Palladium-catalyzed synthesis of 1,2,3,4-tetrahydro-5 H -2-benzazepin-5-ones

Article abstract of DOI:10.1055/s-0032-1317183

Palladium-catalyzed intermolecular cyclocarbonylation of 2-iodobenzylamines with Michael acceptors produces 1,2,3,4-tetrahydro-5H-2-benzazepin-5-one derivatives in moderate to good yields. This methodology enables the direct preparation of highly function

Full text of DOI:10.1055/s-0032-1317183

LETTER
▌2531
letter
Palladium-Catalyzed Synthesis of 1,2,3,4-Tetrahydro-5H-2-benzazepin-5-ones
Tetrahydro-5H-2-benzazepin-5-ones
Kazumi Okuro, Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Ontario, K1N 6N5,
Canada
Fax +1(613)5625871; E-mail: howard.alper@uottawa.ca
Received: 13.06.2012; Accepted after revision: 09.08.2012
When 2-iodobenzylamine (1a) was treated with diethyl
Abstract: Palladium-catalyzed intermolecular cyclocarbonylation
ethoxycarbonylbut-2-en-1,4-dioate (2a) under the optimal
of 2-iodobenzylamines with Michael acceptors produces 1,2,3,4-
conditions for the carbonylation of 2-iodoaniline with
tetrahydro-5H-2-benzazepin-5-one derivatives in moderate to good
yields. This methodology enables the direct preparation of highly
2a,5,6 3,4,4-triethoxycarbonyl-1,2,3,4-tetrahydro-5H-2-
functionalized 1,2,3,4-tetrahydro-5H-2-benzazepin-5-ones from benzazepin-5-one (3aa) was isolated in 77% yield (Table 1,
readily available starting materials.
entry 1). It should be noted that no γ-benzolactam was
formed, which would result from intramolecular cyclocar-
bonylation of 1a. Although the nature of the phosphane li-
gands in this reaction seems not to be crucial compared to
the reactions of 2-iodoanilines,5 PCy3 (as HBF4 salt)7 is
the best ligand among the phosphanes examined. The re-
action took place to give 3aa in excellent isolated yield
even under 100 psi of carbon monoxide (entry 5), whereas
use of a reduced amount of Et3N caused significant de-
crease in the yield (entry 6).
Key words: cyclocarbonylation, heterocycles, palladium, 1,2,3,4-
tetrahydrobenzazepin-5-one, Michael acceptor
Some 1,2,3,4-tetrahydro-5H-2-benzazepin-5-one deriva-
tives have received attention due to their biological activ-
ities.1 They can also serve as synthetic intermediates for
dual inhibitors of acetylcholinesterases and serotonin
transporters2 as well as inhibitors for the re-uptake of nor-
ephedrine, dopamine, and serotonin.3 However, little is
known about their synthesis, in particular, by means of di-
rect preparation from readily available starting materials.
Most common syntheses rely on the intramolecular
Friedel–Crafts acylation of N-benzyl-β-aminoacids or
their acid chlorides using AlCl3 or polyphosphoric acid
(PPA).3,4 Another example includes oxidation of the cor-
responding alcohols derived from the hydroboration of
1,3-dihydrobenzazepines.2
Having established the optimized conditions, a range of
benzylamines with different substituent patterns were
treated with 2a (Figure 1 and Table 2). The corresponding
1,2,3,4-tetrahydro-5H-2-benzazepin-5-ones 3 were isolat-
ed in moderate to excellent yields (entries 1–6). Note that
substrates having substituents at the ortho position of the
aminomethyl or iodo group also afforded the expected
products in reasonable yields (entries 4–6).
Table 1 Screening for the Intermolecular Cyclocarbonylation of 1a
and 2aa
We have recently demonstrated the palladium-catalyzed
intermolecular cyclocarbonylation of 2-iodoanilines and
diethyl ethoxycarbonylbut-2-en-1,4-dioate affording
2,3,3-triethoxycarbonyl-2,3-dihydro-4(1H)-quinolinone
in moderate to good yields.5 These results encouraged us
to extend the study on the cyclocarbonylation to the reac-
tion of 2-iodobenzylamines with Michael acceptors in-
cluding diethyl ethoxycarbonylbut-2-en-1,4-dioate. We
now wish to report that this method offers a facile ap-
proach toward highly functionalized 1,2,3,4-tetrahydro-
5H-2-benzazepin-5-ones (Scheme 1).
CO2Et
CO2Et
CO2Et
O
CO2Et
I
CO
Pd2(dba)3/ligand
+
NH2
Et3N, MeCN
EtO2C
NH
CO2Et
1a
2a
3aa
Entry Ligand
Amount of CO (psi) Yield (%)b of 3aa
Et3N (equiv)
c
1
2
3
4
5
6
ArP(t-Bu)2
PPh3
10.0
10.0
500
500
500
500
100
100
77
73
85
87
89
68
COOEt
COOEt
O
EtOOC
+
COOEt
E
I
CO
Pd catalyst
P(t-Bu)3HBF4 10.0
E
NH2
PCy3HBF4
PCy3HBF4
PCy3HBF4
10.0
10.0
5.0
NH
R
R
E = COOEt, COMe, CF3
Scheme 1
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol),
Pd2(dba)3CHCl3 (0.025 mmol), ligand (0.1 mmol), Et3N (10 mmol or
5 mmol), MeCN (2 mL), 80 °C, 20 h.
b Isolated yield after column chromatography.
c 2-(Di-tert-butylphosphino)biphenyl.
SYNLETT 2012, 23, 2531–2533
Advanced online publication: 28.09.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317183; Art ID: ST-2012-S0510-L
© Georg Thieme Verlag Stuttgart · New York

2532
K. Okuro, H. Alper
LETTER
Table 2 Synthesis of 1,2,3,4-Tetrahydro-5H-2-benzazepin-5-onea
R1
EtOOC
COOEt
E
R2
R3
I
CO2Et
CO2Et
O
NH2
8
c
b
(52)
R4
O
NH
Cl
2a: E = COOEt
2b: E = Ac
2c: E = CF3
2d: E = Ph
1a: R1 = R2 = R3 = R4 = H
3cb
1b: R1 = R3 = R4 = H, R2 = Cl
1c: R1 = R2 = R4 = H, R3 = Cl
1d: R1 = R2 = R4 = H, R3 = Me
1e: R1 = OMe, R2 = R3 = R4 = H
1f: R1 = R2 = R3 = H, R4 = OMe
1g: R1 = R2 = R3 = H, R4 = F
CO2Et
CO2Et
O
9
g
a
f
b
c
(47)
O
NH
F
Figure 1 The starting materials
3gb
CO2Et
O
Table 2 Synthesis of 1,2,3,4-Tetrahydro-5H-2-benzazepin-5-onea
CO2Et
CF3
10
11
12
44 (54)
Entry
1
2
Product
Yield (%)b
NH
O
CO2Et
CO2Et
3ac
O
CO2Et
CO2Et
CF3
CF3
1
b
a
80
NH
c
(64)
3ba
NH
CO2Et
O
MeO
CO2Et
CO2Et
3fc
2
c
a
93
CO2Et
O
NH
Cl
CO2Et
Ph
16c
3ca
a
d
NH
CO2Et
CO2Et
CO2Et
O
3ad
3
4
d
e
a
a
83
62
a Reaction conditions were the same as in Table 1, entry 5.
b Isolated yield. The values in parentheses are the reaction yields us-
ing 2.0 mmol of 2.
NH
3da
c Reaction was performed at 100 °C.
CO2Et
CO2Et
CO2Et
MeO
O
O
Other Michael acceptors were also examined. When ethyl
2-ethoxycarbonyl-4-oxo-2-pentenoate (2b) was treated
with 1a, 3-acetyl-4,4-diethoxycarbonyl-1,2,3,4-tetra-
hydro-5H-2-benzazepin-5-one (3ab) was formed in 43%
yield (entry 7). Use of an increased amount of 2b to two
equivalents, based on 1a, improved the product yields to
51%. Similarly, the corresponding products, 3cb and 3gb
were isolated from the reaction of 1c and 1g with 2b, re-
spectively (entries 8 and 9). Ethyl 2-ethoxycarbonyl-3-tri-
fluoromethylpropenoate (2c) was also successfully used
as a carbonylation partner, with the corresponding ben-
zazepin-5-ones being isolated in 54–64% yield when two
equivalents were used. These results are in sharp contrast
with those of 2-iodoanilines, where 2b and 2c were not
successfully used.5 When diethyl benzylidenemalonate
(2d) was used as a Michael acceptor, the reaction proceed-
ed to some extent at 100 °C, but the yield of the expected
product 3ad was unsatisfactory (entry 12). In this olefin,
increasing temperature to 120 °C did not improve the
yield (9%).
NH
3ea
CO2Et
CO2Et
CO2Et
5
f
a
NH
69
MeO
3fa
CO2Et
O
CO2Et
CO2Et
NH
6
7
g
a
a
74
F
3ga
CO2Et
CO2Et
O
b
43 (51)
O
NH
A possible reaction mechanism for the formation of 3 con-
sists of the following steps (Scheme 2):5 (1) aza-Michael
3ab
Synlett 2012, 23, 2531–2533
© Georg Thieme Verlag Stuttgart · New York

LETTER
Tetrahydro-5H-2-benzazepin-5-ones
2533
I
I
CO2Et
CO2Et
H
+
NH2
N
CO2Et
EtO2C
CO2Et
1a
2a
E
PdLn
O
CO2Et
CO2Et
E
NH
PdLn
CO2Et
H
N
CO2Et
E
CO
O
CO2Et
CO2Et
PdLn
H
N
E
Scheme 2 A possible reaction mechanism
R.; Hara, T.; Aoyagi, A.; Abe, Y.; Kaneko, T.; Kogen, H.
Bioorg. Med. Chem. 2003, 11, 4389.
addition of 1 to 2 to form the Michael adduct, (2) oxida-
tive addition of Pd(0) to the C–I bond of the adduct,8 (3)
insertion of carbon monoxide into the Pd–C bond to form
aroylpalladium species, and (4) nucleophilic attack of the
internal malonate anion on the aroylpalladium intermedi-
ate to give the product 3 and regeneration of Pd(0) spe-
cies.9 One of the crucial steps for the successful reaction
is the initial aza-Michael addition. The higher nucleophil-
ic reactivity of the aminomethyl group (i.e., 1) compared
to the anilino group (i.e., 2-iodoanilines),5 may allow the
use of a wider range of Michael acceptors (i.e., 2a–c).
(3) (a) Liu, S.; Yang, Y.-L. A.; Sambandam, A.; Molino, B. F.;
Olson, R. E. PCT Int. Appl. WO141082, 2008; Chem. Abstr.
2008, 149, 576408. (b) Molino B. F., Liu S., Sambandam
A., Guzzo P. R., Hu M., Zha C., Nacro K., Manning D. D.,
Isherwood M. L., Fleming K. N., Chu W., Olson R. E.; PCT
Int. Appl. WO011820, 2007; Chem. Abstr. 2007, 146,
184383.
(4) (a) McLean, A.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1
1972, 1084. (b) Macdonald, I.; Proctor, G. R. J. Chem. Soc. C
1970, 1461. (c) Bachand C., Belema M., Deon D. H., Good
A. C., Goodrich J., James C. A., Lavoie R., Lopez O. D.,
Martel A., Meanwell N. A., Nguyen V. N., Romine J. L.,
Ruediger E. H., Snyder L. B., St. Laurent D. R., Yang F.,
Langley D. R., Wang G., Hamann L. G.; US Patent 0202478,
2009; Chem. Abstr. 2009, 151, 267309.
(5) Okuro, K.; Alper, H. J. Org. Chem. 2012, 77, 4420.
(6) General Procedure: A mixture of 1 (1.0 mmol), Michael
acceptor 2 (1.2 mmol or 2.0 mmol), Pd2(dba)3CHCl3 (0.025
mmol, 25.9 mg), PCy3HBF4 (0.1 mmol, 36.8 mg), and Et3N
(10 mmol, 1.01 g) in MeCN (2 mL) was charged in a glass
liner, equipped with a magnetic stirring bar. The glass liner
was then inserted into a 45-mL autoclave. The autoclave was
flushed with CO (5 ×) and pressurized to 100 psi. The
autoclave was heated at 80 °C with stirring. After the
reaction, the autoclave was cooled to r.t. prior to the release
of CO. The solvent was evaporated under reduced pressure,
and the product was purified by silica gel column chroma-
tography with n-hexane and Et2O as the eluent.
In conclusion, we have demonstrated an effective synthet-
ic process for the preparation of 1,2,3,4-tetrahydro-5H-2-
benzazepin-5-ones by palladium-catalyzed intermolecu-
lar cyclocarbonylation of 2-iodobenzylamines and
Michael acceptors. This methodology enables the direct
preparation of highly functionalized 1,2,3,4-tetrahydro-
5H-2-benzazepin-5-ones.
Acknowledgment
We are grateful to the Natural Sciences and Engineering Council of
Canada (NSERC) for support of this research.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
(7) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(8) Tsuji, J. Palladium Reagents and Catalysts; Wiley & Sons:
Hoboken, 1995.
(9) (a) Kobayashi, T.; Tanaka, M. Tetrahedron Lett. 1986, 27,
4745. (b) Negishi, E.; Zhang, Y.; Shimoyama, I.; We, G.
J. Am. Chem. Soc. 1989, 111, 8018.
References
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2531–2533

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