Synthesis and anticonvulsant evaluation of some new 1,3,4,5-tetrahydro-6- Alkoxy-2H-1-benzazepin-2-one derivatives

Article abstract of DOI:10.1007/s00044-013-0871-2

A series of new 1,3,4,5-tetrahydro-6-Alkoxy-2H-1-benzazepin-2-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test. The results of these tests showed that 1,3,4,5-tetrahydro-6-octyloxy-2H-1- benzazepin-2-one (4f) was the most promising compound, with median effective dose (ED₅₀) of 20.4 mg/kg, and protective index (PI) value of 20.1 in the MES test, which is much higher than the PI value of the prototype antiepileptic drug carbamazepine (PI = 8.1), phenytoin (PI = 6.9), phenobarbital (PI = 3.2), and sodium valproate (PI = 1.6). The scPTZ test displayed that 1,3,4,5-tetrahydro-6-heptyloxy-2H-1-benzazepin-2-one (4e) was the most active compound (ED₅₀ = 64.4, PI = 2.6). The possible structure-Activity relationship was discussed.

Full text of DOI:10.1007/s00044-013-0871-2

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-013-0871-2
ORIGINAL RESEARCH
Synthesis and anticonvulsant evaluation of some new 1,3,4,5-
tetrahydro-6-alkoxy-2H-1-benzazepin-2-one derivatives
•
Rong-Bi Han Yun-Peng Shao Hui-Fan Wu
•
•
•
Duo Zhang Feng-Yu Piao
Received: 20 August 2013 / Accepted: 31 October 2013
Ó Springer Science+Business Media New York 2013
Abstract A series of new 1,3,4,5-tetrahydro-6-alkoxy-
2H-1-benzazepin-2-one derivatives were synthesized and
screened for their anticonvulsant activities by the maximal
electroshock (MES) test, subcutaneous pentylenetetrazol
(scPTZ) test, and their neurotoxicity was evaluated by the
rotarod neurotoxicity test. The results of these tests showed
that 1,3,4,5-tetrahydro-6-octyloxy-2H-1-benzazepin-2-one
(4f) was the most promising compound, with median
effective dose (ED50) of 20.4 mg/kg, and protective index
(PI) value of 20.1 in the MES test, which is much higher
than the PI value of the prototype antiepileptic drug car-
bamazepine (PI = 8.1), phenytoin (PI = 6.9), phenobar-
bital (PI = 3.2), and sodium valproate (PI = 1.6). The
scPTZ test displayed that 1,3,4,5-tetrahydro-6-heptyloxy-
2H-1-benzazepin-2-one (4e) was the most active com-
pound (ED50 = 64.4, PI = 2.6). The possible structure–
activity relationship was discussed.
Introduction
Benzazepine derivatives exhibit a broad spectrum of
pharmacological activity. Many members of this family are
widely used as anticonvulsant, anti-anxiety, anti-seizures,
analgesic, seditative, antidepressive and hypnotic, or anti-
inflammatory agents (Josiassen et al., 2008; Schrier et al.,
2006; Achermann et al., 2009).
The chemical structures of benzazepines derivatives are
similar to the structures of benzodiazepines compounds, so
they may have similar or opposite biological activities.
Benzoxazepines are an important group of benzaze-
pines, and also have high pharmacological activities, or can
be used as intermediates in preparing of biologically active
compounds. The present anti-hypertension drugs such as
Libezapril and Benazeprilat contain 2-oxo-benazepine
basic skeleton, growth hormone secretagogue L-692, 429
and L-739, 943 also contain the skeleton. Synthesis and
modification of their structure is one of the research focus
in organic chemistry nowdays.
Keywords 4,5-Dihydro-1H-benzo[b]azepin-2(3H)-one Á
Anticonvulsant activity Á Maximal electroshock test Á
Pentylenetetrazole Á Neurotoxicity Á
The amide bond is a key functional group in organic
chemistry. It plays a major role in the elaboration and
composition of biological and chemical systems (Valeur
and Bradley, 2009; Bode, 2006; Cupido et al., 2007). Many
antiepileptic drugs contain an amide bond, for example,
phenytoin, diazepam, Oxazepam, fludiazepam, phenobar-
bital, carbamazepine, oxcarbazepine, and Progabide.
According to literature reports, for binding to the benzo-
diazepine receptor at least two features are common: an
aromatic ring and a coplanar protonaccepting group in suit-
able distance. Also, the presence of a second out-of-plane,
aromatic ring could potentiate binding to the receptor (Fryer,
1990; Neumeyer and Booth, 1995). Carbonyl groups are
efficient hydrogen bond acceptors, primary and secondary
amines can act as hydrogen bond donor or acceptor form
Structure–activity relationship
R.-B. Han Á Y.-P. Shao Á H.-F. Wu Á D. Zhang Á F.-Y. Piao (&)
Department of Chemistry, College of Science, Yanbian
University, Yanji 133002, Jilin, People’s Republic of China
e-mail: fypiao4989@yahoo.com.cn; fypiao4989@aliyun.com
R.-B. Han Á F.-Y. Piao
Key Laboratory of Natural Resources of Changbai Mountain &
Functional Molecules, Ministry of Education, Yanbian
University, Yanji 133002, Jilin, People’s Republic of China
123

Med Chem Res
Scheme 1 The synthesis route
of compounds 4a–p
hydrogen bonds. Hydrophobic phenyl group can increase
molecular lipophilicity and ability to penetrate the blood–
brain barrier.
On this basis, a series of 2,3,4,5-tetrahydro-7-alkoxy-1H-
2-benzazepin-1-ones were synthesized and tested for anti-
convulsant activity using the maximal electroshock (MES)
and subcutaneous pentylenetetrazole (scPTZ) screens.
Among these compounds, 2,3,4,5-tetrahydro-7-heptyloxy
1H-2-benzazepin-1-one (compound I) displayed the best
activity, having ED50 value of 39.4 mg/kg in the MES test
(Wei et al., 2009).
Fig. 1 The structures of compound I and target compounds
Ketoxime is produced from ketones and hydroxylamine
(Zhao et al., 2008; Waldo and Larock, 2005). When we
used water and ethanol instead of the toluene solvent and
carried the oximation reaction, the compound 1 was
obtained with good yield (95 %). The reaction begins with
nucleophilic addition to the carbonyl group. The addition
product is then protonated and dehydrated. The mechanism
of this oximation reaction had been studied and investi-
gated earlier (College of Central Florida: http://www.cf.edu/
departments/instruction/las/science/chemistry/mechanisms/
oxime-mechanism.htm).
In general, the drug molecules (ligands) and receptors
interactions with drug molecules spatial configuration (con-
formation) have a greater relationship. We hypothesize that
with the introduction of alkoxy or benzyloxy group to 6-posi-
tions of 4,5-dihydro-1H-benzo[b]azepin-2(3H)-one, the anti-
convulsant activity of the resulting compounds 1,3,4,5-
tetrahydro-6-alkoxy-2H-1-benzazepin-2-one can be improved
(Davies et al., 1998; Tahmineh et al., 2003).
Generally, the trans configuration is relatively stable.
6-Methoxy-3,4-dihydronaphthalene-1(2H)-one oxime was
synthesized by our group, and the trans configuration was
determined from its single-crystal structure (Da-Cheng Ji
et al., 2010).
Generally, the anticonvulsant activity of an organic
compound might be increased after the introduction of a
halogen atom. So, the title compounds were designed and
synthesized and screened for their anticonvulsant activity
following MES and scPTZ methods. Their neurotoxicity
was studied by Rotarod test.
The compound 2 was obtained via the Beckmann rear-
rangement of 5-methoxy-3,4-dihydro-naphthalene-1(2H)-
one oxime. When the temperature was too high, a by-product
was produced; On the contrary, when the temperature was
too low, the reaction either did not occur or only partially
occurred, and the reaction did not occur under 90 °C,
occurred only partly from 90 to 110 °C and went to com-
pletion from 110 to 125 °C, when PPA was used as the
catalyst. The mechanism of the Beckmann rearrangement of
ketoxime in the presence of PPA is as shown in Fig. 1, 2, 3.
Alkyl migration in the course of Beckmann rearrange-
ment was favored, leading to the formation of 1,3,4,5-tet-
rahydro-6-methoxy-2H-1-benzazepin-2-one as the only
product. The steric effect was found in our experiments to
predominate over the electron-releasing effect, which could
be attributed to the 5-methoxy group in position meta to the
bond C=N of 5-methoxy-3,4-dihydronaphthalen-1(2H)-one
Results and discussion
Chemistry
Target compounds 4a–p were prepared according to Scheme 1.
The starting material 5-methoxy-3,4-dihydronaphthalen-
1(2H)-one reacted with hydroxylamine hydrochloride in etha-
nol and gave compound 1, which reacted in PPA to produce
compound 2 vis Beckmann rearrangement. Compound 2 was
further demethylated by BBr3 to produce compound 3, which
reacted with appropriate alkyl halide to produce title com-
pounds 4a–p. The structures of all the new compounds were
confirmed by IR, 1H NMR, MS, and elemental analyses.
123

Med Chem Res
Fig. 2 The mechanism of the
Beckmann rearrangement
Fig. 3 The mechanism of
O-demethylation catalyzed by
BBr3
oxime. On the contrary, in our previous work, the ring
expansion rearrangement of (1E)-6-methoxy-3,4-dihydro-
naphthalene-1(2H)-one oxime always produces a mixture
of two isomers, and 2,3,4,5-tetrahydro-7-methoxy-1-H-2-
benzazepin-1-one as the major product in the mixture of
the two possible isomeric benzazepinones because of the
similar sizes of the groups on either end of the C=N double
bond and the electron-donating group (CH3O–) at the
6-position of the oxime (Piao et al., 2013).
Demethylation reactions were carried out according to
published procedure (Wei et al., 2009). The BBr3 coordi-
nates to the methyl ether forming C–O–CH3(BBr3) com-
plexes with a positive formal charge on the O and a formal
negative charge on the B. One Br– leaves and performs an
S2N attack on the CH3 causing it to leave as methyl bromide.
Water will then hydrolyze the ‘‘boronate ester’’ to give
corresponding C–OH,B(OH)3 (boric acid) and 2HBr
(Mcomie et al., 1968).
Generally, Beckmann rearrangements usually involve the
migration of the groups in the trans position to the oxime
hydroxyl, so the products obtained are from trans migration
in most cases. When the C=N double bond connects to the
aryl and alkyl groups at both ends, the aryl group migrates
first to yield the corresponding products (Minze et al., 2006;
Dongmei et al., 2005; Wang et al., 2004). However, a mix-
ture of both the aryl and alkyl migration products will be
obtained when the groups at both ends of the C=N double
bond are similar in size (Ping et al., 2005). 6-Methoxy-3,4-
dihydronaphthalene-1(2H)-one oxime was previously syn-
thesized by our group, and the trans configuration was
determined from its single-crystal structure (Jin et al., 2010).
According to the mechanism of the Beckmann rearrange-
ment, 6-methoxy-3,4-dihydro-naphthalene-1(2H)-one oxime
should produce the title compound.
Compound 3 was converted to the title compounds 4a–p
with 56–81 % yields through the Williamson synthesis.
The general reaction mechanism had been studied and
investigated earlier (Boyd et al., 1992).
Pharmacology
The MES test is regarded as the pharmacologic model of
grand mal, and the scPtz test as the pharmacologic model
of petit mal seizures. Therefore, we carried out those two
tests to evaluate the anticonvulsant activity of the synthe-
sized compounds. Phase-I study was a qualitative assay
involving three mice at common dose levels of 30, 100,
and 300 mg/kg (Table 1). As shown in Table 1, in the
anti-MES test, after drug administration at 30 mg/kg
dose, three compounds (4d–f) showed protection against
123

Med Chem Res
Table 1 Phase-I evaluation of anticonvulsant activity in mice (i.p.)
Compound
R1
MESa
scPTZb
Dosage (mg/kg)
0.5 h
4 hc
Dosage (mg/kg)
0.5 h
4 hc
4a
4b
4c
4d
4e
4f
–C3H7
100
100
100
30
3/5
4/5
4/5
3/5
3/5
4/5
2/5
3/5
5/5
3/5
3/5
5/5
3/5
2/5
2/5
3/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
300
300
300
100
100
100
100
300
300
300
100
100
300
300
300
300
1/5
2/5
3/5
4/5
5/5
5/5
2/5
2/5
2/5
2/5
2/5
3/5
2/5
1/5
1/5
2/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
0/5
–C4H9
–C5H11
–C6H13
–C7H15
30
–C8H17
30
4g
4h
4i
–C9H19
100
300
100
300
300
100
300
300
300
300
–CH2C6H4(o-F)
–CH2C6H4(m-F)
–CH2C6H4(p-F)
–CH2C6H4(o-Cl)
–CH2C6H4(m-Cl)
–CH2C6H4(p-Cl)
–CH2C6H4(p-Br)
–CH2C6H4(p-CH3)
–PhCH2
4j
4k
4l
4m
4n
4o
4p
a
Maximal electroshock seizure test (number of animals protected/number of animals tested)
subcutaneous pentylene tetrazole test (number of animals protected/number of animals tested)
compounds are metabolized/excreted at 4 h
b
c
MES-induced seizure. At a dose of 100 mg/kg six com-
on the anticonvulsant activity of the 6-alkyloxyl deriva-
tives. As the alkyl chain length increased from 3 to 8, the
value of anticonvulsant activity gradually increased and the
compound 4f (with the 6-octyloxy-substituted group) had
the smallest ED50. However, the trend reversed when the
alkyl chain had more than eight carbon atoms. For the
9-benzyloxy-substituted derivatives 4h–p, only two com-
pounds (4i and 4l) exhibited anticonvulsant activity, with
an ED50 of 59.0 mg/kg and 48.1, respectively.
pounds (4a–c, 4g, 4i, and 4l) showed protection, and the
remaining seven compounds (4h, 4j, and 4m–p) were
active at 300 mg/kg. None of the compounds showed
protection in the 4h period. In the anti-scPTZ test, six
compounds (4d–g and 4k–l) exhibited anticonvulsant
activity at a dose of 100 mg/kg.
As a result of preliminary screening, eight compounds
(4a–f, 4i, and 4l) were subjected to phase-II trials for quan-
tification of their anticonvulsant activity (indicated by ED50)
and neurotoxicity (indicated by TD50) in mice. Results of the
quantitative test for selected compounds, along with the data
on the standard drug carbamazepine, phenytoin, phenobar-
bital, and sodium valproate are reported in Table 2. Among
the tested compounds, 1,3,4,5-tetrahydro-6-octyloxy-2H-1-
benzazepin-2-one (4f) gave an ED50 value of 20.4 mg/kg
and a TD50 value of 409.0 mg/kg resulting in a higher pro-
tective index (PI = 20.4) value when compared to carbam-
azepine (PI = 8.1), phenytoin (PI = 6.9), phenobarbital
(PI = 3.2), and sodium valproate (PI = 1.6) in the MES test.
The scPTZ test displayed that 1,3,4,5-tetrahydro-6-hepty-
loxy-2H-1-benzazepin-2-one (4e) was the most active
compound (ED50 = 64.4, PI = 2.6).
In the anti-MES test, comparison of the halogen-
substituted derivatives indicated that different halogen
atoms contributed to the anticonvulsant activity in the order
of Cl [ F [ Br; Comparing the derivatives with different
halogen-substituted positions on the benzyl ring, and only
the derivatives (4i and 4l) substituted at position three of
the benzyl ring displayed to be active. The anticonvulsant
activity of compounds containing substituted benzyloxy
(m-F and m-Cl) was stronger than that of the compound
with non-substituted benzyloxy (4p). One electron donor
derivative (4o) was also designed and prepared, but it did
not show anticonvulsant activity.
Among these derivatives, the compound (4f) exhibited the
strongest anticonvulsant activity with ED50 value of
20.4 mg/kg, which is higher than that of phenytoin (9.5 mg/
kg) and carbamazepine (8.8 mg/kg), but lower than that of
sodium valproate (272 mg/kg) and phenobarbital (21.8 mg/
kg); moreover, its PI value (20.1) is much higher than that of
Analyzing the activities of the synthesized compounds
the following structure–activity relationships were
obtained. For the 7-alkoxy-substituted derivatives 4a–f, the
length of the alkyl chain appeared to have a direct impact
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Med Chem Res
Table 2 Phase-II quantitative anticonvulsant data in mice (test drug administered i.p.)
Comp.
EDa50
TDb50
PIc
MES
scPTZ
Rotarod toxicity
MES
scPTZ
4a
96.1 (106.0–86.1)d
52.7 (62.3–44.6)d
41.3 (52.4–32.6)d
29.9 (33.4-26.8)d
25.9 (29.0–23.1)d
20.4 (22.6–18.5)d
59.0 (68.1–51.2)d
48.1 (58.1–40.0)d
9.5 (8.1–10.4)d
[100
–
–
–
4b
[100
–
–
–
4c
[100
117.8(138.8–99.3)d
136.5(120.1–155.1)d
168.6(146.1–194.5)d
409.0(357.5-471.4)d
–
2.9
4.6
6.5
20.1
–
–
4d
66.6 (76.6–57.8)d
64.4 (71.6–57.9)d
76.0 (89.9–64.3)d
[100
2.1
2.6
5.4
–
4e
4f
4i
4l
[100
–
–
–
Phenytoin
Carbama.
Phenobarbital
Sodium valproate
a
[300
65.5 (52.5–72.9)d
71.6 (45.9–135)d
69 (62.8–72.9)d
426 (369–450)d
6.9
8.1
3.2
1.6
\0.22
\0.22
5.2
2.9
8.8 (5.5–14.1)d
21.8 (21.8–25.5)d
272 (247–338)d
[100
13.2 (5.8–15.9)d
149 (123–177)d
ED50-median effective dose required to assure anticonvulsant protection in 50 % animals
b
c
d
TD50-median toxic dose eliciting minimal neurological toxicity in 50 % animals
PI protective index (TD50/ED50
)
95 % confidence limits given in parentheses
the prototype antiepileptic drug carbamazepine (PI = 8.1),
phenytoin (PI = 6.9), phenobarbital (PI = 3.2), and sodium
valproate (PI = 1.6). In the anti-scPtz test, the anti-PTZ
activities of compounds (4d–f) were stronger than that of the
marked antiepileptic drug carbamazepine, phenytoin, and
sodium valproate, and 1,3,4,5-tetrahydro-6-heptyloxy-2H-
1-benzazepin-2-one (4e) was among the most active com-
pound with ED50 of 64.4 mg/kg, which is much lower than
that of phenytoin ([300), carbamazepine ([100), and
sodium valproate (149 mg/kg).
that of compound I (39.4 mg/kg); and 4f was among the most
active compound with ED50 value of 20.4 in the MES test,
and its PI value (20.1) is much higher than that of the pro-
totype antiepileptic drug carbamazepine (PI = 8.1), phe-
nytoin (PI = 6.9), phenobarbital (PI = 3.2), and sodium
valproate (PI = 1.6). The anti-scPtz activities of the com-
pounds (4d–f) were stronger than that of the marked anti-
epileptic drug carbamazepine, phenytoin, and sodium
valproate, and 4e was among the most active compounds
(ED50 = 64.4).
Pentylenetetrazole has been reported to produce seizures
by inhibiting c-aminobutyric acid (GABA) neurotrans-
mission (Hamilton et al., 1977; Bernasconi et al., 1988).
GABA is the main inhibitory neurotransmitter substance in
the brain, and is widely implicated in epilepsy. Inhibition
of GABAergic neurotransmission has been shown to pro-
mote and facilitate seizures (Arnoldi et al., 1990), while
enhancement of GABAergic neurotransmission is known
to inhibit or attenuate seizures. The synthesized compounds
might enhance GABAergic neurotransmission.
Experimental section
Chemistry
Melting points were determined on X-5 microscope melt-
ing point apparatus, which were uncorrected. IR spectra
were recorded (in KBr) on a FT-IR (IRPRESTIGE-21). 1H
NMR spectra were measured on an AV-300 (Bruker,
Switzerland), and all chemical shifts were given in parts
per million relative to tetramethylsilane. Mass spectra were
measured on a 6400 QQQ LC/MS (Agilent Technologies,
USA). Combustion analyses (C, H, and N) were performed
on a PE-2400 (SHIMADZU). Microanalyses of C, N, and
H were performed using a Heraeus CHN Rapid Analyzer.
The major chemicals were purchased from Alderich
chemical corporation. All other chemicals were of analyt-
ical grade.
Conclusions
A series of novel 1,3,4,5-tetrahydro-6-alkoxy-2H-1-benza-
zepin-2-one derivatives were synthesized and tested for
anticonvulsant activities using MES and scPTZ screens,
which are the most widely employed seizure models for early
identification of candidate anticonvulsants. Their neurotox-
icity was determined by applying the rotorod test. The anti-
convulsant activities of compounds (4d–f) were better than
Target compounds (4a–f) were prepared following the
reaction sequence shown in Scheme 1. The starting material
123

Med Chem Res
5-methoxy-3,4-dihydronaphthalen-1(2H)-one reacted with
hydroxylamine hydrochloride in ethanol and gave com-
pound 1, which reacted in PPA to produce compound 2 vis
Beckmann rearrangement. Compound 2 was further deme-
thylated by BBr3 to produce compound 3, which reacted with
appropriate alkyl halide to produce title compounds 4a–f.
J = 8.1 Hz, 1H, Ar–H), 6.73 (d, J = 1.71 Hz, 1H, Ar–H),
7.16 (t, J = 8.1 Hz, 1H, Ar–H), 8.08 (s,1H, NH). 13C NMR
(DMSO-d6): 21.0 (C4-benzoazpine), 22.4 (C5-benzoazpine),
23.2 (C3-benzoazpine), 55.8 (OCH3), 110.4 (C7-benzoaz-
pine), 115.9 (C9-benzoazpine), 126.8 (C8-benzoazpine),
127.8 (C5a-benzoazpine), 132.5 (C9a-benzoazpine), 153.0
(C6-benzoazpine), 156.8 (C=O); MS: m/z [M?1]?.
The synthesis of 5-methoxy-3,4-dihydronaphthalen-1
(2H)-one oxime (1)
The synthesis of 6-hydroxy-4,5-dihydro-1H-
benzo[b]azepin-2(3H)-one (3)
This compound was prepared from 5-methoxy-3,4-di-
hydronaphthalen-1(2H)-one by oximation with hydroxyl-
amine hydrochloride. To a solution of sodium ethanolate
(11.9 g, 0.18 mol) and hydroxylamine hydrochloride
(10.1 g, 0.145 mol) in 40 ml of H2O, a solution of 6-meth-
oxy-3,4-dihydronaphthalene-1(2H)-one (10.6 g, 0.060 mol)
in 75 ml ethanol was added dropwise. The mixture was
stirred and refluxed for 16–24 h. The solvent was partially
removed under reduced pressure and allowed to sit overnight
at room temperature, and then filtered to give a white solid,
which was dried under vacuum to afford a white solid
product. Yield: 95 %, m.p. 161.2–162.6 °C(lit. Hang et al.,
2008 m.p. 158–160). IR (KBr), cm-1: 3201 (O–H), 1573,
1504, 1443 (C=N, C=C),1260 (C–O). 1H NMR (DMSO-d6
300 MHz), d: 1.76–1.95 (m, 2H, CH2), 2.65–2.94 (m, 4H,
CH2), 3.84 (s, 3H, CH3), 6.83 (d, J = 8.1 Hz,1H, Ar–H),
7.15-7.26 (dd, J = 2.1, 8.8 Hz, 1H, Ar–H), 7.50–7.53 (d,
J = 7.8 Hz, 1H, Ar–H), 8.87 (s, 1H, –OH). 13C NMR
(DMSO-d6): 20.8 (C3-naphthalene), 22.3 (C4-naphthalene),
23.3 (C2-naphthalene), 55.5 (OCH3), 110.4 (C6-naphtha-
lene), 116.2 (C8-naphthalene), 126.6 (C7-naphthalene),
128.9 (C4a-naphthalene), 131.5 (C8a-naphthalene), 155.6
(C=O), 157.8 (C5-naphthalene); MS: m/z [M?1]? 191.1.
Anal. Calcd. for C11H13NO2: C, 69.09; H, 6.85; N, 7.32.
Found: 69.01; H, 6.80; N, 7.39.
This compound was prepared from 6-methoxy-4,5-dihy-
dro-1H-benzo[b]azepin-2(3H)-one by demethylation with
BBr3. Compound 2 (3.06 g, 0.016 mol) in 45 ml of CH2Cl2
was added dropwise to the solution of BBr3 (1.90 ml,
0.0208 mol) in 15 ml of CH2Cl2 under ice bath in N2
protection. Then the mixture was stirred at room temper-
ature for 16–20 h, then 35 ml of water was added and kept
overnight. The white precipitate was filtered and washed
with little amount of water and dichloromethane (30 ml) to
give product 3. Yield: 96.6 %, m.p. 257.7°(lit. Joanna
et al., 2002 bp 387 42). IR (KBr), cm-1: 3238 (O–H),
1
3123 (N–H), 1684 (C=O), 1248 (C–O). H NMR (DMSO-
d6 300 MHz), d: 1.94–2.08 (m, 2H, CH2), 2.13 (t,
J = 6.3 Hz, 2H, CH2), 2.67 (t, 2H, J = 7.2 Hz, CH2), 6.44
(d, J = 7.8 Hz, 1H, Ar–H), 6.60–6.67 (m, 1H, Ar–H),
6.94–7.25 (m, 1H, Ar–H), 9.40, 9.46 (each s, 2H, NH and
OH). 13C NMR (DMSO-d6): 22.2 (C4-benzoazpine), 27.7
(C5-benzoazpine), 33.7 (C3-benzoazpine), 111.9 (C7-ben-
zoazpine), 113.1 (C9-benzoazpine), 120.3 (C5a-benzoaz-
pine), 127.2 (C8-benzoazpine 8), 140.7 (C9a-benzoazpine),
155.5 (C6-benzoazpine), 173.8 (C=O); MS: m/z [M?1]?
177.1. Anal. Calcd. for C10H11NO2: C, 67.78; H, 6.26; N,
7.90. Found: 67.70; H, 6.20; N, 7.96.
The general procedure for the synthesis of 6-alkoxy-4,
The synthesis of 6-methoxy-4,5-dihydro-1H-
5-dihydro-1H-benzo[b]azepin-2(3H)-ones (4a–4p)
benzo[b]azepin-2(3H)-one (2)
This compound was prepared from 6-hydroxy-4,5-dihydro-
1H-benzo[b]azepin-2(3H)-one by etherification with appro-
priate alkyl halide. Compound 3 (1.0632 g, 6 mmol),
sodium hydroxyl (312 mg, 7.8 mmol), and appropriate alkyl
halogen (7.8 mmol) reacted in 60 ml of ethanol for 4–5 h
with refluxing. After the solvent removing, the crude product
was washed with water, dried, and then purified by recrys-
tallization (ethanol/ethyl acetate = 8/1) to afford com-
pounds 4a–4p.
This compound was prepared from 5-methoxy-3,4-di-
hydronaphthalen-1(2H)-one oxime by Beckmann rear-
rangement with PPA. Compound 1 (10 g) and 100 ml PPA
was stirred at 110–120 °C for 20–25 min. Then the mixture
was poured into 400 ml of ice water, extracted with dichlo-
romethane (120 9 3), washed with saturated sodium bicar-
bonate solution, washed with distilled water, and then dried
over anhydrous MgSO4. After evaporating all the solvent,
the pure product 2 was obtained as a white solid. Yield:
80.0 %, m.p. 167.2–168.2°.(lit. Xiao et al., 2012 m.p.
164–165) IR (KBr), cm-1: 3183 (N–H), 1684 (C=O), 1276
6-Propoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (4a)
Yield 56.8 %, m.p. 122.7–123.1 °C. IR (KBr), cm-1: 3190
(N–H), 1674 (C=O), 1095 (C–O), 1277 (C–O). H NMR
1
(C–O). H NMR (DMSO-d6 300 MHz), d: 2.10–2.25 (m,
2H, CH2), 2.35 (t, J = 7.2 Hz, 2H, CH2), 2.87 (t,
1
J = 7.2 Hz, 2H, CH2), 3.84 (s, 3H, CH3), 6.64 (d,
123

Med Chem Res
6-(Hexyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(DMSO-d6 300 MHz) d: 1.05 (t, J = 7.5 Hz, 3H, CH3),
1.71–1.90 (m, 2H, CH2), 2.10–2.27 (m, 2H, CH2), 2.35 (t,
J = 7.5 Hz, 2H, CH2), 2.90 (t, 2H, CH2), 3.93 (t,
J = 6.5 Hz, 2H, CH2), 6.60 (d, J = 8.1 Hz, 1H, Ar–H),
6.71 (d, J = 8.4 Hz, 1H, Ar–H), 7.14 (t, J = 8.5 Hz, 1H,
Ar–H), 7.76 (s, 1H, NH). 13C NMR (DMSO-d6): 10.7
(CH3), 21.9 (C4-benzoazpine), 22.7 (CH2-CH3), 27.9 (C5-
benzoazpine), 33.2 (C3-benzoazpine), 70.1 (OCH2), 108.8
(C7-benzoazpine), 114.2 (C9-benzoazpine), 122.9 (C5a-
benzoazpine), 127.3 (C8-benzoazpine), 139.2 (C9a-ben-
zoazpine), 157.1 (C6-benzoazpine), 175.6 (C=O); MS: m/
z [M?1]? 219.1. Anal. Calcd. for C13H17NO2: C, 71.21; H,
7.81; N, 6.39. Found: 71.28; H, 7.78; N, 6.32.
(4d)
Yield 68.3 %, m.p. 96.9–97.2 °C. IR (KBr), cm-1: 3190 (N–
H), 1670 (C=O), 1090 (C–O), 1250 (C–O). 1H NMR
(DMSO-d6 300 MHz) d: 0.84–0.99 (m, 3H, CH3), 1.29–1.39
(m, 4H, CH2), 1.40–1.55 (m, 2H, CH2), 1.74–1.87 (m, 2H,
CH2), 2.08–2.28 (m, 2H, CH2), 2.35 (t, J = 7.2 Hz, 2H,
CH2), 2.89 (t, J = 7.2 Hz, 2H, CH2), 3.96 (t, J = 6.3 Hz,
2H, CH2), 6.59 (d, J = 8.1 Hz, 1H, Ar–H), 6.71 (d,
J = 8.4 Hz, 1H, Ar–H), 7.14 (t, J = 8.1 Hz, 3H, Ar–H),
7.73 (s, 1H, NH). 13C NMR (DMSO-d6): 14.3 (CH3), 22.1
(C4-benzoazpine), 22.5 (CH2–CH3), 25.7 (CH2–C3H7), 27.9
(C5-benzoazpine), 29.2 (CH2–C4H9), 31.4 (CH2–C2H5),
33.7 (C3-benzoazpine), 68.5 (OCH2), 108.8 (C7-benzoaz-
pine), 114.6 (C9-benzoazpine), 122.1 (C5a-benzoazpine),
127.5 (C8-benzoazpine), 140.6 (C9a-benzoazpine), 156.9
(C6-benzoazpine), 173.7 (C=O); MS: m/z [M?1]? 261.1.
Anal. Calcd. for C16H23NO2: C, 73.53; H, 8.87; N, 5.36.
Found: 73.59; H, 8.80; N, 5.30.
6-Butoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (4b)
Yield 70.0 %, m.p. 105.5–106.2 °C. IR (KBr), cm-1: 3120
(N–H), 1670 (C=O), 1098 (C–O), 1252 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 1.05 (t, J = 7.5 Hz, 3H, CH3),
1.41–1.59 (m, 2H, CH2), 1.71–1.90 (m, 2H, CH2),
2.10–2.26 (m, 2H, CH2), 2.35 (t, J = 7.5 Hz, 2H, CH2),
2.89 (t, J = 7.2 Hz, 2H, CH2), 3.97 (t, J = 6.3 Hz, 2H,
CH2), 6.60 (d, J = 7.8 Hz, 1H, Ar–H), 6.71 (d,
J = 8.1 Hz, 1H, Ar–H), 7.14 (t, J = 8.1 Hz, 3H, Ar–H),
7.82 (s, 1H, NH). 13C NMR (DMSO-d6): 14.2 (CH3), 19.3
(CH2-CH3), 22.1 (C4-benzoazpine), 27.9 (C5-benzoazpine),
31.3 (CH2-C2H5), 33.7 (C3-benzoazpine), 68.2 (OCH2),
108.7 (C7-benzoazpine), 114.6 (C9-benzoazpine), 122.1
(C5a-benzoazpine), 127.5 (C8-benzoazpine), 140.6 (C9a-
benzoazpine), 156.9 (C6-benzoazpine), 173.7 (C=O); MS:
m/z [M?1]? 233.1. Anal. Calcd. for C1H19NO2: C, 72.07;
H, 8.21; N, 6.00. Found: 71.99; H, 8.27; N, 6.08.
6-(Heptyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(4e)
Yield 70.7 %, m.p. 93.1–94.3 °C. IR (KBr), cm-1: 3190
(N–H), 1617 (C=O), 1097 (C–O), 1252 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 0.90 (t, J = 6.6 Hz, 3H, CH3),
1.23–1.40 (m, 6H, CH2), 1.42–1.57 (m, 2H, CH2),
1.68–1.90 (m, 2H, CH2), 2.10–2.28 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.89 (t, J = 7.2 Hz, 2H, CH2), 3.96
(t, J = 6.3 Hz, 2H, CH2), 6.60 (d, J = 7.8 Hz, 1H, Ar–H),
6.71 (d, J = 8.4 Hz, 1H, Ar–H), 7.14 (t, J = 8.4 Hz, 3H,
Ar–H), 7.78 (s, 1H, -NH). 13C NMR (DMSO-d6): 14.4
(CH3), 22.1 (C4-benzoazpine), 22.5 (CH2–CH3), 26.1
(CH2–C4H9), 27.9 (C5-benzoazpine), 28.9 (CH2–C3H7),
29.2 (CH2–C5H11), 31.7 (CH2–C2H5), 33.7 (C3-benzoaz-
pine), 68.5 (OCH2), 108.8 (C7-benzoazpine), 114.6 (C9-
benzoazpine), 122.1 (C5a-benzoazpine), 127.6 (C8-ben-
zoazpine), 140.6 (C9a-benzoazpine), 156.9 (C6-benzoaz-
pine), 173.7 (C=O); MS: m/z [M?1]? 275.1. Anal. Calcd.
for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: 74.20;
H, 9.10; N, 5.02.
6-(Pentyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(4c)
Yield 66.5 %, m.p. 96.5–97.3 °C. IR (KBr), cm-1: 3190 (N–
H), 1672 (C=O), 1090 (C–O), 1252 (C–O). 1H NMR
(DMSO-d6 300 MHz) d: 0.94(t, J = 7.5 Hz, 3H, CH3),
1.29–1.53 (m, 4H, CH2), 1.67–1.90 (m, 2H, CH2), 2.10–2.27
(m, 2H, CH2), 2.35 (t, J = 7.5 Hz, 2H, CH2), 2.89 (t,
J = 7.2 Hz, 2H, CH2), 3.97(t, J = 6.3 Hz, 2H, CH2), 6.60
(d, J = 7.8 Hz, 1H, Ar–H), 6.71 (d, J = 8.4 Hz, 1H, Ar–H),
7.14 (t, J = 8.1 Hz, 3H, Ar–H), 7.80(s, 1H, NH). 13C NMR
(DMSO-d6): 14.4 (CH3), 22.1 (C4-benzoazpine), 22.3 (CH2–
CH3), 27.9 (C5-benzoazpine), 28.3 (CH2–C2H5), 28.9 (CH2–
C3H7), 33.7 (C3-benzoazpine), 68.5 (OCH2), 108.8 (C7-
benzoazpine), 114.6 (C9-benzoazpine), 122.1 (C5a-ben-
zoazpine), 127.6 (C8-benzoazpine), 140.6 (C9a-benzoaz-
pine), 156.9 (C6-benzoazpine), 173.7 (C=O); MS: m/
z [M?1]? 247.1. Anal. Calcd. for C15H21NO2: C, 72.84; H,
8.56; N, 5.66. Found: 72.90; H, 8.50; N, 5.60.
6-(Octyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(4f)
Yield 74.3 %, m.p. 105.4–106.4 °C. IR (KBr), cm-1: 3190
(N–H), 1668 (C=O), 1098 (C–O), 1254 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 0.89 (t, J = 6.6 Hz, 3H, CH3),
1.19–1.37 (m, 8H, CH2), 1.42–1.54 (m, 2H, CH2),
1.72–1.89 (m, 2H, CH2), 2.11–2.27 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.89 (t, J = 7.2 Hz, 2H, CH2), 3.96
(t, J = 6.6 Hz, 2H, CH2), 6.59 (d, J = 7.8 Hz, 1H, Ar–H),
123

Med Chem Res
6.71 (d, J = 8.4 Hz, 1H, Ar–H), 7.14 (t, J = 8.4 Hz, 3H,
Ar–H), 7.78 (s, 1H, –NH). 13C NMR (DMSO-d6): 14.1
(CH3), 21.9 (C4-benzoazpine), 22.7 (CH2–CH3‘), 26.2
(CH2–C5H11), 27.9 (C5-benzoazpine), 29.3 (CH2–C3H7),
29.3 (CH2–C6H13 and CH2–C4H9), 31.8 (CH2–C2H5), 33.2
(C3-benzoazpine), 68.6 (OCH2), 108.8 (C7-benzoazpine),
114.1 (C9-benzoazpine), 123.0 (C5a-benzoazpine), 127.3
(C8-benzoazpine), 139.1 (C9a-benzoazpine), 157.1 (C6-
benzoazpine), 173.5 (C=O); MS: m/z [M?1]? 289.1. Anal.
Calcd. for C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found:
74.77; H, 9.46; N, 4.90.
phenyl), 175.4 (C=O); MS: m/z [M?1]? 285.1. Anal.
Calcd. for C17H16FNO2: C, 71.56; H, 5.65; N, 4.91. Found:
71.50; H, 75.60; N, 4.97.
6-(3-Fluorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4i)
Yield 64.5 %, m.p. 153.1–154.0 °C. IR (KBr), cm-1: 3222
(N–H), 1666 (C=O), 1080 (C–O), 1254 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.12–2.28 (m, 2H, CH2), 2.37 (t,
J = 7.5 Hz, 2H, CH2), 2.95 (t, J = 7.2 Hz, 2H, CH2), 5.08 (s,
2H, CH2-benzyl), 6.65 (d, J = 7.8 Hz, 1H, Ar–H), 6.76 (d,
J = 8.4 Hz, 1H, Ar–H), 6.98–7.08 (m, 1H, Ar–H), 7.09–7.23
(m, 3H, Ar–H), 7.30–7.40 (m, 1H, Ar–H), 7.74 (s, 1H, NH).
13C NMR (DMSO-d6): 22.1 (C4-benzoazpine), 27.9
6-(Nonyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(4g)
Yield 62.9 %, m.p. 95.8–96.3 °C. IR (KBr), cm-1: 3212
(N–H), 1647 (C=O), 1100 (C–O), 1252 (C–O). H NMR
(C5-benzoazpine), 33.2 (C3-benzoazpine), 69.8 (d, JC-F =
1
1.5 Hz, CH2-benzyl), 109.3 (C7-benzoazpine), 114.0 (d,
JC-F = 21.8 Hz, C2-phenyl), 114.9 (d, JC-F = 21.0 Hz, C4-
phenyl), 114.9 (C9-benzoazpine), 122.5 (d, JC-F = 3.0 Hz,
C6-phenyl), 123.3 (C5a-benzoazpine), 127.4 (C8-benzoaz-
pine), 130.2 (d, JC-F = 8.3 Hz, C5-phenyl), 139.4 (C9a-ben-
zoazpine), 139.6 (d, JC-F = 7.5 Hz, C1-phenyl), 156.4 (C6-
benzoazpine), 163.0 (d, JC-F = 244.5 Hz, C3-phenyl), 175.4
(C=O); MS: m/z [M?1]? 285.1. Anal. Calcd. for
C17H16FNO2: C, 71.56; H, 5.65; N, 4.91. Found: 71.50; H,
5.60; N, 4.97.
(DMSO-d6 300 MHz) d: 0.88 (t, J = 6.6 Hz, 3H, CH3),
1.41–1.23 (m, 10H, CH2), 1.56–1.43 (m, 2H, CH2),
1.91–1.73 (m, 2H, CH2), 2.27–2.12 (m, 2H, CH2), 2.35 (t,
J = 7.5 Hz, 2H, CH2), 2.89 (t, J = 7.2 Hz, 2H, CH2), 3.96
(t, J = 6.3 Hz, 2H, CH2), 6.59 (d, J = 7.2 Hz, 1H, Ar–H),
7.14 (t, J = 8.4 Hz, 3H, Ar–H), 6.71 (d, J = 8.1 Hz, 1H,
Ar–H), 7.69 (s, 1H, NH). 13C NMR (DMSO-d6): 14.1
(CH3), 21.9 (C4-benzoazpine), 22.7 (CH2–CH3), 26.2
(CH2-C6H13), 27.9 (C5-benzoazpine), 29.3 (CH2-C3H7),
29.3 (CH2-C4H9), 29.4 (CH2-C5H11), 29.5 (CH2–C7H15),
31.9 (CH2–C2H5), 33.2 (C3-benzoazpine), 68.6 (OCH2),
108.8 (C7-benzoazpine), 114.1 (C9-benzoazpine), 123.0
(C5a-benzoazpine), 127.3 (C8-benzoazpine), 139.1 (C9a-
benzoazpine), 157.2 (C6-benzoazpine), 175.4 (C=O); MS:
m/z [M?1]? 303.1. Anal. Calcd. for C19H29NO2: C, 75.21;
H, 9.63; N, 4.62. Found: 75.29; H, 9.69; N, 4.69.
6-(4-Fluorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4j)
Yield 75.8 %, m.p. 187.6–188.9 °C. IR (KBr), cm-1: 3190
(N–H), 1668 (C=O), 1080 (C–O), 1254 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.09–2.26 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.92 (t, J = 7.2 Hz, 2H, CH2),5.04
(s, 2H, CH2-benzyl), 6.65 (d, J = 7.8 Hz, 1H, Ar–H), 6.78
(d, J = 8.1 Hz, 1H, Ar–H), 7.03–7.21 (m, 3H, Ar–H),
7.34–7.52 (m, 2H, Ar–H), 7.84 (s, 1H, NH). 13C NMR
(DMSO-d6): 22.1 (C4-benzoazpine), 27.9 (C5-benzoaz-
pine), 33.2 (C3-benzoazpine), 70.0 (CH2-benzyl), 109.4
(C7-benzoazpine), 114.9 (C9-benzoazpine), 115.5 (d,
JC-F = 21.0 Hz, C3,5-phenyl), 123.3 (C5a-benzoazpine),
6-(2-Fluorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4h)
Yield 56.2 %, m.p. 183.2–184.3 °C. IR (KBr), cm-1: 3190
(N–H), 1672 (C=O), 1079 (C–O), 1233 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.06–2.25 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.92 (t, J = 7.2 Hz, 2H, CH2), 5.15
(s, 2H, CH2-benzyl), 6.65(d, J = 7.5 Hz, 1H, Ar–H), 6.83
(d, J = 8.1 Hz, 1H, Ar–H), 7.05–7.23 (m, 3H, Ar–H),
7.28–7.38 (m, 1H, Ar–H), 7.48 (t, J = 7.5 Hz, 1H, Ar–H),
7.74 (s, 1H, NH). 13C NMR (DMSO-d6): 19.4 (C4-ben-
zoazpine), 22.1 (C5-benzoazpine), 33.2 (C3-benzoazpine),
64.6 (d, JC-F = 4.5 Hz, CH2-benzyl), 109.5 (C7-benzoaz-
pine), 115.0 (C9-benzoazpine), 115.4 (d, JC-F = 21.0 Hz,
C3-phenyl), 123.4 (C5a-benzoazpine), 124.1 (C5-phenyl),
124.3 (d, JC-F = 3.8 Hz, C1-phenyl), 127.4 (C8-benzoaz-
pine), 129.5 (d, JC-F = 5.3 Hz, C6-phenyl), 129.8 (d,
JC-F = 7.5 Hz, C4-phenyl), 139.1 (C9a-benzoazpine),
157.2 (C6-benzoazpine), 160.5 (d, JC-F = 246.0 Hz, C2-
127.4 (C8-benzoazpine), 129.1 (d, JC-F = 8.3 Hz, C2,6
-
phenyl), 139.4 (C9a-benzoazpine), 156.6 (C6-benzoazpine),
162.5 (d, JC-F = 244.5 Hz, C4-phenyl), 175.5 (C=O); MS:
m/z [M ? 1]? 285.1. Anal. Calcd. for C17H16FNO2: C,
71.56; H, 5.65; N, 4.91. Found: C, 71.50; H, 5.60; N, 4.98.
6-(2-Chlorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4k)
Yield 81.4 %, m.p. 158.5–159.4 °C. IR (KBr), cm-1: 190
(N–H), 1676 (C=O), 1081 (C–O), 1256 (C–O). H NMR
1
123

Med Chem Res
(DMSO-d6 300 MHz) d: 2.13–2.31 (m, 2H, CH2), 2.37 (t,
J = 7.2 Hz, 2H, CH2), 2.96 (t, J = 7.2 Hz, 2H, CH2), 5.12
(s, 2H, CH2-benzyl), 6.66 (d, J = 7.8 Hz, 1H, Ar–H),
6.81(d, J = 8.4 Hz, 1H, Ar–H), 7.12 (t, J = 8.4 Hz, 1H,
Ar–H), 7.27–7.35 (m, 2H, Ar–H), 7.34–7.46 (m, 1H, Ar–
H), 7.48–7.60 (m, 1H, Ar–H), 7.79 (s, 1H, NH). 13C NMR
(DMSO-d6): 22.2 (C4-benzoazpine), 27.9 (C5-benzoaz-
pine), 33.2 (C3-benzoazpine), 67.9 (CH2-benzyl), 109.5
(C7-benzoazpine), 114.9 (C9-benzoazpine), 123.3 (C5a-
benzoazpine), 127.0 (C5-phenyl), 127.4 (C8-benzoazpine),
128.7 (C6-phenyl), 129.1 (C3-phenyl), 129.5 (C4-phenyl),
132.7 (C2-phenyl), 134.7 (C1-phenyl), 139.4 (C9a-ben-
zoazpine), 156.5 (C6-benzoazpine), 175.4 (C=O); MS: m/
z [M?1]? 301.1. Anal. Calcd. for C17H16ClNO2: C, 67.66;
H, 5.34; N, 4.64. Found: 67.60; H, 5.39; N, 4.59.
C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64. Found: 67.60; H,
5.39; N, 4.60.
6-(4-Bromobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4n)
Yield 75.0 %, m.p. 213.4–214.5 °C. IR (KBr), cm-1: 3190
(N–H), 1691 (C=O), 1080 (C–O), 1275 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.10–2.24 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.92 (t, J = 7.2 Hz, 2H, CH2),
5.04(s, 2H, CH2-benzyl), 6.64 (d, J = 8.4 Hz, 1H, Ar–H),
6.76 (d, J = 8.4 Hz, 1H, Ar–H), 7.15 (t, J = 8.7 Hz, 1H,
Ar–H), 7.24–7.38 (m, 2H, Ar–H), 7.48–7.59 (m, 2H, Ar–
H), 7.66 (s, 1H, NH). 13C NMR (DMSO-d6): 22.1 (C4-
benzoazpine), 27.9 (C5-benzoazpine), 33.2 (C3-benzoaz-
pine), 69.9 (CH2-benzyl), 109.3 (C7-benzoazpine), 114.9
(C9-benzoazpine), 121.9 (C4-phenyl), 123.3 (C5a-benzoaz-
pine), 127.4 (C8-benzoazpine), 128.9 (C2,6-phenyl), 131.8
(C3,5-phenyl), 136.0 (C1-phenyl), 139.4 (C9a-benzoazpine),
156.5 (C6-benzoazpine), 175.4 (C=O); MS: m/z [M?1]?
345.0. Anal. Calcd. for C17H16BrNO2: C, 58.97; H, 4.66;
N, 4.05. Found: 758.90; H, 4.60; N, 4.00.
6-(3-Chlorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4l)
Yield 59.3 %, m.p. 149.9–151.0 °C. IR (KBr), cm-1: 3190
(N–H), 1666 (C=O), 1100 (C–O), 1279 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.14–2.27 (m, 2H, CH2), 2.37 (t,
J = 7.2 Hz, 2H, CH2), 2.94 (t, J = 7.2 Hz, 2H, CH2), 5.08
(s, 2H, CH2-benzyl), 6.65 (d, J = 7.8 Hz, 1H, Ar–H), 6.76
(d, J = 8.4 Hz, 1H, Ar–H), 7.15 (t, J = 8.4 Hz, 1H, Ar–
H), 7.28–7.38 (m, 3H, Ar–H), 7.41 (s, 1H, Ar–H), 7.78 (s,
1H, NH). 13C NMR (DMSO-d6): 22.1 (C4-benzoazpine),
27.9 (C5-benzoazpine), 33.2 (C3-benzoazpine), 69.8 (CH2-
benzyl), 109.3 (C7-benzoazpine), 115.0 (C9-benzoazpine),
123.3 (C5a-benzoazpine), 125.2 (C6-phenyl), 127.3 (C2-
phenyl), 127.4 (C8-benzoazpine), 128.2 (C4-phenyl), 129.9
(C5-phenyl), 134.5 (C3-phenyl), 139.1 (C1-phenyl), 139.4
(C9a-benzoazpine), 156.5 (C6-benzoazpine), 175.4 (C=O);
MS: m/z [M?1]? 301.1. Anal. Calcd. for C17H16ClNO2: C,
67.66; H, 5.34; N, 4.64. Found: 67.60; H, 5.39; N, 4.59.
6-(4-Methylbenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4o)
Yield 65.9 %, m.p. 159.7–160.9 °C. IR (KBr), cm-1: 3190
(N–H), 1691 (C=O), 1080 (C–O),1279 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.10–2.24 (m, 2H, CH2),
2.29–2.43 (m, 5H, CH2 and CH3), 2.92 (t, J = 7.2 Hz, 2H,
CH2), 5.04 (s, 2H, CH2-benzyl), 6.62 (d, J = 7.5 Hz, 1H,
Ar–H), 6.80 (d, J = 8.1 Hz, 1H, Ar–H), 7.10–7.24 (m, 3H,
Ar–H), 7.27-7.35 (m, 2H, Ar–H), 7.64 (s, 1H, NH). 13C
NMR (DMSO-d6): 21.2 (CH3), 22.1 (C4-benzoazpine),
27.9 (C5-benzoazpine), 33.2 (C3-benzoazpine), 70.6 (CH2-
benzyl), 109.5 (C7-benzoazpine), 114.6 (C9-benzoazpine),
123.3 (C5a-benzoazpine), 127.3 (C2,6-phenyl), 127.4 (C8-
benzoazpine), 129.3 (C3,5-phenyl), 134.0 (C1-phenyl),
137.8 (C4-phenyl), 139.3 (C9a-benzoazpine), 156.8 (C6-
benzoazpine), 175.5 (C=O); MS: m/z [M?1]? 281.1. Anal.
Calcd. for C18H19NO2: C, 76.84; H, 6.81; N, 4.98. Found:
76.90; H, 6.88; N, 4.90.
6-(4-Chlorobenzyloxy)-4,5-dihydro-1H-benzo[b]azepin-
2(3H)-one (4m)
Yield 69.9 %, m.p. 193.4–194.4 °C. IR (KBr), cm-1: 3205
(N–H), 1662 (C=O), 1088 (C–O), 1277 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.10–2.26 (m, 2H, CH2), 2.36 (t,
J = 7.2 Hz, 2H, CH2), 2.92 (t, J = 7.2 Hz, 2H, CH2), 5.05
(s, 2H, CH2-benzyl), 6.64 (d, J = 8.1 Hz, 1H, Ar–H), 6.76
(d, J = 8.1 Hz, 1H, Ar–H), 7.15 (t, J = 8.1 Hz, 1H, Ar–
H), 7.30–7.51 (m, 4H, Ar–H), 7.50 (s, 1H, NH). 13C NMR
(DMSO-d6): 22.1 (C4-benzoazpine), 27.9 (C5-benzoaz-
pine), 33.2 (C3-benzoazpine), 69.8 (CH2-benzyl), 109.3
(C7-benzoazpine), 114.9 (C9-benzoazpine), 123.3 (C5a-
benzoazpine), 127.4 (C8-benzoazpine), 128.6 (C3,5-phe-
nyl), 128.8 (C2,6-phenyl), 133.8 (C4-phenyl), 135.5 (C1-
phenyl), 139.4 (C9a-benzoazpine), 156.5 (C6-benzoazpine),
175.4 (C=O); MS: m/z [M?1]? 301.1. Anal. Calcd. for
6-(Benzyloxy)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one
(4p)
Yield 73.0 %, m.p. 164.4–165.5 °C. IR (KBr), cm-1: 3190
(N–H), 1662 (C=O), 1080 (C–O), 1256 (C–O). H NMR
1
(DMSO-d6 300 MHz) d: 2.10-2.26 (m, 2H, CH2), 2.59 (t,
J = 7.2 Hz, 2H, CH2), 2.94 (t, J = 7.2 Hz, 2H, CH2), 5.08
(s, 2H, CH2-benzyl), 6.66 (d, J = 7.8 Hz, 1H, Ar–H), 6.80
(d, J = 8.1 Hz, 1H, Ar–H), 7.15 (t, J = 8.1 Hz, 3H, Ar–
H), 7.29-7.51 (m, 5H, Ar–H), 7.77 (s, 1H, NH). 13C NMR
123

Med Chem Res
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