Synthesis, structural elucidation and in vitro antiparasitic activity against Trypanosoma cruzi and Leishmania chagasi parasites of novel tetrahydro-1-benzazepine derivatives

Article abstract of DOI:10.1016/j.bmc.2010.05.018

Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1- benzazepine derivatives were synthesized and fully characterized. All compounds were tested in vitro against both Trypanosoma cruzi and Leishmania chagasi parasites and also for cyt

Full text of DOI:10.1016/j.bmc.2010.05.018

Bioorganic & Medicinal Chemistry 18 (2010) 4721–4739
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, structural elucidation and in vitro antiparasitic activity against
Trypanosoma cruzi and Leishmania chagasi parasites of novel
tetrahydro-1-benzazepine derivatives
b
b
c
Sandra Gómez-Ayala a, Julián A. Castrillón a, Alirio Palma a, , Sandra M. Leal , Patricia Escobar , Alí Bahsas
*
a Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander, A. A. 678, Bucaramanga, Santander, Colombia
b Centro de Investigación de Enfermedades Tropicales, Facultad de Salud, Escuela de Medicina, Departamento de Ciencias Básicas, Universidad Industrial de Santander,
A.A. 678, Bucaramanga, Santander, Colombia
c Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química, Universidad de los Andes, Mérida 5101, Venezuela
a r t i c l e i n f o
a b s t r a c t
Article history:
Forty six new 1,4-epoxy-2-exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepine derivatives were
synthesized and fully characterized. All compounds were tested in vitro against both Trypanosoma cruzi
and Leishmania chagasi parasites and also for cytotoxicity using Vero and THP-1 mammalian cell lines.
Many of the evaluated compounds showed remarkable activity against the epimastigote and intracellular
amastigote forms of T. cruzi, with IC50 values comparable with that of control drug nifurtimox, a nitrofu-
ran derivative currently used in the treatment of Chagas’ disease. Other derivatives were found to have
good activity against L. chagasi promastigotes, with low toxicity against the mammalian cells, but neither
of them was active on intracellular amastigotes of L. chagasi infecting THP-1 macrophages.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 2 February 2010
Revised 3 May 2010
Accepted 5 May 2010
Available online 7 May 2010
Keywords:
Trypanosoma cruzi
Leishmania chagasi
Antiparasitic activity
1,4-Epoxy-2-aryltetrahydro-1-benzazepines
2-Aryl-4-hydroxytetrahydro-1-
benzazepines
´
1. Introduction
countries. The treatments of Chagas disease are based on the use
of nifurtimox and benznidazole, compounds that are effective only
Leishmaniasis and Chagas’ disease are two parasitic infections
that constitute a serious public health problem in many tropical
and subtropical countries and that affect million people living
mainly in poor rural areas. Leishmaniasis is a group of diseases
caused by different species and subspecies of Leishmania, and
transmitted to humans by the phlebotomine sandfly belonged
from the Phlebotumus genus. It is estimated that 12 million people
are infected worldwide, particularly in the developing countries,
with 2 million new incidences occurring yearly.1 For many years,
the classic treatment of leishmaniasis has been based on the use
of pentavalent antimonial drugs. Amphotericin B, aminosidine
(paromomycin), pentamidine and miltefosine have been intro-
duced as second-line therapy.2–7
Chagas’ disease is caused by the infection with the Trypanosoma
cruzi parasite, and transmitted to humans through the feces of in-
fected triatomines insects or by blood transfusions, organ trans-
plantation, placental and orally routes. It is estimated that
between 18 and 20 million people are infected and around 40 mil-
lion people are at risk of infection in almost all Latin-American
in the acute phase of the disease.8
Unfortunately, the current treatments against these both para-
sitic diseases have a number of severe limitations such as paren-
teral administration, poor efficacy, toxic side effects, long course
of treatment, high treatment cost and loss of effectiveness due to
parasites resistance.8–15 Consequently, the development of novel,
safe and affordable compounds with potent anti-leishmanial and
anti-trypanocidal activities are urgently needed. It remains an
important challenge for synthetic and medicinal chemists.
In this context, tetrahydro-1-benzazepine ring system is an
important core in the structures of many biologically active
compounds.16–23 Different tetrahydro-1-benzazepines have been
reported as potent and orally active non-peptide arginine vaso-
pressin antagonists for both V1A and V2 receptors,24–28 potent
inhibitors of cyclin-dependent kinases,29–32 potent and orally
bioavailable growth hormone secretagogue,33–36 agents against
HIV-1 infection,37,38 and as antipsychotics.39,40 Moreover, some
tetrahydro-1-benzazepine derivatives such as paullones also
exhibited potent activity against the parasites which cause the
leishmaniasis and Chagas’ disease, especially as inhibitors of
CRK3 cyclin-dependent kinase of Leishmania mexicana promastig-
otes,41 and T. cruzi dihydrofolate reductase.42 This broad spectrum
* Corresponding author. Tel./fax: +57 7 6349069.
E-mail addresses: apalma@uis.edu.co, alirio.palma@gmail.com (A. Palma).
0968-0896/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2010.05.018

4722
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
well as the determination of their cytotoxicity against the Vero
OH
and THP-1 mammalian cell lines. The present work is a continua-
tion of a structural study of this class of 1,4-epoxybenzazepines
and tetrahydro-1-benzazepin-4-oles, which is itself part of a wider
program aimed at the identification of novel antiparasitic agents.
O
N
N
H
A
B
2. Results and discussion
2.1. Chemistry
R
R
Figure 1. General structures of the novel tetrahydronaphtho[1,2-b]azepine deriv-
atives with antiparasitic activity.
Target tetrahydro-1-benzazepine derivatives 6a–w and 7a–w
were prepared following a multi-step reaction pathways outlined
in Schemes 1–3, a synthetic strategy used previously in our labora-
tory.51,52 Initially, the required key intermediates, substituted orto-
allyl-N-benzylanilines 3a–w, were easily obtained either by
thermal induced aromatic amino-Claisen rearrangement of the
corresponding N-allyl-N-benzyl-anilines using our previous exper-
imental conditions with minor modifications (Scheme 1),51 or by
N-benzylation reaction of the appropriate ortho-allylanilines
(Scheme 2). Thus, N-allylation of N-benzylanilines 1a–n with ex-
cess of allyl bromide (2 equiv) in the presence of sodium carbonate
in dry acetone over reflux gave N-allyl derivatives 2a–n, which
were transformed into the ortho-allylanilines 3a–n by aromatic
amino-Claisen rearrangement using boron trifluoride diethyl ether
complex (BF3ꢀOEt2) as catalyst.53 Optimal conditions were deter-
mined to be excess of BF3ꢀOEt2 (1.2–1.5 equiv) and heating at
125–150 °C for periods ranging from 3 to 5 h. The yields of the
rearranged products 3a–n (67–88%) were not significantly affected
by the nature and positions of the substituents on both the ben-
zene rings of 2a–n precursors.
of biological activity has encouraged research regarding the meth-
odologies to synthesize many derivatives of this heterocyclic sys-
tem.43–49
In our group, we have been working on the synthesis and eval-
uation of novel tetrahydronaphtho[1,2-b]azepine derivatives with
the general structures A and B as antiparasitics (Figure 1).50 We no-
ticed that many of these compounds were active against the epi-
mastigote and promastigote forms of T. cruzi and L. chagasi
parasites, respectively, with IC50 values between 0.50 and
38.77
lM. Three of these compounds were also active against the
intracellular amastigotes of T. cruzi with IC50 values between 9.89
and 18.35 lM, and with slight or without toxicity on Vero mam-
malian cells.50
Encouraged by such positive results, we focused on the replace-
ment of naphthalene ring of compounds A and B by an isostere
benzene ring with the aim of synthesizing new analogues with
comparable or better antiparasitic activity. The purpose of this pa-
per is to report the synthesis, the spectroscopic characterization,
and the antiparasitic activity of two new series of 1,4-epoxy-2-
exo-aryl- and cis-2-aryl-4-hydroxytetrahydro-1-benzazepines, as
However, we found that in the conditions employed for 2a–n,
the amino-Claisen rearrangement of N-allyl-N-benzylanilines
HA
R
R
R
HB
R2
R1
R2
R1
ii
R2
R1
i
N
H
N
N
H
2a-n
1a-n
3a-n
a : R = R1 = R2 = H; b : R = OCF3, R1 = R2 = H; c : R = Br, R1 = R2 = H; d : R = Cl, R1 = R2 = H;
e : R = F, R1 = R2 = H; f : R = R2 = H, R1 = Cl; g : R = R2 = H, R1 = F; h : R = R1 = H, R2 = OCH3;
i : R = R1 = H, R2 = CH3; j : R = R1 = H, R2 = Cl; k : R = R1 = Me, R2 = H; l : R = R1 = Cl, R2 = H;
m : R = Cl, R1 = Br, R2 = H; n : R = F, R1 = Cl, R2 = H
Scheme 1. Preparation of substituted 2-allyl-N-benzylanilines 3a–n. Reagents and conditions: (i) allyl bromide (0.02 mol), Na2CO3 (0.03 mol), dry acetone, reflux, 4–7 h; (ii)
BF3ꢀOEt2 (0.012–0.015 equiv), 125–150 °C, 3–5 h.
R3
R
R3
R
Cl
R
i
R4
5a-d
N
H
H
ii
N
NH2
R4
4a-c
1o-q
3o-w
o : R = R4 = H, R3 = Cl; p : R = R4 = H, R3 = F; q : R = Me, R3 = Cl, R4 = H; r : R = R3 = Cl, R4 = H;
s : R = Cl, R3 = F, R4 = H; t : R = H, R3 = R4 = Cl; u : R = H, R3 = Cl, R4 = F; v : R = R3 = R4 = Cl;
w : R = R3 = Cl, R4 = F
Scheme 2. Preparation of substituted 2-allyl-N-benzylanilines 3o–w. Reagents and reaction conditions: (i) BF3ꢀOEt2 (0.015 equiv), 130–140 °C, 4–6 h. (ii) Benzyl chloride 5a–
d (0.011 mol), Na2CO3 (0.025 mol), DMF, 0 to 25 °C, 3–4 h.

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4723
R
-
O
R
R
R3
N
R3
O
N
R3
R2
R1
+
ii
i
R2
R1
N
H
R4
R2
R4
R4
R1
3a-w
6a-w
OH
R
iii
R3
N
R2
R1
H
R4
7a-w
Scheme 3. Preparation of target compounds 6a–w and 7a–w. Reagents and reaction conditions: (i) Na2WO4ꢀ2H2O (8–10 mol %), 30% H2O2 (0.03 mol), MeOH, 0–25 °C, 36–
72 h; (ii) toluene, 70–90 °C, 3–7 h; (iii) Zn (0.06–0.08 mol), 80% CH3CO2H (excess), 70–90 °C, 4–12 h. or Zn (0.08 mol), glacial CH3CO2H (excess), 37% HCl (0.04 mol), rt, 10–
14 h.
substituted at the ortho-positions of the benzyl fragment with
chlorine and/or fluorine atoms take place with formation of a very
complex mixture of products. As was evidenced by TLC, neither of
them was formed in quantities justifying their isolation and
identification.
In the light of these results, we planned to synthesize the other
key intermediates 3o–w through the alternative route depicted in
Scheme 2, starting from the corresponding substituted mono N-
allylanilines 1o–q. This way, the amino-Claisen rearrangement of
1o–q, followed by treatment of the resultant ortho-allylanilines
4a–c with equimolar amounts of ortho-substituted benzyl chlo-
rides 5a–d at 0 °C to room temperature in dry N,N-dimethylform-
amide (DMF) and in the presence of sodium carbonate provided
the desired intermediates 3o–w in good to excellent yields
(73–84%).
(Scheme 3). Thus, selective oxidation of ortho-allyl-N-benzyl-ani-
lines 3 with 3 fold-excess of hydrogen peroxide (30% H2O2) in
the presence of catalytic amounts of sodium tungstate
(8–10 mol %, Na2WO4ꢀ2H2O)54,55 in methanol at 0 °C to room tem-
perature, and subsequent thermal induced intramolecular 1,3-
dipolar cycloaddition of the generated nitrones gave the expected
1,4-epoxy-2-aryltetrahydro-1-benzazepines 6 in moderate to good
yields (55–76%).
The structures and stereochemistry of all the obtained
1,4-epoxy-cycloadducts 6a–w were determined by means of one
and two dimensional NMR spectroscopy. The assignments of all
the signals to individual H- and C-atoms (see Section 4) have been
made from their chemical shift values, coupling constants, and
confirmed on the basis of COSY, HSQC and HMBC spectra as well
as by comparing with the reference spectra of previously reported
analogues.51 The data derived from these experiments along with
the coupling constants values of the azepinic protons were used
to identify the isolated 1,4-epoxy-cycloadducts as the exo-isomer
Having in hand the required precursors 3, we then turned our
attention to the synthesis of the target 1,4-epoxy-cycloadducts 6
and their reduced 2-aryltetrahydro-1-benzazepin-4-oles
7
Figure 2. X-ray crystal structure of 7-chloro-1,4-epoxy-2-exo-(40-chlorophenyl)-2,3,4,5-tetrahydro-1(1H)-benzazepine 6l and 7-chloro-1,4-epoxy-2-exo-(20-chlorophenyl)-
2,3,4,5-tetrahydro-1(1H)-benzazepine 6r (ORTEP views).56

4724
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
in all the cases. Furthermore, single crystal X-ray diffraction of 1,4-
epoxy-cycloadducts 6k, 6l, 6o, 6r, 6u and 6w (each recrystallized
from heptane) unambiguously confirmed the stereochemical
assignment for these compounds.56,57 The single crystal X-ray struc-
ture of 1,4-epoxy-cycloadducts 6l and 6r are shown in Figure 2.
Finally, the compounds 6 were readily converted into the
corresponding 2-aryl-4-hydroxytetrahydro-1-benzazepines 7 as
exclusively cis diastereoisomers, by reductive cleavage of the N–
O bond with zinc powder in acetic acid at 70–90 °C (for compounds
6a–s) or with zinc powder and hydrochloric acid in glacial acetic
acid at room temperature (for compounds 6t–w). After completion
of the reactions, usually in 4–14 h, the amino-alcohols 7a–w were
isolated by silica gel column chromatography in excellent yields
(76–93%) as high-viscosity yellow oils or crystalline substances.
The structures and stereochemistry of these novel compounds
were determined by 1H NMR and 13C NMR spectroscopy in CDCl3
solution, and all the signals for each individual H- and C-atoms
(see Section 4) were also unambiguously assigned on the basis of
their COSY, HSQC and HMBC spectra as well as by comparing with
the reference spectra of previously reported analogues.51 The cis
stereochemistry at the stereogenic centers 2-C and 4-C of the tet-
rahydroazepine ring was established based on its 2D-NOESY spec-
tra, in which the tertiary proton 2-H at 3.86–5.06 ppm
demonstrates unambiguous NOE cross peak with the stereogenic
4-H proton at 3.76–4.03 ppm, indicating that both tertiary protons
are oriented in the same side of the heterocyclic ring. Conse-
quently, the 2-phenyl (aryl) group is oriented equatorially, since
the proton 2-H appears as a doublets of doublets (dd) with
J1 ꢁ 11 Hz and J2 ꢁ 2 Hz and therefore having exactly one trans-ax-
ial and one cis-equatorial coupling partners, namely 3-Hax and
3-Heq. The 4-hydroxy group is also oriented equatorially, since pro-
ton 4-H appears as triplets of doublets of doublets (tdd) with
J1 ꢁ 11 Hz, J2 ꢁ 4 Hz and J3 ꢁ 2 Hz and therefore having two
trans-axial coupling partners (3-Hax and 5-Hax) and two cis-equato-
rial coupling partners (3-Heq and 5-Heq). The data derived from
NOESY experiments along with the coupling constants values of
Table 1
In vitro antiparasitic activity and cytotoxicity of 1,4-epoxy-2-exo-aryl- (6a–w) and cis-2-aryl-4-hydroxytetrahydro-1-benzazepines 7a–w against T. cruzi and Vero cells
Compd
R
R1
R2
R3
R4
lM
Epimastigotes
IC50/IC90
Intracellular amastigotes
Vero cells
CC50/CC90
SI
IC50/IC90
SI
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
H
H
H
H
H
H
Cl
F
H
H
H
H
H
H
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
>100/>100
26.94/>100
23.4/>100
>3
>100/>100
>100/>100
56.38/43.58
>100/>100
>100/>100
45.37/66.84
>100/>100
>100/>100
>100/>100
>100/>100
45.28/90.03
>100/>100
60.62/>95.42
40.16/103.61
>100/>100
58.58/96.35
51.94/>100
>100/>100
>100/>100
>100/>100
>100/>100
>98.23/>98.23
>100/>100
>100/>100
>100/>100
97.78/99.36
>100/>100
>100/>100
41.82/>100
>100/>100
>100/>100
97.97/>100
>100/>100
50.53/>100
>100/>100
>94.87/>94.87
>100/>100
>100/>100
>100/>100
45.8/73.56
>100/>36.15
>38.13/>38.13
69.92/>100
>100/>100
>32.55 />32.55
>34.15/>34.15
2.3/9.06
>3
>3
>5
>3
>3
>6
>3
>3
>3
>3
4.60
>3
>4
>7
>1
>5
0.96
>1
>1
>3
>3
>0.58
>3
>3
>1
0.43
>2
>3
>7
>3
>3
>3
>3
>6
>0.8
>0.6
>1.9
>3
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
208.3/>300
>300/>300
>300/>286.54
>300/>300
110.89/>300
>300/>300
50.23/>300
108.64/>300
123.19/>300
>300/>300
>300/>300
56.99/>294.99
>300/>300
>300/>300
123.55/262.64
42.14/>300
190.89/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
295.36/>300
>300/>300
76.6/>300
OCF3
Br
Cl
F
H
H
H
H
H
Me
Cl
Cl
F
H
H
Me
Cl
Cl
H
>11
>12
>33
>39
>8
>3
>3
>4
>6
8.97
>20
>10
>8
5.71
>3
3.51
6.17
6.51
>3
>17
>0.56
>6
9.0/35.3
7.68/54.13
34.23/89.38
>100/>100
>100/>100
76.73/>100
45.82/>100
23.23/85.42
14.98/>100
30.12/>100
35.39/85.76
19.4/57.77
>100/>100
14.28/30.45
17.6/43.9
18.92/38.1
>100/>100
17.68/>100
>100/>100
48.08/>100
31.82/>100
26.59/60.35
15.71/57.41
49.58/>100
12.37/>100
65.44/>100
26.37/57.56
30.06/70.19
15.64/54.87
19.62/>100
6.1/35.33
16.45/29.7
27.21/54.36
45.93/>100
49.73/>100
62.97/>100
22.43/67.19
15.34/35.73
17.31/79.94
48.88/>100
>100/>100
14.84/53.02
14.46/34.76
2.33/23.41
H
H
H
Me
Cl
Br
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
H
H
H
Me
Cl
Br
Cl
H
H
H
H
H
H
H
H
H
Cl
Cl
F
6s
6t
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
6u
6v
6w
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
Nfx
H
Cl
Cl
H
OCF3
Br
Cl
F
H
H
H
H
Cl
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
>9
4.64
2.68
3.85
>24
>4
>11
>10
>19
15.05
>49
4.65
2.12
4.21
>6
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
Cl
F
H
H
Me
Cl
Cl
H
H
Cl
Cl
57.69/163.9
193.8/>300
>300/>300
>300/>300
82.37/>300
106.01/>300
182.39/>300
>300/>300
>300/>300
49.91/176.01
92.02/182.44
61.42/>300
>4
>3
1.8
>1
>4
>4
>3
>1
>2
26.70
Cl
Cl
F
Cl
Cl
Cl
Cl
3.67
6.91
10.53
>6
>3
Cl
F
3.36
6.36
26.36
SI: selectivity index; IC: inhibitory concentration; CC: cytotoxic concentration; Nfx: nifurtimox.

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4725
the azepinic protons were used to identify the isolated 2-aryltetra-
hydro-1-benzazepin-4-oles as the cis-isomer with the tetra-
hydroazepine ring in the chair conformation and consequently
proves that their precursors 6 are exo adducts.
the concentration required to kill 50% and 90% of the mammalian
cells (CC50 and CC90). The results are summarized in Tables 1 and
2, along with the analogous data for the reference drugs nifurtimox
and amphotericin B and the data of the selectivity index (SI), which
were obtained by dividing the activity of one compound on mam-
malian cells CC50 by the activity of the same compound (IC50) on
2.2. Biological activity
parasites. In this work, compounds with IC50 >50
IC90 >100 M were classified as inactive, and compounds with
CC50 <100 M were classified as toxic for the mammalian cell lines.
The analysis of the antiparasitic activities of the 1,4-epoxy-cyc-
loadducts 6 and their corresponding amino-alcohols 7 did not
showed a statistical difference between them (p >0.05). The results
also clearly indicate that the substitution pattern on both benzene
rings (benzene of the 1-benzazepine skeleton and benzene as sub-
stituent at the C-2 position) markedly influenced the antiparasitic
activity as well as the cytotoxicity of 6 and 7.
lM and
All the target compounds described in this work were initially
synthesized and further evaluated in vitro assays against the free
and intracellular forms of T. cruzi and L. chagasi parasites as well
as on Vero epithelial cells (the host cells of T. cruzi) and THP-1
transformed human macrophages (the host cells of L. chagasi). In
order to study the effects of structural modifications on inhibitory
activity and cytotoxicity, substituents with different electronic
characteristics have been introduced at the C-7 (para), C-40
(para0-), C-30 (meta0-), C-20 (ortho0-), and C-60 (ortho00-) positions of
the target compounds. The antiparasitic activity and cytotoxicity
of the compounds evaluated were expressed as the concentration
required to inhibit 50% and 90% of parasites (IC50 and IC90), and
l
l
As can be seen from the data in Tables 1 and 2, many of the
tested compounds exhibited remarkable inhibitory activity against
the epimastigote and promastigote forms of T. cruzi and L. chagasi
Table 2
In vitro antiparasitic activity and cytotoxicity of 1,4-epoxy-2-exo-aryl- (6a–w) and cis-2-aryl-4-hydroxytetrahydro-1-benzazepines 7a–w against L. chagasi and THP-1 cells
Compd
R
R1
R2
R3
R4
lM
Promastigotes
IC50/IC90
Intracellular amastigotes
THP-1 cells
CC50/CC90
SI
IC50/IC90
SI
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
H
H
H
H
H
H
Cl
F
H
H
H
H
H
H
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
>100/>100
15.73/34.73
25.52/54.88
40.1/55.44
47.55/>100
38.33/67.54
>100/>100
54.73/>100
52/>100
49.14/70.72
98.96/>100
33.24/50.09
32.52/42.21
35.18/41.79
25.08/>100
40.53/47
41.74/49.46
51.27/>100
23.84/67.28
>100/>100
>100/>100
71.0/>100
>100/>100
>100/>100
35.5/43.21
45.04/>100
22.12/90.56
>100/>100
67.89/>100
>100/>100
97.09/>100
>100/>100
41.23/47.02
>100/>100
14.1/41
>3
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>95.42 />95.42
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>98.23/>98.23
>100/>100
>100/>100
>100/>100
97.65/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>94.87/>94.87
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>100/>100
>32.55/>32.55
73.22/>100
0.08/0.14
>3
>3
>3
>3
>3
>3
>1
>3
>3
>1
>0.74
>3
>2
>3
>1
>2
>0.66
>3
>3
>3
>3
>3
>3
>3
>1
>1
>1
>3
>1
>3
>3
>1
>1
>1
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
>300/>300
182.86/>300
>300/>300
>300/>300
133.98/>300
74.0/125.74
>300/>300
235.54/>286.54
>300/>300
109.67/211.45
199.99/>300
66.75/108.63
>300/>300
>300/>300
>300/>300
>300/>300
>294.99/>294.99
>300/>300
OCF3
Br
Cl
F
H
H
H
H
H
Me
Cl
Cl
F
H
H
Me
Cl
Cl
H
>19
>11
>7
>6
>7
>1
>5
>5
2.73
0.75
>9
7.24
>8
4.37
4.93
1.6
>5
>12
>3
>3
4.15
>3
H
H
H
Me
Cl
Br
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
H
H
H
Me
Cl
Br
Cl
H
H
H
H
H
H
H
H
H
Cl
Cl
F
6s
6t
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
6u
6v
6w
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
7v
7w
AmB
H
Cl
Cl
H
OCF3
Br
Cl
F
H
H
H
H
Cl
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
>3
>300/>300
2.92
4.10
8.50
>3
1.68
>3
103.59/>300
184.52/>300
188.07/>300
>300/>300
113.85/>300
>300/>300
H
OMe
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
>3
>1
>300/>300
176.38/>300
166.58/>300
171.66/>300
49.21/>300
153.11/279.77
100.32/>300
>300/>300
H
4.04
>1
3.49
16.05
5.86
>3
>3
2.06
1.5
2.02
>3
>3
4.06
2.76
439.5
Me
Cl
Cl
F
H
H
Me
Cl
Cl
H
H
Cl
Cl
>0.49
>1.61
>1
>3
>3
>0.85
>0.75
>1
>3
>3
9.54/11.74
17.11/77.74
84.44/>100
>100/>100
41.34/49.35
50.22/>100
54.45/>100
>100/>100
>100/>100
14.66/30.29
39.75/78.51
0.02/0.02
>300/>300
Cl
Cl
F
Cl
Cl
Cl
Cl
85.19/>300
75.53/>300
110.21/273.12
>300/>300
>300/>300
Cl
F
>1
>1
109.87
59.59/>293.25
109.77/213.67
8.79/34.88
SI: selectivity index; IC: inhibitory concentration; CC: cytotoxic concentration; AmB: amphotericin B.

4726
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
parasites, respectively. On T. cruzi assays, nine 1,4-epoxy-cycload-
ducts (6d–f,k,n,o,q–s), with IC50 values of 7.68–35.39 M and IC90
values of 30.45–89.38 M, and thirteen amino-alcohols (7b,c,g–i,
k–m,q–s,v,w), with IC50 values of 6.10–30.06 M and IC90 values
of 29.70–79.94 M, were active against the epimastigote form of
T. cruzi, being the para,para0-dimethyl substituted amino-alcohol
7k, with IC50 = 6.10 M, the most active compound, followed by
1,4-epoxy-cycloadducts 6e and 6d, the para-fluoro and para-chloro
substituted, with IC50 = 7.68 and 9.00 M, respectively. Only three
compounds were active against the amastigote form of T. cruzi, the
para0-chloro-1,4-epoxy-cycloadduct 6f, the para-para0-dimethyl-
1,4-epoxy-cycloadduct 6k, and the para-methyl-ortho0-chloro
disubstituted amino-alcohol 7q, with IC50 values of 45.28–
Merck precoated Silica Gel (60 F254) plates and column chromatog-
raphy was accomplished on Merck Kieselgel 60 70–230 mesh
(ASTM). All the chromatographic solvent proportions were volume
to volume. Melting points were determined with a MEL-TEMP
1201D capillary apparatus and are uncorrected. IR spectra were re-
corded on a Nicolet Avatar 360-FTIR spectrometer and referenced
to polystyrene standard, using cells equipped with potassium bro-
mide windows. 1H and 13C NMR spectra were measured on a Bru-
ker AM-400 spectrometer, using CDCl3 as the solvent. Chemical
shifts (d) and coupling constants (J) values are reported in ppm
and hertz, respectively. Chemical shifts are relative to the solvent
peaks used as reference [CDCl3: dH = 7.26, and dC = 77.0]. A Hew-
lett–Packard (HP) 5890 A series II Gas Chromatograph interfaced
to a HP 5972 Mass Selective Detector with a HP MS ChemStation
Data system was used for MS identification. Elemental analyses
(C, H, N) were performed on a Perkin–Elmer 2400 Series II analyzer.
Compounds 2a,b,d,e,f,i, 3a,b,d,e,f,i, 6a,b,d,e,f,i, and 7a,b,d,e,f,i
were previously synthesized and characterized.51
l
l
l
l
l
l
45.80 lM and IC90 values of 66.84–90.03 lM. These three com-
pounds were also active against the epimastigote form of T. cruzi.
On L. chagasi assays, eleven 1,4-epoxy-cycloadducts (6b–d,f,j,l–
n,p,q,s), with IC50 values of 15.73–49.14
34.73–70.72 M, and nine amino-alcohols (7b,d,j,l–n,q,v,w), with
IC50 values of 9.54–41.34 M and IC90 values between 11.74 and
90.56
lM and IC90 values of
l
l
l
M, were active against the promastigote form of L. chagasi.
4.2. General procedure for the synthesis of N-allyl-N-benzylani-
lines 2a–n
In these series of compounds, the para-chloro-para0-bromo disub-
stituted amino-alcohol 7m displayed the most remarkable inhibi-
tory activity (IC50 = 9.54
7v with IC50 = 14.10 and 14.66
l
M), followed by amino-alcohols 7l and
M, respectively. We also found
To a stirred solution of N-benzylanilines 1a–n (0.01 mol) and
anhydrous sodium carbonate (0.03 mol) in dry acetone (50 mL)
was slowly added allyl bromide (0.02 mol). The reaction mixture
was then stirred at reflux for 4–7 h (TLC control). Each mixture
was filtered and the filtrate was concentrated under reduced
pressure. The remaining organic residue was purified by column
chromatography on silica gel using heptane–ethyl acetate (compo-
sitions ranged from 70:1 to 30:1 v/v) as eluent to give compounds
2a–n as low-viscosity colorless oils.
l
that none of the compounds evaluated was active against the intra-
cellular amastigote form of L. chagasi at any of the concentrations
tested (Table 2). It is also important to note that the 1,4-epoxy-cyc-
loadducts 6d,f,n,q,s, and the amino-alcohols 7b,l,m,q,v,w, proved
to have inhibitory properties against the epimastigote and promas-
tigote forms of both T. cruzi and L. chagasi parasites, respectively.
On mammalian cell assays, only eight compounds (6q,v and
7c,l,m,q,v,w) were toxics for the Vero cells, and six compounds
(6k,q and 7l,q,r,v) were also toxics for the THP-1 mammalian cells.
These results suggest that the para-para0-dimethyl, para-methyl-
ortho0-chloro- and para-ortho0-ortho00-trichloro substitution pat-
terns in the 6a-w series, as well as the para-bromo-, para-para0-di-
chloro-, para-chloro-para0-bromo-, para-methyl-ortho0-chloro-,
para-ortho0-dichloro-, para-ortho0-ortho00-trichloro- and para-
ortho0-dichloro-ortho00-fluoro substitution patterns increase their
cytotoxicity against both mammalian cell lines.
4.2.1. N-Allyl-N-benzylaniline (2a)
1.83 g (82%). IR (liquid film): v = 1643 (C@C allyl), 919 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.08 (2H, dd, J = 6.8,
.
2.0 Hz, –CH2–CH@), 4.61 (2H, s, –N–CH2–), 5.23–5.29 (2H, m,
@CH2), 5.91–6.00 (1H, m, –CH@), 6.76 (1H, t, J = 7.8 Hz, 4-H),
6.79 (2H, d, J = 8.0 Hz, 2-H, 6-H), 7.25 (2H, dd, J = 7.8, 0.8 Hz, 3-H,
5-H), 7.32 (3H, t, J = 7.6 Hz, 20-H, 40-H, 60-H), 7.38 (2H, t,
J = 7.6 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 53.1 (–CH2–
CH@), 54.1 (–N–CH2–), 112.5 (2-C, 6-C), 116.4 (@CH2), 116.6 (4-
0
0
0
0
´
C), 126.7 (2 -C, 4 -C, 6 -C), 129.2 (3-C, 5 -C), 129.3 (3-C, 5-C),
133.8 (–CH@), 139.1 (10-C), 149.1 (1-C). MS (EI): m/z (%) = 223
(51) [M+], 197 (2), 196 (11), 182 (3), 180 (8), 91 (100), 77 (32),
65 (15).
3. Conclusion
In an attempt to find novel antiparasitic agents, we have syn-
thesized and fully characterized two new series of 1,4-epoxy-2-
exo-aryl- (6a–w) and cis-2-aryl-4-hydroxytetrahydro-1-benzaze-
pine (7a–w) derivatives that showed relevant inhibitory activity
against the epimastigote and promastigote forms of T. cruzi and
L. chagasi parasites, respectively. Taking into account the inhibitory
activity against both the epimastigote and amastigote forms of T.
cruzi observed during the present study, compounds 6f, 6k and
7q revealed the most promising. However, considering the cyto-
toxic profile to Vero cells, only the para0-chloro-1,4-epoxy-cycload-
duct 6f as well as the para-para0-dimethyl-1,4-epoxy-cycloadduct
6k may serve as possible candidates for further structural modifi-
cations in order to improve their antitrypanosomal activity.
4.2.2. N-Allyl-N-benzyl-4-trifluoromethoxyaniline (2b)
2.46 g (80%). IR (liquid film): v = 1642 (C@C allyl), 919 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.04 (2H, d, J = 4.8 Hz,
.
–CH2–CH@), 4.57 (2H, s, –N–CH2–), 5.23–5.29 (2H, m, @CH2),
5.90–5.98 (1H, m, –CH@), 6.67 (2H, d, J = 9.2 Hz, 2-H, 6-H), 7.05
(2H, d, J = 9.2 Hz, 3-H, 5-H), 7.26 (2H, d, J = 7.6 Hz, 20-H, 60-H),
7.28 (1H, t, J = 7.2 Hz, 40-H), 7.36 (2H, t, J = 7.2 Hz, 30-H, 50-H). 13C
NMR (100 MHz, CDCl3): d = 53.6 (–CH2–CH@), 54.5 (–N–CH2–),
112.9 (2-C, 6-C), 116.8 (@CH2), 118.4 (q, J = 250.0 Hz, 4-OCF3),
122.2 (3-C, 5-C), 126.7 (20-C, 60-C), 127.2 (40-C), 128.9 (30-C, 50-C),
133.3 (–CH@), 138.5 (10-C), 140.1 (4-C), 147.80 (1-C). MS (EI): m/
z (%) = 307 (38) [M+], 280 (3), 266 (2), 264 (4), 91 (100), 161 (5),
65 (16).
4. Experimental
4.1. Chemistry
4.2.3. N-Allyl-N-benzyl-4-bromoaniline (2c)
2.41 g (80%). IR (liquid film): v = 1642 (C@C allyl), 919 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.01 (2H, dd, J = 4.8,
.
4.1.1. General
All the reagents and solvents were purchased from commercial
suppliers (Aldrich, Merck), and used without further purification.
Analytical thin layer chromatography (TLC) was performed on
2.4 Hz, –CH2–CH@), 4.54 (2H, s, –N–CH2–), 5.18–5.24 (2H, m,
@CH2), 5.84–5.94 (1H, m, –CH@), 6.60 (2H, d, J = 8.8 Hz, 2-H,
6-H), 7.24 (2H, dd, J = 7.6, 2.2 Hz, 20-H, 60-H), 7.25 (2H, d,

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4727
J = 8.8 Hz, 3-H, 5-H), 7.27 (1H, td, J = 8.0, 2.2 Hz, 40-H), 7.35 (2H, t,
J = 7.6 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 53.5
(–CH2–CH@), 54.4 (–N–CH2–), 108.8 (4-C), 114.5 (2-C, 6-C), 116.8
(@CH2), 126.7 (3-C, 5-C), 127.2 (40-C), 128.8 (20-H, 60-H), 131.9
(30-H, 50-H), 133.2 (–CH@), 138.3 (10-C), 147.9 (1-C). MS (EI): m/z
(%) = 301 (79Br, 30) [M+], 260 (3), 258 (3), 130 (20), 155 (13), 91
(100), 76 (10).
J = 8.0 Hz, 4-H), 6.73 (2H, d, J = 8.4 Hz, 2-H, 6-H), 6.79 (1H, dd,
J = 7.8, 2.3 Hz, 40-H), 6.82 (1H, br s, 20-H), 6.85 (1H, d, J = 7.8 Hz,
60-H), 7.19 (2H, t, J = 8.0 Hz, 3-H, 5-H), 7.25 (1H, t, J = 7.8 Hz,
50-H). 13C NMR (100 MHz, CDCl3): d = 53.2 (–CH2–CH@), 54.2
(–N–CH2–), 55.3 (30-OCH3), 112.2 (20-C), 112.5 (40-C), 112.6 (2-C,
6-C), 116.5 (@CH2), 116.7 (4-C), 119.0 (60-C), 129.3 (3-C, 5-C),
129.8 (50-C), 133.8 (–CH@), 141.0 (10-C), 149.1 (1-C), 160.1 (30-C).
MS (EI): m/z (%) = 253 (66) [M+], 227 (3), 226 (10), 121 (100), 104
(20), 91 (23), 77 (30).
4.2.4. N-Allyl-N-benzyl-4-chloroaniline (2d)
2.00 g (78%). IR (liquid film): v = 1643 (C@C allyl), 921 (@C-H al-
lyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.01 (2H, dd, J = 6.0,
.
4.2.9. N-Allyl-N-(30-methylbenzyl)aniline (2i)
2.0 Hz, –CH2–CH@), 4.54 (2H, s, –N–CH2–), 5.18–5.23 (2H, m,
@CH2), 5.83–5.93 (1H, m, –CH@), 6.64 (2H, d, J = 8.8 Hz, 2-H,
6-H), 7.13 (2H, d, J = 8.8 Hz, 3-H, 5-H), 7.23 (2H, d, J = 7.6 Hz, 20-
H, 60-H), 7.26 (1H, d, J = 7.4 Hz, 40-H), 7.34 (2H, t, J = 7.4 Hz, 30-H,
50-H). 13C NMR (100 MHz, CDCl3): d = 53.5 (–CH2–CH@), 54.4
(–N–CH2–), 113.8 (2-C, 6-C), 116.7 (@CH2), 122.0 (4-C), 126.6 (20-
C, 60-C), 127.1 (40-C), 128.8 (30-C, 50-C), 129.0 (3-C, 5-C), 133.3
(–CH@), 138.5 (10-C), 147.6 (1-C). MS (EI): m/z (%) = 257 (35Cl, 42)
[M+], 230 (6), 216 (3), 214 (4), 91 (100), 111 (15), 65 (18).
1.66 g (70%). IR (liquid film): v = 1640 (C@C allyl), 918 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.43 (3H, s, 30-CH3),
.
4.11 (2H, dd, J = 6.0, 1.5 Hz, –CH2–CH@), 4.61 (2H, s, –N–CH2–),
5.27–5.32 (2H, m, @CH2), 5.94–6.03 (1H, m, –CH@), 6.79 (1H, t,
J = 8.4 Hz, 4-H), 6.82 (2H, d, J = 8.4 Hz, 2-H, 6-H), 7.15 (2H, d,
J = 8.0 Hz, 40-H, 60-H), 7.17 (1H, s, 20-H), 7.29 (2H, t, J = 8.4 Hz,
3-H, 5-H), 7.32 (1H, t, J = 8.0 Hz, 50-H). 13C NMR (100 MHz, CDCl3):
d = 21.6 (30-CH3), 53.1 (–CH2–CH@), 54.1 (–N–CH2–), 112.5 (2-C,
6-C), 116.4 (@CH2), 116.6 (4-C), 123.8 (60-C), 127.3 (20-C), 127.7
(40-C), 128.6 (50-C), 129.2 (3-C, 5-C), 133.8 (–CH@), 138.3 (30-C),
139.1 (10-C), 149.2 (1-C). MS (EI): m/z (%) = 237 (51) [M+], 210
(8), 196 (3), 194 (8), 105 (100), 77 (49), 51 (12).
4.2.5. N-Allyl-N-benzyl-4-fluoroaniline (2e)
1.95 g (81%). IR (liquid film): v = 1643 (C@C allyl), 920 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.01 (2H, dd, J = 6.4,
.
1.2 Hz, –CH2–CH@), 4.54 (2H, s, –N–CH2–), 5.19–5.26 (2H, m,
@CH2), 5.86–5.96 (1H, m, –CH@), 6.65–6.69 (2H, m, 2-H, 6-H),
6.90–6.94 (2H, m, 3-H, 5-H), 7.26 (2H, dd, J = 7.6, 1.2 Hz, 20-H, 60-
H), 7.28 (1H, t, J = 7.6 Hz, 40-H), 7.36 (2H, td, J = 7.6, 1.2 Hz, 30-H,
50-H). 13C NMR (100 MHz, CDCl3): d = 53.9 (–CH2–CH@), 54.9
(–N–CH2–), 113.8 (d, J = 10.0 Hz, 2-C, 6-C), 115.6 (d, J = 20.0 Hz,
3-C, 5-C), 116.6 (@CH2), 126.8 (20-C, 60-C), 127.0 (40-C), 128.7 (30-
C, 50-C), 133.8 (–CH@), 139.0 (10-C), 145.7 (1-C), 155.9 (d,
J = 230.0 Hz, 4-C). MS (EI): m/z (%) = 241 (44) [M+], 164 (12), 150
(80), 148 (24), 135 (23), 91 (100), 95 (3).
4.2.10. N-Allyl-N-(30-chlorobenzyl)aniline (2j)
2.19 g (85%). IR (liquid film): v = 1641 (C@C allyl), 921 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.07 (2H, dd, J = 5.8,
.
1.5 Hz, –CH2–CH@), 4.57 (2H, s, –N–CH2–), 5.23–5.28 (2H, m,
@CH2), 5.90–5.99 (1H, m, –CH@), 6.76 (2H, dd, J = 8.0, 2.0 Hz,
2-H, 6-H), 6.78 (1H, td, J = 8.0, 2.0 Hz, 4-H), 7.19 (1H, dd, J = 8.0,
2.0 Hz, 60-H), 7.26 (2H, t, J = 8.0 Hz, 3-H, 5-H), 7.28 (1H, d,
J = 8.0 Hz, 40-H), 7.29 (1H, t, J = 8.0 Hz, 50-H), 7.31 (1H, s, 20-H).
13C NMR (100 MHz, CDCl3): d = 53.3 (–CH2–CH@), 53.8 (–N–
CH2–), 112.6 (2-H, 6-C), 116.7 (@CH2), 117.1 (4-C), 124.8 (60-C),
126.8 (40-C), 127.2 (20-C), 129.3 (3-C, 5-C), 130.0 (50-C), 133.5 (–
CH@), 134.7 (30-C), 141.5 (10-C), 148.8 (1-C). MS (EI): m/z
(%) = 257 (35Cl, 63) [M+], 230 (22), 216 (6), 214 (8), 125 (100),
77 (68), 99 (3).
4.2.6. N-Allyl-N-(40-chlorobenzyl)aniline (2f)
2.14 g (83%). IR (liquid film): v = 1643 (C@C allyl), 920 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.07 (2H, dd, J = 5.0,
.
1.5 Hz, –CH2–CH@), 4.57 (2H, s, –N–CH2–), 5.23–5.30 (2H, m,
@CH2), 5.91–6.00 (1H, m, –CH@), 6.77 (2H, dd, J = 8.0, 2.0 Hz, 2-
H, 6-H), 6.81 (1H, t, J = 8.0 Hz, 4-H), 7.25 (2H, t, J = 8.0 Hz, 3-H, 5-
H), 7.29 (2H, d, J = 9.0 Hz, 20-H, 60-H), 7.35 (2H, d, J = 9.0 Hz, 30-H,
50-H). 13C NMR (100 MHz, CDCl3): d = 53.1 (–CH2–CH@), 53.4
(–N–CH2–), 112.5 (2-C, 6-C), 116.5 (@CH2), 116.8 (4-C), 128.0 (20-
C, 60-C), 128.7 (30-C, 50-C), 129.1 (3-C, 5-C), 132.4 (40-C), 133.5
(–CH@), 137.5 (10-C), 148.7 (1-C). MS (EI): m/z (%) = 257 (35Cl, 35)
[M+], 231 (2), 230 (8), 125 (100), 99 (3), 77 (33), 51 (10).
4.2.11. N-Allyl-N-(40-methylbenzyl)-4-methylaniline (2k)
2.13 g (90%). IR (liquid film): v = 1641 (C@C allyl), 917 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.35 (3H, s, 4-CH3),
.
2.44 (3H, s, 40-CH3), 4.07 (2H, d, J = 5.0 Hz, –CH2–CH@), 4.59 (2H,
s, –N–CH2–), 5.25–5.32 (2H, m, @CH2), 5.95–6.02 (1H, m, –CH@),
6.76 (2H, d, J = 8.0 Hz, 2-H, 6-H), 7.11 (2H, d, J = 8.0 Hz, 3-H, 5-H),
7.22 (2H, d, J = 8.0 Hz, 20-H, 60-H), 7.25 (2H, d, J = 8.0 Hz, 30-H,
13
50-H). C NMR (100 MHz, CDCl3): d = 20.3 (4-CH3), 21.2 (40-CH3),
53.3 (–N–CH2–), 54.1 (–CH2–CH@), 112.8 (2-C, 6-C), 116.3
(@CH2), 125.7 (4-C), 126.8 (20-C, 60-C), 129.3 (30-C, 50-C), 129.8
(3-C, 5-C), 134.1 (–CH@), 136.2 (10-C), 136.4 (40-C), 147.0 (1-C).
MS (EI): m/z (%) = 237 (63) [M+], 210 (13), 160 (17), 146 (9), 118
(21), 91 (100), 65 (22).
4.2.7. N-Allyl-N-(40-fluorobenzyl)aniline (2g)
1.86 g (77%). IR (liquid film): v = 1642 (C@C allyl), 924 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 4.03 (2H, d, J = 4.9 Hz,
.
–CH2–CH@), 4.54 (2H, s, –N–CH2–), 5.21–5.26 (2H, m, –CH2@),
5.89–5.96 (1H, m, –CH@), 6.75–6.77 (3H, m, 2-H, 4-H, 6-H), 7.04
(2H, tt, J = 8.7, 2.0 Hz, 30-H, 50-H), 7.21–7.28 (4H, m, 3-H, 5-H,
20-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 53.2 (CH2–CH@), 53.6
(–N–CH2–), 112.7 (2-C, 6-C), 115.5 (d, J = 21.2 Hz, 30-C, 50-C),
116.6 (@CH2), 116.9 (4-C), 128.3 (d, J = 10.0 Hz, 20-C, 60-C), 129.3
(3-C, 5-C), 133.7 (–CH@), 134.6 (10-C), 148.9 (1-C), 162.0 (d,
J = 243.1 Hz, 40-C). MS (EI): m/z (%) = 241 (37) [M+], 215 (2), 214
(6), 109 (100), 83 (11), 77 (22), 51 (5).
4.2.12. N-Allyl-N-(40-chlorobenzyl)-4-chloroaniline (2l)
2.42 g (83%). IR (liquid film): v = 1638 (C@C allyl), 922 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.99 (2H, dd, J = 5.6,
.
1.6 Hz, –CH2–CH@), 4.49 (2H, s, –N–CH2–), 5.17–5.24 (2H, m,
@CH2), 5.83–5.92 (1H, m, –CH@), 6.62 (2H, d, J = 9.2 Hz, 2-H, 6-
H), 7.14 (2H, d, J = 9.2 Hz, 3-H, 5-H), 7.17 (2H, d, J = 8.6 Hz, 20-H,
60-H), 7.31 (2H, d, J = 8.6 Hz, 30-H, 50-H). 13C NMR (100 MHz,
CDCl3): d = 53.5 (–CH2–CH@), 53.9 (–N–CH2–), 113.9 (2-C, 6-C),
116.9 (@CH2), 122.8 (4-C), 128.0 (20-C, 60-C), 128.9 (3-C, 5-C),
129.1 (30-C, 50-C), 132.8 (40-C), 133.1 (–CH@), 137.1 (10-C), 147.4
(1-C). MS (EI): m/z (%) = 291 (35Cl, 35) [M+], 264 (4), 250 (3), 248
(3), 125 (100), 111 (14), 99 (4).
4.2.8. N-Allyl-N-(30-methoxybenzyl)aniline (2h)
1.82 g (72%). IR (liquid film): v = 1641 (C@C allyl), 920 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.78 (3H, s, 30-OCH3),
.
4.02 (2H, d, J = 5.0 Hz, –CH2–CH@), 4.53 (2H, s, –N–CH2–),
5.18–5.23 (2H, m, @CH2), 5.86–5.95 (1H, m, –CH@), 6.70 (1H, t,

4728
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4.2.13. N-Allyl-N-(40-bromobenzyl)-4-chloroaniline (2m)
2.99 g (89%). IR (liquid film): v = 1641 (C@C allyl), 921 (@C–H
(100 MHz, CDCl3): d = 36.5 (–CH2–), 48.2 (–N–CH2–), 110.7 (6-C),
116.3 (@CH2), 117.4 (4-C), 123.5 (2-C), 127.1 (5-C), 127.4 (20-C,
60-C), 127.7 (40-C), 128.6 (30-C, 50-C), 129.8 (3-C), 136.0 (–CH@),
139.5 (10-C), 146.1 (1-C). MS (EI): m/z (%) = 223 (47) [M+], 195
(4), 194 (15), 132 (100), 130 (30), 117 (26), 91 (86).
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.98 (2H, dd, J = 4.8,
.
1.7 Hz, –CH2–CH@), 4.47 (2H, s, –N–CH2–), 5.16–5.23 (2H, m,
@CH2), 5.83–5.90 (1H, m, –CH@), 6.61 (2H, d, J = 8.9 Hz, 2-H, 6-
H), 7.10 (2H, d, J = 8.4 Hz, 20-H, 60-H), 7.13 (2H, d, J = 8.9 Hz, 3-H,
5-H), 7.44 (2H, d, J = 8.4 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3):
d = 53.7 (–CH2–CH@), 54.0 (–N–CH2–), 114.0 (2-C, 6-C), 117.0
(@CH2), 120.9 (40-C), 122.2 (4-C), 128.5 (3-C, 5-C), 129.1 (20-C, 60-
C), 131.9 (30-C, 50-C), 133.1 (–CH@), 138.2 (10-C), 144.2 (1-C). MS
(EI): m/z (%) = 337 (79Br, 35Cl, 43) [M+], 310 (10), 294 (7), 169
(100), 111 (23), 89 (27), 63 (10).
4.3.2. 2-Allyl-N-benzyl-4-trifluoromethoxyaniline (3b)
2.15 g (70%). IR (liquid film): v = 3444 (N–H), 1637 (C@C allyl),
920 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.32 (2H,
.
d, J = 6.4 Hz, –CH2–), 4.22 (1H, br s, NH), 4.36 (2H, s, –N–CH2–),
5.13 (1H, dq, J = 17.0, 1.6 Hz, @CHAHB), 5.20 (1H, dq, J = 10.0,
1.6 Hz, @CHAHB), 5.96 (1H, ddt, J = 17.0, 10.0, 6.0 Hz, –CH@), 6.58
(1H, d, J = 8.4 Hz, 6-H), 6.99 (1H, s, 3-H), 7.00 (1H, d, J = 8.4 Hz,
5-H), 7.31–7.38 (5H, m, 20-H, 30-H, 40-H, 50-H, 60-H). 13C NMR
(100 MHz, CDCl3): d = 36.3 (–CH2–), 48.5 (–N–CH2–), 111.0 (6-C),
117.2 (@CH2), 120.5 (5-C), 120.9 (q, J = 260.0 Hz, 4-OCF3), 123.0
(3-C), 124.9 (2-C), 127.5 (20-C, 40-C, 60-C), 128.9 (30-C, 50-C), 135.0
(–CH@), 139.0 (10-C), 140.6 (4-C), 144.9 (1-C). MS (EI): m/z
(%) = 307 (23) [M+], 266 (1), 230 (8), 216 (48), 214 (12), 201 (5),
91 (100).
4.2.14. N-Allyl-N-(40-chlorobenzyl)-4-fluoroaniline (2n)
2.29 g (83%). IR (liquid film): v = 1642 (C@C allyl), 923 (@C–H
allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.97 (2H, d, J = 5.2 Hz,
.
–CH2–CH@), 4.47 (2H, s, –N–CH2–), 5.18–5.23 (2H, m, @CH2),
5.84–5.93 (1H, m, –CH@), 6.62–6.66 (2H, m, 2-H, 6-H), 6.91 (2H,
td, J = 9.2, 2.2 Hz, 3-H, 5-H), 7.19 (2H, d, J = 8.4 Hz, 20-H, 60-H),
7.30 (2H, d, J = 8.4 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3):
d = 54.0 (–CH2–CH@), 54.4 (–N–CH2–), 114.0 (d, J = 10.0 Hz, 2-C,
6-C), 115.6 (d, J = 30.0 Hz, 3-C, 5-C), 116.9 (@CH2), 128.2 (20-C, 60-
C), 128.9 (30-C, 50-C), 132.7 (40-C), 133.6 (–CH@), 137.5 (10-C),
145.4 (1-C), 155.7 (d, J = 240.0 Hz, 4-C). MS (EI): m/z (%) = 275
4.3.3. 2-Allyl-N-benzyl-4-bromoaniline (3c)
2.20 g (73%). IR (liquid film): v = 3438 (N–H), 1634 (C@C allyl),
919 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.28 (2H,
.
(
35Cl, 34) [M+], 248 (4), 232 (4), 125 (100), 99 (5), 95 (26), 69 (2).
d, J = 6.1 Hz, –CH2–), 4.12 (1H, br s, NH), 4.32 (2H, s, –N–CH2–),
5.10 (1H, dq, J = 17.2, 1.5 Hz, @CHAHB), 5.16 (1H, dq, J = 10.2,
1.5 Hz, @CHAHB), 5.93 (1H, ddt, J = 17.2, 10.2, 6.1 Hz, @CH–), 6.48
(1H, d, J = 8.4 Hz, 6-H), 7.17 (1H, d, J = 2.3 Hz, 3-H), 7.20 (1H, dd,
J = 8.4, 2.3 Hz, 5-H), 7.27–7.37 (5H, m, 20-H, 30-H, 40-H, 50-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 36.2 (–CH2–), 48.3 (–N–
CH2–), 109.3 (4-C), 112.5 (6-C), 117.1 (@CH2), 125.8 (2-C), 127.5
(20-C, 60-C), 127.5 (40-C), 128.8 (30-C, 50-C), 130.4 (5-C), 132.4 (3-
C), 135.2 (–CH@), 139.1 (10-C), 145.3 (1-C). MS (EI): m/z (%) = 301
4.3. General procedures for the synthesis of 2-allyl-N-benzylan-
ilines 3a–w
Procedure 1: A mixture of substituted N-allyl-N-benzylanilines
2a–n (0.01 mol) and boron trifluoride diethyl ether complex,
(BF3ꢀOEt2, 0.012–0.015 equiv), was heated at 125–150 °C for
3–5 h. After cooling to room temperature, the reaction mixture
was neutralized with a saturated sodium carbonate solution to
pH 8 and extracted with dichloromethane (3 ꢃ 50 mL). The com-
bined organic extracts were dried over anhydrous sodium sulfate,
filtered and then concentrated under reduced pressure. The
remaining organic residue was purified by column chromatogra-
phy on silica gel using heptane–ethyl acetate (compositions ranged
from 50:1 to 20:1) as eluent to yield compounds 3a–n as low-vis-
cosity maroon oils.
Procedure 2: To an ice-cooled and stirred solution of substituted
ortho-allylanilines 4a–c (0.010 mol) and anhydrous sodium car-
bonate (0.025 mol) in dry N,N-dimethylformamide (20 mL), was
slowly added the corresponding substituted benzyl chloride 5a–d
(0.011 mol) in N,N-dimethylformamide (3 mL). Each mixture was
stirred at 0 °C for 3–4 h and allowed to reach room temperature
(TLC control). The mixture was poured onto water (100 mL) and
then extracted with dichloromethane (3 ꢃ 50 mL). The combined
organic extracts were dried over anhydrous sodium sulfate, filtered
and then concentrated under reduced pressure. The remaining or-
ganic residue was purified by column chromatography on silica gel
using heptane–ethyl acetate (compositions ranged from 50:1 to
20:1) as eluent to yield compounds 3o–w as low-viscosity maroon
oils or maroon crystals (compound 3v).
(
79Br, 17) [M+], 210 (10), 211 (3), 209 (3), 131 (37), 91 (100), 65
(30).
4.3.4. 2-Allyl-N-benzyl-4-chloroaniline (3d)
2.27 g (88%). IR (liquid film): v = 3444 (N-H), 1636 (C@C allyl),
920 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.32 (2H,
.
d, J = 6.0 Hz, –CH2–), 4.12 (1H, br s, NH), 4.37 (2H, s, –N–CH2–),
5.11 (1H, dq, J = 17.0, 1.6 Hz, @CHAHB), 5.17 (1H, dq, J = 10.0,
1.6 Hz, @CHAHB), 5.95 (1H, ddt, J = 17.0, 10.0, 6.0 Hz, @CH–), 6.57
(1H, d, J = 8.4 Hz, 6-H), 7.11 (1H, d, J = 2.4 Hz, 3-H), 7.12 (1H, dd,
J = 8.4, 2.4 Hz, 5-H), 7.31–7.43 (5H, m, 20-H, 30-H, 40-H, 50-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 36.2 (–CH2–), 48.3 (–N–
CH2–), 112.0 (6-C), 117.1 (@CH2), 122.1 (4-C), 125.4 (2-C), 127.4
(5-C, 20-C, 40-C, 60-C), 128.8 (30-C, 50-C), 129.6 (3-C), 135.2
(–CH@), 139.1 (10-C), 144.7 (1-C). MS (EI): m/z (%) = 257 (35Cl, 24)
[M+], 229 (2), 228 (4), 214 (2), 166 (29), 164 (9), 91 (100).
4.3.5. 2-Allyl-N-benzyl-4-fluoroaniline (3e)
2.10 g (86%). IR (liquid film): v = 3440 (N–H), 1636 (C@C allyl),
917 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.32 (2H,
.
d, J = 6.4 Hz, –CH2–), 4.06 (1H, br s, NH), 4.34 (2H, s, –N–CH2–),
5.12 (1H, dq, J = 17.0, 1.6 Hz, @CHAHB), 5.19 (1H, dq, J = 10.0,
1.6 Hz, @CHAHB), 5.97 (1H, ddt, J = 17.0, 10.0, 6.4 Hz, @CH–), 6.57
(1H, dd, J = 8.0, 8.0 Hz, 6-H), 6.83 (1H, td, J = 8.0, 3.0 Hz, 5-H),
6.85 (1H, d, J = 8.0 Hz, 3-H), 7.29–7.37 (5H, m, 20-H, 30-H, 40-H, 50-
H, 60-H). 13C NMR (100 MHz, CDCl3): d = 35.7 (–CH2–), 48.3 (–N–
CH2–), 111.1 (6-C), 113.0 (d, J = 30.0 Hz, 5-C), 116.1 (d,
J = 30.0 Hz, 3-C), 116.4 (@CH2), 125.0 (d, J = 10.0 Hz, 2-C), 126.8
(40-C), 126.9 (20-C, 60-C), 128.2 (30-C, 50-C), 134.6 (–CH@), 138.8
(10-C), 141.8 (1-C), 155.3 (d, J = 240.0 Hz, 4-C). MS (EI): m/z
(%) = 241 (44) [M+], 164 (12), 150 (80), 148 (24), 135 (23), 91
(100), 95 (3).
4.3.1. 2-Allyl-N-benzylaniline (3a)
1.60 g (72%). IR (liquid film): v = 3438 (N–H), 1634 (C@C allyl),
915 (@C–H allyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3): d = 3.37 (2H,
d, J = 6.0 Hz, –CH2–), 4.16 (1H, br s, NH), 4.40 (2H, s, –N–CH2–),
5.12 (1H, dq, J = 16.0, 1.6 Hz, @CHAHB), 5.17 (1H, dq, J = 10.0,
1.6 Hz, @CHAHB), 6.02 (1H, ddt, J = 16.0, 10.0, 6.0 Hz, @CH–), 6.69
(1H, dd, J = 7.2, 0.8 Hz, 6-H), 6.77 (1H, td, J = 7.2, 0.8 Hz, 4-H),
7.13 (1H, dd, J = 7.2, 1.4 Hz, 3-H), 7.18 (1H, td, J = 7.6, 1.4 Hz, 5-
H), 7.30–7.42 (5H, m, 20-H. 30-H, 40-H, 50-H, 60-H). 13C NMR

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4729
4.3.6. 2-Allyl-N-(40-chlorobenzyl)aniline (3f)
4.3.10. 2-Allyl-N-(30-chlorobenzyl)aniline (3j)
1.93 g (75%). IR (liquid film): v = 3440 (N-H), 1636 (C@C allyl),
918 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.44 (2H,
1.93 g (75%). IR (liquid film): v = 3439 (N–H), 1635 (C@C al-
lyl), 917 (@C–H allyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3): d = 3.36
.
(2H, d, J = 6.0 Hz, –CH2–), 4.12 (1H, br s, NH), 4.35 (2H, s, –N–
CH2–), 5.12 (1H, dq, J = 17.0, 1.6 Hz, @CHAHB), 5.17 (1H, dq,
J = 10.0, 1.6 Hz, @CHAHB), 6.00 (1H, ddt, J = 17.0, 10.0, 6.0 Hz,
–CH@), 6.59 (1H, d, J = 8.0 Hz, 6-H), 6.76 (1H, t, J = 8.0 Hz, 4-H),
7.11 (1H, dd, J = 8.0, 1.6 Hz, 3-H), 7.15 (1H, td, J = 8.0, 1.6 Hz,
5-H), 7.31 (2H, d, J = 8.4 Hz, 20-H, 60-H), 7.34 (2H, d, J = 8.4 Hz,
30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 36.5 (–CH2–), 47.4
(–N–CH2–), 110.8 (6-C), 116.6 (@CH2), 117.6 (4-C), 123.6 (2-C),
127.7 (20-C, 60-C), 128.6 (30-C, 50-C), 128.7 (5-C), 129.9 (3-C),
132.8 (40-C), 135.9 (–CH@), 138.0 (10-C), 145.8 (1-C). MS (EI):
m/z (%) = 257 (35Cl, 32) [M+], 229 (2), 228 (6), 132 (100), 130
(26), 117 (21), 125 (75).
d, J = 6.0 Hz, –CH2–), 4.43 (2H, s, –N–CH2–), 5.21 (1H, dq, J = 17.0,
1.6 Hz, @CHAHB), 5.25 (1H, dq, J = 10.0, 1.6 Hz, @CHAHB), 6.07 (1H,
ddt, J = 17.0, 10.0, 6.0 Hz, –CH@), 6.65 (1H, d, J = 8.0 Hz, 6-H),
6.83 (1H, t, J = 8.0 Hz, 4-H), 7.19 (1H, t, J = 8.0 Hz, 5-H), 7.21 (1H,
d, J = 8.0 Hz, 3-H), 7.44 (1H, s, 20-H), 7.30–7.35 (3H, m, 40-H, 50-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 36.7 (–CH2–), 47.7 (–N–
CH2–), 110.9 (6-C), 116.5 (@CH2), 117.8 (4-C), 123.8 (2-C), 125.4
(60-C), 127.4 (20-C), 127.5 (40-C), 127.9 (5-C), 130.0 (50-C), 130.1
(3-C), 134.6 (30-C), 136.1 (–CH@), 141.9 (10-C), 145.9 (1-C). MS
(EI): m/z (%) = 257 (35Cl, 22) [M+], 229 (22), 228 (4), 132 (100),
130 (29), 117 (25), 125 (26).
4.3.11. 2-Allyl-N-(40-methylbenzyl)-4-methylaniline (3k)
2.18 g (87%). IR (liquid film): v = 3431 (N–H), 1634 (C@C allyl),
4.3.7. 2-Allyl-N-(40-fluorobenzyl)aniline (3g)
1.83 g (76%). IR (liquid film): v = 3437 (N–H), 1634 (C@C allyl),
921 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.33 (3H,
.
917 (@C-H allyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3): d = 3.36 (2H,
s, 4-CH3), 2.42 (3H, s, 40-CH3), 3.37 (2H, d, J = 6.0 Hz, –CH2–), 4.36
(2H, s, –N–CH2–), 5.15 (1H, dq, J = 17.2, 1.6 Hz, @CHAHB), 5.19
(1H, dq, J = 10.0, 1.6 Hz, @CHAHB), 6.03 (1H, ddt, J = 17.2, 10.0,
6.0 Hz, @CH–), 6.65 (1H, d, J = 8.0 Hz, 6-H), 6.97 (1H, d, J = 1.6 Hz,
3-H), 7.02 (1H, dd, J = 8.0, 1.6 Hz, 5-H), 7.22 (2H, d, J = 8.0 Hz, 30-
H, 50-H), 7.32 (2H, d, J = 8.0 Hz, 20-H, 60-H). 13C NMR (100 MHz,
CDCl3): d = 20.5 (4-CH3), 21.2 (40-CH3), 36.6 (–CH2–), 48.4
(–N–CH2–), 111.2 (6-C), 116.3 (@CH2), 123.9 (2-C), 126.7 (4-C),
127.6 (20-C, 60-C), 128.1 (5-C), 129.4 (30-C, 50-C), 130.7 (3-C),
136.3 (–CH@), 136.6 (10-C), 136.8 (40-C), 144.0 (1-C). MS (EI): m/z
(%) = 251 (56) [M+], 222 (9), 160 (7), 146 (72), 132 (17), 131 (23),
105 (100), 91 (8).
d, J = 6.2 Hz, –CH2–), 4.08 (1H, br s, NH), 4.34 (2H, s, –N–CH2–),
5.11 (1H, dq, J = 17.1, 1.6 Hz, @CHAHB), 5.16 (1H, dq, J = 10.1,
1.6 Hz, @CHAHB), 5.99 (1H, ddt, J = 17.1, 10.1, 6.2 Hz, –CH@), 6.64
(1H, d, J = 8.0 Hz, 6-H), 6.77 (1H, t, J = 7.4 Hz, 4-H), 7.05 (2H, tt,
J = 8.6, 2.0 Hz, 30-H, 50-H), 7.11 (1H, dd, J = 7.4, 1.5 Hz, 3-H), 7.16
(1H, td, J = 8.0, 1.5 Hz, 5-H), 7.34 (2H, dd, J = 8.4, 8.5 Hz, 20-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 36.5 (–CH2–), 47.6 (–N–
CH2–), 111.1 (6-C), 115.4 (d, J = 21.2 Hz, 30-C, 50-C), 116.3 (@CH2),
117.8 (4-C), 123.8 (2-C), 127.7 (5-C), 129.0 (d, J = 8.0 Hz, 20-C, 60-
C), 129.9 (3-C), 134.9 (10-C), 136.0 (–CH@), 145.6 (1-C), 162.0 (d,
J = 243.5 Hz, 40-C). MS (EI): m/z (%) = 241 (42) [M+], 132 (86), 117
(19), 109 (100), 91 (6), 77 (8), 65 (4).
4.3.12. 2-Allyl-N-(40-chlorobenzyl)-4-chloroaniline (3l)
4.3.8. 2-Allyl-N-(30-methoxybenzyl)aniline (3h)
2.15 g (74%). IR (liquid film): v = 3444 (N–H), 1635 (C@C allyl),
1.70 g (67%). IR (liquid film): v = 3438 (N-H), 1634 (C@C allyl),
920 (@C-H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.30 (2H,
.
916 (@C-H allyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3): d = 3.36 (2H,
d, J = 6.0 Hz, –CH2–), 4.15 (1H, br s, NH), 4.32 (2H, s, –N–CH2–),
5.12 (1H, dq, J = 17.0, 1.7 Hz, @CHAHB), 5.19 (1H, dq, J = 10.0,
1.7 Hz, @CHAHB), 5.95 (1H, ddt, J = 17.0, 10.0, 6.0 Hz, @CH–), 6.48
(1H, d, J = 9.0 Hz, 6-H), 7.07 (1H, dd, J = 9.0, 2.8 Hz, 5-H), 7.07
(1H, d, J = 2.8 Hz, 3-H), 7.27 (2H, d, J = 8.4 Hz, 20-H, 60-H), 7.33
(2H, d, J = 8.4 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 36.3
(–CH2–), 47.6 (–N–CH2–), 112.0 (6-C), 117.1 (@CH2), 122.4 (4-C),
125.5 (2-C), 127.4 (5-C), 128.7 (20-C, 60-C), 128.9 (30-C, 50-C),
129.7 (3-C), 133.1 (40-C), 135.1 (–CH@), 137.6 (10-C), 144.5 (1-C).
MS (EI): m/z (%) = 291 (35Cl, 29) [M+], 180 (7), 166 (38), 164 (11),
152 (9), 125 (100), 111 (2).
d, J = 6.2 Hz, –CH2–), 3.82 (3H, s, 30-OCH3), 4.35 (2H, s, –N–CH2–),
5.12 (1H, dq, J = 17.1, 1.5 Hz, @CHAHB), 5.15 (1H, dq, J = 10.2,
1.5 Hz, @CHAHB), 6.00 (1H, ddt, J = 17.1, 10.2, 6.2 Hz, –CH@), 6.65
(1H, d, J = 8.0 Hz, 6-H), 6.74 (1H, td, J = 7.3, 1.0 Hz, 4-H), 6.84 (1H,
dd, J = 8.2, 2.4 Hz, 40-H), 6.94 (1H, br s, 20-H), 6.97 (1H, d,
J = 8.0 Hz, 60-H), 7.10 (1H, dd, J = 7.3, 1.6 Hz, 3-H), 7.15 (1H, td,
J = 8.0, 1.6 Hz, 5-H), 7.28 (1H, t, J = 8.0 Hz, 50-H). 13C NMR
(100 MHz, CDCl3): d = 36.8 (–CH2–), 48.4 (–N–CH2–), 55.4
(30-OCH3), 111.0 (6-C), 112.8 (40-C), 113.2 (20-C), 116.5 (@CH2),
117.6 (4-C), 119.9 (60-C), 123.8 (2-C), 128.0 (5-C), 129.9 (50-C),
130.1 (3-C), 136.3 (–CH@), 141.4 (10-C), 146.4 (1-C), 160.2 (30-C).
MS (EI): m/z (%) = 253 (33) [M+], 224 (10), 146 (17), 132 (100),
121 (67), 91 (23), 77 (13).
4.3.13. 2-Allyl-N-(40-bromobenzyl)-4-chloroaniline (3m)
2.52 g (75%). IR (liquid film): v = 3444 (N–H), 1634 (C@C allyl),
920 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.29 (2H,
.
4.3.9. 2-Allyl-N-(30-methylbenzyl)aniline (3i)
d, J = 6.1 Hz, –CH2–), 4.29 (2H, s, –N–CH2–), 5.10 (1H, dq, J = 17.1,
1.7 Hz, @CHAHB), 5.17 (1H, dq, J = 10.1, 1.7 Hz, @CHAHB), 5.93 (1H,
ddt, J = 17.1, 10.1, 6.1 Hz, @CH–), 6.46 (1H, d, J = 9.3 Hz, 6-H),
7.06 (1H, d, J = 2.5 Hz, 3-H), 7.06 (1H, dd, J = 9.3, 2.5 Hz, 5-H),
7.21 (2H, d, J = 8.4 Hz, 20-H, 60-H), 7.46 (2H, d, J = 8.4 Hz, 30-H, 50-
H). 13C NMR (100 MHz, CDCl3): d = 36.3 (–CH2–), 47.7 (–N–CH2–),
112.1 (6-C), 117.1 (@CH2), 121.2 (40-C), 122.5 (4-C), 125.5 (2-C),
127.4 (5-C), 129.1 (20-C, 60-C), 129.8 (3-C), 131.9 (30-C, 50-C),
135.2 (–CH@), 138.1 (10-C), 144.8 (1-C). MS (EI): m/z (%) = 337
1.75 g (74%). IR (liquid film): v = 3439 (N–H), 1635 (C@C allyl),
914 (@C-H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.45 (3H, s,
.
30-CH3), 3.41 (2H, d, J = 6.0 Hz, –CH2–), 4.21 (1H, br s, NH), 4.39
(2H, s, –N–CH2–), 5.17 (1H, dq, J = 17.0, 1.6 Hz, @CHAHB), 5.20
(1H, dq, J = 10.0, 1.6 Hz, @CHAHB), 6.05 (1H, ddt, J = 17.0, 10.0,
6.0 Hz, –CH@), 6.74 (1H, d, J = 8.0 Hz, 6-H), 6.82 (1H, td, J = 8.0,
1.0 Hz, 4-H), 7.16 (1H, dd, J = 8.0, 1.0 Hz, 3-H), 7.17 (1H, d,
J = 1.6 Hz, 20-H), 7.23 (1H, dd, J = 8.0, 1.6 Hz, 40-H), 7.25 (1H, dd,
J = 8.0, 1.6 Hz, 60-H), 7.27 (1H, td, J = 8.0, 1.0 Hz, 5-H), 7.30 (1H, t,
(
79Br, 35Cl, 33) [M+], 180 (13), 169 (100), 131 (57), 89 (37), 77
13
J = 8.0 Hz, 50-H). C NMR (100 MHz, CDCl3): d = 21.5 (30-CH3),
(20), 63 (20).
36.6 (–CH2–), 48.3 (–N–CH2–), 110.9 (6-C), 116.4 (@CH2), 117.5
(4-C), 123.7 (2-C), 124.6 (60-C), 127.8 (20-C), 128.0 (40-C), 128.3
(50-C), 128.6 (5-C), 129.9 (3-C), 136.1 (–CH@), 138.3 (30-C), 139.5
(10-C), 146.3 (1-C). MS (EI): m/z (%) = 237 (41) [M+], 209 (4), 208
(11), 132 (100), 130 (24), 117 (17), 105 (64).
4.3.14. 2-Allyl-N-(40-chlorobenzyl)-4-fluoroaniline (3n)
1.98 g (72%). IR (liquid film): v = 3441 (N–H), 1638 (C@C allyl),
918 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.31 (2H,
.
d, J = 6.0 Hz, –CH2–), 4.0 (1H, br s, NH), 4.30 (2H, s, –N–CH2–),

4730
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
5.11 (1H, dq, J = 17.0, 1.7 Hz, @CHAHB), 5.18 (1H, dq, J = 10.0, 1.7 Hz,
@CHAHB), 5.95 (1H, ddt, J = 17.0, 10.0, 6.0 Hz, @CH–), 6.49 (1H, dd,
J = 9.0, 8.0 Hz, 6-H), 6.82 (1H, td, J = 9.0, 3.0 Hz, 5-H), 6.85 (1H, dd,
J = 8.0, 3.0 Hz, 3-H), 7.28 (2H, d, J = 8.6 Hz, 20-H, 60-H), 7.32 (2H, d,
J = 8.6 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 36.3 (–CH2–),
48.1 (–N–CH2–), 111.7 (d, J = 10.0 Hz, 6-C), 113.6 (d, J = 20.0 Hz,
5-C), 116.8 (d, J = 20.0 Hz, 3-C), 117.0 (@CH2), 125.7 (d,
J = 10.0 Hz, 2-C), 128.8 (20-C, 60-C), 128.9 (30-C, 50-C), 133.1 (40-C),
135.2 (–CH@), 137.9 (10-C), 142.1 (1-C), 156.0 (d, J = 240.0 Hz, 4-
C). MS (EI): m/z (%) = 275 (35Cl, 30) [M+], 246 (5), 164 (8), 150
(83), 148 (22), 135 (19), 125 (100).
7.21–7.25 (2H, m, 30-H, 50-H), 7.38–7.41 (2H, m, 40-H, 60-H). 13C
NMR (100 MHz, CDCl3): d = 36.2 (–CH2–), 46.5 (–N–CH2–), 111.9
(6-C), 117.2 (@CH2), 122.2 (4-C), 124.9 (2-C), 127.1 (30-C), 127.5
(5-C), 128.8 (50-C), 129.0 (60-C), 129.5 (40-C), 129.8 (3-C), 133.6
(20-C), 135.2 (–CH@), 137.2 (10-C), 144.6 (1-C). MS (EI): m/z
(%) = 291 (35Cl, 77) [M+], 263 (2), 180 (13), 166 (67), 164 (16),
151 (6), 131 (100), 125 (91).
4.3.19. 2-Allyl-4-chloro-N-(20-fluorobenzyl)aniline (3s)
2.29 g (83%). IR (liquid film): v = 3443 (N–H), 1628 (C@C allyl),
920 (@C-H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.31 (2H,
.
d, J = 6.1 Hz, –CH2–), 4.41 (2H, s, –N–CH2–), 5.11 (1H, dq, J = 17.1,
1.6 Hz, @CHAHB), 5.17 (1H, dq, J = 10.1, 1.6 Hz, @CHAHB), 5.94 (1H,
ddt, J = 17.1, 10.1, 6.1 Hz, @CH–), 6.56 (1H, d, J = 8.4 Hz, 6-H),
7.05–7.12 (4H, m, 3-H, 5-H, 30-H, 50-H), 7.24–7.34 (2H, m, 40-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 36.1 (–CH2–), 41.8 (d,
J = 4.4 Hz, –N–CH2–), 112.1 (6-C), 115.4 (d, J = 21.2 Hz, 30-C),
117.0 (@CH2), 122.4 (4-C), 124.2 (d, J = 3.56 Hz, 50-C), 125.6 (2-C),
125.7 (d, J = 16.0 Hz, 10-C), 127.3 (5-C), 128.9 (d, J = 8.0 Hz, 60-C),
129.2 (d, J = 5.0 Hz, 40-C), 129.6 (3-C), 135.0 (–CH@), 144.1 (1-C),
160.9 (d, J = 244.4 Hz, 20-C). MS (EI): m/z (%) = 275 (35Cl, 15) [M+],
180 (2), 166 (100), 164 (9), 151 (12), 131 (74), 109 (58).
4.3.15. 2-Allyl-N-(20-chlorobenzyl)aniline (3o)
2.03 g (79%). IR (liquid film): v = 3440 (N–H), 1634 (C@C allyl),
916 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.41 (2H,
.
d, J = 6.1 Hz, –CH2–), 4.51 (2H, s, –N–CH2–), 5.16 (1H, dq, J = 17.0,
1.7 Hz, @CHAHB), 5.20 (1H, dq, J = 10.2, 1.7 Hz, @CHAHB), 6.04 (1H,
ddt, J = 17.0, 10.2, 6.1 Hz, @CH–), 6.62 (1H, d, J = 8.0 Hz, 6-H),
6.78 (1H, td, J = 7.4, 1.0 Hz, 4-H), 7.14 (1H, dd, J = 7.4, 1.6 Hz,
3-H), 7.17 (1H, td, J = 8.0, 1.6 Hz, 5-H), 7.23–7.28 (2H, m, 30-H,
50-H), 7.40–7.45 (2H, m, 40-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 36.5 (–CH2–), 45.7 (–N–CH2–), 111.0 (6-C), 116.4 (@CH2),
117.7 (4-C), 123.8 (2-C), 126.9 (30-C), 127.7 (5-C), 128.3 (50-C),
128.9 (60-C), 129.5 (40-C), 129.9 (3-C), 133.2 (20-C), 135.9 (–CH@),
136.6 (10-C), 145.5 (1-C). MS (EI): m/z (%) = 257 (35Cl, 32) [M+],
229 (1), 146 (16), 132 (100), 130 (25), 117 (22), 115 (34).
4.3.20. 2-Allyl-N-(20,60-dichlorobenzyl)aniline (3t)
2.33 g (80%). IR (liquid film): v = 3394 (N–H), 1634 (C@C allyl),
915 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.29 (2H,
.
d, J = 6.2 Hz, –CH2–), 4.60 (2H, s, –N–CH2–), 5.06 (1H, dq, J = 17.3,
1.6 Hz, @CHAHB), 5.10 (1H, dq, J = 10.1, 1.6 Hz, @CHAHB), 5.95 (1H,
ddt, J = 17.3, 10.1, 1.6 Hz, @CH–), 6.78 (1H, td, J = 7.4, 0.9 Hz,
4-H), 6.94 (1H, d, J = 8.0 Hz, 6-H), 7.09 (1H, dd, J = 7.4, 1.2 Hz,
3-H), 7.20 (1H, t, J = 8.0 Hz, 40-H), 7.24 (1H, td, J = 7.9, 1.2 Hz,
5-H), 7.35 (2H, d, J = 8.0 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3):
d = 36.5 (–CH2–), 44.1 (–N–CH2–), 111.6 (6-C), 116.5 (@CH2), 118.1
(4-C), 124.6 (2-C), 127.8 (5-C), 128.7 (30-C, 50-C), 129.5 (3-C), 130.0
(40-C), 134.9 (10-C), 136.0 (–CH@), 136.3 (20-C, 60-C), 146.1 (1-C).
MS (EI): m/z (%) = 291 (35Cl, 13) [M+], 263 (1), 146 (5), 132 (100),
130 (25), 117 (22), 159 (23).
4.3.16. 2-Allyl-N-(20-fluorobenzyl)aniline (3p)
1.95 g (81%). IR (liquid film): v = 3439 (N–H), 1634 (C@C allyl),
916 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.37 (2H,
.
d, J = 6.2 Hz, –CH2–), 4.46 (2H, s, –N–CH2–), 5.14 (1H, dq, J = 16.8,
1.6 Hz, @CHAHB), 5.17 (1H, dq, J = 10.2, 1.6 Hz, @CHAHB), 6.01 (1H,
ddt, J = 16.8, 10.2, 6.2 Hz, @CH–), 6.67 (1H, d, J = 7.8 Hz, 6-H),
6.76 (1H, td, J = 7.4, 1.0 Hz, 4-H), 7.07–7.11 (2H, m, 30-H, 50-H),
7.12 (1H, dd, J = 7.4, 1.4 Hz, 3-H), 7.17 (1H, td, J = 7.8, 1.4 Hz,
5-H), 7.25–7.28 (1H, m, 40-H), 7.38 (1H, td, J = 7.6, 1.4 Hz, 60-H).
13C NMR (100 MHz, CDCl3): d = 36.6 (–CH2–), 41.9 (d, J = 4.3 Hz,
–N–CH2–), 111.1 (6-C), 115.4 (d, J = 21.3 Hz, 30-C), 116.5 (@CH2),
117.9 (4-C), 124.0 (2-C), 124.3 (d, J = 3.6 Hz, 50-C), 126.4 (d,
J = 14.4 Hz, 10-C), 127.9 (5-C), 128.9 (d, J = 8.1 Hz, 60-C), 129.5 (d,
J = 4.4 Hz, 40-C), 130.1 (3-C), 136.1 (–CH@), 145.9 (1-C), 161.0 (d,
J = 244.3 Hz, 20-C). MS (EI): m/z (%) = 241 (42) [M+], 213 (2), 146
(8), 132 (100), 130 (23), 117 (23), 109 (51).
4.3.21. 2-Allyl-N-(60-chloro-20-fluorobenzyl)aniline (3u)
2.12 g (77%). IR (liquid film): v = 3419 (N–H), 1634 (C@C allyl),
916 (@C-H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.30 (2H,
.
d, J = 6.2 Hz, –CH2–), 4.25 (1H, br s, NH), 4.53 (2H, s, –N–CH2–),
5.08 (1H, dq, J = 17.2, 1.6 Hz, @CHAHB), 5.12 (1H, dq, J = 10.2,
1.6 Hz, @CHAHB), 5.96 (1H, ddt, J = 17.2, 10.2, 6.2 Hz, @CH–), 6.76
(1H, t, J = 7.4 Hz, 4-H), 6.94 (1H, d, J = 8.1 Hz, 6-H), 7.00–7.05 (1H,
m, 30-H), 7.08 (1H, dd, J = 7.4, 0.6 Hz, 3-H), 7.19–7.24 (3H, m, 5-H,
40-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 36.5 (–CH2–), 39.6 (d,
J = 3.4 Hz, –N–CH2–), 111.3 (6-C), 114.4 (d, J = 23.2 Hz, 30-H),
116.5 (@CH2), 118.0 (4-C), 124.5 (2-C), 125.1 (d, J = 18.0 Hz, 10-C),
125.7 (d, J = 3.5 Hz, 50-C), 127.8 (5-C), 129.5 (d, J = 9.7 Hz, 40-C),
130.0 (3-C), 135.8 (d, J = 5.0 Hz, 60-C), 136.0 (–CH@), 145.7 (1-C),
161.8 (d, J = 247.5 Hz, 20-C). MS (EI): m/z (%) = 291 (35Cl, 29) [M+],
180 (7), 166 (38), 164 (11), 152 (9), 125 (100), 111 (2).
4.3.17. 2-Allyl-N-(20-chlorobenzyl)-4-methylaniline (3q)
2.28 g (84%). IR (liquid film): v = 3437 (N–H), 1634 (C@C allyl),
914 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.27 (3H,
.
s, 4-CH3), 3.36 (2H, d, J = 6.2 Hz, –CH2–), 4.47 (2H, s, –N–CH2–),
5.09 (1H, dq, J = 17.0, 1.4 Hz, @CHAHB), 5.17 (1H, dq, J = 10.1,
1.4 Hz, @CHAHB), 6.01 (1H, ddt, J = 17.0, 10.1, 6.2 Hz, @CH–), 6.52
(1H, d, J = 8.7 Hz, 6-H), 6.94 (1H, d, J = 2.0 Hz, 3-H), 6.97 (1H, dd,
J = 8.7, 2.0 Hz, 5-H), 7.21–7.24 (2H, m, 30-H, 50-H), 7.38–7.41 (2H,
m, 40-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 20.5 (4-CH3), 36.6
(–CH2–), 46.2 (–N–CH2–), 111.5 (6-C), 116.4 (@CH2), 124.2 (2-C),
127.0 (30-C), 127.2 (4-C), 128.1 (5-C), 128.4 (50-C), 129.1 (60-C),
129.6 (40-C), 130.9 (3-C), 134.4 (20-C), 136.2 (–CH@), 137.6 (10-C),
143.3 (1-C). MS (EI): m/z (%) = 271 (35Cl, 42) [M+], 243 (1), 160
(10), 146 (100), 144 (24), 131 (51), 125 (29).
4.3.22. 2-Allyl-4-chloro-N-(20,60-dichlorobenzyl)aniline (3v)
Maroon crystals, 2.38 g (73%), mp: 70–71 °C (from heptane). IR
(KBr): v = 3399 (N–H), 1629 (C@C allyl), 912 (@C–H allyl) cmꢂ1. 1H
NMR (400 MHz, CDCl3): d = 3.29 (2H, d, J = 6.2 Hz, –CH2–), 4.56 (2H,
s, –N–CH2–), 5.05 (1H, dq, J = 17.1, 1.6 Hz, @CHAHB), 5.12 (1H, dq,
J = 10.1, 1.6 Hz, @CHAHB), 5.87 (1H, ddt, J = 17.1, 10.1, 6.2 Hz,
@CH–), 6.84 (1H, d, J = 8.6 Hz, 6-H), 7.04 (1H, d, J = 2.5 Hz, 3-H),
7.16 (1H, dd, J = 8.6, 2.5 Hz, 5-H), 7.19 (1H, t, J = 8.0 Hz, 40-H),
7.34 (2H, d, J = 8.0 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3):
d = 36.1 (–CH2–), 44.2 (–N–CH2–), 112.9 (6-C), 117.2 (@CH2),
122.9 (4-C), 126.4 (2-C), 127.4 (5-C), 128.7 (30-C, 50-C), 129.6
4.3.18. 2-Allyl-N-(20-chlorobenzyl)-4-chloroaniline (3r)
2.33 g (80%). IR (liquid film): v = 3444 (N–H), 1635 (C@C allyl),
919 (@C–H allyl) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 3.31 (2H,
.
d, J = 6.2 Hz, –CH2–), 4.44 (2H, s, –N–CH2–), 5.13 (1H, dq, J = 17.1,
1.7 Hz, @CHAHB), 5.17 (1H, dq, J = 10.2, 1.7 Hz, @CHAHB), 5.96 (1H,
ddt, J = 17.1, 10.2, 6.2 Hz, @CH–), 6.47 (1H, d, J = 8.3 Hz, 6-H),
7.05 (1H, dd, J = 8.3, 2.3 Hz, 5-H), 7.06 (1H, d, J = 2.3 Hz, 3-H),

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4731
(40-C), 129.7 (3-C), 134.5 (10-C), 135.1 (–CH@), 136.2 (20-C, 60-C),
144.4 (1-C). MS (EI): m/z (%) = 325 (35Cl, 14) [M+], 180 (8), 166
(71), 164 (14), 159 (44), 151 (5), 131 (100).
(q, J = 257.0 Hz, 7-OCF3), 122.2 (6-C), 123.3 (9-C), 126.3 (20-C,
60-C), 127.1 (40-C), 127.3 (5a-C), 128.5 (30-C, 50-C), 143.3 (10-C),
146.8 (d, J = 1.9 Hz, 7-C), 149.1 (9a-C). MS (EI): m/z (%) = 321 (22)
[M+], 304 (13), 292 (2), 278 (4), 214 (5), 188 (100), 175 (2), 161
(1). Anal. Calcd for C17H14F3NO2: C, 63.55; H, 4.39; N, 4.36. Found:
C, 63.42; H, 4.50; N, 4.28.
4.3.23. 2-Allyl-4-chloro-N-(60-chloro-20-fluorobenzyl)aniline
(3w)
2.50 g (81%). IR (liquid film): v = 3422 (NH), 1637 (C@C allyl),
920 (allyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3): d = 3.23 (2H, d,
4.4.3. 7-Bromo-1,4-epoxy-2-exo-phenyl-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6c)
J = 6.2 Hz, –CH2–), 4.48 (2H, d, J = 1.2 Hz, –N–CH2–), 5.06 (1H, dq,
J = 17.1, 1.4 Hz, @CHAHB), 5.14 (1H, dq, J = 10.1, 1.4 Hz, @CHAHB),
5.89 (1H, ddt, J = 17.1, 10.1, 6.2 Hz, @CH–), 6.82 (1H, d, J = 8.6 Hz,
6-H), 7.01 (1H, dd, J = 9.3, 5.0 Hz, 30-H), 7.03 (1H, d, J = 2.6 Hz,
3-H), 7.14 (1H, dd, J = 8.6, 2.6 Hz, 5-H), 7.19–7.23 (2H, m, 40-H,
50-H). 13C NMR (100 MHz, CDCl3): d = 36.1 (–CH2–), 39.7 (d,
J = 3.0 Hz, –N–CH2–), 112.5 (6-C), 114.5 (d, J = 24.0 Hz, 30-H),
117.1 (@CH2), 124.7 (d, J = 18.0 Hz, 10-C), 125.7 (4-C), 125.8 (2-C),
126.3 (5-C), 127.4 (d, J = 3.5 Hz, 50-C), 129.6 (3-C), 129.7 (d,
J = 4.0 Hz, 40-C), 135.0 (–CH@), 135.7 (d, J = 6.0 Hz, 60-C), 144.1
(1-C), 161.7 (d, J = 247.0 Hz, 20-C). MS (EI): m/z (%) = 309 (35Cl,
25) [M+], 180 (6), 166 (54), 164 (15), 151 (6), 131 (100), 143 (68).
White crystals, 1.99 g (63%), mp: 83–85 °C (from heptane). IR
(KBr): v = 1024 (–C–O–), 975 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.54 (1H, d, J = 16.8 Hz, 5-HA), 2.57–2.67 (2H, m, 3-
HAHB), 3.40 (1H, dd, J = 16.8, 5.3 Hz, 5-HB), 4.58 (1H, dd, J = 8.3,
2.9 Hz, 2-H), 4.96 (1H, ddd, J = 7.1, 5.2, 1.9 Hz, 4-H), 6.97 (1H, d,
J = 8.0 Hz, 9-H), 7.27 (1H, t, J = 8.0 Hz, 40-H), 7.29 (1H, s, 6-H),
7.30 (1H, d, J = 8.0 Hz, 8-H), 7.36 (2H, t, J = 8.0 Hz, 30-H, 50-H),
7.45 (2H, d, J = 8.0 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.7 (5-C), 42.7 (3-C), 74.8 (4-C), 75.5 (2-C), 119.1 (7-C), 123.9
(9-C), 126.5 (20-C, 60-C), 127.2 (40-C), 127.9 (5a-C), 128.7 (30-C,
50-C), 129.9 (8-C), 132.8 (6-C), 143.5 (10-C), 149.8 (9a-C). MS (EI):
m/z (%) = 315 (79Br, 31) [M+], 298 (11), 286 (6), 208 (11), 184
(100), 132 (40), 104 (54), 77 (80). Anal. Calcd for C16H14BrNO: C,
60.78; H, 4.46; N, 4.43. Found: C, 60.91; H, 4.21; N, 4.57.
4.4. General procedure for the synthesis of 2-exo-aryl-1,4-
epoxytetrahydro-1-benzazepines 6a–w
To an ice-cooled and stirred solution of substituted ortho-allyl-
N-benzylanilines 3a–w (0.010 mol) and catalytic amounts of so-
dium tungstate dehydrated (8–10 mol %) in methanol (40 mL),
was added dropwise 30% aqueous hydrogen peroxide solution
(0.030 mol). The resulting mixture was then stirred at room tem-
perature for 36–72 h. Each mixture was filtered and the filtrate
concentrated under reduced pressure. Toluene (50 mL) was added
to the remaining organic residue and the resulting solution was
heated at 70–90 °C for 3–7 h. After cooling to room temperature,
toluene was removed under reduced pressure and the crude mate-
rial was purified by column chromatography on silica gel using
heptane–ethyl acetate (compositions ranged from 40:1 to 10:1
v/v) as eluent to give compounds 6a–w.
4.4.4. 7-Chloro-1,4-epoxy-2-exo-phenyl-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6d)
Maroon viscous oil, 1.76 g (65%). IR (liquid film): v = 1026 (–C–
O–), 997 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.53 (1H, d,
J = 16.8 Hz, 5-HA), 2.57–2.68 (2H, m, 3-HAHB), 3.39 (1H, dd, J = 16.8,
5.4 Hz, 5-HB), 4.59 (1H, dd, J = 8.3, 3.0 Hz, 2-H), 4.95 (1H, ddd,
J = 6.0, 5.4, 2.0 Hz, 4-H), 7.03 (1H, d, J = 8.2 Hz, 9-H), 7.14 (1H, s,
6-H), 7.15 (1H, d, J = 8.2 Hz, 8-H), 7.29 (1H, t, J = 7.4 Hz, 40-H),
7.38 (2H, t, J = 7.4 Hz, 30-H, 50-H), 7.47 (2H, d, J = 7.6 Hz, 20-H,
60-H). 13C NMR (100 MHz, CDCl3): d = 34.5 (5-C), 42.4 (3-C), 74.5
(2-C), 75.3 (4-C), 123.3 (9-C), 126.7 (20-C, 60-C), 126.9 (8-C), 127.0
(40-C), 127.2 (5a-C), 128.5 (30-C, 50-C), 129.7 (6-C), 131.1 (7-C),
143.7 (10-C), 149.3 (9a-C). MS (EI): m/z (%) = 271 (35Cl, 34) [M+],
254 (13), 242 (4), 228 (3), 164 (6), 138 (100), 125 (6), 111 (3). Anal.
Calcd for C16H14ClNO: C, 70.72; H, 5.19; N, 5.15. Found: C, 70.81; H,
5.35; N, 5.02.
4.4.1. 1,4-Epoxy-2-exo-phenyl-2,3,4,5-tetrahydro-1(1H)-benzaze-
pine (6a)
Maroon viscous oil, 1.45 g (61%). IR (liquid film): v = 1026 (–C–
O–), 997 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.58 (1H, d,
J = 16.5 Hz, 5-HA), 2.61–2.69 (2H, m, 3-HAHB), 3.45 (1H, dd, J = 16.5,
5.4 Hz, 5-HB), 4.62 (1H, dd, J = 11.2, 4.4 Hz, 2-H), 4.99 (1H, ddd,
J = 6.4, 5.6, 2.4 Hz, 4-H), 7.12 (1H, dd, J = 6.6, 2.1 Hz, 9-H), 7.15–
7.24 (3H, m, 6-H, 7-H, 8-H), 7.30 (1H, t, J = 7.6 Hz, 40-H), 7.39
(2H, t, J = 7.6 Hz, 30-H, 50-H), 7.50 (2H, d, J = 7.2 Hz, 20-H, 60-H).
13C NMR (100 MHz, CDCl3): d = 34.6 (5-C), 42.7 (3-C), 75.1 (4-C),
75.3 (2-C), 121.9 (9-C), 125.2 (5a-C), 125.9 (7-C), 126.4 (20-C,
60-C), 126.5 (8-C), 126.9 (40-C), 128.4 (30-C, 50-C), 129.8 (6-C),
143.8 (10-C), 150.9 (9a-C). MS (EI): m/z (%) = 237 (40) [M+], 220
(24), 208 (7), 194 (14), 130 (7), 104 (100), 91 (25), 77 (31). Anal.
Calcd for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.08;
H, 6.24; N, 5.82.
4.4.5. 1,4-Epoxy-2-exo-phenyl-7-fluoro-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6e)
Maroon viscous oil, 1.50 g (59%). IR (liquid film): v = 1027
(–C-O–), 998 (–N–O–) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.55
.
(1H, d, J = 16.9 Hz, 5-HA), 2.58–2.68 (2H, m, 3-HAHB), 3.41 (1H,
dd, J = 16.9, 5.5 Hz, 5-HB), 4.59 (1H, dd, J = 8.0, 3.6 Hz, 2-H), 4.95
(1H, ddd, J = 7.2, 5.2, 2.6 Hz, 4-H), 6.86 (1H, d, J = 9.2 Hz, 6-H),
6.88 (1H, td, J = 8.6, 2.0 Hz, 8-H), 7.07 (1H, dd, J = 8.4, 5.2 Hz, 9-
H), 7.28 (1H, t, J = 7.6 Hz, 40-H), 7.38 (2H, t, J = 7.6 Hz, 30-H, 50-H),
7.47 (2H, d, J = 7.6 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.8 (5-C), 42.5 (3-C), 74.4 (4-C), 75.3 (2-C), 113.4 (d,
J = 21.0 Hz, 8-C), 116.1 (d, J = 21.0 Hz, 6-C), 123.5 (d, J = 8.6 Hz,
9-C), 126.3 (20-C, 60-C), 127.0 (40-C), 127.3 (d, J = 8.3 Hz, 5a-C),
128.5 (30-C, 50-C), 143.5 (10-C), 146.5 (d, J = 3.0 Hz, 9a-C), 161.0
(d, J = 244.0 Hz, 7-C). MS (EI): m/z (%) = 255 (40) [M+], 238 (17),
226 (5), 212 (6), 148 (7), 122 (100), 109 (9), 95 (5). Anal. Calcd
for C16H14FNO: C, 75.28; H, 5.53; N, 5.49. Found: C, 75.11; H,
5.76; N, 5.62.
4.4.2. 1,4-Epoxy-2-exo-phenyl-7-trifluoromethoxy-2,3,4,5-tetra-
hydro-1(1H)-benzazepine (6b)
White crystals, 1.77 g (55%), mp: 63–64 °C (from heptane). IR
(KBr): v = 1026 (–C–O–), 998 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.57 (1H, d, J = 16.8 Hz, 5-HA), 2.58–2.70 (2H, m, 3-
HAHB), 3.43 (1H, dd, J = 16.8, 5.4 Hz, 5-HB), 4.62 (1H, dd, J = 8.2,
3.3 Hz, 2-H), 4.97 (1H, ddd, J = 7.6, 5.4, 2.3 Hz, 4-H), 7.03 (1H, s,
6-H), 7.05 (1H, d, J = 8.4 Hz, 8-H), 7.12 (1H, d, J = 8.4 Hz, 9-H),
7.29 (1H, t, J = 7.3 Hz, 40-H), 7.38 (2H, t, J = 8.0 Hz, 30-H, 50-H),
7.47 (2H, d, J = 8.0 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.7 (5-C), 42.7 (3-C), 74.5 (2-C), 75.3 (4-C), 119.4 (8-C), 120.1
4.4.6. 1,4-Epoxy-2-exo-(40-chlorophenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6f)
Maroon viscous oil, 1.71 g (63%). IR (liquid film): v = 1013
(–C–O–), 984 (–N–O–) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.56
.
(1H, d, J = 16.6 Hz, 5-HA), 2.52–2.64 (2H, m, 3-HAHB), 3.42 (1H,
dd, J = 16.6, 5.5 Hz, 5-HB), 4.59 (1H, dd, J = 8.0, 3.2 Hz, 2-H), 4.96

4732
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
(1H, ddd, J = 6.0, 5.4, 2.0 Hz, 4-H), 7.07 (1H, dd, J = 6.2, 2.1 Hz, 9-H),
7.12–7.22 (3H, m, 6-H, 7-H, 8-H), 7.33 (2H, d, J = 8.6 Hz, 30-H, 50-H),
7.42 (2H, d, J = 8.4 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.7 (5-C), 42.7 (3-C), 74.8 (2-C), 75.2 (4-C), 121.9 (9-C), 125.2
(5a-C), 126.1 (7-C), 126.7 (8-C), 127.9 (20-C, 60-C), 128.6 (30-C, 50-
C), 129.8 (6-C), 132.6 (40-C), 142.3 (10-C), 150.3 (9a-C). MS (EI):
m/z (%) = 271 (35Cl, 21) [M+], 254 (13), 242 (3), 228 (3), 130 (5),
104 (100), 91 (14), 77 (25). Anal. Calcd for C16H14ClNO: C, 70.72;
H, 5.19; N, 5.15. Found: C, 70.90; H, 5.35; N, 5.08.
(1H, d, J = 16.4 Hz, 5-HA), 2.55–2.65 (2H, m, 3-HAHB), 3.42 (1H,
dd, J = 16.4, 5.6 Hz, 5-HB), 4.59 (1H, dd, J = 7.6, 4.0 Hz, 2-H), 4.96
(1H, ddd, J = 6.8, 5.6, 2.4 Hz, 4-H), 7.08 (1H, dd, J = 8.0, 2.0 Hz, 9-
H), 7.15–7.20 (3H, m, 6-H, 7-H, 8-H), 7.27 (1H, t, J = 8.4 Hz, 50-H),
7.31 (1H, d, J = 8.4 Hz, 60-H), 7.53 (1H, s, 20-H). 13C NMR
(100 MHz, CDCl3): d = 34.7 (5-C), 42.6 (3-C), 74.9 (2-C), 75.2
(4-C), 122.0 (9-C), 124.7 (60-C), 125.3 (5a-C), 126.3 (7-C), 126.8
(8-C, 40-C), 127.2 (20-C), 129.8 (50-C), 130.0 (6-C), 134.5 (30-C),
145.9 (10-C), 150.3 (9a-C). MS (EI): m/z (%) = 271 (35Cl, 32) [M+],
254 (18), 242 (4), 228 (9), 130 (6), 104 (100), 91 (15), 77 (24). Anal.
Calcd for C16H14ClNO: C, 70.72; H, 5.19; N, 5.15. Found: C, 70.60; H,
5.12; N, 5.26.
4.4.7. 1,4-Epoxy-2-exo-(40-fluorophenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6g)
Maroon viscous oil, 1.61 g (63%). IR (liquid film): v = 1015 (–C–
O–), 999 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.56 (1H, d,
J = 16.6 Hz, 5-HA), 2.56–2.61 (2H, m, 3-HAHB), 3.43 (1H, dd, J = 16.6,
5.4 Hz, 5-HB), 4.61 (1H, dd, J = 8.0, 3.0 Hz, 2-H), 4.98 (1H, ddd,
J = 6.0, 5.4, 2.3 Hz, 4-H), 7.05 (2H, t, J = 8.7 Hz, 30-H, 50-H), 7.10
(1H, dd, J = 8.2, 2.1 Hz, 9-H), 7.15–7.21 (3H, m, 6-H, 7-H, 8-H),
7.43–7.47 (2H, m, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.7 (5-C), 42.6 (3-C), 74.9 (2-C), 75.3 (4-C), 115.3 (d,
J = 22.0 Hz, 30-C, 50-C), 122.0 (9-C), 125.3 (5a-C), 126.2 (7-C),
126.7 (8-C), 128.3 (d, J = 7.0 Hz, 20-C, 60-C), 130.0 (6-C), 139.6 (d,
J = 3.0 Hz, 10-C), 150.4 (9a-C), 162.0 (d, J = 244.0 Hz, 40-C). MS (EI):
m/z (%) = 255 (35Cl, 37) [M+], 238 (21), 225 (7), 133 (14), 104
(100), 91 (14), 78 (25), 65 (12). Anal. Calcd for C16H14FNO: C,
75.28; H, 5.53; N, 5.49. Found: C, 75.14; H, 5.67; N, 5.57.
4.4.11. 1,4-Epoxy-2-exo-(40-methylphenyl)-7-methyl-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6k)
White crystals, 1.72 g (65%), mp: 101–103 °C (from heptane).
IR (KBr): v = 1022 (–C–O–), 979 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.31 (3H, s, 7-CH3), 2.35 (3H, s, 40-CH3),
2.51 (1H, d, J = 16.5 Hz, 5-HA), 2.57–2.64 (2H, m, 3-HAHB), 3.39
(1H, dd, J = 16.5, 4.6 Hz, 5-HB), 4.57 (1H, dd, J = 7.1, 3.5 Hz, 2-H),
4.96 (1H, ddd, J = 6.8, 5.0, 2.6 Hz, 4-H), 6.98 (1H, d, J = 8.2 Hz, 8-
H), 6.95 (1H, br s, 6-H), 7.00 (1H, d, J = 8.2 Hz, 9-H), 7.17 (2H, d,
J = 7.9 Hz, 30-H, 50-H), 7.35 (2H, d, J = 7.9 Hz, 20-H, 60-H). 13C
NMR (100 MHz, CDCl3): d = 21.2 (7-CH3), 21.2 (40-CH3), 34.9 (5-
C), 42.6 (3-C), 75.3 (4-C), 75.6 (2-C), 121.9 (9-C), 125.0 (5a-C),
126.6 (20-C, 60-C), 127.4 (8-C), 129.3 (30-C, 50-C), 130.4 (6-C),
135.7 (7-C), 136.8 (40-C), 140.9 (10-C), 148.2 (9a-C). MS (EI): m/z
(%) = 265 (35) [M+], 248 (18), 222 (10), 207 (5), 146 (7), 132
(23), 118 (100), 103 (12), 91 (30), 77 (18), 65 (9), 51 (5). Anal.
Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.40;
H, 7.28; N, 5.22.
4.4.8. 1,4-Epoxy-2-exo-(30-methoxyphenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6h)
Maroon viscous oil, 1.73 g (65%). IR (liquid film): v = 1031 (–C–
O–), 999 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.56 (1H, d,
J = 16.6 Hz, 5-HA), 2.60–2.67 (2H, m, 3-HAHB), 3.43 (1H, dd, J = 16.6,
5.3 Hz, 5-HB), 3.85 (3H, s, 30-OCH3), 4.62 (1H, dd, J = 7.8, 3.9 Hz, 2-
H), 4.98 (1H, ddd, J = 6.5, 5.3, 2.5 Hz, 4-H), 6.83 (1H, dd, J = 8.2,
2.4 Hz, 40-H), 7.03 (1H, d, J = 7.6 Hz, 60-H), 7.11 (1H, d, J = 2.4 Hz,
20-H), 7.11–7.22 (4H, m, 6-H, 7-H, 8-H, 9-H), 7.29 (1H, t,
J = 7.9 Hz, 50-H). 13C NMR (100 MHz, CDCl3): d = 34.7 (5-C), 42.7
(3-C), 55.4 (30-OCH3), 75.2 (2-C), 75.5 (4-C), 112.2 (20-C), 112.7
(40-C), 118.9 (60-C), 122.1 (9-C), 125.4 (5a-C), 126.2 (7-C), 126.7
(8-C), 129.6 (50-C), 129.9 (6-C), 145.3 (10-C), 150.5 (9a-C), 159.9
(30-C). MS (EI): m/z (%) = 267 (35Cl, 90) [M+], 250 (40), 224 (20),
134 (60), 104 (100), 91 (33), 78 (30), 65 (20). Anal. Calcd for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.22; H, 6.19;
N, 5.34.
4.4.12. 7-Chloro-1,4-epoxy-2-exo-(40-chlorophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6l)
White crystals, 2.32 g (76%), mp: 133–134 °C (from heptane). IR
(KBr): v = 1024 (–C–O–), 982 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.54 (1H, d, J = 16.8 Hz, 5-HA), 2.54–2.61 (2H, m,
3-HAHB), 3.38 (1H, d, J = 16.8, 5.6 Hz, 5-HB), 4.54 (1H, dd, J = 7.4,
3.6 Hz, 2-H), 4.93 (1H, dd, J = 6.5, 4.8, Hz, 4-H), 7.00 (1H,
d, J = 8.4 Hz, 9-H), 7.14 (1H, d, J = 8.4 Hz, 8-H), 7.16 (1H, d,
J = 2.4 Hz, 6-H), 7.32 (2H, d, J = 8.4 Hz, 30-H, 50-H), 7.38 (2H, d,
J = 8.4 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 34.6 (5-C),
42.6 (3-C), 74.8 (2-C, 4-C), 123.4 (9-C), 127.0 (8-C), 127.3 (5a-C),
127.9 (20-C, 60-C), 128.7 (30-C, 50-C), 129.8 (6-C), 131.4 (7-C),
132.9 (40-C), 142.0 (10-C), 148.9 (9a-C). MS (EI): m/z (%) = 305
4.4.9. 1,4-Epoxy-2-exo-(30-methylphenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6i)
(
35Cl, 31) [M+], 288 (12), 276 (3), 262 (5), 164 (7), 138 (100), 125
(13), 111 (5). Anal. Calcd for C16H13C l2NO: C, 62.76; H, 4.28; N,
4.57. Found: C, 62.88; H, 4.20; N, 4.50.
Maroon viscous oil, 1.68 g (67%). IR (liquid film): v = 1034 (–C–
O–), 997 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.42 (3H, s,
30-CH3), 2.58 (1H, d, J = 16.8 Hz, 5-HA), 2.57–2.69 (2H, m, 3-HAHB),
3.45 (1H, dd, J = 16.8, 5.4 Hz, 5-HB), 4.63 (1H, dd, J = 7.9, 3.4 Hz,
2-H), 4.99 (1H, ddd, J = 7.6, 5.9, 2.8 Hz, 4-H), 7.12 (2H, dd, J = 8.0,
1.6 Hz, 9-H, 60-H), 7.16–7.24 (3H, m, 6-H, 7-H, 8-H), 7.25–7.30
(2H, m, 40-H, 50-H), 7.38 (1H, br s, 20-H). 13C NMR (100 MHz, CDCl3):
d = 21.6 (30-CH3), 34.8 (5-C), 42.6 (3-C), 75.2 (2-C), 75.5 (4-C), 122.0
(9-C), 123.6 (40-C), 125.4 (5a-C), 125.9 (8-C), 126.5 (7-C), 127.0
(20-C), 127.7 (60-C), 128.3 (50-C), 129.9 (6-C), 138.6 (30-C), 143.7
(10-C), 150.8 (9a-C). MS (EI): m/z (%) = 251 (55) [M+], 234 (36),
222 (10), 208 (12), 130 (8), 104 (100), 91 (33), 77 (22). Anal. Calcd
for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.39; H, 6.69; N,
5.49.
4.4.13. 7-Chloro-1,4-epoxy-2-exo-(40-bromophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6m)
White crystals, 2.66 g (76%), mp: 144–146 °C (from heptane).
IR (KBr): v = 1020 (–C–O–), 983 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.52 (1H, d, J = 16.9 Hz, 5-HA), 2.53–2.59
(2H, m, 3-HAHB), 3.38 (1H, dd, J = 16.9, 5.4 Hz, 5-HB), 4.52 (1H,
dd, J = 7.5, 3.8 Hz, 2-H), 4.93 (1H, ddd, J = 7.2, 5.4, 2.8 Hz, 4-H),
7.00 (1H, d, J = 8.3 Hz, 9-H), 7.13 (1H, br s, 6-H), 7.14 (1H, dd,
J = 8.3, 2.2 Hz, 8-H), 7.33 (2H, d, J = 8.5 Hz, 30-H, 50-H), 7.47
(2H, d, J = 8.5 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.6 (5-C), 42.6 (3-C), 74.8 (2-C, 4-C), 121.1 (40-C), 123.4
(9-C), 127.0 (8-C), 127.3 (5a-C), 128.3 (20-C, 60-C), 129.8 (6-C),
131.5 (7-C), 131.7 (30-C, 50-C), 142.5 (10-C), 148.9 (9a-C). MS
(EI): m/z (%) = 351 (79Br, 35Cl, 20) [M+], 334 (10), 182 (13), 152
(13), 139 (100), 102 (23), 89 (30), 77 (30). Anal. Calcd for
C16H13BrClNO: C, 54.81; H, 3.74; N, 3.99. Found: C, 54.77; H,
3.81; N, 3.90.
4.4.10. 1,4-Epoxy-2-exo-(30-chlorophenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6j)
Maroon viscous oil, 1.71 g (63%). IR (liquid film): v = 1024
(–C–O–), 1000 (–N–O–) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.56
.

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4733
4.4.14. 1,4-Epoxy-2-exo-(40-chlorophenyl)-7-fluoro-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6n)
J = 7.7, 1.2 Hz, 50-H), 7.36 (1H, dd, J = 7.7, 1.2 Hz, 30-H), 7.89 (1H,
dd, J = 7.7, 1.6 Hz, 60-H). 13C NMR (100 MHz, CDCl3): d = 34.8 (5-
C), 42.6 (3-C), 72.7 (2-C), 75.2 (4-C), 122.0 (9-C), 125.1 (5a-C),
127.0 (50-C), 127.4 (8-C), 128.0 (60-C), 128.1 (40-C), 129.2 (30-C),
130.4 (6-C), 132.2 (20-C), 135.8 (7-C), 141.4 (10-C), 148.0 (9a-C).
MS (EI): m/z (%) = 285 (35Cl, 51) [M+], 268 (18), 256 (2), 242 (4),
144 (4), 118 (100), 91 (18), 77 (19). Anal. Calcd for C17H16ClNO:
C, 71.45; H, 5.64; N, 4.90. Found: C, 71.56; H, 5.60; N, 4.81.
Maroon viscous oil, 1.94 g (67%). IR (liquid film): v = 1015 (–C–
O–), 998 (–N–O–) cmꢂ1. 1H NMR (400 MHz, CDCl3): d = 2.53 (1H, d,
J = 16.8 Hz, 5-HA), 2.53–2.62 (2H, m, 3-HAHB), 3.39 (1H, dd, J = 16.8,
5.6 Hz, 5-HB), 4.53 (1H, dd, J = 7.2, 4.0 Hz, 2-H), 4.93 (1H, ddd,
J = 6.4, 5.6, 2.6 Hz, 4-H), 6.83–6.88 (2H, m, 6-H, 8-H), 7.03 (1H,
dd, J = 8.4, 5.2 Hz, 9-H), 7.32 (2H, d, J = 8.0 Hz, 30-H, 50-H), 7.39
(2H, d, J = 8.0 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 34.9
(5-C), 42.7 (3-C), 74.6 (2-C), 74.8 (4-C), 113.7 (8-C), 116.3 (d,
J = 20.0 Hz, 6-C), 123.5 (d, J = 10.0 Hz, 9-C), 127.4 (5a-C), 127.9
(20-C, 60-C), 128.7 (30-C, 50-C), 132.9 (40-C), 142.2 (10-C), 146.3
(9a-C), 160.8 (d, J = 250.0 Hz, 7-C). MS (EI): m/z (%) = 289 (35Cl,
20) [M+], 272 (8), 260 (2), 246 (2), 148 (5), 122 (100), 109 (9), 95
(5). Anal. Calcd for C16H13C lFNO: C, 66.33; H, 4.52; N, 4.83. Found:
C, 66.19; H, 4.59; N, 4.88.
4.4.18. 7-Chloro-1,4-epoxy-2-exo-(20-chlorophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6r)
White crystals, 2.14 g (70%), mp: 167–169 °C (from heptane).
IR (KBr): v = 1030 (–C–O–), 1000 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.49 (1H, dddd, J = 12.8, 7.7, 2.8, 1.2 Hz, 3-
HB), 2.55 (1H, d, J = 16.8 Hz, 5-HA), 2.70 (1H, ddd, J = 12.8, 8.6,
1.6 Hz, 3-HA), 3.39 (1H, dd, J = 16.8, 5.4 Hz, 5-HB), 4.86 (1H, dd,
J = 8.6, 2.8 Hz, 2-H), 4.90 (1H, ddd, J = 7.1, 5.4, 0.8 Hz, 4-H), 7.03
(1H, d, J = 8.2 Hz, 9-H), 7.15 (1H, s, 6-H), 7.16 (1H, d, J = 8.2 Hz,
8-H), 7.22 (1H, td, J = 7.7, 1.6 Hz, 40-H), 7.31 (1H, dd, J = 7.7,
0.9 Hz, 30-H), 7.34 (1H, td, J = 7.8, 0.9 Hz, 50-H), 7.84 (1H, dd,
J = 7.8, 1.6 Hz, 60-H). 13C NMR (100 MHz, CDCl3): d = 34.5 (5-C),
42.4 (3-C), 72.4 (2-C), 74.6 (4-C), 123.4 (9-C), 126.8 (8-C), 126.9
(30-C), 127.2 (40-C), 127.3 (5a-C), 127.7 (60-C), 129.1 (50-C), 129.6
(6-C), 131.3 (7-C), 132.0 (20-C), 140.7 (10-C), 148.8 (9a-C). MS
(EI): m/z (%) = 305 (35Cl, 20) [M+], 288 (7), 276 (1), 262 (1), 164
(5), 138 (100), 125 (12), 111 (4). Anal. Calcd for C16H13C l2NO:
C, 62.76; H, 4.28; N, 4.57. Found: C, 62.65; H, 4.20; N, 4.65.
4.4.15. 1,4-Epoxy-2-exo-(20-chlorophenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6o)
White crystals, 1.71 g (63%), mp: 112–114 °C (from heptane).
IR (KBr): v = 1033 (–C–O–), 999 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.50 (1H, dddd, J = 12.7, 7.7, 2.8, 1.2 Hz, 3-
HB), 2.58 (1H, d, J = 16.6 Hz, 5-HA), 2.74 (1H, ddd, J = 12.7, 8.7,
1.6 Hz, 3-HA), 3.44 (1H, dd, J = 16.6, 5.3 Hz, 5-HB), 4.91–4.94
(2H, m, 2-H, 4-H), 7.10 (1H, dd, J = 8.1, 2.0 Hz, 9-H), 7.16–7.21
(3H, m, 6-H, 7-H, 8-H), 7.22 (1H, td, J = 7.5, 1.5 Hz, 40-H), 7.32
(1H, dd, J = 7.5, 1.1 Hz, 30-H), 7.35 (1H, td, J = 7.7, 1.1 Hz, 50-H),
7.90 (1H, dd, J = 7.7, 1.5 Hz, 60-H). 13C NMR (100 MHz, CDCl3):
d = 34.6 (5-C), 42.4 (3-C), 72.5 (2-C), 75.0 (4-C), 122.0 (9-C),
125.3 (5a-C), 126.1 (7-C), 126.6 (8-C), 126.9 (30-C), 127.8 (60-C),
128.0 (40-C), 129.1 (50-C), 129.8 (6-C), 132.0 (20-C), 141.1 (10-C),
150.3 (9a-C). MS (EI): m/z (%) = 271 (35Cl, 50) [M+], 254 (19),
242 (2), 228 (2), 130 (4), 104 (100), 91 (25), 77 (26). Anal. Calcd
for C16H14ClNO: C, 70.72; H, 5.19; N, 5.15. Found: C, 70.81; H,
5.28; N, 5.08.
4.4.19. 7-Chloro-1,4-epoxy-2-exo-(20-fluorophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6s)
Yellow crystals, 1.91 g (66%), mp: 86–87 °C (from heptane). IR
(KBr): v = 1027 (–C–O–), 999 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.55 (1H, d, J = 16.8 Hz, 5-HA), 2.54–2.61 (1H, m, 3-
HB), 2.64 (1H, ddd, J = 12.9, 8.4, 2.0 Hz, 3-HA), 3.40 (1H, dd,
J = 16.8, 5.4 Hz, 5-HA), 4.84 (1H, d, J = 6.4 Hz, 2-H), 4.93 (1H,
ddd, J = 7.1, 5.4, 1.8 Hz, 4-H), 7.03 (1H, td, J = 7.8, 1.0 Hz, 30-H),
7.04 (1H, d, J = 7.8 Hz, 9-H), 7.14 (1H, br s, 6-H), 7.15 (1H, d,
J = 7.8 Hz, 8-H), 7.18 (1H, td, J = 7.7, 1.0 Hz, 50-H), 7.24–7.28
(1H, m, 40-H), 7.44 (1H, td, J = 7.7, 1.6 Hz, 60-H). 13C NMR
(100 MHz, CDCl3): d = 34.7 (5-C), 42.0 (3-C), 69.0 (d, J = 2.0 Hz,
2-C), 74.8 (4-C), 115.2 (d, J = 21.0 Hz, 30-C), 123.5 (9-C), 124.3
(d, J = 4.0 Hz, 50-C), 127.0 (8-C), 127.3 (5a-C), 127.9 (d,
J = 4.0 Hz, 60-C), 128.7 (d, J = 8.0 Hz, 40-C), 129.8 (6-C), 130.5 (d,
J = 14.0 Hz, 10-C), 131.5 (7-C), 149.0 (9a-C), 159.9 (d,
J = 244.0 Hz, 20-C). MS (EI): m/z (%) = 289 (35Cl, 32) [M+], 272
(8), 260 (4), 246 (3), 164 (3), 138 (100), 125 (6), 111 (2). Anal.
Calcd for C16H13C lFNO: C, 66.33; H, 4.52; N, 4.83. Found: C,
66.27; H, 4.60; N, 4.89.
4.4.16. 1,4-Epoxy-2-exo-(20-fluorophenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (6p)
Yellow crystals, 1.61 g (63%), mp: 54–55 °C (from heptane). IR
(KBr): v = 1029 (–C-O–), 998 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.55 (1H, dddd, J = 12.7, 7.7, 2.8, 1.4 Hz, 3-HB), 2.57
(1H, d, J = 16.6 Hz, 5-HA), 2.66 (1H, ddd, J = 12.7, 8.5, 1.9 Hz, 3-
HA), 3.44 (1H, dd, J = 16.6, 5.4 Hz, 5-HB), 4.91 (1H, br d,
J = 7.8 Hz, 2-H), 4.96 (1H, ddd, J = 7.5, 5.6, 1.2 Hz, 4-H), 7.04 (1H,
ddd, J = 8.2, 8.0, 1.2 Hz, 30-H), 7.10 (1H, dd, J = 6.4, 1.7 Hz, 9-H),
7.15–7.27 (5H, m, 6-H, 7-H, 8-H, 40-H, 50-H), 7.80 (1H, td, J = 7.6,
1.7 Hz, 60-H). 13C NMR (100 MHz, CDCl3): d = 34.8 (5-C), 42.1
(3-C), 69.0 (d, J = 2.5 Hz, 2-C), 75.1 (4-C), 115.0 (d, J = 21.3 Hz,
30-C), 122.1 (9-C), 124.3 (d, J = 3.4 Hz, 50-C), 125.4 (5a-C), 126.2
(7-C), 126.8 (8-C), 128.0 (d, J = 4.0 Hz, 60-C), 128.6 (d, J = 8.1 Hz,
40-C), 129.9 (6-C), 130.8 (d, J = 13.2 Hz, 10-C), 150.4 (9a-C), 159.9
(d, J = 243.4 Hz, 20-C). MS (EI): m/z (%) = 255 (43) [M+], 238 (15),
226 (4), 212 (5), 130 (4), 104 (100), 91 (17), 77 (15). Anal. Calcd
for C16H14FNO: C, 75.28; H, 5.53; N, 5.49. Found: C, 75.14; H,
5.62; N, 5.42.
4.4.20. 1,4-Epoxy-2-exo-(20,60-dichlorophenyl)-2,3,4,5-tetrahy-
dro-1(1H)-benzazepine (6t)
White crystals, 1.98 g (65%), mp: 171–172 °C (from heptane). IR
(KBr): v = 1022 (–C–O–), 996 (–N–O–) cmꢂ1 1H NMR (400 MHz,
.
CDCl3): d = 2.44 (1H, ddd, J = 12.9, 9.3, 1.9 Hz, 3-HA), 2.61 (1H, d,
J = 16.6 Hz, 5-HA), 3.37 (1H, dddd, J = 12.9, 7.6, 3.0, 1.0 Hz, 3-HB),
3.47 (1H, dd, J = 16.6, 5.4 Hz, 5-HB), 5.15 (1H, ddd, J = 7.4, 5.4,
1.9 Hz, 4-H), 5.41 (1H, dd, J = 9.3, 3.0 Hz, 2-H), 7.13–7.19 (3H, m,
6-H, 7-H, 40-H), 7.20 (1H, td, J = 8.0, 2.5 Hz, 8-H), 7.25 (1H, dd,
J = 8.0, 1.0 Hz, 9-H), 7.37 (2H, d, J = 8.0 Hz, 30-H, 50-H). 13C NMR
(100 MHz, CDCl3): d = 34.7 (5-C), 38.4 (3-C), 72.2 (2-C), 76.2
(4-C), 122.2 (9-C), 125.6 (5a-C), 126.2 (7-C), 126.7 (8-C), 129.1
(6-C), 129.9 (40-C), 130.1 (30-C, 50-C), 135.9 (10-C), 136.1 (20-C,
60-C), 151.3 (9a-C). MS (EI): m/z (%) = 305 (35Cl, 8) [M+], 288 (4),
276 (1), 262 (2), 130 (1), 104 (100), 91 (25), 77 (18). Anal. Calcd
for C16H13C l2NO: C, 62.76; H, 4.28; N, 4.57. Found: C, 62.85; H,
4.19; N, 4.51.
4.4.17. 1,4-Epoxy-2-exo-(20-chlorophenyl)-7-methyl-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6q)
White crystals, 2.03 g (71%), mp: 122–124 °C (from heptane).
IR (KBr): v = 1017 (–C–O–), 969 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.34 (3H, s, 7-CH3), 2.48 (1H, dddd,
J = 12.8, 7.7, 2.8, 1.5 Hz, 3-HB), 2.54 (1H, d, J = 16.7 Hz, 5-HA),
2.73 (1H, ddd, J = 12.8, 8.7, 1.8 Hz, 3-HA), 3.39 (1H, dd, J = 16.7,
5.4 Hz, 5-HB), 4.89 (1H, dd, J = 8.7, 2.8 Hz, 2-H), 4.90 (1H, ddd,
J = 6.9, 5.4, 1.8 Hz, 4-H), 6.98 (2H, d, J = 6.4 Hz, 8-H, 9-H), 6.99
(1H, br s, 6-H), 7.22 (1H, td, J = 7.7, 1.6 Hz, 40-H), 7.33 (1H, td,

4734
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4.4.21. 1,4-Epoxy-2-exo-(60-chloro-20-fluorophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6u)
sulfate, filtered and then concentrated under reduced pressure. The
remaining crude material was purified by column chromatography
on silica gel using heptane–ethyl acetate (compositions ranged
from 15:1 to 1:1 v/v) as eluent to give amino-alcohols 7a–s.
Procedure 2: To a stirred solution of the appropriately substi-
tuted 1,4-epoxy-cycloadducts 6t–w (0.010 mol) in glacial acetic
acid (10–15 mL) was added zinc powder (0.080 mol) and hydro-
chloric acid (37% HCl, 0.040 mol). The resulting mixture was then
stirred at room temperature for 10–14 h (TLC control). Each mix-
ture was filtered and the filtrate was neutralized with a 25%
ammonium hydroxide solution to pH 8, and then extracted with
ethyl acetate (3 ꢃ 50 mL). The combined organic extracts were
dried over anhydrous sodium sulfate, filtered and then concen-
trated under reduced pressure. The remaining crude material
was purified by column chromatography on silica gel using hep-
tane–ethyl acetate (compositions ranged from 15:1 to 1:1 v/v) as
eluent to give amino-alcohols 7t–w.
White crystals, 1.88 g (65%), mp: 160–161 °C (from heptane).
IR (KBr): v = 1025 (–C–O–), 991 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.39 (1H, dddd, J = 12.6, 8.8, 4.7, 2.2 Hz, 3-
HB), 2.58 (1H, d, J = 16.4 Hz, 5-HA), 3.07 (1H, ddd, J = 12.6, 7.7,
0.8 Hz, 3-HA), 3.45 (1H, dd, J = 16.4, 5.1 Hz, 5-HB), 5.11 (1H, ddd,
J = 7.3, 5.1, 2.0 Hz, 4-H), 5.17 (1H, dd, J = 8.8, 0.9 Hz, 2-H), 7.00
(1H, ddd, J = 8.2, 8.0, 1.4 Hz, 30-H), 7.12–7.25 (6H, m, 6-H, 7-H,
8-H, 9-H, 40-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 35.1 (5-C),
38.2 (d, J = 6.2 Hz, 3-C), 70.8 (d, J = 2.7 Hz, 2-C), 75.8 (d,
J = 1.8 Hz, 4-C), 115.9 (d, J = 25.0 Hz, 30-C), 122.1 (9-C), 125.5
(5a-C), 125.8 (d, J = 3.3 Hz, 50-C), 126.2 (7-C), 126.7 (8-C), 127.1
(d, J = 14.5 Hz, 10-C), 129.5 (d, J = 10.4 Hz, 40-C), 129.9 (6-C),
136.1 (d, J = 6.7 Hz, 60-C), 150.3 (9a-C), 161.9 (d, J = 248.0 Hz, 20-
C). MS (EI): m/z (%) = 289 (35Cl, 32) [M+], 272 (7), 260 (1), 246
(3), 130 (4), 104 (100), 91 (10), 77 (10). Anal. Calcd for C16H13
C
lFNO: C, 66.33; H, 4.52; N, 4.83. Found: C, 66.22; H, 4.59; N, 4.88.
4.5.1. cis-4-Hydroxy-2-phenyl-2,3,4,5-tetrahydro-1(1H)-
benzazepine (7a)
4.4.22. 7-Chloro-1,4-epoxy-2-exo-(20,60-dichlorophenyl)-2,3,4,5-
tetrahydro-1(1H)-benzazepine (6v)
White crystals, 2.15 g (90%), mp: 97–99 °C (from heptane–
Yellow crystals, 2.14 g (63%), mp: 60–61 °C (from heptane). IR
ethyl acetate, 20:1). IR (KBr): v = 3341 (NH, OH) cmꢂ1
.
1H NMR
(KBr): v = 1024 (–C–O–), 977 (–N–O–) cmꢂ1
.
1H NMR (400 MHz,
(400 MHz, CDCl3): d = 2.14 (1H, ddd, J = 11.1, 10.7, 10.5 Hz, 3-
Hax), 2.22 (1H, ddt, J = 10.7, 2.9, 1.9 Hz, 3-Heq), 3.03 (1H, dt,
J = 13.6, 1.9 Hz, 5-Heq), 3.13 (1H, dd, J = 13.6, 10.5 Hz, 5-Hax),
3.88 (1H, tdd, J = 10.2, 2.9, 1.9 Hz, 4-Hax), 3.98 (1H, dd, J = 11.1,
1.9 Hz, 2-Hax), 6.70 (1H, d, J = 7.6 Hz, 9-H), 6.92 (1H, t, J = 7.6 Hz,
7-H), 7.10 (1H, t, J = 7.6 Hz, 8-H), 7.18 (1H, d, J = 7.6 Hz, 6-H),
7.35 (1H, t, J = 6.9 Hz, 40-H), 7.39 (2H, d, J = 6.9 Hz, 20-H, 60-H),
7.43 (2H, t, J = 7.0 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3):
d = 44.7 (5-C), 48.5 (3-C), 61.3 (2-C), 70.0 (4-C), 120.1 (9-C),
121.8 (7-C), 126.6 (20-C, 60-C), 127.4 (8-C), 127.8 (40-C), 128.0
(5a-C), 129.9 (30-C, 50-C), 131.6 (6-C), 145.1 (10-C), 149.4 (9a-C).
MS (EI): m/z (%) = 239 (100) [M+], 221 (3), 220 (16), 195 (72),
194 (94), 118 (98), 106 (57), 91 (30), 77 (27). Anal. Calcd for
C16H17NO: C, 80.30; H, 7.16; N, 5.85. Found: C, 80.44; H, 7.03;
N, 5.76.
CDCl3): d = 2.41 (1H, ddd, J = 12.9, 9.3, 1.9 Hz, 3-HA), 2.59 (1H, d,
J = 16.7 Hz, 5-HA), 3.37 (1H, dddd, J = 12.9, 7.5, 3.1, 1.2 Hz, 3-HB),
3.42 (1H, dd, J = 16.7, 5.3 Hz, 5-HB), 5.13 (1H, ddd, J = 7.4, 5.3,
1.8 Hz, 4-H), 5.36 (1H, dd, J = 9.3, 3.1 Hz, 2-H), 7.13–7.17 (3H, m,
6-H, 8-H, 40-H), 7.18 (1H, dd, J = 7.9, 0.6 Hz, 9-H), 7.36 (2H, d,
J = 8.0 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 34.6 (5-C),
38.4 (3-C), 72.2 (2-C), 75.7 (4-C), 123.6 (9-C), 126.9 (8-C), 127.6
(5a-C), 129.3 (6-C), 129.8 (40-C), 130.1 (30-C, 50-C), 135.5 (10-C),
131.5 (7-C), 136.1 (20-C, 60-C), 149.7 (9a-C). MS (EI): m/z (%) = 339
(
35Cl, 9) [M+], 324 (2), 312 (1), 298 (1), 164 (4), 138 (100), 125
(9), 111 (4). Anal. Calcd for C16H12Cl3NO: C, 56.42; H, 3.55; N,
4.11. Found: C, 56.50; H, 3.62; N, 4.03.
4.4.23. 7-Chloro-1,4-epoxy-2-exo-(60-chloro-20-fluorophenyl)-
2,3,4,5-tetrahydro-1(1H)-benzazepine (6w)
White crystals, 1.97 g (61%), mp: 156–157 °C (from heptane).
4.5.2. cis-4-Hydroxy-2-phenyl-7-trifluoromethoxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7b)
IR (KBr): v = 1024 (–C–O–), 973 (–N–O–) cmꢂ1
.
1H NMR
(400 MHz, CDCl3): d = 2.37 (1H, dddd, J = 12.7, 8.8, 4.7, 2.3 Hz, 3-
HB), 2.56 (1H, d, J = 16.6 Hz, 5-HA), 3.09 (1H, ddd, J = 12.7, 7.6,
0.8 Hz, 3-HA), 3.42 (1H, dd, J = 16.6, 5.1 Hz, 5-HB), 5.08–5.13
(2H, m, 2-H, 4-H), 7.01 (1H, ddd, J = 8.1, 7.7, 1.7 Hz, 30-H), 7.13
(1H, s, 6-H), 7.15–7.25 (3H, m, 8-H, 9-H, 40-H), 7.26 (1H, dd,
J = 8.4, 1.7 Hz, 50-H). 13C NMR (100 MHz, CDCl3): d = 35.2 (5-C),
38.4 (d, J = 6.2 Hz, 3-C), 71.2 (d, J = 2.7 Hz, 2-C), 75.8 (d,
J = 1.8 Hz, 4-C), 116.6 (d, J = 25.0 Hz, 30-C), 124.3 (9-C), 126.6 (d,
J = 3.4 Hz, 50-C), 127.5 (d, J = 14.6 Hz, 10-C), 127.7 (8-C), 128.2
(5a-C), 130.5 (d, J = 10.5 Hz, 40-C), 130.6 (6-C), 132.2 (7-C), 136.9
(d, J = 6.7 Hz, 60-C), 149.7 (9a-C), 162.9 (d, J = 252.1 Hz, 20-C). MS
(EI): m/z (%) = 323 (35Cl, 17) [M+], 306 (3), 294 (1), 280 (1), 164
(3), 138 (100), 125 (6), 111 (4). Anal. Calcd for C16H12Cl2FNO: C,
59.28; H, 3.73; N, 4.32. Found: C, 59.16; H, 3.60; N, 4.21.
Maroon viscous oil, 2.49 g (77%). IR (liquid film): v = 3354 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.13 (1H, ddd, J = 12.9,
.
11.2, 9.9 Hz, 3-Hax), 2.20 (1H, ddt, J = 12.9, 4.2, 2.0 Hz, 3-Heq),
2.98 (1H, dt, J = 13.6, 2.2 Hz, 5-Heq), 3.01 (1H, dd, J = 13.6,
10.1 Hz, 5-Hax), 3.88 (1H, tdd, J = 10.0, 4.1, 1.6 Hz, 4-Hax), 3.96
(1H, dd, J = 11.2, 2.3 Hz, 2-Hax), 6.67 (1H, d, J = 8.4 Hz, 9-H), 6.93
(1H, dd, J = 8.4, 2.4 Hz, 8-H), 7.04 (1H, d, J = 2.4 Hz, 6-H), 7.31–
7.45 (5H, m, 20-H, 30-H, 40-H, 50-H, 60-H). 13C NMR (100 MHz,
CDCl3): d = 44.4 (5-C), 48.1 (3-C), 61.1 (2-C), 69.5 (4-C), 120.0
(8-C), 120.6 (q, J = 256.0 Hz, 7-OCF3), 120.8 (9-C), 124.2 (6-C),
126.4 (20-C, 60-C), 128.0 (40-C), 129.0 (30-C, 50-C), 129.5 (5a-C),
143.5 (7-C), 144.3 (10-C), 147.8 (9a-C). MS (EI): m/z (%) = 323
(80) [M+], 305 (3), 304 (10), 279 (67), 278 (73), 202 (100), 190
(55), 175 (4), 161 (1). Anal. Calcd for C17H16F3NO2: C, 63.15; H,
4.99; N, 4.33. Found: C, 63.07; H, 4.87; N, 4.41.
4.5. General procedures for the synthesis of cis-2-aryl-4-
hydroxy-2,3,4,5-tetrahydro-1(1H)-benzazepines 7a–w
4.5.3. 7-Bromo-cis-4-hydroxy-2-phenyl-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7c)
Procedure 1: To a stirred solution of the appropriately substi-
tuted 1,4-epoxy-cycloadducts 6a–s (0.010 mol) in 80% acetic acid
(10–30 mL) was added zinc powder (0.060–0.080 mol). The result-
ing mixture was then stirred at 70–90 °C for 4–12 h (TLC control).
After cooling to room temperature, each mixture was filtered and
the filtrate was neutralized with a 25% ammonium hydroxide solu-
tion to pH 8, and then extracted with ethyl acetate (3 ꢃ 50 mL).
The combined organic extracts were dried over anhydrous sodium
Maroon viscous oil, 2.73 g (86%). IR (liquid film): v = 3346 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.11 (1H, ddd, J = 12.9,
.
11.3, 10.45 Hz, 3-Hax), 2.20 (1H, ddt, J = 12.9, 4.1, 2.0 Hz, 3-Heq),
2.95 (1H, dt, J = 13.6, 1.9 Hz, 5-Heq), 3.06 (1H, dd, J = 13.6, 10.0 Hz,
5-Hax), 3.86 (1H, tdd, J = 10.0, 4.1, 2.0 Hz, 4-Hax), 3.94 (1H, dd,
J = 11.3, 2.0 Hz, 2-Hax), 6.56 (1H, d, J = 8.3 Hz, 9-H), 7.16 (1H, dd,
J = 8.3, 2.2 Hz, 8-H), 7.29 (1H, d, J = 2.2 Hz, 6-H), 7.32–7.41 (5H,
m, 20-H, 30-H, 40-H, 50-H, 60-H). 13C NMR (100 MHz, CDCl3):

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4735
d = 44.2 (5-C), 48.2 (3-C), 61.2 (2-C), 69.8 (4-C), 113.9 (7-C), 121.8
(9-C), 126.5 (20-C, 60-C), 128.1 (40-C), 129.2 (30-C, 50-C), 130.2 (5a-
C), 130.3 (8-C), 134.2 (6-C), 144.5 (10-C), 148.4 (9a-C). MS (EI): m/
z (%) = 317 (79Br, 80) [M+], 300 (10), 299 (7), 273 (40), 272 (23),
193 (60), 117 (100), 105 (57), 89 (50). Anal. Calcd for C16H16BrNO:
C, 60.39; H, 5.07; N, 4.40. Found: C, 60.27; H, 5.17; N, 4.36.
Heq), 3.01 (1H, d, J = 13.6 Hz, 5-Heq), 3.13 (1H, dd, J = 13.6, 10.5 Hz,
5-Hax), 3.86 (1H, tdd, J = 10.1, 4.4, 1.5 Hz, 4-Hax), 3.95 (1H, dd,
J = 10.8, 2.6 Hz, 2-Hax), 6.74 (1H, d, J = 7.7 Hz, 9-H), 6.93 (1H, t,
J = 7.6 Hz, 7-H), 7.06 (2H, t, J = 8.6 Hz, 30-H, 50-H), 7.10 (1H, td,
J = 7.7, 1.2 Hz, 8-H), 7.17 (1H, d, J = 7.6 Hz, 6-H), 7.34–7.43 (2H,
m, 20-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 44.6 (3-C), 48.5 (5-
C), 60.8 (2-C), 70.0 (4-C), 115.6 (d, J = 21.2 Hz, 30-C, 50-C), 120.5
(9-C), 122.4 (7-C, 5a-C), 127.8 (8-C), 128.2 (d, J = 7.9 Hz, 20-C, 60-
C), 131.8 (6-C), 140.4 (10-C), 148.7 (9a-C), 162.4 (d, J = 244.7 Hz,
40-C). MS (EI): m/z (%) = 257 (63) [M+], 239 (7), 238 (13), 213
(63), 212 (80), 118 (90), 106 (100), 91 (37), 77 (33), 65 (17). Anal.
Calcd for C16H16FNO: C, 74.69; H, 6.27; N, 5.44. Found: C, 74.77; H,
6.18; N, 5.36.
4.5.4. 7-Chloro-cis-4-hydroxy-2-phenyl-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7d)
Maroon viscous oil, 2.22 g (81%). IR (liquid film): v = 3350 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.11 (1H, ddd, J = 13.1,
.
11.3, 10.0 Hz, 3-Hax), 2.19 (1H, ddt, J = 13.1, 4.2, 2.1 Hz, 3-Heq),
2.95 (1H, dt, J = 13.5, 1.9 Hz, 5-Heq), 3.10 (1H, dd, J = 13.5,
10.2 Hz, 5-Hax), 3.85 (1H, tdd, J = 10.0, 4.0, 1.5 Hz, 4-Hax), 3.92
(1H, dd, J = 11.3, 2.2 Hz, 2-Hax), 6.61 (1H, d, J = 8.3 Hz, 9-H), 7.03
(1H, dd, J = 8.3, 2.5 Hz, 8-H), 7.14 (1H, d, J = 2.4 Hz, 6-H), 7.31–
7.43 (5H, m, 20-H, 30-H, 40-H, 50-H, 60-H). 13C NMR (100 MHz,
CDCl3): d = 44.1 (5-C), 48.1 (3-C), 61.2 (2-C), 69.6 (4-C), 121.4
(9-C), 126.5 (20-C, 60-C), 127.3 (7-C, 8-C), 128.1 (40-C), 129.9 (30-
C, 50-C), 129.9 (5a-C), 131.3 (6-C), 144.5 (10-C), 147.8 (9a-C). MS
(EI): m/z (%) = 273 (35Cl, 100) [M+], 255 (3), 254 (12), 229 (86),
228 (72), 152 (90), 140 (66), 125 (11), 111 (4), 99 (7). Anal. Calcd
for C16H16ClNO: C, 70.20; H, 5.89; N, 5.12. Found: C, 70.32; H,
5.78; N, 5.21.
4.5.8. cis-4-Hydroxy-2-(30-methoxyphenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7h)
Yellow crystals, 2.42 g (90%), mp: 95–96 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3337 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.11 (1H, ddd, J = 12.8, 11.3, 10.0 Hz, 3-
Hax), 2.21 (1H, ddt, J = 12.8, 4.1, 2.0 Hz, 3-Heq), 3.02 (1H, dt,
J = 13.5, 2.2 Hz, 5-Heq), 3.11 (1H, dd, J = 13.5, 10.1 Hz, 5-Hax),
3.85 (3H, s, 30-OCH3), 3.88 (1H, tdd, J = 9.9, 4.0, 1.2 Hz, 4-Hax),
3.95 (1H, dd, J = 11.3, 2.0 Hz, 2-Hax), 6.70 (1H, dd, J = 8.0, 1.0 Hz,
9-H), 6.87 (1H, dd, J = 8.1, 1.6 Hz, 40-H), 6.91 (1H, td, J = 8.0,
1.0 Hz, 7-H), 6.98 (1H, d, J = 1.6 Hz, 20-H), 6.99 (1H, d, J = 8.1 Hz,
60-H), 7.08 (1H, td, J = 8.0, 1.0 Hz, 8-H), 7.17 (1H, dd, J = 8.0,
1.0 Hz, 6-H), 7.30 (1H, t, J = 8.1 Hz, 50-H). 13C NMR (100 MHz,
CDCl3): d = 44.7 (5-C), 48.6 (3-C), 55.4 (30-OCH3), 61.3 (2-C), 70.1
(4-C), 112.1 (20-C), 113.4 (40-C), 118.9 (60-C), 120.3 (9-C), 121.9
(7-C), 127.6 (8-C), 128.1 (5a-C), 130.1 (50-C), 131.8 (6-C), 146.5
(10-C), 149.3 (9a-C), 160.2 (30-C). MS (EI): m/z (%) = 269 (90)
[M+], 251 (3), 250 (7), 225 (63), 224 (70), 145 (7), 118 (100),
106 (57), 91 (33), 77 (23). Anal. Calcd for C17H19NO2: C, 75.81;
H, 7.11; N, 5.20. Found: C, 75.92; H, 7.00; N, 5.28.
4.5.5. 7-Fluoro-cis-4-hydroxy-2-phenyl-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7e)
Maroon viscous oil, 2.39 g (93%). IR (liquid film): v = 3355 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.10 (1H, ddd, J = 12.9,
.
11.2, 10.1 Hz, 3-Hax), 2.19 (1H, ddt, J = 12.9, 4.0, 2.2 Hz, 3-Heq),
2.93 (1H, dt, J = 13.5, 2.0 Hz, 5-Heq), 3.11 (1H, dd, J = 13.5,
10.5 Hz, 5-Hax), 3.76 (1H, tdd, J = 10.1, 3.8, 1.3 Hz, 4-Hax), 3.89
(1H, dd, J = 11.2, 2.2 Hz, 2-Hax), 6.63 (1H, dd, J = 8.4, 5.2 Hz, 9-
H), 6.77 (1H, td, J = 8.3, 3.1 Hz, 8-H), 7.14 (1H, dd, J = 9.2, 3.1 Hz,
6-H), 7.33–7.42 (5H, m, 20-H, 30-H, 40-H, 50-H, 60-H). 13C NMR
(100 MHz, CDCl3): d = 44.3 (5-C), 48.3 (3-C), 61.4 (2-C), 69.6 (4-
C), 113.6 (d, J = 22.0 Hz, 8-C), 117.7 (d, J = 22.0 Hz, 6-C), 121.1
(d, J = 8.1 Hz, 9-C), 126.3 (20-C, 60-C), 127.8 (40-C), 128.9 (30-C,
50-C), 130.1 (d, J = 7.4 Hz, 5a-C), 144.4 (10-C), 145.2 (9a-C), 158.0
(d, J = 239.9 Hz, 7-C). MS (EI): m/z (%) = 257 (57) [M+], 239 (2),
238 (9), 213 (47), 212 (64), 136 (100), 124 (53), 109 (24), 95
(8), 83 (14). Anal. Calcd for C16H16FNO: C, 74.69; H, 6.27; N,
5.44. Found: C, 74.60; H, 6.33; N, 5.48.
4.5.9. cis-4-Hydroxy-2-(30-methylphenyl)-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7i)
Maroon viscous oil, 2.30 g (91%). IR (liquid film): v = 3356 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.14 (1H, ddd, J = 12.9,
.
11.0, 10.4 Hz, 3-Hax), 2.21 (1H, ddt, J = 12.9, 4.1, 2.1 Hz, 3-Heq),
2.41 (3H, s, 30-CH3), 3.03 (1H, dt, J = 13.5, 2.0 Hz, 5-Heq), 3.13
(1H, dd, J = 13.5, 10.2 Hz, 5-Hax), 3.88 (1H, tdd, J = 9.9, 4.1,
1.5 Hz, 4-Hax), 3.94 (1H, dd, J = 11.0, 2.3 Hz, 2-Hax), 6.70 (1H, d,
J = 7.8 Hz, 9-H), 6.92 (1H, td, J = 7.5, 0.9 Hz, 7-H), 7.10 (1H, td,
J = 7.6, 0.8 Hz, 8-H), 7.17 (1H, br d, J = 7.5 Hz, 40-H), 7.18 (1H, d,
J = 7.6 Hz, 6-H), 7.23 (1H, d, J = 7.4 Hz, 60-H), 7.27 (1H, br s, 20-
H), 7.30 (1H, t, J = 7.4 Hz, 50-H). 13C NMR (100 MHz, CDCl3):
d = 21.4 (30-CH3), 44.5 (5-C), 48.3 (3-C), 61.1 (2-C), 70.0 (4-C),
120.1 (9-C), 121.7 (7-C), 123.4 (60-C), 127.1 (20-C), 127.4 (8-C),
128.0 (5a-C), 128.5 (40-C), 128.8 (50-C), 131.6 (6-C), 138.6 (30-C),
144.6 (10-C), 149.2 (9a-C). MS (EI): m/z (%) = 253 (87) [M+], 235
(2), 234 (9), 209 (70), 208 (88), 118 (100), 106 (55), 91 (50), 77
(29), 65 (21). Anal. Calcd for C17H19NO: C, 80.60; H, 7.56; N,
5.53. Found: C, 80.73; H, 7.50; N, 5.61.
4.5.6. cis-2-(40-Chlorophenyl)-4-hydroxy-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7f)
Maroon viscous oil, 2.41 g (88%). IR (liquid film): v = 3348 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.08 (1H, ddd, J = 12.9,
.
11.2, 10.0 Hz, 3-Hax), 2.13 (1H, ddt, J = 12.9, 4.2, 2.0 Hz, 3-Heq),
3.00 (1H, dt, J = 13.4, 2.1 Hz, 5-Heq), 3.10 (1H, dd, J = 13.4, 10.2 Hz,
5-Hax), 3.85 (1H, tdd, J = 10.0, 4.1, 1.6 Hz, 4-Hax), 3.93 (1H, dd,
J = 11.2, 2.3 Hz, 2-Hax), 6.70 (1H, dd, J = 7.8, 0.8 Hz, 9-H), 6.92 (1H,
td, J = 7.4, 1.0 Hz, 7-H), 7.09 (1H, td, J = 7.7, 1.4 Hz, 8-H), 7.16 (1H,
d, J = 7.4 Hz, 6-H), 7.35 (4H, d, J = 8.0 Hz, 20-H, 30-H, 50-H, 60-H).
13C NMR (100 MHz, CDCl3): d = 44.5 (5-C), 48.3 (3-C), 60.5 (2-C),
69.8 (4-C), 120.2 (9-C), 122.0 (7-C), 127.5 (8-C), 127.8 (20-C, 60-C),
128.0 (5a-C), 129.0 (30-C, 50-C), 131.6 (6-C), 133.4 (40-C), 143.0
(10-C), 148.8 (9a-C). MS (EI): m/z (%) = 273 (35Cl, 78) [M+], 255
(10), 254 (12), 229 (68), 228 (63), 118 (100), 106 (89), 91 (33),
77 (45), 65 (19). Anal. Calcd for C16H16ClNO: C, 70.20; H, 5.89; N,
5.12. Found: C, 70.31; H, 6.02; N, 5.01.
4.5.10. cis-2-(30-Chlorophenyl)-4-hydroxy-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7j)
Maroon viscous oil, 2.34 g (87%). IR (liquid film): v = 3347 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.08 (1H, ddd, J = 13.0,
.
11.2, 10.2 Hz, 3-Hax), 2.17 (1H, ddt, J = 13.0, 4.0, 2.0 Hz, 3-Heq),
3.00 (1H, dt, J = 13.5, 1.9 Hz, 5-Heq), 3.11 (1H, dd, J = 13.5, 10.2 Hz,
5-Hax), 3.85 (1H, tdd, J = 10.2, 3.6, 2.8 Hz, 4-Hax), 3.93 (1H, dd,
J = 11.2, 1.6 Hz, 2-Hax), 6.70 (1H, d, J = 8.0 Hz, 9-H), 6.93 (1H, t,
J = 8.0 Hz, 7-H), 7.10 (1H, td, J = 8.0, 1.0 Hz, 8-H), 7.16 (1H, d,
J = 8.0 Hz, 6-H), 7.29–7.32 (3H, m, 40-H, 50-H, 60-H), 7.44 (1H, s,
20-H). 13C NMR (100 MHz, CDCl3): d = 44.5 (5-C), 48.2 (3-C), 60.7
4.5.7. cis-2-(40-Fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7g)
Maroon viscous oil, 2.34 g (91%). IR (liquid film): v = 3340 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.01–2.21 (2H, m, 3-Hax-
.

4736
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
(2-C), 69.7 (4-C), 120.2 (9-C), 122.0 (7-C), 124.6 (60-C), 126.0 (20-C),
127.5 (50-C), 127.9 (5a-C), 128.0 (40-C), 130.2 (8-C), 131.6 (6-C),
134.6 (30-C), 146.5 (10-C), 148.7 (9a-C). MS (EI): m/z (%) = 273
(400 MHz, CDCl3): d = 2.06 (1H, ddd, J = 12.9, 11.8, 10.5 Hz, 3-
Hax), 2.14 (1H, ddt, J = 12.9, 4.0, 2.0 Hz, 3-Heq), 2.91 (1H, dt,
J = 13.5, 2.0 Hz, 5-Heq), 3.09 (1H, dd, J = 13.5, 10.0 Hz, 5-Hax),
3.81 (1H, tdd, J = 10.0, 4.0, 2.0 Hz, 4-Hax), 3.86 (1H, dd, J = 11.8,
2.0 Hz, 2-Hax), 6.64 (1H, dd, J = 8.8, 5.2 Hz, 9-H), 6.77 (1H, td,
J = 8.8, 3.2 Hz, 8-H), 6.87 (1H, dd, J = 9.6, 3.2 Hz, 6-H), 7.33 (2H,
d, J = 8.8 Hz, 20-H, 60-H), 7.35 (2H, d, J = 8.8 Hz, 30-H, 50-H). 13C
NMR (100 MHz, CDCl3): d = 44.4 (5-C), 48.5 (3-C), 60.9 (2-C),
69.5 (4-C), 113.8 (d, J = 20.0 Hz, 8-C), 117.9 (d, J = 20.0 Hz, 6-C),
121.4 (9-C), 127.9 (20-C, 60-C), 129.2 (30-C, 50-C), 130.3 (d,
J = 10.0 Hz, 5a-C), 133.7 (40-C), 143.0 (10-C), 145.0 (9a-C), 158.3
(d, J = 230.0 Hz, 7-C). MS (EI): m/z (%) = 291 (35Cl, 78) [M+], 273
(2), 272 (9), 247 (1), 246 (50), 136 (100), 124 (82), 109 (27), 95
(8), 83 (16). Anal. Calcd for C16H15ClFNO: C, 65.87; H, 5.18; N,
4.80. Found: C, 65.81; H, 5.23; N, 4.73.
(
35Cl, 45) [M+], 255 (2), 254 (9), 229 (35), 228 (30), 118 (100),
106 (49), 91 (27), 77 (32), 65 (13). Anal. Calcd for C16H16ClNO: C,
70.20; H, 5.89; N, 5.12. Found: C, 70.32; H, 5.82; N, 5.20.
4.5.11. cis-4-Hydroxy-2-(40-methylphenyl)-7-methyl-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7k)
Maroon viscous oil, 2.32 g (87%). IR (liquid film): v = 3340 (NH,
OH) cmꢂ1 1H NMR (400 MHz, CDCl3): d = 2.11 (1H, ddd, J = 13.4,
.
11.1, 10.2 Hz, 3-Hax), 2.18 (1H, ddt, J = 13.4, 4.0, 2.0 Hz, 3-Heq),
2.28 (3H, s, 7-CH3), 2.35 (3H, s, 40-CH3), 2.96 (1H, dt, J = 13.6,
1.95 Hz, 5-Heq), 3.10 (1H, dd, J = 13.6, 10.2 Hz, 5-Hax), 3.85 (1H,
tdd, J = 10.1, 4.1, 2.5 Hz, 4-Hax), 3.90 (1H, dd, J = 11.1, 2.3 Hz, 2-
Hax), 6.59 (1H, d, J = 7.8 Hz, 9-H), 6.88 (1H, dd, J = 7.8, 1.4 Hz, 8-H),
6.99 (1H, s, 6-H), 7.19 (2H, d, J = 8.0 Hz, 30-H, 50-H), 7.31 (2H, d,
J = 8.0 Hz, 20-H, 60-H). 13C NMR (100 MHz, CDCl3): d = 20.7 (7-CH3),
21.3 (40-CH3), 44.6 (5-C), 48.8 (3-C), 61.3 (2-C), 70.3 (4-C), 120.2
(9-C), 126.5 (20-C, 60-C), 128.0 (5a-C, 8-C), 129.7 (30-C, 50-C), 131.2
(7-C), 132.4 (6-C), 137.6 (40-C), 142.1 (10-C), 147.0 (9a-C). MS (EI):
m/z (%) = 267 (100) [M+], 249 (2), 248 (7), 223 (71), 222 (65), 132
(51), 120 (73), 91 (27), 77 (18), 65 (7). Anal. Calcd for C18H21NO:
C, 80.86; H, 7.92; N, 5.24. Found: C, 80.80; H, 8.03; N, 5.15.
4.5.15. cis-2-(20-Chlorophenyl)-4-hydroxy-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7o)
White crystals, 2.35 g (86%), mp: 141–142 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3278 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.10 (1H, ddd, J = 12.7, 11.4, 10.0 Hz, 3-Hax),
2.26 (1H, ddt, J = 12.7, 3.7, 1.9 Hz, 3-Heq), 3.02 (1H, dt, J = 13.5,
2.0 Hz, 5-Heq), 3.15 (1H, dd, J = 13.5, 10.0 Hz, 5-Hax), 3.92 (1H, tdd,
J = 10.2, 3.5, 2.9 Hz, 4-Hax), 4.45 (1H, br d, J = 11.4 Hz, 2-Hax), 6.80
(1H, br s, 9-H), 6.95 (1H, t, J = 7.5 Hz, 7-H), 7.13 (1H, td, J = 7.5,
1.1 Hz, 8-H), 7.20 (1H, dd, J = 7.5, 1.1 Hz, 6-H), 7.26 (1H, td, J = 7.6,
1.3 Hz, 40-H), 7.33 (1H, t, J = 7.6 Hz, 50-H), 7.41 (1H, dd, J = 7.8,
1.3 Hz, 30-H), 7.69 (1H, dd, J = 7.6, 1.3 Hz, 60-H). 13C NMR
(100 MHz, CDCl3): d = 44.7 (5-C), 46.6 (3-C), 56.3 (2-C), 70.0 (4-C),
120.5 (9-C), 122.0 (7-C), 127.1 (60-C), 127.5 (50-C, 8-C), 128.2
(5a-C), 128.8 (40-C), 129.8 (30-C), 131.5 (6-C), 132.7 (20-C), 141.9
(10-C), 149.0 (9a-C). MS (EI): m/z (%) = 273 (35Cl, 73) [M+], 256
(11), 254 (10), 229 (39), 228 (29), 118 (100), 106 (48), 91 (26), 77
(33), 65 (15). Anal. Calcd for C16H16ClNO: C, 70.20; H, 5.89; N,
5.12. Found: C, 70.33; H, 5.80; N, 5.18.
4.5.12. 7-Chloro-cis-2-(40-chlorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)- benzazepine (7l)
White crystals, 2.70 g (88%), mp: 106–107 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3354 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.04 (1H, dd, J = 12.8, 11.6 Hz, 3-Hax), 2.14
(1H, ddt, J = 12.8, 4.0, 1.8 Hz, 3-Heq), 2.93 (1H, d, J = 13.6 Hz,
5-Heq), 3.05 (1H, dd, J = 13.6, 10.5 Hz, 5-Hax), 3.82 (1H, tdd,
J = 10.1, 4.4, 2.2 Hz, 4-Hax), 3.89 (1H, dd, J = 11.6, 2.0 Hz, 2-Hax),
6.61 (1H, d, J = 8.0 Hz, 9-H), 7.03 (1H, dd, J = 8.0, 2.4 Hz, 8-H), 7.13
(1H, d, J = 2.4 Hz, 6-H), 7.34 (2H, d, J = 7.6 Hz, 20-H, 60-H), 7.36 (2H,
d, J = 7.6 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 44.3 (5-C),
48.2 (3-C), 60.6 (2-C), 69.2 (4-C), 121.5 (9-C), 126.7 (7-C), 127.3
(8-C), 127.9 (20-C, 60-C), 129.3 (30-C, 50-C), 129.8 (5a-C), 131.3 (6-
C), 133.7 (40-C), 142.9 (10-C), 147.5 (9a-C). MS (EI): m/z (%) = 307
4.5.16. cis-2-(20-Fluorophenyl)-4-hydroxy-2,3,4,5-tetrahydro-
1(1H)-benzazepine (7p)
White crystals, 2.26 g (88%), mp: 89–90 °C (from heptane–ethyl
(
35Cl, 62) [M+], 289 (2), 288 (7), 263 (54), 262 (34), 152 (72), 140
acetate, 20:1). IR (KBr): v = 3356 (NH, OH) cmꢂ1 1H NMR
.
(100), 125 (29), 111 (9), 99 (9). Anal. Calcd for C16H15Cl2NO: C,
62.35; H, 4.91; N, 4.54. Found: C, 62.40; H, 4.98; N, 4.51.
(400 MHz, CDCl3): d = 2.14 (1H, ddd, J = 12.7, 11.5, 10.2 Hz, 3-
Hax), 2.21 (1H, ddt, J = 12.7, 4.0, 2.4 Hz, 3-Heq), 3.02 (1H, dt,
J = 13.5, 2.0 Hz, 5-Heq), 3.14 (1H, dd, J = 13.5, 10.3 Hz, 5-Hax), 3.89
(1H, tdd, J = 10.2, 4.0, 2.0 Hz, 4-Hax), 4.36 (1H, dd, J = 11.5, 2.4 Hz,
2-Hax), 6.74 (1H, d, J = 7.6 Hz, 9-H), 6.93 (1H, td, J = 7.6, 1.0 Hz,
7-H), 7.07–7.12 (1H, m, 8-H), 7.18 (1H, d, J = 7.6 Hz, 6-H), 7.28–
7.34 (3H, m, 30-H, 40-H, 50-H), 7.61 (1H, td, J = 7.5, 1.6 Hz, 60-H).
13C NMR (100 MHz, CDCl3): d = 44.6 (5-C), 47.1 (3-C), 53.2 (d,
J = 2.5 Hz, 2-C), 70.0 (4-C), 115.8 (d, J = 22.2 Hz, 30-C), 120.5 (9-C),
122.2 (7-C), 124.8 (d, J = 3.6 Hz, 50-C), 127.4 (d, J = 3.9 Hz, 60-C),
127.6 (8-C), 128.3 (5a-C), 129.3 (d, J = 8.3 Hz, 40-C), 131.4 (d,
J = 13.6 Hz, 10-C), 131.7 (6-C), 149.1 (9a-C), 159.5 (d, J = 245.1 Hz,
20-C). MS (EI): m/z (%) = 257 (83) [M+], 239 (3), 238 (16), 213
(78), 212 (100), 118 (87), 106 (48), 91 (19), 77 (13), 65 (5). Anal.
Calcd for C16H16FNO: C, 74.69; H, 6.27; N, 5.44. Found: C, 74.80;
H, 6.35; N, 5.32.
4.5.13. cis-2-(40-Bromophenyl)-7-chloro-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7m)
White crystals, 3.10 g (88%), mp: 150–151 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3352 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.06 (1H, ddd, J = 12.9, 11.3, 10.6 Hz, 3-Hax),
2.15 (1H, ddt, J = 12.9, 3.9, 1.9 Hz, 3-Heq), 2.94 (1H, d, J = 13.6 Hz,
5-Heq), 3.07 (1H, dd, J = 13.6, 10.5 Hz, 5-Hax), 3.83 (1H, tdd,
J = 10.5, 4.0, 2.6 Hz, 4-Hax), 3.89 (1H, dd, J = 11.2, 2.1 Hz, 2-Hax),
6.95 (1H, d, J = 8.0 Hz, 9-H), 7.03 (1H, dd, J = 8.0, 2.3 Hz, 8-H), 7.14
(1H, d, J = 2.3 Hz, 6-H), 7.29 (2H, d, J = 8.4 Hz, 20-H, 60-H), 7.36 (2H,
d, J = 8.4 Hz, 30-H, 50-H). 13C NMR (100 MHz, CDCl3): d = 44.2 (5-C),
48.1 (3-C), 60.8 (2-C), 69.6 (4-C), 121.7 (9-C), 121.9 (40-C), 127.3
(8-C), 127.4 (7-C), 128.3 (20-C, 60-C), 129.8 (5a-C), 131.4 (6-C),
132.3 (30-C, 50-C), 142.9 (10-C), 147.5 (9a-C). MS (EI): m/z (%) = 353
(
79Br, 35Cl, 77) [M+], 335 (13), 334 (17), 309 (57), 308 (43), 182
4.5.17. cis-2-(20-Chlorophenyl)-4-hydroxy-7-methyl-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7q)
(40), 140 (100), 104 (30), 89 (30), 77 (43). Anal. Calcd for
C16H15BrClNO: C, 54.49; H, 4.29; N, 3.97. Found: C, 54.61; H, 4.20;
N, 4.05.
White crystal, 2.56 g (89%), mp: 128–130 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3284 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.06 (1H, ddd, J = 12.3, 11.3, 10.3 Hz,
3-Hax), 2.24 (1H, ddt, J = 12.3, 3.5, 1.3 Hz, 3-Heq), 2.27 (3H, s,
7-CH3), 2.96 (1H, dt, J = 13.5, 2.7 Hz, 5-Heq), 3.12 (1H, dd, J = 13.5,
10.6 Hz, 5-Hax), 3.89 (1H, tdd, J = 10.3, 3.5, 2.7 Hz, 4-Hax), 4.39
(1H, dd, J = 11.3, 1.3 Hz, 2-Hax), 6.68 (1H, d, J = 7.7 Hz, 9-H), 6.92
4.5.14. cis-2-(40-Chlorophenyl)-7-fluoro-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7n)
White crystals, 2.57 g (88%), mp: 130–132 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3358 (NH, OH) cmꢂ1 1H NMR
.

S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
4737
(1H, d, J = 7.7 Hz, 8-H), 7.00 (1H, s, 6-H), 7.26 (1H, td, J = 7.9, 1.4 Hz,
40-H), 7.34 (1H, td, J = 7.9, 1.0 Hz, 50-H), 7.41 (1H, dd, J = 7.9, 1.0 Hz,
30-H), 7.67 (1H, dd, J = 7.9, 1.4 Hz, 60-H). 13C NMR (100 MHz,
CDCl3): d = 20.7 (7-CH3), 44.8 (5-C), 46.8 (3-C), 56.6 (2-C), 70.2
(4-C), 120.6 (9-C), 127.3 (60-C), 127.6 (50-C), 128.1 (8-C), 128.4
(5a-C), 128.8 (40-C), 129.9 (30-C), 131.5 (7-C), 132.3 (6-C), 132.8
(20-C), 141.9 (10-C), 146.9 (9a-C). MS (EI): m/z (%) = 287 (35Cl, 85)
[M+], 270 (9), 268 (8), 243 (44), 242 (27), 132 (100), 120 (60),
105 (9), 91 (4), 79 (6). Anal. Calcd for C17H18ClNO: C, 70.
(10). Anal. Calcd for C16H15Cl2NO: C, 62.35; H, 4.91; N, 4.54. Found:
C, 62.27; H, 5.03; N, 4.61.
4.5.21. cis-2-(60-Chloro-20-fluorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)- benzazepine (7u)
Maroon crystals, 2.45 g (84%), mp: 55–56 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3349 (NH, OH) cmꢂ1. H NMR
(400 MHz, CDCl3): d = 2.10 (1H, ddd, J = 12.7, 11.4, 9.9 Hz, 3-Hax),
2.26 (1H, ddt, J = 12.7, 3.7, 1.9 Hz, 3-Heq), 3.02 (1H, dt, J = 13.5,
2.0 Hz, 5-Heq), 3.15 (1H, dd, J = 13.5, 9.9 Hz, 5-Hax), 3.92 (1H, tt,
J = 9.9, 2.9 Hz, 4-Hax), 4.45 (1H, d, J = 11.4 Hz, 2-Hax), 6.80 (1H, br.
s, 9-H), 6.95 (1H, t, J = 7.4 Hz, 7-H), 7.13 (1H, td, J = 7.5, 1.1 Hz,
8-H), 7.26 (1H, td, J = 7.4, 1.3 Hz, 40-H), 7.20 (1H, dd, J = 7.4, 1.1 Hz,
6-H), 7.69 (1H, dd, J = 7.8, 1.3 Hz, 30-H), 7.33 (1H, d, J = 7.6 Hz, 50-
H). 13C NMR (100 MHz, CDCl3): d = 44.2 (5-C), 46.6 (3-C), 55.5 (2-
C), 70.3 (4-C), 115.8 (d, J = 22.1 Hz, 30-C), 120.6 (9-C), 122.1 (7-C),
126.1 (50-C), 127.5 (8-C), 128.0 (d, J = 14.0 Hz, 10-C), 128.6 (5a-C),
129.6 (40-C), 131.8 (6-C), 134.2 (d, J = 8.0 Hz, 60-C), 148.6 (9a-C),
163.3 (d, J = 245.0 Hz, 20-C). MS (EI): m/z (%) = 291 (35Cl, 38) [M+],
273 (1), 272 (5), 247 (28), 246 (19), 118 (100), 106 (34), 91 (24),
77 (15), 65 (10). Anal. Calcd for C16H15ClFNO: C, 65.87; H, 5.18; N,
4.80. Found: C, 65.81; H, 5.24; N, 4.84.
4.5.18. 7-Chloro-cis-2-(20-chlorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7r)
White crystals, 2.67 g (87%), mp: 132–134 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3280 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.07 (1H, dd, J = 12.7, 11.3 Hz, 3-Hax), 2.24
(1H, ddt, J = 12.7, 3.8, 1.9 Hz, 3-Heq), 2.95 (1H, dt, J = 13.6, 2.0 Hz,
5-Heq), 3.09 (1H, dd, J = 13.6, 10.2 Hz, 5-Hax), 3.89 (1H, tdd,
J = 10.2, 3.8, 1.0 Hz, 4-Hax), 4.39 (1H, dd, J = 11.3, 1.9 Hz, 2-Hax),
6.71 (1H, d, J = 8.3 Hz, 9-H), 7.05 (1H, dd, J = 8.3, 2.4 Hz, 8-H),
7.16 (1H, d, J = 2.4 Hz, 6-H), 7.27 (1H, td, J = 7.8, 2.0 Hz, 40-H),
7.33 (1H, td, J = 7.8, 1.2 Hz, 50-H), 7.41 (1H, dd, J = 7.8, 1.2 Hz,
30-H), 7.64 (1H, dd, J = 7.8, 2.0 Hz, 60-H). 13C NMR (100 MHz,
CDCl3): d = 44.4 (5-C), 46.3 (3-C), 56.5 (2-C), 69.8 (4-C), 121.8
(9-C), 127.0 (7-C), 127.2 (8-C), 127.4 (60-C), 127.7 (50-C), 129.1
(40-C), 130.0 (30-C), 130.2 (5a-C), 131.3 (6-C), 132.8 (20-C), 141.6
(10-C), 148.0 (9a-C). MS (EI): m/z (%) = 307 (35Cl, 79) [M+], 290
(12), 288 (8), 263 (69), 262 (23), 152 (100), 140 (69), 125 (24),
111 (5), 99 (7). Anal. Calcd for C16H15Cl2NO: C, 62.35; H, 4.91; N,
4.54. Found: C, 62.27; H, 5.03; N, 4.61.
4.5.22. 7-Chloro-cis-2-(20,60-dichlorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7v)
Yellow crystals, 2.90 g (85%), mp: 60–61 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3361 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.15 (1H, ddt, J = 13.0, 3.8, 1.2 Hz, 3-Heq),
2.55 (1H, ddd, J = 13.0, 11.7, 10.0 Hz, 3-Hax), 3.08 (1H, dt, J = 13.5,
2.0 Hz, 5-Heq), 3.17 (1H, dd, J = 13.5, 9.0 Hz, 5-Hax), 3.89 (1H, tdd,
J = 8.5, 4.1, 2.5 Hz, 4-Hax), 4.67 (1H, d, J = 11.7 Hz, 2-Hax), 6.73
(1H, d, J = 7.7 Hz, 9-H), 6.93 (1H, td, J = 7.5, 1.0 Hz, 7-H), 7.08 (1H,
dd, J = 8.0, 1.7 Hz, 30-H), 7.10 (1H, td, J = 7.5, 1.7 Hz, 8-H), 7.18
(1H, dd, J = 7.3, 1.7 Hz, 6-H), 7.21–7.24 (2H, m, 40-H, 50-H). 13C
NMR (100 MHz, CDCl3): d = 41.1 (3-C), 43.0 (5-C), 57.1 (2-C), 70.1
(4-C), 121.0 (9-C), 126.1 (7-C), 127.3 (8-C), 129.0 (30-C, 50-C),
129.3 (5a-C, 40-C), 131.4 (6-C), 135.0 (20-C, 60-C), 137.9 (10-C),
147.5 (9a-C). MS (EI): m/z (%) = 341 (35Cl, 31) [M+], 324 (6), 322
(4), 297 (25), 296 (5), 152 (100), 140 (31), 125 (13), 111 (10), 99
(11). Anal. Calcd for C16H14Cl3NO: C, 56.08; H, 4.12; N, 4.09. Found:
C, 56.16; H, 4.20; N, 3.99.
4.5.19. 7-Chloro-cis-2-(20-fluorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7s)
White crystals, 2.42 g (83%), mp: 124–125 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3289 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.13–2.21 (2H, m, 3-HaxHeq), 2.96 (1H, d,
J = 13.6 Hz, 5-Heq), 3.43 (1H, dd, J = 13.6, 10.5 Hz, 5-Hax), 3.87 (1H,
tdd, J = 10.5, 3.0, 2.1 Hz, 4-Hax), 4.31 (1H, dd, J = 10.7, 2.4 Hz,
2-Hax), 6.69 (1H, d, J = 8.0 Hz, 9-H), 7.04 (1H, dd, J = 8.0, 2.0 Hz,
8-H), 7.10 (1H, d, J = 9.8 Hz, 30-H), 7.15 (1H, d, J = 2.0 Hz, 6-H),
7.18 (1H, t, J = 7.5 Hz, 50-H), 7.28–7.33 (1H, m, 40-H), 7.58 (1H, td,
J = 7.5, 1.6 Hz, 60-H). 13C NMR (100 MHz, CDCl3): d = 44.2 (5-C),
46.7 (3-C), 53.3 (2-C), 69.7 (4-C), 115.9 (d, J = 22.0 Hz, 30-C), 121.8
(9-C), 124.9 (d, J = 3.5 Hz, 50-C), 127.1 (7-C), 127.4 (d, J = 4.4 Hz,
60-C), 127.4 (8-C), 129.5 (d, J = 8.3 Hz, 40-C), 130.2 (5a-C), 130.8
(10-C), 131.3 (6-C), 147.8 (9a-C), 159.5 (d, J = 245.2 Hz, 20-C). MS
(EI): m/z (%) = 291 (35Cl, 100) [M+], 273 (2), 272 (12), 246 (85),
245 (64), 152 (68), 140 (48), 125 (9), 111 (3), 99 (4). Anal. Calcd
for C16H15ClFNO: C, 65.87; H, 5.18; N, 4.80. Found: C, 65.80; H,
5.25; N, 4.77.
4.5.23. 7-Chloro-cis-2-(60-chloro-20-fluorophenyl)-4-hydroxy-
2,3,4,5-tetrahydro-1(1H)-benzazepine (7w)
Maroon crystals, 2.47 g (76%), mp: 111–112 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3355 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.14 (1H, ddt, J = 12.7, 3.3, 1.6 Hz, 3-Heq),
2.53 (1H, ddd, J = 12.7, 11.7, 10.2 Hz, 3-Hax), 3.02–3.11 (2H, m,
5-HeqHax), 3.94 (1H, tdd, J = 8.9, 4.7, 0.2 Hz, 4-Hax), 4.65 (1H, d,
J = 11.7 Hz, 2-Hax), 6.64 (1H, d, J = 8.4 Hz, 9-H), 7.03 (1H, dd,
J = 8.4, 2.1 Hz, 8-H), 7.07 (1H, dd, J = 7.2, 3.3 Hz, 30-H), 7.15 (1H,
d, J = 2.1 Hz, 6-H), 7.22–7.25 (2H, m, 40-H, 50-H). 13C NMR
(100 MHz, CDCl3): d = 43.4 (5-C), 43.7 (3-C), 55.3 (2-C), 70.0
(4-C), 115.8 (d, J = 23.5 Hz, 30-C), 121.4 (9-C), 126.2 (50-C), 126.6
(7-C), 127.3 (8-C), 128.7 (d, J = 16.0 Hz, 10-C), 129.7 (d, J = 4.0 Hz,
40-C), 129.8 (5a-C), 131.4 (6-C), 134.3 (d, J = 7.1 Hz, 60-C), 147.7
(9a-C), 161.2 (d, J = 244.0 Hz, 20-C). MS (EI): m/z (%) = 325 (35Cl,
72) [M+], 307 (2), 306 (7), 281 (58), 280 (21), 152 (100), 140 (44),
125 (10), 111 (4), 99 (9). Anal. Calcd for C16H14Cl2FNO: C, 58.91;
H, 4.33; N, 4.29. Found: C, 58.80; H, 4.42; N, 4.18.
4.5.20. cis-2-(20,60-Dichlorophenyl)-4-hydroxy-2,3,4,5-
tetrahydro-1(1H)-benzazepine (7t)
Maroon crystals, 2.61 g (85%), mp: 67–68 °C (from heptane–
ethyl acetate, 20:1). IR (KBr): v = 3351 (NH, OH) cmꢂ1 1H NMR
.
(400 MHz, CDCl3): d = 2.02 (1H, ddd, J = 13.1, 11.7, 9.6 Hz, 3-Hax),
2.77 (1H, ddt, J = 13.1, 4.1, 1.2 Hz, 3-Heq), 3.12 (1H, dd, J = 14.1,
2.0 Hz, 5-Heq), 3.16 (1H, dd, J = 14.1, 8.2 Hz, 5-Hax), 4.03 (1H, tdd,
J = 8.4, 5.0, 1.4 Hz, 4-Hax), 5.06 (1H, dd, J = 11.7, 2.2 Hz, 2-Hax),
6.69 (1H, d, J = 7.8 Hz, 9-H), 6.89 (1H, td, J = 7.4, 1.0 Hz, 7-H), 7.08
(1H, td, J = 7.6, 1.4 Hz, 8-H), 7.16 (1H, d, J = 7.4 Hz, 6-H), 7.17 (1H,
t, J = 8.0 Hz, 40-H), 7.40 (2H, d, J = 8.0 Hz, 30-H, 50-H). 13C NMR
(100 MHz, CDCl3): d = 41.5 (3-C), 43.5 (5-C), 57.2 (2-C), 70.5 (4-
C), 119.9 (9-C), 121.6 (7-C), 127.3 (5a-C), 127.6 (8-C), 128.9 (30-C,
50-C), 129.2 (40-C), 131.9 (6-C), 135.0 (20-C, 60-C), 138.1 (10-C),
148.9 (9a-C). MS (EI): m/z (%) = 307 (35Cl, 18) [M+], 289 (1), 288
(4), 263 (13), 262 (5), 118 (100), 106 (22), 91 (23), 77 (15), 65
4.6. Biological assays
4.6.1. Parasites, cells and compounds
Epimastigotes of T. cruzi (strain 320I01 isolated and character-
ized by Katerine Luna, CINTROP-UIS)58 were cultured in infusion

4738
S. Gómez-Ayala et al. / Bioorg. Med. Chem. 18 (2010) 4721–4739
tryptose liver (LIT) medium supplemented with heat inactivated
fetal calf serum (hiFCS) at 28 °C. Promastigotes of L. chagasi
(MHOM/BR/74/PP75) were maintained at 28 °C in RPMI 1640 med-
ium (Gibco) containing hemin (Sigma), HEPES (Gibco) and 10% of
hiSBF.
Research Center of Excellence CENIVAM (contract No. 432) for
financial support.
Supplementary data
The Vero (ATCC) and THP-1 (ATCC) cells were cultured in RPMI
medium plus 5% of hiSBF at 37 °C, 5% CO2 and 95% of humidity. Nif-
urtimox (Nfx) and amphotericin B (AmB) were used as reference
drugs.
Stock solutions of the tested compounds and reference drugs
were prepared in dimethyl sulfoxide (DMSO, Sigma) 100 ꢃ concen-
trated. Work solutions were prepared on culture medium before
the experiment.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2010.05.018.
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lM, and all concentrations were
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Acknowledgments
The authors would like to thank Colombian Institute for Science
and Research (COLCIENCIAS, Grant No. 1102-405-20350), and the

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