Synthesis and anticancer activity evaluation of benzo[6,7]oxepino[3,2-b] pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2020.131473

A cascade reaction of 3-hydroxy-2-methylpyridine 1-oxide and substituted 2-fluorobenzal-dehydes involving nucleophilic aromatic substitution (S_NAr) and Knoevenagel condensation has been developed. This reaction provided easy access to benzo[6,7]oxepino[3,2-b]pyridine 1-oxide derivatives in moderate to good yields. Subsequent reduction of these compounds provided their deoxygenated forms in good to excellent yields. Moreover, some of the synthesized compounds were found to be active against human colorectal cancer cells (HCT-116 cell lines) with IC₅₀ values in the range of 24.95–45.80 μM.

Full text of DOI:10.1016/j.tet.2020.131473

Tetrahedron 76 (2020) 131473
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and anticancer activity evaluation of benzo[6,7]oxepino[3,2-
b] pyridine derivatives
Phanida Thongaram a 1, Suparerk Borwornpinyo , Phongthon Kanjanasirirat ,
,
b
,
1
b
b
c
a, **
Kedchin Jearawuttanakul , Mesayamas Kongsema , Nutthawat Chuanopparat
Paiboon Ngernmeesri
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
Department of Biotechnology and Excellent Center for Drug Discovery, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand
Department of Zoology, Faculty of Science, Kasetsart University, Bangkok, 10900, Thailand
,
a, *
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 May 2020
Received in revised form
A cascade reaction of 3-hydroxy-2-methylpyridine 1-oxide and substituted 2-fluorobenzal-dehydes
involving nucleophilic aromatic substitution (S Ar) and Knoevenagel condensation has been developed.
N
This reaction provided easy access to benzo[6,7]oxepino[3,2-b]pyridine 1-oxide derivatives in moderate
to good yields. Subsequent reduction of these compounds provided their deoxygenated forms in good to
excellent yields. Moreover, some of the synthesized compounds were found to be active against human
22 July 2020
Accepted 3 August 2020
Available online 16 August 2020
colorectal cancer cells (HCT-116 cell lines) with IC50 values in the range of 24.95e45.80
mM.
©
2020 Elsevier Ltd. All rights reserved.
Keywords:
Anticancer
Benzo[6,7]oxepino[3,2-b]pyridine
Nucleophilic aromatic substitution
Knoevenagel condensation
1
. Introduction
catalyzed coupling reaction [6] or the Friedel-Crafts acylation [7]
can also be used to synthesize dibenzo[b,f]oxepine scaffolds. Other
methods include the Wagner-Meerwein rearrangement [8], intra-
molecular McMurry reaction [9], manganese(III)based oxidative
1,2-radical rearrangement [10], and sequential Heck reaction and
palladium-catalyzed cyclization [11].
Benzo[6,7]oxepino[3,2-b]pyridine (2) is an analog of compound
1, in which a carbon atom at the 1 position is replaced by a nitrogen.
There are only two methods available to synthesize benzo[6,7]
oxepino[3,2-b]pyridine derivatives [12]. For example, pyridines
10a‒10c were prepared in three steps from 3-bromo-6-
methoxypicolinaldehyde (8) and phosphate esters 9a‒9c (Scheme
1) [12a,12b].
These syntheses began with a Horner-Wadsworth-Emmons
(HWE) reaction (47e51% yields) followed by removal of the MOM
protecting group (75e88% yields) and finally an Ullmann coupling
reaction (31e64% yields). The other method used the intra-
molecular Friedel-Crafts alkylation-dehydration reaction to form
the seven-membered ring of a tetracyclic product, whose structure
is quite different from our target [12c].
Dibenzo[b,f]oxepine (1) (Fig. 1) is an important framework in
medicinal chemistry. It can be found in the core structure of several
bioactive natural products. For example, bauhinoxepin A (3) and
bauhinoxepin B (4) isolated from the roots of Bauhinia saccocalyx
displayed significant antimycobacterial activity [1]. Pacharin (5)
and bauhiniastatins 2e3 (6e7) isolated from the roots of Bauhinea
purpurea were found to exhibit significant growth inhibition
against several human cancer cell lines [2].
There are several methods to prepare substituted dibenzo[b,f]
oxepines. For example, the Ullmann-type coupling reaction has
been used to form biaryl ethers [3], which can subsequently un-
dergo ring-closing metathesis [3a,4] or the Friedel-Crafts acylation
to form the seven-membered ring [3b,3c,5]. The combination of
N
nucleophilic aromatic substitution reaction (S Ar) and palladium-
*
Corresponding author.
* Corresponding author.
E-mail addresses: fscinwc@ku.ac.th (N. Chuanopparat), fscipbn@ku.ac.th
*
We became interested in the synthesis of benzo[6,7]oxepino
[3,2-b]pyridine derivatives because we envisioned that they could
(
P. Ngernmeesri).
1
These authors contributed equally to this work.
be synthesized in one pot from 3-hydroxy-2-methylpyridine (11)
https://doi.org/10.1016/j.tet.2020.131473
040-4020/© 2020 Elsevier Ltd. All rights reserved.
0

2
P. Thongaram et al. / Tetrahedron 76 (2020) 131473
Table 1
Optimization of reaction conditions by varying temperature and time.a
ꢀ
Yield (%)b
15a 2a
Entry
Temp. ( C)
Time (h)
24d
1
3ac
16a
1
2
3
4
5
6
7
8
9
rt.
60
90
120
140
153
120
140
153
6
3
5
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2
d
24
10
e
8
e
e
e
e
e
18
56
60
66
51
56
46
trace
e
12
Fig. 1. Structures of dibenzo[b,f]oxepine (1), benzo[6,7]oxepino[3,2-b] pyridine (2) and
natural products containing the dibenzo[b,f]oxepine core structure.
e
4
4
4
e
e
24
24
24
36
a
Reaction conditions: 14 (0.80 mmol), 12a (1.30 mmol), Cs
2
CO
3
(2.90 mmol),
DMF (3 mL).
b
c
Isolated yields.
For entries 3 and 5e9, a small amount of compound 13a was still observed by
TLC analysis but it was not isolated.
d
Compound 14 was not completely consumed.
The reaction was terminated after compound 14 was completely consumed.
e
Scheme 1. A known method to synthesize benzo [6,7]oxepino[3,2-b] pyridine
derivatives.
reaction took place. Treatment of intermediate 13a with LHMDS in
and substituted 2-fluorobenzaldehydes 12 (Scheme 2). It has been
ꢀ
THF also resulted no reaction after 24 h (ꢁ78 C to rt). Treating
known that the methyl (‒CH
3
)
group of 2-methylpyridine
¼ 41) [14]
ꢀ
intermediate 13a with LDA or n-BuLi for 24 h (ꢁ78 C to rt) or
(
pK
a
¼ 34) [13] is more acidic than that of toluene (pK
a
t
ꢀ
heating it with BuOK in DMSO at 100 C for 1 h resulted in complex
because the C]N double bond adjacent to the methyl group can act
as an electron-withdrawing group, thus increasing the acidity of
this methyl group. Therefore, with a suitable base, we expected that
an intermolecular nucleophilic aromatic substitution reaction
would occur first to give biaryl ethers 13, which would then un-
dergo an intramolecular Knoevenagel condensation reaction to
give desired compounds 2.
mixtures of unidentified products. Surprisingly, when the reaction
ꢀ
was carried out with NaH in THF at 60 C for 18 h, the formyl group
(‒CHO) of compound 13a was reduced to the corresponding alcohol
(35% yield). The identity of this alcohol was unambiguously
4
confirmed by reducing compound 13a with NaBH .
To overcome the difficulty of cyclization, 3-hydroxy-2-methyl-
pyridine (11) was then oxidized with mCPBA to form the more
reactive 3-hydroxy-2-methylpyridine 1-oxide (14) (87% yield) [16].
The N-oxide functionality of this compound can act as an electron-
withdrawing group, thus increasing the acidity of the adjacent
methyl group, which in turn would facilitate the desired cyclization.
The reaction of N-oxide 14 with 2-fluorobenzaldehyde (12a) was
2
. Results and discussion
2 3
We previously employed Cs CO as a base in DMF at elevated
temperatures for this type of transformation when we synthesized
substituted indolo[1,2-a]quinolines [15]. Therefore, we began our
initially performed with Cs
2 3
CO as a base and DMF as a solvent
(Table 1). At room temperature, most of starting material 14 still
studies by heating a mixture of 3-hydroxy-2-methylpyridine (11),
ꢀ
remained after 24 h (entry 1). Fortunately, benzo[6,7]oxepino[3,2-
b]pyridine 1-oxide (16a) was obtained, albeit in a very low yield
2
-fluorobenzaldehyde (12a), and Cs
2
CO
3
in DMF at 120 C. After 1 h,
the corresponding biaryl ether 13a was obtained in 94% yield. Un-
fortunately, the seven-membered ring of benzo[6,7]oxepino[3,2-b]
pyridine (2a) could not be formed even when the reaction mixture
(2%). In addition, uncyclized intermediate 15a and its deoxygenated
form (13a) were also obtained in 3% and 6% yields, respectively.
ꢀ
ꢀ
When the temperature was raised to 60 C (entry 2), the yield of
6a increased to 18%, but compounds 13a, 14 and 15a were still
was heated at reflux (153 C) for 24 h. We also attempted to use a
1
two-step protocol by treating intermediate 13a with stronger bases
such as KOH or LiOH in DMF at elevated temperatures, but no
ꢀ
present after 24 h. When the reaction was performed at 90 C for
2 h (entry 3), 14 was completely consumed, and the desired
product was obtained in 56% yield. When the temperature was
1
ꢀ
ꢀ
raised to 120 C and 140 C (entries 5e6), the reaction rate was
greatly accelerated. Both of the reactions went to completion
within 4 h, and the yields of 16a were improved to 62% and 66%,
respectively. However, when the temperature was raised above
ꢀ
1
40 C, the yield dropped to 51% as shown in entry 6. The deoxy-
genation of N-heteroarene N-oxides under basic conditions at an
elevated temperature (160 C) has been reported by Bjørsvik and
Scheme 2. Proposed one-pot synthesis of benzo[6,7]oxepino[3,2-b]pyridine and its
derivatives.
ꢀ

P. Thongaram et al. / Tetrahedron 76 (2020) 131473
3
Table 2
Table 3
a
Optimization of reaction conditions by varying base and time.
Optimization of reaction conditions by varying leaving group, solvent, temperature
and time.
a
Entry
Base
Time (h)b
Yield (%)c
1
3ad
16a
Yield (%)b
ꢀ
Entry
X
Solvent
Temp. ( C)
Time (h)
2c
1e
2
3
4
5
6
7
Li
Na
CO
CO
KOH
CO
4
4
4
4
2
8
2
4
2
0
0
0
2
3
1
3a
16a
2
CO
3
20
e
e
e
e
11
0
K
2
3
20
66
30
6
73
0
1
2
3
4
5
6
7
8
F
DMF
DMF
DMF
DMF
140
140
140
140
120
140
11
8
73
6
d
Cs
2
3
Cl
Br
I
F
F
F
F
F
18
18
d
15
1
13
7
t
d
BuOK
PO
18
c
K
3
4
DMF
6
4
12
7
52
49
0
e
c
8
9
Et
3
N
DMSO
dioxane
toluene
acetonitrile
e
f
d
DBU
0
0
101
24
24
8
5
0
f
d
111
0
0
a
Reaction conditions: 14 (0.80 mmol), 12a (1.30 mmol), base (2.90 mmol), DMF
e
f
d
9
82
24
(
3 mL).
b
c
a
The reaction was terminated after compound 14 was completely consumed.
Isolated yields.
For entries 3e6, a small amount of compound 13a was still observed by TLC
3 4
Reaction conditions: 14 (0.80 mmol), 12 (1.30 mmol), K PO (2.90 mmol), sol-
vent (3 mL).
d
b
c
d
e
f
Isolated yields.
analysis but it was not isolated.
The reaction was terminated after compound 14 was completely consumed.
Compound 14 was not completely consumed.
A complex mixture of unidentified products was obtained.
Reflux temperature.
e
A complex mixture of unidentified products was obtained.
coworkers [17]. Therefore, we also attempted to repeat the re-
actions in entries 4e6 with longer reaction times to deoxygenate
ꢀ
in Table 3). Since the reactivity of the benzaldehyde in the S
reaction depends on the polar effect, replacing the fluorine atom of
-fluorobenzaldehyde (12a) with a chlorine, bromine or iodine
N
Ar
compound 16a to product 2a. The reactions performed at 120
C
ꢀ
and 140 C for 24 h still provided compounds 16a in slightly lower
yields (entries 7e8) compared to those performed for 4 h. Fortu-
nately, compound 2a was obtained when the reaction was per-
formed at reflux for 24 h (entry 9). However, the reaction yield was
low (36%) because decomposition also occurred. Therefore, we
turned our goal to first synthesize 16a since it was formed much
faster and in a much higher yield than 2a. Compound 16a would
then be reduced to 2a in a subsequent step.
2
atom gave lower yields as expected. We also tried to lower the
ꢀ
temperature to 120 C (entry 5), but the product yield decreased
quite dramatically. Then, we tried to replace DMF with DMSO,
dioxane, toluene and acetonitrile (entries 6e9). Among these sol-
vents, we found that only DMSO gave the desired product in a
moderate yield (49%). Therefore, DMF was still the best solvent for
this transformation. We also attempted to expand the scope of this
reaction by replacing the aldehyde with less electrophilic sub-
In addition to product 16a or 2a, a small amount of by-product
13a also formed in entries 3e9 as indicated by TLC analysis but we
strates: a ketone and an ester. For this purpose, a mixture of 14 and
only attempted to isolate this by-product from the reaction per-
0
ꢀ
2 -fluoroacetophenone in the presence of K
3
PO
4
in DMF was heated
formed at 120 C for 4 h (8%, entry 4). We assumed that this
ꢀ
at 140 C for 24 h (see supporting information). This reaction pro-
compound was formed from the deoxygenation of intermediate
N
ceeded very slowly and only the S Ar reaction took place to give the
15a or the reaction between compound 11, generated from the
corresponding biaryl ether N-oxide and its deoxygenated form in
deoxygenation of 14, and 12a.
0
very low yields (15% and 11%, respectively). When 2 -fluoroace-
Then, various bases were investigated in order to search for the
optimal conditions (Table 2). For this study, the solvent employed
tophenone was replaced with methyl 2-fluorobenzoate, the cor-
responding biaryl ether N-oxide and its deoxygenated form were
obtained in only trace amounts (1% and 4% yields, respectively).
Because of these disappointing results, we only focused on using
benzaldehydes as a starting material.
ꢀ
was DMF, and the temperature was selected as 140 C since it
provided the desired product with the highest yield in Table 1. We
first attempted to replace Cs
2 3 2 3 2 3 2 3
CO with Li CO , Na CO and K CO
(
entries 1e3) but Cs CO still gave the best result (entry 4). Other
2
3
t
With the optimized reaction conditions in hand, benzo[6,7]
oxepino[3,2-b]pyridine 1-oxide analogs were then synthesized
stronger bases such as KOH and BuOK gave disappointing results
ꢁ
(
entries 5 and 6, respectively) possibly because HO could act as a
t
ꢁ
from various substituted 2-fluorobenzaldehydes (Table 4). The re-
nucleophile in a competing S
N
Ar reaction and BuO was too bulky
PO (entry 7) gave
a better yield (73%) in a shorter reaction time compared to the use
ꢀ
actions were performed in DMF at 140 C in the presence of K
3
PO
4
for this transformation. Surprisingly, the use of K
3
4
as a base. As shown in entries 1e2 and 4e23, most of the reactions
gave substituted benzo[6,7]oxepino[3,2-b]pyridine 1-oxides (16a‒
16b and 16d‒16w) in moderate to good yields. In entry 3, where
2,4-difluorobenzaldehyde was employed, the desired pyridine 1-
oxide (2c) was obtained in a very low yield (2%). Our attempt to
of Cs
2
CO
¼
3
. This could be due to the fact that K
3
PO
4
(pK
(pK
a
of
of
2
ꢁ
HPO
HCO
4
12.32) is stronger base than Cs CO
a
2
3
a
ꢁ
3
¼ 10.33) [18]. Although the improvement was not significant,
K
3
PO
as the best base for further optimization. It should be noted that by-
product 13a still formed (11% yield) with the use of K PO . Organic
bases such as Et N and DBU were also employed. Unfortunately,
4 2 3 3 4
is much cheaper than Cs CO . Therefore, K PO was selected
3 4 2 3
improve the reaction yield by replacing K PO with Cs CO was
unsuccessful. The presence of an additional fluorine atom at the
para position relative to the carbonyl group lowered the reaction
yield. This was presumably because this fluorine atom could act as a
3
4
3
they only gave complex mixtures of unidentified products.
Next, we investigated the effect of leaving groups by performing
3 4
the reaction with K PO as a base and DMF as solvent (entries 1e4
leaving group in a competing S
N
Ar reaction, thus producing a biaryl
ether intermediate that could not be cyclized to a seven-membered

Table 4
a
Synthesis of substituted benzo [6,7]oxepino[3,2-b]pyridine 1-oxides.

P. Thongaram et al. / Tetrahedron 76 (2020) 131473
5
ring. However, we were unable to isolate this intermediate to
confirm our hypothesis. When benzo[6,7]oxepino[3,2-b]pyridine
of 5 ppm of the theoretically calculated value, and measurements
are given in Da. Infrared (IR) spectra were recorded on a Bruker,
EQUINOX 55 Fourier transform infrared (FT-IR) spectrometer using
KBr disc or NaCl. Melting points (m.p.) were determined using a
melting point apparatus by hot-stage microscope from Bibby Stuart
Scientific Company. All reactions were monitored by thin-layer
1
4
-oxide analogs were treated with Zn in aqueous NH Cl and THF,
the desired deoxygenated forms (2a‒2b and 2d‒2w) were obtained
in good to excellent yields (Table 5). Due to the limited amount, the
deoxygenation of 2c was not performed. It should be noted that the
nitro group (‒NO
NH ) under these reaction conditions.
Moreover, we attempted to prepare benzo [6,7]oxepino[3,2-b]
2
) of 16w was also reduced to an amino group (‒
chromatography (TLC) performed on a silica gel 60Å F
254
2
aluminum sheet. Visualization of the developed chromatogram was
performed by UV absorbance at 254 nm and 368 nm. Flash column
chromatography was performed on silica gel F60 (mesh size
pyridine 1-oxide analogs from nitrogen-containing aromatic alde-
hydes (Scheme 3). In this synthesis, 2-fluorobenzaldehyde (12a)
40e63 mm) purchased from SiliCycle Inc.
was
replaced
with
2-fluoronicotinaldehyde
(12x),
3-
All commercially available reagents were used without further
purification unless otherwise noted. All reactions were set up under
a nitrogen or an argon atmosphere and anhydrous reactions were
performed using flame-dried glassware and standard syringe/
septum techniques. Anhydrous solvents were obtained either by
fluoroisonicotinaldehyde (12y) or 3-fluoropicolinaldehyde (12z),
and the corresponding oxepinodipyridine 1-oxides (16x‒16z) were
obtained in relatively low yields (23%, 21% and 33%, respectively).
4
Reduction of 16x with Zn in aqueous NH Cl and THF provided
oxepino-dipyridine 2x in 32% yield. Surprisingly, the C]C double
bond at the 10 and 11 positions of compounds 16y and 16z were
also reduced with this reagent to give compounds 17y and 17z in
filtration through molecular sieves (CH
3 3
CN, CHCl ) or by distillation
over CaH (CH Cl CH CN, 1,4-dioxane, toluene). N,N-Dime-
2
2
2
,
3
thylformamide (DMF) and dimethyl sulfoxide (DMSO) were dried
over 3Å molecular sieve, for 3 days followed by distillation under
high vacuum and stored over in 3Å molecular sieve. Methanol
(MeOH) was distilled from magnesium under a nitrogen atmo-
sphere. Other solvents were used from commercial bottles.
6
2
9% and 39% yields, respectively (reduction of 16z also gave 2z in
5% yield). We proposed that compounds 16y and 16z were
generated via intermediates 18y and 18z, respectively, since the
nitrogen atom at the Y and Z position can stabilize a negative
charge.
All of the synthesized benzo [6,7]oxepino[3,2-b]pyridines, their
analogs and intermediates 13a were tested against breast cancer
cell lines (MCF-7 and MDA-MB-231) and colorectal cancer cell lines
4.2. Synthesis of 2-[(2-methylpyridin-3-yl)oxy]benzaldehyde (13a)
To a suspension of 3-hydroxy-2-methylpyridine (11) (500 mg,
(
HCT-116) at the Excellent Center for Drug Discovery (ECDD) (see
2 3
4.58 mmol) and Cs CO (3.00 g, 9.17 mmol) in DMF (6 mL) was
supporting information). We found that 13a, 16x and 16y could
inhibit the growth of the HCT-116 cell line with IC50 values of 24.95,
added 2-fluorobenzaldehyde (12a) (770
m
L, 7.31 mmol) under a
ꢀ
nitrogen atmosphere. The reaction mixture was stirred at 120 C for
1 h, then allowed to cool down to room temperature and diluted
with water (100 mL). The resulting mixture was extracted with
EtOAc (3 ꢂ 100 mL). The combined organic layer was dried over
4
5.80 and 45.58 mM, respectively (Table 6).
3
. Conclusion
2 4
Na SO , and the solvent was removed under reduced pressure. The
We were able to synthesize substituted benzoxepino[3,2-b]
pyridines in 2 steps from 3-hydroxy-2-methylpyridine 1-oxide. Our
successful strategy included a cascade reaction involving nucleo-
residue was purified by flash column chromatography on silica gel
(EtOAc/hexane ¼ 1:3) to afford 2-[(2-methylpyridin-3-yl)oxy]
benzaldehyde (13a) as a yellow solid (918 mg, 94% yield). R
f
¼ 0.19
ꢀ
philic aromatic substitution (S
N
Ar) and Knoevenagel condensation
(EtOAc/hexane ¼ 1:3); m.p. 68e70 C; IR (KBr) 1693, 1600,
ꢁ
1 1
to provide benzo [6,7]oxepino[3,2-b]pyridine 1-oxides and a
reduction reaction of these N-oxide derivatives to provide benzo
1477 cm ; H NMR (400 MHz, CDCl
3
)
d
10.54 (d, J ¼ 0.8 Hz, 1H),
8.36 (dd, J ¼ 4.7, 1.5 Hz, 1H), 7.94 (dd, J ¼ 7.8, 1.8 Hz, 1H), 7.50 (dd,
J ¼ 8.3, 7.3, 1.8 Hz, 1H), 7.24 (dd, J ¼ 8.1, 1.6 Hz, 1H), 7.22e7.14 (m,
[
6,7]oxepino[3,2-b]pyridines. Most of the desired products were
obtained in moderate to good overall yields. Moreover, compounds
3a, 16x and 16y were active against colorectal cancer cell lines
HCT-116) with IC50 values in the range of 24.95e45.80 M.
13
2H), 6.70 (dd, J ¼ 8.4, 1.0 Hz, 1H), 2.52 (s, 3H); C NMR (100 MHz,
1
(
CDCl
3
)
d
189.0, 159.3, 151.6, 150.5, 145.4, 136.0, 129.1, 127.0, 126.4,
þ
(M þ H)þ
m
123.6, 122.5, 117.0, 19.5; HRMS (ESI) calcd for C13
requires 214.0863, found 214.0885.
H12NO
2
4
. Experimental section
4.3. Synthesis of 3-hydroxy-2-methylpyridine 1-oxide (14)
4.1. General
To a solution of 3-hydroxy-2-methylpyridine (11) (1.00 g,
1
Proton nuclear magnetic resonance ( H NMR) spectra were
9.17 mmol) in CHCl
3
(20 mL) was added 70e75% mCPBA (2.06 g,
ꢀ
recorded on a 400 MHz spectrometer and carbon nuclear magnetic
resonance (13C NMR) spectra were recorded on a 100 MHz spec-
trometer using VARIANUNITY INOVA 400 spectrometer. Chemical
11.92 mmol) at 0 C. The resulting mixture was stirred vigorously at
room temperature for 1 h. The desired product 14 precipitated as a
white solid, which was collected by filtration and washed several
ꢀ
shifts (
relative to the solvent residual signal of CDCl
2.50 ppm) or CD OD ( 3.31 ppm). Chemical shifts (
NMR spectra are reported in parts per million relative to the center
line of CDCl 77.16 ppm), DMSO-d 39.52 ppm) or CD OD (
9.0 ppm). Multiplicities are given as the following abbreviations: s
d
) for 1H NMR spectra are reported in parts per million
times with EtOAc (998 mg, 87% yield). m.p. 182e184 C; IR (KBr)
ꢁ
1 1
3
(d
7.26 ppm), DMSO-
3391, 1570 cm
;
H NMR (400 MHz, MeOD)
d
7.92 (dd, J ¼ 6.4,
13
d
6
(d
3
d
d) for
C
0.5 Hz, 1H), 7.19 (dd, J ¼ 8.3, 6.6 Hz, 1H), 7.04 (m, 1H), 2.44 (s, 3H);
13
C NMR (100 MHz, MeOD)
d 156.0, 132.3, 124.0, 116.7, 10.6; HRMS
þ
3
(
d
6
(d
3
d
6 7 2
(ESI) calcd for C H NO
Na (M þ Na)þ requires 148.0369, found
4
148.0388.
(
(
singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd
doublet of doublets), and br (broad). Coupling constants (J) are
4.4. General procedure for the synthesis of substituted benzo [6,7]
reported in hertz (Hz). High-resolution mass spectra (HRMS) were
recorded on a Bruker, micro-TOPQIII spectrometer using an elec-
trospray ionization mode (ESI) or an atomic pressure chemical
ionization (APCI). HRMS data were given in m/z within a tolerance
oxepino[3,2-b]pyridine 1-oxides (16a‒16w)
To a suspension of 3-hydroxy-2-methylpyridine 1-oxide (14)
(200 mg, 1.60 mmol) and K PO (1.22 g, 5.76 mmol) in DMF (4 mL)
3 4

6
P. Thongaram et al. / Tetrahedron 76 (2020) 131473
Table 5
a
Reduction of substituted benzo[6,7]oxepino[3,2-b]pyridine 1-oxides.
Table 6
a,b
Evaluation of anticancer activity in human colorectal cancer cells (HCT-116).
Entry
1
Compound
IC50 (mM)
2
3
Scheme 3. Synthesis of benzo [6,7]oxepino[3,2-b]pyridine 1-oxide analogs and their
deoxygenated forms using nitrogen-containing aromatic aldehydes.
was added substituted 2-fluorobenzaldehyde (12a‒12w)
(
2.56 mmol) under a nitrogen atmosphere. The reaction mixture
ꢀ
a
was stirred at 140 C until 14 was completely consumed (monitored
by TLC). The reaction mixture was then allowed to cool down to
room temperature and diluted with water (100 mL). The resulting
mixture was extracted with EtOAc (3 ꢂ 100 mL). The combined
DMSO was used as vehicle in the test of all compounds.
Doxorubicin was used as a positive control (IC50 ¼ 6.65
b
mM).
(
16a‒16w): R
f
(16a‒16w) z 0.15 (EtOAc/hexane ¼ 3:1).
2 4
organic layer was dried over Na SO , and the solvent was removed
Benzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16a): The reaction
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (EtOAc/hexane ¼ 3:1) to afford the
desired substituted benzo [6,7]oxepino [3,2-b]pyridine 1-oxide
was completed in 2 h, and the desired product was obtained as a
light yellow solid (247 mg, 73% yield). m.p. 182e184 C; IR (KBr)
ꢀ

P. Thongaram et al. / Tetrahedron 76 (2020) 131473
7
ꢁ
ꢀ
as a brown solid (212 mg, 54% yield). m.p. 243e245 C; IR (KBr)
3
d
073, 1597, 1481, 1425, 1249, 1190 cm 1; 1H NMR (400 MHz, CDCl
3
)
ꢁ1 1
8.16 (dd, J ¼ 5.0, 2.7 Hz, 1H), 7.41e7.31 (m, 2H), 7.23 (dd, J ¼ 7.6,
3077, 1596, 1473, 1429, 1282, 1187 cm ; H NMR (400 MHz, CDCl
3
)
2
.2 Hz, 1H), 7.20 (dd, J ¼ 7.0, 1.2 Hz, 1H), 7.18e7.13 (m, 3H), 7.05 (d,
d
8.13 (dd, J ¼ 6.5, 1.0 Hz, 1H), 7.45e7.32 (m, 3H), 7.19 (dd, J ¼ 8.4,
13
13
J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
)
d
156.6, 156.4, 136.6,
6.6 Hz, 1H), 7.17e7.08 (m, 2H), 7.04 (d, J ¼ 11.8 Hz, 1H); C NMR
(100 MHz, CDCl 155.9, 151.3, 142.5, 137.0, 134.0, 131.7, 131.3,
128.2, 127.0, 126.5, 124.6, 122.1, 119.9; HRMS (ESI) calcd for
1
35.2, 131.2, 130.0, 129.7, 126.2, 124.3, 121.2, 121.0, 119.9; HRMS (ESI)
3
) d
þ
calcd for C13
34.0537.
H
9
NO
2
Na (M þ Na)þ requires 234.0525, found
þ
þ
2
C
13
H
8
ClNO
2
Na (M þ Na) requires 268.0136, found 268.0145.
3
-(2-formylphenoxy)-2-methylpyridine 1-oxide (15a): When 2-
fluorobenzaldehyde (12a) was employed, a by-product 15a was
7-Chlorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16g): The
reaction was completed in 2 h, and the desired product was ob-
ꢀ
also isolated as a light yellow solid. R
f
¼ 0.08 (EtOAc: hexane ¼ 3:1);
tained as a brown solid (216 mg, 55% yield). m.p. 218e220 C; IR
ꢀ
ꢁ1 1
m.p. 129e131 C; IR (KBr) 2852, 1694, 1601, 1478, 1276, 1211, 1075,
(KBr) 3079, 1595, 1480, 1432, 1288, 1195 cm ; H NMR (400 MHz,
CDCl
8.11 (d, J ¼ 6.3 Hz, 1H), 7.35 (d, J ¼ 11.8 Hz, 1H), 7.21e7.14
(m, 4H), 7.11 (t, J ¼ 9.0 Hz, 1H), 6.97 (d, J ¼ 11.8 Hz, 1H); C NMR
(100 MHz, CDCl 156.1, 142.6, 136.9, 136.5, 133.6, 130.6, 128.5,
126.5, 124.5, 122.0, 121.7, 118.9; HRMS (ESI) calcd for C13 Cl
ꢁ1
1
7
90 cm
J ¼ 6.3 Hz, 1H), 8.02 (dd, J ¼ 7.7, 1.8 Hz, 1H), 7.68 (td, J ¼ 8.4, 8.0,
.8 Hz, 1H), 7.43 (t, J ¼ 7.6 Hz, 1H), 7.33e7.29 (m, 1H), 7.04 (d,
;
H NMR (400 MHz, CDCl
3
)
d
10.34 (s, 1H), 8.52 (d,
3
) d
13
1
3
) d
13
J ¼ 8.5 Hz, 1H), 7.00 (d, J ¼ 8.2 Hz, 1H), 2.74 (s, 3H); C NMR
H
8
þ
þ
(
100 MHz, CDCl
3
)
d
188.1,156.1,154.1,136.3,135.4,131.1,127.2,125.9,
NO
2
Na (M þ Na) requires 268.0136, found 268.0148.
þ
1
(
22.9, 119.5, 119.4, 11.6; HRMS (ESI) calcd for C13
H11N NaO
3
8-Chlorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16h): The
þ
M þ Na) requires 252.0631, found 252.0646.
reaction was completed in 2 h, and the desired product was ob-
ꢀ
6
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16b): The
tained as a brown solid (260 mg, 66% yield). m.p. 180e182 C; IR
ꢁ
1 1
reaction was completed in 4 h, and the desired product was ob-
tained as a light brown solid (198 mg, 54% yield). m.p. 213e215 C;
(KBr) 3084, 1598, 1477, 1432, 1254, 1190 cm ; H NMR (400 MHz,
CDCl
ꢀ
3
)
d
8.11 (dd, J ¼ 6.4, 1.0 Hz, 1H), 7.38 (d, J ¼ 11.9 Hz, 1H), 7.29
ꢁ1
1
IR (KBr) 3079, 1580, 1468, 1430, 1287, 1190 cm
;
H NMR
8.22 (dd, J ¼ 6.4, 1.2 Hz, 1H), 7.40 (d, J ¼ 11.9 Hz,
H), 7.33e7.28 (m, 1H), 7.24 (dd, J ¼ 8.5, 6.4 Hz, 1H), 7.20e7.11 (m,
(dd, J ¼ 8.6, 2.6 Hz, 1H), 7.19 (d, J ¼ 2.4 Hz, 1H), 7.18e7.14 (m, 1H),
7.10 (d, J ¼ 8.2 Hz, 1H), 7.09 (d, J ¼ 8.6 Hz, 1H), 6.93 (d, J ¼ 11.8 Hz,
(
400 MHz, CDCl
3
) d
13
1
2
3
1H); C NMR (100 MHz, CDCl ) d 156.4, 155.1, 142.5, 136.8, 133.3,
13
H), 7.08 (dd, J ¼ 11.9, 1.2 Hz, 1H), 7.00 (dt, J ¼ 7.4, 1.7 Hz, 1H);
C
131.5, 131.3, 130.8, 129.5, 124.7, 122.6, 118.8; HRMS (ESI) calcd for
þ
þ
NMR (100 MHz, CDCl
3
)
d
155.9 (d, J ¼ 82.1 Hz), 153.0, 143.6 (d,
C
13
H
8
ClNO
2
Na (M þ Na) requires 268.0136, found 268.0131.
J ¼ 12.8 Hz), 142.6, 137.0, 133.9 (d, J ¼ 3.3 Hz), 132.3, 126.3 (d,
9-Chlorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16i): The re-
J ¼ 7.7 Hz), 124.7 (d, J ¼ 3.6 Hz), 124.6, 122.1 (d, J ¼ 0.6 Hz), 119.4,
action was completed in 2 h, and the desired product was obtained
þ
ꢀ
1
(
17.9 (d, J ¼ 19.0 Hz); HRMS (ESI) calcd for C13
H
8
2
FNO Na
as a white solid (244 mg, 62% yield). m.p. 199e201 C; IR (KBr)
þ
ꢁ1 1
M þ Na) requires 252.0431, found 252.0461.
3056, 1593, 1480, 1424, 1260, 1184 cm ; H NMR (400 MHz, CDCl
8.13 (d, J ¼ 6.2 Hz, 1H), 7.43 (d, J ¼ 12.0 Hz, 1H), 7.36 (d, J ¼ 12.0 Hz,
1H), 7.30e7.24 (m, 2H), 7.19 (dd, J ¼ 8.3, 6.5 Hz, 1H), 7.15e7.08 (m,
3
)
7
-Fluorobenzo[6,7oxepino[3,2-b]pyridine 1-oxide (16c): The re-
d
action was completed in 4 h, and the desired product was obtained
as a white solid (5 mg, 2% yield). Since the desired product was
obtained in a very small amount, C NMR data could not be ob-
13
2H); C NMR (100 MHz, CDCl
3
) d 158.1, 156.6, 142.5, 136.9, 134.3,
13
131.4, 131.1, 128.3, 127.4, 124.7, 122.5, 120.0, 118.8; HRMS (ESI) calcd
ꢁ
1
1
þ
þ
tained. IR (KBr) 3068, 1611, 1501, 1428, 1261, 1099 cm
;
H NMR
8.13 (dd, J ¼ 6.4, 0.9 Hz, 1H), 7.32 (d, J ¼ 11.9 Hz,
H), 7.24e7.13 (m, 1H), 7.18e7.15 (m, 1H), 7.11 (d, J ¼ 8.3 Hz, 1H),
.99 (d, J ¼ 11.8 Hz, 1H), 6.96e6.88 (m, 2H); HRMS (ESI) calcd for
for C13
H
8
Cl NO
2
Na (M þ Na) requires 268.0136, found 268.0128.
(
400 MHz, CDCl
3
)
d
6-Bromobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16j): The re-
1
6
C
action was completed in 2 h, and the desired product was obtained
ꢀ
as a white solid (292 mg, 63% yield). m.p. 239e241 C; IR (KBr)
þ
þ
ꢁ1 1
H
13 8
FNO
2
Na (M þ Na) requires 252.0431, found 252.0436.
3076, 1595, 1473, 1433, 1280, 1186 cm ; H NMR (400 MHz, CDCl
8.11 (d, J ¼ 6.3 Hz, 1H), 7.58 (dd, J ¼ 7.9, 1.3 Hz, 1H), 7.44e7.38 (m,
2H), 7.22e7.14 (m, 2H), 7.07 (d, J ¼ 7.8 Hz, 1H), 7.02 (d, J ¼ 12.6 Hz,
3
)
8
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16d): The
d
reaction was completed in 3 h, and the desired product was ob-
tained as a slightly brown solid (155 mg, 46% yield). m.p.
13
1H); C NMR (100 MHz, CDCl
3
) d 155.9, 152.4, 142.4, 136.9, 134.3,
ꢀ
ꢁ1 1
2
26e228 C; IR (KBr) 3069, 1580, 1480, 1432, 1255, 1189 cm ; H
NMR (400 MHz, CDCl
8.22 (dd, J ¼ 6.0, 1.7 Hz, 1H), 7.39 (d,
J ¼ 11.8 Hz, 1H), 7.25e7.18 (m, 2H), 7.14 (dd, J ¼ 8.9, 4.7 Hz, 1H), 7.05
dd, J ¼ 8.9, 7.6, 3.0 Hz, 1H), 7.00 (d, J ¼ 11.8 Hz, 1H), 6.93 (dd, J ¼ 8.5,
.0 Hz, 1H); 13C NMR (100 MHz, CDCl
160.2 (d, J ¼ 245.1 Hz),
56.6, 152.6, 142.5, 136.8, 133.6 (d, J ¼ 2.0 Hz), 131.3 (d, J ¼ 8.4 Hz),
133.9, 131.6, 129.0, 127.0, 124.5, 122.1, 119.9, 116.1; HRMS (ESI) calcd
þ
þ
3
)
d
for C13
H
8
BrNO
2
Na (M þ Na) requires 311.9631, found 311.9619.
7-Bromobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16k): The
(
3
1
1
reaction was completed in 4 h, and the desired product was ob-
ꢀ
3
)
d
tained as a brown solid (279 mg, 60% yield). m.p. 222e224 C; IR
ꢁ
1 1
(KBr) 3082, 1590, 1478, 1431, 1287, 1194 cm ; H NMR (400 MHz,
CDCl
8.08 (dd, J ¼ 6.4, 0.8 Hz, 1H), 7.39e7.30 (m, 3H), 7.15 (dd,
J ¼ 8.4, 6.5 Hz, 1H), 7.11e7.04 (m, 2H), 6.94 (d, J ¼ 11.8 Hz, 1H);
NMR (100 MHz, CDCl 156.8, 156.2, 142.6, 136.9, 133.7, 130.8,
129.4, 128.9, 124.9, 124.6, 124.3, 121.8, 118.9; HRMS (ESI) calcd for
24.7, 122.7, 122.6, 118.9, 117.5 (d, J ¼ 23.5 Hz), 116.0 (d, J ¼ 23.9 Hz);
3
) d
þ
13
HRMS (ESI) calcd for C13
found 252.0450.
H FNO
8
2
Na (M þ Na)þ requires 252.0431,
C
3
) d
9
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16e): The re-
action was completed in 2 h, and the desired product was obtained
þ
þ
C
13
H
8
BrNO
2
Na (M þ Na) requires 311.9631, found 311.9615.
ꢀ
as a white solid (125 mg, 34% yield). m.p. 254e256 C; IR (KBr)
8-Bromobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16l): The re-
ꢁ1 1
3
d
074, 1614, 1458, 1427, 1255, 1189 cm ; H NMR (400 MHz, CDCl
3
)
action was completed in 2 h, and the desired product was obtained
ꢀ
8.10 (d, J ¼ 6.3 Hz, 1H), 7.39 (d, J ¼ 12.0 Hz, 1H), 7.31 (td, J ¼ 8.3,
as a brown solid (209 mg, 45% yield). m.p. 183e185 C; IR (KBr)
ꢁ1 1
6
.3 Hz, 1H), 7.20 (d, J ¼ 11.6 Hz, 1H), 7.16 (d, J ¼ 6.4 Hz, 1H), 7.09 (d,
3086, 1597, 1476, 1431, 1255, 1190 cm ; H NMR (400 MHz, CDCl
8.09e8.03 (m, 1H), 7.41 (dd, J ¼ 8.6, 2.4 Hz,1H), 7.36 (d, J ¼ 11.8 Hz,
1H), 7.32 (d, J ¼ 2.4 Hz, 1H), 7.14 (dd, J ¼ 8.3, 6.5 Hz, 1H), 7.06 (d,
3
)
13
J ¼ 8.4 Hz, 1H), 6.97 (d, J ¼ 8.6 Hz, 1H), 6.93 (d, J ¼ 8.4 Hz, 1H);
C
d
NMR (100 MHz, CDCl
1
3
)
d
160.1 (d, J ¼ 253.7 Hz), 158.0, 156.4, 142.8,
13
36.9, 131.4 (d, J ¼ 10.3 Hz), 127.2 (d, J ¼ 6.1 Hz), 124.7, 122.4 (d,
J ¼ 8.4 Hz, 1H), 7.01 (d, J ¼ 8.6 Hz, 1H), 6.90 (d, J ¼ 11.8 Hz, 1H);
NMR (100 MHz, CDCl 156.3, 155.6, 142.4, 136.8, 133.7, 133.1,
132.4, 131.7, 124.7, 123.0, 122.7, 119.0, 118.7; HRMS (ESI) calcd for
C
J ¼ 1.4 Hz), 119.1, 119.0, 117.0 (d, J ¼ 3.5 Hz), 113.2 (d, J ¼ 21.7 Hz);
3
) d
þ
HRMS (ESI) calcd for C13
found 252.0446.
H FNO
8
2
Na (M þ Na)þ requires 252.0431,
þ
þ
C
13
H
8
BrNO Na (M þ Na) requires 311.9631, found 311.9609.
9-Bromobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16 m): The
reaction was completed in 2 h, and the desired product was
2
6
-Chlorobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16f): The re-
action was completed in 4 h, and the desired product was obtained

8
P. Thongaram et al. / Tetrahedron 76 (2020) 131473
ꢀ
obtained as a brown solid (255 mg, 55% yield). m.p. 181e183 C; IR
(
130.9, 123.9, 122.6, 119.3, 118.9, 111.8, 107.3, 55.8; HRMS (ESI) calcd
ꢁ1
1
þ
þ
KBr) 3049, 1590, 1478, 1428, 1261, 1183 cm ; H NMR (400 MHz,
CDCl
8.12 (d, J ¼ 6.2 Hz, 1H), 7.46 (dd, J ¼ 7.8, 1.3 Hz, 1H), 7.41 (d,
J ¼ 12.0 Hz, 1H), 7.36e7.27 (m, 1H), 7.24e7.10 (m, 4H); C NMR
100 MHz, CDCl 157.9, 156.6, 142.3, 136.9, 133.9, 131.4, 130.8,
for C14
H
11NO
3
Na (M þ Na) requires 264.0631, found 264.0649.
3
)
d
8-Methoxybenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16t): The
13
reaction was completed in 4 h, and the desired product was ob-
ꢀ
(
3
)
d
tained as a yellow solid (112 mg, 29% yield). m.p. 166e168 C; IR
ꢁ1 1
1
C
29.9, 124.7, 124.2, 122.5, 120.7, 118.6; HRMS (ESI) calcd for
(KBr) 3058, 1590, 1497, 1428, 1258, 1191 cm ; H NMR (400 MHz,
CDCl
8.11 (dd, J ¼ 6.1, 1.3 Hz, 1H), 7.35 (d, J ¼ 11.8 Hz, 1H),
7.20e7.04 (m, 2H), 7.08 (d, J ¼ 8.8 Hz, 1H), 6.99 (d, J ¼ 11.8 Hz, 1H),
þ
þ
H
13 8
BrNO
2
Na (M þ Na) requires 311.9631, found 311.9636.
3
) d
8
-Iodobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16n): The re-
13
action was completed in 4 h, and the desired product was obtained
6.86 (dd, J ¼ 8.8, 3.0 Hz, 1H), 6.71 (d, J ¼ 3.0 Hz, 1H), 3.78 (s, 3H);
NMR (100 MHz, CDCl 157.4, 156.8, 150.4, 142.8, 136.5, 134.9,
130.5, 124.4, 122.0, 121.6, 119.4, 116.5, 114.2, 55.9; HRMS (ESI) calcd
C
ꢀ
as a slightly brown solid (313 mg, 58% yield). m.p. 182e184 C; IR
3
) d
ꢁ
1 1
(
KBr) 3075, 1595, 1474, 1428, 1254, 1116 cm ; H NMR (400 MHz,
CDCl
8.16 (dt, J ¼ 6.4, 1.6 Hz, 1H), 7.65 (dd, J ¼ 8.5, 2.2 Hz, 1H),
.55 (d, J ¼ 2.2 Hz, 1H), 7.38 (d, J ¼ 11.8 Hz, 1H), 7.20 (dd, J ¼ 8.2, 6.4,
þ
þ
3
)
d
for C14
H
11NO
3
Na (M þ Na) requires 264.0631, found 264.0649.
7
1
9-Methoxybenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16u): The
13
.3 Hz, 1H), 7.16e7.08 (m, 1H), 6.98e6.86 (m, 2H); C NMR
reaction was completed in 6 h, and the desired product was ob-
ꢀ
(
100 MHz, CDCl 156.4, 156.3, 142.4, 139.8, 138.4, 136.8, 133.3,
31.9, 124.6, 123.2, 122.3, 119.4, 89.7; HRMS (ESI) calcd for
3
)
d
tained as a light yellow solid (224 mg, 58% yield). m.p. 236e238 C;
ꢁ
1
1
1
C
IR (KBr) 3050, 1599, 1468, 1432, 1280, 1192 cm
(400 MHz, CDCl
;
H NMR
þ
þ
H
13 8
INO
2
Na (M þ Na) requires 359.9492, found 359.9505.
3
)
d
8.06 (dd, J ¼ 6.3, 1.3 Hz, 1H), 7.35 (d, J ¼ 12.0 Hz,
6
-Methylbenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16o): The
1H), 7.32e7.27 (m, 2H), 7.11 (dd, J ¼ 8.4, 6.3 Hz,1H), 7.06 (dd, J ¼ 8.4,
reaction was completed in 6 h, and the desired product was ob-
tained as a slightly brown solid (177 mg, 49% yield). m.p.
1.0 Hz, 1H), 6.78 (d, J ¼ 8.1 Hz, 1H), 6.72 (d, J ¼ 8.3 Hz, 1H), 3.84 (s,
13
3
3H); C NMR (100 MHz, CDCl ) d 158.3, 157.8, 156.4, 136.6, 131.4,
ꢀ
ꢁ1 1
;
1
64e166 C; IR (KBr) 3077, 1594, 1477, 1430, 1281, 1185 cm
NMR (400 MHz, CDCl
8.09 (dd, J ¼ 5.5, 2.1 Hz, 1H), 7.33 (d,
J ¼ 11.8 Hz, 1H), 7.23 (dd, J ¼ 6.1, 2.9 Hz, 1H), 7.19e7.11 (m, 2H),
H
130.0, 124.1, 120.4, 119.3, 118.7, 113.4, 108.2, 56.2; HRMS (ESI) calcd
þ
þ
3
)
d
for C14
H
11NO
3
Na (M þ Na) requires 264.0631, found 264.0646.
8-(Trifluoromethyl)benzo [6,7]oxepino[3,2-b]pyridine 1-oxide
(16v): The reaction was completed in 1 h, and the desired prod-
uct was obtained as a light yellow solid (103 mg, 23% yield). m.p.
84e86 C; IR (NaCl) 3067, 2920, 1446, 1340, 1168, 1112, 906 cm
H NMR (400 MHz, CDCl
13
7
3
.10e7.00 (m, 3H), 2.46 (s, 3H); C NMR (100 MHz, CDCl ) d 156.4,
1
54.7, 143.2, 136.5, 135.2, 132.7, 130.6, 129.9, 127.7, 125.6, 124.0,
Na (M þ Na)þ
þ
ꢀ
ꢁ1
;
121.0, 118.9, 16.7; HRMS (ESI) calcd for C14
requires 248.0682, found 248.0710.
H11NO
2
1
3
)
d
8.12 (dd, J ¼ 6.3, 1.2 Hz, 1H), 7.60 (dd,
7
-Methylbenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16p): The
J ¼ 8.5, 2.2 Hz, 1H), 7.49 (d, J ¼ 2.2 Hz, 1H), 7.43 (d, J ¼ 11.9 Hz, 1H),
7.26 (d, J ¼ 8.4 Hz, 1H), 7.19 (dd, J ¼ 8.5, 6.4 Hz, 1H), 7.12 (d,
reaction was completed in 2 h, and the desired product was ob-
tained as a sticky brown amorphous (144 mg, 40% yield). m.p.
13
J ¼ 8.4 Hz, 1H), 7.01 (d, J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
)
ꢀ
ꢁ1 1
;
1
67e169 C; IR (KBr) 3047, 1597, 1476, 1428, 1256, 1191 cm
NMR (400 MHz, CDCl
8.34 (dd, J ¼ 6.3, 1.4 Hz, 1H), 7.35e7.28 (m,
H), 7.27 (s, 1H), 7.13 (d, J ¼ 7.7 Hz, 1H), 7.08 (d, J ¼ 11.8 Hz, 1H), 7.03
H
d 158.8, 156.0, 142.4, 137.0, 133.8, 130.2, 128.9, 128.6, 128.1 (q,
3
)
d
J ¼ 3.6 Hz), 127.2 (q, J ¼ 3.7 Hz), 124.9, 122.6, 122.0, 120.0; HRMS
þ
(M þ H)þ requires 280.0580, found
2
(
(ESI) calcd for C14
280.0574.
H
9
F
3
NO
2
13
dd, J ¼ 7.7, 1.6, 0.8 Hz, 1H), 6.99 (d, J ¼ 1.6 Hz, 1H), 2.36 (s, 3H);
C
NMR (100 MHz, CDCl
3
)
d
156.4,156.2,142.7,136.7,136.6,130.0,127.1,
8-Nitrobenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16w): The re-
action was completed in 1 h, and the desired product was obtained
þ
1
26.5, 124.3, 121.8, 119.3, 21.2; HRMS (ESI) calcd for C14
H
11NO
2
Na
þ
ꢀ
(
M þ Na) requires 248.0682, found 248.0685.
as a light brown solid (131 mg, 32% yield). m.p. 240e242 C; IR
ꢁ
1 1
8
-Methylbenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16q): The
(NaCl) 3061, 1519, 1474, 1344, 1287, 1187 cm ; H NMR (400 MHz,
CDCl
reaction was completed in 6 h, and the desired product was ob-
tained as a slightly brown solid (205 mg, 57% yield). m.p.
3
)
d
8.21 (dd, J ¼ 8.8, 2.8 Hz, 1H), 8.14e8.07 (m, 2H), 7.47 (d,
J ¼ 11.9 Hz, 1H), 7.29 (d, J ¼ 8.9 Hz, 1H), 7.21 (dd, J ¼ 8.5, 6.5 Hz, 1H),
ꢀ
ꢁ1
1
13
1
89e191 C; IR (KBr) 3069, 1598, 1475, 1434, 1288, 1197 cm ; H
NMR (400 MHz, CDCl
8.06 (dd, J ¼ 6.2, 1.4 Hz, 1H), 7.33 (d,
J ¼ 11.8 Hz, 1H), 7.15e7.09 (m, 2H), 7.09e7.02 (m, 2H), 7.01 (d,
7.12 (dt, J ¼ 8.5, 0.9 Hz, 1H), 7.01 (d, J ¼ 11.9 Hz, 1H); C NMR
3
)
d
3
(100 MHz, CDCl ) d 160.9, 155.7, 145.6, 142.0, 137.2, 132.4, 130.8,
126.0, 125.2, 125.0, 123.7, 122.5, 118.7; HRMS (ESI) calcd for
13
þ
(M þ H)þ requires 257.0557, found 257.0559.
J ¼ 1.8 Hz, 1H), 6.98 (d, J ¼ 11.8 Hz, 1H), 2.30 (s, 3H); C NMR
C
13
H
9
N
2
O
4
(
100 MHz, CDCl 156.6, 154.7, 142.9, 136.5, 135.8, 134.8, 131.7,
3
) d
1
C
30.3, 129.5, 124.2, 121.3, 121.0, 118.7, 20.8; HRMS (ESI) calcd for
4.5. General procedure for the synthesis of substituted benzo [6,7]
oxepino[3,2-b]pyridines (2a‒2b, 2d‒2w)
þ
þ
14
H
11NO
2
Na (M þ Na) requires 248.0682, found 248.0708.
6-Methoxybenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16r): The
reaction was completed in 4 h, and the desired product was ob-
To a solution of substituted benzo [6,7]oxepino[3,2-b]pyridine
1-oxide (50 mg, 0.24 mmol) in THF (2 mL) was added a 0.2 M so-
lution of NH Cl in water (2 mL) followed by zinc powder (46 mg,
4
ꢀ
tained as a light brown solid (251 mg, 65% yield). m.p. 160e162 C;
ꢁ
1
1
IR (KBr) 3008, 1574, 1473, 1434, 1278, 1196 cm
400 MHz, CDCl
8.11 (d, J ¼ 6.3 Hz, 1H), 7.38 (d, J ¼ 11.8 Hz, 1H),
.27 (d, J ¼ 9.7 Hz,1H), 7.17 (d, J ¼ 6.5 Hz,1H), 7.15e7.10 (m, 1H), 7.07
d, J ¼ 11.7 Hz, 1H), 6.98 (dd, J ¼ 8.2, 1.2 Hz, 1H), 6.82 (d, J ¼ 6.6 Hz,
H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl
156.4, 151.7, 144.5,
;
H NMR
(
3
)
d
0.71 mmol). The reaction mixture was stirred at room temperature
for 1 h. The resulting mixture was filtered through a Celite® pad,
and the filtrate was diluted with EtOAc (20 mL). The filtrate was
washed with water (3 ꢂ 25 mL). The organic layer was dried over
7
(
1
3
) d
1
43.0, 136.5, 134.6, 131.2, 126.1, 124.2, 121.5, 121.1, 119.4, 113.6, 56.3;
2 4
Na SO , and the solvent was removed under reduced pressure. The
þ
HRMS (ESI) calcd for C14
found 264.0644.
H11NO
3
Na (M þ Na)þ requires 264.0631,
residue was purified by flash column chromatography on silica gel
(EtOAc/hexanes ¼ 1:3) to afford the desired substituted benzo
7-Methoxybenzo [6,7]oxepino[3,2-b]pyridine 1-oxide (16s): The
[6,7]-oxepino[3,2-b]pyridine (2a‒2b, 2d‒2w):
R
f
(2a‒2b, 2d‒
reaction was completed in 4 h, and the desired product was ob-
2v) z 0.22 (EtOAc/hexane ¼ 1:3) and R
f
(2w) ¼ 0.22 (EtOAc/
ꢀ
tained as a brown solid (239 mg, 62% yield). m.p. 181e183 C; IR
hexane ¼ 1:1).
ꢁ
1 1
(
KBr) 3081, 1612, 1478, 1424, 1260, 1190 cm ; H NMR (400 MHz,
CDCl
8.09 (dd, J ¼ 6.2, 1.0 Hz, 1H), 7.23 (d, J ¼ 11.8 Hz, 1H),
.16e7.06 (m, 3H), 6.96 (d, J ¼ 11.8 Hz, 1H), 6.76e6.68 (m, 2H), 3.82
Benzo [6,7]oxepino[3,2-b]pyridine (2a): The desired product was
ꢀ
3
)
d
obtained as a white solid (42 mg, 89% yield). m.p. 67e69 C; IR (KBr)
ꢁ
1 1
7
(
3055,1579, 1484, 1438, 1182 cm ; H NMR (400 MHz, CDCl
3
) d 8.37
1
3
3
s, 3H); C NMR (100 MHz, CDCl ) d 162.6, 157.7, 155.8, 136.7, 134.9,
(dd, J ¼ 4.6, 1.4 Hz, 1H), 7.46 (dd, J ¼ 8.1, 1.4 Hz, 1H), 7.32 (dd, J ¼ 8.0,

P. Thongaram et al. / Tetrahedron 76 (2020) 131473
9
7
.2, 1.8 Hz, 1H), 7.24e7.12 (m, 4H), 6.90 (2 ꢂ s, 2 ꢂ 1H); 13C NMR
product was obtained as a white solid (51 mg, 93% yield). m.p.
ꢀ
ꢁ1 1
(
100 MHz, CDCl
3
)
d
157.3, 153.7, 150.1, 145.9, 132.9, 131.4, 130.6,
126e128 C; IR (KBr) 3062, 1588, 1556, 1439, 1244, 1183 cm ; H
NMR (400 MHz, CDCl
8.43 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.49 (dd,
J ¼ 8.1, 1.2 Hz, 1H), 7.30e7.22 (m, 4H), 7.17e7.12 (m, 1H), 7.06 (d,
130.0, 130.0, 128.9, 125.5, 124.3, 121.3; HRMS (ESI) calcd for
3
) d
þ
þ
C
13
H
10NO (M þ H) requires 196.0757, found 196.0752.
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine (2b): The desired
product was obtained as a white solid (45 mg, 90% yield). m.p.
1
3
6
J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 158.8, 153.8, 149.8,
146.4, 134.1, 132.3, 130.4, 129.3, 128.7, 128.4, 126.9, 124.5, 119.9;
HRMS (ESI) calcd for C13
ꢀ
ꢁ1
1
ClNO (M þ H)þ requires 230.0367,
þ
9
7e99 C; IR (KBr) 3062, 1578, 1472, 1443, 1268, 1192 cm
NMR (400 MHz, CDCl
8.42 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.58 (dd,
J ¼ 8.1, 1.2 Hz, 1H), 7.28 (dd, J ¼ 5.4, 2.7 Hz, 1H), 7.18e7.05 (m, 2H),
;
H
H
9
3
) d
found 230.0383.
6-Bromobenzo [6,7]oxepino[3,2-b]pyridine (2j): The desired
product was obtained as a white solid (65 mg, 99% yield). m.p.
13
7.01e6.90 (m, 3H);
C NMR (100 MHz, CDCl
3
)
d
154.6 (d,
ꢀ
ꢁ1 1
J ¼ 204.4 Hz), 153.2, 149.8, 146.3, 144.1 (d, J ¼ 12.5 Hz), 132.5, 132.2
136e138 C; IR (KBr) 3061, 1558, 1434, 1233, 1175 cm
(400 MHz, CDCl
8.42 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.81 (dd, J ¼ 8.2,
1.0 Hz, 1H), 7.58 (dd, J ¼ 7.9, 1.5 Hz, 1H), 7.31e7.25 (m, 1H), 7.18 (dd,
; H NMR
(
(
C
d, J ¼ 0.8 Hz), 131.9 (d, J ¼ 3.4 Hz), 129.2, 125.5 (d, J ¼ 7.7 Hz), 124.7
d, J ¼ 3.5 Hz), 124.5, 117.2 (d, J ¼ 19.2 Hz); HRMS (ESI) calcd for
3
) d
þ
þ
13
13
H
8
9
FNO (M þ H) requires 214.0663, found 214.0683.
J ¼ 7.7, 1.4 Hz, 1H), 7.06e6.90 (m, 3H); C NMR (100 MHz, CDCl
3
)
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine (2d): The desired
d
153.3, 152.9, 149.6, 146.4, 133.7, 132.1, 132.1, 131.8, 129.7, 129.0,
BrNO (M þ H)þ
þ
product was obtained as a white solid (49 mg, 88% yield). m.p.
126.3, 124.5, 116.1; HRMS (ESI) calcd for C13
requires 273.9862, found 273.9879.
H
9
ꢀ
ꢁ1 1
113e115 C; IR (KBr) 3057, 1581, 1491, 1417, 1249, 1191 cm
; H
NMR (400 MHz, CDCl
J ¼ 8.1, 1.2 Hz, 1H), 7.29e7.23 (m, 1H), 7.15 (dd, J ¼ 8.8, 4.8 Hz, 1H),
3
)
d
8.40 (dd, J ¼ 4.6, 1.3 Hz, 1H), 7.47 (dd,
7-Bromobenzo [6,7]oxepino[3,2-b]pyridine (2k): The desired
product was obtained as a white solid (53 mg, 81% yield). m.p.
ꢀ
ꢁ1 1
7
3
d
.01 (dd, J ¼ 7.8, 3.0 Hz,1H), 6.97 (d, J ¼ 11.4 Hz,1H), 6.91 (dd, J ¼ 8.7,
127e129 C; IR (KBr) 3034, 1587, 1480, 1442, 1229, 1181 cm ; H
NMR (400 MHz, CDCl
13
.0 Hz, 1H), 6.84 (d, J ¼ 11.6 Hz, 1H); C NMR (100 MHz, CDCl
159.9 (d, J ¼ 243.7 Hz), 153.7, 153.1 (d, J ¼ 2.6 Hz), 149.6, 146.1,
32.5,131.7 (d, J ¼ 2.0 Hz), 131.4 (d, J ¼ 8.4 Hz), 128.7, 124.6,122.4 (d,
J ¼ 8.7 Hz), 116.8 (d, J ¼ 23.4 Hz), 115.9 (d, J ¼ 23.6 Hz); HRMS (ESI)
3
)
3
)
d
8.40 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.46 (dd,
J ¼ 8.1, 1.0 Hz, 1H), 7.37 (d, J ¼ 1.9 Hz, 1H), 7.32e7.28 (m, 1H), 7.25
(dd, J ¼ 8.1, 4.7 Hz, 1H), 7.08 (d, J ¼ 8.2 Hz, 1H), 6.93 (d, J ¼ 11.6 Hz,
1
13
1H), 6.84 (d, J ¼ 11.6 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 157.4,
þ
þ
calcd for C13
-Fluorobenzo [6,7]oxepino[3,2-b]pyridine (2e): The desired
product was obtained as a white solid (49 mg, 95% yield). m.p.
H
9
FNO (M þ H) requires 214.0663, found 214.0681.
153.4,149.7,146.3,131.8,131.8,130.8,129.1,128.9,128.7,124.7,124.5,
BrNO (M þ H)þ requires
þ
9
123.6; HRMS (ESI) calcd for C13
273.9862, found 273.9875.
H
9
ꢀ
ꢁ1 1
1
(
1
28e130 C; IR (KBr) 3064, 1561, 1437, 1232, 1176 cm
400 MHz, CDCl
8.32 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.38 (dd, J ¼ 8.1,
.0 Hz, 1H), 7.23e7.13 (m, 2H), 7.03 (d, J ¼ 11.7 Hz, 1H), 6.93e6.87
;
H NMR
8-Bromobenzo [6,7]oxepino[3,2-b]pyridine (2l): The desired
product was obtained as a white solid (49 mg, 75% yield). m.p.
3
)
d
ꢀ
ꢁ1 1
147e149 C; IR (KBr) 3036, 1478, 1442, 1229, 1181 cm
(400 MHz, CDCl
; H NMR
13
(
d
m, 2H), 6.82 (dd, J ¼ 9.4, 8.4, 1.1 Hz, 1H); C NMR (100 MHz, CDCl
160.2 (d, J ¼ 252.2 Hz), 158.7 (d, J ¼ 4.7 Hz), 153.6, 149.9, 146.3,
32.2, 130.6 (d, J ¼ 10.5 Hz), 128.9, 124.9 (d, J ¼ 6.6 Hz), 124.5, 119.1
3
)
3
)
d
8.40 (dd, J ¼ 4.6, 1.3 Hz, 1H), 7.46 (dd, J ¼ 8.1,
1.0 Hz, 1H), 7.42 (dd, J ¼ 8.5, 2.4 Hz, 1H), 7.35 (d, J ¼ 2.4 Hz, 1H),
7.29e7.23 (m, 1H), 7.07 (d, J ¼ 8.5 Hz, 1H), 6.95 (d, J ¼ 11.6 Hz, 1H),
1
13
(
(
d, J ¼ 14.4 Hz), 116.8 (d, J ¼ 3.3 Hz), 112.5 (d, J ¼ 22.0 Hz); HRMS
6.82 (d, J ¼ 11.6 Hz, 1H).; C NMR (100 MHz, CDCl
3
) d 156.2, 153.6,
FNO (M þ H)þ requires 214.0663, found
þ
149.6, 146.2, 133.1, 132.7, 132.4, 131.9, 131.4, 128.8, 124.6, 123.0,
ESI) calcd for C13
H
9
BrNO (M þ H)þ requires
þ
214.0683.
118.9; HRMS (ESI) calcd for C13
273.9862, found 273.9873.
H
9
6-Chlorobenzo [6,7]oxepino[3,2-b]pyridine (2f): The desired
product was obtained as a white solid (44 mg, 79% yield). m.p.
9-Bromobenzo [6,7]oxepino[3,2-b]pyridine (2 m): The desired
product was obtained as a white solid (55 mg, 83% yield). m.p.
ꢀ
ꢁ1 1
;
1
(
0
27e129 C; IR (KBr) 3053, 1613, 1441, 1257, 1181 cm
400 MHz, CDCl
8.33 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.62 (dd, J ¼ 8.2, 1.4,
.4 Hz, 1H), 7.32 (dd, J ¼ 7.7, 1.9 Hz, 1H), 7.22e7.16 (m, 1H), 7.04 (dd,
J ¼ 7.7, 1.8 Hz, 1H), 6.99 (t, J ¼ 7.7 Hz, 1H), 6.89 (d, J ¼ 11.7 Hz, 1H),
H NMR
ꢀ
ꢁ1 1
3
)
d
129e131 C; IR (KBr) 3063, 1586, 1551, 1438, 1242, 1181 cm
NMR (400 MHz, CDCl
; H
3
)
d
8.43 (dd, J ¼ 4.7, 1.3 Hz, 1H), 7.48 (dd,
J ¼ 8.0, 1.0 Hz, 1H), 7.44 (dd, J ¼ 6.1, 3.1 Hz, 1H), 7.28 (t, J ¼ 3.1 Hz,
1H), 7.25 (s, 1H), 7.19 (s, 1H), 7.18 (d, J ¼ 3.1 Hz, 1H), 7.05 (d,
13
6
.84 (d, J ¼ 11.7 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 153.3, 151.9,
13
149.7, 146.4, 132.1, 132.0, 131.9, 130.7, 129.6, 128.2, 126.9, 125.8,
J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 158.5, 153.9, 149.6,
þ
þ
124.5; HRMS (ESI) calcd for C13
H
9
ClNO (M þ H) requires
146.4, 132.2, 131.9, 130.8, 130.2, 129.9, 128.7, 124.5, 124.2, 120.6;
BrNO (M þ H)þ requires 273.9862,
þ
2
30.0367, found 230.0386.
HRMS (ESI) calcd for C13
found 273.9881.
H
9
7-Chlorobenzo [6,7]oxepino[3,2-b]pyridine (2g): The desired
product was obtained as a white solid (51 mg, 93% yield). m.p.
8-Iodobenzo [6,7]oxepino[3,2-b]pyridine (2n): The desired
product was obtained as a white solid (55 mg, 71% yield). m.p.
ꢀ
ꢁ1 1
;
1
(
1
39e141 C; IR (KBr) 3057, 1564, 1481, 1444, 1183 cm
400 MHz, CDCl
8.38 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.44 (dd, J ¼ 8.1,
.0 Hz, 1H), 7.23 (dd, J ¼ 8.1, 4.7 Hz, 1H), 7.19 (s, 1H), 7.12 (d,
H NMR
ꢀ
ꢁ1
1
3
)
d
163e165 C; IR (KBr) 3054, 1440, 1226, 1177 cm
(400 MHz, CDCl
8.39 (dd, J ¼ 4.7, 1.5 Hz, 1H), 7.61 (dd, J ¼ 8.4,
2.2 Hz, 1H), 7.54 (d, J ¼ 2.2 Hz, 1H), 7.47 (dd, J ¼ 8.2, 1.4 Hz, 1H),
;
H NMR
3
) d
1
3
J ¼ 1.5 Hz, 2H), 6.89 (d, J ¼ 11.6 Hz, 1H), 6.83 (d, J ¼ 11.6 Hz, 1H);
C
1
3
NMR (100 MHz, CDCl 157.4, 153.4,149.7,146.3,135.8,131.8,131.7,
3
)
d
7.29e7.23 (m, 1H), 6.99e6.92 (m, 2H), 6.81 (d, J ¼ 11.6 Hz, 1H);
NMR (100 MHz, CDCl 156.9, 153.5, 145.7, 139.2, 138.4, 132.1,
131.9, 131.5, 129.1, 124.5, 123.2, 88.9; HRMS (ESI) calcd for
INO (M þ H) requires 321.9723, found 321.9719.
6-Methylbenzo [6,7]oxepino[3,2-b]pyridine (2o): The desired
product was obtained as a white solid (50 mg, 99% yield). m.p.
93e95 C; IR (KBr) 3055, 1440, 1226, 1182 cm ; H NMR (400 MHz,
CDCl
8.36 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.49 (dd, J ¼ 8.1, 1.4 Hz, 1H),
7.22e7.16 (m, 2H), 7.06e6.99 (m, 2H), 6.94e6.86 (m, 2H), 2.49 (s,
C
1
30.6, 128.9, 128.7, 125.8, 124.5, 121.9; HRMS (ESI) calcd for
3
) d
þ
þ
C
H
13 9
ClNO (M þ H) requires 230.0367, found 230.0385.
-Chlorobenzo [6,7]oxepino[3,2-b]pyridine (2h): The desired
product was obtained as a white solid (50 mg, 91% yield). m.p.
þ
þ
8
C
13
H
9
ꢀ
ꢁ1 1
127e129 C; IR (KBr) 3039, 1593, 1484, 1443, 1185 cm ; H NMR
ꢀ
ꢁ1 1
(
7
6
CDCl
1
(
400 MHz, CDCl
3
)
d
8.40 (d, J ¼ 3.7 Hz, 1H), 7.46 (d, J ¼ 8.0 Hz, 1H),
.31e7.22 (m, 2H), 7.19 (d, J ¼ 2.4 Hz, 1H), 7.12 (d, J ¼ 8.6 Hz, 1H),
3
) d
13
.95 (d, J ¼ 11.6 Hz,1H), 6.82 (d, J ¼ 11.6 Hz,1H); C NMR (100 MHz,
13
3
)
d
155.7, 153.6, 149.6, 146.2, 132.6, 131.5, 131.4, 130.7, 130.1,
3H); C NMR (100 MHz, CDCl
3
) d 155.2, 153.6, 150.5, 145.8, 133.3,
þ
29.4, 128.8, 124.6, 122.5; HRMS (ESI) calcd for C13
H
9
ClNO
132.1, 130.9, 130.4, 130.0, 128.9, 127.7, 124.9, 123.9, 16.8; HRMS (ESI)
þ
þ
þ
M þ H) requires 230.0367, found 230.0378.
calcd for C14
H
12NO (M þ H) requires 210.0913, found 210.0926.
9-Chlorobenzo [6,7]oxepino[3,2-b]pyridine (2i): The desired
7-Methylbenzo [6,7]oxepino[3,2-b]pyridine (2p): The desired

10
P. Thongaram et al. / Tetrahedron 76 (2020) 131473
þ
product was obtained as a white solid (15 mg, 30% yield). m.p.
for C14
H
9
F
3
NO (M þ H)þ requires 264.0631, found 264.0637.
ꢀ
ꢁ1
1
6
(
1
0e62 C; IR (KBr) 3057, 1610, 1501, 1443, 1184 cm
400 MHz, CDCl
8.35 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.44 (dd, J ¼ 8.1,
.2 Hz, 1H), 7.20 (dd, J ¼ 8.1, 4.7 Hz, 1H), 7.09 (d, J ¼ 7.7 Hz, 1H), 7.00
;
H NMR
Benzo [6,7]oxepino[3,2-b]pyridin-8-amine (2w): The reaction
was completed in 24 h, and the desired product was obtained as a
yellow solid (23 mg, 46% yield). m.p. 91e93 C; IR (NaCl) 3401,
3
)
d
ꢀ
1
1
3
ꢁ1
(
s, 1H), 6.96 (d, J ¼ 7.7 Hz, 1H), 6.91e6.80 (m, 2H), 2.34 (s, 3H);
C
2922, 1579, 1495, 1444, 1262, 1203, 1025 cm ; H NMR (400 MHz,
DMSO-d
NMR (100 MHz, CDCl
3
)
d
159.7,157.0,145.7,141.2,132.8,130.3,129.7,
6
)
d
8.34 (dd, J ¼ 4.6, 1.5 Hz, 1H), 7.58 (dd, J ¼ 8.1, 1.4 Hz, 1H),
1
28.8, 127.0, 126.1, 124.0, 121.7, 21.1; HRMS (ESI) calcd for
7.36 (dd, J ¼ 8.1, 4.6 Hz, 1H), 6.95 (d, J ¼ 8.5 Hz, 1H), 6.88 (d,
J ¼ 11.6 Hz,1H), 6.77 (d, J ¼ 11.6 Hz,1H), 6.56 (dd, J ¼ 8.5, 2.8 Hz,1H),
þ
þ
C
14
H
12NO (M þ H) requires 210.0913, found 210.0915.
-Methylbenzo [6,7]oxepino[3,2-b]pyridine (2q): The desired
product was obtained as a white solid (50 mg, 99% yield). m.p.
13
8
6.48 (d, J ¼ 2.7 Hz, 1H), 5.05 (s, 2H).; C NMR (100 MHz, DMSO-d
6
)
d
153.8, 149.8, 147.5, 146.7, 145.9, 133.6, 130.9, 130.0, 128.9, 125.0,
ꢀ
ꢁ1
1
þ
11 2
H N O
(M þ H)þ re-
9
(
1
3e95 C; IR (KBr) 3061, 1583, 1493, 1444, 1203 cm
400 MHz, CDCl
8.35 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.43 (dd, J ¼ 8.1,
.2 Hz, 1H), 7.19 (dd, J ¼ 8.1, 4.7 Hz, 1H), 7.10 (dd, J ¼ 8.2, 1.6 Hz, 1H),
;
H NMR
121.7, 116.0, 114.2; HRMS (ESI) calcd for C13
quires 211.0866, found 211.0875.
3
) d
7
2
.06 (d, J ¼ 8.1 Hz, 1H), 7.00 (d, J ¼ 1.6 Hz, 1H), 6.91e6.82 (m, 2H),
4.6. Synthesis of benzo [6,7]oxepino[3,2-b]pyridine analogs using
nitrogen-containing aromatic aldehydes
.29 (s, 3H); 13C NMR (100 MHz, CDCl
) d 155.1, 153.8, 150.1, 145.8,
3
1
35.0,132.9,131.3,131.1,130.3,129.6,128.7,124.2,120.9, 20.7; HRMS
12NO (M þ H)þ requires 210.0913, found
þ
4.6.1. Typical procedure for the synthesis of benzo [6,7]oxepino[3,2-
b]pyridines 1-oxide analogs (16x‒16z)
(
ESI) calcd for C14
10.0919.
H
2
6-Methoxybenzo [6,7]oxepino[3,2-b]pyridine (2r): The desired
To a suspension of 3-hydroxy-2-methylpyridine 1-oxide (14)
product was obtained as a white solid (40 mg, 74% yield). m.p.
3 4
(200 mg, 1.60 mmol) and K PO (1.22 g, 5.76 mmol) in DMF (4 mL),
nitrogen-containing aromatic aldehyde (12x‒12z) (2.56 mmol) was
ꢀ
ꢁ1 1
91e93 C; IR (KBr) 3006,1569,1469,1438,1271,1182 cm ; H NMR
(
1
3
CDCl
1
(
400 MHz, CDCl
3
)
d
8.39 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.63 (dd, J ¼ 8.1,
added under a nitrogen atmosphere. The reaction mixture was
stirred at 140 C until 14 was completely consumed (monitored by
ꢀ
.4 Hz, 1H), 7.29e7.23 (m, 1H), 7.10 (t, J ¼ 7.9 Hz, 1H), 7.01e6.93 (m,
13
H), 6.84 (dd, J ¼ 7.7, 1.5 Hz, 1H), 3.95 (s, 3H); C NMR (100 MHz,
TLC). The reaction mixture was then allowed to cool down to room
temperature and diluted with water (100 mL). The resulting
mixture was extracted with EtOAc (3 ꢂ 100 mL). The combined
3
)
d
153.6, 151.8, 150.3, 145.9, 145.2, 132.7, 131.4, 129.4, 125.3,
þ
24.2, 121.2, 113.1, 56.3, 29.8; HRMS (ESI) calcd for C14
H12NO
2
þ
M þ H) requires 226.0863, found 226.0884.
2 4
organic layer was dried over Na SO , and the solvent was removed
7-Methoxybenzo [6,7]oxepino[3,2-b]pyridine (2s): The desired
under reduced pressure. The residue was purified by flash column
chromatography on silica gel (5% MeOH in CH Cl ) to afford the
desired benzo [6,7]oxepino[3,2-b]pyridine 1-oxide analog (16x‒
16z): R z 0.22 (5% MeOH in CH Cl ).
product was obtained as a white solid (52 mg, 97% yield). m.p.
6
(
1
6
1
2
2
ꢀ
ꢁ1
1
1e63 C; IR (KBr) 3051, 1577, 1494, 1443, 1197 cm
; H NMR
400 MHz, CDCl
3
)
d
8.34 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.41 (dd, J ¼ 8.1,
f
2
2
.3 Hz, 1H), 7.18 (dd, J ¼ 8.1, 4.7 Hz, 1H), 7.10 (d, J ¼ 8.4 Hz, 1H),
Oxepino[2,3-b:6,7-b’]dipyridine 1-oxide (16x): The reaction was
completed in 4 h, and the desired product was obtained as a brown
.85e6.74 (m, 2H), 6.73 (d, J ¼ 2.5 Hz, 1H), 6.69 (dd, J ¼ 8.4, 2.5 Hz,
H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl
)
d
162.0, 158.3, 153.1,
solid (78 mg, 23% yield). m.p. 150e152 C; IR (KBr) 2984, 1480, 1427,
ꢀ
3
ꢁ1 1
1
50.3, 145.9, 132.6, 130.8, 129.0, 128.8, 123.9, 122.8, 111.2, 107.1, 55.7;
1269, 1074, 801 cm ; H NMR (400 MHz, CDCl
3
)
d
8.31 (dd, J ¼ 4.9,
þ
(M þ H)þ requires 226.0863, found
HRMS (ESI) calcd for C14
26.0881.
H12NO
2
1.9 Hz, 1H), 8.14 (dd, J ¼ 6.5, 1.2 Hz, 1H), 7.66 (dd, J ¼ 7.5, 1.9 Hz, 1H),
7.45 (d, J ¼ 11.8 Hz, 1H), 7.31 (dt, J ¼ 8.5, 0.9 Hz, 1H), 7.26e7.19 (m,
2
13
8-Methoxybenzo [6,7]oxepino[3,2-b]pyridine (2t): The desired
2H), 6.96 (d, J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 160.3,
product was obtained as a white solid (53 mg, 98% yield). m.p.
8
NMR (400 MHz, CDCl
154.9, 149.2, 141.8, 139.4, 136.8, 131.9, 124.9, 124.6, 122.7, 122.6,
ꢀ
ꢁ1
1
þ
(M þ Na)þ requires
9e91 C; IR (KBr) 3065, 1599, 1577, 1495, 1442, 1202 cm
;
H
120.0; HRMS (ESI) calcd for C12
235.0478, found 235.0472.
H
8
N
2
NaO
2
3
) d
8.36 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.44 (dd,
J ¼ 8.1, 1.1 Hz, 1H), 7.21 (dd, J ¼ 8.1, 4.7 Hz, 1H), 7.10 (d, J ¼ 8.8 Hz,
Oxepino[3,2-b:7,6-c’]dipyridine 1-oxide (16y): The reaction was
1
1
d
H), 6.91 (d, J ¼ 11.6 Hz, 1H), 6.86 (d, J ¼ 9.6 Hz, 1H), 6.84e6.81 (m,
completed in 4 h, and the desired product was obtained as a brown
13
ꢀ
H), 6.71 (d, J ¼ 3.0 Hz, 1H), 3.77 (s, 3H); C NMR (100 MHz, CDCl
3
)
solid (71 mg, 21% yield). m.p. 217e219 C; IR (KBr) 2878, 1488,
ꢁ
1 1
157.0, 154.0, 151.0, 150.0, 145.8, 132.7, 131.8, 130.6, 128.7, 124.3,
1433,1277, 1066, 787 cm ; H NMR (400 MHz, CDCl
3
)
d
8.50 (s, 1H),
þ
(M þ H)þ
1
21.9, 115.7, 114.3, 55.8; HRMS (ESI) calcd for C14
H12NO
2
8.45 (d, J ¼ 4.9 Hz, 1H), 8.11 (dd, J ¼ 6.4, 1.2 Hz, 1H), 7.57 (d,
requires 226.0863, found 226.0881.
J ¼ 11.8 Hz, 1H), 7.22 (dd, J ¼ 8.5, 6.4 Hz, 1H), 7.20e7.12 (m, 2H), 6.96
1
3
9-Methoxybenzo [6,7]oxepino[3,2-b]pyridine (2u): The desired
(d, J ¼ 11.8 Hz, 1H); C NMR (100 MHz, CDCl
3
) d 157.0, 152.7, 146.8,
product was obtained as a white solid (52 mg, 97% yield). m.p.
142.6, 137.3, 136.9, 131.5, 126.3, 125.6, 123.1, 118.4; HRMS (ESI) calcd
ꢀ
ꢁ1
1
þ
þ
1
27e129 C; IR (KBr) 3053, 1603, 1469, 1444, 1271 cm ; H NMR
400 MHz, CDCl
8.38 (dd, J ¼ 4.7, 1.3 Hz, 1H), 7.46 (dd, J ¼ 8.1,
.3 Hz, 1H), 7.32e7.23 (m, 2H), 7.22 (dd, J ¼ 8.1, 4.7 Hz, 1H), 6.94 (d,
J ¼ 11.8 Hz, 1H), 6.84 (d, J ¼ 8.2 Hz, 1H), 6.71 (d, J ¼ 8.3 Hz, 1H), 3.86
for C12
H
8
N
2
NaO
2
(M þ Na) requires 235.0478, found 235.0477.
(
1
3
)
d
Oxepino[3,2-b:6,7-b’]dipyridine 1-oxide (16z): The reaction was
completed in 4 h, and the desired product was obtained as a brown
ꢀ
solid (112 mg, 33% yield). m.p. 227e229 C; IR (KBr) 2981, 1477,
13
ꢁ1 1
(
s, 3H); C NMR (100 MHz, CDCl
3
)
d
159.0, 157.7, 153.6, 150.7, 145.9,
3
1424, 1288, 1027, 780 cm ; H NMR (400 MHz, CDCl ) d 8.45 (dd,
1
30.7, 130.2, 128.8, 127.6, 124.0, 119.3, 113.5, 107.6, 56.1; HRMS (ESI)
J ¼ 4.7, 1.4 Hz, 1H), 8.09 (dd, J ¼ 6.4, 1.2 Hz, 1H), 7.58 (d, J ¼ 12.1 Hz,
þ
þ
calcd for C14
H
12NO
2
(M þ H) requires 226.0863, found 226.0882.
1H), 7.48 (dd, J ¼ 8.2, 1.4 Hz, 1H), 7.30 (dd, J ¼ 8.2, 4.7 Hz, 1H),
13
8
-(Trifluoromethyl)benzo [6,7]oxepino[3,2-b]pyridine (2v): The
7.23e7.13 (m, 2H), 7.10 (dt, J ¼ 8.4, 0.9 Hz, 1H); C NMR (100 MHz,
reaction was completed in 24 h, and the desired product was ob-
tained as a brown solid (25 mg, 39% yield). m.p. 140e142 C; IR
CDCl
3
)
d
156.3, 153.1, 148.9, 146.8, 142.1, 136.9, 135.1, 128.9, 125.1,
ꢀ
þ
(M þ Na)þ
124.7, 123.8, 118.1; HRMS (ESI) calcd for C12
requires 235.0478, found 235.0486.
H
8
N
2
NaO
2
ꢁ1
1
(
(
2
NaCl) 3078, 2926, 1478, 1421, 1333, 1189, 1119 cm
400 MHz, CDCl
8.41 (dd, J ¼ 4.7, 1.4 Hz, 1H), 7.58 (dd, J ¼ 8.4,
.3 Hz, 1H), 7.53e7.48 (m, 2H), 7.32e7.27 (m, 2H), 7.02 (d,
;
H NMR
3
) d
4.6.2. Typical procedure for the synthesis of benzo [6,7]oxepino
[3,2-b]pyridine analogs
To a solution of benzo [6,7]oxepino[3,2-b]pyridine 1-oxide
analog (16x‒16z) in THF (2 mL) was added a 0.2 M solution of
13
J ¼ 11.6 Hz, 1H), 6.91 (d, J ¼ 11.7 Hz, 1H); C NMR (100 MHz, CDCl
159.4, 153.3, 149.1, 145.8, 132.3, 131.8, 130.3, 129.2, 128.2, 127.4 (q,
J ¼ 3.6 Hz), 127.1 (q, J ¼ 3.7 Hz), 124.7, 121.8, 100.0; HRMS (ESI) calcd
3
)
d

P. Thongaram et al. / Tetrahedron 76 (2020) 131473
11
NH
4
Cl in water (2 mL) followed by zinc powder (46 mg, 0.71 mmol).
free media containing MTT into the same well and then addi-
ꢀ
The reaction mixture was stirred at room temperature for 1 h. The
resulting mixture was filtered through a Celite® pad, and the
filtrate was diluted with EtOAc (20 mL). The filtrate was washed
tional incubation for 3 h at 37 C, 5% CO
2
. After 3 h incubation, the
serum-free media containing MTT was removed out and added
DMSO into the same well and then measurement of MTT absor-
bance at 570 nm by Multi-Mode Microplate Reader (ENVISION).
with water (3 ꢂ 25 mL). The organic layer was dried over Na
2 4
SO ,
and the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography on silica gel (100%
EtOAc) to afford the deoxygenated product.
Declaration of competing interest
Oxepino[2,3-b:6,7-b’]dipyridine (2x): The desired product was
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
obtained as a white solid (11 mg, 32% yield). R
f
¼ 0.56 (100% EtOAc);
ꢀ
ꢁ1
1
m.p. 135e138 C; IR (KBr) 2976,1424, 1248, 1181, 811 cm ; H NMR
(
1
7
400 MHz, CDCl
.9 Hz, 1H), 7.75 (dd, J ¼ 8.2, 1.4 Hz, 1H), 7.64 (dd, J ¼ 7.5, 2.0 Hz, 1H),
.38 (dd, J ¼ 8.2, 4.8 Hz, 1H), 7.21 (dd, J ¼ 7.5, 4.8 Hz, 1H), 7.08 (d,
3
)
d
8.43 (dd, J ¼ 4.8, 1.4 Hz, 1H), 8.30 (dd, J ¼ 4.8,
Acknowledgements
1
3
J ¼ 11.6 Hz, 1H), 6.88 (d, J ¼ 11.6 Hz, 1H); C NMR (100 MHz, CDCl
3
)
Financial support was provided by the Thailand Research Fund
(DBG5480018), the Royal Golden Jubilee Advanced Program
(RAP61K0005) under the Thailand Research Fund, the Science
Achievement Scholarship of Thailand (SAST), the Center of Excel-
lence for Innovation in Chemistry (PERCH-CIC), Ministry of Higher
Education, Science, Research and Innovation, the Department of
Chemistry, and the Faculty of Science, Kasetsart University.
d
161.0, 152.1, 148.7, 148.5, 146.3, 139.2, 132.6, 130.2, 129.8, 124.9,
þ
9 2
H N O
(M þ H)þ requires
1
1
24.6, 122.0; HRMS (ESI) calcd for C12
97.0709, found 197.0696.
1
0,11-Dihydrooxepino[3,2-b:7,6-c’]dipyridine (17y): The product
was obtained as a light brown oil (33 mg, 69% yield). R
¼ 0.31 (100%
EtOAc); IR (NaCl) 3054,1602, 1549, 1447, 1275, 1101, 807, 735 cm
f
ꢁ1
;
1
H NMR (400 MHz, CDCl
3
)
d
8.51 (s, 1H), 8.33 (dd, J ¼ 4.7, 1.5 Hz,1H),
8
4
2
.29 (d, J ¼ 4.9 Hz, 1H), 7.56 (dd, J ¼ 8.2, 1.5 Hz, 1H), 7.22 (dd, J ¼ 8.2,
Appendix A. Supplementary data
.7 Hz,1H), 7.15 (d, J ¼ 4.9 Hz,1H), 3.45e3.39 (m, 2H), 3.26e3.17 (m,
13
H); C NMR (100 MHz, CDCl
3
)
d
153.3, 153.0, 151.4, 145.0, 144.8,
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131473.
1
C
42.8, 139.7, 128.6, 124.8, 122.8, 33.7, 29.2; HRMS (ESI) calcd for
H
Oxepino[3,2-b:6,7-b’]dipyridine (2z): The desired product was
þ
þ
12
11
N
2
O
(M þ H) requires 199.0866, found 199.0850.
References
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f
¼ 0.42 (100% EtOAc);
ꢀ
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1
1
Chim. Acta 87 (2004) 175e179.
8
7
(
(
12 cm ; H NMR (400 MHz, CDCl
3
)
d
8.43 (dd, J ¼ 4.6, 1.5 Hz, 2H),
13
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ESI) calcd for C12
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)
d
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1
1
3
1
1
f
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ꢁ1 1
180, 1094, 806 cm ; H NMR (400 MHz, CDCl
3
)
d
8.32 (dd, J ¼ 4.7,
[
[
.5 Hz, 2H), 7.49 (dd, J ¼ 8.1, 1.5 Hz, 2H), 7.17 (dd, J ¼ 8.2, 4.7 Hz, 2H),
.41 (s, 4H); 13C NMR (100 MHz, CDCl
22.7, 32.8; HRMS (ESI) calcd for C12
)
d
153.0, 151.8, 144.7, 128.6,
3
2
039e2046.
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þ
H
11
N
2
O
(M þ H) requires
[
99.0866, found 199.0876.
1
[
4
.7. Evaluation of anticancer activity at the Excellent Center for
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ꢀ
2
incubated at 37 C and 5% CO for 24 h. After 24 h incubation, the
[
[
[
[
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M (For Primary screening) and additional incu-
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. After 24 h incubation, the culture
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media containing compound was removed out and added serum-