A base promoted cyclization of N-propargylaminopyridines. Synthesis of imidazo[1,2-a]pyridine derivatives

Article abstract of DOI:10.1021/ol200508x

Chemical equations presented. A base promoted cyclization of the protected N-propargylaminopyridines was shown to be an efficient method for the preparation of imidazo[1,2-a]pyridine derivatives. The reactions were carried out with a small excess of base,

Full text of DOI:10.1021/ol200508x

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2286–2289
A Base Promoted Cyclization of
N-Propargylaminopyridines. Synthesis of
Imidazo[1,2-a]pyridine Derivatives
Suren Husinec,† Rade Markovic,‡ Milos Petkovic,§ Veselin Nasufovic,§ and
Vladimir Savic*,§
Institute of Chemistry, Technology and Metallurgy, Centre for Chemistry, P.O. Box
815, Njegoseva 12, 11000 Belgrade, Serbia, University of Belgrade, Faculty of
Chemistry, Studentski Trg 12-16, 11000 Belgrade, Serbia, and University of Belgrade,
Faculty of Pharmacy, Vojvode Stepe 450, 11221 Belgrade, Serbia
vladimir.savic@pharmacy.bg.ac.rs
Received March 1, 2011
ABSTRACT
A base promoted cyclization of the protected N-propargylaminopyridines was shown to be an efficient method for the preparation of imidazo[1,2-a]
pyridine derivatives. The reactions were carried out with a small excess of base, at room temperature or slightly above producing the heterocyclic
products in moderate to good yields. The stereoelectronic properties of substituents on the pyridine ring were shown to influence the cyclization
process.
The imidazo[1,2-a]pyridine scaffold (Figure 1) is present
in a large number of compounds showing an impressive
variety of biological properties.1
It is also a core structure of several drugs such as
zolpidem (hypnotic), alpidem (anxiolytic), and zolimidine
(antiulcer).
A number of synthetic methods have been designed for
the preparation of this heterocyclic skeleton with majority
of them relying on the formation of the imidazole ring.2
The most common process involves the condensation of
2-aminopyridines with R-halocarbonyl compounds, either
in solution3aÀc or in the solid phase.3dÀh
Perhaps, a more versatile method, producing the 3-ami-
no derivatives, involves three-component coupling trans-
formations.4 Condensation reactions of aldehydes, 2-ami-
nopyridine, and isocyanides is usually carried out in the
presence of acidic catalysts, either protic or Lewis acids. In
† Institute of Chemistry, Technology and Metallurgy.
‡ University of Belgrade, Faculty of Chemistry.
§ University of Belgrade, Faculty of Pharmacy.
(1) For selected recent examples of biological activity, see: Antibiotic
activity: (a) Lhassani, M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.;
Chapat, J.-P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.;
Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271. Antiinflammatory
activity:(b) Rupert, K. C.; Henry, J. R.; Dodd, J. H.; Wadsworth, S. A.;
Cavender, D. E.; Olini, G. C.; Fahmy, B.; Siekierka, J. Bioorg. Med.
Chem. Lett. 2003, 13, 347. Antibacterial activity:(c) Rival, Y.; Grassy,
G.; Michel, G. Chem. Pharm. Bull. 1992, 40, 1170. Bradykinin B2
receptor antagonists:(d) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.;
Sawada, Y.; Imai, K.; Inamura, N.; Asano, M.; Hatori, C.; Katayama,
A.; Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 564. Antiulcer activity:
(f) Katsura, Y.; Nishino, S.; Inoue, Y.; Tomoi, M.; Takasugi, H. Chem.
Pharm. Bull. 1992, 40, 371. Cyclin dependent kinase inhibitors:(g)
Hamdouchi, C.; Zhong, B.; Mendoza, J.; Collins, E.; Jaramillo, C.; De
Diego, J. E.; Robertson, D.; Spencer, C. D.; Anderson, B. D.; Watkins,
S. A.; Zhanga, F.; Brooks, H. B. Bioorg. Med. Chem. Lett. 2005, 15,
1943. GABA receptor agonists:(h) Goodacre, S. C.; Street, L. J.; Hallett,
D. J.; Crawforth, J. M.; Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis,
R. T.; Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S. M.; Pike,
A.; Brown, N.; Wafford, K. A.; Marshall, G.; Castro, J. L.; Atack, J. R.
J. Med. Chem. 2006, 49, 35. Benzodiazepine receptor agonists:(i)
Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra,
M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42, 3934.
(2) For selected recent examples, see: (a) Guchhait, S. K.; Madaan, C.
Org. Biomol. Chem. 2010, 8, 3631. (b) Rousseau, A. L.; Matlaba, P.;
Parkinson, C. J. Tetrahedron Lett. 2007, 48, 4079. (c) DiMauro, E. F.;
Kennedy, J. M. J. Org. Chem. 2007, 72, 1013. (d) Aginagalde, M.; Vara,
Y.; Arrieta, A.; Zangi, R.; Cebolla, V. L.; Delgado-Camon, A.; Cossio,
F. P. J. Org. Chem. 2010, 75, 2776. (e) Adib, M.; Mohamadi, A.; Sheikhi,
E.; Ansari, S.; Bijanzadeh, H. Synlett 2010, 1606. (f) Kiselyov, A. S.
Tetrahedron Lett. 2006, 47, 2941. (g) Kiselyov, A. S. Tetrahedron Lett.
2005, 46, 4487. (h) Dai, W.; Petersen, J. L.; Wang, K. K. J. Org. Chem.
2005, 70, 6647.
r
10.1021/ol200508x
Published on Web 03/29/2011
2011 American Chemical Society

pyridine derivatives have been reported in the literature,
but they employed acid as a solvent or a strong acidic
conditions (HCOOH or H2SO4) and high temperatures.7
Since our transformation offers some advantages, we
decided to investigate it in more detail.
Table 1. Optimization of the Reaction Conditions
Figure 1. Imidazo[1,2-a]pyridine derivatives.
the past decade several transformations based on metal
catalysis havebeen discovered.5 Particularly interesting is a
recently reported condensation process of 2-aminopyri-
dines, aldehydes, and terminal alkynes catalyzed by the
binary catalytic system Cu(I)/Cu(II).5a This method pro-
vides an efficient approach to functionalizing C(2) and
C(3) of the imidazopyridine skeleton and was used for the
one-pot synthesis of alpidem and zolpidem.
entrya
solvent
THF
t °Cb
base
yield (%)c
1
2
3
4
5
6
7
8
9
rt/5 min
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
NaOH
NaH
70
DMSO
DMSO
benzene
THF/tBuOH
THF
rt/16 h
37(45)
31(41)
47(65)
À
60 °C/16 h
60 °C/16 h
60 °C/3 h
60 °C/16 h
60 °C/16 h
60 °C/3 h
60 °C/16 h
Our continuing interest in the chemistry of allenes and
alkynes6 prompted a study which resulted in the discovery
of a new process for the preparation of imidazo[1,2-a]
pyridine derivatives. Attempts to synthesize allene by the
base promoted alkyne isomerization of N-propargylated
aminopyridine 1 resulted in the formation of a compound
which did not contain the allenic moiety. The reaction was
carried out in THF using a slight excess of tBuOK as a base
(Table 1, entry 1), at room temperature to afford the
product in 70% yield after essentially just a few minutes,
À
THF
17(40)
À
MeOH
THF
NaOH
DBU
À
a The reactions were performed using the following conditions: 1
(0.3 mmol), base (0.36 mmol) in solvent (3 mL) at indicated tempera-
tures. b Reactions were initially carried out at rt and then at indi-
cated temperatures. c Isolated yields and, in parentheses, yield based
on conversion.
1
as judged by TLC. Analysis of H/13C NMR and mass
After the initial results we briefly investigated the effects
of various reaction parameters in order to optimize the
reaction conditions (Table 1). The use of a more polar
solvent, such as DMSO (Table 1, entries 2 and 3), either at
room temperature or at 60 °C over significantly longer
reaction times than in the initial experiment, resulted in
incomplete reactions and consequently lower yields.
Slightly better results were produced with nonpolar ben-
zene as a solvent (Table 1, entry 4) but with no general
improvement. Attempts to use THF/tBuOH (v/v, 1:2)
resulted in complete inhibition of the reaction (Table 1,
entry 5). Several bases were also investigated. While
NaOH, in either MeOH or THF (Table 1, entries 6 and
8), resulted in recovery of the starting materials, NaH in
THF (Table 1, entry 7) afforded the expected product but
in an unsatisfactory yield. On the other hand, a weak base
such as DBU (Table 1, entry 9) was shown to be inefficient.
In addition to the above experiments, attempts were made
to decrease the amount of base under the conditions out-
lined in Table 1. Unfortunately, the reaction carried out
with 20 mol % of tBuOK afforded only a proportional
amount of the product. This brief study showed the super-
iority of the initially used reaction conditions, and they
were employed for further investigation of the cyclization
process.
spectral data fully supported the structure of compound 2.
Very few examples of the related cyclization process of the
(3) For selected recent examples, see: (a) Byth, K. F.; Culshaw, J. D.;
Green, S.; Oakes, S. E.; Thomas, A. P. Bioorg. Med. Chem. Lett. 2004,
14, 2245. (b) Ismail, M. A.; Brun, R.; Wenzler, T.; Tanious, F. A.;
Wilson, W. D.; Boykin, D. W. J. Med. Chem. 2004, 47, 3658. (c)
Ikemoto, T.; Wakimasu, M. Heterocycles 2001, 55, 99. (d) Kamal, A.;
Devaiah, V; Reddy, K. L.; Rajenda; Shetti, R. V. C. R. N. C.;
Shankaraiah, N J. Comb. Chem. 2007, 9, 267. (e) Chen, Y.; Lam, Y.;
Lai, Y.-H. Org. Lett. 2002, 4, 3935. (f) Kazzouli, S. E.; Berteina-Raboin,
S.; Mouaddib, A.; Guillaumet, G. Tetrahedron Lett. 2003, 44, 6265. (g)
Ueno, M.; Togo, H. Synthesis 2004, 2673. (h) Masquelin, T.; Bui, H.;
Brickley, B.; Stephenson, G.; Schwerkoske, J.; Hulme, C. Tetrahedron
Lett. 2006, 47, 2989.
(4) For selected examples, see: (a) Masquelin, T.; Bui, H.; Brickley,
B.; Stephenson, G.; Schwerkosked, J.; Hulmea, C. Tetrahedron Lett.
2006, 47, 2989. (b) Lyon, M. A.; Kercher, T. S. Org. Lett. 2004, 6, 4989.
(c) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47,
3031. (d) Ireland, S. M.; Tye, H.; Whittaker, M. Tetrahedron Lett. 2003,
44, 4369.
(5) (a) Chernyak, N.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2743. (b) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem.
Soc. 2010, 132, 13217. (c) Loones, K. T. J.; Maes, B. U. W.; Meyers, C.;
Deruytter, J. J. Org. Chem. 2006, 71, 260. (d) Barun, O.; Ila, H.;
Junjappa, H. J. Org. Chem. 2000, 65, 1583.
(6) (a) Husinec, S.; Jadranin, M.; Markovic, R.; Petkovic, M.; Savic,
V.; Todorovic, N. Tetrahedron Lett. 2010, 51, 4066. (b) Grigg, R.;
Blacker, J.; Kilner, C.; McCaffrey, S.; Savic, V.; Sridharan, V. Tetra-
hedron 2008, 64, 8177. (c) Cleghorn, L. A. T.; Grigg, R.; Savic, V.; Simic,
M. Tetrahedron 2008, 64, 8731.
(7) (a) Roma, G.; Di Braccio, M.; Grossi, G.; Piras, D.; Ballabeni, V.;
Tognolini, M.; Bertoni, S.; Barocelli, E. Eur. J. Med. Chem. 2010, 45,
352. (b) Beaulieu, F.; Ouellet, C.; Ruediger, E. H.; Belema, M.; Qiu, Y.;
Yang, X.; Banville, J.; Burke, J. R.; Gregor, K. R.; MacMaster, J. F.;
Martel, A.; McIntyre, K. W.; Pattoli, M. A.; Zusi, F. C.; Vyas, D.
Bioorg. Med. Chem. Lett. 2007, 17, 1233. (c) Reisch, J.; Scheer, M. J.
Heterocycl. Chem. 1988, 25, 677.
Having optimized the reaction conditions we further
explored the scope of this transformation (Table 2).
The required propargylated pyridine substrates were
synthesized using the standard two-step procedure (see
Org. Lett., Vol. 13, No. 9, 2011
2287

Table 2. Cyclisation Reactions of N-Propargyl Aminopyridines
a The cyclizations of 3 to form 4 were performed using the following conditions: 3 (0.3 mmol), tBuOK (0.36 mmol), THF (3 mL), room temperature, 5
min (entries 2, 3, 5À7, 11, 12) or 50 °C/16 h (entries 1, 4, 8À10, 13). b Isolated yields after column chromatography.
Supporting Information), and these results will be dis-
cussed elsewhere. The cyclization step was carried out as
outlined in Table 1, employing tBuOK as a base in THF as
a solvent. Methyl derived pyridines, 3aÀ3d and 3i, af-
forded products 4aÀ4d and 4i in good yields (Table 2,
entries 1À4 and 9), but derivatives possessing a methyl
substituent close to the reacting moieties, at C(3) or C(6)
(3a, 3d, and 3i), required higher temperatures and longer
reaction times. This is not surprising since, due to steric
effects, they are likely to prevent the molecule from
adopting the planar (or near planar) conformation neces-
sary for the cyclization step to occur. Variation of sub-
stituents at C(5) did not influence the reaction significantly
(Table 2, entries 5À8 and 10À12), and all products were
isolated in yields ranging from 51 to 72%. Due to their
position the C(5) substituents are not expected to influence
the reaction sterically. On the other hand, their electronic
features may affect the process by altering the pyridine
nitrogen nucleophilicity. Therefore the higher reaction
temperatures and longer reaction times required for com-
pounds 3hÀ3j (Table 2, entries 8 and 10) could be attrib-
uted to the electronic effects of the C(5) substituents. The
base employed in all of these transformations, tBuOK,
proved to be compatible with potentially reactive func-
tionalities such as the pyridylhalide (Table 2, entries 5 and
6) or an R,β-unsaturated ester (Table 2, entry 8). Contrary
to the 3-methyl compound 3a, the derivative 3m possessing
bromine at the same position (Table 2, entry 13) did not
afford the expected product even at a higher temperature
and longer reaction time (70 °C, 16 h). This surprising
outcome is most likely a result of the stereoelectronic effect
of the bromine substituent. In order for the cyclization to
occur the propargyl group should be orientated toward the
pyridine nitrogen. This positions the Boc moiety close to
the C(3) substituent causing repulsive interactions of the
Br/O electron densities.
We also carried out several experiments in order to gain
further insight into the cyclization process. Attempts to
cyclize the unprotected aminopyridine 5 (Figure 2) using
either NaH or BuLi as a base did not result in product
formation. This result may suggest that the Boc removal
step probably does not precede the cyclization step.
Additionally, attempts to cyclize compound 6 (Figure 2),
possessing a methyl group on the alkyne terminus, failed as
well, although it is not clear at present whether this was
caused by the steric effects of an additional substituent or
by the absence of the terminal alkyne CÀH bond. We were
also unable to cyclize pyrimidine derivative 7 (Figure 2),
which possesses less nucleophilic nitrogens than the pyr-
idine derivatives discussed above. Finally, attempts were
2288
Org. Lett., Vol. 13, No. 9, 2011

made to monitor the cyclization reaction by 1H NMR, and
for this purpose we selected the transformation of 3d
leading to 4d. Although the majority of the reactions take
a few minutes, this one is slower, and when monitored by
TLC, the formation of an intermediate product was ob-
served. The reaction was carried out in DMSO-d6, and the
1H NMR was recorded immediately after mixing the
reactants in the solvent. Analysis of the spectrum showed
the disappearance of the terminal alkyne CÀH and the
CH2 groups completely, partial formation of the product,
and additional signals in the region δ 5.7À7.8, with a
distinctive doublet at δ 5.72.
Table 3. Variations of the N-Protecting Group
a The reactions were performed using the following conditions:
8 (0.3 mmol), tBuOK (0.36 mmol), THF (3 mL) at indicated tempera-
tures. b Isolated yields after column chromatography.
while the N-benzoyl derivative (Table 3, entry 3) produced
only a trace amount of the product. Contrary to these, the
N-acetyl substituent (Table 3, entry 2) was as efficient as
Boc in affording the product after just a few minutes in
68% yield.
In conclusion, a mild and efficient intramolecular
cyclization of the protected N-propargylated pyridine
derivatives leading to imidazo[1,2-a]pyridines has been
developed. The transformation affords the products under
basic conditions in good yields, in most cases at room
temperature. The stereoelectronic properties of the sub-
stituents on the pyridine ring were shown to influence the
cyclization process.
Figure 2. Reactivity of other derivatives.
These results suggest intermediate formation of the
allene via the alkyneÀallene isomerization promoted by
tBuOK as the first step.8 The isomerization may be
followed by the cyclization involving the allene/pyridine
nitrogen moieties9 and subsequent removal of the Boc
group.
The proposed cascade implies that the N-Boc function-
ality is not essential, and therefore some related N-protect-
ing groups were explored. When the Boc group was
replaced by the tosyl substituent (Table 3, entry 1) the
reaction resulted in the recovery of the starting material,
Acknowledgment. Financial support from the Serbian
Ministry of Science (Grant No. 172009) is greatly appre-
ciated. We thank the Faculties of Pharmacy and Chem-
istry, Belgrade University, for their assistance. We would
also like to thank Dr. A. E. A. Porter for fruitful
discussions.
(8) For a recent review, see: Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc.
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Landor, P. D.; Johnson, A.; Fomum, Z. T.; Mbafor, J. T.; Nkengfack,
A. E. J. Chem. Soc., Perkin Trans. 1 1988, 975.
Supporting Information Available. Experimental de-
tails. This material is available free of charge via the
Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 9, 2011
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