Nickel-Catalyzed Intramolecular Nucleophilic Addition of Aryl Halides to Aryl Ketones for the Synthesis of Benzofuran Derivatives

Article abstract of DOI:10.1055/s-0040-1706662

A nickel-catalyzed intramolecular nucleophilic addition reaction of aryl halides to aryl ketones for the formation of benzofuran derivatives has been developed. A number of substrates bearing electron-donating or electron-withdrawing groups were subjected to the standard reaction conditions, giving the corresponding products in moderate to good yields.

Full text of DOI:10.1055/s-0040-1706662

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, 1842–1848
paper
1842
en
X.-R. Zhu, C.-L. Deng
Paper
Synthesis
Nickel-Catalyzed Intramolecular Nucleophilic Addition of Aryl Ha-
lides to Aryl Ketones for the Synthesis of Benzofuran Derivatives
Xiao-Rui Zhua
Chen-Liang Deng*a,b
O
[Ni]/ligand
Zn powder
Ar
O
I
Ar
R2
R2
a College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325035,
P. R. of China
b Institute of New Materials & Industry Technology,
Wenzhou University, Wenzhou 325035,
P. R. of China
MeCN, 110 °C
R1
O
R1
18 examples
up to 90% yield
dcl78@wzu.edu.cn
CeMholelaneiClg-oLdeircaorlnef7sgC8ph@Doewenmndzgiuns.tgerdyAuau.ncthndoMr aterials Engineering, Wenzhou University, Wenzhou 325035, P. R. of China
Received: 10.11.2020
Accepted after revision: 11.12.2020
Published online: 25.01.2021
The oxidative addition of aromatic or vinyl halides to
palladium or nickel salts for the formation of C–C bonds is
one of the most efficient strategies in organic synthesis.6
Well-established methods for the construction of C–C
bonds through Pd(0)/Ni(0)-catalyzed cross-coupling in-
clude the Kumada–Corriu reaction7 and the Negishi8 and
Suzuki8a,9 couplings. The scope and application of these re-
actions has been fully explored. These methods have reli-
able yields and good functional-group tolerance. However,
these strategies usually suffer from some drawbacks, in-
cluding the need for strong bases, multistep processes, and
harsh reaction conditions. The synthesis of benzofurans via
nickel-catalyzed intramolecular nucleophilic addition has
been less explored than other methods. Recently, Huang, Lv,
and co-workers have described a highly enantioselective
and straightforward nickel-catalyzed protocol to construct
chiral 3-hydroxy-2,3-dihydrobenzofurans with high yield,
good functional-group tolerance, and excellent enantio-
DOI: 10.1055/s-0040-1706662; Art ID: ss-2020-g0579-op
Abstract A nickel-catalyzed intramolecular nucleophilic addition re-
action of aryl halides to aryl ketones for the formation of benzofuran
derivatives has been developed. A number of substrates bearing elec-
tron-donating or electron-withdrawing groups were subjected to the
standard reaction conditions, giving the corresponding products in
moderate to good yields.
Key words nickel, zinc powder, intramolecular addition, cyclization,
benzofuran
Benzofuran moieties are ubiquitous structural skele-
tons1 that are present in both natural products and synthet-
ic pharmaceuticals and have remarkable biological and
therapeutic activities2 (Figure 1 3). Several synthetic strate-
gies for the construction of benzofuran skeletons from dif-
ferent starting materials have been developed.4 Phenols
have attracted much attention as starting materials
(Scheme 1, eq. 1, 2). Among the strategies, transition-
metal-catalyzed cross-coupling reactions have emerged as
an alternative and have attracted much attention for their
atom and step economy.5
O
Ar
I
strong base
two steps
Br
Br
R1
Ar
Ar
R2
R1
(1)
(2)
R2
OH
O
Ar
O
MW
R1
R1
base
O
OH
HO
HO
H
O
HO
R1
OMe
Y
X
Ni(PPh3)4/ligand
Mn, iPrOH
R1
OH
(3)
R2
HO
MeO
R2
OMe
Y
X = Br, I
O
Y = O, CH2
OH
O
O
MDR-1339
HO
Malibatol A
[Ni]/ligand
Zn powder
Ar
O
I
Ar
this work
R2
R2
MeCN, 110 °C
Figure 1 Example natural products or drugs containing benzofuran
O
R1
moieties
R1
Scheme 1 Synthetic methods for the construction of benzofurans
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1843
X.-R. Zhu, C.-L. Deng
Paper
Synthesis
selectivity (Scheme 1, eq. 3).10 However, the development of
a simple and highly efficient nickel-catalyzed intramolecu-
lar nucleophilic addition reaction to synthesize benzo-
furans remains highly desirable. Herein, we report a simple
and convenient protocol for the formation of benzofuran
derivatives that is conducted through a nickel-catalyzed in-
tramolecular nucleophilic addition process (Scheme 1).
The substrate 2-(2-iodophenoxy)-1-phenylethanone11
(1a) was chosen to optimize the reaction conditions, and
the results are shown in Table 1. Firstly, in the presence of
Ni(dppp)2Cl2 (5 mol%), 2,2′-bipyridine (10 mol%), and Zn
powder (2 equiv), the product 3-phenylbenzofuran (2a)
was isolated in 17% yield under an N2 atmosphere (Table 1,
entry 1). Absence of the ligand or Ni catalyst resulted in no
target product being detected by GC-MS analysis (Table 1,
entries 2, 3). These results prompted us to pursue more ef-
ficient reaction conditions. A series of ligands, including
PCy3, S-Phos (2-dicyclohexylphosphino-2′,6′-dimethoxybi-
phenyl), DABCO (1,4-diazabicyclo[2.2.2]octane), and 1,10-
Phen (1,10-phenanthroline), were tested. The results indi-
cated that 1,10-Phen was the most efficient ligand (Table 1,
entries 4–7). Subsequently, various solvents, including
MeOH, toluene, DCE, THF, and PrCN, were investigated, and
MeCN was found to give the best yield (Table 1, entries 7–
12). Then, four other nickel catalysts, Ni(OTf)2, Ni(PPh3)2Br2,
Ni(cod)2Cl2, and NiCl2·6H2O, were examined. The results
demonstrated that all of the nickel catalysts had reactivity
for the cyclization, with Ni(OTf)2 and Ni(dppp)2Cl2 provid-
ing the best yields (Table 1, entries 6, 13–16). The effect of
temperature was also evaluated; an increased or decreased
reaction temperature reduced the yield of the target prod-
uct (Table 1, entries 17, 18). Finally, an increase in the load-
ing of Zn powder or decrease in the amount of [Ni] and li-
gand also decreased the yield of 2a (Table 1, entries 19, 20).
With this optimized procedure in hand, we aimed to ex-
pand the scope of the coupling reaction by screening a
range of substrates 1; the results are summarized in Table 2.
Initially, the electronic effects of substrates 1 were exam-
ined. The results indicated that substrates bearing electron-
withdrawing or electron-donating groups were well toler-
ated in the reaction and produced the corresponding prod-
ucts in moderate to good yields. For example, substrates
1b–1d, possessing electron-donating groups on the ring,
were suitable for the cyclization, giving the target products
in moderate yields (Table 2, entries 1–3). Similar results
were achieved when substrates 1e–1g were employed for
this transformation (Table 2, entries 4–6). Use of the steri-
cally hindered substrates 1h and 1i resulted in the corre-
sponding products 2h and 2i being isolated in 54% and 23%
yields, respectively (Table 2, entries 7, 8). Interestingly, two
bromo-substituted substrates 1j and 1k also performed
well in this transformation, producing the de-brominated
product 2a in moderate yields (Table 2, entries 9, 10). The
bromine atoms were reduced by the Zn powder. Com-
pounds with substitutions on the Ar group were also inves-
tigated and shown to be good substrates for the cyclization.
For example, compounds 1l and 1m, bearing Me and OMe
groups on the Ar ring, reacted smoothly to afford products
2j and 2k in 89% and 59% yields, respectively (Table 2, en-
tries 11, 12). The halo-containing substrates 1n–1q facili-
tated the reaction, and the cyclization products 2l–2o were
obtained in 27%–65% yields (Table 2, entries 13–16). Sub-
strate 1r also served as an efficient substrate and furnished
product 2p in 75% yield (Table 2, entry 17). Use of substrate
1s resulted in a 65% yield of target product 2q, isolated un-
der standard conditions (Table 2, entry 18). Gratifyingly,
when 2-(2-iodophenoxy)-1-phenylpropan-1-one (1t) was
subjected to the reaction, the 2,3-disubstituted benzofuran
2r was afforded in 55% yield (Table 2, entry 19). Cyclization
of the bromo-containing substrate 1u also proceeded rapid-
ly to give a 30% yield of product 2a (Table 2, entry 20).
Table 1 Screening for Optimal Conditionsa
O
Ph
[Ni]/ligand
O
Zn powder
Ph
solvent, N2, 110 °C
O
I
1a
2a
Entry
[Ni]
Ligand
Solvent
Yieldb
1
2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
–
2,2′-bpy
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeOH
toluene
DCE
17
ND
ND
ND
ND
trace
89
3
–
4
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(OTf)2
PCy3
5
S-Phos
6
DABCO
7
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
8
67
9
20
10
11
12
13
14
15
16
17c
18d
19e
20f
19
THF
trace
50
PrCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
90
Ni(PPh3)2Br2
Ni(cod)2Cl2
NiCl2·6H2O
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
Ni(dppp)2Cl2
39
trace
72
69
trace
46
61
a Reaction conditions: 1a (0.2 mmol), [Ni] (10 mol%), ligand (10 mol%), Zn
powder (2 equiv) in solvent (2 mL) under N2 at 110 °C for 24 h.
b Isolated yield.
c At 130 °C.
d At 80 °C.
e Zn powder (3 equiv).
f [Ni] (3 mol%), ligand (6 mol%).
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848

1844
X.-R. Zhu, C.-L. Deng
Paper
Synthesis
Table 2 Exploration of the Scope of Substrates 1a
Entry
9c
1
2
Products
Yield
(%)b
Ni(OTf)2 or Ni(dppp)2Cl2 (5 mol%)
1,10-Phen (10 mol%)
O
Ar
O
O
O
I
Zn powder (2 equiv)
Ar
O
I
R2
1j
2a
2a
61
R2
MeCN (2 mL), N2, 110 °C
O
R1
R1
Br
Br
2
1
O
I
Entry
1
2
Products
Yield
10c
1k
63
89
(%)b
O
O
O
O
1c
2c
3c
4c
1b
1c
1d
1e
2b
2c
2d
2e
55
O
O
I
11c
1l
2j
I
O
O
O
I
Et
70
46
75
79
O
Et
O
O
I
12c
1m
2k
59
O
O
O
O
tBu
O
tBu
I
O
O
O
O
O
O
I
13
14c
15
1n
1o
1p
2l
32
65
41
O
O
F
Cl
Cl
F
I
Cl
O
O
O
O
I
2m
Cl
O
I
5c
6c
7
1f
2f
F
F
O
O
O
O
I
O
I
Cl
1g
1h
1i
2g
2h
2i
48
54
23
2n
Cl
Cl
Cl
Cl
Cl
O
O
O
O
O
O
I
O
O
I
16c
1q
1r
2o
2p
27
75
Cl
Cl
O
O
I
O
8
O
I
17c
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848

1845
X.-R. Zhu, C.-L. Deng
Paper
Synthesis
Table 2 (continued)
Ph
OZnX
Ni(OTf)2 or
Ni(dppp)2Cl2
Ph
OH
Entry
1
2
Products
Yield
(%)b
O
2a
1,10-Phen
O
C
D
O
Zn powder
H2O
N
N
Ni0X2
O
O
I
ZnX2
ZnX2
Ph
X = OTf or Cl
18
1s
2q
65
I
O
NiΙΙ
N
N
N
Ni0
N
O
O
1a
B
O
O
N
NiΙΙ
N
O
I
19
20
1t
2r
55
30
I
O
Ph
O
A
Scheme 3 Proposed mechanism
O
1u
2a
Br
a Reaction conditions: 1a (0.2 mmol), Ni(OTf)2 (10 mol%), 1,10-Phen (10
mol%), Zn powder (2 equiv) in MeCN (2 mL) under N2 at 110 °C for 24 h.
b Isolated yield.
Chemicals were either purchased or purified by standard techniques.
1H NMR and 13C NMR spectra were measured on a 500 MHz spec-
trometer (1H: 500 MHz, 13C: 125 MHz), using CDCl3 as the solvent
with TMS as an internal standard at r.t. Chemical shifts are given in 
relative to TMS, and the coupling constants J are given in Hz. High-
resolution mass spectra were recorded on an ESI-Q-TOF mass spec-
trometer. All reactions were conducted under a nitrogen atmosphere
by using standard Schlenk techniques. Column chromatography was
performed by using EM silica gel 60 (300–400 mesh).
c Ni(dppp)2Cl2 (10 mol%) was used.
The synthesis of benzofuran 2a through a one-pot
method was also achieved (Scheme 2). The reaction of 2-io-
dophenol with 2-bromo-1-phenylethanone proceeded well
in the presence of Ni(dppp)2Cl2, ligand, Zn powder, K2CO3,
and MeCN and led to the formation of target 2a in 30% yield.
Benzofurans 2a–2r; General Procedure
Ni(dppp)2Cl2 (5 mol%)
Ph
A flame-dried Schlenk tube with a magnetic stirring bar was charged
with 1 (0.2 mmol), Ni(OTf)2 (5 mol%), Zn powder (2 equiv), 1.10-Phen
(10 mol%), and MeCN (2 mL) under a nitrogen atmosphere. The reac-
tion mixture was stirred at 110 °C for 16 h. After the reaction com-
pleted, the reaction mixture was filtered and evaporated under vacu-
um. The residue was purified by flash column chromatography (hex-
ane) to afford the desired products.
1,10-Phen (10 mol%)
O
OH
I
Zn powder (2 equiv)
Br
+
Ph
K2CO3 (1.5 equiv)
O
MeCN (2 mL), N2, 110 °C
2a, 30%
Scheme 2 One-pot method for the synthesis of 2a
3-Phenylbenzofuran (2a)2
Based on previous reports, as well as our experimental
results,12 a possible mechanism is outlined in Scheme 3. Ini-
tially, the nickel salts combine with the bidentate ligand
1,10-Phen and are then reduced to Ni(0) by the Zn powder.
This is followed by oxidative addition of 1a to generate the
Ni(II) species A. The Ni(II) species A, through an intramolec-
ular nucleophilic addition process, produces intermediate
B. Subsequently, transmetalation of B by ZnX2 leads to the
Zn intermediate C and regeneration of the Ni catalyst. Final-
ly, intermediate C, via demetallization and dehydration pro-
cesses, affords the target product 2a.
In summary, we have developed a nickel-catalyzed in-
tramolecular nucleophilic addition reaction for the forma-
tion of benzofuran derivatives. Various functional groups
were tolerated well under the standard reaction conditions,
regardless of electronic effects, and the target products
were formed in moderate to good yields.
Yellow oil (32.2 mg, 83% yield).
1H NMR (500 MHz, CDCl3):  = 7.74 (d, J = 8.0 Hz, 1 H), 7.67 (s, 1 H),
7.54 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.36 (t, J = 7.5 Hz, 2 H),
7.27–7.23 (m, 2 H), 7.20 (t, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 155.8, 141.3, 132.1, 128.9, 127.5,
127.4, 126.5, 124.5, 123.0, 122.3, 120.4, 111.7.
LRMS (EI, 70 eV): m/z (%) = 193 (M+, 100), 165 (98), 164 (66), 194 (34),
166 (31).
5-Methyl-3-phenylbenzofuran (2b)2
Yellow oil (22.9 mg, 55% yield).
1H NMR (500 MHz, CDCl3):  = 7.66 (s, 1 H), 7.58–7.57 (m, 3 H), 7.42–
7.37 (m, 3 H), 7.30 (t, J = 7.0 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 2.41 (s, 3
H).
13C NMR (125 MHz, CDCl3):  = 154.2, 141.4, 132.4, 132.2, 128.8,
127.4, 127.3, 126.5, 125.7, 122.0, 120.1, 111.2, 21.4.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848

1846
X.-R. Zhu, C.-L. Deng
Paper
Synthesis
LRMS (EI, 70 eV): m/z (%) = 206 (M+, 100), 207 (33), 206 (31), 164 (23),
178 (22), 177 (19), 89 (16).
1H NMR (500 MHz, CDCl3):  = 7.62 (s, 1 H), 7.57 (d, J = 7.5 Hz, 2 H),
7.51 (s, 1 H), 7.40 (t, J = 7.5 Hz, 2 H), 7.28 (t, J = 7.5 Hz, 1 H), 7.26 (s, 1
H), 2.32 (s, 3 H), 2.30 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 154.8, 140.6, 133.7, 132.5, 131.6,
5-Ethyl-3-phenylbenzofuran (2c)
128.9, 127.4, 127.2, 124.3, 121.8, 120.4, 112.1, 20.4, 20.1.
Yellow oil (31.1 mg, 70% yield).
LRMS (EI, 70 eV): m/z (%) = 220 (M+, 100), 205 (40), 221 (35), 219 (27),
177 (20).
HRMS (ESI): calcd for C16H14ONa+ ([M + Na]+): 245.0937; found:
245.0929.
1H NMR (500 MHz, CDCl3):  = 7.75 (s, 1 H), 7.65–7.63 (m, 3 H), 7.49–
7.44 (m, 3 H), 7.37 (t, J = 7.5 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 1 H), 2.77 (q,
J = 7.5 Hz, 2 H), 1.29 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 154.4, 141.5, 139.2, 132.3, 128.9,
127.5, 127.4, 126.5, 124.8, 122.1, 119.0, 111.4, 29.0, 16.4.
LRMS (EI, 70 eV): m/z (%) = 205 (M+, 100), 220 (64), 206 (32), 221 (25),
1-Phenylnaphtho[2,1-b]furan (2i)5
177 (17).
Yellow oil (11.3 mg, 23% yield).
HRMS (ESI): calcd for C16H14ONa+ ([M + Na]+): 245.0937; found:
245.0939.
1H NMR (500 MHz, CDCl3):  = 7.99 (d, J = 8.0 Hz, 1 H), 7.94 (d, J = 8.0
Hz, 1 H), 7.77 (d, J = 9.0 Hz, 1 H), 7.70 (d, J = 10.0 Hz, 2 H), 7.61 (d, J =
6.5 Hz, 2 H), 7.52 (t, J = 7.5 Hz, 2 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.43 (t, J =
7.5 Hz, 1 H), 7.35 (t, J = 7.5 Hz, 1 H).
5-(tert-Butyl)-3-phenylbenzofuran (2d)3
13C NMR (125 MHz, CDCl3):  = 153.2, 141.7, 133.1, 130.8, 129.9,
Yellow oil (23.0 mg, 46% yield).
128.9, 128.6, 127.9, 126.0, 125.9, 124.5, 124.3, 123.4, 120.7, 112.6.
LRMS (EI, 70 eV): m/z (%) = 244 (M+, 100), 215 (63), 213 (25), 245 (19).
1H NMR (500 MHz, CDCl3):  = 7.72 (s, 1 H), 7.65 (s, 1 H), 7.55 (d, J =
7.5 Hz, 2 H), 7.41–7.38 (m, 3 H), 7.34–7.29 (m, 2 H), 1.31 (s, 9 H).
13C NMR (125 MHz, CDCl3):  = 154.0, 146.1, 141.5, 132.3, 129.0,
127.6, 127.3, 126.1, 122.5, 122.4, 116.3, 111.0, 34.8, 31.9.
3-(p-Tolyl)benzofuran (2j)7
Yellow oil (37.2 mg, 89% yield).
LRMS (EI, 70 eV): m/z (%) = 233 (M+, 100), 234 (46), 248 (31), 249 (28),
104 (16).
1H NMR (500 MHz, CDCl3):  = 7.73 (d, J = 8.0 Hz, 1 H), 7.65 (s, 1 H),
7.44 (d, J = 7.5 Hz, 3 H), 7.24 (t, J = 7.5 Hz, 1 H), 7.21–7.17 (m, 3 H),
2.31 (s, 3 H).
5-Fluoro-3-phenylbenzofuran (2e)3
13C NMR (125 MHz, CDCl3):  = 155.8, 141.0, 137.2, 129.6, 129.1,
Yellow oil (31.8 mg, 75% yield).
127.4, 126.6, 124.4, 122.9, 122.1, 120.4, 111.7, 21.2.
LRMS (EI, 70 eV): m/z (%) = 206 (M+, 100), 207 (32), 164 (23), 205 (17).
1H NMR (500 MHz, CDCl3):  = 7.67 (s, 1 H), 7.46 (d, J = 7.0 Hz, 2 H),
7.37–7.32 (m, 4 H), 7.26 (t, J = 7.5 Hz, 1 H), 6.97–6.92 (m, 1 H).
13C NMR (125 MHz, CDCl3):  = 159.5 (JC–F = 236.3 Hz), 152.0, 142.9,
131.5, 129.0, 127.7, 127.3, 122.6, 112.42, 112.40, 112.3 (JC–F = 13.8
Hz), 106.0 (JC–F = 25.0 Hz).
3-(4-Methoxyphenyl)benzofuran (2k)2
Yellow oil (26.4 mg, 59% yield).
LRMS (EI, 70 eV): m/z (%) = 211 (M+, 100), 182 (64), 212 (26), 183 (21),
91(14).
1H NMR (500 MHz, CDCl3):  = 7.73–7.64 (m, 2 H), 7.50–7.45 (m, 3 H),
7.28–7.21 (m, 2 H), 6.93 (d, J = 8.0 Hz, 2 H), 3.78 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 159.1, 155.7, 140.7, 128.6, 126.7,
124.5, 124.4, 122.8, 121.8, 120.3, 114.4, 111.7, 55.3.
6-Chloro-3-phenylbenzofuran (2f)8
LRMS (EI, 70 eV): m/z (%) = 222 (M+, 100), 207 (67), 152 (45), 223 (41),
Yellow oil (36.0 mg, 79% yield).
1H NMR (500 MHz, CDCl3):  = 7.63–7.59 (m, 2 H), 7.48–7.43 (m, 3 H),
7.37–7.34 (m, 2 H), 7.26 (t, J = 7.5 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1 H).
151 (26).
3-(4-Chlorophenyl)benzofuran (2l)8
13C NMR (125 MHz, CDCl3):  = 155.8, 141.8, 131.4, 130.5, 129.0,
127.7, 127.4, 125.2, 123.7, 122.2, 120.9, 112.3.
Yellow oil (14.6 mg, 32% yield).
LRMS (EI, 70 eV): m/z (%) = 227 (M+, 100), 164 (82), 226 (40), 228 (33),
163 (26), 82 (25), 229 (24), 162 (21), 165 (14).
1H NMR (500 MHz, CDCl3):  = 7.66 (d, J = 7.5 Hz, 1 H), 7.63 (s, 1 H),
7.44–7.42 (m, 3 H), 7.31 (d, J = 8.5 Hz, 2 H), 7.24 (t, J = 7.0 Hz, 1 H),
7.19 (t, J = 7.5 Hz, 1 H).
5-Chloro-3-phenylbenzofuran (2g)3
13C NMR (125 MHz, CDCl3):  = 155.8, 141.4, 133.3, 130.5, 129.1,
128.6, 126.1, 124.7, 123.1, 121.2, 120.1, 111.8.
Yellow oil (22.0 mg, 48% yield).
LRMS (EI, 70 eV): m/z (%) = 227 (M+, 100), 164 (89), 226 (48), 228 (38),
82 (29), 163 (26), 229 (25), 162 (24), 165 (24).
1H NMR (500 MHz, CDCl3):  = 7.65 (s, 1 H), 7.62 (s, 1 H), 7.44 (d, J =
8.0 Hz, 2 H), 7.33 (t, J = 7.5 Hz, 2 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.24 (d, J =
7.5 Hz, 1 H), 7.16 (d, J = 8.5 Hz, 1 H).
3-(4-Fluorophenyl)benzofuran (2m)4
13C NMR (125 MHz, CDCl3):  = 154.1, 142.5, 131.2, 129.0, 128.7,
127.8, 127.7, 127.4, 124.8, 122.0, 120.1, 112.7.
Yellow oil (27.2 mg, 65% yield).
LRMS (EI, 70 eV): m/z (%) = 226 (M+, 100), 164 (63), 227 (40), 228 (37),
165 (26), 82 (23), 163 (18).
1H NMR (500 MHz, CDCl3):  = 7.67 (d, J = 7.5 Hz, 1 H), 7.63 (s, 1 H),
7.49–7.44 (m, 3 H), 7.26 (t, J = 7.5 Hz, 1 H), 7.21 (t, J = 7.5 Hz, 1 H), 7.06
(t, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3):  = 162.3 (JC–F = 245.0 Hz), 155.7, 141.1,
129.1, 128.0, 126.4, 124.6, 123.0, 121.3, 120.1, 115.9 (JC–F = 22.5 Hz),
111.8.
4,5-Dimethyl-3-phenylbenzofuran (2h)
White solid (24.1 mg, 54% yield), mp 50–52 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848

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X.-R. Zhu, C.-L. Deng
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Synthesis
LRMS (EI, 70 eV): m/z (%) = 211 (M+, 100), 182 (73), 212 (46), 183 (23),
91 (15).
Funding Information
We thank the National Natural Science Foundation of China (No.
21102104) and Wenzhou Science
G20190029) for their financial support.
& Technology Bureau (No.
3-(3,4-Dichlorophenyl)benzofuran (2n)
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Yellow oil (21.5 mg, 41% yield).
1H NMR (500 MHz, CDCl3):  = 7.70–7.67 (m, 2 H), 7.63 (s, 1 H), 7.47
(d, J = 8.5 Hz, 1 H), 7.44 (d, J = 8.0 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.29
(t, J = 7.5 Hz, 1 H), 7.24 (t, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 155.8, 141.8, 133.1, 132.2, 131.4,
130.9, 129.1, 126.6, 125.8, 125.0, 123.4, 120.3, 120.0, 112.0.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706662.
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LRMS (EI, 70 eV): m/z (%) = 261 (M+, 100), 263 (67), 260 (43), 262 (42),
198 (29), 99 (16), 264 (15), 163 (13).
References
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3-(2-Chlorophenyl)benzofuran (2o)
Yellow oil (12.3 mg, 27% yield).
1H NMR (500 MHz, CDCl3):  = 7.76 (s, 1 H), 7.51–7.45 (m, 4 H), 7.29–
7.23 (m, 3 H), 7.20 (t, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3):  = 155.0, 143.5, 133.5, 131.5, 130.6,
130.2, 128.9, 127.0, 126.8, 124.5, 122.9, 120.8, 119.2, 111.7.
LRMS (EI, 70 eV): m/z (%) = 226 (M+, 100), 164 (73), 228 (38), 227 (37),
165 (27), 82 (25).
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3-(o-Tolyl)benzofuran (2p)4
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Yellow oil (31.2 mg, 75% yield).
1H NMR (500 MHz, CDCl3):  = 7.62 (s, 1 H), 7.56 (d, J = 8.0 Hz, 1 H),
7.46 (d, J = 7.5 Hz, 1 H), 7.39 (d, J = 7.0 Hz, 1 H), 7.35–7.30 (m, 3 H),
7.29–7.24 (m, 2 H), 2.32 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 155.1, 142.2, 136.9, 130.9, 130.5,
130.4, 127.84, 127.83, 125.8, 124.4, 122.7, 121.4, 120.7, 111.6, 20.5.
LRMS (EI, 70 eV): m/z (%) = 206 (M+, 100), 205 (74), 178 (34), 177 (29),
207 (29).
3-(Naphthalen-2-yl)benzofuran (2q)
White solid (31.5 mg, 65% yield), mp 59–61 °C.
1H NMR (500 MHz, CDCl3):  = 8.03 (s, 1 H), 7.87–7.83 (m, 2 H), 7.81–
7.77 (m, 3 H), 7.65 (d, J = 8.5 Hz, 1 H), 7.49 (d, J = 8.5 Hz, 1 H), 7.44–
7.39 (m, 2 H), 7.31–7.24 (m, 2 H).
13C NMR (125 MHz, CDCl3):  = 155.9, 141.7, 133.7, 132.7, 129.5,
128.6, 127.9, 127.8, 126.4, 126.0, 125.9, 125.8, 124.6, 123.1, 122.2,
120.5, 111.8.
LRMS (EI, 70 eV): m/z (%) = 242 (M+, 100), 243 (68), 213 (45), 107 (22),
214 (18).
HRMS (ESI): calcd for C18H12ONa+ ([M + Na]+): 267.0780; found:
267.0784.
2-Methyl-3-phenylbenzofuran (2r)6
Yellow oil (22.9 mg, 55% yield).
1H NMR (500 MHz, CDCl3):  = 7.50 (d, J = 7.5 Hz, 1 H), 7.44–7.37 (m, 5
H),7.28 (t, J = 7.0 Hz, 1 H), 7.20–7.14 (m, 2 H), 2.46 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 154.0, 151.3, 132.9, 128.9, 128.8,
128.7, 126.9, 123.5, 122.6, 119.3, 116.9, 110.7, 12.8.
(8) (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111,
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Chem. Commun. 1977, 683.
LRMS (EI, 70 eV): m/z (%) = 206 (M+, 100), 205 (51), 130 (30), 207 (30),
177 (21), 178 (17).
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Synthesis
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, 1842–1848