Synthesis of 5-benzyl-4-aryl-octahydro-1H-benzo[b][1,5]diazepin-2-ones as potent antidepressant and antimicrobial agents

Article abstract of DOI:10.1007/s00044-013-0694-1

The present study describes the chemical synthesis and pharmacological evaluation of a new series of 11 compounds of aryloctahydrobenzo[b][1,5]- diazepin-2-one in the forced-swimming test in mice. Three compounds (3e, 3f and 3h) exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration. The potent compounds did not show any neurotoxicity in the rotarod test, and the preliminary results are promising enough to warrant further studies around this scaffold. All the compounds were also screened for antimicrobial activity against P. aeruginosa, E. coli, S. Aureus and B. subtilis strains. Some of the compounds possessed marked antimicrobial activities comparable to that of reference drug, Ciprofloxacin. Springer Science+Business Media 2013.

Full text of DOI:10.1007/s00044-013-0694-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2014) 23:2070–2079
DOI 10.1007/s00044-013-0694-1
ORIGINAL RESEARCH
Synthesis of 5-benzyl-4-aryl-octahydro-1H-benzo[b][1,5]diazepin-
2-ones as potent antidepressant and antimicrobial agents
•
Mariappan Babu Kasi Pitchumani
•
Penugonda Ramesh
Received: 24 March 2013 / Accepted: 6 August 2013 / Published online: 6 October 2013
Ó Springer Science+Business Media New York 2013
Abstract The present study describes the chemical syn-
thesis and pharmacological evaluation of a new series of 11
compounds of aryloctahydrobenzo[b][1,5]-diazepin-2-one
in the forced-swimming test in mice. Three compounds
(3e, 3f and 3h) exhibited impressive antidepressant activ-
ity, measured in terms of percentage decrease in immo-
bility duration. The potent compounds did not show any
neurotoxicity in the rotarod test, and the preliminary results
are promising enough to warrant further studies around this
scaffold. All the compounds were also screened for anti-
microbial activity against P. aeruginosa, E. coli, S. Aureus
and B. subtilis strains. Some of the compounds possessed
marked antimicrobial activities comparable to that of ref-
erence drug, Ciprofloxacin.
problem with the current antidepressant therapies is the sev-
eral side effects (e.g. anti-cholinergic, gastrointestinal dis-
tress, anxiety, insomnia and sexual dysfunction) produced by
thesedrugsbesidestheir slowonsetofaction(Mendels,1992).
Clinical limitations and adverse effects of currently used
antidepressants necessitate continuous development of novel,
efficient and safe drugs for the treatment of depression.
Benzodiazepines were first introduced for the treatment of
anxiety, then later on, they have been used as sedatives, an-
ticonvulsants, antibacterial, antifungal and muscle relaxants
(Shader and Greenblatt, 1993; Schutz and Benzodiazepines,
1982; Landquist, 1984; Failli et al., 2006; Hadac et al., 2006).
Many benzodiazepine and their derivatives underwent
extensive investigations aimed to assess their potential bene-
ficial effects on human health. The recognition of key struc-
tural features within benzodiazepine family is crucial for the
design and development of new analogues with improved
activity and for the characterization of their mechanism of
action and potential side effects. The different substituents in
the benzodiazepine nucleus strongly influence the biological
activity of the resulting derivatives. Therefore, considerable
attention has been drawn to devise improved methods for the
preparation of 1,5-benzodiazepinones.
Keywords Benzodiazepines ꢀ Forced swim test ꢀ
Disc diffusion method ꢀ Antidepressant ꢀ
Antibacterial activity
Introduction
Depression is one of the most prevalent psychopathologies
and its therapy relies on classical antidepressant drugs such as
monoamine oxidase inhibitors and drugs that inhibit the re-
uptake of catecholamines (Richelson, 1994). A common
A scrutiny of literature on pharmacological properties of
1,4-benzodiazepines emphasised that there was scanty
information on the medicinal properties of the isomeric
1,5-benzodiazepine derivatives (Srinivas et al., 2007; Saini
et al., 2008; Hekmatshoar et al., 2009; Escobar et al.,
2009). Further, there is virtually no record of synthesis of
any derivative of either 1,4- or 1,5-benzodiazepine bearing
phenyl ring is saturated (Yadav et al., 2004; Guzen et al.,
2006; Vaghei and Veisi, 2010; Polshettiwar and Varma,
2008; Madhav and Rajitha, 2008; Insuasty et al., 2008).
These observations prompted us to undertake the synthesis
of a series of 5-benzyl-4-aryloctahydrobenzo[b][1,5]diazepin-
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-013-0694-1) contains supplementary
material, which is available to authorized users.
M. Babu ꢀ K. Pitchumani ꢀ P. Ramesh (&)
Department of Natural Products Chemistry, School of
Chemistry, Madurai Kamaraj University, Madurai 625021,
Tamil Nadu, India
e-mail: npc_ramesh@yahoo.co.in; npc_ramesh@yahoo.com
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Med Chem Res (2014) 23:2070–2079
2071
2-ones with a view to evaluate them for antidepressant and
antimicrobial activities.
ATCC 9027, Escherichia coli ATCC 35218, Staphylococcus
aureus ATCC 6538 and Bacillus subtilis ATCC 6631) by
disc diffusion method (Smyth et al., 1991; Reid Pelczar and
Cohn, 1989) using MH medium (Mueller–Hinton medium).
Clomipramine (the antidepressant drug) and Ciprofloxacin
(the antibacterial drug) were used as reference standards.
All compounds 1a–k (Babu et al., 2012) were homo-
geneous on TLC and contained nitrogen. The presence of
Results and discussion
The general synthetic route to the core octahydro-1H–ben-
zo[b][1,5] diazepin-2-one scaffold can be seen in Scheme 1.
Reaction of the 1-benzyl-2-aryldecahydroquinolin-4-one
1a–k with hydroxylamine hydrochloride provided the
intermediate oximes 2a–k, which served as an useful pre-
cursors for construction of the desired products. Selective
Beckmann rearrangement of the oximes induced by thionyl
chloride afforded the 5-benzyl-4-aryl-octahydro-1H-
benzo[b][1,5]diazepin-2-ones 3a–k. All the intermediates
and final products were characterized by their analytical and
spectroscopic data.
CO function was evident from an IR band at 1,722 cm-1
.
1
In the H NMR spectrum of 1a, the one-proton doublet of
doublet (J = 12.0 and 2.4) centered at d 3.37 was ascribed
to N-benzylic methine proton (H-2, NCH/) based on its
multiplicity pattern that arises due to its coupling interac-
tion with the adjacent axial (Ha) and equatorial (He) pro-
tons of C-3, while the two-proton singlet at d 3.71 was
assigned to N-benzylic methylene protons. The upfield
complex multiplet (12H) in the region d 1.16–2.85 was
associated with methylene and methine protons of the
heterocyclic ring, and the aromatic protons (10H) resonated
as complex multiplet in the region d 7.25–7.74. The 13C
NMR spectrum of 1a registered only seven signals for
The newly synthesized compounds (3a–k) were screened
for antidepressant activity by forced swim test (FST) (Porsolt
et al., 1977; Porsolt et al., 1978) and antibacterial activity
against four bacterial strains (Pseudomonas aeruginosa
Scheme 1 Beckmann
rearrangement of oxime to 1,5-
benzodiazepinone 3a–k
O
N
NOH
O
H
N
NH2OH. HCl
SOCl2
Ar
dry ether
EtOH
N
NaOAc /
Ar
N
∇
Ar
1 a-k
2 a-k
3 a-k
ArCHO
φCH2NH2
O
Me
3
i
Ar
Ar
3
e
Ar
3
a
Cl
NO2
Cl
Br
H3CO
b
c
f
g
h
O
H3CO
H3CO
j
O
O2N
Br
k
d
N
Cl
123

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Med Chem Res (2014) 23:2070–2079
aliphatic carbons which were grouped into five methylene
and two methine carbons based on DEPT-135 experiment.
The far downfield signal at d 198.28 substantiated the IR
band at 1,722 cm-1 was assigned to oxo function of the
six-membered ring. Thus, based on the spectroscopic data,
compound 1a was formulated as 1-benzyl-2-phenyldeca-
hydroquinolin-4-one; its identity was further confirmed by
HMBC experiment. The MS of 1a with its molecular ion
and base peaks at m/z 319 (10), 242 (Mþꢁ ꢁ C6H5ꢂ), along
with diagnostic fragment ions 291 (Mþꢁ ꢁ CO), 292
[(Mþꢁ þ Hꢂ)–CO], further supported the structure assigned
to 1a based on NMR spectral data.
OH
3
N
4
N
5
8
OH
10
9
6
7
1
2
N
Ph
N
Ph
Ph
Ph
2a (E)-oxime
Fig. 1 Chair form representation of t-decahydroqinoline oxime
H
O
O
2
3
N
NH
1
The presence of oxime in compounds 2a–k was evident
by an IR band at 3,419 cm-1, (oxime hydroxyl) and
1,591 cm-1 (C=N stretching band) and by the absence of
characteristic IR band (at 1,722 cm-1) for the oxo function
N
N
5
4
Ph
Ph
Ph
Ph
3a (A)
1
of its precursor 1a. The H NMR spectrum displayed, in
3a (B)
addition to signals due to protons of N-benzylic methine (d
3.12 dd) and N-benzylic methylene (d 3.56, s), a downfield
one-proton signal at d 11.04 that exchanged with D2O and
disappeared on acetylation (Ac2O/Py, room temperature)
was assigned to oxime hydroxy. The 13C NMR spectrum of
2a displayed signals for nine aliphatic carbon atoms which
were grouped into six methylene and three methine carbons
based on DEPT experiment. The only one downfield car-
bon signal at d 158.71 was assigned to ipso carbon
(C=NOH) (Breitmaier and Voelter, 1987).
N-H
φ
O
N
X
1
A comparison of the spectroscopic data (IR, H NMR
Fig. 2 Chair form representation of 1,5-benzodiazepinones
and 13C NMR) of 2a with that of its precursor 1a estab-
lished the structure of the oxime beyond doubt. However,
the oxime 2a can exist in two isomeric forms Z and E dif-
fering in the spatial orientation of the oxime hydroxyl. A
choice between the two isomeric forms, Z and E, was made
based on the assumption that Z-isomer was subjected to
A1,3-type of interaction, and therefore was less stable than
E-isomer in which no such interaction exists.
in it. The presence of lactam ring in 3a was evident from IR
bands at 3,316 cm-1 (NH stretch), 1,678 cm-1(C=O of
amide) and by the appearance of fragment ion at m/z 291
(Mþꢁ ꢁꢂ NCO). This conclusion was also supported by its 1H
NMR spectrum which displayed in addition to signals due to
protons of –NCHPh (d 4.02, dd) and –NCH2Ph (d 3.62, s), a
downfield sharp one-proton signal at d 8.62 assignable to the
proton of –NH–CO group. The downfield shift in signal due
to N-benzylic methine proton (–NCHPh) (d 4.02 dd) relative
Further support for the assignment of E-configuration for
the oxime 2a is based on the generalization that oximation of
a ketone results in an upfield shift in a-carbon atoms of the
oxime; the magnitude of the shift is much larger in syn a-
carbon atom than in anti a-carbon atom (Breitmaier and
Voelter, 1987). A comparison of 13C NMR spectral data of
the oxime 2a with that of its precursor 1a (ketone) disclosed
that the C-3 (C-a) of the former resonated at higher field (d
34.58) than that of the latter (d 49.35); a large upfield shift of
14.77 ppm in C-3 of 2a proves that the oxime OH was syn to
C-3 and hence, the configuration of the oxime 2a was
E. Based on the spectroscopic data and on the above gen-
eralisation, the oxime 2a was formulated as E-1-benzyl-2-
phenyloctahydroquinolin-4-one oxime (Fig. 1).
to that of its precursor 2a (d 3.12 dd) is noteworthy. The 13
C
NMR spectrum of 3a resembled that of its precursor 2a
(oxime) in all respects except for the presence of a downfield
signal at d 176.82 which was assigned to amide carbon. Thus,
1
a comparison of spectroscopic data (IR, H NMR and 13C
NMR) of 3a with that of its precursor 2a (oxime) proved
beyond doubt the formation of lactam ring in 3a (Fig. 2).
It was well established that during Beckmann rear-
rangement, the group anti to oxime hydroxy is the one that
migrates, although there are some exceptions. Since the
structure of the oxime 2a (the precursor of 3a) has been
established as E-oxime, the 4–10 bond of 2a which is anti
to oxime hydroxy is expected to migrate during Beckmann
rearrangement to afford 3a (A).
Compound 3a, the product of Beckmann rearrangement
contained nitrogen and its MS recorded molecular ion peak
at m/z 334 (26) revealing the presence of two nitrogens atoms
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Med Chem Res (2014) 23:2070–2079
2073
O
H
N
Table 1 Antidepressant activity of the compounds 3a–k
(176.8)
(46.5)
Compounds
3a–k
Duration of
immobility in
secs.
%
Neurotoxicity
coordination time in
secs. (mean SEM)
change
from
controla
(4.02)
H
(54.8)
N
(mean SEM)
(58.9)
(138.6)
2)
a (Ph)
40.1 3.06
52.2 1.93
69.3 5.52
34.0 3.53
28.7 2.51
26.3 3.71
32.6 4.67
25.3 2.88
34.0 3.42
39.4 2.39
-81.56 100.33 1.80
CH2
(3.6
b (2-Cl)
-78.23
-71.10
-85.82
-88.03
-89.03
-86.40
-89.44
-85.82
-83.56
95.17 2.52
91.33 3.27
93.67 2.98
90.83 2.34
96.50 2.67
97.83 2.26
93.50 3.97
92.34 3.09
97.17 2.36
(138.6)
c (2-Br)
(128.9)
d (4-Br)
e (4-Cl)
Fig. 3 Selected HMBC correlations for 3a
f (3,4-OMe)
g (4-OMe)
h (4-NO2)
i (3-NO2)
A choice in favour of 3a (A) has been arrived based on
HMBC experiment. A scrutiny of HMBC spectrum of the
product of Beckmann rearrangement 3a (Fig. 3), revealed
that the proton signal at 4.02 (H-3, dd) correlated with carbon
signal at d 176.8 (amide CO). An examination of reference
structures for isomeric lactams 3a (A) and 3a (B) disclosed
that such inverse three bond correlation between N-benzylic
methine proton (–NCH/) (d 4.02 dd) and carbonyl carbon of
amide group (–CONH) (d 176.8) was possible only in
structure 3a (A) but not in 3a (B). Therefore, the product of
Beckmann rearrangement 3a was characterised as 5-benzyl-
4-phenyloctahydro-1H-benzo[b][1,5]diazepin-2-(3H)-one.
j (3-
chromonyl)
k (2-chloro-
quinolin-3-
yl)
35.3 3.53
-85.27
98.33 2.93
Clomipramine 18.68 2.25
-92.21 110.83 1.49
Control
112.4 2.88
–
a
Compounds were tested at 20 mg kg-1 dose level, ip
Although, methoxyl in 4-position can exert both elec-
tron-withdrawing inductive (-I) and electron-donating
mesomeric effect (?M), in the absence of direct conjuga-
tion of 4-aryl group with heterocyclic ring, its -I effect
dominates over ?M effect, that is, it can be regarded as an
electron-withdrawing group.
In vitro antidepressant activity
The main objective of this study is to modulate the effect
on CNS by varying the nature of the nuclear substituents of
the aryl group at C-4. Table 1 shows the results of the
primary screening of the synthesised compounds 3a–k by
FST. The majority of the synthesised compounds exhibited
considerable antidepressant potential as evident from the
reduction of duration of immobility values and high-per-
centage decrease in immobility duration (% DID) values.
Among 11 compounds tested, 8 compounds (3d, 3e, 3f,
3g, 3h, 3i, 3j and 3k) showed potent antidepressant activ-
ity; the dimethoxy compound (entry 3f) was substantially
more active than the unsubstituted compound 3a, further
the introduction of the electron-withdrawing groups Cl and
NO2 in 4 and 3, 4 positions (3e, 3h, 3i) and methoxyls in
either 4 position (3g) or in 3 and 4 positions (3f) of C-4 and
C-4 aryl group increased the activity significantly and
substitution with a bulky chromone and quinoline groups
(entry 3j and 3k) for aryl group at C-4 did result in a
significant increase in activity.
Evidently, the introduction of electron-withdrawing
groups in 4- and 3-positions resulted in a significant
increase in potency, although such groups are also steri-
cally bulky. The decreased activity on introduction of
electron-withdrawing groups into ortho position of C-4 aryl
group may be attributed to steric hindrance felt by the
ortho-substituent either by the adjacent methylene (C-3) or
by the N-benzylic methylene group. Such steric hindrance
which may operate in whatever conformation the aryl and
N–CH2Ph groups adopt, may force the C-4 aryl group out
of its receptor-binding site. However, such steric hindrance
is not felt by meta and para substituents of C-4 aryl group.
In vitro antibacterial activity
The data generated from antibacterial study (Table 2)
revealed that the majority of the synthesized compounds
(3a–k) showed variable inhibition activities against the
tested strains and all of them showed moderate to good
antibacterial activity as compared to that of the standard.
Of all the compounds in series, 3b, 3c, 3d, 3f, 3g, 3h and 3i
showed significant inhibition against Gram-negative
In contrast, the introduction of electron-withdrawing
groups in the ortho position (3b, 3c) gave compounds with
lower potency than the unsubstituted compound 3a. In
particular, compound 3c (2–Br) was ineffective while 3d
(4–Br) induced a marked reduction of the duration of
immobility.
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Med Chem Res (2014) 23:2070–2079
Experimental section
Table 2 In vitro antibacterial activity of the compounds, 3a–k
Compounds
Zone of inhibition in mm at 10 lg/mL
General
Gram-negative
bacteria
Gram-positive
bacteria
Melting points were determined in open capillary tubes and
were uncorrected. The purity of the compounds was
checked on silica gel-G plates (TLC) and visualised using
iodine/UV lamp. IR spectra were recorded on a Schimadzu
FT-IR spectrophotometer using KBr pellets. 1H NMR
spectra were recorded on a Bruker Avance 300 MHz NMR
spectrometer in CDCl3 using TMS as an internal standard.
Elemental analyses were carried out with Elementer-Vario
EL III elemental analyzer. Microanalyses (C and H) of new
compounds agreed with the theoretical values within
0.4 %.
P. aeruginosa E. coli S. aureus B. subtilis
ATCC 9027 ATCC ATCC
35218 6538
ATCC
6631
a (Ph)
6
9
5
8
4
5
7
9
7
5
6
5
4
6
5
3
8
5
4
4
5
6
9
8
6
4
6
5
3
7
3
6
3
4
6
b (2-Cl)
c (2-Br)
15
10
10
7
d (4-Br)
e (4-Cl)
f (3,4-OMe)
g (4-OMe)
h (4-NO2)
i (3-NO2)
j (3-chromonyl)
12
15
10
8
Antidepressant assay
k (2-chloro- quinolin-
3-yl)
13
Behavioural despair or FST was proposed as a model to test
antidepressant activity by Porsolt et al. It was suggested that
mice or rats when forced to swim in restricted space from
where they cannot escape are induced to a characteristic
behaviour of immobility. This behaviour reflects a state of
despair which can be reduced by several agents which are
therapeutically effective in human depression. This behav-
ioural despair test was employed to assess the antidepressant
activity of newly synthesized compounds 3a–k. Albino rats
of 150–180 g in a group of six each were used and on the first
day of the experiment (pretest session), rats were individu-
ally placed in a cylindrical recipient (Plexiglass cylinder) of
dimensions (diameter 20 cm, height 40 cm) containing
30 cm of water at 25 1 °C. The animals were left to swim
for 15 min before being removed, dried and returned to their
cages. The procedure was repeated 24 h later, in 5 min swim
session (test session). The test compounds (20 mg/kg), and
clomipramine (20 mg/kg) separately were administered as
suspension in aqueous DMSO. During 5 min test session, the
duration of immobility was recorded. Immobility time is the
time spent by the rat floating in water without struggling,
making only those moment necessary to keep the head above
the water. The results of FST have been summarized in
Table 1. % DID for test and standard drugs was calculated
using following formula:
Ciproflaxacin
12
9
18
9
Gram-positive bacterial strain—S. aureus (ATCC 6538). Gram-neg-
ative bacterial strain—P. aeruginosa (ATCC 9027)
strains, whereas 3a, 3c, 3h and 3k registered significant
activity against Gram-positive strains. Compounds 3c and
3k showed significant inhibitory activity against all bac-
terial strains in comparison to that of the standard.
Conclusions
In conclusion, readily available starting materials have
been successfully utilised to develop synthetic pathways in
devising compounds incorporating the 1,5-benzodiazepine
nucleus with a substituted C-4 aryl moiety, and most of
these compounds significantly reduced the duration of
immobility at a very low dose of 20 mg/kg in FST, the
potency of which was comparable to that of the standard
drug such as clomipramine (20 mg/kg), ip underlying their
antidepressant potential. Further, the most potent com-
pounds 3e and 3f did not show any neurotoxicity in the
rotarod test and the preliminary results are promising
enough to warrant further detailed mechanistic and anti-
depressant studies on this scaffold. From the antimicrobial
activity studies, it was concluded that among all 1,5-ben-
zodiazepine derivatives, antibacterial activity increases
with electron-withdrawing groups at o-substitution,
whereas compounds 3c and 3k showed overall maximum
activity against both the strains.
% DID ¼ ½A ꢁ Bꢃ=A ꢄ 100;
where A is the duration of immobility (s) in control group
and B is the duration of immobility (s) in test group.
Antibacterial activity
The antibacterial activity was assessed by disc diffusion
method. Compounds 3a–k were evaluated in vitro activity
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Med Chem Res (2014) 23:2070–2079
2075
1-Benzyl-2-phenyldecahydroquinolin-4(1H)-one
against Gram-positive strains: S. aureus and B. subtilis;
Gram-negative strains: P. aeruginosa and E. coli at a
concentration of 10 lg/mL in meat peptone agar medium.
Ciprofloxacin (10 lg/mL) was used as a standard for
antibacterial screening. For each biological activity test,
two to three experiments were performed and the average
zone of inhibition is reported in Table 2.
oxime (2a)
m.p. 124–126 °C; (aq. ethanol) yield: 68 %. IR (KBr,
cm-1): 3419 (OH str.), 1591 (–CN str.), 1519 (NO asym.
str.), 1139 (–CN str.). 1H NMR (ppm, CDCl3): d 1.20–2.46
(m, 12H, 59CH2 and 29CH), 3.12 (dd, 1H, J = 12.3 and
2.1 Hz, –NCH/), 3.56 (s, 2H, NCH2/), 7.11–7.42 (m,
10H, ArH), 11.04 (s, 1H, N–OH). 13C NMR (ppm, CDCl3):
22.6, 24.9, 28.4, 32.5, 41.7, 53.9, 65.4 (NCH2/), 68.2
(NCH/), 125.6, 126.0, 127.3, 128.6, 136.4, 137.4, 158.7.
DEPT-135: d 22.21 (;), 24.35 (;), 26.72 (;), 29.46 (;),
34.58 (;), 42.35 (:), 55. 34 (:), 65.95 (;) (NCH2/), 67.52
(:) (NCH/), 127.76 (:), 128.51 (:), 129.02 (:). Anal.
Calcd for C22H26N2O: C 79.00 %; H 7.84 %. Found: C
79.02 %; H 7.82 %.
Neurotoxicity
Minimal motor impairment was measured in rats by the
rotarod method. The rats were trained to stay on an
accelerating rotarod rotating at 30 rpm over 120 s. The
trained animals were injected intraperitoneally with the test
compounds 3a–k at doses of 100 mg/kg, 30 min prior to
the test session. Neurotoxicity was indicated by the
inability of the animal to maintain equilibrium on the
rotating rod, and results are reported as duration for which
the animal is able to balance on the moving rod (i.e. till the
animal falls) is noted as coordination time (mean SEM).
1-Benzyl-2-chlorophenyldecahydroquinolin-4(1H)-one
oxime (2b)
m.p. 142–143 °C; (aq. ethanol) yield: 71 %. 1H NMR
(ppm, CDCl3): d 1.20–2. 64 (m, 12H, 59CH2 and 29CH),
3. 25 (dd, 1H, J = 12.0 and 2.4 Hz, –NCH/), 3.58 (s, 2H,
NCH2/), 7.23–7.72 (m, 9H, ArH), 11.14 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.6, 25.6, 26.0, 28.4, 33.4, 39.6,
53.6, 64.4 (NCH2/), 67.2 (NCH/), 125.6, 126.0, 127.3,
128.6, 130.5, 137.4, 138.4, 162.4. Anal. Calcd for
C22H25ClN2O: C 71.63 %; H 6.83 %. Found: C 71.62 %;
H 6.82 %.
Synthesis of (t) 1-benzyl-2-phenyloctahydroquinolin-
4(1H)-one (1a–k) (Babu et al., 2012)
To an ethanolic solution of 1-acetylcyclohexene (0.01 mol),
benzylamine (0.01 mol), benzaldehyde (0.01 mol) and cat-
alytic amount of piperidine were added and the reaction
mixture was refluxed for 5 h. After the completion of the
reaction (as monitored by TLC), the contents were concen-
trated, cooled and poured into crushed ice. The resulting
mass was extracted with chloroform, washed with water,
dried and concentrated in vacuo; crystallisation from aq.
ethanol gave pure compound 1a.
1-Benzyl-2-bromophenyldecahydroquinolin-4(1H)-one
oxime (2c)
m.p. 165–167 °C; (aq. ethanol) yield: 74 %. 1H NMR
(ppm, CDCl3): d 1.12–2.53 (m, 12H, 59CH2 and 29CH),
3.31 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.65 (s, 2H,
NCH2/), 7.16–7.55 (m, 10H, ArH), 11.12 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 23.2, 25.3, 27.3, 35.6, 40.2, 54.3,
65.3 (NCH2/), 67.2 (NCH/), 125.4, 126.7, 127.5, 128.7,
136.9, 137.0, 162.5. Anal. Calcd for C22H25BrN2O: C
63.93 %; H 6.10 %. Found: C 63.94 %; H 6.11 %.
1
m.p. 165–167 °C; H NMR (ppm, CDCl3): d 1.0–2.7
(m, 12H, 4 CH2 and 2 CH, –COCH2), 3.5 (dd, 1H,
J = 8 Hz, 1.5 Hz, –N–CH/), 3.7 (s, 2H, –N–CH2–Ph),
7.2–7.4 (m, 10H, Ar–H); 13C NMR (ppm, CDCl3): 25.6,
29.3 (–COCH2), 49.5, 55.6 (–NCH-9), 61.5 (–N–CH/),
65.7 (–N–CH2/), 125.6, 128.8, 139.5, 146.9, 198.2 (C=O).
DEPT-135 (ppm): d 25.69 (;), 28.62 (;), 49.36 (;), 55.50
(:) (–NCH-9), 59.56 (:) (N–CH/), 68.40 (;) (–N–CH2/),
125.67 (:), 126.28 (:), 129.56 (:), 134.00 (:), 139.14 (:).
1-Benzyl-4-bromophenyldecahydroquinolin-4(1H)-one
oxime (2d)
Typical procedure for the synthesis of 1-benzyl-2-
aryldecahydroquinolin-4(1H)-one oximes (2a–k)
m.p. 148–149 °C; (aq. ethanol) yield: 64 %. 1H NMR
(ppm, CDCl3): d 1.24–2.65 (m, 12H, 59CH2 and 29CH),
3.26 (dd, 1H, J = 12.6 and 2.4 Hz, –NCH/), 3.57 (s, 2H,
NCH2/), 7.16–7.62 (m, 10H, ArH), 11.14 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 23.6, 25.2, 29.2, 31.3, 40.5, 54.6,
65.1 (NCH2/), 68.3 (NCH/), 124.6, 125.6, 127.4, 128.3,
135.7, 136.4, 159.8. Anal. Calcd for C22H25BrN2O: C
63.93 %; H 6.10 %. Found: C 63.91 %; H 6.09 %.
To an ethanolic solution of compounds 1a–k (0.01 mol), an
aqueous solution of hydroxylamine hydrochloride
(0.05 mol) and crystalline sodium acetate (0.05 mol) was
added and the reaction mixture was refluxed on a water-
bath for 3 h and left overnight; the solid that separated was
filtered, washed with water, dried and crystallised from aq.
ethanol.
123

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Med Chem Res (2014) 23:2070–2079
1-Benzyl-4-chlorophenyldecahydroquinolin-4(1H)-one
3.12 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.56 (s, 2H,
NCH2/), 7.11–7.42 (m, 10H, ArH), 11.04 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.6, 24.9, 28.4, 32.5, 41.7, 53.9,
65.4 (NCH2/), 68.2 (NCH/), 125.6, 126.0, 127.3, 128.6,
136.4, 137.4, 158.7. Anal. Calcd for C22H25N3O3: C
69.64 %; H 6.64 %. Found: C 69.63 %; H 6.62 %.
oxime (2e)
m.p. 134–135 °C; (aq. ethanol) yield: 70 %. 1H NMR
(ppm, CDCl3): d 1.16–2.65 (m, 12H, 59CH2 and 29CH),
3.26 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.60 (s, 2H,
NCH2/), 7.20–7.55 (m, 9H, ArH), 11.10 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.2, 23.7, 26.3, 34.5, 40.2, 54.5,
65.9 (NCH2/), 67.7 (NCH/), 125.6, 126.5, 127.5, 128.7,
135.4, 137.2, 159.4. Anal. Calcd for C22H25ClN2O: C
71.63 %; H 6.83 %. Found: C 71.64 %; H 6.81 %.
1-Benzyl-4-(4-oxo-4H-chromen-3-yl)-decahydroquinolin-
4(1H)-one oxime (2j)
m.p. 147–148 °C; (aq. ethanol) yield: 74 %. 1H NMR
(ppm, CDCl3): d 1.21–2.56 (m, 12H, 59CH2 and 29CH),
3.22 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.54 (s, 2H,
NCH2/), 7.10–7.82 (m, 10H, ArH), 11.12 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.6, 25.5, 28.4, 34.2, 40.7, 54.3,
65.4 (NCH2/), 68.5 (NCH/), 125.1, 126.3, 127.4, 128.5,
136.2, 137.4, 160.4. Anal. Calcd for C25H26N2O3: C
74.60 %; H 6.51 %. Found: C 74.62 %; H 6.52 %.
1-Benzyl-3,4-dimethoxyphenyldecahydroquinolin-4(1H)-
one oxime (2f)
m.p. 150–151 °C; (aq. ethanol) yield: 73 %. 1H NMR
(ppm, CDCl3): d 1.22–2.16 (m, 12H, 59CH2 and 29CH),
3.32 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.55 (s, 2H,
NCH2/), 7.18–7.62 (m, 8H, ArH), 11.12 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.5, 24.6, 28.2, 31.6, 40.7, 54.2,
65.6 (NCH2/), 67.4 (NCH/), 125.4, 126.5, 127.2, 128.5,
136.6, 138.2, 160.4. Anal. Calcd for C24H30N2O3: C
73.07 %; H 7.66 %. Found: C 73.05 %; H 7.67 %.
1-Benzyl-4-(2-chloroquinolin-3-yl)decahydroquinolin-
4(1H)-one oxime (2k)
m.p. 141–142 °C; (aq. ethanol) yield: 71 %. 1H NMR
(ppm, CDCl3): d 1.23–2.56 (m, 12H, 59CH2 and 29CH),
3.22 (dd, 1H, J = 12.3 and 2.1 Hz, -NCH/), 3.56 (s, 2H,
NCH2/), 7.10–7.92 (m, 10H, ArH), 11.14 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 22.6, 24.9, 28.4, 33.5, 40.7, 53.9,
65.4 (NCH2/), 68.2 (NCH/), 125.6, 126.0, 127.3, 128.6,
136.4, 138.4, 159.2. Anal. Calcd for C25H29N3O: C 77.
48 %; H 7.54 %. Found: C 77.50 %; H 7.53 %.
1-Benzyl-4-methoxyphenyldecahydroquinolin-4(1H)-one
oxime (2g)
m.p. 169–170 °C; (aq. ethanol) yield: 65 %. 1H NMR
(ppm, CDCl3): d 1.22–2.55 (m, 12H, 59CH2 and 29CH),
3.20 (dd, 1H, J = 12.3 and 2.1 Hz, –NCH/), 3.56 (s, 2H,
NCH2/), 7.20–7.76 (m, 9H, ArH), 11.14 (s, 1H, N–OH).
13C NMR (ppm, CDCl3): 23.2, 25.1, 28.2, 31.8, 39.5, 53.5,
65.2 (NCH2/), 68.1 (NCH/), 125.5, 126.5, 127.2, 128.5,
136.5, 137.3, 161.7. Anal. Calcd for C23H28N2O2: C
75.79 %; H 7.74 %. Found: C 75.80 %; H 7.75 %.
Typical procedure for the synthesis of 5-benzyl-4-
aryloctahydro-1H-benzo[b][1,5] diazepin-2(3H)-ones
(3a–k)
To a solution of decahydroquinoline-2-one oximes 2 a–
k (0.01 mol) in dry ether (25 mL) taken in a R.B. flask
fitted with a double-surface condenser carrying a CaCl2
guard tube, freshly distilled thionyl chloride (0.05 mol)
was added and the reaction mixture was refluxed on a
water-bath for 1 h. After completion of the reaction (TLC),
the excess of ether and thionyl chloride were removed in
vacuo and the residue was treated with water. The solid
that separated was filtered, washed with water and dried;
crystallisation from ethylacetate-petroleum ether (2:1)
afforded compounds 3a–k.
1-Benzyl-4-nitrophenyldecahydroquinolin-4(1H)-one
oxime (2h)
m.p. 125–126 °C; (aq. ethanol) yield: 62 %. 1H NMR (ppm,
CDCl3): d 1.18–2.05 (m, 12H, 59CH2 and 29CH), 3.26 (dd,
1H, J = 12.3 and 2.1 Hz, –NCH/), 3.62 (s, 2H, NCH2/),
7.22–8.24 (m, 10H, ArH), 11.24 (s, 1H, N–OH). 13C NMR
(ppm, CDCl3): 22.6, 25.6, 26.4, 28.9, 32.5, 40.7, 56.9, 65.4
(NCH2/), 67.2 (NCH/), 125.6, 126.0, 127.3, 128.6, 136.4,
145.4, 146.3, 162.7. Anal. Calcd for C22H25N3O3: C
69.64 %; H 6.64 %. Found: C 69.65 %; H 6.63 %.
5-Benzyl-4-phenyloctahydro-1H-benzo[b][1,5]diazepin-
1-Benzyl-3-nitrophenyldecahydroquinolin-4(1H)-one
2(3H)-one (3a)
oxime (2i)
Yield: 77 %; m.p. 156–157 °C (ethyl acetate–petroleum
ether). IR (KBr, cm-1): 3316 (NH str.), 3160 (aromatic–
CH str.), 1678 (CO), 1220–1070 (CN str.). 1H NMR (ppm,
m.p. 154–156 °C; (aq. ethanol) yield: 69 %. 1H NMR
(ppm, CDCl3): d 1.20–2.46 (m, 12H, 59CH2 and 29CH),
123

Med Chem Res (2014) 23:2070–2079
2077
CDCl3): d 1.16–2.61 (m, 12H, 59CH2 and 29CH), 3.62 (s,
2H, NCH2/), 4.02 (dd, 1H, J = 12.6 and 1.8 Hz, NCH/),
7.04–7.39 (m, 10H, ArH), 8.62 (s, 1H, –NHCO). 13C NMR
(ppm, CDCl3): 22.5, 24.8, 25.4, 32.4, 46.5, 51.2, 54.8
(NCH/), 56.5, 58.9 (NCH2/), 125.4, 126.4, 127.5, 128.9,
138.6, 176.8 (CO). DEPT-135: d 23.45 (;), 25.93 (;), 27.51
(;), 32.28 (;), 44.71 (;), 51.44 (:), 53.81 (:) (NCH/),
56.73 (:), 59.52 (;) (NCH2/), 125.05 (:), 127.45 (:),
128.71(:). MS (FAB?, m/z, %): 334 (M?.). Anal. Calcd
for C22H26N2O: C 79.00 %; H 7.84 %. Found: C 79.03 %;
H 7.83 %.
DEPT-135: d 24.72 (;), 25.56 (;), 27.37 (;), 32.25 (;),
44.20 (:), 49.63 (:), 54.34 (:) (NCH/), 56.56 (:), 59.56 (;)
(NCH2 /), 127.43 (:), 128.30 (:), 129.42 (:), 132.75 (:).
5-Benzyl-4-(4-chlorophenyl)octahydro-1H-
benzo[b][1,5]diazepin-2(3H)-one (3e)
Viscous paste; yield: 74 %. IR (KBr, cm-1): 3344 (NH
str.), 1671 (CO str.). 1H NMR (ppm, CDCl3): d 1.3–3.1 (m,
12H, 59CH2 and 2CH), 3.6 (s, 2H, NCH2/), 4.3 (dd, 1H,
J = 11.4 and 1.8 Hz, NCH/), 7.28–7.64 (m, 9H, ArH), 9.2
(s, 1H, NHCO). 13C NMR (ppm, CDCl3): 24.6, 25.6, 27.2,
32.6, 45.5, 51.3 (NCH/), 56.8, 59.4 (NCH2/), 123.7,
127.1, 128.4, 128.8, 138.3, 145.4, 146.2, 172.6 (CO).
DEPT-135: d 24.64 (;), 25. 36 (;), 27.27 (;), 32.44 (;),
44.54 (:), 51.35 (:), 53.52 (:) (NCH/), 56.32 (;), 59.67 (:)
(NCH2/), 123.30 (:), 128.43 (:), 127.63 (:), 128.63 (:).
5-Benzyl-4-(2-chlorophenyl)octahydro-1H-
benzo[b][1,5]diazepin-2(3H)-one (3b)
m.p. 191–193 °C (ethyl acetate – pet. ether); yield: 62 %.
1
IR (KBr, cm-1): 3344 (NH str.), 1653 (NHCO). H NMR
(ppm, CDCl3): d 1.34–3.08 (m, 12H, 59CH2 and 29CH),
3.6 (s, 2H, NCH2/), 4.1 (dd, 1H, J = 12.0 and 2.4 Hz,
NCH/), 7.2–7.5 (m, 9H, ArH), 9.1 (s, 1H, NHCO). 13C
NMR (ppm, CDCl3): 24.6, 25.5, 27.6, 32.6, 45.2, 53.4
(NCH/), 56.8, 59.9 (NCH2/), 123.4, 127.0, 128.4, 128.3,
138.0, 145.5, 146.4, 172.0 (CO). DEPT-135: d 24.62 (;),
25.46 (;), 27.47 (;), 32.93 (;), 44.43 (:), 51.43 (:), 53.03
(:) (NCH/), 56.72 (:), 59.26 (;) (NCH2/), 123.53 (:),
128.63 (:), 127.63 (:), 128.45 (:).
5-Benzyl-4-(3,4-dimethoxyphenyl)octahydro-1H-
benzo[b][1,5]diazepin-2(3H)-one (3f)
m.p. 145 °C (ethyl acetate–petroleum ether); yield: 76 %.
IR (KBr, cm-1): 3355 (–NH str.), 1656 (CO str.). 1H NMR
(ppm, CDCl3): d 1.2–2.9 (m, 12H, 59CH2 and 29CH), 3.6
(s, 2H, NCH2/), 3.9 (s, 6H, 29OCH3), 4.1 (dd, 1H,
J = 12.6 and 2.1 Hz, NCH/), 6.74–7.47 (m, 8H, ArH), 9.1
(s, 1H, NHCO). 13C NMR (ppm, CDCl3): 24.8, 25.5, 27.1,
32.8, 45.3, 51.3, 52.2 (NCH/), 56.2 (OCH3), 56.8, 59.4
(NCH2/), 116.7, 120.4, 121.1, 127.1, 128.2, 131.3, 137.2,
147.2, 149.3, 172.7 (CO).
5-Benzyl-4-(2-bromophenyl)octahydro-1H-
benzo[b][1,5]diazepin-2(3H)-one (3c)
m.p. 217–218 °C (ethyl acetate–petroleum ether); yield:
1
73 %. IR (KBr, cm-1): 3371 (NH str.), 1649 (NHCO). H
5-Benzyl-4-(4-methoxyphenyl)octahydro-1H-
NMR (ppm, CDCl3): d 1.1–3.2 (m, 12H, 59CH2 and
29CH), 3.6 (s, 2H, NCH2/), 4.1 (dd, 1H, J = 12.6 and
2.4 Hz, NCH/), 7.2–7.6 (m, 9H, ArH), 9.3 (s, 1H, NHCO).
13C NMR (ppm, CDCl3): 24.6, 25.5, 27.6, 32.6, 45.2, 50.4,
51.8 (NCH/), 56.9, 60.1(NCH2/), 123.4, 127.0, 128.4,
129.3, 132.0, 138.0, 139.5, 172.3 (CO). DEPT-135: d 24.62
(;), 25.36 (;), 27.77 (;), 32.45 (;), 44.40 (:), 49.33 (:),
53.44 (:) (NCH/), 59.26 (;) (NCH2/), 127.43 (:), 128.20
(:), 129.32 (:), 132.75 (:).
benzo[b][1,5]diazepin-2(3H)-one (3g)
m.p. 154 °C (ethyl acetate–petroleum ether); yield: 72 %.
IR (KBr, cm-1): 3347 (–NH str.), 1652 (CO str.). 1H NMR
(ppm, CDCl3): d 1.2–3.0 (m, 12H, 59CH2 and 29CH), 3.6
(s, 2H, NCH2/), 3.9 (s, 3H, 19OCH3), 4.2(dd, 1H,
J = 12.3 and 2.4 Hz, NCH/), 6.82–7.45 (m, 7H, ArH), 9.0
(s, 1H, NHCO). 13C NMR (ppm, CDCl3): 24.6, 25.4, 27.7,
31.4, 45.6, 53.2, 52.3 (NCH/), 55.2 (OCH3), 56.5, 59.7
(NCH2/), 115.7, 122.0, 124.1, 125.1, 126.2, 130.3, 135.3,
145.6, 149.3, 173.2 (CO).
5-Benzyl-4-(4-bromophenyl)octahydro-1H-
benzo[b][1,5]diazepin-2(3H)-one (3d)
5-Benzyl-4-(4-nitrophenyl)octahydro-1H-
m.p. 181–182 °C, (ethyl acetate–petroleum ether), yield:
benzo[b][1,5]diazepin-2(3H)-one (3h)
1
74 %. IR (KBr, cm-1): 3374 (NH str.), 1642 (CO str.). H
NMR (ppm, CDCl3): d 1.15–3.16 (m, 12H, 59CH2 and
2CH), 3.6 (s, 2H, NCH2/), 4.2 (dd, 1H, J = 11.7 and
2.1 Hz, NCH/), 7.16–7.92 (m, 9H, ArH), 9.2 (s, 1H,
NHCO). 13C NMR (ppm, CDCl3): 24.8, 25.4, 27.3, 32.5,
45.8, 50.4, 51.3 (NCH/), 56.8, 59.2 (NCH2 /), 123.1,
127.8, 128.6, 129.2, 132.4, 138.3, 139.1, 172.2 (CO).
m.p. 201–202 °C (ethyl acetate–petroleum ether);
yield:72 %. IR (KBr, cm-1): 3342 (NH str.), 1654 (C=O
str. in ring), 1564 (NO2, asym. str.). 1H NMR (ppm,
CDCl3): d 1.2–3.1 (m, 12H, 59CH2 and 29CH), 3.6 (s,
2H, NCH2/), 4.2 (dd, 1H, J = 12.0 and 2.1 Hz, NCH/),
7.3–8.2 (m, 9H, ArH), 9.1(s, 1H, NHCO). 13C NMR (ppm,
123

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Med Chem Res (2014) 23:2070–2079
CDCl3): 24.6, 25.6, 27.6, 32.8, 44.3, 51.3, 54.2 (NCH/),
56.2, 59.3 (NCH2/), 123.4, 127.1, 128.2, 137.2, 145.2,
146.3, 172.1 (CO).
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J = 11.7 and 2.1 Hz, NCH/), 7.2–8.2 (m, 9H, ArH), 9.2
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1
IR (KBr, cm-1): 3349 (NH str.), 1645 (CO str.). H NMR
(ppm, CDCl3): d 1.1–3.4 (m, 12H, 59CH2 and 2CH), 3.6 (s,
2H, NCH2/), 4.1 (dd, 1H, J = 11.4 and 1.5 Hz, NCH/), 6.8
(s, 1H, H-20), 7.3–8.3 (m, 9H, ArH), 9.2 (s, 1H, NHCO). 13C
NMR (ppm, CDCl3): 24.6, 25.3, 27.7, 32.5, 36.1, 46.6, 53.8
(NCH/), 56.1, 59.7 (NCH2/), 116.9, 123.8, 125.2, 127.3,
128.4, 135.2, 138.9, 150.2, 156.7, 174.3 (NHC=O), 179.3
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5-Benzyl-4-(2-chloroquinolin-3-
yl)octahydrobenzo[b][1,5]diazepin-2(3H)-one (3k)
m.p. 162 °C; (ethyl acetate–petroleum ether), yield: 63 %.
IR (KBr, cm-1): 3324 (–NH str.), 1652 (C=O str. in ring).
1H NMR (ppm, CDCl3): d 1.1–3.4 (m, 12H, 59CH2 and
2CH), 3.6(s, 2H, NCH2/), 4.1(dd, 1H, J = 11.1 and
1.5 Hz, NCH/), 7.1–8.0 (m, 10H, ArH), 9.1 (s, 1H,
NHCO). 13C NMR (ppm, CDCl3): 24.6, 25.1, 27.8, 32.3,
36.7, 45.2, 51.7(NCH/), 56.4, 59.3 (NCH2/), 116.5,
125.2, 127.4, 128.5, 129.3, 135.4, 137.9, 138.1, 150.8,
157.0, 174.2 (C=O). DEPT-135: d 24.35 (;), 25.11 (;),
27.96 (;), 32.72 (;), 36.76 (;), 46.08 (:), 53.42 (:) (NCH/),
56.39 (;) (NCH2/), 57.82 (:), 116.72 (:), 123.06 (:), 125.20
(:), 127.18 (:), 128.54 (:), 129.10 (:), 135.71 (:), 137.32 (:),
150.84 (:).
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