Synthesis of novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-disubstituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones derivatives via regioselective thionation and nucleophilic substitutions reactions

Article abstract of DOI:10.1016/j.tet.2013.04.089

An efficient synthesis leading to novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-disubstituted 3H-pyrido[2,3-e][1,4] diazepin-5-ones derivatives is presented, using the condensation of ethyl 2-(benzylamino)acetate or ethyl 2-(4-methoxybenzylamino)acetate with 1H-pyrido[3,2-d][1,3]oxazine-2,4-diones and 1H-pyrido[2,3-d][1,3]oxazine-2,4- diones. This synthesis gives 4-substituted 3-hydro-1H-pyrido[3,2-e][1,4] diazepine-2,5-diones and 4-benzyl-3,4-dihydro-1H-pyrido[2,3-e][1,4]diazepine-2, 5-diones in good yields. Finally, after a regioselective thionation and nucleophilic substitutions reactions, various bis-functionalized 1,4-diazepines were easily obtained in excellent yields. These results open an access way to a library of novel bis-functionalized pyrido-1,4-diazepines.

Full text of DOI:10.1016/j.tet.2013.04.089

Accepted Manuscript
Synthesis of novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-
disubstituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones derivatives via regioselective
thionation and nucleophilic substitutions reactions
Abderrahman El Bouakher, Gildas Prié, Mina Aadil, Mohamed Akssira, Marie-Claude
Viaud-Massuard
PII:
S0040-4020(13)00649-2
10.1016/j.tet.2013.04.089
TET 24289
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 March 2013
Revised Date: 16 April 2013
Accepted Date: 18 April 2013
Please cite this article as: El Bouakher A, Prié G, Aadil M, Akssira M, Viaud-Massuard M-C, Synthesis
of novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-disubstituted 3H-pyrido[2,3-e]
[1,4]diazepin-5-ones derivatives via regioselective thionation and nucleophilic substitutions reactions,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.04.089.
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Synthesis of novel 2,4-disubstituted 3H-pyrido[3,2-e] Leave this area blank for abstract info.
[1,4]diazepin-5-ones and 2,4-disubstituted 3H-
pyrido[2,3-e][1,4]diazepin-5-ones derivatives via
regioselective thionation and nucleophilic
substitutions reactions
Abderrahman El Bouakher a, b, Gildas Prié a, Mina Aadil b, Mohamed Akssira b, *, Marie-Claude
Viaud-Massuard a, *
aEA 6306 IMT, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, Université de Tours, 37200 Tours, France
bLaboratoire de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 20800 Mohammedia, Morocco

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-
disubstituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones derivatives via regioselective
thionation and nucleophilic substitutions reactions
Abderrahman El Bouakher a, b, Gildas Prié a, Mina Aadil b, Mohamed Akssira b, *, Marie-Claude Viaud-
Massuard a, *
a EA 6306 IMT, UFR des Sciences Pharmaceutiques, 31 Avenue Monge, Université de Tours, 37200 Tours, France
b Laboratoire de Chimie Bioorganique & Analytique, URAC 22, Université Hassan II Mohammedia-Casablanca, BP 146, 20800 Mohammedia, Morocco
ARTICLE INFO
ABSTRACT
An efficient synthesis leading to novel 2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones
and 2,4-disubstituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones derivatives is presented, using the
condensation of ethyl 2-(benzylamino)acetate or ethyl 2-(4-methoxybenzylamino)acetate with
1H-pyrido[3,2-d][1,3]oxazine-2,4-diones and 1H-pyrido[2,3-d][1,3]oxazine-2,4-diones. This
synthesis gives 4-substituted 3-hydro-1H-pyrido[3,2-e][1,4]diazepine-2,5-diones and 4-benzyl-
Article history:
Received
Received in revised form
Accepted
Available online
3,4-dihydro-1H-pyrido[2,3-e][1,4]diazepine-2,5-diones in good yields. Finally, after
a
Keywords:
Azaisatoïc anhydride
Regioselective thionation
Nucleophilic substitution
regioselective thionation and nucleophilic substitutions reactions, various bis-functionalized
1,4-diazepines were easily obtained in excellent yields. These results open an access way to a
library of novel bis-functionalized pyrido-1,4-diazepines.
2,4-Disubstituted 3H-pyrido[3,2-e] [1,4]diazepin-5-
ones
2009 Elsevier Ltd. All rights reserved.
2,4-Disubstituted 3H-pyrido[2,3-e] [1,4]diazepin-5-
ones
1. Introduction
There have also been several reports of benzodiazepines as
potential anticancer agents,7 including BMS-214662,7a a known
farnesyltransferase (FTase) inhibitor, and Bz-423 V7b (Figure
1,4-Benzodiazepines are important biomolecules with a wide
array of biological activities and therapeutic uses. The
exploration of privileged structures in drug discovery is a
rapidly emerging theme in medicinal chemistry. The term
“privileged structure” was first coined by Evans et al. in 1988
and was defined as “a single molecular framework able to
provide ligands for diverse receptors”. This group noted the
ability of polyfunctionalized 1,4-benzodiazepin-2-ones to bind
to cholecystokinin family (CCKs) (e.g. I), gastrin, or central
benzodiazepine receptors.1 The benzodiazepine scaffold is also
found in neurokinin-1 antagonists, enzyme inhibitors such as
κ-secretase inhibitors (e.g. II) and farnesyl:protein transferase
inhibitors (e.g. III), as well as in ion channel ligands, such as
the delayed rectifier K+ current modulator (e.g. IV)2,3 (Figure 1).
1).
O
O
N
N
NH
O
NH
O
O
F
F
N
N
N
H
N
H
N
I
II
O
S
CO2H
N
HN
O
N
O
N
O
N
NH2
SH
N
H
F
Benzodiazepines are primarily known for their actions on the
central nervous system. In addition to their established
anxiolytic activities, 1,4-benzodiazepines also display
antibiotic,4 antimalarial,5 and anti-HIV6 activities.
N
III
IV
O
N
N
Cl
* Corresponding authors. Tel.: +212 523314705; fax: +212 52331 5353 (M. A.);
tel.: +33 24 736 7227; fax: +33 24 736 7229 (M.-C. V.-M.).
E-mail addresses: akssira@uh2m.ac.ma (M. Akssira), marie-claude.viaud-
massuard@univ-tours.fr (M.-C. Viaud-Massuard).
V
HO
Figure 1. Some polyfunctionalized 1,4-benzodiazepines.

ACCEPTED MANUSCRIPT
2
Tetrahedron
According to medicinal chemists, the true utility of privileged
structures is the ability to synthesize a library based upon a
particular core scaffold and screen it against a variety of
different receptors, yielding several active compounds. This was
illustrated by Bunin et al. using the benzodiazepine scaffold.
Thus, having developed various series of 1,4-benzodiazepin-2-
ones, they selected a small library of 192 molecules and screen
it against the cholecystokinin A receptor, yielding active
The starting compound in the first serie (compounds 6-16 and
17-19) was the 1H-pyrido[3,2-d][1,3]oxazine-2,4-dione 1,
which was obtained starting from the Boc protected
3-aminopyridine-2-carboxylic acid with good yields using an
excess of thionyl chloride in CH2Cl2 at reflux for 18 h.13 The
latter was synthesized from commercially available pyridine-
2,3-dicarboxylic acid.14
compounds.8 Therefore,
a
larger library of 1680
Compound 1 was then condensed with commercially available
1,4-benzodiazepin-2-ones was synthesized and screened against
a large number of receptor and enzyme targets. As a result,
inhibitors of pp60s-src tyrosine kinase and ligands that block an
autoimmune DNA-antibody interaction implicated in systemic
lupus erythematosus were identified.9
ethyl
2-(benzylamino)acetate
or
ethyl
2-(4-
methoxybenzylamino)acetate in DMF at reflux for 18 h in the
presence of Et3N yielding respectively compounds 4-benzyl-
3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepine-2,5-dione
4-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[3,2-e][1,4]
diazepine-2,5-dione 3 (75%, 70%).
2
and
Thus, intensive attempts have been made to discover new
synthetic routes to access this type of skeleton and to produce
modified ring systems with potential biological activities.10 In
particular, heterocycle-fused diazepine derivatives, such as the
pyridodiazepines, have exhibited anticonvulsant activities.11
Our ongoing research program looking for novel bioisosters of
1,4-benzodiazepines12 led us to develop a short and convenient
synthesis of 2,4-disubstituted 3H-pyrido[3,2-e] [1,4]diazepin-5-
ones 6-19 and 2,4-disubstituted 3H-pyrido[2,3-e][1,4]diazepin-
5-ones 23-24 derivatives (Figure 2). Moreover, these
compounds have become interesting targets for further
modifications aimed at preparing various fused or substituted
derivatives.
Subsequently, dilactam 2 or 3 was regioselectively thionated by
heating with Lawesson’s reagent in THF at 100 °C for 2 h. The
reaction mixture was then simply cooled to room temperature
and filtered to give pure monothiolactam 4 or 5 in excellent
yields (97%, 95%) (Scheme 1). The formation of dithiolactam
was not observed in the presence of a large excess of Lawesson
reagent or elongation of the reaction time. The highly
regioselective formation of monothiolactam may be due to
steric effect by the 4-(4-methoxybenzyl) or benzyl groups in
compounds 2, 3 or 21.
Finally, monothiolactam 4 or 5 was treated with various amines
in the presence of HgCl2 providing amidines 6-16 and 17-19 in
good yields 78%-98% (Table 1).
To prepare 23-24 regioisomers, we started from 2-amino
nicotinic acid, which was converted into 1H-pyrido[2,3-d]
[1,3]oxazine-2,4-dione 20 using ethyl chloroformate for 12 h in
toluene at 100 °C.15 Compound 20 was then condensed with
commercially available ethyl 2-(benzylamino)acetate in DMF at
reflux for 18 h in the presence of Et3N yielding 4-benzyl-3,4-
dihydro-1H-pyrido[2,3-e][1,4]diazepine-2,5-dione 21 in good
yield (70%). The dilactam 21 was subsequently converted to
monothiolactam 22 using Lawesson’s reagent by heating in
THF at 100 °C for 1 h. The reaction mixture was then simply
cooled to room temperature and filtered to give pure 22 in
excellent yield (98%) (Scheme 1). Finally, thiolactam 22 was
treated with morpholine or pyrrolidine in the presence of HgCl2
affording amidines 23 and 24 in good yields (80%, 90%) (Table
1).
Figure 2. Targeted structures.
2. Results and discussion
We present here an efficient and rapid synthesis of
2,4-disubtituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones 6-19 and
2,4-disubtituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones 23-24
derivatives.
Scheme 1. Reagents and conditions: (a) ethyl 2-(benzylamino)acetate or ethyl 2-(4-methoxybenzylamino)acetate (1.2 equiv), DMF/Et3N, reflux; 18 h; (b)
Lawesson’s reagent (1 equiv), THF, 100 °C, 2 h; (c) HgCl2 (1.2 equiv), amines (1.2 equiv), THF, reflux, 1 h.

ACCEPTED MANUSCRIPT
Table 1. Results of amination of compounds 4, 5 and 22.
Entry
product
yielda
Entry
product
yielda
Entry
product
yielda
Ph
OCH3
N
N
N
N
NH
N
N
1
89%
7
80%
90%
90%
85%
13
90%
N
N
6
N
N
N
N
O
O
O
12
18
Ph
N
O
F
S
N
N
NH
N
N
N
2
3
4
80%
85%
88%
8
14
15
16
85%
90%
80%
N
N
N
N
N
N
O
O
O
7
13
19
O
F
O
Cl
N
NH
O
N
N
N
9
N
N
N
N
N
N
O
O
N
14
8
23
Ph
N
O
N
NH
N
N
N
10
N
N
N
N
N
N
N
O
O
15
24
9
O
Ph
N
NH
N
N
NH
5
97%
11
78%
N
N
N
O
N
N
16
10
O
N
N
NH
N
6
85%
12
90%
N
N
N
N
O
17
O
11
O
a isolated yields after purification by column chromatography.

ACCEPTED MANUSCRIPT
4
Tetrahedron
4.3. General Procedure for the synthesis of compounds 4, 5
and 22.
3. Conclusion
In summary, we have described the synthesis of novel
2,4-disubstituted 3H-pyrido[3,2-e][1,4]diazepin-5-ones and 2,4-
disubstituted 3H-pyrido[2,3-e][1,4]diazepin-5-ones derivatives.
The reactions all employ commercial or readily-available starting
materials, and are performed under very simple experimental
conditions and straightforward work-up, which makes them
potentially useful for drug synthesis. This efficient strategy
should provide easy access to a range of 1,4-pyridodiazepine
alkaloids and their analogues.
Lawesson’s reagent (1.87 g, 4.62 mmol) was added to a
suspension of dilactam 2, 3, or 21 (4.62 mmol) in 100 mL of
THF. The mixture was heated at 100 °C for 2 h then the yellow
solid was filtered to yield pure 4, 5 or 22 in excellent yields.
4.3.1. 4-Benzyl-2-thioxo-3,4-dihydro-1H-pyrido[3,2-e][1,4]
diazepin-5(2H)-one (4). Yield 97%; m.p. 255 °C; νmax (neat)
3048, 3031, 1657, 1592, 1386 cm-1; 1H NMR (300 MHz, DMSO-
d6): δ = 4.20 (s, 2H), 4.73 (s, 2H), 7.28-7.40 (m, 5H), 7.60-7.64
(m, 1H), 7.68-7.71 (m, 1H), 8.60-8.62 (m, 1H), 12.60 (s, NH);
13C NMR (75 MHz, DMSO-d6): δ = 51.4, 57.3, 126.8, 128.0,
128.3 (2CH), 129.0 (2CH), 129.8, 135.1, 136.0, 143.7, 147.5,
164.7, 199.7; HRMS-FIA (m/z): [M+H]+ calcd for C15H13N3OS:
284.0852, found: 284.0830.
4. Experimental section
4.1. General
All reactions were carried out under an inert atmosphere. IR
spectra were recorded on a Bruker Alpha-T FT-IR spectrometer
1
(ATR platinum Diamond). H and 13C NMR were recorded on a
Bruker Avance DPX300 spectrometer (300 MHz 1H, 75 MHz
13C), the deuterated solvents indicated were used. For the
purification chromatography, silica gel (60-200 mesh) was used.
Thin layer chromatography (TLC) was carried out on Merck
silica gel 60F254 precoated plates. Melting points were
determined in open capillary tubes and are uncorrected. HRMS
were performed on a Thermo Q Exactive LC-MS HR/AM
Orbitrap. Commercial starting materials and dry solvents were
obtained and used as received. Chemicals products were obtained
from the following sources: Aldrich and Acros organics.
4-(4-Methoxybenzyl)-2-thioxo-3,4-dihydro-1H-pyrido
[3,2-e][1,4]diazepin-5(2H)-one (5). Yield 95%; m.p. 329 °C;
1
νmax (neat) 3047, 2994, 1661, 1511, 1240 cm-1; H NMR (300
MHz, DMSO-d6): δ = 3.74 (s, 3H), 4.17 (s, 2H), 4.89 (s, 2H),
6.93 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.59-7.63 (m,
1H), 7.67-7.70 (m, 1H), 8.59-8.61 (m, 1H), 12.57 (s, NH); 13C
NMR (75 MHz, DMSO-d6): δ = 50.7, 55.5, 56.9, 114.4 (2CH),
126.8, 128.9, 129.7, 129.9 (2CH), 135.0, 143.8, 147.5, 159.2,
164.5, 199.8; HRMS-FIA (m/z): [M+H]+ calcd for C16H15N3O2S:
314.0958, found: 314.0933.
4.2. General Procedure for the synthesis of compounds 3, 4
and 23
4-Benzyl-2-thioxo-3,4-dihydro-1H-pyrido[2,3-e][1,4]
diazepin-5(2H)-one (22). Yield 98%; m.p. 213 °C; νmax (neat)
A suspension of azaisatoic anhydride 1 or 20 14 (1 g, 6 mmol) and
1
3064, 2928, 1646, 1593, 1352, 1134 cm-1; H NMR (300 MHz,
ethyl
2-(benzylamino)acetate
or
ethyl
2-(4-
DMSO-d6): δ = 4.26 (s, 2H), 4.76 (s, 2H), 7.26-7.39 (m, 5H),
7.42-7.46 (m, 1H), 8.30-8.33 (m, 1H), 8.62-8.64 (m, 1H), 12.78
(s, NH); 13C NMR (75 MHz, DMSO-d6): δ = 51.6, 58.3, 121.9,
123.0, 128.0, 128.3 (2CH), 129.0 (2CH), 136.9, 141.5, 148.9,
152.3, 165.5, 200.3; HRMS-FIA (m/z): [M+H]+ calcd for
C15H13N3OS: 284.0852, found: 284.0830.
methoxybenzylamino)acetate (7.25 mmol) in 10 mL of DMF and
2 mL (14.8 mmol) of Et3N was heated to reflux for 18 h. The
solvent was evaporated, and the crude product was purified by
chromatography to give 2, 3 or 21.
4.2.1. 4-Benzyl-3,4-dihydro-1H-pyrido[3,2-e][1,4]diazepine-2,5-
dione (2). Yield 75%; m.p. 240 °C; νmax (neat) 3259 (br), 3076,
2916, 1694, 1634, 1447, 1118 cm-1; 1H NMR (300 MHz, DMSO-
d6): δ = 3.94 (s, 2H), 4.78 (s, 2H), 7.26-7.39 (m, 5H), 7.51-7.58
(m, 2H), 8.49-8.51 (m, 1H), 10.53 (s, NH); 13C NMR (75 MHz,
DMSO-d6): δ = 50.8, 51.8, 126.7, 127.9, 128.2 (2CH), 129.0
(2CH), 129.5, 134.9, 137.3, 143.0, 146.1, 165.3, 170.3; HRMS-
FIA (m/z): [M+H]+ calcd for C15H13N3O2: 268.1080, found:
268.1059.
4.4. General Procedure for the synthesis of compounds 6-19
and 23-24
A suspension of 4, 5 or 22 (0.28 mmol) and mercuric chloride
(0.9 g, 0.34 mmol) in dry THF (5 mL) was heated to 100 °C and
an amine (0.34 mmol) was added. After 1 h, the solution became
black (formation of mercuric sulfide). The reaction mixture was
filtered through Celite and then washed with methanol. The
filtrate was then concentrated, and the crude product was purified
by chromatography (DCM/MeOH 96/4) to give respectively 6-
16, 17-19 or 24-25.
4.2.2.4-(4-Methoxybenzyl)-3,4-dihydro-1H-pyrido[3,2-e][1,4]
diazepine-2,5-dione (3). Yield 70%; m.p. 213 °C; νmax (neat)
1
3076, 2902, 2837, 1701, 1642, 1232 cm-1; H NMR (300 MHz,
DMSO-d6): δ = 3.74 (s, 3H), 3.89 (s, 2H), 4.69 (s, 2H), 6.90 (d, J
= 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H), 7.5-7.56 (m, 2H), 8.49-
8.50 (m, 1H), 10.48 (s, NH); 13C NMR (75 MHz, DMSO-d6): δ =
50.5, 51.1, 55.5, 114.4 (2CH), 126.6, 129.3, 129.4, 129.8 (2CH),
134.9, 142.7, 145.0, 159.1, 165.2, 170.3; HRMS-FIA (m/z):
[M+H]+ calcd for C16H15N3O3: 298.1186, found: 298.1163.
4.4.1. 4-Benzyl-2-(pyrrolidin-1-yl)-3H-pyrido[3,2-e][1,4]
diazepin-5(4H)-one (6). Yield 89%; m.p. 216 °C; νmax (neat)
1
2978, 2959, 2871, 1631, 1595, 1570 cm-1; H NMR (300 MHz,
CDCl3): δ = 1.72-1.82 (m, 4H), 3.05 (s, 2H), 3.45-3.52 (m, 2H),
3.91 (s, 2H), 4.97 (s, 2H), 7.27-7.38 (m, 6H), 7.48-7.52 (m, 1H),
8.45-8.47 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 24.5, 25.7,
44.3, 47.6, 51.6, 126.1, 127.7 (2CH), 127.9, 128.8 (2CH), 135.1,
142.0, 144.1, 145.0, 157.0, 167.3; HRMS-FIA (m/z): [M+H]+
calcd for C19H20N4O: 321.1701, found: 321.1684.
4.2.3. 4-Benzyl-3,4-dihydro-1H-pyrido[2,3-e][1,4]diazepine-2,5-
dione (21). Yield 70%; m.p. 180 °C; 1H NMR (300 MHz,
CDCl3): δ = 3.90 (s, 2H), 4.88 (s, 2H), 7.28-7.31 (m, 1H), 7.34-
7.40 (m, 5H), 8.43-8.46 (m, 1H), 8.60 (d, J = 3.1 Hz, 1H), 9.06
(s, NH); 13C NMR (75 MHz, CDCl3): δ = 50.2, 52.1, 120.4,
128.2, 128.4 (2CH), 128.6, 128.9 (2CH), 135.8, 141.8, 148.2,
152.0, 169.1, 176.2; HRMS-FIA (m/z): [M+H]+ calcd for
C15H13N3O2: 268.1080, found: 268.1059.
4.4.2. 4-Benzyl-2-thiomorpholino-3H-pyrido[3,2-e][1,4]
diazepin-5(4H)-one (7). Yield 80%; m.p. 231 °C; νmax (neat)
1
3020, 2967, 2914, 2845, 1640, 1567, 1414 cm-1; H NMR (300
MHz, CDCl3): δ = 2.57 (s, 4H), 3.71 (s, 4H), 3.88 (s, 2H), 4.78
(bs, 1H), 4.98 (bs, 1H), 7.28-7.40 (m, 6H), 7.44-7.47 (m, 1H),

ACCEPTED MANUSCRIPT
8.50-8.52 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 27.2, 40.7,
48.1, 51.1, 125.9, 128.0 (2CH), 128.1, 128.9 (2CH), 134.9,
135.1, 142.4, 144.5, 144.7, 157.3, 167.1; HRMS-FIA (m/z):
[M+H]+ calcd for C19H20N4OS: 353.1431, found: 353.1402.
CDCl3): δ = 44.9, 46.7, 51.6, 114.1, 114.3, 114.7, 115.0, 123.5,
123.5, 125.9, 127.8, 128.3 (2CH), 128.7 (2CH), 129.9, 130.0,
135.1, 136.4, 140.5, 140.6, 142.7, 144.0, 145.2, 157.5, 161.2,
164.4, 166.9; HRMS-FIA (m/z): [M+H]+ calcd for C22H19FN4O:
375.1616, found: 375.1585.
4.4.3. 4-Benzyl-2-morpholino-3H-pyrido[3,2-e][1,4]diazepin-
5(4H)-one (8). Yield 85%; m.p. 227 °C; νmax (neat) 2957, 2856,
4-Benzyl-2-(2-chloro-3-fluorobenzylamino)-3H-pyrido[3,2-
1
1631, 1594, 1569 cm-1; H NMR (300 MHz, CDCl3): δ = 3.43-
e][1,4]diazepin-5(4H)-one (14). Yield 90%; m.p. 163 °C; νmax
1
3.56 (m, 8H), 3.88 (s, 2H), 4.91 (s, 2H), 7.28-7.41 (m, 6H), 7.49
(d, J = 8.2 Hz, 1H), 8.52 (d, J = 3.1Hz, 1H); 13C NMR (75 MHz,
CDCl3): δ = 40.8, 45.5 (2CH2), 51.3, 66.3, 125.9, 127.9 (2CH),
128.1, 129.0 (2CH), 134.9, 136.3, 142.4, 144.6, 144.7, 158.0,
167.1; HRMS-FIA (m/z): [M+H]+ calcd for C19H20N4O:
337.1659, found: 337.1631.
(neat) 3282 (br), 3063, 3028, 2919, 1617, 1210, 715 cm-1; H
NMR (300 MHz, CDCl3): δ = 3.72 (s, 2H), 4.54 (s, 2H), 4.82 (s,
2H), 5.71 (s, NH), 7.17-7.37 (m, 9H), 7.49 (d, J = 8.1 Hz, 1H),
8.35 (d, J = 3.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): δ = 43.2,
45.7, 51.5, 125.8, 126.9, 127.9, 128.5 (2CH), 128.8 (2CH),
129.5, 130.4, 133.7, 135.2, 136.3, 142.9, 144.3, 145.1, 157.0,
166.5; HRMS-FIA (m/z): [M+H]+ calcd for C22H18ClFN4O:
409.1226, found: 391.1289; MS (IS): m/z 409 (M+H).
4.4.4. 4-Benzyl-2-(4-phenylpiperazin-1-yl)-3H-pyrido[3,2-e]
[1,4]diazepin-5(4H)-one (9). Yield 88%; m.p. 199 °C; νmax (neat)
1
2977, 2959, 2871, 1628, 1592, 1568 cm-1; H NMR (300 MHz,
4.4.9. 4-Benzyl-2-(phenethylamino)-3H-pyrido[3,2-e][1,4]
CDCl3): δ = 3.11 (s, 4H), 3.64 (s, 4H), 3.95 (s, 2H), 4.93 (s, 2H),
6.91-6.96 (m, 3H), 7.28-7.41 (m, 8H), 7.51-7.54 (m, 1H), 8.52-
8.54 (m, 1H); 13C NMR (75 MHz, CDCl3): δ = 40.9, 46.8 (2CH2),
49.1, 49.2, 51.2, 116.6 (2CH), 120.7, 126.0, 128.0 (2CH), 128.1,
129.0 (2CH), 129.3 (2CH), 134.9, 136.3, 142.4, 144.6, 144.7,
150.6, 157.8, 167.2; HRMS-FIA (m/z): [M+H]+ calcd for
C25H25N5O: 412.2132, found: 412.2100.
diazepin-5(4H)-one (15). Yield 85%; m.p. 203 °C; νmax (neat)
1
3253 (br), 3063, 3027, 2944, 1636, 1611, 1579 cm-1; H NMR
(300 MHz, CDCl3): δ = 2.75-2.80 (m, 2H), 3.48-3.53 (m, 2H),
3.62 (s, 2H), 4.77 (s, 2H), 5.25 (s, NH), 7.14-7.17 (m, 2H), 7.25-
7.36 (m, 9H), 7.48-7.51 (m, 1H), 8.39-8.41 (m, 1H); 13C NMR
(75 MHz, CDCl3): δ = 34.6, 42.6, 46.7, 51.3, 125.8, 126.5, 127.9,
128.4, 128.5 (2CH), 128.6 (2CH), 128.7 (2CH), 128.7 (2CH),
134.8, 136.5, 138.8, 143.0, 144.2, 157.3, 166.8; HRMS-FIA
(m/z): [M+H]+ calcd for C23H22N4O: 371.1166, found: 371.1837.
4.4.5. 4-Benzyl-2-(4-benzylpiperazin-1-yl)-3H-pyrido[3,2-e]
[1,4]diazepin-5(4H)-one (10). Yield 97%; m.p. 157 °C; νmax
1
4.4.10. 2-(2-(1H-indol-2-yl)ethylamino)-4-benzyl-3H-pyrido
[3,2-e][1,4]diazepin-5(4H)-one (16). Yield 78%; m.p. 283 °C;
νmax (neat) 3270 (br), 3107, 1623, 1600, 1566 cm-1; 1H NMR (300
MHz, CDCl3): δ = 2.23-2.97 (m, 2H), 3.56 (d, J = 5.1 Hz, 2H),
3.78 (s, 2H), 4.24 (bs, 1H), 5.09 (bs, 1H), 6.97-7.10 (m, 2H), 7.17
(s, 1H), 7.31-7.41 (m, 8H), 7.59 (d, J = 7.4 Hz, 1H), 7.87 (s, 1H),
8.29 (s, 1H), 10.87 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 24.6,
41.9, 45.6, 51.1, 111.9, 112.2, 118.7, 121.4, 123.3, 126.1, 127.7,
127.9 (2CH), 128.9 (2CH), 134.4, 136.7, 137.8, 143.2, 143.5,
143.5, 145.8, 145.8, 158.8, 166.4; HRMS-FIA (m/z): [M+H]+
calcd for C25H23N5O: 410.9175, found: 410.1944.
(neat) 3030, 2930, 2800, 1631, 1594, 1567 cm-1; H NMR (300
MHz, CDCl3): δ = 2.4 (s, 4H), 3.46-3.98 (m, 8H), 4.61 (s, 1H),
5.18 (s, 1H), 7.28-7.38 (m, 11H), 7.43-7.47 (m, 1H), 8.48-8.50
(m, 1H); 13C NMR (75 MHz, CDCl3): δ = 40.6, 45.2, 51.0, 62.7,
125.9, 127.4, 128.0, 128.0 (2CH), 128.4 (2CH), 129.0 (2CH),
129.2 (2CH), 134.9, 136.3, 137.2, 142.4, 144.5, 157.7, 167.2;
HRMS-FIA (m/z): [M+H]+ calcd for C26H27N5O: 426.2288,
found: 426.2255.
4.4.6. 4-Benzyl-2-(benzylamino)-3H-pyrido[3,2-e][1,4]diazepin-
5(4H)-one (11). Yield 98%; m.p. 213 °C; νmax (neat) 3253 (br),
3030, 2947, 2936, 1606, 1556 cm-1; 1H NMR (300 MHz, CDCl3):
δ = 3.71 (s, 2H), 4.42 (s, 2H), 4.80 (s, 2H), 5.61 (s, NH), 7.19-
7.27 (m, 7H), 7.28-7.34 (m, 4H), 7.47-7.50 (m, 1H), 8.33-8.35
(m, 1H); 13C NMR (75 MHz, CDCl3): δ = 45.6, 46.8, 51.5, 125.9,
127.5, 127.9, 128.1 (2CH), 128.5 (2CH), 128.6 (2CH), 128.7
(2CH), 135.0, 137.7, 142.8, 144.2, 145.3, 157.3, 166.9; HRMS-
FIA (m/z): [M+H]+ calcd for C22H20N4O: 357.1710, found:
357.1681.
4.4.11. 4-(4-Methoxybenzyl)-2-(pyrrolidin-1-yl)-3H-pyrido[3,2-
e][1,4]diazepin-5(4H)-one (17). Yield 90%; m.p. 174 °C; νmax
1
(neat) 2990, 2968, 2882, 1595, 1561, 1511 cm-1; H NMR (300
MHz, CDCl3): δ = 1.82 (s, 4H), 3.13 (s, 2H), 3.48-3.56 (m, 2H),
3.81 (s, 3H), 3.90 (s, 2H), 4.90 (s, 2H), 6.87 (d, J = 8.4 Hz, 2H),
7.27 (d, J = 7.2 Hz, 2H), 7.40 (d, J = 3.3 Hz, 1H), 7.54 (d, J = 7.1
Hz, 1H), 8.45 (s, 1H); 13C NMR (75 MHz, CDCl3): δ = 24.5,
25.8, 44.0, 47.8, 51.0, 55.4, 114.2 (2CH), 126.28, 128.2, 129.2
(2CH), 135.5, 141.6, 144.1, 145.1, 157.0, 159.4, 167.4; HRMS-
FIA (m/z): [M+H]+ calcd for C20H22N4O2: 351.1815, found:
351.1792.
4.4.7. 4-Benzyl-2-(3-methoxybenzylamino)-3H-pyrido[3,2-e]
[1,4]diazepin-5(4H)-one (12). Yield 80%; m.p. 163 °C; 1H NMR
(300 MHz, CDCl3): δ = 3.64 (s, 2H), 3.83 (s, 3H), 4.48 (s, 2H),
4.86 (s, 2H), 5.14 (bs, NH), 6.87-6.96 (m, 2H), 7.21-7.29 (m,
4H), 7.30-7.36 (m, 4H), 7.51-7.54 (m, 1H), 8.44-8.45 (m, 1H);
13C NMR (75 MHz, CDCl3): δ = 41.3, 45.9, 51.4, 55.3, 110.4,
120.6, 125.4, 125.7, 127.9, 128.5 (2CH), 128.7 (2CH), 129.1,
129.1, 130.1, 134.8, 136.2, 143.0, 144.4, 150.9, 156.9, 157.5,
166.7; HRMS-FIA (m/z): [M+H]+ calcd for C23H22N4O2:
387.1815, found: 387.1786.
4.4.12. 4-(4-Methoxybenzyl)-2-(4-phenylpiperazin-1-yl)-3H-
pyrido[3,2-e][1,4]diazepin-5(4H)-one (18). Yield 98%; m.p. 257
°C; νmax (neat) 3006, 2891, 1629, 1597, 1574 cm-1; 1H NMR (300
MHz, CDCl3): δ = 3.13 (s, 4H), 3.69 (s, 4H), 3.76 (s, 3H), 4.01
(s, 2H), 4.83 (bs, 2H), 6.87-6.97 (m, 5H), 7.27-7.40 (m, 5H),
7.50-7.53 (m, 1H), 8.51-8.53 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ = 40.6 (2CH2), 45.3 (2CH2), 49.3, 50.5, 55.3, 114.4
(2CH), 116.6 (2CH), 118.7, 120.7, 125.9, 128.2, 129.3 (2CH),
129.3 (2CH), 134.8, 142.5, 144.5, 144.7, 150.7, 157.9, 159.5,
167.0; HRMS-FIA (m/z): [M+H]+ calcd for C26H27N5O2:
442.2237, found: 442.2205.
4.4.8. 4-Benzyl-2-(3-fluorobenzylamino)-3H-pyrido[3,2-e][1,4]
diazepin-5(4H)-one (13). Yield 90%; m.p. 199 °C; νmax (neat)
1
3252 (br), 2959, 2871, 1597, 1560, 1205 cm-1; H NMR (300
MHz, CDCl3): δ = 3.78 (s, 2H), 4.43 (s, 2H), 4.78 (s, 2H), 6.30
(s, NH), 6.91-6.99 (m, 3H), 7.17-7.22 (m, 6H), 7.28-7.32 (m,
1H), 7.45-7.48 (m, 1H), 8.29-8.30 (m, 1H); 13C NMR (75 MHz,

ACCEPTED MANUSCRIPT
6
Tetrahedron
4.4.13. 2-(4-Benzylpiperazin-1-yl)-4-(4-methoxybenzyl)-3H-
pyrido[3,2-e][1,4]diazepin-5(4H)-one (19). Yield 95%; m.p. 193
°C; νmax (neat) 3001, 2890, 2832, 1629, 1595, 1573 cm-1; 1H
NMR (300 MHz, CDCl3): δ = 2.45 (s, 4H), 3.45-3.57 (m, 6H),
3.83 (s, 3H), 4.48 (s, 2H), 4.48 (bs, 1H), 5.15 (bs, 1H), 6.88 (d, J
= 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 7.31-7.37 (m, 6H), 7.42-
7.45 (m, 1H), 8.48-8.50 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
= 40.3, 50.2 (2CH2), 52.6, 52.6 (2CH2), 55.4, 62.7, 114.4 (2CH),
125.8 (2CH), 127.5, 127.6, 128.3, 128.5 (2CH), 129.2, 129.4
(2CH), 134.8, 142.6, 144.5, 157.8, 159.4, 167.1; HRMS-FIA
(m/z): [M+H]+ calcd for C27H29N5O2: 456.2394, found: 456.2361.
4. Thuston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433–465.
5. Nallan, L.; Bauer, K. D.; Bendale, P.; Rivas, K.; Yokoyama, K.;
Hornéy, C. P.; Pendyala, P. R.; Floyd, D.; Lombardo, L. J.;
Williams, D. K.; Hamilton, A.; Sebti, S.; Windsor, W. T.; Weber,
P. C.; Buckner, F. S.; Chakrabarti, D.; Gelb, M. H.; Van Voorhis,
W. C. J. Med. Chem. 2005, 48, 3704–3713.
6. Kukla, M. J.; Breslin, H. J.; Diamond, C. J.; Grous, P. P.; Ho, C.
Y.; Miranda, M.; Rodgers, J. D.; Sherrill, R. G.; De Clercq, E.;
Pauwels, R.; Andries, K.; Moens, L. J.; Janssen, M. A. C.;
Janssen, P. A. J. J. Med. Chem. 1991, 34, 3187–3197.
7. (a) Hunt, J. T.; Ding, C. Z.; Batorsky, R.; Bednarz, M.; Bhide, R.;
Cho, Y.; Chong, S.; Chao, S.; Gullo-Brown, J.; Guo, P.; Kim, S.
H.; Lee, F. Y. F.; Leftheris, K.; Miller, A.; Mitt, T.; Patel, M.;
Penhallow, B. A.; Ricca, C.; Rose, W. C.; Schmidt, R.;
Slusarchyk, W. A.; Vite, G.; Manne, V. J. Med. Chem. 2000, 43,
3587–3595; (b) Sundberg, T. B.; Ney, G. M.; Subramanian, C.;
Opipari, A. W.; Glick, G. D. Cancer Res. 2006, 66, 1775–1782;
(c) Dourlat, J.; Liu, W.; Greash, N.; Garbay, C. Bioorg. Med.
Chem. Lett. 2007, 17, 2527–2530.
4-Benzyl-2-(pyrrolidin-1-yl)-3H-pyrido[2,3-e][1,4]diazepin-
5(4H)-one (23). Yield 90%; m.p. 170 °C; νmax (neat) 2967, 2875,
1
1639, 1596, 1560 cm-1; H NMR (300 MHz, CDCl3): δ = 1.67-
1.73 (m, 4H), 2.94 (s, 2H), 3.60 (s, 2H), 3.96 (s, 2H), 4.22 (s,
2H), 7.12-7.16 (m, 1H), 7.24-7.28 (m, 2H), 7.32-7.36 (m, 3H),
8.45-8.48 (m, 1H), 8.70-8.72 (m, 1H); 13C NMR (75 MHz,
CDCl3): δ = 24.2, 25.6, 45.3, 47.7, 48.4, 51.9, 117.6, 122.4, 127.6
(2CH), 128.1, 128.9 (2CH), 136.2, 142.6, 151.6, 156.9, 158.4,
167.2; HRMS-FIA (m/z): [M+H]+ calcd for C19H20N4O:
321.1710, found: 321.1687.
8. Bunin, B. A.; Plunkett, M. J.; Ellman, J. A. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 4708–4712.
9. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555-600.
10. Some review articles on the synthesis of 1, 4-benzodiazepines: (a)
Joshi, B.; Chauhan, M. Ind. J. Heterocycl. Chem. 1996, 6, 157–
164; (b) Walser, A.; Fryer, R. I. Chem. Heterocycl. Compd. 1991,
50, 431–543; (c) Walser, A.; Fryer, R. I. Chem. Heterocycl.
Compd. 1991, 50, 545–629; (d) Walser, A.; Fryer, R. I. Chem.
Heterocycl. Compd. 1991, 50, 631–848; (e) Walser, A.; Fryer, R.
I. Chem. Heterocycl. Compd. 1991, 50, 849–946; (f) Bunin, B. A.;
Plunkett, M. J. Methods Enzymol. 1996, 267, 448–465; (g) Van
den Bogaert, A. M.; Nelissen, J.; Ovaere, M.; Van Meervelt, L.;
Compernolle, F.; De Borggraeve, W. M. Eur. J. Org. Chem. 2010,
5397–5401; (h) Legerén, L.; Domínguez, D. Tetrahedron Lett.
2010, 51, 4053–4057; (i) Geng, B.; Basarab, G.; Comita-Prevoir,
J.; Gowravaram, M.; Hill, P.; Kiely, A.; Loch, J.; MacPherson, L.;
Morningstar, M.; Mullen, G.; Osimboni, E.; Satz, A.; Eyermann,
C.; Lundqvist T. Bioorg. Med. Chem. Lett. 2009, 19, 930–936; (j)
Correa, A.; Tellitu, I.; Dominguez, E.; Moreno, I.; Martin R. S. J.
Org. Chem. 2005, 70, 2256–2264; (k) Zhou, Y.; Li, J.; Ji, X.;
Zhou, W.; Zhang, X.; Qian, W.; Jiang, H.; Liu H. J. Org. Chem.
2011, 76, 1239–1249; (l) Buettelmann, B.; Ballard, T. M.; Gasser,
R.; Fischer, H.; Hernandez, M.-C.; Knoflach, F.; Knust, H.;
Stadler, H.; Thomas, A. W.; Trube, G. Bioorg. Med. Chem. Lett.
2009, 19, 5958–5961; (m) Spencer, J.; Rathnam, R. P.; Harvey,
A. L.; Clements, C. J.; Clark, R. L.; Barrett, M. P.; Wong, P. E.;
Male, L.; Coles, S. J.; Mackay, S. P. Bioorg. Med. Chem. 2011,
19, 1802–1815.
4.4.14. 4-Benzyl-2-morpholino-3H-pyrido[2,3-e][1,4]diazepin-
5(4H)-one (24). Yield 80%; m.p. 192 °C; νmax (neat) 3051, 2961,
1
2853, 1618, 1594, 1563 cm-1; H NMR (300 MHz, CDCl3): δ =
3.02-3.05 (m, 2H), 3.56-3.81 (m, 6H), 3.92 (s, 2H), 4.87 (s, 2H),
7.09-7.13 (m, 1H), 7.24-7.28 (m, 2H), 7.35-7.41 (m, 3H), 8.37-
8.41 (m, 1H), 8.61-8.63 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
= 41.6, 45.2, 51.5, 66.3, 118.1, 121.7, 127.8 (2CH), 128.2, 129.1
(2CH), 136.1, 140.8, 152.4, 158.0, 158.7, 167.8; HRMS-FIA
(m/z): [M+H]+ calcd for C19H20N4O2: 337.1659, found: 337.1633.
Acknowledgments
We gratefully acknowledge that this work was funded by the
Moroccan Ministry of Education, CNRST, through project
URAC 22, and RePAM, through a Doctoral Grant. We are
grateful to Monika Ghosh for the translation assistance.
References
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2, 949–957.

ACCEPTED MANUSCRIPT
Table 1. Results of amination of compounds 4, 5 and 22.
Entry
product
yielda
Entry
product
yielda
Entry
product
yielda
Ph
OCH3
N
N
N
N
NH
N
N
1
89%
7
80%
90%
90%
85%
13
90%
N
N
N
N
N
N
O
6
O
O
12
18
Ph
N
O
F
S
N
N
NH
N
N
N
2
3
4
80%
85%
88%
8
14
15
16
85%
90%
80%
N
N
N
N
N
N
O
O
O
7
13
19
O
F
O
Cl
N
NH
O
N
N
N
9
N
N
N
N
N
N
O
O
N
14
8
23
Ph
N
O
N
NH
N
N
N
10
N
N
N
N
N
N
N
O
O
15
24
9
O
Ph
N
NH
N
N
NH
5
97%
11
78%
N
N
N
O
N
N
10
O
16
N
N
NH
N
6
85%
12
90%
N
N
N
N
O
17
O
11
O

ACCEPTED MANUSCRIPT
a isolated yields after purification by column chromatography.

ACCEPTED MANUSCRIPT
Figure 1. Some polyfunctionalized 1,4-benzodiazepines.
O
O
N
N
NH
O
NH
O
O
F
F
N
N
N
H
N
H
N
I
II
O
S
CO2H
N
HN
O
N
O
N
O
NH2
SH
N
H
N
F
N
III
IV
O
N
N
Cl
V
HO

ACCEPTED MANUSCRIPT
Figure 2. Targeted structures.

ACCEPTED MANUSCRIPT
Scheme 1. Reagents and conditions: (a) ethyl 2-(benzylamino)acetate or ethyl 2-(4-methoxybenzylamino)acetate (1.2 equiv), DMF/Et3N,
reflux; 18 h; (b) Lawesson’s reagent (1 equiv), THF, 100 °C, 2 h; (c) HgCl2 (1.2 equiv), amines (1.2 equiv), THF, reflux, 1 h.