Synthetic study directed toward derivatives of biologically active indolo[2,3-a]carbazole

Article abstract of DOI:10.3987/COM-09-S(S)79

Various derivatives of (6R (*),6aR (*))-6-chloro-6a-hydroxy-5, 6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one (8) and 6-cyano-5- hydroxyindolo[2,3-a]-carbazole (9) are prepared. Preparations of (6R (*),6aR (*),11aR (*))-6-chloro-11a-cyano-6a-hydroxy- (11) and 12-substituted 6-(Z)-aminomethylidene-5,6,6a, 11,11a,12-hexahydroindolo[2,3-a] carbazole-5-ones (15) are also reported.

Full text of DOI:10.3987/COM-09-S(S)79

HETEROCYCLES, Vol. 80, No. 2, 2010
1027
HETEROCYCLES, Vol. 80, No. 2, 2010, pp. 1027 - 1045. © The Japan Institute of Heterocyclic Chemistry
Received, 27th July, 2009, Accepted, 4th September, 2009, Published online, 8th September, 2009
DOI: 10.3987/COM-09-S(S)79
SYNTHETIC STUDY DIRECTED TOWARD DERIVATIVES OF
BIOLOGICALLY ACTIVE INDOLO[2,3-a]CARBAZOLE1 #
Masako Sato, Yoshiaki Suzuki, Fumio Yamada, and Masanori Somei*‡
Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
e-mail address: somei.home@topaz.plala.or.jp
Abstract – Various derivatives of (6R*,6aR*)-6-chloro-6a-hydroxy-5,6,6a,12-
tetrahydroindolo[2,3-a]carbazole-5-one (8) and 6-cyano-5-hydroxyindolo[2,3-a]-
carbazole (9) are prepared. Preparations of (6R*,6aR*,11aR*)-6-chloro-11a-
cyano-6a-hydroxy-
(11)
and
12-substituted
6-(Z)-aminomethylidene-
5,6,6a,11,11a,12-hexahydroindolo[2,3-a]carbazole-5-ones (15) are also reported.
We have proposed a new concept for evaluating originality and efficiency of synthetic method
introducing three measures such as originality rate, intellectual property factor, and application potential
factor and defined an ideal synthetic method.2 In our continuing research, we have created a synthetic
method,3 as one of the concrete example of the ideal synthesis, for 6-cyano-5-methoxy-12-
methylindolo[2,3-a]carbazole (1, Scheme 1) isolated from blue-green alga Nostoc sphaericum (strain
EX-5-1) by Moore and co-workers.4 The synthesis starts from indigo (2) and consists of six steps. Every
compound involved in the synthesis has either a useful function or a biological activity. Thus, starting
material is a widely used dye5 and the target 1 is a cytotoxic and antiviral alkaloid.4 The compound 3
exhibits potent biological activity against telomerase.6 In addition, we have discovered as intellectual
properties that 4, 6, and 7 are potent inhibitors of blood platelet aggregation7 while 5 is a promising
a2-blocker.8
It is natural, therefore, that we would expect to discover a compound becoming medicine in the future
among derivatives of biologically active 5 and 7. Now, we wish to report the synthesis of various
derivatives of 5 and 7. Interesting formations of (6R*,6aR*,11aR*)-6-chloro-11a-cyano-6a-hydroxy-
# Dedicated to the 80th birthday of Prof. Emeritus, Akira Suzuki, Hokkaido University.
‡ Professor Emeritus of Kanazawa University. Present address: 56-7 Matsuhidai, Matsudo-shi, Chiba
270-2214, Japan.

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HETEROCYCLES, Vol. 80, No. 2, 2010
5,6,6a,11,11a,12-hexahydro-
(11)
and
12-substituted
(Z)-6-aminomethylidene-5,6,11,12-
tetrahydroindolo[2,3-a]carbazole-5-one (15) are also reported.
Scheme 1
OAc
O
OAc
Cl
6
Sn
88%
CHCl2COCl
85%
aq. NH3
98%
HO
H
N
H
N
H
N
O
5
4
1
N
H
N
H
O
N
H
N
11
O
HN
12
4
5
2
3
CHCl2
indigo
Me2SO4
quant.
Cl
CN
CN
HO
O
MeI
NaCN
quant.
OMe
OH
86%
N
N
H
N
H
MeN
N
N
1
7
6
Me
Me
Scheme 2
CN
Cl
N
CN
OH
Cl
HO
HO
OH
O
O
5
N
H
N
N
H
N
H
NC
HN
N
HN
R
R
8
9
10
11
R
R
8/9
R
8/9
8/9
g
h
i
j
k
l
Cl
HO
a
b
c
d
e
f
CH2(CH2)2Me
CH2CH=CH2
CH2C CH
CH2Ph
CH2CH2Ph
CH2CH=CHPh (E)
m
n
o
p
q
r
CH2(CH2)2CO2Et
CH2CH=CHCl (Z)
CH2CH=CHCl (E)
COMe
CH2CO2H
CH2(CH2)2CN
OR1
CH2CN
CH2CONMe2
CH2CO2Me
CH2CH2CO2Me
CH2COPh
CH2CH2CH2Br
N
H
NC
N
R2
R1 R2
12
12
a
b
H H
Ac Ac
Hb
N
H
NHAc
O
Hc
Ha
CHO
OH
CN
O
OMe
N
H
N
N
N
H
H
H
N
N
N
N
H2C
R
R
PhH2C
R
15
a
b
CH2
13
14
16
CH2(CH2)2Me
CH2Ph
H2C
Me
First, the compound 5 was prepared according to our procedures3 from indigo in three steps in 73%
overall yield. Subsequent treatment of 5 in N,N-dimethylformamide (DMF) in the presence of K2CO3
with n-butyl iodide, allyl bromide, propargyl bromide, benzyl bromide, phenethyl bromide, and
(E)-cinnamyl bromide provided 8a, 8b, 8c, 8d, 8e, and 8f in the respective yields of 71, 96, 50, 78, 57,
and 96% (Scheme 2). Similar treatment of 5 with reagents having a cyano or a carbonyl group such as

HETEROCYCLES, Vol. 80, No. 2, 2010
1029
chloroacetonitrile, N,N-dimethyl-2-chloroacetamide, methyl bromoacetate, methyl acrylate, and phenacyl
bromide afforded 8g, 8h, 8i, 8j, and 8k in the respective yields of 62, 90, 72, 26, and 97%. Although the
reaction of 1,3-dibromopropane with 5 similarly proceeded to give 8l in 45% yield, ethyl 4-bromobutylate
did not react with 5 at all. To overcome the problem, change of the base from K2CO3 to NaH in
anhydrous DMF was successful to obtain the desired 8m in 59% yield.
In the reaction of 5 with an E,Z mixture of 1,3-dichloropropene, NaH in anhydrous DMF was the reaction
conditions of choice, providing 12-(Z)- 8n and 12-(E)-(3-chloroallyl) derivatives 8o in 42 and 24% yields,
respectively. Under similar reaction conditions, 5 reacted with acetyl chloride to produce 12-acetyl
compound 8p in 41% yield.
With
various
12-substituted
(6R*,6aR*)-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]-
carbazole-5-one in hand, we next employed our reductive cyanation which realized transformation of 6 to
7. Thus, the treatment of 8a with NaCN in DMF-H2O provided 12-n-butyl-6-cyano-5-
hydroxyindolo[2,3-a]carbazole (9a) in 85% yield. A possible reaction mechanism is shown in Scheme 3.
The initial step would be a nucleophilic substitution for 6b-chloride by cyanide from the back side to give
A. After dehydration, the resultant B can form C by general acid promoted cyanide addition to the
6-position. Subsequent cyanide attack at one of the geminal cyano groups of C achieves the reductive
cyanation with the liberation of dicyan and an enolate of 9a. The other possible route is the enolization of
5-carbonyl of A, followed by the addition of cyanide at the imine carbon (C11a) from the less sterically
hindered a-side culminating in the formation of D. Subsequent cyanide attack at the 11a-cyano group and
concomitant general acid promoted elimination of 6ab-hydroxy group liberates dicyan and 9a.
Scheme 3. Possible Mechanism
NaCN, DMF-H2O, rt, 30 min
8a
9a
85%
– (CN)2
HO—H
– (CN)2
CN
CN
CN
NC CN
HO
CN
N
CN
N
–H2O
HO
N
OH
CN
O
O
O
N
H
N
N
H
N
N
HO—H
n-Bu
n-Bu
n-Bu
n-Bu
NC
A
B
C
D
CN
CN
On the basis of above results, the reductive cyanation was applied to 8b—h and 8m resulting in the
formations of 9b, 9c, 9d, 9e, 9f, 9g, 9h, and 9m in the respective yields of 91, 72, 98, 85, 80, 54, 95, and
72%. In the case of 8i, the reductive cyanation formed 9i and 9q in 17 and 43% yields, respectively.
Similar reaction of 8k removed the 12-phenacyl group to afford 10 in 27% yield together with 16% yield
of starting material.

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HETEROCYCLES, Vol. 80, No. 2, 2010
The structures of 9a—i and 9m,q were established unequivocally by pursuing X-ray single-crystal
analysis of 9a as a representative of them and the results are shown in Figure 1 and Table 1. It is
interesting to note that this type of compounds 9 tends to involve a recrystallization solvent molecule in
crystals. In fact, the ORTEP drawing of 9a demonstrates EtOAc molecule.
Figure 1. ORTEP Drawing of 9a (R=0.049)
Figure 2. ORTEP Drawing of 11 (R=0.085)
The reaction of 8l with NaCN in DMF-H2O provided 9l and 9r in 23 and 23% yields, respectively. The
reaction of about 4:1 mixture of 8n and 8o produced 9n and 9o in 41 and 14% yields, respectively. It is
interesting to note that the similar reaction of 8p afforded 10 and the unexpected (6R*,6aR*,11aR*)-6-
chloro-11a-cyano-6a-hydroxy-5,6,6a,11,11a,12-hexahydroindolo[2,3-a]carbazole-5-one (11) in 22 and
74% yields, respectively, though formation of the desired 9p was not observed at all.
Reduction of 11 with NaBH4 proceeded slowly from the less hindered ꢀ-side to provide 5ꢁ-hydroxy
compound 12a in 47% yield. Further treatment of 12a with acetic anhydride gave 5ꢁ-acetoxy compound
12b in 30% yield. Comparing 1H-NMR spectra of 12a and 12b, the coupling constant between H5 and H6
is shown to be 8.2 Hz, which proved their stereochemistries as shown in the Scheme 2.
It should be noted that the absorption bands of cyano group of 11, 12a, and 12b were very weak or almost
invisible in their infrared spectra. Therefore, X-ray single-crystal analysis of 11 was necessary for the
determination of the structure. The results shown in Figure 2 and Table 2 demonstrate both the presence
of the cyano group at the 11a-position and the stereochemistries of 6, 6a, and 11a positions being all R*.
Methylation of 9d with ethereal diazomethane smoothly proceeded to afford the corresponding methoxy
compound 13 in 82% yield. All attempts to hydrolyze the 6-cyano group of 13 to 6-carboxy or
6-carbamoyl group with base were unsuccessful. Under severe conditions such as treatment of 13 with
solid NaOH in refluxing ethylene glycol resulted in the methyl ether cleavage to afford 9d in 62% yield.
Further attempt to obtain 6-formyl type compound 14 by the reaction of 9 with diisobutyl aluminum
hydride (DIBAL) proceeded in an unexpected way. Thus the reduction of 9a and 9d with DIBAL
1
afforded 15a and 15b in 73 and 47% yields, respectively. In the H-NMR spectrum of 15a, hydrogen
bonded Ha was observed at lower ꢂ 12.0 (1H, dd, J=13.8, 8.2 Hz), while Hb and Hc protons appeared at
ꢂ 8.60 (1H, brt, J=8.2 Hz) and 8.84 (1H, dd, J=13.8, 8.2 Hz), respectively. On the addition of D2O, both

HETEROCYCLES, Vol. 80, No. 2, 2010
1031
Ha and Hb protons disappeared and Hc collapsed to a singlet. Similar phenomena were observed in case
of 15b. Further treatment of 15a with Ac2O afforded N-acetyl compound 16 in 87% yield. These results
prove the 6-aminomethylidene structures of 15a,b.
A possible reaction mechanism for the transformation of 9 to 15 is shown in Scheme 4. The initial
reaction of DIBAL with 9 forms aluminum complex A, followed by the intramolecular reduction of
cyano group with hydride to afford B. Hydrolysis of B affords an enol form compound C which
tautomerizes to a carbonyl form product 15 forming a stable enamide system.
Scheme 4
R = CH2(CH2)2Me or CH2Ph
9
DIBAL
H
N
N
C
H
N
H
NH
OH
Al R'
O
Al R'
O
H
O
H2O
N
N
N
H
N
H
R'2Al
R'2Al
N
N
N
N
R
R
R
R
15
A
B
C
In summary, we succeeded in preparing various derivatives of 8 and 9, together with new classes of
compound, 11 and 15. Biological evaluations of new compounds in this report are in progress.
EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected.
Infrared (IR) spectra were recorded with a Shimadzu IR-420 or Horiba FT-720 spectrophotometer and
proton nuclear magnetic resonance (1H-NMR) spectra with a JEOL GSX-500 spectrometer with
tetramethylsilane as an internal standard. Mass spectra (MS) were recorded on a JEOL JMS-SX102A
instruments. Column chromatography was performed on silica gel (SiO2, 100—200 mesh, from Kanto
Chemical Co., Inc.) throughout the present study.
(6R*,6aR*)-12-n-Butyl-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one (8a)
from (6R*,6aR*)-6-Chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one (5) —
General Procedure A: K2CO3 (72.1 mg, 0.52 mmol) and n-butyl iodide (0.34 mL, 2.90 mmol) were
added to a solution of 5 (48.1 mg, 0.15 mmol) in DMF (3.0 mL), and the mixture was stirred for 20 min
at rt. After addition of H2O under ice cooling, the whole was extracted with EtOAc. The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was
column-chromatographed on SiO2 with EtOAc–hexane (1:5, v/v) to give 8a (40.1 mg, 71%). 8a: mp
187—189˚C (decomp., orange prisms, recrystallized from CHCl3). IR (KBr): 3421, 1653, 1479, 1346,
1
1086, 754 cm-1. H-NMR (CDCl3) ꢀ: 0.97 (3H, t, J=7.4 Hz), 1.39—1.50 (2H, m), 1.87—2.00 (2H, m),
3.11 (1H, s, disappeared on addition of D2O), 4.63 (1H, ddd, J=14.1, 8.2, 6.4 Hz), 4.76 (1H, s), 4.87 (1H,
ddd, J=14.1, 8.2, 6.4 Hz), 7.35 (1H, td, J=7.7, 1.2 Hz), 7.39 (1H, td, J=7.7, 1.2 Hz), 7.47 (1H, td, J=7.7,

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HETEROCYCLES, Vol. 80, No. 2, 2010
1.2 Hz), 7.50 (1H, d, J=7.7 Hz), 7.50 (1H, td, J=7.7, 1.2 Hz), 7.72 (1H, d, J=7.7 Hz), 7.92 (1H, d, J=7.7
Hz), 8.39 (1H, d, J=7.7 Hz). MS m/z: 380 and 378 (M+). Anal. Calcd for C22H19N2O2Clꢀ1/8H2O: C,
69.33; H, 5.09; N, 7.35. Found: C, 69.38; H, 5.11; N, 7.24.
(6R*,6aR*)-12-Allyl-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one
(8b)
from 5 — In the general procedure A, K2CO3 (754 mg, 5.44 mmol), allyl bromide (2.70 mL, 31.1 mmol),
5 (501 mg, 1.56 mmol), and DMF (10.0 mL) were used. The reaction time was 30 min. After
column-chromatography, 8b (540 mg, 96%) was obtained. 8b: mp 202—203˚C (decomp., yellow prisms,
recrystallized from EtOAc). IR (KBr): 3400, 3110, 1665, 1562, 1457, 1333, 1140, 1087, 1017, 789, 747
cm-1. 1H-NMR (DMSO-d6) ꢀ: 5.16 (1H, dd, J=17.1, 1.5 Hz), 5.22 (1H, dd, J=10.3, 1.5 Hz), 5.35 (1H, s),
5.36 (1H, dd, J=16.3, 5.4 Hz), 5.53 (1H, dd, J=16.3, 5.4 Hz), 6.07—6.16 (1H, m), 6.84 (1H, s), 7.39 (1H,
t, J=8.1 Hz), 7.40 (1H, t, J=8.1 Hz), 7.50 (1H, t, J=7.5 Hz), 7.55 (1H, t, J=7.5 Hz), 7.75 (1H, d, J=8.1
Hz), 7.77 (1H, d, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz), 8.19 (1H, d, J=8.1 Hz). MS m/z: 364 and 362 (M+).
Anal. Calcd for C21H15N2O2Cl: C, 69.52; H, 4.17; N, 7.72. Found: C, 69.49; H, 4.17; N, 7.41.
(6R*,6aR*)-6-Chloro-6a-hydroxy-12-propargyl-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one
(8c) from 5 — In the general procedure A, K2CO3 (44.2 mg, 0.32 mmol), propargyl bromide (0.14 mL,
1.83 mmol), 5 (29.5 mg, 0.09 mmol), and DMF (2.0 mL) were used. The reaction time was 1 h. After
column-chromatography, 8c (16.5 mg, 50%) was obtained. 8c: mp 248˚C (decomp., dark yellow powder,
1
recrystallized from EtOAc–hexane). IR (KBr): 3359, 3286, 1653, 1475, 1086, 791, 746 cm-1. H-NMR
(DMSO-d6) ꢀ: 3.48 (1H, t, J=2.5 Hz), 5.38 (1H, d, J=1.5 Hz, collapsed to s on addition of D2O), 5.66 (1H,
dd, J=17.9, 2.5 Hz), 5.78 (1H, dd, J=17.9, 2.5 Hz), 6.91 (1H, d, J=1.5 Hz, disappeared on addition of
D2O), 7.41 (1H, td, J=7.7, 1.3 Hz), 7.45 (1H, td, J=7.7, 1.3 Hz), 7.56 (1H, td, J=7.7, 1.3 Hz), 7.56 (1H,
td, J=7.7, 1.3 Hz), 7.81 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=7.7 Hz), 7.84 (1H, d, J=7.7 Hz), 8.19 (1H, d,
J=7.7 Hz). MS m/z: 362 and 360 (M+). Anal. Calcd for C21H13N2O2Clꢀ1/2H2O: C, 68.21; H, 3.82; N, 7.58.
Found: C, 68.00; H, 3.73; N, 7.33.
(6R*,6aR*)-12-Benzyl-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one (8d)
from 5 — In the general procedure A, K2CO3 (619 mg, 4.48 mmol), benzyl bromide (3.10 mL, 25.6
mmol), 5 (413 mg, 1.28 mmol), and DMF (8.0 mL) were used. The reaction time was 75 min. After
column-chromatography, 8d (411 mg, 78%) was obtained. 8d: mp 219.5—221.5 ˚C (yellow prisms,
1
recrystallized from EtOAc–hexane). IR (KBr): 3356, 1685, 1577, 1473, 1142, 771 cm-1. H-NMR
(DMSO-d6) ꢀ: 5.41 (1H, s), 5.99 (1H, d, J=15.8 Hz), 6.18 (1H, d, J=15.8 Hz), 6.91 (1H, br s, disappeared
on addition of D2O), 7.26 (1H, t, J=7.2 Hz), 7.30 (2H, t, J=7.2 Hz), 7.37 (2H, d, J=7.2 Hz), 7.40 (1H, td,
J=7.4, 1.2 Hz), 7.42 (1H, td, J=7.4, 1.2 Hz), 7.42 (1H, td, J=7.4, 1.2 Hz), 7.54 (1H, td, J=7.4, 1.2 Hz),
7.64 (1H, d, J=7.4 Hz), 7.75 (1H, d, J=7.4 Hz), 7.86 (1H, d, J=7.4 Hz), 8.19 (1H, d, J=7.4 Hz). MS m/z:
414 and 412 (M+). Anal. Calcd for C25H17N2O2Clꢀ1/2H2O: C, 71.17; H, 4.30; N, 6.64. Found: C, 71.32; H,

HETEROCYCLES, Vol. 80, No. 2, 2010
1033
4.25; N, 6.49.
(6R*,6aR*)-6-Chloro-6a-hydroxy-12-phenethyl-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one
(8e) from 5 — In the general procedure A, K2CO3 (45.0 mg, 0.33 mmol), phenethyl bromide (0.25 mL,
1.86 mmol), 5 (30.0 mg, 0.09 mmol), and DMF (2.0 mL) were used. The reaction time was 1 h. After
column-chromatography, 8e (22.6 mg, 57%) was obtained. 8e: mp 183—184 ˚C (yellow needles,
1
recrystallized from EtOAc–hexane). IR (KBr): 3361, 1655, 1477, 1146, 746 cm-1. H-NMR (DMSO-d6)
ꢀ: 3.19 (2H, td, J=13.8, 6.8 Hz), 4.83 (1H, ddd, J=13.8, 8.6, 6.8 Hz ), 5.04 (1H, ddd, J=13.8, 8.6, 6.8 Hz),
5.36 (1H,s), 6.84 (1H, br s, disappeared on addition of D2O), 7.21 (1H, br t, J=7.4 Hz), 7.30 (2H, t, J=7.4
Hz), 7.35 (2H, d, J=7.4 Hz), 7.37 (1H, t, J=7.5 Hz), 7.41 (1H, t, J=7.5 Hz), 7.43 (1H, t, J=7.5 Hz), 7.58
(1H, t, J=7.5 Hz), 7.73 (1H, d, J=7.5 Hz), 7.84 (1H, d, J=7.5 Hz), 7.86 (1H, d, J=7.5 Hz), 8.15 (1H, d,
J=7.5 Hz). MS m/z: 428 and 426 (M+). Anal. Calcd for C26H19N2O2Clꢀ1/2H2O: C, 71.64; H, 4.62; N, 6.43.
Found: C, 71.86; H, 4.43; N, 6.40.
(6R*,6aR*)-6-Chloro-12-(E)-cinnamyl-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-
one (8f) from 5 — In the general procedure A, K2CO3 (157 mg, 1.14 mmol), cinnamyl bromide (0.79 mL,
6.49 mmol), 5 (105 mg, 0.32 mmol), and DMF (6.0 mL) were used. The reaction time was 1 h. After
column-chromatography, 8f (137 mg, 96%) was obtained. 8f: mp 205—208˚C (brown plates,
1
recrystallized from EtOAc—hexane). IR (KBr): 3390, 1648, 1579, 1473, 1145, 757 cm-1. H-NMR
(DMSO-d6) ꢀ: 5.36 (1H, d, J=1.5 Hz, collapsed to s on addition of D2O), 5.51 (1H, ddd, J=16.5, 5.9, 1.2
Hz), 5.71 (1H, ddd, J=16.5, 5.9, 1.2 Hz), 6.53 (1H, dt, J=16.5, 5.9 Hz), 6.69 (1H, d, J=16.5 Hz), 6.85
(1H, d, J=1.5 Hz, disappeared on addition of D2O), 7.22 (1H, t, J=7.4 Hz), 7.28 (2H, t, J=7.4 Hz), 7.37
(2H, d, J=7.4 Hz), 7.40 (1H, td, J=7.6, 1.2 Hz), 7.41 (1H, td, J=7.6, 1.2 Hz), 7.50 (1H, td, J=7.6, 1.2 Hz),
7.55 (1H, td, J=7.6, 1.2 Hz), 7.80 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=7.6 Hz), 8.20
(1H, d, J=7.6 Hz). MS m/z: 440 and 438 (M+). Anal. Calcd for C27H19N2O2Clꢀ1/2EtOAc: C, 72.12; H,
4.80; N, 5.80. Found: C, 71.84; H, 4.68; N, 5.83.
(6R*,6aR*)-6-Chloro-12-cyanomethyl-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one
(8g) from 5 — In the general procedure A, K2CO3 (159 mg, 1.15 mmol), chloroacetonitrile (0.42 mL,
6.56 mmol), 5 (106 mg, 0.33 mmol), and DMF (3.0 mL) were used. The reaction time was 15 min. After
column-chromatography, 8g (72.6 mg, 62%) was obtained. 8g: mp 249.5—251.5˚C (decomp., yellow
prisms, recrystallized from EtOAc). IR (KBr): 3350, 1648, 1615, 1574, 1472, 1345, 1083, 797, 780, 747
cm-1. 1H-NMR (DMSO-d6) ꢀ: 5.41 (1H, d, J=1.5 Hz, collapsed on addition of D2O), 5.99 (1H, d, J=18.1
Hz), 6.10 (1H, d, J=18.1 Hz), 6.95 (1H, d, J=1.5 Hz, disappeared on addition of D2O), 7.42 (1H, td,
J=7.6, 1.1 Hz), 7.49 (1H, td, J=7.6, 1.1 Hz), 7.57 (1H, td, J=7.6, 1.1 Hz), 7.62 (1H, td, J=7.6, 1.1 Hz),
7.82 (1H, d, J=7.6 Hz), 7.85 (1H, d, J=7.6 Hz), 7.95 (1H, d, J=7.6 Hz), 8.21 (1H, d, J=7.6 Hz). Anal.
Calcd for C20H12N3O2Cl: C, 66.40; H, 3.34; N, 11.61. Found: C, 66.70; H, 3.33; N, 11.37.

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(6R*,6aR*)-6-Chloro-12-N,N-dimethylcarbamoylmethyl-6a-hydroxy-5,6,6a,12-tetrahydroin-dolo-
[2,3-a]carbazole-5-one (8h) from 5 — In the general procedure A, K2CO3 (89.2 mg, 0.65 mmol),
N,N-dimethyl-2-chloroacetamide (0.66 mL, 6.46 mmol), 5 (104 mg, 0.32 mmol), and DMF (6.0 mL)
were used. The reaction time was 1.5 h. After column-chromatography, 8h (118 mg, 90%) was obtained.
8h: mp 257—258˚C (decomp., dark brown prisms, recrystallized from MeOH). IR (KBr): 3410, 1670,
1
1647, 1583, 1481, 775, 756 cm-1. H-NMR (DMSO-d6) ꢀ: 2.90 (3H, s), 3.24 (3H, s), 5.31 (1H, s), 5.64
(1H, d, J=16.8 Hz), 5.81 (1H, d, J=16.8 Hz), 6.83 (1H, s, disappeared on addition of D2O), 7.37 (1H, td,
J=7.5, 1.2 Hz), 7.39 (1H, td, J=7.5, 1.2 Hz), 7.47 (1H, td, J=7.5, 1.2 Hz), 7.52 (1H, td, J=7.5, 1.2 Hz),
7.66 (1H, d, J=7.5 Hz), 7.72 (1H, d, J=7.5 Hz), 7.82 (1H, d, J=7.5 Hz), 8.17 (1H, d, J=7.5 Hz). MS m/z:
409 and 407 (M+). Anal. Calcd for C22H18N3O3Clꢀ1/4H2O: C, 64.08; H, 4.52; N, 10.19. Found: C, 64.21;
H, 4.52; N, 10.00.
(6R*,6aR*)-6-Chloro-6a-hydroxy-12-methoxycarbonylmethyl-5,6,6a,12-tetrahydroindolo[2,3-a]-
carbazole-5-one (8i) from 5 — In the general procedure A, K2CO3 (68.2 mg, 0.48 mmol), methyl
bromoacetate (0.16 mL, 1.61 mmol), 5 (51.8 mg, 0.16 mmol), and DMF (2.0 mL) were used. The
reaction time was 30 min. After column-chromatography, 8i (45.8 mg, 72%) was obtained. 8i: mp
223—224.5˚C (decomp., brown prisms, recrystallized from EtOAc). IR (KBr): 3415, 1749, 1655, 1479,
1
1342, 1086, 1012, 800, 777, 756 cm-1. H-NMR (DMSO-d6) ꢀ: 3.74 (3H, s), 5.36 (1H, s), 5.58 (1H, d,
J=18.0 Hz), 5.81 (1H, d, J=18.0 Hz), 6.84 (1H, s, disappeared on addition of D2O), 7.39 (1H, t, J=7.8
Hz), 7.42 (1H, t, J=7.8 Hz), 7.48—7.56 (2H, m), 7.73 (1H, d, J=7.8 Hz), 7.79 (1H, d, J=7.8 Hz), 7.82
(1H, d, J=7.8 Hz), 8.18 (1H, d, J=7.8 Hz). Anal. Calcd for C21H15N2O4Cl: C, 63.89; H, 3.83; N, 7.10.
Found: C, 63.65; H, 3.84; N, 6.89.
(6R*,6aR*)-6-Chloro-6a-hydroxy-12-[2-(methoxycarbonyl)ethyl]-5,6,6a,12-tetrahydroindolo[2,3-a]-
carbazole-5-one (8j) from 5 — In the general procedure A, K2CO3 (68.7 mg, 0.47 mmol), methyl
acrylate (0.29 mL, 3.16 mmol), 5 (50.8 mg, 0.16 mmol), and DMF (3.0 mL) were used. The reaction time
was 30 min. After column-chromatography, 8j (17.0 mg, 26%) and the unreacted 5 (18.5 mg, 36%) were
obtained in the order of elution. 8j: mp 216.5—218˚C (decomp., yellow powder, recrystallized from
EtOAc). IR (KBr): 3431, 1714, 1680, 1583, 1479, 1439, 1215, 1146, 773, 754 cm-1. 1H-NMR (DMSO-d6)
ꢀ: 3.02 (2H, t, J=7.2 Hz), 3.58 (3H, s), 4.86 (1H, dt, J=14.2, 7.2 Hz), 5.14 (1H, dt, J=14.2, 7.2 Hz), 5.33
(1H, d, J=1.5, collapsed on addition of D2O), 6.79 (1H, d, J=1.5, disappeared on addition of D2O), 7.39
(1H, td, J=7.7, 1.2 Hz), 7.40 (1H, td, J=7.7, 1.2 Hz), 7.51 (1H, td, J=7.7, 1.2 Hz), 7.55 (1H, td, J=7.7,
1.2 Hz), 7.77 (1H, d, J=7.7 Hz), 7.83 (1H, d, J=7.7 Hz), 7.87 (1H, d, J=7.7 Hz), 8.17 (1H, d, J=7.7 Hz).
Anal. Calcd for C22H17N2O4Cl: C, 64.59; H, 4.19; N, 6.66. Found: C, 64.63; H, 4.19; N, 6.85.
(6R*,6aR*)-6-Chloro-6a-hydroxy-12-phenacyl-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one
(8k) from 5 — In the general procedure A, K2CO3 (172 mg, 1.25 mmol), phenacyl bromide (1.42 g, 7.10

HETEROCYCLES, Vol. 80, No. 2, 2010
1035
mmol), 5 (115 mg, 0.33 mmol), and DMF (6.0 mL) were used. The reaction time was 1.5 h. After
column-chromatography, 8k (152 mg, 97%) was obtained. 8k: mp 217—219˚C (yellow plates,
1
recrystallized from EtOAc—hexane). IR (KBr): 3372, 1697, 1579, 1475, 1230, 752 cm-1. H-NMR
(DMSO-d6) ꢀ: 5.36 (1H, d, J=1.4 Hz, collapsed to s on addition of D2O), 6.38 (1H, d, J=18.3 Hz), 6.52
(1H, d, J=18.3 Hz), 6.84 (1H, d, J=1.4 Hz, disappeared on addition of D2O), 7.34 (1H, td, J=7.6, 1.3 Hz),
7.42 (1H, td, J=7.6, 1.3 Hz), 7.45 (1H, td, J=7.6, 1.3 Hz), 7.47 (1H, td J=7.6, 1.3 Hz), 7.51 (1H, d, J=8.3
Hz), 7.67 (2H, t, J=8.3 Hz), 7.76 (1H, d, J=7.6 Hz), 7.77 (1H, t, J=8.3 Hz), 7.80 (1H, d, J=7.6 Hz), 8.17
(1H, d, J=7.6 Hz), 8.18 (1H, d, J=7.6 Hz), 8.21 (1H, d, J=7.6 Hz). MS m/z: 442 and 440 (M+). Anal.
Calcd for C26H17N2O3Cl: C, 70.83; H, 3.89; N, 6.35. Found: C, 70.67; H, 3.91; N, 6.24.
(6R*,6aR*)-12-(3-Bromopropyl)-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-
5-one (8l) from 5 — In the general procedure A, K2CO3 (45.7 mg, 0.33 mmol), 1,3-dibromopropane
(0.19 mL, 1.89 mmol), 5 (30.5 mg, 0.09 mmol), and DMF (2.0 mL) were used. The reaction time was 50
min. After column-chromatography, 8l (18.9 mg, 45%) was obtained. 8l: mp 148—150˚C (orange plates,
1
recrystallized from CHCl3). IR (KBr): 3400, 1651, 1581, 1479, 1080, 758 cm-1. H-NMR (CDCl3) ꢀ:
2.51—2.63 (2H, m), 3.12 (1H, br s, disappeared on addition of D2O), 3.46 (1H, ddd, J=10.4, 6.9, 5.7 Hz),
3.52 (1H, ddd, J=10.4, 6.9, 5.7 Hz), 4.76 (1H, s), 4.80 (1H, ddd, J=14.2, 7.6, 6.5 Hz), 5.02 (1H, dt,
J=14.4, 7.1 Hz), 7.36 (1H, td, J=7.8, 1.1 Hz), 7.41 (1H, td, J=7.8, 1.1 Hz), 7.50 (1H, td, J=7.8, 1.1 Hz),
7.52 (1H, td, J=7.8, 1.1 Hz), 7.62 (1H, d, J=7.8 Hz), 7.73 (1H, d, J=7.8 Hz), 7.92 (1H, d, J=7.8 Hz), 8.39
81
(1H, d, J=7.8 Hz). HR-MS (FAB+): Calcd for C21H16N2O2 Br37Cl: 447.0112. Found: 447.0084.
79
81
C21H16N2O2 Br37Cl: 445.0132. Found: 445.0109. C21H16N2O2 Br35Cl: 445.0141. Found: 445.0109.
79
C21H16N2O2 Br35Cl: 443.0162. Found: 443.0132. Anal. Calcd for C21H16N2O2BrClꢀ1/4H2O: C, 56.27; H,
3.71; N, 6.25. Found: C, 56.33; H, 3.65; N, 5.95.
(6R*,6aR*)-6-Chloro-12-[3-(ethoxycarbonyl)propyl]-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]-
carbazole-5-one (8m) from 5 — General Procedure B: A solution of 5 (28.9 mg, 0.09 mmol) in
anhydrous DMF (2.0 mL) was added to 60% NaH (3.7 mg, 0.09 mmol) at 0°C with stirring under argon
atmosphere. After additional stirring at rt, ethyl 4-bromobutylate (0.26 mL, 1.79 mmol) was added and
the mixture was stirred fot 1 h at rt. After addition of EtOAc, the whole was washed successively with
H2O, brine, and dried over Na2SO4, then evaporated under reduced pressure to leave an oil, which was
column-chromatographed repeatedly on SiO2 with EtOAc–hexane (1:2, v/v) to give 8m (23.2 mg, 59%)
and unreacted 5 (2.80 mg, 10%) in the order of elution. 8m: (brown viscous oil). IR (film): 3367, 1707,
1
1672, 1579, 1481, 1200, 750 cm-1. H-NMR (CDCl3) ꢀ: 1.15 (3H, t, J=7.1 Hz), 2.17 (2H, q, J=7.1 Hz),
2.38— 2.43 (2H, m), 4.04 (2H, q, J=7.1 Hz), 4.70 (1H, dt, J=14.2, 7.1 Hz), 4.91 (1H, dt, J=14.2, 7.1 Hz),
5.32 (1H, d, J=1.3 Hz, collapsed to s on addition of D2O), 6.82 (1H, d, J=1.3 Hz, disappeared on addition
of D2O), 7.39 (1H, t, J=7.8 Hz), 7.41 (1H, t, J=7.8 Hz), 7.52 (1H, td, J=7.8, 1.2 Hz), 7.55 (1H, td, J=7.8,

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1.2 Hz), 7.76 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=7.8 Hz), 7.84 (1H, d, J=7.8 Hz), 8.19 (1H, d, J=7.8 Hz).
37
35
HR-MS m/z: Calcd for C24H21N2O4 Cl: 438.1160. Found: 438.1140. C24H21N2O4 Cl: 436.1189. Found:
436.1184.
(6R*,6aR*)-6-Chloro-12-[(Z)-3-chloroallyl]- (8n) and -12-[(E)-3-chloroallyl]-6a-hydroxy-5,6,6a,12-
tetrahydroindolo[2,3-a]carbazole-5-one (8o) from 5 — In the general procedure B, 5 (63.5 mg, 0.20
mmol), anhydrous DMF (4.0 mL), 60% NaH (7.90 mg, 0.20 mmol), and (E,Z) mixture of
1,3-dichloropropene (0.36 mL, 3.94 mmol) were used. After repeated column-chromatography, 8n (32.9
mg, 42%), 8o (18.4 mg, 24%), and unreacted 5 (9.10 mg, 14%) were obtained in the order of elution. 8n:
mp 207—209˚C (decomp., yellow powder, recrystallized from EtOAc). IR (KBr): 3381, 1649, 1616,
1581, 1475, 802, 754, 739 cm-1. 1H-NMR (DMSO-d6) ꢀ: 5.34 (1H, s), 5.48 (1H, ddd, J=16.1, 6.5, 2.3 Hz),
5.73 (1H, ddd, J=16.1, 6.5, 2.3 Hz), 6.17 (1H, q, J=6.5 Hz), 6.63 (1H, dt, J=6.5, 2.3 Hz), 6.84 (1H, br s,
disappeared on addition of D2O), 7.40 (1H, td, J=7.6, 1.1 Hz), 7.43 (1H, td, J=7.6, 1.1 Hz), 7.53 (1H, td,
J=7.6, 1.1 Hz), 7.55 (1H, td, J=7.6, 1.1 Hz), 7.68 (1H, d, J=7.6 Hz), 7.78 (1H, d, J=7.6 Hz), 7.84 (1H, d,
J=7.6 Hz), 8.19 (1H, d, J=7.6 Hz). MS m/z: 400, 398, and 396 (M+). Anal. Calcd for
C21H14N2O2Cl2ꢀ1/4H2O: C, 62.78; H, 3.64; N, 6.97. Found: C, 63.00; H, 3.58; N, 6.95. 8o: brown oil. IR
(film): 3417, 1653, 1577, 1471, 1146, 748 cm-1. 1H-NMR (DMSO-d6) ꢀ: 5.34 (1H, d, J=1.5 Hz, collapsed
to s on addition of D2O), 5.36 (1H, ddd, J=13.4, 6.8, 1.7 Hz), 5.53 (1H, ddd, J=13.4, 6.8, 1.7 Hz), 6.30
(1H, dt, J=13.4, 6.8 Hz), 6.74 (1H, d, J=13.4 Hz), 6.81 (1H, d, J=1.5 Hz, disappeared on addition of
D2O), 7.40 (1H, td, J=7.6, 1.1 Hz), 7.42 (1H, t, J=7.6 Hz), 7.52 (1H, td, J=7.6, 1.1 Hz), 7.55 (1H, td,
J=7.6, 1.1 Hz), 7.80 (1H, d, J=7.6 Hz), 7.84 (1H, d, J=7.6 Hz), 7.87 (1H, d, J=7.6 Hz), 8.18 (1H, d,
37
37
J=7.6 Hz). HR-MS m/z: Calcd for C21H14N2O2 Cl2: 400.0374. Found: 400.0339. C21H14N2O2 Cl35Cl:
35
398.0403. Found: 398.0406. C21H14N2O2 Cl2: 396.0433. Found: 396.0449.
(6R*,6aR*)-12-Acetyl-6-chloro-6a-hydroxy-5,6,6a,12-tetrahydroindolo[2,3-a]carbazole-5-one (8p)
from 5 — In the general procedure B, 5 (47.4 mg, 0.15 mmol), anhydrous DMF (2.0 mL), 60% NaH
(5.80 mg, 0.15 mmol), and acetyl chloride (0.21 ml, 2.94 mmol) were used. After repeated
column-chromatography, 8p (22.2 mg, 41%) and unreacted 5 (10.9 mg, 23%) were obtained in the order
of elution. 8p: mp 209—211˚C (decomp., yellow fine needles, recrystallized from EtOAc). IR (KBr):
1
3332, 1695, 1685, 1571, 1284, 1263, 760 cm-1. H-NMR (DMSO-d6) ꢀ: 2.92 (3H, s), 5.31 (1H, s), 7.08
(1H, br s, disappeared on addition of D2O), 7.44 (1H, td, J=7.9, 1.3 Hz ), 7.52 (1H, t, J=7.9 Hz), 7.58 (1H,
td, J=7.9, 1.3 Hz), 7.61 (1H, td, J=7.9 Hz), 7.80 (1H, d, J=7.9 Hz), 7.83 (1H, d, J=7.9 Hz), 8.22 (2H, d,
J=7.9 Hz). MS m/z: 366 and 364 (M+). Anal. Calcd for C20H13N2O3ClꢀEtOAc: C, 63.65; H, 4.67; N, 6.19.
Found: C, 63.42; H, 4.53; N, 6.37.
12-n-Butyl-6-cyano-5-hydroxyindolo[2,3-a]carbazole (9a) from 8a — General Procedure C: NaCN
(239 mg, 5.72 mmol) was added to a solution of 8a (61.5 mg, 0.16 mmol) in DMF (4.0 mL) and H2O (2.0

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1037
mL), and the mixture was stirred for 0.5 h at rt. After addition of H2O, the whole was extracted with
EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to
leave an oil, which was column-chromatographed on SiO2 with EtOAc–hexane (1:3, v/v) to give 9a (48.9
mg, 85%). 9a: mp 251—253˚C (pale gray powder, recrystallized from EtOAc). IR (KBr): 3311, 2206,
1
1705, 1630, 1576, 1414, 737 cm-1. H-NMR (DMSO-d6) ꢀ: 0.81 (3H, t, J=7.4 Hz), 1.28 (2H, sex, J=7.4
Hz), 1.82 (2H, quin, J=7.4 Hz), 4.86 (2H, t, J=7.4 Hz), 7.27 (1H, t, J=7.7 Hz), 7.31 (1H, t, J=7.7 Hz),
7.48 (1H, t, J=7.7 Hz), 7.50 (1H, t, J=7.7 Hz), 7.72 (1H, d, J=7.7 Hz), 7.74 (1H, d, J=7.7 Hz), 8.39 (1H,
d, J=7.7 Hz), 8.45 (1H, d, J=7.7 Hz), 10.7 (1H, s, disappeared on addition of D2O), 11.5 (1H, s,
disappeared on addition of D2O). MS m/z: 353 (M+). Anal. Calcd for C23H19N3O: C, 78.16; H, 5.42; N,
11.89. Found: C, 77.95; H, 5.47; N, 11.69.
12-Allyl-6-cyano-5-hydroxyindolo[2,3-a]carbazole (9b) from 8b — In the general procedure C, NaCN
(1.50 g, 28.9 mmol), 8b (349 mg, 0.96 mmol), DMF (18.0 mL), and H2O (9.0 mL) were used. After
column-chromatography, 9b (294 mg, 91%) was obtained. 9b: mp 236.5—238˚C (decomp., pale gray
cotton fibers, recrystallized from Et2O–hexane). IR (KBr): 3440, 2110, 1625, 1458, 1416, 1354, 1168,
1
916, 736 cm-1. H-NMR (DMSO-d6) ꢀ: 4.75 (1H, d, J=17.4 Hz), 5.06 (1H, d, J=10.5 Hz), 5.49—5.53
(2H, m), 6.10—6.20 (1H, m), 7.26 (1H, t, J=7.6 Hz), 7.33 (1H, t, J=7.6 Hz), 7.47 (1H, t, J=7.6 Hz), 7.49
(1H, t, J=7.6 Hz), 7.69 (2H, d, J=7.6 Hz), 8.39 (1H, d, J=7.6 Hz), 8.44 (1H, d, J=7.6 Hz), 10.73 (1H, br s,
disappeared on addition of D2O), 11.53 (1H, s, disappeared on addition of D2O). MS m/z: 337 (M+). Anal.
Calcd for C22H15N3O: C, 78.32; H, 4.48; N, 12.46. Found: C, 78.08; H, 4.47; N, 12.29.
6-Cyano-5-hydroxy-12-propargylindolo[2,3-a]carbazole (9c) from 8c — In the general procedure C,
NaCN (112 mg, 2.29 mmol), 8c (27.5 mg, 0.08 mmol), DMF (2.0 mL), and H2O (1.0 mL) were used.
After column-chromatography, 9c (18.5 mg, 72%) was obtained. 9c: mp 268—270˚C (decomp., pale
brown powder, recrystallized from CHCl3). IR (KBr): 3454, 3263, 2206, 1633, 1460, 1242, 742 cm-1.
1H-NMR (DMSO-d6) ꢀ: 3.30—3.31 [1H, m, clearly appeared at 3.23 (1H, t, J=2.2 Hz) on addition of
D2O], 5.75 (2H, d, J=2.2 Hz), 7.28 (1H, t, J=7.8 Hz), 7.36 (1H, t, J=7.8 Hz), 7.49 (1H, t, J=7.8 Hz), 7.54
(1H, t, J=7.8 Hz), 7.72 (1H, d, J=7.8 Hz), 7.81 (1H, d, J=7.8 Hz), 8.39 (1H, d, J=7.8 Hz), 8.46 (1H, d,
J=7.8 Hz), 10.8 (1H, s, disappeared on addition of D2O), 11.7 (1H, s, disappeared on addition of D2O).
MS m/z: 335 (M+). Anal. Calcd for C22H13N3Oꢀ1/2H2O: C, 76.73; H, 4.10; N, 12.20. Found: C, 76.86; H,
3.91; N, 11.96.
12-Benzyl-6-Cyano-5-hydroxyindolo[2,3-a]carbazole (9d) from 8d — In the general procedure C,
NaCN (123 mg, 3.06 mmol), 8d (32.9 mg, 0.08 mmol), DMF (2.0 mL), and H2O (1.0 mL) were used.
After column-chromatography, 9d (30.1 mg, 98%) was obtained. 9d: mp 243—244˚C (decomp., gray
1
needles, recrystallized from EtOAc). IR (KBr): 3282, 2200, 1635, 1576, 1169, 739 cm-1. H-NMR
(DMSO-d6) ꢀ: 6.13 (2H, s), 7.14—7.25 (5H, m), 7.27 (1H, td, J=7.7, 1.7 Hz), 7.32 (1H, td, J=7.7, 1.7

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Hz), 7.43 (1H, td, J=7.7, 1.7 Hz), 7.46 (1H, td, J=7.7, 1.7 Hz), 7.64 (1H, d, J=7.7 Hz), 7.65 (1H, d, J=7.7
Hz), 8.40 (1H, d, J=7.7 Hz), 8.46 (1H, d, J=7.7 Hz), 10.8 (1H, br s, disappeared on addition of D2O),
11.7 (1H, s, disappeared on addition of D2O). MS m/z: 387 (M+). Anal. Calcd for C26H17N3O: C, 80.60; H,
4.42; N, 10.85. Found: C, 80.46; H, 4.47; N, 10.78.
12-Benzyl-6-cyano-5-hydroxyindolo[2,3-a]carbazole (9d) from 13 — Crushed NaOH powder (675 mg,
16.9 mmol) was added to a solution of 13 (9.6 mg, 0.02 mmol) in ethylene glycol (3.0 mL), and the
mixture was refluxed for 2 h with stirring. After addition of H2O, the whole was extracted with EtOAc.
The extract was washed with H2O and brine, dried over Na2SO4, and evaporated under reduced pressure
to leave an oil, which was column-chromatographed on SiO2 with EtOAc–hexane (1:3, v/v) to give 9d
(5.7 mg, 62%).
6-Cyano-5-hydroxy-12-phenethylindolo[2,3-a]carbazole (9e) from 8e — In the general procedure C,
NaCN (117 mg, 2.27 mmol), 8e (32.3 mg, 0.08 mmol), DMF (2.0 mL), and H2O (1.0 mL) were used.
After column-chromatography, 9e (25.8 mg, 85%) was obtained. 9e: mp 255—257˚C (decomp., pale
brown powder, recrystallized from acetone). IR (KBr): 3282, 2212, 1628, 1410, 1238, 742, 700 cm-1.
1H-NMR (DMSO-d6) ꢀ: 3.10 (2H, t, J=7.2 Hz), 5.12 (2H, t, J=7.2 Hz ), 7.04—7.08 (1H, m), 7.11 (4H, d,
J=4.4 Hz), 7.26 (1H, t, J=7.9 Hz), 7.27 (1H, t, J=7.9 Hz), 7.38 (1H, td, J=7.9, 0.98 Hz), 7.48 (1H, td,
J=7.9, 0.98 Hz), 7.54 (1H, d, J=7.9 Hz), 7.72 (1H, d, J=7.9 Hz), 8.34 (1H, d, J=7.9 Hz), 8.45 (1H, d,
J=7.9 Hz), 10.7 (1H, br s, disappeared on addition of D2O), 11.6 (1H, s, disappeared on addition of D2O).
MS m/z: 401 (M+). Anal. Calcd for C27H19N3OꢀH2O: C, 77.31; H, 5.05; N, 10.02. Found: C, 77.37; H,
4.85; N, 9.81.
12-(E)-Cinnamyl-6-Cyano-5-hydroxyindolo[2,3-a]carbazole (9f) from 8f — In the general procedure
C, NaCN (159 mg, 3.23 mmol), 8f (47.3 mg, 0.10 mmol), DMF (3.0 mL), and H2O (1.5 mL) were used.
After column-chromatography, 9f (35.8 mg, 80%) was obtained. 9f: yellow viscous oil. IR (film): 3467,
1
2216, 1631, 1414, 1173, 741 cm-1. H-NMR (DMSO-d6) ꢀ: 5.66 (2H, d, J=5.1 Hz), 6.44 (1H, d, J=15.9
Hz), 6.56 (1H, dt, J=15.9, 5.1 Hz), 7.17 (1H, t, J=7.4 Hz), 7.22 (2H, t, J=7.4 Hz), 7.26 (2H, d, J=7.4 Hz),
7.28 (1H, t, J=7.7 Hz), 7.34 (1H, t, J=7.7 Hz), 7.47 (1H, td, J=7.7, 0.88 Hz), 7.50 (1H, td, J=7.7, 0.88
Hz), 7.71 (1H, d, J=7.7 Hz), 7.77 (1H, d, J=7.7 Hz), 8.41 (1H, d, J=7.7 Hz), 8.45 (1H, d, J=7.7 Hz), 10.8
(1H, br s, disappeared on addition of D2O), 11.6 (1H, s, disappeared on addition of D2O). HR-MS m/z:
Calcd for C28H19N3O: 413.1528. Found: 413.1529.
6-Cyano-12-cyanomethyl-5-hydroxyindolo[2,3-a]carbazole (9g) from 8g — In the general procedure
C, NaCN (1.45 g, 27.8 mmol), 8g (333 mg, 0.93 mmol), DMF (24.0 mL), and H2O (12.0 mL) were used.
After column-chromatography, 9g (168 mg, 54%) was obtained. 9g: mp 272.5—275˚C (decomp., pale
gray powder, recrystallized from EtOAc–hexane). IR (KBr): 3300, 2230, 1630, 1580, 1414, 1320, 1178,
902, 745 cm-1. 1H-NMR (DMSO-d6) ꢀ: 6.17 (2H, s), 7.31 (1H, t, J=8.0 Hz), 7.42 (1H, t, J=8.0 Hz), 7.53

HETEROCYCLES, Vol. 80, No. 2, 2010
1039
(1H, t, J=8.0 Hz), 7.56 (1H, t, J=8.0 Hz), 7.73 (1H, d, J=8.0 Hz), 7.88 (1H, d, J=8.0 Hz), 8.41 (1H, d,
J=8.0 Hz), 8.47 (1H, d, J=8.0 Hz), 10.93 (1H, s, disappeared on addition of D2O), 11.90 (1H, s,
disappeared on addition of D2O). MS m/z: 336 (M+). Anal. Calcd for C21H12N4Oꢀ1/8H2O: C, 74.49; H,
3.65; N, 16.55. Found: C, 74.70; H, 3.62; N, 16.25.
6-Cyano-12-N,N-dimethylcarbamoylmethyl-5-hydroxyindolo[2,3-a]carbazole (9h) from 8h — In the
general procedure C, NaCN (119 mg, 2.43 mmol), 8h (33.1 mg, 0.81 mmol), DMF (2.0 mL), and H2O
(1.0 mL) were used. After column-chromatography, 9h (29.6 mg, 95%) was obtained. 9h: mp >300˚C
1
(gray powder, recrystallized from MeOH). IR (KBr): 3311, 2216, 1651, 1635, 1412, 742 cm-1. H-NMR
(DMSO-d6) ꢀ: 2.86 (3H, s), 3.33 (3H, s), 5.75 (2H, s), 7.27 (1H, t, J=7.8 Hz), 7.31 (1H, t, J=7.8 Hz), 7.45
(1H, t, J=7.8 Hz), 7.47 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=7.8 Hz), 7.67 (1H, d, J=7.8 Hz), 8.38 (1H, d,
J=7.8 Hz), 8.45 (1H, d, J=7.8 Hz), 10.7 (1H, br s, disappeared on addition of D2O), 11.5 (1H, s,
disappeared on addition of D2O). HR-MS m/z: Calcd for C23H18N4O2: 382.1430. Found: 382.1421.
6-Cyano-5-hydroxy-12-methoxycarbonylmethyl-
(9i)
and
12-Carboxymethyl-6-cyano-5-
hydroxyindolo[2,3-a]carbazole (9q) from 8i — In the general procedure C, NaCN (395 mg, 7.64 mmol),
8i (100 mg, 0.25 mmol), DMF (4.0 mL), and H2O (2.0 mL) were used. After column-chromatography, 9i
(15.5 mg, 17%) was obtained. The aqueous layer was made acidic by adding aq. 8% HCl and extracted
with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced
pressure to leave a residue, which was column-chromatographed on SiO2 with CHCl3–MeOH–AcOH
(46:5:0.5, v/v) to give 9q (38.6 mg, 43%). 9i: mp >300 ˚C (pale gray powder, recrystallized from
1
EtOAc–hexane). IR (KBr): 3410, 2220, 1720, 1630, 1458, 1417, 1240, 1177, 737 cm-1. H-NMR
(DMSO-d6) ꢀ: 3.69 (3H, s), 5.80 (2H, s), 7.28 (1H, t, J=7.3 Hz), 7.35 (1H, t, J=7.3 Hz), 7.45—7.52 (2H,
m), 7.65 (1H, d, J=7.3 Hz), 7.66 (1H, d, J=7.3 Hz), 8.39 (1H, d, J=7.7 Hz), 8.44 (1H, d, J=7.7 Hz),
10.79 (1H, s, disappeared on addition of D2O), 11.65 (1H, s, disappeared on addition of D2O). HR-MS
m/z: Calcd for C22H15N3O3: 369.1114. Found: 369.1114. 9q: mp 198—200˚C (decomp., gray powder,
recrystallized from MeOH–H2O). IR (KBr): 3367, 2208, 1724, 1631, 1462, 1412, 1323, 1173, 741, 428
1
cm-1. H-NMR (DMSO-d6) ꢀ: 5.64 (2H, s), 7.26 (1H, t, J=7.8 Hz), 7.33 (1H, t, J=7.8 Hz), 7.41—7.51
(2H, m), 7.63 (1H, d, J=8.3 Hz), 7.65 (1H, d, J=8.3 Hz), 8.38 (1H, d, J=7.8 Hz), 8.43 (1H, d, J=7.8 Hz),
10.74 (1H, br s, disappeared on addition of D2O), 11.70 (1H, s, disappeared on addition of D2O). MS m/z:
355 (M+). Anal. Calcd for C21H13N3O3ꢀ1/2H2O: C, 69.22; H, 3.87; N, 11.53. Found: C, 69.20; H, 3.92; N,
11.27.
12-(3-Bromopropyl)-6-cyano- (9l) and 6-Cyano-12-(3-cyanopropyl)-5-hydroxyindolo[2,3-a]-
carbazole (9r) from 8l — In the general procedure C, NaCN (107 mg, 2.18 mmol), 8l (32.2 mg, 0.07
mmol), DMF (2.0 mL), and H2O (1.0 mL) were used. After column-chromatography, 9l (6.9 mg, 23%)
and 9r (6.1 mg, 23%) were obtained in the order of elution. 9l: (brown viscous oil). IR (film): 3423, 2210,

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HETEROCYCLES, Vol. 80, No. 2, 2010
1633, 1454, 1246, 746 cm-1. 1H-NMR (DMSO-d6) ꢀ: 2.40 (2H, q, J=6.9 Hz), 3.56 (2H, t, J=6.9 Hz), 4.95
(2H, t, J=6.9 Hz), 7.28 (1H, t, J=7.7 Hz), 7.34 (1H, t, J=7.7 Hz), 7.49 (1H, td, J=7.7, 1.2 Hz), 7.53 (1H,
td, J=7.7, 1.2 Hz), 7.73 (1H, d, J=7.7 Hz), 7.78 (1H, d, J=7.7 Hz), 8.40 (1H, d, J=7.7 Hz), 8.46 (1H, d,
J=7.7 Hz), 10.8 (1H, br s, disappeared on addition of D2O), 11.6 (1H, s, disappeared on addition of D2O).
HR-MS m/z: Calcd for C22H16N3O81Br: 419.0456. Found: 419.0491. C22H16N3O79Br: 417.0477. Found:
1
417.0451. 9r: (brown viscous oil). IR (film): 3342, 2262, 2210, 1633, 1452, 1400, 756 cm-1. H-NMR
(DMSO-d6) ꢀ: 2.19 (2H, q, J=7.3 Hz), 2.61 (2H, t, J=7.3 Hz), 4.89 (2H, t, J=7.3 Hz), 7.28 (1H, t, J=8.0
Hz), 7.34 (1H, t, J=7.7 Hz), 7.49 (1H, t, J=8.0 Hz), 7.53 (1H, t, J=8.0 Hz), 7.72 (1H, d, J=8.0 Hz), 7.77
(1H, d, J=8.0 Hz), 8.40 (1H, d, J=8.0 Hz), 8.46 (1H, d, J=8.0 Hz), 10.8 (1H, s, disappeared on addition
of D2O), 11.6 (1H, s, disappeared on addition of D2O). HR-MS m/z: Calcd for C23H16N4O: 364.1324.
Found: 364.1324.
6-Cyano-12-[3-(ethoxycarbonyl)propyl]-5-hydroxyindolo[2,3-a]carbazole (9m) from 8m — In the
general procedure C, NaCN (301 mg, 5.83 mmol), 8m (84.8 mg, 0.19 mmol), DMF (4.0 mL), and H2O
(2.0 mL) were used. After column-chromatography, 9m (53.3 mg, 72%) was obtained. 9m: mp
258—260˚C (pale brown powder, recrystallized from CHCl3). IR (KBr): 3292, 2210, 1711, 1633, 1242,
1
1169, 741 cm-1. H-NMR (DMSO-d6) ꢀ: 1.07 (3H, t, J=7.1 Hz), 2.13 (2H, quin, J=7.2 Hz), 2.41 (2H, t,
J=7.2 Hz), 3.95 (2H, q, J=7.1 Hz), 4.86 (2H, t, J=7.2 Hz), 7.28 (1H, t, J=7.8 Hz), 7.33 (1H, t, J=7.8 Hz),
7.49 (1H, td, J=7.8, 1.7 Hz), 7.51 (1H, td, J=7.8, 1.7 Hz), 7.72 (1H, d, J=7.8 Hz), 7.76 (1H, d, J=7.8 Hz),
8.39 (1H, d, J=7.8 Hz), 8.46 (1H, d, J=7.8 Hz), 10.7 (1H, br s, disappeared on addition of D2O), 11.6 (1H,
s, disappeared on addition of D2O). MS m/z: 411 (M+). Anal. Calcd for C25H21N3O3ꢀ1/2H2O: C, 71.41; H,
5.27; N, 9.99. Found: C, 71.58; H, 5.28; N, 9.78.
12-(Z)-3-Chloroallyl- (9n) and 12-(E)-3-Chloroallyl)-6-cyano-5-hydroxyindolo[2,3-a]carbazole (9o)
from 8n and 8o — In the general procedure C, NaCN (208 mg, 4.25 mmol), about 2:1 mixture of 8n and
8o (56.2 mg, 0.14 mmol), DMF (3.0 mL), and H2O (1.5 mL) were used. After repeated
column-chromatography, 9n (21.5 mg, 41%) and 9o (7.3 mg, 14%) were obtained in the order of elution.
9n: >300 ˚C (gray powder, recrystallized from EtOAc). IR (KBr): 3454, 2208, 1628, 1412, 742 cm-1.
1H-NMR (DMSO-d6) ꢀ: 5.64 (2H, d, J=6.6 Hz), 6.12 (1H, q, J=6.6 Hz), 6.58 (1H, d, J=6.6 Hz), 7.28 (1H,
t, J=7.9 Hz), 7.35 (1H, t, J=7.9 Hz), 7.48 (1H, t, J=7.9 Hz), 7.52 (1H, t, J=7.9 Hz), 7.59 (1H, d, J=7.9
Hz), 7.70 (1H, d, J=7.9 Hz), 8.40 (1H, d, J=7.9 Hz), 8.46 (1H, d, J=7.9 Hz), 10.8 (1H, br s, disappeared
on addition of D2O), 11.7 (1H, s, disappeared on addition of D2O). HR-MS (FAB+) m/z: Calcd for
C22H15N3O37Cl: 374.0874. Found: 374.0908. C22H15N3O35Cl: 372.0903. Found: 372.0892. 9o: (pale pink
1
viscous oil). IR (film): 3448, 2218, 1630, 1464, 1417, 742 cm-1. H-NMR (DMSO-d6) ꢀ: 5.53 (2H, br d,
J=6.3 Hz), 6.25 (1H, dt, J=12.9, 6.3 Hz), 6.51 (1H, d, J=12.9 Hz), 7.28 (1H, t, J=7.8 Hz), 7.34 (1H, t,
J=7.8 Hz), 7.48 (1H, td, J=7.8, 1.7 Hz), 7.51 (1H, td, J=7.8, 1.7 Hz), 7.71 (1H, d, J=7.8 Hz), 7.77 (1H, d,

HETEROCYCLES, Vol. 80, No. 2, 2010
1041
J=7.8 Hz), 8.40 (1H, d, J=7.8 Hz), 8.45 (1H, d, J=7.8 Hz), 10.8 (1H, br s, disappeared on addition of
D2O), 11.6 (1H, br s, disappeared on addition of D2O). HR-MS m/z: Calcd for C22H14N3O37Cl: 373.0796.
Found: 373.0790. C22H14N3O35Cl: 371.0825.Found: 371.0819.
6-Cyano-5-hydroxyindolo[2,3-a]carbazole (10) and (6R*,6aR*,11aR*)-6-chloro-11a-cyano-6a-
hydroxy-5,6,6a,11,11a,12-hexahydroindolo[2,3-a]carbazole-5-one (11) from 8p — In the general
procedure C, NaCN (109 mg, 2.23 mmol), 8p (27.1 mg, 0.74 mmol), DMF (2.0 mL), and H2O (1.0 mL)
were used. After repeated column-chromatography with EtOAc–hexane (1:2, v/v) and CHCl3–MeOH
(99:1, v/v), 10 (19.2 mg, 74%) and 11 (5.6 mg, 22%) were obtained in the order of elution. 10: mp
>300˚C (pale gray powder, recrystallized from CHCl3). IR (KBr): 3373, 2208, 1646, 1569, 1389, 1351,
1
1324, 1236, 743 cm-1. H-NMR (DMSO-d6) ꢀ: 7.25 (1H, td, J=0.9, 7.8 Hz), 7.28 (1H, d, J=7.8 Hz),
7.42—7.47 (2H, m), 7.73 (2H, ddd, J=0.9, 5.9, 6.7 Hz), 8.33 (1H, d, J=7.8 Hz), 8.39 (1H, d, J=7.8 Hz),
10.62 (1H, br s, disappeared on addition of D2O), 11.62 (1H, br s, disappeared on addition of D2O), 11.59
(1H, s, disappeared on addition of D2O). Anal. Calcd for C19H11N3O: C, 76.76; H, 3.73; N, 14.13. Found:
C, 76.81; H, 3.63; N, 14.12. 11: mp 231—233˚C (yellow prisms, recrystallized from CHCl3). IR (KBr):
1
3465, 2219 (very weak), 1673, 1468, 773 cm-1. H-NMR (DMSO-d6) ꢀ: 5.17 (1H, br s, disappeared on
addition of D2O), 6.79 (1H, d, J=7.7 Hz), 6.85 (1H, td, J=7.7, 1.2 Hz), 7.20 (1H, td, J=7.7, 1.2 Hz), 7.27
(1H, td, J=7.7, 1.2 Hz), 7.35 (1H, td, J=7.7, 1.2 Hz), 7.37 (1H, s, disappeared on addition of D2O), 7.42
(1H, s, disappeared on addition of D2O), 7.47 (1H, d, J=7.7 Hz), 7.63 (1H, d, J=7.7 Hz), 7.95 (1H, d,
J=7.7 Hz), 12.6 (1H, br s, disappeared on addition of D2O). HR-MS (FAB+) m/z: Calcd for
37
35
C13H12N3O2 Cl: 352.0667. Found: 352.0701. C13H12N3O2 Cl: 350.697. Found: 350.0703. Anal. Calcd
for C13H12N3O2Clꢀ1/2CHCl3: C, 57.20; H, 3.08; N, 10.26. Found: C, 56.94; H, 3.12; N, 9.99.
6-Cyano-5-hydroxyindolo[2,3-a]carbazole (10) from 8k — In the general procedure C, NaCN (11.2
mg, 3.23 mmol), 8k (47.3 mg, 0.10 mmol), DMF (2.0 mL), and H2O (0.1 mL) were used. After
column-chromatography, unreacted 8k (5.5 mg, 16%) and 10 (6.1 mg, 27%) were obtained in the order of
elution.
(5R*,6S*,6aR*,11aR*)-6-Chloro-11a-cyano-5,6a-dihydroxy-5,6,6a,11,11a,12-hexahydroindolo[2,3-
a]carbazole (12a) from 11 — NaBH4 (4.5 mg, 0.12 mmol) was added to a solution of 11 (14.1 mg, 0.04
mmol) in MeOH (2.0 mL), and the mixture was stirred for 1.5 h at rt. After addition of H2O, the whole
was extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave a residue, which was column-chromatographed on SiO2 with EtOAc–hexane
(1:3, v/v) to give 12a (6.6 mg, 47%) and unreacted 11 (7.5 mg, 53 %) in the order of elution. 12a: yellow
viscous oil. IR (film): 3342, 2235 (almost invisible), 1655, 1585, 748 cm-1. 1H-NMR (DMSO-d6) ꢀ: 3.93
(1H, d, J=8.5 Hz), 5.06 (1H, t, J=8.5 Hz, collapsed to d on addition of D2O), 5.72 (1H, t, J=8.5 Hz,
disappeared on addition of D2O), 6.83 (1H, d, J=7.5 Hz), 6.87 (1H, td, J=7.5, 1.3 Hz), 7.06 (1H, t, J=7.5

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HETEROCYCLES, Vol. 80, No. 2, 2010
Hz), 7.13 (1H, s, disappeared on addition of D2O), 7.15 (1H, s, disappeared on addition of D2O), 7.19 (1H,
td, J=7.5, 1.3 Hz), 7.21 (1H, td, J=7.5, 1.3 Hz), 7.48 (1H, d, J=7.5 Hz), 7.51 (1H, d, J=7.5 Hz), 7.81 (1H,
d, J=7.5 Hz), 11.3 (1H, s, disappeared on addition of D2O). HR-MS (FAB+) m/z: Calcd for
37
35
C19H15N3O2 Cl: 354.0824. Found: 354.0871. C19H15N3O2 Cl: 352.0853. Found: 352.0846.
(5R*,6S*,6aR*,11aR*)-6-Chloro-11a-cyano-5,12-diacetyl-6a-hydroxy-5,6,6a,11,11a,12-hexahydro-
indolo[2,3-a]carbazole (12b) from 12a — Ac2O (1.0 mL) was added to a solution of 12a (10.0 mg, 0.03
mmol) in pyridine (2.0 mL), and the mixture was stirred for 14 h at rt. After evaporation of the solvent
under reduced pressure, the residue was column-chromatographed on SiO2 with EtOAc–hexane (1:3, v/v)
to give 12b (3.7 mg, 30%) and unreacted 12a (5.7 mg, 57 %) were obtained in the order of elution. 12b:
1
pale yellow oil. IR (film): 3390, 1749, 1705, 1610, 1373, 744 cm-1. H-NMR (DMSO-d6 + 5% D2O,
90°C) ꢀ: 2.13 (3H, s), 2.96 (3H, s), 4.41 (1H, d, J=8.3 Hz), 6.56 (1H, d, J=8.3 Hz), 6.90 (1H, td, J=7.5,
1.7 Hz), 6.97 (1H, d, J=7.5 Hz), 7.24 (1H, td, J=7.5, 1.7 Hz), 7.37—7.42 (2H, m), 7.48 (1H, d, J=7.5 Hz),
37
7.52 (1H, td, J=7.5, 1.7 Hz), 7.94 (1H, d, J=7.5 Hz). HR-MS (FAB+) m/z: Calcd for C23H19N3O4 Cl:
35
438.1035. Found: 438.1040. C23H19N3O4 Cl: 436.1004. Found: 436.1051.
12-Benzyl-6-cyano-5-methoxyindolo[2,3-a]carbazole (13) from 9d — Excess amount of ethereal
CH2N2 was added to a solution of 9d (88.0 mg, 0.22 mmol) in MeOH (6.0 mL) and the mixture was
stirred for 1.5 h at rt. The solvent was evaporated under reduced pressure to leave an oil, which was
column-chromatographed on SiO2 with CHCl3–MeOH–28% aq. NH3 (46:0.5:0.05, v/v) to give 13 (75.1
mg, 82%). 13: mp 228.0—228.5˚C (colorless needles, recrystallized from EtOAc). IR (KBr): 3338, 2208,
1
1628, 1560, 1390, 741 cm-1. H-NMR (DMSO-d6) ꢀ: 4.26 (3H, s), 6.16 (2H, s), 7.19 (2H, t, J=7.7 Hz),
7.20 (1H, t, J=7.7 Hz ), 7.24 (1H, d, J=7.7 Hz), 7.26 (1H, d, J=7.7 Hz), 7.33 (1H, t, J=7.4 Hz), 7.38 (1H,
t, J=7.4 Hz), 7.50 (1H, td, J=7.4, 1.9 Hz), 7.51 (1H, td, J=7.4, 1.9 Hz), 7.69 (1H, d, J=7.4 Hz), 7.71 (1H,
d, J=7.4 Hz), 8.29 (1H, d, J=7.4 Hz), 8.48 (1H, d, J=7.4 Hz), 11.9 (1H, s, disappeared on addition of
D2O). MS m/z: 401 (M+). Anal. Calcd for C27H19N3Oꢀ1/2H2O: C, 79.00; H, 4.91; N, 10.24. Found: C,
79.09; H, 4.90; N, 9.99.
6-(Z)-Aminomethylidene-12-n-butyl-5,6,11,12-tetrahydroindolo[2,3-a]carbazole-5-one (15a) from
9a — General Procedure D: A 1.0 M solution of DIBAL in toluene (2.7 mL, 2.67 mmol) was added to a
solution of 9a (31.4 mg, 0.09 mmol) in anhydrous THF (2.0 mL) under ice cooling and the mixture was
stirred under N2 atmosphere at rt for 3 h. After addition of MeOH and aq. Rochelle salt, the whole was
extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was column-chromatographed on SiO2 with CHCl3–MeOH (99:1,
v/v) to give 15a (23.0 mg, 73%). 15a: mp 170—172˚C (decomp., dark yellow prisms, recrystallized from
1
EtOAc). IR (KBr): 3400, 1628, 1610, 1577, 1560, 1421, 737 cm-1. H-NMR (DMSO-d6) ꢀ: 0.82 (3H, t,
J=7.4 Hz), 1.29 (2H, sex, J=7.4 Hz), 1.81 (2H, quin, J=7.4 Hz), 4.77 (2H, t, J=7.4 Hz), 7.14 (1H, td,

HETEROCYCLES, Vol. 80, No. 2, 2010
1043
J=7.8, 1.2 Hz), 7.22 (1H, t, J=7.8 Hz), 7.29 (1H, t, J=7.8 Hz), 7.31 (1H, td, J=7.8, 1.2 Hz), 7.62 (1H, d,
J=7.8 Hz), 7.63 (1H, d, J=7.8 Hz), 8.02 (1H, d, J=7.8 Hz), 8.47 (1H, d, J=7.8 Hz), 8.60 (1H, br t, J=8.2
Hz, disappeared on addition of D2O), 8.84 (1H, dd, J=13.8, 8.2 Hz, collapsed to s on addition of D2O),
11.1 (1H, s, disappeared on addition of D2O), 12.0 (1H, dd, J=13.8, 8.2 Hz, disappeared on addition of
D2O). HR-MS m/z: Calcd for C23H21N3O: 355.1685. Found: 355.1693.
6-(Z)-Aminomethylidene-12-n-benzyl-5,6,11,12-tetrahydroindolo[2,3-a]carbazole-5-one (15b) from
9d — In the general procedure D, DIBAL (1.4 mL, 1.45 mmol), 9d (18.7 mg, 0.05 mmol), THF (2.0 mL)
were used. The reaction time was 19 h. After column-chromatography, 15b (6.9 mg, 47%) was obtained.
15b: mp 207—209˚C (decomp., yellow powder, recrystallized from EtOAc). IR (KBr): 3450, 1628, 1610,
1
1577, 1560, 1410, 742 cm-1. H-NMR (DMSO-d6) ꢀ: 6.04 (2H, s), 7.12—7.28 (9H, m), 7.53 (1H, d,
J=7.5 Hz), 7.54 (1H, d, J=7.5 Hz), 8.04 (1H, d, J=7.5 Hz), 8.49 (1H, dd, J=7.5, 1.7 Hz), 8.68 (1H, br t,
J=8.4 Hz, disappeared on addition of D2O), 8.88 (1H, dd, J=13.6, 8.4 Hz, collapsed to s on addition of
D2O), 11.2 (1H, s, disappeared on addition of D2O), 12.1 (1H, dd, J=13.6, 8.4 Hz, disappeared on
addition of D2O). HR-MS (FAB+) m/z: Calcd for C26H20N3O: 390.1606. Found: 390.1631.
6-Acetoaminomethylidene-12-n-butyl-5,6,11,12-tetrahydroindolo[2,3-a]carbazole-5-one (16) from
15a — Ac2O (0.75 mL) was added to a solution of 15a (16.1 mg, 0.05 mmol) in pyridine (1.5 mL), and
the mixture was stirred for 1.5 h at rt. After evaporation of the solvent under reduced pressure, the residue
was column-chromatographed on SiO2 successively with EtOAc–hexane (1:3, v/v) and
CHCl3–MeOH–28% aq. NH3 (46:0.5:0.05, v/v) to give 16 (15.7 mg, 87%). 16: red viscous oil. IR (film):
1
3354, 1685, 1620, 1610, 1552, 1415, 1273, 752, 739 cm-1. H-NMR (CDCl3) ꢀ: 0.92 (3H, t, J=7.5 Hz),
1.37 (2H, sex, J=7.5 Hz), 1.81 (2H, quin, J=7.5 Hz), 2.28 (3H, s), 4.02 (2H, t, J=7.5 Hz), 7.17 (1H, dd,
J=7.3, 1.6 Hz), 7.25 (1H, td, J=7.3, 1.6 Hz), 7.30 (1H, td, J=7.3, 1.6 Hz), 7.32 (1H, td, J=7.3, 1.6 Hz),
7.34 (1H, td, J=7.3, 1.6 Hz), 7.42 (1H, d, J=7.3 Hz), 7.91 (1H, d, J=7.3 Hz), 8.24 (1H, s, disappeared on
addition of D2O), 8.44 (1H, dd, J=7.3, 1.6 Hz), 8.59 (1H, d, J=10.4 Hz, collapsed to s on addition of
D2O), 13.4 (1H, d, J=10.4 Hz, disappeared on addition of D2O). HR-MS m/z: Calcd for C25H23N3O2:
397.1791. Found: 397.1790.
X-Ray Crystallographic Analysis of 9a and 11— All measurements were made on a Rigaku AFC5R
diffract meter with graphite monochromated Cu-Kꢀ radiation (ꢁ=1.54178 Å). The structure was solved
by direct methods using MITHRIL.9 Non-hydrogen atoms were refined anisotropically.
9a: a single crystal (0.20x0.20x0.30 mm) was obtained by recrystallization from EtOAc. Crystal data:
–
C23H19N3OꢀC4H8O2, M=441.53, triclinic, space group P1 (#2), a=10.626 (1)Å, b=12.276 (1)Å, c=9.912
(1)Å, ꢀ=104.474 (8)°, ꢂ=110.402 (9)°, ꢃ=81.84 (1)°, V=1431.8 (2)Å3, Z=2, Dcalc=1.252 g/cm3,
F(000)=468, and μ(CuKꢀ)=6.26 cm–1. The final cycle of full-matrix least-squares refinement was based
on 2807 observed reflections (I >3.00ꢄ (I), 2ꢅ < 120.2°) and 386 variable parameters. The final

1044
HETEROCYCLES, Vol. 80, No. 2, 2010
refinement converged with R=0.049 and Rw=0.059.
11: a single crystal (0.20x0.10x0.20 mm) was obtained by recrystallization from CHCl3. Crystal data:
C19H12N3O2, M=349.78, monoclinic, space group P21/a (#14), a=14.408 (5)Å, b=14.096 (3)Å, c=17.928
(4)Å, ꢀ=93.60 (2)°, V=3634 (2)Å3, Z=8, Dcalc=1.278 g/cm3, F(000)=1440, and μ(CuKꢁ)=20.08 cm–1.
The final cycle of full-matrix least-squares refinement was based on 2139 observed reflections (I >3.00ꢂ
(I), 2ꢃ < 120.4°) and 583 variable parameters. The final refinement converged with R=0.085 and
Rw=0.091.
9a
11
Table 1. Positional parameters and B (eq) for 9a
atom
x
y
z
B (eq)
atom
C (25)
C (26)
C (27)
H (1)
x
y
z
B (eq)
5.7 (1)
O (1)
O (2)
O (3)
N (1)
N (2)
N (3)
C (1)
0.1896 (2)
0.8726 (2)
0.7980 (3)
0.0708 (2)
0.2986 (2)
–0.0727 (2)
0.4849 (2)
0.5501 (3)
0.5126 (3)
0.4083 (2)
0.3407 (2)
0.2318 (2)
0.1590 (2)
0.0627 (2)
0.0400 (2)
–0.0494 (2)
–0.1435 (2)
–0.2120 (3)
–0.1906 (3)
–0.0988 (2)
–0.0274 (2)
0.1126 (2)
0.2103 (2)
0.3802 (2)
–0.0130 (2)
0.3138 (2)
0.4179 (2)
0.4549 (3)
0.5509 (4)
0.7723 (5)
0.0654 (1)
0.2458 (2)
0.0789 (2)
0.5274 (2)
0.4020 (1)
0.1111 (2)
0.3141 (2)
0.2129 (2)
0.1118 (2)
0.1100 (2)
0.2114 (2)
0.2423 (2)
0.1778 (2)
0.2318 (2)
0.3508 (2)
0.4286 (2)
0.4178 (2)
0.5135 (2)
0.6193 (2)
0.6326 (2)
0.5367 (2)
0.4148 (2)
0.3601 (2)
0.3122 (2)
0.1663 (2)
0.5187 (2)
0.5752 (2)
0.6848 (2)
0.7498 (3)
0.2105 (4)
0.2830 (2)
0.4463 (2)
0.4049 (3)
0.3777 (2)
0.6128 (2)
–0.0436 (2)
0.7977 (3)
0.8240 (3)
0.7237 (3)
0.5931 (3)
0.5630 (2)
0.4405 (2)
0.3048 (2)
0.2019 (2)
0.2369 (2)
0.1542 (2)
0.0126 (3)
–0.0309 (3)
0.0626 (3)
0.2020 (3)
0.2456 (3)
0.3728 (2)
0.4755 (2)
0.6663 (2)
0.0641 (3)
0.6928 (3)
0.6672 (3)
0.7781 (3)
0.7514 (5)
0.6095 (4)
5.17 (7)
6.8 (1)
9.5 (1)
4.45 (7)
4.22 (7)
6.4 (1)
4.9 (1)
5.4 (1)
5.2 (1)
4.6 (1)
3.99 (8)
3.86 (8)
4.01 (8)
3.86 (3)
3.77 (8)
3.92 (8)
4.6 (1)
5.4 (1)
5.5 (1)
5.1 (1)
4.11 (8)
3.90 (8)
3.85 (8)
4.11 (8)
4.53 (9)
4.3 (1)
4.5 (1)
5.3 (1)
7.9 (2)
7.6 (2)
0.8209 (3)
0.8428 (5)
0.7667 (9)
0.509 (2)
0.623 (3)
0.557 (3)
0.384 (2)
–0.157 (2)
–0.274 (3)
–0.242 (3)
–0.081 (2)
0.100 (3)
0.141 (3)
0.342 (2)
0.221 (2)
0.387 (3)
0.500 (2)
0.493 (3)
0.377 (3)
0.578 (4)
0.506 (3)
0.636 (3)
0.784 (4)
0.818 (5)
0.690 (4)
0.8414
0.1822 (2)
0.0413 (4)
–0.0363 (6)
0.389 (2)
0.213 (2)
0.044 (2)
0.038 (2)
0.342 (2)
0.505 (2)
0.687 (2)
0.706 (2)
0.590 (2)
0.023 (2)
0.516 (2)
0.560 (2)
0.586 (2)
0.522 (2)
0.667 (2)
0.729 (2)
0.822 (3)
0.769 (3)
0.706 (3)
0.294 (3)
0.169 (3)
0.194 (3)
0.1026
0.4815 (3)
0.2759 (6)
0.1729 (8)
0.869 (3)
0.915 (3)
0.740 (3)
0.528 (3)
–0.052 (3)
–0.126 (3)
0.028 (3)
0.267 (3)
0.449 (3)
0.199 (3)
0.805 (3)
0.670 (2)
0.563 (3)
0.674 (2)
0.881 (3)
0.779 (3)
0.837 (4)
0.657 (4)
0.750 (4)
0.661 (4)
0.677 (4)
0.585 (4)
0.2341
13.3 (3)
21.5 (5)
5.95 (2)
6.40 (2)
6.28 (2)
5.15 (1)
5.09 (1)
6.00 (1)
6.98 (2)
5.72 (1)
5.73 (2)
6.84 (2)
5.66 (1)
5.14 (1)
5.93 (2)
4.98 (1)
7.68 (2)
6.35 (2)
10.11 (3)
8.47 (2)
8.73 (2)
12.09 (4)
12.49 (4)
9.56 (3)
15.7
H (2)
H (3)
H (4)
C (2)
H (5)
C (3)
H (6)
C (4)
H (7)
C (5)
H (8)
C (6)
H (9)
C (7)
H (10)
H (11)
H (12)
H (13)
H (14)
H (15)
H (16)
H (17)
H (18)
H (19)
H (20)
H (21)
H (22)
H (23)
H (24)
H (25)
H (26)
H (27)
C (8)
C (9)
C (10)
C (11)
C (12)
C (13)
C (14)
C (15)
C (16)
C (17)
C (18)
C (19)
C (20)
C (21)
C (22)
C (23)
C (24)
0.9349
0.0096
0.3072
15.7
0.6867
–0.0365
0.1940
24.4
0.7501
–0.0229
0.0803
24.4
0.8146
–0.1098
0.1789
24.4

HETEROCYCLES, Vol. 80, No. 2, 2010
1045
Table 2. Positional parameters and B (eq) for 11
x
y
z
B (eq)
3.4 (6)
4.4 (6)
3.8 (8)
3.6 (8)
5.0 (9)
5.2 (3)
3.1 (8)
5 (1)
atom
C (14)
C (15)
C (16)
C (17)
C (18)
C (19)
H (1)
x
y
z
B (eq)
6 (1)
atom
0.7922 (7)
0.7431 (8)
0.870 (1)
0.648 (1)
0.721 (1)
0.9116 (3)
0.948 (1)
1.032 (2)
1.104 (1)
1.091 (1)
1.005 (1)
0.938 (1)
0.841 (1)
0.847 (1)
0.759 (1)
0.691 (1)
0.612 (1)
0.555 (1)
0.483 (1)
0.2474 (7)
0.0971 (7)
0.426 (1)
0.406 (1)
0.479 (1)
0.1120 (3)
0.409 (1)
0.455 (1)
0.418 (2)
0.339 (1)
0.295 (1)
0.329 (1)
0.206 (1)
0.212 (1)
0.102 (1)
0.258 (1)
0.263 (1)
0.196 (1)
0.225 (1)
0.6700 (7)
0.4962 (6)
0.5746 (1)
0.4915 (8)
0.6840 (9)
0.5924 (3)
0.595 (1)
0.599 (1)
0.649 (1)
0.692 (1)
0.685 (1)
0.635 (1)
0.6145 (8)
0.5558 (8)
0.5139 (9)
0.4996 (9)
0.4514 (8)
0.413 (1)
0.372 (2)
0.451 (1)
0.503 (1)
0.581 (1)
0.713 (1)
0.794 (1)
0.752 (1)
0.864 (7)
0.991 (7)
1.14 (1)
0.322 (1)
0.304 (2)
0.359 (1)
0.349 (1)
0.378 (1)
0.434 (1)
0.469 (6)
0.247 (7)
0.30 (1)
0.369 (1)
0.408 (1)
0.449 (1)
0.5217 (8)
0.5773 (9)
0.639 (1)
0.539 (6)
0.714 (6)
0.725 (8)
0.665 (6)
0.579 (5)
0.522 (6)
0.420 (9)
0.360 (5)
0.342 (6)
0.410 (8)
0.497 (6)
0.719 (5)
O (1)
O (2)
N (1)
N (2)
N (3)
Cl (1)
C (1)
C (2)
C (3)
C (4)
C (5)
C (6)
C (7)
C (8)
C (9)
C (10)
C (11)
C (12)
C (13)
6 (1)
3.9 (9)
2.7 (8)
2.8 (8)
3.4 (9)
–2 (3)
0 (2)
H (2)
5 (1)
H (3)
5 (4)
5 (1)
H (4)
0.450 (8)
0.501 (6)
0.230 (8)
0.13 (1)
0 (3)
1.147 (8)
1.044 (6)
0.889 (7)
0.56 (1)
3.3 (9)
3.5 (9)
2.5 (7)
2.7 (8)
4 (1)
H (5)
–2 (2)
1 (3)
H (6)
H (7)
5 (5)
H (8)
0.444 (6)
0.382 (7)
0.49 (1)
0.194 (6)
0.333 (7)
0.442 (9)
0.453 (6)
0.267 (6)
–1 (2)
1 (2)
H (9)
2.8 (7)
3.6 (8)
6 (1)
H (10)
H (11)
H (12)
2 (4)
0.658 (7)
0.804 (6)
–2 (2)
–1 (2)
7 (1)
REFERENCES AND NOTES
1. This report is Part 136 of a series entitled “The Chemistry of Indoles.” Part 135: K. Yamada, Y.
Tanaka, and M. Somei, Heterocycles, 2009, 79, 635.
2. Review: M. Somei, Heterocycles, 2008, 75, 1021 and references cited therein.
3. M. Somei, F. Yamada, Y. Suzuki, S. Ohmoto, and H. Hayashi, Heterocycles, 2004, 64, 483; H.
Hayashi, Y. Suzuki, and M. Somei, Heterocycles, 1999, 51, 1233; H. Hayashi, S. Ohmoto, and M.
Somei, Heterocycles, 1997, 45, 1647.
4. G. Knübel, L. K. Larsen, R. E. Moore, I. A. Levine, and G. M. L. Patterson, J. Antibiotics, 1990, 43,
1236.
5. Review of indigo dye: P. E. McGovern and R. H. Michel, Acc. Chem. Res., 1990, 23, 152 and
references cited therein.
6. Potent biological activity of 3 and its derivatives was reported: T. Ebara, T. Takahashi, and M.
Maeda, Abstract of Papers, No. 2, 120th Annual Meeting of Pharmaceutical Society of Japan, Gifu,
March, 2000, p. 136.
7. M. Somei, J. Kimura, and S. Takano, JP Patent 4248814 (2009).
8. The invention is now under application for a patent.
9. C. J. Gilmore, J. Appl. Cryst., 1984, 17, 42.