Convenient synthesis of substituted benzo[e][1,2,4]- or [d][1,2,6]oxadiazepines, benzo[f][1,3,5]triazocines from N-aryliminoesters

Article abstract of DOI:10.1016/j.tet.2017.01.063

We report herein a short and efficient synthesis of benz[e][1,2,4]- or [d][1,2,6]oxadiazepines and benzo[f][1,3,5]triazocines from easily prepared N-aryl iminoesters. The strategy involves a bis-nucleophile reagent (hydroxylamine or guanidine) that promotes a one-step ring closure from the starting functionalized iminoesters.

Full text of DOI:10.1016/j.tet.2017.01.063

Accepted Manuscript
Convenient synthesis of substituted benzo[e][1,2,4]- or [d][1,2,6]oxadiazepines,
benzo[f][1,3,5]triazocines from N-aryliminoesters
Tarak Saied, Nourchaine Jelaiel, Lotfi Mohamed Efrit, Yves Fort, Corinne Comoy
PII:
S0040-4020(17)30098-4
10.1016/j.tet.2017.01.063
TET 28433
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 September 2016
Revised Date: 12 January 2017
Accepted Date: 26 January 2017
Please cite this article as: Saied T, Jelaiel N, Efrit LM, Fort Y, Comoy C, Convenient synthesis of
substituted benzo[e][1,2,4]- or [d][1,2,6]oxadiazepines, benzo[f][1,3,5]triazocines from N-aryliminoesters,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.01.063.
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Convenient synthesis of substituted
benzo[e][1,2,4]- or [d][1,2,6]oxadiazepines,
benzo[f][1,3,5]triazocines from N-
aryliminoesters
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Saied Tarak,a,b Jelaiel Nourchaine,b Efrit Lotfi Mohamed,b Fort Yvesa and Comoy Corinnea,*
a Groupe Hétérocycles: Réactivité et Interaction (HécRIn), SRSMC UMR CNRS 7565, Université de Lorraine, B.P. 239, Boulevard des Aiguillettes, F-
54506 Vandoeuvre-lès-Nancy, France, E-mail: corinne.comoy@univ-lorraine.fr
b Laboratoire de Synthèse Organique et Hétérocyclique, Département de Chimie, Faculté des Sciences de Tunis, 2092 El Manar-Tunis, Tunisie

1
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Tetrahedron
journal homepage: www.elsevier.com
Convenient Synthesis of Substituted Benz[e][1,2,4]- or [d][1,2,6]oxadiazepines,
Benzo[f][1,3,5]triazocines from N-Aryliminoesters
Saied Tarak,a,b Jelaiel Nourchaine,b Efrit Lotfi Mohamed,b Fort Yvesa and Comoy Corinnea*
a Groupe Hétérocycles: Réactivité et Interaction (HécRIn), SRSMC UMR CNRS 7565, Université de Lorraine, B.P. 239, Boulevard des Aiguillettes, F-54506
Vandoeuvre-lès-Nancy, France, E-mail: corinne.comoy@univ-lorraine.fr
b Laboratoire de Synthèse Organique et Hétérocyclique, Département de Chimie, Faculté des Sciences de Tunis, 2092 El Manar-Tunis, Tunisie
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We report herein a short and efficient synthesis of benz[e][1,2,4]- or [d][1,2,6]oxadiazepines and
benzo[f][1,3,5]triazocines from easily prepared N-aryl iminoesters. The strategy involves a bis-
nucleophile reagent (hydroxylamine or guanidine) that promotes a one-step ring closure from the
starting functionalized iminoesters.
Available online
2016 Elsevier Ltd. All rights reserved
.
Keywords:
Condensed ring system
Nitrogen heterocycles
Benzoxadiazepines
Benzotriazocines
Synthetic method
1. Introduction
synthetic strategies are reported in the literature. To the best of
our knowledge, the first published synthetic pathways of those 8-
membered condensed heterocycles have been reported more than
forty years ago. The most widely reported sequence leads to the
synthesis of benzotriazocine moiety by using addition reaction of
hydrazines or amines as nucleophiles with carbonyls and analogs,
nitrile, ester or amide aryl derivatives,12 or, as described more
recently, imidoyl chloride and analogs.13 One example of
nucleophilic attack of hydrazone with chloroacetamido aryl
derivatives has been reported too.14 On the other hand, [1,4,5]-
benzotriazocines are obtained by treatment of quinazoline N-
oxide with hydrazine,15 while the [1,3,4]-isomer can be
synthesized using hetero Diels Alder cycloaddition starting from
benzazetes with tetrazides, followed by spontaneous extrusion of
nitrogen.16 In light of this review, we have considered that the
development of new efficient and short synthetic pathways to
such heterocycles remains a major challenge to enable their
study. So, among the different isomers of benzoxadiazepine core,
the benzo[e][1,2,4]- and [d][1,2,6]-isomers as well as
benzo[f][1,3,5]triazocines were chosen as targets of our research
(figure 1). We report herein a short and convenient access to the
entitled structures using aryliminoester as precursor.
Considering chemical reactivity as well as potential biological
activity, condensed heterocycles containing more than one
heteroatom appear to be attractive targets in organic chemistry.
Because the development of convenient synthesis of such species
remains an exciting challenge, we focused our attention on the
synthesis of benzoxadiazepine and benzotriazocine scaffolds.
Benzoxadiazepines and benzotriazocines are condensed
heterocycles resulting from combination of benzene ring and,
respectively, a 7-membered heterocycle bearing one oxygen and
two nitrogen atoms or an 8-membered heterocycle bearing three
nitrogen atoms.
Although
some
articles
and
patents
describe
benzoxadiazepines and their activities as stimulant to the central
nervous system,1 muscle relaxant,2 tranquilizer, anti-bacterial,
anti-inflammatory3 or pesticides,4 the synthesis of these
heterocycles has been scarcely investigated in the literature.
Benzoxadiazepines are reported as intermediates in the synthesis
of quinazolines,5 benzoxadiazepines,6 or benzimidazoles.7 More
recently, several oxadiazepine ring closure procedures have been
reported involving diazonium coupling reactions as key-step,8 as
well as cyclocondensation9 or Pd-catalyzed N-arylation of
amidoximes.10 Similarly, for benzotriazocines, only few patents
have reported their potential biological activities11 as analgesic
and sedative or psychotropic agents. Probably due to their
complex and sensitive structure, syntheses of benzotriazocines
have not been particularly studied and a limited number of
Figure 1. Expected 7- or 8-membered heterocycles.

2
Tetrahedron
ACCEPTED MANUSCRIPT
2. Results and discussion
Reaction using only 1.0 equivalent of hydroxylamine in
ethanol (EtOH) as solvent for 12 h at room temperature yielded a
poor amount of expected heterocycle 2a (entry 1, 17%). While
similar results were obtained by using an excess of
hydroxylamine for a reaction time of 12 h at room temperature
(entry 2, 1.6 equiv, 21%), a significant increase was observed
after stirring at room temperature for 24 h (entry 3, 58%).
However, a longer reaction time (entry 4, 72 h, 59%) or the use
of 2 equivalents of hydroxylamine (entries 5 and 6, 52 and 54%
respectively) did not significantly improve the yield.
Iminoesters, as promising intermediates for the synthesis of
polycondensed heterocycles, were easily prepared by
condensation of substituted aryl amines, using an excess of the
appropriate orthoester (1.7 equiv), in the presence of acetic acid
as catalyst. Expected derivatives were obtained in good to
excellent yields (table 1, 81-96%).
Table 1. Synthesis of iminoesters 1a-h.
Therefore, we decided to use the optimized conditions (see
table 2, entry 3) to extend the scope of the procedure to the
synthesis of various benz[e][1,2,4]oxadiazepin-5(3H)-ones (2a-
c). As shown in table 3, the expected 7-membered heterocycles
2a-c were obtained in good yields (58, 61 and 74% yield
respectively). It should be stated here that the reaction sequence
easily tolerates the presence of a bromine atom on the aromatic
ring (2c). Thereafter, with the aim to synthesize heterocyclic-
imine analogs, the same reaction conditions were applied from
cyanophenyl iminoesters 1c-d as starting material. After 24 h in
the presence of hydroxylamine (1.6 equiv) in EtOH at room
temperature, the expected benz[e][1,2,4]oxadiazepin-5(3H)-
imines 2d-e have also been obtained in good yields (61 and 79%
respectively). Based on these first results, we decided to extend
the scope of the sequence to benzoyl- or acetylphenyl iminoesters
1e-g containing a carbonyl group as second electrophilic unit.
Unfortunately, treatment of benzoyliminoester 1e by
hydroxylamine did not afford the anticipated product 3a’.
Instead, as revealed by mass spectroscopy and NMR analyses, a
dehydration step that cannot be planned from 3a’occurred during
leading to the formation of compound 3a. A new mechanism
pathway allowed us to propose a structure for 3a (Scheme 1).
More specifically, from 1a-d and 1h, benzoxadiazepine ring
closure involves an N-nucleophilic addition of hydroxylamine on
the iminoester substituent that exhibits a higher reactivity
compared to the ester or nitrile groups. Consequently, a N=C-N
link is formed in the intermediate compound. Then residual
hydroxyl function reacts with the ester or nitrile moiety leading
to expected heterocycle 2a-e.
X
Y
R1
Me
Et
R2
Yields (%)a
1a
1b
1c
1d
1e
1f
COOEt
COOEt
CN
H
Et
84
92
85
89
93
96
94
81
H
Me
Et
H
Me
Et
CN
H
Me
Me
Et
COPh
COCH3
COCH3
4-Cl
H
Et
Me
Et
1g
1h
H
Me
Me
COOMe 4-Br
Et
a Isolated yield after purification by reduced pressure distillation
(0.1 mmHg).
Since substrates 1a-h exhibit two electrophilic active sites
(ester, nitrile or ketone and iminoester respectively), a one-pot
ring closure strategy was implemented using bis-nucleophile
reagents to prepare the desired condensed heterocycles.
At first, the preparation of benz[e][1,2,4]oxadiazepine ring 2a
was studied, requiring hydroxylamine as bis-nucleophile reagent
(table 2). Indeed, the choice of this reagent was directly related to
our aim to prepare the entitled 7-membered condensed cyclic
system from iminoester as starting material. Given the relative
positions of the two electrophilic centers on the substrate (imino
ester and ester or nitrile or carbonyl), the selected reagent has to
possess a nitrogen and an oxygen nucleophilic sites in adjacent
position, therefore hydroxylamine seems to be an unavoidable
choice.
Table 2. Screening of reaction conditions for preparation of 2-
methylbenz[e][1,2,4]oxadiazepin-5(3H)-one (2a).
Scheme 1. Formation of benz[e][1,2,6]oxadiazepine 3a versus
benz[e][1,2,4]oxadiazepine 3a’.
Conversely, concerning carbonyl-iminoester 1e, the carbonyl
group appears to be more electrophilic than the iminoester.
Consequently, the N-condensation of hydroxylamine occurs first
on the carbonyl group. Then, the residual hydroxyl nucleophile
reacts with the iminoester group to afford [1,2,6]-isomer 3a in
very good yield (85%) (table 3). These results show that the
nature of the second electrophilic site is essential to control the
chemo-selectivity of cyclocondensation, to subsequently afford
the desired heterocyclic isomers.
entry
NH2OH
(n equiv)
Time (h) Yields (%)a
1
2
3
4
5
6
1.0
1.6
1.6
1.6
2.0
2.0
12
12
24
72
24
72
17
21
58
59
52
54
Two additional examples were carried out from 1f and 1g as
substrates affording benz[e][1,2,6]-oxadiazepines 3b-c in good
yields (73 and 79% respectively).
a Isolated yield after purification by precipitation and
successive washes in Et2O.

3
ACCEPTED MANUSCRIPT
Table 3. Preparation of benzoxadiazepines 2a-e and 3a-c.
Y
R1
Me
Et
Yield (%)a
Y
H
H
R1
Me
Et
Yield (%)a
R1
Et
R3
Y
Yields (%)a
2a
2b
2c
H
58
61
74
2d
2e
61
79
3a
3b
3c
Ph
7-Cl
H
85
73
79
H
Me
Et
Me
Me
7-Br
Et
H
a Isolated yield after purification by precipitation and successive washes in Et2O.
Next, we focused our attention on the preparation of the 8-
membered heterocyclic benzotriazocine scaffold. Because the
target structure was the [1,3,5]-isomer, guanidine (HN=C(NH2)2)
was selected as bis-nucleophile to allow the desired N=C-N=C-N
link formation.
Table 4. Screening of reaction conditions for preparation of 4-
amino-2-methylbenzo[f][1,3,5]triazocin-6(5H)-one (4a).
As reported in table 4, optimization of reaction conditions was
performed. When only one equivalent of guanidine was used in
EtOH as solvent for 12 h at room temperature, no transformation
was observed and the starting iminoester 1a was recovered
unchanged (entry 1). Furthermore, when increased amount of
guanidine (1.6 equiv) was involved, no trace of expected
benzotriazocine 4a was detected, regardless of the reaction
temperature (RT or 79 °C). Starting material was recovered once
again (entries 2 and 3). To activate the nucleophilic attack on
aryliminoester 1a, an acid catalyst was added to the reaction
medium (HCOOH, APTS or AcOH). While no interesting result
was observed in the presence of formic acid or APTS (entries 4-
7, degradation of substrate or no conversion were observed), the
reaction conditions using acetic acid as catalyst, for 24 h and with
1.6 equivalent of reagent led to target heterocycle 4a in 6% yield
for reaction performed at room temperature and 39% yield at
79°C (entries 8 and 9). Finally, a significant increase in yield was
observed (63%, entry 10) when a larger excess of guanidine was
used (2.0 equivalent). However, it should be noted that an
increased reaction time (entry 11, 48h) led to degradation of
product 4a and, consequently, to a decreased yield.
entry
Acid
catalyst
T°C
HN=C(NH2)2
(n equiv)
Time
(h)
Yields
(%)a
b
1
-
25
25
79
25
79
25
79
25
79
79
79
1.0
1.6
1.6
1.6
1.6
1.6
1.6
1.6
1.6
2.0
2.0
12
12
12
24
24
24
24
24
24
24
48
-
b
2
-
-
b
3
-
-
c
4
HCOOH
HCOOH
APTS
APTS
AcOH
AcOH
AcOH
AcOH
-
c
5
-
b
6
-
b
7
-
8
6
9
39
63
57d
10
11
aIsolated yield after purification by precipitation and successive
washes in Et2O. b 1a was recovered unchanged. cdegradation of 1a was
observed. d degradation of 4a was observed by refluxing for 48h.
The optimized conditions (entry 10) were applied starting
from iminoesters 1a-f for the preparation of various
benzotriazocines
(table
5).
Thus
4-amino-
benzo[f][1,3,5]triazocin-6(5H)-ones 4a-b were easily obtained
from iminoesters 1a and b in 63 and 69% yield respectively.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Concerning reaction from iminoesters 1c-d, the nucleophilic
bearing a carbonyl function, afforded very good results, and the
addition of guanidine on the cyano moiety allowed the expected
ring closure to happen. Interestingly, the structure of the new
promising derivatives 5a and 5b (53 and 66% yield respectively)
features a second amino group in position-6, that appears to be an
asset for further functionalization. Finally, iminoesters 1e-f,
expected 8-membered heterocycles were isolated in 78 and 59%
respectively. Here, the dehydration of hydroxylated intermediates
resulting from the cyclocondensation step was easily carried out
and led spontaneously to the expected aromatic systems.
Table 5. Preparation of benzotriazocines 4a-b and 5a-d.
R1
Me
Et
Yield (%)a
R1
Me
Et
Yield (%)a
R1
Et
R3
Y
Yields (%)a
4a
4b
63
69
5a
5b
53
66
5c
Ph
Me
8-Cl
H
78
59
5d
Me
a Isolated yield after purification by precipitation and successive washes in Et2O.
cyclohexane 1/9). Purification by reduced pressure distillation
(0.1 mmHg) afforded the expected compounds as oils.
3. Conclusion
To conclude, we proposed here short and convenient routes to
various functionalized benz[e][1,2,4]- or [1,2,6]oxadiazepines
and benzo[f][1,3,5]triazocines, in good overall yields, starting
from readily available arylamines (in 49-79% and 45-72% yields
respectively). Besides, we highlighted the importance to have a
second electrophilic substituent to direct the ring closure towards
the [1,2,4]- or [1,2,6]-isomers of benzoxadiazepines. Moreover,
the entitled condensed heterocycles prove to be versatile
substrates to envision subsequent functionalization involving, for
4.2.1. Ethyl N-(2-carbethoxyphenyl)acetimidate (1a).
1
Yield 84%. bp 113 °C (0.1 mmHg); H NMR δH (250 MHz,
3
3
CDCl3) 1.27 (t, 3H, JHH = 6.0 Hz, CH3CH2), 1.34 (t, 3H, JHH
=
9.0 Hz, CH3CH2), 3.69-3.74 (m, 2H, CH2), 4.20-4.27 (m, 2H,
CH2); 6.67-7.90 (m, 4H, Harom); 13C NMR δC (63 MHz, CDCl3)
14.2, 15.2, 16.7, 18.3, 57.3, 60.5, 121.9, 122.6, 131.1, 132.8,
150.1, 160.6, 166.6.
4.2.2. Methyl N-(2-carbethoxyphenyl)propionimidate (1b).
examples,
N-alkylation
or
acylation,
regioselective
lithiation/electrophilic trapping sequences as well as Pd-catalyzed
cross couplings.
1
Yield 92%. bp 123 °C (0.1 mmHg); H NMR δH (250 MHz,
CDCl3) 1.02 (q, 3H,3JHH = 6.0 Hz, CH3-CH2-C=N), 1.30 (t, 3H,
3JHH = 9.0 Hz, CH3CH2O), 2.05-2.11 (m, 2H, CH2CH3), 3.81 (s,
3H, CH3O), 4.22-4.37 (m, 2H, CH2O), 6.54-7.90 (m, 4H, Harom);
13C NMR δC (63 MHz, CDCl3) 10.1, 14.1, 23.8, 53.2, 60.3, 115.8,
124.3, 127.1, 127.8, 133.6, 134.1, 144.2, 166.3, 168.0.
4. Experimental section
4.1. General Methods:
1
The H and 13C NMR spectroscopic data were recorded at
1
250 MHz for H NMR and 63 MHz for 13C NMR, and CDCl3
4.2.3. Ethyl N-(2-cyanophenyl)acetimidate (1c).
1
with TMS as the internal standard (for H NMR) or DMSO-d6
1
Yield 85%. bp 137 °C (0.1 mmHg); H NMR δH (250 MHz,
were used as solvent. HRMS spectra were recorded on a
micrOTOF-Q spectrometer. MS data were recorded on a GC–
MS-QP2010 spectrometer. Melting temperatures were recorded
CDCl3) 1.26-1.32 (m, 3H, CH3CH2O), 1.78 (s, 3H, CH3-C=N),
4.22-4.29 (m, 2H, CH2-O), 6.78–7.50 (m, 4H, Harom); 13C NMR
δC (63 MHz, CDCl3) 13.9, 20.0, 62.2, 105.0, 117.3, 121.7, 123.0,
132.6, 133.1, 152.4, 162.4.
with
a thermostatic oil bath device. All reagents were
commercially available and purified by distillation when
necessary.
4.2.4. Methyl N-(2-cyanophenyl)propionimidate (1d).
4.2. General procedure for the synthesis of iminoesters (1a-h).
1
Yield 89%. bp 145 °C (0.1 mmHg); H NMR δH (250 MHz,
CDCl3) 1.10 (t, 3H, 3JHH = 7.0 Hz, CH3CH2), 2.17 (q, 2H, JHH
=
3
To a solution of selected arylamine (30 mmol, 1.0 equiv.) and
appropriate orthoester (50.0 mmol, 1.7 equiv.) were added few
drops of acetic acid. The resulting mixture was then stirred at
reflux for 5 h. Reaction was monitored by TLC (ethyl acetate/
7.0 Hz, CH2), 3.82 (s, 3H, CH3O), 6.84-7.57 (m, 4H, Harom); 13C
NMR δC (63 MHz, CDCl3) 10.2, 23.1, 53.2, 104.9, 110.6, 115.9,
122.6, 133.7, 150.6, 163.7, 166.5, 167.9.
4.2.5. Methyl N-(2-benzoyl-4-chlorophenyl)propionimidate (1e).

5
1
Yield 93%. bp 209 °C (0.1 mmHg); H NMR δH (250 MHz,
Yield 74%. m.p 176-178 °C; 1H NMR δH (250 MHz, DMSO-d6
ACCEPTED MANUSCRIPT
CDCl3) 0.98 (t, 3H, JHH = 9.0 Hz, CH3CH2C=N), 2.07 (q, 3JHH
=
D2O) 1.22 (t, 3H, 3JHH = 7.0 Hz, CH3), 2.85 (q, 2H, 3JHH = 7.0 Hz,
3
9.0 Hz, 2H, CH2), 3.23 (s, 3H, CH3O), 6.72-7.77 (m, 8H, Harom);
13C NMR δC (63 MHz, CDCl3) 10.3, 23.7, 53.1, 118.5, 123.3,
128.0, 128.3, 128.9, 129.0, 129.6, 131.3, 132.8, 134.0, 137.3,
145.8, 165.4, 196.0.
CH2), 7.55 (d, 1H, 3JHH = 9.0 Hz, Harom), 7.81 (dd, 1H, 3JHH = 9.0
4
3
Hz, JHH = 4.5 Hz, Harom), 8.04 (d, 1H, JHH = 4.5 Hz, Harom); 13
C
NMR δC (63 MHz, DMSO-d6) 10.2, 25.8, 117.3, 122.5, 127.3,
129.1, 135.4, 144.5, 157.7, 159.3; ESI-HRMS calcd for
C10H9BrN2O2 (M+H+): 271.2353, found: 271.2436.
4.2.6. Ethyl N-(2-acetylphenyl)acetimidate (1f).
4.3.4. 2-Methyl benz[e][1,2,4]oxadiazepin-5(3H)-imine (2d).
1
Yield 96%. bp 121 °C (0.1 mmHg); H NMR δH (250 MHz,
3
CDCl3) 1.35 (t, 3H, JHH = 7.0 Hz, CH3CH2), 1.76 (s, 3H,
Yield 61%. m.p 145-147 °C; 1H NMR δH (250 MHz, DMSO-
3
CH3C=N), 2.49 (s, 3H, CH3CO), 4.25 (q, 2H, JHH = 7.0 Hz,
d6 D2O) 2.61 (s, 3H, CH3); 7.35-7.43 (m, 1H, Harom), 7.59-7.71
3
CH2), 6.70-7.68 (m, 4H, Harom); 13C NMR δC (63 MHz, CDCl3)
14.6, 17.0, 30.7, 62.1, 122.7, 123.1, 129.6, 131.6, 132.8, 146.7,
161.8, 201.3.
(m, 2H, , Harom), 8.11 (d, 1H, JHH = 7.0 Hz, Harom); 13C NMR δC
(63 MHz, DMSO-d6) 21.1, 118.7, 125.0, 125.1, 125.9, 127.4,
132.6, 145.4, 154.8, 161.6, 161.7; ESI-HRMS calcd for C9H9N3O
(M+2H+): 177.0699, found: 177.0659.
4.2.7. Methyl N-(2-acetylphenyl)propionimidate (1g).
4.3.5. 2-Ethyl benz[e][1,2,4]oxadiazepin-5(3H)-imine (2e).
Yield 79%. m.p 161-163 °C; 1H NMR δH (250 MHz, DMSO-
1
Yield 94%. bp 122 °C (0.1 mmHg); H NMR δH (250 MHz,
3
3
CDCl3) 1.03 (t, 3H, JHH = 7.0 Hz, CH3CH2), 2.11 (q, 2H, JHH
=
3
3
7.0 Hz, CH2), 2.50 (s, 3H, CH3CO), 3.83 (s, 3H, OCH3), 6,61-
7,69 (m, 4H, Harom); 13C NMR δC (63 MHz, CDCl3) 10.7, 24.0,
30.8, 53.7, 116.0, 117.5, 122.7, 129.6, 132.8, 148.3, 165.2,
201.29.
d6) 1.29 (t, 3H, JHH = 8.0 Hz, CH3), 3.04 (q, 2H, JHH = 8.0 Hz,
CH2), 7.52 (t, 1H, 3JHH = 8.0Hz, Harom), 7.65-7.75 (m, 2H, Harom),
8.21 (d, 1H, 3JHH = 8.0 Hz, Harom), 8.43 (s, 2H, NH); 13C NMR δC
(63 MHz, DMSO-d6) 10.8, 26.2, 113.1, 123.2, 126.9, 128.3,
131.7, 141.3, 150.8, 158.76; ESI-HRMS calcd for C10H11N3O
(M+H+): 190.0991, found: 190.0975.
4.2.8. Methyl N-(2-carbomethoxy-4-bromophenyl)propionimidate
(1h).
4.3.6. 7-Chloro-2-ethyl-5-phenyl benz[d][1,2,6]oxadiazepine
(3a).
1
Yield 81%. bp 127 °C (0.1 mmHg); H NMR δH (250 MHz,
3
3
CDCl3) 1.06 (t, 3H, JHH = 7.0 Hz, CH3CH2), 2.09 (q, 2H, JHH
=
7.0 Hz, CH2), 3.59 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 6,64-8.04
(m, 3H, Harom); 13C NMR δC (63 MHz, CDCl3) 10.3, 21.1, 51.1,
52.8, 118.0, 122.1, 123.9, 134.1, 136.9, 144.2, 165.7, 170.9.
Yield 85%. m.p 188-190 °C; 1H NMR δH (250 MHz, CDCl3)
3
3
1.47 (t, 3H, JHH = 7.0 Hz, CH3), 3.26 (q, 2H, JHH = 7.0 Hz,
CH2), 7.36-7.62 (m, 7H, Harom), 7.93 (d, 1H, 3JHH = 8.0 Hz, Harom);
13C NMR δC (63 MHz, CDCl3) 10.2, 26.1, 123.7, 124.5, 128.9,
129.0, 129.1, 129.5, 130.1, 130.5, 131.4, 134.7, 138.9, 149.0,
162.1; ESI-HRMS calcd for C16H13ClN2O (M+H+): 285.0820,
found: 285.0789.
4.3. General procedure for the synthesis of benzoxadiazepines
(2a-e) and (3a-c).
Hydroxylamine hydrochloride (0.34 g, 50.0 mmol, 1.0 equiv)
in ethanol (EtOH) (5 mL) was added to a solution of sodium
ethylate (0.12 g, 50.0 mmol, 1.0 equiv) in EtOH (4 mL) at 0 °C,
under nitrogen atmosphere. After stirring and filtration, free
hydroxylamine in EtOH was then obtained. Then, to a solution of
iminoesters 1a-h (3.0 mmol, 1.0 equiv) in EtOH (4 mL) was
added hydroxylamine (6.0 mmol, 2.0 equiv). Reaction mixture
was stirred for 24 h at room temperature. After solvent
evaporation, crude product was obtained by precipitation in
petroleum ether and then purification was carried out by
successive washings with diethyl ether (Et2O). The expected
products 2a-e and 3a-c were obtained as solid.
4.3.7. 2,5-Dimethyl benz[d][1,2,6]oxadiazepine (3b).
Yield 73%. m.p 144-146 °C; 1H NMR δH (250 MHz, DMSO-
3
d6) 2.84 (s, 3H, CH3), 2.86 (s, 3H, CH3), 7.54 (t, 1H, JHH = 7.0
3
3
Hz, Harom), 7.67 (t, 1H, JHH = 7.0 Hz, Harom), 7.79 (d, 1H, JHH
=
7.0 Hz, Harom ), 7.86 (dd, 1H, 3JHH = 7.0 Hz, 4JHH = 1.0 Hz, Harom);
13C NMR δC (63 MHz, DMSO-d6) 13.2, 20.8, 123.4, 123.7,
128.7, 128.8, 131.0, 140.1, 150.9, 157.9; ESI-HRMS calcd for
C10H10N2O (M+H+): 175.0866, found: 175.0883.
4.3.8. 2-Ethyl-5-methyl benz[d][1,2,6]oxadiazepine (3c).
Yield 79%. m.p 149-151 °C; 1H NMR δH (250 MHz, DMSO-
4.3.1. 2-Methyl benz[e][1,2,4]oxadiazepin-5(3H)-one (2a).
3
d6) 1.29 (t, 3H, JHH = 7.0 Hz, CH3), 2.57 (s, 3H, CH3), 3.12 (q,
Yield 58%. m.p. 159-161 °C; 1H NMR δH (250 MHz, DMSO-d6)
2H, 3JHH3 = 7.0 Hz, CH2), 7.65 (dt, 1H, 3JHH = 7.0 Hz, Harom), 7.77
3
4
2.63 (s, 3H, CH3), 7.48-7.55 (m, 1H, Harom), 7.64-7.69 (m, 2H,
(t, 1H, JHH = 7.0 Hz, Harom), 7.89 (dd, 1H, JHH = 7.0 Hz, JHH =
Harom), 8.20 (d, 1H, 3JHH = 8.0 Hz, Harom), 8.46 (brs, 1H, NH); 13
C
3.0 Hz, Harom), 8.08 (dd, 1H, 3JHH = 7.0 Hz, 4JHH = 3.0 Hz, Harom).
13C NMR δC (63 MHz, DMSO-d6) 10.6, 13.6, 26.0, 123.7, 124.4,
128.6, 129.2, 131.3, 139.2, 150.6, 160.4. ESI-HRMS calcd for
C11H12N2O (M+H+): 189.1028, found: 189.0122.
NMR δC (63 MHz, DMSO-d6) 21.0, 113.2, 123.2, 126.9, 128.1,
131.7, 141.3, 150.9, 155.5; ESI-HRMS calcd for C9H8N2O2 (M):
176.0828, found: 176.0843.
4.3.2. 2-Ethyl benz[e][1,2,4]oxadiazepin-5(3H)-one (2b).
Yield 61%. m.p. 171-173 °C; 1H NMR δH (250 MHz,
4.4. General procedure for the synthesis of benzotriazocines (4a-
b) and (5a-d).
3
3
DMSO-d6) 1.29 (t, 3H, JHH = 7.0 Hz, CH3), 3.01 (q, 2H, JHH
=
Guanidinium hydrochloride (0.57 g, 6.0 mmol, 1.0 equiv) in
ethanol (EtOH) (5 mL) was added to a solution of sodium
ethylate (0.41 g, 6.0 mmol, 1 equiv) in EtOH (4 mL) at 0 °C,
under nitrogen atmosphere. After stirring and filtration, free
guanidine in EtOH was then obtained. Then, to solution of
iminoesters 1a-f (3.0 mmol, 1.0 equiv) in EtOH (4 mL) was
added guanidine (6.0 mmol, 2.0 equiv), in the presence of few
drops of acetic acid. Reaction mixture was refluxing for 24 h.
After solvent evaporation, crude product was obtained by
precipitation in petroleum ether and then purification was carried
7.0Hz, CH2), 7.39-7.43 (m, 1H, Harom), 7.61-7.74 (m, 1H, Harom),
3
8.02 (d, 1H, JHH = 8.0 Hz, Harom); 13C NMR δC (63 MHz,
DMSO-d6) 10.95, 26.34, 118.63, 125.04, 125.85, 127.58, 132.46,
145.32, 158.15, 161.68. ESI-HRMS calcd for C10H10N2O2
(M+H)+: 191.0815, found: 191.0866.
4.3.3. 7-Bromo-2-ethyl benz[e][1,2,4]oxadiazepin-5(3H)-one
(2c).

6
Tetrahedron
ACCEPTED MANUSCRIPT
out by successive washings with diethyl ether (Et2O). The
The authors gratefully acknowledge financial support from the
Centre National de la Recherche Scientifique (CNRS), the
Université de Lorraine and the Université El Manar-Tunis.
Brigitte Fernette, Sandrine Adach and Fabien Lachaud are
thanked for technical assistance and for recording NMR and MS
spectra.
expected products 4a-b or 5a-d were obtained as solid.
4.4.1. 4-Amino-2-methyl benzo[f][1,3,5]triazocin-6(5H)-one
(4a).
Yield 63%. m.p. 192-194 °C; 1H NMR δH (250 MHz,
3
DMSO-d6) 1.61 (s, 3H, CH3), 6.34 (t, 1H, J = 7.0 Hz, Harom),
3
References and notes
6.49 (t, 1H, J = 7.0 Hz, Harom), 6.66 (br s, 2H, NH2), 6.88-6.96
(m, 1H, Harom), 7.65-7.75 (m, 1H, Harom), 8.30 (s, 1H, NH); 13C
NMR δC (63 MHz, DMSO-d6). 25.4, 114.5, 115.8, 121.0, 130.5,
132.4, 150.7, 160.3, 167.7, 175.2. ESI-HRMS calcd for
C10H10N4O (M): 202.0849, found: 202.1124.
1. (a) Petigara, R. B.; Yale, H. L. U.S. Patent 4, 134, 975, 1979; (b)
Bristol, J. A.; Yale, H. L. U.S. Patent 4, 062, 852, 1977.
2. Petigara, R. B.; Yale, H. L. U.S. Patent 3, 856, 801, 1974; Chem.
Abstr. 1975, 82, 31362s.
3. Reddy, P. S. N.; Reddy, P. P.; Padmaja, K.; Shailja, G.; Reddy, D.
S. Indian J. Chem. 1996, 35, 1110-1112.
4. Singh, G.; Singh, C.; Kaur, H. Asian J. Chem. 1995, 7, 735-741.;
Chem. Abstr. 1996, 124, 86970e.
5. Sulkowski, T. S.; Childress, S. J. J. Org. Chem., 1962, 27, 4424-
4426.
4.4.2. 4-Amino-2-ethyl benzo[f][1,3,5]triazocin-6(5H)-one (4b).
Yield 69%. m.p. 191-193 °C; 1H NMR δH (250 MHz,
3
3
DMSO-d6) 1.24 (t, 3H, JHH = 7.0 Hz, CH3), 2.68 (q, 2H, JHH
=
3
7.0 Hz, CH2), 6.00 (br s, 1H, NH), 7.37 (t, 1H, JHH = 7.0 Hz,
Harom), 7.57-7.65 (m, 1H, Harom), 7.67 (br s, 2H, NH2), 7.69-7.71
6. Field, G.; Sternbach, L. H. J. Org. Chem. 1968, 33, 4438-4440.
7. Mazurkiewicz, R. Monatsh. Chem. 1988, 119, 1279-1287.
8. (a) El-Rady, E. A. J. Heterocyclic. Chem. 2002, 39, 1109-1110.
(b) Abd El Latif, F. M.; El-Rady, E. A.; Khalil, M. A. Phosphorus,
Sulfur and Silicon 2002, 177, 2497-2505. (c) El-Rady, E. A. J.
Chin. Chem. Soc. 2004, 51, 859-862.(a) Tandon, V. K.; Kumar,
M. Tetrahedron Lett. 2004, 45, 4185-4187. (b) Svetlik, J.; Liptaj,
T. J. Chem; Soc., Perkin Trans. 1 2002, 1, 1260-1265. (c)
10. Abele, E.; Rubina, K.; Golomba, L.; Abele, R. Heterocyclic Lett.
2012, 2, 85-89. (b) Golomba, L.; Abele, E.; Belyakov, S. Chem.
Heterocycl. Compd 2012, 47, 1598-1600.
11. See for example :(a) Shindo, M.; Kakimoto, M.; Nagano, H.
German Patent 2, 216,837, Oct. 26, 1972. (b) Shindo, M.;
Kakimoto, M.; Nagano, H.; Fujimura, Y. German Patent
2,308,064, Sept. 6, 1973. (c) Nagano, H.; Shindo, M.; Kakimoto,
M. Japanese Patent 74 51, 292, May 18, 1974. (d) Shindo, M.;
Kakimoto, M.; Nagano, H.; Fujimura, Y. Japanese Patent 74
26,292, Mar. 8, 1974. (d) M. Shindo, M. Kakimoto, H. Nagano. Y.
Fujimura and C. Yasuo, German Offen. 2,308,064 730906; Chem
Abstr., 79. 126537, 1973. (e) Chugai Pharmaceutical Co., Japan
Patent 56 001.313 B4 810113; Chem. Abstr., 95. 7363, 1981.
12. (a) Plescia, S.; Ajello, E.; Sprio, V. J. Heterocyclic Chem. 1975,
12, 199-202. (b) Daniels, J. K.; Peet, N. P. J. Heterocyclic Chem.
1978, 15, 1309-1311and references cited herein. (c) Bertha, F.;
Hornyak, G.; Zauer, K.; Lempert, K. Tetrahedron 1983, 39, 1199-
1201. (d) Hornyak, G.; Lempert, K.; Pjecka, E.; Toth, G.
Tetrahedron 1985, 41, 2847-2854. (e) Lin, W. O.; Souza
Coutinho, E. Monatsh. Chem. 1983, 114, 1231-1235. (f) Costanzo,
A.; Bruni, F.; Guerrini, G.; Selleri, S.; Aiello, P. M.; Lamberti, C.
J. Heterocyclic Chem. 1992, 29, 1499-1505. (g) Korakas, D.;
Kimbaris, A.; Varvounis, G. Tetrahedron 1996, 52, 10751-10760.
13. (a) Fathalla, W.; Pazdera, P. Molecules 2002, 7, 96-103. (b)
Spirkova, K.; Bucko, M.; Stankovsky, S; ARKIVOC 2005, 5, 96-
102. (c) Vasylyshyn, R.; Demydchuk, B. A.; Rusanov, E. B.;
Brovarets, V. S. Synthetic Commun. 2014, 44, 714-719.
3
(m, 1H, Harom), 8.14 (d, 1H, JHH = 7.0 Hz, Harom); 13C NMR δC
(63 MHz, DMSO-d6) 13.3, 32.9, 113.5, 124.1, 125.1, 127.7,
133.2, 151.0, 162.6, 168.2, 168.3. ESI-HRMS calcd for
C11H12N4O (M): 216.1006, found: 216.1255.
4.4.3. 2-Methyl benzo[f][1,3,5]triazocine-4,6-diamine (5a).
1
Yield 53% %. m.p. 168-170 °C; H NMR δH (250 MHz,
3
DMSO-d6) 1.72 (s, 3H, CH3), 7.46 (t, 1H, JHH = 7.0 Hz, Harom),
7.66 (d, 2H, 3JHH = 7.0 Hz, Harom), 7.78 (br s, 4H, NH2), 8.26 (dd,
3
3
1H, JHH = 7.0 Hz, JHH = 2.0 Hz, Harom); 13C NMR δC (63 MHz,
DMSO-d6) 25.7, 113.0, 123.9, 124.9, 127.2, 133.0, 159.6, 162.2,
163.6, 176.1. ESI-HRMS calcd for C10H11N5 (M): 202.1098,
found: 202.1087.
4.4.4. 2-Ethyl benzo[f][1,3,5]triazocine-4,6-diamine (5b).
Yield 66%. m.p. 172-174 °C; 1H NMR δH (250 MHz,
3
3
DMSO-d6) 1.25 (t, 3H, JHH = 7.0 Hz, CH3), 2.66 (q, 2H, JHH
=
3
7.0 Hz, CH2), 5.97 (br s, 2H, NH2), 7.36 (d, 1H, JHH = 7.0 Hz,
Harom), 7.58-7.70 (m, 4H, Harom, NH2), 8.14 (d, 1H, 3JHH = 7.0 Hz,
Harom); 13C NMR δC (63 MHz, DMSO-d6) 13.3, 32.9, 113.5,
124.1, 125.1, 127.7, 133.2, 151.0, 162.6, 168.3, 176.1. ESI-
HRMS calcd for C11H13N5 (M+H+): 216.1224, found: 216.1229.
4.4.5. 8-Chloro-2-ethyl-6-phenyl benzo[f][1,3,5]triazocin-4-
amine (5c).
Yield 78%. m.p. 178-180 °C; 1H NMR δH (250 MHz,
3
DMSO-d6) δH = 1.39 (t, 3H, JHH = 7.0 Hz, CH3), 4.48 (q, 2H,
3JHH = 7.0 Hz, CH2), 5.94 (br s, 1H, NH2), 6.96 (br s, 1H, NH2),
3
7.51-7.58 (m, 6H, Harom), 7.69 (dd, 1H, JHH = 2.0 Hz3JHH = 7.0
14. Natsugari, H.; Meguro, K.; Kuwada, Y. Chem. Pharm. Bull. 1979,
27, 2084-2092.
3
Hz, Harom), 7.84 (d, 1H, JHH = 7.0 Hz, Harom); 13C NMR δC (63
MHz, DMSO-d6) 14.9, 62.1, 114.1, 124.5, 124.7, 129.0, 129.3
(2C), 129.4 (2C), 129.6, 129.9, 130.5, 136.8, 145.6, 150.5, 162.0.
ESI-HRMS calcd for C17H15ClN4 (M+H+): 311.1058, found:
311.052.
15. (a) Meguro, K.; Kuwada, Y. Tetrahedron Lett. 1970, 11, 4039-
4042. (b) Kamiya, K.; Wada, Y.; Nishikawa, M. Chem. Pharm.
Bull. 1973, 21, 1520-1529. (c) Meguro, K.; Kuwada, Y. Chem.
Pharm. Bull. 1973, 21, 2375-2381.
16. Adger, B. M.; Rees, C. W.; Storr, R. C. J. Soc. Chem. Perkin 1,
1975, 45-52.
4.4.6. 2,6-Dimethyl benzo[f][1,3,5]triazocin-4-amine (5d).
Yield 59%. m.p. 166-168 °C; 1H NMR δH (250 MHz,
DMSO-d6) δH = 2.11 (s, 3H, CH3), 2.38 (s, 3H, CH3), 5.00 (br s,
3
3
2H, NH2), 7.08 (t, 1H, JHH = 8.0 Hz, Harom), 7.14 (d, 1H, JHH
=
8.0 Hz, Harom), 7.26 (d, 1H, 3JHH = 7.0 Hz, Harom),7.71 (d, 1H, 3JHH
= 7.0 Hz, Harom);13C NMR δC (63 MHz, DMSO-d6) 13.5, 15.8,
116.9, 121.6, 124.8, 127.1, 129.2, 139.4, 141.9, 160.24, 163.8.
ESI-HRMS calcd for C11H12N4 (M+H+): 201.1104, found:
201.1080.
Acknowledgments