New derivatives of dibenzo[b,e][1,4]diazepin-1-ones by an efficient synthesis and spectroscopy

Article abstract of DOI:10.1002/jhet.5570440128

(Chemical Equation Presented) An efficient synthesis of four steps to obtain twelve new derivatives of 3,3-dimethyl-2,3,4,5,10,11-hexahydro-8-[(o-; and p-methoxy)phenoxy]-11-[(o-; and p-R)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1- ones IV, 1-12 with possible

Full text of DOI:10.1002/jhet.5570440128

Jan-Feb 2007
183
New Derivatives of Dibenzo[b,e][1,4]diazepin-1-ones by an
Efficient Synthesis and Spectroscopy
Eduardo Cortés Cortés*[a][1], Ana L. Valencia Cornejo [b]
and Olivia García-Mellado de Cortés [b]
[a] Instituto de Química [2], Universidad Nacional Autónoma de México. Circuito Exterior, Ciudad
Universitaria, Coyoacán 04510, México, D.F.
[b] F.E.S., Cuautitlán-UNAM, Av. 1° de Mayo s/n, Campo 1, Cuautitlán Izcalli, Edo. de México 5470; México
Received May 22, 2006
H
O
I
H 5
N
4
3
+
OH
6
9
4a
11
5a
II
2
7
8
NO2
NH2
R
1
11a
+
III
9a
O
O
1'
N
1''
Cl
10
2''
OCH3
H
3''
6'
5'
2'
3'
6''
4''
5''
R
4'
OCH3
IV, 1-12
An efficient synthesis of four steps to obtain twelve new derivatives of 3,3-dimethyl-2,3,4,5,10,11-
hexahydro-8-[(o-; and p-methoxy)phenoxy]-11-[(o-; and p-R)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-
ones IV, 1-12 with possible biological and pharmacological activity as anticonvulsant and schizophrenia
treatment in the central nervous system (CNS). The final products were obtained by condensation and
cyclization between 3-{4-[(o-; and p-methoxy)phenoxy]-1,2-phenylenediamine}-5,5-dimethyl-2-cyclo-
hexenone with (o-; and p-R)benzaldehyde. The structure of all products was corroborated by spectroscopy
of ir, 1H-nmr, 13C-nmr, with bidimensional experiments and MS in Low and high resolution with Collision-
Induced Dissociation experiments (CID).
J. Heterocyclic Chem., 44, 183 (2007).
INTRODUCTION
96-99% yield. The 3,4-diaminophenylether derivatives II,
were obtained by hydrogenation of the derivatives I in
The Clozapine is the best representative example of the
1,4-dibenzodiazepine activity as an atypical antipsychotic
agent with good efficiency in the treatment of schizo-
phrenia [3,4]; and as an antipsychotic drug [5-10].
Our last report about the synthesis of 8-chloro derivates
of 1H-dibenzo[b,e][1,4]diazepin-1-one, which have poten-
tially useful pharmacological properties, was published in
2002 and 2004 [11-12].
R
1
2
3
4
5
6
7
8
9
o-OCH3
o-OCH3
o-OCH3
o-OCH3
o-OCH3
o-OCH3
p-OCH3
p-OCH3
p-OCH3
o-CH3
p-CH3
o-Cl
H
N
C
p-Cl
A
B
o-OCH3
p-OCH3
o-CH3
p-CH3
o-Cl
p-Cl
o-OCH3
p-OCH3
O
O
N
H
E
D
R
RESULTS AND DISCUSSION
10 p-OCH3
11 p-OCH3
12 p-OCH3
OCH3
We described in this report the synthesis of twelve new
derivatives and spectral properties 3,3-dimethyl-2,3,4,5,
10,11-hexahydro-8-[(o-; and p-methoxy)phenyl]-11-[(o-;
and p-R)phenyl]-1H-dibenzo[b,e][1,4]diazepin-1-ones IV,
1-12 (Figure 1). The synthesis of these compounds was
carried out as shown in Scheme 1.
The reaction of 5-choro-2-nitroaniline with the (o-; and
p-methoxy)phenol at reflux in anhydrous dimethylform-
amide in presence of anhydrous potassium carbonate, was
heated for five hours. After cooling, the reaction mixture
was diluted with water, the 3-amine-4-nitrophenyl-[(o-;
and p-methoxy)phenyl]ether I, that was precipitated and
was collected by filtration with suction and obtained in a
IV, 1-12
Figure 1
ethanol in presence of Pd/C 10% under a pressure of 60
pounds/inch2 at room temperature with magnetic stirring
for 24 hours. When the hydrogenation was finished the
catalyst was removed by filtration and the solution was
evaporated under reduced pressure; the 3,4-diamino-
phenyl-[(o-; and p-methoxy)phenyl]ether II, was obtained
in a 72-85%.
Treatment of the derivatives II with the 5,5-dimethyl-
1,3-cyclohexanedione at reflux in anhydrous benzene with

184
E. Cortés Cortés, A. L. Valencia Cornejo, O. Garcia-Mellado de Cortés
Vol 44
a Dean-Stark apparatus was performed for 24 hours to
obtain the 3-{4-[(o- and p-methoxy)phenyl]-1,2-phenyl-
enediamine}-5,5-dimethyl-2-cyclohexenone III, in 72-
78% yield.
Treatment of 1 x 10-3 mole of compound III, with 1 x
10-3 mole of the corresponding (o-; and p-R)benzaldehyde
in the presence of 0.5 mL of glacial acetic acid at reflux in
10 mL of ethanol for 2-4 hours afforded the 1H-
dibenzo[b,e][1,4]diazepin-1-ones IV, 1-12 in a 76-98%
yield.
consistent with N-H, deuterium oxide exchangeable. The
others aromatic protons appears as a multiplet signal and
AA'BB' systems at ꢀ 6.45-7.50. The signals for the R=
OCH3 substituted were also observed in ꢀ 3.69-3.85.
The 13C-nmr spectra data for compounds IV, 1-12 are
given in Table 1. The signals were confirmed by using
HETCOR, COSY, FLOCK, NOESY, and DEPT nmr
experiments operating at 300 and 500 MHz. The mass
spectra of compounds IV, 1-12 exhibit a stable molecular
ion with a relative abundance of 35-68%. The base peak is
Scheme 1
OH
H2
NO2
K2CO3
+
NO2
NH2
NH2
Pd/C 10%
Cl
O
ETHANOL
DMF
NH2
O
NH2
OCH3
II
I
OCH3
OCH3
O
+
O
O
4
4
5
H
H
3
5
H
3
6
4a
6'
N
N
+
1'
2'
5a
2
6
7
8
C
5'
4'
A
B
1
1
2
R
11a
1''
11
9a
O
O
O
1'
O
N
NH2
9
3'
2''
10
1''
2''
E
H
3''
4''
6''
5''
6'
5'
2'
6''
D
III
3'
4' OCH3
3''
5''
R
4''
OCH3
IV, 1-12
The infrared spectrum of compounds IV, 1-12 displayed
absorptions at 3409-4316 cm-1 for N-H stretching, at 1616-
1620 cm-1 for C=O stretching, at 1368-1373 and 1309-1325
cm-1 for C-N stretching, at 1259-1268 and 1111-1117 cm-1
for C-O stretching and the corresponding absorptions for
aromatic and R-substituents.
In the 1H-nmr spectra the presence of two singlet
signals (2 x 3H) at ꢀ 1.03-1.12 and 1.08-1.15 were
assigned to the methyl protons joined at C-3. The
presence of a doublet at ꢀ 2.11-2.27 and 2.20-2.32 was
consistent with the methylene protons at C-2. Other
doublet signals at ꢀ 2.38-2.51 and 2.53-2.61 were
assigned at the methylene protons on C-4. The presence
of a singlet at ꢀ 5.85-6.21 was consistent with the methine
proton on C-11; the signal doublet at ꢀ 5.93-6.10 was
assigned at one aromatic protons on C-9; the presence of a
signal doublet of doublet at ꢀ 6.19-6.39 was consistent
with the one aromatic proton on C-7; the signal doublet at
ꢀ 6.67-6.87 was assigned at one aromatic protons on C-6.
The presence of a broad proton signal at ꢀ 6.31-9.96 was
the ion at m/z [M-(76+R)]+. The main fragmentation was
consistent with the assigned structures and the mass
spectra of the compound IV, 1-12 includes ions of m/z
corresponding to molecular ion [M]+; [M-1]+; [M-CH3]+;
[M-(NH2)]+; [M-R]+; [M-HR]+; [M-(R+NH2)]+; [M-
(C4H9)]+; [M-(C5H8O)]+; [M-(C5H9O)]+ and m/z 83.
The proposed fragmentation pathways leading to the
formation of a number of important daughter ions have
been confirmed by the corresponding parent ion spectra,
using collision-induced dissociation (CID) experiments.
The elemental composition of the molecular ion and the
principal fragment ion were determined by exact mass
measurements.
EXPERIMENTAL
The ir spectra were recorded on a Nicolet Magna TR-750
spectrophotometer. The 1H-nmr spectra were recorded on a
Varian Unity 300 spectrometer operating at 300 MHz and the
13C-nmr spectra were recorded on
a Varian Unity 500

Jan-Feb 2007
New Derivatives of Dibenzo[b,e][1,4]diazepin-1-ones
185
phenoxy]-1,2-phenylendiamine II (1 x 10-2 mole) in 20 mL of
benzene were heated at reflux for 24 hours, afforded compound
III with a 72-78% yield.
spectrometer operating at 125 MHz in deuterochloroform
solution containing tetramethylsilane as the internal standard
with chemical shifts ꢀ (ppm) expressed downfield from tetra-
methylsilane. The mass spectra were measured on a JEOL JMS-
AC505 and JEOL MS-SX 102A high-resolution mass spectro-
meter with accurate mass determination of the molecular ion and
the principal fragment ions, using the direct inlet system. The
spectra were recorded by electron impact at an ionization
chamber temperature of 190° and ionizing electron energy of 70
eV.
General Procedure for the Synthesis of the 3,3-
Dimethyl-2,3,4,5,10,11-Hexahydro-8-[(o-; and p-methoxy)-
phenyl]-11-[(o-; and p-R)phenyl]-1H-dibenzo[b,e][1,4]-
diazepin-1-ones IV, 1-12. A mixture of 1x10-3 mole of the
cyclohexenone III; 1x10-3 mole of the (o-; and p-
R)benzaldehyde, 0.5 mL of acetic acid glacial in 5.0 mL
ethanol was heated at reflux for 3-4 hours. The reaction
mixture was cooled to room temperature and evaporated at
vacuum to yield a semisolid. The residual semisolid was
purified by crystallization from hexane-ethyl acetate to yield
compounds IV, 1-12, in a 76-98%.
Compounds I and II were prepared following methods
developed by us, with modifications [13,11].
General Procedure for the Synthesis of the 3-{4-[(o- and p-
Methoxy)phenyl]-1,2-phenylenediamine}-5,5-dimethyl-2-cyclo-
hexenone III. A mixture of 1 x 10-2 mole of the 5,5-dimethyl-
1,3-cyclohexanedione (Dimedone) and 4-[(o-; and p-methoxy)-
3,3-Dimethyl-8-[(o-methoxy)phenoxy]-11-[(o-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
Table 1
13C NMR Spectral Data for Compounds 1-12
4
H5
5a N
3
4a
6
A
9
2
7
8
C
B
1
11a
1''
11
9a
O
2''
E
O
N
10
1'
3''
4''
H
6'
5'
2'
3'
6''
D
5'' R
4'
OCH3
IV, 1-12
Compounds
-OCH3
R
1
2
3
4
5
6
7
8
9
10
11
12
o-OCH3 o-OCH3 o-OCH3 o-OCH3 p-OCH3 p-OCH3 p-OCH3 p-OCH3 p-OCH3 p-OCH3
o-OCH3
o-CH3
o-OCH3
p-CH3
o-Cl
p-Cl
o-OCH3 p-OCH3
o-CH3
p-CH3
o-Cl
p-Cl
o-OCH3 p-OCH3
C-1
C-2
C-3
C-4
C-4a
C-5a
C-6
C-7
C-8
C-9
C-9a
C-11
C-11a
C-1'
C-2'
C-3'
C-4'
C-5'
C-6'
C-1''
C-2''
C-3''
C-4''
C-5''
C-6''
193.9
49.7
32.3
193.8
49.7
32.2
193.6
49.6
32.3
193.7
49.7
32.3
193.6
49.8
32.3
193.6
49.7
32.3
46.3
158.1
126.8
120.9
111.3
153.5
111.2
138.6
57.5
111.1
153.0
150.6
128.2
123.9
120.8
119.7
145.9
128.2
113.5
136.0
113.5
128.2
27.8
28.7
55.8
-
193.9
49.7
32.4
46.2
155.3
127.3
120.9
111.8
153.9
111.4
135.2
55.4
111.0
154.0
114.6
119.4
150.8
119.4
114.6
141.1
138.4
130.6
126.7
125.2
125.7
27.9
28.6
-
193.8
49.7
32.3
46.2
155.4
126.7
121.0
111.3
153.7
111.3
135.9
57.8
110.9
154.1
114.6
119.6
150.8
119.4
114.6
140.6
127.0
128.9
138.7
128.9
127.0
27.8
28.7
-
193.7
49.7
32.3
46.1
155.4
126.9
120.9
111.9
154.2
111.3
133.6
56.1
109.2
154.8
114.6
119.5
150.7
119.5
114.6
139.8
138.8
129.6
128.2
126.2
127.6
28.1
28.5
-
193.8
49.6
32.3
46.2
155.5
126.6
121.1
111.7
153.8
111.4
132.2
57.6
110.2
154.4
114.8
119.7
150.7
119.7
114.8
142.3
128.3
128.5
138.3
128.5
128.3
27.8
28.6
-
191.7
49.5
31.7
44.2
156.5
127.0
120.8
110.1
154.5
109.8
130.8
52.6
108.4
155.0
114.3
119.0
150.4
119.0
114.3
140.0
139.9
127.0
127.5
126.5
126.6
27.7
28.3
-
193.7
49.7
32.2
46.1
155.4
126.8
121.0
111.4
153.6
111.3
136.0
57.6
110.9
154.1
114.6
119.6
150.8
119.6
114.6
138.7
128.1
113.4
136.0
113.4
128.1
27.7
28.7
-
46.1
46.1
46.2
46.3
46.2
153.9
127.5
120.8
111.7
153.3
111.2
141.2
55.3
111.0
153.3
150.4
131.1
130.5
125.2
118.9
146.1
138.3
129.7
129.7
112.5
126.7
27.8
153.7
126.8
121.0
111.3
153.4
111.2
140.6
57.8
110.8
153.7
150.5
129.6
123.9
120.8
119.2
135.9
128.8
127.0
129.5
127.0
128.8
27.7
154.6
127.1
120.8
112.0
153.4
111.3
138.6
56.0
109.3
145.9
150.4
129.6
123.9
127.6
118.9
133.6
139.8
129.6
129.6
128.2
126.2
28.1
154.0
126.5
121.0
111.4
153.5
110.9
138.2
57.6
110.4
153.4
150.8
124.3
112.7
121.0
119.8
145.6
128.2
128.5
142.3
128.5
128.2
27.8
156.8
130.0
119.8
111.6
154.4
111.3
139.6
53.9
110.2
153.2
150.5
129.9
123.8
120.9
119.0
146.3
139.7
128.0
128.5
124.2
126.9
28.1
C-3(CH3)
C-3(CH3)
C2'-OCH3
C2''-OCH3
C4'-OCH3
C4''-OCH3
C2''-CH3
C4''-CH3
28.5
55.8
-
28.7
55.8
-
28.5
55.8
-
28.6
55.9
-
28.7
55.8
55.2
-
-
-
-
55.1
54.9
-
-
-
-
-
55.6
-
19.6
-
55.6
-
-
21.0
55.6
-
-
55.6
-
-
55.5
55.0
-
-
19.5
-
-
-
-
-
-
-
-
-
-
-
-
55.0
-
-
20.9
-
-
-
Note: The numbering of the phenyl ring is only for the assignment of the chemical shifts of the carbon in 13C nmr spectra.

186
E. Cortés Cortés, A. L. Valencia Cornejo, O. Garcia-Mellado de Cortés
Vol 44
(1). This compound was obtained as a brown-reddish solid in a
90% yield; mp 108°; ir (chloroform): ꢀ N-H 3415, C=O 1620,
C-N 1371 and 1313, C-O 1261 and 1116 cm-1; 1H-nmr (deutero-
chloroform): ꢁ 1.03 and 1.09 (s, 6H, C3-CH3); 2.15 (d, 1H,
J=16.3 Hz, 2-Ha); 2.25 (d, 1H, J=16.3 Hz, 2-Hb); 2.45 (d, 1H,
J=15.6 Hz, 4-Ha); 2.48 (s, 3H, C2''-CH3); 2.57 (d, 1H, J=15.6 Hz,
4-Hb); 3.72 (s, 3H, C2'-OCH3); 5.95 (d, 1H, J=2.5 Hz, 9-H); 6.10
(s, 1H, 11-H); 6.34 (dd, 1H, J=2.4, 8.5 Hz, 7-H); 6.49 (dd, 1H,
J=1.4, 7.9 Hz, 6'-H); 6.64 (bs, 2H, N-H, deuterium oxide
exchangeable); 6.76 (d, 1H, J=8.7 Hz, 6-H); 6.80 (dt, 1H, J=1.2;
7.4 Hz, 5'-H); 6.91 (dt, 1H, J=1.4, 7.1 Hz, 5''-H); 6.97 (dd, 1H,
J=1.4, 7.9 Hz, 6''-H); 7.03 (dt, 1H, J=1.1, 6.5 Hz, 4'-H); 7.26 (dt,
1H, J=1.2, 6.4 Hz, 4''-H); 7.50 (dd, 1H, J=1.2, 8.0 Hz, 3'-H);
7.57 (dd, 1H, J=1.3, 7.3 Hz, 3''-H); ms: m/z 454 (M+). Anal.
Calcd. for C29H30N2O3: C, 76.62; H, 6.65; N, 6.16. Found: C,
76.52; H, 6.72; N, 6.24.
3,3-Dimethyl-8-[(o-metoxy)phenoxy]-11-[(p-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(2). This compound was obtained as a brown-reddish solid in a
93% yield; mp 103°, ir (chloroform): ꢀ N-H 3415; C=O 1619;
C-N 1371 and 1319, C-O 1261 and 1116 cm-1; 1H-nmr (deutero-
chloroform): ꢁ 1.03 and 1.08 (s, 6H, C3-CH3); 2.19 (s, C4''-CH3);
2.19 (d, 1H, J=16.2 Hz, 2-Ha); 2.28 (d, 1H, J=16.2 Hz, 2-Hb);
2.40 (d, 1H, J=15.8 Hz, 4-Ha); 2.55 (d, 1H, J=15.8 Hz, 4-Hb);
3.74 (C2'-OCH3); 5.86 (s, 1H, 11-H); 6.03 (d, 1H, J=2.5 Hz, 9-
H); 6.31 (bs, 2H, N-H, deuterium oxide exchangeable); 6.35 (dd,
1H, J=2.5, 8.6 Hz, 7-H); 6.60 (dd, 1H, J=1.5, 7.9 Hz, 6'-H); 6.73
(d, 1H, J=8.6 Hz, 6-H); 6.80 (dt, 1H, J=1.5, 7.7 Hz, 5'-H); 6.90
and 6.92 (AA'BB”, 4H, J=9.0 Hz, phenyl protons of “E” ring);
7.03 (dt, 1H, J=1.6, 7.7 Hz, 4'-H); 7.14 (dd, 1H, J=1.2, 7.8 Hz,
3'-H); ms: m/z 454 (M+). Anal. Calcd. for C29H30N2O3: C, 76.62;
H, 6.65; N, 6.16. Found: C, 76.71; H, 6.56; N, 6.06.
J=1.5, 7.7 Hz, 4'-H); 6.96 and 7.08 (AA'BB”, 4H, J=8.5 Hz,
phenyl protons of “E” ring); 7.03 (dd, 1H, J=1.5, 8.0 Hz, 3'-H);
ms: m/z 474 (M+); 476 [M+2]+. Anal. Calcd. for C28H27ClN2O3:
C, 70.80; H, 5.73; N, 5.90. Found: C, 70.71; H, 5.80; N, 5.96.
3,3-Dimethyl-8-[(o-metoxy)phenoxy]-11-[(o-methoxy)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(5). This compound was obtained as a brown-reddish solid in a
87% yield; mp 79°; ir (chloroform): ꢀ N-H 3416, C=O 1620, C-
1
N 1373 and 1320, C-O 1259 and 1116 cm-1; H-nmr (deutero-
chloroform): ꢁ 1.12 and 1.14 (s, 6H, C3-CH3); 2.27 (d, 1H,
J=16.5 Hz, 2-Ha); 2.32 (d, 1H, J=16.5 Hz, 2-Hb); 2.45 (d, 1H,
J=15.6 Hz, 4-Ha); 2.59 (d, 1H, J=15.6 Hz, 4-Hb); 3.76 (s, 3H,
C2''-OCH3); 3.79 (s, 3H, C2'-OCH3); 6.00 (d, 1H, J=2.7 Hz, 9-H);
6.14 (s, 1H, 11-H); 6.30 (dd, 1H, J=2.5, 8.5 Hz, 7-H); 6.45 (dd,
1H, J=1.5, 7.6 Hz, 6'-H); 6.66 (dd, 1H, J=1.4, 8.4 Hz, 6''-H);
6.67 (d, 1H, J=8.8 Hz, 6-H); 6.76 (dt, 1H, J=1.4; 7.0 Hz, 5''-H);
6.79 (dt, 1H, J=1.5, 6.9 Hz, 5'-H); 7.00 (dt, 1H, J=1.2, 7.4 Hz,
4''-H); 7.02 (dt, 1H, J=1.4, 7.5 Hz, 4'-H); 7.14 (dd, 1H, J=1.2,
8.1 Hz, 3'-H); 7.15 (dd, 1H, J=1.3, 7.0 Hz, 3''-H); 7.24 (bs, 2H,
N-H, deuterium oxide exchangeable); ms: m/z 470 (M+). Anal.
Calcd. for C29H30N2O4: C, 74.02; H, 6.43; N, 5.95. Found: C,
74.12; H, 6.50; N, 5.87.
3,3-Dimethyl-8-[(o-metoxy)phenoxy]-11-[(p-methoxy)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(6). This compound was obtained as a brown-reddish solid in a
79% yield; mp 84°, ir (chloroform): ꢀ N-H 3409; C=O 1616; C-
1
N 1368 and 1318, C-O 1260 and 1111 cm-1; H-nmr (deutero-
chloroform): ꢁ 1.06 and 1.12 (s, 6H, C3-CH3); 2.21 (d, 1H,
J=16.2 Hz, H-2a); 2.30 (d, 1H, J=16.2 Hz, 2-Hb); 2.38 (d, 1H,
J=15.9 Hz, 4-Ha); 2.55 (d, 1H, J=15.9 Hz, 4-Hb); 3.70 (s, 3H,
C4''-OCH3); 3.72 (s, 3H, C2'-OCH3); 5.86 (s, 1H, 11-H); 6.04 (d,
1H, J=2.7 Hz, 9-H); 6.38 (dd, 1H, J=2.7, 8.7 Hz, 7-H); 6.62 and
6.95 (AA'BB', 4H, J=8.7 Hz, phenyl protons of “E” ring); 6.63
(dd, 1H, J=1.5, 7.9 Hz, 6'-H); 6.68 (d, 1H, J=8.4 Hz, 6-H); 6.82
(dt, 1H, J=1.5, 7.7 Hz,5'-H); 6.94 (dd, 1H, J=1.5, 8.1, 3'-H); 7.03
(dt, 1H, J=1.5, 7.8 Hz, 4'-H); 7.22 (bs, 2H, N-H, deuterium
oxide exchangeable); ms: m/z 470 (M+). Anal. Calcd. for
C29H30N2O4: C, 74.02; H, 6.43; N, 5.95. Found: C, 74.10; H,
6.38; N, 6.02.
3,3-Dimethyl-8-[(o-metoxy)phenoxy]-11-[(o-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(3). This compound was obtained as a brown-reddish solid in a
91% yield; mp 116°; ir (chloroform): ꢀ N-H 3414, C=O 1619,
C-N 1371 and 1309, C-O 1261 and 1115 cm-1; 1H-nmr (deutero-
chloroform): ꢁ 1.11 and 1.14 (s, 6H, C3-CH3); 2.23 (d, 1H,
J=16.2 Hz, 2-Ha); 2.31 (d, 1H, J=16.2 Hz, 2-Hb); 2.49 (d, 1H,
J=15.8 Hz, 4-Ha); 2.61 (d, 1H, J=15.8 Hz, 4-Hb); 3.75 (s, 3H,
C2'-OCH3); 6.10 (d, 1H, J=2.5 Hz, 9-H); 6.20 (s, 1H, 11-H); 6.34
(dd, 1H, J=2.5, 8.6 Hz, 7-H); 6.49 (dd, 1H, J=1.7, 7.9 Hz, 6'-H);
6.69 (d, 1H, J=8.8 Hz, 6-H); 6.79 (dt, 1H, J=1.6; 6.9 Hz, 5'-H);
6.92 (dd, 1H, J=1.4, 8.4 Hz, 6''-H); 7.01 (dt, 1H, J=1.5, 6.9 Hz,
5''-H); 7.02 (dt, 1H, J=1.4, 7.4 Hz, 4'-H); 7.26 (dt, 1H, J=1.2, 7.8
Hz, 4''-H); 7.31 (bs, 2H, N-H, deuterium oxide exchangeable);
7.33 (dd, 1H, J=1.4, 8.1 Hz, 3'-H); 7.39 (dd, 1H, J=1.6, 6.5 Hz,
3''-H); ms: m/z 474 (M+); 476 [M+2]+. Anal. Calcd. for
C28H27ClN2O3: C, 70.80; H, 5.73; N, 5.90. Found: C, 70.89; H,
5.66; N, 5.81.
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(o-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (7).
This compound was obtained as a brown-reddish solid in a 98%
yield; mp 82°; ir (chloroform): ꢀ N-H 3416, C=O 1620, C-N 1371
and 1318, C-O 1267 and 1116 cm-1; 1H-nmr (deuterochloroform):
ꢁ 1.07 and 1.13 (s, 6H, C3-CH3); 2.18 (d, 1H, J=16.2 Hz, 2-Ha);
and 2.28 (d, 1H, J=16.3 Hz, 2-Hb); 2.48 (d, 1H, J=15.6 Hz, 4-Ha);
2.51 (s, 3H, C2''-CH3); 2.61 (d, 1H, J=15.6 Hz, 4-Hb); 3.77 (s, 3H,
C4'-OCH3); 5.93 (d, 1H, J=2.4 Hz, 9-H); 6.10 (s, 1H, 11-H); 6.32
(dd, 1H, J=2.4, 8.7 Hz, 7-H); 6.63 (dd, 1H, J=1.8, 7.9 Hz, 6''-H);
6.63 and 6.76 (AA'BB', 4H, J=8.7 Hz, phenyl protons of “D”
ring); 6.72 (bs, 2H, N-H, deuterium oxide exchangeable); 6.76 (d,
1H, J=8.8 Hz, 6-H); 6.82 (dt, 1H, J=1.3; 7.1 Hz, 5''-H); 6.98 (dt,
1H, J=1.2, 7.1 Hz, 4''-H); 7.07 (dd, 1H, J=1.2, 6.9 Hz, 3''-H); ms:
m/z 454 (M+). Anal. Calcd. for C29H30N2O3: C, 76.62; H, 6.65; N,
6.16. Found: C, 76.68; H, 6.58; N, 6.07.
3,3-Dimethyl-8-[(o-metoxy)phenoxy]-11-[(p-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(4). This compound was obtained as an orange solid in a 90%
yield; mp 114°, ir (chloroform): ꢀ N-H 3414; C=O 1619; C-N
1
1370 and 1313, C-O 1263 and 1114 cm-1; H-nmr (deutero-
chloroform): ꢁ 1.05 and 1.12 (s, 6H, C3-CH3); 2.20 (d, 1H,
J=16.5 Hz, 2-Ha); 2.29 (d, 1H, J=16.5 Hz, 2-Hb); 2.42 (d, 1H,
J=16.2 Hz, 4-Ha); 2.56 (d, 1H, J=16.2 Hz, 4-Hb); 3.74 (C2'-
OCH3); 5.85 (s, 1H, 11-H); 6.01 (d, 1H, J=2.7 Hz, 9-H); 6.39
(dd, 1H, J=2.4, 8.5 Hz, 7-H); 6.63 (dd, 1H, J=1.5, 7.9 Hz, 6'-H);
6.69 (bs, 2H, N-H, deuterium oxide exchangeable); 6.70 (d, 1H,
J=8.4 Hz, 6-H); 6.85 (dt, 1H, J=1.5, 7.7 Hz, 5'-H); 6.92 (dt, 1H,
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(p-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(8). This compound was obtained as a brown-reddish solid in a
91% yield; mp 120°, ir (chloroform): ꢀ N-H 3416; C=O 1619;
C-N 1370 and 1319, C-O 1268 and 11132 cm-1; 1H-nmr
(deuterochloroform): ꢁ 1.05 and 1.11 (s, 6H, C3-CH3); 2.20 (d,
1H, J=16.2 Hz, 2-Ha); 2.22 (s, C4''-CH3); 2.29 (d, 1H, J=16.2 Hz,

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New Derivatives of Dibenzo[b,e][1,4]diazepin-1-ones
187
2-Hb); 2.40 (d, 1H, J=15.9 Hz, 4-Ha); 2.55 (d, 1H, J=15.9 Hz, 4-
Hb); 3.77 (C4'-OCH3); 5.86 (s, 1H, 11-H); 6.03 (d, 1H, J=2.4 Hz,
9-H); 6.32 (dd, 1H, J=2.4, 8.4 Hz, 7-H); 6.69 (d, 1H, J=8.7 Hz,
6-H); 6.70 and 6.78 (AA'BB', 4H, J=8.7 Hz, phenyl protons of
“D” ring); 6.92 (s, 4H, J=9.0 Hz, phenyl protons of “E” ring);
9.96 (bs, 2H, N-H, deuterium oxide exchangeable); ms: m/z 454
(M+). Anal. Calcd. for C29H30N2O3: C, 76.62; H, 6.65; N, 6.16.
Found: C, 76.72; H, 6.60; N, 6.26.
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(o-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(9). This compound was obtained as a brown-reddish solid in a
98% yield; mp 96°; ir (chloroform): ꢀ N-H 3415, C=O 1620, C-N
1371 and 1320, C-O 1268 and 1116 cm-1; 1H-nmr (deutero-
chloroform): ꢁ 1.12 and 1.15 (s, 6H, C3-CH3); 2.23 (d, 1H, J=16.2
Hz, 2-Ha); 2.32 (d, 1H, J=16.2 Hz, 2-Hb); 2.48 (d, 1H, J=15.6 Hz,
4-Ha); 2.61 (d, 1H, J=15.6 Hz, 4-Hb); 3.77 (s, 3H, C4'-OCH3);
6.09 (d, 1H, J=2.7 Hz, 9-H); 6.21 (s, 1H, 11-H); 6.29 (dd, 1H,
J=2.5, 8.6 Hz, 7-H); 6.64 and 6.78 (AA'BB', 4H, J=8.7 Hz, phenyl
protons of “D” ring); 6.67 (d, 1H, J= 8.7 Hz, 6-H); 6.73 (bs, 2H,
N-H, deuterium oxide exchangeable); 6.67 (dd, 1H, J=1.8, 9.2 Hz,
6''-H); 6.91 (dt, 1H, J=1.2, 7.2 Hz, 5''-H); 7.04 (dt, 1H, J=1.5, 7.7
Hz, 4''-H); 7.28(dd, 1H, J=1.8, 8.5 Hz, 3''-H); ms: m/z 474 (M+);
476 [M+2]+. Anal. Calcd. for C28H27ClN2O3: C, 70.80; H, 5.73; N,
5.90. Found: C, 70.90; H, 5.82; N, 5.99.
Hz, 6''-H); 6.86 (dd, 1H, J=1.8, 7.8 Hz, 3''-H); 6.87 (dt, 1H, J=1.8;
7.3 Hz, 5''-H); 6.89 (d, 1H, J=8.1 Hz, 6-H); 7.09 (dt, 1H, J=1.8,
6.9 Hz, 4''-H); 8.80 (bs, 2H, N-H, deuterium oxide exchangeable);
ms: m/z 470 (M+). Anal. Calcd. for C29H30N2O4: C, 74.02; H,
6.43; N, 5.95. Found: C, 73.93; H, 6.33; N, 6.02.
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(p-methoxy)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (12).
This compound was obtained as a brown-reddish solid in a 78%
yield; mp 128°, ir (chloroform): ꢀ N-H 3416; C=O 1619; C-N
1
1371 and 1325, C-O 1265 and 1117 cm-1; H-nmr (deutero-
chloroform): ꢁ 1.05 and 1.10 (s, 6H, C3-CH3); 2.20 (d, 1H,
J=16.5 Hz, H-2a); 2.29 (d, 1H, J=16.5 Hz, 2-Hb); 2.38 (d, 1H,
J=15.9 Hz, 4-Ha); 2.53 (d, 1H, J=15.9 Hz, 4-Hb); 3.69 (s, 3H,
C4''-OCH3); 3.77 (s, 3H, C4'-OCH3); 5.85 (s, 1H, 11-H); 6.02 (d,
1H, J=2.7 Hz, 9-H); 6.33 (dd, 1H, J=2.4, 8.6 Hz, 7-H); 6.66 and
6.95 (AA'BB”, 4H, J=8.4 Hz, phenyl protons of “E” ring); 6.69
(d, 1H, J= 8.7 Hz, 6-H); 6.69 and 6.79 (AA'BB', 4H, J=8.7 Hz,
phenyl protons of “D” ring); 7.26 (bs, 2H, N-H, deuterium oxide
exchangeable); ms: m/z 470 (M+). Anal. Calcd. for C29H30N2O4:
C, 74.02; H, 6.43; N, 5.95. Found: C, 73.95; H, 6.36; N, 6.04.
Acknowledgement. This work was supported by UNAM-
DGAPA project IN 225503. We wish to thank to J. Pérez for
their assistance in the acquisition of the mass spectral data, H.
Rios for the nmr determination; and M. Adaya for the ir
determination.
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(p-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(10). This compound was obtained as an orange solid in a 82%
yield; mp 133°, ir (chloroform): ꢀ N-H 3415; C=O 1619; C-N
REFERENCES AND NOTES
1
1370 and 1315, C-O 1268 and 1112 cm-1; H-nmr (deutero-
[1] Author to whom correspondence should be addressed.
[2] Contribution No. 2638 from Instituto de Química, UNAM
[3] S. Schreiber, V. Getslev, M. M. Backer, R. Weizman and C.
G. Pink, Pharmacology Biochemistry and Behavior, 64, 75 (1999).
[4] A. Fitton and R. C. Heel, Drugs, 40, 722 (1990).
[5] J. Angst, D. Bente, P. Berwer, H. Heimann, H. Helmohen
and H. Hippus, Pharmakopsychiatr. Neuro-Psychopharmakol., 4, 201
(1971).
[6] J. F. Nash, H. Y. Meltzer and G. A. Gudelsky, Eur. J.
Pharmacol., 151, 463-469 (1988).
[7] M. Picker, Pharmacol. Biochem. Behav., 30, 603 (1998).
[8] M. J. Picker and C.A. Massie, Pharmacol. Biochem. Behav.,
31, 953 (1988).
[9] C. D. Kilts, C. M. Anderson, G. Bissette, T. D. Ely and C. B.
Nemeroff, Biochem. Pharmacol., 37, 1547-1554 (1988).
[10] B. A. B. McMillen, , E. A Da Vanzo, A. H. Song, S. M. Scott
and M. E. Rodríguez, Eur. J. Pharmacol., 160, 149 (1989).
[11] E. Cortés C., A. M. Hernández S., and O. García M., J.
Heterocyclic Chem., 39, 55 (2002).
[12] E. Cortés C., M. Adaya B. and O. García M., J. Heterocyclic
Chem., 41, 277 (2004).
[13] E. Cortés C., and L.A. Araluce A., J. Heterocyclic Chem., 34,
745 (1997).
chloroform): ꢁ 1.05 and 1.11 (s, 6H, C3-CH3); 2.21 (d, 1H,
J=16.2 Hz, 2-Ha); 2.309 (d, 1H, J=16.2 Hz, 2-Hb); 2.42 (d, 1H,
J=15.9 Hz, 4-Ha); 2.55 (d, 1H, J=15.9 Hz, 4-Hb); 3.77 (C4'-
OCH3); 5.85 (s, 1H, 11-H); 6.00 (d, 1H, J=2.7 Hz, 9-H); 6.35
(dd, 1H, J=2.4, 8.6 Hz, 7-H); 6.70 and 6.81 (AA'BB”, 4H, J=9.0
Hz, phenyl protons of “D” ring); 6.71 (d, 1H, J=8.1 Hz, 6-H);
6.85 (bs, 2H, N-H, deuterium oxide exchangeable); 6.95 and
7.09 (AA'BB”, 4H, J=8.4 Hz, phenyl protons of “E” ring); ms:
m/z 474 (M+); 476 [M+2]+. Anal. Calcd. for C28H27ClN2O3: C,
70.80; H, 5.73; N, 5.90. Found: C, 70.73; H, 5.63; N, 5.80.
3,3-Dimethyl-8-[(p-metoxy)phenoxy]-11-[(o-methoxy)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one (11).
This compound was obtained as a yellow solid in a 76% yield; mp
196°; ir (chloroform): ꢀ N-H 3416, C=O 1619, C-N 1372 and
1
1320, C-O 1265 and 1114 cm-1; H-nmr (deuterochloroform): ꢁ
1.12 and 1.13 (s, 6H, C3-CH3); 2.11 (d, 1H, J=16.1 Hz, 2-Ha), and
2.20 (d, 1H, J=16.1 Hz, 2-Hb); 2.51 (d, 1H, J=15.9 Hz, 4-Ha);
2.61 (d, 1H, J=15.9 Hz, 4-Hb); 3.74 (s, 3H, C2''-OCH3); 3.83 (s,
3H, C4'-OCH3); 5.94 (s, 1H, 11-H); 6.0 (d, 1H, J=2.4 Hz, 9-H);
6.19 (dd, 1H, J=2.7, 7.4 Hz, 7-H); 6.61 and 6.81 (AA'BB”, 4H,
J=9.0 Hz, phenyl protons of “D” ring); 6.81 (dd, 1H, J=1.8, 9.3