N-Boc-4-aminopyrazole-5-carbaldehydes in Friendl?nder synthesis of pyrazolo[4,3-b]pyridines

Article abstract of DOI:10.1007/s10593-019-02468-8

[Figure not available: see fulltext.] N-Boc-4-aminopyrazole-5-carbaldehydes reacted with aryl, hetaryl, alkyl, and cycloalkyl ketones containing methylene groups. The reactions were accomplished in refluxing acetic acid in the presence of pyrrolidine and resulted in the formation of 5-substituted and carbo[b]fused pyrazolo[4,3-b]pyridines.

Full text of DOI:10.1007/s10593-019-02468-8

DOI 10.1007/s10593-019-02468-8
Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
N-Boc-4-aminopyrazole-5-carbaldehydes in Friendländer synthesis
of pyrazolo[4,3-b]pyridines
Georgiy G. Yakovenko1,2*, Oleh A. Lukianov2,
Andriy V. Bol'but2,3, Mykhailo V. Vovk2
1 National University ''Kyiv-Mohyla Academy'',
2 Hrygorija Skovorody St., Kyiv 04655, Ukraine; e-mail: chemgeorge@i.ua
2 Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
5 Murmanska St., Kyiv 02094, Ukraine; е-mail: mvovk@ioch.kiev.ua
3 Enamine Ltd.,
78 Chervonotkatska St., Kyiv 02094, Ukraine; e-mail: bolbut@ukr.net
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2019, 55(4/5), 379–385
Submitted January 22, 2019
Accepted February 13, 2019
N-Boc-4-aminopyrazole-5-carbaldehydes reacted with aryl, hetaryl, alkyl, and cycloalkyl ketones containing methylene groups. The
reactions were accomplished in refluxing acetic acid in the presence of pyrrolidine and resulted in the formation of 5-substituted and
carbo[b]fused pyrazolo[4,3-b]pyridines.
Keywords: 4-aminopyrazole-5-carbaldehydes, ketones, pyrazolo[4,3-b]pyridines, Friendländer reaction.
The Friendländer reaction, representing a very capable
approach to the synthesis of quinolines, was discovered
more than 130 years ago1 and still has not lost its great
significance in the field of organic chemistry.2 It can be
described as acid- or base-catalyzed or thermally initiated
cyclocondensation of aromatic o-amino-substituted
aldehydes or ketones with carbonyl compounds containing
activated methylene groups.3,1с Throughout the history of
its development, the applicability of Friendländer reaction
has been extended to a series of nitrogen-containing
heterocyclic aminocarbonyl compounds. Notable examples
of the latter include aminonicotinic aldehydes that are used
in the synthesis of biologically important 1,6- and
1,8-naphthyridine derivatives.4 Performing the Friend-
länder reaction with some types of azolylamino aldehydes
has also been described in the literature, in particular,
5-amino-4-formylimidazole,5 5-aminoisoxazole-4-carbalde-
hyde,6 and 5-amino-1,2,3-triazole-4-carbaldehyde have
been used.7 However, the best explored among such
substrates are 5-aminopyrazole-4-carbaldehydes,8 which
are used in the synthesis of pyrazolo[3,4-b]pyridines, some
of which have been characterized as antibacterial agents,9
as well as selective inhibitors of acetylcholinesterase10 and
chemokine receptor CCR2.11
In contrast to the stable 5-aminopyrazole-4-carbalde-
hydes, their isomers 4-aminopyrazole-5-carbaldehydes
have not been isolated as individual compounds. Only
4-amino-3-tert-butyl-1-methylpyrazole-5-carbaldehyde has
been described, after it was generated in situ from its 4-nitro
analog, the condensation of which with acetophenone led
to the respective pyrazolo[4,3-b]pyridine.12 Studying this
series of structures has revealed compounds with anti-
viral,13 anti-inflammatory,14 antitumor,15 and bactericidal16
properties. For this reason, it is of major synthetic
importance to search for a simple and preparatively
convenient method that would help to build pyrazolo-
[4,3-b]pyridine framework using the classical Friendländer
reaction, which was also the goal of this study.
It has been previously demonstrated that some o-amino-
benzaldehydes17 and 3(4)-amino(iso)nicotinaldehydes18
under the conditions of Friendländer reaction can undergo
self-condensation, and for this reason, it is preferable to use
their N-Boc-substituted derivatives. We considered it
worthwhile to employ this approach also for the synthesis
0009-3122/19/55(4/5)-0379©2019 Springer Science+Business Media, LLC
379

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
Scheme 2
NHBoc
of 4-aminopyrazole-5-carbaldehydes, especially because
one of such compounds – 4-(Boc-amino)-1-methylpyrazole-
5-carbaldehyde (3а) – has been described in patent litera-
ture.19 We extended the applicability of the method proposed
for its synthesis to a series of derivatives 3b–d and first
perfomed Boc-acylation of 4-aminopyrazoles 1b–d in the
presence of catalytic amounts of DMAP, followed by the
formylation of N-Boc-substituted aminopyrazoles 2b–d by
the action of n-BuLi and DMF (in the case of compound 2b)
or n-BuLi and ethyl formate (in the cases of compounds
2с,d).
N
Ph
O
N
O
+
N
N
N
Me
Ph
Me
Me
4a
5a
3a
Table 1. Optimization of reaction conditions for the
cyclocondensation of compounds 3a and 4a in refluxing АсОН*
The content of
compound 5а, %**
Entry
Catalyst (equiv)
Time, h
Scheme 1
1
2
3
4
5
6
7
8
AcONH4 (0.5)
AcONH4 (1.0)
6
6
6
2
4
4
4
4
26
54
62
45
76
74
68
65
Pyrrolidine (0.5)
Pyrrolidine (1.0)
Pyrrolidine (1.0)
Pyrrolidine (2.0)
Piperidine (1.0)
Morpholine (1.0)
The cyclocondensation reactions of N-Boc-aminoaryl-
(hetaryl) aldehydes that are described in the literature were
performed with various reactants and reaction conditions:
MeONa in MeOH,18a sequential treatment of the reaction
mixtures with t-BuOK and HCl,17а CF3COOH and
NaOH,18b,c or by using CF3COOH as a solvent.18d We
optimized the Friendländer reaction of N-Boc-amino-
formylpyrazoles and ketones using aminoaldehyde 3а and
acetophenone 4а as the example with respect to solvents,
catalysts, and reaction conditions by following the reaction
progress by LC-MS analysis (Scheme 2). We found that the
reaction did not proceed in EtOH, MeCN, or 1,4-dioxane as
solvent in the presence of 0.1, 0.5, or 1.0 equiv of catalyst
(KОН, EtONa, AcONH4, H2SO4, piperidine) at room
temperature, while resinification of the reaction mixtures
started at 50°С, and was significantly accelerated at reflux.
No major changes in the results were observed when using
CF3COOH as solvent and catalyst at room temperature, but
formation of the respective N-trifluoroacetylaminoformyl-
pyrazole occurred at reflux. The reaction gave positive
results when performed in refluxing AcOH in the presence of
AcONH4 or organic secondary amines (Scheme 2, Table 1).
Thus, refluxing reactants 3а and 4а for 6 h with 0.5 equiv
of АсONH4 resulted in 26% content of pyrazolo[4,3-b]-
pyridine 5а in the reaction mixture (entry 1). Doubling the
amount of catalyst also doubled the yield of product 5a
(entry 2). However, the use of an equimolar amount of
secondary cycloalkylamines was more effective (entries 5–7),
with the best results (76% content of product 5а at full
conversion of the starting reactants) obtained when using
pyrrolidine. It is important to note that adding more than
1 equiv of catalyst practically did not affect the yield of the
target product.
* Compound 3а (1.2 mmol), compound 4а (1.21 mmol), АсОН (30 ml).
** The content of compound 5а in the reaction mixture according to LC-
MS analysis.
obtained results enabled us to thoroughly assess the
correlation between the structure of reactant and the
selectivity of the cyclocondensation processes. In
particular, the best yields of the target products 5а–c,e–j
were observed in the reactions of 1-alkyl- and (α-pyridyl)-
pyrazoles 3a,b,d with acetophenones 4а–е and isonicotinyl
methyl ketone 4f. When 4-aminoacetophenone 4е was used
in this series of experiments, N-acetyl derivative 5е was
isolated from the reaction mixture while acetate 5h was
obtained in the case of 4-pyridinyl methyl ketone 4f.
Comparing the yields of the isomeric products 5с (52%) and
5d (36%) indicated that the steric parameters of 2-bromo-
phenyl methyl ketone 4е had great importance for the
cyclization process. The majority of reactions failed when
using 1-phenyl-substituted pyrazole 3с and only in the case
of ketone 4f it was possible to isolate pyrazolopyridine 5і
in 22% yield.
Compared to acetophenones, dialkyl and cycloalkyl
ketones 4g–l were found to be less convenient reactants in
cyclocondensation with aminoaldehydes 3a,b,d, probably
due to the greater tendency toward side reactions: 5-alkyl-
pyrazolopyridines 5k–q were obtained in 13–44% yields
and their carbo[b]fused analogs 5r–t – in 19–43% yields.
Remarkably, using acetone derivative 4і allowed to isolate
only the product of its condensation with pyrazole 3b,
namely, pyrazolopyridine 5o as an individual compound in
29% yield. It should be also noted that in the case of
unsymmetrical hexan-2-one (4j) the cyclocondensation of
aminoformylpyrazole 3а involved both the methyl and
methylene groups, giving a mixture of isomers 5m and 5n
in 43% overall yield in approximately 2.5:1 ratio. These
isomers were separated by preparative liquid
chromatography.
The identified optimum conditions for the synthesis of
pyrazolopyridine 5а were tested by performing
Friendländer reaction of N-Boc-4-amino-5-formylpyrazoles
3b–d with aryl(hetaryl) methyl ketones 4a–f, dialkyl
ketones 4g–j, and cycloalkyl ketones 4k,l (Scheme 3). The
380

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
Scheme 3
NHBoc
N
R3
R2
N
O
H
N
+
R2
N
CHO
R3
N
N
AcOH
, 4–6 h
13–70%
R1
R1
4a–l
5a–t
3a–d
4 a R2 = H, R3 = Ph; b R2 = H, R3 = 4-MeC6H4; c R2 = H, R3 = 4-BrC6H4; d R2 = H, R3 = 2-BrC6H4; e R2 = H, R3 = 4-H2NC6H4;
f R2 = H, R3 = 4-Py; g R2 = Me, R3 = Et; h R2 = H, R3 = i-Pr; i R2 = H, R3 = Me; j R2 = H, R3 = n-Bu; k R2 + R3 = (CH2)2; l R2 + R3 = (CH2)3
Me
Br
NHAc
N
N
N
N
N
N
N
N
N
N
Br
N
N
N
N
N
Me
Me
Me
Me
Me
5a (70%)
N
5b (63%)
5c (48%)
5d (32%)
5e (69%)
N
Ph
Me
Br
NH+AcO–
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
t-Bu
t-Bu
t-Bu
Ph
5f (59%)
5g (54%)
Me
5h (58%)
5i (22%)
5j (38%)
Me
N
N
N
N
Me
N
Me
Me
Me
Me
N
N
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
t-Bu
5k (36%)
5l (44%)
5m (30%)
5n (13%)
5o (29%)
N
N
N
N
N
Me
Me
Me
Me
5q (43%)
N
N
N
N
Me
N
N
N
N
N
N
t-Bu
t-Bu
N
N
5t (53%)
5s (39%)
5p (30%)
5r (19%)
When discussing the possible mechanism of the studied
Friendländer reaction and considering the earlier studies,20
it appeared logical that the first stage in this process is
crotonic condensation catalyzed by pyrrolidine, leading to
the E-enone А, which was present in the amount of 35% in
the reaction mixture when performing the condensation of
compounds 3а and 4а in АсОН at 50°С. The subsequent
acid-catalyzed isomerization of E-enone А led to the
intermediate В having Z-configuration. Removal of the Boc
protecting group generated the intermediate С, which
subsequently underwent cyclodehydration, providing the
target product 5.
aldehyde 3а with hexan-2-one (4j) at the methyl or
1
methylene group, respectively. Н NMR spectrum of the
major isomer 5m featured the characteristic doublet signals
of Н-6 and Н-7 protons at 7.28 and 8.02 ppm with a spin-
spin coupling constant of 8.8 Hz, while the spectrum of the
minor isomer 5n contained singlet signals of the 6-CH3
protons at 2.55 ppm and Н-7 proton at 7.80 ppm.
Thus, we have shown the possibility of performing
Friendländer reaction in the series of 4-(Boc-amino)-
pyrazole-5-carbaldehydes, opening a convenient synthetic
access to 5-substituted and carbo[b]fused pyrazolo[4,3-b]-
pyridines.
The structures of all synthesized starting compounds
3b–d and products 5а–t were confirmed by NMR spectro-
scopy and LC-MS analysis. It was important to correctly
identify the structures of the regioisomeric compounds
5m,n formed from the initial condensation of amino-
Experimental
IR spectra were recorded on a Bruker Vertex 70 FT-IR
spectrometer for samples in KBr pellets. Н and 13С NMR
1
spectra were acquired on a Varian VXR-400 instrument
Scheme 4
Boc
Boc
NHBoc
NH
2O
N
R3
R2
N
H
NH
NH O
H+
R3
R2
R2
H+
O
R3
R2
N
O
+
R2
R3
N
N
N
N
R3
N
N
– CO2
– i-C4H8
N
– H2O
– H2O
N
N
R1
R1
R1
4
5
O
3
R1
R1
E-A
Z-B
Z-C
381

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
(400 and 126 MHz, respectively) according to pulsed
152.7. Mass spectrum, m/z (Irel, %): 261 [М+Н]+ (100).
Found, %: C 60.21; H 6.33; N 21.38. C13H16N4O2.
Calculated, %: C 59.99; H 6.20; N 21.52.
Fourier technique for samples in DMSO-d6 (compounds
3d, 5a–с,e–j,m–o,q,t) or in CDCl3 (compounds 2b–d, 3b,c,
5d,k,l,p–s), using TMS as internal standard. Mass spectra
were recorded on an Agilent LC/MSD SL system equipped
with a Zorbax SB-C18 column 4.6 × 15 mm, 1.8 µm (PN
82(c)75-932), the solvent was DMSO, electrospray
ionization at atmospheric pressure. Preparative HPLC of
compounds 5m and 5n was performed using a Teledyne
Synthesis of compounds 3b–d (General method). A
solution of carbamate 2b–d (0.36 mol) in THF (1200 ml)
was cooled to –78°С under argon atmosphere and treated
by adding 2.5 М solution of n-BuLi in hexanе (317 ml,
2.2 equiv). The reaction mixture was stirred for 2–3 h at the
temperature range from –78 to –70°С. The reaction mixture
was then treated at the same temperature with DMF (29.3 g,
0.4 mol, in the case of carbamate 2b), heated to room
temperature, and stirring was continued overnight. After 10–
12 h, the reaction mixture was quenched with saturated
aqueous solution of NH4Cl (200 ml). In the case of
carbamates 2c,d, the reaction mixture was treated with
ethyl formate (27 g, 0.365 mol), stirred for 0.25 h, the
temperature was raised to –20°С, and saturated aqueous
solution of NH4Cl (200 ml) was added at once. In both
cases, the mixture was further stirred for 20–30 min and
extracted with MTBE (3×200 ml). The organic layer was
washed twice with saturated aqueous NaCl solution, dried
over anhydrous Na2SO4, filtered through a layer of silica
gel, and evaporated. The oily residue was taken up in 3:2
mixture of MTBE–hexane (150 ml), stirred, the obtained
precipitate was then filtered off and air-dried.
Isco
Combiflash
Companion
preparative
liquid
chromatograph (eluent MTBE–MeCN, 9:1). Elemental
analysis was performed with a PerkinElmer 2400 Series
CHN Analyzer at the Analytical Laboratory of the Institute
of Organic Chemistry, National Academy of Sciences of
Ukraine. Melting points were determined on a Kofler
bench and were not corrected.
The starting 4-aminopyrazoles 1а–d were provided by
Enamine Ltd. (Kyiv, Ukraine). Compounds 2а and 3а were
synthesized according to a published procedure.19
Synthesis of compounds 2b–d (General method). A
solution of 4-aminopyrazole 1b–d (1.03 mol) in THF
(1400 ml) was cooled to 0°С, then DMAP (5.03 g, 0.041 mol)
was added to the stirred solution, followed by slow
addition of di(tert-butyl) dicarbonate (229 g, 1.05 mol)
over 30 min. The mixture was maintained at the indicated
temperature for 1 h, allowed to warm to the room
temperature, and stirred for further 4–6 h. The reaction
mixture was then heated at 40°С for 1 h, evaporated,
extracted with MTBE (800 ml). The obtained oily product
was diluted with 3:2 MTBE–hexane mixture (300 ml),
stirred, the precipitate that formed was filtered off and air-
dried.
tert-Butyl
(1-tert-butyl-5-formyl-1Н-pyrazol-4-yl)-
carbamate (3b). Yield 86.8 g (90%), lilac-colored powder,
mp 93–94°C. IR spectrum, ν, cm–1: 3373 (N–H), 1696, 1719
1
(С=О). H NMR spectrum, δ, ppm: 1.57 (9H, s, С(CH3)3);
1.72 (9H, s, С(CH3)3); 8.00 (1H, s, Н-3); 8.70 (1H, s, NH);
10.36 (1H, s, CH=O). 13C NMR spectrum, δ, ppm: 25.1;
30.6; 61.2; 67.4; 116.5; 126.9; 131.2; 152.1; 180.9. Mass
spectrum, m/z (Irel, %): 268 [М+Н]+ (100). Found, %:
C 58.62; H 8.07; N 15.59. C13H21N3O3. Calculated, %:
C 58.41; H 7.92; N 15.72.
tert-Butyl (1-tert-butyl-1Н-pyrazol-4-yl)carbamate (2b).
Yield 230 g (93%), violet powder, mp 72–73°C. IR spect-
rum, ν, cm–1: 3273 (N–H), 1710 (С=О). 1H NMR spectrum,
δ, ppm (J, Hz): 1.50 (9H, s, С(CH3)3); 1.56 (9H, s, С(CH3)3);
6.25 (1H, s, NH); 7.33 (1H, s, H-5); 7.80 (1H, s, H-3).
13C NMR spectrum, δ, ppm: 27.9; 29.2; 58.0; 79.7; 116.6;
120.4; 128.9; 152.8. Mass spectrum, m/z (Irel, %): 240
[М+Н]+ (100). Found, %: C 60.02; H 8.71; N 17.44.
C12H21N3O2. Calculated, %: C 60.23; H 8.84; N 17.56.
tert-Butyl (1-phenyl-1Н-pyrazol-4-yl)carbamate (2c).21
Yield 193 g (72%), brown powder, mp 93–94°C. IR spect-
rum, ν, cm–1: 3290 (N–H), 1706 (С=О). 1H NMR spectrum,
δ, ppm (J, Hz): 1.52 (9H, s, С(CH3)3); 6.53 (1H, s, NH);
7.24 (1H, t, J = 7.6, Н Ar); 7.42 (2H, t, J = 7.6, Н Ar); 7.54
(1H, s, Н-5); 7.66 (2H, d, J = 7.6, Н Ar); 8.21 (1H, s, Н-3).
13C NMR spectrum, δ, ppm: 28.1; 79.0; 116; 117.8; 124.6;
125.7; 129.5; 132.4; 139.8; 152.7. Mass spectrum, m/z (Irel, %):
260 [М+Н]+ (100). Found, %: C 64.68; H 6.72; N 16.11.
C14H17N3O2. Calculated, %: C 64.85; H 6.61; N 16.20.
tert-Butyl [1-(pyridin-2-yl)-1Н-pyrazol-4-yl]carbamate
(2d).22 Yield 253 g (94%), gray powder, mp 88–89°C.
tert-Butyl (5-formyl-1-phenyl-1Н-pyrazol-4-yl)carba-
mate (3с). Yield 74.6 g (72%), pale-pink powder, mp 97–
98°C. IR spectrum, ν, cm–1: 3382 (N–H), 1701, 1722
1
(С=О). H NMR spectrum, δ, ppm: 1.54 (9H, s, С(CH3)3);
7.48–7.56 (5H, m, Н Ph); 8.33 (1H, s, NH); 8.52 (1H, s,
H-3); 9.89 (1H, s, CH=O). 13C NMR spectrum, δ, ppm:
28.3; 81.5; 125.0; 126.0; 128.9; 129.7; 130.7; 130.8; 138.3;
152.5; 181.7. Mass spectrum, m/z (Irel, %): 288 [М+Н]+
(100). Found, %: C 62.45; H 5.77; N 14.74. C15H17N3O3.
Calculated, %: C 62.71; H 5.96; N 14.63.
tert-Butyl [5-formyl-1-(pyridin-2-yl)-1Н-pyrazol-4-yl]-
carbamate (3d). Yield 70.5 g (68%), beige powder,
mp 82–83°C. IR spectrum, ν, cm–1: 3388 (N–H), 1696,
1
1728 (С=О). H NMR spectrum, δ, ppm (J, Hz): 1.50 (9H,
s, С(CH3)3); 7.45 (1H, t, J = 5.6, H Py); 7.90 (1H, d,
J = 8.4, H Py); 8.06 (1H, t, J = 6.8, Н Py); 8.21 (1H, s,
NH); 8.52 (1H, d, J = 4.4, H Pyr); 8.81 (1H, s, Н-3); 10.97
(1H, s, CH=O). 13C NMR spectrum, δ, ppm: 28.3; 81.5;
114.7; 122.0; 126.4; 131.9; 132.0; 138.9; 147.7; 152.6;
152.7; 186.1. Mass spectrum, m/z (Irel, %): 289 [М+Н]+
(100). Found, %: C 58.51; H 5.74; N 19.65. C14H16N4O3.
Calculated, %: C 58.32; H 5.59; N 19.43.
1
IR spectrum, ν, cm–1: 3287 (N–H), 1698 (С=О). H NMR
spectrum, δ, ppm (J, Hz): 1.50 (9H, s, С(CH3)3); 6.43 (1H,
s, NH); 7.12 (1H, t, J = 5.6, Н Py); 7.70–7.78 (2H, m, Н-5,
H Py); 7.88 (1H, d, J = 8.4, Н Py); 8.34 (1H, d, J = 4.0,
Н Py); 8.60 (1H, s, Н-3). 13C NMR spectrum, δ, ppm: 28.1;
79.1; 111.2; 114.8; 121.4; 124.8; 133.6; 139.2; 148.2; 150.9;
Synthesis of compounds 5a–t (General method). A
solution of N-Boc-aminopyrazole carbaldehyde 3a–d
382

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
(0.02 mol) in AcOH (100 ml) was treated by adding
153.9. Mass spectrum, m/z (Irel, %): 290 [М(81Br)+Н]+ (90),
288 [М(79Br)+Н]+ (100). Found, %: C 54.04; H 3.59;
N 14.49. C13H10BrN3. Calculated, %: C 54.19; H 3.50;
N 14.58.
ketone 4a–l (0.022 mol) and pyrrolidine (1.4 g, 0.02 mol),
stirred for 1 h at room temperature and then refluxed for 4–
6 h, while controlling the reaction progress with TLC. The
mixture was cooled, the solvent was evaporated, and the
obtained oily residue was diluted with H2O (150 ml). In the
case of aryl(hetaryl) ketones, the obtained precipitate was
filtered off, washed with hexane (50 ml), dried, and
crystallized from 1:5 mixture of MTBE–МеCN
(compounds 5a,b,q,t) or МеCN (compounds 5с–j). In the
case of dialkyl and cycloalkyl ketones, the oily product was
extracted with AcOEt (2×75 ml), the organic layer was
washed with aqueous NaHCO3 and NaCl solutions, dried,
and evaporated. The residue was diluted with 2:1 mixture
of PhMe–MTBE (90 ml) and refluxed for 10 min, the
solution was decanted, evaporated at reduced pressure, the
obtained product was crystallized from 1:1 mixture of
PhMe–MTBE (compounds 5k,l,о,p,r,s).
N-[4-(1-Methyl-1Н-pyrazolo[4,3-b]pyridinyl)phenyl]acet-
amide (5е) was obtained from compounds 3а and 4e. Yield
1
3.67 g (69%), yellow powder, mp 180–182°C. H NMR
spectrum, δ, ppm (J, Hz): 2.08 (3H, s, CH3); 4.08 (3Н, s,
CH3); 7.71 (2Н, d, J = 8.0, H Ar); 7.96 (1Н, d, J = 8.8,
H-6); 8.0 (2Н, d, J = 8.0, H Ar); 8.17 (1Н, d, J = 8.8, H-7);
8.26 (1Н, s, H-3); 10.13 (1Н, s, NH). 13C NMR spectrum,
δ, ppm: 22.5; 36.3; 118.3; 119.4; 127.6; 129.9; 133.3;
134.1; 140.4; 141.6; 144.1; 152.1; 168.9. Mass spectrum,
m/z (Irel, %): 267 [М+Н]+ (100). Found, %: C 67.44; H 5.36;
N 20.91. C15H14N4O. Calculated, %: C 67.65; H 5.30; N 21.04.
1-(tert-Butyl)-5-(p-tolyl)-1Н-pyrazolo[4,3-b]pyridine
(5f) was obtained from compounds 3b and 4b. Yield 2.67 g
(59%), light-brown powder, mp 172–173°C. 1H NMR
spectrum, δ, ppm (J, Hz): 1.72 (9Н, s, С(CH3)3); 2.36 (3H,
s, CH3); 7.30 (2Н, d, J = 8.2, H Ar); 7.87 (1Н, d, J = 8.0,
H-6); 8.01 (2Н, d, J = 8.2, H Ar); 8.26 (1Н, s, H-3); 8.37
(1Н, d, J = 8.0, H-7). 13C NMR spectrum, δ, ppm: 20.8;
29.3; 60.2; 117.4; 121.2; 126.6; 128.3; 129.2; 129.4; 132.0;
134.4; 136.2; 151.5. Mass spectrum, m/z (Irel, %): 266 [М+Н]+
(100). Found, %: C 76.79; H 7.06; N 15.99. C17H19N3.
Calculated, %: C 76.95; H 7.22; N 15.84.
1-Methyl-5-phenyl-1Н-pyrazolo[4,3-b]pyridine (5а)
was obtained from compounds 3а and 4а. Yield 2.93 g
(70%), dark-brown powder, mp 155–156°C. 1H NMR
spectrum, δ, ppm (J, Hz): 3.94 (3Н, s, CH3); 7.44–7.51
(3Н, m, Н Ph); 7.99 (1H, d, J = 8.5, H-6); 8.14 (2H, d,
J = 7.0, H Ph); 8.20 (1H, d, J = 8.5, H-7); 8.31 (1Н, s,
Н-3). 13C NMR spectrum, δ, ppm: 36.4; 118.8; 119.5;
127.3; 129.1; 129.2; 132.3; 133.6; 139.6; 141.7; 152.5.
Mass spectrum, m/z (Irel, %): 210 [М+Н]+ (100). Found, %:
C 74.44; H 5.24; N 19.98. C13H11N3. Calculated, %:
C 74.62; H 5.30; N 20.08.
1-Methyl-5-(4-methylphenyl)-1Н-pyrazolo[4,3-b]-
pyridine (5b) was obtained from compounds 3а and 4b.
Yield 2.81 g (63%), brown powder, mp 157–158°C.
1H NMR spectrum, δ, ppm (J, Hz): 2.36 (3H, s, CH3); 4.09
(3Н, s, CH3); 7.30 (2Н, d, J = 8.0, Н Ar); 7.97 (1Н, d,
J = 8.0, Н-6); 8.03 (2Н, d, J = 8.0, Н Ar); 8.20 (1Н, d,
J = 8.0, Н-7); 8.28 (1Н, s, Н-3). 13C NMR spectrum, δ, ppm:
21.3; 36.4; 118.5; 119.4; 127.2; 129.8; 132.2; 133.5; 136.8;
138.7; 141.7; 152.5. Mass spectrum, m/z (Irel, %): 224 [М+Н]+
(100). Found, %: C 75.14; H 5.72; N 18.71. C14H13N3.
Calculated, %: C 75.31; H 5.87; N 18.82.
5-(4-Bromophenyl)-1-methyl-1Н-pyrazolo[4,3-b]-
pyridine (5c) was obtained from compounds 3а and 4c.
Yield 2.77 g (48%), orange powder, mp 174–176°C.
1H NMR spectrum, δ, ppm (J, Hz): 4.11 (3Н, s, CH3); 7.69
(2Н, d, J = 8.0, Н Ar); 8.04 (1Н, d, J = 8.0, Н-6); 8.11 (2Н,
d, J = 8.0, Н Ar); 8.25 (1Н, d, J = 8.0, Н-7); 8.32 (1Н, s, Н-3).
13C NMR spectrum, δ, ppm: 36.5; 118.6; 119.7; 122.8; 129.3;
132.2; 132.4; 133.6; 138.7; 141.7; 151.2. Mass spectrum,
m/z (Irel, %): 290 [М(81Br)+Н]+ (94), 288 [М(79Br)+Н]+
(100). Found, %: C 54.37; H 3.59; N 14.47. C13H10BrN3.
Calculated, %: C 54.19; H 3.50; N 14.58.
5-(2-Bromophenyl)-1-methyl-1Н-pyrazolo[4,3-b]pyridine
(5d) was obtained from compounds 3а and 4d. Yield 1.85 g
(32%), light-yellow powder, mp 170–171°C. 1H NMR
spectrum, δ, ppm (J, Hz): 4.12 (3Н, s, CH3); 7.38 (1Н, t,
J = 8.0, Н Ar); 7.48–7.60 (3Н, m, H-6, Н Ar); 7.67 (1Н, d,
J = 8.0, Н Ar); 7.81 (1Н, d, J = 8.0, Н-7); 8.26 (1Н, s, Н-3).
13C NMR spectrum, δ, ppm: 36.5; 118.5; 122.0; 122.4;
128.3; 130.6; 132.0; 132.2; 133.4; 133.5; 141.2; 141.8;
5-[(4-Bromophenyl)-1-(tert-butyl)]-1Н-pyrazolo[4,3-b]-
pyridine (5g) was obtained from compounds 3b and 4c.
Yield 3.57 g (54%), brown powder, mp 178–180°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.70 (9Н, s, С(CH3)3);
7.64 (2Н, d, J =7.6, H Ar); 7.86 (1Н, d, J = 7.8, H-6); 8.05
(2Н, d, J = 7.6, H Ar); 8.28 (1Н, s, H-3); 8.35 (1Н, d, J = 7.8,
H-7). 13C NMR spectrum, δ, ppm: 29.7; 60.7; 117.9; 121.8;
122.8; 129.2; 130.6; 132.2; 136.2; 138.6; 143.0; 150.7.
Mass spectrum, m/z (Irel, %): 332 [М(81Br)+Н]+ (98), 330
[М(79Br)+Н]+ (100). Found, %: C 58.41; H 4.74; N 12.55.
C16H16BrN3. Calculated, %: C 58.19; H 4.88; N 12.72.
4-[1-(tert-Butyl)-1Н-pyrazolo[4,3-b]pyridin-5-yl]pyridin-
ium acetate (5h) was obtained from compounds 3b and 4f.
Yield 2.92 g (58%), dark-brown powder, mp 180–182°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.74 (9Н, s, С(CH3)3);
1.90 (3H, s, CH3COO); 8.06 (1Н, d, J = 8.0, H-6); 8.10
(2Н, d, J = 5.6, H Py); 8.37 (1Н, s, H-3); 8.51 (1Н, d, J = 8.0,
H-7); 8.70 (2Н, d, J = 5.6, H Py). The pyridinium NH proton
exchanged with residual water molecules in the deuterated
solvent. 13C NMR spectrum, δ, ppm: 21.5; 29.7; 60.9;
118.3; 121.4; 121.9; 130.9; 133.0; 143.1; 146.3; 149.2;
150.7; 172.5. Mass spectrum, m/z (Irel, %): 253 [М–AcO]+
(100). Found, %: C 65.12; H 6.36; N 17.82. C17H20N4O2.
Calculated, %: C 65.37; H 6.45; N 17.94.
1-Phenyl-5-(pyridin-4-yl)-1Н-pyrazolo[4,3-b]pyri-
dine (5i) was obtained from compounds 3с and 4f. Yield
1.19 g (22%), dark-brown powder, mp 192–194°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.38–7.65 (5Н, m,
Н Ph); 7.84 (2Н, d, J = 6.4, Н Py); 8.14 (1Н, s, H-3); 8.23
(1Н, d, J = 7.6, Н-6); 8.46 (1Н, d, J = 7.6, Н-7); 8.73 (2Н,
d, J = 6.4, Н Py). 13C NMR spectrum, δ, ppm: 107.3;
120.2; 120.9; 121.5; 122.4; 124.0; 127.7; 127.8; 130.4;
137.0; 139.2; 139.5; 150.7. Mass spectrum, m/z (Irel, %): 273
383

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
[М+Н]+ (100). Found, %: C 75.16; H 4.59; N 20.41.
spectrum, δ, ppm (J, Hz): 1.70 (9Н, s, С(CH3)3); 2.61 (3Н,
s, CH3); 7.30 (1Н, d, J = 8.8, Н-6); 8.10 (1Н, s, Н-3); 8.37
(1Н, d, J = 8.8, Н-7). 13C NMR spectrum, δ, ppm: 23.6;
29.7; 60.7; 121.3; 122.5; 130.2; 130.5; 140.6; 153.0. Mass
spectrum, m/z (Irel, %): 190 [М+Н]+ (100). Found, %: C 69.64;
H 7.81; N 22.01. C11H15N3. Calculated, %: C 69.81;
H 7.99; N 22.20.
1-(tert-Butyl)-5-ethyl-6-methyl-1Н-pyrazolo[4,3-b]-
pyridine (5p) was obtained from compounds 3b and 4g.
Yield 1.30 g (30%), dark-brown powder, mp 92–93°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.30 (3Н, t, J = 7.6,
CH3); 1.72 (9Н, s, С(CH3)3); 2.44 (3Н, s, CH3),; 2.88 (2Н,
q, J = 7.6, CH2); 7.73 (1Н, s, Н-7); 8.08 (1Н, s, Н-3).
13C NMR spectrum, δ, ppm: 12.7; 19.8; 28.4; 29.7; 60.1;
120.8; 128.8; 130.5; 131.5; 140.9; 157.1. Mass spectrum, m/z
(Irel, %): 218 [М+Н]+ (100). Found, %: C 71.99; H 8.72;
N 19.18. C13H19N3. Calculated, %: C 71.85; H 8.81;
N 19.34.
5-Ethyl-6-methyl-1-(pyridin-2-yl)-1Н-pyrazolo[4,3-b]-
pyridine (5q) was obtained from compounds 3d and 4g.
Yield 2.05 g (43%), brown powder, mp 108–109°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.29 (3Н, t, J = 7.6, CH3);
2.48 (3Н, s, CH3); 2.89 (2Н, q, J =7.6, CH2); 7.31–7.35
(1Н, m, Н Py); 7.98–8.03 (2Н, m, Н Py); 8.51 (1Н, s, Н-7);
8.56 (1Н, d, J = 4.8, Н Py); 8.77 (1Н, s, Н-3). 13C NMR
spectrum, δ, ppm: 12.5; 19.9; 28.5; 112.9; 121.2; 123.2; 131.2;
131.5; 137.4; 139.7; 141.5; 148.5; 153.8; 159.4. Mass spectrum,
m/z (Irel, %): 239 [М+Н]+ (100). Found, %: C 70.68; H 5.97;
N 23.35. C14H14N4. Calculated, %: C 70.57; H 5.92; N 23.51.
1-Methyl-5,6-dihydro-1Н-cyclobuta[b]pyrazolo[3,4-е]-
pyridine (5r) was obtained from compounds 3a and 4k.
Yield 0.6 g (19%), yellow powder, mp 107–108°C. 1H NMR
spectrum, δ, ppm (J, Hz): 3.00–3.04 (2Н, m, CH2); 3.28–3.32
(2Н, m, CH2); 3.91 (3Н, s, CH3); 7.29 (1Н, s, Н-7); 7.94 (1Н,
s, Н-3). 13C NMR spectrum, δ, ppm: 25.3; 33.6; 36.4; 56.5;
112.4; 132.3; 134.8; 138.5; 140.6. Mass spectrum, m/z
(Irel, %): 160 [М+Н]+ (100). Found, %: C 68.11; H 5.61;
N 26.57. C9H9N3. Calculated, %: C 67.90; H 5.70; N 26.40.
1-(tert-Butyl)-1,5,6,7-tetrahydrocyclopenta[b]pyrazolo-
[4,3-е]pyridine (5s) was obtained from compounds 3b and
4l. Yield 1.68 g (39%), orange powder, mp 88–89°C.
1H NMR spectrum, δ, ppm (J, Hz): 1.73 (9Н, s, С(CH3)3);
2.17–2.22 (2Н, m, CH2); 3.00–3.08 (4Н, m, 2CH2); 7.80
(1Н, s, Н-7); 8.06 (1Н, s, Н-3). 13C NMR spectrum, δ, ppm:
24.4; 29.6; 30.8; 33.0; 60.2; 116.0; 130.9; 131.3; 135.4;
141.2; 161.7. Mass spectrum, m/z (Irel, %): 216 [М+Н]+
(100). Found, %: C 72.71; H 7.79; N 19.43. C13H17N3.
Calculated, %: C 72.52; H 7.96; N 19.52.
C17H12N4. Calculated, %: C 74.98; H 4.44; N 20.58.
5-Phenyl-1-(pyridin-2-yl)-1Н-pyrazolo[4,3-b]pyri-
dine (5j) was obtained from compounds 3d and 4a. Yield
1
3.06 g (38%), dark-gray powder, mp 174–175°C. H NMR
spectrum, δ, ppm (J, Hz): 7.36 (1Н, t, J = 7.6, Н Ph); 7.46–
7.53 (3Н, m, Н Ph, H-6); 8.01–8.05 (2Н, m, Н Ph); 8.12–
8.18 (3Н, m, Н Py); 8.59 (1Н, d, J = 5.4, Н Py); 8.71 (1Н,
s, Н-3); 9.08 (1Н, d, J = 8.2, Н-7). 13C NMR spectrum,
δ, ppm: 113.0; 120.4; 121.5; 124.3; 127.4; 128.6; 129.1;
129.3; 129.5; 138.1; 139.0; 139.8; 148.6; 153.5; 154.1. Mass
spectrum, m/z (Irel, %): 273 [М+Н]+ (100). Found, %:
C 74.79; H 4.38; N 20.47. C17H12N4. Calculated, %:
C 74.98; H 4.44; N 20.58.
5-Ethyl-1,6-dimethyl-1Н-pyrazolo[4,3-b]pyridine (5k)
was obtained from compounds 3a and 4g. Yield 1.36 g
1
(36%), orange powder, mp 115–116°C. H NMR spectrum,
δ, ppm (J, Hz): 1.30 (3Н, t, J = 8.0, CH3); 2.45 (3Н, s,
CH3); 2.88 (2Н, q, J = 8.0, CH2); 4.02 (3Н, s, CH3); 7.43
(1Н, s, Н-7); 8.08 (1Н, s, Н-3). 13C NMR spectrum, δ, ppm:
12.8; 19.9; 28.9; 35.7; 117.3; 129.3; 132.2; 132.8; 139.8;
158.1. Mass spectrum, m/z (Irel, %): 176 [М+Н]+ (100).
Found, %: C 68.72; H 7.33; N 23.81. C10H13N3. Calculated,
%: C 68.54; H 7.48; N 23.98.
5-Isopropyl-1-methyl-1Н-pyrazolo[4,3-b]pyridine (5l)23
was obtained from compounds 3a and 4h. Yield 1.54 g
1
(44%), beige powder, mp 110–111°C. H NMR spectrum,
δ, ppm (J, Hz): 1.23 (6Н, d, J = 6.8, 2CH3); 3.08 (1Н, hept,
J = 6.8, CH); 3.94 (3Н, s, CH3); 7.10 (1Н, d, J = 8.8, Н-6);
7.58 (1Н, d, J = 8.8, Н-7); 8.00 (1Н, s, Н-3). 13C NMR
spectrum, δ, ppm: 23.2; 35.8; 36.2; 118.9; 119.6; 132.0;
132.7; 140.9; 162.5. Mass spectrum, m/z (Irel, %): 176 [М+Н]+
(100). Found, %: C 69.38; H 7.55; N 23.84. C10H13N3.
Calculated, %: C 68.54; H 7.48; N 23.98.
5-Butyl-1-methyl-1Н-pyrazolo[4,3-b]pyridine
(5m)
was obtained from compounds 3a and 4j. Yield 1.34 g
1
(30%), dark-yellow oily liquid. H NMR spectrum, δ, ppm
(J, Hz): 0.87–0.91 (3Н, m, CH3); 1.25–1.31 (2Н, m, CH2);
1.64–1.69 (2Н, m, CH2); 2.81–2.86 (2Н, m, CH2); 4.04
(3Н, s, CH3); 7.28 (1Н, d, J = 8.8, Н-6); 8.02 (1Н, d,
J = 8.8, Н-7); 8.12 (1Н, s, Н-3). 13C NMR spectrum,
δ, ppm: 14.2; 22.3; 32.1; 36.2; 37.6; 118.5; 121.0; 131.8;
132.5; 141.1; 157.7. Mass spectrum, m/z (Irel, %): 190
[М+Н]+ (100). Found, %: C 69.65; H 8.13; N 22.08.
C11H15N3. Calculated, %: C 69.81; H 7.99; N 22.20.
1,6-Dimethyl-5-propyl-1Н-pyrazolo[4,3-b]pyridine (5n)
was obtained from compounds 3a and 4j. Yield 0.38 g
(13%), orange crystals, mp 108–109°C. 1H NMR spectrum,
δ, ppm (J, Hz): 0.99 (3Н, t, J = 7.2, CH3); 1.62–1.69 (2Н,
m, CH2); 2.55 (3Н, s, CH3); 2.68 (2Н, t, J = 7.2, CH2); 4.01
(3Н, s, CH3); 7.80 (1Н, s, Н-7); 8.04 (1Н, s, H-3). 13C NMR
spectrum, δ, ppm: 14.2; 22.9; 23.0; 35.2; 36.1; 117.2;
132.2; 132.7; 134.0; 140.0; 153.1. Mass spectrum, m/z
(Irel, %): 190 [М+Н]+ (100). Found, %: C 69.63; H 7.92;
N 22.31. C11H15N3. Calculated, %: C 69.81; H 7.99;
N 22.20.
1-(Pyridin-2-yl)-5,6-dihydro-1Н-cyclobuta[b]pyrazolo-
[4,3-b]pyridine (5t) was obtained from compounds 3d and
4k. Yield 2.36 g (53%), brown powder, mp 121–122°C.
1H NMR spectrum, δ, ppm (J, Hz): 3.18–3.22 (2Н, m,
CH2); 3.41–3.45 (2Н, m, CH2); 7.33–7.37 (1Н, m, Н Py);
8.03 (2Н, d, J = 4.8, Н Py); 8.51 (1Н, s, Н-7); 8.55 (1Н, d,
J = 4.8, Н Py); 8.74 (1Н, s, Н-3). 13C NMR spectrum, δ, ppm:
25.6; 33.7; 113.3; 117.2; 121.4; 133.0; 137.3; 139.8; 140.5;
142.8; 148.4; 153.8; 161.9. Mass spectrum, m/z (Irel, %):
223 [М+Н]+ (100). Found, %: C 70.52; H 4.41; N 25.07.
C13H10N4. Calculated, %: C 70.26; H 4.54; N 25.21.
1-(tert-Butyl)-5-methyl-1Н-pyrazolo[4,3-b]pyridine (5o)
was obtained from compounds 3b and 4e. Yield 1.09 g
(29%), light-brown powder, mp 88–89°C. 1H NMR
384

Chemistry of Heterocyclic Compounds 2019, 55(4/5), 379–385
2007, 5, 61. (b) Li, A.-H.; Beard, D. J.; Coate, H.; Honda, A.;
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