A copper-mediated cyclization reaction of hydrazine with enediynones providing pyrazolo[1,5-a]pyridines

Article abstract of DOI:10.1039/c0ob00756k

2,7-Disubstituted pyrazolo[1,5-a]pyridines were synthesized in good chemical yields by the reaction of enediynones with hydrazine, followed by addition of copper chloride. This reaction can tolerate many functional groups.

Full text of DOI:10.1039/c0ob00756k

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A copper-mediated cyclization reaction of hydrazine with enediynones
providing pyrazolo[1,5-a]pyridines†
Hung-Chou Wu,a Long-Chih Hwanga and Ming-Jung Wu*b
Received 21st September 2010, Accepted 15th November 2010
DOI: 10.1039/c0ob00756k
2,7-Disubstituted pyrazolo[1,5-a]pyridines were synthesized
in good chemical yields by the reaction of enediynones with
hydrazine, followed by addition of copper chloride. This
reaction can tolerate many functional groups.
Molecules that contain the pyrazolo[1,5-a]pyridine substructure
exhibit a broad spectrum of biological activities. For instance,
the 3-carboxypyrazolo[1,5-a]pyridines have been shown to be
potent and selective 5HT3-antagonists in vitro and in vivo.1
The 2,3-disubstituted pyrazolo[1,5-a]pyridines were evaluated as
potent p38 kinase inhibitors and exhibit good anti-inflammatory
activity2 while other substituted pyrazolo[1,5-a]pyridines exhibit
anti-herpetic activity3 and a series of aminomethyl-substituted
pyrazolo[1,5-a]pyridines were recently reported to be high affinity
D4 receptor ligands.4 However, synthetic methods to construct
the pyrazolo[1,5-a]pyridine skeleton are still limited. The most
general method is the regioselective [3+2] cycloaddition of N-
aminopyridines with alkenes5 or alkynes.6 Another method is the
thermal cyclization of pyridinyl aziridines.2a,7 In a continuation
of our study on the cyclization of enediynes to heterocycles,8 we
report herein a new method for the synthesis of pyrazolo[1,5-
a]pyridines by the reaction of enediynones with hydrazine medi-
ated by copper chloride.
The synthesis of enediynone 1a starting from commercially
available cis-1,2-dichloroethylene (2) is outlined in Scheme 1. The
palladium-catalyzed coupling reaction of 2 with 1-octyne (3a)
under reaction conditions reported in the literature9 gave vinyl
chloride 4a in 62% yield. Compound 4a was then coupled with
propargyl alcohol 5a under the same reaction conditions to give
enediynol 6a in 88% yield. Finally, oxidation of 6a with MnO2 gave
Scheme 1
enediynone 1a in 92% yield. Our first attempt at the cyclization
of enediynone 1a was the treatment of 1a with five equivalents of
(eqn (1)) None of the expected pyrazolo[1,5-a]pyridine adduct 8a
was observed. When the same reaction mixture was heated at reflux
with stirring for six days, pyrazolo[1,5-a]pyridine 8a was isolated
in 14% yield along with 7a in 73% yield. (eqn (2)) Although the
yield of the desired product is low, this result encouraged us to
continue the investigation of this cyclization reaction.
It has been demonstrated that copper(I) can catalyze the in-
tramolecular hydroamidation of alkynes.10 Therefore the copper(I)
catalysis of the cyclization of the enynylpyrazine 7a to the cascade
product 8a was investigated. Copper iodide has little effect on the
reaction, however copper chloride provided much more promising
results. When the reaction mixture of 1a and five equivalents
hydrazine in the presence of one equivalent of hydrogen chloride
in methanol at room temperature for six hours. The cyclization
product that was obtained was eneynylpyrazine 7a in 90% yield.
aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical
University, Kaohsiung, Taiwan
bDepartment of Chemistry, National Sun Yat-sen University, Kaohsiung,
Taiwan. E-mail: mijuwu@faculty.nsysu.edu.tw; Fax: +886-7-5253909
† Electronic supplementary information (ESI) available: Representative
experimental procedure and spectroscopic data for all newly synthe-
sized products. CCDC reference numbers 792989–792991. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob00756k
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Table 1 Cascade cyclization of enediynones to pyrazolo[1,5-a]pyridines
8a–m
of hydrazine along with four equivalents of copper chloride
were heated in refluxing acetonitrile for one day, pyrazolo[1,5-
a]pyridine 8a was obtained in 53% yield along with 9a in 32% yield.
(eqn (3)) The structure of 9a was unambiguously determined by
X-ray crystallography. (Fig. 1) This structure presented another
2
example of an (h -alkyne)-copper complex11 and it is apparently
the intermediate to the final product 8a. We therefore dissolved
9a in acetonitrile and heated the reaction mixture at reflux for
30 h. This led to the virtually complete conversion of 9a to 8a.
(eqn (4)) We then treated 1a with five equivalents of hydrazine and
four equivalents of copper chloride in refluxing acetonitrile for
30 h to give 8a in 90% yield.
Entry
Enediynones
Products/yields (%)
1
2
3
4
5
6
7
8
1a, R = C6H13
8a/75
8b/80
8c/74
8d/75
8e/13 (9e/72)
8f/69
1b, R = C4H9
1c, R = C5H11
1d, R = iso-butyl
1e, R = tert-butyl
1f, R = C6H5
1g, R = o-CH3C6H4
1h, R = m-CH3C6H4
1i, R = p-CH3C6H4
1j, R = o-CH3OC6H4
1k, R = m-CH3OC6H4
1l, R = p-CH3OC6H4
1m, R = p-NO2C6H4
8g/61
8h/46
8i/63
9
10
11
12
13
8j/73
8k/45
8l/73
8m/45
obtained in 80% and 74%, respectively. Compound 1d, which
contains a more sterically hindered iso-butyl group provided
product 8d in 75% yield.
Fig. 1 ORTEP drawing of complex 9a.
However when the substituent on the terminal alkyne is a
tert-butyl group, the yield of product 8e drops to 13%. The
major product isolated in this reaction is complex 9e. (Table 1,
entry 5). The structure of 9e was unambiguously determined by
X-ray crystallography as shown in Fig. 2. Unlike the complex
9a, complex 9e is a complex of a 1 : 1 ratio of copper with
enynylpyrazine. We also find that complex 9e is very stable. Heating
a solution of 9e in acetonitrile for two days led to very little
conversion to 8e and about 90% of 9e remains unchanged. On
the other hand, 2,7-diarylpyrazolo[1,5-a]pyridines 8f–m were also
prepared in modest to good yields (Table 1, entries 6–13). When
a phenyl ring bearing an electron-withdrawing group is on the
terminus alkyne, such as compound 1m, the desired pyrazolo[1,5-
a]pyridine 8m was obtained in 45% yield. (Table 1, entry 13) The
lower yield in this case could be due to the low electron density of
(3)
(4)
Although we have accomplished a cascade cyclization reaction
of enediynone 1a to pyrazolo[1,5-a]pyridine 8a in good chemical
yield, a liability of this process is the large amounts of hydrazine
and copper chloride that are needed. It is known that copper(I) or
(II) may form a complex with hydrazine and further decomposition
to copper particles.12 It is possible that this happens under the
previous conditions. In order to reduce the amount of hydrazine
and copper used in this reaction, we revised the reaction process
by addition of two equivalents of hydrazine to the acetonitrile
solution of 1a and heating the reaction mixture to 60 ◦C. This
reaction was monitored by TLC and was found that 1a was
completely converted to 7a within one hour. One equivalent of
copper chloride was added into the reaction mixture and it was
stirred at reflux temperature for 30 h. The pyrazolo[1,5-a]pyridine
8a was obtained in 75% yield after column chromatography on
silica gel. (Table 1, entry 1)
3
the triple bond to disfavor the formation of the (h -alkyne)-copper
complex.
After optimizing the reaction conditions, attention was turned
to the scope and limitations of the method. Thus, eneynones
1b–m were prepared according to the procedure outlined in
Scheme 1. All of the enynones were employed in the cascade
cyclization reaction under the optimal reaction conditions. The
results are summarized in Table 1. When enediynones containing
a straight chain alkyl group on the terminus of the alkyne, such as
compounds 1b and 1c, pyrazolo[1,5-a]pyridines 8b and 8c were
Fig. 2 ORTEP drawing of complex 9e.
The substituent effects on the other phenyl ring were also
examined. Enediynones 1n–r were synthesized using the procedure
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Table 2 Cascade cyclization of enediynones to pyrazolo[1,5-a]pyridines
8n–r
Acknowledgements
We thank the National Science Council of the Republic of China
for financial support.
Notes and references
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Entry
Enediynones
Products/yields (%)
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3
4
5
1n, R = C6H13; R¢ = OCH3
1o, R = C6H5; R¢ = OCH3
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95% yields. Treatment of 1n–r with two equivalents of hydrazine,
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reaction conditions provided pyrazolo[1,5-a]pyridines 8n–r in 42–
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In summary, we have developed a new synthetic method for 2,7-
disubstituted pyrazolo[1,5-a]pyridines in good chemical yields by
the reaction of enediynones with hydrazine promoted by copper
chloride. This reaction can tolerate many functional groups.
Since pyrazolo[1,5-a]pyridines are important heterocycles in both
pharmaceutical science and materials chemistry, we believe the
synthetic method described here may have a strong impact in
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672 | Org. Biomol. Chem., 2011, 9, 670–672
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The Royal Society of Chemistry 2011
©