Synthesis of tetrahydro-3-benzazepines

Article abstract of DOI:10.1016/j.tet.2012.10.017

A synthetic route toward tetrahdro-3-benzazepines 1a-f starting with 2a and 2b in modest total yield is described. The facile route was carried by Henry reaction of aldehydes 3a-e with nitroalkanes and NH₄OAc at reflux, reduction of the resulti

Full text of DOI:10.1016/j.tet.2012.10.017

Tetrahedron 68 (2012) 10272e10279
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Synthesis of tetrahydro-3-benzazepines
,
a
a
b
Meng-Yang Chang a , Chieh-Kai Chan , Shin-Ying Lin , Ru-Ting Hsu
*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
b Department of Medical Imaging and Radiology, ShuZen College of Medicine and Management, Luju, Kaohsiung 821, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic route toward tetrahdro-3-benzazepines 1aef starting with 2a and 2b in modest total yield is
described. The facile route was carried by Henry reaction of aldehydes 3aee with nitroalkanes and
NH4OAc at reflux, reduction of the resulting nitroalkenes 4aeh with LAH at rt followed by protection
with K2CO3 and PhSO2Cl at rt, one-pot oxidative cleavage annulation of olefins 5aeh with the one-pot
combination of OsO4/NaIO4 at reflux, and hydrogenation of the corresponding enamines 6aef. Alde-
hydes 3aee was prepared from 2a and 2b in moderate yield of three-step.
Received 16 September 2012
Received in revised form 2 October 2012
Accepted 4 October 2012
Available online 12 October 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Tetrahydro-3-benzazepines
Claisen rearrangement
Henry reaction
One-pot combination
Oxidative cleavage annulation
1. Introduction
reduction and sulfonation with PhSO2Cl, and then (3) an oxidative
cleavage annulation with the combination of OsO4/NaIO4 followed
An interesting functionalized tetrahydro-3-benzazepine ring
system has become a versatile class of compounds that have found
use in drug discovery.1,2 The unique framework of 3-benzazepine
has also been found to be widespread among benzindenoazepine
and rhoeadine alkaloids and a considerable number of attempts
have been developed to the skeleton.3 The adopted synthetic routes
are described in Fig. 1. Basically, the key transformations include
condensation of ketoacid with a nitrogen atom or amino-acid,4
intramolecular ring expansion or rearrangement reaction,5 elec-
trophilic aromatic substitution reaction,6 Heck cross-coupling
reaction,1a,b,7 and Pummerer cyclization.8
by hydrogenation.
Four 2-allylbenzaldehydes 3aeb and 3dee were easily provided
from commercially available compound 2a in moderate overall
three-step yields, according to reported procedures, with a reaction
sequence of O-allylation and a Claisen rearrangement followed by
O-methylation.10 3c was prepared from one-pot ortho-metalative
PhBCl2-mediated double alkylation of compound 2b with LDA,
MeO
N
MeO
MeO
MeO
MeO
MeO
CF3
2. Results and discussion
N
CHO
N
Me
Ar
ref 6e
With our experience in using the one-pot combination of OsO4/
NaIO4 for the synthesis of substituted isoquinolines9a and benzo[g]
indazoles,9b we believed that it may be possible to develop this
methodology for preparing the skeleton of tetrahydro-3-
benzazepine 1 (see Fig. 2). As shown in Scheme 1, a facile syn-
thetic route was employed to create the skeleton 1, starting with
isovanillin (2a) and 3-hydroxybenzaldehyde (2b) via (1) a Claisen
rearrangement of 3-O-allyl compound, (2) a Henry (nitroaldol) re-
action of 2-allylbenzaldehydes 3, followed by LAH-mediated
S
N2
Ph
O
ref 8
ref 5b
O
3
N
H
ref 4e-4f
ref 4c-4d
Tetrahydro-3-benzazepine
Me
HO
O
O
H2N
O
ref 5c
MeO
MeO
O
HO
ArCH=N-TMS
+ NaN3
* Corresponding author. Tel.: þ886 7 3121101x2220; e-mail addresses: my-
chang@kmu.edu.tw, mychang624@yahoo.com.tw (M.-Y. Chang).
Fig. 1. Synthetic strategies toward tetrahydro-3-benzazepine.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.017

M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
OMe
10273
OMe
condition was treated at rt, compound 6a provided a 75% yield
within a period of 4 h. After adjusting the reaction temperature
from rt to 60 ꢀC and overall reaction time from 4 h to 2 h, the de-
sired compound 6a, with a similar yield (73%), was observed. Under
the abovementioned one-pot combination OsO4/NaIO4/HOAc con-
dition, compounds 6bef provided 58e75% yields, as shown in
Table 1.
MeO
ref 9a
MeO
O
N
OMe
Ar
Ar
isoquinolines
MeO
oxidative cleavage
annulation
OMe
OMe
CHO
MeO
MeO
ref 9b
The possible mechanism for the formation of compound 6a is
described in Scheme 3. The initial event may be considered as the
formation of intermediate I with the proton/oxocarbenium ions
from HOAc-mediated annulation. Intermediate II, with a seven-
membered ring, is yielded via the nitrogen lone pair promoted
intramolecular ring-closure on intermediate I. After a proton ex-
change of intermediate II and sequential dehydration of in-
termediate III, the bicyclic tetrahydro-3-benzazepine 6a was
produced. Finally, compounds 1aef were accomplished with
80e94% yields by the hydrogenation of compounds 6aef with
hydrogen in the presence of a catalytic amount of 10% palladium on
activated carbon (Table 1).
Ar
Ar
N
N
N
N
Ar
benzo[g]indazoles
Ar
Fig. 2. Synthetic route of isoquinolines and benzo[g]indazoles.
oxidative cleavage annulation Claisen rearrangement
X
R
R
HO
X
5
R
1
R
R
R
1
O
O
known
1
3
N
S
Ph
2
(ref 10)
R
2
CHO
CHO
2
Y
Next, boron trifluoride etherate promoted the efficient addi-
tion of compound 6a with trimethylsilyl cyanide and N-bromo-
Henry reaction
1
3
2
X / Y = H, Me; R = OMe; R / R = H, OMe
1
2
succinimide (1.2 equiv) resulting in compound
7 (82%) via
Scheme 1. Synthetic route of tetrahydro-3-benzazepines 1.
a bromination reaction of enamine, as shown in Scheme 4. A lone-
pair of nitrogen atoms promoted the ring-opening of the bromi-
nium ion. Then, the cyanide ion can trap the formed iminium ion
followed by O-methylation in a moderate yield.11 Next, a NH4OAc-
mediated Henry (nitroaldol) reaction of skeleton 3 was employed
to create the skeleton of (E)-nitroalkenes 4aeh with nitromethane
or nitroethane.12 Compounds 4aed with (E)-form and compounds
4eeh with (E,E)-form were synthesized in 80e92% yields by the
NH4OAc-mediated Henry condensation of compounds 3aee (R/R1/
R2¼H or OMe; X/Y¼H, Me or Ph) with nitromethane and nitro-
ethane. We found that compounds 4c, 4f, and 4h (Y¼Me) also
provided similar yields (86%, 80%, and 82%) to the others at reflux
for 2 h. However, a NH4OAc-mediated Henry reaction of compound
3a with nitromethylbenzene failed to isolate the desired nitro-
alkene product and compound 3a was recovered as the major
product under the above reaction conditions. Furthermore, com-
pounds 5aeh were obtained as a single isomer with the 60e80%
yields via the reduction of compounds 4aeh with LAH in THF
placed in an ice bath for 2 h, followed by treatment of the corre-
sponding primary amine with PhSO2Cl and K2CO3 at rt for 4 h, as
shown in Scheme 2. With the previous synthetic experience,9 we
attempted to construct the bicyclic skeleton of 3-benzazepines 1 by
the combination of OsO4/NaIO4/HOAc via the facile one-pot oxi-
dative cleavage of compounds 5aeh and subsequent hydrogena-
tion of the corresponding compounds 6aef.
and eliminate bromide by a-proton abstraction. The a-amino ni-
trile and related derivatives with an important bioactive compo-
nent are key ingredients in therapeutic agents for pharmaceutical
research.14,15
3. Conclusion
In summary, we have successfully presented a synthetic route
for the synthesis of tetrahydro-3-benzazepines 1aef via Henry
nitroaldol condensation, reduction, sulfonation, and oxidative
cleavage annulation with the one-pot combination of OsO4/NaIO4/
HOAc. This synthesis begins from simple starting materials and
reagents, and provides a new synthetic route toward the skeleton of
3-benzazepines.
4. Experimental section
4.1. General
All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were
R
X
R
X
X
R
R
R
MeNO or EtNO ,
2
R
R
1) LAH, THF, 2h
Z
R
R
1
2
1
1
Z
Z
O
Y
NH OAc, reflux, 4h
2) PhSO Cl, K CO ,
4
2
2
3
S
Ph
CHO
2
2
2
N
CH Cl , rt, 2h
2
2
O
H
(yield of two-step)
Y
NO
2
R = R = OMe,
1
2
3a, R = X = Z = H
3b, R = Z = H, X = Me
R = R = OMe,
R
= R = OMe, Z = Ph
5a (70%) 5e (78%)
5b (68%) 5f (63%)
5c (60%) 5g (80%)
5d (73%) 5h (66%)
2
1
1
2
R = OMe,
4a, R = X = Y = Z = H (88%)
4e, R = X = Y = H (89%)
2
2
2
3c, R = R = X = Z = H
4b, R = Y = Z = H, X = Me (92%) 4f, R = X = H, Y = Me (80%)
1
2
R
1
= R = OMe,
4c, R = X = Z = H, Y = Me (86%) R = R = OMe, Z = Me
2
1
2
3d, R = X = H, Z = Ph
3e, R = X = H, Z = Me
R = OMe,
4g, R = X = Y = H (90%)
4d, R = R = X = Y = Z = H (80%) 4h, R = X = H, Y = Me (82%)
1
2
Scheme 2. Reaction of skeleton 5.
Reports in the literature have described the improved procedure
for the oxidative cleavage of olefins by the OsO4eNaIO4 system.13 In
order to initiate the work, one-pot oxidative cleavage of the olefinic
group of compound 5a was first examined. When the reaction
routinely carried out under an atmosphere of dry nitrogen with
magnetic stirring. Products in organic solvents were dried with
anhydrous MgSO4 before concentration in vacuo. Melting points
were determined with a SMP3 melting apparatus. 1H and 13C NMR

10274
M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
Table 1
Synthesis of tetrahdro-3-benzazepines 1aefaec
X
X
X
R
R
R
Z
R
R
R
R
OsO , NMO, NaIO ,
O
O
S Ph
O
R
R
H , Pd/C
2
1
1
4
4
1
O
Y
N
Y
S
O
Ph
N
Y
then HOAc, THF/H O
Ph 2
EtOAc
S
2
2
2
N
O
H
5a~5h
6a~6f
1a~1f
Entry
1
Reactants 5
Products 6/Yielda (%)
Products 1/Yieldb (%)
OMe
OMe
OMe
MeO
MeO
MeO
O
O
O
N
S
Ph
N
S
Ph
S
O
Ph
Ph
Ph
5a
6a/75
1a/92
N
H
O
O
Me
OMe
OMe
Me
Me
OMe
OMe
OMe
OMe
MeO
MeO
MeO
O
O
O
S
O
2
N
N
S
Ph
Ph
N
N
S
Ph
Ph
5b
6b/61
1b/83
N
H
O
O
MeO
MeO
MeO
O
S
O
S
O
S
O
Me
3
4
5c
6c/70
1c/84
O
O
N
H
Me
Me
OMe
OMe
OMe
O
S
O
O
S
N
Ph
N S Ph
Ph
N
O
O
O
5d
H
6d/58
1d/90
Ph
O
MeO
MeO
MeO
O
O
5
6
7
N
S
Ph
N
S
Ph
S
O
Ph
Ph
MeO
N
H
O
O
MeO
MeO
5e
6e/66
1e/94
Me
O
MeO
MeO
MeO
O
S
O
S
N
N
Ph
Ph
N
N
Ph
Ph
S
O
MeO
N
H
O
O
MeO
MeO
5f
6e/72
1e/94
Ph
O
MeO
MeO
MeO
O
S
O
S
Me
S
O
Ph
Ph
MeO
O
O
MeO
6f/62
MeO
1f/82
N
H
Me
Me
5g
Me
O
MeO
MeO
MeO
O
S
O
S
Me
N
Ph
N
Ph
8
S
O
MeO
O
O
MeO
6f/70
MeO
1f/80
N
H
Me
Me
5h
a
For the optimal reaction conditions: (i) compounds 5aeh (1.0 mmol), OsO4 (2.5% in THF, 1 mL), NMO (50% in H2O, 2.2 mmol), THF/H2O (v/v¼1/1, 20 mL), rt, 2 h, (ii) NaIO4
(1.2 mmol), rt, 1 h, (iii) HOAc (1 mL), rt, 1 h.
b
Compounds 6aef (0.5 mmol), 10% Pd on charcoal (15 mg), EtOAc (10 mL), rt, 4 h.
c
The isolated products were >95% pure as determined by 1H NMR analysis.
OMe
OMe
H
O
CN
MeO
MeO
1) OsO
OH
NBS, TMSCN
MeO
MeO
4
4
O
O
2) NaIO
MeO
MeO
O
O
N
S
Ph
N S Ph
O
5a
BF -OEt , CH Cl
2
S
Ph
3
2
2
N
H
Ph
O
O
N S
H
3) HOAc
O
7 (82%)
6a
I
II
Scheme 4. Synthesis of compound 7.
H
MeO
MeO
OH
2
MeO
MeO
O
O
-H O
2
6a
N
S
Ph
N S Ph
O
spectra were recorded on a Varian INOVA-400 spectrometer oper-
ating at 200/400 and at 100 MHz, respectively. Chemical shifts (
are reported in parts per million (ppm) and the coupling constants
O
d
)
III
IV
Scheme 3. The possible mechanism of compound 6a.
(J) are given in Hertz. High resolution mass spectra (HRMS) were

M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
10275
measured with a mass spectrometer Finnigan/Thermo Quest MAT
95XL. X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD). Elemental analyses were
carried out with Heraeus Vario III-NCSH, Heraeus CHNeOS-Rapid
Analyzer or Elementar Vario EL III.
16.8 Hz, 1H, trans-CH]CH2), 3.85 (s, 3H, OCH3), 3.58 (dt, J¼1.6,
5.6 Hz, 2H, CH2CH]CH2); 13C NMR (100 MHz, CDCl3):
157.91 (Cq),
138.26 (Cq), 136.95 (CH), 135.75 (Cq), 130.33 (Cq), 129.41 (Cq),
127.80 (CH), 119.27 (CH), 115.66 (CH2), 113.47 (CH), 55.84 (CH3),
29.83 (CH2); Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98; N, 6.39.
Found: C, 65.98; H, 6.16; N, 6.50.
d
4.2. A representative procedure of skeleton 4 is as follows
4.2.5. 2-Cinnamyl-3,4-dimethoxy-1-(2-nitrovinyl)benzene
(4e). Yield¼89% (1.45 g); colorless solid; mp¼129e130 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C19H20NO4 326.1392, found 326.1398; 1H NMR (400 MHz, CDCl3):
Ammonium acetate (NH4OAc, 390 mg, 5.0 mmol) was added to
a solution of skeleton 3 (5.0 mmol) in nitromethane or nitroethane
(MeNO2 or EtNO2, 10 mL) at rt. The reaction mixture was stirred at
reflux for 6 h. The reaction mixture was cooled to rt. Saturated
NaHCO3(aq) (5 mL) was added to the reaction mixture and the sol-
vent was concentrated. The residue was diluted with water (10 mL)
and the mixture was extracted with EtOAc (3ꢁ20 mL). The com-
bined organic layers were washed with brine, dried, filtered, and
evaporated to afford crude product. Purification on silica gel (hex-
anes/EtOAc¼10/1e6/1) afforded skeleton 4.
d
8.34 (d, J¼13.6 Hz, 1H, CH]CHNO2), 7.49 (d, J¼13.6 Hz, 1H, CH]
CHNO2), 7.34e7.19 (m, 5H, aromatic CH), 7.00 (s, 1H, aromatic CH),
6.81 (s, 1H, aromatic CH), 6.39e6.25 (m, 2H, CH]CHPh), 3.93 (s, 3H,
OCH3), 3.92 (s, 3H, OCH3), 3.67 (d, J¼5.6 Hz, 2H, CH2CH]CHPh); 13
C
NMR (100 MHz, CDCl3): d 152.73 (Cq),148.07 (Cq),136.87 (Cq),136.28
(Cq), 136.02 (CH), 135.74 (CH), 131.81 (CH), 128.52 (2ꢁ, CH), 128.04
(CH), 127.43 (CH), 126.15 (2ꢁ, CH), 120.72 (Cq), 113.24 (CH2), 109.15
(CH), 56.06 (CH3), 56.03 (CH3), 36.36 (CH2);Anal. Calcd for C19H19NO4:
C, 70.14; H, 5.89; N, 4.31. Found: C, 70.37; H, 6.22; N, 4.47.
4.2.1. 2-Allyl-3,4-dimethoxy-1-(2-nitrovinyl)benzene (4a). Yield¼88%
(1.09 g); yellowish oil; HRMS (ESI, Mþþ1) calcd for C13H16NO4
250.1079, found 250.1080; 1H NMR (400 MHz, CDCl3):
d
8.20 (d,
4.2.6. 1-Cinnamyl-4,5-dimethoxy-2-((E)-2-nitroprop-1-enyl)benzene
(4f). Yield¼80% (1.36 g); colorless gum; HRMS (ESI, Mþþ1) calcd
for C20H22NO4 340.1549, found 340.1550; 1H NMR (400 MHz,
J¼13.2 Hz,1H, CH]CHNO2), 7.45 (d, J¼13.2 Hz, 1H, CH]CHNO2), 7.35
(d, J¼8.8 Hz, 1H, aromatic CH), 6.86 (d, J¼8.8 Hz, 1H, aromatic CH),
6.01e5.91 (m, 1H, CH]CH2), 5.07 (dq, J¼1.6, 10.4 Hz, 1H, cis-CH]
CH2), 4.90 (dq, J¼1.6, 17.2 Hz, 1H, trans-CH]CH2), 3.92 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 3.61 (dt, J¼1.6, 5.2 Hz, 2H, CH2CH]CH2); 13C NMR
CDCl3):
d 8.25 (s, 1H, CH]C(CH3)NO2), 7.33e7.24 (m, 5H, aromatic
CH), 6.83 (s, 1H, aromatic CH), 6.78 (s, 1H, aromatic CH), 6.36 (d,
J¼15.6 Hz, 1H CH]CHPh), 6.23 (dt, J¼6.4, 15.6 Hz, 1H, CH]CHPh),
3.92 (s, 3H, OCH3), 3.89 (s, 3H, OCH3), 3.55 (dd, J¼1.2, 6.4 Hz, 2H,
CH2CH]CHPh), 2.36 (d, J¼0.8 Hz, 3H, CH]C(CH3)NO2); 13C NMR
(100 MHz, CDCl3):
d
155.75 (Cq), 147.68 (Cq), 136.92 (CH), 136.16 (2ꢁ,
CH), 135.09 (Cq), 123.97 (CH), 122.34 (Cq), 116.27 (CH2), 110.76 (CH),
60.99 (CH3), 55.79 (CH3), 30.12 (CH2); Anal. Calcd for C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.81; H, 6.32; N, 5.90.
(100 MHz, CDCl3):
d 150.39 (Cq), 147.35 (Cq), 137.04 (Cq), 133.52
(Cq), 132.52 (CH), 131.59 (CH), 128.52 (2ꢁ, CH), 127.72 (CH), 127.33
(CH), 126.14 (2ꢁ, CH), 126.10 (CH), 123.38 (Cq), 112.99 (CH2), 112.18
(CH), 56.15 (CH3), 55.98 (CH3), 36.86 (CH2), 14.04 (CH3).
4.2.2. 1,2-Dimethoxy-3-(1-methylallyl)-4-(2-nitrovinyl)benzene
(4b). Yield¼92% (1.21 g); yellowish oil; HRMS (ESI, Mþþ1) calcd for
C14H18NO4 264.1236, found 264.1240; 1H NMR (400 MHz, CDCl3):
4.2.7. 1-But-2-enyl-4,5-dimethoxy-2-(2-nitrovinyl)benzene
(4g). Yield¼90% (1.18 g); colorless solid; mp¼110e111 ꢀC (recrys-
tallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd for
C14H18NO4 264.1236, found 264.1244; 1H NMR (400 MHz, CDCl3):
d
8.49 (d, J¼13.6 Hz, 1H, CH]CHNO2), 7.35 (d, J¼13.6 Hz, 1H, CH]
CHNO2), 7.28 (d, J¼8.4 Hz, 1H, aromatic CH), 6.84 (d, J¼8.4 Hz, 1H,
aromatic CH), 6.14 (ddd, J¼4.4, 10.4, 17.2 Hz, 1H, CH]CH2), 5.17
(ddd, J¼1.2, 2.4, 10.4 Hz, 1H, cis-CH]CH2), 5.10 (ddd, J¼1.2, 2.4,
17.2 Hz, 1H, trans-CH]CH2), 4.30e4.26 (m, 1H, CH2CH]CH2), 3.92
(s, 3H, OCH3), 3.81 (s, 3H, OCH3), 1.43 (d, J¼7.2 Hz, 3H, CH3); 13C
d
8.28 (d, J¼13.2 Hz, 1H, CH]CHNO2), 7.47 (d, J¼13.2 Hz, 1H, CH]
CHNO2), 6.96 (s, 1H, aromatic CH), 6.73 (s, 1H, aromatic CH),
5.56e5.40 (m, 2H, CH]CHCH3), 3.93 (s, 3H, OCH3), 3.90 (s, 3H, OCH3),
3.44 (dt, J¼1.2, 5.6 Hz, 2H, CH2CH]CHCH3), 1.67 (ddd, J¼1.6, 3.2,
NMR (100 MHz, CDCl3):
d 155.70 (Cq), 147.56 (Cq), 141.86 (CH),
140.42 (Cq), 138.23 (CH), 135.70 (CH), 124.57 (CH), 122.09 (Cq),
114.27 (CH2),110.62 (CH), 61.07 (CH3), 55.81 (CH3), 34.66 (CH), 19.59
(CH3).
6.4 Hz, 3H, CH2CH]CHCH3); 13C NMR (100 MHz, CDCl3):
d 152.68
(Cq), 147.88 (Cq), 137.02 (Cq), 136.57 (CH), 135.53 (CH), 129.09 (CH),
127.43 (CH),120.53 (Cq),113.16 (CH2),109.09 (CH), 56.06 (CH3), 55.99
(CH3), 36.16 (CH2),17.87 (CH3); Anal. Calcd for C14H17NO4: C, 63.87; H,
6.51; N, 5.32. Found: C, 64.01; H, 6.34; N, 5.58.
4.2.3. 2-Allyl-3,4-dimethoxy-1-(2-nitropropenyl)benzene
(4c). Yield¼86% (1.13 g); yellowish oil; HRMS (ESI, Mþþ1) calcd for
C14H18NO4 264.1236, found 264.1238; 1H NMR (400 MHz, CDCl3):
4.2.8. 1-But-2-enyl-4,5-dimethoxy-2-(2-nitropropenyl)benzene
(4h). Yield¼82% (1.14 g); colorless gum; HRMS (ESI, Mþþ1) calcd
for C15H20NO4 278.1392, found 278.1389; 1H NMR (400 MHz,
d
8.13 (s, 1H, CH]C(CH3)NO2), 7.02 (d, J¼8.4 Hz, 1H, aromatic CH),
6.86 (d, J¼8.8 Hz, 1H, aromatic CH), 5.93e5.84 (m, 1H, CH]CH2),
5.02 (dq, J¼1.6,10.0 Hz,1H, cis-CH]CH2), 4.90 (dq, J¼1.6,17.2 Hz,1H,
trans-CH]CH2), 3.91 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.47 (dt, J¼1.6,
6.0 Hz, 2H, CH2CH]CH2), 2.32 (d, J¼0.8 Hz, 3H, CH]C(CH3)NO2);
CDCl3):
d 8.19 (s, 1H, CH]C(CH3)NO2), 6.76 (s, 1H, aromatic CH),
6.75 (s, 1H, aromatic CH), 5.50e5.40 (m, 2H, CH]CHCH3), 3.91 (s,
3H, OCH3), 3.86 (s, 3H, OCH3), 3.28 (dd, J¼1.6, 5.6 Hz, 2H, CH2CH]
CHCH3), 2.35 (d, J¼0.8 Hz, 3H, CH2CH]CHCH3), 1.65 (d, J¼5.6 Hz,
13C NMR (100 MHz, CDCl3):
d
153.86 (Cq), 147.47 (Cq), 135.77 (2ꢁ,
Cq), 133.88 (Cq), 132.48 (CH), 125.29 (CH), 125.01 (CH), 115.76 (CH2),
110.13 (CH), 60.95 (CH3), 55.71 (CH3), 31.09 (CH2), 13.91 (CH3).
3H, CH]C(CH3)NO2); 13C NMR (100 MHz, CDCl3):
d 150.30 (Cq),
147.07 (2ꢁ, Cq), 134.52 (Cq), 132.73 (CH), 128.63 (CH), 127.05 (CH),
123.10 (Cq), 112.83 (CH2), 112.10 (CH), 56.10 (CH3), 55.89 (CH3),
36.55 (CH2), 17.83 (CH3), 13.99 (CH3).
4.2.4. 2-Allyl-1-methoxy-3-(2-nitrovinyl)benzene (4d). Yield¼80%
(880 mg); colorless solid; mp¼55e57 ꢀC (recrystallized from hex-
anes and EtOAc); HRMS (ESI, Mþþ1) calcd for C12H14NO3 220.0974,
4.3. A representative procedure of skeleton 5 is as follows
found 220.0977; 1H NMR (400 MHz, CDCl3):
d
8.29 (d, J¼13.6 Hz,
1H, CH]CHNO2), 7.48 (d, J¼13.6 Hz, 1H, CH]CHNO2), 7.26 (t,
J¼7.6 Hz, 1H, aromatic CH), 7.13 (d, J¼7.6 Hz, 1H, aromatic CH), 7.00
(d, J¼7.6 Hz, 1H, aromatic CH), 5.98e5.88 (m, 1H, CH]CH2), 5.03
(dq, J¼1.6, 2.8, 10.0 Hz, 1H, cis-CH]CH2), 4.91 (dq, J¼1.6, 2.8,
Lithium aluminum hydride (LiAlH4, 300 mg, 8.0 mmol) was
added to a solution of skeleton 4 (2.0 mmol) in THF (20 mL) at rt.
The reaction mixture was stirred at rt for 4 h. Saturated NH4Cl(aq)
(5 mL) was added to the reaction mixture and the solvent was

10276
M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
concentrated. The residue was diluted with water (10 mL) and the
mixture was extracted with EtOAc (3ꢁ20 mL). The combined or-
ganic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product. Without further purification,
potassium carbonate (K2CO3, 420 mg, 3.0 mmol) was added to the
resulting product in CH2Cl2 (20 mL) at rt. Then, phenylsulfonyl
chloride (PhSO2Cl, 430 mg, 2.4 mmol) was added to the reaction
mixture at rt. The reaction mixture was stirred at rt for 4 h. Water
(5 mL) was added to the reaction mixture and the solvent was
concentrated. The residue was diluted with water (10 mL) and the
mixture was extracted with EtOAc (3ꢁ20 mL). The combined or-
ganic layers were washed with brine, dried, filtered, and evapo-
rated to afford crude product. Purification on silica gel (hexanes/
EtOAc¼8/1e4/1) afforded skeleton 5.
for C18H22NO3S 332.1320, found 332.1323; 1H NMR (400 MHz,
CDCl3): 7.83e7.79 (m, 2H, aromatic CH), 7.59e7.54 (m, 1H, aro-
d
matic CH), 7.51e7.46 (m, 2H, aromatic CH), 7.11 (t, J¼7.6 Hz, 1H,
aromatic CH), 6.76 (dd, J¼0.8, 7.6 Hz, 1H, aromatic CH), 6.67 (dd,
J¼0.8, 7.6 Hz, 1H, aromatic CH), 5.89 (m, 1H, CH2CH]CH2), 4.87 (dq,
J¼1.6, 10.0 Hz, 1H, cis-CH]CH2), 4.79 (dq, J¼1.6, 17.2 Hz, 1H, trans-
CH]CH2), 4.60 (br t, J¼5.6 Hz, 1H, NH), 3.79 (s, 3H, OCH3), 3.33 (dt,
J¼1.6, 5.6 Hz, 2H, CH2CH]CH2), 3.18 (dt, J¼7.6, 13.6 Hz, 2H,
CH2CH2N), 2.78 (t, J¼7.6 Hz, 2H, CH2CH2N); 13C NMR (100 MHz,
CDCl3):
d 157.81 (Cq), 139.89 (Cq), 137.22 (Cq), 136.67 (Cq), 132.55
(CH), 129.05 (2ꢁ, CH), 127.21 (CH), 127.00 (2ꢁ, CH), 126.59 (CH),
121.88 (CH), 114.50 (CH2), 109.12 (CH), 55.58 (CH3), 43.68 (CH2),
32.85 (CH2), 29.86 (CH2).
4.3.5. N-[2-(2-Cinnamyl-3,4-dimethoxyphenyl)-1-methylethyl]ben-
zenesulfonamide (5e). Yield¼78% (680 mg); colorless oil; HRMS
(ESI, Mþþ1) calcd for C25H28NO4S 438.1739, found 438.1743; 1H
4.3.1. N-[2-(2-Allyl-3,4-dimethoxyphenyl)ethyl]benzenesulfonamide
(5a). Yield¼70% (505 mg); colorless oil; HRMS (ESI, Mþþ1) calcd
for C19H24NO4S 362.1426, found 362.1434; 1H NMR (400 MHz,
NMR (400 MHz, CDCl3):
d 7.77e7.74 (m, 2H, aromatic CH),
CDCl3):
d
7.83e7.80 (m, 2H, aromatic CH), 7.59e7.55 (m, 1H, aro-
7.49e7.46 (m, 1H, aromatic CH), 7.39e7.35 (m, 2H, aromatic CH),
7.31e7.16 (m, 5H, aromatic CH), 6.66 (s, 1H, aromatic CH), 6.59 (s,
1H, aromatic CH), 6.29e6.18 (m, 2H, CH2CH]CHPh), 5.05 (t,
J¼6.0 Hz, 1H, NH), 3.80 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.39 (d,
J¼4.8 Hz, 2H, CH2CH]CHPh), 3.13 (dd, J¼7.2, 14.4 Hz, 2H,
CH2CH2NH), 2.77 (t, J¼7.2 Hz, 2H, CH2CH2NH); 13C NMR (100 MHz,
matic CH), 7.51e7.47 (m, 2H, aromatic CH), 6.77 (d, J¼8.4 Hz, 1H,
aromatic CH), 6.72 (d, J¼8.4 Hz, 1H, aromatic CH), 5.90e5.80 (m, 1H,
CH2CH]CH2), 4.90 (dq, J¼2.0, 10.4 Hz, 1H, cis-CH]CH2), 4.78 (dq,
J¼2.0,17.6 Hz,1H, trans-CH]CH2), 4.52 (t, J¼6.4 Hz,1H, NH), 3.83 (s,
3H, OCH3), 3.77 (s, 3H, OCH3), 3.33 (dt, J¼2.0, 6.0 Hz, 2H, CH2CH]
CH2), 3.14 (q, J¼7.2 Hz, 2H, CH2CH2NH), 2.71 (t, J¼7.2 Hz, 2H,
CDCl3):
d 147.64 (Cq), 147.37 (Cq), 139.76 (Cq), 137.13 (Cq), 132.39
CH2CH2NH); 13C NMR (100 MHz, CDCl3):
d
151.58 (Cq), 147.58 (Cq),
(CH), 130.57 (CH), 130.07 (Cq), 129.06 (CH), 128.91 (2ꢁ, CH), 128.38
(2ꢁ, CH), 127.82 (CH), 127.02 (Cq), 126.77 (2ꢁ, CH), 125.96 (2ꢁ, CH),
113.21 (CH2), 112.88 (CH), 55.84 (CH3), 55.80 (CH3), 43.91 (CH2),
35.69 (CH2), 32.66 (CH2).
139.91 (Cq), 136.99 (Cq), 132.58 (CH), 132.03 (Cq), 129.06 (2ꢁ, CH),
128.92 (CH), 127.00 (2ꢁ, CH), 124.89 (CH), 115.03 (CH2), 110.48 (CH),
60.74 (CH3), 55.62 (CH3), 43.75 (CH2), 32.36 (CH2), 30.34 (CH2).
4.3.2. N-{2-[3,4-Dimethoxy-2-(1-methylallyl)phenyl]ethyl}benzene-
sulfonamide (5b). Yield¼68% (510 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C20H26NO4S 376.1583, found 376.1580; 1H NMR
4.3.6. (E)-N-(2-(But-2-enyl)-4,5-dimethoxyphenethyl)benzenesulfo-
namide (5f). Yield¼63% (472 mg); colorless oil; HRMS (ESI, Mþþ1)
calcd for C20H26NO4S 376.1583, found 376.1588; 1H NMR (400 MHz,
(400 MHz, CDCl3):
d
7.84e7.81 (m, 2H, aromatic CH), 7.59e7.55 (m,
CDCl3):
d
7.80 (d, J¼8.0 Hz, 2H, aromatic CH), 7.59e7.47 (m, 3H,
1H, aromatic CH), 7.52e7.47 (m, 2H, aromatic CH), 6.74 (d, J¼8.4 Hz,
1H, aromatic CH), 6.70 (d, J¼8.4 Hz, 1H, aromatic CH), 6.08 (ddd,
J¼1.6, 10.4, 17.2 Hz, 1H, CH(CH3)CH]CH2), 4.91 (dt, J¼1.6, 10.8 Hz,
1H, cis-CH]CH2), 4.88 (dt, J¼1.6, 17.2 Hz, 1H, trans-CH]CH2), 4.49
(br t, J¼6.4 Hz, 1H, NH), 3.86e3.80 (m, 2H, CH2CH2NH), 3.82 (s, 3H,
OCH3), 3.77 (s, 3H, OCH3), 3.15e3.09 (m,1H, CH(CH3)CH]CH2), 2.77
(t, J¼7.2 Hz, 2H, CH2CH2NH), 1.31 (d, J¼7.2 Hz, 3H, CH(CH3)CH]
aromatic CH), 6.62 (s, 1H, aromatic CH), 6.53 (s, 1H, aromatic CH),
5.49e5.32 (m, 2H, CH2CH]CHCH3), 4.47 (br t, J¼6.4 Hz, 1H, NH),
3.84 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.17e3.13 (m, 4H, CH2CH]
CHCH3þCH2CH2NH), 2.74 (t, J¼7.2 Hz, 2H, CH2CH2NH), 1.62 (dd,
J¼1.2, 6.0 Hz, 3H, CH2CH]CHCH3); 13C NMR (100 MHz, CDCl3):
d
147.76 (Cq), 147.32 (Cq), 139.90 (Cq), 132.57 (Cq), 131.15 (CH),
129.93 (Cq), 129.05 (2ꢁ, CH), 126.97 (2ꢁ, CH), 126.40 (CH), 126.30
(CH), 113.24 (CH2), 112.78 (CH), 55.95 (CH3), 55.90 (CH3), 43.90
(CH2), 35.51 (CH2), 32.39 (CH2), 17.81 (CH3).
CH2); 13C NMR (100 MHz, CDCl3):
d 152.04 (Cq), 148.06 (Cq), 142.90
(Cq), 139.80 (Cq), 137.69 (Cq), 132.61 (CH), 129.08 (2ꢁ, CH), 127.98
(CH), 127.03 (2ꢁ, CH), 125.51 (CH), 112.86 (CH), 110.45 (CH), 60.57
(CH3), 55.59 (CH3), 44.14 (CH2), 36.80 (CH2), 33.28 (CH), 19.29 (CH3).
4.3.7. (E)-N-(1-(2-Cinnamyl-4,5-dimethoxyphenyl)propan-2-yl)ben-
zenesulfonamide (5g). Yield 80% (721 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C26H30NO4S 452.1896, found 452.1900; 1H NMR
4.3.3. N-[2-(2-Allyl-3,4-dimethoxyphenyl)-1-methylethyl]benzene-
sulfonamide (5c). Yield¼60% (450 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C20H26NO4S 376.1583, found 376.1586; 1H NMR
(400 MHz, CDCl3):
d 7.76e7.74 (m, 2H, aromatic CH), 7.50e7.46 (m,
1H, aromatic CH), 7.40e7.36 (m, 2H, aromatic CH), 7.35e7.30 (m,
5H, aromatic CH), 6.73 (s, 1H, aromatic CH), 6.61 (s, 1H, aromatic
CH), 6.32e6.30 (m, 2H, CH2CH]CHPh), 5.25 (t, J¼6.0 Hz, 1H, NH),
3.86 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 3.56e3.50 (m, 2H, CH2CH]
CHPh), 3.46e3.40 (m, 1H, CH2CH(CH3)NH), 2.99 (t, J¼7.2 Hz, 2H,
CH2CH(CH3)NH), 1.62 (dd, J¼1.2, 6.0 Hz, 3H, CH2CH(CH3)NH); 13C
(400 MHz, CDCl3):
d 7.70e7.67 (m, 2H, aromatic CH), 7.53e7.49 (m,
1H, aromatic CH), 7.42e7.38 (m, 2H, aromatic CH), 6.69 (d, J¼8.4 Hz,
1H, aromatic CH), 6.64 (d, J¼8.4 Hz,1H, aromatic CH), 5.86e5.76 (m,
1H, CH2CH]CH2), 4.94 (dq, J¼1.6, 10.0 Hz, 1H, cis-CH]CH2), 4.79
(dq, J¼1.6, 17.2 Hz,1H, trans-CH]CH2), 4.59 (br d, J¼6.8 Hz, 1H, NH),
3.83 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.45e3.41 (m, 1H,
CH2CH(CH3)N), 3.29e3.24 (m, 2H, CH2CH]CH2), 2.67 (dd, J¼7.2,
14.0 Hz,1H, CH2CH(CH3)N), 2.56 (dd, J¼7.2,14.0 Hz,1H, CH2CH(CH3)
N),1.13 (d, J¼6.4 Hz, 3H, CH2CH(CH3)N); 13C NMR (100 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d 147.65 (Cq), 147.83 (Cq), 139.92 (Cq),
137.44 (Cq), 133.01 (CH), 131.32 (CH), 130.22 (Cq), 129.59 (CH),
128.30 (2ꢁ, CH), 128.34 (2ꢁ, CH), 127.28 (CH), 127.32 (Cq), 126.37
(2ꢁ, CH), 125.26 (2ꢁ, CH), 113.81 (CH2), 112.91 (CH), 55.44 (CH3),
556.12 (CH3), 43.94 (CH2), 35.12 (CH2), 34.21 (CH2), 18.28 (CH3).
d
151.47 (2ꢁ, Cq), 147.44 (Cq), 140.42 (Cq), 137.11 (Cq), 132.28 (CH),
132.08 (CH), 128.83 (2ꢁ, CH), 126.87 (2ꢁ, CH), 125.55 (CH), 115.05
(CH2), 110.22 (CH), 60.67 (CH3), 55.56 (CH3), 50.71 (CH), 40.15 (CH2),
30.35 (CH2), 21.78 (CH3); Anal. Calcd for C20H25NO4S: C, 63.97; H,
6.71; N, 3.73. Found: C, 64.12; H, 6.92; N, 3.55.
4.3.8. (E)-N-(1-(2-(But-2-enyl)-4,5-dimethoxyphenyl)propan-2-yl)-
benzenesulfonamide (5h). Yield 66% (515 mg); colorless oil; HRMS
(ESI, Mþþ1) calcd for C21H28NO4S 390.1739, found 390.1744; 1H
NMR (400 MHz, CDCl3):
d 7.65e7.62 (m, 2H, aromatic CH),
4.3.4. N-[2-(2-Allyl-3-methoxyphenyl)ethyl]benzenesulfonamide
7.50e7.46 (m, 1H, aromatic CH), 7.38e7.34 (m, 2H, aromatic CH),
6.53 (s, 1H, aromatic CH), 6.40 (s, 1H, aromatic CH), 5.45e5.33 (m,
(5d). Yield¼73% (480 mg); colorless oil; HRMS (ESI, Mþþ1) calcd

M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
10277
2H, CH2CH]CHCH3), 4.92 (br s, 1H, NH), 3.83 (s, 3H, OCH3), 3.71 (s,
3H, OCH3), 3.44e3.37 (m, 1H, CH2CH(CH3)NH), 3.16e3.04 (m, 2H,
CH2CH]CHCH3), 2.68 (dd, J¼8.0, 14.0 Hz, 1H, CH2CH(CH3)NH), 2.55
(dd, J¼6.8, 14.0 Hz, 1H, CH2CH(CH3)NH), 1.65 (d, J¼5.2 Hz, 3H,
CH2CH]CHCH3), 1.16 (d, J¼6.4 Hz, 3H, CH2CH(CH3)NH); 13C NMR
CH2CH(CH3)N), 0.79 (d, J¼6.4 Hz, 3H, CH2CH(CH3)N); 13C NMR
(100 MHz, CDCl3):
d 151.06 (Cq), 145.69 (Cq), 138.73 (Cq), 132.90
(CH), 129.18 (3ꢁ, 2CHþCq), 128.97 (CH), 126.89 (2ꢁ, CH), 125.03
(CH), 123.94 (CH), 110.10 (CH), 101.21 (CH), 60.57 (CH3), 55.65 (CH3),
51.95 (CH), 40.00 (CH2), 17.44 (CH3); Anal. Calcd for C19H21NO4S: C,
63.49; H, 5.89; N, 3.90. Found: C, 63.55; H, 6.11; N, 4.10.
(100 MHz, CDCl3):
d 147.54 (Cq), 146.92 (Cq), 140.30 (Cq), 132.12
(CH), 130.94 (Cq), 130.05 (Cq), 128.68 (2ꢁ, CH), 127.34 (CH), 126.73
(2ꢁ, CH), 126.34 (CH), 113.20 (CH2), 112.87 (CH), 55.75 (CH3), 55.72
(CH3), 51.04 (CH), 39.83 (CH2), 35.40 (CH2), 21.95 (CH3), 17.78 (CH3).
4.4.4. 3-Benzenesulfonyl-6-methoxy-2,3-dihydro-1H-benzo[d]aze-
pine (6d). Yield¼58% (183 mg); colorless solid; mp¼109e111 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C17H18NO3S 316.1007, found 316.1011; 1H NMR (400 MHz,
4.4. A representative procedure of skeleton 6 is as follows
CDCl3):
d 7.83e7.81 (m, 2H, aromatic CH), 7.59e7.48 (m, 3H, aro-
A solution of 2.5% osmium tetraoxide (OsO4, 1 mL, in THF) was
added to a solution of skeleton 5 (1.0 mmol) in the co-solvent of
THF (10 mL) and water (10 mL). N-Methylmorpholine-N-oxide
(NMO, 50% in water, 500 mg, 2.2 mmol) was added to the reaction
mixture at rt. The reaction mixture was stirred at rt for 2 h. Then,
sodium periodate (NaIO4, 257 mg, 1.2 mmol) was added to the re-
action mixture at rt. The reaction mixture was stirred at rt for 1 h.
Acetic acid (1 mL) were added to the reaction mixture at rt. The
reaction mixture was stirred at rt for 1 h. The overall synthetic
procedure had to be monitored by TLC until the reaction was
completed. 10% NaHSO3(aq) (5 mL) was added to the reaction mix-
ture and the solvent was concentrated. The residue was diluted
with water (10 mL) and the mixture was extracted with EtOAc
(3ꢁ20 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to yield crude compound. Purifica-
tion on silica gel (hexanes/EtOAc¼7/1e4/1) afforded skeleton 6.
matic CH), 7.03 (t, J¼8.0 Hz, 1H, aromatic CH), 6.95 (d, J¼11.2 Hz, 1H,
CH]CHN), 6.72 (dd, J¼0.8, 8.0 Hz, 1H, aromatic CH), 6.60 (d,
J¼7.6 Hz,1H, aromatic CH), 6.15 (d, J¼11.2 Hz,1H, CH]CHN), 3.83 (s,
3H, OCH3), 3.78e3.75 (m, 2H, CH2CH2N), 2.79e2.77 (m, 2H,
CH2CH2N); 13C NMR (100 MHz, CDCl3):
d 156.62 (Cq), 141.05 (CH),
138.41 (Cq), 132.99 (CH), 129.27 (2ꢁ, CH), 127.97 (2ꢁ, CH), 126.89
(Cq), 124.90 (CH), 123.00 (Cq), 121.15 (CH), 108.66 (CH), 102.32 (CH),
55.68 (CH3), 47.61 (CH2), 35.92 (CH2); Anal. Calcd for C17H17NO3S: C,
64.74; H, 5.43; N, 4.44. Found: C, 64.95; H, 5.62; N, 4.68.
4.4.5. 3-Benzenesulfonyl-7,8-dimethoxy-2,3-dihydro-1H-benzo[d]
azepine (6e). For compound 5e: yield¼66% (228 mg); For com-
pound 5f: yield¼72% (248 mg); colorless oil; HRMS (ESI, Mþþ1)
calcd for C18H20NO4S 346.1113, found 346.1119; 1H NMR (400 MHz,
CDCl3):
d 7.83e7.80 (m, 2H, aromatic CH), 7.60e7.49 (m, 3H, aro-
matic CH), 6.81 (d, J¼10.4 Hz, 1H, CH]CHN), 6.64 (s, 1H, aromatic
CH), 6.50 (s, 1H, aromatic CH), 5.59 (d, J¼10.4 Hz, 1H, CH]CHN),
3.84 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 3.78e3.74 (m, 2H, CH2CH2N),
4.4.1. 3-Benzenesulfonyl-6,7-dimethoxy-2,3-dihydro-1H-benzo[d]
azepine (6a). Yield¼75% (260 mg); colorless oil; HRMS (ESI, Mþþ1)
calcd for C18H20NO4S 346.1113, found 346.1120; 1H NMR (400 MHz,
2.74e2.72 (m, 2H, CH2CH2N); 13C NMR (100 MHz, CDCl3):
d 147.31
(Cq), 147.21 (Cq), 138.52 (CH), 133.01 (2ꢁ, Cq), 131.75 (CH), 129.29
(2ꢁ, CH), 126.95 (2ꢁ, CH), 123.79 (CH), 113.47 (CH), 112.43 (CH),
109.87 (CH), 55.92 (2ꢁ, CH3), 47.16 (CH2), 35.76 (CH2).
CDCl3):
d 7.83e7.81 (m, 2H, aromatic CH), 7.60e7.56 (m, 1H, aro-
matic CH), 7.53e7.49 (m, 2H, aromatic CH), 6.97 (d, J¼11.2 Hz, 1H,
CH]CHN), 6.67 (d, J¼8.4 Hz,1H, aromatic CH), 6.63 (d, J¼8.4 Hz,1H,
aromatic CH), 6.10 (d, J¼11.2 Hz, 1H, CH]CHN), 3.81 (s, 3H, OCH3),
3.79 (s, 3H, OCH3), 3.75 (dt, J¼4.8, 9.2 Hz, 2H, CH2CH2N), 2.73 (dt,
4.4.6. 7,8-Dimethoxy-2-methyl-3-(phenylsulfonyl)-2,3-dihydro-1H-
benzo[d]azepine (6f). For compound 5g: yield¼62% (223 mg); for
compound 5h: yield¼70% (250 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C19H22NO4S 360.1270, found 360.1276; 1H NMR
J¼4.8, 9.2 Hz, 2H, CH2CH2N); 13C NMR (100 MHz, CDCl3):
d 151.28
(Cq), 146.45 (Cq), 138.44 (Cq), 133.05 (CH), 132.79 (Cq), 129.29 (2ꢁ,
CH), 128.43 (Cq), 126.98 (2ꢁ, CH), 125.78 (CH), 123.76 (CH), 110.05
(CH),102.46 (CH), 60.67 (CH3), 55.84 (CH3), 47.76 (CH2), 35.36 (CH2);
Anal. Calcd for C18H19NO4S: C, 62.59; H, 5.54; N, 4.06. Found: C,
62.67; H, 5.58; N, 4.18.
(400 MHz, CDCl3):
d 7.85e7.82 (m, 2H, aromatic CH), 7.58e7.48 (m,
3H, aromatic CH), 6.81 (dd, J¼1.6, 10.8 Hz, 1H, CH]CHN), 6.65 (s, 1H,
aromatic CH), 6.48 (s, 1H, aromatic CH), 5.59 (d, J¼10.8 Hz, 1H, CH]
CHN), 4.71e4.64 (m, 1H, CH2CH(CH3)N), 3.83 (s, 3H, OCH3), 3.80 (s,
3H, OCH3), 2.71 (dd, J¼6.0, 15.6 Hz, 1H, CH2CH(CH3)N), 2.27 (d,
J¼15.6 Hz, 1H, CH2CH(CH3)N), 0.79 (d, J¼6.8 Hz, 3H, CH2CH(CH3)N);
4.4.2. 3-Benzenesulfonyl-6,7-dimethoxy-5-methyl-2,3-dihydro-1H-
benzo[d]azepine (6b). Yield¼61% (220 mg); colorless oil; HRMS
(ESI, Mþþ1) calcd for C19H22NO4S 360.1270, found 360.1277; 1H
13C NMR (100 MHz, CDCl3):
(CH), 129.18 (2ꢁ, CH), 128.14 (Cq), 127.85 (Cq), 126.95 (2ꢁ, CH),
121.72 (CH), 113.36 (CH), 112.58 (CH), 108.94 (CH), 55.82 (2ꢁ, CH3),
51.21 (CH), 40.43 (CH2), 17.34 (CH3).
d
147.26 (2ꢁ, Cq), 138.76 (Cq), 132.87
NMR (400 MHz, CDCl3):
d 7.66e7.63 (m, 2H, aromatic CH),
7.50e7.45 (m, 1H, aromatic CH), 7.40e7.35 (m, 2H, aromatic CH),
6.84 (d, J¼8.0 Hz, 1H, aromatic CH), 6.74 (d, J¼8.0 Hz, 1H, aromatic
CH), 6.28 (br q, J¼1.2 Hz, 1H, C(CH3)]CHN), 3.84 (t, J¼6.0 Hz, 2H,
CH2CH2N), 3.83 (s, 3H, OCH3), 3.53 (s, 3H, OCH3), 2.68 (t, J¼6.0 Hz,
2H, CH2CH2N), 2.09 (d, J¼1.2 Hz, 3H, C(CH3)]CHN); 13C NMR
4.5. A representative procedure of skeleton 1 is as follows
Palladium on activated carbon (10%, 15 mg) was added to a so-
lution of skeleton 6 (0.5 mmol) in EtOAc (10 mL) at rt. Then hy-
drogen was bubbled into the mixture for 10 min, and stirring
occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hex-
anes/EtOAc¼7/1e4/1) afforded skeleton 1.
(100 MHz, CDCl3):
d 151.84 (Cq), 146.61 (Cq), 138.96 (Cq), 132.33
(Cq), 132.28 (Cq), 131.75 (Cq), 131.15 (CH), 128.76 (2ꢁ, CH), 126.91
(2ꢁ, CH), 123.21 (CH), 122.44 (CH), 111.45 (CH), 60.38 (CH3), 56.74
(CH3), 55.85 (CH2), 31.78 (CH2), 19.53 (CH3).
4.4.3. 3-Benzenesulfonyl-6,7-dimethoxy-2-methyl-2,3-dihydro-1H-
benzo[d]azepine (6c). Yield¼70% (251 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C19H22NO4S 360.1270, found 360.1276; 1H NMR
4.5.1. 3-Benzenesulfonyl-6,7-dimethoxy-2,3,4,5-tetrahydro-1H-benzo-
[d]azepine (1a). Yield¼92% (160 mg); colorless solid; mp¼90e91 ꢀC
(recrystallized from hexanes and EtOAc); HRMS (ESI, Mþþ1) calcd
for C18H22NO4S 348.1270, found 349.1273; 1H NMR (400 MHz,
(400 MHz, CDCl3): d 7.86e7.83 (m, 2H, aromatic CH), 7.58e7.48 (m,
3H, aromatic CH), 6.98 (dd, J¼1.6,11.2 Hz,1H, CH]CHN), 6.66 (s, 2H,
aromatic CH), 6.09 (d, J¼10.8 Hz, 1H, CH]CHN), 4.69e4.62 (m, 1H,
CH2CH(CH3)N), 3.80 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 2.72 (dd,
J¼6.4, 15.2 Hz, 1H, CH2CH(CH3)N), 2.25 (d, J¼15.2 Hz, 1H,
CDCl3): d 7.76e7.74 (m, 2H, aromatic CH), 7.55e7.45 (m, 3H, aromatic
CH), 6.77 (d, J¼8.4 Hz, 1H, aromatic CH), 6.64 (d, J¼8.4 Hz, 1H, aro-
matic CH), 3.80 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.29e3.27 (m, 4H,

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M.-Y. Chang et al. / Tetrahedron 68 (2012) 10272e10279
CH2CH2N), 3.12e3.09 (m, 2H, CH2CH2N), 2.95e2.92 (m, 2H,
CH2CH2N); 13C NMR (100 MHz, CDCl3):
151.42 (Cq), 146.44 (Cq),
oil; HRMS (ESI, Mþþ1) calcd for C19H24NO4S 362.1426, found
d
362.1428; 1H NMR (400 MHz, CDCl3):
d 7.76e7.74 (m, 2H, aromatic
138.15 (Cq), 134.37 (Cq), 133.91 (Cq), 132.45 (CH), 129.01 (2ꢁ, CH),
127.15 (2ꢁ, CH), 124.40 (CH), 109.80 (CH), 60.96 (CH3), 55.68 (CH3),
48.68 (CH2), 48.38 (CH2), 36.47 (CH2), 27.27 (CH3); Anal. Calcd for
C18H21NO4S: C, 62.23; H, 6.09; N, 4.03. Found: C, 62.35; H, 6.28;
N, 4.31.
CH), 7.50e7.43 (m, 3H, aromatic CH), 6.52 (s, 1H, aromatic CH), 6.51
(s, 1H, aromatic CH), 4.47e4.43 (m, 1H, CH2CH(CH3)N), 4.09e4.03
(m, 1H, CH2CH2N), 3.81 (s, 6H, OCH3), 3.12 (dd, J¼2.8, 14.8 Hz, 1H,
CH2CH2N), 3.08e3.01 (m, 1H, CH2CH(CH3)N), 2.95e2.88 (m, 1H,
CH2CH(CH3)N), 2.71e2.66 (m, 1H, CH2CH2N), 2.59 (dd, J¼6.4,
14.8 Hz, 1H, CH2CH2N), 0.80 (d, J¼6.8 Hz, 3H, CH2CH(CH3)N); 13C
4.5.2. 3-Benzenesulfonyl-8,9-dimethoxy-1-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepine (1b). Yield¼83% (150 mg); colorless oil; HRMS
(ESI, Mþþ1) calcd for C19H24NO4S 362.1426, found 362.1430; 1H
NMR (100 MHz, CDCl3): d 147.09 (Cq), 146.99 (Cq), 141.38 (Cq),
132.05 (CH), 131.83 (Cq), 129.11 (CH), 128.90 (2ꢁ, CH), 126.75 (2ꢁ,
CH), 114.20 (CH), 112.98 (CH), 55.97 (CH3), 55.85 (CH3), 50.02 (CH),
42.13 (CH2), 40.94 (CH2), 36.51 (CH2), 14.47 (CH3).
NMR (400 MHz, CDCl3): d 7.78e7.75 (m, 2H, aromatic CH), 7.51e7.42
(m, 3H, aromatic CH), 6.73 (d, J¼8.4 Hz, 1H, aromatic CH), 6.66 (d,
J¼8.4 Hz, 1H, aromatic CH), 4.45e4.41 (m, 1H, CH(CH3)CH2N),
4.11e4.10 (m, 1H, CH(CH3)CH2N), 3.81 (s, 3H, OCH3), 3.72 (s, 3H,
OCH3), 3.22 (dd, J¼2.8,14.8 Hz, 1H, CH(CH3)CH2N), 3.11e3.05 (m, 1H,
CH2CH2N), 2.93e2.89 (m, 1H, CH2CH2N), 2.70e2.66 (m, 1H,
CH2CH2N), 2.55 (dd, J¼6.4, 14.8 Hz, 1H, CH2CH2N), 0.79 (d, J¼6.8 Hz,
4.6. 3-Benzenesulfonyl-8,9-dimethoxy-4,5-dihydro-3H-benzo-
[d]azepine-2-carbonitrile (7)
N-Bromosuccinimide (NBS, 90 mg, 0.5 mmol) was added to
a solution of compound 6a (173 mg, 0.5 mmol) with trimethylsilyl
cyanide (TMSCN, 3 mL) in CH2Cl2 (10 mL) at rt. The reaction mixture
was stirred at rt for 5 min. Boron trifluoride etherate (BF3$OEt2,
w0.1 mL) was added to the reaction mixture. The reaction mixture
was stirred at rt for 3 h. Saturated NaHCO3(aq) solution (2 mL) was
added to the reaction mixture and the solvent was concentrated
under reduced pressure. The residue was extracted with EtOAc
(3ꢁ30 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/ethyl acetate¼6/
1e3/1) afforded compound 7. Yield¼82% (152 mg); colorless oil;
HRMS (ESI, Mþþ1) calcd for C19H19N2O4S 371.1066, found 371.1070;
3H, CH(CH3)CH2N); 13C NMR (100 MHz, CDCl3):
d 151.78 (Cq), 147.32
(Cq), 141.39 (Cq), 134.88 (Cq), 132.23 (CH), 130.92 (CH), 129.04 (2ꢁ,
CH), 126.90 (2ꢁ, CH), 126.12 (Cq), 1010.32 (CH), 61.02 (CH3), 52.17
(CH3), 48.18 (CH), 44.12 (CH2), 40.87 (CH2), 28.42 (CH2), 16.01 (CH3).
4.5.3. 3-Benzenesulfonyl-6,7-dimethoxy-2-methyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepine (1c). Yield¼84% (152 mg); colorless oil; HRMS
(ESI, Mþþ1) calcd for C19H24NO4S 362.1426, found 362.1428; 1H
NMR (400 MHz, CDCl3): d 7.79e7.76 (m, 2H, aromatic CH), 7.53e7.42
(m, 3H, aromatic CH), 6.70 (d, J¼8.4 Hz, 1H, aromatic CH), 6.63 (d,
J¼8.4 Hz, 1H, aromatic CH), 4.49e4.45 (m, 1H, CH2CH(CH3)N),
4.12e4.06 (m, 1H, CH2CH2N), 3.81 (s, 3H, OCH3), 3.69 (s, 3H, OCH3),
3.31 (ddd, J¼1.6, 6.4, 15.2 Hz, 1H, CH2CH2N), 3.11 (dd, J¼2.8, 14.4 Hz,
1H, CH2CH(CH3)N), 2.98 (ddd, J¼1.6, 10.4, 14.4 Hz, 1H, CH2CH(CH3)
N), 2.66e2.59 (m, 1H, CH2CH2N), 2.62 (dd, J¼6.0, 14.4 Hz, 1H,
CH2CH2N), 0.78 (d, J¼6.8 Hz, 3H, CH2CH(CH3)N); 13C NMR (100 MHz,
1H NMR (400 MHz, CDCl3):
d 7.91e7.88 (m, 2H, aromatic CH),
7.57e7.53 (m, 1H, aromatic CH), 7.49e7.44 (m, 2H, aromatic CH),
7.37 (s, 1H, CH]C(CN)N), 6.82 (br s, 2H, aromatic CH), 3.83 (s, 3H,
OCH3), 3.80 (s, 3H, OCH3), 3.81 (t, J¼5.2 Hz, 2H, CH2CH2N), 2.99 (d,
J¼5.2 Hz, 2H, CH2CH2N); 13C NMR (100 MHz, CDCl3):
d 150.95 (Cq),
CDCl3):
d 151.45 (Cq), 146.30 (Cq), 141.40 (Cq), 133.71 (Cq), 132.08,
147.74 (Cq), 138.57 (Cq), 133.30 (CH), 132.32 (Cq), 130.53 (CH),
129.09 (2ꢁ, CH), 127.38 (2ꢁ, CH), 125.78 (Cq), 124.73 (CH), 116.96
(Cq), 114.11 (CH), 111.72 (Cq), 61.29 (CH3), 55.89 (CH3), 50.91 (CH2),
35.61 (CH2).
130.41 (CH), 128.94 (2ꢁ, CH), 126.78 (2ꢁ, CH), 125.62 (Cq), 109.63
(CH), 60.88 (CH3), 55.57 (CH3), 49.89 (CH), 42.10 (CH2), 41.00 (CH2),
27.47 (CH2), 15.45 (CH3).
4.5.4. 3-Benzenesulfonyl-6-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]-
azepine (1d). Yield¼90% (143 mg); colorless gum; HRMS (ESI,
Mþþ1) calcd for C17H20NO3S 318.1164, found 318.1166; 1H NMR
Acknowledgements
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 99-2113-M-037-
006-MY3).
(400 MHz, CDCl3):
d 7.77e7.74 (m, 2H, aromatic CH), 7.59e7.44 (m,
3H, aromatic CH), 7.06 (d, J¼7.6 Hz, 1H, aromatic CH), 6.72 (d,
J¼7.6 Hz, 1H, aromatic CH), 6.68 (d, J¼7.6 Hz, 1H, aromatic CH), 3.76
(s, 3H, OCH3), 3.31e3.28 (m, 2H, CH2CH2N), 3.26e2.24 (m, 2H,
CH2CH2N), 3.12e3.10 (m, 2H, CH2CH2N), 3.00e2.97 (m, 2H,
Supplementary data
CH2CH2N); 13C NMR (100 MHz, CDCl3):
d 156.59 (Cq), 142.49 (Cq),
Scanned photocopies of 1H and 13C NMR spectral data were
supported. Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2012.10.017.
132.67 (Cq), 132.43 (CH), 128.99 (2ꢁ, CH), 127.66 (Cq), 127.21 (2ꢁ,
CH), 127.14 (CH), 121.61 (CH), 109.14 (CH), 55.65 (CH3), 48.20 (CH2),
48.13 (CH2), 36.69 (CH2), 26.00 (CH2).
References and notes
4.5.5. 3-Benzenesulfonyl-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-benzo-
[d]azepine (1e). For compound 5e / 6e, yield¼94% (163 mg); for
compound 5f / 6e, yield¼94% (163 mg); colorless oil; HRMS (ESI,
Mþþ1) calcd for C18H22NO4S 348.1270, found 348.1270; 1H NMR
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d 7.75e7.73 (m, 2H, aromatic CH), 7.54e7.44 (m,
3H, aromatic CH), 6.59 (s, 2H, aromatic CH), 3.80 (s, 6H, OCH3),
3.29e3.27 (m, 4H, CH2CH2N), 2.93e2.90 (m, 4H, CH2CH2N); 13C NMR
(100 MHz, CDCl3):
(CH), 128.95 (2ꢁ, Cq), 127.02 (2ꢁ, CH), 126.21 (CH), 113.13 (2ꢁ, CH),
55.88 (2ꢁ, CH3), 48.53 (2ꢁ, CH2), 36.42 (2ꢁ, CH2).
d
146.92 (2ꢁ, Cq), 138.05 (Cq), 132.46 (Cq), 132.41
4.5.6. 7,8-Dimethoxy-2-methyl-3-phenylsulfonyl-2,3,4,5-tetrahydro-
1H-benzo[d]azepine (1f). For compound 5g
(148 mg); for compound 5h / 6f, yield¼80% (144 mg); colorless
/
6f, yield¼82%

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