Synthesis of bridgehead nitrogen heterocycles on a solid surface

Article abstract of DOI:10.1081/SCC-200051674

Bridgehead nitrogen heterocycles were synthesized from heteroaromatic amidines and cyclic or acyclic α-bromoketones under solvent-free conditions at room temperature on a solid surface in excellent yields, which are higher than those obtained with hithert

Full text of DOI:10.1081/SCC-200051674

This article was downloaded by: [University of Hong Kong Libraries]
On: 04 October 2013, At: 12:58
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Bridgehead Nitrogen
Heterocycles on a Solid Surface
Shashikanth Ponnala a , S. T. V. S. Kiran Kumar a , Bashir A. Bhat a & Devi
Prasad Sahu a
a Division of Medicinal and Process Chemistry, Central Drug Research
Institute, Lucknow, India
Published online: 21 Aug 2006.
To cite this article: Shashikanth Ponnala , S. T. V. S. Kiran Kumar , Bashir A. Bhat & Devi Prasad Sahu
(2005) Synthesis of Bridgehead Nitrogen Heterocycles on a Solid Surface , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 35:7, 901-906, DOI: 10.1081/
SCC-200051674
To link to this article: http://dx.doi.org/10.1081/SCC-200051674
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 901–906, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051674
Synthesis of Bridgehead Nitrogen
Heterocycles on a Solid Surface#
Shashikanth Ponnala, S. T. V. S. Kiran Kumar,
Bashir A. Bhat, and Devi Prasad Sahu
Division of Medicinal and Process Chemistry, Central Drug Research
Institute, Lucknow, India
Abstract: Bridgehead nitrogen heterocycles were synthesized from heteroaromatic
amidines and cyclic or acyclic a-bromoketones under solvent-free conditions at
room temperature on a solid surface in excellent yields, which are higher than those
obtained with hitherto-known methods of syntheses.
Keywords: Bridgehead nitrogen heterocycles, solid surface, solvent free synthesis,
Alumina
INTRODUCTION
The bridgehead nitrogen heterocycles, especially the fused imidazoles, are an
important class of heterocyclic compounds because of their wide use in
medicinal and agro chemistry as scaffolds for generation of pharmacologically
active agents. Their antiviral,[1] antiulcer,[2] antimircobial,[3] antifungal,[4]
herbicidal,[5] antileprotic,[6] and immunosuppressive agents,[7] have been
explored. More recently, 2-arylimidazo [1,2-a] pyridines were described as
ligands for detecting b amyloid (A b) plaques in the brain, whose production
is a pivotal event in the pathology of Alzheimer’s disease.[8]
The bridgehead nitrogen heterocycles are accessible in moderate yield
by solution-phase reaction of corresponding heteroaromatic amidines with
Received in India November 16, 2004
#CDRI Communication No. 6545.
Address correspondence to Devi Prasad Sahu, Division of Medicinal and
Process Chemistry, Central Drug Research Institute, Lucknow 226001, India.
Tel.: 91-522-2212411-18; Fax: 091-(522)-2623405; E-mail: dpsahu@rediffmail.com

902
S. Ponnala et al.
appropriate a-haloketones or equalents.[7,9,10] There are numerous methods to
synthesize fused imidazoles.[5,7,9] The limitations of most of the existing
synthetic protocols are realized in terms of harsh reaction conditions (i.e.,
higher temperature and longer reaction time). Newer methods of synthesis of
these bioactive heterocycles continue to attract attention to attain experimental
simplicity and effectiveness.
To best of our knowledge, there is no report so far of solid-surface-
mediated synthesis of various fused imidazoles using Al2O3, although
Verma et al. have reported synthesis of fused thiazolines and their derivatives
using clay under microwave irradiation.[11a]
RESULTS AND DISCUSSION
The results incorporated in Table 1 demonstrate the generality and scope of
Al2O3 as a solid-surface mediated[11b] cyclization of structurally diverse
heteroaromatic amidines with substituted phenacyl bromides under solvent-
free conditions. All the reactions were carried out with one equivalent of
each reactant and 10 equivalent of activated Al2O3, at room temperature
and stirred for the time showed in the Table 1.
The stirring of a mixture of 2-aminopyridine, phenacyl bromide, and
alumina (neutral, mesh 60–120) without any solvents at ambient temperature
for the period of time shown in Table 1 smoothly furnished imidazo
[1,2-a]pyridines 1a–o in excellent yield (Scheme 1). The products were con-
veniently isolated by extraction with organic solvents (CHCl3) and purified
either by recrystallization or column chromatography. By adopting similar
synthetic protocols, imidazo[1,2-a]pyrimidines 1p–t (Scheme 1) and
benzo[d]imidazo[2,1-b]thiazole 4a-e (Scheme 2) were synthesized in
excellent yields from 2-aminopyrimidine and 2-aminothiazoles respectively.
Condensation of heteroaromatic amidines with cyclic a-haloketones such as
a-bromo-1-tetralone and ethyl 4-chloroacetoacetate gave poor yields and
4-bromo acetoacetate gave good yields under similar conditions. Thus the
annulations of 2-bromo 1-tetralone with 2-aminopyridine on alumina
furnished tetracyclic 5,6-dihydro-naphtho [10,20:4,5]imidazo[1,2-a]pyridine 3
in 30% yield. Reaction of 2-aminopyridine with ethyl 4-bromoacetoacetate
gave imidazo [1,2-a] pyrid-2-yl-acetic acid ester 2 in 70% yield.
The structure of all fused imidazoles were confirmed by spectroscopic data.
Thus in the IR spectrum, the keto-carbonyl showed a peak at 1696cm21 and
C55N stretching peak at 1597 cm21. The 13C NMR spectrum of 2-(4-chloro-
phenyl)-imidazo[1,2-a]pyridine showed 9-sp2 carbons and 4-sp carbons that
1
confirmed the proposed structure. The H NMR spectra of the cycloadduct
added conclusive support for the proposed structure. Moreover, the presence
of molecular ion peak at 229 (M þ H)þ in the FAB mass spectrum confirmed
the formation of cycloadduct.

Synthesis of Bridgehead Nitrogen Heterocycles
903
Table 1. Fused imadazoles from phenacyl beomides and 2-heteroaromatic amidines
Entry
Compound No.
Time (h)
Yield (%)
mp8C
171
216
Lit. mp8C
1.
2
1a
1b
1c
1d
1e
1f
3
3
92
88
86
86
89
85
80
79
72
76
70
82
79
85
68
30
70
72
79
77
78
73
70
72
77
76
71
172[13a]
215–216[9]
[9]
3.
3
205–207
132–134
137
208
4
3
134[9]
137[12d]
134[9]
5.
3
6.
3
132
7
1g
1h
1i
3.5
3.5
3.5
3.5
3.5
2.5
2.5
2.5
3.5
6
174 (D)
207
228
m
8.
209[12b]
227–228[13b]
224[13b]
204–207[9]
m
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
1j
223–224
204–207
145–147
215
1k
1l
1m
1n
1o
3
216–217[13c]
m
240–242
172–173
128–130
n
172–174[13c]
m
2
4
n[13d]
1p
1q
1r
1s
1t
4
190–191
226–228
223–226
268–270
226–227
105–107
180–181
163–165
159–160
178–180
193[3a]
228[3a]
226[3a]
270[3a]
228[3a]
106[7]
4
4
4
4
4a
4b
4c
4d
4e
12
12
12
12
12
181[7]
164[7]
160[7]
181[7]
m ¼ Lit. is not available. n ¼ Liquid.
In summary, we have developed an efficient synthetic route for the prep-
aration of fused imidazoles using Al2O3 as a solid surface.
EXPERIMENTAL
General procedure for the preparation of fused imidazoles: Neutral Al2O3
(1.0 g, 10 mmol), amidine (1 mmol), and phenacyl bromide (1 mmol), were
stirred at ambient temperature. After completion of the reaction, the contents
were diluted with chloroform (5 ml) and filtered through a celite pad, washed
with 2 ml of chloroform, and evaporated. The residue was purified by

904
S. Ponnala et al.
Scheme 1.
Scheme 2.
chromatography on silica gel using hexane-ethyl acetate as eluent to give the
required product.
ACKNOWLEDGMENT
S. K. P and B. A. B are thankful to I.C.M.R (New Delhi) and Council of
Scientific & Industrial Research (CSIR) respectively for financial support.
We are thankful to SAIF, CDRI for providing the spectroscopic and analytical
data of synthesized compounds.

Synthesis of Bridgehead Nitrogen Heterocycles
REFERENCES
905
1. (a) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache, Y; Chapat, J. P. Syntheis
and antiviral activity of 3-substituted Imidazo[1,2-a] pyridines. Bioorg. Med.
Chem. Lett. 1994, 4, 1937; (b) Lhassani, M.; Chavignon, O.; Chezal, J. M.;
Teluade, J. C.; Chapat, J. P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De
Clercq, E.; Gueiffier, A. Synthesis and antiviral activity of imidazo[1,2-a]
pyridines. Eur. J. Med. Chem. 1999, 34, 271; (c) Gueiffier, A.; Lhassani, M.;
Elhakmaoui, A.; Snoeck, R.; Andrei, G.; Chavignon, O.; Teluade, J. C.;
Kerbal, A.; Essassi, M.; Debouzy, J. C.; Witurowo, M.; Blache, Y.;
Balzarini, J.; De Clercq, E.; Chapat, J. P. Synthesis of acyclo-C-nucleosides in
the imidazo[1,2-a] pyridine and pyrimidine series as antiviral agents. J. Med.
Chem. 1996, 39, 2856.
2. (a) Kaminsky, J. J.; Doweyko, A. M. Antiulcer agents. 6. Analysis of the in vitro
biochemical and in vivo gastric antisecretory activity of substituted Imidazo[1,2-a]
pyridines and related analogues using comparative molecular field analysis and
hypothetical active site lattice methodologies. J. Med. Chem. 1997, 40, 427;
(b) Kaminsky, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn, D. J.;
Elliot, A. J.; Lovey, R. G.; Guzik, H.; Chiu, P. J. S.; Long, J. F.; McPhail, A. T.
Antiulcer agents. 4. Conformational considerations and the antiulcer activity of
substituted Imidazo[1,2-a]pyridines and related analogues. J. Med. Chem. 1989,
32, 1686; (c) Kaesura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Taksugi, H.
Studies on antiulcer drugs. II. Synthesis and antiulcer activity of imidazo[1,2-a]
pyridinyl-2-alkylaminobenzoxazoles and 5, 6, 7, 8-tetrahydro imidazo[1,2-a]
pyridinyl derivatives. Chem. Pharm. Bull. 1992, 40 (2), 371–380.
3. (a) Rival, Y.; Grassy, G.; Michael, G. Synthesis and antibacterial activity of some
Imidazo[1,2-a]pyridine derivatives. Chem. Pharm. Bull. 1992, 40, 1170;
(b) Rewankar, G. R.; Matthews, J. R.; Robins, R. K. Synthesis and antimicrobial
activity of certain Imidazo [1,2-a] pyrimidines. J. Med. Chem. 1975, 18, 1253.
4. Beeswick, P. J.; Campbell, I. B.; Naylor, A. Preparation of cyclooxygenase-2-inhi-
biting 2,3-diphenylimidazo [1,2-a] pyrimidine anti-inflammatories. PCT. Int. Appl.
WO 9 631 509, 1996; Chem. Abstr. 1997, 126, 8117j.
5. Franke, H.; Geisler, J.; Hartfiel, U.; Franke, W.; Dorfmeister, G.; Ganzer, M.;
Johahann, G.; Rees, R. Herbicidal 2-phenyl-5, 6,7,8-tetrahydroimidazo [1,2-a]
pyridines. Ger. offen. DE. 4 120 108, 1991; Chem. Abstr. 1992, 118, 213075v.
6. Saldbols, I. V.; Liers, S. H.; Alekseeva, L. N. A.; Brizgd, B. Synthesis in the
methyl-2-furyl ketone series. XII. 5-Nitro-2-furyl substituted imidazo heterocyclic
compounds with a common nitrogen atom. Khim. Farm. Zh 1967, 1; [Chem. Abst.
1968, 68, 2856].
7. Yasumase, T.; Arima, H.; Tomioka, K.; Yamada, T.; Murase, K. Imidazo [1,2-a]
benzothiazoles. 2. New immunosuppressive agents. J. Med. Chem. 1986, 29,
386–394.
8. Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plossl, K.; Hou, C.;
Holtzman, D. M.; Kung, H. F. Stracture-Activity relationship of imidazo [1,2-a]
pyridines as ligands for detecting b-amyloid plaques in the brain. J. Med. Chem.
2003, 46, 237.
9. Tomoda, H.; Hirano, T.; Saito, S.; Mutai, T.; Araki, K. Substituent effects on
fluoresent properties of imidazo [1,2-a] pyridine based compounds. Bull. Chem.
Soc. Jpn. 1999, 72, 1327–1334.

906
S. Ponnala et al.
10. Raival, Y.; Grassy, G.; Taudou, A.; Calle, R. E. Antifungal activity in vitro of some
imidazo [1,2-a] pyridine derivatives. Eur. J. Med. Chem. 1991, 26, 13–18.
11. (a) Verma, R. S.; Kumar, D.; Liesen, P. Solid state synthesis of 2-aryloxybenzo [b]
furans, 1,3-thiazoles and 3-aryal-5, 6-dihydro imidazo [2,1-b] thiazoles from
a-tosyloxy ketones using microwave irradiation. J. Chem. Soc., Perkin Trans. 1.
1998, 4093; (b) Kabalka, G. W.; Pagni, R. M. Organic reactions on Alumina.
Tetrahedron. 1997, 53, 7999–8065.
12. (a) Buu-Hoi, Ng. D.; Hoan, N. Thiophene series. III. Indoles, napthindoles, pyrro-
lidines and pyrimidazoles derived from the thiaophene nucleus. Res. Trav. Chim.
1949, 68, 441; Chem. Abstr. 1950, 44, 2977d]; (b) Buu-Hoi, Ng. Ph.; Xuong, Ng.
D.; Suu, V. T. New N, N1-disubstituted thioureasand ureas of biological interest.
J. Chem. Soc. 1958, 2815–2821. [Chem. Abstr. 1950, 44, 2977e];
(c) Adams, R.; Pachter, I. J. The action of alkali on bromopyrimidopyrimidones.
J. Am. Chem. Soc. 1954, 76, 1845–1847; (d) Singh, S. P.; Naithani, R.;
Prakasm, O. A facile [hydroxy (tosyloxy) iodo] benzene mediated synthesis of
substituted imidazo [1,2-a] pyridines. Indian Chem. Soc. 1998, 72, 770–772.
13. (a) Buu-Hoi, Ng. D.; Jacquignon, P.; Xuong, Ng. D.; Lavit, D. J. Org. Chem. 1954,
19, 1370; (b) Katritzky, A. R.; Qui, G.; Long, Q.-H.; He, H.-Y.; Steel, P. J.
Efficient syntheses of imidazolo [1,2-a] pyridines and [2,1-a] isoquinolines. J.
Org. Chem. 2000, 65 (26), 9201–9205; (c) Mattu, F.; Marongiu, E. Synthesis of
methyl phenyl imidazo [1,2-a] pyridine isomers of pharmaceutical interest. Ann.
Chim. 1964, 5, 496–509; (d) Cesare, C.; Ambrogio, I.; Giorgio, F. Synthesis
and pharmacological activity of imidazo [1,2-a] pyridine-2-acetic and 2,3-dicar-
boxylic acid and related compounds. Farmaco. Ed. Sci. 1968, 23 (12), 1141–1148.