Facile synthesis of 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by reductive cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides

Article abstract of DOI:10.1016/j.tetlet.2018.12.029

A facile and efficient method was developed for the synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones from 2-chloro-N-(2-nitrobenzyl)acetamides through a reductive cyclization using iron-ammonium chloride in ethanol–water in good yields. This method provides a simple approach to these benzodiazepine-3-ones which are of high value in the field of medicinal chemistry research.

Full text of DOI:10.1016/j.tetlet.2018.12.029

Accepted Manuscript
Facile Synthesis of 4-Substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones
by Reductive Cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides
Leandro D. Sasiambarrena, Ivan A. Barri, Guido G. Fraga, Rodolfo D. Bravo,
Agustín Ponzinibbio
PII:
S0040-4039(18)31472-2
https://doi.org/10.1016/j.tetlet.2018.12.029
TETL 50492
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 October 2018
1 December 2018
13 December 2018
Please cite this article as: Sasiambarrena, L.D., Barri, I.A., Fraga, G.G., Bravo, R.D., Ponzinibbio, A., Facile
Synthesis of 4-Substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by Reductive Cyclization of 2-chloro-N-
(2-nitrobenzyl)acetamides, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.029
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Facile Synthesis of 4-Substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by
Reductive Cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides
Leandro D. Sasiambarrena,* Ivan A. Barri, Guido G. Fraga, Rodolfo D. Bravo, Agustín
Ponzinibbio
*Centro de Estudio de Compuestos Orgánicos CEDECOR UNLP-CIC, Departamento de
Química, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, La Plata,
1900, Argentina.
Fe, NH4Cl
H
NO2
N
EtOH-H2O
N
O
N
2 steps, one pot process
R
30-77% yields
R
Cl
O
R= alkyl, aryl, 2-phenylethyl

Facile Synthesis of 4-Substituted 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones by
Reductive Cyclization of 2-chloro-N-(2-nitrobenzyl)acetamides
Leandro D. Sasiambarrena, Ivan A. Barri, Guido G. Fraga, Rodolfo D. Bravo, Agustín
Ponzinibbio
*Centro de Estudio de Compuestos Orgánicos CEDECOR UNLP-CIC, Departamento de Química, Facultad de
Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115, La Plata, 1900, Argentina.
Keywords:
1,4-benzodiazepines
2-chloro-N-(2-nitrobenzyl)acetamides
Iron-ammonium chloride reduction
2-nitrobenzylamines
ABSTRACT
A facile and efficient method was developed for the synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones from
2-chloro-N-(2-nitrobenzyl)acetamides through a reductive cyclization using iron-ammonium chloride in ethanol-
water in good yields. This method provides a simple approach to these benzodiazepine-3-ones which are of high
value in the field of medicinal chemistry research.
Introduction
1,4-Benzodiazepinone compounds (1,4-BDZ) are important heterocycles due to their biological
activity and they have been extensively investigated. They are well known for their use as
sedatives, myorelaxing agents, anticonvulsants and anxiolytics.1 Diazepam and clonazepam are
two examples that contain the 1,4-benzodiazepinone moiety (Figure 1).
O
H
N
O
N
N
O
N
O2N
N
Cl
NH
Cl
HO
Protein kinase C
modulator
Diazepam
Clonazepam
HCl
HO2C
.
HN
H
N
O
N
O
N
Lotrafiban (SB-214857)
Figure 1. Examples of bioactive 1,4-benzodiazepinones
 Corresponding author. Tel.: +054-221-424-3104; e-mail address: sasiamba@quimica.unlp.edu.ar (L. D.
Sasiambarrena, Ph. D.).

Although the pyrrolo-1,4-BDZ and 1,4-BDZ-2-ones were widely studied, the analogues 1,2,4,5-
tetrahydro-1,4-benzodiazepine-3-ones were less investigated. They have recently attracted
considerable attention due to their high AT2 receptor affinity and GPIIb/IIIa antagonistical
activity.2 Another known compound1with this skeleton is the antithrombotic Lotrafiban (SB-
214857).3 Also, these heterocycles, have been described as a protein kinase C modulator4 and as
γ-turn mimetics.5
A number of synthetic approaches to 1,4-BDZ-3-ones have appeared during the last decade, the
intramolecular cyclization of the heterocyclic ring is the key step. This particular reaction has
been reported to take place by intramolecular nucleophilic aromatic substitution2a,5-6 as well as
the addition of Grignard reagents to 2-aminobenzonitriles7 or intramolecular 1,3-dipolar
cycloadditions.8 Other methods include retro-Michael amidation,3b palladium-catalyzed N-
arylation,9 cascade coupling/condensation process of 2-bromobenzylamines with aminoacids10
and Ullmann’s aryl amination.11 Also cyclization processes involving an Ugi reaction as a first
step have been reported recently.12
As part of our ongoing efforts in the synthesis of biologically active heterocycles,13 and due the
interest that these substances have for us as potential antiepileptic agents, we designed and
developed a simple method, that requires the use of inexpensive reagents and mild reaction
conditions, to afford the corresponding N-substituted 1,4-benzodiazepinones in good yields.
This method involves the synthesis of novel N-substituted 2-chloro-N-(2-
nitrobencyl)acetamides 3 as cyclization reactants. In a second step, the chloroacetamides
undertake intramolecular cyclization by the use of iron and ammonium chloride in ethanol-
water to afford the desired 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones 5.
Results and discussion
The synthesis of these novel chloroacetamides is described in Scheme 1.
O
1) NH2R, EtOH, r.t.
2) NaBH4, 0 °C
NO2
N
NO2
Cl
NO2
NHR
Cl
2 h-24 h
CHO
TEA, toluene
reflux
2
3
1
R
Cl
2 h-24 h
O
Scheme 1. N-substitutes 2-chloro-N-(2-nitrobenzyl)acetamides two step synthesis.
At first step, N-substituted N-(2-nitrobenzyl)amines 2 were prepared by reductive amination of
o-nitrobenzaldehyde 1 using a standard method and NaBH4 as a reduction agent.14 2-
Nitrobenzylamines (2) were obtained in good yields and subsequently underwent amidation
with chloroacetyl chloride in toluene at reflux to afford the chloroacetamides 3. Due to the slow
rotation around the N-CO bond, these compounds exist in CDCl3 solution as a mixture of Z/E
rotamers that were detected by 1H-NMR and 13C-NMR.
As shown in Table 1 the desired products were obtained in good yields after 2 hours when the
N-substituent was alkyl or aralkyl. They required longer reaction times when R was aryl due to
the less nucleophilic nitrogen of the aryl group.

Table 1 Synthesis of 2-chloro-N-(2-nitrobenzyl)acetamides
O
NO2
N
Cl
NO2
NHR
Cl
TEA, toluene
110 °C
2
3
R
Cl
2 h-24 h
O
Entry
1
2
3
4
R
Me
Et
Pr
i-Pr
Product
Time (h)
mp (°C)
78-79
oil
81-83
oil
Yield (%)
65
3a
3b
3c
3d
3e
3f
2
2
2
2
2
79
72
82
83
5
6
n-Bu
Bn
oil
oil
2
77
7
8
9
10
11
12
13
4-fluorobenzyl
2-phenylethyl
phenyl
4-bromophenyl
4-methylphenyl
2-chlorophenyl
2-fluorophenyl
3g
3h
3i
3j
3k
3l
2
2
oil
oil
75
85
88
82
76
75
89
24
24
24
24
24
78-80
101-102
oil
93-95
94-96
3m
Reaction conditions: 2 (3.0 mmol), chloroacetyl chloride (3.0 mmol), TEA (3.0 mmol), toluene 10 ml, 110 °C
Having obtained the corresponding chloroacetamides we proposed an annulation process to
synthesize the novel 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones heterocycles. A reductive
cyclization reaction may take place, the –NO2 group of 3 is first reduced by iron to obtain 2-
chloro-N-(2-aminobenzyl)acetamides 4 that could undergo an intramolecular SN2 reaction to
afford 5 in a one-pot process of two steps (Scheme 2).
H
Fe, NH4Cl
EtOH-H2O
NO2
N
NH2
N
N
- HCl
O
N
3
4
5
R
R
Cl
R
Cl
O
O
Scheme 2. One-pot reductive cyclization process for the synthesis of 1,2,4,5-tetrahydro-1,4-
benzodiazepine-3-ones 5
After evaluating different reductive agents and reactions conditions15 the final target molecules
(1,4-BDZ-3-ones 5) were synthesized by reaction of 3 with iron dust and ammonium chloride in
a mixture of ethanol and water at reflux.16
The cyclization reactions afforded the desired products in good yields.17 The best results were
obtained when substrates with R = alkyl or aralkyl were used after refluxing the reaction
mixture for 2-6 h (Table 2). When substrates with R = aryl were subjected to reaction it was
possible to isolate and identified the intermediate 4 in some examples. This behavior must be
due steric effects since annulation rate process is slower for these substrates. However, after

longer reaction times the transformation of 4 into 1,4-BDZ-3-ones 5 was achieved. The novel
1,4-BDZ-3-ones were fully characterized by elemental analysis, 1H-NMR and 13C-NMR.
Table 2. Synthesis of 4-substituted 1,2,4,5-tetrahydro-1,4-benzodiazepine-3-ones 5
H
NO2
N
Fe, NH4Cl
EtOH-H2O
O
N
N
reflux
2 h-24 h
R
R
Cl
3
5
O
Entry
1
R
Product
Time (h)
mp (°C)
138-139
Yield (%)
68
H
N
O
O
Me
6
2
6
N
5a
H
N
2
3
Et
Pr
184-185
122-124
65
55
N
5b
H
N
O
N
5c
H
N
O
4
5
i-Pr
2
6
90-91
84-86
77
70
N
5d
H
N
O
n-Bu
N
5e
H
N
O
6
7
Bn
6
2
165-166
135-136
67
67
N
5f
H
N
O
4-fluorobenzyl
N
F
5g
H
N
O
N
8
9
2-phenylethyl
phenyl
6
2
2
147-148
156-158
178-180
69
39
30
5h
H
N
O
N
5i
H
N
O
N
10
4-bromophenyl
5j
Br
H
N
O
N
11
4-methylphenyl
24
175-176
42
5k
H
N
O
N
12
13
2-chlorophenyl
2-fluorophenyl
24
24
152-154
152-153
40
38
5l
Cl
H
N
O
N
F

Conclusions
In conclusion, we have developed a facile and efficient synthesis of new 4-substituted 1,2,4,5-
tetrahydro-1,4-benzodiazepine-3-ones in good yields by reductive cyclization of novel N-
substituted 2-chloro-N-(2-nitrobencyl)acetamides under mild reaction conditions. Efforts to
evaluate the affinity of 1,4-BDZ-3-ones to the BDZ-bs of GABAA by radioligand assays and the
corresponding in vivo experiments are currently initiated with the invaluable aid of specialized
partners.18
Acknowledgments
This work was generously supported by funds provided by Universidad Nacional de La Plata,
Argentina (Proyecto I+D 11X/763, PPID X015 and PPID X029) and CIC (Comisión de
Investigaciones Científicas, Provincia de Buenos Aires, Argentina). Authors wish to thank
Comisión de Investigaciones Científicas de la Provincia de Buenos Aires (CICPBA), UNLP and
CONICET for their active support to the present work. We express deep thanks to Lic. Omar E.
Guaymás (CICPBA) for assistance in the preparation and characterization of some compounds
and other valuable advice.
References and notes
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(17) Compounds 5, general procedure: compound 3 (1 mmol) was dissolved in ethanol (10 ml) and 560 mg (10
mmol) of iron dust was added at room temperature. The mixture was heated at 80 °C and 540 mg of
ammonium chloride in 5 ml of water were added dropwise. The reaction was monitored by TLC (CH2Cl2) until
it was complete, cooled, filtered through celite and concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 (20 ml) washed with water (10 ml), dried (Na2SO4) and the solvent evaporated to afford
crude benzodiazepinone 5 as a white solid which was purified by recrystallization from ethanol or column
chromatography (CH2Cl2).
4-Methyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5a)
C10H12N2O; found C, 68.27; H, 6.80; N, 15.92%; requires C, 68.16; H, 6.86; N, 15.90; O, 9.08%. 1H NMR (600
MHz, Chloroform-d): δ 7.07 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 6.54 (d, J =
8.0 Hz, 1H), 4.51 (s, 2H), 4.13 (s, 2H), 3.78 (s br, 1H), 3.07 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 169.87,
145.75, 129.77, 129.38, 119.47, 117.84, 116.72, 53.93, 49.25, 34.50.
4-Ethyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5b)
C11H14N2O; found C, 69.38; H, 7.44; N, 14.75%; requires C, 69.45; H, 7.42; N, 14.73; O, 8.41%. 1H NMR (600
MHz, Chloroform-d) δ 7.06 (t, J = 7.7 Hz, 1H), 6.91 (d, J = 7.5 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 6.53 (d, J =
8.1 Hz, 1H), 4.52 (s, 2H), 4.17 (s br, 1H), 4.12 (s, 2H), 3.53 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 169.31, 145.78, 129.55, 129.25, 120.28, 117.99, 116.72, 51.74, 49.49, 42.16, 13.57.
4-Propyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5c)
C12H16N2O; found C, 70.62; H, 8.00; N, 13.73%; requires C, 70.56; H, 7.90; N, 13.71; O, 7.83%. 1H NMR (600
MHz, Chloroform-d) δ 7.05 (t, J = 7.1 Hz, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.62 (t, J = 7.4 Hz, 1H), 6.52 (d, J =
8.0 Hz, 1H), 4.52 (s, 2H), 4.20 (s, 1H), 4.13 (d, J = 5.3 Hz, 2H), 3.47 – 3.41 (m, 2H), 1.55 (h, J = 7.4 Hz, 2H),
0.84 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 169.66, 145.76, 129.60, 129.23, 120.11, 117.91,
116.66, 52.23, 49.44, 49.05, 21.65, 11.35.
4-Isopropyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5d)
C12H16N2O; found C, 70.58; H, 8.05; N, 13.60%; requires C, 70.56; H, 7.90; N, 13.71; O, 7.83%. 1H NMR (600
MHz, Chloroform-d) δ 7.07 – 7.00 (m, 1H), 6.91 (d, J = 7.3 Hz, 1H), 6.61 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 8.0
Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 4.87 (hept, J = 6.8 Hz, 1H), 4.46 (s, 2H), 4.18 (s br, 1H), 4.13 (s, 2H), 1.12
(d, J = 6.8 Hz, 6H). 13C NMR (151 MHz, CDCl3) δ 169.36, 145.77, 129.39, 128.95, 120.64, 117.89, 116.51,
49.54, 45.16, 44.62, 20.48.
4-Butyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5e)
C13H18N2O; found C, 69.38; H, 7.44; N, 14.75%; requires C, 71.53; H, 8.31; N, 12.83; O, 7.33%. 1H NMR (600
MHz, Chloroform-d) δ 7.08 – 7.03 (m, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 6.52 (d, J = 8.0
Hz, 1H), 4.51 (s, 2H), 4.20 (s br, 1H), 4.12 (d, J = 4.7 Hz, 2H), 3.48 (t, J = 7.4 Hz, 2H), 1.54 – 1.47 (m, 2H),
1.26 (h, J = 7.4 Hz, 2H), 0.87 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz, CDCl3) δ 169.60, 145.78, 129.58,
129.23, 120.14, 117.92, 116.67, 52.15, 49.47, 47.11, 30.46, 20.09, 13.89.
4-Bencyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5f)
C16H16N2O; found C, 76.10; H, 6.48; N, 11.25%; requires C, 76.16; H, 6.39; N, 11.10; O, 6.34%. 1H NMR (600
MHz, Chloroform-d) δ 7.36 – 7.31 (m, 2H), 7.31 – 7.25 (m, 3H), 7.08 (td, J = 7.7, 1.6 Hz, 1H), 6.75 (dd, J =
7.5, 1.5 Hz, 1H), 6.63 – 6.55 (m, 2H), 4.71 (s, 2H), 4.47 (s, 2H), 4.31 (s br, 1H), 4.24 (d, J = 5.3 Hz, 2H). 13
C
NMR (151 MHz, CDCl3) δ 170.00, 145.76, 137.07, 129.78, 129.24, 128.70, 128.17, 127.59, 119.61, 117.90,
116.64, 51.08, 49.85, 49.37.
4-(4-Fluorobencyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5g)
C16H15FN2O; found C, 71.13; H, 5.66; N, 10.20%; requires C, 71.10; H, 5.59; F, 7.03; N, 10.36; O, 5.92. H
1
NMR (600 MHz, Chloroform-d) δ 7.21 (dd, J = 8.4, 5.5 Hz, 2H), 7.05 (td, J = 7.7, 1.6 Hz, 1H), 6.97 (t, J = 8.6
Hz, 2H), 6.70 (dd, J = 7.5, 1.5 Hz, 1H), 6.60 – 6.55 (m, 1H), 6.54 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 4.44 (s, 2H),
4.20 (s, 2H), 4.18 (s br, 1H). 13C NMR (151 MHz, CDCl3) δ 170.00, 163.16, 161.53, 145.70, 132.94, 132.92,
129.89, 129.84, 129.74, 129.33, 119.67, 118.10, 116.72, 115.64, 115.50, 51.20, 49.45, 49.38.
4-(2-Phenylethyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5h)
C17H18N2O; found C, 76.60; H, 6.85; N, 10.40%; requires C, 76.66; H, 6.81; N, 10.52; O, 6.01%. 1H NMR (600
MHz, Chloroform-d) δ 7.28 (dd, J = 8.0, 6.7 Hz, 2H), 7.24 – 7.19 (m, 1H), 7.20 – 7.16 (m, 2H), 7.08 (td, J =
7.7, 1.6 Hz, 1H), 6.84 (dd, J = 7.6, 1.5 Hz, 1H), 6.64 (td, J = 7.4, 1.2 Hz, 1H), 6.54 (dd, J = 8.0, 1.1 Hz, 1H),
4.45 (s, 2H), 4.18 (s br, 1H), 4.12 (d, J = 3.6 Hz, 2H), 3.79 – 3.72 (m, 2H), 2.87 (dd, J = 8.3, 6.7 Hz, 2H). 13
C
NMR (151 MHz, CDCl3) δ 169.62, 145.74, 138.95, 129.61, 129.24, 128.89, 128.56, 126.47, 120.05, 118.01,
116.72, 53.01, 49.63, 49.41, 34.83.
4-Phenyl-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5i)
C15H14N2O; found C, 75.50; H, 6.03; N, 11.76%; requires C, 75.61; H, 5.92; N, 11.76; O, 6.71%. 1H NMR (600
MHz, Chloroform-d) δ 7.38 (dd, J = 8.5, 7.2 Hz, 2H), 7.30 – 7.25 (m, 3H), 7.13 (td, J = 7.7, 1.6 Hz, 1H), 6.94
(dd, J = 7.5, 1.5 Hz, 1H), 6.69 (td, J = 7.4, 1.1 Hz, 1H), 6.61 (dd, J = 8.1, 1.1 Hz, 1H), 4.98 (s, 2H), 4.33 (s,
3H). 13C NMR (151 MHz, CDCl3) δ 169.19, 145.65, 143.02, 129.70, 129.49, 129.21, 126.89, 126.03, 119.98,
118.16, 116.79, 55.60, 49.81.
4-(4-Bromophenyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5j)
C15H13BrN2O; found C, 56.87; H, 4.02; N, 8.90%; requires C, 56.80; H, 4.13; Br, 25.19; N, 8.83; O, 6.24%. 1H
NMR (600 MHz, Chloroform-d) δ 7.50 – 7.44 (m, 2H), 7.17 – 7.08 (m, 3H), 6.90 (dd, J = 7.5, 1.6 Hz, 1H),

6.67 (td, J = 7.4, 1.2 Hz, 1H), 6.58 (dd, J = 8.1, 1.2 Hz, 1H), 4.92 (s, 2H), 4.29 (s br, 3H). 13C NMR (151 MHz,
CDCl3) δ 169.14, 145.56, 141.93, 132.29, 129.65, 129.63, 127.68, 120.29, 119.63, 118.30, 116.85, 55.47,
49.72.
4-(4-Methylphenyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5k)
C16H16N2O; found C, 76.01; H, 6.45; N, 11.29%; requires C, 76.16; H, 6.39; N, 11.10; O, 6.34%. 1H NMR (600
MHz, Chloroform-d) δ 7.20 – 7.07 (m, 5H), 6.89 (d, J = 7.4 Hz, 1H), 6.66 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 8.0
Hz, 1H), 4.92 (s, 2H), 4.32 – 4.24 (m, 3H), 2.34 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 169.17, 145.54,
140.36, 136.68, 130.21, 129.89, 129.75, 129.61, 129.35, 125.80, 119.99, 118.05, 116.69, 114.27, 55.59, 49.70,
21.06.
4-(2-Chlorophenyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5l)
C15H13ClN2O; found C, 66.21; H, 4.77; N, 10.41%; requires C, 66.06; H, 4.80; Cl, 13.00; N, 10.27; O, 5.87%.
1H NMR (500 MHz, Chloroform-d) δ 8.71 (s, 1H), 7.35 (dd, J = 7.9, 1.6 Hz, 1H), 7.32 – 7.22 (m, 3H), 7.16 (td,
J = 7.7, 1.6 Hz, 1H), 7.11 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 7.9 Hz, 1H), 6.97 (td, J = 7.6, 1.5 Hz, 1H), 4.44 (s,
2H), 4.08 (s, 2H). 13C NMR (126 MHz, CDCl3) δ 172.62, 147.47, 137.24, 130.91, 130.49, 129.09, 128.82,
128.57, 127.88, 125.26, 124.65, 122.63, 120.39, 57.49, 55.03.
4-(2-Fluorophenyl)-1,2,4,5-tetrahydro-1,4-benzodiazepine-3-one (5m)
C15H13FN2O; found C, 70.53; H, 5.16; N, 10.99%; requires C, 70.30; H, 5.11; F, 7.41; N, 10.93; O, 6.24%. 1H
NMR (600 MHz, Chloroform-d) δ 7.28 – 7.23 (m, 1H), 7.19 (t, J = 7.7 Hz, 1H), 7.14 – 7.06 (m, 3H), 6.84 (d, J
= 7.5 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 4.86 (s, 2H), 4.33 – 4.22 (m, 3H). 13C NMR
(151 MHz, CDCl3) δ 169.41, 158.21, 156.55, 145.61, 129.85, 129.51, 129.11, 128.91, 124.70, 119.89, 118.26,
116.94, 116.73, 55.48, 49.44.
(18) (a) Duarte, F. S.; Marder, M.; Hoeller, A. A.; Duzzioni, M.; Mendes, B. G.; Pizzolatti, M.G.; De Lima, T. C.
M. Psychopharmacology 2008, 197, 351. (b) Villalba, M. L.; Enrique, A. V.; Higgs, J.; Castaño,
R. A.; Goicoechea, S.; Taborda, F. D.; Gavernet, L.; Lick, I. D.; Marder, M.; Bruno Blanch, L. E. Eur. J.
Pharmacol. 2016, 774, 55. (c) Loscalzo, L. M.; Wasowski, C.; Paladini, A. C.; Marder, M. Eur. J. Pharmacol.
2008, 580, 306. (d) Wasowski, A.; Gavernet, L.; Barrios, I. A.; Villalba, M. L.; Pastore, V.; Samaja, G.;
Enrique, A.; Bruno-Blanch, L. E.; Marder, M. Biochem. Pharmacol. 2012, 83, 253.
Fe, NH4Cl
H
NO2
N
EtOH-H2O
N
O
N
2 steps, one pot process
R
30-77% yields
R
Cl
O
R= alkyl, aryl, 2-phenylethyl

 N-Substituted N-(2-nitrobenzyl)amines were prepared from o-nitrobenzaldehyde
 2-Chloro-N-(2-nitrobenzyl)acetamides exist as a two rotamers mixture in solution
 Reductive Cyclization provides an easy method to achieve 1,4-benzodiazepinones
 New 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones were prepared and characterized