Efficient synthesis of functionalized benzazepine derivatives utilizing intramolecular mitsunobu reaction

Article abstract of DOI:10.3987/COM-05-S(K)58

The 5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine derivative (2), which is a typical metabolite of mozavaptan (1) having the 2,3,4,5-tetrahydro-1H-benzazepine skeleton, was synthesized by utilizing the intramolecular Mitsunobu reaction of the corresponding

Full text of DOI:10.3987/COM-05-S(K)58

HETEROCYCLES, Vol. 66, 2005
481
HETEROCYCLES, Vol. 66, 2005, pp. 481 – 502. © The Japan Institute of Heterocyclic Chemistry
Received, 16th September, 2005, Accept, 16th November, 2005, Published online, 18th November, 2005. COM-05-S(k)58
EFFICIENT SYNTHESIS OF FUNCTIONALIZED BENZAZEPINE
DERIVATIVES UTILIZING INTRAMOLECULAR MITSUNOBU
REACTION
Tadaaki Ohtani, * Yoshikazu Kawano, Kazuyoshi Kitano, Jun Matsubara,
Makoto Komatsu, Minoru Uchida, Fujio Tabusa, and Yoshimitsu Nagaoa
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co., Ltd.,
Kagasuno 463-10 Kawauchi-cho, Tokushima 771-0192, Japan
aGraduate School of Pharmaceutical Sciences, The University of Tokushima,
Sho-machi, Tokushima 770-8505, Japan
Abstract - The 5-hydroxy-2,3,4,5-tetrahydro-1H-benzazepine derivative (2),
which is a typical metabolite of mozavaptan (1) having the 2,3,4,5-tetrahydro-1H-
benzazepine skeleton, was synthesized by utilizing the intramolecular Mitsunobu
reaction of the corresponding 2-(4-hydroxybutyl)aniline derivative. In the intra-
molecular Mitsunobu reaction, effect of the substituent group on nitrogen atom,
influence of the functional group applying to synthesis of the other metabolites (3,
4 and 5) and utilization of synthesis of 2-substituent benzazepine derivatives were
investigated.
INTRODUCTION
Benzazepines are important heterocyclic compounds that are used for a variety of applications with
pharmaceuticals. The 2,3,4,5-tetrahydro-1H-benzazepine derivative has been applied to drugs as
vasopressin V2 receptor antagonists1-3 (e. g., mozavaptan,1 tolvaptan2) and an agonist4 (OPC-51803). In
metabolic studies of mozavaptan (1), we found the 5-hydroxy, 5-methylamino, 5-amino and 5-oxo
metabolites (2, 3, 4 and 5)5 which were produced by oxidation at the 5-position of the benzazepine ring
(Figure 1). These metabolites having the 2,3,4,5-tetrahydro-1H-benzazepine ring showed potent
vasopressin V2 receptor antagonist activity.3 Usually, the 1-substituted 2,3,4,5-tetrahydro-5-
oxobenzazepine derivatives, which were available intermediates for synthesis of the 5-substituted
benzazepine compounds, have been prepared by the Dieckmannn condensation of N-substituted ethyl
---------------------------
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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HETEROCYCLES, Vol. 66, 2005
3-(2-methoxycarbonylphenylamino)butyrate with potassium tert-butoxide in toluene, followed by
hydrolysis with acetic acid and hydrochloric acid.6 However, this method involves a limitation for the
introduction of substituent groups at the 3-, 4-, and 5-positions of the 2,3,4,5-tetrahydro-1H-benzazepine
ring because of harsh conditions. On the other hand, the Mitsunobu reaction7 has been widely utilized in
organic synthesis and has been applied to esterification8 and etherification,9 the N-alkylation of the
electron-deficient nitrogen atom10 and heterocyclization11 because it proceeds under the mild conditions.
Here, we wish to report an efficient synthesis of 2,3,4,5-tetrahydro-1H- benzazepine derivatives utilizing
the intramolecular Mitsunobu reaction.
NHMe
NH
O
NMe
OH
2
2
5
4
3
1
N
N
N
2
N
N
O
O
O
O
O
NH
NH
NH
NH
NH
O
O
O
O
O
Me
Me
Me
Me
Me
3
4
5
Mozavaptan (1)
2
Figure 1
Synthesis
The Mitsunobu reaction is effected by a variety of nucleophiles,12 which are the nitrogen atom substituted
with electron withdrawing groups in our system. As the substituent groups on the nitrogen atom, we chose
two types of electron-withdrawing groups. One is the general protecting groups (6a, 6b and 6f) and the
other is the substituent groups (6c-e) which can be converted to the target compounds. Thus we first
examined the effect of electron-withdrawing groups on the nitrogen atom of the
2-[4-hydroxy-1-methoxymethoxybutyl]- aniline derivatives (eq. 1).
OMOM
OMOM
Me
SO2-
CF3CO-
CO-
EWG; a
Intramolecular
Mitsunobu reaction
OH
(1)
b
c
NHEWG
N
O2N
I
EWG
6a-f
7a-f
d
e
CO-
CONH
CO-
Me
tBuOCO-
f
The substrates (6a-f) were synthesized as shown in Scheme 1. The alcohol (8)13 was treated with
chloromethyl methyl ether (MOMCl) and i-Pr2NEt to give the methoxymethyl (MOM) ether (9) in 90%
yield. Hydroboration of 9 followed by treatment with alkaline hydrogen peroxide afforded the primary
alcohol (10) in 85% yield. The alcohol (10) was allowed to react with 2,3-dihydropyran (DHP) and
pyridinium p-toluenesulfonate (PPTS) quantitatively to obtain the tetrahydropyranyl (THP) compound (11).

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483
Hydrogenetion of 11 in the presence of PtO2 gave the aniline (12) in 99% yield. Treatment of the aniline
(12) with p-toluenesulfonyl chloride (TsCl), carboxylic acid chloride or acid anhydride followed by
deprotection of the THP group, furnished the substrates (6a-f) in moderate yields.
Scheme 1
OH
OMOM
OMOM
OH
MOMCl, i-Pr NEt
1) BH , THF
DHP, PPTS
CH Cl
2
3
CH Cl
2) NaOOH
2
2
2
2
NO
NO
NO
2
2
2
8
9
10
OMOM
OMOM
1) EWG-Cl or
OMOM
OTHP
OTHP
OH
H , PtO
2
(EWG) O
2
2
EtOH
2) 3N HCl or
PPTS
NO
NH
NHEWG
2
2
11
12
6a-f
Me
SO2-
CF3CO-
CO-
d
e
I
CO-
CO-
EWG; a
EWG-Cl;
TsCl, ArCOCl
b
c
CONH
(EWG) O;
2
Boc O, (CF CO) O
Me
2
3
2
tBuOCO-
O2N
f
For the typical procedure of the intramolecular Mitsunobu reactions employing the substrates (6a-f), the
primary alcohols (6a-f, 0.26 mmol) were treated with diethyl azodicarboxylate (1.2 eq.) and PPh3 (1.2 eq.)
in THF (3 mL) at room temperature. All results are summarized in Table 1.
a
Table 1 Effect of Electron-withdrawing Group on Intramolecular Mitsunobu Reaction
OMOM
OMOM
OH
DEAD, PPh
3
THF
rt
NHEWG
N
EWG
7a-f
6a-f
Entry
EWG
Substrate
Time
Product
Yield(%)
Ts
2 h
3 h
1 d
100
85
6a
6b
6c
1
2
3
7a
7b
7c
CF3CO
4-NO2-C6H4CO
88
4
5
6
6d
6e
6f
4-I-C6H4CO
4-(2-Me-C6H4)CONH-C6H4CO
1 d
1 d
85
36
7d
7e
7f
Boc
Boc
1 d
1 d
58
85
b
7
6f
7f
a. All reactions, except Entry 7, were carried out with stirring a mixture of substrate (0.26 mmoL), PPh
(1.2 eq.) and DEAD (1.2 eq.) in THF (3 mL) at rt. b. Reaction was carried out by stirring a mixture of
3
substrate (0.26 mmoL), PPh (2 eq.) and DEAD (2 eq.) in THF (3 mL) under refluxing conditions.
3
The reaction of the p-toluenesulfonyl anilides (6a) for 2 hours yielded benzazepine (7a) quantitatively
(Entry 1). Although the N-acylbenzazepines (7b-d) were also obtained from the corresponding alcohols
(6b-d) in good yields, their reaction times except for that of 6b were longer than the case of 6a (Entries 2-4).

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Compound (7e) was obtained in a low yield (Entry 5) due to the production of unknown by-products. The
yield of 7f was also low (Entry 6), however, no by-product was observed in the reaction. Thus, this reaction
was carried out under refluxing conditions for 1 day. As we expected, 7f was obtained in better yield (Entry
7). It was found that the electron-withdrawing groups on the nitrogen atom affect the reaction time and the
yield of the benzazepine products (7a-f) through these reactions.
Next, in order to investigate the influence of the functional groups at the 1-position of the 4-hydroxybutyl
groups in this reaction system, we selected suitable substrates (6g-i) (eq. 2).
1
2
1
2
R R
R R
1
2
Intramolecular
Mitsunobu reaction
g: R =NMe , R =H
2
OH
1
2
O
(2)
h: R =NMeBoc, R =H
NHTs
N
1
2
i: R =NPhth, R =H
NPhth=
N
Ts
1
2
j: R , R =O
O
6g-j
7g-j
The substrate (6g) was synthesized as shown in Scheme 2. The alcohol (8) was treated with tert-butyl-
dimethylsilyl chloride (TBDMSCl) and imidazole to give the tert-butyldimethylsilyl (TBS) ether (13) in
90% yield. Compounds (14) and (15) were synthesized by the same method as compounds (9) and (10)
respectively. Desilylation of 15 with tetrabutylammonium fluoride (TBAF) gave compound (16) in 97%
yield. Treatment of the resulting alcohol (16) with phthalimide, PPh3, and DEAD afforded compound (17)
in 72% yield. Hydrogenation of 17 followed by treatment with TsCl and pyridine gave 18 in 33% yield.
Deprotection of the tetrahydropyranyl group of 18 was carried out by treatment with 3N hydrochloric acid
(HCl) to give 6g in quantitative yield.
Scheme 2
OH
OTBS
OTBS
OH
TBDMSCl, Im.
DMF
1) BH , THF
DHP, PPTS
CH Cl
3
2) NaOOH
2
2
NO
NO
NO
2
2
2
8
13
14
OTBS
OH
phthalimide,
NPhth
1) H , PtO ,
EtOH
2
2
OTHP
OTHP
OTHP
OTHP
TBAF
DEAD, PPh
3
THF
THF
2) TsCl, py,
CH Cl
NO
NO
NO
2
2
2
2
2
15
16
17
NPhth
NPhth
OH
3N HCl
EtOH
NHTs
NHTs
18
6g
The substrates (6h and 6i) were synthesized as shown in Scheme 3. The reaction of 16 with DEAD and PPh3
followed by treatment with diphenylphosphory azide (DPPA) gave 19 in 86% yield. The azide (19) was

HETEROCYCLES, Vol. 66, 2005
485
treated with PPh3, hydrolyzed, and then subjected to protection of the resulting amino group with
di-tert-butyl dicarbonate (Boc2O) to give 20 in 92% yield. Methylation of the carbamate (20) with
iodomethane in the presence of NaH afforded 21 (97% yield), which was hydrogenated on PtO2 to give 22
in quantitative yield. The aniline (22) was treated with TsCl and pyridine followed by deprotection of the
THP group furnished 6h in 78% yield. Deprotection of the Boc group of 6h with 6N HCl followed by
reductive methylation using aqueous formaldehyde and sodium cyanoborohydride gave 6i in 92% yield.
Scheme 3
NHBoc
OH
N
3
1) PPh ,THF
1) DEAD, PPh ,
THF
3
3
NaH, MeI
DMF
OTHP
OTHP
OTHP
OH
OTHP
2) H O
2
2) DPPA
3) Boc O
NO
NO
NO
2
2
2
2
20
16
19
1) TsCl, py,
CH Cl
NMeBoc
NMeBoc
NMeBoc
OTHP
OH
H , PtO
1) 6N HCl, EtOH
2) MeCHO,
2
2
2
2
EtOH
2) 3N HCl, EtOH
NO
NH
NHTs
2
2
NaBH CN,
3
21
22
6h
AcOH
NMe
2
NHTs
6i
The substrate (6j) was synthesized as shown in Scheme 4. Hydrogenation of 15 on PtO2 afforded 23 (75%
yield), which was treated with TsCl and pyridine to give 24 in 92% yield. Desilylation (96% yield) of 24
with TBAF followed by oxidation of the resulting alcohol (25) with o-iodoxybenzoic acid (IBX) afforded
26 in 66% yield. The ketone (26) was treated with 3N HCl to give 6j in 78% yield.
Scheme 4
OTBS
OTBS
OTBS
OTHP
OTHP
OTHP
H , PtO
TsCl, py
CH Cl
TBAF
THF
2
2
EtOH
NO
NH
2
2
NHTs
2
2
15
23
24
O
OH
O
OTHP
OTHP
OH
3N HCl
EtOH
IBX
DMSO
NHTs
NHTs
NHTs
26
25
6j
The results of the intramolecular Mitsunobu reaction employing the substrates (6a and 6g-j) bearing
various 1-substituted 4-hydroxybutyl group are summarized in Table 2. In all the reactions, the substrates
were converted to the desired products within 3 hours at rt. The reaction of 6g and 6h gave the

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HETEROCYCLES, Vol. 66, 2005
corresponding benzazepines (7g) and (7h) in good yields (Entries 2 and 3). However, the yield of 7j was
moderate (77%, Entry 5) and that of 7i was low (36%, Entry 4), due to the formation of unknown products.
Table 2 Intramolecular Mitsunobu Reaction of the Compounds Bearing
1-Substituted 4-Hydroxybutyl Groups *
O
R
R
O
OH
OH
DEAD, PPh
3
THF
rt
NHTs
NHTs
N
N
,
,
Ts
Ts
6a, g-i
6j
7j
7a, g-i
Entry
Substrate
R
Time
Product
Yield(%)
OMOM
NPhth
2 h
3 h
3 h
100
96
6a
6g
6h
7a
7g
7h
1
2
3
NMeBoc
100
4
5
6i
6j
NMe2
3 h
3 h
7i
7j
36
77
-
* All reactions were carried out with stirring a mixture of substrate (0.26 mmol), PPh (1.2 eq.) and
3
DEAD (1.2 eq.) in THF (3 mL) at rt.
Finally, in order to apply this methodlogy to the synthesis of the 2-substituted benzazepine derivatives, we
examined the cyclization reaction of the model substrates (27a and 27b) bearing the secondary or tertiary
hydroxyl group (eq. 3).
1
Intramolecular
Mitsunobu reaction
R
2
R
(3)
1
OH
R
NHTs
N
2
R
1
2
Ts
a: R =Me, R =H
27a,b
1
2
b: R =R =Me
28a,b
The substrates (27a) and (27b) were synthesized as shown in Scheme 5. The reaction of the lactam (29)14
with NaH and TsCl afforded 30 in 83% yield. The secondary alcohol (27a) was prepared by the reduction
of 30 with diisobutylalminium hydride (DIBAL) followed by treatment with methylmagnesium bromide in
58% yield. The tertiary alcohol (27b) was obtained by treatment of 30 with excess methylmagnesium
bromide in 83% yield.
Scheme 5
a
1) DIBAL, CH Cl
2) MeMgBr, THF
or
2
2
1
R
2
R
NaH, TsCl
DMF
OH
b
NHTs
N
H
N
O
O
MeMgBr,THF
Ts
1
2
27a (R =Me, R =H)
29
30
1
2
27b (R =Me, R =Me)
The result of the intramolecular Mitsunobu reaction using compounds (27a) and (27b) are summarized in
Table 3. The reaction of the secondary alcohol (27a) rapidly proceeded within 3 hours to give the

HETEROCYCLES, Vol. 66, 2005
487
benzazepine (28a) in 92% yield (Entry 1), but the tertiary alcohol (27b) was not converted to the desirable
cyclized product (28b) even after a day reaction (Entry 2).
Table 3 Intramolecular Mitsunobu Reaction of Secondary and Tertiary Alcohols *
1
R
2
R
DEAD, PPh
3
1
OH
THF
rt
R
NHTs
N
2
R
Ts
27a,b
28a,b
R2
R1
Entry
Yield(%)
Substrate
Time
Product
Me
Me
H
3 h
1 d
92
0
27a
27b
28a
28b
1
2
Me
*All reactions were carried out with stirring a mixture of substrate (0.26 mmol), PPh (1.2 eq.) and
3
DEAD (1.2 eq.) in THF (3 mL) at rt.
In conclusion, we have established the efficient synthesis of the benzazepine derivatives by the
intramolecular Mitsunobu reaction. We also succeeded in the synthesis of the benzazepine derivatives
bearing the functional groups at the 5-position as well as mozavaptan and its metabolites.
EXPERIMENTAL
All melting points were determined using a Yamato MP-21 apparatus and are uncorrected. The IR spectra
1
were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrophotometer. The H NMR (250 MHz)
and 13C NMR (62.5 MHz) spectra were recorded by a Bruker AVANCE DPX 250 spectrometer. Chemical
shifts are given in δ values (ppm) using tetramethylsilane (TMS) as the internal standard. The HRMS
spectra were recorded by a JEOL JMS-SX 102A mass spectrometer. Elementary combution analyses were
performed using a Yamaco CHN CORDER MT-5. All reactions were monitored by TLC employing a 0.25
mm silica gel plate (Merck 5715; 60 F254). Column chromatography was carried out on silica gel (Kanto
Chemical Silicagel 60 (spherical); 63-210 μm) and NH-silica gel (Fuji Silysia Chemical Chromatorex
NH-DM1020; 100 μm. All reagents were used as purchased.
2-(1-Methoxymethoxybut-3-enyl)nitrobenzene (9)
Chloromethyl methyl ether (1.2 mL, 0.15 mol) was added to a solution of 8 (5.7g, 30 mmol) and i-Pr2NEt
(30.8 mL, 0.18 mol) in CH2Cl2 (30 mL), and the mixture was refluxed for 2.5 h. The reaction mixture was
cooled to 0 °C, poured into 2.4N HCl and then extracted with CH2Cl2. The extract was washed with a
saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography (silica gel; eluent, hexane/AcOEt = 11/1 - 9/1) to give 9 (6.5 g, 90%) as a yellow
oil. 1H NMR (CDCl3) δ (ppm): 2.43-2.68 (2H, m), 3.31 (3H, s), 4.48 (1H, d, J = 6.8 Hz), 4.58 (1H, d, J = 6.8

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HETEROCYCLES, Vol. 66, 2005
Hz), 5.04-5.17 (2H, m), 5.29 (1H, dd, J = 4.3, 8.0 Hz), 5.92 (1H, tdd, J = 7.0, 10.0, 17.0 Hz), 7.36-7.46 (1H,
m), 7.57-7.68 (1H, m), 7.76 (1H, dd, J = 1.5, 8.0 Hz), 7.93 (1H, dd, J = 1.3, 8.3 Hz). 13C NMR (CDCl3) δ
(ppm): 41.9, 55.8, 73.2, 95.2, 117.7, 124.3, 128.1, 128.5, 133.2, 134.1, 138.0, 148.3. IR (neat): 2951, 1527,
1347, 1155, 1099, 1023, 919 cm-1. HRFAB-MS calcd for C12H15NO4Li (M+Li)+: 244.1161, found:
244.1183.
2-(4-Hydroxy-1-methoxymethoxybutyl)nitrobenzene (10)
A solution of the borane-THF complex in THF (1 mol/L, 32 mL, 32 mmol) was added to a stirring solution
of 9 (6.4 g, 27 mmol) in THF (65 mL) at –40 °C under a nitrogen atmosphere. The mixture was warmed to
0 °C and stirred for 7 h. Water (10 mL), 5N NaOH solution (23 mL) and 30% H2O2 (33 mL) were added in
this order at 0–5 °C and the mixture was stirred at rt overnight. The reaction mixture was then poured into
water and extracted with AcOEt. The extract was washed with water, brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent,
hexane/CH2Cl2/AcOEt = 2/1/1 - 2/1/2) to give 11 (5.8 g, 85%) as a yellow oil. 1H NMR (CDCl3) δ (ppm):
1.53 (1H, t, J = 5.5 Hz), 1.69-2.03 (4H, m), 3.32 (3H, s), 3.65-3.77 (2H, m), 4.46 (1H, d, J = 6.8 Hz), 4.57
(1H, d, J = 6.8 Hz), 5.19-5.28 (1H, m), 7.36-7.46 (1H, m), 7.57-7.67 (1H, m), 7.75 (1H, dd, J = 1.5, 8.0 Hz),
7.93 (1H, dd, J = 1.3, 8.3 Hz). 13C NMR (CDCl3) δ (ppm): 29.1, 34.2, 55.9, 62.3, 73.4, 95.3, 124.3, 128.1,
128.3, 133.3, 138.6, 148.3. IR (neat): 3413, 2950, 1526, 1345, 1150, 1098, 1030 cm-1. HRFAB-MS calcd
for C12H17NO5Li (M+Li)+: 262.1267, found: 262.1259.
2-[1-Methoxymethoxy-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (11)
A solution of 10 (3.7 g, 14 mmol), 3,4-dihydro-2H-pyrane (2.0 mL, 22 mmol) and pyridinium p-toluene-
sulfonate (728 mg, 2.9 mmol) in CH2Cl2 (37 mL) was stirred at rt for 15 h. The reaction mixture was poured
into a saturated NaHCO3 solution and then extracted with CH2Cl2. The extract was washed with brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
1
eluent, hexane/AcOEt = 3/1) to give 11 (4.9 g, quantitative) as a yellow oil. H NMR(CDCl3) δ (ppm):
1.43-2.01 (10H, m), 3.31 (3H, s), 3.37-3.55 (2H, m), 3.72-3.91 (2H, m), 4.43-4.50 (1H, m), 4.53-4.62 (2H,
13
m), 5.18-5.27 (1H, m), 7.36-7.45 (1H, m), 7.57-7.67 (1H, m), 7.71-7.78 (1H, m), 7.87-7.94 (1H, m). C
NMR (CDCl3) δ (ppm): 19.5, 19.6, 25.4, 26.2, 26.3, 30.7, 34.5, 34.8, 55.8, 62.2, 62.3, 66.9, 67.3, 73.3, 73.5,
95.2, 95.3, 98.79, 98.84, 124.2, 128.0, 128.4, 133.1, 138.6, 148.4. IR (neat): 2944, 1527, 1352, 1076, 1033
cm-1. HRFAB-MS calcd for C17H25NO6Li (M+Li)+: 346.1842, found: 346.1816.
2-[1-Methoxymethoxy-4-(tetrahydropyran-2-yloxy)butyl]aniline (12)
A mixture of 11 (3.0 g, 8.8 mmol) and PtO2 (300 mg) in EtOH (30 mL) was stirred at rt for 2 h under a
hydrogen atmosphere. The mixture was filtered and the residue was washed with EtOH. The filtrate was

HETEROCYCLES, Vol. 66, 2005
489
then concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent, hexane/
AcOEt = 4/1 - 2/1) to give 12 (2.7 g, 99%) as a yellow oil. 1H NMR (CDCl3) δ (ppm) 1.4: 0-2.15 (10H, m),
3.32-3.54 (5H, m, including 3.39, s), 3.70-3.92 (2H, m), 4.17 (2H, br. s), 4.50-4.70 (4H, m), 6.59-6.73 (2H,
m), 6.98-7.11 (2H, m). 13C NMR (CDCl3) δ (ppm): 19.6, 25.4, 26.5, 30.67, 30.77, 30.81, 55.7, 62.2, 67.20,
67.23, 77.9, 78.0, 93.91, 93.93, 98.8, 116.6, 118.1, 124.7, 128.5, 129.2, 144.58, 144.61. IR (neat): 3369,
2944, 1617, 1496, 1456, 1120, 1032, 751 cm-1. HRFAB-MS calcd for C17H27NO4 M+: 309.1940, found:
309.1919.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-p-toluenesufonamide (6a)
p-Toluenesulfonyl chloride (616 mg, 3.2 mmol) was added to a solution of 12 (500 mg, 1.6 mmol) and
pyridine (0.8 mL, 0.01 mol) in CH2Cl2 (5 mL) and the mixture was refluxed for 3 h. The reaction mixture
was poured into water and then extracted with CH2Cl2. The extract was washed with 2.4N HCl, a saturated
NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (NH-silica gel; eluent, hexane/AcOEt = 2/1 - 1/1) to give the N-tosylated product as a
colorless oil. 3N HCl (3.5 mL) was added to a solution of the above-mentioned product in MeOH (7 mL)
and the resulting mixture was stirred at rt for 1 h. The mixture was poured into water and then extracted with
AcOEt. The extract was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent,
hexane/AcOEt = 1/1) to give 6a (556 mg, 91%) as a colorless oil. 1H NMR (CDCl3) δ (ppm): 1.22-1.82 (5H,
m), 2.83 (3H, s), 3.35 (3H, s), 3.48-3.62 (2H, m), 4.38 (1H, d, J = 6.8 Hz), 4.50 (1H, d, J = 6.8 Hz), 4.53
(1H, dd, J = 5.5, 8.3 Hz), 7.00-7.12 (2H, m), 7.18-7.29 (3H, m), 7.54-7.61 (1H, m), 7.66-7.75 (2H, m), 8.33
(1H, br s). 13C NMR (CDCl3) δ (ppm): 21.4, 28.7, 32.1, 55.9, 62.2, 94.3, 121.8, 124.6, 127.0, 128.5, 128.6,
129.6, 131.1, 135.3, 137.0, 143.8. IR (neat): 3268, 2949, 1599, 1495, 1335, 1161, 1092, 1030, 923, 815,
761, 662 cm-1. HRFAB-MS calcd for C19H25NO5LiS (M+Li)+: 386.1613, found: 386.1588.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-trifluoroacetamide (6b)
Trifluoroacetic anhydride was added to a solution of 12 (500 mg, 1.6 mmol) in pyridine (5 mL) and the
mixture was stirred overnight at rt. The reaction mixture was poured into 1N HCl and then extracted with
AcOEt. The extract was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent,
hexane/AcOEt = 6/1 - 4/1) to give the N-trifluoroacetyl product as a pale yellow oil. 3N HCl (3 mL) was
added to a solution of the above-mentioned product in MeOH (6 mL) and the rusulting mixture was stirred
at rt for 1 h. The reaction mixture was poured into water and then extracted with AcOEt. The extract was
washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue

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was purified by column chromatography (silica gel; eluent, hexane/AcOEt = 2/1 - 1/1) to give 6b (439 mg,
1
85%) as a colorless oil. H NMR (CDCl3) δ (ppm): 1.36-1.92 (4H, m, including 1.40, t, J = 5.0 Hz),
1.95-2.12(1H, m), 3.39 (3H, s), 3.60-3.72 (2H, m), 4.62 (1H, d, J = 6.8 Hz), 4.65 (1H, d, J = 6.8 Hz), 4.74
(1H, dd, J = 6.8, 7.8 Hz), 7.15-7.21 (2H, m), 7.30-7.42 (1H, m), 8.19 (1H, d, J = 8.0 Hz), 10.11 (1H, br s). IR
(neat): 3301, 2950, 1732, 1594, 1546, 1454, 1283, 1156, 1027, 908, 762, 723 cm-1. HRFAB-MS calcd for
C14H18NO4F3Li (M+Li)+: 328.1348, found: 328.1359.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-4-nitrobenzamide (6c)
As a yellow oil, 6c (975 mg, 89%) was obtained by the same treatment of 12 (900 mg, 2.9 mmol) with
4-nitrobenzoyl chloride (810 mg, 4.4 mmol) as the case of 6b. 1H NMR (CDCl3) δ (ppm): 1.32-1.99 (4H,
m), 2.02-2.20 (1H, m), 3.41 (3H, s), 5.54-5.73 (2H, m), 4.68 (1H, d, J = 6.8 Hz), 4.71 (1H, d, J = 6.8 Hz),
4.77 (1H, t, J = 7.3 Hz), 7.09-7.24 (2H, m), 7.33-7.45 (1H, m), 8.04-8.18 (2H, m), 8.30-8.46 (3H, m), 9.93
(1H, br s). 13C NMR (CDCl3) δ (ppm): 29.1, 31.7, 56.1, 62.1, 79.1, 94.6, 122.7, 124.0, 124.9, 128.2, 128.9,
129.0, 129.6, 136.0, 140.3, 149.6, 162.9. IR (neat): 3344, 2948, 1678, 1604, 1590, 1526, 1450, 1348, 1313,
1027, 853, 761, 714 cm-1. HRFAB-MS calcd for C19H23N2O6 (M+H)+: 375.1556, found: 375.1579.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-4-iodobenzamide (6d)
As a white powder, 6d (643 mg, 87%) was obtained by the same treatment of 12 (500 mg, 1.6 mmol) with
1
4-iodobenzoyl chloride (646 mg, 2.4 mmol) as the case of 6b. mp 96-99 °C (Et2O-hexane). H NMR
(CDCl3) δ (ppm): 1.33-1.97 (4H, m, including 1.37, t, J = 5.3 Hz), 1.99-2.18 (1H, m), 3.40 (3H, s),
3.54-3.68 (2H, m), 4.66 (1H, d, J = 6.8 Hz), 4.69 (1H, d, J = 6.8 Hz), 4.74 (1H, t, J = 7.3 Hz), 7.05-7.21 (2H,
m), 7.30-7.42 (1H, m), 7.61-7.72 (2H, m), 7.81-7.93 (2H, m), 8.37 (1H, d, J = 8.0 Hz), 9.75 (1H, br s). 13C
NMR (CDCl3) δ (ppm): 29.2, 31.5, 56.1, 62.2, 79.3, 94.5, 98.9, 122.6, 124.4, 128.6, 128.9, 129.0, 129.2,
134.2, 136.5, 138.0, 164.3. IR (KBr): 3417, 3227, 2943, 1645, 1536, 1494, 1322, 1098, 1062, 1036, 966,
761 cm-1. HRFAB-MS calcd for C19H23NO4I (M+H)+: 456.0672, found: 456.0657.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-4-(o-toluoylamino)benzamide (6e)
As a colorless amorphous solid, 6e (535 mg, 72%) was obtained by the same treatment of 12 (500 mg, 1.6
mmol) with 4-(o-toluoylamino)benzoyl chloride (663 mg, 2.4 mmol) as the case of 6b. 1H NMR (CDCl3) δ
(ppm): 1.40-1.98 (4H, m), 2.00-2.19 (1H, m), 2.52 (3H, s), 3.42 (3H, s), 3.53-3.67 (2H, m), 4.67 (1H, d, J =
6.8 Hz), 4.70 (1H, d, J = 6.8 Hz), 4.76 (1H, t, J = 7.3 Hz), 7.04-7.21 (2H, m), 7.22-7.45 (4H, m), 7.51 (1H,
d, J = 7.8 Hz), 7.72-7.86 (3H, m), 7.89-8.00 (2H, m), 8.37 (1H, d, J = 8.0 Hz), 9.77 (1H, br s). 13C NMR
(CDCl3) δ (ppm): 19.8, 29.2, 31.5, 56.0, 62.1, 79.1, 94.4, 119.6, 122.8, 124.3, 125.8, 126.7, 128.1, 128.7,
129.0, 129.6, 130.1, 130.5, 131.2, 135.9, 136.5, 136.6, 141.4, 164.6, 168.5. IR (KBr): 3294, 2946, 1659,

HETEROCYCLES, Vol. 66, 2005
491
1592, 1514, 1447, 1317, 1263, 1024, 763 cm-1. HRFAB-MS calcd for C27H31N2O5 (M+H)+: 463.2233,
found: 463.2231.
N-[2-(4-Hydroxy-1-methoxymethoxybutyl)phenyl]-tert-butylcarbamate (6f)
A solution of 12 (500 mg, 1.6 mmol) and tert-butyl dicarbonate (0.74 mL, 3.2 mmol) in THF (5 mL) was
refluxed for 1 d. The reaction mixture was concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, hexane/AcOEt = 9/1 - 4/1) to give the N-tert-butyloxycarbonyl
compound as a colorless amorphous solid. Pyridinium p-toluenesulfonate (72 mg, 0.29 mmol) was added to
a solution of the above-mentioned product in EtOH (6mL) and the resulting mixture was stirred at 40 °C for
7 h. The reaction mixture was poured into water and then extracted with AcOEt. The extract was washed
with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica gel; eluent, hexane/AcOEt = 2/1) to give 6f (416 mg, 79%) as a
colorless oil. 1H NMR (CDCl3) δ (ppm): 1.39-1.94 (13H, m, including 1.52, s), 1.95-2.13 (1H, m), 3.39
(3H, s), 3.65 (2H, t, J = 6.5 Hz), 4.57 (1H, d, J = 6.8 Hz), 4.61 (1H, d, J = 6.8 Hz), 4.67 (1H, dd, J = 6.5, 7.5
Hz), 6.99 (1H, dt, J = 1.3, 7.5 Hz), 7.11 (1H, dd, J = 1.8, 7.5 Hz), 7.22-7.32 (1H, m), 7.85 (1H, br s),
7.90-7.99 (1H, m). 13C NMR (CDCl3) δ (ppm): 28.4, 29.2, 31.3, 55.9, 62.4, 78.5, 80.2, 94.2, 121.6, 123.0,
128.6, 128.8, 128.9, 136.9, 153.3. IR (neat): 3378, 2936, 1729, 1590, 1523, 1448, 1236, 1158, 1024, 756
cm-1. HRFAB-MS calcd for C17H27NO5 M+: 325.1889, found: 325.1903.
2-(1-tert-Butyldimethylsiloxybut-3-enyl)nitrobenzene (13)
tert-Butyldimethylsilyl chloride (19.6 g, 0.13 mol) was added to a solution of 8 (20.9 g, 0.11 mmoL) and
imidazole (26.6 g, 0.39 mol) in DMF (100 mL) and the mixture was stirred at rt for 12 h. The reaction
mixture was poured into water and then extracted with AcOEt. The extract was washed with water, brine,
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica
gel; eluent, hexane/AcOEt = 32/1) to give 13 (30.0 g, 90%) as a yellow oil. 1H NMR (CDCl3) δ (ppm):
-0.16 (3H, s), 0.02 (3H, s), 0.87 (9H, s), 2.31-2.46 (1H, m), 2.47-2.60 (1H, m), 4.97-5.09 (2H, m), 5.37 (1H,
dd, J = 4.0, 7.3 Hz), 5.75-5.95 (1H, m), 7.34-7.43 (1H, m), 7.57-7.66 (1H, m), 7.83 (1H, dd, J = 1.5, 8.0 Hz),
7.89 (1H, dd, J = 1.3, 8.3 Hz). 13C NMR (CDCl3) δ (ppm): -5.02, -4.97, 18.1, 25.7, 44.4, 69.6, 117.8,
123.9, 127.7, 128.8, 133.0, 134.3, 140.7, 147.1. IR (neat): 3078, 2956, 2930, 2858, 1610, 1529, 1346, 1258,
1091, 915, 836, 778, 745 cm-1. HRFAB-MS calcd for C16H24NO3Si (M-H)+: 306.1526, found: 306.1534.
2-(1-tert-Butyldimethylsiloxy-4-hydroxybutyl)nitrobenzene (14)
As a yellow oil, 14 (21.5 g, 87%) was obtained by the same treatment of 13 (23.3 g, 76 mmol) as that of 10.
1H NMR (CDCl3) δ (ppm): -0.19 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.40-1.97 (5H, m), 3.60-3.74 (2H, m),
5.29-5.40 (1H, m), 7.34-7.43 (1H, m), 7.57-7.66 (1H, m), 7.83 (1H, dd, J = 1.5, 8.0 Hz), 7.89 (1H, dd, J =

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1.3, 8.3 Hz). 13C NMR (ppm): -5.1, -4.9, 18.1, 25.7, 28.8, 36.3, 62.6, 69.4, 124.0, 127.7, 128.7, 133.1,
141.1, 147.0. IR (neat): 3332, 2930, 1526, 1343, 1252, 1060, 835, 775 cm-1. HRFAB-MS calcd for
C16H27NO4Si M+: 325.1709, found: 325.1702.
2-[1-tert-Butyldimethylsiloxy-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (15)
As a yellow oil, 15 (25.6 g, 95%) was obtained by the same treatment of 14 (21.4 g, 66 mmol) as that of 11.
1H NMR (CDCl3) δ (ppm): -0.18 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.43-1.92 (10H, m), 3.34-3.53 (2H, m),
3.68-3.91 (2H, m), 4.51-4.59 (1H, m), 5.30-5.39 (1H, m), 7.32-7.41 (1H, m), 7.54-7.64 (1H, m), 7.78-7.89
(2H, m). 13C NMR (CDCl3) δ (ppm): -5.1, -5.0, 18.1, 19.58, 19.60, 25.5, 25.7, 25.8, 25.9, 30.7, 36.6, 36.8,
62.2, 62.3, 67.1, 67.4, 69.4, 69.5, 98.8, 123.9, 127.6, 128.8, 132.9, 141.2, 141.3, 147.2. IR (neat): 2953,
2858, 1528, 1472, 1349, 1259, 1077, 1035, 837, 778 cm-1. HRFAB-MS calcd for C21H35NO5LiSi (M+Li)+:
416.2445, found: 416.2448.
2-[1-Hydroxy-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (16)
A solution of 15 (3.0 g, 7.3 mmol) and tetra-n-butylammonium fluoride (1 mol/L in THF, 15 mL, 15 mmol)
in THF (15 mL) was stirred at rt for 6 h. The reaction mixture was concentrated in vacuo. The residue was
added to water and then extracted with AcOEt. The extract was washed with water, brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent,
hexane/AcOEt = 4/1 - 2/1) to give 16 (2.1 g, 97%) as a yellow oil. 1H NMR (CDCl3) δ (ppm): 1.45-2.12
(10H, m), 3.41-3.62 (3H, m), 3.79-3.95 (2H, m), 4.59-4.67 (1H, m), 5.25-5.35 (1H, m), 7.35-7.45 (1H, m),
13
7.58-7.67 (1H, m), 7.82-7.93 (2H, m). C NMR (CDCl3) δ (ppm): 19.4, 19.6, 25.3, 26.5, 26.6, 30.46,
30.54, 36.1, 36.3, 62.3, 62.5, 67.3, 67.7, 69.0, 69.1, 98.9, 99.1, 124.2, 127.7, 128.0, 128.1, 133.3, 140.38,
140.41, 147.7. IR (neat): 3419, 2945, 1526, 1350, 1120, 1023, 856, 745 cm-1. HRFAB-MS calcd for
C15H21NO5Li (M+Li)+: 302.1580, found: 302.1566.
2-[1-N-Phthalimidoyl-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (17)
Diethyl azodicarboxylate (1.2 mL, 7.6 mmol) was added to a solution of 16 (2.1 g, 7.1 mmoL), phthalimide
(1.1 g, 7.5 mmol) and PPh3 (2.0 g, 7.6 mmol) in THF (30 mL) and the mixture was stirred at rt for 1.5 h
under a nitrogen atmosphere. The reaction mixture was concentrated in vacuo and then the residue was
purified by column chromatography (NH-silica gel; eluent, hexane/AcOEt = 9/1 - 8/2) to give 17 (2.2 g,
72%) as a yellow oil. 1H NMR (CDCl3) δ (ppm): 1.38-1.92 (8H, m), 2.26-2.48 (1H, m), 2.65-2.87 (1H, m),
3.39-3.54 (2H, m), 3.72-3.91 (2H, m), 4.53-4.62 (1H, m), 5.89-6.02 (1H, m), 7.36-7.46 (1H, m), 7.53-7.63
(1H, m), 7.65-7.75 (2H, m), 7.76-7.86 (3H, m), 7.96-8.05 (1H, m). 13C NMR (CDCl3) δ (ppm): 19.5, 25.4,
27.0, 27.1, 28.5, 28.8, 30.6, 49.8, 50.0, 62.3, 66.4, 66.8, 98.9, 123.3, 124.1, 128.6, 130.1, 131.47, 131.49,

HETEROCYCLES, Vol. 66, 2005
493
132.8, 134.1, 134.2, 134.3, 149.4, 168.3. IR (neat): 2943, 2870, 1774, 1714, 1530, 1353, 1120, 1076, 1033,
726 cm-1. HRFAB-MS calcd for C23H24N2O6Li (M+Li)+: 431.1794, found: 431.1796.
N-[2-[1-(N-Phthalimidoyl)-4-(tetrahydropyran-2-yloxy)butyl]phenyl]-p-toluenesufonamide (18)
A mixture of 17 (1.0 g, 2.4 mmol) and PtO2 (100 mg) in AcOEt (10 mL) was stirred at rt for 3 h under a
hydrogen atmosphere. The mixture was filtered and the residue was washed with AcOEt. The filtrate was
concentrated in vacuo to give a crude product as a yellow oil. p-Toluenesulfonyl chloride (900 mg, 4.7
mmol) was added to a solution of the above-mentioned product and pyridine (1.2 mL, 15 mmol) in CH2Cl2
(10 mL) and the resulting mixture was refluxed for 3 h. The reaction mixture was poured into 0.6N HCl and
then extracted with CH2Cl2. The extract was washed with 0.1N HCl, a saturated NaHCO3 solution, brine,
dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography
(NH-silica gel; eluent, hexane/AcOEt = 4/1 - 1/1 and then silica gel; eluent, hexane/CH2Cl2/AcOEt = 4/2/1
- 2/1/1) to give 18 (429 mg, 33%) as a colorless amorphous solid. 1H NMR (CDCl3) δ (ppm): 1.03-1.31 (2H,
m), 1.42-1.89 (7H, m), 2.37 (3H, s), 2.52-2.76 (1H, m), 3.16-3.30 (1H, m), 3.42-3.67 (2H, m), 3.75-3.89
(1H, m), 4.46-4.54 (1H, m), 4.80-4.91 (1H, m), 7.15-7.33 (4H, m), 7.55-7.62 (1H, m), 7.63-7.82 (7H, m),
8.14-8.22 (1H, m). IR (KBr): 3239, 2942, 2869, 1768, 1713, 1494, 1386, 1335, 1165, 1092, 1033, 815, 722,
666 cm-1. Anal. Calcd for C30H32N2O6S: C, 65.67; H, 5.88; N, 5.11. Found: C, 65.59; H, 5.89; N, 4.76.
N-[2-[4-Hydroxy-1-(N-phthalimidoyl)butyl]phenyl]-p-toluenesufonamide (6g)
3N HCl (3.5 mL) was added to a solution of 18 (612mg, 1.1 mmol) in MeOH (8 mL) and the mixture was
stirred at rt for 1 h. The reaction mixture was poured into water and then extracted with AcOEt. The extract
was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel; eluent, hexane/AcOEt = 7/3 and then
CH2Cl2/MeOH = 40/1) to give 6g (526 mg, quantitative) as a colorless amorphous solid. 1H NMR (CDCl3)
δ (ppm): 1.04-1.33 (3H, m, including 1.27, t, J = 5.3 Hz), 1.53-1.72 (1H, m), 2.38 (3H, s), 2.58-2.77 (1H,
m), 3.46-3.59 (2H, m), 4.92 (1H, dd, J = 6.0, 10.0 Hz), 7.15-7.33 (3H, m), 7.54 (1H, dd, J = 1.5, 8.0 Hz),
7.64-7.83 (8H, m), 8.17 (1H, br s). 13C NMR (CDCl3) δ (ppm): 21.4, 26.7, 29.8, 49.7, 61.9, 123.5, 126.3,
126.6, 127.1, 128.9, 129.1, 129.6, 131.3, 132.6, 134.3, 134.4, 137.0, 143.7, 169.0. IR (KBr): 3535, 3234,
2932, 1769, 1704, 1494, 1387, 1333, 1163, 1092, 722, 665 cm-1. HRFAB-MS calcd for C25H25N2O5S
(M+H)+: 465.1484, found: 465.1512.
2-[1-Azido-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (19)
A solution of diethyl azodicarboxylate (2.4 mL, 15 mmol) in THF (5 mL) and then a solution of
diphenylphosphryl azide (3.2 mL, 15 mmol) in THF (5 mL) were successively added in this order to a
solution of 16 (4.0 g, 14 mmol) and PPh3 (3.9 g, 15 mmol) in THF (40 mL) at 0 °C under a nitrogen

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atmosphere, and the resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was poured into a
saturated NaHCO3 solution and then extracted with AcOEt. The extract was washed with brine, dried over
Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (NH-silica gel;
1
eluent, hexane/AcOEt = 32/1 - 16/1) to give 19 (3.9 g, 86%) as a yellow oil. H NMR (CDCl3) δ (ppm):
1.38-2.06 (10H, m), 3.36-3.56 (2H, m), 3.71-3.91 (2H, m), 4.53-4.62 (1H, m), 5.23-5.34 (1H, m), 7.39-7.54
(1H, m), 7.62-7.73 (2H, m), 7.90-7.98 (1H, m). 13C NMR (CDCl3) δ (ppm): 19.5, 19.6, 25.4, 26.4, 30.61,
30.62, 33.7, 34.0, 60.8, 60.9, 62.27, 62.32, 66.6, 66.8, 98.8, 98.9, 124.60, 124.61, 128.5, 128.7, 133.6,
133.7, 135.67, 135.70, 148.2. IR (neat): 2943, 2098, 1527, 1351, 1121, 1075, 1033, 787, 744 cm-1.
HRFAB-MS calcd for C15H21N4O4 (M+H)+: 321.1563, found: 321.1580.
2-[1-tert-Butoxycarbonylamino-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (20)
A solution of 19 (3.8 g, 12 mmol) and PPh3 (3.8 g, 14 mmol) in THF (40 mL) was stirred at rt for 13 h. After
the addition of water, the mixture was stirred at 60 °C for 3.5h. Di-tert-butyl dicarboxylate (4.1 mL) was
added to the stirring mixture cooled down to rt and then the mixture was stirred at rt for 2.5 h. The reaction
mixture was poured into 0.2N HCl and then extracted with AcOEt. The extract was washed with a saturated
NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, hexane/AcOEt = 3/1) to give 20 (4.2 g, 92%) as a yellow oil. 1H NMR
(CDCl3) δ (ppm): 0.95-2.09 (19H, m), 3.34-3.60 (2H, m), 3.68-3.99 (2H, m), 4.50-4.64 (1H, m), 4.85-5.68
(2H, m), 7.32-7.44 (1H, m), 7.47-7.65 (2H, m), 7.81-7.97 (1H, m). IR (neat): 3338, 2943, 1704, 1527, 1366,
1167, 1023, 856, 786 cm-1. HRFAB-MS calcd for C20H31N2O6 (M+H)+: 395.2182, found: 395.2164.
2-[1-(N-Methyl-tert-butoxycarbonylamino)-4-(tetrahydropyran-2-yloxy)butyl]nitrobenzene (21)
A 60% dispersion of NaH in oil (183 mg, 4.6 mmol) was added to a solution of 20 (1.5 g, 3.8 mmol) and
MeI (0.40 mL, 6.4 mmol) in THF (15 mL) at 0 °C. The mixture was stirred at 0°C for 1 h and then at rt for
5 h. The reaction mixture was poured into water and then extracted with AcOEt. The extract was washed
with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
1
chromatography (NH-silica gel; eluent, hexane/AcOEt = 6/1) to give 21 (1.5 g, 97%) as a yellow oil. H
NMR (CDCl3) δ (ppm): 1.33-2.13 (19H, m, including 1.41, s), 2.66-2.80 (3H, m), 3.40-3.57 (2H, m),
3.75-3.94 (2H, m), 4.54-4.63 (1H, m), 5.62-5.75 (1H, m), 7.35-7.44 (1H, m), 7.45-7.59 (2H, m), 7.67-7.76
(1H, m). IR (neat): 2944, 2872, 1694, 1531, 1455, 1392, 1367, 1258, 1141, 1076, 1034, 869, 783 cm-1.
HRFAB-MS calcd for C21H33N2O6 (M+H)+: 409.2339, found: 409.2334.
2-[1-(N-Methyl-tert-butoxycarbonylamino)-4-(tetrahydropyran-2-yloxy)butyl]aniline (22)
As a yellow oil, 22 (1.3 g, quantitative) was synthesized from 21 (1.4 g, 3.4 mmol) by the same method as
that for 12. 1H NMR (CDCl3) δ (ppm): 1.37-2.19 (19H, m, including 1.48, s), 2.52 (3H, s), 3.41-3.58 (2H,

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m), 3.75-3.95 (2H, m), 4.03-4.69 (3H, m, including 4.38, br s), 5.06-5.45 (1H, m), 6.59-6.76 (2H, m),
7.01-7.19 (2H, m). IR (neat): 3456, 3370, 3252, 2942, 1670, 1458, 1392, 1366, 1329, 1139, 1033, 870, 749
cm-1. HRFAB-MS calcd for C21H35N2O4 (M+H)+: 379.2597, found: 379.2608.
N-[2-[4-Hydroxy-1-(N-methyl-tert-butoxycarbonylamino)butyl]phenyl]-p-toluenesufonamide (6h)
p-Toluenesulfonyl chloride (1.2 g, 6.3 mmol) was added to a solution of 21 (1.2 mg, 3.2 mmol) and
pyridine (1.5 mL, 19 mol) in CH2Cl2 (12 mL), and then the mixture was refluxed for 1.5 h. The reaction
mixture was poured into water and then extracted with CH2Cl2. The extract was washed with water, 0.5N
HCl, a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (NH-silica gel; eluent, hexane/AcOEt = 6/1 - 2/1) to give the
N-tosylated product as a pale yellow amorphous solid. Pyridinium p-toluenesulfonate (130 mg, 0.52 mmol)
was added to a solution of the above-mentioned product in EtOH (14 mL) and the rusulting mixture was
stirred at 40 °C for 7 h. The reaction mixture was poured into water and then extracted with AcOEt. The
extract was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel; eluent, CH2Cl2/MeOH = 50/1 - 45/1) to
1
give 6h (1.1 g, 78%) as a colorless amorphous solid. H NMR (CDCl3) δ (ppm): 1.02-1.68 (13H, m,
including 1.33, t, J = 5.0 Hz, 1.50, s), 1.80-2.01 (1H, m), 2.36 (3H, s), 2.49 (3H, s), 3.44-3.70 (2H, m), 4.87
(1H, dd, J = 5.5, 9.8 Hz), 7.03-7.32 (5H, m), 8.69-9.89 (3H, m), 9.35 (1H, br s). IR (KBr): 3454, 3178, 2936,
2866, 1621, 1494, 1455, 1397, 1338, 1162, 1092, 934, 814, 766, 688, 666 cm-1. Anal. Calcd for
C23H32N2O5S: C, 61.58; H, 7.19; N, 6.24. Found: C, 61.46; H, 7.02; N, 6.07.
N-[2-[4-Hydroxy-1-(N,N-dimethylamino)butyl]phenyl]-p-toluenesufonamide (6i)
6N HCl (3 mL) was added to a solution of 6h (580 mg, 1.3 mmol) in MeOH (12 mL) and the mixture was
stirred at rt for 2h and then at 60 °C for 0.5 h. The reaction mixture was poured into 0.5N NaOH solution,
saturated with NaCl and then extracted with CH2Cl2. The extract was washed with brine, dried over
Na2SO4, concentrated in vacuo to afford the crude product as a white powder. An aqueous solution of
formaldehyde (0.6 mL), NaBH3CN (132 mg, 2.1 mmol) and AcOH (0.4 mL) were added in this order to a
solution of the above-mentioned product in MeOH (10 mL) at 0 °C. The mixture was stirred at rt for 2.5 h.
5N NaOH (2 mL) and then brine was added to the mixture. It was then extracted with CH2Cl2 and the extract
was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, CH2Cl2/MeOH = 100/0 - 100/1) to give 6i (432 mg, 92%) as a colorless
amorphous solid. 1H NMR (CDCl3) δ (ppm): 0.79-0.99 (1H, m), 1.07-1.29 (1H, m), 1.46 (1H, dtd, J = 5.0,
10.8, 13.0 Hz), 1.79-1.99 (1H, m), 2.23 (6H, s), 2.37 (3H, m), 2.95 (1H, dd, J = 4.3, 10.8 Hz), 3.33 (1H,
quint., J = 6.3 Hz), 3.37 (1H, quint., 6.3 Hz), 6.87-6.97 (2H, m), 7.11-7.28 (3H, m), 7.46-7.56 (1H, m),

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13
7.72-7.82 (2H, m). C NMR (CDCl3) δ (ppm): 21.4, 26.3, 30.2, 43.0, 62.3, 71.7, 119.0, 122.8, 126.9,
128.0, 128.9, 129.5, 129.9, 137.1, 137.8, 143.3. IR (KBr): 3369, 3056, 2964, 1594, 1485, 1448, 1271, 1229,
1123, 1084, 1051, 1031, 970, 813, 752, 658 cm-1. Anal. Calcd for C19H26N2O3S: C, 62.96; H, 7.23; N, 7.73.
Found: C, 62.79; H, 7.12; N, 7.49.
2-[1-tert-Butyldimethylsiloxy-4-(tetrahydropyran-2-yloxy)butyl]aniline (23)
As a yellow oil, 23 (2.1 g, 75%) was synthesized from 15 (3.0 g, 7.3 mmol) by the same method as that of
12. 1H NMR (CDCl3) δ (ppm): -0.11 (3H, s), 0.06 (3H, s), 0.87 (9H, m), 1.38-2.11 (10H, m), 3.30-3.55 (2H,
m), 3.65-3.94 (2H, m), 4.29 (2H, br s), 4.50-4.59 (1H, m), 4.64 (1H, dd, J = 6.0, 7.8 Hz), 6.54-6.70 (2H, m),
6.92 (1H, dd, J = 1.5, 7.5 Hz), 7.03 (1H, dt, J = 1.5, 7.5 Hz). 13C NMR (CDCl3) δ (ppm): -5.2, -4.9, 18.1,
19.57, 19.63, 25.5, 25.6, 25.8, 26.6, 30,7, 33.0, 33.1, 62.2, 62.3, 67.36, 67.41, 98.8, 98.9, 116.7, 117.8,
127.9, 128.1, 144.5. IR (neat): 3459, 3369, 2951, 2857, 1616, 1497, 1462, 1257, 1137, 1121, 1034, 836,
778, 748 cm-1. HRFAB-MS calcd for C21H37NO3Si M+: 379.2543, found: 379.2532.
N-[2-[1-tert-Butyldimethylsiloxy-4-(tetrahydropyran-2-yloxy)butyl]phenyl]-p-toluenesufonamide
(24)
p-Toluenesulfonyl chloride (1.0 g, 5.2 mmol) was added to a solution of 23 (1.0 g, 2.6 mmol) and pyridine
(1.3 mL, 16 mol) in CH2Cl2 (10 mL) and the mixture was refluxed for 3 h. The reaction mixture was poured
into 0.4N HCl and then extracted with CH2Cl2. The extract was washed with 0.1N HCl, saturated NaHCO3
solution, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column
chromatography (silica gel; eluent, hexane/AcOEt = 9/1 - 4/1) to give 24 (1.3 g, 92%) as a pale yellow oil.
1H NMR (CDCl3) δ (ppm): -0.08 (3H, s), 0.09 (3H, s), 0.91 (9H, s), 1.08-1.92 (10H, m), 2.37 (3H, s),
3.06-3.24 (1H, m), 3.41-3.60 (2H, m), 3.74-3.91 (1H, m), 4.44-4.53 (1H, m), 4.54-4.65 (1H, m), 6.86-6.99
13
(2H, m), 7.13-7.28 (3H, m), 7.55-7.64 (1H, m), 7.70-7.79 (2H, m), 8.85 (1H, br s). C NMR (CDCl3) δ
(ppm): -5.2, -5.1, 18.1, 19.7, 21.4, 25.4, 25.7, 26.3, 30.7, 34.59, 34.65, 62.4, 66.9, 67.0, 77.6, 98.87, 98.94,
119.9, 120.0, 123.2, 123.3, 127.0, 128.1, 128.2, 129.5, 131.5, 131.6, 136.1, 137.5, 143.49, 143.53. IR
(neat): 3249, 2952, 2859, 1586, 1495, 1342, 1165, 1035, 839, 780 cm-1. Anal. Calcd for C28H43NO5SSi: C,
63.00; H, 8.12; N, 2.62. Found: C, 62.74; H, 7.87; N, 2.31.
N-[2-[1-Hydroxy-4-(tetrahydropyran-2-yl)oxybutyl]phenyl]-p-toluenesufonamide (25)
As a pale yellow amorphous solid, 25 (3.1 g, 96%) was synthesized from 24 (4.1 g, 7.7 mmol) by the same
1
method as that of 16. H NMR (CDCl3) δ (ppm): 1.46-1.94 (10H, m), 2.37 (3H, s), 3.28-3.63 (2H, m),
3.69-3.97 (3H, m), 4.58-4.74 (2H, m), 6.95-7.06 (2H, m), 7.12-7.29 (3H, m), 7.44-7.54 (1H, m), 7.67-7.76
(2H, m), 8.73-8.92 (1H, m). 13C NMR (CDCl3) δ (ppm): 19.59, 19.64, 21.4, 25.19, 25.24, 26.6, 26.7, 30.49,

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30.54, 34.8, 35.0, 62.6, 62.7, 67.4, 67.7, 74.6, 74.7, 99.2, 99.3, 121.3, 124.1, 127.1, 127.7, 128.2, 129.5,
132.8, 135.9, 137.2, 143.49, 143.53. IR (neat): 3237, 2946, 1586, 1495, 1337, 1161, 1092, 1022, 813, 759,
662 cm-1. HRFAB-MS calcd for C22H29NO5S M+: 419.1766, found: 419.1796.
N-[2-[1-Oxo-4-(tetrahydropyran-2-yloxy)butyl]phenyl]-p-toluenesufonamide (26)
A solution of 25 (1.2 g, 2.9 mmol) and o-iodoxybenzoic acid (1.0 g, 3.6 mmol) was stirred at rt for 14 h. A
solution of 25% Na2S2O4 saturated with NaHCO3 was added to the stirring mixture and the mixture was
stirred at rt for 1 h. The reaction mixture was poured into water and then extracted with AcOEt. The extract
was washed with a saturated NaHCO3 solution, water, brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel; eluent, hexane/AcOEt = 2/1) to give 26
(810 mg, 66%) as a pale yellow amorphous solid. 1H NMR (CDCl3) δ (ppm): 1.43-2.02 (8H, m), 2.36 (3H,
s), 2.96-3.07 (2H, m), 3.38-3.56 (2H, m), 3.72-3.90 (2H, m), 4.50-4.59 (1H, m), 7.00-7.10 (1H, m),
7.16-7.25 (2H, m), 7.39-7.49 (1H, m), 7.65-7.77 (3H, m), 7.85 (1H, dd, J = 1.5, 8.0 Hz), 11.43 (1H, br s).
13C NMR (CDCl3) δ (ppm): 19.7, 21.4, 24.5, 25.4, 30.7, 36.3, 62.6, 66.3, 99.1, 119.4, 122.4, 122.6, 127.2,
129.6, 131.0, 134.5, 136.6, 139.9, 143.8, 204.1. IR (KBr): 2943, 1651, 1602, 1577, 1494, 1452, 1342, 1161,
1091, 1033, 922, 814, 756, 662 cm-1. HRFAB-MS calcd for C22H27NO5LiS (M+Li)+: 424.1770, found:
424.1772.
N-[2-[4-Hydroxy-1-oxobutyl]phenyl]-p-toluenesufonamide (6j)
As colorless needles, 6j (457 mg, 78%) was synthesized from 26 (743 mg, 1.8 mmol) by the same method as
that of 6g, mp 114-117 °C (AcOEt - hexane). 1H NMR (CDCl3) δ (ppm): 1.49 (1H, t, J = 5.3 Hz), 1.84-2.00
(2H, m), 2.36 (3H, s), 3.04 (2H, t, J = 7.0 Hz), 3.70 (2H, q, J = 5.3 Hz), 7.00-7.11 (1H, m), 7.17-7.25 (2H,
13
m), 7.39-7.50 (1H, m), 7.64-7.77 (3H, m), 7.85 (1H, dd, J = 1.3, 8.0 Hz), 11.37 (1H, br s). C NMR
(CDCl3) δ (ppm): 21.5, 26.9, 36.1, 61.8, 119.3, 122.3, 122.7, 127.2, 129.6, 131.0, 134.7, 136.5, 139.9,
143.9, 204.4. IR (KBr): 3301, 3051, 2955, 1660, 1495, 1340, 1186, 1172, 1160, 1092, 915, 760, 706 cm-1.
Anal. Calcd for C17H19NO4S: C, 61.24; H, 5.74; N, 4.20. Found: C, 61.08; H, 5.63; N, 3.81.
1-(p-Toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (30)
A 60% dispersion of NaH in oil (500 mg, 13 mmol) was added to a solution of 2,3,4,5-tetrahydro-1H-
1-benzazepin-2-one (29) (2.0 g, 12 mmol) in THF (30 mL) , and the mixture was stirred at rt for 30 mim.
p-Toluenesulfonyl chloride (2.4 g, 13 mmol) was added to the mixture at 0 °C. The mixture was stirred at rt
for 2 h. The reaction mixture was poured into an aqueous citric acid solution and then extracted with
AcOEt. The extract was washed with a saturated NaHCO3 solution, brine, dried over Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography (silica gel; eluent,
1
hexane/AcOEt = 6/1 - 3/1) to give 30 (3.2 g, 83%) as a colorless amorphous solid. H NMR (CDCl3) δ

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(ppm): 1.66-1.97 (1H, m), 2.00-2.29 (3H, m), 2.41-2.61 (5H, m, including 2.45, s), 7.18-7.26 (1H, m),
7.29-7.22 (4H, m), 7.48-7.58 (1H, m), 7.87-7.96 (2H, m). IR (KBr): 2917, 1708, 1488, 1365, 1168, 1138,
1087, 765, 686, 654 cm-1. Anal. Calcd for C17H17NO3S: C, 64.74; H, 5.43; N, 4.44. Found: C, 64.34; H,
5.41; N, 4.19.
N-[2-(4-Hydroxypentyl)phenyl]-p-toluenesufonamide (27a)
A solution of DIBAL in toluene (1 mol/L, 2.5 mL, 2.5 mmol) was added to a solution of 30 (750 mg, 2.4
mmol) in THF (15 mL) under a nitrogen atmosphere at –78 °C, and the mixture was stirred at the same
temperature for 1 d. The reaction mixture was quenched with MeOH, then poured into an aqueous NH4Cl
solution and extracted with AcOEt. The extract was washed with a saturated NH4Cl solution, brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel;
eluent, hexane/CH2Cl2/AcOEt = 8/3/1 - 4/2/1) to give the reduced product as a colorless amorphous solid. A
solution of MeMgBr in THF (0.93 mol/L, 4.1 mL, 3.8 mmol) was added to a solution of the above-
mentioned product in THF (10 mL) under a nitrogen atmosphere at 0 °C, and the mixture was stirred at the
same temperature for 2 d. The reaction mixture was poured into a saturated NH4Cl solution and then
extracted with AcOEt. The extract was washed with water, brine, dried over Na2SO4 and concentrated in
vacuo. The residue was purified by column chromatography (silica gel; eluent, hexane/CH2Cl2/AcOEt =
4/2/1 - 2/1/1) to give 27a (465 mg, 58%) as a pale yellow oil. 1H NMR (CDCl3) δ (ppm): 1.13-1.64 (7H, m,
including 1.23, d, J = 6.3 Hz), 1.85 (1H, br s), 2.25-2.50 (5H, m, including 2.37, s), 3.87-4.03 (1H, m),
7.02-7.24 (5H, m), 7.36-7.44 (1H, m), 7.57-7.67 (2H, m), 7.73 (1H, br s). 13C NMR (CDCl3) δ (ppm): 21.5,
24.1, 27.0, 30.2, 36.4, 68.3, 123.6, 125.6, 126.8, 127.1, 129.5, 129.8, 134.6, 135.2, 136.8, 143.5. IR (neat):
3503, 3278, 2966, 2927, 1599, 1493, 1329, 1159, 1092, 923, 815, 757, 663 cm-1. HRFAB-MS calcd for
C18H23NO3S M+: 333.1399, found: 333.1421.
N-[2-(4-Hydroxy-4-methylpentyl)phenyl]-p-toluenesufonamide (27b)
A solution of MeMgBr in THF (0.93 mol/L, 4.1 mL, 3.7 mmol) was added to a solution of 30 (400 mg, 1.3
mmol) in THF (5 mL) under an argon atmosphere at rt. The mixture was then refluxed for 2 h. The reaction
mixture was cooled to 0 °C, then poured into a saturated NH4Cl solution and extracted with AcOEt. The
extract was washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography (silica gel; eluent, hexane/AcOEt = 2/1) to give 27b (365 mg, 83%) as
a colorless oil. 1H NMR (CDCl3) δ (ppm): 1.24 (6H, s), 1.34-1.46 (2H, m), 1.47-1.63 (2H, m), 1.78 (1H, br
s), 2.31-2.44 (5H, m, including 2.37, s), 7.01-7.25 (5H, m), 7.36-7.45 (1H, m), 7.57-7.66 (2H, m), 7.79 (1H,
13
br s). C NMR (CDCl3) δ (ppm): 21.5, 25.2, 29.8, 30.9, 40.9, 71.7, 123.7, 125.7, 126.7, 127.1, 129.4,
129.8, 134.6, 135.3, 136.8, 143.4. IR (neat): 3510, 3279, 2969, 1599, 1493, 1330, 1160, 1092, 911, 814,

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758, 662 cm-1. HRFAB-MS calcd for C19H25NO3S M+: 347.1555, found: 347.1552.
General procedure of intramolecular Mitsunobu reaction with substrate (6a-j) and (27a,b)
Diethyl azodicarboxylate (50 μL, 0.32 mmol) was added to a solution of the substrate (6a-j and 27a,b, 0.26
mmoL) and PPh3 (84 mg, 0.32 mmol) in THF (3 mL) under a nitrogen atmosphere at 0 °C and the resulting
mixture was stirred at rt within 1d. After removal of the THF, the residue was purified by column
chromatography (NH-silica gel; eluent, hexane/AcOEt = 9/1 – 7/3) to obtain the benzazepin 7a-j and 28a.
These yields are listed in Tables 1-3 and their spectrum data are listed below.
5-Methoxymethoxy-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (7a)
As a white powder, mp 67-70 °C (CH2Cl2 - hexane). 1H NMR (CDCl3) δ (ppm): 1.43-2.04 (4H, m), 2.41
(3H, s), 3.05-3.42 (4H, m, including 3.29, s), 3.90-4.19 (1H, m), 4.23-4.40 (2H, m, including 4.33, d, J = 6.5
Hz), 4.53 (1H, d, J = 6.5 Hz), 7.18-7.37 (5H, m), 7.38-7.46 (1H, m), 7.60-7.69 (2H, m). IR (KBr): 2941,
1596, 1495, 1445, 1327, 1157, 1104, 1090, 1028, 814, 773, 710 cm-1. Anal. Calcd for C19H23NO4S: C,
63.13; H, 6.41; N, 3.88. Found: C, 63.16; H, 6.30; N, 3.64.
5-Methoxymethoxy-1-trifluoroacetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (7b)
As a colorless oil. 1H NMR (CDCl3) δ (ppm): 1.52-1.88 (2H, m), 2.02-2.33 (1.4H, m), 2.44-2.68 (0.6H, m),
2.71-2.95 (1H, m), 3.34 (1.8H, s), 3.38 (1.2H, s), 4.40 (0.6H, d, J = 7.0 Hz), 4.43 (0.6H, d, J = 7.0 Hz),
4.52-4.71 (1.4H, m, including 4.63, d, J = 6.8 Hz), 4.73-4.86 (1.4H, m, including 4.78, d, J = 6.8 Hz),
7.15-7.39 (3.2H, m), 7.40-7.48 (0.4H, m), 7.56-7.65 (0.4H, m). IR (neat): 2936, 1697, 1496, 1426, 1201,
1149, 1034, 919, 757 cm-1. Anal. Calcd for C14H16NO3F3: C, 55.44; H, 5.32; N, 4.62. Found: C, 55.46; H,
5.40; N, 4.37.
5-Methoxymethoxy-1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (7c)
1
As a pale yellow amorphous solid. H NMR (CDCl3) δ (ppm): 1.18-1.30 (2H, m), 1.60-1.91 (2H, m),
2.75-3.06 (1H, m), 3.40 (1.5H, s), 3.45 (1.5H, s), 4.54-4.79 (2H, m), 4.80-4.94 (1H, m), 4.97-5.18 (1H, m),
6.52-6.68 (1H, m), 6.89-7.05 (1H, m), 7.05-7.19 (0.5H, m), 7.19-7.30 (1H, m), 7.31-7.46 (1H, m),
7.51-7.65 (1.5H, m), 7.91-8.12 (2H, m). IR (KBr): 2921, 1641, 1529, 1409, 1352, 1313, 1144, 1098, 1023,
850 cm-1. Anal. Calcd for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86. Found: C, 63.81; H, 5.72; N, 7.65.
5-Methoxymethoxy-1-(4-iodobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (7d)
1
As a colorless oil. H NMR (CDCl3) δ (ppm): 1.59-1.87 (2H, m), 1.93-2.56 (2H, m), 2.70-3.00 (1H, m),
3.37 (1.2H, s), 3.42 (1.8H, s), 4.58-4.78 (2H, m), 4.79-4.91 (1H, m), 4.96-5.14 (1H, m), 6.54-6.70 (1H, m),
6.86-7.06 (2H, m), 7.06-7.31 (2.6H, m), 7.40-7.61 (2.4H, m). IR (neat): 2938, 1644, 1583, 1489, 1397,

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1312, 1145, 1029, 1008, 918, 835, 750 cm-1. HRFAB-MS calcd for C19H21NO3I (M+H)+: 438.0566, found:
438.0567.
5-Methoxymethoxy-1-[4-(o-toluoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (7e)
As a colorless amorphous solid. 1H NMR (CDCl3) δ (ppm): 1.59-1.90 (2H, m), 1.94-2.52 (5H, m, including
2.46, s), 2.67-3.05 (1H, m), 3.30-3.49 (3H, m, including 3.39, s, 3.44, s), 4.50-4.96 (3H, m), 4.96-5.24 (1H,
m), 6.55-6.79 (1H, m), 6.93-7.69 (12H, m). IR (KBr): 3289, 3256, 2946, 1678, 1625, 1595, 1525, 1395,
1322, 1026, 846, 761 cm-1. Anal. Calcd for C27H28N2O4: C, 72.95; H, 6.35; N, 6.30. Found: C, 72.96; H,
6.35; N, 6.02.
5-Methoxymethoxy-1-tert-butoxycarbony-2,3,4,5-tetrahydro-1H-1-benzazepine (7f)
As a colorless oil. 1H NMR (CDCl3) δ (ppm): 1.08-4.97 (21H, m, including 1.34, s, 1.51, s, 3.35, br. s),
6.88-7.67 (4H, m). IR (neat): 2930, 1702, 1391, 1365, 1314, 1165, 1035, 926, 834, 760 cm-1. HRFAB-MS
calcd for C17H26NO4 (M+H)+: 308.1862, found: 308.1854.
5-(N-Phthalimidoyl)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (7g)
1
As colorless needles, mp 216-218 °C (CH2Cl2 - hexane). H NMR (CDCl3) δ (ppm): 1.70-2.07 (3H, m),
2.40-2.60 (4H, m, including 2.46, s), 3.07 (1H, ddd, J = 3.3, 11.3, 14.5 Hz), 4.44 (td, J = 3.8, 14.5 Hz), 5.35
(1H, dd, J = 1.8, 11.3 Hz), 6.84-6.95 (1H, m), 7.09-7.25 (2H, m), 7.29-7.45 (3H, m), 7.70-7.82 (4H, m),
7.83-7.94 (2H, m). IR (KBr): 2924, 1779, 1714, 1390, 1372, 1336, 1155, 1091, 886, 723, 711, 690, 650
cm-1. Anal. Calcd for C25H22N2O4S: C, 67.25; H, 4.97; N, 6.27. Found: C, 67.28; H, 5.02; N, 6.12.
5-(N-Methyl-tert-butoxycarbonylamino)-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine
(7h)
As a colorless amorphous solid. 1H NMR (CDCl3) δ (ppm): 1.43 (9H, br s), 1.65-2.24 (4H, m), 2.43 (3H, s),
2.60-3.39 (4H, m, including 2.83, br s), 3.93-4.40 (1H, m), 4.53-5.40 (1H, m), 6.93-7.38 (6H, m), 7.63-7.83
(2H, m). IR (KBr): 2937, 1689, 1344, 1156, 1094, 858, 776, 710, 698 cm-1. Anal. Calcd for C23H30N2O4S:
C, 64.16; H, 7.02; N, 6.51. Found: C, 63.95; H, 6.87; N, 6.30.
2-Methyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-1-benzazepine (28a)
As colorless granular, mp 90-92 °C (CH2Cl2 - hexane). 1H NMR (CDCl3) δ (ppm): 0.94 (3H, d, J = 7.0 Hz),
1.31-1.71 (3H, m), 1.82-2.01 (1H, m), 2.20-2.48 (5H, m, including 2.41, s), 4.56-4.74 (1H, m), 7.03-7.78
(6H, m), 7.54-7.67 (2H, m). IR (KBr): 2931, 1494, 1455, 1335, 1164, 1135, 1092, 1034, 932, 824, 769, 687,
659 cm-1. Anal. Calcd for C18H21NO2S: C, 68.54; H, 6.71; N, 4.44. Found: C, 68.43; H, 6.54; N,
4.14.

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