Palladium-catalyzed α-arylation of aryloxyketones for the synthesis of 2,3-Disubstituted benzofurans

Article abstract of DOI:10.1021/jo500885w

A highly efficient palladium-catalyzed α-arylation of aryloxyketones has been developed, allowing for facile installation of various (hetero)aryl groups at C2 position in good to excellent yields. Subsequent cyclodehydration of the resulting α-arylated ar

Full text of DOI:10.1021/jo500885w

Article
pubs.acs.org/joc
Palladium-Catalyzed α‑Arylation of Aryloxyketones for the Synthesis
of 2,3-Disubstituted Benzofurans†
Jin Ho Lee, Myungock Kim, and Ikyon Kim*
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon
406-840, Republic of Korea
S
* Supporting Information
ABSTRACT: A highly efficient palladium-catalyzed α-aryla-
tion of aryloxyketones has been developed, allowing for facile
installation of various (hetero)aryl groups at C2 position in
good to excellent yields. Subsequent cyclodehydration of the
resulting α-arylated aryloxyketones provided rapid access to
diverse 2,3-disubstitured benzofurans.
conducted with 4-bromoanisole (2.5 equiv), Pd(OAc)2 (4 mol
%), phosphine ligand (8 mol %), and NaH (1.1 equiv) in THF
(3 mL) at 120 °C. Screening of suitable phosphine ligand for
this transformation revealed that SPhos gave the best isolated
yield of the desired product 5a (entries 1−8). Other bases such
as NaOt-Bu or KOt-Bu furnished the inferior results (entries 9
and 10). Replacement of THF by toluene decreased the
chemical yield (entry 11). While reactions at 100 °C provided
comparable results, lowering the reaction temperature to 80 °C
led to incomplete conversion and decreased yield (entries 12
and 13). Likewise, reducing the amount of 4-bromoanisole
resulted in incomplete conversion and lower chemical yields
(entries 14 and 15). Use of 1.3 equiv of NaH rather gave
unsatisfactory results (entry 16). Use of 4-iodoanisole yielded
the product in 38% yield although yield improvement was
observed at 80 °C (entry 17).
INTRODUCTION
■
Benzofuran ubiquitously found in various natural products and
functional materials constitutes an important class of chemical
backbones.1 As a subclass, 2,3-disubstituted benzofurans
embedded in a number of natural products and pharmaceuticals
exhibit a broad spectrum of biological activities, prompting
development of a number of efficient synthetic strategies for
this heterocyle (Figure 1).2
2,3-Disubstituted benzofurans, traditionally, have been
synthesized by transition metal-catalyzed cross-coupling re-
actions of prefunctionalized benzofurans such as C2-halo-
genated3 or stannylated4 benzofurans with aryl boronic acids or
aryl halides. Guided by powerful C−H activation technologies,
direct arylation of 2- or 3-substituted benzofurans with aryl
halides have also appeared.5 More recently, oxidative
dehydrogenative cross-coupling approach6 to install heteroaryl
moiety at C2 site of benzofurans was reported, although the
scope and yields are still limited. Despite all these advances,
development of more direct synthetic methods to access to this
skeleton is in high demand. Our recent contribution to this area
has resulted in efficient synthetic routes to several 2,3-
benzofuran-containing natural products.7,8
Having found optimal conditions for α-arylation of
aryloxyketones, we reacted 4a with several aryl bromides
under optimized conditions as shown in Scheme 2. Not only
electron-rich aryl groups but also electron-poor aryl groups
were introduced in good yields. Heterocycle such as pyridine
can be incorporated to afford 5n in 42% yield.
In both cases, we have employed direct arylation protocol to
install aryl group at the C2 position of benzofurans. In one case
as illustrated in Scheme 1a, however, we observed dimerized
benzofuran product 3 as a byproduct under the direct arylation
conditions. Although research to find reaction conditions to
minimize the formation of the dimer is plausible with
benzofuran 1, alternatively, we envisioned that introduction
of aryl group at C2 site via palladium-catalyzed α-arylation of
aryloxyketone9,10 followed by dehydrative cyclization would
give the desired 2,3-disubstituted benzofuran product as a way
to avoid this problem (Scheme 1b).
Substrate scope of this reaction was further investigated by
exposing other aryloxyketones with several aryl bromides under
optimized conditions. The results are shown in Scheme 3.
Various functional groups attached to aryloxyketones seemed
compatible under these reaction conditions. Substrates
containing methoxyl, phenyl, fluoro, or chloro groups under-
went smooth α-arylation to give the corresponding products in
good to excellent yields. Aryloxyketone bearing a methox-
ycarbonyl group at R1 site reacted with 4-bromoanisole and
ethyl 4-bromobenzoate to afford 5ac and 5ad, respectively
(entries 13 and 14). Substrates possessing multiple substituents
at R1 and R2 positions (4i−4k) were also allowed to react with
several aryl bromides to furnish the desired products, 5aj−5ao
RESULTS AND DISCUSSION
■
To evaluate this idea, we began our studies with 4a11 and 4-
bromoanisole as substrates to optimize the reaction conditions
for α-arylation (Table 1). Reactions of 4a (0.236 mmol) were
Received: April 20, 2014
© XXXX American Chemical Society
A
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Article
Figure 1. Some natural products having a 2,3-disubstituted benzofuran unit.
Scheme 1. Novel Approach to 2,3-Disubstituted Benzofurans
(entries 20−25). Larger scale experiments were conducted with
several substrates to produce the corresponding α-arylated
compounds in good yields (entries 2, 5, 6, 21, 24, and 25).
Finally, cyclodehydration of the resulting 2-arylated arylox-
yketones was attempted (Scheme 4).12 Several different
reaction conditions were screened for cyclization. Dehydrative
cyclization of 5 under the influence of catalytic amounts of
PTSA provided the corresponding benzofurans in good yields
(7, 9, 10, 13−16). In some cases, more than stoichiometric
amounts of catalyst were required for efficient conversion (6, 8,
and 12).13 Upon exposure to PPTS (0.1 equiv) in refluxing
toluene to trigger cyclization,14 5aj was transformed to 2,3-
diarylbenzofuran 2, previously employed as an important
intermediate for the syntheses of permethylated analogues of
viniferifuran, malibatol A, and shoreaphenol as well as
diptoindonesin G.7 In cases of 5v and 5aa, use of Bi(OTf)3
gave better isolation yields of the desired products (8 and
11).15
benzofurans in high yields. In particular, efficiency of this
protocol was further demonstrated by facile and effective
construction of a key intermediate utilized previously en route
to several natural products bearing a 2,3-disubstituted
benzofuran unit. Extension of this method for the synthesis
of other heterocycles is currently in progress.
EXPERIMENTAL SECTION
■
General Methods. Unless specified, all reagents and starting
materials were purchased from commercial sources and used as
received without purification. “Concentrated” refers to the removal of
volatile solvents via distillation using a rotary evaporator. “Dried” refers
to pouring onto, or passing through, anhydrous magnesium sulfate
followed by filtration. Flash chromatography was performed using
silica gel (230−400 mesh) with hexanes, ethyl acetate, and
dichloromethane as eluent. All reactions were monitored by thin-
layer chromatography on 0.25 mm silica plates (F-254) visualizing
1
with UV light. H and 13C NMR spectra were recorded on 400 MHz
In summary, we have successfully employed palladium-
catalyzed α-arylation as a means to install a variety of aryl
groups at the C2 position of aryloxyketones. Subsequent
cyclization of the resulting adducts afforded 2,3-disubstituted
NMR spectrometer and were described as chemical shifts, multiplicity
(s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling
constant in hertz (Hz), and number of protons. IR spectra were
recorded on FT-IR using diamond ATR technique and were described
B
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a
Hz, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.55−6.51 (m, 3H), 5.20 (s, 2H),
3.88 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.1,
164.2, 161.0, 159.4, 130.7, 130.1, 127.8, 114.2, 107.4, 106.8, 101.6,
70.8, 55.7, 55.5; HRMS (ESI-QTOF) calcd for [C16H17O4]+ m/z
273.1121, found 273.1128.
Table 1. Reaction Optimization
2-([1,1′-Biphenyl]-4-yloxy)-1-(4-methoxyphenyl)ethanone (4d).
White solid: mp 123.5−124.2 °C (695.8 mg, 87%); IR (ATR) ν =
3353, 3037, 2969, 2910, 2842, 1682, 1594, 1510, 1485, 1457, 1367,
1
1298, 1263, 1227 cm−1; H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
temperature
b
entry
ligand
PPh3
base
NaH
solvent
(°C)
yield (%)
8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.41 (t,
J = 8.0 Hz, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 6.97
(d, J = 8.0 Hz, 2H), 5.26 (s, 2H), 3.89 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 193.2, 164.2, 157.8, 140.8, 134.8, 130.7, 128.9, 128.4, 127.8,
126.9, 115.2, 114.2, 71.0, 55.7; HRMS (ESI-QTOF) calcd for
[C21H19O4]+ m/z 319.1329, found 319.1327.
2-(4-Chlorophenoxy)-1-phenylethanone (4e). White solid: mp
92.2−94.4 °C (lit. 95−97 °C)18 (433.8 mg, 70%); IR (ATR) ν = 3375,
3062, 2901, 2851, 1693, 1580, 1487, 1434, 1285, 1208 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.2 Hz,
1H), 7.51 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 9.2 Hz, 2H), 6.87 (d, J = 8.8
Hz, 2H), 5.27 (s, 2H); 13C NMR (100 MHz, CDCl3) δ194.2, 156.8,
134.5, 134.2, 129.6, 129.0, 128.2, 126.7, 116.3, 71.1; HRMS (Q-TOF)
calcd for [C14H12ClO2]+ m/z 247.0520, found 247.0519.
2-(4-(tert-Butyl)phenoxy)-1-phenylethanone (4f). White solid: mp
67.3−68.2 °C (lit. 67−68 °C)19 (357.3 mg, 53%); IR (ATR) ν = 3390,
2957, 2900, 1702, 1609, 1512, 1434, 1414, 1289, 1226 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz,
1H), 7.50 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.2
Hz, 2H), 5.25 (s, 2H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ
194.9, 155.9, 144.5, 134.8, 134.0, 129.0, 128.3, 126.5, 114.4, 71.1, 34.3,
31.6; HRMS (ESI-QTOF) calcd for [C18H21O2]+ m/z 269.1536,
found 269.1533.
1
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
THF
THF
THF
THF
THF
THF
120
120
120
120
120
120
120
120
120
120
120
100
80
33
2
BINAP
Xantphos
XPhos
t-BuXPhos
JohnPhos
RuPhos
SPhos
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaOt-Bu
KOt-Bu
NaH
NaH
NaH
NaH
NaH
NaH
NaH
30
3
67
4
76
5
53
6
46
7
99
8
99.5
37
9
SPhos
10
11
12
13
SPhos
59
SPhos
80
SPhos
92−95
60
SPhos
c
14
SPhos
120
120
120
120
94
d
15
SPhos
87
e
16
SPhos
84
f
g
17
SPhos
38, 50
a
A mixture of 4a (0.236 mmol), 4-bromoanisole (2.5 equiv),
Pd(OAc)2 (4 mol %), phosphine ligand (8 mol %), and base (1.1
equiv) in solvent (3 mL) was heated at 120 °C for 2 h unless
b
c
otherwise noted. Isolated yield (%) 4-Bromoanisole (2.0 equiv) was
Methyl 3-(2-oxo-2-phenylethoxy)benzoate (4g). Pale brown solid:
mp 117.5−118.0 °C (448.1 mg, 66%); IR (ATR) ν = 3406, 2900,
2843, 1703, 1582, 1486, 1428, 1289, 1209 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.64 (t, J
= 6.8 Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 8.0
Hz, 1H), 7.19 (dd, J = 2.8, 8.4 Hz, 1H), 5.35 (s, 2H), 3.90 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.0, 166.9, 158.1, 134.6, 134.2, 131.7,
129.8, 129.1, 128.2, 123.1, 120.4, 115.0, 70.8, 52.4; HRMS (ESI-
QTOF) calcd for [C16H17O4]+ m/z 271.0965, found 271.0965.
1-(4-Fluorophenyl)-2-phenoxyethanone (4h). White solid: mp
88.6−89.5 °C (416.4 mg, 71%); IR (ATR) ν = 3066, 2901, 2846,
1701, 1588, 1495, 1431, 1299, 1222 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.06 (dd, J = 5.6, 8.8 Hz, 2H), 7.29 (t, J = 8.8 Hz, 2H), 7.17
(t, J = 8.8 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H),
d
e
used. 4-Bromoanisole (1.5 equiv) was used. NaH (1.3 equiv) was
f
g
used. 4-Iodoanisole was used. Reaction conducted at 80 °C.
as wavenumbers (cm−1). HRMS were measured with electrospray
ionization (ESI) and Q-TOF mass analyzer.
General Procedure for the Synthesis of 4.16 A mixture of
appropriate 2-bromoacetophenone (2.512 mmol), phenol (1.25
equiv), and K2CO3 (1.5 equiv) in acetone (8.0 mL) was stirred at
80 °C for 2 h. The reaction mixture was concentrated under reduced
pressure to give the crude residue which was diluted with ethyl acetate
and washed with water. The water layer was extracted with ethyl
acetate two more times. The combined organic layers were dried over
MgSO4 and concentrated in vacuo to give a crude mixture which was
purified by silica gel column chromatography (hexane:ethyl acetate:di-
chloromethane) to afford 4.
5.21 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 193.5, 166.3 (d, JCF
254.6 Hz), 158.0, 131.2 (d, JCF = 9.4 Hz), 129.8, 121.9, 116.3, 116.1,
114.9, 71.1; HRMS (ESI-QTOF) calcd for [C14H12FO2]+ m/z
231.0816, found 231.0824.
=
2-Phenoxy-1-phenylethanone (4a). White solid: mp 72.6−73.3 °C
(lit. 72.5−73.0 °C)17 (490.8 mg, 92%); IR (ATR) ν = 3065, 1703,
1596, 1497, 1447, 1386, 1300, 1223 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.50 (t, J =
7.6 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.95 (d,
J = 8.0 Hz, 2H), 5.28 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 194.7,
158.1, 134.7, 134.0, 129.7, 129.0, 128.3, 121.8, 114.9, 70.9; HRMS
(ESI-QTOF) calcd for [C14H13O2]+ m/z 213.0910, found 213.0913.
2-(4-Methoxyphenoxy)-1-(4-methoxyphenyl)ethanone (4b). Pale
brown solid: mp 67.2−69.4 °C (622.5 mg, 91%); IR (ATR) ν = 3065,
3008, 2842, 1695, 1599, 1505, 1450, 1384, 1318, 1262, 1224 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 9.2 Hz, 2H), 6.96 (d, J = 8.8
Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 6.82 (d, J = 9.2 Hz, 2H), 5.16 (s,
2H), 3.88 (s, 3H), 3.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
193.6, 164.1, 154.5, 152.4, 130.7, 127.8, 116.1, 114.8, 114.1, 71.8, 55.8,
55.7; HRMS (ESI-QTOF) calcd for [C16H17O4]+ m/z 273.1121,
found 273.1121.
Methyl 3-(2-(3,5-dimethoxyphenyl)-2-oxoethoxy)-5-methoxy-
benzoate (4i).7a White solid: mp 105.4−106.9 °C (869.0 mg, 96%);
IR (ATR) ν = 3093, 2947, 2898, 2841, 1721, 1591, 1437, 1323, 1296,
1235 cm−1; H NMR (400 MHz, CDCl3) δ 7.23 (dd, J = 1.2, 2.0 Hz,
1
1H), 7.19 (dd, J = 1.2, 2.0 Hz, 1H), 7.11 (d, J = 2.0 Hz, 2H), 7.38 (t, J
= 2.0 Hz, 1H), 6.70 (t, J = 2.0 Hz, 1H), 5.28 (s, 2H), 3.90 (s, 3H), 3.85
(s, 6H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 193.5, 166.8,
161.2, 160.8, 159.1, 136.3, 132.3, 108.5, 107.6, 106.8, 106.2, 105.9,
70.8, 55.8, 55.79, 52.4; HRMS (ESI-QTOF) calcd for [C19H21O7]+ m/
z 361.1282, found 361.1274.
2-(3,4-Dimethoxyphenoxy)-1-phenylethanone (4j). White solid:
mp 78.3−78.9 °C (649.8 mg, 95%); IR (ATR) ν = 3379, 2941, 2836,
1699, 1593, 1508, 1440, 1304, 1263, 1225 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.51 (t, J =
7.6 Hz, 2H), 6.75 (d, J = 8.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.39
(dd, J = 2.8, 8.8 Hz, 1H), 5.23 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.8, 152.8, 150.1, 144.3, 134.8, 134.0,
129.0, 128.3, 111.7, 104.0, 101.7, 71.6, 56.5, 56.0; HRMS (ESI-QTOF)
calcd for [C16H17O4]+ m/z 273.1121, found 273.1119.
2-(3-Methoxyphenoxy)-1-(4-methoxyphenyl)ethanone (4c). Pale
brown solid: mp 48.1−49.5 °C (608.8 mg, 89%); IR (ATR) ν = 3008,
2959, 2836, 1692, 1591, 1490, 1454, 1433, 1309, 1263, 1231 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 2H), 7.18 (t, J = 7.6
C
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a
Scheme 2. α-Arylation of 4a with Aryl Bromides
a
A mixture of 4a (0.236 mmol), ArBr (2.5 equiv), Pd(OAc)2 (4 mol %), SPhos (8 mol %), and NaH (1.1 equiv) in THF (3 mL) was heated at 120
b
°C for 2 h unless otherwise noted. Isolated yields (%) are in parentheses.
2-(3,5-Dimethoxyphenoxy)-1-(3-methoxyphenyl)ethanone (4k).
White solid: mp 92.1−93.5 °C (1137.9 mg, 77%); IR (ATR) ν =
3403, 2898, 2839, 1711, 1598, 1476, 1429, 1262, 1192 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.55 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.40 (t, J
= 8.0 Hz, 1H), 7.16 (dd, J = 2.4, 8.0 Hz, 1H), 6.13−6.11 (m, 3H), 5.22
(s, 2H), 3.87 (s, 3H), 3.76 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
194.0, 161.7, 160.1, 160.0, 136.0, 130.0, 120.6, 120.56, 112.5, 93.9,
70.9, 55.7, 55.5; HRMS (ESI-QTOF) calcd for [C17H19O5]+ m/z
303.1227, found 303.1226.
General Procedure for the Synthesis of 5. A mixture of
aryloxyketone 4 (0.236 mmol), aryl bromide (2.5 equiv), palladium
acetate (4 mol %), and SPhos (8 mol %) in THF (3.0 mL) was added
60% NaH (1.1 equiv) at rt. The reaction mixture was sealed in a 7 mL
vial and heated at 120 °C for 2 h. The reaction mixture was quenched
with water and concentrated under reduced pressure to give the crude
residue which was diluted with ethyl acetate and washed with water.
The water layer was extracted with ethyl acetate two more times. The
combined organic layers were dried over MgSO4 and concentrated in
vacuo to give a crude mixture which was purified by silica gel column
chromatography (hexane:ethyl acetate:dichloromethane) to afford 5.
2-(4-Methoxyphenyl)-2-phenoxy-1-phenylethanone (5a). Color-
less oil (74.8 mg, 99.5%): IR (ATR) ν = 3060, 2936, 1694, 1594, 1519,
1490, 1447, 1344, 1214 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.03 (d,
J = 8.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.41
(t, J = 7.6 Hz, 2H), 7.23 (t, J = 7.6 Hz, 2H), 6.96−6.89 (m, 5H) 6.35
(s, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 196.0, 160.1,
157.7, 134.8, 133.6, 129.7, 129.3, 129.2, 128.8, 127.4, 121.8, 115.8,
D
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a
Scheme 3. α-Arylation of 4b−4k with Aryl Bromides
a
A mixture of 4 (0.236 mmol), ArBr (2.5 equiv), Pd(OAc)2 (4 mol %), SPhos (8 mol %), and NaH (1.1 equiv) in THF (3 mL) was heated at 120
b
c
°C for 2 h unless otherwise noted. Isolated yields (%). 0.708 mmol of 4 was used
114.6, 82.3, 55.4; HRMS (ESI-QTOF) calcd for [C21H19O3]+ m/z
319.1329, found 319.1325.
1592, 1491, 1456, 1428, 1348, 1287, 1204, 1153 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.41
(t, J = 7.6 Hz, 2H), 7.24−7.22 (m, 2H), 6.97−6.94 (m, 3H), 6.72 (s,
2H), 6.41 (s, 1H), 6.25 (s, 1H), 3.77 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 196.0, 161.3, 157.6, 137.7, 134.6, 133.7, 129.7, 129.5, 128.7,
121.9, 115.8, 105.4, 100.7, 83.0, 55.6; HRMS (ESI-QTOF) calcd for
[C22H21O4]+ m/z 349.1434, found 349.1430.
2-Phenoxy-1-phenyl-2-(3,4,5-trimethoxyphenyl)ethanone (5d).
White gum (69.7 mg, 78%): IR (ATR) ν = 3062, 2936, 1680, 1589,
1494, 1450, 1421, 1334, 1273, 1219, 1119 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (t, J =
7.6 Hz, 2H), 7.28−7.24 (m, 2H), 6.99−6.94 (m, 3H), 6.77 (s, 2H),
6.28 (s, 1H), 3.84 (s, 6H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 204.3, 153.8, 133.8, 129.8, 129.3, 128.8, 122.0, 115.8, 104.6, 82.9,
2-(3,4-Dimethoxyphenyl)-2-phenoxy-1-phenylethanone (5b).
Colorless oil (78.9 mg, 96%): IR (ATR) ν = 2934, 1692, 1594,
1
1512, 1461, 1340 cm−1; H NMR (400 MHz, CDCl3) δ 8.04 (d, J =
7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.24−
7.23 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.97−6.94 (m,
3H), 6.86 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H) 3.87 (s, 3H), 3.86 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 195.9, 157.7, 149.6, 149.5, 134.8,
133.6, 129.7, 129.2, 128.7, 127.7, 121.8, 120.6, 115.8, 111.3, 110.4,
82.4, 56.1, 56.0; HRMS (ESI-QTOF) calcd for [C22H21O4]+ m/z
349.1434, found 349.1433.
2-(3,5-Dimethoxyphenyl)-2-phenoxy-1-phenylethanone (5c).
Colorless oil (57.6 mg, 70%): IR (ATR) ν = 3060, 2934, 1694,
E
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a
Scheme 4. Dehydrative Cyclization of 5 to Benzofurans
a
b
A solution of 5 (0.1 mmol) in the presence of PTSA (0.1 equiv) in toluene (3 mL) was heated at 130 °C unless otherwise noted. Isolated yields
c
d
e
(%) are in parentheses. PTSA (1 equiv) was used. Bi(OTf)3 (2 equiv) was used in CH2Cl2 at 100 °C. Bi(OTf)3 (0.2 equiv) was used in toluene at
90 °C. PPTS (0.1 equiv) was used in toluene. PTSA (2 equiv) was used.
f
g
56.4; HRMS (ESI-QTOF) calcd for [C23H23O5]+ m/z 379.1540,
found 379.1542.
13C NMR (100 MHz, CDCl3) δ193.2, 157.5, 146.5, 136.1, 133.9,
131.7, 131.4, 130.0, 129.8, 129.4, 129.2, 128.8, 128.6, 122.1, 115.8,
82.5, 61.4, 14.5; HRMS (ESI-QTOF) calcd for [C23H21O4]+ m/z
361.1434, found 361.1435.
2-(3,5-Dimethylphenyl)-2-phenoxy-1-phenylethanone (5e).
White solid: mp 115.5−117.8 °C (68.7 mg, 92%); IR (ATR) ν =
1
3053, 2918, 1685, 1584, 1483 cm−1; H NMR (400 MHz, CDCl3) δ
4-(2-Oxo-1-phenoxy-2-phenylethyl)benzonitrile (5h). Brown gum
(52.5 mg, 71%): IR (ATR) ν = 3061, 2924, 2228, 1694, 1593, 1491,
8.04 (d, J = 8.4 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz,
2H), 7.25−7.22 (m, 2H), 7.18 (s, 2H), 6.96−6.92 (m, 4H), 6.30 (s,
1H), 2.30 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 196.1, 157.8,
138.8, 135.2, 134.7, 133.6, 130.7, 129.7, 129.4, 128.7, 125.4, 121.7,
115.7, 82.9, 21.5; HRMS (ESI-QTOF) calcd for [C22H21O2]+ m/z
317.1536, found 317.1535.
Ethyl 4-(2-oxo-1-phenoxy-2-phenylethyl)benzoate (5f). Colorless
oil (74.8 mg, 88%): IR (ATR) ν = 3061, 2980, 1703, 1698, 1594, 1491,
1447, 1413, 1366, 1273, 1219, 1103 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.0 Hz, 2H), 7.67 (d, J
= 8.4 Hz, 2H), 7.54 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.27−
7.24 (m, 2H), 6.99−6.95 (m, 3H), 6.36 (s, 1H), 4.36, (q, J = 7.2 Hz,
2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.8,
166.2, 140.4, 134.4, 133.0, 130.9, 130.3, 129.8, 129.5, 128.8, 127.1,
122.2, 115.8, 82.9, 61.3, 14.5; HRMS (ESI-QTOF) calcd for
[C23H21O4]+ m/z 361.1434, found 361.1437.
1
1447, 1410, 1217 cm−1; H NMR (400 MHz, CDCl3) δ 8.01 (d, J =
7.6 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.55 (t,
J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.28−7.24 (m, 2H), 6.99 (t, J
= 7.6 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H); 13C NMR (100
MHz, CDCl3) δ195.4, 157.0, 140.8, 134.1, 132.8, 129.9, 129.5, 128.9,
127.7, 122.4, 118.5, 115.6, 112.7, 82.4; HRMS (ESI-QTOF) calcd for
[C21H16NO2]+ m/z 314.1176, found 314.1178.
3-(2-Oxo-1-phenoxy-2-phenylethyl)benzonitrile (5i). White solid:
mp 83.1−86.1 °C (53.2 mg, 72%); IR (ATR) ν = 3061, 2230, 1692,
1
1593, 1489, 1211 cm−1; H NMR (400 MHz, CDCl3) δ 8.02 (d, J =
8.4 Hz, 2H), 7.92 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz,
1H), 7.57 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6
Hz, 2H), 7.29−7.25 (m, 2H), 6.99 (t, J = 7.2 Hz, 1H), 6.94 (d, J = 8.4
Hz, 2H), 6.33 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 195.5, 157.0,
137.3, 134.2, 134.1, 132.4, 131.5, 130.7, 130.0, 129.9, 129.5, 128.9,
122.5, 118.5, 115.6, 113.3, 82.0; HRMS (ESI-QTOF) calcd for
[C21H16NO2]+ m/z 314.1176, found 314.1179.
Ethyl 3-(2-oxo-1-phenoxy-2-phenylethyl)benzoate (5g). Colorless
oil (66.3 mg, 78%): IR (ATR) ν = 3062, 2981, 1716, 1707, 1594, 1491,
1
1446, 1369, 1281, 1218, 1186 cm−1; H NMR (400 MHz, CDCl3) δ
2-(4-Nitrophenyl)-2-phenoxy-1-phenylethanone (5j). Brown oil
(66.9 mg, 85%): IR (ATR) ν = 3069, 2925, 1698, 1587, 1543, 1492,
8.27 (s, 1H), 8.05−8.01 (m, 3H), 7.77 (d, J = 8.0 Hz, 1H), 7.54 (t, J =
7.6 Hz, 1H) 7.49−7.40 (m, 3H), 7.27−7.24 (m, 2H), 6.99−6.95 (m,
3H), 6.40 (s, 1H), 4.38 (q, J = 6.8 Hz, 2H), 1.39 (t, J = 6.8 Hz, 3H);
1
1445, 1361, 1211 cm−1; H NMR (400 MHz, CDCl3) δ 8.24 (d, J =
8.4 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.8 Hz, 2H), 7.56 (t,
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J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.29−7.25 (m, 2H), 7.00 (t, J
= 7.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.39 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 195.3, 157.0, 148.1, 142.8, 134.2, 134.1, 130.0, 129.5,
128.9, 127.9, 124.2, 122.5, 115.7, 82.3; HRMS (ESI-QTOF) calcd for
[C20H16NO4]+ m/z 334.1074, found 334.1069.
2-(4-Fluorophenyl)-2-phenoxy-1-phenylethanone (5k). White
solid: mp 91.4−92.9 °C (65.1 mg, 90%); IR (ATR) ν = 3071, 2923,
1688, 1590, 1492, 1448, 1361, 1298, 1259, 1218 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 8.0 Hz, 2H), 7.56−7.52 (m, 3H) 7.41 (t, J
= 7.6 Hz, 2H), 7.26−7.22 (m, 2H), 7.07 (t, J = 7.6 Hz, 2H), 6.98−6.92
(m, 3H), 6.34 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 195.9, 163.0
(d, JCF = 246.7 Hz), 157.5, 134.5, 133.8, 131.3 (d, JCF = 3.3 Hz), 129.8,
129.4 (d, JCF = 8.3 Hz), 129.3, 128.8, 122.0, 116.1 (d, JCF = 21.7 Hz),
115.7, 82.1; HRMS (ESI-QTOF) calcd for [C20H16FO2]+ m/z
307.1129, found 307.1121.
102.2, 82.1, 55.6, 55.4; HRMS (ESI-QTOF) calcd for [C22H20ClO4]+
m/z 383.1045, found 383.1042.
2-([1,1′-Biphenyl]-4-yloxy)-1,2-bis(4-methoxyphenyl)ethanone
(5r). Yellow gum (81.1 mg, 81%): IR (ATR) ν = 3193, 2923, 2837,
1681, 1596, 1510, 1484, 1458, 1420, 1362, 1305, 1227, 1166 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.07 (d, J = 9.2 Hz, 2H), 7.51−7.45 (m,
6H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 7.00 (d, J = 8.4
Hz, 2H), 6.92 (d, J = 7.2 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.33 (s,
1H), 3.84 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
194.5, 163.9, 160.1, 157.4, 151.9, 140.8, 134.7, 131.8, 129.0, 128.8,
128.4, 127.8, 127.6, 126.9, 116.0, 114.6, 114.0, 82.4, 55.6, 55.4; HRMS
(ESI-QTOF) calcd for [C28H25O4]+ m/z 425.1747, found 425.1746.
2-([1,1′-Biphenyl]-4-yloxy)-1-(4-methoxyphenyl)-2-(3,4,5-
trimethoxyphenyl)ethanone (5s). Colorless oil (301.9 mg, 88%): IR
(ATR) ν = 3002, 2936, 1683, 1594, 1507, 1485, 1459, 1419, 1330,
1262, 1229, 1170, 1125 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08 (d,
J = 8.0 Hz, 2H), 7.52−7.47 (m, 4H), 7.40 (t, J = 7.6 Hz, 2H), 7.29 (t, J
= 7.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 6.80
(s, 2H), 6.27 (s, 1H), 3.86 (s, 6H), 3.85 (s, 3H), 3.84 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 194.3, 164.1, 157.3, 153.8, 140.7, 138.4,
134.9, 131.8, 131.1, 128.9, 128.4, 127.5, 127.0, 126.9, 116.0, 114.1,
104.6, 82.9, 61.0, 56.4, 55.6; HRMS (ESI-QTOF) calcd for
[C30H29O6]+ m/z 485.1959, found 485.1963.
2-(4-Chlorophenoxy)-2-(4-methoxyphenyl)-1-phenylethanone
(5t). Yellow gum (55.8 mg, 67%): IR (ATR) ν = 3061, 2956, 1691,
1594, 1510, 1486, 1446, 1359, 1224, 1173 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.00 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.6 Hz, 1H), 7.46−7.40
(m, 4H), 7.18 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 6.85 (d, J
= 8.4 Hz, 2H), 6.31 (s, 1H), 3.78 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 195.5, 160.2, 156.3, 134.6, 133.8, 129.6, 129.2, 128.8, 126.9,
126.7, 117.2, 114.7, 82.5, 55.4; HRMS (ESI-QTOF) calcd for
[C21H18ClO3]+ m/z 353.0939, found 353.0941.
2-(4-Chlorophenoxy)-2-(3,4-dimethoxyphenyl)-1-phenyletha-
none (5u). Yellow oil (56.9 mg, 63%): IR (ATR) ν = 3059, 2933,
1691, 1593, 1512, 1487, 1462, 1419, 1259, 1226 cm−1; 1H NMR (400
MHz, CDCl3); δ 8.01 (d, J = 8.0 Hz, 2H), 7.55 (t, J = 7.6 Hz, 1H),
7.43 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 8.4 Hz,
1H), 7.02 (s, 1H), 6.88−6.85 (m, 3H), 6.30 (s, 1H), 3.86 (s, 3H), 3.86
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 195.5, 156.3, 149.8, 149.6,
134.7, 133.8, 129.6, 129.2, 128.8, 127.2, 126.8, 120.8, 117.2, 111.4,
110.4, 82.7, 56.1, 56.0; HRMS (ESI-QTOF) calcd for [C22H20ClO4]+
m/z 383.1045, found 383.1046.
4-(1-(4-Chlorophenoxy)-2-oxo-2-phenylethyl)benzonitrile (5v).
Colorless gum (204.4 mg, 83%): IR (ATR) ν = 3062, 2923, 2227,
1688, 1589, 1487, 1440, 1420, 1269, 1190 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 7.6 Hz, 2H), 7.69 (s, 4H), 7.57 (t, J = 7.6 Hz,
1H), 7.43 (t, J = 7.6 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 7.2
Hz, 2H), 6.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 195.0, 155.6,
140.3, 134.3, 134.0, 132.9, 129.9, 129.4, 129.0, 127.7, 127.5, 118.4,
117.0, 112.9, 82.6; HRMS (ESI-QTOF) calcd for [C21H15ClNO2]+ m/
z 348.0786, found 348.0788.
2-(4-Chlorophenyl)-2-phenoxy-1-phenylethanone (5l). White
solid: mp 107.1−110.6 °C (64.0 mg, 84%); IR (ATR) ν = 3061,
1
1694, 1594, 1489, 1447, 1218 cm−1; H NMR (400 MHz, CDCl3) δ
8.02 (d, J = 7.6 Hz, 2H), 7.55−7.50 (m, 3H), 7.41 (t, J = 7.6 Hz, 2H),
7.35 (d, J = 8.0 Hz, 2H), 7.26−7.23 (m, 2H), 6.98−6.92 (m, 3H), 6.31
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 195.8, 157.4, 134.8, 134.4,
134.1, 133.9, 129.8, 129.4, 129.3, 128.8, 128.7, 122.1, 115.7, 82.2;
HRMS (ESI-QTOF) calcd for [C20H16ClO2]+ m/z 323.0833, found
323.0832.
2-Phenoxy-1-phenyl-2-(3-(trifluoromethyl)phenyl)ethanone
(5m). White solid: mp 79.6−81.4 °C (54.7 mg, 65%); IR (ATR) ν =
3063, 2923, 1682, 1594, 1492, 1447, 1326, 1215, 1162, 1121 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 2H), 7.88 (s, 1H),
7.76 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.56−7.48 (m, 2H),
7.42 (t, J = 7.6 Hz, 2H), 7.27−7.24 (m, 2H), 6.99−6.95 (m, 3H), 6.37
(s, 1H); 13C NMR (100 MHz, CDCl3) δ195.8, 157.3, 136.7, 134.3,
134.0, 131.5 (d, JCF = 32.1 Hz), 130.5, 129.9, 129.6, 129.4, 128.9, 125.7
(q, JCF = 3.6 Hz), 124.1 (q, JCF = 3.8 Hz), 122.3, 115.7, 82.4; HRMS
(ESI-QTOF) calcd for [C21H16F3O2]+ m/z 357.1097, found 357.1099.
2-Phenoxy-1-phenyl-2-(pyridin-3-yl)ethanone (5n). Brown oil
(28.7 mg, 42%): IR (ATR) ν = 3062, 2923, 1739, 1687, 1590,
1
1488, 1449, 1419, 1269, 1190 cm−1; H NMR (400 MHz, CDCl3) δ
8.85 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.89
(d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H),
7.32 (dd, J = 4.8, 8.0 Hz, 1H), 7.28−7.24 (m, 2H), 7.00−6.94 (m,
3H), 6.41 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 195.4, 157.2,
150.1, 148.9, 135.1, 134.3, 134.1, 131.5, 129.9, 129.3, 128.9, 124.0,
122.3, 115.7, 80.6; HRMS (ESI-QTOF) calcd for [C19H16NO2]+ m/z
290.1176, found 290.1173.
2-(4-Methoxyphenoxy)-1,2-bis(4-methoxyphenyl)ethanone (5o).
Colorless oil (60.7 mg, 68%): IR (ATR) ν = 3002, 2933, 1681, 1596,
1503, 1460, 1359, 1305, 1212, 1167 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.04 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.90−6.86
(m, 6H), 6.76 (d, J = 9.2 Hz, 2H), 6.19 (s, 1H), 3.82 (s, 3H), 3.77 (s,
3H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.9, 163.8,
159.9, 154.5, 151.9, 131.7, 128.9, 128.1, 127.7, 117.1, 114.7, 114.5,
113.9, 83.3, 55.7, 55.6, 55.4; HRMS (ESI-QTOF) calcd for
[C23H23O5]+ m/z 379.1540, found 379.1545.
2-(4-Methoxyphenoxy)-1-(4-methoxyphenyl)-2-(3,4,5-
trimethoxyphenyl)ethanone (5p). White gum (270.1 mg, 87%): IR
(ATR) ν = 3067, 2934, 1671, 1593, 1502, 1459, 1421, 1331, 1219,
1178, 1120 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz,
2H), 6.91−6.88 (m, 4H), 6.79−6.77 (m, 4H), 6.13 (s, 1H), 3.84 (s,
9H), 3.82 (s, 3H), 3.73 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
194.7, 163.9, 154.6, 153.7, 151.8, 138.2, 131.8, 131.5, 127.6, 117.0,
114.8, 113.9, 104.4, 83.9, 60.9, 56.3, 55.7, 55.6; HRMS (ESI-QTOF)
calcd for [C25H27O7]+ m/z 439.1751, found 439.1756.
Ethyl 4-(1-(4-Chlorophenoxy)-2-oxo-2-phenylethyl)benzoate
(5w). Yellowish gum (39.1 mg, 42%): IR (ATR) ν = 3063, 2979,
1702, 1697, 1595, 1486, 1446, 1413, 1366, 1273, 1226 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 7.6 Hz,
2H), 7.64 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.41 (d, J = 7.6
Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.33 (s,
1H), 4.36 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 195.3, 166.1, 155.9, 139.8, 134.2, 134.1, 131.1, 130.4,
129.7, 129.4, 128.9, 127.2, 117.1, 83.0, 61.3, 14.5; HRMS (ESI-QTOF)
calcd for [C23H20ClO4]+ m/z 395.1045, found 395.1049.
2-(4-(tert-Butyl)phenoxy)-2-(4-methoxyphenyl)-1-phenyletha-
none (5x). White solid: mp 119.2−119.5 °C (78.7 mg, 89%); IR
(ATR) ν = 3069, 2959, 1686, 1606, 1509, 1443, 1360, 1304, 1232,
2 - ( 4- C h l o ro ph e n y l) - 2 -( 3 - m e t h o x y ph e n o x y ) - 1 - ( 4 -
methoxyphenyl)ethanone (5q). White gum (57.8 mg, 64%): IR
(ATR) ν = 3069, 2932, 1683, 1593, 1488, 1453, 1255, 1197 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 8.0
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.4 Hz, 1H), 6.88 (d, J =
8.4 Hz, 2H), 6.53−6.50 (m, 3H), 6.25 (s, 1H), 3.83 (s, 3H), 3.74 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 194.1, 164.1, 161.0, 158.7,
134.7, 134.4, 131.8, 130.2, 129.2, 128.6, 127.2, 114.1, 107.7, 107.4,
1
1184 cm−1; H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.0 Hz, 2H),
7.51 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.40 (t, J = 7.6 Hz,
2H), 7.24 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8
Hz, 2H), 6.31 (s, 1H), 3.76 (s, 3H), 1.25 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 196.2, 160.0, 155.5, 144.3, 134.8, 133.6, 129.3, 129.1,
G
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128.7, 127.6, 126.5, 115.1, 114.5, 82.3, 55.4, 34.2, 31.6; HRMS (ESI-
QTOF) calcd for [C25H27O3]+ m/z 375.1955, found 375.1956.
2-(4-(tert-Butyl)phenoxy)-2-(3,4-dimethoxyphenyl)-1-phenyle-
thanone (5y). White solid: mp 123.2−124.2 °C (82.1 mg, 86%); IR
(ATR) ν = 3057, 2965, 1681, 1590, 1509, 1459, 1416, 1366, 1258,
1233 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.0 Hz, 2H),
7.53 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.25 (d, J = 8.4 Hz,
2H), 7.10 (d, J = 8.0 Hz, 1H), 7.05 (s, 1H), 6.88−6.84 (m, 3H), 6.30
(s, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 1.26 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 196.2, 155.5, 149.5, 144.4, 134.8, 133.6, 129.3, 128.7, 127.9,
126.5, 120.6, 115.2, 111.3, 110.4, 82.5, 56.1, 56.0, 34.2, 31.6; HRMS
(ESI-QTOF) calcd for [C26H29O4]+ m/z 405.2060, found 405.2061.
Ethyl 4-(1-(4-(tert-butyl)phenoxy)-2-oxo-2-phenylethyl)benzoate
(5z). Colorless gum (82.6 mg, 84%): IR (ATR) ν = 3059, 2959, 1715,
1706, 1607, 1509, 1447, 1412, 1364, 1272, 1230 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H),
7.66 (d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.2 Hz,
2H), 7.25 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.33 (s, 1H),
4.35 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H), 1.26 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 196.0, 166.2, 155.2, 144.8, 140.6, 134.4,
133.8, 130.8, 130.2, 129.5, 128.8, 127.1, 126.6, 115.1, 82.9, 61.2, 34.2,
31.6, 14.4; HRMS (ESI-QTOF) calcd for [C27H29O4]+ m/z 417.2060,
found 417.2056.
(m, 5H), 6.26 (s, 1H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
194.8, 165.9 (d, JCF = 254.4 Hz), 160.1, 157.6, 132.1 (d, JCF = 9.3 Hz),
129.7, 128.8, 127.2, 121.9, 116.0, 115.8, 115.7, 114.6, 82.6, 55.4;
HRMS (ESI-QTOF) calcd for [C21H18FO3]+ m/z 337.1234, found
337.1233.
2-(3,4-Dimethoxyphenyl)-1-(4-fluorophenyl)-2-phenoxyetha-
none (5af). White solid: mp 76.5−77.1 °C (80.4 mg, 93%); IR (ATR)
1
ν = 3068, 2934, 1692, 1594, 1510, 1461, 1414, 1339, 1218 cm−1; H
NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 5.6, 7.2 Hz, 2H), 7.26−7.23
(m, 2H), 7.10−7.04 (m, 4H), 6.98−6.93 (m, 3H), 6.87 (d, J = 8.4 Hz,
1H), 6.25 (s, 1H), 3.87 (s, 3H), 3.86 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 194.7, 157.6, 149.6, 132.2, 132.1, 129.8, 127.6, 122.0, 120.2,
116.1, 115.8, 115.76, 111.4, 110.2, 82.8, 56.1, 56.0; HRMS (ESI-
QTOF) calcd for [C22H20FO4]+ m/z 367.1340, found 367.1347.
4-(1-(4-Fluorophenoxy)-2-oxo-2-phenylethyl)benzonitrile (5ag).
Colorless oil (61.8 mg, 79%): IR (ATR) ν = 3068, 2924, 2229,
1
1694, 1593, 1490, 1409, 1217 cm−1; H NMR (400 MHz, CDCl3) δ
8.07 (dd, J = 5.2, 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4
Hz, 2H), 7.29−7.25 (m, 2H), 7.08 (t, J = 8.4 Hz, 2H), 7.00 (t, J = 7.2
Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.27 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 194.1, 166.2 (d, JCF = 255.7 Hz), 156.9, 140.7, 132.8, 132.4
(d, JCF = 9.5 Hz), 130.0, 127.4, 122.6, 118.4, 116.2, 116.0, 115.5, 112.7,
82.8; HRMS (ESI-QTOF) calcd for [C21H15FNO2]+ m/z 332.1081,
found 332.1085.
2-(4-(tert-Butyl)phenoxy)-1-phenyl-2-(3-(trifluoromethyl)phenyl)-
ethanone (5aa). White solid: mp 100.1−100.8 °C (88.6 mg, 91%); IR
(ATR) ν = 3070, 2962, 1685, 1597, 1510, 1449, 1364, 1327, 1217
1-(4-Fluorophenyl)-2-phenoxy-2-(3-(trifluoromethyl)phenyl)-
ethanone (5ah). White solid: mp 85.9−86.9 °C (76.9 mg, 87%); IR
(ATR) ν = 3073, 2960, 1691, 1593, 1494, 1453, 1410, 1326, 1225
cm−1; 1H NMR (400 MHz, CDCl3) δ 8.08 (t, J = 6.8 Hz, 2H), 7.87 (s,
1H), 7.76 (d, J = 7.2 Hz, 1H), 7.53 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.6
Hz, 1H), 7.29−7.25 (m, 2H), 7.08 (t, J = 8.0 Hz, 2H), 7.01−6.95 (m,
3H), 6.29 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 194.6, 166.2 (d, JCF
= 255.2 Hz), 157.2, 136.6, 132.3 (d, JCF = 9.4 Hz), 131.5 (d, JCF = 32.6
Hz), 130.5 (d, JCF = 3.1 Hz), 130.2, 130.0, 129.6, 125.8 (q, JCF = 3.8
Hz), 123.7 (q, JCF = 3.2 Hz), 122.4, 116.2, 116.0, 115.6, 82.8; HRMS
(ESI-QTOF) calcd for [C21H15F4O2]+ m/z 375.1003, found 375.1005.
Ethyl 4-(2-(4-fluorophenyl)-2-oxo-1-phenoxyethyl)benzoate
(5ai). Colorless oil (80.4 mg, 90%): IR (ATR) ν = 3067, 2981,
1713, 1705, 1594, 1491, 1410, 1366, 1272, 1219 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.10−8.06 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.28−
7.24 (m, 2H), 7.07 (t, J = 8.4 Hz, 2H), 6.99 (d, J = 7.2 Hz, 1H), 6.95
(d, J = 8.4 Hz, 2H), 6.28 (s, 1H), 4.37 (q, J = 7.2 Hz, 2H), 1.38 (t, J =
7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 194.6, 166.2, 157.3,
140.2, 132.4, 132.4, 131.0, 130.3, 129.9, 126.8, 122.3, 116.1, 115.9,
83.3, 61.3, 14.5; HRMS (ESI-QTOF) calcd for [C23H20FO4]+ m/z
379.1340, found 379.1343.
1
cm−1; H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 7.6 Hz, 2H), 7.87
(s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55−7.47
(m, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 6.89 (d, J =
8.4 Hz, 2H), 6.34 (s, 1H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 196.0, 155.1, 145.0, 136.9, 134.4, 134.0, 131.6, 131.3, 130.5, 129.5,
129.5, 128.8, 126.7, 125.6 (q, JCF = 3.8 Hz), 124.1 (q, JCF = 3.9 Hz),
115.1, 82.5, 34.3, 31.6; HRMS (ESI-QTOF) calcd for [C25H24F3O2]+
m/z 413.1723, found 413.1721.
4-(1-(4-(tert-Butyl)phenoxy)-2-oxo-2-phenylethyl)benzonitrile
(5ab). Colorless oil (80.2 mg, 92%): IR (ATR) ν = 3060, 2959, 2229,
1695, 1605, 1509, 1447, 1363, 1231 cm−1; 1H NMR (400 MHz,
CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 2H), 7.67 (d, J
= 8.0, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.27 (d, J
= 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.30 (s, 1H), 1.26 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 195.6, 154,9 145.2, 141.1, 134.2, 134.1,
132.8, 129.5, 128.9, 127.7, 126.7, 118.6, 115.1, 112.6, 82.5, 34.3, 31.6;
HRMS (ESI-QTOF) calcd for [C25H24NO2]+ m/z 370.1802, found
370.1805.
Methyl 3-(1-(4-methoxyphenyl)-2-oxo-2-phenylethoxy)benzoate
(5ac). Colorless oil (53.3 mg, 60%): IR (ATR) ν = 3066, 2951, 1718,
1694, 1585, 1510, 1486, 1445, 1282, 1249, 1216 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H), 7.64−7.62 (m, 2H), 7.53 (t,
J = 7.6 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.30
(t, J = 7.6 Hz, 1H), 7.15−7.12 (m, 1H), 6.91 (d, J = 8.4 Hz, 2H), 6.42
(s, 1H), 3.86 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
195.5, 166.8, 160.2, 157.6, 134.7, 133.7, 131.7, 129.7, 129.3, 129.2,
128.8, 127.0, 123.0, 120.8, 116.6, 114.7, 82.3, 55.4, 52.3; HRMS (ESI-
QTOF) calcd for [C23H21O5]+ m/z 377.1384, found 377.1383.
Methyl 3-(1-(4-(ethoxycarbonyl)phenyl)-2-oxo-2-phenylethoxy)-
benzoate (5ad). Colorless oil (83.9 mg, 85%): IR (ATR) ν = 3069,
2952, 1715, 1706, 1587, 1486, 1445, 1367, 1271 cm−1; 1H NMR (400
MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz, 2H), 8.01 (d, J = 7.6 Hz, 2H),
7.67−7.65 (m, 4H), 7.54 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H),
7.32 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 4.36 (q,
J = 7.2 Hz, 2H), 3.88 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 195.2, 166.7, 166.2, 157.3, 139.9, 134.4, 134.0, 131.9,
131.1, 130.4, 129.9, 129.4, 128.9, 127.3, 123.4, 120.6, 116.5, 82.8, 61.3,
52.4, 14.5; HRMS (ESI-QTOF) calcd for [C25H23O6]+ m/z 419.1489,
found 419.1482.
Methyl 3-(2-(3,5-dimethoxyphenyl)-1-(4-methoxyphenyl)-2-ox-
oethoxy)-5-methoxybenzoate (5aj). Yellow gum (92.5 mg, 84%):
IR (ATR) ν = 3092, 2950, 1718, 1707, 1590, 1510, 1456, 1427, 1346,
1297, 1244, 1202, 1150 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.46 (d,
J = 8.4 Hz, 2H), 7.22 (s, 1H), 7.18 (s, 1H), 7.14 (s, 2H), 6.90 (d, J =
8.4 Hz, 2H), 6.71 (s, 1H), 6.61 (s, 1H), 6.38 (s, 1H), 3.86 (s, 3H),
3.78 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 194.9, 166.7, 160.9,
160.8, 160.2, 158.6, 136.4, 132.2, 129.4, 126.9, 114.7, 109.0, 108.2,
107.3, 106.9, 106.0, 82.0, 55.7, 55.4, 52.4; HRMS (ESI-QTOF) calcd
for [C26H27O8]+ m/z 467.1700, found 467.1706.
Methyl 3-(2-(3,5-dimethoxyphenyl)-1-(4-(ethoxycarbonyl)-
phenyl)-2-oxoethoxy)-5-methoxybenzoate (5ak). Yellow gum
(259.2 mg, 72%): IR (ATR) ν = 2935, 1714, 1590, 1455, 1428,
1347, 1274 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.0 Hz,
2H), 7.64 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (s, 1H), 7.13 (s, 2H),
6.72 (s, 1H), 6.62 (s, 1H), 6.41 (s, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.87
(s, 3H), 3.79 (s, 3H), 3.78 (s, 6H), 1.37 (t, J = 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 194.6, 166.6, 166.1, 160.9, 158.3, 139.8, 136.0,
132.4, 131.1, 130.4, 127.4, 109.0, 108.5, 107.3, 107.1, 106.3, 82.5, 61.3,
55.8, 55.7, 52.5, 14.5; HRMS (ESI-QTOF) calcd for [C28H29O9]+ m/z
509.1806, found 509.1805.
1-(4-Fluorophenyl)-2-(4-methoxyphenyl)-2-phenoxyethanone
(5ae). White solid: mp 75.1−77.6 °C (67.5 mg, 85%); IR (ATR) ν =
3064, 2954, 1689, 1591, 1492, 1460, 1409, 1358, 1257, 1219 cm−1; 1H
NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 6.0, 8.4 Hz, 2H), 7.47 (d, J =
8.4 Hz, 2H), 7.26−7.22 (m, 2H), 7.06 (t, J = 8.4 Hz, 2H), 6.97−6.90
Ethyl 4-(1-(3,4-dimethoxyphenoxy)-2-oxo-2-phenylethyl)-
benzoate (5al). Yellowish gum (80.4 mg, 81%): IR (ATR) ν =
3062, 2932, 1713, 1704, 1596, 1508, 1447, 1413, 1366, 1272, 1226,
1
1194 cm−1; H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.0 Hz, 2H),
H
dx.doi.org/10.1021/jo500885w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
8.01 (d, J = 8.4 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.54 (t, J = 7.6 Hz,
1H), 7.41 (t, J = 7.6 Hz, 2H), 6.69 (d, J = 8.8 Hz, 1H), 6.62 (d, J = 2.8
Hz, 1H), 6.37 (dd, J = 2.8, 8.8 Hz, 1H), 6.30 (s, 1H), 4.36 (q, J = 7.2
Hz, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 196.1, 166.2, 151.9, 150.0, 144.5, 140.5,
134.5, 133.9, 130.9, 130.3, 129.4, 128.8, 127.1, 111.6, 105.3, 102.1,
83.5, 61.3, 56.4, 56.0, 14.5; HRMS (ESI-QTOF) calcd for
[C25H25O6]+ m/z 421.1646, found 421.1643.
2-(4-Chlorophenyl)-2-(3,4-dimethoxyphenoxy)-1-phenyletha-
none (5am). Brown gum (58.7 mg, 65%): IR (ATR) ν = 3062, 2932,
1693, 1595, 1507, 1446, 1408, 1362, 1259, 1226, 1193 cm−1; 1H NMR
(400 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.56−7.50 (m, 3H),
7.40 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.8 Hz,
1H), 6.61 (d, J = 2.4 Hz, 1H), 6.35 (dd, J = 2.4, 8.4 Hz, 1H), 6.25 (s,
1H), 3.81 (s, 3H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
196.1, 151.9, 150.0, 144.4, 134.9, 134.5, 134.2, 133.9, 129.3, 128.8,
128.76, 111.5, 105.2, 102.1, 82.9, 56.4, 56.0; HRMS (ESI-QTOF)
calcd for [C22H20ClO4]+ m/z 383.1045, found 383.1046.
(t, J = 7.2 Hz, 1H), 6.89 (d, J = 8.4 Hz, 2H), 6.73 (s, 2H), 3.96 (s,
3H), 3.84 (s, 3H), 3.81 (s, 6H); 13C NMR (100 MHz, CDCl3) δ
160.0, 153.9, 153.5, 151.4, 141.8, 136.8, 131.1, 128.9, 128.6, 127.6,
127.0, 124.2, 123.2, 118.3, 116.3, 114.1, 111.3, 106.9, 61.2, 56.4, 55.5;
HRMS (ESI-QTOF) calcd for [C30H27O5]+ m/z 467.1853, found
467.1858.
4-(5-Chloro-3-phenylbenzofuran-2-yl)benzonitrile (8). Yellow
solid: mp 213.2−215.4 °C (14.2 mg, 43%); IR (ATR) ν = 3063,
1
2921, 2224, 1603, 1443, 1258 cm−1; H NMR (400 MHz, CDCl3) δ
7.74 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.54−7.48 (m, 4H),
7.45−7.44 (m, 3H), 7.34 (dd, J = 2.0, 8.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 152.7, 149.6, 134.5, 132.4, 131.5, 131.4, 129.62,
129.60, 129.3, 128.8, 127.2, 126.2, 120.3, 120.2, 118.8, 112.5, 111.9;
HRMS (ESI-QTOF) calcd for [C21H13ClNO]+ m/z 330.0680, found
330.0686.
5-(tert-Butyl)-2-(4-methoxyphenyl)-3-phenylbenzofuran (9).
White solid: mp 125.7−126.8 °C (22.5 mg, 63%); IR (ATR) ν =
3061, 2953, 1608, 1565, 1511, 1471, 1363, 1245, 1174 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 2H), 7.48−7.38 (m, 5H),
7.32−7.24 (m, 3H), 7.02 (d, J = 8.4 Hz, 2H), 3.89 (s, 3H), 1.36 (s,
9H); 13C NMR (100 MHz, CDCl3) δ 159.2, 152.3, 150.6, 146.2,
131.1, 131.07, 130.2, 128.5, 128.2, 127.0, 125.3, 122.8, 117.5, 116.1,
114.6, 110.5, 55.4, 34.9, 32.0; HRMS (ESI-QTOF) calcd for
[C25H25O2]+ m/z 357.1849, found 357.1847.
5-(tert-Butyl)-2-(3,4-dimethoxyphenyl)-3-phenylbenzofuran (10).
White solid: mp 118.1−119.2 °C (31.7 mg, 82%); IR (ATR) ν = 3057,
2948, 1574, 1512, 1462, 1441, 1407, 1371, 1311, 1248, 1227 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.67 (d, J = 6.8 Hz, 2H), 7.48−7.47 (m,
2H), 7.40 (d, J = 8.8 Hz, 1H), 7.33−7.25 (m, 3H), 7.08 (d, J = 8.0 Hz,
1H), 7.01−6.99 (m, 2H), 3.97 (s, 3H), 3.81 (s, 3H), 1.36 (s, 9H); 13C
NMR (100 MHz, CDCl3) δ 152.3, 150.7, 149.4, 148.6, 146.2, 131.0,
130.1, 128.5, 128.3, 127.0, 125.6, 122.8, 122.2, 117.6, 116.1, 113.0,
111.8, 110.6, 56.0, 35.0, 32.0; HRMS (ESI-QTOF) calcd for
[C26H27O3]+ m/z 387.1955, found 387.1949.
4-(1-(3,5-Dimethoxyphenoxy)-2-(3-methoxyphenyl)-2-oxoethyl)-
benzonitrile (5an). Brown gum (208.5 mg, 73%): IR (ATR) ν = 3072,
2935, 2228, 1694, 1592, 1458, 1427, 1319, 1262, 1202, 1146 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.68 (s, 4H), 7.60 (d, J = 7.6 Hz, 1H),
7.50 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.33 (s,
1H), 6.11 (s, 3H), 3.81 (s, 3H), 3.72 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 194.9, 161.8, 160.0, 158.9, 140.7, 135.5, 132.8, 129.9, 127.9,
121.9, 120.7, 118.5, 113.7, 112.8, 94.6, 94.3, 82.0, 55.6, 55.5; HRMS
(ESI-QTOF) calcd for [C24H22NO5]+ m/z 404.1492, found 404.1489.
2-(3,5-Dimethoxyphenoxy)-2-(4-fluorophenyl)-1-(3-
methoxyphenyl)ethanone (5ao). Yellow gum (182.4 mg, 65%): IR
(ATR) ν = 3074, 2937, 1694, 1591, 1508, 1458, 1426, 1322, 1264,
1
1225, 1202, 1144 cm−1; H NMR (400 MHz, CDCl3) δ 7.61 (d, J =
7.6 Hz, 1H), 7.55−7.51 (m, 3H), 7.32 (t, J = 8.0 Hz, 1H), 7.09−7.04
(m, 3H), 6.33 (s, 1H), 6.11 (d, J = 0.8 Hz, 2H), 6.08 (s, 1H), 3.80 (s,
3H), 3.71 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 195.3, 163.0 (d, JCF
= 246.7 Hz), 161.6, 159.6 (d, JCF = 64.6 Hz), 135.8, 131.2 (d, JCF = 3.2
Hz), 129.8, 129.5 (d, JCF = 8.4 Hz), 121.7, 120.4, 116.3, 116.1, 113.5,
94.6, 94.1, 81.7, 55.5, 55.46; HRMS (ESI-QTOF) calcd for
[C23H22FO5]+ m/z 397.1446, found 397.1445.
General Procedure for the Synthesis of 2, 6−16. A mixture of
2-arylated aryloxyketone 5 (0.1 mmol) and catalyst in toluene (3.0
mL) was heated at 130 °C. The reaction mixture was concentrated
under reduced pressure to give the crude residue, which was purified
by silica gel column chromatography (hexane:ethyl acetate:dichloro-
methane) to afford 2, 6−16.
Methyl 3-(3,5-dimethoxyphenyl)-6-methoxy-2-(4-
methoxyphenyl)benzofuran-4-carboxylate (2).7 Brown solid: mp
139.9−143.5 °C (23.8 mg, 53%); IR (ATR) ν = 3097, 2929, 1714,
1621, 1595, 1572, 1510, 1460, 1322, 1242 cm−1; 1H NMR (400 MHz,
Acetone-d6) δ 7.40 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.19 (s, 1H), 7.09
(d, J = 8.0 Hz, 2H), 6.67 (s, 2H), 6.41 (s, 1H), 3.95 (s, 3H), 3.87 (s,
3H), 3.64 (s, 6H), 3.16 (s, 3H); 13C NMR (100 MHz, Acetone-d6) δ
167.8, 161.8, 160.4, 158.8, 156.2, 152.0, 133.0, 132.0, 127.3, 127.2,
122.2, 118.8, 115.1, 114.0, 105.3, 101.6, 99.7, 56.5, 55.8, 55.6, 51.9;
HRMS (ESI-QTOF) calcd for [C26H25O7]+ m/z 449.1595, found
449.1599.
2-(4-Chlorophenyl)-6-methoxy-3-(4-methoxyphenyl)benzofuran
(6). White solid: mp 114.7−119.6 °C (lit. 117 °C)20 (34.3 mg, 94%);
IR (ATR) ν = 3060, 2922, 1585, 1510, 1485, 1453, 1399, 1371, 1343,
1270, 1244 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz,
2H), 7.39 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 7.6
Hz, 2H), 7.07 (s, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.8 Hz,
1H), 3.88 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 159.4, 158.7,
155.1, 148.4, 133.6, 130.9, 129.7, 128.8, 127.7, 124.8, 123.9, 120.5,
117.8, 114.7, 112.2, 95.8, 55.9, 55.5; HRMS (ESI-QTOF) calcd for
[C22H18ClO3]+ m/z 365.0939, found 365.0938.
5-(tert-Butyl)-3-phenyl-2-(3-(trifluoromethyl)phenyl)benzofuran
(11). White solid: mp 97.6−99.3 °C (30.0 mg, 76%); IR (ATR) ν =
3066, 2959, 1612, 1451, 1365, 1323, 1279, 1243, 1205, 1163, 1121
1
cm−1; H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.73 (d, J = 8.0
Hz, 1H), 7.51−7.43 (m, 9H), 7.37 (t, J = 7.6 Hz, 1H), 1.36 (s, 9H);
13C NMR (100 MHz, CDCl3) δ 152.5, 149.1, 146.6, 132.5, 131.8,
129.8, 129.7, 129.4, 129.0, 128.2, 124.7 (q, JCF = 3.7 Hz), 123.7 (q, JCF
= 4.0 Hz), 123.5, 119.3, 116.3, 110.7, 35.0, 32.0; HRMS (ESI-QTOF)
calcd for [C25H22F3O]+ m/z 395.1617, found 395.1615.
Methyl 3-(3,5-dimethoxyphenyl)-2-(4-(ethoxycarbonyl)phenyl)-
6-methoxybenzofuran-4-carboxylate (12).7a Yellow solid: mp
125.6−127.7 °C (25.0 mg, 51%); IR (ATR) ν = 3084, 2925, 1720,
1713, 1594, 1493, 1457, 1423, 1376, 1349, 1313, 1272, 1192 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0
Hz, 2H), 7.26 (s, 1H), 7.24 (s, 1H), 6.52 (s, 1H), 6.49 (s, 2H), 4.36
(q, J = 7.2 Hz, 2H), 3.92 (s, 3H), 3.77 (s, 6H), 3.25 (s, 3H), 1.38 (t, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.8, 166.3, 161.4,
158.1, 155.8, 150.3, 136.0, 134.5, 129.7, 126.4, 126.2, 121.2, 119.4,
113.3, 107.4, 100.5, 99.5, 61.2, 56.2, 55.6, 51.7, 14.5; HRMS (ESI-
QTOF) calcd for [C28H27O8]+ m/z 491.1700, found 491.1703.
Ethyl 4-(5,6-dimethoxy-3-phenylbenzofuran-2-yl)benzoate (13).
White solid: mp 135.4−137.5 °C (28.2 mg, 70%); IR (ATR) ν = 3076,
2925, 1711, 1605, 1476, 1307, 1266 cm−1; 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.50−7.45
(m, 5H), 7.13 (s, 1H), 6.86 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.98 (s,
3H), 3.87 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.4, 149.2, 149.2, 148.5, 147.2, 135.1, 132.8, 129.8, 129.3,
129.2, 128.1, 125.9, 122.2, 120.0, 101.3, 95.2, 61.1, 56.54, 56.47, 14.5;
HRMS (ESI-QTOF) calcd for [C25H23O5]+ m/z 403.1540, found
403.1545.
2-(4-Chlorophenyl)-5,6-dimethoxy-3-phenylbenzofuran (14). Or-
ange solid: mp 154.6−155.9 °C (21.9 mg, 60%); IR (ATR) ν = 3049,
3-(4-Methoxyphenyl)-5-phenyl-2-(3,4,5-trimethoxyphenyl)-
benzofuran (7). Yellow solid: mp 170.0−171.7 °C (19.6 mg, 42%); IR
(ATR) ν = 2928, 2830, 1602, 1579, 1511, 1456, 1408, 1382, 1301,
1232, 1171 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.66−7.65 (m, 3H),
7.61−7.58 (m, 3H), 7.55−7.53 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.33
1
2928, 1599, 1475, 1307 cm−1; H NMR (400 MHz, CDCl3) δ 7.52−
7.43 (m, 7H), 7.26−7.24 (m, 2H), 7.11 (s, 1H), 6.87 (s, 1H), 3.97 (s,
3H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 147.1,
133.6, 133.0, 131.2, 129.8, 129.6, 129.3, 128.8, 128.0, 127.7, 126.6,
I
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122.2, 118.4, 101.3, 95.2, 56.6, 56.5; HRMS (ESI-QTOF) calcd for
[C22H18ClO3]+ m/z 365.0939, found 365.0937.
(3) (a) Gill, G. S.; Grobelny, D. W.; Chaplin, J. H.; Flynn, B. L. J. Org.
Chem. 2008, 73, 1131. (b) Tiano, M.; Belmont, P. J. Org. Chem. 2008,
73, 4101. (c) Alvey, L.; Prado, S.; Saint-Joanis, B.; Michel, S.; Koch,
M.; Cole, S. T.; Tillequin, F.; Janin, Y. L. Eur. J. Med. Chem. 2009, 44,
2497. (d) Masters, K.-S.; Flynn, B. L. Org. Biomol. Chem. 2010, 8,
1290. (e) Geary, L. M.; Hultin, P. G. Eur. J. Org. Chem. 2010, 29, 5563.
(f) Chiummiento, L.; Funicello, M.; Lopardo, M. T.; Lupattelli, P.;
Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012, 188.
(4) (a) Clough, J. M.; Mann, I. S.; Widdowson, D. A. Tetrahedron
Lett. 1987, 28, 2645. (b) Trejo, A.; Arzeno, H.; Browner, M.; Chanda,
S.; Cheng, S.; Comer, D. D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J.;
Lovejoy, B.; Freire-Moar, J.; Lim, J.; McIntosh, J.; Miller, J.; Papp, E.;
Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.; Song, K.; Villasenor,
A.; Warren, S. D.; Welch, M.; Weller, P.; Whiteley, P. E.; Zeng, L.;
Goldstein, D. M. J. Med. Chem. 2003, 46, 4702.
(5) Compared with other heterocycles such as indoles and
benzothiophenes, benzofurans have been less employed for direct
arylation reactions. For direct C2-arylation of benzofurans, see:
(a) Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji,
A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles 1990, 31, 1951.
(b) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga, K.;
Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.; Honma,
R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257. (c) Hughes, C. C.;
Trauner, D. Angew. Chem., Int. Ed. 2002, 41, 1569. (d) Nandurkar, N.
S.; Bhanushali, M. J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett.
2008, 49, 1045. (e) Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am.
4-(4,6-Dimethoxy-3-(3-methoxyphenyl)benzofuran-2-yl)-
benzonitrile (15). Yellow solid: mp 201.9−202.8 °C (25.8 mg, 67%);
IR (ATR) ν = 3070, 2960, 2217, 1594, 1572, 1498, 1457, 1426, 1366,
1319, 1278, 1235, 1211 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.56 (d,
J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.6 Hz, 1H),
7.01−6.93 (m, 3H), 6.70 (s, 1H), 6.30 (s, 1H), 3.89 (s, 3H), 3.81 (s,
3H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.4, 159.6,
156.3, 155.3, 146.4, 135.3, 134.4, 132.2, 129.5, 126.3, 122.7, 120.7,
119.1, 115.8, 113.8, 113.2, 110.3, 95.0, 87.9, 55.9, 55.6, 55.4; HRMS
(ESI-QTOF) calcd for [C24H20NO4]+ m/z 386.1387, found 386.1388.
2-(4-Fluorophenyl)-4,6-dimethoxy-3-(3-methoxyphenyl)-
benzofuran (16). Brown gum (28.4 mg, 75%): IR (ATR) ν = 3068,
2960, 1595, 1572, 1496, 1426, 1366, 1319, 1279, 1235, 1210 cm−1; 1H
NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 5.6, 8.0 Hz, 2H), 7.29 (t, J =
8.0 Hz, 1H), 7.03−7.01 (m, 2H), 6.96−6.91 (m, 3H), 6.69 (s, 1H),
6.30 (s, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 3.68 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 162.2 (d, JCF = 246.6 Hz), 159.4 (d, JCF = 4.3 Hz),
155.9, 154.9, 148.0, 134.9, 129.2, 128.4 (d, JCF = 8.0 Hz), 127.3 (d, JCF
= 3.4 Hz), 123.2, 117.1, 116.0, 115.6, 115.3, 113.5, 113.0, 94.8, 88.0,
55.9, 55.6, 55.4; HRMS (ESI-QTOF) calcd for [C23H20FO4]+ m/z
379.1340, found 379.1343.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of compounds 2, 4, 5−16. This
material is available free of charge via the Internet at http://
pubs.acs.org.
́
Chem. Soc. 2008, 130, 15185. (f) Liegault, B.; Lapointe, D.; Caron, L.;
Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826. (g) Matsuda, S.;
Takahashi, M.; Monguchi, D.; Mori, A. Synlett 2009, 1941. (h) Tamba,
S.; Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org. Chem. 2010,
75, 6998. (i) Fowler, K. J.; Ellis, J. L.; Morrow, G. W. Synth. Commun.
2013, 43, 1676. For direct C3-arylation of benzofurans, see: (j) Ionita,
M.; Roger, J.; Doucet, H. ChemSusChem 2010, 3, 367. (k) Roy, D.;
Mom, S.; Royer, S.; Lucas, D.; Hierso, J.-C.; Doucet, H. ACS Catal.
AUTHOR INFORMATION
■
Corresponding Author
*Tel.: +82 32 749 4515. Fax: +82 32 749 4105. E-mail:
ikyonkim@yonsei.ac.kr.
2012, 2, 1033. (l) Carrer, A.; Brinet, D.; Florent, J.-C.; Rousselle, P.;
̈
Bertounesque, E. J. Org. Chem. 2012, 77, 1316.
Notes
(6) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. Org. Lett. 2007, 9, 3137. (b) Xi, P.; Yang, F.; Qin, S.; Zhao, D.; Lan,
J.; Gao, G.; Hu, C.; You, J. J. Am. Chem. Soc. 2010, 132, 1822.
(c) Kuhl, N.; Hopkinson, M. N.; Glorius, F. Angew. Chem., Int. Ed.
2012, 51, 8230. (d) Dong, J.; Long, Z.; Song, F.; Wu, N.; Guo, Q.;
Lan, J.; You, J. Angew. Chem., Int. Ed. 2013, 52, 580.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by Nano·Material Technology
Development Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education, Science and Technology (2012M3A7B4049656).
(7) (a) Kim, I.; Choi, J. Org. Biomol. Chem. 2009, 7, 2788. (b) Kim,
K.; Kim, I. Org. Lett. 2010, 12, 5314.
(8) For our other contribution to the synthesis of benzofurans, see:
(a) Kim, I.; Lee, S.-H.; Lee, S. Tetrahedron Lett. 2008, 49, 6579.
(b) Kim, I.; Kim, K.; Choi, J. J. Org. Chem. 2009, 74, 8492.
(9) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740. (b) Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 11108. (c) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1997, 119, 12382. (d) Diedrichs, N.; Ragot, J. P.; Thede, K.
Eur. J. Org. Chem. 2005, 1731. (e) Sido, A. S. S.; Boulenger, L.;
DEDICATION
■
†This paper is dedicated to the memory of my friend, Dr.
Junwon Kim, who passed away on April 2013.
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(13) Incomplete conversion was observed with catalytic amount of
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