Solid-Phase Synthesis of Imidazo[1,2-a]pyridine Using Sodium Benzenesulfinate as a Traceless Linker

Article abstract of DOI:10.1021/ol026797b

(equation presented) The preparation of the first library of imidazo[1,2-a]pyridine derivatives on a solid support is described. A sulfone linker strategy was applied in the synthesis. Key steps involved in the solid-phase synthetic procedure include (i)

Full text of DOI:10.1021/ol026797b

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3935-3937
Solid-Phase Synthesis of
Imidazo[1,2-a]pyridine Using Sodium
Benzenesulfinate as a Traceless Linker
Yu Chen, Yulin Lam,* and Yee-Hing Lai
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlamyl@nus.edu.sg
Received August 27, 2002
ABSTRACT
The preparation of the first library of imidazo[1,2-a]pyridine derivatives on a solid support is described. A sulfone linker strategy was applied
in the synthesis. Key steps involved in the solid-phase synthetic procedure include (i) r-haloketone resin formation by sulfinate f sulfone
alkylation, (ii) imidazo[1,2-a]pyridine ring formation by treatment with 2-aminopyridine, (iii) sulfone anion alkylation, and (iv) traceless product
release by oxidation−elimination. A library of 12 imidazo[1,2-a]pyridines was synthesized.
Central to the effective application of solid-phase organic
synthesis (SPOS) is the choice of linker, through which the
reactive intermediates are attached to the solid support and
from which the target molecules can be efficiently cleaved
from the resin.1 Methods of immobilizing compounds to the
solid phase for combinatorial synthesis initially relied upon
traditional solid-phase peptide linkers, which resulted in the
release of carboxylic acids, esters, or amides from the ester-
or amide-bound substrate.2 Immobilization techniques that
afford alternative residual functional groups are highly
desirable. In this regard, one of our interests is to develop
the sulfone linker via polymer-bound sodium benzene-
sulfinate 1 and explore new applications for it in SPOS.
Sodium benzenesulfinate has been widely used in the
preparation of sulfone, which plays an important role in
organic synthesis,3 but the application of 1 in solid-phase
synthesis has received relatively less attention. Previous
reports from other laboratories4,5 and ours6 have demonstrated
the use of 1 as a solid support for SPOS and shown the
resulting sulfone linker derived from 1 to be a versatile and
robust tether that offers various on-resin functionalization
or cleavage with additional changes.
Imidazo[1,2-a]pyridine moieties represent important build-
ing blocks in both natural and synthetic bioactive compounds,
which have been shown to possess diverse therapeutic
activities.7 Hence they are interesting targets in the develop-
ment of new drug leads. A large number of solution-phase
synthetic pathways are available for the preparation of
imidazo[1,2-a]pyridines but, to our knowledge, there have
been no previous reports on the solid-phase synthesis of these
(4) (a) Cheng, W. C.; Wong, M.; Olmstead, M. M.; Kurth, M. J. Org.
Lett. 2002, 4, 741-744. (b) Cheng, W. C.; Lin, C. C.; Kurth, M. J.
Tetrahedron Lett. 2002, 43, 2967-2970. (c) Cheng, W. C.; Olmstead, M.
M.; Kurth, M. J. J. Org. Chem. 2001, 66, 5528. (d) Cheng, W. C.; Halm,
C.; Evarts, J. B.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1999, 64,
8557. (e) Halm, C.; Evarts, J.; Kurth, M. J. Tetrahedron Lett. 1997, 38,
7709-7712
(5) (a) Huang, W.; Cheng, S.; Sun, W. Tetrahedron Lett. 2001, 42, 1973-
1974. (b) Farrall, M. J.; Frechet, J. M. J. Org. Chem. 1976, 41, 3877. (c)
Fyles, T. M.; Leznoff, C. C. Can J. Chem. 1976, 54, 935. (d) Fyles, T. M.;
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2157.
(2) Bunin, B. A. The Combinatorial Index; Academic Press: San Diego,
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Oxford, 1993.
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10.1021/ol026797b CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

compounds. Herein, we describe the utilization of 1 as a
linker for the synthesis of imidazo[1,2-a]pyridine derivatives.
Key steps in the synthesis of imidazo[1,2-a]pyridines from
1 include (i) R-haloketone resin formation by sulfinate f
sulfone alkylation, (ii) imidazo[1,2-a]pyridine ring formation
by treatment with 2-aminopyridines, (iii) sulfone anion
alkylation with epoxides, and (iv) traceless product release
by oxidation-elimination (Scheme 1). Since a variety of
Scheme 2. Solution-Phase Study
Scheme 1. Sulfinate SPOS to Imidazo[1,2-a]pyridine
reagents can be used in steps ii and iii, the overall strategy
appears to be applicable for library generation.
Solution-Phase Synthesis of Imidazo[1,2-a]pyridine. In
a preliminary solution-phase study, two reaction systems
were analyzed for step i (Scheme 2). Treatment of sodium
benzenesulfinate 7 with 1,3-dichloropropan-2-one in the
presence of NBu4HSO4 and CH3CN at room temperature
gave 1-benzenesulfonyl-3-chloropropan-2-one 8a and the
undesired product, 1,3-bis-benzenesulfonylpropan-2-one, 9
in 64 and 15% yields, respectively. However, replacement
of NBu4HSO4/CH3CN with NBu4I/KI/DMF resulted in
almost quantitative formation of 8a and 1-benzenesulfonyl-
3-iodopropan-2-one 8b and only traces of 9. Refluxing a 1
equiv mixture of 8a and 8b with 2 equiv of 2-amino-5-
chloropyridine in anhydrous DME gave 2-benzenesulfonyl-
methyl-6-chloroimidazo[1,2-a]pyridine 10 in 66% yield.
Attempts to R-alkylate 10 with 2-bromoacetophenone under
various conditions (NaOEt/THF, NaOEt/MeOH/DMF, BuLi/
HMPA/THF, K2CO3/DMF, or NaH/NBu4Br/DMF) did not
provide the desired 3-benzenesulfonyl-3-(6-chloroimidazo-
[1,2-a]pyridin-2-yl)-1-phenylpropan-1-one 11, and compound
10 was recovered. To effect the formation of 11, compound
10 was treated with epoxystyrene according to the procedure
of Kurth and co-workers4b to provide 12. Subsequent
oxidation with the Jones reagent8 gave 11, which was not
very stable and thus immediately treated with 10% NaOH
to give 6j in 85% yield. Oxidation of 12 via the Swern
oxidation gave less clean products, although the reaction
proceeded with concomitant elimination of the sulfone linker.
Solid-Phase Synthesis of Imidazo[1,2-a]pyridine.
With the solution-phase synthetic pathway to imidazo[1,2-
(7) (a) Amin, K.; Dahlstrom, M.; Nordberg, P.; Starke, I. Patent WO
001000, 2000. (b) Farrerons Gallemi, C.; Miquel Bono, I. J.; Fernandez
Serrat, A. M.; Monserrat Vidal, C.; Lagunas Arnal, C.; Gimenez Guasch,
F.; Fenandez Garcia, A. Patent WO 0008024, 2000. (c) Gueiffier, A.;
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Blache, Y.; Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med. Chem. 1996,
39, 2856-2859. (d) Silvestre, J.; Leeson, P. A.; Castaner, J. Drugs Fut.
1998, 23, 598-601. (e) Hamdouchi, C.; Blas, J.; Prado, M.; Gruber, J.;
Heinz, B. A.; Vance, L. J. Med. Chem. 1999, 42, 50-59.
(8) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem.
Soc. 1953, 2548-2560.
3936
Org. Lett., Vol. 4, No. 22, 2002

a]pyridine established, we proceeded to develop the solid-
phase route to these compounds. Sodium benzenesulfinate
resin 1 in NBu4I/KI/DMF was allowed to react with 1,3-
dichloro-propan-2-one at room temperature (Scheme 1). The
formation of the supported R-haloketones 2a and 2b could
be monitored by KBr FTIR for the appearance of a new
carbonyl stretch (νmax, 1740 cm-1). Treatment of 2a or 2b
with substituted 2-aminopyridines in anhydrous DME af-
forded the imidazo[1,2-a]pyridine resin 3. This transforma-
tion was monitored by FTIR for the disappearance of the
carbonyl stretch. Alkylation of resin 3 with epoxides gave
resin 4, which could not be reliably analyzed by FTIR.
Hence, we proceeded to oxidize resin 4 with Jones reagent
followed by sulfinate elimination with 10% NaOH to release
the target molecule from the solid support. To illustrate the
versatility of this chemistry, a library of 12 compounds (6a-
efforts to eventually obtain 6f and 6l. However, we found
that the reaction proceeds with cis-2,3-epoxybutane but not
with trans-2,3-epoxybutane. This may presumably be due
to the greater steric hindrance in trans-2,3-epoxybutane.
In addition to the alkylation via sulfone anion epoxide-
opening reaction, we have also examined the use of chloro-
methyltrimethylsilane as an alkylating agent (Scheme 3).4b
Scheme 3. Alkylation via â-Silyl Sulfone Formation
1
l) was prepared (Figure 1). H NMR analysis of these
Resin 3 was allowed to react with dimsyl anion (5 equiv)
followed by chloromethyltrimethylsilane (10 equiv) in THF.
The formation of the â-silyl sulfone resin 13 was easily
monitored for the appearance of a new Si-C stretch by KBr
FTIR (νmax, 1249 cm-1). The product 14 was cleaved from
the resin by treatment with TBAF/THF to provide an overall
yield of 15-23%.
In summary, we have developed the first example of a
solid-phase synthesis of imidazo[1,2-a]pyridines. The use of
a sulfone moiety as a linker in the reaction benefits the solid-
phase synthetic route as it not only makes isolation of the
product easier but its chemical versatility also adds to the
diversity of the library.
Figure 1. Library of Imidazo[1,2-a]pyridines.
Acknowledgment. We thank the National University of
Singapore for financial support of this work.
compounds indicates that only the (E)-stereoisomer was
obtained (J ) 15.6 Hz and NOESY data). Except for 6f and
6l, the overall yields of all other compounds were 17-26%
(purities >95% by NMR), indicating an average yield of
greater than 70% for each step of the five solid-phase
reactions.
Supporting Information Available: Detailed experi-
mental procedure, NMR and MS data of all compounds, and
1H and 13C NMR spectra of 6a, 6f, 6j, and 14b. This material
is available free of charge via the Internet at http://pubs.acs.org.
For the alkylation of resin 3 with epoxides, we have used
both cis-2,3-epoxybutane and trans-2,3-epoxybutane in our
OL026797B
Org. Lett., Vol. 4, No. 22, 2002
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