Novel synthesis of naphthobenzazepines from N-bromobenzylnaphthylamines by regioselective C-H activation utilizing the intramolecular coordination of an amine to Pd

Article abstract of DOI:10.1055/s-2003-39911

In a biaryl coupling reaction of N-bromobenzylnaphthylamine using Pd reagent, the intramolecular coordination of the benzylamino group to Pd causes the regioselective C-H activation at the peri-position to the amine group on the naphthalene ring to produc

Full text of DOI:10.1055/s-2003-39911

LETTER
1141
Novel Synthesis of Naphthobenzazepines from N-Bromobenzylnaphthyl-
amines by Regioselective C-H Activation Utilizing the Intramolecular
Coordination of an Amine to Pd
N
ovel Synthesis
a
of
N
aphth
k
obenzazepin
aes shi Harayama,* Tomonori Sato, Akihiro Hori, Hitoshi Abe, Yasuo Takeuchi
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 21 April 2003
the amino group of 4 (Scheme 2).7 Therefore, we envi-
sioned that the intramolecular biaryl coupling reaction of
N-bromobenzylnaphthylamine (A) using Pd reagent
would afford a new skeletal compound, naphthobenza-
Abstract: In a biaryl coupling reaction of N-bromobenzylnaphthyl-
amine using Pd reagent, the intramolecular coordination of the ben-
zylamino group to Pd causes the regioselective C-H activation at the
peri-position to the amine group on the naphthalene ring to produce
a new skeletal compound, naphthobenzazepine, in good to excellent zepine (B), via an oxidative addition to Pd(0) and coordi-
yield.
nation 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 clarity).8,9
Key words: C-H activation, heterocycles, palladium, regioselectiv-
ity, synthetic methods
Palladium-assisted aryl-aryl coupling reactions have been
used to synthesize many condensed aromatic com-
pounds.1 Recently, we reported that intramolecular biaryl
coupling reactions of N-arylbenzamides using palladium
reagents were a very versatile way to synthesize con-
densed aromatic lactams, some of which are transformed
into several alkaloids.2–5 In the intramolecular biaryl cou-
pling reaction of N-naphthylbenzamide (1) using a Pd re-
agent, a small amount of naphthobenzazepinone (3) is
obtained along with the expected benzo[c]phenanthridone
(2), as shown in Scheme 1.2,4–6
R2
PdII
R2
PdII
R2
Pd0
Br
Br
R1
R1
R1
N
Me
N
N
Me
Me
R2
A
– Pd0
R1
N
Me
B
Scheme 3 Synthetic strategy of naphthylbenzazepine (B) from N-
benzylnaphthylamine (A) using regioselective C-H activation by Pd
R2
R2
Pd
R2
+
X
R3
R1
R3
R4
R1
Br
R1
N
N
Me
Br
Br
R4
N
Me
O
R2
+
O
Me
O
N
HN
R2
(X = OTf, Br, I)
R1
Me
Me
1
R1
2 (major)
3 (minor)
6
7
8
Scheme 1 Pd-assisted biaryl coupling reaction of N-naphthyl-
benzamide (1)
Scheme 4 Synthesis of N-(6¢-bromobenzyl)-1-naphthylamine (8).
Reagents and conditions: Method A: K2CO3, Bu4NI, DMF, 100 °C,
1–2 h; Method B: i-Pr2NEt, DMF, 100 °C, 1 h
Me
Me
Cl
Pd
Cl
Me
Me
N
N
Li2PdCl4
MeOH
First, the biaryl coupling reaction of N-(bromoben-
zyl)naphthylamine (8a) was examined in relation to syn-
thetic studies of fagaridine and decarine.5 A compound
(8a) was synthesized from 6-bromo-3-isopropoxy-2-
methoxybenzyl bromide (6a)10 and N-methyl-6,7-methyl-
enedioxy-1-naphthylamine (7a)4 by applying Method A
(see Scheme 4 and run 1, Table 1). Then, the coupling re-
action using Pd reagents was investigated. After many ex-
periments, the biaryl coupling reaction using Pd(OAc)2
(0.2 equiv), (o-tol)3P (0.4 equiv), and K2CO3 (2 equiv) in
DMF proceeded smoothly to provide naphthobenzazepine
(9a), a new skeletal compound, in 71% yield. The struc-
tures of the products (9a and 11a) were elucidated from
elemental analyses and 1H NMR data, in which 9a showed
Pd
N
Me
Me
4
5
Scheme 2 Palladacycle of naphthylamine (4)
In 1967, Cope et al. reported that cyclopalladation reac-
tions of naphthylamine (4) with palladium (II) chlorides
gave palladacycle (5) selectively, indicating that regiose-
lective C-H bond activation occurs at the peri-position to
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,08,1141,1144,ftx,en;U07303ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1142
T. Harayama et al.
LETTER
Table 1 Results of Reaction of Benzylbromide (6) and Naphthyl-
amines (7)
amines (7)16 using Method A or B in high yields, as shown
in Scheme 4 and Table 1. The results of the coupling reac-
tion of 8 using Pd reagent are summarized in Table 2. N-
Bromobenzylnaphthylamines (8b–e), which possess a
methylenedioxy group or no substituent group on the
naphthalene ring, produced only naphthobenzazepines
(9b–e)18 in moderate to high yields (see runs 2–5,
Table 2). Interestingly, N-bromobenzylnaphthylamines
(8f and g), which possess a methoxy group at C7 on the
naphthalene ring, produced naphthobenzazepines (9f and
g)18 and benzo[c]phenanthridines (10f19 and g20) along
with debromo-products (11f and g)21 (see runs 6 and 7,
Table 2). The methoxy group at C7 on the naphthalene
ring might hinder the coupling reaction at the peri-posi-
tion (C8 position) to the amino group on the naphthalene
ring.22
Substituent
Meth- Prod- Yield
od
A
A
A
A
A
B
B
B
B
uct
8a
8b
8c
8d
8e
8f
(%)
R1 = OMe, R2 = i-PrO, R3 + R4 = OCH2O
R1 = R2 = R3 = R4 = H
71
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
70
63
98
95
8g
8h
8i
74
R1 = R2 = H, R3 = OMe, R4 = i-PrO
R1 = R2 = R3 = OMe, R4 = i-PrO
quant.
96
N-Bromobenzylnaphthylamines (8h and i) possessing a
bulky isopropoxy group relative to a methoxy group at C7
on the naphthalene ring produced only benzo[c]phenan-
thridines (10h and 10i) along with debromo- and demeth-
ylated-products (11 and 12)21 (see runs 8 and 9, Table 2).
These results strongly indicate that a relatively bulky sub-
stituent at the C7 position makes the peri-palladation un-
favorable, as shown in Scheme 6. The structures of the
products were elucidated from elemental analyses, MS
only one singlet signal (d = 7.02 ppm) due to the aromatic
proton in addition to the signals due to five aromatic pro-
tons and N-methyl signal (d = 3.01 ppm).12
By contrast, the biaryl coupling reaction of N-naphthyl-
benzamide (1, X = Br) with Pd gave mainly 2, as shown
in Scheme 2 and furthermore, the reaction of N-acetyl
amide (13)13 afforded N-acetyl benzo[c]phenanthridine
(14)15 and N-acetyl naphthobenzazepine (15)15 in 45%
and 55% yields, respectively (Scheme 5). These prove the
contribution of the benzylamino group to the production
of 9a, as shown in Scheme 3.
1
data, and H NMR data. Some selected data are given in
the References and Notes. Compounds (9c,e,f,g) showed
only one singlet signal due to the aromatic proton and
compounds (10f,h,i) showed two singlet signals due to
the aromatic protons, in addition to the signals due to
other aromatic protons. Especially, the d values of the
N-methyl signals were very diagnostic for structure elu-
cidation. N-Methyl signals appeared at d = 2.97–3.08 ppm
for the naphthobenzazepines (9), d = 2.62–2.65 for the
Next, the coupling reaction of N-(6¢-bromobenzyl)-1-
naphthylamines (8) using the system combining
Pd(OAc)2, (o-tol)3P, and K2CO3 was investigated. The
starting materials (8) for the coupling reaction were syn- benzo[c]phenanthridines (10), and d = 2.75–2.84 ppm for
thesized from dibromides (6) and N-methyl-1-naphthyl-
the amides (11).
O
Pd(OAc)2
(o-tol)3P
K2CO3
O
O
O
O
O
Br
+
N
iPrO
iPrO
N
N
DMF
reflux, 2h
iPrO
MeO
OMe
O
OMe
O
O
14
(45%)
15
(55%)
13
Scheme 5 Biaryl coupling reaction of amide (13)
R3
R4
R3
R4
Br
Pd
R4 = OPri
R4 = OMe
8
R
R
N
N
10
R3
Me
Me
Pd
Br
R4
7
R3
R
R3
N
R4
Me
R4
R4 = OMe
R4 = H
R3 + R4 = OCH2O
Br
8
8
Pd
R
R
N
N
Me
9
Me
Scheme 6 Proposed mechanism for biaryl coupling reaction of N-(bromobenzyl)naphthylamine (8) by Pd
Synlett 2003, No. 8, 1141–1144 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Naphthobenzazepines
1143
Table 2 Results of Coupling Reaction of Substituted N-(6-bromobenzyl)-N-methyl-1-naphthylamines (8) in DMF under Refluxa
R3
R4
R3
R4
R3
R3
R4
Pd(OAc)2
(o-tol)3P
R4
+
+
Br
N
N
R2
R2
R
Me
R1
N
K2CO3
R1
10
R2
N
R2
Me
DMF, reflux
R1
Me
R1
R = Me (11)
R = H (12)
8
9
Run
Substrate
Yield (%)
9
10
11
trace
–
12
–
1
2
3
4
5
6
7
8
9
8a
R1 = OMe, R2 = i-PrO, R3 + R4 = OCH2O
R1 = R2 = R3 = R4 = H
71
81
86
44
60
22
18
–
–
8b
8c
8d
8e
8f
–
–
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
–
8g
8h
8i
10
20
26
R1 = R2 = H, R3 = OMe, R4 = i-PrO
R1 = R2 = R3 = OMe, R4 = i-PrO
–
a All reactions were carried out using 0.2 equiv of Pd(OAc)2, 0.4 equiv of (o-Tol)3P, and 2 equiv of K2CO3 under Ar atmosphere for 2 h.
(6) Harayama, T.; Hori, A.; Nakano, Y.; Akiyama, T.; Abe, H.;
Takeuchi, Y. Heterocycles 2002, 58, 159.
(7) (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.
(8) Dyker, G. Angew. Chem. Int. Ed. 1999, 38, 1698.
(9) (a) Clark, P. W.; Dyke, S. F. J. Organomet. Chem. 1985,
243, 389. (b) Martín-Mature, B.; Matero, C.; Cárdenas, D.
J.; 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.
(10) 6-Bromo-3-isopropoxy-2-methoxybenzyl bromide (6a) was
prepared from 3-isopropoxy-2-methoxybenzaldehyde11 in
54% yield via reduction with NaBH4 and bromination with
Br2.
Note that in a biaryl coupling reaction of N-bromobenzyl-
naphthylamine using Pd reagent, the intramolecular coor-
dination of the benzylamino group to Pd causes
regioselective C-H activation to produce a new skeletal
compound, naphthobenzazepine, and the bulkiness of the
substituent at C7 on the naphthalene ring affects the regio-
selectivity of the biaryl coupling reaction.
Acknowledgment
The authors are indebted to the SC-NMR Laboratory of Okayama
University for the NMR experiments.
References
(11) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem.
1998, 63, 9139.
(1) (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley
and Sons, Inc.: New York, 1995, 125–252. (b) Li, J. J.;
Gribble, G. W. Palladium in Heteocyclic Chemistry;
Pergamon: Oxford, 2000. (c) Hassan, J.; Sevignon, M.;
Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102,
1359.
(2) (a) Harayama, T.; Akiyama, T.; Akamatsu, H.; Kawano, K.;
Abe, H.; Takeuchi, Y. Synthesis 2001, 444. (b) Harayama,
T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.; Akiyama, T.;
Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001,
523.
(3) (a) Harayama, T.; Shibaike, K. Heterocycles 1998, 49, 191.
(b) Harayama, T.; Akiyama, T.; Nakano, Y.; Nishioka, H.;
Abe, H.; Takeuchi, Y. Chem. Pharm. Bull. 2002, 50, 519.
(4) Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.;
Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis
2002, 237.
(12) Selected 1H NMR data (200 MHz, CDCl3): Compound 9a:
d = 3.01 (3 H, s, N-Me), 6.57 (1 H, br. d, J = 7.0 Hz), 6.86 (1
H, d, J = 8.5 Hz), 7.02 (1 H, s), 7.08 (1 H, br. d, J = 7.0 Hz),
7.14 (1 H, t, J = 7.0 Hz), 7.41 (1 H, d, J = 8.5 Hz).
Compound 11a: d = 2.75 (3 H, s, N-Me), 7.11 (1 H, s), 7.75
(1 H, s).
(13) Compound 13 was prepared from 6-bromo-3-hydroxy-2-
methoxybenzaldehyde14 in 48% yield via etherification with
isopropyl bromide, reductive alkylation with 6,7-
methylenedioxy-1-naphthylamine and NaBH4, and N-
acetylation.
(14) Nakanishi, T.; Suzuki, M. J. Prod. Chem. 1998, 61, 1263.
(15) Selected 1H NMR data (200 MHz, CDCl3): Compound 14:
d = 3.80 (1 H, d, J = 15.4 Hz, ArCHAHBN), 6.25 (1 H, d,
J = 15.4 Hz, ArCHAHBN), 6.93 (1 H, d, J = 8.6 Hz), 7.13 (1
H, s), 7.28 (1 H, s), 7.52 (1 H, d, J = 8.6 Hz), 7.62 (1 H, d,
J = 8.6 Hz), 7.69 (1 H, d, J = 8.6 Hz).Compound 15:
d = 3.93 (1 H, d, J = 15.8 Hz, ArCHAHBN), 5.97 (1 H, d,
(5) Harayama, T.; Sato, T.; Nakano, Y.; Abe, H.; Takeuchi, Y.
Heterocycles 2003, 59, 293.
Synlett 2003, No. 8, 1141–1144 ISSN 1234-567-89 © Thieme Stuttgart · New York

1144
T. Harayama et al.
LETTER
J = 15.8 Hz, ArCHAHBN), 6.84 (1 H, d, J = 8.8 Hz), 7.10 (1
H, dd, J = 7.6, 1.4 Hz), 7.17 (1 H, s), 7.29 (1 H, t, J = 7.8
Hz), 7.59 (1 H, d, J = 8.8 Hz), 7.61 (1 H, dd, J = 7.8, 1.4 Hz).
(19) Selected 1H NMR data (200 MHz, CDCl3): Compound 10f:
d = 2.65 (3 H, s, N-Me), 7.14 (1 H, s), 7.54 (1 H, d, J = 8.6
Hz), 7.66 (1 H, s), 7.79 (1 H, d, J = 8.6 Hz). Compound 10g:
Mp 180–183 °C (lit.20 186–188 °C). Compound 10h:
d = 2.63 (3 H, s, N-Me), 7.14 (1 H, s), 7.53 (1 H, d, J = 8.6
Hz), 7.69 (1 H, s), 7.78 (1 H, d, J = 8.6 Hz). Compound 10i:
d = 2.62 (3 H, s, N-Me), 6.94 (1 H, d, J = 8.4 Hz), 7.13 (1 H,
s), 7.50 (1 H, d, J = 8.4 Hz), 7.51 (1 H, d, J = 8.6 Hz), 7.69
(1 H, s), 7.71 (1 H, d, J = 8.6 Hz).
(16) 6,7-Dimethoxy-N-methyl-1-naphthylamine (7f) and 7-
isopropoxy-6-methoxy-N-methyl-1-naphthylamine (7h)
were prepared from 6,7-dimethoxy-1-naphthylamine13 and
7-isopropoxy-6-methoxy-1-naphthylamine17 in 86% and
76% yields, respectively, via trifluoroacetylation,
methylation with MeI and hydrolysis with alkaline aqueous
EtOH.
(20) Wu, S.-J.; Chen, I.-S.; Chern, C.-Y.; Teng, C.-M.; Wu, T.-S.
J. Chin. Chem. Soc. 1996, 43, 195.
(17) Stermitz, F. R.; Gillespie, J. P.; Amoros, L. G.; Romero, R.;
Stermitz, T. A. J. Med. Chem. 1975, 18, 708.
(21) Selected 1H NMR data (200 MHz, CDCl3): Compound 11f:
d = 2.82 (3 H, s, N-Me), 7.04 (1 H, dd, J = 7.4, 1.2 Hz), 7.13
(1 H, s), 7.63 (1 H, s). Compound 11g: d = 2.84 (3 H, s, N-
Me), 6.86 (1 H, dd, J = 8.0, 1.4 Hz), 7.12 (1 H, s), 7.59 (1 H,
s). Compound 11h: d = 2.81 (3 H, s, N-Me), 7.02 (1 H, dd,
J = 7.6, 1.2 Hz), 7.13 (1 H, s), 7.62 (1 H, s). Compound 11i:
d = 2.84 (3 H, s, N-Me), 6.87 (1 H, dd, J = 8.0, 1.2 Hz), 7.11
(1 H, s), 7.56 (1 H, s). Compound 12g: d = 6.56 (1 H, br d,
J = 7.2 Hz), 7.02 (1 H, s), 7.10 (1 H, s). Compound 12h:
d = 6.55 (1 H, dd, J = 7.0, 1.4 Hz), 7.12 (1 H, s), 7.18 (1 H,
s). Compound 12i: d = 6.60 (1 H, dd, J = 7.4, 1.2 Hz), 7.01
(1 H, s), 7.11 (1 H, s).
(18) Selected 1H NMR data (200 MHz, CDCl3): Compound 9b:
d = 3.05 (3 H, s, N-Me). Compound 9c: d = 2.97 (3 H, s, N-
Me), 7.06 (1 H, s). Compound 9d: d = 3.08 (3 H, s, N-Me),
6.92 (1 H, d, J = 8.6 Hz), 7.14 (1 H, d, J = 8.6 Hz).
Compound 9e: d = 3.00 (3 H, s, N-Me), 6.88 (1 H, d, J = 8.6
Hz), 7.03 (1 H, s), 7.45 (1 H, d, J = 8.6 Hz). Compound 9f:
d = 2.98 (3 H, s, N-Me), 3.48 (3 H, s, OMe), 7.07 (1 H, s).
Compound 9g: d = 3.03 (3 H, s, N-Me), 3.48 (3 H, s, OMe),
6.85 (1 H, d, J = 8.8 Hz), 7.03 (1 H, s), 7.27 (1 H, d, J = 8.8
Hz).
(22) (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.
Synlett 2003, No. 8, 1141–1144 ISSN 1234-567-89 © Thieme Stuttgart · New York