A conformational restriction approach to the development of dual inhibitors of acetylcholinesterase and serotonin transporter as potential agents for Alzheimer's disease

Article abstract of DOI:10.1016/S0968-0896(03)00452-8

Alzheimer's disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC₅₀=101 nM) and SERT (IC₅₀=42 nM), but its AChE inhibition activity was less than donepezil (IC₅₀=10 nM). Here, we report the conformationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC₅₀=14 nM) and SERT (IC₅₀=6 nM).

Full text of DOI:10.1016/S0968-0896(03)00452-8

Bioorganic & Medicinal Chemistry 11 (2003) 4389–4415
A Conformational Restriction Approach to the Development of
Dual Inhibitors of Acetylcholinesterase and Serotonin Transporter
as Potential Agents for Alzheimer’s Disease
Narihiro Toda,a Keiko Tago,a Shinji Marumoto,a Kazuko Takami,a Mayuko Ori,a
Naho Yamada,a Kazuo Koyama,b Shunji Naruto,b Kazumi Abe,c Reina Yamazaki,c
Takao Hara,c Atsushi Aoyagi,c Yasuyuki Abe,c Tsugio Kanekoc and Hiroshi Kogena,*
aExploratory Chemistry Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
bResearch Information Department, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
cNeuroscience and Immunology Research Laboratories, Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan
Received 14 May 2003; revised 14 May 2003; accepted 3 July 2003
Abstract—Alzheimer’s disease (AD) has been treated with acetylcholinesterase (AChE) inhibitors such as donepezil. However, the
clinical usefulness of AChE inhibitors is limited mainly due to their adverse peripheral effects. Depression seen in AD patients has
been treated with serotonin transporter (SERT) inhibitors. We considered that combining SERT and AChE inhibition could
improve the clinical usefulness of AChE inhibitors. In a previous paper, we found a potential dual inhibitor, 1, of AChE (IC50=101
nM) and SERT (IC50=42 nM), but its AChE inhibition activity was less than donepezil (IC50=10 nM). Here, we report the con-
formationally restricted (R)-18a considerably enhanced inhibitory activity against AChE (IC50=14 nM) and SERT (IC50=6 nM).
# 2003 Elsevier Ltd. All rights reserved.
Introduction
Thus, AChE–SERT dual inhibitors would be a novel
class of anti-AD drugs with greater clinical efficacy than
known AChE inhibitors, since the antidepressive effect
resulting from SERT inhibition could bring further
alleviation of the symptoms of AD and a reduction of
dose-related adverse effects caused by an excessive
AChE inhibition.
Alzheimer’s disease (AD) affecting the aged is a neuro-
degenerative disorder characterized by a progressive
deterioration in cognitive function.1 The reduction in
cholinergic neurotransmission is believed to be one of
the major causes of memory impairments in AD
patients. Increasing the level of acetylcholine has been
regarded as one of the most promising methods for the
palliative treatment of AD.2 At present, several acetyl-
cholinesterase (AChE) inhibitors have been introduced
to the market such as tacrine,3 donepezil4 and rivas-
tigmine.5 However, the clinical efficacy of marketed
AChE inhibitors is limited mainly due to their adverse
peripheral effects.6 AD patients often suffer from psy-
chiatric disorder-related symptoms, such as irritability,
anxiety and depression.7 Depression in AD patients has
been successfully treated with serotonin transporter
(SERT) inhibitors8 that lack anticholinergic action.
In our previous paper,9 we designed novel AChE–SERT
dual inhibitors by the hybridization of rivastigmine
(AChE inhibitor) and fluoxetine10 (SERT inhibitor)
based on a hypothetical model of the AChE active site.
Among all the compounds, (S)-dimethyl carbamic acid
4-[1-methylamino-3-(4-nitrophenoxy)propyl]
phenyl
ester (1) showed the most potent inhibitory activity
against both AChE (IC50=101 nM) and SERT
(IC50=42 nM), but its AChE inhibition activity was less
than donepezil (IC50=10 nM) in our in vitro assay.
Here, we report that conformationally constrained
derivatives with six- or seven-membered ring, especially
(R)-18a, show considerably stronger inhibitory poten-
cies against AChE and SERT than previously reported
compound 1.
*Corresponding author. Tel.:+81-3-3492-3131; fax:+81-3-5436-8570;
e-mail: hkogen@shina.sankyo.co.jp
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00452-8

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N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
Chemistry
tion and treatment with dimethylcarbamyl chloride,
furnished intermediate 4. The ethyl ester group was
reduced with LiAlH4 and the resulting primary alcohol
was reacted with various phenols under the Mitsunobu
reaction conditions. Deprotection of the Boc group
afforded the derivatives 6a–g and 7a,b. A methyl group
was introduced to the secondary amine moiety by the
Eshweiler–Clarke reaction to give the derivatives 9a–g
and 10a,b. Derivative 8 was prepared using the similar
method via compound 5.
Our rigid analogues of compound 1 were designed by
linking the methylamine moiety and ortho-carbon atom
of phenyl ring with a carbon chain of appropriate length
(Fig. 1).
Preparation of the 1,2,3,4-tetrahydroisoquinoline deri-
vatives (n=0) using the Bischler–Napieralski reaction is
shown in Scheme 1. Methoxyphenethylamine 2 was
treated with ethyl malonyl chloride to give an N-acyl-
ated compound. The 1,2,3,4-tetrahydroisoquinoline
skeleton was constructed by the Bischler–Napieralski
Scheme 2 shows the synthesis of the rigid derivatives
having a saturated (20a,b and 21a,b) or unsaturated
(17a,b and 18a–h) seven-membered ring (n=1). We
formed the seven-membered ring by the ring-closing
olefin metathesis reaction,13 which is a very effective
method for making rings of various sizes. Treatment of
dihydroxybenzaldehyde 11 with dimethylcarbamyl
chloride using sodium hydride or pyridine selectively
provided a mono-carbamate product. The remaining
phenol was converted to an aryl triflate by treatment
with trifuluoromethanesulfonic anhydride. The result-
ing triflate was reacted with tributylvinylstannane by the
Stille reaction14 to give styrene compound 12. The aldol
reaction with ethyl acetate followed by reduction of the
ethyl ester with LiBH4 furnished the diol. Selective pro-
tection of the primary alcohol with t-BuPh2SiCl and
imidazole provided benzyl alcohol 13. Bromination of
13 using carbon tetrabromide and triphenylphosphine
gave benzyl bromide. The benzyl bromide was treated
with allylamine in acetonitrile, followed by N-Boc pro-
tection to afford 14, the precursor for ring-closing olefin
metathesis. Ring-closing olefin metathesis of 14 with
Grubbs catalyst 1513 successfully gave a seven-mem-
bered ring product. Deprotection of the silyl group with
TBAF furnished primary alcohol 16. Treatment of 16
with various phenols under Mitsunobu reaction condi-
tions and deprotection of the Boc group provided deri-
vatives 17a,b. N-Methylation by the Eshweiler–Clarke
reaction gave the derivatives 18a–h. Derivatives 20a,b
and 21a,b were synthesized from 19, prepared by the
hydrogenation of intermediate 16, in a similar manner
as above.
reaction using POCl3 or polyphosphate ester (PPE).12
11
Following hydrogenation of the exo double bond with
Adams’ catalyst provided compound 3. Demethylation
of 3 with boron tribromide, followed by N-Boc protec-
Figure 1. Our conformational restriction approach used in the devel-
opment of novel AChE–SERT dual inhibitors.
Scheme 3 shows the synthesis of the exo olefin deriva-
tive 24 and substituted olefin derivatives 26a–d. Hydro-
boration of 16b with borane in THF, followed by an
oxidation reaction,15 furnished a regioisomeric mixture
of alcohols, most notably a benzyl alcohol. From this
mixture of regio isomers, benzyl alcohol was selectively
oxidized with manganese oxide to give ketone 22.
Compound 22 was reacted with p-nitrophenol under
Mitsunobu reaction conditions, following treatment
with HCl and Boc protection of the amino group affor-
ded 23. This ketone was converted to an exo olefin
by the Wittig reaction. The olefin was deproteced and
N-methylated to give derivative 24. The enolate of
ketone 23 was reacted with 2-[N,N-bis(trifluoromethyl-
sulfonyl)amino]-5-chloropyridine16 to provide vinyl tri-
flate 25. Vinyl triflate 25 was coupled with
organostannanes or organoborons in the presence of a
palladium catalyst. Further deprotection and N-methyl-
ation of the resulting products led to derivatives 26a–d.
Scheme 1. Reagents and conditions: (a) ethyl malonyl chloride,
K2CO3, CH2Cl2, 0 ꢀC; (b) POCl3 or PPE, 80 ꢀC; (c) H2, PtO2, AcOH,
rt; (d) BBr3, CH2Cl2, ꢁ78 ꢀC to rt; (e) Boc2O, THF, rt; (f) Me2NCOCl,
K2CO3, DMF, rt; (g) LiAlH4, THF, ꢁ78 to 0 ꢀC; (h) phenol, DEAD,
PPh3, THF, rt; (i) 2N HCl–AcOEt, rt; (j) 1-fluoro-4-nitrobenzene,
NaH, DMF; (k) 37% HCHO aq, HCO2H, 80 ꢀC.

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4391
The asymmetric synthesis of (R)-18a is shown in Scheme 4.
Phenol 2717 was protected with a methoxymethyl
(MOM) group and the Horner–Wadsworth–Emmons
reaction provided a,b-unsaturated ester 28. Compound
28 was subjected to chiral amination by a method
reported by Davies.18 The resulting amine was protected
with a Boc group to furnish (R)-30 (99% ee).19 Com-
pound (R)-30 was reacted with dimethylcarbamyl chlor-
ide and reduced with LiAlH4 to afford primary alcohol
(R)-31. Alcohol (R)-31 was reacted with p-nitrophenol
under Mitsunobu reaction conditions, and the following
treatment with HCl and Boc protection gave (R)-32.
This phenol was converted to a triflate and the Stille
reaction with tributylvinylstannane provided a styrene
compound. Following allylation of the N-Boc-protected
amine afforded (R)-33. Ring-closing olefin metathesis of
(R)-33 with Grubbs catalyst 1513 provided a seven-
membered ring product. Deprotection of the Boc group
and the Eshweiler–Clarke methylation furnished (R)-
18a. Enantiomer (S)-18a was prepared by the same
method using chiral amine (R)-29.
derivatives containing a 1,2,3,4-tetrahydroisoquinoline
skeleton (6a,b, 7a,b, 8, 9a–g and 10a,b). In the previous
paper,9 we revealed that a nitro group for substituent X
on the phenyl ether moiety and para-carbamate sub-
stitution were crucial for potent dual inhibitory activ-
ities.
However,
1,2,3,4-tetrahydroisoquinoline
derivatives were reinvestigated with respect to sub-
stituent X using, in particular, an electron-withdrawing
group, and ideal carbamate position. A series of 1,2,3,4-
tetrahydroisoquinoline derivatives that was observed
had dramatically enhanced inhibitory activity toward
AChE, but their inhibitory activity toward SERT had
almost disappeared. We supposed that conformational
restriction of the flexible amine moiety resulted in the
appropriate binding to AChE. The reason for the dis-
appearance of anti-SERT activity could not be deter-
mined because we had no information on the structure
of SERT. Among the compounds with 1,2,3,4-tetra-
hydroisoquinoline structure, 6a (R=H, X=4-NO2)
showed the most potent inhibitory activity against
AChE (IC50=8 nM). In comparison with compound 1
(IC50=101 nM against AChE), 6a was about 13 times
more active against AChE. Similarly to our previous
results,9 compound 6a possessed a 4-NO2 group as
substituent X and 6-substituted carbamate moiety on
the 1,2,3,4-tetrahydroisoquinoline skeleton.
Results and Discussion
All rigid derivatives were assayed for their in vitro inhi-
bitions of AChE (mouse brain) and SERT (rat synap-
tosome). The protocols used here are described in the
Experimental.
Next, we examined the rigid derivatives 20a,b, 21a,b
containing a saturated seven-membered ring and 17a,b,
18a–h containing an unsaturated seven-membered ring
(Table 2). Compounds 20a,b (R=H) and 21a,b
(R=Me) showed higher inhibitory potencies against
Table 1 summarizes the inhibitory activities against
AChE and SERT of the conformationally restricted
Scheme 2. Reagents and conditions: (a) Me2NCOCl, NaH, DMF, rt or Me2NCOCl, py, CH2Cl2, rt; (b) Tf2O, py, CH2Cl2, 0 ꢀC; (c) (CH2=CH)
(n-Bu)3Sn, Pd(PPh3)4, LiCl, dioxane, 100 ꢀC; (d) AcOEt, LDA, THF, ꢁ78 ꢀC; (e) LiBH4, THF, rt; (f) t-BuPh2SiCl, imidazole, DMF, rt; (g) CBr4,
PPh3, CH2Cl2, rt; (h) allylamine, CH3CN, rt; (i) Boc2O, Et3N, THF, 50 ꢀC; (j) 15 (10 mol%), CH2Cl2, 45 ꢀC; (k) TBAF, THF, rt; (l) H2, Pd/C,
MeOH, rt; (m) phenol, DEAD, PPh3, THF, rt; (n) 2 N HCl–EtOAc, rt; (o) 37% HCHO aq, HCO2H, 80 ꢀC.

4392
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
AChE but much lower potencies against SERT simi-
larly to 1,2,3,4-tetrahydroquinoline derivatives. Com-
pounds 17a,b (R=H) which possessed a double bond
on the seven-membered ring also exhibited good inhibi-
tory activities but only against AChE, whereas com-
pounds 18a–e (R=Me) surprisingly showed potent
inhibitory activities against not only AChE but also
SERT. We have not determined the reason for this
striking improvement in anti-SERT activities obtained
by changing the secondary amine (R=H) to a tertiary
amine (R=Me) on the seven-membered ring. However,
it is clear that the olefin moiety on the seven-membered
ring is essential for the inhibitory potency of SERT as
can be seen by comparing derivatives 18a–e with 21a,b.
Compound 18a was the most potent dual inhibitor of
AChE (IC50=66 nM) and SERT (IC50=63 nM).
Changing the substitution position of the dimethylcar-
bamate from 7 to 6 (18f) and 8 (18g,h) resulted in the
loss of inhibitory potency for SERT.
Table 3 shows the effects of changing the substituent on
the olefin moiety of compound 18a. Derivatives 26a,b,
Scheme 3. Reagents and conditions: (a) BH3, THF, 0 ꢀC to rt then NaBO3, 0 ꢀC to rt; (b) MnO2, CH2Cl2, rt; (c) p-nitrophenol, DEAD, PPh3, THF,
rt; (d) 2N HCl–AcOEt, rt; (e) Boc2O, Et3N, THF, rt; (f) Ph3P+CH3Brꢁ, t-BuOK, benzene, 80 ꢀC; (g) 37% HCHO aq., HCO2H, 80 ꢀC; (h) 2-(5-Cl-
Py)NTf2, LHMDS, THF, ꢁ78 ꢀC; (i) see scheme.
Scheme 4. Reagents and conditions: (a) MOMCl, i-Pr2NEt, CH2Cl2, 0 ꢀC, 79%; (b) (EtO)2P(O)CH2CO2Et, NaH, THF, 0 ꢀC, 99%; (c) (i) (S)-29,
n-BuLi, THF, ꢁ78 ꢀC; (ii) H2, 20% Pd(OH)2/C, MeOH–H2O–AcOH (20:2:1), rt, 67% (two steps); (d) Boc2O, Et3N, MeOH, rt, 97%; (e) Me2N-
COCl, K2CO3, DMF, rt, 97%; (f) LiAlH4, THF, ꢁ50 to 0 ꢀC, 82%; (g) p-nitrophenol, DEAD, PPh3, THF, rt; (h) concd HCl, MeOH, rt, 68% (two
steps); (i) Boc2O, Et3N, MeOH, rt, 85%; (j) (i) Tf2O, py, CH2Cl2, 0 ꢀC; (ii) (CH2¼CH)(n-Bu)3Sn, Pd(PPh3)4, LiCl, dioxane, 100 ꢀC, 86% (two steps);
(k) allyl bromide, NaH, DMF, 0 ꢀC to rt, 86%; (l) 15 (10 mol%), CH2Cl2 (15 mM), 45 ꢀC, 96%; (m) 2 N HCl–AcOEt, rt, 96%; (n) (i) 37% HCHO
aq, HCO2H, 80 ꢀC, 78%.

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4393
Table 1. In vitro AChE and SERT inhibition activity of 1,2,3,4-tetra-
hydroisoquinoline derivatives
which have small substituents (R0=Me, vinyl) main-
tained their inhibitory activities against AChE
(IC50=60 and 43 nM, respectively), but lost their inhi-
bitory activities against SERT (both IC50=>1000 nM).
Derivative 26d, which has a large substituent (R0=
p-chlorophenyl), had little inhibitory activity against
both AChE (IC50=>1000 nM) and SERT
(IC50=>1000 nM). exo Olefin derivative 24 also had
little inhibitory activity against SERT (IC50=>1000
nM). These results revealed that a 1,2-di-substitued
internal olefin was essential for SERT inhibition.
Compda Carbamate position
R
X
IC50 (nM)
Compound 18a was the most potent dual inhibitor and
the activity of both enantiomers of 18a was evaluated,
as shown in Table 4. The enantiomer (R)-18a showed
extremely potent inhibitory activities against both
AChE (IC50=14 nM) and SERT (IC50=6 nM).
AChEb SERTc
6a
6b
7a
7b
9a
9c
9d
9b
9e
9f
6–
6–
7–
7–
6–
6–
6–
6–
6–
6–
6–
5–
7–
7–
H
H
H
H
Me
4-NO2
4-Cl
4-NO2
4-Cl
4-NO2
8
17
101
219
11
>1000
>1000
>1000
>1000
940
Me 3-Me-4-NO2
16
11
170
125
Table 3. Effect of various substituents on the inhibitory activity of
18a
Me
Me
Me
Me
Me
Me
Me
Me
3-NO2
4-Cl
4-F
33
49
34
20
660
>1000
>1000
>1000
750
4-Br
9g
8
10a
10b
4-OMe
4-NO2
4-NO2
4-Cl
56
161
265
>1000
520
aCompounds were tested as their hydrocloride salts.
bFrom mouse brain.
cFrom rat synaptosome.
Compda
R0
IC50 (nM)
AChEb
SERTc
18a
26a
26b
26c
26d
24
H
Me
Vinyl
2-Thienyl
4-Cl-Ph
66
60
43
150
63
>1000
>1000
>1000
>1000
>1000
Table 2. In vitro AChE and SERT inhibition activity of derivatives
with a seven-membered ring
>1000
27
aCompounds were tested as their hydrocloride salts.
bFrom mouse brain.
cFrom rat synaptosome.
Table 4. In vitro AChE and SERT inhibition activity of 18a
enantiomers
Compda Carbamate position
R
X
IC50 (nM)
AChEb SERTc
20a
20b
21a
21b
17a
17b
18a
18b
18c
18d
18e
18f
7–
7–
7–
7–
7–
7–
7–
7–
7–
7–
7–
6–
8–
8–
H
H
Me
Me
H
4-NO2
4-Cl
4-NO2
4-Cl
4-NO2
3-Me-4-Cl
4-NO2
55 >1000
215 >1000
61 >1000
116 >1000
92 >1000
153 >1000
H
Me
66
103
139
135
285
146
63
61
71
850
62
900
Me 3-Me-4-Cl
Compda
IC50 (nM)
Me
Me
Me
4-Cl
4-F
4-CF3
AChEb
SERTc
rac-18a
(R)-18a
(S)-18a
66
14
609
63
6
930
Me 3-Me-4-Cl
Me
Me
18g
18h
4-NO2
4-Cl
>1000 >1000
>1000 >1000
aCompounds were tested as their hydrocloride salts.
bFrom mouse brain.
cFrom rat synaptosome.
aCompounds were tested as their hydrocloride salts.
bFrom mouse brain.
cFrom rat synaptosome.

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N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
Although both 1 and its enantiomer showed similar
levels of AChE inhibition,9 (R)-18a showed a 44 times
stronger inhibitory activity against AChE than (S)-18a.
This difference of AChE inhibition would result from
the conformational rigidity of 18a. Similarly (R)-18a
exhibited a 155 times stronger inhibitory activity against
SERT than (S)-18a. Compound (R)-18a showed extre-
mely weak inhibitory activities against butylcholinester-
ase, choline acetyltransferase, norepinephrine and
dopamine transporters. In this way, we were able to
further develop the AChE—SERT dual inhibitor 1
(IC50=101 and 42 nM, respectively) to (R)-18a
(IC50=14 and 6 nM, respectively), which had an equal
potency to donepezil (IC50=10 nM) and a 30 times
more potent activity than fluoxetine (IC50=180 nM).
was performed on 0.25 mm pre-coated Merck silica gel
60 F254 plates. Column chromatography was performed
on Merck silica gel 60 (230–400 mesh).
(6-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid
ethyl ester (3b).11 To a solution of 2b (1.00 g, 6.60
mmol) and K2CO3 (1.10 g, 8.00 mmol) in CH2Cl2 (10
mL) was added ethyl malonyl chloride (0.92 mL, 7.20
mmol) at 0 ꢀC. The reaction mixture was stirred for 30
min at 0 ꢀC. After dilution with water (50 mL), the
mixutre was extracted with CH2Cl2 (30 mLꢂ2), and the
combined organic layers were washed with water (30
mL) and brine (30 mL), dried over Na2SO4, filtered and
evaporated. The residue was purified by silica gel col-
umn chromatography (hexane–AcOEt 1:1 to 1:2) to give
an amide (1.10 g, 63%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) d ppm: 1.26 (t, 3H, J=7.5 Hz), 2.81
(t, 2H, J=7.0 Hz), 3.27 (s, 2H), 3.55 (q, 2H, J=7.0 Hz),
3.80 (s, 3H), 4.17 (q, 2H, J=7.5 Hz), 6.75–6.80 (m, 3H),
7.08 (br s, 1H), 7.22 (t, 1H, J=8.0 Hz).
Conclusion
We have designed and synthesized conformationally
restricted derivatives by linking a methylamine moiety
to the ortho-carbon atom of the phenyl ring in 1 as
potential dual inhibitors of AChE and SERT for AD.
1,2,3,4-Tetrahydroisoquinoline derivative 6a showed a
much greater inhibitory activity against AChE (IC50=8
nM) but loss of inhibitory activity against SERT
(IC50=>1000 nM). Saturated seven-membered ring
derivatives 20a (R=H) and 21a (R=Me) were found to
have lost their anti-SERT activity as did six-membered
ring derivative 6a. Surprisingly, compound 18a
(R=Me) which possessed a double bond in its seven-
membered ring showed potent inhibitory activities
against not only AChE (IC50=66 nM) but also SERT
(IC50=63 nM). Our conformational restriction
approach finally led to find (R)-18a which was an
extremely potent inhibitor of both AChE (IC50=14
nM) and SERT (IC50=6 nM). (R)-18a is an interesting
compound that forms a novel class of treatment drugs
for AD. Further pharmacological evaluation of (R)-18a
is underway.
The solution of the above amide (20.8 g, 78.4 mmol) in
POCl3 (60 mL) was stirred for 4 h at 80 ꢀC. The mixture
was poured into iced water. This was neutralized with
K2CO3, and extracted with AcOEt (300 mLꢂ2). The
combined organic extracts were washed with brine (300
mLꢂ2), dried over Na2SO4, filtered and evaporated.
Purification by silica gel column chromatography (hex-
ane–AcOEt 1:1) yielded 1-carbethoxymethylene-6-
methoxy-1,2,3,4-tetrahydroisoquinoline (7.56 g) as a
1
yellow oil. H NMR (500 MHz, CDCl3) d ppm: 1.30 (t,
3H, J=7.5 Hz), 2.88 (t, 2H, J=7.0 Hz), 3.43 (dt, 2H,
J=3.0, 7.0 Hz), 3.84 (s, 3H), 4.16 (q, 2H, J=7.5 Hz),
5.08 (s, 1H), 6.70 (d, 1H, J=2.5 Hz), 6.80 (dd, 1H,
J=2.5, 9.0 Hz), 7.62 (d, 1H, J=9.0 Hz), 9.04 (br s, 1H).
To a solution of 1-carbethoxymethylene-6-methoxy-
1,2,3,4-tetrahydroisoquinoline (7.56 g) in AcOH (50
mL) was added PtO2 (400 mg). The reaction mixture
was stirred for 3 h under hydrogen atmosphere at room
temperature. The mixture was filtered through a Celite
pad, and the solvent was concentrated in vacuo. The
residue was neutralized with 1 N NaOH and K2CO3,
and then extracted with AcOEt (300 mLꢂ2). The com-
bined organic extracts were washed with brine (300
mLꢂ2), dried over Na2SO4, filtered and evaporated.
Purification by silica gel column chromatography
(AcOEt to AcOEt–MeOH 5:1) gave 3b (4.88 g, 25% for
Experimental
Chemistry
General information. Unless otherwise noted, all reac-
tions were carried out in oven-dried glassware under a
nitrogen atmosphere. Tetrahydrofuran (THF) was dis-
tilled from sodium metal/benzophenone ketyl. Di-
chloromethane (CH2Cl2) was distilled from calcium
hydride. All other dry solvents were purchased from
Aldrich in SureSealTM containers. All other commer-
cially obtained reagents were used as purchased. 1H
NMR and 13C NMR spectra were recorded on a Varian
400 or 500 spectrometer. The following abbreviations
were used to explain the multiplicities: s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet,
br=broadened. Infrared spectra were recorded on a
JASCO FT-IR-8900 spectrometer. Mass spectra were
obtained on a JEOL HX-100, a SX-102A or a JMS-AX-
505H mass spectrometer. Optical rotations were mea-
sured on a JASCO P-1030 polarimeter. Analytical TLC
1
2 steps) as a yellow oil. H NMR (400 MHz, CDCl3) d
ppm: 1.26 (t, 3H, J=7.2 Hz), 2.67–2.76 (m, 2H), 2.80–
2.87 (m, 2H), 3.01 (ddd, 1H, J=5.2, 7.6, 12.4 Hz), 3.19
(dt, 1H, J=5.2, 12.4 Hz), 3.77 (s, 3H), 4.17 (q, 2H,
J=7.2 Hz), 4.41 (dd, 1H, J=3.2, 9.6 Hz), 6.63 (d, 1H,
J=2.8 Hz), 6.72 (dd, 1H, J=2.8, 8.8 Hz), 7.01 (d, 1H,
J=8.8 Hz).
(5-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid
ethyl ester (3a). This was prepared by a method similar
to that used for 3b using polyphosphate ester instead of
POCl3.
1
Amide. H NMR (500 MHz, CDCl3) d ppm: 1.27 (t,
3H, J=7.0 Hz), 2.86 (t, 2H, J=7.0 Hz), 3.26 (s, 2H),

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4395
3.53 (q, 2H, J=7.0 Hz), 3.84 (s, 3H), 4.17 (q, 2H, J=7.0
Hz), 6.87 (d, 1H, J=8.0 Hz), 6.90 (t, 1H, J=8.0 Hz),
7.10 (br s, 1H), 7.14 (dd, 1H, J=2.0, 8.0 Hz), 7.22 (t,
1H, J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm:
14.0, 30.0, 39.8, 41.4, 55.2, 61.4, 110.3, 120.5, 127.2,
127.8, 130.5, 157.5, 164.8, 169.3; IR (film) cmꢁ1: 3299,
2939, 1739, 1654, 1552, 1495, 1245, 1032, 756; HRMS
calcd for C14H19NO4 (M)+ 265.1314, found 265.1316.
2.59–2.90 (m, 4H), 3.23–3.30 (m, 0.5H), 3.32–3.42 (m,
0.5H), 3.84–3.92 (m, 0.5H), 4.02–4.10 (m, 0.5H), 4.08–
4.18 (m, 2H), 5.26 (br s, 1H), 5.46 (t, 0.5H, J=7.0 Hz),
5.56 (t, 0.5H, J=7.0 Hz), 6.60 (s, 1H), 6.62–6.68 (m,
1H), 7.02 (d, 1H, J=8.0 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 28.4, 28.6, 37.5, 38.7, 42.0, 42.5, 51.2,
51.9, 60.5, 77.5, 80.0, 80.4, 113.7, 115.1, 115.2, 127.9,
128.2, 128.3, 135.8, 136.0, 154.5, 154.7, 154.8, 170.9; IR
(CHCl3) cmꢁ1: 3596, 3356, 2982, 1728, 1685, 1421, 1368,
1293, 1250, 1161, 1042; HRMS calcd for C18H26NO5
(M+H)+ 336.1811, found 336.1817.
1
3a. H NMR (400 MHz, CDCl3) d ppm: 1.26 (t, 3H,
J=7.6 Hz), 2.67 (t, 2H, J=5.6 Hz), 2.74 (dd, 1H,
J=9.2, 16.0 Hz), 2.85 (dd, 1H, J=3.6, 16.0 Hz), 3.01
(dt, 1H, J=6.0, 12.4 Hz), 3.19 (dt, 1H, J=5.6, 12.4 Hz),
3.81 (s, 3H), 4.18 (q, 2H, J=7.6 Hz), 4.44 (dd, 1H,
J=3.6, 9.2 Hz), 6.71 (t, 2H, J=8.4 Hz), 7.12 (t, 1H,
J=8.4 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 14.2,
23.6, 40.0, 41.1, 52.6, 55.3, 60.5, 107.5, 118.0, 124.4,
126.1, 138.7, 157.2, 172.3; IR (CHCl3) cmꢁ1: 2940, 1724,
1587, 1470, 1262, 1165; HRMS calcd for C14H20NO3
(M+H)+ 250.1443, found 250.1430.
To a solution of the above compound (1.70 g, 5.07
mmol) and K2CO3 (1.03 g, 7.50 mmol) in DMF (5 mL)
was added Me2NCOCl (0.690 mL, 7.50 mmol) at room
temperature. The reaction mixture was stirred for 2.5 h
at room temperature. After dilution with water (20 mL),
the mixture was extracted with AcOEt (20 mLꢂ2), and
the combined organic layers were washed with brine (30
mL), dried over Na2SO4, filtered and evaporated. The
residue was purified by silica gel column chromato-
graphy (hexane–AcOEt 2:1 to 1:1) to give 4a (1.97 g,
(7-Methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)acetic acid
ethyl ester (3c). This was prepared by a method similar
to that used for 3b using polyphosphate ester instead of
POCl3.
1
95%) as a colorless oil. H NMR (500 MHz, CDCl3) d
ppm: 1.25 (t, 3H, J=7.0 Hz), 1.47 (s, 9H), 2.62–2.98 (m,
4H), 3.00 (s, 3H), 3.08 (s, 3H), 3.18–3.26 (m, 0.5H),
3.32–3.40 m, (0.5H), 3.90–3.92 (m, 0.5H), 4.10–4.18 (m,
2.5H), 5.53 (t, 0.5H, J=7.0 Hz), 5.64 (t, 0.5H, J=7.0
Hz), 6.89 (s, 1H), 6.89–6.97 (m, 1H), 7.14–7.19 (m, 1H);
13C NMR (100 MHz, CDCl3) d ppm: 28.3, 28.6, 36.4,
36.7, 37.0, 38.5, 41.9, 42.3, 51.1, 51.9, 60.3, 76.5, 77.5,
79.8, 80.2, 119.8, 121.7, 122.0, 127.6, 128.0, 133.4, 135.5,
135.8, 150.1, 154.3, 154.4, 154.9, 170.7, 171.1; IR
(CHCl3) cmꢁ1: 2982, 1721, 1686, 1392, 1368, 1288, 1247,
1163, 1037; HRMS calcd for C21H31N2O6 (M+H)+
407.2182, found 407.2187.
1
Amide. H NMR (400 MHz, CDCl3) d ppm: 1.27 (t,
3H, J=7.2 Hz), 2.78 (t, 2H, J=6.4 Hz), 3.27 (s, 2H),
3.50 (q, 2H, J=6.8 Hz), 3.79 (s, 3H), 4.17 (q, 2H, J=6.8
Hz), 6.85 (d, 2H, J=8.0 Hz), 7.08 (br s, 1H), 7.12 (d,
2H, J=8.0 Hz).
1
3c. H NMR (400 MHz, CDCl3) d ppm: 1.26 (t, 3H,
J=7.6 Hz), 2.65-2.79 (m, 3H), 2.84 (dd, 1H, J=3.6,
16.4 Hz), 2.96–3.02 (m, 1H), 3.18 (dt, 1H, J=5.6, 12.4
Hz), 3.77 (s, 3H), 4.18 (q, 2H, J=7.2 Hz), 4.42 (dd, 1H,
J=2.8, 9.6 Hz), 6.62 (d, 1H, J=2.0 Hz), 6.72 (dd, 1H,
J=2.0, 8.0 Hz), 7.01 (d, 1H, J=8.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 14.2, 28.9, 40.8, 41.3, 52.8,
55.3, 60.6, 111.0, 112.5, 127.5, 130.3, 138.5, 157.7, 172.3;
IR (CHCl3) cmꢁ1: 2957, 1724, 1611, 1503, 1288, 1256,
1162, 1038; HRMS calcd for C14H20NO3 (M+H)+
250.1443, found 250.1442.
7-Dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-3,4-di-
hydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
(4b). This was prepared by the method used for 4a.
1
N-Boc-protected phenol. H NMR (500 MHz, CDCl3)
d ppm: 1.22–1.27 (m, 3H), 1.47 (s, 9H), 2.67 (br d, 2H,
J=15.5 Hz), 2.74–2.90 (m, 2.5H), 3.20–3.26 (m, 0.5H),
3.34–3.40 (m, 0.5H), 3.93–4.00 (m, 0.5H), 4.06–4.18 (m,
2H), 5.47 (br t, 0.5H, J=6.0 Hz), 5.64 (br t, 0.5H,
J=6.0 Hz), 6.66 (br s, 0.5H), 6.68 (d, 1H, J=9.0 Hz),
6.82 (br s, 0.5H), 6.97-7.00 (m, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 14.1, 27.4, 27.6, 28.4, 37.8,
38.9, 41.6, 42.3, 51.8, 52.2, 60.8, 77.5, 80.4, 113.2, 113.5,
1145, 114.8, 125.3, 126.2, 129.9, 130.1, 137.1, 137.6,
6-Dimethylcarbamoyloxy-1-ethoxycarbonylmethyl-3,4-di-
hydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester
(4a). To a solution of 3b (4.88 g, 19.6 mmol) in CH2Cl2
(30 mL) was added BBr3 in CH2Cl2 (30 mL, 1.0 M)
dropwise at ꢁ78 ꢀC. The mixture was stirred for 3 h at
room temperature. The reaction was quenched with
water (10 mL) and neutralized with saturated aq
NaHCO3. The product was extracted with CH2Cl2 (40
mLꢂ2). The combined organic solution was washed
with brine (40 mL), dried over Na2SO4, filtered and
evaporated to give phenol (2.10 g). To a solution of this
phenol (2.10 g) in THF (20 mL), Boc2O (2.84 g, 13.0
mmol) was added at room temperature. The mixture
was stirred for 1 h at room temperature. The solvent
was concentrated in vacuo. The residue was purified by
silica gel column chromatography (hexane–AcOEt 10:1
to 1:1) to give an N-Boc-protected phenol (1.72 g, 26%
154.2, 154.4, 154.8, 170.7, 171.0; IR (CHCl3) cmꢁ1
:
3597, 3363, 1729, 1685, 1423, 1368, 1270, 1164; HRMS
calcd for C18H26NO5 (M+H)+ 336.1811, found
336.1818.
1
4b. H NMR (500 MHz, CDCl3) d ppm: 1.25 (t, 3H,
J=7.0 Hz), 1.46 (s, 9H), 2.64–2.80 (m, 4H), 2.80–2.88
(m, 0.5H), 3.00 (s, 3H), 3.08 (s, 3H), 3.18-3.25 (m,
0.5H), 3.31–3.39 (m, 0.5H), 3.91–3.99 (m, 0.5H), 4.10–
4.20 (m, 2H), 5.53 (br t, 0.5H, J=10.5 Hz), 5.63 (br t,
0.5H, J=10.5 Hz), 6.92–6.95 (m, 1H), 6.95 (s, 1H),
7.08–7.12 (m, 1H); 13C NMR (100 MHz, CDCl3) d ppm:
14.1, 14.2, 27.8, 28.3, 36.4, 36.7, 37.2, 42.2, 51.4, 52.1,
1
for two steps) as a colorless oil. H NMR (500 MHz,
CDCl3) d ppm: 1.25 (t, 3H, J=8.0 Hz), 1.48 (s, 9H),

4396
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
60.6, 80.2, 119.9, 120.6, 129.5, 129.8, 131.3, 137.4, 137.5,
149.7, 154.2, 154.8, 170.6; IR (CHCl3) cmꢁ1: 2982, 1721,
1687, 1392, 1250, 1166; HRMS calcd for C21H31N2O6
(M+H)+ 407.2182, found 407.2184.
2H), 3.32–3.35 (m, 1H), 3.48–3.58 (m, 1H), 4.23 (dt, 1H,
J=4.4, 9.6 Hz), 4.53–4.59 (m, 1H), 4.82 (br s, 1H), 6.94
(d, 1H, J=2.0 Hz), 7.03 (dd, 1H, J=2.0, 9.0 Hz), 7.05
(d, 2H, J=8.8 Hz), 7.14 (d, 1H, J=9.0 Hz), 8.18 (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 25.6,
33.7, 36.4, 36.7, 39.0, 52.0, 64.6, 114.8, 121.2, 122.4,
125.9, 127.5, 127.6, 132.9, 141.9, 151.1, 154.4, 163.1; IR
(KBr) cmꢁ1: 2935, 2770, 1722, 1593, 1510, 1388, 1340,
1262, 1171, 1110, 1024, 849, 753; HRMS calcd for
C20H24N3O5 (M+H)+ 386.1716, found 386.1719.
Dimethylcarbamic
1,2,3,4-tetrahydroisoquinolin-6-yl ester hydrochloride salt
acid
1-[2-(4-nitrophenoxy)ethyl]-
.
(6a HCl). To a solution of 4a (1.97 g, 4.84 mmol) in
THF (30 mL) was added LiAlH4 (270 mg, 7.2 mmol) at
ꢁ78 ꢀC. The reaction mixture was stirred for 20 min at
ꢁ78 ꢀC and for another 20 min at 0 ꢀC. To the reaction
mixture was successively added water (0.3 mL), 15% aq
NaOH (0.3 mL), water (0.9 mL) and MgSO4. After fil-
tration, organic solvent was concentrated in vacuo. The
residue was purified by silica gel column chromato-
graphy (hexane–AcOEt 1:1 to AcOEt) to provide an
alcohol (1.38 g, 78%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d ppm: 1.49 (s, 9H), 1.74 (t, 1H,
J=12.4 Hz), 2.00–2.10 (m, 1H), 2.71 (dt, 1H, J=4.4,
16.0 Hz), 2.86–2.94 (m, 1H), 3.00 (s, 3H), 3.09 (s, 3H),
3.54 (t, 1H, J=11.0 Hz), 3.65 (br, 1H), 4.02 (dt, 1H,
J=4.4, 12.4 Hz), 4.12 (br, 0.8H), 4.23 (br, 0.2H), 5.30
(d, 1H, J=12.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 6.93 (dd,
1H, J=2.0, 8.0 Hz), 7.15 (d, 1H, J=8.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 28.3, 28.8, 36.4, 36.7, 38.1,
38.9, 50.1, 58.5, 80.6, 119.9, 121.7, 127.8, 134.5, 135.1,
149.7, 154.9, 156.2; IR (CHCl3) cmꢁ1: 3424, 2981, 2942,
1713, 1660, 1392, 1247, 1163, 1043; HRMS calcd for
C19H29N2O5 (M+H)+ 365.2077, found 365.2092.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-
1,2,3,4-tetrahydroisoquinolin-6-yl ester hydrochloride salt
.
(6b HCl). This was prepared by the method used for 6a.
6b. 1H NMR (400 MHz, CDCl3) d ppm: 2.09–2.18 (m,
1H), 2.26–2.34 (m, 1H), 2.70–2.84 (m, 2H), 2.97–3.04
(m, 1H), 3.00 (s, 3H), 3.09 (s, 3H), 3.14–3.20 (m, 1H),
4.04–4.23 (m, 3H), 6.83–6.87 (m, 3H), 6.90 (dd, 1H,
J=2.8, 8.8 Hz), 7.12 (d, 1H, J=8.0 Hz), 7.22 (d, 2H,
J=8.8 Hz; 13C NMR (100 MHz, CDCl3) d ppm: 29.9,
35.7, 36.4, 36.6, 40.3, 52.7, 65.7, 115.8, 119.4, 122.1,
125.4, 127.0, 129.2, 135.7, 136.5, 149.5, 155.0, 157.5; IR
(CHCl3) cmꢁ1: 2937, 1712, 1492, 1391, 1246, 1171;
HRMS calcd for C20H24N2O3Cl (M+H)+ 375.1475,
found 375.1488.
1
.
6b HCl. H NMR (400 MHz, CDCl3) d ppm: 2.43–
2.62 (m, 2H), 3.00 (s, 3H), 3.09 (s, 3H), 3.09–3.13 (m,
2H), 3.28–3.38 (m, 1H), 3.48–3.58 (m, 1H), 4.05–4.12
(m, 1H), 4.32–4.40 (m, 1H), 4.82 (br s, 1H), 6.90 (d, 2H,
J=8.8 Hz), 6.93 (s, 1H), 7.01 (d, 1H, J=8.8 Hz), 7.13
(d, 1H, J=8.8 Hz), 7.21 (d, 2H, J=8.8 Hz), 9.52 (br s,
1H); 13C NMR (100 MHz, CDCl3) d ppm: 25.6, 33.8,
36.4, 36.7, 39.0, 52.2, 64.1, 116.1, 121.0, 122.2, 126.2,
127.6, 127.8, 129.4, 133.0, 150.9, 154.5, 156.7; IR (KBr)
cmꢁ1: 2932, 2734, 1727, 1492, 1385, 1243, 1165, 823;
HRMS calcd for C20H24N2O3Cl (M+H)+ 375.1475,
found 375.1484.
To a solution of the alcohol (200 mg, 0.548 mmol), 4-
nitrophenol (83.5 mg, 0.600 mmol), and Ph3P (172 mg,
0.657 mmol) in THF (10 mL) was added 40% diethyl
azodicaboxylic acid toluene solution (286 mg, 0.657
mmol) dropwise at 0 ꢀC. The reaction mixture was stir-
red for 1 h at room temperature, and then concentrated
in vacuo. The residue was purified by silica gel column
chromatography (hexane–AcOEt 1:1 to 1:2) to give
N-Boc-protected 6a. This compound was treated with
2 N HCl in AcOEt (6 mL). After stirring for 12 h at
room temperature, the reaction mixture was neutralized
with saturated aq NaHCO3 and extracted with AcOEt
(10 mLꢂ2). The combined organic extracts were washed
with brine (10 mL), dried over Na2SO4, filtered and
evaporated. Purification by silica gel column chromato-
graphy (AcOEt to AcOEt–MeOH 5:1) yielded 6a (148
mg, 70% for two steps) as a colorless oil.
Dimethylcarbamic
1,2,3,4-tetrahydroisoquinolin-7-yl ester hydrochloride salt
acid
1-[2-(4-nitrophenoxy)ethyl]-
.
(7a HCl). This was prepared by the method used for 6a.
1
Alcohol. H NMR (500 MHz, CDCl3) d ppm: 1.49 (s,
9H), 1.77 (t, 1H, J=13.5 Hz), 2.02–2.11 (m, 1H), 2.71
(dt, 1H, J=4.0, 15.5 Hz), 2.85-2.92 (m, 1H), 3.00 (s,
3H), 3.09 (s, 3H), 3.09–3.16 (m, 1H), 3.54 (t, 1H,
J=12.0 Hz), 3.64 (br s, 1H), 4.03 (dt, 1H, J=4.0, 12.5
Hz), 4.07 (br s, 0.8H), 4.25 (br s, 0.2H), 5.29 (d, 1H,
J=10.0 Hz), 6.92 (s, 1H), 6.93 (d, 1H, J=8.0 Hz), 7.09
(d, 1H, J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 28.2, 28.3, 36.4, 36.7, 38.4, 38.7, 50.4, 58.4, 80.6,
120.0, 120.1, 129.4, 130.8, 138.6, 149.8, 154.9, 156.1; IR
(CHCl3) cmꢁ1: 3424, 2940, 1714, 1662, 1392, 1248, 1164;
HRMS calcd for C19H29N2O5 (M+H)+ 365.2077,
found 365.2069.
6a. 1H NMR (500 MHz, CDCl3) d ppm: 2.16–2.23 (m,
1H), 2.30–2.34 (m, 1H), 2.71–2.83 (m, 2H), 3.00–3.05
(m, 1H), 3.01 (s, 3H), 3.09 (s, 3H), 3.14–3.20 (m, 1H),
4.16–4.23 (m, 2H), 4.31–4.36 (m, 1H), 6.87 (d, 1H,
J=2.0 Hz), 6.92 (dd, 1H, J=2.0, 8.0 Hz), 6.98 (d, 2H,
J=9.5 Hz), 7.13 (d, 1H, J=8.0 Hz), 8.20 (d, 2H, J=9.5
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 29.8, 35.5,
36.4, 36.7, 40.2, 52.4, 66.2, 114.5, 119.5, 122.2, 125.9,
126.9, 135.4, 136.5, 141.4, 149.6, 155.0, 164.0; IR
(CHCl3) cmꢁ1: 2939, 1712, 1593, 1512, 1498, 1391, 1343,
1263, 1172, 1111, 1020, 846; HRMS calcd for
C20H24N3O5 (M+H)+ 386.1716, found 386.1716.
7a. 1H NMR (400 MHz, CDCl3) d ppm: 2.04–2.23 (m,
1H), 2.30–2.38 (m, 1H), 2.68–2.82 (m, 2H), 2.99–3.05
(m, 1H), 3.00 (s, 3H), 3.09 (s, 3H), 3.14–3.21 (m, 1H),
4.16–4.24 (m, 2H), 4.31–4.36 (m, 1H), 6.90 (dd, 1H,
J=2.0, 8.8 Hz), 6.91 (s, 1H), 6.98 (d, 2H, J=8.4 Hz),
1
.
6a HCl. H NMR (400 MHz, CDCl3) d ppm: 2.50–
2.70 (m, 2H), 3.00 (s, 3H), 3.09 (s, 3H), 3.09–3.16 (m,

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4397
7.08 (d, 1H, J=8.8 Hz), 8.20 (d, 2H, J=8.4 Hz); 13C
NMR (100 MHz, CDCl3) d ppm: 29.2. 35.3, 36.4, 36.7,
40.4, 52.6, 66.1, 114.5, 119.2, 119.8, 125.9, 130.2, 132.1,
3.01 (s, 3H), 3.07–3.12 (m, 1H), 3.09 (s, 3H), 3.70 (t, 1H,
J=5.5 Hz), 3.96–4.01 (m, 1H), 4.25 (dt, 1H, J=8.0, 8.5
Hz), 6.87 (d, 1H, J=2.5 Hz), 6.91 (d, 3H, J=9.0 Hz),
7.11 (d, 1H, J=9.0 Hz), 8.17 (d, 2H, J=9.0 Hz); 13C
NMR (100 MHz, CDCl3) d ppm: 25.8, 34.0, 36.4, 36.7,
42.7, 47.7, 60.1, 65.8, 114.5, 119.6, 121.7, 125.8, 127.9,
133.9, 135.9, 141.3, 149.5, 155.0, 164.1; IR (CHCl3)
cmꢁ1: 2941, 1712, 1593, 1512, 1498, 1391, 1342, 1264,
1172, 1111, 1018, 846; HRMS calcd for C21H26N3O5
(M+H)+ 400.1873, found 400.1865.
139.5, 141.4, 149.5, 155.0, 164.0; IR (CHCl3) cmꢁ1
:
2939, 1713, 1593, 1512, 1498, 1391, 1342, 1264, 1173,
1111, 1020; HRMS calcd for C20H24N3O5 (M+H)+
386.1716, found 386.1729.
1
.
7a HCl. H NMR (500 MHz, CDCl3) d ppm: 2.55–
2.69 (m, 2H), 2.98 (s, 3H), 3.07 (s, 3H), 3.09–3.18 (m,
2H), 3.34 (quint, 1H, J=7.0 Hz), 3.58 (quint, 1H,
J=6.0 Hz), 4.27 (dt, 1H, J=5.0, 10.0 Hz), 4.52–4.57 (m,
1H), 4.80–4.82 (m, 1H), 6.94 (d, 1H, J=2.0 Hz), 7.02 (dd,
1H, J=2.0, 8.0 Hz), 7.05 (d, 2H, J=9.0 Hz), 7.14 (d, 1H,
J=8.0 Hz), 8.16 (d, 2H, J=9.0 Hz); 13C NMR (100MHz,
CDCl3) d ppm: 25.1, 33.5, 36.4, 36.7, 39.4, 52.2, 64.6,
114.9, 119.9, 121.9, 125.8, 128.3, 130.3, 131.6, 141.9, 150.5,
154.5, 163.1; IR (CHCl3) cmꢁ1: 2970, 2767, 1720, 1593,
1514, 1499, 1391, 1344, 1260, 1172, 1111; HRMS calcd for
C20H24N3O5 (M+H)+ 386.1716, found 386.1719.
1
.
9a HCl. H NMR (400 MHz, CDCl3) d ppm: 2.19–
2.27 (m, 1H), 2.89 (d, 3H, J=5.2 Hz), 3.02 (s, 3H),
3.04–3.20 (m, 3H), 3.10 (s, 3H), 3.32–3.40 (m, 1H),
3.71–3.80 (m, 1H), 4.14–4.20 (m, 1H), 4.50 (t, 1H,
J=6.4 Hz), 4.60–4.65 (m, 1H), 7.02–7.10 (m, 5H), 8.23
(d, 2H, J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 22.0, 26.9, 34.8, 36.5, 36.8, 40.6, 44.8, 61.0, 64.5,
114.7, 121.6, 122.6, 126.0, 126.3, 129.0, 130.5, 142.0,
151.7, 154.3, 163.0; IR (KBr) cmꢁ1: 2932, 2529, 1722,
1591, 1511, 1388, 1341, 1260, 1172, 1110, 1029, 849;
HRMS calcd for C21H26N3O5 (M+H)+ 400.1873,
found 400.1879.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-
1,2,3,4-tetrahydroisoquinolin-7-yl ester hydrochloride salt
.
(7b HCl). This was prepared by the method used for 6a.
Compounds 9b–g and 10a, b were prepared by the
method used for 9a.
7b. 1H NMR (400 MHz, CDCl3) d ppm: 2.04–2.27 (m,
1H), 2.28–2.35 (m, 1H), 2.69–2.82 (m, 2H), 2.97–3.03
(m, 1H), 3.00 (s, 3H), 3.09 (s, 3H), 3.15–3.22 (m, 1H),
4.04–4.11 (m, 1H), 4.14–4.23 (m, 2H), 6.84 (d, 2H,
J=8.8 Hz), 6.89 (dd, 1H, J=2.0, 9.6 Hz), 6.90 (s, 1H),
7.07 (d, 1H, J=9.6 Hz), 7.22 (d, 2H, J=8.8 Hz); 13C
NMR (100 MHz, CDCl3) d ppm: 29.3, 35.5, 36.4, 36.7,
40.6, 52.9, 65.6, 115.8, 119.2, 119.7, 125.4, 129.2, 130.1,
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-2-
methyl-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydro-
1
.
chloride salt (9b HCl). 9b: H NMR (500 MHz, CDCl3)
d ppm: 2.20 (dt, 2H, J=5.5, 7.0 Hz), 2.46 (s, 3H), 2.68–
2.74 (m, 2H), 2.81–2.88 (m, 1H), 3.00 (s, 3H), 3.08 (s,
3H), 3.09–3.14 (m, 1H), 3.70 (t, 1H, J=4.5 Hz), 3.87
(dt, 1H, J=7.0, 9.5 Hz), 4.12 (dt, 1H, J=7.0, 9.5 Hz),
6.80 (d, 2H, J=9.0 Hz), 6.85 (d, 1H, J=3.0 Hz), 6.89
(dd, 1H, J=3.0, 9.0 Hz), 7.11 (d, 2H, J=8.0 Hz), 7.20
(d, 2H, J=8.5 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 25.6, 34.3, 36.4, 36.6, 42.6, 47.3, 60.0, 65.2, 115.8,
119.5, 121.6, 125.2, 128.1, 129.2, 134.2, 135.7, 149.5,
155.0, 157.6; IR (CHCl3) cmꢁ1: 2940, 1712, 1492, 1391,
1246, 1171, 909; HRMS calcd for C21H26N2O3Cl
(M+H)+ 389.1632, found 389.1616.
132.1, 139.8, 149.4, 155.1, 157.5; IR (CHCl3) cmꢁ1
:
2937, 1713, 1492, 1391, 1249, 1171, 826; HRMS calcd
for C20H24N2O3Cl (M+H)+ 375.1475, found 375.1472.
1
.
7b HCl. H NMR (500 MHz, CDCl3) d ppm: 2.52–
2.62 (m, 2H), 2.99 (s, 3H), 3.02–3.14 (m, 2H), 3.07 (s,
3H), 3.29–3.34 (m 1H), 3.54–3.59 (m, 1H), 4.11 (dt, 1H,
J=6.0, 9.5 Hz), 4.33–4.37 (m, 1H), 4.82 (t, 1H, J=6.0
Hz), 6.91 (d, 2H, J=8.5 Hz), 6.92 (s, 1H), 7.01 (dd, 1H,
J=3.0, 8.5 Hz), 7.14 (d, 1H, J=8.5 Hz), 7.20 (d, 2H,
J=8.5 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 25.1,
33.6, 36.4, 36.7, 39.4, 52.3, 64.1, 116.2, 119.9, 121.8, 126.1,
128.5, 129.3, 130.2, 131.8, 150.4, 154.5, 156.7; IR (CHCl3)
cmꢁ1: 2968, 2768, 1720, 1586, 1492, 1391, 1247, 1171.
1
.
9b HCl. H NMR (400 MHz, CDCl3) d ppm: 2.11–
2.20 (m, 1H), 2.88 (s, 3H), 3.02 (s, 3H), 3.00–3.22 (m,
3H), 3.10 (s, 3H), 3.33–3.42 (m, 1H), 3.70–3.80 (m, 1H),
3.95–4.05 (m, 1H), 4.35–4.92 (m, 1H), 4.53 (br s, 1H),
6.88 (d, 2H, J=9.2 Hz), 7.02 (dd, 2H, J=2.8, 8.0 Hz),
7.04 (s, 1H), 7.10 (d, 2H, J=8.0 Hz), 7.25 (d, 2H, J=9.2
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 22.2, 34.9,
36.4, 36.7, 40.6, 45.0, 61.1, 63.8, 115.8, 121.4, 122.4,
126.3, 129.2, 129.5, 130.6, 151.6, 154.3, 156.6; IR (film)
cmꢁ1: 3423, 2936, 2622, 1720, 1493, 1390, 1240, 1171,
1044, 827, 754; HRMS calcd for C21H26N2O3Cl
(M+H)+ 389.1632, found 389.1629.
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydrochlo-
.
ride salt (9a HCl). Compound 6a (31 mg, 0.080 mmol)
was dissolved in a mixture of HCO2H (0.5 mL) and
37% aq HCHO (0.5 mL) and stirred for 3 h at 80 ꢀC.
After cooling to room temperature, saturated aq
NaHCO3 (10 mL) was added and extracted with AcOEt
(20 mLꢂ2). The extracts were washed with brine (20
mL), dried over Na2SO4, filtered and evaporated in
vacuo. Purification by silica gel column chromato-
graphy (AcOEt to AcOEt–MeOH 5:1) to give 9a (27
mg, 84%) as a colorless oil.
Dimethylcarbamic acid 2-methyl-1-[2-(3-methyl-4-nitro-
phenoxy)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl
ester
hydrochloride salt (9c HCl). 9c: 1H NMR (500 MHz,
CDCl3) d ppm: 2.25 (q, 2H, J=6.5 Hz), 2.46 (s, 3H),
2.61 (s, 3H), 2.69–2.76 (m, 2H), 2.81–2.88 (m, 1H), 3.01
(s, 3H), 3.09 (s, 3H), 3.09–3.14 (m, 1H), 3.70 (t, 1H,
J=6.0 Hz), 3.96 (dt, 1H, J=6.0, 9.5 Hz), 4.22 (dt, 1H,
.
9a. 1H NMR (500 MHz, CDCl3) d ppm: 2.22–2.33 (m,
2H), 2.46 (s, 3H), 2.67–2.75 (m, 2H), 2.81–2.87 (m, 1H),

4398
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
J=6.5, 10.0 Hz), 6.74 (t, 1H, J=3.0 Hz), 6.76 (dd, 1H,
J=3.0, 8.5 Hz), 6.87 (d, 1H, J=2.0 Hz), 6.92 (dd, 1H,
J=2.0, 8.0 Hz), 7.11 (d, 1H, J=8.0 Hz), 8.06 (d, 1H,
J=8.5 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 21.6,
34.1, 36.4, 36.7, 42.6, 47.5, 60.1, 65.4, 112.4, 117.8,
119.7, 121.7, 127.5, 128.0, 137.0, 142.0, 149.7, 154.9,
162.5; IR (CHCl3) cmꢁ1: 2940, 1713, 1580, 1511, 1391,
1340, 1254, 1173, 1080, 1035; HRMS calcd for
C22H28N3O5 (M+H)+ 414.2029, found 414.2011.
155.1, 156.1, 158.0; IR (CHCl3) cmꢁ1: 2940, 1712, 1505,
1391, 1249, 1173, 909, 829; HRMS calcd for
C21H26N2O3F (M+H)+ 373.1928, found 373.1922.
1
.
9e HCl. H NMR (500 MHz, CDCl3) d ppm: 2.10–
2.20 (m, 1H), 2.89 (d, 3H, J=4.0 Hz), 3.02 (s, 3H),
3.02–3.24 (m, 3H), 3.10 (s, 3H), 3.32–3.40 (m, 1H),
3.72–3.80 (m, 1H), 3.96–4.02 (m, 1H), 4.34–4.40 (m,
1H), 4.52–4.58 (m, 1H), 6.88–6.91 (m, 2H), 6.99 (d, 2H,
J=8.0 Hz), 7.03 (d, 1H, J=7.5 Hz), 7.04 (s, 1H), 7.12
(d, 1H, J=7.5 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 22.1, 35.0, 36.4, 36.7, 40.6, 45.0, 61.1, 64.0, 115.6,
115.9, 116.0, 121.4, 122.4, 126.5, 129.3, 130.5, 151.5,
154.2, 154.3, 156.6, 158.5; IR (CHCl3) cmꢁ1: 2967,
2347, 1721, 1506, 1392, 1248, 1171, 1047, 829.
1
.
9c HCl. H NMR (500 MHz, CDCl3) d ppm: 2.20 (br
s, 1H), 2.64 (s, 3H), 2.89 (s, 3H), 3.02 (s, 3H), 3.00–3.25
(m, 2H), 3.10 (s, 3H), 3.36 (br s, 1H), 3.75 (br s, 1H),
4.13 (br s, 1H), 4.23 (br, 1H), 4.50 (br s, 1H), 4.56 (br s,
1H), 6.86 (s, 2H), 7.04–7.10 (m, 3H), 8.09 (d, 1H, J=9.5
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 21.6, 22.0,
34.8, 36.5, 36.8, 40.7, 44.9, 50.7, 61.1, 64.3, 112.5, 118.0,
121.6, 122.6, 127.6, 129.1, 130.5, 137.2, 142.7, 151.7,
154.4, 161.4; IR (CHCl3) cmꢁ1: 3631, 2967, 2337, 1722,
1590, 1513, 1392, 1342, 1253, 1171, 1016.
Dimethylcarbamic acid 1-[2-(4-bromophenoxy)ethyl]-2-
methyl-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydro-
1
.
chloride salt (9f HCl). 9f: H NMR (500 MHz, CDCl3)
d ppm: 2.18–2.23 (m, 2H), 2.46 (s, 3H), 2.69–2.74 (m,
2H), 2.82–2.88 (m, 1H), 3.01 (s, 3H), 3.09 (s, 3H), 3.09–
3.14 (m, 1H), 3.70 (t, 1H, J=5.5 Hz), 3.88 (dt, 1H,
J=7.0, 8.5 Hz), 4.13 (dt, 1H, J=7.0, 9.5 Hz), 6.77 (d,
2H, J=9.0 Hz), 6.87 (d, 1H, J=3.0 Hz), 6.91 (dd, 1H,
J=3.0, 9.0 Hz), 7.11 (d, 1H, J=9.0 Hz), 7.35 (d, 2H,
J=9.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 25.6,
34.3, 36.4, 36.6, 42.6, 47.3, 60.0, 65.1, 112.5, 116.4,
119.5, 121.6, 128.1, 132.1, 134.1, 135.7, 149.5, 155.0,
158.1; IR (CHCl3) cmꢁ1: 2940, 1712, 1488, 1391, 1285,
1248, 1171, 1022; HRMS calcd for C21H26N2O3Br
(M+H)+ 433.1127, found 433.1111.
Dimethylcarbamic acid 2-methyl-1-[2-(3-nitrophenoxy)-
ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydrochlor-
1
.
ide salt (9d HCl). 9d. H NMR (400 MHz, CDCl3) d
ppm: 2.26 (q, 2H, J=6.8 Hz), 2.46 (s, 3H), 2.68–2.76
(m, 2H), 2.81–2.88 (m, 1H), 3.00 (s, 3H), 3.09 (s, 3H),
3.10–3.14 (m, 1H), 3.71 (t, 1H, J=6.0 Hz), 3.98 (dt, 1H,
J=6.8, 8.8 Hz), 4.25 (dt, 1H, J=7.2, 9.6 Hz), 6.87 (d,
1H, J=2.0 Hz), 6.92 (dd, 1H, J=2.0, 8.8 Hz), 7.12 (d,
2H, J=8.8 Hz), 7.19 (dd, 1H, J=2.0, 8.0 Hz), 7.39 (t,
1H, J=8.0 Hz), 7.72 (t, 1H, J=2.0 Hz), 7.79 (dd, 1H,
J=2.0, 8.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm:
25.6, 34.1, 36.4, 36.6, 42.6, 47.4, 60.0, 65.6, 108.9, 115.5,
119.6, 121.6, 121.7, 128.0, 129.8, 133.9, 135.8, 149.1,
155.0, 159.5; IR (CHCl3) cmꢁ1: 2941, 1713, 1531, 1391,
1351, 1251, 1172, 1022; HRMS calcd for C21H26N3O5
(M+H)+ 400.1873, found 400.1872.
1
.
9f HCl. H NMR (500 MHz, CDCl3) d ppm: 2.08–
2.20 (m, 2H), 2.89 (d, 3H, J=5.0 Hz), 3.02 (s, 3H),
3.02–3.21 (m, 2H), 3.10 (s, 3H), 3.31–3.39 (m, 1H),
3.60–3.70 (m, 1H), 3.98–4.02 (m, 1H), 4.37–4.41 (m,
1H), 4.50–4.55 (m, 1H), 6.83 (d, 2H, J=9.5 Hz), 7.03 (d,
1H, J=8.5 Hz), 7.04 (s, 1H), 7.09 (d, 1H, J=8.5 Hz),
7.40 (d, 1H, J=9.5 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 22.1, 34.9, 36.4, 36.7, 40.6, 44.9, 61.1, 63.7, 113.6,
116.3, 116.4, 121.4, 122.4, 126.4, 129.2, 130.5, 132.4,
151.6, 154.3, 157.2; IR (CHCl3) cmꢁ1: 2967, 2317, 1722,
1488, 1391, 1247, 1172, 1046, 908.
1
.
9d HCl. H NMR (500 MHz, CDCl3) d ppm: 2.19–
2.35 (m, 1H), 2.86–2.92 (m, 1H), 2.919 (d, 3H, J=5.0
Hz), 3.02 (s, 3H), 3.05–3.24 (m, 2H), 3.10 (s, 3H), 3.35–
3.41 (m, 1H), 3.73–3.81 (m, 1H), 4.12–4.18 (m, 1H),
4.51–4.60 (m, 2H), 7.05 (d, 1H, J=9.0 Hz), 7.07 (s, 1H),
7.11 (d, 1H, J=9.0 Hz), 7.34 (dd, 1H, J=2.0, 8.0 Hz),
7.48 (t, 1H, J=8.0 Hz), 7.75 (d, 1H, J=2.0 Hz), 7.86
(dd, 1H, J=2.0, 8.0 Hz); 13C NMR (100 MHz, CDCl3)
d ppm: 22.0, 34.8, 36.4, 36.7, 40.6, 44.8, 61.0, 64.3,
109.5, 116.3, 121.1, 121.6, 122.5, 126.3, 129.1, 130.3,
Dimethylcarbamic acid 1-[2-(4-methoxyphenoxy)ethyl]-
2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydro-
1
.
chloride salt (9g HCl). 9g. H NMR (500 MHz, CDCl3)
d ppm: 2.14–2.23 (m, 2H), 2.46 (s, 3H), 2.67–2.74 (m,
2H), 2.83–2.89 (m, 1H), 3.00 (s, 3H), 3.08 (s, 3H), 3.10–
3.14 (m, 1H), 3.72 (t, 1H, J=6.0 Hz), 3.76 (s, 3H), 3.84–
3.90 (m, 1H), 4.10 (dt, 1H, J=6.5, 9.0 Hz), 6.79–6.84
(m, 4H), 6.85 (d, 1H, J=2.0 Hz), 6.89 (dd, 1H, J=2.0,
8.5 Hz), 7.11 (d, 1H, J=8.5 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 25.5, 34.6, 36.4, 36.6, 42.5, 47.2, 55.7,
60.0, 65.4, 114.5, 115.5, 119.4, 121.6, 128.2, 134.4, 135.6,
149.5, 153.1, 153.6, 155.0; IR (CHCl3) cmꢁ1: 2939, 1712,
1509, 1391, 1249, 1174, 1039, 909; HRMS calcd for
C22H29N2O4 (M+H)+ 385.2128, found 385.2117.
130.5, 149.2, 151.7, 154.3, 158.5; IR (CHCl3) cmꢁ1
2969, 2337, 1723, 1532, 1392, 1353, 1248, 1171.
:
Dimethylcarbamic acid 1-[2-(4-fluorophenoxy)ethyl]-2-
methyl-1,2,3,4-tetrahydroisoquinolin-6-yl ester hydro-
1
.
chloride salt (9e HCl). 9e. H NMR (500 MHz, CDCl3)
d ppm: 2.18–2.22 (m, 2H), 2.46 (s, 3H), 2.68–2.73 (m,
2H), 2.85 (dt, 1H, J=7.0, 19.5 Hz), 3.00 (s, 3H), 3.09 (s,
3H), 3.09–3.13 (m, 1H), 3.70 (t, 1H, J=5.5 Hz), 3.87
(dt, 1H, J=7.0, 8.5 Hz), 4.11 (dt, 1H, J=6.5, 9.0 Hz),
6.80–6.82 (m, 2H), 6.85 (d, 1H, J=3.0 Hz), 6.90 (dd,
1H, J=3.0, 8.0 Hz), 6.91–6.96 (m, 2H), 7.11 (d, 1H,
J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 25.6,
34.4, 36.4, 36.6, 42.6, 47.3, 60.0, 65.4, 115.4, 115.5,
115.6, 115.7, 119.5, 121.6, 128.1, 135.7, 149.5, 155.0,
1
.
9g HCl. H NMR (500 MHz, CDCl3) d ppm: 2.08–
2.16 (m, 2H), 2.89 (d, 3H, J=4.5 Hz), 3.01 (s, 3H),
3.02–3.24 (m, 1H), 3.10 (s, 3H), 3.32–3.38 (m, 1H), 3.78
(s, 3H), 3.94–4.00 (m, 1H), 4.28–4.36 (m, 1H), 4.54–4.60

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4399
(m, 1H), 6.85 (d, 2H, J=9.0 Hz), 6.89 (d, 2H, J=9.0
Hz), 7.02 (d, 1H, J=8.0 Hz), 7.04 (s, 1H), 7.14 (d, 1H,
J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 22.2,
35.1, 36.4, 36.7, 40.6, 45.1, 55.7, 61.1, 63.9, 114.7, 115.5,
121.3, 122.3, 126.6, 129.4, 130.6, 151.5, 152.2, 154.2,
154.4; IR (CHCl3) cmꢁ1: 2965, 2347, 1721, 1509, 1391,
1248, 1171, 1048.
(5-Dimethylcarbamoyloxy-2-methyl-1,2,3,4-tetrahydro-
isoquinolin-1-yl)acetic acid ethyl ester (5). To a solution
of 3a (320 mg, 1.28 mmol) in CH2Cl2 (10 mL) was
added BBr3 in CH2Cl2 (3.0 mL, 1.0 M) dropwise at
ꢁ30 ꢀC. The mixture was stirred for 3 h at room tem-
perature. The reaction was quenched with 1 N NaOH
(10 mL). The product was extracted with CH2Cl2 (10
mLꢂ2). The combined organic solution was dried over
Na2SO4, filtered and evaporated to give a phenol (111
mg). This phenol (110 mg) was dissolved in a mixture of
HCO2H (1.0 mL) and 37% aq HCHO (1.0 mL) and
stirred for 3 h at 80 ꢀC. After cooling to room tempera-
ture, saturated aq NaHCO3 (10 mL) was added and
extracted with AcOEt (10 mLꢂ3). The extracts were
washed with brine (20 mL), dried over Na2SO4, filtered
and evaporated. Purification by silica gel column
chromatography (AcOEt to AcOEt–MeOH 10:1) gave a
N-methyl product (85 mg, 27% for two steps) as a col-
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-1,2,3,4-tetrahydroisoquinolin-7-yl ester hydrochlor-
1
.
ide salt (10a HCl). 10a. H NMR (500 MHz, CDCl3) d
ppm: 2.22–2.32 (m, 2H), 2.46 (s, 3H), 2.67–2.73 (m, 2H),
2.81–2.86 (m, 1H), 3.00 (s, 3H), 3.08 (s, 3H), 3.08–3.13
(m, 1H), 3.70 (t, 1H, J=5.5 Hz), 3.99–4.04 (m, 1H), 4.26
(q, 1H, J=8.5 Hz), 6.89–6.93 (m, 4H), 7.08 (d, 1H,
J=7.5 Hz), 8.17 (d, 2H, J=9.5 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 25.2, 33.9, 36.4, 36.7, 42.7,
47.9, 60.3, 65.7, 114.5, 119.7, 120.2, 125.8, 129.6, 131.5,
138.1, 141.2, 149.6, 155.0, 164.1; IR (CHCl3) cmꢁ1
:
orless oil. H NMR (400 MHz, CDCl3) d ppm: 1.26 (t,
1
2941, 1713, 1593, 1512, 1498, 1391, 1342, 1264, 1172,
1111, 1018; HRMS calcd for C21H26N3O5 (M+H)+
400.1873, found 400.1852.
3H, J=6.4 Hz), 2.46 (s, 3H), 2.54 (ddd, 1H, J=2.8, 5.2,
16.8 Hz), 2.59 (dd, 1H, J=6.0, 11.6 Hz), 2.71–2.80 (m,
1H), 2.81 (dd, 1H, J=8.0, 15.2 Hz), 2.88 (ddd, 1H,
J=2.8, 6.0, 13.2 Hz), 3.08–3.15 (m, 1H), 4.09–4.21 (m,
3H), 6.62 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0 Hz),
7.01 (t, 1H, J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 14.1, 18.6, 40.5, 41.8, 45.2, 59.5, 60.5, 112.5, 119.4,
1
.
10a HCl. H NMR (500 MHz, CDCl3) d ppm: 2.22–
2.29 (m, 1H), 2.90 (d, 3H, J=5.0 Hz), 2.96 (s, 3H), 3.05
(s, 3H), 3.07–3.23 (m, 3H), 3.36–3.38 (m, 1H), 3.73–3.78
(m, 1H), 4.22–4.26 (m, 1H), 4.44–4.48 (m, 1H), 4.58–
4.62 (m, 1H), 6.87 (d, 1H, J=2.0 Hz), 7.05–7.10 (m,
3H), 7.25 (d, 1H, J=7.5 Hz), 8.23 (d, 2H, J=8.5 Hz);
13C NMR (100 MHz, CDCl3) d ppm: 21.5, 34.7, 36.4,
36.7, 40.6, 45.2, 61.1, 64.5, 114.9, 121.5, 122.6, 125.9,
130.4, 141.9, 150.6, 154.3, 163.0; IR (KBr) cmꢁ1: 2928,
2561, 1726, 1593, 1389, 1343, 1264, 1173, 845. Anal.
120.7, 126.4, 138.4, 153.3, 172.2; IR (CHCl3) cmꢁ1
:
3600, 2941, 1726, 1589, 1465, 1271, 1154, 1036; HRMS
calcd for C14H20NO3 (M+H)+ 250.1443, found
250.1440.
To a solution of the above compound (85 mg, 0.34
mmol) and K2CO3 (276 mg, 2.0 mmol) in DMF (5 mL)
was added Me2NCOCl (92 mL, 1.0 mmol) at room
temperature. The reaction mixture was stirred for 12 h
at room temperature. After dilution with water (10 mL),
the mixture was extracted with AcOEt (10 mLꢂ2). The
combined organic layers were washed with brine (20
mL), dried over Na2SO4, filtered and evaporated. The
residue was purified by silica gel column chromato-
graphy (AcOEt to AcOEt–MeOH 5:1) to give 5 (65 mg,
.
.
calcd for C21H25N3O5 HCl H2O: C, 56.69; H, 6.12; N,
9.44. Found: C, 56.99; H, 5.91; N, 9.78.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-2-
methyl-1,2,3,4-tetrahydroisoquinolin-7-yl ester hydro-
chloride salt (10b HCl). 10b. 1H NMR (400 MHz,
.
CDCl3) d ppm: 2.20 (q, 2H, J=6.2 Hz), 2.45 (s, 3H),
2.64–2.74 (m, 2H), 2.80–2.88 (m, 1H), 3.00 (s, 3H), 3.07
(s, 3H), 3.09–3.14 (m, 1H), 3.70 (t, 1H, J=5.6 Hz), 3.88
(dt, 1H, J=6.4, 9.6 Hz), 4.13 (dt, 1H, J=7.2, 9.6 Hz),
6.81 (d, 2H, J=8.8 Hz), 6.87 (s, 1H), 6.89 (d, 1H, J=8.8
Hz), 7.06 (d, 1H, J=8.8 Hz), 7.20 (d, 2H, J=8.8 Hz);
13C NMR (100 MHz, CDCl3) d ppm: 25.0, 34.3, 36.4,
36.6, 42.6, 47.6, 60.3, 65.1, 115.9, 119.6, 120.2, 125.2,
129.1, 129.5, 131.4, 138.4, 149.5, 155.0, 157.6; IR
(CHCl3) cmꢁ1: 2940, 1713, 1492, 1391, 1247, 1171;
HRMS calcd for C21H26N2O3Cl (M+H)+ 389.1632,
found 389.1621.
1
59%) as a colorless oil. H NMR (400 MHz, CDCl3) d
ppm: 1.25 (t, 3H, J=6.8 Hz), 2.45 (s, 3H), 2.45–2.51 (m,
1H), 2.61 (dd, 1H, J=4.8, 15.2 Hz), 2.73–2.84 (m, 3H),
3.01 (s, 3H), 3.06–3.10 (m, 1H), 3.12 (s, 3H), 4.13–4.21
(m, 3H), 6.96 (dd, 2H, J=2.4, 7.6 Hz), 7.15 (d, 1H,
J=7.6 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 14.1,
18.7, 36.4, 36.7, 38.6, 41.9, 44.9, 59.4, 60.4, 120.0, 124.4,
126.3, 126.9, 138.5, 149.3, 154.4, 172.0; IR (CHCl3)
cmꢁ1: 2940, 1721, 1391, 1171, 909; HRMS calcd for
C17H25N2O4 (M+H)+ 321.1814, found 321.1822.
1
.
10b HCl. H NMR (500 MHz, CDCl3) d ppm: 2.14–
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-1,2,3,4-tetrahydroisoquinolin-5-yl ester hydrochlor-
2.22 (m, 1H), 2.89 (d, 3H, J=4.5 Hz), 2.97 (s, 3H), 3.02
(s, 3H), 3.02–3.13 (m, 2H), 3.21 (br d, 1H, J=15.5 Hz),
3.31–3.38 (m, 1H), 3.71–3.78 (m, 1H), 4.03–4.09 (m,
1H), 4.37–4.42 (m, 1H), 4.50 (t, 1H, J=6.5 Hz), 6.86 (d,
1H, J=2.0 Hz), 6.91 (d, 2H, J=8.5 Hz), 7.09 (dd, 1H,
J=2.0, 8.5 Hz), 7.24 (d, 1H, J=8.5 Hz), 7.25 (d, 2H,
J=8.5 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 21.7,
34.8, 36.3, 36.7, 40.7, 45.5, 61.2, 63.8, 116.1, 121.6, 122.5,
.
ide salt (8 HCl). To a solution of 5 (65 mg, 0.20 mmol)
in THF (10 mL) was added LiAlH4 (7.6 mg, 0.20 mmol)
at ꢁ20 ꢀC. The reaction mixture was stirred for 20 min
at ꢁ20 ꢀC. To the reaction mixture was successively
added 1 N NaOH (0.3 mL) and MgSO4. After filtration,
the organic layer was concentrated in vacuo to give an
alcohol (48 mg, 86%) as a colorless oil. 1H NMR
(500 MHz, CDCl3) d ppm: 1.95–2.10 (m, 2H), 2.50 (s,
3H), 2.55–2.60 (m, 1H), 2.71–2.77 (m, 2H), 3.02 (s, 3H),
126.2, 129.4, 130.2, 150.6, 154.3, 156.6; IR (KBr) cmꢁ1
2929, 2560, 1730, 1492, 1388, 1243, 1171, 823.
:

4400
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
3.12 (s, 3H), 3.23–3.28 (m, 1H), 3.68–3.72 (m, 1H),
3.78–3.86 (m, 2H), 6.91 (d, 1H, J=8.0 Hz), 6.97 (d, 1H,
J=8.0 Hz), 7.17 (t, 1H, J=8.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 18.5, 35.5, 36.4, 36.7, 42.1,
45.8, 62.7, 64.8, 119.9, 124.5, 126.5, 127.1, 137.7, 149.1,
154.4; IR (CHCl3) cmꢁ1: 2947, 1718, 1462, 1391, 1172,
909; HRMS calcd for C15H23N2O3 (M+H)+ 279.1708,
found 279.1693.
J=2.0, 8.0 Hz), 7.53 (d, 1H, J=8.0 Hz), 9.84 (s, 1H),
11.21 (s, 1H); 13C NMR (100 MHz, CDCl3) d ppm:
36.5, 36.7, 110.3, 113.8, 118.15, 134.7, 153.4, 158.3,
163.1, 195.3; IR (KBr) cmꢁ1: 1730, 1645, 1389, 1214,
1185, 810; HRMS calcd for C10H11NO4 (M)+ 209.0688,
found 209.0671. Anal. calcd for C10H11NO4: C, 57.41;
H, 5.30; N, 6.70. Found: C, 57.15; H, 5.29; N, 6.51.
To a solution of the above compound (2.60 g, 12.4
mmol) and pyridine (1.61 mL, 20.0 mmol) in CH2Cl2
(30 mL) was added trifluoromethanesulfonic anhydride
(2.35 mL, 14.0 mmol) at 0 ꢀC. The reaction mixture was
stirred for 1 h at 0 ꢀC, quenched with water (20 mL),
and extracted with CH2Cl2 (20 mLꢂ2). The extracts
were washed with 1 N HCl (20 mL) and brine (20 mL)
and dried over Na2SO4. After filtration, the solvent was
removed under reduced pressure to give the triflate (4.14
g). To a solution of the triflate (4.13 g) in 1,4-dioxane
(15 mL) were added Pd(PPh3)4 (693 mg, 0.600 mmol),
LiCl (1.54 g, 36.4 mmol), 2,6-di-t-butylphenol (5 mg)
and (CH2¼CH)(n-Bu)3Sn (4.23 mL, 14.5 mmol). The
reaction mixture was stirred for 3 h at 100 ꢀC. After
adding saturated aq KF (10 mL), the mixture was fil-
tered and evaporated in vacuo. The residue was diluted
with water (40 mL) and extracted with AcOEt (50
mLꢂ2). The combined organic layers were washed with
1 N HCl (40 mL) and brine (40 mL), dried over Na2SO4,
filtered and evaporated in vacuo. Purification by silica
gel column chromatography (hexane–AcOEt 10:1 to
1:1) gave styrene 12b (2.11 g, 79% for two steps) as a
To a solution of the above alcohol (48 mg, 0.17 mmol)
and 1-fluoro-4-nitrobenzene (26 mg, 0.19 mmol) in
DMF (5 mL) was added 55% NaH (13 mg, 0.30 mmol)
at room temperature. The reaction mixture was stirred
for 30 min at room temperature. The reaction was
quenched with water (10 mL). The product was extrac-
ted with AcOEt (10 mL), and the combined organic
layers were washed with brine (10 mL), dried over
Na2SO4, filtered and evaporated. Purification by pre-
parative TLC (AcOEt–MeOH 10:1) gave 8 (27 mg,
1
39%) as a colorless oil. H NMR (400 MHz, CDCl3) d
ppm: 2.26 (q, 2H, J=6.4 Hz), 2.45 (s, 3H), 2.46–2.56
(m, 1H), 2.71–2.80 (m, 2H), 3.02 (s, 3H), 3.09–3.16 (m,
1H), 3.13 (s, 3H), 3.73 (t, 1H, J=6.0 Hz), 4.10 (dt, 1H,
J=6.4, 9.6 Hz), 4.27 (dt, 1H, J=6.4, 9.6 Hz), 6.93 (d,
2H, J=8.4 Hz), 6.97 (d, 1H, J=7.6 Hz), 7.00 (d, 1H,
J=7.6 Hz), 7.18 (t, 1H, J=7.6 Hz), 8.18 (d, 2H, J=8.4
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 19.3, 34.2,
36.4, 36.7, 42.4, 46.5, 59.9, 65.8, 114.5, 120.0, 124.3,
125.8, 126.4, 141.3, 149.2, 154.4, 164.1; IR (film) cmꢁ1
:
2938, 1723, 1591, 1511, 1387, 1338, 1263, 1170, 1028,
848, 753; HRMS calcd for C21H26N3O5 (M+H)+
400.1872, found 400.1867.
1
colorless oil. H NMR (400 MHz, CDCl3) d ppm: 3.04
(s, 3H), 3.12 (s, 3H), 5.53 (dd, 1H, J=1.6, 11.2 Hz), 5.72
(d, 1H, J=18.0 Hz), 7.21 (dd, 1H, J=2.4, 8.0 Hz), 7.33
(d, 1H, J=2.4 Hz), 7.53 (dd, 1H, J=11.2, 18.0 Hz), 7.84
(d, 1H, J=8.0 Hz), 10.24 (s, 1H); 13C NMR (100 MHz,
CDCl3) d ppm: 36.5, 36.7, 119.9, 120.2, 121.2, 129.9,
1
.
8 HCl. H NMR (400 MHz, CDCl3) d ppm: 2.23–2.27
(m, 1H), 2.87 (dd, 1H, J=5.2, 14.0 Hz), 2.89 (d, 3H,
J=5.2 Hz), 2.97–3.11 (m, 2H), 3.04 (s, 3H), 3.15 (s, 3H),
3.41–3.49 (mt, 1H), 3.68–3.72 (m, 1H), 4.16–4.21 (m,
1H), 4.54 (t, 1H, J=6.4 Hz), 4.61–4.65 (m, 1H), 6.99 (d,
1H, J=7.2 Hz), 7.05 (d, 2H, J=8.8 Hz), 7.16 (d, 1H,
J=7.2 Hz), 7.33 (t, 1H, J=7.2 Hz), 8.23 (d, 2H, J=8.8
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 16.8, 34.8,
36.5, 36.9, 40.3, 44.0, 60.7, 64.5, 114.7, 122.7, 122.8,
125.1, 126.0, 128.5, 130.8, 142.0, 149.8, 153.7, 163.0; IR
(CHCl3) cmꢁ1: 2970, 2322, 1722, 1594, 1516, 1392,
1344, 1258, 1169, 909; HRMS calcd for C21H26N3O5
(M+H)+ 400.1872, found 400.1870.
132.7, 132.9, 142.2, 153.8, 155.7, 191.1; IR (film) cmꢁ1
:
2935, 1728, 1692, 1601, 1387, 1226, 1169, 807; HRMS
calcd for C12H13NO3 (M)+ 219.0896, found 219.0896.
Dimethylcarbamic acid 3-formyl-2-vinylphenyl ester
(12a). Mono-carbamate. Mp 122–124 ꢀC; 1H NMR
(400 MHz, CDCl3) d ppm: 3.03 (s, 3H), 3.15 (s, 3H),
7.01 (t, 1H, J=8.0 Hz), 7.37 (dd, 1H, J=1.6, 8.0 Hz),
7.45 (dd, 1H, J=1.6, 8.0 Hz), 9.91 (s, 1H), 11.13 (s, 1H);
13C NMR (100MHz, CDCl3) d ppm: 36.5, 36.8, 119.4,
121.8, 130.4, 130.4, 139.7, 153.8, 154.0, 196.3; IR (KBr)
cmꢁ1: 1725, 1654, 1458, 1388, 1234, 1158, 852, 741. Anal.
Dimethylcarbamic acid 4-formyl-3-vinylphenyl ester
(12b). To a suspension of 55% NaH (5.74 g, 239
mmol) in DMF (100 mL) was added compound 11b
(15.0 g, 109 mmol) at 0 ꢀC. After the reaction mixture
was stirred for 30 min at 0 ꢀC, Me2NCOCl (10.1 mL,
110 mmol) was added at 0 ꢀC and stirred for 2 h at room
temperature. After dilution with water (300 mL), the
mixture was neutralized with concentrated HCl and
extracted with AcOEt (200 mLꢂ2). The combined
organic layers were washed with water (300 mLꢂ2) and
brine (200 mLꢂ2), dried over Na2SO4, filtered and eva-
porated. The residue was purified by silica gel column
chromatography (hexane–AcOEt 5:1 to 1:2) to give a
mono-carbamate (6.78 g, 30%) as a colorless solid. Mp
.
calcd for C10H11NO4 0.1H2O: C, 56.92; H, 5.35; N, 6.64;
O, 31.09. Found: C, 56.82; H, 5.16; N, 6.66; O, 30.95.
12a. 1H NMR (400 MHz, CDCl3) d ppm: 3.02 (s, 3H),
3.13 (s, 3H), 5.42 (dd, 1H, J=1.6, 18.4 Hz), 5.76 (dd,
1H, J=1.6, 11.6 Hz), 6.92 (dd, 1H, J=11.6, 18.4 Hz),
7.36 (dd, 1H, J=1.6, 8.0 Hz), 7.42 (t, 1H, J=8.0 Hz),
7.79 (dd, 1H, J=1.6, 8.0 Hz), 10.22 (s, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 36.4, 36.8, 124.4, 126.0,
128.1, 135.2, 135.3, 149.4, 154.1, 191.6; IR (film) cmꢁ1
:
2934, 1726, 1458, 1387, 1235, 1162, 754; HRMS calcd
for C12H13NO3 (M)+ 219.0896, found 219.0898.
ꢀ
1
58–60 C; H NMR (400 MHz, CDCl3) d ppm: 3.02 (s,
3H), 3.10 (s, 3H), 6.77 (d, 1H, J=2.0 Hz), 6.82 (dd, 1H,
Dimethylcarbamic acid 3-formyl-4-vinylphenyl ester
1
(12c). Mono-carbamate: H NMR (400 MHz, CDCl3) d

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4401
ppm: 2.96 (s, 3H), 3.05 (s, 3H), 6.91 (d, 1H, J=8.8 Hz),
7.22 (dd, 1H, J=2.9, 8.8 Hz), 7.29 (dd, 1H, J=2.9 Hz),
9.78 (s, 1H), 10.81 (s, 1H).
To a solution of the diol (4.44 g, 16.7 mmol), Et3N (4.18
mL, 30.0 mmol) and 4-dimethylaminopyridine (10 mg)
in CH2Cl2 (40 mL) was added t-butyldiphenylsilyl
chloride (4.67 g, 17.0 mmol) at 0 ꢀC. The mixture was
stirred for 5 h at room temperature. After the addition
of water (30 mL), the aqueous solution was extracted
with CH2Cl2 (40 mLꢂ2). The combined organic extracts
were washed with 1 N HCl (40 mL) and brine (40 mL),
dried over Na2SO4, filtered and evaporated. Purification
by silica gel column chromatography (hexane–AcOEt
2:1–1:1) provided 13b (5.87 g, 70%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d ppm: 1.09 (s, 9H), 1.85–
1.90 (m, 2H), 3.01 (s, 3H), 3.10 (s, 3H), 3.32 (s, 1H),
3.84–3.93 (m, 2H), 5.27 (d, 1H, J=10.5 Hz), 5.28–5.33
(br m, 1H), 5.60 (d, 1H, J=17.0 Hz), 6.97 (dd, 1H,
J=10.5, 17.0 Hz), 7.05 (dd, 1H, J=2.5, 9.0 Hz), 7.19 (d,
1H, J=2.5 Hz), 7.38–7.45 (m, 6H), 7.51 (d, 1H, J=9.0
Hz), 7.69 (d, 4H, J=7.0 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 19.1, 26.8, 36.4, 36.7, 40.0, 62.8, 69.5,
116.8, 118.9, 121.1, 126.5, 127.8, 129.8, 133.0, 133.4,
135.5, 136.2, 138.5, 150.6, 154.9; IR (film) cmꢁ1: 3457,
2931, 1725, 1389, 1227, 1176, 1111, 704; HRMS calcd
for C30H37NO4SiNa (M+Na)+ 526.2390, found
526.2393.
12c. 1H NMR (400 MHz, CDCl3) d ppm: 2.98 (s, 3H),
3.08 (s, 3H), 5.46 (d, 1H, J=11.0 Hz), 5.63 (dd, 1H,
J=1.5, 17.6 Hz), 7.30 (dd, 1H, J=2.9, 8.8 Hz), 7.43 (dd,
1H, J=11.0, 17.6 Hz), 7.52 (d, 1H, J=8.8 Hz), 7.54
(d, 1H, J=2.9 Hz), 10.22 (s, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 36.4, 36.7, 119.4, 123.3,
127.4, 128.6, 132.5, 133.6, 137.5, 151.2, 191.2; IR
(CHCl3) cmꢁ1: 2937, 1724, 1485, 1389, 1170; HRMS
calcd for C12H13NO3Na (M+Na)+ 242.0794, found
242.0795.
Dimethylcarbamic acid 4-[3-(tert-butyldiphenylsilanyl-
oxy)-1-hydroxypropyl]-3-vinylphenyl ester (13b). To a
solution of i-Pr2NH (1.26 g, 12.5 mmol) in THF (30
mL) was added n-BuLi in hexane (7.20 mL, 1.6 M)
dropwise at ꢁ20 ꢀC. After stirring for 20 min at ꢁ20 ꢀC,
AcOEt (1.07 mL, 11.0 mmol) was added to the reaction
mixture at ꢁ78 ꢀC. After stirring for 20 min at ꢁ78 ꢀC, a
solution of 12b (2.11 g, 9.62 mmol) in THF was added
to the reaction mixture at ꢁ78 ꢀC. The mixture was
stirred for 30 min at ꢁ78 ꢀC and quenched with satu-
rated aq NH4Cl (40 mL). The product was extrcted with
AcOEt (40 mLꢂ2) and the organic solution was washed
with water (40 mL) and brine (40 mL), dried over
Na2SO4, filtered and evaporated. Purification by silica
gel column chromatography (hexane–AcOEt 1:1 to 1:2)
afforded a benzyl alcohol (2.95 g, 99%) as a colorless
Dimethylcarbamic acid 3-[3-(tert-butyldiphenylsilanyl-
oxy)-1-hydroxypropyl]-2-vinylphenyl ester (13a). Benzyl
1
alcohol: H NMR (400 MHz, CDCl3) d ppm: 1.28 (t,
3H, J=7.2 Hz), 2.61–2.70 (m, 2H), 2.99 (s, 3H), 3.07 (s,
3H), 3.21 (d, 1H, J=2.8 Hz), 4.19 (q, 2H, J=7.2 Hz),
5.35–5.39 (m, 1H), 5.43 (dd, 1H, J=2.0, 17.6 Hz), 5.55
(dd, 1H, J=2.0, 11.6 Hz), 6.64 (dd, 1H, J=11.6, 17.6
Hz), 7.05 (dd, 1H, J=1.2, 8.0 Hz), 7.30 (t, 1H, J=8.0
Hz), 7.45 (d, 1H, J=8.0 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 14.1, 36.3, 36.7, 42.2, 60.3, 66.9, 121.3,
122.2, 122.6, 128.2, 129.6, 129.8, 141.7, 148.6, 154.6,
172.5; IR (CHCl3) cmꢁ1: 2985, 1720, 1390, 1171, 1021;
HRMS calcd for C16H21NO5Na (M+Na)+ 330.1317,
found 330.1320.
1
oil. H NMR (500 MHz, CDCl3) d ppm: 1.28 (t, 3H,
J=7.5 Hz), 2.65 (d, 2H, J=6.0 Hz), 3.01 (s, 3H), 3.10
(s, 3H), 3.23–3.25 (m, 1H), 4.19 (q, 2H, J=7.5 Hz), 5.35
(d, 1H, J=11.0 Hz), 5.38–5.43 (m, 1H), 5.63 (d, 1H,
J=17.0 Hz), 6.99 (dd, 1H, J=11.0, 17.0 Hz), 7.05 (d,
1H, J=8.5 Hz), 7.20 (s, 1H), 7.52 (d, 1H, J=8.5 Hz);
13C NMR (125 MHz, CDCl3) d ppm: 36.1, 36.3, 42.4,
60.5, 66.4, 117.0, 118.8, 121.0, 126.4, 132.9, 136.2, 136.5,
150.6, 154.5, 171.9; IR (film) cmꢁ1: 3452, 2982, 1727,
1389, 1223, 1173; HRMS calcd for C16H21NO5Na
(M+Na)+ 330.1317, found 330.1304.
1
Diol. H NMR (400 MHz, CDCl3) d ppm: 1.88–2.00
(m, 2H), 2.38 (br s, 1H), 2.74 (br s, 1H), 2.99 (s, 3H),
3.08 (s, 3H), 3.86 (br s, 2H), 5.22 (d, 1H, J=8.0 Hz),
5.42 (dd, 1H, J=2.4, 18.4 Hz), 5.54 (dd, 1H, J=2.4,
11.6 Hz), 6.65 (dd, 1H, J=11.6, 18.4 Hz), 7.04 (dd, 1H,
J=1.6, 8.0 Hz), 7.32 (t, 1H, J=8.0 Hz), 7.48 (d, 1H,
J=8.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 36.3,
36.7, 39.2, 61.6, 70.7, 121.0, 121.8, 122.8, 128.1, 129.4,
129.9, 143.7, 148.5, 154.7; IR (CHCl3) cmꢁ1: 2943, 1719,
1391, 1249, 1172, 1046; HRMS calcd for C14H19NO4Na
(M+Na)+ 288.1212, found 288.1212.
To a solution of the alcohol (5.28 g, 17.2 mmol) in THF
(50 mL) was added LiBH4 (544 mg, 25.0 mmol) at
ꢁ20 ꢀC. The reaction mixture was stirred for 1 h at
room temperature. The reaction mixture was quenched
with water (20 mL) and 1 N HCl (20 mL). The product
was extracted with AcOEt (40 mLꢂ2) and the organic
solution was dried over Na2SO4, filtered and evapo-
rated. Purification by silica gel column chromatography
(AcOEt to AcOEt–MeOH 5:1) provided a diol (4.44 g,
1
97%) as a colorless oil. H NMR (500 MHz, CDCl3) d
13a. 1H NMR (400 MHz, CDCl3) d ppm: 1.09 (s, 9H),
1.83–1.95 (m, 2H), 2.99 (s, 3H), 3.07 (s, 3H), 3.32 (d,
1H, J=3.2 Hz), 3.82–3.92 (m, 2H), 5.26 (dt, 1H, J=2.0,
8.0 Hz), 5.39 (dd, 1H, J=2.0, 18.4 Hz), 5.47 (dd, 1H,
J=2.0, 11.6 Hz), 6.62 (dd, 1H, J=11.6, 18.4 Hz), 7.02
(dd, 1H, J=1.6, 8.0 Hz), 7.29 (t, 1H, J=8.0 Hz), 7.37–
7.46 (m, 6H), 7.49 (dd, 1H, J=1.6, 8.0 Hz), 7.67–7.70
(m, 4H); 13C NMR (100 MHz, CDCl3) d ppm: 19.1,
26.8, 36.3, 36.7, 39.7, 62.6, 69.6, 120.7, 121.6, 122.7,
127.7, 127.9, 129.2, 129.8, 130.0, 133.0, 133.1, 135.5,
135.6, 143.9, 148.5, 154.7; IR (CHCl3) cmꢁ1: 3485, 2932,
ppm: 1.78–1.90 (m, 2H), 2.88 (s, 1H), 3.00 (s, 3H), 3.10
(s, 3H), 3.44 (s, 1H), 3.77 (br s, 2H), 5.14–5.19 (m, 1H),
5.32 (d, 1H, J=11.0 Hz), 5.60 (d, 1H, J=17.5 Hz), 6.96
(dd, 1H, J=11.0, 17.5 Hz), 7.03 (dd, 1H, J=2.5, 8.5
Hz), 7.17 (d, 1H, J=2.5 Hz), 7.51 (d, 1H, J=8.5 Hz);
13C NMR (125 MHz, CDCl3) d ppm: 36.4, 36.6, 39.3,
61.3, 70.3, 117.0, 119.0, 121.2, 126.6, 133.2, 136.3, 138.5,
150.5, 155.0; IR (CHCl3) cmꢁ1: 2943, 1714, 1391, 1250,
1175, 1049; HRMS calcd for C14H19NO4 (M)+
265.1314, found 265.1322.

4402
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
1
1719, 1390, 1250, 1172, 1111, 935; HRMS calcd for
C30H37NO4SiNa (M+Na)+ 526.2390, found 526.2379.
colorless oil. H NMR (500 MHz, CDCl3) d ppm: 1.06
(s, 9H), 1.79–1.84 (m, 2H), 3.00 (dd, 1H, J=7.0, 16.0
Hz), 3.02 (s, 3H), 3.07–3.12 (m, 1H), 3.10 (s, 3H), 3.65
(dt, 1H, J=5.0, 11.0 Hz), 3.76 (dt, 1H, J=5.0, 11.0 Hz),
4.32 (t, 1H, J=6.0 Hz), 5.04 (d, 1H, J=11.0 Hz), 5.11
(d, 1H, J=17.5 Hz), 5.24 (d, 1H, J=11.0 Hz), 5.56 (d,
1H, J=17.5 Hz), 5.81–5.89 (m, 1H), 7.02 (dd, 1H,
J=3.0, 9.0 Hz), 7.15 (dd, 1H, J=11.0, 17.5 Hz), 7.19 (d,
1H, J=3.0 Hz), 7.26–7.44 (m, 6H), 7.63–7.68 (m, 4H);
13C NMR (100 MHz, CDCl3) d ppm: 19.1, 26.8, 36.4,
36.7, 40.3, 50.0, 54.8, 61.6, 77.4, 115.7, 116.5, 119.0,
121.2, 127.2, 127.6, 127.7, 129.6, 133.6, 133.7, 134.0,
135.5, 135.6, 137.0, 138.0, 138.2, 150.1, 154.9; IR (film)
cmꢁ1: 2932, 1726, 1472, 1386, 1171, 1111, 917, 704;
HRMS calcd for C33H43N2O3Si (M+H)+ 543.3043,
found 543.3027.
Dimethylcarbamic acid 3-[3-(tert-butyldiphenylsilany-
loxy)-1-hydroxypropyl]-4-vinylphenyl ester (13c). Benzyl
alcohol: H NMR (400 MHz, CDCl3) d ppm: 1.24 (t,
1
3H, J=7.2 Hz), 2.57 (d, 1H, J=16.8 Hz), 2.63 (dd, 1H,
J=3.7, 16.8 Hz), 2.97 (s, 3H), 3.05 (s, 3H), 4.16 (q, 2H,
J=7.2 Hz), 5.29 (d, 1H, J=11.0 Hz), 5.37 (dd, 1H,
J=3.7, 8.8 Hz), 5.55 (d, 1H, J=16.8 Hz), 6.90 (dd, 1H,
J=11.0, 16.8 Hz), 7.00 (dd, 1H, J=2.9, 8.0 Hz), 7.26 (d,
1H, J=2.9 Hz), 7.40 (d, 1H, J=8.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 14.1, 36.4, 36.6, 42.3, 60.9,
66.7, 116.8, 118.6, 121.1, 127.2, 132.2, 133.0, 140.7,
151.4, 154.7, 172.4; IR (CHCl3) cmꢁ1: 2985, 1719, 1484,
1390, 1173, 1020; HRMS calcd for C16H21NO5Na
(M+Na)+ 330.1317, found 330.1315.
To a solution of the allylbenzylamine (1.80 g, 3.31
mmol) and Et3N (1.12 mL, 8.00 mmol) in THF (20 mL),
Boc2O (870 mg, 4.00 mmol) was added at room tem-
perature. The mixture was stirred for 3 h at 50 ꢀC. The
solvent was concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane–
AcOEt 5:1–1:1) to give 14b (1.90 g, 89%) as a colorless
13c. 1H NMR (400 MHz, CDCl3) d ppm: 1.05 (s, 9H),
1.79–1.95 (m, 2H), 2.97 (s, 3H), 3.05 (s, 3H), 3.80–3.89
(m, 2H), 5.20 (dd, 1H, J=1.5, 11.0 Hz), 5.27 (dd, 1H,
J=3.7, 8.8 Hz), 5.52 (dd, 1H, J=1.5, 17.6 Hz), 6.89 (dd,
1H, J=11.0, 17.6 Hz), 6.99 (dd, 1H, J=2.2, 8.8 Hz),
7.35 (d, 1H, J=2.2 Hz), 7.33–7.43 (m, 7H), 7.64–7.67
(m, 4H); 13C NMR (100 MHz, CDCl3) d ppm: 19.1,
26.8, 36.4, 36.6, 39.9, 62.8, 69.5, 116.0, 118.5, 120.6,
127.0, 127.8, 129.8, 132.0, 132.9, 133.0, 133.4, 135.5,
143.0, 151.4, 154.8; IR (CHCl3) cmꢁ1: 3482, 2932, 1715,
1472, 1390, 1248, 1174, 1263, 918, 822; HRMS calcd for
C30H37NO4SiNa (M+Na)+ 526.2390, found 526.2366.
1
oil. H NMR (400 MHz, CDCl3) d ppm: 1.04 (s, 9H),
1.38 (s, 9H), 2.10–2.30 (m, 2H), 3.02 (s, 3H), 3.11 (s,
3H), 3.24–3.60 (br, 2H), 3.67 (q, 1H, J=8.0 Hz), 3.72–
3.82 (m, 1H), 4.72–4.79 (m, 0.4H), 4.79 (d, 0.6H, J=9.6
Hz), 5.24 (d, 1H, J=11.2 Hz), 5.37 (br, 1H), 5.51 (br,
1H), 5.55 (d, 1H, J=17.6 Hz), 6.98 (d, 1H, J=8.0 Hz),
7.01 (dd, 1H, J=11.2, 17.6 Hz), 7.19 (d, 1H, J=8.0 Hz),
7.22 (d, 1H, J=2.4 Hz), 7.32–7.43 (m, 5H), 7.60 (br s,
1.6H), 7.66 (d, 2.4H, J=7.2 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 19.2, 24.8, 26.9, 28.4, 35.1, 36.4, 36.7,
45.5, 51.0, 51.7, 61.6, 79.3, 115.4, 116.4, 119.2, 120.3,
127.4, 127.6, 129.3, 133.5, 133.8, 135.0, 135.2, 135.3,
139.6, 150.7, 154.4; IR (CHCl3) cmꢁ1: 2932, 1715, 1678,
1391, 1172, 1111; HRMS calcd for C38H51N2O5Si
(M+H)+ 643.3567, found 643.3569.
Allyl[3-(tert-butyldiphenylsilanyloxy)-1-(4-dimethylcarba-
moyloxy-2-vinylphenyl)propyl]carbamic acid tert-butyl
ester (14b). To a solution of compound 13b (3.00 g,
5.95 mmol) and CBr4 (3.98 g, 12.0 mmol) in CH2CH2
(20 mL) was added Ph3P (3.14 g, 12.0 mmol) at room
temperature. The reaction mixture was stirred for 1 h at
room temperature. The solvent was evaporated in
vacuo. The residue was purified by silica gel column
chromatography (hexane–AcOEt 5:1 to 2:1) to furnish a
benzyl bromide (2.62 g, 78%) as a colorless oil. 1H
NMR (500 MHz, CDCl3) d ppm: 1.05 (s, 9H), 2.26–2.33
(m, 1H), 2.41–2.48 (m, 1H), 3.02 (s, 3H), 3.10 (s, 3H),
3.74 (dt, 1H, J=5.0, 9.0 Hz), 3.86–3.90 (m, 1H), 5.40 (d,
1H, J=10.5 Hz), 5.66 (d, 1H, J=17.0 Hz), 5.70 (dd, 1H,
J=5.0, 9.0 Hz), 7.04 (dd, 1H, J=2.0, 9.0 Hz), 7.10 (dd,
1H, J=10.5, 17.0 Hz), 7.19 (d, 1H, J=2.0 Hz), 7.33–
7.43 (m, 6H), 7.46 (d, 1H, J=9.0 Hz), 7.60 (d, 2H,
J=7.5 Hz), 7.69 (d, 2H, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3) d ppm: 19.2, 26.8, 36.4, 36.7, 41.8,
47.8, 61.2, 118.1, 119.7, 121.5, 127.6, 127.7, 128.4, 129.6,
129.7, 133.3, 133.4, 133.5, 135.4, 135.5, 135.6, 135.7,
137.7, 151.2, 154.5; IR (CHCl3) cmꢁ1: 2932, 1717, 1391,
1174, 1110; HRMS calcd for C30H36NO3BrSiK
(M+K)+ 604.1285, found 604.1278.
Allyl[3-(tert-butyldiphenylsilanyloxy)-1-(3-dimethylcarb-
amoyloxy-2-vinylphenyl)propyl]carbamic acid tert-butyl
ester (14a). Benzyl bromide. 1H NMR (500 MHz,
CDCl3) d ppm: 1.05 (s, 9H), 2.26–2.33 (m, 1H), 2.38–
2.45 (m, 1H), 3.00 (s, 3H), 3.08 (s, 3H), 3.75 (dt, 1H,
J=5.0, 9.5 Hz), 3.89 (dt, 1H, J=4.0, 9.5 Hz), 5.54 (dd,
1H, J=2.0, 18.5 Hz), 5.59 (dd, 1H, J=2.0, 12.0 Hz),
5.75 (dd, 1H, J=4.0, 10.0 Hz), 6.71 (dd, 1H, J=12.0,
18.5 Hz), 7.07 (d, 1H, J=8.0 Hz), 7.28 (t, 1H, J=8.0
Hz), 7.34–7.45 (m, 6H), 7.61 (d, 1H, J=6.0 Hz), 7.68–
7.71 (m, 3H).
Allylbenzylamine. 1H NMR (400 MHz, CDCl3) d
ppm: 1.05 (s, 9H), 1.79–1.88 (m, 2H), 2.95–3.10 (m, 2H),
2.99 (s, 3H), 3.06 (s, 3H), 3.67 (dt, 1H, J=5.2, 11.2 Hz),
3.74–3.80 (m, 1H), 4.28 (dd, 1H, J=5.2, 8.4 Hz), 5.02
(dd, 1H, J=1.6, 11.4 Hz), 5.09 (dd, 1H, J=1.6, 16.8
Hz), 5.34 (dd, 1H, J=2.0, 17.6 Hz), 5.44 (dd, 1H,
J=2.0, 11.6 Hz), 5.79–5.89 (m, 1H), 6.68 (dd, 1H,
J=11.6, 17.6 Hz), 6.99 (d, 1H, J=8.0 Hz), 7.25 (t, 1H,
J=8.0 Hz), 7.34–7.44 (m, 7H), 7.63–7.68 (m, 4H); 13C
NMR (100 MHz, CDCl3) d ppm: 19.1, 26.8, 36.3, 36.7,
50.0, 55.5, 61.7, 115.5, 120.4, 121.0, 123.1, 127.6, 127.8,
To a solution of the benzyl bromide (2.62 g, 4.62 mmol)
in CH3CN (20 mL) was added allylamine (1.87 mL, 25.0
mmol) at room temperature. The reaction mixture was
stirred for 12 h at room temperature. The solvent was
evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane–AcOEt 2:1 to
AcOEt) to give an allylbenzylamine (1.82 g, 72%) as a

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4403
129.5, 129.6, 130.5, 131.1, 133.6, 133.7, 135.5, 135.6,
137.1, 143.9, 148.6, 154.7; IR (CHCl3) cmꢁ1: 2932,
1718, 1390, 1249, 1173, 1110; HRMS calcd for
C33H43N2O3Si (M+H)+ 543.3043, found 543.3060.
918, 823; HRMS calcd for C38H50N2O5SiNa
(M+Na)+ 665.3387, found 665.3404.
7-Dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihy-
drobenzo[c]azepine-2-carboxylic acid tert-butyl ester
(16b). To a solution of 14b (360 mg, 0.56 mmol) in
CH2Cl2 (40 mL) was added Grubbs catalyst 15 (48 mg,
0.056 mmol). The reaction mixture was stirred for 3 h at
45 ꢀC. The organic solvent was removed under reduced
pressure, and the residue was purified by silica gel col-
umn chromatography (hexane–AcOEt 5:1 to 2:1) to give
closed-ring compound (330 mg, 96%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d ppm: 1.09 (s, 9H), 1.32
(s, 9H), 1.92 (br, 1H), 2.11 (br, 1H), 3.02 (s, 3H), 3.10 (s,
3H), 3.57 (br, 1H), 3.70 (br, 2H), 4.92 (br, 0.4H), 5.39
(br, 0.6H), 5.76 (d, 1H, J=12.0 Hz), 6.30 (d, 1H,
J=12.0 Hz), 6.90 (dd, 1H, J=2.0, 8.0 Hz), 6.93 (d, 1H,
J=2.0 Hz), 7.13 (d, 1H, J=8.0 Hz), 7.36–7.45 (m, 6H),
7.66 (d, 4H, J=7.0 Hz); 13C NMR (125 MHz, CDCl3) d
ppm: 19.1, 26.8, 28.1, 28.2, 33.6, 36.3, 36.5, 43.8, 56.2,
56.3, 59.8, 60.6, 79.6, 79.8, 119.2, 119.7, 124.5, 124.8,
127.6, 128.3, 128.5, 129.5, 129.6, 130.4, 131.2, 133.5,
135.4, 135.5, 138.8, 150.2, 154.7, 155.5; IR (CHCl3)
cmꢁ1: 2932, 1713, 1684, 1392, 1250, 1168, 1111; HRMS
calcd for C36H47N2O5Si (M+H)+ 615.3219, found
615.3237.
14a. 1H NMR (400 MHz, CDCl3) d ppm: 1.03 (s, 9H),
1.36 (s, 9H), 2.13–2.18 (m, 1H), 2.23–2.32 (m, 1H), 2.98
(s, 3H), 3.05 (s, 3H), 3.38–3.53 (br, 2H), 3.63–3.68 (m,
1H), 3.70–3.80 (m, 1H), 4.74–4.80 (m, 1H), 4.79 (d, 1H,
J=10.0 Hz), 5.34–5.44 (m, 4H), 6.58 (dd, 1H, J=12.0,
17.6 Hz), 7.05 (d, 1H, J=8.0 Hz), 7.12 (d, 1H, J=8.0
Hz), 7.21 (d, 1H, J=8.0 Hz), 7.32–7.43 (m, 6H), 7.59 (br
s, 2H), 7.65 (d, 2H, J=8.0 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 19.1, 26.8, 28.3, 25.3, 36.3, 36.7, 61.7,
77.4, 115.7, 120.2, 122.5, 127.2, 127.6, 129.5, 130.1,
132.5, 135.5, 135.6, 149.0; IR (CHCl3) cmꢁ1: 2932, 1718,
1680, 1452, 1392, 1171, 1111, 909; HRMS calcd for
C38H50N2O5SiNa (M+Na)+ 665.3387, found 665.3412.
Allyl[3-(tert-butyldiphenylsilanyloxy)-1-(5-dimethylcarb-
amoyloxy-2-vinylphenyl)propyl]carbamic acid tert-butyl
ester (14c). Benzyl bromide: 1H NMR (400 MHz,
CDCl3) d ppm: 1.01 (s, 9H), 2.22–2.31 (m, 1H), 2.33–
2.41 (m, 1H), 2.97 (s, 3H), 3.05 (s, 3H), 3.71 (dt, 1H,
J=4.8, 11.0 Hz), 3.83–3.89 (m, 1H), 5.33 (dd, 1H,
J=1.5, 11.0 Hz), 5.59 (dd, 1H, J=1.5, 17.6 Hz), 5.67
(dd, 1H, J=4.4, 9.5 Hz), 7.02 (d, 1H, J=8.8 Hz), 7.04
(dd, 1H, J=11.0, 17.6 Hz), 7.20 (d, 1H, J=2.2 Hz),
7.29–7.40 (m, 7H), 7.55–7.68 (m, 4H); 13C NMR
(100 MHz, CDCl3) d ppm: 19.2, 26.5, 26.8, 36.4, 36.7,
41.7, 47.7, 61.2, 117.5, 120.3, 121.9, 127.6, 127.7, 127.8,
129.6, 129.7, 133.2, 133.3, 133.4, 134.7, 135.4, 139.9,
151.3, 154.5; IR (CHCl3) cmꢁ1: 2932, 1721, 1742, 1390,
1248, 1173, 1111, 823; HRMS calcd for C30H36NO3Br-
SiNa (M+Na)+ 588.1546, found 588.1523.
To a solution of this closed-ring compound (1.82 g, 2.96
mmol) in THF (10 mL) was added tetra-
butylammonium fluoride in THF (6.0 mL, 1.0 M) at
room temperature. The mixture was stirred for 1 h at
room temperature and quenched with water (40 mL).
The product was extracted with AcOEt (40 mLꢂ2) and
the organic solution was washed with water (40 mL)
and brine (40 mL), dried over Na2SO4, filtered and
evaporated. Purification by silica gel column chromato-
graphy (hexane–AcOEt 1:1 to AcOEt) provided 16b
Allylbenzylamine. 1H NMR (400 MHz, CDCl3) d
ppm: 1.06 (s, 9H), 1.82 (q, 2H, J=5.8 Hz), 2.99–3.12
(m, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.67 (dt, 1H, J=5.8,
11.0 Hz), 3.76 (dd, 1H, J=5.1, 11.0 Hz), 3.82 (t, 1H,
J=5.8 Hz), 4.34 (t, 1H, J=5.8 Hz), 5.04 (d, 1H, J=11.0
Hz), 5.12 (d, 1H, J=16.8 Hz), 5.22 (d, 1H, J=11.0 Hz),
5.53 (dd, 1H, J=1.5, 16.8 Hz), 5.82–5.91 (m, 1H), 7.00
(dd, 1H, J=2.2, 8.8 Hz), 7.11 (dd, 1H, J=11.0, 16.8
Hz), 7.22 (d, 1H, J=2.2 Hz), 7.33–7.45 (m, 7H), 7.64–
7.68 (m, 4H); 13C NMR (100 MHz, CDCl3) d ppm: 19.1,
26.8, 36.4, 36.6, 49.9, 55.0, 61.7, 115.9, 119.1, 127.1,
127.6, 127.7, 129.5, 129.6, 133.5, 133.6, 133.9, 135.5,
135.6, 151.6, 154.8; IR (CHCl3) cmꢁ1: 2932, 1719, 1472,
1390, 1259, 1174, 1110, 918; HRMS calcd for
C33H43N2O3Si (M+H)+ 543.3043, found 543.3042.
1
(1.07 g, 96%) as a colorless oil. H NMR (500 MHz,
CDCl3) d ppm: 1.30 (s, 5H), 1.40 (s, 4H), 1.90–2.08 (m,
1H), 2.07–2.24 (br, 1H), 3.00 (s, 3H), 3.09 (s, 3H), 3.59
(br s, 1H), 3.65 (br s, 1H), 3.76–3.88 (br, 0.4H), 3.98 (d,
0.6H, J=19.0 Hz), 4.58 (d, 0.6H, J=19.0 Hz), 4.78–
5.10 (br, 0.4H), 4.92–5.20 (br, 0.4H), 5.31 (br t, 0.6H,
J=7.5 Hz), 5.77–5.83 (m, 1H), 6.32 (d, 0.6H, J=11.5
Hz), 6.39 (d, 0.4H, J=13.0 Hz), 6.92 (dd, 1H, J=2.0,
8.0 Hz), 6.95 (s, 1H), 7.13 (d, 0.6H, J=8.0 Hz), 7.25, (d,
0.4H, J=8.9 Hz); 13C NMR (125 MHz, CDCl3) d ppm:
28.0, 28.2, 33.2, 33.8, 36.2, 36.5, 44.0, 44.8, 56.0, 56.8,
58.8, 58.9, 79.9, 119.2, 119.8, 124.4, 124.7, 128.3, 128.9,
129.8, 129.9, 131.3, 134.8, 138.0, 138.7, 150.1, 154.7,
154.9, 155.4; IR (CHCl3) cmꢁ1: 2980, 1713, 1686, 1392,
1368, 1250, 1167, 1040; HRMS calcd for C20H29N2O5
(M+H)+ 377.2076, found 377.2073.
14c. 1H NMR (400 MHz, CDCl3) d ppm: 0.93 (s, 9H),
1.27 (s, 9H), 2.00–2.21 (m, 2H), 2.92 (s, 3H), 3.01 (s,
3H), 3.33 (br, 2H), 3.54–3.64 (m, 1H), 3.71 (br, 1H),
4.68 (br, 2H), 5.12 (d, 1H, J=11.0 Hz), 5.19–5.50 (m,
2H), 6.86–6.93 (m, 1H), 6.94 (br s, 1H), 7.21–7.30 (m,
7H), 7.35 (d, 1H, J=8.8 Hz), 7.49 (br s, 2H), 7.55 (d,
2H, J=7.3 Hz); 13C NMR (100 MHz, CD3OD) d ppm:
19.9, 27.3, 28.7, 35.7, 36.7, 36.9, 46.5, 61.5, 62.5, 97.2,
116.4, 121.9, 122.2, 128.7, 128.8, 130.7, 130.8, 134.7,
135.2, 136.6, 136.7, 139.1, 152.3, 156.5; IR (CHCl3)
cmꢁ1: 2932, 1720, 1678, 1451, 1392, 1251, 1171, 1111,
6-Dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-
benzo[c]azepine-2-carboxylic acid tert-butyl ester (16a).
1
closed-ring compound: H NMR (400 MHz, CDCl3) d
ppm: 1.08 (s, 9H), 1.31 (s, 9H), 1.97 (br, 1H), 2.20 (br,
1H), 3.01 (s, 3H), 3.13 (s, 3H), 3.56 (br, 1H), 3.68 (br,
2H), 4.63–4.90 (m, 1H), 5.37 (br, 1H), 5.82 (d, 1H,
J=12.4 Hz), 6.53 (d, 1H, J=12.4 Hz), 6.98 (d, 1H,
J=8.0 Hz), 7.03 (d, 1H, J=8.0 Hz), 7.15 (t, 1H, J=8.0
Hz), 7.35–7.45 (m, 6H), 7.65 (d, 4H, J=7.2 Hz); 13C

4404
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
NMR (100 MHz, CDCl3) d ppm: 19.2, 21.0, 26.9, 28.0,
28.2, 28.3, 33.1, 36.4, 36.7, 60.3, 80.0, 121.5, 126.9,
127.7, 129.6, 133.5, 135.5, 150.0, 154.5, 155.5; IR
(CHCl3) cmꢁ1: 2932, 1723, 1685, 1390, 1251, 1165, 1110;
HRMS calcd for C36H46N2O5SiNa (M+Na)+
637.3074, found 637.3059.
37.5, 37.8, 49.8, 58.1, 67.1, 115.4, 120.5, 125.8, 126.7,
128.0, 129.5, 136.8, 137.1, 142.1, 142.2, 151.2, 155.6,
164.8; IR (CHCl3) cmꢁ1: 2939, 1714, 1593, 1512, 1498,
1391, 1343, 1264, 1172, 1112, 1020, 846; HRMS calcd for
C21H24N3O5 (M+H)+ 398.1716, found 398.1743.
1
.
17a HCl. H NMR (400 MHz, CDCl3) d ppm: 2.38–
16a. 1H NMR (400 MHz, CDCl3) d ppm: 1.31 (s,
5.4H), 1.42 (s, 3.2H), 1.88–2.28 (m, 2H), 3.02 (s, 3H),
3.13 (s, 3H), 3.59 (br s, 1H), 3.66 (br s, 1H), 3.85–4.05
(br, 0.4H), 3.98 (d, 0.6H, J=15.6 Hz), 4.41 (d, 0.6H,
J=15.6 Hz), 4.60–5.00 (br, 0.4H), 5.00–5.20 (br, 0.4H),
5.35 (br t, 0.6H, J=7.2 Hz), 5.86–5.91 (m, 1H), 6.56 (d,
0.6H, J=12.4 Hz), 6.64 (d, 0.4H, J=12.4 Hz), 6.99–
7.26 (m, 3H); 13C NMR (100 MHz, CDCl3) d ppm: 27.8,
28.2, 28.3, 33.0, 33.3, 36.4, 36.8, 55.6, 59.5, 80.2, 121.8,
2.44 (m, 1H), 2.71–2.76 (m, 1H), 2.97 (s, 3H), 3.07 (s,
3H), 3.75 (br d, 1H, J=18.4 Hz), 3.97–4.00 (m, 2H),
4.09–4.15 (m, 1H), 4.85 (1H, dd, J=6.0, 9.6 Hz), 5.95
(dt, 1H, J=4.4, 11.6 Hz), 6.68 (d, 1H, J=11.6 Hz), 6.88
(d, 2H, J=8.8 Hz), 6.98 (dd, 1H, J=2.0, 8.0 Hz), 7.07
(d, 1H, J=2.0 Hz), 7.32 (d, 1H, J=8.0 Hz), 8.14 (d, 2H,
J=8.8 Hz), 9.90 (br s, 1H), 10.71 (br s, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 28.6, 36.4, 36.7, 42.5, 56.3,
64.7, 114.6, 121.4, 124.2, 124.8, 125.8, 130.4, 132.1,
136.0, 141.7, 152.0, 154.3, 163.1; IR (CHCl3) cmꢁ1:
2972, 2658, 1722, 1593, 1514, 1498, 1392, 1343, 1260,
1171, 1112; HRMS calcd for C21H24N3O5 (M+H)+
398.1716, found 398.1743.
125.9, 126.5, 127.0, 131.9, 154.5; IR (CHCl3) cmꢁ1
:
2980, 1722, 1685, 1390, 1252, 1164, 1044; HRMS calcd
for C20H29N2O5 (M+H)+ 377.2076, found 377.2078.
8-Dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3-dihydro-
benzo[c]azepine-2-carboxylic acid tert-butyl ester (16c).
Closed-ring compound. H NMR (400 MHz, CDCl3) d
Dimethylcarbamic acid 1-[2-(4-chloro-3-methylphenoxy)-
ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydro-
.
chloride salt (17b HCl). This was prepared by the
method used for 6a.
1
ppm: 1.04 (s, 9H), 1.28 (s, 9H), 1.88 (br, 1H), 2.05 (br,
1H), 2.97 (s, 3H), 3.05 (s, 3H), 3.54 (br, 1H), 3.63 (br,
2H), 4.59–4.84 (m, 1H), 5.30 (br, 1H), 5.57–5.67 (m,
1H), 6.29 (d, 1H, J=14.7 Hz), 6.93–7.01 (m, 2H), 7.09–
7.12 (m, 1H), 7.31–7.40 (m, 6H), 7.61–7.63 (m, 4H); 13C
NMR (100 MHz, CD3OD) d ppm: 20.1, 27.4, 28.5, 28.6,
34.6, 36.7, 36.8, 45.1, 57.8, 58.2, 61.4, 61.5, 81.4, 81.6,
97.2, 121.3, 128.8, 128.9, 129.3, 130.9, 131.0, 132.3,
134.4, 134.5, 134.6, 136.6, 151.2, 156.4, 157.3; IR
(CHCl3) cmꢁ1: 2932, 1721, 1685, 1391, 1367, 1250, 1168,
1110; HRMS calcd for C36H46N2O5SiNa (M+Na)+
637.3074, found 637.3074.
1
17b. H NMR (400 MHz, CDCl3) d ppm: 2.22 (dd,
1H, J=2.0, 6.0 Hz), 2.25 (d, 1H, J=7.2 Hz), 2.32 (s,
3H), 3.01 (s, 3H), 3.09 (s, 3H), 3.66 (ddd, 1H, J=2.4,
3.6, 19.6 Hz), 3.76 (dt, 1H, J=2.4, 19.6 Hz), 3.98 (dt,
1H, J=6.0, 9.6 Hz), 4.08 (dt, 1H, J=6.0, 9.6 Hz), 4.21
(t, 1H, J=8.0 Hz), 5.93 (dt, 1H, J=3.6, 12.4 Hz), 6.38
(d, 1H, J=12.4 Hz), 6.67 (dd, 1H, J=3.2, 8.8 Hz), 6.77
(d, 1H, J=3.2 Hz), 6.86 (dd, 1H, J=3.2, 8.0 Hz), 6.99
(d, 1H, J=3.2 Hz), 7.08 (d, 1H, J=8.0 Hz), 7.20 (d, 1H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm:
20.3, 31.3, 36.4, 36.7, 48.5, 57.2, 65.2, 113.1, 117.0, 119.5,
124.8, 125.6, 127.4, 128.7, 129.5, 135.7, 136.3, 136.9,
141.4, 150.2, 154.9, 157.4; IR (CHCl3) cmꢁ1: 2935, 1714,
1484, 1391, 1247, 1171, 909; HRMS calcd for
C22H26N2O3Cl (M+H)+ 401.1632, found 401.1628.
16c. 1H NMR (400 MHz, CDCl3) d ppm: 1.26 (s,
5.4H), 1.36 (s, 3.2H), 1.85–2.15 (m, 2H), 2.96 (s, 3H),
3.06 (s, 3H), 3.55 (br, 2H), 3.82 (br, 0.4H), 3.94 (d,
0.6H, J=18.3 Hz), 4.55 (d, 0.6H, J=20.5 Hz), 4.57 (br,
0.4H), 5.01 (br, 0.4H), 5.22 (br t, 0.6H, J=7.3 Hz),
5.68–5.75 (m, 1H), 6.33 (d, 0.6H, J=12.4 Hz), 6.39 (d,
0.4H, J=12.4 Hz), 6.99–7.01 (m, 2H), 7.13 (d, 1H,
J=8.8 Hz);13C NMR (100 MHz, CD3OD) d ppm:
28.4, 28.6, 34.4, 34.6, 36.7, 36.8, 57.7, 59.1, 59.2,
61.5, 81.4, 81.6, 97.2, 121.3, 123.2, 129.3, 130.5,
1
.
17b HCl. H NMR (400 MHz, CDCl3) d ppm: 2.29 (s,
3H), 2.31–2.40 (m, 1H), 2.63–2.72 (m, 1H), 2.97 (s, 3H),
3.07 (s, 3H), 3.75 (br d, 1H, J=18.0 Hz), 3.80 (dt, 1H,
J=5.2, 8.8 Hz), 3.95 (br s, 1H), 3.98 (q, 1H, J=5.2 Hz),
4.83 (1H, dd, J=5.2, 9.6 Hz), 5.94 (dt, 1H, J=4.4, 11.6
Hz), 6.59 (dd, 1H, J=2.0, 8.8 Hz), 6.67 (d, 1H, J=11.6
Hz), 6.69 (d, 1H, J=2.0 Hz), 6.98 (dd, 1H, J=2.0, 8.0
Hz), 7.06 (d, 1H, J=2.0 Hz), 7.15 (d, 1H, J=8.0 Hz),
7.30 (d, 1H, J=8.8 Hz), 9.87 (br s, 1H), 10.65 (br s, 1H);
13C NMR (100 MHz, CDCl3) d ppm: 20.2, 29.0, 36.4,
36.7, 42.5, 56.3, 64.0, 113.2, 117.1, 121.3, 124.1, 124.6,
126.2, 129.5, 130.4, 130.5, 132.3, 136.0, 137.0, 151.9,
154.3, 156.7; IR (CHCl3) cmꢁ1: 2970, 2694, 1722, 1576,
1483, 1391, 1250, 1170, 1040.
131.1, 134.2, 151.2, 156.5, 157.4; IR (CHCl3) cmꢁ1
:
2979, 1720, 1686, 1479, 1454, 1392, 1250, 1167, 1040;
HRMS calcd for C20H29N2O5 (M+H)+ 377.2076,
found 377.2075.
Dimethylcarbamic acid 1-[2-(4-nitrophenoxy)ethyl]-2,3-
dihydro-1H-benzo[c]azepin-7-yl ester hydrochloride salt
.
(17a HCl). This was prepared by the method used for 6a.
1
17a. H NMR (400 MHz, CDCl3) d ppm: 2.23–2.35
(m, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.67 (ddd, 1H,
J=2.0, 3.6, 20.4 Hz), 3.77 (dt, 1H, J=2.4, 20.4 Hz),
4.14 (dt, 1H, J=6.0, 8.8 Hz), 4.19–4.27 (m, 2H), 5.95
(dt, 1H, J=3.6, 12.4 Hz), 6.40 (d, 1H, J=12.4 Hz), 6.88
(dd, 1H, J=2.0, 8.0 Hz), 6.95 (d, 2H, J=9.2 Hz), 7.00,
(d, 1H, J=2.0 Hz), 7.08 (d, 1H, J=8.0 Hz), 8.19 (d, 2H,
J=9.2 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 32.3,
Compounds 18a–h were prepared by the method used
for 9a.
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)e-
thyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydrochlo-
1
.
ride salt (18a HCl). 18a. H NMR (400 MHz, CDCl3)

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4405
d ppm: 2.05–2.13 (m, 1H), 2.23–2.33 (m, 1H), 2.28 (s,
3H), 3.01 (s, 3H), 3.09 (s, 3H), 3.46 (dd, 1H, J=3.6,
19.6 Hz), 3.87 (dt, 1H, J=2.0, 19.6 Hz), 3.97–4.02
(m, 1H), 4.06–4.12 (m, 2H), 5.81 (ddd, 1H, J=2.8,
4.4, 12.4 Hz), 6.37 (d, 1H, J=12.4 Hz), 6.89 (dd, 1H,
J=3.0, 8.0 Hz), 6.92 (d, 2H, J=8.8 Hz), 7.00 (d, 1H,
J=3.0 Hz), 7.04 (d, 1H, J=8.0 Hz), 8.19 (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 31.3,
36.3, 36.6, 41.4, 53.2, 64.0, 65.6, 114.2, 119.6, 124.2,
125.5, 128.6, 129.5, 132.3, 135.9, 137.8, 141.0, 150.1,
154.4, 163.6; IR (CHCl3) cmꢁ1: 2938, 1714, 1593,
1513, 1498, 1391, 1343, 1263, 1172, 1112, 1024, 846;
HRMS calcd for C22H26N3O5 (M+H)+ 412.1872,
found 412.1902.
1250, 1170, 1041, 1022; HRMS calcd for C23H28N2O3Cl
(M+H)+ 415.1788, found 415.1793.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-2-
methyl-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydro-
chloride salt (18c HCl). 18c: 1H NMR (400 MHz,
.
CDCl3) d ppm: 1.94–2.03 (m, 1H), 2.16–2.24 (m, 1H),
2.24 (s, 3H), 2.97 (s, 3H), 3.05 (s, 3H), 3.40 (dd, 1H,
J=3.7, 19.8 Hz), 3.78–3.93 (m, 3H), 4.05 (t, 1H, J=8.0
Hz), 5.75 (ddd, 1H, J=2.9, 4.4, 12.5 Hz), 6.32 (d, 1H,
J=12.5 Hz), 6.75 (d, 2H, J=8.8 Hz), 6.84 (dd, 1H,
J=2.2, 8.0 Hz), 6.95 (d, 1H, J=2.2 Hz), 7.01 (d, 1H,
J=8.0 Hz), 7.16 (d, 2H, J=8.8 Hz); IR (film) cmꢁ1
:
2931, 1722, 1491, 1386, 1242, 1167, 1028, 824.
1
1
.
.
18a HCl. H NMR (400 MHz, CDCl3) d ppm: 2.12–
18c HCl. H NMR (400 MHz, CDCl3) d ppm: 1.98–
2.09 (m, 1H), 2.65 (d, 3H, J=4.4 Hz), 2.74–2.82 (m,
1H), 2.98 (s, 3H), 3.06 (s, 3H), 3.61–3.66 (m, 1H), 3.73
(d, 1H, J=19.8 Hz), 3.83–3.88 (m, 1H), 4.83 (d, 1H,
J=18.3 Hz), 4.72 (d, 1H, J=11.7 Hz), 5.78 (d, 1H,
J=13.2 Hz), 6.60 (d, 1H, J=13.2 Hz), 6.68 (d, 2H,
J=8.8 Hz), 6.99 (dd, 1H, J=2.2, 8.0 Hz), 7.10 (d, 1H,
J=8.0 Hz), 7.15 (d, 1H, J=2.2 Hz), 7.16 (d, 2H, J=8.8
Hz); IR (KBr) cmꢁ1: 2933, 2436, 1723, 1492, 1388, 1243,
1170, 1020, 825; HRMS calcd for C22H26N2O3Cl
(M+H)+ 401.1632, found 401.1624.
2.21 (m, 1H), 2.60 (s, 3H), 2.85–2.93 (m, 1H), 3.02 (s,
3H), 3.10 (s, 3H), 3.81 (dd, 1H, J=4.4, 19.6 Hz), 3.85–
3.90 (m, 1H), 4.06 (dt, 1H, J=5.2, 9.6 Hz), 4.39 (d, 1H,
J=19.6 Hz), 4.77 (d, 1H, J=11.6 Hz), 5.85 (ddd, 1H,
J=3.2, 4.4, 12.4 Hz), 6.36 (d, 1H, J=12.4 Hz), 6.86 (d,
2H, J=8.8 Hz), 7.04 (dd, 1H, J=2.4, 8.8 Hz), 7.14 (d,
1H, J=8.8 Hz), 7.21 (d, 1H, J=2.4 Hz), 8.16 (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 29.7,
36.2, 36.5, 40.3, 51.0, 64.0, 65.4, 114.1, 121.5, 121.8,
125.3, 125.6, 127.4, 129.7, 131.5, 134.2, 141.1, 151.9,
153.5, 162.4; IR (CHCl3) cmꢁ1: 2971, 2222, 1725, 1594,
1514, 1498, 1469, 1392, 1344, 1258, 1171, 1112, 1021,
909, 846; HRMS calcd for C22H26N3O5 (M+H)+
412.1872, found 412.1870.
Dimethylcarbamic acid 1-[2-(4-fluorophenoxy)ethyl]-2-
methyl-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydro-
chloride salt (18d HCl). 18d. 1H NMR (400 MHz,
.
CDCl3) d ppm: 1.93–2.04 (m, 1H), 2.13–2.23 (m, 1H),
2.25 (s, 3H), 2.97 (s, 3H), 3.05 (s, 3H), 3.42 (dd, 1H,
J=4.4, 20.5 Hz), 3.77-3.91 (m, 3H), 4.02–4.10 (m, 1H),
5.75 (ddd, 1H, J=2.9, 4.4, 12.5 Hz), 6.33 (d, 1H,
J=12.5 Hz), 6.76 (dd, 2H, J=4.4, 8.8 Hz), 6.85 (dd,
1H, J=2.2, 8.0 Hz), 6.90 (d, 2H, J=8.8 Hz), 6.95 (d,
1H, J=2.2 Hz), 7.02 (d, 1H, J=8.0 Hz); IR (film)
cmꢁ1: 2932, 1723, 1506, 1387, 1245, 1207, 1168, 1032,
829.
Dimethylcarbamic acid 1-[2-(4-chloro-3-methylphenox-
y)ethyl]-2-methyl-2,3-dihydro-1H-benzo[c]azepin-7-yl es-
ter hydrochloride salt (18b HCl). 18b. 1H NMR
.
(400 MHz, CDCl3) d ppm: 1.97–2.05 (m, 1H), 2.19–2.26
(m, 1H), 2.28 (s, 3H), 2.32 (s, 3H), 3.01 (s, 3H), 3.09 (s,
3H), 3.45 (dd, 1H, J=4.4, 20.4 Hz), 3.81–3.96 (m, 3H),
4.08 (dd, 1H, J=6.4, 8.8 Hz), 5.80 (ddd, 1H, J=2.4, 4.4,
12.4 Hz), 6.36 (d, 1H, J=12.4 Hz), 6.64 (dd, 1H, J=2.0,
8.0 Hz), 6.74 (d, 1H, J=2.0 Hz), 6.88 (dd, 1H, J=2.0,
8.0 Hz), 6.99 (d, 1H, J=2.0 Hz), 7.06 (d, 1H, J=8.0
Hz), 7.19 (d, 1H, J=8.0 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 20.2, 31.6, 36.4, 36.7, 41.6, 53.2, 64.4,
64.9, 113.2, 117.0, 119.8, 124.5, 125.6, 129.0, 129.5,
130.1, 132.4, 136.1, 136.8, 138.3, 150.4, 154.8, 157.4; IR
(CHCl3) cmꢁ1: 2934, 1714, 1483, 1391, 1246, 1171, 1034,
909; HRMS calcd for C23H28N2O3Cl (M+H)+
415.1788, found 415.1793.
1
.
18d HCl. H NMR (500 MHz, CDCl3) d ppm: 2.07–
2.13 (m, 1H), 2.61 (d, 3H, J=4.9 Hz), 2.80–2.86 (m,
1H), 3.04 (s, 3H), 3.12 (s, 3H), 3.66–3.71 (m, 1H), 3.79
(dd, 1H, J=4.9, 20.5 Hz), 3.90 (dt, 1H, J=4.9, 8.8 Hz),
4.40 (d, 1H, J=19.5 Hz), 4.78–4.82 (m, 1H), 5.83 (d,
1H, J=12.7 Hz), 6.66 (d, 1H, J=12.7 Hz), 6.74–6.76
(m, 2H), 6.94 (d, 2H, J=8.8 Hz), 7.05 (dd, 1H, J=2.9,
8.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.20 (d, 1H, J=2.9
Hz); IR (KBr) cmꢁ1: 3428, 2933, 2461, 1724, 1507, 1389,
1209, 1169, 1019, 831; HRMS calcd for C22H26N2O3F
(M+H)+ 385.1928, found 385.1930.
1
.
18b HCl. H NMR (400 MHz, CDCl3) d ppm: 2.03–
2.12 (m, 1H), 2.30 (s, 3H), 2.60 (d, 3H, J=5.2 Hz),
2.77–2.86 (m, 1H), 3.02 (s, 3H), 3.10 (s, 3H), 3.65 (dt,
1H, J=4.4, 9.6 Hz), 3.78 (dd, 1H, J=2.0, 4.4 Hz), 3.88
(dt, 1H, J=5.2, 8.8 Hz), 4.37 (d, 1H, J=17.2 Hz), 4.79
(dt, 1H, J=3.6, 12.4 Hz), 5.82 (ddd, 1H, J=2.8, 4.4,
12.4 Hz), 6.55 (dd, 1H, J=2.8, 8.8 Hz), 6.64 (d, 2H,
J=12.4 Hz), 6.68 (d, 1H, J=2.8 Hz), 7.04 (dd, 1H,
J=2.8, 8.8 Hz), 7.15 (d, 1H, J=8.8 Hz), 7.17 (d, 1H,
J=8.8 Hz), 7.19 (d, 1H, J=2.8 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 20.2, 30.2, 36.5, 36.7, 40.6,
51.3, 63.4, 66.0, 113.0, 117.1, 121.9, 122.0, 126.0, 126.3,
128.2, 129.5, 130.4, 132.1, 134.5, 137.0, 152.4, 154.1,
156.6; IR (CHCl3) cmꢁ1: 2969, 2230, 1724, 1483, 1392,
Dimethylcarbamic acid 2-methyl-1-[2-(4-trifluoromethyl-
phenoxy)ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl ester
1
.
hydrochloride salt (18e HCl). 18e. H NMR (400 MHz,
CDCl3) d ppm: 2.02–2.10 (m, 1H), 2.23–2.29 (m, 1H),
2.29 (s, 3H), 3.01 (s, 3H), 3.09 (s, 3H), 3.42–3.49 (m,
1H), 3.85–3.96 (m, 2H), 4.00–4.05 (m, 1H), 4.08–4.13
(m, 1H), 5.80 (ddd, 1H, J=2.9, 4.4, 12.5 Hz), 6.37 (d,
1H, J=12.5 Hz), 6.89 (dd, 1H, J=2.9, 8.0 Hz), 6.93 (d,
2H, J=8.0 Hz), 7.00 (d, 1H, J=2.9 Hz), 7.06 (d, 1H,
J=8.0 Hz), 7.52 (d, 2H, J=8.0 Hz); IR (film) cmꢁ1
2932, 1724, 1615, 1386, 1328, 1256, 1164, 1111, 837,
:

4406
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
756; HRMS calcd for C23H26N2O3F3 (M+H)+
435.1896, found 435.1902.
1343, 1263, 1171, 1111, 1022, 846; HRMS calcd for
C22H26N3O5 (M+H)+ 412.1872, found 412.1868.
1
1
.
.
18e HCl. H NMR (400 MHz, CDCl3) d ppm: 2.05–
18g HCl. H NMR (400 MHz, CD3OD) d ppm: 2.29–
2.13 (m, 1H), 2.55 (d, 3H, J=4.4 Hz), 2.77–2.87 (m,
1H), 2.98 (s, 3H), 3.06 (s, 3H), 3.69–3.77 (m, 2H), 3.91–
3.96 (m, 1H), 4.34 (d, 1H, J=19.0 Hz), 4.73 (d, 1H,
J=11.0 Hz), 5.79 (d, 1H, J=12.5 Hz), 6.62 (d, 1H,
J=12.5 Hz), 6.81 (d, 2H, J=8.8 Hz), 6.99 (dd, 1H,
J=2.2, 8.0 Hz), 7.09 (d, 1H, J=8.0 Hz), 7.16 (d, 1H,
2.37 (m, 1H), 2.55–2.63 (m, 1H), 2.90 (s, 6H), 2.99 (s,
3H), 3.84–3.90 (m, 1H), 4.08–4.31 (m, 3H), 5.86 (ddd,
1H, J=3.7, 7.8, 12.8 Hz), 6.80 (d, 1H, J=12.8 Hz), 7.02-
7.05 (m, 3H), 7.21 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=8.4
Hz), 8.19 (d, 2H, J=9.4 Hz); 13C NMR (100 MHz,
CD3OD) d ppm: 36.5, 36.8, 42.3, 53.7, 65.5, 67.7, 97.2,
116.0, 123.0, 124.3, 125.5, 126.7, 130.9, 132.4, 135.1,
137.5, 143.1, 152.4, 155.9, 164.7; IR (CHCl3) cmꢁ1: 2971,
2219, 1726, 1594, 1498, 1391, 1343, 1259, 1168, 1112, 846.
J=2.2 Hz), 7.46 (d, 2H, J=8.8 Hz); IR (KBr) cmꢁ1
:
2934, 2466, 1725, 1615, 1389, 1329, 1255, 1168, 1112,
1067, 839; HRMS calcd for C23H26N2O3F3 (M+H)+
435.1896, found 435.1895.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-2-
methyl-2,3-dihydro-1H-benzo[c]azepin-8-yl ester hydro-
Dimethylcarbamic acid 1-[2-(4-chloro-3-methylphenoxy)-
ethyl]-2-methyl-2,3-dihydro-1H-benzo[c]azepin-6-yl ester
chloride salt (18h HCl). 18h. 1H NMR (400 MHz,
.
1
.
hydrochloride salt (18f HCl). 18f. H NMR (400 MHz,
CDCl3) d ppm: 2.00–2.08 (m, 1H), 2.20–2.27 (m, 1H),
2.29 (s, 3H), 2.99 (s, 3H), 3.04 (s, 3H), 3.46 (dd, 1H,
J=3.7, 20.0 Hz), 3.84–4.00 (m, 3H), 4.05 (t, 1H, J=8.0
Hz), 5.74 (ddd, 1H, J=2.2, 4.4, 12.5 Hz), 6.40 (d, 1H,
J=12.5 Hz), 6.81–6.83 (m, 3H), 6.97 (dd, 1H, J=2.9,
8.8 Hz), 7.19–7.21 (m, 3H).
CDCl3) d ppm: 2.04–2.12 (m, 1H), 2.21–2.28 (m, 1H),
2.30 (s, 3H), 2.32 (s, 3H), 3.02 (s, 3H), 3.15 (s, 3H), 3.47
(dd, 1H, J=3.6, 19.6 Hz), 3.81–3.87 (m, 2H), 3.94 (dt,
1H, J=5.6, 8.8 Hz), 4.11 (t, 1H, J=7.2 Hz), 5.88 (ddd,
1H, J=2.4, 3.6, 12.4 Hz), 6.59 (d, 1H, J=12.4 Hz), 6.63
(dd, 1H, J=3.2, 8.0 Hz), 6.73 (d, 1H, J=3.2 Hz), 6.95
(d, 1H, J=8.0 Hz), 6.99 (dd, 1H, J=1.2, 8.0 Hz), 7.13
(t, 1H, J=8.0 Hz), 7.19 (d, 1H, J=8.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 20.3, 30.7, 36.4, 36.8, 53.7,
65.0, 113.1, 117.0, 121.0, 121.6, 125.6, 126.4, 127.5,
127.7, 129.5, 136.8, 149.7, 154.6, 157.4; IR (CHCl3)
cmꢁ1: 2935, 1720, 1483, 1389, 1168, 1037, 909; HRMS
calcd for C23H28N2O3Cl (M+H)+ 415.1788, found
415.1789.
1
.
1 8 hHCl. H NMR (400 MHz, CD3OD) d ppm: 2.21–
2.29 (m, 1H), 2.50–2.57 (m, 1H), 2.95 (s, 6H), 3.02 (s,
3H), 3.66–3.72 (m, 1H), 4.01–4.13 (m, 2H), 4.28 (br d,
1H, J=18.4 Hz), 5.85 (dt, 1H, J=4.0, 12.8 Hz), 6.79 (d,
1H, J=12.8 Hz), 6.87 (d, 2H, J=8.8 Hz), 7.03 (d, 1H,
J=2.4 Hz), 7.20–7.25 (m, 3H), 7.48 (d, 1H, J=8.8 Hz);
13C NMR (100 MHz, CD3OD) d ppm: 36.6, 36.8, 64.8,
67.8, 81.1, 97.2, 117.2, 124.2, 125.5, 127.1, 130.3, 131.0,
132.3, 135.1, 152.4, 155.9, 158.4; IR (CHCl3) cmꢁ1
:
1
.
18f HCl. H NMR (400 MHz, CDCl3) d ppm: 2.14–
2970, 2222, 1726, 1492, 1391, 1248, 1168; HRMS calcd
for C22H26N2O3Cl (M+H)+ 401.1632, found 401.1635.
2.21 (m, 1H), 2.30 (s, 3H), 2.64 (d, 3H, J=4.8 Hz),
2.78–2.89 (m, 1H), 3.04 (s, 3H), 3.18 (s, 3H), 3.65 (dt,
1H, J=4.4, 10.0 Hz), 3.78 (d, 1H, J=19.2 Hz), 3.89 (dt,
1H, J=5.2, 10.0 Hz), 4.34 (dd, 1H, J=3.6, 19.2 Hz),
4.79 (dt, 1H, J=3.6, 12.4 Hz), 5.91 (dt, 1H, J=3.6, 12.4
Hz), 6.52 (dd, 1H, J=2.8, 8.8 Hz), 6.67 (d, 1H, J=2.8
Hz), 6.88 (d, 1H, J=12.4 Hz), 7.04 (d, 1H, J=7.2 Hz),
7.15–7.32 (m, 3H); 13C NMR (100 MHz, CDCl3) d ppm:
20.2, 20.5, 29.6, 36.5, 36.9, 41.0, 51.4, 63.6, 66.5, 113.0,
113.2, 117.0, 122.7, 123.6, 124.4, 126.3, 126.7, 128.2,
129.5, 129.7, 133.0, 137.0, 150.7, 154.0, 156.6; IR
(CHCl3) cmꢁ1: 2970, 2250, 1726, 1471, 1387, 1245, 1166,
1042, 1020.
7-Dimethylcarbamoyloxy-1-(2-hydroxyethyl)-1,3,4,5-tet-
rahydrobenzo[c]azepine-2-carboxylic acid tert-butyl ester
(19). To a solution of 16b (207 mg, 0.550 mmol) in
MeOH (10 mL) was added 10% Pd/C (27 mg). The
reaction mixture was stirred for 1 h under a hydrogen
atmosphere at room temperature. Pd/C was removed by
filtration and filtrate was evaporated in vacuo. Purifica-
tion by silica gel column chromatography (hexane–
AcOEt 1:1 to AcOEt) provided 19 (189 mg, 91%) as a
1
colorless oil. H NMR (400 MHz, CDCl3) d ppm: 1.36
(s, 5.4H), 1.45 (s, 3.6H), 1.68–1.84 (br, 1H), 1.86–2.00
(br, 1H), 1.88–2.06 (br, 0.4H), 2.06–2.18 br, (0.6H),
2.22–2.44 (br, 1H), 2.83 (br s, 2H), 3.00 (s, 3H), 3.08 (s,
3H), 3.55–3.68 (br, 1H), 3.67 (br s, 2H), 3.75–3.90 (br,
1H), 5.03–5.18 (br, 0.4H), 5.38–5.52 (br, 0.6H), 6.88 (s,
2H), 7.15 (br s, 0.4H), 7.24 (br s, 0.6H); 13C NMR
(100 MHz, CDCl3) d ppm: 14.2, 27.5, 28.4, 33.6, 35.2,
36.4, 36.6, 55.9, 59.1, 77.6, 80.1, 118.7, 119.2, 123.6,
129.3, 141.0, 150.2, 154.9; IR (CHCl3) cmꢁ1: 2938, 1713,
1680, 1478, 1392, 1252, 1168, 909; HRMS calcd for
C20H31N2O5 (M+H)+ 379.2233, found 379.2244.
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-2,3-dihydro-1H-benzo[c]azepin-8-yl ester hydro-
chloride salt (18g HCl). 18g: 1H NMR (400 MHz,
.
CDCl3) d ppm: 2.06–2.15 (m, 1H), 2.25–2.35 (m, 1H),
2.30 (s, 3H), 2.97 (s, 3H), 3.04 (s, 3H), 3.47 (dd, 1H,
J=4.4, 20.0 Hz), 3.86 (d, 1H, J=20.0 Hz), 4.02–4.15
(m, 3H), 5.75 (ddd, 1H, J=2.9, 4.4, 12.5 Hz), 6.42 (d,
1H, J=12.5 Hz), 6.63 (dd, 1H, J=3.2, 8.0 Hz), 6.73 (d,
1H, J=3.2 Hz), 6.95 (d, 1H, J=8.0 Hz), 6.84 (d, 1H,
J=2.2 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.97 (dd, 1H,
J=2.2, 8.0 Hz), 7.22 (d, 1H, J=8.0 Hz), 8.18 (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 31.4,
36.3, 36.6, 41.3, 53.2, 64.5, 65.7, 76.7, 114.6, 120.3,
122.3, 125.8, 128.9, 132.0, 132.8, 141.3, 150.1, 154.5,
163.9; IR (CHCl3) cmꢁ1: 2938, 1719, 1593, 1498, 1390,
Dimethylcarbamic
2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl ester hydro-
acid
1-[2-(4-nitrophenoxy)ethyl]-
.
chloride salt (20a HCl). This was prepared by the
1
method used for 6a. 20a. H NMR (400 MHz, CDCl3) d
ppm: 1.53–1.64 (m, 2H), 1.75–1.80 (m, 1H), 2.18–2.26

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4407
.
(m, 1H), 2.36–2.44 (m, 1H), 2.90 (dd, 1H, J=7.2, 12.4
Hz), 3.01 (s, 3H), 3.02–3.06 (m, 1H), 3.09 (s, 3H), 3.33
(dt, 1H, J=4.4, 14.0 Hz), 4.11 (dd, 1H, J=5.2, 10.4
Hz), 4.25 (dt, 1H, J=6.0, 9.6 Hz), 4.34 (q, 1H, J=7.6
Hz), 6.89 (dd, 1H, J=2.8, 8.0 Hz), 6.94 (d, 1H, J=2.8
Hz), 6.98 (d, 2H, J=9.6 Hz), 7.15 (d, 1H, J=8.0 Hz),
8.20 (d, 2H, J=9.6 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 30.1, 33.1, 35.3, 36.4, 50.3, 56.7, 66.7, 77.2, 114.5,
118.9, 123.2, 125.9, 126.1, 141.4, 143.6, 150.2, 154.9,
164.1; IR (CHCl3) cmꢁ1: 2934, 1713, 1593, 1512, 1498,
1390, 1342, 1264, 1172, 1111, 1019; HRMS calcd for
C21H26N3O5 (M+H)+ 400.1873, found 400.1870.
hydrochloride salt (21a HCl). This was prepared by the
method used for 9a.
1
21a. H NMR (400 MHz, CDCl3) d ppm: 1.60–1.80
(m, 2H), 2.10 (br s, 3H), 2.25–2.32 (m, 1H), 2.35–2.48
(m, 1H), 2.91 (br s, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.22–
3.33 (m, 1H), 4.10–4.30 (m, 4H), 6.88 (dd, 1H, J=2.4,
8.0 Hz), 6.93 (d, 1H, J=2.4 Hz), 6.96 (d, 2H, J=8.8
Hz), 7.08 (d, 1H, J=8.0 Hz), 8.18 (d, 2H, J=8.8 Hz);
13C NMR (100 MHz, CDCl3) d ppm: 30.4, 35.9, 36.4,
36.6, 66.7, 114.5, 118.7, 125.8, 141.3, 154.9, 164.1; IR
(CHCl3) cmꢁ1: 2934, 1713, 1593, 1512, 1498, 1390, 1343,
1265, 1173, 909; HRMS calcd for C22H28N3O5
(M+H)+ 414.2029, found 414.2042.
1
.
20a HCl. H NMR (400 MHz, CD3OD) d ppm: 1.90–
2.00 (m, 1H), 2.00–2.12 (m, 1H), 2.49–2.58 (m, 1H),
2.68–2.76 (m, 1H), 2.94 (s, 3H), 2.98–3.08 (m, 1H), 3.08
(s, 3H), 3.18 (dd, 1H, J=11.2, 13.2 Hz), 3.40–3.46 (m,
1H), 3.52–3.57 (m, 1H), 3.98–4.06 (m, 1H), 4.24 (dt, 1H,
J=4.8, 10.4 Hz), 6.95 (dd, 1H, J=2.0, 8.8 Hz), 7.02–
7.05 (m, 3H), 7.31 (d, 1H, J=8.8 Hz), 8.17, (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CD3OD) d ppm: 14.5,
20.8, 26.1, 30.4, 34.0, 36.7, 36.9, 61.5, 66.2, 115.9, 121.3,
125.5, 126.8, 131.7, 143.2, 144.6, 153.6, 156.4, 164.7; IR
(KBr) cmꢁ1: 2939, 1718, 1592, 1512, 1385, 1342, 1264,
1171, 1113, 1021; HRMS calcd for C21H26N3O5
(M+H)+ 400.1873, found 400.1870.
1
.
21a HCl. H NMR (400 MHz, CDCl3) d ppm: 2.00–
2.19 (m, 2H), 2.40 (br s, 1H), 2.55–2.68 (m, 1H), 2.68 (d,
3H, J=4.8 Hz), 2.86 (dd, 1H, J=4.8, 18.0 Hz), 3.02 (s,
3H), 3.09 (s, 3H), 3.12–3.28 (m, 1H), 3.35 (d, 1H,
J=16.4 Hz), 3.76–3.85 (m, 1H), 3.92–4.00 (m, 1H), 4.11
(dt, 1H, J=6.4, 10.4 Hz), 4.52 (d, 1H, J=9.2 Hz), 6.83
(d, 2H, J=9.6 Hz), 6.92–6.95 (m, 1H), 7.06–7.10 (m,
2H), 8.15 (d, 2H, J=9.6 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 21.0, 29.6, 33.9, 36.4, 36.7, 39.4, 51.1,
64.9, 68.2, 114.5, 120.5, 125.8, 127.6, 133.2, 141.3, 141.8,
152.5, 154.1, 162.9, 174.4; IR (CHCl3) cmꢁ1: 2966, 2310,
1722, 1594, 1391, 1343, 1259, 1172, 1111; HRMS calcd
for C22H28N3O5 (M+H)+ 414.2029, found 414.2048.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-
2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl ester hydro-
.
chloride salt (20b HCl). This was prepared by the
method used for 6a.
Dimethylcarbamic acid 1-[2-(4-chlorophenoxy)ethyl]-2-
methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl ester
.
hydrochloride salt (21b HCl). This was prepared by the
method used for 9a.
1
20b. H NMR (400 MHz, CDCl3) d ppm: 1.59–1.64
(m, 2H), 1.73–1.80 (m, 1H), 2.14–2.23 (m, 1H), 2.31–
2.39 (m, 1H), 2.90 (dd, 1H, J=8.0, 14.0 Hz), 3.01 (s,
3H), 3.04 (dt, 1H, J=3.6, 14.0 Hz), 3.09 (s, 3H), 3.32
(dt, 1H, J=4.4, 14.0 Hz), 4.07–4.13 (m, 2H), 4.18 (q,
1H, J=8.0 Hz), 6.84 (d, 2H, J=8.4 Hz), 6.86 (dd,
1H, J=2.8, 8.0 Hz), 6.92 (d, 1H, J=2.8 Hz), 7.15 (d,
1H, J=8.0 Hz), 7.22 (d, 2H, J=8.4 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 30.2, 33.3, 35.3, 36.4, 36.7,
50.3, 57.0, 66.1, 115.9, 118.8, 123.1, 125.4, 126.2,
129.2, 141.4, 143.6, 150.0, 155.0, 157.6; IR (CHCl3)
cmꢁ1: 2933, 1713, 1492, 1390, 1248, 1172; HRMS
calcd for C21H26N2O3Cl (M+H)+ 389.1632, found
389.1637.
1
21b. H NMR (400 MHz, CDCl3) d ppm: 1.60–1.78
(m, 2H), 2.10 (br s, 3H), 2.20–2.30 (m, 1H), 2.32–2.42
(m, 1H), 2.91 (br s, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.22–
3.32 (m, 1H), 3.96–4.20 (m, 4H), 6.82 (d, 2H, J=8.8
Hz), 6.87 (dd, 1H, J=2.0, 8.0 Hz), 6.91 (d, 1H, J=2.0
Hz), 7.08 (d, 1H, J=8.0 Hz), 7.21 (d, 2H, J=8.8 Hz);
13C NMR (100 MHz, CDCl3) d ppm: 22.1, 30.6, 35.9,
36.4, 36.6, 66.1, 115.8, 118.5, 123.5, 125.2, 129.2, 149.5,
154.9, 157.6; IR (CHCl3) cmꢁ1: 2933, 1712, 1492, 1390,
1247, 1172, 909; HRMS calcd for C22H28N2O3Cl
(M+H)+ 403.1788, found 403.1806.
1
.
21b HCl. H NMR (400 MHz, CDCl3) d ppm: 1.98–
1
.
20b HCl. H NMR (400 MHz, CDCl3) d ppm: 2.01–
2.17 (m, 2H), 2.41 (br s, 1H), 2.50–2.62 (m, 1H), 2.67 (d,
3H, J=4.4 Hz), 2.87 (d, 1H, J=14.0 Hz), 3.02 (s, 3H), 3.09
(s, 3H), 3.21 (t, 1H, J=14.0 Hz), 3.34 (d, 1H, J=14.0
Hz), 3.65–3.74 (m, 2H), 3.94 (dt, 1H, J=4.0, 9.2 Hz),
4.53 (d, 1H, J=10.8 Hz), 6.68 (d, 2H, J=8.8 Hz), 6.77 (d,
1H, J=8.4 Hz), 6.94 (dd, 1H, J=2.4, 8.4 Hz), 7.05 (d, 1H,
J=2.4 Hz), 7.17 (d, 2H, J=8.8 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 20.5, 21.0, 29.8, 33.8, 36.4, 36.7, 39.5, 51.1,
64.2, 68.3, 115.8, 120.3, 124.8, 126.0, 127.8, 129.3, 133.3,
141.2, 152.4, 154.2, 156.6, 174.6; IR (CHCl3) cmꢁ1: 2966,
2315, 1721, 1492, 1391, 1247, 1171; HRMS calcd for
C22H28N2O3Cl (M+H)+ 403.1788, found 403.1808.
2.20 (m, 2H), 2.52–2.61 (m, 1H), 2.78–2.88 (m, 1H),
2.90–3.00 (m, 1H), 2.99 (s, 3H), 3.02–3.11 (m, 1H), 3.08
(s, 3H), 3.25–3.40 (m, 2H), 3.93 (q, 1H, J=8.8 Hz), 4.11
(dt, 1H, J=4.4, 9.2 Hz), 4.77 (br s, 1H), 6.79 (d, 2H,
J=9.6 Hz), 6.96 (dd, 1H, J=2.4, 8.8 Hz), 6.99 (d, 1H,
J=2.4 Hz), 7.19, (d, 2H, J=9.6 Hz), 7.22 (d, 1H, J=8.8
Hz), 9.84 (br s, 1H), 9.91 (br s, 1H); 13C NMR
(100 MHz, CDCl3) d ppm: 24.0, 30.6, 32.2, 36.4, 36.7,
44.3, 57.7, 64.2, 115.9, 120.1, 123.8, 126.0, 129.3, 129.4,
130.3, 141.2, 152.0, 154.4, 156.8; IR (CHCl3) cmꢁ1:2965,
2724, 1720, 1492, 1390, 1248, 1171; HRMS calcd for
C21H26N2O3Cl (M+H)+ 389.1632, found 389.1645.
7-Dimethylcarbamoyloxy-1-(2-hydroxyethyl)-5-oxo-1,3,4,
5-tetrahydrobenzo[c]azepine-2-carboxylic acid tert-butyl
ester (22). To a solution of 16b (3.07 g, 8.16 mmol) in
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yl
ester

4408
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
THF (20 mL) was added a solution of BH3 in THF
(10.8 mL, 16.3 mmol) at 0 ꢀC. After stirring for 12 h at
room temperature, another solution of BH3 in THF
(10.8 mL, 16.3 mmol) was added at 0 ꢀC and stirred for
3 h at room ꢀtemperature. After quenching with water
NMR (125 MHz, CDCl3) d ppm: 29.0, 36.6, 37.1, 37.4,
39.1, 39.8, 44.5, 57.5, 57.9, 65.7, 66.2, 81.6, 115.0, 123.3,
126.0, 126.6, 131.1, 131.5, 136.1, 140.4, 142.3, 152.0,
154.9, 155.3, 164.2, 203.9; IR (CHCl3) cmꢁ1: 2979, 1724,
1686, 1594, 1514, 1392, 1342, 1263, 1161, 1112, 1031,
846; HRMS calcd for C26H31N3O8Na (M+Na)+
536.2009, found 536.2009.
.
(20 mL) at 0 C, NaBO3 4H2O (12.3 g, 80.0 mmol) was
added to the reaction mixture at 0 ꢀC and stirred for 2 h
at room temperature. The organic solvent was evapo-
rated and water (20 mL) was added. The product was
extracted with AcOEt (40 mLꢂ2) and washed with
brine (30 mL). Then it was dried over Na2SO4, filtered
and evaporated. Purification by silica gel column chro-
matography (AcOEt to AcOEt–MeOH 5:1) provided a
regioisomeric mixture of an alcohol (2.65 g) as a color-
less oil. To a solution of this mixture of alcohol (2.65 g)
in CH2Cl2 (30 mL) was added manganese oxide (7.95 g)
at room temperature. The reaction mixture was stirred
for 2 h at room temperature. After filtration through a
Celite pad, the solvent was removed in vacuo. Purifica-
tion by silica gel column chromatography (hexane–
AcOEt 1:1 to AcOEt) gave 22 (1.87 g, 58% for two
steps) as a colorless oil. 1H NMR (500 MHz, CD3OD) d
ppm: 1.34–1.48 (br, 9H), 2.94 (br s, 2H), 2.98 (s, 3H),
3.11 (s, 3H), 3.44–3.54 (m, 2H), 3.73 (br, 1H), 3.96 (br,
1H), 5.38 (br, 0.5H), 5.49 (br, 0.5H), 7.23–7.25 (m, 2H),
7.38 (br s, 1H); 13C NMR (125 MHz, CD3OD) d ppm:
28.5, 36.7, 36.9, 39.3, 39.8, 44.8, 57.4, 58.0, 59.3, 81.9,
123.2, 126.0, 131.3, 131.7, 139.0, 141.0, 152.0, 156.1,
156.6, 204.6; IR (CHCl3) cmꢁ1: 3439, 2980, 1722, 1681,
1478, 1410, 1392, 1257, 1161, 1055, 888; HRMS calcd
for C20H28N2O6Na (M+Na)+ 415.1845, found
415.1849.
Dimethylcarbamic acid 2-methyl-5-methylene-1-[2-(4-ni-
trophenoxy)ethyl]-2,3,4,5-tetrahydro-1H-benzo[c]azepin-
7-yl ester hydrochloride salt (24 HCl). To a solution of
.
23 (435 mg, 0.848 mmol) and Ph3P+CH3Brꢁ (607 mg,
1.70 mmol) in benzene (5 mL) was added a solution of
t-BuOK in THF (1.70 mL, 1.0 M) at 80 ꢀC. The mixture
was stirred for 1 h at 80 ꢀC. After quenching with water
(10 mL), the product was extracted with AcOEt (10
mLꢂ2) and washed with brine (10 mL), dried over
Na2SO4, filtered and evaporated. Purification by silica
gel column chromatography (hexane–AcOEt 2:1–1:1)
gave an exo methylene compound (106 mg, 24%) as a
colorless oil. 1H NMR (500 MHz, CD3OD) d ppm: 1.35
(s, 9H), 2.29–2.61 (m, 4H), 2.98 (s, 3H), 3.10 (s, 3H),
3.40–3.51 (m, 1H), 3.97–4.04 (m, 2H), 4.16 (br d, 1H,
J=13.5 Hz), 5.15 (s, 1H), 5.25 (s, 1H), 5.34 (br t, 0.5H,
J=7.5 Hz), 5.43 (br t, 0.5H, J=7.5 Hz), 6.92–6.98 (m,
2H), 7.05 (d, 2H, J=9.0 Hz), 7.17 (d, 0.5H, J=8.0 Hz),
7.22 (d, 0.5H, J=8.0 Hz), 8.17–8.21 (m, 2H); 13C NMR
(125 MHz, CD3OD) d ppm: 26.6, 32.6, 36.7, 36.8, 38.3,
38.9, 44.5, 57.8, 58.6, 66.5, 66.7, 81.4, 81.7, 115.7, 116.7,
117.8, 121.3, 124.0, 126.7, 126.8, 127.1, 130.9, 131.5,
136.5, 136.6, 142.8, 144.3, 144.5, 150.4, 152.0, 156.6,
157.0, 165.3; IR (film) cmꢁ1: 2975, 1723, 1690, 1593, 1514,
1390, 1340, 1263, 1163, 1020, 846, 753; HRMS calcd for
C27H33N3O7Na (M+Na)+ 534.2216, found 534.2224.
7-Dimethylcarbamoyloxy-1-[2-(4-nitrophenoxy)ethyl]-5-
oxo-1,3,4,5-tetrahydrobenzo[c]azepine-2-carboxylic acid
tert-butyl ester (23). N-Boc-deprotected 23 was pre-
pared by the method used for 6a.
Compound 24 was prepared by the method used for 9a
from the above compound.
1
N-Boc-deprotected 23. H NMR (500 MHz, CDCl3) d
24. 1H NMR (400 MHz, CDCl3) d ppm: 2.29–2.43 (m,
2H), 2.36 (s, 3H), 2.64 (br, 1H), 2.96–3.05 (m, 2H), 3.01
(s, 3H), 3.09 (s, 3H), 3.36–3.42 (m, 1H), 3.93–3.96 (m,
2H), 4.02–4.07 (m, 1H), 5.07 (d, 1H, J=1.6 Hz), 5.12 (s,
1H), 6.89 (d, 2H, J=8.8 Hz), 6.92 (dd, 1H, J=2.4, 8.0
Hz), 7.00 (d, 1H, J=2.4 Hz), 7.04 (d, 1H, J=8.0 Hz),
8.17 (d, 2H, J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d
ppm: 31.6, 32.1, 36.4, 36.7, 40.0, 52.1, 64.9, 66.2, 114.3,
115.4, 119.8, 122.2, 125.6, 129.8, 134.4, 141.1, 143.6,
149.8, 150.4, 154.5, 163.7; IR (CHCl3) cmꢁ1: 2934, 1714,
1593, 1512, 1390, 1343, 1264, 1171, 1112, 1020, 909;
HRMS calcd for C23H28N3O5 (M+H)+ 426.2029,
found 426.2008.
ppm: 2.22–2.29 (m, 1H), 2.31–2.38 (m, 1H), 2.82–2.92
(m, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.18 (t, 2H, J=5.5
Hz), 4.09 (dt, 1H, J=6.0, 9.5 Hz), 2.25 (dt, 1H, J=6.0,
8.5 Hz), 4.40 (dd, 1H, J=5.0, 8.0 Hz), 6.92 (d, 2H,
J=9.0 Hz), 7.26 (s, 2H), 7.32 (s, 1H), 8.18 (d, 2H,
J=9.0 Hz); 13C NMR (125 MHz, CDCl3) d ppm: 35.0,
36.4, 36.7, 40.7, 44.7, 56.2, 65.7, 114.4, 121.6, 125.1,
125.8, 127.6, 138.0, 140.4, 141.5, 150.7, 154.4, 163.7,
204.7; IR (CHCl3) cmꢁ1: 2941, 1720, 1594, 1514, 1499,
1390, 1342, 1263, 1171, 1111, 909; HRMS calcd for
C21H24N3O6 (M+H)+ 414.1665, found 414.1659.
To a solution of the above N-Boc-deprotected 23 (1.22
g, 2.95 mmol) and Et3N (0.840 mL, 6.00 mmol) in THF
(20 mL) was added Boc2O (964 mg, 4.42 mmol) at room
temperature. The mixture was stirred for 1 h at room
temperature. The solvent was concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (hexane–AcOEt 2:1–1:2) to give 23 (1.20 g,
1
.
24 HCl. H NMR (500 MHz, CD3OD) d ppm: 2.49–
2.94 (m, 4H), 2.91 (s, 3H), 2.99 (s, 3H), 3.11 (s, 3H),
3.45–3.59 (m, 1.5H), 3.76–3.95 (m, 1.5H), 4.08–4.14 (m,
1H), 4.77–4.80 (m, 1H), 5.30 (s, 0.5H), 5.33 (s, 0.5H),
5.46 (s, 0.5H), 5.47 (s, 0.5H), 6.97 (d, 2H, J=9.0 Hz),
7.04 (dd, 0.5H, J=3.0, 8.0 Hz), 7.09 (d, 0.5H, J=8.0
Hz), 7.14 (d, 1H, J=3.0 Hz), 7.31 (d, 0.5H, J=8.0 Hz),
7.39 (br s, 0.5H), 8.17 (d, 2H, J=9.0 Hz); 13C NMR
(125 MHz, CD3OD) d ppm: 27.4, 30.3, 32.0, 36.7, 36.9,
40.1, 51.9, 54.5, 65.6, 68.8, 115.8, 119.4, 120.1, 122.4,
122.5, 124.0, 124.6, 126.6, 126.7, 134.4, 142.9, 144.7,
1
79%) as a colorless oil. H NMR (500 MHz, CDCl3) d
ppm: 1.42 (s, 9H), 2.13 (br, 1H), 2.43–2.50 (m, 1H), 2.95
(br, 2H), 3.01 (s, 3H), 3.09 (s, 3H), 3.86–4.01 (br, 4H),
5.43 (br, 0.5H), 5.61 (br, 0.5H), 6.88 (d, 2H, J=8.5 Hz),
7.21 (br, 2H), 7.36 (s, 1H), 8.17 (d, 2H, J=8.5 Hz); 13C

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4409
145.4, 146.0, 146.6, 154.1, 156.0, 164.6; IR (KBr) cmꢁ1
3426, 2932, 2454, 1724, 1591, 1511, 1387, 1341, 1261,
1200, 1169, 1110, 850, 753; HRMS calcd for
C23H28N3O5 (M+H)+ 426.2029, found 426.2029.
:
1H NMR (500 MHz, CDCl3) d ppm: 2.15 (s, 3H), 2.18
(br, 1H), 2.27–2.33 (m, 1H), 2.38–2.45 (m, 1H), 3.01 (s,
3H), 3.04 (dd, 1H, J=6.0, 15.0 Hz), 3.11 (s, 3H), 3.27
(dd, 1H, J=6.0, 15.0 Hz), 3.96 (dd, 1H, J=5.5, 9.0 Hz),
4.15 (dt, 1H, J=5.5, 10.0 Hz), 4.22 (dt, 1H, J=6.5, 10.0
Hz), 5.98 (t, 1H, J=6.0 Hz), 6.93 (d, 2H, J=9.0 Hz),
7.03 (dd, 1H, J=2.0, 8.0 Hz), 7.13 (d, 1H, J=2.0 Hz),
7.27 (d, 1H, J=8.0 Hz), 8.16 (d, 2H, J=9.0 Hz); 13C
NMR (125 MHz, CDCl3) d ppm: 22.8, 32.7, 36.3, 36.5,
44.5, 53.8, 66.6, 114.3, 119.9, 120.2, 125.7, 126.2, 127.2,
137.2, 137.6, 141.2, 142.1, 150.4, 154.7, 163.8; IR
(CHCl3) cmꢁ1: 2947, 1714, 1593, 1513, 1391, 1342, 1263,
1173, 1111, 1018, 909, 846.
7-Dimethylcarbamoyloxy-1-[2-(4-nitrophenoxy)ethyl]-5-
trifluoromethanesulfonyloxy-1,3-dihydrobenzo[c]azepine-
2-carboxylic acid tert-butyl ester (25). To a solution of
compound 23 (1.04 g, 2.02 mmol) in THF (10 mL) was
added a solution of LHMDS in THF (2.43 mL, 1.0 M)
at ꢁ78 ꢀC and the mixture was stirred for 30 min at
ꢁ78 ꢀC. To the reaction mixture was added 2-[N,N-bis
(trifluoromethylsulfonyl)amino]-5-chloropyridine (1.19
g, 3.03 mmol) at ꢁ78 ꢀC. The resulting mixture was
stirred for 1 h at ꢁ78 ꢀC. After quenching with water
(10 mL) at ꢁ78 ꢀC, the product was extracted with
AcOEt (20 mLꢂ2) and washed with water (10 mL).
Then it was dried over Na2SO4, filtered and evaporated.
Purification by silica gel column chromatography (hex-
ane–AcOEt 5:1 to 1:1) gave 25 (1.28 g, 98%) as a col-
orless oil. 1H NMR (400 MHz, CD3OD) d ppm: 1.25 (s,
9H), 2.35 (br, 1H), 2.53 (br, 1H), 2.93 (s, 3H), 3.06 (s,
3H), 3.93–4.24 (br, 3H), 5.24–5.23 (br, 1H), 6.27 (br s,
1H), 6.99 (d, 2H, J=8.8 Hz), 7.05–7.12 (m, 1H), 7.27–
7.30 (m, 2H), 8.13 (d, 2H, J=8.8 Hz); 13C NMR
(125 MHz, CD3OD) d ppm: 28.4, 30.3, 36.7, 36.9, 42.8,
57.6, 58.3, 66.6, 82.3, 115.8, 121.5, 121.7, 123.8, 126.0,
126.8, 131.9, 132.4, 137.7, 138.2, 142.9, 144.9, 145.1, 152.5,
156.0, 156.3, 165.1; IR (CHCl3) cmꢁ1: 2979, 1724, 1691,
1594, 1514, 1498, 1414, 1392, 1342, 1262, 1170, 1140, 1113,
991, 859; HRMS calcd for C27H30N3O10F3SNa
(M+Na)+ 668.1502, found 668.1498.
Compound 26a was prepared by the method used for 9a
from the above compound.
1
26a. H NMR (500 MHz, CDCl3) d ppm: 2.11–2.18
(m, 1H), 2.14 (s, 3H), 2.29 (s, 1H), 2.31–2.37 (m, 1H),
2.88 (d, 2H, J=6.0 Hz), 3.02 (s, 3H), 3.11 (s, 3H), 3.83
(t, 1H, J=7.5 Hz), 3.98 (dt, 1H, J=5.5, 9.0 Hz), 4.08–
4.13 (m, 1H), 5.95 (t, 1H, J=6.0 Hz), 6.90 (d, 2H,
J=9.0 Hz), 7.01 (dd, 1H, J=2.0, 8.0 Hz), 7.15 (d, 1H,
J=2.0 Hz), 7.17 (d, 1H, J=8.0 Hz), 8.16 (d, 2H, J=9.0
Hz); 13C NMR (125 MHz, CDCl3) d ppm: 22.4, 32.2,
36.3, 36.6, 42.1, 52.8, 63.1, 66.5, 114.4, 120.2, 125.7,
129.8, 134.7, 138.3, 141.1, 141.2, 150.6, 154.7, 163.9; IR
(CHCl3) cmꢁ1: 2942, 1714, 1593, 1512, 1498, 1390, 1342,
1264, 1172, 1112, 1024, 909, 846; HRMS calcd for
C23H27N3O5Na (M+Na)+ 448.1848, found 448.1861.
1
.
26a HCl. H NMR (500 MHz, CD3OD) d ppm: 2.22
(s, 3H), 2.60–2.85 (br, 2H), 2.75 (s, 3H), 2.99 (s, 3H),
3.02 (br s, 1H), 3.11 (s, 3H), 3.62 (br, 0.5H), 3.81 (br,
0.5H), 3.83 (br, 0.5H), 4.04 (br, 0.5H), 4.11 (br, 0.5H),
4.27 (br, 0.5H), 4.57 (br, 0.5H), 4.69 (br, 0.5H), 6.11 (br
s, 1H), 6.90 (br, 1H), 6.96 (br, 1H), 7.15 (br, 0.5H), 7.30
(br, 0.5H), 7.35 (s, 1H), 7.55 (br, 0.5H), 7.78 (br, 0.5H),
8.08 (br s, 2H); 13C NMR (125 MHz, CD3OD) d ppm:
21.7, 28.0, 35.5, 36.7, 36.9, 43.5, 52.5, 53.4, 59.1, 66.5,
115.8, 120.1, 121.8, 122.6, 123.3, 126.7, 129.9, 130.8,
134.0, 142.8, 145.0, 148.0, 154.2, 156.0, 164.7; IR
(CHCl3) cmꢁ1: 2967, 2336, 1725, 1594, 1514, 1498, 1391,
1260, 1171, 1112, 846; HRMS calcd for C23H28N3O5
(M+H)+ 426.2029, found 426.2009.
Dimethylcarbamic acid 2,5-dimethyl-1-[2-(4-nitrophenoxy)-
ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydro-
.
chloride salt (26a HCl). To a solution of 25 (300 mg,
0.465 mmol) in DMF (5 mL) were added Pd(PPh3)4 (27
mg, 0.023 mmol), LiCl (59.3 mg, 1.40 mmol) and Me4Sn
(77 mL, 0.56 mmol). The reaction mixture was stirred
for 4 h at 100 ꢀC. After adding water (10 mL), the mix-
ture was extracted with AcOEt (10 mLꢂ2). The com-
bined organic layers were washed with water (10 mL)
and brine (10 mL), dried over Na2SO4, filtered and
evaporated in vacuo. Purification by silica gel column
chromatography (hexane–AcOEt 5:1 to 1:1) gave a
1
related compound (153 mg, 64%) as a colorless oil. H
NMR (500 MHz, CD3OD) d ppm: 1.44 (s, 9H), 2.13 (s,
3H), 2.17 (br, 1H), 2.42 (br, 1H), 2.97 (s, 3H), 3.08 (s,
3H), 3.36–3.52 (br, 1H), 3.78 (br, 1H), 3.92 (br, 1H),
4.27 (dd, 1H, J=6.0, 15.0 Hz), 5.17–5.25 (br, 1H), 5.93
(t, 1H, J=6.0 Hz), 6.88 (br s, 2H), 6.96 (d, 1H, J=8.0
Hz), 7.18 (s, 1H), 7.22 (d, 1H, J=8.0 Hz), 8.08 (br s,
2H); 13C NMR (125 MHz, CD3OD) d ppm: 22.7,
23.2, 34.1, 36.7, 36.9, 43.1, 59.8, 67.1, 67.4, 81.5,
115.6, 121.8, 122.0, 122.3, 125.1, 126.0, 126.6, 132.4,
132.7, 136.5, 139.5, 141.3, 142.5, 152.5, 155.5, 156.3,
165.1; IR (CHCl3) cmꢁ1: 2979, 1716, 1676, 1593,
1512, 1391, 1342, 1263, 1168, 1298, 1020, 846;
HRMS calcd for C27H33N3O7Na (M+Na)+
534.2217, found 534.2213.
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-5-vinyl-2,3-dihydro-1H-benzo[c]azepin-7-yl
ester
hydrochloride salt (26b HCl). To a solution of 25 (100
mg, 0.155 mmol) in NMP (5 mL) were added
.
.
Pd2(dba)3 CHCl3 (3.9 mg, 0.0038 mmol), Ph3As (4.7
mg, 0.015 mmol), LiCl (20.0 mg, 0.464 mmol) and
(CH2¼CH)(n-Bu)3Sn (54 mL, 0.19 mmol). The reaction
mixture was stirred for 2 h at room temperature. After
adding saturated aq KF (10 mL), the mixture was
extracted with AcOEt (10 mLꢂ2). The combined
organic layers were washed with brine (10 mL), dried
over Na2SO4, filtered and evaporated. Purification by
preparative TLC (hexane–AcOEt 2:1) gave a related
1
compound (53 mg, 65%) as a colorless oil. H NMR
(500 MHz, CD3OD) d ppm: 1.47 (s, 9H), 2.15 (br, 1H),
2.35 (br, 1H), 2.98 (s, 3H), 3.10 (s, 3H), 3.20 (dd, 1H,
J=7.5, 13.5 Hz), 3.72–3.80 (br, 1H), 3.92 (br, 1H), 4.45
The above compound was deprotected by the method
used for 6a.

4410
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
(br, 1H), 5.22 (br, 1H), 5.26 (d, 1H, J=10.5 Hz), 5.35
(d, 1H, J=17.5 Hz), 6.16 (t, 1H, J=8.0 Hz), 6.63 (dd,
1H, J=10.5, 17.5 Hz), 6.89 (d, 2H, J=8.5 Hz), 7.03 (dd,
1H, J=2.0, 8.0 Hz), 7.16 (d, 1H, J=2.0 Hz), 7.30 (d,
1H, J=8.0 Hz), 8.11 (d, 2H, J=8.5 Hz); 13C NMR
(125 MHz, CD3OD) d ppm: 28.7, 34.7, 36.7, 36.9, 41.6,
42.3, 60.2, 67.3, 81.7, 115.6, 118.3, 122.7, 124.5, 126.7,
127.3, 133.3, 136.7, 138.1, 142.6, 145.3, 152.2, 155.4,
156.4, 165.2; IR (CHCl3) cmꢁ1: 2979, 1718, 1678, 1593,
1513, 1391, 1342, 1262, 1168, 1112, 1025, 846; HRMS
calcd for C28H33N3O7Na (M+Na)+ 546.2216, found
546.2203.
1343, 1259, 1171, 1112, 908; HRMS calcd for
C24H28N3O5 (M+H)+ 438.2029, found 438.2027.
Dimethylcarbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-5-thiophen-2-yl-2,3-dihydro-1H-benzo[c]azepin-7-yl
.
ester hydrochloride salt (26c HCl). To a solution of 25
(300 mg, 0.465 mmol) in 1,4-dioxane (5 mL) were added
Pd(PPh3)4 (40 mg, 0.034 mmol), K3PO4 (218 mg, 1.03
mmol) and 2-thienylboronic acid (96 mg, 0.75 mmol).
The reaction mixture was stirred for 6 h at 85 ꢀC. After
adding water (10 mL), the mixture was extracted with
AcOEt (10 mLꢂ2). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, filtered
and evaporated in vacuo. Purification by silica gel col-
umn chromatography (hexane–AcOEt 5:1–2:1) gave the
corresponding compound (62 mg, 16%) as a colorless
The above compound was deprotected by the method
used for 6a.
1H NMR (500 MHz, CDCl3) d ppm: 2.29–2.36 (m, 1H),
2.41–2.48 (m, 1H), 2.93 (dd, 1H, J=7.0, 13.5 Hz), 3.01
(s, 3H), 3.10 (s, 3H), 3.26 (dd, 1H, J=7.0, 13.5 Hz), 3.92
(t, 1H, J=7.0 Hz), 4.14 (dt, 1H, J=6.0, 10.0 Hz), 4.21
(dt, 1H, J=7.0, 8.5 Hz), 5.23 (d, 1H, J=11.0 Hz), 5.36
(d, 1H, J=17.5 Hz), 6.18 (t, 1H, J=7.0 Hz), 6.57 (dd,
1H, J=11.0, 17.5 Hz), 6.93 (d, 2H, J=9.0 Hz), 7.11 (dd,
1H, J=2.0, 9.0 Hz), 7.16 (d, 1H, J=2.0 Hz), 7.36 (d,
1H, J=9.0 Hz), 8.16 (d, 2H, J=9.0 Hz); 13C NMR
(125 MHz, CDCl3) d ppm: 32.9, 36.4, 36.6, 42.9, 52.9,
66.7, 114.4, 116.8, 121.0, 122.0, 125.8, 126.3, 128.2,
136.8, 137.1, 138.8, 141.3, 142.4, 150.2, 154.7, 163.8; IR
(CHCl3) cmꢁ1: 2939, 1717, 1593, 1513, 1390, 1342, 1263,
1390, 1112, 1019, 846.
oil. H NMR (500 MHz, CD3OD) d ppm: 1.49 (s, 9H),
1
2.26 (br, 1H), 2.39 (br, 1H), 2.97 (s, 3H), 3.08 (s, 3H),
3.25 (br, 1H), 3.81 (br, 1H), 3.98 (br, 1H), 4.53 (br, 1H),
5.32 (br, 1H), 6.44 (t, 1H, J=7.5 Hz), 6.92 (d, 2H,
J=8.0 Hz), 7.02 (s, 1H), 7.02–7.04 (m, 1H), 7.09 (dd,
1H, J=2.0, 8.0 Hz), 7.12 (d, 1H, J=2.0 Hz), 7.36 (d,
1H, J=8.0 Hz), 7.40 (d, 1H, J=5.0 Hz), 8.13 (d, 2H,
J=8.0 Hz); 13C NMR (125 MHz, CD3OD) d ppm: 28.7,
35.0, 36.7, 36.9, 41.6, 42.3, 60.4, 67.4, 81.7, 115.7, 123.3,
123.8, 124.8, 126.7, 126.9, 127.8, 128.7, 133.2, 136.9,
139.9, 141.0, 142.6, 144.4, 152.4, 155.3, 156.2, 165.1; IR
(CHCl3) cmꢁ1: 2979, 1719, 1676, 1593, 1512, 1392, 1342,
1263, 1166, 1112, 1024; HRMS calcd for
C30H33N3O7SNa (M+Na)+ 602.1937, found 602.1924.
Compound 26b was prepared by the method used for 9a
from the above compound.
The above compound was deprotected by the method
used for 6a.
1
26b. H NMR (400 MHz, CDCl3) d ppm: 2.11–2.20
1H NMR (500 MHz, CDCl3) d ppm: 2.35–2.41 (m, 1H),
2.46–2.52 (m, 1H), 2.57 (br, 1H), 2.96 (dd, 1H, J=7.0,
13.5 Hz), 2.99 (s, 3H), 3.07 (s, 3H), 3.31 (dd, 1H, J=7.0,
13.5 Hz), 4.06 (dd, 1H, J=6.0, 8.0 Hz), 4.15 (dt, 1H,
J=5.5, 10.0 Hz), 4.23 (dt, 1H, J=6.5, 10.0 Hz), 6.50 (t,
1H, J=7.0 Hz), 6.91 (d, 2H, J=9.0 Hz), 6.95 (d, 1H,
J=5.0 Hz), 7.16 (dd, 1H, J=2.0, 8.0 Hz), 7.18 (s, 1H),
7.24 (d, 1H, J=5.0 Hz), 7.41 (d, 1H, J=8.0 Hz), 8.15
(d, 2H, J=9.0 Hz); 13C NMR (125 MHz, CDCl3) d
ppm: 33.0, 36.3, 36.6, 42.9, 53.1, 66.7, 114.4, 121.7,
122.4, 124.9, 125.7, 126.3, 126.4, 127.4, 137.1, 138.1,
140.4, 141.4, 143.8, 150.4, 154.6, 163.8; IR (CHCl3)
cmꢁ1: 2939, 1719, 1593, 1513, 1391, 1342, 1263, 1171,
1112, 909; HRMS calcd for C25H26N3O5S (M+H)+
480.1594, found 480.1587.
(m, 1H), 2.30 (s, 3H), 2.32–2.39 (m, 1H), 2.73 (dd, 1H,
J=7.2, 11.6 Hz), 2.82 (dd, 1H, J=7.2, 11.6 Hz), 3.02 (s,
3H), 3.10 (s, 3H), 3.79 (t, 1H, J=7.2 Hz), 3.95 (dt, 1H,
J=6.4, 8.8 Hz), 4.12 (dt, 1H, J=6.4, 9.6 Hz), 5.24 (d,
1H, J=10.8 Hz), 5.36 (d, 1H, J=17.6 Hz), 6.16 (t, 1H,
J=7.6 Hz), 6.57 (dd, 1H, J=10.8, 17.6 Hz), 6.90 (d, 2H,
J=8.8 Hz), 7.08 (dd, 1H, J=2.4, 8.0 Hz), 7.20 (d, 1H,
J=2.4 Hz), 7.23 (d, 1H, J=8.0 Hz), 8.16 (d, 2H, J=8.8
Hz); 13C NMR (125 MHz, CDCl3) d ppm: 32.6, 36.4,
36.6, 42.3, 52.3, 62.4, 66.6, 114.4, 117.1, 120.8, 122.4,
125.8, 127.2, 129.8, 134.5, 136.7, 137.7, 141.3, 143.5,
150.3, 154.6, 164.0; IR (CHCl3) cmꢁ1: 2943, 1717, 1593,
1512, 1390, 1342, 1264, 1172, 1112, 1022, 909; HRMS
calcd for C24H28N3O5 (M+H)+ 438.2029, found
438.2027.
Compound 26c was prepared by the method used for 9a
from the above compound.
1
.
26b HCl. H NMR (500 MHz, CDCl3) d ppm: 2.55–
2.70 (br, 4H), 2.91 (br s, 2H), 3.03 (s, 3H), 3.08–3.22 (m,
1H), 3.12 (s, 1H), 3.72–3.91 (m, 1H), 4.23 (br, 1H), 4.32
(br, 0.5H), 4.67 (br, 0.5H), 5.34–5.47 (m, 2H), 6.28–6.31
(m, 1H), 6.58–6.65 (m, 1H), 6.81 (d, 1H, J=9.0 Hz),
6.88 (d, 1H, J=9.0 Hz), 7.17–7.31 (m, 2H), 7.33 (d,
0.5H, J=9.0 Hz), 7.58 (d, 0.5H, J=9.0 Hz), 8.13 (d, 2H,
J=9.0 Hz); 13C NMR (125 MHz, CDCl3) d ppm: 27.0,
34.3, 36.4, 36.7, 51.2, 52.0, 56.6, 65.1, 65.3, 114.3, 114.5,
120.0, 121.1, 122.5, 122.6, 123.2, 125.8, 128.2, 134.9,
139.4, 141.7, 147.0, 152.4, 152.6, 153.9, 162.9, 163.0; IR
(CHCl3) cmꢁ1: 2968, 2337, 1725, 1594, 1515, 1498, 1391,
1
26c. H NMR (500 MHz, CDCl3) d ppm: 2.17–2.24
(m, 1H), 2.34 (s, 3H), 2.35–2.42 (m, 1H), 2.75–2.84 (m,
2H), 2.99 (s, 3H), 3.07 (s, 3H), 3.87 (t, 1H, J=8.0 Hz),
3.97 (dt, 1H, J=6.5, 9.0 Hz), 4.14 (dt, 1H, J=5.5, 9.0
Hz), 6.46 (t, 1H, J=7.0 Hz), 6.88 (d, 2H, J=8.5 Hz),
6.96 (d, 1H, J=5.0 Hz), 7.01 (t, 1H, J=5.0 Hz), 7.13
(dd, 1H, J=2.0, 7.5 Hz), 7.20 (d, 1H, J=2.0 Hz), 7.24–
7.28 (m, 2H), 8.15 (d, 2H, J=8.5 Hz); 13C NMR
(125 MHz, CDCl3) d ppm: 32.8, 36.3, 36.6, 42.4, 52.3,
62.8, 66.6, 114.4, 121.4, 122.8, 124.1, 125.1, 125.7, 126.3,

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4411
1
127.5, 129.8, 134.9, 139.1, 139.3, 141.2, 143.7, 150.5,
154.5, 163.9; IR (CHCl3) cmꢁ1: 2943, 1719, 1593, 1512,
1390, 1342, 1263, 1171, 1112, 1023, 909; HRMS calcd
for C26H28N3O5S (M+H)+ 494.1750, found 494.1748.
26d. H NMR (500 MHz, CDCl3) d ppm: 2.14–2.19
(m, 1H), 2.34 (m, 1H), 2.35 (s, 3H), 2.87 (d, 2H, J=7.0
Hz), 2.97 (s, 3H), 3.03 (s, 3H), 3.87 (t, 1H, J=8.0 Hz),
4.01 (dt, 1H, J=6.0, 10.0 Hz), 4.18 (dt, 1H, J=7.0, 10.0
Hz), 6.35 (t, 1H, J=6.5 Hz), 6.81 (d, 1H, J=3.0 Hz),
6.91 (d, 2H, J=8.5 Hz), 7.10 (dd, 1H, J=3.0, 8.0 Hz),
7.22 (d, 2H, J=8.5 Hz), 7.27 (d, 1H, J=8.0 Hz), 7.32
(d, 2H, J=8.5 Hz), 8.17 (d, 2H, J=8.5 Hz); 13C NMR
(125 MHz, CDCl3) d ppm: 32.9, 36.3, 36.6, 42.7, 52.7,
63.2, 66.5, 114.4, 121.3, 122.9, 125.7, 126.3, 128.6, 129.4,
130.0, 133.7, 135.8, 139.2, 139.6, 141.3, 144.5, 150.5,
154.5, 163.9; IR (CHCl3) cmꢁ1: 2943, 1720, 1593, 1512,
1391, 1342, 1263, 1171, 1112, 1015, 909; HRMS calcd
for C28H29N3O5Cl (M+H)+ 522.1796, found 522.1784.
1
.
26c HCl. H NMR (400 MHz, CD3OD) d ppm: 2.62–
2.89 (m, 2H), 2.73 (s, 3H), 2.92 (s, 3H), 3.05 (s, 3H), 3.32
(br, 0.5H), 3.88 (br, 0.5H), 3.91–4.09 (m, 2H), 4.29–4.32
(m, 1H), 4.66–4.78 (m, 1H), 6.46–6.52 (m, 1H), 6.85–
6.88 (m, 2H), 6.94 (d, 0.5H, J=2.8 Hz), 6.98 (dd, 0.5H,
J=3.6, 5.2 Hz), 7.03 (dd, 0.5H, J=3.6, 5.2 Hz), 7.08 (d,
0.5H, J=2.8 Hz), 7.21–7.24 (m, 1H), 7.38 (dd, 1H,
J=2.0, 8.8 Hz), 7.45 (d, 0.5H, J=5.2 Hz), 7.47 (d, 0.5H,
J=5.2 Hz), 7.61 (br, 0.5H), 7.85 (d, 0.5H, J=8.8 Hz),
8.02–8.06 (m, 2H); 13C NMR (100 MHz, CD3OD) d
ppm: 28.0, 35.4, 36.7, 36.9, 52.6, 53.5, 58.9, 60.0, 66.4,
66.8, 115.6, 117.7, 124.1, 124.4, 126.5, 128.6, 128.8,
128.9, 129.5, 130.5, 142.0, 142.8, 144.3, 145.0, 153.8,
155.7, 164.3, 164.4; IR (CHCl3) cmꢁ1: 2968, 2317,
1726, 1594, 1514, 1391, 1343, 1259, 1169; HRMS
calcd for C26H28N3O5S (M+H)+ 494.1750, found
494.1737.
1
.
26d HCl. H NMR (500 MHz, CD3OD) d ppm: 2.68–
2.88 (m, 2H), 2.83 (s, 3H), 2.94 (s, 3H), 3.06 (s, 3H), 3.40
(br, 0.5H), 3.86 (br, 0.5H), 4.02–4.06 (m, 1H), 4.16–4.21
(m, 1H), 4.36–4.39 (m, 1H), 4.69–4.83 (br, 1H), 6.53–
6.60 (m, 1H), 6.94–6.97 (m, 4H), 7.25 (d, 1H, J=8.5
Hz), 7.33 (d, 1H, J=8.5 Hz), 7.39–7.42 (m, 2H), 7.68
(br, 0.5H), 7.93 (d, 0.5H, J=7.5 Hz), 8.09–8.11 (m, 2H);
13C NMR (125 MHz, CD3OD) d ppm: 27.9, 35.5, 36.7,
36.9, 52.6, 53.5, 59.2, 66.5, 66.9, 115.8, 120.7, 124.2,
124.5, 126.7, 126.8, 129.9, 130.1, 130.9, 136.3, 136.4,
138.3, 143.0, 143.3, 150.3, 150.8, 154.0, 154.1, 164.6,
164.7; IR (CHCl3) cmꢁ1: 2968, 2307, 1726, 1594, 1515,
1497, 1391, 1343, 1259, 1168, 1112; HRMS calcd for
C28H29N3O5Cl (M+H)+ 522.1796, found 522.1801.
Dimethylcarbamic acid 5-(4-chlorophenyl)-2-methyl-1-[2-
(4-nitrophenoxy)ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-
.
yl ester hydrochloride salt (26d HCl). The Suzuki cou-
pling was performed by the method used for 26c.
Coupling product. 1H NMR (400 MHz, CDCl3) d
ppm: 1.49 (s, 9H), 2.22 (br, 1H), 2.38–2.46 (m, 1H), 2.96
(s, 3H), 3.03 (s, 3H), 3.32 (dd, 1H, J=6.0, 13.2 Hz), 3.78
(br, 1H), 3.93 (br, 1H), 4.47–4.60 (br, 1H), 5.21–5.31
(br, 1H), 6.32 (t, 1H, J=7.2 Hz), 6.79 (br s, 2H), 6.82 (d,
1H, J=2.0 Hz), 7.05 (dd, 1H, J=2.0, 8.4 Hz), 7.23 (d,
2H, J=8.4 Hz), 7.24 (br, 1H), 7.33 (d, 2H, J=8.4 Hz),
8.15 (br s, 2H); 13C NMR (100 MHz, CDCl3) d ppm:
28.5, 34.1, 36.4, 36.6, 41.0, 58.8, 66.1, 80.1, 114.2, 121.8,
123.7, 124.4, 125.6, 128.5, 129.1, 131,6, 133.8, 135.8,
138.6, 138.9, 141.1, 144.4, 145.1, 150.7, 153.5, 154.1,
163.4; IR (CHCl3) cmꢁ1: 2979, 1721, 1677, 1593, 1513,
1392, 1342, 1262, 1168, 1111, 1015, 845.
3-(4-Benzyloxy-2-methoxymethoxyphenyl)acrylic
acid
ethyl ester (28). To a solution of 27 (44.9 g, 197 mmol)
in CH2Cl2 (200 mL) were added (i-Pr)2NH (52.0 mL,
300 mmol) and methoxymethyl chloride (20.5 mL, 270
mmol) at 0 ꢀC. The reaction mixture was stirred for 18 h
at room temperature. After adding water (200 mL), the
aqueous layer was extracted with CH2Cl2 (300 mL). The
combined organic extracts were washed with brine (300
mL), dried over Na2SO4, filtered and evaporated. The
residue was purified by silica gel column chromato-
graphy (hexane–AcOEt 5:1–1:1) to give an aldehyde
1
(42.2 g, 79%) as a colorless oil. H NMR (500 MHz,
The above compound was deprotected by the method
used for 6a.
CDCl3) d ppm: 3.51 (s, 3H), 5.11 (s, 2H), 5.26 (s, 2H),
6.68 (dd, 1H, J=2.0, 9.0 Hz), 6.80 (d, 1H, J=9.0 Hz),
7.34–7.43 (m, 5H), 7.81 (d, 1H, J=9.0 Hz), 9.72 (s, 1H),
11.46 (s, 1H); 13C NMR (100 MHz, CDCl3) d ppm:
56.4, 70.3, 94.6, 101.5, 108.4, 119.6, 127.6, 128.3, 128.7,
130.3, 135.8, 161.4, 165.0, 188.2; IR (film) cmꢁ1: 1679,
1600, 1499, 1393, 1258, 1155, 1112, 1078, 992, 924, 816,
736, 697; HRMS calcd for C16H16O4Na (M+Na)+
295.0946, found 295.0931.
1H NMR (500 MHz, CDCl3) d ppm: 2.33–2.40 (m, 1H),
2.45–2.51 (m, 1H), 2.96 (s, 3H), 3.04 (s, 3H), 3.07 (dd,
1H, J=6.5, 13.0 Hz), 3.38 (dd, 1H, J=6.5, 13.0 Hz),
4.05 (dt, 1H, J=6.0, 8.0 Hz), 4.18 (dt, 1H, J=6.0, 10.0
Hz), 4.26 (dt, 1H, J=6.0, 10.0 Hz), 6.38 (t, 1H, J=7.0
Hz), 6.79 (d, 1H, J=2.0 Hz), 6.93 (d, 2H, J=9.0 Hz),
7.13 (dd, 1H, J=2.0, 8.0 Hz), 7.24 (d, 2H, J=9.0 Hz),
7.32 (d, 2H, J=9.0 Hz), 7.39 (d, 1H, J=8.0 Hz), 8.17
(d, 2H, J=9.0 Hz); 13C NMR (125 MHz, CDCl3) d
ppm: 32.9, 36.2, 36.5, 43.7, 53.4, 66.6, 114.3, 121.4,
122.4, 125.6, 126.3, 127.5, 128.4, 129.3, 133.4, 138.1,
139.4, 140.6, 141.2, 143.2, 150.2, 154.4, 163.7; IR
(CHCl3) cmꢁ1: 2939, 1719, 1593, 1513, 1391, 1343, 1263,
1171, 1112, 1015, 909, 846; HRMS calcd for
C27H27N3O5Cl (M+H)+ 508.1639, found 508.1631.
To a suspension of 55% NaH (1.57 g, 36.0 mmol) in
THF (100 mL) was added (EtO)2POCH2CO2Et (7.17 g,
32.0 mmol) at 0 ꢀC. The reaction mixture was stirred for
30 min at 0 ꢀC. To the reaction mixture was added the
above aldehyde (7.46 g, 27.4 mmol) at 0 ꢀC. The reac-
tion mixture was stirred for 2 h at 0 ꢀC and quenched
with water (200 mL). The mixture was extracted with
AcOEt (200 mLꢂ2). The combined extracts were washed
with water (100 mL) and brine (100 mL), dried over
Na2SO4, filtered and evaporated. Purification by silica
gel column chromatography (hexane–AcOEt 5:1–1:1)
Compound 26d was prepared by the method used for 9a
from the above compound.

4412
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
gave 28 (9.32g, 99%) as a colorless oil. 1H NMR
(400 MHz, CDCl3) d ppm: 1.32 (t, 3H, J=7.2 Hz), 3.47
(s, 3H), 4.24 (q, 2H, J=7.2 Hz), 5.05 (s, 2H), 5.21 (s,
2H), 6.39 (d, 1H, J=16.0 Hz), 6.62 (dd, 1H, J=2.0, 8.8
Hz), 6.81 (d, 1H, J=2.0 Hz), 7.30–7.43 (m, 5H), 7.45 (d,
1H, J=8.8 Hz), 7.95 (d, 1H, J=16.0 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 14.4, 56.2, 60.2, 70.1, 94.6,
102.1, 108.1, 116.3, 117.3, 127.5, 128.1, 128.6, 129.6,
136.3, 139.6, 157.4, 161.6, 167.8; IR (film) cmꢁ1: 1706,
1605, 1503, 1261, 1162, 1077, 994, 736, 697; HRMS
calcd for C20H22O5Na (M+Na)+ 365.1365, found
365.1354.
1216, 1156, 1076, 1002, 950, 756, 655; HRMS calcd for
C13H20NO5 (MꢁOAc)+ 270.1342, found 270.1339;
[a]2D3=ꢁ8.0ꢀ (c 0.82, MeOH).
To a solution of the amine AcOH salt (4.26 g, 12.9
mmol) and Et3N (3.26 mL, 26.0 mmol) in MeOH (20
mL) was added Boc2O (3.27 g, 15.0 mol) dropwise at
room temperature. The reaction mixture was stirred for
30 min at room temperature and concentrated in vacuo.
Purification by silica gel column chromatography (hex-
ane–AcOEt 2:1–1:2) provided (R)-30 (4.64 g, 97%) as a
colorless solid. Mp 82–86 ꢀC, 1H NMR (500 MHz,
CDCl3) d ppm: 1.16 (t, 3H, J=7.0 Hz), 1.43 (s, 9H),
2.79 (dd, 1H, J=7.0, 14.5 Hz), 2.86 (dd, 1H, J=6.0,
14.5 Hz), 3.45 (s, 3H), 4.05 (q, 2H, J=7.0 Hz), 4.85–
5.20 (m, 3H), 5.43 (br s, 0.2H), 5.81 (d, 0.8H, J=8.0
Hz), 6.28 (d, 1H, J=8.0 Hz), 6.50 (br s, 1H), 6.57 (br s,
1H), 6.98 (d, 1H, J=8.0 Hz); 13C NMR (125 MHz,
CDCl3) d ppm: 14.7, 29.0, 40.7, 49.1, 56.8, 61.3, 80.4,
94.7, 102.8, 108.8, 121.3, 129.4, 155.8, 157.5, 172.2; IR
(KBr) cmꢁ1: 3355, 2982, 1699, 1687, 1616, 1510, 1368,
1272, 1172, 1019, 953, 839; HRMS calcd for
C18H27NO7Na (M+Na)+ 392.1686, found 392.1692.
Anal. calcd for C18H27NO7: C, 58.52; H, 7.37; N, 3.79.
Found: C, 58.71; H, 7.38; N, 3.83; [a]2D3=+42.6ꢀ (c
0.86, CHCl3).
3-tert-Butoxycarbonylamino-3-(4-hydroxy-2-methoxyme-
thoxyphenyl)propionic acid ethyl ester [(R)-30]. To a
solution of (S)-N-benzyl-1-phenylethyl amine [(S)-29]
(4.24 g, 20.1 mmol) in THF (40 mL) was added n-butyl
lithium in hexane (12.4 mL, 1.6 M) at ꢁ78 ꢀC. The
solution was stirred for 30 min at ꢁ78 ꢀC. To the solu-
tion was added a solution of 28 (4.32 g, 12.6 mmol) in
THF (20 mL) at ꢁ78 ꢀC. After stirring for 30 min at this
temperature, the reaction mixture was quenched with
saturated aq NH4Cl (40 mL) at ꢁ78 ꢀC, and then
extracted with AcOEt (50 mLꢂ2). The organic layers
were washed with brine (50 mL), dried over Na2SO4,
filtered and evaporated. The residue was purified by
silica gel flash column chromatography (hexane–AcOEt
10:1–5:1) to give a benzyl amine (7.21 g) as a yellow oil.
This compound was used in the following reaction
without further purification. Purified compound: 1H
NMR (500 MHz, CDCl3) d ppm: 0.98 (t, 3H, J=7.0
Hz), 1.23 (d, 3H, J=7.0 Hz), 2.60 (dd, 1H, J=9.0, 13.5
Hz), 2.73 (dd, 1H, J=7.0, 15.0 Hz), 3.47 (s, 3H), 3.73
(dd, 2H, J=14.5, 22.5 Hz), 3.79–3.92 (m, 2H), 4.08 (q,
1H, J=7.0 Hz), 4.80 (dd, 1H, J=6.0, 8.0 Hz), 5.03 (s,
2H), 5.15 (dd, 2H, J=7.0, 17.0 Hz), 6.61 (dd, 1H,
J=2.5, 8.5 Hz), 6.83 (d, 1H, J=2.5 Hz), 7.13–7.44 (m,
16H); 13C NMR (100 MHz, CDCl3) d ppm: 13.9, 14.5,
24.4, 39.0, 50.6, 51.6, 53.5, 56.1, 56.3, 57.5, 59.9, 70.0,
94.7, 102.3, 107.0, 123.0, 126.3, 126.5, 126.7, 127.6,
127.8, 127.9, 128.0, 128.1, 128.3, 128.4, 128.5, 129.4,
136.9, 142.0, 144.5, 156.6, 158.9, 171.7; IR (CHCl3)
cmꢁ1: 2981, 1728, 1608, 1503, 1494, 1454, 1375, 1254,
1155, 1114, 1074, 1010; HRMS calcd for C36H40O5Na
(M+Na)+ 576.2726, found 576.2710; [a]2D3=ꢁ16.3ꢀ (c
1.04, CHCl3).
[1-(4-Dimethylcarbamoyloxy-2-methoxymethoxyphenyl)-
3-hydroxy-propyl]carbamic acid tert-butyl ester [(R)-31].
To a solution of phenol (R)-30 (2.35 g, 6.36 mmol) and
K2CO3 (1.80 g, 13.0 mmol) in DMF (10 mL) was added
Me2NCOCl (0.65 mL, 7.0 mmol). The reaction mixture
was stirred for 3 h at room temperature. After dilution
with water (30 mL), the mixture was extracted with
AcOEt (40 mLꢂ2), and the combined organic layers
were washed with brine (40 mL) and dried over Na2SO4.
The residue was purified by silica gel column chroma-
tography (hexane–AcOEt 2:1–1:2) to give a carbamate
1
(2.73 g, 97%) as a colorless oil. H NMR (500 MHz,
CDCl3) d ppm: 1.17 (t, 3H, J=7.0 Hz), 1.41 (s, 9H),
2.77–2.89 (m, 2H), 2.99 (s, 3H), 3.07 (s, 3H), 3.49 (s,
3H), 4.01–4.10 (m, 2H), 5.24 (dd, 2H, J=7.0, 10.0 Hz),
5.30 (br s, 1H), 5.74 (br d, 1H, J=9.0 Hz), 6.73 (dd, 1H,
J=2.0, 9.0 Hz), 6.89 (d, 1H, J=2.0 Hz), 7.23 (d, 1H,
J=9.0 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 14.1,
28.4, 36.4, 36.7, 39.8, 48.2, 56.3, 60.5, 79.4, 94.3, 108.2,
114.7, 126.2, 128.4, 151.6, 154.6, 154.7, 154.8, 171.1; IR
(CHCl3) cmꢁ1: 1714, 1496, 1391, 1254, 1167, 1001;
HRMS calcd for C21H32N2O8Na (M+Na)+ 463.2056,
found 463.2051; [a]2D3=+25.3ꢀ (c 1.09, CHCl3).
To a solution of the above benzyl amine (7.21 g) in
MeOH–H2O–AcOH (20:2:1, 92 mL) was added 20%
Pd(OH)2/C (1.8 g). The reaction mixture was stirred for
4 h under a hydrogen atmosphere at room temperature.
Pd(OH)2/C was removed by filtration and the filtrate
was evaporated in vacuo to give an amine AcOH salt
(2.77 g, 67% for two steps) as a colorless solid. 1H
NMR (400 MHz, CD3OD) d ppm: 1.20 (t, 3H, J=7.6
Hz), 1.90 (s, 3H), 2.93 (dd, 1H, J=6.0, 16.4 Hz), 2.98
(dd, 1H, J=8.8, 16.4 Hz), 3.49 (s, 3H), 4.13 (q, 2H,
J=7.6 Hz), 4.71 (t, 1H, J=7.4 Hz), 5.24 (s, 2H), 6.45
(dd, 1H, J=2.4, 8.8 Hz), 6.69 (d, 1H, J=2.8 Hz), 7.12
(d, 1H, J=8.8 Hz); 13C NMR (100 MHz, CD3OD) d
ppm: 14.4, 23.5, 39.0, 49.2, 56.6, 62.1, 95.6, 103.3, 109.7,
To a solution of the carbamate (4.68 g, 10.6 mmol) in
THF (30 mL) was added LiAlH4 (524 mg, 13.8 mmol)
at ꢁ50 ꢀC. The reaction mixture was stirred for 10 min
at ꢁ50 ꢀC and for 15 min at 0 ꢀC. To the reaction mix-
ture were successively added water (0.5 mL), 15% aq
NaOH (0.5 mL), water (1.5 mL) and MgSO4. After fil-
tration, the organic solvent was concentrated in vacuo.
Purification by silica gel column chromatography (hex-
ane–AcOEt 2:1 to AcOEt) gave compound (R)-31 (3.48
1
g, 82%) as a colorless oil. H NMR (400 MHz, CDCl3)
d ppm: 1.43 (s, 9H), 1.94 (dt, 2H, J=4.8, 6.0 Hz), 3.00
(s, 3H), 3.08 (s, 3H), 3.30 (br s, 1H), 3.49 (s, 3H), 3.61–
117.3, 127.5, 130.1, 157.4, 160.7, 171.9; IR (film) cmꢁ1
2982, 1731, 1615, 1596, 1554, 1512, 1472, 1404, 1300,
:

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4413
3.74 (m, 2H), 5.06 (q, 1H, J=5.6 Hz), 5.23 (dd, 2H,
J=6.4, 10.8 Hz), 5.47 (d, 1H, J=9.6 Hz), 6.74 (dd, 1H,
J=2.4, 8.8 Hz), 6.90 (d, 1H, J=2.4 Hz), 7.19 (d, 1H,
J=8.8 Hz); 13C NMR (125 MHz, CDCl3) d ppm: 29.0,
37.1, 37.4, 39.0, 49.4, 57.1, 59.7, 80.5, 95.1, 105.4, 109.3,
115.8, 127.8, 128.8, 129.1, 152.2, 155.3, 155.7, 157.3; IR
(CHCl3) cmꢁ1: 3451, 1715, 1497, 1392, 1253, 1166, 1050,
1000, 941, 875; HRMS calcd for C19H30N2O7Na
(M+Na)+ 421.1950, found 421.1950; [a]2D3=+48.0ꢀ
(c 1.09, CHCl3).
Hz), 8.17 (d, 2H, J=9.6 Hz), 8.33 (br s, 1H); 13C NMR
(125 MHz, CDCl3) d ppm: 29.0, 34.3, 37.1, 37.4, 49.0,
66.8, 81.0, 111.5, 113.6, 115.1, 125.1, 126.5, 128.6, 142.1,
152.1, 155.8, 156.1, 157.0, 164.5; IR (CHCl3) cmꢁ1
:
3209, 1712, 1593, 1498, 1392, 1342, 1263, 1171, 1112,
1050, 1023, 966, 846; HRMS calcd for C23H29N3O8Na
(M+Na)+ 498.1852, found 498.1854; [a]2D3=ꢁ2.7ꢀ (c
1.91, CHCl3).
Allyl[1-(4-dimethylcarbamoyloxy-2-vinylphenyl)-3-(4-ni-
trophenoxy)propyl]carbamic acid tert-butyl ester [(R)-
33]. To a solution of phenol (R)-32 (1.69 g, 3.55 mmol)
and pyridine (1.15 mL, 14.2 mmol) in CH2Cl2 (10 mL)
was added Tf2O (0.72 mL, 4.2 mmol) at 0 ꢀC. The reac-
tion mixture was stirred for 10 min at 0 ꢀC, quenched
with water (20 mL) and extracted with CH2Cl2 (20
mLꢂ2). The extracts were washed with 0.5 N HCl (20
mL) and brine (20 mL), and dried over Na2SO4. After
filtration, the solvent was removed under reduced pres-
sure to give a triflate (1.89 g). To a solution of the tri-
flate (1.89 g) in dioxane (20 mL) were added Pd(PPh3)4
(410 mg, 0.355 mmol), LiCl (451 mg, 10.6 mmol), 2,6-
di-t-butylphenol (5 mg) and (CH2¼CH)(n-Bu)3Sn (1.14
mL, 3.90 mmol). The reaction mixture was stirred for 2
h at 100 ꢀC. After cooling to room temperature, satu-
rated aq KF (10 mL) was added to the reaction mixture.
The resulting solution was concentrated in vacuo and
diluted with water (40 mL). The aqueous layer was
extracted with AcOEt (50 mLꢂ2). The combined
organic layers were washed with 1N HCl (40 mL) and
brine (40 mL), and dried over Na2SO4, filtered and
evaporated. The residue was purified by silica gel col-
umn chromatography (hexane–AcOEt 5:1–1:1) to give a
[1-(4-Dimethylcarbamoyloxy-2-hydroxyphenyl)-3-(4-ni-
trophenoxy)propyl]carbamic acid tert - butyl ester [(R) -
32]. To a solution of alcohol (R)-31 (3.00 g, 7.53
mmol), 4-nitrophenol (1.15 g, 8.28 mmol) and Ph3P
(2.96 g, 11.3 mmol) in THF (20 mL) was added a 40%
diethyl azodicarboxylic acid toluene solution (4.92 g,
11.3 mmol) dropwise at 0 ꢀC. The reaction mixture was
stirred for 1 h at room temperature, and then con-
centrated in vacuo. The residue was purified by silica gel
column chromatography (hexane–AcOEt 2:1–1:2) to
give a 4-nitrophenoxy ether derivative (6.49 g). This
compound was used in the following reaction without
further purification.
To a solution of the 4-nitrophenoxy ether derivative
(6.49 g) in MeOH (21 mL) was added concentrated HCl
(8 mL) at room temperature. The reaction mixture was
stirred for 18 h at room temperature. Then, the reaction
mixture was quenched with 15% aq NaOH and adjus-
ted to pH 10 by the addition of saturated aq NaHCO3.
The resulting mixture was extracted with AcOEt (50
mLꢂ2). The combined organic layers were dried over
Na2SO4, filtered and evaporated. The residue was puri-
fied by silica gel column chromatography (AcOEt to
AcOEt–MeOH 5:1) to give an amine (1.91 g, 68%) as a
colorless solid. Mp 146–147 ꢀC, 1H NMR (400 MHz,
CDCl3) d ppm: 2.26 (q, 2H, J=6.8 Hz), 2.99 (s, 3H),
3.07 (s, 3H), 3.96 (dt, 1H, J=6.8, 9.6 Hz), 4.09 (dt, 1H,
J=5.2, 9.6 Hz), 4.44 (t, 1H, J=6.8 Hz), 6.51 (dd, 1H,
J=2.0, 8.0 Hz), 6.61 (d, 1H, J=2.0 Hz), 6.83 (d, 1H,
J=8.0 Hz), 6.91 (d, 2H, J=9.4 Hz), 8.20 (d, 2H, J=9.4
Hz); 13C NMR (100 MHz, CDCl3) d ppm: 36.7, 37.6,
37.8, 67.1, 112.2, 113.4, 115.4, 123.4, 126.9, 129.3, 142.6,
153.0, 155.6, 159.4, 164.3; IR (KBr) cmꢁ1: 2938, 1711,
1592, 1510, 1387, 1340, 1263, 1177, 1110, 1011, 848,
753, 659; HRMS calcd for C18H22N3O6 (M+H)+
376.1509, found 376.1512. Anal. calcd for C18H21N3O6:
C, 57.59; H, 5.64; N, 11.19. Found: C, 57.63; H, 5.65; N,
11.13; [a]2D3=ꢁ110.0ꢀ (c 0.61, CHCl3).
1
styrene derivative (1.47 g, 86%) as a colorless oil. H
NMR (400 MHz, CDCl3) d ppm: 1.40 (s, 9H), 2.24 (br
m, 2H), 3.02 (s, 3H), 3.10 (s, 3H), 3.97 (dt, 1H, J=5.8,
9.6 Hz), 4.06 (dt, 1H, J=6.2, 9.6 Hz), 5.02 (br s, 1H),
5.23 (br s, 1H), 5.29 (d, 1H, J=11.2 Hz), 5.56 (dd, 1H,
J=1.2, 17.2 Hz), 6.90 (d, 2H, J=9.6 Hz), 7.05 (dd, 1H,
J=2.0, 8.0 Hz), 7.07 (br s, 1H), 7.20 (d, 1H, J=2.0 Hz),
7.26 (d, 1H, J=8.0 Hz), 8.18 (d, 2H, J=9.6 Hz); 13C
NMR (125 MHz, CDCl3) d ppm: 28.3, 35.5, 36.4, 36.6,
47.6, 65.6, 79.4, 114.2, 117.3, 119.4, 121.3, 125.5, 126.0,
133.0, 135.8, 137.4, 141.1, 150.4, 154.5, 154.8, 163.3; IR
(CHCl3) cmꢁ1: 1593, 1497, 1391, 1342, 1263, 1172, 1112,
846; HRMS calcd for C25H31N3O7Na (M+Na)+
508.2060, found 508.2066; [a]2D3=ꢁ20.4ꢀ (c 0.78,
CHCl3).
To a suspension of 55% NaH (216 mg, 9.00 mmol) in
DMF (10 mL) was added a solution of the styrene
derivative (1.47 g, 3.03 mmol) in DMF (5 mL) at 0 ꢀC.
The reaction mixture was stirred for 30 min at 0 ꢀC. To
the reaction mixture was added allyl bromide (0.78 mL,
9.00 mmol) at 0 ꢀC. The reaction mixture was stirred for
2 h at 0 ꢀC and an additional 2 h at room temperature.
After addition of water (30 mL), the aqueous layer was
extracted with AcOEt (30 mLꢂ2). The combined
organic extracts were washed with brine (30 mL), dried
over Na2SO4, filtered and evaporated in vacuo. Pur-
ification by silica gel column chromatography (hexane–
AcOEt 2:1–1:1) gave (R)-33 (1.37 g, 86%) as a colorless
To a solution of the amine (1.19 g, 5.10 mmol) and
Et3N (1.53 mL, 11.0 mmol) in MeOH (10 mL) was
added Boc2O (1.22 g, 5.60 mmol) dropwise at room
temperature. The reaction mixture was stirred for 1 h at
room temperature and concentrated in vacuo. Purifica-
tion by silica gel column chromatography (hexane–
AcOEt 2:1–AcOEt) provided (R)-32 (2.07 g, 85%) as a
1
colorless oil. H NMR (400 MHz, CDCl3) d ppm: 1.41
(s, 9H), 2.26–2.38 (m, 2H), 3.02 (s, 3H), 3.08 (s, 3H),
3.96–4.02 (m, 1H), 4.05–4.11 (m, 1H), 4.97 (br s, 1H),
5.29 (br s, 1H), 6.59 (d, 1H, J=8.0 Hz), 6.64 (d, 1H,
J=2.0 Hz), 6.90 (d, 2H, J=9.6 Hz), 7.08 (d, 1H, J=8.0
1
oil. H NMR (400 MHz, CDCl3) d ppm: 1.34 (s, 9H),

4414
N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
2.28–2.38 (br m, 1H), 2.40–2.50 (br m, 1H), 2.95 (s, 3H),
3.04 (s, 3H), 3.42 (br s, 2H), 3.97 (dt, 1H, J=6.2, 8.8
Hz), 4.06 (m, 1H), 4.82 (m, 2H), 5.23 (d, 1H, J=11.2
Hz), 5.41 (br s, 1H), 5.53 (d, 1H, J=17.6 Hz), 5.65 (br s,
1H), 6.86 (d, 2H, J=9.6 Hz), 6.94 (dd, 1H, J=10.0,
17.6 Hz), 7.01 (d, 1H, J=8.4 Hz), 7.19 (s, 1H), 7.27 (d,
1H, J=8.4 Hz), 8.11 (d, 2H, J=9.6 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 29.5, 32.6, 37.6, 37.8, 46.6,
52.3, 67.2, 81.0, 115.4, 117.0, 118.0, 120.7, 121.7, 126.8,
128.5, 134.0, 134.7, 135.8, 140.9, 142.3, 152.2, 155.5,
156.2, 164.7; IR (CHCl3) cmꢁ1: 1716, 1678, 1593, 1513,
1392, 1342, 1264, 1172, 1111, 1025, 922, 846; HRMS
calcd for C28H35N3O7Na (M+Na)+ 548.2373, found
548.2352; [a]2D3=+92.0ꢀ (c 1.12, CHCl3).
(M+H)+ 398.1716, found 398.1743; [a]2D3=ꢁ92.2ꢀ (c
0.80, CHCl3).
The above amine (672 mg, 1.69 mmol) was dissolved in
a mixture of HCO2H (5 mL) and 37% aq HCHO (5
mL) and stirred for 3 h at 80 ꢀC. After cooling to room
temperature, saturated aq NaHCO3 (20 mL) was added
and extracted with AcOEt (20 mLꢂ2). The extracts
were washed with brine (30 mL), dried over Na2SO4,
filtered and evaporated in vacuo. Purification by silica
gel column chromatography (AcOEt to AcOEt–MeOH
1
5:1) gave (R)-18a (543 mg, 78%) as a colorless oil. H
NMR (400 MHz, CDCl3) d ppm: 2.05–2.13 (m, 1H),
2.23–2.33 (m, 1H), 2.28 (s, 3H), 3.01 (s, 3H), 3.09 (s,
3H), 3.46 (dd, 1H, J=3.6, 19.6 Hz), 3.87 (dt, 1H,
J=2.0, 19.6 Hz), 3.97–4.02 (m, 1H), 4.06–4.12 (m, 2H),
5.81 (ddd, 1H, J=2.8, 4.4, 12.4 Hz), 6.37 (d, 1H,
J=12.4 Hz), 6.89 (dd, 1H, J=3.0, 8.0 Hz), 6.92 (d, 2H,
J=8.8 Hz), 7.00, (d, 1H, J=3.0 Hz), 7.04 (d, 1H, J=8.0
Hz), 8.19 (d, 2H, J=8.8 Hz); 13C NMR (100 MHz,
CDCl3) d ppm: 31.3, 36.3, 36.6, 41.4, 53.2, 64.0, 65.6,
114.2, 119.6, 124.2, 125.5, 128.6, 129.5, 132.3, 135.9,
Dimethyl-carbamic acid 2-methyl-1-[2-(4-nitrophenoxy)-
ethyl]-2,3-dihydro-1H-benzo[c]azepin-7-yl ester hydro-
.
chloride salt [(R)-18a HCl]. To a solution of allyl amine
(R)-33 (1.27 g, 2.33 mmol) in CH2Cl2 (150 mL) was
added Grubbs catalyst 15 (198 mg, 0.233 mmol). The
reaction mixture was stirred for 3 h at 45 ꢀC. The
organic solvent was removed under reduced pressure
and the residue was purified by silica gel column chro-
matography (hexane–AcOEt 2:1–1:1) to give a closed-
ring compound (1.11 g, 96%) as a colorless oil. 1H
NMR (400 MHz, CDCl3) d ppm: 1.30 (s, 6H), 1.38 (s,
3H), 2.25–2.55 (br m, 2H), 3.00 (s, 3H), 3.09 (s, 3H),
3.80–4.10 (br m, 3H), 4.74 (br d, 0.34H, J=19.2 Hz),
4.99 (br s, 0.66H), 5.19 (br s, 0.66H), 5.35 (br m, 0.34H),
5.80 (d, 0.34H, J=12.4 Hz), 5.86 (d, 0.66H, J=12.4
Hz), 6.37 (d, 1H, J=12.4 Hz), 6.87–6.94 (m, 3H), 6.98 (s,
1H), 7.06 (br s, 0.66H), 7.19 (d, 0.34H, J=8.8 Hz), 8.16–
8.21 (m, 2H); 13C NMR (125 MHz, CDCl3) d ppm: 28.9,
29.0, 30.7, 37.1, 37.3, 44.8, 46.2, 56.8, 57.6, 66.0, 66.2,
80.9, 81.0, 115.1, 120.3, 120.7, 125.7, 125.8, 126.6,
129.2, 129.4, 130.1, 130.5, 131.1, 132.0, 135.5, 135.8,
138.0, 138.3, 142.3, 151.3, 155.3, 155.4, 156.0, 164.3; IR
(CHCl3) cmꢁ1: 1714, 1514, 1498, 1392, 1342, 1262,
1171, 1112, 1026, 846; HRMS calcd for C26H31N3O7Na
(M+Na)+ 520.2060, found 528.2058; [a]2D3=ꢁ40.9ꢀ (c
0.98, CHCl3).
137.8, 141.0, 150.1, 154.4, 163.6; IR (CHCl3) cmꢁ1
:
2938, 1714, 1593, 1513, 1498, 1391, 1343, 1263, 1172,
1112, 1024, 846; HRMS calcd for C22H26N3O5
(M+H)+ 412.1872, found 412.1902; [a]2D3=ꢁ72.3ꢀ (c
1.25, CHCl3).
(R)-18a HCl. 1H NMR (400 MHz, CDCl3) d ppm:
.
2.12–2.21 (m, 1H), 2.60 (s, 3H), 2.85–2.93 (m, 1H), 3.02
(s, 3H), 3.10 (s, 3H), 3.81 (dd, 1H, J=4.4, 19.6 Hz),
3.85–3.90 (m, 1H), 4.06 (dt, 1H, J=5.2, 9.6 Hz), 4.39 (d,
1H, J=19.6 Hz), 4.77 (d, 1H, J=11.6 Hz), 5.85 (ddd,
1H, J=3.2, 4.4, 12.4 Hz), 6.36 (d, 1H, J=12.4 Hz), 6.86
(d, 2H, J=8.8 Hz), 7.04 (dd, 1H, J=2.4, 8.8 Hz), 7.14
(d, 1H, J=8.8 Hz), 7.21 (d, 1H, J=2.4 Hz), 8.16 (d, 2H,
J=8.8 Hz); 13C NMR (100 MHz, CDCl3) d ppm: 29.7,
36.2, 36.5, 40.3, 51.0, 64.0, 65.4, 114.1, 121.5, 121.8,
125.3, 125.6, 127.4, 129.7, 131.5, 134.2, 141.1, 151.9,
153.5, 162.4; IR (CHCl3) cmꢁ1: 2971, 2222, 1725, 1594,
1514, 1498, 1469, 1392, 1344, 1258, 1171, 1112, 1021,
909, 846; HRMS calcd for C22H26N3O5 (M+H)+
412.1873, found 412.1870; [a]2D3=ꢁ25.0ꢀ (c 0.70, CHCl3).
The closed-ring compound (955 mg, 1.92 mmol) was
treated with 2 N HCl in AcOEt (10 mL). After stirring
for 18 h at room temperature, the reaction mixture was
concentrated under reduced pressure. To the residue
was added saturated aq NaHCO3. The aqueous solution
was extracted with AcOEt (20 mLꢂ2). The combined
organic layers were washed with brine (20 mL), dried
over Na2SO4, filtered and evaporated in vacuo to give
Biological methods
In vitro AChE inhibition assay. AChE activity was mea-
sured in duplicate by the spectrophotometric method of
Ellman et al.20 with some modifications. Brain homo-
genate was used as the enzyme source. The whole brain
except for the cerebellum was homogenized in 9
volumes of 100 mM sodium phosphate buffer (pH 7.0).
The test compounds were dissolved in dimethyl sulph-
oxide (DMSO). The AChE activity was expressed as a
change in OD at 412 nm.
1
an amine (730 mg, 96%) as a colorless oil. H NMR
(400 MHz, CDCl3) d ppm: 2.23–2.35 (m, 2H), 3.01 (s,
3H), 3.09 (s, 3H), 3.67 (ddd, 1H, J=2.0, 3.6, 20.4 Hz),
3.77 (dt, 1H, J=2.4, 20.4 Hz), 4.14 (dt, 1H, J=6.0, 8.8
Hz), 4.19-4.27 (m, 2H), 5.95 (dt, 1H, J=3.6, 12.4 Hz),
6.40 (d, 1H, J=12.4 Hz), 6.88 (dd, 1H, J=2.0, 8.0 Hz),
6.95 (d, 2H, J=9.2 Hz), 7.00, (d, 1H, J=2.0 Hz), 7.08
(d, 1H, J=8.0 Hz), 8.19 (d, 2H, J=9.2 Hz); 13C NMR
(100 MHz, CDCl3) d ppm: 32.3, 37.5, 37.8, 49.8, 58.1,
67.1, 115.4, 120.5, 125.8, 126.7, 128.0, 129.5, 136.8,
137.1, 142.1, 142.2, 151.2, 155.6, 164.8; IR (CHCl3)
cmꢁ1: 2939, 1714, 1593, 1512, 1498, 1391, 1343, 1264,
1172, 1112, 1020, 846; HRMS calcd for C21H24N3O5
In vitro SERT inhibition assay. The whole brain except
for the cerebellum was homogenized in 100 mM sodium
phosphate buffer (pH 7.0) and synaptosome was pre-
pared. The uptake of [3H]5-HT into the synaptosome
was determined at 37 ꢀC in the presence and absence of
the test compounds. The blank was determined by
measuring the uptake of [3H]5-HT at 4 ꢀC.

N. Toda et al. / Bioorg. Med. Chem. 11 (2003) 4389–4415
4415
References and Notes
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