Preparation of a 1-unsubstituted-2,3-dihydro-1-benzazepine derivative

Article abstract of DOI:10.3987/COM-07-11025

We developed a three-step method of producing a 1-unsubstituted-2,3-dihydro-1-benzazepine derivative (2) from 11. The alkylation of 9, obtained from 11, and the subsequent intramolecular condensation of 12 in dialkyl carbonate with a metal alcoholate were

Full text of DOI:10.3987/COM-07-11025

HETEROCYCLES, Vol. 71, No. 5, 2007
1183
HETEROCYCLES, Vol. 71, No. 5, 2007, pp. 1183 - 1192. © The Japan Institute of Heterocyclic Chemistry
Received, 8th February, 2007, Accepted, 8th March, 2007, Published online, 9th March, 2007. COM-07-11025
PREPARATION OF A 1-UNSUBSTITUTED-2,3-DIHYDRO-1-
BENZAZEPINE DERIVATIVE
Atsuko Nishiguchi,* Tomomi Ikemoto, Tatsuya Ito, Shotaro Miura, and
Kiminori Tomimatsu
Chemical Development Laboratories, Takeda Pharmaceutical Company Limited,
2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan, E-mail:
Nishiguchi_Atsuko@takeda.co.jp
Abstract
–
We developed
a
three-step method of producing
a
1-unsubstituted-2,3-dihydro-1-benzazepine derivative (2) from 11. The alkylation
of 9, obtained from 11, and the subsequent intramolecular condensation of 12 in
dialkyl carbonate with a metal alcoholate were conducted in one pot to afford
1-benzazepine (13) in good yield. 13 was then hydrolyzed to give 2 in 48%
overall yield from 11. Furthermore, we synthesized the orally active CCR5
antagonist intermediate 18 from 2.
INTRODUCTION
In order to develop orally active CC chemokine receptor (CCR5) antagonists, medium ring heterocycles
were investigated by Baba and Shiraishi et al.,1 and a 2,3-dihydro-1-benzazepine system (Figure 1, A)
was selected as one of the scaffolds. The intermediate (1) was utilized for the preparation of various
derivatives (Figure 1).
H
N
1: R1=OMe, R2=Br
2: R1=OH, R2=Br
N
R2
COR1
O
A
Figure 1
In their research,1f the intermediate (1) was prepared through a ketone (4) in good quality, however, there
were several drawbacks to large scale production as follows (Scheme 1); 1) The preparation of 1 was a
multistep process and the yield was considerably low (9 steps, 7% yield), 2) the process was inefficient
owing to the application of two protective groups (tosyl and Boc groups), and 3) chromatographic

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HETEROCYCLES, Vol. 71, No. 5, 2007
purification unsuitable for mass-production was needed. Therefore, we focused on the facile preparation
of 1 or its equivalent compound (2).
1) Boc2O
2) (MeO)2CO
1) TsCl
2) Br(CH2)3CO2Et
3) H2SO4
3) NaBH4
4) MsCl
5) DBU
H
Boc
N
N
NH2
HCl
1
Br
Br
CO2Me
Br
O
4
CO2Me
3
5
Scheme 1
RESULTS AND DISCUSSION
During our investigation of intramolecular Claisen-type condensation, we had already found that the
reaction using metal alcoholate in dialkyl carbonate was effective at producing
a
2,3-dihydro-1-benzazepines in high yield.2 However, all of the benzazepines obtained were N-alkylated.
Hence, we planned to synthesize N-unsubstituted benzazepines via intramolecular cyclization of
N-tosylated o-formylanilinobutyrates.
TsCl
NH2
OH
NHTs
OH
NHTs
CHO
Ts
N
CO2R4
pyridine
MnO2
80%
95%
Br
CHO
6
7
8
12
12a: R4=Me; 89%
12b: R4=Et; 89%
path A
NaOR4, (R4O)2CO
13a: R4=Me; 71%
13b: R4=Et; 73%
Ts
Br(CH2)3CO2R4
Br2, AcONa
AcOH
K2CO3
93%
N
F
NHTs
TsNH2, K2CO3
1) Br(CH ) CO R4
CHO
Br
Br
CHO
Br
2 3
2
86%
CO2R4
11
9
13
K2CO3
2) NaOR4
(R4O)2CO
path C
Red-Al
morphorine
50%
13a: R4=Me; 63%
13b: R4=Et; 54%
NH2
TsCl, pyridine
NHTs
Br
CO2Me
Br
CO2Me
87%
3
10
path B
Scheme 2
To establish an efficient synthetic route, we attempted to prepare an intermediate (9) from three different
materials as follows (Scheme 2, paths A, B and C). First of all, amino alcohol (6) as a starting material
was treated with TsCl and pyridine3 followed by MnO2 to give aldehyde (8). The intermediate (9) was
obtained after bromination of 8 using Br2 and AcONa in acetic acid in 70% yield from 6 (path A).

HETEROCYCLES, Vol. 71, No. 5, 2007
1185
In path B,4 o-anilinobenzoate (3) was subjected to tosylation followed by Red-Al reduction at –10 ℃ to
produce 9 in 50% yield, while the reduction of ester (10) with 2 equivalents of DIBAL-H at –78 ℃ gave
a mixture of 9 and the corresponding alcohol.
In path C, formylphenylfluoride (11) could be efficiently converted to 9 using TsNH2 and K2CO3 in
DMSO in 86% yield. Therefore, path C was favorable as a shorter, high-yielding process.
The alkylation of 9 with alkyl 4-bromobutyrate and K2CO3 in DMF gave 12 in excellent yield. The
intramolecular condensation of 12 proceeded smoothly in the presence of sodium alcoholate in dialkyl
carbonate to give 13 in good yield. Moreover, these two-step reactions, alkylation of 9 and the subsequent
intramolecular condensation, could be performed in one-pot to give 13.5
Table 1. Deprotection of 13a
Ts
N
H
N
Ts
N
H
N
Br
Br
Br
Br
CO2Me
CO2H
CO2H
CO2Me
13a
2
14
15
Ratio of Productsa
Entry
Acids (v/w)
Temp.
13
14
15
2
Yield
(%)
(°C)
90
1
2
3
4
5
conc. HCl (3), AcOH (5)
60% HClO4 (3), AcOH (5)
MsOH (2), AcOH (5),
8
1
5
-
81
63
48
1
-
8
100
90
1
1
6
3
34
41
81
91
conc. H2SO4 (5), AcOH (10),
90
conc. H2SO4 (2) / H2O (0.2), AcOH (4) 90
-
-
88
a HPLC area % (measured at 254 nm).
The deprotection of 13 by several kinds of acids was examined (Table 1). The treatment of 13 with conc.
HCl in acetic acid mainly afforded carboxylic acid (14) since the ester moiety was predominantly
hydrolyzed (entry 1). The reaction using HClO4 or MsOH did not proceed completely to give the mixture
of 2 and 14 (entries 2, 3). The conc. H2SO4 and H2O in acetic acid could lead to smooth detosylation of
13 to give 2 in high yield (entries 4, 5).7 The desired acid 2 was isolated easily by crystallization from the
reaction mixture in 88% yield.
The preparation of the CCR5 antagonist intermediate (18) from 2 was subsequently investigated (Scheme
3). Carboxylic acid (16) was afforded in 84% yield by acetylation of 2 with AcCl and pyridine.
Suzuki-Miyaura coupling of 16 and boronic acid (17) with a catalytic amount of Pd(PPh3)4 in EtOH
provided 18 in 87% yield.

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HETEROCYCLES, Vol. 71, No. 5, 2007
B(OH)2
Ac
N
Ac
N
N
AcCl, py
17
O
2
CO2H
Br
Pd(PPH3)4
N
CO2H
16
18
O
Scheme 3
In conclusion, we accomplished the effective synthesis of 2 by intramolecular Claisen-type condensation
that was performed with sodium alcoholate in alkyl dicarbonate. Three different approaches were
undertaken, and the desired product (2) was synthesized in only three steps via the most efficient path C
without any chromatographic purification. In addition, a CCR5 antagonist intermediate (18) was obtained
from 2 in good yield.
EXPERIMENTAL
General
Melting points were recorded on a Yanagimoto micro melting apparatus and were uncorrected. IR spectra
1
13
were recorded on a Horiba FT-210 spectrophotometer. H and C NMR spectra were recorded on a
1
Brüker DPX-300. H NMR spectra are reported as follows: chemical shifts in ppm (δ) downfield from
tetramethylsilane as an internal standard, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; br, broad
13
and m, multiplet), coupling constants spectra (Hz) and integration. C NMR spectra were recorded in
ppm (δ) relative to the central line for CDCl3 at 77 ppm and DMSO-d6 at 39.7 ppm. Column
chromatography was performed with a Wakogel C-200 (75-150mm). Elemental analyses and mass
spectra were carried out by Takeda Analytical Research Laboratories Limited.
[path A]
N-[2-(Hydroxymethyl)phenyl]-4-methylbenzensulfonamide (7)
To a solution of 2-aminobenzyl alcohol (6) (30.0 g, 244 mmol) and pyridine (39.4 mL, 488 mmol) in
THF (150 mL) was added a solution of TsCl (46.4 g, 244 mmol) in THF (150 mL) below 10 °C, and the
mixture was stirred for 1.5 h at rt. It was then quenched with water and extracted with AcOEt. The
organic solution was washed with 2M HCl and brine. The solution was dried over Na2SO4, concentrated,
and triturated with diisopropyl ether for 0.5 h at rt to give 7 (64.5 g, 95%) as a white solid. Mp
148-150 °C. Anal. Calcd for C14H15NO3S: C, 60.41; H, 5.55; N, 4.95. Found: C, 60.41; H, 5.55; N, 4.95.
1H NMR (300 MHz, CDCl3): δ = 1.61 (1H, brs), 2.38 (3H, s), 4.40 (2H, s), 7.00-7.09 (2H, m), 7.20-7.28
(4H, m), 7.43 (1H, d, J = 8.0 Hz), 7.65 (2H, d, J = 8.3 Hz). IR (KBr, cm-1): 3438, 3072, 1457, 1317, 1153,
1091, 1031, 717, 563.

HETEROCYCLES, Vol. 71, No. 5, 2007
1187
N-(2-(Formylphenyl)-4-methylbenzensulfonamide (8)
To a solution of 7 (20.0 g, 72.1 mmol) in acetone (300 mL) was added activated MnO2 (36.4 g, 418.3
mmol), and the mixture was stirred for 15 h at rt. The solid was filtered off and washed with acetone, and
the combined mother solution was concentrated. The resulting residue was triturated with diisopropyl
ether and filtrated to give 8 (15.8 g, 80%) as a pale yellow solid. Mp 136-137 °C. Anal. Calcd for
C14H13NO3S: C, 61.07; H, 4.76; N, 5.09. Found: C, 60.88; H, 4.70; N, 4.93. 1H NMR (300 MHz, CDCl3,):
δ = 2.36 (3H, s), 7.12-7.26 (3H, m), 7.47-7.52 (1H, m), 7.58 (1H, d, J = 6.0 Hz), 7.67 (1H, d, J = 9.0 Hz),
7.77 (2H, d, J = 6.0 Hz), 9.82 (1H, s), 10.76 (1H, brs). IR (KBr, cm-1): 1673, 1494, 1409, 1340, 1157,
1087, 929, 840, 759, 565.
N-(4-Bromo-2-formylphenyl)-4-methybenzenesulfonamide (9) from 8
To a mixture of 8 (1.0 g, 3.63 mmol) and AcONa (0.33 g, 4.00 mmol) in 90% aq. AcOH (10 mL) was
added Br2 (0.22 mL, 4.36 mmol), and the mixture was stirred for 2 h at rt. Subsequently, Br2 (0.44 mL,
8.72 mmol) was added and the mixture was again stirred for 2 h. To the reaction mixture was added 0.5M
Na2S2O3 (10 mL), and the stirring was continued for 0.5 h. The resulting solid was filtrated and washed
with water to give 9 (1.2 g, 93%) as a pale yellow solid. Mp 130-131 °C. Anal. Calcd for C14H12NO3BrS:
C, 47.47; H, 3.41; N, 3.95. Found: C, 47.77; H, 3.45; N, 3.89. 1H NMR (300 MHz, CDCl3): δ = 2.38 (3H,
s), 7.26 (2H, d, J = 9.0 Hz), 7.57-7.71 (3H, m), 7.76 (2H, d, J = 9.0 Hz), 9.76 (1H, s), 10.65 (1H, s). IR
(KBr, cm-1): 1679, 1479, 1186, 1162.
[path B]
Methyl 5-bromo-2-{[(4-methylphenylsulfonyl)amino]benzoate (10)
To a solution of methyl 5-bromo-2-aminobenzoate (3) (200 g, 869 mmol) in pyridine (600 mL) was
added TsCl (174 g, 913 mmol), and the mixture was stirred for 3 h at rt. It was then quenched with water
and extracted with AcOEt. The organic solution was washed with 2M HCl, brine, and water. The solution
was concentrated and triturated with diisopropyl ether to give 10 (291 g, 87%) as a pale yellow solid. Mp
122-123 °C. Anal. Calcd for C15H14NO4BrS: C, 46.89; H, 3.67; N, 3.65. Found: C, 46.88; H, 3.54; N,
3.60. 1H NMR (300 MHz, CDCl3): δ = 2.37 (3H, s), 3.88 (3H, s), 7.23 (2H, d, J = 8.2 Hz), 7.53 (1H, dd, J
= 8.9, 2.3 Hz), 7.61 (1H, d, J = 8.9 Hz), 7.72 (2H, d, J = 8.2 Hz), 8.03 (1H, d, J = 2.3 Hz), 10.50 (1H, s).
IR (KBr, cm-1): 1698, 1479, 1434, 1394, 1340, 1305, 1247, 1157, 1087.
9 from 10
To a solution of Red-Al® (37.5 g, 130 mmol) in toluene (35 mL) was added a solution of morpholine
(12.5 mL, 143 mmol) in toluene (25 mL) at 0-5 oC under an argon atmosphere. This Red-Al®–morpholine
solution was added to a solution of 10 (5.0 g, 13.0 mmol) in toluene (50 mL) at –10 °C, and the mixture
was stirred for 2 h. After 20% sulfuric acid (500 mL) was added, the reaction mixture was extracted with

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HETEROCYCLES, Vol. 71, No. 5, 2007
AcOEt. The organic solution was washed with water, concentrated, and purified by silica-gel
chromatography (toluene) to give 9 (2.3 g, 50%).
[path C]
9 from 11
To a suspension of p-tosylamide (1.7 g, 10.0 mmol) and K2CO3 (1.4 g, 10.0 mmol) in 50% aq. DMSO (10
mL) was added 11 (1.0 g, 5.0 mmol), and the mixture was stirred for 1 h at 130 °C. To the reaction
mixture was added 2M HCl (7.5 mL), and the stirring was continued for 1 h at the same temperature. The
mixture was cooled to rt, and stirred for 3 h. The resulting solid was filtrated and washed with water to
give 9 (1.5 g, 86%).
Ethyl 4-{(4-bromo-2-formylphenyl)[(4-methylphenyl)sulfonyl]amino}butanoate (12b)
To a solution of 9 (3.0 g, 8.47 mmol) and ethyl 4-bromobutyrate (1.82 mL, 12.7 mmol) in DMF (9 mL)
was added K2CO3 (1.7 g, 12.7 mmol), and the mixture was stirred for 4 h at 70 °C. It was then quenched
with 2M HCl and extracted with AcOEt. The organic solution was washed with brine and water. The
solution was dried over Na2SO4 and concentrated. The resulting solid was triturated with diisopropyl
ether for 1 h at rt to give 12b (3.5 g, 89%) as a white solid. Mp 99-100 °C. Anal. Calcd for
1
C20H22NO5BrS: C, 51.29; H, 4.73; N, 2.99. Found: C, 51.29; H, 4.70; N, 2.90. H NMR (300 MHz,
CDCl3): δ = 1.22 (3H, t, J = 7.1 Hz), 1.72-1.82 (2H, m), 2.35 (2H, t, J = 7.1 Hz), 2.44 (3H, s), 3.30-3.40
(1H, m), 3.8-3.95 (1H, m), 4.09 (2H, q, J = 7.1 Hz), 6.60 (1H, d, J = 8.5 Hz), 7.27 (1H, d, J = 2.6 Hz),
7.30 (1H, s), 7.42-7.45 (2H, m), 7.56-7.61 (1H, m), 8.14 (1H, d, J = 2.4 Hz), 10.36 (1H, s). IR (KBr,
cm-1): 1740, 1684, 1596.
Methyl 4-{(4-bromo-2-formylphenyl)[(4-methylphenyl)sulfonyl]amino}butanoate (12a)
Using a similar procedure above (preparation of 12b). Yield 89%. Mp 137-138 °C. Anal. Calcd for
1
C19H20NO5BrS: C, 50.23; H, 4.44; N, 3.08. Found: C, 50.22; H, 4.47; N, 3.04. H NMR (300 MHz,
CDCl3): δ = 1.67-1.82 (2H, m), 2.34-2.38 (2H, m), 2.44 (3H, s), 3.31-3.45 (1H, m), 3.63 (3H, s),
3.82-3.91 (1H, m), 6.60 (1H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.58 (1H,
dd, J = 8.5, 2.4 Hz), 8.12 (1H, d, J = 2.4 Hz), 10.34 (1H, s). IR (KBr, cm-1): 1743, 1683, 1597.
Ethyl 7-bromo-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (13b)
from 12b
To a solution of 12b (1.00 g, 2.14 mmol) in diethyl carbonate (20 mL) was added NaOEt (20% EtOH
solution, 0.87 g, 2.56 mmol), and the mixture was stirred for 3 h at rt. It was then neutralized with 2M
HCl and extracted with AcOEt. The organic solution was washed with brine, dried over Na2SO4, and
concentrated. The resulting residue was crystallized from 2-PrOH and filtrated to give 13b (0.70 g, 73%)

HETEROCYCLES, Vol. 71, No. 5, 2007
1189
as a pale yellow crystal. Mp 109-110 °C (2-PrOH). Anal. Calcd for C20H20NO4BrS: C, 53.34; H, 4.48; N,
3.11. Found: C, 53.18; H, 4.45; N, 3.00. 1H NMR (300 MHz, CDCl3): δ = 1.29 (3H, t, J = 7.0 Hz), 2.35
(3H, s), 2.86 (2H, t, J = 5.7 Hz), 3.86 (2H, t, J = 5.7 Hz), 4.18 (2H, q, J = 7.0 Hz), 7.13 (2H, d, J = 8.0
Hz), 7.18 (1H, s), 7.41 (2H, d, J = 8.0 Hz), 7.44-7.53 (3H, m). IR (KBr, cm-1): 1714, 1348, 1243, 1162,
1087.
Methyl 7-bromo-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (13a)
from 12a
Compound 13a was prepared from 12a and NaOMe in dimethylcarbonate using a similar procedure to
above (preparation of 13b). A pale yellow solid. Yield 71%. Mp 138-139 °C (iPr2O). Anal. Calcd for
1
C19H18NO4BrS: C, 52.30; H, 4.16; N, 3.21. Found: C, 52.14; H, 4.21; N, 3.12. H NMR (300 MHz,
CDCl3); δ = 2.38 (3H, s), 2.84-2.88 (2H, m), 3.73 (3H, s), 3.84-3.88 (2H, m), 7.12-7.26 (3H, m),
7.42-7.53 (5H, m). IR (KBr, cm-1): 1708, 1629, 1433.
13a from 9 (one-pot reaction)
To a solution of 9 (1.00 g, 2.82 mmol) and methyl 4-bromobutyrate (0.77 g, 4.23 mmol) in DMF (3 mL)
was added K2CO3 (0.58 g, 4.23 mmol), and the mixture was stirred for 4 h at 90 °C. It was then cooled to
rt. Dimethyl carbonate (20 mL) and NaOMe (28% MeOH solution, 1.09 g, 5.65 mmol) were added and
the reaction mixture was stirred for 3 h at rt. It was neutralized with 2M HCl and extracted with AcOEt.
The organic solution was washed with brine, dried over Na2SO4, and concentrated. The resulting residue
was crystallized from diisopropyl ether and filtrated to give 13a (0.78 g, 63%).
13b from 9 (one-pot reaction)
Compound (13b) was prepared from 9 and methyl 4-bromobutyrate using a similar procedure to above
(preparation of 13a). Yield 54%.
7-Bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (2) from 13b
To a suspension of 13b (1.0 g, 2.22 mmol) in AcOH (4 mL) was added conc. H2SO4 (2 mL), and the
mixture was stirred for 2 h at 90 °C. Subsequently, water (0.2 mL) was added and the reaction mixture
was stirred for 6 h. It was then concentrated, 10% aqueous NaOH (32 mL) and water (10 mL) were added.
The resulting solid was filtered off and washed with water. The combined mother solution was adjusted
to pH 3.0-3.5 with 2M HCl. The solid was filtrated to give 2 (0.5 g, 86%) as a pale yellow solid. Mp
213-214°C. Anal. Calcd for C11H10NO2Br: C, 49.28; H, 3.76; N, 5.22. Found: C, 49.24; H, 3.76; N, 5.20.
1H NMR (300 MHz, DMSO-d6): δ = 2.69 (2H, t, J = 4.3Hz), 3.20 (2H, t, J = 4.3Hz), 6.67 (1H, d, J =
8.7Hz), 6.92 (1H, brs), 7.16 (1H, dd, J = 8.7, 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.45 (1H, s). IR (KBr,
cm-1); 1660, 1282, 1180.

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HETEROCYCLES, Vol. 71, No. 5, 2007
In addition, 2 was prepared from 13a using a similar procedure to above (preparation of 2 from 13b).
Yield 88%.
1-Acetyl-7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (16)
To a solution of 2 (4.0 g, 15.0 mmol) and pyridine (5.9 g, 75.0 mmol) in N-methylpyrrolidone (32 mL)
was added AcCl (3.2 mL, 45.0 mmol) at 5-10 °C, and the mixture was stirred for 0.5 h at rt. After 6M
HCl (16 mL) was added to the reaction mixture at 25-35 °C, the solution was extracted with toluene. The
organic solution was washed with water and extracted with 1M NaOH. The aqueous solution was
adjusted to pH 1-2 with 6M HCl. The resulting solid was filtrated to give 16 (3.9 g, 84%) as a pale yellow
solid. Mp 200-201 °C. Anal. Calcd for C13H12NO3Br: C, 50.34; H, 3.90; N, 4.52. Found: C, 50.38; H;
1
3.85, N, 4.49. H NMR (300 MHz, DMSO-d6): δ = 1.92 (3H, s), 2.73 (3H, m), 4.51 (1H, m), 7.28-7.30
(1H, m), 7.56-7.58 (2H, m), 7.84-7.87 (1H, m). IR (KBr, cm-1): 3467, 3436, 1656, 1621, 1294.
1-Acetyl-7-(4-morpholin-4-ylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (18)1f
To a suspension of 16 (250 mg, 0.81 mmol), 17 (250 mg, 1.21 mmol), K2CO3 (334 mg, 2.42 mmol) in
water (1 mL), EtOH (1 mL) and toluene (4 mL) was added Pd(PPh3)4 (47 mg, 0.04 mmol) under an
atmosphere of argon, and the mixture was refluxed for 1.5 h. It was then cooled to rt and extracted with
1M NaOH. The aqueous solution was adjusted to pH 2.8 with 6M HCl and extracted with AcOEt. To the
organic solution were added Na2SO4 and activated charcoal, and the mixture was stirred for 10 min. The
solid was filtered off and washed with AcOEt. The combined mother solution was concentrated, and
crystallized from MeOH. The resulting solid was filtrated to give 18 (276 mg, 87%) as a pale yellow solid.
Mp 263-264 °C (MeOH). Anal. Calcd for C23H24N2O2•0.2 H2O: C, 70.39; H, 6.16; N, 7.14. Found: C,
1
69.75; H, 6.21; N, 7.07. H NMR (DMSO-d6): δ = 1.95 (3H, s), 2.75 (3H, m), 3.14-3.19 (4H, m),
3.73-3.76 (4H, m), 4.56 (1H, m), 7.01 (2H, d, J = 8.7 Hz), 7.44 (1H, d, J = 8.2 Hz), 7.62-7.65 (3H, m),
7.74 (1H, s), 7.87 (1H, s). IR (KBr, cm-1): 3388, 1704, 1623, 1606, 1492, 1228, 1216.
ACKNOWLEDGEMENTS
We would like to thank Mr. Kokichi Yoshida, Mr. Yuzuru Saito, and Dr. Shokyo Miki for their
encouragement throughout this work.
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HETEROCYCLES, Vol. 71, No. 5, 2007
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and S. Hashiguchi, Chem. Pharm. Bull., 2004, 52, 63. d) Y. Aramaki, M. Seto, T. Okawa, T. Oda, N.
Kanzaki, and M. Shiraishi, Chem. Pharm. Bull., 2004, 52, 254. e) M. Seto, Y. Aramaki, T. Okawa,
N. Miyamoto, K. Aikawa, N. Kanzaki, S. Niwa, Y. Iizawa, M. Baba, and M. Shiraishi, Chem.
Pharm. Bull., 2004, 52, 818. f) M. Seto, Y. Aramaki, T. Okawa, N. Miyamoto, K. Aikawa, N.
Kanzaki, S. Niwa, Y. Iizawa, M. Baba, and M. Shiraishi, Chem. Pharm. Bull., 2004, 52, 577. g) M.
Seto, N. Miyamoto, K. Aikawa, Y. Aramaki, N. Kanzaki, Y. Iizawa, M. Baba, and M. Shiraishi,
Bioorg. Med. Chem., 2005, 13, 363.
2. a) T. Ikemoto, T. Ito, A. Nishiguchi, and K. Tomimatsu, Tetrahedron Lett., 2004, 45, 9335. b) T.
Ikemoto, T. Ito, A. Nishiguchi, S. Miura, and K. Tomimatsu, Org. Process Res. Dev., 2005, 9, 168.
3. In the early stages of this work, the alkylation of Boc-protected (5) or pivaloyl-protected (5) did not
proceed completely. Thus, we chose the tosyl group for N-protection in this series.
4. a) R. Kanazawa and T. Tokoroyama, Synthesis, 1976, 526. b) M. Muraki and T. Mukaiyama, Chem.
Lett., 1975, 875. c) T. Abe, T. Haga, S. Negi, Y. Morita, K. Takayanagi, and K. Hamamura,
Tetrahedron, 2001, 57, 2701.
5. This reaction condition was also effective for the intramolecular condensation of the diester (19) that
was afforded by the alkylation of 10 with methyl 4-bromobutyrate and K2CO3 in 92% yield. The
cyclization of 19 under the typical conditions of Dieckmann condensation, using tBuOK in tBuOH at
50 ℃, afforded 20 in only 54% yield.6 In contrast, our method using the combination of NaOMe
and dimethyl carbonate gave a drastically increased yield, 91%. The reduction of 20 followed by a
one-pot reaction consisting of mesylation and β-elimination gave 13 in 56% yield. (Although the
reduction of 20 by NaBH4 provided the corresponding alcohol accompanied by an overreduced diol,
the crude mixture was subjected to the next reaction without any purification.)
Ts
Ts
N
N
CO2Me
10
13
1) NaBH4
CO2Me 2) MsCl
pyridine
Br
CO2Me
NaOMe
(MeO)2CO
95%
Br
Br(CH2)3CO2Me
K2CO3
19
HO
20
92%
3) DBU
56%
Methyl 5-bromo-2-{(4-methoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino}benzoate (19)
To a solution of 10 (30.0 g, 78.1 mmol) and methyl 4-bromobutyrate (17.0 g, 93.7 mmol) in DMF
(120 mL) was added K2CO3 (21.6 g, 156.2 mmol), and the mixture was stirred for 8 h at 90 °C. It
was then quenched with water and extracted with AcOEt. The organic solution was washed with
brine and water, and concentrated. The resulting solid was triturated with diisopropyl ether for 2 h

1192
HETEROCYCLES, Vol. 71, No. 5, 2007
at rt to give 19 (34.9 g, 92%) as a white solid. Mp 100-101 °C. Anal. Calcd for C20H22NO6BrS: C,
1
49.59; H, 4.58; N, 2.89. Found: C, 49.56; H, 4.57; N, 2.82. H NMR (300 MHz, CDCl3): δ =
1.86-1.90 (2H, m), 2.41 (3H, s), 2.41-2.48 (2H, m), 3.40-3.80 (2H, m), 3.64 (3H, s), 3.83 (3H, s),
6.76 (1H, d, J = 8.5 Hz), 7.23-7.26 (2H, m), 7.43-7.46 (2H, m), 7.53 (1H, dd, J = 8.5, 2.4 Hz), 7.99
(1H, d, J = 2.4 Hz). IR (KBr, cm-1): 1736, 1722, 1351.
Methyl 7-bromo-5-hydroxy-1-[(4-methylphenyl)sulfonyl]-2,3-dihydro-1H-1-benzazepine-4-
carboxylate (20)
To a solution of 19 (30.0 g, 61.9 mmol) in dimethyl carbonate (300 mL) was added NaOMe (28%
MeOH solution, 9.2 g, 170.2 mmol), and the mixture was stirred for 2 h at 70 °C. It was then
neutralized with 2M HCl and extracted with AcOEt. The organic solution was washed with brine
and water, and concentrated. The resulting residue was crystallized from MeOH and filtrated to
give 20 (26.5 g, 95%) as a white crystal. Mp 137-138 °C (MeOH). Anal. Calcd for C19H18NO5BrS:
C, 50.45; H, 4.01; N, 3.10. Found: C, 50.45; H, 4.02; N, 3.01. 1H NMR (300 MHz, CDCl3): δ = 2.28
(2H, t, J = 6.3 Hz), 2.40 (3H, s), 3.72 (3H, s), 4.07 (2H, t, J = 6.3 Hz), 7.15-7.18 (2H, m), 7.36-7.45
(3H, m), 7.60-7.64 (2H, m), 11.8 (1H, s). IR (KBr, cm-1): 1619, 1581, 1481.
13a from 20
To a solution of 20 (20.0 g, 44.2 mmol) in THF (200 mL) and water (20 mL) was added NaBH4 (3.3
g, 88.4 mmol) at –10 to –5 °C, and the mixture was stirred for 2 h. It was then neutralized with 2M
HCl and extracted with AcOEt. The organic solution was washed with brine, saturated aqueous
NaHCO3, and water, and concentrated. The resulting residue was dissolved with THF (200 mL),
and NEt3 (24.6 mL, 170.8 mmol) was added. To the solution was added MsCl (6.8 mL, 88.4 mmol)
in an ice bath, and the mixture was stirred for 2 h at rt. Subsequently, DBU (33.5 mL, 221.0 mL)
was added, and stirred for 1 h. It was then quenched with water and extracted with AcOEt. The
organic solution was washed with brine, dried over MgSO4, and concentrated. The resulting residue
was crystallized from MeOH and filtrated to give 13a (10.8 g, 56%, based on 20).
6. M. Lennon, A. McLean, I. McWatt, and G. R. Proctor, J. Chem. Soc., Perkin Trans. 1, 1974, 1828.
7. a) G. R. McCall, G. R. Proctor, and L. Purdie, J. Chem. Soc. (C)., 1970, 1126. b) A. Cromarty, G. R.
Proctor, and M. Shabbir, J. Chem. Soc., Perkin Trans. 1, 1972, 2012.