Regiocontrolled construction of furo[3,2-c]pyran-4-one derivatives by palladium-catalyzed cyclization of propargylic carbonates with 4-hydroxy-2-pyrones

Article abstract of DOI:10.1021/jo3027092

The reaction of propargylic carbonates with 4-hydroxy-2-pyrones in the presence of a palladium catalyst is described. By the choice of the reaction temperature, two types of the substituted furo[3,2-c]pyran-4-one derivatives were regioselectively synthesized, respectively.

Full text of DOI:10.1021/jo3027092

Note
pubs.acs.org/joc
Regiocontrolled Construction of Furo[3,2‑c]pyran-4-one Derivatives
by Palladium-Catalyzed Cyclization of Propargylic Carbonates with
4‑Hydroxy-2-pyrones
Masahiro Yoshida,* Tomomi Nakagawa, Kouki Kinoshita, and Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
S
* Supporting Information
ABSTRACT: The reaction of propargylic carbonates with 4-
hydroxy-2-pyrones in the presence of a palladium catalyst is
described. By the choice of the reaction temperature, two types
of the substituted furo[3,2-c]pyran-4-one derivatives were
regioselectively synthesized, respectively.
uro[3,2-c]pyran-4-ones are one of the important classes of
describe a novel methodology for the synthesis of furo[3,2-
c]pyran-4-one derivatives by the palladium-catalyzed reaction of
propargylic carbonates with 4-hydroxy-2-pyrones, in which the
regioselectivity of the reaction can be completely altered
depending on the reaction temperature.
The initial attempts were employed using methyl 1-phenyl-2-
propynyl carbonate (1a) and 4-hydroxy-5,6-dimethyl-2H-
pyran-2-one (2a) (Table 1). When 1a and 2a were reacted
F
heteroaromatic molecules which are components in a
variety of biologically active natural products.1 For this reason,
considerable effort has been devoted toward developing a novel
synthetic method for these compounds.2,3 However, the
number of applications to the synthesis of natural products is
limited,3 and development of a more practical and an efficient
methodology for the synthesis of substituted furo[3,2-c]pyran-
4-ones is still required.
The reactivity of propargylic esters with nucleophiles in the
presence of palladium catalyst have received considerable
attention and has been extensively studied for the synthesis of
complex molecules.4 The reaction of propargylic compounds
with bis-nucleophiles is one of the most studied processes to
date.5 In this reaction, a substrate having two nucleophilic
moieties within the molecule reacted sequentially with the (π-
propargyl)palladium complex, resulting from propargylic
compounds and palladium catalysts, to afford the cyclized
product (Scheme 1). Various hetero- and carbocyclic molecules
can be synthesized in one step by the choice of adequately
designed nucleophilic molecules. In planning our further
investigation of this cyclization process, we focused on the
nucleophilic activity of 4-hydroxy-2-pyrones. Herein, we
Table 1. Effect of Temperature in the Reaction of 1a with 2a
entry
temp (°C)
time (min)
product
3aa only
total yield (%)
1
2
3
4
5
25
50
360
60
5
89
85
85
86
79
3aa only
80
3aa only
100
120
5
3aa:4aa = 1:1.9
4aa only
5
Scheme 1
with 5 mol % of Pd2(dba)3·CHCl3 and 20 mol % DPPF in
NMP at 25 °C, the reaction successfully proceeded to give the
2-phenyl-substituted furopyranone 3aa in 89% yield as the sole
product (Table 1, entry 1). It is interesting to note that the 3-
benzylidene-subsituted furopyranone 4aa6 was also obtained as
the reaction temperature was increased. While the reactions at
Received: December 12, 2012
Published: January 30, 2013
© 2013 American Chemical Society
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Note
50 and 80 °C afforded the product 3aa solely (entries 2 and 3),
the regioisomer 4aa was produced together with 3aa when the
reaction was carried out at 100 °C (3aa:4aa = 1:1.9, 86% yield
in entry 4). Furthermore, 4aa was exclusively obtained in 79%
yield in the reaction at 120 °C (entry 5). From these results, it
is clear that the regioselectivity of the reaction is completely
altered depending on the reaction temperature.
Table 3. Reactions using Substituted Substrates 1b−f with 2a
We next conducted the reactions of various 3-substituted 4-
hydroxy-2-pyrones 2b−g with 1a (Table 2). When the reaction
entry
R
temp (°C)
product
yield (%)
Table 2. Reactions using Substituted Substrates 2b−g with
1a
1
2
p-fluorophenyl (1b)
o-fluorophenyl (1c)
3-furyl (1d)
25
25
3ba
3ca
3da
3ea
3fa
90
73
82
93
73
73
60
50
67
3
40
4
1-naphthyl (1e)
pentyl (1f)
25
5
25
6
p-fluorophenyl (1b)
o-fluorophenyl (1c)
3-furyl (1d)
120
120
120
120
120
4ba
4ca
4da
4ea
7
8
9
1-naphthyl (1e)
pentyl (1f)
10
(entries 1 and 2). Similarly, the corresponding products 3da,ea
were obtained in good yields from the reactions using 3-furyl-
and 1-naphthyl-substituted substrates 1d,e at low temperature
(entries 3 and 4). The reactions of the substrate 1f, which has a
pentyl group, also afforded the cyclized product 3fa in 73%
yield (entry 5). When the substrates 2b−e were subjected to
the reactions at 120 °C, the corresponding regioisomers 4ba−
ea were selectively produced in good yields, respectively
(entries 6−9). On the other hand, an unidentified mixture was
only obtained from the reaction of pentyl-substituted substrate
1f at 120 °C (entry 10).
We next attempted the reaction using propargylic carbonate
1g, which contains a phenyl group at the terminal position
(Scheme 2). When the palladium-catalyzed reactions of 1g with
Scheme 2
of 2b, having no substituent on the 3-position of the pyrone
ring, was carried out at 25 °C, the 2-phenyl-substituted
furopyranone 3ab was obtained in 47% yield (entry 1). Under
the same reaction conditions, the substrates 2c−f containing an
ethyl, a heptyl, an allyl, and a benzyl group, respectively, were
converted to the corresponding products 3ac−af in moderate
yields, respectively (entries 2−5). Similarly, the furopyranone
3ag was successfully obtained in 71% yield from the reaction of
the propargyl-substituted substrate 2g at 50 °C (entry 6). On
the other hand, when the 4-hydroxy-2-pyrones 2b−g were
subjected to the reaction at 120 °C, the corresponding 3-
benzylidene-subsituted furopyranones 4ab−ag were produced
as the sole products in each cases (entries 7−12).
Table 3 shows the examinations using various propargylic
carbonates 1b−f having a substituent at the propargylic
position. Under the reaction conditions at 25 °C, the substrates
1b,c containing a p-fluoro- and an o-fluorophenyl group
successfully reacted with 2a to produce the 2-aryl-substituted
furopyranones 3ba,ca in 90% and 73% yields, respectively
2a were carried out at 25 and 120 °C, the corresponding
products 3aa and 4aa, which were the same products from the
reaction of 1a with 2a, were obtained in 93% and 84% yields,
respectively. Since in all cases the resulting products 3aa−ag,
3ba−fa and 4aa−ag, 4ba−ea had been obtained as the sole
products, it was determined that the regioselectivity of the
reaction can be completely controlled depending on the
reaction temperature.
To clarify the regioselective outcome in the cyclization
reaction, the reactivity of the resulting product 3aa with
palladium at high temperature was examined. When 3aa was
treated with 5 mol % of Pd2(dba)3·CHCl3 and 20 mol % DPPF
in NMP at 120 °C, the regioisomer 4aa was produced as a
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Note
mixture with unreacted 3aa and the endo-olefinic isomer 5
(Scheme 3). The result clearly indicates that conversion of the
product 3 to the regioisomer 4 occurred during the reaction.
reaction of pentyl-substituted substrate 1f at 120 °C (entry 10
in Table 3), it is expected that β-elimination of palladium from
the corresponding (π-allyl)palladium intermediate would occur
prior to the cyclization.5l
In summary, the studies described above have resulted in the
regioselective synthesis of substituted furo[3,2-c]pyran-4-one
derivatives by a palladium-catalyzed nucleophilic cyclization of
propargylic carbonates with 4-hydroxy-2-pyrones. The regiose-
lectivity of the reaction can be completely controlled depending
on the reaction temperature. This methodology provides a new
protocol for the synthesis of biologically active natural products
containing a furopyranone moiety.
Scheme 3
EXPERIMENTAL SECTION
■
General Considerations. All nonaqueous reactions were carried
out under a positive atmosphere of argon in dried glassware unless
otherwise indicated. Materials were obtained from commercial
suppliers and used without further purification except when otherwise
noted. Solvents were dried and distilled according to the standard
protocol. The phrase “residue upon workup” refers to the residue
obtained when the organic layer was separated and dried over
anhydrous MgSO4 and the solvent was evaporated under reduced
pressure. Propargylic carbonates 1a,d−g5b,j and 4-hydroxy-2-pyrones
2a−g9 were prepared according to the procedures described in the
literature.
A plausible mechanism for the production of the
furopyranones 3 and 4 is shown in Scheme 4. By reaction
Scheme 4
General Procedure for the Synthesis of Propargylic
Carbonates 1. Synthesis of 1b. To a stirred solution of 1-(4-
fluorophenyl)prop-2-yn-1-ol (660 mg, 4.40 mmol) in CH2Cl2 (20 mL)
were added methyl chloroformate (0.41 mL, 5.28 mmol), and pyridine
(1.10 mL, 13.2 mmol) at 0 °C, and stirring was continued for 1 h at
the same temperature. The reaction mixture was diluted with aqueous
NH4Cl and extracted with AcOEt. The combined extracts were
washed with brine. The residue upon workup was chromatographed
on silica gel with hexane/AcOEt (1/7 v/v) as eluent to give
propargylic carbonate 1b (844 mg, 4.06 mmol, 92%) as a yellow oil.
1-(4-Fluorophenyl)prop-2-yn-1-yl Methyl Carbonate (1b): yield:
1
92%, 844 mg, yellow oil; IR (neat) 1752, 1260 cm−1; H NMR (400
MHz, CDCl3) δ 2.73 (1H, d, J = 2.4 Hz), 3.82 (3H, s), 6.26 (1H, d, J =
2.4 Hz), 7.05−7.11 (2H, m), 7.52−7.56 (2H, m); 13C NMR (100
MHz, CDCl3) δ 55.1 (CH3), 68.6 (CH), 76.6 (Cq), 79.3 (CH), 115.7
(CH, d, J = 21.5 Hz), 129.8 (CH, d, J = 8.3 Hz), 131.8 (Cq), 154.7
(Cq), 163.2 (Cq, d, J = 247.8 Hz); HRMS (ESI, TOF) m/z calcd for
C11H10O3F [M + H]+ 209.0614, found 209.0614.
1-(2-Fluorophenyl)prop-2-yn-1-yl Methyl Carbonate (1c): yield
1
81%, 1.01 g, pale yellow oil; IR (neat) 1756, 1260 cm−1; H NMR
(400 MHz, CDCl3) δ 2.72 (1H, d, J = 2.4 Hz), 3.83 (3H, s), 6.57 (1H,
d, J = 2.4 Hz), 7.07−7.12 (1H, m), 7.18−7.22 (1H, m) 7.35−7.41
(1H, m), 7.67−7.72 (1H, m); 13C NMR (100 MHz, CDCl3) δ 55.2
(CH3), 63.3 (CH, d, J = 5.0 Hz), 76.4 (Cq), 78.6 (CH), 115.7 (CH, d,
J = 20.6 Hz), 123.2 (Cq, d, J = 13.3 Hz), 124.4 (CH, d, J = 3.3 Hz),
129.4 (CH, d, J = 2.5 Hz), 131.3 (CH, d, J = 8.2 Hz) 154.5 (Cq),
160.1 (Cq, d, J = 249.5 Hz); HRMS (ESI, TOF) m/z calcd for
C11H9O3FNa [M + Na]+ 231.0433, found 231.0433.
General Procedure for the Synthesis of Furopyranones 3.
Synthesis of 3aa. To a stirred solution of propargylic carbonate 1a
(50.9 mg, 268 μmol) in NMP (2.0 mL) were added 4-hydroxy-5,6-
dimethyl-2H-pyran-2-one (2a; 45.0 mg, 321 μmol), Pd2(dba)3·CHCl3
(13.9 mg, 13.4 μmol), and DPPF (29.7 mg, 53.5 μmol) at 25 °C, and
stirring was continued for 6 h at the same temperature under an argon
atmosphere. After filtration of the reaction mixture using a small
amount of silica gel followed by concentration, the residue was
chromatographed on silica gel with AcOEt/hexane (1/4 v/v) as eluent
to give the 2-phenyl-substituted furopyranone 3aa (60.7 mg, 239
μmol, 89%) as colorless needles.
with the palladium catalyst, the propargylic carbonate 1 is
transformed to the (π-propargyl)palladium complex 6, which
reacts with the 4-hydroxy-2-pyrone 2 to lead to the (π-allyl)
palladium intermediate 7. The intermediate 7 is further
subjected to intramolecular attack of the hydroxy anion to
produce the cyclized product 3 or 4. The observed
regioselectivity dependence on the reaction temperature is
likely the result of kinetic and thermodynamic control in the
cyclization process.7 In the reaction at low temperature, it is
expected that the cyclization occurs via path A, which would be
more favorable than path B,8 leading to 3 as the kinetic product.
On the other hand, there would be equilibrium between the
products and (π-allyl)palladium intermediate 7 at high
temperature. As a result, this reversible process furnished the
thermodynamically more stable product 4 via path B. The
result from the reaction of the propargylic carbonates 1a,j to
produce the same product 3aa (Table 1 and Scheme 3)
supports a hypothesis that both reactions proceed via the
formation of the common (π-allyl)palladium intermediate 7. As
a reason for the formation of the unidentified mixture in the
6,7-Dimethyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-4(3H)-
one (3aa): yield 89%, 60.7 mg, colorless needles (MeOH, mp 92.9−
1
94.9 °C); IR (neat) 3034, 2929, 1728, 1564 cm−1; H NMR (400
MHz, CDCl3) δ 1.96 (3H, s), 2.29 (3H, s), 4.76 (1H, d, J = 2.8 Hz),
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Note
5.73 (1H, t, J = 3.2 Hz), 6.18 (1H, dd, J = 2.8 and 3.2 Hz), 7.34−7.42
(5H, m); 13C NMR (100 MHz, CDCl3) δ 9.0 (CH3), 17.5 (CH3),
90.6 (CH), 101.7 (Cq), 103.4 (Cq), 103.7 (CH2), 127.6 (CH), 128.8
(CH), 129.2 (CH), 138.1 (Cq), 142.7 (Cq), 159.3 (Cq), 162.2 (Cq),
173.7 (Cq); HRMS (ESI) m/z calcd for C16H14O3Na [M + Na]+
277.0841, found 277.0838.
172.5 (Cq); HRMS (ESI, TOF) m/z calcd for C24H28O3SiNa [M +
Na]+ 415.1705, found 415.1702.
2-(4-Fluorophenyl)-6,7-dimethyl-3-methylene-2H-furo[3,2-c]-
pyran-4(3H)-one (3ba): yield 90%, 58.7 mg, yellow needles (CHCl3,
1
mp 220.0−222.1 °C); IR (neat) 2928, 1727, cm−1; H NMR (400
MHz, CDCl3) δ 1.95 (3H, s), 2.26 (3H, s), 4.75 (1H, d, J = 2.4 Hz),
5.75 (1H, d, J = 3.2 Hz), 6.17 (1H, dd, J = 2.4 and 3.2 Hz), 7.08−7.12
(2H, m), 7.34−7.37 (2H, m); 13C NMR (100 MHz, CDCl3) δ 9.0
(CH3), 17.5 (CH3), 89.9 (CH), 101.8 (Cq), 103.4 (Cq), 104.0 (CH2),
115.8 (CH, d, J = 22.3 Hz), 129.8 (CH, d, J = 8.2 Hz), 134.1 (Cq, d, J
= 3.3 Hz), 142.6 (Cq), 159.3 (Cq), 162.4 (Cq), 163.3 (Cq, d, J =
247.0 Hz), 173.6 (Cq); HRMS (ESI, TOF) m/z calcd for C16H13O3F
[M]+ 272.0849, found 272.0848.
6-Methyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-4(3H)-one
(3ab): yield 47%, 15.4 mg, colorless needles (Et2O, mp 95.2−96.3
1
°C); IR (neat) 3091, 2920, 1732 1572 cm−1; H NMR (400 MHz,
CDCl3) δ 2.32 (3H, s), 4.78 (1H, d, J = 2.4 Hz), 5.73 (1H, d, J = 3.2
Hz), 6.03 (1H, s), 6.19 (1H, dd, J = 2.4 and 3.2 Hz), 7.34−7.44 (5H,
m); 13C NMR (100 MHz, CDCl3) δ 20.7 (CH3), 90.9 (CH), 95.9
(CH), 100.6 (Cq), 101.9 (Cq), 103.9 (CH2), 127.6 (CH), 128.9
(CH), 129.4 (CH), 138.0 (Cq), 141.9 (Cq), 166.7 (Cq), 173.6 (Cq);
HRMS (ESI) m/z calcd for C15H12O3 [M]+ 240.0786, found
240.0782.
2-(2-Fluorophenyl)-6,7-dimethyl-3-methylene-2H-furo[3,2-c]-
pyran-4(3H)-one (3ca): yield 73%, 47.8 mg, colorless plates (MeOH,
1
mp 119.8−121.3 °C); IR (neat) 2928, 2630, 1728 cm−1; H NMR
(400 MHz, CDCl3) δ 1.96 (3H, s), 2.29 (3H, s), 4.82 (1H, d, J = 2.8
Hz), 5.73 (1H, d, J = 2.8 Hz), 6.50 (1H, t, J = 2.8 Hz), 7.11−7.19 (2H,
m), 7.25−7.33 (1H, m), 7.36−7.41 (1H, m); 13C NMR (100 MHz,
CDCl3) δ 9.0 (CH3), 17.5 (CH3), 84.5 (CH, d, J = 3.3 Hz), 101.7
(Cq), 103.4 (Cq), 103.6 (CH2), 115.8 (CH, d, J = 21.5 Hz), 124.5
(CH, d, J = 3.3 Hz), 125.5 (Cq, d, J = 2.4 Hz), 128.9 (CH, d, J = 3.3
Hz), 131.0 (CH, d, J = 8.3 Hz), 141.9 (Cq), 159.2 (Cq), 160.8 (Cq, d,
J = 248.7 Hz), 162.3 (Cq), 173.8 (Cq); HRMS (ESI) m/z calcd for
C16H13O3F [M]+ 272.0849, found 272.0850.
7-Ethyl-6-methyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-
4(3H)-one (3ac): yield 78%, 60.0 mg, colorless needles (MeOH, mp
1
87.2−88.5 °C); IR (neat) 2971, 1730, 1560 cm−1; H NMR (400
MHz, CDCl3) δ 1.09 (3H, t, J = 7.4 Hz), 2.30 (3H, s), 2.41 (2H, q, J =
7.4 Hz), 4.77 (1H, d, J = 2.4 Hz), 5.72 (1H, d, J = 3.2 Hz), 6.19 (1H,
dd, J = 2.4 and 3.2 Hz), 7.32−7.42 (5H, m); 13C NMR (100 MHz,
CDCl3) δ 13.7 (CH3), 17.1 (CH3), 17.7 (CH2), 90.5 (CH), 102.1
(Cq), 103.7 (CH2), 109.7 (Cq), 127.3 (CH), 128.8 (CH), 129.2
(CH), 138.4 (Cq), 142.7 (Cq), 159.3 (Cq), 162.0 (Cq), 173.6 (Cq);
HRMS (ESI, TOF) m/z calcd for C17H16O3Na [M + Na]+ 291.0997,
found 291.0995.
2-(Furan-3-yl)-6,7-dimethyl-3-methylene-2H-furo[3,2-c]pyran-
4(3H)-one (3da): yield 82%, 41.6 mg, colorless needles (CHCl3, mp
1
130.9−132.6 °C); IR (neat) 3133, 2926, 1723, 1563 cm−1; H NMR
7-Heptyl-6-methyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-
4(3H)-one (3ad): yield 64%, 58.0 mg, yellow oil; IR (neat) 2926, 2855,
1732, 1560 cm−1; 1H NMR (400 MHz, CDCl3) δ 0.86 (3H, t, J = 6.8
Hz), 1.22−1.47 (10H, m), 2.29 (3H, s), 2.37 (2H, t, J = 7.6 Hz), 4.76
(1H, d, J = 2.4 Hz), 5.71 (1H, d, J = 3.2 Hz), 6.17 (1H, dd, J = 2.4 and
3.2 Hz); 13C NMR (100 MHz, CDCl3) δ 14.0 (CH3), 17.3 (CH3),
22.5 (CH2), 24.1 (CH2), 28.9 (CH2), 29.0 (CH2), 29.1 (CH2), 31.6
(CH2), 90.5 (CH), 101.1 (Cq), 103.6 (CH2), 108.5 (Cq), 127.3
(CH), 128.8 (CH), 129.1 (CH), 138.4 (Cq), 142.8 (Cq), 159.3 (Cq),
162.2 (Cq), 173.8 (Cq); HRMS (ESI) m/z calcd for C22H26O3 [M]+
338.1882, found 338.1888.
(400 MHz, CDCl3) δ 1.94 (3H, s), 2.27 (3H, s), 4.87 (1H, d, J = 2.8
Hz), 5.73 (1H, d, J = 3.2 Hz), 6.21 (1H, dd, J = 2.8 and 3.2 Hz), 6.41
(1H, dd, J = 1.6 and 0.8 Hz), 7.45 (1H, t, J = 1.6 Hz), 7.58 (1H, dd, J =
1.6 and 0.8 Hz); 13C NMR (100 MHz, CDCl3) δ 9.0 (CH3), 17.5
(CH3), 83.2 (CH), 101.6 (Cq), 103.4 (CH2), 103.5 (Cq), 109.2
(CH), 123.2 (Cq), 141.5 (Cq), 142.0 (CH), 144.1 (CH), 159.3 (Cq),
162.2 (Cq), 173.6 (Cq); HRMS (ESI) m/z calcd for C14H12O4Na [M
+ Na]+ 267.0633, found 267.0639.
6,7-Dimethyl-3-methylene-2-(naphthalen-1-yl)-2H-furo[3,2-c]-
pyran-4(3H)-one (3ea): yield 93%, 60.0 mg, yellow powder (MeOH,
1
mp 149.7−151.5 °C); IR (neat) 2927, 1724, 1563 cm−1; H NMR
7-Allyl-6-methyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-
4(3H)-one (3ae): yield 47%, 38.9 mg, yellow oil; IR (neat) 3064, 1732,
1560 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 3.14 (2H, dt,
J = 5.6 and 1.6 Hz), 4.78 (1H, d, J = 2.4 Hz), 5.01 (1H, dq, J = 17.2
and 1.6 Hz), 5.06 (1H, dq, J = 10.4 and 1.6 Hz), 5.72 (2H, d, J = 2.8
Hz), 5.81 (1H, ddt, J = 17.2, 10.4, and 5.6 Hz), 6.19 (1H, dd, J = 2.4
and 2.8 Hz), 7.36−7.43 (5H, m); 13C NMR (100 MHz, CDCl3) δ 17.3
(CH3), 27.9 (CH2), 90.6 (CH), 101.9 (Cq), 103.8 (CH2), 105.7 (Cq),
115.9 (CH2), 127.3 (CH), 128.8 (CH), 129.2 (CH), 133.6 (CH),
138.2 (Cq), 142.7 (Cq), 159.1 (Cq), 163.3 (Cq), 173.4 (Cq); HRMS
(ESI, TOF) m/z calcd for C18H16O3 [M]+ 280.1099, found 280.1093.
7-Benzyl-6-methyl-3-methylene-2-phenyl-2H-furo[3,2-c]pyran-
4(3H)-one (3af): yield 70%, 37.7 mg, yellow oil; IR (neat) 3030, 1731,
1559 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.33 (3H, s), 3.76 (2H, s),
4.79 (1H, d, J = 2.8 Hz), 5.72 (1H, d, J = 3.2 Hz), 6.18 (1H, dd, J = 2.8
and 3.2 Hz) 7.14−7.38 (10H, m); 13C NMR (100 MHz, CDCl3) δ
17.8 (CH3), 29.8 (CH2), 90.6 (CH), 102.1 (Cq), 104.0 (CH2), 107.4
(Cq), 126.6 (CH), 127.1 (CH), 128.0 (CH), 128.6 (CH), 128.8
(CH), 129.1 (CH), 138.2 (Cq), 138.2 (Cq), 142.6 (Cq), 159.1 (Cq),
163.5 (Cq), 173.5 (Cq); HRMS (ESI, TOF) m/z calcd for C22H18O3
[M]+ 330.1256, found 330.1263.
(400 MHz, CDCl3) δ 1.93 (3H, s), 2.30 (3H, s), 4.81 (1H, d, J = 2.4
Hz), 5.81 (1H, d, J = 3.2 Hz), 6.93 (1H, dd, J = 2.4 and 3.2 Hz), 7.47−
7.59 (4H, m), 7.90−7.94 (2H, m), 8.01−8.03 (1H, m); 13C NMR
(100 MHz, CDCl3) δ 9.0 (CH3), 17.5 (CH3), 88.5 (CH), 102.1 (Cq),
103.6 (Cq), 104.1 (CH2), 123.4 (CH), 125.2 (CH), 126.0 (CH),
126.7 (CH), 126.8 (CH), 128.9 (CH), 130.1 (CH), 131.5 (Cq), 132.9
(Cq), 134.0 (Cq), 141.8 (Cq), 159.5 (Cq), 162.3 (Cq), 173.7 (Cq);
HRMS (ESI, TOF) m/z calcd for C20H16O3 [M]+ 304.1099, found
304.1097.
6,7-Dimethyl-3-methylene-2-pentyl-2H-furo[3,2-c]pyran-4(3H)-
one (3fa): yield 73%, 36.1 mg, yellow oil; IR (neat) 2931, 1730, 1565
cm−1; 1H NMR (400 MHz, CDCl3) δ 0.90 (3H, t, J = 7.2 Hz), 1.31−
1.58 (6H, m), 1.69−1.78 (1H, m), 1.81−1.89 (1H, m), 1.95 (3H, s),
2.25 (3H, s), 4.83 (1H, d, J = 2.4 Hz), 5.27−5.31 (1H, m), 5.59 (1H,
d, J = 2.8 Hz); 13C NMR (100 MHz, CDCl3) δ 9.0 (CH3), 13.9
(CH3), 17.4 (CH3), 22.4 (CH2), 23.8 (CH2), 31.5 (CH2), 36.0
(CH2,), 89.8 (CH), 100.9 (CH2), 101.9 (Cq), 103.5 (Cq), 143.0
(Cq), 159.6 (Cq), 161.8 (Cq), 174.1 (Cq); HRMS (ESI, TOF) m/z
calcd for C15H20O3Na [M + Na]+ 271.1310, found 271.1312.
General Procedure for the Synthesis of Furopyranones 4.
Synthesis of 4aa. To a stirred solution of propargylic carbonate 1a
(52.1 mg, 274 μmol) in NMP (2.0 mL) were added 4-hydroxy-5,6-
dimethyl-2H-pyran-2-one (2a; 46.0 mg, 329 μmol), Pd2(dba)3·CHCl3
(14.2 mg, 13.8 μmol), and DPPF (30.4 mg, 54.8 μmol) at room
temperature. The reaction mixture was immediately heated to 120 °C,
and stirring was continued for 5 min at the same temperature under an
argon atmosphere. After filtration of the reaction mixture using a small
amount of silica gel followed by concentration, the residue was
chromatographed on silica gel with AcOEt/hexane (1/4 v/v) as eluent
to give the 3-benzylidene-substituted furopyranone 4aa (55.3 mg, 217
μmol, 79%) as colorless blocks.
7-[3-(tert-Butyldimethylsilyl)prop-2-yn-1-yl]-6-methyl-3-methyl-
ene-2-phenyl-2H-furo[3,2-c]pyran-4(3H)-one (3ag): yield 71%, 72.9
mg, colorless needles (MeOH, mp 106.8−108.4 °C); IR (neat) 2952,
1
2928, 2176, 1735, 1560 cm−1; H NMR (400 MHz, CDCl3) δ 0.06
(6H, s), 0.89 (9H, s), 2.39 (3H, s), 3.34 (2H, s), 4.79 (1H, d, J = 2.8
Hz), 5.73 (1H, d, J = 3.2 Hz), 6.21 (1H, d, J = 2.8 and 3.2 Hz), 7.34−
7.41 (5H, m); 13C NMR (100 MHz, CDCl3) δ −4.6 (CH3), 15.1
(CH2), 16.5 (Cq), 17.8 (CH3), 26.0 (CH3), 84.3 (Cq), 91.0 (CH),
101.8 (Cq), 102.1 (Cq), 104.1 (CH2), 104.3 (Cq), 127.5 (CH), 128.9
(CH), 129.3 (CH), 138.1 (Cq), 142.6 (Cq), 158.9 (Cq), 163.9 (Cq),
1690
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The Journal of Organic Chemistry
Note
(Z)-3-Benzylidene-6,7-dimethyl-2H-furo[3,2-c]pyran-4(3H)-one
(4aa): yield 79%, 55.3 mg, colorless blocks (CHCl3, mp 229.6−231.8
°C); IR (neat) 1712, 1560 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.00
(3H, s), 2.29 (3H, s), 5.54 (2H, d, J = 3.2 Hz), 7.16−7.23 (4H, m),
7.35−7.39 (2H, m); 13C NMR (100 MHz, CDCl3) δ 9.1 (CH3), 17.4
(CH3), 77.1 (CH2), 103.3 (Cq), 103.6 (Cq), 117.9 (CH), 126.4
(CH), 127.7 (CH), 128.7 (CH), 132.1 (Cq), 137.4 (Cq), 159.5 (Cq),
161.4 (Cq), 174.0 (Cq); HRMS (ESI, TOF) m/z calcd for C16H15O3
[M + H]+ 255.1021, found 255.1024.
X-ray Crystallographic Analysis of Compound 4aa. A colorless
block crystal having approximate dimensions of 0.80 × 0.50 × 0.30
mm was mounted on a glass fiber. All measurements were made on a
Rigaku RAXIS RAPID imaging plate area detector with graphite-
monochromated Mo Kα radiation. The structure was solved by direct
methods (SIR97) and expanded using Fourier techniques (DIR-
DIF99). The non-hydrogen atoms were refined anisotropically.
Hydrogen atoms were refined using the riding model. The final
cycle of full-matrix least-squares refinement on F was based on 2277
observed reflections (I > 0.00σ(I)) and 186 variable parameters and
converged (largest parameter shift was 0.00 times its esd) with
δ 2.32 (3H, s), 3.80 (2H, s), 5.54 (2H, d, J = 2.8 Hz), 7.15−7.39 (11H,
m); 13C NMR (100 MHz, CDCl3) δ 17.7 (CH3), 29.8 (CH2), 77.2
(CH2), 103.7 (Cq), 107.3 (Cq), 118.2 (CH), 126.5 (CH), 126.7
(CH), 127.7 (CH), 127.9 (CH), 128.7 (CH), 128.7 (CH), 131.8
(Cq), 137.3 (Cq), 138.1 (Cq), 159.3 (Cq), 162.7 (Cq), 173.6 (Cq);
HRMS (ESI, TOF) m/z calcd for C22H19O3 [M + H]+ 331.1334,
found 331.1337.
(Z)-3-Benzylidene-7-[3-(tert-butyldimethylsilyl)prop-2-yn-1-yl]-6-
methyl-2H-furo[3,2-c]pyran-4(3H)-one (4ag): yield 64%, 64.9 mg,
yellow needles (CHCl3, mp 109.9−112.5 °C); IR (neat) 2952, 2927,
1
2856, 2171, 1718, 1560 cm−1; H NMR (400 MHz, CDCl3) δ 0.07
(6H, s), 0.91 (9H, s), 2.40 (3H, s), 3.38 (2H, s), 5.56 (2H, d, J = 3.2
Hz), 7.16−7.26 (4H, m), 7.36−7.40 (2H, m); 13C NMR (100 MHz,
CDCl3) δ −4.7 (CH3), 15.0 (CH2), 16.5 (Cq), 17.7 (CH3), 26.0
(CH3), 77.3 (CH2), 84.4 (Cq), 101.8 (Cq), 103.6 (Cq), 104.3 (Cq),
118.2 (CH), 126.5 (CH), 127.8 (CH), 128.7 (CH), 131.8 (Cq), 137.2
(Cq), 159.0 (Cq), 163.1 (Cq), 172.6 (Cq); HRMS (ESI, TOF) m/z
calcd for C24H29O3Si [M + H]+ 393.1886, found 393.1885.
(Z)-3-(4-Fluorobenzylidene)-6,7-dimethyl-2H-furo[3,2-c]pyran-
4(3H)-one (4ba): yield 73%, 62.3 mg, colorless needles (CHCl3, mp
1
220.0−222.1 °C); IR (neat) 2922, 1710, 1563 cm−1; H NMR (400
unweighted and weighted agreement factors of R = 0.084 and Rw
=
0.155. Crystal data for 4aa: C16H14O3, Mr = 254.28, triclinic, space
MHz, CDCl3) δ 2.00 (3H, s), 2.29 (3H, s), 5.50 (2H, d, J = 3.2 Hz),
7.04−7.16 (5H, m); 13C NMR (100 MHz, CDCl3) δ 9.1 (CH3), 17.4
(CH3), 76.9 (CH2), 103.2 (Cq), 103.6 (Cq), 115.7 (CH, d, J = 21.4
Hz), 116.8 (CH), 129.2 (CH, d, J = 7.3 Hz), 131.6 (Cq), 133.6 (Cq),
159.5 (Cq), 161.3 (Cq, d, J = 246.2 Hz), 161.5 (Cq), 173.9 (Cq);
HRMS (ESI, TOF) m/z calcd for C16H14O3F [M + H]+ 273.0927,
found 273.0927.
group P1 (No. 2), a = 7.3396(6) Å, b = 8.7082(6) Å, c = 9.9553(9) Å,
̅
β = 74.592(3)°, V = 611.71(9) Å3, Z = 2, Dc = 1.380 g/cm3, F(000) =
268.00, μ(Mo Kα) = 0.95 cm−3.
(Z)-3-Benzylidene-6-methyl-2H-furo[3,2-c]pyran-4(3H)-one
(4ab): yield 69%, 29.4 mg, yellow needles (CHCl3, mp 187.7−190.4
°C); IR (neat) 1720, 1573 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.33
(3H, s), 5.54 (2H, d, J = 3.2 Hz), 6.08 (1H, s), 7.16−7.24 (4H, m),
7.35−7.39 (2H, m); 13C NMR (100 MHz, CDCl3) δ 20.7 (CH3), 77.2
(CH2), 96.0 (CH), 103.4 (Cq), 118.0 (CH), 126.5 (CH), 127.8
(CH), 128.7 (CH), 131.3 (Cq), 137.2 (Cq), 159.5 (Cq), 165.8 (Cq),
173.8 (Cq); HRMS (ESI, TOF) m/z calcd for C15H12O3 [M]+
240.0786, found 240.0784.
(Z)-3-(2-Fluorobenzylidene)-6,7-dimethyl-2H-furo[3,2-c]pyran-
4(3H)-one (4ca): yield 60%, 45.1 mg, yellow needles (CHCl3, mp
1
208.6−212.1 °C); IR (neat) 2360, 1719, cm−1; H NMR (400 MHz,
CDCl3) δ 1.99 (3H, s), 2.29 (3H, s), 5.45 (2H, d, J = 3.2 Hz), 7.05−
7.27 (5H, m); 13C NMR (100 MHz, CDCl3) δ 9.0 (CH3), 17.5
(CH3), 77.2 (CH2), 103.2 (Cq), 103.6 (Cq), 110.0 (CH, d, J = 5.0
Hz), 115.8 (CH, d, J = 23.1 Hz), 124.0 (CH, d, J = 4.1 Hz), 125.2 (Cq,
d, J = 13.2 Hz), 128.1 (CH, d, J = 9.1 Hz), 128.3 (CH, d, J = 3.4 Hz),
134.3 (Cq), 159.3 (Cq), 159.7 (Cq, d, J = 248.6 Hz), 161.8 (Cq),
174.6 (Cq); HRMS (ESI, TOF) m/z calcd for C16H13O3F [M]+
272.0849, found 272.0850.
(Z)-3-Benzylidene-7-ethyl-6-methyl-2H-furo[3,2-c]pyran-4(3H)-
one (4ac): yield 71%, 54.0 mg, yellow needles (MeOH, mp 205.5−
1
206.9 °C); IR (neat) 2963, 1720, 1558 cm−1; H NMR (400 MHz,
CDCl3) δ 1.13 (3H, t, J = 7.6 Hz), 2.31 (3H, s), 2.44 (2H, q, J = 7.6
Hz), 5.55 (2H, d, J = 3.2 Hz), 7.16−7.23 (4H, m), 7.36−7.39 (2H,
m); 13C NMR (100 MHz, CDCl3) δ 13.6 (CH3), 17.0 (CH3), 17.8
(CH2), 77.0 (CH2), 103.6 (Cq), 109.9 (Cq), 117.9 (CH), 126.4
(CH), 127.7 (CH), 128.7 (CH), 132.0 (Cq), 137.4 (Cq), 159.5 (Cq),
161.2 (Cq), 173.8 (Cq); HRMS (ESI, TOF) m/z calcd for
C17H16O3Na [M + Na]+ 291.0997, found 291.1004.
(Z)-3-(Furan-3-ylmethylene)-6,7-dimethyl-2H-furo[3,2-c]pyran-
4(3H)-one (4da): yield 50%, 43.0 mg, yellow needles (CHCl3, mp
1
186.3−190.2 °C); IR (neat) 2357, 1708, 1568 cm−1; H NMR (400
MHz, CDCl3) δ 1.99 (3H, s), 2.29 (3H, s), 5.35 (2H, d, J = 3.2 Hz),
6.34−6.36 (1H, m), 6.94 (1H, t, J = 3.2 Hz), 7.36−7.38 (1H, m),
7.43−7.45 (1H, m); 13C NMR (100 MHz, CDCl3) δ 9.0 (CH3), 17.4
(CH3), 77.1 (CH2), 102.9 (Cq), 103.7 (Cq), 107.4 (CH), 109.7
(CH), 123.5 (Cq), 130.8 (Cq), 140.2 (CH), 143.5 (CH), 149.5 (Cq),
161.2 (Cq), 174.2 (Cq); HRMS (ESI, TOF) m/z calcd for C14H12O4
[M]+ 244.0736, found 244.0740.
(Z)-3-Benzylidene-7-heptyl-6-methyl-2H-furo[3,2-c]pyran-4(3H)-
one (4ad): yield 61%, 55.2 mg, yellow needles (MeOH, mp 152.1−
1
153.9 °C); IR (neat) 2953, 2927, 2855, 1724 cm−1; H NMR (400
MHz, CDCl3) δ 0.89 (3H, t, J = 7.0 Hz), 1.25−1.53 (10H, m), 2.30
(3H, s), 2.40 (2H, t, J = 7.8 Hz), 5.54 (2H, d, J = 3.2 Hz), 7.16−7.26
(4H, m), 7.35−7.39 (2H, m); 13C NMR (100 MHz, CDCl3) δ 14.0
(CH3), 17.3 (CH3), 22.6 (CH2), 24.3 (CH2), 29.0 (CH2), 29.1 (CH2),
29.2 (CH2), 31.7 (CH2), 77.0 (CH2), 103.5 (Cq), 108.6 (Cq), 117.8
(CH), 126.4 (CH), 127.7 (CH), 128.7 (CH), 132.1 (Cq), 137.3 (Cq),
159.5 (Cq), 161.4 (Cq), 173.9 (Cq); HRMS (ESI, TOF) m/z calcd
for C22H26O3Na [M + Na]+ 361.1780, found 361.1780.
(Z)-6,7-Dimethyl-3-(naphthalen-1-ylmethylene)-2H-furo[3,2-c]-
pyran-4(3H)-one (4ea): yield 67%, 53.1 mg, yellow powder (CHCl3,
1
mp 198.8−202.3 °C); IR (neat) 2360, 1702, 1560 cm−1; H NMR
(400 MHz, CDCl3) δ 2.00 (3H, s), 2.32 (3H, s), 5.48 (2H, d, J = 3.2
Hz), 7.21−7.22 (1H, m), 7.44−7.55 (3H, m), 7.74−7.76 (1H, m),
7.80−7.86 (2H, m), 8.21−8.23 (1H, m); 13C NMR (100 MHz,
CDCl3) δ 9.1 (CH3), 17.5 (CH3), 77.2 (CH2), 103.3 (Cq), 103.7
(Cq), 114.8 (CH), 123.9 (CH), 124.6 (CH), 125.2 (CH), 126.1
(CH), 126.2 (CH), 127.4 (CH), 128.4 (CH), 131.4 (Cq), 133.8 (Cq),
134.2 (Cq), 134.4 (Cq), 159.6 (Cq), 161.6 (Cq), 174.5 (Cq); HRMS
(ESI, TOF) m/z calcd for C20H16O3 [M]+ 304.1099, found 304.1096.
3,6,7-Trimethyl-2-phenyl-4H-furo[3,2-c]pyran-4-one (5): yield
16% from 3aa, 5.0 mg, colorless needles (CHCl3, mp 157.0−158.2
°C); IR (neat) 2360, 2341, 1735 cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.20 (3H, s), 2.32 (3H, s), 2.57 (3H, s), 7.31−7.37 (1H, m), 7.45−
7.52 (2H, m), 7.68−7.71 (2H, m); 13C NMR (100 MHz, CDCl3) δ
9.2 (CH3), 10.0 (CH3), 16.8 (CH3), 103.3 (Cq), 110.3 (Cq), 115.0
(CHq), 126.0 (CH), 127.9 (CH), 128.7 (CH), 130.3 (Cq), 149.8
(Cq), 155.4 (Cq), 160.4 (Cq), 161.1 (Cq); HRMS (ESI, TOF) m/z
calcd for C16H15O3 [M + H]+ 255.1021, found 255.1020.
(Z)-7-Allyl-3-benzylidene-6-methyl-2H-furo[3,2-c]pyran-4(3H)-
one (4ae): yield 68%, 47.2 mg, yellow needles (CHCl3, mp 184.1−
1
187.6 °C); IR (neat) 2923, 1720, 1560 cm−1; H NMR (400 MHz,
CDCl3) δ 2.29 (3H, s), 3.18 (2H, dt, J = 5.6 and 1.6 Hz), 5.04 (1H,
dq, J = 16.8 and 1.6 Hz), 5.09 (1H, dq, J = 10.4 and 1.6 Hz), 5.54 (2H,
d, J = 3.2 Hz), 5.84 (1H, ddt, J = 16.8, 10.4, and 5.6 Hz), 7.16−7.23
(4H, m), 7.35−7.39(2H, m); 13C NMR (100 MHz, CDCl3) δ 17.3
(CH3), 28.0 (CH2), 77.1 (CH2), 103.5 (Cq), 105.9 (Cq), 116.1
(CH2), 118.0 (CH), 126.4 (CH), 127.7 (CH), 128.7 (CH), 131.9
(Cq), 133.6 (CH), 137.3 (Cq), 159.3 (Cq), 162.5 (Cq), 173.6 (Cq);
HRMS (ESI, TOF) m/z calcd for C18H16O3 [M]+ 280.1099, found
280.1089.
(Z)-7-Benzyl-3-benzylidene-6-methyl-2H-furo[3,2-c]pyran-4(3H)-
one (4af): yield 64%, 55.4 mg, yellow needles (MeOH, mp 197.0−
1
198.3 °C); IR (neat) 1728, 1557 cm−1; H NMR (400 MHz, CDCl3)
1691
dx.doi.org/10.1021/jo3027092 | J. Org. Chem. 2013, 78, 1687−1692

The Journal of Organic Chemistry
Note
J. Chem. 1993, 11, 91. (d) Labrosse, J.-R.; Lhoste, P.; Sinou, D.
Tetrahedron Lett. 1999, 40, 9025. (e) Labrosse, J.-R.; Lhoste, P.; Sinou,
D. Org. Lett. 2000, 2, 527. (f) Damez, C.; Labrosse, J.-R.; Lhoste, P.;
Sinou, D. Tetrahedron Lett. 2003, 44, 557. (g) Duan, X.-H.; Liu, X.-Y.;
Guo, L.-N.; Liao, M.-C.; Liu, W.-M.; Liang, Y.-M. J. Org. Chem. 2005,
70, 6980. (h) Yoshida, M.; Higuchi, M.; Shishido, K. Tetrahedron Lett.
2008, 49, 1678. (i) Yoshida, M.; Higuchi, M.; Shishido, K. Org. Lett.
2009, 11, 4752. (j) Yoshida, M.; Higuchi, M.; Shishido, K. Tetrahedron
2010, 66, 2675. (k) Yoshida, M.; Sugimura, C.; Shishido, K. Org. Lett.
2011, 13, 3482. (l) Yoshida, M.; Ohno, S.; Shishido, K. Chem. Eur. J.
2012, 18, 1604.
ASSOCIATED CONTENT
■
S
* Supporting Information
A CIF file and figures giving X-ray crystallographic data for 4aa
1
and H and 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yoshi@tokushima-u.ac.jp
Notes
■
(6) The structure of the resulting product 4aa was confirmed by an
X-ray crystallographic analysis.
(7) For other examples of regio- or stereochemical control depending
on the reaction temperature, see: (a) Blaskovich, M. A.; Rickards, R.
W. Tetrahedron Lett. 1998, 39, 3617. (b) Arai, Y.; Nakazaki, J.; Segawa,
H. Tetrahedron Lett. 2008, 49, 5810. (c) Alonso, F.; Davies, S. G.;
Elend, A. S.; Smith, A. D. Org. Biomol. Chem. 2009, 7, 518.
(8) It is known that intramolecular nucleophilic attack at the (π-allyl)
palladium predominantly occurs at the more substituted carbon.4,5
(9) Yoshida, M.; Takai, H.; Shishido, K. Heterocycles 2010, 82, 881.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This study was supported in part by a Grant-in-Aid for the
Encouragement of Young Scientists (B) from the Japan Society
for the Promotion of Science (JSPS) and the Program for the
Promotion of Basic and Applied Research for Innovations in
the Bio-oriented Industry (BRAIN).
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