Direct β-arylation of furans with aryl iodides catalyzed by dinuclear palladium complexes

Article abstract of DOI:10.3987/COM-17-13824

Dinuclear palladium complexes formed by a chelate-bridging ligand showed β-selectivity in the direct arylation of furans with iodoarenes. In contrast, the arylation using PPh₃ or bpy as ligands gave α-arylfurans as major products. The arylation

Full text of DOI:10.3987/COM-17-13824

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HETEROCYCLES, Vol. 94, No. 12, 2017
HETEROCYCLES, Vol. 94, No. 12, 2017, pp. 2222 - 2228. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 18th October, 2017, Accepted, 30th October, 2017, Published online, 10th November, 2017
DOI: 10.3987/COM-17-13824
DIRECT β-ARYLATION OF FURANS WITH ARYL IODIDES
CATALYZED BY DINUCLEAR PALLADIUM COMPLEXES
Takahiro Goto, Hayate Kato, and Naofumi Tsukada*
Department of Chemistry, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka
422-8529, Japan. e-mail: tsukada.naofumi@shizuoka.ac.jp
Abstract – Dinuclear palladium complexes formed by a chelate-bridging ligand
showed β-selectivity in the direct arylation of furans with iodoarenes. In contrast,
the arylation using PPh3 or bpy as ligands gave α-arylfurans as major products.
The arylation can be applied to several furans bearing functional groups except
electron-withdrawing groups.
Direct arylation of aryl C-H bonds catalyzed by transition-metal complexes has attracted considerable
attention as an alternative to the conventional palladium-catalyzed cross-coupling reactions.1 The direct
arylation has the advantage of enabling a more straightforward access to target molecules without
prefunctionalization, and thus minimizing side products in fewer steps. However, difficulty in controlling
of site-selectivity is a considerable problem for the direct arylation because there are several aryl C-H
bonds in starting materials in most cases. While this issue is difficult to be solved for the reaction of
benzene rings, the reaction of heteroarenes such as pyrroles, furans and thiophenes often proceeds with
high site-selectivity due to an electronic effect of hetero atoms. Actually, there have been a lot of reports
for α-selective direct arylation of the heteroarenes (Scheme 1).2 Although β-selective direct arylation is
desired as a complementary reaction, the number of reports for the β-selective reaction has been still
limited, especially for the reaction of furans.3 The β-arylation of thiophenes has been reported by several
groups in the last decade.4-10 The efficient β-selective arylation of pyrroles was reported by Itami and
Yamaguchi's group in 2014.11 In contrast, there is no efficient method for the β-arylation of furans, except
the arylation of furans bearing directing groups12 or furans in which the α positions are already
substituted.13 In 1985, Itahara demonstrated an oxidative coupling between furans and arenes, giving a
mixture of β-aryl- and α-arylfurans in a ratio of 2:1.14 However, stoichiometric amounts of palladium and
large excess amounts of arenes were necessary for this reaction. Herein, we report a palladium-catalyzed
arylation of furans with iodoarenes, giving β-arylfurans as major products.

HETEROCYCLES, Vol. 94, No. 12, 2017
2223
H
α-arylation
R
Ar
Y
H
β
R
transition-metal catalysts
and arylating reagents
well-known
H
α
Y
Ar
R
Y = NR', O, S
H
β-arylation
Y
limited reports
Scheme 1. Site-selectivity in transition metal-catalyzed arylation of pyrroles, furans and thiophenes
We previously reported that the reaction of thiophenes with iodoarenes in the presence of dinuclear
palladium catalysts 1a or 1b gave β-arylthiophenes with high site-selectivity (Figure 1).10,15 Thus, the
application of the complexes 1a and 1b to the arylation of furans was investigated. The reaction of
2-n-pentylfuran with iodobenzene in the presence of acetoxy complex 1a and Ag2CO3 showed good β-
selectivity and gave 2-n-pentyl-4-phenylfuran 3a and 2-n-propyl-5-phenylfuran 3b in a ratio of 5.3:1
although the yield was moderate (Table1, entry 1). No unreacted furan and no multi-arylated furan were
observed at all. The rest of 2-n-pentylfuran seems to be oligomerized or polymerized. While the reaction
with trifluoroacetoxy complex 1b gave a similar result, p-tolyl complex 1c was ineffective as a catalyst
(entries 2 and 3). Carboxyl ligands may be essential for the arylation. By addition of a half equivalent of
the chelate-bridging ligand dpfamH (2), the reaction using palladium acetate also afforded 3a as a major
product although the yield and selectivity are lower (entry 4). The dinuclear structure of the catalysts may
be essential for the arylation. When equimolar amounts of 2 and palladium were used, the reaction did not
proceed, not giving any products (entry 5). The reaction without 2 afforded the α-arylfuran 3b as a major
product in a lower yield (entry 6). The addition of ordinary phosphine and nitrogen ligands such as PPh3,
dppp and bpy did not switch the α-selectivity (entries 7-9).
N
N
N
N
H
Ph2P
PPh2
PPh2
PPh2
Pd
Pd
1a (R = AcO)
1b (R = CF3CO2)
1c (R = p-Tol)
O
H
dpfamH (2)
R
R
Figure 1. Dinuclear palladium complexes and chelate-bridging ligand dpfamH

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HETEROCYCLES, Vol. 94, No. 12, 2017
Table 1. Palladium-catalyzed reactions of 2-n-pentylfuran with iodobenzenea
Ph
catalyst
+
+
Ph-I
n-C5H10
n-C5H10
Ph
n-C5H10
O
O
Ag2CO3
toluene, 120 °C, 15 h
O
3a
3b
Entry
Catalyst (mol%)
1a (5)
Additive (mol%)
Yieldb (%)
3a:3bc
5.3:1
4.9:1
1:2.3
4.0:1
1
2
3
4
5
6
7
8
–
41
32
2
1b (5)
–
1c (5)
–
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
2 (5)
33
trace
15
12
10
20
2 (10)
–
1:1.3
1:1.7
1:3.0
1:>99
PPh3 (10)
dppp (10)
bpy (10)
9
a
A mixture of 2-n-pentylfuran (0.30 mmol), iodobenzene (0.30 mmol), and Ag2CO3 (0.30 mmol) in toluene
b
(1.5 mL) was stirred at 120 °C for 15 h in the presence of the catalyst and the additive. GC yields.
c
Determined by GC.
Table 2 summarizes the results of the reaction of various furans with various iodoarenes in the presence
of 1a.16,17 The reaction of 2-benzylfuran afforded 2-benzyl-4-phenylfuran 4a selectively (entries 1 and 2).
2-Benzyl-3-phenylfuran was not observed at all. This result shows that the benzylic position is not
reactive and the benzyl group does not affect the site-selectivity in the reaction with 1a.12h The reaction
tolerates benzyl ether, silyl ether and acetal, giving β-phenylfurans 6a-8a selectively (entries 3-5).
Although formyl and methoxycarbonyl groups are also tolerated, the reaction of furfural and methyl
2-furoate afforded only α-phenylfurans 9b and 10b with high site-selectivity (entries 6 and 7). Both the
yield and the site-selectivity were decreased in the reaction of 2,3-dimethylfuran, probably due to steric
repulsion of the methyl group at the C3 position (entry 8). In the reaction of 3-silyloxymethylfuran, the
β-selectivity was improved although the yield was low (entry 9). Coordination of palladium to the
substituent would affect the site-selectivity. The reaction of iodoarenes substituted with electron-donating
groups at the para and meta positions gave β-arylfurans 13a, 14a and 16a with good site-selectivity
(entries 10, 11 and 13). A substituent at the ortho position decreased the product yield (entry 12). The
reaction of iodoarenes substituted with electron-withdrawing groups also proceeded to give arylfurans
17-20 (entries 14-17). However, the β-selectivity is lower than that in the reaction with iodobenzene. The
reaction of p-iodonitrobenzene afforded α-arylfuran 20b as a major product (entry 17).

HETEROCYCLES, Vol. 94, No. 12, 2017
2225
Table 2. Palladium-catalyzed reactions of furans with iodoarenesa
R"
R'
R'
R'
R"
5 mol% 1a
I
+
+
R
Ag2CO3
toluene, 120 °C, 15 h
R"
R
R
O
O
O
4a-20a
4b-20b
Entry
1
R
R'
H
R"
H
H
H
H
H
H
H
H
Product
4
Yieldb (%)
41
a:bc
Bn
4.9:1
5.3:1
2.7:1
4.3:1
2.7/1
1:>99
1:>99
1.6:1
6.1:1
5.3:1
4.0:1
3.0:1
2.8:1
2.7:1
3.0:1
1.6:1
1:1.4
2
CH2-p-Tol
CH2OBn
CH2OTBS
CH2OTHP
CHO
H
5
40
3
H
6
54
4
H
7
52
5
H
8
50
6
H
9
23
7
CO2Me
Me
H
10
11
12
13
14
15
16
17
18
19
20
70
8
Me
10
9
H
CH2OTBS
H
28
10
11
12
13
14
15
16
17
n-C5H10
n-C5H10
n-C5H10
n-C5H10
n-C5H10
n-C5H10
n-C5H10
n-C5H10
H
H
H
H
H
H
H
H
p-Me
44
m-Me
o-Me
50
19
m-MeO
p-MeCO
p-MeOCO
p-CF3
p-NO2
40
38
47
25
35
a
A mixture of a furan (0.30 mmol), a iodoarene (0.30 mmol), and Ag2CO3 (0.30 mmol) in toluene (1.5 mL) was
stirred at 120 °C for 15 h in the presence 1a (0.015 mmol). b Isolated yields. c Determined by GC.
To gain insight into the mechanism of the arylation, some reactions of the dinuclear palladium complexes
with reagents used in the arylation were investigated. The reaction of the acetoxy complex 1a with
2-n-pentylfuran or iodobenzene gave mixtures of many unidentified complexes. Next, the reaction of
iodo-bridged palladium complex 1d was performed (Scheme 2). The complex 1d is one of plausible
intermediates in the arylation using p-iodotoluene. The reaction of 1d with 2-n-pentylfuran gave only a
trace amount of arylated furan 13. Addition of Ag2CO3 increased the yield of 13 to 6%. However, only
α-isomer 13b was obtained. The reaction in the presence of Ag2CO3 and AcOH afforded a 1:1 mixture of
13a and 13b in low yield. Since high β-selectivity was not observed in the reaction of 1d with
2-n-pentylfuran, the complex 1d may not be an intermediate of the catalysis. Details of the reaction
mechanism are unclear at the present time.

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HETEROCYCLES, Vol. 94, No. 12, 2017
N
N
Ag2CO3 and/or AcOH
toluene, 120 °C, 15 h
+
13a + 13b
Ph2P
p-Tol
PPh2
p-Tol
Pd
Pd
n-C5H10
20 equiv
I
O
low yield
low β-selectivity
1d
Scheme 2. Reaction of iodo-bridged p-tolylpalladium 1d with 2-n-pentylfuran
In summary, we found that the direct arylation of furans with iodoarenes proceeds with good β-selectivity
by using dinuclear palladium complexes formed by the chelate-bridging ligand 2 as catalysts. The
arylation can be applied to several furans bearing functional groups except electron-withdrawing groups.
Mechanistic studies and applications of the catalysts to other site-selective coupling reactions are in
progress.
ACKNOWLEDGEMENTS
This work was supported by the JSPS KAKENHI Grant No. JP16K05770.
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16. Typical procedure for direct arylation of furans with iodoarenes: To a mixture of 1a (0.015 mmol, 14
mg) and Ag2CO3 (0.30 mmol, 83 mg) were added toluene (1.5 mL) and then benzylfuran (0.30 mmol,
45 µL) and iodobenzene (0.30 mmol, 33 µL) in a pressure vial. After stirring at 120 °C for 15 h, the
mixture was cooled to room temperature and filtered through a short plug of silica gel using EtOAc
as an eluent. Evaporation of the filtrate and silica gel column chromatography (hexane) of the
residue gave a mixture of 4a and 4b in 41% yield (29 mg). Analytical pure 4a was obtained by flash
1
column chromatography. 4a: H NMR (CDCl3, 600 MHz) δ 7.62 (s, 1H), 7.44 (d, J = 7.6 Hz, 2H),
7.36-7.21 (m, 8H), 6.32 (s, 1H), 4.00 (s, 2H); 13C NMR (CDCl3, 151 MHz) δ 155.74, 137.80, 137.28,
132.62, 128.75, 128.70, 128.56, 127.08, 126.80, 126.60, 125.66, 105.58, 34.62; HRMS (EI): calcd
for C17H14O: 234.1045. Found; 234.1016.
17. Spectral data for representative products. 6a: 1H NMR (CDCl3, 600 MHz) δ 7.71 (s, 1H), 7.47 (d, J =
7.6 Hz, 2H), 7.40-7.23 (m, 8H), 6.64 (s, 1H), 4.59 (s, 2H), 4.51 (s, 2H); 13C NMR (CDCl3, 151 MHz)
δ 152.82, 138.56, 137.78, 132.31, 128.79, 128.44, 127.93, 127.77, 127.12, 127.03, 125.77, 108.55,
1
72.02, 63.96; HRMS (EI): calcd for C18H16O2: 264.1150. Found; 264.1135. 15a: H NMR (CDCl3,
600 MHz) δ 7.37 (s, 1H), 7.32 (m, 1H), 7.24-7.17 (m, 3H), 6.18 (s, 1H), 2.65 (t, J = 7.6 Hz, 2H),
2.39 (s, 3H), 1.68 (m, 2H), 1.39-1.33 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 151 MHz)
δ 156.47, 138.02, 135.62, 132.71, 130.58, 129.00, 126.86, 126.08, 125.84, 106.55, 31.42, 28.01,
1
27.65, 22.42, 21.25, 14.02; HRMS (EI): calcd for C16H20O: 228.1514. Found; 228.1465. 18a: H
NMR (CDCl3, 600 MHz) δ 8.02 (d, J = 8.9 Hz, 2H), 7.68 (s, 1H), 7.51 (d, J = 8.9 Hz, 2H), 6.33 (s,
1H), 3.92 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.68 (m, 2H), 1.39-1.31 (m, 4H), 0.91 (t, J = 7.6 Hz, 3H);
13C NMR (CDCl3, 151 MHz) δ 166.93, 158.26, 137.68, 137.52, 130.11, 128.16, 126.08, 125.31,
103.72, 52.03, 31.32, 28.01, 27.57, 22.40, 13.98; HRMS (EI): calcd for C17H20O3: 272.1412. Found;
272.1379.