A novel total synthesis of isocryptolepine based on a microwave-assisted tandem Curtius rearrangement and aza-electrocyclic reaction

Article abstract of DOI:10.1016/j.tet.2012.03.055

A new entry to the total synthesis of isocryptolepine (cryptosanguinolentine), isolated from Cryptolepis sanguinolenta, was achieved by constructing a tetracyclic ring system through a microwave-assisted tandem Curtius rearrangement and electrocyclic reac

Full text of DOI:10.1016/j.tet.2012.03.055

Tetrahedron 68 (2012) 4274e4279
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A novel total synthesis of isocryptolepine based on a microwave-assisted tandem
Curtius rearrangement and aza-electrocyclic reaction
,
a
a
a
b
Kaori Hayashi a, Tominari Choshi a , Kyoko Chikaraishi , Aimi Oda , Rikako Yoshinaga , Noriyuki Hatae ,
*
Minoru Ishikura c, Satoshi Hibino a
,
*
a Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama, Hiroshima 729-0292, Japan
b Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Matsuyama University, 4-2 Bunkyo-cho, Matsuyama, Ehime 790-8578, Japan
c Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new entry to the total synthesis of isocryptolepine (cryptosanguinolentine), isolated from Cryptolepis
sanguinolenta, was achieved by constructing a tetracyclic ring system through a microwave-assisted
Received 22 February 2012
Received in revised form 12 March 2012
Accepted 17 March 2012
tandem Curtius rearrangement and electrocyclic reaction of an aza 6
lactam was converted to isocryptolepine in a four-step sequence.
p-electron system. The tetracyclic
Available online 29 March 2012
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
consecutive Pd-catalyzed amination and arylation of the resulting
4-(2-chloroanilino)quinoline. The Mohan group4h in 2005 and
Kumar group4i in 2009 groups independently reported a short-step
synthesis of 1a in a high yield by the Fischer indole procedure. In
2007, the Miki group4j reported the total synthesis of 1a by an in-
teresting intermolecular decarboxylative Heck-type reaction. The
Joule group4k in 1998, Kundu group4l in 2009, and Kraus group4m in
2010 reported the synthesis of 1a by a modified Pictet-Spengler
Isocryptolepine (1a: cryptosanguinolentine) is an important
indolo[3,2-c]quinoline alkaloid, isolated from Cryptolepis sangui-
nolenta, and used in folk medicine as an antimalarial agent.1 Iso-
meric indoloquinoline alkaloids of cryptolepine (1b) and
neocryptolepine (1c) displaying similar activity were also found in
the same plant (Fig. 1).1 Isoneocryptolepine (1d), though not yet
found in nature, has potent antiplasmodial activity comparable to
that of 1a, 1b, and 1c.2 All of these compounds function as DNA-
intercalating agents and strongly inhibit human topoisomerase II.3
A linear indolo[3,2-c]quinoline, isocryptolepine (1a), was syn-
thesized using various strategies. In 1997, the Timari group4a
reported the first total synthesis of isocryptolepine (1a) by a Pd-
catalyzed cross-coupling reaction of 3-bromoquinoline and o-
substituted phenylboronic acid, followed by the formation of an
indole part using the nitrene insertion reaction. In 1999 and 2001,
the Molina group4b,c reported the synthesis of 1a by the application
of cyclization of o-vinylsubstituted arylheterocumulene under mi-
crowave irradiation, followed by the nitrene procedure. The Kraus
group4d in 2010, reported the synthesis of 1a by an intramolecular
Wittig reaction, followed by the nitrene process. The Mohan
group4e,f provided two oxidative photochemical routes to 1a by the
formation of a quinoline part using a Schiff base between aniline
and indole-4-carbaldehyde, and by the formation of an indole part
from 4-(2-chloroanilino)quinoline in 2002 and 2006, respectively.
The Maes group4g in 2003 also reported a total synthesis of 1a by
10
9
11
N
N
8
1
7
2
N
3
6
Me
N5
4
cryptolepine (1b)
Me
isocryptolepine (1a)
N
N
N
N
Me
Me
neocryptolepine (1c)
isoneocryptolepine (1d)
* Corresponding authors. E-mail address: hibino@fupharm.fukuyama-u.ac.jp
(S. Hibino).
Fig. 1.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.055

K. Hayashi et al. / Tetrahedron 68 (2012) 4274e4279
4275
reaction for synthesis of the quinoline part. Recently, the Kusurkar
group4n reported the synthesis of 1a by the construction of
-car-
Known compound 5 was obtained in excellent yield from
a SuzukieMiyaura coupling reaction between the indole-2-boronic
acid 6 and methyl 2-iodobenzoate (7), followed by deprotection of
the N-Boc group of 8 in two steps according to the reported pro-
cedure10 (Scheme 2).
g
boline based on an intramolecular thermal electrocyclization using
our reported strategy.5
We are currently interested in the synthesis of fused pyridine
ring systems based on a thermal electrocyclic reaction of an aza 6p-
electron system.6 In this context, we developed the synthesis of PhIP
Beaumont method
and DMIP having an imidazo[4,5-b]pyridine,6,7a grossularines hav-
ing an
a
-carboline,6,7b and imiquimod having an imidazo[4,5-c]
quinoline6,7c by a thermal electrocyclic reaction of a 2-aza 6
p-
I
electron system using an isocyanate, according to a modified Eloy’s
pyrido-annulation.8 In addition, we have recently reported the
construction of several fused pyridine ring systems, such as furo[3,2-
h]isoquinoline,9a,b phenanthridine,9c benzo[c]phenanthridine,9d,e
+
B(OH)2
N
CO2Me
Boc
azaanthraquinone,9f and
b
-carboline9g alkaloids, using a micro-
-elec-
7
6
wave-assisted thermal electrocyclic reaction of a 1-aza 6
p
tron system.6 In the present work, we describe the total synthesis of
isocryptolepine (1a) by new construction of an indolo[3,2-c]quin-
oline ring system based on a microwave-assisted tandem Curtius
rearrangement followed by a thermal electrocyclic reaction of a 2-
Boc
Pd(PPh3)4
N
2M Na2CO3
aza 6p-electron system.
DME
reflux, 12 h
99%
CO2Me
2. Results and discussion
8
We planned to form the indolo[3,2-c]quinoline nucleus 2 using
a microwave-assisted thermal electrocyclic reaction of a 2-aza 6p-
HN
electron system of a 2-(indol-2-yl)phenylisocyanate 3, derived from
cleavage at a position of a C6eC6a bond of 2. An isocyanate 3 would
be prepared by Curtius rearrangement of an 2-(indol-2-yl)benzoic
acid (4), which is easily obtained from the known methyl 2-(indol-
2-yl)benzoate 510 as illustrated in the retrosynthetic analysis
(Scheme 1).
TFA
CH2Cl2
rt, 12 h
94%
CO2Me
5
Scheme 2.
N
HN
For synthesis of the indolo[3,2-c]quinoline ring, treatment of the
known ester 5 with an aqueous 1 M LiOH in THF afforded the
benzoic acid 411 in 30% yield along with tetracyclic lactam 911,12 as
a major product (65%). The carboxylic acid 4 was treated with
diphenylphosphoryl azide (DPPA)13 at 60 ꢀC in the presence of
triethylamine to give the unstable isocyanate 3. After replacing the
benzene with 1,2-dichlorobenzene without isolation, the mixture
was heated at 180 ꢀC for 15 min to produce the indolo[3,2-c]
quinoline 10 together with isomeric lactam 11 as an inseparable
mixture (1:1, 59% yield) (Scheme 3).
6a
6
N
N
OH
Me
2
isocryptolepine (1a)
Based on these experimental results, the starting material was
changed to N-Boc-2-indolylbenzoic acid 12 to prevent intra-
molecular amide formation (Scheme 4). Methyl N-Boc-indo-
lylcarboxylate 8 with aqueous LiOH gave the carboxylic acid 12
(71% yield), which was treated with DPPA at 50 ꢀC to yield the
isocyanate 13 (71%). When 13 was heated in 1,2-dichlorobenzene at
180 ꢀC for 15 min, an N-Boc-indolo[3,2-c]quinoline 14 was not
detected at all, but the indolo[3,2-c]quinoline 10, along with
elimination of the N-Boc group, was obtained in only low yield (6%)
(Scheme 4).
HN
HN
O
C
CO2H
4
N
3
We then selected a methoxymethyl (MOM) group of a less
sterically-hindered protecting group (Scheme 5). For the synthesis
of N-MOM-indolylbenzoate 15, treatment of 5 with MOMCl in the
presence of NaH afforded N-MOM-indolylbenzoate 15 in excellent
yield (91%). Subsequenthydrolysis of the ester15 with 1 MLiOH gave
the N-MOM-carboxylic acid 16 (98%). Surprisingly, treatment of the
carboxylic acid 16 with DPPA in benzene at 60 ꢀC for 1.5 h provided
the N-MOM-indolo[3,2-c]quinoline 18 (41%) without the isolation of
isocyanate 17 (Table 1, run 1). It was considered that this result
HN
CO2Me
5
Scheme 1.

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K. Hayashi et al. / Tetrahedron 68 (2012) 4274e4279
O
Boc
DPPA
Et3N
N
1 M LiOH
1 M LiOH
5
N
8
THF
THF
benzene
50 oC, 1.5 h
71%
60 oC, 12 h
60 oC, 12 h
COOH
12
9: 65%
71%
+
Boc
N
HN
DPPA
Et3N
O
1,2-dichlorobenzene
180 oC, 15 min
C
benzene
N
CO2H
50 oC, 1.5 h
4: 30%
13
HN
Boc
N
HN
O
1,2-dichlorobenzene
180 oC, 15 min
C
N
N
H
O
N
H
O
3
14: Not detection
10
Scheme 4.
O
HN
HN
3. Conclusion
N
+
We established a new and efficient total synthesis of iso-
cryptolepine 1a (cryptosanguinolentine) in 57.6% overall yield in
seven steps from the readily accessible known starting material 5.
The key novel step described here is the microwave-assisted tan-
dem Curtius rearrangement with DPPA and electrocyclic ring clo-
N
H
O
11
10
unseparable mixture (1:1)
sure of an aza 6p-electron system. Further application of this
Scheme 3.
tandem methodology to various types of alkaloids including a fused
pyridine ring system is under investigation in our laboratory.
proceeded by Curtius rearrangement followed by a thermal elec-
trocyclic reaction in one pot. As shown in Table 1, this tandem re-
action was investigated in further detail. Reaction time,
temperature, solvent, and microwave parameters were examined.
First, when the reaction time under the same conditions as run 1 was
increased from 1.5 h to 3 h, the yield improved from 41% to 83% (run
2). The use of toluene instead of benzene provided the more
promising result at the same temperature (runs 3 and 4). When the
reaction was performed in toluene at 60 ꢀC under microwave irra-
diation, product 18 was obtained in excellent yield and the reaction
time was decreased (runs 4 and 5). The microwave-assisted condi-
tion of run 7 was more effective than the conventional condition
(run 6) in terms of the yield, which increased from 89% to 99%.
To complete the total synthesis (Scheme 6), treatment of the
lactam 18 with trifluoromethanesulfonic anhydride (Tf2O) and
pyridine afforded the triflate 19, which was subjected to a reductive
cleavage of the trifluoromethanesulfonyloxy group of 20 with pal-
ladium(II) acetate and 1,3-bis(diphenylphosphino)propane in the
presence of triethylsilane in DMF at 60 ꢀC according to Katsuki’s
procedure14 to produce the N-MOM-indoloquinoline 20. Sub-
sequently, treatment of 20 with MeOH, trimethyl orthoformate,
and trifluoromethanesulfonic acid in nitromethane according to
our previously reported method15 gave the indolo[3.2-c]quinoline
21 in 96% yield. Finally, methylation of 21 with methyl iodide in
toluene according to Kundu’s procedure4l afforded isocryptolepine
(1a). The physical and spectroscopic data of our synthetic iso-
cryptolepine (1a) were identical with those of the previously
reported data.1,4n
4. Experimental section
4.1. General
All non-aqueous reactions were carried out under an atmo-
sphere of nitrogen in dried glassware unless otherwise noted.
Solvents were dried and distilled according to standard protocols.
Analytical thin-layer chromatography was performed with Silica
gel 60PF254 (Merck). Silica gel column chromatography was per-
formed with Silica gel 60 (70e230 mesh, Merck). All melting points
were determined on Yanagimoto micro melting point apparatus
and are uncorrected. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a JEOL AL-300 at 300 MHz. Chemical
shifts are reported relative to Me4Si (d 0.00). NMR spectra was
measured with CDCl3 unless otherwise noted. Multiplicity is in-
dicated by one or more of the following: s (singlet); d (doublet); t
(triplet); q (quartet); m (multiplet); br (broad). Carbon nuclear
magnetic resonance (13C NMR) spectra were recorded on a JEOL AL-
300 at 75 MHz. Chemical shifts are reported relative to CDCl3
(d
77.0) and DMSO-d6 39.7). Infrared spectra were recorded with
(d
ATR method using a Shimadzu FTIR-8000 spectrophotometer and
technologies DuraScop. Low and high resolution mass spectra were
recorded on JEOL JMS-700 spectrometers by direct inlet system.
4.1.1. 2-(1H-Indol-2-yl)benzoic acid 4 and 6H-Isoindolo[2,1-a]indol-
6-one 9. A mixture of N-Boceindolylbenzoate 510 (620 mg,

K. Hayashi et al. / Tetrahedron 68 (2012) 4274e4279
4277
MOM
Et3SiH
Pd(OAc)2
dppp
MOM
NaH
N
N
MOMCl
Tf2O, Py
5
18
DMF
rt, 12 h
91%
DMF
60 oC, 1 h
91%
CH2Cl2
rt, 30 min
83%
COOMe
15
N
OTf
19
MOM
MeOH
N
DPPA
MOM
CH(OMe)3
CF3SO3H
1 M LiOH
Et3N
N
HN
THF
60 oC, 12 h
98%
solvents
COOH
16
MeNO2
100 oC, 30 min
N
N
20
1) MeI
21
96%
MOM
MOM
N
N
N
toluene
reflux, 2 h
O
C
N
H
O
N
2) 28% NH4OH
90%
N
17
18
Me
1a
Scheme 5.
Scheme 6.
Table 1
Synthesis of Indolo[3,2-c]quinolin-6-one (18) by Microwave-assisted Tandem
Reaction
cooling to an ambient temperature, the mixture was acidified with
a 10% HCl solution, and then the resulting mixture was extracted
with EtOAc. The EtOAc layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give the benzoic acid 12
Run
Solvents
MWa
Temp (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
Benzene
Benzene
Toluene
Toluene
Toluene
Toluene
Toluene
d
d
d
d
þ
60
60
60
60
60
1.5
3
0.5
3
0.5
10 min
10 min
41
83
68
89
94
89
99
(41 mg, 71%), mp 145e148 ꢀC (EtOAcehexane). IR (ATR)
n
: 3059,
1701 cmꢁ1 1H NMR (300 MHz CDCl3)
d
: 1.24 (9H, s), 6.45 (1H, s), 7.24
(1H, t, J¼6.2 Hz), 7.33 (1H, t, J¼6.2 Hz), 7.44 (1H, t, J¼6.2 Hz), 7.49
(1H, d, J¼6.2 Hz), 7.54 (1H, d, J¼8.0 Hz), 7.59 (1H, t, J¼6.2 Hz), 8.09
(1H, d, J¼6.2 Hz), 8.25 (1H, d, J¼8.0 Hz). MS (EI) m/z: 337 (Mþ);
HRMS (EI) Calcd for C20H19NO4: 337.1314. Found: 337.1319.
d
þ
100
100
a
Discover (CEM corp.).
4.1.3. 2-[N-(tert-Butoxycarbonyl)-1H-indol-2-yl]phenylisocyanate
13. A solution of benzoic acid 12 (100 mg, 0.30 mmol), DPPA
(194 mL, 0.90 mmol), and Et3N (127 mL, 0.90 mmol) in toluene (3 mL)
2.5 mmol) and 1 M LiOH (12.5 mL) in THF (10 mL) was heated at
60 ꢀC for 12 h. After cooling to an ambient temperature, the mixture
was extracted with EtOAc. The EtOAc layer was washed with water
and brine, derived over Na2SO4 and concentrated in vacuo to give
the lactam 9 (356 mg, 65%). The water layer was acidified with
a 10% HCl solution, and then the resulting mixture was extracted
with EtOAc. The EtOAc layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo to give the benzoic acid 4
(180 mg, 30%). 4: mp 155e156 ꢀC (EtOAcehexane) (lit.11 mp
were stirred under microwave irradiation at 100 ꢀC for 1.5 h. After
cooling to an ambient temperature, the reaction mixture was
concentrated in vacuo. The residue was purified by column chro-
matography (silica gel, 10 g) using EtOAcehexane (1:9 v/v) as an
eluent to give the gummy isocyanate 13 (71 mg, 71%), which was
used without any further purification, but the following data were
obtained. IR (ATR) n d:
: 2277, 1727 cmꢁ1 1H NMR (300 MHz CDCl3)
155e157 ꢀC). IR (ATR) : 3361, 1718 cmꢁ1 1H NMR (300 MHz CDCl3)
n
1.25 (9H, s), 6.59 (1H, s), 6.84 (1H, br.s), 7.19 (1H, d, J¼6.4 Hz), 7.27
(1H, d, J¼8.4 Hz), 7.32 (1H, d, J¼6.4 Hz), 7.37e7.46 (1H, m), 7.60 (1H,
d, J¼8.0 Hz), 8.20 (1H, d, J¼8.0 Hz), 8.30 (1H, d, J¼8.4 Hz). MS (EI) m/
z: 334 (Mþ).
d
: 6.73 (1H,s), 7.12 (1H, t, J¼6.2 Hz), 7.21 (1H, t, J¼6.7 Hz), 7.40 (1H,
d, J¼7.7 Hz), 7.45 (1H, d, J¼6.4 Hz) 7.59 (1H, d, J¼6.2 Hz), 7.64 (1H, d,
J¼7.7 Hz), 7.74 (1H, d, J¼6.7 Hz),7.97 (1H, d, J¼6.4 Hz), 9.30 (1H, br
s). MS (EI) m/z: 237 (Mþ); HRMS (EI) Calcd for C15H11NO2: 237.0790.
Found: 237.0800. 9: mp 146e148 ꢀC (EtOAcehexane) (lit.12 mp
150e151 ꢀC). IR (ATR) : 1722 cmꢁ1 1H NMR (300 MHz CDCl3)
n d:
4.1.4. 5,7-Dihydroindolo[3,2-c]quinolin-6-one 10. A solution of iso-
cyanate 10 (50 mg, 0.15 mmol) in 1,2-dichlorobenzene (2 mL) was
heated at 180 ꢀC for 15 min. After cooling to an ambient tempera-
ture, the reaction mixture was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, 10 g) using
EtOAcehexane (1:1 v/v) as an eluent to give the indoloquinone 10
6.63 (1H,s), 7.16 (1H, t, J¼6.0 Hz), 7.29e7.38 (2H, m), 7.46 (1H, d,
J¼7.2 Hz), 7.49e7.54 (2H, m), 7.77 (1H, d, J¼6.0 Hz), 7.90 (1H, d,
J¼7.2 Hz). MS (EI) m/z: 219 (Mþ); HRMS (EI) Calcd for C15H9NO:
219.0684. Found: 219.0709.
(2 mg, 6%), mp 337e339 ꢀC (EtOAcehexane). IR (ATR)
1H NMR (300 MHz DMSO-d6)
: 7.23e7.31 (2H, m), 7.36 (1H, t,
J¼6.4 Hz), 7.44e7.53 (2H, m), 7.60 (1H, d, J¼8.0 Hz), 8.19 (1H, d,
n
: 1637 cmꢁ1
4.1.2. 2-[N-(tert-Butoxycarbonyl)-1H-indol-2-yl]benzoic acid 12. A
mixture of N-MOM indolylbenzoate 5 (60 mg, 0.17 mmol) and 1 M
LiOH (0.85 mL) in THF (10 mL) was heated at 60 ꢀC for 12 h. After
d

4278
K. Hayashi et al. / Tetrahedron 68 (2012) 4274e4279
J¼8.0 Hz), 11.41 (1H, s), 12.55 (1H, s). MS (EI) m/z: 234 (Mþ). HRMS
122.1, 122.9, 123.0, 126.8, 127.0, 129.2, 129.9, 140.9, 144.1, 144.1,
149.6. MS (EI) m/z: 410 (Mþ); HRMS (EI) Calcd for C18H13F3N2O4S:
410.0548. Found: 410.0557.
(EI) Calcd for C15H10N2O: 234.0793. Found: 234.0778.
4.1.5. Methyl 2-[(N-methoxymethyl)indol-2-yl]benzoate 15. A solu-
tion of methyl indolylbenzoate 5 (964 mg, 3.8 mmol) in DMF
(10 mL) was added to a suspension of NaH (456 mg, 11.4 mmol) in
DMF (10 mL) under cooling with ice. After stirring at rt for 30 min,
4.1.9. N-(Methoxymethyl)indolo[3,2-c]quinoline 20. A mixture of
triflate 19 (50 mg, 0.12 mmol), triethylsilane (191
Pd(OAc)2 (0.45 mg, 2 mol), and dppp (0.8 mg, 2
m
L, 1.2 mmol),
m
mmol) in DMF
chloromethyl methyl ether (866
mL, 11.4 mmol) was added drop-
(3 mL) were heated at 60 ꢀC for 1 h. After cooling to an ambient
temperature, the reaction mixture was quenched with water, and
then extracted with EtOAc. The EtOAc layer was washed with an
aqueous NaHCO3 (saturated) solution and brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 10 g) using EtOAcehexane (1:1 v/v) as
an eluent to give the indoloquinoline 20 (29 mg, 91%), mp
wise to the reaction mixture under cooling with ice, and stirred at rt
for 12 h. The reaction mixture was quenched with an aqueous
NH4Cl (saturated) solution, and then extracted with EtOAc. The
EtOAc layer was washed with brine, dried over Na2SO4 and con-
centrated in vacuo. The residue was purified by column chroma-
tography (silica gel, 20 g) using EtOAcehexane (1:10 v/v) as an
eluent to give the oily N-MOM indolylbenzoate 15 (1.02 g, 91%). IR
151e153 ꢀC (EtOAcehexane). 1H NMR (300 MHz CDCl3)
d: 3.50 (3H,
(ATR)
n
: 1724 cmꢁ1 1H NMR (300 MHz CDCl3)
d: 3.14 (3H, s), 3.63
s), 6.04 (2H, s), 7.44 (1H, t, J¼7.7 Hz), 7.58 (1H, t, J¼7.7 Hz), 7.65e7.79
(3H, s), 5.26 (2H, s), 6.46 (1H, s), 7.16 (1H, t, J¼7.7 Hz), 7.45e7.63 (6H,
(3H, m), 8.27 (1H, d, J¼7.7 Hz), 8.31 (1H, d, J¼7.7 Hz), 8.65 (1H, d,
m), 7.96 (1H, d, J¼7.7 Hz). 13C NMR (75 MHz CDCl3)
d
: 52.2, 55.7,
J¼7.7 Hz), 9.59 (1H, s). 13C NMR (75 MHz CDCl3)
d: 56.2, 75.6, 109.5,
75.0, 103.2, 110.1, 120.6, 122.1, 128.2, 128.7, 129.9, 130.2, 131.4, 132.1,
132.7, 137.3, 139.6, 139.7, 167.5. MS (EI) m/z: 295 (Mþ); HRMS (EI)
Calcd for C18H17NO3: 295.1208. Found: 295.1231.
116.0,117.9, 120.0, 121.9, 122.2, 122.9, 126.1, 126.3, 128.0, 130.5, 140.1,
140.9, 144.4, 147.0. MS (EI) m/z: 262 (Mþ); HRMS (EI) Calcd for
C17H14N2O: 262.1106. Found: 262.1091.
4.1.6. 2-[(N-Methoxymethyl)indol-2-yl]benzoic acid 16. A mixture
of N-MOM indolylbenzoate 15 (1.02 g, 3.5 mmol) and 1 M LiOH
(17 mL) in THF (20 mL) was heated at 60 ꢀC for 12 h. After cooling to
an ambient temperature, the mixture was acidified with a 10% HCl
solution, and then the resulting mixture was extracted with EtOAc.
The EtOAc layer was washed with brine, dried over Na2SO4 and
concentrated in vacuo to give the benzoic acid 16 (965 mg, 98%), mp
4.1.10. 11H-Indolo[3,2-c]quinoline 21. CF3SO3H (26
was added to a solution of indoloquinoline 20 (25 mg, 0.10 mmol),
MeOH (43 L, 1.0 mmol) and CH(OMe)3 (109 L, 1.0 mmol) in
mL, 0.30 mmol)
m
m
MeNO2 (2 mL) under cooling with ice, and then was heated at
100 ꢀC for 1 h. After cooling to an ambient temperature, the re-
action mixture was quenched with an aqueous Na2CO3 (saturated)
solution, and then extracted with EtOAc. The EtOAc layer was
washed with brine, dried over Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography (silica gel, 5 g)
using EtOAcehexane (1:1 v/v) as an eluent to give the indoloqui-
noline 21 (20 mg, 96%), mp 333e334 ꢀC (CHCl3ehexane). 1H NMR
126e128 ꢀC (EtOAcehexane). IR (ATR)
(300 MHz CDCl3) : 3.12 (3H, s), 5.23 (2H, s), 6.51 (1H, s), 7.18 (1H, t,
n
: 3047, 1685 cmꢁ1 1H NMR
d
J¼7.7 Hz), 7.27 (1H, t, J¼5.8 Hz), 7.47e7.65 (5H, m), 8.03 (1H, d,
J¼5.8 Hz). 13C NMR (75 MHz CDCl3)
d: 55.7, 74.9, 103.7, 110.0, 120.5,
120.6, 122.3,128.2,129.0,130.7,131.1,132.1,132.8,132.9,137.4,139.2,
170.8. MS (EI) m/z: 281 (Mþ); HRMS (EI) Calcd for C17H15NO3:
281.1052. Found: 281.1033.
(300 MHz DMSO-d6)
d
: 7.34 (1H, d, J¼7.2 Hz), 7.49 (1H, d, J¼7.2 Hz),
7.62e7.76 (3H, m), 8.13 (1H, d, J¼7.2 Hz), 8.31 (1H, d, J¼7.9 Hz), 8.50
(1H, d, J¼7.9 Hz), 9.58 (1H, s), 12.72 (1H, s). 13C NMR (75 MHz
DMSO-d6) d: 111.9, 114.3, 117.1, 120.5, 120.7, 121.9, 122.1, 125.6, 125.7,
4.1.7. N-(Methoxymethyl)indolo[3,2-c]quinolin-6-one 18. A solution
128.1, 129.6, 138.8, 139.8, 144.9, 145.4. MS (EI) m/z: 218 (Mþ); HRMS
of benzoic acid 16 (50 mg, 0.18 mmol), DPPA (97
mL, 0.45 mmol),
(EI) Calcd for C15H10N2: 218.0844. Found: 218.0826.
and Et3N (64 L, 0.45 mmol) in toluene (3 mL) were stirred under
m
microwave irradiation at 100 ꢀC for 10 min. After cooling to an
ambient temperature, the reaction mixture was concentrated in
vacuo. The residue was purified by column chromatography (silica
gel, 10 g) using EtOAcehexane (1:3 v/v) as an eluent to give the
indoloquinolone 18 (49 mg, 99%), mp 272e274 ꢀC (CHCl3ehexane).
4.1.11. Isocryptolepine 1a. A mixture of indoloquinoline 21 (20 mg,
0.092 mmol) and MeI (1.1 mL, 18 mmol) in toluene (3 mL) were
refluxed for 2 h. After cooling to an ambient temperature, the re-
action mixture was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, 5 g) using MeOHeCHCl3
(3:97 v/v) as an eluent to give isocryptolepine hydroiodide (1a-HI).
To obtain the free base, 28% ammonia (20 mL) was added to a so-
lution of 1a-HI in CH2Cl2 (30 mL), and then stirred for 10 min. The
organic layer was separated and the aqueous layer was further
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried over Na2SO4 and concentrated in vacuo to give
isocryptolepine (1a) (19 mg, 90%) as yellow powder, mp 191e193 ꢀC
(CHCl3-hexane) (lit.,4n mp 192e193 ꢀC). 1H NMR (300 MHz DMSO-
IR (ATR) n d: 3.51 (3H, s), 5.95
: 1643 cmꢁ1 1H NMR (300 MHz CDCl3)
(2H, s), 7.32e7.57 (5H, m), 7.65 (1H, d, J¼8.4 Hz), 8.41 (1H, d,
J¼8.4 Hz), 8.59 (1H, d, J¼8.4 Hz). 13C NMR (75 MHz CDCl3)
d: 56.3,
75.3, 109.0, 109.4, 112.8, 117.0, 122.5, 122.5, 122.6, 123.7, 124.3, 125.0,
129.3, 138.0, 140.1, 141.3, 161.1. MS (EI) m/z: 278 (Mþ); HRMS (EI)
Calcd for C17H14N2O2: 278.1055. Found: 278.1071.
4.1.8. N-(Methoxymethyl)-6-(trifluoromethanesulfonyloxy)indolo
[3,2-c]quinoline 19. Tf2O (86
of methyl indoloquinolone 18 (95 mg, 0.34 mmol) and pyridine
(82 L, 1.02 mmol) in CH2Cl2 (5 mL) under cooling with ice. After
m
L, 0.51 mmol) was added to a solution
d6)
d
: 4.27 (3H, s), 7.24 (1H, t, J¼7.1 Hz), 7.43 (1H, t, J¼7.9 Hz), 7.69
(1H, d, J¼7.9 Hz), 7.77e7.87 (2H, m), 8.06 (1H, d, J¼8.0 Hz), 8.12 (1H,
m
d, J¼7.1 Hz), 8.78 (1H, d, J¼8.0 Hz), 9.36 (1H, s). 13C NMR (75 MHz
stirring at rt for 30 min, the reaction mixture was quenched with
water, and then extracted with EtOAc. The EtOAc layer was washed
with brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, 10 g)
using EtOAcehexane (1:9 v/v) as an eluent to give the triflate 19
DMSO-d6) d: 41.7, 116.4, 116.9, 117.0, 119.2, 120.2, 120.5, 123.9, 124.9,
125.3, 125.9, 129.6, 135.7, 137.9, 152.1, 152.4. MS (EI) m/z: 232 (Mþ);
HRMS (EI) Calcd for C16H12N2: 232.1000. Found: 232.1008.
(116 mg, 83%), mp 154e156 ꢀC (EtOAcehexane). IR (ATR)
n
: 1404,
Acknowledgements
1199 cmꢁ1 1H NMR (300 MHz CDCl3)
d
: 3.52 (3H, s), 6.06 (2H, s),
7.51 (1H, t, J¼7.7 Hz), 7.63 (1H, t, J¼7.7 Hz), 7.69e7.82 (3H, m), 8.19
This work was partly supported by a Grant-in Aid for Scientific
Research (C) (No. 23590143) of the Japan Society for the Promotion
of Science (JSPS).
(1H, d, J¼7.7 Hz), 8.31 (1H, d, J¼7.7 Hz), 8.67 (1H, d, J¼7.7 Hz). 13C
NMR (75 MHz CDCl3) d: 56.5, 75.6, 109.6, 112.3, 117.8, 119.7, 120.9,

K. Hayashi et al. / Tetrahedron 68 (2012) 4274e4279
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Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2012.03.055. These data in-
clude MOL files and InChIKeys of the most important compounds
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