Improved synthesis and reaction of 11-chloroneocryptolepines, strategic scaffold for antimalaria agent, and their 6-methyl congener from indole-3-carboxylate

Article abstract of DOI:10.1002/jhet.1617

Various 11-chloro-5-methyl-5H-indolo[2,3-b]quinolines (neocryptolepines) with different substituents on the quinoline ring, key intermediates for antimalaria agents, are prepared from the substituted N-methylanilines, easily accessible by the N-methylatio

Full text of DOI:10.1002/jhet.1617

1106
Improved Synthesis and Reaction of 11-Chloroneocryptolepines, Strategic
Scaffold for Antimalaria Agent, and Their 6-Methyl Congener from
Indole-3-carboxylate
Vol 51
Li Wang,a Wen-Jie Lu,a Tomohito Odawara,a Ryuhei Misumi,a Zhen-Wu Mei,a Wei Peng,a
b
a
*
Ibrahim El-Tantawy El-Sayed, and Tsutomu Inokuchi
aDivision of Chemistry and Biotechnology, Graduate School of Natural Science and Technology, Okayama
University, 3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530, Japan
bChemistry Department, Faculty of Science, El Menoufeia University, Shebin El Koom, Egypt
*
E-mail: inokuchi@cc.okayama-u.ac.jp
Received November 10, 2011
DOI 10.1002/jhet.1617
Published online 30 January 2014 in Wiley Online Library (wileyonlinelibrary.com).
Cl
Cl
R1
OMe
R1
Cl
O
+
R = H
N
N
N
R = Me
N
N
NHR
H
Me
Me
R1 = H, Cl, Br, F, Me, CF3,
OMe, NHAc, CO2Me
o, m, p-substituted
11 examples
four steps
38% overall yields
totally three steps,
42~76% overall yields
Nu
Nu
N3
NH2
NH
N
R1
Cl
N
N
N
Me
Me
Various 11-chloro-5-methyl-5H-indolo[2,3-b]quinolines (neocryptolepines) with different substituents on the
quinoline ring, key intermediates for antimalaria agents, are prepared from the substituted N-methylanilines, easily
accessible by the N-methylation of anilines, and indole-3-carboxylate as a counterpart. This protocol is benign in
terms of the reduced number of steps to reach the target, compared with the known method using anilines, and easy
product purification. Alternatively, their 6-methyl congener is prepared by N-methylation of the indole moiety of
2-arylaminoindole-3-carboxylate followed by successive cyclization and chlorination. 11-Chloroneocryptolepines
are found more reactive than their 6-methyl congener in the nucleophilic substitution at the C11 position.
J. Heterocyclic Chem., 51, 1106 (2014).
INTRODUCTION
has a lower affinity for DNA and topoisomerase II compared
with cryptolepine I [5c] (Scheme 1).
Extracts from the root bark of the African medicinal plant
Cryptolepis sanguinolenta (Lindl.) Schlechter (Periplocaeae)
have traditionally been used for endemic diseases such as
malaria fever in west and central Africa [1]. This plant
contains several alkaloids with isomeric indoloquinoline
skeletons, representative examples of which are cryptolepine
(I), neocryptolepine (cryptoteckieine) (II), and cryptosangui-
nolentine (III) [2,3].
These indoloquinolines I–III show, in spite of their rela-
tively simple chemical structures, interesting biological
activities, namely antiplasmodial [3a], antibacterial [3b],
antifungal [3b], and antimalarial [3c,d]. Accordingly, these
structural motifs have been used as several drug leads to find
more active compounds for human diseases such as cancer
and bacteria or protozoal infections [4]. Unfortunately,
cryptolepine I is a DNA intercalating agent and an inhibitor
of topoisomerase II, resulting in a high level of cytotoxicity
[5]. On the other hand, neocryptolepine II, a minor alkaloid
of C. sanguinolenta, showed an antiplasmodial activity
against chloroquine-resistant Plasmodium falciparum and
Many synthetic approaches to construct the neocryptole-
pine structure have been developed, which involve
the thermal decomposition of enyne–carbodiimides [6],
decomposition of 2-(1-benzotriazoyl)quinoline (Graebe–Ull-
mann reaction) in polyphosphoric acid [7], intramolecular
N-arylation of chloro-3-(2-aminophenyl)quinolone [8], a
Staudinger–aza-Wittig reaction followed by an electrocyclic
ring-closure process [9], condensation of isatin and oxindole
[10], bromination of 1,3-bis(2-nitrophenyl)propan-2-one
followed by Favorskii rearrangement and reductive cycliza-
tion [11], intramolecular acylation of 2-(N-arylamino)-3-
indolecarboxylate [12], and others [13].
In spite of these previous developments in synthetic routes
to the indole[2,3-b]quinolines, versatile access to this class of
compounds deserves to be investigated to find more active
ones and gain further insight into the mechanistic rationale of
their biological action. Among these reported approaches, the
method involving the co-amination of indole-3-carboxylate
with anilines and the subsequent intramolecular aromatic
© 2014 HeteroCorporation

July 2014
Improved Synthesis and Reaction of 11-Chloroneocryptolepines and Their 6-Methyl
Congener from Indole-3-carboxylate
1107
Scheme 1
attention to achieving the methylation at the initial stage or
use of the N-methylanilines as the starting point [14]. In this
paper, we report an improved and versatile protocol for the
synthesis of the 2-substituted, 3-substituted, or 4-substituted
11-chloroneocypotolepines 6, 14, and 18 starting from
indole-3-carboxylate 2 and substituted N-methylanilines 7,
10, and 15, respectively. Alternatively, we developed new
access to their 6-methyl congener 22 by N-methylation at
the stage of the intermediate 3, available from anilines 1
and 2, followed by the reaction sequence involving cycliza-
tion and dehydrative chlorination.
N
N
N
N
N
N
CH3
CH3
CH3
I, Cryptolepine
II, Neocryptolepine
III, Cryptosanguinolentine
acylation sequence, first reported by Bergman et al. [12c],
is of value in terms of the availability of various anilines
1 (Scheme 2, Route 1). Thus, the method allows for the
formation of the neocryptolepine core with a substitution in
position 2 from the 4-substituted anilines 1.
During our attempts to execute this sequence to prepare
various neocryptolepine analogues, however, we have
encountered difficulties such as an incompleteness and long
reaction time associated with the methylation step due
to the low solubility of the intermediate, for example, 5g
(R1 = OMe) (Route 1, Scheme 2). Therefore, we turned our
RESULTS AND DISCUSSION
As shown in Route 3 of Scheme 2, we first examined
the methylation of the intermediate 4, obtained by the
co-amination of the indole 2 with 4-chloroaniline (1b, R1 =Cl)
by the action of N-chlorosuccinimide followed by cycliza-
tion upon heating at 250ꢀC in diphenyl ether. Thus, the
Scheme 2. Planned routes to 11-chloroneocryptolepines 6.
[Route 1]
R1
O
MeO
R1
MeO2C
i
ii
+
N
N
N
H
H
H
NH2
1
2
3
9
Cl
11
10
O
Cl
1
R1
R1
R1
2
3
8
D
iii
iv
[Methylation]
C
A
B
7
N 6
N
H
N
N5
N
H
N
H
4
Me
11-Chloroneocryptolepines 6
4
5
[Route 2]
R1
O
O
MeO
R1
R1
iii
i
ii
+
2
6
N
N
N
N
H
H
Me
Me
NHMe
7
8
9
a, R1 = H; b, R1 = Cl; c, R1 = Br; d, R1 = F; e, R1 = Me; f, R1 = CF3; g, R1 =
OMe; h, R1 = NHAc; i, R1 = CO2Me; j, R1 = NO2
[Route 3]
4
iv
iii
9
6
[Methylation]
Reagents and Conditions: (i) a, N-chlorosuccinimide, 1,4-dimethylpiperazine;
b, trichloroacetic acid; (ii) diphenyl ether, reflux; (iii) POCl3, toluene, reflux;
(iv) a, MeI, THF, reflux; b, NH4OH. Applied equally to Schemes 3 and 4 and
Table 1.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1108
L. Wang, W.-J. Lu, T. Odawara, R. Misumi, Z.-W. Mei, W. Peng, I. E.-T. El-Sayed, and T. Inokuchi
Vol 51
treatment of 4b (R1 = Cl) with MeI–NaH led exclusively to
methylation on the quinolone ring, giving 9b (R1 = Cl) in
95% yield. However, this route 3 is still problematic,
because the yield of the cyclization of 3b to 4b is not very
good, only 50%, and the handling of compound 4 is
cumbersome because of low solubility.
3-chloro-N-methylaniline 10 was combined with the indole-3-
carboxylate 2 to give 2-anilinoindole 11. Thermal cyclization
of 11 in the same manner as above produced the tetracyclic
12 and 13 as a mixture of 4.3:1 regioisomers. The major
isomer 12, formed by acylation at the 4-position to the Cl sub-
stituent, was separated by recrystallization from pyridine and
converted to the corresponding 3,11-dichloroneocypotolepine
14 by treatment with POCl3. On the other hand, the cyclization
of 16, derived from 3-chloroaniline 15, smoothly proceeded to
give the desired indoloquinolone 17 by heating at 250ꢀC in
diphenyl ether. The chlorination of 17 with POCl3 afforded
the 4,11-dichloroneocryptolepine 18 in good yield, as
described in Scheme 3.
We then paid our attention to the synthesis of the 6-methyl-
6H-indole[2,3-b]quinoline 22, a congener of neocryptolepines,
from the intermediate 3b (R1 = Cl), because their C2-
aminoalkylamino or C9-aminoalkylamino derivatives were
shown to possess potent cytotoxic DNA topoisomerase II
inhibitions by Wietrzyk et al.. [15]. As shown in Scheme 4,
the successive treatment of 3b with NaH and MeI produced
the N-methylated indoles 19 as a major product (61%) along
Accordingly, we examined the synthesis of the neocrypto-
lepine structure 6 using N-methylanilines 7 as the source of
the structural counterpart [Route 2 in Scheme 2] [15]. Thus,
7b (R1 = Cl) was treated with NCS followed by the addition
of indole-3-carboxylate 2, giving the 2-N-(N-methylanilino)
indole-3-carboxylate 8b (R1 = Cl) in 75% yield. Upon heating
at 250ꢀC in diphenyl ether, 8b (R1 = Cl) underwent cycliza-
tion, forming the tetracyclic ketone 9b (R1 = Cl) in 90% yield,
which was much convenient in the implementation and led to
higher overall yield compared with Route 1. The chlorination
of 9b (R1 = Cl) with POCl3 smoothly proceeded to afford the
11-chloroneocrypotolepine 6b (R1 = Cl) with high purity.
Subsequently, the procedure for the synthesis of a series
of 6 based on Route 2 was applied to various N-methylanilines
7 to ensure its utility. Thus, as shown in Table 1, the N-
methylanilines 7 bearing the substituent R1, such as halogens,
that is, 7c (R1 =Br), 7d (R1 = F), methyl 7e, trifluoromethyl 7f,
methoxy 7g, N-acetamido 7h, and methoxycarbonyl 7i were
successfully converted to the corresponding 6 through the
respective intermediates 8 and 9 (entries 1–9). This protocol
is versatile in terms of the reduced number of overall steps
along with improved overall yields and high purity of the
desired 11-chloroneocryptolepines 6, compared with the ones
that were sequentially prepared from 2 through 3, 4, and 5
(Scheme 2, Route 1). Conversely, our attempts to combine
the N-methylaniline 7j bearing NO2 with the indole-3-
carboxylate 2 were unsuccessful, presumably because of low
reactivity of amino group of 7j (entry 10).
Scheme 3. Syntheses of 3,11-dichloroneocryptolepines and 4,11-
dichloroneocryptolepines.
O
MeO
Cl
MeO2C
+
ii
i
N
H
Cl
N
N
H
NHMe
10
Me
11
2
O
O
Cl
+
N
N
H
Cl
N
N
H
H
Furthermore, we examined the effect of the substituents
of aniline core on the regioselectivity of the cyclization. Thus,
Me
12
(4.3:1)
13
Cl
Table 1
iii
Substrate scope for the synthesis of 11-chloroneocryptolepines 6 through
8 and 9 (Route 2 in Scheme 2).
12
N
Cl
N
Me
14
i
ii
iii
7
þ
2
! 8 ! 9
!
6
Products, yields (%)
O
MeO
MeO2C
i
ii
+
Entry
R1
8
9
6
N
H
Cl
N
N
H
NHMe
15
1
2
3
4
5
H
a
b
c
d
e
f
83
75
82
82
77
80
89
88
66
nd
98
90
84
75
72
85
87
82
68
nd
94
94
90
85
83
84
86
67
94
nd
Cl
Me
CI
Br
F
2
16
Cl
O
Me
6
CF3
iii
7
8
9
10
OMe
NHAc
CO2Me
NO2
g
h
i
N
N
N
H
N
Cl
Me
Cl
Me
17
j
18
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Improved Synthesis and Reaction of 11-Chloroneocryptolepines and Their 6-Methyl
Congener from Indole-3-carboxylate
1109
Scheme 4. N-Methylation of the intermediate 3b and conversion to 2,11-dichloro-6-methyl-6H-indolo[2,3-b]quinoline.
O
O
O
MeO
MeO
MeO
Cl
Cl
Cl
[Methylation]
i
+
N
N
N
N
N
N
H
19
H
Me
Me
Me
20
H
3b (R1 = Cl)
O
Cl
N
Cl
Cl
iii
ii
19
N
N
Me
N
H
Me
21
22
with a small amount of bismethylated 20 (20%). Selective
methylation on the indole nitrogen rather than on the nitrogen
atom of benzenamine of 3b can be ascribable to the difference
of the pKa value of aniline NH (approximately 30 in DMSO)
and indole NH (approximately 21 in DMSO) [16]. Before
ring closure, the compound 19 was isolated and then cyclized
into the tetracyclic 21 upon heating at 250ꢀC in diphenyl
ether. Dehydrative chlorination of 21 with POCl3 gave the
desired 22.
Having succeeded in the benign access to 11-chloroneo-
cryptolepines 6 and their 6-methyl-6H-isomer 22, we exam-
ined some nucleophilic substitution reactions on the C11
positions of them and compared their reactivities. Amination
of 6b (R1 = Cl) with 1,3-propanediamine proceeded at 80ꢀC
within 30 min, giving 23 in 97% yield, whereas the same
amination reaction of 22 occurred at 120ꢀC for 4 h, giving
the corresponding amine 25 in 70% yield [12a]. On the other
hand, azidation of 6b (R1 = Cl) with sodium azide produced
the desired azide 24 in good yield, whereas the reaction of
22 with NaN3 led to decomposition along with a recovery
of the starting material. Namely, 22 is less reactive for nucle-
ophilic substitution compared with 6, as shown in Scheme 5.
In summary, we developed an efficient procedure for the
synthesis of 11-chloroneocryptolepines and their 6-methyl
congener from indole-3-carboxylate, which are useful as a
scaffold for the preparation of antimalaria and anticancer
agents. The protocol for 11-chloroneocryptolepines 6 is suc-
cessful for the anilines bearing halogens, alkyl,
trifluoromethyl, methoxy, N-acetamido, and alkoxycarbonyl
groups (11 examples with 33–76% overall yield in totally three
steps), whereas the aniline substituted with NO2 was not. Reac-
tivity at the C11-position of these 11-chloroneocryptolepines
and their congener toward the nucleophiles were discussed,
and 11-chloroneocryptolepines are shown more reactive
than their congener, albeit whose aminoalkylamination at
the C11 position is shown to be feasible. Preparation of
various 11-aminated derivatives from 6 and 22 for bioactive
testing is now under active investigation.
Scheme 5. Nucleophilic substitution at the C11 position of 6b (R1 = CI) and 22.
NH2
Cl
NH
DMF
Cl
Cl
Cl
80°C/30min
+
+
NH2(CH2)3NH2
N
N
N
N
Me
23
24
Me
6b
N3
DMSO
60°C
NaN3
6b
N
N
Me
NH2
Cl
N
NH
N
DMF
120°C/4h
Cl
Cl
+
NH2(CH2)3NH2
N
N
Me
Me
22
25
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1110
L. Wang, W.-J. Lu, T. Odawara, R. Misumi, Z.-W. Mei, W. Peng, I. E.-T. El-Sayed, and T. Inokuchi
Vol 51
1508, 1466, 1273, 1213, 1163, 1098, 1072, 820, 762, 742. Anal.
Calcd for C17H15FN2O2: C, 68.45; H, 5.07; N, 9.39. Found:
C, 68.62; H, 4.80; N, 9.29.
EXPERIMENTAL
Materials: the starting N-methylanilines, 7a–g, 7j, 10, 15,
commercially available, were used as received, and other ones
such as 7h and 7i were prepared by N-methylation of the
corresponding anilines.
Methyl 2-(methyl(p-tolyl)amino)-1H-indole-3-carboxylate
(8e). White solid (568.5 mg, 77% yield), mp 170.9–171.8ꢀC;
Rf =0.20 (EtOAc/hexanes = 1:5). 1H-NMR (600 MHz, CDCl3):
d 8.10 (d, J = 8.22 Hz, 1H), 7.29–7.12 (m, 3H), 7.12–7.01
(m, 2H), 6.87 (dd, J = 8.51, 2.05 Hz, 2H), 3.85 (d, J = 2.35 Hz,
3H), 3.55–3.36 (m, 3H), 2.30 (s, 3H); 13C-NMR (150 MHz,
CDCl3): d 164.6, 148.8, 144.4, 131.7, 130.9, 129.9, 126.9, 122.3,
121.8, 121.2, 117.6, 110.1, 96.6, 50.8, 40.4, 20.6; IR (KBr,
cmꢁ1) 3279, 2945, 1668, 1560, 1518, 1443, 1332, 1275, 1215,
1163, 1105, 1074, 802, 743, 721. Anal. Calcd for C18H18N2O2:
C, 73.45; H, 6.16; N, 9.53. Found: C, 73.41; H, 6.12; N, 9.44.
Methyl 2-(methyl(4-(trifluoromethyl)phenyl)amino)-1H-
indole-3-carboxylate (8f). White solid (692.4 mg, 80% yield),
mp 142.9–144.7ꢀC; Rf = 0.20 (15% EtOAc/hexanes=1:5).
1H-NMR (600 MHz, CDCl3): d 8.37 (br s, 1H), 8.23–8.12
(m, 1H), 7.45 (d, J = 8.80 Hz, 2H), 7.35–7.27 (m, 3H), 6.78
(d, J = 8.80 Hz, 2H), 3.81 (s, 3H), 3.43 (s, 3H); 13C-NMR
(150MHz, CDCl3): d 164.3, 150.1, 145.4, 132.0, 126.4, 126.4,
126.4, 126.3, 126.2, 123.7 (d, J = 270.41 Hz), 123.5, 122.3, 121.9,
121.0 (q, J = 32.42 Hz), 113.7, 111.0, 100.2, 51.0, 39.5; 19F-NMR
(564MHz, CDCl3): d ꢁ61.64; IR (KBr, cmꢁ1) 3358, 3279, 2951,
1741, 1709, 1668, 1616, 1553, 1523, 1458, 1331, 1275, 1196,
1153, 1117, 1061, 829, 754. Anal. Calcd for C18H15F3N2O2:
C, 62.07; H, 4.34; N, 8.04. Found: C, 61.89; H, 4.28; N, 7.52.
Methyl 2-((4-methoxyphenyl)(methyl)amino)-1H-indole-
3-carboxylate (8g). White solid (689.1 mg, 89% yield),
mp 141.3–143.5ꢀC; Rf = 0.30 (EtOAc/hexanes= 1:3). 1H-NMR
(600MHz, CDCl3): d 8.06 (d, J = 7.92 Hz, 1H), 7.98 (br s, 1H),
7.24–7.07 (m, 3H), 7.05–6.96 (m, 2H), 6.92–6.79 (m, 2H), 3.86
(d, J = 2.05 Hz, 3H), 3.80 (d, J =2.05 Hz, 3H), 3.50 (br s, 3H);
13C-NMR (150MHz, DMSO-d6): d 164.7, 155.4, 149.9, 140.1,
131.6, 127.2, 121.9, 121.7, 121.0, 120.86, 114.8, 109.9, 94.7,
55.6, 50.7, 41.1; IR (KBr, cmꢁ1) 3314, 2949, 1667, 1550, 1508,
1445, 1327, 1250, 1209, 1074, 1036, 826, 791, 758. Anal. Calcd
for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C, 69.74;
H, 5.69; N, 8.90.
Synthesis of methyl 2-((4-chlorophenyl)(methyl)amino)-1H-
indole-3-carboxylate (8b): a typical procedure. To the argon
flushed solution of methyl indole-3-carboxylate (438.0 mg,
2.5 mmol) in CH2Cl2 (5 mL), a mixture of N-chlorosuccinimide
(367.1 mg, 2.75 mmol) and N,N0-dimethylpiperazine (142.7 mg,
1.25 mmol) in CH2Cl2 (1 mL) was added dropwise at 0ꢀC. The
mixture was stirred at 0ꢀC for 2 h, and a solution of trichloroacetic
acid (102.1 mg, 0.625 mmol) and 4-chloro-N-methylaniline
(708.0 mg, 5 mmol) in CH2Cl2 (2 mL) was then added dropwise.
The reaction was allowed to warm to room temperature and further
stirred for 3.5 h. The mixture was consecutively washed with
saturated aqueous NaHCO3, 1N HCl, brine, and water. The
organic phase was dried over anhydrous MgSO4 and concentrated
under reduced pressure. The crude product was purified by column
chromatography (SiO2, n-hexane/ethyl acetate = 7/1) to give methyl
2-((4-chlorophenyl)(methyl)amino)-1H-indole-3-carboxylate
592.6 mg (75% yield). White solid, mp 178.7–181.4ꢀC, Rf =0.50
1
(EtOAc/hexanes = 1:3). H-NMR (600 MHz, CDCl3): d 8.28 (br s,
1H), 8.17–8.09 (m, 1H), 7.33–7.21 (m, 3H), 7.20–7.16 (m, 2H),
6.77–6.73 (m, 2H), 3.82 (s, 3H), 3.41 (s, 3H); 13C-NMR
(150 MHz, CDCl3): d 164.5, 146.9, 145.9, 131.9, 129.0, 126.4,
125.0, 123.0, 122.0, 121.5, 116.5, 110.7, 98.6, 50.9, 39.8; IR
(KBr, cmꢁ1) 3233, 3188, 1676, 1517, 1437, 1346, 1269, 1233,
1194, 1117, 1067, 781, 754, 716. Anal. Calcd for C17H15ClN2O2:
C, 64.87; H, 4.80; N, 8.90. Found: C, 64.81; H, 4.28; N, 8.73.
Methyl 2-(methyl(phenyl)amino)-1H-indole-3-carboxylate(8a).
White solid (585.0 mg, 83% yield), mp 133.6–135.1ꢀC; Rf = 0.40
(EtOAc/hexanes = 1:5). 1H-NMR (600 MHz, CDCl3): d 8.21
(d, J = 15.26 Hz, 1H), 8.13 (d, J = 7.34Hz, 1H), 7.29–7.18
(m, 5H), 6.93 (t, J = 7.34 Hz, 1H), 6.91–6.86 (m, 2H), 3.83
(d, J = 2.64 Hz, 3H), 3.46 (d, J = 2.35 Hz, 3H); 13C-NMR
(150 MHz, CDCl3): d 164.5, 147.8, 147.0, 131.7, 129.2, 126.7,
122.7, 121.9, 121.5, 120.6, 116.3, 110.4, 98.0, 50.8, 40.0; IR
(KBr, cmꢁ1) 3293, 2945, 1668, 1555, 1443, 1337, 1271, 1211,
1086, 746, 716, 694. Anal. Calcd for C17H16N2O2: C, 72.84;
H, 5.75; N, 9.99. Found: C, 72.98; H, 5.59; N, 10.00.
Methyl 2-((4-bromophenyl)(methyl)amino)-1H-indole-3-
carboxylate (8c). White solid (733.4 mg, 82% yield), mp 164.1–
165.7ꢀC; Rf = 0.50 (EtOAc/hexanes = 1:3). 1H-NMR (600 MHz,
CDCl3): d 8.24 (br s, 1H), 8.17–8.10 (m, 1H), 7.35–7.30 (m, 2H),
7.29–7.19 (m, 4H), 6.72–6.65 (m, 2H), 3.83 (s, 3H), 3.40 (s, 3H);
13C-NMR (150MHz, CDCl3): d 164.4, 146.7, 146.4, 131.9,
131.8, 126.4, 123.1, 122.1, 121.6, 116.9, 112.3, 110.7, 99.0, 50.3,
39.8; IR (KBr, cmꢁ1) 3279, 2947, 1667, 1557, 1493, 1445, 1329,
1273, 1219, 1163, 1105, 1070, 802, 745. Anal. Calcd for
C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80. Found: C, 56.77; H,
4.11; N, 7.65.
Methyl 2-((4-acetamidophenyl)(methyl)amino)-1H-indole-3-
carboxylate (8h). White solid (743.5 mg, 88% yield), mp 189.1–
190.9ꢀC; Rf = 0.50 (EtOAc). 1H-NMR (600 MHz, DMSO-d6):
d 11.82 (s, 1H), 9.76 (s, 1H), 7.96–7.84 (m, 1H), 7.50–7.36 (m, 2H),
7.36–7.24 (m, 1H), 7.20–7.08 (m, 2H), 6.82–6.62 (m, 2H), 3.63
(d, J= 1.47 Hz, 3H), 1.99 (d, J=1.47Hz, 3H); 13C-NMR (150 MHz,
DMSO-d6): d 167.6, 163.6, 148.1, 143.3, 132.5, 132.1, 126.4, 121.8,
121.0, 120.3, 120.2, 115.8, 111.2, 95.8, 50.3, 39.9, 23.8; IR
(KBr, cmꢁ1) 3333, 2949, 1674, 1512, 1454, 1389, 1265, 1213, 1115,
1067, 816, 756, 725. Anal. Calcd for C19H19N3O3: C, 67.64;
H, 5.68; N, 12.46. Found: C, 67.35; H, 5.66; N, 12.13.
Methyl 2-((4-(methoxycarbonyl)phenyl)(methyl)amino)-1H-
indole-3-carboxylate (8i). White solid (556.2 mg, 66% yield),
mp 217.9–219.8ꢀC; Rf = 0.20 (EtOAc/hexanes = 1:3). 1H-NMR
(600 MHz, DMSO-d6): d 12.25 (br s, 1H), 8.00 (d, J = 7.92 Hz,
1H), 7.81 (d, J = 8.80 Hz, 2H), 7.39 (d, J = 7.63 Hz, 1H), 7.29–
7.15 (m, 2H), 6.73 (d, J = 8.80 Hz, 2H), 3.78 (s, 3H), 3.66
(s, 3H), 3.37 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): d 166.1,
163.5, 151.7, 145.3, 132.6, 130.7, 125.8, 122.7, 121.5, 121.0,
Methyl 2-((4-fluorophenyl)(methyl)amino)-1H-indole-3-carboxylate
(8d).
White solid (611.5mg, 82% yield), mp 151.4–152.4ꢀC;
Rf = 0.40 (EtOAc/hexanes = 1:3). 1H-NMR (600MHz, CDCl3):
d 8.22 (br s, 1H), 8.10 (d, J =7.63 Hz, 1H), 7.25–7.21 (m, 3H),
6.96 (m, 2H), 6.86–6.84 (m, 2H), 3.82 (d, J = 1.80Hz, 3H), 3.44
(s, 3H); 13C-NMR (150MHz, CDCl3): d 164.5, 158.5, 156.9,
148.1, 143.4, 131.7, 126.7, 122.7, 122.0, 121.4, 118.1, 118.0,
115.9, 115.8, 110.4, 97.4, 50.8, 40.4; 19F-NMR (564 MHz,
CDCl3): d ꢁ123.42; IR (KBr, cmꢁ1) 3192, 2951, 1670, 1555,
119.0, 112.9, 111.8, 98.4, 51.6, 50.6, 39.1; IR (KBr, cmꢁ1
)
3225, 2945, 1719, 1672, 1609, 1545, 1516, 1458, 1284, 1170,
1113, 1069, 835, 764, 741. Anal. Calcd for C19H18N2O4:
C, 67.44; H, 5.36; N, 8.28. Found: C, 67.44; H, 5.30; N 8.19.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Improved Synthesis and Reaction of 11-Chloroneocryptolepines and Their 6-Methyl
Congener from Indole-3-carboxylate
1111
Methyl 2-((3-chlorophenyl)(methyl)amino)-1H-indole-3-
2-Bromo-5-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one
carboxylate (11). White solid (757.6mg, 96% yield), mp 147.4–
149.0ꢀC; Rf = 0.20 (EtOAc/hexanes = 1:5). 1H-NMR (600 MHz,
CDCl3): d 8.55 (br s, 1H), 8.26–8.07 (m, 1H), 7.35–7.20 (m, 3H),
7.10 (t, J = 8.07 Hz, 1H), 6.83 (dt, J = 7.92, 0.88Hz, 1H), 6.76
(t, J = 2.05 Hz, 1H), 6.65–6.60 (m, 1H), 3.81 (s, 3H), 3.37 (s, 3H);
13C-NMR (150 MHz, CDCl3): d 164.4, 148.6, 146.2, 135.0,
131.9, 130.0, 126.3, 123.2, 122.1, 121.7, 119.7, 114.8, 113.1,
110.9, 99.4, 50.9, 39.7; IR (KBr, cmꢁ1) 3187, 2947, 1667, 1601,
1551, 1485, 1462, 1333, 1281, 1267, 1217, 1105, 1080, 791, 764,
737, 719. Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N,
8.90. Found: C, 64.66; H, 4.65; N, 8.66.
(9c). Pale gray solid (587.7 mg, 84% yield), mp >370ꢀC.
1H-NMR (600 MHz, DMSO-d6):
d 12.16 (s, 1H), 8.44
(d, J = 2.64 Hz, 1H), 8.19 (d, J = 7.63Hz, 1H), 7.95–7.83 (m, 1H),
7.77 (d, J = 8.80 Hz, 1H), 7.53–7.41 (m, 1H), 7.36–7.19 (m, 2H),
3.97 (s, 3H); 13C-NMR (150MHz, DMSO-d6): d 170.0, 146.9,
138.1, 134.8, 133.5, 127.8, 126.3, 123.8, 123.2, 121.4, 120.2,
118.0, 114.4, 110.9, 33.5; IR (KBr, cmꢁ1) 3185, 1607, 1574,
1537, 1510, 1460, 1418, 1267, 1248, 1198, 802, 741, 700. Anal.
Calcd for C16H11BrN2O: C, 58.74; H, 3.39; N, 8.56. Found:
C, 58.81; H, 2.98; N, 8.38.
2-Fluoro-5-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one (9d).
1
Pale brown solid (458.4 mg, 75% yield), mp >370ꢀC. H-NMR
Methyl 2-((2-chlorophenyl)(methyl)amino)-1H-indole-3-
carboxylate (16). After the solution of trichloroacetic acid and
2-chloro-N-methylaniline in CH2Cl2 was added, the reaction was
allowed to warm to room temperature and further stirred for 12 h.
White solid (657.0 mg, 83% yield), mp 152.3–153.7ꢀC; Rf =0.20
(600MHz, DMSO-d6): d12.13 (s, 1H), 8.23 (dd, J = 7.63,
0.59 Hz, 1H), 7.99–8.11 (m, 1H), 7.88 (dd, J = 9.24, 3.96 Hz,
1H), 7.72–7.61 (m, 1H), 7.59–7.44 (m, 1H), 7.40–7.20 (m, 2H),
4.01 (d, J = 0.88 Hz, 3H); 13C-NMR (150MHz, DMSO-d6):
d 170.9 (d, J = 2.24 Hz), 158.9, 157.3, 147.5, 136.3, 135.4, 126.5,
126.5, 124.3, 123.6, 121.8, 120.7, 119.4 (d, J = 24.13 Hz), 118.4,
118.3, 111.4, 110.6 (d, J = 22.47 Hz), 102.7, 34.2; 19F-NMR
(564MHz, DMSO-d6): d ꢁ120.58; IR (KBr, cmꢁ1) 3142, 3098,
2984, 1618, 1587, 1553, 1518, 1460, 1435, 1269, 1233, 802,
781, 740, 708. Anal. Calcd for C16H11FN2O: C, 72.17; H, 4.16;
N, 10.52. Found: C, 71.82; H, 3.70; N 10.30.
(EtOAc/hexanes = 1:5). 1H-NMR (600 MHz, CDCl3):
d 8.28
(d, J= 15.85 Hz, 1H), 8.02 (d, J= 7.92 Hz, 1H), 7.48–7.36 (m, 1H),
7.28–7.21 (m, 2H), 7.18–7.14 (m, 1H), 7.14–7.10 (m, 2H), 7.10–
7.06 (m, 1H), 3.72 (s, 3H), 3.51 (s, 3H); 13C-NMR (150 MHz,
CDCl3): d 164.8, 150.3, 144.4, 131.7, 131.0, 130.6, 128.0, 127.7,
126.6, 126.2, 121.7, 121.4, 120.5, 109.9, 92.3, 50.4, 41.3; IR (KBr,
cmꢁ1) 3246, 3228, 1636, 1537, 1487, 1458, 1367, 1215, 1188,
1165, 1113, 1051, 791, 758, 731. Anal. Calcd for C17H15ClN2O2:
C, 64.87; H, 4.80; N, 8.90. Found: C, 65.03; H, 4.62; N, 8.81.
Methyl 2-(4-chlorophenylamino)-1H-indole-3-carboxylate (3b).
White solid (623.2mg 83% yield), mp 136.0–137.0ꢀC; Rf = 0.45
(EtOAc/hexanes = 1:5). 1H-NMR (600 MHz, CDCl3): d 8.97
(br s, 1H), 8.29 (d, J = 4.99 Hz, 1H), 7.82 (d, J = 7.92Hz, 1H),
7.43–7.30 (m, 2H), 7.23–7.11 (m, 4H), 7.10–7.00 (m, 1H), 3.93
(s, 3H); 13C-NMR (150MHz, CDCl3): d 167.8, 148.9, 137.0,
131.5, 130.1, 129.9, 126.0, 122.5, 122.1, 121.0, 119.4, 109.9,
86.8, 50.7; IR (KBr, cmꢁ1) 3304, 1663, 1634, 1587, 1568, 1495,
1443, 1393, 1323, 1260, 1207, 1090, 816, 783, 743, 696.
2,5-Dimethyl-5H-indolo[2,3-b]quinolin-11(6H)-one (9e).Pale
gray solid (366.4 mg, 72% yield), mp >370ꢀC. 1H-NMR
(600 MHz, DMSO-d6): d 12.01 (s, 1H), 8.24–8.12 (m, 2H),
7.69 (dd, J = 8.80, 0.88 Hz, 1H), 7.58 (d, J = 8.51 Hz, 1H), 7.51–
7.42 (m, 1H), 7.31–7.17 (m, 2H), 3.96 (d, J = 1.47 Hz, 3H),
2.47 (s, 3H); 13C-NMR (150 MHz, DMSO-d6): d 171.4, 146.8,
137.3, 134.7, 132.3, 130.7, 125.3, 124.6, 124.1, 122.7, 121.1,
120.1, 115.2, 110.7, 102.2, 33.2, 20.5; IR (KBr, cmꢁ1) 3180,
3012, 1614, 1594, 1548, 1520, 1460, 1420, 1271, 1250, 1173,
1065, 806, 772, 743, 708. Anal. Calcd for C17H14N2O:
C, 77.84; H, 5.38; N, 10.68. Found: C, 77.24; H, 5.08; N 10.50.
5-Methyl-2-(trifluoromethyl)-5H-indolo[2,3-b]quinolin-11(6H)-
one (9f). Gray solid (557.9 mg, 85% yield), >353.2ꢀC decompose.
Synthesis of 2-chloro-5-methyl-5H-indolo[2,3-b]quinolin-
11(6H)-one (9b): a typical procedure.
The methyl 2-((4-
1H-NMR (600 MHz, DMSO-d6):
d 12.19 (s, 1H), 8.60
chlorophenyl)(methyl)amino)-1H-indole-3-carboxylate was refluxed
in diphenyl ether (8 mL) at 250ꢀC for 2 h. The solid was filtered
and washed with diethyl ether to give 2-chloro-5-methyl-5H-indolo
[2,3-b]quinolin-11(6H)-one 479.3 mg (90% yield). Gray solid, mp
(d, J= 1.47 Hz, 1H), 8.18 (d, J= 7.34 Hz, 1H), 8.03–7.85 (m, 2H),
7.44 (d, J = 7.34 Hz, 1H), 7.32–7.18 (m, 2H), 3.96 (s, 3H);
13C-NMR (150 MHz, DMSO-d6): d 170.4, 146.9, 141.2, 134.7,
127.0, 125.4 (d, J= 270.46 Hz), 124.1, 123.5, 123.3, 123.0
(d, J= 3.02 Hz), 122.0 (q, J= 31.67 Hz), 121.5, 120.3, 116.7,
111.0, 102.9, 33.6; 19F-NMR (564 MHz, DMSO-d6): d ꢁ59.38; IR
(KBr, cmꢁ1) 3175, 1634, 1607, 152, 1549, 1460, 1327, 1296,
1198, 1115, 1082, 816, 748, 687; HRMS (ESI) Calcd for
C17H10F3N2O [M-H]ꢁ 315.0745. Found: 315.0745.
1
>370ꢀC; H-NMR (600 MHz, DMSO-d6): d 12.16 (s, 1H), 8.30
(d, J= 2.64 Hz, 1H), 8.25–8.20 (m, 1H), 7.90–7.86 (m, 1H),
7.82 (dd, J= 9.10, 2.64 Hz, 1H), 7.53 (dt, J= 7.92, 0.88 Hz, 1H),
7.35–7.24 (m, 2H), 4.02 (s, 3H); 13C-NMR (150 MHz, DMSO-d6):
d 170.1 146.9, 137.8, 134.8, 130.8, 126.5, 125.9, 124.7, 123.8,
123.2, 121.4, 120.2, 117.8, 110.9, 102.6, 33.6; IR (KBr, cmꢁ1
)
2-Methoxy-5-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one
(9g). Pale gray solid (535.4mg, 87% yield), mp 353.1–357.2ꢀC.
1H-NMR (600 MHz, DMSO-d6): d 12.02 (s, 1H), 8.31–8.18
(m, 1H), 7.88 (d, J = 3.23 Hz, 1H), 7.80 (d, J = 9.10 Hz, 1H),
7.55–7.46 (m, 1H), 7.46–7.37 (m, 1H), 7.28 (ddd, J = 18.63, 7.63,
1.32 Hz, 2H), 4.01 (s, 3H), 3.92 (s, 3H); 13C-NMR (150MHz,
DMSO-d6): d 171.9, 155.4, 147.6, 135.8, 134.6, 126.6, 125.0,
123.7, 122.0, 121.1, 121.0, 117.8, 111.6, 107.5, 102.9, 56.3, 34.3;
IR (KBr, cmꢁ1) 3146, 3096, 1616, 1580, 1549, 1516, 1458, 1238,
1063, 1038, 808, 770, 742, 706. Anal. Calcd for C17H14N2O2:
C, 73.37; H, 5.07; N, 10.07. Found: C, 73.25; H, 4.71; N, 9.97.
N-(5-Methyl-11-oxo-6,11-dihydro-5H-indolo[2,3-b]quinolin-
2-yl)acetamide (9h). Dark brown solid (552.1 mg, 82% yield),
3180, 1611, 1576, 1541, 1514, 1460, 1421, 1269, 1202, 806, 743,
706. Anal. Calcd for C16H11ClN2O: C, 67.97; H, 3.92; N, 9.91.
Found: C, 67.80; H, 3.14; N, 9.68.
5-Methyl-5H-indolo[2,3-b]quinolin-11(6H)-one (9a). Pale gray
solid (476.0 mg, 98% yield), mp >370ꢀC. 1H-NMR (600 MHz,
DMSO-d6): d 12.12 (br s, 1H), 8.43 (dd, J= 7.92, 2.05 Hz, 1H),
8.29–8.19 (m, 1H), 7.90–7.72 (m, 2H), 7.56–7.50 (m, 1H), 7.44
(ddd, J= 7.92, 6.75, 1.17 Hz, 1H), 7.36–7.20 (m, 2H), 4.02 (s, 3H);
13C-NMR (150 MHz, DMSO-d6): d 171.5, 146.9, 139.2, 134.7,
131.2, 125.8, 124.7, 124.1, 122.8, 121.7, 121.2, 120.1, 115.2,
110.8, 102.3, 33.3; IR (KBr, cmꢁ1) 3136, 3067, 1613, 1578, 1541,
1460, 1391, 1308, 1248, 1213, 878, 723, 679.
1
mp >370ꢀC. H-NMR (600 MHz, DMSO-d6): d 12.01 (s, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1112
L. Wang, W.-J. Lu, T. Odawara, R. Misumi, Z.-W. Mei, W. Peng, I. E.-T. El-Sayed, and T. Inokuchi
Vol 51
10.18 (s, 1H), 8.51 (d, J = 2.35 Hz, 1H), 8.19 (d, J = 7.04 Hz, 1H),
8.06 (dd, J = 9.10, 2.64 Hz, 1H), 7.75 (d, J = 9.10 Hz, 1H), 7.51–
7.41 (m, 1H), 7.31–7.16 (m, 2H), 3.96 (s, 3H), 2.09 (s, 3H); 13C-
NMR (150 MHz, DMSO-d6): d 171.3, 168.2, 146.7, 135.1,
134.8, 133.9, 124.9, 124.1, 123.0, 122.7, 121.1, 120.1, 115.6,
115.0, 110.7, 102.0, 33.3, 24.0; IR (KBr, cmꢁ1) 3237, 1692,
1620, 1582, 1535, 1458, 1418, 1308, 1252, 812, 740. Anal.
Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
70.81; H, 4.52; N, 13.69.
Synthesis of 2,11-dichloro-5-methyl-5H-indolo[2,3-b]quinoline
(6b): a typical procedure. To a suspension of 2-chloro-5-methyl-
5H-indolo[2,3-b]quinolin-11(6H)-one (479.3 mg, 1.0 equiv) in
toluene (8 mL), phosphoryl chloride (10.4 g, 6.24 mL, 40.0 equiv)
was added. The mixture was heated at reflux for 6 h and then
poured into an ice–bath with stirring. The temperature should not
be higher than 30ꢀC. Removal of the liquid was by filtration, and
the solid was sequentially washed with ether, aqueous saturated
NaHCO3, and water. The orange product was dried in a vacuum
over P2O51 (477.8 mg, 94% yield). Orange solid, mp 211.1–
Methyl 5-methyl-11-oxo-6,11-dihydro-5H-indolo[2,3-b]quinoline-
2-carboxylate (9i). Pale gray solid (354.1 mg, 70% yield), >356.6ꢀC
215.9ꢀC ; H-NMR (600 MHz, CDCl ): d 8.30 (d, J = 7.63 Hz,
.
3
1
decompose. H-NMR (600 MHz, DMSO-d6): d 12.21 (s, 1H), 8.96
1H), 8.27 (d, J = 2.35 Hz, 1H), 7.67–7.60 (m, 2H), 7.57–7.50
(m, 2H), 7.23 (t, J = 7.48 Hz, 1H), 4.23 (s, 3H); 13C-NMR
(150 MHz, CDCl3): d 154.9, 154.8, 135.1, 134.2, 131.0, 130.2,
128.1, 125.6, 125.0, 124.0, 123.4, 120.5, 119.9, 117.7, 115.7,
33.3; IR (KBr, cmꢁ1) 3410, 3048, 1632, 1560, 1520, 1487, 1444,
1263, 1234, 1194, 1140, 1109, 1072, 961, 789, 756, 737.
11-Chloro-5-methyl-5H-indolo[2,3-b]quinoline (6a). Orange
solid (451.0 mg, 94% yield), mp 176.0–177.0ꢀC. 1H-NMR
(600MHz, DMSO-d6): d 8.45–8.37 (m, 2H), 8.09 (d, J =8.51 Hz,
1H), 7.97 (ddd, J =8.51, 7.04, 1.47Hz, 1H), 7.68–7.61 (m, 2H),
7.57 (td, J = 7.63, 1.17 Hz, 1H), 7.31–7.23 (m, 1H), 4.34 (s, 3H);
13C-NMR (150 MHz, CDCl3): d 154.6, 153.7, 136.7, 136.3,
131.2, 129.8, 126.0, 124.3, 123.8, 123.3, 122.5, 120.5, 119.2,
117.3, 114.3, 33.6; IR (KBr, cmꢁ1) 3399, 1630, 1572, 1522,
1491, 1439, 1416, 1273, 1234, 1074, 750.
2-Bromo-11-chloro-5-methyl-5H-indolo[2,3-b]quinoline (6c).
Orange solid (559.6mg, 90% yield), mp 203.2–205.1ꢀC.
1H-NMR (600 MHz, CDCl3): d 8.44 (d, J = 2.05 Hz, 1H), 8.31
(d, J = 7.63 Hz, 1H), 7.81 (dd, J = 8.95, 2.20Hz, 1H), 7.66
(d, J = 7.92 Hz, 1H), 7.59–7.49 (m, 2H), 7.29–7.21 (m, 1H), 4.30
(s, 3H); 13C-NMR (150MHz, CDCl3): d 153.9, 153.6, 135.4,
134.8, 134.1, 130.3, 128.2, 125.0, 124.0, 122.9, 120.9, 120.6,
117.3, 116.1, 116.0, 33.9; IR (KBr, cmꢁ1) 3393, 3082, 1630,
1560, 1518, 1485, 1464, 1258, 1234, 1192, 1107, 957, 871, 756.
Anal. Calcd for C16H10BrClN2: C, 55.60; H, 2.92; N, 8.11.
Found: C, 55.33; H, 2.85; N, 7.83.
(d, J= 2.05 Hz, 1H), 8.28–8.12 (m, 2H), 7.84 (d, J=8.80Hz, 1H),
7.48 (d, J= 7.63 Hz, 1H), 7.36–7.17 (m, 2H), 3.98 (s, 3H), 3.91
(s, 3H); 13C-NMR (150 MHz, DMSO-d6): d 171.0, 165.9, 146.9,
142.0, 134.7, 130.9, 127.8, 124.2, 123.7, 123.2, 122.5, 121.5, 120.3,
115.8, 111.0, 102.9, 52.1, 33.7; IR (KBr, cmꢁ1) 3090, 2949, 1714,
1632, 1605, 1576, 1547, 1458, 1287, 1250, 1202, 1113, 764, 743.
Anal. Calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15. Found:
C, 70.26; H, 4.21; N, 9.07.
3-Chloro-5-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one
(12). After recrystallization from pyridine/EtOAc/hexane, the
crude product was purified to give the regioisomer 16 as pale gray
1
solid (322.5 mg, 47% yield), mp >370ꢀC. H-NMR (600 MHz,
DMSO-d6): d 12.15 (s, 1H), 8.36 (d, J = 8.51 Hz, 1H), 8.18
(d, J = 7.63 Hz, 1H), 7.87 (d, J = 1.76Hz, 1H), 7.48
(d, J = 7.92 Hz, 1H), 7.41 (dd, J = 8.51, 1.76 Hz, 1H), 7.31–7.20
(m, 2H), 3.97 (s, 3H); 13C-NMR (150MHz, DMSO-d6): d 170.8,
146.9, 140.1, 136.0, 134.7, 127.7, 123.8, 123.4, 123.1, 121.9,
121.4, 120.2, 115.1, 110.9, 102.5, 33.6; IR (KBr, cmꢁ1) 3091,
2978, 1607, 1574, 1533, 1514, 1458, 1383, 1248, 1211, 1099,
909, 781, 743. Anal. Calcd for C16H11ClN2O: C, 67.97; H, 3.92;
N, 9.91. Found: C, 67.42; H, 3.66; N, 9.77.
4-Chloro-5-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one
(17). Dark gray solid (300.3 mg, 51% yield), mp >370ꢀC.
1H-NMR (600 MHz, DMSO-d6):
d 12.22 (s, 1H), 8.36
(dd, J= 7.92, 1.47 Hz, 1H), 8.15 (d, J= 7.34 Hz, 1H), 7.82
(dd, J= 7.63, 1.47 Hz, 1H), 7.50 (d, J= 7.63 Hz, 1H), 7.38
(t, J= 7.78 Hz, 1H), 7.21–7.31 (m, 2H), 4.12 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6): d 170.7, 149.6, 138.3, 134.8, 134.3, 134.2,
128.5, 125.2, 123.3, 123.2, 121.5, 121.3, 120.3, 111.2, 102.7, 41.1;
IR (KBr, cmꢁ1) 3057, 1609, 1576, 1537, 1460, 1389, 1258, 1206,
1067, 768, 748; HRMS (ESI) Calcd for C16H10ClN2O [Mꢁ H]ꢁ
281.0482. Found: 281.0469.
2-Chloro-5H-indolo[2,3-b]quinolin-11(6H)-one (4b). Off white
solid (276.7 mg, 50% yield), mp >370ꢀC. 1H-NMR (600 MHz,
DMSO-d6): d 12.48 (s, 1H), 11.79 (s, 1H), 8.29–8.10 (m, 2H),
7.68 (d, J= 1.47 Hz, 2H), 7.55–7.41 (m, 1H), 7.34–7.13 (m, 2H);
13C-NMR (150 MHz, DMSO-d6): d 170.8, 145.3, 136.9, 135.1,
130.7, 126.0, 124.7, 124.3, 123.5, 123.0, 121.0, 120.1, 119.7,
111.0, 102.0; IR (KBr, cmꢁ1) 3287, 3094, 1645, 1620, 1584,
1520, 1456, 1410, 1337, 912, 806, 727, 698.
11-Chloro-2-fluoro-5-methyl-5H-indolo[2,3-b]quinoline (6d).
1
Orange solid (417.6 mg, 85% yield), mp 171.6–174.0ꢀC. H-NMR
(600 MHz, CDCl3): d 8.32 (d, J= 7.63 Hz, 1H), 8.01 (dd, J=9.39,
2.05 Hz, 1H), 7.66 (d, J= 7.92 Hz, 1H), 7.60 (dd, J= 9.39, 4.11 Hz,
1H), 7.55 (t, J= 7.48 Hz, 1H), 7.51–7.43 (m, 1H), 7.23
(t, J= 7.34 Hz, 1H), 4.27 (s, 3H); 13C-NMR (150 MHz, CDCl3):
d 158.6, 157.0, 154.9 (d, J= 11.2 Hz), 134.5, 133.3, 130.2, 125.7,
124.0, 123.2, 120.4, 120.0 (d, J= 7.54 Hz), 119.4 (d, J= 19.6 Hz),
117.53, 116.0 (d, J= 9.0 Hz), 110.8 (d, J= 24.1 Hz), 33.5;
19F-NMR (564 MHz, CDCl3): d ꢁ119.20; IR (KBr, cmꢁ1) 3366,
1634, 1574, 1528, 1489, 1441, 1344, 1273, 1236, 1184, 1138,
1072, 995, 767, 754. Anal. Calcd for C16H10ClFN2: C, 67.50;
H, 3.54; N, 9.84. Found: C, 67.46; H, 3.42; N, 9.67.
11-Chloro-2,5-dimethyl-5H-indolo[2,3-b]quinoline (6e). Orange
solid (326.1 mg, 83% yield), mp 206.1–209.1ꢀC. 1H-NMR
(600 MHz, DMSO-d6): d 8.57–8.50 (d, J= 7.80 Hz, 1H), 8.39–8.28
(m, 2H), 8.08–8.01 (d, J= 9.00 Hz, 1H), 7.82–7.72 (m, 2H),
7.56–7.49 (t, J= 7.80 Hz, 1H), 4.49 (s, 3H), 2.63 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6): d 147.2, 140.6, 140.4, 136.8, 135.8, 134.5,
130.8, 124.7, 123.8, 123.5, 120.9, 119.4, 119.2, 117.4, 113.0, 37.2,
20.7; IR (KBr, cmꢁ1) 3061, 1634, 1601, 1574, 1524, 1493, 1443,
1418, 1269, 1236, 1192, 1136, 1074, 966, 754, 740.
2-Chloro-6-methyl-5H-indolo[2,3-b]quinolin-11(6H)-one (21).
1
Off white solid (480.6mg, 92.4% yield), mp >370ꢀC. H-NMR
(600 MHz, DMSO-d6): d 12.24 (s, 1H), 8.11–8.31 (m, 2H),
7.83–7.72 (m, 1H), 7.69 (dd, J = 8.80, 2.64 Hz, 1H), 7.54
(d, J = 7.92 Hz, 1H), 7.41–7.21 (m, 2H), 3.90 (s, 3H); 13C-NMR
(150 MHz, DMSO-d6): d 170.5, 145.7, 136.8, 136.2, 130.8,
126.3, 124.8, 124.3, 123.0, 122.9, 121.4, 120.1, 119.8, 109.2,
101.4, 29.2; IR (KBr, cmꢁ1) 3142, 3072, 2996, 1641, 1580, 1533,
1470, 1420, 1246, 1130, 812, 745. Anal. Calcd for C16H11ClN2O:
C, 67.97; H, 3.92; N, 9.91. Found: C, 67.78; H, 3.65; N, 9.60.
11-Chloro-5-methyl-2-(trifluoromethyl)-5H-indolo[2,3-b]
quinoline (6f). Orange solid (492.0mg, 84% yield), mp 206.3–
209.5ꢀC. 1H-NMR (600 MHz, CDCl3): d 8.57 (s, 1H), 8.26
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2014
Improved Synthesis and Reaction of 11-Chloroneocryptolepines and Their 6-Methyl
Congener from Indole-3-carboxylate
1113
(d, J = 7.63 Hz, 1H), 7.90 (dd, J =8.80, 1.47 Hz, 1H), 7.69–7.64 (m,
1H), 7.62 (d, J = 7.92 Hz, 1H), 7.51 (t, J = 7.63Hz, 1H), 7.22 (t,
J = 7.48 Hz, 1H), 4.26 (s, 3H); 13C-NMR (150 MHz, CDCl3):
d 154.8, 154.5, 138.2, 135.1, 130.3, 127.0 (d, J = 2.80Hz), 125.7,
124.8–124.4 (m), 124.2, 124.0, 123.6 (d, J = 4.49Hz), 123.2,
121.0, 118.5, 117.8, 115.0 33.5; 19F-NMR (564MHz, CDCl3):
d ꢁ61.75; IR (KBr, cmꢁ1) 3399, 2953, 1626, 1572, 1530, 1497,
1452, 1339, 1254, 1234, 1150, 1123, 1086, 964, 760. Anal. Calcd
for C17H10ClF3N2: C, 61.00; H, 3.01; N, 8.37. Found: C, 61.23;
H, 2.84; N, 8.21.
2,11-Dichloro-5H-indolo[2,3-b]quinoline (5b).
Yellow
solid (204.7 mg, 69% yield), >310ꢀC decompose. 1H-NMR
(600 MHz, DMSO-d6): d 12.15 (br s, 1H), 8.51 (d, J = 7.92 Hz,
1H), 8.31 (s, 1H), 8.05 (dd, J = 9.10, 0.88 Hz, 1H), 7.83–7.78
(m, 1H), 7.66–7.60 (m, 1H), 7.55 (d, J = 7.92 Hz, 1H), 7.35
(t, J = 7.63 Hz, 1H); 13C-NMR (150 MHz, DMSO-d6): d 152.7,
144.9, 141.8, 132.8, 129.9, 129.6, 129.4, 128.3, 123.8, 122.0,
122.0, 120.4, 118.9, 115.8, 111.3; IR (KBr, cmꢁ1) 3152, 3109,
1638, 1616, 1572, 1485, 1460, 1410, 1344, 1256, 1240, 1223,
1086, 962, 812, 734.
11-Chloro-2-methoxy-5-methyl-5H-indolo[2,3-b]quinoline (6g).
2,11-Dichloro-6-methyl-6H-indolo[2,3-b]quinoline (22). Yellow
solid (410.0 mg, 80% yield), mp 170.9–173.3ꢀC. 1H-NMR
(600 MHz, CDCl3): d 8.47 (dd, J= 7.63, 0.59 Hz, 1H), 8.23
(d, J= 2.35 Hz, 1H), 7.94 (d, J= 8.80 Hz, 1H), 7.64–7.52 (m, 2H),
7.36–7.27 (m, 2H), 3.86 (s, 3H); 13C-NMR (150 MHz, CDCl3):
d 152.1, 144.9, 142.6, 134.1, 129.9, 129.2, 129.1, 128.8, 124.1,
1
Red solid (486.1 mg, 86% yield), mp 152.8–156.2ꢀC. H-NMR
(600 MHz, DMSO-d6): d 8.48–8.42 (m, 1H), 8.15–8.08 (m, 1H),
7.86–7.79 (m, 1H), 7.71–7.63 (m, 2H), 7.63–7.56 (m, 1H), 7.32–
7.24 (m, 1H), 4.38 (s, 3H), 4.02 (s, 3H); 13C-NMR (150 MHz,
DMSO-d6): d 156.2, 155.6, 155.1, 134.9, 132.6, 130.4, 124.9,
124.4, 123.9, 122.3, 120.3, 119.7, 118.2, 106.5, 56.6, 34.2; IR
(KBr, cmꢁ1) 3260, 2965, 1634, 1602, 1574, 1493, 1447, 1350,
1269, 1240, 1220, 1194, 1136, 1074, 1038, 839, 756, 737. Anal.
Calcd for C17H13ClN2O: C, 68.81; H, 4.42; N, 9.44. Found:
C, 68.53; H, 4.38; N, 9.19.
122.7, 122.6, 120.4, 119.2, 115.8, 108.5, 27.7; IR (KBr, cmꢁ1
)
3057, 2930, 1638, 1604, 1560, 1485, 1473, 1397, 1265, 1246,
1126, 1086, 1001, 820, 739. Anal. Calcd for C16H10Cl2N2:
C, 63.81; H, 3.35; N, 9.30. Found: C, 63.88; H, 3.36; N 9.14.
Preparation of methyl 2-(4-chlorophenylamino)-1-methyl-
1H-indole-3-carboxylate (19). To the argon flushed suspension of
NaH (52 mg, 1.3 mmol, 1.3 equiv, 60% oil suspension) in THF
(5 mL) at 0ꢀC, a solution of methyl 2-(4-chlorophenylamino)-1H-
indole-3-carboxylate 3b (300.7 mg, 1 mmol, 1.0 equiv) in THF
(5 mL) was added dropwise. The reaction mixture was stirred at
0ꢀC for 0.5 h. Then, MeI (283.9 mg, 2 mmol, 2.0 equiv) was added.
The reaction was warmed to room temperature and kept on stirring
for 0.5 h. The reaction was quenched with aqueous saturated
NaHCO3. The THF was removed under vacuum and extracted with
EtOAc for three times. The combined organic layers were washed
with brine and water and then dried over anhydrous MgSO4.
Further purification was achieved by column chromatography
(SiO2, n-hexane/ethyl acetate = 20:1) to give methyl 2-(4-
chlorophenylamino)-1-methyl-1H-indole-3-carboxylate 19 192.8 mg
(61% yield). White solid, mp 161.9–162.2ꢀC; Rf =0.50 (EtOAc/
hexanes = 1:5).1H-NMR (600 MHz, CDCl3): d 8.25 (s, 1H), 8.02–
7.89 (m, 1H), 7.32–7.16 (m, 5H), 6.95–6.82 (m, 2H), 3.92 (s, 3H),
3.39 (s, 3H); 13C-NMR (150 MHz, CDCl3): d 167.4, 148.5, 141.3,
134.9, 129.5, 128.2, 125.4, 122.2, 121.7, 120.8, 120.3, 109.0, 92.7,
50.9, 31.3; IR (KBr, cmꢁ1) 3289, 3053, 2947, 1659, 1564, 1489,
1439, 1390, 1260, 1215, 1186, 1101, 1022, 833, 806, 785, 742.
Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found:
C, 64.83; H, 4.79; N 8.80.
Methyl 2-((4-chlorophenyl)(methyl)amino)-1-methyl-1H-
indole-3-carboxylate (20). The reaction was carried out by
the same procedure with 19. Red oil (67.2 mg, 20% yield);
Rf = 0.40 (EtOAc/hexanes = 1:5). 1H-NMR (600 MHz,
CDCl3): d 8.26–8.16 (m, 1H), 7.40–7.30 (m, 3H), 7.18–7.12
(m, 2H), 6.54–6.46 (m, 2H), 3.81 (s, 3H), 3.55 (s, 3H), 3.37
(s, 3H); 13C-NMR (150 MHz, CDCl3): d 164.3, 146.7 146.3,
133.8, 129.0, 128.6, 125.6, 123.6, 123.1, 122.2, 121.9,
114.1, 109.8, 99.95, 50.8, 38.9, 28.8; IR (cmꢁ1) 3053, 2949,
1738, 1697, 1605, 1547, 1495, 1393, 1200, 1099, 1020, 818,
752, 698. Anal. Calcd for C18H17ClN2O2: C, 65.75; H, 5.21;
N, 8.52. Found: C, 65.54; H, 4.84; N, 8.33.
N-(11-chloro-5-methyl-5H-indolo[2,3-b]quinolin-2-yl)acetamide
(6h). Red solid (390.8 mg, 67% yield), >232ꢀC decompose. 1H-NMR
(600 MHz, DMSO-d6): d 10.29 (br s, 1H), 8.66 (br s, 1H), 8.33–8.11
(m, 1H), 8.06–7.74 (m, 2H), 7.64–7.36 (m, 2H), 7.23–7.01 (m, 1H),
4.41–3.96 (m, 3H), 2.17–2.03 (m, 3H); 13C-NMR (150 MHz,
DMSO-d6): d 168.5, 155.1, 154.2, 134.4, 134.3, 132.7, 129.3,
123.8, 123.5, 123.3, 123.1, 119.3, 118.1, 117.2, 115.8, 113.2, 32.9,
24.0; IR (KBr, cmꢁ1) 3337, 1630, 1574, 1489, 1466, 1442, 1420,
1265, 1236, 1192, 1134, 1070, 878, 758; HRMS (ESI) Calcd for
C18H13ClN3O [Mꢁ H]ꢁ 322.0747. Found: 322.0754.
Methyl 11-chloro-5-methyl-5H-indolo[2,3-b]quinoline-2-
carboxylate (6i). Orange solid (326.0 mg, 94% yield), mp
280.9–283.0ꢀC. 1H-NMR (600 MHz, CDCl3): d 8.95 (s, 1H), 8.29
(d, J = 8.22 Hz, 2H), 7.74–7.57 (m, 2H), 7.52 (t, J = 7.48 Hz, 1H),
13
7.22 (t, J = 7.48 Hz, 1H), 4.24 (s, 3H), 4.00 (s, 3H);
C-NMR
(150 MHz, CDCl3): d 166.0, 155.1, 154.5, 139.2, 135.7, 131.3,
130.1, 128.2, 125.4, 123.9, 123.8, 123.5, 120.9, 118.5, 117.8,
114.3, 52.4, 33.4; IR (KBr, cmꢁ1) 2949, 1709, 1616, 1560, 1526,
1495, 1437, 1298, 1246, 1230, 1116, 1071, 766, 743. Anal. Calcd
for C18H13ClN2O2: C, 66.57; H, 4.03; N, 8.63. Found: C, 66.31;
H, 3.84; N, 8.46.
3,11-Dichloro-5-methyl-5H-indolo[2,3-b]quinoline (14). Orange
solid (323.0 mg, 94% yield), mp 214.4–217.2ꢀC. 1H-NMR
(600 MHz, CDCl3): d 8.31 (dd, J = 8.22, 4.99 Hz, 2H), 7.75–7.68
(m, 2H), 7.56 (t, J = 7.63 Hz, 1H), 7.48 (dd, J = 8.80, 1.76 Hz,
1H), 7.30–7.24 (m, 1H), 4.33 (s, 3H); 13C-NMR (150 MHz,
CDCl3): d 154.1, 152.9, 137.9, 137.2, 135.9, 130.1 127.3, 124.2,
123.8, 123.3, 123.0, 121.1, 117.8 117.4, 114.3, 33.9; IR (KBr,
cmꢁ1) 3399, 1631, 1607, 1557, 1516, 1491, 1443, 1263, 1234,
1105, 1069, 955, 878, 756.
4,11-Dichloro-5-methyl-5H-indolo[2,3-b]quinoline (18). Red
solid (246.1 mg, 78% yield), mp 211.4–213.0ꢀC. 1H-NMR
(600 MHz, CDCl3): d 8.36–8.28 (m, 2H), 7.76 (dd, J= 7.92,
1.47 Hz, 1H), 7.69 (d, J= 7.92 Hz, 1H), 7.57–7.52 (m, 1H),
7.34 (t, J= 7.78 Hz, 1H), 7.24 (t, J= 7.48 Hz, 1H), 4.59 (s, 3H);
13C-NMR (150 MHz, CDCl3): d 157.0, 155.0, 135.3 (d, J=4.5Hz),
134.4, 130.2, 125.8, 125.3, 124.1, 123.6, 122.6, 122.1, 121.4,
120.8, 117.9, 40.7; IR (KBr, cmꢁ1) 3057, 1640, 1551, 1518, 1483,
1447, 1433, 1261, 1240, 1219, 1142, 1063, 806, 772, 758, 716.
Anal. Calcd for C18H13ClN2O2: C, 63.81; H, 3.35; N, 9.30. Found:
C, 63.46; H, 3.32; N, 9.07.
N-(3-aminopropyl)-2-chloro-5-methyl-5,11a-dihydro-4aH-indolo
[2,3-b]quinolin-11-amine (23). Yellow solid (32.9 mg, 97%
yield); Rf = 0.16 (EtOAc/MeOH = 20:1). 1H-NMR (400 MHz,
CDCl3): d 8.06 (d, J= 1.20, 1H), 7.96 (d, J= 7.60, 1H), 7.75
(d, J= 7.60, 1H), 7.58–7.55 (m, 1H), 7.49 (d, J= 9.20, 1H), 7.42
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1114
L. Wang, W.-J. Lu, T. Odawara, R. Misumi, Z.-W. Mei, W. Peng, I. E.-T. El-Sayed, and T. Inokuchi
Vol 51
(t, J= 7.20, 1H), 7.17 (t, J= 7.20, 1H), 4.16 (s, 3H), 3.97 (s, 2H), 3.03
(t, J= 5.20, 2H), 1.80–1.74 (m, 2H); 13C-NMR (100 MHz, CDCl3): d
156.7, 152.6, 147.3, 136.3, 129.9, 125.8, 125.6, 124.1, 123.7, 121.7,
118.7, 117.3, 117.0, 115.8, 106.4, 49.7, 41.5, 32.7, 32.3; IR (KBr,
cmꢁ1) 3433, 1620, 1586, 1557, 1493, 1443, 1418, 1279, 1248, 797,
756, 731.
A.; Van Poel, B.; Pieters, L.; Claeys, M.; Berghe, D. V.; Kambu, K.;
Tona, L.; Vlietinck, A. J. Planta Med 1996, 62, 22; (c) Grellier, P.;
Ramiaramanana, L.; Millerioux, V.; Deharo E.; Schrével, J.; Frappier,
F.; Trigalo, F.; Bodo, B.; Pousset, J. L. Phytother Res 1996, 10, 317;
(d) Wright, C. W.; Phillipson, J. D.; Awe, S. O.; Kirby, G. C.; Warhurst,
D. C.; Quetin-Leclercq, J.; Angenot, L. Phytother Res 1996, 10, 361; (e)
Kirby, G. C.; Paine, A.; Warhurst, D. C.; Noamese, B. K.; Phillipson, J.
D.; Paine, A.; Warhurst, D. C.; Noamese, B. K.; Phillipson, J. D. Phytother
Res 1995, 9, 359.
11-Azido-2-chloro-5-methyl-5H-indolo[2,3-b]quinoline (24).
Brown solid (59.2 mg, 96% yield); Rf = 0.56 (EtOAc/
1
[4] Reviews: (a) Lavrado, J.; Moreira, R.; Paulo, A. Curr Med
Chem 2010, 17, 2348; (b) Kumar, E. V.; Etukala, J. R.; Ablordeppey, S.
Y. Min-Rev Med Chem 2008, 8, 538.
MeOH = 20:1). H-NMR (400 MHz, CDCl3): d 8.29 (d, J = 2.00,
1H), 7.96 (d, J = 8.00, 1H), 7.70–7.65 (m, 2H), 7.60–7.52
(m, 2H), 7.27 (t, J = 8.00, 1H), 4.25 (s, 3H); 13C-NMR
(100 MHz, CDCl3): d 155.9, 154.4, 137.3, 135.5, 131.2, 129.3,
127.5, 124.3, 124.0, 121.7, 120.3, 117.8, 117.4, 115.6, 33.2; IR
(KBr, cmꢁ1) 3449, 2122, 1626, 1560, 1524, 1489, 1283, 1236,
1109, 804, 760.
N-(3-Aminopropyl)-2-chloro-6-methyl-6H-indolo[2,3-b]
quinolin-11-amine (25). Yellow oil (23.7 mg, 70% yield);
Rf = 0.50 (EtOAc/MeOH = 4:1). 1H-NMR (400 MHz, CDCl3):
d 8.19 (d, J= 2.40, 1H), 8.06 (d, J= 8.00, 1H), 7.96 (d, J= 9.20,
1H), 7.55 (dd, J= 8.80, 2.40, 1H), 7.52–7.48 (m, 1H), 7.38
(d, J= 7.60, 1H), 7.28 (t, J= 7.60, 1H), 6.03 (br s, 1H), 3.92 (s, 3H),
3.85 (t, J= 4.80, 2H), 2.99 (t, J= 6.40, 2H), 1.90–1.84 (m, 2H);
13C-NMR (100 MHz, CDCl3): d 154.2, 148.2, 146.3, 141.3, 129.4,
129.2, 126.3, 126.0, 122.2, 122.1, 120.4, 119.7, 118.5, 108.2,
104.1, 48.8, 41.0, 33.7, 27.7; IR (cmꢁ1) 3354, 2931, 1668, 1601,
1566, 1489, 1441, 1395, 1316, 1250, 1123, 822, 743; HRMS (ESI)
Calcd for C19H18ClN4 [M ꢁ H]ꢁ 337.122. Found: 337.1205.
[5] (a) Guittat, L.; Alberti, P.; Rosu, F.; Van Miert, S.; Thetiot, E.;
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Hostyn, S.; Van Baelen, G.; Lemière, G.; Maes, B. U. W.; Cos, P.; Maes,
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Acknowledgements. We are grateful to Okayama University for the
support and to the Advanced Science Research Center for the NMR
experiments and EA. We are thankful to Prof. S. Nakashima for the
HRMS analyses. We thank the Ministry of Education, Culture,
Sports, Science and Technology (MEXT) for the scholarship to
L. W. and Air Water Inc. for the generous gift of indoles.
REFERENCES AND NOTES
[13] James, K. M.; Willetts, N.; Procter, D. J Org Lett 2008, 10, 1203.
[14] To our knowledge, one example deals with the use of N-
methylated aniline for the synthesis of indolequinolone structure; see
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DOI 10.1002/jhet