Rational use of substituted N-allyl and N,N-diallylanilines in the stereoselective synthesis of novel 2-alkenyltetrahydro-1-benzazepines

Article abstract of DOI:10.1016/j.tet.2010.08.067

Two new series of 1,4-epoxy-2-exo-vinyl(isopropenyl)tetrahydro-1- benzazepines and cis-2-vinyl(isopropenyl)-4-hydroxytetrahydro-1-benzazepines were prepared by an efficient three/four-step route from available substituted N,N-diallylanilines and mono N-al

Full text of DOI:10.1016/j.tet.2010.08.067

Tetrahedron 66 (2010) 8392e8401
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Rational use of substituted N-allyl and N,N-diallylanilines in the stereoselective
synthesis of novel 2-alkenyltetrahydro-1-benzazepines
,
b
Lina María Acosta a, Alirio Palma a , Alí Bahsas
*
a Laboratorio de Síntesis Orgánica, Escuela de Química, Universidad Industrial de Santander. A. A. 678, Bucaramanga, Colombia
b 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:
Received 2 June 2010
Received in revised form 24 August 2010
Accepted 27 August 2010
Available online 16 September 2010
Two new series of 1,4-epoxy-2-exo-vinyl(isopropenyl)tetrahydro-1-benzazepines and cis-2-vinyl(iso-
propenyl)-4-hydroxytetrahydro-1-benzazepines were prepared by an efficient three/four-step route
from available substituted N,N-diallylanilines and mono N-allylanilines. The amino-Claisen rearrange-
ment and the sequential oxidation/intramolecular 1,3-dipolar cycloaddition reactions were used as the
key steps in this synthesis. All the synthesized compounds were fully characterized by IR, GCeMS and
NMR techniques.
Keywords:
1,4-Epoxy-2-alkenyltetrahydro-1-
benzazepines
Ó 2010 Elsevier Ltd. All rights reserved.
2-Alkenyl-4-hydroxytetrahydro-1-
benzazepines
Intramolecular 1,3-dipolar cycloaddition
ortho-Allylanilines
N-Allylanilines
1. Introduction
ortho-allyl-N-benzyl-substituted a
-naphthylamines.10 Moreover,
we have also shown that many of the above mentioned compounds
possess remarkable activity in vitro against epimastigote and
promastigote forms of T. cruzi and L. chagasi parasites.11
In order to enhance the utility of our method, and as part of
a program to identify structurally novel anti-parasitic compounds
against both T. cruzi and L. chagasi parasites, we are now describing
the synthesis and structural elucidation of two new series of 1,4-
epoxy-2-vinyl(isopropenyl)tetrahydro-1-benzazepines 5aee/6aef
The tetrahydro-1-benzazepine ring system is a crucial phar-
macophore in drug discovery and many of its derivatives exhibit
a broad spectrum of biological activity. Medicinal chemists are of-
ten attracted to this type of compounds as a promising therapeutic
agents, for instance as renal and cardiovascular agents,1 potential
anti-tumor,2 and neuroleptic agents3 as well as promising antihy-
pertensives.4 Other tetrahydro-1-benzazepine derivatives have
been also reported as orally bioavailable growth hormone secre-
tagogue,5 inhibitors of Trypanosoma cruzi dihydrofolate reductase,6
and potent antagonists of platelet-activating factor7 and glycine.8
The functionalization of tetrahydro-1-benzazepine ring is an
efficient strategy to enhance its pharmacological activity and/or
offer more interesting properties. Consequently, it is not surprising
that a significant number of synthetic methods have been de-
veloped for the synthesis of new derivatives of this heterocyclic
system.9 For our part, recently we described a simple and efficient
synthetic pathway to obtain novel 1,4-epoxy-2-aryltetrahydro-1-
benzazepines as well as 1,4-epoxy-2-aryl-tetrahydro-naphtho[1,2-
b]azepines and their reduced tetrahydro-1-benzazepinols starting
from available ortho-allyl-N-benzyl-substituted anilines and
and
4-hydroxy-2-vinyl(isopropenyl)tetrahydro-1-benzazepines
7aee/8aef, using the sequence of selective oxidation and intra-
molecular 1,3-dipolar cycloaddition of N-alkenyl-ortho-allylanilines
as the key step. To the best of our knowledge, these 2-alkenyl
substituted tetrahydro-1-benzazepines have not been yet de-
scribed in the literature. Nevertheless, two closely related 2-vinyl
analogues were prepared by three different research groups, but
using another synthetic pathways.12
2. Results and discussion
Our synthetic strategy to target compounds is depicted in
Schemes 1 and 2. As shown in Scheme 1, the key intermediates
2aee and 4aef were prepared in one or two steps from the readily
available N,N-diallylanilines 1aee and mono N-allylanilines 1fek,
respectively. Thus, the thermal induced aromatic amino-Claisen
* Corresponding author. Fax: þ57 76 349069; e-mail addresses: alirio.palma@
gmail.com, apalma@uis.edu.co (A. Palma).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.08.067

L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
8393
Table 1
rearrangement of 1aek was effectively promoted using 1 or
1.5 equiv of boron trifluoride diethyl ether complex as the cata-
lyst.13 After several preliminary experiments, we found that the
most suitable reaction times and temperatures to reach the desired
rearranged products were 1e4 h and 130e140 ꢀC for the N,N-dia-
llylaniline derivatives, and 6e8 h and 120e140 ꢀC for the mono
N-allylaniline derivatives, respectively. Even though the con-
sumption of the starting substrates were complete as was evi-
denced by TLC, the isolated yields of 2aee and 3aef ranged from
moderate to good, essentially unaffected by the nature and posi-
tions of the substituents on the benzene ring of anilines 1 (Table 1).
However, in the conditions employed, the partial isomerization of
the formed ortho-allylanilines and the formation of the indoline
products, two possible side reactions, as well as non-identifiable
degradation products, were also observed in the 1H NMR spectra of
the analyzed crude reaction mixtures, thereby reducing the yields
of the expected products.
Preparation of ortho-allylanilines 2aee and 3aef by amino-Claisen rearrangement of
N,N-diallylanilines 1aee and mono N-allylanilines 1fek
1
[BF3$OEt2] equiv
Time (h)
Temperature (ꢀC)
2 and 3a (Yield, %)
1a
1b
1c
1d
1e
1f
1g
1h
1i
1
1
1
1
4
4
4
2
1
7
8
8
6
6
6
135
140
140
130
130
135
140
140
130
130
120
2a (62)
2b (66)
2c (63)
2d (65)
2e (70)
3a (65)
3b (70)
3c (68)
3d (73)
3e (76)
3f (58)
1
1.5
1.5
1.5
1.5
1.5
1.5
1j
1k
a
Yields are for isolated, chromatographically pure products.
R3
a: R = R1 = R2 = R3 = H
b: R = R1 = R3 = H, R2 = Cl
R2
c: R = R1 = R3 = H, R2 = F
d: R2 = R3 = H, R = CH3, R1 = Cl
e: R = R2 = H, R1 = R3 = CH3
R1
N
R
H
2a-e
R4 = allyl
i
R3
R3
R3
a: R = R1 = R2 = R3 = H
R2
R1
R2
R1
R2
b: R = R1 = R3 = H, R2 = Cl
c: R = R1 = R3 = H, R2 = F
d: R2 = R3 = H, R = CH3, R1 = Cl
e: R = R2 = H, R1 = R3 = CH3
f: R1 = R3 = H, R = R2 = Cl
R4
N
ii
R4 = H
iii
R1
N
NH 2
R
1a-k
R
H
R
CH3
3a-f
4a-f
Scheme 1. Reagents and reaction conditions: (i) BF3$OEt2 (0.01 equiv), 130e140 ꢀC, 1e4 h; (ii) BF3$OEt2 (0.015 equiv), 120e140 ꢀC, 6e8 h; (iii) Methallyl chloride (10 mmol), Na2CO3
(30 mmol), KI (5 mol %), dry DMF, rt, 12e20 h.
R3
R3
R3
R2
R1
R2
R1
R2
R1
ii
i
O
iii
-
O
N
N
R4
N
R4 = H, CH3
+
R
R
R
R4
H
R4
2a-e, 4a-f
5a-e, 6a-f
5a/7a: R = R1 = R2 = R3 = R4 = H
5b/7b: R = R1 = R3 = R4 = H, R2 = Cl
5c/7c: R = R1 = R3 = R4 = H, R2 = F
R3
OH
R2
R1
5d/7d: R = CH3, R1 = Cl, R2 = R3 = R4 = H
5e/7e: R = R2 = R4 = H, R1 = R3 = CH3
6a/8a: R = R1 = R2 = R3 = H, R4 = CH3
6b/8b: R = R1 = R3 = H, R2 = Cl, R4 = CH3
6c/8c: R = R1 = R3 = H, R2 = F, R4 = CH3
6d/8d: R = R4 = CH3, R1 = Cl, R2 = R3 = H
6e/8e: R = R2 = H, R1 = R3 = R4 = CH3
6f/8f: R = R2 = Cl, R1 = R3 = H, R4 = CH3
N
R4
R
H
7a-e, 8a-f
Scheme 2. Reagent and reaction conditions: (i) 30% H2O2 (30 mmol), Na2WO4$2H2O (10 mol %), MeOH, 0e25 ꢀC, 6e72 h; (ii) Toluene, 80e110 ꢀC, 4e7 h; (iii) Zn (100 mmol), glacial
CH3CO2H (70 mmol), 37% HCl (70 mmol), 0 ꢀC, 0.5e2 h.
With the first key precursors 2aee in hand, we turned our at-
tention to the N-methallylation of the rearranged products 3aef in
order to obtain the second key precursors, namely ortho-allyl-N-
methallylanilines 4aef. A typical reaction procedure involves the
slow addition of an equimolar amount of methallyl chloride to 3aef
in dry DMF in the presence of sodium carbonate and small amounts

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L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
of KI, and stirring the reaction mixtures for 12e20 h at room
temperature. In this manner, compounds 4aef were obtained as
low-viscosity maroon oils in good yields (67e88%), after column
chromatography purification.
heating, yielding the corresponding 1,4-epoxy-cycloadducts 5aee
and 6aef, which were isolated by silica gel column chromatogra-
phy as maroon oils or crystalline substances in moderate to good
yields (Table 2). In all the cases, the formation of only one of the
two possible 1,4-epoxy-cycloadducts (endo and exo) was observed
in the 1H NMR spectra of the crude reaction mixtures along with
others non-identifiable degradation products.
The preparation of the 1,4-epoxy-cycloadducts 5aee and 6aef
was carried out in the next step of our approach, and involved
treating the obtained key intermediates 2aee and 4aef in metha-
nol with excess of 30% H2O2 solution in the presence of 10 mol % of
sodium tungstate as the catalyst, according to the methodology
reported by Murahashi.14 The formation of the corresponding
nitrones was monitored by TLC by consumption of the starting
ortho-allylanilines. After completion of the oxidation process, the
catalyst and the excess of hydrogen peroxide along with the
methanol were removed by extraction from the reaction mixtures,
and the remaining organic residues (nitrones) were dissolved in
toluene and then heated to promote their intramolecular 1,3-di-
polar cycloaddition across the pendant allylic fragment connected
to the ortho position (Scheme 2).
We have found that the substitution pattern on the benzene
ring of both key intermediates 2 and 4 plays a considerable in-
fluence on the formation of their nitrones; 5,6- and 4,6-di-
substituted ortho-allylanilines (2d, 4d, and 4f) required longer
reaction times (72 h) than the 3,5-disubstituted ones (2e and 4e)
(8 h), presumably due to steric factors associated with the pres-
ence of methyl group or chlorine atom at the C-6 position inhib-
iting the effective oxidation of the eNHeCH2e framework. In turn,
the oxidation of the non-substituted and 4-substituted ortho-
allylanilines (R2¼H, Cl, F) proceeds more easily than that of their
3,5-disubstituted analogues, giving the corresponding nitrones in
6 h (Table 2). As was also evidenced by TLC, the consumption of all
the nitrones generated from 2 and 4 took place after 4e7 h of
Structural elucidation of 5aee and 6aef was mainly based on
NMR studies. In the 1H NMR spectra of 5aee, the signal attributed
to tertiary H-2 proton appears at
d 3.89e4.02 as doublets of dou-
blets of doublets (ddd) due to coupling with vicinal 3-HAHB aze-
3
pinic protons (3J¼7.4e8.3 Hz and J¼2.1e2.8 Hz) and vicinal 10-H
olefinic proton (3J¼6.9e75 Hz), while in the spectra of 6aef the
same proton appears at
d 3.85e3.96 as doublets of doublets (dd)
due to coupling with 3-HAHB protons (3J¼8.3e8.9 Hz and
3J¼2.2e2.9 Hz). The signal attributed to 4-H proton in 1,4-epoxy-
cycloadducts of type 5 and 6 appears at
d 4.83e4.91 as doublets of
doublets of doublets (ddd) due to coupling with vicinal 3-HAHB
(3J¼1.4e2.2 Hz and 3J¼7.1e7.8 Hz) and 5-HB (3J¼5.3e5.8 Hz) pro-
tons. Extensive COSY, DEPT-135, HSQC, and HMBC measurements
allowed the assignment of all the signals and correlations to in-
dividual H- and C-atoms (see Experimental section). The data de-
rived from these experiments along with the coupling constants
values of the six azepinic protons were used to identify the isolated
1,4-epoxy-cycloadducts as the exo-isomer in all the cases. In order
to provide undoubted structural proof, the X-ray diffraction anal-
ysis was carried out for compounds 5a, 6d, and 6f.15 The X-ray
crystal structures of 5a and 6d are shown in Fig. 1. Crystallographic
data for the structures 5a, 6d, and 6f have been deposited with the
Cambridge Crystallographic Data Centre under the numbers CCDC
774910, CCDC 774914, and CCDC 774915, respectively.
All the above information clearly indicates that the stereo-
chemical outcome of the 1,3-dipolar cycloaddition is the conse-
quence of an exo approach of the internal olefinic moiety with
regard to the transient dipole (nitrone) generated from 2aee and
4aef to produce exclusively the corresponding 2-exo-stereoisomer.
These results are in full agreement with those obtained previously
in our laboratory.10
Table 2
Preparation of 1,4-epoxy-cycloadducts 5aee and 6aef from ortho-allylanilines 2aee
and 4aef
ortho-
Allylaniline
Conditions (temperature, ꢀC/time, h)
5 and 6a
(Yield, %)
Oxidation
1,3-Dipolar
cycloaddition
In the last step of our synthetic route, the reductive cleavage of
the NeO bond of the isolated 1,4-epoxy-cycloadducts to obtain the
desired 2-alkenyl-substituted tetrahydro-1-benzazepin-4-ols was
examined. We conducted the reductive cleavage of 5aee and 6aef
by treatment with excess of zinc powder in a mixture of glacial
acetic acid and concentrated hydrochloric acid at 0 ꢀC, and stirring
the reaction mixtures for 0.5e2.0 h. In the conditions employed, the
reductive cleavage of the NeO bridged bond proceeded very easy
with the formation of the expected cis-2-alkenyltetrahydro-1-
benzazepinols, which were isolated by silica gel column chroma-
tography in excellent yields (90e95%) as high-viscosity oils or
crystalline substances.
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
4f
0e25/6
0e25/6
0e25/6
25/72
0e25/8
0e25/6
0e25/6
0e25/6
25/72
80/4
80/4
80/4
110/7
80/5
80/4
80/4
80/4
110/7
80/7
110/7
5a (58)
5b (50)
5c (48)
5d (57)
5e (55)
6a (49)
6b (52)
6c (50)
6d (65)
6e (60)
6f (63)
0e25/8
25/72
a
Yields are for isolated, chromatographically pure products.
Fig. 1. X-ray crystal structures of 1,4-epoxy-2-exo-vinyl-2,3,4,5-tetrahydro-1(1H)-benzazepine 5a and 8-chloro-9-methyl-1,4-epoxy-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1
(1H)-benzazepine 6d (ORTEP views).15

L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
8395
The structures and stereochemistry of these novel compounds
were determined by 1H NMR and 13C NMR spectroscopy. All the
signals for each individual H- and C-atoms (see Experimental
section) were also unambiguously assigned on the basis of their
COSY, HSQC and HMBC spectra. The cis stereochemistry at the
stereogenic centers 2-C and 4-C of the tetrahydroazepine ring was
established based on its 2D-NOESY spectra, in which the tertiary
proton 2-H at 3.39e3.82 ppm (for compounds 7aee) and
3.32e3.43 ppm (for compounds 8aef) demonstrates un-
ambiguous NOE cross peak with the stereogenic 4-H proton at
3.79e4.15 ppm (for compounds 7aee) and 3.77e3.88 ppm (for
compounds 8aef), indicating that both protons are oriented in the
same side of the heterocyclic ring. Consequently, the 2-alkenyl
group is oriented equatorially, since the proton 2-H appears as
doublets of doublets of doublets (ddd, for compounds 7aee) due
to coupling with 3-Hax (3J¼9.9e11.2 Hz), 3-Heq (3J¼1.9e2.4 Hz)
and vicinal olefinic proton eCH] (3J¼7.4e7.5 Hz); in the case of
compounds 8aef, the proton 2-H appears as doublets of doublets
(dd) with J1¼11 Hz and J2¼1.5 Hz and therefore having exactly one
trans-axial and one cis-equatorial coupling partners, namely 3-
Hax and 3-Heq. The 4-hydroxy group is also oriented equatorially,
since proton 4-H appears as doublets of doublets of doublets (ddd,
for both 7aee and 8aef compounds) with J1¼9.5 Hz, J2¼4 Hz, and
J3¼2 Hz and therefore having two trans-axial coupling partners
(3-Hax and 5-Hax) and two cis-equatorial coupling partners (3-Heq
and 5-Heq). The data derived from NOESY experiments along with
the coupling constants values of the six azepinic protons were
used to identify the isolated 2-aryltetrahydro-1-benzazepin-4-ols
as the cis-isomer with the tetrahydroazepine ring in the chair
conformation and consequently proves that their precursors 5 and
6 are exo adducts. The structure assignment of 7a, 7b, and 7c was
supported by an X-ray crystallography determination.16 The X-ray
crystal structure of 7a is shown in Fig. 2. Crystallographic data for
the structures 7a, 7b, and 7c have been deposited with the Cam-
bridge Crystallographic Data Centre under the numbers CCDC
728210, CCDC 728212, and CCDC 72821, respectively.
interest in medicinal chemistry, especially as anti-parasitic agents. In
line with this purpose, preliminary results obtained clearly indicate
they exhibit remarkable activity against the epimastigote and amas-
tigote forms of T. cruzi as well as against promastigote form of
L. chagasi parasite. Detailed results from this biological study will be
reported in the near future elsewhere.
4. Experimental
4.1. General
All the reagents and solvents were purchased from Sigmae
Aldrich or Merck companies, and used without further purification.
Monitoring of the reactions was performed using silica gel TLC
plates (silica Merck 60 F254). Spots were visualized by UV light at
254 and 365 nm. Column chromatography was performed on
Merck Kieselgel 60e230 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 recorded on a Nicolet Avatar 360-FTIR
spectrometer and referenced to polystyrene standard, using cells
equipped with potassium bromide windows. 1H and 13C NMR
spectra were measured on a Bruker AM-400 and Bruker Ultrashield
400 spectrometers, using CDCl3 as the solvent. Chemical shifts (d)
and coupling constants (J) values are reported in parts per million
and hertz, respectively. Chemical shifts are relative to the solvent
peaks used as reference [CDCl3: dH¼7.26, and dC¼77.0]. For 1H NMR,
the assignments are: q¼quartet, t¼triplet, d¼doublet, s¼singlet,
br¼broad, and m¼multiplet. Multiplet refers to unresolved reso-
nances from one or more protons having intractable 1He1H cou-
pling constants. A HewlettePackard (HP) 5890 A series II Gas
Chromatograph interfaced to an HP 5972 Mass Selective Detector
with an HP MS ChemStation Data system was used for MS identi-
fication. Elemental analyses (C, H, N) were performed on a Per-
kineElmer 2400 Series II analyzer.
The following ortho-allylanilines are known compounds and
have physical and spectral data in agreement with those reported
in the literature: 2aec17 and 3aec,e.18
4.2. General procedure for the synthesis of rearranged
products 2 and 3
A mixture of the appropriately substituted N,N-diallylanilines
1aee (10 mmol) or mono N-allylanilines 1fek and boron trifluoride
diethyl ether complex (10 mmol, 1.25 mL for 1aee derivatives, and
15 mmol, 1.88 mL for 1fek derivatives) was heated at 120e140 ꢀC
for 1e8 h. The reaction mixtures were neutralized with saturated
sodium carbonate solution and then extracted with CH2Cl2
(2ꢁ100 mL). The organic layers were dried over anhydrous sodium
sulfate and the solvent removed under reduced pressure. The crude
products were purified by column chromatography on silica gel,
eluting with mixtures of heptane and ethyl acetate (compositions
in the range from 100:1 to 70:1 v/v for 3aee, and 50:1 to 10:1 v/v
for 3fek) to obtain rearranged products as low-viscosity maroon
oils. Spectral data and elemental analysis for previously unreported
ortho-allylanilines 2d, 2e, 3d, and 3f are listed below:
Fig. 2. X-ray crystal structure of cis-4-hydroxy-2-vinyl-2,3,4,5-tetrahydro-1(1H)-ben-
zazepine 7a (ORTEP view).16
3. Conclusion
4.2.1. N,6-Diallyl-3-chloro-2-methylaniline (2d). IR (liquid film)
nmax: 3380 (NeH), 1638 (C]C allyl), 917 (]CeH allyl) cmꢂ1 1H
.
In summary, the present work describes a simple and efficient
stereoselective synthesisofnovel1,4-epoxy-2-exo-vinyl(isopropenyl)
tetrahydro-1-benzazepines and cis-2-vinyl(isopropenyl)-4-hydroxy-
tetrahydro-1-benzazepines; compounds that are not otherwise
readily accessible. We believe the method is flexible enough to allow
the synthesis of many analogues, simply by varying the alkenylic
substituent on the nitrogen atom. These compounds are of special
NMR (400 MHz, CDCl3)
d
: 7.03 (1H, d, J¼8.2 Hz, 4-H), 6.94 (1H, d,
J¼8.2 Hz, 3-H), 6.04e5.91 (2H, m, eCH]), 5.31e5.14 (2H, m,
NeCH2eCH]CH2), 5.14e5.02 (2H, m, eCH2eCH]CH2), 3.54 (2H,
dt, J¼5.9, 1.3 Hz, NeCH2), 3.37 (2H, d, J¼6.1 Hz, eCH2e), 2.37 (s, 2-
CH3). 13C NMR (100 MHz, CDCl3)
d: 147.7 (1-C), 136.8 (CH]), 136.3
(CH]), 133.9 (5-C), 130.2 (2-C), 129.3 (6-C), 128.4 (3-C), 123.4, (4-C),
116.4 (]CH2), 116.3 (]CH2), 52.1 (NeCH2), 36.7 (eCH2), 15.4

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L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
(2-CH3). MS (EI-70 eV) m/z (%): 221 (Mþ, 35Cl, 20),180 (42), 178 (67),
145 (100), 144 (63), 130 (49), 115 (23). Anal. Calcd for C13H16ClN: C,
70.42; H, 7.27; N, 6.32. Found: C, 70.30; H, 7.15; N, 6.41%.
CDCl3) d: 146.0 (1-C), 142.6 (CH2]Ce), 136.1 (CH] allyl), 129.8 (3-
C), 127.6 (5-C), 123.5 (2-C), 117.2 (4-C), 116.2 (]CH2 allyl), 110.8
(eC]CH2), 110.8 (6-C), 49.8 (NeCH2e), 36.6 (eCH2e allyl), 20.5
(]CeCH3). MS (EI-70 eV) m/z (%): 187 (Mþ, 41), 146 (50), 132 (91),
131 (69), 130 (100), 118 (70). Anal. Calcd for C13H17N: C, 83.37; H,
9.15; N, 7.48. Found: C, 83.51; H, 9.02; N, 7.40%.
4.2.2. N,2-Diallyl-3,5-dimethylaniline (2e). IR (liquid film) nmax
3432 (NeH), 1636 (C]C allyl), 915 (]CeH allyl) cmꢂ1 1H NMR
(400 MHz, CDCl3) : 6.48 (1H, s, 4-H), 6.38 (1H, s, 6-H), 6.00e5.91
:
.
d
(2H, m, eCH]), 5.28e5.06 (2H, m, NeCH2eCH]CH2), 5.17e5.03
(2H, m, eCH2eCH]CH2), 3.79 (2H, dt, J¼5.3, 1.7 Hz, NeCH2e),
3.34 (2H, dt, J¼5.7, 1.6 Hz, eCH2e), 2.29 (3H, s, 5-CH3), 2.26 (3H, s,
4.3.2. 2-Allyl-4-chloro-N-(2-methylallyl)aniline (4b). Reaction time:
12 h. Yield: 1.77 g (80%). IR (liquid film) nmax: 3444 (NeH),1636 (C]
C allyl), 917 (]CeH allyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 7.09
3-CH3). 13C NMR (100 MHz, CDCl3)
d
: 146.6 (1-C), 137.1 (3-C),
(1H, dd, J¼8.6, 2.6 Hz, 5-H), 7.04 (1H, d, J¼2.6 Hz, 3-H), 6.51 (1H, d,
J¼8.6 Hz, 6-H), 5.94 (1H, ddt, J¼17.0, 10.2, 6.2 Hz, CH] allyl), 5.18
(1H, dq, J¼10.2, 1.6 Hz, ]CHAH allyl), 5.14 (1H, dq, J¼17.0, 1.6 Hz, ]
CHHB allyl), 4.93 (1H, br s, ]CHAH), 4.90 (1H, br s, ]CHHB), 3.69
(2H, s, NeCH2e), 3.28 (2H, d, J¼6.2 Hz, eCH2e allyl), 1.79 (3H, br s,
136.9 (5-C), 136.1 (CH]), 135.7 (CH]), 121.0 (4-C), 119.4 (2-C),
116.3 (]CH2), 115.6 (]CH2), 110.3 (6-C), 47.1 (NeCH2), 31.6
(eCH2), 21.9 (5-CH3), 20.4 (3-CH3). MS (EI-70 eV) m/z (%): 201
(Mþ, 36), 160 (56), 158 (86), 146 (43), 145 (100), 144 (56), 130 (30),
115 (21). Anal. Calcd for C14H19N: C, 83.53; H, 9.51; N, 6.96. Found:
C, 83.69; H, 9.42; N, 7.08%.
CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
d: 144.6 (1-C), 142.2
(CH2]Ce), 135.1 (CH] allyl), 129.4 (3-C), 127.2 (5-C), 125.0 (2-C),
121.6 (4-C), 116.8 (]CH2 allyl), 111.7 (6-C), 110.9 (eC]CH2), 49.7
(NeCH2e), 36.2 (CH2e allyl), 20.4 (]CeCH3). MS (EI-70 eV) m/z
(%): 221(Mþ, 35Cl, 36), 180 (36), 166 (59), 165 (30), 164 (53), 131
(100), 130 (78). Anal. Calcd for C13H16ClN: C, 70.42; H, 7.27; N, 6.32.
Found: C, 70.35; H, 7.17; N, 6.20%.
4.2.3. 6-Allyl-3-chloro-2-methylaniline (3d). IR (liquid film) nmax
3482 (NeH), 3399 (NeH), 1622 (C]C allyl), 918 (]CeH allyl) cmꢂ1
1H NMR (400 MHz, CDCl3)
:
.
d
: 6.86 (1H, d, J¼8.0 Hz, 3-H), 6.80 (1H, d,
J¼8.0 Hz, 4-H), 5.93 (1H, ddt, J¼17.1, 10.3, 5.8 Hz, eCH]), 5.16 (1H,
dq, J¼10.3, 1.8 Hz, ]CHAH), 5.12 (1H, dq, J¼17.1, 1.8 Hz, ]CHHB),
3.29 (2H, dt, J¼5.8, 1.8 Hz, eCH2e), 2.27 (3H, s, 6-CH3). 13C NMR
4.3.3. 2-Allyl-4-fluoro-N-(2-methylallyl)aniline (4c). Reaction time:
14 h. Yield: 1.54 g (75%). IR (liquid film) nmax: 3440 (NeH),1637 (C]
(100 MHz, CDCl3) d: 144.3 (1-C), 135.6 (CH]), 133.1 (5-C), 128.2 (3-
C), 121.9 (2-C), 120.0 (6-C), 118.9 (4-C), 116.5 (]CH2), 36.6 (eCH2),
14.0 (6-CH3). MS (EI-70 eV) m/z (%): 181 (Mþ, 35Cl, 100), 166 (39),
146 (48), 131 (83), 130 (46). Anal. Calcd for C10H12ClN: C, 66.12; H,
6.66; N, 7.71. Found: C, 66.00; H, 6.81; N, 7.56%.
C allyl), 919 (]CeH allyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 6.85
(1H, dd, J¼8.3, 3.0 Hz, 3-H), 6.82e6.80 (1H, m, 5-H), 6.54 (1H, dd,
J¼8.3, 4.8 Hz, 6-H), 5.93 (1H, ddt, J¼17.1, 10.2, 6.2 Hz, CH] allyl),
5.16 (1H, dq, J¼10.2,1.5 Hz, ]CHAH allyl), 5.13 (1H, dq, J¼17.1,1.5 Hz,
]CHHB allyl), 4.93 (1H, br s, ]CHAH), 4.89 (1H, br s, ]CHHB), 3.68
(2H, d, J¼6.1 Hz, NeCH2e), 3.30 (2H, d, J¼6.2 Hz, eCH2e allyl), 1.79
4.2.4. 2-Allyl-4,6-dichloroaniline (3f). IR (liquid film) nmax: 3480
(NeH), 3389 (NeH), 1624 (C]C allyl), 921 (]CeH allyl) cmꢂ1. 1H
(3H, d, J¼0.4 Hz, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
d: 156.7
NMR (400 MHz, CDCl3)
d
: 7.18 (1H, d, J¼2.4 Hz, 5-H), 6.95 (1H, d,
(d, J¼231.0 Hz, 4-C), 142.5 (1-C), 135.4 (CH] allyl), 125.1 (d,
J¼10.1 Hz, 2-C),117.0 (]CH2 allyl),116.6 (d, J¼22.4 Hz, 3-C),113.5 (d,
J¼21.5 Hz, 5-C), 111.4 (CH2]Ce), 111.4 (6-C), 110.2 (eC]CH2), 50.6
(NeCH2e), 36.4 (eCH2e allyl), 20.7 (]CeCH3). MS (EI-70 eV) m/z
(%): 205(Mþ, 35), 164 (44), 150 (77), 149 (62), 148 (100), 136 (76),
135 (55). Anal. Calcd for C13H16FN: C, 76.06; H, 7.86; N, 6.82. Found:
C, 76.29; H, 8.00; N, 6.71%.
J¼2.4 Hz, 3-H), 5.90 (1H, ddt, J¼17.2, 10.2, 6.1 Hz, eCH]), 5.18 (1H,
dq, J¼10.2, 1.6 Hz, ]CHAH), 5.12 (1H, dq, J¼17.2, 1.6 Hz, ]CHHB),
4.10 (2H, br s, -NH2), 3.28 (2H, d, J¼6.1 Hz, eCH2e). 13C NMR
(100 MHz, CDCl3) d: 140.3 (1-C), 134.4 (CH]), 128.5 (3-C), 127.2 (5-
C), 126.4 (2-C), 122.6 (4-C), 120.2 (6-C), 117.5 (]CH2), 36.7 (eCH2).
MS (EI-70 eV) m/z (%): 201 (Mþ, 35Cl, 93), 186 (74), 151 (80), 131
(100), 130 (80). Anal. Calcd for C9H9Cl2N: C, 53.49; H, 4.49; N, 6.93.
Found: C, 53.33; H, 4.38; N, 7.07%.
4.3.4. 6-Allyl-3-chloro-2-methyl-N-(2-methylallyl)aniline
(4d). Reaction time: 20 h. Yield: 1.62 g (69%). IR (liquid film) nmax
3372 (NeH), 1637 (C]C allyl), 918 (]CeH allyl) cmꢂ1 1H NMR
(400 MHz, CDCl3)
:
4.3. General procedure for the synthesis of 2-allyl-N-(2-
methylallyl)anilines 4
.
d
: 7.02 (1H, d, J¼8.2 Hz, 4-H), 6.93 (1H, d,
J¼8.2 Hz, 5-H), 5.96 (1H, ddt, J¼17.1, 10.1, 6.1 Hz, CH] allyl), 5.12
(1H, dq, J¼10.1, 1.5 Hz, ]CHAH allyl), 5.07 (1H, br s, ]CHAH), 5.05
(1H, dq, J¼17.1, 1.5 Hz, ]CHHB allyl), 4.92 (1H, br s, ]CHHB), 3.43
(2H, s, NeCH2e), 3.37 (2H, d, J¼6.1 Hz, eCH2e allyl), 2.36 (3H, s, 2-
To a mixture of 2-allylanilines 3aef (10 mmol) with sodium
carbonate (30 mmol, 3.18 g) and potassium iodide (5 mol %) in DMF
(25 mL) was slowly added an equimolar amount of methallyl
chloride (10 mmol, 0.97 mL) at room temperature. The reaction
mixtures were stirred for 12e20 h (TLC control) and then extracted
with CH2Cl2 (2ꢁ100 mL) and washed with enough water to elim-
inate DMF. The combined organic layers were dried over anhydrous
sodium sulfate, and the solvent removed under reduced pressure.
The crude products were purified by silica gel column chroma-
tography (heptane/ethyl acetate; compositions in the range from
90:1 to 60:1 v/v) to give 4aef as low-viscosity maroon oils.
CH3), 1.83 (3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
d: 147.9
(1-C), 144.0 (CH2]Ce), 136.9 (CH] allyl), 133.8 (3-C), 130.2 (6-C),
129.3 (2-C), 128.4 (5-C), 123.3 (4-C), 116.3 (]CH2 allyl), 111.3
(eCH2]Ce), 55.2 (NeCH2e), 36.5 (CH2e allyl), 21.0 (]CeCH3),
15.6 (2-CH3). MS (EI-70 eV) m/z (%): 235 (Mþ, 35Cl, 15), 194 (24), 180
(45), 179 (27), 178 (56), 145 (100), 144 (58), 130 (41), 115 (21). Anal.
Calcd for C14H18ClN: C, 71.32; H, 7.70; N, 5.94. Found: C, 71.53; H,
7.57; N, 5.82%.
4.3.1. 2-Allyl-N-(2-methylallyl)aniline (4a). Reaction time: 12 h.
Yield: 1.37 g (73%). IR (liquid film) nmax: 3444 (NeH), 1637 (C]C
4.3.5. 2-Allyl-3,5-dimethyl-N-(2-methylallyl)aniline (4e). Reaction
time: 16 h. Yield: 1.44 g (67%). IR (liquid film) nmax: 3440 (NeH),
allyl), 918 (]CeH allyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
: 7.17 (1H,
1634 (C]C allyl), 922 (]CeH allyl) cmꢂ1 1H NMR (400 MHz,
.
td, J¼7.8, 1.3 Hz, 5-H), 7.08 (1H, dd, J¼7.8, 1.3 Hz, 3-H), 6.73 (1H, t,
J¼7.8 Hz, 4-H), 6.63 (1H, d, J¼7.8 Hz, 6-H), 5.99 (1H, ddt, J¼17.4, 10.1,
6.2 Hz, CH] allyl), 5.16 (1H, dq, J¼10.1, 1.6 Hz, ]CHAH allyl), 5.13
(1H, dq, J¼17.4, 1.6 Hz, ]CHHB allyl), 4.97 (1H, br s, ]CHAH), 4.91
(1H, br s, ]CHHB), 3.73 (2H, s, NeCH2e), 3.35 (2H, d, J¼6.2 Hz,
eCH2e allyl), 1.83 (3H, br s, CH2]CeCH3). 13C NMR (100 MHz,
CDCl3)
d
: 6.45 (1H, s, 4-H), 6.31 (1H, s, 6-H), 5.90 (1H, ddt, J¼17.0,
10.3, 5.7 Hz, CH] allyl), 5.06 (1H, dq, J¼10.3, 2.0 Hz, ]CHAH allyl),
5.02 (1H, dq, J¼17.0, 2.0 Hz, ]CHHB allyl), 4.94 (1H, br s, ]CHAH),
4.88 (1H, br s, ]CHHB), 3.67 (2H, s, NeCH2e), 3.32 (2H, dt, J¼5.7,
2.0 Hz, eCH2e allyl), 2.26 (3H, s, 3-CH3), 2.25 (3H, s, 5-CH3), 1.79
(3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
d: 145.4 (1-C),

L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
8397
143.0 (CH2]Ce), 136.8 (3-C), 136.6 (5-C), 135.5 (CH] allyl), 120.5
(CeN), 1048 (CeO), 985 (NeO), 924 (]CeH vinyl) cmꢂ1
(400 MHz, CDCl3)
.
1H NMR
(4-C), 118.9 (2-C), 115.4 (]CH2 allyl),110.8 (eCH2]Ce), 109.8 (6-C),
50.1 (NeCH2e), 31.6 (CH2e allyl), 21.6 (3H, 5-CH3), 20.8 (3H, 3-
CH3), 20.2 (]CeCH3). MS (EI-70 eV) m/z (%): 215 (Mþ, 42), 174 (36),
160 (83), 159 (59), 158 (94), 146 (79), 145 (100), 144 (55), 130 (33),
115 (21). Anal. Calcd for C15H21N: C, 83.67; H, 9.83; N, 6.50. Found:
C, 83.80; H, 9.69; N, 6.38%.
d
: 7.11 (1H, dd, J¼8.4, 2.4. Hz, 8-H), 7.07 (1H, d,
J¼2.4 Hz, 6-H), 6.97 (1H, d, J¼8.4 Hz, 9-H), 5.97 (1H, ddd, J¼17.1,
10.4, 7.1 Hz, eCH]), 5.21 (1H, dt, J¼17.1, 1.2 Hz, ]CHAH), 5.11 (1H,
dt, J¼10.4, 1.2 Hz, ]CHHB), 4.84 (1H, ddd, J¼7.5, 5.4, 2.1 Hz, 4-H),
3.96 (1H, ddd, J¼7.4, 7.1, 2.4 Hz, 2-H), 3.41 (1H, br dd, J¼16.7, 5.4 Hz,
5-HB), 2.44 (1H, br d, J¼16.7 Hz, 5-HA), 2.33 (1H, dddd, J¼12.5, 7.5,
2.4, 1.1 Hz, 3-HB), 2.25 (1H, ddd, J¼12.5, 7.4, 2.1 Hz, 3-HA). 13C NMR
4.3.6. 2-Allyl-4,6-dichloro-N-(2-methylallyl)aniline (4f). Reaction
time: 20 h. Yield: 2.24 g (88%). IR (liquid film) nmax: 3386 (NeH),
(100 MHz, CDCl3) d: 148.8 (9a-C), 139.7 (eCH]), 131.2 (7-C), 129.7
(6-C), 127.3 (5a-C), 126.8 (8-C), 123.4 (9-C), 114.9 (]CH2), 74.8 (2-C),
74.3 (4-C), 40.1 (3-C), 34.7 (5-C). MS (EI-70 eV) m/z (%): 221 (Mþ,
35Cl, 46), 204 (15), 191 (6), 164 (12), 139 (62), 138 (100), 112 (23).
Anal. Calcd for C12H12ClNO: C, 65.02; H, 5.46; N, 6.32. Found: C,
65.52; H, 5.28; N, 6.52%.
1640 (C]C allyl), 920 (]CeH allyl) cmꢂ1 1H NMR (400 MHz,
.
CDCl3)
d
: 7.22 (1H, d, J¼2.4 Hz, 5-H), 7.04 (1H, d, J¼2.4 Hz, 3-H), 5.93
(1H, ddt, J¼17.1, 10.1, 6.3 Hz, CH] allyl), 5.16 (1H, dq, J¼10.1, 1.6 Hz,
]CHAH allyl), 5.10 (1H, dq, J¼17.1, 1.6 Hz, ]CHHB allyl), 5.02 (1H, br
s, ]CHAH), 4.89 (1H, br s, ]CHHB), 3.54 (2H, s, NeCH2e), 3.40 (2H,
d, J¼6.3 Hz, eCH2e allyl), 1.80 (3H, s, CH2]CeCH3). 13C NMR
4.4.3. 7-Fluoro-2-exo-vinyl-2,3,4,5-tetrahydro-1,4-epoxybenzo[b]-
azepine (5c). Yield: 0.98 g (48%). Pale yellow oil. Rf: 0.29 (7% ethyl
acetate/heptane). IR (liquid film) nmax: 1642 (C]C vinyl), 1253
(100 MHz, CDCl3) d: 143.6 (CH2]Ce), 143.1 (1-C), 136.1 (CH] allyl),
134.7 (2-C), 129.3 (3-C), 127.7 (4-C), 127.4 (5-C), 126.9 (6-C), 117.2
(]CH2 allyl), 111.8 (eCH2]Ce), 54.9 (NeCH2e), 36.2 (CH2e allyl),
20.8 (]CeCH3). MS (EI-70 eV) m/z (%): 255 (Mþ, 35Cl, 12), 214 (42),
200 (65), 199 (48), 198 (70), 165 (100), 164 (69), 151 (36), 130 (70),
115 (24). Anal. Calcd for C13H15Cl2N: C, 60.95; H, 5.90; N, 5.47.
Found: C, 60.73; H, 6.07; N, 5.33%.
(CeN), 1049 (CeO), 996 (NeO), 923 (]CeH vinyl) cmꢂ1 1H NMR
.
(400 MHz, CDCl3)
d: 7.03 (1H, dd, J¼8.0, 7.0 Hz, 9-H), 6.88 (1H, td,
J¼8.0, 3.0. Hz, 8-H), 6.84 (1H, dd, J¼8.0, 2.0 Hz, 6-H), 5.98 (1H, ddd,
J¼17.3, 10.3, 7.5 Hz, eCH]), 5.21 (1H, dt, J¼17.3, 1.2 Hz, ]CHAH),
5.11 (1H, dt, J¼10.3, 1.2 Hz, ]CHHB), 4.84 (1H, ddd, J¼7.5, 5.5,
2.2 Hz, 4-H), 3.95 (1H, ddd, J¼8.1, 7.5, 2.8 Hz, 2-H), 3.32 (1H, br dd,
J¼16.9, 5.5 Hz, 5-HB), 2.60 (1H, dddd, J¼12.5, 7.5, 2.8, 1.2 Hz, 3-HB),
2.45 (1H, br d, J¼16.9 Hz, 5-HA), 2.33 (1H, ddd, J¼12.5, 8.1, 2.2 Hz,
4.4. General procedure for the synthesis of 2-exo-
vinyltetrahydro-1,4-epoxybenzo[b]azepines 5 and 2-exo-
(prop-1-en-2-yl)tetrahydro-1,4-epoxy-benzo[b]azepines 6
3-HA). 13C NMR (100 MHz, CDCl3)
d
: 160.5 (d, J¼234.0 Hz, 7-C),
145.9 (9a-C), 139.7 (eCH]), 127.1 (d, J¼8.2 Hz, 5a-C), 123.3 (d,
J¼8.5 Hz, 9-C), 116.0 (d, J¼22.3 Hz, 6-C), 114.6 (]CH2), 113.3 (d,
J¼22.4 Hz, 8-C), 74.6 (2-C), 74.0 (4-C), 39.9 (3-C), 34.8 (5-C). MS (EI-
70 eV) m/z (%): 205 (Mþ, 35), 188 (13), 175 (7), 148 (17), 123 (46),
122 (100), 96 (33). Anal. Calcd for C12H12FNO: C, 70.23; H, 5.89; N,
6.82. Found: C, 70.59; H, 5.73; N, 6.69%.
For the preparation of compounds 5 and 6, sodium tungstate
dihydrate (10 mol % Na2WO4$2H2O, 0.33 g), followed by 30%
aqueous hydrogen peroxide solution (30 mmol, 10.2 mL), were
added to a stirred and cooled (ice-bath) solution of the appropri-
ately substituted 2-allyl-N-alkenylaniline 2 or 4 (10 mmol) in
methanol (30 mL). The resulting mixtures were stirred at 0 ꢀC for
2 h and then at ambient temperature for additionally 4e70 h. Each
mixture was filtered and then extracted with ethyl acetate and
dried over anhydrous sodium sulfate. The solvent was removed
under reduced pressure and toluene (30 mL) was added to the
organic black residue. The resulting solution was heated at
80e110 ꢀC for 4e7 h. After cooling each solution to ambient tem-
perature, the solvent was removed under reduced pressure and the
crude product was purified by chromatography on silica gel using
heptane/ethyl acetate (compositions in the range from 60:1 to 10:1
v/v) as eluent.
4.4.4. 8-Chloro-9-methyl-2-exo-vinyl-2,3,4,5-tetrahydro-1,4-epoxy-
benzo[b]azepine (5d). Yield: 1.34 g (57%). Pale yellow oil. Rf: 0.39
(7% ethyl acetate/heptane). IR (liquid film) nmax: 1638 (C]C vinyl),
1267 (CeN), 1052 (CeO), 975 (NeO), 925 (]CeH vinyl) cmꢂ1 1H
.
NMR (400 MHz, CDCl3)
d: 7.10 (1H, d, J¼8.1 Hz, 7-H), 6.85 (1H, d,
J¼8.1 Hz, 6-H), 5.97 (1H, ddd, J¼17.2, 10.3, 6.9 Hz, eCH]), 5.26 (1H,
dt, J¼17.2, 1.3 Hz, ]CHAH), 5.13 (1H, dt, J¼10.3, 1.3 Hz, ]CHHB),
4.87 (1H, ddd, J¼7.6, 5.3, 2.0 Hz, 4-H), 3.89 (1H, ddd, J¼8.3, 6.9,
2.4 Hz, 2-H), 3.30 (1H, dd, J¼16.7, 5.3 Hz, 5-HB), 2.40 (1H, br d,
J¼16.7 Hz, 5-HA), 2.36 (3H, s, 9-CH3), 2.33 (1H, dddd, J¼12.6, 7.6,
2.4, 1.3 Hz, 3-HB), 2.23 (1H, ddd, J¼12.6, 8.3, 2.0 Hz, 3-HA). 13C NMR
4.4.1. 2-exo-Vinyl-2,3,4,5-tetrahydro-1,4-epoxybenzo[b]azepine
(5a). Yield: 1.08 g (58%). Colorless crystals, mp 62 ꢀC (heptane). Rf:
0.32 (7% ethyl acetate/heptane). IR (KBr) nmax: 1640 (C]C vinyl),
(100 MHz, CDCl3) d: 149.4 (9a-C), 139.4 (eCH]), 132.3 (9-C), 128.9
(8-C), 127.8 (6-C), 126.0 (7-C), 123.4 (5a-C), 114.7 (]CH2), 74.6 (4-
C), 73.1 (2-C), 40.1 (3-C), 34.4 (5-C), 13.7 (9-CH3). MS (EI-70 eV) m/z
(%): 235 (Mþ, 35Cl, 51), 218 (18), 205 (9), 178 (9), 153 (100), 152 (54),
126 (9). Anal. Calcd for C13H14ClNO: C, 66.24; H, 5.99; N, 5.94.
Found: C, 66.55; H, 6.07; N, 5.88%.
1261 (CeN), 1049 (CeO), 992 (NeO), 920 (]CeH vinyl) cmꢂ1 1H
.
NMR (400 MHz, CDCl3)
d
: 7.15 (1H, td, J¼8.0, 2.0 Hz, 8-H), 7.09 (1H,
td, J¼8.0, 2.0 Hz, 7-H), 7.07 (1H, dd, J¼8.0, 2.0 Hz, 6-H), 7.05 (1H, dd,
J¼8.0, 2.0 Hz, 9-H), 6.01 (1H, ddd, J¼17.2, 10.4, 7.1 Hz, eCH]), 5.22
(1H, dt, J¼17.2, 1.1 Hz, ]CHAH), 5.12 (1H, dt, J¼10.4, 1.1 Hz, ]CHHB),
4.87 (1H, ddd, J¼7.1, 5.3, 2.2 Hz, 4-H), 4.01 (1H, ddd, J¼7.9, 7.1,
2.1 Hz, 2-H), 3.36 (1H, br dd, J¼16.4, 5.3 Hz, 5-HB), 2.47 (1H, br d,
J¼16.4 Hz, 5-HA), 2.33 (1H, dddd, J¼12.2, 7.1, 2.1, 1.1 Hz, 3-HB), 2.28
4.4.5. 6,8-Dimethyl-2-exo-vinyl-2,3,4,5-tetrahydro-1,4-epoxybenzo-
[b]azepine (5e). Yield: 1.18 g (55%). Pale yellow oil. Rf: 0.31 (7% ethyl
acetate/heptane). IR (liquid film) nmax: 1641 (C]C vinyl), 1272
(CeN), 1053 (CeO), 990 (NeO), 919 (]CeH vinyl) cmꢂ1 1H NMR
.
(1H, ddd, J¼12.2, 7.9, 2.2 Hz, 3-HA). 13C NMR (100 MHz, CDCl3)
d:
(400 MHz, CDCl3) d: 6.84 (1H, s, 7-H), 6.76 (1H, s, 9-H), 6.03 (1H,
150.2 (9a-C), 140.1 (eCH]), 129.8 (6-C), 126.6 (8-C), 126.0 (7-C),
125.3 (5a-C), 122.0 (9-C), 114.6 (]CH2), 74.8 (2-C, 4-C), 40.1 (3-C),
39.8 (5-C). MS (EI-70 eV) m/z (%): 187(Mþ, 44), 170 (28), 157 (10),
130 (22), 105 (41), 104 (100), 78 (25). Anal. Calcd for C12H13NO: C,
76.98; H, 7.00; N, 7.48. Found: C, 76.39; H, 7.12; N, 7.21%.
ddd, J¼17.2, 10.3, 7.1 Hz, eCH]), 5.23 (1H, dt, J¼17.2, 1.9 Hz, ]
CHAH), 5.15 (1H, dt, J¼10.3, 1.9 Hz, ]CHHB), 4.91 (1H, ddd, J¼7.5,
5.5, 2.0 Hz, 4-H), 4.02 (1H, ddd, J¼8.3, 7.1, 2.4 Hz, 2-H), 3.11 (1H, br
dd, J¼16.7, 5.5 Hz, 5-HB), 2.54 (1H, br d, J¼16.7 Hz, 5-HA), 2.33 (1H,
dddd, J¼12.6, 7.5, 2.4, 1.1 Hz, 3-HB), 2.27 (3H, s, 8-CH3), 2.23 (1H,
ddd, J¼12.6, 8.3, 2.0 Hz, 3-HA), 2.13 (3H, s, 6-CH3). 13C NMR
4.4.2. 7-Chloro-2-exo-vinyl-2,3,4,5-tetrahydro-1,4-epoxybenzo[b]-
azepine (5b). Yield: 1.11 g (50%). Pale yellow oil. Rf: 0.32 (7% ethyl
acetate/heptane). IR (liquid film) nmax: 1632 (C]C vinyl), 1250
(100 MHz, CDCl3) d: 149.9 (9a-C), 140.2 (eCH]), 137.5 (6-C), 136.0
(8-C), 128.0 (7-C), 120.3 (5a-C), 120.1 (9-C), 114.5 (]CH2), 74.8 (4-C),
74.7 (2-C), 40.5 (3-C), 33.1 (5-C), 20.9 (8-CH3), 18.5 (6-CH3). MS

8398
L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
(EI-70 eV) m/z (%): 215 (Mþ, 49), 198 (23), 185 (9), 158 (9), 133 (100),
132 (60), 106 (14). Anal. Calcd for C14H17NO: C, 78.10; H, 7.96; N,
6.51. Found: C, 77.86; H, 8.05; N, 6.33%.
J¼0.6 Hz, ]CHAH), 4.87 (1H, br s, ]CHHB), 4.84 (1H, ddd, J¼7.4, 5.6,
1.4 Hz, 4-H), 3.85 (1H, dd, J¼8.8, 2.4 Hz, 2-H), 3.31 (1H, br dd, J¼16.6,
5.6 Hz, 5-HB), 2.43 (1H, br d, J¼16.6 Hz, 5-HA), 2.42 (1H, dddd,
J¼12.5, 7.4, 2.4, 1.0 Hz, 3-HB), 2.35 (3H, s, 9-CH3), 2.22 (1H, ddd,
J¼12.5, 8.8, 1.4 Hz, 3-HA), 1.83 (3H, s, CH2]CeCH3). 13C NMR
4.4.6. 2-exo-(Prop-1-en-2-yl)-2,3,4,5-tetrahydro-1,4-epoxybenzo[b]-
azepine (6a). Yield: 0.98 g (49%). Yellow viscous oil. Rf: 0.45 (7%
ethyl acetate/heptane). IR (liquid film) nmax: 1648 (C]C iso-
propenyl), 1259 (CeN), 1055 (CeO), 980 (NeO), 913 (]CeH
(100 MHz, CDCl3)
d
: 150.5 (9a-C), 145.3 (eC¼), 132.5 (8-C), 129.2 (9-
C), 127.9 (6-C), 126.0 (7-C), 123.7 (5a-C), 111.3 (]CH2), 75.6 (2-C),
74.7 (4-C), 39.3 (3-C), 34.5 (5-C), 19.4 (CH2]CeCH3), 14.0 (9-CH3).
MS (EI-70 eV) m/z (%): 249 (Mþ, 35Cl, 53), 232 (16), 219 (3), 192 (6),
153 (100), 152 (53), 126 (9). Anal. Calcd for C14H16ClNO: C, 67.33; H,
6.46; N, 5.61. Found: C, 67.76; H, 6.29; N, 5.42%.
isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 7.11 (1H, td, J¼8.3,
2.2 Hz, 8-H), 7.10 (1H, td, J¼8.3, 1.4 Hz, 7-H), 7.09 (1H, dd, J¼8.3,
2.2 Hz, 6-H), 7.04 (1H, dd, J¼8.3, 1.4 Hz, 9-H), 5.04 (1H, d, J¼0.7 Hz,
]CHAH), 4.86 (1H, ddd, J¼7.6, 5.4, 1.7 Hz, 4-H), 4.84 (1H, d,
J¼0.7 Hz, ]CHHB), 3.96 (1H, dd, J¼8.7, 2.7 Hz, 2-H), 3.36 (1H, br dd,
J¼16.6, 5.4 Hz, 5-HB), 2.48 (1H, br d, J¼16.6 Hz, 5-HA), 2.44 (1H,
dddd, J¼12.6, 7.6, 2.7, 1.2 Hz, 3-HB), 2.25 (1H, ddd, J¼12.6, 8.7,
1.7 Hz, 3-HA), 1.86 (3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
4.4.10. 6,8-Dimethyl-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxybenzo[b]azepine (6e). Yield: 1.37 g (60%). Pale yellow viscous
oil. Rf: 0.40 (7% ethyl acetate/heptane). IR (liquid film) nmax: 1650
(C]C isopropenyl), 1272 (CeN), 1065 (CeO), 922 (]CeH iso-
d
: 150.9 (9a-C), 145.6 (eC¼), 129.7 (6-C), 126.4 (8-C), 125.7 (7-C),
propenyl), 912 (NeO) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 6.83 (1H,
125.2 (5a-C), 121.7 (9-C), 111.1 (]CH2), 76.7 (2-C), 74.8 (4-C), 38.6
(3-C), 34.5 (5-C), 19.6 (CH2]CeCH3). MS (EI-70 eV) m/z (%): 201
(Mþ, 63), 184 (8), 171 (3), 130 (15), 105 (45), 104 (100), 78 (31). Anal.
Calcd for C13H15NO: C, 77.58; H, 7.51; N, 6.96. Found: C, 77.91; H,
7.26; N, 6.72%.
s, 7-H), 6.73 (1H, s, 9-H), 5.04 (1H, dd, J¼1.8, 0.9 Hz, ]CHAH), 4.90
(1H, ddd, J¼7.5, 5.4, 1.6 Hz, 4-H), 4.86 (1H, d, J¼1.4 Hz, ]CHHB),
3.94 (1H, dd, J¼8.9, 2.9 Hz, 2-H), 3.12 (1H, br dd, J¼16.5, 5.4 Hz, 5-
HB), 2.43 (1H, dddd, J¼12.5, 7.5, 2.9, 1.3 Hz, 3-HB), 2.29 (1H, br d,
J¼16.5 Hz, 5-HA), 2.27 (3H, s, 6-CH3), 2.22 (1H, ddd, J¼12.5, 8.9,
1.6 Hz, 3-HA), 2.15 (3H, s, 8-CH3), 1.86 (3H, s, CH2]CeCH3). 13C
4.4.7. 7-Chloro-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-
benzo[b]azepine (6b). Yield: 1.22 g (52%). Pale yellow viscous oil. Rf:
0.49 (7% ethyl acetate/heptane). IR (liquid film) nmax: 1650 (C]C
isopropenyl), 1259 (CeN), 1080 (CeO), 980 (NeO), 913 (]CeH
NMR (100 MHz, CDCl3)
d
: 150.7 (9a-C), 145.9 (eC¼), 137.4 (6-C),
136.0 (8-C), 128.0 (7-C), 120.4 (5a-C), 119.9 (9-C), 111.0 (]CH2),
77.0 (2-C), 74.9 (4-C), 39.2 (3-C), 32.9 (5-C), 21.0 (8-CH3), 19.7
(CH2]CeCH3), 18.5 (6-CH3). MS (EI-70 eV) m/z (%): 229 (Mþ, 56),
212 (9), 199 (3), 158 (9), 133 (100), 132 (53), 106 (12). Anal. Calcd
for C15H19NO: C, 78.56; H, 8.35; N, 6.11. Found: C, 78.93; H, 8.16;
N, 5.89%.
isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 7.10 (1H, dd, J¼8.4,
2.9 Hz, 8-H), 7.07 (1H, br s, 6-H), 6.98 (1H, d, J¼8.4 Hz, 9-H), 5.02
(1H, s, ]CHAH), 4.86 (1H, s, ]CHHB), 4.84 (1H, ddd, J¼7.6, 5.4,
1.7 Hz, 4-H), 3.90 (1H, dd, J¼8.6, 2.4 Hz, 2-H), 3.32 (1H, br dd,
J¼16.8, 5.4 Hz, 5-HB), 2.46 (1H, br d, J¼16.8 Hz, 5-HA), 2.44 (1H,
dddd, J¼12.6, 7.6, 2.4, 1.3 Hz, 3-HB), 2.21 (1H, ddd, J¼12.6, 8.6,
1.7 Hz, 3-HA), 1.89 (3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
4.4.11. 7,9-Dichloro-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxybenzo[b]azepine (6f). Yield: 1.69 g (63%). Colorless crystals,
mp 97 ꢀC (heptane). Rf: 0.45 (7% ethyl acetate/heptane). IR (KBr)
nmax: 1648 (C]C isopropenyl), 1279 (CeN), 1060 (CeO), 927
(]CeH isopropenyl), 915 (NeO) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
: 149.3 (9a-C), 145.1 (eC¼), 131.0 (7-C), 129.6 (6-C), 127.2 (5a-C),
126.6 (8-C), 123.1 (9-C), 111.4 (]CH2), 77.0 (2-C), 74.3 (4-C), 38.6 (3-
C), 34.4 (5-C), 19.6 (CH2]CeCH3). MS (EI-70 eV) m/z (%): 235 (Mþ,
35Cl, 64), 218 (52), 205 (3), 164 (10), 139 (66), 138 (100), 112 (21).
Anal. Calcd for C13H14ClNO: C, 66.24; H, 5.99; N, 5.94. Found: C,
66.02; H, 5.82; N, 6.16%.
d
: 7.22 (1H, d, J¼2.1 Hz, 8-H), 7.01 (1H, d, J¼2.1 Hz, 6-H), 5.09 (1H,
br s, ]CHAH), 4.92 (1H, br s, ]CHHB), 4.86 (1H, ddd, J¼7.5, 5.8,
1.6 Hz, 4-H), 3.95 (1H, dd, J¼8.3, 2.7 Hz, 2-H), 3.33 (1H, br dd,
J¼16.9, 5.8 Hz, 5-HB), 2.50 (1H, dddd, J¼12.8, 7.5, 2.7, 1.2 Hz, 3-HB),
2.44 (1H, br d, J¼16.9 Hz, 5-HA), 2.15 (1H, ddd, J¼12.8, 8.3, 1.6 Hz,
4.4.8. 7-Fluoro-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-
benzo[b]azepine (6c). Yield: 1.10 g (50%). Pale yellow viscous oil. Rf:
0.45 (7% ethyl acetate/heptane). IR (liquid film) nmax: 1647 (C]C
isopropenyl), 1249 (CeN), 1098 (CeO), 979 (NeO), 915 (]CeH
3-HA), 1.89 (3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
d:
146.1 (9a-C), 144.9 (eC¼), 130.9 (7-C), 129.1 (5a-C), 128.3 (6-C),
127.9 (9-C), 127.4 (8-C), 111.9 (]CH2), 75.5 (2-C), 74.6 (4-C), 38.4
(3-C), 34.6 (5-C), 20.0 (CH2]CeCH3). MS (EI-70 eV) m/z (%): 269
(Mþ, 35Cl, 59), 252 (6), 239 (3), 198 (17), 173 (76), 172 (100), 145
(9). Anal. Calcd for C13H13Cl2NO: C, 57.80; H, 4.85; N, 5.18. Found:
C, 58.02; H, 4.93; N, 5.35%.
isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 6.99 (1H, dd, J¼8.6,
5.3 Hz, 9-H), 6.84 (1H, dd, J¼8.6, 2.8 Hz, 8-H), 6.79 (1H, dd, J¼8.4,
2.8 Hz, 6-H), 5.03 (1H, d, J¼0.7 Hz, ]CHAH), 4.86 (1H, d, J¼1.3 Hz,
]CHHB), 4.83 (1H, ddd, J¼7.8, 5.5, 1.7 Hz, 4-H), 3.89 (1H, dd, J¼8.7,
2.2 Hz, 2-H), 3.33 (1H, br dd, J¼16.8, 5.5 Hz, 5-HB), 2.47 (1H, br d,
J¼16.8 Hz, 5-HA), 2.44 (1H, dddd, J¼12.7, 7.8, 2.2, 1.3 Hz, 3-HB), 2.23
(1H, ddd, J¼12.7, 8.7, 1.7 Hz, 3-HA), 1.84 (3H, s, CH2]CeCH3). 13C
4.5. General procedure for the synthesis of cis-2-
vinyltetrahydro-1H-benzo[b]azepinols 7 and cis-2-(prop-1-en-
2-yl)-tetrahydro-1H-benzo[b]azepinols 8
NMR (100 MHz, CDCl3)
d
: 160.6 (d, J¼242.4 Hz, 7-C), 147.0 (d,
J¼2.7 Hz, 9a-C), 145.6 (eC¼), 127.5 (d, J¼8.1 Hz, 5a-C), 123.4 (d,
J¼8.5 Hz, 9-C), 116.2 (d, J¼22.3 Hz, 6-C), 113.4 (d, J¼22.4 Hz, 8-C),
111.3 (]CH2), 76.9 (2-C), 74.4 (4-C), 38.9 (3-C), 34.9 (5-C), 19.8
(CH2]CeCH3). MS (EI-70 eV) m/z (%): 219 (Mþ, 58), 148 (15), 123
(49), 122 (100), 96 (23). Anal. Calcd for C13H14FNO: C, 71.21; H, 6.44;
N, 6.39. Found: C, 70.98; H, 6.21; N, 6.53%.
To a stirred and cooled (ice-bath) solutions of 1,4-epoxy-cyclo-
adducts 5aee or 6aef (10 mmol) in MeOH (25 mL), were added
glacial acetic acid (70 mmol, 4 mL), zinc powder (100 mmol, 6.54 g),
and hydrochloric acid (37% HCl, 70 mmol, 6.81 mL). The resulting
reaction mixtures were then stirred at 0 ꢀC for additional 0.5e2 h
(TLC control). Each mixture was filtered and the filtrate was neu-
tralized with a 25% ammonium hydroxide solution to pH¼8, and
then extracted with ethyl acetate (3ꢁ50 mL). The combined organic
extracts were dried over anhydrous sodium 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 10:1 to 1:1 v/v)
as eluent to give 7aee and 8aef.
4.4.9. 8-Chloro-9-methyl-2-exo-(prop-1-en-2-yl)-2,3,4,5-tetrahy-
dro-1,4-epoxybenzo[b]azepine (6d). Yield: 1.62 g (65%). Colorless
crystals, mp 94 ꢀC (heptane). Rf: 0.52 (7% ethyl acetate/heptane). IR
(KBr) nmax: 1650 (C]C isopropenyl), 1274 (CeN), 1095 (CeO), 970
(NeO), 918 (]CeH isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d:
7.10 (1H, d, J¼8.2 Hz, 7-H), 6.86 (1H, d, J¼8.2 Hz, 6-H), 5.11 (1H, d,

L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
8399
4.5.1. cis-2-Vinyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-ol
(7a). Reaction time: 0.5 h. Yield: 1.76 g (93%). Colorless crystals,
mp 103 ꢀC (heptane). Rf: 0.28 (33% ethyl acetate/heptane). IR
(KBr) nmax: 3287 (NH/OH), 1241 (CeN), 1095 (CeO), 935 (]CeH
ddd, J¼9.4, 4.5, 2.0 Hz, 4-Hax), 3.39 (1H, ddd, J¼9.9, 7.5, 1.9 Hz, 2-
Hax), 2.94 (1H, dd, J¼12.0, 9.4 Hz, 5-Hax), 2.90 (1H, dt, J¼12.0,
2.0 Hz, 5-Heq), 2.27 (3H, s, 9-CH3), 2.10 (1H, ddd, J¼12.7, 4.5,
1.9 Hz, 3-Heq), 1.75 (1H, ddd, J¼12.7, 9.9, 9.4 Hz, 3-Hax). 13C NMR
vinyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
: 7.16 (1H, d, J¼7.4 Hz, 6-
(100 MHz, CDCl3) d: 148.4 (9a-C), 140.4 (eCH]), 132.9 (8-C),
H), 7.09 (1H, td, J¼7.4, 1.2 Hz, 8-H), 6.89 (1H, td, J¼7.4, 1.0 Hz, 7-
H), 6.75 (1H, d, J¼7.4 Hz, 9-H), 5.99 (1H, ddd, J¼17.4, 10.3, 7.4 Hz,
]CH), 5.27 (1H, d, J¼17.4 Hz, ]CHAH), 5.16 (1H, d, J¼10.3 Hz,
]CHHB), 3.80 (1H, ddd, J¼9.5, 3.9, 1.6 Hz, 4-Hax), 3.47 (1H, ddd,
J¼10.3, 7.4, 2.0 Hz, 2-Hax), 3.02 (1H, dd, J¼12.8, 9.5 Hz, 5-Hax),
2.96 (1H, dt, J¼12.8, 1.6 Hz, 5-Heq), 2.13 (1H, ddd, J¼12.8, 3.9,
2.0 Hz, 3-Heq), 1.80 (1H, ddd, J¼12.8, 10.3, 10.0 Hz, 3-Hax). 13C
129.4 (6-C), 127.1 (5a-C), 124.4 (9-C), 122.1 (7-C), 115.7 (]CH2),
69.5 (4-C), 58.5 (2-C), 45.5 (3-C), 43.4 (5-C), 14.4 (9-CH3). MS (EI-
70 eV) m/z (%): 237 (Mþ, 35Cl, 100), 220 (21), 218 (33), 210 (12),
194 (48), 193 (27), 192 (70), 178 (70), 166 (85), 165 (48), 155 (12),
154 (58). Anal. Calcd for C13H16ClNO: C, 65.68; H, 6.78; N, 5.89.
Found: C, 65.96; H, 6.60; N, 6.05%.
NMR (100 MHz, CDCl3)
d
: 148.5 (9a-C), 140.6 (eCH]), 131.5 (6-C),
4.5.5. 6,8-Dimethyl-cis-2-vinyl-2,3,4,5-tetrahydro-1H-benzo[b]aze-
pin-4-ol (7e). Reaction time: 1 h. Yield: 2.04 g (94%). Colorless
crystals, mp 99 ꢀC (heptane). Rf: 0.30 (33% ethyl acetate/heptane).
IR (KBr) nmax: 3274 (NH/OH), 1294 (CeN), 1072 (CeO), 930 (]CeH
128.1 (5a-C), 127.4 (8-C), 121.8 (7-C), 120.2 (9-C), 115.4 (]CH2),
69.7 (4-C), 58.9 (2-C), 46.1 (3-C), 44.3 (5-C). MS (EI-70 eV) m/z
(%): 189 (Mþ, 91), 172 (11), 170 (33), 162 (8), 146 (26), 145 (28),
144 (100), 130 (65), 118 (92), 117 (54), 107 (11), 106 (46). Anal.
Calcd for C12H15NO: C, 76.16; H, 7.99; N, 7.40. Found: C, 75.93; H,
7.80; N, 7.53%.
vinyl) cmꢂ1 1H NMR (400 MHz, CDCl3)
. d: 6.66 (1H, s, 6-H), 6.46
(1H, s, 9-H), 5.98 (1H, ddd, J¼17.4, 10.3, 7.4 Hz, ]CH), 5.26 (1H, dt,
J¼17.4, 1.1 Hz, ]CHAH), 5.15 (1H, dd, J¼10.3, 1.1 Hz, ]CHHB), 3.80
(1H, ddd, J¼9.3, 4.1, 2.2 Hz, 4-Hax), 3.48 (1H, ddd, J¼11.2, 7.4, 2.4 Hz,
2-Hax), 3.11 (1H, dt, J¼13.8, 2.2 Hz, 5-Heq), 2.86 (1H, dd, J¼13.8,
9.3 Hz, 5-Hax), 2.33 (3H, s, 6-CH3), 2.24 (3H, s, 8-CH3), 2.10 (1H,
dddd, J¼12.9, 4.1, 2.4, 1.8 Hz, 3-Heq), 1.79 (1H, ddd, J¼12.9, 11.2,
4.5.2. 7-Chloro-cis-2-vinyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-
ol (7b). Reaction time: 0.5 h. Yield: 2.07 g (95%). Colorless crystals,
mp 118 ꢀC (heptane). Rf: 0.28 (33% ethyl acetate/heptane). IR (KBr)
nmax
:
3298 (NH/OH), 1252 (CeN), 1090 (CeO), 928 (]CeH
: 7.10 (1H, d, J¼2.4 Hz, 6-H),
9.3 Hz, 3-Hax). 13C NMR (100 MHz, CDCl3)
d: 149.0 (9a-C), 140.9
vinyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
(eCH]), 137.6 (6-C), 136.3 (8-C), 125.0 (7-C), 123.9 (5a-C), 119.0 (9-
C), 115.2 (]CH2), 69.4 (4-C), 59.2 (2-C), 45.5 (3-C), 37.8 (5-C), 20.8
(6-CH3), 20.8 (8-CH3). MS (EI-70 eV) m/z (%): 217 (Mþ, 57), 198 (14),
184 (9), 172 (68), 158 (78), 146 (100), 145 (59), 134 (49), 91(37).
Anal. Calcd for C14H19NO: C, 77.38; H, 8.81; N, 6.45. Found: C, 77.59;
H, 8.36; N, 6.25%.
7.02 (1H, dd, J¼8.3, 2.4 Hz, 8-H), 6.68 (1H, d, J¼8.3 Hz, 9-H), 5.96
(1H, ddd, J¼17.5, 10.3, 7.4 Hz, ]CH), 5.27 (1H, d, J¼17.5 Hz, ]CHAH),
5.16 (1H, d, J¼10.3 Hz, ]CHHB), 3.79 (1H, ddd, J¼9.5, 3.9, 2.2 Hz, 4-
Hax), 3.43 (1H, ddd, J¼10.2, 7.4, 2.0 Hz, 2-Hax), 2.96 (1H, dd, J¼12.6,
9.5 Hz, 5-Hax), 2.90 (1H, dt, J¼12.6, 2.2 Hz, 5-Heq), 2.12 (1H, ddd,
J¼13.0, 3.9, 2.0 Hz, 3-Heq), 1.78 (1H, ddd, J¼13.0, 10.2, 10.0 Hz, 3-
Hax). 13C NMR (100 MHz, CDCl3)
d
: 146.9 (9a-C), 140.2 (eCH]),
4.5.6. cis-2-(Prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-
4-ol (8a). Reaction time: 0.5 h. Yield: 1.83 g (90%). Viscous maroon
oil. Rf: 0.32 (33% ethyl acetate/heptane). IR (liquid film) nmax: 3352
132.1 (6-C), 129.8 (5a-C), 127.1 (8-C), 126.6 (7-C), 121.4 (9-C), 115.8
(]CH2), 69.3 (4-C), 59.1 (2-C), 45.8 (3-C), 44.0 (5-C). MS (EI-70 eV)
m/z (%): 223 (Mþ, 35Cl, 100), 206 (21), 204 (30), 196 (7), 180 (58), 179
(37), 178 (94), 164 (57), 152 (68), 151 (46), 141 (11), 140 (44). Anal.
Calcd for C12H14ClNO: C, 64.43; H, 6.31; N, 6.26. Found: C, 64.02; H,
6.15; N, 6.50%.
(NH/OH), 1253 (CeN), 1097 (CeO), 906 (]CeH isopropenyl) cmꢂ1
.
1H NMR (400 MHz, CDCl3)
d
: 7.12 (1H, d, J¼7.4 Hz, 6-H), 7.08 (1H, td,
J¼7.6, 1.4 Hz, 8-H), 6.88 (1H, td, J¼7.4, 1.0 Hz, 7-H), 6.72 (1H, d,
J¼7.6 Hz, 9-H), 5.02 (1H, br s, ]CHAH), 4.88 (1H, d, J¼2.8 Hz,
]CHHB), 3.79 (1H, ddd, J¼9.6, 3.7, 2.1 Hz, 4-Hax), 3.38 (1H, dd,
J¼11.2, 2.1 Hz, 2-Hax), 2.99 (1H, dd, J¼13.6, 9.2 Hz, 5-Hax), 2.92 (1H,
dt, J¼13.6, 2.1 Hz, 5-Heq), 2.10 (1H, ddd, J¼12.7, 3.7, 2.1 Hz, 3-Heq),
1.88 (1H, ddd, J¼12.7, 11.2, 10.0 Hz, 3-Hax), 1.86 (3H, s, CH2]CeCH3).
4.5.3. 7-Fluoro-cis-2-vinyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-4-
ol (7c). Reaction time: 0.5 h. Yield: 1.93 g (93%). Colorless crystals,
mp 127 ꢀC (heptane). Rf: 0.26 (33% ethyl acetate/heptane). IR (KBr)
nmax
:
3289 (NH/OH), 1253 (CeN), 1092 (CeO), 932 (]CeH
: 6.89 (1H, dd, J¼8.0, 2.4 Hz,
13C NMR (100 MHz, CDCl3)
d
: 149.1 (9a-C), 148.0 (eC¼), 131.5 (6-C),
vinyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
127.8 (5a-C), 127.4 (8-C), 121.6 (7-C), 119.9 (9-C), 111.4 (]CH2), 69.8
(4-C), 61.9 (2-C), 45.0 (3-C), 44.4 (5-C), 19.3 (CH2]CeCH3). MS (EI-
70 eV) m/z (%): 203 (Mþ, 55), 188 (4), 186 (5), 184 (6), 162 (31), 160
(11), 159 (14),144 (38),130 (17),118 (100), 117 (23), 107 (5),106 (24).
Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C, 77.13;
H, 8.25; N, 6.68%.
6-H), 6.82 (1H, td, J¼7.6, 2.4 Hz, 8-H), 6.75 (1H, dd, J¼7.6, 4.8 Hz, 9-
H), 6.11 (1H, ddd, J¼16.4, 10.0, 7.5 Hz, ]CH), 5.48 (1H, dt, J¼16.4,
1.0 Hz, ]CHAH), 5.38 (1H, dd, J¼10.0,1.0 Hz, ]CHHB), 4.15 (1H, ddd,
J¼9.2, 4.0, 2.0 Hz, 4-Hax), 3.82 (1H, ddd, J¼10.4, 7.5, 2.0 Hz, 2-Hax),
3.46 (1H, dd, J¼12.0, 9.2 Hz, 5-Hax), 3.36 (1H, dt, J¼12.0, 2.0 Hz, 5-
Heq), 2.67 (1H, ddd, J¼11.6, 4.0, 2.0 Hz, 3-Heq), 2.38 (1H, ddd, J¼11.6,
10.4, 10.4 Hz, 3-Hax). 13C NMR (100 MHz, CDCl3)
d
: 158.3 (d,
4.5.7. 7-Chloro-cis-2-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-benzo
[b]azepin-4-ol (8b). Reaction time: 0.5 h. Yield: 2.18 g (92%). Vis-
cous maroon oil. Rf: 0.35 (33% ethyl acetate/heptane). IR (liquid
film) nmax: 3344 (NH/OH), 1253 (CeN), 1100 (CeO), 903 (]CeH
J¼230.0 Hz, 7-C),144.6 (9a-C),140.5 (eCH]),130.4 (d, J¼8.0 Hz, 5a-
C), 121.4 (d, J¼10.0 Hz, 9-C), 117.9 (d, J¼20.0 Hz, 6-C), 115.7 (]CH2),
113.7 (d, J¼20.0 Hz, 8-C), 69.5 (4-C), 59.3 (2-C), 46.2 (3-C), 44.2 (5-
C). MS (EI-70 eV) m/z (%): 207 (Mþ, 60),190 (7),188 (21),180 (7),164
(27), 163 (27), 162 (90), 148 (67), 136 (100), 135 (55), 125 (13), 124
(45). Anal. Calcd for C12H14FNO: C, 69.55; H, 6.81; N, 6.76. Found: C,
69.91; H, 6.60; N, 6.53%.
isopropenyl) cmꢂ1 1H NMR (400 MHz, CDCl3)
. d: 7.10 (1H, d,
J¼2.4 Hz, 6-H), 7.02 (1H, dd, J¼8.3, 2.4 Hz, 8-H), 6.69 (1H, d,
J¼8.3 Hz, 9-H), 5.04 (1H, br s, ]CHAH), 4.89 (1H, t, J¼1.4 Hz,
]CHHB), 3.77 (1H, ddd, J¼9.4, 3.4, 2.1 Hz, 4-Hax), 3.43 (1H, dd,
J¼11.3, 2.0 Hz, 2-Hax), 2.98 (1H, dd, J¼11.3, 9.4 Hz, 5-Hax), 2.92 (1H,
dt, J¼11.3, 2.1 Hz, 5-Heq), 2.10 (1H, ddd, J¼12.9, 3.4, 2.0 Hz, 3-Heq),
1.85 (1H, ddd, J¼12.9, 11.3, 9.4 Hz, 3-Hax), 1.83 (3H, s, CH2]CeCH3).
4.5.4. 8-Chloro-9-methyl-cis-2-vinyl-2,3,4,5-tetrahydro-1H-benzo[b]
azepin-4-ol (7d). Reaction time: 2 h. Yield: 2.23 g (94%). Colorless
crystals, mp 63 ꢀC (heptane). Rf: 0.33 (33% ethyl acetate/heptane).
IR (KBr) nmax: 3397 (NH/OH), 1250 (CeN), 1103 (CeO), 928
13C NMR (100 MHz, CDCl3)
d
: 147.5 (eC¼), 147.0 (9a-C), 131.1 (6-C),
129.7 (5a-C), 129.6 (7-C), 127.1 (8-C), 121.3 (9-C), 111.8 (]CH2), 69.5
(4-C), 62.1 (2-C), 44.7 (3-C), 44.0 (5-C), 19.2 (CH2]CeCH3). MS (EI-
70 eV) m/z (%): 237 (Mþ, 35Cl, 87), 222 (8), 220 (8), 218 (7), 196 (55),
194 (20), 193 (23), 178 (32), 164 (17), 152 (100), 151 (10), 141 (12),
(]CeH vinyl) cmꢂ1 1H NMR (400 MHz, CDCl3)
. d: 6.91 (2H, br s,
6-H, 7-H), 6.01 (1H, ddd, J¼17.4, 10.3, 7.5 Hz, ]CH), 5.28 (1H, d,
J¼17.4 Hz, ]CHAH), 5.17 (1H, d, J¼10.3 Hz, ]CHHB), 3.79 (1H,

8400
L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
140 (32). Anal. Calcd for C13H16ClNO: C, 65.68; H, 6.78; N, 5.89.
Found: C, 65.17; H, 7.03; N, 5.68%.
4-Hax), 3.41 (1H, dd, J¼11.2, 1.2 Hz, 2-Hax), 3.00 (1H, dt, J¼13.6,
2.5 Hz, 5-Heq), 2.91 (1H, dd, J¼13.6, 8.8 Hz, 5-Hax), 2.10 (1H, ddd,
J¼13.2, 4.0, 1.2 Hz, 3-Heq), 1.86 (3H, s, CH2]CeCH3), 1.84 (1H, ddd,
4.5.8. 7-Fluoro-cis-2-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-benzo
[b]azepin-4-ol (8c). Reaction time: 0.5 h. Yield: 2.06 g (93%). Viscous
maroon oil. Rf: 0.32 (33% ethyl acetate/heptane). IR (liquid film)
J¼13.2,11.2, 9.7 Hz, 3-Hax). 13C NMR (100 MHz, CDCl3)
: 147.1 (eC¼),
d
144.1 (9a-C), 130.3 (5a-C), 129.8 (6-C), 127.1 (8-C), 125.0 (7-C), 124.3
(9-C), 112.2 (]CH2), 69.2 (4-C), 61.0 (2-C), 43.8 (3-C), 43.7 (5-C), 19.3
(CH2]CeCH3). MS (EI-70 eV) m/z (%): 271 (Mþ, 35Cl, 40), 256 (9), 254
(6), 252 (6), 230 (49), 228 (17), 227 (9), 212 (40), 198 (17), 186 (100),
185 (17), 175 (17), 174 (34). Anal. Calcd for C13H15Cl2NO: C, 57.37; H,
5.56; N, 5.15. Found: C, 57.25; H, 5.63; N, 5.29%.
nmax
:
3350 (NH/OH), 1258 (CeN), 1112 (CeO), 904 (]CeH
: 6.84 (1H, dd, J¼9.1,
isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
2.8 Hz, 6-H), 6.76 (1H, td, J¼8.4, 2.8 Hz, 8-H), 6.65 (1H, dd, J¼8.4,
5.0 Hz, 9-H), 5.03 (1H, br s, ]CHAH), 4.88 (1H, t, J¼1.4 Hz, ]CHHB),
3.77 (1H, ddd, J¼10.0, 3.9, 2.2 Hz, 4-Hax), 3.32(1H, dd, J¼11.3,1.2Hz, 2-
Hax), 2.99 (1H, dd, J¼13.6,10.0 Hz, 5-Hax), 2.89 (1H, dt, J¼13.6, 2.2 Hz,
5-Heq), 2.10 (1H, ddd, J¼12.8, 3.9, 2.0 Hz, 3-Heq),1.85 (1H, ddd, J¼12.8,
11.3, 10.0 Hz, 3-Hax), 1.84 (3H, s, CH2]CeCH3). 13C NMR (100 MHz,
Acknowledgements
The authors would like to acknowledge for the financial support
due by the Colombian Institute for Science and Research (COL-
CIENCIAS, grant No 1102e408-20563), and the Research Center of
Excellence CENIVAM (contract No 432). A. P. also thanks Dr. E.
Stashenko (Laboratory of Chromatography, School of Chemistry,
Industrial University of Santander) for providing GCeMS spectra.
CDCl3)
d
:158.1 (d, J¼238.0 Hz, 7-C),148.1 (eC¼),145.5 (9a-C),130.0 (d,
J¼8.0 Hz, 5a-C),121.1 (d, J¼8.0 Hz, 9-C),117.9 (d, J¼22.0 Hz, 6-C),113.7
(d, J¼22.0 Hz, 8-C), 111.6 (]CH2), 69.8 (4-C), 62.3 (2-C), 45.3 (3-C),
44.4 (5-C), 19.5 (CH2]CeCH3). MS (EI-70 eV) m/z (%): 221 (Mþ, 49),
206 (3), 204 (3), 202 (3), 180 (31), 178 (9), 177 (14), 162 (37), 149 (6),
136 (100), 135 (20), 125 (6), 124 (26). Anal. Calcd for C13H16FNO: C,
70.56; H, 7.29; N, 6.33. Found: C, 70.26; H, 7.45; N, 6.43%.
Supplementary data
4.5.9. 8-Chloro-9-methyl-cis-2-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-
1H-benzo[b]azepin-4-ol (8d). Reaction time: 2 h. Yield: 2.26 g
(90%). Colorless crystals, mp 101 ꢀC (heptane). Rf: 0.33 (33% ethyl
acetate/heptane). IR (KBr) nmax: 3396 (NH/OH), 1257 (CeN), 1106
(CeO), 905 (]CeH isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
Selected 1H, 13C and NOESY NMR spectra as well as GCeMS
spectra of compounds 5e8 are provided. Supplementary data as-
sociated with this article can be found in online version at
doi:10.1016/j.tet.2010.08.067. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
d
: 6.91 (1H, d, J¼8.2 Hz, 6-H), 6.88 (1H, d, J¼8.2 Hz, 7-H), 5.07 (1H,
br s, ]CHAH), 4.91 (1H, t, J¼1.4 Hz, ]CHHB), 3.79 (1H, ddd, J¼9.5,
4.1, 2.2 Hz, 4-Hax), 3.35 (1H, dd, J¼11.3, 1.3 Hz, 2-Hax), 2.99 (1H, dd,
J¼13.6, 10.1 Hz, 5-Hax), 2.89 (1H, dt, J¼13.6, 2.2 Hz, 5-Heq), 2.26 (3H,
s, 9-CH3), 2.08 (1H, ddd, J¼12.7, 4.1, 1.3 Hz, 3-Heq), 1.84 (1H, ddd,
J¼12.7, 11.3, 9.5 Hz, 3-Hax), 1.86 (3H, s, CH2]CeCH3). 13C NMR
References and notes
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(100 MHz, CDCl3)
d: 148.9 (9a-C), 148.1 (eC¼), 133.1 (8-C), 129.6 (6-
C), 126.9 (5a-C), 124.3 (9-C), 121.9 (7-C), 111.9 (]CH2), 69.8 (4-C),
61.6 (2-C), 44.5 (3-C), 44.1 (5-C), 19.5 (CH2]CeCH3), 14.4 (9-CH3).
MS (EI-70 eV) m/z (%): 251 (Mþ, 35Cl, 54), 236 (3), 234 (3), 232 (3),
210 (31), 208 (11), 207 (9), 192 (30), 178 (14), 166 (100), 165 (14),
155 (31), 154 (6). Anal. Calcd for C14H18ClNO: C, 66.79; H, 7.21; N,
5.56. Found: C, 67.01; H, 7.45; N, 5.39%.
4.5.10. 6,8-Dimethyl-cis-2-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-
benzo[b]azepin-4-ol (8e). Reaction time: 1 h. Yield: 2.19 g (95%).
Viscous maroon oil. Rf: 0.37 (33% ethyl acetate/heptane). IR (liquid
film) nmax: 3346 (NH/OH), 1264 (CeN), 1106 (CeO), 906 (]CeH
isopropenyl) cmꢂ1. 1H NMR (400 MHz, CDCl3)
d: 6.63 (1H, s, 7-H),
6.43 (1H, s, 9-H), 5.02 (1H, br s, ]CHAH), 4.86 (1H, t, J¼1.4 Hz,
]CHHB), 3.81 (1H, ddd, J¼9.2, 3.9, 2.0 Hz, 4-Hax), 3.43 (1H, dd,
J¼11.3, 2.0 Hz, 2-Hax), 3.09 (1H, dt, J¼13.9, 2.0 Hz, 5-Heq), 2.86 (1H,
dd, J¼13.9, 9.0 Hz, 5-Hax), 2.31 (3H, s, 6-CH3), 2.22 (3H, s, 8-CH3),
2.06 (1H, ddd, J¼13.1, 3.9, 2.0 Hz, 3-Heq), 1.85 (1H, ddd, J¼13.1, 11.3,
9.4 Hz, 3-Hax), 1.83 (3H, s, CH2]CeCH3). 13C NMR (100 MHz, CDCl3)
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d
: 149.3 (9a-C), 148.2 (eC¼), 137.7 (6-C), 136.3 (8-C), 124.6 (7-C),
123.7 (5a-C), 118.6 (9-C), 111.2 (]CH2), 69.8 (4-C), 61.9 (2-C), 44.0
(3-C), 37.7 (5-C), 20.8 (8-CH3), 19.3 (6-CH3), 19.3 (CH2]CeCH3). MS
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(100), 131 (26), 91 (27). Anal. Calcd for C15H21NO: C, 77.88; H, 9.15;
N, 6.05. Found: C, 77.99; H, 9.05; N, 5.97%.
4.5.11. 7,9-Dichloro-cis-2-(prop-1-en-2-yl)-2,3,4,5-tetrahydro-1H-
benzo[b]azepin-4-ol (8f). Reaction time: 2 h. Yield: 2.44 g (90%).
Viscous maroon oil. Rf: 0.44 (33% ethyl acetate/heptane). IR (liquid
film) nmax: 3360 (NH/OH), 1267 (CeN), 1104 (CeO), 906 (]CeH
isopropenyl) cmꢂ1 1H NMR (400 MHz, CDCl3)
. d: 7.21 (1H, d,
J¼2.4 Hz, 8-H), 7.01 (1H, d, J¼2.4 Hz, 6-H), 5.09 (1H, br s, ]CHAH),
4.92 (1H, t, J¼1.4 Hz, ]CHHB), 3.88 (1H, ddd, J¼9.7, 4.0, 2.5 Hz,

L.M. Acosta et al. / Tetrahedron 66 (2010) 8392e8401
8401
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