Direct access to 2-aminopyrazolo[1,5-a]pyridines via N-amination/cyclization reactions of 2-pyridineacetonitriles

Article abstract of DOI:10.1016/j.tetlet.2014.08.087

We describe the straightforward synthesis of 6-substituted-2-aminopyrazolo[1,5-a]pyridines from 2-pyridineacetonitriles by N-amination with O-(mesitylsulfonyl)hydroxylamine and subsequent base-promoted cyclization. This N-amination/intramolecular cyclization reaction allows access to a variety of 6-substituted-2-aminopyrazolo[1,5-a]pyridines in a one-pot procedure, in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2014.08.087

Accepted Manuscript
Direct access to 2-aminopyrazolo[1,5-a]pyridines via N-amination/cyclization
reactions of 2-pyridineacetonitriles
Yosuke Nishigaya, Kentaro Umei, Eri Yamamoto, Yasushi Kohno, Shigeki Seto
PII:
S0040-4039(14)01440-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.08.087
TETL 45054
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 July 2014
5 August 2014
25 August 2014
Please cite this article as: Nishigaya, Y., Umei, K., Yamamoto, E., Kohno, Y., Seto, S., Direct access to 2-
aminopyrazolo[1,5-a]pyridines via N-amination/cyclization reactions of 2-pyridineacetonitriles, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.08.087
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Yosuke Nishigaya, Kentaro Umei, Eri Yamamoto, Yasushi Kohno, and Shigeki Seto*

1
Tetrahedron Letters
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Direct access to 2-aminopyrazolo[1,5-a]pyridines via N-amination/cyclization
reactions of 2-pyridineacetonitriles
Yosuke Nishigaya, Kentaro Umei, Eri Yamamoto, Yasushi Kohno, and Shigeki Seto*
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
We describe the straightforward synthesis of 6-substituted-2-aminopyrazolo[1,5-a]pyridines
from 2-pyridineacetonitriles by N-amination with O-(mesitylsulfonyl)hydroxylamine and
subsequent base-promoted cyclization. This N-amination/intramolecular cyclization reaction
allows access to a variety of 6-substituted-2-aminopyrazolo[1,5-a]pyridines in a one-pot
procedure, in moderate to good yields.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 2-aminopyrazolo[1,5-a]pyridine
Keyword_2
N-amination/cyclization
Keyword_3 2-pyridineacetonitrile
Keyword_4 medicinal chemistry programs
Keyword_5
The pyrazolo[1,5-a]pyridine scaffold is the focus of continued
scientific interest because therapeutic value has been
demonstrated for several pyrazolo[1,5-a]pyridine derivatives,
including phosphodiesterase inhibitors,1 cyclooxygenase
inhibitors,2 and adenosine A1 receptor antagonists.3,4 The recent
patent literature includes reports of some biologically active 2-
aminopyrazolo[1,5-a]pyridine derivatives (Fig. 1) for specific
targets.5,6 Despite the attractive features for medicinal chemistry
programs, general methods for the synthesis of 2-
aminopyrazolo[1,5-a]pyridines (1) have not yet received serious
attention.
position, it could be removed by heating under acidic
conditions.10,14,15
To test the feasibility of the sequential approach (that is, the
intermolecular cyclization of N-aminopyridinium salt with
malononitrile and the subsequent removal of C-3 substituent), we
investigated the synthesis of 6-chloro-2-aminopyrazolo[1,5-
a]pyridine (1b), in which we have a special interest for our drug
discovery program (Scheme 1A). Unfortunately, the reaction of
3-chloro-N-aminopyridinium salt (2b) with malononitrile
afforded low yields of chloro-2-aminopyrazolo[1,5-a]pyridine-3-
carbonitriles as the mixture of regioisomers 3ba and 3bb (0.7%
and 15%, respectively; path A, Scheme 1A).
A slight
improvement in yield was observed when malononitrile was
changed to ethyl 3-ethoxy-3-iminopropanoate (3% 4ba, 36%
4bb; path B, Scheme 1A). The desired isomer 4ba successfully
afforded the target compound 1b by the hydrolysis and the
subsequent decarboxylation. Unfortunately, however, the
regioselectivity problem of 4ba and 4bb on the intermolecular
cyclization still remains unresolved.
Figure 1. Some bioactive 2-aminopyrazolo[1,5-a]pyridines and
target compound (1).
We next focused on the intramolecular cyclization approach
starting from 2-pyridineacetonitriles (5). Suzue et al. disclosed
the synthesis of 2-aminopyrazolo[1,5-a]pyridine (1a) from 2-
pyridineacetonitrile (5a) through the cyclization of pyridine-2-
acetamidoxime with acetic anhydride, followed by deacetylation
in boiling hydrochloric acid in three steps with a 25% overall
yield.16 However, this reaction remains poorly valued
synthetically due to the low yield and the harsh reaction
conditions, which obstruct the general synthesis of 2-
aminopyrazolo[1,5-a]pyridines with divergent substituents.
Meanwhile, the N-amination/intramolecular cyclization reaction
of 2-alkynyl-pyridines for the construction of pyrazolo[1,5-
a]pyridine core has been published,17,18 however, there is no sign
Over the past several decades,
a variety of synthetic
approaches for pyrazolo[1,5-a]pyridine derivatives have been
successfully developed;7–9 among them, the intermolecular
cyclization reaction of N-aminopyridinium salt and alkyne or
alkene is one of the most powerful methods for the construction
of the pyrazolo[1,5-a]pyridine skeleton.7,10–12 In this context, Jung
et al. synthesized 3-cyano-2-aminopyrazolo[1,5-a]pyridine, using
the intermolecular cyclization between N-aminopyridinium salt
and malononitrile.13 Although such intermolecular cyclization
products usually have a carboxyl group or its isostere at the C3
∗ Corresponding author. Tel.: +81-280-2201; fax: +81-280-57-1293; e-mail: shigeki.seto@mb.kyorin-pharm.co.jp

2
Tetrahedron Letters
of the synthesis of 1 nor the use of a nitrile group for the
Table 1. Stepwise synthesis of 2-aminopyrazolo[1,5-a]pyridine (1a)
intramolecular cyclization reaction. We reasoned that in the
presence of O-(mesitylsulfonyl)hydroxylamine, the N-amination
of 5 could occur first to produce intermediate 6, which could then
undergo intramolecular cyclization to afford the target product 1
under basic condition (Scheme 1B). Herein, we disclose the N-
amination/cyclization reaction of 5 to directly provide 1 with
diverse functional groups at moderate to high yield in a mild two-
step, one-pot direct procedure.
The successful preparation of the desired product 1a from 2-
pyridineacetonitrile (5a) via aminopyridinium salt 6a promoted
us to conduct a two-step one-pot procedure using a sequential N-
amination/cyclization process without isolation of the
intermediate 6a (Table 2, entry 1). The process starts from the
treatment of 5a with O-(mesitylsulfonyl)hydroxylamine in
dichloromethane to yield N-amination intermediate. After
changing the solvent to methanol, the reaction was treated with
potassium carbonate and afforded 1a at an 88% yield.
We then synthesized
a
variety of substituted 2-
pyridineacetonitriles 5b–h, including novel compounds, via
nucleophilic aromatic substitution onto 2-halo-pyridines 7 with
sodium cyanoacetate24 (for 5b, 5c, 5g, method A), or
(cyanomethyl)lithium25 (for 5d, 5e, 5h, method B), and the
Scheme 1. (A) Initial challenges: intermolecular approaches. (B)
Our novel method for direct, one-pot synthesis.
nucleophilic substitution of 2-(halomethyl)pyridine
8 with
sodium cyanide26,27 (for 5f, method C), as shown in Scheme 2.
We began our investigation of the synthesis of 2-
aminopyrazolo[1,5-a]pyridine (1a) by a stepwise procedure
starting from 2-pyridineacetonitrile (5a). The N-amination
reaction19,20
(mesitylsulfonyl)hydroxylamine21,22
of
5a
with
freshly
afforded
prepared O-
1-amino-2-
(cyanomethyl)pyridinium mesitylsulfonate (6a) in good yield.
Considering the general synthesis of pyrazolo[1,5-a]pyridines by
the reaction of aminopyridinium salts and electron-deficient
alkynes,23 we examined the ring-closing reaction of 6a under
basic condition as shown in Table 1.
Scheme 2. Synthesis of substrates 5.
When 6a was treated with potassium carbonate in methanol
(MeOH), the reaction proceeded smoothly at room temperature
(rt) and afforded the desired cyclized product 1a at 92% yield
(entry 1). Changing the base to cesium carbonate or potassium
phosphate afforded 1a in moderate yields (64% entry 2, 56%
entry 3, respectively). An organic base such as 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) or triethylamine (Et3N) is
acceptable to provide 1a at good yield (89% entry 4, 90% entry 5,
respectively). With potassium carbonate as an appropriate base,
we next examined the solvent effect. The use of N,N-
dimethylformamide (DMF) or dimethyl sulfoxide (DMSO) as a
solvent provided good yields of the desired product 1a (91%
entry 6, and 83% entry 7, respectively), whereas 1,4-dioxane was
ineffective (42% entry 4), which shows that a polar solvent has a
positive influence on this transformation. The same solvent effect
was observed when methanol was replaced by dichloromethane,
using triethylamine as a base (90% for MeOH entry 5 vs. 66%
for CH2Cl2 entry 9).
With substrates 5b–h in hand, we investigated the scope of the
sequential N-amination/cyclization reaction of 5b–h (Table 2,
entries 2–8). In most cases, moderate to good yields of the
corresponding 2-aminopyrazolo[1,5-a]pyridines were delivered.
Notably,
a good yield of 2-amino-6-methoxypyrazolo[1,5-
a]pyridine (1f) was obtained for substrate 5-methoxy-2-
pyridineacetonitrile (5f) bearing a electron-donating group (90%,
entry 6). When 5-(trifluoromethyl)-2-pyridineacetonitrile (5g)
containing an electron-withdrawing group was subjected to this
transformation, a moderate yield (70%) of the desired product 1g
was achieved as well. When other 2-pyridineacetonitrile
derivatives bearing Cl, Br, I, or Me groups were applied to the
reaction, the desired products 1b–e were also obtained at
moderate yields (entries 2–5).

3
Table 2. Scope and limitations of N-amination/cyclization reactions
3
1) O-(mesitylsulfonyl)hydroxylamine,
CH2Cl2, rt, 1 h.
CN
R
5
R
NH2
N
N
2) K2CO3, MeOH, 0 oC, 1 h,
then rt, 1 h.
N
5
1
entry no. substrate
R
H
yield (%)
88
product (1)
1
2
5a
5b
1a
1b
NH2
Scheme 3. Plausible reaction pathway
Having developed a reliable method for the synthesis of 2-
aminopyrazolo[1,5-a]pyridines (1), we applied further
N
N
N
NH2
5-Cl
66
N
a
Cl
transformation (Scheme 4). We obtained 6-chloro-2-
hydroxypyrazolo[1,5-a]pyridine (9) when 1b was treated with
50% aq. H2SO4 at 100°C for 2 h. We also performed the
alkylation of the amino group by the treatment of 1b with bis(2-
chloroethyl)ether in the presence of N,N-diisopropylethylamine
in DMF at 110°C for 2 h, to provide morpholine 10.
NH2
NH2
NH2
3
4
5
5c
5d
5e
5-Br
5-I
1c
1d
1e
83*
51
N
N
N
N
N
N
Br
I
5-Me
51
Me
NH2
NH2
6
7
5f
5-OMe
5-CF3
1f
90
70
N
N
N
N
MeO
F3C
5g
1g
Me
NH2
8
5h
3-Me, 5-Br
1h
50
N
N
Br
Scheme 4. Derivatization of 1b
* DMF was used instead of MeOH for the second step reaction .
In conclusion, we established a simple and general method for
the preparation of 6-substituted-2-aminopyrazolo[1,5-a]pyridines
(1) starting from 2-pyridineacetnitriles (5) by using the N-
amination/cyclization reaction. This reaction occurs in a two-step
one pot procedure. This new synthetic approach could be applied
to the synthesis of a variety of substituted-2-aminopyrazolo[1,5-
a]pyridines that must be useful for new building blocks for
medicinal chemistry programs.
A plausible reaction pathway is shown in Scheme 3. The
pyridine 5a reacts with O-(mesitylsulfonyl)hydroxylamine to
form N-aminopyridinium salt 6a, which undergoes a base-
promoted intramolecular cyclization reaction to provide 2-
aminopyrazolo[1,5-a]pyridine as imine–amine equilibrium (1a’
and 1a).
10. Boekelheide, V.; Fedoruk, N. A. J. Org. Chem. 1968, 33, 2062–
2064.
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∗ Corresponding author. Tel.: +81-280-2201; fax: +81-280-57-1293; e-mail: shigeki.seto@mb.kyorin-pharm.co.jp

4
Tetrahedron
(mesitylsulfonyl)hydroxylamine (MSH) be prepared
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(mesitylsulfonyl)oxyacetimidate and perchloric acid in
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Minamikawa, J.; Ikeda, M. Synthesis, 1977, 1.
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Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
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