One-pot synthesis of substituted dibenzoxazepinones and pyridobenzoxazepinones using octacarbonyldicobalt as an effective CO source

Article abstract of DOI:10.1080/00397911.2019.1695277

A facile one-pot protocol for the synthesis of substituted dibenzoxazepinones and pyridobenzoxazepinones from commercially available aryl/heteroaryl halides and amino phenols using octacarbonyldicobalt (Co₂(CO)₈) as an effective metal carbonyl source has been demonstrated. This method proceeds via the sequential coupling of aryl/heteroaryl halides with aminophenol by amidation and intramolecular cyclization to give dibenzoxazepinones/pyridobenzoxazepinones.

Full text of DOI:10.1080/00397911.2019.1695277

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
One-pot synthesis of substituted
dibenzoxazepinones and pyridobenzoxazepinones
using octacarbonyldicobalt as an effective CO
source
Kavitha Anchan, Poongavanam Baburajan, Nagaswarupa H. Puttappa &
Sujit Kumar Sarkar
To cite this article: Kavitha Anchan, Poongavanam Baburajan, Nagaswarupa H. Puttappa
& Sujit Kumar Sarkar (2019): One-pot synthesis of substituted dibenzoxazepinones and
pyridobenzoxazepinones using octacarbonyldicobalt as an effective CO source, Synthetic
Communications, DOI: 10.1080/00397911.2019.1695277
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1695277
One-pot synthesis of substituted dibenzoxazepinones and
pyridobenzoxazepinones using octacarbonyldicobalt as an
effective CO source
Kavitha Anchana,b, Poongavanam Baburajanb, Nagaswarupa H. Puttappac, and
Sujit Kumar Sarkarb
b
aResearch and Development Centre, Bharathiar University, Coimbatore, India; Discovery Chemistry,
c
Syngene International Limited, Bangalore, India; PG Department of Chemistry, Davangere University,
Davangere, India
ABSTRACT
ARTICLE HISTORY
Received 24 October 2019
A facile one-pot protocol for the synthesis of substituted dibenzoxa-
zepinones and pyridobenzoxazepinones from commercially available
aryl/heteroaryl halides and amino phenols using octacarbonyldico-
balt (Co2(CO)8) as an effective metal carbonyl source has been dem-
onstrated. This method proceeds via the sequential coupling of aryl/
heteroaryl halides with aminophenol by amidation and intramolecu-
lar cyclization to give dibenzoxazepinones/pyridobenzoxazepinones.
KEYWORDS
Amidation; Co2(CO)8;
dibenzoxazepinones; intra-
molecular cyclization;
pyridobenzoxazepinones
GRAPHICAL ABSTRACT
Introduction
The 6/7/6 fused tricyclic heterocycles, especially pyridobenzoxazepinones, dibenzoxaze-
pinones and its derivatives, constitute a key building block for number of biologically
active molecules.[1,2] Dibenzoxazepinones were isolated as natural products from the
leaves of Carex distachya (a and b, I) and mycemycins A–E (a–e, II) from the ethanolic
extracts of mycelia of two different streptomycetes (Fig. 1).[3]
The derivatives of pyridobenzoxazepinones and dibenzoxazepinone have been
found to show many biological activities such as anti-tumor,[4] H4R agonist,[5] anti-
inflammatory activities,[6] and non-nucleoside inhibitors of HIV-1 reverse
CONTACT Poongavanam Baburajan
India; Nagaswarupa H. Puttappa
baburajan29@gmail.com
nagaswarupa77@gmail.com
Syngene International Limited, Bangalore, 560099,
Davangere University, Davangere, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

2
K. ANCHAN ET AL.
O
O
O
R1
R2
OR1
HN
HN
R4
O
O
HO
O
R
R3
I
II
a) R = R1 = CH3
b) R = R1 = H
a) R1 = OMe, R2 = R3 = R4 = H
b) R1 = OMe, R2 = R3 = H, R4 = Cl
c) R1 = OMe, R2 = Cl, R3 = CH3, R4 = Cl
d) R1 = NH2, R2 = Cl, R3 = CH3, R4 = H
e) R1 = NH2, R2 = Cl, R3 = CH3, R4 = Cl
Figure 1. Chemical structures of dibenzoxazepinones from Carex distachya (a and b, I) and mycemy-
cins A–E (a–e, II).
transcriptase.[7] Furthermore, the dibenzoxazepinone and pyridobenzoxazepinone com-
pounds are precursor for the synthesis of numerous pharmaceutical agents with various
biological activities. For example, nitroxazepine brand name Sintamil (III) bearing
dibenzoxazepinone skeleton is used as an antidepressant agent.[8] Amoxapine (IV),[9]
a
derived skeleton of dibenzoxazepinone is a marketed antidepressant drug. Loxapine
(V),[10] is a typical antipsychotic medication used in the treatment of schizophrenia
(Fig. 2). 5-(4-Methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]-benzoxazepine, JL 13
with potential atypical antipsychotic activity[11] (Fig. 3) is derived from pyridobenzoxa-
zepinone derivative.
Conventional methods to prepare dibenzoxazepinones and their derivatives involve
traditional intermolecular cyclization of ortho-amino phenols with ortho halo benzoic
acids [5,12]/or ortho-nitro benzoic acids,[13] or through a reduction – lactamization
route.[14] Pyridobenzoxazepinones and their derivatives can be prepared either by con-
densation/SNAr sequence of ortho-halo nicotinoyl chloride/ortho-halo nicotinic acid
with ortho-amino phenols or by Smiles rearrangement of ortho halo nicotinamide with
ortho-halo phenols.[15] Alper and coworkers reported an intramolecular carbonylation
for the synthesis of dibenzoxazepinones by employing a palladium-complexed den-
drimers.[16] Yunfei and coworkers reported a synthesis of dibenzoxazepinone com-
pounds from 2-(aryloxy)benzamides through hypervalent iodine(III)-mediated oxidative
cyclization.[17] Recently, phenyliodine(III) diacetate-mediated synthesis of diaryl ethers
with an o-CHO and secondary amine substituents upon subsequent treatment with
NaBH(OAc)3 and PCC provided dibenzoxazepines and dibenzoxazepinones, respectively
was reported.[18] All these routes usually involve multistep synthesis, the isolation of
intermediates, severe conditions and low yields of products are obtained in some cases.
Thus, developing an innovative, general and highly efficient route to synthesize the skel-
eton of dibenzoxazepinones and pyridobenzoxazepinones from commercially available
reagents is an interesting and challenging topic for organic chemists. The transition
metal-catalyzed carbonylation has become an important tool in organic synthesis.[19]
Wu and coworkers have reported (Scheme 1) the one- pot fusion of palladium-catalyzed
carbonylative SNAr approach for the synthesis of dibenzoxazepinones,[20a]

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3
.HCl
N
NH
N
N
N
N
O
N
N
Cl
Cl
Cl
O
O
O
V
IV
Amoxapine
III
Loxapine
Nitroxazepine
Figure 2. Representative biologically active dibenzoxazepinones and their derivatives.
N
N
N
Cl
O
N
JL 13
Figure 3. Potential atypical antipsychotic JL 13 (AAP).
Scheme 1. Benzoxazepinone synthesis by using CO gas.
pyridobenzoxazepinones,[20b] chromones,[20c] thiochromenones,[20d] using CO gas as a
carbonylation source. These reactions involve initial evacuation of toxic CO gas and
high pressure of CO gas (10 bar). Although the methodology is useful in the industry
on a large scale, the toxicity of CO gas as well as the requirement of special pressure
reaction set-ups make it inconvenient in small-scale laboratory and library (analo-
gous) synthesis.
In our previous work, we have described the synthesis of benzamides, phthalazinones
and b-ketoesters using CO2(CO)8 as a successful in situ CO source.[21] Based on that, in
our present work, we have focused on developing an one-pot protocol for the rapid
ring construction of dibenzoxazepinones, pyridobenzoxazepinones and their derivatives
using CO2(CO)8 as an effective in situ-generated, stoichiometric CO source starting
from readily available raw materials. Moreover, reactions were carried out using a com-
mercially available sealed tubes or Microwave vials.
Results and discussion
Initially, 1-bromo-2-fluorobenzene (1a) and 2-amino phenol (2a) (Table 1) were
selected as the model substrate to optimize the reaction conditions including

4
K. ANCHAN ET AL.
Table 1. Optimization of reaction conditions for the synthesis of dibenzoxazepinone.
O
Co2(CO)8,
Br
F
H2N
HO
HN
NH
Pd(OAc)2, xantphos
OH
+
+
O
base, solvent
O
F
1a
3a
4a
2a
Entry
Solvent
Temp (ꢀC)
Base
DMAP
DMAP
Time (h)
Yield (%)a 3a
1
2
3
4
5
6
7
8
1,4-Dioxane
Toluene
THF
1,4-Dioxane
DMF
DMSO
NMP
90
90
90
2
2
2
2
2
2
2
2
2
5
5
5
8
12
16
2
7
5
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DBU
DABCO
DBU
DBU
DBU
DBU
12
16
22
18
17
20
22
35
45
42
62
84
89
35b
62b
120
120
120
120
120
150
150
150
150
150
150
150
90
DMA
DMF
DMF
9
10
11
12
13
14
15
16
17
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
90
DBU
8
Notes. All the reactions were executed with 1-bromo-2-fluorobenzene 1a (1 mmol), 2-amino phenol 2a (1 mmol),
Pd(OAc)2 (5 mol%), xantphos (5 mol%), base (2.5 mmol), solvent (10 V) and Co2(CO)8 (0.25 mmol).
aYield of isolated products. bisolated yields of Un-cyclised 4a was isolated.
optimization of the catalysts, ligands, bases, and solvents. Guided by the literature and
our own results, a preliminary study was carried out on a 1 mmol of 1a, 1 mmol of 2a
using DMAP, Pd(OAc)2, xantphos and CO2(CO)8 in DMSO at 150 ꢀC for 5 h in a sealed
tube. We obtained a mixture of dibenzoxazepinone 3a and uncyclized product 4a in
low yields. Further investigation on bases, solvents and temperature systems were con-
ducted. Among the tested solvents, we found that DMF was the best solvent (Table 1,
entry 5). Investigations on the tested bases revealed that the highest yield was achieved
when DBU was used (Table 1, entry 15) at 150 ꢀC for 16 h.
All the reactions were carried out by the conventional heating method and the yields
were concluded by an average isolated yield of reactions performed twice. By the con-
trolled experiment conditions (Table 1 entry 16 and 17), we found that the reaction
proceeds via the aminocarbonylation followed by cyclization. The optimization of the
catalytic system employed in the study has been carried out and the result indicated
that Pd(OAc)2/xantphos was found to be the best system. Further, the scope and gener-
ality of the method was next explored under the optimized reaction conditions (Table 1,
entry 15). A variety of dibenzoxazepinones (3a–3k) were synthesized in good to excellent
yields. Several useful functional groups of both the aryl halides (I, Br) and amino phenols
were tolerated in the reaction condition (Table 2).
The accessibility of this method was further explored by the synthesis of pyridoben-
zoxazepinones. Initially, we have attempted with our optimized reaction condition as
that of dibenzoxazepinones (Table 1, entry 15) starting from 3-bromo-2-chloro pyridine

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5
Table 2. Synthesis of substituted dibenzoxazepinones.
O
R'
Co2(CO)8,
Br, I
H2N
HO
NH
Pd(OAc)2, xantphos
R'
R
R
+
DBU, DMF,
150 oC, 16 h
F, Cl
O
3
1
2
Entry Substrate (1)
Substrate (2)
Product (3)
Yield (%)a
89
Br
H2N
HO
1
F
Br
H2N
HO
2
X = F, 91,
X = Cl, 79
X
Br
H2N
HO
Cl
3
88
72
85
F
F
Br
F
H2N
HO
4
5
Br
F
X
H2N
HO
6
7
X= Br, 92,
X =I, 90
F
Br
X
H2N
HO
X = F, 90,
X = Cl, 74
(continued)

6
K. ANCHAN ET AL.
X
F
H2N
HO
8
X=Br, 72,
X=I, 75
O
O
Br
F
H2N
HO
9
76
80
77
H2N
HO
Br
F
10
11
O
H2N
HO
Br
F
Notes. All the reactions were executed with 1 (1 mmol), 2 (1 mmol), Pd(OAc)2 (5 mol%), xantphos (5 mol%), Co2(CO)8
a
(0.25 mmol), DBU (2.5 mmol), DMF (10 V), 150 ꢀC and 16 h. Yields quoted are isolated yields.
and 2-amino phenol. As anticipated, the reaction got completed but the isolated yield
was poor (27%). Then, we studied the reaction by reducing the reaction temperature
and isolated 82% of the desired product 7a at 135 ꢀC for 12 h (Table 3, entry 1). Further
reducing the temperature did not improve the yield. Next, we tried the same reaction
condition with 3-bromo-2-fluoro pyridine and 2-amino phenol, and surprisingly ended
up with a very low yield (<5%). Further, we optimized the temp and base in the reac-
tion and identified the optimum reaction condition is DMAP as base at 120 ꢀC for flu-
oro substituted aryl halides. Finally, we explored a variety of heteroaryl halides (5a–5j)
with various amino phenols and isolated corresponding pyridobenzoxazepinones
(7a–7j) in moderate yields by appropriate reaction conditions.
To conclude, we have demonstrated this method to be a parallel synthesis technique
(20 reactions sequence). All the above-synthesized benzoxazepinone (3a–3k and 7a–7j)
compounds were experimented on 100 mg scale of corresponding aryl/heteroaryl halide
and the isolated yields were similar to the previously reported yields. Then, we explored
in gram scale (1 g and 5 g scale) and isolated a moderate yield (Scheme 2). The consist-
ency of yields obtained encouraged us to synthesize a potential atypical antipsychotic mol-
ecule JL 13 (AAP) by carbonylation synthetic sequence (Scheme 2, Steps – 1, 2 and 3).[1]

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7
Table 3. Synthesis of substituted pyridobenzoxazepinones.
Entry Substrate (5) Substrate (6)
Product (7)
Yield (%)a
O
Br
X
H2N
HO
NH
1
2
3
X= F, 76,
X= Cl, 82
N
N
N
N
O
7a
Br
X
H2N
HO
Cl
Cl
X= F, 70,
X= Cl, 65
H2N
HO
Br
X
X= F, 78,
X= Cl, 72
H2N
HO
Cl
Cl
Br
X
4
X= F, 68,
X= Cl, 56
N
N
Br
X
H2N
HO
5
6
7
X= F, 88,
X= Cl, 81
Br
Cl
H2N
HO
67
73
N
N
Br
Cl
H2N
HO
Cl
(continued)

8
K. ANCHAN ET AL.
Br
Cl
H2N
HO
8
71
N
Br
Cl
H2N
HO
9
70
73
N
N
Br
Cl
H2N
HO
O
NH
10
N
O
7j
Notes. All the reactions were executed with 5 (1 mmol), 6 (1 mmol), Pd(OAc)2 (5 mol%), xantphos (5 mol%), DMF (10 V)
and Co2(CO)8 (0.25 mmol).
aYields quoted are isolated yields. When X ¼ F, reaction was executed with DMAP (2.5 mmol) as a base at 120 ꢀC for
8 h. When X ¼ Cl, reaction was executed with DBU (2.5 mmol) as a base at 135 ꢀC for 12 h.
Scheme 2. Synthesis of 7b and 5-(4-Methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]-benzoxazepine
(JL 13, AAP).
Conclusion
We have successfully developed an effective method for the synthesis of dibenzoxazepi-
nones and pyridobenzoxazepinones by employing one-pot amino carbonylation followed
by etherification using CO2(CO)8 as an effective in situ CO source. The aryl halides and
heteroaryl halides were separately optimized and isolated good to moderate yields.
These reactions were performed in regular laboratory fume hood without the

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9
requirement of much precautions, such as handling the carbon monoxide cylinders, ini-
tial CO evacuation of the reaction vessels and special fume hood. We believe the meth-
odology can be significant in the synthesis of various new bio-significant molecules
constituted of dibenzoxazepinones and pyridobenzoxazepinones core. These reactions
can be performed using common sealed tubes/glass pressure tubes. This method is very
convenient in academic and laboratory small scale studies as well as library (analogous)
synthesis as the special pressure reaction equipments are not involved.
Experimental
Commercially available reagents were used as received in this work. Purification of
1
products was performed by silica-gel column chromatography. H NMR spectra were
obtained using a 300-MHz or 400-MHz spectrometer. 13C NMR spectra were obtained
from a 75-MHz or 100-MHz spectrometer. All 1H and 13C NMR experiments are
reported in parts per million (ppm) downfield from tetramethylsilane (TMS) and were
measured relative to the signals for residual chloroform in the deuterated solvents. The
mass spectra were recorded on liquid chromatography–mass spectrometry (LCMS). All
the spectral data matched well with the literature descriptions. For the unknown com-
pounds were further characterized by elemental analysis (CHN).
General experimental procedure
General procedure for the synthesis of substituted dibenzoxazepinones
A sealed tube equipped with a magnetic stir bar was charged with the corresponding 1-
bromo-2-fluoro (or chloro) benzene/1-fluoro-2-iodobenzene (1 mmol), amino phenol
(1 mmol), Pd(OAc)2 (5 mol%), xantphos (5 mol%) and DBU (2.5 mmol). The tube was
purged with argon. Then DMF (10 V) was added followed by the addition of CO2(CO)8
(0.25 mmol). The tube was closed with seal plug instantly. The reaction tube was placed
in a preheated oil bath at 150 ꢀC for 16 h. On completion, the reaction mixture was
cooled to room temperature, added water and ethyl acetate (1:1). Precipitated solid was
filtered through a celite bed. The bed was washed thoroughly with ethyl acetate.
Organic layer was separated. Aqueous layer was extracted with EtOAc. The combined
organic layers were washed with water, brine, dried over anhydrous sodium sulfate.
Organic layer was concentrated under reduced pressure and purified by flash column
chromatography on silica gel (230–400 mesh) with ethyl acetate and petroleum ether as
eluent to afford the corresponding dibenzoxazepinone.
General procedure for the synthesis of substituted pyridobenzoxazepinones
A sealed tube equipped with a magnetic stir bar was charged with the corresponding 3-
bromo-2-fluoropyridine (1 mmol), amino phenol (1 mmol), Pd(OAc)2 (5 mol%), xant-
phos (5 mol%) and DMAP (2.5 mmol). The tube was purged with argon. Then DMF
(10 V) was added followed by the addition of CO2(CO)8 (0.25 mmol). The tube was
closed with seal plug instantly. The reaction tube was placed in a preheated oil bath at
120 ꢀC to 135 ꢀC for 8–12 h. On completion, the reaction mixture was cooled to room

10
K. ANCHAN ET AL.
temperature, added water and ethyl acetate (1:1). Precipitated solid was filtered through
a celite bed. The bed was washed thoroughly with ethyl acetate. Organic layer was sepa-
rated. Aqueous layer extracted with EtOAc. The combined organic layers were washed
with water, brine, dried over anhydrous sodium sulfate. Organic layer was concentrated
under reduced pressure and purified by flash column chromatography on silica gel
(230–400 mesh) with ethyl acetate and petroleum ether as eluent to afford the corre-
sponding pyridobenzoxazepinone.
Selected spectroscopic data
Dibenzo[b,f][1,4]oxazepin-11(10H)-one (3a)[16,19a]
Following the general procedure using 1-bromo-2-fluorobenzene (175 mg, 1 mmol) and
2-aminophenol (110 mg, 1 mmol) provided 188 mg (89% yield) of 3a as a white solid.
1H-NMR (400 MHz, DMSO-d6): d 10.54 (s, 1H), 7.77 (dd, J ¼ 1.60, 7.80 Hz, 1H),
7.64–7.59 (m, 1H), 7.36–7.30 (m, 3H), 7.19–7.11 (m, 3H); 13C-NMR (100 MHz, CDCl3):
d 167.5, 159.7, 150.9, 134.5, 132.0, 130.6, 125.9, 125.8, 125.2, 125.1, 121.7, 121.3, 120.8;
LCMS (APCI-MS) Calcd. for C13H9NO2: 211.06, found [M þ H]þ ¼ 212.4.
Benzo[b]pyrido[3,2-f][1,4]oxazepin-5(6H)-one (7a)[19b]
Following the general procedure using 3-bromo-2-fluoropyridine (175 mg, 1 mmol) and
2-aminophenol (109 mg, 1 mmol) provided 161 mg (76% yield) of 7a as a white solid.
Following the general procedure using 3-bromo-2-chloropyridine (190 mg, 1 mmol) and
2-aminophenol (109 mg, 1 mmol) provided 174 mg (82% yield) of 7a as a white solid.
1H-NMR (400 MHz, DMSO-d6): d 10.75 (s, 1H), 8.51 (dd, J ¼ 1.96, 4.74Hz, 1H), 8.28
(dd, J ¼ 1.92, 7.58Hz, 1H), 7.47 (dd, J ¼ 4.80, 7.56 Hz, 1H), 7.36–7.34 (m, 1H), 7.26–7.16
(m, 3H); 13C-NMR (100 MHz, DMSO-d6): d 164.4, 162.4, 152.5, 148.2, 142.5, 130.6,
126.5, 125.6, 122.6, 121.9, 121.8, 120.1; LCMS (APCI-MS) Calcd. for C12H8N2O2:
212.05, found [M þ H]þ ¼ 213.2.
5-(4-Methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]-benzoxazepine (JL 13)[1]
A
solution of 8-chlorobenzo[b]pyrido[3,2-f][1,4]oxazepin-5(6H)-one 7b (100 mg,
0.41 mmol) in POCl3 (2 mL) was heated to reflux for 16 h. On completion, the reaction
mixture was cooled to RT; the excess phosphorus oxychloride was removed under
reduced pressure. The residue obtained was co-evaporated with toluene (2 ꢁ 10 mL) to
afford crude iminochloride as a brown sticky residue which was used without further
purification. It was dissolved in toluene (2 mL), and an excess of 1-methylpiperazine
(406 mg, 4.1 mmol) was added. The mixture was heated to reflux for 2 h. The solvent
was then evaporated under reduced pressure, and the residue was dissolved in chloro-
form (15 mL) and washed with water (2 ꢁ 10 mL), brine (1 ꢁ 10 mL), dried over anhyd-
rous sodium sulfate filtered through a cotton plug and concentrated under reduced
pressure to afford crude. Crude obtained was purified by flash column chromatography
on silica gel (230–400 mesh) with MeOH and dichloromethane as eluent to afford
133 mg (75% yield) of JL 13 as beige solid. 1H-NMR (400 MHz, CDCl3): d 8.51

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11
(dd, J ¼ 1.20, 4.60 Hz, 1H), 7.60 (dd, J ¼ 1.20, 8.20 Hz, 1H), 7.43 (dd, J ¼ 4.40, 8.20 Hz,
1H), 7.16 (d, J ¼ 2.80 Hz, 1H), 7.06 (d, J ¼ 8.40 Hz, 1H), 06.91 (dd, J ¼ 2.40, 8.60 Hz,
1H), 3.74–3.73 (m, 4H), 2.60–2.50 (m, 4H), 2.38 (s, 3H); LCMS (APCI-MS) Calcd. for
C17H17ClN4O: 328.10, found [M þ H]þ ¼ 329.0.
1
Full experimental details, H and 13C NMR spectra. This material can be found via
the “Supplementary Content” section of this article webpage
Acknowledgements
The authors are thankful to Dr. Subhendu Kumar Mohanty, Dr. Sathya Shanker, Karthik T. Pai,
and Dr. Raman Bakshi, for their help, support and encouragement throughout this work.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Kavitha is grateful to Syngene International Ltd, Bangalore, India, for financial support and the
permission for higher education (Ph.D.).
References
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