Catalyst-Free Synthesis of 2,3-Dihydrobenzofurans via a Formal [4+1] Annulation of Propargylamines with Sulfur Ylides

Article abstract of DOI:10.1021/acs.joc.9b01557

A simple, general route to the 2,3-dihydrobenzofurans substituted at C3 by an aryethynyl or aryl group, starting from propargylamine and its derivatives with benzoyl sulfonium salts, has been developed. This reaction involved an in situ generated o-quinone methide (o-QM) intermediate followed by [4+1] annulation with sulfur ylides. Notably, this protocol's features include moderate to excellent yields and remarkable diastereoselectivity (>20:1 dr in general), easy performance, as well as applicability to versatile 2,3-dihydrobenzofurans with aryethynyl or an aryl group via C-C and C-O bond formation in one pot without any catalyst in an aqueous mixed solvent.

Full text of DOI:10.1021/acs.joc.9b01557

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Article
Catalyst-Free Synthesis of 2,3-Dihydrobenzofurans via a
Formal [4+1] Annulation of Propargylamines with Sulfur Ylides
Xinwei He, Mengqing Xie, Qiang Tang, Youpeng Zuo, Ruxue Li, and Yongjia Shang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01557 • Publication Date (Web): 21 Aug 2019
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Catalyst-Free Synthesis of 2,3-Dihydrobenzofurans
via a Formal [4+1] Annulation of Propargylamines
with Sulfur Ylides
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Xinwei He,* Mengqing Xie, Qiang Tang, Youpeng, Zuo, Ruxue Li, Yongjia Shang*
Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui
Laboratory of Molecule-Based Materials (State Key Laboratory Cultivation Base),
College of Chemistry and Materials Science, Anhui Normal University, Wuhu
241002, P.R. China
Graphic Abstract
Ar1
n
O
N
Catalyst-free
Ar2
O
S+
Br-
+
Ar2
THF or MeCN:H2O
R
Ar1
n
O
OH
(n = 0, 1)
Mild conditions
Valuable products
Operational simplicity
Broad substrate scope
Alkynyl and vinyl group tolerated
> 50 examples, up to 95% yield, >20:1 dr
Abstract: A simple, general route to the 2,3-dihydrobenzofurans substituted at C3 by
an aryethynyl or aryl group, starting from propargylamine and its derivatives with
benzoyl sulfonium salts, has been developed. This reaction involving in situ generated
o-quinone methide (o-QM) intermediate followed by [4+1] annulation with sulfur
ylides. Notably, this protocol features are moderate to excellent yields and remarkable
diastereoselectivity (>20:1 dr in general), easy performance, as well as applicability to
versatile 2,3-dihydrobenzofurans with aryethynyl or aryl group via C-C and C-O bond
formation in one-pot without any catalyst in an aqueous mixed solvent.
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INTRODUCTION
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The 2,3-dihydrobenzofuran skeleton is an important structural unit that
ubiquitously appears not only in numerous complex natural products but also
synthetic drugs with diverse bioactivities.1 For example, the natural product
megapodiol can be used as a potential antileukemic agent,2 (–)-tremetone and
(–)-hydroxytremetone, isolated from Eupatorium urticaefolium (Compositae), have
insecticidal properties.3 In addition, (2R,3S)-3,4′-di-O-methylcedrusin4 and annullatin
A were isolated from the leaves of Cordyceps annullata and Mitrephora teysmannii,
respectively. Moreover, the potent agonistic activity of these compounds toward the
cannabinoid receptors CB1 and CB2 has been demonstrated (Figure 1).5 Given their
intriguing biological activities, highly convenient methods for their synthesis have
been constantly pursued over a long time and a variety of approaches have been
developed.6 Various efficient strategies have been developed for the preparation of
chiral dihydrobenzofurans, such as kinetic resolution,7 asymmetric synthesis from
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chiral
reagents,8
or
asymmetric
catalysis.9
Meanwhile,
various
2,3-dihydrobenzofurans have been synthesized by a variety of powerful methods,
such as metal-mediated transformation,10 organocatalytic [3+2] annulations,11
intramolecular
cyclizations,12
and
electrocyclizations.13
Recently,
[4+1]-cycloannulation14,15 of orthoquinone methides (o-QMs) with carbenoid
compounds as an obvious strategy has been developed.16,17 Despite the remarkable
progress achieved in this area, the development of simple and efficient strategy to
2,3-disubstituted-2,3-dihydrobenzofurans using readily available o-QMs precursors
under catalyst-free conditions remains a challenging goal.
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O
O
5
6
7
8
OH
R1
O
O
(-)-tremetone: R1 = H
HO
megapodiol
(-)-hydroxytremetone: R1 = OH
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OH
HO
O
OH
O
O
O
O
O
annullatin A
(2R, 3S)-3,4'-di-o-methycedrusin
Figure 1. Selection of 2,3-dihydrobenzofuran natural products.
Propargylamines are useful and versatile building blocks in organic synthesis18
because they have two functional groups, which are amenable to further diverse
transformations.19 Recently, we synthesized a novel propargylamines containing an
hydroxy group, and demonstrated the fruitful reactions between benzoylacetonitriles
or β-keto esters and propargylamines used as o-AQMs (alkynyl o-quinone methide)
precursors for the synthesis of 2-aryl-4H-chromenes, polysubstituted furans,
furo[3,4-c]coumarins, and 4-styrylcoumarins.20 Inspired by elegant previous reports21
and in line with our long-standing interest in propargylamine chemistry, we
speculated that a novel 2-benzoyl-3-aryethynyl-2,3-dihydrobenzofurans would be
synthesized from 2-(3-aryl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol and benzoyl
sulfonium bromides under catalyst-free conditions (Scheme 1). Herein, we report our
new
results
on
the
synthesis
of
2-benzoyl-3-aryl/3-arylethynyl-2,3-dihydrobenzofurans from propargylamines and its
derivatives with benzoyl sulfonium bromides under catalyst-free conditions. The
starting materials propargylamines can be readily prepared from A3-coupling
reactions of commercially available salicylaldehydes, amines, and alkynes.22
Ar1
n
O
N
S+
Br-
Ar2
Ar2
O
R
Ar1
R
n
R
Ar1
[4+1] annulation
n
O
O
OH
(n = 0, 1)
via o-AQM
NH
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Scheme 1. Design plan for the synthesis of 2,3-dihydrobenzofurans.
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RESULTS AND DISCUSSION
At the outset of this study, we first performed a reaction between
2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol (1a),
dimethyl(2-oxo-2-phenylethyl) sulfonium bromide (2a) in aqueous acetone : water
(v/v 2:1) as mixed solvent at 100 °C for h. Gratifyingly,
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=
2
phenyl(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3aa) was obtained
in 46% yield without forming the aromatic product (Table 1, entry 1). Inspired by this
initial result, we tested the effect of different mixed solvents, including diethyl
ether/H2O,
toluene/H2O,
DCM
(dichlomethane)/H2O,
DMSO
(dimethylsulfoxide)/H2O, THF (tetrahydrofuran)/H2O, and CH3CN/H2O (Table 1,
entries 2-7). The mixed solvent of THF/H2O was found to be the most effective one
among these mixed solvents (Table 1, entry 6). To improve the yield, we carried out
further optimization studies with other ratios of THF and H2O, but they were found to
be less effective at this transformation (Table 1, entries 8-12). Variation of the
reaction temperature confirmed that 100 °C was the optimal condition for this
protocol, with lower and higher temperatures affording decreased yields (Table,
entries 13, 14). Surprisingly, when the reaction was carried out for 1 h, the highest
reaction yield (82%) was observed (Table 1, entry 15), and a dramatic decrease yield
was obtained by reducing the reaction time to 0.5 h (Table 1, entry 16).
Subsequently, other A3-coupling derived propargylamines were also tested. The
desired product 3aa could also be successfully attained, albeit in decreased yields
when morpholine- and pyrrolidine-derived propargylamines (1a′ and 1b′) were used
as substrates (Table 1, entries 17, 18). Tetrahydroisoquinoline-derived
propargylamine 1c′, however, failed to give the targeted product (Table 1, entry 19).
Control experiments revealed that no reaction occurred when other ylides (2a′ and
2b′) were used as substrates (Table 1, entries 20, 21), the [4+1] annulation of the
ylides to propargylamines still remains challenging. Finally, the optimized reaction
conditions were achieved in the mixed solvent of THF/H2O at 100 °C for 1 h without
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any catalyst (Table 1, entry 15).
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Table 1. Optimization of the reaction conditions.a
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Ph
O
N
Conditions
S+
+
Ph
O
Ph
Br-
Ph
2a
O
OH
1a
3aa: >20:1 dr
Entry
1
Solvent (2:1)
Acetone/H2O
Ether/H2O
Toluene/H2O
DCM/H2O
DMSO/H2O
THF/H2O
CH3CN/H2O
H2O
Temp. (°C)
100
100
100
100
100
100
100
100
100
100
100
100
80
Time (h)
Yield (%)b
46
2
2
2
38
3
2
41
4
2
51
5
2
67
6
2
82
7
2
60
8
2
Trace
Trace
51
9
THF
2
10c
11d
12e
13
14
15
16
17f
18g
19h
20i
21j
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
THF/H2O
2
2
NR
54
2
2
66
120
100
100
100
100
100
100
100
2
68
1
82
0.5
1
62
24
1
45
1
NR
NR
NR
1
1
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a
Reaction conditions: 2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol
5
6
(1a, 0.2 mmol), dimethyl(2-oxo-2-phenylethyl)sulfonium bromide (2a, 0.24
7
8
b
c
d
mmol) in solvent (3 mL). Isolated yields. Solvent ratio = 1:1. Solvent
9
e
f
g
ratio = 1:2. Solvent ratio = 4:1. Using 1a′ instead of 1a. Using 1b′
instead of 1a. h Using 1c′ instead of 1a. i Using 2a′ instead of 2a. j Using 2b′
instead of 2a.
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O
O
Ph
P+
Br-
O
Et
N+
Br-
N
N
Ph
Ph
Et
Et
N
Ph
Ph
2a'
2b'
Ph
OH
1a'
OH
OH
1c'
1b'
With acceptable optimized reaction conditions in hand, we then evaluated the
reaction scope for propargylamines using benzoyl sulfonium bromide 2a as a model
substrate (Table 2). The phenyl ring of Ar1 group bearing halide substituents (F, Cl,
Br) and other electron-donating groups (CH3, OCH3) were well tolerated and gave the
corresponding products (3ba-3fa) in good yields. Propargylamines bearing various
substituents with diverse electronic and steric properties at the para- and
ortho-position to the hydroxy group, reacted smoothly to generate the desired
products in good yields (72%-90%). It is worth mentioning that the substrate with a
bulky tert-butyl group at the ortho- and para-position to the hydroxy of the
propargylamine was also tolerated in the reaction to give the corresponding product
3qa in 90% yield. Subsequently, we also found that when the propargylamines
bearing with a strongly electron-withdrawing group (NO2) at the para-position to the
hydroxy group was treated with 2a, the expected product 3ra was obtained, albeit in
lower yield (55%). Additionally, for alkynyl bearing a n-pentyl substituent rather
than an aryl group, generally the expected product 3sa could be obtained smoothly in
70% yields.
Table 2. Substrate scope of propargylamines.a,b
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Ar1
5
6
7
8
O
N
THF/H2O (2:1)
S+
+
100 oC, 1 h
Ph
Ph
O
Br-
2a
R
R
Ar1
O
9
OH
1
10
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3aa-3sa
>20:1 dr
R
R
R
Ph
H3C
Ph
O
Ph
O
O
O
O
O
3ga: R = H, 90%
3ha: R = Cl, 82%
3ia: R = Br, 85%
3aa: R = H, 82%
3ba: R = CH3, 83%
3ca: R = OCH3, 77%
3da: R = F, 76%
3ea: R = Cl, 83%
3fa: R = Br, 80%
X-ray of 3ga
(CCDC 1919858)
R
OCH3
CH3
Ph
O
H3CO
Br
Cl
Ph
O
Ph
Ph
O
OCH3
O
O
O
O
O
3pa: 76%
3ja: R = H, 85%
3oa: 72%
3na: 77%
3ka: R = CH3, 84%
3la: R = OCH3, 74%
3ma: R = Br, 73%
tBu
Ph
O2N
Ph
Ph
O
O
O
O
O
O
tBu
3qa: 90%
3sa: 70%
3ra: 55%
aReaction
conditions:
propargylamines
1
(0.2
mmol),
dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 2a (0.24 mmol) in THF/H2O
= 2:1 (3 mL), 100 °C for 1 h. bIsolated yields and all of the dr > 20:1.
We then investigated the generality of benzoyl sulfonium bromides 2 using
propargylamines 1a as a model substrate under the optimized conditions (Table 3).
The reaction proceeded smoothly with a range of substituents at the ortho-, meta-, and
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para-positions on the phenyl ring of the Ar2 group, leading to the formation of diverse
2,3-dihydrobenzofurans (3ab-3am) in moderate to good yields (60%-83%).
Gratifyingly, phenyl, mesyl, and trifluoromethyl groups were well tolerated,
generating the desired products 3ak, 3al, 3am in 63%, 60%, and 76% yields,
respectively. A multisubstituted benzoyl sulfonium bromide were also suitable for this
annulation, giving the corresponding product 3aj in 83% yield. In addition, benzoyl
sulfonium bromide bearing β-2-naphthyl or heteroaromatic rings (such as 2-furyl, or
2-thienyl) also reacted efficiently, affording the products 3an, 3ao, and 3ap in 66%,
72%, and 82% yields, respectively. During our study of the scope of sulfonium
bromides 2 for the construction of 2,3-dihydrobenzofurans 3, we were surprised to
find that when a non-aromatic sulfonium bromide (2q) was treated with 1a, the
expected product 3aq was obtained in 57% yield.
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Table 3. Substrate scope of sulfur ylides.a,b
Ph
O
N
THF/H2O (2:1)
100 oC, 1 h
S+
Br-
+
Ar2
Ar2
O
2
Ph
OH
1a
O
3ab-3aq
>20:1 dr
Ph
Ph
Ph
Ph
R
R
Br
Br
O
O
O
O
O
O
O
O
3ah: 70%
3ai: 66%
3ae: R = F, 66%
3af: R = Cl, 77%
3ag: R = Br, 70%
3ab: R = CH3, 80%
3ac: R = Et, 64%
3ad: R = OCH3, 74%
CH3
O
O
Ph
Ph
Ph
Ph
CH3
Ph
S
CF3
CH3
O
O
O
3ak: 63%
O
O
3al: 60%
O
O
O
3aj: 83%
3am: 76%
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Ph
Ph
Ph
Ph
5
6
7
S
O
8
9
O
O
O
O
O
O
O
O
3an: 66%
3ao: 72%
3ap: 82%
3aq: 57%
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aReaction conditions: 2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol 1a
(0.2 mmol), benzoyl sulfonium bromides 2 (0.24 mmol) in THF/H2O = 2:1 (3
mL), 100 °C for 1 h. bIsolated yields and all of the dr > 20:1.
Given that the alkynyl group was retained in the present approach, we speculated
that the 2-benzoyl-3-aryl-2,3-hydrobenzofurans would be obtained from
2-(aryl(piperidin-1-yl)methyl)phenols without the alkynyl group substituent on the
propargylamines through the similarly process. Based on this assertion, we next
subjected 2-(aryl(piperidin-1-yl)methyl)phenols 4, which are easily available by the
Petasis boronic Mannich reaction of salicylaldehydes, phenylboronic acid, and
piperidine, to the otherwise identical reaction conditions above. To our delight, the
desired products 5aa was obtained in 53% yield as shown in Table S1 in the
Supporting Information (SI) (entry 1). Next, we tried to optimize the reaction
conditions for this reaction by changing the solvents from THF/H2O (2:1, v/v) to
CH3CN/H2O (1:1, v/v) at 100 °C, and the yield of the corresponding product 5aa
dramatically increased to 90% (see the SI, Table S1, entry 5).
Subsequently, using these optimized reaction conditions and by varying
2-(aryl(piperidin-1-yl)methyl)phenols 4 and benzoyl sulfonium bromides 2, a series of
2-aroyl-3-aryl-2,3-dihydrobenzofurans 5 were prepared. As shown in Table 4, the
reactions of 2-(aryl(piperidin-1-yl)methyl)phenols 4 with benzoyl sulfonium bromides
2 proceeded well to give the desired products 5 irrespective of the substitution
patterns on the phenyl ring of the 2-(aryl(piperidin-1-yl)methyl)phenols. Various
moderately electron-donating (Me, OMe) and electron-withdrawing (F, Cl, Br) groups
were compatible, provided the corresponding products in 60%-95% yields. Notably,
unlike in the case of substrate 1, substrates 4 with a strongly electron-withdrawing
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group (NO2) in the para-position to the hydroxy was also tolerated in the reaction to
give the desired products 5ma, 5na in 70% and 77% yields, respectively. Likewise,
substrates 2 substituted with moderate electron-donating or electron-withdrawing
groups reacted efficiently to afford the corresponding products 5ac-5ah in 66%-73%
yields. The introduction of a strongly electron-withdrawing group (e.g. mesyl) and a
phenyl group resulted in decreased yields of the desired products 5ak, 5al which were
formed in yields of 58% and 60% yields, respectively.
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Table
4.
Synthesis
of
2-benzoyl-3-aryl-2,3-hydrobenzofurans
from
2-(aryl(piperidin-1-yl)methyl)phenols and benzoyl sulfonium bromides.a,b
Ar1
Ar1
O
O
MeCN/H2O (1:1)
100 oC, 1 h
S+
Br-
N
R
+
Ar2
R
Ar2
O
2
OH
4
5 (>20:1 dr)
CH3
R
R
H3CO
H3C
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
H3CO
5ga: 81%
5ha: 89%
5aa: R = H, 90%
5ba: R = CH3, 95%
5ca: R = F, 60%
5da: R = Br, 68%
5ea: R = H, 92%
5fa: R = CH3, 82%
R
R
R
Cl
Br
O
O2N
O
O
Ph
O
Ph
Ph
5ma: R = H, 70%
5na: R = CH3, 77%
O
O
5ia: R = H, 72%
5ka: R = H, 70%
X-ray of 5ka
(CCDC 1919859)
5ja: R = CH3, 78%
5la: R = CH3, 70%
Ph
O
Ph
O
Ph
Ph
O
O
O
O
O
Ph
O
Cl
5ac: 73%
5ah: 73%
5ae: R = F, 66%
5af: R = Cl, 70%
5oa: 77%
R
Br
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Ph
Ph
Ph
Ph
O
O
O
O
CH3
O
6
O
O
O
7
5an: 83%
5aj: 74%
5ak: 58%
5al: 60%
8
SO2CH3
CH3
Ph
9
10
11
12
13
14
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23
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a
Reaction conditions: 2-(aryl(piperidin-1-yl)methyl)phenol 4 (0.2 mmol),
benzoyl sulfonium bromides 2 (0.24 mmol) in MeCN/H2O = 1:1 (2 mL), 100
°C for 1 h. b Isolated yields and all of the dr > 20:1.
Furthermore,
we
carried
out
a
gram-scale
(1a,
reaction
mmol)
of
2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol
5
and
dimethyl(2-oxo-2-phenylethyl)sulfonium bromide (2a, 6 mmol) under the standard
conditions, and the corresponding product 3aa was isolated in 73% (1.18 g) yield
(Scheme 2), which showed promise for this synthetic methodology as a useful tool in
piratical synthetic terms. In addition, by utilizing these conditions, the formal [4+1]
annulation
of
(E)-2-(3-phenyl-1-(piperidin-1-yl)allyl)phenol
6a
with
dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 2a also delivered the corresponding
2-benzoyl-3-styryl-2,3-dihydrobenzofuran 7aa in 75% yield (Scheme 2b). Finally, we
employed a chiral benzoyl sulfonium bromides 8a derived from D-biotin
N-succinimidyl ester to conduct our reaction, the desired product 3aa was obtained in
40% yield with high diastereoselectivity (>20:1 dr), albeit with insufficient
enantioselective control (Scheme 3c). Additional efforts are necessary to meet current
challenges and explore opportunities in this emerging field.
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a) Gram-scale synthesis
N
Ph
O
THF/H2O (2:1)
100 oC, 1 h
S+
Br-
+
Ph
O
Ph
9
Ph
2a (6 mmol)
O
OH
1a (5 mmol)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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44
45
46
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49
50
51
52
53
54
55
56
57
58
59
60
3aa (1.18g, 73% yield)
b) Synthesis of 2-benzoyl-3-styryl-2,3-dihydrobenzofuran
Ph
Ph
O
N
THF/H2O (2:1)
100 oC, 1 h
S+
Br-
+
Ph
Ph
O
O
2a
OH
6a
7aa: 75%, >20:1 dr
c) Asymmetric synthesis
H
Ph
H
O
N
O
THF/H2O (2:1)
100 oC, 1 h
NH
N
S+
Ph
O
+
Ph
H
Br-
8a
O
Ph
O
OH
1a
3aa: 40% yield
>20:1 dr, <5% ee
N
O
O
O
Scheme 2. Further studies of the [4+1] annulation: Gram-scale synthesis, substrate
scope, and asymmetric synthesis.
Control experiments were carried out to gain preliminary insight into the reaction
mechanism (Scheme 3). Initially, propargyamine 1a reacted with
2-bromo-1-phenylethanone under the standard conditions, the final product 3aa could
be detected only in trace yield (Scheme 3a). In the presence of dimethylsulfane (1.0
equiv.), the target product 3aa was obtained with 72% yield (Scheme 3b), illustrating
that the dimethyl(2-oxo-2-phenylethyl)sulfonium bromide 2a was initially formed and
then reacted with propargylamine 1a to provide the annulated product 3aa. Whereas,
treatment of catalytic amount of dimethylsulfane (10 mol%) in this three-component
reaction, only 44% yield of the product was obtained. Next, we employed the known
sulfur ylide 9a derived from sulfoxonium salts23 instead of 2a to conduct our reaction
(Scheme 3c). Unfortunately, only trace 3aa could be detected.
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9
Ph
N
O
THF/H2O (2:1)
100 oC, 1 h
+
Br
(a)
Ph
O
Ph
Ph
O
OH
1a
3aa: trace
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
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60
N
O
THF/H2O (2:1)
100 oC, 1 h
S
+
+
Br
(b)
Ph
O
Ph
Ph
O
OH
1a
3aa: 72% yield, >20:1 dr
Ph
N
O
O
S
THF/H2O (2:1)
100 oC, 1 h
+
Ph
(c)
Ph
9a
Ph
O
O
OH
1a
3aa: trace
Scheme 3. Control experiments.
To elucidate the formation of the [4+1] annulation process, a deuteration study was
then performed under the standard conditions as shown in Scheme 4. Initially, an H/D
exchange of benzoyl sulfonium bromides 2 was carried out in the presence of D2O.
1
From this reaction, the H NMR analysis revealed that all hydrogen atoms on the
methylene group of 2 were exchanged with deuterium atoms within 10 minutes.
Subsequently, when deuterium oxide was used instead of water as a part of the
solvent, both more than 99% of products 3aa′ and 5aa′ were deuterated at the
2-position of the furan ring, indicating the dimethyl(2-oxo-2-phenylethyl)sulfonium
bromide 2a acted as a C1 synthon in this process.
Ph
N
H
Ph
O
D
Ph
OH
1a
O
THF/D2O
O
S+
Br-
2a
MeCN/D2O
3aa': 78% yield
Ph
Ph
Ph
H
O
N
Ph
O
D
OH
4a
5aa': 85% yield
Scheme 4. The deuteration experiments.
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Based on the experimental results above and previous literature reports,24
a
7
8
9
plausible mechanism for this reaction was proposed as shown in Scheme 5 (3aa as
example). Initially, propargylamine 1a released piperidine to furnish an alkynyl
o-quinone methide (o-AQM) intermediate, at the same time, benzoyl sulfonium salt
2a transformed into the corresponding sulfur ylide A in the presence of piperidine as
base. Subsequently, intermediate B resulted from an intermolecular 1,4-conjugate
addition of the sulfur ylide A to o-AQM intermediate. Finally, the configuration of the
intermediate B is stable enough to allow a stereospecific SN2 reaction to produce the
observed trans-selective 2,3-dihydrobenzofuran 3aa by removing dimethyl sulfide.
HBr
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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33
34
35
36
37
38
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
O
O
H
Ph
S+
Br-
S
Ph
Ph
O
2a
S+
O-
A
Ph
Ph
O
SN2 reaction
1,4-conjugate
addition
NH
Ph
O
3aa
S
N
Ph
O
Ph
OH
B
o-AQM
1a
Scheme 5. A plausible mechanism for the synthesis of 2,3-dihydrobenzofurans.
CONCLUSION
In summary, we have successfully developed an efficient and convergent approach
for generation of o-AQM or o-QM intermediates from the readily available
propargylamines or 2-(aryl(piperidin-1-yl)methyl)phenols under mild conditions, and
their reactions with benzoyl sulfonium salts for the synthesis of
2,3-dihydrobenzofuran derivatives were investigated. The flexibility of this strategy
permits rapid access to a variety of structurally distinct dihydrobenzofurans bearing
an arylethynyl or aryl group at the C3 position. The advantages of this methodology
include the readily available starting materials, operational simplicity, versatile
functional groups tolerance and use of an aqueous mixed solvent under mild
catalyst-free conditions.
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Experiment Sections
General comments
7
8
9
Unless otherwise specified, all reagents and starting materials were purchased from
commercial sources and used as received, and the solvents were purified and dried
using standard procedures. The chromatography solvents were technical grade and
distilled prior to use. Flash chromatography was performed using 200-300 mesh silica
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11
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1
gel with the indicated solvent system according to standard techniques. The H and
13C NMR data were recorded on 400 MHz or 500 MHz and 100 MHz or 125 MHz
NMR spectrometers, unless otherwise specified. Chemical shifts (δ) in parts per
1
million are reported relative to the residual signals of chloroform (7.26 ppm for H
and 77.16 ppm for 13C), and all 13C NMR were recorded with proton broadband
decoupling and indicated as 13C{1H} NMR. Multiplicities are described as s (singlet),
d (doublet), t (triplet), q (quartet), or m (multiplet), and the coupling constants (J) are
reported in Hertz. HRMS analysis with a quadrupole time-of-flight mass spectrometer
yielded ion mass/charge (m/z) ratios in atomic mass units. IR spectra were measured
as dry films (KBr), and the peaks are reported in terms of wave number (cm-1). The
melting points were measured using SGWX-4 melting point apparatus.
Literature procedures were used for the preparation of propargylamines 1a-1s20, 22
and 2-(aryl(piperidin-1-yl)methyl)phenols 4a-4m.25 Substrates 1j-1l, 4c, 4d, 4g, 4o,
and 6a were new compounds.
4-Methoxy-2-(3-phenyl-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol (1j). The title
compound was obtained from 2-hydroxy-5-methoxybenzaldehyde (3 mmol),
phenylacetylene (3.6 mmol) and piperidine (3.6 mmol) using the general procedure
described in reference22a as a yellow solid (818 mg) in 85% yield; mp 109-110 °C; 1H
NMR (400 MHz, CDCl3) δ 7.57–7.52 (m, 2H), 7.39–7.34 (m, 3H), 7.21–7.17 (m,
1H), 6.81–6.76 (m, 2H), 5.07 (s, 1H), 3.77 (s, 3H), 2.87–2.55 (m, 4H), 1.67 (s, 6H);
13C{1H} NMR (100 MHz, CDCl3) δ 152.5, 151.4, 131.9, 128.6, 128.4, 122.6, 122.2,
116.7, 114.7, 114.0, 89.9, 82.2, 61.1, 55.8, 26.0, 24.0; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C21H24NO2 322.1807; Found 322.1810.
4-Methoxy-2-(1-(piperidin-1-yl)-3-(p-tolyl)prop-2-yn-1-yl)phenol (1k). The title
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compound was obtained from 2-hydroxy-5-methoxybenzaldehyde (3 mmol),
1-ethynyl-4-methylbenzene (3.6 mmol) and piperidine (3.6 mmol) using the general
procedure described in reference22a as a yellow solid (824 mg) in 82% yield; mp
9
1
105–106 °C; H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.0 Hz, 2H), 7.20–7.18 (m,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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1H), 7.15 (d, J = 8.0 Hz, 2H), 6.79-6.76 (m, 2H), 5.05 (s, 1H), 3.76 (s, 3H), 2.76-2.64
(m, 3H), 2.37 (s, 3H), 1.95–1.10 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.6,
151.5, 138.9, 131.9, 129.3, 122.4, 119.6, 116.8, 114.9, 114.1, 90.1, 81.6, 61.2, 55.9,
26.2, 24.2, 21.7; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO2 336.1964;
Found 336.1967.
4-methoxy-2-(3-(4-methoxyphenyl)-1-(piperidin-1-yl)prop-2-yn-1-yl)phenol
(1l).
The title compound was obtained from 2-hydroxy-5-methoxybenzaldehyde (3 mmol),
1-ethynyl-4-methoxybenzene (3.6 mmol) and piperidine (3.6 mmol) using the general
procedure described in reference22a as a yellow solid (916 mg) in 87% yield; mp
1
116–117 °C; H NMR (400 MHz, CDCl3) δ 7.50–7.43 (m, 2H), 7.17–7.14 (m, 1H),
6.89-6.84 (m, 2H), 6.76-6.74 (m, 2H), 5.02 (s, 1H), 3.29 (s, 3H), 3.26 (s, 3H),
13
2.72-2.62 (m, 3H), 1.72–1.42 (m, 7H); C{1H} NMR (100 MHz, CDCl3) δ 160.1,
152.7, 151.7, 133.6, 122.7, 116.9, 115.1, 114.3, 114.2, 90.1, 81.0, 61.4, 56.1, 55.7,
26.3, 24.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C22H26NO3 352.1913; Found
352.1915.
2-((4-Fluorophenyl)(piperidin-1-yl)methyl)phenol (4c). The title compound was
obtained from salicylaldehyde (3 mmol), (4-fluorophenyl)boronic acid (3.6 mmol)
and piperidine (3.6 mmol) using the general procedure described in reference25a as a
1
white solid (769 mg) in 90% yield; mp 122–124 °C; H NMR (400 MHz, CDCl3) δ
12.45 (s, 1H), 7.44–7.30 (m, 2H), 7.13–7.07 (m, 1H), 7.01–6.94 (m, 2H), 6.90-6.81
(m, 2H), 6.73–6.65 (m, 1H), 4.44 (s, 1H), 2.56-2.24 (m, 3H), 1.74-1.37 (m, 7H);
13C{1H} NMR (100 MHz, CDCl3) δ 162.3 (JC-F = 245.2 Hz), 157.0, 135.4, 130.39,
129.08 (JC-F = 2.4 Hz), 128.5, 125.5 (JC-F = 3.2 Hz), 119.2, 117.0, 115.6 (JC-F = 21.2
Hz), 75.7, 52.5, 26.1, 24.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C18H21FNO
286.1607; Found 286.1610.
2-((4-Bromophenyl)(piperidin-1-yl)methyl)phenol (4d). The title compound was
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obtained from salicylaldehyde (3 mmol), (4-bromophenyl)boronic acid (3.6 mmol)
and piperidine (3.6 mmol) using the general procedure described in reference25a as a
7
8
1
light yellow solid (890 mg) in 86% yield; mp 125–127 °C; H NMR (400 MHz,
9
CDCl3) δ 12.34 (s, 1H), 7.41 (d, J = 8.8 Hz, 2H), 7.32–7.24 (m, 2H), 7.12–7.07 (m,
1H), 6.83 (d, J = 8.0 Hz, 2H), 6.70–6.65 (m, 1H), 4.40 (s, 1H), 2.51–2.22 (m, 3H),
10
11
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60
13
1.82–1.12 (m, 7H); C{1H} NMR (100 MHz, CDCl3) δ 157.1, 138.8, 132.1, 130.6,
129.2, 128.8, 125.3, 122.0, 119.4, 117.2, 76.1, 52.8, 26.2, 24.3; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C18H21BrNO 346.0807; Found 346.0804.
4-Methoxy-2-(piperidin-1-yl(p-tolyl)methyl)phenol (4g). The title compound was
obtained from 2-hydroxy-5-methoxybenzaldehyde (3 mmol), p-tolylboronic acid (3.6
mmol) and piperidine (3.6 mmol) using the general procedure described in
1
reference25a as a white solid (821 mg) in 88% yield; mp 121-123 °C; H NMR (400
MHz, CDCl3) δ 12.03 (s, 1H), 7.31–7.24 (m, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.78–6.74
(m, 1H), 6.67–6.62 (m, 1H), 6.47-6.43 (m, 1H), 4.35 (s, 1H), 3.64 (s, 3H), 2.47-2.32
(m, 3H), 2.29 (s, 3H), 1.67–1.37 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 152.3,
150.8, 137.6, 136.5, 129.4, 128.7, 126.4, 117.1, 115.0, 113.2, 76.3, 55.6, 52.6, 26.1,
24.2, 21.1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H26NO2 312.1964; Found
312.1968.
5-Chloro-2-(phenyl(piperidin-1-yl)methyl)phenol (4o). The title compound was
obtained from 4-chloro-2-hydroxybenzaldehyde (3 mmol), phenylboronic acid (3.6
mmol) and piperidine (3.6 mmol) using the general procedure described in
1
reference25a as a white solid (767 mg) in 85% yield; mp 118–120 °C; H NMR (400
MHz, CDCl3) δ 13.00 (s, 1H), 7.37–7.25 (m, 5H), 6.83 (d, J = 2.0 Hz, 1H), 6.76 (d, J
= 8.0 Hz, 1H), 6.63 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 4.46 (s, 1H), 2.57–2.27 (m, 3H),
1.68–1.37 (m, 7H); 13C{1H} NMR (100Hz, CDCl3) δ 158.5, 138.8, 133.9, 130.3,
129.0, 128.3, 124.2, 119.2, 117.3, 76.0, 52.5, 26.2, 24.2; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C18H21ClNO 302.1312; Found 302.1311.
(E)-2-(3-Phenyl-1-(piperidin-1-yl)allyl)phenol (6a). The title compound was
obtained from salicylaldehyde (3 mmol), (E)-styrylboronic acid (3.6 mmol) and
piperidine (3.6 mmol) using the general procedure described in reference25a as a
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colorless oil (351 mg) in 40% yield; H NMR (400 MHz, CDCl3) δ 7.44–7.38 (m,
5
6
2H), 7.37–7.29 (m, 2H), 7.28–7.23 (m, 1H), 7.20–7.12 (m, 1H), 7.04–6.98 (m, 1H),
7
8
6.90–6.82 (m, 1H), 6.82–6.74 (m, 1H), 6.60 (d, J = 15.6 Hz, 1H), 6.40 (dd, J = 16.0
9
13
Hz, 9.6 Hz, 1H), 4.14 (d, J = 9.6 Hz, 1H), 2.60 (s, 4H), 1.88–1.36 (m, 6H); C{1H}
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NMR (100 MHz, CDCl3) δ 157.4, 136.5, 133.6, 128.7, 128.7, 128.4, 127.9, 126.6,
126.5, 124.9, 119.2, 116.6, 73.5, 51.6, 26.1, 24.3; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C20H23NO 294.1852; Found 294.1854.
General procedure for the preparation of benzoyl sulfonium bromides 2.
Dimethyl sulfide (5 mmol) was added to a solution of 2-bromoacetophenone
derivatives (5 mmol) in acetone (10 mL). After the mixture had been stirred for 12 h,
the residue was filtered and washed with acetone. The solid product (2a-2q) was used
as sulfonium bromide without further purification. All sulfonium salts were known
compounds and prepared according to the previous reported method.26
General
procedure
for
the
synthesis
of
the
2-benzoyl-3-arylethynyl-2,3-dihydrobenzofuran derivatives 3.
A mixture of propargylamine 1a (0.2 mmol) and benzoyl sulfonium salts 2 (0.24
mmol) in THF/H2O (2:1, v/v, 3 mL) was heated to 100 °C in an oil bath for 2 h. After
the reaction was complete (as determined using TLC), the reaction mixture was
cooled to room temperature, extracted with CH2Cl2 (3 × 10 mL), and washed with
brine. The organic layers were combined, dried over Na2SO4, filtered, and then
evaporated under vacuum. The residue was purified using flash column
chromatography with a silica gel (200-300 mesh), using ethyl acetate and petroleum
ether (1:40-1:60, v/v) as the elution solvent to give desired product 3.
Phenyl(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone
(3aa).
This
compound was purified by column chromatography (ethyl acetate/petroleum ether =
1
1:60) to afford a yellow oil in 82% yield (53 mg); H NMR (500 MHz, CDCl3) δ
8.21–8.15 (m, 2H), 7.70–7.60 (m, 1H), 7.58–7.51 (m, 2H), 7.46–7.38 (m, 3H),
7.33–7.27 (m, 3H), 7.25–7.20 (m, 1H), 7.02–6.96 (m, 1H), 6.92 (d, J = 8.5 Hz, 1H),
6.02 (d, J = 7.8 Hz, 1H), 4.98 (d, J = 7.8 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 193.9, 158.6, 134.8, 134.5, 132.2, 129.9, 129.7, 129.2, 128.8, 128.7, 126.6, 125.3,
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123.1, 122.2, 110.7, 88.6, 87.9, 83.8, 37.4; IR (KBr) v 1692, 1598, 1477, 1446, 1225,
1052, 957, 878, 760, 744, 689 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H17O2 325.1223; Found 325.1220.
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Phenyl(3-(p-tolylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone
(3ba).
This
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1:60) to afford a colorless oil in 83% yield (56 mg); H NMR (500 MHz, CDCl3) δ
8.20–8.15 (m, 2H), 7.67–7.62 (m, 1H), 7.56–7.51 (m, 2H), 7.40 (d, J = 7.5 Hz, 1H),
7.33 (d, J = 8.0 Hz, 2H), 7.25–7.20 (m, 1H), 7.11 (d, J = 8.5 Hz, 2H), 7.02–6.97 (m,
1H), 6.92 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 2.35
(s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 194.0, 158.6, 138.9, 134.7, 134.5, 132.0,
129.9, 129.7, 129.45 129.2, 126.7, 125.4, 122.2, 120.0, 110.7, 88.6, 87.1, 83.9, 37.5,
21.9; IR (KBr) v 1695, 1598, 1485, 1446, 1238, 1057, 962, 865, 807, 763, 687 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H19O2 339.1380; Found 339.1383.
(3-((4-Methoxyphenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3ca). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 77% yield (54 mg); 1H NMR
(500 MHz, CDCl3) δ 8.19–8.16 (m, 2H), 7.68–7.62 (m, 1H), 7.57–7.51 (m, 2H),
7.42–7.34 (m, 3H), 7.25–7.19 (m, 1H), 7.01–6.96 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H),
6.85–6.81 (m, 2H), 6.01 (d, J = 7.5 Hz, 1H), 4.95 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 194.1, 160.1, 158.6, 134.8, 134.4, 133.6, 129.8,
129.7, 129.2, 126.8, 125.3, 122.2, 115.2, 114.3, 110.7, 88.7, 86.4, 83.7, 55.7, 37.5; IR
(KBr) v 1694, 1597, 1487, 1446, 1239, 1058, 964, 878, 760, 744, 688 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H19O3 355.1329; Found 355.1322.
(3-((4-Fluorophenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3da). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a colorless oil in 76% yield (52 mg); 1H
NMR (500 MHz, CDCl3) δ 8.19–8.15 (m, 2H), 7.68–7.63 (m, 1H), 7.57–7.51 (m,
2H), 7.43–7.38 (m, 3H), 7.25–7.20 (m, 1H), 7.03–6.97 (m, 3H), 6.92 (d, J = 8.0 Hz,
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1H), 5.99 (d, J = 7.5 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H); C{1H} NMR (125 MHz,
CDCl3) δ 193.8, 162.9 (d, JC-F = 248.8 Hz), 134.8, 134.5, 134.1 (d, JC-F = 8.4 Hz),
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129.9, 129.8, 129.2, 126.5, 125.3, 122.3, 119.2, 119.2, 116.1, 115.9, 110.7, 88.6, 87.6,
82.7, 37.2; IR (KBr) v 1700, 1593, 1501, 1472, 1225, 1154, 1086, 962, 865, 839, 684
cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H16FO2 343.1129; Found
343.1121.
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(3-((4-Chlorophenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3ea). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 83% yield (59 mg); 1H NMR
(500 MHz, CDCl3) δ 8.18–8.15 (m, 2H), 7.68–7.62 (m, 1H), 7.57–7.51 (m, 2H),
7.41–7.38 (m, 1H), 7.37–7.33 (m, 2H), 7.30–7.26 (m, 2H), 7.25–7.20 (m, 1H),
7.02–6.96 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 7.5 Hz, 1H), 5.01 (d, J = 7.5
Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 193.8, 158.6, 134.8, 134.7, 134.5,
133.4, 129.9, 129.8, 129.2, 129.0, 126.4, 125.3, 122.3, 121.6, 110.7, 88.9, 88.54, 82.7,
37.2; IR (KBr) v 1697, 1598, 1501, 1472, 1224, 1156, 1086, 952, 865, 747, 684 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H16ClO2 359.0833; Found 359.0837,
361.0830
(3-((4-Bromophenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3fa).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow solid in 80% yield (64 mg); mp 80-82 °C; H NMR
(500 MHz, CDCl3) δ 8.18–8.15 (m, 2H), 7.69–7.63 (m, 1H), 7.57–7.51 (m, 2H),
7.46–7.42 (m, 2H), 7.41–7.37 (m, 1H), 7.30–7.27 (m, 2H), 7.25–7.21 (m, 1H),
7.01–6.97 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.99 (d, J = 7.5 Hz, 1H), 5.00 (d, J =
13
7.5); C{1H} NMR (125 MHz, CDCl3) δ 193.8, 158.6, 134.8, 134.5, 133.6, 132.0,
129.9, 129.8, 129.2, 126.4, 125.3, 123.1, 122.3, 122.1, 110.7, 89.2, 88.5, 82.8, 37.2;
IR (KBr) v 1700, 1593, 1498, 1467, 1228, 1154, 1086, 952, 865, 839, 681 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H16BrO2 403.0328; Found 403.0320,
405.0311.
(5-Methyl-3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3ga).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow oil in 90% yield (61 mg); H NMR (500 MHz,
CDCl3) δ 8.23–8.12 (m, 2H), 7.76–7.58 (m, 1H), 7.57–7.48 (m, 2H), 7.48–7.41 (m,
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1H), 5.99 (d, J = 7.5 Hz, 1H), 4.95 (d, J = 7.5 Hz, 1H), 2.32 (s, 3H); C{1H} NMR
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(125 MHz, CDCl3) δ 194.1, 156.6, 134.8, 134.4, 132.2, 131.7, 130.2, 129.9, 129.2,
128.7, 128.7, 126.5, 125.7, 123.2, 110.2, 88.7, 88.0, 83.7, 37.4, 21.2; IR (KBr) v
1700, 1598, 1483, 1446, 1237, 1052, 962, 865, 807, 763, 685 cm-1; HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C24H19O2 339.1380; Found 339.1378.
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(3-((4-Chlorophenyl)ethynyl)-5-methyl-2,3-dihydrobenzofuran-2-yl)(phenyl)methan
one (3ha). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 82% yield (61 mg); 1H NMR
(500 MHz, CDCl3) δ 8.22–8.10 (m, 2H), 7.72–7.59 (m, 1H), 7.58–7.50 (m, 2H),
7.40–7.32 (m, 2H), 7.30–7.26 (m, 2H), 7.19 (s, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.80 (d,
J = 8.0 Hz, 1H), 5.97 (d, J = 7.5 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 2.32 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 193.9, 156.5, 134.8, 134.5, 133.4, 131.8, 130.2,
129.9, 129.7, 129.3, 129.2, 129.0, 126.3, 125.7, 121.7, 110.3, 89.1, 88.6, 82.6, 37.2,
21.2; IR (KBr) v 1700, 1598, 1501, 1476, 1237, 1063, 962, 865, 807, 763, 684 cm-1;
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H17ClO2 373.0920; Found 373.0928,
375.0917.
(3-((4-Bromophenyl)ethynyl)-5-methyl-2,3-dihydrobenzofuran-2-yl)(phenyl)methan
one (3ia). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 85% yield (71 mg); 1H NMR
(500 MHz, CDCl3) δ 8.15 (d, J = 8.0 Hz, 2H), 7.67–7.62 (m, 1H), 7.58–7.48 (m, 2H),
7.46–7.41 (m, 2H), 7.33 –7.27 (m, 2H), 7.19 (s, 1H), 7.01 (d, J = 8.5 Hz, 1H),
6.83–6.76 (m, 1H), 5.95 (d, J = 7.3 Hz, 1H), 4.96 (d, J = 7.3 Hz, 1H), 2.32 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 193.9, 156.5, 134.8, 134.5, 133.6, 131.9, 131.8,
130.2, 129.9, 129.2, 126.3, 125.7, 123.0, 122.1, 110.3, 89.3, 88.6, 82.7, 37.2, 21.2; IR
(KBr) v 1700, 1593, 1483, 1446, 1237, 1052, 962, 867, 807, 766, 683 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H18BrO2 417.0485; Found 417.0489, 419.0526.
(5-Methoxy-3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3ja). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 85% yield (60 mg); 1H NMR
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(500 MHz, CDCl3) δ 8.23–8.14 (m, 2H), 7.69– 7.60 (m, 1H), 7.57–7.50 (m, 2H),
7.48–7.40 (m, 2H), 7.35–7.27 (m, 3H), 7.01–6.94 (m, 1H), 6.86–6.78 (m, 1H),
6.79–6.74 (m, 1H), 5.99 (d, J = 7.8 Hz, 1H), 4.98 (d, J = 7.8 Hz, 1H), 3.79 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 194.0, 155.5, 152.7, 134.8, 134.4, 132.2, 129.9,
129.2, 128.8, 128.7, 127.5, 123.1, 115.2, 110.9, 110.8, 88.9, 87.7, 83.9, 56.5, 37.6; IR
(KBr) v 1696, 1597, 1487, 1446, 1240, 1058, 964, 878, 762, 745, 683 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H19O3 355.1329; Found 355.1328.
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(5-Methoxy-3-(p-tolylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3ka). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 84% yield (62 mg); 1H NMR
(500 MHz, CDCl3) δ 8.22–8.15 (m, 2H), 7.70–7.60 (m, 1H), 7.57–7.49 (m, 2H),
7.38–7.30 (m, 2H), 7.17–7.06 (m, 2H), 6.99–6.94 (m, 1H), 6.85–6.79 (m, 1H),
6.79–6.74 (m, 1H), 5.99 (d, J = 8.0 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 3.79 (s, 3H),
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2.35 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ 194.1, 155.5, 152.7, 138.9, 134.8,
134.42, 132.1, 129.9, 129.5, 129.2, 127.6, 120.0, 115.2, 111.0, 110.8, 89.0, 86.9, 84.1,
56.5, 37.8, 21.9; IR (KBr) v 1695, 1597, 1485, 1446, 1239, 1057, 964, 878, 760, 744,
687 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H21O3 369.1485; Found
369.1485.
(5-Methoxy-3-((4-methoxyphenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)met
hanone (3la). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 74% yield (57 mg); 1H NMR
(500 MHz, CDCl3) δ 8.21–8.13 (m, 2H), 7.70–7.58 (m, 1H), 7.57–7.50 (m, 2H),
7.42–7.34 (m, 2H), 7.01–6.95 (m, 1H), 6.88–6.80 (m, 3H), 6.78–6.73 (m, 1H), 5.98
(d, J = 7.5 Hz, 1H), 4.96 (d, J = 7.5 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 194.1, 160.1, 155.5, 152.7, 134.8, 134.4, 133.6, 129.9, 129.2,
127.7, 115.1, 114.3, 111.0, 110.8, 89.0, 86.2, 83.8, 56.4, 55.7, 37.8; IR (KBr) v 1694,
1595, 1487, 1440, 1239, 1059, 964, 875, 760, 744, 688 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C25H21O4 385.1434; Found 385.1442.
(3-((4-Bromophenyl)ethynyl)-5-methoxy-2,3-dihydrobenzofuran-2-yl)(phenyl)meth
anone (3ma). This compound was purified by column chromatography (ethyl
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acetate/petroleum ether = 1:60) to afford a red oil in 73% yield (63 mg); H NMR
(500 MHz, CDCl3) δ 8.19–8.14 (m, 2H), 7.68–7.62 (m, 1H), 7.56–7.50 (m, 2H),
7.47–7.41 (m, 2H), 7.32–7.27 (m, 2H), 6.97–6.94 (m, 1H), 6.83–6.80 (m, 1H),
6.79–6.74 (m, 1H), 5.96 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 7.5 Hz, 1H), 3.78 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 193.8, 155.6, 152.6, 134.8, 134.5, 133.6, 132.0,
130.0, 129.2, 127.3, 123.1, 122.1, 115.2, 111.0, 110.9, 89.0, 88.8, 82.9, 56.5, 37.5; IR
(KBr) v 1700, 1592, 1485, 1446, 1237, 1052, 962, 867, 803, 766, 681 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H18BrO3 433.0434; Found 433.0425, 435.0459.
(5-Chloro-3-(p-tolylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3na).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow oil in 77% yield (57 mg); H NMR (500 MHz,
CDCl3) δ 8.19–8.13 (m, 2H), 7.74–7.62 (m, 1H), 7.58–7.50 (m, 2H), 7.38–7.31 (m,
2H), 7.21–7.10 (m, 3H), 6.86–6.81 (m, 1H), 6.04 (d, J = 7.3 Hz, 1H), 4.95 (d, J = 7.3
Hz, 1H), 2.35 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 193.5, 156.7, 139.6, 134.6,
134.6, 132.1, 129.9, 129.7, 129.5, 129.3, 128.6, 127.0, 125.5, 119.7, 111.7, 89.1, 86.2,
84.5, 37.3, 21.9; IR (KBr) v 1700, 1598, 1511, 1467, 1228, 1112, 962, 852, 813, 766,
681 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H18ClO2 373.0920; Found
373.0919, 375.0883.
(5-Bromo-3-((4-methoxyphenyl)ethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)meth
anone (3oa). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 72% yield (62 mg); 1H NMR
(500 MHz, CDCl3) δ 8.18–8.13 (m, 2H), 7.73–7.61 (m, 1H), 7.57–7.51 (m, 2H),
7.50–7.48 (m, 1H), 7.41–7.34 (m, 2H), 7.34–7.29 (m, 1H), 6.90–6.76 (m, 3H), 6.02
(d, J = 7.5 Hz, 1H), 4.95 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 193.4, 160.2, 157.8, 134.6, 133.6, 132.5, 129.9, 129.2, 128.4, 114.9, 114.4,
114.0, 112.2, 89.1, 85.5, 84.3, 55.7, 37.2; IR (KBr) v 1700, 1606, 1469, 1326, 1291,
1109, 962, 867, 813, 766, 687 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H18BrO3 433.0434; Found 433.0438, 435.0427.
(7-Methoxy-3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone
(3pa). This compound was purified by column chromatography (ethyl
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(400 MHz, CDCl3) δ 8.21–8.15 (m, 2H), 7.69–7.61 (m, 1H), 7.58–7.49 (m, 2H),
7.45–7.39 (m, 2H), 7.34–7.28 (m, 3H), 7.10–6.98 (m, 1H), 6.98–6.91 (m, 1H),
6.88–6.81 (m, 1H), 6.07 (d, J = 7.6 Hz, 1H), 4.99 (d, J = 7.6 Hz, 1H), 3.89 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 193.3, 146.8, 144.8, 134.3, 134.1, 131.8, 129.5,
128.9, 128.5, 128.3, 127.3, 122.7, 122.6, 116.9, 112.5, 88.4, 87.3, 83.6, 56.2, 37.6; IR
(KBr) v 1696, 1597, 1489, 1446, 1247, 1058, 964, 872, 762, 747, 683 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H19O3 355.1329; Found 355.1326.
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(5,7-Di-tert-butyl-3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanon
e (3qa). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 90% yield (78 mg); 1H NMR
(400 MHz, CDCl3) δ 8.22–8.15 (m, 2H), 7.71–7.60 (m, 1H), 7.58–7.50 (m, 2H),
7.49–7.42 (m, 2H), 7.35–7.27 (m, 4H), 7.23–7.19 (m, 1H), 5.97 (d, J = 7.6 Hz, 1H),
4.97 (d, J = 7.6 Hz, 1H), 1.36 (s, 9H), 1.33 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3)
δ 194.0, 153.8, 144.7, 134.6, 133.9, 132.8, 131.8, 129.5, 128.7, 128.3, 125.9, 123.2,
123.0, 119.3, 88.2, 88.2, 83.1, 36.8, 34.7, 34.3, 31.8, 29.4; IR (KBr) v 1740, 1595,
1487, 1443, 1228, 1180, 1015, 1015, 881, 762, 745, 692 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C31H33O2 437.2475; Found 437.2480.
(5-Nitro-3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3ra).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a Yellow oil in 55 % yield (40 mg); H NMR (400 MHz,
CDCl3) δ 8.34–8.28 (m, 1H), 8.24– 8.13 (m, 3H), 7.72–7.67 (m, 1H), 7.60–7.54 (m,
2H), 7.48–7.42 (m, 2H), 7.38–7.29 (m, 3H), 6.99 (d, J = 8.8 Hz, 1H), 6.21 (d, J = 7.2
13
Hz, 1H), 5.06 (d, J = 7.2 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ 192.0, 163.2,
143.1, 134.6, 133.8, 131.9, 129.5, 129.1, 128.9, 128.5, 128.0, 126.7, 122.0, 121.6,
110.4, 89.5, 85.6, 84.6, 36.2; IR (KBr) v 1700, 1602, 1472, 1348, 1297, 1125, 1043,
981, 874, 812, 743, 681 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C23H15NO4
370.1074; Found 370.1069.
(3-(Oct-1-yn-1-yl)-2,3-dihydrobenzofuran-2-yl)(phenyl)methanone (3sa). This
compound was purified by column chromatography (ethyl acetate/petroleum ether =
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1:60) to afford a yellow oil in 70% yield (46 mg); H NMR (400 MHz, CDCl3) δ
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8.19–8.11 (m, 2H), 7.68–7.62 (m, 1H), 7.56–7.49 (m, 2H), 7.31 (d, J = 7.6 Hz, 1H),
7.23–7.16 (m, 1H), 6.99–6.93 (m, 1H), 6.89 (d, J = 8.4 Hz, 1H), 5.88 (d, J = 7.6 Hz,
1H), 4.67 (d, J = 7.6 Hz, 1H), 2.42–2.15 (m, 2H), 1.57–1.45 (m, 2H), 1.44–1.34 (m,
2H), 1.33–1.24 (m, 4H), 0.88 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
193.9, 158.2, 134.4, 134.0, 129.5, 129.1, 128.8, 126.9, 124.8, 121.7, 110.2, 88.5, 84.1,
78.2, 36.8, 31.3, 28.7, 28.6, 22.6, 18.8, 14.1; IR (KBr) v 1696, 1597, 1465, 1450,
1240, 1058, 964, 878, 762, 720, 683 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H25O2 333.1849; Found 333.1839.
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(3-(Phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(p-tolyl)methanone (3ab). This
compound was purified by column chromatography (ethyl acetate/petroleum ether =
1:60) to afford a yellow oil in 80% yield (54 mg); 1H NMR (400 MHz, CDCl3 ) δ 8.08
(d, J = 8.4 Hz, 2H), 7.48–7.37 (m, 3H), 7.3–7.28 (m, 5H), 7.22 (d, J = 15.6 Hz, 1H),
6.99 (d, J = 14.8 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 7.6 Hz, 1H), 4.98 (d, J
= 7.6 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 193.5, 158.7, 145.5,
132.3, 132.2, 130.0, 129.9, 129.7, 128.8, 128.7, 126.7, 125.3, 123.2, 122.2, 110.7,
88.5, 88.0, 83.8, 37.4, 22.2; IR (KBr) v 1700, 1593, 1483, 1450, 1237, 1052, 962,
865, 803, 763, 685 cm-1 ; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H19O2
339.1380; Found 339.1386.
(4-Ethylphenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ac).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow oil in 64% yield (45 mg); H NMR (500 MHz,
CDCl3) δ 8.10 (d, J = 8.5 Hz, 2H), 7.48–7.34 (m, 5H), 7.33–7.29 (m, 3H), 7.25–7.18
(m, 1H), 7.03–6.96 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.01 (d, J = 7.8 Hz, 1H), 4.98
(d, J = 7.8 Hz, 1H), 2.75 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H); 13C{1H} NMR
(125 MHz, CDCl3) δ 193.5, 164.2, 158.7, 151.7, 132.5, 132.2, 130.1, 129.7, 128.7,
128.7, 126.7, 125.3, 123.2, 122.2, 110.7, 88.5, 88.0, 83.8, 37.41, 29.5, 15.5; IR (KBr)
v 1967, 1598, 1487, 1450, 1237, 1052, 962, 865, 807, 720, 685 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C25H21O2 353.1536; Found 353.1541.
(4-Methoxyphenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone
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(3ad).
This compound was purified by column chromatography (ethyl
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acetate/petroleum ether = 1:60) to afford a yellow oil in 74% yield (52 mg); 1H NMR
(500 MHz, CDCl3) δ 8.29–8.11 (m, 2H), 7.52–7.34 (m, 3H), 7.33–7.28 (m, 3H), 7.21
(d, J = 15.5 Hz, 1H), 7.06–6.94 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 7.5 Hz,
1H), 4.99 (d, J = 7.5 Hz, 1H), 3.90 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 192.3,
164.7, 158.7, 132.3, 132.2, 129.7, 128.7, 128.7, 127.9, 126.8, 125.3, 123.2, 122.2,
114.5, 110.6, 88.5, 88.1, 83.7, 56.0, 37.4; IR (KBr) v 1694, 1597, 1487, 1446, 1239,
1058, 964, 878, 760, 744, 688 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C24H19O3 355.1329; Found 355.1335.
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(4-Fluorophenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ae).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow oil in 76% yield (52 mg); H NMR (500 MHz,
CDCl3) δ 8.26–8.18 (m, 2H), 7.47–7.38 (m, 3H), 7.34–7.29 (m, 3H), 7.25–7.18 (m,
3H), 7.04–6.97 (m, 1H), 6.92 (d, J = 8.0 Hz, 1H), 5.97 (d, J = 7.8 Hz, 1H), 5.01 (d, J
= 7.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ 192.0, 166.5 (d, JC-F = 255.1 Hz),
158.1, 132.4, 132.3, 131.8, 131.0 (d, JC-F = 2.6 Hz), 129.4, 128.5, 128.4, 126.2, 125.0,
122.7, 122.0, 116.2 (d, JC-F = 21.8 Hz), 110.3, 88.2, 87.4, 83.5, 36.8; IR (KBr) v 1700,
1597, 1503, 1475, 1229, 1088, 964, 837, 760, 744, 688 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C23H16FO2 343.1129; Found 343.1130.
(4-Chlorophenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3af).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a colorless oil in 77% yield (55 mg); H NMR (500 MHz,
CDCl3) δ 8.14–8.10 (m, 2H), 7.53–7.50 (m, 2H), 7.45–7.39 (m, 3H), 7.34–7.29 (m,
3H), 7.22 (d, J = 15.0 Hz, 1H), 7.00 (t, J = 15.0 Hz, 1H), 6.90 (d, J = 7.0 Hz, 1H),
5.94 (d, J = 7.5 Hz, 1H), 5.00 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 192.9, 158.4, 141.1, 133.2, 132.2, 131.3, 129.8, 129.6, 128.9, 128.7, 126.5, 125.4,
123.0, 122.4, 110.7, 88.7, 87.7, 83.9, 37.2; IR (KBr) v 1700, 1596, 1501, 1472, 1224,
1156, 1086, 952, 863, 747, 692 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H16ClO2 359.0833; Found 359.0839, 361.0829.
(4-Bromophenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ag).
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CDCl3) δ 8.08–8.02 (m, 2H), 7.72–7.66 (m, 2H), 7.46–7.39 (m, 3H), 7.36–7.29 (m,
3H), 7.23 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 7.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.95
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(d, J = 7.5 Hz, 1H), 4.99 (d, J = 7.5 Hz, 1H); C{1H} NMR (100 MHz, CDCl3) δ
192.8, 158.0, 133.1, 132.2, 131.8, 131.0, 129.6, 129.4, 128.5, 128.4, 126.1, 125.0,
122.6, 122.0, 110.3, 88.2, 87.3, 83.5, 36.8; IR (KBr) v 1700, 1605, 1498, 1467, 1228,
1154, 1092, 963, 865, 849, 682 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C23H16BrO2 403.0328; Found 403.0333, 405.0303.
(3-Bromophenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ah).
This compound was purified by column chromatography (ethyl acetate/petroleum
ether = 1:60) to afford a yellow oil in 70% yield (56 mg); 1H NMR (500 MHz, CDCl3
) δ 8.31 (t, J = 2.0 Hz, 1H), 8.13–8.09 (m, 1H), 7.79–7.75 (m, 1H), 7.49–7.38 (m,
4H), 7.35–7.28 (m, 3H), 7.25–7.21 (m, 1H), 7.05–6.97 (m, 1H), 6.92 (d, J = 7.5 Hz,
1H), 5.95 (d, J = 7.5 Hz, 1H), 4.98 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 192.4, 158.0, 136.9, 136.2, 132.50, 131.9, 130.4, 129.4, 128.5, 128.3, 128.1,
126.0, 125.0, 123.2, 122.6, 122.0, 110.4, 88.2, 87.2, 83.7, 36.9; IR (KBr) v 1701,
1604, 1503, 1467, 1228, 1154, 1086, 952, 865, 821, 685 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C23H16BrO2 403.0328; Found 403.0321, 405.0326.
(2-Bromophenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ai).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:60) to afford a yellow oil in 66% yield (53 mg); H NMR (500 MHz,
CDCl3) δ 7.70–7.65 (m, 1H), 7.54–7.47 (m, 1H), 7.45–7.33 (m, 5H), 7.32–7.26 (m,
3H), 7.21 (d, J = 8.0 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.92
(d, J = 8.0 Hz, 1H), 4.90 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
207.2, 198.9, 158.1, 138.5, 133.8, 132.4, 131.8, 129.6, 129.4, 128.4, 128.3, 127.4,
126.1, 124.9, 122.7, 122.0, 119.8, 110.4, 89.9, 87.0, 83.4, 37.5; IR (KBr) v 1700,
1603, 1498, 1467, 1220, 1154, 1086, 952, 865, 829, 684 cm-1; HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C23H16BrO2 403.0328; Found 403.0334, 405.0340.
(2,4-Dimethylphenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone
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(3aj). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a Yellow oil in 83% yield (58 mg); 1H NMR
(500 MHz, CDCl3) δ 7.94 (d, J = 8.0 Hz, 1H), 7.47–7.41 (m, 3H), 7.36–7.30 (m, 3H),
7.27–7.22 (m, 1H), 7.21–7.16 (m, 2H), 7.03–6.99 (m, 1H), 6.93 (d, J = 8.0 Hz, 1H),
6.00 (d, J = 7.8 Hz, 1H), 4.94 (d, J = 7.8 Hz, 1H), 2.59 (s, 3H), 2.43 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 196.0, 158.4, 143.4, 140.9, 133.3, 131.8, 131.4, 130.7,
129.3, 128.3, 128.3, 126.5, 126.4, 124.9, 122.8, 121.7, 110.3, 89.0, 87.7, 83.3, 37.2,
21.9, 21.6; IR (KBr) v 1695, 1598, 1485, 1446, 1237, 1057, 962, 865, 807, 763, 685
cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C25H21O2 353.1536; Found 353.1533.
[1,1'-Biphenyl]-4-yl(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone
(3ak). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:40) to afford a white solid in 63% yield (50 mg); mp
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141-143 C; H NMR (400 MHz, CDCl3) δ 8.30–8.21 (m, 2H), 7.81–7.73 (m, 2H),
7.69–7.63 (m, 2H), 7.5–7.39 (m, 6H), 7.36–7.28 (m, 3H), 7.23 (d, J = 8.0 Hz, 1H),
7.00 (d, J = 7.2 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.06 (d, J = 7.4 Hz, 1H), 5.02 (d, J
= 7.4 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.2, 158.3, 146.8, 139.7, 133.0,
131.8, 130.1, 129.4, 129.1, 128.5, 128.5, 128.4, 127.5, 127.4, 126.2, 125.0, 122.7,
121.9, 110.4, 88.2, 87.5, 83.5, 37.0; IR (KBr) v 1682, 1600, 1480, 1406, 1267, 1175,
962, 836, 807, 763, 692 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C29H21O2
401.1536; Found 401.1537.
(4-(Methylsulfonyl)phenyl)(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methano
ne (3al). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:12) to afford a yellow oil in 60% yield (48 mg); 1H NMR
(400 MHz, CDCl3) δ 8.36 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 2H), 7.47–7.40 (m,
3H), 7.35–7.28 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.90 (d, J
= 8.0 Hz, 1H), 5.98 (d, J = 7.6 Hz, 1H), 5.04 (d, J = 7.6 Hz, 1H), 3.11 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ 192.8, 157.8, 144.9, 138.4, 131.8, 130.5, 129.5,
128.6, 128.4, 127.9, 126.0, 125.1, 122.4, 122.3, 110.4, 88.5, 87.0, 83.7, 44.4, 36.6; IR
(KBr) v 1706, 1595, 1476, 1456, 1217, 1086, 952, 865, 807, 763, 687 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C24H19O4S 403.0999; Found 403.1002.
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(3-(Phenylethynyl)-2,3-dihydrobenzofuran-2-yl)(4-(trifluoromethyl)phenyl)methano
ne (3am). This compound was purified by column chromatography (ethyl
acetate/petroleum ether = 1:60) to afford a yellow oil in 76% yield (59 mg); 1H NMR
(500 MHz, CDCl3) δ 8.30–8.26 (m, 2H), 7.82–7.78 (m, 2H), 7.45–7.39 (m, 3H),
7.33–7.28 (m, 3H), 7.25–7.21 (m, 1H), 7.03–6.99 (m, 1H), 6.91 (d, J = 8.0 Hz, 1H),
5.98 (d, J = 7.5 Hz, 1H), 5.03 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3)
δ 193.3, 158.3, 137.5, 135.6 (q, JC-F = 32.5 Hz), 132.2, 130.3, 129.8, 128.9, 128.7,
126.4, 126.2 (q, JC-F = 3.5 Hz), 125.4, 124.0 (q, JC-F = 253.7 Hz), 122.5, 110.7,
88.8, 87.5, 84.0, 37.1; IR (KBr) v 1703, 1543, 1480, 1446, 1325, 1067, 960, 860, 807,
752, 689 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C24H16F3O2 393.1097;
Found 393.1091.
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Naphthalen-2-yl(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3an).
This compound was purified by column chromatography (ethyl acetate/petroleum
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ether = 1:40) to afford a yellow oil in 66% yield (49 mg); H NMR (400 MHz,
CDCl3) δ 8.77 (s, 1H), 8.26–8.11 (m, 1H), 8.04–7.84 (m, 3H), 7.71–7.51 (m, 2H),
7.48–7.40 (m, 3H), 7.36–7.27 (m, 3H), 7.23 (d, J = 7.6 Hz, 1H), 7.05–6.92 (m, 2H),
6.19 (d, J = 7.6 Hz, 1H), 5.04 (d, J = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ
193.5, 158.3, 136.1, 132.5, 131.9, 131.8, 131.7, 130.0, 129.4, 129.1, 128.8, 128.4,
128.3, 127.9, 127.0, 126.3, 125.0, 124.5, 122.7, 121.9, 110.4, 88.2, 87.7, 83.6, 37.2;
IR (KBr) v 1690, 1595, 1485, 1446, 1227, 1049, 965, 865, 807, 760, 687 cm-1; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C27H19O2 375.1380; Found 375.1371.
Furan-2-yl(3-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)methanone (3ao). This
compound was purified by column chromatography (ethyl acetate/petroleum ether =
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1:60) to afford a yellow oil in 72% yield (45 mg); H NMR (500 MHz, CDCl3) δ
7.76–7.71 (m, 1H), 7.54 (d, J = 3.5 Hz, 1H), 7.46–7.38 (m, 3H), 7.34–7.27 (m, 3H),
7.23 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.64–6.61
(m, 1H), 5.75 (d, J = 7.5 Hz, 1H), 4.94 (d, J = 7.5 Hz, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 182.9, 158.2, 150.4, 148.1, 131.8, 129.4, 128.4, 128.3, 126.2, 125.0, 122.7,
122.0, 121.1, 112.7, 110.3, 88.3, 87.3, 83.5, 37.5; IR (KBr) v 1676, 1598, 1477, 1446,
1409, 1222, 978, 855, 823, 753, 692 cm-1; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
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