Novel synthesis of a new skeletal compound benzonaphthazepine by regioselective C-H activation utilizing the intramolecular coordination of an amine to Pd

Article abstract of DOI:10.1055/s-2004-822371

The novel synthesis of a new skeletal compound, benzonaphthazepine, from N-bromobenzylnaphthylamine using a Pd reagent is described. In the biaryl coupling reaction of N-bromobenzylnaphthylamine using a Pd reagent, the intramolecular coordination of the b

Full text of DOI:10.1055/s-2004-822371

1446
PAPER
Novel Synthesis of a New Skeletal Compound Benzonaphthazepine by
Regioselective C-H Activation Utilizing the Intramolecular Coordination
of an Amine to Pd
N
ovel Synthesis
a
of
a
N
ew
k
S
keletal
C
om
a
pound Ben
s
zonaphth
h
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Fax +81(86)2517963; E-mail: harayama@pharm.okayama-u.ac.jp
Received 2 April 2004
respectively, indicating that regioselective C-H bond acti-
Abstract: The novel synthesis of a new skeletal compound, ben-
zonaphthazepine, from N-bromobenzylnaphthylamine using a Pd
reagent is described. In the biaryl coupling reaction of N-bromoben-
zylnaphthylamine using a Pd reagent, the intramolecular coordina-
vation occurs at the ortho position relative to the methyl-
ene group of 1 and the peri position relative to the amino
group of 2, respectively (see Scheme 2).5 Therefore, we
tion of the benzylamino group to Pd causes regioselective C-H envisioned that the intramolecular biaryl coupling reac-
activation at the peri position relative to the amine group on the
naphthalene ring, producing benzonaphthazepine in good to excel-
lent yield. The bulkiness of the substituent at C7 on the naphthalene
ring affects the regioselectivity of the biaryl coupling reaction.
tion of N-(2-bromobenzyl)naphthylamine D using Pd re-
agent would afford
a
new skeletal compound,
benzonaphthazepine E, directly, via oxidative addition to
Pd(0) and coordination of the amine to Pd(II), followed by
the regioselective electrophilic substitution of Pd(II) at the
peri position and reductive elimination of Pd(0), as shown
in Scheme 3 (phosphine ligands are omitted for clari-
ty).1c,6
Key Words: C-H activation, heterocycles, palladium, regioselec-
tivity, coordination
Palladium-assisted biaryl coupling reactions have been
used to synthesize many polycyclic aromatic com-
pounds.1 Recently, we reported that intramolecular biaryl
coupling reactions of 2-halo-N-arylbenzamides using pal-
ladium reagents were very useful methods to synthesize
polycyclic aromatic lactams, some of which can be trans-
formed into several condensed heteroaromatic alkaloids.2
Moreover, we succeeded in synthesizing pyrroloquinazo-
line alkaloids, luotonine A and B, and pyrrolophenanthri-
dine alkaloids using this method.3 In the biaryl coupling
reaction of 2-halo-N-naphthylbenzamide A using a Pd re-
agent, a small amount of benzonaphthazepinone C, which
is a new skeletal compound, was always obtained along
with the expected benzo[c]phenanthridone B, as shown in
Scheme 1.2b,c,2e–g Since benzonaphthazepine, which is the
parent skeleton of C, is a new skeletal compound, we
planned to develop a general synthetic method for ben-
zonaphthazepine utilizing a Pd-assisted biaryl coupling
reaction. The results are the subject of this paper.4
To verify the coordination effect of the amine on the in-
tramolecular biaryl coupling reaction, the coupling reac-
tion of N-(2-bromobenzyl)naphthylamine (5a) was first
examined in relation to synthetic studies of fagaridine and
decarine,2f because 2-bromo-N-naphthylbenzamide (A)
gave B as a major product and C as a minor product.2b,c,2e–g
R2
R2
R2
X
Pd
R1
R1
R1
+
N
N
N
Me
Me
B (major)
O
O
Me
O
(X = OTf, Br, I)
C (minor)
A
Scheme 1 Pd-assisted biaryl coupling reaction of N-naphthylbenz-
amide A
Compound 5a was synthesized from 6-bromo-3-isopro-
poxy-2-methoxybenzyl bromide (6a), which was pre-
pared from 3-isopropoxy-2-methoxybenzaldehyde7 in
54% yield via reduction with NaBH4 and bromination
with Br2, and N-methyl-6,7-methylenedioxy-1-naphthyl-
In 1967, Cope et al. reported that cyclopalladation reac-
tions of benzylamine 1 and naphthylamine 2 with palladi-
um (II) chlorides selectively gave palladacycles 3 and 4,
Me
N
Me
Cl
Me
Pd
Me
Me Me
N
N
Li2PdCl4
MeOH
Cl
Cl
Pd
N
Me
Pd
Li2PdCl4
MeOH
Pd
Cl
N
N
Me
Me
Me
Me
Me
2
4
1
3
Scheme 2 Palladacycles of benzylamine 1 and naphthylamine 2
SYNTHESIS 2004, No. 9, pp 1446–1456
x
x
.
x
x
.2
0
0
4
Advanced online publication: 12.05.2004
DOI: 10.1055/s-2004-822371; Art ID: C01504SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Synthesis of a New Skeletal Compound Benzonaphthazepine
1447
R2
R2
R2
Pd0
Br
PdII
PdII
Br
R1
R1
R1
N
N
N
Me
R2
Me
Me
D
– Pd0
R1
N
Me
E
Scheme 3 Synthetic strategy of naphthylbenzazepine E from N-benzylnaphthylamine D using regioselective C-H activation by Pd
amine (7a)2e in the presence of K2CO3 and Bu4NI in DMF Moreover, in order to prove the contribution of the amine
at 100 °C (Table 1, entry 1). Then, we investigated the group, the biaryl coupling reaction of N-acetate 11 was
coupling reaction using a system combining Pd(OAc)2, examined. Compound 11 was prepared by the acetylation
P(o-tol)3, and Ag2CO3 in degassed DMF under reflux, be- of N-benzylnaphthylamine 10, which was synthesized
cause the coupling reaction of bromo-naphthobenzamide from 6-bromo-3-hydroxy-2-methoxybenzaldehyde9 via
A under the same reaction conditions produced B and C etherification with isopropyl bromide, followed by reduc-
in good to excellent yields. However, no coupling reaction tive alkylation with 6,7-methylenedioxy-1-naphthyl-
occurred (Table 2, entry 1). Subsequently, coupling reac- amine and NaBH4. The reaction of 11 using Pd afforded
tions under various conditions were examined and the re- N-acetyl benzo[c]phenanthridine 12 and N-acetyl ben-
sults are summarized in Table 2.8 Using K2CO3, KHCO3, zonaphthazepine 13 in 45% and 55% yields, respectively
or Cs2CO3 as the base, the biaryl coupling reaction pro- (see Scheme 4). This strongly supports the contribution of
ceeded smoothly to provide only benzonaphthazepine 8a, the benzylamino group to the production of 8a, as shown
a new skeletal compound, in good yields (Table 2, entries in Scheme 3.
10–13), while organic bases were not effective (Table 2,
Next, in order to examine the generality of this method,
entries 2–4). The reaction using Cy3P as a ligand gave 8a
we examined the coupling reaction of N-(6¢-bromoben-
in a good yield as well as that using (o-tol)3P (Table 2, en-
zyl)-1-naphthylamines 5b–i using a system combining
try 13). We decided to use (o-tol)3P as the ligand, because
Pd(OAc)2, P(o-tol)3, and K2CO3 in degassed DMF. For
it was easier to separate each product from the extracts.
this, 6,7-dimethoxy-N-methyl-1-naphthylamine (7c) and
7-isopropoxy-6-methoxy-N-methyl-1-naphthylamine (7d)
The structures of the products (8a and 9a) were elucidated
using elemental analyses and 1H NMR data, in which 8a
were first prepared from 6,7-dimethoxy-1-naphthyl-
showed only one singlet signal (d = 7.02) due to the aro-
matic proton in addition to the signals due to other aromat-
ic protons. This indicates that the coordination of the
amine group to Pd is very important for the production of
8a via the intramolecular biaryl coupling reaction.
amine10 and 7-isopropoxy-6-methoxy-1-naphthylamine10
in 86% and 76% yields, respectively, via trifluoroacetyl-
ation, methylation with MeI, and alkaline hydrolysis.
Then, the starting materials (5b–i) for the coupling reac-
tion were synthesized from dibromides 6a–c11 and N-
Table 1 Synthesis of N-(6¢-Bromobenzyl)-1-naphthylamine 5 from Benzyl Bromide 6 and Naphthylamine 7
Entry
Substituent
Methoda
Product
5a
Yield (%)
1
2
3
4
5
6
7
8
9
R1 = OMe, R2 = Oi-Pr, R3 + R4 = OCH2O
R1 = R2 = R3 = R4 = H
A
A
A
A
A
B
B
B
B
71
5b
98
R1 = R2 = H, R3 + R4 = OCH2O
R1 = R2 = OMe, R3 = R4 = H
R1 = R2 = OMe, R3 + R4 = OCH2O
R1 = R2 = H, R3 = R4 = OMe
R1 = R2 = R3 = R4 = OMe
5c
70
5d
63
5e
98
5f
95
5g
74
R1 = R2 = H, R3 = OMe, R4 = Oi-Pr
R1 = R2 = R3 = OMe, R4 = Oi-Pr
5h
quant.
96
5i
a Method A: K2CO3, Bu4NI, DMF, 100 °C, 1–2 h; Method B: i-Pr2NEt, DMF, 100 °C, 1 h.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

1448
T. Harayama et al.
PAPER
Table 2 Results of the Coupling Reaction of N-(6-Bromo-3-isopropoxy-2-methoxybenzyl)-N-methyl-6,7-methylenedioxy-1-naphthylamine
(5a) in DMF under Refluxa
Entry
Ligand (L/Pd)
Base
Time (h)
Yield (%)
8a
–
9a
5a
55
69
63
65
–
1
2
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
Cy3P (2)
Ag2CO3
Et3N
12
6
6
4
4
8
4
6
4
2
2
3
2
2
2
2
2
6
18
18
–
–
3
pyridine
DBU
–
4
–
trace
56
41
–
5
KOH
13
13
–
6
t-BuOK
Li2CO3
Na2CO3
CaCO3
K2CO3
KHCO3
Cs2CO3
K2CO3
K2CO3
KOAc
KOAc
K2CO3
–
–
7
99
61
93
18
7
8
13
–
13
–
9
10
11
12
13
14b
15c
16d
17
18
76
66
75
75
48
–
trace
–
12
8
10
–
DPPP (1)
–
9
–
–
96
39
74
79
–
–
–
–
–
–
P(o-tol)3 (2)
–
12
a All reactions were carried out using Pd(OAc)2 (0.2 equiv), P(o-tol)3 (0.4 equiv), and base (2 equiv) under Ar atmosphere.
b One equiv of Bu3P was added.
c Reaction was carried out using KOAc (5.5 equiv) at 130 °C.
d Reaction was carried out using KOAc (5.5 equiv) and N-methyl-6,7-methylenedioxy-1-naphthylamine (7a) was obtained in 20 % yield.
methyl-1-naphthylamines 7a2e–d using Method A or B lene ring was examined and they produced ben-
(see the experimental section) in high yields, as shown in zo[c]phenanthridines (14h and 14i) along with debromo-
Table 1. Subsequently, the coupling reaction of 5 using a and demethylated products (9 and 15) (Table 3, entries 8
Pd reagent was examined, and the results are summarized and 9). These results strongly support the proposed mech-
in Table 3. N-Bromobenzylnaphthylamines 5b–e that anism shown in Scheme 5. The structures of the products
possess a methylenedioxy group or no substituent group were elucidated using 1H NMR data, elementary analysis,
on the naphthalene ring produced only benzonapht- and MS data. The d values of the N-methyl signals were
hazepines 8b–e in moderate to high yields (Table 3, en- especially useful for structure elucidation. N-Methyl sig-
tries 2–5). Interestingly, N-bromobenzylnaphthylamines nals appeared at d = 2.97–3.08 for the benzonaphtha-
5f and 5g that possess a methoxy group at C7 on the naph- zepines 5, d = 2.62–2.65 for the benzo[c]phenanthridines
thalene ring produced benzonaphthazepines 8f and 8g) 14, and d = 2.75–2.84 for the dibromo amines 9.
and benzo[c]phenanthridines 14f and 14g12 (Figure 1)
along with debromo-products 9f and 9g (Table 3, entries
6 and 7). The proposed mechanism is illustrated in
To examine the effect of the location of the leaving group
on the coupling reaction using Pd, N-benzylbromonaph-
thylamine 16, which possesses a bromo group on the
Scheme 5. The methoxy group at C7 on the naphthalene
naphthalene ring as the leaving group, was synthesized.
ring might hinder the coupling reaction at the peri position
Bromonaphthylamine 7e was prepared from 2-bromo-
(C8 position) relative to the amino group on the naphtha-
6,7-methylenedioxy-1-naphthylamine14 in 78% total yield
lene ring.13 Subsequently, the reaction of N-bromobenzyl-
via trifluoroacetylation, N-methylation with MeI, and hy-
naphthylamines 5h and 5i) possessing a bulky isopropoxy
drolysis with alkaline. N-Benzylation of 7e with benzyl
group relative to a methoxy group at C7 on the naphtha-
bromide using Method A in Table 1 gave 16 in 98% yield.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of a New Skeletal Compound Benzonaphthazepine
1449
R3
Br
R4
Br
N
R2
Me
Br
R1
R2
R1
5
R1=OMe, R2=OiPr, R3+R4=OCH2O
R1=R2=R3=R4=H
R1=R2=H, R3+R4=OCH2O
R1=R2=OMe, R3=R4=H
R1=R2=OMe, R3+R4=OCH2O
R1=R2=H, R3=R4=OMe
R1=R2=R3=R4=OMe
5a :
5b :
5c :
5d :
5e :
5f :
6
6a : R1=OMe, R2=OiPr,
6b : R1=R2=H,
6c : R1=R2=OMe,
5g :
5h :
5i :
R1=R2=H, R3=OMe, R4=OiPr
R1=R2=R3=OMe, R4=OiPr
R3
R4
R3
N
R2
Me
X
R4
R1
HN
Me
8
7a : R3+R4=OCH2O, X=H
7b : R3=R4=H, X=H
7c : R3=R4=OMe, X=H
7d : R3=OMe, R4=OiPr, X=H
7e : R3+R4=OCH2O, X=Br
8a : R1=OMe, R2=OiPr, R3+R4=OCH2O
8b : R1=R2=R3=R4=H
8c : R1=R2=H, R3+R4=OCH2O
8d : R1=R2=OMe, R3=R4=H
8e : R1=R2=OMe, R3+R4=OCH2O
8f : R1=R2=H, R3=R4=OMe
8g : R1=R2=R3=R4=OMe
R3
R3
R4
R4
N
N
O
O
R2
R2
R
Me
R1
R1
X
N
R
9 : R = Me
15 : R = H
14
f : R1=R2=H, R3=R4=OMe
g : R1=R2=R3=R4=OMe
h : R1=R2=H, R3=OMe, R4=OiPr
i : R1=R2=R3=OMe, R4=OiPr
16 : R=Me, X=Br
17 : R=X=H
Figure 1
O
Pd(OAc)2
(o-tol)3P
K2CO3
O
O
O
O
O
Br
+
N
iPrO
iPrO
N
DMF
reflux, 2h
N
iPrO
OMe
O
R
OMe
O
MeO
12
(45%)
13
(55%)
10 R=H
11 R=Ac
Scheme 4 Biaryl coupling reaction of amide 11
The coupling reaction of 16 using Pd(OAc)2, P(o-tol)3, Consequently, in a biaryl coupling reaction of N-bro-
and K2CO3 in degassed DMF gave a debromo-demethyl mobenzylnaphthylamine 5 using a Pd reagent, the in-
compound 17 and N-methyl-6,7-methylenedioxy-1-naph- tramolecular coordination of the benzylamino group to Pd
thylamine (7a)2e in 59% and 29% yields, respectively, and causes regioselective C-H activation to produce a new
no coupling product. The proposed mechanism is shown skeletal compound, benzonaphthazepine 8, and the bulki-
in Scheme 6. The elimination of a proton from the coordi- ness of the substituent at C7 on the naphthalene ring af-
nated intermediate (F) may help to relieve the strain on the fects the regioselectivity of the biaryl coupling reaction.
four-membered ring.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

1450
T. Harayama et al.
PAPER
Table 3 Results of the Coupling Reaction of Substituted N-(6-Bromobenzyl)-N-methyl-1-naphthylamines 5 in DMF under Refluxa
Entry
Substrate
Yield (%)
8
14
–
9
15
–
1
2
3
4
5
6
7
8
9
5ab
5b
5c
5d
5e
5f
R1 = OMe, R2 = Oi-Pr, R3 + R4 = OCH2O
R1 = R2 = R3 = R4 = H
76
81
86
44
60
22
18
–
trace
–
–
–
R1 = R2 = H, R3 + R4 = OCH2O
R1 = R2 = OMe, R3 = R4 = H
R1 = R2 = OMe, R3 + R4 = OCH2O
R1 = R2 = H, R3 = R4 = OMe
R1= R2 = R3 = R4 = OMe
–
–
–
–
–
–
–
–
–
33
34
44
53
12
10
11
11
–
5g
5h
5i
10
20
26
R1 = R2 = H, R3 = OMe, R4 = Oi-Pr
R1 = R2 = R3 = OMe, R4 = Oi-Pr
–
a All reactions were carried out using Pd(OAc)2 (0.2 equiv), P(o-Tol)3 (0.4 equiv), and K2CO3 (2 equiv) under Ar atmosphere for 2 h.
b See entry 10 in Table 2.
R1
R2
R1
R2
Br
R2=OiPr
R2=OMe
Pd
8
R
R
N
N
Me
Me
14
R1
R2
Pd
Br
7
R
N
R1
Me
R1
R2
R2
5
Br
R2=OMe
R2=H
8
Pd
R
N
R
N
Me
R1+R2=OCH2O
8
Me
Scheme 5 Proposed mechanism for the biaryl coupling reaction of N-(bromobenzyl)naphthylamine 5 with Pd
O
O
Br
Br
O
Pd
(a)
Pd
Pd
O
(a)
+
CH2
17
N
16
N
CH2
H
(b)
H
F
Br
Pd
O
O
7a
+
CH3
N
(b)
Scheme 6 Proposed mechanism for the reaction of N-benzyl-1-naphthylamine 16 with Pd
ternal standard TMS (d = 0.0) and the coupling constants are given
in Hz. MS spectra were obtained on a VG-70SE spectrometer. Col-
umn chromatography was carried out with Merck silica gel (230–
400 mesh) and Wako activated alumina (300 mesh). All the exper-
iments were carried out in an argon atmosphere, unless otherwise
noted, and the extract was washed with brine, dried over anhyd
K2CO3, and filtered, and the filtrate was concentrated to dryness un-
Melting points were measured on a micro-melting point hot-stage
apparatus (Yanagimoto) and are uncorrected. IR spectra were re-
corded on JASCO A-102 or FT/IR 350 spectrophotometers, and 1H
NMR spectra in CDCl3 were recorded on JNM-MY60FT (60 MHz),
Varian VXR-200 (200 MHz), or VXR-500 (500 MHz) spectrome-
ters. NMR spectral data are reported in ppm downfield from the in-
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

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Novel Synthesis of a New Skeletal Compound Benzonaphthazepine
1451
der reduced pressure. Pd(OAc)2 was treated with boiling benzene
and the mixture was filtered while hot. The hot filtrate was then con-
centrated to dryness to give purified Pd(OAc)2.
6,7-Dimethoxy-N-methyl-1-naphthylamine (7c)
IR (KBr): 3400 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.02 (s, 3 H), 3.99 (s, 3 H), 4.01
(s, 3 H), 6.57 (dd, J = 7.4, 1.2 Hz, 1 H), 7.03 (s, 1 H), 7.10 (s, 1 H),
7.14 (dd, J = 8.4, 1.2 Hz, 1 H), 7.26 (dd, J = 8.4, 7.2 Hz, 1 H).
6-Bromo-3-isopropoxy-2-methoxybenzylBromide(6a);Typical
Procedure
Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C,
71.85; H, 6.66; N, 6.36.
To a suspension of NaBH4 (195 mg, 5.15 mmol) in anhyd MeOH
(40 mL) was added 3-isopropoxy-2-methoxybenzaldehyde6 (2.0 g,
1.03 mmol) and the mixture was stirred for 30 min at r.t. The reac-
tion mixture was poured into water and extracted with EtOAc. The
residue dissolved in CHCl3 was subjected to column chromatogra-
phy on silica gel. Elution with EtOAc–hexane (1:5) gave 3-isopro-
poxy-2-methoxybenzylalcohol (1.86 g, 92%) as a colorless oil. To
the solution of 3-isopropoxy-2-methoxybenzylalcohol (1.5 g, 7.64
mmol) in CHCl3 (80 mL) was then added dropwise a solution of
bromine (0.47 mL, 9.17 mmol) in CHCl3 (10 mL) under ice-cool-
ing. The mixture was stirred for 3 h at r.t. and the solvent was evap-
orated under reduced pressure. The residue was dissolved in CHCl3
and subjected to column chromatography on silica gel. Elution with
EtOAc–hexane (1:20) gave 6a (1.52 g, 59%); colorless needles; mp
61–62 °C (Et2O).
7-Isopropoxy-6-methoxy-N-methyl-1-naphthylamine (7d);
Typical Procedure
To a solution of 7-isopropoxy-6-methoxy-1-naphthylamine9 (578
mg, 2.50 mmol) in anhyd pyridine (7 mL) was added TFAA (494
mL, 3.50 mmol). The reaction mixture was stirred at r.t. for 30 min
and poured into ice water. The mixture was made to acidic with
10% HCl and extracted with EtOAc. To a solution of the residue in
anhyd acetone (5 mL) were added MeI (331 mL, 5.00 mmol) and
solid NaOH (100 mg, 2.50 mmol). The reaction mixture was re-
fluxed for 30 min and the solvent was removed under reduced pres-
sure. The residue was dissolved in EtOH (15 mL) and aq 5% NaOH
solution (8 mL), and refluxed for 1.5 h. The reaction mixture was
diluted with water and the precipitates were collected by filtration.
The crystalline mass was recrystallized from EtOAc to give 7d (463
mg, 76%) as colorless needles; mp 168–170 °C.
3-Isopropoxy-2-methoxybenzylalcohol
IR (CHCl3): 3463 cm–1.
IR (KBr): 3390, 1255, 1030 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.37 (d, J = 6.5 Hz, 6 H), 3.90 (s,
3 H), 4.56 (septet, J = 6.0 Hz, 1 H), 4.68 (s,2 H), 6.87–7.02 (m, 3 H).
1H NMR (200 MHz, CDCl3): d = 1.44 (d, J = 6.2 Hz, 2 × 3 H), 3.01
(s, 3 H), 3.96 (s, 3 H), 4.69 (septet, J = 6.2 Hz, 1 H), 6.53 (d, J = 7.4
Hz, 1 H), 7.11–7.29 (m, 4 H).
FAB–MS: m/z calcd for C11H16O3: 196.1099; found: 196.1134.
6-Bromo-3-isopropoxy-2-methoxybenzyl Bromide (6a)
1H NMR (200 MHz, CDCl3): d = 1.36 (d, J = 6.0 Hz, 6 H), 3.98 (s,
3 H), 4.52 (septet, J = 6.0 Hz, 1 H), 4.70 (s, 2 H), 6.77 (d, J = 9.0
Hz, 1 H), 7.23 (d, J = 9.0 Hz, 1 H).
Anal. Calcd for C15H19NO2: C, 73.44; H, 7.81; N, 5.71. Found: C,
73.35; H, 7.60; N, 5.51.
Preparation of N-Benzyl-N-methyl-1-naphthylamines 5 (Table
1); Typical Procedure
FAB–MS: m/z = 336 [M]+, 338 [M + 2]+, 340 [M + 4]+.
Method A: To a suspension of N-methyl-1-naphthylamines 7a–c
(4.00 mmol), Bu4NI (148 mg, 0.40 mmol), and K2CO3 (1.10 g, 8.00
mmol) in anhyd DMF (20 mL) were added bromobenzyl bromides
6a–c (4.00 mmol), and the reaction mixture was stirred for 1–2 h at
100 °C. The mixture was poured into water and extracted with
EtOAc. The residue was dissolved in CHCl3 and subjected to col-
umn chromatography on silica gel.
Anal. Calcd for C11H14Br2O2: C, 39.08; H, 4.17. Found: C, 39.32;
H, 4.23.
6,7-Dimethoxy-N-methyl-1-naphthylamine (7c); Typical Proce-
dure
To a solution of 6,7-dimethoxy-1-naphthylamine8 (3.12 g, 15.35
mmol) in anhyd pyridine (40 mL) was added TFAA (3.30 mL,
23.03 mmol). The reaction mixture was stirred at r.t. for 30 min and
poured into ice water. The mixture was made acidic with 10% HCl
and extracted with EtOAc. The residue was recrystallized from
EtOAc–hexane to give N-(6,7-dimethoxy-1-naphthyl)trifluoroace-
tamide (4.00 g, 87%) as colorless needles; mp 146–147 °C. To the
solution of N-(6,7-dimethoxy-1-naphthyl)trifluoroacetamide (4.26
g, 14.24 mmol) and MeI (3.54 mL, 56.94 mmol) in anhyd acetone
(120 mL) was added solid KOH (3.20 g, 56.94 mmol). The reaction
mixture was refluxed for 45 min and the solvent removed under re-
duced pressure. The residue was dissolved in EtOH (80 mL) and aq
5% NaOH solution (80 mL), and refluxed for 15 min. The reaction
mixture was diluted with water and extracted with Et2O. The resi-
due dissolved in CHCl3 was subjected to column chromatography
on Al2O3. Elution with hexane–EtOAc (10:1) gave 7c (2.54 g, 82%)
as colorless needles; mp 168–170 °C (MeOH).
Method B: To a solution of N-methyl-1-naphthylamines (7c and
7d) (1.00 mmol) and i-Pr2NEt (348 mL, 2.00 mmol) in anhyd DMF
(4 mL) were added bromobenzyl bromides 6b and 6c (1.10 mmol)
and the reaction mixture was stirred for 1 h at 100 °C. The mixture
was diluted with EtOAc and the entire organic layer was washed
with brine. The residue was dissolved in CHCl3 and subjected to
column chromatography on silica gel.
N-(6-Bromo-3-isopropoxy-2-methoxybenzyl)-N-methyl-6,7-
methylenedioxy-1-naphthylamine (5a)
Elution with EtOAc–hexane (1:20) gave 5a (71%) as colorless
prisms; mp 110–111 °C (EtOH).
IR (KBr): 1248, 1034 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.34 (d, J = 6.2 Hz, 6 H), 2.71 (s,
3 H), 3.85 (s, 3 H), 4.36 (s, 2 H), 4.52 (septet, J = 6.0 Hz, 1 H), 6.00
(s, 2 H), 6.73–7.79 (m, 7 H).
N-(6,7-Dimethoxy-1-naphthyl)trifluoroacetamide
IR (KBr): 3256, 1705 cm–1.
Anal. Calcd for C23H24BrNO4: C, 60.27; H, 5.28; N, 3.06. Found: C,
60.17; H, 5.26; N, 2.87.
1H NMR (200 MHz, CDCl3): d = 3.99 (s, 3 H), 4.01 (s, 3 H), 6.92
(s, 1 H), 7.16 (s, 1 H), 7.36 (dt, J = 8.0, 7.9 Hz, 1 H), 7.57 (br d, J =
7.9 Hz, 1 H), 7.68 (br d, J = 8.0 Hz, 1 H), 8.07 (br s, 1 H).
N-(2-Bromobenzyl)-N-methyl-1-naphthylamine (5b)
Elution with EtOAc–hexane (1:30) gave 5b (98%) as a colorless oil.
IR (CHCl3): 3011 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.88 (s, 3 H), 4.37 (s, 2 H), 7.10–
8.25 (m, 11 H).
Anal. Calcd for C14H12F3NO3: C, 56.19; H, 4.04; N, 4.68. Found: C,
56.38; H, 4.02; N, 4.66.
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T. Harayama et al.
PAPER
Anal. Calcd for C18H16BrN: C, 66.27; H, 4.94; N, 4.29. Found: C,
65.96; H, 5.15; N, 4.26.
IR (KBr): 1260, 1025 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.18 (s, 3 H), 1.21 (s, 3 H), 2.90
(s, 3 H), 3.96 (s, 3 H), 4.25 (septet, J = 6.0 Hz, 1 H), 4.28 (s, 2 H),
7.12 (s, 1 H), 7.07–7.21 (m, 2 H), 7.27 (dd, J = 8.0, 7.4 Hz, 1 H),
7.35–7.42 (m, 3 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 7.4 Hz, 1
H).
N-(6-Bromobenzyl)-N-methyl-6,7-methylenedioxy-1-naphthyl-
amine (5c)
Elution with EtOAc–hexane (1:30) gave 5c (70%) as colorless
prisms; mp 91–92 °C (EtOH).
IR (KBr): 1239, 1036 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.80 (s, 3 H), 4.30 (s, 2 H), 6.02
(s, 2 H), 7.09–7.70 (m, 9 H).
Anal. Calcd for C22H24BrNO2: C, 63.77; H, 5.84; N, 3.38. Found: C,
63.81; H, 5.69; N, 3.30.
N-(6-Bromo-2,3-dimethoxybenzyl)-7-isopropoxy-6-methoxy-N-
methyl-1-naphthylamine (5i)
Elution with EtOAc–hexane (1:10) gave 5i (96%) as colorless nee-
dles; mp 116.5–118 °C (i-PrOH).
Anal. Calcd for C19H16BrNO2: C, 61.64; H, 4.36; N, 3.78. Found: C,
61.35; H, 4.65; N, 3.70.
N-(6-Bromo-2,3-dimethoxybenzyl)-N-methyl-1-naphthyl-
amine (5d)
Elution with EtOAc–hexane (1:15) gave 5d (63%) as a colorless oil.
IR (CHCl3): 3014 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.82 (s, 3 H), 3.80 (s, 3 H), 3.88
(s, 3 H), 4.34 (s, 2 H), 6.84–8.34 (m, 9 H).
FAB–MS: m/z = 385 [M]+, 387 [M + 2]+.
IR (KBr): 1250, 1010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.42 (d, J = 6.0 Hz, 2 × 3 H), 2.74
(s, 3 H), 3.76 (s, 3 H), 3.84 (s, 3 H), 3.96 (s, 3 H), 4.41 (s, 2 H), 4.71
(septet, J = 6.0 Hz, 1 H), 6.73 (d, J = 8.8 Hz, 1 H), 7.10 (s, 1 H),
7.20–7.33 (m, 3 H), 7.42 (d, J = 7.2 Hz, 1 H), 7.72 (s, 1 H).
Anal. Calcd for C24H28BrNO4: C, 60.76; H, 5.95; N, 2.95. Found: C,
60.94; H, 6.20; N, 2.65.
FAB–MS: m/z calcd for C20H20BrNO2: 385.0677; found: 385.0736.
Coupling Reaction of N-(6-Bromo-3-isopropoxy-2-methoxy-
benzyl)-N-methyl-6,7-methylenedioxy-1-naphthylamine (5a)
under Various Conditions (Table 2); General Procedure
Compound 5a (0.3 mmol) was reacted with Pd(OAc)2 (0.2 equiv),
a phosphine ligand, and a base in degassed DMF (8 mL) using
Pd(OAc)2 and the phosphine ligand in the ratios indicated in
Table 2, and base (2 equiv) for the times and at the temperatures in-
dicated in the Table 2. Then, the reaction mixture was diluted with
EtOAc and the precipitate was removed by filtration. The residue
dissolved in CHCl3 was subjected to column chromatography on
silica gel. Elution with EtOAc–hexane (1:30) gave 5a. Successive
elution with the same solvent gave N-(3-isopropoxy-2-methoxy-
benzyl)-N-methyl-6,7-methylenedioxy-1-naphthylamine (9a) and
then 7,8-dihydro-10-isopropoxy-9-methoxy-7-methyl-1,2-methyl-
enedioxybenzo[e]naphth[1,8-bc]azepine (8a).
N-(6-Bromo-2,3-dimethoxybenzyl)-N-methyl-6,7-methylene-
dioxy-1-naphthylamine (5e)
Elution with EtOAc–hexane (1:10) gave 5e (98%) as colorless
prisms; mp 97–98 °C (EtOH).
IR (KBr): 1247, 1072 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.70 (s, 3 H), 3.83 (s, 3 H), 3.85
(s, 3 H), 4.37 (s, 2 H), 6.00 (s, 2 H), 6.74 (d, J = 8.8 Hz, 1 H), 7.09
(s, 1 H), 7.18–7.42 (m, 4 H), 7.77 (s, 1 H).
Anal. Calcd for C21H20BrNO4: C, 58.62; H, 4.68; N, 3.26. Found: C,
58.35; H, 4.73; N, 3.25.
N-(2-Bromobenzyl)-6,7-dimethoxy-N-methyl-1-naphthyl-
amine (5f)
Elution with EtOAc–hexane (1:10) gave 5f (95%) as colorless nee-
dles; mp 120–123 °C (Et2O).
8a
Colorless prisms; mp 128–129 °C (EtOAc).
IR (KBr): 1260, 1020 cm–1.
IR (KBr): 1250, 1042 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.90 (s, 3 H), 3.65 (s, 3 H), 3.98
(s, 3 H), 4.29 (s, 2 H), 7.11 (s, 1 H), 7.08–7.19 (m, 2 H), 7.29 (dd, J
= 8.0, 7.6 Hz, 1 H), 7.33 (dd, J = 7.4, 1.4 Hz, 1 H), 7.39–7.42 (m, 2
H), 7.58 (dd, J = 8.0, 1.2 Hz, 1 H), 7.80 (dd, J = 7.4, 1.4 Hz, 1 H).
1H NMR (200 MHz, CDCl3): d = 1.42 (d, J = 6.0 Hz, 2 × 3 H), 3.01
(s, 3 H), 3.92 (s, 3 H), 4.38 (s, 2 H), 4.64 (septet, J = 6.0 Hz, 1 H),
5.98 (s, 2 H), 6.57 (d, J = 7.5 Hz, 1 H), 6.86 (d, J = 7.5 Hz, 1 H),
7.02 (s, 1 H), 7.08 (d, J = 7.0 Hz, 1 H), 7.14 (t, J = 7.5 Hz, 1 H), 7.41
(d, J = 8.5 Hz, 1 H).
Anal. Calcd for C20H20BrNO2: C, 62.19; H, 5.22; N, 3.63. Found: C,
62.11; H, 5.28; N, 3.56.
Anal. Calcd for C23H23NO4: C, 73.19; H, 6.14; N, 3.71. Found: C,
73.10; H, 6.10; N, 3.64.
N-(6-Bromo-2,3-dimethoxybenzyl)-N-methyl-6,7-dimethoxy-1-
naphthylamine (5g)
9a
Elution with EtOAc–hexane (1:10) gave 5g (74%) as colorless
prisms; mp 111–112 °C (EtOH).
IR (KBr): 1252, 1012 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.76 (s, 3 H), 3.73 (s, 3 H), 3.83
(s, 3 H), 3.98 (s, 3 H), 3.99 (s, 3 H), 4.39 (s, 2 H), 6.72 (d, J = 8.8
Hz, 1 H), 7.09 (s, 1 H), 7.24–7.36 (m, 3 H), 7.44 (dd, J = 7.5, 1.6
Hz, 1 H), 7.74 (s, 1 H).
Colorless prisms; mp 93–94 °C (EtOH).
IR (KBr): 1250, 1039 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38 (d, J = 6.1 Hz, 6 H), 2.75 (s,
3 H), 3.83 (s, 3 H), 4.23 (s, 2 H), 4.57 (septet, J = 6.1 Hz, 1 H), 6.02
(s, 2 H), 6.84 (dd, J = 7.8, 1.6 Hz, 1 H), 7.01 (dd, J = 7.8, 7.8 Hz, 1
H), 7.09 (dd, J = 7.8, 1.2 Hz, 1 H), 7.11 (s, 1 H), 7.13 (dd, J = 7.8,
1.6 Hz, 1 H), 7.26 (dd, J = 7.8, 7.8 Hz, 1 H), 7.38 (br d, J = 7.8 Hz,
1 H), 7.75 (s, 1 H).
Anal. Calcd for C22H24BrNO4: C, 59.20; H, 5.42; N, 3.14. Found: C,
59.12; H, 5.18; N, 3.14.
Anal. Calcd for C23H25NO4: C, 72.80; H, 6.64; N, 3.69. Found: C,
73.07; H, 6.70; N, 3.66.
N-(2-Bromobenzyl)-7-isopropoxy-6-methoxy-N-methyl-1-
naphthylamine (5h)
Elution with EtOAc–hexane (1:30) gave 5h (quantitative) as color-
less needles; mp 102–103 °C (MeOH).
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of a New Skeletal Compound Benzonaphthazepine
1453
N-(6-Bromo-3-isopropoxy-2-methoxybenzyl)-6,7-methylene-
dioxy-1-naphthylamine (10); Typical Procedure
and subjected to chromatography through silica gel. Elution with
EtOAc–hexane (1:2) gave 12 (18.1 mg, 45%) and successive elu-
tion with the same solvent gave 13 (22.4 mg, 55%).
To a mixture of 6-bromo-3-hydroxy-2-methoxybenzaldehyde7 (100
mg, 0.43 mmol) and K2CO3 (210 mg, 1.52 mmol) in anhyd DMF
(15 mL) was added i-PrBr (50 mL, 0.52 mmol), and the reaction
mixture was stirred at 100 °C for 2 h. The mixture was poured into
water and extracted with Et2O. The residue was dissolved in CHCl3
and subjected to chromatography on silica gel. Elution with
EtOAc–hexane (1:19) gave 6-bromo-3-isopropoxy-2-methoxyben-
zaldehyde (105 mg, 89%) as pale yellow needles, mp 32–35 °C
(Et2O). A solution of 6-bromo-3-isopropoxy-2-methoxybenzylal-
dehyde (500 mg, 1.83 mmol) and 6,7-methylenedioxy-1-naphthyl-
amine (343 mg, 1.83 mmol) in EtOH (3 mL) was refluxed for 2 h.
After evaporating the solvent, the residue was dissolved in EtOH (5
mL), NaBH4 (1.39 g, 36.6 mmol) was added to the solution, and the
mixture was refluxed for 1 h. The solvent was evaporated under re-
duced pressure and the residue was diluted with water, and then ex-
tracted with CHCl3. The residue was dissolved in CHCl3 and
subjected to chromatography on alumina. Elution with EtOAc–hex-
ane (1:20) gave 10 (569 mg, 70%) as colorless prisms; mp 80–83 °C
(EtOH).
12
Colorless prisms; mp 176–177 °C (Et2O).
IR (KBr): 1660 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.39 (d, J = 6.0 Hz, 3 H), 1.41 (d,
J = 6.0 Hz, 3 H), 1.79 (s, 3 H), 3.80 (d, J = 15.4 Hz, 1 H), 3.97 (s, 3
H), 4.62 (septet, J = 6.0 Hz, 1 H), 6.08 (br d, J = 2.4 Hz, 2 H), 6.25
(d, J = 15.4 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.15 (s, 1 H), 7.28
(s, 1 H), 7.52 (d, J = 8.6 Hz, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.69 (d,
J = 8.6 Hz, 1 H).
Anal. Calcd for C24H23NO5: C, 71.10; H, 5.72; N, 3.45. Found: C,
69.81; H, 5.77; N, 3.24.
13
Colorless prisms; mp 86–88 °C (Et2O).
IR (KBr): 1635 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.42 (d, J = 6.0 Hz, 2 × 3 H), 2.00
(s, 3 H), 3.93 (d, J = 15.8 Hz, 1 H), 4.16 (s, 3 H), 4.62 (septet, J =
6.0 Hz, 1 H), 5.89 (br s, 1 H), 5.97 (d, J = 15.8 Hz, 1 H), 6.17 (br s,
1 H), 6.84 (d, J = 8.8 Hz, 1 H), 7.10 (dd, J = 7.6, 1.4 Hz, 1 H), 7.17
(s, 1 H), 7.29 (dt, J = 7.8, 7.6 Hz, 1 H), 7.59 (d, J = 8.8 Hz, 1 H),
7.61 (dd, J = 7.8, 1.4 Hz, 1 H).
6-Bromo-3-isopropoxy-2-methoxybenzaldehyde
IR (KBr): 1684 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.38 (d, J = 6.1 Hz, 2 × 3 H), 3.94
(s, 3 H), 4.55 (septet, J = 6.1 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 7.31
(d, J = 8.8 Hz, 1 H), 10.34 (s, 1 H).
FAB–MS: m/z calcd for C24H24NO5: 406.1654; found: 406.1637.
FAB-MS: m/z calcd for C11H13BrO3: 272.0048; found: 272.0001.
Coupling Reaction of N-Bromobenzyl-N-methyl-1-naphthyl-
amines (5b–i) Using Palladium Reagent (Table 3); General Pro-
cedure
To a solution of 5b–i (0.2 mmol) in degassed DMF (3 mL) were
added Pd(OAc)2 (8.8 mg, 0.04 mmol), P(o-tol)3 (24.4 mg, 0.08
mmol), and K2CO3 (55.2 mg, 0.4 mmol), and the reaction mixture
was stirred for 2 h under reflux. Then, the mixture was diluted with
EtOAc and the precipitate was removed by filtration. The filtrate
was washed with brine. The residue was dissolved in CHCl3 and
subjected to column chromatography on silica gel.
N-(6-Bromo-3-isopropoxy-2-methoxybenzyl)-6,7-methylene-
dioxy-1-naphthylamine (10)
IR (KBr): 1247, 1042 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.37 (d, J = 6.0 Hz, 2 × 3 H), 3.86
(s, 3 H), 4.54 (septet, J = 6.0 Hz, 1 H), 4.43 (br s, 1 H), 4.55 (s, 2 H),
5.99 (s, 2 H), 6.75–7.30 (m, 7 H).
Anal. Calcd for C22H22BrNO4: C, 59.47; H, 4.99; N, 3.15. Found: C,
59.21; H, 5.13; N, 3.14.
N-(6-Bromo-3-isopropoxy-2-methoxybenzyl)-N-(6,7-methyl-
enedioxy-1-naphthyl)acetamide (11); Typical Procedure
To a solution of 10 (190 mg, 0.427 mmol) in anhyd pyridine (2 mL)
was added Ac2O (81 mL, 0.853 mmol). The reaction mixture was
stirred at r.t. overnight and poured into 10% HCl and then extracted
with EtOAc. The residue was dissolved in CHCl3 and subjected to
chromatography through silica gel. Elution with EtOAc–hexane
(1:20) gave 11 (161 mg, 77%) as colorless prisms; mp 134–135 °C
(Et2O).
7,8-Dihydro-7-methylbenzo[e]naphth[1,8-b,c]azepine (8b)
Elution with EtOAc–hexane (1:50) gave 8b (81%) as a pale yellow
oil.
IR (CHCl3): 3022 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.05 (s, 3 H), 4.26 (s, 2 H), 6.67
(dd, J = 5.0, 4.0 Hz, 1 H), 7.05–7.95 (m, 9 H).
FAB-MS: m/z [M]+ calcd for C18H15N: 245.1204; found: 245.1161.
IR (KBr): 1654 cm–1.
7,8-Dihydro-7-methyl-1,2-methylenedioxybenzo[e]naphth[1,8-
b,c]azepine (8c)
Elution with EtOAc–hexane (1:30) gave 8c (86%) as colorless
prisms; mp 125–126 °C (EtOAc).
1H NMR (200 MHz, CDCl3): d = 1.22 (d, J = 6.1 Hz, 3 H), 1.24 (d,
J = 6.1 Hz, 3 H), 1.76 (s, 3 H), 3.25 (s, 3 H), 4.35 (septet, J = 6.1 Hz,
1 H), 4.82 (d, J = 13.6 Hz, 1 H), 5.69 (d, J = 13.6 Hz, 1 H), 6.06 (s,
2 H), 6.64 (d, J = 8.8 Hz, 1 H), 7.26 (dd, J = 7.4, 1.2 Hz, 1 H), 7.02–
7.56 (m, 5 H).
IR (KBr): 1278, 1051 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.97 (s, 3 H), 4.24 (br s, 2 H), 5.99
(s, 2 H), 6.48 (dd, J = 6.8, 2.2 Hz, 1 H), 7.06 (s, 1 H), 7.09–7.40 (m,
5 H), 7.73 (br d, J = 7.2 Hz, 1 H).
Anal. Calcd for C24H24BrNO5: C, 59.27; H, 4.97; N, 2.88. Found: C,
59.10; H, 4.78; N, 2.87.
Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
79.05; H, 5.47; N, 4.74.
5-Acetyl-5,6-dihydro-8-isopropoxy-7-methoxy-2,3-methylene-
dioxybenzo[c]-phenanthridine (12) and 7-Acetyl-7,8-dihydro-
10-isopropoxy-9-methoxy-1,2-methylenedioxyben-
7,8-Dihydro-9,10-dimethoxy-7-methylbenzo[e]naphth[1,8-
b,c]azepine (8d)
Elution with EtOAc–hexane (1:30) gave 8d (44%) as pale yellow
prisms; mp 119–121 °C (EtOAc).
zo[e]naphth[1,8-bc]azepine (13); Typical Procedure
To a solution of compound 11 (48.6 mg, 0.100 mmol) in DMF (2
mL) were added Pd(OAc)2 (4.5 mg, 0.020 mmol), P(o-tol)3 (12.2
mg, 0.040 mmol), and K2CO3 (27.6 mg, 0.200 mmol). The reaction
mixture was refluxed for 1 h and diluted with EtOAc. The precipi-
tate was removed by filtration. The residue was dissolved in CHCl3
IR (KBr): 1231, 1036 cm–1.
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T. Harayama et al.
PAPER
1H NMR (200 MHz, CDCl3): d = 3.08 (s, 3 H), 3.93 (s, 2 × 3 H),
4.43 (br s, 2 H), 6.63 (dd, J = 6.2, 2.8 Hz, 1 H), 6.92 (d, J = 8.6 Hz,
1 H), 7.14 (d, J = 8.6 Hz, 1 H), 7.23–7.46 (m, 4 H), 7.71 (dd, J = 8.0,
1.6 Hz, 1 H).
FAB–MS: m/z [M]+ calcd for C20H19NO2: 305.1215; found:
305.1264.
and successive elution with the same solvent gave 6,7-dimethoxy-
N-(2,3-dimethoxybenzyl)-N-methyl-1-naphthylamine (9g) (10%).
Elution with EtOAc–hexane (1:6) gave 2,3,7,8-tetramethoxy-5-
methyl-5,6-dihydrobenzo[c]phenanthridine (14g) (34%) and elu-
tion with EtOAc–hexane (1:4) gave 6,7-dimethoxy-N-(2,3-meth-
oxybenzyl)-1-naphthylamine (15g) (10%).
8g
7,8-Dihydro-9,10-dimethoxy-7-methyl-1,2-methylenedioxyben-
zo[e]naphtha-[1,8-bc]-azepine (8e)
Elution with EtOAc–hexane (1:50) gave 8e (60%) as pale yellow
prisms; mp 128–129 °C (EtOAc).
Colorless amorphous solid.
IR (CHCl3): 1230, 1020 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.03 (s, 3 H), 3.45 (s, 3 H), 3.93
(s, 3 H), 3.95 (s, 3 H), 3.99 (s, 3 H), 4.43 (br s, 2 H), 6.46 (d, J = 7.5
Hz, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 7.03 (s, 1 H), 7.07 (d, J = 7.5 Hz,
1 H), 7.18 (dd, J = 8.0, 7.5 Hz, 1 H), 7.27 (d, J = 8.8 Hz, 1 H).
IR (KBr): 1276, 1065 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.00 (s, 3 H), 3.91 (s, 3 H),3.92 (s,
3 H), 4.39 (br s, 2 H), 5.98 (s, 2 H), 6.58 (dd, J = 7.2, 1.8 Hz, 1 H),
6.88 (d, J = 8.6 Hz, 1 H), 7.03 (s, 1 H), 7.08 (dd, J = 7.8, 1.8 Hz, 1
H), 7.15 (t, J = 7.8, 7.2 Hz, 1 H), 7.45 (d, J = 8.6 Hz, 1 H).
FAB–MS: m/z [M]+ calcd for C22H23NO4: 365.1627; found:
365.1641.
FAB–MS: m/z [M + 1]+ calcd for C21H20NO4: 350.1392; found:
350.1422.
9g
Colorless needles; mp 102–104 °C (MeOH).
Isolation of Products from Coupling Reaction of N-(2-Bro-
mobenzyl)-6,7-dimethoxy-N-methyl-1-naphthylamine (5f)
Elution with EtOAc–hexane (1:30) gave 7,8-dihydro-1,2-
dimethoxy-7-methyl-benzo[e]naphth[1,8-b,c]azepine (8f) (22%)
and successive elution with the same solvent gave N-benzyl-6,7-
dimethoxy-N-methyl-1-naphthylamine (9f) (12%). Elution with
EtOAc–hexane (1:10) gave 2,3-dimethoxy-5-methyl-5,6-dihy-
drobenzo[c]phenanthridine (14f) (33%).
IR (KBr): 1260, 1045 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.84 (s, 3 H), 3.77 (s, 3 H), 3.78
(s, 3 H), 3.88 (s, 3 H), 3.99 (s, 3 H), 4.29 (s, 2 H), 6.86 (dd, J = 8.0,
1.4 Hz, 1 H), 7.05–7.12 (m, 3 H), 7.28 (dd, J = 8.0, 7.6 Hz, 1 H),
7.30 (d, J = 7.6 Hz, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.59 (s, 1 H).
Anal. Calcd for C22H25NO4: C, 71.91; H, 6.86; N, 3.81. Found: C,
71.68; H, 6.94; N, 3.65.
14g
8f
Colorless prisms; 180–183 °C (CHCl3–MeOH) (lit.10 186–188 °C)
Colorless amorphous solid.
IR (CHCl3): 1240, 1020 cm–1.
15g
1H NMR (500 MHz, CDCl3): d = 2.98 (s, 3 H), 3.46 (s, 3 H), 3.81
(br s, 1 H), 4.00 (s, 3 H), 4.75 (br s, 1 H), 6.52 (br s, 1 H), 7.07 (s, 1
H), 7.09 (d, J = 8.0 Hz, 1 H), 7.19 (dd, J = 8.0, 8.0 Hz, 1 H), 7.25–
7.31 (m, 3 H), 7.58 (d, J = 8.5 Hz, 1 H).
FAB–MS: m/z [M]+ calcd for C20H19NO2: 305.1416; found:
305.1415.
Colorless needles; mp 140–142 °C (CHCl3–MeOH).
IR (KBr): 3380, 1255, 1030 cm–1
1H NMR (300 MHz, CDCl3): d = 3.89 (s, 2 × 3 H), 3.99 (s, 2 × 3 H),
4.52 (s, 2 H), 6.56 (d, J = 7.2 Hz, 1 H), 6.87–7.26 (m, 7 H).
FAB–MS: m/z = 353 [M]+
Anal. Calcd for C21H23NO4: C, 71.37; H, 6.86; N, 3.96. Found: C,
70.91; H, 6.56; N, 3.62.
9f
Colorless needles; mp 91–92.5 °C (MeOH).
IR (KBr): 1260, 1030 cm–1.
Isolation of Products from Coupling Reaction of N-(2-Bro-
mobenzyl)-6,7-dimethoxy-N-methyl-1-naphthylamine (5h)
Elution with EtOAc–hexane (1:50) gave 7-isopropoxy-6-methoxy-
N-(2,3-dimethoxybenzyl)-N-methyl-1-naphthylamine (9h) (11%)
and elution with EtOAc–hexane (1:30) gave 3-isopropoxy-2-meth-
oxy-5-methyl-5,6-dihydrobenzo[c]phenanthridine (14h) (44%).
Elution with EtOAc–hexane (1:6) gave N-benzyl-7-isopropoxy-6-
methoxy-1-naphthylamine (15h) (20%).
1H NMR (200 MHz, CDCl3): d = 2.82 (s, 3 H), 3.83 (s, 3 H), 4.00
(s, 3 H), 4.25 (s, 2 H), 7.04 (dd, J = 7.4, 1.2 Hz, 1 H), 7.13 (s, 1 H),
7.24–7.49 (m, 7 H), 7.63 (s, 1 H).
Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
77.96; H, 6.74; N, 4.47.
14f
Colorless prisms; 144–146 °C (MeOH).
9h
Colorless oil.
IR (CHCl3): 1255, 1010 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.31 (s, 3 H), 1.34 (s, 3 H), 2.81
(s, 3 H), 3.97 (s, 3 H), 4.25 (s, 2 H), 4.49 (septet, J = 6.0 Hz, 1 H),
7.02 (dd, J = 7.6, 1.2 Hz, 1 H), 7.13 (s, 1 H), 7.22–7.45 (m, 7 H),
7.62 (s, 1 H).
IR (KBr): 1255, 1030 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.65 (s, 3 H), 4.02 (s, 3 H), 4.08
(s, 3 H), 4.22 (s, 2 H), 7.14 (s, 1 H), 7.28–7.32 (m, 2 H), 7.40 (ddd,
J = 7.2, 6.6, 2.4 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 7.66 (s, 1 H),
7.79 (d, J = 8.6 Hz, 1 H), 7.80 (d, J = 7.2 Hz, 1 H).
Anal. Calcd for C20H19NO2: C, 78.66; H, 6.27; N, 4.59. Found : C,
79.06; H, 6.32; N, 4.66.
FAB–MS: m/z [M]+ calcd for C22H25NO2: 335.1885; found:
335.1862.
Isolation of Products from Coupling Reaction of N-(6-Bromo-
2,3-dimethoxybenzyl)-6,7-dimethoxy-N-methyl-1-naphthyl-
amine (5g)
14h
Colorless prisms; 159–161 °C (MeOH).
Elution with EtOAc–hexane (1:10) gave 7,8-dihydro-1,2,9,10-tet-
ramethoxy-7-methyl-benz[e]naphtha[1,8-b,c]azepine (8g) (18%)
IR (KBr): 1255, 1045 cm–1.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

PAPER
Novel Synthesis of a New Skeletal Compound Benzonaphthazepine
1455
1H NMR (200 MHz, CDCl3): d = 1.49 (s, 3 H), 1.52 (s, 3 H), 2.63
(s, 3 H), 3.99 (s, 3 H), 4.21 (s, 2 H), 4.85 (septet, J = 6.0 Hz, 1 H),
7.14 (s, 1 H), 7.28–7.32 (m, 2 H), 7.39 (ddd, J = 7.2, 6.6, 2.4 Hz, 1
H), 7.53 (d, J = 8.6 Hz, 1 H), 7.69 (s, 1 H), 7.78 (d, J = 8.6 Hz, 1 H),
7.80 (d, J = 7.0 Hz, 1 H).
from Et2O–hexane to give N-(2-bromo-6,7-methylenedioxy-1-
naphthyl)trifluoroacetamide (632 mg, 88%) as colorless needles,
mp 182–183 °C. To the solution of N-(2-bromo-6,7-methylene-
dioxy-1-naphthyl)trifluoroacetamide (2.50 g, 6.90 mmol) and MeI
(1.72 mL, 27.62 mmol) in anhyd acetone (200 mL) was added solid
KOH (1.60 g, 27.62 mmol). The reaction mixture was refluxed for
50 min and the solvent was removed under reduced pressure. The
residue was dissolved in EtOH (80 mL) and aq 5% NaOH solution
(80 mL), and refluxed for 30 min. The reaction mixture was diluted
with water and extracted with Et2O. The residue was recrystallized
from EtOH to give 7e (1.71 g, 89%) as colorless needles; mp 83–84
°C.
Anal. Calcd for C22H23NO2: C, 79.25; H, 6.95; N, 4.20. Found: C,
79.39; H, 6.83; N, 4.08.
15h
Colorless needles; mp 125–127 °C (MeOH).
IR (KBr): 3410, 1250, 1035 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.40 (s, 3 H), 1.43 (s, 3 H), 3.96
(s, 3 H), 4.49 (s, 2 H), 4.68 (septet, J = 6.0 Hz, 1 H), 6.55 (dd, J =
7.0, 1.4 Hz, 1 H), 7.12 (s, 1 H), 7.16–7.49 (m, 8 H).
N-(2-Bromo-6,7-methylenedioxy-1-naphthyl)trifluoroacet-
amide
IR (KBr): 3320, 1714 cm–1.
Anal. Calcd for C21H23NO2: C, 78.47; H, 7.21; N, 4.36. Found: C,
78.74; H, 7.46; N, 3.89.
1H NMR (200 MHz, CDCl3): d = 6.09 (s, 2 H), 7.02 (s, 1 H), 7.13
(s, 1 H), 7.53 (d, J = 8.8 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.90 (br
s, 1 H).
Isolation of Products from Coupling Reaction of N-(2-Bro-
mobenzyl)-6,7-dimethoxy-N-methyl-1-naphthylamine (5i)
Elution with EtOAc–hexane (1:50) gave 7-isopropoxy-6-methoxy-
N-(2,3-dimethoxybenzyl)-N-methyl-1-naphthylamine (9i) (11%)
and elution with EtOAc–hexane (1:50) gave 3-isopropoxy-2,7,8-tri-
Anal. Calcd for C13H7BrF3NO3: C, 43.12; H, 1.95; N, 3.87. Found:
C, 42.89; H, 2.27; N, 3.75.
2-Bromo-N-methyl-6,7-methylenedioxy-1-naphthylamine (7e)
IR (KBr): 3347, 1244, 1037 cm–1.
methoxy-5-methyl-5,6-dihydrobenzo[c]phenanthridine
(14i)
(53%). Elution with EtOAc–hexane (1:10) gave 7-isopropoxy-N-
(2,3-methoxybenzyl)-6-methoxy-1-naphthylamine (15i) (26%).
1H NMR (200 MHz, CDCl3): d = 2.89 (s, 3 H), 3.78 (br s, 1 H), 6.06
(s, 2 H), 7.06 (s, 1 H), 7.20 (d, J = 8.7 Hz, 1 H), 7.40 (d, J = 8.7 Hz,
1 H), 7.49 (s, 1 H).
9i
Colorless needles; mp 102–104 °C (MeOH).
IR (KBr): 1260, 1030 cm–1.
Anal. Calcd for C12H10BrNO2: C, 51.45; H, 3.60; N, 5.00. Found: C,
51.25; H, 3.78; N, 4.91.
1H NMR (200 MHz, CDCl3): d = 1.25 (s, 3 H), 1.28 (s, 3 H), 2.84
(s, 3 H), 3.76 (s, 3 H), 3.88 (s, 3 H), 3.96 (s, 3 H), 4.29 (s, 2 H), 4.40
(septet, J = 6.0 Hz, 1 H), 6.87 (dd, J = 8.0, 1.2 Hz, 1 H), 7.04–7.41
(m, 6 H), 7.56 (s, 1 H).
N-Benzyl-N-methyl-2-bromo-6,7-methylenedioxy-1-naphthyl-
amine (16); Typical Procedure
To a suspension of N-methyl-1-naphthylamine 7e (560 mg, 2.00
mmol), Bu4NI (148 mg, 0.40 mmol), and K2CO3 (553 mg, 4.00
mmol) in anhyd DMF (4 mL) was added benzyl bromide (0.48 mL,
4.00 mmol), and the reaction mixture was stirred for 2 h at 100 °C.
The mixture was poured into water and extracted with Et2O. The
residue was dissolved in CHCl3 and subjected to column chroma-
tography on silica gel. Elution with EtOAc–hexane (1:30) gave 16
(724 mg, 98%) as a colorless oil.
Anal. Calcd for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found: C,
72.69; H, 7.18; N, 3.36.
14i
Colorless needles; mp 127–131 °C.
1H NMR (200 MHz, CDCl3): d = 1.48 (s, 3 H), 1.52 (s, 3 H), 2.62
(s, 3 H), 3.88 (s, 3 H), 3.93 (s, 3 H), 3.98 (s, 3 H), 4.31 (s, 2 H), 4.85
(septet, J = 6.0 Hz, 1 H), 6.94 (d, J = 8.4 Hz, 1 H), 7.13 (s, 1 H), 7.50
(d, J = 8.4 Hz, 1 H), 7.51 (d, J = 8.6 Hz, 1 H), 7.69 (s, 1 H), 7.71 (d,
J = 8.6 Hz, 1 H).
IR (CHCl3): 1241, 1041 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.82 (s, 3 H), 4.28 (d, J = 13.8 Hz,
2 H), 4.52 (d, J = 13.8 Hz, 2 H), 6.05 (d, J = 1.8 Hz, 1 H), 7.07 (s, 1
H), 7.29–7.48 (m, 6 H), 7.75 (s, 1 H).
FAB–MS: m/z = 369 [M]+, 371 [M + 2]+.
FAB–MS: m/z [M]+ calcd for C19H16BrNO2: 369.0364; found:
Anal. Calcd for C24H27NO4: C, 73.26; H, 6.92; N, 3.56. Found: C,
73.10; H, 6.52; N, 3.42.
369.0364.
15i
Colorless needles; mp 117–118 °C (MeOH).
IR (KBr): 3380, 1250, 1035 cm–1.
Coupling Reaction of N-Benzyl-N-methyl-2-bromo-6,7-methyl-
enedioxy-1-naphthylamine (16) Using Pd Reagent
1H NMR (200 MHz, CDCl3): d = 1.40 (s, 3 H), 1.43 (s, 3 H), 3.90
(s, 3 H), 3.96 (s, 3 H), 4.51 (s, 2 H), 4.68 (septet, J = 6.0 Hz, 1 H),
6.60 (dd, J = 7.4, 1.2 Hz, 1 H), 6.86–7.25 (m, 7 H).
To a solution of compound 16 (107 mg, 0.289 mmol) in degassed
DMF (6 mL) were added Pd(OAc)2 (13.0 mg, 0.058 mmol), P(o-
tol)3 (35.2 mg, 0.116 mmol), and K2CO3 (79.9 mg, 0.578 mmol).
The reaction mixture was refluxed for 4 h and diluted with EtOAc.
The precipitate was removed by filtration. The residue was dis-
solved in CHCl3 and subjected to column chromatography on silica
gel. Elution with EtOAc–hexane (1:10) gave N-benzyl-6,7-methyl-
enedioxy-1-naphthylamine (17) (47.0 mg, 59%), and successive
elution with the same solvent gave 7a2e (13.3 mg, 29%).
Anal. Calcd for C23H27NO4: C, 72.42; H, 7.13; N, 3.67. Found: C,
72.08; H, 6.97; N, 3.57.
2-Bromo-N-methyl-6,7-methylenedioxy-1-naphthylamine (7e);
Typical Procedure
To a solution of 2-bromo-6,7-methylenedioxy-1-naphthylamine14
(533 mg, 2.00 mmol) in anhyd pyridine (4 mL) was added TFAA
(0.42 mL, 3.00 mmol). The reaction mixture was stirred at r.t. for 30
min and poured into ice water. The mixture was made acidic with
10% HCl and extracted with EtOAc. The residue was recrystallized
17
Colorless prisms; mp 146–147 °C (EtOH).
IR (KBr): 3393, 1242, 1044 cm–1.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York

1456
T. Harayama et al.
PAPER
(3) (a) Harayama, T.; Morikami, Y.; Shigeta, Y.; Abe, H.;
Takeuchi, Y. Synlett 2003, 847. (b) Harayama, T.; Hori, A.;
Abe, H.; Takeuchi, Y. Tetrahedron 2004, 60, 1611.
(4) Preliminary communication: Harayama, T.; Sato, T.; Hori,
A.; Abe, H.; Takeuchi, Y. Synlett 2003, 1141.
1H NMR (200 MHz, CDCl3): d = 4.31 (br s, 1 H), 4.46 (s, 2 H), 6.02
(s, 2 H), 6.58 (dd, J = 7.4, 1.4 Hz, 1 H), 7.10–7.48 (m, 9 H).
Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C,
78.19; H, 5.60; N, 5.05.
(5) (a) Cope, A. C.; Friedrich, E. C. J. Am. Chem. Soc. 1968, 90,
909. (b) Bruce, M. I. Angew. Chem., Int. Ed. Engl. 1977, 16,
73.
(6) (a) Clark, P. W.; Dyke, S. F. J. Organomet. Chem. 1985,
243, 389. (b) Martín-Mature, B.; Mateo, C. J.; Cárdenas, D.;
Echavarren, A. M. Chem.–Eur. J. 2001, 7, 2341. (c) Dyker,
G. Chem. Ber. 1997, 243, 1567. (d) Jia, C.; Piao, D.;
Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y. Science
2000, 287, 1992.
Acknowledgments
The authors are indebted to the SC-NMR Laboratory of Okayama
University for the NMR experiments.
References
(1) (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley
& Sons Inc.: New York, 1995, 125–252. (b) Li, J. J.;
Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000. (c) Dyker, G. Angew. Chem. Int.
Ed. 1999, 38, 1698. (d) Hassan, J.; Sevignon, M.; Gozzi, C.;
Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(2) (a) Harayama, T.; Shibaike, K. Heterocycles 1998, 49, 191.
(b) Harayama, T.; Akiyama, T.; Akamatsu, H.; Kawano, K.;
Abe, H.; Takeuchi, Y. Synthesis 2001, 444. (c) Harayama,
T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.;
Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001,
523. (d) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka,
H.; Abe, H.; Takeuchi, Y. Chem. Pharm. Bull. 2002, 50,
519. (e) Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike,
K.; Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis
2002, 237. (f) Harayama, T.; Hori, A.; Nakano, Y.;
(7) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem.
1998, 63, 9139.
(8) The coupling reaction of 5a using Pd2(dba)3 (0.2 equiv) in
degassed DMF gave no product and this was accompanied
by decomposition of the starting material.
(9) Nakanishi, T.; Suzuki, M. J. Prod. Chem. 1998, 61, 1263.
(10) Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.;
Stermitz, T. A. J. Med. Chem. 1975, 18, 708.
(11) Dalla, V.; Cotelle, P. Tetrahedron 1999, 55, 6923.
(12) Wu, S.-J.; Chen, I.-S.; Chern, C.-Y.; Teng, C.-M.; Wu, T.-S.
J. Chin. Chem. Soc. 1996, 43, 195.
(13) (a) Vila, J. M.; Suarez, A.; Pereira, M. T.; Gayoso, E.;
Gayoso, M. Polyhedron 1987, 6, 1003. (b) Teijido, B.;
Fernández, A.; López-Torres, M.; Castro-Juiz, S.; Suárez,
A.; Ortigueira, J. M.; Vila, J. M.; Fernández, J. J. J.
Organomet. Chem. 2000, 598, 71.
Akiyama, T.; Abe, H.; Takeuchi, Y. Heterocycles 2002, 58,
159. (g) Harayama, T.; Sato, T.; Nakano, Y.; Abe, H.;
Takeuchi, Y. Heterocycles 2003, 59, 293.
(14) Green, G. R.; Mann, I. S.; Mullane, M.; McKillop, A.
Tetrahedron 1998, 54, 9875.
Synthesis 2004, No. 9, 1446–1456 © Thieme Stuttgart · New York