Synthesis of dihydro-1-benzazepines

Article abstract of DOI:10.3987/COM-13-12729

A synthetic route toward the benzannulated dihydro-1-benzazepines (8) with two oxygenated groups starting with 2-methoxy-5-nitrophenol (2) in high total yield is described. Two key routes are carried by Claisen rearrangement of allyl phenyl ethers (3) and ring-closing metathesis of dienes (7).

Full text of DOI:10.3987/COM-13-12729

HETEROCYCLES, Vol. 87, No. 7, 2013
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HETEROCYCLES, Vol. 87, No. 7, 2013, pp. 1519 - 1536. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 14th April, 2013, Accepted, 20th May, 2013, Published online, 21st May, 2013
DOI: 10.3987/COM-13-12729
SYNTHESIS OF DIHYDRO-1-BENZAZEPINES
Meng-Yang Chang,* Chieh-Kai Chan, and Shin-Ying Lin
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University,
Kaohsiung 807, Taiwan. Email: mychang@kmu.edu.tw
Abstract – A synthetic route toward the benzannulated dihydro-1-benzazepines
(8) with two oxygenated groups starting with 2-methoxy-5-nitrophenol (2) in high
total yield is described. Two key routes are carried by Claisen rearrangement of
allyl phenyl ethers (3) and ring-closing metathesis of dienes (7).
INTRODUCTION
A 1-benzazepine ring system is a key pharmacophore for a drug candidate and its probability for clinical
trials, for example, renal and cardiovascular agents, anti-tumor and neuroleptic agents, and potent
inhibitors and antagonists.1-6 It possesses a bicyclic benzannulated framework and is also known to be
widespread among promising therapeutic agents. A considerable number of attempts have been made to
develop the skeleton. The adopted synthetic routes are described in Figure 1.7-12 Basically, the key
transformations for enhancing the potential biological properties include intramolecular free radical
ring-expansion,7 Claisen-type condensation of dicarbonyl compounds,8 Schmidt or Beckmann
rearrangement of 1-tetralone, transition metal-mediated tandem coupling reaction of aniline with alkenes
(e.g., Pd, Rh, Ir, Ru, Ni, Mo),10,11 1,3-dipolar cycloaddition of nitrone,12 and other approaches.13
1,3-dipolar
cycloaddition
O
N
H
O
Br
O
CO2Et
ref 12
N
H
ref 7
N
H
ref 11
free radical
ring expansion
Rh-promoted
hydroacylation
ref 8
CO2Me
N
H
1
1
I
H
ref 10
O
ref 9
HO
NH2
Pd-promoted
tandem Heck reaction
N
H
Claisen-type
condensation
NaN3 or Schmidt or Beckmann
NH2OH rearrangement
O
Figure 1. Synthetic Strategies toward 1-Benzazepine (1)

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HETEROCYCLES, Vol. 87, No. 7, 2013
RESULTS AND DISCUSSION
Compounds 5a~5l were easily acquired from commercially available 2-methoxy-5-nitrophenol (2) in
moderate three-step yields overall, according to reported procedures, with a reaction sequence of
O-allylation for 2 (R = H, allyl; R = Ph, cinnamyl; R = Me, crotyl) and a Claisen rearrangement of 3a~3c,
followed by O-alkylation of the corresponding 4a~4c (R3 = methyl, isopropyl, n-butyl, 3-phenylpropyl,
n-octyl, n-dodecyl, cyclopentyl, benzyl, 3-methoxyphenylmethyl). There are a number of processes
available to report this Claisen rearrangement, but generally, the skeleton of allyloxybenzene, with a nitro
group, is not chosen as the best substrate because the nitro group exhibits a strong electron-withdrawing
effect and thermal instability to easily generate complex results under the heating conditions.14 To date,
there have been few investigations into synthesizing the skeleton of 2-allyl-3-nitrophenol using a thermal
Claisen rearrangement as the key step.15 By controlling the reaction temperature and time, better results
were detected in the refluxing decalin solution. After screening substrates, solvents, temperature and time,
we found that entry 1 provided the optimized condition and a better yield, as shown in Table 1.
HO
O
R
R
1
X
R
1
X
R X
decalin
Br
R
MeO
MeO
3
MeO
MeO
Y
Y
K CO , acetone
2
3
K CO , acetone
heating
2
3
NO
NO
2
R
2
NO
R
NO
2
2
2
2
2
3a, R=H (95%)
3b, R=Ph (92%)
4a, R =OH, R =X=Y=H (72%)
R =X=Y=H, R =,
2 1
1
2
4b, R =OH, Y=Ph, R =X=H (80%) 5a, OMe (92%); 5b, O-CHMe (88%)
2
1
2
3c, R=Me (90%)
4c, R =OH, X=Me, R =Y=H (66%) 5c, O-n-C H (88%); 5d, O-(CH ) Ph (83%)
1
2
4
9
2 3
5e, O-n-C H (91%); 5f, O-n-C
H
(85%)
8
17
12 25
5g, O-C H (88%); 5h, OCH Ph (92%)
5
9
2
5i, OCH -3-MeOPh (90%)
2
R =X=H, Y=Ph, R =,
1
2
5j, OMe (70%); 5k, O-n-C H (60%)
4
9
R =Y=H, X=Me, R =,
2
1
5l, OMe (82%)
Scheme 1. Synthesis of skeleton (5)
Table 1. Claisen rearrangement conditions of skeleton (3)a-b
Entry
Reactant 3
Solvent
decalin
decalin
decalin
decalin
DMF
PhNMe2
toluene
decalin
decalin
decalin
Temp (oC)
reflux
reflux
140
Time (h)
1.5
4 / 3, Yield (%)c
4a, 72 / 3a, trace
4a, 25 / 3a, trace
4a, 30 / 3a, 45
4a, 35 / 3a, 36
4a, 40 / 3a, 43
4a, 30 / 3a, 13
4a, ~10 / 3a, 78
4b, 70 / 3b, 14
4b, 80 / 3b, trace
4c, 66 / 3c, 11
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3.0
3.0
6.0
1.5
1.5
1.5
1.0
1.5
140
reflux
reflux
reflux
reflux
reflux
reflux
b
10
1.5
aThe reactions were run on a 3.0 mmol scale with 3a~3c. 4a~4c was >95% pure as determined by NMR
c
analysis. The unknown mixture was isolated in different yield (entry 1, 15%; entry 2, 58%; entry 3, 16%;
entry 4, 22%; entry 5, 10%; entry 6; 50%; entry 7, <10%; entry 8, 11%; entry 9, <10%; entry 10, 17%).

HETEROCYCLES, Vol. 87, No. 7, 2013
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For the generation of 4a, the optimal reaction condition of Claisen rearrangement should be in a refluxing
decalin for a period of 1.5 h. When the reaction time is increased to 3 h, the desired 4a is isolated in a
25% yield and the insoluble black solid is isolated as the unknown product (58%). To decrease the
generation of major unknown products, we tried to decrease the reaction temperature and increase the
reaction time. However, the major 3a is recovered and an unknown mixture is still produced, as shown in
entries 3~4. When changing the reaction solvent to three other solvents (DMF, PhNMe2, toluene), 4a
provided poorer yields than entry 1 (see entries 5~7). Also, entries 8~10 exhibited similar results for the
formation of 4b and 4c.16
R
X
R
X
R
1
X
1
1
1) Zn, 10% HCl, MeOH
2) K CO , PhSO Cl
3) K CO , allylBr
2 3
MeO
MeO
MeO
Y
Y
Y
H
O
2
3
2
R
NO
R
N
R
2
N
2
2
2
(yield of two-step)
S
S
O
O
O
Ph
Ph
5a-j/5l
R =X=Y=H, R =,
6a, OMe (80%); 6b, O-n-C H (70%)
R =X=Y=H, R =,
2 1
7a, OMe (90%); 7b, O-n-C H (83%)
7c, O-(CH ) Ph (84%); 7d, O-n-C H (87%)
2 3 8 17
2
1
4
9
4 9
6c, O-(CH ) Ph (70%); 6d, O-n-C H (77%)
2 3
12 25
8
17
6e, O-n-C
H
(72%)
7e, O-n-C
H
(82%)
12 25
R =X=H, Y=Ph, R =, 6f, OMe (47%)
R =X=H, Y=Ph, R =,
1
2
1
1
2
R =Y=H, X=Me, R =,
7f, OMe (40%)
2
6g, OMe (74%)
R =Y=H, X=Me, R =,
2
1
R =X=Y=H, R =,
7g, OMe (81%)
2
1
6h, OH (from 5b, 80%; 5g, 68%; 5h, 75%; 5i, 69%) R =X=Y=H, R =,
2
1
7h, O-allyl (85%)
Scheme 2. Synthesis of skeleton (7)
Furthermore, conversion of skeleton 5 into 6 affords 47%~80% yields via the activated zinc-mediated
reduction with the presence of 10% HCl in MeOH at rt for 2 h followed by treatment of the corresponding
aniline with phenylsulfonyl chloride (PhSO2Cl) and K2CO3 at rt for 4 h, as shown in Scheme 2. Then,
7a~7h are prepared by allylation of 6a~6h in 40%~90% yields. Under the above mentioned conditions,
compounds 5b, 5g, 5h and 5i, are converted to 6h in 80%, 68%, 75% and 69% yields, respectively.
Notably, the R1 group of 5b (isopropyloxy), 5g (cyclopentyloxy), 5h (benzyloxy) and 5i
(3-methoxybenzyloxy) are easily transformed to the hydroxyl group due to the sensitivity of the
secondary alkyl or benzyl group under the acidic reduction condition. The structure of 6h was determined
using single-crystal X-ray analysis.17 For two N-sulfonylation and allylation reactions, the isolated yields
of 6f and 7f from 5j and 6f (Y = Ph) are relatively poorer (47% or 40%). We envisioned that
N-sulfonylation should exhibit in the methylene position between the phenyl and cinnamyl group to cause
the complex reaction under a mild basic condition. Because acetone could be used as the same reaction
solvent for N-sulfonylation and N-allylation, a combination of the two steps was required. We chose 5a
as the substrate to examine the one-pot reaction. In comparing the two routes, we found that the one-pot

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HETEROCYCLES, Vol. 87, No. 7, 2013
reaction provided 7a in a higher yield (80%) than the three-step reaction process (72%) did. The one-pot
method provides a rapid process to generate 7. To construct 8, 7 with the diallyl group was subjected to
an intramolecular ring-closing metathesis (RCM) by using Grubbs second generation catalyst in CH2Cl2
according to reported conditions.18-20 8a~8g in 80%~93% yields were isolated, as shown in Scheme 3.
With the results, a rapid synthetic route for establishing the dihydro-1-benzazepine skeleton could be
found.
X
R
R
X
1
1
Grubbs II
CH Cl
MeO
MeO
Y
2
2
R
R
2
N
S
N
2
S
O
O
O
O
Ph
Ph
7a~7g
R =X=Y=H, R =,
2
1
8a, OMe (93%); 8b, O-n-C H (84%)
4
9
8c, O-(CH ) Ph (88%); 8d, O-n-C H (90%)
2 3
8 17
8e, O-n-C
H
12 25
(88%)
R =X=H, Y=Ph, R =,
1
2
8f, OMe (80%)
R =Y=H, X=Me, R =,
2
1
8g, OMe (82%)
Scheme 3. Synthesis of skeleton (8)
O
OH
O
O
MeO
MeO
MeO
MeO
Grubbs
K CO , allylBr
2
3
+
I or II cat.
N
S
NH
N
S
N
S
S
O
Ph
O
O
O
O
O
O
O
Ph
Ph
Ph
7h (85%)
6h
Grubbs II cat., 8h (62%)
Grubbs I cat., 8h (47%)
9 (30%)
9 (44%)
Scheme 4. Synthesis of compounds (8h) and (9)
Under this synthetic sequence, 8h and 9 were synthesized in 62% and 30% via the double allylation of 6h
and ring-closing metathesis of 7h with three allyl groups, as shown in Scheme 4. Attempts to achieve sole
O- or N-allylation of 6h failed due to the competitive allylation of 6h. Interestingly, when reaction of 7h
was treated with Grubbs first generation catalyst in CH2Cl2, the yields from 8h (47%) and 9 (44%)
provided a nearly 1/1 ratio. For the two kinds of Grubbs catalysts, both major products were 8h during
reaction conditions.
CONCLUSION
In summary, we have successfully presented a synthetic route for the synthesis of 8a~8h via Claisen
rearrangement, reduction, sulfonylation, allylation and ring-closing metathesis. This synthesis begins with

HETEROCYCLES, Vol. 87, No. 7, 2013
1523
simple starting materials and reagents, and provides a new synthetic route toward the skeleton of
1-benzazepines.
EXPERIMENTAL
General. THF was distilled prior to use. All other reagents and solvents were obtained from commercial
sources and used without further purification. Reactions were routinely carried out under an atmosphere
of dry nitrogen with magnetic stirring. Products in organic solvents were dried with anhydrous
magnesium sulfate before concentration in vacuo. Melting points were determined with a SMP3 melting
1
13
apparatus. H and C NMR spectra were recorded on a Varian INOVA-400 spectrometer operating at
400 and at 100 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the
coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were 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 CHN-OS-Rapid Analyzer or Elementar Vario EL III.
A representative synthetic procedure of skeleton (3) is as follows: K2CO3 (1.38 g, 10.0 mmol) was added
to a solution of 2 (845 mg, 5.0 mmol) in acetone (30 mL) at rt. The reaction mixture was stirred at rt for
10 min. Different allylic bromide (7.5 mmol, for 3a, allyl bromide 900 mg; for 3b, cinnamyl bromide,
1.48 g; for 3c, crotyl bromide, 1.00 g) was added to the reaction mixture at rt. The reaction mixture was
stirred at reflux for 10 h. The reaction was monitored by TLC until 2a was consumed. The reaction
mixture was cooled to rt, concentrated, and partitioned with EtOAc (3 x 30 mL) and water. The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc=10/1~8/1) afforded 3a~3c.
2-Allyloxy-1-methoxy-4-nitrobenzene (3a). Yield 95% (995 mg); Yellowish solid; mp 85-87 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C10H12NO4 210.0766, found
1
210.0770; H NMR (400 MHz, CDCl3): δ 7.93-7.91 (dd, J = 2.8, 8.8 Hz, 1H), 7.75 (d, J = 2.8 Hz, 1H),
6.92 (d, J = 8.8 Hz, 1H), 6.13-6.03 (m, 1H), 5.46 (dq, J = 1.6, 17.2 Hz, 1H), 5.36 (dq, J = 1.6, 10.4 Hz,
1H), 4.68 (dt, J = 1.6, 5.6 Hz, 2H), 3.97 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.83, 147.69, 141.30,
131.94, 119.09, 117.93, 110.04, 108.12, 70.05, 56.41; Anal. Calcd for C10H11NO4: C, 57.41; H, 5.30; N,
6.70. Found: C, 57.62; H, 5.22; N, 6.92.
2-Cinnamyloxy-1-methoxy-4-nitrobenzene (3b). Yield 92% (1.31 g); Yellowish solid; mp 112-114 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C16H16NO4 286.1079, found
1
286.1083; H NMR (400 MHz, CDCl3): δ 7.89 (dd, J=2.4, 8.8 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H),
7.42-7.41 (m, 2H), 7.36-7.24 (m, 3H), 6.89 (d, J = 9.2 Hz, 1H), 6.77 (d, J = 16.0 Hz, 1H), 6.43 (dt, J = 6.0,

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HETEROCYCLES, Vol. 87, No. 7, 2013
16.0 Hz, 1H), 4.78 (d, J=6.0 Hz, 2H), 3.95 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 154.65, 147.48,
141.01, 135.82, 134.14, 128.36 (2x), 127.92, 126.45 (2x), 122.75, 117.71, 109.87, 107.81, 69.66, 56.15;
Anal. Calcd for C16H16NO4: C, 67.36; H, 5.30; N, 4.91. Found: C, 57.62; H, 5.22; N, 5.19.
2-But-2-enyloxy-1-methoxy-4-nitrobenzene (3c). Yield 90% (1.01 g); Yellowish solid; mp 70-72 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C11H14NO4 224.0923, found
224.0928; 1H NMR (400 MHz, CDCl3): δ 7.90 (dd, J = 2.4, 8.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 6.90 (d,
J = 9.2 Hz, 1H), 5.97-5.88 (m, 1H), 5.80-5.72 (m, 1H), 4.59 (dd, J = 1.2, 6.0 Hz, 2H), 3.96 (s, 3H), 1.77
(dd, J = 1.2, 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 154.80, 147.83, 141.30, 132.14, 124.78, 117.69,
109.90, 107.88, 69.94, 56.38, 17.86; Anal. Calcd for C11H13NO4: C, 59.19; H, 5.87; N, 6.27. Found: C,
59.41; H, 6.02; N, 6.56.
A representative synthetic procedure of skeleton (4) is as follows: Decalin (8 mL) was added to a
solution of 3 (3.0 mmol) at rt. The reaction mixture was stirred at reflux for 1.5 h. The reaction mixture
was cooled to rt. Decalin was evaporated to afford crude product under reduced pressure. Purification on
silica gel (hexanes/EtOAc = 8/1~4/1) afforded 4a~4c.
2-Allyl-6-methoxy-3-nitrophenol (4a). In Table 1, entry 1; Yield 72% (450 mg); Yellowish oil; HRMS
(ESI, M++1) calcd for C10H12NO4 210.0766, found 210.0771; 1H NMR (400 MHz, CDCl3): δ 7.62 (d, J =
9.2 Hz, 1H), 6.80 (d, J = 9.2 Hz, 1H), 6.05-6.95 (m, 1H), 5.96 (s, 1H), 5.07 (dq, J = 1.6, 17.2 Hz, 1H),
5.04 (dq, J = 1.6, 10.4 Hz, 1H), 3.98 (s, 3H), 3.74 (dt, J = 1.6, 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3):
δ 149.86 (2x), 144.18, 134.61, 121.88, 117.56, 115.90, 107.47, 56.37, 29.74.
2-Methoxy-5-nitro-4-(3-phenylallyl)phenol (4b). In Table 1, entry 9; Yield 80% (684 mg); Yellowish oil;
HRMS (ESI, M++1) calcd for C16H16NO4 286.1079, found 286.1083; 1H NMR (400 MHz, CDCl3): δ 7.61
(s, 1H), 7.37-7.20 (m, 5H), 6.77 (s, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.36 (dt, J = 6.4, 16.0 Hz, 1H), 5.75 (s,
1H), 3.96 (s, 3H), 3.84 (dt, J = 1.2, 6.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 150.47, 144.03, 137.09,
131.85, 130.14, 129.30, 128.52 (2x), 127.34, 127.21, 126.17 (2x), 112.54, 111.66, 56.35, 36.73.
6-Methoxy-2-(1-methylallyl)-3-nitrophenol (4c). In Table 1, entry 10; Yield 66% (441 mg); Yellowish
solid; mp 100-102 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C11H14NO4
224.0923, found 224.0924; 1H NMR (400 MHz, CDCl3): δ 7.32 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.8 Hz,
1H), 6.31-6.22 (m, 1H), 6.04 (s, 1H), 5.10 (dt, J = 1.6, 17.2 Hz, 1H), 5.05 (dt, J = 1.6, 10.4 Hz, 1H),
4.03-3.99 (m, 1H), 3.96 (s, 3H), 1.51 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 149.42, 144.41,
140.15 (2x), 125.58, 116.58, 114.52, 107.47, 56.36, 36.45, 17.91; Anal. Calcd for C11H13NO4: C, 59.19;
H, 5.87; N, 6.27. Found: C, 59.35; H, 5.98; N, 6.45.
A representative synthetic procedure of skeleton (5) is as follows: K2CO3 (280 mg, 2.0 mmol) was added

HETEROCYCLES, Vol. 87, No. 7, 2013
1525
to a solution of 4 (1.0 mmol) in acetone (10 mL) at rt. The reaction mixture was stirred at rt for 10 min.
Different alkyl halide (1.5 mmol, for 5a, 5j and 5l, methyl iodide, 210 mg; for 5b, isopropyl bromide, 185
mg; for 5c and 5k, n-butyl bromide, 206 mg; for 5d, 3-phenylpropyl bromide, 300 mg; for 5e, n-octyl
bromide, 290 mg; for 5f, n-dodecyl bromide, 375 mg; for 5g, cyclopentyl bromide, 225 mg; for 5h,
benzyl bromide, 260 mg; for 5i, 3-methoxyphenylmethyl bromide, 305 mg) was added to the reaction
mixture at rt. The reaction mixture was stirred at reflux for 10 h. The reaction mixture was cooled to rt,
concentrated, and partitioned with EtOAc (3 x 30 mL) and water. The combined organic layers were
washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure.
Purification on silica gel (hexanes/EtOAc = 10/1~8/1) afforded 5a~5l.
2-Allyl-3,4-dimethoxy-1-nitrobenzene (5a). Yield 92% (205 mg); Yellowish oil; HRMS (ESI, M++1)
calcd for C11H14NO4 224.0923, found 224.0928; 1H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.8 Hz, 1H),
6.86 (d, J = 8.8 Hz, 1H), 6.03-5.93 (m, 1H), 5.05-4.98 (m, 2H), 3.95 (s, 3H), 3.84 (s, 3H), 3.77 (dt, J = 1.6,
13
6.0 Hz, 2H); C NMR (100 MHz, CDCl3): δ 156.85, 147.58, 142.90, 134.39, 130.40, 121.93, 115.93,
109.29, 61.10, 56.06, 30.04.
2-Allyl-3-isopropoxy-4-methoxy-1-nitrobenzene (5b). Yield 88% (221 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C13H18NO4 252.1236, found 252.1242; H NMR (400 MHz, CDCl3): δ 7.75 (d, J = 9.2
Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 5.95-5.85 (m, 1H), 5.02-4.95 (m, 2H), 4.60-4.54 (m, 1H), 3.92 (s, 3H),
13
3.80 (dt, J = 1.6, 6.0 Hz, 2H), 1.29 (d, J = 6.0 Hz, 6H); C NMR (100 MHz, CDCl3): δ 156.75, 145.29,
142.88, 134.92, 130.39, 121.29, 115.87, 108.96, 75.42, 55.97, 30.18, 22.50 (2x).
2-Allyl-3-butoxy-4-methoxy-1-nitrobenzene (5c). Yield 88% (233 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C14H20NO4 266.1392, found 266.1394; H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 9.2
Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.01-5.91 (m, 1H), 5.03-4.97 (m, 2H), 3.94 (t, J = 6.8 Hz, 2H), 3.93 (s,
13
3H), 3.78 (dt, J = 1.6, 6.0 Hz, 2H), 1.81-1.74 (m, 2H), 1.57-1.46 (m, 2H), 0.98 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl3): δ 156.93, 146.89, 142.50, 135.39, 130.39, 121.75, 115.82, 109.18, 73.41, 56.03,
32.22, 30.04, 19.10, 13.86.
2-Allyl-3-(1-phenylpropyloxy)-4-methoxy-1-nitrobenzene (5d). Yield 92% (300 mg); Yellowish oil;
HRMS (ESI, M++1) calcd for C19H22NO4 328.1549, found 328.1552; 1H NMR (400 MHz, CDCl3): δ 7.81
(d, J = 8.8 Hz, 2H), 7.33-7.29 (m, 1H), 7.26-7.19 (m, 3H), 6.84 (d, J = 9.2 Hz, 1H), 6.02-5.92 (m, 1H),
5.03-4.96 (m, 2H), 3.98 (t, J = 6.4 Hz, 2H), 3.91 (s, 3H), 3.78 (dt, J = 1.2, 5.6 Hz, 2H), 2.94 (t, J = 7.2 Hz,
2H), 2.17-2.09 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 156.85, 146.76, 142.96, 141.57, 135.34, 130.35,
128.43 (2x), 128.38 (2x), 125.93, 121.83, 115.86, 109.18, 72.81, 55.98, 32.11, 31.76, 30.09.
2-Allyl-4-methoxy-1-nitro-3-octyloxybenzene (5e). Yield 91% (292 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C18H28NO4 322.2018, found 322.2022; H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 9.2
Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.01-5.92 (m, 1H), 5.03-4.96 (m, 2H), 3.93 (t, J = 6.8 Hz, 2H), 3.93 (s,

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3H), 3.78 (dt, J = 2.0, 6.4 Hz, 2H), 1.82-1.75 (m, 2H), 1.50-1.42 (m, 2H), 1.37-1.28 (m, 8H), 0.89 (t,
13
J=7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 156.94, 146.86, 142.93, 135.38, 130.40, 121.79, 115.82,
109.13, 73.73, 56.03, 31.81, 30.14, 20.06, 29.37, 29.23, 25.86, 22.64, 14.01.
2-Allyl-3-dodecyloxy-4-methoxy-1-nitrobenzene (5f). Yield 85% (320 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C22H36NO4 378.2644, found 378.2646; H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 9.2
Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.01-5.91 (m, 1H), 5.03-4.96 (m, 2H), 3.93 (t, J = 6.8 Hz, 2H), 3.93 (s,
3H), 3.78 (dt, J = 2.0, 6.4 Hz, 2H), 1.92-1.75 (m, 2H), 1.50-1.42 (m, 2H), 1.36-1.26 (m, 16H), 0.88 (t, J =
13
7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 156.93, 146.88, 142.96, 135.38, 130.40, 121.75, 115.82,
109.16, 73.74, 56.03, 31.91, 31.15, 30.06, 29.65, 29.62, 29.60, 29.57, 29.41, 29.34, 25.87, 22.67, 14.11.
2-Allyl-3-cyclopentyloxy-4-methoxy-1-nitrobenzene (5g). Yield 88% (244 mg); Yellowish oil; HRMS
(ESI, M++1) calcd for C15H20NO4 278.1392, found 278.1397; 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J =
9.2 Hz, 1H), 6.83 (d, J = 9.2 Hz, 1H), 5.95-5.85 (m, 1H), 5.01-4.94 (m, 2H), 4.91-4.87 (m, 1H), 3.92 (s,
13
3H), 3.77 (dt, J = 1.6, 6.0 Hz, 2H), 1.89-1.59 (m, 8H); C NMR (100 MHz, CDCl3): δ 156.53, 145.66,
142.33, 134.93, 130.19, 121.15, 115.79, 109.13, 85.29, 55.97, 32.81 (2x), 30.05, 23.60 (2x).
2-Allyl-3-benzyloxy-4-methoxy-1-nitrobenzene (5h). Yield 92% (275 mg); Yellowish solid; mp 68-70 C
(recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C17H18NO4 300.1236, found
300.1242; 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 9.2 Hz, 1H), 7.47-7.33 (m, 5H), 6.89 (d, J = 9.2 Hz,
1H), 5.99-5.89 (m, 1H), 5.02-4.93 (m, 2H), 5.01 (s, 2H), 3.97 (s, 3H), 3.76 (dt, J = 1.6, 6.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ 156.88, 146.37, 143.06, 136.99, 135.26, 130.66, 128.49 (2x), 128.21, 128.07
(2x), 122.08, 115.97, 109.31, 75.07, 56.11, 30.15; Anal. Calcd for C17H17NO4: C, 68.21; H, 5.72; N, 4.68.
Found: C, 68.45; H, 6.10; N, 4.82.
2-Allyl-3-(3-methoxybenzyloxy)-4-methoxy-1-nitrobenzene (5i). Yield 90% (296 mg); Yellowish gum;
HRMS (ESI, M++1) calcd for C18H20NO5 330.1342, found 330.1348; 1H NMR (400 MHz, CDCl3): δ 7.83
(d, J = 9.2 Hz, 1H), 7.31 (t, J = 9.2 Hz, 1H), 7.04 (s, 1H), 7.03 (d, J = 9.2 Hz, 1H), 6.89 (d, J = 9.2 Hz,
2H), 6.00-5.90 (m, 1H), 5.03-4.95 (m, 2H), 4.99 (s, 2H), 3.96 (s, 3H), 3.83 (s, 3H), 3.77 (dt, J = 1.6, 6.0
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 159.61, 156.78, 146.16, 142.79, 138.42, 135.19, 130.41, 129.39,
122.00, 120.04, 115.83, 113.55, 113.33, 109.24, 74.74, 55.99, 55.09, 30.05.
4,5-Dimethoxy-1-nitro-2-(3-phenylallyl)benzene (5j). Yield 70% (209 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C17H18NO4 300.1236, found 300.1243; H NMR (400 MHz, CDCl3): δ 7.64 (s, 1H),
7.36-7.19 (m, 5H), 6.79 (s, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.37 (dt, J = 6.4, 16.0 Hz, 1H), 3.95 (s, 3H),
13
3.94 (s, 3H), 3.87 (dd, J = 1.2, 6.4 Hz, 2H); C NMR (100 MHz, CDCl3): δ 153.14, 147.38, 137.09,
131.92, 130.47, 128.52 (2x), 127.35, 127.07, 126.70, 126.18 (2x), 113.13, 108.23, 56.34, 56.31, 36.89.
5-n-Butoxy-4-methoxy-1-nitro-2-(3-phenylallyl)benzene (5k). Yield 60% (205 mg); Yellowish oil;
HRMS (ESI, M++1) calcd for C20H24NO4 342.1705, found 342.1711; 1H NMR (400 MHz): δ 7.63 (s, 1H),

HETEROCYCLES, Vol. 87, No. 7, 2013
1527
7.36-7.15 (m, 5H), 6.77 (s, 1H), 6.47 (d, J = 16.0 Hz, 1H), 6.35 (dt, J = 6.4, 16.0 Hz, 1H), 4.07 (t, J = 5.8
Hz, 2H), 3.93 (s, 3H), 3.86 (dd, J = 0.8, 6.4 Hz, 2H), 1.89-1.82 (m, 2H), 1.52-1.46 (m, 2H), 0.99 (t, J =
7.6 Hz, 3H); 13C NMR (100 MHz): δ 153.51, 146.94, 137.13, 131.84, 130.19, 128.74, 128.51 (2x), 127.32,
127.18, 126.17 (2x), 113.29, 109.38, 69.13, 56.34, 36.90, 30.93, 19.12, 13.79.
1,2-Dimethoxy-3-(1-methylallyl)-4-nitrobenzene (5l). Yield 82% (194 mg); Yellowish oil; HRMS (ESI,
1
M++1) calcd for C12H16NO4 238.1079, found 238.1081; H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.8
Hz, 1H), 6.82 (d, J = 9.2 Hz, 1H), 6.14 (ddd, J = 6.0, 10.4, 16.4 Hz, 1H), 5.08-5.02 (m, 2H), 4.02-3.98 (m,
1H), 3.92 (s, 3H), 3.85 (s, 3H), 1.48 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 156.11, 147.95,
141.02, 134.30, 121.87, 120.59, 114.19, 109.40, 60.89, 56.97, 36.15, 18.84.
A representative synthetic procedure of skeleton (6) is as follows: Activated zinc (24 mg, 1.2 mmol) was
added to a solution of 5 (1.0 mmol) in MeOH (8 mL) at rt. Then, 10% HCl aqueous solution was added to
the mixture, and stirring occurred at rt for 2 h. The reaction mixture was filtered and evaporated to yield
crude product. Without further purification, K2CO3 (280 mg, 2.0 mmol) was added to a solution of crude
product in acetone (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. Then, benzenesulfonyl
chloride (265 mg, 1.5 mmol) was added to reaction mixture. The reaction mixture was stirred at rt for 4 h.
The reaction mixture was concentrated, and partitioned with EtOAc (3 x 30 mL) and water. The
combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product
under reduced pressure. Purification on silica gel (hexanes/EtOAc = 10/1~8/1) afforded 6a~6h.
N-(2-Allyl-3,4-dimethoxyphenyl)benzenesulfonamide (6a). Yield 80% (266 mg); Colorless solid; mp
121-123 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C17H20NO4S
1
334.1113, found 334.1118; H NMR (400 MHz, CDCl3): δ 7.70-7.67 (m, 2H), 7.57-7.53 (m, 1H),
7.45-7.41 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.48 (s, 1H), 5.83-5.73 (m, 1H),
5.03 (dd, J = 1.6, 10.4 Hz, 1H), 4.84 (dq, J = 1.6, 17.2 Hz, 1H), 3.84 (s, 3H), 3.69 (s, 3H), 2.97 (dt, J =
13
1.6, 5.6 Hz, 2H); C NMR (100 MHz, CDCl3): δ 151.48, 146.96, 139.60, 135.68, 132.76, 128.85 (2x),
128.14, 127.84, 126.86 (2x), 121.91, 115.93, 110.38, 60.86, 55.59, 28.62. Anal. Calcd for C17H19NO4S: C,
61.24; H, 5.74; N, 4.20. Found: C, 61.52; H, 5.93; N, 4.36.
N-(2-Allyl-3-butoxy-4-methoxyphenyl)benzenesulfonamide (6b). Yield 70% (263 mg); Colorless oil;
1
HRMS (ESI, M++1) calcd for C20H26NO4S 376.1583, found 376.1588; H NMR (400 MHz, CDCl3): δ
7.66-7.63 (m, 2H), 7.55-7.51 (m, 1H), 7.43-7.39 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 8.8 Hz,
1H), 6.41 (s, 1H), 5.80-5.71 (m, 1H), 5.03 (dd, J = 1.6, 10.4 Hz, 1H), 4.83 (dq, J = 1.6, 17.2 Hz, 1H), 3.81
(s, 3H), 3.78 (t, J = 7.2 Hz, 2H), 2.90 (dt, J = 1.6, 5.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.45-1.36 (m, 2H), 0.91
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.61, 146.23, 139.67, 135.76, 132.77, 128.90 (2x),
128.80, 127.95, 126.87 (2x), 121.73, 116.07, 110.44, 73.22, 55.66, 32.11, 28.75, 19.03, 13.77.

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N-[2-Allyl-4-methoxy-3-(3-phenylpropoxy)phenyl]benzenesulfonamide (6c). Yield 70% (306 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C25H28NO4S 438.1739, found 438.1743; 1H NMR (400 MHz,
CDCl3): δ 7.69-7.66 (m, 2H), 7.54-7.50 (m, 1H), 7.43-7.38 (m, 2H), 7.32-7.26 (m, 2H), 7.22-7.19 (m, 3H),
7.15 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.46 (s, 1H), 5.81-5.72 (m, 1H), 5.04 (dd, J = 1.6, 10.4
Hz, 1H), 4.85 (dq, J = 1.6, 17.2 Hz, 1H), 3.85 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 2.95 (dt, J = 1.6, 5.6 Hz,
2H), 2.76 (t, J = 7.6 Hz, 2H), 2.04-1.97 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 151.50, 146.08, 141.61,
139.59, 135.65, 132.76, 128.87 (2x), 128.31 (2x), 128.24 (2x), 127.99, 127.93, 126.82 (2x), 125.76,
121.84, 116.06, 110.40, 72.66, 55.58, 32.06, 31.66, 28.77.
N-(2-Allyl-4-methoxy-3-octyloxyphenyl)benzenesulfonamide (6d). Yield 77% (332 mg); Colorless solid;
mp 63-64 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C24H34NO4S
1
432.2209, found 432.2213; H NMR (400 MHz, CDCl3): δ 7.69-7.64 (m, 2H), 7.59-7.52 (m, 1H),
7.44-7.39 (m, 2H), 7.17 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.37 (s, 1H), 5.81-5.71 (m, 1H),
5.05 (dd, J = 1.6, 10.4 Hz, 1H), 4.84 (dq, J = 1.6, 17.2 Hz, 1H), 3.83 (s, 3H), 3.76 (t, J = 6.4 Hz, 2H), 2.89
(dt, J = 1.6, 5.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.39-1.24 (m, 10H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 151.64, 146.27, 139.72, 135.79, 133.84, 132.81, 129.24, 128.94 (2x), 126.90 (2x),
121.75, 116.18, 110.49, 73.63, 55.71, 31.79, 30.08, 29.32, 29.19, 28.80, 25.86, 22.61, 14.07. Anal. Calcd
for C24H33NO4S: C, 66.79; H, 7.71; N, 3.25. Found: C, 66.92; H, 7.56; N, 3.38.
N-(2-Allyl-3-dodecyloxy-4-methoxyphenyl)benzenesulfonamide (6e). Yield 72% (351 mg); Colorless
oil; HRMS (ESI, M++1) calcd for C28H42NO4S 488.2835, found 488.2836; 1H NMR (400 MHz, CDCl3):
δ 7.68-7.64 (m, 2H), 7.58-7.51 (m, 1H), 7.43-7.39 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 8.8 Hz,
1H), 6.40 (s, 1H), 5.81-5.71 (m, 1H), 5.04 (dd, J = 1.6, 10.4 Hz, 1H), 4.84 (dq, J = 1.6, 17.2 Hz, 1H), 3.82
(s, 3H), 3.77 (t, J = 6.4 Hz, 2H), 2.91 (dt, J = 1.6, 5.6 Hz, 2H), 1.68-1.61 (m, 2H), 1.38-1.20 (m, 18H),
0.87 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 151.62, 146.25, 139.69, 135.78, 132.79, 129.23,
128.92 (2x), 126.89 (2x), 121.73, 116.11, 110.45, 73.59, 55.68, 31.86, 30.06, 29.60, 29.58 (2x), 29.56,
29.52, 29.34, 29.29, 28.78, 25.83, 22.63, 14.07.
N-[4,5-Dimethoxy-2-(3-phenylallyl)phenyl]benzenesulfonamide (6f). Yield 47% (192 mg); Colorless
solid; mp 113-115 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for
1
C23H24NO4S 410.1426, found 410.1432; H NMR (400 MHz): δ 7.74-7.71 (m, 2H), 7.55-7.51 (m, 1H),
7.42-7.38 (m, 2H), 7.27-7.24 (m, 4H), 7.22-7.17 (m, 1H), 6.76 (s, 1H), 6.73 (s, 1H), 6.61 (s, 1H), 6.24 (dt,
J = 1.2, 16.0 Hz, 1H), 6.04 (dt, J = 6.4, 16.0 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.15 (dt, J = 1.6, 5.6 Hz,
13
2H); C NMR (100 MHz): δ 147.76, 147.52, 139.31, 136.73, 132.74, 131.21, 128.84 (2x), 128.37 (2x),
127.60, 127.37, 127.24, 127.16 (2x), 126.34, 126.05 (2x), 112.46, 110.32, 55.81, 55.75, 34.22.
N-[3,4-Dimethoxy-2-(1-methylallyl)phenyl]benzenesulfonamide (6g). Yield 74% (257 mg); Colorless
1
oil; HRMS (ESI, M++1) calcd for C18H22NO4S 348.1270, found 348.1278; H NMR (400 MHz): δ

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1529
7.78-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.47-7.43 (m, 2H), 7.10 (d, J = 8.8 Hz, 1H), 6.75 (br s, 1H), 6.72 (d,
J = 9.2 Hz, 1H), 5.98-5.90 (m, 1H), 5.19 (dd, J = 1.2, 10.4 Hz, 1H), 5.10 (dd, J = 1.2, 17.6 Hz, 1H),
13
4.02-3.98 (m, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 1.08 (d, J = 7.2 Hz, 3H); C NMR (100 MHz): δ 150.90,
147.21, 141.78, 140.01, 132.81, 131.32, 128.93 (2x), 128.22, 127.16 (2x), 119.25, 114.61, 110.57, 60.96,
55.71, 33.62, 16.88.
N-(2-Allyl-3-hydroxy-4-methoxyphenyl)benzenesulfonamide (6h). For 5b, Yield 80% (255 mg); For 5g,
Yield 68% (217 mg); For 5h, Yield=75% (240 mg); For 5i, Yield 69% (220 mg); Colorless solid; mp
113-115 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C16H18NO4S
1
320.0957, found 320.0956; H NMR (400 MHz, CDCl3): δ 7.72-7.69 (m, 2H), 7.56-7.52 (m, 1H),
7.45-7.40 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.44 (br s, 1H), 5.81-5.71 (m, 1H),
5.76 (br s, 1H), 5.01 (dq, J = 1.6, 10.0 Hz, 1H), 4.87 (dq, J = 1.6, 17.2 Hz, 1H), 3.85 (s, 3H), 3.01 (dt, J =
13
1.6, 5.6 Hz, 2H); C NMR (100 MHz, CDCl3): δ 145.04, 143.57, 139.72, 135.19, 132.80, 128.93 (2x),
128.39, 126.98 (2x), 119.87, 117.13, 115.78, 108.65, 55.97, 28.36; Anal. Calcd for C16H17NO4S: C,
60.17; H, 5.37; N, 4.39. Found: C, 60.49; H, 5.52; N, 4.68. Single-crystal X-Ray diagram: crystal of 6h
was grown by slow diffusion of EtOAc into a solution of 6h in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the orthorhombic crystal system, space group P b c a, a = 14.0992(8) Å, b =
14.5823(9) Å, c = 15.0416(9) Å, V = 3092.5(3) Å3, Z = 8, dcalcd = 1.376 g/cm3, F(000) = 1352, 2θ range
2.42~28.27o, R indices (all data) R1 = 0.0439, wR2=0.1182.
A representative synthetic procedure of skeleton (7) is as follows: K2CO3 (138 mg, 1.0 mmol) was added
to a solution of 6 (0.5 mmol) in acetone (8 mL) at rt. The reaction mixture was stirred at rt for 10 min.
Allyl bromide (180 mg, 1.5 mmol) was added to the reaction mixture at rt. The reaction mixture was
stirred at reflux for 10 h. The reaction mixture was cooled to rt, concentrated, and partitioned with EtOAc
(3 x 30 mL) and water. The combined organic layers were washed with brine, dried, filtered and
evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc =
10/1~8/1) afforded 7a~7h.
N-Allyl-N-(2-allyl-3,4-dimethoxyphenyl)benzenesulfonamide (7a). Yield 90% (168 mg); Colorless oil;
1
HRMS (ESI, M++1) calcd for C20H24NO4S 374.1426, found 374.1433; H NMR (400 MHz, CDCl3): δ
7.72-7.69 (m, 2H), 7.60-7.56 (m, 1H), 7.50-7.45 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 8.8 Hz,
1H), 5.99-5.89 (m, 1H), 5.76-5.66 (m, 1H), 5.01-4.92 (m, 4H), 4.14 (dd, J = 6.4, 14.4 Hz, 1H), 4.02 (dd, J
= 7.2, 14.4 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 3.47-3.44 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 152.74,
148.04, 139.12, 136.97, 135.41, 132.72, 132.56, 130.55, 128.71 (2x), 127.86 (2x), 124.76, 119.11, 115.14,
109.49, 60.47, 55.50, 55.03, 30.65.
N-Allyl-N-(2-allyl-3-butoxy-4-methoxyphenyl)benzenesulfonamide (7b). Yield 83% (172 mg); Colorless

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solid; mp 73-75 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for C23H30NO4S
1
416.1896, found 416.1897; H NMR (400 MHz, CDCl3): δ 7.73-7.70 (m, 2H), 7.65-7.58 (m, 1H),
7.50-7.45 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.98-5.89 (m, 1H), 5.77-5.67 (m,
1H), 5.00-4.92 (m, 4H), 4.14-4.00 (m, 2H), 3.92-3.86 (m, 2H), 3.81 (s, 3H), 3.45-3.39 (m, 2H), 1.76-1.66
13
(m, 2H), 1.52-1.42 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 152.89, 147.38,
139.29, 137.04, 135.56, 133.06, 132.85, 132.54, 128.73 (2x), 127.93 (2x), 124.74, 119.09, 115.08, 109.45,
72.53, 55.54, 55.07, 32.30, 30.81, 19.09, 13.89.
N-Allyl-N-[2-allyl-4-methoxy-3-(3-phenylpropoxy)phenyl]benzenesulfonamide (7c). Yield 84% (200
mg); Colorless oil; HRMS (ESI, M++1) calcd for C28H32NO4S 478.2052, found 478.2055; 1H NMR (400
MHz, CDCl3): δ 7.74-7.72 (m, 2H), 7.65-7.58 (m, 1H), 7.50-7.46 (m, 2H), 7.31-7.21 (m, 5H), 6.63 (d, J =
8.8 Hz, 1H), 6.41 (d, J = 8.8 Hz, 1H), 6.02-5.93 (m, 1H), 5.79-5.69 (m, 1H), 5.03-4.95 (m, 4H), 4.13-3.94
(m, 4H), 3.80 (s, 3H), 3.49-3.48 (m, 2H), 2.82 (dt, J = 2.4, 7.6 Hz, 2H), 2.13-2.06 (m, 2H); 13C NMR (100
MHz, CDCl3): δ 152.74, 147.17, 141.88, 139.12, 136.97, 135.43, 132.76, 132.54, 130.53, 128.69 (2x),
128.38 (2x), 128.22 (2x), 127.85 (2x), 125.70, 124.72, 119.09, 115.11, 109.39, 71.90, 55.43, 55.02, 32.14,
31.88, 30.78.
N-Allyl-N-(2-allyl-4-methoxy-3-octyloxyphenyl)benzenesulfonamide (7d). Yield 87% (205 mg);
Colorless solid; mp 60-61 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for
C27H38NO4S 472.2522, found 472.2525; 1H NMR (400 MHz, CDCl3): δ 7.72-7.70 (m, 2H), 7.60-7.57 (m,
1H), 7.50-7.46 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 5.98-5.89 (m, 1H), 5.77-5.67
(m, 1H), 4.99-4.92 (m, 4H), 4.15-3.85 (m, 4H), 3.80 (s, 3H), 3.44-3.42 (m, 2H), 1.78-1.70 (m, 2H),
13
1.45-1.39 (m, 2H), 1.35-1.25 (m, 8H), 0.89 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 152.89,
147.37, 139.26, 137.04, 135.57, 132.84, 132.56, 130.58, 128.74 (2x), 127.93 (2x), 124.72, 119.11, 115.09,
109.41, 72.85, 55.53, 55.08, 31.80, 30.81, 30.20, 29.39, 29.23, 25.86, 22.63, 14.63.
N-Allyl-N-(2-allyl-3-dodecyloxy-4-methoxyphenyl)benzenesulfonamide (7e). Yield 82% (216 mg);
Colorless solid; mp 66-67 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for
C31H46NO4S 528.3148, found 528.3152; 1H NMR (400 MHz, CDCl3): δ 7.74-7.70 (m, 2H), 7.60-7.56 (m,
1H), 7.52-7.46 (m, 2H), 6.61 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 8.8 Hz, 1H), 5.99-5.89 (m, 1H), 5.78-5.67
(m, 1H), 5.01-4.92 (m, 4H), 4.15-3.85 (m, 4H), 3.80 (s, 3H), 3.45-3.43 (m, 2H), 1.77-1.68 (m, 2H),
13
1.45-1.27 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (100 MHz, CDCl3): δ 152.86, 147.35, 139.23,
137.02, 135.53, 132.81, 132.53, 130.57, 128.70 (2x), 127.89 (2x), 124.67, 119.06, 115.05, 109.39, 72.81,
55.50, 55.05, 31.84, 30.79, 30.18, 29.61, 29.56 (2x), 29.41 (2x), 29.28, 25.84, 22.61, 14.05; Anal. Calcd
for C31H45NO4S: C, 70.55; H, 8.59; N, 2.65. Found: C, 70.68; H, 8.81; N, 2.49.
N-Allyl-N-[4,5-dimethoxy-2-(3-phenylallyl)phenyl]benzenesulfonamide (7f). Yield 40% (90 mg);

HETEROCYCLES, Vol. 87, No. 7, 2013
1531
Colorless solid; mp 130-132 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for
C26H28NO4S 450.1739, found 450.1742; 1H NMR (400 MHz, CDCl3): δ 7.76-7.73 (m, 2H), 7.64-7.59 (m,
1H), 7.54-7.49 (m, 2H), 7.38-7.35 (m, 2H), 7.32-7.28 (m, 2H), 7.23-7.19 (m, 1H), 6.76 (s, 1H), 6.45 (d, J
= 15.6 Hz, 1H), 6.26 (dt, J = 7.2, 15.6 Hz, 1H), 5.99 (s, 1H), 5.84-5.74 (m, 1H), 5.06-4.98 (m, 2H), 4.39
(dd, J = 6.0, 13.6 Hz, 1H), 3.88 (dd, J = 7.6, 13.6 Hz, 1H), 3.83 (s, 3H), 3.68 (dd, J = 1.2, 7.2 Hz, 1H),
13
3.56 (dd, J = 1.2, 7.2 Hz, 1H), 3.52 (s, 3H); C NMR (100 MHz, CDCl3): δ 148.91, 146.97, 138.93,
137.49, 134.28, 132.70, 132.56 (2x), 131.46, 129.01, 128.84 (2x), 128.49 (2x), 128.06 (2x), 127.07,
126.10 (2x), 119.49, 112.30, 111.32, 55.83, 55.66, 55.12, 34.15; Anal. Calcd for C26H28NO4S: C, 69.46;
H, 6.05; N, 3.12. Found: C, 69.66; H, 6.29; N, 3.29.
N-Allyl-N-[3,4-dimethoxy-2-(1-methylallyl)phenyl]benzenesulfonamide (7g). Yield 81% (157 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C21H26NO4S 388.1583, found 388.1587; 1H NMR (200 MHz,
CDCl3): δ 7.78-7.73 (m, 2H), 7.57-7.50 (m, 3H), 6.58 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 8.4 Hz, 1H),
6.28-6.05 (m, 1H), 5.85-5.62 (m, 1H), 5.00-4.92 (m, 4H), 4.25-4.20 (m, 1H), 3.82 (s, 3H), 3.79 (s, 3H),
3.80-3.77 (m, 2H), 1.41 (d, J = 7.2 Hz, 3H).
N-Allyl-N-(2-allyl-3-allyloxy-4-methoxyphenyl)benzenesulfonamide (7h). Yield 85% (170 mg);
Colorless solid; mp 60-62 C (recrystallized from hexanes and EtOAc); HRMS (ESI, M++1) calcd for
C22H26NO4S 400.1583, found 400.1584; 1H NMR (400 MHz, CDCl3): δ 7.72-7.69 (m, 2H), 7.60-7.56 (m,
1H), 7.50-7.46 (m, 2H), 6.62 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 8.8 Hz, 1H), 6.10-6.02 (m, 1H), 6.01-5.89
(m, 1H), 5.77-5.66 (m, 1H), 5.35 (dq, J = 1.6, 17.2 Hz, 1H), 5.20 (dq, J = 1.6, 10.4 Hz, 1H), 5.00-4.92 (m,
4H), 4.54-4.43 (m, 2H), 4.13 (dd, J = 6.4, 14.4 Hz, 1H), 4.03 (dd, J = 7.2, 14.4 Hz, 1H), 3.80 (s, 3H), 3.44
(dt, J = 1.6, 6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 152.76, 146.85, 139.14, 136.85, 135.57, 134.18,
132.73, 132.56, 130.55, 128.71 (2x), 127.84 (2x), 124.92, 119.10, 116.89, 115.14, 109.43, 73.32, 55.51,
55.02, 30.84; Anal. Calcd for C22H25NO4S: C, 66.14; H, 6.31; N, 3.51. Found: C, 66.35; H, 6.18; N, 3.72.
A representative synthetic procedure of skeleton (8) and compound (9) is as follows: Grubbs 2nd catalyst
(24 mg, 2.83 mmol%) was added to a solution of 7 (0.3 mmol) in CH2Cl2 (10 mL) at rt for 1 h. The
reaction mixture was concentrated and partitioned with EtOAc (3 x 20 mL) and water. The combined
organic layers were washed with brine, dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc=10/1~8/1) afforded 8a~8h and 9.
1-Benzenesulfonyl-6,7-dimethoxy-2,5-dihydro-1H-benzo[b]azepine (8a). Yield 93% (96 mg); Colorless
oil; HRMS (ESI, M++1) calcd for C18H20NO4S 346.1131, found 346.1137; 1H NMR (400 MHz, CDCl3):
δ 7.77-7.74 (m, 2H), 7.57-7.53 (m, 1H), 7.47-7.42 (m, 2H), 7.01 (d, J = 8.8 Hz, 1H), 6.73 (d, J =8 .8 Hz,
1H), 5.67-5.61 (m, 1H), 5.45-5.40 (m, 1H), 4.38-4.36 (br m, 2H), 3.84 (s, 3H), 3.68 (s, 3H), 2.98 (br s,
2H); 13C NMR (100 MHz, CDCl3): δ 152.83, 145.62, 141.47, 135.63, 132.41, 131.81, 128.84 (2x), 126.99

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HETEROCYCLES, Vol. 87, No. 7, 2013
(2x), 126.16, 125.60, 125.24, 109.70, 60.90, 55.72, 49.46, 22.90.
1-Benzenesulfonyl-6-butoxy-7-methoxy-2,5-dihydro-1H-benzo[b]azepine (8b). Yield 84% (98 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C21H26NO4S 388.1583, found 388.1584; 1H NMR (400 MHz,
CDCl3): δ 7.77-7.72 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.41 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 6.71 (d, J =
8.8 Hz, 1H), 5.65-5.59 (m, 1H), 5.44-5.39 (m, 1H), 4.36 (br s, 2H), 3.84 (s, 3H), 3.78 (t, J = 6.4 Hz, 2H),
13
2.94 (br s, 2H), 1.69-1.61 (m, 2H), 1.48-1.39 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H); C NMR (100 MHz,
CDCl3): δ 152.88, 141.46, 135.72, 132.36, 128.97, 128.80 (2x), 126.95 (2x), 126.83, 126.10, 125.36,
125.28, 109.71, 73.27, 55.70, 49.43, 32.06, 23.03, 19.08, 13.78.
1-Benzenesulfonyl-7-methoxy-6-(3-phenylpropoxy)-2,5-dihydro-1H-benzo[b]azepine (8c). Yield 88%
(119 mg); Colorless oil; HRMS (ESI, M++1) calcd for C26H28NO4S 450.1739, found 450.1742; 1H NMR
(400 MHz, CDCl3): δ 7.76-7.74 (m, 2H), 7.55-7.51 (m, 1H), 7.44-7.40 (m, 2H), 7.32-7.26 (m, 2H),
7.22-7.18 (m, 3H), 7.04 (dd, J = 0.8, 8.8 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 5.63-5.58 (m, 1H), 5.44-5.41
(m, 1H), 4.38 (br s, 2H), 3.84 (t, J = 6.4 Hz, 2H), 3.82 (s, 3H), 2.95 (br s, 2H), 2.78 (t, J = 7.6 Hz, 2H),
2.06-1.99 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 152.77, 144.69, 141.61, 141.38, 135.64, 132.36,
131.65, 128.79 (2x), 128.34 (2x), 128.27 (2x), 126.90 (2x), 126.11, 125.78, 125.46, 125.16, 109.66, 72.69,
55.63, 49.39, 32.10, 31.59, 23.04.
1-Benzenesulfonyl-7-methoxy-6-octyloxy-2,5-dihydro-1H-benzo[b]azepine (8d). Yield 90% (120 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C25H34NO4S 444.2209, found 444.2213; 1H NMR (400 MHz,
CDCl3): δ 7.76-7.72 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.41 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.72 (d, J =
8.8 Hz, 1H), 5.66-5.59 (m, 1H), 5.44-5.39 (m, 1H), 4.37 (br s, 2H), 3.82 (s, 3H), 3.77 (t, J = 6.4 Hz, 2H),
13
2.94 (br s, 2H), 1.70-1.63 (m, 2H), 1.41-1.35 (m, 2H), 1.31-1.28 (m, 8H), 0.88 (t, J = 7.2 Hz, 3H); C
NMR (100 MHz, CDCl3): δ 152.86, 144.84, 141.43, 135.69, 132.35, 131.64, 128.80 (2x), 126.93 (2x),
126.08, 125.36, 125.26, 109.65, 73.59, 55.67, 49.42, 31.75, 29.98, 29.28, 29.17, 25.84, 23.02, 22.57,
14.03.
1-Benzenesulfonyl-6-dodecyloxy-7-methoxy-2,5-dihydro-1H-benzo[b]azepine (8e). Yield 88% (132
mg); Colorless oil; HRMS (ESI, M++1) calcd for C29H42NO4S 500.2835, found 500.2839; 1H NMR (400
MHz, CDCl3): δ 7.76-7.72 (m, 2H), 7.57-7.51 (m, 1H), 7.46-7.42 (m, 2H), 7.02 (d, J = 8.8 Hz, 1H), 6.72
(d, J = 8.8 Hz, 1H), 5.65-5.59 (m, 1H), 5.44-5.40 (m, 1H), 4.42 (br s, 2H), 3.83 (s, 3H), 3.77 (t, J = 6.4 Hz,
13
2H), 2.93 (br s, 2H), 1.71-1.60 (m, 2H), 1.41-1.26 (m, 18H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (100
MHz, CDCl3): δ 152.92, 144.92, 141.51, 135.76, 132.39, 131.71, 128.84 (2x), 127.01 (2x), 126.13,
125.43, 125.33, 109.72, 73.67, 55.74, 49.47, 31.89, 30.05, 29.64, 29.60, 29.57, 29.40, 29.33, 25.91, 23.09,
23.09, 22.66, 14.10.
1-Benzenesulfonyl-7,8-dimethoxy-2,5-dihydro-1H-benzo[b]azepine (8f). Yield 80% (83 mg); Colorless
oil; HRMS (ESI, M++1) calcd for C18H20NO4S 346.1113, found 346.1115; 1H NMR (400 MHz, CDCl3):

HETEROCYCLES, Vol. 87, No. 7, 2013
1533
δ 7.76-7.72 (m, 2H), 7.56-7.52 (m, 1H), 7.45-7.43 (m, 2H), 6.77 (s, 1H), 6.49 (s, 1H), 5.62-5.55 (m, 1H),
5.46-5.41 (m, 1H), 4.19 (br s, 2H), 3.82 (s, 3H), 3.77 (s, 3H), 2.75 (br s, 2H); 13C NMR (100 MHz,
CDCl3): δ 148.51, 147.41, 141.34, 133.17, 132.39, 130.58, 128.76 (2x), 127.09 (2x), 125.68, 125.35,
113.33, 111.70, 55.92, 55.84, 48.99, 31.98.
1-Benzenesulfonyl-6,7-dimethoxy-5-methyl-2,5-dihydro-1H-benzo[b]azepine (8g). Yield 82% (88 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C19H22NO4S 360.1270, found 360.1274; 1H NMR (400 MHz,
CDCl3): δ 7.94-7.91 (m, 2H), 7.63-7.54 (m, 3H), 6.70 (d, J = 8.8 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H),
5.91-5.85 (m, 1H), 5.54-5.50 (m, 1H), 4.68 (dd, J = 4.8, 17.2 Hz, 1H), 4.13-4.06 (m, 1H), 3.83 (s, 3H),
3.79 (s, 3H), 3.71 (d, J = 17.2 Hz, 1H), 1.51 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 152.45,
146.07, 142.28, 138.95, 132.54, 132.47, 132.31, 129.20 (2x), 127.05 (2x), 124.70, 122.19, 109.85, 61.07,
55.75, 49.45, 31.12, 21.73.
6-Allyloxy-1-benzenesulfonyl-7-methoxy-2,5-dihydro-1H-benzo[b]azepine (8h). Yield 62% (69 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C20H22NO4S 372.1270, found 372.1277; 1H NMR (400 MHz,
CDCl3): δ 7.76-7.74 (m, 2H), 7.57-7.53 (m, 1H), 7.46-7.42 (m, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.73 (d, J =
8.8 Hz, 1H), 6.02-5.92 (m, 1H), 5.64-5.59 (m, 1H), 5.44-5.40 (m, 1H), 5.28 (dq, J = 1.2, 17.2 Hz, 1H),
5.18 (dq, J = 1.2, 10.4 Hz, 1H), 4.36 (br s, 2H), 4.34 (dt, J = 1.2, 6.0 Hz, 2H), 3.84 (s, 3H), 2.94 (br s,
2H); 13C NMR (100 MHz, CDCl3): δ 152.88, 144.34, 141.51, 135.91, 133.86, 132.40, 131.74, 128.84 (2x),
127.01 (2x), 126.09, 125.73, 125.29, 117.84, 109.70, 74.20, 55.75, 49.45, 23.25.
N-Allyl-N-(9-methoxy-2,5-dihydrobenzo[b]oxepin-6-yl)benzenesulfonamide (9). Yield 30% (33 mg);
Colorless oil; HRMS (ESI, M++1) calcd for C20H22NO4S 372.1270, found 372.1273; 1H NMR (400 MHz,
CDCl3): δ 7.71-7.68 (m, 2H), 7.60-7.56 (m, 1H), 7.50-7.46 (m, 2H), 6.62 (d, J = 8.4 Hz, 1H), 6.38 (d, J =
8.8 Hz, 1H), 5.77-5.67 (m, 2H), 5.41-5.37 (m, 1H), 5.03-4.96 (m, 2H), 4.64-4.53 (m, 2H), 4.26 (ddt, J =
13
1.2, 6.0, 14.0 Hz, 1H), 3.88 (dd, J = 7.2, 14.0 Hz, 1H), 3.83 (s, 3H), 3.48-3.45 (m, 2H); C NMR (100
MHz, CDCl3): δ 152.30, 147.19, 140.56, 139.17, 132.56, 132.44, 128.83 (2x), 128.57, 127.71 (2x),
127.20, 125.45, 124.92, 119.27, 109.42, 70.37, 55.76, 55.09, 25.44.
ACKNOWLEDGEMENTS
The authors would like to thank the National Science Council of the Republic of China for its financial
support.
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SUPPLEMENTARY MATERIAL
Scanned photocopies of 1H and 13C NMR spectral data were supported.