Selective Friedel-Crafts Acylation Reactions of 2-Arylphenoxyacetic Acids: A Simple and Efficient Methodology to Synthesize Dibenzoxepine and Arylcoumaranone Derivatives

Article abstract of DOI:10.1055/s-0034-1380211

Intramolecular Friedel-Crafts acylation reactions of 2-arylphenoxyacetic acids are accomplished using trifluoroacetic anhydride or trifluoromethanesulfonic acid at 0 °C or room temperature. Depending on the reaction conditions, dibenzoxepines or arylcoumaranones are obtained in good yields and with high selectivities (83-100%). Plausible mechanistic pathways for the selective formation of the different reaction products are discussed.

Full text of DOI:10.1055/s-0034-1380211

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3049–3060
paper
3049
J. Wang et al.
Paper
Synthesis
Selective Friedel–Crafts Acylation Reactions of 2-Arylphenoxy-
acetic Acids: A Simple and Efficient Methodology to Synthesize
Dibenzoxepine and Arylcoumaranone Derivatives
R2
R2
Jialin Wanga,b
Jiaqi Liua,b
R2
R1
TfOH (30 equiv)
TFAA (5 equiv)
TFA, 25 °C
Hao Lana,b
Wenyi Chu*a,b
Zhizhong Sun*a,b
R1
O
R1
O
CHCl3, 0 °C to r.t.
O
O
O
O
HO
23 target molecules
yield 77–86%
selectivity 100%
10 target molecules
yield 80–92%
selectivity > 83%
a School of Chemistry and Materials Science, Heilongjiang
University, 150080, Harbin, P. R. of China
b Key Laboratory of Chemical Engineering Process & Technolo-
gy for High-Efficiency Conversion, College of Heilongjiang
Province, 150080, Harbin, P. R. of China
wenyichu@hlju.edu.cn
Sunzz@hlju.edu.cn
R1
Received: 10.03.2015
Accepted after revision: 17.04.2015
Published online: 19.06.2015
R
O
R
DOI: 10.1055/s-0034-1380211; Art ID: ss-2015-h0152-op
NH
R2
R
Abstract Intramolecular Friedel–Crafts acylation reactions of 2-aryl-
phenoxyacetic acids are accomplished using trifluoroacetic anhydride
or trifluoromethanesulfonic acid at 0 °C or room temperature. Depend-
ing on the reaction conditions, dibenzoxepines or arylcoumaranones
are obtained in good yields and with high selectivities (83–100%). Plau-
sible mechanistic pathways for the selective formation of the different
reaction products are discussed.
O
I
II
OH
HO
Me
Me
O
Key words Friedel–Crafts acylations, 2-arylphenoxyacetic acids,
dibenzoxepines, arylcoumaranones, regioselectivity
O
Me
Me
The synthesis of cycloketones represents an important
area of research due to their wide spectrum of therapeutic
applications.1,2 Among them, dibenzoxepines and coumara-
nones are present in numerous therapeutic natural prod-
ucts. Dibenzoxepine derivatives have been described as ex-
tremely potent agonists of the TRPA1 receptor (I);3 they are
also effective against H-29 human colon adenocarcinoma
and human breast cancer cells (II),4 and are useful as nucle-
ar hormone receptor modulators (III).5 In addition, they are
used extensively for the treatment of anxiety and depres-
sion (Figure 1).6 Coumaranone derivatives are important in-
termediates for the synthesis of various bioactive com-
pounds such as the heliquinomycin analogues (IV) and au-
rones (V) (Figure 1),7 which have received significant
attention in medicinal and pharmaceutical chemistry.8 The
therapeutic potential of coumaranones has been highlight-
ed in recent studies reporting their anticancer, antimicrobi-
al, antiparasitic, and antiviral activities.9
O
O
R1
III
O
O
R1
OAc
R
R
O
IV
V
Figure 1 Examples of dibenzoxepine and coumaranone derivatives
clization of o-acylphenols,10 Pummerer rearrangement and
intramolecular cyclization,11 intramolecular etherifica-
tion,7b,12 nucleophilic substitution/cyclization,13 polyphos-
phoric acid (PPA) promoted dehydration/cyclization,14 etc.
Most of these methods involve multistep procedures and
relatively harsh reaction conditions, and deliver low yields
and regioselectivities,15 hence their applications have been
somewhat constrained. Inter- and intramolecular Friedel–
Crafts acylations of aromatic rings are considered to be the
most fundamental methods for the synthesis of cycloke-
tones.16 However, acylating reagents such as acyl halides17
and anhydrides18 are unstable and sensitive to air. In con-
Owing to the diverse biological activities of compounds
containing dibenzoxepine and coumaranone moieties,
many different methods have been developed for the syn-
thesis of these scaffolds. Examples include oxidative cy-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3049–3060

3050
J. Wang et al.
Paper
Synthesis
trast, carboxylic acids19 are cheap, readily available, and are
stable to light and air, and can therefore be considered as
good alternatives to other acylating reagents.
In our work, we found that the Friedel–Crafts acylation
of 2-arylphenoxyacetic acids 1 occurred under different
conditions to afford selectively compounds 2 and 3 in good
yields and high regioselectivities (Scheme 1). The sub-
strates 1 were obtained in good yields via Suzuki–Miyaura
cross-coupling reactions (Table 1), but because of their low
reactivity, their utilization in Friedel–Crafts reactions re-
mains a challenging problem.
Initially, we screened different catalysts and reagents for
the selective acylation of (2-phenyl)phenoxyacetic acid (1a)
(Table 2). No products were obtained from the reaction of
compound 1a with cyanuric chloride (TCT) in the presence
of aluminum chloride (AlCl3)20 at room temperature (Table
2, entry 1). In addition, H-ZSM-5 (Zeolite Scony Mobile
Number 5), hydrofluoric acid (HF), and sulfuric acid (H2SO4)
were used in the acylation reaction,21,22 but none of the de-
sired products were observed (Table 2, entries 2–4). When
polyphosphoric acid (PPA) or Eaton’s reagent was used,23,24
low yields of the corresponding dibenzoxepine product 2a
were obtained (Table 2, entries 5 and 6). With the aim of in-
creasing the yield and regioselectivity of the reaction, or-
ganic superacid and acid anhydride catalyzed Friedel–
Crafts acylation reactions25 were examined. Treatment of
1a with trifluoroacetic anhydride (TFAA) or methanesul-
fonic anhydride (MSAA) gave the corresponding product 2a
in 70% and 45% yields (Table 2, entries 7 and 8). We next ex-
amined the effects of strong acids (MSA, ClSO3H, and TfOH)
on the reaction. Methanesulfonic acid (MSA) and chlorosul-
fonic acid (ClSO3H) were effective catalysts for the synthesis
of dibenzoxepine 2a in 33% and 37% yields (Table 2, entries
9 and 10), respectively. To our surprise, trifluoromethane-
sulfonic acid (TfOH) furnished 2a in 17% yield and arylcou-
maranone 3a in 55% yield (Table 2, entry 11). According to
these experimental results, trifluoroacetic anhydride and
R2
Br
(HO)2B
OEt
+
O
R1
O
R2
R2
R2
R1
R1
R1
OH
O
O
O
O
O
O
dibenzoxepines 2
arylcoumaranones 3
1
Scheme 1 Intramolecular selective Friedel–Crafts acylations proceed-
ing via a carboxylic acid
Table 1 Synthesis of 2-Arylphenoxyacetic Acids 1 by Suzuki–Miyaura Cross-Coupling Reactionsa
R2
R2
R1
(HO)2B
1)
2)
Br
O
Pd(PPh3)4, K2CO3, N2
OEt
O
O
R1
20% NaOH then 10% HCl
O
HO
1
Entry
R1
R2
Product
Yield (%)b
Entry
R1
R2
m-Cl
Product
Yield (%)b
1
2
H
H
1a
1b
1c
1d
1e
1f
85
87
85
88
86
91
89
94
95
93
86
89
13
14
15
16
17
18
19
20
21
22
23
24
m-Me
m-Me
m-F
1m
1n
1o
1p
1q
1r
85
84
84
89
84
80
83
83
82
84
82
74
m-Me
H
H
m-F
H
3
p-Me
4
m-Me
m-Me
p-MeO
m-MeO
m-Me
p-MeO
m-MeO
H
p-Me
m-F
p-Me
5
m-Me
H
m-F
m,p-(MeO)2
p-Ph
6
H
7
H
1g
1h
1i
m-Me
p-MeO
m-Ph
m-Me
p-MeO
m-Me
p-Ph
1s
8
m,p-(MeO)2
m,p-(MeO)2
m,p-(MeO)2
m-Cl
p-Ph
1t
9
H
1u
1v
1w
1x
10
11
12
1j
Naphth
Naphth
o-Cl
1k
1l
H
m-F
a Reaction conditions: aryl bromide (10.0 mmol), arylboronic acid (12.0 mmol), K2CO3 (2.5 mmol), Pd(PPh3)4 (0.3 mmol), toluene (25 mL), 85 °C, N2 atm, 12 h,
then 20% NaOH solution, reflux, 3 h, then 10% HCl (ice–H2O bath temperature), pH adjusted to 2–3.
b Yield of isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3049–3060

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Synthesis
trifluoromethanesulfonic acid were effective reagents for
the selective synthesis of compounds 2a and 3a, respective-
ly.
(2-phenyl)phenoxyacetic acid (1a) (1 mmol), trifluoroace-
tic anhydride (5 equiv), trifluoroacetic acid (5 mL), 25 °C, 24
hours.
Table 2 Effects of Different Reagents on the Selective Acylation Reac-
tion of 1a
Table 3 Optimization of the Reaction Conditions for the Synthesis of
2a in the Presence of Trifluoroacetic Anhydride (TFAA)
catalyst
TFAA
+
solvent
solvent
24 h
O
O
O
O
O
O
O
OH
1a
OH
O
O
O
2a
3a
1a
2a
Yielda,b
Entry Reagent (equiv)
Solvent
Temp
(°C)
Time
(h)
Product
(Yield)a
Entry
TFAA (equiv)
Solvent
Temp (°C)
1
2
3
4
5
5
5
CHCl3
TFA
TFA
25
25
40
25
25
70%
82%
82%
64%
82%
1b
2
3
4
5
6
7
8
9
TCT/AlCl3 (1.2)
H-ZSM-5 (0.5)
HFc
CHCl3
PhNO2
–
25
160
25
25
80
80
25
80
25
25
12
12
12
12
2
NR
NR
5
NR
1
TFA
c
H2SO4
–
NR
10
TFA
PPAc
–
2a (22%)
2a (26%)
2a (70%)
2a (45%)
2a (33%)
a Yield of isolated product 2a.
Eaton’s reagentc,d
TFAA (5)
–
2
b Selectivity is 100%.
CHCl3
PhNO2
CHCl3
CHCl3
24
12
12
12
MSAA (1.3)
MSA (30)
Having identified the optimum conditions for the reac-
tion, we next studied the applicability of our protocol to
various substrates. The results of these studies are summa-
rized in Table 4. Substrates containing electron-donating
groups (Table 4, entries 2–10) and/or electron-withdrawing
groups (Table 4, entries 11–17) reacted smoothly, giving
good yields of the expected products (82–86%) and excel-
lent regioselectivities (100%). Besides these examples, we
also examined the effects of phenyl and naphthyl substitu-
ents on the aryl rings of substrates 1. The corresponding
products 2 were obtained in good yields of 77–83% (Table 4,
entries 18–23). This strategy showed an excellent tolerance
toward a range of substituents (Me, MeO, F, Cl, Ph, etc.).
Following our preliminary investigations (Table 2), we
next optimized the conditions for the selective acylation re-
action of substrate 1a in the presence of trifluoromethane-
sulfonic acid as the catalyst in order to synthesize arylcou-
maranone 3a (Table 5). It was clear from the results that the
temperature played an important role in the reaction.
When the reaction temperature was decreased from 35 °C
to 0 °C, the yield of compound 3a increased from a trace
amount to 66%, and the yield of 2a decreased from 67% to
8% (Table 5, entries 1–4). When the reaction temperature
was slowly increased from 0 °C to room temperature, com-
pound 3a was obtained in an excellent yield of 85% (Table 5,
entry 5). The amount of trifluoromethanesulfonic acid was
also optimized by varying its number of equivalents from
10 to 40. When the amount of trifluoromethanesulfonic
acid was increased from 10 to 30 equivalents, the yield of
compound 3a increased from 15% to 85% (Table 5, entries
5–7). A further increase in the amount of trifluoromethane-
sulfonic acid to 40 equivalents did not result in any signifi-
10
ClSO3H (30)
2a (37%),
3a (trace)
11
TfOH (30)
CHCl3
25
15
2a (17%),
3a (55%)
a Yield of isolated product 2a or 3a. NR = no reaction.
b Cyanuric chloride (1.6 equiv) and pyridine (1 equiv) were used as addi-
tives.
c The reagent also serves as the solvent.
d Eaton’s reagent is composed of a 1:10 solution by weight of P2O5 in MSA.
On the basis of these results, we next optimized the
conditions for the selective acylation reaction of 1a in the
presence of trifluoroacetic anhydride to prepare compound
2a (Table 3). Initially, the effect of the solvent was studied,
and the results showed that trifluoroacetic acid (TFA) was
superior to chloroform (Table 3, entries 1 and 2). Subse-
quently, the effects of temperature were examined; there
was no change in the yield when the temperature was
raised to 40 °C (Table 3, entries 2 and 3). Finally, the effect
of the amount of trifluoroacetic anhydride was examined
by varying the number of equivalents. Increasing the
amount of trifluoroacetic anhydride from one to five equiv-
alents resulted in an increased yield of the desired product
from 64% to 82%, but increasing the amount of trifluoroace-
tic anhydride to 10 equivalents did not improve the yield
further (Table 3, entries 2, 4 and 5). The optimum amount
of trifluoroacetic anhydride was found to be five equiva-
lents. It is important to note that the regioselectivity to-
ward compound 2a was 100%. The optimum reaction con-
ditions for the synthesis of dibenzoxepine 2a are as follows:
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3049–3060

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J. Wang et al.
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Synthesis
Table 4 Synthesis of Dibenzoxepines 2a
R1
R2
R2
R1
TFAA (5 equiv)
TFA, 25 °C, 24 h
O
OCH2COOH
O
1
2
Entry
R1
R2
Product
Yield (%)b
Entry
R1
R2
m-Cl
Product
Yield (%)b
1
2
H
H
2a
2b
2c
2d
2e
2f
82
84
83
82
84
84
83
86
85
84
82
80
13
14
15
16
17
18
19
20
21
22
23
m-Me
m-Me
m-F
2m
2n
2o
2p
2q
2r
83
81
82
84
85
80
83
81
80
79
77
m-Me
H
H
m-F
3
p-Me
H
4
m-Me
m-Me
p-MeO
m-MeO
m-Me
p-MeO
m-MeO
H
p-Me
m-F
p-Me
m,p-(MeO)2
p-Ph
5
m-Me
H
m-F
6
H
7
H
2g
2h
2i
m-Me
p-MeO
m-Ph
m-Me
p-MeO
p-Ph
2s
8
m,p-(MeO)2
m,p-(MeO)2
m,p-(MeO)2
m-Cl
p-Ph
2t
9
H
2u
2v
2w
10
11
12
2j
Naphth
Naphth
2k
2l
H
m-F
a Reaction conditions: 1 (1 mmol), TFAA (5 equiv), TFA (5 mL), 25 °C, 24 h.
b Yield of isolated product after purification by column chromatography. The selectivity in each case is 100%.
cant increase in the yield of 3a (Table 5, entry 8). Hence the
optimum amount of trifluoromethanesulfonic acid was 30
equivalents.
The optimum reaction conditions for the synthesis of
arylcoumaranone 3a are as follows: (2-phenyl)phenoxy-
acetic acid (1a) (1 mmol), CHCl3 (3 mL), slow addition of tri-
fluoromethanesulfonic acid (30 equiv) at 0 °C, then stirring
at room temperature for 15 hours.
Using the optimized conditions, the substrate scope of
the Friedel–Crafts acylation reaction to synthesize arylcou-
maranones 3, selectively, was examined (Table 6). A sub-
strate with an electron-donating group on the phenyl ring
A gave a slightly higher yield of the corresponding product
3 than an example with an electron-donating substituent
on the phenyl ring B (Table 6, entries 2 and 3). The presence
of an electron-withdrawing group on the phenyl ring B did
not affect the yield of the corresponding products 3 (Table
6, entries 4–7 and 11). In contrast, when an electron-with-
drawing fluorine substituent was present on the phenyl
ring A of substrate 1, the corresponding product 3 was not
obtained (Table 6, entry 8). When a phenyl group was locat-
ed on the phenyl ring B, there was no obvious effect on the
efficiency of the reactions and products 3 were furnished in
similar yields (Table 6, entries 9 and 10).
Plausible reaction pathways for the selective Friedel–
Crafts acylation reactions of substrate 1 are illustrated in
Scheme 2. An intermediate carboxylic acid anhydride (4) is
formed by the reaction of trifluoroacetic anhydride and
substrate 1. Steric effects present in intermediate 4 might
improve the regioselectivity of the acylation and are benefi-
cial for the formation of product 2. Under the influence of
the strong acid, trifluoromethanesulfonic acid, the interme-
diate sulfonic anhydride 5 is formed via elimination of wa-
ter. As trifluoromethanesulfonate (TfO–) is a good leaving
group, intermediate 5 is transformed into ionic intermedi-
Table 5 Optimization of the Reaction Conditions for the Synthesis of
3a in the Presence of Trifluoromethanesulfonic Acid (TfOH)
TfOH
CHCl3
OCH2COOH
O
O
O
O
1a
3a
2a
Entry
TfOH (equiv) Temp (°C)
Time (h)
Product (yield)a
1
2
3
4
5
6
7
8
30
30
30
30
30
10
20
40
35
25
15
0
5
9
3a (trace), 2a (67%)
3a (55%), 2a (26%)
3a (62%), 2a (17%)
3a (66%), 2a (8%)
3a (85%), 2a (12%)
3a (15%), 2a (61%)
3a (34%), 2a (32%)
3a (85%), 2a (12%)
15
15
15
15
15
15
0–25b
0–25b
0–25b
0–25b
a Yield of isolated product.
b TfOH was slowly added at 0 °C, and then the reaction mixture was stirred
at room temperature for the appropriate amount of time.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3049–3060

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Synthesis
Table 6 Synthesis of Arylcoumaranones 3a
R2
R2
R1
R2
R1
R1
B
A
TfOH (30 equiv)
B
A
A
B
CHCl3, 0–25 °C
15 h
O
O
O
OCH2COOH
O
1
3
2
Entry
Reactant
R1
R2
Yield of 3 (selectivity)b
Yield of 2 (selectivity)b
1
2
1a
1b
1c
1k
1l
H
H
85% (89%)
89% (91%)
80% (83%)
87% (91%)
88% (90%)
90% (94%)
92% (95%)
–
10% (11%)
9% (9%)
m-Me
H
H
3
p-Me
m-Cl
m-F
m-Cl
m-F
H
16% (17%)
9% (9%)
4
H
5
H
9% (10%)
6% (6%)
6
1m
1n
1o
1r
m-Me
m-Me
m-F
H
7
5% (5%)
8
30% (100%)
15% (15%)
10% (11%)
–
9
p-Ph
p-Ph
o-Cl
83% (85%)
85% (89%)
87% (100%)
10
11
1s
1x
m-Me
m-Me
a Reaction conditions: 1 (1 mmol), CHCl3 (3 mL), TfOH (30 equiv), 0–25 °C, 15 h.
b Yield of isolated product after purification by column chromatography.
R2
R2
R1
R1
TFAA–TFA
O
O
O
O
F3C
O
HO
CF3SO3H
O
1
4
TFA
slow
R2
H2O
R2
R1
R1
R2
R1
O
O
O
O
O
O
O
3
2
5
O
S
O
– H+
CF3
H+
R2
R1
+
HO
O
R2
R1
A
B
CF3SO3H
O
6
O
Scheme 2 Plausible mechanisms for the selective Friedel–Crafts acylation reactions
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3049–3060

3054
J. Wang et al.
Paper
Synthesis
ate 6, under acidic conditions, by removal of the trifluoro-
methanesulfonate group. As intermediate 6 exhibits less
steric hindrance, the acylation products 2 and 3 can be ob-
tained selectively under the appropriate conditions. The se-
lectivity of the reaction was related to the nature of the
substituents present on substrates 1. The presence of elec-
tron-donating groups on the phenyl ring A facilitated the
generation of products 3. In contrast, the formation of
products 2 was favored when an electron-donating group
was located on the phenyl ring B. The selectivities were also
related to the reaction temperature. A low temperature fa-
cilitated the formation of arylcoumaranones 3, whilst high-
er temperatures resulted in moderate to good yields of
dibenzoxepines 2.
In conclusion, we have developed simple and efficient
Friedel–Crafts acylations of acids 1 for the synthesis of cy-
cloketones by using the simple reagents trifluoromethane-
sulfonic acid and trifluoroacetic anhydride at moderate
temperatures. Depending on the reaction conditions,
dibenzoxepine or arylcoumaranone derivatives are ob-
tained in good yields and with high selectivities. The proto-
col is applicable to a variety of substrates 1 giving good to
excellent yields of the corresponding products. In addition,
plausible reaction mechanisms have been discussed.
Dibenzo[b,d]oxepin-7(6H)-one (2a)
Yield: 169 mg (82%); white solid; mp 77.3–80.0 °C; Rf = 0.42 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2920, 1679, 1446, 1210, 1052, 746, 719 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.78 (dd, J = 12.0, 4.5 Hz, 2 H),
7.72–7.65 (m, 2 H), 7.57 (td, J = 7.6, 1.1 Hz, 1 H), 7.47 (td, J = 7.7, 1.7
Hz, 1 H), 7.38 (td, J = 7.6, 1.3 Hz, 1 H), 7.27 (dd, J = 7.9, 1.2 Hz, 1 H),
4.91 (s, 2 H).
13C NMR (101 MHz, DMSO-d6): δ = 203.46, 156.35, 136.11, 135.90,
133.76, 132.54, 130.46, 130.21, 129.41, 128.91, 128.17, 126.08,
121.40, 82.58.
.
HRMS (EI): m/z [M + H]+ calcd for C14H11O2: 211.0760; found:
211.0752.
UV/Vis (EtOH): λmax = 309 nm.
Anal. Calcd for C14H10O2: C, 79.98; H, 4.79. Found: C, 79.95; H, 4.81.
2-Methyldibenzo[b,d]oxepin-7(6H)-one (2b)
Yield: 188 mg (84%); white solid; mp 106.6–109.3 °C; Rf = 0.36 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2967, 2908, 1674, 1497, 1283, 1024, 830, 762, 691 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.77 (t, J = 7.4 Hz, 2 H), 7.66 (d,
J = 7.4 Hz, 1 H), 7.55 (td, J = 7.6, 1.2 Hz, 1 H), 7.48 (d, J = 1.7 Hz, 1 H),
7.25 (dd, J = 8.1, 1.6 Hz, 1 H), 7.14 (d, J = 8.1 Hz, 1 H), 4.86 (s, 2 H), 2.37
(s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 203.66, 154.19, 136.25, 135.96,
135.17, 133.65, 132.14, 130.84, 130.48, 129.29, 128.87, 128.05,
121.04, 82.57, 20.41.
.
Unless otherwise stated, all the reactions were carried out in air. Aryl
bromides, Lewis acids, Brønsted acids, solid acid catalysts and arylbo-
ronic acids were purchased from Aladdin or Alfa, and were used with-
out purification. Bases and solvents were purchased from Kermel
Chemical Co. Ltd. All reactions were magnetically stirred and moni-
tored by thin-layer chromatography (TLC) using Haiyang® Silica Gel
60 F254 plates (made by Branch of Qingdao Haiyang Chemical Co., Ltd
of China), the plates were made visual by fluorescence quenching at
254 nm or 365 nm. Column chromatography was performed using
Acros silica gel (60–200 μm, 60 Å). Petroleum ether (PE) refers to the
fraction boiling in the 30–60 °C range. Melting points were measured
with a Shenguang melting point apparatus. Infrared spectra (FT-IR)
were recorded on a Perkin-Elmer Spectrum TwoTM spectrophotome-
ter. 1H and 13C NMR spectra were recorded on a Bruker Avance 400
spectrometer (as CDCl3 or DMSO-d6 solutions) using TMS as an inter-
nal standard. High-resolution mass spectrometry (HRMS) was carried
out using a Shimadzu LCMS-IT-TOF mass spectrometer. UV/Vis spec-
tra were obtained using a Perkin-Elmer Lambda 950 spectrophotom-
eter. Elemental analyses were obtained using a Perkin–Elmer 2400
Series II CHNS/O Analyzer.
HRMS (EI): m/z [M + H]+ calcd for C15H13O2: 225.0916; found:
225.0920.
UV/Vis (EtOH): λmax = 310 nm.
Anal. Calcd for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.32; H, 5.40.
9-Methyldibenzo[b,d]oxepin-7(6H)-one (2c)
Yield: 186 mg (83%); white solid; mp 55.9–56.7 °C; Rf = 0.35 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2989, 2924, 1682, 1482, 1286, 1048, 811, 750, 679 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.72 (s, 1 H), 7.56 (dd, J = 7.7, 1.7 Hz, 1
H), 7.49 (dd, J = 8.0, 1.5 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.37 (td,
J = 7.6, 1.7 Hz, 1 H), 7.29 (td, J = 7.5, 1.4 Hz, 1 H), 7.21 (dd, J = 7.9, 1.3
Hz, 1 H), 4.82 (s, 2 H), 2.45 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 204.26, 157.00, 138.31, 136.06,
134.72, 134.52, 133.45, 130.30, 130.15, 130.04, 129.67, 126.14,
121.52, 82.95, 21.15.
HRMS (EI): m/z [M + H]+ calcd for C15H13O2: 225.0916; found:
225.0918.
UV/Vis (EtOH): λmax = 318 nm.
Dibenzo[b,d]oxepin-7(6H)-ones 2; General Procedure
Biphenyl carboxylic acid 1 (1 mmol) was dissolved in dry TFA (5 mL)
and treated with TFAA (5 equiv). The resulting mixture was stirred at
25 °C for 24 h and then quenched with ice–H2O and extracted twice
with CHCl3. The combined organic layers were washed with H2O and
sat. Na2CO3 solution, dried over anhydrous MgSO4, and concentrated
under vacuum. Purification of the crude residue by column chroma-
tography afforded dibenzo[b,d]oxepin-7(6H)-ones 2 as white solids.
Anal. Calcd for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.35; H, 5.39.
2,9-Dimethyldibenzo[b,d]oxepin-7(6H)-one (2d)
Yield: 196 mg (82%); white solid; mp 83.7–85.1 °C; Rf = 0.35 (PE–
EtOAc, 6:1).
FT-IR (KBr): 3003, 2917, 1681, 1494, 1274, 1046, 824, 760 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 0.6 Hz, 1 H), 7.49–7.43 (m, 2
H), 7.34 (d, J = 1.7 Hz, 1 H), 7.16 (dd, J = 8.2, 1.8 Hz, 1 H), 7.09 (d, J = 8.1
Hz, 1 H), 4.78 (s, 2 H), 2.44 (s, 3 H), 2.39 (s, 3 H).
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13C NMR (101 MHz, CDCl3): δ = 204.64, 154.78, 138.17, 136.10,
135.62, 134.63, 134.60, 133.00, 130.68, 130.67, 129.98, 129.54,
121.16, 82.98, 21.18, 21.15.
HRMS (EI): m/z [M + H]+ calcd for C16H15O2: 239.1073; found:
239.1068.
9,10-Dimethoxy-2-methyldibenzo[b,d]oxepin-7(6H)-one (2h)
Yield: 245 mg (86%); white solid; mp 151.4–154.2 °C; Rf = 0.32 (PE–
EtOAc, 6:1).
FT-IR (KBr): 3015, 2924, 2851, 1674, 1462, 1267, 1024, 821, 787, 697
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 1.7 Hz, 1 H), 7.34 (s, 1 H),
7.20 (dd, J = 8.1, 1.5 Hz, 1 H), 7.14 (s, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 4.76
(s, 2 H), 3.97 (s, 3 H), 3.86 (s, 3 H), 2.38 (s, 3 H).
UV/Vis (EtOH): λmax = 321 nm.
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.63; H, 5.93.
2,10-Dimethyldibenzo[b,d]oxepin-7(6H)-one (2e)
13C NMR (101 MHz, CDCl3): δ = 202.31, 154.86, 153.56, 148.88,
135.42, 132.74, 131.97, 130.49, 130.39, 128.77, 121.10, 111.78,
111.73, 56.38, 56.26, 21.16.
HRMS (EI): m/z [M + H]+ calcd for C17H17O4: 285.1128; found:
285.1130.
Yield: 200 mg (84%); white solid; mp 51.0–53.8 °C; Rf = 0.36 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2987, 2923, 1669, 1499, 1290, 1072, 815, 760 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.69 (d, J = 7.9 Hz, 1 H), 7.49 (d,
J = 3.2 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.27–7.20 (m, 1 H), 7.12 (d,
J = 8.1 Hz, 1 H), 4.81 (s, 2 H), 2.45 (s, 3 H), 2.37 (s, 3 H).
.
UV/Vis (EtOH): λmax = 294 nm.
Anal. Calcd for C17H16O4: C, 71.82; H, 5.67. Found: C, 71.84; H, 5.66.
13C NMR (101 MHz, CDCl3): δ = 203.93, 155.02, 144.49, 137.37,
135.61, 133.85, 133.13, 130.92, 130.83, 130.18, 129.90, 129.00,
121.21, 82.92, 21.94, 21.18.
3,9,10-Trimethoxydibenzo[b,d]oxepin-7(6H)-one (2i)
Yield: 256 mg (85%); white solid; mp 206.5–207.2 °C; Rf = 0.33 (PE–
EtOAc, 6:1).
HRMS (EI): m/z [M + H]+ calcd for C16H15O2: 239.1073; found:
FT-IR (KBr): 2957, 2910, 1673, 1503, 1273, 1034, 833, 692 cm–1
.
239.1070.
1H NMR (400 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.47 (d, J = 8.8 Hz, 1 H),
6.93 (s, 1 H), 6.86 (dd, J = 8.6, 2.4 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 4.77
(s, 2 H), 4.00 (s, 3 H), 3.97 (s, 3 H), 3.86 (s, 3 H).
UV/Vis (EtOH): λmax = 310 nm.
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.66; H, 5.93.
3-Methoxydibenzo[b,d]oxepin-7(6H)-one (2f)
13C NMR (101 MHz, CDCl3): δ = 201.76, 161.13, 158.19, 153.78,
148.55, 132.24, 130.80, 128.12, 125.35, 112.39, 111.83, 111.56,
106.39, 82.23, 56.39, 56.35, 55.81.
HRMS (EI): m/z [M + H]+ calcd for C17H17O5: 301.1077; found:
301.1079.
Yield: 202 mg (84%); white solid; mp 113.4–115.7 °C; Rf = 0.38 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2997, 2926, 1678, 1438, 1281, 1038, 822, 761 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.78 (dd, J = 7.8, 1.3 Hz, 1 H), 7.74
(td, J = 7.7, 1.4 Hz, 1 H), 7.62 (d, J = 8.7 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1
H), 7.50 (td, J = 7.6, 1.1 Hz, 1 H), 6.96 (dd, J = 8.7, 2.6 Hz, 1 H), 6.84 (d,
J = 2.6 Hz, 1 H), 4.89 (s, 2 H), 3.82 (s, 3 H).
.
UV/Vis (EtOH): λmax = 247, 295 nm.
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.97; H, 5.38.
13C NMR (101 MHz, DMSO-d6): δ = 203.29, 160.89, 157.50, 136.32,
135.34, 133.77, 130.96, 129.05, 129.00, 127.39, 124.59, 112.23,
106.55, 82.32, 55.51.
HRMS (EI): m/z [M + H]+ calcd for C15H13O3: 241.0865; found:
241.0860.
2,9,10-Trimethoxydibenzo[b,d]oxepin-7(6H)-one (2j)
Yield: 252 mg (84%); white solid; mp 172.6–173.8 °C; Rf = 0.33 (PE–
EtOAc, 6:1).
FT-IR (KBr): 3007, 2923, 2845, 1667, 1498, 1207, 1029, 865, 791, 694
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.33 (s, 1 H), 7.25 (d, J = 2.9 Hz, 1 H),
7.16 (t, J = 4.4 Hz, 2 H), 6.96 (dd, J = 8.7, 3.0 Hz, 1 H), 4.75 (s, 2 H), 3.97
(s, 3 H), 3.86 (s, 3 H), 3.82 (s, 3 H).
UV/Vis (EtOH): λmax = 248 nm.
Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.97; H, 5.06.
2-Methoxydibenzo[b,d]oxepin-7(6H)-one (2g)
13C NMR (101 MHz, DMSO-d6): δ = 201.73, 156.78, 153.12, 150.00,
148.46, 133.19, 130.64, 128.14, 121.86, 115.19, 114.69, 112.19,
111.14, 82.08, 55.97, 55.63, 55.59.
HRMS (EI): m/z [M + H]+ calcd for C17H17O5: 301.1077; found:
301.1076.
Yield: 199 mg (83%); white solid; mp 91.5–94.1 °C; Rf = 0.38 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2953, 2926, 1687, 1497, 1286, 1048, 829, 770 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.78 (ddd, J = 7.4, 3.8, 1.1 Hz, 2 H),
7.71 (dd, J = 8.2, 1.2 Hz, 1 H), 7.57 (td, J = 7.6, 1.3 Hz, 1 H), 7.19 (t,
J = 5.6 Hz, 2 H), 7.00 (dd, J = 8.7, 3.1 Hz, 1 H), 4.86 (s, 2 H), 3.82 (s, 3 H).
.
UV/Vis (EtOH): λmax = 257, 291 nm.
Anal. Calcd for C17H16O5: C, 67.99; H, 5.37. Found: C, 67.98; H, 5.38.
13C NMR (101 MHz, DMSO-d6): δ = 203.91, 156.89, 149.91, 136.15,
136.06, 133.64, 133.25, 129.36, 128.84, 128.26, 122.22, 115.72,
114.60, 82.76, 55.54.
10-Chlorodibenzo[b,d]oxepin-7(6H)-one (2k)
Yield: 201 mg (82%); white solid; mp 170.1–172.0 °C; Rf = 0.40 (PE–
EtOAc, 6:1).
HRMS (EI): m/z [M + H]+ calcd for C15H13O3: 241.0865; found:
FT-IR (KBr): 2910, 1682, 1439, 1288, 1069, 815, 763 cm–1
.
241.0864.
1H NMR (400 MHz, CDCl3): δ = 7.87 (d, J = 8.4 Hz, 1 H), 7.56 (dd,
J = 10.2, 1.9 Hz, 2 H), 7.43 (ddd, J = 9.4, 8.1, 1.9 Hz, 2 H), 7.35–7.31 (m,
1 H), 7.24 (d, J = 8.0 Hz, 1 H), 4.82 (s, 2 H).
UV/Vis (EtOH): λmax = 301 nm.
Anal. Calcd for C15H12O3: C, 74.99; H, 5.03. Found: C, 74.98; H, 5.04.
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13C NMR (101 MHz, CDCl3): δ = 202.75, 157.17, 140.15, 138.88,
134.57, 132.25, 131.39, 131.18, 130.38, 129.57, 128.40, 126.41,
121.78, 82.81.
HRMS (EI): m/z [M + H]+ calcd for C14H10ClO2: 245.0370; found:
245.0375.
HRMS (EI): m/z [M + H]+ calcd for C15H12FO2: 243.0822; found:
243.0825.
UV/Vis (EtOH): λmax = 246 nm.
Anal. Calcd for C15H11FO2: C, 74.37; H, 4.58; F, 7.84;. Found: C, 74.39;
H, 4.57; F, 7.82.
UV/Vis (EtOH): λmax = 269 nm.
2-Fluorodibenzo[b,d]oxepin-7(6H)-one (2o)
Anal. Calcd for C14H9ClO2: C, 68.72; H, 3.71; Cl, 14.49. Found: C, 68.71;
H, 3.70; Cl, 14.50.
Yield: 187 mg (82%); white solid; mp 131.6–132.2 °C; Rf = 0.38 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2924, 2854, 1693, 1496, 1268, 1048, 825, 773 cm–1
.
10-Fluorodibenzo[b,d]oxepin-7(6H)-one (2l)
Yield: 183 mg (80%); white solid; mp 133.1–134.9 °C; Rf = 0.39 (PE–
EtOAc, 6:1).
1H NMR (400 MHz, DMSO-d6): δ = 7.79 (t, J = 7.3 Hz, 2 H), 7.70 (d,
J = 7.3 Hz, 1 H), 7.58 (ddd, J = 13.2, 9.1, 1.8 Hz, 2 H), 7.30 (dd, J = 7.4,
2.5 Hz, 2 H), 4.91 (s, 2 H).
FT-IR (KBr): 2937, 1685, 1491, 1263, 1043, 877, 761 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.89 (dd, J = 8.7, 6.2 Hz, 1 H), 7.75
(dd, J = 7.8, 1.6 Hz, 1 H), 7.55 (dd, J = 10.4, 2.6 Hz, 1 H), 7.50 (td, J = 7.7,
1.6 Hz, 1 H), 7.45–7.36 (m, 2 H), 7.28 (dd, J = 7.9, 1.2 Hz, 1 H), 4.91 (s,
2 H).
13C NMR (101 MHz, DMSO-d6): δ = 203.26, 159.58 (d, J = 240 Hz),
152.60, 136.04, 134.95, 134.31 (d, J = 9 Hz), 133.83, 129.63, 129.04,
128.78, 123.27 (d, J = 9 Hz), 116.85 (d, J = 23 Hz), 116.42 (d, J = 24 Hz),
82.70.
13C NMR (101 MHz, DMSO-d6): δ = 201.92, 165.10 (d, J = 250 Hz),
156.36, 139.16 (d, J = 9 Hz), 132.55, 132.52, 131.99 (d, J = 110 Hz),
131.14, 130.50, 126.15, 121.53, 116.03 (d, J = 23 Hz), 115.43 (d, J = 24
Hz), 82.26.
HRMS (EI): m/z [M + H]+ calcd for C14H10FO2: 229.0666; found:
229.0668.
HRMS (EI): m/z [M + H]+ calcd for C14H10FO2: 229.0666; found:
229.0665.
UV/Vis (EtOH): λmax = 289 nm.
Anal. Calcd for C14H9FO2: C, 73.68; H, 3.97; F, 8.32. Found: C, 73.67; H,
3.98; F, 8.33.
UV/Vis (EtOH): λmax = 267 nm.
2-Fluoro-9-methyldibenzo[b,d]oxepin-7(6H)-one (2p)
Anal. Calcd for C14H9FO2: C, 73.68; H, 3.97; F, 8.32. Found: C, 73.69; H,
3.99; F, 8.31.
Yield: 204 mg (84%); white solid; mp 121.7–123.3 °C; Rf = 0.35 (PE–
EtOAc, 6:1).
FT-IR (KBr): 3026, 2918, 1682, 1489, 1270, 1049, 824, 768 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.61 (s, 3 H), 7.54 (dd, J = 9.6, 2.2
.
10-Chloro-2-methyldibenzo[b,d]oxepin-7(6H)-one (2m)
Yield: 214 mg (83%); white solid; mp 109.8–112.2 °C; Rf = 0.40 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2923, 2854, 1685, 1498, 1292, 1045, 813, 793 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 2.0
Hz, 1 H), 7.43 (dd, J = 8.4, 2.1 Hz, 1 H), 7.35 (d, J = 1.6 Hz, 1 H), 7.21
(ddd, J = 8.1, 2.1, 0.6 Hz, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 4.78 (s, 2 H),
2.41 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 203.10, 154.98, 140.04, 139.02,
136.01, 134.65, 131.82, 131.71, 131.35, 130.73, 129.44, 128.27,
121.43, 82.86, 21.16.
Hz, 1 H), 7.31–7.24 (m, 2 H), 4.89 (s, 2 H), 2.42 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 203.21, 159.54 (d, J = 240 Hz),
152.50, 138.49, 135.76, 134.51, 134.28 (d, J = 9 Hz), 132.30, 129.66,
129.26, 123.16 (d, J = 9 Hz), 116.48 (d, J = 23 Hz), 116.19 (d, J = 24 Hz),
82.53, 20.48.
HRMS (EI): m/z [M + H]+ calcd for C15H12FO2: 243.0822; found:
243.0824.
.
UV/Vis (EtOH): λmax = 312 nm.
Anal. Calcd for C15H11FO2: C, 74.37; H, 4.58; F, 7.84. Found: C, 74.38; H,
4.56; F, 7.83.
HRMS (EI): m/z [M + H]+ calcd for C15H12ClO2: 259.0527; found:
259.0529.
2-Fluoro-9,10-dimethoxydibenzo[b,d]oxepin-7(6H)-one (2q)
UV/Vis (EtOH): λmax = 246 nm.
Yield: 246 mg (85%); white solid; mp 186.0–188.2 °C; Rf = 0.33 (PE–
Anal. Calcd for C15H11ClO2: C, 69.64; H, 4.29; Cl, 13.70. Found: C,
69.65; H, 4.28; Cl, 13.71.
EtOAc, 6:1).
FT-IR (KBr): 2976, 2923, 2850, 1665, 1497, 1247, 1027, 825, 774 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 7.67 (dd, J = 10.0, 2.7 Hz, 1 H), 7.36
(s, 1 H), 7.29–7.21 (m, 2 H), 7.17 (s, 1 H), 4.82 (s, 2 H), 3.98 (s, 3 H),
3.87 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 200.91, 159.47 (d, J = 240 Hz),
153.15, 152.54, 148.72, 134.11 (d, J = 9 Hz), 129.48, 128.04, 122.79 (d,
J = 9 Hz), 116.48 (d, J = 23 Hz), 116.06 (d, J = 24 Hz), 112.37, 111.21,
81.89, 56.00, 55.63.
10-Fluoro-2-methyldibenzo[b,d]oxepin-7(6H)-one (2n)
Yield: 196 mg (81%); white solid; mp 110.3–111.4 °C; Rf = 0.35 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2981, 2915, 1680, 1485, 1287, 1072, 872, 757 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 7.87 (dd, J = 8.7, 6.2 Hz, 1 H), 7.54
(dd, J = 10.2, 2.3 Hz, 2 H), 7.40 (td, J = 8.5, 2.6 Hz, 1 H), 7.28 (dd, J = 8.1,
1.5 Hz, 1 H), 7.15 (d, J = 8.1 Hz, 1 H), 4.85 (s, 2 H), 2.37 (s, 3 H).
.
HRMS (EI): m/z [M + H]+ calcd for C16H14FO4: 289.0877; found:
13C NMR (101 MHz, DMSO-d6): δ = 202.07, 165.07 (d, J = 250 Hz),
154.19, 139.32 (d, J = 9 Hz), 135.31, 132.31, 132.21, 131.77 (d, J = 155
Hz), 131.49, 130.75, 121.14, 115.86 (d, J = 23 Hz), 115.27 (d, J = 24 Hz),
82.22, 20.37.
289.0879.
UV/Vis (EtOH): λmax = 247, 291 nm.
Anal. Calcd for C16H13FO4: C, 66.66; H, 4.55; F, 6.59. Found: C, 66.68; H,
4.54; F, 6.58.
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9-Phenyldibenzo[b,d]oxepin-7(6H)-one (2r)
13C NMR (101 MHz, CDCl3): δ = 203.84, 156.23, 140.24, 139.31,
136.98, 136.21, 133.66, 133.51, 129.57, 129.46, 129.09, 128.97,
128.91, 128.20, 127.53, 127.09, 121.75, 82.88.
HRMS (EI): m/z [M + H]+ calcd for C20H15O2: 287.1073; found:
287.1071.
Yield: 229 mg (80%); white solid; mp 121.0–122.8 °C; Rf = 0.38 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2918, 1677, 1477, 1234, 1055, 805, 754 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.09 (dd, J = 8.2, 2.1 Hz, 1 H), 8.04
(d, J = 2.0 Hz, 1 H), 7.82–7.73 (m, 4 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.50–
7.36 (m, 3 H), 7.29 (dd, J = 7.9, 1.1 Hz, 1 H), 4.95 (s, 2 H).
.
UV/Vis (EtOH): λmax = 306 nm.
Anal. Calcd for C20H14O2: C, 83.90; H, 4.93. Found: C, 83.92; H, 4.92.
13C NMR (101 MHz, DMSO-d6): δ = 203.29, 156.44, 139.72, 138.41,
136.37, 135.08, 132.13, 131.72, 130.55, 130.25, 130.12, 129.16,
128.15, 126.83, 126.66, 126.12, 121.46, 82.48.
2-Methylbenzo[b]naphtho[2,3-d]oxepin-7(6H)-one (2v)
Yield: 217 mg (79%); white solid; mp 164.9–167.0 °C; Rf = 0.34 (PE–
EtOAc, 6:1).
HRMS (EI): m/z [M + H]+ calcd for C20H15O2: 287.1073; found:
FT-IR (KBr): 2969, 2915, 2879, 1682, 1232, 1054, 757 cm–1
.
287.1072.
1H NMR (400 MHz, DMSO-d6): δ = 8.25 (d, J = 8.6 Hz, 1 H), 8.05 (dd,
J = 9.6, 6.7 Hz, 2 H), 7.71 (d, J = 8.6 Hz, 1 H), 7.67–7.60 (m, 2 H), 7.56
(d, J = 1.6 Hz, 1 H), 7.28 (dd, J = 8.1, 1.6 Hz, 1 H), 7.19 (d, J = 8.1 Hz, 1
H), 5.07 (s, 2 H), 2.39 (s, 3 H).
13C NMR (101 MHz, DMSO-d6): δ = 206.15, 153.96, 135.46, 134.12,
133.69, 132.56, 132.31, 130.92, 130.76, 129.43, 128.19, 127.84,
126.72, 126.30, 125.63, 121.22, 86.22, 20.45.
UV/Vis (EtOH): λmax = 253, 281, 324 nm.
Anal. Calcd for C20H14O2: C, 83.90; H, 4.93. Found: C, 83.92; H, 4.92.
2-Methyl-9-phenyldibenzo[b,d]oxepin-7(6H)-one (2s)
Yield: 249 mg (83%); white solid; mp 82.4–84.7 °C; Rf = 0.33 (PE–
EtOAc, 6:1).
FT-IR (KBr): 3028, 2918, 1678, 1480, 1264, 1052, 829, 752 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 8.07 (dd, J = 8.2, 2.1 Hz, 1 H), 8.02
(d, J = 2.1 Hz, 1 H), 7.80–7.75 (m, 3 H), 7.53 (dd, J = 10.2, 4.8 Hz, 3 H),
7.44 (t, J = 7.3 Hz, 1 H), 7.27 (dd, J = 8.1, 1.6 Hz, 1 H), 7.16 (d, J = 8.1 Hz,
1 H), 4.90 (s, 2 H), 2.39 (s, 3 H).
.
HRMS (EI): m/z [M + H]+ calcd for C19H15O2: 275.1073; found:
275.1076.
UV/Vis (EtOH): λmax = 260 nm.
Anal. Calcd for C19H14O2: C, 83.19; H, 5.14. Found: C, 83.20; H, 5.15.
13C NMR (101 MHz, DMSO-d6): δ = 203.46, 154.28, 139.59, 138.43,
136.40, 135.20, 131.71, 131.59, 130.92, 130.36, 130.11, 129.12,
128.10, 126.80, 126.62, 121.09, 82.45, 20.44.
3-Methoxybenzo[b]naphtho[2,3-d]oxepin-7(6H)-one (2w)
Yield: 224 mg (77%); white solid; mp 157.1–160.8 °C; Rf = 0.34 (PE–
EtOAc, 6:1).
HRMS (EI): m/z [M + H]+ calcd for C21H17O2: 301.1229; found:
FT-IR (KBr): 2982, 2904, 1672, 1443, 1214, 1030, 802, 733 cm–1
.
301.1230.
1H NMR (400 MHz, DMSO-d6): δ = 8.21 (d, J = 8.6 Hz, 1 H), 8.08–8.00
(m, 2 H), 7.64 (ddd, J = 21.1, 13.6, 7.8 Hz, 4 H), 7.01 (dd, J = 8.6, 2.2 Hz,
1 H), 6.90 (d, J = 2.2 Hz, 1 H), 5.12 (s, 2 H), 3.84 (s, 3 H).
UV/Vis (EtOH): λmax = 284 nm.
Anal. Calcd for C21H16O2: C, 83.98; H, 5.37. Found: C, 83.97; H, 5.36.
3-Methoxy-9-phenyldibenzo[b,d]oxepin-7(6H)-one (2t)
13C NMR (101 MHz, DMSO-d6): δ = 206.14, 160.85, 157.28, 134.22,
133.06, 132.35, 132.28, 131.35, 129.68, 128.16, 127.81, 126.48,
126.32, 125.60, 124.94, 112.38, 106.96, 86.00, 55.53.
HRMS (EI): m/z [M + H]+ calcd for C19H15O3: 291.1022; found:
291.1025.
Yield: 256 mg (81%); white solid; mp 140.7–143.4 °C; Rf = 0.31 (PE–
EtOAc, 6:1).
FT-IR (KBr): 2964, 2837, 1677, 1476, 1294, 1032, 815, 770 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 2.0 Hz, 1 H), 7.87 (dd,
J = 8.1, 2.1 Hz, 1 H), 7.69–7.65 (m, 2 H), 7.55 (dd, J = 9.7, 8.6 Hz, 2 H),
7.47 (t, J = 7.5 Hz, 2 H), 7.38 (t, J = 7.4 Hz, 1 H), 6.89 (dd, J = 8.7, 2.6 Hz,
1 H), 6.79 (d, J = 2.6 Hz, 1 H), 4.86 (s, 2 H), 3.86 (s, 3 H).
.
UV/Vis (EtOH): λmax = 254, 273 nm.
Anal. Calcd for C19H14O3: C, 78.61; H, 4.86. Found: C, 78.63; H, 4.85.
13C NMR (101 MHz, CDCl3): δ = 203.51, 161.32, 158.00, 140.08,
139.42, 135.98, 135.77, 132.02, 130.84, 129.71, 128.94, 128.07,
127.87, 126.98, 125.02, 112.32, 106.42, 82.51, 55.58.
HRMS (EI): m/z [M + H]+ calcd for C21H17O3: 317.1178; found:
317.1180.
7-Phenylbenzofuran-3(2H)-ones 3; General Procedure
Biphenyl carboxylic acid 1 (1.0 mmol) was dissolved in dry CHCl3 (3.0
mL), and TfOH (30 mmol, 2.64 mL) was added slowly at 0 °C under
stirring. The resulting mixture was stirred at r.t. for 15 h, and then
quenched with ice–H2O and extracted twice with CHCl3. The com-
bined organic layers were washed with H2O and sat. Na2CO3 solution,
dried over anhydrous MgSO4, and concentrated under vacuum. Purifi-
cation of the crude residue by column chromatography afforded 7-
phenylbenzofuran-3(2H)-ones 3 as yellow solids.
UV/Vis (EtOH): λmax = 288 nm.
Anal. Calcd for C21H16O3: C, 79.73; H, 5.10. Found: C, 79.71; H, 5.11.
2-Phenyldibenzo[b,d]oxepin-7(6H)-one (2u)
Yield: 229 mg (80%); white solid; mp 132.5–134.6 °C; Rf = 0.35 (PE–
7-Phenylbenzofuran-3(2H)-one (3a)
EtOAc, 6:1).
Yield: 179 mg (85%); yellow solid; mp 89.1–92.4 °C; Rf = 0.40 (PE–
EtOAc, 5:1).
FT-IR (KBr): 3029, 1689, 1480, 1268, 1054, 774, 757 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.93 (dd, J = 7.8, 1.2 Hz, 1 H), 7.77 (d,
J = 2.2 Hz, 1 H), 7.72–7.67 (m, 1 H), 7.65–7.57 (m, 4 H), 7.49 (ddd,
J = 22.8, 10.5, 4.5 Hz, 3 H), 7.40–7.35 (m, 1 H), 7.30 (d, J = 8.3 Hz, 1 H),
4.88 (s, 2 H).
FT-IR (KBr): 2924, 2854, 1737, 1424, 1261, 1025, 993, 762, 698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.63 (m, 4 H), 7.49 (t, J = 7.5 Hz, 2
H), 7.40 (t, J = 7.4 Hz, 1 H), 7.20 (t, J = 7.6 Hz, 1 H), 4.70 (s, 2 H).
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13C NMR (101 MHz, CDCl3): δ = 200.22, 171.35, 137.20, 135.10,
FT-IR (KBr): 2922, 1726, 1480, 1258, 1191, 994, 840, 719 cm–1
.
128.90, 128.65, 128.37, 127.76, 123.24, 122.78, 122.10, 74.89.
HRMS (EI): m/z [M + H]+ calcd for C14H11O2: 211.0760; found:
211.0755.
1H NMR (400 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 1 H), 7.70 (d, J = 7.7
Hz, 1 H), 7.54–7.40 (m, 3 H), 7.20 (t, J = 7.6 Hz, 1 H), 7.10 (td, J = 8.1,
1.8 Hz, 1 H), 4.71 (s, 2 H).
UV/Vis (EtOH): λmax = 245, 341 nm.
13C NMR (101 MHz, CDCl3): δ = 199.90, 171.13, 163.13 (d, J = 244 Hz),
137.16 (d, J = 8 Hz), 137.01, 130.38 (d, J = 8 Hz), 126.39, 124.22,
123.85, 122.84, 122.27, 115.68 (d, J = 22 Hz), 115.22 (d, J = 21 Hz),
74.94.
HRMS (EI): m/z [M + H]+ calcd for C14H10FO2: 229.0666; found:
229.0664.
Anal. Calcd for C14H10O2: C, 79.98; H, 4.79. Found: C, 79.96; H, 4.80.
5-Methyl-7-phenylbenzofuran-3(2H)-one (3b)
Yield: 199 mg (89%); yellow solid; mp 145.3–148.0 °C; Rf = 0.36 (PE–
EtOAc, 5:1).
UV/Vis (EtOH): λmax = 243, 341 nm.
FT-IR (KBr): 2969, 2919, 1726, 1481, 1257, 1031, 879, 771 cm–1
.
Anal. Calcd for C14H9FO2: C, 73.68; H, 3.97; F, 8.32. Found: C, 73.66; H,
3.98; F, 8.33.
1H NMR (400 MHz, CDCl3): δ = 7.73–7.68 (m, 2 H), 7.57 (d, J = 1.7 Hz, 1
H), 7.50–7.44 (m, 3 H), 7.39 (t, J = 7.4 Hz, 1 H), 4.68 (s, 2 H), 2.42 (s, 3
H).
7-(3-Chlorophenyl)-5-methylbenzofuran-3(2H)-one (3m)
13C NMR (101 MHz, CDCl3): δ = 200.33, 169.87, 138.47, 135.22,
132.40, 128.86, 128.61, 128.28, 127.26, 122.69, 122.06, 75.15, 20.93.
HRMS (EI): m/z [M + H]+ calcd for C15H13O2: 225.0916; found:
225.0918.
Yield: 231 mg (90%); yellow solid; mp 143.9–146.7 °C; Rf = 0.35 (PE–
EtOAc, 5:1).
FT-IR (KBr): 2983, 2928, 1734, 1473, 1255, 998, 876, 772, 694 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.72 (t, J = 1.6 Hz, 1 H), 7.60 (dt, J = 7.4,
1.5 Hz, 1 H), 7.56 (d, J = 1.6 Hz, 1 H), 7.48 (d, J = 0.9 Hz, 1 H), 7.38 (tt,
J = 4.7, 3.4 Hz, 2 H), 4.69 (s, 2 H), 2.43 (s, 3 H).
.
UV/Vis (EtOH): λmax = 250, 349 nm.
Anal. Calcd for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.31; H, 5.39.
13C NMR (101 MHz, CDCl3): δ = 200.01, 169.62, 138.24, 136.97,
134.80, 132.53, 130.07, 128.66, 128.28, 126.70, 125.72, 123.38,
122.24, 75.20, 20.90.
HRMS (EI): m/z [M + H]+ calcd for C15H12ClO2: 259.0527; found:
259.0526.
7-(p-Tolyl)benzofuran-3(2H)-one (3c)
Yield: 180 mg (80%); yellow solid; mp 86.4–88.6 °C; Rf = 0.35 (PE–
EtOAc, 5:1).
FT-IR (KBr): 2987, 2922, 1728, 1455, 1293, 1057, 998, 832, 793 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.73 (dd, J = 7.4, 1.3 Hz, 1 H), 7.65 (dd,
J = 7.7, 1.3 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 2 H), 7.29 (d, J = 7.9 Hz, 2 H),
7.18 (t, J = 7.6 Hz, 1 H), 4.69 (s, 2 H), 2.41 (s, 3 H).
.
UV/Vis (EtOH): λmax = 242, 348 nm.
Anal. Calcd for C15H11ClO2: C, 69.64; H, 4.29; Cl, 13.70. Found: C,
69.63; H, 4.27; Cl, 13.72.
13C NMR (101 MHz, CDCl3): δ = 200.34, 171.40, 138.32, 136.98,
132.16, 129.61, 128.50, 127.77, 122.90, 122.74, 122.02, 74.87, 21.46.
HRMS (EI): m/z [M + H]+ calcd for C15H13O2: 225.0916; found:
225.0913.
7-(3-Fluorophenyl)-5-methylbenzofuran-3(2H)-one (3n)
Yield: 223 mg (92%); yellow solid; mp 126.4–127.7 °C; Rf = 0.33 (PE–
EtOAc, 5:1).
UV/Vis (EtOH): λmax = 253, 341 nm.
FT-IR (KBr): 2991, 2923, 1734, 1475, 1274, 1190, 998, 780 cm–1
.
Anal. Calcd for C15H12O2: C, 80.34; H, 5.39. Found: C, 80.36; H, 5.38.
1H NMR (400 MHz, CDCl3): δ = 7.57 (d, J = 1.6 Hz, 1 H), 7.46 (qd,
J = 13.7, 7.8 Hz, 4 H), 7.09 (td, J = 8.4, 2.5 Hz, 1 H), 4.69 (s, 2 H), 2.43 (s,
3 H).
7-(3-Chlorophenyl)benzofuran-3(2H)-one (3k)
Yield: 212 mg (87%); yellow solid; mp 107.8–110.6 °C; Rf = 0.38 (PE–
EtOAc, 5:1).
13C NMR (101 MHz, CDCl3): δ = 200.05, 169.64, 163.13 (d, J = 244 Hz),
138.23, 137.30 (d, J = 8 Hz), 132.51, 130.33 (d, J = 8 Hz), 125.88,
124.17 (d, J = 3 Hz), 123.33, 122.24, 115.62 (d, J = 22 Hz), 115.11 (d, J =
21 Hz), 75.18, 20.90.
HRMS (EI): m/z [M + H]+ calcd for C15H12FO2: 243.0822; found:
243.0824.
FT-IR (KBr): 2911, 1731, 1442, 1288, 1084, 990, 772, 684 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.66 (m, 3 H), 7.60 (d, J = 7.4 Hz, 1
H), 7.39 (ddd, J = 10.9, 8.1, 4.9 Hz, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 4.71 (s,
2 H).
13C NMR (101 MHz, CDCl3): δ = 199.88, 171.12, 137.03, 136.84,
134.83, 130.12, 128.73, 128.40, 126.73, 126.24, 123.90, 122.85,
122.27, 74.96.
UV/Vis (EtOH): λmax = 259, 348 nm.
Anal. Calcd for C15H11FO2: C, 74.37; H, 4.58; F, 7.84. Found: C, 74.38; H,
4.59; F, 7.83.
HRMS (EI): m/z [M + H]+ calcd for C14H10ClO2: 245.0370; found:
245.0373.
7-([1,1′-Biphenyl]-4-yl)benzofuran-3(2H)-one (3r)
UV/Vis (EtOH): λmax = 242, 339 nm.
Yield: 238 mg (83%); yellow solid; mp 184.8–187.5 °C; Rf = 0.38 (PE–
EtOAc, 5:1).
Anal. Calcd for C14H9ClO2: C, 68.72; H, 3.71; Cl, 14.49. Found: C, 68.73;
H, 3.69; Cl, 14.51.
FT-IR (KBr): 2915, 1734, 1480, 1298, 1067, 997, 764 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.78 (m, 3 H), 7.74–7.70 (m, 2 H),
7.70–7.63 (m, 3 H), 7.47 (t, J = 7.5 Hz, 2 H), 7.41–7.36 (m, 1 H), 7.22 (t,
J = 7.6 Hz, 1 H), 4.73 (s, 2 H).
7-(3-Fluorophenyl)benzofuran-3(2H)-one (3l)
Yield: 201 mg (88%); yellow solid; mp 102.1–104.7 °C; Rf = 0.35 (PE–
EtOAc, 5:1).
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13C NMR (101 MHz, CDCl3): δ = 200.18, 171.40, 141.24, 140.76,
137.01, 134.01, 129.09, 129.01, 127.78, 127.63, 127.33, 123.28,
122.85, 122.15, 74.94.
HRMS (EI): m/z [M + H]+ calcd for C20H15O2: 287.1073; found:
287.1075.
(2) (a) Bentley, W. K. In The Isoquinoline Alkaloids, Part 5, Vol. 1;
Ravindranath, B., Ed.; Harwood Academic: Bangalore, 1998, 93–
106. (b) Castedo, L.; Suau, R. In The Alkaloids, Part 6, Vol. 29;
Brossi, A., Ed.; Academic Press: Orlando, 1986, 287–324.
(3) Gijsen, H. J. M.; Berthelot, D.; Zaja, M.; Brone, B.; Geuens, I.;
Mercken, M. J. Med. Chem. 2010, 53, 7011.
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Tetrahedron 1996, 52, 11307. (b) Kithsiri Wijeratne, E. M.;
Lesliebn Gunatilaka, A. A.; Kingston, D. G. I.; Haltiwanger, R. C.;
Eggleston, D. S. Tetrahedron 1995, 51, 7877.
UV/Vis (EtOH): λmax = 269, 344 nm.
Anal. Calcd for C20H14O2: C, 83.90; H, 4.93. Found: C, 83.91; H, 4.95.
7-([1,1′-Biphenyl]-4-yl)-5-methylbenzofuran-3(2H)-one (3s)
(5) Richey, N. R.; Yu, H. Org. Process Res. Dev. 2009, 13, 315.
(6) Olivera, R.; SanMartin, R.; Churruca, F.; Domínguez, E. J. Org.
Chem. 2002, 67, 7215.
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(b) Hawkins, I.; Handy, S. T. Tetrahedron 2013, 69, 9200.
(8) (a) Hadj-esfandiari, N.; Navidpour, L.; Shadnia, H.; Amini, M.;
Samadi, N.; Faramarzid, A. M.; Shafiee, A. Bioorg. Med. Chem.
Lett. 2007, 17, 6354. (b) Charrier, C.; Clarhaut, J.; Gesson, P. J.;
Estiu, G.; Wiest, O.; Roche, J.; Bertrand, P. J. Med. Chem. 2009, 52,
3112.
Yield: 255 mg (85%); yellow solid; mp 152.8–154.4 °C; Rf = 0.34 (PE–
EtOAc, 5:1).
FT-IR (KBr): 3034, 2923, 1719, 1480, 1257, 1029, 990, 842, 769 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.5 Hz, 2 H), 7.71 (d, J = 8.5
Hz, 2 H), 7.66–7.62 (m, 3 H), 7.47 (t, J = 7.5 Hz, 3 H), 7.38 (t, J = 7.4 Hz,
1 H), 4.71 (s, 2 H), 2.44 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 200.30, 169.91, 141.11, 140.77,
138.25, 134.11, 132.46, 129.07, 128.96, 127.74, 127.58, 127.31,
126.79, 122.74, 122.11, 75.17, 20.95.
(9) (a) Bandgar, R. B.; Patil, A. S.; Korbad, L. B.; Biradar, C. S.; Nile, N.
S.; Khobragade, N. C. Eur. J. Med. Chem. 2010, 45, 3223.
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Boumendjel, A. Bioorg. Med. Chem. 2010, 18, 5724.
(c) Haudecoeur, R.; Ahmed-Belkacem, A.; Yi, W.; Fortune, A.;
Brillet, R.; Belle, C.; Nicolle, E.; Pallier, C.; Pawlotsky, M. J.;
Boumendjel, A. J. Med. Chem. 2011, 54, 5395. (d) Shin, Y. S.; Shin,
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5, 4911.
HRMS (EI): m/z [M + H]+ calcd for C21H17O2: 301.1229; found:
301.1232.
UV/Vis (EtOH): λmax = 274, 294, 343 nm.
Anal. Calcd for C21H16O2: C, 83.98; H, 5.37. Found: C, 83.96; H, 5.38.
7-(2-Chlorophenyl)-5-methylbenzofuran-3(2H)-one (3x)
Yield: 225 mg (87%); yellow solid; mp 115.2–118.0 °C; Rf = 0.36 (PE–
EtOAc, 5:1).
FT-IR (KBr): 2976, 2928, 1715, 1469, 1250, 1037, 996, 885, 764 cm–1
.
(10) (a) Moriarty, M. R.; Prakash, O.; Prakash, I. J. Chem. Soc., Chem.
Commun. 1984, 1342. (b) Fan, R.; Sun, Y.; Ye, Y. Org. Lett. 2009,
11, 5174.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.49 (m, 2 H), 7.43 (d, J = 1.1 Hz, 1
H), 7.37 (ddd, J = 9.3, 5.8, 3.0 Hz, 3 H), 4.64 (s, 2 H), 2.42 (s, 3 H).
(11) Amick, R. D. J. Heterocycl. Chem. 1975, 12, 1051.
(12) Alipour, M.; Khoobi, M.; Nadri, H.; Sakhteman, A.; Moradi, A.;
Ghandi, M.; Shafiee, A. F. A. Arch. Pharm. 2013, 346, 577.
(13) Okombi, S.; Rival, D.; Bonnet, S.; Mariotte, M. A.; Perrier, E.;
Boumendjel, A. J. Med. Chem. 2006, 49, 329.
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Manriquez, M. J.; Molins, E.; Roig, A. J. Organomet. Chem. 2005,
690, 1340.
(15) (a) Merour, Y. J.; Cossais, F. J. Heterocycl. Chem. 1991, 28, 1875.
(b) Prakash, O.; Goyal, S. Synthesis 1992, 629. (c) Khanna, S. M.;
Garg, P. C.; Kapoor, P. R. Synth. Commun. 1992, 22, 2555.
(d) Thakkar, K.; Cushman, M. J. Org. Chem. 1995, 60, 6499.
(e) Beney, C.; Mariotte, M. A.; Boumendjel, A. Heterocycles 2001,
55, 967. (f) Diedrichs, N.; Ragot, P. J.; Thede, K. Eur. J. Org. Chem.
2005, 1731.
(16) (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem. Int.
Ed. 2004, 43, 550; Angew. Chem. 2004, 116, 560. (b) Bandini, M.;
Emer, E.; Tommasi, S.; Umani-Ronchi, A. Eur. J. Org. Chem. 2006,
3527. (c) Gore, H. P. Chem. Rev. 1955, 55, 229.
13C NMR (101 MHz, CDCl3): δ = 200.13, 169.91, 140.10, 134.31,
133.74, 131.86, 131.76, 130.11, 129.81, 127.02, 125.31, 123.55,
121.60, 75.36, 20.85.
HRMS (EI): m/z [M + H]+ calcd for C15H12ClO2: 259.0527; found:
259.0532.
UV/Vis (EtOH): λmax = 343 nm.
Anal. Calcd for C15H11ClO2: C, 69.64; H, 4.29; Cl, 13.70. Found: C,
69.67; H, 4.26; Cl, 13.73.
Acknowledgment
We are grateful for financial support from the Research Project of the
Natural Science Foundation of Heilongjiang Province of China (No.
B201208).
Supporting Information
(17) (a) Carmichael, D.; Floch, L. P.; Le Goff, X. F.; Piechaczyk, O.;
Seeboth, N. Chem. Eur. J. 2010, 16, 14486. (b) Davis, C. M.;
Groshens, J. T. Synth. Commun. 2011, 41, 255. (c) Kobayashi, S.;
Iwamoto, S. Tetrahedron Lett. 1998, 39, 4697. (d) Murashige, R.;
Hayashi, Y.; Ohmori, S.; Torii, A.; Aizu, Y.; Muto, Y.; Murai, Y.;
Oda, Y.; Hashimoto, M. Tetrahedron 2011, 67, 641.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380211.
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