Efficient Route for the Synthesis of Diverse Heteroannelated 5-Cyanopyridines

Article abstract of DOI:10.1055/a-1360-9852

The new efficient, convenient protocol for the synthesis of heteroannelated 3-cyanopyridines and pyrimidines starting from diverse aminoheterocycles and 3,3-dimethoxy-2-formylpropionitrile sodium salt was elaborated. The advantages and improvements of the

Full text of DOI:10.1055/a-1360-9852

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–I
paper
A
en
A. P. Mityuk et al.
Paper
Synthesis
Efficient Route for the Synthesis of Diverse Heteroannelated
5-Cyanopyridines
Andrey P. Mityuka
Andrii Hrebonkina
Pavlo S. Lebeda,b
Galyna P. Grabchukb
Dmitriy M. Volochnyuk*a,b,c
Sergey V. Ryabukhin*a,b
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-4
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a Enamine Ltd., 78 Chervonotkatska str., Kyiv, Ukraine
s.v.ryabukhin@gmail.com
d.volochnyuk@gmail.com
b Taras Shevchenko National University of Kyiv,
60 Volodymyrska str., Kyiv, Ukraine
c Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, 5 Murmanska str., Kyiv, Ukraine
Corresponding Authors
Received: 21.09.2020
Accepted after revision: 18.01.2021
Published online: 18.01.2021
O
N
O
O
O
O
OH
DOI: 10.1055/a-1360-9852; Art ID: ss-2020-t0627-op
OH
NH2
N
Abstract The new efficient, convenient protocol for the synthesis of
heteroannelated 3-cyanopyridines and pyrimidines starting from di-
verse aminoheterocycles and 3,3-dimethoxy-2-formylpropionitrile so-
dium salt was elaborated. The advantages and improvements of the
procedure compared to previously known methods are shown. The
scope and limitations of the method are determined. The impact of the
structural features on regioselectivity are discussed. The preparative-
ness, scalability, and application scope of the elaborated protocol are
demonstrated by the synthesis of five heteroannelated 3-cyanopyri-
dines in quantities up to 100 grams.
N
N
H
Amlexanox
anti-inflammatory
Ozenoxacin
antibiotic
Br
N
CF3
F
O
O
N
N
N
N
H
H
OH
O
N
N
Key words aminoheterocycles, heterocyclization, heteroannelated 3-
cyanopyridines, heteroannelated 3-cyanopyrimidines, 2-dimethoxy-3-
hydroxyacrylonitrile
Bedaquiline
antimycobacterial
TLK-19705
autoimmune diseases
Figure 1 Examples of bioactive fused pyridines
Fused pyridines find application in various fields of me-
dicinal and agrochemistry.1 In recent years, researchers
from all over the world have claimed biological activity of
such compounds. The scope of their utilization is very wide.
The mentioned compounds have been used as anti-inflam-
matory,5 antiallergic,2 antidiabetic,3 antimicrobial,4 and an-
ticancer5 agents. In most cases, examples of fused pyridines
for successful application in the pointed fields were repre-
sented by species with the quinoline and imidazo[1,2-a]-
pyridine cores (Figure 1). Other heteroannelated pyridine
cores can also possess high biological activity, but scarce
studies thereof can be explained, in particular, by the limit-
ed access to their functionalized derivatives.
block-collection enhancement in a cost-effective and lab-
friendly manner,6 heteroannelated 5-cyanopyridines were
selected as the target products of the research. Such a selec-
tion could be explained by a lot of options to transform the
cyano group into other function,7 as well as the potential to
introduce heteroannelated pyridine cores into promising
biologically active scaffolds as substituents using the com-
mon reactions of nitriles.8
Nowadays, various methods were proposed for the syn-
thesis of 5-functionalized heteroaryl[b]pyridines. Such
methods can be divided into three groups: the pyridine ring
has been built on the other heterocyclic core; the additional
heterocyclic ring has been constructed on a pyridine ring;
the substrates, obtained in the two previous ways, have
been modified.
Therefore, fused pyridines with different annelated het-
erocycles have drawn our attention. In our ongoing efforts
towards in-house medicinal-chemistry-relevant building-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. P. Mityuk et al.
Paper
Synthesis
The first group almost fully consists of the condensa-
tions of (hetero)arylamines and 1,3-binucleophilic re-
agents. A wide arsenal of different reagents used as 1,3-bi-
nuclephiles ensures a very huge diversity of the function in
the 5-position.9 Previously, we reported the introduction of
the carboxylic function by the cyclization of (hetero)aro-
matic amines with 5-formyluracil followed by the hydroly-
sis of the urea obtained.10 To prepare esters in a one-pot
manner, sodium 2-(dimethoxymethyl)-3-ethoxy-3-oxo-
prop-1-en-1-olate was proposed.11 This approach is an
ideological extension of the use of sodium 2-cyano-3,3-di-
methoxyprop-1-en-1-olate for the synthesis of hetero-
aryl[3,4-b]pyridines with cyano group in the fifth posi-
tion.12 For 5-nitro- and 5-bromo-substituted representa-
tives, a method was developed based on the use of nitro-13
and bromomalonealdehyde.14 All these methods are sum-
marized in Scheme 1.
pyridine and heteroaromatic cycle. This group of methods
is acceptable for obtaining new compounds with conven-
tional core, but not to obtain new scaffolds.
The third group contains well-known transformations
like C–C couplings (acetylene, alkene, or aryl addition), re-
duction of acetylene, hydrolysis of nitriles, synthesis of am-
ides from carboxylic acids, amines from nitro-substituted
compounds. This group was not considered in our research,
since our aim was to develop a new procedure for pyridine
ring assembling.
Earlier we have shown that cyclization of the hetaryl-
amines with 1,3-binucleophilic reagents led to different de-
rivatives of hetarylpyridines.10 From the other hand, we de-
veloped the method for preparation of acids which allowed
us to produce various potential building blocks.10a Unfortu-
nately, the flaw of this method was the scale limitations. So,
we decided to develop new methods or to optimize old
ones for obtaining new types of building blocks based on
heteroannelated pyridines. Nitriles were selected as the
substrates because such compounds can be easily turned
out into substances with maximum diversity of functional
groups – amines, ketones, acids, esters, amides, amidines,
etc.
O
O
N
O
X =
Method A
X
OH
Het
O
N
Het
NH2
N
High yields
Up to 100 g scale
Moderate diversity
Mityuk et al. 2009
O
O
As the starting point of our research, we have taken the
original procedure of Benoit and co-workers, who described
the synthesis of pyrrolo-, thiopheno-, and pyrazolopyri-
dines based on the reaction of aminoheterocycles 1 with
X =
O
O–Na+
Method B
X
O
Het
Het
Het
N
O
O
NH2
Medium yields
Up to 20 g scale
Low diversity
Levacher et al. 1994
3,3-dimethoxy-2-formylpropionitrile sodium salt
3
(Scheme 2). Unfortunately, the information in this paper
was too fragmentary, the scales were small, and the scope
was not determined. Our objective was to introduce a large
number of diverse aminoheterocycles in this reaction (Fig-
ure 2). Moreover, we decided to expand this reaction on the
formation of pyrimidines by the replacement of -CH-
aminoheterocycle 1 to -NH analogue 2. So, the additional
optimization and scope determination were needed.
Br
Br
O
Method C
X
X =
Het
N
O
NH2
High yields
Up to 20 g scale
Moderate diversity
Taylor et al. 1988
O
N+
O
N+
O–
O
X =
O–
Method D
X
Het
Het
Het
O
NH2
N
High yields
Milligram scale
High diversity
Iaroshenko et al. 2015
O
N
O
Method E
X
O
O–Na+
O–Na+
X =
Het
O
N
NH2
N
3
N
X
X
N
Benoit et al. 1987
Het
Het
Moderate yields
Up to 1 g scale
Low diversity
NH2
N
X = C: 1a–m
X = N: 2a–h
X = C: 4a–t
X = N: 5a–i
Scheme 1 The literature data for the synthesis of 5-functionalized het-
eroannelated pyridines
Scheme 2 General scheme for the synthesis of heteroannelated pyri-
dines 4 and pyrimidines 5
The second group does not have so many representa-
tives as the first one. The poor variety of substituents at the
5th position is the main characteristic of this group. We
found that only alkyl- and halogen-substituted derivatives
were obtained by this route,15 unlike the diversity of the
first-group compounds. Another problem to use this strate-
gy for increasing the chemical space of new cores is the fact
that it does not lead to form new unique combinations of
First of all, we decided to decrease the temperature of
the reaction mixture and HCl concentration to avoid the de-
composition of heterocycles, which were unstable in harsh
acidic conditions. The idea was that such changes would al-
low us to expand the scope of the reaction to less stable
heterocycles than thiophene, pyrazole, and pyrrole with
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

C
A. P. Mityuk et al.
Paper
Synthesis
N
N
N
N
N
N
N
NH2
N
NH2
NH2
N
O
NH2
NH2
N
NH
NH2
N
N
NH
NH2
NH
NH2
1a
1b
1c
1d
1e
O
O
Br
O
O
O
O
N
NH2
2a
2b
2c
O
N
O
N
O
O
N
NH2
NH2
NH2
O
O
N
NH2
NH
NH2
N
N
NH
NH
NH2
1j
1g
1l
1h
1i
1f
N
NH2
O
O
S
S
O
O
N
N
NH2
2d
2e
2f
N
S
NH2
NH2
NH2
1m
S
O
NH2
O
NH
NH
N
1o
1k
1n
NH
N
NH2
N
NH2
Br
N
NH2
2g
O
O
N
2h
2i
N
N
NH2
NH2
NH2
N
NH2
O
NH2
1p
1q
1r
1s
1t
Figure 2 The set of substrates 1a–t and 2a–i used to determine the scope of amine condensation with sodium salt of 2-dimethoxy-3-hydroxyacrylo-
nitrile
stabilizing acceptor substituents. The next step was the op-
timization of the solvent and its quantity to generate more
soft reaction conditions. The reaction time and reagents ra-
tio were then also optimized (Table 1).
tive yields (78–94%). Introduction of a strong electron-
accepting group into the aminopyrrole ring (1q) adhered
the reaction, the product yield was also high. On the other
hand, the reaction between 3,3-dimethoxy-2-formylpropi-
onitrile sodium salt 3 and compounds more sensitive to ac-
ids like aminoisoxazoles 1e,f and aminofurane 1i passed
not so efficiently. The yields in the reaction mixture was
lower (68–78%), and the target compounds formed with
moderate preparative yields (61–74%). In the case of amino-
isoxazole 1g and aminopyrrole 1p the products were de-
tected only in trace amounts in the reaction mixture. Thus,
it can be concluded that the reaction does not occur upon
the decrease in substrates stability towards acids. We also
found that aminoheterocycles 1j,n,o did not react with 3
under optimized conditions; this observation can be ex-
plained by the lower activity of -C–H. Aromatic amines
also could be the substrates of the reaction. The same prin-
ciples of scope determination were acceptable for them.
From the tested anilines, 1s was similar to the thiophenes
1k–m and could form the benzannelated pyridine 4s in a
92% yield. Instead, the reaction did not take place with 1r
and 1t as the substrates. The reason was that 1r has only
one additional -donating group (OMe). Moreover, it is lo-
cated in the para position to amine unlike to 1s (two OMe
groups in meta positions). In this case, the donating effect
on -CH in 1r is much lower, and the activity to electrophil-
ic substitution is less. From the other side, the activity of
-CH in compound 1t is enough but the instability of the
latter under the acidic conditions occurred.
As we can see from Table 1, the reaction took place at
room temperature, and the temperature increase is not
needed (entry 2). The optimal reaction time was 24 hours
(entry 8). The longer reaction time did not result in a signif-
icant increase in the product yield (entry 9). It was found
that alcohols were the best solvents (entries 10–12). We
chose MeOH (entries 10–14) for further studies due to the
higher solubility of the compound in it. Also, in our opinion,
MeOH had good outlooks for scale-up. Amounts of MeOH
and HCl were also minimized to increase the scale-up pros-
pects (entries 17 and 22). Finally, the optimal reagents ra-
tio, i.e., 20% excess of the salt 3, was found. The validated
conditions were 1 mmol of starting aminoheterocycle 1 in 4
mL of MeOH, 1.2 mmol of 3, 0.4 mL of HCl, room tempera-
ture, 24 hours. Under these conditions, the yield of the
model aminothiophene 1m was 93% with an isolated yield
of 87% after the neutralization of the reaction mixture by a
saturated solution of NaHCO3 to pH 7–8, extraction by
CHCl3, evaporation and preparative liquid gradient chroma-
tography (10% EtOAc in hexane).
On the next stage, the aminoheterocycles 1a–t and 2a–i
were tested in the elaborated procedure (Table 2). The ami-
nopyrazoles 1a–d, aminouracile 1h, and aminothiophenes
1k–m showed excellent results with high yields of the final
products (>85%) in the reaction mixture and high prepara-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

D
A. P. Mityuk et al.
Paper
Synthesis
Table 1 Optimization Protocols on the Model Substrate 1m
Table 2 Yields, Melting Points, and MS Data of Products 4 and 5
Starting Product
material
MS m/z Yield (g, %)a Mp (°C)
[M + 1]
O
N
S
HCl(conc)
S
O
O–Na+
1a
159.2
0.69, 87
172
89
NH3
various
conditions
N
N
(65.6, 83)b
N
N
N
1m
Temperature
3
4m
N
4a
Entry
Conditions
Temp (°C)
Yield (%)a
1b
187.2
0.77, 83
N
1
0
44
76
74
67
1m (1 mmol),
3 (1.2 mmol),
HCl (0.4 mL),
MeOH (2 mL),
8 h
N
N
2
rt (ca. 25)
N
3
40
65
4
4b
Time
Entry
5
1c
173.2
215.2
0.81, 94
0.92, 86
144
N
Conditions
Time (h)
Yield (%)a
N
N
4
57
76
82
86
87
N
1m (1 mmol),
3 (1.2 mmol),
HCl (0.4 mL),
MeOH (2 mL),
r.t.
6
8
4c
7
12
24
48
1d
134–152c
8
N
9
N
N
Solvent
Entry
10
N
Conditions
Solvent
MeOH
EtOH
Yield (%)a
4d
86
85
82
64
78
1m (1 mmol),
3 (1.2 mmol),
HCl (0.4 mL),
solvent (2 mL),
r.t., 24 h
11
1e
160.2
188.2
0.49, 61
0.69, 74
125
67
N
12
i-PrOH
MeCN
dioxane
N
O
13
N
4e
14
Amount of solvent (mL for 1 mmol)
1f
N
Entry
15
Conditions
Value (mL)
Yield (%)a
1
76
85
93
93
91
89
N
O
N
16
2
1m (1 mmol),
3 (1.2 mmol),
HCl (0.4 mL),
MeOH,
4f
17
4
1h
217.0
0.94, 87
167
O
18
6
(98.4, 91)b
N
r.t., 24 h
19
8
N
20
10
O
N
N
Amount of HCl (mL of 35% solution for mmol)
4h
Entry
21
Conditions
Value (mL)
0.2
Yield (%)a
1i
203.2
219.0
247.1
0.65, 64
162
N
N
72
93
94
91
88
O
O
1m (1 mmol),
3,
HCl (0.4 mL),
MeOH (4 mL),
r.t., 24 h
22
0.4
O
S
23
0.6
N
4i
24
0.8
1k
1l
0.85, 78
168
25
1.0
(82.9, 76)b
O
O
Reagent ratio (1m/3)
Entry
26
Conditions
Ratio (mmol)
1:0,8
Yield (%)a
N
4k
64
82
92
93
92
85
1.06, 86
175–177
27
1:1
N
1m,
3,
HCl (0.4 mL),
MeOH (4 mL),
r.t., 24 h
O
28
1:1.1
S
O
29
1:1.2
N
30
1:1.4
4l
31
1:1.8
a Yield was determined by LCMS of quenched reaction mixture.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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A. P. Mityuk et al.
Paper
Synthesis
Starting Product
material
MS m/z Yield (g, %)a Mp (°C)
[M + 1]
Starting Product
material
MS m/z Yield (g, %)a Mp (°C)
[M + 1]
1m
161.1
0.74, 93
148
2i
183.2
0.69, 76
100–122c
N
N
S
N
N
N
N
4m
5i
1q
225.0
0.90, 80
163
N
a The isolated yield for pure compound obtained is given.
N
b The isolated yield for the scale-up to 0.5 mol of starting materials 1 and 2.
c The specified substance decomposes during the measurement of melting
point.
N
N
To further expand the elaborated procedure scope, we
replaced the CCN binucleophiles into NCN. A representative
set of NH-containing aminoheterocycles 2a–g and amidines
2h,i was examined in the reaction. Compound 2a was a
classical model substrate for investigating the place of pri-
mary attack by the electrophile, which we successfully used
previously.10b The exclusive regioselective formation of pyr-
azolopyrimidine 5a in high yield indicated that the reaction
began from one of the nitrogen atoms followed by cycliza-
tion of the other. The possible pathway is shown in Scheme
3. The structure of 5a was proved by NMR analysis. The
characteristic proton bound to pyrazolic carbon is present
as a singlet at  = 6.7 ppm.
4q
1s
217.0
158.2
0.99, 92
0.65, 82
182–183
O
N
O
N
4s
2a
159
N
N
N
N
5a
2b
222.2/
224.8
0.85, 76
130–153c
N
(74.7, 67)b
N
N
Other compounds also demonstrated excellent efficacy
under the reaction conditions. All pyrimidines of type 5
were obtained in high preparative yields (73–96%), except
5g, due to the low stability of the starting aminotetrazole
2g under the reaction conditions. It should be noted that
the reaction regioselectivity depends on the nucleophilic
properties of the reaction centers. In the case of aminotri-
azole 2f, where the reaction could involve two nitrogen at-
oms, only triazolopyrimidine 5f formed. Such a reaction
pathway could be explained by the higher nucleophilicity of
the nitrogen atom in position 1 compared to nitrogen in po-
sition 4. The structure of 5f has been proven by the X-ray
crystal structure determination16 (Figure 3).
The procedure was also explored for scale-up to multi-
gram quantity (up to 100 g). The compounds 4a,h,k and
5b,f were obtained in 118–199 g quantity.
All data, including structures of the obtained com-
pounds, parent ion peaks in mass spectra melting points
and isolated yields, are summarized in Table 2.
In conclusion, the new, updated procedure for the reac-
tion of aminoheterocycles and amidines with 3,3-dime-
thoxy-2-formylpropionitrile sodium salt leading to hetero-
annelated pyridines and/or pyrimidines was elaborated.
Compared to the previously reported methods, the princi-
pal advantages were more mild conditions (r.t., lower quan-
tity of HCl, optimized amount of the solvent). These chang-
es allowed us to expand the scope and limitation of the re-
action, to increase the yields, and to scale-up the process up
to 100 g of products. It was shown that stability under the
acidic reaction conditions and sufficient activity of nucleo-
N
Br
5b
2c
170.2
0.81, 96
204
187
N
N
N
N
N
5c
2d
215.0
[M – 1]
1.01, 93
0.53, 73
N
N
N
N
O
O
5d
2e
145.2
146.0
182.0
227
N
N
N
N
N
N
5e
2f
0.57, 79
183
(58.8, 81)b
N
N
N
5f
2h
0.76, 84
107–123c
N
N
N
5h
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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A. P. Mityuk et al.
Paper
Synthesis
O
O
N
H
N
N
N
NH
O
NH2
N
H
N
H
H
2a
A
N
N
+
O
N
O
N
5a
N
B
O
O–Na+
NH
2 N
N
H
3
Scheme 3 Possible pathway for regioselective formation of 5a
General Procedure for the Formation of 4 and 5 by the Cyclization
of Aminoheterocycles 1 and 2 with 3,3-Dimethoxy-2-formylpropi-
onitrile Sodium Salt 3
Salt 3 (6 mmol) was dissolved in MeOH (3 mL), then the concentrated
aqueous solution of HCl (0.5 mL) and 1 or 2 (5 mmol) in MeOH (5 mL)
were added. The reaction mixture was stirred for 4 h at r.t. After this,
the additional MeOH (2 mL) and HCl (1.5 mL) were added. The reac-
tion mixture was additionally stirred for 12 h at r.t. Then the saturat-
ed solution of NaHCO3 was added dropwise to the reaction mixture
until pH 7–8. After this, the target compound was extracted by CHCl3
(3 × 30 mL). The organic layers were separated, combined, and dried
over Na2SO4. The solvent was removed by evaporation under reduced
pressure. The product was purified by preparative gradient chroma-
tography on silica gel with 10% EtOAc in hexane. The compounds 4 or
5 were obtained as white powders. Yields, melting points, and LCMS
data are given in Table 2. NMR data and Rf (for chromatographic puri-
fication using 10% EtOAc in hexane) are given below.
Figure 3 The X-ray molecular structure for compound 5f
philic centers were the main criteria for the substrates for
the efficient reaction. The sensitivity of the reaction prod-
ucts to the reagents nucleophilicity was rather high, allow-
ing excellent regioselectivity. As a result, the advantages of
the new methodology were demonstrated by the synthesis
of 20 target heteroannelated pyridines/pyrimidines. Five
new exclusive building blocks were obtained from readily
available precursors with 67–91% yield in up to 100 g quan-
tities.
1-Methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4a)
Rf = 0.24.
1H NMR (400 MHz, DMSO-d6):  = 8.88 (dt, J = 15.5, 1.8 Hz, 2 H), 8.32
(d, J = 1.7 Hz, 1 H), 4.06 (d, J = 1.7 Hz, 3 H).
13C NMR (101 MHz, DMSO-d6):  = 34.34, 101.65, 114.50, 118.46,
134.01, 136.95, 149.93, 151.13.
MS [M + 1]: m/z = 159.2.
The solvents were purified by the standard procedures. All starting
materials were obtained from Enamine Ltd. Analytical TLC was per-
formed using Polychrom SI F254 plates. Column chromatography was
performed using Kieselgel Merck 60 (230–400 mesh) as the station-
ary phase. 1H NMR and 13C NMR spectra were measured on a Bruker
170 Avance 500 spectrometer (at 500 MHz for 1H and 126 MHz for
13C) and Varian Unity Plus 400 spectrometer (at 400 MHz for 1H, 126
or 101 MHz for 13C). Elemental analyses were performed at the Labo-
ratory of Organic Analysis, Institute of Organic Chemistry, National
Academy of Sciences of Ukraine. Their results were found to be in
good agreement (±0.4%) with the calculated values. Mass spectra
were measured on Agilent 1100 LCMSD SL instrument (chemical ion-
ization (APCI)) and Agilent 5890 Series II 5972 GCMS instrument
(electron impact ionization (EI)). The X-ray diffraction data sets were
collected with a CMOS diffractometer. Programs used: data collection,
APEX3 V2016.1-0;47 cell refinement and data reduction, SAINT
V8.37A;48 absorption correction, SADABS V2014/7;49 structure solu-
tion; structure refinement, SHELXL-2015.16
Anal. Calcd for C8H6N4: C, 60.75; H, 3.82; N, 35.42. Found: C, 61.09; H,
3.89; N, 35.32.
1-(Propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4b)17
Rf = 0.21.
1H NMR (500 MHz, DMSO-d6):  = 8.83 (d, J = 12.5 Hz, 2 H), 8.48–8.12
(m, 1 H), 5.42–4.81 (m, 1 H), 1.46 (dd, J = 6.8, 3.1 Hz, 6 H).
13C NMR (126 MHz, DMSO-d6):  = 21.62, 48.57, 101.29, 114.28,
117.90, 133.40, 136.39, 148.51, 150.26.
MS [M + 1]: m/z = 187.2.
Anal. Calcd for C10H10N4: C, 64.5; H, 5.41; N, 30.09. Found: C, 64.65; H,
5.44; N, 29.98.
1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (4c)
Rf = 0.19.
1H NMR (500 MHz, DMSO-d6):  = 8.86–8.80 (m, 2 H), 3.99 (s, 3 H),
2.52 (d, J = 1.8 Hz, 3 H).
The 3,3-dimethoxy-2-formylpropionitrile sodium salt 3 was prepared
by the original procedure of Benoit.12
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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Synthesis
13C NMR (126 MHz, DMSO-d6):  = 11.81, 33.34, 100.04, 113.57,
118.06, 135.78, 141.74, 150.51.
Anal. Calcd for C10H6N2O3: C, 59.41; H, 2.99; N, 13.86. Found: C, 59.52;
H, 3.22; N, 14.23.
MS [M + 1]: m/z = 173.2.
Methyl 5-Cyanothieno[2,3-b]pyridine-2-carboxylate (4k)
Rf = 0.39.
1H NMR (500 MHz, DMSO-d6):  = 9.12 (s, 1 H), 9.00 (s, 1 H), 8.27 (s, 1
Anal. Calcd for C9H8N4: C, 62.78; H, 4.68; N, 32.54. Found: C, 62.58; H,
4.92; N, 32.84.
H), 3.93 (s, 3 H).
1-tert-Butyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile
13C NMR (126 MHz, DMSO):  = 22.65, 53.68, 54.24, 99.97, 106.32,
(4d)
Rf = 0.16.
117.50, 129.15, 131.77, 139.02, 151.31, 162.06.
1H NMR (500 MHz, DMSO-d6):  = 8.27 (s, 1 H), 2.01 (s, 3 H), 1.23 (s, 9
MS [M + 1]: m/z = 219.0.
H).
Anal. Calcd for C10H6N2O2S: C, 55.04; H, 2.77; N, 12.84; S, 14.69.
Found: C, 55.38; H, 2.87; N, 13.13; S, 15.02.
13C NMR (126 MHz, DMSO):  = 11.95, 28.74, 28.93, 59.86, 99.97,
115.07, 118.12, 135.70, 140.34, 149.40, 149.86.
Ethyl 5-Cyano-3-methylthieno[2,3-b]pyridine-2-carboxylate (4l)
Rf = 0.31.
1H NMR (500 MHz, DMSO-d6):  = 8.98 (s, 1 H), 8.88 (d, J = 9.1 Hz, 1
H), 4.37 (p, J = 6.2 Hz, 2 H), 2.68 (d, J = 6.5 Hz, 3 H), 1.36 (q, J = 6.7 Hz,
3 H).
MS [M + 1]: m/z = 215.2.
Anal. Calcd for C12H14N4: C, 67.27; H, 6.59; N, 26.15. Found: C, 66,89;
H, 6.26; N, 26.33.
3-Methyl-[1,2]oxazolo[5,4-b]pyridine-5-carbonitrile (4e)
Rf = 0.33.
13C NMR (126 MHz, DMSO):  = 12.66, 13.98, 61.76, 105.27, 117.05,
127.83, 132.43, 136.88, 139.03, 150.87, 151.05, 161.64, 162.72.
1H NMR (400 MHz, DMSO-d6):  = 9.05 (s, 2 H), 2.56 (s, 3 H).
MS [M + 1]: m/z = 247.1.
13C NMR (101 MHz, CDCl3):  = 11.39, 106.09, 114.74, 117.77, 139.78,
154.97, 158.00, 170.32.
Anal. Calcd for C10H6N2O2S: C, 55.04; H, 2.77; N, 12.84; S, 14.69.
Found: C, 54.77; H, 2.61; N, 12.53; S, 14.37.
MS [M + 1]: m/z = 160.2.
Anal. Calcd for C8H5N3O: C, 60.38; H, 3.17; N, 26.4. Found: C, 60.22; H,
3.32; N, 26.53.
Thieno[3,2-b]pyridine-6-carbonitrile (4m)12
Rf = 0.49.
1H NMR (500 MHz, DMSO-d6):  = 9.07 (s, 1 H), 8.98 (s, 1 H), 8.47 (d,
J = 5.3 Hz, 1 H), 7.68 (s, 1 H).
13C NMR (126 MHz, DMSO):  = 103.07, 117.64, 124.63, 131.87,
3-(Propan-2-yl)-[1,2]oxazolo[5,4-b]pyridine-5-carbonitrile (4f)
Rf = 0.31.
1H NMR (500 MHz, DMSO-d6):  = 1.41–1.38 (m, 6 H), 9.19 (s, 1 H),
9.05 (s, 1 H), 3.41 (p, J = 6.8 Hz, 1 H).
135.61, 138.08, 148.96, 157.48.
MS [M + 1]: m/z = 161.1.
13C NMR (126 MHz, DMSO-d6):  = 20.26, 26.70, 105.09, 112.02,
116.61, 138.75, 153.77, 164.22, 169.44.
Anal. Calcd for C8H4N2S: C, 59.98; H, 2.52; N, 17.49; S, 20.01. Found: C,
60.19; H, 2.47; N, 17.76; S, 19.66.
MS [M + 1]: m/z = 188.2.
Anal. Calcd for C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C, 63.81;
H, 4.87; N, 22.12.
1-tert-Butyl-1H-pyrrolo[2,3-b]pyridine-3,5-dicarbonitrile (4q)
Rf = 0.24.
1H NMR (400 MHz, DMSO-d6):  = 8.84–8.79 (m, 1 H), 8.73 (d, J = 3.2
Hz, 2 H), 1.75 (s, 9 H).
1,3-Dimethyl-2,4-dioxo-1H,2H,3H,4H-pyrido[2,3-d]pyrimidine-6-
carbonitrile (4h)18
Rf = 0.19.
13C NMR (101 MHz, DMSO):  = 28.95, 59.87, 83.58, 102.92, 114.88,
118.26, 120.40, 133.02, 139.38, 146.80, 147.49.
1H NMR (500 MHz, DMSO-d6):  = 9.11 (d, J = 2.1 Hz, 1 H), 8.76 (d, J =
2.3 Hz, 1 H), 3.55 (s, 3 H), 3.28 (s, 3 H).
MS [M + 1]: m/z = 225.0.
13C NMR (126 MHz, DMSO-d6):  = 28.24, 29.48, 103.27, 109.51,
110.41, 110.46, 116.39, 140.77, 150.63, 152.38, 156.76, 159.56.
Anal. Calcd for C13H12N4: C, 69.62; H, 5.39; N, 24.98. Found: C, 69.68;
H, 5.72; N, 25.11.
MS [M + 1]: m/z = 217.0.
5,7-Dimethoxyquinoline-3-carbonitrile (4s)19
Anal. Calcd for C10H8N4O2: C, 55.56; H, 3.73; N, 25.91. Found: C, 55.43;
H, 3.85; N, 26.08.
Rf = 0.42.
1H NMR (400 MHz, DMSO-d6):  = 9.05 (d, J = 2.1 Hz, 1 H), 8.83 (d, J =
2.2 Hz, 1 H), 7.08 (d, J = 2.2 Hz, 1 H), 6.82 (d, J = 2.1 Hz, 1 H), 3.99 (s, 3
H), 3.96 (s, 3 H).
13C NMR (101 MHz, DMSO):  = 56.43, 56.91, 100.20, 100.60; 102.70,
118.31, 136.03, 136.29, 140.33, 151.52, 156.31, 164.50.
Methyl 5-Cyanofuro[2,3-b]pyridine-2-carboxylate (4i)
Rf = 0.21.
1H NMR (500 MHz, DMSO-d6):  = 8.98 (s, 1 H), 8.87 (s, 1 H), 7.87 (s, 1
H), 3.94 (s, 3 H).
MS [M + 1]: m/z = 217.0.
13C NMR (126 MHz, CDCl3):  = 53.36, 106.44, 113.61, 117.44, 119.69,
138.58, 146.47, 151.37, 158.82, 162.48.
Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C, 66.9;
H, 4.45; N, 13.04.
MS [M + 1]: m/z = 203.2.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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2-Methylpyrazolo[1,5-a]pyrimidine-6-carbonitrile (5a)
Rf = 0.35.
1H NMR (500 MHz, DMSO-d6):  = 9.81 (d, J = 2.1 Hz, 1 H), 8.69 (t, J =
1H NMR (500 MHz, DMSO-d6):  = 10.28 (q, J = 2.7, 2.1 Hz, 1 H), 9.21
(q, J = 2.7, 2.2 Hz, 1 H), 8.91–8.84 (m, 1 H).
13C NMR (126 MHz, DMSO):  = 97.57, 114.53, 143.87, 154.53, 155.93,
158.01.
1.8 Hz, 1 H), 6.70 (s, 1 H), 2.45 (s, 3 H).
13C NMR (126 MHz, DMSO):  = 14.29, 93.42, 97.79, 97.79, 115.49,
MS [M + 1]: m/z = 146.0.
141.61, 147.93, 148.98, 158.28.
Anal. Calcd for C6H3N5: C, 49.66; H, 2.08; N, 48.26. Found: C, 49.58; H,
1.92; N, 48.51.
MS [M + 1]: m/z = 158.2.
Anal. Calcd for C8H6N4: C, 60.75; H, 3.82; N, 35.42. Found: C, 60.95; H,
3.95; N, 35.82.
2-Phenylpyrimidine-5-carbonitrile (5h)21
Rf = 0.43.
3-Bromopyrazolo[1,5-a]pyrimidine-6-carbonitrile (5b)20
Rf = 0.46.
1H NMR (500 MHz, DMSO-d6):  = 10.01 (d, J = 2.0 Hz, 1 H), 8.85 (d, J =
1H NMR (500 MHz, DMSO-d6):  = 9.31 (d, J = 2.6 Hz, 1 H), 8.43–8.35
(m, 2 H), 7.56 (dt, J = 15.1, 7.2 Hz, 3H ).
13C NMR (126 MHz, DMSO):  = 107.24, 116.03, 129.07, 129.51,
132.91, 136.07, 161.28, 165.09.
2.0 Hz, 1 H), 8.60 (s, 1 H).
13C NMR (126 MHz, DMSO):  = 85.68, 95.56, 114.91, 143.31, 144.13,
MS [M + 1]: m/z = 182.0.
147.84, 150.45.
Anal. Calcd for C11H7N3: C, 72.92; H, 3.89; N, 23.19. Found: C, 73.22; H,
3.68; N, 23.35.
MS [M + 1]: m/z = 222.2/224.8.
Anal. Calcd for C7H3BrN4: C, 37.7; H, 1.36; N, 25.12; Br, 35.83. Found:
C, 37.62; H, 1.48; N, 24.81; Br, 36.1.
2-(Pyridin-3-yl)pyrimidine-5-carbonitrile (5i)
Rf = 0.36.
Pyrazolo[1,5-a]pyrimidine-3,6-dicarbonitrile (5c)
Rf = 0.48.
1H NMR (500 MHz, DMSO-d6):  = 10.22 (s, 1 H), 9.14 (s, 1 H), 8.99 (s,
1H NMR (500 MHz, DMSO-d6):  = 9.49 (d, J = 2.3 Hz, 1 H), 9.46 (s, 1
H), 9.40 (s, 1 H), 8.77 (dd, J = 4.8, 1.8 Hz, 1 H), 8.66 (dt, J = 8.0, 2.1 Hz, 1
H), 7.59 (dd, J = 8.0, 4.8 Hz, 1 H).
13C NMR (126 MHz, DMSO):  = 107.41, 115.31, 124.03, 131.20,
135.85, 149.55, 152.67, 160.96, 163.27.
1 H).
13C NMR (126 MHz, DMSO):  = 83.15, 97.88, 112.33, 114.36, 144.23,
149.59, 150.04, 153.79.
MS [M + 1]: m/z = 183.2.
Anal. Calcd for C10H6N4: C, 65.93; H, 3.32; N, 30.75. Found: C, 66.05; H,
3.29; N, 30.56.
MS [M + 1]: m/z = 170.2.
Anal. Calcd for C8H3N5: C, 56.81; H, 1.79; N, 41.4. Found: C, 56.44; H,
2.09; N, 41.55.
General Procedure for Scale-Up of Heterocyclization
Salt 3 (0.55 mol) was dissolved in MeOH (350 mL), then concentrated
aqueous solution of HCl (50 mL) and 1a,h,k or 2b,f (0.5 mol) in MeOH
(550 mL) were added. The reaction mixture was stirred for 4 h at r.t.
After this, an additional MeOH (2 mL) and HCl (1.5 mL) were added.
The reaction mixture was additionally stirred for 12 h at r.t. Then, the
saturated solution of NaHCO3 was added dropwise to the reaction
mixture for pH = 7–8. After this, the target compound was extracted
by CHCl3 (5 × 500 mL). The organic layer was separated, combined,
and dried over Na2SO4. The solvent was removed by evaporation un-
der reduced pressure. The pure product was separated by flash gradi-
ent chromatography on silica gel with hexanes–EtOAc (1:0 to 1:1).
The compounds 4a,h,k or 5b,f were obtained as white powders.
Yields are given in Table 2.
Ethyl 6-Cyanopyrazolo[1,5-a]pyrimidine-3-carboxylate (5d)
Rf = 0.42.
1H NMR (400 MHz, CDCl3):  = 9.15 (d, J = 2.2 Hz, 1 H), 8.82 (d, J = 2.2
Hz, 1 H), 8.69 (s, 1 H), 4.42 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, DMSO):  = 14.78, 60.51, 97.26, 104.03, 115.20,
144.12, 146.98, 150.20, 153.36, 161.57.
MS [M – 1]: m/z = 215.0 NEG.
Anal. Calcd for C10H8N4O2: C, 55.56; H, 3.73; N, 25.91. Found: C, 55.77;
H, 3.61; N, 25.59.
Imidazo[1,2-a]pyrimidine-6-carbonitrile (5e)
Rf = 0.42.
1H NMR (500 MHz, DMSO-d6):  = 9.81 (d, J = 2.4 Hz, 1 H), 8.80 (d, J =
2.3 Hz, 1 H), 8.06 (s, 1 H), 7.90 (s, 1 H).
Funding Information
13C NMR (126 MHz, DMSO):  = 94.95, 113.50, 115.47, 136.48, 142.33,
146.41, 149.43.
The work was funded by Enamine Ltd. and supported by the Ministry
of Education and Science of Ukraine (Grant Number 0120U102179).
M
in
i
Eotsrydfucationa
n
dScienUcoefkrain(e
0
1
2
0
U
1
0
2
1
7
9)E
n
amin(e
)
MS [M + 1]: m/z = 145.2.
Anal. Calcd for C7H4N4: C, 58.33; H, 2.8; N, 38.87. Found: C, 58.03; H,
2.49; N, 38.6.
Acknowledgment
The authors thank Prof. Andrey Tolmachev for his encouragement and
support and Mr. Dmytro Yehorov for his help in manuscript prepara-
tion.
[1,2,4]Triazolo[1,5-a]pyrimidine-6-carbonitrile (5f)
Rf = 0.38.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–I

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A. P. Mityuk et al.
Paper
Synthesis
Supporting Information
(8) North, M. Comprehensive Organic Functional Group Transforma-
tions II, Vol. 3; Katritzky, A.; Taylor, R., Ed.; Elsevier: Amsterdam,
2004, 621.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1360-9852.
S
u
p
p
ortingI
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formati
o
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u
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p
ortingInformati
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(9) Iaroshenko, V. O.; Mkrtchyan, S.; Volochnyuk, D. M.; Langer, P.;
Sosnovskikh, V. Y.; Ostrovskyi, D.; Dudkin, S.; Kotljarov, A. V.;
Miliutina, M.; Savych, I.; Tolmachev, A. A. Synthesis 2010, 2749.
(10) (a) Mityuk, A. P.; Volochnyuk, D. M.; Ryabukhin, S. V.; Plaskon,
A. S.; Shivanyuk, A.; Tolmachev, A. A. Synthesis 2009, 1858.
(b) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2007, 1861. (c) Ryabukhin, S. V.;
Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A. Synthesis
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