Synthesis, anti-parasitic activity and QSAR study of a new library of polysubstituted tetrahydronaphtho[1,2-b]azepines

Article abstract of DOI:10.1007/s00044-018-2232-7

A new series of twenty two 2-exo-aryl(heteroaryl)-1,4-epoxytetrahydronaphtho[1,2-b]azepines 8–10 and eighteen cis-2-aryl(heteroaryl)-4-hydroxytetrahydronaphtho[1,2-b]azepines 11–13 were synthesized, and most of them were tested for their ability to inhibit the in vitro growth of the extracellular forms of Trypanosoma cruzi and Leishmania infantum parasites. Cell toxicity was also determined on Vero and THP-1 mammalian cells. Seventeen compounds exhibited potent activity against the epimastigotes (IC₅₀ lower than 20 μM), without cytotoxicity on Vero cells. Ten compounds also showed remarkable anti-leishmanial properties against the promastigote form of the parasite (IC₅₀ lower than 20 μM), but most of them were found cytotoxic for HTP-1 cells. We have also performed a quantitative structure activity relationship analysis by means of the multivariate lineal regression (MLR) technique with a family of ninety-four tetrahydro-1-benzazepine and tetrahydronaphtho[1,2-b]azepine derivatives with anti-parasitic activity. The aim of this study is to develop a tool that permits us to elucidate the structural features, which influence in the bioactivity of these compounds. The QSAR prediction models for Trypanosoma cruzi and Leishmania infantum were acceptable with a correlation coefficient values (R) of 0.668 and 0.852, respectively, in the prediction of those activities.

Full text of DOI:10.1007/s00044-018-2232-7

MEDICINAL
CHEMISTRY
RESEARCH
Medicinal Chemistry Research
https://doi.org/10.1007/s00044-018-2232-7
ORIGINAL RESEARCH
Synthesis, anti-parasitic activity and QSAR study of a new library of
polysubstituted tetrahydronaphtho[1,2-b]azepines
Andrés Felipe Yépes1 Alí Bahsas2 Patricia Escobar3 Justo Cobo4 Alirio Palma1 Juan C. Garro Martinez5
Ricardo Enriz5
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Received: 29 April 2018 / Accepted: 31 July 2018
© Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
A new series of twenty two 2-exo-aryl(heteroaryl)-1,4-epoxytetrahydronaphtho[1,2-b]azepines 8–10 and eighteen cis-2-aryl
(heteroaryl)-4-hydroxytetrahydronaphtho[1,2-b]azepines 11–13 were synthesized, and most of them were tested for their
ability to inhibit the in vitro growth of the extracellular forms of Trypanosoma cruzi and Leishmania infantum parasites. Cell
toxicity was also determined on Vero and THP-1 mammalian cells. Seventeen compounds exhibited potent activity against
the epimastigotes (IC50 lower than 20 µM), without cytotoxicity on Vero cells. Ten compounds also showed remarkable anti-
leishmanial properties against the promastigote form of the parasite (IC50 lower than 20 µM), but most of them were found
cytotoxic for HTP-1 cells. We have also performed a quantitative structure activity relationship analysis by means of the
multivariate lineal regression (MLR) technique with a family of ninety-four tetrahydro-1-benzazepine and tetrahydronaphtho
[1,2-b]azepine derivatives with anti-parasitic activity. The aim of this study is to develop a tool that permits us to elucidate
the structural features, which influence in the bioactivity of these compounds. The QSAR prediction models for
Trypanosoma cruzi and Leishmania infantum were acceptable with a correlation coefficient values (R) of 0.668 and 0.852,
respectively, in the prediction of those activities.
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Keywords 2-exo-aryl(heteroaryl)-1,4-epoxytetrahydronaphtho[1,2-b]azepines cis-2-aryl(heteroaryl)-4-
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hydroxytetrahydronaphtho[1,2-b]azepines Anti-parasitic activity Structure activity relationship (SAR) Quantitative
structure-activity relationship (QSAR)
Introduction
there are no vaccines available (Hotez et al. 2011; Diniz
et al. 2013). Chagas disease (American trypanosomiasis) is
caused by the flagellate protozoan Trypanosoma cruzi,
mainly transmitted by the infected feces of triatomine bugs.
Nevertheless, it could also be transmitted by blood trans-
fusions and organs transplant, as well as congenitally and
orally from contaminated food. Chagas disease is a devas-
tating and neglected disease, which affects about 6 million
to 7 million people worldwide, mostly in Latin America,
and causes approximately 10,000 deaths annually, and it is
responsible for 89% of death from tropical-clustered
Chagas disease and leishmaniasis remain a major public
health problem due to the inadequate therapy, and because
These authors contributed equally: Alirio Palma, Juan C. Garro
Martinez.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00044-018-2232-7) contains supplementary
material, which is available to authorized users.
3
* Juan C. Garro Martinez
Departamento de Ciencias Básicas, Escuela de Medicina, Centro
jcgarro@unsl.edu.ar
de Investigación de Enfermedades Tropicales, Universidad
Industrial de Santander, A. A. 678, Bucaramanga, Colombia
1
Laboratorio de Síntesis Orgánica, Escuela de Química,
4
Inorganic and Organic Department, University of Jaén, Campus
Las Lagunillas s/n, 23071 Jaén, Spain
Universidad Industrial de Santander, A. A. 678,
Bucaramanga, Colombia
5
Facultad de Química, Bioquímica y Farmacia, IMIBIO,
CONICET, Universidad Nacional de San Luis, Chacabuco 915,
5700 San Luis, Argentina
2
Departamento de Química, Laboratorio de RMN, Grupo de
Productos Naturales, Universidad de los Andes, Mérida 5101,
Venezuela

Medicinal Chemistry Research
Fig. 1 The 2-
aryltetrahydronaphtho[1,2-b]
azepine series and 2-aryl
(heteroaryl)tetrahydro-1-
benzazepine series
diseases in the region. In addition, Chagas disease causes
over US$ 1.2 billion/year of productivity loss in seven of
the countries where it is endemic (Rodrigues-Coura and
Albajar-Viñas 2010; Crompton et al. 2010; Ayo et al. 2013;
Jackson et al. 2013; World Health Organization 2016).
Chagas disease presents an initial acute phase with a high
number of parasites circulating the blood followed by a
chronic phase which, in approximately 30% of the infected
people, leads after several years to cardiac, digestive, neu-
rological, or mixed clinical alterations (Rodrigues–Coura
and Albajar–Viñas 2010). Nifurtimox (recently dis-
continued) and benznidazole are the two drugs available for
treatment during the acute and asymptomatic chronic phases
of disease. Unfortunately, these drugs have poor efficacy in
the chronic stage of the disease and are related to several
side effects (Rodriques–Coura and de Castro 2002; Urbina
2010; Olivieri et al. 2010; Pinazo et al. 2010), and drug
resistant strains have been observed (Kessler et al. 2013,
Wiggers et al. 2013, Serafim et al. 2014).
Leishmaniasis is a poverty-related group of diseases
caused by several species of protozoan parasites belonging
to the family Trypanosomatidae and genus Leishmania, and
transmitted by the bite of more than 30 different species of
sand flies (Mishra et al. 2007, World Health Organization
2012). They are digenetic parasites that proliferate as motile
promastigotes in the gut of sand flies and as amastigotes
inside vertebrate-host macrophages. There are two main
forms of leishmaniasis, cutaneous (the most common), and
visceral leishmaniasis, also known as Kala-azar (the most
severe form, fatal in 85–90% of untreated cases). Leish-
maniasis is currently prevalent in four continents, being
endemic in 98 countries, leading to about 5,00,000 new
cases and 50,000 annual deaths, mostly due to the visceral
form (Alvar et al. 2012). In most of the developing coun-
tries the therapy is still based on pentavalent antimonials,
sodium stibogluconate (Pentostam), and meglumine anti-
moniate (Glucantime), developed more than 50 years ago as
first-line drugs, whereas amphotericin B (both the free and
liposomal amphotericin B), pentamidine isothionate, par-
omomycin, and miltefosine are used as second-line che-
motherapy. Unfortunately, all these drugs present several
side-effects and are toxic and expensive, and have low
availability, variable effectiveness, and high risk of resis-
tance (Croft and Yardley 2002; Sundar and Chakravarty
2013; Perez-Victoria et al. 2003).
Although some progress has been made in the develop-
ment of alternative drugs to treat these two diseases, efforts
directed toward the discovery of non-toxic, safer, cheaper,
and more effective chemotherapeutic agents are urgently
needed (Barrett and Croft 2012; Molina et al. 2014;
Espuelas et al. 2012; Marín et al. 2013; Chauhan et al. 2013;
Galiana-Roselló et al. 2013).
The tetrahydro-1-benzazepine nucleus is frequently
encountered as scaffold in medicinal chemistry (Bankir
et al. 2001; Abraham 1994; Morita et al. 2003; Barberis
et al. 1999; Decaux 2001), as this heterocyclic unit is pre-
sent in an extensively studied class of potent and orally
active non-peptide arginine-vasopressin antagonists for both
V
1A and V2 receptors, (Shimada et al. 2000; Kakefuda et al.
2002; Tsunoda et al. 2003 2005; Matthews et al. 2003; Yea
et al. 2008) as potent inhibitors of cyclin-dependent kinases
Schultz et al. 1999; Sielecki et al. 2000; Kunick et al. 2000,
2006), as potent and orally bioavailable growth hormone
secretagogue (Schoen et al. 1994; De Vita and Wyvratt
1996; De Vita et al. 1998; Ankersen 2002), and as agents
against HIV-1 infection (Seto et al. 2005). Furthermore,
some molecules containing this frame have been described
as promising anti-leishmanicidal and anti-chagasic agents
(Knockaert et al. 2002; Zuccotto et al. 2001).
In preceding studies, we have established that com-
pounds bearing a substituted 2-aryltetrahydronaphtho[1,2-
b]azepine scaffold, like in compounds I and II (Fig. 1),
possess remarkable anti-parasitic activity against both the
extracellular and intracellular forms of T. cruzi and L.
infantum parasites (Palma et al. 2009a, 2009b). Moreover,
we have also synthetized series of compounds of the types
III and IV (Fig. 1), in which the naphthalene ring of the
tetrahydronaphtho[1,2-b]azepine system was replaced by
benzene, and have analyzed the consequences of such
structural modification, as well as the role of the sub-
stituents attached at C–2 position for their anti-chagasic and
anti-leishmanicidal activities (Gómez–Ayala et al. 2010;
Blanco et al. 2014).
In order to determine the anti-parasitic activity of new
compounds, containing the structural scaffolds I and II, we
describe the syntheses of 22 new 2-exo-aryl(heteroaryl)-1,4-
epoxytetrahydronaphtho[1,2-b]azepines 8–10 and 18 new
cis-2-aryl(heteroaryl)-4-hydroxy-tetrahydronaphtho[1,2-b]
azepines 11–13. We have also carried out the corresponding
bio-assays to check their ability to inhibit the in vitro
growth of the extracellular forms of T. cruzi and L. infantum

Medicinal Chemistry Research
parasites along with an in vitro cytotoxicity evaluation on
Vero and THP-1 mammalian cells. The choice of sub-
stituents presented in compounds 8–10 and 11–13 at C-2
position was considered in the previously described
structure-activity relationships on compounds of the series
III and IV (Gómez–Ayala et al. 2010; Blanco et al. 2014).
On the other hand, taking the advantage to obtain a rela-
tively extended library, formed by more than 90 com-
pounds, we have developed a quantitative structure activity
relationship (QSAR) analysis by means of the Multivariate
lineal regression (MLR) technique, with the aim to elucidate
the structural features, which influence in the bioactivity of
these compounds to attempt predictive models able to
orientate the synthesis of new derivatives with even greater
anti-parasitic activity.
The chemical structures of all the synthesized compounds
were then fully characterized on the basis of their physi-
cochemical and spectral data (see Experimental section),
and the relative configurations of tertiary methynic C–2 and
C–4 carbons and the conformation of the tetrahydroazepine
ring in compounds 8–12 were unambiguously determined
on the basis of single-crystal X-ray analysis, which con-
firmed what we had deduced by means of 1H NMR
experiments (Palma et al. 2009a, 2009b; Yépes et al. 2013a,
2013b).
Anti-parasitic activity and cytotoxicity for the newly
synthetized compounds
Anti-parasitic activity in vitro assays with T. cruzi epimas-
tigotes and L. infantum promastigotes, as well as cytotoxi-
city with Vero epithelial cells (the host cells of T. cruzi) and
THP-1 transformed human macrophages (the host cells of L.
infantum) were conducted, as previously reported (Gómez-
Ayala et al. 2010; Blanco et al. 2014). Nifurtimox and
amphotericin B were used as control under the same assay
conditions. Considering the low antiparasitic activity that
revealed compounds of the type IV bearing a substituted
furan ring at C-2 position (Blanco et al. 2014), in this work
compounds 13 were not evaluated. The obtained results are
listed in Tables 1 and 2. From the results observed in both
tables, it is clear that some of these new compounds dis-
played a significant anti-parasitic activity. Unfortunately, we
do not know the mechanism of action (at molecular level)
for compounds reported here. Therefore, indirect approaches
are the only option we have in order to better understand the
structural requirements to produce the biological response;
thus, in the next sections we present the results obtained by
using both techniques SAR and QSAR analysis.
Results and discussion
Chemistry
The diastereoselective synthesis of the target compounds 8–
10 and 11–13 was achieved employing the synthetic routes,
previously described by our group (Palma et al. 2009a,
2009b; Gómez-Ayala et al. 2010; Blanco et al. 2014) and
are illustrated in Scheme 1. Synthetically available 2-allyl-
α-naphthylamines (Palma et al. 2009a, 2009b) 1a,b were
condensed with substituted benzaldehydes 2a–i, 2-
thiophenecarboxaldehydes
3a–d
and
2-
furancarboxaldehydes 4a–c in refluxing methanol to
afford the corresponding imine intermediates, which were
further reduced with sodium borohydride to give key
intermediates 5a–j, 6a–g, and 7a–c. These key inter-
mediates were oxidized with an excess of hydrogen per-
oxide (30% H2O2) in the presence of sodium tungstate
(Na2WO4·2H2O) to afford the corresponding nitrones,
which then undergo an internal 1,3-dipolar cycloaddition to
generate the targeted 2-exo-aryl(heteroaryl)-1,4-epox-
ycycloadducts 8a–j, 9a–g, and 10a–e. Finally, reductive
cleavage of the N–O bond of 8, 9, and 10 by treatment with
an excess of zinc in a mixture of glacial acetic acid and
concentrated hydrochloric acid at temperature ranging from
0–25 oC afforded the target cis-2-aryl(heteroaryl)-4-hydro-
xytetrahydronaphtho[1,2-b]azepines 11a–h, 12a–f, and
13a–d. As it was previously observed with other structural
analogs (Blanco et al. 2014), the reductive cleavage of
bromo-substituted cycloadduct 9g also afforded the debro-
minated tetrahydronaphtho[1,2-b]azepin-4-ol 12a instead of
the expected 5-bromo-substituted tetrahydronaphtho[1,2-b]
azepin-4-ol. Additionally, all attempts to furnish the
reductive cleavage of nitro-substituted 1,4-epoxy-cycload-
ducts 8i, 8j, and 10e resulted in the formation of a very
complex mixture of non-identifiable degradation products.
Qualitative structure-activity relationship analysis (SAR)
As observed from Table 1, the anti-parasitic activity and
cytotoxicity of the tested 1,4-epoxycycloadducts depend on
the presence or absence of bromine atom at C–6 position
and upon the nature and the substitution pattern of the
aromatic rings at C–2 position. These results indicated that
most of the 6-bromo substituted derivatives of the series 8
did not display any activity against epimastigotes of T. cruzi
and promastigotes of L. infantum; only compounds 8c and
8d showed moderate and good anti-epimastigote activity
with IC50 values of 29.7 µM and 11.9 µM, respectively.
Non-brominated compounds 8i and 8j, bearing meta- and
para-nitrophenyl groups at C–2, also displayed good anti-
parasitic activity. The nitro derivative 8i was inactive
against promastigotes (IC50 = 98.6 µM), but it is active
against epimastigotes (IC50 = 17.5 µM). While, the com-
pounds 8j has the best activity of the series 8 against the

Medicinal Chemistry Research
Scheme 1 Synthesis of the target compounds 8–13
epimastigotes (IC50 = 8.6 µM) and promastigotes (IC50
5.0 µM).
=
against epimastigotes (IC50 = 8.3 µM) and 9e the most
active against promastigotes (IC50 = 10.9 µM).
From the series 9, bearing a substituted thiophene ring at
C–2 position, derivatives 9a, 9b, 9e, and 9g showed low to
high anti-parasitic activity with IC50 values ranging from
54.1 to 8.3 µM against epimastigotes, and 29.3 to 10.9 µM
against promastigotes. The compound 9g is the most active
Out of four compounds of the series 10, bearing a sub-
stituted furan ring at C–2 position, only derivatives 10d and
10e displayed a good anti-parasitic activity with IC50 values
of 9.6 and 8.6 µM against epimastigotes, and 15.4 µM and
13.9 µM against promastigotes, respectively.

Medicinal Chemistry Research
Table 1 In vitro activity of
tested compounds 8–10 (2-exo-
aryl(heteroaryl)-1,4-
epoxytetrahydronaphtho[1,2-b]
azepines) against extracellular
forms of T. cruzi and L.
infantum parasites and
Comp.
X
R
R1
R2
R3 T. cruzi
epimastigotes IC50 CC50 (µM) promastigotes IC50 cells CC50
Vero cells L. infantum
THP-1
(µM)
(µM)
(µM)
8a
–
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
>821.8
1543.7
1431.5
>1574.6
>1518.8
140.6
344.9
121.6
260.30
>903.3
>903.3
>808.6
>779.2
1295.0
497.5
>1953.8
>808.6
>845.0
50.9
485.1
>787.2
117.4
40.1
1293.8
100.0
29.7
8b
–
H
CH3 107.7
8c
–
CH3
OCH3
H
H
29.7
mammalian cells expressed as
IC50 and CC50
8d
–
H
11.9
>1518.8
591.3
1101.2
1212.3
1083.15
>903.3
>903.3
>808.6
>779.2
338.8
>976.9
314.5
>808.6
845.0
1082.6
22.5
8e
–
Cl
H
591.3
>751.9
>692.9
>751.9
116.4
692.9
604.45
98.6
8f
–
Br Cl
Br Cl
H
8g
–
H
Cl
8h
–
H
H
H
Br
Br
H
H
H
H
Br
H
H
H
H
H
CH3 >996.18
8i
–
H
NO2
H
H
H
–
–
–
–
–
–
–
–
–
–
17.5
8.6
8j
–
NO2
H
5.0
9a
S
S
S
S
S
S
O
O
O
O
H
27.8
54.1
338.8
11.3
314.5
8.3
20.1
9b
H
CH3
H
29.3
9d
H
777.5
10.9
9e
H
CH3
H
9f
CH3
H
590.4
21.6
9g
Br
10a
10c
10d
10e
Nif.
Amph. B
H
H
54.5
60.0
9.6
142.7
60.3
H
H
H
CH3
NO2
94.5
15.4
H
8.6
85.4
13.9
931.4
–
4.0
67.5
–
–
–
0.01
29.7
With respect to the tested 2-aryl(thiophen-2-yl)-sub-
stituted 4-hydroxytetrahydronaphtho[1,2-b]azepines 11 and
12 (Table 2), only compounds 11a and 12f were inactive
against promastigotes. The rest of the analogs of these two
series showed low to remarkable activity against epimasti-
gotes (IC50 values ranging from 42.2 to 2.47 µM), and
promastigotes (IC50 values ranging from 48.2 to 7.7 µM).
Among the active compounds, derivatives 11b (IC50 = 7.1
µM), 11f (IC50 = 6.3 µM), 11g (IC50 = 3.3 µM) and 11h
(IC50 = 2.47 µM) exhibited the highest anti-epimastigote
activity, whereas derivatives 11b (IC50 = 7.7 µM), 11d
(IC50 = 9.6 µM), and 11e (IC50 = 8.9 µM) were the most
active against promastigotes.
Cytotoxic assays showed that most of the tested com-
pounds of the series 8–10 have CC50 values higher than
100 µM, demonstrating that all of the active compounds
were far less cytotoxic (excepting 8c and 10d, which dis-
played a limited cytotoxicity on HTP-1 cells) than the
reference drugs, nifurtimox and amphotericin B. In majority
of the cases the tested compounds of the series 11 and 12
were more cytotoxic for Vero and HTP-1 cells than their
precursors 8–10.
epimastigote activity than substitutions with methyl and
nitro groups, as was observed in compounds 8d, 8c, and 8i,
respectively. However, the para substitution of benzene
ring with a nitro group (8j) resulted in the most active
compound of the series 8 for both the epimastigote and
promastigote forms of the parasites. The IC50 values 8i and
8j indicated that the para position is more favorable than
the meta position for providing anti-parasitic activity on
nitro-derivatives. Other substitution patterns led to total loss
of anti-parasitic activity, as was observed in compounds 8a,
8b, 8e, 8f, 8g, and 8h.
The introduction of methyl (9e) and bromo (9g) sub-
stituents on the position 5 of thiophene ring in compounds
of the series 9, resulted in increased anti-epimastigote and
anti-promastigote activities. In addition, there is an emer-
ging pattern of decreasing anti-parasitic activity when the
methyl group is changed from position 5 to 3 on the thio-
phene ring (9f), or when the bromine atom is incorporated at
C–7 position of the base nucleus (9b).
Within the series 10, the substitution of furan ring on
position 5 with methyl (10d) and nitro (10e) groups also
rendered compounds with improved anti-epimastigote and
anti-promastigote activities as compared to the non-
substituted analogs 10a and 10c.
The structure-activity relationships (SARs) analysis
showed that meta substitution of benzene ring with a
methoxyl group render a compound with better anti-

Medicinal Chemistry Research
Table 2 In vitro activity of
tested compounds 11–12 (cis-2-
aryl(heteroaryl)-4-hydroxy-
tetrahydronaphtho[1,2-b]
azepines) against extracellular
forms of T. cruzi and L.
infantum parasites and
Comp.
X
R
R1
R2
R3
H
T. cruzi
Vero
L. infantum
THP-1
epimastigotesa IC50 cellsc
promastigotese IC50 cellsf
(µM)b
CC50
(µM)
CC50
(µM)
(µM)d
11a
–
–
–
–
–
–
–
–
S
S
S
Br
Br
Br
Br
Br
H
H
H
H
H
H
12.2
25.3
113.2
46.9
54.4
16.0
10.0
40.1
36.05
74.0
65.9
>970.5
67.5
–
617.1
7.7
24.0
7.1
11b
11c
H
CH3 7.1
mammalian cells expressed as
IC50 and CC50
CH3
OCH3
H
H
20.0
12.6
9.6
20.0
178.5
11.1
45.1
59.8
41.60
67.2
192.3
ND
11d
11e
H
11.7
11.1
6.3
Cl
H
8.9
11f
Br Cl
Br Cl
H
48.2
11.8
36.19
42.5
16.6
58.5
–
11g
H
Cl
3.3
11h
12d
12e
H
H
H
H
H
H
CH3 2.47
H
H
–
–
–
42.2
17.0
10.0
4.0
H
CH3
H
12f
CH3
Nif.g
Amph. Bg
–
–
0.01
29.7
N.D. not determined
aTrypanosoma cruzi strain 320I04 were treated for 72 h at 27 °C with tested compounds
bInhibitory concentration IC50 was the concentration required for 50% growth inhibition
cAfrican green monkey kidney cell line (Vero, ATCC) were treated for 72 h at 37 °C with tested compounds
dCytotoxic concentration CC50 was the concentration required for 50% mammalian cell killing
eLeishmania infantum strain MHOM/BR/74/PP75 were treated for 72 h at 27 °C with tested compounds
fTransformed human acute monocytic leukemia cell line (THP-1, ATCC) were treated for 72 h at 37 °C with
tested compounds
gReference drugs (nifurtimox and amphotericin B)
In the compounds of the series 11, the most potent
compounds against epimastigotes (even more active than
nifurtimox) were the 7-bromo-substituted derivatives 11f
and 11g, bearing 4-chloro- and 2,4-dichlorophenyl moieties
at C–2, respectively. Whereas the derivatives 11b, 11d, and
11e, bearing 2-methyl-, 3-methoxy- and 2-chlorophenyl
moieties at C–2, respectively, emerged as the most active
compounds against L. infantum promastigotes. Finally, the
non-bromo-substituted derivative 11h in which the benzene
ring at C–2 is 2-methylphenyl is the most active compounds
against T. cruzi epimastigotes.
against promastigotes, respectively. Although being inac-
tive against promastigotes (IC50 = 617.1 µM), compound
11a was active against epimastigotes (IC50 = 12.2 µM).
Finally, the IC50 values of compounds of the series 12 show
that the anti-parasitic activity did not improve by the
replacement of the substituted benzene ring by a substituted
thiophene ring. In this series of compounds, the presence of
a 5-methyl-2-thiophenyl moiety (12e) is more favorable
than the presence of a 3-methyl-2-thiophenyl moiety (12f)
for enhancing the anti-epimastigote and anti-promastigote
activities.
Unfortunately, the above molecules have significant
cytotoxicity on both the Vero and THP-1 cells. As shown
by the comparison of the activities of derivatives 11h and
11b, the incorporation of a bromine atom at C–7 position
slightly reduced the anti-epimastigote activity (from 2.47 to
7.1 µM), but substantially enhanced the anti-promastigote
activity (from 36.19 to 7.1 µM); similar effect on the
activities was observed when the chlorine atom is changed
from position 4 (11f) to position 2 (11e) on the phenyl
moiety. Moreover, the 7-bromo-substituted derivatives 11d
and 11e, bearing 3-methoxy- and 2-chlorophenyl moieties
at C–2, demonstrated a strong affinity for the extracellular
parasite forms with IC50 values of 11.7 and 11.1 µM against
epimastigotes, and IC50 values of 9.6 µM and 8.9 µM
Quantitative structure-activity relationship analysis (QSAR)
At this step of our study, we were interested in obtaining a
model that allowed us to predict the potential anti-parasitic
activity of these compounds. Thus, a QSAR analysis was
carried out by searching the optimal linear regression
equations by means of the Replacement Method (RM)
approach (Duchowicz et al. 2006; Mercader et al. 2010),
which minimizes their standard deviation (S). A total of 94
compounds, tables 5S-10S, previously described (Palma
et al. 2009a, 2009b; Gómez-Ayala et al. 2010; Blanco et al.
2014), were included in the dataset. In these tables the

Medicinal Chemistry Research
A)
compounds are identified as I, II, III, and IV, which cor-
responds to each type of compound in Fig. 1.
0.5
0
We analyzed the regression that includes the most
“representative” d = 1–10 molecular descriptors. To define
the maximum number of molecular descriptors in the lineal
regression we consider the “rule of thumb”, which states
that at least six data points should be present per fitting
parameter, i.e., (Ntrain/d ≥ 6), where Ntrain is the number of
compounds of training set and d is the number of molecular
descriptors.
-0.5
-1
-1.5
-2
Training set
Validaꢀon set
-2.5
QSAR for the growth inhibition of Trypanosoma cruzi
epimastigotes Table 1S of the supplementary material
summarized the main statistical parameters of the QSAR
model for the inhibition of Trypanosoma cruzi epimasti-
gotes. We considered that a model with five molecular
descriptors shows an acceptable quality in accordance with
the number of independent variables. The equation of
selected QSAR model is:
-2.5
-2
-1.5
-1
-0.5
0
0.5
Experimental -log(IC50)
B)
1.5
1
Training set
Validaꢀon set
2.5 S
IIId
0.5
0
ÀlogðIC50Þ ¼ À27:533 þ 0:09ðATSC1iÞ À 0:185ðnBondsMÞ
þ6:458ðSpMax3 BhvÞ þ 0:098ðRDF45vÞ þ 2:773ðDiÞ
-0.5
-1
N ¼ 71 d ¼ 5
N
train=d ¼ 14:2
IId
Ii
IVaa
Rtrain ¼ 0:828 R2train ¼ 0:686 Strain ¼ 0:291 RMS ¼ 0:278
-1.5
0
10
20
30
40
50
60
70
80
90 100
Rval ¼ 0:499 Sval ¼ 0:495 Rloo ¼ 0:785 Sloo ¼ 0:323
Rlmo ¼ 0:694 Slmo ¼ 0:376 Srand ¼ 0:434
Compounds
Fig. 2 Trypanosoma cruzi Epimastigote QSAR model. a Predicted
versus Experimental values of −log(IC50). b Residual of predicted
values
The results of the validation reveal that model have an
acceptable predictive capacity, according to the known
criterions (Rval ≥ 0.500 and Srand > Strain). Figure 2a shows
the linear trend of the relationship of the predicted and
experimental values. The residuals values are plotted in the
Fig. 2b. From this figure it can be appreciated that
compounds IId and IIId present a residual value close to
the 2.5 S limit (dotted line). However, these compounds
were not considered outliers. Within the validation set, only
compounds Ii and IVaa exhibit a residual value higher than
the limit of deviation standard.
The molecular descriptors involved in the QSAR model are
listed in Table 2S. The table presents the maximum
correlation, the standardized regression coefficients of the
molecular descriptors and a brief description of them. The
maximum correlation between the descriptors of the model is
0.825, given by nBondsM and SpMax3_Bhv. The standar-
dized coefficient specifies the importance of the descriptor on
the biological activity, and the sign indicates whether the
relationship is direct or indirect. The standardized regression
coefficients values plot is presented in the Fig. 3.
direct relationship of this descriptor with the –log(IC50).
This descriptor is defined as the average centered Broto-
Moreau autocorrelation–lag 1/weighted by first ionization
potential, and to have strong empirical relationship to
electron distribution of the molecule as a whole (Todeschini
and Consonni 2009). The standardized regression coeffi-
cients magnitudes for the rest of the molecular descriptors
(0.516, −0.428, 0.375, 0.313) suggest that they comple-
ment each other in QSAR equation and the negative values
in nBondsM indicate its indirect relationship with the –log
(IC50).
QSAR for the growth inhibition of Leishmania infantum
promastigotes The statistical parameters of QSAR models
(from 1 to 10 descriptors) for the inhibition of Leishmania
infantum promastigotes are listed in the Table 3S. In this
case, the model containing six molecular descriptors was
considered appropriate, with an acceptable quality for the
training and validation sets. The mathematical equation of
The most important descriptor for the activity is
SpMax3_Bhv (0.910), whole positive value expresses a

Medicinal Chemistry Research
A) -0.5
Di
RDF45v
-1
-1.5
-2
SpMax3_Bhv
nBondsM
ATSC1i
Training set
Validaꢀon set
-2.5
-0.5
0
0.5
1
-2.5
-2
-1.5
-1
-0.5
Standardized coefficients
Experimental -log(IC50)
Fig. 3 Standardized regression coefficients values of the molecular
descriptors for Trypanosoma cruzi Epimastigote QSAR model
B)
1.5
Training set
Validaꢀon set
2.5 S
1
0.5
0
selected QSAR model is:
ÀlogðIC50Þ ¼ 3:224 À 2:35 Â 10À4ðVR1 DziÞ
À0:633ðSpMax5 BhmÞ À 1:170ðSpMax6 BhvÞ
À0:044ðRDF35uÞ þ 0:041ðRDF60sÞ þ 0:014ðVmÞ
-0.5
-1
N ¼ 67 d ¼ 6
N
train=d ¼ 11:1
Rtrain ¼ 0:757 R2train ¼ 0:572 Strain ¼ 0:218 RMS ¼ 0:206
-1.5
0
10
20
30
40
50
60
70
80
90 100
Rval ¼ 0:589 Sval ¼ 0:301 Rloo ¼ 0:650 Sloo ¼ 0:279
Rlmo ¼ 0:554 Slmo ¼ 0:392 Srand ¼ 0:278
Compounds
Fig. 4 Leishmania infantum Promastigote QSAR model. a Predicted
versus Experimental values of −log(IC50). b Residual of predicted
values
The statistical parameters indicate that model has a
suitable predictive power for both, the training set (Rtrain
=
0.757, Strain = 0.218) and the validation set (Rval = 0.589,
Sval = 0.301). Figure 3 shows the predicted and experi-
mental –log(IC50) values plot and the residual values
graphic. Figure 4a suggests the existence of a linear trend
between the predicted and experimental values, while Fig.
4b indicates that there are no compounds outside the 2.5 S
limit (dotted line).
Table 4S presents the maximum correlation, the standar-
dized regression coefficients of the molecular descriptors
and a brief description of molecular descriptors involved in
the QSAR model. The maximum correlation value (0.684)
indicates that there is a low relationship between the
descriptors of model and the information is not overlapping.
Figure 5 shows the standardized regression coefficients
values plot.
Vm
RDF60s
RDF35u
SpMax6_Bhv
SpMax5_Bhm
VR1_Dzi
-1
-0.5
0
0.5
1
Standardized coefficients
Fig. 5 Standardized regression coefficients values of the molecular
descriptors for Trypanosoma cruzi Epimastigote QSAR model
The two most important descriptors for the activity
present positive values of the standardized regression
coefficients and a direct relationship with the –log(IC50);
Vm (0.816) and RDF60s (0.679). The Vm descriptor is one
of the most used in the QSAR model and it is relate to the
molecular volume.58 While RDF60s is a radial distribution
function at 6.0 Å inter-atomic distances weighted by relative
I-state.57 The rest of the molecular descriptors have negative
standardized regression coefficients values (−0.299,

Medicinal Chemistry Research
Table 3 Experimental anti-parasitic activity and QSAR prediction
percentage is achieve only for the compound 8j. It is clear
that Trypanosoma cruzi model has problem to predict cor-
rectly the activity of compounds of the series 11. This may
be due to they have a molecular structure different to the
ones investigated in the training set.
Trypanosoma cruzi
Leishmania infantum
epimastigotes −log(IC50)
promastigotes −log(IC50)
Experimental
Predicted
Experimental
Predicted
8a
−2.915
−2.032
−1.473
−1.076
−2.772
−2.876
−2.841
−2.998
−1.243
−0.934
−1.444
−1.733
−2.530
−1.053
−2.497
−0.919
−1.736
−1.778
−0.934
−0.982
−1.086
−0.851
−1.301
−1.068
−1.045
−0.799
−0.519
−0.393
−1.625
−1.230
−1.000
−2.454
−1.272
−2.722
−1.443
−2.298
−2.290
−2.204
−2.599
−0.735
−0.875
−0.766
−0.730
−0.889
−0.862
−0.679
−0.883
−0.841
−0.995
−0.403
−1.024
−0.313
−0.475
−2.461
−1.100
−0.211
−0.219
−0.118
−0.510
−0.507
−0.853
−0.378
−2.686
−2.896
−2.070
−1.603
−2.876
−2.066
−2.841
−2.781
−1.994
−0.699
−1.303
−1.467
−2.891
−1.037
−2.771
−1.334
−2.154
−1.780
−1.143
−1.188
−2.790
−0.886
−1.100
−0.982
−0.949
−1.683
−1.072
−1.559
−1.628
−1.220
−1.767
−1.708
−1.395
−1.580
−1.149
−1.816
−1.609
−1.520
−1.610
−1.257
−1.426
−1.498
−1.509
−1.491
−1.451
−1.633
−1.261
−1.665
−1.681
−1.260
−1.810
−1.266
−1.212
−1.128
−0.932
−1.241
−0.785
−0.859
−1.601
−1.898
−1.813
−1.870
8b
8c
Conclusions
8d
8e
We report here a new library of twenty two 2-exo-aryl
(heteroaryl)-1,4-epoxytetrahydronaphtho[1,2-b]azepines
8f
8g
and
eighteen
cis-2-aryl(heteroaryl)-4-hydro-
xytetrahydronaphtho[1,2-b]azepines. Seventeen compounds
exhibited potent activity against the T. cruzi epimastigotes
(IC50 lower than 20 µM), without cytotoxicity or with just
limited effect on Vero cells. In addition, ten compounds
also showed remarkable anti-leishmanial properties against
the L. infantum promastigotes (IC50 lower than 20 µM),
however in some of them were found cytotoxic effects for
HTP-1 cells.
Both SAR and QSAR analyses were carried out for the
compounds reported here. Thus, we performed a quantita-
tive structure activity relationship analysis by means of the
multivariate lineal regression (MLR) technique for a family
of ninety four tetrahydro-1-benzazepine and tetra-
hydronaphtho[1,2-b]azepine derivatives. The QSAR pre-
diction models obtained for the extracellular forms of
Trypanosoma cruzi and Leishmania infantum parasites were
acceptable with a correlation coefficient values (R) of 0.668
and 0.852, respectively. From our results, it is clear that the
QSAR study reported here might predict the potential anti-
parasitic effect of non-synthesized compounds with an
acceptable degree of accuracy. Such information could be
useful in order to know a priori the putative activity of new
anti-parasitic compounds structurally related to these series.
8h
8i
8j
9a
9b
9d
9e
9f
9g
10a
10c
10e
10d
11a
11b
11c
11d
11e
11f
11g
11h
12d
12e
12f
Materials and methods
−0.301, −0.315, −0.532), indicating an indirect relation-
ship of these descriptors with the –log(IC50).
General
All the reagents and solvents were purchased from com-
mercial suppliers (Aldrich, Merck), and used without fur-
ther purification. Monitoring of the reactions was performed
using silica gel TLC plates (silica Merck 60 F254). Column
chromatography purification was performed on Merck
Kieselgel 230–400 mesh (ASTM). Melting points were
determined with a MEL–TEMP 1201D capillary apparatus
and are uncorrected. IR spectra were recorded on a Bruker
Tensor 27 spectrometer (equipped with a platinum ATR
Anti-parasitic activity prediction for the newly synthetized
compounds We apply the established QSAR models to
predict the anti-parasitic activity of the newly synthesized
compounds. These results are presented in Table 3. The
Trypanosoma cruzi model presents a correlation coefficient
(R) of 0.668, a standard deviation of 0.852 and the residue
average is −0.430. Both models show acceptable values for
QSAR prediction. However, same compounds accuse a
poor prediction. The compounds 8c, 9f, 11a, 11c, 11e, and
11f show an error in the prediction higher than 60% for
Trypanosoma cruzi. While for Leishmania infantum this
1
cell). H and 13C NMR spectra were measured on a Bruker
AM–400 spectrometer, using CDCl3 as the solvent. Che-
mical shifts (δ) and coupling constants (J) values are

Medicinal Chemistry Research
reported in ppm and hertz, respectively. Chemical shifts are
relative to the solvent peaks used as reference [CDCl3: δH =
7.26, and δC = 77.0]. A Hewlett–Packard (HP) 5890 A
series II Gas Chromatograph interfaced to a HP 5972 Mass
Selective Detector with a HP MS ChemStation Data system,
and a High Resolution Mass Spectrometer Waters Micro-
mass AutoSpect NT (equipped with a direct inlet probe)
operating at 70 eV were used for MS identification. All the
compounds described here were synthetized according to
the experimental conditions reported in previous related
works (Gómez-Ayala et al. 2010; Blanco et al. 2014).
19.4 (2’–CH3). GC–MS (EI, 70 eV): m/z (%) 365 (M+•,
79Br, 18), 274 (2), 260 (10), 246 (4), 180 (70), 105 (100).
2–Allyl–4–bromo–N–(3–methylbenzyl)–1–naphthylamine
(5c)
Colorless viscous oil. Yield: 88%. IR (liquid film, cm−1): ṽ
1
3361 (N–H), 1637 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.27 (dd, J = 7.1, 2.1 Hz, 1H, H–8),
8.24 (dd, J = 8.0, 1.6 Hz, 1H, H–5), 7.62 (s, 1H, H–3),
7.54–7.60 (m, 2H, H–6, H–7), 7.28 (t, J = 7.5 Hz, 1H, H–
5’), 7.24 (s, 1H, H–2’), 7.18–7.22 (m, 1H, H–4’), 7.14–7.18
(m, 1H, H–6’), 5.94 (ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH),
5.14 (dq, J = 10.1, 1.6 Hz, 1H, =CH2(H–cis)), 5.03 (dq, J =
17.1, 1.6 Hz, 1H, =CH2(H–trans)), 4.28 (s, 2H, N–CH2), 3.40
Physicochemical and spectral data for 2–allyl–N–
aryl(heteroaryl)methylnaphthylamines (5a–j), (6a–
g), and (7a–e)
(dt, J = 6.0, 1.6 Hz, 2H, –CH2–), 2.40 (s, 3H, 3´–CH3). 13
C
2–Allyl–N–benzyl–4–bromo–1–naphthylamine (5a)
NMR (100 MHz, CDCl3): δ 142.5 (C1), 139.6 (C1’), 138.4
(C3’), 136.0 (=CH), 132.2 (C3), 132.1 (C4a), 130.4 (C8a),
129.0 (C2), 128.7 (C5’), 128.4 (C2’), 127.8 (C4’), 126.8
(C6), 126.4 (C7), 125.1 (C6’), 124.0 (C5, C8), 117.6 (C4),
116.7 (=CH2), 55.2 (N–CH2), 36.1 (–CH2–), 21.5 (3’–
CH3). GC–MS (EI, 70 eV): m/z (%) 365 (M+•, 79Br, 7), 274
(2), 260 (5), 246 (2), 180 (100), 105 (92).
Colorless viscous oil. Yield: 93%. IR (liquid film, cm−1): ṽ
1
3361 (N–H), 1636 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.28 (dd, J = 7.5, 2.2 Hz, 1H, H–8),
8.26 (dd, J = 7.5, 2.3 Hz, 1H, H–5), 7.54–7.62 (m, 2H, H–
6, H–7), 7.62 (s, 1H, H–3), 7.32–7.42 (m, 5H, H–2’, H–3’,
H–4’, H–5’, H–6’), 5.94 (ddt, J = 17.1, 10.1, 6.0 Hz, 1 H,
=CH), 5.14 (dq, J = 10.1, 1.5 Hz, 1H, =CH2(H–cis)), 5.03
(dq, J = 17.1, 1.5 Hz, 1H, =CH2(H–trans)), 4.35 (s, 2H, N–
CH2), 3.34 (dt, J = 6.0, 1.5 Hz, 2H, –CH2–). 13C NMR
(100 MHz, CDCl3): δ 142.6 (C1), 139.8 (C1’), 136.0
(=CH), 132.2 (C3), 132.1 (C4a), 130.4 (C8a), 128.9 (C2),
128.0 (C3’, C5’), 127.9 (C8), 127.7 (C4’), 127.6 (C2’, C6’),
126.7 (C6), 126.4 (C7), 123.9 (C5), 117.0 (C4), 116.7
(=CH2), 55.1 (N–CH2), 36.1 (–CH2–). GC–MS (EI, 70 eV):
m/z (%) 351 (M+•, 79Br, 31), 274 (2), 260 (10), 246 (1), 180
(100), 91 (55).
2–Allyl–4–bromo–N–(3–methoxybenzyl)–1–naphthylamine
(5d)
Colorless viscous oil. Yield: 90%. IR (liquid film, cm−1): ṽ
1
3361 (N–H), 1635 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.24 (dd, J = 8.0, 1.6 Hz, 1H, H–8),
8.22 (dd, J = 8.0, 1.6 Hz, 1H, H–5), 7.60 (s, 1H, H–3), 7.58
(td, J = 8.0, 1.6 Hz, 1H, H–7), 7.55 (td, J = 8.0, 1.6 Hz, 1H,
H–6), 7.29 (t, J = 7.8 Hz, 1H, H–5’), 6.96 (d, J = 7.8 Hz,
1H, H–6’), 6.94 (d, J = 2.2 Hz, 1H, H–2’), 6.87 (dd, J =
7.8, 2.2 Hz, 1H, H–4’), 5.93 (ddt, J = 17.2, 10.1, 6.0 Hz,
1H, =CH), 5.13 (dq, J = 10.1, 1.7 Hz, 1H, =CH2(H–cis)),
5.02 (dq, J = 17.2, 1.7 Hz, 1H, =CH2(H–trans)), 4.29 (s, 2H,
N–CH2), 3.38 (dt, J = 6.0, 1.7 Hz, 2H, –CH2–), 3.30 (s, 3H,
3’–OCH3). 13C NMR (100 MHz, CDCl3): δ 160.1 (C3’),
142.3 (C1), 141.3 (C1’), 136.1 (=CH), 132.3 (C3), 132.1
(C4a), 130.4 (C8a), 129.8 (C5’), 129.2 (C2), 127.8 (C8),
126.8 (C6), 126.5 (C7), 123.9 (C5), 120.3 (C2’), 120.2
(C4’), 117.1 (C4), 116.8 (=CH2), 113.3 (C6’), 55.3
(OCH3), 55.0 (N–CH2), 36.1 (–CH2–).GC–MS (EI, 70 eV):
m/z (%) 381 (M+•, 79Br, 20), 274 (2), 260 (14), 246 (1), 180
(100), 121 (74).
2–Allyl–4–bromo–N–(2–methylbenzyl)–1–naphthylamine
(5b)
Colorless viscous oil. Yield: 92%. IR (liquid film, cm−1): ṽ
1
3363 (N–H), 1637 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.29 (dd, J = 8.0, 1.7 Hz, 1H, H–8),
8.27 (dd, J = 8.0, 1.8 Hz, 1H, H–5), 8.00 (td, J = 8.0, 1.7
Hz, 1H, H–6), 7.65 (s, 1H, H–3), 7.61 (td, J = 8.0, 1.8 Hz,
1H, H–7), 7.50–7.54 (m, 1H, H–6’), 7.21–7.34 (m, 3H, H–
3’, H–4’, H–5’), 5.97 (ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =
CH), 5.17 (dq, J = 10.1, 1.6 Hz, 1H, =CH2(H–cis)), 5.05 (dq,
J = 17.1, 1.6 Hz, 1H, =CH2(H–trans)), 4.35 (s, 2H, N–CH2),
3.42 (dt, J = 6.0, 1.6 Hz, 2H, –CH2–), 2.35 (s, 3H, 2’–CH3).
13C NMR (100 MHz, CDCl3): δ 142.9 (C1), 137.9 (C1’),
136.0 (=CH), 132.2 (C3, C4a), 132.1 (C2’), 130.6 (C3’),
130.5 (C8a), 130.4 (C5’), 128.9 (C2), 128.4 (C6’), 127.7
(C8), 127.6 (C4’), 126.8 (C6), 126.4 (C7), 124.0 (C5),
117.0 (C4), 116.7 (=CH2), 52.5 (N–CH2), 35.7 (–CH2–),
2–Allyl–4–bromo–N–(2–chlorobenzyl)–1–naphthylamine
(5e)
Colorless viscous oil. Yield: 90%. IR (liquid film, cm−1): ṽ
1
3367 (N–H), 1636 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.26 (dd, J = 7.5, 2.6 Hz, 1H, H–8),

Medicinal Chemistry Research
8.24 (dd, J = 7.5, 2.6 Hz, 1H, H–5), 7.55–7.62 (m, 2H, H–
6, H–7), 7.59 (s, 1H, H–3), 7.45 (dd, J = 7.0, 1.2 Hz, 1H,
H–3’), 7.30 (td, J = 7.0, 1.2 Hz, 1H, H–5’), 7.27 (td, J =
7.0, 1.8 Hz, 1H, H–6’), 7.23 (td, J = 7.0, 1.8 Hz, 1H, H–4’),
5.92 (ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH), 5.13 (dq, J =
10.1, 1.6 Hz, 1H, =CH2(H–cis)), 5.06 (dq, J = 17.1, 1.6 Hz,
1H, =CH2(H–trans)), 4.43 (s, 2H, N–CH2), 3.37 (dt, J = 6.0,
1.6 Hz, 2H, –CH2–). 13C NMR (100 MHz, CDCl3): δ 142.2
(C1), 137.4 (C1’), 136.0 (=CH), 133.7 (C2’), 132.1 (C3,
C4a), 130.2 (C8a, C6’), 129.7 (C3’), 129.0 (C2, C5’), 127.8
(C8), 127.1 (C4’), 126.8 (C6), 126.5 (C7), 123.9 (C5),
117.2 (C4), 116.7 (=CH2), 52.5 (N–CH2), 36.0 (–CH2–).
GC–MS (EI, 70 eV): m/z (%) 385 (M+•, 79Br, 35Cl, 15), 274
(3), 260 (10), 246 (2), 180 (100), 125 (20).
(C7), 123.8 (C5), 117.5 (C4), 116.7 (=CH2), 51.5 (N–CH2),
36.2 (–CH2–). GC–MS (EI, 70 eV): m/z (%) 421 (M+•, 79Br,
35Cl, 10), 274 (1), 260 (7), 246 (2), 180 (100), 159 (20).
4.2.8. 2–Allyl–N–(2–methylbenzyl)–1–naphthylamine (5h)
Pale Yellow viscous oil. Yield: 78%. IR (liquid film, cm−1):
1
ṽ 3363 (N–H), 1635 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.25 (dd, J = 9.0, 1.0 Hz, 1H, H–8),
7.87 (dd, J = 7.6, 2.0 Hz, 1H, H–5), 7.59 (d, J = 8.4 Hz,
1H, H–4), 7.58 (dd, J = 7.6, 1.6 Hz, 1H, H–6’), 7.33 (d, J
= 8.4 Hz, 1H, H–3), 7.43–7.49 (m, 2H, H–6, H–7), 7.27–7.
30 (m, 3H, H–3’, H–4’, H–5’), 5.98–6.05 (m, 1H, =CH),
5.01–5.15 (m, 2H, =CH2), 4.36 (s, 2H, N–CH2), 3.59 (dt, J
= 6.4, 1.6 Hz, 2H, –CH2–), 2.36 (s, 3H, 2’–CH3). 13C NMR
(100 MHz, CDCl3): δ 143.0 (C1), 138.4 (C1’), 136.9 (C2’,
=CH), 134.0 (C4a), 130.5 (C5’), 129.3 (C8a), 128.7 (C5),
128.5 (C6’), 128.3 (C3), 127.9 (C2), 127.5 (C4’), 126.4
(C3’), 125.7 (C7), 125.4 (C6), 123.4 (C4, C8), 116.1
(=CH2), 52.7 (N–CH2), 36.5 (–CH2–), 19.2 (2’–CH3). GC–
MS (EI, 70 eV): m/z (%) 318 (M+•, 31), 277 (1), 274 (2),
196 (1), 182 (100), 136 (3).
2–Allyl–4–bromo–N–(4–chlorobenzyl)–1–naphthylamine
(5f)
Colorless viscous oil. Yield: 90%. IR (liquid film, cm−1): ṽ
1
3361 (N–H), 1635 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.22 (dd, J = 8.4, 1.6 Hz, 1H, H–8),
8.20 (dd, J = 7.6, 1.6 Hz, 1H, H–5), 7.59 (s, 1H, H–3), 7.57
(td, J = 7.6, 1.6 Hz, 1H, H–7), 7.55 (td, J = 7.6, 1.6 Hz, 1H,
H–6), 7.33 (d, J = 8.5 Hz, 2H, H–3’, H–5’), 7.28 (d, J =
8.5 Hz, 2H, H–2’, H–6’), 5.91 (ddt, J = 17.1, 10.1, 6.0 Hz,
1H, =CH), 5.12 (dq, J = 10.1, 1.5 Hz, 1H, =CH2(H–cis)),
5.00 (dq, J = 17.1, 1.5 Hz, 1H, =CH2(H–trans)), 4.27 (s, 2H,
N–CH2), 3.35 (dt, J = 6.0, 1.5 Hz, 2H, –CH2–).13C NMR
(100 MHz, CDCl3): δ 141.8 (C1), 138.1 (C1’), 136.0
(=CH), 133.5 (C4’), 132.2 (C3), 132.1 (C4a), 130.2 (C8a),
129.1 (C2), 129.4 (C3’, C5’), 128.9 (C2’, C6’), 127.8 (C8),
126.8 (C6), 126.6 (C7), 123.8 (C5), 117.3 (C4), 116.5
(=CH2), 55.1 (N–CH2), 36.3 (–CH2–). GC–MS (EI, 70 eV):
m/z (%) 385 (M+•, 79Br, 35Cl, 14), 274 (1), 260 (7), 246 (3),
180 (100), 125 (43).
2–Allyl–N–(3–nitrobenzyl)–1–naphthylamine (5i)
Yellow viscous oil. Yield: 78%. IR (liquid film, cm−1): ṽ
3360 (N–H), 1641(C=Callyl), 1528 (–NO2), 1348 (–NO2),
1
919 (=C–Hallyl). H NMR (400 MHz, CDCl3): δ 8.34 (s,
1H, H–2’), 8.18 (dd, J = 8.3, 1.1 Hz, 1H, H–8), 8.13 (dd, J
= 8.2, 0.4 Hz, 1H, H–5), 7.73 (d, J = 8.4 Hz, 1H, H–6’),
7.65 (d, J = 7.0 Hz, 1H, H–4), 7.57 (t, J = 8.4 Hz, 1H, H–
5’), 7.43–7.52 (m, 2H, H–6, H–7), 7.47 (d, J = 7.0 Hz, 1H,
H–3), 7.30 (d, J = 8.4 Hz, 1H, H–4’), 6.00 (ddt, J = 17.1,
10.1, 6.0 Hz, 1H, =CH), 5.12 (dq, J = 10.1, 1.6 Hz, 1H,
=CH2(H–cis)), 5.01 (dq, J = 17.1, 1.6 Hz, 1H, =CH2(H–trans)),
4.41 (s, 2H, N–CH2), 3.47 (dt, J = 6.0, 1.6 Hz, 2H, –CH2–).
13C NMR (100 MHz, CDCl3): δ 148.6 (C1’), 142.0 (C3’),
141.7 (C1), 136.7 (=CH2), 134.0 (C4a), 133.9 (C6’), 129.3
(C8a), 128.6 (C4’), 128.1 (C2, C4), 125.9 (C3, C6), 125.5
(C7), 123.9 (C5’), 123.0 (C5), 122.7 (C8), 122.4 (C2’),
116.3 (=CH2), 53.8 (N–CH2), 36.5 (–CH2–). GC–MS (EI,
70 eV): m/z (%) 318 (M+•, 36), 196 (6), 182 (100), 168 (1),
136 (11).
2–Allyl–4–bromo–N–(2,4–dichlorobenzyl)–1–
naphthylamine (5g)
Yellow viscous oil. Yield: 88%. IR (liquid film, cm−1): ṽ
1
3363 (N–H), 1637 (C=Callyl), 914 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.21 (dd, J = 7.5, 1.5 Hz, 1H, H–8),
8.17 (dd, J = 7.5, 1.5 Hz, 1H, H–5), 7.57 (td, J = 7.5, 1.5
Hz, 1H, H–7), 7.54 (td, J = 7.5, 1.5 Hz, 1H, H–6), 7.53 (s,
1H, H–3), 7.43 (d, J = 2.0 Hz, 1H, H–3’), 7.18 (dd, J = 8.1,
2.0 Hz, 1H, H–5’), 7.25 (d, J = 8.1 Hz, 1H, H–6’), 5.90
(ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH), 5.12 (dq, J = 10.1,
1.6 Hz, 1H, =CH2(H–cis)), 5.03 (dq, J = 17.1, 1.6 Hz, 1H,
=CH2(H–trans)), 4.37 (s, 2H, N–CH2), 3.35 (dt, J = 6.0, 1.6
Hz, 2H, –CH2–). 13C NMR (100 MHz, CDCl3): δ 141.0
(C1), 135.8 (=CH), 135.6 (C1’), 134.4 (C2’), 134.1 (C4’),
132.2 (C3, C6’), 132.0 (C4a), 130.4 (C8a), 129.5 (C3’),
129.4 (C2), 127.8 (C5’), 127.4 (C8), 126.8 (C6), 126.6
2–Allyl–N–(4–nitrobenzyl)–1–naphthylamine (5j)
Yellow viscous oil. Yield: 79%. IR (liquid film, cm−1): ṽ
3354 (N–H), 1522 (–NO2), 1350 (–NO2), 1637 (C=Callyl),
1
917 (=C–Hallyl). H NMR (400 MHz, CDCl3): δ 8.22 (d, J
= 8.4 Hz, 2H, H–3’, H–5’), 8.10 (dd, J = 7.1, 1.9 Hz, 1H,
H–8), 7.84 (dd, J = 7.8, 2.3 Hz, 1H, H–5), 7.58 (d, J = 8.4
Hz, 2H, H–2’, H–6’), 7.57 (d, J = 8.3 Hz, 1H, H–4), 7.42–
7.51 (m, 2H, H–6, H–7), 7.29 (d, J = 8.3 Hz, 1H, H–3),

Medicinal Chemistry Research
5.99 (ddt, J = 17.1, 10.2, 6.0 Hz, 1H, =CH), 5.10 (dq, J =
10.1, 1.6 Hz, 1H, =CH2(H–cis)), 4.99 (dq, J = 17.1, 1.5 Hz,
1H, =CH2(H–trans)), 4.41 (s, 2H, N–CH2), 3.44 (dt, J = 6.0,
1.6 Hz, 2H, –CH2–). 13C NMR (100 MHz, CDCl3): δ 147.8
(C1’), 147.4 (C4’), 141.9 (C1), 136.6 (=CH), 134.0 (C4a),
129.0 (C8a), 128.7 (C4), 128.6 (C3), 128.5 (C5), 128.0
(C2), 125.9 (C6), 125.5 (C7), 124.0 (C3’, C5’), 123.9 (C2’,
C6’), 122.9 (C8), 116.2 (=CH2), 54.2 (N–CH2), 36.8 (–
CH2–). GC–MS (EI, 70 eV): m/z (%) 318 (M+•, 29), 196
(5), 182 (100), 168 (1), 136 (7).
2–Allyl–4–bromo–N–(3–methylthiophen–2–ylmethyl)–1–
naphthylamine (6c)
Colorless viscous oil. Yield: 70%. IR (liquid film, cm−1): ṽ
1
3360 (N–H), 1636 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.24 (dd, J = 7.0, 2.1 Hz, 1H, H–8),
8.20 (dd, J = 7.0, 2.0 Hz, 1H, H–5), 7.58 (s, 1H, H–3), 7.56
(td, J = 7.0, 2.1 Hz, 1H, H–7), 7.55 (td, J = 7.0, 2.1 Hz, 1H,
H–6), 7.16 (d, J = 5.1 Hz, 1H, H–5’), 6.82 (d, J = 5.1 Hz,
1H, H–4’), 5.91 (ddt, J = 17.0, 10.2, 6.0 Hz, 1H, =CH),
5.12 (dq, J = 10.2, 1.5 Hz, 1H, =CH2(H–cis)), 5.02 (dq, J =
17.0, 1.5 Hz, 1H, =CH2(H–trans)), 4.36 (s, 2H, N–CH2), 3.35
(dt, J = 6.0, 1.5 Hz, 2H, –CH2–), 2.01 (s, 3H, 3’–CH3).13C
NMR (100 MHz, CDCl3): δ 142.4 (C1), 136.1 (C2’), 136.0
(=CH), 134.2 (C3’), 132.2 (C3), 132.1 (C4a), 130.5 (C8a),
130.3 (C5’), 129.2 (C2), 127.7 (C5), 126.8 (C7), 126.5
(C6), 123.2 (C8, C4’), 117.3 (C4), 116.9 (=CH2), 47.3 (N–
CH2), 36.1 (–CH2–), 13.6 (3’–CH3). GC–MS (EI, 70 eV):
m/z (%) 371 (M+•, 79Br, 2), 274 (3), 260 (3), 246 (2), 180
(14), 111 (100).
2–Allyl–4–bromo–N–(thiophen–2–ylmethyl)–1–
naphthylamine (6a)
Colorless viscous oil. Yield: 75%. IR (liquid film, cm−1): ṽ
1
3360 (N–H), 1635 (C=Callyl), 916 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.20 (dd, J = 8.7, 1.2 Hz, 1H, H–8),
7.57 (dd, J = 8.4, 1.5 Hz, 1H, H–5), 7.53 (ddd, J = 8.7, 7.2,
1.5 Hz, 1H, H–7), 7.51 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H, H–6),
7.23 (s, 1H, H–3), 7.19 (dd, J = 3.2, 0.7 Hz, 1H, H–5’),
6.95 (dd, J = 3.5, 3.5 Hz, 1H, H–4’), 6.91 (dd, J = 3.5, 0.7
Hz, 1H, H–3’), 5.88 (ddt, J = 17.1, 10.2, 6.1 Hz, 1H, =CH),
5.07 (dq, J = 10.2, 1.8 Hz, 1H, =CH2(H–cis)), 4.97 (dq, J =
17.1, 1.8 Hz, 1H, =CH2(H–trans)), 4.40 (s, 2H, N–CH2), 3.39
(dt, J = 6.1, 1.8 Hz, 2H, –CH2–). 13C NMR (100 MHz,
CDCl3): δ 142.9 (C1), 141.3 (C2’), 136.0 (=CH), 131.7
(C4a), 128.7 (C8a), 128.4 (C3), 127.8 (C2), 127.8 (C5),
126.8 (C7), 126.6 (C5’), 126.5 (C6), 125.2 (C4’), 124.9
(C3’), 123.8 (C8), 117.2 (C4), 116.6 (=CH2), 49.4 (N–
2–Allyl–N–(thiophen–2–ylmethyl)–1–naphthylamine (6d)
Colorless viscous oil. Yield: 76%. IR (liquid film, cm−1): ṽ
3361 (N–H), 1629 (C=Callyl), 916 (=C–Hallyl).1H NMR
(400 MHz, CDCl3): δ 8.24 (dd, J = 8.4, 1.2 Hz, 1H, H–8),
7.87 (dd, J = 8.4, 1.2 Hz, 1H, H–5), 7.55 (ddd, J = 8.4, 7.0,
1.2 Hz, 1H, H–7), 7.50 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H, H–6),
7.33 (d, J = 8.4 Hz, 1H, H–3), 7.29 (dd, J = 5.2, 1.2 Hz,
1H, H–5’), 7.02 (d, J = 5.2, 3.2 Hz, 1H, H–4’), 6.99 (dd, J
= 3.2, 0.8 Hz, 1H, H–3’), 6.02 (ddt, J = 17.2, 10.2, 6.0 Hz,
1H, =CH), 5.14 (dq, J = 10.2, 1.6 Hz, 1H, =CH2(H–cis)),
5.07 (dq, J = 17.2, 1.6 Hz, 1H, =CH2(H–trans)), 4.55 (s, 2H,
N–CH2), 3.38 (dt, J = 6.0, 1.6 Hz, 2H, –CH2–). 13C NMR
(100 MHz, CDCl3): δ 142.3 (C1), 141.9 (C2’), 137.1
(=CH), 134.3 (C4a), 129.5 (C8a), 128.9 (C3), 128.8 (C2),
127.3 (C7, C4’), 126.2 (C3’), 125.8 (C6), 125.7 (C5), 124.2
(C4), 123.6 (C8), 116.5 (=CH2), 49.7 (N–CH2), 36.8 (–
CH2–). GC–MS (EI, 70 eV): m/z (%) 279 (M+•, 40), 196
(1), 182 (36), 168 (6), 97 (100).
CH2), 36.3 (–CH2–). GC–MS (EI, 70 eV): m/z (%) 357 (M
+•
,
79Br, 6), 274 (1), 260 (3), 246 (2), 97 (100).
2–Allyl–4–bromo–N–(5–methylthiophen–2–ylmethyl)–1–
naphthylamine (6b)
Colorless viscous oil. Yield: 78%. IR (liquid film, cm−1): ṽ
1
3362 (N–H), 1635 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.22 (dd, J = 7.1, 2.2 Hz, 1H, H–8),
8.20 (dd, J = 7.1, 2.3 Hz, 1H, H–5), 7.60 (s, 1H, H–3), 7.56
(td, J = 7.1, 2.3 Hz, 1H, H–7), 7.55 (td, J = 7.1, 2.2 Hz, 1H,
H–6), 6.61 (dd, J = 3.3, 1.0 Hz, 1H, H–4’), 6.68 (d, J = 3.3
Hz, 1H, H–3’), 5.94 (ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH),
5.13 (dq, J = 10.1, 1.6 Hz, 1H, =CH2(H–cis)), 5.03 (dq, J =
17.1, 1.6 Hz, 1H, =CH2(H–trans)), 4.37 (s, 2H, N–CH2), 3.40
2–Allyl–N–(5–methylthiophen–2–ylmethyl)–1–
naphthylamine (6e)
(dt, J = 6.0, 1.6 Hz, 2H, –CH2–), 2.48 (s, 3H, 5’–CH3). 13
C
Colorless viscous oil. Yield: 80%. IR (liquid film, cm−1): ṽ
1
NMR (100 MHz, CDCl3): δ 142.3 (C1), 140.6 (C2’), 139.4
(C5’), 136.3 (=CH), 132.2 (C3, C4a), 130.4 (C8a), 129.2
(C2), 127.7 (C5), 126.8 (C7), 126.4 (C6), 125.3 (C3’),
125.0 (C4’), 124.0 (C8), 117.3 (C4), 115.2 (=CH2), 49.5
(N–CH2), 35.8 (–CH2–), 15.5 (5’–CH3). GC–MS (EI, 70
eV): m/z (%) 371 (M+•, 79Br, 3), 274 (2), 182 (4), 260 (4),
111 (100).
3361 (N–H), 1636 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 30 (br d, J = 8.8 Hz, 1H, H–8), 7.90
(br d, J = 8.4 Hz, 1H, H–5), 7.62 (d, J = 8.4 Hz, 1H, H–4),
7.58 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H, H–7), 7.52 (ddd, J =
8.0, 7.0, 1.2 Hz, 1H, H–6), 7.36 (d, J = 8.4 Hz, 1H, H–3),
6.80 (d, J = 3.2 Hz, 1H, H–4’), 6.70 (dd, J = 3.2, 1.0 Hz,
1H, H–3’), 6.07 (ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH),
5.18 (dq, J = 10.1, 1.6 Hz, 1H, =CH2(H–cis)), 5.12 (dq, J =

Medicinal Chemistry Research
17.1, 1.6 Hz, 1H, =CH2(H–trans)), 4.48 (s, 2H, N–CH2), 3.55
2–Allyl–4–bromo–N–(furan–2–ylmethyl)–1–naphthylamine
(7a)
(dt, J = 6.0, 1.6 Hz, 2H, –CH2–), 2.57 (s, 3H, 5’–CH3). 13
C
NMR (100 MHz, CDCl3): δ 142.6 (C1), 141.4 (C2’), 139.7
(C5’), 137.2 (=CH), 134.3 (C4a), 129.6 (C8a), 129.0 (C5),
128.8 (C3), 128.5 (C2), 126.1 (C7), 125.7 (C6), 125.4
(C4’), 125.3 (C3’), 123.9 (C4), 123.7 (C8), 116.5 (=CH2),
50.1 (N–CH2), 36.9 (–CH2–), 15.9 (5’–CH3). GC–MS (EI,
70 eV): m/z (%) 293 (M+•, 10), 196 (1), 182 (4), 168 (4),
111 (100).
Colorless viscous oil. Yield: 74%. IR (liquid film, cm−1): ṽ
3370 (N–H), 1636 (C=Callyl), 916 (=C–Hallyl). H NMR
1
(400 MHz, CDCl3): δ 8.22 (dd, J = 7.0, 1.6 Hz, 1H, H–8),
8.20 (dd, J = 7.0, 1.5 Hz, 1H, H–5), 7.58 (s, 1H, H–3), 7.57
(td, J = 7.0, 1.5 Hz, 1H, H–7), 7.55 (td, J = 7.0, 1.6 Hz, 1H,
H–6), 7.41 (dd, J = 1.9, 0.8 Hz, 1H, H–5’), 6.31 (dd, J =
3.1, 1.9 Hz, 1H, H–4’), 6.06 (dd, J = 3.1, 0.8 Hz, 1H, H–
3’), 5.93 (ddt, J = 17.1, 10.0, 6.1 Hz, 1H, =CH), 5.15 (dq,
J = 10.0, 1.5 Hz, 1H, =CH2(H–cis)), 5.05 (dq, J = 17.1, 1.5
Hz, 1H, =CH2(H–trans)), 4.28 (s, 2H, N–CH2), 3.33 (dt, J =
6.1, 1.5 Hz, 2H, –CH2–). 13C NMR (100 MHz, CDCl3): δ
153.6 (C2’), 142.2 (C5’), 142.1 (C1), 136.3 (=CH), 132.2
(C3), 132.1 (C4a), 129.2 (C2), 129.1 (C8a), 127.4 (C5),
126.7 (C7), 126.4 (C6), 124.0 (C8), 117.0 (C4), 116.4
(=CH2), 110.6 (C4’), 107.2 (C3’), 47.4 (N–CH2), 35.8 (–
CH2–). GC–MS (EI, 70 eV): m/z (%) 341 (M+•, 79Br, 8),
274 (1), 260 (6), 246 (1), 81 (100).
2–Allyl–N–(3–methylthiophen–2–ylmethyl)–1–
naphthylamine (6f)
Colorless viscous oil. Yield: 81%. IR (liquid film, cm−1): ṽ
1
3360 (N–H), 1635 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.27 (dd, J = 8.4, 1.2 Hz, 1H, H–8),
7.86 (br d, J = 7.2 Hz, 1H, H–5), 7.58 (br d, J = 8.4 Hz, 1H,
H–4), 7.54 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, H–7), 7.48 (ddd,
J = 7.2, 7.0, 1.2 Hz, 1H, H–6), 7.31 (br d, J = 8.4 Hz, 1H,
H–3), 7.19 (d, J = 5.2 Hz, 1H, H–5’), 6.86 (d, J = 5.2 Hz,
1H, H–4’), 6.00 (ddt, J = 17.2, 10.0, 6.4 Hz, 1H, =CH),
5.13 (dq, J = 10.2, 1.5 Hz, 1H, =CH2(H–cis)), 5.06 (dq, J =
17.2, 1.6 Hz, 1H, =CH2(H–trans)), 4.43 (s, 2H, N–CH2), 3.46
2–Allyl–4–bromo–N–(5–methylfuran–2–ylmethyl)–1–
naphthylamine (7b)
(dt, J = 6.4, 1.6 Hz, 2H, –CH2–), 2.08 (s, 3H, 3’–CH3). 13
C
NMR (100 MHz, CDCl3): δ 142.6 (C1), 137.1 (=CH),
136.9 (C2’), 134.3 (C4a, C3’), 130.6 (C5’), (129.7 (C8a),
128.9 (C5), 128.8 (C3), 128.6 (C2), 126.1 (C7), 125.7 (C6),
124.0 (C4), 123.7 (C8), 123.4 (C4’), 116.4 (=CH2), 47.8
(N–CH2), 36.8 (–CH2–), 14.0 (3’–CH3). GC–MS (EI, 70
eV): m/z (%) 357 (M+•, 3), 274 (2), 260 (4), 246 (1), 180
(12), 111 (100).
Colorless viscous oil. Yield: 82%. IR (liquid film, cm−1): ṽ
1
3369 (N–H), 1635 (C=Callyl), 917 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.21 (dd, J = 8.5, 2.0 Hz, 1H, H–8),
8.20 (dd, J = 8.6, 1.0 Hz, 1H, H–5), 7.57 (s, 1H, H–3), 7.56
(td, J = 8.6, 1.0 Hz, 1H, H–7), 7.54 (td, J = 8.6, 2.0 Hz, 1H,
H–6), 5.93 (ddt, J = 17.1, 10.0, 6.1 Hz, 1H, =CH), 5.92 (d,
J = 3.2 Hz, 1H, H–3’), 5.87 (d, J = 3.2 Hz, 1H, H–4’), 5.13
(dq, J = 10.0, 1.6 Hz, 1H, =CH2(H–cis)), 5.06 (dq, J = 17.1,
1.6 Hz, 1H, =CH2(H–trans)), 4.20 (s, 2H, N–CH2), 3.35 (dt, J
= 6.1, 1.6 Hz, 2H, –CH2–), 2.31 (s, 3H, 5’–CH3). 13C NMR
(100 MHz, CDCl3): δ 151.8 (C2’), 151.6 (C5’),142.4 (C1),
136.2 (=CH), 132.1 (C3), 130.4 (C8a), 132.0 (C4a), 129.0
(C2), 127.7 (C5), 126.7 (C7), 126.4 (C6), 124.0 (C8), 117.0
(C4), 116.6 (=CH2), 108.1 (C3’), 106.3 (C4’), 47.6 (N–
2–Allyl–N–(5–bromothiophen–2–ylmethyl)–1–
naphthylamine (6g)
Colorless viscous oil. Yield: 78%. IR (liquid film, cm−1): ṽ
1
3360 (N–H), 1628 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.19 (br d, J = 8.4 Hz, 1H, H–8), 7.86
(br d, J = 8.4 Hz, 1H, H–5), 7.59 (d, J = 8.4 Hz, 1H, H–4),
7.53 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H, H–7), 7.49 (ddd, J =
8.4, 7.0, 1.2 Hz, 1H, H–6), 7.32 (d, J = 8.4 Hz, 1H, H–3),
6.96 (d, J = 3.8 Hz, 1H, H–4’), 6.71 (dd, J = 3.8, 1.0 Hz,
1H, H–3’), 6.02 (ddt, J = 16.8, 10.2, 6.0 Hz, 1H, =CH),
5.14 (dq, J = 10.2, 1.6 Hz, 1H, =CH2(H–cis)), 5.05 (dq, J =
16.8, 1.6 Hz, 1H, =CH2(H–trans)), 4.43 (s, 2H, N–CH2), 3.50
(dt, J = 6.0, 1.6 Hz, 2H, –CH2–). 13C NMR (100 MHz,
CDCl3): δ 142.0 (C1), 145.6 (C2’), 137.0 (=CH), 134.3
(C4a), 130.0 (C4’), 129.5 (C8a), 129.0 (C3), 128.8 (C5),
128.7 (C2), 126.2 (C7), 125.8 (C6), 125.4 (C3’), 124.3
(C4), 123.4 (C8), 116.5 (=CH2), 111.5, (C5’), 50.0 (N–
CH2), 35.9 (–CH2–). GC–MS (EI, 70 eV): m/z (%) 355 (M
+•
,
79Br, 4), 274 (1), 260 (2), 246 (2), 95 (100).
2–Allyl–N–(furan–2–ylmethyl)–1–naphthylamine (7c)
Colorless viscous oil. Yield: 77%. IR (liquid film, cm−1): ṽ
1
3369 (N–H), 1634 (C=Callyl), 915 (=C–Hallyl). H NMR
(400 MHz, CDCl3): δ 8.23 (br d, J = 8.4 Hz, 1H, H–8), 7.84
(br d, J = 8.1 Hz, 1H, H–5), 7.55 (d, J = 8.4 Hz, 1H, H–4),
7.51 (ddd, J = 8.4, 8.1, 1.5 Hz, 1H, H–7), 7.47 (td, J = 8.1,
1.2 Hz, 1H, H–6), 7.43 (dd, J = 3.0, 0.7 Hz, 1H, H–5’), 7.28
(d, J = 8.4 Hz, 1H, H–3), 6.33 (dd, J = 3.0, 1.8 Hz, 1H, H–
4’), 6.11 (d, J = 3.0 Hz, 1H, H–3’), 5.99 (ddt, J = 17.1,
10.1, 6.0 Hz, 1H, =CH), 5.12 (dq, J = 10.1, 1.5 Hz, 1H,
CH2), 36.9 (–CH2–). GC–MS (EI, 70 eV): m/z (%) 357 (M
+•
,
79Br, 8), 196 (1), 182 (39), 175 (100).

Medicinal Chemistry Research
=CH2(H–cis)), 5.06 (dq, J = 17.1, 1.5 Hz, 1H, =CH2(H–trans)),
4.32 (s, 2H, N–CH2), 3.41 (dt, J = 6.0, 1.5Hz, 2H, –CH2–).
13C NMR (100 MHz, CDCl3): δ 153.7 (C2’), 142.2 (C5’),
142.0 (C1), 136.9 (=CH), 133.9 (C4a), 128.6 (C8a), 128.4
(C3, C5), 128.1 (C2), 125.7 (C7), 125.4 (C6), 123.6 (C8),
123.4 (C4), 116.1 (=CH2), 107.2 (C3’), 47.0 (N–CH2), 36.6
(–CH2–). GC–MS (EI, 70 eV): m/z (%) 263 (M+•, 28), 196
(1), 182 (34), 168 (60), 81 (100).
Physicochemical and spectral data for (2SR,4RS)–2–
aryl(heteroaryl)–1,4–epoxy–2,3,4,5–tetrahydro–
naphtho[1,2–b]azepines (8a–j), (9a–g), and (10a–e)
(2SR,4SR)–7–Bromo–2–phenyl–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8a)
Reaction time: 35 h. Yield: 49%. White solid, mp 123 °C
1
(heptane). IR (KBr, cm−1): ṽ 1044 (C–O), 996, (N–O). H
2–Allyl–N–(5–methylfuran–2–ylmethyl)–1–naphthylamine
(7d)
NMR (400 MHz, CDCl3): δ 8.26 (br d, J = 8.2 Hz, 1H, H–
11), 8.19 (br d, J = 8.2 Hz, 1H, H–8), 7.58 (td, J = 8.2, 1.0
Hz, 1H, H–9), 7.57 (d, J = 7.6 Hz, 2H, H–2’, H–6’), 7.56
(s, 1H, H–6), 7.51 (td, J = 8.2, 1.1 Hz, 1H, H–10), 7.44 (t, J
= 7.6 Hz, 2H, H–3’, H–5’), 7.34 (t, J = 7.6 Hz, 1H, H–4’),
5.07 (ddd, J = 7.2, 5.3, 1.9 Hz, 1H, H–4), 4.73 (dd, J = 8.3,
2.8 Hz, 1H, H–2), 3.55 (dd, J = 16.8, 5.3 Hz, 1H, HB–5),
2.69 (dddd, J = 12.6, 7.2, 2.8, 0.8 Hz, 1H, HB–3), 2.63
(ddd, J = 12.6, 8.3, 1.9 Hz, 1H, HA–3), 2.61 (br d, J = 16.8
Hz, 1H, HA–5). 13C NMR (100 MHz, CDCl3): δ 145.6
(C11b), 143.6 (C1’), 131.1 (C6), 131.0 (C7a), 128.9
(C11a), 128.8 (C3’, C5’), 127.3 (C4’), 127.2 (C8), 127.1
(C9, C2’, C6’), 126.4 (C10), 122.6 (C11), 122.1 (C5a),
119.6 (C7), 75.4 (C4), 74.5 (C2), 43.2 (C3), 35.0 (C5). GC–
MS (EI, 70 eV): m/z (%) 365 (M+•, 79Br, 35Cl, 10), 335 (7),
322 (5), 257 (9), 231 (2), 220 (100), 193 (2). HR–MS (EI–
MS) m/z calcd. for C20H16BrNO, 365.0415; found,
365.0421.
Colorless viscous oil. Yield: 76%. IR (liquid film, cm−1):
ṽ 3369 (N–H), 1635 (C=Callyl), 917 (=C–Hallyl). 1H NMR
(400 MHz, CDCl3): δ 8.24 (br d, J = 8.4 Hz, 1H, H–8),
7.84 (br d, J = 8.4 Hz, 1H, H–5), 7.55 (d, J = 8.2 Hz, 1H,
H–4), 7.51 (td, J = 8.4, 1.4 Hz, 1H, H–7), 7.45 (td, J =
8.4, 1.1 Hz, 1H, H–6), 7.29 (d, J = 8.2 Hz, 1H, H–3), 6.01
(ddt, J = 17.1, 10.1, 6.0 Hz, 1H, =CH), 5.99 (d, J = 3.0
Hz, 1H, H–3’), 5.91 (dd, J = 3.0, 1.0 Hz, 1H, H–4’), 5.14
(dq, J = 10.1, 1.2 Hz, 1H, =CH2(H–cis)), 5.09 (dq, J =
17.1, 1.2 Hz, 1H, =CH2(H–trans)), 4.26 (s, 2H, N–CH2),
3.46 (dt, J = 6.0, 1.2 Hz, 2H, –CH2–), 2.35 (s, 3H, 5’-
CH3). 13C NMR (100 MHz, CDCl3): δ 151.9 (C2’), 151.7
(C5’), 142.3 (C1), 136.9 (=CH), 133.9 (C4a), 129.3
(C8a), 128.5 (C3), 128.4 (C5), 128.0 (C2), 125.6 (C7),
125.3 (C6), 123.5 (C4, C8), 115.9 (=CH2), 108.1 (C3’),
106.2 (C4’), 47.0 (N–CH2), 36.2 (–CH2–), 13.9 (5’–CH3).
GC–MS (EI, 70 eV): m/z (%) 277 (M+•, 8), 196 (1), 182
(3), 168 (6), 95 (100).
(2SR,4SR)–7–Bromo–2–(o–tolyl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8b)
2–Allyl–N–(5–nitrofuran–2–ylmethyl)–1–naphthylamine
(7e)
Reaction time: 60 h. Yield: 50%. Pale yellow solid, mp 177
°C (heptane). IR (KBr, cm−1): ṽ 1048 (C–O), 1000 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.21 (br d, J = 7.3 Hz, 1H,
H–11), 8.19 (br d, J = 8.0 Hz, 1H, H–8), 8.09 (br d, J = 7.7
Hz, 1H, H–6’), 7.58 (s, 1H, H–6), 7.56 (td, J = 8.2, 1.1 Hz,
1H, H–9), 7.48 (td, J = 8.2, 0.9 Hz, 1H, H–10), 7.37 (t, J =
7.7 Hz, 1H, H–5’), 7.25 (td, J = 7.6, 1.1 Hz, 1H, H–4’),
7.19 (br d, J = 7.6 Hz, 1H, H–3’), 5.02 (ddd, J = 7.9, 5.4,
1.5 Hz, 1H, H–4), 4.80 (dd, J = 8.6, 2.9 Hz, 1H, H–2), 3.55
(dd, J = 16.9, 5.4 Hz, 1H, HB–5), 2.70 (ddd, J = 12.2, 8.6,
1.5 Hz, 1H, HA–3), 2.63 (br d, J = 16.9 Hz, 1H, HA–5), 2.47
(dddd, J = 12.2, 7.9, 2.9, 1.2 Hz, 1H, HB–3), 2.17 (s, 3H,
2’–CH3). 13C NMR (100 MHz, CDCl3): δ 145.9 (C11b),
141.8 (C1’), 133.9 (C2’), 131.0 (C6), 130.3 (C7a, C3’),
128.9 (C11a), 127.4 (C9), 127.3 (C4’), 127.2 (C10), 127.0
(C8), 126.5 (C5’), 125.7 (C6’), 122.6 (C11), 122.3 (C5a),
119.6 (C7), 75.4 (C4), 72.0 (C2), 43.4 (C3), 35.1 (C5), 19.7
(2’–CH3). GC–MS (EI, 70 eV): m/z (%) 379 (M+•, 79Br, 8),
349 (3), 336 (6), 220 (100), 193 (4). HR–MS (EI–MS) m/z
calcd. for C21H18BrNO, 379.0566; found, 379.0572.
Colorless viscous oil. Yield: 70%. IR (liquid film, cm−1): ṽ
3373 (N–H), 1636 (C=Callyl), 1497 (–NO2), 1356 (–NO2),
918 (=C–Hallyl). 1H NMR (400 MHz, CDCl3): δ 8.11 (dd, J
= 8.3, 1.1 Hz, 1H, H–8), 7.85 (dd, J = 7.4, 1.2 Hz, 1H, H–
5), 7.59 (d, J = 8.5 Hz, 1H, H–4), 7.52 (td, J = 8.3, 1.2 Hz,
1H, H–7), 7.47 (td, J = 7.4, 1.1 Hz, 1H, H–6), 7.29 (d, J =
8.5 Hz, 1H, H–3), 7.24 (d, J = 3.6 Hz, 1H, H–4’), 6.33 (d, J
= 3.6 Hz, 1H, H–3’), 6.01 (ddt, J = 17.1, 10.1, 5.9 Hz, 1H,
=CH), 5.15 (dq, J = 10.1, 1.7 Hz, 1H, =CH2(H–cis)), 5.06
(dq, J = 17.1, 1.7 Hz, 1H, =CH2(H–trans)), 4.41 (s, 2H, N–
CH2), 3.48 (dt, J = 5.9, 1.7 Hz, 2H, –CH2–). 13C NMR
(100 MHz, CDCl3): δ 157.6 (C5’), 151.9 (C2’), 141.0 (C1),
136.5 (=CH), 134.0 (C4a), 129.0 (C8a), 128.7 (C5), 128.6
(C3), 128.5 (C2), 126.1 (C7), 125.6 (C6), 124.3 (C4), 122.7
(C8), 116.2 (=CH2), 112.8 (C4’), 110.7 (C3’), 47.0 (N–
CH2), 36.6 (–CH2–). GC–MS (EI, 70 eV): m/z (%) 308 (M
+•, 34), 196 (14), 182 (74), 167 (100), 126 (20).

Medicinal Chemistry Research
(2SR,4SR)–7–Bromo–2–(m–tolyl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8c)
NMR (400 MHz, CDCl3): δ 8.21 (br d, J = 7.2 Hz, 1H, H–
11), 8.17 (dd, J = 7.3, 1.1 Hz, 1H, H–8), 8.16 (dd, J = 7.8,
1.3 Hz, 1H, H–6’), 7.60 (s, 1H, H–6), 7.58 (td, J = 7.2, 1.3
Hz, 1H, H–9), 7.49 (td, J = 7.2, 1.3 Hz, 1H, H–10), 7.43
(td, J = 7.8, 1.3 Hz, 1H, H–5’), 7.39 (td, J = 8.0, 1.3 Hz,
1H, H–4’), 7.29 (dd, J = 7.9, 1.6 Hz, 1H, H–3’), 5.03 (ddd,
J = 7.7, 5.4, 1.5 Hz, 1H, H–4), 4.96 (dd, J = 8.6, 2.7 Hz,
1H, H–2), 3.57 (dd, J = 16.9, 5.4 Hz, 1H, HB–5), 2.81 (ddd,
J = 12.8, 8.6, 1.5 Hz, 1H, HA–3), 2.54 (dddd, J = 12.8, 7.7,
2.7, 0.9 Hz, 1H, HB–3), 2.65 (br d, J = 16.9 Hz, 1H, HA–5).
13C NMR (100 MHz, CDCl3): δ 145.3 (C11b), 140.9 (C1’),
132.0 (C2’), 131.1 (C7a), 131.0 (C6), 129.4 (C4’), 128.8
(C11a), 128.3 (C3’), 127.8 (C9), 127.4 (C10), 127.3 (C5’),
127.2 (C8), 122.5 (C11), 122.4 (C5a, C6’), 119.8 (C7), 75.3
(C4), 71.8 (C2), 43.4 (C3), 34.8 (C5). GC–MS (EI, 70 eV):
m/z (%) 399 (M+•, 79Br, 35Cl, 1), 365 (100), 348 (6), 335
(4), 322 (2). HR–MS (EI–MS) m/z calcd. for
C20H15BrClNO, 399.0022; found, 399.0026.
Reaction time: 58 h. Yield: 51%. Yellow solid, mp 80 °C
1
(heptane). IR (KBr, cm−1): ṽ 1046 (C–O), 992 (N–O). H
NMR (400 MHz, CDCl3): δ 8.27 (br d, J = 8.3 Hz, 1H, H–
11), 8.19 (br d, J = 8.3 Hz, 1H, H–8), 7.59 (d, J = 7.7 Hz,
1H, H–6’), 7.58 (td, J = 8.3, 0.8 Hz, 1H, H–9), 7.55 (s, 1 H,
H–6), 7.50 (td, J = 8.2, 0.8 Hz, 1H, H–10), 7.41 (s, 1H, H–
2’), 7.33 (t, J = 7.7 Hz, 1H, H–5’), 7.16 (br d, J = 7.7 Hz,
1H, H–4’), 5.07 (ddd, J = 7.0, 5.4, 1.6 Hz, 1H, H–4), 4.70
(dd, J = 8.3, 2.8 Hz, 1H, H–2), 3.55 (dd, J = 16.8, 5.3 Hz,
1H, HB–5), 2.68 (dddd, J = 12.5, 7.0, 2.8, 0.9 Hz, 1H, HB–
3), 2.63 (ddd, J = 12.5, 8.3, 1.6 Hz, 1H, HA–3), 2.60 (br d,
J = 16.8 Hz, 1H, HA–5), 2.44 (s, 3H, 3’–CH3). 13C NMR
(100 MHz, CDCl3): δ 145.7 (C11b), 143.3 (C1’), 138.4
(C3’), 131.0 (C6), 130.1 (C7a), 128.8 (C11a), 128.0 (C4’),
127.3 (C10, C6’), 127.2 (C8), 127.1 (C9), 127.0 (C2’),
123.6 (C5’), 122.5 (C11), 122.1 (C5a), 119.5 (C7), 75.3
(C4), 74.6 (C2), 43.0 (C3), 34.7 (C5), 21.6 (3’–CH3). GC–
MS (EI, 70 eV): m/z (%) 379 (M+•, 79Br, 11), 349 (4), 336
(4), 220 (100), 193 (3). HR–MS (EI–MS) m/z calcd. for
C21H18BrNO, 379.0563; found, 379.0572.
(2SR,4SR)–7–Bromo–2–(4–chlorophenyl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (8f)
Reaction time: 61 h. Yield: 48%. Yellow solid, mp 181 °C
1
(heptane). IR (KBr, cm−1): ṽ 1047 (C–O), 958 (N–O). H
(2SR,4SR)–7–Bromo–2–(3–methoxyphenyl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (8d)
NMR (400 MHz, CDCl3): δ 8.28 (br d, J = 8.5 Hz, 1H, H–
11), 8.18 (br d, J = 8.5 Hz, 1H, H–8), 7.52–7.58 (m, 2H, H–
9, H–10), 7.55 (s, 1H, H–6), 7.48 (d, J = 7.6 Hz, 2H, H–2’,
H–6’), 7.38 (d, J = 7.6 Hz, 2H, H–3’, H–5’), 5.06 (ddd, J =
8.0, 5.1, 1.4 Hz, 1H, H–4), 4.66 (dd, J = 8.4, 2.0 Hz, 1H,
H–2), 3.53 (dd, J = 16.7, 5.1 Hz, 1H, HB–5), 2.69 (m, 2H,
HA–3, HB–3), 2.70 (br d, J = 16.7 Hz, 1H, HA–5). 13C
NMR (100 MHz, CDCl3): δ 145.2 (C11b), 142.0 (C1’),
133.0 (C4’), 131.0 (C6, C7a), 128.9 (C3’, C5’), 128.8
(C11a), 127.7 (C2’, C6’), 127.3 (C8), 127.2 (C9, C10),
122.3 (C11), 122.1 (C5a), 119.8 (C7), 75.4 (C4), 73.8 (C2),
Reaction time: 57 h. Yield: 48%. Viscous yellow oil. IR
1
(liquid film, cm−1): ṽ 1048 (C–O), 991 (N–O). H NMR
(400 MHz, CDCl3): δ 8.26 (br d, J = 8.3 Hz, 1H, H–11),
8.18 (br d, J = 8.3 Hz, 1H, H–8), 7.87 (dd, J = 8.0, 2.3 Hz,
1H, H–4’), 7.58 (td, J = 8.1, 1.0 Hz, 1H, H–9), 7.55 (s, 1H,
H–6), 7.50 (td, J = 8.2, 1.1 Hz, 1H, H–10), 7.34 (t, J = 7.9
Hz, 1H, H–5’), 7.18 (br d, J = 2.3 Hz, 1H, H–2’), 7.10 (d, J
= 7.9 Hz, 1H, H–6’), 5.06 (ddd, J = 7.0, 5.4, 1.5 Hz, 1H,
H–4), 4.89 (dd, J = 8.3, 2.8 Hz, 1H, H–2), 3.87 (s, 3H, 3’–
OCH3), 3.54 (dd, J = 16.8, 5.4 Hz, 1H, HB–5), 2.66 (dddd,
J = 12.5, 7.0, 2.8, 1.0 Hz, 1H, HB–3), 2.61 (ddd, J = 12.5,
8.3, 1.5 Hz, 1H, HA–3), 2.60 (br d, J = 16.8 Hz, 1H, HA–5).
13C NMR (100 MHz, CDCl3): δ 159.9 (C3’), 145.6 (C11b),
145.2 (C1’), 131.1 (C6), 131.0 (C7a), 129.8 (C5’), 128.8
(C11a), 127.3 (C10), 127.2 (C9, C8), 122.5 (C11), 122.2
(C5a), 119.6 (C7), 118.8 (C6’), 112.5 (C4’), 112.1 (C2’),
75.4 (C4), 74.2 (C2), 43.4 (C3), 34.7 (C5), 55.5 (3’–OCH3).
GC–MS (EI, 70 eV): m/z (%) 395 (M+•, 79Br, 3), 365 (1),
352 (1), 220 (100), 193 (1). HR–MS (EI–MS) m/z calcd. for
C21H18BrNO2, 395.0509; found, 395.0521.
43.1 (C3), 34.8 (C5). GC–MS (EI, 70 eV): m/z (%) 399 (M
+•
,
79Br, 35Cl, 5), 369 (3), 356 (2), 220 (100), 193 (3). HR–
MS (EI–MS) m/z calcd. for C20H15BrClNO, 399.0008;
found, 399.0021.
(2SR,4SR)–7–Bromo–2–(2,4–dichlorophenyl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (8g)
Reaction time: 60 h. Yield: 49%. White solid, mp 192 °C
1
(heptane). IR (KBr, cm−1): ṽ 1045 (C–O), 993 (N–O). H
NMR (400 MHz, CDCl3): δ 8.19 (br d, J = 8.3 Hz, 1H, H–
11), 8.11 (br d, J = 8.7 Hz, 1H, H–8), 8.09 (d, J = 8.9 Hz,
1H, H–6’), 7.57 (s, 1H, H–6), 7.56 (td, J = 8.7, 1.2 Hz, 1H,
H–9), 7.47 (td, J = 8.3, 1.2 Hz, 1H, H–10), 7.40 (dd, J =
8.9, 2.0 Hz, 1H, H–5’), 7.39 (d, J = 2.0 Hz, 1H, H–3’), 5.00
(ddd, J = 7.9, 5.4, 1.5 Hz, 1H, H–4), 4.87 (dd, J = 8.6, 2.8
Hz, 1H, H–2), 3.54 (dd, J = 16.9, 5.4 Hz, 1H, HB–5), 2.76
(ddd, J = 12.8, 8.6, 1.5 Hz, 1H, HA–3), 2.62 (br d, J = 16.9
(2SR,4SR)–7–Bromo–2–(2–chlorophenyl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (8e)
Reaction time: 61 h. Yield: 48%. Pale yellow solid, mp 17 °
C (heptane). IR (KBr, cm−1): ṽ 1054 (C–O), 955 (N–O). 1H

Medicinal Chemistry Research
Hz, 1H, HA–5), 2.50 (dddd, J = 12.8, 7.9, 2.8, 1.3 Hz, 1H,
HB–3). 13C NMR (100 MHz, CDCl3): δ 145.3 (C11b),
139.9 (C1’), 133.7 (C4’), 133.0 (C2’), 131.3 (C7a), 131.2
(C6), 129.2 (C6’), 129.0 (C11a), 127.8 (C9, C5’), 127.7
(C10), 127.6 (C8, C3’), 122.6 (C5a), 122.5 (C11), 120.4
(C7), 75.7 (C4), 71.9 (C2), 43.9 (C3), 35.3 (C5). GC–MS
(EI, 70 eV): m/z (%) 432 (M+•, 79Br, 35Cl, 1), 399 (100),
382 (5), 369 (3), 356 (1). HR–MS (EI–MS) m/z calcd. for
C20H14BrCl2NO, 432.9639; found, 432.9636.
(C6), 126.6 (C9), 126.0 (C10, C7), 122.2 (C11), 121.7
(C4’), 121.1 (C2’), 120.9 (C5a), 75.8 (C4), 73.6 (C2), 43.3
(C3), 35.2 (C5). GC–MS (EI, 70 eV): m/z (%) 332 (M+•,
10), 302 (1), 289 (7), 142 (100), 115 (31). HR–MS (EI–MS)
m/z calcd. for C20H16N2O3, 332.1160; found, 332.1161.
(2SR,4SR)–2–(4–Nitrophenyl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8j)
Reaction time: 58 h. Yield: 50%. Yellow solid, mp 64 °C
(2SR,4SR)–2–(o–Tolyl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8h)
(heptane). IR (KBr, cm−1): ṽ 1519 (–NO2), 1342 (–NO2),
1048 (C–O), 960 (N–O). H NMR (400 MHz, CDCl3): δ
1
8.27 (d, J = 8.5 Hz, 2H, H–3’, H–5’), 8.11 (dd, J = 7.6, 1.8
Hz, 1H, H–11), 7.81 (dd, J = 7.6, 1.7 Hz, 1H, H–8), 7.75
(d, J = 8.5 Hz, 2H, H–2’, H–6’), 7.66 (d, J = 8.3 Hz, 1H,
H–7), 7.47 (td, J = 7.6, 1.8 Hz, 1H, H–10), 7.44 (td, J =
7.6, 1.8 Hz, 1H, H–9), 7.23 (d, J = 8.3 Hz, 1H, H–6), 5.09
(ddd, J = 6.9, 5.2, 1.4 Hz, 1H, H–4), 4.81 (dd, J = 8.7, 2.5
Hz, 1H, H–2), 3.59 (dd, J = 16.9, 5.2 Hz, 1H, HB–5), 2.72
(ddd, J = 12.4, 8.7, 1.4 Hz, 1H, HA–3), 2.65 (br d, J = 16.9
Hz, 1H, HA–5), 2.60 (dddd, J = 12.4, 6.9, 2.5, 1.0 Hz, 1H,
HB–3). 13C NMR (100 MHz, CDCl3): δ 151.0 (C4’), 147.2
(C1’), 144.7 (C11b), 132.7 (C7a), 128.0 (C8), 127.4 (C6),
127.3 (C11a, C2’, C6’), 126.7 (C9), 126.3 (C10), 126.1
(C7), 124.1 (C3’, C5’), 121.6 (C11), 121.0 (C5a), 75.9
(C4), 73.7 (C2), 43.2 (C3), 35.1 (C5). GC–MS (EI, 70 eV):
m/z (%) 332 (M+•, 12), 302 (1), 289 (7), 142 (100), 115
(31). HR–MS (EI–MS) m/z calcd. for C20H16N2O3,
332.1158; found, 332.1161.
Reaction time: 58 h. Yield: 47%. Pale yellow solid, mp 198
°C (heptane). IR (KBr, cm−1): ṽ 1046 (C–O), 995 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.15 (dd, J = 8.0, 1.0 Hz,
1H, H–11), 8.10 (dd, J = 8.0, 1.3 Hz, 1H, H–8), 7.79 (dd, J
= 7.2, 1.5 Hz, 1H, H–6’), 7.64 (d, J = 8.5 Hz, 1H, H–7),
7.44 (td, J = 8.0, 1.3 Hz, 1H, H–10), 7.40 (td, J = 8.0, 1.0
Hz, 1H, H–9), 7.35 (t, J = 7.2 Hz, 1H, H–5’), 7.24 (d, J =
7.2 Hz, 1H, H–3’), 7.22 (td, J = 7.2, 1.0 Hz, 1H, H–4’),
7.16 (d, J = 8.5 Hz, 1H, H–6), 5.03 (ddd, J = 8.2, 5.2, 1.8
Hz, 1H, H–4), 4.81 (dd, J = 8.8, 2.8 Hz, 1H, H–2), 3.59
(dd, J = 16.8, 5.2 Hz, 1H, HB–5), 2.73 (ddd, J = 12.0, 8.8,
1.8 Hz, 1H, HA–3), 2.64 (d, J = 16.8, 1H, HA–5), 2.47
(dddd, J = 12.0, 7.2, 2.8, 0.8 Hz, 1H, HB–3), 2.16 (s, 3H,
2’–CH3). 13C NMR (100 MHz, CDCl3): δ 145.9 (C11b),
142.2 (C1’), 134.0 (C2’), 132.7 (C7a), 130.2 (C3’), 127.8
(C8), 127.7 (C11a), 127.4 (C6), 126.9 (C4’), 126.4 (C10,
C6’), 126.0 (C5’), 125.8 (C9), 125.6 (C7), 122.3 (C11),
121.1 (C5a), 75.7 (C4), 72.0 (C2), 43.7 (C3), 35.3 (C5),
19.6 (2’–CH3). GC–MS (EI, 70 eV): m/z (%) 301 (M+•, 41),
272 (7), 258 (21), 142 (80), 115 (100). HR–MS (EI–MS) m/
z calcd. for C21H19NO, 301.1473; found, 301.1467.
(2SR,4SR)–7–Bromo–2–(thiophen–2–yl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (9a)
Reaction time: 39 h. Yield: 52%. Pale Yellow solid, mp
139 °C (heptane). IR (KBr, cm−1): ṽ 1044 (C–O), 996 (N–
1
(2SR,4SR)–2–(3–Nitrophenyl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (8i)
O). H NMR (400 MHz, CDCl3): δ 8.38 (dd, J = 7.3, 2.4
Hz, 1H, H–11), 8.18 (dd, J = 7.3, 2.1 Hz, 1H, H–8), 7.59
(td, J = 7.3, 2.4 Hz, 1H, H–9), 7.57 (td, J = 7.3, 2.1 Hz, 1H,
H–10), 7.54 (s, 1H, H–6), 7.30 (dd, J = 4.2, 2.0 Hz, 1H, H–
5’), 7.02 (dd, J = 4.3, 2.0 Hz, 1H, H–3’), 7.00 (dd, J = 4.2,
4.3 Hz, 1H, H–4’), 5.12 (ddd, J = 7.7, 5.3, 1.8 Hz, 1H, H–
4), 4.94 (dd, J = 8.3, 2.0 Hz, 1H, H–2), 3.56 (dd, J = 16.9,
5.3 Hz, 1H, HB–5), 2.81 (dddd, J = 12.6, 7.7, 2.0, 1.0 Hz,
1H, HB–3), 2.60 (br d, J = 16.9 Hz, 1H, HA–5), 2.56 (ddd,
J = 12.6, 8.3, 1.8 Hz, 1H, HA–3). 13C NMR (100 MHz,
CDCl3): δ 147.3 (C2’), 144.7 (C11b), 133.1 (C7a), 131.0
(C6), 128.0 (C11a), 127.4 (C8, C10), 127.3 (C9), 126.9
(C5’), 125.0 (C4’), 124.1 (C3’), 122.6 (C11), 121.0 (C5a),
120.0 (C7), 75.6 (C4), 70.9 (C2), 42.7 (C3), 35.1 (C5). GC–
MS (EI, 70 eV): m/z (%) 371 (M+•, 79Br, 18), 341 (5), 328
(7), 257 (4), 231 (2), 220 (100), 193 (1). HR–MS (EI–MS)
m/z calcd. for C18H14BrNOS, 370.9976; found, 370.9979.
Reaction time: 58 h.Yield: 48%. Pale yellow solid. mp 137 °
C (heptane). IR (KBr, cm−1): ṽ 1525 (–NO2), 1325 (–NO2),
1
1046 (C–O), 1004 (N–O). H NMR (400 MHz, CDCl3): δ
8.39 (s, 1H, H–2’), 8.16 (ddd, J = 8.0, 2.0, 0.8 Hz, 1H, H–
4’), 7.95 (ddd, J = 8.0, 2.0, 0.8, Hz, 1H, H–6’), 7.81 (dd, J
= 7.0, 2.7 Hz, 1H, H–11), 7.79 (dd, J = 7.0, 2.5 Hz, 1H, H–
8), 7.64 (d, J = 8.4 Hz, 1H, H–7), 7.57 (t, J = 7.6 Hz, 1H,
H–5’), 7.41–7.47 (m, 2H, H–9, H–10), 7.21 (d, J = 8.4 Hz,
1H, H–6), 5.09 (ddd, J = 7.3, 5.5, 1.8 Hz, 1H, H–4), 4.80
(dd, J = 8.6, 2.8 Hz, 1H, H–2), 3.57 (dd, J = 16.7, 5.5 Hz,
1H, HB–5), 2.70 (ddd, J = 12.5, 8.6, 1.8 Hz, 1H, HA–3),
2.63 (br d, J = 16.7 Hz, 1H, HA–5), 2.60 (dddd, J = 12.5,
7.3, 2.8, 1.0 Hz, 1H, HB–3). 13C NMR (100 MHz, CDCl3):
δ 148.6 (C3’), 145.9 (C1’), 144.7 (C11b), 132.9 (C6’),
132.7 (C7a), 129.7 (C5’), 128.0 (C8), 127.5 (C11a), 127.4

Medicinal Chemistry Research
(2SR,4SR)–7–Bromo–2–(5–methylthiophen–2–yl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (9b)
7.49 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H, H–9), 7.29 (dd, J = 4.5,
1.7 Hz, 1H, H–5’), 7.21 (d, J = 8.4 Hz, 1H, H–6), 7.04 (dd,
J = 4.6, 1.7 Hz, 1H, H–3’), 7.02 (td, J = 4.6, 4.5 Hz, 1H,
H–4’), 5.12 (ddd, J = 7.8, 5.2, 2.0 Hz, 1H, H–4), 4.97 (dd,
J = 8.2, 1.8 Hz, 1H, H–2), 3.58 (dd, J = 16.8, 5.2 Hz, 1H,
HB–5), 2.77–2.83 (m, 1H, HB–3), 2.62 (br d, J = 16.8 Hz,
1H, HA–5), 2.56–2.61 (m, 1H, HA–3). 13C NMR (100 MHz,
CDCl3): δ 147.8 (C2’), 144.7 (C11b), 132.7 (C7a), 127.9
(C8), 127.6 (C11a), 127.3 (C6), 126.8 (C5’), 126.5 (C10),
126.0 (C9), 125.9 (C7), 124.8 (C4’), 124.0 (C3’), 122.2
(C11), 120.9 (C5a), 75.5 (C4), 70.9 (C2), 42.9 (C3), 35.3
(C5). GC–MS (EI, 70 eV): m/z (%) 293 (M+•, 18), 263 (3),
250 (24), 180 (6), 142 (100), 115 (26). HR–MS (EI–MS) m/
z calcd. for C18H15NOS, 293.0868; found, 293.0874.
Reaction time: 40 h. Yield: 47%. White solid, mp 122 °C
1
(heptane). IR (KBr, cm−1): ṽ 1050 (C–O), 989 (N–O). H
NMR (400 MHz, CDCl3): δ 8.37–8.41 (m, 1H, H–11),
8.15–8.22 (m, 1H, H–8), 7.54–7.63 (m, 2H, H–9, H–10),
7.53 (s, 1H, H–6), 6.79 (d, J = 3.4 Hz, 1H, H–3’), 6.65 (dd,
J = 3.2, 0.8 Hz, 1H, H–4’), 5.06–5.12 (m, 1H, H–4), 4.97
(br d, J = 7.9 Hz, 1H, H–2), 3.54 (dd, J = 16.8, 5.3 Hz, 1H,
HB–5), 2.77 (dddd, J = 12.0, 7.5, 2.0, 1.0 Hz, 1H, HB–3),
2.62 (br d, J = 16.8 Hz, 1H, HA–5), 2.51 (s, 3H, 5’–CH3),
2.43–2.53 (m, 1H, HA–3). 13C NMR (100 MHz, CDCl3): δ
144.8 (C11b), 144.2 (C2’), 139.5 (C5’), 132.0 (C7a), 131.0
(C6), 128.9 (C11a), 127.4 (C9, C10), 127.3 (C8), 124.8
(C4’), 124.0 (C3’), 122.7 (C11), 122.0 (C5a), 119.9 (C7),
75.2 (C4), 70.9 (C2), 42.4 (C3), 34.9 (C5), 15.4 (5’–CH3).
GC–MS (EI, 70 eV): m/z (%) 385 (M+•, 79Br, 8), 355 (3),
342 (6), 257 (4), 231 (3), 220 (100), 193 (3). HR–MS (EI–
MS) m/z calcd. for C19H16BrNOS, 385.0134; found,
385.0136.
(2SR,4SR)–2–(5–Methylthiophen–2–yl)–2,3,4,5–tetrahydro–
1,4–epoxynaphtho[1,2–b]azepine (9e)
Reaction time: 36 h. Yield: 50%. Pale yellow solid, mp 132
°C (heptane). IR (KBr, cm−1): ṽ 1048 (C–O), 991 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.38 (br d, J = 8.4 Hz, 1H,
H–11), 7.80 (br d, J = 8.4 Hz, 1H, H–8), 7.63 (d, J = 8.4
Hz, 1H, H–7), 7.53 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H, H–10),
7.47 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H, H–9), 7.20 (d, J = 8.4
Hz, 1H, H–6), 6.81 (dd, J = 3.2, 0.4 Hz, 1H, H–4’), 6.66
(dd, J = 3.2, 1.0 Hz, 1H, H–3’), 5.10 (ddd, J = 7.6, 5.2, 2.0
Hz, 1H, H–4), 4.89 (br d, J = 8.4 Hz, 1H, H–2), 3.57 (dd, J
= 16.8, 5.2 Hz, 1H, HB–5), 2.78 (dddd, J = 12.8, 7.6, 2.0,
1.2 Hz, 1H, HB–3), 2.60 (br d, J = 16.8 Hz, 1H, HA–5), 2.54
(ddd, J = 12.8, 8.4, 1.6 Hz, 1H, HA–3), 2.52 (s, 3H, 5’–
CH3). 13C NMR (100 MHz, CDCl3): δ 145.5 (C11b), 145.1
(C2’), 139.7 (C5’), 133.0 (C7a), 128.2 (C8), 127.9 (C11a),
127.6 (C6), 126.7 (C9), 126.2 (C10), 126.1 (C7), 125.0
(C4’), 124.1 (C3’), 122.5 (C11), 121.1 (C5a), 75.7 (C4),
71.4 (C2), 42.8 (C3), 35.6 (C5), 15.7 (5’–CH3). GC–MS
(EI, 70 eV): m/z (%) 307 (M+•, 18), 277 (4), 264 (30), 180
(8), 142 (100), 115 (25). HR–MS (EI–MS) m/z calcd. for
C20H17NOS, 307.1033; found, 307.1031.
(2SR,4SR)–7–Bromo–2–(3–methylthiophen–2–yl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (9c)
Reaction time: 34 h. Yield: 44%. Pale yellow solid, mp 145
°C (heptane). IR (KBr, cm−1): ṽ 1041 (C–O), 988 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.30 (dd, J = 8.4, 0.7 Hz,
1H, H–11), 8.18 (dd, J = 8.3, 1.0 Hz, 1H, H–8), 7.59 (td, J
= 8.3, 0.7 Hz, 1H, H–9), 7.55 (s, 1H, H–6), 7.51 (td, J =
8.4, 1.0 Hz, 1H, H–10), 7.20 (d, J = 5.1 Hz, 1H, H–5’), 6.82
(dd, J = 5.1, 0.8 Hz, 1H, H–4’), 5.12 (ddd, J = 7.5, 5.5, 2.1
Hz, 1H, H–4), 4.95 (dd, J = 8.0, 2.6 Hz, 1H, H–2), 3.56
(dd, J = 16.9, 5.5 Hz, 1H, HB–5), 2.67 (dddd, J = 12.5, 7.5,
2.6, 1.2 Hz, 1H, HB–3), 2.62 (ddd, J = 12.5, 8.0, 2.1 Hz,
1H, HA–3), 2.60 (br d, J = 16.9 Hz, 1H, HA–5), 2.14 (s, 3H,
3’–CH3). 13C NMR (100 MHz, CDCl3): δ 144.9 (C11b),
140.7 (C2’), 132.3 (C3’), 131.0 (C6, C7a), 129.8 (C5’),
128.7 (C11a), 127.4 (C8), 127.3 (C10), 127.2 (C9), 122.6
(C4’), 122.0 (C5a), 121.9 (C11), 119.9 (C7), 75.3 (C4),
69.8 (C2), 43.2 (C3), 34.9 (C5), 14.2 (3’–CH3). GC–MS
(EI, 70 eV): m/z (%) 385 (M+•, 79Br, 14), 355 (5), 342 (7),
257 (1), 231 (1), 220 (100), 193 (1). HR–MS (EI–MS) m/z
calcd. for C19H16BrNOS, 385.0137; found, 385.0136.
(2SR,4SR)–2–(3–Methylthiophen–2–yl)–2,3,4,5–tetrahydro–
1,4–epoxynaphtho[1,2–b]azepine (9f)
Reaction time: 28 h. Yield: 50%. Pale yellow solid, mp 149
°C (heptane). IR (KBr, cm−1): ṽ 1045 (C–O), 986 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.26–8.29 (m, 1H, H–11),
7.79–7.81 (m, 1H, H–8), 7.64 (d, J = 8.4 Hz, 1H, H–7),
7.44–7.49 (m, 2H, H–9, H–10), 7.21 (d, J = 8.4 Hz, 1H, H–
6), 7.20 (d, J = 5.0 Hz, 1H, H–5’), 6.82 (d, J = 5.0 Hz, 1H,
H–4’), 5.13 (ddd, J = 7.2, 5.2, 2.0 Hz, 1H, H–4), 4.99 (dd,
J = 8.0, 2.8 Hz, 1H, H–2), 3.59 (dd, J = 16.8, 5.2 Hz, 1H,
HB–5), 2.68 (dddd, J = 12.4, 7.2, 2.8, 0.8 Hz, 1H, HB–3),
2.62 (br d, J = 16.8 Hz, 1H, HA–5), 2.59–2.65 (m, 1H, HA–
3), 2.15 (s, 3H, 3’–CH3). 13C NMR (100 MHz, CDCl3): δ
(2SR,4SR)–2–(Thiophen–2–yl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (9d)
Reaction time: 34 h. Yield: 48%. Pale yellow solid, mp 134
°C (heptane). IR (KBr, cm−1): ṽ 1041 (C–O), 986 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.39 (br d, J = 8.2 Hz, 1H,
H–11), 7.81 (br d, J = 8.2 Hz, 1H, H–8), 7.65 (d, J = 8.4
Hz, 1H, H–7), 7.53 (ddd, J = 8.2, 6.8, 1.4 Hz, 1H, H–10),

Medicinal Chemistry Research
145.3 (C11b), 141.4 (C2’), 132.9 (C7a), 132.4 (C3’), 130.0
(C5’), 128.2 (C8), 127.9 (C11a), 127.6 (C6), 126.7 (C9),
126.3 (C10), 126.1 (C7), 123.5 (C4’), 122.6 (C11), 121.0
(C5a), 75.8 (C4), 70.0 (C2), 43.7 (C3), 35.5 (C5), 14.5 (3’–
CH3). GC–MS (EI, 70 eV): m/z (%) 307 (M+•, 14), 277 (3),
264 (14), 180 (9), 142 (100), 115 (31). HR–MS (EI–MS) m/
z calcd. for C19H17NOS, 307.1019; found, 307.1031.
eV): m/z (%) 355 (M+•, 79Br, 12), 325 (6), 312 (7), 257 (2),
231 (2), 220 (100), 193 (3). HR–MS (EI–MS) m/z calcd. for
C18H14BrNO2, 355.0207, found, 355.0208.
(2SR,4SR)–7–Bromo–2–(5–methylfuran–2–yl)–2,3,4,5–
tetrahydro–1,4–epoxynaphtho[1,2–b]azepine (10b)
Reaction time: 39 h. Yield: 48%. Pale Yellow solid, mp
(2SR,4SR)–2–(5–bromothiophen–2–yl)–2,3,4,5–tetrahydro–
1,4–epoxynaphtho[1,2–b]azepine (9g)
123 °C (heptane). IR (KBr, cm−1): ṽ 1054 (C–O), 989 (N–
O). H NMR (400 MHz, CDCl3): δ 8.49 (dd, J = 7.7, 2.2
1
Hz, 1H, H–11), 8.18 (dd, J = 7.7, 2.2 Hz, 1H, H–8), 7.60
(td, J = 7.7, 2.2 Hz, 1H, H–10), 7.59 (td, J = 7.7, 2.2 Hz,
1H, H–9), 7.53 (s, 1H, H–6), 6.29 (dd, J = 3.0 Hz, 1H, H–
3’), 5.98 (dd, J = 3.0, 2.8 Hz, 1H, H–4’), 5.08 (ddd, J =
7.8, 5.3, 1.6 Hz, 1H, H–4), 4.68 (dd, J = 8.6, 2.2 Hz, 1H,
H–2), 3.54 (dd, J = 16.7, 5.3 Hz, 1H, HB–5), 2.85 (dddd,
J = 12.6, 7.8, 2.2, 1.0 Hz, 1H, HB–3), 2.59 (br d, J = 16.7
Hz, 1H, HA–5), 2.40 (ddd, J = 12.6, 8.6, 1.6 Hz, 1H, HA–
3), 2.36 (s, 3H, 5’–CH3). 13C NMR (100 MHz, CDCl3): δ
153.2 (C2’), 152.1 (C5’), 144.9 (C11b), 130.9 (C7a),
130.8 (C6), 127.9 (C11a), 127.2 (C8, C9), 127.1 (C10),
122.6 (C11), 122.0 (C5a), 119.7 (C7), 107.6 (C3’), 106.1
(C4’), 74.7 (C4), 68.6 (C2), 38.3 (C3), 34.5 (C5), 13.7
(5’–CH3). GC–MS (EI, 70 eV): m/z (%) 369 (M+•, 79Br,
13), 339 (3), 326 (9), 231 (4), 220 (100), 193 (4). HR–MS
(EI–MS) m/z calcd. for C19H16BrNO2, 369.0363; found,
369.0364.
Reaction time: 20 h. Yield: 49%. Pale yellow solid, mp 135
°C (heptane). IR (KBr, cm−1): ṽ 1044 (C–O), 981 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.33 (br d, J = 8.4 Hz, 1H,
H–11), 7.82 (br d, J = 8.4 Hz, 1H, H–8), 7.66 (d, J = 8.4
Hz, 1H, H–7), 7.55 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, H–10),
7.50 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, H–9), 7.21 (d, J = 8.4
Hz, 1H, H–6), 6.97 (d, J = 3.8 Hz, 1H, H–4’), 6.76 (dd, J =
3.8, 1.0 Hz, 1H, H–3’), 5.11 (ddd, J = 7.6, 5.2, 2.0 Hz, 1H,
H–4), 4.88 (dd, J = 8.4, 2.0 Hz, 1H, H–2), 3.59 (dd, J =
16.8, 5.2 Hz, 1H, HB–5), 2.75 (dddd, J = 12.4, 7.6, 2.0, 0.8
Hz, 1H, HB–3), 2.63 (br d, J = 16.8 Hz, 1H, HA–5), 2.57
(ddd, J = 12.4, 8.4, 2.0 Hz, 1H, HA–3). 13C NMR (100
MHz, CDCl3): δ 149.7 (C2’), 144.5 (C11b), 133.0 (C7a),
129.8 (C4’), 128.3 (C8), 127.8 (C11a), 127.6 (C6), 126.9
(C10), 126.4 (C9), 126.3 (C7), 124.3 (C3’), 122.2 (C11),
121.1 (C5a), 112.0 (C5’), 75.8 (C4), 71.3 (C2), 42.8 (C3),
35.6 (C5). GC–MS (EI, 70 eV): m/z (%) 371 (M+•, 79Br, 8),
341 (4), 328 (7), 180 (5), 154 (2), 142 (100), 115 (27). HR–
MS (EI–MS) m/z calcd. for C18H14BrNOS, 370.9980;
found, 370.9979.
(2SR,4SR)–2–(Furan–2–yl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (10c)
Reaction time: 36 h. Yield: 51%. White solid, mp 96 °C
1
(2SR,4SR)–7–Bromo–2–(furan–2–yl)–2,3,4,5–tetrahydro–
1,4–epoxynaphtho[1,2–b]azepine (10a)
(heptane). IR (KBr, cm−1): ṽ 1051 (C–O), 996 (N–O). H
NMR (400 MHz, CDCl3): δ 8.47 (dd, J = 8.4, 0.9 Hz, 1H,
H–11), 7.81 (dd, J = 8.4, 1.1 Hz, 1H, H–8), 7.64 (d, J = 8.4
Hz, 1H, H–7), 7.56 (td, J = 8.4, 1.1 Hz, 1H, H–10), 7.50
(td, J = 8.4, 0.9 Hz, 1H, H–9), 7.48 (dd, J = 3.3, 1.9 Hz,
1H, H–5’), 7.20 (d, J = 8.4 Hz, 1H, H–6), 6.45 (dd, J = 3.1,
3.3 Hz, 1H, H–4’), 6.42 (dd, J = 3.1, 1.9 Hz, 1H, H–3’),
5.10 (ddd, J = 7.9, 5.3, 1.7 Hz, 1H, H–4), 4.77 (dd, J = 8.6,
2.3 Hz, 1H, H–2), 3.57 (dd, J = 16.7, 5.3 Hz, 1H, HB–5),
2.87 (dddd, J = 12.7, 7.9, 2.3, 1.5 Hz, 1H, HB–3), 2.62 (br
d, J = 16.7 Hz, 1H, HA–5), 2.44 (ddd, J = 12.7, 8.6, 1.7 Hz,
1H, HA–3). 13C NMR (100 MHz, CDCl3): δ 155.7 (C2’),
144.9 (C11b), 142.6 (C5’), 132.6 (C7a), 127.9 (C8), 127.6
(C11a), 127.3 (C6), 126.5 (C9), 125.9 (C10), 125.8 (C7),
122.9 (C11), 120.9 (C5a), 110.4 (C4’), 106.6 (C3’), 75.5
(C4), 68.7 (C2), 38.8 (C3), 35.1 (C5). GC–MS (EI, 70 eV):
m/z (%) 277 (M+•, 27), 247 (4), 234 (25), 180 (4), 142
(100), 115 (22). HR–MS (EI–MS) m/z calcd. for
C18H15NO2, 277.1097; found, 277.1103.
Reaction time: 39 h. Yield: 50%. Pale yellow solid, mp 187
°C (heptane). IR (KBr, cm−1): ṽ 1049 (C–O), 993 (N–O).
1H NMR (400 MHz, CDCl3): δ 8.49 (dd, J = 7.6, 2.0 Hz,
1H, H–11), 8.20 (dd, J = 7.6, 2.1 Hz, 1H, H–8), 7.61 (td, J
= 7.6, 2.1 Hz, 1H, H–10), 7.59 (td, J = 7.6, 2.0 Hz, 1H, H–
9), 7.53 (s, 1H, H–6), 7.48 (dd, J = 3.2, 1.8 Hz, 1H, H–5’),
6.44 (d, J = 3.2 Hz, 1H, H–4’), 6.41 (dd, J = 3.2, 1.8 Hz,
1H, H–3’), 5.09 (ddd, J = 7.8, 5.3, 1.8 Hz, 1H, H–4), 4.73
(dd, J = 8.6, 2.5 Hz, 1H, H–2), 3.54 (dd, J = 16.8, 5.3 Hz,
1H, HB–5), 2.85 (dddd, J = 12.6, 7.8, 2.5, 1.1 Hz, 1H, HB–
3), 2.60 (br d, J = 16.8 Hz, 1H, HA–5), 2.42 (ddd, J = 12.6,
8.6, 1.8 Hz, 1H, HA–3). 13C NMR (100 MHz, CDCl3): δ
155.1 (C2’), 144.9 (C11b), 142.4 (C5’), 131.1 (C7a), 130.9
(C6), 128.7 (C11a), 127.4 (C8, C9), 127.3 (C10), 122.7
(C11), 122.0 (C5a), 119.0 (C7), 110.5 (C3’), 106.8 (C4’),
74.9 (C4), 68.9 (C2), 38.7 (C3), 34.9 (C5). GC–MS (EI, 70

Medicinal Chemistry Research
(2SR,4SR)–2–(5–Methylfuran–2–yl)–2,3,4,5–tetrahydro–
1,4–epoxynaphtho[1,2–b]azepine (10d)
Physicochemical and spectral data for cis–2–aryl
(heteroaryl)–4–hydroxy–2,3,4,5–tetrahydronaphtho
[1,2–b]azepines (11a–h), (12a–f), and (13a–d)
Reaction time: 31 h. Yield: 50%. White solid, mp 117 °C
1
(heptane). IR (KBr, cm−1): ṽ 1054 (C–O), 991 (N–O). H
7–Bromo–cis–2–phenyl–2,3,4,5–tetrahydro–1H–naphtho
[1,2–b]azepin–4–ol (11a)
NMR (400 MHz, CDCl3): δ 8.47 (dd, J = 8.1, 1.2 Hz, 1H,
H–11), 7.80 (dd, J = 8.1, 1.2 Hz, 1H, H–8), 7.63 (d, J = 8.4
Hz, 1H, H–7), 7.56 (td, J = 8.1, 1.2 Hz, 1H, H–10), 7.48
(td, J = 8.1, 1.0 Hz, 1H, H–9), 7.19 (d, J = 8.4 Hz, 1H, H–
6), 6.31 (d, J = 2.9 Hz, 1H, H–3’), 5.99 (dd, J = 2.9, 0.8 Hz,
1H, H–4’), 5.11 (ddd, J = 7.8, 5.3, 1.8 Hz, 1H, H–4), 4.71
(dd, J = 8.5, 2.2 Hz, 1H, H–2), 3.57 (dd, J = 16.7, 5.3 Hz,
1H, HB–5), 2.87 (dddd, J = 12.8, 7.8, 2.2, 1.1 Hz, 1H, HB–
3), 2.61 (br d, J = 16.7 Hz, 1H, HA–5), 2.41 (ddd, J = 12.8,
8.5, 1.8 Hz, 1H, HA–3), 2.37 (s, 3H, 5’–CH3). 13C NMR
(100 MHz, CDCl3): δ 153.5 (C2’), 152.2 (C5’), 145.1
(C11b), 132.7 (C7a), 127.9 (C8), 127.6 (C11a), 127.3 (C6),
126.4 (C9), 125.9 (C10), 125.8 (C7), 122.3 (C11), 120.9
(C5a), 107.4 (C3’), 106.4 (C4’), 75.1 (C4), 68.7 (C2), 38.6
(C3), 35.2 (C5), 14.0 (5’–CH3). GC–MS (EI, 70 eV): m/z
(%) 291 (M+•, 20), 261 (3), 248 (22), 180 (7), 142 (100),
115 (26). HR–MS (EI–MS) m/z calcd. for C19H17NO2,
291.1261; found, 291.1259.
Reaction time: 12 h. Yield: 70%. White solid, mp 147 °C
(heptane). IR (KBr, cm−1): ṽ 3322 (N–H, O–H), 1267 (C–
N), 1013 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.22 (br d,
J = 8.3 Hz, 1H, H–11), 7.66 (s, 1H, H–6), 7.61 (br d, J =
8.3 Hz, 1H, H–8), 7.53 (td, J = 8.3, 1.0 Hz, 1H, H–9), 7.48
(t, J = 8.3 Hz, 1H, H–4’), 7.45 (t, J = 8.3 Hz, 2H, H–3’, H–
5’), 7.44 (t, J = 8.3 Hz, 1H, H–10), 7.42 (dd, J = 8.3, 1.6
Hz, 2H, H–2’, H–6’), 4.40 (br s, 1H, NH), 4.01 (dd, J =
12.0, 6.3 Hz, 1H, Hax–2), 3.94 (tdd, J = 9.8, 3.4, 1.8 Hz,
1H, Hax–4), 3.28 (dd, J = 16.6, 9.8 Hz, 1H, Hax–5), 3.12 (dt,
J = 13.6, 1.8 Hz, 1H, Heq–5), 2.16–2.33 (m, 2H, Hax–3,
Heq–3), 2.01 (br s, 1H, 4–OH). 13C NMR (100 MHz,
CDCl3): δ 144.4 (C11b), 144.1 (C1’), 133.4 (C6), 131.7
(C7a), 128.3 (C4’), 128.1 (C3’, C5’), 128.0 (C8), 127.5
(C11a), 126.8 (C10), 126.7 (C2’, C6’), 126.5 (C9), 125.3
(C5a), 120.6 (C11), 114.1 (C7), 69.7 (C4), 61.3 (C2), 47.4
(C3), 44.1 (C5). GC–MS (EI, 70 eV): m/z (%) 367 (M+•,
79Br, 78), 323 (25), 290 (2), 246 (7), 234 (100), 219 (2).
HR–MS (EI–MS) m/z calcd. for C20H18BrNO, 367.0559;
found, 367.0572.
(2SR,4SR)–2–(5–Nitrofuran–2–yl)–2,3,4,5–tetrahydro–1,4–
epoxynaphtho[1,2–b]azepine (10e)
Reaction time: 34 h. Yield: 51%. Pale yellow solid, mp 147
°C (heptane/ethyl acetate 2:1). IR (KBr, cm−1): ṽ 1494 (–
NO2), 1356 (–NO2), 1048 (C–O), 993 (N–O). H NMR
7–Bromo–cis–2–(o–tolyl)–2,3,4,5–tetrahydro–1H–naphtho
[1,2–b]azepin–4–ol (11b)
1
(400 MHz, CDCl3): δ 8.28 (dd, J = 8.2, 1.0 Hz, 1H, H–11),
7.81 (dd, J = 8.2, 1.2 Hz, 1H, H–8), 7.66 (d, J = 8.4 Hz,
1H, H–7), 7.54 (td, J = 8.2, 1.2 Hz, 1H, H–10), 7.48 (td, J
= 8.2, 1.0 Hz, 1H, H–9), 7.36 (d, J = 3.7 Hz, 1H, H–4’),
7.20 (d, J = 8.4 Hz, 1H, H–6), 6.84 (d, J = 3.7 Hz, 1H, H–
3’), 5.09 (ddd, J = 7.8, 5.3, 1.6 Hz, 1H, H–4), 4.77 (dd, J =
8.4, 1.3 Hz, 1H, H–2), 3.57 (dd, J = 16.9, 5.3 Hz, 1H, HB–
5), 2.87 (dddd, J = 12.9, 7.8, 1.3, 1.1 Hz, 1H, HB–3), 2.64
(br d, J = 16.9 Hz, 1H, HA–5), 2.53 (ddd, J = 12.9, 8.4, 1.6
Hz, 1H, HA–3). 13C NMR (100 MHz, CDCl3): δ 159.2
(C2’), 151.7 (C5’), 143.9 (C11b), 132.7 (C7a), 128.1 (C8),
127.3 (C11a), 127.2 (C6), 126.8 (C9), 126.5 (C10), 126.2
(C7), 121.5 (C11), 120.9 (C5a), 112.9 (C4’), 109.9 (C3’),
75.6 (C4), 68.4 (C2), 39.1 (C3), 34.9 (C5). GC–MS (EI, 70
eV): m/z (%) 322 (M+•, 10), 292 (2), 279 (4), 180 (10), 142
(100), 115 (38). HR–MS (EI–MS) m/z calcd. for
C18H14N2O2, 322.0958; found, 322.0954.
Reaction time: 12 h. Yield: 79%. White solid, mp 147 °C
(heptane). IR (KBr, cm−1): ṽ 3377 (N–H, O–H), 1267 (C–
N), 1027 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.23 (br d,
J = 8.3 Hz, 1H, H–11), 7.70 (br d, J = 7.5 Hz, 2H, H–6’),
7.66 (s, 1H, H–6), 7.61 (br d, J = 8.3 Hz, 1H, H–8), 7.53 (t,
J = 8.3 Hz, 1H, H–9), 7.43 (td, J = 8.3, 1.0 Hz, 1H, H–10),
7.24 (dd, J = 7.5, 0.9 Hz, 1H, H–3’), 7.33 (td, J = 7.5, 1.5
Hz, 1H, H–5’), 7.28 (td, J = 7.5, 1.5 Hz, 1H, H–4’), 4.64 (br
s, 1H, NH), 4.25 (dd, J = 11.3, 1.7 Hz, 1H, Hax–2), 3.95
(tdd, J = 10.1, 4.1, 1.7 Hz, 1H, Hax–4), 3.36 (dd, J = 13.5,
10.1 Hz, 1H, Hax–5), 3.14 (br d, J = 13.5 Hz, 1H, Heq–5),
2.28 (ddd, J = 13.0, 11.3, 10.1 Hz, 1H, Hax–3), 2.22 (ddt, J
= 13.0, 4.1, 1.7 Hz, 1H, Heq–3), 2.28 (s, 3H, 2’–CH3), 2.00
(br s, 1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ 143.7
(C11b), 142.0 (C1’), 134.8 (C2’), 133.6 (C6), 131.6 (C7a),
131.0 (C4’), 128.0 (C8, C3’,C5’), 127.5 (C11a), 126.8
(C10), 126.7 (C9), 125.8 (C6’), 125.6 (C5a), 120.4 (C11),
115.3 (C7), 69.9 (C4), 57.2 (C2), 46.2 (C3), 44.1 (C5), 19.8
(2’–CH3). GC–MS (EI, 70 eV): m/z (%) 381 (M+•, 79Br,
26), 337 (8), 290 (1), 246 (6), 234 (100), 219 (1). HR–MS
(EI–MS) m/z calcd. for C20H18BrNO, 381.0732; found,
381.0728.

Medicinal Chemistry Research
7–Bromo–cis–2–(m–tolyl)–2,3,4,5–tetrahydro–1H–naphtho
[1,2–b]azepin–4–ol (11c)
7–Bromo–cis–2–(2–chlorophenyl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (11e)
Reaction time: 10 h. Yield: 82%. Yellow solid, mp 80 °C
(heptane). IR (KBr, cm−1): ṽ 3306 (N–H, O–H), 1242 (C–
N), 1015 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.23 (dd, J
= 8.3, 1.2 Hz, 1H, H–11), 7.65 (s, 1H, H–6), 7.63 (dd, J =
8.3, 1.0 Hz, 1H, H–8), 7.53 (td, J = 8.3, 1.0 Hz, 1H, H–9),
7.44 (td, J = 8.3, 1.2 Hz, 1H, H–10), 7.33 (t, J = 7.6 Hz,
1H, H–5’), 7.31 (s, 1H, H–2’), 7.28 (d, J = 7.6 Hz, 1H, H–
6’), 7.21 (d, J = 7.6 Hz, 1H, H–4’), 4.50 (br s, 1H, NH),
3.97 (dd, J = 10.2, 3.8 Hz, 1H, Hax–2), 3.91 (tdd, J = 9.9,
3.5, 2.2 Hz, 1H, Hax–4), 3.30 (dd, J = 13.5, 9.9 Hz, 1H,
Hax–5), 3.11 (dd, J = 13.5, 2.2 Hz, 1H, Heq–5), 2.20–2.31
(m, 2H, Hax–3, Heq–3), 2.42 (s, 3H, 3’–CH3), 2.11 (br s, 1H,
4–OH). 13C NMR (100 MHz, CDCl3): δ 144.1 (C11b),
143.8 (C1’), 139.0 (C3’), 133.5 (C6), 131.6 (C7a), 129.2
(C6’), 129.0 (C4’), 128.1 (C8, C5’), 127.7 (C11a), 127.3
(C2’), 126.7 (C10), 126.5 (C9), 125.5 (C5a), 120.5 (C11),
114.9 (C7), 69.6 (C4), 61.7 (C2), 47.1 (C3), 44.3 (C5), 21.6
(3’–CH3). GC–MS (EI, 70 eV): m/z (%) 381 (M+•, 79Br,
50), 337 (18), 290 (1), 246 (10), 234 (100), 219 (1). HR–
MS (EI–MS) m/z calcd. for C21H20BrNO, 381.0735; found,
381.0733.
Reaction time: 8 h. Yield: 80%. Pale Yellow solid, mp 84 °
C (heptane). IR (KBr, cm−1): ṽ 3376 (N–H, O–H), 1268
1
(C–N), 1038 (C–O). H NMR (400 MHz, CDCl3): δ 8.22
(br d, J = 8.4 Hz, 1H, H–11), 7.75 (dd, J = 7.7, 1.2 Hz, 1H,
H–6’), 7.66 (br d, J = 8.4 Hz, 1H, H–8), 7.66 (s, 1H, H–6),
7.53 (t, J = 8.4 Hz, 1H, H–9), 7.43 (t, J = 8.4 Hz, 1H, H–
10), 7.41 (br d, J = 7.7 Hz, 1H, H–3’), 7.40 (t, J = 7.7 Hz,
1H, H–5’), 7.31 (td, J = 7.7, 1.2 Hz, 1H, H–4’), 4.55 (dd, J
= 11.3, 1.6 Hz, 1H, Hax–2), 4.23 (br s, 1H, NH), 3.99 (tdd,
J = 9.8, 3.5, 1.8 Hz, 1H, Hax–4), 3.27 (dd, J = 13.6, 9.8 Hz,
1H, Hax–5), 3.14 (br d, J = 13.6 Hz, 1H, Heq–5), 2.27 (ddt,
J = 12.7, 3.5, 1.6 Hz, 1H, Heq–3), 2.18 (ddd, J = 12.7, 11.3,
9.8 Hz, 1H, Hax–3), 2.04 (br s, 1H, 4–OH). 13C NMR (100
MHz, CDCl3): δ 144.0 (C11b), 141.6 (C1’), 133.5 (C6),
132.8 (C2’), 131.6 (C7a), 129.2 (C4’), 128.0 (C3’, C5’),
127.9 (C8), 127.8 (C11a), 127.2 (C10), 126.8 (C6’), 126.5
(C9), 125.4 (C5a), 120.7 (C11), 114.9 (C7), 69.6 (C4), 56.5
(C2), 46.0 (C3), 44.3 (C5). GC–MS (EI, 70 eV): m/z (%)
401 (M+•, 79Br, 35Cl, 98), 357 (30), 290 (3), 246 (11), 234
(100), 219 (2). HR–MS (EI–MS) m/z calcd. for
C20H17BrClNO, 401.0180; found, 401.0182.
7–Bromo–cis–2–(3–methoxyphenyl)–2,3,4,5–tetrahydro–
1H–naphtho[1,2–b]azepin–4–ol (11d)
7–Bromo–cis–2–(4–chlorophenyl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (11f)
Reaction time: 12 h. Yield: 77%. Viscous yellow oil. IR
Reaction time: 12 h. Yield: 75%. Yellow solid, mp 109 °C
(heptane). IR (KBr, cm−1): ṽ 3354 (N–H, O–H), 1267 (C–
N), 1013 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.22 (br d,
J = 8.3 Hz, 1H, H–11), 7.64 (s, 1H, H–6), 7.58 (br d, J =
8.3 Hz, 1H, H–8), 7.53 (t, J = 8.3 Hz, 1H, H–9), 7.45 (t, J
= 8.3 Hz, 1H, H–10), 7.40–7.42 (m, 4H, H–2’, H–3’, H–5’,
H–6’), 4.31 (br s, 1H, NH), 3.95–3.99 (m, 1H, Hax–2),
3.87–3.94 (m, 1H, Hax–4), 3.25 (dd, J = 13.5, 9.9 Hz, 1H,
Hax–5), 2.61 (br d, J = 13.5 Hz, 1H, Heq–5), 2.17–2.22 (m,
2H, Hax–3, Heq–3), 2.05 (br s, 1H, 4–OH). 13C NMR (100
MHz, CDCl3): δ 143.8 (C11b), 142.7 (C1’), 134.0 (C4’),
133.5 (C6), 131.6 (C7a), 129.5 (C3’, C5’), 128.2 (C2’,
C6’), 128.1 (C8), 127.7 (C11a), 126.7 (C10), 126.6 (C9),
125.5 (C5a), 120.3 (C11), 115.1 (C7), 69.7 (C4), 60.6 (C2),
(liquid film, cm−1): ṽ 3382 (N–H, O–H), 1265 (C–N), 1038
1
(C–O). H NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 8.2,
1.1 Hz, 1H, H–11), 7.65 (s, 1H, H–6), 7.64 (dd, J = 8.2, 0.7
Hz, 1H, H–8), 7.53 (td, J = 8.2, 0.7 Hz, 1H, H–9), 7.45 (td,
J = 8.2, 1.1 Hz, 1H, H–10), 7.35 (t, J = 8.1 Hz, 1H, H–5’),
7.06 (d, J = 2.4 Hz, 1H, H–2’), 7.05 (dd, J = 8.1, 0.7 Hz,
1H, H–6’), 6.92 (ddd, J = 8.1, 2.4, 0.7 Hz, 1H, H–4’), 4.67
(br s, 1H, NH), 4.01 (dd, J = 10.0, 4.3 Hz, 1H, Hax–2), 3.93
(tdd, J = 9.9, 3.6, 2.3 Hz, 1H, Hax–4), 3.84 (s, 3H, 3’–
OCH3), 3.33 (dd, J = 13.5, 9.9 Hz, 1H, Hax–5), 3.12 (dt, J
= 13.5, 2.3 Hz, 1H, Heq–5), 2.29–2.33 (m, 2H, Hax–3, Heq–
3), 2.10 (br s, 1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ
160.3 (C3’), 145.4 (C1’), 143.2 (C11b), 133.4 (C6), 131.6
(C7a), 130.4 (C5’), 128.2 (C8), 127.7 (C11a), 126.8 (C10),
126.7 (C9), 125.7 (C5a), 120.6 (C11), 119.1 (C2’), 115.3
(C7), 113.8 (C4’), 112.3 (C6’), 69.6 (C4), 61.6 (C2), 55.6
(3’–OCH3), 46.9 (C3), 44.0 (C5). GC–MS (EI, 70 eV): m/z
(%) 397 (M+•, 79Br, 28), 353 (8), 290 (1), 246 (9), 234
(100), 219 (1).
47.3 (C3), 44.1 (C5). GC–MS (EI, 70 eV): m/z (%) 401 (M
+•
,
79Br, 35Cl, 20), 357 (9), 290 (1), 246 (6), 234 (100), 219
(1).
7–Bromo–cis–2–(2,4–dichlorophenyl)–2,3,4,5–tetrahydro–
1H–naphtho[1,2–b]azepin–4–ol (11g)
Reaction time: 12 h. Yield: 72%. Pale yellow solid, mp 80 °
C (heptane). IR (KBr, cm−1): ṽ 3354 (N–H, O–H), 1267
1
(C–N), 1040 (C–O). H NMR (400 MHz, CDCl3): δ 8.23
(dd, J = 8.4, 1.2 Hz, 1H, H–11), 7.72 (d, J = 8.4 Hz, 1H,

Medicinal Chemistry Research
H–6’), 7.68 (br d, J = 8.4 Hz, 1H, H–8), 7.65 (s, 1H, H–6),
7.55 (td, J = 8.4, 1.2 Hz, 1H, H–9), 7.47 (td, J = 8.4, 1.2
Hz, 1H, H–10), 7.47 (d, J = 2.1 Hz, 1H, H–3’), 7.36 (dd, J
= 8.4, 2.1 Hz, 1H, H–5’), 4.51 (dd, J = 10.2, 3.3 Hz, 1H,
Hax–2), 4.45 (br s, 1H, NH), 3.96 (tdd, J = 10.1, 4.6, 2.3 Hz,
1H, Hax–4), 3.34 (dd, J = 13.5, 10.1 Hz, 1H, Hax–5), 3.11
(br d, J = 13.5 Hz, 1H, Heq–5), 2.09–2.30 (m, 2H, Heq–3,
Hax–3), 2.07 (br s, 1H, 4–OH). 13C NMR (100 MHz,
CDCl3): δ 142.1 (C11b), 139.2 (C1’), 133.8 (C4’), 133.5
(C6), 133.0 (C2’), 131.6 (C7a), 129.9 (C3’), 128.8 (C6’),
128.3 (C5’), 128.1 (C8), 127.6 (C11a), 127.0 (C10), 126.9
(C9), 125.7 (C5a), 120.7 (C7, C11), 69.1 (C4), 56.8 (C2),
1H, Hax–4), 3.29 (dd, J = 13.6, 10.0 Hz, 1H, Hax–5), 3.11
(dt, J = 13.6, 2.0 Hz, 1H, Heq–5), 2.46 (ddt, J = 12.2, 4.1,
1.9 Hz, 1H, Heq–3), 2.30 (ddd, J = 12.2, 11.7, 10.0 Hz, 1H,
Hax–3), 1.96 (br s, 1H, 4–OH). 13C NMR (100 MHz,
CDCl3): δ 147.2 (C2’), 143.5 (C11b), 133.4 (C6), 131.5
(C7a), 128.0 (C8), 127.9 (C11a), 127.1 (C5’), 126.8 (C10),
126.7 (C9), 125.7 (C5a), 124.8 (C4’), 124.3 (C3´), 120.7
(C11), 115.2 (C7), 69.5 (C4), 55.7 (C2), 47.8 (C3), 43.9
(C5). GC–MS (EI, 70 eV): m/z (%) 373 (M+•, 79Br, 11), 329
(2), 290 (1), 246 (4), 234 (100), 219 (5). HR–MS (EI–MS)
m/z calcd. for C18H14BrNOS, 370.9976; found, 370.9979.
45.6 (C3), 44.0 (C5). GC–MS (EI, 70 eV): m/z (%) 437 (M
,
7–Bromo–cis–2–(5–methylthiophen–2–yl)–2,3,4,5–
tetrahydro–1H–naphtho[1,2–b]azepin–4–ol (12b)
+•
79Br, 35Cl, 14), 393 (10), 290 (1), 246 (8), 234 (100),
219 (1). HR–MS (EI–MS) m/z calcd. for C20H16BrCl2NO,
434.9795; found, 434.9792.
Reaction time: 2 h. Yield: 70%. Pale yellow solid, mp 53 °C
(heptane). IR (KBr, cm−1): ṽ 3364 (N–H, O–H), 1268 (C–
N), 1022 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.22 (dd, J
= 8.0, 1.3 Hz, 1H, H–11), 7.76 (dd, J = 8.0, 1.1 Hz, 1H, H–
8), 7.63 (s, 1H, H–6), 7.54 (td, J = 8.0, 1.1 Hz, 1H, H–9),
7.51 (td, J = 8.0, 1.1 Hz, 1H, H–10), 6.89 (d, J = 3.4 Hz,
1H, H–3’), 6.68 (dd, J = 3.4, 1.0 Hz, 1H, H–4’), 4.41 (br s,
1H, NH), 4.22 (dd, J = 11.6, 2.0 Hz, 1H, Hax–2), 3.91 (tdd,
J = 9.9, 4.0, 2.0 Hz, 1H, Hax–4), 3.26 (dd, J = 13.6, 9.9 Hz,
1H, Hax–5), 3.08 (dt, J = 13.6, 2.0 Hz, 1H, Heq–5), 2.42
(ddt, J = 12.6, 4.0, 2.0 Hz, 1H, Heq–3), 2.25 (ddd, J = 12.6,
11.6, 9.9 Hz, 1H, Hax–3), 2.53 (s, 3H, 5’–CH3), 2.03 (br s,
1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ 144.8 (C2’),
143.6 (C11b), 139.4 (C5’), 133.5 (C6), 131.6 (C7a), 128.1
(C8), 127.8 (C11a), 126.8 (C10), 126.7 (C9), 125.6 (C5a),
125.0 (C4’), 124.3 (C3’), 120.7 (C11), 115.0 (C7), 69.7
(C4), 56.1 (C2), 47.7 (C3), 43.9 (C5), 15.6 (5’–CH3). GC–
MS (EI, 70 eV): m/z (%) 387 (M+•, 79Br, 10), 343 (4), 290
(2), 246 (3), 234 (100), 219 (2). HR–MS (EI–MS) m/z
calcd. for C19H18BrNOS, 387.0305; found, 387.0292.
cis–2–(o–Tolyl)–2,3,4,5–tetrahydro–1H–naphtho[1,2–b]
azepin–4–ol (11h)
Reaction time: 12 h. Yield: 65%. Pale yellow solid, mp 116
°C (heptane). IR (KBr, cm−1): ṽ 3322 (N–H, O–H), 1278
1
(C–N), 1025 (C–O). H NMR (400 MHz, CDCl3): δ 7.83
(dd, J = 7.6, 1.1 Hz, 1H, H–11), 7.73 (d, J = 8.0 Hz, 1H,
H–6’), 7.62 (dd, J = 8.0, 1.0 Hz, 1H, H–8), 7.48 (d, J = 8.4
Hz, 1H, H–7), 7.40–7.42 (m, 2H, H–9, H–10), 7.35 (d, J =
8.4 Hz, 1H, H–6), 7.28–7.36 (m, 1H, H–5’), 7.25–7.28 (m,
2H, H–3’, H–4’), 4.37 (br s, 1H, NH), 4.27 (dd, J = 11.2,
2.0 Hz, 1H, Hax–2), 3.96 (tdd, J = 10.0, 4.4, 2.6 Hz, 1H,
Hax–4), 3.39 (dd, J = 13.2, 10.0 Hz, 1H, Hax–5), 3.20 (dt, J
= 13.2, 1.6 Hz, 1H, Heq–5), 2.19–2.32 (m, 2H, Hax–3, Heq–
3), 2.29 (s, 3H, 2’–CH3). 13C NMR (100 MHz, CDCl3): δ
143.9 (C11b), 142.5 (C1’), 134.8 (C2’), 133.6 (C7a), 131.0
(C3’), 130.1 (C6), 128.9 (C8), 127.8 (C4’), 127.1 (C11a),
126.3 (C6’), 125.9 (C5’), 125.8 (C10), 125.4 (C9), 124.5
(C5a), 122.0 (C7), 119.9 (C11), 70.1 (C4), 57.0 (C2), 46.7
(C3), 44.8 (C5), 19.6 (2’–CH3). GC–MS (EI, 70 eV): m/z
(%) 303 (M+•, 60), 259 (22), 168 (29), 156 (100), 141 (8).
HR–MS (EI–MS) m/z calcd. for C21H21NO, 303.1622;
found, 303.1623.
7–Bromo–cis–2–(3–methylthiophen–2–yl)–2,3,4,5–
tetrahydro–1H–naphtho[1,2–b]azepin–4–ol (12c)
Reaction time: 2 h. Yield: 85%. Yellow solid, mp 65 °C
(heptane). IR (KBr, cm−1): ṽ 3352 (N–H, O–H), 1269 (C–
N), 1039 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.23 (dd, J
= 8.4, 1.4 Hz, 1H, H–11), 7.66 (s, 1H, H–6), 7.65 (br d, J
= 8.4 Hz, 1H, H–8), 7.54 (td, J = 8.4, 1.1 Hz, 1H, H–9),
7.48 (td, J = 8.4, 1.4 Hz, 1H, H–10), 7.24 (d, J = 5.1 Hz,
1H, H–5’), 6.89 (d, J = 5.1 Hz, 1H, H–4’), 4.36 (br s, 1H,
NH), 4.34 (dd, J = 11.1, 2.5 Hz, 1H, Hax–2), 3.90–3.99 (m,
1H, Hax–4), 3.29 (dd, J = 13.5, 10.0 Hz, 1H, Hax–5), 3.12
(dt, J = 13.5, 2.0 Hz, 1H, Heq–5), 2.36 (ddt, J = 12.1, 3.5,
2.5 Hz, 1H, Heq–3), 2.29 (ddd, J = 12.1, 11.1, 10.0 Hz, 1H,
Hax–3), 2.20 (s, 3H, 3’–CH3), 1.93 (br s, 1H, 4–OH). 13C
NMR (100 MHz, CDCl3): δ 143.7 (C11b), 140.5 (C2’),
133.6 (C7a, C3’), 133.5 (C6), 130.3 (C5’), 128.3 (C8),
7–Bromo–cis–2–(thiophen–2–yl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (12a)
Reaction time: 3 h. Yield: 82%. Pale yellow solid, mp 66 °C
(heptane). IR (KBr, cm−1): ṽ 3349 (N–H, O–H), 1268 (C–
N), 1023 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J
= 8.4, 1.5 Hz, 1H, H–11), 7.75 (br d, J = 8.4 Hz, 1H, H–8),
7.66 (s, 1H, H–6), 7.56 (td, J = 8.4, 1.2 Hz, 1H, H–9), 7.51
(td, J = 8.4, 1.5 Hz, 1H, H–10), 7.34 (dd, J = 5.1, 1.1 Hz,
1H, H–5’), 7.14 (dd, J = 3.5, 1.1 Hz, 1H, H–3’), 7.07 (dd, J
= 5.1, 3.5 Hz, 1H, H–4’), 4.43 (br s, 1H, NH), 4.34 (dd, J
= 11.7, 1.9 Hz, 1H, Hax–2), 3.95 (tdd, J = 10.0, 4.1, 2.0 Hz,

Medicinal Chemistry Research
127.6 (C11a), 126.8 (C10), 126.6 (C9), 125.4 (C5a), 123.4
(C4’), 120.4 (C11), 115.0 (C7), 69.8 (C4), 54.3 (C2), 47.9
(C3), 44.1 (C5), 13.9 (3’–CH3). GC–MS (EI, 70 eV): m/z
(%) 387 (M+•, 79Br, 8), 343 (1), 290 (1), 246 (4), 234 (100),
219 (1).
cis–2–(3–Methylthiophen–2–yl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (12f)
Reaction time: 2 h. Yield: 80%. Yellow solid, mp 160 °C
(heptane). IR (KBr, cm−1): ṽ 3300 (N–H, O–H), 1273 (C–
N), 1032 (C–O). 1H NMR (400 MHz, CDCl3): δ 7.86 (dd, J
= 7.0, 2.8 Hz, 1H, H–11), 7.70 (dd, J = 7.0, 2.4 Hz, 1H, H–
8), 7.49 (br d, J = 8.4, 1H, H–7), 7.43–7.47 (m, 2H, H–9,
H–10), 7.36 (br d, J = 8.4, 1H, H–6), 6.90 (d, J = 3.2 Hz,
1H, H–5’), 6.69 (dd, J = 3.2, 0,8 Hz, 1H, H–4’), 4.40 (br s,
1H, NH), 4.38 (dd, J = 11.2, 2.4 Hz, 1H, Hax–2), 3.96–4.00
(m, 1H, Hax–4), 3.36 (dd, J = 13.6, 10.0 Hz, 1H, Hax–5),
3.19 (dt, J = 13.6, 2.4 Hz, 1H, Heq–5), 2.29–2.41 (m, 2H,
Hax–3, Heq–3), 2.23 (s, 3H, 3’–CH3), 2.24 (br s, 1H, 4–OH).
13C NMR (100 MHz, CDCl3): δ 144.0 (C11b), 141.1 (C2’),
133.8 (C7a), 133.7 (C3’), 130.4 (C5’), 130.3 (C6), 129.1
(C8), 126.6 (C11a), 126.2 (C10), 125.6 (C9), 124.7 (C5a),
123.5 (C4’), 122.2 (C7), 120.2 (C11), 70.1 (C4), 54.6 (C2),
48.4 (C3), 44.8 (C5), 14.4 (3’–CH3). GC–MS (EI, 70 eV):
m/z (%) 309 (M+•, 14), 265 (1), 212 (1), 168 (6), 156 (100),
141 (7). HR–MS (EI–MS) m/z calcd. for C19H19NOS,
309.1194; found, 309.1187.
cis–2–(Thiophen–2–yl)–2,3,4,5–tetrahydro–1H–naphtho
[1,2–b]azepin–4–ol (12d)
Reaction time: 2 h. Yield: 77%. Pale brown oil. IR (liquid
film, cm−1): ṽ 3357 (N–H, O–H), 1273 (C–N), 1025 (C–O).
1H NMR (400 MHz, CDCl3): δ 7.84 (dd, J = 7.4, 2.0 Hz,
1H, H–11), 7.75–7.77 (m, 1H, H–8), 7.44–7.50 (m, 2H, H–
9, H–10), 7.49 (br d, J = 8.0 Hz, 1H, H–7), 7.35 (br d, J =
8.0 Hz, 1H, H–6), 7.32 (dd, J = 5.1, 1.4 Hz, 1H, H–5’), 7.14
(dd, J = 3.5, 1.4 Hz, 1H, H–3’), 7.06 (dd, J = 5.1, 3.5 Hz,
1H, H–4’), 4.44 (br s, 1H, NH), 4.36 (dd, J = 11.6, 2.0 Hz,
1H, Hax–2), 3.96 (tdd, J = 10.0, 3.5, 1.8 Hz, 1H, Hax–4),
3.27 (dd, J = 13.6, 10.0 Hz, 1H, Hax–5), 3.17 (dt, J = 13.6,
1.8 Hz, 1H, Heq–5), 2.48 (ddt, J = 12.4, 4.0, 2.0 Hz, 1H,
Heq–3), 2.34 (ddd, J = 12.4, 11.6, 10.0 Hz, 1H, Hax–3), 2.16
(br s, 1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ 147.9
(C2’), 143.9 (C11b), 133.9 (C7a), 130.0 (C6), 129.1 (C8),
127.3 (C5’), 127.0 (C11a, C4’), 126.3 (C10), 125.7 (C9),
125.1 (C5a), 124.3 (C3’), 122.5 (C7), 120.6 (C11), 70.0
(C4), 56.3 (C2), 48.5 (C3), 44.7 (C5). GC–MS (EI, 70 eV):
m/z (%) 295 (M+•, 22), 251 (4), 212 (1), 168 (6), 156 (100),
141 (5).
7–Bromo–cis–2–(furan–2–yl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (13a)
Reaction time: 0.7 h. Yield: 72%. Yellow solid, mp 58 °C
(heptane). IR (KBr, cm−1): ṽ 3344 (N–H, O–H), 1271 (C–
N), 1015 (C–O). 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, J
= 7.0, 2.8 Hz, 1H, H–11), 7.93 (dd, J = 7.5, 1.9 Hz, 1H, H–
8), 7.64 (s, 1H, H–6), 7.52–7.60 (m, 2H, H–9, H–10), 7.51
(dd, J = 1.9, 0.7 Hz, 1H, H–5’), 6.42 (dd, J = 3.2, 1.9 Hz,
1H, H–4’), 6.34 (dd, J = 3.2, 0.8 Hz, 1H, H–3’), 4.73 (br s,
1H, NH), 4.13 (dd, J = 11.8, 2.0 Hz, 1H, Hax–2), 3.94 (tdd,
J = 9.8, 4.1, 2.0 Hz, 1H, Hax–4), 3.26 (dd, J = 13.5, 9.8 Hz,
1H, Hax–5), 3.08 (dt, J = 13.5, 2.0 Hz, 1H, Heq–5), 2.46
(ddt, J = 12.7, 4.1, 2.0 Hz, 1H, Heq–3), 2.22 (ddd, J = 12.7,
11.8, 9.8 Hz, 1H, Hax–3), 2.01 (br s, 1H, 4–OH). 13C NMR
(100 MHz, CDCl3): δ 155.9 (C2’), 143.4 (C11b), 142.4
(C5’), 133.5 (C6), 131.7 (C7a), 128.1 (C11a), 128.0 (C8),
126.8 (C10), 126.7 (C9), 126.0 (C5a), 120.7 (C11), 115.3
(C7), 110.8 (C4’), 106.0 (C3’), 69.3 (C4), 53.7 (C2), 44.0
(C3), 43.4 (C5). GC–MS (EI, 70 eV): m/z (%) 357 (M+•,
79Br, 20), 313 (5), 290 (1), 246 (4), 234 (100), 219 (3).
cis–2–(5–Methylthiophen–2–yl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (12e)
Reaction time: 2 h. Yield: 79%. Viscous brown oil. IR
(liquid film, cm−1): ṽ 3359 (N–H, O–H), 1276 (C–N), 1022
1
(C–O). H NMR (400 MHz, CDCl3): δ 7.83 (dd, J = 7.0,
2.6 Hz, 1H, H–11), 7.78 (dd, J = 7.2, 2.0 Hz, 1H, H–8),
7.42–7.48 (m, 2H, H–9, H–10), 7.46 (br d, J = 8.4 Hz, 1H,
H–7), 7.32 (br d, J = 8.4 Hz, 1H, H–6), 7.26 (d, J = 5.2 Hz,
1H, H–3’), 6.92 (d, J = 5.2 Hz, 1H, H–4’), 4.44 (br s, 1H,
NH), 4.23 (dd, J = 11.6, 2.0 Hz, 1H, Hax–2), 3.93 (tdd, J =
10.0, 4.0, 2.0 Hz, 1H, Hax–4), 3.31 (dd, J = 13.2, 10.0 Hz,
1H, Hax–5), 3.14 (dt, J = 13.2, 2.0 Hz, 1H, Heq–5), 2.54 (s,
3H, 5’–CH3), 2.42 (ddt, J = 12.4, 4.0, 2.0 Hz, 1H, Heq–3),
2.27 (ddd, J = 12.4, 11.6, 10.0 Hz, 1H, Hax–3), 2.08 (br s,
1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ 145.5 (C2’),
144.0 (C11b), 139.5 (C5’), 133.9 (C7a), 130.2 (C6), 129.1
(C8), 126.9 (C11a), 126.2 (C10), 125.7 (C9), 125.3 (C4’),
124.9 (C5a), 124.4 (C3’), 122.3 (C7), 120.5 (C11), 70.1
(C4), 56.5 (C2), 48.2 (C3), 44.7 (C5), 15.8 (5’–CH3). GC–
MS (EI, 70 eV): m/z (%) 309 (M+•, 26), 265 (5), 212 (1),
168 (7), 156 (100), 141 (4).
7–Bromo–cis–2–(5–methylfuran–2–yl)–2,3,4,5–tetrahydro–
1H–naphtho[1,2–b]azepin–4–ol (13b)
Reaction time: 1.5 h. Yield: 82%. Viscous yellow oil. IR
(liquid film, cm−1): ṽ 3351 (N–H, O–H), 1271 (C–N), 1023
1
(C–O). H NMR (400 MHz, CDCl3): δ 8.22 (dd, J = 7.2,
2.0 Hz, 1H, H–11), 7.90 (dd, J = 8.0, 2.2 Hz, 1H, H–8),
7.64 (s, 1H, H–6), 7.51–7.60 (m, 2H, H–9, H–10), 6.20 (d,

Medicinal Chemistry Research
J = 3.0 Hz, 1H, H–3’), 5.99 (dd, J = 3.0, 0.9 Hz, 1H, H–4’),
4.70 (br s, 1H, NH), 4.07 (dd, J = 11.5, 2.0 Hz, 1H, Hax–2),
3.93 (tdd, J = 9.8, 4.0, 2.0 Hz, 1H, Hax–4), 3.25 (dd, J =
13.6, 9.8 Hz, 1H, Hax–5), 3.08 (dt, J = 13.6, 2.0 Hz, 1H,
Heq–5), 2.42 (ddt, J = 12.4, 4.0, 2.0 Hz, 1H, Heq–3), 2.37 (s,
3H, 5’–CH3), 2.21 (ddd, J = 12.4, 11.5, 9.8 Hz, 1H, Hax–3),
2.02 (br s, 1H, 4–OH). 13C NMR (100 MHz, CDCl3): δ
154.0 (C2’), 152.0 (C5’), 143.7 (C11b), 133.4 (C6), 131.6
(C7a), 128.0 (C8, C11a), 126.7 (C10), 126.6 (C9), 125.8
(C5a), 120.6 (C11), 115.0 (C7), 106.7 (C4’), 106.4 (C3’),
69.3 (C4), 53.9 (C2), 44.0 (C3), 43.4 (C5), 13.8 (5’–CH3).
GC–MS (EI, 70 eV): m/z (%) 371 (M+•, 79Br, 6), 327 (1),
290 (1), 246 (20), 234 (100), 219 (2).
1H, Heq–3), 2.24 (ddd, J = 12.1, 11.6, 9.9 Hz, 1H, Hax–3),
2.38 (s, 3H, 5’–CH3), 1.72 (br s, 1H, 4–OH). 13C NMR
(100 MHz, CDCl3): δ 151.9 (C5’), 154.4 (C2’), 143.7
(C11b), 133.5 (C7a), 129.9 (C6), 128.8 (C8), 126.7 (C11a),
125.8 (C10), 125.4 (C9), 124.9 (C5a), 122.0 (C7), 120.1
(C11), 106.4 (C3’), 105.5 (C4’), 69.7 (C4), 54.2 (C2), 44.4
(C3), 43.8 (C5), 14.1 (5’–CH3). GC–MS (EI, 70 eV): m/z
(%) 293 (M+•, 14), 249 (1), 212 (1), 168 (17), 156 (100),
141 (6).
QSAR analysis
Dataset and biological activity
cis–2–(Furan–2–yl)–2,3,4,5–tetrahydro–1H–naphtho[1,2–b]
azepin–4–ol (13c)
A total of 94 compounds, synthetized in our laboratory and
previously published (Palma et al. 2009a, 2009b; Gómez-
Ayala et al. 2010; Blanco et al. 2014), were included in the
dataset. Their anti-parasitic activity (IC50) evaluated against
the extracellular form of Trypanosoma cruzi and Leishma-
nia infantum parasites were converted to −log(IC50) and
used as depended variable in two different QSAR models.
The biological activity was evaluated by a single protocol at
the same laboratory in identical experimental conditions
(Gómez-Ayala et al. 2010; Blanco et al. 2014). The com-
pounds with IC50 identified in the Tables as >100 were
consider outlier to QSAR models, due they do not have a
defined IC50 value. The Tables 5S–10S in the Supplemen-
tary Material display a listing of the compounds used to
develop the QSAR models and their experimental biologi-
cal activities. The dataset was divided into training set and
validation set with a percentage of 80/20. To setup the sets
we used the k-means clustering technique (Mamy et al.
2015). Thus, we performed a rational sets partition avoiding
the random selection which is sometimes inappropriate
(Andrada et al. 2015).
Reaction time: 0.5 h. Yield: 77%. Viscous yellow oil. IR
(liquid film, cm−1): ṽ 3359 (N–H, O–H), 1285 (C–N), 1031
1
(C–O). H NMR (400 MHz, CDCl3): δ 7.94 (br d, J = 8.2
Hz, 1H, H–11), 7.84 (br d, J = 8.2 Hz, 1H, H–8), 7.53 (td, J
= 8.2, 1.2 Hz, 1H, H–9), 7.51 (dd, J = 1.9, 0.8 Hz, 1H, H–
5’), 7.47 (d, J = 8.3 Hz, 1H, H–7), 7.46 (td, J = 8.2, 1.3 Hz,
1H, H–10), 7.32 (d, J = 8.3 Hz, 1H, H–6), 6.43 (dd, J = 3.1,
1.9 Hz, 1H, H–4’), 6.35 (dd, J = 3.1, 0.8 Hz, 1H, H–3’),
4.75 (br s, 1H, NH), 4.15 (dd, J = 11.6, 2.0 Hz, 1H, Hax–2),
3.95 (tdd, J = 10.0, 4.0, 2.0 Hz, 1H, Hax–4), 3.31 (dd, J =
13.5, 10.0 Hz, 1H, Hax–5), 3.14 (dt, J = 13.5, 2.0 Hz, 1H,
Heq–5), 2.47 (ddt, J = 12.5, 4.0, 2.0 Hz, 1H, Heq–3), 2.25
(ddd, J = 12.5, 11.6, 10.0 Hz, 1H, Hax–3), 1.83 (br s, 1H, 4–
OH). 13C NMR (100 MHz, CDCl3): δ 156.4 (C2’), 143.7
(C11b), 142.1 (C5’), 133.7 (C7a), 129.8 (C6), 128.9 (C8),
126.9 (C11a), 126.2 (C10), 125.5 (C9), 125.0 (C5a), 122.2
(C7), 120.2 (C11), 110.7 (C4’), 105.8 (C3’), 69.5 (C4), 54.0
(C2), 44.6 (C3), 43.8 (C5). GC–MS (EI, 70 eV): m/z (%)
279 (M+•, 28), 235 (4), 212 (1), 168 (7), 156 (100), 141 (4).
HR–MS (EI–MS) m/z calcd. for C18H17NO2, 279.1246;
found, 279.1259.
Structure and molecular descriptors
The molecular structures were optimized with MOPAC
09 software (Stewart 2008) using the semiempirical PM6
(parametric method-6) method (Stewart 2007). Then, a set
of 1875 molecular descriptors of different types were
calculated by PaDEL software (Yap 2011). They inclu-
ded, acidic group count, ALOGP, APol, Aromatic atoms
count, Aromatic bonds count, Atom count, Autocorrela-
tion, Barysz matrix, Basic group count, BCUT, Bond
count, BPol, Burden modified eigenvalues, Carbon types,
Chi, Constitutional, Crippen logP and MR, Detour matrix,
Eccentric connectivity index, Atom type electro-
topological state, Extended topochemical atom, FMFDe-
scriptor, Fragment complexity, Hbond acceptor count,
Hbond donor count, Hybridization ratio, Information
content, Kappa shape indices, Largest chain, Largest Pi
cis–2–(5–Methylfuran–2–yl)–2,3,4,5–tetrahydro–1H–
naphtho[1,2–b]azepin–4–ol (13d)
Reaction time: 1.5 h. Yield: 78%. Viscous yellow oil. IR
(liquid film, cm−1): ṽ 3395 (N–H, O–H), 1276 (C–N), 1022
1
(C–O). H NMR (400 MHz, CDCl3): δ 7.92 (br d, J = 8.2
Hz, 1H, H–11), 7.84 (br d, J = 8.2 Hz, 1H, H–8), 7.50 (td, J
= 8.2, 1.0 Hz, 1H, H–9), 7.46 (d, J = 8.3 Hz, 1H, H–7),
7.45 (td, J = 8.2, 1.3 Hz, 1H, H–10), 7.31 (d, J = 8.3 Hz,
1H, H–6), 6.20 (d, J = 3.0 Hz, 1H, H–3’), 5.99 (dd, J = 3.0,
1.0 Hz, 1H, H–4’), 4.74 (br s, 1H, NH), 4.09 (dd, J = 11.6,
2.0 Hz, 1H, Hax–2), 3.94 (tdd, J = 9.9, 4.1, 2.2 Hz, 1H, Hax–
4), 3.30 (dd, J = 13.7, 9.9 Hz, 1H, Hax–5), 3.13 (dt, J =
13.7, 2.2 Hz, 1H, Heq–5), 2.43 (ddt, J = 12.1, 4.1, 2.2 Hz,

Medicinal Chemistry Research
system, Longest aliphatic chain, Mannhold LogP,
McGowan volume, Molecular distance edge, Molecular
linear free energy relation, Path counts, Petitjean number,
Ring count, Rotatable bonds count, Rule of five, Topo-
logical, Van der Waals volume, Vertex adjacency infor-
mation (magnitude), Walk counts, Weight, Weighted
path, Wiener numbers, XLogP, Zagreb index, 3D auto-
correlation, Charged partial surface area, Gravitational
index, Length over breadth, Moment of inertia, Petitjean
shape index, RDF, and WHIM. To avoid redundant
information, the descriptors with a correlation higher than
0.9 were removed from the total set.
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