Traceless synthetic approach towards oxaza-dicyclopenta[a,h]naphthalenes under solvent-free condition: A basic alumina-supported green protocol

Article abstract of DOI:10.1016/j.tetlet.2013.03.095

A novel class of oxaza-dicyclopenta[a,h]naphthalenes was efficiently constructed from furo[3,2-h]quinoliniums through a 1,3-dipolar cycloaddition reaction employing basic alumina as the solid support. The distinguished features of this methodology encompa

Full text of DOI:10.1016/j.tetlet.2013.03.095

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Traceless synthetic approach towards oxaza-dicyclopenta[a,h]naphthalenes
under solvent-free condition: a basic alumina-supported green protocol
Rupankar Paira, Shyamal Mondal, Arpan Chowdhury, Maitreyee Banerjee, Arindam Maity, Abhijit Hazra,
⇑
Nirup B. Mondal
Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of oxaza-dicyclopenta[a,h]naphthalenes was efficiently constructed from furo[3,2-h]quin-
oliniums through a 1,3-dipolar cycloaddition reaction employing basic alumina as the solid support.
The distinguished features of this methodology encompass high yield, minimal reaction time, operational
simplicity and general applicability coupled with structural novelty of the products. The intermediate
furo[3,2-h]quinoliniums were easily derived through a two-step methodology, namely a tandem Sono-
gashira–alkynylation–cyclization, followed by quaternization of the furo[3,2-h]quinoline scaffold.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 January 2013
Revised 19 March 2013
Accepted 22 March 2013
Available online xxxx
Keywords:
Oxaza-dicyclopenta[a,h]naphthalene
Furo[3,2-h]quinolinium
1,3-Dipolar cycloaddition
Basic alumina
Green chemistry
The conclusion of Human Genome Project (HGP) in 2003 has
delivered the DNA-sequence information of a wide variety of gen-
omes ranging from microbial to macro species, which led the
chemists to construct newer and more diversified organic scaffolds
and the biologists to explore these libraries on DNA and protein
targets.1 Among several such chemical scaffolds, heterocyclic com-
pounds have always held the centre stage because more than half
of the bioactive natural products contain differently modified
mono or polynuclear heterocyclic cores as an essential part of their
skeleton.2 Among them benzo[b]furans and indolizines constitute
crucial structural components of a wide variety of bioactive drug
candidates of both synthetic and natural origin.3 They are well
known for their antitumor,4 antifungal,5 antiviral,6 antibacterial,7
antileishmanial,8 analgesic,9 antioxidant,10 antiinflammatory11
and agrochemical12 properties. Apart from these, benzo[b]furans
display protein phosphatase 1B inhibitory13 and 5-lipoxygenase
(5-LO) inhibitory properties14 as well as 5-HT2 and 5-HT3 antago-
nist activity,15 while indolizines function as aromatase inhibitor,16
calcium entry blocker17 and histamine H3 receptor antagonists.18
From pharmaceutical point of view these are the characteristics
of potential drug candidates for the treatment of cancer, cardiovas-
cular diseases, diabetes, migraines, dementia and anxiety.4a,15
Therefore, construction of newer and more complex chemical enti-
ties featuring benzo[b]furan or indolizine cores in their skeleton
and screening of these libraries for the identification of newer lead
molecules has garnered immense importance. We contemplated
that combining the two units in one composite structure as shown
in Figure 1 may lead to novel biologically active entities, for exam-
ple, oxaza-dicyclopenta[a,h]naphthalenes. A survey of the litera-
ture brought out to our surprise that no synthetic attempts have
been made on this ring type, nor are there any reports of their
bio-evaluation studies. Thus, in continuation of our decade long
investigations on the development of structurally unique bioactive
heterocyclic compounds,5b,19 we decided to take up the synthesis
of a new class of chemical species having oxaza-dicyclopen-
ta[a,h]naphthalene as the core moiety. The synthetic scheme was
planned to utilize furo[3,2-h]quinoliniums as the stepping stone
towards the final compounds. We also tried to focus our attention
on the application of green tools from our recently developed
green tool box20 in this task, because development of environmen-
tally-friendly modifications of hazardous chemical conversions is
increasingly gaining importance due to the rapidly growing global
environmental legislation now-a-days.21 In this report, we disclose
the results of our recent synthetic studies on the construction of
differently substituted oxaza-dicyclopenta[a,h]naphthalenes under
solvent-free solid supported condition.
Our plans to reach the targeted composites involved a two
phase synthetic effort, which began with the formation of the de-
sired cyclization precursor. Initially, the dual function of basic alu-
mina as a base as well as solid support was efficiently harnessed
for our recently developed tandem Sonogashira cross-coupling-
cyclization protocol, which eventually yielded the furo[3,2-h]quin-
olines (3a–c) from 5-chloro-8-hydroxyquinoline (1) and appropri-
⇑
Corresponding author. Tel.: +91 33 2473 3491; fax: +91 33 2473 5197.
E-mail address: nirup@iicb.res.in (N.B. Mondal).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.095
Please cite this article in press as: Paira, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.095

2
R. Paira et al. / Tetrahedron Letters xxx (2013) xxx–xxx
on an oil bath for 12 h at 90 °C to obtain the product to the extent
of 43% only, which unambiguously proved the superiority of
microwave irradiation. The products and their yield of formation
are summarized in Table 3.
Finally, we performed an investigation on the reusability of this
solid support to determine its importance for both academic and
industrial application. It was observed that the support material
becomes almost as active as a fresh sample after proper washing
with water and acetone followed by calcination at 150 °C, and
can be recycled 3–4 times without affecting its activity noticeably
(Fig. 2).
The mechanism of the cycloaddition is expected to proceed
with an initial deprotonation of 5b by basic alumina, thereby gen-
erating 1,3-dipole I, which immediately attacks the dipolarophile
6c for a [3+2] cycloaddition reaction followed by aromatization,
leading to the product 7g (Scheme 2). Structure of 7g was prelim-
inarily confirmed by its 1H NMR analysis.24 Disappearance of peaks
for the methylene hydrogens (d = 6.99) and the ring hydrogen
+
N
N
O
O
Figure 1. Hypothetical composite of benzo[b]furan and indolizine cores.
ate terminal alkynes (2a–c).20d Quaternization of the quinoline
motif in the next step of this strategy was then satisfactorily done
x-bromo-acetophenone (4) under refluxing condition in ace-
tonitrile (Scheme 1), which furnished the cyclization precursors
(5a–c) in reasonable yield (Table 1).
with
With these furo[3,2-h]quinoliniums in our possession, we
moved towards the final phase for the construction of our targeted
heterocycles. Initial efforts were directed towards optimization
reactions using furo[3,2-h]quinolinium 5a and diethyl acetylene
dicarboxylate 6a as the reaction partners in the presence of differ-
ent bases and refluxing in different solvents. As brought out by the
entries in Table 2, the reactions employing variable combinations
of solvents and bases, however, ended up with discouraging results
producing only 10–15% yield of the desired product (7a). Even our
recently developed resin-assisted route5b also failed to improve the
yield beyond 31% (entry 5). Thus we opted for a newer protocol
and among the plenty of possible tools, the combination of basic
alumina with microwave irradiation appealed to us most. It is a
widely used heterogeneous catalyst and has gained prominence
in several areas of organic synthesis.22
(d = 9.66)
a to the quaternary ammonium centre of 5b, coupled
with the appearance of a newly developed singlet proton at
d = 6.97 in the spectrum of 7g, assigned to the only available proton
of the newly formed fused pyrrole unit, signalled the success of the
reaction. Besides, a triplet at d = 1.44 and a quartet at d = 4.43 were
assigned to the ethyl group of the carbethoxy group. There were
fourteen other singlets and multiplets in the aromatic region
(d = 6.66–8.41), assigned to the aromatic protons of 7g. These
assignments were further supported by its 13C NMR spectra. Sig-
nals for the methylene (d = 67.1 in 5b) and the methine carbon
(d = 145.0 in 5b)
a to the quaternary ammonium centre were ab-
An encouraging result with a substantial improvement in the
product yield (57%) was obtained in the initial attempt for carrying
out the reaction (1,3-dipolar cycloaddition) using basic alumina at
80 °C (180 W); this could eventually be raised to 93% at 90 °C
(180 W) (entry 7). In order to establish the benefits of employing
microwave as the heating source, the same reaction was performed
sent, being replaced by peaks for quaternary carbons at d = 125.1
and 139.3, respectively. Signals attributable to one additional qua-
ternary carbon centre (d = 107.6), a methine carbon (d = 127.0) and
a methyl peak in the aliphatic region (d = 14.5) were also in accord
with the proposed structure of the cycloadduct 7g. Eighteen other
Cl
Cl
Cl
Ar
(2a-c)
ω-Bromoacetophenone (4)
N
N
O
O
ref. 22e
MeCN/Reflux
N
O
OH
1
(3a-c)
(5a-c)
R
R
(a; R = H, b; R = F, c; R = Me)
Scheme 1. Synthesis of cyclization precursors.
Table 1
Synthesis of cyclization precursor’s 5a–ca,b
Cl
Cl
Cl
N
N
N
O
O
O
Br
Br
O
Br
O
O
H3C
F
5c (82%)
5b (75%)
5a (81%)
aAll the reactions were performed in acetonitrile under refluxing condition.
bIsolated yield.
Please cite this article in press as: Paira, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.095

R. Paira et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
signals in the 13C NMR spectra were assigned to the remaining
methine and quaternary carbon centres. In addition to the NMR
studies, the HRMS analysis of 7g also agrees with the proposed
skeleton. However, the most convincing evidence in this regard
was obtained from the single crystal X-ray crystallographic analy-
sis of 7g, which explicitly proved its structure, as obvious from the
ORTEP diagram shown in Figure 3.
In conclusion, we have explored the use of basic alumina as a
reactive solid support system for the synthesis of some oxaza-dicy-
clopenta[a,h]naphthalene analogues through a 1,3-dipolar cyclo-
Table 2
Optimization of conditions of reaction between 5a and 6a
Entry Base
Solvent
Time (h) Temp (°C) Yielda (%)
1
2
3
4
5
6
7
DBU
DCM
DCM
Methanol
Acetonitrile
10
10
12
12
Reflux
Reflux
Reflux
Reflux
rt
15
11
11
Na2CO3
Na2CO3
Cs2CO3
10
Amberlite resin Water/CHCl3 12
31
Basic alumina
Basic alumina
—
—
5 min
5 min
80
90
57b
93b
a
Isolated yield.
b
The reactions were performed under microwave irradiation at 180 W.
Table 3
Synthesis of oxaza-dicyclopenta[a,h]naphthalene analoguesa,b
Cl
Cl
R2
R3
Basic Alumina, 180 W
R2
N
N
O
+
O
R3
O
O
R1
R1
5a-c
6a-d
7a-l
Cl
Cl
Cl
Cl
CO2Me
N
CO2Et
CO2Et
CO2Et
CO2Et
N
CO2Me
CO2Me
N
N
O
O
O
O
O
O
O
O
CO2Et
7d (93%)
7a (93%)
7b (91%)
7c (95%)
Cl
Cl
Cl
Cl
CO2Me
N
CO2Me
CO2Me
CO2Et
CO2Et
N
N
N
O
O
O
O
O
O
O
O
F
F
F
F
7h (87%)
7e (88%)
7f (91%)
7g (90%)
Cl
Cl
Cl
Cl
CO2Me
CO2Me
CO2Me
N
N
CO2Et
CO2Et
N
N
O
O
O
O
O
O
O
O
H3C
H3C
H3C
H3C
7i (90%)
7j (91%)
7l (83%)
7k (88%)
aAll the reactions were performed under microwave irradiation (180 W) at 90 °C.
bIsolated yield.
Please cite this article in press as: Paira, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.095

4
R. Paira et al. / Tetrahedron Letters xxx (2013) xxx–xxx
addition reaction in solvent-free media under microwave irradia-
tion. The easy availability and reusability of the solid support, elim-
ination of the use of any acid or solvent, cost-effectiveness of the
process, operational simplicity and the use of environmentally be-
nign techniques make it an important green methodology. Further-
more, a detailed study on the DNA-intercalation properties and
cytotoxic activities of both furo[3,2-h]quinoliniums and oxaza-
dicyclopenta[a,h]naphthalene analogues is currently under investi-
gation in our laboratory and will be reported in due course. To the
best of our knowledge, this is the first report of basic alumina-sup-
ported oxaza-dicyclopenta[a,h]naphthalene synthesis.
Acknowledgments
We would like to thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial support in the form of fel-
lowships to R.P., S.M., A.M., and A.H. We are indebted to Mr. E. Pad-
Figure 2. Reusability of the basic alumina tested using 5a and 6a. The reactions
were performed with 5a (3.3 mmol) and 6a (3.3 mmol), using 400 mg basic alumina
at 90 °C for 5 min.23
Cl
Cl
Cl
CO2Et
1,3-dipolar
CO2Et
N
N
N
Basic Alumina
O
O
O
O
cycloaddition/
Aromatization
Br
O
H
H
O
6c
F
F
F
II
I
5b
Cl
[-2H]
N
CO2Et
O
(Arial Oxidation)
O
F
7g
Scheme 2. Plausible mechanistic pathway for the basic alumina supported synthesis of oxaza-dicyclopenta[a,h]naphthalene analogues.
Figure 3. ORTEP representation of compound 7g, the displacement ellipsoid is drawn at a probability of 50%.
Please cite this article in press as: Paira, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.095

R. Paira et al. / Tetrahedron Letters xxx (2013) xxx–xxx
5
18. Chai, W.; Breitenbucher, J. G.; Kwok, A.; Li, X.; Wong, V.; Carruthers, N. I.;
Lovenberg, T. W.; Mazur, C.; Wilson, S. J.; Axe, F. U.; Jones, T. K. Bioorg. Med.
Chem. Lett. 2003, 13, 1767–1770.
manaban and Mr. K. Sarkar for NMR and mass spectral analysis and
also to Dr. B. Achari, Emeritus Scientist, CSIR, for critical sugges-
tions and encouragement.
19. (a) Sahu, N. P.; Pal, C.; Mondal, N. B.; Banerjee, S.; Raha, M.; Kundu, A. P.; Basu,
P. A.; Ghosh, M.; Roy, K.; Bandyopadhyay, S. Biorg. Med. Chem. 2002, 10, 1687–
1693; (b) Dutta, R.; Mandal, D.; Panda, N.; Mondal, N. B.; Banerjee, S.; Kumar,
S.; Weber, M.; Lugar, P.; Sahu, N. P. Tetrahedron Lett. 2004, 45, 9361–9364; (c)
Paira, P.; Hazra, A.; Kumar, S.; Paira, R.; Sahu, K. B.; Naskar, S.; Saha, P.; Mondal,
S.; Maity, A.; Banerjee, S.; Mondal, N. B. Bioorg. Med. Chem. Lett. 2009, 19, 4786–
4789; (d) Palit, P.; Hazra, A.; Maity, A.; Vijayan, R. S. K.; Manoharan, P.;
Banerjee, S.; Mondal, N. B.; Ghoshal, N.; Ali, N. Antimicrob. Agents Chemother.
2012, 56, 432–445; (e) Sahu, K. B.; Ghosh, S.; Banerjee, M.; Maity, A.; Mondal,
S.; Paira, R.; Saha, P.; Naskar, S.; Hazra, A.; Banerjee, S.; Samanta, A.; Mondal, N.
B. Med. Chem. Res. 2012. http://dx.doi.org/10.1007/s00044-012-0011-4.
20. (a) Saha, P.; Naskar, S.; Paira, P.; Hazra, A.; Sahu, K. B.; Paira, R.; Banerjee, S.;
Mondal, N. B. Green Chem. 2009, 7, 931–934; (b) Paira, R.; Paira, P.; Maity, A.;
Mondal, S.; Hazra, A.; Sahu, K. B.; Naskar, S.; Saha, P.; Banerjee, M.; Mondal, N.
B. Tetrahedron Lett. 2010, 51, 3200–3204; (c) Naskar, S.; Saha, P.; Paira, R.;
Mondal, S.; Maity, A.; Sahu, K. B.; Hazra, A.; Paira, P.; Banerjee, S.; Mondal, N. B.
Tetrahedron Lett. 2010, 51, 1437–1440; (d) Saha, P.; Naskar, S.; Paira, R.;
Mondal, S.; Maity, A.; Sahu, K. B.; Paira, P.; Hazra, A.; Bhattacharya, D.;
Banerjee, S.; Mondal, N. B. Synthesis 2010, 486–492; (e) Paira, R.; Mondal, S.;
Maity, A.; Sahu, K. B.; Naskar, S.; Saha, P.; Hazra, A.; Kundu, S.; Banerjee, S.;
Mondal, N. B. Tetrahedron Lett. 2011, 52, 5516–5520.
Supplementary data
Supplementary data (copies of 1H NMR and 13C NMR spectra of
all the products) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2013.03.095.
Crystallographic data in CIF format are available free of charge
via the Internet at CCDC 902797. These data can be obtained free
of charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html
(or from the Cambridge Crystallographic Data Centre, 12, Union
Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam.ac.uk).
References and notes
1. Current logic of the drug discovery field was reviewed by: Breinbauer, R.;
Vetter, I. R.; Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 2878–2890. and
references therein.
2. Katritzky, A. K.; Rees, C. W. In Comprehensive Heterocyclic Chemistry; Bird, C. W.,
Cheeseman, G. W. H., Eds.; Pergamon: New York, NY, 1984; pp 1–38.
3. (a) Donnelly, D. M. X.; Meegan, M. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon Press: New York, 1984; Vol. 4, (b) Pyne, S. G.
Curr. Org. Synth. 2005, 2, 39–57; (c) Ito, M.; Kibayashi, C. Tetrahedron Lett. 1990,
31, 5065–5068; (d) Toyooka, N.; Zhou, D.; Nemoto, H. J. Org. Chem. 2008, 73,
4575–4577.
4. (a) Erber, S.; Ringshandl, R.; von Angerer, E. Anti-Cancer Drug Des. 1991, 6, 417–
426; (b) Olden, K.; Breton, P.; Grzegorzevski, K.; Yasuda, Y.; Gause, B. L.;
Creaipe, O. A.; Newton, S. A.; White, S. L. Pharmacol. Ther. 1991, 50, 285–290; (c)
Jaffrezou, J. P.; Levade, T.; Thurneyssen, O.; Chiron, M.; Bordier, C.; Attal, M.;
Chatelain, P.; Laurent, G. Cancer Res. 1992, 52, 1352–1359; (d) Ahrens, P. B.;
Ankel, H. J. Biol. Chem. 1987, 262, 7575–7579.
5. (a) McAllister, G. D.; Hartley, R. C.; Dawson, M. J.; Knaggs, A. R. J. Chem. Soc.,
Perkin Trans. 1 1998, 3453–3457; (b) Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.;
Saha, P.; Paira, R.; Sahu, K. B.; Paira, P.; Ghosh, S.; Sinha, C.; Samanta, A.;
Banerjee, S.; Mondal, N. B. Eur. J. Med. Chem. 2011, 46, 2132–2140.
6. (a) Medda, S.; Jaisankar, P.; Manna, R. K.; Pal, B.; Giri, V. S.; Basu, M. K. J. Drug
Target 2003, 11, 123–128; (b) Galal, S. A.; El-All, A. S. A.; Abdallah, M. M.; El-
Diwani, H. I. Bioorg. Med. Chem. Lett. 2009, 19, 2420–2428.
7. (a) Gundersen, L.-L.; Negussie, A. H.; Rise, F.; Østby, O. B. Arch. Pharm.
Pharm. Med. Chem. 2003, 336, 191–195; (b) Luo, X.; Pedro, L.; Milic, V.;
Mulhovo, S.; Duarte, A.; Duarte, N.; Ferreira, M. J. U. Planta Med. 2012, 78,
148–153.
8. (a) Bolle, L. D.; Andrei, G.; Snoeck, R.; Zhang, Y.; Lommel, A. V.; Otto, M.;
Bousseau, A.; Roy, C.; Clercq, E. D.; Naesens, L. Biochem. Pharmacol. 2004, 67,
325–336; (b) Miert, S. V.; Dyck, S. V.; Schmidt, T. J.; Brun, R.; Vlietinck, A.;
Lemie‘re, G.; Pieters, L. Bioorg. Med. Chem. 2005, 13, 661–669.
9. (a) Campagna, F.; Carotti, A.; Casini, G.; Macripo, M. Heterocycles 1990, 31, 97–
107; (b) Radl, S.; Hezky, P.; Konvicka, P.; Krejci, I. Chem. Inform. Abstract: Chem.
Inform. 2001, 32. doi: http://dx.doi.org/10.1002/chin.200103104.
10. (a) Østby, O. B.; Dalhus, B.; Gundersen, L.-L.; Rise, F.; Bast, A.; Haenen, G. R. M.
M. Eur. J. Org. Chem. 2000, 3763–3770; (b) Teklu, S.; Gundersen, L.-L.; Larsen, T.;
Malterud, K. E.; Rise, F. Bioorg. Med. Chem. 2005, 13, 3127–3139; (c) Rindhe, S.
S.; Rode, M. A.; Karale, B. K. Indian J. Pharm. Sci. 2010, 72, 231–235.
11. (a) Malonne, H.; Hanuise, J.; Fontaine, J. Pharm. Pharmacol. Commun. 1998, 4,
241–243; (b) Gubin, J.; Luchetti, J.; Mahaux, J.; Nisato, D.; Rosseels, G.; Clinet,
M.; Polster, P.; Chatlain, P. J. Med. Chem. 1992, 35, 981–988; (c) Ragab, F. A. E. F.;
Eid, N. M.; Hassan, G. S.; Nissan, Y. M. Chem. Pharm. Bull. 2012, 60, 110–120.
12. (a) Wei, X.-D.; Hu, Y.-F.; Hu, H.-W. J. Chem. Soc., Perkin Trans. 1 1993, 2487–
2489; (b) Zhou, J.; Hu, Y.; Hu, H. Synthesis 1999, 166–170; http://
shodhganga.inflibnet.ac.in/bitstream/10603/2211/11/11_chapter%202.pdf
13. Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W. X.; McDevitt, R.;
Adebayo, F. O.; Sawicki, D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med.
Chem. 2000, 43, 1293–1310.
21. (a) Bai, L.; Wang, J. X.; Zhang, Y. Green Chem. 2003, 5, 615–617; (b) Pironti, V.;
Colonna, S. Green Chem. 2005, 7, 43–45; (c) Nuchter, M.; Ondruschka, B.;
Bonrath, W.; Gum, A. Green Chem. 2004, 6, 128–141.
22. (a) Bram, G.; Loupy, A.; Villemin, D. In Solid Supports and Catalysts in Organic
Synthesis; Smith, K., Ed.; Ellis Horwood Prentice Hall: Chichester, 1992; p 302.
Chapter 12; (b) Varma, R. S. Green Chem. 1999, 1, 43–55.
23. General procedure for the synthesis of oxaza-dicyclopenta[a,h]naphthalene
analogues (7a–l): 3.3 mmol furo[3,2-h]quinolinium derivatives (5a–c) and
3.3 mmol dialkyl acetylene diacetates or monoalkyl acetylene monoacetates
(6a–d) were placed in a RB flask (25 ml.) and dissolved in a minimum amount
of chloroform. Basic alumina (0.4 g) was then added to the solution and the
organic solvent was then evaporated to dryness under reduced pressure. After
fitting the flask with a septum the mixture was subjected to irradiation in a
microwave reactor (CEM, Discover, USA) at 90 °C (180 W) for appropriate
amount of time (as monitored by TLC). After completion of the reaction the
reaction mixture was cooled and chloroform was added to it and the slurry was
stirred at room temperature for 10 min. The mixture was then filtered through
a sintered glass funnel. The filtrate was then evaporated to dryness under
reduced pressure and the residue was purified by flash chromatography to
isolate the product (7a–l). In the recycling experiment the residue, obtained
after vacuum filtration of the reaction mixture, was washed with alkaline
water and acetone (2–3 times) and subjected to calcination at 150 °C.
24. Spectral data of representative compounds: (a) 10-Benzoyl-5-chloro-2-phenyl-1-
oxa-10a-aza-dicyclopenta[a,h]naphthalene-8,9-dicarboxylic acid dimethyl ester
(7a): Brown solid. 93% yield; mp 230–232 °C; Rf (20% ethyl acetate/hexane)
0.35; IR (KBr, m ;
max): 2920, 2851, 1681, 1566, 1457 cmÀ1 1H NMR (300 MHz,
CDCl3): d 3.51 (s, 3H), 3.94 (s, 3H), 7.00 (s, 1H),7.10 (m, 3H), 7.21 (m, 1H), 7.29
(s, 1H), 7.41 (m, 2H), 7.59 (m, 1H), 7.78 (s, 1H), 7.93 (m, 2H), 8.23 (d, J = 9.9 Hz,
1H), 8.39 (d, J = 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 52.1 (CH3), 52.2 (CH3),
102.1 (CH), 105.5 (C), 117.3 (CH), 119.5 (CH), 120.8 (C), 121.6 (C), 125.5
(CH),125.6 (2CH), 127.6 (2CH), 128.5 (2CH), 128.6 (C), 128.7 (2CH), 128.8 (C),
129.3 (CH), 130.0 (C), 130.1 (2CH), 130.9 (C), 133.5 (CH), 137.6 (C), 137.8 (C),
142.0 (C), 158.1 (C), 163.8 (C), 166.0 (C), 184.7 (C); HRMS (ESI) m/z calcd for
C
31H20ClNO6: [M+Na]+ 560.0871; found: 560.0879. (b) 10-Benzoyl-5-chloro-2-
phenyl-1-oxa-10a-aza-dicyclopenta[a,h]naphthalene-8,9-dicarboxylic acid diethyl
ester (7b): Brown solid. 91% yield; mp 231–232 °C; Rf (20% ethyl acetate/
hexane) 0.35; IR (KBr,
m ;
max): 2921, 2854, 1690, 1569, 1450 cmÀ1 1H NMR
(600 MHz, CDCl3): d 1.11 (m, 3H), 1.40 (m, 3H), 3.83 (m, 2H), 4.40 (m, 2H), 6.99
(s, 1H), 7.09 (t, J = 7.8 Hz, 2H), 7.21 (m, 3H), 7.43 (t, J = 7.8 Hz, 2H), 7.60 (t,
J = 7.8 Hz, 1H), 7.76 (m, 1H), 7.98 (m, 2H), 8.23 (d, J = 9.6 Hz, 1H), 8.42 (d,
J = 9.6 Hz, 1H); 13C NMR (150 MHz, CDCl3): d 13.7 (CH3), 14.3 (CH3), 60.7 (CH2),
61.8 (CH2), 101.9 (CH), 105.4 (C), 117.1 (CH), 119.2 (CH), 120.7 (C), 121.5 (),
125.1 (CH), 125.4 (2 CH), 127.3 (C), 128.2 (C), 128.3 (2 CH), 128.5 (2CH), 128.6
(C), 129.0 (CH), 129.9 (C), 130.1 (2 CH), 130.6 (C), 133.3 (CH), 137.5 (C), 137.8
(C), 141.8 (C), 157.7 (C), 163.0 (C), 165.4 (C), 184.5 (C); HRMS (ESI) m/z calcd for
C
33H24ClNO6: [M+Na]+ 588.1184; found: 588.1172. (c) 10-Benzoyl-5-chloro-2-
(4-fluoro-phenyl)-1-oxa-10a-aza-dicyclopenta[a,h]naphthale-ne-8-carboxylic
acid ethyl ester (7g): Brown solid. 90% yield; mp 246–248 °C; Rf (20% ethyl
14. McCallion, G. D. Curr. Org. Chem. 1999, 3, 67–76.
acetate/hexane) 0.35; IR (KBr, m ;
max): 2921, 2851, 1690, 1576, 1457 cmÀ1 1H
15. Watanabe, Y.; Yoshiwara, H.; Kanao, M. J. Heterocycl. Chem. 1993, 30, 445–451.
16. Sonnet, P.; Dallemagne, P.; Guillon, J.; Engueard, C.; Stiebing, S.; Tangue, J.;
Bureau, B.; Rault, S.; Auvray, P.; Moslemi, S.; Sourdaine, P.; Seralini, G.-E. Bioorg.
Med. Chem. 2000, 8, 945–955.
17. (a) Gupta, S. P.; Mathur, A. N.; Nagappa, A. N.; Kumar, D.; Kumaran, S. Eur. J.
Med. Chem. 2003, 38, 867–873; (b) Poty, C.; Gibon, V.; Evrard, G.; Norberg, B.;
Vercauteren, D. P.; Gubin, J.; Chatelain, P.; Durant, F. Eur. J. Med. Chem. 1994, 29,
911–923.
NMR (300 MHz, CDCl3): d 1.44 (t, J = 7.2 Hz, 3H), 4.43 (m, 2H), 6.66 (t, J = 8.7 Hz,
2H), 6.97 (s, 1H), 7.17 (m, 2H), 7.63 (t, J = 7.5 Hz, 2H), 7.78 (m, 3H), 8.25 (m,
3H), 8.41 (d, J = 9.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d 14.5 (CH3), 60.3 (CH2),
101.3 (CH), 107.6 (C), 115.4 (2CH), 115.6 (CH), 117.0 (CH), 118.8 (CH), 120.4
(C), 121.9 (C), 124.9 (CH), 125.1 (C), 127.0 (CH), 127.1 (CH), 127.2 (C), 128.7 (2
CH), 128.7 (C), 130.3 (C), 130.4 (2 CH), 130.5 (C), 133.2 (CH), 137.4 (C), 139.3
(C), 142.0 (C), 156.4 (C), 164.1 (C), 183.4 (C); HRMS (ESI) m/z calcd for
C
30H19ClFNO4: [M+Na]+ 534.0879; found: 534.0893.
Please cite this article in press as: Paira, R.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.095