Short synthesis of 5-substituted-2,3,4,5-Tetrahydro-Benzo[f][1,4] Thiazepines by using a modified pictet-spengler reaction

Article abstract of DOI:10.3987/COM-17-13705

5-Substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6) were synthesized using a modified Pictet-Spengler reaction of N-formyliminium ion (4) as the key step. The cyclization of 4 was found to be affected by the acidity of the reaction media, which depended on the structure of the benzene ring. The cyclization of the substrates (4a-g) lacking an electron-donating substituent at the benzene ring proceeded smoothly by using a mixed acid catalyst of trifluoroacetic acid and a small amount of trifluoromethanesulfonic acid, thus giving N-formylbenzothiazepines (5a-g) in good yields. On the other hand, in the case of substrates (4h-j) with the OMe group at the benzene ring, although the cyclization proceeded by use of trifluoroacetic acid as the sole catalyst to give the products (5h-j), the mixed acid catalyst did not induce the cyclization reaction to any extent. The modified Pictet-Spengler reaction, which constitutes imination of 2-(phenylthio)ethanamine (1a) with aldehydes (2), and formylation of the resulting imines (3), followed by the acid-catalyzed cyclization of N-formyliminium ion (4), could be carried out as a one-pot procedure, thus providing a convenient methodology for synthesizing various 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6).

Full text of DOI:10.3987/COM-17-13705

HETEROCYCLES, Vol. 94, No. 6, 2017
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HETEROCYCLES, Vol. 94, No. 6, 2017, pp. 1063 - 1073. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 31st March, 2017, Accepted, 24th April, 2017, Published online, 8th May, 2017
DOI: 10.3987/COM-17-13705
SHORT SYNTHESIS OF 5-SUBSTITUTED-2,3,4,5-TETRAHYDRO-
BENZO[f][1,4]THIAZEPINES BY USING
A
MODIFIED PICTET-
SPENGLER REACTION
Toshiaki Saitoh,1 Michikazu Kitabatake,2,3 Yuuko Sugihara,2 Yuuki Ono,2
Yoshie Horiguchi,2 and Kunihiko Mohri2,*
1
Nihon Pharmaceutical University, 10281 Komuro, Inamachi, Kitaadachi-gun,
Saitama 362-0806, Japan
2 Showa Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Machida,
Tokyo 194-0042, Japan: E-mail: mohri@ac.shoyaku.ac.jp
3 Permachem Asia LTD, 1500-18 Misawa, Kikugawa, Shizuoka 439-0023, Japan
Abstract – 5-Substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6) were
synthesized using a modified Pictet-Spengler reaction of N-formyliminium ion (4)
as the key step. The cyclization of 4 was found to be affected by the acidity of the
reaction media, which depended on the structure of the benzene ring. The
cyclization of the substrates (4a-g) lacking an electron-donating substituent at the
benzene ring proceeded smoothly by using a mixed acid catalyst of trifluoroacetic
acid and a small amount of trifluoromethanesulfonic acid, thus giving
N-formylbenzothiazepines (5a-g) in good yields. On the other hand, in the case of
substrates (4h-j) with the OMe group at the benzene ring, although the cyclization
proceeded by use of trifluoroacetic acid as the sole catalyst to give the products
(5h-j), the mixed acid catalyst did not induce the cyclization reaction to any extent.
The modified Pictet-Spengler reaction, which constitutes imination of
2-(phenylthio)ethanamine (1a) with aldehydes (2), and formylation of the
resulting imines (3), followed by the acid-catalyzed cyclization of
N-formyliminium ion (4), could be carried out as a one-pot procedure, thus
providing
a
convenient
methodology
for
synthesizing
various
5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6).

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HETEROCYCLES, Vol. 94, No. 6, 2017
INTRODUCTION
The Pictet-Spengler reaction is one of the key reactions for synthesizing 1,2,3,4-tetrahydroisoquinoline
and heteroaryl homologs, which constitute an important class of naturally occurring bioactive substances.1
The reaction involves an acid-catalyzed cyclization of the intermediate imine formed by condensation of
an arylethylamine with an aldehyde. We recently improved this key cyclization reaction by substituting
N-formyliminium ion for the imine. This modified Pictet-Spengler reaction provides a highly efficient and
convenient method for synthesizing 1-substituted and 1,1-disubstituted-1,2,3,4-tetrahydroisoquinolines,2,3
1-substituted and 1,1-disubstituted-1,2,3,4-tetrahydro-β-carbolines,4,5 1-substituted-2,3-dihydro-1H-
isoindoles (isoindolines),6 4-substituted and 4,4-disubstituted-4,5,6,7-tetrahydrothieno[3,2-c]pyridines,7
and 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepines.8 In the synthesis of these compounds, the
N-formyliminium ion, as anticipated, exhibits stronger electrophilic properties than the imine. Thus, the
modified Pictet-Spengler reaction proceeds under mild acidic conditions, even with substrates in which
the aromatic ring lacks electron-donating groups and with sterically congested substrates derived from
ketones. Furthermore, we have demonstrated that this reaction can be applied to construct not only a
six-membered ring system but also five- and seven-membered ones.
In this report, we describe the synthesis of 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines using
the modified Pictet-Spengler reaction. Although several methods have previously been reported for the
synthesis of benzothiazepines,9-12 this approach to constructing the benzothiazepine ring system using the
Pictet-Spengler reaction is hitherto unknown. Development of this new method for the synthesis of
benzothiazepines should contribute not only to heterocyclic chemistry but also to pharmacology.
RESULTS AND DISCUSSION
The substrate for the modified Pictet-Spengler reaction, the N-formyliminium ion (4), was prepared in a
one-pot procedure as follows (Scheme 1).
The condensation reaction of 2-(phenylthio)ethanamine (1a) (1.0 mol equiv) and aldehyde (2) (1.3 mol
equiv) to form imine (3) was carried out by heating in titanium(IV) tetraisopropoxide (1.2 mol equiv) at
70 °C for 2 h without using any solvent. The imine (3) thus formed in situ, upon heating in a solution of a
large amount of acetic-formic anhydride (30 mol equiv) at 70 °C for 2 h, yielded N-formyliminium ion
(4). The reaction mixture of 4 was used as the substrate for the acid-catalyzed cyclization reaction, after
removal of excess acetic-formic anhydride by evaporation in vacuo. We found that the cyclization of the
N-formyliminium ion (4a) was difficult compared with that of the oxa-analog (8) reported in the
preceding paper.8 Thus, heating of 4a with trifluoroacetic acid (TFA) (60 mol equiv) at 70 °C for 16 h
gave the N-formylbenzothiazepine (5a) only in 25% yield (run 1). A longer reaction time (48 h) did not
improve the yield. However, addition of acetic anhydride (1 mol equiv) did improve the yield of 5a (54%)

HETEROCYCLES, Vol. 94, No. 6, 2017
1065
R1
S
R1
HCO2H-Ac2O
S
R1
S
H2N
Ti(O-iPr)4
N CHO
H
N
1
R2
R2
H
a: R1= H, b: R1=OMe
3
4
R2CHO
2
A) TFA or
For Compounds 3-6
For Compound 2
B) TFA-TFSA-Ac2O
R1
R2
R2
R1
a: phenyl
b: c-hexyl
c: c-pentyl
d: n-pentyl
e: n-butyl
f: n-propyl
g: ethyl
S
H
H
a
b
phenyl
R1
HCl
S
c-hexyl
N
CHO
H
H
c
d
c-pentyl
n-pentyl
NH
R2
R2
H
H
H
e
f
g
h
i
n-butyl
n-propyl
ethyl
5
6
OMe
OMe
OMe
phenyl
n-pentyl
n-butyl
j
Scheme 1. Synthesis of 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines
(run 2). This suggested that the benzene ring carrying a sulfur atom does not have enough nucleophilic
character to induce this cyclization reaction. T. Ohwada and colleagues demonstrated in their
investigations of dication chemistry that the Pictet-Spengler cyclization reaction was greatly facilitated by
increasing acidity in the reaction media, and that a super acid such as trifluoromethanesulfonic acid
(TFSA) activated the electrophilic carbon of the C=N group.13,14 Thus, reaction of 4a with a mixed acid
catalyst consisting of TFA (60 mol equiv), acetic anhydride (1 mol equiv) and TFSA (1 mol equiv) at
70 °C for 16 h proceeded smoothly to give 5a in quantitative yield (run 3). The reaction of other
N-formyliminium ions (4b-g) with the mixed acid catalyst under similar conditions also provided the
corresponding N-formylbenzothiazepines (5b-g). The substrates having c-hexyl (4b), c-pentyl (4c),
n-pentyl (4d), n-butyl (4e), n-propyl (4f), and ethyl (4g) yielded the corresponding 5-alkyl-substituted
benzothiazepines (5b-g) in 72, 27, 72, 76, 62, and 30% yields, respectively (runs 4, 5, 9-12) (Table 1). In
the case of c-pentyl (4c), the use of two molar equivalents of TFSA slightly improved the yield of 5c
(36%) (run 6). However, a longer reaction time (24 h) at 70 °C completely decomposed the product (5c).
This suggested that the decreased yield of 5c may be attributed to the thermal instability of 5c. In order to
improve the yield, we examined the cyclization under lower temperature. The use of one molar equivalent
of TFSA did not induce the cyclization at room temperature for 48 h at all (run 7). However, the reaction
proceeded at room temperature for 48 h by using five molar equivalents of TFSA to give the product (5c)
in 62% yield (run 8).

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HETEROCYCLES, Vol. 94, No. 6, 2017
In the case of 4h containing an electron-donating OMe group on the benzene ring, as expected, the
cyclization proceeded smoothly by use of TFA as the sole catalyst at 70 °C for 16 h to give the
N-formylbenzothiazepine (5h) in 78% yield (run 14). The cyclizations of n-pentyl (4i) and n-butyl (4j)
analogs also occurred upon treatment with TFA under similar conditions to give the corresponding
N-formylbenzothiazepines (5i) and (5j) in yields of 82% and 55%, respectively (runs 15, 16). In contrast,
the TFSA-catalyzed reaction of 4h under similar conditions induced extensive decomposition and no
identifiable products could be obtained. The expected product (5h) was not detected by TLC (run 13).
This failure of the cyclization in stronger acidic media using TFSA can be ascribed to protonation of the
electron-rich OMe group on the benzene ring, since the formed oxonium cation (7) reduces the
nucleophilic character of the benzene ring. Thus, TFSA greatly deactivates the nucleophilic center of the
cyclized carbon and inhibits the cyclization reaction (Scheme 2).
H+
H
S
O
S
O
Me
Me
TFSA
5h
N CHO
H
N CHO
H
Ph
Ph
7
4h
Scheme 2. Cyclization reaction of N-formyliminium ion (4h) under mixed acid catalyzed (TFA-TFSA-Ac2O)
reaction condition
A similar phenomenon was observed in the TFSA-catalyzed reaction of the oxa-analog (8) carrying an
oxygen at the benzene ring. As reported in the preceding paper, the reaction of 8 with TFA smoothly
induced the cyclization to yield the product (9).8 However, the reaction of 8 by TFSA as an additional
reagent did not produce the cyclized product (9) to any extent. This failure of the cyclization can also be
attributed to the protonation of an electron-rich oxygen moiety on the benzene ring, which reduced its
O
O
TFA
N
N CHO
H
CHO
Ph
Ph
9
8
TFSA
H
O
H+
N CHO
H
Ph
10
Scheme 3. Cyclization reaction of N-formyliminium ion (8) under acidic reaction condition

HETEROCYCLES, Vol. 94, No. 6, 2017
1067
nucleophilic character (Scheme 3). The hydrolysis of 5 with hydrochloric acid afforded the
5-substituted-2,3,4,5-tetrahydrobenzothiazepines (6) in good yields, as shown in Table 1.
The structures of the products were determined using MS, IR, 1H-NMR, and 13C-NMR spectroscopy.15
Table 1. Synthesis of 5-substituted-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines (6) using the Modified
Pictet-Spengler reaction
Hydrolysis of 5
Products (6)
Modified Pictet-Spengler Reaction
Substrates (4)
Reagents (mol eq)
Products (5)
Conditions
Run
R1
H
R2
Ac2O
TFA
60
TFSA
Temp (°C) Time (h)
Yield (%)
Yield (%)
phenyl
phenyl
1
2
4a
4a
70
70
16
16
5a
5a
25
54
6a 80
H
60
1
H
H
phenyl
60
60
3
4
4a
4b
1
1
1
1
70
70
16
16
5a 100
c-hexyl
5b
5c
5c
72
27
36
6b 100
6c 100
H
H
60
60
5
6
4c
4c
c-pentyl
c-pentyl
1
2
1
1
70
70
16
16
H
H
60
60
7
8
4c
4c
c-pentyl
c-pentyl
1
5
1
1
rt
rt
48
48
5c
5c
0
62
H
H
n-pentyl
n-butyl
60
60
9
4d
4e
1
1
1
1
70
70
10
10
5d
5e
72
76
6d 100
6e 95
10
H
H
60
60
11
12
4f
n-propyl
1
1
1
1
70
70
10
10
5f
62
30
6f
70
4g
ethyl
5g
6g 80
OMe
OMe
phenyl
phenyl
60
60
4h
4h
1
1
70
70
16
16
5h
5h
0
13
14
78
6h 94
OMe
OMe
60
60
15
16
4i
4j
n-pentyl
n-butyl
70
70
16
16
5i
5j
82
55
6i
6j
86
96
Thus, the modified Pictet-Spengler reaction of 2-(arylthio)ethanamines and aldehydes via
N-formyliminium ions presents a convenient method for synthesizing various 5-substituted
2,3,4,5-tetrahydrobenzo[f][1,4]thiazepines. Furthermore, this study demonstrates that the cyclization is
greatly affected by the acidity of the reaction media, which depended on the structure of the substrate, and
therefore, the selection of acid catalysts is critically important to the modified Pictet-Spengler reaction.
EXPERIMENTAL
Unless otherwise noted, the following procedures were adopted. Melting points were determined using a
Yanagimoto SP-M1 hot-stage melting point apparatus and are uncorrected. IR spectra were acquired on

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HETEROCYCLES, Vol. 94, No. 6, 2017
KBr disks using a HORIBA FT-710 spectrophotometer, and the values are given in cm−1. NMR spectra
were acquired using a JEOL JNM-AL 300 (1H-NMR, 300 MHz; 13C-NMR, 75 MHz) NMR spectrometer
in CDCl3 with tetramethylsilane as an internal standard, and the chemical shifts are given as δ values.
HRFAB-MS spectra were recorded using a JEOL-MS700 spectrometer with glycerol as the matrix. TLC
was performed on Merck precoated Silica gel 60 F254 plates. Column chromatography was carried out
with silica gel (Wakogel C-200). The organic extract from each reaction mixture was washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo to dryness.
Modified Pictet-Spengler reaction of 2-(phenylthio)ethanamine (1a) and aldehyde (2). General
procedure: A mixture of 1a (0.5 g, 3.26 mmol), aldehyde (2) (1.2 mol equiv), and Ti(O-iPr)4 (1.2 mol
equiv) was heated at 70 °C for 2 h under an argon atmosphere. A solution of acetic-formic anhydride (30
mol equiv) (prepared from HCO2H [30 mol equiv] and Ac2O [30 mol equiv]) was added to the reaction
mixture at 0 °C, then the mixture was heated at 70 °C for 2 h. After removal of excess acetic-formic
anhydride by heating in vacuo, TFA (60 mol equiv), TFSA (1-5 mol equiv) and acetic anhydride (1 mol
equiv) were added to the reaction mixture and heated at 70 °C or stirred at room temperature for 10-48 h
(as shown in Table 1). The reaction mixture was diluted with MeOH (100 mL) and passed through a short
SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca. 50 mL, and the
resulting residue was extracted with CHCl3. After removal of the extraction solvent in vacuo, the residue
was purified by chromatography over SiO2 and elution with AcOEt-hexane (1:1-1:3) to give (5).
N-Formyl-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5a): Yellow plates recrystallized from
1
Et2O, mp 127-129 °C. IR: 1658, 1596. H-NMR: 2.67-2.74, (2H, m, C2-H), 3.25-3.33, 3.64-3.81,
4.52-4.60 (total 2H, each m, C3-H), 6.16, 6.95 (total 1H, each s, C5-H), 7.04-7.51 (9H, m, Ar-H), 8.24,
8.57 (total 1H, each s, CHO). HR-FABMS m/z MH+: Calcd for C16H16NOS: 270.0953. Found: 270.0964.
N-Formyl-5-cyclohexyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5b): Yellow gum. IR: 1671, 1589.
1H-NMR: 0.78-1.80 (11H, m, cyclohexyl-CH2 and C1’-H), 2.78-3.12 (3H, m, C2-H and C3-H), 3.79-3.88
(1H, m, C3-H), 4.07-4.17 (0.5H, m, C5-H), 5.11 (0.5H, d, J = 11 Hz, C5-H), 7.09-7.51 (4H, m, Ar-H),
8.10, 8.19 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd for C16H22NOS: 276.1422. Found:
276.1433.
N-Formyl-5-cyclopentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5c): Yellow gum. IR: 1670, 1560.
1H-NMR: 1.00-1.89 (9H, m, cyclopentyl-CH2 and C1’-H), 2.80, 2.86 (2H, dt, J = 5, 6 Hz, C2-H),
3.42-3.69 (1H, m, C3-H), 3.93 (1H, d, J = 4 Hz, C3-H), 4.21 (0.5H, d, J = 13 Hz, C5-H), 5.13 (0.5H, d, J
= 12 Hz, C5-H), 7.13-7.54 (4H, m, Ar-H), 8.10, 8.21 (total 1H, each s, CHO). HR-FABMS m/z (MH+):
Calcd for C15H20NOS: 262.1265. Found: 262.1272.
N-Formyl-5-pentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5d): Yellow gum. IR: 1670, 1590, 1540.
1H-NMR: 0.84-0.91 (3H, m, CH3), 1.20-1.34 (6H, m, pentyl-CH2), 2.05-2.45 (2H, m, C1’-H), 2.79-2.83

HETEROCYCLES, Vol. 94, No. 6, 2017
1069
(1H, m, C2-H), 2.86-2.90 (1H, m, C2-H), 3.82-3.97 (2H, m, C3-H), 4.62-4.67, 5.36-5.41 (total 1H, each
m, C5-H), 7.11-7.54 (4H, m, Ar-H), 8.08, 8.21 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd
for C15H22NOS: 264.1423. Found: 264.1429.
N-Formyl-5-butyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5e): Yellow gum. IR: 1677, 1664, 1465.
1H-NMR: 0.89, 0.91 (total 3H, each t, J = 7 Hz, CH3), 1.24-1.43 (4H, m, butyl-CH2), 2.16-2.46 (2H, m,
C1’-H), 2.80-2.90 (2H, m, C2-H), 3.82-3.92 (2H, m, C3-H), 4.62-4.67, 5.38-5.43 (total 1H, each m,
C5-H), 7.13-7.54, (4H, m, Ar-H), 8.08, 8.20 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd for
C14H20NOS: 250.1265. Found: 250.1276.
N-Formyl-5-propyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5f): Yellow plates recrystallized from
1
Et2O. mp 87-88 °C. IR: 1670, 1652, 1585. H-NMR: 0.95, 0.97 (total 3H, each t, J = 7 Hz, CH3),
1.18-1.43 (2H, m, propyl-CH2), 2.13-2.38 (1H, m, C1’-H), 2.35-2.46 (1H, m, C1’-H), 2.79-2.90,
3.82-3.92 (total 4H, each m, C2-H and C3-H), 4.64-4.69, 5.38-5.43 (total 1H, each m, C5-H), 7.13-7.54,
(4H, m, Ar-H), 8.08, 8.20 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd for C13H18NOS:
236.1109. Found: 236.1096.
N-Formyl-5-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5g): Yellow gum. IR: 1671, 1589.
1H-NMR: 0.89, 0.97 (3H, each t, J = 7 Hz, CH3), 2.21-2.58 (2H, m, C1’-H), 2.80-2.90 (2H, m, C2-H),
3.87-3.92 (2H, m, C3-H), 4.52-4.58, 5.30-5.32 (total 1H, each m, C5-H), 7.12-7.55 (4H, m, Ar-H), 8.09,
8.21 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd for C12H16NOS: 222.0953. Found:
222.0960.
Modified Pictet-Spengler reaction of 2-(3-methoxyphenylthio)ethanamine (1b) and aldehyde (2).
General procedure: A mixture of (1b) (0.5 g, 2.73 mmol), aldehyde (2) (1.2 mol equiv), and Ti(O-iPr)4
(1.2 mol equiv) was heated at 70 °C for 2 h under an argon atmosphere. A solution of acetic-formic
anhydride (30 mol equiv) (prepared from HCO2H [30 mol equiv] and Ac2O [30 mol equiv]) was added to
the reaction mixture at 0 °C, then the mixture was heated at 70 °C for 2 h. After removal of excess
acetic-formic anhydride by heating in vacuo, TFA (60 mol equiv) was added to the reaction mixture and
heated at 70 °C for 16 h. The reaction mixture was diluted with MeOH (100 mL) and passed through a
short SiO2 column (CHCl3-MeOH) to remove TiO2. The eluent was concentrated in vacuo to ca. 50 mL,
and the resulting residue was extracted with CHCl3. After removal of the extraction solvent in vacuo, the
residue was purified by chromatography over SiO2 and elution with AcOEt-hexane (1:1-1:3) to give (5).
N-Formyl-8-methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5h): Yellow prisms
recrystallized from Et2O, mp 132-139 °C. IR: 1681, 1660, 1641, 1594. 1H-NMR: 2.71-2.95 (2H, m, C2-H),
3.16-3.76, 4.52-4.57 (total 2H, each m, C3-H), 3.78, 3.82 (total 3H, each s, OCH3), 6.03, 6.90 (total 1H,
each s, C5-H), 6.78-7.38 (8H, m, Ar-H), 8.31, 8.47 (total 1H, each s, CHO). HR-FABMS m/z (MH+):
Calcd for C17H18NO2S: 300.1059. Found: 300.1053.

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HETEROCYCLES, Vol. 94, No. 6, 2017
N-Formyl-8-methoxy-5-pentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5i): Yellow oil. IR: 1671,
1
1596. H-NMR: 0.84-0.91 (3H, m, CH3), 1.26-1.33 (7H, m, pentyl-CH2 and C1’-H), 2.10-2.44 (2H, m,
C2-H and C1’-H), 2.80-2.90 (2H, m, C2-H and C3-H), 3.77, 3.78 (total 3H, each s, OCH3), 3.85-3.95 (1H,
m, C3-H), 4.56-4.61, 5.32-5.36 (total 1H, each m, C5-H), 6.73, 7.76 (total 1H, each dd, J = 9, 3 Hz,
C7-H), 7.03, 7.08 (total 1H, each d, J = 3 Hz, C9-H), 7.14, 7.31 (total 1H, each d, J = 9 Hz, C6-H), 8.06,
8.19 (total 1H, each s, CHO). HR-FABMS m/z (MH+): Calcd for C16H24NO2S: 294.1527. Found:
294.1537.
N-Formyl-5-butyl-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (5j): Yellow oil. IR: 1671,
1596. 1H-NMR: 0.94, 0.97 (total 3H, each t, J = 7 Hz, CH3), 1.27-1.42 (4H, m, butyl-CH2), 2.10-2.41 (2H,
m, C1’-H), 2.82-2.90 (2H, m, C2-H), 3.77, 3.78 (total 3H, each s, OCH3), 3.84-4.00 (2H, m, C3-H),
4.58-4.63, 5.33-5.39 (total 1H, each m, C5-H), 6.73, 6.76 (total 1H, each dd, J = 8, 3 Hz, C7-H), 7.03,
7.08 (total 1H, each d, J = 3 Hz, C9-H), 7.14, 7.31 (total 1H, each d, J = 8 Hz, C6-H), 8.06, 8.19 (total 1H,
each s, CHO). HR-EIMS m/z (M+): Calcd for C15H21NO2S: 279.1293. Found: 279.1282.
Hydrolysis of N-formyl -2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (5). General procedure:
A solution of (5) (100 mg) in EtOH (5 mL) and 10% HCl aqueous solution (5 mL) was refluxed for 16-48
h under an argon atmosphere. The reaction mixture was diluted with water, made alkaline with 10%
NaOH solution, and extracted with CHCl3. The residue was purified by column chromatography over
SiO2 with MeOH-CHCl3 (9:1) to give (6).
5-Phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6a): Reaction time: 16 h. Yellow gum. IR: 1646,
1
1600, 1565. H-NMR: 2.95-3.01 (1H, m, C2-H), 3.13-3.18 (1H, m, C2-H), 3.44 (2H, t, J = 4 Hz, C3-H),
5.94 (1H, s, C5-H), 6.85-6.88 (1H, m, Ar-H), 7.09-7.53 (8H, m, Ar-H). 13C-NMR: 28.9 (C2), 46.8 (C3),
63.7 (C5), 128.4 (Ph-CHx2), 128.7 (Ar-CH), 128.8 (Ar-CH), 129.0 (Ph-CHx2), 129.5 (Ar-CH), 131.2
(Ar-CH), 134.8 (Ph-C), 135.2 (C5a), 137.7 (C9a). HR-FABMS m/z (MH+): Calcd for C15H16NS: 242.0102.
Found: 242.0092.
5-Cyclohexyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6b): Reaction time: 16 h. Yellow gum. IR:
1670, 1596. 1H-NMR: 0.80-0.88 (1H, m, cyclohexyl-CH2), 1.12-1.43 (5H, m, cyclohexyl-CH2), 1.62-1.66
(2H, m, cyclohexyl-CH2), 1.87-1.90 (1H, m, cyclohexyl-CH2), 2.27-2.30 (1H, m, cyclohexyl-CH2),
2.83-2.85 (1H, m, C1’-H), 3.00-3.05 (1H, m, C2-H), 3.30-3.41 (2H, m, C2-H and C3-H), 3.61-3.65 (1H,
m, C3-H), 4.36 (1H, d, J = 11 Hz, C5-H), 7.23-7.32 (3H, m, Ar-H), 7.43 (1H, dd, J = 6, 2 Hz, Ar-H).
13C-NMR: 25.0 (cyclohexyl-CH2), 25.1 (cyclohexyl-CH2), 25.4 (cyclohexyl-CH2), 28.4 (C2), 29.8
(cyclohexyl-CH2), 29.9 (cyclohexyl-CH2), 34.3 (C1’), 43.0 (C3), 66.1 (C5), 128.0 (Ar-CH), 128.9
(Ar-CH), 131.4 (Ar-CH), 133.7 (Ar-CH), 133.8 (C5a), 135.7 (C9a). HR-FABMS m/z (MH+): Calcd for
C16H22NS: 248.1473. Found: 248.1469.

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5-Cyclopentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6c): Reaction time: 16 h. Yellow gum. IR:
1
1571, 1540. H-NMR: 1.01-1.07 (1H, m, cyclopentyl-CH2), 1.57-1.83 (6H, m, cyclopentyl-CH2),
2.02-2.27 (1H, m, cyclopentyl-CH2), 3.04 (1H, m, C1’-H), 3.21-3.34 (3H, m, C2-H and C3-H), 3.54-3.60
(1H, m, C3-H), 4.48 (1H, d, J = 11 Hz, C5-H), 7.23-7.40 (3H, m, Ar-H), 7.53 (1H, dd, J = 8, 1 Hz, Ar-H).
13C-NMR: 25.1 (cyclopentyl-CH2), 25.7 (cyclopentyl-CH2), 28.6 (C2), 31.31 (cyclopentyl-CH2), 31.4
(cyclopentyl-CH2), 39.1 (C1’), 44.2 (C3), 66.2 (C5), 128.8 (Ar-CH), 129.5 (Ar-CH), 130.4 (Ar-CH),
134.1 (Ar-CH), 134.4 (C5a), 137.0 (C9a). HR-FABMS m/z (MH+): Calcd for C14H20NS: 234.1316.
Found: 234.1321.
5-Pentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6d): Reaction time: 16 h. Yellow gum. IR: 1623,
1
1598. H-NMR: 0.86-0.88 (3H, m, CH3), 1.10-1.48 (6H, m, pentyl-CH2), 2.15-2.30 (1H, m, C1’-H),
2.40-2.55 (1H, m, C1’-H), 2.95-3.05 (1H, m, C2-H), 3.15-3.22 (2H, m, C2-H, and C-3-H), 3.45-3.60 (1H,
m, C3-H), 4.81 (1H, d, J = 5 Hz, C5-H), 7.30-7.44 (3H, m, Ar-H), 7.56 (1H, d, J = 8 Hz, Ar-H).
13C-NMR: 13.9 (CH3), 22.4 (pentyl-CH2), 26.0 (pentyl-CH2), 28.5 (pentyl-CH2), 29.4 (C1’), 31.3 (C2),
44.2 (C3), 60.1 (C5), 128.8 (Ar-CH), 129.7 (Ar-CHx2), 133.9 (Ar-CH), 135.2x2 (C5a and C9a).
HR-FABMS m/z (MH+): Calcd for C14H22NS: 236.1473 Found: 236.1484.
5-Butyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6e): Reaction time: 16 h. Yellow gum. IR: 1654,
1
1571. H-NMR: 0.97 (3H, t, J = 7 Hz, CH3), 1.19-1.42 (4H, m, butyl-CH2), 2.24-2.35 (1H, m, C1’-H),
2.42-2.55 (1H, m, C1’-H), 3.02-3.08 (1H, m, C2-H), 3.20-3.36 (2H, m, C2-H and C3-H), 3.52-3.58 (1H,
m, C3-H), 4.80 (1H, dd, J = 9, 6 Hz, C5-H), 7.29-7.43 (3H, m, Ar-H), 7.56 (1H, dd, J = 7, 1 Hz, Ar-H).
13C-NMR: 13.8 (CH3), 19.6 (butyl-CH2), 22.2 (butyl-CH2), 28.3 (C1’), 29.6 (C2), 44.3 (C3), 60.2 (C5),
128.8x2 (Ar-CH), 129.6 (Ar-CH), 133.9 (Ar-CH), 135.0 (C5a), 135.4 (C9a). HRMS m/z (MH+): Calcd for
C12H18NS: 222.1316. Found: 222.1306.
5-Propyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6f): Reaction time: 16 h. Yellow gum. IR: 1654.
1H-NMR: 0.98 (3H, t, J = 7 Hz, CH3), 1.10-1.40 (4H, m, propyl-CH2), 2.24-2.35 (1H, m, C1’-H),
2.48-2.60 (1H, m, C1’-H), 3.02-3.09 (1H, m, C2-H), 3.20-3.36 (2H, m, C2-H and C3-H), 3.52-3.58 (1H,
13
m, C3-H), 4.78-4.83 (1H, m, C5-H), 7.27-7.54 (4H, m, Ar-H). C-NMR: 13.8 (CH3), 22.3 (propyl-CH2),
28.4 (C1’), 29.6 (C2), 44.3 (C3), 60.2 (C5), 128.8 (Ar-CH), 129.6x2 (Ar-CH), 133.9 (Ar-CH), 135.2
(C5a), 135.5 (C9a). HR-FABMS m/z (MH+): Calcd for C12H18NS: 208.1160. Found: 208.1155.
5-Ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6g): Reaction time: 16 h. Yellow oil. IR: 1670.
1H-NMR: 0.97 (3H, t, J = 7 Hz, CH3), 1.75-2.00 (2H, m, C1’-H), 2.54-2.74 (2H, m, C2-H), 3.15-3.23 (1H,
m, C3-H), 3.36-3.44 (1H, m, C2-H), 4.09 (1H, dd, J = 8, 6 Hz, C5-H), 7.01-7.08 (1H, m, Ar-H), 7.16-7.18
13
(2H, m, Ar-H), 7.50 (1H, d, J = 7 Hz, Ar-H). C-NMR: 11.8 (CH3), 26.9 (CH2), 35.5 (C2), 50.5 (C3),
62.3 (C5), 126.0 (Ar-CH), 126.4 (Ar-CH), 127.8 (Ar-CH), 133.4 (Ar-CH), 136.2 (C5a), 148.4 (C9a).
HR-FABMS m/z (MH+): Calcd for C11H16NS: 194.1004. Found: 194.1011.

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8-Methoxy-5-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6h): Reaction time: 24 h. Colorless
1
solid. IR: 1594, 1560. H-NMR: 2.71-2.92 (2H, m, C2-H), 3.34 (1H, ddd, J = 13, 10, 3 Hz, C3-H),
3.51-3.58 (1H, m, C3-H), 3.74 (3H, s, OCH3), 5.59 (1H, s, C5-H), 6.51 (1H, d, J = 8 Hz, C6-H), 6.58 (1H,
dd, J = 8, 3 Hz, C7-H), 7.17 (1H, d, J = 3 Hz, C9-H), 7.25-7.39 (5H, m, Ph-H). 13C-NMR: 35.5 (C2), 51.3
(C3), 55.4 (OCH3), 63.9 (C5), 109.2 (C9), 112.9 (C6), 118.4 (C7), 126.8 (Ph-CH), 127.5 (Ph-CH), 128.3
(Ph-CH), 129.3 (Ph-CH), 124.3 (Ph-CH), 137.0 (Ph-C), 141.5 (C5a), 143.5 (C9a), 157.6 (C8).
HR-FABMS m/z (MH+): Calcd for C16H18ONS: 272.1109. Found: 272.1104
8-Methoxy-5-pentyl-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6i): Reaction time: 48 h. Yellow oil.
1
IR: 1675, 1596, 1565. H-NMR: 0.96 (3H, t, J = 7 Hz, CH3), 1.25-1.52 (6H, m, pentyl-CH2), 1.78-1.98
(2H, m, C1’-H), 2.63-2.88 (2H, m, C2-H), 3.20-3.28 (1H, m, C3-H), 3.41-3.48 (1H, m, C3-H), 3.78 (3H,
s, OCH3), 4.18 (1H, dd, J = 8, 6 Hz, C5-H), 6.77 (1H, dd, J = 8, 3 Hz, C7-H), 7.14 (1H, d, J = 3 Hz,
13
C9-H), 7.16 (1H, d, J = 8 Hz, C6-H). C-NMR: 14.1 (CH3), 22.6 (pentyl-CH2), 26.9 (pentyl-CH2), 32.0
(pentyl-CH2), 34.3 (C1’), 35.7 (C2), 50.4 (C3), 55.3 (OCH3), 60.0 (C5), 113.2 (C7), 118.4 (C9), 127.0
(C6), 137.2 (C5a), 140.9 (C9a), 157.5 (C8). HR-FABMS m/z (MH+): Calcd for C15H24ONS: 266.1579.
Found: 266.1573.
5-Butyl-8-methoxy-2,3,4,5-tetrahydrobenzo[f][1,4]thiazepine (6j): Reaction time: 48 h. Yellow oil. IR:
1596, 1565, 1540. 1H-NMR: 0.93 (3H, t, J = 7 Hz, CH3), 1.25-1.53 (4H, m, butyl-CH2), 1.76-2.09 (2H, m,
C1’-H), 2.56-2.81 (2H, m, C2-H), 3.11-3.20 (1H, m, C3-H), 3.32-3.41 (1H, m, C2-H), 3.77(3H, s, OCH3),
4.10 (1H, dd, J = 8, 6 Hz, C5-H), 6.70 (1H, dd, J = 8, 3 Hz, C7-H), 7.06 (1H, d, J = 3 Hz, C9-H), 7.09
(1H, d, J = 8 Hz, C6-H). 13C-NMR: 14.1 (CH3), 22.8 (butyl-CH2), 29.4 (butyl-CH2), 34.0 (C1’), 35.7 (C2),
50.4 (C3), 55.3 (OCH3), 59.9 (C5), 113.2 (C7), 118.4 (C9), 127.0 (C6), 137.0 (C5a), 140.8 (C9a), 157.5
(C8). HR-FABMS m/z (MH+): Calcd for C13H20ONS: 252.1422. Found: 252.1419.
REFERENCES AND NOTES
1. G. Bringmann, C. T. Ewers, and R. Walter, Comprehensive Organic Synthesis, ed. by B. M. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, Vol. 6, pp. 736-740.
2. Y. Horiguchi, H. Kodama, M. Nakamura, T. Yoshimura, K. Hanezi, H. Hamada, T. Saitoh, and T.
Sano, Chem. Pharm. Bull., 2002, 50, 253.
3. M. Kitabatake, J. Nagai, K. Abe, Y. Tsuchiya, K. Ogawa, T. Yokoyama, K. Mohri, K. Taguchi, and
Y. Horiguchi, Eur. J. Med. Chem., 2009, 44, 4034.
4. Y. Horiguchi, M. Nakamura, A. Kida, H. Kodama, T. Saitoh, and T. Sano, Heterocycles, 2003, 59,
691.
5. Y. Horiguchi, M. Nakamura, T. Saitoh, and T. Sano, Chem. Pharm. Bull., 2003, 51, 1368.
6. M. Kitabatake, T. Saitoh, T. Sano, and Y. Horiguchi, Heterocycles, 2009, 78, 1177.

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7. M. Kitabatake, A. Hashimoto, T. Saitoh, T. Sano, K. Mohri, and Y. Horiguchi, Heterocycles, 2010,
81, 1903.
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10. A. Nefzi, N. A. Ong, M. A. Giulianotti, J. M. Ostresh, and R. A. Houghten, Tetrahedron Lett., 1999,
40, 4939.
11. M. K. Schwarz, D. Tumelty, and M. A. Gallop, J. Org. Chem., 1999, 64, 2219.
12. A. R. Katritzky, Y.-J. Xu, H.-Y. He, and S. Mehta, J. Org. Chem., 2001, 66, 5590.
13. A. Yokoyama, T. Ohwada, and K. Shudo, J. Org. Chem., 1999, 64, 611.
14. S. Nakamura, M. Tanaka, T. Taniguchi, M. Uchiyama, and T. Ohwada, Org. Lett., 2003, 5, 2087.
15. The 1H- and 13C-NMR spectra of N-formyl compounds (5) exhibited complex signals attributable to
13
rotational isomerism of the N-CO bond. Therefore, C-NMR spectra of cyclized products were
assigned based on measurements of N-deformyl derivatives (6).