Synthesis of pyrido[2,3-b][1,4]benzoxazepines via a Friedel-Crafts cyclization

Article abstract of DOI:10.1007/s10593-016-1883-x

(Formula Presented.) An efficient and practical method has been developed for the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]benzoxazepines via a Friedel-Crafts reaction of readily accessible 2-phenoxypyridin-3-amines and aromatic acids.

Full text of DOI:10.1007/s10593-016-1883-x

DOI 10.1007/s10593-016-1883-x
Chemistry of Heterocyclic Compounds 2016, 52(5), 326–330
Synthesis of pyrido[2,3-b][1,4]benzoxazepines
via a Friedel−Crafts cyclization
1
1
1
1
1
Sigen Guo , Xinran Zhong , Bowen Gong , Hongming Cui , Jinbao Xiang *
1
Center for Combinatorial Chemistry and Drug Discovery,
School of Pharmaceutical Sciences Jilin University,
1
266 Fujin Road, Changchun, Jilin 130021, P. R. China
е-mail: jbxiang@jlu.edu.cn
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted March 25, 2016
Accepted May 12, 2016
2
016, 52(5), 326–330
2
R2
R CO2H
NH2
O
N
O
SnCl4, POCl3
R1
R1

N
N
up to 95% yield
An efficient and practical method has been developed for the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]benzoxazepines via
a Friedel−Crafts reaction of readily accessible 2-phenoxypyridin-3-amines and aromatic acids.
Keywords: 2-phenoxypyridin-3-amine, pyrido[2,3-b][1,4]benzoxazepine, tricyclic compounds, Friedel−Crafts cyclization.
The development of practical methods to provide access
to drug-like heterocycles often plays an important role in
[2,3-b][1,4]benzoxazepines 4 could be readily prepared by
the reaction of key precursors 3, prepared from simple
2-chloro-3-nitropyridine (1) and phenol, with different
commercially available carboxylic acids (Scheme 1).
The key precursors 3 were synthesized in a two-step
sequence as depicted in Scheme 2. The commercially
available 2-chloro-3-nitropyridine (1) was treated with
1
drug discovery projects. Pyrido[2,3-b][1,4]benzoxazepine
derivatives represent an exciting field of research in
medicinal chemistry due to their biological activity,
including the effects as non-nucleoside inhibitors of HIV-1
2
reverse transcriptase and the influence on central nervous
system.3 However, the synthesis of 6-aryl-substituted
pyrido[2,3-b][1,4]benzoxazepine derivatives has rarely
appeared in literature. Thus far only one five-stage route
for the synthesis of 6-aryl-substituted pyrido[2,3-b][1,4]-
benzoxazepine derivatives has been reported, which
phenols in DMF in the presence of K
CO , giving the
2
3
respective substituted 3-nitropyridines 2a–c in excellent
yields. The reduction of nitro groups in compounds 2a–c
8
with H
Fe/NH
2
in the presence of Pd/C in EtOAc/MeOH or with
9
4
Cl in refluxing EtOH/H O furnished the desired
2
entailed the Suzuki coupling of 6-chlorobenzo[f]pyrido[2,3-b]-
precursors 3 in high yields.
4
[
1,4]oxazepine with phenylboronic acid. An efficient
Initially, the precursor 3a was selected to test the reaction
synthetic method to access 6-aryl-substituted pyrido[2,3-b]-
conditions required to generate pyrido[2,3-b][1,4]benzoxaze-
5
[
1,4]benzoxazepines would be useful for the exploration of
pines 4. Previously, polyphosphoric acid (PPA)/POCl
3
,
6
/MeCN7 were reported to be
biological activity of this class of compounds.
4
SnCl /POCl
3
,
and POCl
3
The research performed at our Center of Combinatorial
Chemistry to prepare heterocyclic scaffolds and libraries led
to the development of several methodologies employing
Friedel−Crafts cyclization reactions as the key transfor-
mations.5 We envisioned that 6-aryl-substituted pyrido-
effective reagents for promoting Friedel−Crafts cyclization
reactions. When compound 3a and PhCO
2
H were treated
for 14 h, the cyclization
with PPA in refluxing POCl
3
product 4a was obtained in only 28% yield, and the
intermediate amide 5a was obtained in 48% yield (Table 1,
–7
Scheme 1
0
009-3122/16/52(5)-0326©2016 Springer Science+Business Media New York
326

Chemistry of Heterocyclic Compounds 2016, 52(5), 326–330
Scheme 2
Table 1. Optimization of the cyclization conditions
R2
O
R2
NH2
2
N
O
NH
R CO2H (1.5 equiv)
+
Conditions
N
O
N
N
O
3
a
4a
5a,b
Entry
R2
Conditions
Time
Product 4 (yield, %)
Product 5 (yield, %)
1
2
3
4
5
6
7
Ph
Ph
Ph
Et
Et
Et
Et
PPA (1.5 equiv), POCl
SnCl (2.0 equiv), POCl
POCl (4.0 equiv), MeCN, Δ
3
, Δ
14 h
12 h
21 h
10 min
1 h
4a (28)
5a (48)
–
4
3
, Δ
4a (90)
3
–
–
–
–
–
5a (88)
5b (76)
–
SnCl
4
4
(2.0 equiv), POCl
(2.0 equiv), POCl
3
3
, Δ
, Δ
SnCl
SnCl
4
4
(2.0 equiv), POCl
(2.0 equiv), POCl
3
3
, 80°C
, 80°C
2 h
5b (85)
–
SnCl
14 h
entry 1). The treatment of precursor 3a and PhCO
SnCl in refluxing POCl for 12 h gave the desired product
a in 90% yield (entry 2). When the above reaction was
carried out with POCl in refluxing MeCN, only the
2
H with
Table 2. Preparation of pyrido[2,3-b][1,4]benzoxazepines 4a–o
4
3
4
3
intermediate amide 5a was produced (entry 3). We also
attempted to expand the cyclization reaction to aliphatic
acids. However, the treatment of precursor 3a and
propionic acid with SnCl
pyridobenzoxazepine; the amide 5b was isolated instead in
6% yield (entry 4). The amide 5b appeared to be labile
4
in POCl did not give the desired
3
Entry
R1
R2
Time, h Product Yield, %
7
1
2
3
4
5
6
7
8
9
H
H
Ph
12
9
4a
4b
4c
4d
4e
4f
90
92
89
88
93
64
72
0*
91
93
92
95
68
64
72
under the reaction conditions, as the longer reaction time
resulted in its decomposition (entry 5). Decreasing of the
reaction temperature generated the amide 5b in 85% yield
without the desired cyclization product (entry 6), while
prolonged reaction time again led to decomposition (entry 7).
Having identified the optimal reaction conditions (entry 2),
we investigated the reactions of precursors 3a–c with several
aromatic acids. The results are summarized in Table 2.
As presented in Table 2, various aromatic acids parti-
cipated in the cyclization reaction effectively to produce
the expected pyrido[2,3-b][1,4]benzoxazepines 4 in good to
excellent yields (entries 1–7). Both electron-donating
6 4
p-MeC H
H
p-MeOC6H
4
11
20
25
12
20
12
11
9
H
p-FC
6
H
4
H
m-O NC
2
6
H
4
H
Furan-2-yl
Pyridin-3-yl
(E)-2-Phenylethenyl
Ph
H
4g
4h
4i
H
Me
Me
Me
Me
Br
Br
Br
1
0
p-MeC
p-FC
p-O NC
Ph
p-MeC
p-O NC H
6
H
4
4j
(
entries 2, 3) and electron-withdrawing (entries 4, 5) substi-
11
6
H
4
21
22
50
48
120
4k
4l
tuted benzoic acids were tolerated. The reaction proceeded
faster when benzoic acids with an electron-donating group
were employed (entries 2 and 3 vs entries 4 and 5). Two
examples of heteroaromatic acids were also tested: 2-furoic
acid and nicotinic acid (entries 6 and 7), and the reactions
gave lower yields of oxazepines than the reactions with
benzoic acid derivatives. The application of (E)-cinnamic
1
1
1
2
3
4
2
6
H
4
4m
4n
4o
6
H
4
15
2
6
4
*
N-(2-Phenoxypyridin-3-yl)cinnamamide (5h) was isolated in 80% yield
after 10 min, while longer reaction time led to its decomposition.
3
27

Chemistry of Heterocyclic Compounds 2016, 52(5), 326–330
acid in this reaction failed to give the desired product 4h
134.6; 135.7; 151.7; 151.8; 155.5. Mass spectrum, m/z:
+
(
entry 8). In order to determine the electronic effects of the
295 [M+H] .
substituents, precursors 3 with either electron-donating or
electron-withdrawing functional groups were tested (entries
Synthesis of 2-aryloxy-substituted pyridin-3-amines
3a,b (General method). A 10% Pd/C catalyst (1.22 g) was
added to a stirred solution of 2-aryloxy-3-nitropyridine 2a
(12.2 g, 56.5 mmol) or 2b (12.2 g, 53.0 mmol) in EtOAc
(100 ml) and MeOH (100 ml). The resulting suspension
9
–15). Tuning the electron density of the benzene ring had
significant effects on both the reaction rates and yields
(
entry 9 vs entry 1 vs entry 13). The presence of a bromo
substituent in precursors 3 appears to reduce both the
reaction rate and yield of the final products.
was stirred at room temperature under H atmosphere
2
(1 bar) for 10 h. The reaction mixture was filtered through
Celite and the filtrate was concentrated in vacuo. Purifica-
tion by flash chromatography (petroleum ether–EtOAc, 3:1
(v/v)) afforded the desired product 3a or 3b.
In conclusion, we have developed an efficient and
practical strategy for the synthesis of 6-aryl-substituted
pyrido[2,3-b][1,4]benzoxazepines via
a Friedel−Crafts
reaction of readily accessible 2-phenoxypyridin-3-amines
and aromatic acids in good to excellent yields. Drug-like
structures based on these heterocycles could be of interest
in chemical biology and drug discovery.
2-Phenoxypyridin-3-amine (3a). Yield 8.6 g (82%).
White solid. Mp 105–107°C (petroleum ether–EtOAc) (mp
106°C (petroleum ether)1 ). H NMR spectrum, δ, ppm
0a
1
(J, Hz): 3.93 (2H, br. s, NH
2
); 6.81–6.85 (1H, m, H Py);
7
.01 (1H, d, J = 7.5, H Py); 7.12–7.19 (3H, m, H Ph); 7.38
Experimental
13
(
2H, t, J = 7.8, H Ph); 7.56 (1H, d, J = 4.8, H Py). C NMR
1H and 13C NMR data were obtained on a Varian
Mercury 300 NMR spectrometer (300 and 75 MHz,
spectrum, δ, ppm: 119.6; 120.8; 122.2; 124.3; 129.6; 132.1;
+
135.8; 151.7; 154.4. Mass spectrum, m/z: 187 [M+H] .
respectively) with TMS as internal standard and CDCl
3
as
2-(p-Tolyloxy)pyridin-3-amine (3b). Yield 9.0 g (85%).
1
solvent unless otherwise stated. Mass spectra and HPLC
data was recorded on an Agilent 1100 LC/MS system with
Alltech ELSD 2000 (ESI). High-resolution mass spectra
White solid. Mp 129–131°C. H NMR spectrum, δ, ppm
(J, Hz): 2.34 (3H, s, CH
3
); 3.94 (2H, br. s, NH ); 6.79–6.83
2
(1H, m, H Py); 6.99–7.04 (3H, m, H Ph, H Py); 7.18 (2H,
(
HRMS) were obtained on a time-of-flight (TOF) mass
d, J = 8.7, H Ph); 7.55 (1H, dd, J = 5.7, J = 1.5, H Py).
13
spectrometer (ESI). Melting points were determined on a
XT5 melting point apparatus and were not corrected. Phos-
C NMR spectrum, δ, ppm: 20.9; 119.2; 120.9; 121.9;
130.1; 131.8; 134.0; 135.8; 151.9; 152.2. Found, m/z:
+
phorus oxychloride (POCl
3
) was freshly distilled. DMF was
201.1034 [M+H] . C12
H
13
2
N O. Calculated, m/z: 201.1022.
dried on CaH
2
and distilled. All other commercial reagents
Synthesis of 2-(4-bromophenoxy)pyridin-3-amine (3c).
2-(4-Bromophenoxy)-3-nitropyridine (2c) (10.3 g, 35 mmol),
were used as received without additional purification.
Synthesis of 3-nitro-2-phenoxypyridines 2a–c (General
iron powder (5.90 g, 105 mmol), and NH Cl (1.87 g,
4
method). Anhydrous K
2
CO
3
(10.4 g, 75.2 mmol) was
35 mmol) were added in sequence to a mixture of water
(30 ml) and EtOH (120 ml). The reaction mixture was
stirred and heated to reflux for 1 h and filtered through
Celite, and the filtrate was concentrated in vacuo. The
residue was diluted with water (120 ml) and extracted with
EtOAc (3×40 ml). The combined organic phase was
added to a stirred solution of 2-chloro-3-nitropyridine (1)
10.0 g, 63.0 mmol) and the appropriate phenol (75.2 mmol)
in DMF (150 ml). The resulting solution was stirred for
(
2
–3 h at 80°C. The reaction mixture was then poured into
water and the precipitate was filtered off, washed with
water, and then dried to give the desired product 2.
washed with brine, dried over anhydrous Na
2
SO , and
4
3
-Nitro-2-phenoxypyridine (2a). Yield 13.0 g (95%).
concentrated in vacuo to give 2-(4-bromophenoxy)pyridin-
3-amine (3c). Yield 8.2 g (88%). Light-red solid. Mp 117–
10
Yellow solid. Mp 90–91°C (DMF–H O) (mp 94°C (EtOH) ).
2
1
1
H NMR spectrum, δ, ppm (J, Hz): 7.13–7.20 (3H, m,
H Ph, H Py); 7.29 (1H, t, J = 7.5, H Ph); 7.43–7.48 (2H, m,
119°C. H NMR spectrum, δ, ppm (J, Hz): 3.91 (2H, br. s,
NH ); 6.84–6.88 (1H, m, H Py); 7.04 (3H, d, J = 9.0, H Ph,
2
1
3
H Ph); 8.33–8.38 (2H, m, H Py). C NMR spectrum,
H Py); 7.49 (2H, d, J = 8.7, H Ph); 7.55 (1H, dd, J = 4.8,
13
δ, ppm: 118.4; 121.8; 125.9; 129.8; 134.7; 135.5; 151.9;
J = 1.5, H Py). C NMR spectrum, δ, ppm: 117.2;
+
1
52.7; 155.9. Mass spectrum, m/z: 217 [M+H] .
119.9; 122.4; 122.8; 131.9; 132.6; 135.7; 151.4; 153.3.
+
3
-Nitro-2-(p-tolyloxy)pyridine (2b). Yield 13.4 g (92%).
Yellow solid. Mp 95–96°C (DMF–H O) (mp 112°C (benzene–
petroleum ether) ). H NMR spectrum, δ, ppm (J, Hz):
.38 (3H, s, CH ); 7.06 (2H, d, J = 8.4, H Ph); 7.11–7.15
1H, m, H Py); 7.24 (2H, d, J = 9.0, H Ph); 8.33–8.37 (2H,
Found, m/z: 264.9982 [M+H] . C11
H
10BrN O. Calculated, m/z:
2
2
264.9971.
11
1
Synthesis of pyrido[2,3-b][1,4]benzoxazepines 4a–o
and amides 5a,b,h (General method). The appropriate 2-aryl-
oxypyridin-3-amine 3 (1.0 mmol), aromatic acid (1.5 mmol),
2
3
(
13
m, H Py). C NMR spectrum, δ, ppm: 21.0; 118.2; 121.5;
30.4; 134.6; 135.5; 135.6; 150.4; 151.9; 156.2. Mass
and SnCl
4
(2.0 mmol) were dissolved in POCl (5 ml).
3
1
After the mixture was refluxed for the appropriate time, the
mixture was poured into ice water (20 ml) and treated with
5 N aqueous NaOH to pH 9–10. The resulting solution was
extracted with EtOAc (3×20 ml). The combined organic
+
spectrum, m/z: 231 [M+H] .
2
-(4-Bromophenoxy)-3-nitropyridine (2c). Yield 17.8 g
(
(
(
96%). Yellow solid. Mp 91–93°C (DMF–H O) (mp 95°C
2
1
1
1
benzene–petroleum ether) ). H NMR spectrum, δ, ppm
J, Hz): 7.07–7.10 (2H, m, H Ph); 7.17–7.21 (1H, m,
phase was washed with saturated Na
2
CO and brine, dried
3
over anhydrous Na
2
SO , and concentrated in vacuo. Puri-
4
H Py); 7.54–7.57 (2H, m, H Ph); 8.33–8.40 (2H, m, H Py).
fication by flash chromatography (petroleum ether–EtOAc,
10:1 (v/v)) afforded the desired product 4a–o or amide 5a,b,h.
1
3
C NMR spectrum, δ, ppm: 118.8; 119.0; 123.7; 132.9;
3
28

Chemistry of Heterocyclic Compounds 2016, 52(5), 326–330
6
-Phenylpyrido[2,3-b][1,4]benzoxazepine (4a). Yield
125.2; 125.4; 130.3; 133.9; 135.5; 137.3; 145.6; 146.3;
1
+
2
45 mg (90%). Yellow solid. Mp 102–104°C. H NMR
152.2; 155.9; 157.2; 160.2. Found, m/z: 263.0831 [M+H] .
spectrum, δ, ppm (J, Hz): 7.19–7.26 (3H, m, H Ph, H Py);
C
16
H
11
N
2
O . Calculated, m/z: 263.0815.
2
7
8
.44–7.56 (5H, m, H Ph); 7.80–7.83 (3H, m, H Ph, H Py);
6-(Pyridin-3-yl)pyrido[2,3-b][1,4]benzoxazepine (4g).
1
3
.15 (1H, dd, J = 4.8, J = 1.8, H Py). C NMR spectrum,
Yield 197 mg (72%). Yellow solid. Mp 124–126°C.
1
δ, ppm: 122.0; 122.4; 124.8; 126.7; 128.2; 129.8; 130.8;
H NMR spectrum, δ, ppm (J, Hz): 7.19–7.30 (3H, m,
1
1
31.2; 133.6; 135.5; 137.2; 139.4; 145.6; 156.0; 160.0;
H Ph, H Py); 7.40–7.45 (1H, m, H Ph); 7.50 (1H, d,
J = 8.1, H Ph); 7.60–7.64 (1H, m, H Ph); 7.84 (1H, dd,
J = 7.8, J = 1.8, H Py); 8.15–8.20 (2H, m, H Py); 8.75–
+
68.4. Found, m/z: 273.1057 [M+H] . C18
H
13
2
N O. Calcu-
lated, m/z: 273.1022.
13
6
-(p-Tolyl)pyrido[2,3-b][1,4]benzoxazepine (4b). Yield
8.76 (1H, m, H Py); 9.04 (1H, d, J = 1.8, H Py). C NMR
spectrum, δ, ppm: 122.5; 122.7; 123.2; 125.3; 126.1; 130.7;
1
2
63 mg (92%). Yellow solid. Mp 180–182°C. H NMR
spectrum, δ, ppm (J, Hz): 2.43 (3H, s, CH
3
); 7.16–7.28
134.2; 135.1; 135.3; 137.1; 137.5; 146.3; 150.9; 151.6; 155.9;
+
(
(
5H, m, H Ph, H Py); 7.46 (1H, d, J =7.5, H Ph); 7.52–7.58
1H, m, H Ph); 7.72 (2H, d, J = 7.8, H Ph); 7.80 (1H, dd,
160.2; 166.0. Found, m/z: 274.0989 [M+H] . C17
Calculated, m/z: 274.0975.
H
12
N O.
3
J = 7.8, J = 1.5, H Py); 8.13 (1H, dd, J = 4.5, J = 1.5,
8-Methyl-6-phenylpyrido[2,3-b][1,4]benzoxazepine (4i).
13
H Py). C NMR spectrum, δ, ppm: 21.4; 122.0; 122.3;
Yield 260 mg (91%). Yellow solid. Mp 149–151°C.
1
1
1
2
24.8; 126.8; 128.9; 129.8; 131.2; 133.4; 135.6; 136.7;
H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s, CH ); 7.02
3
37.1; 141.2; 145.3; 156.1; 160.0; 168.3. Found, m/z:
(1H, s, H Ph); 7.22–7.28 (2H, m, H Ph, H Py); 7.37 (1H, s,
+
87.1204 [M+H] . C19
H
15
N
2
O. Calculated, m/z: 287.1179.
H Ph); 7.47–7.55 (3H, m, H Ph); 7.83 (3H, t, J = 7.5, H Ph,
13
6
-(4-Methoxyphenyl)pyrido[2,3-b][1,4]benzoxazepine
4c). Yield 268 mg (89%). Yellow solid. Mp 126–128°C.
H Py); 8.15 (1H, d, J = 3.3, H Py). C NMR spectrum,
δ, ppm: 20.9; 121.8; 122.4; 126.4; 128.4; 129.9; 130.9;
(
1
H NMR spectrum, δ, ppm (J, Hz): 3.88 (3H, s, CH
3
); 6.97
131.3; 134.4; 134.7; 135.6; 137.3; 139.6; 145.6; 156.3;
+
(
2H, d, J = 9.0, H Ph); 7.19–7.28 (3H, m, H Ph, H Py);
158.1; 168.6. Found, m/z: 287.1187 [M+H] . C19
Calculated, m/z: 287.1179.
H
15
2
N O.
7
.46 (1H, d, J = 8.1, H Ph); 7.52–7.55 (1H, m, H Ph); 7.76–
.81 (3H, m, H Ph, H Py); 8.12 (1H, dd, J = 4.8, J = 1.8,
7
8-Methyl-6-(p-tolyl)pyrido[2,3-b][1,4]benzoxazepine (4j).
13
H Py). C NMR spectrum, δ, ppm: 55.5; 113.7; 122.1;
Yield 280 mg (93%). Yellow solid. Mp 204–206°C.
1
1
1
3
22.5; 124.9; 126.8; 131.3; 131.7; 132.0; 133.5; 135.8;
H NMR spectrum, δ, ppm (J, Hz): 2.26 (3H, s, CH ); 2.43
3
37.1; 145.2; 156.2; 160.1; 162.0; 167.7. Found, m/z:
(3H, s, CH ); 7.01 (1H, s, H Ph); 7.18–7.22 (1H, m, H Py);
3
+
03.1136 [M+H] . C19
H
15
N
2
O
2
. Calculated, m/z: 303.1128.
7.27 (2H, d, J = 7.8, H Ph); 7.34 (2H, s, H Ph); 7.72 (2H, d,
J = 8.1, H Ph); 7.77 (1H, dd, J = 7.2, J = 1.8, H Py); 8.11
6
-(4-Fluorophenyl)pyrido[2,3-b][1,4]benzoxazepine (4d).
13
Yield 255 mg (88%). Yellow solid. Mp 107–109°C.
(1H, dd, J = 4.5, J = 1.8, H Py). C NMR spectrum, δ, ppm:
1
H NMR spectrum, δ, ppm (J, Hz): 7.14 (2H, d, J = 8.4,
20.7; 21.5; 121.6; 122.3; 126.4; 129.0; 129.8; 131.3; 134.1;
H Ph); 7.18–7.27 (3H, m, H Ph, H Py); 7.48 (1H, d,
J = 8.1, H Ph); 7.55–7.59 (1H, m, H Ph); 7.78–7.86 (3H,
m, H Ph, H Py); 8.16 (1H, dd, J = 4.5, J = 1.8, H Py).
134.5; 135.6; 136.7; 137.0; 141.2; 145.2; 156.2; 157.9;
+
168.4. Found, m/z: 301.1345 [M+H] . C20
H
17
2
N O. Calcu-
lated, m/z: 301.1335.
1
3
C NMR spectrum, δ, ppm: 115.3; 115.6; 122.3; 122.6;
6-(4-Fluorophenyl)-8-methylpyrido[2,3-b][1,4]benzox-
azepine (4k). Yield 280 mg (92%). Yellow solid. Mp 166–
1
1
25.1; 126.6; 131.1; 132.0; 132.1; 133.9; 135.5; 135.62;
1
35.66; 137.3; 145.8; 156.0; 160.1; 162.9; 166.3; 167.2.
168°C. H NMR spectrum, δ, ppm (J, Hz): 2.28 (3H, s,
+
Found, m/z: 291.0966 [M+H] . C18
H
2
12FN O. Calculated,
CH ); 6.98 (1H, s, H Ph); 7.13–7.27 (3H, m, H Ph, H Py);
3
m/z: 291.0928.
7.36 (2H, d, J = 1.2, H Ph); 7.76–7.87 (3H, m, H Ph,
13
6
-(3-Nitrophenyl)pyrido[2,3-b][1,4]benzoxazepine (4e).
H Py); 8.14 (1H, dd, J = 4.5, J = 1.8, H Py). C NMR
spectrum, δ, ppm: 20.9; 115.3; 115.6; 121.9; 122.5; 126.2;
131.1; 132.0; 132.1; 134.5; 134.8; 135.5; 137.2; 145.7;
Yield 295 mg (93%). Yellow solid. Mp 233–235°C.
1
H NMR spectrum, δ, ppm (J, Hz): 7.16–7.19 (1H, m,
H Ph); 7.23–7.31 (2H, m, H Py); 7.51 (1H, d, J = 8.4,
H Ph); 7.60–7.68 (2H, m, H Ph); 7.87 (1H, dd, J = 7.8,
J = 2.1, H Py); 8.12–8.15 (1H, m, H Ph); 8.20–8.22 (1H,
m, H Py); 8.35–8.39 (1H, m, H Ph); 8.75 (1H, t, J = 1.8,
156.2; 158.0; 162.9; 166.2; 167.3. Found, m/z: 305.1101
+
[M+H] . C19
H
14FN O. Calculated, m/z: 305.1085.
2
8-Methyl-6-(4-nitrophenyl)pyrido[2,3-b][1,4]benzox-
azepine (4l). Yield 315 mg (95%). Yellow solid. Mp 220–
13
1
H Ph). C NMR spectrum, δ, ppm: 122.5; 122.6; 124.6;
25.2; 125.3; 125.8; 129.3; 130.3; 134.3; 135.0; 135.5;
222°C. H NMR spectrum, δ, ppm (J, Hz): 2.29 (3H, s,
1
CH ); 6.91 (1H, s, H Ph); 7.26–7.30 (1H, m, H Py); 7.36–
3
1
37.5; 141.0; 146.5; 148.3; 155.7; 160.2; 165.8. Found, m/z:
7.43 (2H, m, H Ph); 7.84 (1H, dd, J = 7.8, J = 1.8, H Py);
8.02 (2H, d, J = 8.4, H Ph); 8.19–8.21 (1H, m, H Py); 8.33
+
3
18.0890 [M+H] . C18
H
12
N
3
O . Calculated, m/z: 318.0873.
3
13
6
-(Furan-2-yl)pyrido[2,3-b][1,4]benzoxazepine (4f).
(2H, d, J = 8.7, H Ph). C NMR spectrum, δ, ppm: 20.7;
Yield 168 mg (64%). Yellow solid. Mp 131–132°C.
122.0; 122.5; 123.4; 125.5; 130.4; 130.6; 134.8; 134.9; 135.0;
1
H NMR spectrum, δ, ppm (J, Hz): 6.58–6.60 (1H, m,
137.5; 145.1; 146.4; 148.9; 155.7; 157.9; 166.2. Found, m/z:
+
H furan); 6.91 (1H, d, J = 3.6, H furan); 7.21–7.30 (2H, m,
H Ph, H Py); 7.45–7.48 (1H, m, H Ph); 7.58 (2H, t, J = 7.2,
H Ph); 7.72 (1H, t, J = 0.6, H furan); 7.84 (1H, dd, J = 7.8,
J = 1.8, H Py); 8.13 (1H, dd, J = 4.8, J = 1.8, H Py).
332.1045 [M+H] . C19
H
14
N
3
O . Calculated, m/z: 332.1030.
3
8-Bromo-6-phenylpyrido[2,3-b][1,4]benzoxazepine (4m).
Yield 239 mg (68%). Yellow solid. Mp 136–138°C.
1
H NMR spectrum, δ, ppm (J, Hz): 7.25–7.29 (1H, m,
1
3
C NMR spectrum, δ, ppm: 112.3; 118.1; 122.1; 122.7;
H Py); 7.34–7.37 (2H, m, H Ph); 7.47–7.58 (3H, m, H Ph);
3
29

Chemistry of Heterocyclic Compounds 2016, 52(5), 326–330
7
.66 (1H, dd, J = 8.4, J = 2.4, H Ph); 7.82 (3H, d, J = 7.8,
m, H Ph); 7.23–7.28 (1H, m, H Ph); 7.39–7.47 (5H, m,
H Ph, H Py); 7.56–7.59 (2H, m, H Ph); 7.80 (1H, d,
J = 15.6, PhCH=CHCO); 7.82–7.86 (1H, m, H Ph); 8.01
(1H, s, H Py); 8.89 (1H, dd, J = 7.8, J = 1.8, NH).
H Ph, H Py); 8.16 (1H, dd, J = 4.8, J = 1.5, H Py).
1
3
C NMR spectrum, δ, ppm: 118.1; 122.8; 124.0; 128.5;
1
1
C
28.6; 129.9; 131.3; 133.6; 135.3; 136.5; 138.9; 146.0;
+
13
48.4; 155.7; 159.1; 167.0. Found, m/z: 351.0138 [M+H] .
C NMR spectrum, δ, ppm: 119.3; 120.7; 121.5; 123.9;
18
8
H
12BrN
2
O. Calculated, m/z: 351.0128.
125.2; 128.2; 128.4; 129.0; 129.8; 130.2; 134.6; 140.9;
+
-Bromo-6-(p-tolyl)pyrido[2,3-b][1,4]benzoxazepine (4n).
143.0; 152.5; 153.5; 164.5. Found, m/z: 317.1294 [M+H] .
Yield 233 mg (64%). Yellow solid. Mp 177–179°C.
C
20
H
17
N
2
O . Calculated, m/z: 317.1285.
2
1
H NMR spectrum, δ, ppm (J, Hz): 2.45 (3H, s, CH ); 7.23–
3
7
.36 (5H, m, H Ph, H Py); 7.65 (1H, dd, J = 8.7, J = 2.7,
The Supplementary information file containing LC-MS
data and NMR spectra of the synthesized compounds is
available online at http://link.springer.com/journal/10593.
H Ph); 7.71 (2H, d, J = 8.1, H Ph); 7.80 (1H, dd, J = 7.5,
J = 1.8, H Py); 8.14 (1H, dd, J = 4.8, J = 1.8, H Py).
1
3
C NMR spectrum, δ, ppm: 21.5; 117.8; 122.6; 123.7;
1
1
28.3; 129.1; 129.6; 133.5; 135.2; 135.9; 136.2; 137.2;
This work was supported by a grant from the Sci-Tech
Development Project of Jilin Province in China
(No. 20160520039JH) and a grant from the Norman
Bethune Program of Jilin University (No. 2015330).
Additional support was provided by Changchun Discovery
Sciences, Ltd.
41.6; 145.5; 155.5; 158.8; 166.6. Found, m/z: 365.0299
+
[
M+H] . C19
H
14BrN O. Calculated, m/z: 365.0284.
2
8
-Bromo-6-(4-nitrophenyl)pyrido[2,3-b][1,4]benzox-
azepine (4o). Yield 285 mg (72%). Yellow solid. Mp 235–
1
2
37°C. H NMR spectrum, δ, ppm (J, Hz): 7.26 (1H, s,
H Ph); 7.30–7.34 (1H, m, H Ph, H Py); 7.39 (1H, d,
References
J = 8.7, H Ph); 7.72 (1H, dd, J = 8.4, J = 2.1, H Ph); 7.86
(
1H, dd, J = 7.8, J = 1.8, H Py); 8.02 (2H, d, J = 8.7,
1
. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
H Ph); 8.22 (1H, dd, J = 4.8, J = 1.8, H Py); 8.35 (2H, d,
2
003, 103, 893. (b) Petuškovs, A.; Shubin, K. Chem.
13
J = 8.4, H Ph). C NMR spectrum, δ, ppm: 118.4; 123.0;
23.8; 124.4; 127.7; 130.7; 132.9; 134.8; 137.1; 137.9; 144.4;
47.0; 148.3; 155.2; 159.1; 164.7. Found, m/z: 395.9981
Heterocycl. Compd. 2016, 52, 84. [Khim. Geterotsikl. Soedin.
2016, 52, 84.]
1
1
2. Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.;
Behnke, M. L.; Kapadia, S. R.; McNeil, D. W.; Wu, J. C.;
Chow, G. C.; Adams, J. J. Med. Chem. 1992, 35, 1887.
3. Liégeois, J.-F. F.; Rogister, F. A.; Bruhwyler, J.; Damas, J.;
Nguyen, T. P.; Inarejos, M.-O.; Chleide, E. M. G.;
Mercier, M. G. A.; Delarge, J. E. J. Med. Chem. 1994, 37, 519.
+
[
M+H] . C18
H
11BrN
3
O . Calculated, m/z: 395.9978.
3
N-(2-Phenoxypyridin-3-yl)benzamide (5a). Yield 255 mg
1
(
88%). White solid. Mp 120–122°C. H NMR spectrum,
δ, ppm (J, Hz): 7.05–7.09 (1H, m, H Py); 7.18–7.26 (3H,
m, H Ph); 7.28–7.60 (5H, m, H Ph, H Py); 7.86–7.93 (3H,
m, H Ph); 8.58 (1H, s, H Py); 8.91 (1H, d, J = 8.1, NH).
4
. (a) Shapiro, G.; Moncuso, J.; Pierre, T.; Leit, S.; Deziel, R.;
David, S.; Richard, C.; Chantigny, Y. A.; Patrick, B. WO
Patent 2008055068A2. (b) Rogers, K.; Patzke, H. WO Patent
1
3
C NMR spectrum, δ, ppm: 119.3; 121.6; 123.7; 125.4;
1
1
27.2; 128.1; 129.0; 129.8; 132.3; 134.4; 141.0; 152.7;
2
009137462A2. (c) Chesworth, R.; Shapiro, G.; Beaulieu, P.;
+
53.4; 165.9. Found, m/z: 291.1147 [M+H] . C18
H
15
N
2
O
2
.
Chantigny, Y.; Mancuso, J.; Deziel, R.; Leit, S.; Tessier, P.;
Smil, D. WO Patent 2009137499A1.
Calculated, m/z: 291.1128.
N-(2-Phenoxypyridin-3-yl)propionamide (5b). Yield
5. (a) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X. Org.
Lett. 2005, 7, 1541. (b) Fu, R.; Xu, X.; Dang, Q.; Bai, X.
J. Org. Chem. 2005, 70, 10810.
1
2
06 mg (85%). White solid. Mp 86–87°C. H NMR
spectrum, δ, ppm (J, Hz): 1.28 (3H, t, J = 7.5, CH
3
); 2.49
6
7
8
. Xu, X.; Guo, S.; Dang, Q.; Chen, J.; Bai, X. ACS Comb. Sci.
007, 9, 773.
. Shi, F.; Xu, X.; Zheng, L.; Dang, Q.; Bai, X. ACS Comb. Sci.
(
(
2H, q, J = 7.5, CH
2H, m, H Ph); 7.22–7.27 (1H, m, H Ph); 7.40–7.46 (2H,
2
); 6.99–7.03 (1H, m, H Py); 7.13–7.16
2
m, H Ph, H Py); 7.81 (2H, dd, J = 5.1, J = 1.8, H Ph, H Py);
2
008, 10, 158.
1
3
8
.76 (1H, dd, J = 8.1, J = 1.8, NH). C NMR spectrum,
. Herpin, T. F.; Morton, G. C.; Rehfuss, R. P.; Lawrence, R. M.;
Poss, M. A.; Roberge, J. Y.; Gungor, T. WO Patent
δ, ppm: 9.6; 31.0; 119.3; 121.5; 123.7; 125.3; 128.0; 129.8;
+
1
40.7; 152.3; 153.4; 172.7. Found, m/z: 243.1142 [M+H] .
. Calculated, m/z: 243.1128.
N-(2-Phenoxypyridin-3-yl)cinnamamide (5h). Yield
2
005070920A1.
C
14
H
15
N
2
O
2
9
. Todd, R. S.; Huxley, P. WO Patent 2014199164A1.
10. (a) Eatough, J. J.; Fuller, L. S.; Good, R. H.; Smalley, R. K.
J. Chem. Soc. C 1970, 1874. (b) Takahashi, T.; Shibasaki, J.
J. Pharm. Soc. Jpn. 1949, 69, 408.
1
2
53 mg (80%). White solid. Mp 117–118°C. H NMR
spectrum, δ, ppm (J, Hz): 6.64 (1H, d, J = 15.3,
1
1. EI-Bardan, A. A. J. Phys. Org. Chem. 1999, 12, 347.
PhCH=CHCO); 7.03–7.07 (1H, m, H Py); 7.16–7.19 (2H,
3
30