C-H and C-Si functionalization of furan derivatives: Palladium-catalyzed homocoupling and arylation reactions

Article abstract of DOI:10.1055/s-0029-1217537

Palladium-catalyzed arylation reactions of benzofuran derivatives are shown to take place at the carbon - hydrogen bond or carbon - silicon bond adjacent to the oxygen atom. A variety of furan derivatives are obtained in good yields. Georg Thieme Verlag S

Full text of DOI:10.1055/s-0029-1217537

LETTER
1941
C–H and C–Si Functionalization of Furan Derivatives: Palladium-Catalyzed
Homocoupling and Arylation Reactions
C–H
a
nd C–Si
h
Functionaliz
i
ation o
g
f
Furan Deri
evatives ru Matsuda, Masabumi Takahashi, Daiki Monguchi, Atsunori Mori*
Department of Chemical Science and Engineering, Kobe University, 1-1 Rokkodai, Nada, Kobe 657-8501, Japan
Fax +81(78)8036181; E-mail: amori@kobe-u.ac.jp
Received 24 March 2009
benzene (3a), 4-methoxy-iodobenzene (3b), and ethyl 4-
Abstract: Palladium-catalyzed arylation reactions of benzofuran
derivatives are shown to take place at the carbon–hydrogen bond or
carbon–silicon bond adjacent to the oxygen atom. A variety of furan
derivatives are obtained in good yields.
iodobenzoate (3c) were found to react at the C–H bond ad-
jacent to the oxygen atom to afford the coupling product
4. The reaction with electron-deficient aryl iodide appears
to result in a relatively superior yield. In addition to ben-
zofuran (1), furfural (5) also reacted with 3b and 3c to
give the arylated product 6b and 6c, respectively.
Key words: C–H arylation, benzofuran, palladium, homocoupling
reaction, cross-coupling reaction
PdCl2(PhCN)2
(3 mol%)
AgF (2 equiv x 3)
We have recently shown that five-membered heteroaro-
matic compounds such as thiophene and thiazole undergo
transition-metal-catalyzed homocoupling1 and arylation
reactions2 at the C–H bond adjacent to the sulfur atom.
The reactions have shown to proceed under mild condi-
tions to form a carbon–carbon bond. Comparing with the
related coupling with organometallic reagents such as
boron, tin, Grignard, and zinc,3 the direct coupling at the
C–H bond is much straightforward and shows high atom
efficiency.4,5 Our concern is centered if the reaction oc-
curs at the C–H bond of furan derivatives,6 which possess
oxygen atom in the five-membered aromatic ring, under
the conditions for thiazoles and thiophenes. We herein de-
scribe that palladium-catalyzed homocoupling and aryla-
tion reactions takes place at the carbon–hydrogen bond
adjacent to the oxygen atom.
H
O
O
DMSO, 11 h, 60 °C
O
2 56%
1
Scheme 1
Table 1 CH Arylation of Furan Derivativesa
Furan derivative
Aryl iodide
Product Yield (%)b
4a
41c
I
O
3a
1
1
4b
4c
6b
6c
41
I
OMe
We first examined the homocoupling of benzofuran (1).
The reaction was carried out in the presence of PdCl2(Ph-
CN)2 (3 mol%) in anhydrous DMSO at 60 °C. The addi-
tion of AgF as an activator was carried out three times (2
+ 2 + 2 equiv) with stirring for 3 hours, 3 hours, and 5
hours, respectively, to afford the corresponding homocou-
pling product 2 in 56% yield.7 In sharp contrast with the
case of thiophene and thiazole derivatives,1 it was found
to be important to perform the reaction with carefully de-
hydrated DMSO, otherwise significant decrease of the
yield occurred to result in giving a much lower yield de-
spite complete consumption of 1 probably due to the hy-
drolytic decomposition leading to unidentified byproducts
(Scheme 1).
3b
1
53
I
CO2Et
3c
3b
33
CHO
O
5
5
3c
40c,d
a The reaction was carried out with 1 (0.5 mmol), of PdCl2(PPh3)2 (3
mol%), ArI 3 (0.6 mmol), and AgF (3 × 0.5 mmol) in DMSO (2 mL)
at 100 °C for 6 h (3 × 2 h).
b Unless noted, isolated yield was shown.
c The yield was estimated by 1H NMR using trichloroethene as an in-
ternal standard.
d The reaction was carried out with AgNO3/KF (4 × 0.5 equiv)
The palladium-catalyzed C–H arylation of 1 with several
aryl iodides were then carried out. The reaction conditions
employed was also similar to the related arylation of
thiophenes and thiazoles.2,4 As summarized in Table 1,
reactions proceeded in moderate to good yields. Iodo-
With the reaction conditions to undergo C–H arylation
reactions of furan derivatives with aryl iodide 3, it was
found that functionalization of the related C–Si bond of
furans took place in a similar manner.8 When the trimeth-
ylsilylated benzofuran (7) was treated with 3a in the pres-
ence of 3 mol% of PdCl2(PPh3)2 and AgF (2 × 1 equiv) at
100 °C, the coupling product was obtained in 46% yield.
SYNLETT 2009, No. 12, pp 1941–1944
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.07.2009
DOI: 10.1055/s-0029-1217537; Art ID: U03309ST
© Georg Thieme Verlag Stuttgart · New York

1942
S. Matsuda et al.
LETTER
The reaction was found to take place with several aryl io- The plausible reaction mechanism of furan arylation at the
dides as shown in Table 2. The reaction with the combina- C–H bond and the C–Si bond would be electrophilic sub-
tion of AgNO3 and KF, in which in situ formation of AgF stitution of the hydrogen or silicon atom with palladium
would occur, also proceeded to afford 4a in a comparable affording the corresponding organopalladium species A
yield. Aryl iodides bearing an electron-withdrawing or (Scheme 3).9 Following reductive elimination would lead
-donating group were subjected to the reaction. In partic- to the product 4. The mechanism of homocoupling would
ular, the use of 4-nitro-iodobenzene (3f) and 4-cyano- be the double substitution reaction and the reductive cou-
iodobenzene (3g) underwent the arylation reaction in ex- pling leading to 2 through difuryl palladium intermediate
cellent yields. An activator, AgF or AgNO3/KF, was ap- B. These reactions would occur similarly to the case of
peared to be effective in the functionalization of silylated thiophene and thiazole derivatives, which we have shown
furan derivatives, while the attempted coupling reaction previously.1,2 The silver species employed as an activator
of 7 and 3c with TBAF that was a well-known reaction was confirmed in the reactions of thiophene and thiazole
promoter for Hiyama coupling8 resulted to afford only a derivatives to be transformed into AgI, while Ag(0) was
trace amount of the coupling product 4c.
obtained in homocoupling.
Table 2 Arylation of TMS-benzofuran (7) with Aryl Iodidea
O
Aryl
+
Aryl–I
TMS
Aryl
PdLn
1
O
O
X
or
7
3
4
[Pd]
Aryl
AgF
O
Aryl iodide 3
PhI (3a)
Additive (equiv)
AgF (1 + 1)
Time
Yield (%)b
TMS
O
A
2 × 2 h 46
7
4
AgNO3/KF (6 × 0.25)
6 × 1 h 52
PdX2
AgF
AgF (1 + 1)
1 h + 2 h 53
or
7
2
1
2
[Pd]
4-MeOC6H4I (3b)
O
2
AgNO3/KF (6 × 0.25)
6 × 1 h 47
6 × 1 h 75
6 × 1 h 43
6 × 1 h 54
6 × 1 h 86
6 × 1 h 85
B
4-EtOCOC6H4I (3c) AgNO3/KF (6 × 0.25)
Scheme 3 Plausible mechanism of C–H and C–Si homocoupling
and arylation reactions
4-F3CC6H4I (3d)
C6F5I (3e)
AgNO3/KF (6 × 0.25)
AgNO3/KF (6 × 0.25)
AgNO3/KF (6 × 0.25)
AgNO3/KF (6 × 0.25)
Worthy of note is that the trialkylated silyl group can be
employed for the coupling reaction by the activation of
AgNO3/KF system. Although coupling reactions of orga-
nosilanes with various electrophiles are shown to proceed
by the catalysis of transition-metal complex, available sil-
icon species have been limited to those bearing heteroat-
om substituents on silicon,8 otherwise, transmetalation of
the trialkylsilyl group with transition metal hardly occurs.
Accordingly, the reaction of trimethylsilylated furan de-
rivatives would be induced by the effect of the oxygen
atom of furan. Indeed, the reaction of 2-naphthyl(trimeth-
yl)silane (8) with 3c in the presence of a palladium cata-
lyst under similar conditions (AgNO3/KF as an activator)
resulted in considerably lower yield to afford 9c
(Scheme 4).
4-O2NC6H4I (3f)
4-NCC6H4I (3g)
a The reaction was carried out with 7 (0.5 mmol), ArI 3 (0.6 mmol),
PdCl2(PPh3)2 (3 mol%), AgF or AgNO3/KF in DMSO (1 mL) at 100
°C.
b Isolated yield.
Homocoupling of trimethylsilyl benzofuran (7) also pro-
ceeded in a similar manner. Treatment of 7 with 3 mol%
of PdCl2(PhCN)2 and AgNO3/KF (2 equiv) at 60 °C for
four hours in DMSO afforded the homocoupling product
2 in 75% yield after stirring at 60 °C for six hours. The
yield of 2 was also superior to the case of C–H homocou-
pling (Scheme 2).
In summary, we showed that the palladium-catalyzed aryl-
ation and homocoupling reactions of furan derivatives us-
ing the AgNO3/KF system as an activator take place at the
carbon–hydrogen or the carbon–silicon bond adjacent to
the oxygen atom to afford the corresponding coupling
products in moderate to good yields. In the functionaliza-
tion of furan derivatives at the carbon–silicon bond, the
AgNO3/KF system served as an effective activator show-
PdCl2(PhCN)2
(3 mol%)
AgNO3/KF (4 equiv)
SiMe3
DMSO, 6 h, 60 °C
O
O
O
7
2 75%
Scheme 2
Synlett 2009, No. 12, 1941–1944 © Thieme Stuttgart · New York

LETTER
C–H and C–Si Functionalization of Furan Derivatives
1943
Rossi, R. Tetrahedron 2007, 63, 1970. (f) Bellina, F.;
TMS
I
COOEt
+
Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 6, 1379.
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8
3c
PdCl2(PPh3)2
(3 mol%)
COOEt
AgNO3/KF
DMSO, 100 °C, 24 h
9c 14%
Scheme 4
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(f) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60,
8991. (g) Kakiuchi, F.; Kochi, T. Synthesis 2008, 3013.
(6) CH functionalization of furans: (a) Itahara, T.; Hashimoto,
M.; Yumisashi, H. Synthesis 1984, 255. (b) McClure, M. S.;
Glover, B.; McSorley, E.; Millar, A.; Osterhout, M. H.;
Roschangar, F. Org. Lett. 2001, 3, 1677. (c) Glover, B.;
Harvey, K. A.; Liu, B.; Sharp, M. J.; Tymoschenko, M. F.
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Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y.
Heterocycles 1990, 31, 1951.
ing that arylation and homocoupling of trimethylsilylated
furan are a novel class of reactions. These methods are ef-
fective for the functionalization reactions of furan deriva-
tives, which are potentially employed as several advanced
organic materials showing light-emitting characteristics,
etc.10
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research on Priority Areas, ‘Advanced Molecular Transformation
of Carbon Resources’ and Special Coordination Funds for Promo-
ting Science and Technology, Creation of Innovation Centers for
Advanced Interdisciplinary Research Areas (Innovative Bioproduc-
tion Kobe), by Ministry of Education, Culture, Sports, Science, and
Technology (MEXT), Japan
(7) Fractional addition of silver was shown to improve the yield
of the coupling product in the reactions of thiophene
derivatives.1b,2c
(8) (a) Hiyama, T. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998, 421. (b) Denmark, S. E.; Sweis, R. F.
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004, 163.
(9) (a) Sugie, A.; Kobayashi, K.; Suzaki, Y.; Osakada, K. Chem.
Lett. 2006, 35, 1100. (b) Mori, A.; Sugie, A.; Furukawa, H.;
Suzaki, Y.; Osakada, K.; Akita, M. Chem. Lett. 2008, 38,
542. (c) Sugie, A.; Furukawa, H.; Suzaki, Y.; Osakada, K.;
Akita, M.; Monguchi, D.; Mori, A. Bull. Chem. Soc. Jpn.
2009, 82, 555.
References and Notes
(1) (a) Masui, K.; Ikegami, H.; Mori, A. J. Am. Chem. Soc.
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H.; Kobayashi, N.; Mori, A.; Funahashi, M.; Tamaoki, N.
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M.; Osakada, K.; Kawamoto, M.; Ikeda, T. J. Am. Chem.
Soc. 2003, 125, 1700. (b) Masui, K.; Mori, A.; Okano, K.;
Takamura, K.; Kinoshita, M.; Ikeda, T. Org. Lett. 2004, 6,
2011. (c) Kobayashi, K.; Sugie, A.; Takahashi, M.; Masui,
K.; Mori, A. Org. Lett. 2005, 7, 5083. (d) Kobayashi, K.;
Mohamed Ahmed, M. S.; Mori, A. Tetrahedron 2006, 62,
9548. (e) Arai, N.; Takahashi, M.; Mitani, M.; Mori, A.
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Ikeda, T. Chem. Asian J. 2007, 2, 301. (g) Mori, A.;
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Heterocycles 2009, 77, 151.
(10) Experimental Procedure for the Homocoupling Reaction
of 1
To a 50 mL Schlenk tube equipped with a magnetic stirring
bar were added PdCl2 (PhCN)2 (5.8 mg, 0.015 mmol),
DMSO (3 mL), benzofuran (1, 55 mL, 0.5 mmol), and AgF
(127 mg, 1.0 mmol) in one portion, and the resulting mixture
was stirred at r.t. for 3 h. Additional AgF (2 × 1.0 mmol)
were then added, and stirring was continued for further 3 h
and 5 h, respectively. The reaction mixture was passed
through a Celite pad to remove a solid residue, and the cake
was washed repeatedly with Et2O. The filtrate was washed
with H2O twice (2 × 50 mL) and brine (50 mL). Then, the
organic layer was dried over anhyd MgSO4 and concentrated
under reduced pressure to leave a crude solid, which was
purified by chromatography on silica gel to afford 33 mg of
2 (56%).
(3) Metal-Catalyzed Cross-Coupling Reaction; Diederich, F.;
Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998.
(4) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. (b) Bold,
G.; Fässler, A.; Capraro, H.-G.; Cozens, R.; Klimkait, T.;
Lazdins, J.; Mestan, J.; Poncioni, B.; Rösel, J.; Stover, D.;
Tintelnot-Blomley, M.; Acemoglu, F.; Beck, W.; Boss, E.;
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46, 7996. (e) Bellina, F.; Calandri, C.; Cauteruccio, S.;
2,2¢-Bibenzofuran (2)11
Mp 202–203 °C. 1H NMR (500 MHz, CDCl3): d = 7.17 (s, 2
H), 7.25–7.37 (m, 4 H), 7.55 (d, J = 8.0 Hz, 2 H), 7.63 (d,
J = 8.2 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 103.7,
Synlett 2009, No. 12, 1941–1944 © Thieme Stuttgart · New York

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S. Matsuda et al.
LETTER
for further 5 times. After cooling to r.t., the mixture was
passed through a Celite pad, which was washed with EtOAc
repeatedly. The filtrate was washed with H2O twice. Then
the organic layer was dried over anhyd MgSO4 and
concentrated under reduced pressure to leave a crude solid,
which was purified by chromatography on silica gel to afford
99 mg of 4 (75%).12
111.3, 121.4, 123.3, 125.1, 128.5, 147.7, 155.1. IR (KBr):
1441, 1256, 1173, 1049, 876, 804, 750 cm–1.
Experimental Procedure for the C–Si Arylation Reaction
of 7 and 3c
To a 25 mL Schlenk tube equipped with a magnetic stirring
bar were added, PdCl2 (PPh3)2 (10.5 mg, 0.015 mmol),
DMSO (1 mL), 2-trimethylsilylbenzofuran (7, 95 mg, 0.5
mmol), and ethyl 4-iodobenzoate (6c, 165 mg, 0.6 mmol)
under argon atmosphere. The mixture was heated in an oil
bath at 100 °C, KF (7.3 mg, 0.125 mmol), and AgNO3 (21.2
mg, 0.125 mmol) were added in one portion, and the
resulting mixture was continued for 1 h. Addition of AgNO3/
KF (0.125 mmol) and stirring for 1 h at 100 °C were repeated
(11) Ionkin, A. S.; Marshall, W. J. Organometallics 2004, 23,
3276.
(12) Nakatani, S.; Ikura, M.; Yamamoto, S.; Nishita, Y.; Itadani,
S.; Habashita, H.; Sugiura, T.; Ogawa, K.; Ohno, H.;
Takahashi, K.; Nakai, H.; Toda, M. Bioorg. Med. Chem.
2006, 14, 5402.
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