Microwave-assisted synthesis of difuran and furan-thiophene via Suzuki coupling

Article abstract of DOI:10.1002/jccs.200500119

2-Tetrahydropyranyloxymethylated difuran and furanthiophene compounds have been obtained in high yields from the coupling of furan boronic acid/furfuryl boronic acid by focused microwave irradiation.

Full text of DOI:10.1002/jccs.200500119

Journal of the Chinese Chemical Society, 2005, 52, 849-852
849
Communication
Microwave-assisted Synthesis of Difuran and Furan-Thiophene via Suzuki
Coupling
Yu-Sheng Lin (
), Chiao-Yang Lin (
),
Deng-Yi Huang (
Department of Chemistry, National Dong Hwa University, Shou-Feng, Hualien 974, Taiwan, R.O.C.
) and Thomas Y. R. Tsai* (
)
2-Tetrahydropyranyloxymethylated difuran and furanthiophene compounds have been obtained in high
yields from the coupling of furan boronic acid/furfuryl boronic acid by focused microwave irradiation.
Keywords: Suzuki coupling; Microwave; Difuran; Furan-thiophene.
INTRODUCTION
Carbon-carbon bond formation via Suzuki coupling of
terpart (Table 1). Focused microwave irradiation is known to
provide a shorter reaction time and higher yield than those of
conventional thermal reactions. Therefore, a number of the
microwave-assisted cross coupling reactions have been re-
ported.8 Moreover, the use of water as a co-solvent is also
known to increase the product yield by 20%. Microwave irra-
diation and the water co-solvent were therefore employed in
our coupling reactions.
organoboran compounds with organic halides provides a
mild method for synthesis of various functionalized com-
pounds,1 especially biaryls.2 Recently, we have been inter-
ested in the synthesis of furan derivatives not only because
they are common to many natural occurrences of flavors and
fragrances, such as terpenoids, ionphores, and lipids, but also
because they are key intermediates in the pharmaceutical in-
dustry3 and in synthetic chemistry.4 For example, biologi-
cally important porphyrin or porphycene are responsible for
oxygen transport and storage5 and replacements of one or
more pyrroles by furan or thiophene to form tetraoxaporphy-
rins and dioxadithiaprophycene.6
RESULTS AND DISCUSSION
To synthesize the organohalide counterpart, commer-
cially available methyl 2-furoate 1 was first allowed to react
with Br2 and AlCl3 to produce methyl 5-bromo-2-furoate 2
(Scheme I). The ester 2 was then reacted with NaBH4 to pro-
duce a primary alcohol. To reduce the undesired side reac-
tions, the alcohol functional group was protected by THP to
give a tetrahydropyranyl ether 3. By the precise reaction
conditions and sequences commercially available, methyl 2-
thenoate 4 was first converted to the bromide 5, which was
then converted to 6 in good yield. To synthesize the organo-
boran counterpart, furfuryl alcohol was protected first by
THP to produce 8. This compound was then reacted with
Despite the important role of furan in chemistry, reports
on difuran and furan-thiophene compounds are very few. In
this work we set out a coupling strategy using Suzuki reaction
to synthesize 2-tetrahydropyranyloxymethylated difuran and
furan-thiophene compounds, which were hitherto unknown
and are potentially important toward the synthesis of poly-
meric species. Thus, furan boronic acid and furfuryl boronic
acid 9 were used as the boron counterpart, and tetrahydro-
pyranyl ethers 3 and 67 were used as the organohalide coun-
Scheme I
O
O
O
Br , AlCl
2
1. NaBH THF
4,
3
3
O
S
O
O
Br
Br
Br
Br
OCH
OCH
OTHP
OTHP
3
3
3
3
CH Cl
2. DHP, PPTS
(93% over 2 steps)
2
2
86%
1
3
2
O
1. NaBH THF
4,
Br , AlCl
2
S
S
OCH
OCH
2. DHP, PPTS
(95% over 2 steps)
CH Cl
2
2
4
5
6

850 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Lin et al.
Table 1. Microwave and conventionally heated Suzuki coupling of furanyl halides and furan
boronic acids10
Microwave heateda
Conventionally heatedb
Entry
1
Product
Reaction Time Yield
Reaction Time
(h)
Yield
(%)
(min)
(%)
15
93
12
82
2
3
4
10
15
10
92
97
96
9
71
79
65
14
20
5
6
15
10
89
86
16
19
69
47
7
8
9
15
10
5c
94
97
98
14
18
10
66
53
76
10
5c
97
10
73
a 1 mol of aryl bromide, 1.2 mol boronic acid, 2 mol % Pd(PPh3)4, 0.1 mol of TBAB, 3 mol of
K2CO3. Microwave irradiation 150W or 120W (70 °C).
b Placed into oil bath at 70 °C.
c Microwave irradiation 200W.
n-butyllithium, followed by trimethyl borate and then sulfu-
ric acid to give furfuryl boronic acid 9 (Scheme II).
conditions with conventional reaction conditions were em-
ployed. A substantially long reaction time was required (9 to
20 h), and a lower product yield (47-79%).
In the general preparation method, aryl bromide (1 mol)
as an organohalide and furano boric acid (1.2 mol) as an
organo boron were dissolved in a mixture of 1,4-dioxane and
water (2:1 by volume). To this solution, a base (K2CO3, 3
mol), phase transfer catalyst TBAB (0.1 mol)9 and Pd(PPh3)4
catalyst (2 mol %) were added. Reaction of the resultant so-
lution was carried out in a focused microwave reaction (op-
erated at 150 or 120W, 70 °C). An excellent yield (86-97%)
was obtained within 10 to 15 min. For comparison, reaction
In conclusion, the synthesis of potentially useful inter-
mediates comprising THP functionalized difuran and furan-
thiophene heterocyclics was reported. In this coupling reac-
tion, aryl bromide and THP functionalized furano boron com-
pound were reacted in a microwave reactor to give the desired
product in excellent yield in a short period of time. This
method can be employed for synthesizing oligofurans or
mixed furan-thiophene oligomers.
Scheme II
O
O
DHP, PPTS
CH Cl , 95%
O
1. n-BuLi, THF
(HO) B
2
OTHP
OH
OTHP
2. B(OMe)
3
2
2
3. H SO
2
4
9
7
8
76%

Suzuki Coupling with Microwave
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 851
Scheme III
O
O
Pd(PPh3)4
O
O
O
O
Br
B(OH)2
H3CO
THPO
H3CO
OTHP
+
K2CO3, TBAB
1,4-Dioxane/H2O
(2 : 1)
2
Entry 1
9
O
O
Pd(PPh3)4
K2CO3, TBAB
O
O
O
O
Br
B(OH)2
H3CO
H3CO
+
1,4-Dioxane/H2O
(2 : 1)
Entry 2
2
Scheme IV
O
B(OH)2
Pd(PPh3)4
THPO
O
+
N
OTHP
OTHP
K2CO3, TBAB
1,4-Dioxane/H2O
(2 : 1)
N
Br
9
Entry 9
Br
N
N
O
B(OH)2
Pd(PPh3)4
THPO
O
+
K2CO3, TBAB
1,4-Dioxane/H2O
(2 : 1)
9
Entry 10
EXPERIMENTAL
Entry 3: 1H NMR (300 MHz, CDCl3) d: 6.52 (d, J = 3.2
Hz, 2H), 6.39 (d, J = 3.2 Hz, 2H), 4.75 (s, 1H), 4.73-4.51 (m,
4H), 3.97-3.85 (m, 2H), 3.57-3.54 (m, 2H), 1.76-1.52 (m,
12H); 13C NMR (75 MHz) d: 151.1, 146.6, 111.2, 106.0, 97.2,
62.0, 60.5, 30.3, 25.4, 19.2; MS (FAB, m/z): 362.2; HRMS
calcd for C20H26O6: 362.1729. Found: 352.1731.
Entry 4: 1H NMR (300 MHz, CDCl3) d: 7.41 (d, J = 1.6
Hz, 1H), 6.57 (d, J = 3.3 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H),
6.46-6.45 (t, J = 1.8 Hz, 1H), 6.40 (d, J = 3.2 Hz, 1H), 4.76 (s,
1H), 4.75-4.51 (dd, J = 12.9 Hz, 2H), 3.92-3.83 (m, 1H),
3.58-3.54 (m, 1H), 1.73-1.52 (6H, m); 13C NMR (75 MHz)
d: 151.0, 146.77, 141.79, 114.62, 111.37, 111.20, 105.75,
105.32, 97.26, 62.05, 60.59, 30.38, 25.44, 19.19; MS (FAB,
m/z): 248.1; HRMS calcd for C14H16O4: 248.1049. Found:
248.1051.
Entry 5: 1H NMR (300 MHz, CDCl3) d: 7.99 (d, J = 1.4
Hz, 1H), 7.72 (d, J = 3.9 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H),
6.47 (d, J = 3.3 Hz, 1H), 6.40 (d, J = 3.7 Hz, 1H ), 4.76 (s, 1H),
4.73-4.51 (dd, J = 12.9 Hz, 2H), 4.01-3.89 (m, 4H), 3.59-3.55
(m, 1H), 1.78-1.56 (6H, m); 13C NMR (75 MHz) d: 134.1,
130.4, 125.2, 122.7, 111.7, 111.3, 108.1, 106.2, 97.4, 62.0,
60.6, 52.3, 52.2, 30.3, 25.4, 19.1; IR (KBr): 1719.69, 1437.9,
1286.5, 1252.9, 1118.9, 1022.8; MS (FAB, m/z): 322.0;
HRMS calcd for C16H18O5S: 322.0875. Found: 322.0880.
Entry 6: 1H NMR (300 MHz, CDCl3) d: 7.99 (d, J = 1.4
Hz, 1H), 7.65 (d, J = 1.4 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H),
All reagents were purchased from Acros, Aldrich
Chimie, and Fluka and used without further purification. IR
spectra were taken as KBr plates. H and 13C NMR spectra
1
were recorded in CDCl3 solution at 300 and 75 MHz spec-
trometer. TLC analysis was performed used glass plate with
silica gel 60 F254. Flash column chromatography was carried
out using 200-300 mesh silica gel.
Entry 1: 1H NMR (300 MHz, CDCl3) d: 7.2 (d, J = 3.6
Hz, 1H), 6.75 (d, J = 3.4 Hz, 1H), 6.63 (d, J = 3.4 Hz, 1H),
6.41 (d, J = 3.4 Hz, 1H), 4.73 (s, 1H), 4.71-4.49 (dd, J = 3.1
Hz, 2H), 3.95-3.85 (m, 4H), 3.55-3.52 (m, 1H), 1.81-1.50 (m,
6H); 13C NMR (75 MHz) d: 159.0, 152.7, 149.7, 145.3, 143.1,
119.8, 111.4, 108.8, 106.8, 97.4, 62.0, 60.5, 51.9, 30.3, 25.3,
19.1; IR (KBr): 2946.7, 2863.8, 1731.76, 1554.3, 1461.8,
1307.5, 1137.8, 1027.9; MS (FAB, m/z): 306.1; HRMS calcd
for C16H18O6: 306.1103. Found: 306.1109.
Entry 2: 1H NMR (300 MHz, CDCl3) d: 7.71 (d, J = 3.5
Hz, 1H), 7.26-7.23 (d, J = 3.6 Hz, 1H), 6.82 (d, J = 3.5 Hz,
1H), 6.64-6.63 (d, J = 3.6 Hz, 1H), 6.29-6.28 (t, J = 1.7 Hz,
1H), 3.92 (s, 3H); 13C NMR (75 MHz) d: 159.1, 149.7, 145.3,
143.2, 119.9, 111.8, 108.2, 106.7, 51.9, 29.7; IR (KBr):
1726.3, 1517.5, 1448.6, 1303.1, 1213.7, 1138.6 cm-1; MS
(FAB, m/z): 192.1; HRMS calcd for C10H8O4: 192.0423.
Found: 192.0430.

852 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Lin et al.
6.53 (d, J = 3.2 Hz, 1H), 6.47-6.46 (t, J = 1.83 Hz, 1H), 3.92
(s, 3H); 13C NMR (75 MHz) d: 141.9, 134.2, 130.4, 125.0,
122.61, 112.0, 111.5, 105.5, 52.37, 52.25; IR (KBr): 1714.98,
1459.1, 1440.2, 1257.8, 1088.45; MS (FAB, m/z): 208.0;
HRMS calcd for C10H8O3S: 208.0194. Found: 208.0196.
Entry 7: 1H NMR (300 MHz, CDCl3) d: 7.39 (d, J = 3.2
Hz, 1H), 7.19 (d, J = 3.3 Hz, 1H), 6.39-6.35 (m, 2H), 4.89-
4.55 (m, 6H), 3.97-3.83 (m, 1H), 3.59-3.50 (m, 1H), 1.92-
1.50 (m, 12H); 13C NMR (75 MHz) d: 151.12, 150.58, 146.67,
141.80, 132.04, 124.01, 119.32, 111.24, 106.00, 105.35,
97.22, 97.17, 97.05, 63.06, 62.12, 62.05, 60.65, 60.59, 31.95,
25.44, 19.20; MS (FAB, m/z): 378.1; HRMS calcd for
C20H26O5S: 378.1501. Found: 378.1493.
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Entry 8: 1H NMR (300 MHz, CDCl3) d: 7.40-7.39 (m,
2H), 7.17 (d, J = 1.1 Hz, 1H), 6.45-6.42 (m, 2H), 4.90 (s, 1H),
4.86-4.72 (dd, J = 3.4 Hz, 2H), 3.92-3.85 (m, 1H), 3.59-3.55
(m, 1H), 1.67-1.53 (6H, m); 13C NMR (75 MHz) d: 150.90,
141.87, 141.36, 132.13, 123.99, 119.1, 111.3, 104.65, 97.07,
63.08, 62.14, 30.42, 25.45, 19.19; MS (FAB, m/z): 264.0;
HRMS calcd for C14H16O3S: 264.0820. Found: 264.0813.
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1997, 53, 14437. (c) Sakurai, H.; Tsukuda, T.; Hirao, T. J.
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10. For example (Entry 1), to bromide 2 (2.05 g, 10 mmol) in
1,4-dioxane (20 mL) and water (10 mL), boronic acid 9 was
added. The reaction mixture was carried out in a focused mi-
crowave reaction (150W, 70 °C, 15 min) and washed with
ether (3 ´ 50 mL). The organic layers were combined, dried
over anhydrous MgSO4 and concentrated. The crude com-
pound was purified by silica gel column chromatography
(Hexane/ethyl acetate, 8/2, v/v). A yellow oil was obtained
(2.85 g, 93%).
1
Entry 9: H NMR (300 MHz, CDCl3) d: 8.58 (d, J =
4.9 Hz, 1H), 7.72-7.71 (t, J = 2.3 Hz, 2H), 7.15-7.02 (t, J =
1.7 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 3.2 Hz,
1H), 4.78 (s, 1H), 4.78-4.56 (dd, J = 13.0 Hz, 2H), 3.93-3.92
(m, 1H), 3.59-3.57 (m, 1H), 1.75-1.52 (m, 6H); 13C NMR
(75.4 MHz, CDCl3) d: 153.5, 151.2, 150.0, 137.5, 117.8,
111.7, 109.6, 97.5, 62.1, 60.7, 30.3, 25.4, 19.1; MS (FAB,
m/z): 259.1; HRMS calcd for C15H17NO3: 259.1208. Found:
259.1211.
Entry 10: 1H NMR (300 MHz, CDCl3) d: 8.59 (d, J =
4.6 Hz, 1H), 7.58 (t, J = 6.2 Hz, 1H), 6.90 (d, J = 3.6 Hz, 1H),
6.50 (d, J = 3.4 Hz, 1H), 4.77-4.55 (dd, J = 13.1 Hz, 2H),
3.95-3.88 (m, 1H), 3.60-3.58 (m, 1H), 1.79-1.53 (m, 6H); 13
C
NMR (75.4 MHz, CDCl3) d: 154.30, 150.74, 138.65, 118.04,
111.91, 110.74, 97.60, 62.11, 60.69, 30.36, 25.38, 19.13; MS
(FAB, m/z): 259.1; HRMS calcd for C15H17NO3: 259.1208.
Found: 259.1205.
ACKNOWLEDGEMENTS
We thank the National Dong Hwa University Depart-
ment of Chemistry for support of this work. In addition, we
thank Professor Ivan J. B. Lin for his helpful discussions.
Received January 31, 2005.