Basic alumina supported one-pot synthesis of structurally diverse pyridine/quinolinine-fused novel diazepanium, diazocanium, imidazodilinium and tetrahydro-pyrimidiniums

Article abstract of DOI:10.1016/j.tetlet.2011.01.134

Basic alumina supported solvent-free one-pot synthesis of pyridine-fused polycyclic diazepaniums was achieved under microwave irradiation. The process was successfully extended to the synthesis of pyridine-fused bicyclic imidazolidiniums and tetrahydro-pyrimidiniums and also of tri- and tetracyclic diaza-heterocycle-fused quinoliniums. The dual characteristic of basic alumina, a solid support as well as a base, was successfully employed in the current investigation. The method emerged to be an effective route in terms of product yield, reaction time, and ease of purification and most importantly for environment friendly protocols.

Full text of DOI:10.1016/j.tetlet.2011.01.134

Tetrahedron Letters 52 (2011) 1653–1657
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Basic alumina supported one-pot synthesis of structurally diverse
pyridine/quinolinine-fused novel diazepanium, diazocanium,
imidazodilinium and tetrahydro-pyrimidiniums
Rupankar Paira, Arindam Maity, Shyamal Mondal, Subhendu Naskar, Krishnendu B. Sahu,
⇑
Pritam Saha, Abhijit Hazra, E. Padmanaban, Sukdeb Banerjee, 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:
Basic alumina supported solvent-free one-pot synthesis of pyridine-fused polycyclic diazepaniums was
achieved under microwave irradiation. The process was successfully extended to the synthesis of pyri-
dine-fused bicyclic imidazolidiniums and tetrahydro-pyrimidiniums and also of tri- and tetracyclic
diaza-heterocycle-fused quinoliniums. The dual characteristic of basic alumina, a solid support as well
as a base, was successfully employed in the current investigation. The method emerged to be an effective
route in terms of product yield, reaction time, and ease of purification and most importantly for environ-
ment friendly protocols.
Received 16 December 2010
Revised 20 January 2011
Accepted 27 January 2011
Available online 3 February 2011
Keywords:
Diazepaniums
Diazocaniums
Imidazodiliniums
Tetrahydro-pyrimidiniums
Basic alumina
Microwave
Ó 2011 Elsevier Ltd. All rights reserved.
Pharmacophores of several bioactive entities are often found to
posses seven-membered ring heterocycles. Among them, the aze-
panes are found in synthetic glycosides and antibacterials,1 in sev-
eral antidepressants like, imipramine, clomipramine, desipramine,
lofepramine, metapramine, quinupramine, etc. and also in b-N-
acetylhexosaminidase inhibitors.2 However, the most important
member of this class, which provides the central core motif for
quite a lot of scaffolds, is the diazepane ring system, which is found
in a number of marketed drugs.3 Besides these, several receptors,4,5
inhibitors,6–9 antagonists,10 T-type calcium channel blockers,11 etc.
are found to consist of this important heterocycle in their core.
Thus, construction and structural modification of this class of com-
pounds has gained a lot of importance in recent times. Although
reports regarding the synthesis of diazepanes are available in the
literature, the incorporation of this family of compounds into a
fused ring system, especially the fusion with nitrogen-heterocycles
in a single step, is virtually unexplored.12
high affinity towards DNA16 has also attracted attention in the
recent years. Furthermore, the gifted bioactivities of a variety of
heterocyclic ammonium salts17 like, CFTR activation,18 DNA-inter-
calation,19 antiproliferative activity,19 antimalarial and antileish-
manial activity20 made them crucial to the biologists for
screening against various cell lines, as well as to the organic chem-
ists for the establishment of shorter synthetic routes through the
greener modifications of reaction conditions, in a cost-effective
manner, from easily available starting materials.
As part of our ongoing research on the establishment of concise
synthetic routes to structurally diverse polynuclear N-heteroarocy-
cles through the development of newer environmentally benign
technologies, recently we reported a few distinguished methodol-
ogies,21 where microwave irradiation was employed in order to
achieve higher energy efficiency and enhancement of both the rate
of reaction and the product yield. Our particular interest was on
the use of solid supports like silica and alumina, which are basi-
cally inorganic oxides and possess excellent ability to adsorb the
organic compounds on their surface without absorbing or restrict-
ing the transmission of microwave irradiation.22 Besides this, the
homogenous dispersion of active sites, associated selectivity and
easy work-up schedule made the solid-supported reactions more
advantageous over the conventional solution phase reactions.
Being fascinated by such widespread bioactivities of heterocy-
clic quaternary ammonium salts, diazepanes and its lower and
Besides the diazepaniums, the quinolinium derivatives have
also received much attention due to their interesting biological
activities.13 They can selectively block the apamine-sensitive Ca+2
activated K+ channels14 and inhibit the human choline kinase.15
Their antiproliferative activity against the HT-29 cell line15 and
⇑
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 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.134

1654
R. Paira et al. / Tetrahedron Letters 52 (2011) 1653–1657
higher-membered ring analogues,23 we contemplated developing a
methodology through an environmentally benign catalytic system
and our continuous search enabled us to explore the dual character
of basic alumina, a solid support as well as a base. Initially, we suc-
ceeded in the synthesis of pyrido-fused diaza heterocycles using
basic alumina under microwave irradiation and synthesized sev-
eral 5–7-membered diaza-heterocycle-fused pyridiniums. The use-
fulness of basic alumina in pyridine systems prompted us to
explore its application further, in the synthesis of 6–8-membered
diazaheterocycle-fused tri- and tetracyclic diazaquinoliniums.
In this letter, we wish to disclose a simple, efficient and green
protocol for the selective synthesis of pyridine/quinoline-fused
polycyclic diazepaniums, imidazolidiniums, tetrahydro-pyrimidi-
niums and diazocaniums under the basic alumina supported cata-
lytic system.
Our initial effort was to optimize the reaction condition for the
condensation of 2-aminopyridine (1a) and 1,4-dibromobutane
(2a). Attempts using several non-nucleophilic organic bases like,
Et3N, DBU, etc. under the conventional solution-phase methods
were frustrating, yielding the product 3a to the extent of 6–10%
(Table 1, entries 1–4). Therefore, the coupling was reinvestigated
by replacing the bases by a stronger base NaH. This, however, also
failed to show any improvement in the outcome (Table 1, entries 5
and 6) and had to be discarded. We next tested a solid support sys-
tem to condense 1a and 2a. However, with silica as the support and
using K2CO3 or Cs2CO3 as the base, the starting materials were
recovered unaltered even after irradiating the reaction mixture
(Table 2, entries 1–3) for 20 min at 190 °C (180 W). The yield im-
proved to 19% when silica was replaced by neutral alumina (Table
2, entry 4). We then turned our attention to basic alumina as the
solid support and ended up with an improvement in the yield up
to 56%, when the model substrates (1a and 2a) were irradiated at
75 °C (180 W) using K2CO3 as the base (Table 2, entry 5). To im-
prove the yield further, the reaction temperature was enhanced
to 90 °C, leading to maximization of the product yield (92%) in
5 min even in the absence of K2CO3 (Table 2, entries 6–8). It is wor-
thy of mention that only 38% of product 3a was obtained when the
condensation of 1a and 2a was attempted using an oil bath at
120 °C for 10 h (Table 2, entry 9) under the usual heating proce-
dure, which evidently established the usefulness of microwave
irradiation, over the conventional heating.
Table 2
Optimization of reaction condition between 1a and 2a using different solid supports
in the reactiona
Entry
Solid support-base
Time (min)
Temp. (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
Silica gel–K2CO3
Silica gel–K2CO3
Silica gel–Cs2CO3
Neutral alumina–Cs2CO3
Basic alumina–K2CO3
Basic alumina
Basic alumina
Basic alumina
Basic alumina
5
20
15
20
2
1
5
10
10 h
80
190
85
180
75
90
90
120
120
NRc
NR
NR
19
56
74
92d
92
38e
a
All the solid-supported reactions were performed by using 1a and 2a under
microwave irradiation at 180 W.
b
Isolated yield.
NR = No reaction.
Both in absence and presence of K2CO3.
In heating condition, using an oil bath.
c
d
e
After fruitfully constructing these pyridine-fused polycyclic dia-
zepanium derivatives, we focused our attention towards the syn-
thesis of its lower ring homologues under similar reaction
conditions. Thus, 2a, 2b and 2c were first replaced with 1,2-dibro-
moethane (2d), which was cyclized with pyridine-2-amines (1a,
1b) and the corresponding dihydroimidazopyridiniums (3d, 3e)
were isolated in 70–71% yield (Table 3, entries 4 and 5). Similar
reaction of 1,3-dibromopropane (2e) with 2-aminopyridine (1a),
under identical reaction condition successfully yielded the corre-
sponding tetrahydropyridopyrimidiniums (3f) in excellent yield
(Table 3, entry 6).
After the successful application of basic alumina in the pyridine
system we decided to test it in the quinoline family and the study
was extended by replacing pyridine-2-amines with quinolin-8-
amine (4). Reactions with various dibromoalkanes ( 2a, 2d, 2e)
under the optimal set of reaction conditions indeed produced the
corresponding quinoliniums (5a–c) in excellent yields (79–88%).
On moving from liquid dibromoalkanes ( 2a, 2d, 2e) to the solid
benzylic dibromide 2b, the method again proved successful and
the corresponding tetracyclic dihydrobenzodiazocino-quinolinium
bromide 5d was synthesized in 92% yield (Table 4, entry 4). In all
the cases the methodology was able to restrict the reaction up to
the quinolinium stage and prevented their oxidation to the corre-
sponding quinolones. Thus, a complete and selective synthesis of
diaza-heterocycle-fused quinoliniums was achieved in this basic
alumina promoted reaction system, without the formation of quin-
olones or any other unwanted side products. All the products were
characterized by NMR and mass spectral analyses.
The promising performance of basic alumina could be ascribed
to the presence of Al–OÀ groups on the alumina surface21b that
play a key role in the annulations of pyridines and quinolines with
aliphatic and benzylic dibromides. As depicted in Scheme 1, the
dibromide 2b gets linked to the solid support by forming an inter-
mediate (II), through a simple substitution reaction. Subsequent
alkylation of the ring nitrogen of pyridine24 or the amine group
of quinoline25 then extends the linkage to form the intermediates
III and IV, respectively, where the benzene ring acts as the linker
between the solid support and the nitrogen heterocycle. The inter-
mediates then lead to the formation of the products (V and VI),
through rapid cyclization and the abstraction of the highly acidic
ammonium proton (in case of III) by basic alumina. We presume
that the key factor responsible for such high catalytic activity of ba-
sic alumina is its ability to bring the two reactants at close proxim-
ity. The unsurpassed efficiency of basic alumina for effecting such
condensation, compared to the other two solid supports, may be
attributed to the availability of aluminoxide groups in its surface.
However, the formation of fused diazepane ring system was not
limited only to the bicyclic system; the tricyclic diazepanium was
also obtained in high yields by replacing the dihaloalkane 2a with
1,2-bis-(bromomethyl)benzene 2b (Table 3, entry 2). The study
was then further extended by replacing 2b with 2,3-bis-bromo-
methyl-naphthalene 2c, which was reacted with pyridine-2-amine
under the optimal set of reaction conditions and the corresponding
tetracyclic diazepanium was successfully isolated in high yield
(Table 3, entry 3). The progress of the reactions in all the cases
was only upto the diazepanium stage; their oxidation to the corre-
sponding pyridones was never encountered. Thus, complete and
selective syntheses of pyridine-fused polycyclic diazepaniums
were achieved in this system.
Table 1
Optimization of reaction condition between 1a and 2a using solution-phase methods
Entry
Solvent
Base
Time (h)
Temp. (°C)
Yielda (%)
1
2
3
4
5
6
Et3N
Et3N
DBU
DBU
NaH
NaH
DCM
DCM
DCM
DCM
DMSO
DMF
10
10
12
10
12
12
rt
40
rt
80
85
85
10
10
6
10
14
14
a
Isolated yield.

R. Paira et al. / Tetrahedron Letters 52 (2011) 1653–1657
1655
Table 3
Construction of bi-, tri- and tetracyclic 5–7-membered diaza-heterocycle-fused pyridiniums (3a–f) from pyridine-2-amine under the optimal set of reaction condition
Entry
Pyridine derivative
Dibromide
Producta
Time (min)
Yieldb (%)
Br
Br
N
N
NH
NH
NH
2
2
1
5
92
95
Br
2a
1a
3a
Br
Br
N
N
NH
Br
2b
2
4
1a
3b
Br
Br
N
N
NH
NH
2
Br
2c
1a
3
6
91
3c
Br
N
N
NH
NH
2
4
5
8
71
70
Br
Br
1a
2d
3d
Br
Br
Br
N
N
NH
NH
11
2
Br
Br
2d
1b
3e
Br
N
NH
N
NH
Br
2
6
5
89
Br
1a
2e
3f
a
All the reactions were performed using basic alumina as solid support under microwave irradiation at 180 W.
Isolated yield.
b
An investigation on the reusability of the solid support was
also performed. The results reveal that proper washing with
alkaline water, followed by acetone, and subsequent calcination
at 150 °C can regenerate the solid support without attenuating its
catalytic activity and one can recycle it 3–4 times
(Fig. 1).
Table 4
Construction of tri-, and tetracyclic diaza-heterocycle-fused quinoliniums (5a–d) from quinoline-8-amine under the optimal set of reaction condition
Entry
Quinoline derivative
Dibromide
Producta
Time (min)
Yieldb (%)
Br
Br
N
N
Br
Br
2d
1
4
88
NH2
HN
4
5a
Br
Br
N
N
2e
2
7
82
NH2
HN
4
5b
(continued on next page)

1656
R. Paira et al. / Tetrahedron Letters 52 (2011) 1653–1657
Table 4 (continued)
Entry
Quinoline derivative
Dibromide
Producta
Time (min)
10
Yieldb (%)
Br
Br
N
N
Br
Br
3
79
HN
HN
NH2
2a
4
5c
Br
Br
N
N
NH2
4
2
92
2b
4
5d
a
All the reactions were performed using basic alumina as solid support under microwave irradiation at 180 W.
Isolated yield.
b
H2N
NH
N
N
sic
Ba
O
O
N
Br Br
Alumina
/-H
Al O
O
n
NH2
Br
V
III
O
O
O
O
O
O
Al
O
Al O
n
n
I
II
N
N
NH
NH2
HN
O
O
N
Al O
O
n
IV
VI
Scheme 1. Plausible mechanistic pathway for the basic alumina supported synthesis of (a) fused pyridiniums (b) fused polycyclic diaza-quinolinium cations.
solid support, in solvent-free condition under microwave irradia-
tion. The easy availability and reusability of solid-support, elimina-
tion of the use of any base or solvent, cost-effectiveness of the
process, operational simplicity, use of environmentally benign
80
techniques and, most importantly, the general applicability of the
methodology both for the smaller and larger ring systems and also
for the synthesis of tri- and tetracyclic diazaquinoliniums26,27b
60
make it a novel green methodology for the synthesis of newer het-
eroaromatics. The structural similarity of the newly synthesized
tri- and tetracyclic diazepaniums with a number of well known
antidepressants and also the structural uniqueness of the
pyrido-fused bicyclic imidazolidiniums, diazepaniums, and tetra-
hydro-pyrimidiniums may lead to the identification of newer
heteroaromatics having potential biological activity. To the best
of our knowledge, this is the first report of basic alumina supported
synthesis of pyridine/quinoline-fused diaza-heterocyclic cations.
40
20
0
1
2
3
4
5
Acknowledgements
No. of cycles
We thank the Council of Scientific and Industrial Research
(CSIR), New Delhi, for financial support in the form of fellowships
to R.P., A.M., S.M., S.N., K.B.S., P.S. and A.H. We are also thankful
to Dr. B. Achari, Emeritus Scientist, CSIR, for useful suggestions
and encouragement. Our special thanks are due to Professor B.C.
Ranu of IACS, Kolkata, for his generous cooperation in utilizing
the MW instrument.
Figure 1. Reusability of the basic alumina tested using 1a and 2a. The reactions
were performed with 1a (3.3 mmol) and 2a (6 mmol), using 400 mg basic alumina
at 90 °C for 5 min.
In conclusion, we have unveiled the scope of synthesizing pyr-
idine-fused heteroaromatics from26,27a 2-aminopyridines and ali-
phatic/benzylic dibromides, using basic alumina as a reactive

R. Paira et al. / Tetrahedron Letters 52 (2011) 1653–1657
1657
17. Brana, M. F.; Cacho, M.; Gradillas, A.; de Pascual-Teresa, B.; Ramos, A. Curr.
Pharm. Des. 2001, 7, 1745–1780.
Supplementary data
18. Galietta, L. J. V.; Springsteel, M. F.; Eda, M.; Niedzinski, E. J.; By, K.; Haddadin,
M. J.; Kurth, M. J.; Nantz, M. H.; Verkman, A. S. J. Biol. Chem. 2001, 276, 19723–
19728.
19. Martínez, V.; Burgos, C.; Alvarez-Builla, J.; Fernández, G.; Domingo, A.; García-
Nieto, R.; Gago, F.; Manzanares, I.; Cuevas, C.; Vaquero, J. J. J. Med. Chem. 2004,
47, 1136–1148.
20. (a) Howarth, J.; Hanlon, K. Tetrahedron Lett. 2001, 42, 751–754; (b) Howarth, J.;
Hanlon, K. Bioorg. Med. Chem. Lett. 2003, 13, 2017–2020.
21. (a) Naskar, S.; Paira, P.; Paira, R.; Mondal, S.; Maity, A.; Hazra, A.; Sahu, K. B.;
Saha, P.; Banerjee, S.; Luger, P.; Weber, M.; Mondal, N. B. Tetrahedron 2010, 66,
5196–5203; (b) Saha, P.; Naskar, S.; Paira, P.; Hazra, A.; Sahu, K. B.; Paira, R.;
Banerjee, S.; Mondal, N. B. Green Chem. 2009, 11, 931–934.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.134.
References and notes
1. Barluenga, S.; Simonsen, K. B.; Littlefield, E. S.; Ayida, B. K.; Vourloumis, D.;
Winters, G. C.; Takahashi, M.; Shandrick, S.; Zhao, Q.; Han, Q.; Hermann, T.
Bioorg. Med. Chem. Lett. 2004, 14, 713–718.
2. Li, H.; Marcelo, F.; Bello, C.; Vogel, P.; Butters, T. D.; Rauter, A. P.; Zhang, Y.;
Sollogoub, M.; Blériot, Y. Bioorg. Med. Chem. 2009, 17, 5598–5604.
3. (a) Piek, T.; van Weeren-Kramer, J.; van Wilgenburg, H.; Zeegers, A.; Leeuwin, R.
S. Neurosci. Res. Commun. 2001, 28, 85–93; (b) Nakamoto, H.; Ogasawara, Y.;
Kajiya, F. Hypertens. Res. 2008, 31, 315–324; (c) Bailey, A. M.; Paulsen, I. T.;
Piddock, L. V. J. Antimicrob. Agents Chemother. 2008, 52, 3604–3611.
4. Bedürftig, S.; Wünsch, B. Eur. J. Med. Chem. 2009, 44, 519–525.
5. Sikazwe, D. M. N.; Nkansah, N.; Altundas, T. R.; Zhu, X. Y.; Roth, B. L.; Setola, V.;
Ablordeppey, S. Y. Bioorg. Med. Chem. 2009, 17, 1716–1723.
6. Shankaran, K.; Donnelly, K. L.; Shah, S. K.; Caldwell, C. G.; Chen, P.; Hagmann,
W. K.; MacCoss, M.; Humes, J. L.; Pacholok, S. G.; Kelly, T. M.; Grant, S. K.; Wong,
K. K. Bioorg. Med. Chem. Lett. 2004, 14, 5907–5911.
7. Koshio, H.; Hirayama, F.; Ishihara, T.; Taniuchi, Y.; Sato, K.; Sakai-Moritani, Y.;
Kaku, S.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S. Bioorg. Med.
Chem. 2004, 12, 2179–2191.
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.
Ch. 12; (b) Varma, R. S. Green Chem. 1999, 1, 43–55.
23. (a) Sharma, V.; Crankshaw, C. L.; Piwnica-Worms, D. J. Med. Chem. 1996, 39,
3483–3490; (b) Tomizawa, M.; Zhang, N.; Durkin, K. A.; Olmstead, M. M.;
Casida, J. E. Biochemistry 2003, 42, 7819–7827; (c) Oppong, K. A.; Ellis, C. D.;
Laufersweiler, M. C.; O’Neil, S. V.; Wang, Y.; Soper, D. L.; Baize, M. W.; Wos, J. A.;
De, B.; Bosch, G. K.; Fancher, A. N.; Lu, W.; Suchanek, M. K.; Wang, R. L.;
Demuth, T. P., Jr. Bioorg. Med. Chem. Lett. 2005, 15, 4291–4294; (d) Audouze, K.;
Nielsen, E. O.; Olsen, G. M.; Ahring, P.; Joergensen, T. D.; Peters, D.; Liljefors, T.;
Balle, T. J. Med. Chem. 2006, 49, 3159–3171.
24. Frampton, R.; Johnson, C. D.; Katritzky, A. R. Justus Liebigs Ann. Chem. 1971, 749,
12.
25. Elderfield, R. C.; Rubin, L. E. J. Am. Chem. Soc. 1953, 75, 2963–2970.
26. General reaction procedure: 3.3 mmol 2-aminopyridine derivatives (1a, 1b) or
8-aminoquinoline (4) and 6 mmol dibromoalkanes or benzylic dibromides
8. Orvieto, F.; Branca, D.; Giomini, C.; Jones, P.; Koch, U.; Ontoria, J. M.; Palumbi,
M. C.; Rowley, M.; Toniatti, C.; Muraglia, E. Bioorg. Med. Chem. Lett. 2009, 19,
4196–4200.
9. Pikul, S.; Dunham, K. M.; Almstead, N. G.; De, B.; Natchus, M. G.; Taiwo, Y. O.;
Williams, L. E.; Hynd, B. A.; Hsieh, L. C.; Janusz, M. J.; Gu, F.; Mieling, G. E. Bioorg.
Med. Chem. Lett. 2001, 11, 1009–1013.
(2a–e) were placed in
a round bottomed flask (25 ml) and dissolved in
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
10. (a) Cox, C. D.; Breslin, M. J.; Whitman, D. B.; Schreier, J. D.; McGaughey, G. B.;
Bogusky, M. J.; Roecker, A. J.; Mercer, S. P.; Bednar, R. A.; Lemaire, W.; Bruno, J.
G.; Reiss, D. R.; Harrell, C. M.; Murphy, K. L.; Garson, S. L.; Doran, S. M.;
Prueksaritanont, T.; Anderson, W. B.; Tang, C.; Roller, S.; Cabalu, T. D.; Cui, D.;
Hartman, G. D.; Young, S. D.; Koblan, K. S.; Winrow, C. J.; Renger, J. J.; Coleman,
P. J. J. Med. Chem. 2010, 53, 5320–5332; (b) Cole, A. G.; Stroke, I. L.; Brescia, M.
R.; Simhadri, S.; Zhang, J. J.; Hussain, Z.; Snider, M.; Haskell, C.; Ribeiro, S.;
Appell, K. C.; Henderson, I.; Webb, M. L. Bioorg. Med. Chem. Lett. 2006, 16, 200–
203; (c) Ly, K. S.; Letavic, M. A.; Keith, J. M.; Miller, J. M.; Stocking, E. M.;
Barbier, A. J.; Bonaventure, P.; Lord, B.; Jiang, X.; Boggs, J. D.; Dvorak, L.; Miller,
K. L.; Nepomuceno, D.; Wilson, S. J.; Carruthers, N. I. Bioorg. Med. Chem. Lett.
2008, 18, 39–43.
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 methanol
was added to it and the slurry was stirred at room temperature for 10 min. The
mixture was then vacuum 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. 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.
27. (a) Spectral data for 3a: Brown solid. 92% yield; mp 236–238 °C; Rf (30% ethyl
acetate–methanol) 0.35; IR (KBr,
m ;
max): 1290, 1438, 3533 cmÀ1 1H NMR
11. Gu, S. J.; Lee, J. K.; Pae, A. N.; Chung, H. J.; Rhim, H.; Han, S. Y.; Min, S. J.; Cho, Y.
S. Bioorg. Med. Chem. Lett. 2010, 20, 2705–2708.
(300 MHz, DMSO-d6): d 1.90 (2H, m), 2.08 (2H, m), 3.57 (2H, m), 4.50 (2H, m),
6.94 (1H, m), 7.05 (1H, m), 7.87 (1H, m), 8.07 (1H, m); 13CNMR (75 MHz.,
DMSO-d6): d 24.3 (CH2), 24.6 (CH2), 43.0 (CH2), 55.9 (CH2), 113.9 (CH), 117.2
(CH), 141.4 (CH), 141.9 (CH), 156.6 (C); HRMS (ESI) m/z calcd for C9H13N2:
[MÀBr]+ 149.1073; found: 149.1065. (b) Spectral data for 5a: Brown oil. 88%
12. (a) Cheng, D.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T. Org. Lett. 2007, 9,
5175–5178; (b) Mandereau, J.; Xuong, E. N. T.; Reynaud, P. Eur. J. Med. Chem.
1974, 9, 344; (c) Zajac, M. A. J. Org. Chem. 2008, 73, 6899–6901.
13. Cox, O.; Jackson, H.; Vargas, V. A.; Baez, A.; Colon, J. I.; Gonzalez, B. C.; Leon, M.
D. J. Med. Chem. 1982, 25, 1378–1381.
14. Rosa, J. C.; Galanakis, D.; Ganellin, C. R.; Dunn, P. M.; Jenkinson, D. H. J. Med.
Chem. 1998, 41, 2–5.
15. Martín, R. S.; Campos, J. M.; García, A. C.; López, O. C.; Coronel, M. B.; González,
A. R.; Gallo, M. A.; Lacal, J. C.; Espinosa, A. J. Med. Chem. 2005, 48, 3354–3363.
16. Molina, A.; Vaquero, J. J.; Navio, J. L. G.; Builla, J. A.; Teresa, B. d. P.; Gago, F.;
Rodrigo, M. M.; Ballesteros, M. J. Org. Chem. 1996, 61, 5587–5599.
yield; Rf (30% ethyl acetate–methanol) 0.35; IR (KBr,
mmax): 1431, 1500,
3461 cmÀ1 1H NMR (600 MHz., D2O): d 3.78 (2H, m), 4.96 (2H, m), 7.32 (1H,
;
m), 7.52 (1H, m), 7.67 (1H, m), 7.89 (1H, m), 8.89 (2H, m); 13C NMR (150 MHz.,
DMSO-d6): d 38.2, (CH2), 55.4 (CH2), 116.3 (CH), 117.6 (CH), 121.0 (CH), 126.8
(C), 130.4 (C), 130.5 (CH), 138.3 (C), 145.2 (CH), 146.5 (CH) ; HRMS (ESI) m/z
calcd for C11H11N2: [MÀBr]+ 171.0917; found: 171.0931.