Copper-mediated oxidative [3 + 2]-annulation of nitroalkenes and pyridinium imines: Efficient synthesis of 3-fluoro- A nd 3-nitro-pyrazolo[1,5-: A] pyridines

Article abstract of DOI:10.1039/c9ob02668a

An efficient route to pyrazolo[1,5-a]pyridines by Cu(OAc)₂-promoted oxidative [3 + 2]-annulation of nitroalkenes with in situ generated pyridinium imines is developed. The reaction with α-fluoronitroalkenes enables the first preparative synthesis of 3-fluoro-pyrazolo[1,5-a]pyridines. Cycloaddition with α-unsubstituted nitroalkenes provides access to 3-nitro-pyrazolo[1,5-a]pyridines in excellent yields. A broad transformation scope was demonstrated. Both electron-rich and electron-deficient nitroalkenes as well as different aminopyridinium salts can be used for the assembly of the target pyrazolo[1,5-a]pyridines. The related aza-heterocycles, namely, pyrazolo[1,5-a]pyrazines and pyrazolo[1,5-b]pyridazines, were successfully prepared via the present methodology. The possible mechanism of the reaction is discussed.

Full text of DOI:10.1039/c9ob02668a

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Tabolin, Y. V. Nelyubina, V. Nenajdenko and S. Ioffe, Org. Biomol. Chem., 2020, DOI:
10.1039/C9OB02668A.
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21 December 2017
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C9OB02668A
ARTICLE
Copper-mediated oxidative [3+2]-annulation of nitroalkenes and
pyridinium imines: efficient synthesis of 3-fluoro- and 3-nitro-
pyrazolo[1,5-a]pyridines
Received 00th January 20xx,
Accepted 00th January 20xx
Vladimir A. Motornov,a,b Andrey A. Tabolin,*a Yulia V. Nelyubina,c Valentine G. Nenajdenko,d Sema
L. Ioffea
An efficient route to pyrazolo[1,5-a]pyridines by Cu(OAc)2-promoted oxidative [3+2]-annulation of nitroalkenes with in situ
generated pyridinium imines was developed. The reaction with α-fluoronitroalkenes provides the first preparative
synthesis of 3-fluoro-pyrazolo[1,5-a]pyridines. The cycloaddition with α-unsubstituted nitroalkenes opens access to
3-nitro-pyrazolo[1,5-a]pyridines in excellent yields. Broad scope of transformation was demonstrated. Both electron-rich
and electron-deficient nitroalkenes as well as different aminopyridinium salts can be used for the assembly of target
pyrazolo[1,5-a]pyridines. The related aza-heterocycles, namely, pyrazolo[1,5-a]-pyrazines and pyrazolo[1,5-b]pyridazines
were successfully prepared via the present methodology. Possible mechanism of the reaction is discussed.
DOI: 10.1039/x0xx00000x
efficient synthesis of α-fluoronitroalkenes,14 a promising type
of monofluorinated building blocks.15 Particularly, they behave
as useful synthetic equivalents of fluoroalkynes in the
Introduction
Pyrazolo[1,5-a]pyridines are medicinally relevant heterocycles1
featuring anti-inflammatory drug Ibudilast that has found
application for treatment of asthma and stroke (Figure 1).
These heterocycles were shown to possess wide range of
biological activity, such as antiviral (hepatitis C,2 herpex3),
hypnotic,4 diuretic,5 and antipsychotic,6,7 Pyrazolo[1,5-
a]pyridines are considered as indole bioisosteres8 having
higher metabolic stability. Therefore, their chemistry attracts a
lot of attention.
synthesis of fluorinated heterocycles.16-19
O
Ibudilast
O
N
(KetasTM
)
treatment of
OH
asthma and stroke
N
N
N
N
H
N
FK 453
diuretic
The most general route for the construction of
pyrazolopyridine core is the [3+2]-annulation reaction9
between pyridine-N-imines and electron-deficient alkynes,
bearing carbonyl or ester groups (Scheme 1).10,11 Similar
approach based on Pd-mediated oxidative cycloaddition
between N-benzoyliminopyridines and alkenyl halides has
been proposed recently to prepare 3-unsubstituted
pyrazolo[1,5-a]pyridines using silver salt as an oxidant.12
However, selectively substituted derivatives of pyrazolo[1,5-
a]pyridine and especially fluorinated ones are hardly accessible
via [3+2]-cycloaddition because of low stability/availability of
the corresponding alkynes.13 Recently, we have reported
N
N
Cl
O
N
N
F
N
N
N
O
CF3
HN
N
OH
hepatitis C virus
H
replication inhibitor
GW3733
H
herpes simplex viruses
replication inhibitor
Figure 1. Bioactive pyrazolo[1,5-a]pyridines.
Nowadays, organofluorine chemistry is one of the most
important fields of organic chemistry.20 Unique properties of
fluorinated compounds made them intensively exploited in
pursuit of new construction materials, components of liquid
crystalline compositions, agrochemicals and pharmaceuticals.
About 20-25% of currently used drugs and agrochemicals
contain at least one fluorine atom.21 Fluorinated heterocycles
are of special interest for medicinal chemistry and drug
a.N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
Leninsky prosp. 47, Moscow, 119991, Russia. E-mail: tabolin87@mail.ru
b.Higher Chemical College, D. I. Mendeleev University of Chemical Technology of
Russia, Miusskaya sq. 9, Moscow 125047, Russia.
c. A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of
Sciences, Vavilov str. 28, Moscow, 119991, Russia.
d.Department of Chemistry, M. V. Lomonosov Moscow State University, Leninskie
Gory 1, Moscow 119991, Russia.
Electronic Supplementary Information (ESI) available: [Experimental data, copies of
NMR spectra, CIF-files]. See DOI: 10.1039/x0xx00000x
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Journal Name
was unchanged. To our delight, simple heating VtiehweArrtieclaecOtniolinne
DOI: 10.1039/C9OB02668A
mixture up to 55°C was sufficient to obtain complete
Previous reports:
R
EWG
R'
EWG
conversion. Under these conditions high yield of target
product 3a was detected after 6 h of reaction (Scheme 2).
Other solvents studied gave lower yields. Application of higher
temperature (70°C) resulted in acceleration of the process,
however, yield of 3a dropped down to 41%. In the absence of
copper salt no consumption of starting nitroalkene 1a was
observed indicating its necessity for the reaction.
Base, [O]
R
R
N
N
N
R'
X-
N
EWG = COR'', CO2R''
NH2
R
H
X
[Pd], PR3
R'
R'
AgOBz,
1,4-dioxane
N
N
X = I, Br
NBz
This work:
R
F
F
novel fluorinated
pyrazolo[1,5-a]pyridines
NO2
Ar
N
N
up to 85%
Cu(OAc)2·H2O,
2,6-lutidine
N
DCE, 55°C
NO2
Br-
NH2
R
H
Ar
Scheme 2 Initial findings and screening of the reaction conditions. Yields were
determined by 19F NMR with internal standard (C6F6).
N
N
NO2
up to 93%
Scheme 1 Approaches to the synthesis of various pyrazolo[1,5-a]pyridines via [3+2]-
With these reaction conditions in hand, the scope of this new
reaction was investigated (Scheme 3). First, the influence of
annulation
the nature of fluoronitrostyrenes
number of alkenes possessing electronically different
substituents was tested in the reaction with
1 was studied. Thus, a
design.22 However, despite pharmaceutical attractiveness of
3-fluoro-pyrazolo[1,5-a]pyridines, currently only very rare
examples of synthesis of these compounds can be found in
patent literature. Direct fluorination of some pyrazolo[1,5-
a]pyridines by Selectfluor has been used for this aim, however
only low yields were demonstrated.23 As a result, new efficient
methods for the preparation of fluorinated pyrazolo[1,5-
a]pyridines are highly demanding since the direct fluorination
has a significant drawback of functional group tolerance.
1
N-aminopyridinium bromide 2a (Scheme 3). Gratifyingly, the
reaction appeared to be very general working perfectly with
nitrostyrenes having either electron rich- or electron poor aryl
ring to produce the desired products in high isolated yields up
to 85%. Electron-neutral substrates (4-chlorophenyl-, 4-
bromophenyl-,
4-fluorophenyl
and
p-tolyl-substituted
examples) gave the corresponding pyrazolopyridines 3a-3d in
good yields after 6-12 hours at 55°C. Electron-deficient
4-methoxycarbonyl- and 4-CF3-substituted fluoronitroalkenes
Herein we report new convenient method for the synthesis of
3-fluoro-pyrazolo[1,5-a]pyridines
via
copper-mediated
oxidative [3+2]-annulation strategy and study of applicability
of this approach to the synthesis of 3-nitro-pyrazolo[1,5-
a]pyridines.
1e,f afforded the products 3e,f in shorter time albeit in slightly
lower yields. On the contrary, electron-rich 4-methoxyphenyl
and 3,4-dimethoxyphenyl-substituted nitroalkenes afforded
the products 3g,h after prolonged heating (26-28 hours),
however, excellent yields were obtained. Meta- as well as
sterically hindered ortho-substituted nitroalkenes also gave
corresponding products 3i,j in good yields. The synthesis of
pyrazolopyridines is scalable as was demonstrated for 3 mmol
(0.5 gram) of 3b with no loss in yield.
Results and discussion
Copper(II)-mediated oxidative annulation reactions are useful
tool for the preparation of indolizines and related pyridine-
annulated heterocycles.24 Recently we have described a
method for the synthesis of indolizines based on oxidative
annulation between nitroalkenes and pyridinium ylides
mediated by the mild copper diacetate/lutidine system.17 We
expected that annulation of nitroalkenes with pyridine-N-
Next, the scope of aminopyridinium salts
2
was studied.
the
4-Methyl-aminopyridinium bromide afforded
corresponding 5-substituted pyrazolopyridine 3k in 48% yield.
Godd yields were also achieved for ester (3l) and 1,3-dioxolan-
2-yl- (3m) substituted substrates. Moreover, isonicotinate
derivative 3l did not require elevated temperature for the
preparation. Various regioselectivitites were observed for 3-
substituted pyridinium salts. In the case of 3-bromo-
substituted pyridinium salt the product 3n was obtained in
high yield, though prolonged heating at 65°C was necessary to
achieve complete conversion. It was found that the reaction
proceeds regioselectively to give 4-substituted isomer 3n with
imines can proceed in
conditions. We initiated our study with the model reaction
between fluoronitroalkene 1a and aminopyridinium salt 2a
a similar manner under these
.
However, target pyrazolo[1,5-a]pyridine 3a was obtained in
only 3% yield when the conditions we previously described for
indolizine synthesis (DCE, Cu(OAc)2∙H2O, 2,6-lutidine, 0°C-rt)
were used. It was found that the reaction proceeds much
more slowly and main amount of the starting nitroalkene 1a
2 | J. Name., 2012, 00, 1-3
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minor amonts (12%) of 6-substituted isomer. We believe that
electronic factors rather than steric hindrance determine the
regioselectivity of cyclization in this case similarly to the
synthesis of indolizines.17,25 The reaction with 3-methyl-1-
aminopyridinium bromide afforded mixture of two
regioisomeric pyrazolopyridines 3o/3o’ in 3:1 ratio, with the
preference of formation of 4-substituted isomer 3o similar to
previously described synthesis of indolizines.17 In contrast,
electron withdrawing ester group in m-position gave 6-
substituted pyrazolo[1,5-a]pyridine 3p as major product.
Additionally in this cases diminished chemoselectivity was
observed as corresponding 3-nitro-substituted product 5g was
isolated in substantial yield of 20% (see also discussion of
mechanism). Unfortunately, amino-substituted pyridinium
salts (p-Me2N, p-BocNH, m-CH2NHAc) failed to give desired
View Article Online
DOI: 10.1039/C9OB02668A
R
F
Cu(OAc) ·H O
(1.5 eq2uiv.2)
Ar
F
R
Ar
2,6-lutidine
(5 equiv.),
DCE, MS4Å, 55°C
N
N
An-
N
NO2
NH2
1
3
2
An = Br or OTs
(2 equiv.)
, X = Cl, 73%, 6 h
3a
F
, X = Br, 67%, 6 h; (74%, 20 h)a
3b
3c
3d
3e
3f
3g
(X-ray)
, X = F, 78%, 6 h
X
, X = Me, 79%, 12 h
, X = CO Me, 65%, 9 h
N
N
2
, X = CF , 68%, 3.5 h
3
, X = OMe, 85%, 26 hb
F
F
OMe
OMe
OMe
N
N
N
N
products
3. Also, the attempts to prepare 8-substituted
, 81%
3h
, 64%
3i
7 h
pyrazolo[1,5-a]pyridines from 2-substituted aminopyridinium
salts were unsuccessful, as these salts were found unreactive
even at 80°C.
28 hb
F
F
Cl
Me
1
The structures of obtained products were supported by H
Ar
and 13C NMR spectra (including 2D) as well as by HRMS data.
For the p-bromophenyl derivative 3b single crystal X-ray
analysis was also performed (Figure 2).26
N
N
N
N
, Ar = 4-BrC H -,
3k
6
4
, 80%
8 h
3j
48%
5 h
O
F
F
EtO2C
O
Ar
Ar
N
N
N
N
, Ar = 4-BrC H -,
3m
, Ar = 4-BrC H -,
85%
6 h at r.t.
3l
6
4
6
4
68%
21 h
F
Br
Me
4
F
F
+
Ar
6
Ar
Ar
N
N
N
N
Me
N
N
, Ar = 4-BrC H -,
3n
6
4
3o
3o'
84%
36 hc
Ar = 4-BrC6H4-,
= (3:1)
total yield 67%, 4 h
:
3o 3o'
F
NO2
N
F
Ar
MeO2C
4
Ar
Ar
+
+
N
N
N
N
N
6
MeO2C
6
MeO2C
3p
3p'
Ar = 4-BrC6H4-,
= (2.6:1:1.7)
5g
:
:
3p 3p' 5g
total yield 64%, 2.5 h
Scheme
3
Synthesis of 3-fluoro-pyrazolo[1,5-a]pyridines
3
from different
fluoronitroalkenes 1 (0.08-0.25 mmol) and aminopyridinium salts 2. Yields refer to
isolated products 3. aYield for the reaction on 3 mmol scale in brackets. b 2.3 equiv. of 2
was used. c Reaction at 65°C .
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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unexpected result was obtained for the reaction with tert-
View Article Online
DOI: 10.1039/C9OB02668A
butyl-substituted nitroalkene 4e, where 2-unsubstituted 3-
nitro-pyrazolopyridine 5e was isolated in 85% yield.
Apparently, the loss of tert-butyl group took place. The
mechanism of this transformation was not studied in detail,
however most probably elimination of t-Bu cation takes place
and this observation is in agreement with the mechanism
discussed below. Another peculiarity was observed for
nicotinic ester-derived products 5g,h. While the regiochemical
outcome was similar to products 3p providing 6-carbmethoxy
Figure 2 General view of the compound 3b in representation of atoms via thermal
products
5, the chemoselectivity was diminished due to
ellipsoids at 50% probability level.
denitration and formation of 3-unsubstituted derivatives 6a,b
.
Annulation of α-chloronitroalkenes with pyridinium imines is
of special interest. Elimination of either HCl or HNO2 may be
expected affording nitro- or chloro-substituted heterocycles,
R'
NO2
Cu(OAc)2·H2O
H
R
(1.5 equiv.),
+
2,6-lutidine (5 equiv.),
DCE, MS4Å, 55°C
R'
R
N
An-
N
respectively.27 It was found that the reaction of nitroalkene
with the salt 2a afforded mixture of nitrated pyrazolopyridines
5c with minor amount of 3-chloro-pyrazolopyridine (Scheme
7
NO2
N
NH2
5
4
2
8
An = Br or OTs
(2 equiv.)
5). Therefore, elimination of HCl proceeds preferably. We
decided to demonstrate importance of leaving group for the
reaction using bromo-substituted substrate. As expected, the
NO2
NO2
Ph
X
reaction with α-bromonitroalkene
9
proceeded 100%
N
N
N
N
chemoselectively to form nitro-derivative 5c as single
product.28
, X = Cl, 88%, 2 h
, X = H, 93%, 2 h
, X = OMe, 86%, 4 h
5a
, 87%
5d
2 h
5b
5c
Me
NO2
NO2
NO2
+
Ph
H
Ph
N
N
N
N
Me
N
N
5f
5f'
, 85%
5e
(for R = t-Bu), 11 h
:
= 4:1,
5f 5f'
total yield 84%, 2 h
NO2
H
R
R
+
N
N
N
N
MeO2C
MeO2C
- 60%,
5g
4
5
6
Scheme
5 Oxidative annulation of pyridinium imines with α-chloro- and α-
+
, R = 4-BrC H -,
- 17%, 2.5 h
6a
5g 6a
6
bromonitroalkenes. i: Cu(OAc)2∙H2O (1.5 equiv.), 2,6-lutidine (5-equiv.) DCE, MS 4Å,
+
, R = Ph,
- 53%,
- 19%, 1 h
6b
5h 6b
5h
55°C, 24 h.
Scheme 4 Synthesis of 3-nitro-pyrazolo[1,5-a]pyridines 5 from nitroalkenes 4 and
aminopyridinium salts 2. Yields refer to isolated products 5.
To the best of our knowledge only two reports of
pyrazolopyridine synthesis based on nitroalkene/pyridinium
imine cycloaddition have been published in the literature.
However, under oxidant-free conditions formation of mixture
of 3-nitro and 3-unsubstituted heterocycles has been
observed.29 Application of air as oxidant was demonstrated to
obtain nitro-substituted heterocycles.30 Our methodology for
the preparation of pyrazolo[1,5-a]pyridines involving
Cu(OAc)2∙H2O/2,6-lutidine oxidation system has many
advantages. Target products were obtained in high yield using
shorter reaction times. Moreover, not only aromatic but
aliphatic nitroalkenes can be used for the synthesis.
Next, we decided to study applicability of the present method
to other nitroalkenes. It was found that the approach is very
general and can be used for the synthesis of other
pyrazolopyridines as well. First, the reaction of
α-unsubstituted nitroalkenes
was studied. It was found to proceed smoothly under the same
conditions to afford 3-nitro-pyrazolo[1,5-a]pyridines in
4 with aminopyridinium salts 2
5
excellent yields (Scheme 4). In this case the reaction was
complete after 2-4 hours of heating at 55°C for the neutral
(5a,b) and electron-rich (5c) substrates. It is important to note
that aliphatic nitroalkene 4d was tolerated under the reaction
conditions to provide the corresponding product 5d in
excellent yield. Regioselectivity of the preparation of 3-nitro
derivatives is similar to fluorinated ones. The reaction with
3-methyl-1-aminopyridinium bromide afforded the mixture of
nitro-substituted products 5f/5f’ in the 4:1 ratio. An
The observed reactivity patterns allow us to propose a
mechanism for the studied transformation. Dependence of the
reaction rate on the electronic properties of aryl groups
indicates to stepwise, rather than concerted [3+2]-mechanism
(Scheme 6). Most probably, Michael addition (formation of the
anion
A
) is the rate-determining step of the process that is
4 | J. Name., 2012, 00, 1-3
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significantly slowing down for electron-rich nitroalkenes.
Importantly, lower concentration of the anionic species in the
solution may be responsible for the slight increase of yields in
these cases, because oligomerization of anionic species is
suppressed. We can also note that copper salt may promote
Michael addition to nitroalkenes.31 Next, intramolecular
View Article Online
DOI: 10.1039/C9OB02668A
Y
An-
N
X
NH2
2
F
NO2
X = CH, Y = N
or X = N, Y = CH
An = Br or OTs
R'
R
Y
Y
R or
R
N
N
NO2
i
N
N
X
X
cyclization of
A resulted in formation of unstable adduct B. As
(R' = F)
1
10
(for
11
(for )
4
was already mentioned, regioselectivity of this cyclization
depends on electronic properties of the substituents as
electron donating ones predominantly led to 4-isomer
or
)
1
(R' = H)
4
F
F
(
3n,o,5f) while electron accepting ones led to 6-isomer (3p,
5g,h). Oxidation of
to form intermediate D32-34 followed by
elimination of nitrous acid resulted in formation of aromatic
heterocycle The chemoselective synthesis of nitro
derivatives can be explained by tautomerization of (for X =
H) to nitroenamine , that precludes elimination of nitrite
anion and ultimately lead to oxidation into nitro-derivatives
N
N
Br
OMe
B
N
N
N
N
N
, 37%
10b
, 41%
10a
18 h
49 h
3
.
F
F
5
D
F
Br
OMe
5
.
N
N
N
N
N
Here we should also note the possible influence of the
substituents on the reaction pathway. Thus, erosion of
chemoselectivities observed for m-nicotinate derivatives
, 55%
10c
, 47%
10d
25 h
18 h
(X-ray)
NO2
F
(product mixtures 3p+5g
attributed to conjugation of bridgehead nitrogen atom with
EWG-group (structure ), that makes formation of (that
leads to ) and (that leads to ) less favorable. Similarly, it
should also increase the oxidation potential of and decrease
, 5g,h+6, see above) may be
N
OMe
F
G
E
N
N
N
N
N
3
F
5
, 79%
11a
, 58%
10e
3 h
6 h
B
the stability of cation radical
opportunities for side-reactions.
C
. Overall, this increase the
NO2
NO2
NO2
Ph
Ph
N
Ph
N
N
N
N
N
N
N
N
N
NH2
Br-
, 76%
11b
18 h
, 61%
11c
, 65%
11d
2 h
2 h
NO2
X
NO2
NO2
2
R
Scheme 7 Synthesis of pyrazolo[1,5-a]pyrazines and pyrazolo[1,5-a]pyridazines 10,11
via oxidative aza-[3+2]-annulation.26 i: Cu(OAc)2∙H2O (1.5 equiv.), 2,6-lutidine (5 equiv.)
DCE, MS 4Å, 55°C.
X
[Cu]
Cu(II)
R
X
2,6-lutidine
(Lut)
NH
-Cu(I)
N
N+ NH
R
1,4
A
B
Finally, we decided to demonstrate the possibility of the
synthesis of some aza-derivatives of pyrazolopyridines using
the present methodology (Scheme 7).35 Novel fluorinated
pyrazolo[1,5-a]pyrazines and pyrazolo[1,5-b]pyridazines 10
were successfully obtained from the corresponding
NO2
X
NO2
N
O2N
X
R
R
R
path (b)
X = H
Cu(II)
NH
NH
-Cu(I)
-2H+
N
N
N
aminodiazinium salts
2 and fluoronitroalkenes 1. However,
C
D
F
more prolonged heating was necessary to achieve complete
conversion for these substrates. It was found that the method
provided efficient synthesis of the corresponding 3-nitro
derivatives 11 as well.
path (a)
X = F
-
Cu(II)
Lut
-NO2
[-H2]
NO2
F
X
H
Lut
-LutH+
R
R
R
N
N
N
N
N
N
Experimental
E
5
3
General experimental
X
NO2
All reactions were performed in oven-dried (150 °C) glassware.
Most of the chemicals were acquired from commercial sources
R
N
N
EWG
and used as received. Starting fluoronitroalkenes
1 were
G
prepared by radical nitration of corresponding
Scheme 6 Proposed reaction mechanism.
fluorobromostyrenes (see ESI).14 N-aminoazinium bromides
2a,b,e,f,h,i were prepared by literature procedure,36 albeit
using HBr instead of HI. N-aminoazinium tosylates 2c,d,g,j
were prepared by amination of corresponding azines with
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TsONH2.37 TLC were performed on silica coated on aluminium 143 °C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 6.72 V(tie,wJA=rtic6le.6OnHlinze,
with UV254 indicator. Visualization was accomplished with UV. 1H, H6), 7.07 (dd, J = 8.9, 7.0 Hz, 1H, HD5O),I:71.04.1903(d9/,CJ9O=B80.2966H8zA,
Column chromatography was performed on silica (0.04–0.063 1H, H4), 7.59 (d, J = 8.5 Hz, 2H, CHAr), 7.90 (d, J = 8.5 Hz, 2H,
mm, 60 Å). High resolution mass spectra were acquired at TOF CHAr), 8.27 (d, J = 7.0 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): δ
3
4
spectrometer using electrospray ionization (ESI). Melting 112.2 (C6-H), 115.1 (d, JCF = 4.3 Hz, C4-H), 122.5 (d, JCF = 2.1
4
points were determined on a Koffler melting point apparatus Hz, C5-H), 122.6 (C-Br), 128.1 (C7-H), 128.3 (d, JCF = 4.4 Hz,
3
and are uncorrected. NMR spectra were recorded at the 300 CHAr), 128.9 (d, 2JCF = 28.0 Hz, C3a), 129.8 (d, JCF = 4.2 Hz, CAr),
2
1
MHz (1H NMR), 75 MHz (13C NMR), and 282 MHz (19F NMR) 131.9 (CHAr), 136.8 (d, JCF = 4.6 Hz, C2), 137.9 (d, JCF = 247.1
frequencies at 300 K unless otherwise stated. Chemical shifts
are given relative to the (residual) solvent peak.38 Multiplicities m/z calcd. for [C13H879BrFN2 + H+]: 290.9928, found: 290.9932.
2-(4-Fluorophenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3c
Pyrazolo[1,5-a]pyridine 3c was obtained
Hz, C3-F). 19F NMR (282 MHz, CDCl3): δ -180.6 (s). HRMS (ESI):
are assigned as
(quadruplet),
Assignment of signals was made basing on 2D NMR (1H-1H
COSY, 1H-13C HSQC, 1H-13C HMBC) for selected compounds (3a
3i 3l, 3m 3o 3p 5d-g, 6a 10a,c,d,e, 11) and then extended
s
(singlet),
d (doublet), t (triplet), q
m
(multiplet), br (broad), app (apparent).
from
α-fluoronitroalkene 1c (37 mg, 0.2 mmol) and
N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 6 h). Column chromatography
(eluent: 9:1 PE/EtOAc) afforded 3c (36 mg, 78%) as white solid.
Rf = 0.42 (PE/EtOAc, 3:1) (UV), mp = 112-115°C (CHCl3). 1H
NMR (300 MHz, CDCl3): δ 6.70 (app t, J = 6.9 Hz, 1H, H6), 7.07
(dd, J = 8.9, 7.0 Hz, 1H, H5), 7.16 (t, J = 8.7 Hz, 2H, CHAr), 7.48
(d, J = 8.9 Hz, 1H, H4), 8.01 (dd, J = 8.7, 5.5 Hz, 2H, CHAr), 8.27
(d, J = 7.0 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): δ 112.0 (C6-
,
,
,
,
,
, 8,
to other products. Note: Signal of C3–NO2 often could not be
unambiguously identified in 1D 13C NMR due to quadrupole
broadening/low intensity, although it can be assigned based
on HMBC (see products 5d,e, 11b,d).
General procedure for the synthesis of pyrazolo[1,5-
a]pyridines and their derivatives.
3
2
H), 115.0 (d, JCF = 4.2 Hz, C4-H), 115.6 (d, JCF= 21.6 Hz, CHAr),
4
122.5 (d, JCF = 2.0 Hz, C5-H), 128.1 (C7-H), 128.6 (dd, JCF = 8.2,
To the stirred suspension of N-aminoazinium salt
2 (0.4 mmol,
2 equiv.) powdered 4Å molecular sieves (100 mg), and 2,6-
lutidine (107 mg, 1 mmol, 5 equiv.) in 1,2-dichloroethane (2
ml) copper acetate monohydrate (60 mg, 0.3 mmol, 1.5 equiv.)
4.4 Hz, CHAr), 128.8 (d,2JCF = 27.6 Hz, C3a), 132.9 (app t, JCF
=
8.5 Hz, CAr), 137.0 (d, 2JCF = 4.6 Hz, C2), 137.6 (d, 1JCF = 246.2 Hz,
C3-F), 162.9 (d, JCF = 248.0 Hz, CAr-F). 19F NMR (282 MHz,
1
and nitroalkene
1 or 4 (0.2 mmol, 1.0 equiv.) were added. The
CDCl3): δ -112.7 (s, CAr-F), -181.7 (s, С3-F). HRMS (ESI): m/z
calcd. for [C13H8F2N2 + H+]: 231.0728, found: 231.0732.
2-(4-Methylphenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3d
mixture was heated at 55°C for 4-28 h, then evaporated under
reduced pressure after addition of silica gel. The crude product
was purified by column chromatography (PE/EtOAc) to afford
Pyrazolo[1,5-a]pyridine
3d
was
obtained
from
pyrazolo[1,5-a]pyridines
2-(4-Chlorophenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3a
Pyrazolo[1,5-a]pyridine 3a was obtained
3.
α-fluoronitroalkene 1d (21.7 mg, 0.12 mmol) and
N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 12 h). Column chromatography
(eluent: 9:1 PE/EtOAc) afforded 3d (21.5 mg, 79%) as slightly
yellow solid. Rf = 0.48 (PE/EtOAc, 3:1) (UV), mp = 93-95 °C
(CHCl3). 1H NMR (300 MHz, CDCl3): δ 2.41 (s, 3H, Me), 6.69 (t, J
= 6.9 Hz, 1H, H6), 7.02-7.09 (m, 1H, H5), 7.29 (d, J = 8.0 Hz, 2H,
CHAr), 7.48 (d, J = 8.7 Hz, 1H, H4), 7.92 (d, J = 8.0 Hz, 2H, CHAr),
8.29 (d, J = 6.9 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): δ 21.4
from
α-fluoronitroalkene 1a (50.4 mg, 0.25 mmol) and
N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 6 h). Column chromatography
(eluent: 7:1 PE/EtOAc) afforded 3a (45 mg, 73%) as slightly
yellow solid. Rf = 0.45 (PE/EtOAc, 3:1) (UV), mp = 131-133 °C
(CHCl3). 1H NMR (300 MHz, CDCl3): δ 6.71 (t, J = 6.8 Hz, 1H, H6),
7.07 (dd, J = 8.5, 7.0 Hz, 1H, H5), 7.45 (m, 3H), 7.96 (d, J = 8.3
Hz, 2H, CHAr), 8.26 (d, J = 7.0 Hz, 1H, H7). 13C NMR (75 MHz,
(Me), 111.7 (C6-H), 114.9 (d, 3JCF = 4.2 Hz, C4-H), 122.3 (d, 4JCF
=
4
3
3
CDCl3, 1H-13C HSQC): δ 112.1 (C6-H), 115.0 (d, JCF = 4.2 Hz, C4-
2.1 Hz, C5-H), 126.8 (d, JCF = 4.2 Hz, CHAr), 128.0 (d, JCF = 4.0
Hz, CAr), 128.1 (C7-H), 128.8 (d,2JCF = 28.2 Hz, C3a), 129.5
4
4
H), 122.5 (d, JCF = 1.8 Hz, C5-H), 128.0 (d, JCF = 3.8 Hz, CHAr),
128.0 (C7-H), 128.8 (d,2JCF = 27.4 Hz, C3a), 128.9 (CHAr), 129.3
1
2
(CHAr), 137.8 (d, JCF = 246.0 Hz, C3-F), 138.0 (d, JCF = 4.6 Hz,
C2), 138.5 (CAr). 19F NMR (282 MHz, CDCl3): δ -181.5 (s). HRMS
(ESI): m/z calcd. for [C14H11FN2 + H+]: 227.0979, found:
227.0978.
3
(d, JCF = 3.0 Hz, CAr), 134.3 (C-Cl), 136.7 (d, JCF = 4.6 Hz, C2),
2
1
137.8 (d, JCF = 247.2 Hz, C3-F). 19F NMR (282 MHz, CDCl3): δ -
180.7 (s). HRMS (ESI): m/z calcd. for [C13H835ClFN2 + H+]:
247.0433, found: 247.0440.
2-(4-(Methyloxycarbonyl)phenyl)-3-fluoro-pyrazolo[1,5-a]pyridine
3e
2-(4-Bromophenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3b
Pyrazolo[1,5-a]pyridine
3e
was
obtained
from
Pyrazolo[1,5-a]pyridine
3b
was
obtained
from
α-fluoronitroalkene 1e (33.8 mg, 0.15 mmol) and
N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 9 h). Column chromatography
(eluent: 5:1 PE/EtOAc) afforded 3e (26.5 mg, 65%) as white
solid. Rf = 0.41 (PE/EtOAc, 3:1) (UV), mp = 138-140 °C (CHCl3).
1H NMR (300 MHz, CDCl3): δ 3.95 (s, 3H, CO2Me), 6.76 (td, J =
6.8, 0.8 Hz, 1H, H6), 7.09 (dd, J = 8.7, 7.0 Hz, 1H, H5), 7.52 (d, J
= 8.9 Hz, 1H, H4), 8.11 (d, J = 8.7 Hz, 2H, CHAr), 8.15 (d, J = 8.7
α-fluoronitroalkene 1b (49.2 mg, 0.2 mmol) and
N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 6 h). Column chromatography
(eluent: 7:1 PE/EtOAc) afforded 3b (39 mg, 67%) as white solid.
For the 3 mmol scale synthesis, 3b was obtained from 1b (738
mg, 3 mmol) and 2a (1.5 equiv.) as white solid (642 mg, 74%,
reaction time 20 h). Rf = 0.46 (PE/EtOAc, 3:1) (UV), mp = 142-
6 | J. Name., 2012, 00, 1-3
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3
Hz, 2H, CHAr), 8.30 (d, J = 7.0 Hz, 1H, H7). 13C NMR (75 MHz, CHAr), 111.3 (CHAr), 111.6 (C6-H), 114.8 (d, JCF = 4.0 Hz, C4-H),
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4
CDCl3): δ 52.2 (Me), 112.5 (C6-H), 115.2 (d, 3JCF = 4.3 Hz, C4-H), 119.9 (d, JCF = 5.0 Hz, CHAr), 122.4 (dD, O4JI:CF10=.1013.99/CH9Oz,B0C256-6H8)A,
122.6 (d, JCF = 2.2 Hz, C5-H), 126.6 (d, JCF = 4.5 Hz, CHAr), 123.7 (3JCF = 4.0 Hz, CAr), 128.0 (C7-H), 128.8 (d, JCF = 28.4 Hz,
4
4
2
128.1 (C7-H), 128.9 (d,2JCF = 28.1 Hz, C3a), 129.8 (CAr), 130.0 C3a), 137.6 (d, 1JCF = 245.3 Hz, C3-F), 137.9 (d, 2JCF = 4.5 Hz, C2),
2
1
(CHAr), 135.2 (d, JCF = 4.2 Hz, C2), 136.7 (CAr), 138.4 (d, JCF
243.3 Hz, C3-F), 166.8 (
O2Me). 19F NMR (282 MHz, CDCl3): δ - 181.7 (s). HRMS (ESI): m/z calcd. for [C15H13FN2O2+ H+]:
179.5 (s). HRMS (ESI): m/z calcd. for [C15H11FN2O2 + H+]: 273.1034, found: 273.1034.
=
149.2 (C-OMe), 149.5 (C-
OMe). 19F NMR (282 MHz, CDCl3): δ -
C
2-(3-Methoxyphenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3i
Pyrazolo[1,5-a]pyridine 3i was obtained
from α-fluoronitroalkene 1i (39.4 mg, 0.2 mmol) and
271.0877, found: 271.0875.
2-(4-Trifluoromethylphenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3f
from
Pyrazolo[1,5-a]pyridine
3f
was
obtained
α-fluoronitroalkene 1f (59 mg, 0.25 mmol) and N-aminopyridinium salt 2a (2.0 equiv.) following the general
N-aminopyridinium salt 2a (2.0 equiv.) following the general procedure (reaction time 7 h). Column chromatography
procedure (reaction time 3.5 h). Column chromatography (eluent: 9:1 to 5:1 PE/EtOAc) afforded 3i (31 mg, 64%) as
(eluent: 9:1 PE/EtOAc) afforded 3f (48 mg, 68%) as white solid. slightly yellow solid. Rf = 0.32 (PE/EtOAc, 3:1) (UV), mp = 146-
1
Rf = 0.52 (PE/EtOAc, 3:1) (UV), mp = 124-125 °C (CHCl3). H 150°C (CHCl3). 1H NMR (300 MHz, CDCl3, 1H-1H COSY): δ 2.96 (s,
NMR (300 MHz, CDCl3): δ 6.75 (td, J = 7.0, 1.2 Hz, 1H, H6), 7.09 3H, OMe), 6.70 (td, J = 6.9, 1.3 Hz, 1H, H6), 6.95 (dd, J = 8.5, 2.2
(dd, J = 8.9, 7.0 Hz, 1H, H5), 7.51 (app d, J = 8.9 Hz, 1H, H4), Hz, 1H, CHAr), 7.05 (dd, J = 8.9, 6.9 Hz, 1H, H5), 7.39 (t, J = 7.9
7.72 (d, J = 8.1 Hz, 2H, CHAr), 8.14 (d, J = 8.1 Hz, 2H, CHAr), 8.26 Hz, 1H, CHAr), 7.49 (d, J = 8.9 Hz, 1H, H4), 7.60 (d, J = 2.2 Hz, 1H,
(d, J = 7.0 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): δ 112.6 (C6- CHAr), 7.64 (d, J = 7.9 Hz, 1H, CHAr), 8.29 (d, J = 6.9 Hz, 1H, H7).
3
4
1
1
H), 115.3 (d, JCF = 4.3 Hz, C4-H), 122.7 (d, JCF = 1.8 Hz, C5-H), 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ 55.4
124.1 (q, JCF= 271.9 Hz, CF3), 125.6 (q, JCF = 3.6 Hz, CHAr), (OMe), 111.8 (d, 4JCF = 3.9 Hz, CHAr), 112.0 (C6-H), 114.7 (CHAr),
1
3
126.9 (d, JCF = 4.5 Hz, CHAr), 128.1 (C7-H), 128.9 (d,2JCF = 28.1 115.1 (d, JCF = 4.2 Hz, C4-H), 119.5 (d, JCF = 4.7 Hz, CHAr),
4
3
4
3
4
Hz, C3a), 130.2 (q, 2JCF = 32.5 Hz, C-CF3), 134.3 (d, JCF = 4.7 Hz, 122.4 (d, JCF = 1.9 Hz, C5-H), 128.1 (C7-H), 128.8 (d,2JCF = 28.3
CAr), 136.3 (d, 2JCF = 4.4 Hz, C2), 138.2 (d, 1JCF = 247.9 Hz, C3-F). Hz, C3a), 129.8 (CHAr), 132.1 (d, 3JCF = 3.9 Hz, CAr), 137.8 (d, JCF
2
19F NMR (282 MHz, CDCl3): δ -62.7 (s, 3F, CF3), -180.0 (s, 1F, C3- = 4.8 Hz, C2), 137.9 (d, JCF = 246.7 Hz, C3-F), 159.9 (C-OMe).
1
F). HRMS (ESI): m/z calcd. for [C14H8F4N2 + H+]: 281.0696, 19F NMR (282 MHz, CDCl3): δ -180.7 (s). HRMS (ESI): m/z calcd.
found: 281.0697.
2-(4-Methoxyphenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3g
for [C14H11FN2O + H+]: 243.0928, found: 243.0934.
2-(2-Chlorophenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3j
Pyrazolo[1,5-a]pyridine
3g
was
obtained
from Pyrazolo[1,5-a]pyridine
3j
was
obtained
from
α-fluoronitroalkene 1g (39.4 mg, 0.20 mmol) and α-fluoronitroalkene 1j (31 mg, 0.15 mmol) and
N-aminopyridinium salt 2a (2.3 equiv.) following the general N-aminopyridinium salt 2a (2.0 equiv.) following the general
procedure (reaction time 26 h). Column chromatography procedure (reaction time 8 h). Column chromatography
(eluent: 5:1 PE/EtOAc) afforded 3g (41 mg, 85%) as yellow (eluent: 19:1 to 7:1 PE/EtOAc) afforded 3j (30 mg, 80%) as
1
solid. Rf = 0.38 (PE/EtOAc, 3:1) (UV), mp = 155-156 °C (CHCl3). white semisolid. Rf = 0.34 (PE/EtOAc, 3:1) (UV). H NMR (300
1H NMR (300 MHz, CDCl3): δ 3.87 (s, 3H, OMe), 6.68 (td, J = 6.8, MHz, CDCl3): δ 6.76 (dd, J = 7.1, 1.1 Hz, 1H, H6), 7.11 (dd, J =
1.0 Hz, 1H, H6), 7.01 (d, J = 8.8 Hz, 2H, CHAr), 7.04 (dd, J = 8.2, 8.8, 6.9 Hz, 1H, H5), 7.34-7.41 (m, 2H), 7.50-7.64 (m, 3H), 8.33
7.1 Hz, 1H, H5), 7.46 (d, J = 8.9 Hz, 1H, H4), 7.97 (d, J = 8.8 Hz, (d, J = 7.1 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): δ 112.1 (C6-
3
4
2H, CHAr), 8.27 (d, J = 7.1 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3): H), 115.3 (d, JCF = 4.2 Hz, C4-H), 122.5 (d, JCF = 2.1 Hz, C5-H),
δ 55.3 (OMe), 111.5 (C6-H), 114.2 (CHAr), 114.8 (d, 3JCF = 4.2 Hz, 126.7 (CHAr), 128.1 (d, JCF = 27.5 Hz, C3a), 128.2 (C7-H), 129.9
2
C4-H), 122.3 (d, 4JCF = 1.8 Hz, C5-H), 123.4 (d, 3JCF = 4.0 Hz, CAr), (d, JCF = 3.5 Hz, CAr), 130.0 (CHAr), 130.1 (CHAr), 132.1 (CHAr),
3
128.0 (C7-H), 128.2 (d, JCF = 4.2 Hz, CHAr), 128.6 (d,2JCF = 28.0 133.9 (C-Cl), 137.3 (d, JCF = 8.3 Hz, C2), 137.7 (d, JCF = 244.6
4
2
1
Hz, C3a), 137.5 (d, 1JCF = 245.3 Hz, C3-F), 137.9 (d, 2JCF = 4.8 Hz, Hz, C3-F). 19F NMR (282 MHz, CDCl3): δ -176.8 (s). HRMS (ESI):
C2), 159.9 (C
-
OMe). 19F NMR (282 MHz, CDCl3): δ -182.1 (s). m/z calcd. for [C13H835ClFN2 + H+]: 247.0433, found: 247.0443.
HRMS (ESI): m/z calcd. for [C14H11FN2O + H+]: 243.0928, found:
243.0935.
2-(4-Bromophenyl)-3-fluoro-5-methyl-pyrazolo[1,5-a]pyridine 3k
Pyrazolo[1,5-a]pyridine
α-fluoronitroalkene 1b (49.2 mg, 0.2 mmol) and
from N-aminopyridinium salt 2b (2.0 equiv.) following the general
3k
was
obtained
from
2-(3,4-Dimethoxyphenyl)-3-fluoro-pyrazolo[1,5-a]pyridine 3h
Pyrazolo[1,5-a]pyridine
3h
was
obtained
α-fluoronitroalkene 1h (18 mg, 0.078 mmol) and procedure (reaction time 5 h). Column chromatography
N-aminopyridinium salt 2a (2.3 equiv.) following the general (eluent: 9:1 PE/EtOAc) afforded 3k (29.5 mg, 48%) as white
procedure (reaction time 28 h). Column chromatography solid. Rf = 0.50 (PE/EtOAc, 3:1) (UV), mp = 128-130 °C (CHCl3).
(eluent: 4:1 PE/EtOAc) afforded 3h (17.5 mg, 81%) as slightly 1H NMR (300 MHz, CDCl3): δ 2.37 (s, 3H, Me), 6.53 (dd, J = 7.2,
yellow amorphous solid. Rf = 0.13 (PE/EtOAc, 3:1) (UV). 1H 1.7 Hz, 1H, H6), 7.22 (br s, 1H, H4), 7.58 (d, J = 8.5 Hz, 2H,
NMR (300 MHz, CDCl3): δ 3.94 (s, 3H, OMe), 4.00 (s, 3H, OMe), CHAr), 7.88 (d, J = 8.5 Hz, 2H, CHAr), 8.14 (d, J = 7.2 Hz, 1H, H7).
3
6.69 (td, J = 7.1, 1.2 Hz, 1H, H6), 6.98 (d, J = 8.1 Hz, 1H, CHAr), 13C NMR (75 MHz, CDCl3): δ 21.2 (Me), 113.1 (d, JCF = 4.2 Hz,
6
7.07 (dd, J = 8.8, 6.8 Hz, 1H, H5), 7.48 (d, J = 8.8 Hz, 1H, H4), C4-H), 115.0 (C6-H), 122.5 (d, JCF = 0.7 Hz, C-Br), 127.3 (C7-H),
7.62 (m, 2H, CHAr), 8.28 (d, J = 7.1 Hz, 1H, H7). 13C NMR (75 128.3 (d, 4JCF = 4.4 Hz, CHAr), 129.0 (d,2JCF = 28.1 Hz, C3a), 131.9
4
MHz, CDCl3): 55.9 (OMe), 56.0 (OMe), 109.7 (d, JCF = 4.0 Hz, (CHAr), 130.0 (d, JCF = 4.1 Hz, CAr), 133.4 (d, JCF = 2.1 Hz, C5),
3
4
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2
1
137.0 (d, JCF = 4.8 Hz, C2), 137.1 (d, JCF = 245.6 Hz, C3-F). 19F H6), 7.51 (d, J = 7.1 Hz, 1H, H5), 7.74 (d, J = 8.5 Hz, 2H, CHAr),
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NMR (282 MHz, CDCl3): δ -181.7 (s). HRMS (ESI): m/z calcd. for 7.88 (d, J = 8.5 Hz, 2H, CHAr), 8.58 (d, JD=O7I:.110.1H0z3,91/CH9,OHB072).66183CA
[C14H1079BrFN2 + H+]: 305.0084, found: 305.0081.
NMR (100 MHz, DMSO-d6, 363 K): δ 107.6 (d, 3JCF = 5.4 Hz, C4),
Ethyl 2-(4-bromophenyl)-3-fluoropyrazolo[1,5-a]pyridine-5- 113.5 (C6-H), 122.9 (C-Br), 127.3 (d,2JCF = 19.0 Hz, C3a), 127.5
4
(d, JCF = 2.1 Hz, C5-H), 128.5 (C7-H), 129.0 (d, JCF = 4.5 Hz,
4
carboxylate 3l
3
2
Pyrazolo[1,5-a]pyridine
3l
was
obtained
from CHAr), 129.6 (d, JCF = 4.4 Hz, CAr), 132.5 (CHAr), 137.7 (d, JCF =
α-fluoronitroalkene 1b (49 mg, 0.2 mmol) and 4.9 Hz, C2), 137.8 (d, JCF = 251.3 Hz, C3-F). 19F NMR (376 MHz,
N-aminopyridinium salt 2c (2.0 equiv.) following the general DMSO-d6, 363 K): -175.6 (s). HRMS (ESI): m/z calcd. for
procedure (reaction time 6 h at r.t.). Column chromatography [C13H779Br81BrFN2 + H+]: 370.9013, found: 370.9000.
1
2-(4-Bromophenyl)-3-fluoro-4-methyl-pyrazolo[1,5-a]pyridine 3o
(eluent: 30:1, then 5:1, PE/EtOAc) afforded 3l (61 mg, 85%) as
slightly yellow solid. Rf = 0.50 (PE/EtOAc, 3:1) (UV), mp = 158-
159 °C (CHCl3). 1H NMR (300 MHz, CDCl3): δ 1.45 (t, J = 7.1 Hz,
3H, CH3), 4.43 (q, J = 7.1 Hz, 2H, CH2), 7.30 (d, J = 7.3 Hz, 1H,
H6), 7.60 (d, J = 8.5 Hz, 2H, CHAr), 7.89 (d, J = 8.5 Hz, 2H, CHAr),
8.26 (s, 1H, H4), 8.27 (d, J = 7.3 Hz, 1H, H7). 13C NMR (75 MHz,
CDCl3, 1H-13C HSQC): δ 14.3 (Me), 61.7 (CH2), 111.3 (C6-H),
and 2-(4-bromophenyl)-3-fluoro-6-methyl-pyrazolo[1,5-a]pyridine
3o’
Pyrazolo[1,5-a]pyridines 3o/3o’ were obtained from
α-fluoronitroalkene 1b (49.2 mg, 0.2 mmol) and
N-aminopyridinium salt 2f (2.0 equiv.) following the general
procedure (reaction time 4 h). Column chromatography
(eluent: 9:1 PE/EtOAc) afforded 3o/3o’ (41 mg, 3o/3o’ = 3:1,
total yield 67%) as white solid. Rf = 0.49 (PE/EtOAc, 3:1) (UV),
mp (for mixture) = 126-127 °C and then 135-136 °C (CHCl3).
3
4
118.1 (d, JCF = 4.7 Hz, C4-H), 123.0 (C-Br), 124.9 (d, JCF = 2.4
2
Hz, C5), 127.8 (C7-H), 127.9 (d, JCF = 28.1 Hz, C3a), 128.3 (d,
3
4JCF = 4.4 Hz, CHAr), 129.2 (d, JCF = 4.1 Hz, CAr), 132.0 (CHAr),
2
1
1
137.7 (d, JCF = 4.7 Hz, C2), 139.8 (d, JCF = 252.3 Hz, C3-F),
164.6 (C=O). 19F NMR (282 MHz, CDCl3): δ -176.5 (s, 1F). HRMS
(ESI): m/z calcd. for [C16H1279BrFN2O2 + H+]: 363.0139, found:
363.0133.
Major isomer (3o): H NMR (300 MHz, CDCl3): δ 2.57 (s, 3H,
Me), 6.60 (t, J = 6.8 Hz, 1H, H6), 6.76 (d, J = 6.8 Hz, 1H, H5),
7.61 (d, J = 8.5 Hz, 2H, CHAr), 7.91 (d, J = 8.5 Hz, 2H, CHAr), 8.10
1
(d, J = 6.9 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3, H-13C HSQC):
4
4
δ 17.2 (d, JCF = 2.8 Hz, Me), 112.3 (C6-H), 121.9 (d, JCF = 1.8
2-(4-Bromophenyl)-5-(1,3-dioxolan-2-yl)-3-
fluoropyrazolo[1,5-a]pyridine 3m
3
Hz, C5-H), 122.4 (br s, C-Br), 125.7 (C7-H), 127.2 (d, JCF = 4.2
4
Hz, C4), 128.2 (d, JCF = 4.3 Hz, CHAr), 129.0 (d,2JCF = 23.4 Hz,
Pyrazolo[1,5-a]pyridine
3m
was
obtained
from
3
C3a), 129.9 (d, JCF = 4.2 Hz, CAr), 131.8 (CHAr), 136.6 (d, JCF
2
α-fluoronitroalkene 1b (49 mg, 0.2 mmol) and
N-aminopyridinium salt 2d (2.0 equiv.) following the general
procedure (reaction time 21 h). Column chromatography
(eluent: 9:1, then 3:1, PE/EtOAc) afforded 3m (48 mg, 68%) as
white solid. Rf = 0.23 (PE/EtOAc, 3:1) (UV), mp = 151-153 °C
(CHCl3). 1H NMR (300 MHz, CDCl3): δ 4.06-4.18 (m, 4H,
CH2CH2), 5.84 (s, 1H, CH–O), 6.84 (dd, J = 7.3, 1.7 Hz, 1H, H6),
7.61 (d, J = 8.5 Hz, 2H, CHAr), 7.62 (s, 1H, H4), 7.91 (d, J = 8.5
Hz, 2H, CHAr), 8.28 (d, J = 7.3 Hz, 1H, H7). 13C NMR (75 MHz,
=
1
5.2 Hz, C2), 139.0 (d, JCF = 247.4 Hz, C3-F). 19F NMR (282 MHz,
1
CDCl3): δ -178.7 (s). Minor isomer (3o’): H NMR (300 MHz,
CDCl3): δ 2.31 (s, 3H, Me), 6.91 (d, J = 9.1 Hz, 1H, H5), 7.38 (d, J
= 9.1 Hz, 1H, H4), 7.60 (d, J = 8.8 Hz, 2H, CHAr), 7.90 (d, J = 8.8
1
Hz, 2H, CHAr), 8.05 (s, 1H, H7). 13C NMR (75 MHz, CDCl3, H-13C
3
HSQC, characteristic signals): δ 18.2 (Me), 114.3 (d, JCF = 4.3
Hz, C4-H), 125.8 (s, C5-H and C7-H). 19F NMR (282 MHz, CDCl3):
δ -180.7 (s). HRMS (ESI): m/z calcd. for [C14H1079BrFN2 + H+]:
305.0084, found: 305.0078.
1
CDCl3, H-13C HSQC, 1H-13C HMBC): δ 65.5 (CH2), 102.3 (CH–O),
3
110.5 (C6-H), 112.9 (d, JCF = 4.3 Hz, C4-H), 122.7 (C-Br), 128.2
Methyl 2-(4-bromophenyl)-3-fluoropyrazolo[1,5-a]pyridine-6-
2
(C7-H), 128.2 (d, JCF = 27.4 Hz, C3a), 128.3 (d, JCF = 4.4 Hz,
4
carboxylate
fluoropyrazolo[1,5-a]pyridine-4-carboxylate 3p’
Pyrazolo[1,5-a]pyridines 3p,p’ were obtained
3p
and
Methyl
2-(4-bromophenyl)-3-
3
4
CHAr), 129.7 (d, JCF = 4.3 Hz, CAr), 131.9 (CHAr), 133.3 (d, JCF
=
2.0 Hz, C5), 137.4 (d, 2JCF = 4.9 Hz, C2), 138.5 (d, 1JCF = 248.0 Hz,
C3-F). 19F NMR (282 MHz, CDCl3): δ -179.6 (s, 1F). HRMS (ESI):
m/z calcd. for [C16H1279BrFN2O2 + H+]: 363.0139, found:
363.0135.
from
α-fluoronitroalkene 1b (74 mg, 0.3 mmol) and
N-aminopyridinium salt 2g (2.0 equiv.) following the general
procedure (reaction time 2.5 h). Column chromatography
(eluent: 9:1, then 3:1, PE/EtOAc) afforded two fractions: (1)
pure 3p (33 mg, 32%), Rf = 0.43 (PE/EtOAc, 3:1) (UV), slightly
4-Bromo-2-(4-bromophenyl)-3-fluoropyrazolo[1,5-a]pyridine 3n
Pyrazolo[1,5-a]pyridine
3n
was
obtained
from
α-fluoronitroalkene 1b (24.6 mg, 0.1 mmol) and
N-aminopyridinium salt 2e (2 equiv.) similarly to the general
procedure at 65°C (reaction time 36 h). Column
chromatography (eluent: 9:1 PE/EtOAc) afforded 3n (31 mg,
84%, contains ca. 12% of corresponding 6-bromo-isomer) as
white solid. Rf = 0.44 (PE/EtOAc, 3:1) (UV), mp = 207-210 °C
(CHCl3). Note: compound 3n has very low solubility at r.t. even
yellow solid (2) mixture of 5g and 3p’ (35 mg, 5g:3p’ = 1.7:1.0,
yields: 5g – 20%, 3p’ – 12%), Rf = 0.30 (PE/EtOAc, 3:1) (UV),
slightly yellow amorphous solid. 3p: mp = 156-157 °C (CHCl3).
1H NMR (300 MHz, CDCl3): δ 3.97 (s, 3H, CO2Me), 7.49 (d, J =
9.4 Hz, 1H, H4), 7.60-7.63 (m, 3H, CHAr and H5), 7.91 (d, J = 8.4
1
Hz, 2H, CHAr), 9.00 (s, 1H, H7). 13C NMR (75 MHz, CDCl3, H-13C
1
3
HSQC, H-13C HMBC): δ 52.5 (CO2Me), 114.4 (d, JCF = 4.3 Hz,
1
4
C4-H), 116.1 (C6), 122.1 (d, JCF = 2.0 Hz, C5-H), 123.4 (C-Br),
in DMSO-d6. H NMR (300 MHz, CDCl3, 300 K): δ 3.87 (s, 3H,
4
128.5 (d, JCF = 4.4 Hz, CHAr), 129.0 (CAr), 129.3 (d, JCF = 29.4
2
OMe), 6.60 (t, J = 7.1 Hz, 1H, H6), 7.27-7.30 (m, 1H, H5), 7.62
(d, J = 8.5 Hz, 2H, CHAr), 7.91 (d, J = 8.5 Hz, 2H, CHAr), 8.26 (d, J
= 7.1 Hz, 1H, H7). 19F NMR (282 MHz, CDCl3, 300 K): -174.4 (s).
1H NMR (400 MHz, DMSO-d6, 363 K): δ 6.84 (t, J = 7.1 Hz, 1H,
1
Hz, C3a), 132.0 (CHAr), 132.3 (C7-H), 138.4 (d, JCF = 249.3 Hz,
C3-F), 140.2 (d, JCF = 5.1 Hz, C2), 165.0 (C=O). 19F NMR (282
2
MHz, CDCl3): δ -178.8 (s). HRMS (ESI): m/z calcd. for
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 9 of 13
Organic & Biomolecular Chemistry
Journal Name
[C15H1079BrFN2O2 + H+]: 348.9982, found: 348.9982. 3p’
ARTICLE
:
1H salt 2a (2.0 equiv.) following the general procedure (reaction
View Article Online
NMR (300 MHz, CDCl3, COSY): δ 4.03 (s, 3H, CO2Me), 6.78 (t, J time 2 h). Column chromatography D(OeIl:u1e0.n10t:39/9C:91OBt0o26618:1A
= 7.1 Hz, 1H, H6), 7.62 (d, J = 8.5 Hz, 2H, CHAr), 7.85 (d, J = 7.1 PE/EtOAc) afforded 5b (35 mg, 87%) as a dark yellow oil, which
Hz, 1H, H5), 7.94 (d, J = 8.5 Hz, 2H, CHAr), 8.43 (d, J = 7.1 Hz, solidifies upon storage in a refrigerator. Rf = 0.24 (PE/EtOAc,
1
1
1
1
1H, H7). 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C HMBC, 3:1) (UV). H NMR (300 MHz, CDCl3, H-1H COSY): δ 3.13-3.18
characteristic signals): δ 52.6 (CO2Me), 110.5 (C6-H), 128.4 (C5- (m, 2H, PhCH2), 3.49-3.54 (m, 2H, C2-CH2), 7.11 (app t, J = 6.9
4
H), 128.6 (d, JCF = 4.5 Hz, CHAr), 132.0 (CHAr), 132.3 (C7-H). 19F Hz, 1H, H6), 7.18-7.36 (m, 5H, CHPh), 7.64 (app dd, J = 8.2, 7.7
NMR (282 MHz, CDCl3): δ -168.5 (s).
2-(4-Chlorophenyl)-3-nitro-pyrazolo[1,5-a]pyridine 5a
Hz, 1H, H5), 8.35 (d, J = 8.9 Hz, 1H, H4), 8.49 (d, J = 6.9 Hz, 1H,
H7). 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ
30.2 (C2-CH2), 33.8 (PhCH2), 115.5 (C6-H), 118.6 (C4-H), 122.5
(br s, C-NO2), 126.1 (CHPh), 128.4 (CHPh), 128.5 (CHPh), 129.3
(C7-H), 130.7 (C5-H), 137.7 (C3a), 141.0 (CPh), 154.4 (C2). HRMS
(ESI): m/z calcd. for [C15H13N3O2 + H+]: 268.1081, found:
268.1087.
1
1
Pyrazolo[1,5-a]pyridine 5a was obtained from α-unsubstituted
nitroalkene 4a (37 mg, 0.2 mmol) and N-aminopyridinium salt
2a (2.0 equiv.) following the general procedure (reaction time
2 h). Column chromatography (eluent: 3:1 PE/EtOAc) afforded
5a (48.5 mg, 88%) as yellow solid. Rf = 0.17 (PE/EtOAc, 3:1)
(UV), mp = 206-210 °C (dec.) (CHCl3). NMR matches previously
reported data.30
3-Nitro-pyrazolo[1,5-a]pyridine 5e
Pyrazolo[1,5-a]pyridine 5e was obtained from α-unsubstituted
nitroalkene 4e (25.8 mg, 0.2 mmol) and N-aminopyridinium
salt 2a (2.0 equiv.) following the general procedure with
heating at 60 °C for 11 h. Column chromatography (eluent: 3:1
to 1:1 PE/EtOAc) afforded 5e (28 mg, 85%) as a yellow solid. Rf
= 0.17 (PE/EtOAc, 3:1) (UV), mp = 181-182 °C (CHCl3). (Lit.:
182 °C,39 186 °C (CHCl3)40). 1H NMR (300 MHz, CDCl3, 1H-1H
COSY): δ 7.18 (t, J = 7.0 Hz, 1H, H6), 7.70 (dd, J = 8.7, 7.0 Hz,
1H, H5), 8.38 (d, J = 8.7 Hz, 1H, H4), 8.60 (d, J = 7.0 Hz, 1H, H7),
2-Phenyl-3-nitro-pyrazolo[1,5-a]pyridine 5b
Pyrazolo[1,5-a]pyridine 5b was obtained from α-unsubstituted
nitroalkene 4b (14.9 mg, 0.1 mmol) and N-aminopyridinium
salt 2a (2.0 equiv.) following the general procedure (reaction
time 2 h). Column chromatography (eluent: 3:1 PE/EtOAc)
afforded 5b (22.5 mg, 93%) as yellow solid. Rf = 0.17
(PE/EtOAc, 3:1) (UV), mp = 194-195 °C (CHCl3). NMR matches
previously reported data.30
1
1
8.64 (s, 1H, H2). 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C
HMBC): δ 115.7 (C6-H), 118.5 (C4-H), 125.0 (C3), 130.0 (C7-H),
130.9 (C5-H), 136.2 (C3a), 140.5 (C2-H). HRMS (ESI): m/z calcd.
for [C7H5N3O2+ H+]: 164.0455, found: 164.0457.
2-(4-Methoxyphenyl)-3-nitro-pyrazolo[1,5-a]pyridine 5c
1. via reaction of N-aminopyridinium salt 2a with
α-unsubstituted nitroalkene 4c: Pyrazolo[1,5-a]pyridine 5c was
obtained from α-unsubstituted nitroalkene 4c (35.8 mg, 0.2
mmol) and N-aminopyridinium salt 2a (2.0 equiv.) following
2-Phenyl-3-nitro-4-methyl-pyrazolo[1,5-a]pyridine 5f and 2-
phenyl-3-nitro-6-methyl-pyrazolo[1,5-a]pyridine 5f’
the general procedure (reaction time
4 h). Column
chromatography (eluent: 9:1 to 1:1 PE/EtOAc) afforded 5c (47 Pyrazolo[1,5-a]pyridines 5f/5f’ were obtained from
mg, 86%) as yellow solid. α-unsubstituted nitroalkene 4b (29.8 mg, 0.2 mmol) and
2. via reaction of N-aminopyridinium salt 2a with N-aminopyridinium salt 2f (2.0 equiv.) following the general
α-chlorosubstituted nitroalkene : To the stirred suspension of procedure (reaction time 2 h). Column chromatography
6
N-aminopyridinium bromide 2a (106 mg, 0.6 mmol, 2 equiv.) (eluent: 9:1 PE/EtOAc) afforded 5f/5f’ (42 mg, 5f:5f’ = 4:1,
powdered 4Å molecular sieves (150 mg), and 2,6-lutidine (160 total yield 84%) as yellow amorphous solid. Rf = 0.24
1
mg, 1.5 mmol, 5 equiv.) in DCE (2 ml) copper acetate (PE/EtOAc, 3:1) (UV). Major isomer (5f): H NMR (300 MHz,
1
monohydrate (90 mg, 0.45 mmol, 1.5 equiv.) and CDCl3, H-1H COSY): δ 2.71 (s, 3H, Me), 7.01 (t, J = 7.1 Hz, 1H,
chloronitroalkene
7 (64 mg, 0.3 mmol, 1.0 equiv.) were added. H6), 7.33 (d, J = 7.1 Hz, 1H, H5), 7.46-7.54 (m, 3H, m-Ph and p-
The mixture was heated at 55°C for 24 h, then evaporated Ph), 7.72-7.76 (m, 2H, o-Ph), 8.42 (d, J = 7.1 Hz, 1H, H7). 13C
under reduced pressure after addition of silica gel. The crude NMR (75 MHz, CDCl3, 1H-13C HSQC, 1H-13C HMBC): δ 20.4 (Me),
product was purified by column chromatography (9:1 114.9 (C6-H), 127.3 (C7-H), 128.3 (CHPh), 129.2 (C4), 129.3
PE/EtOAc) to afford 3-nitro-pyrazolo[1,5-a]pyridine 5c (43.5 (CHPh), 129.6 (CHPh), 130.3 (CPh), 130.4 (C5-H), 136.5 (C3a),
1
mg, 54%) as yellow solid and 3-chloro-pyrazolo[1,5-a]pyridine 151.4 (C2). Minor isomer (5f’), characteristic signals: H NMR
(300 MHz, CDCl3, 1H-1H COSY): δ 2.46 (s, 3H, Me), 7.46-7.54 (m,
8
(11 mg, 14%) as white semisolid.
3. via reaction of N-aminopyridinium salt 2a with 3H, m-Ph and p-Ph), 7.53-7.56 (m, 1H, H5), 7.81-7.84 (m, 2H, o-
: Application of the above Ph), 8.33 (d, J = 9.0 Hz, 1H, H4), 8.36 (s, 1H, H7). 13C NMR (75
α-bromosubstituted nitroalkene
conditions (as for reaction 2a
9
1
1
+6
) to bromonitroalkene
9
(51.6 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ 18.1 (Me), 118.4
mg, 0.2 mmol) afforded 3-nitro-pyrazolo[1,5-a]pyridine as (C4-H), 126.4 (C6), 127.6 (C7-H), 128.2 (CHPh), 129.9 (CHPh),
single product according to the NMR of crude mixture. Column 133.6 (C5-H). HRMS (ESI): m/z calcd. for [C14H11N3O2 + H+]:
chromatography (7:1 PE/EtOAc) afforded 5c (42 mg, 78%) as 254.0924, found: 254.0917.
Methyl 2-(4-bromophenyl)-3-nitropyrazolo[1,5-a]pyridine-6-
carboxylate 5g and Methyl 2-(4-bromophenyl)pyrazolo[1,5-
a]pyridine-6-carboxylate 6a
yellow solid.
Rf = 0.11 (PE/EtOAc, 3:1) (UV), mp = 147-149 °C (CHCl3). NMR
matches previously reported data.30
2-(2-Phenylethyl)-3-nitro-pyrazolo[1,5-a]pyridine 5d
Pyrazolo[1,5-a]pyridines 5g and 6a were obtained from
nitroalkene 4f (45 mg, 0.2 mmol) and N-aminopyridinium salt
Pyrazolo[1,5-a]pyridine 5d was obtained from α-unsubstituted
nitroalkene 4d (35.8 mg, 0.2 mmol) and N-aminopyridinium
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Organic & Biomolecular Chemistry
Page 10 of 13
ARTICLE
Journal Name
2g (2.0 equiv.) following the general procedure (reaction time (eluent: 4:1 PE/EtOAc) afforded 10a (24 mg, 41%) as white
View Article Online
2.5 h). Column chromatography (eluent: 9:1, then 3:1, solid. Rf = 0.14 (PE/EtOAc, 3:1) (UVD),OIm: 10p.10=39/1C698O-B10720668°CA
PE/EtOAc) afforded 6a (11 mg, 17%) as white solid and 5g (45 (PE/EtOAc). 1H NMR (300 MHz, CDCl3): δ 7.62 (d, J = 8.3 Hz, 2H,
mg, 60%) as slightly yellow amorphous solid. 5g: Rf = 0.30 CHAr), 7.84 (d, J = 4.5 Hz, 1H, H6), 7.91 (d, J = 8.3 Hz, 2H, CHAr),
1
1
(PE/EtOAc, 3:1) (UV). H NMR (300 MHz, CDCl3, H-1H COSY): δ 8.19 (d, J = 4.5 Hz, 1H, H7), 9.05 (s, 1H, H4). 13C NMR (75 MHz,
4.05 (s, 3H, CO2Me), 7.65-7.74 (m, 4H, CHAr), 8.23 (d, J = 9.3 Hz, CDCl3, H-13C HSQC): δ 121.0 (C7-H), 123.4 (d, JCF = 0.6 Hz, C-
1
6
1H, H5), 8.47 (d, J = 9.3 Hz, 1H, H4), 9.26 (s, 1H, H7). 13C NMR Br), 124.9 (d,2JCF = 28.8 Hz, C3a), 128.5 (d, JCF = 4.4 Hz, CHAr),
4
(75 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ 53.1 (CO2Me), 128.8 (d, 3JCF = 4.3 Hz, CAr), 129.6 (C6-H), 132.1 (CHAr), 137.2 (d,
1
1
118.7 (C4-H), 120.0 (C6), 125.0 (C-Br), 128.5 (CAr), 129.6 (CHAr), 2JCF = 5.3 Hz, C2), 138.2 (d, 1JCF = 254.2 Hz, C3-F), 142.1 (d, 3JCF
=
130.3 (C5-H), 131.5 (CHAr), 131.6 (CHAr), 132.6 (C7-H), 139.4 5.0 Hz, C4-H). 19F NMR (282 MHz, CDCl3): δ -175.6 (s). HRMS
(C3a), 152.7 (C2), 163.8 (C=O). HRMS (ESI): m/z calcd. for (ESI): m/z calcd. for [C12H779BrFN3+ H+]: 291.9880, found:
[C15H1079BrN3O4 + H+]: 375.9927, found: 375.9935. 6a: Rf = 0.42 291.9881.
1
(PE/EtOAc, 3:1) (UV), mp = 167-171 °C (CHCl3). H NMR (300 3-Fluoro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyrazine 10b
MHz, CDCl3): δ 3.98 (s, 3H, CO2Me), 6.84 (s, 1H, H3), 7.53 (d, J = Pyrazolo[1,5-a]pyrazine 10b was obtained from α-
9.3 Hz, 1H, H4), 7.61 (d, J = 8.5 Hz, 2H, CHAr), 7.67 (d, J = 9.3 Hz, fluoronitroalkene 1g (19.7 mg, 0.1 mmol) and
1H, H5), 7.86 (d, J = 8.5 Hz, 2H, CHAr), 9.20 (s, 1H, H7). 13C NMR N-aminopyrazinium salt 2h (2.0 equiv.) following the general
1
1
(75 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ 52.4 (CO2Me), procedure (reaction time 49 h). Column chromatography
94.9 (C3-H), 115.9 (C6), 117.2 (C4-H), 123.2 (C5-H and C-Br), (eluent: 4:1, then 1:1, PE/EtOAc) afforded 10b (9.0 mg, 37%) as
128.2 (CHAr), 129.6 (CAr), 132.0 (CHAr), 132.5 (C7-H), 142.7 white solid. Rf = 0.13 (PE/EtOAc, 3:1) (UV), mp = 144-146 °C
(C3a), 155.2 (C2), 165.4 (C=O). HRMS (ESI): m/z calcd. for (CHCl3). 1H NMR (300 MHz, CDCl3): δ 3.90 (s, 3H, OMe), 7.05 (d,
[C15H1179BrN2O2 + H+]: 331.0077, found: 331.0072.
Methyl 3-nitro-2-phenylpyrazolo[1,5-a]pyridine-6-carboxylate 5h
J = 8.7 Hz, 2H, CHAr), 7.81 (d, J = 4.9 Hz, 1H, H6), 8.00 (d, J = 8.7
Hz, 2H, CHAr), 8.21 (d, J = 4.5 Hz, 1H, H7), 9.04 (s, 1H, H4). 13C
NMR (75 MHz, CDCl3): δ 55.3 (OMe), 114.4 (CHAr), 121.0 (C7-
and Methyl 2-phenylpyrazolo[1,5-a]pyridine-6-carboxylate 6b
3
2
H), 122.4 (d, JCF = 4.5 Hz, CAr), 124.8 (d, JCF = 26.4 Hz, C3a),
Pyrazolo[1,5-a]pyridines 5h and 6b were obtained from
nitroalkene 4b (44.5 mg, 0.3 mmol) and N-aminopyridinium
salt 2g (2.0 equiv.) following the general procedure (reaction
time 1 h). Column chromatography (eluent: 9:1, then 3:1,
PE/EtOAc) afforded 6b (14 mg, 19%) as white solid and 5h (47
mg, 53 %) as slightly yellow solid. 5h: Rf = 0.26 (PE/EtOAc, 3:1)
4
128.5 (d, JCF = 4.4 Hz, CHAr), 128.8 (d, JCF = 4.3 Hz, CAr), 128.4
3
4
(d, JCF = 4.2 Hz, CHAr), 129.0 (C6-H), 137.8 (d, JCF = 252.6 Hz,
1
2
C3-F), 138.4 (d, JCF = 5.9 Hz, C2), 141.7 (d, 3JCF = 5.0 Hz, C4-H),
160.4 (CAr–OMe). 19F NMR (282 MHz, CDCl3): δ -177.4 (s).
HRMS (ESI): m/z calcd. for [C13H10FN3O+ H+]: 244.0881, found:
244.0884.
1
(UV), mp = 148-150 °C (CHCl3). H NMR (300 MHz, CDCl3): δ
2-(4-Bromophenyl)-3-fluoro-pyrazolo[1,5-b]pyridazine 10c
4.02 (s, 3H, CO2Me), 7.40-7.53 (m, 3H, CHPh), 7.79-7.82 (m, 2H,
CHPh), 8.19 (dd, J = 9.3, 1.1 Hz, 1H, H5), 8.43 (d, J = 9.3 Hz, 1H,
H4), 9.23 (br s, 1H, H7). 13C NMR (75 MHz, CDCl3): δ 52.9
(CO2Me), 118.6 (C4-H), 119.8 (C6), 123.0 (C3–NO2), 128.2
(CHPh), 129.6 (CPh), 129.9 (CHPh), 130.0 (C5-H), 130.2 (CHPh),
132.6 (C7-H), 139.3 (C3a), 153.8 (C2), 163.8 (C=O). HRMS (ESI):
m/z calcd. for [C15H11N3O4 + H+]: 298.0822, found: 298.0819.
6b: Rf = 0.36 (PE/EtOAc, 3:1) (UV), mp = 152-154 °C (CHCl3)
(Lit.: 136-138 °C24b). NMR matches previously reported data.24b
3-Chloro-2-(4-methoxyphenyl)-pyrazolo[1,5-a]pyridine 8
Pyrazolo[1,5-b]pyridazine 10c was obtained from α-
fluoronitroalkene 1b (49.2 mg, 0.2 mmol) and
N-aminopyridazinium salt 2i (2.0 equiv.) following the general
procedure (reaction time 18 h). Column chromatography
(eluent: 7:1 PE/EtOAc) afforded 10c (30 mg, 55%) as white
solid. Rf = 0.21 (PE/EtOAc, 3:1) (UV), mp = 163-165 °C
1
(PE/EtOAc). H NMR (300 MHz, CDCl3): δ 6.96 (dd, J = 9.0, 4.4
Hz, 1H, H5), 7.61 (d, J = 8.5 Hz, 2H, CHAr), 7.96 (dd, J = 9.1, 1.8
Hz, 1H, H4), 8.00 (d, J = 8.5 Hz, 2H, CHAr), 8.26 (dd, J = 4.4, 1.8
Hz, 1H, H6). 13C NMR (75 MHz, CDCl3, 1H-13C HSQC): δ 115.1 (d,
4JCF = 3.4 Hz, C5-H), 122.6 (d,2JCF = 27.2 Hz, C3a), 123.1 (br s, C-
Obtained as a side-product in the synthesis of product 5c via
reaction
of
N-aminopyridinium
salt
2a
with
3
4
Br), 124.1 (d, JCF = 4.5 Hz, C4-H), 128.6 (d, JCF = 4.4 Hz, CHAr),
3
α-chlorosubstituted nitroalkene
7
(see above). Rf = 0.34
129.1 (d, JCF = 4.2 Hz, CAr), 132.0 (CHAr), 135.0 (d, 2JCF = 4.5 Hz,
(PE/EtOAc, 3:1) (UV). H NMR (300 MHz, CDCl3, H-1H COSY): δ
3.87 (s, 3H, OMe), 6.78 (td, J = 7.0, 1.2 Hz, 1H, H6), 7.02 (d, J =
8.9 Hz, 2H, CHAr), 7.17 (dd, J = 8.6, 7.2 Hz, 1H, H5), 7.52 (app d,
J = 8.6 Hz, 1H, H4), 8.02 (d, J = 8.9 Hz, 2H, CHAr), 8.40 (app d, J =
1
1
C2), 136.9 (d, 1JCF = 253.7 Hz, C3-F), 142.4 (C6-H). 19F NMR (282
MHz, CDCl3): δ -177.3 (s). HRMS (ESI): m/z calcd. for
[C12H779BrFN3 + H+]: 291.9880, found: 291.9882.
7.0 Hz, 1H, H7). 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C
HMBC): δ 55.3 (OMe), 112.2 (C6-H), 114.0 (CHAr), 116.0 (C4-H),
123.8 (C5-H), 124.1 (CAr), 128.5 (C7-H), 129.3 (CHAr), 138.4
1
1
3-Fluoro-2-(4-methoxyphenyl)pyrazolo[1,5-b]pyridazine 10d
Pyrazolo[1,5-b]pyridazine
10d
was
obtained
from
α-fluoronitroalkene 1g (38.5 mg, 0.2 mmol) and
N-aminopyridazinium salt 2j (2.0 equiv.) following the general
procedure (reaction time 25 h). Column chromatography
(eluent: 5:1, then 3:1, PE/EtOAc) afforded 10d (22.5 mg, 47%)
as white solid. Rf = 0.17 (PE/EtOAc, 3:1) (UV), mp = 123-125 °C
(C3a), 148.6 (C2), 160.0 (C-OMe). HRMS (ESI): m/z calcd. for
[C14H1135ClN2O + H+]: 259.0633, found: 259.0632.
2-(4-Bromophenyl)-3-fluoro-pyrazolo[1,5-a]pyrazine 10a
Pyrazolo[1,5-a]pyrazine 10a was obtained from α-
fluoronitroalkene 1b (49.2 mg, 0.2 mmol) and
N-aminopyrazinium salt 2h (2.0 equiv.) following the general
procedure (reaction time 18 h). Column chromatography
1
(CHCl3). H NMR (300 MHz, CDCl3): δ 3.89 (s, 3H, OMe), 6.94
(dd, J = 9.1, 4.4 Hz, 1H, H5), 7.04 (d, J = 8.7 Hz, 2H, CHAr), 7.91
(dd, J = 9.1, 1.9 Hz, 1H, H4), 8.06 (dd, J = 8.6 Hz, 2H, CHAr), 8.20
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Journal Name
ARTICLE
1
(dd, J = 4.4, 1.9 Hz, 1H, H6). 13C NMR (75 MHz, CDCl3, H-13C Pyrazolo[1,5-b]pyridazine 11c was obtained from nitroalkene
View Article Online
DOI: 10.1039/C9OB02668A
1
4
HSQC, H-13C HMBC): δ 55.3 (OMe), 114.3 (CHAr), 114.8 (d, JCF 4b (22.3 mg, 0.15 mmol) and N-aminopyridazinium salt 2j (2.0
2
= 3.2 Hz, C5-H), 122.5 (d, overlapped, JCF ≈ 27 Hz, C3a), 122.7 equiv.) following the general procedure (reaction time 2 h).
(d, overlapped, 3JCF = 3.9 Hz, CAr), 123.8 (d, JCF = 4.5 Hz, C4-H), Column chromatography (eluent: 5:1, then 1:1, PE/EtOAc)
3
4
2
128.5 (d, JCF = 4.3 Hz, CHAr), 136.0 (d, JCF = 4.2 Hz, C2), 136.5 afforded 11c (22 mg, 61%) as slightly yellow solid. Rf = 0.32
1
1
(d, JCF = 252.2 Hz, C3-F), 141.7 (C6-H), 160.2 (CAr–OMe). 19F (PE/EtOAc, 1:1) (UV), mp = 112-115 °C (CHCl3). H NMR (300
NMR (282 MHz, CDCl3): δ -179.0 (s). HRMS (ESI): m/z calcd. for MHz, CDCl3): δ 7.51-7.56 (m, 4H, 3×CHPh and H5), 7.88-7.92 (m,
[C13H10FN3O + H+]: 244.0881, found: 244.0889.
2H, CHo-Ph), 8.60 (dd, J = 4.5, 1.9 Hz, 1H, H6), 8.80 (dd, J = 9.1,
1.9 Hz, 1H, H4). 13C NMR (75 MHz, CDCl3, 1H-13C HSQC): δ 122.0
from (C5-H), 128.1 (C4-H), 128.3 (CHPh), 129.2 (C3a), 130.1 (CHPh),
3-Fluoro-2-(4-fluorophenyl)pyrazolo[1,5-b]pyridazine 10e
Pyrazolo[1,5-b]pyridazine
10e
was
obtained
α-fluoronitroalkene 1c (37 mg, 0.2 mmol) and 130.3 (CHPh), 133.0 (CPh), 144.6 (C6-H), 149.7 (C2). HRMS (ESI):
N-aminopyridazinium salt 2j (2.0 equiv.) following the general m/z calcd. for [C12H8N4O2 + H+]: 241.0720, found: 241.0723.
procedure (reaction time 3 h). Column chromatography 3-Nitro-2-phenethylpyrazolo[1,5-b]pyridazine 11d
(eluent: 3:1, then 2:1, PE/EtOAc) afforded 10e (27 mg, 58%) as Pyrazolo[1,5-b]pyridazine 11d was obtained from nitroalkene
white solid. Rf = 0.23 (PE/EtOAc, 3:1) (UV), mp = 132-137 °C 4d (26.6 mg, 0.15 mmol) and N-aminopyridazinium salt 2j (2.0
1
(CHCl3). H NMR (300 MHz, CDCl3): δ 6.98 (dd, J = 9.1, 4.4 Hz, equiv.) following the general procedure (reaction time 2 h).
1H, H5), 7.20 (t, J = 8.7 Hz, 2H, CHAr), 7.94 (dd, J = 9.1, 1.9 Hz, Column chromatography (eluent: 5:1, then 1:1, PE/EtOAc)
1H, H4), 8.10 (dd, J = 8.7, 5.5 Hz, 2H, CHAr), 8.24 (dd, J = 4.4, 1.9 afforded 11d (26.5 mg, 65%) as slightly yellow oil. Rf = 0.13
1
Hz, 1H, H6). 13C NMR (75 MHz, CDCl3, 1H-13C HSQC, 1H-13C (PE/EtOAc, 1:1) (UV). H NMR (300 MHz, CDCl3): δ 3.18-3.23
HMBC): δ 115.0 (d, 4JCF = 3.2 Hz, C5-H), 115.9 (d, 2JCF = 21.7 Hz, (m, 2H, PhCH2), 3.57-3.62 (m, 2H, C2-CH2), 7.21-7.37 (m, 5H,
2
3
CHAr), 122.6 (d, JCF = 27.3 Hz, C3a), 124.1 (d, JCF = 4.5 Hz, C4- Ph), 7.50 (dd, J = 9.0, 4.5 Hz, 1H, H5), 8.56 (dd, J = 4.5, 1.9 Hz,
H), 126.3 (br s, CAr), 129.0 (dd, JCF = 8.3, 4.4 Hz, CHAr), 135.2 (d, 1H, H6), 8.73 (dd, J = 9.0, 1.9 Hz, 1H, H4). 13C NMR (75 MHz,
2JCF = 4.8 Hz, C2), 136.6 (d, 1JCF = 252.6 Hz, C3-F), 142.2 (C6-H), CDCl3, 1H-13C HSQC, 1H-13C HMBC): δ 29.9 (C2-CH2), 33.9
1
163.1 (d, JCF = 249.2 Hz, CAr-F). 19F NMR (282 MHz, CDCl3): δ - (PhCH2), 121.9 (C5-H and C3–NO2), 126.3 (CHPh), 127.5 (C4-H),
112.2 (s, 1F), -178.5 (s, 1F). HRMS (ESI): m/z calcd. for 128.5 (2×CHPh), 132.4 (C3a), 140.8 (CPh), 144.1 (C6-H), 152.2
(C2). HRMS (ESI): m/z calcd. for [C14H12N4O2 + H+]: 269.1033,
found: 269.1024.
[C12H7F2N3 + H+]: 232.0681, found: 232.0676.
2-(4-Methoxyphenyl)-3-nitro-pyrazolo[1,5-a]pyrazine 11a
Pyrazolo[1,5-a]pyrazine 11a was obtained from α-
unsubstituted nitroalkene 4c (35.8 mg, 0.2 mmol) and N-
aminopyrazinium salt 2h (2.0 equiv.) following the general
procedure (reaction time 6 h). Column chromatography
(eluent: 7:1 PE/EtOAc) afforded 11a (38.2 mg, 79%) as yellow
solid. Rf = 0.37 (PE/EtOAc, 3:1) (UV), mp = 186-188°C (CHCl3).
Conclusions
In conclusion, a new highly efficient method for the synthesis
of 3-fluoro- and 3-nitro-pyrazolo[1,5-a]pyridines was
developed. Application of Cu(OAc)2∙H2O/2,6-lutidine oxidative
system provided an access to the pharmaceutically attractive
fluorinated pyrazolopyridines. Moreover, corresponding nitro-
substituted heterocycles were also prepared by the present
method in excellent yields. In addition, novel fluorinated
pyrazolo[1,5-a]pyridazines and pyrazolo[1,5-b]pyrazines were
prepared for the first time using the present methodology.
1
1H NMR (300 MHz, CDCl3, H-1H COSY): δ 3.89 (s, 3H, OMe),
7.03 (d, J = 8.7 Hz, 2H, CHAr), 7.83 (d, J = 8.7 Hz, 2H, CHAr), 8.29
(d, J = 4.2 Hz, 1H, H6), 8.46 (d, J = 4.2 Hz, 1H, H7), 9.80 (s, 1H,
1
1
H4). 13C NMR (75 MHz, CDCl3, H-13C HSQC, H-13C HMBC): δ
55.4 (OMe), 113.9 (CHAr), 121.1 (CAr), 121.4 (C7-H), 131.7
(CHAr), 132.6 (C3a), 133.6 (C6-H), 145.0 (C4-H), 151.5 (C2),
161.5 (C-OMe). HRMS (ESI): m/z calcd. for [C13H10N4O3 + H+]:
271.0826, found: 271.0829.
Conflicts of interest
3-Nitro-2-(2-phenylethyl)pyrazolo[1,5-a]pyrazine 11b
Pyrazolo[1,5-a]pyrazine 11b was obtained from nitroalkene 4d
(17.7 mg, 0.1 mmol) and N-aminopyrazinium salt 2h (2.0
equiv.) following the general procedure (reaction time 18 h).
There are no conflicts to declare.
Column chromatography (eluent: 3:1, PE/EtOAc) afforded
9
Acknowledgements
(20.5 mg, 76%) as slightly yellow. Rf = 0.17 (PE/EtOAc, 3:1)
1
(UV), mp = 138-139 °C (CHCl3). H NMR (300 MHz, CDCl3): δ
This work was supported by the Russian Foundation for Basic
Research (grant 18-03-00810). The authors thank Dr. N. G.
Kolotyrkina and Dr. A. O. Chizhov (N. D. Zelinsky Institute of
Organic Chemistry) for registration of HRMS. X-ray diffraction
data for product 3b were collected with the financial support
from Ministry of Science and Higher Education of the Russian
Federation using the equipment of the Center for molecular
composition studies of INEOS RAS. Crystal structure
determination for product 10c was performed in the
3.14-3.19 (m, 2H, PhCH2), 3.54-3.59 (m, 2H, C2-CH2), 7.21-7.36
(m, 5H, Ph), 8.29 (d, J = 4.5 Hz, 1H, H6), 8.43 (dd, J = 4.5, 1.1
Hz, 2H, H7), 9.77 (d, J = 1.1 Hz, 1H, H4). 13C NMR (75 MHz,
CDCl3, 1H-13C HSQC, 1H-13C HMBC): δ 29.8 (C2-CH2), 33.8
(PhCH2), 121.5 (C7-H), 123.6 (C3-NO2), 126.4 (CHPh), 128.5
(CHPh), 128.6 (CHPh), 131.8 (C3a), 133.4 (C6-H), 140.5 (CPh),
144.4 (C4-H), 154.3 (C2). HRMS (ESI): m/z calcd. for
[C14H12N4O2+ H+]: 269.1033, found: 269.1028.
3-Nitro-2-phenylpyrazolo[1,5-b]pyridazine 11c
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 11
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ARTICLE
Journal Name
2588; (c) S. Opekar, R. Pohl, P. Beran, L. RulisekVaienwdArPtic.leBOenielinre,
Chem. Eur. J., 2014, 20, 1453.
Department of Structural Studies of Zelinsky Institute of
Organic Chemistry.
DOI: 10.1039/C9OB02668A
16 L. V. Politanskaya, G. A. Selivanova, E. V. Panteleeva, E. V.
Tretyakov, V. E. Platonov, P. V. Nikul'shin, A. S. Vinogradov,
Ya. V. Zonov, V. M. Karpov, T. V. Mezhenkova, A. V. Vasilyev,
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E. V. Shchegolkov, V. I. Saloutin, V. B. Sokolov, A. Yu.
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Astakhova, B. A. Shainyan, A. A. Tabolin, S. L. Ioffe, V. M.
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34 We believe that both atmospheric oxygen and excess of
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35 Recent publication on pyrazolo[1,5-a]pyrazines and
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