1 H), 7.23 (d, J = 8.3 Hz, 1 H), 7.10–7.02 (m, 2 H),
6.83–6.79 (m, 2 H), 3.88 (s, 3 H), 3.78 (s, 3 H).
4-Hydroxy-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-2H-ben-
zo[g]chromen-2-one (3f)
Yield: 94 mg (91%); white solid.
IR (KBr): 3433, 3234, 2916, 2844, 1769, 1679, 1610, 1478, 1416,
1391, 1273, 1175, 1047, 954, 723 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1181–1190

1188
S.-C. Shen et al.
PAPER
13C NMR (100 MHz, acetone-d6): δ = 173.9, 169.2, 154.6, 151.6,
147.3, 146.1, 130.3, 125.4, 121.9, 120.4, 119.1, 116.3, 115.7, 77.2,
61.2, 56.3.
3-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)-4-phenyl-2H-chro-
men-2-one (6a)
Yield: 91 mg (86%); white solid; mp 197–198 °C.
HRMS (EI, 70 eV): m/z [M]+ calcd for C19H14O7: 354.0740; found:
354.0757.
IR (KBr): 3435, 3075, 2926, 1767, 1725, 1605, 1565, 1454, 1362,
1282, 1061, 994, 767, 756, 720, 706 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.79 (d, J = 7.6 Hz, 1 H), 7.61–
7.53 (m, 3 H), 7.50–7.45 (m, 2 H), 7.42–7.40 (m, 2 H), 7.35 (s, 1 H),
7.33 (s, 1 H), 7.20 (t, J = 7.9 Hz, 1 H), 7.10 (s, 1 H), 7.04–7.02 (m,
1 H), 6.35 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.1, 158.7, 156.1, 153.2, 148.1,
132.6, 129.0, 128.9, 128.4, 128.1, 124.4, 121.3, 116.7, 76.9.
6-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-[1,3]dioxolo[4,5-e]iso-
benzofuran-8(6H)-one (3k)
Yield: 93 mg (92%); white solid.
IR (KBr): 3436, 2938, 2839, 1737, 1657, 1604, 1530, 1460, 1421,
1272, 1054, 767, 730 cm–1.
1H NMR (500 MHz, acetone-d6): δ = 8.03 (d, J = 7.5 Hz, 1 H), 7.36
(t, J = 7.7 Hz, 1 H), 7.08 (s, 1 H), 7.06–6.92 (m, 2 H), 6.92 (d,
J = 7.8 Hz, 1 H), 6.64 (d, J = 7.8 Hz, 1 H), 6.11 (s, 2 H).
HRMS (EI, 70 eV): m/z [M]+ calcd for C23H14O4: 354.0892; found:
354.0891.
13C NMR (125 MHz, acetone-d6): δ = 174.8, 169.3, 164.3, 155.3,
148.6, 146.8, 144.5, 131.2, 126.3, 123.6, 122.8, 116.5, 114.5, 113.6,
111.7, 103.6, 94.4, 79.8.
4-(4-Isopropoxyphenyl)-3-(3-oxo-1,3-dihydroisobenzofuran-1-
yl)-2H-chromen-2-one (6b)
Yield: 108 mg (87%); white solid; mp 163–164 °C.
HRMS (EI, 70 eV): m/z [M]+ calcd for C18H10O7: 338.0427; found:
338.0434.
IR (KBr): 3430, 2973, 1767, 1724, 1605, 1506, 1447, 1350, 1280,
1247, 1122, 1055, 990, 846, 721 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 7.3 Hz, 1 H), 7.61–
7.53 (m, 2 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.35–7.27 (m, 3 H), 7.22–
7.13 (m, 2 H), 7.05–7.03 (m, 2 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.41
(s, 1 H), 4.63–4.61 (m, 1 H), 1.41–1.38 (m, 6 H).
13C NMR (125 MHz, CDCl3): δ = 170.3, 158.7, 156.6, 153.3, 148.3,
132.5, 129.9, 128.9, 128.3, 124.3, 121.2, 116.8, 116.0, 115.9, 70.1,
29.6, 21.9.
3-(6-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-hydroxy-
2H-chromen-2-one (3l)
Yield: 91 mg (81%); white solid.
IR (KBr): 3433, 2890, 1776, 1676, 1590, 1543, 1450, 1355, 1287,
1115, 731 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 7.85–7.54 (m, 3 H), 7.43–7.36
(m, 2 H), 7.11–6.95 (m, 3 H).
HRMS (EI, 70 eV): m/z [M + Na]+ calcd for C26H20O5Na: 435.1203;
found: 435.1195.
13C NMR (100 MHz, DMSO-d6): δ = 174.0, 173.9, 170.7, 170.5,
155.0, 154.5, 154.4, 131.3, 127.9, 127.1, 126.5, 125.6, 125.0, 122.6,
116.3, 116.2, 89.4.
HRMS (EI, 70 eV): m/z [M + Na]+ calcd for C17H9BrO5Na:
394.9526; found: 394.9533.
3-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)-4-(p-tolyl)-2H-chro-
men-2-one (6c)
Yield: 98 mg (89%); white solid; mp 158–159 °C.
IR (KBr): 3432, 2916, 2844, 1769, 1733, 1603, 1451, 1356, 1282,
1185, 1055, 994, 758, 726, 719 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.3 Hz, 1 H), 7.61–
7.53 (m, 2 H), 7.49 (t, J = 7.4 Hz, 1 H), 7.39–7.24 (m, 5 H), 7.20 (t,
J = 7.3 Hz, 1 H), 7.10 (d, J = 7.3 Hz, 2 H), 6.33 (s, 1 H), 2.43 (s, 3
H).
13C NMR (125 MHz, CDCl3): δ = 170.2, 158.5, 156.5, 153.3, 148.1,
139.4, 132.5, 129.5, 128.9, 128.4, 128.2, 124.3, 121.2, 116.7, 77.1,
21.2.
2-Oxo-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-2H-chromen-
4-yl trifluoromethanesulfonate (4)
Tf2O (0.25 mL, 1.5 equiv) was added to a cooled (ice–H2O bath)
mixture of compound 3a (294 mg, 1 mmol) and Et3N (0.22 mL, 1.5
mmol) in anhyd CH2Cl2 (10 mL) under an N2 atm. The resulting
mixture was stirred for 3 h and then concentrated under reduced
pressure. The obtained residue was purified by flash chromatogra-
phy on silica gel to give the corresponding triflate 4 (383 mg, 90%)
as a white solid.
Yield: 383 mg (90%); white solid; mp 170–171 °C.
HRMS (EI, 70 eV): m/z [M]+ calcd for C24H16O4: 368.1049; found:
368.1050.
IR (KBr): 3451, 3076, 1769, 1735, 1631, 1608, 1576, 1494, 1459,
1429, 1357, 1311, 1282, 1241, 1211, 1125, 1053, 1037, 1013, 992,
906, 850, 757, 741, 721, 598, 538 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.5 Hz, 1 H), 7.84 (d,
J = 8.0 Hz, 1 H), 7.73 (t, J = 7.9 Hz, 1 H), 7.67 (t, J = 7.3 Hz, 1 H),
7.59 (t, J = 7.4 Hz, 1 H), 7.54–7.46 (m, 2 H), 7.38 (d, J = 8.3 Hz, 1
H), 6.61 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 157.0, 154.6, 153.0, 145.9,
135.0, 134.4, 129.9, 127.3, 125.9, 125.6, 124.1, 122.1, 120.2 (q, J =
319 Hz), 117.3, 116.4, 114.2, 73.4.
4-(4-Methoxyphenyl)-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-
2H-chromen-2-one (6d)
Yield: 100 mg (87%); white solid; mp 167–168 °C.
IR (KBr): 3435, 2947, 2921, 2839, 1767, 1730, 1604, 1509, 1452,
1355, 1283, 1247, 1176, 1058, 1031, 758, 720, 564 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 7.4 Hz, 1 H), 7.60–
7.51 (m, 2 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.33–7.26 (m, 3 H), 7.20 (t,
J = 7.1 Hz, 1 H), 7.12–7.06 (m, 3 H), 6.95 (d, J = 8.2 Hz, 1 H), 6.36
(s, 1 H), 3.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 170.3, 160.3, 156.4, 153.3, 148.2,
133.7, 132.5, 129.8, 128.9, 128.2, 124.3, 121.2, 120.2, 116.7, 114.4,
77.1, 55.4.
HRMS (EI, 70 eV): m/z [M + H]+ calcd for C18H10F3O7S:
4427.0094; found: 427.0087.
4-Substituted Chromen-2-ones 6; General Procedure
PdCl2(PPh3)2 (10.5 mg, 5 mol%) was added to a mixture of triflate
4 (128 mg, 0.3 mmol), arylboronic acid 5 (0.33 mmol, 1.1 equiv), 2
M Na2CO3 (aq) (0.9 mmol, 3 equiv) in THF (2 mL), in a Schlenk
tube under an N2 atm. The mixture was stirred at 50 °C for the ap-
propriate period of time (see Table 3). Following completion of the
reaction (monitored by TLC), the mixture was purified directly by
flash column chromatography on silica gel to afford the correspond-
ing product 6.
HRMS (EI, 70 eV): m/z [M]+ calcd for C24H16O5: 384.0998; found:
384.0999.
3-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)-4-[4-(trifluorometh-
yl)phenyl]-2H-chromen-2-one (6e)
Yield: 109 mg (86%); white solid; mp 155–156 °C.
IR (KBr): 3436, 3300, 2917, 2850, 1773, 1736, 1638, 1604, 1453,
1323, 1283, 1163, 1135, 1107, 1065, 759, 722 cm–1.
Synthesis 2013, 45, 1181–1190
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of Coumarin-Containing Phthalides
1189
1H NMR (400 MHz, CDCl3): δ = 7.82 (d, J = 8.3 Hz, 1 H), 7.71 (d,
J = 7.3 Hz, 1 H), 7.61–7.53 (m, 4 H), 7.47 (t, J = 7.3 Hz, 1 H), 7.37–
7.34 (m, 2 H), 7.21 (t, J = 8.3 Hz, 1 H), 7.10 (d, J = 7.3 Hz, 1 H),
6.91 (d, J = 8.2 Hz, 1 H), 6.38 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 169.9, 158.9, 154.6, 153.3, 148.1,
136.0, 134.1, 133.1, 131.5 (q, J = 32.6 Hz), 129.3 (q, J = 3.4 Hz),
128.6, 126.7 (q, J = 269.3 Hz), 126.6, 126.1, 125.9, 124.8, 122.6,
121.6, 120.6, 119.7, 117.0, 76.6.
IR (KBr): 3432, 2916, 2849, 1766, 1728, 1604, 1560, 1453, 1280,
1058, 981, 754, 729 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 8.2 Hz, 1 H), 7.55–
7.50 (m, 2 H), 7.47 (d, J = 6.4 Hz, 1 H), 7.43 (t, J = 7.4 Hz, 1 H),
7.31–7.08 (m, 6 H), 6.37 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.2, 157.9, 152.9, 149.5, 147.7,
133.8, 132.8, 129.1, 128.6, 127.9, 127.8, 125.5, 124.6, 121.4, 120.2,
116.7, 77.0.
19F NMR (400 MHz, CDCl3): δ = –63.4 (s).
HRMS (EI, 70 eV): m/z [M]+ calcd for C24H13F3O4: 422.0766;
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H12O4S: 360.0456;
found: 360.0454.
found: 422.0763.
3-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)-4-(thien-3-yl)-2H-
chromen-2-one (6j)
4-(4-Fluorophenyl)-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-
2H-chromen-2-one (6f)
Yield: 105 mg (94%); white solid; mp 194–195 °C.
Yield: 100 mg (93%); white solid; mp 166–167 °C.
IR (KBr): 3434, 3101, 2921, 1766, 1725, 1601, 1560, 1453, 1344,
1281, 1056, 981, 785, 759, 721 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 7.3 Hz, 1 H), 7.53–
7.45 (m, 3 H), 7.41–7.39 (m, 2 H), 7.25–7.23 (m, 2 H), 7.18–7.05
(m, 3 H), 6.37 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.1, 158.6, 153.0, 152.0, 133.8,
132.7, 131.9, 129.0, 127.8, 127.5, 125.5, 124.5, 121.2, 120.0, 116.7,
76.9.
IR (KBr): 3424, 3060, 2921, 1770, 1726, 1604, 1560, 1508, 1454,
1360, 1283, 1225, 1060, 991, 759, 718, 557 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 7.3 Hz, 1 H), 7.63–
7.55 (m, 2 H), 7.50 (t, J = 8.2 Hz, 1 H), 7.42–7.39 (m, 1 H), 7.36 (d,
J = 8.3 Hz, 2 H), 7.28–7.24 (m, 1 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.07–
7.00 (m, 3 H), 6.40 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.1, 163.0 (d, J = 248.8 Hz),
158.8, 155.3, 153.3, 148.2, 134.0, 132.9, 130.6 (d, J = 8.0 Hz),
130.1 (d, J = 7.8 Hz), 129.2, 128.2, 127.9, 126.7, 125.5, 124.6,
121.4, 120.4, 120.1, 116.9, 116.1 (d, J = 21.3 Hz), 116.1, 76.8.
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H12O4S: 360.0456;
found: 360.0459.
19F NMR (400 MHz, CDCl3): δ = –111.2 (s).
HRMS (EI, 70 eV): m/z [M]+ calcd for C23H13FO4: 372.0798;
Acknowledgment
found: 372.0794.
Financial support from the National Natural Science Foundation of
China (21072031 and 20802009), and the Shanghai Municipal
Committee of Science and Technology (10ZR1404100) is greatly
acknowledged.
4-[4-(tert-Butyl)phenyl]-3-(3-oxo-1,3-dihydroisobenzofuran-1-
yl)-2H-chromen-2-one (6g)
Yield: 120 mg (98%); white solid; mp 213–214 °C.
IR (KBr): 3442, 2957, 1768, 1733, 1602, 1565, 1452, 1363, 1280,
1053, 995, 756, 723 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.3 Hz, 1 H), 7.61–
7.52 (m, 3 H), 7.47–7.41 (m, 2 H), 7.35–7.32 (m, 3 H), 7.21 (t,
J = 8.2 Hz, 1 H), 7.11 (d, J = 7.3 Hz, 2 H), 6.37 (s, 1 H), 1.37 (s, 9
H).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References
13C NMR (100 MHz, CDCl3): δ = 170.6, 157.0, 153.6, 152.8, 148.5,
134.1, 132.9, 129.5, 129.2, 128.6, 128.5, 128.2, 127.1, 126.2, 126.1,
125.7, 124.7, 121.6, 120.4, 120.1, 117.0, 77.4, 35.1, 31.5.
HRMS (EI, 70 eV): m/z [M]+ calcd for C27H22O4: 410.1518; found:
410.1525.
(1) For selected examples, see: (a) Murakami, A.; Gao, G.;
Omura, M.; Yano, M.; Ito, C.; Furukawa, H.; Takahashi, D.;
Koshimizu, K.; Ohigashi, H. Bioorg. Med. Chem. Lett. 2000,
10, 59. (b) Maier, W.; Schmidt, J.; Nimtz, M.; Wray, V.;
Strack, D. Phytochemistry 2000, 54, 473. (c) García-Argáez,
A. N.; Ramírez Apan, T. O.; Delgado, H. P.; Velazquez, G.;
Martinez-Vazquez, M. Planta Med. 2000, 66, 279. (d) Zhou,
P.; Takaishi, Y.; Duan, H.; Chen, B.; Honda, G.; Itoh, M.;
Takeda, Y.; Kodzhimatov, O. K.; Lee, K.-H. Phytochemistry
2000, 53, 689. (e) Khalmuradov, M. A.; Saidkhodzhaev, A.
I. Chem. Nat. Compd. 1999, 35, 364. (f) Kamalam, M.;
Jegadeesan, M. Indian Drugs 1999, 36, 484. (g) Tan, R. X.;
Lu, H.; Wolfender, J. L.; Yu, T. T.; Zheng, W. F.; Yang, L.;
Gafner, S.; Hostettmann, K. Planta Med. 1999, 65, 64.
(h) Vlietinck, A. J.; De Bruyne, T.; Apers, S.; Pieters, L. A.
Planta Med. 1998, 64, 97. (i) Bal-Tembe, S.; Joshi, D. D.;
Lakdawala, A. D. Indian J. Chem., Sect. B: Org. Chem. Incl.
Med. Chem. 1996, 35, 518. (j) Silvan, A. M.; Abad, M. J.;
Bermejo, P.; Villar, A.; Sollhuber, M. J. Nat. Prod. 1996, 59,
1183. (k) Yang, Y. M.; Hyun, J. W.; Sung, M. S.; Chung, H.
S.; Kim, B. K.; Paik, W. H.; Kang, S. S.; Park, J. G. Planta
Med. 1996, 62, 353. (l) Pereira, N. A.; Pereira, B. M. R.;
Nascimento, M. C.; Parente, J. P.; Mors, W. B. Planta Med.
1994, 60, 99. (m) Wu, J.; Liao, Y.; Yang, Z. J. Org. Chem.
2001, 66, 3642.
4-(Furan-2-yl)-3-(3-oxo-1,3-dihydroisobenzofuran-1-yl)-2H-
chromen-2-one (6h)
Yield: 60 mg (58%); white solid; mp 181–182 °C.
IR (KBr): 3419, 3157, 3044, 2921, 1772, 1723, 1603, 1540, 1454,
1380, 1353, 1280, 1211, 1185, 1055, 1016, 1001, 753, 721, 590
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 7.3 Hz, 1 H), 7.69 (d,
J = 1.8 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.60–7.56 (m, 2 H), 7.54–
7.49 (m, 2 H), 7.36–7.27 (m, 2 H), 6.84 (d, J = 3.6 Hz, 1 H), 6.67–
6.66 (m, 1 H), 6.48 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 170.4, 158.2, 153.4, 147.9, 145.1,
144.4, 143.9, 133.9, 132.7, 129.2, 127.5, 126.9, 125.6, 124.6, 121.7,
121.1, 118.4, 117.0, 115.1, 111.9, 77.3.
HRMS (EI, 70 eV): m/z [M]+ calcd for C21H12O5: 344.0685; found:
344.0687.
3-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)-4-(thien-2-yl)-2H-
chromen-2-one (6i)
Yield: 88 mg (82%); white solid; mp 215–216 °C.
(2) For selected examples, see: (a) Gellert, M.; O’Dea, M. H.;
Itoh, T.; Tomizawa, J. I. Proc. Natl. Acad. Sci. U.S.A. 1976,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1181–1190

1190
S.-C. Shen et al.
PAPER
73, 4474. (b) Murray, R. D. H.; Méndez, J.; Brown, S. A.
The Natural Coumarins: Occurrence, Chemistry, and
Biochemistry; Wiley: New York, 1982. (c) Ali, J. A.;
Jackson, A. P.; Howells, A. J.; Maxwell, A. Biochemistry
1993, 32, 2717. (d) Schio, L.; Chatreaux, F.; Klich, M.
Tetrahedron Lett. 2000, 41, 1543. (e) Xia, Y.; Yang, Z.-Y.;
Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.; Lee,
K.-H. J. Med. Chem. 2001, 44, 3932. (f) Chen, Y.-L.; Fang,
K.-C.; Sheu, J.-Y.; Hsu, S.-L.; Tzeng, C.-C. J. Med. Chem.
2001, 44, 2374. (g) Yamaguchi, T.; Fukuda, T.; Ishibashi,
F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755.
J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B.
Angew. Chem. Int. Ed. 2005, 44, 3275.
(6) (a) Lei, J.-G.; Hong, R.; Yuan, S.-G.; Lin, G.-Q. Synlett
2002, 927. (b) Chen, W.-W.; Xu, M.-H.; Lin, G.-Q.
Tetrahedron Lett. 2007, 48, 7508. (c) Wang, Z.-Q.; Feng,
C.-G.; Xu, M.-H.; Lin, G.-Q. J. Am. Chem. Soc. 2007, 129,
5336. (d) Lin, H.; Sun, X.-W. Tetrahedron Lett. 2008, 49,
5343. (e) Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2008, 10, 1259. (f) Zhang, B.; Xu, M.-H.; Lin, G.-Q.
Org. Lett. 2009, 11, 4712.
(7) The structural data have been deposited with the Cambridge
Crystallographic Data Centre (CCDC) with reference
number, CCDC 918175. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ [fax: +44(1223)336033, e-mail:
deposit@ccdc.cam.ac.uk].
(3) (a) Devon, T. K.; Scott, A. I. Handbook of Naturally
Occurring Compounds; Vol. 1; Academic Press: New York,
1975, 249–264. (b) Beck, J. J.; Chou, S.-C. J. Nat. Prod.
2007, 70, 891. (c) Atta-ur-Rahman, Bioactive Natural
Products (Part L), In Studies in Natural Products
Chemistry; Vol. 32; Elsevier Science: Oxford, 2006.
(d) Bentley, R. Chem. Rev. 2000, 100, 3801. (e) Shi, X.-Y.;
Li, C.-J. Adv. Synth. Catal. 2012, 354, 2933. (f) Yoganathan,
K.; Rossant, C.; Ng, S.; Huang, Y.; Butler, M. S.; Buss, A.
D. J. Nat. Prod. 2003, 66, 1116. (g) Zhou, J.; Gupta, K.;
Yao, J.; Ye, K.; Panda, D.; Giannakakaou, P.; Joshi, H. C.
J. Biol. Chem. 2002, 277, 39777.
(8) Wu, J.; Yang, Z.; Fathi, R.; Zhu, Q. US20040180950, 2004;
Chem. Abstr. 2004, 141, 260449.
(9) For selected examples, see: (a) Tsuji, J. Palladium Reagents
and Catalysts: New Perspectives for the 21st Century;
Wiley: New York, 2004. (b) Hassan, J.; Sévignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359. (c) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller,
M. Angew. Chem. Int. Ed. 2010, 49, 9047. (d) Diebold, C.;
Derible, A.; Becht, J.-M.; Drian, C. L. Tetrahedron 2013, 69,
264. (e) Scientific Background on the Nobel Prize in
Chemistry 2010: Palladium-Catalyzed Cross Couplings in
Organic Synthesis; The Royal Swedish Academy of
Sciences: Stockholm, 2010. (f) Shi, Z.; He, C. J. Org. Chem.
2004, 69, 3669. (g) Jia, C. G.; Piao, D. G.; Oyamada, J. Z.;
Lu, W. J.; Kitamura, T.; Fujiwara, Y. Science 2000, 287,
1992. (h) Fürstner, A.; Mamane, V. J. Org. Chem. 2002, 67,
6264. (i) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett.
2003, 5, 1055. (j) Youn, S. W.; Pastine, S. J.; Sames, D. Org.
Lett. 2004, 6, 581. (k) Martin-Matute, B.; Nevado, C.;
Cardenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003,
125, 5757. (l) Jia, C.; Piao, D.; Kitamura, T.; Fujiwara, Y.
J. Org. Chem. 2000, 65, 7516. (m) Diederich, F.; Stang, P. J.
Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH:
Weinheim, 1998. (n) Miyaura, N. Chem. Rev. 1995, 95,
2457. (o) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427.
(p) Heck, R. F. Palladium Reagents in Organic Synthesis;
Academic Press: San Diego, 1985.
(10) For selected samples, see: (a) Miyaura, N. Top. Curr. Chem.
2002, 219, 11. (b) Suzuki, A. J. Organomet. Chem. 1999,
576, 137. (c) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed.
2002, 31, 3176. (d) Zhang, L.; Meng, T.-H.; Fan, R.-H.; Wu,
J. J. Org. Chem. 2007, 72, 7279. (e) Wang, Z.-R.; Wu, J.
Tetrahedron 2008, 64, 1736. (f) Zhang, S.-S.; Wang, Z.-Q.;
Xu, M.-H.; Lin, G.-Q. Org. Lett. 2010, 12, 5546. (g) Ganina,
O. G.; Daras, E.; Bourgarel-Rey, V.; Peyrot, V.; Andresyuk,
A. N.; Finet, J.-P.; Fedorov, A. Y.; Beletskaya, I. P.;
Combes, S. Bioorg. Med. Chem. 2008, 16, 8806. (h) Gao,
W.; Luo, Y.; Ding, Q.-P.; Peng, Y.-Y.; Wu, J. Tetrahedron
Lett. 2010, 51, 136. (i) Vishnumurthy, K.; Makriyannis, A.
J. Comb. Chem. 2010, 12, 664. (j) Vieira, L. C. C.; Paixão,
M. W.; Corrêa, A. G. Tetrahedron Lett. 2012, 53, 2715.
(k) da Conceição Silva, A.; Senra, J. D.; Aguiar, L. C. S.;
Simas, A. B. C.; de Souza, A. L. F.; Malta, L. F. B.; Antunes,
O. A. C. Tetrahedron Lett. 2010, 51, 3883.
(4) (a) Druzgala, P.; Becker, C. WO2005100336, 2005; Chem.
Abstr. 2005, 143, 405800. (b) Druzgala, P.; Zhang, X-M.;
Pfister, J. R. US20040220258, 2004; Chem. Abstr. 2004,
141, 395419. (c) Lin, G.-Q.; Zhang, B.; Chen, W.-W.; Sun,
X.-W.; Li, R.; Xu, M.-H. CN101455661, 2009; Chem. Abstr.
2009, 151, 156250.
(5) (a) Grieco, P. A. Organic Synthesis in Water; Blackie
Academic and Professional: London, 1998. (b) Li, C.-J.;
Chan, T.-H. Organic Reactions in Aqueous Media; Wiley:
New York, 1997. (c) Lu, G.-P.; Cai, C.; Lipshutz, B. H.
Green Chem. 2013, 15, 105. (d) Hiraiz, H.; Uozumi, Y.
Chem. Commun. 2010, 46, 1103. (e) Savant, M. M.;
Pansuriya, A. M.; Bhuva, C. V.; Kapuriya, N.; Patel, A. S.;
Audichya, V. B.; Pipaliya, P. V.; Naliapara, Y. T. J. Comb.
Chem. 2010, 12, 176. (f) Li, C.-J.; Chen, L. Chem. Soc. Rev.
2006, 35, 68. (g) Pratt, L. A. Chem. Rev. 2002, 102, 2625.
(h) Carril, M.; SanMartin, R.; Tellitu, I.; Dominguez, E.
Org. Lett. 2006, 8, 1467. (i) Das, S.; Thakur, A. J. Eur. J.
Org. Chem. 2011, 2301. (j) Fischmeister, C.; Doucet, H.
Green Chem. 2011, 13, 741. (k) Li, C.-J. Chem. Rev. 2005,
105, 3095. (l) Herrerias, C. I.; Yao, X.; Li, Z.; Li, C.-J.
Chem. Rev. 2007, 107, 2546. (m) Butler, R. N.; Coyne, A. G.
Chem. Rev. 2010, 110, 6302. (n) Cornils, B.; Herrmann, W.
A. Aqueous-Phase Organometallic Catalysis: Concept and
Applications, 2nd ed.; Wiley-VCH: Weinheim, 2004.
(o) Ballini, R.; Barboni, L.; Fringeulli, F.; Pamieri, A.;
Pizzo, F.; Vaccaro, L. Green Chem. 2007, 9, 823. (p) Joó, F.;
Kathó, A. J. Mol. Catal. A: Chem. 1997, 116, 3. (q) Rideout,
D. C.; Breslow, R. J. Am. Chem. Soc. 1980, 102, 7816.
(r) Diels, O.; Alder, K. Ann. Chem. 1931, 490, 243.
(s) Lindström, U. M. Organic Reactions in Water;
Blackwell: Oxford, 2007. (t) Rasouli, M. A.; Mahdavi, M.;
Ranjbar, P. R.; Saeedi, M.; Shafiee, A.; Foroumadi, A.
Tetrahedron Lett. 2012, 53, 7088. (u) Lipshutz, B. H.; Taft,
B. R.; Abela, A. R.; Ghorai, S.; Karsovskiy, A.; Duplais, C.
Platinum Met. Rev. 2012, 56, 62. (v) Narayan, S.; Muldoon,
Synthesis 2013, 45, 1181–1190
© Georg Thieme Verlag Stuttgart · New York