An expeditious I2-catalyzed entry into 6H-indolo[2,3-b]quinoline system of cryptotackieine

Article abstract of DOI:10.1021/jo901361x

(Chemical Equation Presented) A synthesis of a series of novel 6H-indolo[2,3-b]-quinolines with different substituents on the quinoline ring is described. The method involves reaction of indole-3-carboxyaldehyde with aryl amines in the presence of a catal

Full text of DOI:10.1021/jo901361x

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and transcription1a and also exhibit strong antiplasmodial
An Expeditious I2-Catalyzed Entry into
6H-Indolo[2,3-b]quinoline System of Cryptotackieine
activity.4
Prakash T. Parvatkar,†,‡ Perunninakulath S. Parameswaran,*,†
and Santosh G. Tilve*,‡
†National Institute of Oceanography, Dona Paula, Goa
403 004, India, and ‡Department of Chemistry,
Goa University, Taleigao Plateau, Goa 403 206, India
FIGURE 1. Cryptolepine 1, neocryptolepine (cryptotackieine) 2,
and isocryptolepine (cryptosanguinolentine) 3.
param@nio.org; stilve@unigoa.ac.in
Received June 26, 2009
In continuation of our interest5 in indoloquinoline alka-
loids, we report herein a novel one-pot synthesis of indolo-
[2,3-b]quinolines using iodine as catalyst. Our retrosynthetic
analysis (Scheme 1) indicated that if 3H-indolinium cation 6a
or 6b is generated, it should be possible for nitrogen of aniline
7a to make a nucleophilic attack followed by annulation
and subsequent oxidation should lead to 6H-indolo[2,3-b]-
quinoline 4a.
SCHEME 1. Retrosynthesis of 6H-indolo[2,3-b]quinoline 4a
A synthesis of a series of novel 6H-indolo[2,3-b]-
quinolines with different substituents on the quinoline
ring is described. The method involves reaction of indole-
3-carboxyaldehyde with aryl amines in the presence of a
catalytic amount of iodine in refluxing diphenyl ether to
yield indolo[2,3-b]quinolines in one-pot. The present
approach provides a new route for the synthesis of
polycyclic structures related to an alkaloid cryptotack-
ieine (neocryptolepine).
To test this hypothesis, we initially heated indole-3-car-
boxyaldehyde 8 with excess aniline 7a in refluxing diphenyl
ether in the presence of acetic acid. It was observed that only
Schiff’s base 9 was formed. Recently the use of iodine has
received considerable attention as an inexpensive, environ-
mentally tolerable, and readily available mild Lewis acid for
different organic transformations.6 So, a few crystals of
iodine were added to the above reaction mixture containing
Schiff’s base and the heating was continued for further 10 h.
This resulted in the formation of two solid products. The
more polar solid was found to be acetanilide 10 while the less
polar 6H-indolo[2,3-b]quinoline 4a (Scheme 2).
In order to optimize the reaction conditions, the reaction was
studied with different concentrations of these reagents (Table 1).
Initially the reactions were carried out with two equiva-
lents of aniline 7a and varying concentrations of iodine
(entries 1-6). In the absence of iodine (entry 1), no formation
of product 4a was observed. The optimum concentration of
iodine required was determined to be 0.1 equiv (entry 3).
In recent years indoloquinoline alkaloids have received
considerable interest due to their interesting biological prop-
erties.1 The roots of West African plant Cryptolepis sangui-
nolenta, a rich source of indoloquinoline alkaloids have been
traditionally used by the Ghanaian healers to treat a variety
of health 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.2 Cryptolepine 1, neocryptolepine (cryptotackieine)
2, and isocryptolepine (cryptosanguinolentine) 3 (Figure 1)
are three major metabolites out of thirteen alkaloids isolated
from this plant.3 Chemically these are isomeric indoloqui-
nolines, but more importantly they inhibit DNA replication
(1) (a) Molina, A.; Vaquero, J. J.; Garcia-Navio, J. L.; Alvarez-Builla, J.;
de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros, M. J. Org.
Chem. 1996, 61, 5587–5599. (b) Cimanga, K.; De Bruyne, T.; Pieters, L.;
Vlietinck, A. J.; Turger, C. A. J. Nat. Prod. 1997, 60, 688–691.
(2) (a) Molina, P.; Alazarin, M.; Vidal, A. J. Chem. Soc., Chem Commun.
1990, 1277–1279. (b) Sundaram, G. S. M.; Venkatesh, C.; Syam Kumar, U.
K.; Ila, H.; Junjappa, H. J. Org. Chem. 2004, 69, 5760–5762.
(3) (a) Cimanga, K.; De Bruyne, T.; Pieters, L.; Claeys, M.; Vlietinck, A.
Tetrahedron Lett. 1996, 37, 1703–1706. (b) Sharaf, M. H. M.; Schiff, P. L. Jr.;
Tackie, A. N.; Phoebe, C. H.; Martin, G. E. J. Heterocycl. Chem. 1996, 33,
239–243. (c) Pousset, J.-L.; Martin, M.-T.; Jossang, A.; Bodo, B.
Phytochemistry 1995, 39, 735–736.
(5) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Tetrahedron Lett.
2007, 48, 7870–7872.
(6) (a) Lin, C.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2006,
71, 6588–6591. (b) Liu, Z.; Liu, L.; Shafiq, Z.; Wu, Y.-C.; Wang, D.; Chen,
Y.-J. Tetrahedron Lett. 2007, 48, 3963–3967. (c) Zhang, X.; Rao, W.; Chan,
P. W. H. Synlett 2008, 2204–2208. (d) Wang, X.-S.; Li, Q.; Wu, J.-R.; Li,
Y.-L. Synth. Commun. 2009, 39, 702–715.
(4) Grellier, P.; Ramiaramanana, L.; Millerioux, V.; Deharo, E.;
Schrevel, J.; Frappier, F.; Trigalo, F.; Bodo, B.; Pousset, J. L. Phytotherapy
Res. 1996, 10, 317–321.
DOI: 10.1021/jo901361x
r
Published on Web 09/29/2009
J. Org. Chem. 2009, 74, 8369–8372 8369
2009 American Chemical Society

Parvatkar et al.
JOCNote
SCHEME 2. Synthesis of 6H-indolo[2,3-b]quinoline 4a
SCHEME 3. Proposed Mechanism for the Formation of 4a
TABLE 1. Reaction of Indole-3-carboxyaldehyde with Aniline
TABLE 2. Reaction of Indole-3-carboxyaldehyde with Aniline in Ab-
sence of Acetic Acid
entry
I2 (equiv)
7a (equiv)
yield (%) of 4a
1
2
3
4
5
6
7
8
9
10
0.0
0.05
0.1
0.2
0.5
1.0
0.1
0.1
0.1
0.1
2
2
2
2
2
2
1
1.5
3
4
0
20
23
21
18
12
0
19
23
23
entry
I2 (equiv)
7a (equiv)
yield (%) of 4a
1
2
3
4
5
6
0.1
0.1
0.1
0.1
0.05
0.3
1
1.5
2
3
2
0
30
45
45
34
37
2
When the reactions were carried out by varying the amount
of aniline 7a and keeping the concentration of iodine as 0.1
equiv (entries 7-10), it was observed that with one equiva-
lent of aniline 7a, no product 4a (entry 7) was forming. The
maximum yield of 4a was obtained when two or more than
two equivalents of the aniline (entries 3, 9, and 10) were used.
We initially thought that HI generated in the reaction media
may have catalyzed the reaction to give the desired product 4a.
However, when HI was tried directly as a catalyst instead of I2,
no formation of product 4a was observed (monitored by tlc).
On the basis of the above studies, a plausible mechanism for the
formation of 4a is given in Scheme 3.
Thus, initial electrophilic attack of iodine on 9 generates
3-iodo-indolinium cation 11. Subsequent nucleophilic attack
by aniline 7a on 11 will lead to 2-N-phenyl substituted indole
12. Intramolecular electrophilic substitution leading to
annulated structure 14 via 13 followed by expulsion of
aniline may form 15. Further, departure of iodine followed
by oxidation7 could lead to aromatized heterocycle 4a.
As acetanilide 10 was forming due to the presence of acetic
acid in the reaction medium, the reaction was carried out in
absence of it. It took 18 h for the formation of Schiff’s base 9
and a further 8 h to complete the reaction giving only one
product 4a and the yield was doubled to 45%.
As acetic acid was used for the formation of Schiff’s base,
we thought of using iodine itself as an agent for its formation
and further transformations.
Thus, the mixture of indole-3-carboxyaldehyde 8, aniline 7a
and iodine were refluxed in diphenyl ether. To our delight, the
reaction was complete in 12 h. The yield of the product 4a was
found to be 45%. Since the yield had increased in the absence
of acetic acid, we studied the influence of the amount of iodine
and aniline 7a on the yield (Table 2). However, no further
improvement in yields was observed. The modest yield is due to
the decomposition of the Schiff’s base intermediate under the
reaction condition and also some loss during purification by
column chromatography owing to its low solubility.
(7) Nandha Kumar, R.; Suresh, T.; Mohan, P. S. Tetrahedron Lett. 2002,
43, 3327–3328.
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Parvatkar et al.
JOCNote
TABLE 3. Synthesis of Different Indoloquinolines Using I2 as a Catalyst
b,c). The reaction with m-bromo-aniline gave 3-bromo-indolo-
[2,3-b]quinoline in 44% yield (entry g). The reaction was also
studied with amino heterocycle 3-amino pyridine to obtain the
corresponding product in 29% yield (entry h).
The common route among the reported8-19 methods for
the synthesis of 6H-indolo[2,3-b]quinoline involves building
of an indole ring on a quinoline precursor, while the present
route describes the construction of a quinoline ring on an
indole precursor.
In conclusion, we have developed a new one-pot method
for the assembly of substituted indoloquinolines by sequen-
tial imination, nucleophilic addition, and annulation cata-
lyzed by iodine. Though the yields are moderate, this method
is easy and short, which makes it attractive.
Experimental Section
General. Melting points are uncorrected. 1H NMR (300 MHz)
and 13C NMR (75 MHz) spectra were recorded in DMSO-d6.
TMS was used as an internal reference. Chromatographic puri-
fication was conducted by column chromatography using neutral
alumina.
General Procedure for the Synthesis of Different Indoloquino-
lines. Indole-3-carboxyaldehyde (8) (3.46 mmol), aryl amines
(7a-h) (6.92 mmol) and iodine (0.35 mmol) was refluxed in
diphenyl ether (20 mL) for 12 h. After cooling, the reaction
mixture was chromatographed on alumina and diphenyl ether
was removed using hexanes as an eluent. Excess aryl amines
(except 3-amino-pyridine) were eluted using 5% ethyl acetate in
hexanes. Further elution with 20% ethyl acetate in hexanes
afforded the indoloquinolines (4a-h).
6H-Indolo[2,3-b]quinoline (4a). Yield 45% (0.3394 g); yellow
solid; mp >300 °C; Lit.15 342-346 °C. Spectral data are
identical with those reported.5,14,15
8H-Indolo[2,3-b]benzo[h]quinoline (4b). Yield 48% (0.4450 g);
gray solid; mp 264-268 °C. IR (KBr) 3348, 3053, 1609, 1491,
1462, 1385, 1364, 1258, 1234, 1147, 1105, 1018, 899, 812, 797,
746, 685 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.31 (m, 1H),
7.57 (m, 2H), 7.74 (m, 2H), 7.81 (d, 1H, J = 9 Hz), 8.02 (m, 2H),
8.31 (d, 1H, J = 7.5 Hz), 9.11 (s, 1H), 9.26 (d, 1H, J = 9.0 Hz),
12.01 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 111.6,
117.4, 120.2, 120.8, 121.2, 122.1, 123.9, 124.4, 126.7, 127.2, 128.2
(3 ꢀ C), 128.4, 131.0, 133.7, 141.2, 144.4, 152.4; HRMS m/z
[M þ H]þ 269.1070 (calcd for C19H13N2, 269.1079).
8H-Indolo[2,3-b]benzo[f]quinoline (4c). Yield 53% (0.4914 g);
gray solid; mp >300 °C. IR (KBr) 3400, 3152, 1614, 1519, 1445,
1398, 815, 740 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.32 (m,
1H), 7.57 (s, 2H), 7.64 (m, 1H), 7.78 (dd, 1H, J = 6.9 Hz, 7.5 Hz),
7.94 (d, 1H, J = 9 Hz), 8.06 (dd, 2H, J = 8.4 Hz, 9 Hz), 8.43 (d,
1H, J = 7.2 Hz), 9.03 (d, 1H, J = 8.4 Hz), 10.03 (s, 1H), 11.87 (s,
1H, NH); 13C NMR (75 MHz, DMSO-d6) δ 111.6, 117.2, 119.9,
120.2, 121.1, 122.3, 123.0, 123.8, 126.4, 127.5, 127.8, 128.2,
129.0, 130.3, 130.4, 131.0, 141.3, 146.4, 152.8; HRMS m/z
[M þ H]þ 269.1070 (calcd for C19H13N2, 269.1079).
aYield of the isolated products.
The potential biological activities of these indoloquinolines
prompted us to check the feasibility of making the library of
such compounds (Table 3). As methyl-substituted indolo[2,3-b]-
quinolines have shown promising anticancer activity,8-10
we prepared 2-, 3-, and 4-methyl substituted indolo[2,3-b]-
quinolines from corresponding toluidines in 38-41% yield
(entries d-f). Next, we tried the reaction with naphthylamines
(R and β), to get the corresponding annulated pentacyclic
benzo-indolo[2,3-b]quinolines in 48 and 53% yield (entries
(11) Dhanabal, T.; Sangeetha, R.; Mohan, P. S. Tetrahedron 2006, 62,
6258–6263.
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De Pauw-Gillet, M.-C.; van den Heuvel, H.; Claeys, M.; Lemiere, F.;
Esmans, E. L.; Rozenski, J.; Quirijnen, L.; Maes, L.; Dommisse, R.; Lemiere,
G. L. F.; Vlietinck, A.; Pieters, L. J. Med. Chem. 2002, 45, 3497–3508.
(9) Peczynska-Czoch, W.; Pognan, F.; Kaczmarek, L.; Boratynski, J.
J. Med. Chem. 1994, 37, 3503–3510.
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B.-P.; Danuta, D.; Joanna, W.; Adam, O.; Magdalena, S.; Anna, J.; Anna,
J.; Arkadiusz, K.; Wanda, P.-C. Anticancer Res. 2005, 25, 2857–2868.
(13) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts,
G.; Pieters, L.; Haemers, A.; Dommisse, R. A. Synlett 2003, 615–618.
(14) Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925–932.
(15) Molina, P.; Fresneda, P. M.; Delgado, S. Synthesis 1999, 326–329.
(16) Alajarin, M.; Molina, P.; Vidal, A. J. Nat. Prod. 1997, 60, 747–748.
(17) Timari, G.; Soos, T.; Hajos, G. Synlett 1997, 1067–1068.
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J. Org. Chem. Vol. 74, No. 21, 2009 8371

Parvatkar et al.
JOCNote
4-Methyl-6H-Indolo[2,3-b]quinoline (4d). Yield 41% (0.3291 g);
yellow solid; mp 230-232 °C. IR (KBr) 3142, 3090, 1614, 1580,
3-Bromo-6H-Indolo[2,3-b]quinoline (4g). Yield 44% (0.4506 g);
brown solid; mp 260-264 °C. IR (KBr) 3375, 3132, 1614, 1508,
1
1460, 1408, 1329, 1230, 1126, 908, 820, 787, 737, 696 cm-1; H
1472, 1358, 1242, 939, 798, 740 cm-1 1H NMR (300 MHz,
;
NMR (300 MHz, DMSO-d6) δ 2.77 (s, 3H), 7.26 (dd, 1H,
J = 6.9, 7.2 Hz), 7.37 (dd, 1H, J = 7.2, 7.5 Hz), 7.46-7.52 (m,
2H), 7.59 (d, 1H, J = 6.9 Hz), 7.95 (d, 1H, J= 7.8 Hz), 8.25 (d, 1H,
J = 7.5 Hz), 9.01 (s, 1H), 11.80 (s, 1H, -NH); 13CNMR(75 MHz,
DMSO-d6) δ 18.9, 111.3, 118.0, 120.0, 120.7, 122.2, 122.8, 123.9,
127.1, 128.4, 128.5, 129.2, 134.6, 141.9, 145.8, 152.8; HRMS m/z
[M þ H]þ 233.1076 (calcd for C16H13N2, 233.1078).
DMSO-d6) δ 7.30 (dd, 1H, J = 6.9, 7.2 Hz), 7.52 - 7.62 (m, 2H),
7.65 (d, 1H, J = 8.1 Hz), 7.84 (d, 1H, J = 7.5 Hz), 8.02 (d, 1H,
J = 8.7 Hz), 8.44 (d, 1H, J = 7.5 Hz), 9.22 (s, 1H), 11.90 (s,
1H, -NH);13C NMR(75MHz, DMSO-d6) δ 111.6, 119.6, 120.4,
120.5, 122.3 (2 ꢀ C), 122.9, 126.7, 127.2, 127.8, 129.3 (2 ꢀ C),
129.5, 142.2, 153.5; HRMS m/z [M þ H]þ 297.0037 (calcd for
C15H10N2Br, 296.0027).
6H-Indolo[2,3-b][1,7]naphthyridine (4h). Yield 29% (0.2213 g);
brown solid; mp >300 °C. IR (KBr) 3302, 3130, 1508, 1357, 1226,
935, 815, 738 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.37 (m,
1H), 7.53 (t, 1H, J = 7.2 Hz), 7.73 (d, 1H, J = 8.1 Hz), 7.80 (m,
1H), 8.37 (d, 1H, J = 7.8 Hz), 8.53 (d, 1H, J = 8.4 Hz), 9.01 (s,
1H), 9.68 (s, 1H), 13.0 (s, 1H, -NH); 13C NMR (75 MHz, DMSO-
d6) δ 112.5, 117.4, 120.5, 120.9, 121.7, 123.5, 126.2, 134.1, 137.1,
139.3, 139.6, 140.5, 145.7, 148.9; HRMS m/z [M þ H]þ 220.0864
(calcd for C14H10N3, 220.0874).
2-Methyl-6H-Indolo[2,3-b]quinoline (4e). Yield 38% (0.3050 g);
yellow solid; mp >300 °C. IR (KBr) 3400, 3121, 1614, 1519, 1471,
1404, 1232, 848, 740 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 2.50
(s, 3H), 7.25 (m, 1H), 7.49 (m, 2H), 7.56 (d, 1H, J = 8.7 Hz), 7.86
(s, 1H), 7.88 (d, 1H, J = 8.7 Hz), 8.24 (d, 1H, J = 7.8 Hz), 8.93 (s,
1H), 11.59 (s, 1H, -NH); 13C NMR (75 MHz, DMSO-d6) δ 21.4,
111.3, 118.3, 120.0, 120.7, 122.2, 124.1, 127.2 (two carbons), 127.7,
128.5, 131.4, 132.2, 141.8, 145.2, 152.9; HRMS m/z [M þ H]þ
233.1087 (calcd for C16H13N2, 233.1078).
3-Methyl-6H-Indolo[2,3-b]quinoline (4f). Yield 40% (0.3210 g);
yellow solid; mp 228-230 °C. IR (KBr) 3402, 3138, 1614, 1497,
1462, 1232, 908, 798, 740 cm-1; 1H NMR (300 MHz, DMSO-d6) δ
2.55 (s, 3H), 7.26 (m, 1H), 7.32 (d, 1H, J = 7.8 Hz), 7.48 (m, 2H),
7.76 (s, 1H), 7.99 (d, 1H, J = 8.1 Hz), 8.22 (d, 1H,
J = 7.5 Hz), 8.97 (s, 1H), 11.63 (s, 1H, -NH); 13C NMR
(75 MHz, DMSO-d6) δ 22.0, 111.3, 117.6, 120.0, 120.9, 122.0,
122.2, 125.4, 126.4, 127.7, 128.3, 128.8, 138.9, 141.7, 147.0, 153.4;
HRMS m/z [M þ H]þ 233.1078 (calcd for C16H13N2, 233.1078).
Acknowledgment. We thank IISc, Bangalore for HRMS
and CSIR, New Delhi for the financial support. P.T.P is
thankful to CSIR for awarding Senior Research Fellowship.
Supporting Information Available: Copies of 1H, 13C NMR,
and HRMS of all the compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
8372 J. Org. Chem. Vol. 74, No. 21, 2009