Synthesis and pharmacological evaluation of new 1-hydroxy-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepines as norepinephrine potentiators

Article abstract of DOI:10.1248/cpb.57.443

4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH) (1a) and its derivatives form a new class of compounds which possess norepinephrine (NE) potentiating activity. As a new series of compounds, 1-hydroxy-1-phenyl-2,3,4, 5-tetrahydro-1H-3-be

Full text of DOI:10.1248/cpb.57.443

May 2009
Chem. Pharm. Bull. 57(5) 443—445 (2009)
443
Synthesis and Pharmacological Evaluation of New 1-Hydroxy-1-phenyl-
2,3,4,5-tetrahydro-1H-3-benzazepines as Norepinephrine Potentiators
Miyuki IKEUCHI, Masako IKUTA, Miyuki HARIKI, Motoki IKEUCHI, Shigeki MARUYAMA, Mari NAKASE,
Kumiko SAKAMOTO, Yasuko YOSHIOKA, Aiko YAMAUCHI, and Masaru KIHARA*
Faculty of Pharmaceutical Sciences, The University of Tokushima; 1–78 Sho-machi, Tokushima 770–8505, Japan.
Received August 5, 2008; accepted February 21, 2009; published online February 23, 2009
4-Hydroxy-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH) (1a) and its derivatives form a new
class of compounds which possess norepinephrine (NE) potentiating activity. As a new series of compounds, 1-
hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines (2a—f) were synthesized by the intramolecular Barbier
reaction of N-[2-(2-iodophenyl)ethyl]phenacylamines (6a—f) with n-BuLi as a key reaction step. The potentiat-
ing activities of the benzazepines 2a—f on the contraction of rat anococcygeus muscle induced by NE were
tested. Among the compounds tested in this study, compound 2a showed moderate potentiating activity (the ac-
tivity ratio was 7.3-fold at 3ꢀ10ꢁ5 M).
Key words norepinephrine potentiator; norepinephrine reuptake inhibitor; 3-benzazepine; Barbier reaction; N-(phenyl-
ethyl)phenacylamine
Amine reuptake inhibitors have been developed as anti- have a halogen atom on the 1-phenyl group of 2a are inter-
depressants. Tricyclic antidepressants such as desipramine esting as new NE potentiators. This paper describes the syn-
prevent the neuronal reuptake of either norepinephrine (NE) thesis and NE potentiating activity of the 3-benzazepines
or serotonin (5-HT).1) In the past decade a number of nontri- 2a—f.
cyclic antidepressants, including selective serotonin reuptake
In previous papers, we reported on the convenient synthe-
inhibitors (SSRI) as well as 5-HT and NE reuptake inhibitors sis of PI-OH (1a) and its related compounds,9) 3-hydroxy-
(SNRI) such as fluvoxamine and milnacipran, which have di- 3-phenylindoles,10) and 1,2-diphenyl-1-hydroxy-3-methyl-
minished cardiovascular and anticholinergic liability, have 2,3,4,5-tetrahydro-1H-3-benzazepine (3)11) by the intramo-
been developed.2) Atomoxetine, a selective inhibitor of NE lecular Barbier reaction of the corresponding N-benzyl- and
reuptake, has recently attracted much interest in the treatment N-phenylphenacylamines, and N-[2-(2-iodophenyl)ethyl]-a-
of attention deficit hyperactivity disorder (ADHD)3) (Fig. 1).
phenylphenacylamines with n-butyllithium (n-C4H9Li), both
We have reported on the synthesis of 4-hydroxy-2-methyl- in good yields.
4-phenyl-1,2,3,4-tetrahydroisoquinoline (PI-OH) (1a)4,5) and
Thus, we synthesized 1-hydroxy-1-phenyl-2,3,4,5-tetrahy-
the strong NE potentiating activity of PI-OH (1a) was found dro-1H-3-benzazepines (2a—f) by the intramolecular Bar-
to be due to inhibition of NE reuptake. The potency of PI- bier reaction of N-[2-(2-iodophenyl)ethyl]-N-methylphenacyl-
OH (1a) was greater than that of the tricyclic antidepressant amines (6a—f) as a key reaction step as shown in Chart 1.
desipramine.6) We have also studied the structure–activity re- The condensation of N-methyl-2-(2-iodophenyl)ethylamine
lationships of the PI-OH (1a) analogues and have identified (4) with phenacyl bromides (5a—f)7) gave the phenacyl-
the importance of the 2-phenylethanolamine moiety of PI- amines 6a—f. Intramolecular cyclization of 6a—f with n-
OH for NE potentiation.7,8) In addition, we have evaluated the BuLi afforded the 3-benzazepines 2a—f in a yield of 14.7—
substitution effects on the 4-phenyl group of PI-OH (1a) and 38.7% along with the reduced compounds 7a—f of the start-
have found that the activity of 1b bearing a chlorine atom at ing materials 6a—f in a yield of 18.4—49.3%, respectively.
the para position of the 4-phenyl group was greater than that Although compound 2a was obtained in a moderate yield
of PI-OH (1a), however, the activity of the meta chloro ana- (38.7%) with the reduced compound 7a in a yield of 18.4%,
logue 1c was less potent than that of PI-OH (1a).7)
the halogenated compounds 2b—f were produced in low
From these findings, 1-hydroxy-1-phenyl-2,3,4,5-tetrahy- yields (14.7—23.6%) with the reduced compounds 7b—f in
dro-1H-3-benzazepine (2a) and the derivatives 2b—f which
Fig. 1
Chart 1
∗ To whom correspondence should be addressed. e-mail: mkihara@mxi.netwave.or.jp
© 2009 Pharmaceutical Society of Japan

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Vol. 57, No. 5
Table 1. Potentiating Activities of 1-Hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines (2a—f) on the Response of Rat Anococcygeus Muscle to
Norepinephrine
pD2 value (activity ratio)a)
Compound
nb)
Concentration (M) of test compound
0
3ꢀ10ꢁ7
10ꢁ6
3ꢀ10ꢁ6
10ꢁ5
3ꢀ10ꢁ5
PI-OH (1a)
8
8
8
7
5
8
6
5.97ꢄ0.05
(1.0)
6.37ꢄ0.04
(1.0)
6.09ꢄ0.06
(1.0)
6.07ꢄ0.03
(1.0)
6.16ꢄ0.05
(1.0)
6.18ꢄ0.06
(1.0)
6.19ꢄ0.06
(1.0)
6.47ꢄ0.12
(3.5)
6.84ꢄ0.09
(7.7)
6.54ꢄ0.06
(1.5)
6.11ꢄ0.10
(1.8)
6.35ꢄ0.07
(2.0)
6.17ꢄ0.08
(1.0)
6.37ꢄ0.11
(1.6)
6.18ꢄ0.08
(1.0)
7.13ꢄ0.09
(14.6)
6.68ꢄ0.07
(2.2)
6.31ꢄ0.12
(2.0)
6.64ꢄ0.09
(3.9)
6.30ꢄ0.09
(1.4)
6.65ꢄ0.11
(2.9)
6.05ꢄ0.18
(0.9)
7.28ꢄ0.08
(20.5)
7.02ꢄ0.08
(4.8)
6.35ꢄ0.11
(1.9)
6.66ꢄ0.08
(4.0)
6.40ꢄ0.08
(1.7)
6.64ꢄ0.07
(3.0)
6.25ꢄ0.06
(1.2)
7.34ꢄ0.10
(19.7)
7.18ꢄ0.10
(7.3)
2a
2b
2c
2d
2e
2f
6.31ꢄ0.10
(1.1)
6.23ꢄ0.05
(1.5)
6.44ꢄ0.07
(1.9)
6.54ꢄ0.08
(2.4)
6.32ꢄ0.08
(1.4)
a) Activity ratio was calculated as the antilogarithm of the difference between the pD2 values for NE obtained in the presence and absence of the test compounds. b) n is the
number of experiments.
higher yields (35.1—49.3%).
Jꢂ8.3 Hz), 7.77 (1H, d, Jꢂ7.6 Hz), 7.37 (2H, d, Jꢂ8.3 Hz), 6.87 (1H, m),
3.83 (2H, s), 2.91 (2H, m), 2.78 (2H, m), 2.46 (3H, s). HR-MS m/z: Calcd
for C17H17ClINO: 413.0043 (Mꢃ). Found: 413010.
The potentiating effects of the 3-benzazepines 2a—f as
well as PI-OH (1a) on the contraction of rat anococcygeus
muscle induced by NE were determined by the methods re-
ported in our previous papers.6—8) The results of these experi-
ments are shown in Table 1. Of the compounds prepared in
this study, compound 2a had no substituent on the 4-phenyl
group and had moderate potentiating activity (activity ratio
was 7.3-fold at 3ꢀ10ꢁ5 M).
4-(4-Chlorophenyl)isoquinoline 1b showed greater poten-
tiating activity7) than PI-OH (1a), whereas 1-(4-chloro-
phenyl)-3-benzazepine 2b in addition to 2d—f showed no
activity, even though 1-(3-chlorophenyl) derivative 2c re-
vealed almost the same activity as 2a. These results indicated
that 4-hydroxy-4-phenylisoqinoline with an ethanolamine
moiety and a six-membered ring such as PI-OH (1a) was the
preferred structure for the inhibition of NE reuptake rather
than the 1-hydroxy-1-phenyl-3-benzazepines 2a—f con-
structed with a seven-membered ring expanded from the iso-
quinoline structure of PI-OH (1a).
3-Chloro-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (6c)
Compound 4 (1.985 g, 7.60 mmol) was reacted with 5c (0.801 g, 3.43 mmol)
in dioxane (20 ml) under reflux for 2 h to give a crude oil (1.777 g). This was
subjected to column chromatography on SiO2 with CH2Cl2–AcOEt (10 : 1)
to afford 6c as a pale brown oil (1.108 g, 78.1%). 1H-NMR (CDCl3) d: 7.98
(1H, dd, Jꢂ1.7, 1.7 Hz), 7.87 (1H, d-like, Jꢂ8.1 Hz), 7.78 (1H, d,
Jꢂ7.6 Hz), 7.52 (1H, d-like, Jꢂ8.1 Hz), 7.38 (1H, d, Jꢂ8.1 Hz), 6.87 (1H,
m), 3.86 (2H, s), 2.97 (2H, m), 2.74 (2H, m), 2.48 (3H, s). HR-MS m/z:
Calcd for C17H17ClINO: 413.0043 (Mꢃ). Found: 413.0018.
4-Fluoro-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (6d)
Compound 4 (5.741 g, 22.0 mmol) was reacted with 5d (2.377 g, 11.0 mmol)
in dioxane (50 ml) under reflux for 2 h to give a crude oil (5.268 g). This was
subjected to column chromatography on SiO2 with CH2Cl2–AcOEt (7 : 1) to
1
afford 6d as a pale yellow oil (2.462 g, 28.2%). H-NMR (CDCl3) d: 8.02
(2H, dd, Jꢂ8.8, 5.4 Hz), 7.78 (1H, d, Jꢂ8.1 Hz), 7.21 (2H, m), 6.87 (1H, m),
3.85 (2H, s), 2.96 (2H, m), 2.74 (2H, m), 2.47 (3H, s). HR-MS m/z: Calcd
for C17H17FINO: 397.0339 (Mꢃ). Found: 397.0335.
4-Bromo-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (6e)
Compound 4 (5.335 g, 20.4 mmol) was reacted with 5e (2.860 g, 10.3 mmol)
in dioxane (60 ml) under reflux for 2 h to give a crude oil (7.519 g). This was
subjected to column chromatography on SiO2 with CH2Cl2–AcOEt (10 : 1)
to afford 6e as a yellow oil (1.981 g, 21.2%). 1H-NMR (CDCl3) d: 7.84 (2H,
d, Jꢂ8.6 Hz), 7.77 (1H, d, Jꢂ7.8 Hz), 7.54 (2H, d, Jꢂ8.6 Hz), 7.24 (2H, m),
6.88 (1H, m), 3.84 (2H, s), 2.94 (2H, m), 2.76 (2H, m), 2.47 (3H, s). HR-MS
m/z: Calcd for C17H17BrINO: 457.9617 (Mꢃ). Found: 457.9658.
N-[2-(2-Iodophenyl)ethyl]-N-methyl-4-trifluoromethylphenacylamine
(6f) Compound 4 (4.418 g, 16.9 mmol) was reacted with 5f (2.224 g,
8.33 mmol) in dioxane (50 ml) under reflux for 2 h to give a crude oil
(3.656 g). This was subjected to column chromatography on SiO2 with
CH2Cl2–AcOEt (15 : 1) to afford 6f as a yellow oil (2.522 g, 67.7%). 1H-
NMR (CDCl3) d: 8.08 (2H, d, Jꢂ7.8 Hz), 7.77 (1H, d, Jꢂ8.1 Hz), 7.66 (2H,
d, Jꢂ8.1 Hz), 7.21 (2H, m), 6.87 (1H, m), 3.89 (2H, s), 2.94 (2H, m), 2.77
(2H, m), 2.48 (3H, s). HR-MS m/z: Calcd for C18H17F3INO: 447.0315 (Mꢃ).
Found: 447.0314.
Experimental
General All melting points are given as uncorrected values. IR spectra
were obtained with a Perkin-Elmer 1720 infrared fourier transform spec-
trometer. High-resolution mass (HR-MS) spectra were recorded on a JEOL
JMS-D 300 spectrometer. 1H-NMR spectra were recorded on a JEOL JNM-
FX 200 spectrometer with tetramethylsilane as a standard.
N-[2-(2-Iodophenyl)ethyl]-N-methylphenacylamine (6a)
A solution
of N-methyl-2-(2-iodophenyl)ethylamine (4) (1.228 g, 4.70 mmol), phenacyl
bromide (5a) (0.468 g, 2.35 mmol) in dioxane (10 ml) was stirred at room
temperature for 5 h. The mixture was filtered and the filtrate was evaporated
to give an oil (1.124 g). This was subjected to column chromatography on
SiO2 with CH2Cl2–n-hexane–AcOEt (3 : 3 : 1) to afford 6a as a pale brown
oil (0.622 g, 69.5%). 1H-NMR (CDCl3) d: 8.01 (2H, d, Jꢂ8.1 Hz), 7.79 (1H,
d, Jꢂ8.6 Hz), 6.87 (1H, m), 3.92 (2H, s), 2.94 (2H, m), 2.80 (2H, m), 2.50
(3H, s). IR (KBr) cmꢁ1: 1741. HR-MS m/z: Calcd for C17H18INO: 378.0355
(Mꢃ). Found: 378.0301.
1-Hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(2a) n-BuLi (0.42 ml of 1.6 M solution in n-hexane, 0.67 mmol) was added
to a solution of 6a (0.195 g, 0.51 mmol) in dry tetrahydrofuran (THF) (5 ml)
under N2 at ꢁ78 °C. The mixture was stirred for 10 min at ꢁ78 °C and then
at room temperature for 10 min. H2O (20 ml) was added and the mixture was
extracted with ether (20 mlꢀ4). The extract was dried over MgSO4 and
evaporated to give a brown oil (0.142 g). This was subjected to column chro-
matography on SiO2 with CH2Cl2–AcOEt (1 : 1). The first fraction gave 7a
Compounds 6b—f were prepared in the same way as 6a.
4-Chloro-N-[2-(2-iodophenyl)ethyl]-N-methylphenacylamine (6b)
Compound 4 (1.028 g, 3.93 mmol) was treated with 5b (0.417 g, 1.78 mmol)
in dioxane (10 ml) to give a crude oil (0.793 g). This was subjected to col-
umn chromatography on SiO2 with CH2Cl2–AcOEt (50 : 1) to afford 6b as
a pale brown oil (0.301 g, 40.8%). 1H-NMR (CDCl3) d: 7.93 (2H, d,
1
as a pale brown oil (0.0235 g, 18.4%). H-NMR (CDCl3) d: 7.96 (2H, dd,
Jꢂ8.0, 1.5 Hz), 7.64—7.10 (8H, m), 3.88 (2H, s), 2.84 (2H, s), 2.45 (3H, s).

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445
BuLi (3.5 ml of 1.6 M solution in n-hexane, 5.6 mmol) in dry THF (30 ml).
The crude oily product (1.512 g) was subjected to column chromatography
on SiO2 with CH2Cl2–acetone (5 : 1). The first fraction gave 7e as a pale
brown oil (0.670 g, 46.5%). 1H-NMR (CDCl3) d: 7.80 (2H, d, Jꢂ8.3 Hz),
7.53 (2H, d, Jꢂ8.3 Hz), 7.40—7.12 (5H, m), 3.81 (2H, s), 2.83 (4H, s), 2.43
(3H, s). FAB-MS m/z: Calcd for C17H18BrNO: 332.0650 (MꢃH). Found:
332.0669. The second fraction gave 2e as a yellow oil (0.266 g, 18.5%). 1H-
NMR (CDCl3) d: 7.49 (2H, d, Jꢂ8.6 Hz), 7.32 (2H, d, Jꢂ8.6 Hz), 7.11 (3H,
m), 6.76 (1H, d, Jꢂ7.8 Hz), 3.23 (1H, ddd, Jꢂ12.0, 9.0, 2.5 Hz), 3.20 (1H, d,
Jꢂ12.7 Hz), 3.11—2.84 (2H, m), 2.90 (1H, d, Jꢂ12.7 Hz), 2.58 (1H, ddd,
Jꢂ11.8, 9.3, 2.5 Hz), 2.50 (3H, s). HR-MS m/z: Calcd for C17H18BrNO:
331.0610 (Mꢃ). Found: 331.0572.
HR-MS m/z: Calcd for C17H19NO: 252.1387 (Mꢁ1). Found: 252.1362. The
second fraction gave 2a as a pale yellow oil (0.0504 g, 38.7%). 1H-NMR
(CDCl3) d: 7.36 (5H, m), 7.10 (3H, m), 6.79 (1H, d, Jꢂ7.2 Hz), 3.30 (1H,
ddd, Jꢂ12.5, 9.5, 2.5 Hz), 3.25 (1H, d, Jꢂ12.7 Hz), 2.96 (2H, m), 2.94 (1H,
d, Jꢂ12.7 Hz), 2.60 (1H, ddd, Jꢂ11.5, 9.5, 2.5 Hz), 2.49 (3H, s). HR-MS
m/z: Calcd for C17H19NO: 253.1463 (Mꢃ). Found: 253.1464.
The oily product 2a was converted to the hydrochloride as colorless nee-
dles (mp 215—218 °C (decomp.) from MeOH–acetone). IR (KBr) cmꢁ1
:
3385, 2943. Anal. Calcd for C17H19NO·HCl·1/5 H2O: C, 69.59; H, 7.01; N,
4.77. Found: C, 69.97; H, 6.89; N, 4.74.
The 3-benzazepines 2b—f were prepared in the same way as 2a.
1-(4-Chlorophenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine (2b) Compound 6b (1.027 g, 2.48 mmol) was treated with n-
BuLi (2.5 ml of 1.6 M solution in n-hexane, 4.0 mmol) in dry THF (10 ml).
The crude oily product (0.786 g) was subjected to column chromatography
on SiO2 with CH2Cl2–AcOEt (7 : 1). The first fraction gave 7b as a pale yel-
low oil (0.257 g, 36.1%). 1H-NMR (CDCl3) d: 7.89 (2H, d, Jꢂ8.3 Hz),
7.40—7.12 (5H, m), 7.35 (2H, d, Jꢂ8.3 Hz), 3.76 (2H, s), 2.81 (4H, m),
2.40 (3H, s). HR-MS m/z: Calcd for C17H18ClNO: 287.1078 (Mꢃ). Found:
287.1080. The second fraction gave 2b as a yellow oil (0.155 g, 21.7%). 1H-
NMR (CDCl3) d: 7.38 (2H, d, Jꢂ8.5 Hz), 7.32 (2H, d, Jꢂ8.5 Hz), 7.09 (3H,
m), 6.77 (1H, d, Jꢂ8.3 Hz), 3.28 (1H, ddd, Jꢂ12.5, 9.5, 2.5 Hz), 3.20 (1H, d,
Jꢂ12.7 Hz), 3.12—2.80 (2H, m), 2.86 (1H, d, Jꢂ12.7 Hz), 2.58 (1H, ddd,
Jꢂ11.7, 9.5, 2.5 Hz), 2.49 (3H, s). HR-MS m/z: Calcd for C17H18ClNO:
287.1080 (Mꢃ). Found: 287.1077.
The oily product 2e was converted to the hydrochloride as colorless cubes
(mp 223—224 °C from MeOH–acetone). IR (KBr) cmꢁ1: 3219, 2712. Anal.
Calcd for C17H18BrNO·HCl·1/3 H2O: C, 54.49; H, 5.20; N, 3.74. Found: C,
54.62; H, 5.15; N, 3.50.
1-Hydroxy-3-methyl-1-(4-trifluoromethylphenyl)-2,3,4,5-tetrahydro-
1H-3-benzazepine (2f) Compound 6f (2.482 g, 5.55 mmol) was treated
with n-BuLi (4.0 ml of 1.6 M solution in n-hexane, 6.72 mmol) in dry THF
(10 ml). The crude oily product (1.994 g) was subjected to column chro-
matography on SiO2 with CH2Cl2–AcOEt (1 : 1). The first fraction gave 7f as
a pale brown oil (0.879 g, 49.3%). 1H-NMR (CDCl3) d: 8.00 (2H, d,
Jꢂ8.1 Hz), 7.61 (2H, d, Jꢂ8.3 Hz), 7.20 (5H, m), 3.79 (2H, s), 2.80 (4H, s),
2.39 (3H, s). HR-MS m/z: Calcd for C17H18F3NO: 321.1314 (Mꢃ). Found:
1
321.1317. The second fraction gave 2f as a yellow oil (0.262 g, 14.7%). H-
NMR (CDCl3) d: 7.64 (2H, d, Jꢂ8.8 Hz), 7.58 (2H, d, Jꢂ8.8 Hz), 7.20—
6.91 (3H, m), 6.69 (1H, d, Jꢂ8.1 Hz), 3.29 (1H, ddd, Jꢂ12.5, 9.5, 2.5 Hz),
3.24 (1H, d, Jꢂ12.7 Hz), 3.16—2.80 (2H, m), 2.88 (1H, d, Jꢂ12.7 Hz), 2.59
(1H, ddd, Jꢂ12.0, 9.5, 2.5 Hz), 2.50 (3H, s). HR-MS m/z: Calcd for
C17H18F3NO: 321.1315 (Mꢃ). Found: 321.1318.
The oily product 2f was converted to the hydrochloride as colorless cubes
(mp 224 °C from MeOH–acetone). IR (KBr) cmꢁ1: 3236, 2582. Anal. Calcd
for C17H18BrNO·HCl: C, 60.42; H, 5.35; N, 3.91. Found: C, 60.18; H, 5.19;
N, 3.92.
Pharmacology Detailed methods used for the evaluation of compounds
2a—f were reported in previous papers7,8) from our laboratory. Isolated rat
anococcygeus muscles were used for the potentiating activity assays of 2a—
f in response to NE, which were evaluated from a shift in the concentration–
response curves of NE. The ability of a compound to potentiate the action of
NE was expressed as the activity ratio, which was determined from the an-
tilogarithm of the difference between the pD2 values for NE (negative loga-
rithm of the molar concentration of the agonist producing 50% of the maxi-
mum response) in the presence and absence of the test compounds.
The oily product 2b was converted to the hydrochloride as colorless cubes
(mp 217—219 °C from MeOH–acetone). IR (KBr) cmꢁ1: 3230, 2717. Anal.
Calcd for C17H18ClNO·HCl·1/5 H2O: C, 62.28; H, 5.96; N, 4.24. Found: C,
62.47; H, 5.99; N, 4.14.
1-(3-Chlorophenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine (2c) Compound 6c (1.077 g, 2.60 mmol) was treated with n-
BuLi (2.0 ml of 1.6 M solution in n-hexane, 3.2 mmol) in dry THF (6 ml).
The crude oily product (0.892 g) was subjected to column chromatography
on SiO2 with CH2Cl2–AcOEt (3 : 2). The first fraction gave 7c as a pale yel-
low oil (0.263 g, 35.1%). 1H-NMR (CDCl3) d: 7.94 (1H, dd, Jꢂ1.7, 1.7 Hz),
7.81 (1H, d, Jꢂ7.8 Hz), 7.48 (1H, d, Jꢂ8.1 Hz), 7.28 (1H, d, Jꢂ8.8 Hz),
7.24 (5H, m), 3.78 (2H, s), 2.79 (4H, m), 2.40 (3H, s). HR-MS m/z: Calcd
for C17H18ClNO: 286.0997 (Mꢁ1). Found: 286.0973. The second fraction
1
gave 2c as a yellow oil (0.177 g, 23.6%). H-NMR (CDCl3) d: 7.49 (1H, t-
like, Jꢂ2.0 Hz), 7.28 (3H, m), 7.12—6.99 (3H, m), 6.76 (1H, d, Jꢂ8.1 Hz),
3.30 (1H, ddd, Jꢂ12.5, 9.5, 2.5 Hz), 3.19 (1H, d, Jꢂ12.7 Hz), 3.12—2.80
(2H, m), 2.86 (1H, d, Jꢂ12.7 Hz), 2.56 (1H, ddd, Jꢂ12.0, 9.5, 2.5 Hz), 2.47
(3H, s). HR-MS m/z: Calcd for C17H18ClNO: 287.1078 (Mꢃ). Found:
287.1053.
References
The oily product 2c was converted to the hydrochloride as colorless cubes
(mp 220—222.5 °C from MeOH–acetone). IR (KBr) cmꢁ1: 3247, 2580.
Anal. Calcd for C17H18ClNO·HCl: C, 62.97; H, 5.91; N, 4.32. Found: C,
62.55; H, 5.78; N, 4.23.
1) Smith C. B., Hollingsworth P. J., “Biochemical and Pharmacological
Aspects of Depression,” ed. by Tipton K. F., Youdim M. B. H., Taylor
& Francis, London, 1989, pp. 69—81.
2) Puech A., Montgomery S. A., Prost J. F., Solles A., Briley M., Int.
Clin. Psychopharmacol., 12, 99—108 (1997).
3) Glase S. A., Dooley D. J., “Annual Reports in Medicinal Chemistry,”
Vol. 22, ed. by Doherty A. M., Academic Press, Inc., New York, 2004,
pp. 3—12.
4) Kihara M., Ishida Y., Kobayashi S., J. Chem. Res. S, 1987, 236—237
(1987).
5) Kihara M., Kashimoto M., Kobayashi Y., Kobayashi S., Tetrahedron
Lett., 37, 5347—5348 (1990).
6) Ishida Y., Koga N., Nanbu T., Kihara M., Kobayashi S., Br. J. Pharma-
col., 94, 19—26 (1988).
7) Kihara M., Kashimoto M., Kobayashi Y., Nagao Y., Moritoki H.,
Chem. Pharm. Bull., 42, 67—73 (1994).
8) Kihara M., Ikeuchi M., Adachi S., Nagao Y., Moritoki H., Yamaguchi
M., Taira Z., Chem. Pharm. Bull., 43, 1543—1546 (1995).
9) Kihara M., Kashimoto M., Kobayashi Y., Tetrahedron, 48, 67—78
(1992).
10) Kihara M., Iwai M., Nagao Y., Heterocycles, 41, 2279—2287 (1995).
11) Kaito C., Sakamoto K., Sakamoto M., Yamauchi A., Kihara M., Hete-
rocycles, 68, 2319—2326 (2006).
1-(4-Fluorophenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine (2d) Compound 6d (2.422 g, 6.10 mmol) was treated with n-
BuLi (8.0 ml of 1.6 M solution in n-hexane, 12.8 mmol) in dry THF (20 ml).
The crude oily product (1.709 g) was subjected to column chromatography
on SiO2 with CH2Cl2–acetone (2 : 1). The first fraction gave 7d as a pale yel-
low oil (0.617 g, 37.5%). 1H-NMR (CDCl3) d: 7.98 (2H, dd, Jꢂ9.0, 5.4 Hz),
7.32—7.12 (5H, m), 7.04 (2H, t-like, Jꢂ8.8 Hz), 3.76 (2H, s), 2.81 (4H, m),
2.39 (3H, s). FAB-MS m/z: Calcd for C17H18FNO: 272.1451 (MꢃH). Found:
272.1461. The second fraction gave 2d as a yellow oil (0.306 g, 18.5%). 1H-
NMR (CDCl3) d: 7.39 (2H, dd, Jꢂ9.0, 5.6 Hz), 7.16—6.98 (5H, m), 6.79
(1H, d, Jꢂ7.6 Hz), 3.23 (1H, ddd, Jꢂ12.5, 9.5, 2.5 Hz), 3.20 (1H, d,
Jꢂ12.7 Hz), 3.06—2.80 (2H, m), 2.86 (1H, d, Jꢂ12.7 Hz), 2.57 (1H, m),
2.47 (3H, s). HR-MS m/z: Calcd for C17H18FNO: 271.1373 (Mꢃ). Found:
271.1366.
The oily product 2d was converted to the hydrochloride as colorless cubes
(mp 203.5—204 °C from MeOH–acetone). IR (KBr) cmꢁ1: 3215, 2716.
Anal. Calcd for C17H18FNO·HCl: C, 66.34; H, 6.22; N, 4.55. Found: C,
66.33; H, 6.22; N, 4.53.
1-(4-Bromophenyl)-1-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-
benzazepine (2e) Compound 6e (1.978 g, 4.32 mmol) was treated with n-