Novel synthesis of fused indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines

Article abstract of DOI:10.1055/s-2004-820039

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by 5-endo cyclization was developed and used to synthesize fused indoles.

Full text of DOI:10.1055/s-2004-820039

LETTER
907
Novel Synthesis of Fused Indoles by the Palladium-Catalyzed Cyclization of
N-Cycloalkenyl-o-haloanilines
N
ovel Synthesis
a
of Fuse
d
I
k
ndoles eshi Watanabe, Shigeru Arai, Atsushi Nishida*
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
Fax +81(43)2902909; E-mail: nishida@p.chiba-u.ac.jp
Received 17 November 2003
R
Abstract: A new palladium-catalyzed cyclization of N-alkenyl-o-
haloanilines with selective isomerization of a double bond followed
by 5-endo cyclization was developed and used to synthesize fused
indoles.
p-TsOH
R
PhH
+
O
N
H
reflux
NH2
MeO2C
CO2Me
16 h (X = Br)
or
39 h (X = I)
Key words: heterocycles, indole, palladium, synthesis
2a (R = Br, 68%)
2b (R = I, 60%)
R = Br (1.1 equiv)
I (2 equiv)
1
The intramolecular Heck reaction1 is an important and
powerful method for the construction of carbocyclic and
heterocyclic compounds. The synthesis of indoles using
this reaction has also been widely studied starting from
the pioneering work by Mori and Ban.2,3 However, the
synthesis of fused indoles by palladium-catalyzed cy-
clization using N-cycloalkenyl-o-haloanilines, which are
readily obtained from cyclic 1,3-diketones,3d,e,g,i has not
been fully investigated, although the skeleton is involved
in many important biologically active indole alkaloids.
There has been no report on cyclization using enamine B,
obtained from cyclic b-ketoesters, which can be expected
to give fused indolenines A with a quaternary carbon cen-
ter at C3 of indole (Scheme 1). In connection with our re-
cent work on the synthesis of indole alkaloids, we were
interested in the synthesis of fused indoles with medium-
sized rings using the reaction shown in Scheme 1.
R
Pd(PPh3)4
Table 1
N
H
CO2Me
2a'
Pd(PPh3)2I
N
CO2Me
H
NH
3
CO2Me
4
Scheme 2
hours to give bromo- or iodophenylenamine (2a and 2b),
respectively. The resulting bromophenylenamine 2a was
reacted with Pd(PPh3)4 in the presence of Et3N in CH3CN
at 80 °C for 22 hours, and gave fused indole 3 in 46%
yield (Table 1). Considering the structure of 3, cyclization
might proceed via intermediate 2a¢ (R = PdX), which
would be generated from 2a by selective isomerization of
a double bond.
CO2Me
MeO2C
R
Pd
N
N
H
B
Since 3 is also useful for indole alkaloid synthesis, the re-
action in Scheme 2 was studied further. Reducing the
amount of palladium(0) resulted in a low yield of 3 (run
2), and the reaction of iodophenylenamine (2b) was stud-
ied next. When iodophenylenamine 2b was treated with
30 mol% of palladium(0), no desired 3 was obtained (run
3). However, the reaction of 2b with an equimolar amount
of palladium(0) gave Pd complex 4 as a crystalline solid
in 86% yield. Its structure was unambiguously determined
by X-ray crystallographic analysis (Figure 1) and shows
that palladium metal is oxidatively inserted into the car-
bon-iodine bond without isomerization of a double bond.
When the isolated palladium complex 4 was treated with
Ag3PO4 (1 equiv)4 in N,N-dimethylacetamide (DMA) at
100 °C for 35 hours, we were pleased to find that 3 was
obtained in 25% yield. Therefore, the reaction of 2b using
30 mol% of Pd(0) in the presence of Ag3PO4 was investi-
gated in several solvents (runs 5–8).5 Finally, the desired
A
MeO2C
O
R
+
NH2
R = Br or I
1
Scheme 1
Thus, o-bromo- or o-iodoaniline was heated in benzene
with 2-methoxycarbonylcyclooctanone (1) in the pres-
ence of 1.1–2.0 equivalents of p-TsOH at reflux for 16–39
SYNLETT 2004, No. 5, pp 0907–0909
Advanced online publication: 23.03.2004
0
2.
0
4.
2
0
0
4
DOI: 10.1055/s-2004-820039; Art ID: U24303ST.pdf
© Georg Thieme Verlag Stuttgart · New York

908
T. Watanabe et al.
LETTER
Table 1 Synthesis of 3 from 2 by Palladium-Catalyzed Cyclization
Entry
X
Pd(PPh3)4 (mol%) Additive (equiv)
Solvent
MeCN
MeCN
MeCN
MeCN
DMA
Temp (°C)
80
Time (h)
22
Product (%)
3 (46)
1
2
3
4
5
6
7
8
Br (2a)
Br (2a)
I (2b)
I (2b)
I (2b)
I (2b)
I (2b)
I (2b)
100
30
Et3N (2.4)
Et3N (2.4)
Et3N (2.4)
Et3N (2.4)
Ag3PO4 (2)
Ag3PO4 (2)
Ag3PO4 (1)
Ag3PO4 (1)
80
64
3 (25)
30
80
24
3 (0)a
100
30
80
32
4 (86)
100
100
100
100
10
3 (51)
30
DMF
16
3 (65)
30
NMP
16
3 (82)
10
DMSO
15
3 (quant.)
a A mixture of 2b and 4 (2:1) was obtained.
Kopsia alkaloids, lapidilectine A (8) and lapidilectam (9),
have been isolated from the stem and bark of Kopsia
lapidelecta (Figure 1).6 Although their biological activi-
ties have not been fully investigated, some Kopsia plants
are used in China to treat rheumatoid arthritis, dropsy and
tonsillitis. These Kopsia alkaloids have a unique structure
in which an indole skeleton is fused to azacyclooctane to
form an azocino[5,4-b]indole skeleton. Due to this com-
plex structure, Kopsia alkaloids have attracted the interest
of synthetic chemists, and lapidilectine B (10) has recent-
ly been synthesized (Figure 2).7
I
NH2
I
n
n
(2 equiv)
O
N
H
p-TsOH (1 equiv)
PhH, reflux
10–15 h
CO2Me
CO2Me
5
6a (75%)
6b (57%)
6c (68%)
a: n = 1, b: n = 2, c: n = 3
Figure 1 X-ray structure of Pd complex 4 (hydrogens are omitted
for clarity. This crystal structure was deposited at the Cambridge
Crystallographic Data Centre, CCDC231397)
n
Pd(PPh3)4
Ag3PO4 (1 equiv)
CO2Me
DMSO, 100 °C
N
H
3 was obtained in quantitative yield by treatment of 2b
with 10 mol% of Pd(PPh3)4 and Ag3PO4 (1 equiv) in
DMSO (entry 8).
Table 2
7
Scheme 3
Other fused indoles containing smaller rings were also
prepared under similar conditions (Scheme 3 and
Table 2).
O
CO2Me
N
CO2Me
N
N
N
Table 2 Palladium-Catalyzed Cyclization of 6
MeO2C
CO2Me
MeO2C
CO2Me
Lapidilectam (9)
Substrate
Pd(PPh3)4 (mol%) Time (h)
Product (%)
7a (39)
Lapidilectine A (8)
6a
6b
6c
10
30
30
23
16
17
O
N
O
7b (40)
N
7c (59)
MeO2C
Lapidilectine B (10)
Figure 2 Kopsia lapidilecta alkaloids
Synlett 2004, No. 5, 907–909 © Thieme Stuttgart · New York

LETTER
Novel Synthesis of Fused Indoles
909
1) Br
CO2Et
References
Bs
K2CO3, acetone
60 °C, 2 days (100%)
(1) (a) Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. I and II; Negishi, E., Ed.; John Wiley and
Sons, Inc.: New York, 2002. (b) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry; Elsevier Science Ltd.:
Oxford, 2000.
N
H2NBs
O
2) t-BuOK, PhMe,
(Bs = SO2Ph)
reflux, 25 h (33%)
EtO2C
11
I
(2) Mori, M.; Ban, Y. Tetrahedron Lett. 1977, 18, 1037.
(3) Synthesis of indoles by palladium-catalyzed cyclization of
N-alkenyl-o-haloanilines, see: (a) Caddick, S.; Kofie, W.
Tetrahedron Lett. 2002, 43, 9347. (b) Michael, J. P.; de
Koning, C. B.; Petersen, R. L.; Stanbury, T. V. Tetrahedron
Lett. 2001, 42, 7513. (c) Latham, E. J.; Stanforth, S. P. J.
Chem. Soc, Perkin Trans. 1 1997, 2059. (d) Blache, Y.;
Sinibaldi-Troin, M.-E.; Voldoire, A.; Chavignon, O.;
Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P. J. Org. Chem.
1997, 62, 8553. (e) Chen, L. C.; Yang, S. C.; Wang, H. M.
Synthesis 1995, 385. (f) Michael, J. P.; Chang, S.-F.;
Wilson, C. Tetrahedron Lett. 1993, 34, 8365. (g)Sakamoto,
T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990,
215. (h) Kasahara, A.; Izumi, T.; Murakami, S.; Yanai, H.;
Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927. (i) Iida,
H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 45, 2938.
(4) (a) Sato, Y.; Watanabe, S.; Shibasaki, M. Tetrahedron Lett.
1992, 33, 2589. (b) Sato, Y.; Honda, T.; Shibasaki, M.
Tetrahedron Lett. 1992, 33, 2593. (c) Sato, Y.; Nukui, S.;
Sodeoka, M.; Shibasaki, M. Tetrahedron 1994, 50, 371.
(5) While other silver salts, such as Ag2CO3, AgPF6, AgOTf,
and AgBF4, also promoted this reaction, they were less
effective.
I
Bs
N
NH2
(2 equiv)
N
p-TsOH (1 equiv)
PhH
H
CO2Et
12 (58%)
reflux, 4 d
Bs
N
Pd(PPh3)4
(10 mol%)
Ag3PO4 (1 eq)
N
DMSO, 100 °C
18 h
CO2Et
H
13 (69%)
Scheme 4
We were also interested in the synthesis of these alkaloids
and applied our new cyclization to synthesize the azocino-
indole skeleton 13 (Scheme 4). Thus, azocine derivative
11,8 which was prepared from benzenesulfonamide in two
steps, was condensed with o-iodoaniline to give enamine
12 in 58% yield. Enamine 12 was converted to azocino-
indole 139 in 69% yield under the optimized conditions
described above.
(6) Awang, K.; Sévenet, T.; Païs, M.; Hadi, A. H. A. J. Nat.
Prod. 1993, 56, 1134.
(7) Pearson, W. H.; Mi, Y.; Lee, I. Y.; Stoy, P. J. Am. Chem.
Soc. 2001, 123, 6724.
(8) Lennon, M.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1
1979, 2009.
In conclusion, we have developed a new type of palladi-
um-catalyzed cyclization, which proceeds via selective
isomerization of a double bond in the enamine structure
followed by 5-endo cyclization. This reaction is useful for
synthesizing fused indoles.
(9) Experimental Procedure for the Synthesis of 13: A
mixture of enamine 12 (0.15 g, 0.28 mmol), Ag3PO4 (0.12 g,
0.28 mmol), and Pd(PPh3)4 (32 mg, 28 mmol) was heated (18
h) with stirring in DMSO (1.0 mL) at 100 °C under Ar. The
mixture was diluted with Et2O at r.t., and filtered through a
celite pad. The filtrate was concentrated and the residue was
purified by silica gel column chromatography (EtOAc:n-
hexane, 1:5) to give 13 as a colorless oil (79 mg, 69%). 1H
NMR (600 MHz, CDCl3): d = 1.35 (t, J = 7.1 Hz, 3 H), 1.87
(td, J = 2.8, 12.9 Hz, 1 H), 2.18 (ddd, J = 3.9, 12.6, 14.8 Hz,
1 H), 2.56 (t, J = 12.1 Hz, 1 H), 2.66 (tt, J = 5.0, 12.9 Hz, 1
H), 2.94 (ddd, J = 3.0, 12.1, 15.1 Hz, 1 H), 3.13 (ddd,
J = 1.4, 3.6, 15.1 Hz, 1 H), 3.48 (dd, J = 4.1, 15.1 Hz, 1 H),
4.12 (dt, J = 3.9, 13.2 Hz, 1 H), 4.24–4.32 (m, 2 H), 4.37 (dd,
J = 5.2, 12.7 Hz, 1 H), 7.06 (td, J = 1.1, 7.1 Hz, 1 H), 7.13
(td, J = 1.1, 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.42 (d,
J = 8.0 Hz, 1 H), 7.47 (td, J = 1.4, 7.7 Hz, 2 H), 7.54 (tt,
Acknowledgment
This research was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas (A) ‘Exploitation of Multi-Element Cyclic
Molecules’ and a Grant-in-Aid for Exploratory Research from the
Ministry of Education, Culture, Sports, Science and Technology,
Japan. Financial support from The Uehara Memorial Foundation
and The Naito Foundation is also gratefully acknowledged.
J = 1.4, 7.2 Hz, 1 H), 7.78–7.80 (m, 2 H), 9.11 (s, 1 H). 13
C
NMR (150 MHz, CDCl3): d = 14.3, 25.8, 36.5, 39.4, 48.5,
53.7, 61.6, 111.2, 111.3, 117.6, 119.5, 121.9, 127.0, 129.2,
130.9, 132.7, 135.5, 139.1, 174.8.
Synlett 2004, No. 5, 907–909 © Thieme Stuttgart · New York