Palladium-catalyzed intramolecular hydroarylation of 4-benzofuranyl alkynoates. Approach to angelicin derivatives

Article abstract of DOI:10.1021/jo300021a

Intramolecular hydroarylation of 4-benzofuranyl alkynoates using Pd(OAc)₂ as catalyst took place selectively and efficiently, giving angular furocoumarin derivatives in high yields. The parent angelicin was obtained in 80% yield by this method.

Full text of DOI:10.1021/jo300021a

Note
pubs.acs.org/joc
Palladium-Catalyzed Intramolecular Hydroarylation of
4-Benzofuranyl Alkynoates. Approach to Angelicin Derivatives
Tsugio Kitamura* and Kensuke Otsubo
Department of Chemistry and Applied Chemistry, Graduate School of Science and Engineering, Saga University, Honjo-machi, Saga
840-8502, Japan
S
* Supporting Information
ABSTRACT: Intramolecular hydroarylation of 4-benzofuranyl alkynoates
using Pd(OAc)2 as catalyst took place selectively and efficiently, giving
angular furocoumarin derivatives in high yields. The parent angelicin was
obtained in 80% yield by this method. The starting 4-benzofuranyl alkynoates
were easily accessible from readily available 4-hydroxybenzofurans and
alkynoic acids.
urocoumarins are an important class of tricyclic aromatic
compounds consisting of a fused structure of coumarin and
furan nucleuses. They have long attracted much attention
because of their biological and industrial applications. Among
furocoumarin derivatives, psoralen (1) and angelicin (2)
(shown in Figure 1) are naturally occurring or synthetic
condensation,6 the Pechmann reaction,7 the Wittig reaction,5d,8
and related reactions.9
F
Intramolecular hydroarylation of alkynes is an efficient and
promising method for synthesizing carbocyclic and heterocyclic
aromatic compounds.10 Recently, several coumarin derivatives
have been prepared by transition-metal-catalyzed hydro-
arylation reactions.11 However, to the best of our knowledge,
there are no reports on the synthesis of furocoumarins by the
hydroarylation methodology (Scheme 1). In this paper, we
Scheme 1. Pyrone-Constructing Methodology Using
Intramolecular Hydroarylation
Figure 1. Representative furocoumarins.
compounds and are known to possess a high photobiological
activity, as discussed in many reviews.1 To summarize briefly,
psoralen and its analogues cause cell damage by covalent
binding to DNA on UVA irradiation (400−320 nm). Many
human skin diseases, such as psoriasis, T-cell lymphoma, and
vitiligo are commonly treated with a combination of psoralens
and UVA radiation. However, the linear psoralens cause
undesirable side effects such as genotoxicity2 and risk of skin
cancer3 because of their cross-linking with DNA. Angelicin and
its analogues exhibit interesting pharmacological activity, but
the angular structure reduces the undesirable side effects.4
Therefore, considerable attention has recently been paid to
angular furocoumarins such as 2.
report for the first time an efficient synthesis of furocoumarins
by palladium-catalyzed intramolecular hydroarylation.
Starting 4-hydroxybenzofuran derivatives 2 were synthesized
by conventional methods, as shown in Scheme 2. 4-
Hydroxybenzofuran (2a) was readily prepared in 60% yield
by aromatization of commercial 6,7-dihydro-1-benzofuran-
4(5H)-one (1) using palladium charcoal and 1-dodecene.12 2-
Hexyl-4-hydroxybenzofuran (2b) and 4-hydroxy-2-phenylben-
zofuran (2c) were conveniently prepared by the Sonogashira−
Hagihara coupling of 2-iodoresorcinol (3) with 1-octyne and
phenylacetylene in 50 and 60% yields, respectively. Then, 4-
benzofuranyl alkynoates 5 were prepared by condensation of 4-
hydroxybenzofurans 2 with alkynoic acids 4 using dicyclohex-
ylcarbodiimide (DCC) and 4-(dimethylamino)pyridine
(DMAP) (Scheme 3). The results are given in Table 1.
For the reasons mentioned above, many synthetic methods
for furocoumarins have been extensively developed so far.1a,b,g,5
There are two main approaches to construct the furocoumarin
skeleton, namely, furan-ring construction and pyrone-ring
construction. Among these methods, the methodology fusing
a furan ring on a coumarin nucleus has been traditionally and
widely applied for the synthesis of furocoumarins.1a,b On the
other hand, hydroxybenzofuran derivatives have been used for
the furocoumarin synthesis via the pyrone-ring construction as
starting materials, and the synthetic method involves the Perkin
Received: January 4, 2012
Published: February 28, 2012
© 2012 American Chemical Society
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Note
Scheme 2. Synthesis of 4-Hydroxybenzofurans 2
Table 2. Intramolecular Hydroarylation of 5
alkynoate 5
a
b
entry
R1
R2
furocoumarin 6
yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
6a
6b
6c
6d
6e
6f
80
84
80
95
70
71
86
83
74
80
87
81
Me
n-C5H11
Ph
n-C6H13
n-C6H13
n-C6H13
n-C6H13
Ph
H
Me
n-C5H11
Ph
6g
6h
6i
c
9
H
10
11
12
Ph
Me
6j
Scheme 3. Synthesis of 4-Benzofuranyl Alkynoates 5
Ph
n-C5H11
Ph
6k
6l
Ph
a
Reaction conditions: 5 (1 mmol), Pd(OAc)2 (0.01 mmol), TFA (0.5
b
mL), CH2Cl2 (0.5 mL), 30 °C, 5 h. Isolated yields by column
chromatography on silica gel. 24 h.
c
and phenyl, the furocoumarin derivatives 6b−d were obtained
in high yields of 80−95% (entries 2−4). Moreover, even if the
substituents like hexyl and phenyl groups existed on the
benzofuran, the furocoumarin derivatives 6e−l were obtained
in high yields of 70−87% (entries 5−12). Therefore, the
methodology using intramolecular hydroarylation is an
excellent method for furocoumarin synthesis because of its
convenient procedure and the high yield of products.
Thus, 4-hydroxybenzofurans 2 can be readily prepared and can
be transformed into 4-benzofuryl alkynoates 5.
Table 1. Synthesis of 4-Benzofuranyl Alkynoates 5
b
hydroxybenzofuran 2,
alkynoic acid 4,
product
5
yield
(%)
a
entry
R1
R2
To understand the role of TFA, we attempted the
intramolecular hydroarylation in the absence of TFA. The
same reaction of 5j (R1 = Ph, R2 = Me) was conducted in
CH2Cl2 in the absence of TFA at 30 °C for 5 h. The product 6j
was not observed, and the starting material was recovered
unchanged. Therefore, it is considered that TFA plays
important roles in this intramolecular hydroarylation reaction.
A possible mechanism is shown in Scheme 5. First, TFA
1
2
H
H
5a
5b
5c
5d
5e
5f
66
74
84
80
62
74
75
71
69
90
90
98
H
Me
3
H
n-C5H11
Ph
4
H
5
n-C6H13
n-C6H13
n-C6H13
n-C6H13
Ph
H
6
Me
7
n-C5H11
Ph
5g
5h
5i
8
9
H
Scheme 5. Possible Mechanism for Intramolecular
Hydroarylation Affording Furocoumarins
10
11
12
Ph
Me
5j
Ph
n-C5H11
Ph
5k
5l
Ph
a
Reaction conditions: 2 (3 mmol), 4 (3 mmol), DCC (3 mmol),
b
DMAP (0.3 mmol), CH2Cl2 (3 mL), rt, 3 h. Isolated yields by
column chromatography on silica gel.
The intramolecular hydroarylation reaction of 4-benzofuranyl
alkynoates was performed in the presence of palladium catalyst
in a mixed solvent of TFA and CH2Cl2, as shown in Scheme 4.
When the 4-benzofuranyl alkynoates were allowed to react at
30 °C for 5 h using 1 mol % of Pd(OAc)2, the furanocoumarins
were obtained in high yields. The results are given in Table 2.
The reaction of unsubstituted 4-benzofuranyl propiolate 5a
gave furanocoumarin 6a, i.e., angelicin, in 80% yield (entry 1).
Even when the substituents on the acetylenic bond were alkyl
Scheme 4. Intramolecular Hydroarylation of 5
undergoes ligand exchange of Pd(OAc)2 with acetate ion to
generate Pd(OCOCF3)2,13 which shows a higher reactivity due
to the increased electrophilicity. Second, TFA promotes the
protonation of the resulting palladium complex. Thus, the
resulting reactive palladium species (+PdL) coordinates with
the triple bond to induce intramolecular electrophilic aromatic
substitution, and then a furanocoumaryl palladium complex is
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Note
4-Benzofuranyl Propiolate (5a). The product was obtained in
66% yield as a colorless oil: H NMR (300 MHz, CDCl3) δ 3.10 (s,
formed. The resulting furanocoumaryl palladium complex
undergoes protonation by TFA to give furocoumarin 6, and
the palladium species (+PdL) is regenerated.
1
1H), 6.70−6.71 (m, 1H), 7.05−7.09 (m, 1H), 7.25−7.31 (m, 1H),
7.43 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 73.9, 77.2, 103.6, 110.0, 114.9, 120.7, 124.4, 142.6, 145.3,
150.3, 156.1; HRMS (EI) calcd for C11H6O3 186.0317, found
186.0318.
In summary, we have demonstrated a highly efficient
synthesis of furocoumarins by palladium-catalyzed intra-
molecular hydroarylation of 4-benzofuranyl alkynoates. The
4-benzofuranyl alkynoates are readily prepared by condensation
of easily available 4-hydroxybenzofurans and alkynoic acids.
Because of the simplicity of the process and the high yield of
the product, this procedure is the best method for angelicin
derivatives.
4-Benzofuranyl Butynoate (5b). The product was obtained in
1
74% yield as a colorless oil: H NMR (300 MHz, CDCl3) δ 2.00 (s,
3H), 6.71 (s, 1H), 7.04 (d, J = 8 Hz, 1H), 7.25 (t, J = 8 Hz, 1H), 7.39
(d, J = 8 Hz, 1H), 7.57 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 3.6,
71.8, 88.4, 103.7, 109.6, 115.0, 120.9, 124.3, 142.9, 145.1, 151.2, 156.1;
HRMS (EI) calcd for C12H8O3 200.0473, found 200.0470.
4-Benzofuranyl Octynoate (5c). The product was obtained in
84% yield as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J =
7.2 Hz, 3H), 1.30−1.43 (m, 4H), 1.58−1.65 (m, 2H), 2.40 (t, J = 7.2
Hz, 2H), 6.72−6.73 (m, 1H), 7.03−7.06 (m, 1H), 7.28 (t, J = 8.0 Hz,
1H), 7.40−7.43 (m, 1H), 7.60 (d, J = 2.4 Hz, 1H); 13C NMR (75
MHz,CDCl3) δ 13.7, 18.6, 21.9, 27.0, 30.8, 72.5, 92.6, 103.7, 109.6,
115.0, 120.9, 124.3, 143.0, 145.0, 151.3, 156.1; HRMS (EI) calcd for
C16H16O3 256.1099, found 256.1102.
4-Benzofuranyl Phenylpropiolate (5d). The product was
obtained in 80% yield as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 6.77 (d, J = 1.2 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 7.28−7.33
(m, 1H), 7.37−7.51 (m, 4H), 7.61−7.67 (m, 3H); 13C NMR (75
MHz,CDCl3) δ 80.0, 88.9, 103.7, 109.7, 115.0, 119.0, 120.9, 124.4,
128.5, 130.9, 133.0, 143.0, 145.1, 151.6, 156.1; HRMS (EI) calcd for
C17H10O3 262.0630, found 262.0634.
EXPERIMENTAL SECTION
■
Synthesis of 2-Iodoresorcinol.14 To resorcinol (1.10 g, 10
mmol) were added water (10 mL), iodine (2.72 g, 10.7 mmol), and
NaHCO3 (0.94 g, 11.2 mmol), and the mixture was stirred at room
temperature for 20 min. After the reaction, the remaining iodine was
quenched with aqueous sodium sulfite. The product was extracted
with ether, concentrated under reduced pressure, and purified by
column chromatography on silica gel with CH2Cl2/hexane as eluent.
2-Iodoresorcinol was obtained in 70% yield (1.65 g) as a colorless
solid: mp 101.2−104.0 °C; 1H NMR (300 MHz, acetone-d6) δ 6.49(d,
J = 8.1 Hz, 2H), 7.02 (t, J = 8.1 Hz, 1H), 8.73 (s, 2H); 13C NMR (75
MHz, acetone-d6) δ 75.3, 106.9, 130.2, 158.4.
Synthesis of 4-Hydroxybenzofuran (2a).12a A mixture of 6,7-
dihydro-1-benzofuran-4(5H)-one (1, 4.71 g, 34.6 mmol), Pd−C (3.1
g), 1-dodecene (10 mL), and decalin (60 mL) was refluxed for 24 h
with stirring under argon atmosphere. After the reaction, ethanol was
added to the reaction mixture, and the resulting precipitates were
filtered off. The filtrate was concentrated under reduced pressure and
submitted to column chromatography on silica gel. Elution with
hexane/EtOAc gave 2.78 g (60%) of 2a as colorless oil: 1H NMR (300
MHz, CDCl3) δ 5.80 (s, 1H), 6.60−6.63 (m, 1H), 6.83 (d, J = 1.8 Hz,
1H), 7.11−7.12 (m, 2H), 7.51−7.52 (m, 1H); 13C NMR (75 MHz,
CDCl3) δ 103.3, 104.5, 107.9, 116.7, 124.9, 143.7, 149.1, 156.6.
Synthesis of Substituted 4-Hydroxybenzofurans 2. A mixture
of 2-iodoresorcinol (3, 2.36 g, 10 mmol), 1-octyne or phenylacetylene
(20 mmol), PdCl2(PPh3)2 (246 mg, 0.35 mmol), CuI (100 mg, 0.525
mmol), Et3N (20 mL), and DMF (25 mL) was heated at 60 °C with
stirring under argon atmosphere. After reacting for 12 h, the reaction
mixture was slightly acidified with diluted HCl and extracted with
ether. The ethereal solution was dried over anhydrous Na2SO4 and
concentrated under reduced pressure. The residue was submitted to
column chromatography on silica gel. The product was isolated by
elution with CH2Cl2/hexane.
2-Hexylbenzofuran-4-yl Propiolate (5e). The product was
1
obtained in 62% yield as colorless oil. H NMR (300 MHz, CDCl3)
δ 0.77−0.81 (m, 3H), 1.16−1.30 (m, 6H), 1.58−1.67 (m, 2H), 2.64 (t,
J = 7.7 Hz, 2H), 2.98 (s, 1H), 6.22 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H),
7.05−7.11 (m, 1H), 7.21−7.23 (m, 1H); 13C NMR (75 MHz, CDCl3)
δ 14.0, 22.5, 27.4, 28.4, 28.8, 31.5, 74.2, 76.8, 98.9, 109.4, 114.6, 122.2,
123.2 141.8, 150.4, 155.9, 160.5; HRMS (EI) calcd for C17H18O3
270.1256, found 270.1257.
2-Hexylbenzofuran-4-yl Butynoate (5f). The product was
obtained in 74% yield as a colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.80 (t, J = 6.9 Hz, 3H), 1.17−1.32 (m, 6H), 1.61−1.66 (m,
2H), 1.96 (s, 3H), 2.65 (t, J = 7.5 Hz, 2H), 6.23 (d, J = 0.6 Hz, 1H),
6.88 (d, J = 8 Hz, 1H), 7.09 (t, J = 8 Hz, 1H), 7.22 (d, J = 8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 3.8, 13.9, 22.4, 27.4, 28.3, 28.8, 31.4,
72.0, 88.0, 98.9, 109.0, 114.7, 122.3, 123.1, 142.1, 151.3, 155.9, 160.3;
HRMS (EI) calcd for C18H20O3 284.1412, found 284.1414.
2-Hexylbenzofuran-4-yl Octynoate (5g). The product was
obtained in 75% yield as colorless oil: 1H NMR (300 MHz, CDCl3) δ
0.78−0.85 (m, 6H), 1.17−1.35 (m, 10H), 1.47−1.57 (m, 2H), 1.59−
1.68 (m, 2H), 2.26−2.31 (m, 2H), 2.64 (t, J = 8.1 Hz, 2H), 6.24 (s,
1H), 6.88 (d, J = 8 Hz, 1H), 7.08 (t, J = 8 Hz, 1H), 7.21 (d, J = 8. Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 14.0, 18.7, 22.0, 22.5, 27.1,
27.4, 28.3, 28.8, 30.9, 31.5, 72.6, 92.4, 99.0, 109.0, 114.7, 122.4, 123.1,
142.2, 151.5, 155.9, 160.2; HRMS (EI) calcd for C22H28O3 340.2038,
found 340.2039.
2-Hexyl-4-hydroxybenzofuran (2b). The product was obtained
in 50% yield as colorless oil: 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J
= 6.9 Hz, 3H), 1.26−1.38 (m, 6H), 1.67−1.77 (m, 2H), 2.73 (t, J = 7.2
Hz, 2H), 5.19 (s, 1H), 6.42 (s, 1H), 6.56−6.59 (m, 1H), 7.03−7.04
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.5, 27.6, 28.4, 28.8,
31.6, 98.2, 104.1, 107.7, 117.9, 123.7, 148.4, 156.3, 158.7; HRMS (EI)
calcd for C14H18O2 218.1307, found 218.1306.
2-Hexylbenzofuran-4-yl Phenylpropiolate (5h). The product
was obtained in 71% yield as colorless oil: 1H NMR (300 MHz,
CDCl3) δ 0.76 (t, J = 6.9 Hz, 3H), 1.14−1.26 (m, 6H), 1.53−1.63 (m,
2H), 2.59 (t, J = 7.5 Hz, 2H), 6.25 (d, J = 0.9 Hz, 1H), 6.89−6.92 (m,
1H), 7.05 (t, J = 8.1 Hz, 1H), 7.18−7.32 (m, 4H), 7.45−7.48 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 14.0, 22.5, 27.4, 28.4, 28.8, 31.5, 80.2,
88.8, 99.0, 109.2, 114.8, 119.3, 122.4, 123.2, 128.6, 131.0, 133.1, 142.2,
151.8, 155.9, 160.4; HRMS (EI) calcd for C23H22O3 346.1569, found
346.1570.
4-Hydroxy-2-phenylbenzofuran (2c). The product was ob-
tained in 60% yield as colorless crystals: mp 165−167 °C; H NMR
(300 MHz, acetone-d6) δ 6.71−6.74 (m, 1H), 7.08−7.18 (m, 2H),
7.34−7.39 (m, 2H), 7.44- 7.50 (m, 2H), 7.90−7.93 (m, 2H), 8.91 (s,
1H); 13C NMR (75 MHz, acetone-d6) δ 99.7, 103.6, 108.8, 119.4,
125.3, 126.2, 129.2, 129.7, 131.3, 152.0, 154.9, 157.3. Anal. Calcd for
C14H10O2: C, 79.98; H, 4.79. Found: C, 79.83; H, 4.80.
Synthesis of 4-Benzofuranyl Alkynoates 5. A mixture of 4-
hydroxybenzofuran 2 (3 mmol), alkynoic acid 4 (3 mmol), and DMAP
(37 mg, 0.3 mmol) in CH2Cl2 (3 mL) was stirred at 0 °C for 5 min.
To the mixture was added DCC (619 mg, 3 mmol), stirred at 0 °C for
5 min, and then stirred at room temperature for 3 h. The resulting
precipitates were filtered off, and the filtrate was treated with diluted
HCl. The product was extracted with CH2Cl2, concentrated under
reduced pressure, and isolated by column chromatography on silica gel
with CH2Cl2/hexane as eluent.
1
2-Phenylbenzofuran-4-yl Propiolate (5i). The product was
1
obtained in 69% yield as white crystals: mp 88 °C; H NMR (300
MHz, CDCl3) δ 3.11 (s, 1H, CH), 6.94 (d, J = 0.9 Hz, 1H), 7.04−7.07
(m, 1H), 7.24−7.46 (m, 5H), 7.83−7.86 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 74.2, 76.6, 98.2, 109.8, 115.2, 122.6, 124.3, 125.2,
128.8, 129.0, 129.8, 142.4, 150.4, 156.9, 156.6. Anal. Calcd for
C17H10O3: C, 77.85; H, 3.84. Found: C, 77.59; H, 3.94.
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Note
2-Phenylbenzofuran-4-yl Butynoate (5j). The product was
obtained in 90% yield as white crystals: mp 89−91 °C; 1H NMR (300
MHz, CDCl3) δ 2.03 (s, 3H), 6.94 (d, J = 0.9 Hz, 1H), 7.02−7.05 (m,
1H), 7.24 (t, J = 8.0 Hz, 1H), 7.28−7.42 (m, 5H), 7.80−7.83 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 3.8, 71.9, 88.5, 98.3, 109.4, 115.2,
122.7, 124.3, 125.0, 128.7, 128.9, 129.8, 142.6, 151.3, 155.9, 156.3.
Anal. Calcd for C18H12O3: C, 78.25; H, 4.38. Found: C, 78.19; H, 4.37.
2-Phenylbenzofuran-4-yl Octynoate (5k). The product was
obtained in 90% yield as a pale yellow oil: 1H NMR (300 MHz,
CDCl3) δ 0.89 (t, J = 7.1 Hz, 3H), 1.24−1.43 (m, 4H), 1.54−1.64 (m,
2H), 2.37 (t, J = 7.1 Hz, 2H), 6.95 (d, J = 0.9 Hz, 1H), 7.02−7.05 (m,
1H), 7.21−7.42 (m, 5H), 7.80−7.83 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 13.8, 18.7, 22.0, 27.0, 30.9, 72.5, 92.73, 98.3, 109.4, 115.2,
122.7, 124.2, 125.0, 128.7, 128.8, 129.7, 142.7, 151.4, 155.9, 156.2.
Anal. Calcd for C22H20O3: C, 79.50; H, 6.06. Found: C, 79.51; H, 6.13.
2-Phenylbenzofuran-4-yl Phenylpropiolate (5l). The product
157.0, 160.9, 161.1. Anal. Calcd for C17H18O3: C, 75.53; H, 6.71.
Found: C, 75.53; H, 6.69.
8-Hexyl-4-methyl-2H-furo[2,3-h]-1-benzopyran-2-one (6f).
The product was obtained in 71% yield as white crystals: mp 66−67
1
°C; H NMR (300 MHz, CDCl3) δ 0.87−0.92 (m, 3H), 1.29−1.42
(m, 6H), 1.69−1.79 (m, 2H), 2.42 (d, J = 1.2 Hz, 3H), 2.77 (t, J = 7.2
Hz, 2H), 6.16 (d, J = 1.2 H, 1H), 6.65 (d, J = 0.9 Hz, 1H), 7.26 (dd, J
= 0.9, 8.7 Hz, 1H), 7.34 (d, J = 8.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.8, 19.1, 22.4, 27.3, 28.2, 28.6, 31.3, 99.0, 107.5, 112.2,
114.1, 117.9, 119.0, 146.9, 153.4, 156.7, 160.7, 160.8. Anal. Calcd for
C18H20O3: C, 76.03; H, 7.09. Found: C, 75.90; H, 7.08.
8-Hexyl-4-pentyl-2H-furo[2,3-h]-1-benzopyran-2-one (6g).
The product was obtained in 86% yield as white crystals: mp 61−62
1
°C; H NMR (300 MHz, CDCl3) δ 0.76−0.83 (m, 6H), 1.18−1.33
(m, 10H), 1.55−1.65 (m, 4H), 2.60−2.68 (m, 4H), 6.05 (s, 1H), 6.56
(d, J = 0.9 Hz, 1H), 7.17 (dd, J = 0.9, 8.7 Hz, 1H), 7.28 (d, J = 8.7 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 13.6, 13.7, 22.1, 22.3, 27.2, 27.7,
28.0, 28.5, 31.2, 31.3, 32.0, 99.0, 107.4, 110.9, 113.3, 118.0, 118.7,
147.0, 156.4, 157.2, 160.6, 160.7. Anal. Calcd for C22H28O3: C, 77.61;
H, 8.29. Found: C, 77.69; H, 8.28.
1
was obtained in 98% yield as white crystals: mp 126−128 °C; H
NMR (300 MHz, CDCl3) δ 6.92 (d, J = 0.6 Hz, 1H), 7.00−7.03 (m,
1H), 7.14−7.43 (m, 8H), 7.55−7.58 (m, 2H), 7.75−7.78 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 80.2, 89.1, 98.4, 109.6, 115.3, 119.2, 122.8,
124.4, 125.1, 128.7, 128.8, 128.9, 129.9, 131.1, 133.2, 142.8, 151.8,
156.1, 156.4; HRMS (EI) calcd for C23H14O3 338.0943, found
338.0945.
8-Hexyl-4-phenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6h).
The product was obtained in 83% yield as a pale yellow oil: 1H
NMR (300 MHz, CDCl3) δ 0.90 (t, J = 6.9 Hz, 3H), 1.33−1.41 (m,
6H), 1.72−1.82 (m, 2H), 2.81 (t, J = 7.4 Hz, 2H), 6.31 (s, 1H), 6.78
(s, 1H), 7.28 (s, 2H), 7.45−7.53 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 13.8, 22.3, 27.2, 28.1, 28.6, 31.2, 99.1, 107.5, 112.3, 113.1,
118.2, 121.5, 128.2, 128.5, 129.3, 135.8, 147.5, 156.6, 156.7, 160.6,
160.9; HRMS (EI) calcd for C23H22O3 346.1569, found 346.1572.
8-Phenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6i). The prod-
Synthesis of Furocoumarins 6 by Pd-Catalyzed Intra-
molecular Hydroarylation. A mixture of alkynoate 5 (1 mmol)
and Pd(OAc)2 (2.2 mg, 0.01 mmol) in CH2Cl2 (0.5 mL) and TFA
(0.5 mL) was stirred at 30 °C for 5 h. In the case of 6i (R1 = Ph, R2 =
H), the mixture was stirred for 24 h. The reaction mixture was
neutralized with NaHCO3, extracted with CH2Cl2, and concentrated
under reduced pressure. The product was isolated by column
chromatography on silica gel using CH2Cl2/hexane as eluent.
2H-Furo[2,3-h]-1-benzopyran-2-one (6a). The product was
1
uct was obtained in 74% yield as white crystals: mp 220−223 °C; H
1
NMR (300 MHz, CDCl3) δ 6.37 (d, J = 9.6 Hz, 1H), 7.26−7.49 (m,
6H), 7.77 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 7.2 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 98.2, 108.5, 113.7, 114.1, 118.7, 123.6, 125.1, 128.9,
129.2, 129.5, 144.4, 148.1, 157.0, 157.2, 160.8. Anal. Calcd for
C17H10O3: C, 77.85; H, 3.84. Found: C, 77.56; H, 3.95.
obtained in 80% yield as white crystals: mp 135−137 °C; H NMR
(300 MHz, CDCl3) δ 6.38 (d, J = 9.6 Hz, 1H), 7.12 (d, J = 2.4 Hz,
1H), 7.37 (d, J = 8.6 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.69 (d, J = 2.4
Hz, 1H), 7.8 (d, J = 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
104.0, 108.7, 113.5, 114.1, 116.9, 123.8, 144.4, 145.8, 148.5, 157.3,
160.7. Anal. Calcd for C11H6O3: C, 70.97; H, 3.25. Found: C, 70.57;
H, 3.29.
4-Methyl-8-phenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6j).
The product was obtained in 80% yield as white crystals: mp 182−
183 °C; 1H NMR (300 MHz, CDCl3) δ 2.40 (d, J = 1.2 Hz, 1H), 6.17
(d, J = 1.2 Hz, 1H), 7.19 (s, 1H), 7.33−7.45 (m, 5H), 7.75−7.78 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 19.2, 98.2, 107.9, 112.6, 114.5,
118.4, 120.1, 124.8, 128.8, 129.0, 129.3, 147.3, 153.4, 156.7, 156.8,
169.6. Anal. Calcd for C18H12O3: C, 78.25; H, 4.38. Found: C, 78.32;
H, 4.15.
4-Methyl-2H-furo[2,3-h]-1-benzopyran-2-one (6b). The prod-
1
uct was obtained in 84% yield as white crystals: mp 186−189 °C; H
NMR (300 MHz, CDCl3) δ 2.48 (d, J = 1.2 Hz, 3H), 6.24 (q, J = 1.2
Hz, 1H), 7.11 (dd, J = 0.9, 2.4 Hz, 1H), 7.41 (dd, J = 0.9, 8.7 Hz, 1H),
7.49 (d, J = 8.7 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 19.3, 104.2, 108.3, 112.7, 114.4, 116.8, 120.4, 145.7, 147.8,
153.5, 157.1, 160.7. Anal. Calcd for C12H8O3: C, 72.00; H, 4.03.
Found: C, 72.09; H, 4.12.
4-Pentyl-8-phenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6k).
The product was obtained in 87% yield as white crystals: mp 135−
4-Pentyl-2H-furo[2,3-h]-1-benzopyran-2-one (6c). The prod-
1
136 °C; H NMR (300 MHz, CDCl3) δ 0.94 (t, J = 6.9 Hz, 3H),
1
uct was obtained in 80% yield as white solid: mp 159−160 °C; H
1.36−1.49 (m, 4H), 1.69−1.79 (m, 2H), 2.82 (t, J = 7.7 Hz, 2H), 6.27
(s, 1H), 7.37−7.55 (m, 6H), 7. 88 (d, J = 7.2 Hz, 2H); 13C NMR (75
MHz, CDCl3) δ 13.9, 22.4, 27.8, 31.5, 32.3, 98.4, 107.9, 111.4, 113.9,
118.7, 119.9, 124.9, 128.8, 129.0, 129.4, 147.6, 156.6, 156.8, 157.4,
160.9. Anal. Calcd for C22H20O3: C, 79.50; H, 6.06. Found: C, 79.25;
H, 6.14.
4,8-Diphenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6l). The
product was obtained in 81% yield as white crystals: mp 205−206
°C; 1H NMR (300 MHz, CDCl3) δ 6.35 (s, 1H), 7.37−7.56 (m, 11H),
7.86−7.90 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 98.5, 108.0, 112.9,
113.8, 118.9, 122.8, 125.0, 128.4, 128.8, 128.9, 129.2, 129.5, 129.6,
135.9, 148.2, 156.8, 157.0, 157.1, 160.8. Anal. Calcd for C23H14O3: C,
81.64; H, 4.17. Found: C, 81.81; H, 4.11.
NMR (300 MHz, CDCl3) δ 0.93 (t, J = 6.9 Hz, 3H), 1.41−1.43 (m,
4H), 1.68−1.79 (m, 2H), 2.80 (t, J = 7.7 Hz, 2H), 6.24 (s, 1H), 7.12
(d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 8.7 Hz, 1H),
7.66 (d, J = 2.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 13.8, 22.3,
28.0, 31.5, 32.4, 104.3, 108.2, 111.5, 113.8, 117.0, 120.2, 145.6, 148.1,
157.0, 157.5, 161.0. Anal. Calcd for C16H16O3: C, 74.98; H, 6.29.
Found: C, 74.87; H, 6.33.
4-Phenyl-2H-furo[2,3-h]-1-benzopyran-2-one (6d). The prod-
1
uct was obtained in 95% yield as white crystals: mp 165−166 °C; H
NMR (300 MHz, CDCl3) δ 6.32 (s, 1H), 7.15 (dd, J = 0.6, 2.4 Hz,
1H), 7.28−7.38 (m, 2H), 7.43−7.55 (m, 5H), 7.68 (d, J = 2.4 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 104.2, 108.2, 112.7, 113.4, 117.0,
122.9, 128.3, 128.7, 129.5, 135.8, 145.7, 148.4, 156.7, 157.2, 160.6.
Anal. Calcd for C17H10O3: C, 77.85; H, 3.84. Found: C, 77.84; H, 3.93.
8-Hexyl-2H-furo[2,3-h]-1-benzopyran-2-one (6e). The prod-
uct was obtained in 70% yield as yellowish crystals: mp 62−63 °C; 1H
NMR (300 MHz, CDCl3) δ 0.88−0.95 (m, 3H), 1.32−1.40 (m, 6H),
1.67−1.81 (m, 2H), 2.79 (t, J = 7.5 Hz, 2H), 6.34 (d, J = 9.6 Hz, 1H),
6.71 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.76
(d, J = 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.0, 22.5, 27.4,
28.3, 28.8, 31.5, 99.1, 108.2, 113.3, 113.7, 118.2, 122.5, 144.6, 147.7,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of 2a−c, 3, 5a−l, and 6a−l. This
material is available free of charge via the Internet at http://
pubs.acs.org.
2981
dx.doi.org/10.1021/jo300021a | J. Org. Chem. 2012, 77, 2978−2982

The Journal of Organic Chemistry
Note
(13) Marson, A.; Bart van Oort, A.; Mul, W. P. Eur. J. Inorg. Chem.
2002, 3028−3031.
(14) Tsujiyama, S.-i.; Suzuki, K. Org. Synth. 2007, 84, 272−284.
Organic Syntheses; Wiley: New York, 2009; Collect Vol. XI, pp 448−
497.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kitamura@cc.saga-u.ac.jp.
Notes
The authors declare no competing financial interest.
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