Pd-Catalyzed C(sp2)-H Imidoylative Annulation: A General Approach to Construct Dibenzoox(di)azepines

Article abstract of DOI:10.1021/acs.joc.9b00683

A general method to construct the scaffolds of dibenzooxazepine and dibenzodiazepine, through Pd-catalyzed isocyanide insertion and intramolecular C(sp²)-H activation, has been developed. This is the first example of seven-membered heterocycle

Full text of DOI:10.1021/acs.joc.9b00683

Subscriber access provided by UNIV AUTONOMA DE COAHUILA UADEC
Note
Pd-Catalyzed C(sp2)-H Imidoylative Annulation: a
General Approach to Construct Dibenzoox(di)azepines
Weiming Hu, Fan Teng, Huaanzi Hu, Shuang Luo, and Qiang Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00683 • Publication Date (Web): 03 May 2019
Downloaded from http://pubs.acs.org on May 3, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 33
1
The Journal of Organic Chemistry
Pd-Catalyzed C(sp2)−H Imidoylative Annulation: a General
2
Approach to Construct Dibenzoox(di)azepines
3
4
5
6
7
8
9
Weiming Hu,ab Fan Teng,ab Huaanzi Hu,ab Shuang Luo,*ab and Qiang Zhu*ab
a State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan Avenue, Guangzhou 510530 (China), Fax: (+86) 20-3201-5299;
b University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Shijingshan District, Beijing 100049, China
E-mail: luo_shuang@gibh.ac.cn; zhu_qiang@gibh.ac.cn.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABSTRACT
N
O
X
Pd(OAc)2
RI
N
N
NC
R
R
X = NCH3
X = O
A general method to construct the scaffolds of dibenzooxazepine and dibenzodiazepine, through Pd-catalyzed
isocyanide insertion and intramolecular C(sp2)−H activation, has been developed. This is the first example of seven-
membered heterocycle formation by C−H imidoylative annulation.
Dibenzooxazepine and dibenzodiazepine, both of which are seven-membered heterocycles fusing with two aromatic
rings, exist as core structures of several marketed drugs including amoxapine, dibenzepin, nitroxazepine,1 loxapine,
and clozapine,2 for the treatment of depression and schizophrenia (Figure 1). Besides, their derivatives as well as
analogues exhibit diverse biological activities such as histone deacetylase inhibitors,3 antitumor agents,4 calcium
channel antagonists,5a histamine H4 receptor agonists,5b and lachrymatory agents5c (Figure 1). Meanwhile,
dibenzoox(di)azepines can serve as indispensable intermediates for the preparation of secoiridoids and monoterpenoid
alkaloids.6 Therefore, much attention has been paid for their synthesis,7 including ring-expansion,8 Beckmann
rearrangement,9 and other multistep sequences.10 However, the less efficiency of these synthetic routes still awaits for a
straightforward and general approach applicable for both scaffolds of dibenzooxazepine and dibenzodiazepine.11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 33
O
O
N
1
2
3
4
5
6
7
8
Cl
NO2
N
N
N
( )
N
O
N
O
3
N
N
R
nitroxazepine1e-h
R = Me, loxapine2
dibenzepin1d
R = H, amoxapine1a-c
H
N
O
9
Cl
O
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
N
N
NH
( )
O
5
N
clozapine2c
histone deacetylase inhibitor3
antihistaminics I5
Figure 1. Dibenzoox(di)azepine containing drugs or biological active molecules.
Transition metal-catalyzed annulation reaction involving C−H activation has been proven to be an efficient and
atom-economical strategy for the construction of heterocycles.12 In this context, Pd-catalyzed imidoylation of the so-
called functionalized isocyanides,13 followed by intramolecular C−H activation, has gained increasing interest for the
synthesis of N-heterocycles in recent years. For instance, in 2003, Takemoto reported a Pd-catalyzed cascade process
for the construction of indole skeleton via activation of benzylic C(sp3)−H (a, Scheme 1).14 Activation of aromatic
C−H bond by an imidoyl palladium intermediate is more common, as exemplified by recent synthesis of 1H-isoindoles,
phenanthridines and β-carbolines (a and b).15 Enantioselective synthesis of central and planar six-membered cyclic
imines was also realized by desymmetrizing imidoylation of C(sp2)–H bond (b).16 In spite of these achievements, the
preparation of seven-membered heterocycles by C–H imidoylative annulation is still unprecedented, partly due to the
energy barrier during the formation of eight-membered palladacycle intermediates.17 Continuing our interest in
isocyanide chemistry, we envision that seven-membered dibenzooxazepine and dibenzodiazepine scaffolds could be
constructed using 1-isocyano-2-phenoxybenzenes and 2-isocyano-N-phenylanilines as functionalized isocyanides,
respectively (c).
ACS Paragon Plus Environment

Page 3 of 33
The Journal of Organic Chemistry
(a) Five-membered ring
1
2
3
4
R
H
H
ref. 15a
ref. 14
R
N
NC
R2
N
H
NC
R2
R1
R1
5
6
(b) Six-membered ring
7
8
9
CO2Et
NC
CO2Et
N
R
ref. 15b
ref. 15c
H
H
NC
N
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
N
H
N
R
R2
R1
R2
R1
CN
H
CO2Et
Ph
CO2Et
N
R
ref.16a
Ph
ref. 16b
NC
N
Fe
Fe
H
R
(c) This work: seven-membered ring
N
O
X
N
R
N
NC
R
X = NCH3
X = O
Scheme 1. Pd-catalyzed C−H cycloimidoylation
Initially, 1-isocyano-2-phenoxybenzene was chosen to react with iodobenzene 2a. However, product generated
from double isocyanide insertion product was obtained, probably due to the unfavorable reaction distance between the
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
15
C(sp2)-H bond to be activated and the Pd(II) intermediate after isocyanide insertion.
Thus, ortho-substituted
functionalized isocyanide 1a and iodobenzene 2a were selected as model substrates in the reaction. Indeed, the desired
dibenzooxazepine 3a was formed in 15% yield catalyzed by Pd(OAc)2/PPh3 in the presence of Na2CO3 as a base in
DMF (entry 1). Screening of bases revealed that Cs2CO3 could promote the reaction much more efficiently, and 3a was
isolated in 40% yield (entries 2-4). However, the yield could not be improved in other solvents, such as DMSO, 1,4-
dioxane, toluene, or xylene (entries 5-8). Intriguingly, in a co-solvent of DMF/DMSO in 1:1 ratio, the annulation
efficiency was increased dramatically (56%, entry 9). Acidic additives, such as CH3COOH, CF3COOH and PivOH
were subsequently evaluated, suggesting the superiority of PivOH in the current C−H imidoylation process (entries 10-
12). No positive results were observed when varying the reaction temperature or tuning the volume ratio of DMF to
DMSO (entries 12-13). The yield of 3a decreased slightly when the combination of Cs2CO3 and PivOH was replaced
by CsOPiv, and only trace amount of 3a was detected when Cs2CO3 was absent (entries 14-15). The yield decreased
obviously when reducing the loading of palladium (entry 16).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 33
Table 1. Optimization of the reaction conditions.a
1
2
3
O
O
4
5
+
PhI
NC
N
Cl
6
7
Cl
Ph
1a
2a
3a
8
9
Base
Entry
1
Additive
Solvent
DMF
Yieldb (%)
Na2CO3
Cs2CO3
KOtBu
DBU
--
15
40
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2
--
DMF
3
--
DMF
<1
4
--
DMF
<1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOPiv
--
--
--
5
DMSO
36
6
1,4-Dioxane
Toluene
32
--
7
29
--
8
Xylene
10
9
DMF/DMSOc
DMF/DMSOc
DMF/DMSOc
DMF/DMSOc
DMF/DMSO
DMF/DMSOc
DMF/DMSOc
DMF/DMSOc
56
--
CH3COOH
CF3COOH
PivOH
PivOH
--
10
11
12
13
14
15
16
58
22
76, 69d, 75e
66f, 72g
59, 63h
<1
PivOH
PivOH
59i, 8j
Cs2CO3
a Reaction conditions: 2a (0.3 mmol, 1.5 equiv), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), base (0.6 equiv) and additive (1.5 equiv of acid) in solvent (1.0 mL) under
argon atmosphere at 80 oC. A solution of 1a (0.2 mmol, 1.0 equiv) in solvent (1 mL) was added to the reaction mixture via a syringe pump during 1 h. b Isolated yield.
c DMF:DMSO = 1:1. d 70 oC. e 90 oC. f DMF:DMSO = 1:5. g DMF:DMSO = 5:1. hCsOPiv (1.2 equiv). iPd(OAc)2 (5%), PPh3 (10%). jPd(OAc)2 (2%), PPh3 (4%).
With the optimal conditions in hand, we next evaluated the scope of aryl iodide for the preparation of C11
arylated dibenzooxazepines (Scheme 2). Aryl iodides bearing electron-donating substituents in the para- or
meta-position, such as methyl, methoxy and phenyl could react smoothly to provide the corresponding
dibenzooxazepines 3b, 3c and 3k in 71%, 51% and 58% yield, respectively. Meanwhile, aryl iodides
substituted with electron-withdrawing groups were also good aryl sources for this imidoylative annulation
reaction, including halides (3e-3f, 66-78%; 3l-3m, 73-76%), trifluoromethyl (3g, 69%; 3n, 65%), aldehyde
group (3h, 68%), ethoxycarbonyl (3i, 72%; 3o, 70%) and acetyl (3j, 78%). However, ortho-bromo substituted
iodide delivered the desired product 3r in much lower yield (46% vs 66% for 3f and 73% for 3m), suggesting
that the steric effect of iodide was unneglectable. In addition, the compatibility of the functionalities in these
ACS Paragon Plus Environment

Page 5 of 33
The Journal of Organic Chemistry
products, particularly for ester, aldehyde, and halide, provided facile handles for further transformations. 3,4-
and 3,5-disubstituted aryl iodides as well as 1-iodonaphthalene were all compatible, giving the desired
products 3s-3u in 50-72% yields. To prove the practicality of this approach, a 2.0 mmol scale reaction was
carried out, and the product 3a was isolated in a comparable yield of 71%. Unfortunately, when PhBr,
PhOTf, or MeI was used as electrophile in place of aryl iodide, no target product was formed.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
O
O
+
ArI
NC
PivOH (1.5 equiv)
N
Cl
Cl
Ar
Cs2CO3 (0.6 equiv)
DMF/DMSO, 80 oC, Ar
3
2
1a
3a
, R = H, 76%; 71%a
3b
, R = Me, 71%
O
O
3c
, R = OMe, 51%
3k
, R = OMe, 58%
3d
, R = Ph, 68%
, R = Cl, 78%
, R = Br, 66%
3l
3m
, R = Cl, 76%
N
N
3e
3f
Cl
, R = Br, 73%
Cl
3n
3o
, R = CF3, 65%
3g
, R = CF3, 69%
, R = CHO, 68%
, R = COOEt, 72%
, R = COOEt, 70%
3h
R
R
3i
3j
, R = COMe, 78%
O
O
O
O
N
N
N
Cl
N
Cl
Cl
Cl
Cl
R
Cl
3p
, R = Me, 74%
, R = F, 63%
, R = Br, 46%
3q
3r
3s
, 58%
3t
, 50%
3u
, 72%
Scheme 2. The scope of aryl iodides. Reaction conditions: 2 (0.3 mmol, 1.5 equiv), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), PivOH (1.5 equiv) and
Cs2CO3 (0.6 equiv) in solvent (1.0 mL) under argon atmosphere at 80 oC. A solution of 1a (0.2 mmol, 1.0 equiv) in solvent (1 mL) was added to the reaction mixture
via a syringe pump within 1 h, isolated yield. a 2.0 mmol scale.
Next, a variety of 1-isocyano-2-phenoxybenzenes 1 bearing substituents mainly on the non-isocyano aromatic
ring were investigated (Scheme 3). These functionalized isocyanides were readily accessible through nucleophilic
substitution of ortho-fluoro nitrobenzenes with various phenols followed by three steps of routine transformations.
No matter the electronic nature of the para-substituents, these functionalized isocyanides reacted smoothly with
iodobenzene 2a to provide diversified dibenzooxazepine derivatives in similar yields (3v-3y, 3z, and 3aa, 76-
78%). When the substituents were located at the ortho-position, even for the bulky tert-butyl group, the
corresponding dibenzooxazepine products were formed equally well (3ab-3ah, 65-75%).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 33
Pd(OAc)2 (10 mol%)
PPh3 (20 mol%)
O
O
1
2
3
4
Ar1
Ar2
Ph
Ar1
Ar2
+
PhI
PivOH (1.5 equiv)
NC
N
Cs2CO3 (0.6 equiv)
DMF/DMSO, 80 oC, Ar
2a
3
1
5
6
7
8
O
t
O
3v
, R = Bu, 77%
R
3w
, R = OMe, 77%
, R = F, 78%
R
N
3x
3y
N
Ph
Cl
Cl
Ph
R
, R = Cl, 77%
3z
, 76%, R = Cl
9
3aa
, 78%, R = Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R
O
O
O
N
N
N
Ph
Ph
Ph
t
3ab
3ac
3ad
3ae
, R = Bu, 71%
3af
, R = H, 73%
, R = OMe, 65%
i
3ag
, R = Cl, 75%
, R = Br, 73%
3ai
, 69%
, R = Pr, 70%
3ah
, R = Ph, 69%
Scheme 3. Scope of functionalized isocyanides. Reaction conditions: 2a (0.3 mmol, 1.5 equiv), Pd(OAc)2 (10 mol%), PPh3 (20 mol%), PivOH (1.5
equiv) and Cs2CO3 (0.6 equiv) in solvent (1.0 mL) under argon atmosphere at 80 oC. A solution of 1 (0.2 mmol, 1.0 equiv) in solvent (1 mL) was added to the reaction
mixture via a syringe pump within 1 h.
Then, The feasibility of the current Pd-catalyzed C(sp2)−H imidoylative annulation for the construction of
seven-membered heterocycles was further proven in dibenzodiazepine synthesis. As shown in Scheme 4, 2-
isocyano-N-methyl-N-phenylanilines, obtained similarly as 1-isocyano-2-phenoxybenzenes, cyclized well under
the slightly modified conditions. The corresponding diversified dibenzodiazepines were delivered in moderate to
good yields (5a-5g, 45-86%).
Pd(OAc)2 (10 mol%)
N
N
PPh3 (20 mol%)
Ar1
Ar2
Ar1
Ar2
ArI
+
PivOH (1.5 equiv)
NC
N
Cs2CO3 (0.6 equiv)
DMF/DMSO, 80 oC, Ar
Ph
2
5
4
N
N
N
R
N
N
N
Cl
Cl
Cl
Ph
R
Cl
5a
, R = H, 86%
5d
, R = 3,5-diMe, 61%
t
Cl
5b
, R = Bu, 45%
5e
5f
, R = 4-Ph, 73%
5c
, R = Br, 79%
, R = 4-COOMe, 78%
5g
, 76%
Scheme 4. Synthesis of dibenzodiazepines. Reaction conditions: Pd(OAc)2 (10 mol%), PPh3 (20 mol%), PivOH (1.5 equiv) and Cs2CO3 (0.6 equiv)
in solvent (1.0 mL) under argon atmosphere at 80 oC, after being stirred for 20 min, 2a (0.3 mmol, 1.5 equiv) was added. Then a solution of 4 (0.2 mmol, 1.0 equiv) in
solvent (1 mL) was added to the reaction mixture via a syringe pump within 1 h.
Although the requirement of an ortho-substituent in isocyanides 1 and 4 is an obvious limitation of this method,
the substituent could be removed or transformed to other functionalities. For example, the C9-chloride in
dibenzooxazepine 3a could be reduced via Pd-catalysis in 92% yield (eq 1, Scheme 5).18 Furthermore, amination
at this position was also realized successfully through Buchwald–Hartwig cross-coupling,19 affording C9
ACS Paragon Plus Environment

Page 7 of 33
The Journal of Organic Chemistry
aminated product 3ak in 89% yield (eq 2). Besides, replacing aryl iodide with O-benzoyl hydroxylamine also
afforded corresponding amino substituted dibenzooxazepine 3al in 23% yield using toluene as a solvent at 100 oC
(eq 3). Notably, functionalized isocyanide 6, derived from 2-methylindole, cyclized smoothly to deliver a unique
indole-fused analogue 7 in 78% yield (eq 4). Besides, a seven-membered phosphine-containing analogue 9 was
synthesized in good yield (eq 5). These results further demonstrated the viability of the current C(sp2)−H
imidoylative annulation in seven-membered heterocycle synthesis.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
Pd(OAc)2, JohnPhos
eq 1
eq 2
HCOONa, MeOH
92%
N
Ph
Ph
N
Cl
Ph
O
3a
3aj
O
Pd(dba)2, tBuXPhos, PhNH2
89%
N
N
3a
O
HN
Ph
Cl
Cl
Ph
3ak
O
N
Pd(OAc)2,PPh3
+
BzO N
eq 3
toluene, 100 oC
23%
NC
N
Cl
1a
3al
N
N
I
78%
+
eq 4
Ph
CN
N
Cl
Cl
6
2a
7
Ph
O
I
Ph
O
P
P
87%
+
eq 5
N
NC
CHO
2l
8
9
CHO
Scheme 5. Derivatization of 3a and synthesis of structural analogues
In summary, a general and practical synthesis of seven-membered heterocycles via C(sp2)−H imidoylative
annulation has been developed. Diversified dibenzoox(di)azepine derivatives as well as their structural analogues
were synthesized in moderate to good yields. The ubiquitous existence of seven-membered heterocycles including
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 33
dibenzoox(di)azepine in drugs and biological active molecules anticipates the potential application of this
methodology in medicinal chemistry.
1
2
3
4
5
EXPERIMENTAL SECTION
6
7
8
9
General Information: Unless otherwise noted, all chemicals were purchased from commercial suppliers and used
without further purification. 1H NMR、13C NMR spectra were recorded at ambient temperature on a 400 or 500 MHz
NMR spectrometer (100 or 125 MHz for 13C). NMR experiments were reported in δ units, parts per million (ppm), and
were referenced to CDCl3 (7.26 or 77.0 ppm) as the internal standard. The coupling constants J were given in Hz.
High-resolution mass spectra (HRMS) were obtained using a Bruker micro-TOF II focus spectrometer. IR spectra were
recorded on a spectrometer using KBr discs. Column chromatography was performed using EM Silica gel 60 (300-400
mesh). All melting points were uncorrected.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Procedure:
General procedures for the Synthesis of Functionalized Isocyanides 1 (Take 1a as an example)
20
Procedure A: To a solution of 1-chloro-3-fluoro-2-nitrobenzene 10a (3 mmol, 1.0 equiv) and phenol 11a (3
mmol, 1.0 equiv) in DMF (9 mL) was added K2CO3 (3.6 mmol, 1.2 equiv) in air. The reaction mixture was stirred at
100 oC overnight. After cooling down, the reaction mixture was quenched with water (50 mL) and extracted with ethyl
acetate (15 mL × 3). The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4.
The solvent was evaporated, and the crude product was purified by flash column chromatography on silica gel
(hexane/EtOAc, 30:1) to afford 1-chloro-2-nitro-3-phenoxybenzene 12a in 98% yield (732 mg).
Procedure B: To a solution of 12a (2.5 mmol, 1.0 equiv) in EtOH (25 mL) was added iron powder (9.5 mmol, 3.8
o
equiv) and five drops of HCl (4 M) in air. The mixture was refluxed at 80 C for 4~12 hours (monitored by TLC).
After cooling down, the reaction mixture was diluted with EtOAc (20 mL) and passed through a short celite pad. The
solvent was evaporated under reduced pressure and the crude mixture was purified on a silica gel column
(hexane/EtOAc, 30:1) to obtain the corresponding 2-chloro-6-phenoxyaniline 13a in 92% yield (503 mg).
Procedure C: 2-Chloro-6-phenoxyaniline 13a (2.3 mmol, 1.0 equiv) was dissolved in dry THF (0.6 M) in an oven-
dried Schlenk flask in argon. Formic acetic anhydride, prepared by heating formic acid (2.7 equiv) and acetic
anhydride (2.3 equiv) at 55 oC for 2.5 h, was added dropwise to the aniline solution at 0 oC. The combined mixture was
stirred at room temperature for 2 h. Then, the reaction was quenched by adding saturated (sat.) aqueous (aq.) NaHCO3
solution, and extracted with ethyl acetate (EtOAc, 3 times). The combined organic layers were washed with brine,
dried over Na2SO4, and concentrated under vacuum. The crude product N-(2-chloro-6-phenoxyphenyl)formamide 14a
was used for the next step without purification.
Procedure D: The crude product 14a (2.3 mmol) was dissolved in DCM (0.6 M), and Et3N (6.7 equiv) was added in
argon. The solution was cooled to 0 oC and POCl3 (1.7 equiv) was added dropwise. The reaction mixture was stirred at
ACS Paragon Plus Environment

Page 9 of 33
The Journal of Organic Chemistry
0 oC for 1 hour. Then, it was quenched with sat. aq. Na2CO3 and the resulting mixture was stirred for another 1 h. The
mixture was extracted with DCM (3 times) and the combined organic layers were washed with brine, dried over
Na2SO4, and concentrated under vacuum. The desired 1-chloro-2-isocyano-3-phenoxybenzene 1a was purified by flash
column chromatography (hexane/EtOAc, 30:1) in 61% yield (321 mg).
1
2
3
4
5
6
7
8
9
General procedures for the Synthesis of Functionalized Isocyanides 4 (Take 4a as an example)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3-Chloro-N-methyl-2-nitro-N-phenylaniline 17a was prepared according to the literature.21 The functionalized
isocyanides 4 were synthesized by following the general procedures B to D.
General procedures for the Synthesis of Functionalized Isocyanides 6
Procedure E: To a solution of 1-chloro-3-fluoro-2-nitrobenzene 10a (3 mmol, 1.0 equiv) and 2-methylindole 20 (3
mmol, 1.0 equiv) in DMSO (9 mL) was added NaOH (1.5 equiv) in air. The reaction mixture was stirred at room
temperature for 4 h. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (15 mL ×
3). The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. The solvent was
evaporated, and the crude mixture was purified by flash column chromatography on silica gel (hexane/EtOAc, 30:1) to
afford 1-(3-chloro-2-nitrophenyl)-2-methyl-1H-indole 21 in 90% yield (772 mg).
The following steps (steps 2-4) were the same as the general procedures B to D to get 6 in 58% overall yield (462
mg).
General procedures for the Synthesis of Functionalized Isocyanides 8
Compound (2-amino-3-methylphenyl)diphenylphosphine oxide 26 was prepared according to the reported method.22
The following steps were the same as the general procedures B to D to get 8 in 30% overall yield (285 mg).
General Procedure for the Synthesis of Dibenzooxazepines 3
An oven-dried Schlenk tube (25 mL) charged with ArI 2 (0.3 mmol, 1.5 equiv), Pd(OAc)2 (4.5 mg, 10 mol%), PPh3
(10.6 mg, 20 mol%), Cs2CO3 (40 mg, 0.6 equiv), PivOH (35 μl, 1.5 equiv), and 1 mL of solvent (DMF : DMSO, 1:1)
o
was vacuumed and refilled with Ar for 3 times. The tube was placed in an 80 C oil-bath, and a solution of
functionalized isocyanide 1 (0.2 mmol, 1.0 equiv) in 1.0 mL of solvent (DMF : DMSO, 1:1) was added slowly through
a syringe pump during 1 h. At the end of addition, the reaction mixture was cooled to room temperature and 10 mL of
water was added. Then, the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were
washed with saturated brine and dried by anhydrous Na2SO4. The solvent was evaporated under reduced pressure and
the residue was purified on a silica gel column (hexane/EtOAc, 60:1) to obtain the corresponding product 3.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 33
General Procedure for the Synthesis of Dibenzooxazepine 3a in a 2.0 mmol Scale
1
2
3
4
An oven-dried Schlenk tube (100 mL) charged with PhI 2a (335 μL, 3 mmol, 1.5 equiv), Pd(OAc)2 (45 mg, 10
mol%), PPh3 (106 mg, 20 mol%), Cs2CO3 (400 mg, 0.6 equiv), PivOH (350 μL, 1.5 equiv), and 10 mL of solvent
5
6
o
(DMF : DMSO, 1:1) was vacuumed and refilled with Ar for 3 times. The tube was placed in an 80 C oil-bath, and a
7
8
9
solution of functionalized isocyanide 1a (2 mmol, 1.0 equiv) in 10 mL of solvent (DMF : DMSO, 1:1) was added
slowly through a syringe pump during 2 h. At the end of addition, the reaction mixture was cooled to room temperature
and 60 mL of water was added. Then, the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic
layers were washed with saturated brine and dried by anhydrous Na2SO4. The solvent was evaporated under reduced
pressure and the residue was purified on a silica gel column (hexane/EtOAc, 60:1) to obtain 3a in 71% yield (433mg).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Synthesis of amino substituted dibenzooxazepine 3al
An oven-dried Schlenk tube (25 mL) charged with piperidin-1-yl benzoate (0.3 mmol, 61.5mg, 1.5 equiv), Pd(OAc)2
(4.5 mg, 10 mol%), PPh3 (10.6 mg, 20 mol%), Cs2CO3 (40 mg, 0.6 equiv), PivOH (35 μl, 1.5 equiv), and 1 mL of
o
toluene was vacuumed and refilled with Ar for 3 times. The tube was placed in an 100 C oil-bath, and a solution of
functionalized isocyanide 1a (0.2 mmol, 46mg, 1.0 equiv) in 1.0 mL of toluene was added slowly through a syringe
pump during 1 h. At the end of addition, the reaction mixture was cooled to room temperature. The solvent was
evaporated under reduced pressure and the residue was purified on a silica gel column (hexane/EtOAc, 30:1) to obtain
the corresponding product 3al in 23% yield as a colorless oil (14.3 mg).
General Procedure for the Synthesis of Dibenzodiazepines 5
An oven-dried Schlenk tube (25 mL) charged with Pd(OAc)2 (4.5 mg, 10 mol%), PPh3 (10.6 mg, 20 mol%), Cs2CO3
(40 mg, 0.6 equiv), PivOH (35 μL, 1.5 equiv), and 1 mL of solvent (DMF : DMSO, 1:1) was vacuumed and refilled
with Ar for 3 times. The tube was placed in an 80 oC oil-bath. The mixture was stirred for 20 min at this temperature.
ArI 2 (0.3 mmol, 1.5 equiv) was added and a solution of functionalized isocyanide 4 (0.2 mmol, 1.0 equiv) in 1.0 mL
of solvent (DMF : DMSO, 1:1) was added slowly through a syringe pump during 1 h. At the end of addition, the
reaction mixture was cooled to room temperature and 10 mL of water was added. Then, the mixture was extracted with
ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine and dried by anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column
(hexane/EtOAc, 60:1) to obtain the corresponding product 5.
General Procedure for the Synthesis of 7
ACS Paragon Plus Environment

Page 11 of 33
1
The Journal of Organic Chemistry
An oven-dried Schlenk tube (25 mL) charged with Pd(OAc)2 (4.5 mg, 10 mol%), PPh3 (10.6 mg, 20 mol%), Cs2CO3
2
3
4
5
(40 mg, 0.6 equiv), 2a (34 μL, 0.3 mmol, 1.5 equiv), PivOH (35 μL, 1.5 equiv), and 1 mL of 1,4-dioxane was
o
vacuumed and refilled with Ar for 3 times. The tube was placed in an 80 C oil-bath. A solution of 6 (0.2 mmol, 1.0
6
7
8
9
equiv) in 1.0 mL of 1,4-dioxane was added slowly through a syringe pump during 1 h. At the end of addition, the
reaction mixture was cooled to room temperature and 10 mL of water was added. Then, the mixture was extracted with
ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine and dried by anhydrous
Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column
(hexane/EtOAc, 30:1) to obtain product 7 in 78% yield (53.4 mg).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the Synthesis of 9
An oven-dried Schlenk tube (25 mL) charged with Pd(OAc)2 (4.5 mg, 10 mol%), PPh3 (10.6 mg, 20 mol%), Cs2CO3
(40 mg, 0.6 equiv), PivOH (35 μL, 1.5 equiv) and 1 mL of DMF was vacuumed and refilled with Ar for 3 times. The
tube was placed in an 80 oC oil-bath. The mixture was stirred for 20 min at this temperature. 2l (0.3 mmol, 1.5 equiv)
was added to the mixture and a solution of 8 (0.2 mmol, 1.0 equiv) in 1.0 mL of DMF was added slowly through a
syringe pump during 1 h. At the end of addition, the reaction mixture was quenched by adding 10 mL of water and
extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated brine and dried by
anhydrous Na2SO4. The solvent was evaporated, and the crude mixture was purified by flash column chromatography
on silica gel (hexane/EtOAc, 2:1) to obtain product 9 in 87% yield (73.3 mg).
General Procedure for the Redutive Dechlorination of 3a
An oven-dried Schlenk tube (25 mL) charged with a magnetic stirring bar, Pd(OAc)2 (0.5mg, 2 mol%), 2-(di-tert-
butylphosphino) biphenyl (1.2 mg, 4 mol%), sodium formate (13.6 mg, 2.0 equiv), and 2 mL of methanol was
vacuumed and refilled with Ar for 3 times. The reaction mixture was stirred for 5 min at room temperature, then
o
dibenzooxazepine 3a (30.5mg, 0.1 mmol) was added. The tube was placed in an oil-bath (68 C) and the reaction
mixture was stirred for 10 h. The reaction mixture was cooled to room temperature and the solvent was evaporated.
The crude mixture was purified by flash column chromatography on silica gel (hexane/EtOAc, 60:1) to obtain product
3aj in 92% yield (24.9 mg).
General Procedure for the Cross-coupling of 3a
t
An oven-dried Schlenk tube (25 mL) charged with a magnetic stirring bar, Pd(dba)2 (2.9 mg, 5 mol%), BuXPhos
(4.3 mg, 10 mol%), NaOtBu (14 mg, 1.4 equiv), dibenzooxazepine 3a (30.5 mg, 0.1 mmol) and aniline (19 μL, 2.0
equiv) was vacuumed and refilled with Ar for 3 times. The solvent-free reaction mixture was stirred at 110 oC for 24 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 33
Subsequently, the reaction mixture was transferred to a column directly for chromatography purification
1
2
3
(hexane/EtOAc, 60:1) with minimum amount of CH2Cl2 to obtain product 3ak in 89% yield (32.2 mg).
4
5
Characterization Data
6
7
8
Chloro-2-isocyano-3-phenoxybenzene (1a)
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1a (67% overall yield, 460
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.42-7.39 (m, 2H), 7.24-7.17 (m, 3H), 7.08-7.06 (m, 2H), 6.78
(dd, J1= 8.1 Hz, J2 = 1.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.4, 155.1, 154.6, 132.1, 130.1, 129.8, 125.0,
123.6, 119.6, 116.0; HRMS (ESI) m/z calcd for C13H9ClNO+ (M+H)+ 230.0367, found 230.0370.
1-(4-(Tert-butyl)phenoxy)-3-chloro-2-isocyanobenzene (1b)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1b (61% overall yield, 521
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.42-7.40 (m, 2H), 7.21-7.14 (m, 2H), 7.01-6.99 (m, 2H), 6.78
(dd, J1= 8.3 Hz, J2 = 1.4 Hz, 1H), 1.34 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.3, 155.0, 152.6, 148.1, 132.1,
129.7, 127.0, 123.2, 119.3, 115.6, 34.5, 31.4; HRMS (ESI) m/z calcd for C17H17ClNO+ (M+H)+ 286.0993, found
286.0987.
1-Chloro-2-isocyano-3-(4-methoxyphenoxy)benzene (1c)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1c (23% overall yield, 180
1
mg) as a colorless oil. H NMR (CDCl3, 400 MHz) δ 7.19-7.10 (m, 2H), 7.03-6.99 (m, 2H), 6.94-6.90 (m, 2H), 6.68
(dd, J1= 8.4 Hz, J2 = 1.2 Hz, 1H), 3.82 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 172.9, 156.9, 155.6, 147.9, 131.9,
129.8, 122.8, 121.39, 115.1, 114.5, 55.59; HRMS (ESI) m/z calcd for C14H11ClNO2 (M+H)+ 260.0473, found
+
260.0479.
1-Chloro-3-(4-fluorophenoxy)-2-isocyanobenzene (1d)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1d (36% overall yield, 267
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.23-7.17 (m, 2H), 7.12-7.03 (m, 4H), 6.74 (dd, J1= 8.2 Hz, J2 =
1.5 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.6, 159.8 (d, JC-F = 243.1 Hz), 154.8, 150.8 (d, JC-F = 2.6 Hz,
132.3, 129.9, 123.7, 121.3 (d, JC-F = 8.4 Hz), 116.8 (d, JC-F = 23.5 Hz), 115.4; HRMS (ESI) m/z calcd for
C13H8ClFNO+ (M+H)+ 248.0273, found 248.0271.
ACS Paragon Plus Environment

Page 13 of 33
The Journal of Organic Chemistry
1-Chloro-3-(4-chlorophenoxy)-2-isocyanobenzene (1e)
1
2
3
4
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1e (57% overall yield, 448
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.38-7.35 (m, 2H), 7.24-7.20 (m, 2H), 7.02-6.99 (m, 2H), 6.80
5
6
7
(dd, J1= 9.6 Hz, J2 = 1.7 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.8, 154.1, 153.8, 132.4, 130.2, 130.2, 123.0,
124.2, 120.7, 116.2; HRMS (ESI) m/z calcd for C13H8Cl2NO+ (M+H)+ 263.9977, found 263.9980.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(4-Chlorophenoxy)-2-isocyano-3-methylbenzene (1f)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1f (49% overall yield, 357
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.33-7.31 (m, 2H), 7.21 (t, J = 8.0 Hz, 1H), 7.03-6.95 (m, 3H),
6.76 (d, J= 8.3 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 170.7, 154.6, 152.5, 137.3, 129.9, 129.5,
129.3, 125.0, 120.2, 116.1, 18.6; HRMS (ESI) m/z calcd for C14H11ClNO+ (M+H)+ 244.0524, found 244.0525.
1-(4-Bromophenoxy)-2-isocyano-3-methylbenzene (1g)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1g (45% overall yield, 387
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.47 (d, J = 10.9 Hz, 2H), 7.21 (t, J = 10.0 Hz, 1H), 7.03-6.90 (m,
3H), 6.76 (d, J= 10.4 Hz, 1H), 2.47 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 170.7, 155.2, 152.4, 137.3, 132.9,
129.5, 125.0, 120.5, 116.8, 116.2, 18.63; HRMS (ESI) m/z calcd for C14H11BrNO+ (M+H)+ 288.0019, found 288.0011.
1-(2-(tert-butyl)phenoxy)-3-chloro-2-isocyanobenzene (1h)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1h (30% overall yield, 256
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.47-7.45 (m, 1H), 7.22-7.14 (m, 4H), 6.85 (dd, J1 = 7.9 Hz, J2 =
1.5 Hz, 1H), 6.73 (dd, J1 = 8.3 Hz, J2 = 1.3 Hz, 1H), 1.41 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.3, 155.0,
153.6, 141.6, 132.2, 129.8, 127.9, 127.4, 125.0, 123.0, 120.6, 115.3, 34.8, 30.3; HRMS (ESI) m/z calcd for
C17H17ClNO+ (M+H)+ 286.0993, found 286.1003.
1-Chloro-2-isocyano-3-(2-methoxyphenoxy)benzene (1i)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1i (20% overall yield, 156) as
a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.25-7.20 (m, 1H), 7.15-7.07 (m, 3H), 7.03-6.95 (m, 2H), 6.55 (dd, J1 =
8.1 Hz, J2 = 1.6 Hz, 1H), 3.78 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 172.9, 155.2, 151.4, 142.7, 131.7, 129.6,
126.7, 122.6, 122.2, 121.3, 113.7, 113.2, 55.9; HRMS (ESI) m/z calcd for C14H11ClNO2 (M+H)+ 260.0473, found
+
260.0465.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 33
1
2
3
4
1-Chloro-2-isocyano-3-(2-isopropylphenoxy)benzene (1j)
5
6
7
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1j (31% overall yield, 252
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.40-7.38 (m, 1H), 7.25-7.12 (m, 4H), 6.94-6.92 (m, 1H), 6.64
8
9
(dd, J1 = 7.3 Hz, J2 = 1.4 Hz, 1H), 3.20-3.15 (m, 1H), 1.24 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ
173.3, 155.3, 151.7, 140.4, 132.1, 129.8, 127.5, 127.2, 125.8, 122.8, 120.2, 116.7, 114.3, 27.3, 22.9; HRMS (ESI) m/z
calcd for C16H15ClNO+ (M+H)+ 272.0837, found 272.0839.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2-(3-Chloro-2-isocyanophenoxy)-1,1'-biphenyl (1k)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1k (35% overall yield, 320
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.55-7.49 (m, 3H), 7.41-7.33 (m, 4H), 7.30-7.27 (m, 1H), 7.12
(dd, J1 = 8.0 Hz, J2 = 1.3 Hz, 1H), 7.06-7.00 (m, 2H), 6.53 (dd, J1 = 8.2 Hz, J2 = 1.5 Hz, 1H); 13C{1H} NMR (CDCl3,
125 MHz) δ 173.1, 154.7, 151.3, 136.7, 134.4, 131.8, 131.7, 129.5, 129.0, 128.3, 127.6, 126.0, 122.8, 121.1, 114.5;
HRMS (ESI) m/z calcd for C19H13ClNO+ (M+H)+ 306.0680, found 306.0677.
2-Isocyano-1-methyl-3-phenoxybenzene (1l)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1l (66% overall yield, 414
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.40-7.26 (m, 2H), 7.20-7.16 (m, 2H), 7.06-7.03 (m, 2H), 6.99 (d,
J = 7.7 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 2.48 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 170.3, 155.9, 153.1, 137.0,
129.9, 129.4, 124.4, 124.2, 119.1, 115.8, 18.65; HRMS (ESI) m/z calcd for C14H12NO+ (M+H)+ 210.0913, found
210.0908.
1-(2-Chlorophenoxy)-2-isocyano-3-methylbenzene (1m)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1m (59% overall yield, 430
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.50 (dd, J1= 8.0 Hz, J2 = 1.6 Hz, 1H), 7.31-7.28 (m, 1H), 7.21-
7.17 (m, 2H), 7.07 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 5.58 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H);
13C{1H} NMR (CDCl3, 125 MHz) δ 170.7, 152.6, 151.0, 137.0, 130.9, 129.3, 128.1, 126.2, 125.8, 124.4, 121.4, 117.6,
114.2, 18.57; HRMS (ESI) m/z calcd for C14H11ClNO+ (M+H)+ 244.0524, found 244.0529.
1-(2-Bromophenoxy)-2-isocyano-3-methylbenzene (1n)
ACS Paragon Plus Environment

Page 15 of 33
The Journal of Organic Chemistry
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1n (49% overall yield, 421
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.65 (dd, J1= 8.0 Hz, J2 = 1.6 Hz, 1H), 7.33-7.30 (m, 1H), 7.17 (t,
J = 8.0 Hz, 1H), 7.10 (dt, J1 = 7.9 Hz, J2 = 1.5 Hz, 1H), 7.03-6.98 (m, 2H), 6.57 (d, J = 8.2 Hz, 1H), 2.48 (s, 3H);
13C{1H} NMR (CDCl3, 125 MHz) δ 170.7, 152.5, 152.2, 137.1, 134.1, 129.4, 128.8 126.1, 124.5, 121.2, 115.3, 114.5,
18.6; HRMS (ESI) m/z calcd for C14H11BrNO+ (M+H)+ 288.0019, found 288.0012.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1-(2,3-Dimethylphenoxy)-2-isocyano-3-methylbenzene (1o)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 1o (19% overall yield, 135
mg) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.13-7.08 (m, 3H), 6.91 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.9 Hz,
1H), 6.49 (d, J = 8.3 Hz, 1H), 3.48 (s, 3H), 3.33 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 169.8,
153.8, 153.0, 139.1, 136.8, 129.3, 128.7, 126.4, 126.3, 123.2, 117.7, 113.5, 20.0, 18.6, 12.1; HRMS (ESI) m/z calcd for
C16H16NO+ (M+H)+ 238.1226, found 238.1228.
3-Chloro-2-isocyano-N-methyl-N-phenylaniline (4a)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 4a (18% overall yield, 131
1
mg) as a colorless oil. H NMR (CDCl3, 500 MHz) δ 7.32-7.24 (m, 4H), 7.20-7.18 (m, 1H), 6.92 (t, J = 7.4 Hz, 1H),
6.81 (d, J = 7.9 Hz, 2H), 3.35 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.4, 147.8, 147.4, 132.4, 130.1, 129.2,
125.5, 125.2, 120.6, 116.8, 39.9; HRMS (ESI) m/z calcd for C14H12ClN2+ (M+H)+ 243.0684, found 243.0678.
N-(4-(tert-butyl)phenyl)-3-chloro-2-isocyano-N-methylaniline (4b)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 4b (12% overall yield, 108
mg) as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.30-7.22 (m, 4H), 7.17 (dd, J1 = 7.8 Hz, J2 = 1.7 Hz, 1H),6.79-
6.77 (m, 2H), 3.34 (s, 3H), 1.30 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.0, 147.7, 145.3, 143.6, 132.3, 129.9,
125.9, 124.97, 124.7, 116.9, 40.0, 34.0, 31.4; HRMS (ESI) m/z calcd for C18H20ClN2 (M+H)+ 299.1310, found
+
299.1304.
N-(4-bromophenyl)-3-chloro-2-isocyano-N-methylaniline (4c)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 4c (15% overall yield, 145
mg) as a colorless oil. 1H NMR (CDCl3, 500 MHz) δ 7.35-7.32 (m, 4H), 7.21-7.17 (m, 1H), 6.64 (d, J = 10.2 Hz, 2H),
3.32 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.8, 146.8, 146.7, 132.6, 132.0, 130.3, 126.3, 125.7, 117.8, 112.6,
39.8; HRMS (ESI) m/z calcd for C14H11BrClN2+ (M+H)+ 320.9789, found 320.9795.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 33
1
2
3
4
1-(3-Chloro-2-isocyanophenyl)-2-methyl-1H-indole (6)
5
6
7
8
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 6 (58% overall yield, 462 mg)
as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.66-7.50 (m, 3H), 7.37-7.35 (m, 1H), 7.19-7.12 (m, 2H), 6.90 (d, J =
7.2 Hz, 1H), 6.51 (s, 1H), 2.31 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 174.3, 137.7, 136.6, 136.5, 132.4, 130.1,
9
+
129.9, 128.69, 128.7, 121.7, 120.7, 120.0, 109.4, 102.9, 12.8; HRMS (ESI) m/z calcd for C16H12ClN2 (M+H)+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
267.0684, found 267.0677.
(2-Isocyano-3-methylphenyl)diphenylphosphine oxide (8)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 8 (30% overall yield, 285 mg)
as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.78-7.73 (m, 4H), 7.61-7.48 (m, 8H), 7.37 (dt, J1 = 7.7 Hz, J2 = 1.9
Hz, 1H), 3.41 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 173.2, 137.2 (d, Jc-p = 6 Hz), 134.4 (d, Jc-p = 2 Hz), 132.4 (d,
Jc-p = 3 Hz), 132.1 (d, Jc-p = 10 Hz), 13.8 (d, Jc-p = 107 Hz), 129.39 (d, Jc-p = 96 Hz), 128.8, 128.7, 128.6, 19.08; HRMS
(ESI) m/z calcd for C20H17NOP+ (M+H)+ 318.1042, found 318.1042.
9-Chloro-11-phenyldibenzo[b,f][1,4]oxazepine (3a)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3a (46.4 mg, 76% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.91 (d, J = 7.0 Hz, 2H), 7.54-7.45 (m, 4H), 7.30-7.25 (m, 3H), 7.21-7.17
(m, 1H), 7.13-7.07 (m, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.4, 161.7, 153.6, 139.7, 138.2, 133.2, 131.9,
131.2, 130.8, 130.0, 128.2, 127.1, 126.7, 124.8, 121.0, 119.1; HRMS (ESI) m/z calcd for C19H13ClNO (M+H)+
306.0680, found 306.0684; IR (KBr) 3059, 3021, 1610, 1563, 1487, 1440, 1412, 1374, 1315, 1285, 1240, 1220, 1189,
1146, 1108, 1034 cm-1.
9-Chloro-11-(p-tolyl)dibenzo[b,f][1,4]oxazepine (3b)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3b (45.3 mg, 71% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.77 (d, J = 8.1 Hz, 2H), 7.50-7.46 (m, 1H), 7.26-7.23 (m, 5H), 7.16 (dt, J1 =
7.6 Hz, J2 = 1.2 Hz, 1H), 7.10-7.03 (m, 2H), 2.41 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.3, 161.7, 153.7,
141.2, 138.3, 137.0, 133.1, 131.9, 131.3, 130.0, 129.0, 127.2, 126.9, 126.6, 124.8, 120.9, 119.1, 21.5; HRMS (ESI) m/z
calcd for C20H15ClNO (M+H)+ 320.0837, found 320.0841; IR (KBr) 3066, 3028, 2914, 1595, 1561, 1477, 1446, 1432,
1406, 1374, 1315, 1285, 1260, 1240, 1225, 1194, 1182, 1143, 1101, 1035 cm-1.
9-Chloro-11-(4-methoxyphenyl)dibenzo[b,f][1,4]oxazepine (3c)
ACS Paragon Plus Environment

Page 17 of 33
The Journal of Organic Chemistry
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3c (33.5 mg, 51% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.82-7.78 (m, 2H), 7.44-7.40 (m, 1H), 7.21-7.10 (m, 4H), 7.03-6.88 (m, 4H),
3.80 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.6, 162.0, 161.7, 153.6, 138.4, 133.1, 132.3, 131.7, 131.3, 127.1,
126.7, 126.6, 124.7, 120.9, 119.0, 113.6, 55.4; HRMS (ESI) m/z calcd for C20H15ClNO2 (M+H)+ 336.0786, found
336.0783; IR (KBr) 3061, 3028, 2939, 1602, 1590, 1583, 1569, 1490, 1458, 1443, 1369, 1328, 1280, 1222, 1205,
1187, 1182, 1146, 1035 cm-1.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11-([1,1'-Biphenyl]-4-yl)-9-chlorodibenzo[b,f][1,4]oxazepine (3d)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3d (51.8 mg, 68% yield) as a
o
1
yellow solid. m.p. 135-136 C. H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 8.2 Hz, 2H), 7.62-7.57 (m, 4H), 7.45-7.37
(m, 3H), 7.30 (t, J = 7.2 Hz, 1H), 7.24-7.10 (m, 4H), 7.04-6.98 (m, 2H); 13C{1H} NMR (CDCl3, 100 MHz) δ 167.0,
161.8, 153.6, 143.6, 140.4, 138.6, 138.3, 133.3, 132.0, 131.2, 130.5, 128.9, 127.8, 127.2, 127.1, 126.9, 126.7, 124.8,
121.0, 119.2; HRMS (ESI) m/z calcd for C25H17ClNO (M+H)+ 382.0993, found 382.0992; IR (KBr) 3077, 3056, 3027,
1686, 1592, 1566, 1556, 1481, 1446, 1432, 1400, 1316, 1282, 1240, 1226, 1163, 1067, 1035. cm-1.
9-Chloro-11-(4-chlorophenyl)dibenzo[b,f][1,4]oxazepine (3e)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3e (52.9 mg, 78% yield) as a
yellow solid. m.p. 130-131 oC; 1H NMR (CDCl3, 400 MHz) δ 7.75 (d, J = 8.4 Hz, 2H), 7.43-7.39 (m, 1H), 7.33 (d, J =
8.5 Hz, 2H), 7.18-6.97 (m, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.1, 161.7, 153.5, 138.1, 138.0, 137.1, 133.4,
132.0, 131.3, 130. 9, 128.5, 127.4, 126.7, 126.7, 124.9, 121.1, 119.2; HRMS (ESI) m/z calcd for C19H12Cl2NO (M+H)+
340.0290, found 340.0293; IR (KBr) 3065, 1644, 1596, 1562, 1480, 1443, 1397, 1371, 1315, 1268, 1239, 1171, 1141,
1088, 1035 cm-1.
11-(4-Bromophenyl)-9-chlorodibenzo[b,f][1,4]oxazepine (3f)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3f (55.6 mg, 66% yield) as a
yellow solid. m.p. 131-132 oC; 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 7.45-
7.41 (m, 1 H), 7.20-7.08 (m, 4H), 7.03-7.01 (m, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.2, 161.8, 153. 6, 138.6,
138.0, 133.4, 132.0, 131.5, 131.5, 130.9, 129.8, 127.4, 126.7, 125.6, 124.9, 121.1, 119.2; HRMS (ESI) m/z calcd for
C19H12BrClNO (M+H)+ 383.9785, found 383.9782; IR (KBr) 3064, 3020, 1644, 1597, 1587, 1560, 1479, 1443, 1391,
1377, 1313, 1286, 1275, 1265, 1221, 1204, 1171, 1140, 1034 cm-1.
9-Chloro-11-(4-(trifluoromethyl)phenyl)dibenzo[b,f][1,4]oxazepine (3g)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate =: 60:1) gave 3g (51.5 mg, 69% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.93 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.48-7.44 (m, 1H), 7.22-
7.19 (m, 2H), 7.17-7.03 (m, 4H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.0, 161.8, 153.5, 143.0, 137.9, 133.7, 132.4
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 33
(q, JC-F = 32.5 Hz), 132.2, 130.8, 130.3, 127.8, 126.8, 126.7, 125.2 (q, JC-F = 3.8 Hz), 125.0, 124.0 (q, JC-F = 273.8 Hz),
121.2, 119.3; HRMS (ESI) m/z calcd for C20H12ClF3NO (M+H)+ 374.0554, found 374.0552; IR (KBr) 3064, 3012,
1602, 1569, 1514, 1484, 1448, 1434, 1408, 1326, 1315, 1243, 1205, 1126, 1109, 1016 cm-1.
1
2
3
4
5
6
7
8
4-(9-Chlorodibenzo[b,f][1,4]oxazepin-11-yl)benzaldehyde (3h)
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3h (45.3 mg, 68% yield) as a
yellow solid. m.p. 173-174 oC; 1H NMR (CDCl3, 400 MHz) δ 10.02 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.2
Hz, 2H), 7.48-7.43 (m, 1H), 7.22-7.02 (m, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 191. 8, 166.2, 161.9, 153.5,
145.09, 137.9, 137.7, 133.7, 132.3, 130.8, 130.6, 129.5, 127.9, 126.9, 126.8, 125.1, 121.2, 119.3; HRMS (ESI) m/z
calcd for C20H13ClNO2 (M+H)+ 334.0629, found 334.0631; IR (KBr) 3059, 2836, 2739, 1735, 1604, 1594, 1561, 1500,
1484, 1448, 1434, 1414, 1388, 1316, 1285, 1242, 1202, 1159, 1106, 1015 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ethyl 4-(9-chlorodibenzo[b,f][1,4]oxazepin-11-yl)benzoate (3i)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3i (52.3 mg, 72% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.13 (d, J = 8.4 Hz, 2H), 7.96 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 1H), 7.30-
7.25 (m, 2H), 7.21-7.09 (m, 4H), 4.42 (q, J = 7.0 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ
166.5, 166.1, 161.8, 153.5, 143.6, 137.9, 133.5, 132.3, 132.2, 130.9, 129.9, 129.4, 127.7, 126.8, 126.8, 125.0, 121.1,
119.2, 61.2, 14.3; HRMS (ESI) m/z calcd for C22H17ClNO3 (M+H)+ 378.0891, found 378.0885; IR (KBr) 3061, 2979,
2932, 2903, 1717, 1599, 1563, 1505, 1482, 1447, 1434, 1405, 1366, 1308, 1274, 1204, 1145, 1102, 1020 cm-1.
1-(4-(9-Chlorodibenzo[b,f][1,4]oxazepin-11-yl)phenyl)ethanone (3j)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3j (54.1 mg, 78% yield) as a
yellow solid. m.p. 124-125 oC. 1H NMR (CDCl3, 400 MHz) δ 8.04-7.98 (m, 4H), 7.5-7.51 (m, 1H), 7.30-7.25 (m, 2H),
7.22-7.10 (m, 4H), 2.65 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 197.6, 166.3, 161.8, 153.5, 143.7, 138.6, 137.9,
133.5, 132.2, 130.8, 130.2, 128.1, 127.7, 126.8, 125.0, 121.1, 119.2, 26.7; HRMS (ESI) m/z calcd for C21H15ClNO2
(M+H)+ 348.0786, found 348.0780; IR (KBr) 3066, 2994, 2920, 1675, 1596, 1561, 1499, 1480, 1445, 1433, 1402,
1376, 1312, 1269, 1243, 1203, 1142, 1104, 1036 cm-1.
9-Chloro-11-(3-methoxyphenyl)dibenzo[b,f][1,4]oxazepine (3k)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3k (38.9 mg, 58% yield) as a
yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.46-7.40 (m, 2H), 7.33-7.25 (m, 2H), 7.19-7.16 (m, 3H), 7.10 (t, J = 7.5 Hz,
1H), 7.03-6.96 (m, 3H), 3.78 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.1, 161.7, 159.5, 153.6, 141.1, 138.1,
133.2, 132.0, 131.3, 129.1, 127.2, 127.1, 126.6, 124.8, 122.8, 120.9, 119.1, 117.0, 114.9, 55.3; HRMS (ESI) m/z calcd
for C20H15ClNO2 (M+H)+ 336.0786, found 336.0780; IR (KBr) 3067, 3029, 3001, 2937, 1612, 1596, 1581, 1566, 1481,
1462, 1446, 1433, 1376, 1323, 1283, 1222, 1200, 1183, 1172, 1140, 1039 cm-1.
ACS Paragon Plus Environment

Page 19 of 33
The Journal of Organic Chemistry
9-Chloro-11-(3-chlorophenyl)dibenzo[b,f][1,4]oxazepine (3l)
1
2
3
4
5
6
7
8
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3l (51.5 mg, 76% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.82-7.81 (m, 1H), 7.69-7.66 (m, 1H), 7.46-7.38 (m, 2H), 7.30 (t, J = 7.8 Hz,
1H), 7.21-7.17 (m, 2H), 7.14-7.12 (m, 2H), 7.03-7.02 (m, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.0, 161.7,
153.6, 141.5, 137.9, 134.4, 133.5, 132.1, 130.9, 130.8, 129.9, 129.5, 128.2, 127.6, 126.8, 126.7, 125.0, 121.1, 119.2;
HRMS (ESI) m/z calcd for C19H12Cl2NO (M+H)+ 340.0290, found 340.0292; IR (KBr) 3065, 3023, 1604, 1561, 1482,
1467, 1446, 1434, 1406, 1372, 1315, 1286, 1271, 1258, 1243, 1203, 1160, 1108, 1034 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
11-(3-Bromophenyl)-9-chlorodibenzo[b,f][1,4]oxazepine (3m)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate =: 60:1) gave 3m (55.9 mg, 73% yield) as a
yellow solid. m.p. 138-139 oC; 1H NMR (CDCl3, 400 MHz) δ 7.97 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.56-7.53 (m, 1H),
7.46-7.42 (m, 1H), 7.24-7.12 (m, 5H),7.02 (d, J = 4.9 Hz, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ 165.8, 161.7,
153.5, 141.7, 137.8, 133.7, 133.5, 132.8, 132.1, 130.9, 129.8, 128.7, 127.6, 126.8, 126.7, 125.0, 122.5, 121.1, 119.2;
HRMS (ESI) m/z calcd for C19H12BrClNO (M+H)+ 383.9785, found 383.9786; IR (KBr) 3074, 3051, 1681, 1644,
1603, 1559, 1483, 1464, 1447, 1434, 1402, 1314, 1282, 1269, 1258, 1246, 1228, 1203, 1176, 1144, 1067, 1035 cm-1.
9-Chloro-11-(3-(trifluoromethyl)phenyl)dibenzo[b,f][1,4]oxazepine (3n)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3n (48.5 mg, 65% yield) as a
o
1
yellow solid. m.p. 127-129 C; H NMR (CDCl3, 400 MHz) δ 8.08-8.03 (m, 2H), 7.69 (d, J = 6.2 Hz, 1H), 7.53-7.45
(m, 2H), 7.23-7.03 (m, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 165.9, 161.8, 153.6, 140.5, 137.8, 133.7, 133.2,
132.2, 130.9 (q, JC-F = 32.5 Hz), 130.7, 128.9, 127.7, 127.3 (q, JC-F = 3.8 Hz), 126.8, 126.7 (q, JC-F = 3.8 Hz), 126.6,
125.1, 123.9 (q, JC-F = 270 Hz), 121.3,119.3; HRMS (ESI) m/z calcd for C20H12ClF3NO (M+H)+ 374.0554, found
374.0551; IR (KBr) 3084, 3069, 1601, 1561, 1479, 1449, 1436, 1384, 1341, 1301, 1263, 1245, 1203, 1167, 1144,
1106, 1035 cm-1.
Ethyl 3-(9-chlorodibenzo[b,f][1,4]oxazepin-11-yl)benzoate (3o)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3o (50.8 mg, 70% yield) as a
yellow solid. m.p. 128-129 oC; 1H NMR (CDCl3, 400 MHz) δ 8.47 (s, 1H), 8.18-8.15 (m, 2H), 7.56-7.48 (m, 2H), 7.28-
7.08 (m, 6H),4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.5, 166.1,
161.7, 153.6, 140.1, 137.9, 134.1, 133.5, 132.0, 131.7, 131.1, 130.9, 130.7, 128.5, 127.5, 126.8, 126.7, 125.0, 121.1,
119.2, 61.2, 14.2; HRMS (ESI) m/z calcd for C22H17ClNO3 (M+H)+ 378.0891, found 378.0886; IR (KBr) 3063, 3036,
2982, 2962, 2940, 2900, 1718, 1600, 1579, 1563, 1462, 1435, 1390, 1325, 1252, 1159, 1108, 1108, 1019 cm-1.
9-Chloro-11-(o-tolyl)dibenzo[b,f][1,4]oxazepine (3p)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 33
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3p (47.2 mg, 74% yield) as a
1
2
3
4
5
6
7
8
o
1
yellow solid. m.p. 128-129 C; H NMR (CDCl3, 400 MHz) δ 7.54-7.52 (m, 1H), 7.47-7.43 (m, 1H), 7.37-7.33 (m,
1H), 7.29-7.21 (m, 4H), 7.13-7.07 (m, 3H), 6.96-6.94 (m, 1H), 2.31 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 169.7,
160.8, 153.8, 140.4, 138.0, 136.8, 133.2, 132.3, 130.8, 130.4, 130.3, 129.6, 129.2, 127.5, 126.8, 125.8, 125.2, 120.6,
119.3, 20.5; HRMS (ESI) m/z calcd for C20H15ClNO (M+H)+ 320.0837, found 320.0833; IR (KBr) 3061, 3013, 2957,
2922, 1593, 1563, 1477, 1445, 1433, 1376, 1314, 1265, 1241, 1225, 1200, 1173, 1141, 1100, 1030 cm-1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Chloro-11-(2-fluorophenyl)dibenzo[b,f][1,4]oxazepine (3q)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3q (40.7 mg, 63% yield) as a
o
1
yellow solid. m.p. 123-124 C; H NMR (CDCl3, 500 MHz) δ 7.91-7.88 (m, 1H), 7.41-7.37 (m, 2H), 7.23-7.16 (m,
2H), 7.15 (d, J =8.2 Hz, 1H), 7.08-6.99 (m, 5H); 13C{1H} NMR (CDCl3, 125 MHz) δ 164.3, 160.9 (d, JC-F = 251.3 Hz),
160.3, 153.8, 137.7, 133,4, 132.34, 132.27 (d, JC-F = 2.5 Hz), 132.1 (d, JC-F = 2.5 Hz), 129.8 (d, JC-F = 1.3 Hz), 128.4
(d, JC-F = 1.3 Hz), 128.2 (d, JC-F = 11.3 Hz), 127.8, 126.7, 125.2, 124.5 (d, JC-F = 2.5 Hz), 120.8, 119.3, 116.2 (d, JC-F
=
22.5 Hz); HRMS (ESI) m/z calcd for C19H12ClFNO (M+H)+ 324.0586, found 324.0585; IR (KBr) 3057, 3021, 1601,
1577, 1505, 1481, 1446, 1370, 1320, 1285, 1269, 1246, 1223, 1205, 1176, 1140, 1095, 1031 cm-1.
11-(2-Bromophenyl)-9-chlorodibenzo[b,f][1,4]oxazepine (3r)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3r (35.2 mg, 46% yield) as a
yellow solid. m.p. 178-180 oC; 1H NMR (CDCl3, 400 MHz) δ 7.71 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1 H), 7.40
(t, J = 7.4 Hz, 2H), 7.27-7.15 (m, 3H), 7.09-7.02 (m, 3H), 6.86 (d, J = 7.7 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz)
δ 168.3, 161.1, 153.8, 141.5, 137.6, 133.4, 133.3, 132.4, 131.9, 131.0, 129.8, 128.5, 128.1, 127.6, 126.8, 125.3, 122.4,
120.8, 119.5; HRMS (ESI) m/z calcd for C19H12BrClNO (M+H)+ 383.9785, found 383.9786; IR (KBr) 3060, 3009,
1593, 1562, 1479, 1464, 1445, 1433, 1375, 1316, 1290, 1277, 1242, 1199, 1176, 1142, 1107, 1023 cm-1.
9-Chloro-11-(naphthalen-1-yl)dibenzo[b,f][1,4]oxazepine (3s)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3s (41.2 mg, 58% yield) as a
o
1
yellow solid. m.p. 164-165 C; H NMR (CDCl3, 400 MHz) δ 8.37 (d, J = 5.6 Hz, 1H), 7.91-7.88 (m, 2H), 7.73-7.71
(m, 1H), 7.55-7.44 (m, 4H), 7.33-7.27 (m, 2H), 7.18-7.12 (m, 2H), 7.04-7.00 (m, 1H), 6.93-6.90 (m, 1H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 168.9, 160.8, 153.9, 138.2, 138.2, 133.9, 133.3, 132.4, 131.3, 131.0, 130.5, 129.8, 129.2,
128.3, 127.7, 126.9, 126.7, 126.1, 126.1, 125.3, 124.9, 120.7, 119.4; HRMS (ESI) m/z calcd for C23H15ClNO (M+H)+
356.0837, found 356.0839; IR (KBr) 3062, 1605, 1561, 1508, 1483, 1446, 1432, 1393, 1341, 1312, 1275, 1242, 1201,
1162, 1141, 1118, 1075, 1034 cm-1.
9-Chloro-11-(3,5-dimethylphenyl)dibenzo[b,f][1,4]oxazepine (3t)
ACS Paragon Plus Environment

Page 21 of 33
The Journal of Organic Chemistry
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3t (33.3 mg, 50% yield) as a
1
2
1
yellow oil. H NMR (CDCl3, 400 MHz) δ 7.56-7.50 (m, 3H), 7.31-7.20 (m, 3H), 7.21 (dt, J1 = 7.5 Hz, J2 = 0.9 Hz,
1H), 7.17-7.08 (m, 3H), 2.40 (s, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.9, 161.7, 153.7, 139.8, 138.3, 137.8,
133.1, 132.6, 131.9, 131.4, 127.8, 127.4, 127.0, 126.6, 124.8, 120.9, 119.1, 21.34; HRMS (ESI) m/z calcd for
C21H17ClNO (M+H)+ 334.0993, found 334.0998; IR (KBr) 3051, 3013, 2912, 2853, 1601, 1569, 1485, 1445, 1435,
1379, 1330, 1277, 1235, 1206, 1165, 1109, 1031 cm-1.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Chloro-11-(3,4-dichlorophenyl)dibenzo[b,f][1,4]oxazepine (3u)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3u (53.7 mg, 72% yield) as a
o
1
yellow solid. m.p. 137-138 C. H NMR (CDCl3, 400 MHz) δ 7.92 (d, J = 2.0 Hz, 1H), 7.67-7.64 (m, 1H), 7.48-7.44
(m, 2H), 7.23-7.17 (m, 2H), 7.15-7.12 (m, 2H), 7.06-7.02 (m, 2H); 13C{1H} NMR (CDCl3, 75 MHz) δ 164.9, 161.8,
153.5, 139.5, 137.8, 135.2, 133.7, 132.7, 132.1, 131.7, 130.6, 130.3, 129.1, 127.8, 126.8, 126.4, 125.1, 121.3, 119.3;
HRMS (ESI) m/z calcd for C19H11Cl3NO (M+H)+ 373.9901, found 373.9901; IR (KBr) 3058, 1659, 1599, 1569, 1552,
1481, 1465, 1445, 1433, 1374, 1314, 1277, 1267, 1239, 1203, 1172, 1130, 1031 cm-1.
2-(Tert-butyl)-9-chloro-11-phenyldibenzo[b,f][1,4]oxazepine (3v)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3v (55.6 mg, 77% yield) as a
1
yellow oil. H NMR (CDCl3, 400 MHz) δ 7.94-7.91 (m, 2H), 7.52-7.44 (m, 4H), 7.27-7.23 (m, 2H), 7.17 (d, J = 8.6
Hz, 1H), 7.10-7.04 (m, 2H), 1.22 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.7, 159.7, 153.8, 147.7, 139.8, 138.3,
131.9, 130.8, 130.1, 130.1, 128.3, 128.2, 127.0, 126.5, 126.3, 120.2, 119.1, 34.5, 31.2; HRMS (ESI) m/z calcd for
C23H21ClNO (M+H)+ 362.1306, found 362.1299; IR (KBr) 3061, 2962, 2904, 1602, 1569, 1488, 1447, 1435, 1395,
1363, 1321, 1283, 1242, 1174, 1157, 1120, 1098, 1028 cm-1.
9-Chloro-2-methoxy-11-phenyldibenzo[b,f][1,4]oxazepine (3w)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3w (51.6 mg, 77% yield) as a
yellow oil. 1H NMR (CDCl3, 500 MHz) δ 7.85 (d, J = 6.9 Hz, 2H), 7.43-7.35 (m, 3H), 7.18-7.16 (m, 1H), 7.08 (d, J =
8.9 Hz, 1H), 7.00-6.96 (m, 2H), 6.93 (dd, J1 = 8.9 Hz, J2 = 3.1 Hz, 1H), 6.62 (d, J = 3.1 Hz, 1H), 3.58 (s, 3H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 167.0, 156.2, 155.5, 153.9, 139.5, 138.1, 131.9, 130.8, 130.0, 128.2, 127.4, 127.1, 126.5,
121.6, 118.9, 115.3, 114.9, 55.7; HRMS (ESI) m/z calcd for C20H15ClNO2 (M+H)+ 336.0786, found 336.0778; IR
(KBr) 3060, 3006, 3000, 2935, 1063, 1568, 1486, 1447, 1412, 1377, 1333, 1320, 1293, 1268, 1247, 1232, 1198, 1136,
1108, 1036 cm-1.
9-Chloro-2-fluoro-11-phenyldibenzo[b,f][1,4]oxazepine (3x)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3x (50.4 mg, 78% yield) as a
1
yellow oil. H NMR (CDCl3, 500 MHz) δ 7.92 (d, J = 7.1 Hz, 2H), 7.55-7.47 (m, 3H), 7.31-7.28 (m, 1H), 7.25-7.18
(m, 2H), 7.13-7.09 (m, 2H), 6.96-6.94 (m, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 166.0, 159.0 (d, JC-F = 244 Hz),
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 33
157.5 (d, JC-F = 1.3 Hz), 153.5, 139.1, 137.9, 132.1, 131.1, 129.9, 128.4, 128.2 (d, JC-F = 6.3 Hz), 127.4, 126.8, 122.3
(d, JC-F = 7.5 Hz), 119.9 (d, JC-F = 24 Hz), 119.0, 117.3 (d, JC-F = 25 Hz); HRMS (ESI) m/z calcd for C19H12ClFNO
(M+H)+ 324.0586, found 324.0585; IR (KBr) 3075, 3054, 3022, 1613, 1603, 1590, 1569, 1480, 1447, 1406, 1375,
1319, 1272, 1244, 1213, 1154, 1233, 1097, 1027 cm-1.
1
2
3
4
5
6
7
8
9
2,9-Dichloro-11-phenyldibenzo[b,f][1,4]oxazepine (3y)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3y (52.2 mg, 77% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.91-7,89 (m, 2H), 7.56-7.45 (m, 4H), 7.31-7.29 (m, 1H), 7.22-7.19 (m, 2H),
7.13-7.08 (m, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ 165.9, 160.1, 153.3, 139.1, 137.9, 133.1, 132.1, 131.1, 130.6,
130.4, 129.9, 128.5, 128.3, 127.4, 126.9, 122.4, 119.0; HRMS (ESI) m/z calcd for C19H12Cl2NO (M+H)+ 340.0290,
found 340.0285; IR (KBr) 3060, 3051, 1600, 1562, 1474, 1447, 1435, 1390, 1318, 1307, 1269, 1252, 1204, 1174,
1150, 1086, 1028 cm-1.
2-Chloro-9-methyl-11-phenyldibenzo[b,f][1,4]oxazepine (3z)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3z (48.5 mg, 76% yield) as a
yellow solid. m.p 122-123 oC; 1H NMR (CDCl3, 400 MHz) δ 7.87-7.85 (m, 2H), 7.52-7.427 (m, 3H), 7.43 (dd, J1 = 8.7
Hz, J2 = 2.6 Hz, 1H), 7.22-7.20 (m, 2H), 7.12-7.02 (m, 3H), 2.55 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 163.9,
160.4, 152.3, 139.7, 138. 8, 136.6, 132.6, 130.6, 130.3, 129.9, 129.5, 128.7, 128.4, 127.3, 127.3, 122.3, 118.0, 18.28;
HRMS (ESI) m/z calcd for C20H15ClNO (M+H)+ 320.0837, found 320.0831; IR (KBr) 3060, 3021, 2957, 2922, 1607,
1593, 1573, 1561, 1466, 1444, 1390, 1379, 1318, 1309, 1292, 1251, 1201, 1156, 1080, 1022 cm-1.
2-Bromo-9-methyl-11-phenyldibenzo[b,f][1,4]oxazepine (3aa)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3aa (56.6 mg, 78% yield) as a
yellow solid. m.p 141-143 oC; 1H NMR (CDCl3, 500 MHz) δ 7.86 (d, J = 6.7 Hz, 2H), 7.58 (dd, J1 = 8.7 Hz, J2 = 2.4
Hz, 1H), 7.54-7.47 (m, 3H), 7.35 (d, J = 2.4 Hz, 1H), 7.16-7.02 (m, 4H), 2.55 (s, 3H); 13C{1H} NMR (CDCl3, 125
MHz) δ 163., 160.9, 152.3, 139.6, 138.8, 136.5, 135.6, 133.2, 130.7, 129.5, 129.1, 128.4, 127.3, 127.3, 122.7, 118.0,
117.4, 18.28; HRMS (ESI) m/z calcd for C20H15BrNO (M+H)+ 364.0332, found 364.0333; IR (KBr) 3076, 3059, 3020,
2960, 2850, 1606, 1591, 1573, 1557, 1491, 1476, 1466, 1444, 1379, 1318, 1306, 1289, 1270, 1251, 1176, 1114, 1023
cm-1.
4-(Tert-butyl)-9-chloro-11-phenyldibenzo[b,f][1,4]oxazepine (3ab)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ab (51.3 mg, 71% yield) as a
o
1
yellow solid. m.p. 139-140 C; H NMR (CDCl3, 500 MHz) δ 7.80 (d, J = 7.1 Hz, 2H), 7.57-7.41 (m, 4H), 7.30-7.27
(m, 2H), 7.09-7.02 (m, 3H), 1.59 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ 168.9, 162.2, 154.1, 142.3, 140.7, 139.2,
132.3, 131.0, 130.6, 130.2, 123.0, 128.6, 128.1, 126.4, 126.3, 123.8, 120.1, 35.2, 31.6; HRMS (ESI) m/z calcd for
ACS Paragon Plus Environment

Page 23 of 33
The Journal of Organic Chemistry
C23H21ClNO (M+H)+ 362.1306, found 362.1308; IR (KBr) 3077, 3055, 3015, 2998, 2953, 2911, 1607, 1585, 1572,
1563, 1481, 1423, 1377, 1361, 1316, 1278, 1255, 1213, 1174, 1136, 1076 cm-1.
1
2
3
4
5
6
7
9-Chloro-4-methoxy-11-phenyldibenzo[b,f][1,4]oxazepine (3ac)
8
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ac (43.6 mg, 65% yield) as a
1
yellow oil. H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.1 Hz, 2H), 7.55-7.46 (m, 3H), 7.31-7.25 (m, 2H), 7.16-7.10
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(m, 3H), 6.84-6.81 (m, 1H), 3.98 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.2, 153.5, 151.4, 149.9, 139.6, 138.5,
131.7, 130.8, 130.0, 128.3, 128.2, 127.0, 126.6, 124.8, 122.2, 119.6, 115.2, 56.33; HRMS (ESI) m/z calcd for
C20H15ClNO2 (M+H)+ 336.0786, found 336.0790; IR (KBr) 3068, 3025, 3004, 2972, 2941, 1591, 1567, 1473, 1458,
1445, 1432, 1372, 1295, 1232, 1202, 1176, 1140, 1080, 1029 cm-1.
9-Chloro-4-isopropyl-11-phenyldibenzo[b,f][1,4]oxazepine (3ad)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ad (48.9 mg, 70% yield) as a
1
yellow oil. H NMR (CDCl3, 400 MHz) δ 7.94-7.92 (m, 2H), 7.51-7.44 (m, 4H), 7.29 (dd, J1 = 7.8 Hz, J2 = 1.6 Hz,
1H), 7.17-7.06 (m, 4H), 3.85-3.78 (m, 1H), 1.34 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 168.0, 158.5,
153.6, 140.9, 140.1, 138.6, 132.0, 130.7, 130.04, 130.01, 128.7, 128.1, 127.2, 126.8, 126.5, 124.7, 119.3, 26.2, 23.5;
HRMS (ESI) m/z calcd for C22H19ClNO (M+H)+ 348.1150, found 348.1147; IR (KBr) 3061, 3027, 2963, 2927, 1606,
1592, 1570, 1488, 1447, 1432, 1384, 1363, 1304, 1272, 1246, 1197, 1148, 1096, 1031 cm-1.
9-Chloro-4,11-diphenyldibenzo[b,f][1,4]oxazepine (3ae)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ae (52.6 mg, 69% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.01 (d, J = 7.0 Hz, 2H), 7.67 (d, J = 7.0 Hz, 2H), 7.61-7.49 (m, 7H), 7.28-
7.20 (m, 3H), 6.87 (t, J = 8.1 Hz, 1H), 6.26 (d, J = 8.1 Hz, 1H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.5, 158.0,
153.2, 139.9, 138.4, 136.7, 135.1, 133.8, 131.6, 130.9, 130.3, 130.1, 130.0, 128.3, 128.2, 127.9, 127.8, 126.9, 126.5,
124.8, 119.2; HRMS (ESI) m/z calcd for C25H17ClNO (M+H)+ 382.0993, found 382.0992; IR (KBr) 3053, 3033, 1683,
1604, 1592, 1569, 1495, 1446, 1424, 1377, 1318, 1293, 1278, 1265, 1206, 1176, 1161, 1111, 1073, 1024 cm-1.
9-Methyl-11-phenyldibenzo[b,f][1,4]oxazepine (3af)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3af (41.6 mg, 73% yield) as a
o
1
yellow solid. m.p 120-121 C; H NMR (CDCl3, 500 MHz) δ 7.88 (d, J = 6.9 Hz, 2H), 7.52-7.45 (m, 4H), 7.30-7.24
(m, 2H), 7.16 (dt, J1= 7.5 Hz, J2 = 1.0 Hz, 1H), 7.12-7.06 (m, 3H), 2.56 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ
165.4, 162.1, 152.7, 140.3, 139.1, 136.4, 132.8, 130.9, 130.3, 129.7, 128.2, 127.5, 126.99, 126.98, 124.4, 120.9, 118.1,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 33
18.31; HRMS (ESI) m/z calcd for C20H16NO (M+H)+ 286.1226, found 286.1228; IR (KBr) 3053, 3026, 2979, 2953,
1604, 1575, 1480, 1463, 1445, 1427, 1373, 1319, 1282, 1252, 1200, 1175, 1105, 1030 cm-1.
1
2
3
4
5
6
7
4-Chloro-9-methyl-11-phenyldibenzo[b,f][1,4]oxazepine (3ag)
8
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ag (47.9 mg, 75% yield) as a
yellow solid. m.p 118-119 oC; 1H NMR (CDCl3, 500 MHz) δ 7.86 (d, J = 6.8 Hz, 2H), 7.56-7.45 (m, 4H), 7.29 (d, J =
7.7 Hz, 1H), 7.14-7.07 (m, 4H), 2.56 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 164.4, 156.5, 152.0, 139.9, 138.9,
136.3, 132.7, 130.5, 129.5, 129.2, 129.0, 128.2, 127.3, 127.1, 126.7, 124.8, 118.9, 18.25; HRMS (ESI) m/z calcd for
C20H15ClNO (M+H)+ 320.0837, found 320.0839; IR (KBr) 3062, 3024, 2918, 2851, 1603, 1588, 1573, 1489, 1466,
1440, 1374, 1316, 1298, 1222, 1177, 1135, 1078, 1022 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-Bromo-9-methyl-11-phenyldibenzo[b,f][1,4]oxazepine (3ah)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ah (53.0 mg, 73% yield) as a
yellow solid. m.p 236-238 oC; 1H NMR (CDCl3, 500 MHz) δ 7.86 (d, J = 7.1 Hz, 2H), 7.72 (dd, J1 = 7.9 Hz, J2 = 1.4
Hz, 1H), 7.53-7.45 (m, 3H), 7.38 (d, J = 7.7 Hz, 1H), 7.19-7.09 (m, 3H), 7.02 (t, J = 7.9 Hz, 1H), 2.57 (s, 3H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 164.3, 157.5, 152.0, 139.9, 138.7, 136.3, 135.7, 130.5, 130.0, 129.5, 128.9, 128.2, 127.3,
127.1, 125.2, 119.0, 115.7, 18.25; HRMS (ESI) m/z calcd for C20H15BrNO (M+H)+ 364.0332, found 364.0332; IR
(KBr) 3061, 2925, 2947, 2916, 1603, 1588, 1572, 1555, 1490, 1465, 1434, 1373, 1316, 1272, 1233, 1221, 1195, 1157,
1078, 1023 cm-1.
3,4,9-Trimethyl-11-phenyldibenzo[b,f][1,4]oxazepine (3ai)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ai (43.2 mg, 69% yield) as a
o
1
yellow solid. m.p 128-130 C; H NMR (CDCl3, 500 MHz) δ 7.88 (d, J = 7.4 Hz, 2H), 7.50-7.44 (m, 3H), 7.14-7.06
(m, 3H), 6.96 (s, 2H), 2.57 (s, 3H), 2.50 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 165.9, 159.8, 152.6,
142.2, 140. 7, 139.6, 136.3, 130.2, 129.7, 128.7, 128.0, 127.7, 126.8, 126.5, 125.5, 125.1, 118.3, 20.23, 18.28, 12.33;
HRMS (ESI) m/z calcd for C22H20NO (M+H)+ 314.1539, found 314.1534; IR (KBr) 3060, 3023, 2942, 2917, 1602,
1587, 1573, 1466, 1446, 1440, 1410, 1381, 1317, 1276, 1256, 1236, 1203, 1189, 1156, 1080, 1040 cm-1.
11-phenyldibenzo[b,f][1,4]oxazepine (3aj)7b
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3aj (24.9 mg, 92% yield) as a
1
pale yellow oil. H NMR (CDCl3, 400 MHz) δ 7.84-7.81 (m, 2H), 7.51-7.42 (m, 5H), 7.28 (d, J = 9.1 Hz, 1H), 7.21-
7.15 (m, 5H); 13C{1H} NMR (CDCl3, 125 MHz) δ 167.1, 162.0, 152.4, 140.9, 140.1, 133.0, 131.2, 130.4, 129.7,
128.19, 128.16, 127.5, 127.4, 125.6, 124.5, 120.9, 120.7.
ACS Paragon Plus Environment

Page 25 of 33
The Journal of Organic Chemistry
1
2
3
N,11-diphenyldibenzo[b,f][1,4]oxazepin-9-amine (3ak)
4
5
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3ak (32.2 mg, 89% yield) as a
1
6
7
8
9
dark yellow oil. H NMR (CDCl3, 400 MHz) δ 7.81 (dd, J1 = 7.7 Hz, J2 = 1.3 Hz, 2H), 7.54-7.45 (m, 4H), 7.38-7.34
(m, 2H), 7.30-7.28 (m, 3H), 7.23-7.15 (m, 3H), 7.12-7.04 (m, 3H), 6.68 (dd, J1 = 7.3 Hz, J2 = 2.0 Hz, 1H); 13C{1H}
NMR (CDCl3, 125 MHz) δ 165.6, 161.4, 153.3, 142.0, 141.3, 140.0, 133.1, 131.0, 130.4, 129.5, 129.3, 128.3, 128.3,
127.9, 127.7, 124.5, 122.4, 121.2, 120.6, 110.6, 109.6; HRMS (ESI) m/z calcd for C25H19N2O (M+H)+ 363.1492,
found 363.1488.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Chloro-11-(piperidin-1-yl)dibenzo[b,f][1,4]oxazepine (3a1)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 60:1) gave 3a1 (14.3 mg, 23% yield) as a
colorless oil. 1H NMR (CDCl3, 400 MHz) δ 7.45-7.41 (m, 1H), 7.36 (J1 = 7.7 Hz, J2 = 1.6 Hz, 1H), 7.24-7.14 (m, 3H),
7.02 (J1 = 8.1 Hz, J2 = 1.4 Hz, 1H), 6.84 (t, J = 8.1 Hz, 1H), 3.53 (brs, 4H), 1.75-1.63 (m, 6H); 13C{1H} NMR (CDCl3,
125 MHz) δ 160.4, 160.1, 153.1, 138.7, 132.6, 130.5, 129.5, 126.3, 124.9, 123.8, 123.0, 121.2, 118.5, 48.40, 25.95,
24.93.
9-Chloro-5-methyl-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (5a)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5a (54.7 mg, 86% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 8.0 Hz, 2H), 7.47-7.40 (m, 4H), 7.17-7.02 (m, 5H), 6.87 (d, J =
8.1 Hz, 1H), 3.26 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 169.6, 157.5, 148.5, 140.5, 139.6, 131.7, 131.3, 131.1,
130.5, 129.9, 128.9, 128.0, 126.3, 124.9, 123.1, 117.7, 115.8, 37.0; HRMS (ESI) m/z calcd for C20H16ClN2 (M+H)+
319.0997, found 319.0993; IR (KBr) 3059, 3046, 2951, 2920, 1612, 1594, 1580, 1481, 1449, 1432, 1377, 1319, 1301,
1264, 1226, 1150, 1119, 1028 cm-1.
2-(Tert-butyl)-9-chloro-5-methyl-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (5b)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5b ( 33.7 mg, 45% yield) as a
o
1
yellow solid. m.p 122-123 C; H NMR (CDCl3, 400 MHz) δ 7.87 (d, J = 6.9 Hz, 2H), 7.47-7.40 (m, 4H), 7.15-7.11
(m, 2H), 7.04-6.98 (m, 2H), 6.85 (d, J = 8.1 Hz, 1H), 3.23 (s, 3H), 1.21 (s, 9H); 13C{1H} NMR (CDCl3, 125 MHz) δ
169.9, 155.0, 148.7, 145.7, 140.5, 139.7, 131.3, 130.5, 123.0, 128.5, 128.4, 128.2, 128.0, 126.2, 124.8, 117.1, 115.6,
37.0, 34.2, 31.2; HRMS (ESI) m/z calcd for C24H24ClN2 (M+H)+ 375.1623, found 375.1623; IR (KBr) 3055, 3027,
2960, 2920, 1626, 1605, 1593, 1575, 1513, 1498, 1480, 1467, 1450, 1431, 1394, 1362, 1301, 1281, 1253, 1201, 1159,
1108, 1026 cm-1.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 33
2-Bromo-9-chloro-5-methyl-11-phenyl-5H-dibenzo[b,e][1,4]diazepine (5c)
1
2
3
4
5
6
7
8
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5c (62.6 mg, 79% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J = 6.9 Hz, 2H), 7.52-7.43 (m, 4H), 7.22 (d, J = 2.3 Hz, 1H), 7.19-
7.16 (m, 1H),7.05 (t, J = 8.1 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H),3.22 (s, 3H); 13C{1H} NMR
(CDCl3, 125 MHz) δ 168.0, 156.5, 147.9, 139.9, 139.3, 134.4, 133.4, 131.5, 130.8, 130.6, 129.8, 128.3, 126.6, 125.2,
119.4, 116.1, 115.8, 37.04; HRMS (ESI) m/z calcd for C20H15BrClN2 (M+H)+ 397.0102, found 397.0095; IR (KBr)
3059, 2989, 2952, 2921, 1612, 1577, 1561, 1478, 1450, 1433, 1386, 1317, 1302, 1249, 1222, 1176, 1126, 1075, 1028
cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9-Chloro-11-(3,5-dimethylphenyl)-5-methyl-5H-dibenzo[b,e][1,4]diazepine (5d)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5d (42.2 mg, 61% yield) as a
yellow solid. m.p 127-128 oC; 1H NMR (CDCl3, 400 MHz) δ 7.43-7.39 (m, 3H),7.15 (d, J = 7.9 Hz, 1H), 7.10-7.00 (m,
5H), 6.86 (d, J = 8.1 Hz, 1H), 3.25 (s, 3H), 2.36 (s, 6H); 13C{1H} NMR (CDCl3, 125 MHz) δ 170.0, 157.4, 148.5,
140.6, 139.6, 137.5, 132.2, 131.6, 131.2, 131.2, 129.2, 127.7, 126.1, 124.9, 123.0, 117.6, 115.6, 37.0, 21.3; HRMS
(ESI) m/z calcd for C22H20ClN2 (M+H)+ 347.1310, found 347.1308; IR (KBr) 3055, 3009, 2985, 2953, 2917, 1611,
1594, 1561, 1486, 1451, 1434, 1376, 1329, 1305, 1261, 1234, 1121, 1038 cm-1.
11-([1,1'-Biphenyl]-4-yl)-9-chloro-5-methyl-5H-dibenzo[b,e][1,4]diazepine (5e)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5e (57.5mg, 73% yield) as a
yellow solid. m.p 137-138 oC; 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 4H), 7.49-
7.27 (m, 4H), 7.19-7.03 (m, 5H), 6.88 (d, J = 8.2 Hz, 1H), 3.27 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 169.2,
157.6, 148.5, 143.2, 140.5, 139.7, 139.4, 131.7, 131.4, 131.1, 130.4, 128.8, 127.7, 127.2, 126.8, 126.3, 125.0, 123.1,
117.8, 115.8, 37.1; HRMS (ESI) m/z calcd for C26H20ClN2 (M+H)+ 395.1310, found 395.1308; IR (KBr) 3057, 3028,
1613, 1599, 1581, 1556, 1489, 1449, 1431, 1403, 1378, 1317, 1276, 1249, 1266, 1188, 1150, 1079, 1042 cm-1.
Methyl 4-(9-chloro-5-methyl-5H-dibenzo[b,e][1,4]diazepin-11-yl)benzoate (5f)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5f (58.7 mg, 78% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.1 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.48-7.44 (m, 1H), 7.19 (d,
J = 7.1 Hz, 1H), 7.11-7.06 (m, 4H), 6.90 (d, J = 7.5 Hz, 1H), 3.97 (s, 3H), 3.28 (s, 3H); 13C{1H} NMR (CDCl3, 125
MHz) δ 168.8, 166.8, 157. 7, 148.4, 144.6, 139.3, 132.0, 131.6, 130.8, 129.8, 129.3, 128.6, 126.8, 125.0, 123.3, 118.0,
115.9, 52.3, 37.1; HRMS (ESI) m/z calcd for C22H18ClN2O2 (M+H)+ 377.1051, found 377.1050; IR (KBr) 3060, 3022,
2992, 2920, 1615, 1583, 1564, 1482, 1433, 1405, 1306, 1276, 1191, 1177, 1104, 1066 cm-1.
ACS Paragon Plus Environment

Page 27 of 33
The Journal of Organic Chemistry
9-Chloro-11-(3,4-dichlorophenyl)-5-methyl-5H-dibenzo[b,e][1,4]diazepine (5g)
1
2
3
4
5
6
7
8
9
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 5g (58.7 mg, 76% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.94 (d, J = 1.7 Hz, 1H), 7.71 (dd, J1 = 8.4 Hz, J2 = 1.8 Hz, 1H), 7.50 (d, J =
8.4 Hz, 1H), 7.47-7.42 (m, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.09-7.04 (m, 4H), 6.87 (d, J = 8.1 Hz, 1H), 3.25 (s, 3H);
13C{1H} NMR (CDCl3, 125 MHz) δ 167.2, 157.7, 148.3, 140.4, 139.1, 134.7, 132.4, 132.2, 131.5, 131.5, 130.6, 130.1,
129.0, 128.1, 126.9, 125.1, 123.4, 118.1, 116.0, 37.03; HRMS (ESI) m/z calcd for C20H14Cl3N2 (M+H)+ 387.0217,
found 387.0219; IR (KBr) 3062, 2952, 2920, 1613, 1583, 1553, 1491, 1465, 1450, 1432, 1380, 1312, 1279, 1263,
1245, 1198, 1130, 1079, 1029 cm-1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6-Chloro-11-methyl-4-phenylbenzo[2,3][1,4]diazepino[6,7,1-hi]indole (7)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 30:1) gave 7 (53.4 mg,78% yield) as a
yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.68 (d, J = 7.2 Hz, 2H), 7.49-7.40 (m, 4H), 7.27 (d, J = 8.4 Hz, 1H), 7.10-
6.95 (m, 3H), 6.60 (d, J = 8.0 Hz, 1H), 6.57 (s, 1H), 2.61 (s, 3H); 13C{1H} NMR (CDCl3, 125 MHz) δ 171.4, 153.3,
141.2, 140.2, 138.5, 138.4, 132.8, 131.1, 130.4, 130.3, 127.9, 126.9, 126.4, 125.9, 122.3, 122.1, 121.9, 121.1, 110.5,
14.8; HRMS (ESI) m/z calcd for C22H16ClN2 (M+H)+ 343.0997, found 343.1002; IR (KBr) 3057, 3026, 2920, 1615,
1592, 1561, 1476, 1454, 1446, 1415, 1383, 1364, 1295, 1266, 1227, 1179, 1148, 1026 cm-1.
4-(9-Methyl-5-oxido-5-phenyl-5H-dibenzo[b,e][1,4]azaphosphepin-11-yl)benzaldehyde (9)
Flash column chromatography on silica gel (petroleum ether : ethyl acetate = 2:1) gave 9 (73.3 mg, 87% yield) as a
yellow solid. m.p 239-241 oC; 1H NMR (CDCl3, 400 MHz) δ 9.99 (s, 1H), 8.45-8.40 (m, 1H), 8.12-8.07 (m, 1H), 7.73
(d, J = 8.1 Hz, 3H), 7.59-7.33 (m, 7H), 7.23-7.15 (m, 4H), 2.45 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ 191.7,
163.4, 145.3, 137.15 (d, JC-P = 99 Hz), 137.12, 134.5 (d, JC-P = 2 Hz), 133.3 (d, JC-P = 9 Hz), 133.0 (d, JC-P = 11 Hz),
132.0 (d, JC-P = 3 Hz), 131.4 (d, JC-P = 2 Hz), 130.82 (d, JC-P = 10 Hz), 130.77 (d, JC-P = 12 Hz), 130.3 (d, JC-P = 6 Hz),
129.59 (d, JC-P = 20 Hz), 129.61, 129.2 (d, JC-P = 5 Hz), 129.0, 128.13 (d, JC-P = 13 Hz), 126.3 (d, JC-P = 12 Hz), 123.7,
122.7, 18.6; HRMS (ESI) m/z calcd for C27H21NO2P (M+H)+ 422.1304, found 422.1300; IR (KBr) 3052, 2971, 2922,
1608, 1578, 1562, 1501, 1485, 1440, 1407, 1375, 1301, 1270, 1248, 1206, 1179, 1140, 1112, 1038 cm-1.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (NNSFC) (21532009, 21772198, and
21871268) for financial support.
Supporting Information:
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 33
Schemes for the synthesis of functionalized isocyanides along with copies of H, 13C NMR spectra for all isolated
1
1
2
3
compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
4
5
6
REFERENCES
7
8
9
1
(a) Ban, T. A.; Fujimori, M.; Petrie, W. M.; Ragheb, M.; Wilson, W. H. Systematic Studies with Amoxapine, a
New Antidepressant. Int. Pharmacopsych. 1982, 17, 18. (b) Cohen, B. M.; Harris, P. Q.; Altesman, R. I.; Cole, J.
O. Amoxapine: Neuroleptic as well as Antidepressant. Am. J. Psychiatry 1982, 139, 1165. (c) Kapur, S.; Cho, R.;
Jones, C.; McKay, G.; Zipursky, R. B. Is Amoxapine an Atypical Aantipsychotic? Positron-Emission Tomography
Investigation of its Dopamine2 and Serotonin2 Ooccupancy. Biol. Psychiatry 1999, 45, 1217. (d) Rehavi, M.;
Maayani, S.; Goldstein, L.; Assael, M.; Sokolovsky, M. Antimuscarinic Properties of Antidepressants: Dibenzepin.
Psychopharmacology 1977, 54, 35. (e) Balani, N. D.; Parhate, S. M.; Thawani, V. R.; Deshpande, A. M. Effects of
Nitroxazepine on Diastolic Blood Pressure in Mild Hypertensive Patients--a Short Term Clinical Study. Indian J.
Physiol. Pharmacol. 1995, 39, 293. (f) Blackwell, B. Treatment Adherence. Br. J. Psychiatry 1976, 129, 513. (g)
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. Novel Non-nucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2. Tricyclic
Pyridobenzoxazepinones and Dibenzoxazepinones. J. Med. Chem. 1992, 35, 1887. (h) Nagarajan, K. Quino[8,1-bc]
[1,4]Benzoxazepinones - HIV-1 Reverse Transcriptase Inhibitors. J. Indian Chem. Soc. 1997, 74, 831.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2 (a) Chakrabarti, A.; Bagnall, A. M.; Chue, P.; Fenton, M.; Palaniswamy, V.; Wong, W.; Xia, J. The Cochrane
Collaboration; John Wiley & Sons, Ltd.: New York, 2012; (b) Umemiya, H.; Fukasawa, H.; Ebisawa, M.; Eyrolles,
L.; Kawachi, E.; Eisenmann, G.; Gronemeyer, H.; Hashimoto, Y.; Shudo, K.; Kagechika, H. Regulation of
Retinoidal Actions by Diazepinylbenzoic Acids.1 Retinoid Synergists Which Activate the RXR−RAR
Heterodimers. J. Med. Chem. 1997, 40, 4222. (c) Fitton, A.; Heel, R.C. Clozapine A Review of its
Pharmacological Properties, and Therapeutic Use in Schizophrenia. Drugs 1990, 40, 722.
3 (a) Fu, P.; Jamison, M.; La, S.; MacMillan, J. B. Inducamides A-C, Chlorinated Alkaloids from an RNA
Polymerase Mutant Strain of Streptomyces sp.. Org. Lett. 2014, 16, 5656. (b) Nett, M.; Ikeda, H.; Moore, B. S.
Genomic Basis for Natural Product Biosynthetic Diversity in the Actinomycetes. Nat. Prod. Rep. 2009, 26, 1362.
(c) Bok, J. W.; Chiang, Y. M.; Szewczyk, E.; Davidson, Y.; Sanchez, A. D.; Lo, J. F.; Watanabe, H. C.; Strauss, K.;
Reyes- Dominguez, J.; Oakley, B. R.; Wang, C. C.; Keller, N. P. Chromatin-level Regulation of Biosynthetic Gene
Clusters. Nat. Chem. Biol. 2009, 5, 462.
ACS Paragon Plus Environment

Page 29 of 33
The Journal of Organic Chemistry
4 (a) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli,
M.; Valli, C.; Terao, M.; Garattini, E. Antiproliferative and Differentiating Activities of a Novel Series of Histone
Deacetylase Inhibitors. ACS Med. Chem. Lett. 2010, 1, 411. (b) Minucci, S.; Pelicci, P. G. Histone Deacetylase
Inhibitors and the Promise of Epigenetic (and more) Treatments for Cancer. Nat. Rev. Cancer 2006, 6, 38. (c) Yoo,
C. B.; Jones, P. A. Epigenetic Therapy of Cancer: Past, Present and Future. Nat. Rev. Drug Discovery 2006, 5, 37.
5 (a) Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.; Quilliam, M. A.; Walter, J. A.; Howlett, S. E.
Molecular Geometries of Dibenzothiazepinone and Dibenzoxazepinone Calcium Antagonist. Drug Des. Discov.
1995, 12, 337. (b) Smits, R. A.; Lim, H. D.; Stegink, B.; Bakker, R. A.; de Esch, I. J. P.; Leurs, R. Characterization
of the Histamine H4 Receptor Binding Site. Part 1. Synthesis and Pharmacological Evaluation of
Dibenzodiazepine Derivatives. J. Med. Chem. 2006, 49, 4512. (c) Olajos, E. J.; Salem, H. Riot Control Agents:
Pharmacology, Toxicology, Biochemistry and Chemistry. J. Appl. Toxicol. 2001, 21, 355.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6 (a) Trost, B. M.; Greenspan, P. D.; Yang, B. V.; Saulnier, M. G. An Unusual Oxidative Cyclization. A Synthesis
and Absolute Stereochemical Assignment of (-)-Rocaglamide. J. Am. Chem. Soc. 1990, 112, 9022. (b) Tietze, L. F.;
Brand, S.; Pfeiffer, T.; Antel, J.; Harms, K.; Sheldrick, G. M. Intra- and Intermolecular Hetero-Diels-Alder
Reactions.15. Asymmetric Induction in Grignard and Hetero-Diels-Alder Reactions of Chiral .alpha.,.beta.-
Unsaturated Carbonyl Compounds. J. Am. Chem. Soc. 1987, 109, 921. (c) Dols, P. P. M. A.; Folmer, B. J. B.; Kuil,
H.; Hamersma, C. W.; Lucas, H.; Ollero, L.; Rewinkel, J. B. M.; Hermkens, P. H. H. SAR Study of 2,3,4,14b-
Tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]Oxazepines as Progesterone Receptor Agonists. Bioorg. Med. Chem.
Lett. 2008, 18, 1461.
7 For selected reviews of the synthesis of benzoox(di)azepines, see: (a) Zaware, N.; Ohlmeyer, M. Recent Advances
in Dibenzo[b,f][1,4]oxazepine Synthesis. Heterocycl. Commun. 2014, 20, 251. (b) Tsvelikhovsky, D.; Buchwald, S.
L. Concise Palladium-Catalyzed Synthesis of Dibenzodiazepines and Structural Analogues. J. Am. Chem. Soc.
2011, 133, 14228. (c) Ottesen, L. K.; Ek, F.; Olsson, R. Iron-Catalyzed Cross-Coupling of Imidoyl Chlorides with
Grignard Reagents. Org. Lett. 2006, 8, 1771. (d) Shi, F.; Xu, X.; Zheng, L.; Dang, Q.; Bai, X. Method
Development for a Pyridobenzodiazepine Library with Multiple Diversification Points. J. Comb. Chem. 2008, 10,
158. (e) Fu, R.; Xu, X.; Dang, Q.; Bai, X. Synthesis of Novel Tricyclic Pyrimido[4,5-b][1,4]benzothiazepines via
Bischler−Napieralski-Type Reactions. J. Org. Chem. 2005, 70, 10810. (f) Yang, J.; Che, X.; Dang, Q.; Wei, Z.;
Gao, S.; Bai, X. Synthesis of Tricyclic 4-Chloro-pyrimido[4,5-b][1,4]benzodiazepines. Org. Lett. 2005, 7, 1541. (g)
Cale, A. D.; Gero, T. W.; Walker, K. R.; Lo, Y. S.; Welstead, W. J.; Jaques, L. W.; Johnson, A. F.; Leonard, C. A.;
Nolan, J. C.; Johnson, D. N. Benzo- and Pyrido-1,4-oxazepin-5-ones and -thiones: Synthesis and Structure-
ACS Paragon Plus Environment