Synthesis of 2-Substituted Pyrazolo[1,5-a]pyridines through Cascade Direct Alkenylation/Cyclization Reactions

Article abstract of DOI:10.1021/ol902710f

[Chemical equation presented] The synthesis of 2-substituted pyrazolo[1,5-a]pyridines from N-iminopyridinium ylides is described. These medicinally interesting compounds are formed through a cascade process involving a palladium-catalyzed direct alkenylation reaction followed by silver-mediated cyclization. The reaction can be performed with a wide range of electron-poor and electron-rich alkenyl iodides in good yields. This work represents perhaps the most direct route for the preparation of these compounds.

Full text of DOI:10.1021/ol902710f

ORGANIC
LETTERS
2010
Vol. 12, No. 3
516-519
Synthesis of 2-Substituted
Pyrazolo[1,5-a]pyridines through
Cascade Direct Alkenylation/Cyclization
Reactions
James J. Mousseau, Ange´lique Fortier, and Andre´ B. Charette*
Department of Chemistry, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Quebec, Canada H3C 3J7
andre.charette@umontreal.ca
Received November 24, 2009
ABSTRACT
The synthesis of 2-substituted pyrazolo[1,5-a]pyridines from N-iminopyridinium ylides is described. These medicinally interesting compounds
are formed through a cascade process involving a palladium-catalyzed direct alkenylation reaction followed by silver-mediated cyclization.
The reaction can be performed with a wide range of electron-poor and electron-rich alkenyl iodides in good yields. This work represents
perhaps the most direct route for the preparation of these compounds.
Nitrogen-containing heterocycles continue to receive much
interest due to their ubiquity in Nature, as well as their
extensive presence as part of the skeletal backbone of many
therapeutic agents.1 Of these heterocycles, 2-substituted
pyrazolo[1,5-a]pyridines possess important biological activity
(Figure 1). Derivatives of these compounds have been shown
to be effective D3 and D4 agonists and antagonists.2
Consequently, they are applicable in the treatment of several
neurological disorders including schizophrenia, attention-
deficit disorder, and Parkinson’s disease.2 In addition, they
have been reported to exhibit potent antiherpetic and diuretic
activity due to their ability to act as adenosine agonists and
antagonists and may eventually be used in the treatment of
cardiac arrhythmias.3
Although there have been several accounts of pyrazolo[1,5-
a]pyridine synthesis, more often the resulting products possess
substitution at the 3-position.4 Substitution at the 2-position has
(3) (a) Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.;
Samano, V. A.; Ray, J. A.; Freeman, G. A.; Boyd, F. L., Jr.; Sexton, C. J.;
Selleseth, D. W.; Creech, K. L.; Moniri, K. R. Bioorg. Med. Chem. 2005,
13, 2397. (b) Akahane, A.; Katayama, H.; Mitsunaga, T.; Kato, T.;
Kinoshita, T.; Kita, Y.; Kusunoki, T.; Terai, T.; Yoshida, K.; Shiokawa,
Y. J. Med. Chem. 1999, 42, 779. (c) Kuroda, S.; Akahane, A.; Itani, H.;
Nishimura, S.; Durkin, K.; Kinoshita, T.; Tenda, Y.; Sakane, K. Bioorg.
Med. Chem. Lett. 1999, 9, 1979.
(1) (a) Zheng, G.; Dwoskin, L. P.; Deaciuc, A. G.; Zhu, J.; Jones, M. D.;
Crooks, P. A. Bioorg. Med. Chem. 2005, 13, 3899. (b) Wilson, K. J.; van
Niel, M. B.; Cooper, L.; Bloomfield, D.; O’Connor, D.; Fish, L. R.;
MacLeod, A. M. Bioorg. Med. Chem. Lett. 2007, 17, 2643. (c) Campeau,
L.-C.; Fagnou, K. Chem. Soc. ReV. 2007, 36, 1058. (d) Laird, T. Org.
Process Res. DeV. 2006, 10, 851.
(4) For selected examples of synthesis of 3-substituted pyrazolo[1,5-
a]pyridines, see: (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem.
Lett. 1999, 9, 97. (b) Stevens, K. L.; Jung, D. K.; Alberti, M. J.; Badiang,
J. G.; Peckham, G. E.; Veal, J. M.; Cheung, M.; Harris, P. A.; Chamberlain,
S. D.; Peel, M. R. Org. Lett. 2005, 7, 4753. (c) Valenciano, J.; Cuadro,
A. M.; Vaquero, J. J.; Builla, J. A.; Castan˜o, O. J. Org. Chem. 1999, 64,
9001.
(2) (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
2002, 12, 2377. (b) Hasen, J. B.; Weis, J.; Suzdak, P. D.; Eskesen, K. Bioorg.
Med. Chem. Lett. 1994, 4, 695. (c) Bettinetti, L.; Schlotter, K.; Hubner, H.;
Gmeiner, P. J. Med. Chem. 2002, 45, 4594.
10.1021/ol902710f  2010 American Chemical Society
Published on Web 01/07/2010

Scheme 1. Initial Synthesis of Pyrazolo[1,5-a]pyridines
found that altering the base from K2CO3 to Ag2CO3 led to
the formation of 2-phenylpyrazolopyridine 3a. In the crude
reaction mixture, no uncyclized product 4 was observed, and
only unreacted 1a along with 3a and benzoic acid, presum-
ably from the cleavage of the benzoyl moiety, were present.14
Cognizant of the biological relavance of these compounds,
we elected to optimize this transformation (Table 1). Screen-
Figure 1. Examples of biologically relevant 2-substituted pyra-
zolo[1,5-a]pyridines.
been reported with limited scope and often requires lengthy
syntheses, or is not possible without also including a group at
the 3-position.5 As such, the specific, site-selective synthesis
of 2-substituted pyrazolo[1,5-a]pyridines remains a synthetic
challenge.
Table 1. Selected Optimization of 2-Substituted
Pyrazolo[1,5-a]pyridine Synthesis
Direct functionalization processes have emerged as extremely
effective alternatives to traditional cross-coupling reactions.6 In
particular, whereas cross-coupling of both aryl electrophiles and
nucleophiles at the 2-position of pyridine has historically been
difficult, the direct arylation of pyridinium species has been
proven to be remarkably efficient.7 N-Iminopyridinium ylides
have emerged as versitile scaffolds whereby complex pyridine
derivatives can be prepared.8 We have demonstrated that these
activated pyridines can readily undergo a directed diastereose-
lective addition of Grignard reagents to yield 2,6-substituted
tetrahydropyridines,9 as well as asymmetric hydrogenation to
give substituted piperidines with high levels of enantioselec-
tivity.10 Perhaps more pertinant to this account, we have also
shown that they are amenable to direct arylation, and in the
case of 2-alkylpyridinium ylides, direct benzylic arylation
reactions.11 However, to date these ylides have not been applied
in cascade reactions. These processes have garnered much recent
attention due to the high efficiency and cost effectiveness of
performing several transformations within a single reaction
vessel.12 Herein we describe the synthesis of 2-substituted
pyrazolo[1,5-a]pyridines in two steps from pyridine through a
cascade direct alkenylation/cyclization reaction (Scheme 1).
During our work on developing a Pd-catalyzed direct
alkenylation13 reaction on N-iminopyridinium ylides we
entry
Pd
L
Ag
solvent yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 P(t-Bu)3
Pd(OAc)2 P(t-Bu)3
Pd(OAc)2 P(t-Bu)3
Pd(OAc)2 P(t-Bu)3
Pd2dba3
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
PdBr2
AgOTf PhMe
AgOAc PhMe
Ag2CO3 PhMe
AgOBz PhMe
AgOBz PhMe
AgOBz PhMe
AgOBz PhMe
AgOBz PhMe
0
13
45
50
31
52
59
60
63
46
64
63
69
80
P(t-Bu)3
P(t-Bu)3
PPh3
P(2-MePh)3
9
10
11
P(4-MeOPh)3 AgOBz PhMe
P(4-MeOPh)3 AgOBz DMF
P(4-MeOPh)3 AgOBz THF
P(4-MeOPh)3 AgOBz DME
P(4-MeOPh)3 AgOBz 1,4-diox.
P(4-MeOPh)3 AgOBz 1,4-diox.
12b PdBr2
13
PdBr2
PdBr2
14c
a The yield was determined by 1H NMR using 1,3,5-trimethoxybenzene
as an internal standard. b 1 equiv of ylide 1a was used. c 2 equiv of ylide
1a was used.
ing of the silver source determined that AgOBz was ideal
(entries 1-4). PdBr2 was found to be superior to other
sources of Pd (entries 4-6), and though the reaction was
found to be relatively insensitive to the phosphine ligand
employed (entries 6-9), P(4-MeOPh)3 was optimal. Finally,
etheral solvents (entries 10-12) were found to be superior
with 1,4-dioxane chosen due to its relative low volatility. A
slight increase in the loading of ylide 1a gave the optimal
reaction conditions (entry 13).
(5) (a) Takashi, T.; Haruki, S. J. Chem. Soc., Chem. Commun. 1980,
1109. (b) Csanyi, D.; Hajos, G.; Riedl, Z.; Timari, G.; Bajor, Z.; Cochard,
F.; Sapi, J.; Laronze, J.-Y. Bioorg. Med. Chem. Lett. 2000, 10, 1767. (c)
Johns, B. A.; Gudmundsson, K. S.; Turner, E. M.; Allen, S. H.; Jung, D. K.;
Sexton, C. J.; Boyd, F. L.; Peel, M. R. Tetrahedron 2003, 59, 9001. (d)
Nunez, A.; Garcia de Viedna, A.; Martinez-Barrasa, V.; Burgos, C.; Alvarez-
Builla, J. Synlett 2002, 1093. (e) Chen, Z.; Su, M.; Yu, X. Org. Biomol.
Chem. 2009, 7, 4641.
(6) For selected reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. ReV. 2007, 107, 174. (b) Miura, M.; Satoh, T. Top. Organomet.
Chem. 2005, 14, 55. (c) Satoh, T.; Miura, M. Chem. Lett. 2007, 36, 200.
(d) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (e) Seregin,
I. Y.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173. (f) Ellman, J. Science
2007, 316, 1131.
With these conditions in hand, we next explored the scope
of the reaction (Table 2). Both E and Z styryl iodides
Org. Lett., Vol. 12, No. 3, 2010
517

tolerated (entries 3 and 4) giving the desired products in good
yields, though slightly lower yields were noted with the
2-methylstyryl iodide presumably due to increased steric
hindrance. Electron-rich styryl iodides were operable (entries
5 and 6) as were electron-poor substrates (entries 7 and 8).
Chemoselectivity was noted with ꢀ-iodostyrenes bearing
halides on the aromatic moiety. As seen in entries 9 and 10,
the pyazolo[1,5-a]pyridines were obtained in good yield with
no evidence of arylation occurring on the phenyl group.
Furthermore, these substrates represent interesting scaffolds
whereby further structural elaboration can be performed.
Although alkenyl iodides bearing alkyl groups proved
ineffective in the transformation, those containing a cyclo-
propyl unit were quite reactive (entry 11), likely due to the
high s character of the cyclopropane ring. Finally, Z/E dienes
provided the corresponding product in moderate yield (entry
12). It should be noted that in call cases the crude reaction
mixture contains primarily the unreacted ylide and the desired
product. In cases where the observed yields were moderate,
no unreacted alkenyl iodides were noted, suggesting their
degradation during the course of the reaction.
Table 2. Synthesis of 2-Subsituted Pyrazolo[1,5-a]pyridines
through a Tandem Direct Alkenylation/Cyclization Reactiona
Next, we investigated the scope with regards to the
pyridinium ylide (Table 3). A nitrile group at the 4-position
Table 3. Scope of the Pyridinium Ylidea
a Reaction conditions: 1 (2 equiv), 2a (1.0 equiv), PdBr2 (5 mol %),
P(4-MeOPh)3 (15 mol %), AgOBz (3 equiv), 1,4-dioxane (0.2 M), 125 °C,
16 h. b Yield of isolated product.
a Reaction conditions: 1a (2 equiv), 2 (1.0 equiv), PdBr2 (5 mol %),
P(4-MeOPh)3 (15 mol %), AgOBz (3 equiv), 1,4-dioxane (0.2 M), 125 °C,
16 h. b Yield of isolated product.
provided the desired pyrazolo[1,5-a]pyridine (entries 1 and
2), though improved yields for the cascade were observed
with the E alkenes. Substitution on the aryl ring was well
of the pyridinium ring had little effect on the reaction (entry
1). In the case of 3-methyl-N-iminopyridinium ylide there
was a 3:1 preference of reaction at the less hindered site of
518
Org. Lett., Vol. 12, No. 3, 2010

the ring (entry 2). Isoquinolonium ylide 1d was operative,
and quinolonium ylide 1e proved to be exceptionally reactive
(entries 3 and 4). These results correlate with what was
observed in the previously reported direct arylation reaction
with exception of the 3-methylpyridinium, where complete
selectivity was noted.11a
carbonate silver compounds are required, it is thought that
this plays a role in the carbopalladation involving a concerted
metalation/deprotonation (CMD) sequence.15 Furthermore,
as PdBr2 is employed in the reaction in the presence of excess
silver, we cannot discount the possible formation of a more
reactive cationic Pd species. Reductive elimination (B) then
gives the alkenylated pyridinium which undergoes a cycliza-
tion (C). This transient intermediate is thought to exist as
when the 2-styrylpyridinium is subjected to the reaction
conditions 3a is obtained in 56% yield. Interestingly,
however, the application of Ag or Pd alone prove ineffective
in promoting the cyclization. Though Ag is known to
promote such cyclizations, the role of Pd in this process is
under investigation. Elimination of silver with dispropor-
tionation generates Ag(0) that is observed in the reaction
vessel (D). Rearomatization via the explusion of benzoyl
moeity (E) gives the observed product. This may also be
assisted by silver, explaining the requirement of 3 equiv of
AgOBz for the reaction to proceed.
We believe that the reaction proceeds as shown in Scheme
2. The first step involves oxidative addition of the Pd catalyst
Scheme 2. Proposed Reaction Pathway
In summary, we have described the synthesis of 2-sub-
stituted pyrazolo[1,5-a]pyridines in two steps from pyridine.
The products are obtained in good yields, and the process is
believed to proceed through a tandem direct alkenylation/
cyclization pathway. The full scope, mechanistic investiga-
tions, and applications toward the synthesis of complex
biologically relevant molecules is underway and will be
reported in due course.
Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC), Merck Frosst Canada & Co., Boehringer
Ingelheim (Canada), Ltd., the Canada Research Chair
Program, the Canada Foundation for Innovation, and the
Universite´ de Montre´al. J.J.M. is grateful to FQRNT for a
doctoral scholarship. We also thank Dr. James A. Bull
(Universite´ de Montre´al/Imperial College) for insightful
discussions.
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catalyst into the pyridinium ylide (A). Given that acetate/
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2009, 65, 4977.
Supporting Information Available: Experimental pro-
cedures, sample spectra, and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902710F
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