A new synthesis of phenolic 1-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-Benzazepines

Article abstract of DOI:10.3987/COM-05-10554

7,8-Dihydroxy-1-phenyl- and 1-(3- and 4-hydroxyphenyl)-1-hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives (2a,b) and (3a-c) were synthesized by intramolecular Barbier reaction of N-(2-iodophenethyl)-phenacylamines (5a,b) and (12a-c) with n-C_4<

Full text of DOI:10.3987/COM-05-10554

HETEROCYCLES, Vol. 65, No. 12, 2005
2925
HETEROCYCLES, Vol. 65, No. 12, 2005, pp. 2925 - 2935
Received, 5th September, 2005, Accepted, 14th October, 2005, Published online, 14th October, 2005
A NEW SYNTHESIS OF PHENOLIC 1-HYDROXY-1-
PHENYL-2, 3, 4, 5-TETRAHYDRO-1H-3-BENZAZEPINES
Motoki Ikeuchi, Miyuki Ikeuchi, Kumiko Inoue, Syuhei Yamamoto, Aiko
Yamauchi, and Masaru Kihara*
Faculty of Pharmaceutical Sciences, The University of Tokushima, 1-78, Sho-
machi, Tokushima 770-8505, Japan; e-mail: mkihara@ph.tokushima-u.ac.jp
Abstract –
7,8-Dihydroxy-1-phenyl- and 1-(3- and 4-hydroxyphenyl)-1-
hydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine derivatives (2a,b) and (3a-c) were
synthesized by intramolecular Barbier reaction of N-(2-iodophenethyl)-
phenacylamines (5a,b) and (12a-c) with n-C4H9Li as a key reaction step.
INTRODUCTION
3-Benzazepine compounds have attracted considerable interest in the past two decades because of their
therapeutic potential of dopamine D1 antagonists as antipsychotics.1 The discovery of SCH 23390,2 the
first high-affinity and selective D1/D5 antagonist along with the partial agonist SKF 383933 represented a
major break-through in the pharmacology of dopamine receptors.4 In addition, fenoldopam is a selective
peripheral D1 agonist and has been developed as a parenteral treatment for emergencies5 (Figure 1).
We have reported that 4-hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (1a: PI-OH)6 and its
phenolic derivatives (1b,c)7 having an ethanolamine moiety showed the strong norepinephrine (NE)
potentiating activity due to the NE reuptake inhibiting effect. From these facts, phenolic 1-hydroxy-1-
phenyl-2, 3, 4, 5-tetrahydo-1H-3-benzazepine derivatives (2) and (3) bearing the ethanolamine moiety are
interesting compounds in the pharmacological and synthetic points of view. We now report a new
synthetic method for the preparation of phenolic 1-hydroxy-1-phenyl-3-benzazepines (2) and (3).
RESULTS AND DISCUSSION
In our previous papers, we reported the convenient synthesis of PI-OH (1a) and the related compounds,8
and 3-hydroxy-3-phenylindole (4)9 by intramolecular Barbier reaction of corresponding N-benzyl- and N-
phenylphenacylamines with n-C4H9Li in good yields. Thus, we carried out the synthesis of 7, 8-dihydr-

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HETEROCYCLES, Vol. 65, No. 12, 2005
Cl
N-CH
OH
3
1
R
HO
2
NR
NH
HO
HO
2
R
1
R
Fenoldopam
R1=Cl, R2=CH3 (SCH 23390)
R1=OH, R2=H (SKF 38393)
1a-c
OH
a: R1=R2=H (PI-OH)
b: R1=OH, R2=H
c: R1=H, R2=OH
HO
N R
HO
OH
N-CH
OH
3
CH
N
3
OH
2
R
3a-c
1
2a,b
4
R
a: R=CH3
b: R=CH2C6H5
a: R1=OCH3, R2=H
b: R1=OH, R2=H
c: R1=H, R2=OH
Figure 1
RO
RO
CH CH NH TBDMSO
CH CH NHR TBDMSO
CH CH NHR
2 2
2
2
2
2
2
I
TBDMSO
TBDMSO
7a,b
8a,b
9a-d
a:R=H; b: R=TBDMS
a:R=CHO; b: R=COC6H5;
a:R=CHO; b: R=COC6H5
c: R=CH3; d: R=CH2C6H5
TBDMSO
TBDMSO
CH CH NHR
2
2
R
COCH NCH CH
OTBDMS
OTBDMS
I
2
2
2
9c,d
I
5a,b
COCH Br
2
a:R=CH3; b: R=CH2C6H5
10
R
TBDMSO
COCH NCH CH
N R
OH
OTBDMS
OTBDMS
n-C H Li
2
2
2
4
9
+
TBDMSO
11a,b
6a,b
TBAF
a:R=CH3; b: R=CH2C6H5
HO
HO
N R
OH
2a,b
Scheme 1
oxy-1-phenyl-3-benzazepines (2a,b) by intramolecular Barbier reaction of N-methyl- and N-benzyl-N-(2-
iodophenethyl)phenacylamines (5a,b), of which the phenolic hydroxy groups were protected with a
t-butyldimethylsilyl (TBDMS) group (Scheme 1). The key intermediates (5a,b) were prepared by the

HETEROCYCLES, Vol. 65, No. 12, 2005
2927
condensation of phenacyl bromide (10) with phenolic N-alkyl-2-iodophenethylamines (9c,d) protected
with silyl groups, which were obtained by acylation of the silylated phenethylamine (7b) derived from
3,4-dihydroxyphenethylamine (7a), followed by iodination of the products (8a,b) and reduction of the
acyl compounds (9a,b) with diborane.
The cyclization of 5a,b with n-C4H9Li gave the protected 1-phenyl-3-benzazepines (6a,b) in 16.9 and
31.8% yields, along with deiodinated by-products (11a,b) of the starting material (5a,b) in the yields of
24.7 and 31.3%, respectively. Finally the deprotection of the silyl groups in 6a,b with tetrabutyl-
ammonium fluoride (TBAF) gave the target compounds (2a,b).
In the same way for the preparation of 2a,b as described above, the 3-benzazepines (3a-c) with a
substituted 1-phenyl group were synthesized as shown in Scheme 2. The key intermediates (12a-c) were
synthesized by condensation of phenacyl bromides (15a-c) with 2-iodo-N-methylphenethylamine (14).
Compound (14) was prepared by diborane reduction of 2-iodobenzyl cyanide (17) obtained from
2-iodobenzyl bromide (16) with sodium cyanide, followed by formylation of the produced
phenethylamine (18) and then by reduction of the amide (19) in high over all yields from 16.
CH Br
2
CH CN
2
CH CH NH
2 2 2
I
NaCN
BH -THF
3
I
I
16
18
17
CH CH NHCH
2
CH CH NHCHO
2
2
3
2
I
I
HCOOC H -C H OH(1:1)
2
5
2 5
BH -THF
3
14
19
CH CH NHCH
2
2
3
CH
3
I
2
1
14
R
COCH NCH CH
2
2
2
2
R
COCH Br
2
in dioxane
R
I
12a-c
1
R
15a-c
CH
3
2
1
R
R
COCH NCH CH
CH
N
n-C4H9Li
3
2
2
2
+
20a-c
OH
1
2
R
R
2
R
13b,c
a: OCH3
b:
c:
H
H
1
R
OTBDMS
H
OTBDMS
TBAF
CH
N
3
1
2
OH
R
a: OCH3
R
H
b:
c:
H
OH
OH
H
2
R
1
R
3a-c
Scheme 2

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HETEROCYCLES, Vol. 65, No. 12, 2005
Intramolecular Barbier cyclization of 12a with n-C4H9Li gave 4-(4-methoxyphenyl)-3-benzazepine (3a)
in 14.6% yield with a deiodinated by-product (20a) in 26.7% yield. The protected phenolic
3-benzazepines (13b,c) were obtained by the treatment of 12b,c with n-C4H9Li in 20.8 and 17.2% yields,
respectively. Then the deprotection of 13b,c with TBAF gave the 3-benzazepines (3b,c) in 60.9 and
85.6% yields, respectively.
In conclusion, an intramolecular Barbier reaction of N-(2-iodophenethyl)phenacylamines with n-C4H9Li
in this study provides an applicable method for the preparation of 1-hydroxy-1-phenyl-2,3,4,5-tetrahydro-
1H-3- benzazepine derivatives.
EXPERIMENTAL
General
All melting points are given as uncorrected values. IR spectra were taken with a
Perkin-Elmer 1720 infrared fourier transform spectrophotometer. High-resolution mass (HR-MS) spectra
1
were recorded on a JEOL JMS-D 300 spectrometer. H-NMR spectra were recorded on a JEOL JNM-FX
200 spectrometer with TMS as a standard.
2-[3,4-Di(t-butyldimethylsilyloxy)]phenethylamine (7b)
A mixture of the hydrochloride (1.357 g.
7.16 mmol) of 7a, t-butyldimethylsilyl chloride (TBDMSCl) (3.236 g, 21.5 mmol) and imidazole (2.150
g, 35.8 mmol) in dry CH2Cl2 (30 mL) was stirred under N2 at rt for 2 h. The precipitates formed were
filtered. The filtrate was evaporated to give an oil (5.560 g). This was subjected to flash chromatography
1
on SiO with CH Cl -CH OH (5:1) to afford 7b as a pale yellow oil (2.617 g, 95.8 %). H-NMR
2
2
2
3
(CDCl ) δ: 6.75 (1H, d, J=7.8 Hz), 6.67 (1H, d, J=2.2 Hz), 6.62 (1H,dd, J=7.8, 2.0 Hz), 2.90 (2H, t, J=6.6
3
-1
Hz), 1.47 (2H, br s), 0.98 (18H, s), 0.19 (12H, s); IR (liquid film) cm : 2930, 2859, 1295, 910. HR-MS
m/z: Calcd for C20H39NO2Si2: 381.2519 (M+). Found: 381.2520.
2-[3,4-Di(t-butyldimethylsilyloxy)phenyl]-N-formylethylamine (8a)
A mixture of 7b (2.353 g, 6.16
mmol), K2CO3 (8.518 g, 61.6 mmol), and 4A molecular sieves (8 g) in HCOOC2H5-C2H5OH (1:1) (100
mL) was refluxed under N2 for 3 h. The mixture was filtered. The filtrate was evaporated and H2O (50
mL) was added. The mixture was extracted with CH2Cl2 (50 mL x 3). The extract was washed with H2O,
dried over MgSO4, and evaporated to give a pale yellow oil (2.377 g). This was subjected to flash
chromatography on SiO2 with CH2Cl2-acetone (5:1) to give 8a as a pale yellow oil (2.110 g, 83.6 %).
1
H-NMR (CDCl ) δ: 8.11 (1H, s), 6.76 (1H, d, J=7.6 Hz), 6.63 (2H, m), 5.60 (1H, br s), 3.55-3.42 (2H,
3
-1
m), 2.70 (2H, t, J=6.6 Hz), 0.98 (18H, s), 0.19 (12H, s). IR (liquid film) cm : 3286, 3051, 1668, 1254.
HR-MS m/z: Calcd for C21H39NO3Si2: 409.2468 (M+). Found: 409.2437.
2-[4,5-Di(t-butyldimethylsilyloxy)-2-iodophenyl]-N-formylethylamine (9a)
A solution of iodine
(1.187 g, 4.68 mmol) in CHCl3 (80 mL) was added to a solution of 8a (1.192 g, 4.68 mmol) and silver
trifluoroacetate (1.032 g, 4.68 mmol) in CHCl3 (20 mL) under stirring at rt for 15 min. The mixture was

HETEROCYCLES, Vol. 65, No. 12, 2005
2929
filtered and the filtrate was washed with a saturated solution of Na2CO3 in H2O (50 mL). The CHCl3
solution was dried over MgSO4 and evaporated to give a pale yellow oil (2.370 g). This was subjected to
flash chromatography on SiO2 with CH2Cl2-acetone (10:1) to give 9a as a pale yellow oil (2.365 g,
1
94.4 %). H-NMR (CDCl ) δ: 8.16 (1H, s), 7.25 (1H, s), 6.69 (1H, s), 3.56-3.46 (2H, m), 2.84 (2H, t,
3
-1
J=6.8 Hz), 0.98 (18H, s), 0.19 (12H, s). IR (liquid film) cm : 3283, 2981, 2859, 1667, 1256. HR-MS m/z:
Calcd for C21H38NO3ISi2: 535.1436 (M+). Found: 535.1435.
2-[4,5-Di(t-butyldimethylsilyloxy)-2-iodophenyl]-N-methylethylamine (9c)
To a solution of 9a
(2.114 g, 3.95 mmol) in dry THF (10 mL) was added BH3 (11.9 mL of 1M solution in THF, 11.9 mmol).
The mixture was refluxed under N2 for 1 h. C2H5OH (20 mL) was added and the mixture was evaporated
to give a colorless oil (1.988 g). H2O (50 ml) was added and the mixture was extracted with CH2Cl2. The
extract was washed with a saturated solution of K2CO3 in H2O (50 mL x 2), dried over MgSO4, and
evaporated to give a pale yellow oil (1.687 g). This was subjected to flash chromatography on SiO2 with
1
CH Cl -CH OH (5:1) to give 9c as a pale yellow oil (0.673 g, 32.7 %). H-NMR (CDCl ) δ: 7.23 (1H, s),
3
2
2
3
6.72 (1H, s), 2.80 (4H, s), 2.46 (3H, s), 1.74 (1H, br s), 0.98 (9H, s), 0.97 (9H, s), 0.19 (6H, s), 0.18 (6H,
-1
s). IR (liquid film) cm : 2931, 2858, 1256, 910. HR-MS m/z: Calcd for C21H40NO2ISi2: 522.1722 (M+ 1).
Found: 522.1715.
Ν-Βenzoyl-2-[3,4-di(t-butyldimethylsilyloxy)phenyl]ethylamine (8b)
A mixture of benzoyl
chloride (0.813 g, 5.79 mmol) in benzene (15 mL) and 25% NaOH (14 mL, 131 mmol) were added to a
solution of 7b (1.472 g, 3.86 mmol) in benzene (15 mL). The mixture was stirred at rt for 1 h. H2O (100
mL) was added and the mixture was extracted with CH2Cl2 (100 mL x 3). The extract was dried over
MgSO4 and evaporated to give a pale yellow oil (1.641 g). This was subjected to flash chromatography on
1
SiO with CH Cl -acetone (20:1) to give 8b as a colorless oil (1.565 g, 83.5 %). H-NMR (CDCl ) δ:
3
2
2
2
7.67 (2H, dd, J=6.6, 1.7 Hz), 6.78 (1H, d, J=7.8 Hz), 6.69 (1H, s), 6.67 (1H, dd, J=7.8, 2.0 Hz), 6.12 (1H,
br s), 3.66 (2H, t, J=6.8 Hz), 2.80 (2H, t, J=6.8 Hz), 0.98 (9H, s), 0.96 (9H, s), 0.19 (6H, s), 0.16 (6H, s).
-1
IR (liquid film) cm : 3319, 3063, 2931, 2858, 1641. HR-MS m/z: Calcd for C27H43NO3Si2: 485.2780
(M+). Found: 485.2767.
Ν-Βenzoyl-2-[4,5-di(t-butyldimethylsilyloxy)-2-iodophenyl]ethylamine (9b)
In the same way as 8a,
compound (8b) (1.378 g, 2.84 mmol) was treated with silver trifluoroacetate (0.627 g, 2.84 mmol) and
iodine (0.720 g, 2.84 mmol) in CHCl3 (100 mL) to give 9b as colorless needles (from n-hexane) (1.209 g,
1
69.7 %), mp 131℃. H-NMR (CDCl ) δ: 7.73 (2H, d, J=7.3 Hz), 7.26 (1H, s), 6.72 (1H, s), 6.18 (1H, br
3
s), 3.66 (2H, q-like, J=6.6 Hz), 2.94 (2H, t, J=6.8 Hz), 0.97 (9H, s), 0.92 (9H, s), 0.19 (6H, s), 0.12 (6H,
+
s). IR (KBr) cm : 3261, 3076, 2931, 2852, 1632. HR-MS m/z: Calcd for C27H42NO3ISi2: 611.1749 (M ).
-1
Found: 611.1775. Anal. Calcd for C27H42NO3ISi2・1/5H2O: C, 52.70; H, 6.94; N, 2.28. Found: C, 52.59; H,

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HETEROCYCLES, Vol. 65, No. 12, 2005
7.04; N, 1.95.
N-Benzyl-2-[4,5-di(t-butyldimethylsilyloxy)-2-iodophenyl]ethylamine (9d)
In the same way as 9a,
compound (9b) (1.064 g, 1.74 mmol) was treated with BH3 (5.2 mL of 1M solution in THF, 5.2 mmol) in
dry THF (5 mL) under N2 for 6 h to give crude product (1.027 g). This was subjected to flash
chromatography on SiO2 with CH2Cl2-CH3OH (10:1) to give 9d as a pale yellow oil (0.344 g, 33.1 %).
1
H-NMR (CDCl ) δ: 7.36-7.24 (5H, m), 7.22 (1H, s), 6.71 (1H, s), 3.83 (2H, s), 2.82 (4H, s), 1.85 (1H, br
3
-1
s), 0.98 (9H, s), 0.95 (9H, s), 0.18 (6H, s), 0.15 (6H, s). IR (liquid film) cm : 2932, 2858, 1255, 911.
HR-MS m/z: Calcd for C27H44NO2ISi2: 597.1950 (M+). Found: 597.1930.
2-Iodobenzyl Cyanide (17)
A mixture of 2-iodobenzyl bromide (16) (15.998 g, 53.9 mmol), NaCN
(10.037 g, 204.8 mmol) in EtOH (140 mL) was refluxed for 4 h. The mixture was evaporated in vacuo
and H2O (50 mL) was added to the residue. The mixture was extracted with ether (100 mL x 3). The
extract was washed with a saturated solution of NaCl in H2O, dried over MgSO4, and evaporated to give a
crude oil (12.625 g). This was distillated under reduced pressure to give 17 as colorless oil (12.110 g,
1
94.2 %), bp 110-112℃/3 mm Hg. H-NMR (CDCl ) δ: 7.85 (1H, dd, J=7.8, 1.2 Hz), 7.51 (1H, dd, J=7.5,
3
-1
1.2 Hz), 7.37 (1H, ddd, J=7.5, 7.5, 1.2 Hz), 7.03 (1H, ddd, J=7.8, 7.5, 1.2 Hz). IR (liquid film) cm : 3059,
2973, 2252, 1566. HR-MS m/z: Calcd for C8H7NI: 243.9623 (M+1). Found: 243.9624. Anal. Calcd for
C8H6NI: C, 39.53; H, 2.49; N, 5.76. Found: C, 39.58; H, 2.58; N, 5.43.
2-(2-Iodophenyl)ethylamine (18) A solution of 17 (4.053 g, 16.7 mmol) in dry THF (15 mL) was
added dropwise to a solution of BH3 (40 mL of 1M solution in THF, 40 mmol). The mixture was
refluxed for 1 h. C2H5OH (10 mL) was added to the mixture under ice-cooling and 1N HCl-CH3OH (20
mL) was added. The mixture was evaporated to give crude crystals. These were recrystallized from
CH3OH-acetone to afford the hydrochloride of 18 as colorless cubes (3.459 g, 73.5 %), mp 226-237℃.
1
H-NMR (free base; CDCl ) δ: 7.82 (1H, d, J=7.8 Hz), 7.32-7.20 (2H, m), 6.90 (1H, ddd, J=7.8, 7.5, 1.2
3
Hz), 2.92 (4H, m). HR-MS (free base) m/z: Calcd for C8H10NI: 246.9858 (M+). Found: 246.9834. Anal.
Calcd for C8H10NI・HCl: C, 33.88; H, 3.91; N, 4.97. Found: C, 34.15; H, 3.94; N, 4.83.
N-Formyl-2-(2-iodophenyl)ethylamine (19)
In the same way as the formylation of 7a, 18 (4.877 g,
19.7 mmol) was reacted with HCOOC2H5-C2H5OH (1:1) (280 mL) in the presence of K2CO3 (21.2 g,
227.5 mmol) and 4A molecular sieves (22 g) to give crystals. These were subjected to flash
chromatography on SiO2 with CH2Cl2-acetone (1:1) to afford 19 as white crystals (4.875 g, 89.8 %), mp
1
58.0℃. H-NMR (CDCl ) δ: 8.15 (1H, s), 7.83 (1H, dd, J=7.8, 1.0 Hz), 7.36-7.12 (2H, m), 6.93 (1H, m),
3
5.80 (1H, br s), 3.66-3.40 (2H, m), 2.97 (2H, m). HR-MS m/z: Calcd for C9H10NOI: 274.9805 (M+).
Found: 274.9823. Anal. Calcd for C9H10NOI: C, 39.30; H, 3.66; N, 5.09. Found: C, 39.41; H, 3.69; N,
4.71.

HETEROCYCLES, Vol. 65, No. 12, 2005
2931
2-(2-Iodophenyl)-N-methylethylamine (14)
In the same way as 9a, 19 (0.931 g, 3.38 mmol) was
reacted with BH3 (10 mL of 1M solution in THF, 10 mmol) in dry THF (10 mL) to give a white solid.
This was recrystallized from CH3OH-acetone to afford the hydrochloride of 14 as colorless plates (0.927
1
g, 92.0 %), mp 186-189℃. H-NMR (free base, CDCl ) δ: 7.81 (1H, d, J=7.8 Hz), 7.24 (2H, m), 6.88 (1H,
3
m), 2.91 (2H, m), 2.83 (2H, m), 2.48 (3H, s), 1.45 (1H, s). HR-MS m/z: Calcd for C9H12NI: 261.0015
(M+). Found: 261.0015. Anal. Calcd for C9H12NI・HCl: C, 36.33; H, 4.40; N, 4.71. Found: C, 36.31; H,
4.33; N, 4.45.
N-{2-[4,5-Di(t-butyldimethylsilyloxy)-2-iodophenyl]ethyl}-N-methylphenacylamine (5a)
A solution of 9c (0.502 g, 0.96 mmol), phenacyl bromide (10) (0.191 g, 0.96 mmol), and propylene oxide
(0.17 g, 2.9 mmol) in dioxane (5 mL) was heated at 105℃ for 2 h. The mixture was evaporated to give
an oil (0.681 g). This was subjected to flash chromatography on SiO2 with CH2Cl2 - ethyl acetate (15:1) to
1
afford 5a as a pale yellow oil (0.525 g, 85.3 %). H-NMR (CDCl ) δ: 7.99 (2H, dd, J=7.1, 1.7 Hz), 7.55
3
(1H, t, J=7.6 Hz), 7.43 (2H, t, J=7.8 Hz), 7.20 (1H, s), 6.71 (1H, s), 3.92 (2H, s), 2.82 (2H, m), 2.73 (2H,
-1
m), 2.48 (3H, s), 0.98 (9H, s), 0.96 (9H, s), 0.18 (6H, s), 0.17 (6H, s). IR (liquid film) cm : 2931, 2858,
1683, 1255. HR-MS m/z: Calcd for C29H46NO3ISi2: 638.1984 (M-1). Found: 638.1984.
Compounds (5b) and (12a-c) were prepared in the same way as 5a.
N-Benzyl-N-{2-[4,5-di(t-butyldimethylsilyloxy)-2-iodophenyl]ethyl}phenacylamine (5b)
Compound (9d) (0.272 g, 0.45 mmol) was reacted with 10 (0.090 g, 0.45 mmol) and propylene oxide
(0.079 g, 1.35 mmol) in dioxane (3 mL) to give a crude oil (0.381 g). This was subjected to flash
chromatography on SiO2 with CH2Cl2 - n-hexane (3:2) to afford 5b as a pale yellow oil (0.263 g, 80.8 %).
1
H-NMR (CDCl ) δ: 7.94 (2H, dd, J=6.8, 1.5 Hz), 7.58-7.25 (8H, m), 7.17 (1H, s), 6.60 (1H, s), 3.98 (2H,
3
-1
s), 3.87 (2H, s), 2.80 (4H, s), 0.96 (9H, s), 0.95 (9H, s), 0.17 (6H, s), 0.14 (6H, s). IR (liquid film) cm :
3029, 2930, 2858, 1682, 1255, 911. HR-MS m/z: Calcd for C35H50NO3ISi2: 714.2296 (M-1). Found:
714.2269.
4-Methoxy-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (12a)
Compound (14) (1.158 g,
4.43 mmol) was reacted with 15a (1.029 g, 4.43 mmol) and propylene oxide (0.800 g, 13.8 mmol) in
dioxane (20 mL) to give a crude oil (2.557g). This was subjected to flash chromatography on SiO2 with
1
CH Cl - ethyl acetate (8:1) to afford 12a as a pale brown oil (1.074 g, 60.2 %). H-NMR (CDCl ) δ: 7.98
3
2
2
(2H, d, J=8.8, Hz), 7.79 (1H, d, J=7.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.86, 3.87 (5H, each s), 3.08-2.70 (4H,
m), 2.48 (3H, s). HR-MS m/z: Calcd for C18H20NO2I: 409.0540 (M+). Found: 409.0580.
4-t-Butyldimethylsilyloxy-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (12b)
Compound (14) (1.421 g, 5.44 mmol) was reacted with 15b7 (1.752 g, 5.32 mmol) and propylene oxide
(0.988 g, 17.0 mmol) in dioxane (20 mL) to give a crude oil (3.847 g). This was subjected to flash

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HETEROCYCLES, Vol. 65, No. 12, 2005
chromatography on SiO2 with CH2Cl2 - ethyl acetate (5:1) to afford 12b as a pale yellow oil (2.282 g,
1
82.3 %). H-NMR (CDCl ) δ: 7.79 (1H, d, J=7.8, Hz), 7.02 (2H, m), 6.93 (1H, m), 3.96 (2H, s), 3.00 (2H,
3
m), 2.80 (2H, m), 2.54 (3H, s), 0.99 (9H, s), 0.22 (6H, s). HR-MS m/z: Calcd for C23H32NO2ISi: 509.1248
(M+). Found: 509.1246.
3-t-Butyldimethylsilyloxy-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (12c)
Compound (14) (1.290 g, 4.94 mmol) was reacted with 15c7 (1.627 g, 4.94 mmol) and propylene oxide
(0.890 g, 15.3 mmol) in dioxane (20 mL) to give a crude oil (3.265 g). This was subjected to flash
chromatography on SiO2 with CH2Cl2 - ethyl acetate (5:1) to afford 12c as a pale yellow oil (2.006 g,
1
79.7 %). H-NMR (CDCl ) δ: 7.78 (1H, d, J=7.6, Hz), 7.57 (1H, d, J=8.5 Hz), 7.48 (1H, s), 7.03 (1H, dd,
3
J=7.8, 2.7 Hz), 6.86 (1H, m), 3.91 (2H, s), 2.96 (2H, m), 2.77 (2H, m), 2.50 (3H, s), 0.99 (9H,s), 0.27 (6H,
s). HR-MS m/z: Calcd for C23H32NO2ISi: 509.1248 (M+). Found: 509.1220.
7,8-Di(t-butyldimethylsilyloxy)-1-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-bezazepine
(6a)
N, N, N’, N’-Tetramethylethylenediamine (0.068 mL, 0.49 mmol) and n-C4H9Li (0.28 mL of 1.6
M solution in n-hexane, 0.49 mmol) were added to a solution of 5a (0.181 g, 0.28 mmol) in n-hexane (2
mL) under N2 at -78℃. The mixture was stirred for 10 min at -78℃. H2O (20 mL) was added and the
mixture was extracted with ether (20 mL x 3). The extract was dried over MgSO4 and evaporated to give
a pale yellow oil (0.135 g). This was subjected to flash chromatography on SiO2 with CH2Cl2 - acetone
1
(5:1). The first fraction gave 11a as a pale brown oil (0.036 g, 24.7 %). H-NMR (CDCl ) δ: 7.96 (2H, dd,
3
J=6.8, 1.5 Hz), 7.55 (1H, t, J=7.3 Hz), 7.42 (2H, t, J=7.6 Hz), 6.72 (1H, d, J=7.8 Hz), 6.66 (1H, d, J=1.7
Hz), 6.61 (1H, dd, J=7.8, 1.7 Hz), 3.85 (2H, s), 2.73 (4H, s), 2.42 (3H, s), 0.99 (18H, s), 0.18 (6H, s), 0.17
-1
(6H, s). IR (liquid film) cm : 2930, 1683, 1254. HR-MS m/z: Calcd for C29H47NO3Si2: 514.3173 (M+1).
Found: 514.3190.
1
The second fraction gave 6a as a pale yellow oil (0.025 g, 16.9 %). H-NMR (CDCl ) δ: 7.48-7.24 (5H,
3
m), 6.53 (1H, s), 6.06 (1H, s), 3.31 (1H, ddd, J=15.0, 10.6, 2.6 Hz), 3.15 (1H, d, J=12.2 Hz), 3.02 (1H,
ddd, J=15.0, 10.6, 2.6 Hz), 2.99 (1H, d, J=12.2 Hz), 2.67 (1H, ddd, J=14.8, 6.8, 2.5 Hz), 2.49 (3H, s),
-1
2.48 (1H, m), 0.96 (9H, s), 0.79 (9H, s), 0.14 (6H, s), - 0.36 (3H, s), - 0.44 (3H, s). IR (liquid film) cm :
3320, 2929, 2858, 1255. HR-MS m/z: Calcd for C29H47NO3Si2: 513.3094 (M+). Found: 513.3085.
3-Benzazepines (6b), (3a), and (13b,c) were prepared in the same way as 6a.
3-Benzyl-7,8-di(t-butyldimethylsilyloxy)-1-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-bezazepine
(6b)
Compound (5b) (8.192 g, 11.4 mmol) was reacted with n-C4H9Li (11.5 mL of 1.6 M solution
in n-hexane, 18.3 mmol) in dry THF (200 mL). The crude product (7.108 g) was subjected to flash
chromatography on SiO2 with CHCl3. The first fraction gave 11b as a pale yellow oil (2.110 g, 31.3 %).
1
H-NMR (CDCl ) δ: 7.90 (2H, dd, J=7.1, 1.7 Hz), 7.53-7.26 (8H, m), 6.69 (1H, d, J=8.1 Hz), 6.58 (1H,
3

HETEROCYCLES, Vol. 65, No. 12, 2005
2933
s), 6.56 (1H, d, J=8.1 Hz), 3.91 (2H, s), 3.82 (2H, s), 2.96-2.84 (2H, m), 2.78-2.64 (2H, m), 0.97 (18H, s),
-1
0.17 (6H, s), 0.15 (6H, s). IR (liquid film) cm : 3029, 2932, 1682, 1255. HR-MS m/z: Calcd for
C35H51NO3Si2: 589.3407 (M+). Found: 589.3419.
1
The second fraction gave 6b as a pale yellow oil (2.150 g, 31.8 %). H-NMR (CDCl ) δ: 7.45-7.27 (10H,
3
m), 6.50 (1H, s), 6.07 (1H, s), 3.82 and 3.70 (each 1H, d, J=13.4 Hz), 3.28 and 3.16 (each 1H, d, J=12.2
Hz), 3.20-3.00 (2H, m), 2.80-2.36 (2H, m), 0.95 (12H, s), 0.97 (6H, s), 0.13 (6H, s), - 0.34 (3H, s), - 0.46
-1
(3H, s). IR (liquid film) cm : 3356, 3029, 2931, 2858, 1568, 1255. HR-MS m/z: Calcd for C35H51NO3Si2:
589.3407 (M+). Found: 589.3388.
1-Hydroxy-1-(4-methoxyphenyl)-3-methyl-2, 3, 4, 5-tetrahydro-1H-3-bezazepine (3a)
Compound (12a) (0.546 g, 1.33 mmol) was reacted with n-C4H9Li (1.35 mL of 1.6 M solution in
n-hexane, 1.68 mmol) in dry THF (5 mL). The crude product (0.356 g) was subjected to flash
chromatography on SiO2 with CH2Cl2 - ethyl acetate (1:2). The first fraction gave 20a as a pale yellow oil
1
(0.147 g, 26.7 %). H-NMR (CDCl ) δ: 7.96 (2H, d, J=9.0 Hz), 7.27-7.18 (5H, m), 6.88 (2H, d, J=9.0
3
Hz), 3.86 (3H, s), 3.81 (2H, s), 2.83 (4H, s), 2.43 (3H, s). HR-MS m/z: Calcd for C18H21NO2: 282.1493
(M-1). Found: 282.1456.
1
The second fraction gave 3a as a pale yellow oil (0.056 g, 14.6 %). H-NMR (CDCl ) δ: 7.34 (2H, d,
3
J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 3.82 (3H, s), 3.22 (1H, d, J=12.7 Hz), 3.20 (1H, m), 2.92 (2H, m), 2.90
(1H, d, J=12.7 Hz), 2.50 (1H, m), 2.48 (3H, s). HR-MS m/z: Calcd for C18H21NO2: 283.1572 (M+). Found:
283.1581.
1-(4-t-Butyldimethylsilyloxyphenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-bezazepine (13b)
Compound (12b) (1.943g, 3.81 mmol) was reacted with n-C4H9Li (3.45 mL of 1.6 M solution in n-hexane,
5.72 mmol) in dry THF (15 mL). The crude product (1.770 g) was subjected to flash chromatography on
SiO2 with CH2Cl2- ethyl acetate (1:4). The first fraction gave 20b as a pale brown oil (0.433 g, 29.6 %).
1
H-NMR (CDCl ) δ: 7.65-7.20 (7H, m), 7.00(2H, m), 3.90 (3H, s), 3.02 (2H, m), 2.82 (2H, m), 2.50 (3H,
3
s), 1.00 (9H, s), 0.21 (6H, s). HR-MS m/z: Calcd for C23H33NO2Si: 383.2280 (M+). Found: 383.2296.
1
The second fraction gave 13b as a pale yellow oil (0.304 g, 20.8 %). H-NMR (CDCl ) δ: 7.30-6.90 (6H,
3
m), 6.80 (2H, d, J=8.1 Hz), 3.82 (3H, s), 3.42-2.90 (3H, m), 3.18 (1H, d, J=12.7 Hz), 2.94 (1H, d, J=12.7
Hz), 2.78-2.40 (1H, m), 2.49 (3H, s), 0.97 (9H, s), 0.17 (6H, s). HR-MS m/z: Calcd for C23H33NO2Si:
383.2280 (M+). Found: 383.2329.
1-(3-t-Butyldimethylsilyloxyphenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-bezazepine (13c)
Compound (12c) (1.869, 3.67 mmol) was treated with n-C4H9Li (2.75 mL of 1.6 M solution in n-hexane,
4.40 mmol) in dry THF (15 mL). The crude product (1.427 g) was subjected to flash chromatography on
SiO2 with CH2Cl2 - ethyl acetate (1:4). The first fraction gave 20c as a pale brown oil (0.667 g, 34.8 %).

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HETEROCYCLES, Vol. 65, No. 12, 2005
1
H-NMR (CDCl ) δ: 7.54 (1H, dd, J=7.6, 1.0 Hz), 7.45 (1H, dd, J=1.2, 1.0 Hz), 7.31-7.18 (6H, m), 7.02
3
(1H, ddd, J=8.1, 1.2, 1.0 Hz), 3.84 (2H, s), 2.82 (4H, m), 2.45 (3H, s), 0.99 (9H, s), 0.21 (6H, s). HR-MS
m/z: Calcd for C23H33NO2Si: 383.2280 (M+). Found: 383.2262.
1
The second fraction gave 13c as a pale yellow oil (0.242 g, 17.2 %). H-NMR (CDCl ) δ: 7.24-6.95 (6H,
3
m), 6.80 (2H, m), 3.30-3.20 (1H, m), 3.17 (1H, d, J=12.7 Hz), 3.05-2.71 (2H, m), 2.93 (1H, d, J=12.7 Hz),
2.50-2.40 (1H, m), 2.48 (3H, s), 0.97 (9H, s), 0.17 (6H, s). HR-MS m/z: Calcd for C23H33NO2Si: 383.2280
(M+). Found: 383.2279.
3-Methyl-1-phenyl-1, 7, 8-trihydroxy-2, 3, 4, 5-tetrahydro-1H-3-bezazepine (2a)
TBAF (1.65 mL
of 1 M solution in THF, 1.65 mmol) was added to a solution of 6a (0.172 g, 0.33 mmol) in dry THF (10
mL) under ice-cooling. The mixture was stirred for 30 min. H2O (20 mL) was added and the mixture was
extracted with ethyl acetate. The extract was washed with H2O, dried over MgSO4, and evaporated to give
1
a pale brown oil (0.031 g, 31.5 %). H-NMR (acetone-d ) δ: 7.44-7.24 (5H, m), 6.56 (1H, s), 6.48 (1H, s),
6
3.58 (1H, d, J=13.0 Hz), 2.95 (1H, d, J=13.0 Hz), 3.08-2.80 (4H, m), 2.54 (3H, s). HR-MS m/z: Calcd for
C17H17NO2: 267.1258 (M-H2O). Found: 267.1236.
3-Benzazepines (2b) and (3b, c) were prepared in the same way as 2a.
3-Benzyl-1-phenyl-1, 7, 8-trihydroxy-2, 3, 4, 5-tetrahydro-1H-3-bezazepine (2b)
Compound (6b) (0.137 g, 0.23 mmol) was reacted with TBAF (0.70 mL of 1 M solution in THF, 0.70
mmol) in dry THF (3 mL) to give an oil (0.240 g). This was purified by preparative TLC on SiO2 with
1
CH Cl - acetone (2:1) to afford 2b as a pale brown oil (0.023 g, 27.7 %). H-NMR (CD OD) δ: 7.40-7.12
3
2
2
(5H, m), 6.81 (1H, s), 6.52 (1H, s), 3.69 (1H, d, J=13.7 Hz), 3.61(1H, d, J=13.7 Hz), 3.47 (1H, d, J=12.9
Hz), 2.78 (1H, d, J=12.9 Hz), 2.84-2.46 (4H, m). HR-MS m/z: Calcd for C23H21NO2: 343.1571 (M-H2O).
Found: 343.1564.
1- Hydroxy-1-(4-hydroxyphenyl)-3-methyl-2, 3, 4, 5-tetrahydro-1H-3-bezazepine (3b)
Compound (13b) (0.304 g, 0.79 mmol) was reacted with TBAF (1.60 mL of 1 M solution in THF, 1.60
mmol) in dry THF (10 mL) to give an oil (0.253 g). This was subjected to flash chromatography on SiO2
1
with CH Cl - acetone (2:3) to give 3b as a pale yellow oil (0.130 g, 60.9 %). H-NMR (CDCl ) δ:
3
2
2
7.32-6.72 (8H, m), 3.36-2.40 (4H, m), 3.21 (1H, d, J=12.7 Hz), 2.94 (1H, d, J=12.7 Hz), 2.50 (3H, s).
HR-MS m/z: Calcd for C17H19NO2: 269.1415 (M+). Found: 269.1398.
1-Hydroxy-1-(3-hydroxyphenyl)-3-methyl-2, 3, 4, 5-tetrahydro-1H-3-bezazepine (3c)
Compound (13c) (0.205 g, 0.535 mmol) was reacted with TBAF (1.10 mL of 1 M solution in THF, 1.10
mmol) in dry THF (10 mL) to give an oil (0.161 g). This was subjected to flash chromatography on SiO2
1
with CH Cl - acetone (2:3) to give 3c as a pale yellow oil (0.123 g, 85.6 %). H-NMR (acetone-d ) δ:
6
2
2
8.20 (1H, br s), 7.30-7.21 (1H, m), 7.16-7.00 (4H, m), 6.90 (1H, m), 6.82 (1H, m), 6.71 (1H, ddd, J=8.1,

HETEROCYCLES, Vol. 65, No. 12, 2005
2935
2.4, 1.0 Hz), 3.34 (1H, d, J=12.7 Hz), 2.96-2.86 (1H, m), 2.89 (1H, d, J=12.7 Hz), 2.76-2.50 (3H, m),
2.41 (3H, s). HR-MS m/z: Calcd for C17H19NO2: 269.1415 (M+). Found: 269.1376.
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