Synthesis of 2-Benzoylbenzofurans via Palladium(II)-catalyzed Cascade Reactions

Full text of DOI:10.1080/00304948.2020.1862636

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of 2-Benzoylbenzofurans via
Palladium(II)-catalyzed Cascade Reactions
Haofan Luo, Zijuan Wang, Wenteng Chen, Chang He & Guolin Zhang
To cite this article: Haofan Luo, Zijuan Wang, Wenteng Chen, Chang He & Guolin Zhang (2021)
Synthesis of 2-Benzoylbenzofurans via Palladium(II)-catalyzed Cascade Reactions, Organic
Preparations and Procedures International, 53:2, 127-137, DOI: 10.1080/00304948.2020.1862636
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
2021, VOL. 53, NO. 2, 127–137
https://doi.org/10.1080/00304948.2020.1862636
EXPERIMENTAL PAPER
Synthesis of 2-Benzoylbenzofurans via Palladium(II)-
catalyzed Cascade Reactions
Haofan Luo, Zijuan Wang, Wenteng Chen, Chang He, and Guolin Zhang
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou, Zhejiang, China
ARTICLE HISTORY Received 14 May 2020; Accepted 8 August 2020
Transition metal-catalyzed transformation of nitrile functionality plays a decisive role in
synthetic organic chemistry by creating carbon–carbon and carbon–heteroatom bonds.
Larock’s group originally reported the palladium(0) catalyzed conversion of nitriles to
imines.1 Since then, the palladium(II)-catalyzed addition of the unactivated C-H unit to
the polar multiple bonds of nitriles was developed. However, these methods required
harsh reaction conditions and gave low yields.2 In light of this, Lu’s group developed
procedures using arylboronic acids, rather than stable aromatic compounds, to react
with the nitrile group, and this approach significantly improved the reaction effi-
ciency.3–4 There have been several reports of palladium(II)-catalyzed C-C coupling for
the synthesis of heteroaromatic compounds, such as 3-acylindoles,5 3-arylisoquinolines
and 1,3-diarylisoquinolines,6–7 2-arylindoles,8 and 2,4-disubstituted quinazolines.9
Notwithstanding these developments, it remains a desirable goal to obtain a new
method which is more convenient and widely available to synthesize 2-benzoylbenzofur-
ans. Benzofurans have drawn considerable attention due to their wide range of bio-
logical activities including antimicrobial,10 antifungal,11 antiviral12 and anti-HIV13
properties. The benzofuran heterocyclic core is a fundamental structural motif in a ser-
ies of natural products. A number of methods have been developed to synthesize benzo-
furan derivatives using palladium catalysts. Arcadi’s group has performed pioneering
work in the development of palladium-catalyzed intermolecular cyclizations (Scheme
1a).14 Cacchi’s group15 reported the cyclization of alkynes containing nucleophiles pro-
moted by organo-palladium complexes (Scheme 1b).15 Masami’s group developed a
one-pot synthesis of 2-benzoylbenzofurans through palladium-catalyzed 1,2-addition
and oxidation (Scheme 1c),16 and very recently Gong and co-workers have described
the synthesis of 2-aroylindoles and 2-aroylbenzofurans using carbopalladation of
nitriles.17 Herein, we report the palladium(II)-catalyzed cascade reaction of 2-(2-formyl-
phenoxy) acetonitriles with arylboronic acids to afford 2-benzoylbenzofurans (Scheme
1d), provide unambiguous structural insight from X-ray crystallography and offer a
mechanistic interpretation of the reaction.
As a model for exploring the best conditions, we chose the reaction shown in Scheme
1d (R1 ¼ H, R2 ¼ 4-CH3) for the preparation of compound 3a (Table 1). We examined
CONTACT Guolin Zhang
guolinzhang@zju.edu.cn
Zhejiang Province Key Laboratory of Anti-Cancer Drug
Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
ß 2021 Taylor & Francis Group, LLC

128
H. LUO ET AL.
Table 1. Optimization of reaction conditions.a
Entry
Solvent
toluene
n-propanol
DMF
n-propanol
toluene
DMF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
Ligand
Catalyst
Pd(OAc)2
T(ꢀC)
% Yieldb
1
2
3
4
5
6
7
8
L1
L1
L1
–
–
–
L1
L1
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
60
60
60
60
60
60
75
90
105
90
90
90
90
90
90
90
90
90
70
54
trace
11
25
trace
80
83
79
23
66
75
trace
34
73
83
40
82
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14
15c
16d
17e
18f
aReaction conditions: 1 (0.6 mmol), 2 (1.2 mmol, 2.0 equiv.), toluene (3.0 ml) as solvent, catalyst/ligand ratio: 1:1
(30 mol%); the mixture was stirred in a sealed tube for 10 h.
bIsolated yield (%).
c2a (0.3 mmol, 1.0 equiv).
d2a (0.9 mmol, 3.0 equiv).
eCatalyst/ligand ratio: 1:1 (10 mol% of 1a).
fCatalyst/ligand ratio: 1:1 (50 mol% of 1a).
the roles of solvent, ligand, catalyst and temperature in optimizing the yield. After a
thorough examination of these variables, we found that the optimal conditions for pre-
paring 3a were as follows: Pd(OAc)2 (30 mol %) as a catalyst, L1 (30 mol%) as a ligand
in toluene and reaction at 90 ꢀC for 10 h (Table 1, entry 8).
Under the optimal reaction conditions, several 2-(2-formylphenoxy) acetonitriles
1aꢁ1d were employed for the synthesis of 2-benzoylbenzofurans (Table 2). Reacting
with arylboronic acids, all the corresponding products 3a 2 3t were obtained in good
yields, with the single exception of compound 3g. The substituent R1 did not appear to
strongly influence the course of the reaction, even when very bulky (Table 2, entries
8–11). Substrates containing electron-donating substituents on the aromatic ring of the
arylboronic acid, such as the p-methoxy group, smoothly provided the corresponding
products in satisfactory yields (3b, 86%). Substrates bearing electron-withdrawing
groups gave somewhat lower yields (3a-3e, 66%-86%). The data suggest that the steric
effect of R2 strongly influenced the progress of the reaction (3e, 3f and 3g, 70%, 58%

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
129
Table 2. Scope of substrates.a
Entry
1
2
Product
% Yield
1
2
3
4
5
6
7
8
1a R1¼H
1a R1¼H
1a R1¼H
1a R1¼H
1a R1¼H
1a R1¼H
1a R1¼H
2a R2¼4-CH3
2b R2¼4-OCH3
2c R2¼H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
85
86
84
66
70
58
0
72
58
70
57
93
87
90
84
94
77
81
64
69
2d R2¼4-CF3
2e R2¼4-Cl
2f R2¼3-Cl
2g R2¼2-Cl
2a R2¼4-CH3
2d R2¼4-CF3
2c R2¼H
1b R1¼3,5-di-tert-butyl
1b R1¼3,5-di-tert-butyl
1b R1¼3,5-di-tert-butyl
1b R1¼3,5-di-tert-butyl
1c R1¼4-N,N-diethyl
1c R1¼4-N,N-diethyl
1c R1¼4-N,N-diethyl
1c R1¼4-N,N-diethyl
1c R1¼4-N,N-diethyl
1d R1¼5-Cl
9
10
11
12
13
14
15
16
17
18
19
20
2e R2¼4-Cl
2a R2¼4-CH3
2d R2¼4-CF3
2c R2¼H
2e R2¼4-Cl
2b R2¼4-OCH3
2a R2¼4-CH3
2c R2¼H
1d R1¼5-Cl
1d R1¼5-Cl
2d R2¼4-CF3
2e R2¼4-Cl
3s
3t
1d R1¼5-Cl
aStandard reaction conditions: 1 (0.6 mmol), 2 (1.2 mmol, 2.0 equiv.), Pd(OAc)2 (0.18 mmol, 30 mol%), 2,2’-bipyridine
(0.18 mmol, 30 mol%), toluene (3.0 ml) sealed, 90 ꢀC for 10 h; isolated yield.
Figure 1. The X-ray crystal structure of compound 3b.
1
and 0%). All of the new products were characterized by H NMR and 13C NMR spec-
troscopy and HRMS analysis. The melting points of known compounds matched the
values in the literature cited in the Experimental section. New compounds gave satisfac-
tory elemental analyses. The structure of compound 3b was further confirmed by X-ray
crystal structure analysis (Figure 1).
To gain insight into the mechanism, we used LC-HRMS to probe the formation of
intermediates during the course of the reaction. Taking 3l as an example, during the
whole 10-hour reaction, the intermediate E (M þ 1, 326.1751) was detected, which

130
H. LUO ET AL.
Scheme 1. Methods for the synthesis of benzofurans.
indicated the transformation of the nitrile. The putative intermediate F (M þ 1,
215.1179) was not detected, which indicated the cyclization of 1c had not occurred dur-
ing the reaction (Scheme 2a). When the reaction was carried out without 4-methylphe-
nylboric acid 2a under the same conditions, the intermediate F was indeed detected
(Scheme 2b). The results suggest that the two processes are competitive and that cycliza-
tion occurs right after the transformation of the nitrile.
On this basis, a plausible mechanism for the construction of 2-benzoylbenzofurans
could be proposed (Scheme 3). As indicated by the information on the intermediates,
the whole reaction process is divided into two parts: namely, transformation of the

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
131
Scheme 2. Detected intermediates.
nitrile and cyclization. The reaction proceeds by forming intermediate A, generated by
the transmetalation reaction of the palladium(II) catalyst and arylboronic acid. Then,
the nitrile group of 1 coordinates with intermediate A to afford B, which undergoes an
intramolecular insertion to afford intermediate C. The hydrolysis of intermediate C pro-
duces ketone derivative D. Thereafter, the intramolecular aldol-condensation reaction
transforms intermediate D to the corresponding product 3.
In summary, we have described an efficient approach for the preparation of 2-ben-
zoylbenzofurans catalyzed by Pd(OAc)2. Our products were rigorously characterized,
including an unambiguous structure determination from X-ray crystallography.
Mechanistic information implies that this palladium(II)-catalyzed cascade reaction
involves C(sp)–C(sp2) coupling followed by intramolecular cyclization. This attractive
reaction tolerates a wide range of substrates with good yields.

132
H. LUO ET AL.
Scheme 3. Proposed mechanism.
Experimental section
All solvents were purified according to standard methods prior to use. Melting points
€
were recorded on a BUCHI B-540 melting point apparatus. NMR spectra were recorded
1
1
for H NMR at 500 MHz and 13C NMR at 125 MHz. For H NMR, tetramethylsilane
(TMS) served as the internal standard (d ¼ 0). For 13C NMR, TMS (d ¼ 0) was used as
internal standard and spectra were obtained with complete proton decoupling. HRMS
data was obtained using an Agilent Technologies 6224 TOF LC/MS. All reactions were
monitored by TLC with silica gel coated plates, using petroleum ether (PE):ethyl acetate
(EA) ¼ 20:1 as the eluting solvent. Column chromatography was performed by using
100-200 mesh silica gel eluting with ethyl acetate and petroleum ether at ordinary pres-
sure, as noted below. The X-ray crystal structure of compound 3b was determined on a
Rigaku RAXIS-RAPID single-crystal diffractometer.
General procedure for 2-(2-formylphenoxy) acetonitriles 1
In a three-neck flask, salicylaldehyde (8.19 mmol), potassium carbonate (8.19 mmol)
and acetone (15.0 ml) were added successively and stirred for 1 h at room temperature.
Meanwhile chloroacetonitrile (0.68 g, 9.00 mmol) and KI (0.27 g, 0.16 mmol) were mixed
in a round-bottom flask and stirred for 1 h. Then the mixture in the round-bottom flask
was poured into the three-neck flask and stirred for 24 h at room temperature. The pro-
gress of the reaction was monitored using TLC. After the completion of the reaction,
the reaction mixture was diluted with ethyl acetate, washed with brine, and dried over
Na2SO4. After filtration, the solvent was evaporated and the crude product was purified
by chromatography on silica gel (using PE: EA ¼ 20:1).

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
133
General procedure for substituted 2-benzoylbenzofurans 3
In a sealed tube, 1 (0.60 mmol), 2 (1.20 mmol) and toluene (3.0 ml) were added succes-
sively and stirred until all the solid was dissolved. Then Pd(OAc)2 (0.18 mmol) and 2,2’-
bipyridine (0.18 mmol) were added simultaneously. The mixture was stirred at 90 ꢀC for
10 h. After completion of the reaction, the solvent was removed under reduced pressure.
Thereafter, the mixture was diluted with EtOAc and washed with brine. The organic
layer was dried over anhydrous Na2SO4, filtered and evaporated under vacuum, after
which the residue was purified by column chromatography (using petroleum ether/ethyl
acetate ¼ 20/1-100/1) to give the desired product 3.
(1-Benzofuran-2-yl) (4-methylphenyl)-methanone (3a)
Yield 117.7 mg, 85%, pale yellow solid, mp. 60-61 ꢀC (lit. mp. 60 ꢁ 62 ꢀC),18 1H NMR
(500 MHz, CDCl3) d 7.97 (d, J ¼ 8.2 Hz, 2H), 7.73 (d, J ¼ 7.9 Hz, 1H), 7.64 (d,
J ¼ 8.4 Hz, 1H), 7.52 (s, 1H), 7.50 (t, J ¼ 7.8 Hz, 1H), 7.33 (t, J ¼ 7.8 Hz, 1H), 7.34 (d,
þ
J ¼ 8.2 Hz, 2H), 2.47 (s, 3H); HRMS (ESI): m/z calcd for C16H12O2 [M þ H]
:
237.0910, found: 237.0919.
(1-Benzofuran-2-yl) (4-methoxyphenyl)-methanone (3b)
Yield 121.1 mg, 86%, pale yellow solid, mp. 96-98 ꢀC (97 ꢁ 99 ꢀC),18 1H NMR (500 MHz,
CDCl3) d 8.12 (d, J ¼ 8.7 Hz, 2H), 7.73 (d, J ¼ 7.9 Hz, 1H), 7.64 (d, J ¼ 8.4 Hz, 1H), 7.53
(s, 1H), 7.49 (t, J ¼ 7.8 Hz, 1H), 7.33 (t, J ¼ 7.5 Hz, 1H), 7.03 (d, J ¼ 8.7 Hz, 2H), 3.92 (s,
3H); HRMS (ESI): m/z calcd for C16H12O3 [M þ H] þ: 253.0859, found: 253.0861.
(1-Benzofuran-2-yl) phenyl-methanone (3c)
Yield 112.0 mg, 84%, white solid, mp. 89-91 ꢀC (88 ꢁ 90 ꢀC),18 1H NMR (500 MHz,
CDCl3) d 8.04 (d, J ¼ 7.1 Hz, 2H), 7.73 (d, J ¼ 7.9 Hz, 1H), 7.63-7.65 (m, 2H), 7.57 –
þ
7.48 (m, 4H), 7.37 – 7.30 (m, 1H); HRMS (ESI): m/z calcd for C15H10O2 [M þ H]
:
223.0754, found: 223.0745.
(1-Benzofuran-2-yl) (4-trifluoromethylphenyl)-methanone (3d)
Yield 130.5 mg, 66%, pale yellow solid, mp. 155-161 ꢀC (154–160 ꢀC),19 1H NMR
(500 MHz, CDCl3) d 8.16 (d, J ¼ 8.0 Hz, 2H), 7.82 (d, J ¼ 8.1 Hz, 2H), 7.75 (d, J ¼ 7.0,
Hz 1H), 7.65 (d, J ¼ 8.5, Hz, 1H), 7.58 (s, 1H), 7.54 (t, J ¼ 7.2 Hz, 1H), 7.36 (t,
J ¼ 7.6 Hz, 1H); HRMS (ESI): m/z calcd for C16H9F3O2 [M þ H] þ: 291.0627,
found: 291.0628.
(1-Benzofuran-2-yl) (4-chlorophenyl)-methanone (3e)
Yield 92.4 mg, 70%, pale yellow solid, mp. 149-151 ꢀC (150 ꢁ 152 ꢀC),18 1H NMR
(500 MHz, CDCl3) d 8.03 (d, J ¼ 8.5Hz, 2H), 7.74 (d, J ¼ 7.9 Hz, 1H), 7.64 (d, J ¼ 8.4,

134
H. LUO ET AL.
Hz, 1H), 7.55 (d, J ¼ 0.9 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.39 – 7.31 (t, J ¼ 7.5 Hz, 1H);
HRMS (ESI): m/z calcd for C15H9ClO2 [M þ H] þ: 257.0364, found: 257.0359.
(1-Benzofuran-2-yl) (3-chlorophenyl)-methanone (3f)
Yield 104.7 mg, 78%, pale yellow solid mp. 133-135 ꢀC (134 ꢁ 137 ꢀC),20 1H NMR
(500 MHz, CDCl3) d 8.03 (s, 1H), 7.94 (d, J ¼ 7.7 Hz, 1H), 7.75 (d, J ¼ 7.9 Hz, 1H), 7.65
(d, J ¼ 8.4 Hz, 1H), 7.61 (d, J ¼ 8.0 Hz, 1H), 7.57 (s, 1H), 7.47-7.54 (m, 2H), 7.35 (t,
J ¼ 7.5 Hz, 1H); HRMS (ESI): m/z calcd for C15H9ClO2 [M þ H] þ: 257.0364,
found: 257.0366.
(5, 7-Di-tert-butyl-1-benzofuran-2-yl) (4-methylphenyl)-methanone (3h)
Yield 148.5 mg, 72%, A reddish brown oil, 1H NMR (500 MHz, CDCl3) d 8.02 (d,
J ¼ 8.2 Hz, 2H), 7.54 (t, J ¼ 2.0 Hz, 1H), 7.54 (s, 1H), 7.46 (d, J ¼ 1.9 Hz, 1H), 7.33 (d,
J ¼ 7.9 Hz, 2H), 2.46 (s, 3H), 1.55 (s, 9H), 1.39 (s, 9H); 13C NMR (125 MHz, CDCl3) d
183.8, 152.7, 152.5, 146.8, 143.6, 135.1, 134.7, 129.8, 129.1, 127.4, 123.0, 116.7, 116.0,
35.0, 34.6, 31.8, 30.0, 21.8; HRMS (ESI): m/z calcd for C24H28O2 [M þ H] þ: 349.2162,
found: 349.2166.
Anal. Calcd for C24H28O2: C, 82.72; H, 8.10. Found: C, 82.62; H, 7.99.
(5, 7-Di-tert-butyl-1-benzofuran-2-yl) (4-trifluoromethylphenyl)-methanone (3i)
Yield 164.0 mg, 58%, A reddish brown oil, 1H NMR (500 MHz, CDCl3) d 8.19 (d,
J ¼ 8.1 Hz, 2H), 7.80 (d, J ¼ 8.2 Hz, 2H), 7.58 (s, 1H), 7.56 (d, J ¼ 1.9 Hz, 1H), 7.50 (d,
J ¼ 1.9 Hz, 1H), 1.55 (s, 9H), 1.39 (s, 9H); 13C NMR (125 MHz, CDCl3) d 182.9, 153.0,
151.7, 147.3, 140.3, 135.2, 129.8, 127.2, 125.4(q, J ¼ 3.5 Hz), 123.5, 117.1(d, J ¼ 32.5 Hz),
þ
35.0, 34.5, 31.7, 29.9, 29.7; HRMS (ESI): m/z calcd for C24H25F3O2 [M þ H]
402.1807, found: 402.1810.
:
Anal. Calcd for C24H25F3O2: C, 71.63; H, 6.26. Found: C, 71.55; H, 6.12.
(5, 7-Di-tert-butyl-1-benzofuran-2-yl) phenyl-methanone (3j)
Yield 148.5 mg, 70%, A reddish brown oil, 1H NMR (500 MHz, CDCl3) d 8.01 (d,
J ¼ 7.0 Hz, 2H), 7.54-7.56 (m, 1H), 7.44 – 7.47 (m, 4H), 7.39 (d, J ¼ 1.9 Hz, 1H), 1.48 (s,
9H), 1.32 (s, 9H); 13C NMR (125 MHz, CDCl3) d 184.2, 152.8, 152.2, 146.9, 137.5,
135.2, 132.7, 129.6, 128.4, 127.3, 123.2, 116.8, 116.5, 35.0, 34.6, 31.7, 29.9; HRMS (ESI):
m/z calcd for C23H26O2 [M þ H] þ: 335.2006, found: 335.2010.
Anal. Calcd for C23H26O2: C, 82.60; H, 7.84. Found: C, 82.69; H, 7.97.
(5, 7-Di-tert-butyl-1-benzofuran-2-yl) (4-chlorophenyl)-methanone (3k)
1
Yield 119.5 mg, 57%, A reddish brown oil, H NMR (500 MHz, CDCl3) d 8.09 – 8.03
(dt, J ¼ 8.7, 2.0 Hz, 2H), 7.57 (s, 1H), 7.55 (d, J ¼ 1.9 Hz, 1H), 7.53 – 7.50 (dt, J ¼ 8.8,
2.0Hz, 2H), 7.48 (d, J ¼ 1.9 Hz, 1H), 1.54 (s, 9H), 1.39 (s, 9H); 13C NMR (125 MHz,

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
135
CDCl3) d 182.8, 152.8, 152.0, 147.1, 139.2, 135.6, 135.1, 131.0, 128.8, 127.3, 123.4, 116.þ8,
116.5, 35.0, 34.6, 31.7, 29.9; HRMS (ESI): m/z calcd for C23H25ClO2 [M þ H]
369.1616, found: 369.1619.
:
Anal. Calcd for C23H25ClO2: C, 74.89; H, 6.83. Found: C, 74.92; H, 6.78.
(6-N,N-Diethyl-1-benzofuran-2-yl) (4-methylphenyl)-methanone (3l)
1
Yield 160.0 mg, 93%, yellow solid, mp. 140-143 ꢀC, H NMR (500 MHz, CDCl3) d 7.89
(d, J ¼ 8.1 Hz, 2H), 7.47 (d, J ¼ 8.8 Hz, 1H), 7.38 (d, J ¼ 0.9 Hz, 1H), 7.30 (d, J ¼ 7.9 Hz,
2H), 6.81 – 6.71 (m, 2H), 3.44 (q, J ¼ 7.2 Hz, 4H), 2.45 (s, 3H), 1.22 (t, J ¼ 7.1 Hz, 6H).
13C NMR (125 MHz, CDCl3) d 183.2, 159.2, 150.5, 149.3, 142.8, 135.5, 129.3, 129.1,
123.6, 123.6, 118.2, 116.3, 111.2, 92.9, 92.8, 45.1, 45.0, 25.9, 21.7, 12.5; HRMS (ESI): m/z
calcd for C20H21NO2 [M þ H] þ: 308.1645, found: 308.1651.
Anal. Calcd for C20H21NO2: C,78.15; H, 6.89; N, 4.56. Found: C, 78.12; H, 6.87;
N, 4.64.
(6-N,N-Diethyl-1-benzofuran-2-yl) (4-trifluoromethylphenyl)-methanone (3m)
1
Yield 188.6 mg, 87%, red solid, mp. 168-170 ꢀC, H NMR (500 MHz, CDCl3) d 8.00 (d,
J ¼ 8.0 Hz, 2H), 7.70 (d, J ¼ 8.1 Hz, 2H), 7.41 (d, J ¼ 8.8 Hz, 1H), 7.34 (s, 1H), 6.76 –
6.64 (m, 2H), 3.38 (q, J ¼ 7.1 Hz, 4H), 1.16 (t, J ¼ 7.1 Hz, 6H); 13C NMR (125 MHz,
CDCl3) d 180.9, 158.6, 148.8, 140.2, 132.5, 132.3, 128.4, 124.3 (q, J ¼ 3.6 Hz), 123.8,
122.9, 118.2, 115.2, 110.4, 91.5, 44.1, 11.5; HRMS (ESI): m/z calcd for C20H18F3NO2
[M þ H] þ: 362.1362, found: 362.1367.
Anal. Calcd for C20H18F3NO2: C, 66.48; H, 5.02; N, 3.88. Found: C, 66.46; H, 5.07;
N, 3.87.
(6-N,N-Diethyl-1-benzofuran-2-yl) phenyl-methanone (3n)
1
Yield 163.7 mg, 90%, red solid, mp. 150-153 ꢀC, H NMR (500 MHz, CDCl3) d 7.91 –
7.85 (m, 2H), 7.52 – 7.47 (m, 1H), 7.42 (t, J ¼ 7.5 Hz, 2H), 7.39 (d, J ¼ 8.8 Hz, 1H), 7.30
(d, J ¼ 0.9 Hz, 1H), 6.66 – 6.70 (m, 2H), 3.35 (q, J ¼ 7.1 Hz, 4H), 1.14 (t, J ¼ 7.1 Hz, 6H);
13C NMR (125 MHz, CDCl3) d 183.5, 159.4, 150.3, 149.5, 138.2, 132.1, 129.1, 128.4,
123.7, 118.6, 116.3, 111.1, 92.8, 45.1, 12.5. HRMS (ESI): m/z calcd for C19H19NO2
[M þ H] þ: 294.1489, found: 294.1492.
Anal. Calcd for C19H19NO2: C, 77.79; H, 6.53; N, 4.77. Found: C, 77.72; H, 6.47;
N, 4.81.
(6-N,N-Diethyl-1-benzofuran-2-yl) (4-chlorophenyl)-methanone (3o)
1
Yield 164.8 mg, 84%, yellow solid, mp. 164-166 ꢀC, H NMR (500 MHz, CDCl3) d 7.86
(d, J ¼ 8.5 Hz, 2H), 7.40 (d, J ¼ 7.9 Hz, 2H), 7.39 (s, 1H), 7.32 (s, 1H), 6.89 – 6.28 (m,
2H), 3.36 (q, J ¼ 7.1 Hz, 4H), 1.14 (t, J ¼ 7.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) d
182.0, 159.5, 149.6, 138.5, 136.4, 130.6, 128.7, 123.8, 118.7, 116.9, 116.2, 111.3, 92.6,

136
H. LUO ET AL.
þ
45.1, 12.5; HRMS (ESI): m/z calcd for C19H18ClNO2 [M þ H]
: 328.1099,
found: 328.1102.
Anal. Calcd for C19H18ClNO2: C, 69.62; H, 5.53; N, 4.27. Found: C, 69.57; H, 5.44;
N, 4.33.
(6-N,N-Diethyl-1-benzofuran-2-yl) (4-methoxyphenyl)-methanone (3p)
1
Yield 174.3 mg, 94%, yellow solid, mp. 177-180 ꢀC, H NMR (500 MHz, CDCl3) d 8.03
(dd, J ¼ 8.5, 1.4 Hz, 2H), 7.47 (dd, J ¼ 8.7, 1.2 Hz, 1H), 7.39 (s, 1H), 6.99 (dd, J ¼ 8.6,
1.6 Hz, 2H), 6.81 – 6.70 (m, 2H), 3.88 (s, 3H), 3.43 (q, J ¼ 7.0, 1.8Hz, 4H), 1.21 (t,
J ¼ 6.2 Hz, 6H); 13C NMR (125 MHz, CDCl3) d 182.2, 163.0, 159.1, 150.6, 149.2, 131.5,
130.8, 123.5, 117.5, 116.3, 113.7, 111.0, 92.9, 55.5, 45.0, 12.5; HRMS (ESI): m/z calcd for
C20H21NO3 [M þ H] þ: 324.1594, found: 324.1599.
Anal. Calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C, 74.21; H, 6.62;
N, 4.28.
(5-Chloro-1-benzofuran-2-yl) (4-methylphenyl)-methanone (3q)
1
Yield 124.7 mg, 77%, pale yellow solid, mp. 138-140 ꢀC, H NMR (500 MHz, CDCl3) d
7.88 (d, J ¼ 8.2 Hz, 2H), 7.61 (d, J ¼ 2.1 Hz, 1H), 7.48 (d, J ¼ 8.9 Hz, 1H), 7.37 (s, 1H),
7.35 (d, J ¼ 2.1 Hz, 2H), 7.26 (d, J ¼ 7.9 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz,
CDCl3) d 182.7, 153.1, 152.5, 143.1, 133.2, 128.7, 128.5, 128.3, 127.4, 127.2,þ121.5, 114.0,
112.6, 20.7; HRMS (ESI): m/z calcd for C16H11ClO2 [M þ H]
found: 271.0524.
: 271.0520,
Anal. Calcd for C16H11ClO2: C, 70.99; H, 4.10. Found: C, 70.92; H, 4.12.
(5-Chloro-1-benzofuran-2-yl) phenyl-methanone (3r)
1
Yield 124.8 mg, 81%, pale yellow solid, mp. 145-147 ꢀC, H NMR (500 MHz, CDCl3) d
8.04 (dd, J ¼ 8.3, 1.3 Hz, 2H), 7.71 (d, J ¼ 1.8 Hz, 1H), 7.68 – 7.61 (m, 1H), 7.56 (dd,
J ¼ 17.0, 8.6 Hz, 3H), 7.47 (d, J ¼ 0.9 Hz, 1H), 7.47 – 7.43 (m, 1H); 13C NMR (125 MHz,
CDCl3) d 184.1, 154.3, 153.4, 136.9, 133.2, 129.7, 129.5, 128.7, 128.7, 128.3, 122.6, 115.5,
113.7; HRMS (ESI): m/z calcd for C15H9ClO2 [M þ H] þ: 257.0364, found: 257.0368.
Anal. Calcd for C15H9ClO2: C, 70.19; H, 3.53. Found: C, 70.15; H, 3.58.
(5-Chloro-1-benzofuran-2-yl) (4-trifluoromethylphenyl)-methanone (3s)
1
Yield 116.7 mg, 64%, pale y ellow solid, mp. 169-171 ꢀC, H NMR (500 MHz, CDCl3) d
8.08 (d, J ¼ 8.1 Hz, 2H), 7.74 (d, J ¼ 8.2 Hz, 2H), 7.64 (d, J ¼ 1.9 Hz, 1H), 7.50 (d,
J ¼ 8.9 Hz, 1H), 7.44 (d, J ¼ 0.8 Hz, 1H), 7.40 (dd, J ¼ 8.9, 2.1 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d 181.9, 153.4, 151.9, 138.7, 133.3 (q, J ¼ 32.5), 128.9, 128.8, 128.2,
127.0, 124.6 (q, J ¼ 3.7), 121.7, 115.0, 112.7; HRMS (ESI): m/z calcd for C16H8ClF3O2
[M þ H] þ: 325.0238, found: 325.0233.
Anal. Calcd for C16H8ClF3O2: C, 59.19; H, 2.48. Found: C, 59.25; H, 2.39.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
137
(5-Chloro-1-benzofuran-2-yl) (4-chlorophenyl)-methanone (3t)
1
Yield 125.3 mg, 69%, pale yellow solid, mp. 156-158 ꢀC, H NMR (500 MHz, CDCl3) d
7.98 – 7.91 (m, 2H), 7.63 (d, J ¼ 2.1 Hz, 1H), 7.49 (d, J ¼ 8.9 Hz, 1H), 7.47 – 7.43 (m,
2H), 7.41 (d, J ¼ 0.9 Hz, 1H), 7.39 (dd, J ¼ 8.9, 2.1 Hz, 1H); 13C NMR (125 MHz,
CDCl3) d 181.6, 153.2, 152.2, 138.7, 134.0, 129.9, 128.8, 128.0, 127.8, 127.1, 121.6, 114.4,
112.6; HRMS (ESI): m/z calcd for C15H8Cl2O2 [M þ H] þ: 290.9974, found: 290.9979.
Anal. Calcd for C15H8Cl2O2: C, 61.89; H, 2.77. Found: C, 61.79; H, 2.82.
Acknowledgments
This project was supported from the National Key Research and Development Program of China
(No. 2017YFE0102200), the National Natural Science Foundation of China (No. 81673291), and
the Osteoporosis and Breast Cancer Research Center, USA, to Y. Yu.
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