Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short synthesis of doxepin

Article abstract of DOI:10.1016/j.tet.2017.03.085

A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The method takes advantage of a newly developed cooperative system consisting of sustainable FeCl₂ and Cl₂CHOCH₃ as the key components. This methodology is compatible with a wide variety of functional groups in good to excellent yields and high regioselectivity. The synthetic application of new protocol was extended to the synthesis of known tricyclic drug doxepin as well as a small library of oxepin based derivatives. For the first time, the obtained dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-living nematode Caenorhabditis elegans as an effective and cost-efficient model system for anthelmintic discovery.

Full text of DOI:10.1016/j.tet.2017.03.085

Accepted Manuscript
Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with
biological activity. A short synthesis of doxepin
Jimena Scoccia, M. Julia Castro, M. Belén Faraoni, Cecilia Bouzat, Víctor S. Martín,
Darío C. Gerbino
PII:
S0040-4020(17)30342-3
10.1016/j.tet.2017.03.085
TET 28591
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 31 January 2017
Revised Date: 22 March 2017
Accepted Date: 29 March 2017
Please cite this article as: Scoccia J, Castro MJ, Faraoni MB, Bouzat C, Martín VS, Gerbino DC, Iron(II)
promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with biological activity. A short
synthesis of doxepin, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.085.
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oxepin-11(6H)-one derivatives with biological
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Jimena Scoccia,a M. Julia Castro,a,b M. Belén Faraoni,a Cecilia Bouzat,b Víctor S. Martín,c Darío C. Gerbinoa,*
a
INQUISUR, Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Avenida Alem 1253,
8000 Bahía Blanca, Argentina.
b INIBIBB, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET,
Camino La Carrindanga km 7, 8000 Bahía Blanca, Argentina.
c
IUBO, Departamento de Química Orgánica, Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2,
38206 La Laguna, Tenerife, Spain.

1
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Tetrahedron
journal homepage: www.elsevier.com
Iron(II) promoted direct synthesis of dibenzo[b,e]oxepin-11(6H)-one derivatives with
biological activity. A short synthesis of doxepin
Jimena Scoccia,a M. Julia Castro,a,b M. Belén Faraoni,a Cecilia Bouzat,b Víctor S. Martín,c Darío C.
Gerbinoa,*
a INQUISUR, Departamento de Química, Universidad Nacional del Sur (UNS)-CONICET, Avenida Alem 1253, 8000 Bahía Blanca, Argentina.
b
INIBIBB, Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-CONICET, Camino La Carrindanga km 7, 8000 Bahía
Blanca, Argentina.
c IUBO, Departamento de Química Orgánica, Universidad de La Laguna, C/Astrofísico Francisco Sánchez 2, 38206 La Laguna, Tenerife, Spain.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel and efficient synthesis of dibenzo[b,e]oxepin-11(6H)-ones by direct intramolecular
ortho-acylation from readily available 2-(phenoxymethyl)benzoic acids was developed. The
method takes advantage of a newly developed cooperative system consisting of sustainable
FeCl2 and Cl2CHOCH3 as the key components. This methodology is compatible with a wide
variety of functional groups in good to excellent yields and high regioselectivity. The synthetic
application of new protocol was extended to the synthesis of known tricyclic drug doxepin as
well as a small library of oxepin based derivatives. For the first time, the obtained
dibenzo[b,e]oxepinone derivatives were evaluated for their biological activities on the free-
living nematode Caenorhabditis elegans as an effective and cost-efficient model system for
anthelmintic discovery.
Available online
Keywords:
Synthetic methodology
Dibenzo[b,e]oxepin-11(6H)-ones
Intramolecular acylation,
Doxepin,
2017 Elsevier Ltd. All rights reserved
.
Anthelmintic activity.
1. Introduction
“doxepinone”, emerges as an interesting synthetic target. In this
respect, a large number of compounds having this privileged
structure present relevant biological activities, such as
antidepressant, anxiolytic, anticholinergic, antihistaminic,7
antipsychotic,8 analgesic, antipyretic, anti-inflammatory9 and
antitumor drugs (Fig 1).10 The dibenzo[b,e]oxepin-11(6H)-one
motif containing natural products, such as chaetones I and II,
showed remarkable cytotoxic and antimicrobial activities.11
Interestingly, chaetone II also exhibited antitumor activity
against gastric cancer cells BGC823.12 Moreover, the metabolite
pestalachloride B displayed significant antifungal activities
against different plant pathogens.13 Dibenzo[b,e]oxepinones,
isoxepac and skepinone-type of synthetic origin were identified
as potential therapeutic agents for the treatment of inflammatory
diseases, such as rheumatoid arthritis (RA), psoriasis, and
Crohn's disease.14 In addition, these pharmacophores units are
very important in medicinal chemistry due to their proved
therapeutic properties.
Helminthiasis, also known as worm infection, is a serious
problem worldwide resulting in high human morbidity and
enormous economic losses in livestock,1 especially in tropical
and sub-tropical countries. Anthelmintic drugs are used for the
control of parasitic infections caused by helminths.. With the
increasing incidence of drug resistance and the high cost of
existing pharmacological agents, the search for new antiparasitic
drugs of synthetic origin is imperative.2 Caenorhabditis elegans
is a free-living nematode naturally found in soils of temperate
climate, which has become a model organism for parasitic
nematode research. It is also an excellent system for the
screening of compounds with potential anthelmintic activity,
because it is inexpensive, readily available, and easy to work.3 In
addition, C. elegans has extensively used to investigate nematode
behavior, locomotion, reproduction and death.4
Natural products play an important role in drug development,
particularly in antineoplasic, antibiotics and antiparasitic drugs.5
Their structural diversity is a source of inspiration for drug
discovery and the preparation of analogs as simplified,
synthetically more accessible and stable models are broadly
described in the literature.6 In this context, the tricyclic
The biological versatility exhibited by dibenzo[b,e]oxepinones
and their congeners makes them very attractive targets for
synthetic chemists.
dibenzo[b,e]oxepin-11(6H)-one scaffold also known as
———
* Corresponding author. Tel.: +54-291-459-5101; fax: +54-291-459-5187; e-mail: dgerbino@uns.edu.ar
u

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and Discussion
HO
O
OH
HO
O
HO
Cl
2.1. Chemistry
In recent studies, Kong-Wang and co-workers24 established an
O
O
O
HO
Cl
RO
Chaetones I: R = H; II: R = Me
interesting intramolecular acylation of benzyl esters by using the
combined system of FeCl3 with Cl2CHOCH3. This novel reactive
system offered an efficient approach to the privileged structure
xanthone,25 which is structurally closely related to our target
dibenzo[b,e]oxepin-11(6H)-one. However, this protocol is
subjected to some limitations, such as non-availability of starting
materials and low tolerance of electron-withdrawing functional
groups. Inspired by this work, and in order to develop an
operationally simple synthesis of the diaryl fused oxepin-11(6H)-
one core, we decided to study the course of the direct
Pestalachloride B
F
O
OH
O
F
O
N
H
O
O
Isoxepac
Skepinone-type
Figure 1. Representative structures of dibenzo[b,e]oxepin-
11(6H)-ones of biological interest.
Accordingly, the development of efficient methodologies for
the construction of dibenzo[b,e]oxepin-11(6H)-one unit has
represented a considerable synthetic challenge in the field of
organic synthesis. Even though the synthesis of this framework
represents a growing field due to the requirements of medicinal
chemistry researches, a limited number of approaches for their
synthesis has been developed to date.15 Among them, the two
intramolecular
acylation
of
readily
available
2-
(phenoxymethyl)benzoic acids by using different Lewis acids
and dichloromethyl methyl ether (DCME). The strategic concept
of our synthesis is summarized in Scheme 1.
most
common
approaches
for
the
synthesis
of
dibenzo[b,e]oxepinones are: (a) intramolecular C-O bond
formation via Williamson ether synthesis16 and (b)
cyclodehydration or intramolecular Friedel–Crafts acylation
reaction of intermediates with a preformed aryl benzyl ether
Scheme 1. Retrosynthetic analysis for dibenzo[b,e]oxepin-
11(6H)-one framework.
bond.17 However, they often suffer from
a variety of
The required starting materials for the synthesis of
dibenzo[b,e]oxepinones type 1 can easily be obtained by treating
substituted phthalide I with different sodium phenoxides
derivatives II in DMF by modifications to known procedures
(see ESI for experimental details).15a,f An alternative synthetic
route to access the substrates type 2 involves a Williamson
synthesis between methyl 2-(bromomethyl)benzoate derivatives
III and substituted phenoxides II followed by acid hydrolysis
(Scheme 2).
disadvantages, such as poor yields, severe side reactions, high
reaction temperature, prolonged reaction time, requirement of
expensive reagents, low tolerance of functional groups15a,18 and
poor regioselectivity. Similarly, another protocol under much
milder reaction in the presence of trifluoroacetic anhydride has
been developed.19 More recently, a new Parham cyclization
methodology has been developed for the preparation of diaryl
fused oxepinones. This strategy involves the generation of
functionalized aryllithiums by bromine–lithium exchange,
followed by intramolecular cyclization onto an electrophilic
nitrile functional group.20
Doxepin is a dibenzo[b,e]oxepine tricyclic with a tertiary
amine chemical structure, which is marketed as a mixture of
geometric isomers in a ratio of Z:E =15:85. It acts by inhibiting
the reuptake of serotonin and norepinephrine at chemical
synapses. Its primary use is in the treatment of depression21 and it
is also occasionally used in treating anxiety disorders and
insomnia. As result of their therapeutic importance, doxepin and
its congeners are interesting targets for chemical synthesis.
Surprisingly, we found few precedents in the scientific literature
of the total synthesis of this drug.22
Scheme 2. Preparation of 2-(phenoxymethyl)benzoic acids 2.
Method A (2a-2h): NaH (1.5 equiv), DMF, reflux, 24 h; then 1 N
NaOH, 1 M HCl; Method B (2i-2l): K3PO4 (2 equiv), toluene,
reflux, 5 h; then KOH, methanol, reflux.
Herein, we describe the development of a novel and efficient
synthetic strategy for the generation of a small library of
dibenzo[b,e]oxepinones by direct intramolecular acylation of 2-
(phenoxymethyl)benzoic acids by using FeCl2 and Cl2CHOCH3.
To the best of our knowledge, this is the first report of the
construction of seven membered oxygen heterocycles employing
iron (II) and dichloromethyl methyl ether as cooperative system
under mild and simple conditions. The interest and utility of our
methodology was successfully applied as a key transformation in
the synthesis of tricyclic drug doxepin.
We
started
our
study
by
choosing
2-((3-
methoxyphenoxy)methyl)benzoic acid (2c) as model substrate to
optimize the reaction conditions. These results are shown in
Table 1.
Because of our active interest and experience in the area of
green catalysis,25b we first focused our research on the direct
intramolecular acylation of 2c in the presence of environmentally
friendly FeCl3 and DCME, following the protocol reported by
Kong-Wang and co-workers.24 It was observed that the reaction
did not initiate at room temperature or even heating at reflux by
using the cooperative system FeCl3 with DCME in the presence
of dichloromethane as solvent (Table 1, entries 1 and 2). On the
other hand, FeBr3 was also ineffective in attending this reaction
under similar conditions (Table 1, entry 3). Unfortunately,
Based on our experience in the biological evaluation of
antiparasitic agents23 and for the purpose of expanding the
spectrum of pharmacological action of dibenzo[b,e]oxepin-
11(6H)-one scaffold, we decided to test all synthesized
dibenzo[b,e]oxepinones derivatives for their anthelmintic
activities using as the experimental model the nematode C.
elegans.

3
increasing the loading of catalyst to 1 equivalent was ineffective
for the present transformation, recovering the starting material 2c
(Table 1, entry 4). Moreover, when the amount of DCME was
increased to 1.5 equivalents for 24 h, only the substrate 2c was
detected in the crude reaction (Table 1, entry 5). However, to our
surprise the reaction was achieved in absence of FeCl3 by using 1
equivalent of DCME albeit with a poor yield of only 20% (Table
1, entry 6). Further increasing the amount of DCME did not
improve the yield of desired dibenzo[b,e]oxepin-11(6H)-one
(Table 1, entry 7).
showed less or no efficiency in terms of chemical yields (Table
ACCEPTED MANUSCRIPT
1, entries 8-12). Taking into account the results summarized in
Table 1, we choose the Lewis acid FeCl2 for being the most
efficient catalyst for the desired transformation. Control
experiments were performed to prove the necessity of the
coexistence of the catalyst FeCl2 and the agent Cl2CHOCH3. The
experimental results showed that the presence of DCME is
crucial for the success of the reaction (entry 15). When the
amount of DCME was decreased to 0.5 equivalent, a pronounced
decrease was observed (i.e., 43%, Table 1, entry 17). Both the
increase and the decrease of catalyst loading were not effective in
improving yields of the desired transformation (Table 1, entries
18 and 19). Further increase of DCME from 1.0 to 1.5 equivalent
did not improve the yield of 1c (Table 1, entry 16). From the
loading of iron (II) chloride, it could be shown that 0.6 equivalent
of FeCl2 was the optimal choice (Table 1, entry 14 regarding
entries 18 and 19). On other hand, the screening of the reaction
solvent demonstrated that dichloromethane (Table 1, entry 14)
was superior in comparison to toluene and 1,2-dichloroethane
(Table 1, entries 20 and 21). These combined studies
demonstrated that 0.6 equivalent of environmentally friendly
FeCl2 by using 1.0 equivalent of DCME in the presence of
dichloromethane at room temperature exhibited the highest
efficiency for the direct intramolecular acylation from 2c.
Table 1. Optimization of the reaction conditions.a
Entry
Lewis acid
(equiv)
DCME
(equiv)
Time
(h)b
Yield
(%)c
1
2
FeCl3 (0.6)
FeCl3 (0.6)
FeBr3 (0.6)
FeCl3 (1.0)
FeCl3 (0.6)
--
1.0
1.0
1.0
1.0
1.5
1.0
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
--
24
24e
24
24
24
24
24
24
24
3
NRd
NRd
NRd
NRd
NRd
20
3
4
In order to extend the scope and the general efficiency of our
methodology, we also applied this protocol to the synthesis of
twelve functionalized dibenzo[b,e]oxepinones 1a–1l under the
optimized conditions (Table 2).
5
6
7
--
18
Table 2. Scope for the synthesis of functionalized
dibenzo[b,e]oxepin-11(6H)ones.a
8
SnCl4 (0.6)
AlCl3 (0.6)
CuCl2 (0.6)
SnCl2 (0.6)
MgCl2 (0.6)
ZnCl2 (0.6)
FeCl2 (0.6)
FeCl2 (0.6)
FeCl2 (0.6)
FeCl2 (0.6)
FeCl2 (0.4)
FeCl2 (0.8)
FeCl2 (0.6)
FeCl2 (0.6)
NRd
9
10
10
11
12
13
14
15
16
17
18
19
20
21
42
2
52
24
2
NRd
80
2
90
24
5
NRd
1.5
0.5
1.0
1.0
1.0
1.0
90
5
43
5
40
2
80
24f
24g
69
74
a
Standard reactions conditions: substrate 2c (1 mmol),
dichloromethyl methyl ether (DCME), in dichloromethane (0.1 M)
b
at room temperature under argon. Time reaction monitored by
c
TLC and GC-MS.
Quantified by GC analysis using internal
d
e
standard method. NR: no reaction. Reaction was conducted in
f
DCM at reflux. Reaction was carried out in toluene at room
temperature. g Reaction was carried out in 1,2-dichloroethane (DCE)
at room temperature.
a
Reaction conditions: substrate 2 (1 mmol), FeCl2 (0.6 equiv),
Based on the above studies, we decided carry out a systematic
screening of the reaction conditions by treating the model
substrate 2c with various Lewis acid26 in the presence of DCME
in dichloromethane at room temperature (Table 1). As shown in
the Table, we found that FeCl2 and ZnCl2 led to the best results
(Table 1, entries 13 and 14) while other commercially available
catalysts including SnCl4, AlCl3, CuCl2, SnCl2 and MgCl2
DCME (1 equiv), in dichloromethane (0.1 M) at room temperature
under argon. Time reaction monitored by TLC and GC-MS.
Quantified by GC analysis using internal standard method. Isolated
yield after purification (in parentheses). c Reaction was conducted in
1,2-dichloroethane (DCE) at reflux in the presence of FeCl2 (1
equiv).
b
u

4
Tetrahedron
ACCEPTED MANUSCRIPT
The results illustrated in Table 2 indicate that the present
simplicity than the methodologies reported to date.
methodology is compatible with the presence of a wide variety
of functional groups in the substrates 2, including nitro, bromo,
chlorine, alkoxy, alkyl, and a free phenolic hydroxyl group,
affording a set of substituted dibenzo[b,e]oxepinones 1a–1l in
very good to excellent yields. Gratifyingly, treatment of
compound 2k bearing a strong electron-withdrawing group
nitro led to 1k in high yield. The acylation reaction of the
starting materials with electron-donating substituents (2b-2f,
and 2l) proceeded under the optimized reaction conditions in
very good yields (1b-1f and 1l). It should be noted, that by
using our protocol allowed the synthesis of tricyclic fused
rings starting from 2-(phenoxymethyl)benzoic acids 2 bearing
electron-withdrawing groups 1g-1k, thus overcoming one of
the limitations reported by other authors.15a,f The oxepinone 1i
was formed very slowly in the presence of only FeCl2 (0.6
equiv), but the reaction yield was improved to 61% by an
increase in catalyst loading (1 equiv) in the presence of 1,2-
dichloroethane at reflux. In this case, we think that the need to
use 1 equivalent of Lewis acid could be related to that part of
equivalent is preferably coordinated with the strong meta-
director NO2, leaving to the rest available to react with the
corresponding substrate, thus generating carbocation, which
promotes intramolecular acylation desired.27 To our
satisfaction, treatment of compound 2j bearing two electron-
withdrawing groups chlorine, afforded 1j in good yield. The
intramolecular acylation showed total para regioselectivity for
the substrates containing a meta-substituent in the phenolic
ring (1c and 1f). The observed selectivity could be attributed in
terms of a higher thermodynamic stability of the para
regioisomer with respect to the ortho isomer. This reasoning
would be in line with the fact that the acylation reaction could
occur at the less sterically hindered ortho-C–H bond of the 2-
(phenoxymethyl)benzoic acid derivatives used as precursors
(2c and 2f).
Under these mild conditions, no acylation side-products were
detected arising from cooperative system FeCl2 and DCME,
which is not typically employed in Friedel-Crafts acylations. The
work-up and isolation of crude product consisted of operational
simplicity by simple washing with water followed by extraction
with DCM and subsequent treatment with aqueous saturated
NaHCO3, then the combined organic layers were dried over
anhydrous Na2SO4 and the solvent was removed under reduced
pressure. Finally, the desired product was purified by column
chromatography using silica gel 60 or recrystallized from
ethanol. The structures of all dibenzo[b,e]oxepinones 1a-1l were
confirmed on the basis of their spectroscopic data, as provided in
the Experimental section.
Having proved the efficiency and reliability of our
methodology to access the dibenzo[b,e]oxepin-11(6H)-one
framework, we sought to extend the present protocol to the
synthesis of the known drug doxepin.
The classic approach for the synthesis of doxepin uses the
ethyl ester of 2-phenoxymethyl benzoic acid as starting material,
which is easily synthesized by reacting ethyl 2-
bromomethylbenzoate with phenol in the presence of a base.22d
The resulting ester is hydrolyzed into 2-phenoxymethylbenzoic
acid, which is cyclized to dibenzo[b,e]oxepin-11(6H)-one (1a) by
trifluoroacetic acid anhydride. Finally, the target molecule is
obtained by reacting 1a with 3-dimethylaminopropylmagnesium
bromide and the subsequent dehydration of the resulting tertiary
alcohol by hydrochloric acid. This strategy involved five steps of
synthesis with an overall yield of 26%. A more recent
stereoselective synthesis of doxepin was communicated by Luo
et al.22f Thus, the linear synthesis of doxepin required of six steps
and proceeded with an overall yield of 7% starting from 2-
[(trimethylsilyl)ethynyl]benzyl bromide.
Simplified retrosynthetic analysis of doxepin 3 is summarized
in Scheme 3. As a key consideration, we proceed to assemble the
dibenzo[b,e]oxepin-11(6H)-one (1a) scaffold through a direct
intramolecular acylation from 2-(phenoxymethyl)benzoic (2a)
acid mediated by eco-friendly FeCl2 and DCME.
A comparison of our procedure with the typically employed
strategies to perform this kind of ortho-acylation reaction
revealed that the target dibenzo[b,e]oxepin-11(6H)-one is
obtained in much more efficient in terms of yields when
employing our simple and practical protocol (Table 3). In
general, the existing methodologies employ drastic conditions
such as phosphorus pentoxide-ethanol28a,9b (Table 3, entry 1),
polyphosphoric acid9b (Table 3, entry 2), trifluoroacetic
anhydride29 with or without BF3.Et2O (Table 3, entry 4).
However, our protocol substantially differs from these latter
(Table 3, entry 5) in avoiding the use of large amounts of toxic
acid chloride like thionyl chloride9b (Table 3, entry 3), long
reaction times, high temperatures and the generation of
significant quantities of waste upon quenching of the reaction
mixtures, that adversely impact their suitability for a potential
scalability. In addition, our strategy uses simple precursors
without need of previous activation. On the other hand, the
present process allows a greater tolerance of functional groups in
both rings of the starting material and greater operational
Scheme 3. Retrosynthetic analysis to access the doxepin 3.
The
target
3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-
dimethyl propan-1-amine (3) was synthesized in three stages. In
the first stage, the 2-(phenoxymethyl) benzoic acid (2a) was
Table 3. Comparison of the current methodology with some protocols previously reported for the synthesis of dibenzo[b,e]oxepin-
11(6H)ones.
Entry
Reaction conditions
P2O5 (exc.) / EtOH / sulfolane, reflux
Time (h)
5-12
Yield (%)a
20-64
Ref
28a
1
2
3
4
5
polyphosphoric acid (exc.), 100 °C
3-12
38-53
9b
15a
SOCl2 (exc.) / DCE / AlCl3 (1 equiv), reflux
Trifluoroacetic anhydride (2 equiv), DCM, reflux
FeCl2 (0.6 equiv) / DCME (1 equiv) / DCM, rt
2-18
40-79
4-10
41-86
29a
1-12
61-92
Current work
a Isolated yield after purification.

5
easily prepared by treating the commercial available
isobenzofuran-1(3H)-one (I) with sodium phenoxide, which was
obtained by reacting phenol (II) with NaH in the presence of
DMF at reflux. The carboxylic acid 2a was precipitated using a
mineral acid solution. The key intermediate 1a was cyclized by
intramolecular acylation from 2a by using FeCl2 and
dichloromethyl methyl ether (DCME) as cooperative system in
the presence of dichloromethane at room temperature. Finally,
the target molecule 3 was synthesized by reacting 1a with 3-
dimethylaminopropylmagnesium chloride and the subsequent
dehydration of the resulting tertiary alcohol by hydrochloric acid
at reflux in good yield (Scheme 4).
For these compounds, the thrashing rates varied between 60-
ACCEPTED MANUSCRIPT
84% with respect to the control condition. Interestingly,
compound 1a produced a much more significant effect on worm
mobility, leading to a reduction of 80% of the thrashes/ min at 1
mM after a 10-min exposure (Fig 2).
Figure 2. Thrashing rates after 10 min incubation in M9 solution
in the absence (control) or presence of a given compound (1 mM).
Assays were performed on three separate days for each drug. Twenty
animals were tested in each assay. ***P < 0.001.
Scheme 4. Total synthesis of doxepin 3. Conditions: a) NaH (1.5
equiv), DMF, reflux, 24 h; then conc. HCl; b) FeCl2 (0.6 equiv),
DCME (1 equiv), DCM (0.1 M), rt, 3 h; c) 3-(N,N-dimethylamino)
propylmagnesium chloride, toluene, 65 °C, 2h; then conc. HCl, 1 h,
reflux.
When analyzed at a range of concentrations (30 µM to 1.5
mM), compound 1a produced
a concentration-dependent
decrease of the trashing rate, with an IC50 value of 389 ± 50 µM
(Fig 3).
The proportion between (E) and (Z)-isomers in the crude
product was 4 to 1. The structure elucidation of 3 was proved by
its GC-MS, 1H, and 13C NMR spectra analysis.
Increasing the incubation period to 20 min in the presence of 1
mM compound 1a produced complete paralysis of worms.
Thrashing assays are useful to demonstrate short-term and rapid
effects of compounds on the high-frequency C. elegans
locomotion. In these assays, common anthelmintic drugs, such as
levamisole, morantel and pyrantel (1 mM), have been shown to
affect significantly the thrashing rates after 5–10 min in M9
solution, leading to a 90% reduction and producing paralysis of
the majority of animals.31 Thus, we showed that
dibenzo[b,e]oxepin-11(6H)-one 1a produces similar effects to
those mediated by widely-used anthelmintic drugs.
It should be noted that the (E)-isomer was easily separated by
crystallization as maleate salt after treatment of 3 with an
equivalent amount of maleic acid in dry ethanol.
This synthesis of 3 involves only three steps and proceeds
with an overall yield of 44% starting from commercially
available phthalide I, thus overcoming the best chemical yields
reported by other authors22e,f until now. Notably, most
intermediates are crystalline solids and only one of the three steps
required chromatographic purification. Thus, the synthesis of 3
could be performed on a multigram scale enabling us to also
investigate some aspects of the reactivity.
2.2 Anthelmintic activity
In a recent study, doxepin structurally related to our target
dibenzo[b,e]oxepin-11(6H)-one, have been shown to have
anthelmintic activity against the intestinal helminth Ancylostoma
ceylanicum third-stage larvae (L3).30 In this context, and
considering the experience of our group in biological assays
associated with this type of activity, added to the fact that there
are no contributions in the scientific literature on such biological
action, we sought to determine if our synthesized tricyclic
scaffolds act as antiparasitic drugs. To this end, we used C.
elegans as a model of helminthic parasites and measured their
rapid effects on C. elegans mobility by the thrashing assay
method.
The thrashing rate of wild-type worms in M9 buffer (plus 1%
DMSO) was 204 ± 9.3/ min. After a 10-min incubation period
with compounds 1a-1l and doxepin 3 (1 mM), a slight albeit
statistically significant reduction in the thrashing rate was
observed (Fig 2).
Figure 3. Dose-response curve for dibenzo[b,e]oxepin-11(6H)-
one 1a. Thrashing rates were plotted as a percentage of the control
condition in the absence of the drug. Values are mean percentages ±
SD derived from three trials performed on separate days. All
experiments were performed at 20-22 °C.
u

6
Tetrahedron
ACCEPTED MANUSCRIPT
4. Experimental section
Previous reports showed that doxepin 3 produced 60% death
of A. ceylanicum. However, in this work death was evaluated
after 72 h exposure to the drug and, therefore, only long-term
effects were considered.30 In contrast, our assays evaluate short-
term effects since worms are exposed to the drugs for only 10
min. Under these conditions, doxepin 3 produced a very slight
anthelmintic effect on C. elegans. A short-term effect as the one
observed for compound 1a might be mediated by ion channels,
such as ligand-gated ion channels, which are involved in
neuromuscular function and worm locomotion. Typical
anthelmintics, such as pyrantel, morantel, and levamisole, act by
this mechanism.21 In general terms, it was observed that the
introduction of functionality to the tricyclic ring system 1a was
detrimental to biological activity. Interestingly, a marked
decrease in activity was observed for doxepin 3, suggesting that
the carbonyl group was important for the activity. Thus, the
pharmacophore appeared to be the scaffold 1a, which may be
4.1. General
All operations were performed under an argon atmosphere
using standard Schlenk techniques. Solvents were dried and
distilled in accordance with standard procedure.32 Reactions were
monitored by thin-layer chromatography on silica gel plates
(60F-254) visualized under UV light and/or using 5%
phosphomolybdic acid in ethanol. All H and 13C NMR spectra
1
were recorded at room temp. in CDCl3, DMSO-d6 or Acetone-d6
on a Bruker Avance ARX-300 spectrophotometer. Chemical
shifts (δ) are reported in parts per million (ppm) from
tetramethylsilane (TMS) using the residual solvent resonance
(CDCl3: 7.26 ppm for H NMR and 77.16 ppm for 13C NMR;
1
DMSO-d6: 2.50 ppm for H NMR and 39.50 ppm for 13C NMR;
1
1
Acetone-d6: 2.09 ppm for H NMR, 30.60 and 205.87 ppm for
13C NMR). Multiplicities are abbreviated as follows: s = singlet,
d = doublet, t = triplet, q = quartet, m = multiplet; brs = broad
signal). IR spectra were recorded on a Perkin-Elmer Paragon
1000 FT-IR spectrometer in the ATR mode at room temp.
Melting points were determined using a Büchi 510 apparatus and
are not corrected. Mass spectra (EI) were obtained at 70 eV on an
Agilent CG-78903 instrument equipped with a MS-5977A MSD
selective mass detector. The purity of volatile compounds and the
chromatographic analyses (GC) were determined with a GC
Shimadzu (GC-14B) with a flame ionization detector equipped
with a HP-5MS column (30 m × 0.25 mm × 0.25 µm) using
nitrogen as carrier gas. High resolution mass spectra were
recorded on Thermo Fisher LTQ Orbitrap XL, (for EI) and a
Finnigen MAT 95 (for ESI). Flash column chromatography was
performed using Macherey Nagel MN Kieselgel 60M (0.040-
0.063 mm / 230-240 mesh ASTM). All starting materials were of
the best available grade (Aldrich, Merck, Acros or TCI) and were
used without further purification. (CAUTION) Dichloromethyl
methyl ether is a corrosive and acute toxic reagent.
considered as
a
candidate anthelmintic drug. Although
levamisole and pyrantel are effective antiparasitic drugs, the
increment of drug resistance of nematodes to these anthelmintic
drugs as well as to the limited number of available drugs has
become a global concern for veterinary and human health.
Indeed, the combination of drugs is emerging as a strategy
tending to fight against the increase in anthelmintic resistance.
Thus, the identification of novel drugs and pharmacological
targets is urgently required, which enhances the importance of
the anthelmintic action of compound 1a here reported. Thus,
future work will focus on the identification of the
pharmacological target by which compound 1a exerts its
antiparasitic activity. Once this target is known, derivatization of
the active compound to increase its potency and efficacy will be
rationally planned.
3. Conclusions
In the current research, we have developed a new and
complementary methodology for the simple construction of
dibenzo[b,e]oxepin-11(6H)-ones from readily available 2-
(phenoxymethyl)benzoic acids by using FeCl2 and Cl2CHOCH3
as an efficient cooperative system. Unlike other existing standard
Friedel-Crafts approaches, our strategy showed an excellent
tolerance to diverse substituent groups makes the reaction a fairly
general synthesis protocol to diaryl fused oxepin-11(6H)-ones.
Due to the modularity, operational simplicity, and reliability it is
likely that the method will find future exploitation in the
synthesis of compound libraries, and therefore have an impact on
to the field of medicinal chemistry. We are currently working on
the design of some specific experiments aimed at shed light on
the exact reaction mechanism. To probe the general application
of our protocol, we elaborated a short and scalable synthesis of
tricyclic drug doxepin 3 from commercial available phthalide.
The scalability of the process, the simple reaction conditions, and
the low cost of the starting materials, make this new total
synthesis transferable to the pharmaceutical industry. The
synthetic accessibility and significant antiparasitic activity
exhibited by dibenzo[b,e]oxepin-11(6H)-one 1a might be a
promising lead in the search for novel anthelmintic drugs. It is
noteworthy that this is the first report of anthelmintic activity of
this class of oxygenated tricyclic compounds using the free-living
nematode Caenorhabditis elegans as an experimental model
system. Future studies may be directed to identify its mechanism
of action and drug target.
4.2. General procedure for synthesis of 2-(phenoxymethyl)
benzoic acids (2a-2l).
Method A (2a-2h).
Substituted phenol (16 mmol) was added to a stirred
suspension of sodium hydride (24 mmol) in anhydrous DMF (20
mL). Upon cessation of dihydrogen evolution, phthalide (15
mmol), dissolved in the minimum amount of benzene
(CAUTION) and the mixture heated under reflux for 24 h. The
cooled solution was poured into ice water (50 mL) and acidified
with conc. HCl. The formed precipitate was filtered, washed with
water and subsequently dissolved in dichloromethane (50 mL).
The organic layer was washed successively with 20% aq. Na2CO3
(3 × 20 mL) and water (3 × 20 mL), and dried over Na2SO4. The
solvent was distilled off to give a solid. The crude product was
used in the next step without further purification.
2-(phenoxymethyl)benzoic acid (2a).15a Isolated yield: 65%
1
(white solid, 550 mg, 2.41 mmol); mp 112-114 °C; H NMR
(CDCl3, 300 MHz) δ 5.53 (s, 2H), 6.95-7.03 (m, 3H), 7.26-7.34
(m, 2H), 7.40-7.45 (m, 1H), 7.63 (dt, J = 7.6, 1.3 Hz, 1H), 7.81-
7.84 (m, 1H), 8.18 (dd, J = 7.9, 1.2 Hz, 1H). 13C NMR (CDCl3,
75 MHz) δ 68.2, 115.1, 121.2, 126.4, 127.4, 127.5, 129.7, 131.9,
133.8, 140.9, 158.8, 172.2; IR (KBr) ν [cm-1] = 3440, 3051, 2897,
1685, 1594, 1243. HRMS (EI) m/z = 228.0786 calcd for
C14H12O3, found 228.0781.
2-((o-tolyloxy)methyl)benzoic acid (2b).33 Isolated yield: 58%
1
(white solid, 910 mg, 3.75 mmol); mp 137-139 °C; H NMR
(CDCl3, 300 MHz) δ 2.40 (s, 3H), 5.57 (s, 2H), 6.88-6.93 (m,
2H), 7.15-7.21 (m, 2H), 7.44 (t, J = 7.4 Hz, 1H), 7.66 (t, J = 7.4

7
Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 8.21 (d, J = 7.7 Hz, 1H); 13C
Method B (2i-l).
ACCEPTED MANUSCRIPT
NMR (CDCl3, 75 MHz) δ 16.6, 68.1, 111.7, 120.8, 126.4, 127.0,
127.1, 127.2, 127.3, 130.9, 131.8, 133.8, 141.3, 156.8, 172.7. IR
(KBr) ν [cm-1] = 3438, 3058, 2898, 1696, 1595, 1240. HRMS
(EI) m/z = 242.0943 calcd for C15H14O3, found 242.0948.
To a solution of 6.0 g (0.04 mol) of methyl 2-methylbenzoate
derivatives in 38 mL of chloroform, 7.5 g (0.042 mol) of N-
bromosuccinimide and 0.078 g of benzoyl peroxide were added
and carefully warmed up to 65 °C until reaction started. Then the
mixture was refluxed for 5 h. After cooling down to room
temperature, the deposit of succinimide was filtered. The solvent
was removed under reduced pressure and the crude product was
used in the next step without further purification. To a solution
of functionalized methyl 2-(bromomethyl)benzoate (6.55 mmol),
substituted phenol (8.5 mmol), K3PO4 (16.4 mmol) and toluene
20 mL were added to Schlenk under argon. The resulting solution
was stirred to 110 °C for 5 h. The progress of the reaction was
monitored by TLC. The mixture was extracted with EtOAc,
washed with water, brine and the combined organic layers were
dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure. The crude product was used in the next step
without further purification. To the solution of the ester (0.015
mol) in MeOH (73 mL), was added 13 mL aqueous KOH (20%)
and refluxed at 80°C for 5 h. MeOH was removed and the
aqueous phase was washed with DCM. After acidifying with HCl
(10%) the deposit was collected and washed with water.
2-((3-methoxyphenoxy)methyl)benzoic acid (2c). Isolated
yield: 43% (light brown solid, 1.67 g, 6.47 mmol); mp 105-107
1
°C; H NMR (CDCl3, 300 MHz) δ 3.71 (s, 3H), 5.47 (s, 2H),
6.44-6.54 (m, 3H), 7.09-7.18 (m, 3H), 7.34 (t, J = 7.6 Hz, 1H),
7.54 (t, J = 7.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0
Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 55.4, 68.3, 101.7, 106.7,
107.3, 126.5, 127.4, 127.5, 130.1, 131.9, 133.8, 140.8, 160.0,
161.0, 172.6. IR (KBr) ν [cm-1] = 3441, 3055, 2901, 1691, 1594,
1234. HRMS (EI) m/z = 258.0892 calcd for C15H14O4, found
258.0896.
2-((4-methoxyphenoxy)methyl)benzoic acid (2d).34 Isolated
yield: 60% (white solid, 486 mg, 1.88 mmol); mp 163-165 °C; 1H
NMR (CDCl3, 300 MHz) δ 3.72 (s, 3H), 5.46 (s, 2H), 6.85-6.88
(m, 2H), 6.93-6.96 (m, 2H), 7.42-7.47 (m, 1H), 7.62 (dt, J = 7.5,
1.4 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H) 8.07 (dd, J = 7.8, 1.4 Hz,
1H). 13C NMR (CDCl3, 75 MHz) δ 55.9, 69.4, 115.5, 116.6,
128.2, 128.4, 129.3, 131.8, 133.3, 141.0, 153.9, 155.1, 168.4. IR
(KBr) ν [cm-1] = 3431, 3050, 2899, 1693, 1598, 1231. HRMS
(EI) m/z = 258.0892 calcd for C15H14O4, found 258.0897.
2-((4-nitrophenoxy)methyl)benzoic acid (2i). Isolated yield:
40% (white solid, 543 mg, 1.99 mmol); mp 143-145 °C; 1H NMR
(CDCl3, 300 MHz) δ 5.69 (s, 2H), 7.21-7.24 (m, 2H), 7.48-7.53
(m, 1H), 7.62-7.68 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 8.10-8.12
(m, 1H), 8.23-8.26 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 69.7,
116.1, 126.7, 128.8, 128.9, 129.6, 132.0, 133.5, 139.1, 142.6,
164.9, 168.3. IR (KBr) ν [cm-1] = 3240, 2830, 1695, 1598, 1270.
HRMS (EI) m/z = 273.0637 calcd for C14H11NO5, found
273.0641.
2-((2-methoxyphenoxy)methyl)benzoic acid (2e). Isolated
yield: 54% (light brown solid, 1.20 g, 4.70 mmol); mp 123-125
1
°C; H NMR (CDCl3, 300 MHz) δ 3.08 (s, 3H), 5.65 (s, 2H),
6.89-6.95 (m, 4H), 7.38-7.43 (m, 1H), 7.59-7.64 (m, 1H), 7.86 (d,
J = 7.9 Hz, 1H), 8.16-8.19 (m, 1H); 13C NMR (CDCl3, 75 MHz)
δ 55.1, 69.3, 112.0, 114.1, 121.0, 121.6, 126.3, 127.3, 127.4,
131.8, 133.9, 141.0, 148.2, 149.7, 172.6. IR (KBr) ν [cm-1] =
3440, 3052, 2901, 1692, 1595, 1230. HRMS (EI) m/z =
258.0892 calcd for C15H14O4, found 258.0896.
2-((3-hydroxyphenoxy)methyl)benzoic acid (2f).35 Isolated
yield: 53% (light brown solid, 34 mg, 1.39 mmol); mp 113-115
°C; 1H NMR (DMSO-d6, 300 MHz) δ 5.34 (s, 2H), 6.43-6.34 (m,
3H), 7.05-7.10 (m, 1H), 7.42 (dt, J = 7.5, 2.0 Hz, 1H), 7.62-7.57
(m, 2H), 7.89-7.91 (m, 1H), 7.2 (brs, 1H), 12.9 (brs, 1H); 13C
NMR (DMSO-d6, 75 MHz) δ 62.2, 102.2, 108.1, 110.1, 126.3,
127.3, 130.5, 131.0, 131.8, 139.9, 157.1, 160.3, 172.7. IR (KBr) ν
[cm-1] = 3441, 3055, 2900, 1695, 1598, 1235, 1230. HRMS (EI)
m/z = 244.0736 calcd for C14H12O4, found 244.0740.
2-((4-chlorophenoxy)methyl)benzoic acid (2g).15a Isolated
yield: 54% (light brown solid, 86 mg, 3.29 mmol); mp 160-162
°C; 1H NMR (CDCl3, 300 MHz) δ 5.44 (s, 2H), 6.85 (dt, J = 9.0,
3.4 Hz, 2H), 7.17 (dt, J = 9.0, 3.4 Hz, 2H), 7.35 (t, J = 7.4 Hz,
1H), 7.52-7.57 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 8.08-8.11 (m,
1H); 13C NMR (CDCl3, 75 MHz) δ 68.6, 116.4, 126.1, 126.6,
127.5, 127.7, 129.5, 131.9, 133.8, 140.3, 157.4, 172.0. IR (KBr) ν
[cm-1] = 3439, 3050, 2901, 1694, 1599, 1234. HRMS (EI) m/z =
262.0397 calcd for C14H11ClO3, found 262.0401.
2-((2,4-dichlorophenoxy)methyl)benzoic acid (2j). Isolated
yield: 96% (white solid, 455 mg, 1.50 mmol); mp 241-243 °C; 1H
NMR (CDCl3, 300 MHz) δ 5.59 (s, 2H), 6.92-6.95 (m, 1H), 7.19
(dd, J = 8.7, 2.5 Hz, 1H), 7.40-7.48 (m, 2H), 7.68 (dt, J = 7.6, 1.3
Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 8.19 (dd, J = 7.8, 1.2 Hz, 1H);
13C NMR (CDCl3, 75 MHz) δ 69.3, 114.7, 124.0, 126.1, 126.2,
127.3, 127.7, 127.8, 130.2, 132.0, 134.1, 139.9, 153.1, 172.2. IR
(KBr) ν [cm-1] = 3270, 2828, 1699, 1262. HRMS (EI) m/z =
296.0007 calcd for C14H10Cl2O3, found 296.0011.
4-nitro-2-(phenoxymethyl)benzoic acid (2k).15f Isolated yield:
68% (white solid, 464 mg, 1.70 mmol); mp 179-180 °C; 1H NMR
(CDCl3, 300 MHz) δ 5.19 (s, 2H), 6.91-712 (m, 1H), 7.28-7.33
(m, 2H), 7.34-7.68 (m, 2H), 8.30 (dd, J = 7.5 Hz, 1H), 8.45 (dd,
1H), 8.23-8.26 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 67.4,
114.9, 121.5, 121.9, 125.1, 129.4, 129.5, 130.3, 135.6, 144.9,
149.3, 169.8. IR (KBr) ν [cm-1] = 3340, 2880, 1691, 1600, 1524,
1495, 1270. HRMS (EI) m/z = 273.0637 calcd for C14H11NO5,
found 273.0642.
4-methoxy-2-(phenoxymethyl)benzoic acid (2l).15c Isolated
yield: 88% (white solid, 454 mg, 1.76 mmol); mp 160-162 °C; 1H
NMR (CDCl3, 300 MHz) δ 3.73 (s, 3H), 5.42 (s, 2H), 6.87-6.95
(m, 1H), 6.97-7.10 (m, 1H), 7.11-7.18 (m, 2H), 7.24 (dd, 1H),
7.26-7.34 (m, 2H), 7.95 (d, J = 7.5 Hz, 1H); 13C NMR (CDCl3,
75 MHz) δ 55.3, 67.4, 111.5, 112.8, 114.4, 114.9, 121.5, 129.4,
131.1, 137.6, 149.3, 159.9, 168.8. IR (KBr) ν [cm-1] = 3435,
3039, 2905, 1696, 1599, 1241. HRMS (EI) m/z = 258.0892
calcd for C15H14O4, found 258.0896.
2-((4-bromophenoxy)methyl)benzoic acid (2h). Isolated
yield: 65% (white solid, 504 mg, 1.65 mmol); mp 171-173 °C; 1H
NMR (CDCl3, 300 MHz) δ 5.52 (s, 2H), 6.95-7.01 (m, 2H), 7.43-
7.49 (m, 3H), 7.62 (dt, J = 7.6, 1.4 Hz, 1H), 7.73 (d, J = 7.7 Hz,
1H), 8.08 (dd, J = 7.7, 1.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 69.1, 113.4, 120.1, 128.4, 128.5, 131.9, 132.2, 133.4, 140.1,
159.1, 168.3. IR (KBr) ν [cm-1] = 3439, 3050, 2901, 1694, 1599,
1234. HRMS (EI) m/z = 305.9892 calcd for C14H11BrO3, found
305.9896.
u

8
Tetrahedron
4.3. General procedure for synthesis of dibenzo[b,e]oxepin-
7.48 (dt, J = 7.5, 1.3, 1H), 7.74 (dd, J = 7.2, 2.7 Hz, 1H), 7.79
ACCEPTED MANUSCRIPT
(dd, J = 7.5, 1.3 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 56.5,
11(6H)-ones (1a-1l).
74.2, 116.2, 121.5, 123.0, 126.3, 127.9, 129.3, 129.4, 132.8,
135.3, 140.8, 150.7, 151.6, 191.5. MS m/z: 240 (100), 225 (11),
211 (26), 197 (27), 181 (22), 169 (15), 152 (16), 141 (20), 115
(28), 89 (18), 63 (11). IR (KBr) ν [cm-1] = 3070, 2960, 2918,
1711, 1476, 829, 794. HRMS (EI) m/z = 240.0786 calcd for
C15H12O3, found 240.0780.
Functionalized 2-(phenoxymethyl)benzoic acid (1.0 mmol),
FeCl2 (0.6 equiv), dichloromethyl methyl ether (1.0 equiv)
(CAUTION), and CH2Cl2 (10 mL) were added to a Schlenk tube
under argon. The resulting solution was stirred at room
temperature until the completion of the reaction. The progress of
the reaction was monitored by TLC and GC-MS. The reaction
was quenched by addition of water. The mixture was extracted
with CH2Cl2, washed with aqueous saturated NaHCO3 and then
the combined organic layers were dried over anhydrous Na2SO4,
filtered and the solvent was removed under reduced pressure. The
crude product was purified by column chromatography using
silica gel 60 or recrystallized in ethanol.
3-hydroxydibenzo[b,e]oxepin-11(6H)-one (1f). Isolated yield:
1
81% (brown solid, 110 mg, 0.50 mmol); mp 138-140 °C; H
NMR (CDCl3, 300 MHz) δ 5.30 (s, 2H), 6.81-6.87 (m, 1H), 7.03-
7.06 (m, 1H), 7.16 (d, J = 6.5 Hz, 1H), 7.38 (d, J = 6.3 Hz, 1H),
7.50-7.58 (m, 2H), 7.75 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 6.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 74.8, 119.9, 1226., 122.7,
128.0, 129.7, 130.0, 133.0, 134.2, 135.1, 140.5, 147.2, 148.4,
190.6. MS m/z: 226 (100), 197 (43), 181 (17), 164 (14), 152 (15),
141 (21), 115 (17), 89 (15). IR (KBr) ν [cm-1] = 3432, 2966,
2922, 1650, 1270, 1106, 1023, 804. HRMS (EI) m/z = 226.0630
calcd for C14H10O3, found 226.0635.
dibenzo[b,e]oxepin-11(6H)-one (1a).15a Isolated yield: 88%
(white solid, 120 mg, 0.58 mmol, eluent: hexane/EtOAc 90:10);
1
mp 65-67 °C; H NMR (CDCl3, 300 MHz) δ 5.19 (s, 2H), 7.04-
7.15 (m, 2H), 7.35-7.38 (m, 1H), 7.44-7.58 (m, 3H), 7.90 (dd, J =
7.6, 1.3 Hz, 1H), 8.25 (dd, J = 8.0, 1.9 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 73.7, 120.8, 122.2, 125.5, 127.9, 129.3,
129.6, 132.1, 132.8, 135.4, 135.7, 140.7, 161.4, 191.2. MS m/z:
210 (100), 181 (80), 152 (29), 89 (15), 76 (15), 63 (12). IR (KBr)
ν [cm-1] = 2921, 2870, 1653, 1456. HRMS (EI) m/z = 210.0681
calcd for C14H10O2, found 210.0685.
4-methyldibenzo[b,e]oxepin-11(6H)-one (1b).36 Isolated
yield: 90% (white solid, 170 mg, 0.75 mmol, eluent:
hexane/EtOAc 90:10); mp 68-70 °C; 1H NMR (CDCl3, 300
MHz) δ 2.28 (s, 3H), 5.23 (s, 2H), 7.01 (t, J = 7.7 Hz, 1H), 7.35-
7.39 (m, 2H), 7.43-7.49 (m, 1H), 7.55 (dt, J = 7.5, 1.2 Hz, 1H),
7.89 (dd, J = 7.5, 0.8 Hz, 1H), 8.10 (dd, J = 8.3, 1.4 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) δ 16.8, 73.6, 121.6, 125.5, 127.6, 129.3,
129.4, 129.5, 130.0, 132.7, 135.9, 136.4, 140.7, 159.7, 191.6. MS
m/z: 224 (100), 209 (25), 195 (36), 181 (34), 165 (19), 152 (20),
115 (6), 89 (19). IR (KBr) ν [cm-1] = 3068, 2945, 2856, 1654,
1471, 808, 751. HRMS (EI) m/z = 224.0837 calcd for C15H12O2,
found 224.0832.
2-chlorodibenzo[b,e]oxepin-11(6H)-one
(1g).20
Isolated
yield: 75% (white solid, 140 mg, 0.57 mmol); mp 117-119 °C; 1H
NMR (CDCl3, 300 MHz) δ 5.18 (s, 2H), 7.01 (d, J = 8.8 Hz, 1H),
7.35-7.43 (m, 2H), 7.48 (dt, J = 76, 1.1 Hz, 1H), 7.58 (dt, J = 7.6,
1.2 Hz, 1H), 7.89 (dd, J = 7.6, 1.0 Hz, 1H), 8.20 (d, J = 2.7 Hz,
1H); 13C NMR (CDCl3, 75 MHz) δ 73.9, 122.5, 126.4, 127.7,
128.0, 129.6, 129.8, 131.2, 133.2, 135.2, 135.5, 140.0, 159.9,
189.8. MS m/z: 246 (33), 244 (100), 217 (12), 215 (34), 209 (36),
181 (37), 152 (48), 89 (21), 76 (18), 63 (21). IR (KBr) ν [cm-1] =
3071, 2956, 2923, 1646, 1470, 837, 825. HRMS (EI) m/z =
244.0291 calcd for C14H9ClO2, found 244.0295.
2-bromodibenzo[b,e]oxepin-11(6H)-one (1h).39 Isolated
yield: 71% (white solid, 130 mg, 0.46 mmol); mp 122-124 °C; 1H
NMR (CDCl3, 300 MHz) δ 5.18 (s, 2H), 6.95 (d, J = 8.7 Hz, 1H),
7.37 (d, J = 7.2 Hz, 1H), 7.46-7.60 (m, 3H), 7.89 (d, J = 7.5 Hz,
1H), 8.35 (d, J = 2.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 73.9,
114.9, 122.9, 126.8, 128.1, 129.6, 129.8, 133.2, 134.3, 135.4,
138.0, 140.1, 160.4, 189.8. MS m/z: 290 (96), 288 (100), 261
(20), 259 (21), 209 (39), 181 (41), 152 (66), 89 (32), 76 (26), 63
(31). IR (KBr) ν [cm-1] = 3074, 2958, 2930, 1646, 1470, 837,
760. HRMS (EI) m/z = 287.9786 calcd for C14H9BrO2, found
287.9790.
3-methoxydibenzo[b,e]oxepin-11(6H)-one (1c).15c Isolated
yield: 84% (light brown solid, 160 mg, 0.65 mmol, eluent:
1
hexane/EtOAc 90:10); mp 135-137 °C; H NMR (Acetone-d6,
300 MHz) δ 3.86 (s, 3H), 5.25 (s, 2H), 6.54 (d, J = 2.5 Hz, 1H),
6.74 (dd, J = 9.1, 2.5 Hz, 1H), 7.34 (s, 1H), 7.47-7.52 (m, 1H),
7.57-7.63 (m, 1H), 7.84-7.87 (m, 1H), 8.15 (d, J = 9.1 Hz, 1H);
13C NMR (Acetone-d6, 75 MHz) δ 56.7, 74.8, 104.6, 111.7,
129.5, 129.3, 130.4, 130.5, 133.8, 134.8, 137.4, 141.9, 164.7,
166.9, 189.6. MS m/z: 240 (100), 211 (22), 197 (30), 168 (10),
141 (12), 115 (11), 89 (11). IR (KBr) ν [cm-1] = 3065, 2953,
1723, 1490, 853. HRMS (EI) m/z = 240.0786 calcd for C15H12O3,
found 240.0781.
2-nitrodibenzo[b,e]oxepin-11(6H)-one (1i). Isolated yield:
61% (light brown solid, 150 mg, 0.61 mmol, eluent:
1
hexane/EtOAc 90:10); mp 151-153 °C. H NMR (CDCl3, 300
MHz) δ 4.11 (s, 2H), 7.31-7.42 (m, 3H), 7.54 (dt, J = 7.6, 1.3 Hz,
1H), 7.90 (dd, J = 7.6, 0.9 Hz, 1H), 8.11-8.15 (m, 1H), 8.2 (d, J =
2.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 77.4, 122.0, 124.0,
124.2, 127.5, 128.3, 133.2, 134.0, 134.3, 141.1, 145.2, 155.4,
164.3, 207.1. IR (KBr) ν [cm-1] = 3052, 2957, 2929, 1654, 1590,
1260, 800. HRMS (ESI) m/z = 278.0430 calcd for C14H9NNaO4
[M+Na]+, found: 278.0426.
2-methoxydibenzo[b,e]oxepin-11(6H)-one (1d).37 Isolated
1
yield: 90% (white solid, 80 mg, 0.35 mmol); mp 96-98 °C; H
NMR (CDCl3, 300 MHz) δ 3.85 (s, 3H), 5.15 (s, 2H), 6.97-7.00
(m, 1H), 7.07-7.11 (m, 1H), 7.34-7.36 (m, 1H), 7.44-7.58 (m,
2H), 7.69-7.70 (m, 1H), 7.93 (d, J = 7.6 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) δ 55.9, 74.1, 112.5, 122.1, 124.4, 125.6, 127.8,
129.2, 129.9, 132.9, 136.2, 140.0, 154.6, 156.1, 190.6. MS m/z:
240 (100), 225 (38), 211 (18), 197 (20), 169 (11), 141 (22), 115
(28), 89 (13). IR (KBr) ν [cm-1] = 3072, 2962, 2921, 1720, 1486,
829, 796. HRMS (EI) m/z = 240.0786 calcd for C15H12O3, found
240.0782.
4-methoxydibenzo[b,e]oxepin-11(6H)-one (1e).38 Isolated
yield: 87% (light brown solid, 40 mg, 0.17 mmol); mp 70-72 °C;
1H NMR (CDCl3, 300 MHz) δ 3.83 (s, 3H), 5.23 (s, 2H), 6.98-
7.02 (m, 2H), 7.29-7.31 (m, 1H), 7.39 (dt, J = 7.6, 1.2 Hz, 1H),
2,4-dichlorodibenzo[b,e]oxepin-11(6H)-one (1j). Isolated
yield: 70% (white solid, 190 mg, 0.70 mmol, eluent:
1
hexane/EtOAc 90:10); mp 138-140 °C; H NMR (CDCl3, 300
MHz) δ 5.30 (s, 2H), 7.41 (d, J = 7.2 Hz, 1H), 7.50 (dt, J = 7.5,
0.8 Hz, 1H), 7.58-7.63 (m, 2H), 7.87-7.90 (m, 1H), 8.13 (d, J =
2.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 72.6, 124.8, 125.4,
125.5, 126.3, 127.9, 128.0, 128.3, 131.6, 133.2, 133.3, 137.8,
153.8, 187.2; MS m/z: 282 (9), 280 (65), 278 (100), 251 (19),
249 (29), 245 (18), 243 (51), 217 (11), 215 (32), 186 (13), 152
(38), 89 (23), 63 (12). IR (KBr) ν [cm-1] = 3068, 2955, 2926,
1652, 1467, 823, 813. HRMS (EI) m/z = 277.9901 calcd for
C14H8Cl2O2, found 277.9905.

9
8-nitrodibenzo[b,e]oxepin-11(6H)-one (1k).15f Isolated yield:
100 µl of M9 buffer (3 g/L KH2PO4, 6 g/L Na2HPO4, 5 g/L
ACCEPTED MANUSCRIPT
92% (light solid, 230 mg, 0.92 mmol, eluent: hexane/EtOAc
NaCl, 0.25 g/L MgSO4.7H2O) in the absence or presence of the
compound under study (1 mM/DMSO 1%) in a 96-well
microlitre plate. After 10 minutes, the number of thrashes were
counted for 30 s. A single thrash was defined as a complete
change in the direction of bending at the mid body. The
experiments were repeated 3 times for each condition (20 worms
tested each time). All assays were blind and carried out at 20-22
°C. Data are shown as mean ± S.D. Statistical comparisons were
done using the oneway ANOVA with Bonferroni's multiple
comparison posttest. Thrashing rates lower than those of control
worms with p < 0.05 were considered significant. The half-
inhibition concentration, IC50, was obtained from the curve
resulting from the percentage of thrashes/ min in the presence of
compound 1a respect to the buffer condition.
1
90:10); mp 179-181 °C; H NMR (DMSO-d6, 300 MHz) δ 5.45
(s, 2H), 7.12-7.21 (m, 2H), 7.61 (t, J = 7.6, 1.3 Hz, 1H), 7.95-
8.01 (m, 2H), 8.52 (d, J = 2.6 Hz, 1H), 8.55 (s, 1H); 13C NMR
(DMSO-d6, 75 MHz) δ 70.6, 115.1, 123.1, 123.4, 125.1, 127.4,
129.3, 130.6, 133.2, 140.0, 140.8, 147.2, 157.1, 199.7. IR (KBr)
ν [cm-1] = 3050, 2956, 2927, 1653, 1591, 1260, 799. HRMS
(ESI) m/z = 278.0430 calcd for C14H9NNaO4 [M+Na]+, found:
278.0427.
8-methoxydibenzo[b,e]oxepin-11(6H)-one (1l).15c Isolated
yield: 87% (light solid, 210 mg, 0.87 mmol, eluent:
hexane/EtOAc 90:10); mp 130-132 °C; 1H NMR (DMSO-d6, 300
MHz) δ 3.89 (s, 3H), 5.28 (s, 2H), 7.08 (dd, J = 8.7, 2.3 Hz, 1H),
7.10–7.16 (m, 2H), 7.20 (t, J = 7.4 Hz, 1H), 7.58 (brs t, J = 7.6
Hz, 1H), 7.89 (t, J = 8.7 Hz, 1H), 8.20 (dd, J = 8.1, 1.3 Hz, 1H);
13C NMR (DMSO-d6, 75 MHz) δ 55.6, 73.2, 113.1, 114.5, 120.6,
122.2, 125.5, 131.5, 131.8, 132.1, 135.2, 138.8, 160.7, 163.0,
187.7. MS m/z: 240 (100), 211 (20), 197 (27), 168 (12), 141 (11),
115 (10), 89 (12). IR (KBr) ν [cm-1] = 3055, 2953, 2925, 1715,
1495, 851. HRMS (EI) m/z = 240.0786 calcd for C15H12O3, found
240.0782.
Acknowledgments
This work was generously supported by the Consejo Nacional
de Investigaciones Científicas y Técnicas (CONICET), Agencia
Nacional de Promoción Científica y Tecnológica (ANPCyT) and
Universidad Nacional del Sur (UNS) from Argentina to DCG and
CB, and a Grand Challenges Explorations Grant from Bill and
Melinda Gates Foundation to CB (OPP1098404). CB and DCG
are research members of CONICET. MBF is research member of
CIC. JS and MJC thank the CONICET for a postdoctoral
fellowship.
4.4. Synthesis of 3-(dibenzo[b,e]oxepin-11(6H)-ylidene)-N,N-
dimethylpropan-1-amine (3).
3-(N,N-dimethylamino)propylmagnesium
chloride
was
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ACCEPTED MANUSCRIPT
Highlights
• A new synthetic tool for the construction of dibenzo[b,e]oxepinones is proposed.
• The novel reaction conditions showed an excellent tolerance to diverse functional groups.
• This protocol presented better performance than other standard Friedel-Crafts approaches.
• The reliable methodology was efficiently applied to the synthesis of doxepin.
• The fused tricyclic compounds exhibited interesting anthelmintic activity.