Synthesis of substituted furans by platinum-catalyzed cyclization of propargylic oxiranes in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2008.06.043

The reaction of propargylic oxiranes with platinum catalyst in aqueous media is described. Furans having a variety of substituents were conveniently synthesized with high efficiency.

Full text of DOI:10.1016/j.tetlet.2008.06.043

Tetrahedron Letters 49 (2008) 5021–5023
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Synthesis of substituted furans by platinum-catalyzed cyclization
of propargylic oxiranes in aqueous media
*
Masahiro Yoshida , Mohammad Al-Amin, Kennosuke Matsuda, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of propargylic oxiranes with platinum catalyst in aqueous media is described. Furans having
a variety of substituents were conveniently synthesized with high efficiency.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 16 May 2008
Revised 7 June 2008
Accepted 10 June 2008
Available online 13 June 2008
Substituted furans are an important class of heteroaromatic
molecules which are components in a variety of biologically active
natural products and industrially useful compounds.1 They are also
extensively utilized as synthetic intermediates for acyclic, carbo-
cyclic, and heterocyclic compounds in organic synthesis.2 For these
reasons, considerable effort has been devoted toward finding an
efficient synthesis of substituted furans.3 Cycloisomerization of
propargylic oxiranes, in which a variety of reagents activate the
reaction that leads to the corresponding substituted furans, is
one of the most useful methodologies.4 For example, Hashmi
reported the gold-catalyzed cycloisomerization of propargylic
epoxides to furans.4h The reaction allows the synthesis of substi-
tuted furans under mild conditions, but the reaction examples
were limited to only 2,4-disubstituted furans, and the chemical
yields were moderate to low. During the course of our studies on
the reaction of propargylic oxiranes with a transition metal cata-
lyst,5 we focused on the reactivity of the platinum(II) catalyst.6
We describe herein a platinum-catalyzed reaction of propargylic
oxiranes, in which various substituted furans can be conveniently
synthesized in aqueous media with high efficiency.
The initial reactions were carried out using the phenyl-substi-
tuted propargylic oxirane 1a.7 When 1a was treated with
10 mol % of PtCl2 in dioxane at 100 °C for 180 min, the tetra-
hydrobenzofuran 2a was produced in 90% yield (Table 1, entry
1). Further attempts revealed that the presence of water enhanced
the reactivity (entries 2 and 3). Thus, the reaction in dioxane/H2O
(2/1) was complete within 10 min to afford the product 2a in
96% yield (entry 3). The yields of 2a decreased as the temperature
was lowered (entries 4–6). The reaction also proceeded in a mix-
ture of various aqueous solvents to give 2a in good yields (entries
7–11). The reactivity was maintained even in the presence of
5 mol % of platinum catalyst (entry 12), but with 2 mol % of catalyst
Table 1
Platinum-catalyzed cyclizations of 1a
Ph
O
O
Ph
10 mol % PtCl2
1a
2a
Entry
Solvent
Temp (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12a
13b
14c
15d
Dioxane
100
100
100
80
60
25
100
100
100
100
100
100
100
100
25
180
10
10
15
45
600
40
10
10
60
90
87
96
95
61
27
76
86
87
91
83
94
Dioxane/H2O (1/2)
Dioxane/H2O (2/1)
Dioxane/H2O (2/1)
Dioxane/H2O (2/1)
Dioxane/H2O (2/1)
MeCN/H2O (2/1)
THF/H2O (2/1)
DMF/H2O (2/1)
Toluene/H2O (2/1)
DMSO/H2O (2/1)
Dioxane/H2O (2/1)
Dioxane/H2O (2/1)
Dioxane/H2O (2/1)
MeCN
20
10
30
10
34
10
36 h
21 (29)e
a
5 mol % of PtCl2 was used.
2 mol % of PtCl2 was used.
10 mol % of HCl was used.
10 mol % of AuCl3 was used.
b
c
d
e
The yield in parentheses is based on recovered starting material.
the production of 2a decreased (entry 13). The Brønsted acid-cata-
lyzed reaction in the presence of HCl also proceeded, but the yield
was very low (entry 14). When 1a was treated with 10 mol % of
AuCl3 in MeCN at rt in accordance with the Hashmi’s procedure,4h
the product 2a was obtained in 21% yield (entry 15).
Table 2 shows our attempts using various substituted propar-
gylic oxiranes 1b–i. The reaction of 1b, having a butyl group at
the alkynyl position, with PtCl2 yielded the tetrahydrobenzofuran
* Corresponding author. Tel./fax: +81 88 633 7294.
E-mail address: yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.043

5022
M. Yoshida et al. / Tetrahedron Letters 49 (2008) 5021–5023
Table 2
Reactions with various propargylic oxiranes 1b–ia
R
H
O
O
O
R
PtX2
Entry
Substrate
Product
Yield
(%)
R
–X
(X = Cl or OH)
PtX
PtX2
Bu
Bn
O
Bu
Bn
4
1
3
O
1
83
O
R
O
R
2b
HX
1b
+
–
PtX2
–
H
O
PtX
H
O
2
92
5
2
2c
Scheme 1. Proposed reaction mechanism.
1c
OTBDPS
OH
O
OTBDPS
OH
O
Although the cause of the increased reactivity under aqueous con-
ditions is not clear, it is presumed that the platinum hydroxide
complex, which would enhance the reactivity of the proto-demet-
allation from the intermediate 5, exists as an active species in the
aqueous media.9
Information on the reaction mechanism was gained when the
reaction of 1a was conducted in D2O (Scheme 2). In this case,
97% of deuterium was incorporated at the 3-position on the furan
ring to give 2a-D in 89% yield. The result supports the hypothesis
that the reaction proceeds via the formation of the furanyl-plati-
num intermediate 5.
3
4
92
79
2d
1d
O
O
2e
1e
Ph
O
O
Ph
5
6
34
92
To further highlight the potential of this process, we tried to
trap the furanyl-platinum species with electrophilic iodine prior
2f
1f
Ph
O
O
Ph
Ph
O
O
Ph
10 mol % PtCl2
2g
1g
dioxane/D2O (2/1)
100 °C, 10 min
Ph
D
O
O
Ph
1a
2a-D 89%
7
89
97% deuterized
2h
Scheme 2. Reaction in the presence of D2O.
1h
O
O
OH
OH
8
90
Ph
O
NIS
1i
O
2i
Ph
10 mol % PtCl2
a
All reactions were carried out in the presence of 10 mol % of PtCl2 in dioxane/
MeCN/H2O (2/1)
100 °C, 10 min
H2O (2/l) at 100 °C for 10 min.
I
1a
6 69%
(22% in the absence of PtCl2)
O
2b in 83% yield (entry 1). The benzyl- and silyloxyethyl-substituted
propargylic oxiranes 1c and 1d were transformed into the corre-
sponding products 2c and 2d, each in 92% yield (entries 2 and 3).
Furthermore, the propargylic oxirane with a free hydroxyl group,
1e, was converted to 2e in 79% yield (entry 4). When the cyclopen-
tyl-substituted substrate 1f was subjected to the reaction, 5,6-
dihydrocyclopentafuran 2f was obtained in 34% yield (entry 5).
The low yield reflects the difficulties in constructing the strained
5,6-dihydro-4H-cyclopenta[b]furan ring system. Reactions of the
substrates 1g and 1h, which contain seven- and eight-membered
rings, successfully afforded the corresponding furans 2g and 2h
in 92% and 89% yields, respectively (entries 6 and 7). When the
reaction of the acyclic propargylic oxirane 1i was carried out, the
2,4-disubstituted furan 2i was produced in 90% yield (entry 8).8
A plausible mechanism for the reaction is shown in Scheme 1.
The platinum catalyst activates the carbon–carbon triple bond in
the substrate 1 for the addition of the nucleophile by coordination
as shown in 3. The epoxide-oxygen attacks the distal position of
the alkyne to form the cyclized intermediate 4. Aromatization by
elimination of the proton followed by proto-demetallation from
the resulting furanyl-platinum species 5 produces the furan 2.
Ph
I+
7
O
Ph
(HO)2B
OMe
10 mol % Pd(PPh3)4
K2CO3, toluene/EtOH
80 °C, 7 h
OMe
8 98%
6
O
Ph
Ph
10 mol % PdCl2(PPh3)2
10 mol % CuI, Et3N
MeCN, 50 °C, 24 h
Ph
9 93%
Scheme 3. Synthesis of tetra-substituted furans.

M. Yoshida et al. / Tetrahedron Letters 49 (2008) 5021–5023
5023
to protonation.10 Finally, after several attempts, the 3-iodotetra-
hydrobenzofuran 6 was produced in 69% yield as the sole product
when the substrate 1a was treated with NIS in MeCN/H2O (2:1) at
100 °C (Scheme 3). The product 6 was obtained even in the absence
of platinum catalyst, but the yield was decreased to 22%. This result
indicates that the reaction also proceeds via the iodonium interme-
diate 7, but the pathway involving the furanyl-platinum species 5
is preferred. The presence of the iodo functional group on the furan
ring provided an opportunity for further functionalization. For
example, the 4-methoxyphenyl group was introduced to give 8
in 98% yield using the Miyaura–Suzuki coupling reaction of 6 with
4-methoxyphenylboronic acid. Furthermore, 6 underwent Sono-
gashira coupling with phenylacetylene to produce the correspond-
ing 3-alkynylfuran 9 in 93% yield.
In conclusion, we have developed a methodology for the syn-
thesis of substituted furans using a platinum catalyst. The reac-
tions afforded a variety of substituted furans under aqueous
conditions, and the process provided an efficient and convenient
protocol for the preparation of furan derivatives. Efforts to extend
the scope of these reactions and their consequent application to
the syntheses of natural products are currently in progress.
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7. General procedure for platinum-catalyzed reactions: To a stirred solution of the
propargylic oxirane 1a (30.0 mg, 0.151 mmol) in 1,4-dioxane/H2O (2:1) was
added PtCl2 (4.0 mg, 0.015 mmol) at rt. After stirring for 10 min at 100 °C, the
mixture was cooled to rt and diluted with a minimum amount of Et2O. The
solution was then dried over MgSO4 and filtered through a small amount of
silica gel. Concentration at reduced pressure gave the residue, which was
chromatographed on silica gel with pentane Et2O (97:3) as eluent to give the
tetrahydrobenzofuran 2a (28.80 mg, 96%) as a colorless oil. IR (neat) 3079,
Acknowledgements
3058, 2926, 2849, 1634, 1603, 1549, 1486, 1443 cmÀ1 1H NMR (400 MHz,
;
CDCl3) d 7.61 (2H, d, J = 7.2 Hz), 7.39–7.29 (2H, m), 7.19 (1H, t, J = 7.2 Hz), 6.47
(1H, s), 2.66 (2H, t, J = 6.0 Hz), 2.45 (2H, t, J = 6.0 Hz), 1.89–1.86 (2H, m), 1.85–
1.83 (2H, m); 13C NMR (100 MHz, CDCl3) d 151.53, 150.75, 131.38, 128.51,
126.49, 123.19, 118.94, 105.97, 31.83, 29.69, 23.25, 23.10, 23.04, 22.10. HRMS
(ESI) m/z calcd for C14H14ONa 221.0942 (M++Na), found 221.0936.
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 Research Foundation for
Pharmaceutical Sciences.
8. Hashmi also reported the converion of 1i using a gold catalyst, in which the
reaction was complete in 17 h to afford 2i in 80% yield; see Ref. 4h.
9. Enhancement of the reactivity for the gold-catalyzed reaction in water has
been reported: Yao, X.; Li, C.-J. Org. Lett. 2006, 8, 1953.
10. Similar transformations using gold catalysts have been reported: (a) Buzas, A.;
Gagosz, F. Org. Lett. 2006, 8, 515; (b) Buzas, A.; Istrate, F.; Gagosz, F. Org. Lett.
2006, 8, 1957; (c) Crone, B.; Kirsh, S. F. J. Org. Chem. 2007, 72, 5435.
References and notes
1. Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry; Katritzky, A.
R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon, 1996; Vol. 2, p 395.