Efficient synthesis and spectroscopy of 3,3-dimethyl-2,3,4,5,10,11- hexahydro-8-[(o-; and p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1 H-dibezo-[b,e][1,4]diazepin-1-ones

Article abstract of DOI:10.1002/jhet.159

(Chemical Equation Presented) An easy synthesis of four steps to afforded 12 new derivatives of 3,3-dimethyl-2,3,4,5,10,11-hexahydro-8-[(o-; and p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-[b,e][1,4]diazep- in-1-ones IV, 1-12 with potential biological and pharmacological activity as sedative, hypnotic-muscular relaxing, anticonvulsant, and schizophrenia treatment of the central nervous system (CNS). The final products have been obtained with good yields, by condensation and cyclization between 3-{4-[(o-; and p-methyl)phenoxy]-1,2-phenylendiamine}-5,5-dimethyl-2-cyclohexanone III, with the corresponding (o-; and p-R)benzaldehyde. The structure of all derivatives was corroborated by spectroscopy of ir, ¹H, and ¹³C NMR, with bi-dimensional experiments and EI-MS in low and high resolution with collision-induced dissociation experiments (CID).

Full text of DOI:10.1002/jhet.159

November 2009
Efficient Synthesis and Spectroscopy of
3,3-Dimethyl-2,3,4,5,10,11-hexahydro-8-[(o-; and
p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1
H-dibezo-[b,e][1,4]diazepin-1-ones
1113
a
b
b
´
´
´
Eduardo Cortes Cortes, * Ociel E. Andrade Meneses, Olivia Garcıa-Mellado,
c
a
Ofelia Collera Zun˜iga, and Elia Brosla Naranjo-Rodrıguez
´
a
´
´
´
´
Departamento de Sıntesis Organica, Instituto de Quımica, Universidad Nacional Autonoma de
´
´
´
´
Mexico, Circuito Exterior, Ciudad Universitaria, Coyoacan, 04510 Mexico, D.F., Mexico
´
b
´
Departamento de Ciencias Quımicas, Facultad de Estudios Superiores Cuautitlan, Universidad
´
´ ´
Nacional Autonoma de Mexico, Av. 1o. de Mayo s/n Campo No. 1, Cuautitlan Izcalli,
´
´
Estado de Mexico, 54740 Mexico
´
c
´
´
Departamento de Farmacia, Facultad de Quımica, Universidad Nacional Autonoma de Mexico,
´
´ ´
Circuito Interior, Ciudad Universitaria, Coyoacan, 04510 Mexico, D.F., Mexico
*E-mail: ecortes@servidor.unam.mx
Received December 1, 2008
DOI 10.1002/jhet.159
Published online 27 October 2009 in Wiley InterScience (www.interscience.wiley.com).
An easy synthesis of four steps to afforded 12 new derivatives of 3,3-dimethyl-2,3,4,5,10,11-hexahy-
dro-8-[(o-; and p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-[b,e][1,4]diazep-in-1-
ones IV, 1-12 with potential biological and pharmacological activity as sedative, hypnotic-muscular
relaxing, anticonvulsant, and schizophrenia treatment of the central nervous system (CNS). The final
products have been obtained with good yields, by condensation and cyclization between 3-{4-[(o-; and
p-methyl)phenoxy]-1,2-phenylendiamine}-5,5-dimethyl-2-cyclohexanone III, with the corresponding (o-;
1
and p-R)benzaldehyde. The structure of all derivatives was corroborated by spectroscopy of ir, H, and
13C NMR, with bi-dimensional experiments and EI-MS in low and high resolution with collision-
induced dissociation experiments (CID).
J. Heterocyclic Chem., 46, 1113 (2009).
INTRODUCTION
methyl-2,3,4,5,10,11-hexahydro-8-[(o-; and p-methyl)-
phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-
[b,e][1,4]di-azepin-1-ones IV, 1-12 (Fig. 1). The synthe-
sis of the dibenzo[b,e][1,4]diazepin-1-ones IV, 1-12
derivatives was carried out in four steps as shown in the
Scheme 1.
The reaction mixture of 5-chloro-2-nitroaniline with
the (o- and p-methyl)phenol in presence of anhydrous
potassium carbonate at reflux in anhydrous dimethyl-
formamide was heated for 5 h. After cooling, the reac-
tion mixture was diluted with cold water, the 3-amine-4-
nitrophenyl-[(o-; and p-methyl)phenyl]ether I that was
precipitated and collected by filtration with suction was
obtained in a 90–93% yield [8].
The first 1,4- and 1,5-benzodiazepines appeared in the
pharmaceutical industry as tranquilizers in the 1970’s,
their use and interest in recent years has been broader in
areas such as tranquilizer, sedative, hypnotic, muscular
relaxant, anticonvulsant, and schizophrenia treatment in
the central nervous system. The development of new
research projects using benzodiazepines and their appli-
cation has great importance because these types of com-
pounds have been used as antipsycotic drugs [1,2] and
also for their antianaphylactic activity [3].
RESULTS AND DISCUSSION
Hydrogenation of the corresponding ether I in ethanol
in presence of Pd/C 10% under a pressure of 60 pounds/
inch2 at room temperature with magnetic stirring for 22
h, we reduced the nitro group to amine. When the reac-
tion was finished, the catalyst Pd/C 10% was removed
To continue with our research program on the synthe-
sis and determination of biological activity in different
1,4 and 1,5-benzodiazepines [4–7], we described in this
report the synthesis of 12 new derivatives of 3,3-di-
C
V
2009 HeteroCorporation

´ ´
E. C. Cortes, O. E. Andrade Meneses, O. Garcıa-Mellado, O. C. Zun˜iga, and
´
E. B. Naranjo-Rodrıguez
1114
Vol 46
phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-
[b,e][1,4]diazepin-1-ones IV, 1-12 in 54–75% yields.
The infrared spectra of compounds IV, 1-12 displayed
absorptions at 3415–3299 cm–1 for NAH stretching; at
1700–1600 cmꢀ1 for C¼¼O stretching; at 1377–1369
and 1266–1263 cm–1 for CAN stretching; at 1187–1171
and 1114–1012 cm–1 for CAO stretching and the corre-
sponding absorptions for aromatic and R-substituents.
1
In the H NMR spectra the presence of two singlet
signals (2X3H) at d 1.01–1.12 and 1.11–1.15 were
assigned to the methyl protons joined at C-3. The pres-
ence of a doublet at d 2.18–2.31 and 2.28–2.34 was con-
sistent with the methylene protons at C-2; other doublet
signals at d 2.40–2.57 and 2.54–2.64 was assigned to
the methylene protons on C-4. The singlet signal at d
5.84–6.21 was consistent with methine proton on C-11.
The presence of a broad signal deuterium oxide
exchangeable proton a d 6.45–7.76 was consistent with
the NAH. The other signals corresponding at the
aromatic protons of the aromatic ring of dibenzodiaze-
pin-1-one appears as a doublet at d 5.60–6.12 and was
consistent with the proton at C-9; the presence of a sig-
nal doublet of doublet at d 6.26–6.40 correspond at the
proton on C-7 and the signal doublet at d 6.66–6.90 was
assigned at the proton on C-6.
Figure 1. Compounds IV, 1–12.
by filtration through celite and ethanol solution was
evaporated under reduced pressure. The 3,4-diamino-
phenyl-[(o-; and p-methyl)phenyl]ether II [9] was
obtained in very good yield of 95–98%.
Condensation of the derivatives II with 5,5-dimethyl-
1,3-cyclohexanedione at reflux in anhydrous benzene
with a Dean-Stark trap to eliminate the water produced;
afforded after evaporated the ethanol under reduced pres-
sure, the 3-{4-[(o-; and p-methyl)phenoxy]-1,2-phenylen-
diamine}-5,5-dimethyl-2-cyclohexenone III [10,11],
almost pure in 70–75% yield.
The other aromatic protons of the rings phenoxy and
phenyl substituent on the framework of the dibenzodia-
zepin-1-one appears as multiplet and as AA0BB0
systems at d 6.00–7.47. The signals for the methyl sub-
stituent in the aromatic rings were also observed as a
singlet signal at d 2.03–2.51.
Treatment of 1 equiv. of the corresponding 5,5-di-
methyl-2-cyclohexenone III, with 1 equiv. of the corre-
sponding (o-; and p-R2)benzaldehyde in the presence of
0.5 mL of glacial acetic acid at reflux in 10 mL of etha-
nol with magnetic stirring for 2–4 h afforded the 3,3-di-
methyl-2,3,4,5,10,11-hexahydro-8-[(o-; and p-methyl)-
The 13C NMR spectra data for compounds IV, 1-12
are given in Table 1. The signals were confirmed by
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 Efficient Synthesis and Spectroscopy of 3,3-Dimethyl-2,3,4,5,10,11-hexahydro-8-
[(o-; and p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-[b,e][1,4]diazepin-1-ones
1115
Table 1
13C NMR spectral data for compounds 1–12.
Compounds
1
2
3
4
5
6
7
8
9
10
11
12
R1
R2
o-CH3
o-CH3
193.8
49.8
o-CH3
p-CH3
193.6
49.7
o-CH3
o-Cl
193.6
49.7
32.3
o-CH3
p-Cl
193.7
49.7
32.3
o-CH3
o-Br
193.2
49.7
32.3
o-CH3
p-Br
193.3
49.6
p-CH3
o-CH3
193.6
49.6
p-CH3
p-CH3
193.7
49.7
p-CH3
o-Cl
192.7
49.2
32.3
p-CH3
p-Cl
193.6
49.7
32.3
p-CH3
o-Br
193.6
49.7
p-CH3
p-Br
193.8
49.7
C-1
C-2
C-3
C-4
32.3
46.1
32.3
46.4
32.0
45.4
32.4
46.2
32.3
46.3
32.4
46.3
32.3
46.4
46.1
46.5
46.2
46.0
46.2
C-4a
C-5a
C-6
153.8
127.3
120.9
111.5
153.6
111.0
138.5
55.4
110.9
155.0
129.0
130.5
123.2
126.8
118.2
141.2
135.1
131.2
126.7
125.2
125.7
27.9
153.0
126.5
120.9
111.0
153.7
110.9
138.8
57.8
118.5
154.9
140.7
131.3
123.5
126.8
118.6
135.9
128.8
127.0
129.2
127.0
128.8
27.8
153.8
127.1
120.9
111.6
154.7
111.0
138.9
56.1
109.2
154.9
129.1
131.2
123.4
128.1
118.3
133.5
139.9
129.6
126.8
126.1
127.6
28.2
153.1
126.4
121.0
111.3
154.2
110.9
138.4
57.6
110.5
154.8
129.4
131.4
123.7
127.0
118.9
132.3
128.4
128.3
142.2
128.3
128.4
27.9
154.7
127.0
121.0
111.6
154.0
111.1
138.8
58.3
109.5
154.9
129.1
131.3
123.5
126.7
118.4
129.1
141.4
132.9
128.4
126.8
127.7
28.2
154.8
127.0
121.6
111.6
153.6
110.9
137.7
57.6
109.4
154.2
129.1
131.2
123.3
126.9
118.5
129.1
128.9
130.9
142.4
130.9
128.9
27.6
153.8
127.8
121.1
111.9
153.3
111.3
138.6
55.5
111.9
155.3
130.2
117.7
129.9
117.7
130.2
130.4
135.5
132.2
126.9
125.4
125.8
27.8
153.2
127.0
121.0
112.2
153.3
111.0
138.5
57.8
111.0
155.3
130.0
118.0
132.3
118.0
130.0
136.0
127.0
128.8
140.5
128.8
127.0
27.8
156.0
126.8
122.0
112.9
153.7
112.0
139.7
56.1
109.2
155.2
129.9
117.8
132.3
117.8
129.9
133.6
139.7
129.6
128.2
126.2
127.6
28.1
153.5
126.9
121.4
112.4
153.7
112.1
138.3
57.6
110.3
155.1
130.1
118.1
132.3
118.1
130.1
132.5
128.3
128.2
142.2
128.5
128.3
27.8
153.4
127.4
120.9
112.7
154.4
112.3
138.7
58.3
109.6
155.2
130.0
117.7
132.6
117.7
130.0
132.6
142.5
133.0
128.4
126.7
127.7
28.2
153.3
126.8
121.1
112.4
153.8
112.1
138.3
57.7
110.4
155.1
130.1
118.2
132.6
118.2
130.1
129.0
131.2
128.9
142.8
128.9
131.2
27.9
C-7
C-8
C-9
C-9a
C-11
C-11a
C-10
C-20
C-30
C-40
C-500
C-600
C-100
C-200
C-3
C-400
C-500
C-600
C-3(CH3)
C-3(CH3)
28.6
16.0
28.7
16.0
28.5
16.0
28.6
16.0
28.4
16.0
28.6
15.9
28.6
28.8
28.4
28.7
28.5
28.6
0
C2 -CH3
0
C4 -CH3
–
20.6
–
21.0
–
20.6
–
20.6
–
20.6
–
20.7
–
00
C2 -CH3
00
C4 -CH3
19.5
–
–
20.9
–
–
–
–
–
–
–
19.6
–
–
20.6
–
–
–
–
–
–
–
–
–
The numbering of the phenyl ring is only for the assignment of the chemical shifts of the carbon in 13C NMR spectra.
using HETCOR, FLOCK, COSY, 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 24–55%.
The base peak is the ion at m/z [M-(76 þ R2)]þ. The
main fragmentation pathway was consistent with the
assigned structures and the mass spectra of the com-
pounds IV, 1-12 includes ions of m/z corresponding to
molecular ion [M]þ; [M-CH3]þ; [M-CH4]þ; [M-R2]þ;
[M-(R2þ CH4)]þ; [M-28]þ; [M-57]þ; [M-84]þ; [M-
85]þ; [M-(76 þ R2)]þ (the base peak); m/z 363 and 83.
The proposed fragmentation pathways leading to the
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´ ´
E. C. Cortes, O. E. Andrade Meneses, O. Garcıa-Mellado, O. C. Zun˜iga, and
´
E. B. Naranjo-Rodrıguez
1116
Vol 46
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(p-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 2). This compound was obtained as an orange solid in
70% yield; mp 240ꢁ; ir (chloroform): m NAH 3301, C¼¼O
1600, CAN 1376 and 1263, CAO 1185 and 1114 cm–1; 1H
formation of a number of important daughter ions have
been confirmed by the corresponding parent ion spectra,
using collision-induced dissociation experiments (CID).
The elemental composition of the molecular ion and the
principal fragment ion were determined by exact mass
measurements.
NMR (deuterochloroform):
d
1.08 and 1.13 (s, 6H,
0
00
C3A(CH3)2); 2.08 (s, 3H, C2 ACH3); 2.22 (s, 3H, C4 ACH3);
2.22 (d, 1H, J ¼ 16.5 Hz, 2-Ha); and 2.31 (d, 1H, J ¼ 16.5
Hz, 2-Hb); 2.40 (d, 1H, J ¼ 15.6 Hz, 4-Ha); and 2.57 (d, 1H,
J ¼ 15.6 Hz, 4-Hb); 5.86 (s, 1H, 11-H); 5.96 (d, 1H, J ¼ 2.4
Hz, 9-H); 6.32 (dd, 1H, J ¼ 2.7, 8.7 Hz, 7-H); 6.53 (bs, 2H,
NAH, deuterium oxide exchangeable); 6.57 (dd, 1H, J ¼ 1.2,
8.1 Hz, 60-H); 6.66 (d, 1H, J ¼ 8.7 Hz, 6-H); 6.92 (s, 4H, phe-
nyl protons of ‘‘E’’ ring); 6.99 (dt, 1H, J ¼ 1.5, 7.3 Hz, 40-H);
7.06 (dt, 1H, J ¼ 1.5, 7.4 Hz, 50-H); 7.16 (dd, 1H, Jþ¼ 1.2,
6.3 Hz, 30-H); ms (IE ¼ 70 eV): m/z (%) 438 (49) [M ]; 423
(6) [M-R1]þ [M-(CH3)]þ; 422 (9); 381 (6); 354 (7); 353 (6);
EXPERIMENTAL
The ir spectra were recorded on a Nicolet Magna TR-750
spectrophotometer in chloroform. 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 spectrometer operating at 125 MHz in deutero-
chloroform solution containing tetramethylsilane as the internal
standard with chemical shifts d (ppm) expressed downfield
from tetramethylsilane. The mass spectra were measured on a
JEOL JMS-AC505 and JEOL MS-SX 102A high-resolution
mass spectrometer 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 190ꢁC and ionizing
electron energy of 70 eV, using electronic ionization. The
compounds I, II, and III were prepared following methods
developed by us with modifications [8,9,12].
General procedure for the synthesis of the 3,3-dimethyl-
2,3,4,5,10,11-hexahydro-8-[(o-; and p-methyl)phenoxy]-11-
[(o-; and p-substituted)phenyl]-1H-dibenzo[b,e][1,4]diaze-
pin-1-ones IV, 1-12. A mixture of 1 equiv. of the corresponding
3-{4-[(o-; and p-methyl)phenoxy]-1,2-phenylendiamine}-5,5-
dimethyl-2-cyclo-hexenone III; 1 equiv. of the corresponding
(o-; and p-substituted)benzaldehyde, 0.5 mL of acetic acid gla-
cial in 10 mL ethanol was heated at reflux for 2–4 h. The reac-
tion mixture was cooled to room temperature and evaporated
in vacuo to yield a semisolid. The residual semisolid was puri-
fied on a silica gel by choromatography in column and elution
with hexane-ethyl acetate (95:5) to yield the compounds IV,
1–12, in 54–75%.
347 (100) [M-(76
C29H30N2O2: (438.55): C, 79.42; H, 6.90; N, 6.40; Found: C,
79.55; H, 6.76; N, 6.31.
þ
R1)]þ; 83 (4). Anal. Calcd. for
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(o-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 3). This compound was obtained as an orange solid in
75% yield; mp 105–107ꢁ; ir (chloroform): m NAH 3299, C¼¼O
1620, CAN 1376 and 1265, CAO 1186 and 1113 cm–1; 1H
NMR (deuterochloroform):
d
1.12 and 1.15 (s, 6H,
0
C3A(CH3)2); 2.04 (s, 3H, C2 ACH3); 2.23 (d, 1H, J ¼ 16.2
Hz, 2-Ha); and 2.32 (d, 1H, J ¼ 16.2 Hz, 2-Hb); 2.50 (d, 1H,
J ¼ 15.9 Hz, 4-Ha); and 2.61 (d, 1H, J ¼ 15.9 Hz, 4-Hb); 6.0
(dt, 1H, J ¼ 1.2; 7.8 Hz, 500-H); 6.01 (d, 1H, J ¼ 2.4 Hz, 9-
H); 6.21 (s, 1H, 11-H); 6.26 (dd, 1H, J ¼ 2.3, 8.8 Hz, 7-H);
6.43 (dd, 1H, J ¼ 1.0, 7.8 Hz, 60-H); 6.67 (d, 1H, J ¼ 8.7 Hz,
6-H); 6.78 (dd, 1H, J ¼ 1.3, 7.6 Hz, 600-H); 6.88 (bs, 2H,
NAH, deuterium oxide exchangeable); 7.01 (dt, 1H, J ¼ 1.2,
6.6 Hz, 40-H); 7.02 (dt, 1H, J ¼ 1.2, 7.8 Hz, 50-H); 7.03 (dt,
1H, J ¼ 1.5, 7.3 Hz, 400-H); 7.16 (dd, 1H, J ¼ 1.5, 6.5 Hz, 30-
H); 7.27 (dd, 1H, J ¼ 1.2, 6.6 Hz, 300-H); ms (IE ¼ 70 eV):
m/z (%) 460 (15) [M þ 2]þ; 458 (38) [Mþ]; 443 (5) [M-
(CH3)]þ; 442 (9); 423 (20) [M-R1]þ; 401 (4); 374 (5); 373 (4);
347 (100) [M-(76þ R1)]þ; 83 (3). Anal. Calcd. for
C28H27ClN2O2: (458.97): C, 73.27; H, 5.93; N, 6.10; Found:
C, 73.59; H, 5.81; N, 6.25.
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(o-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 1). This compound was obtained as an orange solid in
70% yield; mp 135–136ꢁ; ir (chloroform): m NAH 3415, C¼¼O
1619, CAN 1369 and 1264, CAO 1287 and 1113 cm–1; 1H
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(p-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 4). This compound was obtained as a yellow solid in 70%
yield; mp 220–222ꢁ; ir (chloroform): m NAH 3301, C¼¼O 1585,
CAN 1377 and 1264, CAO 1185 and 1114 cm–1; 1H NMR (deu-
terochloroform): d 1.08 and 1.14 (s, 6H, C3A(CH3)2); 2.08 (s,
NMR (deuterochloroform):
d
1.05 and 1.11 (s, 6H,
0
C3A(CH3)2); 2.05 (s, 3H, C2 ACH3); 2.18 (d, 1H, J ¼ 16.4
Hz, 2-Ha); and 2.28 (d, 1H, J ¼ 16.4 Hz, 2-Hb); 2.43 (d, 1H,
J ¼ 15.8 Hz, 4-Ha); and 2.56 (d, 1H, J ¼ 15.8 Hz, 4-Hb);
0
3H, C2 ACH3); 2.22 (d, 1H, J ¼ 16.5 Hz, 2-Ha); and 2.31 (d, 1H,
J ¼ 16.5 Hz, 2-Hb); 2.42 (d, 1H, J ¼ 16.2 Hz, 4-Ha); and 2.58
(d, 1H, J ¼ 16.2 Hz, 4-Hb); 5.85 (s, 1H, 11-H); 5.94 (d, 1H, J ¼
2.7 Hz, 9-H); 6.36 (dd, 1H, J ¼ 2.4, 8.8 Hz, 7-H); 6.45 (bs, 2H,
NAH, deuterium oxide exchangeable); 6.58 (dd, 1H, J ¼ 1.2, 7.8
Hz, 60-H); 6.68 (d, 1H, J ¼ 8.7 Hz, 6-H); 6.96 and 7.10 (AA0BB0,
4H, J ¼ 8.7 Hz, phenyl protons of ‘‘E’’ ring); 7.0 (dt, 1H, J ¼
1.2, 6.6 Hz, 40-H); 7.11 (dt, 1H, J ¼ 1.2, 6.6 Hz, 50-H); 7.17 (dd,
1H, J ¼ 1.2, 7.5 Hz, 30-H); ms (IE ¼ 70 eV): m/z (%) 460 (16)
[Mþ2]þ; 458 (40) [Mþ]; 443 (4) [M-(CH3)]þ; 442 (6); 401 (6);
374 (6); 373 (6); 347 (100) [M-(76 þ R1)]þ; 83 (3). Anal. Calcd.
for C28H27ClN2O2: (458.97): C, 73.27; H, 5.93; N, 6.10; Found:
C, 73.15; H, 5.80; N, 6.19.
00
2.50 (s, 3H, C2 ACH3); 5.88 (d, 1H, J ¼ 2.6 Hz, 9-H); 6.11
(s, 1H, 11-H); 6.27 (dd, 1H, J ¼ 2.6, 8.6 Hz, 7-H); 6.43 (dd,
1H, J ¼ 1.5, 7.8 Hz, 60-H); 6.64 (dd, 1H, J ¼ 1.1, 7.7 Hz, 600-
H); 6.72 (d, 1H, J ¼ 8.6 Hz, 6-H); 6.81 (dt, 1H, J ¼ 1.0, 7.2
Hz, 500-H); 6.96 (dt, 1H, J ¼ 1.4, 6.2 Hz, 40-H); 6.98 (dt, 1H,
J ¼ 1.5, 6.2 Hz, 400-H); 7.0 (bs, 2H, NAH, deuterium oxide
exchangeable); 7.05 (dt, 1H, J ¼ 2.1; 6.3 Hz, 50-H); 7.06 (dd,
1H, J ¼ 1.2, 8.0 Hz, 30-H); 7.14 (dd, 1H, J ¼ 1.7, 6.6 Hz, 300-
H); ms (IE ¼ 70 eV): m/z (%) 438 (55) [Mþ]; 423 (24) [M-
R1]þ [M-(CH3)]þ; 422 (14); 381 (4); 354 (6); 347 (100) [M-
(76 þ R1)]þ; 83 (5). Anal. Calcd. for C29H30N2O2: (438.55):
C, 79.42; H, 6.90; N, 6.40; Found: C, 79.50; H, 6.80; N, 6.49.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2009 Efficient Synthesis and Spectroscopy of 3,3-Dimethyl-2,3,4,5,10,11-hexahydro-8-
[(o-; and p-methyl)phenoxy]-11-[(o-; and p-substituted)phenyl]-1H-dibezo-[b,e][1,4]diazepin-1-ones
1117
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(o-bromo)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 5). This compound was obtained as an orange solid in
60% yield; mp 72–74ꢁ; ir (chloroform): m NAH 3413, C¼¼O
1700, CAN 1371 and 1266, CAO 1285 and 1113 cm–1; 1H
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(p-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 8). This compound was obtained as a yellow solid in
54% yield; mp 47-49ꢁ; ir (chloroform): m NAH 3415, C¼¼O
1618, CAN 1369 and 1264, CAO 1172 and 1016 cm–1; 1H
NMR (deuterochloroform):
d
1.09 and 1.12 (s, 6H,
NMR (deuterochloroform):
d
1.08 and 1.13 (s, 6H,
0
C3A(CH3)2); 2.03 (s, 3H, C2 ACH3); 2.21 (d, 1H, J ¼ 16.5
Hz, 2-Ha); and 2.30 (d, 1H, J ¼ 16.5 Hz, 2-Hb); 2.51 (d, 1H,
J ¼ 15.3 Hz, 4-Ha); and 2.62 (d, 1H, J ¼ 15.3 Hz, 4-Hb);
6.01 (d, 1H, J ¼ 2.4 Hz, 9-H); 6.14 (s, 1H, 11-H); 6.26 (dd,
1H, J ¼ 2.3, 8.8 Hz, 7-H); 6.43 (dd, 1H, J ¼ 1.8, 7.8 Hz, 60-
H); 6.72 (d, 1H, J ¼ 8.1 Hz, 6-H); 6.77 (dd, 1H, J ¼ 1.8, 6.8
Hz, 600-H); 6.78 (bs, 2H, NAH, deuterium oxide exchange-
able); 6.91 (dt, 1H, J ¼ 1.8, 6.6 Hz, 400-H); 6.94 (dt, 1H, J ¼
1.8; 6.3 Hz, 500-H); 6.97 (dt, 1H, J ¼ 1.8, 7.2 Hz, 40-H); 7.03
(dt, 1H, J ¼ 2.1, 7.5 Hz, 50-H); 7.15 (dd, 1H, J ¼ 1.5, 7.2 Hz,
30-H); 7.44 (dd, 1H, J ¼ 1.5, 6.6 Hz, 300-H); ms (IE ¼ 70 eV):
m/z (%) 504 (24) [M þ 2]þ; 502 (24) [Mþ]; 487 (5) [M-
C3A(CH3)2); 2.21 (d, 1H, J ¼ 16.2 Hz, 2-Ha); and 2.30 (d,
0
1H, J ¼ 16.2 Hz, 2-Hb); 2.23 (s, 3H, C4 ACH3); 2.29 (s, 3H,
00
C4 ACH3); 2.42 (d, 1H, J ¼ 15.9 Hz, 4-Ha); and 2.57 (d, 1H,
J ¼ 15.9 Hz, 4-Hb); 5.88 (s, 1H, 11-H); 6.08 (d, 1H, J ¼ 2.5
Hz, 9-H); 6.38 (dd, 1H, J ¼ 2.5, 8.6 Hz, 7-H); 6.64 and 7.03
(AA0BB0, 4H, J ¼ 8.8 Hz, phenyl protons of ‘‘D’’ ring); 6.72
(d, 1H, J ¼ 8.8 Hz, 6-H); 6.75 (bs, 2H, NAH, deuterium oxide
exchangeable); 6.93 (s, 4H, phenyl protons of ‘‘E’’ ring); ms
(IE ¼ 70 eV): m/z (%) 438 (44) [Mþ]; 423 (8) [M-R1]þ [M-
(CH3)]þ; 422 (6); 381 (8); 354 (10); 353 (9); 347 (100) [M-
(76 þ R1)]þ; 83 (3). Anal. Calcd. for C29H30N2O2: (438.55):
C, 79.42; H, 6.90; N, 6.40; Found: C, 79.51; H, 6.79; N, 6.52.
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(o-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 9). This compound was obtained as a yellow solid in
70% yield; mp 42-44ꢁ; ir (chloroform): m NAH 3413, C¼¼O
1618, CAN 1369 and 1265, CAO 1172 and 1117 cm–1; 1H
(CH3)]þ; 486 (8); 423 (36) [M-R1]þ; 407 (7) [M-(R1
þ
CH4)]þ; 445 (3); 418 (3); 417 (3); 347 (100) [M-(76 þ R1)]þ;
83 (3). Anal. Calcd. for C28H27BrN2O2: (503.34): C, 66.81; H,
5.41; N, 5.57; Found: C, 66.92; H, 5.33 N, 5.50.
3,3-Dimethyl-8-[(o-methyl)phenoxy]-11-[(p-bromo)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 6). This compound was obtained as a brown solid in 73%
yield; mp 208–210ꢁ; ir (chloroform): m NAH 3413, C¼¼O
1618, CAN 1369 and 1266, CAO 1185 and 1112 cm–1; 1H
NMR (deuterochloroform):
d
1.12 and 1.14 (s, 6H,
0
C3A(CH3)2); 2.29 (s, 3H, C4 ACH3); 2.22 (d, 1H, J ¼ 16.4
Hz, 2-Ha); and 2.31 (d, 1H, J ¼ 16.4 Hz, 2-Hb); 2.57 (d, 1H,
J ¼ 16.2 Hz, 4-Ha); and 2.64 (d, 1H, J ¼ 16.2 Hz, 4-Hb);
6.11 (d, 1H, J ¼ 2.7 Hz, 9-H); 6.20 (s, 1H, 11-H); 6.33 (dd,
1H, J ¼ 2.7, 8.4 Hz, 7-H); 6.56 and 7.02 (AA0BB0, 4H, J ¼
8.4 Hz, phenyl protons of ‘‘D’’ ring); 6.74 (bs, 2H, NAH, deu-
terium oxide exchangeable); 6.77 (dd, 1H, J ¼ 1.3, 7.5 Hz,
600-H); 6.82 (d, 1H, J ¼ 8.7 Hz, 6-H); 6.92 (dt, 1H, J ¼ 1.2;
7.5 Hz, 500-H); 7.04 (dt, 1H, J ¼ 1.8, 7.7 Hz, 400-H); 7.28 (dd,
1H, J ¼ 1.5, 7.2 Hz, 300-H); ms (IE ¼ 70 eV): m/z (%) 460
(16) [Mþ2]þ; 458 (40) [Mþ]; 443 (3) [M-(CH3)]þ; 442 (5);
423 (20) [M-R1]þ; 401 (5); 374 (6); 373 (5); 347 (100) [M-(76
þ R1)]þ; 83 (3). Anal. Calcd. for C28H27ClN2O2: (458.97): C,
73.27; H, 5.93; N, 6.10; Found: C, 73.33; H, 5.84; N, 6.22.
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(p-chloro)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 10). This compound was obtained as an orange solid in
54% yield; mp 87–88ꢁ; ir (chloroform): m NAH 3413, C¼¼O
1618, CAN 1369 and 1266, CAO 1173 and 1016 cm–1; 1H
NMR (deuterochloroform):
d
1.07 and 1.13 (s, 6H,
0
C3A(CH3)2); 2.08 (s, 3H, C2 ACH3); 2.20 (d, 1H, J ¼ 16.4
Hz, 2-Ha); and 2.29 (d, 1H, J ¼ 16.4 Hz, 2-Hb); 2.49 (d, 1H,
J ¼ 16.0 Hz, 4-Ha); and 2.58 (d, 1H, J ¼ 16.0 Hz, 4-Hb);
5.60 (d, 1H, J ¼ 2.4 Hz, 9-H); 5.9 (s, 1H, 11-H); 6.37 (dd,
1H, J ¼ 2.5, 8.7 Hz, 7-H); 6.54 (dd, 1H, J ¼ 1.5, 7.5 Hz, 60-
H); 6.9 (d, 1H, J ¼ 8.4 Hz, 6-H); 6.93 and 7.24 (AA0BB0, 4H,
J ¼ 8.4 Hz, phenyl protons of ‘‘E’’ ring); 7.0 (dt, 1H, J ¼ 1.5,
7.4 Hz, 40-H); 7.14 (dt, 1H, J ¼ 1.6, 7.5 Hz, 50-H); 7.18 (dd,
1H, J ¼ 1.5, 7.5 Hz, 30-H); 7.76 (bs, 2H, NAH, deuterium ox-
ide exchangeable);; ms (IE ¼ 70 eV): m/z (%) 504 (31) [M þ
2]þ; 502 (32) [Mþ]; 487 (3) [M-(CH3)]þ; 486 (4); 445 (4);
418 (5); 417 (4); 347 (100) [M-(76 þ R1)]þ; 83 (4). Anal.
Calcd. for C28H27BrN2O2: (503.34): C, 66.81; H, 5.41; N,
5.57; Found: C, 66.70; H, 5.50; N, 5.68.
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(o-methyl)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 7). This compound was obtained as a yellow solid in 51%
yield; mp 102–104ꢁ; ir (chloroform): m NAH 3414, C¼¼O 1617,
CAN 1369 and 1263, CAO 1171 and 1016 cm–1; 1H NMR (deu-
terochloroform): d 1.01 and 1.13 (s, 6H, C3A(CH3)2); 2.19 (d,
1H, J ¼ 16.2 Hz, 2-Ha); and 2.31 (d, 1H, J ¼ 16.2 Hz, 2-Hb);
NMR (deuterochloroform):
d
1.06 and 1.12 (s, 6H,
C3A(CH3)2); 2.20 (d, 1H, J ¼ 16.1 Hz, 2-Ha); and 2.30 (d,
0
1H, J ¼ 16.1 Hz, 2-Hb); 2.30 (s, 3H, C4 ACH3); 2.41 (d, 1H,
J ¼ 15.8 Hz, 4-Ha); and 2.56 (d, 1H, J ¼ 15.8 Hz, 4-Hb);
5.87 (s, 1H, 11-H); 6.05 (d, 1H, J ¼ 2.6 Hz, 9-H); 6.39 (dd,
1H, J ¼ 2.5, 8.6 Hz, 7-H); 6.5 (bs, 2H, NAH, deuterium oxide
exchangeable); 6.63 and 7.06 (AA0BB0, 4H, J ¼ 8.5 Hz, phe-
nyl protons of ‘‘D’’ ring); 6.71 (d, 1H, J ¼ 8.5 Hz, 6-H); 6.96
and 7.10 (AA0BB0, 4H, J ¼ 8.5 Hz, phenyl protons of ‘‘E’’
ring); ms (IE ¼ 70 eV): m/z (%) 460 (12) [M þ 2]þ; 458 (36)
[Mþ]; 443 (3) [M-(CH3)]þ; 442 (5); 401 (5); 374 (6); 373 (5);
0
2.28 (s, 3H, C4 ACH3); 2.48 (d, 1H, J ¼ 16.2 Hz, 4-Ha); and
00
2.54 (d, 1H, J ¼ 16.2 Hz, 4-Hb); 2.51 (s, 3H, C2 ACH3); 6.00 (d,
1H, J ¼ 2.1 Hz, 9-H); 6.14 (s, 1H, 11-H); 6.39 (dd, 1H, J ¼ 2.4,
8.7 Hz, 7-H); 6.55 and 7.01 (AA0BB0, 4H, J ¼ 8.7 Hz, phenyl
protons of ‘‘D’’ ring); 6.75 (bs, 2H, NAH, deuterium oxide
exchangeable); 6.80 (dd, 1H, J ¼ 1.3, 7.6 Hz, 600-H); 6.81 (d, 1H,
J ¼ 7.8 Hz, 6-H); 6.82 (dt, 1H, J ¼ 1.6, 7.6 Hz, 500-H);6.99 (dt,
1H, J ¼ 1.5, 6.2 Hz, 400-H); 7.08 (dd, 1H, J ¼ 1.6, 8.1 Hz, 300-H);
ms (IE ¼ 70 eV): m/z (%) 438 (52) [Mþ]; 423 (19) [M-R1]þ [M-
(CH3)]þ; 422 (12); 381 (3); 354 (5); 353 (4); 347 (100) [M-(76 þ
R1)]þ; 83 (5). Anal. Calcd. for C29H30N2O2: (438.55): C, 79.42;
H, 6.90; N, 6.40; Found: C, 79.51; H, 6.79; N, 6.52.
347 (100) [M-(76
þ
R1)]þ; 83 (4). Anal. Calcd. for
C28H27ClN2O2: (458.97): C, 73.27; H, 5.93; N, 6.10; Found:
C, 73.39; H, 6.03; N, 6.02.
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(o-bromo)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 11). This compound was obtained as an orange solid in
68% yield; mp 99–101ꢁ; ir (chloroform): m NAH 3413, C¼¼O
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

´ ´
E. C. Cortes, O. E. Andrade Meneses, O. Garcıa-Mellado, O. C. Zun˜iga, and
´
E. B. Naranjo-Rodrıguez
1118
Vol 46
1619, CAN 1369 and 1264, CAO 1172 and 1023 cm–1; 1H
NMR (deuterochloroform): 1.12 and 1.15 (s, 6H,
Acknowledgments. This work was supported by UNAM-
´
d
DGAPA project IN225503. The authors wish to thank J. Perez for
C3A(CH3)2); 2.22 (d, 1H, J ¼ 16.5 Hz, 2-Ha); and 2.34 (d,
their assistance in acquisition of the mass spectral data, H. Rios
for the nmr determination, and M. Adaya for ir determination.
´
Contribution No. 2649 from Instituto de Quımica, UNAM.
0
1H, J ¼ 16.5 Hz, 2-Hb); 2.29 (s, 3H, C4 ACH3); 2.50 (d, 1H,
J ¼ 15.9 Hz, 4-Ha); and 2.62 (d, 1H, J ¼ 15.9 Hz, 4-Hb);
6.12 (d, 1H, J ¼ 2.4 Hz, 9-H); 6.16 (s, 1H, 11-H); 6.34 (dd,
1H, J ¼ 2.5, 8.5 Hz, 7-H); 6.55 (dt, 1H, J ¼ 1.2; 6.3 Hz, 500-
H); 6.71 (d, 1H, J ¼ 8.7 Hz, 6-H); 6.78 (dd, 1H, J ¼ 2.1, 7.8
Hz, 600-H); 6.80 (bs, 2H, NAH, deuterium oxide exchange-
able); 6.96 (dt, 1H, J ¼ 1.2, 6.3 Hz, 400-H); 7.26 (s, 4H, phenyl
protons of ‘‘D’’ ring); 7.47 (dd, 1H, J ¼ 2.7, 6.2 Hz, 300-H);
ms (IE ¼ 70 eV): m/z (%) 504 (26) [M þ 2]þ; 502 (25)
[Mþ]; 487 (8) [M-(CH3)]þ; 486 (8); 423 (34) [M-R1]þ; 407
(14) [M-(R1 þ CH4)]þ; 445 (3); 418 (4); 417 (3); 347 (100)
[M-(76 þ R1)]þ; 83 (5). Anal. Calcd. for C28H27BrN2O2:
(503.34): C, 66.81; H, 5.41; N, 5.57; Found: C, 66.73; H, 5.32
N, 5.49.
REFERENCES AND NOTES
[1] Warawa, E. J.; Migler, B. M.; Ohnmacht, C. J.; Needles, G.
C.; Gatos, F. M.; McLaren, C. L.; Nelson, K.; Kirkland, A. L. J Med
Chem 2001, 44, 372.
[2] Shapiro, D. A.; Renock, S.; Arrington, E.; Chiodo, L. A.;
Liu, L. X.; Sibley, D. R.; Roth, B. L.; Mailman, R. Neuropsychophar-
macology 2003, 28, 1400.
[3] Greig, M. E.; Gibbson, A. J.; Young, G. A. J Med Chem
1971, 14, 153.
3,3-Dimethyl-8-[(p-methyl)phenoxy]-11-[(p-bromo)phenyl]-
2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one
(IV, 12). This compound was obtained as a brown solid in
52% yield; mp 170–172ꢁ; ir (chloroform): m NAH 3413, C¼¼O
1618, CAN 1369 and 1266, CAO 1173 and 1012 cm–1; 1H
´
´
[4] Cortes, E.; Salazar, R.; Garcıa, O. J Heterocycl Chem 2001,
38, 663.
[5] Cortes, E.; Ebromares, I.; Garcıa, O. J Heterocycl Chem
2002, 39, 1189.
´
´
NMR (deuterochloroform):
d
1.07 and 1.13 (s, 6H,
´ ´ ´
[6] Cortes, E.; Perez, E.; Garcıa, O. J Heterocycl Chem 2007,
C3A(CH3)2); 2.21 (d, 1H, J ¼ 16.5 Hz, 2-Ha); and 2.309 (d,
44, 189.
0
1H, J ¼ 16.5 Hz, 2-Hb); 2.30 (s, 3H, C4 ACH3); 2.43 (d, 1H,
´ ´ ´
[7] Naranjo, E. B.; Sanchez, I.; Ortiz, A.; Garcıa, O.; Cortes, E.
J ¼ 15.9 Hz, 4-Ha); and 2.58 (d, 1H, J ¼ 15.9 Hz, 4-Hb);
5.84 (s, 1H, 11-H); 6.05 (d, 1H, J ¼ 2.4 Hz, 9-H); 6.64 and
7.07 (AA0BB0, 4H, J ¼ 8.4 Hz, phenyl protons of ‘‘D’’ ring);
6.40 (dd, 1H, J ¼ 2.6, 8.8 Hz, 7-H); 6.58 (bs, 2H, NAH, deu-
terium oxide exchangeable); 6.71 (d, 1H, J ¼ 8.7 Hz, 6-H);
6.91 and 7.25 (AA0BB0, 4H, J ¼ 8.4 Hz, phenyl protons of
‘‘E’’ ring); ms (IE ¼ 70 eV): m/z (%) 504 (23) [M þ 2]þ;
502 (24) [Mþ]; 487 (3) [M-(CH3)]þ; 486 (3); 445 (3); 418 (4);
417 (3); 347 (100) [M-(76 þ R1)]þ; 83 (3). Anal. Calcd. for
C28H27BrN2O2: (503.34): C, 66.81; H, 5.41; N, 5.57; Found:
C, 66.95; H, 5.28; N, 5.68.
Proc West Pharmacol Soc 2007, 49, 126.
´
[8] Cortes, E.; Araluce, L. A. J Heterocycl Chem 1997, 34,
745.
611.
´ ´
[9] Cortes, E.; Sanchez, M. P. J Heterocycl Chem 1999, 36,
´ ´ ´
[10] Cortes, E.; Hernandez, A. M.; Garcıa, O. J Heterocycl
Chem 2002, 39, 55.
´ ´
[11] Cortes, E.; Adaya, M.; Garcıa, O. J Heterocycl Chem 2004,
41, 277.
´
[12] Cortes, E.; Valencia, A. L; Garcia-Mellado, O. J Heterocycl
Chem 2007, 44, 183.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet