Facile synthesis for benzo-1,4-oxazepine derivatives by tandem transformation of C-N coupling/C-H carbonylation

Article abstract of DOI:10.3390/molecules22010053

A tandem transformation of C-N coupling/C-H carbonylation has been developed for the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing 2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions, various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible Cu^I/Cu^III mechanism of C-N coupling/C-H carbonylation transformation was proposed.

Full text of DOI:10.3390/molecules22010053

molecules
Article
Facile Synthesis for Benzo-1,4-Oxazepine
Derivatives by Tandem Transformation of
C-N Coupling/C-H Carbonylation
Xiaojia Zhao, Jiong Zhang, Zeqin Zheng and Runsheng Xu *
Department of Biology and Environment, Zhejiang A&F University, Shaoxing 311800, Zhejiang,
China; 18267573167m@sina.cn (X.Z.); a63214955@sohu.com (J.Z.); 13282210629@163.com (Z.Z.)
* Correspondence: 20140041@zafu.edu.cn; Tel.: +86-575-87760143
Academic Editor: Derek J. McPhee
Received: 21 November 2016; Accepted: 28 December 2016; Published: 30 December 2016
Abstract: A tandem transformation of C-N coupling/C-H carbonylation has been developed for
the synthesis of benzo-1,4-oxazepine pharmaceutically derivatives. Notably, this reaction was
accomplished by various phenylamine with ally halides under carbon dioxide atmosphere employing
2-(2-dimethylamino-vinyl)-1H-inden-1-olcatalyzed. Furthermore, under the optimized conditions,
various benzo-1,4-oxazepine derivatives were obtained in good yields. Finally, a plausible CuI/CuIII
mechanism of C-N coupling/C-H carbonylation transformation was proposed.
Keywords: benzo-1,4-oxazepine; copper catalyst; tandem transformation; C-N coupling; C-H
carbonylation
1. Introduction
The heterocycle benzoxazepines are privileged scaffolds in natural biologically products [
1–4],
pharmaceutical chemistry [ ] and functionalized materials [ 10]. As such, Sintamilv ( ) is an
5,6
7–
I
efficient antidepressant [11]; H1 receptor antagonist (II) is a selective antihistaminic agent [12];
and Sintamil (III) is a benzoxazepine analogue (Scheme 1) [13]. Furthermore, the therapeutic
applications of benzoxazepines are for the central nervous system, along with anti-breast cancer
activity and inhibitors of HIV [14,15].
O
.
HCl
N
O
H
N
NHMe
N
N
O
O
O
II
III
I
Scheme 1. The important benzo-1,4-oxazepine derivatives.
Currently, the challenge in organic synthesis is developing an efficient and eco-friendly protocol,
especially in the area of drug discovery and natural products. Benzoxazepines are generally synthesized
by condensation of 2-aryloxyethylamines with 2-formylbenzoic acid [16]. Others have also been
synthesized from amides [17] and amino acids [18,19]. However, most of these methodologies are
associated with several drawbacks, such as low synthetic efficiency and sensitivity. Thus, a remarkable
gap remains in the search of economical synthesis methods. Tandem transformation is one of the most
Molecules 2017, 22, 53; doi:10.3390/molecules22010053
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effective ways to achieve this goal. Considering the above points, herein we report the tandem reaction
green protocol for the synthesis of benzo-1,4-oxazepine pharmaceutical derivatives.
The reaction conditions were screened based on a model reaction of phenylamine 1a and
(1-chloro-vinyl)-benzene 2a (Table 1). The ligands were mainly based on the derivatives of
2-(2-dimethylamino-vinyl)-1H-inden-1-ol. It was discovered that ligand L1 was the ideal choice for
this transformation (Entries 5–10). CuI exhibited superior catalytic efficiency over all other examined
CuI catalysts (Entries 1–5), and Cs2CO3 turned out to be the proper base additive (Entries 11–12).
Meanwhile, the reaction temperature was 100 ◦C (Entries 15–16).
Table 1. Optimization of the reaction conditions a.
O
NH
2
H
O
Cu salt, Ligand
+
o
CO , base,100 C
2
Cl
Ph
N
Ph
H
2a
1a
3a
Yield (%) b
Entry
Ligand
Cu Salt
Base
1
2
3
4
5
6
7
8
9
10
11
12
13
14
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L1
L1
L1
L1
Cu(OAc)2
CuSO4
CuBr
CuBr2
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
8
0
23
19
81
29
36
47
16
38
42
0
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K3PO4
Cs2CO3
Cs2CO3
61 c
69 d
CuI
R1
R2
N
N
OH
O
L1: R1 = H
L2: R1 = Cl
L3: R1 = CH3
L4: R2 = H
L5: R2 = Cl
L6: R2 = CH3
a
Unless otherwise noted, reactions conditions were 1a (0.5 mmol), 2a (0.6 mmol), Cu salt (10 mol %),
ligand (10 mol %), base (2 eq.), DMSO (4 mL) reacted in CO2 at 100 ◦C for 12 h; b isolated yield; c reaction under
90 ◦C; d reaction under 110 ◦C.
With the optimal conditions established, the reaction scope was further investigated. A wide array
of phenylamine
Phenylamine derivatives bearing either an electron-withdrawing or electron-donating group reacted
smoothly with . This transformation is applicable for para-substituted phenylamines. Chloroethylene
1 and ally halide 2 was subjected to this reaction in moderate to good yields (Table 2).
2
bearing an electron-donating group showed better reactivity than those with an electron-withdrawing
group (All the product spectrums, please see Supplementary Materials).

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Table 2. Synthesis of benzo-1,4-oxazepin-5-one 3 a.
O
NH2
H
O
CuI, L1
R1
R1
+
CO2, Cs2CO3,100 oC
Cl
R2
N
R2
H
1
2
3
Yield (%) b
Entry
R1
R2
Product 3
O
O
1
2
H
H
Ph
81
N
H
3a
O
O
4-CH3C6H4
78
85
N
H
Me
3b
O
O
N
H
3
H
4-ClC6H4
Cl
3c
O
O
4
5
H
CH3
74
79
N
Me
H
3d
O
Cl
O
4-Cl
Ph
N
H
3e
O
Cl
O
N
6
4-Cl
4-CH3C6H4
76
H
3f
Me

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Table 2. Cont.
Yield (%) b
Entry
R1
R2
Product 3
O
O
Cl
7
4-Cl
4-ClC6H4
N
H
86
3g
Cl
O
Cl
O
8
9
4-Cl
CH3
84
76
N
H
Me
3h
O
Me
O
4-CH3
Ph
N
H
3i
O
Me
O
10
4-CH3
4-CH3C6H4
75
N
H
3j
Me
O
Me
O
11
12
4-CH3
4-CH3
4-ClC6H4
82
72
N
H
3k
Cl
O
Me
O
CH3
N
H
Me
3l
a
Reactions conditions were
1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), L1 (10 mol %), Cs2CO3 (2 equiv.),
DMSO (4 mL) at 100 ◦C reacted in CO2 for 10 h; b isolated yield.
Interestingly, we found that 1-bromo-cyclohexene
4
has also been rapidly synthesized in good
yields, and the results are summarized in Table 3. In addition, the reaction works well for both bearing
electron-donating and electron-withdrawing groups.

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Table 3. Synthesis of benzo-1,4-oxazepin-5-one 5 a.
O
NH2
H
O
CuI, L1
R1
R1
+
CO2, Cs2CO3,100 oC
Br
N
H
1
4
5
Yield (%) b
Entry
R1
Product 5
O
O
1
H
78
N
H
5a
O
O
Me
2
3
4-Cl
84
75
N
H
3j
Me
O
Me
O
4-CH3
N
H
5c
a
Reactions conditions were
1
(0.5 mmol), 2 (0.6 mmol), CuI (10 mol %), L1 (10 mol %), Cs2CO3 (2 equiv.),
DMSO (4 mL) at 100 ◦C reacted in CO2 for 10 h; b isolated yield.
On the basis of the above experimental results, we tentatively proposed a reaction mechanism
as shown in Scheme 2. At the beginning, CuI activate
was been formed through copper iodide
coordinating with ligand. Next, complex reacted with vinyl halides by oxidative addition produced
a CuIII complex
. The complex reacted with aniline obtained the key intermediate complex 20 21].
Selective ortho-carbonylation of the phenylamine was determined by Complex . Through the reductive
elimination of Complex , Complex 10 was obtained, which regenerates Complex for the next catalytic
6
6
7
7
8
[
,
9
9
6
cycle [22,23]. However, how the ligand promotes this transformation is a part of ongoing study.
CuI
X
O
Ligand
O
LnCuI
Cs2CO3
6
N
X = Cl, Br
Ph
H
10
LnCuIII
X
O
OLnCuIII
Ph
H
N
7
H
9
Cs2CO3
LnCuI
NH2
LnCuIII
N
H
CO2
Ph
H
8
Scheme 2. A plausible mechanism of the catalytic cycle.

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2. Results and Discussion
O
O
N
H
3a
2-Phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3a): A mixture of phenylamine 1a (0.5 mmol,
46.5 mg), (1-chloro-vinyl)-benzene 2a (0.6 mmol, 83.4 mg), CuI (10 mol %, 9.5 mg), L1◦(10 mol %,
20.1 mg) and Cs2CO3 (2 equiv., 325.8 mg) in DMSO (4 mL) was stirred in CO2 at 100 C for 10 h.
After completion of the reaction, the mixture was quenched with saturated salt water (10 mL);
the solution was extracted with ethyl acetate (3
×
10 mL). The organic layers were combined and
dried over sodium sulfate. The pure product was obtained by flash column chromatography on silica
gel to afford 3a 96.8 mg in 81% yield. The spectroscopic data of all of the products are presented
below. Yellowish oil. 1H-NMR (400 MHz, CDCl3): 7.63 (m, 1H), 7.43 (br, 1H), 7.08–7.43 (m, 8H),
5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.08 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.3, 5.6 Hz, 1H); 13C-NMR
(100 MHz, CDCl3): 168.3, 147.7, 139.1, 132.9, 130.3, 128.6, 127.5, 126.6, 117.8, 116.4, 109.1, 77.6, 60.2;
EIMS (m/z): 239 [M+]; Anal. Calcd. for C15H13NO2: C, 75.30; H, 5.48; N, 5.85; Found: C, 75.62; H, 5.13;
N, 5.68.
O
O
N
H
Me
3b
1
2-p-Tolyl-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3b): Yellowish oil. H-NMR (400 MHz, CDCl3):
7.61 (m, 1H), 7.44 (br, 1H), 7.04–7.31 (m, 7H), 5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.07 (dd, J = 12.3, 8.0 Hz,
1H), 3.95 (dd, J = 12.3, 5.7 Hz, 1H), 2.39 (s, 3H); 13C-NMR (100 MHz, CDCl3): 168.6, 147.8, 138.3, 135.3,
132.3, 130.5, 128.1, 127.6, 118.2, 115.9, 109.5, 77.5, 60.3, 25.2; EIMS (m/z): 253 [M+]; Anal. Calcd. for
C16H15NO2: C, 75.87; H, 5.97; N, 5.53; Found: C, 75.50; H, 6.20; N, 5.88.
O
O
N
H
Cl
3c
1
2-(4-Chloro-phenyl)-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3c): Yellowish oil. H-NMR (400 MHz,
CDCl3): 7.64 (m, 1H), 7.47 (br, 1H), 7.07–7.48 (m, 7H), 5.08 (dd, J = 8.1, 5.6 Hz, 1H), 4.09 (dd, J = 12.3,
8.1 Hz, 1H), 3.95 (dd, J = 12.3, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.7, 139.3, 133.3, 132.4,
130.5, 128.6, 127.8, 118.4, 116.3, 110.1, 77.3, 60.9;EIMS (m/z): 273 [M+]; Anal. Calcd. for C15H12ClNO2:
C, 65.82; H, 4.42; N, 5.12; Found: C, 65.51; H, 4.61; N, 5.33.

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O
O
N
Me
H
3d
1
2-Methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3d): Yellowish oil. H-NMR (400 MHz, CDCl3):
7.62 (m, 1H), 7.42 (br, 1H), 7.05–7.21 (m, 3H), 4.58 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.2, 5.6 Hz,
1H), 3.12–3.71 (m, 1H), 1.35 (d, J = 7.1 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.3, 132.8, 130.4,
118.7, 116.6, 109.7, 77.1, 53.1, 18.2; EIMS (m/z): 177.08 [M+]; Anal. Calcd. for C10H11NO2: C, 67.78;
H, 6.26; N, 7.90; Found: C, 68.14; H, 6.55; N, 7.53.
O
Cl
O
N
H
3e
1
7-Chloro-2-phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3e): Yellowish oil. H-NMR (400 MHz,
CDCl3): 7.63 (m, 1H), 7.43 (br, 1H), 7.10–7.46 (m, 7H), 5.08 (dd, J = 8.1, 5.6 Hz, 1H), 4.10 (dd, J = 12.4,
8.1 Hz, 1H), 3.97 (dd, J = 12.4, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.4, 139.5, 133.2, 130.2,
128.7, 127.5, 126.8, 123.8, 115.4, 109.2, 77.5, 60.2; EIMS (m/z): 273 [M+]; Anal. Calcd. for C15H12ClNO2:
C, 65.82; H, 4.42; N, 5.12; Found: C, 65.70; H, 4.61; N, 5.44.
O
Cl
O
N
H
3f
Me
7-Chloro-2-p-tolyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3f): Yellowish oil. 1H-NMR (400 MHz,
CDCl3): 7.64 (m, 1H), 7.43 (br, 1H), 7.07–7.38 (m, 6H), 5.08 (dd, J = 8.1, 5.9 Hz, 1H), 4.10 (dd, J = 12.4,
8.1 Hz, 1H), 3.96 (dd, J = 12.4, 5.9 Hz, 1H), 2.40 (s, 3H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.1, 139.2,
135.8, 133.4, 130.5, 128.7, 126.9, 123.5, 115.5, 109.3, 77.2, 60.4, 25.7; EIMS (m/z): 287.07 [M+]; Anal. Calcd.
for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87; Found: C, 66.95; H, 4.63; N, 5.23.
O
Cl
O
N
H
3g
Cl

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1
7-Chloro-2-(4-chloro-phenyl)-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3g): Yellowish oil. H-NMR
(400 MHz, CDCl3): 7.66 (m, 1H), 7.46 (br, 1H), 7.09–7.50 (m, 6H), 5.10 (dd, J = 8.2, 5.6 Hz, 1H),
4.11 (dd, J = 12.4, 8.2 Hz, 1H), 3.96 (dd, J = 12.4, 5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.4,
139.6, 133.2, 131.8, 130.2, 128.9, 126.7, 123.8, 115.2, 109.6, 77.5, 60.3; EIMS (m/z): 307 [M+]; Anal. Calcd.
for C15H11Cl2NO2: C, 58.46; H, 3.60; N, 4.55; Found: C, 58.23; H, 3.92; N, 4.67.
O
Cl
O
N
H
Me
3h
1
7-Chloro-2-methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3h): Yellowish oil. H-NMR (400 MHz,
CDCl3): 7.64 (m, 1H), 7.45 (br, 1H), 7.06–7.23 (m, 2H), 4.6 (dd, J = 12.2, 8.1 Hz, 1H), 3.98 (dd, J = 12.2,
5.6 Hz, 1H), 3.12–3.71 (m, 1H), 1.36 (d, J = 7.2 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.5, 147.3,
133.1, 130.2, 123.1, 116.8, 109.3, 77.5, 53.4, 18.3; EIMS (m/z): 211 [M+]; Anal. Calcd. for C10H10ClNO2:
C, 56.75; H, 4.76; N, 6.62; Found: C, 56.89; H, 5.18; N, 6.34.
O
Me
O
N
H
3i
1
7-Methyl-2-phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3i): Yellowish oil. H-NMR (400 MHz,
CDCl3): 7.58 (m, 1H), 7.41 (br, 1H), 7.06–7.40 (m, 7H), 5.00 (dd, J = 8.0, 5.6 Hz, 1H), 4.06 (dd, J = 12.2,
8.0 Hz, 1H), 3.92 (dd, J = 12.2, 5.6 Hz, 1H), 2.40 (s, 3H). 13C-NMR (100 MHz, CDCl3): 168.5, 147.2, 139.4,
133.3, 130.8, 128.9, 127.7, 126.9, 126.2, 116.7, 109.3, 77.8, 60.3, 25.3; EIMS (m/z): 253 [M+]; Anal. Calcd.
for C16H15NO2: C, 75.87; H, 5.97; N, 5.53; Found: C, 75.65; H, 6.28; N, 5.33.
O
Me
O
N
H
3j
Me
1
7-Methyl-2-p-tolyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3j): Yellowish oil. H-NMR (400 MHz,
CDCl3): 7.56 (m, 1H), 7.44 (br, 1H), 7.06–7.36 (m, 6H), 4.98 (dd, J = 7.9, 5.6 Hz, 1H), 4.02 (dd, J = 12.2,
7.9 Hz, 1H), 3.90 (dd, J = 12.2, 5.6 Hz, 1H), 2.39 (s, 6H); 13C-NMR (100 MHz, CDCl3): 168.2, 147.5,
138.3, 135.1, 132.4, 130.8, 128.8, 127.5, 126.2, 116.2, 109.1, 77.2, 60.5, 25.8, 25.3; EIMS (m/z): 267 [M+];
Anal. Calcd. for C17H17NO2: C, 76.38; H, 6.41; N, 5.24; Found: C, 76.69; H, 6.24; N, 5.53.

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O
Me
O
N
H
3k
Cl
1
2-(4-Chloro-phenyl)-7-methyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3k): Yellowish oil. H-NMR
(400 MHz, CDCl3): 7.60 (m, 1H), 7.47 (br, 1H), 7.06-7.44 (m, 6H), 5.08 (dd, J = 8.0, 5.7 Hz, 1H),
4.10 (dd, J = 12.2, 8.0 Hz, 1H), 3.98 (dd, J = 12.2, 5.7 Hz, 1H), 2.42 (s, 3H); 13C-NMR (100 MHz, CDCl3):
168.1, 147.5, 139.6, 133.5, 132.2, 131.1, 128.3, 127.5, 126.4, 115.7, 109.7, 77.4, 60.7, 25.4; EIMS (m/z):
287 [M+]; Anal. Calcd. for C16H14ClNO2: C, 66.79; H, 4.90; N, 4.87; Found: C, 67.09; H, 4.99; N, 4.54.
O
Me
O
N
H
Me
3l
1
2,7-Dimethyl-2,3-dihydro-1H-benzo[e][1,4] xazepine-5-one (3l): Yellowish oil. H-NMR (400 MHz, CDCl3):
7.62 (m, 1H), 7.43 (br, 1H), 7.04–7.20 (m, 2H), 4.56 (dd, J = 12.2, 8.0 Hz, 1H), 3.93 (dd, J = 12.2, 5.4 Hz,
1H), 3.10–3.70 (m, 1H), 2.41 (s, 3H), 1.34 (d, J = 7.0 Hz, 3H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.1,
133.5, 130.9, 126.8, 115.8, 109.2, 77.5, 53.4, 25.3, 18.3; EIMS (m/z): 191 [M+]; Anal. Calcd. for C11H13NO2:
C, 69.09; H, 6.85; N, 7.32; Found: C, 69.41; H, 6.55; N, 7.16.
O
O
N
H
5a
1
5a,6,7,8,9,9a-Hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5a): Yellowish oil. H-NMR
(400 MHz, CDCl3): 7.60 (m, 1H), 7.48 (br, 1H), 7.02–7.39 (m, 3H), 4.22 (dd, J = 11.3, 3.4 Hz, 1H),
3.11 (dd, J = 11.3, 3.5 Hz, 1H), 1.61–1.93 (m, 4H), 1.43–1.52 (m, 4H); 13C-NMR (100 MHz, CDCl3): 168.2,
147.6, 132.6, 130.1, 118.2, 115.9, 108.8, 85.8, 56.1, 28.5, 27.6, 22.9, 21.7; EIMS (m/z): 217 [M+]; Anal. Calcd.
for C13H15NO2: C, 71.87; H, 6.96; N, 6.45; Found: C, 71.72; H, 6.66; N, 6.73.
O
Cl
O
N
H
5b
2-Chloro-5a,6,7,8,9,9a-hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5b): Yellowish oil.
1H-NMR (400 MHz, CDCl3): 7.62 (m, 1H), 7.49 (br, 1H), 7.05–7.43 (m, 2H), 4.26 (dd, J = 11.3, 3.5 Hz,

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1H), 3.11 (dd, J = 11.3, 3.7 Hz, 1H), 1.62–1.95 (m, 4H), 1.43–1.54 (m, 4H); 13C-NMR (100 MHz, CDCl3):
168.3, 147.1, 133.1, 130.4, 122.5, 116.1, 108.2, 85.6, 56.5, 28.8, 27.2, 22.7, 21.5; EIMS (m/z): 251 [M+];
Anal. Calcd. for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56; Found: C, 62.19; H, 5.31; N, 5.34.
O
Me
O
N
H
5c
2-Methyl-5a,6,7,8,9,9a-hexahydro-5H-10-oxa-5-aza-dibenzo[a,d]cyclohepten-11-one (5c): Yellowish oil.
1H-NMR (400 MHz, CDCl3): 7.58 (m, 1H), 7.46 (1H, br), 7.00–7.35 (m, 2H), 4.20 (dd, J = 11.2, 3.2 Hz, 1H),
3.09 (dd, J = 11.2, 3.4 Hz, 1H), 2.40 (s, 3H), 1.60–1.91 (m, 4H), 1.42–1.50 (m, 4H); 13C-NMR (100 MHz,
CDCl3): 168.4, 147.3, 133.4, 130.8, 126.1, 116.1, 108.5, 85.4, 56.3, 28.7, 27.8, 22.8, 21.5; EIMS (m/z):
231 [M+]; Anal. Calcd. for C14H17NO2: C, 72.70; H, 7.41; N, 6.06; Found: C, 72.99; H, 7.28; N, 6.48.
3. Experimental Section
3.1. General Procedure for Preparation of L1–L6
Dimethylformamide dimethyl acetal (DMF-DMA) (10 mmol, 1.19 g) and 1-(1-hydroxy-1H-
inden-2-yl)-ethanone (10 mmol, 1.74 g) were dissolved in p-xylene (5 mL). Additionally, the mixture
was refluxed during a period of 5–12 h, during which time a yellow precipitate formed. The precipitate
was filtered out and washed with petroleum ether three times. The solid was vacuum-dried, and 1.89 g
1
(yield 94%) of a yellow solid were obtained, L1 2-(2-dimethylamino-vinyl)-1H-inden-1-ol. H-NMR
(400 MHz, CDCl3):
δ 7.23 (m, 2H), 7.17–7.07 (t, J = 8.0 Hz, 2H), 7.01–6.90 (t, J = 7.8 Hz, 1H), 6.60 (s, 1H),
6.07–6.05 (d, J = 12 Hz, 1H), 2.47 (s, 3H), 2.42 (s, 3H); 13C-NMR (100 MHz, CDCl3):
δ 146.1, 141.2, 133.8,
130.2, 127.9, 126.9, 123.2,121.2, 120.6, 104.1, 75.4, 46.1, 38.6.
3.2. 2-Phenyl-2,3-dihydro-1H-benzo[e][1,4]oxazepin-5-one (3a)
A mixture of phenylamine 1a (0.5 mmol, 46.5 mg), (1-chloro-vinyl)-benzene 2a (0.6 mmol, 83.4 mg),
CuI (10 mol %, 9.5 mg), L1 (10 mol %, 20.1 mg) and Cs2CO3 (2 equiv., 325.8 mg) in DMSO (4 mL) was
stirred in CO2 at 100 ◦C for 10 h. After completion of the reaction, the mixture was quenched with
saturated salt water (10 mL); the solution was extracted with ethyl acetate (3
layers were combined and dried over sodium sulfate. The pure product was obtained by flash column
×
10 mL). The organic
chromatography on silica gel to afford 3a 96.8 mg in 81% yield. The spectroscopic data of all of the
1
products are represented below. Yellowish oil. H-NMR (400 MHz, CDCl3): 7.63 (m, 1H), 7.43 (br, 1H),
7.08–7.43 (m, 8H), 5.07 (dd, J = 8.0, 5.7 Hz, 1H), 4.08 (dd, J = 12.3, 8.0 Hz, 1H), 3.96 (dd, J = 12.3,
5.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3): 168.3, 147.7, 139.1, 132.9, 130.3, 128.6, 127.5, 126.6, 117.8,
116.4, 109.1, 77.6, 60.2; EIMS (m/z): 239 [M+]; Anal. Calcd. for C15H13NO2: C, 75.30; H, 5.48; N, 5.85;
Found: C, 75.62; H, 5.13; N, 5.68.
4. Conclusions
In conclusion, we have found a green protocol for the synthesis of benzo-1,4-oxazepine derivatives
involving tandem transformation of C-N coupling/C-H carbonylation. The method was economically
viable and relevant to green chemistry.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/21/
1/53/s1.
Acknowledgments: This work was supported by the Natural Science Foundation of Zhejiang Province
(No. LQ15B020004), Natural Science Foundation ZA & FU (No. 04251700011).

Molecules 2017, 22, 53
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Author Contributions: R.S.X. designed the experiments; J.Z. and Z.Z. analyzed the data and wrote the paper;
X.J.Z. performed the experiments.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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2016 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access
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