957
Pyrazolo[1,5-a]pyridines, due to being isosteric to
indole and purine, as well as increased metabolic stability,
are widely used in drug design. For example, they were
used to obtain anti-tuberculosis drugs,
1
EP1 receptor
antagonists,
2
kinase p38 inhibitors.
3
Developed in Japan
drug ibudilast, 2-methyl-1-[2-(propan-2-yl)pyrazolo-[1,5-a]-
pyridin-3-yl]propan-1-one, is an inhibitor of PDE4
phosphodiesterases and is used in the treatment of asthma
and post-stroke conditions.
4
Recently, ibudilast was consi-
dered as a promising agent for the treatment of multiple
sclerosis.
5
In modern medicinal chemistry, much attention is paid
to the introduction of fluorine atoms into organic
molecules.
6
Indeed, about a quarter of new small molecule
drugs approved by the FDA in 2015–2018 contain fluorine
atoms. Examples of the use of fluoropyrazolo[1,5-a]-
pyridine scaffold in the design of drugs for the treatment of
autoimmune diseases
7
and PI3K-γ kinase inhibitors were
reported.
8
The main methods for the preparation of
fluoropyrazolo[1,5-a]pyridine structures are annulation of
the pyrazole ring to the derivatives of N-aminopyridinium
salts
2,9,10
or direct fluorination of the pyrazole ring with N–F
reagents.
11
It is notably that the recently proposed method
for the fluorination of heterocyclic compounds by fluoro-
decarboxylation of the corresponding carboxylic acids by
the action of Selectfluor reagent
12
was successfully applied
to pyrazolo[1,5-a]pyridines.
7,8
The aim of this work was to study the process of
fluorination of 2,3-disubstituted pyrazolo[1,5-a]pyridines
with N–F reagents. Pyrazolopyridines 1a,b (Scheme 1),
which are easily synthesized by the reaction of dimethyl
acetylenedicarboxylate or methyl 3-phenylpropiolate with
pyridinium N-imine, were chosen as model compounds.
13
After adding 1.2 equiv of Selectfluor reagent to pyrazolo-
pyridine 1a,b in anhydrous MeCN, complete consumption
of the fluorinating reagent was observed. Further evapo-
ration of the reaction mixture in the presence of silica gel
and subsequent purification of the resulting product by
column chromatography on SiO
2
led to 3-fluoropyrazolo-
pyridines 2a,b (Scheme 1).
Chemistry of Heterocyclic Compounds 2020, 56(7), 957–960
Synthesis of 3-fluoropyrazolo[1,5-a]pyridines by fluorination
of methyl pyrazolo[1,5-a]pyridine-3-carboxylates
Sabina V. Alieva
1,2
, Aleksey Yu. Vorob'ev
1
*
1
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences,
9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; e-mail: vor@nioch.nsc.ru
2
Novosibirsk State University,
1 Pirogova St., Novosibirsk 630090, Russia
Submitted March 23, 2020
Accepted April 24, 2020
The reaction of methyl esters of pyrazolo[1,5-a]pyridine-2,3-dicarboxylic and 2-phenylpyrazolo[1,5-a]pyridine-3-carboxylic acids with
the fluorinating reagent Selectfluor gave 3-fluoropyrazolo[1,5-a]pyridine-2-carboxylic acid methyl ester and 3-fluoro-2-phenylpyrazolo-
[1,5-a]pyridine. Monitoring the progress of the reaction by
1
H NMR spectroscopy showed the formation of an intermediate fluorine-
containing σ-complex.
Keywords: pyrazolo[1,5-a]pyridines, Selectfluor, electrophilic fluorination.
Scheme 1
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2020, 56(7), 957–960
0009-3122/20/56(7)-0957©2020 Springer Science+Business Media, LLC
DOI 10.1007/s10593-020-02757-7