Syntheses of 4-amino-, 4-hydroxy-, and 4-nitro-1,3,4,5-tetrahydrobenz[cd]indoles and its bromination

Article abstract of DOI:10.3987/COM-13-S(S)74

Simple synthetic method for 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (6) is established from indole-3-carboxaldehyde (7). With 6 in hand, various derivatives of 4-amino-, 4-hydroxy- and 4-amino-4-hydroxymethyl-1,3,4,5-tetrahydrobenz[cd]indoles become readily available. Bromination of 6 afforded useful building blocks for further manipulation. Successful optical resolution of 6 by chiral column chromatography is also reported.

Full text of DOI:10.3987/COM-13-S(S)74

HETEROCYCLES, Vol. 88, No. 1, 2014
493
HETEROCYCLES, Vol. 88, No. 1, 2014, pp. 493 - 520. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2013, Accepted, 25th July, 2013, Published online, 29th July, 2013
DOI: 10.3987/COM-13-S(S)74
SYNTHESES
OF
4-AMINO-,
4-HYDROXY-,
AND
AND
ITS
4-NITRO-1,3,4,5-TETRAHYDROBENZ[cd]INDOLES
BROMINATION1,#
Kyoko Nakagawa, Naokatsu Aoki, Harunobu Mukaiyama, and Masanori
Somei*2
Faculty of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
Corresponding author: e-mail address: somei.home@topaz.plala.or.jp
Abstract – Simple synthetic method for 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole
(6) is established from indole-3-carboxaldehyde (7). With 6 in hand, various
derivatives of 4-amino-, 4-hydroxy- and 4-amino-4-hydroxymethyl-1,3,4,5-
tetrahydrobenz[cd]indoles become readily available. Bromination of 6 afforded
useful building blocks for further manipulation. Successful optical resolution of 6
by chiral column chromatography is also reported.
INTRODUCTION
In recent years, humanity is facing challenges such as the occurrence of food shortage, outbreak of yellow
sand and global warming, increasing number of patients with dementia and osteoporosis in an aging
society. Hoping to contribute to solve the challenges, we have recently created novel leads for potent root
growth promoters,3 anti-osteoporosis agents,4 !2-blockers,5 and inhibitors of platelet aggregation.6
R1 R2
N
CO2H
CO2H
NH2
R
NH2
OH
N
H
N
H
HN
(CH2)15
Me
NH
1
2
3
4
R3
R, Rn = an appropriate substituent
Figure 1
# Dedicated to the 77th birthday of Prof. Victor Snieckus.

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HETEROCYCLES, Vol. 88, No. 1, 2014
In our sequence of challenging study, we have also been much interested in developing biologically
active substance for Parkinson’s disease. Many research groups are working in this field and various
dopamine agonists have been developed. Among them, 4-(N,N-diisopropylamino)-1,3,4,5-tetrahydro-
benz[cd]indole derivatives 17 seems to be most effective (Figure 1). On the other hand, interesting
compounds such as 2,8 3,9 and 410 have been reported and they are expected to have characteristic
pharmacological effects.
R1 R2
N
R1 R2
OR
H2N
CO2H
N
OR3
NH
R3
NR5
NR
NH
R4
A
B
C
D
Figure 2
R, Rn = an appropriate substituent
Our Target Compounds
Taking the above compounds into consideration, as possible dopamine agonists and as our targets, we
settled 4-amino-1,3,4,5-tetrahydrobenz[cd]indoles (type A, shown in general formula, Figure 2),
4-amino-1,3,4,5-tetrahydrobenz[cd]indole-4-carboxylic acids (type B), 4-N-substituted-4-hydroxymethyl-
1,3,4,5-tetrahydrobenz[cd]indoles (type C), and 4-alkoxy-1,3,4,5-tetrahydrobenz[cd]indoles (type D) .
Type A has a part of skeleton of ergot alkaloids,11 whereas type B has a conformationally constrained
structure12 of tryptophans. Therefore, we could expect B is not only as a dopamine agonist but also as a
useful probe to obtain information about the bioactive conformation of a neuropeptide, such as
cholecystokinin (CCK),12 by incorporating B into the peptide. Type C is an analog of a potent dopamine
agonist, 4-N,N-dipropylamino-1,3,4,5-tetrahydrobenz[cd]indole7,13-15 (5, Scheme 1), and type D is its
oxa-analog. To meet our ends, we needed 4-nitro-1,3,4,5-tetrahydrobenz[cd]indole7,13-15 (6) as a common
synthetic intermediate.
RESULTS AND DISCUSSION
Many efforts have been devoted on developing a synthetic method for 6. The shortest synthetic route7
among thus far known7,13-15 is the one through indole-4-carboxaldehyde14 using expensive
2-methyl-3-nitrobenzoic acid as a starting material. Nevertheless it still requires nine steps with low
overall yield.7 On the other hand, we developed a simple four-step synthetic method15 for 6 from readily
available indole-3-carboxaldehyde (7). Furthermore, we succeeded in the syntheses of some of typical
target compounds. We also succeeded in the optical resolution of both enantiomers of 6 by chiral column
chromatography15 aiming at the syntheses of optically active derivatives. This is the full report of

HETEROCYCLES, Vol. 88, No. 1, 2014
495
previous
communications15a,b
in
addition
to
newly
developed
bromine
containing
4-nitro-1,3,4,5-tetrahydrobenz[cd]indole derivatives, which are useful for further manipulation.
I. A Simple Four-Step Synthesis of 4-Nitro-1,3,4,5-tetrahydrobenz[cd]indole (6)
We first prepared 4-methoxycarbonylindole-3-carboxaldehyde16a (8a) in 53% yield from 7 according to
our one pot procedure.16a Conversion of 8a into 4-methoxycarbonyl-3-(2-nitrovinyl)indole (9a) in 91%
yield was attained by aldol reaction with nitromethane. Subsequent reduction of 9a with NaBH4 in MeOH
afforded 4-methoxycarbonyl-3-(2-nitroethyl)indole (10a) in 83% yield. DIBAL reduction of 10a in THF
afforded 4-hydroxymethyl-3-(2-nitroethyl)indole (11) in 99% yield, nevertheless attempts to convert 9a
directly into 11 by LiBH4 reduction gave poor results giving 10a and 11 in 36% and 33% yields,
respectively.
NO2
NO2
R
R
R
CHO
CHO
one pot
Ref.16a
MeNO2
NaBH4
N
H
N
H
N
N
H
8 H
9
10
a) R = CO2Me
b) R = CN
7
a) R = CO2Me
b) R = CN
a) R = CO2Me
b) R = CN
DIBAL
one pot
one pot
NO2
1) DIBAL
2) H2O
NO2
NO2
NO2
1) DIBAL
2) H2O
3) NaBH4
HOCH2
CHO
PCC
NaBH4
Et3N
N
H
N
H
N
H
N
H
13
6
12
11
Zn (Hg)
N
NHR
NH2
R-X
base
N
H
N
H
N
H
15
14
5
a) R = COPh
c) R = CH2CH2Ph
propyl iodide
b) R = COCH2Ph d) R = CH2Et
Scheme 1

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HETEROCYCLES, Vol. 88, No. 1, 2014
Though oxidation of 11 with either active MnO2 or dimethyl sulfoxide–acetic anhydride afforded poor
results, pyridinium chlorochromate (PCC) in pyridine produced 3-(2-nitroethyl)indole-4-carboxaldehyde
(12) in 32% yield. Subsequent treatment of 12 with triethylamine in MeOH at reflux for 1 h afforded 13
in 87% yield. Reduction of 13 cleanly proceeded giving 6 in 80% yield with NaBH4 in MeOH.
Based on our previous findings,16 we realized the following one pot synthesis of
4-cyanoindole-3-carboxaldehyde16 (8b) from 7. In the first step, by the reaction with thallium
tris(trifluoroacetate)17 in trifluoroacetic acid (TFA), 7 was derived to (3-formylindol-4-yl)thallium
bis-trifluoroacetate,18 which was then treated with iodine and cuprous iodide affording
4-iodoindole-3-carboxaldehyde. It was finally converted to 8b in 72% overall yield.
Aldol reaction of 8b16b with nitromethane afforded nitrovinyl compound16b 9b in 88% yield. Subsequent
reduction of 9b with NaBH4 in MeOH gave nitroethyl compound16b 10b in 88% yield. Next, sequential
treatment of 10b, initially with diisobutylaluminum hydride (DIBAL) in anhydrous tetrahydrofuran
(THF) at reflux for 1 h, then with MeOH–water at reflux for 1 h, was found to produce
1,3-dihydro-4-nitrobenz[cd]indole (13) in 61% yield. Since 13 was already converted to 6 as described
above, the attempt at effecting one pot conversion of 10b to 6 was readily attained in 55% yield by adding
the NaBH4 reduction procedure to the above DIBAL and MeOH–water treatment of 10b. Consequently, a
simple four step synthetic method for 6 from 7 with an overall yield of 31% was established with the
originality rate19 of 60%. However, every attempt to convert 9b into 6 in one pot operation was
unsuccessful. Finally, 6 was reduced to 14 with Zn (Hg)–aq. HCl in MeOH at reflux in 99% yield.
N-Substituted derivatives of 14 were prepared as follows. Treatments of 14 with benzoyl chloride and
phenylacetyl chloride in the presence of Et3N afforded amide compounds, 15a and 15b, in 80% and 73%
yields, respectively. The reaction of 14 with phenethyl bromide in the presence of KI and K2CO3 as a base
provided 15c in 61% yield. Excess amount of propyl iodide converted 14 to N-propyl compound 15d and
N,N-dipropyl compound 5 in 4% and 87% yields, respectively, in the presence of K2CO3. In addition, the
compound 5 was derived from 15d in 80% yield by the reaction with propyl iodide in MeCN in the
presence of n-Bu4NBr and K2CO3.
Now that 6 is readily available from 7,15b 6 was converted to 16 by the procedure of Kruse and
co-worker6,7 in 81% yield (Scheme 2). Since 16 is known to isomerize to
1,2-dihydro-4-hydroxybenz[cd]indole having stabler naphthalene skeleton than indole isomer,6,7 Bucherer
reaction of 16 was investigated under careful control of reaction conditions using (NH4)2CO3 and KCN.
The results were the formation of !-aminonitrile 17 and spiro-hydantoin derivative 18 in 11% and 59%
yields, respectively. While, Strecker type reaction of 16 with NH4Cl and KCN produced 17 as major
product (56%) together with 10% yield of 19a. Although 19a was a crystalline solid, it was unstable and
gradually changed back to 16. Isolation of stable 4-acetoxy-4-cyano compound (19b) in 43% yield by the
treatment of 16 with KCN in AcOH, followed by the reaction of the resulting 19a with Ac2O and

HETEROCYCLES, Vol. 88, No. 1, 2014
497
O
NH
O
(NH4)2CO3
KCN
H2N
CN
HN
O
RO
CN
or
NH4Cl, KCN
NH
NH
NH
NH
16
17
18
19
a)
R = H
NaOH
30% H2O2
Ref. 7
b) R = Ac
6
O2N
R
KOt-Bu
HCHO
R
CH2OH
NH
H2N
CONH2
NH
H2N
CO2H
5
4
3
NaOH
H2O
2
1
Zn (Hg)
NH
NH
22
R = CH2OH
R = CH2OAc
23
20
21
a)
b)
a)
R = NH2
b)
R = NHAc
K2CO3, propyl iodide, MeCN
NaBH4
O
NR
O
N
NH
Ac2O
DMSO
CH2OR
NH
R
NHAc
NH
CH2OH
propionyl
chloride
NH
NH
24
26
27
R = H
R = Ac
25
a)
b)
a)
b)
R = COEt
a) R = CH2OCH2SMe
b) R = CHO
LiAlH4
R = H
c) R = CH=NOH
d) R = CN
OR1
OR
O
KH
propyl iodide
TsCl
NR2
NTs
NR
29
a)
b)
30
a) R = Ts
b) R = H
28
a) R1 = H,
b) R1 = H,
R
R
2 = H
2 = CH2Et
R
2 = CH2Et
R = H
R = Ts
c) R1 = Ac,
Scheme 2

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HETEROCYCLES, Vol. 88, No. 1, 2014
pyridine, clearly established the structure of 19a. Next, 17 was converted to amide 20 in 84% yield by the
reaction with 8% NaOH in the presence of 30% H2O2. Subsequent hydrolysis of 20 with 8% NaOH in
MeOH produced the desired type B amino acid 21 in a quantitative yield.
For the synthesis of the type C target compounds, 6 was initially treated with KOt-Bu and then with 37%
formalin to afford 22a in 73% yield. Treatment of 22a with Ac2O provided 22b in 98% yield. Reduction
of 22a with Zn (Hg)–aq. HCl gave 23a in 94% yield.
Treatment of 23a with Ac2O afforded N-acetyl compound 23b in 98% yield. Subsequent oxidation of 23b
with Ac2O-DMSO produced 24a and 24b in 32% and 56% yields, respectively. The reaction of 24b with
hydroxylamine afforded oxime derivative 24c as a single isomer in 95% yield. Further treatment of 24c
with Ac2O at reflux produced 52% yield of 4-acetylamino-4-cyano-1,3,4,5-tetrahydrobenz[cd]indole
(24d), which was alternatively produced by the reaction of 17 with Ac2O in 61% yield. The reaction of
23a with propyl iodide (2 equiv.) in the presence of K2CO3 produced the mono-propyl 25 and the target
compound 27a in 87 and 6% yields, respectively. Although under similar reaction conditions, the longer
reaction time improved the yield of 27a to 53%, various attempts at realizing exclusive production of 27a
were unsuccessful. While, treatment of 25 with propionyl chloride afforded 26a and 26b in 89 and 8%
yields, respectively. Subsequent reduction of 26a with LiAlH4 afforded 27a in 91% yield. Acetylation of
27a with Ac2O afforded 99% yield of 27b.
The type D target compound was produced as follows. Reduction of 16 with NaBH4 afforded
4-hydroxy-1,3,4,5-tetrahydrobenz[cd]indole (28a) in 99% yield. Treatment of 28a with NaH in DMF, and
then with propyl iodide produced 1-propyl compound 28b in 96% yield. The structural proof was
obtained through conversion of 28b into 28c in 75% yield by the reaction with Ac2O. Thus, comparison
1
of H-NMR data of 28b and 28c demonstrated that the C(4)-proton attached to 4-hydroxy group of 28b
shifted to lower magnetic field by ca. 1 ppm in the spectrum of 28c. The fact clearly proved that hydroxy
group was acetylated.
Successive treatment of 28a with NaH in DMF, and then with tosyl chloride produced N-tosyl (29a) and
N,O-ditosyl compound (29b) in 37 and 27% yields, respectively, together with 34% recovery of
unreacted starting material. Treatment of 29a with KH in DMF, and then with propyl iodide afforded
47% yield of the 4-propyloxy compound (30a), which was successfully converted to 30b in 86% yield by
hydrolysis with 8% NaOH.
II. Preparation of Bromine Containing Derivatives
It is well known that the introduction of bromine atom into 2 position of ergot alkaloids11 increases their
biological activity. In addition, organometallic chemistry makes it possible to convert C—Br bond to
C—C, C—N, C—O bonds, etc., for example by employing Heck reaction,20 Stille reaction,21 and so on.
Based on the facts, we tried to introduce bromine atom into the 1,3,4,5-tetrahydrobenz[cd]indole skeleton.

HETEROCYCLES, Vol. 88, No. 1, 2014
499
NO2
NO2
Br
N
NBS
AIBN
Br
NH
Br
6
1) NBS, AIBN
2) photo irradiation
E
31
NO2
4
NO2
NO2
Br
Br
NH
Br
Br
NH
NH
7
Br
8
H
Br
32
33
34
22a
KOt-Bu
Ac2O
NBS, AIBN
HCHO
NO2
O2N
CH2OH
Br
NH
O2N
CH2OH
O2N
CH2OH
Br
Br
Br
Br
NAc
Br
NH
N
Br
F
H
1) NBS, AIBN
35
36
41
Ac2O
2) photo irradiation
3) Ac2O
Ac2O
O2N
CH2OAc
O2N
CH2OAc
O2N
CH2OAc
Br
NH
O2N
CH2OAc
Br
Br
Br
Br
NR
NH
NH
Br
R = H
b) R = Ac
37
38
Br 39
40
a)
Scheme 3
The reaction of 6 with NBS in the presence of AIBN proceeded cleanly to afford 31 in 87% yield
(Scheme 3). Further treatment of 31 with NBS produced unstable intermediate that is deduced to be
2,2a-dibromo-4-nitro-2a,3,4,5-tetrahydrobenz[cd]indole (E). Therefore, after bromination of 31 with NBS,
the whole was irradiated with 100W mercury lamp in an aim to convert E to stable product. As a result,
2,6- (32), 2,8- (33), and 2,7-dibromo-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (34) were produced in the

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HETEROCYCLES, Vol. 88, No. 1, 2014
respective yields of 36%, 2%, and 14% together with unreacted 31 (9%).
Both compounds, 32 and 33, have a pair of ortho-coupled aromatic protons in their 1H-NMR spectra.
Therefore, one of them is a 2,6-dibromo and the other is a 2,8-dibromo compound. The conversion of 32
into 1-acetyl derivative (35) in 62% yield by the reaction with Ac2O proved its structure to be
1
2,6-dibromo compound. Thus, comparison of H-NMR data of 32 and 35 demonstrated that an
ortho-coupled C(8)-proton of 32 shifted to lower magnetic field by ca. 1 ppm by the anisotropy effect of
the introduced 1-acetyl group of 35, proving their assigned structures. In addition, the failure to introduce
an acetyl group into the 1-position of 33 with Ac2O even under forced conditions confirmed its assigned
structure because steric hindrance between C(8)-bromine atom and 1-acetyl group would explain the
results.
Similarly, bromination of 22a with NBS in the presence of AIBN cleanly afforded 36 in 92% yield. As in
the case of 31, further bromination of 36 with NBS produced unstable intermediate which is deduced to
be 2,2a-dibromo-4-hydroxymethyl-4-nitro-2a,3,4,5-tetrahydrobenz[cd]indole (F). Therefore, after
bromination of 36 with NBS, the whole was irradiated with 100W mercury lamp in an aim to convert F to
stable product. Furthermore the reaction mixture was acetylated by Ac2O-pyridine for enabling easy
separation of products. As a result, 2,6-dibromo- (37a) 1-acetyl-2,6-dibromo- (37b), 2-bromo- (38),
2,8-dibromo- (39), and 2,7-dibromo-4-acetoxymethyl-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (40) were
produced in 14%, 14%, 2%, 5%, and 2% yields, respectively.
Acetylation of 37a with Ac2O–pyridine afforded 37b in 80% yields. As in the case of 32 and 35, 37a and
37b showed the anisotropy effect on their C(8) protons by the introduced 1-acetyl group proving the
assigned structures. Proof of the structure of 38 was obtained by its production in 98% yield from 36 by
the acetylation with Ac2O. The structure of 40 was established by alternative synthesis. First,
hydroxymethylation of 34 to 41 was carried out in 60% yield by the treatment with 37% formalin in the
presence of KOt-Bu. Subsequent acetylation of 41 with Ac2O–pyridine afforded 74% yield of 40 which
was identical with the one obtained by the bromination of 36.
III. Optical Resolution15a of 4-Nitro-1,3,4,5-tetrahydrobenz[cd]indole (6)
With the desired compound 6 in hand, we next tried its
optical resolution on semi-preparative chiral column
chromatography, and finally found that optical isomers
of 6 were separable as shown in Chart 1 on Chiralpak
AS column (Daicel Kagaku) using hexane–isopropanol
(18:1, v/v) as an eluent. Syntheses of optically active
derivatives of (+)-6 and (–)-6 are currently under
investigation.

HETEROCYCLES, Vol. 88, No. 1, 2014
501
EXPERIMENTAL
Melting points were determined on a Yanagimoto micro melting point apparatus and are uncorrected.
Infrared (IR) spectra were determined with a Shimadzu IR-420 spectrophotometer, and proton nuclear
magnetic resonance (1H-NMR) spectra with a JEOL JNM-GSX 500 or FX100S spectrometer with
tetramethylsilane as an internal standard. Mass spectra (MS) were recorded on a Hitachi M-80
spectrometer. Preparative thin-layer chromatography (p-TLC) was performed on Merck Kiesel-gel GF254
(Type 60)(SiO2). Column chromatography was performed on silica gel (SiO2, 100-200 mesh, from Kanto
Chemical Co. Inc.) throughout the present study.
4-Cyanoindole-3-carboxaldehyde (8b)16a,b from Indole-3-carboxaldehyde (7) — Compound 7 (101.6
mg, 0.70 mmol) was added to a solution of Tl(OCOCF3)3 in TFA (1.0 mL, 1.2 mol eq) and stirred at rt for
22.5 h. After evaporation of the solvent, DMF (5.0 mL) was added. To the resultant solution, CuI (335.7
mg, 1.76 mmol) and I2 (633.0 mg, 2.49 mmol) were added and stirred at rt for 1 h. Then, CuCN (253.8
mg, 2.83 mmol) was added and heated at 64–71 °C for 1 h under ultrasonic bath. Solids were filtered off
through thin SiO2 layer. They were washed with CH2Cl2–MeOH (9:1, v/v). To the combined mixture of
washings and the filtrate was added H2O. The whole was extracted with CH2Cl2–MeOH (9:1, v/v). The
extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil,
which was subjected to column-chromatography on SiO2 with CH2Cl2–MeOH (99:1, v/v) as an eluent to
give 8b (85.3 mg, 72%). Spectral data of 8b are reported in the reference 16b.
Methyl 3-(2-nitrovinyl)indole-4-carboxylate (9a) from Methyl 3-formylindole-4-carboxylate (8a) —
Dried NH4OAc (33.6 mg, 0.44 mmol) was added to a solution of 8a16a (128.2 mg, 0.63 mmol) in MeNO2
(10.0 mL) and heated at 90–95 °C for 4 h with stirring. After evaporation of the solvent under reduced
pressure, H2O was added. The whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave crystalline solid.
Recrystallization from MeOH–H2O afforded 9a (104.2 mg). Evaporation of the mother liquor leaved an
oil, which was subjected to column-chromatography on SiO2 with CH2Cl2–MeOH (95:5, v/v) as an eluent
to give additional 9a (37.3 mg). Total yield of 9a was 141.5 mg (91%). 9a: mp 121–122 °C (red prisms,
1
recrystallized from MeOH–H2O). IR (KBr): 3240, 1718, 1602, 1252 cm-1. H-NMR (pyridine-d5) ": 3.92
(3H, s), 7.27 (1H, t, J=8.0 Hz), 7.73 (1H, dd, J=8.0, 1.0 Hz), 7.96 (1H, d, J=13.5 Hz), 8.00 (1H, dd, J=8.0,
1.0 Hz), 8.35 (1H, br s), 9.69 (1H, dd, J=13.5, 0.5 Hz). MS m/z: 246 (M+). Anal. Calcd for C12H10N2O4: C,
58.53; H, 4.09; N, 11.38. Found: C, 58.37; H, 3.92; N, 11.29.
4-Cyano-3-(2-nitrovinyl)indole (9b) from (8b) — Dried NH4OAc (201.3 mg, 2.53 mmol) was added to
a solution of 8b (537.7 mg, 3.16 mmol) in CH3NO2 (30.0 mL) and heated at 110–115 °C for 2 h with
stirring. After evaporation of the solvent, formed crystals were filtrated. Crystals were washed with
MeOH–H2O (1:1, v/v, 120.0 mL) to give 9b (569.7 mg). After condensation of mother liquor under

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HETEROCYCLES, Vol. 88, No. 1, 2014
reduced pressure, the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave crystalline solid, which was
subjected to column-chromatography on SiO2 with CH2Cl2–MeOH (95:5, v/v) as an eluent to give
additional 9b (20.2 mg). Total yield of 9b was 589.9 mg (88%). Spectral data of 9b are reported in the
reference 16b.
Methyl 3-(2-Nitroethyl)indole-4-carboxylate (10a) from 9a — NaBH4 (36.8 mg, 0.97 mmol) was
added to a solution of 9a (29.5 mg, 0.12 mmol) in MeOH (10.0 mL) and stirred at rt for 15 min. After
addition of H2O, the mixture was adjusted to pH 1 by adding 3% HCl. The whole was extracted with
CH2Cl2. The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified by column chromatography on SiO2 with CH2Cl2 as an eluent to give 10a (24.6
mg, 83%). 10a: mp 106–107 °C (colorless prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3330,
1697, 1547, 1263, 1205 cm-1. 1H-NMR (CDCl3) ": 3.65 (2H, t, J=7.0 Hz), 3.93 (3H, s), 4.68 (2H, t, J=7.0
Hz), 7.14 (1H, br s), 7.17 (1H, t, J=7.5 Hz), 7.54 (1H, dd, J=7.5, 1.0 Hz), 7.79 (1H, dd, J=7.5, 1.0 Hz),
8.28 (1H, br s). MS m/z: 248 (M+). Anal. Calcd for C12H12N2O4: C, 58.06; H, 4.87; N, 11.29. Found: C,
57.86; H, 4.87; N, 11.26.
4-Cyano-3-(2-nitroethyl)indole (10b) from 9b — NaBH4 (20.2 mg, 0.54 mmol) was added to a solution
of 9b (20.5 mg, 0.10 mmol) in MeOH (4.0 mL) and stirred at rt for 0.5 h. After addition of H2O, the
mixture was adjusted to pH 5 by adding 0.6% HCl. The whole was extracted with CH2Cl2. The extract
was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was
subjected to p-TLC on SiO2 with EtOAc–hexane (1:1, v/v) as a developing solvent. Extraction of the
band having an Rf value of 0.67–0.57 with CH2Cl2–MeOH (95:5, v/v) gave 10b (17.3 mg, 88%). Spectral
data of 10b are reported in the reference 16b.
4-Hydroxymethyl-3-(2-nitroethyl)indole (11) from 10a — DIBAL (1.0 M toluene, 1.6 mL, 1.63 mmol)
was added to a cooled solution of 10a (133.9 mg, 0.54 mmol) in dry THF (5.0 mL) under Ar atmosphere
and the mixture was stirred at rt for 3 h. After addition of MeOH and 10% aq. solution of Rochelle salt,
the whole was adjusted to pH 3 by addition of 0.6% HCl. The whole was extracted with CH2Cl2. 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 CH2Cl2–MeOH (95:5, v/v) as an eluent to give 11
(118.7 mg, 99%). 11: mp 118–119 °C (colorless prisms, recrystallized from CH2Cl2–hexane). IR (KBr):
1
3560, 3320, 1558, 1378, 990, 747 cm-1. H-NMR (CDCl3) ": 3.69 (2H, t, J=7.0 Hz), 4.75 (2H, t, J=7.0
Hz), 4.97 (2H, s), 7.03 (1H, dd, J=7.0, 2.0 Hz), 7.15 (1H, t, J=7.0 Hz), 7.23 (1H, s), 7.36 (1H, dd, J=7.0,
2.0 Hz), 8.15 (1H, br s). MS m/z: 220 (M+). Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72.
Found: C, 59.85; H, 5.46; N, 12.61.
11 from 9a — LiBH4 (29.9 mg, 1.36 mmol) was added to a solution of 9a (30.8 mg, 0.13 mmol) in THF

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503
(3 mL) and stirred at rt for 30 min, then at reflux for 1 h. After addition of H2O, the mixture was made
acidic by adding 0.6% HCl. The whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was subjected
to p-TLC on SiO2 with CH2Cl2–MeOH (98:2, v/v) as a developing solvent. Extraction of the bands having
an Rf value of 0.68–0.36 and 0.34–0.24 with CH2Cl2–MeOH (95:5, v/v) gave 10a (11.1 mg, 36%) and 11
(9.1 mg, 33%), respectively.
3-(2-Nitroethyl)indole-4-carboxaldehyde (12) from 11 — PCC (66.9 mg, 0.31 mmol) was added to a
solution of 11 (34.6 mg, 0.16 mmol) in pyridine (2 mL) and stirred at rt for 2.5 h. EtOH (0.2 mL) was
then added and stirred for 30 min. After addition of CH2Cl2–MeOH (95:5, v/v), the precipitates were
filtered off through thin SiO2 layer. Evaporation of the filtrate under reduced pressure leaves an oil, which
was column-chromatographed on SiO2 with CH2Cl2–MeOH (98:2, v/v) as an eluent. The early fractions
afforded 12 (11.0 mg, 32%). The middle fractions gave 4.5 mg of unknown product (expected to be a
mixture of diastereoisomers of 5-hydroxy-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole from MS and
1H-NMR). The later fractions afforded unreacted 11 (4.7 mg, 14%). 12: mp 159–160 °C (red prisms,
recrystallized from MeOH–H2O). IR (KBr): 3185, 1674, 1538 cm-1. 1H-NMR (10% CD3OD in CDCl3) ":
3.73 (2H, t, J=6.5 Hz), 4.61 (2H, t, J=6.5 Hz), 6.92–7.72 (4H, m), 10.01 (1H, s). MS m/z: 218 (M+). Anal.
Calcd for C11H10N2O3: C, 60.54; H, 4.62; N, 12.84. Found: C, 60.30; H, 4.33; N, 12.45.
4-Nitro-1,3-dihydrobenz[cd]indole (13) from 12 — A solution of 12 (6.7 mg, 0.03 mmol) in a mixture
of Et3N (0.5 mL) and MeOH (2 mL) was refluxed for 1 h. After evaporation of solvent under reduced
pressure, H2O was added. The mixture was adjusted to pH 4.0 by adding 0.6% HCl. The whole was
extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was purified by column-chromatography on SiO2 with
CH2Cl2 as an eluent to give 13 (5.4 mg, 87%). 13: mp 190–190.5 °C (red prisms, recrystallized from
MeOH–H2O). IR (KBr): 3356, 1574, 1491, 1290 cm-1. 1H-NMR (CDCl3) ": 4.33 (2H, br s), 7.01 (1H, dd,
J=7.0, 2.0 Hz), 7.03 (1H, s), 7.10 (1H, t, J=7.0 Hz), 7.19 (1H, dd, J=7.0, 2.0 Hz), 8.09 (2H, br s). MS m/z:
200 (M+). Anal. Calcd for C11H8N2O2: C, 66.00; H, 4.03; N, 13.99. Found: C, 65.94; H, 4.15; N, 13.90.
4-Nitro-1,3,4,5-tetrahydrobenz[cd]indole (6) from 13 — NaBH4 (19.1 mg, 0.50 mmol) was added to a
solution of 13 (22.0 mg, 0.10 mmol) in MeOH (4 mL) and stirred at rt for 0.5 h. After addition of H2O,
the mixture was made acidic by adding a drop of AcOH–H2O (1:1, v/v) and extracted with CH2Cl2. The
extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue
was purified by column chromatography on SiO2 with CH2Cl2–hexane (2:1, v/v) as an eluent to give 6
(17.8 mg, 80%). 6: mp 138.5–139 °C (lit.7 mp 134–135 °C). All spectral data were identical with those of
6 reported by L. I. Kruse et al.7
4-Nitro-1,3-dihydrobenz[cd]indole (13) from (10b) — DIBAL (1.0 M toluene, 1.6 mL, 1.63 mmol) was

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added to a cooled solution of 10b (58.1 mg, 0.27 mmol) in dry THF (1.0 mL) under Ar atmosphere and
the mixture was heated at reflux for 1 h. Then, MeOH–H2O (2:1, v/v, 1.5 mL) was added and the whole
was refluxed for 1 h. After addition of MeOH and 10% aq. solution of Rochelle salt, the whole was
adjusted to pH 3 by addition of 0.6% HCl. The whole was extracted with CH2Cl2–MeOH (95:5, v/v). 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 CH2Cl2 to give 13 (33.5 mg, 61%).
4-Nitro-1,3,4,5-tetrahydrobenz[cd]indole (6) from (10b) — One Pot Synthesis : DIBAL (1.0 M
toluene, 2.90 mL, 2.94 mmol) was added to a cooled solution of 10b (104.2 mg, 0.49 mmol) in dry THF
(3.0 mL) under Ar atmosphere and the mixture was stirred at rt for 1 h. Then, MeOH–H2O (2:1, v/v, 5.0
mL) was added and the whole was refluxed for 1 h. After cooling, DMF (1.0 mL) and NaBH4 (183.5 mg,
4.83 mmol) were added and the mixture was stirred at rt for 20 min. After addition of MeOH, the whole
was adjusted to pH 4 by addition of AcOH–H2O (1:1, v/v). 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 CH2Cl2–hexane (2:1, v/v) to give 6 (53.7 mg, 55%).
4-Amino-1,3,4,5-tetrahydrobenz[cd]indole (14) from 6 — 6% HCl (1 mL) was added to a mixture of
Zn powder (472.2 mg, 7.27 mmol) and HgCl2 (43.9 mg, 0.16 mmol) and stirred for 5 min. Liquid was
decanted off. To the residue was added a solution of 6 (30.3 mg, 0.15 mmol) in MeOH (3 mL) and then
6% HCl (1.5 mL). The whole was heated at reflux for 3 h with stirring. After filtering off the solid, 8%
NaOH was added to make the whole alkaline. The mixture was extracted with CH2Cl2. The extract was
washed with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was
subjected to p-TLC on SiO2 with CHCl3–MeOH–aq. 30% NH3 (46: 5:0.5, v/v) as a developing solvent.
Extraction of the band having an Rf value of 0.50–0.21 with CHCl3–MeOH –30% aq. NH3 (46: 5:0.5, v/v)
afforded 14 (25.6 mg, 99%). 14: mp 129.5–130 °C (lit.7 mp 119–121 °C) colorless prisms, recrystallized
from CH2Cl2–hexane). IR (KBr): 3328, 3072, 2912, 1612, 1603, 1582, 1443, 1344, 1261, 1097, 1058, 937,
746 cm-1. 1H-NMR (5% CD3OD in CDCl3) ": 2.74 (1H, dd, J=15.6, 7.8 Hz), 2.86 (1H, dd, J=15.6, 7.8 Hz),
3.12 (1H, dd, J=15.6, 3.9 Hz), 3.15 (1H, dd, J=15.6, 3.9 Hz), 3.54 (1H, sept, J=3.9 Hz), 6.84 (1H, d,
J=7.5 Hz), 6.89 (1H, s), 7.12 (1H, t, J=7.5 Hz), 7.17 (1H, d, J=7.5 Hz). MS m/z: 172 (M+). Anal. Calcd
for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.61; H, 6.96; N, 15.97.
4-N-Benzoylamino-1,3,4,5-tetrahydrobenz[cd]indole (15a) from 14 — Benzoyl chloride (41.7 mg,
0.30 mmol) was added to a solution of 14 (41.0 mg, 0.24 mmol) in CH2Cl2 (1.5 mL) and Et3N (0.4 mL).
The mixture was stirred at rt for 45 min. After addition of sat. aq. NaHCO3, the whole was extracted with
CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure to leave an oil, which was subjected to p-TLC on SiO2 with CH2Cl2–MeOH (97:3, v/v)
as a developing solvent. Extraction of the band having an Rf value of 0.56–0.35 with CH2Cl2–MeOH

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505
(95:5, v/v) afforded 15a (44.6 mg, 80%). 15a: mp 222–222.5 °C (colorless prisms, recrystallized from
1
MeOH). IR (KBr): 3371, 3230, 1623, 1575, 1532, 1486, 1443, 1429, 1401, 757, 715 cm-1. H-NMR
(CDCl3) ": 3.05 (1H, dd, J=15.5, 5.3 Hz), 3.12 (1H, dd, J=16.2, 5.3 Hz), 3.21 (1H, ddd, J=15.5, 4.0, 1.3
Hz), 3.32 (1H, dd, J=16.2, 4.0 Hz), 4.90–5.03 (1H, m), 6.18 (1H, br d, J=6.9 Hz), 6.89 (1H, dd, J=6.9, 0.9
Hz), 6.94 (1H, br s), 7.11–7.42 (5H, m), 7.53–7.60 (2H, m), 8.01 (1H, br s). MS m/z: 276 (M+). Anal.
Calcd for C18H16N2O: C, 78.24; H, 5.84; N, 10.14. Found: C, 78.30; H, 5.61; N, 10.17.
4-(N-Phenylacetylamino)-1,3,4,5-tetrahydrobenz[cd]indole (15b) from 14 — Phenylacetyl chloride
(55.7 mg, 0.36 mmol) was added to a solution of 14 (30.2 mg, 0.18 mmol) in CH2Cl2 (5 mL) and Et3N
(0.3 mL). The mixture was stirred at rt for 3 h. After addition of sat. aq. NaHCO3, the whole was
extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure to leave an oil, which was subjected to p-TLC on SiO2 with
CHCl3–MeOH–aq. 30% NH3–hexane (92:10:1:1, v/v) as a developing solvent. Extraction of the band
having an Rf value of 0.50–0.27 with CHCl3–MeOH–aq. 30%NH3 (46:5:0.5, v/v) afforded 15b (36.9 mg,
73%). 15b: colorless oil. IR (KBr): 3373, 3266, 3053, 2916, 1642, 1511, 1442, 1341, 749, 720, 692 cm-1.
1H-NMR (CDCl3) ": 2.82 (1H, dd, J=15.2, 5.6 Hz), 2.92 (1H, dd, J=15.8, 5.6 Hz), 3.06 (1H, ddd, J=15.2,
3.9, 1.3 Hz), 3.15 (1H, dd, J=15.8, 3.9 Hz), 3.42 (2H, s), 4.62–4.74 (1H, m), 5.42 (1H, br d, J=6.9 Hz),
6.81 (1H, d, J=6.6 Hz), 6.85 (1H, br s), 7.01–7.23 (7H, m), 8.00 (1H, br s, D2O exchange). High
resolution MS m/z: Calcd for C19H18N2O: 290.1418. Found: 290.1492.
4-N-Phenethylamino-1,3,4,5-tetrahydrobenz[cd]indole (15c) from 14 — Phenethyl bromide (38.1 mg,
0.21 mmol), KI (20.0 mg, 0.12 mmol), and K2CO3 (124.6 mg, 0.90 mmol) were added to a solution of 14
(30.4 mg, 0.18 mmol) in DMF (1.0 mL). The mixture was stirred at reflux for 3 h. After addition of H2O,
the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure to leave an oil, which was subjected to p-TLC on SiO2
with CHCl3–MeOH–aq. 30% NH3 (46:5:0:5, v/v) as a developing solvent. Extraction of the bands having
an Rf value of 0.32–0.21 and 0.74–0.50 with CHCl3–MeOH–aq. 30% NH3 (46:5:0.5, v/v) afforded 15c
(29.8 mg, 61%) and unreacted 14 (3.3 mg, 16%), respectively. 15c: colorless oil. IR (KBr): 3402, 2928,
1603, 1494, 1443, 1342, 1093, 1082, 746, 696 cm-1. 1H-NMR (CDCl3) ": 1.88 (1H, br s, D2O exchange),
2.76 (1H, dd, J=15.0, 9.0 Hz), 2.85 (2H, t, J=7.3 Hz), 2.91 (1H, dd, J=15.0, 9.0 Hz), 3.06 (2H, t, J=7.3
Hz), 3.10–3.20 (1H, m), 3.28–3.35 (1H, m), 6.83 (1H, d, J=6.8 Hz), 6.85 (1H, br s), 7.08–7.17 (2H, m),
7.17–7.23 (3H, m), 7.26–7.31 (2H, m), 7.88 (1H, br s, D2O exchange). High resolution MS m/z: Calcd for
C19H20N2: 276.1625. Found: 276.1629.
4-N-propylamino- (15d) and 4-(N,N-Dipropylamino)-1,3,4,5-tetrahydrobenz[cd]indole (5) from 14
— n-Propyl iodide (124.6 mg, 0.72 mmol) and K2CO3 (365.0 mg, 2.65 mmol) were added to a solution of
14 (31.5 mg, 0.18 mmol) in dry MeCN (1.5 mL). The mixture was heated at reflux for 26 h with stirring.

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After addition of H2O, the whole was extracted with CH2Cl2–MeOH (95:5, v/v). The extract was washed
with brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was
subjected to p-TLC on SiO2 with CHCl3–MeOH–aq. 30% NH3 (46:5:0:5, v/v) as a developing solvent.
Extraction of the bands having an Rf value of 0.93–0.77 and 0.67–0.57 with CHCl3–MeOH–aq. 30% NH3
(46:5:0.5, v/v) afforded 5 (40.8 mg, 87%) and 15d (1.7 mg, 4%), respectively. 15d: pale brown oil. IR
1
(KBr): 3399, 2916, 1605, 1442, 1337, 1941, 743 cm-1. H-NMR (CDCl3) ": 0.94 (3H, t, J=7.3 Hz), 1.58
(2H, sex, J=7.3 Hz), 1.80 (1H, br s, D2O exchange), 2.76 (2H, t, J=7.3 Hz), 2.80 (1H, dd, J=15.6, 8.8 Hz),
2.96 (1H, dd, J=15.6, 9.3 Hz), 3.19 (1H, dt, J=15.6, 3.9 Hz), 3.27–3.35 (1H, m), 6.85 (1H, d, J=6.8 Hz),
6.87 (1H, s), 7.12 (1H, dd, J=7.8, 6.8 Hz), 7.17 (1H, d, J=7.8 Hz). High resolution MS m/z: Calcd for
C14H18N2: 214.1469. Found: 214.1479. 5: pale brown oil. IR (KBr): 3403, 2956, 2935, 1607, 1443, 1339,
1
1069, 743 cm-1. H-NMR (500 MHz, pyridine-d5) ": 0.90 (6H, t, J=7.3 Hz), 1.44 (4H, sex, J=7.3 Hz),
2.50 (4H, t, J=7.3 Hz), 2.90 (1H, ddd, J=14.8, 11.7, 1.5 Hz), 3.00–3.13 (3H, m), 3.30–3.39 (1H, m), 7.02
(1H, d, J=7.3 Hz), 7.20 (1H, br s), 7.28 (1H, dd, J=7.8, 7.3 Hz), 7.39 (1H, d, J=7.8 Hz). High resolution
MS m/z: Calcd for C17H24N2: 256.1938. Found: 256.1980.
4-(N,N-Dipropylamino)-1,3,4,5-tetrahydrobenz[cd]indole (5) from 15d — n-Propyl iodide (177.0 mg,
1.08 mmol), K2CO3 (153.8 mg, 1.11 mmol), and n-Bu4NBr (7.1 mg, 0.02 mmol) were added to a solution
of 15d (23.0 mg, 0.11 mmol) in dry MeCN (2.0 mL). The mixture was heated at reflux for 8 h. The same
work-up and purification as described above afforded 5 (22.2 mg, 80%).
1,3,4,5-Tetrahydrobenz[cd]indole-4-one (16) from 6 — According to the procedure reported by L. I.
Kruse et al.,7 16 was prepared from 6 in 81% yield. 16: mp 150—152 °C (lit.7 mp 146–147 °C, decomp.,
1
colorless needles, recrystallized from EtOAc–hexane). IR (KBr): 3330, 1695, 1446 cm-1. H-NMR
(CDCl3) ": 3.81 (2H, s), 3.89 (2H, s), 6.85 (1H, dd, J=7.1, 1.2 Hz), 6.95 (1H, d, J=1.9 Hz), 7.19 (1H, dd,
J=8.1, 7.1 Hz), 7.23 (1H, d, J=8.1 Hz), 8.06 (1H, br s). MS m/z: 171 (M+). Anal. Calcd for C11H9NO: C,
77.17; H, 5.30; N, 8.18. Found: C, 77.37; H, 5.28; N, 7.98.
4-Amino-4-cyano-1,3,4,5-tetrahydrobenz[cd]indole
(17)
and
Hydantoin-5-spiro-4-(1,3,4,5-
tetrahydrobenz[cd]indole) (18) from 16 — A solution of KCN (45.7 mg, 0.71 mmol) and (NH4)2CO3
(205.3 mg, 2.14 mmol) in H2O (3 mL) was added to a solution of 16 (34.7 mg, 0.0.20 mmol) in MeOH (3
mL). The mixture was heated at 60 °C for 2 h with stirring. 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 CH2Cl2–MeOH (98:2,
v/v) as an eluent to give unreacted 17 (4.4 mg, 11%) and 18 (28.9 mg, 59%) in the order of elution. 17:
mp 129—132 °C (pale green prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3320, 2220, 1605,
1445, 767, 745 cm-1. 1H-NMR (CD3OD) ": 1.74 (2H, br s), 3.14 (1H, d, J=15.0 Hz), 3.24 (1H, d, J=15.6
Hz), 3.40 (1H, d, J=15.0 Hz), 3.43 (1H, d, J=15.6 Hz), 6.91 (1H, d, J=7.0 Hz), 6.99 (1H, d, J=1.3 Hz),

HETEROCYCLES, Vol. 88, No. 1, 2014
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7.14 (1H, dd, J=8.1, 7.0 Hz), 7.24 (1H, d, J=8.1 Hz), 8.00 (1H, br s). MS m/z: 197 (M+). Anal. Calcd for
C12H11N3•1/8H2O: C, 72.25; H, 5.68; N, 21.06. Found: C, 72.31; H, 5.42; N, 21.06. 18: mp 295—297 °C
(colorless prisms, recrystallized from MeOH–H2O). IR (KBr): 3265, 1773, 1703, 1408, 747 cm-1.
1H-NMR (CD3OD) ": 2.96 (1H, dd, J=15.9, 1.9 Hz), 2.98 (1H, ddd, J=15.2, 1.9, 0.7 Hz), 3.30 (1H, dd,
J=15.2, 1.5 Hz), 3.41 (1H, dd, J=15.9, 0.7 Hz), 6.83 (1H, br d, J=7.1 Hz), 7.03 (1H, d J=1.5 Hz), 7.08
(1H, dd, J=8.2, 7.1 Hz), 7.20 (1H, d, J=8.2 Hz). MS m/z: 241 (M+). Anal. Calcd for C13H11N3O2: C, 64.72;
H, 4.60; N, 17.42. Found: C, 64.83; H, 4.74; N, 17.27.
4-Amino-4-cyano- (17) and 4-Cyano-4-hydroxy-1,3,4,5-tetrahydrobenz[cd]indole (19a) from 16 — A
solution of KCN (34.8 mg, 0.53 mmol) and NH4Cl (86.1 mg, 1.61 mmol) in H2O (3 mL) was added to a
solution of 16 (30.1 mg, 0.17 mmol) in MeOH (3 mL). The mixture was heated at 60 °C for 1 h with
stirring. After addition of 8% NaOH and H2O, the whole was extracted with CH2Cl2–MeOH (95:5, v/v).
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 (4:3, v/v) as an eluent to give
unreacted 16 (6.2 mg, 26%), 19a (3.0 mg, 10%), and 17 (16.9 mg, 56%) in the order of elution. 19a:
unstable colorless prisms and mp was not determined. IR (KBr): 3360, 2240, 1260, 1062, 798 cm-1.
1H-NMR (5% CD3OD in CDCl3) ": 3.24 (1H, dd, J=16.5, 1.3 Hz), 3.36 (1H, d, J=15.8 Hz), 3.46 (1H, d,
J=16.5 Hz), 3.49 (1H, d, J=15.8 Hz), 6.89 (1H, d, J=7.0 Hz), 6.98 (1H, s), 7.15 (1H, dd, J=8.2, 7.0 Hz),
7.23 (1H, d, J=8.2 Hz). High resolution MS m/z: Calcd for C12H10N2O: 198.0792. Found: 198.0792.
4-Acetoxy-4-Cyano-1,3,4,5-tetrahydrobenz[cd]indole (19b) from 16 — A solution of KCN (83.0 mg,
1.28 mmol) in H2O (1 mL) was added to a solution of 16 (61.0 mg, 0.36 mmol) in MeOH (2 mL) and
AcOH (1 mL). The whole was heated at 60 °C for 4 h with stirring. After addition of H2O, the whole was
extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was dissolved in pyridine (0.8 mL) and Ac2O (0.4 mL) was added. Stirring
was continued for 15.5 h at rt and the solvent was evaporated under reduced pressure. The residue was
subjected to p-TLC on SiO2 with EtOAc–hexane (1:1, v/v) as a developing solvent. Extraction of the
band having an Rf value of 0.75–0.64 with CH2Cl2 afforded 19b (36.5 mg, 43%). 19b: mp 161—162 °C
1
(colorless needles, recrystallized from MeOH–H2O). IR (KBr): 3430, 1740, 1225, 1045 cm-1. H-NMR
(CDCl3) ": 2.05 (3H, s), 3.51 (1H, d, J=15.2 Hz), 3.59 (1H, d, J=15.9 Hz), 3.71 (2H, br dd, J=15.9, 15.2
Hz), 6.91 (1H, d, J=7.0 Hz), 6.98 (1H, d, J=1.5 Hz), 7.18 (1H, br dd, J=8.0, 7.0 Hz), 7.24 (1H, d, J=8.0
Hz). MS m/z: 240 (M+). Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C, 70.17; H,
4.90; N, 11.78.
4-Amino-1,3,4,5-tetrahydrobenz[cd]indole-4-carboxamide (20) from 17 — 8% NaOH (2 mL) and
30% H2O2 (1 mL) were added to a solution of 17 (90.1 mg, 0.46 mmol) in MeOH (2 mL) and stirred at rt
for 1 h. After addition of H2O, the whole was extracted with CH2Cl2–MeOH (95;5, v/v). The extract was

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washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was
column-chromatographed on SiO2 with CH2Cl2–MeOH (9:1, v/v) to give 20 (83.0 mg, 84%). 20: mp
81—82 °C (colorless needles, recrystallized from MeOH–H2O). IR (KBr): 3440, 3200, 1673, 775 cm-1.
1H-NMR (CD3OD) ": 2.83 (1H, ddd, J=16.1, 1.5, 0.9 Hz), 2.84 (1H, dd, J=15.7, 1.3 Hz), 3.32 (1H, dd,
J=16.1, 1.5 Hz), 3.46 (1H, d, J=15.7 Hz), 6.79 (1H, ddd, J=7.0, 0.9, 0.9 Hz), 6.99 (1H, d, J=1.3 Hz), 7.06
(1H, dd, J=8.3, 7.0 Hz), 7.17 (1H, d, J=8.3 Hz). Anal. Calcd for C12H13N3OꢀH2O: C, 61.79; H, 6.48; N,
18.01. Found: C, 62.08; H, 6.44; N, 17.97. High resolution MS m/z: Calcd for C12H13N3O: 215.1057.
Found: 215.1057.
4-Amino-1,3,4,5-tetrahydrobenz[cd]indole-4-carboxylic acid (21) from 20 — 8% NaOH (2 mL) was
added to a solution of 20 (20.8 mg, 0.09 mmol) in MeOH (1 mL) and stirred at 55 °C for 24 h. After
evaporation of solvent under reduced pressure, the residue was subjected to column-chromatography on
ion-exchange resin (IR 120B) with H2O as an eluent to give 21 (21.2 mg, 100%). 21: mp 275—278 °C
(decomp., pale brown prisms, recrystallized from MeOH-CH2Cl2). IR (KBr): 3410, 1605, 1582, 1370
cm-1. 1H-NMR (D2O) ": 3.21 (2H, d, J=16.5 Hz), 3.46 (1H, d, J=16.5 Hz), 3.61 (1H, d, J=16.5 Hz), 7.00
(1H, d, J=7.1 Hz), 7.21 (1H, s), 7.24 (1H, dd, J=7.9, 7.1 Hz), 7.38 (1H, d, J=7.1 Hz). MS m/z: 216 (M+).
Anal. Calcd for C12H12N2O2ꢀ3/4H2O: C, 62.73; H, 5.26; N, 12.19. Found: C, 62.73; H, 5.51; N, 12.11.
4-Nitro-4-hydroxymethyl-1,3,4,5-tetrahydrobenz[cd]indole (22a) from 6 — KOt-Bu (34.0 mg, 0.30
mmol) was added to a solution of 6 (101.6 mg, 0.50 mmol) in MeOH (6 mL) and stirred for 15 min under
ice cooling. After addition of 37% formalin (41.9 mg, 0.52 mmol), the mixture was stirred at rt for 3 h.
The pH of the mixture was adjusted to 6 by adding 0.6% HCl and the whole was extracted with CH2Cl2.
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 CH2Cl2 as an eluent to give unreacted 6 (6.6 mg,
2%), 16 (2 mg, 2%), and 22a (85.7 mg, 73%) in the order of elution. 22a: mp 154-–155 °C (pale yellow
prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3495, 3335, 1537, 1529, 1447, 1414, 1340, 1077,
1042, 1032, 1018, 753 cm-1. 1H-NMR (CDCl3) ": 3.42 (1H, d, J=16.0 Hz), 3.44 (1H, d, J=16.0 Hz), 3.67
(1H, d, J=16.0 Hz), 3.79 (1H, d, J=16.0 Hz), 3.87 (1H, d, J=12.3 Hz), 3.93 (1H, d, J=12.3 Hz), 6.92 (1H,
d, J=7.3 Hz), 6.97 (1H, s), 7.16 (1H, dd, J=8.3, 7.3 Hz), 7.20 (1H, d, J=8.3 Hz), 7.98 (1H, br s). MS m/z:
232 (M+). Anal. Calcd for C12H12N2O3: C, 62.02; H, 5.21; N, 12.06. Found: C, 61.97; H, 5.22; N, 12.02.
4-Acetoxymethyl-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (22b) from 22a — Ac2O (0.5 mL) was
added to a solution of 22a (45.0 mg, 0.19 mmol) in pyridine (1 mL) and stirred at rt for 2.5 h. After
evaporation of the solvent under reduced pressure, H2O was added. The whole was extracted with
CH2Cl2–MeOH (95:5, v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was column-chromatographed on SiO2 with CH2Cl2–hexane (4:1, v/v) as an
eluent to give 22b (52.0 mg, 98%). 22b: mp 136.5-–137 °C (colorless prisms, recrystallized from

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CH2Cl2–hexane). IR (KBr): 3420, 3120, 1758, 1619, 1609, 1525, 1451, 1362, 1237, 1040, 759, 752 cm-1.
1H-NMR (CDCl3) ": 2.08 (3H, s), 3.38 (1H, d, J=15.6 Hz), 3.45 (1H, d, J=16.6 Hz), 3.74 (1H, d, J=15.6
Hz), 3.83 (1H, d, J=16.6 Hz), 4.42 (1H, d, J=12.2 Hz), 4.47 (1H, d, J=12.2 Hz), 6.92 (1H, d, J=6.8 Hz),
6.97 (1H, br s), 7.16 (1H, dd, J=8.3, 6.3 Hz), 7.20 (1H, d, J=8.3 Hz), 7.99 (1H, br s). MS m/z: 274 (M+).
Anal. Calcd for C14H14N2O4: C, 61.31; H, 5.15; N, 10.21. Found: C, 61.25; H, 5.15; N, 10.15.
4-Amino-4-hydroxymethyl-1,3,4,5-tetrahydrobenz[cd]indole (23a) from 22a — 6% HCl (4 mL) was
added to a mixture of Zn powder (2.462 g, 37.6 mmol) and HgCl2 (310.8 mg, 1.14 mmol) and stirred for 5
min. Liquid was decanted off. To the residue was added a solution of 22a (174.0 mg, 0.75 mmol) in
MeOH (7 mL) and then 6% HCl (7 mL). The whole was heated at reflux for 5 h with stirring. After
filtering off the solid, 8% NaOH was added to make the whole alkaline. The mixture was extracted with
CH2Cl2–MeOH (95:5, v/v). 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–aq.
30% NH3 (46: 5:0.5, v/v) to give 23a (142.8 mg, 94%). 23a: mp 173.5—174.0 °C (colorless prisms,
recrystallized from EtOAc–hexane). IR (KBr): 3235, 1609, 1564, 1445, 1344, 1061, 1040, 992, 707 cm-1.
1H-NMR (CD3OD) ": 2.73 (1H, d, J=15.1 Hz), 2.80 (1H, d, J=16.2 Hz), 2.92 (1H, dd, J=15.1, 1.0 Hz),
3.00 (1H, d, J=16.2 Hz), 3.46 (2H, s), 6.74 (1H, d, J=7.3 Hz), 6.91 (1H, s), 7.02 (1H, dd, J=8.3, 7.3 Hz),
7.12 (1H, d, J=8.3 Hz). MS m/z: 202 (M+). Anal. Calcd for C12H14N2O: C, 71.26; H, 6.98; N, 13.85.
Found: C, 71.08; H, 6.95; N, 13.72.
4-Acetylamino-4-hydroxymethyl-1,3,4,5-tetrahydrobenz[cd]indole (23b) from 23a — Ac2O (1 mL)
was added to a solution of 23a (90.1 mg, 0.19 mmol) in pyridine (1 mL) and stirred at rt for 2 h. Solvent
was evaporated under reduced pressure and the residue was dissolved in MeOH (15 mL). Sat. aq.
NaHCO3 (2 mL) was added and the whole was heated at 50 °C for 17 h. The whole was extracted with
CH2Cl2–MeOH (95:5, v/v). 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 CH2Cl2–MeOH (95:5,
v/v) to give 23b (106.6 mg, 98%). 23b: mp 193—195 °C (colorless prisms, recrystallized from
MeOH–H2O). IR (KBr): 3260, 1622, 1564, 1252, 1063, 747 cm-1. 1H-NMR (CD3OD) ": 1.80 (3H, s), 3.03
(1H, dd, J=15.7, 1.0 Hz), 3.10 (1H, d, J=15.7 Hz), 3.26 (1H, d, J=15.7 Hz), 3.37 (1H, d, J=15.7 Hz), 3.75
(1H, d, J=11.3 Hz), 3.78 (1H, d, J=11.3 Hz), 6.74 (1H, dd, J=7.3, 0.9 Hz), 6.91 (1H, s), 7.01 (1H, dd,
J=8.5, 7.3 Hz), 7.12 (1H, d, J=8.5 Hz). MS m/z: 244 (M+). Anal. Calcd for C14H16N2O2: C, 68.83; H, 6.60;
N, 11.47. Found: C, 68.78; H, 6.54; N, 11.41.
4-Acetylamino-4-methylthiomethoxymethyl-
(24a)
and
4-Acetylamino-4-formyl-1,3,4,5-
tetrahydrobenz[cd]indole and (24b) from 23b — Ac2O (2 mL) was added to dry DMSO (4 mL) and
the mixture was stirred at rt for 30 min. To the mixture was added a solution of 23b (149.4 mg, 0.61
mmol) in dry DMSO (2 mL) and stirring was continued for 12 h. After addition of H2O, the whole was

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extracted with EtOAc. The extract was washed with brine, dried over Na2SO4, and evaporated under
reduced pressure. The residue was column-chromatographed on SiO2 with CH2Cl2–MeOH (95:5, v/v) as
an eluent to give 24a (60.4 mg, 32%) and 24b (83.4 mg, 56%) in the order of elution. 24a: colorless oil.
IR (film): 3410, 3300, 1660, 1518, 1447, 1075, 758 cm-1. 1H-NMR (CDCl3) ": 1.78 (3H, s), 2.15 (3H, s),
2.94 (1H, d, J=15.6 Hz), 3.07 (1H, d, J=16.1 Hz), 3.56 (2H, dd, J=16.1, 15.6 Hz), 3.92 (1H, d, J=18.7 Hz),
3.93 (1H, d, J=18.7 Hz), 4.66 (2H, s), 5.31 (1H, br s), 6.86 (1H, d, J=7.3 Hz), 6.91 (1H, s), 7.13 (1H, dd,
J=8.0, 7.3 Hz), 7.19 (1H, d, J=8.0 Hz), 7.91 (1H, br s). High resolution MS m/z: Calcd for C16H20N2O2S:
304.1244. Found: 304.1292. 24b: mp 244—246 °C (colorless prisms, recrystallized from MeOH–H2O).
IR (KBr): 3370, 3220, 1735, 1642, 1525, 1374, 747 cm-1. 1H-NMR (pyridine-d5) ": 1.83 (3H, s), 3.45 (1H,
d, J=16.2 Hz), 3.48 (1H, d, J=15.7 Hz), 3.52 (1H, d, J=16.2 Hz), 3.59 (1H, d, J=15.7 Hz), 6.88 (1H, br t,
J=7.2 Hz), 7.07 (1H, d, J=0.9 Hz), 7.15 (1H, dd, J=8.0, 7.2 Hz), 7.30 (1H, d, J=8.0 Hz), 8.93 (1H, br s),
10.05 (1H, s), 11.58 (1H, br s). MS m/z: 242 (M+). Anal. Calcd for C14H14N2O2: C, 69.40; H, 5.83; N,
11.56. Found: C, 69.29; H, 5.83; N, 11.46.
4-Acetylamino-4-hydroxyiminomethyl-1,3,4,5-tetrahydrobenz[cd]indole (24c) from 24b
—
NH2OH•HCl (55.9 mg, 0.80 mmol) was added to a solution of 24b (149.5 mg, 0.62 mmol) in pyridine (5
mL) and stirred at rt for 2.5 h. After addition of H2O, the whole was extracted with CH2Cl2–MeOH (95:5,
v/v). The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The
residue was column-chromatographed on SiO2 with CH2Cl2–MeOH (95:5, v/v) to give 24c (150.7 mg,
95%). 24c: mp 119—121 °C (colorless prisms, recrystallized from MeOH–H2O). IR (KBr): 3400, 1644,
1
1515, 1445, 747 cm-1. H-NMR (CD3OD) ": 1.77 (3H, s), 3.19 (1H, dd, J=15.4, 1.1 Hz), 3.26 (1H, d,
J=15.8 Hz), 3.41 (1H, d, J=15.4 Hz), 3.51 (1H, d, J=15.8 Hz), 6.75 (1H, dd, J=8.0, 1.3 Hz), 6.94 (1H, s),
7.03 (1H, dd, J=8.3, 8.0 Hz), 7.14 (1H, dd, J=8.3, 1.3 Hz), 7.61 (1H, s). MS m/z: 257 (M+). Anal. Calcd
for C14H15N3O2: C, 65.35; H, 5.88; N, 16.33. Found: C, 65.12; H, 5.99; N, 16.03.
4-Acetylamino-4-cyano-1,3,4,5-tetrahydrobenz[cd]indole (24d) from 24c — A solution of 24c (117.9
mg, 0.46 mmol) in Ac2O (5 mL) was heated at reflux for 1.5 h with stirring. After addition of H2O, 8%
NaOH was added and the pH was adjusted to 6. The whole was extracted with CH2Cl2–MeOH (95;5, v/v).
The extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The
residue was column-chromatographed on SiO2 with CH2Cl2–MeOH (95:5, v/v) to give 24d (56.5 mg,
52%). 24d: mp 260—262 °C (colorless needles, recrystallized from MeOH–H2O). IR (KBr): 3320, 2240,
1661, 1525, 1300, 755 cm-1. 1H-NMR (pyridine-d5) ": 1.97 (3H, s), 3.68 (1H, d, J=14.3 Hz), 3.74 (1H, d,
J=15.4 Hz), 4.03 (1H, d, J=14.3 Hz), 4.06 (1H, d, J=15.4 Hz), 6.90 (1H, d, J=7.2 Hz), 7.15 (1H, d, J=0.9
Hz), 7.20 (1H, dd, J=8.3, 7.2 Hz), 7.38 (1H, d, J=8.3 Hz), 9.48 (1H, s), 11.83 (1H, br s). MS m/z: 239
(M+). Anal. Calcd for C14H13N3O: C, 70.27; H, 5.48; N, 17.56. Found: C, 70.19; H, 5.50; N, 17.54.
24d from 17 — Ac2O (0.3 mL) was added to a solution of 17 (6.6 mg, 0.03 mmol) in pyridine (0.6 mL)

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and the whole was stirred at rt for 38 h. After evaporation of the solvent under reduced pressure, the
residue was subjected to p-TLC on SiO2 with CH2Cl2–MeOH (95:5, v/v) as a developing solvent.
Extraction of the band having an Rf value of 0.47–0.38 with CH2Cl2–MeOH (95:5, v/v) afforded 24d (4.9
mg, 61%).
4-N-Propylamino-4-hydroxymethyl- (25) and 4-N,N-Dipropylamino-4-hydroxymethyl-1,3,4,5-
tetrahydrobenz[cd]indole (27a) from 23a — a) General Procedure: K2CO3 (909.5 mg, 6.58 mmol) and
n-propyl iodide (154.5 mg, 0.93 mmol) were added to a solution of 23a (88.2 mg, 0.44 mmol) in dry
MeCN (8 mL) and the mixture was heated at reflux for 18 h. After addition of H2O, the whole was
extracted with CH2Cl2–MeOH (95:5, v/v). 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–aq. 30% NH3 (100:3:0.3, v/v) to give 27a (7.9 mg, 6%) and 25 (93.1 mg, 87%), and
unreacted 23 (3.4 mg, 4%) in the order of elution.
b: In the general procedure, K2CO3 (2.822 g, 20.4 mmol), n-propyl iodide (918.0 mg, 5.40 mmol), 23a
(272.5 mg, 1.35 mmol), and dry MeCN (22 mL) were employed and the refluxing time was 51 h. After
the same work-up as described in the general procedure, 27a (174.9 mg, 53%) and 25 (173.5 mg, 45%)
were obtained. 25: mp 132.0—133.0 °C (colorless prisms, recrystallized from CH2Cl2–hexane). IR (KBr):
1
3240, 2970, 2860, 1620, 1608, 1473, 1443, 1334, 1324, 1087, 1025, 925, 847, 753 cm-1. H-NMR
(CDCl3) ": 0.77 (3H, t, J=7.3 Hz), 1.23–1.34 (2H, m), 2.36–2.47 (2H, m), 2.75 (1H, dd, J=15.6, 1.0 Hz),
3.00 (1H, d, J=15.6 Hz), 3.06 (1H, d, J=15.6 Hz), 3.47 (1H, d, J=10.3 Hz), 3.52 (1H, d, J=10.3 Hz), 6.86
(1H, d, J=6.9 Hz), 6.90 (1H, s), 7.13 (1H, dd, J=7.8, 6.9 Hz), 7.18 (1H, d, J=7.8 Hz), 7.91 (1H, br s). MS
m/z: 244 (M+). Anal. Calcd for C15H20N2O: C, 73.74; H, 8.25; N, 11.46. Found: C, 73.73; H, 8.32; N,
11.45. 27a: mp 93.5—95.0 °C (colorless prisms, recrystallized from hexane). IR (KBr): 3318, 2970, 1448,
1088, 1052, 1022, 742 cm-1. 1H-NMR (CDCl3) ": 0.89 (6H, t, J=7.3 Hz), 1.50–1.60 (4H, m), 2.63 (4H, m),
2.92–3.02 (3H, m), 3.17 (1H, d, J=16.1 Hz), 3.20 (2H, s), 6.84 (1H, d, J=6.8 Hz), 6.87 (1H, s), 7.11 (1H,
dd, J=8.0, 6.8 Hz), 7.15 (1H, d, J=8.0 Hz), 7.89 (1H, br s). MS m/z: 286 (M+). Anal. Calcd for C18H26N2O:
C, 75.48; H, 9.15; N, 9.78. Found: C, 75.64; H, 9.16; N, 9.70.
4-(N-Propyl-N-propionyl)amino-4-propionyloxymethyl- (26a) and 4-N-Propionyloxymethyl-4-N-
propylamino-1,3,4,5-tetrahydrobenz[cd]indole (26b) from 25 — A solution of propionyl chloride
(170.8 mg, 1.85 mmol) in CH2Cl2 (2 mL) was added to a solution of 25 (149.2 mg, 0.61 mmol) in the
mixture of CH2Cl2 (8 mL) and Et3N (0.5 mL). The mixture was stirred at rt for 30 min. After addition of
sat. aq. NaHCO3, the whole was heated for 5 min. After addition of H2O, the whole was extracted with
CH2Cl2–MeOH (95:5, v/v). 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 CH2Cl2–MeOH (97:3,
v/v) to give 26a (193.9 mg, 89%) and 26b (13.8 mg, 8%) in the order of elution. 26a: mp 165—166 °C

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(colorless prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3230, 2958, 1735, 1640, 1608, 1197,
1
747 cm-1. H-NMR (CDCl3) ": 0.77 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.3 Hz), 1.16 (3H, t, J=7.3 Hz),
1.38–1.57 (2H, m), 2.23 (2H, q, J=7.3 Hz), 2.35 (2H, q, J=7.3 Hz), 2.92–3.06 (2H, m), 3.09 (1H, d,
J=16.1 Hz), 3.26 (1H, d, J=16.1 Hz), 3.69 (1H, d, J=15.6Hz), 3.79 (1H, d, J=15.6 Hz), 4.60 (1H, d,
J=11.2 Hz), 4.69 (1H, d, J=11.2 Hz), 6.83 (1H, d, J=6.8 Hz), 6.86 (1H, s), 7.12 (1H, dd, J=7.8 and 6.8
Hz), 7.14 (1H, d, J=7.8 Hz), 7.89 (1H, br s). MS (CI) m/z: 357 (M++1). Anal. Calcd for C21H28N2O3: C,
70.76; H, 7.92; N, 7.86. Found: C, 70.69; H, 7.94; N, 7.77. 26b: pale yellow oil. IR (film): 3415, 2960,
1
2950, 1735, 1445, 1185, 748 cm-1. H-NMR (CDCl3) ": 0.80 (3H, t, J=7.3 Hz), 1.15 (3H, t, J=7.5 Hz),
1.37 (2H, sext, J=7.3 Hz), 2.38 (2H, q, J=7.5 Hz), 2.51-2.61 (2H, m), 2.94 (1H, d, J=15.4 Hz), 2.99 (1H,
d, J=15.9 Hz), 3.04 (1H, d, J=15.4 Hz), 3.10 (1H, d, J=15.9 Hz), 4.08 (1H, d, J=11.4 Hz), 4.12 (1H, d,
J=11.4Hz), 6.84 (1H, d, J=6.8 Hz), 6.88 (1H, d, J=0.9 Hz), 7.12 (1H, dd, J=8.0 and 6.8 Hz), 7.17 (1H, d,
J=8.0 Hz), 7.94 (1H, br s). High resolution MS m/z: Calcd for C18H24N2O2: 300.1836. Found: 300.1836.
27a from 26a — LiAlH4 (428.0 mg, 11.3 mmol) was added to a solution of 26a (267.0 mg, 0.75 mmol)
in dry THF (15 mL) and heated at reflux for 1.5 h. After addition of MeOH and 10% aq. solution of
Rochelle salt, the whole was extracted with CHCl3–MeOH–aq. 30% NH3 (46:3:0.3, v/v). 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–aq. 30% NH3 (100:1:0.1, v/v) to give 27a (197.2
mg, 91%).
4-Acetoxymethyl-4-N,N-dipropylamino-1,3,4,5-tetrahydrobenz[cd]indole (27b) from 27a — Ac2O
(0.5 mL) was added to a solution of 27a (20,4 mg, 0.07 mmol) in pyridine (1 mL) and the whole was
stirred at rt for 2 h. After evaporation of the solvent under reduced pressure, the residue was
column-chromatographed on SiO2 with CHCl3–MeOH–aq. 30% NH3 (100:1:0.1, v/v) as an eluent to give
27b (23.1 mg, 99%). 27b: pale brown oil. IR (film): 3400, 2980, 2890, 1720, 1445, 1378, 1238, 742 cm-1.
1H-NMR (CDCl3) ": 0.77 (6H, t, J=7.3 Hz), 1.33–1.42 (4H, m), 1.99 (3H, s), 2.64 (4H, t, J=7.8 Hz), 2.97
(1H, d, J=16.6 Hz), 3.02 (1H, d, J=16.6 Hz), 3.09 (1H, d, J=16.1 Hz), 3.13 (1H, d, J=16.1 Hz), 3.99 (1H,
d, J=11.7 Hz), 4.02 (1H, d, J=11.7 Hz), 6.80 (1H, d, J=7.0 Hz), 6.83 (1H, s), 7.08 (1H, dd, J=8.3, 7.0 Hz),
7.12 (1H, d, J=8.3 Hz), 7.83 (1H, br s). High resolution MS m/z: Calcd for C20H28N2O2: 328.2149. Found:
328.2156.
4-Hydroxy-1,3,4,5-tetrahydrobenz[cd]indole (28a) from 16 — NaBH4 (212.8 mg, 5.56 mmol) was
added to a solution of 16 (109.2 mg, 0.64 mmol) in MeOH (5 mL) and stirred at rt for 20 min. After
addition of H2O, the whole was extracted with CH2Cl2.The extract was washed with brine, dried over
Na2SO4, and evaporated under reduced pressure. The residue was column-chromatographed on SiO2 with
EtOAc–hexane (1:2, v/v) to give 28a (110.4 mg, 99%). 28a: mp 87—88 °C (colorless prisms,
recrystallized from ether–hexane). IR (KBr): 3400, 1440, 1043, 755 cm-1. 1H-NMR (CDCl3) ": 2.95 (1H,

HETEROCYCLES, Vol. 88, No. 1, 2014
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dd, J=15.2, 6.7 Hz), 3.06 (1H, dd, J=15.8, 6.7 Hz), 3.15 (1H, dd, J=15.2, 3.8 Hz), 3.21 (1H, dd, J=15.8,
3.8 Hz), 4.45–4.51 (1H, m), 6.87 (1H, dd, J=6.8, 0.9 Hz), 6.92 (1H, d, J=1.1 Hz), 7.14 (1H, dd, J=8.2, 6.8
Hz), 7.19 (1H, dd, J=8.2, 0.9 Hz), 7.91 (1H, br s). MS m/z: 173 (M+). Anal. Calcd for C11H11NO: C,
76.27; H, 6.40; N, 8.09. Found: C, 76.34; H, 6.43; N, 8.02.
4-Hydroxy-1-propyl-1,3,4,5-tetrahydrobenz[cd]indole (28b) from 28a — A solution of 28a (54.3 mg,
0.31 mmol) in abs. DMF (0.5 mL) was added to 60% NaH (14.7 mg, 0.37 mmol) in a flask cooled on an
ice bath with stirring. Then propyl iodide (81.0 mg, 0.47 mmol) was added and stirred for 3 h at rt. After
addition of sat. aq. NH4Cl, the whole was extracted with EtOAc. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The residue was column-chromatographed on SiO2
with EtOAc–hexane (1:3, v/v) to give 28b (64.5 mg, 96%). 28b: colorless oil. IR (film): 3340, 2930, 1462,
1
1047, 746 cm-1. H-NMR (CDCl3) ": 0.93 (3H, t, J=7.3 Hz), 1.85 (2H, sext, J=7.3 Hz), 2.93 (1H, dd,
J=15.2, 6.8 Hz), 3.04 (1H, dd, J=15.7, 3.6 Hz), 3.13 (1H, ddd, J=15.2, 3.6, 0.9 Hz), 3.19 (1H, dd, J=15.7,
3.6 Hz), 4.03 (2H, t, J=7.3 Hz), 4.43–4.49 (1H, m), 6.80 (1H, s), 6.83 (1H, ddd, J=6.2, 1.5, 0.9 Hz), 7.12
(1H, d, J=8.1 Hz), 7.14 (1H, dd, J=8.1, 6.2 Hz). High resolution MS m/z: Calcd for C14H17NO: 215.1309.
Found: 215.1316.
4-Acetoxy-1-propyl-1,3,4,5-tetrahydrobenz[cd]indole (28c) from 28b — Ac2O (0.5 mL) was added to
a solution of 28b (12.0 mg, 0.06 mmol) in pyridine (1 mL) and the whole was stirred at rt for 15 h. After
evaporation of the solvent under reduced pressure, the residue was purified by column-chromatography
on SiO2 with CH2Cl2–hexane (1:2, v/v) as an eluent to 28c (10.3 mg, 75%). 28c: colorless oil. IR (film):
1740, 1460, 1370, 1244, 1038, 1026, 745 cm-1. 1H-NMR (CDCl3) ": 0.93 (3H, t, J=7.3 Hz), 1.85 (2H, sext,
J=7.3 Hz), 2.04 (3H, s), 2.97 (1H, ddd, J=15.0, 7.9, 1.6 Hz), 3.10 (1H, dd, J=15.7, 7.9 Hz), 3.21 (2H, ddd,
J=15.7, 15.0, 4.4 Hz), 4.02 (2H, dt, J=7.3, 1.4 Hz), 5.40–5.47 (1H, m), 6.77 (1H, s), 6.80 (1H, ddd, J=6.0,
2.6, 1.4 Hz), 7.12 (1H, dd, J=8.0, 6.0 Hz), 7.14 (1H, d, J=8.0 Hz). High resolution MS m/z: Calcd for
C16H19NO2: 257.1415. Found: 257.1417.
4-Hydroxy-1-tosyl- (29a) and 1-Tosyl-4-tosyloxy-1,3,4,5-tetrahydrobenz[cd]indole (29b) from 28a —
A solution of 28a (111.6 mg, 0.65 mmol) in abs. DMF (2 mL) was added to 60% NaH (31.0 mg, 0.78
mmol) in a flask cooled on an ice bath with stirring. Then tosyl chloride (185.3 mg, 0.96 mmol) was
added and stirred at rt for 3 h. After addition of sat. aq. NH4Cl, the whole was extracted with EtOAc. The
extract was washed with brine, dried over Na2SO4, and evaporated under reduced pressure. The residue
was column-chromatographed on SiO2 with CH2Cl2–MeOH (99:1, v/v) to give 29b (84.9 mg, 27%),
unreacted 28a (37.8 mg, 34%), and 29a (77.6 mg, 37%) in the order of elution. 29a: pale purple oil. IR
1
(film): 3380, 1438, 1358, 1175, 1110, 1085, 670, 580 cm-1. H-NMR (CDCl3) ": 2.34 (3H, s), 2.83 (1H,
ddd, J=15.7, 7.2, 1.3 Hz), 2.95 (1H, dd, J=16.1, 7.2 Hz), 3.03 (1H, br dd, J=15.7, 3.8 Hz), 3.11 (1H, dd,
J=16.1, 3.8 Hz), 4.35–4.41 (1H, m), 6.99 (1H, dd, J=7.3, 0.9 Hz), 7.21 (2H, dd, J=8.5, 0.9 Hz), 7.22 (1H,

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HETEROCYCLES, Vol. 88, No. 1, 2014
s), 7.26 (1H, dd, J=8.3, 7.3 Hz), 7.74 (1H, dd, J=8.3, 0.9 Hz), 7.77 (2H, br d, J=8.5 Hz). High resolution
MS m/z: Calcd for C18H17NO3S: 327.0928. Found: 327.0921. 29b: colorless oil. IR (film): 1360, 1187,
1
1178, 1118, 1090, 912, 668 cm-1. H-NMR (CDCl3) ": 2.34 (3H, s), 2.46 (3H, s), 2.97 (1H, ddd, J=16.0,
7.7, 1.4 Hz), 3.05 (1H, ddd, J=16.0, 4.0, 1.0 Hz), 3.08 (2H, d, J=5.9 Hz), 4.98–5.05 (1H, m), 6.89 (1H, d,
J=7.3 Hz), 7.15 (1H, s), 7.22 (1H, dd, J=7.9, 7.3 Hz), 7.22 (2H, dd, J=8.6, 0.9 Hz), 7.31 (2H, dd, J=8.6,
0.9 Hz), 7.72 (1H, d, J=7.9 Hz), 7.74 (4H, t, J=8.6 Hz). High resolution MS m/z: Calcd for C25H23NO5S2:
481.1015. Found: 481.1006.
4-Propyloxy-1-tosyl-1,3,4,5-tetrahydrobenz[cd]indole (30a) from 29a — A solution of 29a (24.0 mg,
0.07 mmol) in abs. DMF (1.5 mL) was added to 35% KH (33.2 mg, 0.29 mmol) in a flask cooled on an
ice bath with stirring. Then propyl iodide (52.3 mg, 0.31 mmol) was added and stirred at rt for 22.5 h.
After addition of H2O, the whole was extracted with EtOAc. The extract was washed with brine, dried
over Na2SO4, and evaporated under reduced pressure. The residue was subjected to p-TLC on SiO2 with
EtOAc–hexane (1:3, v/v) as a developing solvent. Extraction of the bands having an Rf value of
0.14–0.08 and 0.62–0.53 with CH2Cl2–MeOH (95:5, v/v) gave unreacted 29a (4.0 mg, 18%) and 30a
(12.8 mg, 47%), respectively. 30a: pale purple oil. IR (film): 1363, 1175, 1103, 1085, 670, 583 cm-1.
1H-NMR (CDCl3) ": 0.89 (3H, t, J=7.3 Hz), 1.57 (2H, sext, J=7.3 Hz), 2.33 (3H, s), 2.72 (1H, ddd,
J=15.4, 9.1, 1.8 Hz), 2.89 (1H, dd, J=15.8, 9.1 Hz), 3.11 (1H, dd, J=15.4, 4.0 Hz), 3.15 (1H, dd, J=15.8,
4.0 Hz), 3.51 (2H, t, J=7.3 Hz), 3.81–3.88 (1H, m), 6.97 (1H, d, J=7.1 Hz), 7.17 (1H, s), 7.20 (2H, d,
J=8.4 Hz), 7.24 (1H, dd, J=8.2, 7.1 Hz), 7.71 (1H, d, J=8.2 Hz), 7.76 (2H, br d, J=8.4 Hz). High
resolution MS m/z: Calcd for C21H23NO3S: 369.1397. Found: 369.1400.
4-Propyloxy-1,3,4,5-tetrahydrobenz[cd]indole (30b) from 30a — 8% NaOH (1 mL) was added to a
solution of 30a (10.6 mg, 0.03 mmol) and stirred at reflux for 17 h. After adding H2O, the whole was
extracted with CH2Cl2. 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 (1:4,
v/v) to give 30b (6.0 mg, 86%). 30b: colorless oil. IR (film): 3420, 2940, 1445, 1080, 748 cm-1. 1H-NMR
(CDCl3) ": 0.95 (3H, t, J=7.3 Hz), 1.64 (2H, sext, J=7.3 Hz), 2.99 (1H, dd, J=15.4, 9.5 Hz), 3.22–3.29
(2H, m), 3.58 (2H, t, J=7.3 Hz), 3.91–3.98 (1H, m), 6.84 (1H, ddd, J=6.8, 1.6, 0.9 Hz), 6.87 (1H, s), 7.12
(1H, dd, J=8.2, 6.8 Hz), 7.16 (1H, d, J=8.2 Hz), 7.26 (1H, br s). High resolution MS m/z: Calcd for
C14H17NO: 215.1309. Found: 215.1314.
2-Bromo-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (31) from 6 — NBS (116.3 mg, 0.65 mmol) and
AIBN (20.1 mg, 0.12 mmol) were added to a solution of 6 (121.7 mg, 0.60 mmol) in dry CHCl3 (40 mL)
and the mixture was heated at reflux for 30 min with stirring. After cooling, aq. 10% Na2S2O3 was added.
The whole was extracted with CHCl3. 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

HETEROCYCLES, Vol. 88, No. 1, 2014
515
CH2Cl2–hexane (1:1, v/v) to give 31 (147.7 mg, 87%). 31: mp 125—135 °C (decomp., pale yellow
needles, recrystallized from CH2Cl2–hexane). IR (KBr): 3390, 1535, 1440, 1419, 1375, 1339, 1112, 758
1
cm-1. H-NMR (CDCl3) ": 3.39 (1H, dd, J=15.3, 8.3 Hz), 3.42 (1H, dd, J=15.8, 5.5 Hz), 3.52 (1H, dd,
J=15.6, 4.6 Hz), 3.59 (1H, ddd, J=15.8, 8.3, 0.9 Hz), 4.96–5.03 (1H, m), 6.90–6.94 (1H, m), 7.13–7.17
(2H, m), 7.99 (1H, br s). MS m/z: 282, 280 (M+). Anal. Calcd for C11H9BrN2O2: C, 47.00; H, 3.23; N, 9.97.
Found: C, 46.72; H, 3.30; N, 9.73.
2,6-Dibromo- (32), 2,8-Dibromo- (33), 2,7-Dibromo-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (34)
from 31 — NBS (1.614 g, 9.07 mmol) and AIBN (270.7 mg, 4.22 mmol) were added to a solution of 31
(2.298 g, 8.18 mmol) in dry CHCl3 (800 mL) and the mixture was heated at reflux for 1 h with stirring.
After cooling, the whole was irradiated with 100W mercury lamp in quartz bottle for 30 min under Ar
atmosphere. After evaporation of the solvent under reduced pressure, the residue was purified repeatedly
by column-chromatography on SiO2 and HPLC (SiO2, 15 Kgf/cm2, 1.5 mL/min). In the order of elution,
33 (58.7 mg, 2%), 34 (403.8 mg, 14%), unreacted 31 (205.8 mg, 9%), and 32 (1.066 g, 36%) were
obtained. 32: mp 164—167 °C (decomp., yellow needles, recrystallized from nitro CH2Cl2–hexane). IR
(KBr): 3400, 1539, 1440, 1375, 1311, 788 cm-1. 1H-NMR (CDCl3) ": 3.38 (2H, m), 3.52 (1H, dd, J=15.5,
8.6 Hz), 3.58 (1H, dd, J=15.5, 4.9 Hz), 4.98–5.04 (1H, m), 7.04 (1H, d, J=8.6 Hz), 7.30 (1H, d, J=8.6 Hz),
8.04 (1H, br s). MS m/z: 362, 360, 358 (M+). Anal. Calcd for C11H8Br2N2O2: C, 36.70; H, 2.24; N, 7.78.
Found: C, 36.60; H, 2.08; N, 7.73. 33: mp 194—196 °C (decomp., pale yellow needles, recrystallized
1
from CH2Cl2–hexane). IR (KBr): 3330, 1544, 1433, 1373, 1363, 1323, 800 cm-1. H-NMR (CDCl3) ":
3.38 (1H, dd, J=16.1, 5.7 Hz), 3.42 (1H, dd, J=15.7, 7.9 Hz), 3.48 (1H, dd, J=16.1, 4.3 Hz), 3.56 (1H, dd,
J=15.7, 8.4 Hz), 4.95–5.04 (1H, m), 6.83 (1H, d, J=7.7 Hz), 7.27 (1H, d, J=7.7 Hz), 8.10 (1H, br s). MS
m/z: 362, 360, 358 (M+). Anal. Calcd for C11H8Br2N2O2: C, 36.70; H, 2.24; N, 7.78. Found: C, 36.74; H,
2.11; N, 7.74. 34: mp 130—134 °C (decomp., pale yellow needles, recrystallized from CH2Cl2–hexane).
IR (KBr): 3400, 1621, 1542, 1438, 1370, 1320, 1063, 840 cm-1. 1H-NMR (CDCl3) ": 3.38 (1H, dd, J=16.3,
5.5 Hz), 3.42 (1H, dd, J=16.1, 8.8 Hz), 3.47 (1H, dd, J=16.3, 5.5 Hz), 3.58 (1H, dd, J=16.1, 8.8 Hz),
4.95–5.02 (1H, m), 7.08 (1H, d, J=1.1 Hz), 7.32 (1H, d, J=1.1 Hz), 8.02 (1H, br s). MS m/z: 362, 360, 358
(M+). Anal. Calcd for C11H8Br2N2O2: C, 36.70; H, 2.24; N, 7.78. Found: C, 36.70; H, 2.24; N, 7.76.
1-Acetyl-2,6-Dibromo-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (35) from 32 — Ac2O (0.5 mL) was
added to a solution of 32 (122.1 mg, 0.34 mmol) in pyridine (1 mL) and the whole was stirred at rt for 24
h. After addition of sat. aq. NH4Cl, the whole was extracted with CH2Cl2. The extract was washed with
brine, dried over Na2SO4, and evaporated under reduced pressure to leave an oil, which was subjected to
column-chromatography on SiO2 with acetone–hexane (1:5, v/v) as an eluent to give 35 (83.9 mg, 62%).
35: mp 145–147 °C (decomp., pale orange prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 1705,
1540, 1435, 1368, 1290 cm-1. 1H-NMR (CDCl3) ": 2.85 (3H, s), 3.32 (1H, dd, J=16.1, 5.0 Hz), 3.39 (1H,

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dd, J=16.3, 8.1 Hz), 3.54 (1H, dd, J=16.1, 5.0 Hz), 3.58 (1H, dd, J=16.3, 8.1 Hz), 5.00–5.07 (1H, m),
7.46 (1H, d, J=8.8 Hz), 7.96 (1H, d, J=8.8 Hz). MS m/z: 404, 402, 400 (M+). Anal. Calcd for
C13H10Br2N2O3: C, 38.84; H, 2.51; N, 6.97. Found: C, 38.62; H, 2.35; N, 6.85.
2-Bromo-4-hydroxymethyl-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (36) from 22a — NBS (126.8
mg, 0.71 mmol) and AIBN (21.9 mg, 0.13 mmol) were added to a solution of 22a (153.7 mg, 0.66 mmol)
in dry CHCl3 (50 mL) and the mixture was heated at reflux for 30 min with stirring. After evaporation of
the solvent under reduced pressure, the residue was column-chromatographed on SiO2 with
EtOAc–hexane (1:4, v/v) to give 36 (189.2 mg, 92%). mp 160–163 °C (decomp., yellow prisms,
recrystallized from MeOH). IR (KBr): 3485, 3285, 1537, 1441, 1340, 1063, 1022, 858, 763, 745 cm-1.
1H-NMR (CD3OD) ": 3.11 (1H, d, J=16.1 Hz), 3.31 (1H, d, J=16.3 Hz), 3.60 (1H, dd, J=16.1, 1.3 Hz),
3.71 (1H, d, J=16.3 Hz), 3.91 (1H, d, J=11.8 Hz), 3.94 (1H, d, J=11.8 Hz), 6.82 (1H, dd, J=8.2, 0.9 Hz),
7.04 (1H, br t, J=8.2 Hz), 7.08 (1H, dd, J=8.2, 0.9 Hz). MS m/z: 312, 310 (M+). Anal. Calcd for
C12H11BrN2O3: C, 46.32; H, 3.56; N, 9.00. Found: C, 46.22; H, 3.65; N, 8.91.
4-Acetoxymethyl-2,6-dibromo- (37a) 4-Acetoxymethyl-1-acetyl-2,6-dibromo- (37b), 4-Acetoxymethyl-
2-bromo- (38), 4-Acetoxymethyl-2,8-dibromo- (39) and 4-Acetoxymethyl-2,7-dibromo-4-nitro-
1,3,4,5-tetrahydrobenz[cd]indole (40) from 36 — NBS (43.6 mg, 0.25 mmol) and AIBN (7.5 mg, 0.05
mmol) were added to a solution of 36 (70.9 mg, 0.23 mmol) in dry MeCN (20 mL) and the mixture was
heated at reflux for 30 min with stirring. After cooling, the whole was irradiated with 100W mercury
lamp in quartz bottle for 10 min under Ar atmosphere. After evaporation of the solvent under reduced
pressure, the residue was dissolved in pyridine (2 mL). Ac2O (1 mL) was then added and stirred at rt for 1
h. After evaporation of the solvent under reduced pressure, the residue was column-chromatographed
repeatedly on SiO2 with acetone–hexane (1:2, v/v) to give 39 (5.2 mg, 5%), 38 (1.7 mg, 2%), 40 (1.7 mg,
2%), 37a (13.5 mg, 14%), and 37b (14.9 mg, 14%) in the order of elution. 37a: mp 170–173 °C (decomp.,
pale yellow prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3440, 1750, 1550, 1442 cm-1.
1H-NMR (CDCl3) ": 2.11 (3H, s), 3.18 (1H, d, J=16.2 Hz), 3.39 (1H, d, J=16.8 Hz), 3.58 (1H, d, J=16.2
Hz), 3.78 (1H, d, J=16.8 Hz), 4.44 (1H, d, J=12.2 Hz), 4.48 (1H, d, J=12.2 Hz), 7.03 (1H, d, J=8.6 Hz),
7,29 (1H, d, J=8.6 Hz), 8.02 (1H, br s). MS m/z: 434, 432, 430 (M+). Anal. Calcd for
C14H12Br2N2O4•1/4H2O: C, 38.52; H, 2.89; N, 6.42. Found: C, 38.42; H, 2.83; N, 6.35. 37b: mp
149–152 °C (decomp., pale yellow prisms, recrystallized from CHCl3). IR (KBr): 1750, 1708, 1543, 1438,
1
1375, 1300, 1230, 1205, 1040, 812 cm-1. H-NMR (CDCl3) ": 2.13 (3H, s), 2.85 (3H, s), 3.12 (1H, d,
J=17.0 Hz), 3.33 (1H, d, J=17.0 Hz), 3.60 (1H, dd, J=17.0, 1.2 Hz), 3.81 (1H, d, J=17.0 Hz), 4.48 (1H, d,
J=12.1 Hz), 4.51 (1H, d, J=12.1 Hz), 7.45 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=8.8 Hz). MS m/z: 476, 474,
472 (M+). Anal. Calcd for C16H14Br2N2O5•1/4H2O: C, 40.15; H, 3.05; N, 5.85. Found: C, 40.15; H, 2.95; N,
5.77. 38: mp 141–143 °C (decomp., pale yellow prisms, recrystallized from MeOH–H2O). IR (KBr):

HETEROCYCLES, Vol. 88, No. 1, 2014
517
3430, 1755, 1543, 1443, 1205, 1043 cm-1. 1H-NMR (CDCl3) ": 2.09 (3H, s), 3.12 (1H, dd, J=16.1, 0.8 Hz),
3.41 (1H, d, J=16.3 Hz), 3.62 (1H, dd, J=16.1, 0.8 Hz), 3.78 (1H, d, J=16.3 Hz), 4.44 (2H, s), 6.91–6.94
(1H, m), 7.11–7.16 (2H, m), 8.00 (1H, br s). MS m/z: 354, 352 (M+). Anal. Calcd for C14H13BrN2O4: C,
47.61; H, 3.71; N, 7.93. Found: C, 47.52; H, 3.61; N, 7.84. 39: mp 194–197 °C (decomp., colorless
prisms, recrystallized from CH2Cl2–hexane). IR (KBr): 3240, 1737, 1545, 1440, 1372, 1260, 1038 cm-1.
1H-NMR (CDCl3) ": 2.10 (3H, s), 3.20 (1H, d, J=16.5 Hz), 3.34 (1H, d, J=16.5 Hz), 3.63 (1H, dd, J=16.5,
1.0 Hz), 3.75 (1H, d, J=16.5 Hz), 4.46 (2H, s), 6.83 (1H, dd, J=7.7, 1.0 Hz), 7.26 (1H, d, J=7.7 Hz), 8.14
(1H, br s). MS m/z: 434, 432, 430 (M+). Anal. Calcd for C14H12Br2N2O4•1/4H2O: C, 38.52 H, 2.89; N, 6.42.
Found: C, 38.60; H, 2.82; N, 6.41. 40: mp 165–167 °C (decomp., colorless prisms, recrystallized from
MeOH–H2O). IR (KBr): 3290, 1725, 1543, 1443, 1249, 1045 cm-1. 1H-NMR (CDCl3) ": 2.10 (3H, s), 3.19
(1H, d, J=16.3 Hz), 3.35 (1H, d, J=16.5 Hz), 3.61 (1H, d, J=16.3 Hz), 3.76 (1H, d, J=16.5 Hz), 4.42 (1H,
d, J=12.0 Hz), 4.48 (1H, d, J=12.0 Hz), 7.09 (1H, d, J=0.9 Hz), 7.31 (1H, s), 7.99 (1H, br s). MS m/z: 434,
432 (M+). Anal. Calcd for C14H12Br2N2O4: C, 38.92; H, 2.80; N, 6.48. Found: C, 38.97; H, 2.83; N, 6.42.
37b from 37a — Ac2O (1 mL) was added to a solution of 37a (33.1 mg, 0.08 mmol) in pyridine (2 mL)
and the whole was stirred at rt for 1 h. After evaporation of the solvent under reduced pressure, the
residue was subjected to p-TLC on SiO2 with acetone–hexane (2:5, v/v) as a developing solvent.
Extraction of the band having an Rf value of 0.80–0.71 with EtOAc afforded 37b (28.8 mg, 80%).
38 from 36 — Ac2O (0.5 mL) was added to a solution of 36 (50.6 mg, 0.16 mmol) in pyridine (1 mL) and
the whole was stirred at rt for 1 h. After evaporation of the solvent under reduced pressure, the residue
was column-chromatographed on SiO2 with CH2Cl2–hexane (1:1, v/v) as an eluent to give 38 (56.5 mg,
98%).
2,7-Dibromo-4-hydroxymethyl-4-nitro-1,3,4,5-tetrahydrobenz[cd]indole (41) from 34 — KOt-Bu
(44.5 mg, 0.4 mmol) was added to a solution of 34 (236.5 mg, 0.66 mmol) in MeOH (5 mL) and stirred at
rt for 15 min. A solution of 37% HCHO (57.6 mg, 0.71 mmol) was then added and the whole was stirred
at rt for 3 h. After addition of sat. aq. NH4Cl, the whole was extracted with CH2Cl2. 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 (1:4, v/v) to give 34 (68.7 mg, 29%) and 41
(153.0 mg, 60%) in the order of elution. 41: mp 165–168 °C (decomp., pale yellow prisms, recrystallized
from MeOH–H2O). IR (KBr): 3500, 3370, 3220, 1535, 1522, 1443, 1053 cm-1. 1H-NMR (CDCl3) ": 2.02
(1H, br s), 3.22 (1H, d, J=16.1 Hz), 3.36 (1H, d, J=16.5 Hz), 3.57 (1H, d, J=16.1 Hz), 3.72 (1H, d, J=16.5
Hz), 3.92 (1H, d, J=12.5 Hz), 3.95 (1H, d, J=12.5 Hz), 7.09 (1H, d, J=0.9 Hz), 7.31 (1H, d, J=0.9 Hz),
7.96 (1H, br s). MS m/z: 392, 390, 388 (M+). Anal. Calcd for C12H10Br2N2O3: C, 36.95; H, 2.58; N, 7.18.
Found: C, 37.02; H, 2.64; N, 7.18.
40 from 41 — Ac2O (0.5 mL) was added to a solution of 41 (36.1 mg, 0.09 mmol) in pyridine (1 mL) and

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the whole was stirred at rt for 3 h. After evaporation of the solvent under reduced pressure, the residue
was subjected to p-TLC on SiO2 with EtOAc–hexane (1:2, v/v) as a developing solvent. Extraction of the
band having an Rf value of 0.72–0.63 with CH2Cl2 afforded 40 (29.6 mg, 74%).
Optical Resolution of (+)-4-Nitro-1,3,4,5-tetrahydrobenz[cd]indole (6) — Optical resolution of (+)-6
was carried out by HPLC with semi-preparative Chiralpak AS column (Daicel Kagaku ltd.). Thus, 3.0 mL
of a solution of (+)-6 (141.3 mg, 0.70 mmol) in hexane–isopropanol (18:1, v/v, 123.0 mL) was injected to
the column and hexane–isopropanol (18:1, v/v) was used as an eluent employing flow rate 1.0 mL/min.
The eluted optical isomer of 6 was detected by UV detector (280.0 nm). Fractions having retention time
of 60–67 min gave (+)-6. Fractions having retention time of 67–70 min were a mixture of (+)-6 and (–)-6,
while (–)-6 eluted with retention time of 70–78 min. A mixture of (+)-6 and (–)-6 were separated by
repeating the above procedure. Injections and separation of the mixture were repeated over and over again.
Finally, (+)-6 (61.4 mg, 44%) and (–)-6 (57.2 mg, 41%) were obtained.
Purity of each optical isomer was confirmed utilizing HPLC with Chiralpak AS column for analysis with
hexane–isopropanol (18: 1, v/v) as an eluent (flow rate 1.5 mL/min, UV detection 280.0 nm). (+)-6: mp
126.5–127 °C (colorless prisms, recrystallized from MeOH). IR (KBr): 3399, 3117, 2960, 1611, 1604,
1530, 1441, 1418, 1372, 1361, 1345, 1281, 1220, 1080, 987, 872, 840, 812, 774, 753, 560, 517 cm-1.
[ꢁ]D +7.12° (c 0.24, 99.5% EtOH)ꢂ(–)-6: mp 125–126 °C (colorless prisms, recrystallized from
23
MeOH). IR (KBr): 3400, 3118, 2965, 1610, 1605, 1531, 1441, 1418, 1372, 1361, 1345, 1281, 1220, 1080,
987, 872, 840, 812, 774, 753, 560, 518 cm-1. [ꢁ]D23 –7.38° (c 0.25, 99.5% EtOH). 1H-NMR data of (+)-6
and (–)-6 were identical with that of (+)-6.
REFERENCES AND NOTES
1. a) This report is Part 140 of a series entitled “The Chemistry of Indoles”; b) Part 139: F. Yamada, D.
Shinmyo, M. Nakajou, and M. Somei, Heterocycles, 2012, 86, 435.
2. Professor Emeritus of Kanazawa University. Present address: Matsuhidai 56-7, Matsudo, Chiba
270-2214, Japan.
3. a) M. Somei, Heterocycles, 2011, 82, 1007; b) M. Somei, Heterocycles, 2008, 75, 1021; c) M. Somei,
Yakugaku Zasshi, 2008, 128, 527; d) M. Somei, S. Sayama, K. Naka, K. Shinmoto, and F. Yamada,
Heterocycles, 2007, 73, 537.
4. a) A. Hattori, M. Ikegame, S. Yano, M. Somei, and N. Suzuki, Anti-Aging Medicine, 2013, 9, 356; b)
Y. Mikami, M. Somei, and M. Takagi, J. Biochem., 2009, 145, 239; c) Y. Mikami, M. Somei, and M.
Takagi, Endocrine Journal, 2009, 56, 665; d) N. Suzuki, M. Somei, A. Seki, R. J. Reiter, and A.
Hattori, J. Pineal Res., 2008, 45, 229; e) N. Suzuki, M. Somei, K. Kitamura, R. J. Reiter, and A.
Hattori, J. Pineal Res., 2008, 44, 326; f) M. Somei, T. Iwaki, F. Yamada, Y. Tanaka, K. Shigenobu,

HETEROCYCLES, Vol. 88, No. 1, 2014
519
K. Koike, N. Suzuki, and A. Hattori, Heterocycles, 2006, 68, 1565.
5. a) K. Yamada, Y. Tanaka, and M. Somei, Heterocycles, 2009, 79, 635; b) M. Somei, Chemistry,
2007, 62, 116; c) See reference 4f.
6. a) M. Somei, K. Yamada, M. Hasegawa, M. Tabata, Y. Nagahama, H. Morikawa, and F. Yamada,
Heterocycles, 1996, 43, 1855; b) See reference 4f.
7. L. I. Kruse and M. D. Meyer, J. Org. Chem., 1984, 49, 4761.
8. Y. Maki, T. Masugi, T. Hiramitsu, and T. Ogiso, Chem. Pharm. Bull., 1973, 21, 2460.
9. L. Franceschetti, A. G-Aburbeh, M. R. Mahmoud, B. Natalini, and R. Pellicciari, Tetrahedron Lett.,
1993, 34, 3185.
10. T. Iwasaki, H. Yamazaki, T. Nishitani, K. Kondo, and T. Sato, Chem. Pharm. Bull., 1992, 40, 122.
11. a) I. Ninomiya and T. Kiguchi, The Alkaloids, ed. by A. Brossi, Academic Press, New York, 1990,
38, 1; b) M. Somei, Yakugaku Zasshi, 1988, 108, 361.
12. a) D. C. Horwell, P. D. Nichols, and E. Roberts, Tetrahedron Lett., 1994, 35, 939; b) J. Y. L. Chung,
J. T. Wasicak, and A. M. Nadzan, Synth. Commun., 1992, 22, 1039.
13. a) A. Stoll and T. Petrzilka, Helv. Chim. Acta, 1952, 35, 148; b) L. S. Harris and F. C. Uhre, J.
Pharmacol. Exp. Ther., 1960, 128, 358; c) N. J. Bach, E. C. Kornfeld, N. D. Jones, M. O. Chaney, D.
E. Dorman, J. W. Paschal, J. A. Clemens, and E. B. Smalstig, J. Med. Chem., 1980, 23, 481; d) N. J.
Bach, E. C. Kornfeld, J. A. Clemens, and E. B. Smalstig, J. Med. Chem., 1980, 23, 812; e) J. R.
Boissier, L. Nedelec, C. Oberlander, and F. Labrie, Acta Pharm. Suec., Suppl. 2, 1983, 120; f) L.
Nedelec, A. Pierdet, P. Fauveau, C. Euvard, L. Proulx-Ferland, C. Dumont, F. Labrie, and L. R.
Boissier, J. Med. Chem., 1983, 26, 522; g) M. E. Flaugh, D. L. Mullen, R. W. Fuller, and N. R.
Mason, J. Med. Chem., 1988, 31, 1746; h) C. J. Moody, A. L. Beck, and W. J. Coates, Tetrahedron
Lett., 1989, 30, 4017; i) M. J. Martinelli, M. R. Leanna, D. L. Varie, B. C. Peterson, T. J. Kress, J. P.
Wepsiec, and V. V. Khau, Tetrahedron Lett., 1990, 31, 7579; j) D. L. Varie, Tetrahedron Lett., 1990,
31, 7583.
14. a) H. Plieninger, M. Hobel, and V. Liede, Chem. Ber., 1963, 96, 1618; b) M. Somei, Y. Karasawa,
and C. Kaneko, Chem. Lett., 1980, 813; c) A. P. Kozikowski, H. Ishida, and Y.-Y. Chen, J. Org.
Chem., 1980, 45, 3350; d) M. Somei, F. Yamada, Y. Karasawa, and C. Kaneko, Chem. Lett., 1981,
615; e) M. Somei, Y. Karasawa, T. Shoda, and C. Kaneko, Chem. Pharm. Bull., 1981, 29, 249; f) M.
Somei and T. Shoda, Heterocycles, 1982, 17, 417.
15. a) M. Somei, N. Aoki, and K. Nakagawa, Heterocycles, 1994, 38, 1479; b) K. Nakagawa, N. Aoki, H.
Mukaiyama, and M. Somei, Heterocycles, 1992, 34, 2269.
16. a) F. Yamada and M. Somei, Heterocycles, 1987, 26, 1173; b) M. Somei, M. Wakida, and T. Ohta,
Chem. Pharm. Bull., 1988, 36, 1162.

520
HETEROCYCLES, Vol. 88, No. 1, 2014
17. A. McKillop, J. D. Hunt, M. J . Zelesko, J. S. Fowler, E. C. Taylor, G. McGillivray, and F. Kienzle, J.
Am. Chem. Soc., 1971, 93, 4841.
18. M. Somei, F. Yamada, M. Kunimoto, and C. Kaneko, Heterocycles, 1984, 22, 797.
19. a) M. Somei, J. Synth. Org. Chem. Jpn., 1982, 40, 387; b) See also references 3b and 11b.
20. a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945; b) I. P. Beletskaya and A. V.
Cheprakov, Chem. Rev., 2000, 100, 3009.
21. a) P. Espinet and A. M. Echavarren, Angew. Chem., Int. Ed., 2004, 43, 4704; b) J. K. Stille, Angew.
Chem., Int. Ed. Engl., 1986, 25, 508.