Microwave assisted synthesis of indolo[2,3-b]dibenzo[b,g][1,8] naphthyridines

Article abstract of DOI:10.1016/j.tetlet.2012.01.057

We have developed an effective microwave assisted p-TsOH catalyzed synthesis of indolo[2,3-b]dibenzo[b,g][1,8]naphthyridines via a one pot reaction of 3-amino-9-ethylcarbazole and 2-chloro-3-formylquinolines.

Full text of DOI:10.1016/j.tetlet.2012.01.057

Tetrahedron Letters 53 (2012) 1514–1517
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted synthesis of indolo[2,3-b]dibenzo[b,g][1,8]naphthyridines
Ezhumalai Yamuna a, Matthias Zeller b, Karnam Jayarampillai Rajendra Prasad a,
⇑
a Department of Chemistry, Bharathiar University, Coimbatore 641046, India
b Department of Chemistry, Youngstown State University, One University Plaza, Youngstown, OH 44555, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an effective microwave assisted p-TsOH catalyzed synthesis of indolo[2,3-b]dibenzo
Received 29 December 2011
Revised 13 January 2012
Accepted 14 January 2012
Available online 25 January 2012
[b,g][1,8]naphthyridines via
formylquinolines.
a
one pot reaction of 3-amino-9-ethylcarbazole and 2-chloro-3-
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Indolo[2,3-b]dibenzo[b,g]
[1,8]naphthyridine
3-Amino-9-ethylcarbazole
2-Chloro-3-formyl quinoline
P-TSA
Nitrogen-containing heterocycles are widespread in nature and
possess a broad spectrum of biological properties.1–3 Ellipticine, an
alkaloid isolated from Apocyanaceae plants, and several of its deriv-
atives exhibit high efficiency against several types of cancer and
they have shown promising results in the treatment of osteolytic
breast cancer metastases, brain tumours, kidney sarcoma, and
myeloblastic leukaemia (Fig. 1).4 At the same time ellipticine and
its derivatives show only a number of limited toxic side effects,
and they completely lack any hematological toxicity.5 Naphthyri-
dine derivatives have received significant interest due to their
exceptionally broad spectrum of biological activity. Naphthyridine
skeletons are present in many natural as well as synthetic com-
pounds and possess a large range of interesting biological activities
and can potentially be used to treat infections,6 atherosclerosis,
and hyperlididemia,7 osteoporosis,8 and malaria.9 Very recently,
substituted naphthyridines were reported as HIV-1 integrase
inhibitors.10 They also show promising cytotoxicity, anticancer,
and anti-inflammatory activities based on the molecular link
between cancer and inflammation.11a–c
benzo/hetero-fused analogs, present in numerous natural prod-
ucts, show a wide spectrum of physiological activities.20
Microwave-assisted heating has been shown to be an invalu-
able technology in synthesis since it often dramatically reduces
reaction times, typically from days or hours to minutes or even sec-
onds. It can also provide pure products in quantitative yields. Sol-
vent-free reaction techniques were successfully coupled with the
microwave method because they avoid the use of low boiling point
and high vapor pressure solvents, which may sometimes lead to
explosions. Additionally, it can also avoid the use of poisonous
and expensive solvents, and as such can be environmentally be-
nign, and make manipulations much easier. Making use of the
microwave technique for the synthesis of organic compounds un-
der solvent-free conditions thus proved to be an efficient, safe
and environmentally benign technique with shorter reaction
times, high yields, and easier manipulation.21,22 In view of the
above findings and in continuation of our work on the microwave
assisted synthesis of condensed heterocycles23 herein we wish to
report a simple, convenient microwave assisted synthesis of
dibenzo[b,g][1,8]naphthyridines from the reaction of 2-chloro-3-
formyl-quinolines and 3-aminocarbazole in the presence of p-
TsOH as the catalyst with short reaction times and good yield.
In our initial approach, we investigated the reaction of 3-amin-
ocarbazole with 2-chloro-3-formylquinoline using DMF as the
solvent at 80 °C to yield compounds 3, which on further thermoly-
sis afford dibenzo[b,g][1,8]naphthyridines 4 (Scheme 1).24 How-
ever, the yield of the reaction is low. In order to increase the
yield of the product, the same reaction was carried out in the pres-
ence of various catalysts in a Biotage microwave oven. Using as the
catalyst either tin chloride, zinc chloride, aluminium chloride, or
Several synthetic approaches have been developed to form the
naphthyridine ring.12 Benzonaphthyridines have recently been
patented as new generation growth regulators, fungicides,
bactericides, herbicides, and insecticides.13–16 Moreover, some
benzo[h]naphthyridines exhibit remarkable biological and phar-
macological activities such as antimalarial17,18 and as antagonists
of the 5-HT4 receptor.19 The functionalized quinolines and their
⇑
Corresponding author. Tel.: +91 422 2422311; fax: +91 422 2422387.
E-mail address: prasad_125@yahoo.com (K.J. Rajendra Prasad).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.057

E. Yamuna et al. / Tetrahedron Letters 53 (2012) 1514–1517
1515
Figure 1. Structures of ellipticine derivatives.
ferric chloride (entries 4–7 of Table 1) gave only low to moderate
yields. BF3ꢀEt2O (entry 8), on the other hand, showed promising
results. With p-TsOH (para-toluene sulfonic acid) as the catalyst
the reactions proceeded smoothly in an even shorter reaction time
with similar good yields, thus indicating p-TsOH as the most effi-
cient catalyst of those tested (Table 1). In order to optimise the
reaction conditions we evaluated the most appropriate catalyst
loading. With the use of 10 mol %, 15 mol % and 20 mol % of p-TsOH
the yields steadily increased with loading until they reached a
maximum of >90% at 20 mol % catalyst. No additional increase in
yield was observed upon further increasing the load of p-TsOH.
After optimisation of the reaction conditions, we studied the
generality of these conditions to other substrates. Using this
method, 2-chloro-3-formylquinolines were reacted with 3-amino-
9-ethylcarbazole to produce the corresponding dibenzo [b,g][1,8]
naphthyridines under microwave irradiation (Table 2) as shown
in Scheme 2.24
Scheme 1. Synthesis of 12-ethyl-4-methyl-12H-benzo[g]carbazol[3,2-b][1,8]
naphthyridines.
Table 1
Reaction of 3-amino-9-ethylcarbazole with 2-chloro-3-formyl-6-methylquinoline,
under various conditions
The structures of the products were deduced from their elemen-
tal analysis data, and from their IR, mass, 1H NMR and 13C NMR
spectra. The structure of one of the products was also confirmed
by single crystal X-ray diffraction.
In its IR spectrum, the stretching frequencies at 3425 and
1588 cmꢁ1 are due to the presence of NH and C@N groups. The
1H NMR spectrum shows two singlets at d 9.15 and d 9.00, due
to the –N@CH– proton and C04 proton respectively. Other aromatic
protons appear in the region between d 8.15–7.26. Two protons ap-
pear as a quartet at d 4.40 (J = 7.20 Hz) due to N9-CH2CH3. A singlet
Entry
Catalyst (mol %)
Time/min
Conditions (°C)
Yield (%)
4a
1
2
3
4
5
6
7
8
p-TsOH (10)
p-TsOH (15)
p-TsOH (20)
ZnCl2 (20)
FeCl3 (20)
AlCl3 (20)
10
10
10
20
15
15
10
15
90
90
90
90
90
90
90
90
70
76
82
36
40
44
47
59
at d 2.56 is due to C0 –CH3. A triplet at d 1.47 (J = 7.20 Hz) is due to
6
the methyl proton of N9-CH2CH3. Its 13C NMR spectrum shows the
presence of 25 carbons and its mass spectrum shows the molecular
ion peak at m/z 397. All the aforesaid data attest the obtained prod-
uct as N-((2-chloro-6-methylquinolin-3-yl)methylene)-9-ethyl-
9H-carbazol-3-amine (3a). Finally the structure was confirmed by
X-ray diffraction studies (Fig. 2). Similar reactions were carried
out with other quinoline derivatives 2b–e in order to give the
respective products 3b–e.
SnCl4 (20)
BF3ꢀEt2O (20)
Table 2
Reaction of 3-amino-9-ethylcarbazole 1 with substituted 2-chloro-3-formylquino-
lines, in the presence of p-TsOH
The IR spectrum of the obtained product shows a strong absorp-
tion at 1630 cmꢁ1 ascribable to a C@N vibration. The 1H NMR spec-
trum shows four singlets at d 9.29, 9.17, 7.99 and 7.78, which are
due to C14, C15, C7 and C13. Other aromatic protons appear in the
region d 7.65–7.41. Two protons appear as a quartet at d 4.44
(J = 7.20 Hz) due to N12-CH2CH3. A singlet at d 2.55 is due to
C2–CH3. A triplet at d 1.50 (J = 7.20 Hz) is due to the methyl protons
of N12-CH2CH3. Its 13C NMR spectrum shows the presence of 25
carbons and its mass spectrum shows the molecular ion peak
at m/z 361. All the aforesaid data attest the obtained product as
12-ethyl-2-methyl-12H-benzo[g]carbazol[3,2-b][1,8]naphthyridine
(4a).
Entry
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
CH3
H
H
H
OMe
H
CH3
H
H
H
H
H
CH3
H
H
4a
4b
4c
4d
4e
82
85
90
87
85
Scheme 2. Synthesis of 12-ethyl-12H-benzo[g]carbazol[3,2-b][1,8]naphthyridines using p-TsOH.

1516
E. Yamuna et al. / Tetrahedron Letters 53 (2012) 1514–1517
Figure 2. X-ray crystal structure of compound 3a.
Scheme 3. Mechanism for the formation of 12-ethyl-12H-benzol[g]carbazol[3,2-b][1,8]naphthyridine.
We propose the mechanism for the formation of product 4 to
Acknowledgments
include an intermolecular cycloaddition as shown in Scheme 3. Ini-
tially, the fused tetrahydro-pyrimidine intermediate I forms, then
collapses to quinoline-3-ylideneamine species II, which as a result
of intra-molecular rearrangement followed by aromatisation fur-
nishes product 4 with regeneration of 3 thereby completing the
reaction cycle.
In conclusion, we have developed a novel synthesis of ben-
zonaphthyridines from the simple synthons aminocarbazole and
2-chloro-3-formylquinolines. The remarkable catalytic activity of
p-TsOH is superior to the other reported catalysts with respect to
enhanced yields and reduced reaction times. The higher yields,
mild reaction conditions and economic availability of the synthon
and catalyst make this an ecologically friendly procedure for the
synthesis of benzonaphthyridines. Further expansion of the reac-
tion scope and synthetic applications of this methodology are in
progress in our laboratory.
Our sincere thanks go to the Director, ISO Quality Assurance
Cell, IICT, Hyderabad, SAIF, IIT Madras, Chennai, and Madurai
Kamaraj University, Madurai for providing access to their Mass
and NMR spectral facilities. The diffractometer was funded by
NSF Grant 0087210, by the Ohio Board of Regents Grant CAP-
491, and by Youngstown State University.
Supplementary data
Supplementary data (a complete cif file for compound 3a) has
been deposited with the Cambridge Crystallographic Data Centre,
CCDC Deposit # 858672. Copies of the data can be obtained, free
of charge, on application to CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK [fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.

E. Yamuna et al. / Tetrahedron Letters 53 (2012) 1514–1517
1517
19. Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.; Dumuis, A.; Dauphin, F.;
Burau, R.; Pfeifffer, B.; Renard, P.; Rault, S. J. Med. Chem. 2003, 46, 138.
20. Michael, J. Nat. Prod. Rep. 1997, 14, 605.
21. Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH Verlag Gmbh & Co.
KGaA: Weinheim, 2002.
cam.ac.uk) other supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2012.01.057.
22. Hayes, B. L. Microwave Synthesis: Chemistry at the Speed of Light; CEM
Publishing: Matthews, USA, 2002.
References and notes
23. Yamuna, E.; Zeller, M.; Rajendra Prasad, K. J. Tetrahedron Lett. 2011, 52, 6805.
24. General procedure for the synthesis of 12-ethyl-12H-benzo[g]carbazol[3,2-
b][1,8]naphthyridine (4)
1. Knölker, H.-J.; Reddy, K. R. Chem. Rev. 2002, 102, 4303.
2. Knölker, H.-J. Curr. Org. Synth. 2004, 1, 309.
3. Agarwal, S.; Cammerer, S.; Filali, W.; Frohner, W.; Knoll, J.; Krahl, M. P.; Reddy,
K. R.; Knölker, H.-J. Curr. Org. Chem. 2005, 9, 1601.
4. Stiborova, M.; Bieler, C. A.; Wiessler, M.; Frei, E. Biochem. Pharmacol. 2001, 62,
1675.
5. Auclair, C. Arch. Biochem. Biophys. 1987, 259, 1.
6. Kuramato, Y.; Ohshita, Y.; Yoshida, J.; Yazaki, A.; Shiro, M.; Koike, T. J. Med.
Chem. 2003, 46, 1905.
7. O’Connor, S. P.; Robl, J.; Ahmad, S.; Bisaha, S.; Murugesan, N.; Ngu, K.; Shi, Y.;
Stein, P. D.; Soundararajan, N.; Natalie, K. J., Jr.; Kolla, L. R.; Sausker, J.; Quinlan,
S. L.; Fan, J.; Petsch, D.; Guo, Z. WO Patent 051386, June 09, 2005 (CA 2005, 143,
43869).
Method A:
A
mixture of 3-amino-9-ethylcarbazole (1, 1 mmol) and 2-chloro-3-
formylquinolines (2, 1 mmol) was stirred with DMF and heated at 80 °C for
8 h. After the completion of the reaction, the mixture was poured into crushed
ice and filtered. Then, the precipitated product was filtered and washed with
water, dried and recrystallized using ethanol affording 3. This was heated at
180–190 °C. First the solid melted to a red orange oil and at 210–220 °C a
vigorous exothermic reaction began with liberation of a white sublimate. The
reaction almost subsided within 5 min. It was then kept at 250 °C for another
15 min, and then cooled to room temperature. The crude product obtained was
purified by column chromatography over silica gel using petroleum ether:
8. (a) Hartner, F. W.; Hsaio, Y.; Eng, K. K.; Rivera, N. R.; Palucki, M.; Tan, L.; Yasuda,
N.; Hughes, D. L.; Weissman, S.; Zewge, D.; King, T.; Tschaen, D.; Volante, R. P. J.
Org. Chem. 2004, 69, 8723; (b) Yasuda, N.; Hsiao, Y.; Jensen, M. S.; Rivera, N. R.;
Yang, C.; Wells, K. M.; Yau, J.; Palucki, M.; Tan, L.; Dormer, P. G.; Volante, R. P.;
Hughes, D. L.; Reider, P. J. J. Org. Chem. 2004, 69, 1959; (c) Hutchinson, J. H.;
Halczenko, W.; Brashear, K. M.; Breslin, M. J.; Coleman, P. J.; Duong, L. T.;
Fernandez-Metzler, C.; Gentile, M. A.; Fisher, J. E.; Hartman, G. D.; Huff, J. R.;
Kimmel, D. B.; Leu, C. T.; Meissner, R. S.; Merkle, K.; Nagy, R.; Pennypacker, B.;
Perkins, J. J.; Prueksaritanont, T.; Rodan, G. A.; Varga, S. L.; Wesolowski, G. A.;
Zartman, A. E.; Rodan, S. B.; Duggan, M. E. J. Med. Chem. 2003, 46, 4790.
9. Olepu, S.; Suryadevara, P. K.; Rivas, K.; Yokoyama, K.; Verlinde, C. L. M. J.;
Chakrabarti, D.; Voorhis, W. C.; Gelb, M. H. Bioorg. Med. Chem. Lett. 2008, 18,
494.
ethyl acetate (93:7) as an eluant to get
benzo[g]carbazol[3,2-b][1,8]naphthyridines (4).
Method B:
a red solid 12-ethyl-12H-
A
mixture of 3-amino-9-ethylcarbazole (1, 1 mmol), 2-chloro-3-
formylquinolines (2, 1 mmol) and p-TsOH (20 mol %) was heated at 90 °C for
10 min. under microwave irradiation (Biotage microwave oven, 90 °C). The
crude product obtained was purified by column chromatography over silica gel
using petroleum ether: ethyl acetate (93:7) as an eluant to get a red solid 12-
ethyl-12H-benzo[g]carbazol[3,2-b][1,8]naphthyridines (4).
N-((2-Chloro-6-methylquinolin-3-yl)methylene)-9-ethyl-9H-carbazol-3-
amine (3a): Yellow solid (0.373 g, 94%) mp 203 °C; IR (KBr) 3425, 2973, 1686,
1588, 1051 cmꢁ1 1H NMR (500 MHz, CDCl3): d (ppm) 1.47 (t, 3H, J = 7.2 Hz, N-
;
CH2CH3), 2.56 (s, 3H, 6-CH3), 4.40 (q, 2H, J = 7.2 Hz, N-CH2CH3), 7.26 (d t, 1H,
Jo = 7.6 Hz, Jm = 2.00 Hz, 6-H), 7.43 (d, 1H, J = 8.4 Hz, 8-H), 7.46 (d, 1H, J = 8.2 Hz,
1-H), 7.50 (d t, 1H, J = 7.8 Hz, 7-H), 7.58 (d d, 1H, J = 7.8 Hz, 2-H), 7.61 (d d, 1H,
Jo = 8.2 Hz, Jm = 2.0 Hz, 70-H), 7.72 (s, 1H, 50-H), 7.94 (d, 1H, J = 8.4 Hz, 80-H),
8.13 (d, 1H, J = 2.0 Hz, 4-H), 8.15 (d, 1H, J = 7.6 Hz, 5-H), 9.00 (s, 1H, 40-H), 9.15
(s, 1H, CH@N); 13C NMR (125 MHz, CDCl3): d (ppm) 13.9, 21.7, 37. 8, 108. 8,
108.9, 113.4, 119.2, 120.0, 120.7, 123.0, 123.6, 126.1, 127.4, 127.5, 127.9, 128.0,
128.2, 128.4, 133.9, 135.9, 136.5, 143.1, 146.9, 149.5, 152.8; MS: m/z (%) 397
(M+, 100); Anal. Calcd for: C25H20ClN3: C, 75.46; H, 5.07; N, 10.56%. Found: C,
75.48; H, 5.09; N, 10.58%.
10. Bera, S.; Pandey, K. K.; Vora, A. C.; Grandgenett, D. P. J. Mol. Biol. 2011, 410,
831.
11. (a) Roma, G.; Grossi, G.; Braccio, M. D.; Piras, D.; Ballabeni, V.; Tognolini, M.;
Bertoni, S.; Barocelli, E. Eur. J. Med. Chem. 2008, 43, 1665; (b) Roma, G.;
Braccio, M. D.; Grossi, G.; Mattioli, F.; Ghia, M. Eur. J. Med. Chem. 2000, 1021,
35; (c) Atanasova, M.; Ilieva, S.; Galabov, B. Eur. J. Med. Chem. 2007, 42,
1184.
12. (a) Litvinov, V. P. Russ. Chem. Rev. 2004, 73, 637; (b) Schramm, O. G.; Oeser, T.;
Müller, T. J. J. J. Org. Chem. 2006, 71, 3494; (c) Zong, R.; Zhou, H.; Thummel, R. P.
J. Org. Chem. 2008, 73, 4334; (d) Litvinov, V. P. Advances in the Chemistry of
Naphthyridines. In Advanced Heterocyclic Chemistry; Elsevier, San Diego,
2006; Vol. 91, p 189.; (e) Lahue, B. R.; Lo, S.-M.; Wan, Z.-K.; Woo, G. H. C.;
Snyder, J. K. J. Org. Chem. 2004, 69, 7171.
13. Noravyan, A. S.; Paronikyan, E. G.; Vartanyan, S. A. Khim-Farm. Zh. 1985, 19,
790. Chem. Abstr. 1985, 104, 186324.
14. Litvinov, V. P.; Roman, S. V.; Dyachenko, V. D. Usp. Khim. 2000, 69, 218 [Engl.
Transl. Russ., 2000, 69, 201].
15. Chrzastek, L.; Sliwa, W. Australian J. Chem. 1994, 47, 2129.
16. Barbara, B.; Teresa, Z. ARKIVOC 2001, 6, 77.
17. Roseman, K.; Gould, M.; Linfield, M.; Edwards, B. J. Med. Chem. 1970, 13,
230.
12-Ethyl-2-methyl-12H-benzo[g]carbazol[3,2-b][1,8]naphthyridine (4a): Red
solid (0.296 g, 82%); mp 197 °C; Yield: IR (KBr) 3408, 2923, 1630, 1486 cmꢁ1
;
1H NMR (500 MHz, CDCl3): d (ppm) 1.50 (t, 3H, J = 7.2 Hz, N12-CH2CH3), 2.55 (s,
3H, 2-CH3), 4.44 (q, 2H, N12-CH2CH3, J = 7.2 Hz), 7.41 (d, 1H, J = 8.0 Hz, 3-H),
7.50 (s, 1H, 1-H), 7.56 (d, 1H, J = 8.0 Hz, 4-H), 7.65 (d d, 1H, Jo = 8.8 Hz,
Jm = 1.6 Hz, 11-H), 7.78 (s, 1H, 13-H), 7.85 (t, 2H, 9- & 10-H), 7.99 (s, 1H, 7-H),
8.17 (d, 1H, J = 8.0 Hz, 8-H), 9.17 (s, 1H, 15-H), 9.29 (s, 1H, 14-H); 13C NMR
(125 MHz, CDCl3): d (ppm) 13.70 (N12CH2CH3), 18.2, 37.8, 105.5, 106.1, 108.8,
115.7, 118.9, 119.3, 121.4, 121.9, 123.7, 124.4, 126.4, 127.9, 128.5, 129.2, 129.9,
132.6, 134.5, 134.5, 136.3, 139.2, 142.9, 148.6; MS: m/z (%) 361 (M+, 100); Anal.
Calcd for: C25H19N3: C, 83.08; H, 5.30; N, 11.63%. Found: C, 83.02; H, 5.35; N,
11.64%.
18. Gorlitzer, K.; Bode, M.; Jones, P. G.; Jomaa, H.; Wiesner, J. Pharmazie 2007, 62,
15.