A concise synthesis of 6H-Indolo[2,3- B ]quinolines: Formal synthesis of neocryptolepine

Article abstract of DOI:10.1055/s-0031-1290812

A new two-step approach for the synthesis of 6H-indolo[2,3-b]quinolines is described using indole C3 alkylation and a one-pot reduction-cyclization- aromatization sequence. The synthesis of the parent 6H-indolo[2,3-b]quinoline system constitutes a formal synthesis of the alkaloid neocryptolepine (cryptotackieine). Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290812

PAPER
▌1339
paper
A Concise Synthesis of 6H-Indolo[2,3-b]quinolines: Formal Synthesis of
Neocryptolepine
Hari K. Kadam, Prakash T. Parvatkar, Santosh G. Tilve*
Department of Chemistry, Goa University, Taleigao Plateau, Goa 403 206, India
E-mail: stilve@unigoa.ac.in; Fax +91(832)2452886
Received: 07.02.2012; Accepted after revision: 02.03.2012
hibit DNA replication and transcription1 and exhibit
promising antiplasmodial activity.8 It has also been re-
ported that, these compounds and some of their methyl de-
rivatives displays promising antimuscarinic, antibacterial,
antiviral, antimicotic, antihyperglycemic, and cytotoxic
properties in vitro and antitumor activity in vivo.9
Abstract: A new two-step approach for the synthesis of 6H-indo-
lo[2,3-b]quinolines is described using indole C3 alkylation and a
one-pot reduction–cyclization–aromatization sequence. The syn-
thesis of the parent 6H-indolo[2,3-b]quinoline system constitutes a
formal synthesis of the alkaloid neocryptolepine (cryptotackieine).
Key words: alkaloid, alkylation, indoloquinoline, reduction–cycli-
zation, domino reaction
6H-Indolo[2,3-b]quinoline (4a), the immediate precursor
to neocryptolepine (2), shares many biological properties
with neocryptolepine (2) including the ability to interact
with DNA as an intercalator and to inhibit topoisomerase
II activity; it also has antimicrobial and cytotoxic activi-
ty.9c,10 6H-Indolo[2,3-b]quinoline (4a) itself is a natural
product isolated from the leaves of Justicia betonica10b
and is named norcryptotackeine.11,12 Due to their signifi-
cant biological activity and challenging structures, the in-
doloquinolines have been the target of synthetic and
medicinal chemists. Their first synthesis was reported by
Peczynska-Czoch and co-workers9c in 1994, before their
isolation from natural sources. Thereafter, several synthe-
ses of neocryptolepine were accomplished.11–19 Recent
synthetic studies include a photocyclization approach by
Mohan and co-workers,14 via C–N bond formation using
tin(II) chloride dihydrate by Sharma and Kundu,15 using
the Pummerer reaction by Procter and co-workers,16 using
an intramolecular Wittig reaction by Kraus and Guo,17 us-
ing the Friedlander quinoline synthesis followed by re-
duction, diazotization, and cyclization by Haddadin et
al.,12 and a palladium-catalyzed intramolecular direct ary-
lation approach by Hostyn et al.18 We reported the synthe-
sis of 6H-indolo[2,3-b]quinolines by a double reduction–
double cyclization approach in 200719a and a one-pot, io-
dine-catalyzed19b protocol in 2009. More recently, we
have also reported19c an efficient synthesis of neocrypto-
lepine (2) using the Wittig reaction and a one-pot reduc-
tion–cyclization–dehydration sequence.
In the past decade, indoloquinoline alkaloids have re-
ceived attention owing to their striking biological
properties1,2 and novel structural features. A series of tet-
racyclic heteroaromatic compounds based on the indolo-
quinoline framework have been isolated from the roots of
the West African plant Cryptolepis sanguinolenta, which
were traditionally used by Ghanaian healers to treat a va-
riety of disorders including malaria. Since 1974, a decoc-
tion of this plant has been used in the clinical therapy of
rheumatism, urinary tract infections, malaria, and other
diseases.3–6 Cryptolepine (1), neocryptolepine (crypto-
tackieine) (2), and isocryptolepine (cryptosanguinolen-
tine) (3) (Figure 1) are three major metabolites7 out of a
total of thirteen alkaloids isolated from C. sanguinolenta.
Me
N
N
N
Me
N
N
1
2
Me
N
N
N
H
3
4
Figure 1 Cryptolepine (1), neocryptolepine (2), isocryptolepine (3),
and norcryptotackiene (4a)
Continuing our interest19a–d in indoloquinoline alkaloids,
herein we report a simple and concise method for the syn-
thesis of 6H-indolo[2,3-b]quinolines. Our strategy is de-
picted in Scheme 1; alkylation of 1H-indole (5a) at its
more reactive 3-position followed by reductive cycliza-
tion to provide tetracyclic compound 8a that could be ox-
idized to 6H-indolo[2,3-b]quinoline (4a).
Cryptolepine (1) and neocryptolepine (2) are linearly
fused alkaloids with an indolo[3,2-b]quinoline and an in-
dolo[2,3-b]quinoline ring system, respectively, while
isocryptolepine (3) is an angularly fused alkaloid with an
indolo[3,2-c]quinoline ring system. Chemically these are
isomeric indoloquinolines, but more importantly they in-
Thus, 1H-indole (5a) was treated with 2-nitrobenzyl alco-
hol (6a) under Mitsunobu reaction condition, however, no
product formation was observed. Hence alkylation20 was
performed using 2-nitrobenzyl bromide (6b) in acetone–
water (4:1) at 80 °C for 40 hours. Product 7a was obtained
SYNTHESIS 2012, 44, 1339–1342
Advanced online publication: 05.04.2012
DOI: 10.1055/s-0031-1290812; Art ID: SS-2012-T0118-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

1340
H. K. Kadam et al.
PAPER
X
O2N
6a X = OH
6b X = Br
reductive
cyclization
O2N
N
N
H
H
5a
7a
ref. 11,12
[O]
N
N
N
2a
N
N
H
N
H
Me
H
8a
4a
Scheme 1 Synthetic strategy
in 65% yield along with minor amounts of 2-nitrobenzyl workup, the indoloquinoline 4a was obtained directly in
alcohol, a hydrolyzed product. Recently, the alkylation of 63% yield. In this step, reductive cyclization yielded 8a
indole by microwave irradiation21 using water as a solvent which under the reaction condition underwent aromatiza-
has been reported. When the reaction was attempted under tion to lead to 4a. A plausible mechanism for the forma-
these conditions, 7a was obtained in 68% yield after 10 tion 4a is depicted in Scheme 2.
minutes. To achieve a further improvement in the yield,
The synthesis of 6H-indolo[2,3-b]quinoline (4a) consti-
the alkylation was performed using methylmagnesium
tutes the formal synthesis of naturally occurring indolo-
bromide as the base, wherein 7a was obtained in 72%
quinoline alkaloid neocryptolepine (2).
yield. The next step in the projected synthesis was reduc-
After successfully demonstrating the efficacy of our strat-
tive cyclization. This was first attempted using a molyb-
egy with the parent indole 5a, the methodology was ex-
tended to the synthesis of analogues of 6H-indolo[2,3-
b]quinoline, i.e. 9-methoxy- (4b) and 8-chloro-6H-indo-
lo[2,3-b]quinoline (4c) from the corresponding 5-meth-
oxy- and 6-chloroindoles 5b,c (Table 1).
denum catalyst22 without success. Later it was tried using
Cadogan’s protocol23 using triethyl phosphite. This gave
a complex mixture of products. Hence, triphenylphos-
phine in refluxing diphenyl ether24 was used. After usual
Table 1 Synthesis of 6H-Indolo[2,3-b]quinoline and Derivatives
Br
O2N
Ph3P, Ph2O
reflux, 4–6 h
6b
A, B or C
N
O2N
N
R
R
R
H
N
N
H
5
H
7
4
R = H, 5-OMe, 6-Cl
Yielda,b (%) of method
Yielda (%)
Entry
Compound 7
Compound 4
A
B
C
1
65
68
72
63
O2N
N
N
N
H
H
7a
4a
MeO
MeO
O2N
N
2
60
58
61
56
68
65
60
55
N
H
N
H
7b
4b
Cl
Cl
O2N
N
3
N
H
N
H
7c
4c
a Isolated yield.
b Reaction conditions: Method A: Na2CO3, acetone–H2O (4:1), 80 °C, 40 h; Method B: H2O, MW, 200 W, 150 °C, 10 min; Method C: MeMgBr,
toluene, stir, r.t., 12 h.
Synthesis 2012, 44, 1339–1342
© Georg Thieme Verlag Stuttgart · New York

PAPER
6H-Indolo[2,3-b]quinolines
1341
+
2 Ph3P
[O]
N
4a
O2N
– 2 Ph3PO
N
N
N–
N
N
H
H
N
H
H
H
H
Scheme 2 Proposed mechanism
IR (neat): 3417, 2924, 1606, 1519, 1456, 1348 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.47 (s, 2 H), 7.02–7.24 (m, 3 H),
7.33–7.48 (m, 5 H), 7.92 (d, J = 7.5 Hz, 1 H), 8.05 (br s, 1 H).
The overall yield of 6H-indolo[2,3-b]quinolines 4 in this
two-step sequence was found to be in the range 33–45%,
which is comparable with most of the reported methods.
In conclusion, we have developed a new and a concise
two-step method for the synthesis of 6H-indolo[2,3-
b]quinolines using an alkylation and domino reduction–
cyclization–aromatization approach. The usefulness of
the method was demonstrated by synthesizing the ana-
5-Methoxy-3-(2-nitrobenzyl)-1H-indole (7b)
Oily liquid; yield (Method C): 384 mg (68%).
IR (neat): 3415, 2960, 1581, 1521, 1485, 1350 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.82 (s, 3 H), 4.43 (s, 2 H), 6.87
(d, J = 8.0 Hz, 1 H), 6.90 (s, 1 H), 6.97 (s, 1 H), 7.26 (d, J = 8.4 Hz,
logues, 9-methoxy-6H-indolo[2,3-b]quinoline and 8- 1 H), 7.34–7.39 (m, 2 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.92 (d, J = 8.0
Hz, 1 H), 8.03 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.0 (CH2), 56.0 (CH3), 100.0
chloro-6H-indolo[2,3-b]quinoline.
(CH), 112.0 (CH), 112.3 (CH), 112.6 (Cq), 123.9 (CH), 124.6 (CH),
Commercial reagents were purchased from Sigma-Aldrich and used
127.0 (CH), 127.6 (Cq), 131.4 (Cq), 131.7 (CH), 132.8 (CH), 136.0
without further purification. Solvents were distilled prior to use. Re-
(Cq), 149.4 (Cq), 154.0 (Cq).
actions were monitored by TLC (Kieselgel Merck 60) purchased
from Merck. Column chromatography was performed on silica gel
GC-MS: m/z = 282 [M+].
HRMS: m/z [M + Na]+ calcd for C16H14N2O3Na: 305.0902; found:
305.0902.
(60–120 mesh). Flash chromatography was performed on a Combi-
flash Companion with silica gel (230–400 mesh). Infrared spectra
were recorded on Shimadzu FT-IR spectrophotometer. Microwave
reactions were carried out using a Milestone Startsynth microwave
instrument. 1H NMR (300 and 400 MHz) and 13C NMR (75 and 100
MHz) were recorded on a Bruker 300 and Bruker 400 instrument
using DMSO-d6 and CDCl3 as the solvent and TMS as an internal
standard. LCMS were recorded on a Agilent Technologies instru-
ment and GCMS on a Varian GC/MS instrument. HRMS were re-
corded on a MicroMass ES-QTOF. Melting points were recorded
using a Thiele apparatus and are uncorrected.
6-Chloro-3-(2-nitrobenzyl)-1H-indole (7c)
Orange solid; yield (Method C): 373 mg (65%); mp 112–114 °C.
IR (KBr): 3355, 2980, 1562, 1511, 1465, 1346 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.43 (s, 2 H), 6.99 (s, 1 H), 7.05
(d, J = 8.4 Hz, 1 H), 7.35–7.39 (m, 4 H), 7.49 (t, J = 7.6 Hz, 1 H),
7.93 (d, J = 8.0 Hz, 1 H), 8.11 (br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 28.4 (CH2), 111.2 (CH), 113.1
(Cq), 119.7 (CH), 120.3 (CH), 123.8 (CH), 124.7 (CH), 125.8 (Cq),
127.3 (CH), 128.1 (Cq), 131.7 (CH), 133.0 (CH), 135.7 (Cq), 136.6
(Cq), 149.3 (Cq).
3-(2-Nitrobenzyl)-1H-indoles 7a–c; General Procedure
Method A: A mixture of 2-nitrobenzyl bromide (6b, 432 mg, 2
mmol), indole 5a–c (8 mmol), and Na2CO3 (424 mg, 4 mmol) in
acetone–H2O (4:1, 10 mL) were stirred at 80 °C for 40 h. On com-
pletion of the reaction (TLC monitoring), H2O (10 mL) was added
and the mixture was extracted with EtOAc (3 × 20 mL). The com-
bined organic extracts were washed with brine, dried (anhyd
Na2SO4), concentrated under reduced pressure, and purified by
flash chromatography (20% EtOAc–hexanes).
HRMS: m/z [M + Na]+ calcd for C15H11N2O2ClNa: 309.0407;
found: 309.0406.
Indoloquinolines 4a–c; General Procedure
A mixture of 3-substituted indole derivative 7a–c (1 mmol) and
Ph3P (576 mg, 2.2 mmol) were refluxed in Ph2O under a N2 atmo-
sphere for 4–6 h. After cooling, the mixture was chromatographed
(silica gel), Ph2O was removed eluting with hexanes, further elution
with 20% EtOAc–hexanes afforded the indoloquinolines 4a–c.
Method B: A mixture of 2-nitrobenzyl bromide (6b, 432 mg, 2
mmol) and indole 5a–c (2.4 mmol) in H2O (10 mL) were reacted in
MW reactor at 150 °C (200 W) for 10 min. On completion of the
reaction (TLC monitoring), H2O (10 mL) was added and the mix-
ture was extracted with EtOAc (3 × 20 mL). The combined organic
extracts were washed with sat. K2CO3, dried (anhyd Na2SO4), con-
centrated under reduced pressure, and purified by flash chromatog-
raphy.
6H-Indolo[2,3-b]quinoline (4a)
Reaction time: 4 h; yellow solid; yield: 138 mg (63%); mp >300 °C
(Lit.13 342–346 °C).
1H NMR (300 MHz, DMSO-d6): δ = 7.27 (t, J = 7.5 Hz, 1 H), 7.45–
7.56 (m, 3 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.98 (d, J = 9.0 Hz, 1 H),
8.11 (d, J = 9.0 Hz, 1 H), 8.26 (d, J = 9.0 Hz, 1 H), 9.05 (s, 1 H),
11.69 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 111.4 (CH), 118.3 (Cq), 120.1
(CH), 120.7 (Cq), 122.3 (CH), 123.2 (CH), 124.1 (Cq), 127.4 (CH),
128.0 (CH), 128.6 (CH), 129.1 (2 CH), 141.9 (Cq), 146.8 (Cq),
153.3 (Cq).
Method C: Indole 5a–c (2 mmol) was dissolved in dry toluene (10
mL) and cooled to –5 °C. To this was added MeMgBr in Et2O (2.1
mmol) and the mixture was stirred at –5 °C to r.t. for 1 h. The soln
was again cooled to –5 °C and 2-nitrobenzyl bromide (6b, 432 mg,
2 mmol) in dry toluene (2 mL) was added and mixture was stirred
at r.t. for 24 h. On completion of the reaction (TLC monitoring),
H2O (10 mL) was added and the mixture was extracted with EtOAc
(3 × 20 mL). The combined organic extracts were washed with sat.
NH4Cl, dried (anhyd Na2SO4), concentrated under reduced pres-
sure, and purified by flash chromatography.
HRMS: m/z [M + H]+ calcd for C15H11N2: 219.0922; found:
219.0926.
9-Methoxy-6H-indolo[2,3-b]quinoline (4b)
Reaction time: 6 h; light-green solid; yield: 149 mg (60%); mp 284–
286 °C.
3-(2-Nitrobenzyl)-1H-indole (7a)15,20
Oily liquid; yield (Method C): 363 mg (72%).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1339–1342

1342
H. K. Kadam et al.
PAPER
(d) Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B.
1H NMR (400 MHz, DMSO-d6): δ = 3.87 (s 3 H), 7.16 (d, J = 8.8
Hz, 1 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.46 (t, J = 8.4 Hz, 1 H), 7.71 (t,
J = 8.0 Hz, 1 H), 7.88 (s 1 H), 7.96 (d, J = 8.4 Hz, 1 H), 8.08 (d,
J = 8.0 Hz, 1 H), 9.04 (s, 1 H), 11.51 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 56.1 (CH3), 105.8 (CH), 112.1
(CH), 117.0 (CH), 118.6 (Cq), 121.0 (Cq), 123.0 (CH), 123.8 (Cq),
127.4 (CH), 128.1 (CH), 129.1 (2 CH), 136.3 (Cq), 146.8 (Cq),
153.7 (Cq), 154.0 (Cq).
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LCMS: m/z = 249 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C16H12N2ONa: 271.0864; found:
271.0847.
8-Chloro-6H-indolo[2,3-b]quinoline (4c)
Reaction time: 5 h; colorless solid; yield: 139 mg (55%); mp 296–
298 °C.
1H NMR (400 MHz, DMSO-d6): δ = 7.29 (d, J = 8.4 Hz, 1 H), 7.50–
7.52 (m, 2 H), 7.74 (t, J = 8.0 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 1 H),
8.11 (d, J = 8.4 Hz, 1 H), 8.27 (d, J = 8.4 Hz, 1 H), 9.07 (s, 1 H),
11.86 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 111.1 (CH), 117.6 (Cq), 119.7
(Cq), 120.3 (CH), 123.6 (CH), 123.7 (CH), 124.2 (Cq), 127.4 (CH),
128.6 (CH), 129.2 (CH), 129.5 (CH), 132.9 (Cq), 142.6 (Cq), 146.7
(Cq), 153.4 (Cq).
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253.0531.
Acknowledgment
We are grateful to the DST, New Delhi for financial assistance and
IISc., Bangalore for HRMS. Hari K. Kadam is also thankful to
CSIR, New Delhi for a NET Senior Research Fellowship and
Prakash T. Parvatkar is thankful to the UGC, New Delhi for the
award of the Dr. D. S. Kothari Postdoctoral Fellowship.
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