Novel synthesis of fused indoles and 2-substituted indoles by the palladium-catalyzed cyclization of N-cycloalkenyl-o-haloanilines

Article abstract of DOI:10.1016/j.tet.2008.12.028

A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-substituted indoles were synthesized from enaminoesters prepared by condensation of β-ketoesters and o-iodoaniline.

Full text of DOI:10.1016/j.tet.2008.12.028

Tetrahedron 65 (2009) 1327–1335
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel synthesis of fused indoles and 2-substituted indoles by the palladium-
catalyzed cyclization of N-cycloalkenyl-o-haloanilines
*
Jun Maruyama, Hiromichi Yamashita, Takeshi Watanabe, Shigeru Arai, Atsushi Nishida
Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new palladium-catalyzed cyclization of N-alkenyl-o-haloanilines with selective isomerization of
a double bond followed by formal 5-endo-trig cyclization was developed. A variety of fused and 2-
substituted indoles were synthesized from enaminoesters prepared by condensation of b-ketoesters and
Received 7 November 2008
Received in revised form 10 December 2008
Accepted 11 December 2008
Available online 16 December 2008
o-iodoaniline.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Palladium
Heck reaction
Olefin isomerization
Enamine
1. Introduction
(Scheme 1). To realize this scheme, enaminoesters C were prepared
by condensation of o-haloanilines D and b-ketoesters E.
The intramolecular Heck reaction1 is an important and powerful
method for the construction of carbo- and heterocyclic compounds.
The synthesis of indoles using this reaction has also been widely
studied.2,3 However, the synthesis of fused indoles by palladium-
catalyzed cyclization using N-cycloalkenyl-o-haloanilines, which
are readily obtained from cyclic 1,3-diketones,3q,r,t,u,w has not been
fully investigated, although the skeleton is involved in many im-
portant bioactive compounds. We have already reported the novel
synthesis of fused indoles by the palladium-catalyzed cyclization of
N-cycloalkenyl-o-iodoanilines with selective isomerization of
a double bond.4 In this article, we describe the details of this
reaction.
Thus, o-bromo- or o-iodoaniline (1a or 1b) was heated in ben-
zene with 2-methoxycarbonylcyclooctanone (2) in the presence of
1.1–2.0 equiv of p-TsOH at reflux for 16–39 h to give bromo- or
iodophenylenaminoester 3a or 3b, respectively (Scheme 2). The
resulting bromophenylenaminoester 3a was reacted with
Pd(PPh3)4 in the presence of Et3N in CH3CN at 80 ꢀC for 22 h.5 The
structure of the isolated product was determined by spectroscopy
to be fused indole 4 (46%), and no indolenine 5, which was expected
from the formal 5-endo cyclization of intermediate 6, was observed
(Table 1, entry 1). Based on the structure of 4, cyclization might
Y
Y
R1O2C
R1O2C
2. Result and discussion
R2
X
N
H
N
B
In connection with our recent work on the synthesis of indole
alkaloids, we were interested in the synthesis of fused indolines A,
which contain medium-sized rings and two quarternary centers, as
shown in Scheme 1. For the synthesis of A, indolenines B is a possible
intermediate, and may be prepared by the intramolecular Heck re-
action of enaminoesters C. However, there has been no report on
cyclization usingenaminoesters C, obtained fromcyclic-ketoestersE
A
Pd
CO2R1
D
NH2
Y
X
Y
+
R1O2C
O
N
H
E
C
* Corresponding author. Fax: þ81 (43)2902909.
E-mail address: nishida@p.chiba-u.ac.jp (A. Nishida).
Scheme 1. A plan for the synthesis of fused indolines A.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.028

1328
J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
X
MeO2C
+
X
Pd(PPh3)4
Table 1
TsOH
benzene
reflux
N
H
N
H
NH2
O
CO2Me
CO2Me
16 h (X = Br)
or
1a (X = Br, 1.1 equiv)
1b (X = I, 2 equiv)
3a (X = Br, 68%)
2
4
3b (X = I, 62%)
39 h (X = I)
Pd(PPh3)2I
PdX
PdX
NH
CO2Me
MeO2C
isomerization
N
N
H
N
H
CO2Me
CO2Me
5
6
7
8
Scheme 2. Discovery of a new palladium-catalyzed cyclization with selective isomerization of a double bond.
proceed via intermediate 7, which would be generated from 6 by
selective isomerization of a double bond. Since 4 is also useful for
indole alkaloid synthesis, we decided to study this reaction in
detail.
under optimized conditions described above (Scheme 3). When
fused indole containing a six-membered ring was synthesized,
oxidized product 128 was obtained as a side product in low yield.
Furthermore, we extended this methodology to produce fused in-
dole containing a piperidine ring (Scheme 4). However, desired 14
A reduction in palladium(0) loading resulted in a low yield of 4
(entry 2). When iodophenylenaminoester 3b was treated with
30 mol % of palladium(0), no desired 4 was obtained (entry 3).
However, the reaction of 3b with an equimolar amount of palla-
dium(0) gave Pd complex 8 as a crystalline solid in 86% yield (entry
4). Its structure was unambiguously determined by X-ray crystallo-
graphic analysis4,6 and showed that palladium metal is oxidatively
inserted into the carbon–iodine bond without isomerization of
a double bond. When the isolated palladium complex 8 was treated
with Ag3PO4 (1 equiv)7 in N,N-dimethylacetamide (DMA) at 100 ꢀC
for 35 h, cyclized 4 was obtained in 25% yield. Therefore, under the
conditions using 10 mol % Pd(PPh3)4 in the presence of Ag3PO4 in
CH3CN at 80 ꢀC, desired 4 was obtained in 94% yield (entry 5). It is
interesting to note that arylbromide 3a showed higher reactivity
than aryliodide 3b. This difference in reactivity may be explained by
more electronegative character of bromine atom, which activates
intermediate 6.
To optimize the reaction conditions, we examined the effect
of palladium catalysts, silver salts, and solvents on this Heck
reaction. The results are summarized in Table 2. Although the
cyclization in CH3CN was very slow (Table 2, entry 1), a polar
solvent such as DMF, DMA, and NMP gave 4 in short reaction
times (entries 2–4).
The best result for cyclization was obtained when 3b was treated
with 10 mol % of Pd(PPh3)4 and 1 equiv of Ag3PO4 in DMSO to give 4
in quantitative yield (entry 5). Furthermore, 4 was obtained in high
yield with 3 mol % of catalyst loading (entry 6). While other palla-
dium catalysts and other silver salts, such as AgNO3, and AgOTf, also
promoted this reaction, they were less effective (entries 7–18).
Other fused indoles 11 containing smaller rings were also prepared
and oxidized g-carboline 15 were obtained in low yield.
Next, the new palladium-catalyzed cyclization was applied to
several acyclic enaminoesters (Table 3). In the reaction of tri-
substituted enaminoesters 16a3u and 16b, indoles 18a and 18b9
were obtained as major isomers and indoles 17a and 17b10 were
Table 2
Optimization of reaction conditionsa
Pd cat.
Ag salt
I
solvent
N
H
N
H
CO2Me
CO2Me
3b
4
Entry
Pd cat.b
Ag saltc
Solvent
Time
(h)
Yield
(%)
1d
2
3
4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
PdCl2(PPh3)2
PdCl2(PhCN)2
PdCl2
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
AgNO3
Ag2SO3
AgOTf
CH3CN
DMF
DMA
29
1
1
1
1
1
1
1
1
1
1
1
2
4
5
21
1
1
94
83
92
90
Quant
95
20
63
80
75
39
80
71
NMP
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
6e
7
8
9
10
11
12f
13g
14f
15f
16f
17h
18i
Pd(OAc)2
Pd(CN)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
49
18
13
72
50
AgOCOCF3
AgOAc
Ag3PO4
Ag3PO4
Table 1
Synthesis of 4 from 3 by palladium-catalyzed cyclizationa
a
These reactions were performed in the presence of 10 mol % of the palladium
catalyst and 1 equiv of silver salt at 100 ꢀC.
Entry
X
Pd cat.
(mol %)
Additive
(equiv)
Time
(h)
Product (%)
b
The catalysts Pd(dba)2 and Pd/C resulted in the production of unidentified
products.
1
2
3
4
5
Br (3a)
Br (3a)
I (3b)
I (3b)
I (3b)
100
30
30
100
10
Et3N (2.4)
Et3N (2.4)
Et3N (2.4)
Et3N (2.4)
Ag3PO4 (1)
22
64
24
32
29
4 (46)
4 (25)
4 (0)b
8 (86)
4 (94)
c
Silver salts such as Ag2O, Ag2CO3, AgClO4, and AgCl resulted either in recovery of
the starting material or the production of unidentified products.
d
This reaction was performed at 80 ꢀC.
Pd(PPh3)4 (3 mol %).
Silver salt (3 equiv).
Silver salt (1.5 equiv).
Silver salt (0.67 equiv).
Silver salt (0.33 equiv).
e
f
g
a
These reactions were performed in the presence of Pd(PPh3)4 and additive in
CH3CN at 80 ꢀC.
h
i
b
A mixture of 3b and 8 (2:1) was obtained.

J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
1329
2-Iodoaniline
TsOH
I
I
R1
( )n
( )n
H
16a
16b
benzene
reflux
N
H
N
H
O
CO2Me
CO2Me
CO2Et <tri-substituted>
9a (n = 1)
9b (n = 2)
9c (n = 3)
10a (n = 1, 75%)
10b (n = 2, 81%)
10c (n = 3, 83%)
Ln
Pd+
CO2Et
H
Pd(PPh3)4
CO2Et
CO2Et
R1
( )n
(10 mol%)
fast
H
Ag3PO4 (1 eq)
N
H
R1
N
N
H
CO2Me
R1
DMSO
100 °C
N
H
19
21
18
<normal>
major products
11a (n = 1, 43%)
11b (n = 2, 64%) + 12 (11%)
11c (n = 3, 71%)
isomerization
slow
Ln
R1
Pd+ R1
H
H
CO2Me
N
H
N
H
N
H
CO2Et
CO2Et
12
Scheme 3. Scope and limitations of fused indole synthesis.
17
20
<migrated>
minor products
I
Bs
Pd(PPh3)4 (10 mol%)
I
R1
N
Ag3PO4 (1 equiv)
DMSO, 100 °C
R2
16c
16d
<tetra-substituted>
N
H
N
H
CO2Et
CO2Et
13 (Bs=SO2Ph)
Bs
N
N
Ln
+
R2
Pd+
CO2Et
CO2Et
CO2Et
R2
N
H
N
H
CO2Et
R1
14 (15%)
15 (12%)
N
H
N
R1
Scheme 4. Synthesis of piperidine and pyridine fused indoles.
22
24
<normal>
isomerization
obtained in low yield (entries 1 and 2). In contrast, tetra-
substituted enaminoesters 16c and 16d provided indoles 17c and
17d with complete regioselectivity (entries 3 and 4). These results
provide the following mechanistic explanation (Scheme 5).
When the substrates are tri-substituted enaminoesters 16a and
16b, since the rate of insertion (19 to 21) is faster than that of olefin
isomerization of 19 to 20, 18a and 18b are obtained as major
products through a normal Heck reaction pathway. On the other
hand, when the substrates are tetra-substituted enaminoesters 16c
Ln
R1
Pd+ R1
R2
R2
CO2Et
N
H
N
H
CO2Et
23
17
<migrated>
only observed products
Scheme 5. Mechanistic analysis of acyclic enaminoesters.
Table 3
Palladium-catalyzed cyclization of acyclic enaminoesters
and 16d, the rate of insertion of 22 to give 24 is much slower than
that of isomerization of 22 to 23 because the initial coordination of
the double bond to palladium does not proceed due to steric effects
in the reactive conformation.5,11 Therefore, tetra-substituted
enaminoesters 16c and 16d give only 17c and 17d through an olefin
migratory Heck reaction pathway.
In the case of enaminoester 3b, oxidative addition to Pd(0) gives
Pd complex 8. When 8 is treated with Ag3PO4, 16-electron Pdþ
intermediate 25 is generated. At this stage, tetra-substituted olefin
is too bulky to coordinate cationic palladium, and intramolecular
coordination of the carbonyl group to cationic palladium raises the
R1
R2
Pd(PPh3)4
N
H
CO2Et
17
I
R1
(10 mol%)
Ag3PO4 (1 eq)
R2
CO2Et
and/or
N
H
DMSO, 100 °C
CO2Et
16
R1
N
H
18
acidity of g-proton and causes isomerization of the double bond (25
to 26). The resulting tri-substituted enaminoester coordinates to
cationic palladium (26 to 27). From 27, carbopalladation via
Entry
Enaminoester
R1
Time (h)
Products (%)
R2
17
18
a 5-endo process affords 28, and b-hydride elimination produces
1
2
3
4
16a
16b
16c
16d
H
Me
H
H
H
n-Pr
Bn
3.5
4.5
3.0
2.5
17a (17)
17b (6)
17c (67)
17d (82)
18a (79)
18b (86)
d
the indolenine that undergoes tautomerization to furnish the
substituted fused indole 4.3c,f,o,v,w,12 However, we cannot rule out
the another type of cyclization via palladacycle 29 by virtue of the
H
d

1330
J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
PPh3
Pd+
PPh3
PPh3
Pd
X-
X-
I
Isomerization
Ag3PO4
AgI
Pd+
Pd(0)
I
O
O
NH
N
H
NH
O
NH
PPh3
PPh3
X- = Ag2PO4
CO2Me
PPh3
OMe
OMe
OMe
H
3b
-
H
3-
8
25
AgPO42- or PO4
26
PdXLn
β-hydride
5-endo-trig
elimination
cyclization
PPh3
Pd+
N
H
CO2Me
X-
aromatization
28
HN
MeO2C
N
H
Ln
Pd
Ln
Pd
CO2Me
PPh3
4
Reductive
elimination
and/or
27
N
N
H
CO2Me
CO2Me
29a
29b
Scheme 6. Proposed reaction mechanism.
In connection with the total synthesis of Kopsia lapidilecta
alkaloids13 such as lapidilectine A (30), lapidilectam (31), and
lapidilectine B (32)14 (Fig. 1), we were also interested in applying
our new cyclization to synthesize the azocinoindole 35 (Scheme 7).
Thus, azocine derivative 33,15 which was prepared from benzene-
sulfonamide in two steps, was condensed with o-iodoaniline to
give enaminoester 34 in 58% yield. Enaminoester 34 was converted
to azocinoindole 35 in 69% yield under the optimized conditions
described above.
CO2Me
CO2Me
O
N
N
N
N
MeO2C
MeO2C
CO2Me
CO2Me
Lapidilectine A (30)
Lapidilectam (31)
N
O
O
N
MeO2C
3. Conclusion
Lapidilectine B (32)
In conclusion, we have developed a new type of palladium-
catalyzed cyclization of N-cycloalkenyl-o-iodoanilines, which pro-
ceeds via the selective isomerization of a double bond in the
enaminoester structure followed by formal 5-endo-trig cyclization.
This reaction is useful for synthesizing fused and 2-substituted
indoles.
Figure 1. K. lapidilecta alkaloids.
nucleophilicity of the enaminoester unit. While both routes are
possible, additional experiments are needed to clarify the reaction
mechanism (Scheme 6).
4. Experimental
1) Br
CO2Et
K2CO3, acetone
4.1. General methods
Bs
N
60 °C, 2 days, 100%
H2NBs
2) t-BuOK, toluene
O
All reactions involving air- or moisture-sensitive reagents or
intermediates were performed under an inert atmosphere of argon
in glassware. Unless otherwise noted, solvents and reagents were
reagent grade and used without purification. DMF, DMA, and NMP
were distilled from anhydrous MgSO4. DMSO, Et3N, and pyridine
were distilled from CaH2. Benzene was freshly distilled from so-
dium/benzophenone prior to use. Toluene was used as received
from Kanto, Chemical Co., Inc. Analytical and preparative TLC was
carried on E. Merck 0.25 mm silica gel 60 GF254 plates. Flash column
chromatography was performed using Kanto chemical silica gel
reflux, 25 h, 49%
(Bs = SO2Ph)
EtO2C
33
I
NH2 (2 equiv)
I
Bs
N
p-TsOH (1 equiv)
toluene, reflux, 4 days
58%
N
H
CO2Et
34
Bs
60N (40–50
ASTM), Fuji Silysia silica gel (PSQ 60B), or Kanto chemical silica gel
60 N (40–50
m spherical, neutral). CeliteÒ 545 was used for fil-
mm spherical), E. Merck silica gel 60 (230–400 mesh
N
Pd(PPh3)4 (10 mol%)
Ag3PO4 (1 equiv)
m
DMSO, 100 °C, 18 h
69%
tration. Melting points were determined on a Yanagimoto micro
melting point apparatus or were uncorrected. 1H NMR spectra were
taken on 400 or 600 MHz and 13C NMR spectra were taken on 100
N
H
CO2Et
35
Scheme 7. Application to synthesis of the azocinoindole 35.
or 150 MHz instrument (JEOL LNM-GSX 400a, JEOL JMN-ECP 400,

J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
1331
JEOL JMN-ECP 600) in the indicated solvent at room temperature
unless otherwise stated and are reported. Chemical shifts are
reported in parts per million (ppm) downfield from (CH3)4Si (TMS).
Coupling constants are reported in hertz (Hz). Spectral splitting
patterns are designated as follows: s, singlet; br, broad; d, doublet;
t, triplet; q, quartet; m, multiplet. Infrared (IR) spectra were
recorded on JASCO FT/IR-230 spectrometer. MS spectrometry and
elemental analysis were carried out by the Chemical Analysis
Center of Chiba University.
chromatography on silica gel eluted with EtOAc/n-hexane (1:10) to
afford 4 (31.2 mg, 95%) as a colorless oil.
Spectral data of 4: 1H NMR (600 MHz, CDCl3)
d: 1.03–1.10 (m,
1H), 1.33–1.39 (m, 1H), 1.46–1.55 (m, 1H), 1.58–1.66 (m, 2H), 1.86–
1.92 (m, 2H), 2.01–2.07 (m, 1H), 2.58 (ddd, J¼3.0, 12.7, 14.7 Hz, 1H),
3.08 (dt, J¼4.1, 14.7 Hz,1H), 3.79 (s, 3H), 4.12 (dd, J¼4.7,12.4 Hz,1H),
7.07–7.10 (m, 1H), 7.12–7.15 (m, 1H), 7.33 (dd, J¼0.8, 8.0 Hz,1H), 7.52
(d, J¼8.0 Hz, 1H), 8.93 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 23.2,
25.1, 26.5, 31.1, 35.2, 41.1, 52.2, 110.9, 113.6, 117.9, 119.0, 121.3, 127.5,
130.5, 135.4, 175.5; IR (neat) n: 3442, 2924, 2850, 1729, 1462, 1168,
742 cmꢁ1; LRMS (EI) m/z 257 [M]þ; HRMS (FAB) m/z calcd for
4.2. Methyl 2-(2-bromophenylamino)cyclooct-1-
enecarboxylate (3a)
C16H19NO2 [M]þ 257.1416, found 257.1406.
4.5. Methyl 2-(2-iodophenylamino)cyclopent-1-
enecarboxylate (10a)
To a solution of methyl 2-oxocyclooctanecarboxylate (5.0 g,
27 mmol) in benzene (27 mL) in a flask fitted with Dean–Stark
apparatus were added 2-bromoaniline (5.1 g, 30 mmol) and
p-TsOH$H2O (2.6 g, 14 mmol) at room temperature. The mixture
was heated for 14 h under reflux. After filtration of the reaction
mixture through a Celite pad, the filtrate was washed with satu-
rated aqueous NaHCO3 and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
eluted with EtOAc/n-hexane (1:80) to afford 3a (6.25 g, 68%) as
a colorless solid.
To a solution of methyl 2-oxocyclopentanecarboxylate 9a (1.0 g,
7.0 mmol) and 2-iodoaniline (3.1 g, 14.1 mmol) in benzene (30 mL)
in a flask fitted with a Dean–Stark apparatus was added p-TsOH
(1.28 g, 7.0 mmol) at room temperature. The mixture was heated
for 10 h under reflux. After filtration of the reaction mixture
through a Celite pad, the filtrate was washed with saturated
aqueous NaHCO3 and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
eluted with EtOAc/n-hexane (from 1:10 to 1:30) to afford 10a
(1.81 g, 75%) as a colorless solid.
Spectral data of 3a: mp 78–80 ꢀC (n-hexane); 1H NMR
(400 MHz, CDCl3)
3H), 2.02–7.06 (m, 1H), 7.16–7.18 (m, 1H), 7.25–7.29 (m, 1H), 7.59–
7.61 (m, 1H), 10.7 (br s, 1H); 13C NMR (100 MHz, CDCl3)
: 25.6, 26.2,
26.6, 27.1, 29.2, 30.3, 50.8, 97.1, 121.8, 126.5, 127.6, 128.2, 133.0, 139.1,
d: 1.41–1.60 (m, 8H), 2.45–2.51 (m, 4H), 3.73 (s,
Spectral data of 10a: mp 58–60 ꢀC (n-hexane); 1H NMR
d
(400 MHz, CDCl3)
d
: 1.88 (q, J¼7.3 Hz, 2H), 2.59 (t, J¼7.3 Hz, 2H),
2.71 (t, J¼7.3 Hz, 2H), 3.77 (s, 3H), 6.77 (t, J¼7.6 Hz, 1H), 7.13 (dd,
J¼1.2, 8.1 Hz, 1H), 7.26 (t, J¼6.6 Hz, 1H), 7.82 (dd, J¼1.2, 7.8 Hz, 1H),
159.7, 171.0; IR (KBr) n: 2935, 2857, 1604, 1483, 1431, 1246, 1156,
1101, 759 cmꢁ1; LRMS (FAB) m/z 337 [M]þ; HRMS (FAB) calcd for
9.48 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 21.8, 29.0, 33.5, 50.7,
C16H20BrNO2 [M]þ 337.0677, found 337.0687.
92.9, 99.2, 121.7, 124.9, 128.8, 139.6, 141.9, 159.1, 168.4; IR (KBr) n:
2941, 2856, 1656, 1609, 1441, 1276 cmꢁ1; LRMS (EI) m/z 343 [M]þ;
HRMS (FAB) calcd for C13H14INO2 [M]þ 343.0069, found 343.0066.
4.3. Methyl 2-(2-iodophenylamino)cyclooct-1-
enecarboxylate (3b)
4.6. Methyl 2-(2-iodophenylamino)cyclohex-1-
enecarboxylate (10b)
To a solution of methyl 2-oxocyclooctanecarboxylate (3.4 g,
18.46 mmol) in benzene (37 mL) in a flask fitted with Dean–Stark
apparatus were added 2-iodoaniline (8.08 g, 36.9 mmol) and p-
TsOH (95 mg, 0.55 mmol) at room temperature. The mixture was
heated for 43 h under reflux. After filtration of the reaction mixture
through a Celite pad, the filtrate was washed with saturated
aqueous NaHCO3 and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
eluted with EtOAc/n-hexane (1:80) to afford 3b (4.42 g, 62%) as
a colorless solid.
To a solution of methyl 2-oxocyclohexanecarboxylate (9b,
0.1 mL, 0.7 mmol) and 2-iodoaniline (459.9 mg, 2.1 mmol) in ben-
zene (10 mL) in a flask fitted with a Dean–Stark apparatus was
added p-TsOH (60.2 mg, 0.35 mmol) at room temperature. The
mixture was heated for 23 h under reflux. After filtration of the
reaction mixture through a Celite pad, the filtrate was washed with
saturated aqueous NaHCO3 and brine. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel eluted with EtOAc/n-hexane (from 1:10 to 1:4) to afford
10b (203.0 mg, 81%) as a colorless solid.
Spectral data of 3b: mp 62–65 ꢀC (n-hexane); 1H NMR
(400 MHz, CDCl3) d: 1.38–1.44 (m, 2H), 1.51–1.60 (m, 6H), 2.43 (t,
Spectral data of 10b: mp 52–54 ꢀC (n-hexane); 1H NMR
J¼6.1 Hz, 2H), 2.50 (t, J¼6.1 Hz, 2H), 3.74 (s, 3H), 6.90 (td, J¼1.5,
9.0 Hz, 1H), 7.14 (dd, J¼1.2, 7.8 Hz, 1H), 7.30 (td, J¼1.2, 7.8 Hz, 1H),
7.86 (dd, J¼1.5, 7.8 Hz, 1H), 10.59 (br s, 1H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
: 1.58–1.66 (m, 4H), 2.14 (t, J¼5.1 Hz, 2H), 2.37 (t,
J¼6.1 Hz, 2H), 3.70 (s, 3H), 6.87 (td, J¼1.7, 7.6 Hz,1H), 7.13 (dd, J¼1.5,
CDCl3) d: 25.7, 26.1, 26.7, 27.1, 29.1, 30.3, 50.8, 96.9, 99.3, 127.0, 127.9,
7.8 Hz, 1H), 7.28 (td, J¼1.5, 7.8 Hz, 1H), 7.85 (dd, J¼1.5, 8.1 Hz, 1H),
10.40 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 22.2, 22.6, 23.8, 28.0,
128.6, 139.3, 142.3, 159.6, 171.0; IR (KBr) n: 2924, 1648, 1598, 1436,
1245 cmꢁ1; LRMS (EI) m/z 385 [M]þ; HRMS (FAB) calcd for
50.8, 94.2, 98.4, 126.7, 127.2, 128.5, 139.3, 141.8, 155.7, 171.0; IR (KBr)
C16H20INO2 [M]þ 385.0539, found 385.0536.
n
: 2941, 1654, 1594, 1478, 1437, 1244, 1184, 1091 cmꢁ1; LRMS (EI) m/z
357 [M]þ; HRMS (FAB) calcd for C14H16INO2 [M]þ 357.0226, found
357.0249.
4.4. Methyl 6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indole-6-
carboxylate (4) (Table 2, entry 6)
4.7. Methyl 2-(2-iodophenylamino)cyclohept-1-
enecarboxyate (10c)
A suspension of 3b (49.2 mg, 0.128 mmol), Pd(PPh3)4 (4.4 mg,
3.84 mmol), and Ag3PO4 (53.6 mg, 0.128 mmol) in DMSO (1.3 mL)
was heated for 1 h at 100 ꢀC. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
To a solution of methyl 2-oxocycloheptanecarboxylate 9c
(0.1 mL, 0.64 mmol) and 2-iodoaniline (280.4 mg, 1.28 mmol) in
benzene (6.4 mL) in a flask fitted with a Dean–Stark apparatus was

1332
J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
added p-TsOH (55.0 mg, 0.32 mmol) at room temperature. The
mixture was heated for 4 h under reflux. After filtration of the re-
action mixture through a Celite pad, the filtrate was concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography on silica gel eluted with EtOAc/n-hexane
(1:10) to afford an inseparable mixture of 9c (209.3 mg, 0.56 mmol
determined by 1H NMR) and 2-iodoaniline (63.0 mg, 0.29 mmol
determined by 1H NMR) as a yellow oil. To remove 2-iodoaniline,
the mixture (272.3 mg) in benzene (10 mL) was reacted with suc-
cinic anhydride (115.1 mg, 1.15 mmol) in the presence of pyridine
(0.09 mL, 1.15 mmol) and heated for 2 days at 70 ꢀC. After filtration
of the reaction mixture through a Celite pad, the filtrate was
washed with saturated aqueous NaHCO3 and brine. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure to give a residue, which was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (1:10) to
afford 10c (237.6 mg, 83%) as a colorless crystal.
Spectral data of 12: 1H NMR (400 MHz, CDCl3)
7.23–7.29 (m, 2H), 7.46–7.54 (m, 2H), 8.07–8.10 (m, 2H), 8.27 (d,
d: 4.03 (s, 3H),
J¼7.6 Hz, 1H), 9.93 (br s, 1H); IR (neat)
n: 3406, 1676, 1601, 1260,
749 cmꢁ1; Reg# 51035-15-5.
4.10. Methyl 5,6,7,8,9,10-hexahydrocyclohepta[b]indole-6-
carboxylate (11c)
A
suspension of compound 10c (198.0 mg, 0.53 mmol),
Pd(PPh3)4 (61.3 mg, 0.053 mmol), and Ag3PO4 (223.3 mg,
0.53 mmol) in DMSO (5.3 mL) was heated for 2 h at 100 ꢀC. After
filtration of the reaction mixture through a Celite pad, the filtrate
was concentrated under reduced pressure. The resulting residue
was purified by flash column chromatography on silica gel eluted
with EtOAc/n-hexane (from 1:4 to 1:2) to afford 11c (91.0 mg, 71%)
as a yellow oil.
Spectral data of 11c: 1H NMR (400 MHz, CDCl3)
d: 1.75–1.79 (m,
Spectral data of 10c: mp 74–76 ꢀC (EtOAc/n-hexane); 1H NMR
2H),1.85–1.93 (m, 1H), 2.05–2.13 (m, 3H), 2.76–2.92 (m, 2H), 3.76 (s,
3H), 3.95 (dd, 1H, J¼3.4, 7.1 Hz), 7.07–7.15 (m, 2H), 7.29 (d, 1H,
J¼7.3 Hz), 7.50 (d, 1H, J¼7.6 Hz), 8.44 (br s, 1H); 13C NMR (100 MHz,
(400 MHz, CDCl3) d: 1.51–1.55 (m, 2H), 1.60–1.64 (m, 2H), 1.73–1.78
(m, 2H), 2.42–2.45 (m, 2H), 2.56–2.59 (m, 2H), 3.74 (s, 3H), 6.82 (td,
J¼1.5, 7.9 Hz, 1H), 6.95 (d, J¼8.1 Hz, 1H), 7.28 (td, J¼1.3, 7.7 Hz, 1H),
7.85 (dd, J¼1.3, 7.9 Hz, 1H), 10.68 (br s, 1H); 13C NMR (100 MHz,
CDCl3) d: 23.9, 27.9, 29.1, 30.9, 45.1, 52.2, 110.6, 115.1, 118.0, 119.1,
121.3, 128.5, 132.6, 134.5, 173.8; IR (neat) n: 3398, 2924, 1718, 1462,
CDCl3)
d
: 26.0, 26.3, 27.6, 30.2, 31.9, 51.0, 96.5, 100.6, 125.5, 125.9,
1228, 1198 cmꢁ1; LRMS (EI) m/z 243 [M]þ; HRMS (FAB) calcd for
128.5, 139.4, 142.1, 162.2, 170.8; IR (KBr)
n
: 2913, 2848, 1648, 1600,
C15H17NO2 [M]þ 243.1259, found 243.1257.
1250, 1209 cmꢁ1; LRMS (EI) m/z 371 [M]þ; HRMS (FAB) calcd for
C15H18INO2 [M]þ 371.0382, found 371.0370.
4.11. Ethyl 1-(4-benzenesulfonyl)-4-(2-iodophenylamino)-
1,2,5,6-tetrahydropyridine-3-carboxylate (13)
4.8. Methyl 1,2,3,4-tetrahydrocyclopenta[b]indole-3-
carboxylate (11a)
To a solution of ethyl 1-(benzenesulfonyl)-4-oxopiperidine-3-
carboxylate (254.7 mg, 0.82 mmol) and 2-iodoaniline (358.3 mg,
1.64 mmol) in benzene (10 mL) in a flask fitted with a Dean–Stark
apparatus was added p-TsOH (70.3 mg, 0.41 mmol) at room tem-
perature. The mixture was heated for 5 h under reflux. After fil-
tration of the reaction mixture through a Celite pad, the filtrate was
washed with saturated aqueous NaHCO3 and brine. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (from
1:10 to 1:3) to afford 13 (419.1 mg, 81%) as a yellow solid. A colorless
crystal was obtained by recystallization (EtOAc/n-hexane).
A suspension of 10a (276.2 mg, 0.8 mmol), Pd(PPh3)4 (92.4 mg,
0.08 mmol), and Ag3PO4 (334.9 mg, 0.8 mmol) in DMSO (8 mL) was
heated for 5 h at 100 ꢀC. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (1:4) to
afford 11a (74.4 mg, 43%) as a colorless oil.
Spectral data of 11a: 1H NMR (400 MHz, CDCl3)
d: 2.57–3.00 (m,
4H), 3.80 (s, 3H), 4.09–4.14 (m, 1H), 7.08 (td, J¼1.0, 7.1 Hz, 1H), 7.14
(td, J¼1.0, 7.1 Hz, 1H), 7.32 (d, J¼7.8 Hz, 1H), 7.45 (d, J¼7.8 Hz, 1H),
Spectral data of 13: mp 144–146 ꢀC (EtOAc/n-hexane); 1H NMR
8.11 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 23.6, 32.3, 44.2, 52.2,
(400 MHz, CDCl3)
d
: 1.31 (t, J¼7.2 Hz, 3H), 2.30 (t, J¼5.6 Hz, 2H), 3.19
111.7, 119.0, 119.7, 120.8, 121.4, 124.3, 139.2, 141.1, 173.1; IR (neat) n:
(t, J¼5.6 Hz, 2H), 3.92 (s, 2H), 4.21 (q, J¼7.2 Hz, 2H), 6.91 (t,
J¼8.0 Hz, 1H), 7.04 (d, J¼8.0 Hz, 1H), 7.31 (t, J¼8.0 Hz, 1H), 7.55 (t,
J¼8.0 Hz, 2H), 7.62 (t, J¼8.0 Hz, 1H), 7.84 (t, J¼8.0 Hz, 3H), 10.33 (br
3019, 1732, 1449, 1216 cmꢁ1; LRMS (EI) m/z 215 [M]þ; HRMS (FAB)
m/z calcd for C13H13NO2 [M]þ 215.0946, found 215.0927.
s, 1H); 13C NMR (100 MHz, CDCl3)
d: 14.5, 27.6, 42.2, 43.4, 59.7, 90.6,
4.9. Methyl 2,3,4,9-tetrahydro-1H-carbazole-1-carboxylate
(11b) and methyl 9H-carbazole-1-carboxylate (12)
98.4, 127.3, 127.6, 127.6 (2C), 128.9, 129.1 (2C), 132.8, 136.6, 139.5,
140.7, 153.0, 168.2; IR (film) n ;
: 3055, 1666, 1613, 1257, 750 cmꢁ1
LRMS (EI) m/z 512 [M]þ; HRMS (FAB) calcd for C20H22IN2O4S
[MþH]þ 513.0345, found 513.0319.
A suspension of 10b (80.6 mg, 0.23 mmol), Pd(PPh3)4 (26.0 mg,
0.023 mmol), and Ag3PO4 (94.2 mg, 0.23 mmol) in DMSO (2.3 mL)
was heated for 6 h at 100 ꢀC. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (from
1:10 to 1:4) to afford 11b (32.8 mg 64%) and 12 (5.6 mg, 11%) as
a yellow solid, respectively.
4.12. Ethyl 2-(benzenesulfonyl)-2,3,4,5-tetrahydro-1H-
pyrido[4,3-b]indole-4-carboxylate (14) and ethyl 5H-
pyrido[4,3-b]indole-4-carboxylate (15)
A suspension of 13 (285.8 mg, 0.56 mmol), Pd(PPh3)4 (64.7 mg,
0.056 mmol), and Ag3PO4 (234.4 mg, 0.56 mmol) in DMSO (6 mL)
was heated for 24 h at 100 ꢀC. After filtration of the reaction mix-
ture through a Celite pad, the filtrate was concentrated under re-
duced pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (from 1:5
to 1:2) to afford 14 (38.8 mg, 15%) as an orange amorphous solid
and 15 (16.1 mg, 12%) as a colorless solid.
Spectral data of 11b: 1H NMR (400 MHz, CDCl3)
d: 1.78–1.87 (m,
1H), 2.00–2.09 (m, 1H), 2.11–2.25 (m, 2H), 2.72 (td, J¼1.7, 5.9 Hz,
2H), 3.77 (s, 3H), 3.85 (t, J¼5.9 Hz, 1H), 7.08 (td, J¼1.2, 8.1 Hz, 1H),
7.15 (td, J¼1.2, 7.1 Hz, 1H), 7.31 (dd, J¼0.7, 8.1 Hz, 1H), 7.47 (d,
J¼7.8 Hz, 1H), 8.34 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 20.8,
21.9, 26.1, 40.0, 52.4, 110.9, 112.1, 118.4, 119.3, 121.9, 127.4, 129.4,
136.1, 173.1; IR (neat)
n
: 2952, 1734, 1618, 1438, 1241 cmꢁ1; LRMS
Spectral data of 14: 1H NMR (400 MHz, CDCl3)
d: 1.33 (t,
(EI) m/z 229 [M]þ; HRMS (FAB) m/z calcd for C14H15NO2 [M]þ
J¼7.2 Hz, 3H), 3.42–3.47 (m, 1H), 4.02–4.05 (m, 1H), 4.11–4.19 (m,
229.1103, found 229.1119.
2H), 4.27 (q, J¼7.2 Hz, 2H), 4.67 (d, J¼12.0 Hz, 1H), 7.10 (t, J¼8.0 Hz,

J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
1333
1H), 7.19 (t, J¼7.2 Hz, 1H), 7.34 (d, J¼8.0 Hz, 1H), 7.41 (d, J¼7.2 Hz,
1H NMR) and 2-iodoaniline (148.8 mg, determined by 1H NMR) as
a yellow oil. To remove 2-iodoaniline, the mixture (419.9 mg) was
dissolved in benzene (12 mL) and heated with succinic anhydride
(272.2 mg, 2.72 mmol) in presence of pyridine (0.23 mL,
2.72 mmol) for 3 h at 70 ꢀC. After filtration of the reaction mixture
through a Celite pad, the filtrate was washed with saturated
aqueous NaHCO3 and brine. The organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography on silica gel
eluted with EtOAc/n-hexane (1:20) to afford 16d (224.1 mg, 23%) as
a colorless oil.
1H), 7.52–7.62 (m, 3H), 7.89–7.91 (m, 2H), 8.63 (br s, 1H); 13C NMR
(100 MHz, CDCl3)
d: 14.2, 40.0, 43.0, 44.9, 61.9, 107.1, 111.2, 117.8,
119.8, 122.4, 124.8, 127.3, 127.4 (2C), 129.2 (2C), 132.9, 135.9, 137.0,
169.6; IR (film) n ;
: 3450, 3054, 2985, 1731, 1446, 1265, 1169 cmꢁ1
LRMS (EI) m/z 384 [M]þ; HRMS (FAB) calcd for C20H21IN2O4S
[MþH]þ 385.1222, found 385.1215.
Spectral data of 15: mp 186–188 ꢀC (EtOAc/n-hexane); 1H NMR
(400 MHz, CDCl3)
7.37 (t, J¼7.6 Hz, 1H), 7.52–7.58 (m, 2H), 8.16 (d, J¼7.6 Hz, 1H), 9.13
(s, 1H), 9.39 (s, 1H), 9.96 (br s, 1H); 13C NMR (100 MHz, CDCl3)
14.3, 61.3, 108.8, 111.5, 120.91, 120.93, 120.95, 121.5, 127.6, 139.5,
d
: 1.50 (t, J¼7.2 Hz, 3H), 4.53 (q, J¼7.2 Hz, 2H),
d:
Spectral data of 16d: 1H NMR and 13C NMR spectrum of 16d
showed that 16d exists as a mixture of imine–enamine tautomeric
isomers in a ratio of 24:76 at room temperature in CDCl3; 1H NMR
143.8, 145.5, 146.6, 166.7; IR (film) n: 3749, 3434, 3051, 1699, 1604,
1265 cmꢁ1; LRMS (EI) m/z 240 [M]þ; HRMS (FAB) calcd for
C14H13N2O2 [MþH]þ 241.0977, found 241.0965.
(400 MHz, CDCl3)
d
: 1.22 (t, J¼7.2 Hz, 0.76ꢂ3H), 1.24 (t, J¼7.2 Hz,
0.24ꢂ3H), 1.77 (s, 0.24ꢂ3H), 1.88 (s, 0.76ꢂ3H), 3.30 (q, J¼7.6 Hz,
0.24ꢂ1H), 3.38 (q, J¼7.6 Hz, 0.24ꢂ1H), 3.74 (s, 0.76ꢂ2H), 3.85
(t, J¼7.6 Hz, 0.24ꢂ1H), 4.14–4.22 (m, 0.76ꢂ2Hþ0.24ꢂ2H), 6.46
(d, J¼8.0 Hz, 0.24ꢂ1H), 6.75 (t, J¼8.0 Hz, 0.24ꢂ1H), 6.87 (t,
J¼8.0 Hz, 0.76ꢂ1H), 7.05 (d, J¼8.0 Hz, 0.76ꢂ1H), 7.14–7.30 (m,
0.76ꢂ6Hþ0.24ꢂ6H), 7.78 (d, J¼8.0 Hz, 0.24ꢂ1H), 7.85 (d, J¼8.0 Hz,
4.13. (Z)-Ethyl 3-(2-iodophenylamino)-2-butenoate (16a)
To a solution of ethyl acetoacetate (90 mL, 0.68 mmol) and
2-iodoaniline (300 mg, 1.37 mmol) in benzene (7 mL) in a flask
fitted with a Dean–Stark apparatus was added p-TsOH (58 mg,
0.34 mmol) at room temperature. The mixture was heated for 3 h
under reflux. After filtration of the reaction mixture through a Cel-
ite pad, the filtrate was concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel eluted with EtOAc/n-hexane (1:30) to afford 16a
(225.2 mg, quant) as a colorless oil.
0.76ꢂ1H), 11.0 (br s, 0.76ꢂ1H); 13C NMR (100 MHz, CDCl3)
d: 14.2,
14.4,17.1,19.7, 32.9, 35.3, 57.9, 59.4, 61.1, 88.4, 96.5, 97.4,118.9,124.9,
125.5, 126.46, 126.49, 126.6, 127.8, 128.1, 128.4, 128.6, 128.8, 129.0,
138.6, 139.0, 139.3, 141.9, 142.0, 151.8, 156.4, 169.5, 170.7, 170.8; IR
(neat) n: 2979, 1733, 1649, 1598, 1479, 1365, 1253, 1205, 1075,
1015 cmꢁ1; LRMS (EI) m/z 421 [M]þ; HRMS (FAB) calcd for
C19H21INO2 [MþH]þ 422.0617, found 422.0620.
Spectral data 16a: 1H NMR (400 MHz, CDCl3)
d
: 1.30 (t, J¼7.2 Hz,
3H), 1.86 (s, 3H), 4.18 (q, J¼7.2 Hz, 2H), 4.77 (s, 1H), 6.92 (dt, J¼1.6,
8.0 Hz, 1H), 7.16 (dd, J¼1.2, 7.2 Hz, 1H), 7.32 (dt, J¼1.2, 7.2 Hz, 1H),
7.87 (dd, J¼1.6, 8.0 Hz, 1H), 10.18 (br s, 1H); 13C NMR (100 MHz,
4.16. Ethyl (1H-indol-2-yl)acetate (17a) and ethyl 2-methyl-
1H-indole-3-carboxylate (18a)
CDCl3) d: 14.5, 20.1, 58.9, 87.0, 97.7, 126.8, 127.2, 128.7, 139.4, 141.2,
158.1, 170.2; LRMS (EI) m/z 331 [M]þ. Reg# 128942-81-4.
A suspension of 16a (229.3 mg, 0.69 mmol), Pd(PPh3)4 (79.7 mg,
0.069 mmol), and Ag3PO4 (288.8 mg, 0.69 mmol) in DMSO (6.8 mL)
was heated for 3.5 h at 100 ꢀC. After filtration of the reaction mix-
ture through a Celite pad, the filtrate was concentrated under re-
duced pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (from
1:10 to 1:3) to afford 17a (23.1 mg, 17%) and 18a (126.6 mg, 79%) as
a colorless solid, respectively.
4.14. Ethyl 3-(2-iodophenylamino)pent-2-enoate (16b)
To a solution of ethyl 3-oxopentanoate (0.3 mL, 2.1 mmol) and
2-iodoaniline (559.1 mg, 2.52 mmol) in benzene (10 mL) in a flask
fitted with a Dean–Stark apparatus was added p-TsOH (180.6 mg,
1.05 mmol) at room temperature. The mixture was heated for 50 h
under reflux. After filtration of the reaction mixture through a Cel-
ite pad, the filtrate was concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography on
silica gel eluted with EtOAc/n-hexane (1:10) to afford 16b
(275.8 mg, 38%) as a colorless oil.
Spectral data of 17a: 1H NMR (400 MHz, CDCl3)
d: 1.30 (t,
J¼7.2 Hz, 3H), 3.83 (s, 2H), 4.21 (q, J¼7.2 Hz, 2H), 6.35 (s,1H), 7.09 (dt,
J¼1.2, 7.2 Hz, 1H), 7.15 (dt, J¼1.2, 7.2 Hz, 1H), 7.35 (dd, J¼1.2, 7.2 Hz,
1H), 7.54 (dd, J¼1.2, 7.2 Hz, 1H), 8.68 (br s, 1H). Reg# 33588-64-6.
Spectral data of 18a: 1H NMR (400 MHz, CDCl3)
d: 1.45 (t,
Spectral data of 16b: 1H NMR (400 MHz, CDCl3)
d
: 1.03 (t,
J¼7.2 Hz, 3H), 2.75 (s, 3H), 4.40 (q, J¼7.2 Hz, 2H), 7.19 (dt, J¼1.6,
7.1 Hz, 1H), 7.22 (dt, J¼1.6, 7.1 Hz, 1H), 7.31 (dd, J¼1.6, 7.1 Hz, 1H),
8.10 (dd, J¼1.6, 7.1 Hz, 1H), 8.27 (br s, 1H). Reg# 53855-47-3.
J¼7.6 Hz, 3H), 1.30 (t, J¼7.2 Hz, 3H), 2.17 (q,J¼7.6 Hz, 2H), 4.18 (q,
J¼7.2 Hz, 2H), 4.84 (s, 1H), 6.92 (t, J¼8.0 Hz, 1H), 7.15 (d, J¼8.0 Hz,
1H), 7.31 (t, J¼8.0 Hz, 1H), 7.87 (d, J¼8.0 Hz, 1H), 10.10 (br s, 1H); 13C
NMR (100 MHz, CDCl3)
d
: 12.1, 14.5, 25.5, 58.9, 85.2, 98.4, 127.2,
4.17. Ethyl (3-methyl-1H-indol-2-yl)acetate (17b) and ethyl
2-ethyl-1H-indole-3-carboxylate (18b)
127.4, 128.4, 139.4, 141.3, 163.8, 170.5; IR (neat) n: 3428, 2979, 2936,
1653, 1614, 1580, 1457, 1262 cmꢁ1; LRMS (EI) m/z 345 [M]þ; HRMS
(FAB) calcd for C13H17INO2 [MþH]þ 346.0304, found 346.0304.
A
suspension of 16b (212.6 mg, 0.616 mmol), Pd(PPh3)4
(71.1 mg, 0.062 mmol), and Ag3PO4 (257.8 mg, 0.62 mmol) in DMSO
(6 mL) was heated for 4.5 h at 100 ꢀC. After filtration of the reaction
mixture through a Celite pad, the filtrate was concentrated under
reduced pressure. The resulting residue was purified by flash col-
umn chromatography on silica gel eluted with CHCl3 to afford 17b
(8.0 mg, 6%) as a brown solid and 18b (114.6 mg, 86%) as a colorless
solid.
4.15. Ethyl 2-benzyl-3-(2-iodophenylamino)-
2-butenoate (16d)
To
a solution of ethyl 2-benzyl-3-oxobutyrate (0.5 mL,
2.35 mmol) and 2-iodoaniline (617.7 mg, 2.82 mmol) in benzene
(15 mL) in a flask fitted with a Dean–Stark apparatus was added p-
TsOH (202.1 mg, 1.18 mmol) at room temperature. The mixture was
heated for 3 h under reflux. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (1:30) to
afford an inseparable mixture of 16d (271.1 mg, 27% determined by
Spectral data of 17b: 1H NMR (400 MHz, CDCl3)
d: 1.29
(t, J¼7.6 Hz, 3H), 2.56 (s, 3H), 3.76 (s, 2H), 4.20 (q, J¼7.2 Hz, 2H), 7.09
(t, J¼8.0 Hz, 1H), 7.16 (t, J¼8.0 Hz, 1H), 7.31 (d, J¼8.0 Hz, 1H), 7.50 (d,
J¼8.0 Hz, 1H), 8.49 (br s, 1H). Reg# 14190-78-4.
Spectral data of 18b: 1H NMR (400 MHz, CDCl3)
d: 1.31 (t,
J¼7.6 Hz, 3H), 1.44 (t, J¼7.2 Hz, 3H), 3.17 (q, J¼7.6 Hz, 2H), 4.40 (q,

1334
J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
J¼7.2 Hz, 2H), 7.18 (dt, J¼1.6, 7.2 Hz, 1H), 7.22 (dt, J¼1.6, 7.2 Hz, 1H),
7.30 (dd, J¼1.6, 7.0 Hz, 1H), 8.14 (dd, J¼1.6, 7.2 Hz, 1H), 8.79 (br s,
1H). Reg# 94445-86-0.
4H), 4.12(q, J¼7.1 Hz,4H), 7.49–7.79(m, 3H), 7.80(d, J¼7.3 Hz,2H);13
C
NMR (100 MHz, CDCl3) d: 14.2 (2C), 23.9 (2C), 31.0 (2C), 47.8 (2C), 60.5
(2C), 127.1 (2C), 129.1 (2C), 132.5, 139.5, 172.8 (2C); IR (neat) n: 2982,
1732, 1447, 1374, 1338, 1163 cmꢁ1; LRMS (FAB) m/z 386 [MþH]þ;
HRMS (FAB) m/z calcd for C18H28NO6S [MþH]þ 386.1637, found
386.1624.
4.18. Ethyl 3-(1H-indol-2-yl)-pentanate (17c)
To
a
solution of ethyl 2-propyl-3-oxobutyrate (381.7 mg,
To a solution of t-BuOK (1.0 M solution in THF, 16 mL, 16 mmol)
in toluene (400 mL) was added ethyl 4-[phenylsulfonyl-(3-ethoxy-
carbonylpropyl)amino]butyrate (2.0 g, 5.2 mmol) in toluene
(120 mL) dropwisely over 19 h at 120 ꢀC. After the reaction was
quenched by addition of 1 N HCl and water at 0 ꢀC, the mixture was
extracted with EtOAc. The combined organic layers were washed
with brine and dried over Na2SO4. After evaporation under reduced
pressure, the residue was purified by flash column chromatography
on silica gel eluted with EtOAc/n-hexane (from 1:2 to 1:1) to afford
33 (0.87 g, 49%) as brown oil.
2.22 mmol) and 2-iodoaniline (972.5 mg, 4.44 mmol) in benzene
(22 mL) in a flask fitted with a Dean–Stark apparatus was added p-
TsOH (190.9 mg, 1.11 mmol) at room temperature. The mixture was
heated for 19 h under reflux. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with n-hexane to afford an
inseparable mixture of 16c (705.8 mg, 1.89 mmol, 85%, determined
by 1H NMR) and 2-iodoaniline (128.3 mg, determined by 1H NMR).
This impure 16c was employed in the next step without further
purification because 16c was unstable.
Spectral data of 33: 1H NMR and 13C NMR spectrum of 33
showed that 33 existed as a mixture of keto–enol tautomeric iso-
mers in a ratio of 50:50 at room temperature in CDCl3; 1H NMR
A suspension of 16c (273.9 mg, 0.73 mmol), Pd(PPh3)4 (84.4 mg,
0.073 mmol), and Ag3PO4 (305.6 mg, 0.73 mmol) in DMSO (7.3 mL)
was heated for 3 h at 100 ꢀC. After filtration of the reaction mixture
through a Celite pad, the filtrate was concentrated under reduced
pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (1:10) to
afford 17c (120 mg, 67%) as a colorless solid.
(400 MHz, CDCl3)
d
: 1.24 (t, J¼7.1 Hz, 1.5H), 1.26 (t, J¼7.1 Hz, 1.5H),
1.94–2.04 (m, 1.5H), 2.20 (ddd, J¼3.7, 7.1, 14.8 Hz, 1H), 2.24–2.33 (m,
1H), 2.44–2.56 (m, 2.5H), 2.63 (ddd, J¼3.5, 12.4, 13.7 Hz, 0.5H), 3.00
(ddd, J¼3.5, 11.7, 13.7 Hz, 0.5H), 3.17–3.27 (m, 3H), 3.57 (dd, J¼3.5,
11.7 Hz, 0.5H), 4.14 (q, J¼7.1 Hz, 1H), 4.16 (q, J¼7.1 Hz, 1H), 7.48–7.62
(m, 3H), 7.76–7.79 (m, 2H),12.6 (s, 0.5H); 13C NMR (100 MHz, CDCl3)
Spectral data of 17c: mp 46–47 ꢀC (EtOAc/n-hexane); 1H NMR
d: 13.9, 14.2, 26.2, 27.0, 28.9, 30.2, 30.4, 39.4, 46.8, 47.9, 48.5, 50.8,
(400 MHz, CDCl3)
d
: 0.92 (t, J¼7.2 Hz, 3H), 1.26 (t, J¼7.2 Hz, 3H),
55.7, 60.5, 61.3, 97.9, 126.8, 127.4, 129.0, 129.1, 132.3, 132.8, 137.4,
1.29–1.40 (m, 2H), 1.81–1.91 (m, 1H), 1.98–2.07 (m, 1H), 3.80 (t,
J¼7.6 Hz, 1H), 4.11–4.24 (m, 2H), 6.34 (s, 1H), 7.07 (t, J¼7.2 Hz, 1H),
7.14 (t, J¼7.2 Hz, 1H), 7.32 (d, J¼7.2 Hz, 1H), 7.54 (d, J¼7.2 Hz, 1H),
139.3, 169.4, 172.0, 176.2, 206.9; IR (neat) n: 2939, 1739, 1706, 1447,
1333, 1164 cmꢁ1; LRMS (EI) m/z 339 [M]þ; HRMS (FAB) m/z calcd for
C16H22NO5S [MþH]þ 340.1219, found 340.1209.
8.60 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d: 13.6, 14.1, 20.5, 35.6,
45.1, 61.2, 101.1, 110.8, 119.7, 120.1, 121.6, 128.0, 135.5, 136.1, 173.8; IR
4.21. Ethyl 1-benzenesulfonyl-5-(2-iodophenylamino)-
1,2,3,6,7,8-hexahydroazocine-4-carboxylate (34)
(neat) n
: 3373, 1715, 1178, 746 cmꢁ1; LRMS (EI) m/z 245 [M]þ; HRMS
(EI) calcd for C15H19NO2 [M]þ 245.1416, found 245.1406.
To a solution of 33 (120 mg, 0.35 mmol) in benzene (5 mL) in
a flask fitted with Dean–Stark apparatus were added p-TsOH$H2O
(67 mg, 0.35 mmol) and 2-iodoaniline (150 mg, 0.71 mmol). The
mixture was heated for 4 days under reflux. After the reaction
mixture was filtrated through a Celite pad, the filtrate was con-
centrated under reduced pressure to give a residue, which was
purified by flash column chromatography on silica gel eluted with
EtOAc/n-hexane (1:15) to afford 34 (110 mg, 58%) as a colorless
4.19. Ethyl 2-(1H-indol-2-yl)-3-phenylpropionate (17d)
A suspension of 16d (202.0 mg, 0.48 mmol), Pd(PPh3)4 (55.5 mg,
0.048 mmol), and Ag3PO4 (200.9 mg, 0.48 mmol) in DMSO (5 mL)
was heated for 2.5 h at 100 ꢀC. After filtration of the reaction mix-
ture through a Celite pad, the filtrate was concentrated under re-
duced pressure. The resulting residue was purified by flash column
chromatography on silica gel eluted with EtOAc/n-hexane (1:10) to
afford 17d (114.9 mg, 82%) as a colorless solid.
amorphous solid.
1
Spectral data of 34: H NMR (400 MHz, CDCl3, 55 ꢀC)
d
: 1.25 (t,
Spectral data of 17d: 1H NMR (400 MHz, CDCl3)
d: 1.13 (t,
J¼7.1 Hz, 3H), 1.64 (br s, 2H), 2.51 (t, J¼6.4 Hz, 2H), 2.71 (t, J¼5.1 Hz,
2H), 3.21 (t, J¼5.6 Hz, 2H), 3.25 (br s, 2H), 4.14 (q, J¼7.1 Hz, 2H), 6.92
(td, J¼1.2, 7.6 Hz, 1H), 7.15 (dd, J¼1.2, 7.8 Hz, 1H), 7.32 (td, J¼1.2,
J¼7.2 Hz, 3H), 3.17 (dd, J¼6.8, 13.6 Hz, 1H), 3.36 (dd, J¼8.8, 13.6 Hz,
1H), 4.02–4.15 (m, 3H), 6.32 (s, 1H), 7.06–7.37 (m, 8H), 7.53 (d,
J¼7.6 Hz, 1H), 8.59 (br s, 1H). Reg# 332365-87-4.
7.6 Hz, 1H), 7.46–7.55 (m, 3H), 7.77–7.80 (m, 2H), 7.86 (dd, J¼1.2,
13
7.8 Hz, 1H), 10.6 (s, 1H); C NMR (100 MHz, CDCl3, 55 ꢀC)
d
: 14.5,
4.20. Ethyl 1-phenylsulfonyl-5-oxoazocane-4-carboxylate (33)
25.6, 28.3, 29.3, 47.5, 51.5, 59.5, 95.2, 99.5, 127.0 (2C), 127.7, 128.4,
128.9, 129.0 (2C), 132.2, 139.5, 140.0, 142.0, 159.5, 169.8; IR (film) n:
To a solution of benzenesulfonamide (5.0 g, 31.8 mmol) in ac-
etone (100 mL) were added K2CO3 (24 g, 0.17 mmol) and ethyl 4-
bromobutyrate (12 mL, 83.9 mmol) at room temperature. After the
mixture was stirred for 2 days at 60 ꢀC, the reaction was quenched
by addition of water at 0 ꢀC. The mixture was concentrated under
reduced pressure and was extracted with EtOAc. The combined
organic layers were washed with brine and dried over Na2SO4.
After evaporation under reduced pressure, the residue was puri-
fied by flash column chromatography on silica gel eluted with
EtOAc/n-hexane (1:4) to afford ethyl 4-[phenylsulfonyl-(3-ethoxy-
carbonylpropyl)amino]butyrate (13.8 mg, quant) as a pale yellow
oil.
2970, 1653, 1596, 1333, 1258, 1230 cmꢁ1; LRMS (EI) m/z 541
[MþH]þ; HRMS (FAB) m/z calcd for C22H26IN2O4S [MþH]þ
541.0658, found 541.0644.
4.22. Ethyl 3-phenylsulfonyl-2,3,4,5,6,7-hexahydro-1H-
azocino[5,4-b]indole-6-carboxylate (35)
A suspension of compound 34 (150 mg, 0.28 mmol), Pd(PPh3)4
(32 mg, 0.028 mmol), and Ag3PO4 (120 mg, 0.28 mmol) in DMSO
(1.0 mL) was heated for 18 h at 100 ꢀC. After filtration of the re-
action mixture through a Celite pad, the filtrate was concentrated
under reduced pressure. The resulting residue was purified by flash
column chromatography on silica gel eluted with EtOAc/n-hexane
(1:5) to afford 35 (78.5 mg, 69%) as a colorless amorphous solid.
Spectral data of ethyl 4-[phenylsulfonyl-(3-ethoxycarbonyl-
propyl)amino]butyrate: 1H NMR (400 MHz, CDCl3)
6H),1.87 (quintet, J¼7.3 Hz, 4H), 2.34(t, J¼7.3 Hz,4H), 3.18 (t, J¼7.3 Hz,
d
: 1.26 (t, J¼7.1 Hz,

J. Maruyama et al. / Tetrahedron 65 (2009) 1327–1335
1335
Spectral data of 35: 1H NMR (600 MHz, CDCl3)
d: 1.35 (t,
C. Chem.dEur. J. 2005, 11, 2276; (e) Lachnace, N.; April, M.; Joly, M.-A. Synthesis
´
2005, 2571; (f) Jia, Y.; Zhu, J. Synlett 2005, 2469; (g) Nazare, M.; Schneider, C.;
J¼7.1 Hz, 3H), 1.87 (td, J¼2.8, 12.9 Hz, 1H), 2.18 (ddd, J¼3.9, 12.6,
14.8 Hz,1H), 2.56 (t, J¼12.1 Hz,1H), 2.66 (tt, J¼5.0,12.9 Hz,1H), 2.94
(ddd, J¼3.0, 12.1, 15.1 Hz, 1H), 3.13 (ddd, J¼1.4, 3.6, 15.1 Hz, 1H), 3.48
(dd, J¼4.1, 15.1 Hz, 1H), 4.12 (dt, J¼3.9, 13.2 Hz, 1H), 4.24–4.32 (m,
2H), 4.37 (dd, J¼5.2, 12.7 Hz, 1H), 7.06 (td, J¼1.1, 7.1 Hz, 1H), 7.13 (td,
J¼1.1, 8.0 Hz, 1H), 7.33 (d, J¼8.0, Hz, 1H), 7.42 (d, J¼8.0 Hz, 1H), 7.47
(td, J¼1.4, 7.7 Hz, 2H), 7.54 (tt, J¼1.4, 7.2 Hz, 1H), 7.78–7.80 (m, 2H),
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526;
(h) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824; (i)
Kim, G.; Kim, J. H.; Kim, W.; Kim, Y. A. Tetrahedron Lett. 2003, 44, 8207; (j)
Yamazaki, K.; Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011; (k) Caddick,
´
´
S.; Kofie, W. Tetrahedron Lett. 2002, 43, 9347; (l) Garcıa, A.; Rodorıguez, D.;
Castedo, L.; Saa´, C.; Romı´nguez, D. Tetrahedron Lett. 2001, 42, 1903; (m) Michael,
J. P.; de Koning, C. B.; Petersen, R. L.; Stanbury, T. V. Tetrahedron Lett. 2001, 42,
7513; (n) Edmondson, S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2,
1109; (o) Latham, E. J.; Stanforth, S. P. J. Chem. Soc., Perkin Trans. 11997, 2059; (p)
Chen, C.-y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org.
Chem. 1997, 62, 2676; (q) Blache, Y.; Sinibaldi-Troin, M.-E.; Voldoire, A.; Cha-
vignon, O.; Gramain, J.-C.; Teulade, J.-C.; Chapat, J.-P. J. Org. Chem. 1997, 62,
8553; (r) Chen, L. C.; Yang, S. C.; Wang, H. M. Synthesis 1995, 385; (s) Koerber-
9.11 (s, 1H); 13C 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, 126.9 (2C), 127.0, 129.2 (2C),
130.9, 132.7, 135.5, 139.1, 174.8; IR (KBr)
n: 3424, 1710, 1338,
1159 cmꢁ1; LRMS (EI) m/z 413 [MþH]þ; HRMS (FAB) calcd for
´
Ple, K.; Massiot, G. Synlett 1994, 759; (t) Michael, J. P.; Chang, S.-F.; Wilson, C.
C22H24N2O4S [M]þ 412.1457, found 412.1462.
Tetrahedron Lett. 1993, 34, 8365; (u) Sakamoto, T.; Nagano, T.; Kondo, Y.; Ya-
manaka, H. Synthesis 1990, 215; (v) Kasahara, A.; Izumi, T.; Murakami, S.; Yanai,
H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927; (w) Iida, H.; Yuasa, Y.;
Kibayashi, C. J. Org. Chem. 1980, 45, 2938.
Acknowledgements
4. Watanabe, T.; Arai, S.; Nishida, A. Synlett 2004, 907.
5. Madin, A.; O’Donnell, C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am.
Chem. Soc. 2005, 127, 18054.
6. This crystal structure was deposited at The Cambridge Crystallographic Data
Centre, CCDC231397.
7. (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.
8. Molina, P.; Fresneda, P. M.; Almendros, P. Tetrahedron 1993, 49, 1223.
9. Suzuki, H.; Thiruvikraman, S. V.; Osuka, A. Synthesis 1984, 616.
10. Vice, S. F.; Friesen, R. W.; Dmitrienko, G. I. Tetrahedron Lett. 1985, 26, 165.
11. The Heck reaction of tetra-substituted olefins is generally difficult due to steric
effects. There are few successful examples. See: (a) Bra¨se, S.; Wertal (nee
Nu¨ske), H.; Frank, D.; Vidovic´, D.; de Meijere, A. Eur. J. Org. Chem. 2005, 4167; (b)
Meijere, A. D.; Bra¨se, S. J. Organomet. Chem. 1999, 576, 88; (c) Dankwardtj, W.;
Flippin, L. A. J. Org. Chem. 1995, 60, 2312.
This work was supported by a Grant-in-Aid for Scientific Re-
search on Priority Areas ‘Advanced Molecular Transformations of
Carbon Resources’ from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
References and notes
1. (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester, UK, 2003,
Chapter 3; (b) Link, J. T. In Organic Reactions; Overman, L. E., Ed.; Wiley: New
York, NY, 2002; Vol. 60,, Chapter 2 (c) Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, NY, 2002; Vols. I and II;
(d) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry; Elsevier: Oxford,
2000.
2. The pioneering work of the synthesis of indoles using Heck reaction. Mori, M.;
Ban, Y. Tetrahedron Lett. 1977, 18, 1037.
12. Grigg, R.; Savic, V. Chem. Commun. 2000, 873.
´
¨s,
13. Awang, K.; Sevenet, T.; Paı M.; Hadi, A. H. A. J. Nat. Prod. 1993, 56, 1134.
14. Lapidilectine B (32) has been synthesized. See: (a) Pearson, W. H.; Mi, Y.; Lee,
I. Y.; Stoy, P. J. Am. Chem. Soc. 2001, 123, 6724; (b) Pearson, W. H.; Lee, I. Y.; Mi, Y.;
Stoy, P. J. Org. Chem. 2004, 69, 9109.
3. Synthesis of indoles by intramolecular Heck reaction involving formal 5-endo
cyclization of N-alkenyl-o-haloanilines. See: (a) Fuwa, H.; Sasaki, M. Org. Lett.
2007, 9, 3347; (b) Jia, J.; Zhu, J. J. Org. Chem. 2006, 71, 7826; (c) Baran, P. S.;
Hafensteiner, B. D.; Ambhaikar, N. B.; Guerrero, C. A.; Gallagher, J. D. J. Am.
Chem. Soc. 2006, 128, 8678; (d) Barluenga, J.; Fernandez, M. A.; Aznar, F.; Valdes,
15. Lennon, M.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1979, 2009.