Base-mediated synthesis of benzimidazole-fused 1,4-benzoxazepines via sequential intermolecular epoxide ring-opening/intramolecular SNAr reactions

Article abstract of DOI:10.1016/j.tetlet.2020.152491

We have developed a transition-metal-free, practical route to benzimidazole-fused 1,4-benzoxazepines. Operationally, the protocol involves a K₂CO₃-mediated intermolecular ring opening of terminal epoxides by 2-(2-fluorophenyl)benzimi

Full text of DOI:10.1016/j.tetlet.2020.152491

Journal Pre-proofs
Base-mediated synthesis of benzimidazole-fused 1,4-benzoxazepines via se‐
quential intermolecular epoxide ring-opening and intramolecular SNAr reac‐
tions
Runjun Devi, Subhamoy Mukhopadhyay, Arup Jyoti Das, Sajal Kumar Das
PII:
S0040-4039(20)30972-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152491
TETL 152491
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 August 2020
21 September 2020
22 September 2020
Please cite this article as: Devi, R., Mukhopadhyay, S., Jyoti Das, A., Kumar Das, S., Base-mediated synthesis of
benzimidazole-fused 1,4-benzoxazepines via sequential intermolecular epoxide ring-opening and intramolecular
SNAr reactions, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.152491
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Tetrahedron Letters
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Base-mediated synthesis of benzimidazole-fused 1,4-benzoxazepines via sequential
intermolecular epoxide ring-opening and intramolecular SNAr reactions
Runjun Devi,a≠ Subhamoy Mukhopadhyay,a≠ Arup Jyoti Das,a≠ and Sajal Kumar Dasa,
aDepartment of Chemical Sciences, Tezpur University, Napaam, Tezpur, Assam, India-784028
———
ARTICLE INFO
ABSTRACT
≠Equal contributions from RD, SM and AJD; Corresponding author. Tel.: +91-3712-275068; fax: +91-3712-267005;
e-mail: sajalkd@tezu.ernet.in
Article history:
Received
We have developed a transition metal-free practical route to benzimidazole-fused 1,4-
benzoxazepines. Operationally, the protocol involves a K2CO3-mediated intermolecular ring
opening of terminal epoxides by 2-(2-fluorophenyl)benzimidazole, followed by an
intramolecular nucleophilic aromatic substitution (SNAr) reaction of the resulting products in
the presence of NaH. We have also achieved an 11-step synthesis of a chroman-linked
benzimidazole-fused 1,4-benzoxazepine via a phenoxide-ion induced 6-exo intramolecular
epoxide ring-opening and an alkoxide-ion induced intramolecular SNAr reaction as key steps.
Received in revised form
Accepted
Available online
Keywords:
Benzimidazoles
2020 Elsevier Ltd. All rights reserved.
1,4-Benzoxazepines
Hybrid compounds
Epoxide ring-opening
Intramolecular SNAr
Hybrid compounds bearing two or more different core
structures often show characteristic properties that are not
exhibited by the constituent homonuclear scaffolds, thereby
playing very important roles across different branches of
chemical sciences.1 This has made the design and synthesis of
such compounds a well-known research area. Along this line, a
major emphasis has been given on the fusion of two different N-
heterocycles in a single molecule.2 A variety of methods are
available for the implementation of such a strategy – but
achieving the synthesis under complete regio-and/or
stereocontrol with a high level of diversity points remains a
challenging problem. Meanwhile, the privileged benzimidazole
unit (Figure 1) is only second to the indole ring in terms of
ubiquity of benzofused N-heterocycles in small-molecule drugs.3
Parallel to these, decoration of the benzimidazole ring into N-
fused polycyclic systems is constantly advancing for exploring
their untapped synthetic, materials and biological potentials.4 On
the other hand, because of their striking biological profile,
derivatives of 1,4-benzoxazepine (Figure 1) continue to grab the
attention of organic and medicinal chemists as valuable synthetic
targets.5
1,4-benzoxazepine
3
4
7
O
N
N
N
5
2
1
Ar2
Ar1
2
3
1
N
4N
6
5
O
H
H
R2
benzimidazole
R1
1
benzimidazole-fused
1,4-benzoxazepines
Figure 1. The benzimidazole and 1,4-benzoxazepine rings and the targeted
benzimidazole-fused 1,4-benzoxazepines.
Although the protocol successfully delivered 1, the main issue
with the route was the very low overall yield. More particularly,
the first steps involving an intermolecular epoxide ring-opening
were poor yielding (10-30%), due to the weak nucleophilicity of
the NH group of 2, and quick termination of the catalytic cycle
via the formation of unreactive Cu-complexes. Besides, as far as
the epoxide substrates are concerned, only alkyl-substituted
terminal epoxides were employed for this study. In continuation
with our research interest in the development of efficient methods
for N-fused hybrid heterocycles,7 we became interested in
synthesizing benzimidazole-fused 1,4-benzoxazepines 1 (Figure
1). Towards that objective, first we focused on addressing the
low yielding first step of the Chan’s work.
Notably, while benzimidazoles and 1,4-benzoxazepines have
been widely documented, synthesis of benzimidazole-fused 1,4-
benzoxazepines, such as 1 (Figure 1), remains scarcely reported
in the literature. To our knowledge, the only example of the
synthesis of 1 has been reported by Chan and co-workers.6 As
outlined in Scheme 1a, their work mainly involved Cu(OTf)2-
catalyzed intermolecular ring-opening of terminal epoxides 3 by
2-(2-nitrophenyl)-1H-benzimidazoles 2,
followed by NaH-
mediated intramolecular nucleophilic aromatic substitution
(SNAr) of the resulting epoxide ring-opening products 4.

2
Tetrahedron Letters
(a) Previous synthetic strategy
(2.5 equiv) was employed as the base in DMF at 80 °C (entry 5)
– but yield of 6a remained unchanged (entry 4 vs entry 5). Given
the lower cost of K2CO3 than Cs2CO3, we carried out further
optimization studies using K2CO3. Compound 6a was obtained
slightly higher yield, when decreased amount of K2CO3 (1.5
equiv) was used at 80 °C (entry 6). With K2CO3 (1.5 equiv) as
the base, an inferior result was observed on increasing the
reaction temperature to 120 °C (entry 7). Regarding the solvent
impact, the reaction was lower yielding in 1,4-dioxane (entry 8),
MeCN (entry 9) or acetone (entry 10).
O
R
O2N
R
O2N
N
R1
N
N
NaH
3
1
DMF, rt
Cu(OTf)2
MeCN
reflux
N
H
OH
2
R1
(yields: 10- 30%)
4
major problems:
very low overall yields
deactivation of the catalyst Cu(OTf)2 due to complexation
limited to only 4-substituted 2-aryl-1H-benzimidazoles
investigated with only alkyl-substitued terminal epoxides
Table 1. Condition optimization for the intramolecular cyclization
O
O
(b) Our envisioned synthesis
F
O
O
3a
N
N
F
HO
F
R1
N
N
base (equiv), solvent
N
N
R
3
R
N
5
temp, time
1
base
6a
N
H
O
1a
(not formed)
5
R = p-Tol -OCH2-
R1
entrya
base
(equiv)
solvent
temp time
yieldb
(%)
nr
expected advantageous features:
(oC)
(h)
24
higher nucleophilicity of deprotonated the benzimidazole moiety
transition metal-free conditions
1
2
K2CO3 (2.5)
DMF
DMF
rt
should be applicable to all sterically/electronically biased epoxides
possibility of developing a one-pot or telescoped protocol
NaH (2.5)
rt
12
nr
0 (6a)
20 (1a)
84 (6a)
0 (1a)
84 (6a)
0 (1a)
87 (6a)
0 (1a)
80 (6a)
0 (1a)
68 (6a)
0 (1a)
75 (6a)
0 (1a)
60 (6a)
0 (1a)
3
4
NaH (2.5)
DMF
DMF
80
6
Scheme 1. (a) Literature known and (b) our envisioned synthetic route for
the targeted compounds.
K2CO3 (2.5)
Cs2CO3 (2.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
80
80
12
8
We wondered whether this step might be more effective in the
presence of a base than being catalyzed by a Lewis acid like
Cu(OTf)2. We speculated that the deprotonated benzimidazole
moiety might be enough nucleophilic to react with 3 without the
requirement of epoxide ring activation by a Lewis acid.
Moreover, the reaction when mediated by a base would not suffer
from a complex formation. Thus, we envisioned that 2-(2-
fluorophenyl)-benzimidazole 5 and terminal epoxides 3 would
provide 1 via a base-mediated one-pot, two-step reaction
sequence featuring an intermolecular epoxide ring-opening
reaction, followed by an intramolecular SNAr reaction (Scheme
1b). Herein we detail our efforts aiming to execute the proposed
plan.8
5
DMF
6
DMF
80
12
12
12
12
12
7
DMF
120
80
8
dioxane
MeCN
acetone
9
70
10
65
For the validation and optimization studies, reaction of 2-(2-
fluorophenyl)benzimidazole 5 with terminal epoxide 3a was
selected as a model reaction (Table 1). To begin with, a mixture
of 3a and 5 in DMF was reacted with K2CO3 (2.5 equiv) at rt for
24 h. However, such a reaction protocol did not provide any
product — only unreacted 3a and 5 were recovered quantitatively
(Table 1, entry 1). An identical scenario was observed upon
changing the base to NaH (2.5 equiv) (entry 2). With NaH (2.5
equiv), we next conducted the reaction under heating condition
(80 °C) for 12 h (entry 3). Disappointingly, the protocol resulted
in a complex product mixture from which 1a was isolated in
extremely low yield. However, under the heating condition,
switching the base back to K2CO3 (2.5 equiv) delivered epoxide
ring-opening product 6a in 84% yield and tricyclic 1a was not
formed (entry 4). Although the desired final product 1a was not
obtained, we felt that the observed result (formation of 6a) is a
fabulous improvement for the N-alkylation of benzimidazoles
using epoxides as alkylating agents (Scheme 1a vs Table 1, entry
4). Notably, the reaction was significantly faster when Cs2CO3
aReactions were carried out using 5 (0.5 mmol, 1.0 equiv), 3a (0.5 mmol, 1.0
equiv) and base in DMF (5 mL); Isolated yields and nr means no reaction
b
took place.
On the basis of the Table 1 findings, we could summarize
three important features of this reaction. First, the intermolecular
ring-opening of the unactivated epoxide by the deprotonated
benzimidazole moiety required heating condition, as evidenced
by entries 1 and 2. Second, low yield of 1a under forcing reaction
conditions (entry 3) might be due to the loss of 1a via a ring-
opening isomerization.6 Third, for entries 3–10, the in situ
generated alkoxide intermediate undergoes protonation probably
by trace moisture in K2CO3/Cs2CO3 and/or the solvent, thus
preventing the subsequent intramolecular SNAr cyclization to 1a.
Nevertheless, we moved on to utilize 6a, obtained under the
optimized reaction conditions (Table 1, entry 6), in the next step
to complete the job. Towards this objective, compound 6a was
treated with NaH (1.15 equiv) in DMF at rt for 2 h (Scheme 2).

Table 2. Two-step synthesis of benzimidazole-fused 1,4-benzoxazepinesa,b
Delightfully, the reaction offered 1a in high yield (90%) via an
O
intramolecular SNAr cyclization (Scheme 2).
, K2CO3 (1.5 equiv)
1.
F
R
3
N
N
DMF, 80 oC, 12 h
N
O
N
H
O
N
2. NaH (1.15 equiv), DMF
0 oC - rt, 2 h
H/R
1a-i
5
R/H
NaH (1.15 equiv), DMF
O
N
6a
0 oC - rt, 2 h
benzimidazole-fused
1,4-benzoxazepine
entry
epoxide
1a
(90%)
Scheme 2. Synthesis of benzimidazole-fused 1,4-benzoxazepine 1a.
O
N
O
Thus, the intermolecular epoxide ring-opening and
intramolecular SNAr cyclization needed two different reaction
conditions: weak base and heating for the former step and strong
base and room temperature for the latter step. Although, these
antagonistic requirements did not allow us to synthesize 1a under
the envisioned one-pot double cyclization strategy, the
practicability of our method to 1a in high overall yield had
clearly been established at this point. But, we felt that further
improvement of this two-step route would be more useful.
Specifically, we decided to avoid the chromatographic isolation
of the intermediate compound 6a. Thus, a mixture of 5 (1 equiv),
3a (1 equiv) and K2CO3 (1.5 equiv) in DMF was heated at 80 oC
for 12 h, and then the reaction mixture was subjected to
customary workup. Crude 6a thus obtained was next treated with
NaH (1.15 equiv) in DMF at rt for 2 h (Table 2, entry 1). This
revised protocol delivered 1a in 76% isolated yield (over two
steps), which was comparable with that of the stepwise protocol
(Table 1, entry 6 and Scheme 2).
O
N
1
Me
O
3a
1a
(75%)
O
N
O
O
N
2
MeO
O
OMe
1b
(74%)
3b
O
N
O
O
N
O
3
1c
3c
(75%)
O
N
O
N
O
O
4
5
O
O
With this modified protocol, we then utilized 5 and alkyl-
substituted terminal epoxides 3b–g to synthesize benzimidazole-
fused 1,4-benzoxazepines 1b–g in good yields (Table 2, entries
2–9). Noteworthy is that both the intermolecular epoxide ring-
opening step and the subsequent intramolecular SNAr reaction
went very cleanly (TLC analysis) with each substrate. As
expected for an SN2-type reaction, the initial epoxide ring-
opening process took place regioselectively at the terminal
epoxide carbon atom and overall yield remained almost
unaffected on varying the alkyl substituent in the epoxide ring
(entries 2–7). Notably, the synthesis of 1f was particularly
attractive, since the benzyloxy group would offer an opportunity
for further synthetic manipulations (entry 6). It is also worth
observing that previously compound 1g was obtained in only
16% yield from 2-(2-nitrophenyl)-1H-benzimidazole and 3g,
whereas our protocol delivered it in 73% yield.6
c
1d
(74%) [72%]
3d
O
N
O
N
3e
1e
(71%)
OMe
OBn
OBn
O
O
N
N
N
6
7
3f
MeO
1f
(77%)
O
O
N
1g
Although nucleophilic ring-opening reactions of 2-
aryloxiranes regioselectively proceed at the benzylic position in
the presence of a Brønsted/Lewis acid catalyst/promoter, such
reactions under basic or neutral conditions often suffer from poor
regioselectivity.9 While an SN2-type nucleophilic attack can take
place at the terminal epoxide carbon without steric hindrance, the
reaction at the benzylic position is promoted by the -electron-
donating effect of the aryl group. In the SN1 or SN2-type
nucleophilic ring-openings of 2-aryloxiranes under acidic
conditions, the electronic effect predominates over the steric
effect– but often there is no clear winner in the SN2-type
reactions conducted in basic or neutral media, resulting in a
mixture of regioisomeric products. With all these facts in our
mind, we next decided to employ aryl-substituted terminal
epoxides 3h and 3i for the present two-step protocol.
Interestingly, the reaction delivered 1h and 1i as the major
isolated products, respectively, with the initial epoxide ring-
opening occurring at the benzylic position (entries 8 and 9).
(73%)
3g
O
N
N
O
8
Ph
3h
Ph
1h
(73%)
O
N
N
O
9
MeO
3i
OMe
1i
(77%)
aReaction conditions: 3 (0.5 mmol, 1.0 equiv), 5 (0.5 mmol, 1.0 equiv) and
K2CO3 (0.75 mmol, 1.5 equiv) in DMF (5 mL) for the first step; NaH (0.575
b
mmol, 1.15 equiv), DMF (5 mL) for the second step. The percentage values
indicate overall isolated yields. cValue in square bracket indicates isolated
yield of 1d when the reaction was run with 10.0 mmol of each 5 and 3d.

4
Tetrahedron Letters
OH
OBn
m-CPBA, CH2Cl2
While going through recent literature, we found that the
5 steps
ref. 14
observed regioselectivity is in agreement with the results reported
by the research groups of Jones10 and Bakavoli11–but seems to be
in contradiction with Ortiz-Marciales and co-workers’ results.12
Nevertheless, the structures of 1h and 1i were confirmed from a
simple analysis of their 1H and 13C NMR spectra. More
specifically, the NMR spectra show the appearance of the
benzylic proton (marked by red color) and carbon at  5.35 (as a
doublet of doublets) and 52.5 ppm, respectively; whereas the
methylene protons (marked by blue color) and carbon appear at 
4.59–4.50 (as a multiplet) and 81.1 ppm, respectively (Figure 2).
The  values of the benzylic proton and carbon match well with
those reported in literature for N-benzyl-2-arylbenzimidazoles.13
Thus, the isolated product was confirmed to be 1i but not the
regioisomeric product 1i´. Nevertheless, in these two cases, the
reaction also generated minor impurities (possibly due to the lack
of complete regioselectivity in the first step) which were not
isolated and characterized.
OH
0 °C, 6 h
7
8
OBn
OBn
TsCl, Et3N
OH
OTs
CH2Cl2, 0 °C, 12 h
O
O
9
(90%)
10
(89%)
OBn
Pd-C, H2 (balloon)
EtOAc, rt, 2 h
5
, K2CO3, DMF,
N
N
O
80 oC, 12 h
F
11
(75%)
OH
O
OH
K2CO3, DMF
80 oC, 2 h
N
N
N
N
F
O
F
 81.1
N
O
N
N
H
N
O
O
N
H
NaH, DMF
H  4.59-4.50 (m, 2H)
H
O
N
H
0 oC - rt, 2 h
H
 52.5
H
H
12
(65% over three steps)
 5.35
OMe
(dd, J = 7.8, 2.7 Hz)
Scheme 3.
benzoxazepine
Synthesis of chroman-linked benzimidazole-fused 1,4-
OMe
1i
1i
(not formed)
Thus, following the Table 2 reaction conditions, compound 13
and epoxide 3a were reacted (Scheme 4a). Unfortunately, this
attempt resulted in a disappointing note as 1a was not formed,
although the epoxide ring-opening reaction proceeded efficiently
to deliver 14 in 85% yield. We also experienced another failure
while attempting to synthesize 16 from 5 and styrene-derived N-
tosyl aziridine 15. Once again, no cyclization occurred – only N-
alkylation took place to furnish 17. This failure might be due to
the weaker nucleophilicity of the in situ generated bulky
sulfonamide anion. Changing the reaction conditions did not
bring any good news, and the ring-opening of an analogous N-
beznylaziridine substrate could not achieved (not shown here).
Figure 2. Structure elucidation of 1i.
Meanwhile, to check the gram level upscalability of the
protocol, we performed gram-scale reaction of 5 (2.12 g, 10.0
mmol) and 3d (2.00 g, 10.0 mmol) under the optimized reaction
conditions (Table 2, entry 4). The reactions took place without
any substantial loss in efficiency, delivering 1d in 72% yield.
Encouraged by the above-described successful synthesis of
benzimidazole-fused 1,4-benzoxazepines, we planned to extend
this methodology for the synthesis of a benzimidazole-fused 1,4-
benzoxazepine equipped with another privileged scaffold
chroman. Towards that objective, 2-allylphenol 7 was converted
into trans-allylic alcohol 8 following a previously reported five-
step reaction sequence (Scheme 3).14 Next, epoxidation of 8 with
m-CPBA followed by tosylation of the resulting epoxy alchol 9
with TsCl and Et3N delivered epoxy tosylate 10. K2CO3-
(a)
MeO
3a,
1.
K2CO3 (1.5 equiv)
MeO
N
DMF, 80 oC, 12 h
N
HO
1a
N
(not formed)
2. NaH (1.15 equiv), DMF
0 oC - rt, 4 h
R
N
o
H
mediated regioselective alkylation of 5 with 10 in DMF at 80 C
14
(85%)
13
(R = p-Tol -OCH2-)
furnished 11. Exposure of 11 to hydrogenation conditions (Pd-C,
H2) resulted in the chemoselective removal of the benzyl group.
Treatment of the resultant crude phenolic epoxide with K2CO3
resulted in the formation of the corresponding chroman
derivative, which was reacted with NaH to furnish 12. This
(b)
NTs
1.
F
Ph
15
K2CO3 (1.5 equiv)
DMF, 80 oC, 2 h
NTs
Ph
N
N
N
5
N
debenzylation/intramolecular
epoxide
ring-opening
NHTs
2. NaH (1.15 equiv), DMF
0 oC - rt, 4 h
cyclization/intramolecular SNAr reaction provided 12 in 65%
Ph
1
6
overall yield.
17 (
79%)
(not formed)
It has been reported that at least two strong electron-
withdrawing groups are required to activate the -OMe for acting
as a leaving group in SNAr reaction.15 Thus, the -OMe group has
a reputation of being less reactive leaving group in SNAr reaction.
However, this long-lived conception has recently been
challenged while considering methoxyarenes as low cost, ready
available and environmental friendly alternatives to aryl halides
for this chemistry.16 Inspired by these recent reports, we
speculated that 2-(2-methoxyphenyl)benzimidazole 13 might be
useful for the synthesis of benzimidazole-fused 1,4-
benzoxazepines.
Scheme 4. (a) Synthesis of benzimidazole-fused 1,4-benzoxazepine 1a.
In summary, we have demonstrated the efficiency of
sequential epoxide ring-opening and intramolecular SNAr
reactions in the practical and atom-economic synthesis of
benzimidazole-fused 1,4-benzoxazepines. Compared with the
literature method, the synthetic strategy reported herein has the
advantage of much higher overall yields. The synthetic route
appears to be fairly general one, and should be subject to
structural variation with respect to substituent diversity on both
the aromatic subunits and the epoxide ring. Moreover, we have
also demonstrated that the protocol can be used to construct

5.
(a) Sangshetti, J. N.; Ahmad, A. A. S.; Khan, F. A. K.; Zaheer, Z.
Mini-Rev. Org. Chem. 2015, 12, 345–354. (b) Lévai, A.
Heterocycles, 2008, 75, 2155–2185.
Fekner, T.; Gallucci, J.; Chan, M. K. Org. Lett. 2003, 5, 4795–
4798.
(a) Das, J.; Borah, B. J.; Das, S. K.; Org. Biomol. Chem. 2020, 18,
220–224. (b) Das, A. J.; Borgohain, H.; Sarma, B.; Das, S. K.;
Org. Biomol. Chem. 2020, 18, 441–449. (c) Borgohain, H.; Das, S.
K. Tetrahedron Lett. 2019, 60, 2070–2073. (d) Borgohain, H.;
Devi, R.; Dheer, D.; Borah, B. J.; Shankar, R.; Das, S. K. Euro. J.
Org. Chem. 2017, 45, 6671–6679.
This work is a part of PhD thesis: Devi, R. Stereoselective
Synthesis of Functionalized Chromans and Related Heterocycles
via Intramolecular Cyclization Reactions of Epoxides, Aziridines,
and Vicinal Diols, Tepur University 2018.
hitherto unreported chroman-linked benzimidazole-fused 1,4-
benzoxazepine. The developed chemistry should be extendable
for synthesizing other hybrid compounds.
6.
7.
Acknowledgments
We acknowledge the financial support (Grant No.:
02(0306)/17/EMR-II) provided by the Council of Scientific and
Industrial Research (CSIR), New Delhi. RD is thankful also to
CSIR for a providing Senior Research Fellowship.
8.
9.
Supplementary Material
(a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry,
Part B: Reactions and Synthesis, 5th ed.; Plenum:ꢀ New York,
2007; p 1105. (b) Kayser, M. M.; Morand, P. Can. J. Chem. 1980,
58, 302–306. (c) Saddique, F. A.; Zahoor, A. F.; Faiz, S.; Naqvi,
S. A. R.; Usman, M.; Ahmad, M. Synth. Commun. 2016, 46, 831–
868.
Experimental procedures, characterization data for all compounds
1
and copies of H and 13C NMR spectra for all new compounds
are available.
Base-mediated synthesis of benzimidazole-
fused 1,4-benzoxazepines via sequential
intermolecular epoxide ring-opening and
intramolecular SNAr reactions
Leave this area blank for abstract info.
Runjun Devi, Subhamoy Mukhopadhyay, Arup Jyoti Das, and Sajal Kumar Das
O
, K2CO3 (1.5 equiv)
1.
R
F
N
N
DMF, 80 oC, 12 h
N
O
N
H
2. NaH (1.15 equiv), DMF
0 oC - rt, 2 h
R
O
H
H
OH
11 steps
O
N
N
10. Brunelli, N. A.; Long, W.; Venkatasubbaiah, K.; Jones, C. W.
Top. Catal. 2012, 55, 432–438.
11. Mohseni, S.; Bakavoli, M.; Morsali, A. Prog. React. Kinet. Mech.
2014, 39, 89–102.
12. Huang, K.; Wang, H.; Stepanenko, V.; Jesus, M. D.; Torruellas,
C.; Correa, W.; Ortiz-Marciales, M. J. Org. Chem. 2011, 76,
1883–1886.
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Graphical Abstract

6
Tetrahedron Letters
Highlights
 High-yielding synthesis of benzimidazole-
fused 1,4-benzoxazepines has been
achieved.
 The protocol involves transition metal-free
conditions (K2CO3 and NaH).
 The reactions are completely regio- and
diastereoselective.
 An 11 step synthesis of a chroman-linked
benzimidazole-fused 1,4-benzoxazepine has
also been acheived.