Concise synthesis of pyrrolophenanthridine alkaloids using a Pd-mediated biaryl coupling reaction with regioselective C-H activation via the intramolecular coordination of the amine to Pd

Article abstract of DOI:10.1016/j.tet.2003.11.093

The concise synthesis of Amaryllidaceae alkaloids, such as anhydrolycorinone, anhydrolycorin-7-one, assoanine, and oxoassoanine, which have a pyrrolophenanthridine skeleton, was achieved in moderate yield using the Pd-mediated biaryl coupling reaction of

Full text of DOI:10.1016/j.tet.2003.11.093

Tetrahedron 60 (2004) 1611–1616
Concise synthesis of pyrrolophenanthridine alkaloids using a
Pd-mediated biaryl coupling reaction with regioselective C–H
activation via the intramolecular coordination of the amine to Pd
*
Takashi Harayama, Akihiro Hori, Hitoshi Abe and Yasuo Takeuchi
Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka 1-1-1, Okayama 700-8530, Japan
Received 15 October 2003; accepted 29 November 2003
Abstract—The concise synthesis of Amaryllidaceae alkaloids, such as anhydrolycorinone, anhydrolycorin-7-one, assoanine, and
oxoassoanine, which have a pyrrolophenanthridine skeleton, was achieved in moderate yield using the Pd-mediated biaryl coupling reaction
of 1-(2-halobenzyl)-2,3-dihydroindole, which applied the regioselective C–H activation method with intramolecular coordination of the
benzylamino group to Pd.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of 1-(2-bromo-4,5-dimethoxybenzoyl)indole-2,3-
dicarboxylate (10) with Pd(PPh3)4 gave no coupling
product.3 Moreover, it has been reported that the biaryl
coupling reaction of 1-(2-bromobenzyl)-2,3-diphenylindole
(11) gave no coupling product,4a whereas the reaction of
dimethyl 1-(2-bromobenzyl)indole-2,3-dicarboxylate (12)
with Pd(PPh3)4 gave a coupling product (13).3 These results
seem somewhat contradictory (Scheme 1).
The potentially useful pharmacological activities1 and
unique polycyclic structures of pyrrolophenanthridine
(Amaryllidaceae) alkaloids (e.g., 1–8) have led to recent
interest in developing new synthetic methods for these
alkaloids.2,3 Some of these attempts have involved an
intramolecular aryl–aryl coupling reaction with a Pd
reagent as the key step, including the dehydrogenation of
two arenes with Pd(OAc)2 in acetic acid,4 a biaryl coupling
reaction between a monobromoarene and an arene with a Pd
reagent,3,4a,5 and the intramolecular coupling of a bis-
haloarene with a Pd reagent.6 Recently, we reported a
method of synthesizing several benzo[c]phenanthridine
alkaloids using Pd-assisted aryl–aryl coupling reactions of
2-halo-N-naphthylbenzamides via the elimination of a
hydrogen halide.7 To examine the generality of this method,
we tried to apply it to the synthesis of pyrrolophenanthridine
(Amaryllidaceae) alkaloids, especially anhydrolycorin-7-
one (3)1f and oxoassoanine (4),8a which serve as advanced
intermediates in the synthesis of other alkaloids.4b,8b
Recently, we developed a method of synthesizing a new
skeletal compound, naphthobenzazepine, by regioselective
C–H activation using the intramolecular coordination of a
benzylamine to Pd.11 We planned to apply this strategy to
the synthesis of pyrrolophenanthridine (Amaryllidaceae)
alkaloids, such as anhydrolycorine (1)1f,12a and assoanine
(2).12b Interconversion of 1 and 3 or 2 and 4 has already
been accomplished by the air oxidation of 1 or 2, and the
LiAlH4 reduction of 3 or 4.12 We envisioned that the
intramolecular biaryl coupling reaction of 1-(2-halo-
benzyl)dihydroindole (A) using a Pd reagent would afford
dihydropyrrolophenanthridine (C) directly, via an oxidative
addition to Pd(0) and coordination of the amine to Pd(II),
followed by the regioselective electrophilic substitution of
Pd(II) at the C7 position of the dihydroindole moiety
[forming a four-membered palladacycle (B)]13,14 and the
reductive elimination of Pd(0), as shown in Scheme 2. The
details of the results are the subject of this paper.
In this connection, Cai et al. reported that the reaction of
1-(2-bromobenzoyl)-2,3-dihydroindole
(9a)
using
Pd(OAc)2 and K2CO3 in DMA in the absence of a
phosphine ligand afforded 3 in 55% yield.5a,9 In our
hands, the reaction of 1-(2-iodobenzoyl)-2,3-dihydroindole
(9b), which is expected to be more reactive than 9a, under
their reaction conditions did not produce 3, even in the
presence of a phosphine ligand. Miki et al. reported that the
2. Results and discussion
Keywords: Coodination; Palladium; Regioselectivity; Anhydrolycorine;
Assoanine.
First, the Pd-catalyzed coupling reaction of 1-(2-bromo-
benzyl)-2,3-dihydroindole (14)15 was examined as a
preliminary study of the synthesis of these alkaloids
*
Corresponding author. Tel./fax: þ81-86-2517963;
e-mail address: harayama@pharm.okayama-u.ac.jp
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.093

1612
T. Harayama et al. / Tetrahedron 60 (2004) 1611–1616
alkaloids, the starting materials (16a, 16b, and 17a) were
prepared from dihydroindole and 2-bromobenzyl bromides
(18a18a and 19a18b) or 2-iodobenzyl bromides (18b)19a in
the presence of i-Pr2NEt in dry CH3CN in 86–91% yield.
The starting material (17b) was prepared from dihydro-
indole and 2-iodobenzyl bromide (19b)19b in ether in 77%
yield. The intramolecular coupling reactions of 1-(2-
bromobenzyl)dihydroindoles (16a and 17a) using Pd were
examined; the results are summarized in Tables 1 and 2. The
reaction of 16a with Pd(OAc)2, P(o-tol)3, and K2CO3 in
DMF under air gave anhydrolycorin-7-one (3) in 45% yield
(run 1 in Table 1),12a and the reaction in CH3CN did not
proceed (run 2 in Table 1). By contrast, the reaction of 16a
under an oxygen atmosphere, which was intended to
accelerate the oxidation, afforded 3 in only 21% yield (run
¨
3 in Table 1). In this connection, Knolker et al. recently
reported that the reaction of iodo-tetrahydroindole (24) with
Pd(PPh3)4 in DMF under air gave 3 in 29% yield via a
coupling reaction and oxidation.2h The reaction of 16a in
degassed DMF under an Ar atmosphere gave anhydro-
lycorine (1)12a and 320a in 37 and 15% yields, respectively,
along with 20 and 21a (run 4 in Table 1). The reaction of
16a using Ag2CO3 as a base produced only the oxidation
product (21b) in 58% yield (run 7 in Table 1). The reaction
using i-Pr2NEt and DBU as a base did not proceed (runs 8
and 9 in Table 1). The reaction of 17a with Pd(OAc)2, P(o-
tol)3, and K2CO3 in DMF under air gave oxoassoanine
(4)12b in 34% yield (run 1 in Table 2). The reaction of 17a in
degassed DMF under an Ar atmosphere gave assoanine
(2)20b and 4 in 28 and 13% yields, respectively, along with
22 and 23 (run 4 in Table 2). The reaction of 16a and 17a
using PCy3 as a ligand gave the coupling products in better
yield (run 5 in Table 1 and run 5 in Table 2).
To improve the yield, the biaryl coupling reaction of 1-(2-
iodobenzyl)-2,3-dihydroindoles (16b and 17b), which are
more reactive than bromo compounds, was examined. The
results are summarized in Tables 3 and 4. However, the
yields were similar or lower than with bromo compounds.
Unlike bromo compounds (16a and 17a), with iodo
compounds (16b and 17b), Jeffery’s conditions21 gave the
coupling products in higher yields (run 6 in Table 3, and run
4 in Table 4).
Scheme 1. Pyrrolophenanthridine alkaloids and related compounds.
In conclusion, the concise synthesis of pyrrolophenan-
thridine (Amaryllidaceae) alkaloids was accomplished by
applying a strategy utilizing regioselective C–H activation
via intramolecular coordination of the benzylamino group to
Pd.11
Scheme 2. Strategy and proposed mechanism for synthesis of dihydro-
pyrrolophenanthridine (C) from 1-(2-halobenzyl)dihydroindole (A).
(1–4). The reaction of 14 with Pd(OAc)2, P(o-tol)3, and
K2CO3 in DMF under air gave pyrrolophenanthridone (15)
in 35% yield, along with 1-benzyl-2,3-dihydroindole (13%
yield)16 and 1-benzylindole (17% yield).16 These results
suggest that 15 was formed via a biaryl coupling reaction
and concomitant oxidation, because 1-(2-iodobenzoyl)-2,3-
dihydroindole gave 15 in only 8% yield17 and alkaloids (1
and 3) readily undergo oxidation in air.12 Therefore, this
strongly implies that the synthetic strategy shown in
Scheme 2 is applicable to the synthesis of pyrrolophenan-
thridine (Amaryllidaceae) alkaloids.
3. Experimental
3.1. General
Melting points were measured on a micro-melting point hot-
stage apparatus (Yanagimoto) and are uncorrected. IR
spectra were recorded on a JASCO A-102 or JASCO FT/IR
1
350 spectrophotometer, and H NMR spectra in deuterio-
chloroform were recorded on a JNM-MY 60 FT (60 MHz)
or a Varian VXR-200 (200 MHz) spectrometer. NMR
spectra data are reported in parts per million downfield
from tetramethylsilane as an internal standard (d 0.0) and
Next, to study the synthesis of pyrrolophenanthridine

T. Harayama et al. / Tetrahedron 60 (2004) 1611–1616
1613
Table 1. Results of biaryl coupling reaction of 1-[(6-bromo-1,3-benzodioxol-5-yl)methyl)]-2,3-dihydroindole (16a)a
Run
Pd (OAc)2 (mol%)
Ligand (L/Pd)b
Base
Temp. (8C)
Time (h)
Yield (%)
1
3
20
21a
21b
1
B
B
C
A
A
A
B
A
A
B
20
100
20
10
10
10
20
10
10
20
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
Cy3P (2)
t-Bu3P (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
—
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Ag2CO3
i-Pr2NEt
DBU
125
125
125
125
125
125
125
125
125
100
3
48
3
1.5
1
8
5
9
10
31
Trace
No reaction
45
19
6
—
2c
3d
4
—
37
50
21
15
6
Trace
23
17
—
—
8
16
8
13
—
—
—
—
—
58
5
6
7
8
9
10e
6
—
33
—
No reaction
No reaction
—
K2CO3
3
—
—
—
a
The reaction was carried out in degassed DMF under the conditions indicated (A:Ar, B:air, C:O2) and 200 mol% of base was added.
The molar ratio of the ligand and Pd.
CH3CN was used as a solvent.
The starting material (16a) was recovered in 35% yield.
100 mol% of n-Bu4NCl and 300 mol% of K2CO3 were added. The starting material (16a) was recovered in 64% yield.
b
c
d
e
Table 2. Results of biaryl coupling reaction of 1-(2-bromo-4,5-dimethoxybenzyl)-2,3-dihydroindole (17a)a
Run
Pd (OAc)2 (mol%)
Ligand (L/Pd)b
Temp. (8C)
Time (h)
Yield (%)
2
4
22
23
1c
2d
3e
4
B
B
B
A
A
20
10
10
10
10
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
P(o-tol)3 (2)
Cy3P (2)
125
125
160
140
125
3
7
1
2
1
Trace
Trace
Trace
28
34
25
30
13
13
11
9
2
28
26
10
10
17
18
3
5
45
a
The reaction was carried out in degassed DMF under the conditions indicated (A:Ar, B:air) and 200 mol% of K2CO3 was added.
The molar ratio of the ligand and Pd.
The starting material (17a) was recovered in 9% yield.
The starting material (17a) was recovered in 21% yield.
DMA was used as a solvent.
b
c
d
e
the coupling constants are given in Hertz. MS spectra were
was filtered while hot. The hot filtrate was then concentrated
to dryness to give purified Pd(OAc)2.
obtained on a VG-70SE spectrometer. Column chromato-
graphy was carried out with Merck silica gel (230–400
mesh) and Wako activated alumina (300 mesh). All the
experiments were carried out in an argon atmosphere, unless
otherwise noted, and the extract was washed with brine,
dried over anhydrous K2CO3, and filtered, and the filtrate
was concentrated to dryness under reduced pressure.
Pd(OAc)2 was treated with boiling benzene and the mixture
3.2. Coupling reaction of 1-(2-bromobenzyl)-2,3-
dihydroindole (14) with palladium reagent
To a solution of 14 (58 mg, 0.2 mmol) in DMF (1.5 ml)
were added Pd(OAc)2 (2.2 mg, 0.01 mmol), PPh3 (5.3 mg,
0.02 mmol), and K2CO3 (55 mg, 395 mmol), and the
Table 3. Results of biaryl coupling reaction of 1-[(6-iodo-1,3-bezodioxol-5-yl)methyl]-2,3-dihydroindole (16b)a
Run
Pd (OAc)2 (mol%)
Ligand (L/Pd)b
Temp. (8C)
Time (h)
Yield (%)
1
3
20
21a
14
12
12
16
13
12
1
2
3
4
5
6
7c
8d
9
B
A
A
A
A
A
B
B
A
20
5
5
5
5
P(o-tol)3 (2)
P(o-tol)3 (2)
Cy3P (2)
n-Bu3P (2)
t-Bu3P (2)
—
—
—
DPPP
125
125
125
125
125
115
100
100
125
2.5
3.5
1.5
3.5
1
3.5
24
2.3
2
Trace
34
48
35
41
43
16
12
10
13
11
51
47
11
17
21
21
25
24
17
19
13
27
5
50
20
20
5
Trace
Trace
29
Trace
Trace
11
a
The reaction was carried out in degassed DMF under the conditions indicated (A:Ar, B:air) and 200 mol% of K2CO3 was added.
The molar ratio of the ligand and Pd.
100 mol% of n-Bu4NCl and 300 mol% of K2CO3 were added.
b
c
d
100 mol% of n-Bu4NCl and 550 mol% of AcOK were added.

1614
T. Harayama et al. / Tetrahedron 60 (2004) 1611–1616
Table 4. Results of biaryl coupling reaction of 1-(2-iodo-4,5-dimethoxybenzyl)-2,3-dihydroindole (17b)a
Run
Pd (OAc)2 (mol%)
Ligand (L/Pd)b
Temp. (8C)
Time (h)
Yield (%)
2
4
22
23
1
2
B
A
A
A
A
5
5
5
5
5
P(o-tol)3 (2)
P(o-tol)3 (2)
Cy3P (2)
—
125
125
125
115
155
2
2.5
1
4
4
Trace
28
24
43
37
35
15
10
6
16
25
33
22
3
13
15
4
11
19
3
4c
5d
—
6
a
The reaction was carried out in degassed DMF under the conditions indicated (A:Ar, B:air) and 200 mol% of K2CO3 was added.
The molar ratio of the ligand and Pd.
100 mol% of n-Bu4NCl and 300 mol% of K2CO3 were added.
b
c
d
100 mol% of n-Bu4NCl and 550 mol% of AcOK were added.
0
reaction mixture was stirred for 1.6 h at 125 8C. Then, the
C2 –H), 6.43 (1H, dd, J¼0.9, 7.8 Hz, C7–H), 6.68 (1H, ddd,
0
mixture was diluted with AcOEt and the precipitate was
removed by filtration. The filtrate was washed with aqueous
5% NaOH solution and brine. The residue was dissolved in
CHCl3 and subjected to column chromatography through
Al2O3. Elution with hexane–AcOEt (200:1) gave a mixture
of 1-benzyl-2,3-dihydroindole16 and 1-benzylindole.16
Elution with hexane–AcOEt (1:1) gave 4,5-dihydro-7H-
pyrrolo[3,2,1-de]phenanthridin-7-one (15) (19 mg, 35%).
Moreover, a mixture of 1-benzyl-2,3-dihydroindole and
1-benzylindole was dissolved in CHCl3 and subjected to
column chromatography through silica gel. Elution with
hexane gave 1-benzyl-2,3-dihydroindole (6 mg, 13%) and
successive elution with the same solvent gave 1-benzyl-
indole (9 mg, 17%).
J¼0.9, 7.4, 7.8 Hz, C5–H), 6.96 (1H, s, C4 –H), 7.03 (1H, s,
0
C7 –H), 7.01–7.12 (2H, m, C4–H and C6–H). FAB-MS
m/z: 331 (M)þ, 333 (Mþ2)þ. Anal. calcd for C16H14BrNO2:
C, 57.85; H, 4.25; N, 4.22. Found: C, 58.04; H, 4.42; N,
4.28.
3.3.2. 1-[(6-Iodo-1,3-benzodioxol-5-yl)methyl]-2,3-di-
hydroindole (16b). Elution with AcOEt–hexane (1:10)
gave 16b (324 mg, 86%), colorless needles, mp 74.5–
75.5 8C (Et2O). IR (KBr) cm21: 1250, 1040. 1H NMR
(200 MHz, CDCl3) d: 3.02 (2H, t, J¼8.1 Hz, C3–H), 3.40
(2H, t, J¼8.1 Hz, C2–H), 4.15 (2H, s, Ar–CH2N), 5.96 (2H,
0
s, C2 –H), 6.43 (1H, dd, J¼1.0, 8.0 Hz, C7–H), 6.68 (1H,
0
ddd, J¼1.0, 7.2, 7.6 Hz, C5–H), 6.97 (1H, s, C4 –H), 7.06
(1H, dd, J¼7.6, 8.0 Hz, C6–H), 7.11 (1H, d, J¼7.2 þHz, C4–
0
H), 7.28 (1H, s, C7 –H). FAB-MS m/z: 379 (M) . Anal.
3.2.1. 4,5-Dihydro-7H-pyrrolo[3,2,1-de]phenanthridin-
7-one (15). Colorless needles, mp 168–170 8C (CHCl3–
hexane), (lit.17 170–171 8C).
calcd for C16H14BrNO2: C, 50.68; H, 3.72; N, 3.69. Found:
C, 50.91; H, 3.97; N, 3.88.
3.2.2. 1-Benzyl-2,3-dihydroindole. Pale yellow oil, (lit.16
oil). 1H NMR (60 MHz, CDCl3) d: 2.88–3.44 (4H, m, C2–
H and C3–H), 4.23 (2H, s, Ar–CH2N), 6.45–7.33 (9H, m,
Ar–H).
3.3.3. 1-(2-Bromo-4,5-dimethoxybenzyl)-2,3-dihydro-
indole (17a). Elution with AcOEt–hexane (1:10) gave
17a (282 mg, 91%), colorless plates, mp 68–69 8C (Et2O).
IR (KBr) cm21: 1260, 1030. 1H NMR (200 MHz, CDCl3) d:
3.01 (2H, t, J¼8.3 Hz, C3–H), 3.38 (2H, t, J¼8.3 Hz, C2–
H), 3.80 (3H, s, OCH3), 3.88 (3H, s, OCH3), 4.23 (2H, s,
Ar–CH2N), 6.51 (1H, dd, J¼1.0, 7.8 Hz, C7–H), 6.68 (1H,
3.2.3. 1-Benzylindole. Colorless plates, mp 38.5–40 8C
1
(Et2O), (lit.16 43–44 8C). H NMR (60 MHz, CDCl3) d:
0
5.33 (2H, s, Ar–CH2N), 6.55 (1H, d, J¼3.4 Hz, C3–H),
ddd, J¼1.0, 7.2, 7.4 Hz, C5–H), 7.00 (1H, s, C6 –H), 7.05
0
7.04–7.33 (9H, m, Ar–H), 7.62 (1H, d, J¼3.4 Hz, C2–H).
(1H, s, C3 –H), 7.07 (1H, dd, J¼7.4, 7.8 Hz, C6–H), 7.12
(1H, d, J¼7.2 Hz, C4–H). FAB-MS m/z: 347 (M)þ, 349
(Mþ2)þ. Anal. calcd for C16H14BrNO2: C, 58.63; H, 5.21;
N, 4.02. Found: C, 58.53; H, 5.08; N, 3.92.
3.3. General procedure for the synthesis of starting
materials (16a, 16b and 17a)
To a solution of 2-halobenzyl bromides (18a,18a 18b,19b and
19a18b) (3.00 mmol) in dry CH3CN (8 ml) were added
dihydroindole (425 mg, 3.60 mmol), Et4NI (116 mg,
0.45 mmol), and i-Pr2NEt (2.1 ml, 12.3 mmol), and the
reaction mixture was stirred for 30 min at 70 8C. The
mixture was diluted with AcOEt and the entire organic layer
was washed with aqueous 5% NaOH solution and brine. The
residue dissolved in CHCl3 was subjected to column
chromatography through silica gel.
3.3.4. 1-(2-Iodo-4,5-dimethoxybenzyl)-2,3-dihydroindole
(17b). To a solution of 19b19b (1.43 g, 4.00 mmol) in ether
(10 ml) was added dihydroindole (858 mg, 7.20 mmol) and
the reaction mixture was stirred for 1.5 h at rt. After
evaporation of solvent, the residue dissolved in CHCl3 was
subjected to column chromatography through silica gel.
Elution with CHCl3 gave 17b (1.21 g, 77%), colorless
prisms, mp 93–94 8C (Et2O). IR (KBr) cm21: 1255, 1025.
1H NMR (200 MHz, CDCl3) d: 3.01 (2H, t, J¼8.2 Hz, C3–
H), 3.40 (2H, t, J¼8.2 Hz, C2–H), 3.80 (3H, s, OCH3), 3.88
(3H, s, OCH3), 4.20 (2H, s, Ar–CH2–N), 6.50 (1H, dd,
J¼7.8 Hz, C7–H), 6.70 (1H, dd, J¼7.2, 7.4 Hz, C5–H),
3.3.1. 1-[(6-Bromo-1,3-benzodioxol-5-yl)methyl]-2,3-
dihydroindole (16a). Elution with AcOEt–hexane (1:20)
gave 16a (302 mg, 91%), colorless plates, mp 66–67 8C
0
6.99 (1H, s, C6 –H), 7.09 (1H, dd, J¼7.4, 7.8 Hz, C6–H),
1
(Et2O). IR (KBr) cm21: 1245, 1040. H NMR (200 MHz,
7.12 (1H, d, J¼7.2 Hz, C4–H), 7.27 (1H, s, C3 –H). FAB-
0
CDCl3) d: 3.01 (2H, t, J¼8.3 Hz, C3–H), 3.41 (2H, t,
MS m/z: 395 (M)þ. Anal. calcd for C17H18INO2: C, 51.66;
H, 4.59; N, 3.54. Found: C, 51.57; H, 4.75; N, 3.47.
J¼8.3 Hz, C2–H), 4.21 (2H, s, Ar–CH2N), 5.95 (2H, s,

T. Harayama et al. / Tetrahedron 60 (2004) 1611–1616
1615
1
3.4. General procedure for the coupling reaction of
1-halobenzyldihydroindole derivatives (16 and 17) in the
presence of phosphine ligand
(KBr) cm21: 1240, 1035. H NMR (500 MHz, CDCl3) d:
0
5.29 (2H, s, Ar–CH2–N), 5.89 (2H, s, C2 –H), 6.06 (1H, d,
J¼3.5 Hz, C3–H), 6.58 (1H, d, J¼3.5 Hz, C2–H), 7.04 (1H,
0
0
s, C4 –H), 7.12 (1H, s, C7 –H), 7.13 (1H, ddd, J¼1.0, 7.0,
8.0 Hz, C5–H), 7.19 (1H, ddd, J¼1.0, 7.0, 8.0 Hz, C6–H),
7.25 (1H, dd, J¼1.0, 8.0 Hz, C7–H), 7.66 (1H, dd, J¼1.0,
8.0 Hz, C4–H). FAB-MS m/z: 329 (M)þ, 331 (Mþ2)þ.
Anal. calcd for C16H12BrNO2: C, 58.26; H, 3.66; N, 4.24.
Found: C, 58.27; H, 3.93; N, 4.11.
Each compound (16 or 17) (0.3 mmol) was reacted with
Pd(OAc)2, a phosphine ligand, and a base in dry DMF
(8 ml) using Pd(OAc)2 and the phosphine ligand in the
ratios indicated in Tables 1 and 2, and 200 mol% of base for
the times and temperatures indicated in the tables. Then, the
reaction mixture was diluted with AcOEt and the precipitate
was removed by filtration. The filtrate was washed with
aqueous 5% NaOH solution and brine. The residue from 16
was dissolved in CHCl3 and subjected to column chroma-
tography through Al2O3. Elution with hexane–AcOEt
(50:1) gave 20 and elution with hexane–AcOEt (30:1)
gave 21a. Moreover, elution with hexane–AcOEt (15:1)
gave 1 and elution with AcOEt gave 3.
The residue from 17 was dissolved in CHCl3 and subjected
to column chromatography through silica gel. Elution with
hexane–AcOEt (15:1) gave 22. Successive elution with the
same solvent gave 23 and 2, and elution with AcOEt gave 4.
3.4.6. Assoanine (2). Pale yellow needles, mp165.5–168 8C
1
(EtOH), (lit.20b 175–176 8C). H NMR (200 MHz, CDCl3)
d: 3.03 (2H, t, J¼7.8 Hz, C4–H), 3.34 (2H, t, J¼7.8 Hz,
C5–H), 3.90 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.12 (2H, s,
C7–H), 6.67 (1H, s, C8–H), 6.78 (1H, dd, J¼7.4, 7.6 Hz,
C2–H), 7.01 (1H, dd, J¼1.0, 7.4 Hz, C3–H), 7.19 (1H, s,
C11–H), 7.34 (1H, dd, J¼1.0, 7.6 Hz, C1–H). FAB-MS m/z:
268 (Mþ1)þ.
3.4.1. Anhydrolycorine (1). Pale yellow prisms, 110–
112.5 8C (EtOH), (lit.20a 108–111 8C). 1H NMR (200 MHz,
CDCl3) d: 3.02 (2H, t, J¼7.9 Hz, C4–H), 3.33 (2H, t,
J¼7.9 Hz, C5–H), 4.07 (2H, s, C7–H), 5.97 (2H, s,
OCH2O), 6.64 (1H, s, C8–H), 6.76 (1H, dd, J¼7.3,
7.3 Hz, C2–H), 7.01 (1H, dd, J¼1.0, 7.3 Hz, C3–H), 7.16
(1H, s, C11–H), 7.28 (1H, dd, J¼1.0, 7.3 Hz, C1–H). Anal.
calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57. Found: C,
76.49; H, 5.43; N, 5.35.
3.4.7. Oxoassoanine (4). Colorless needles, mp 271–
273 8C (CHCl3–MeOH), (lit.20b 270–271 8C). 1H NMR
(200 MHz, CDCl3) d: 3.43 (2H, t, J¼8.3 Hz, C4–H), 4.04
(3H, s, OCH3), 4.08 (3H, s, OCH3), 4.49 (2H, t, J¼8.3 Hz,
C5–H), 7.20 (1H, dd, J¼7.4, 7.6 Hz, C2–H), 7.28 (1H, d,
J¼1.0, 7.4 Hz, C3–H), 7.52 (1H, s, C11–H), 7.80 (1H, d,
J¼1.0, 7.8 Hz, C1–H), 7.93 (1H, s, C8–H). Anal. calcd for
C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.43; H,
5.57; N, 5.03.
3.4.2. Anhydrolycorin-7-one (3). Pale brown needles, mp
236–237 8C (CHCl3–MeOH), (lit.20a 232–234 8C). 1H
NMR (200 MHz, CDCl3) d: 3.33 (2H, t, J¼8.3 Hz, C4–
H), 4.38 (2H, t, J¼8.3 Hz, C5–H), 6.05 (2H, s, OCH2O),
7.10 (1H, dd, J¼7.6, 7.6 Hz, C2–H), 7.20 (1H, dd, J¼1.2,
7.6 Hz, C3–H), 7.43 (1H, s, C11–H), 7.64 (1H, dd, J¼1.2,
7.6 Hz, C1–H), 7.82 (1H, s, C8–H). Anal. calcd for
C16H11NO3: C, 72.45; H, 4.18; N, 5.28. Found: C, 72.46;
H, 4.38; N, 5.21.
3.4.8. 1-(3,4-Dimethoxybenzyl)-2,3-dihydroindole (22).
Colorless needles, mp 77–78 8C (petr. ether). IR (CHCl3)
cm21: 1260, 1030. 1H NMR (200 MHz, CDCl3) d: 2.97 (2H,
t, J¼8.0 Hz, C3–H), 3.33 (2H, t, J¼8.0 Hz, C2–H), 3.86
(3H, s, OCH3), 3.88 (3H, s, OCH3), 4.21 (2H, s, Ar–CH2N),
6.62–7.14 (7H, m, Ar–H). FAB-MS m/z: 269 (M)þ. Anal.
calcd for C16H12BrNO2: C, 75.81; H, 7.11; N, 5.20. Found:
C, 75.78; H, 7.07; N, 5.19.
3.4.3. 1-[(1,3-Benzodioxol-5-yl)methyl]-2,3-dihydro-
indole (20). Pale yellow oil, (lit.19a oil). 1H NMR
(200 MHz, CDCl3) d: 2.96 (2H, t, J¼8.2 Hz, C3–H), 3.29
(2H, t, J¼8.2 Hz, C2–H), 4.16 (2H, s, Ar–CH2N), 5.95 (2H,
0
s, C2 –H), 6.51 (1H, d, J¼7.6 Hz, Ar–H), 6.63–7.11 (6H,
m, Ar–H). FAB-MS m/z: 253 (M)þ.
3.4.9. 1-(3,4-Dimethoxybenzyl)indole (23). Colorless
needles, mp 61.5–62.5 8C (hexane). IR (KBr) cm21: 1255,
1
3.4.4. 1-[(1,3-Benzodioxol-5-yl)methyl]indole (21a).
Colorless needles, mp 82–83 8C (petr. ether). IR
1025. H NMR (200 MHz, CDCl3) d: 3.77 (3H, s, OCH3),
3.84 (3H, s, OCH3), 5.25 (2H, s, Ar–CH2N), 6.53 (1H, d,
1
(KBr) cm21: 1235, 1040. H NMR (200 MHz, CDCl3) d:
J¼3.6 Hz, C3–H), 6.66–6.70 (2H, m, C2 –H and C6 –H),
0
0
0
5.22 (2H, s, Ar–CH2N), 5.91 (2H, s, C2 –H), 6.53 (1H, d,
0
6.78 (1H, d, J¼8.6 Hz, C5 –H), 7.10 (1H, ddd, J¼6.8,
0
J¼3.4 Hz, C3–H), 6.59 (1H, d, J¼1.4 Hz, C4 –H), 6.63
7.2 Hz, C5–H), 7.11 (1H, d, J¼3.6 Hz, C2–H), 7.18 (1H,
ddd, J¼1.4, 7.2, 8.0 Hz, C6–H), 7.31 (1H, d, J¼8.0 Hz, C7–
H), 7.64 (1H, dd, J¼1.4, 6.8 Hz, C4–H). FAB-MS m/z: 267
(M)þ. Anal. calcd for C16H12BrNO2: C, 76.38; H, 6.41; N,
5.24. Found: C, 76.28; H, 6.26; N, 5.20.
0
(1H, dd, J¼1.4, 7.8 Hz, C6 –H), 6.73 (1H, d, J¼7.8 Hz,
0
C7 –H), 7.10 (1H, ddd, J¼1.4, 6.8, 6.8 Hz, C5–H), 7.12
(1H, d, J¼3.4 Hz, C2–H), 7.18 (1H, ddd, J¼1.4, 6.8,
8.2 Hz, C6–H), 7.30 (1H, dd, J¼1.4, 8.2 Hz, C7–H), 7.64
(1H, dd, J¼1.4, 6.8 Hz, C4–H). FAB-MS m/z: 251 (M)þ.
Anal. calcd for C16H13NO2: C, 76.48; H, 5.21; N, 5.57.
Found: C, 76.32; H, 5.45; N, 5.49.
3.5. General procedure for the coupling reaction of 1-(2-
iodobenzyl)dihydroindole derivatives (16b and 17b)
under phosphine-free conditions (runs 6–8 in Table 3,
and runs 4 and 5 in Table 4)
3.4.5. 1-[(6-Bromo-1,3-benzodioxol-5-yl)methyl]indole
(21b). The residue of run 7 in Table 1 was dissolved in
CHCl3 and subjected to column chromatography through
silica gel. Elution with hexane–AcOEt (20:1) gave 21b,
colorless needles, mp 124.5–125.5 8C (hexane). IR
The 1-(2-iodobenzyl)dihydroindole derivative (0.3 mmol)
was reacted with 0.05 mol% of Pd(OAc)2, 100 mol% of
n-Bu4NCl, and 300 mol% of K2CO3 or 550 mmol% of

1616
T. Harayama et al. / Tetrahedron 60 (2004) 1611–1616
191–195. (b) Harayama, T.; Akiyama, T.; Akamatsu, H.;
Kawano, K.; Abe, H.; Takeuchi, Y. Synthesis 2001, 444–450.
(c) Harayama, T.; Akamatsu, H.; Okamura, K.; Miyagoe, T.;
Akiyama, T.; Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin
Trans. 1 2001, 523–528. (d) Harayama, T.; Akiyama, T.;
Nakano, Y.; Nishioka, H.; Abe, H.; Takeuchi, Y. Chem.
Pharm. Bull. 2002, 50, 519–522. (e) Harayama, T.; Akiyama,
T.; Nakano, Y.; Shibaike, K.; Akamatsu, H.; Hori, A.; Abe, H.;
Takeuchi, Y. Synthesis 2002, 237–241. (f) Harayama, T.;
Hori, A.; Nakano, Y.; Akiyama, T.; Abe, H.; Takeuchi, Y.
Heterocycles 2002, 58, 159–164. (g) Harayama, T.; Sato, T.;
Nakano, Y.; Abe, H.; Takeuchi, Y. Heterocycles 2003, 59,
293–301.
AcOK in dry DMF (4 ml) for the times and at temperature
indicated in Tables 3 and 4. Then, the reaction mixture was
diluted with ether and the precipitates were removed by
filtration. Then, the reaction mixture was diluted with
AcOEt and the precipitates were removed by filtration. The
filtrate was washed with brine. The residue dissolved in
CHCl3 was subjected to column chromatography and the
products (2, 4, 22, and 23) shown in Tables 3 and 4 were
separated by the methods mentioned before.
Acknowledgements
The authors are indebted to the SC-NMR Laboratory of
Okayama University for the NMR spectral measurements.
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